DR CARVER [JC]

A typical example is a patient who had Hodgkin disease in his teens and received mediastinal mantle radiation. Fifteen to 25 years later, the patient has a pacemaker for heart block, coronary artery disease that requires a stent, and most recently has two valves replaced—so aortic and mitral valve replacement because of late radiation effects. This scenario is typical for the “old” days. The 20-year cumulative incidence of radiation-induced cardiac toxicity is 15%-20% (Table, Figure).¹ Sitting with a patient about to begin chest radiation, the absolute risks are unknown but presumed to be less as treatment is delivered according to the modern techniques that you described in the question.

DH They’re so much better now, so this is less common.
JC With the shielding and breath-holding techniques and position changes, doing upright radiation rather than supine, and because the technology has improved both in the delivery of radiation and the technology in understanding where all the radiation is going, in today’s world, we can calculate pretty precisely how much radiation the heart actually receives. Ultimately, with the protective mechanisms that are in place going forward, the risks that I described for that survivor are probably exponentially less than what’s reported in the literature and what we see clinically. Radiation has become much, much safer. There is still probably some small risk of development of late changes, but I don’t think we know what that risk is today because the shielding and things we do to protect the heart have not yet been studied in the long term.

DH Of course, the patient is breathing and there’ll be some movement of the target. Some of the radiation techniques can follow the target despite the breathing?
JC Yes, definitely true. Radiation delivery is much more precise today. Not only has the delivery changed, but so has what we know about the location of potential arterial disease. For example, if you read any textbook, it says that for the coronaries, that it’s ostial and proximal disease of the left main, or the left anterior descending, or the right coronary artery. Today, somebody who gets chest/mediastinal radiation, for either breast cancer, lymphoma, or for a mediastinal tumor, the location of potential disease is more likely to mimic the location of classic coronary disease in the mid-portion of the left anterior descending artery rather than at the ostium. It’s going to be a different disease going forward.^2,3

With administration of the anthracyclines, we try to do whatever protective things we can do. There are some people who believe that continuous infusion is safer for the heart than bolus injection. It’s pretty controversial. Dexrazoxane, which is a chelating agent, has been shown to reduce cardiotoxicity, and using a lipophilic anthracycline preparation may also have less cardiac toxicity.

DH I have a population in which a lot of liposomal doxorubicin is used and I’ve given a lot and rarely if ever get cardiac toxicity. You see that as well?
JC Yes. There’s a significant financial difference between doxorubicin and liposomal doxorubicin; the latter is more expensive. From the standpoint of safety, and from the standpoint of if I ever needed doxorubicin, I would probably jump on that and ask for the liposomal preparation and/or dexrazoxane.

DH For trastuzumab, we are getting echo- cardiograms every 9 weeks. That seems awfully simple, but there’s a whole algorithm we follow for particular change in ejection fraction and watch the drug or stop the drug. Are we doing that correctly?
JC The first statement I would make about that is that there are too many women who need trastuzumab whose therapy has been prematurely stopped because of just looking at the ejection fractions. So, there has to be more to decision-making other than just the number of the ejection fraction. We’re pretty aggressive and tend to try to get women to get the full dose and whatever dose-effective dose they need, especially with curative intent in the adjuvant setting that we make decisions based not only on the ejection fraction.

We also have, I would say, a handful of our medical breast oncologists who do not follow the package insert. We don’t get ejection fractions every 3 cycles. We have substituted a little bit by following biomarkers so that we use N-terminal pro b-type natriuretic peptide (NT-proBNP) to monitor people, either with each cycle or every third cycle. The benefit of BNP is its negative predictive value. If it’s normal, it’s hard to have any clinically significant myocardial dysfunction.

What we’re going to see over – I would hope – the next year or two is that the recommendations about getting echocardiograms frequently will go away.
 

DH That would be welcome because in our electronic medical records, it’s 9 weeks, stop, do this, etc. How about a comment on infusional 5-FU and possibly its cousins, such as capecitabine, and any coronary issues?
JC Let me come back, just one more thing about trastuzumab. For metastatic disease, we do whatever is necessary to continue effective cancer therapy and in the absence of any cardiac symptoms or abnormal physical findings, we continue cancer treatment without any serial echocardiographic monitoring.

DH You think the NT-proBNP might be useful? I know that’s excreted by the kidneys, so that might rise in renal failure, but we can adjust for that.
JC The negative predictive value of having a normal BNP is helpful. I think what I wanted to say was that screening echocardiograms and looking at ejection fraction in low-risk populations probably is clearly not cost-effective. It probably never alters decision making. If you have a 30-year-old person with no cardiac risk factors and no past cardiac history who develops B-cell lymphoma and is going to get anthracycline-based chemotherapy, the likelihood of finding a reason not to give that therapy based on an echocardiogram is quite small. I would even go further and say close to zero. We’ve begun to look at this. There is literature that supports the concept. Also, that in low-risk people – if you can define the low-risk population in an accurate way – for lymphoma patients or women with breast cancer getting either anthracyclines, trastuzumab, or the other human epidermal growth factor receptor-2 (HER2)-directed therapies, there’s probably little yield to even getting a baseline study.

DH Very interesting. I would agree with you.
JC We’re going to talk about 5-FU, of course. The 5-FU thing has become a passion of mine. Over the last two to two-and-a- half years we have gotten very aggressive with treating coronary spasm that’s induced by the fluoropyrimidines. That’s 5-FU and capecitabine, the oral version.

There is an incidence that the literature says is less than 1%. It probably is somewhere between 3% and 5%. It’s a little bit more common than has been reported. The reason is the way that it presents has classically been described in the literature as different than what occurs in real life. It is a phenomenon. It’s the most common cardiac side effect. Sometimes it is large epicardial coronary artery spasm. Sometimes it’s small vessel spasm. You can have chest pain with no electrocardiographic changes or ECG changes without chest pain (so-called silent ischemia). The description doesn’t always sound like classic angina but symptoms are temporally related to getting the drug.

So, we’ve developed a protocol to treat documented spasm as an outpatient to be able to continue those drugs to their logical conclusion from an oncologic standpoint. In fact, we just submitted a manuscript to the American Journal of Cardiology describing our experience and the algorithm of how we treat people. We’re uniquely aggressive in re-challenging patients who’ve had spasm.
 

DH Finally, it occurred to me that we cause problems with radiation. We cause problems with chemotherapy and other infusions. Are there particular cancers that you think of or you’re called in to see that you worry about cardiac involvement by their location? What comes to mind are cases I’ve had in which there is pericardial involvement and tamponade or restrictive pericarditis.
JC We see metastatic disease to the pericardium with breast cancer, lung cancer, and lymphoma. Renal cell has an interesting predilection to go to the pericardium. We’ve seen in the last probably 6 months 2 cases of bladder cancer with pericardial metastases. When we reviewed the literature, we were only able to find 9 or 10 case reports. It’s rare, but it occurs.

Fluid in the pericardium with and without tamponade is increasingly common, and because we do a better job in treating complicated cancer, people successively can receive cycles of sequential chemotherapeutic regimens – they are living longer, their cancer can get more complicated and/or resistant and with it, there’s more time for metastatic disease to occur. Tamponade is a common phenomenon. We always say that at 4 o’clock on Friday we always see somebody who has tamponade. We see a lot of pericardial disease.

Then, another area of a concern is the tyrosine kinase inhibitors that can cause hypertension, which is very common. We’ve become pretty aggressive. The oncologists recognize the importance of being able to follow and treat blood pressures to allow patients to get these treatments. I guess we couldn’t end without talking about checkpoint inhibitors and the recent lay press flurry about reporting myocarditis.
 

DH I haven’t personally experienced that. How common is that, and how do we watch for it?
JC Personally, I’ve seen probably four or five people who were referred because of heart failure on checkpoint inhibitors. For each of them, there was historically something as a preexisting problem before the checkpoint inhibitor. It was coincident that with either fluid changes or blood pressure changes associated with the treatment that they had a flare-up of heart failure.

We have not seen, fortunately, the dynamics that were reported in the New England Journal of Medicine of three people with just rampant failure, incessant ventricular arrhythmias, and death.⁵ There’s probably some signal that may act as a cofactor. We’ve actually joined in a registry with Vanderbilt University in Nashville to try to understand this a little bit better.
 

DH Well, certainly with the proliferation of the checkpoint inhibitors, and so many different tumors, and so much widespread use, it looks like there is a small safety signal there but still yet to be defined. How common is that, and what should we watch for?
JC Actually, it’s serendipitous that yesterday I was walking to the parking lot with one of the nurse practitioners who takes care of the melanoma population. She said to me, “Now, do you think that we should be getting BNP levels on everybody who is getting a checkpoint inhibitor?”

I don’t think that we’re there. Just the awareness to ask the right questions when you see a patient and before starting ask, is this somebody who, in the absence of a checkpoint inhibitor, could be at risk for myocardial disease? Recognize that and use the cardiology and oncology community to work together and try to make sure that you do whatever cardioprotective things you can do and to monitor them a little bit more closely. I’m not sure that everybody who is going to start a checkpoint inhibitor needs a cardiac evaluation, doesn’t need an echocardiogram, and doesn’t need baseline biomarkers to decide if there’s a potential cardiotoxicity problem.
 

DH Well certainly, you’ve raised my awareness. It was not something that I had been thinking of with checkpoint inhibitors. Now, I certainly would if the patient has some comorbid illness that involves the heart, maybe think about it, wait to see how these reports develop, and what you and the registry do.
JC You’ve seen people who get this sort of immunologic reaction that they require steroids for fluid accumulation, rash, or other things that are in this constellation. I wouldn’t be surprised if that group might have some subclinical myocarditis that just gets better when they get treated for the other things.

We have actually been trying to get a quick look at the left ventricle when patients on checkpoint inhibitors present with systemic, noncardiac symptoms to see if there is a cardiac signal we are missing. We have a handheld portable echocardiogram device called a Vscan (General Electric Company, Fairfield, CT). It’s not much bigger than the larger cellphones that are available. We’ve been going to the bedside when people have the reaction and sticking the transducer on to get a feeling of what the ventricle looks like. There’s a lot that we don’t know. It’s a fertile ground for investigation.

DH Well, I couldn’t ask you to end on a higher note than covering the checkpoint inhibitors, which are so popular and so interesting and used everywhere. We’re still managing that whole concept. I want to thank you very much.
JC It was a great pleasure. Thank you.

DR CARVER [JC]

A typical example is a patient who had Hodgkin disease in his teens and received mediastinal mantle radiation. Fifteen to 25 years later, the patient has a pacemaker for heart block, coronary artery disease that requires a stent, and most recently has two valves replaced—so aortic and mitral valve replacement because of late radiation effects. This scenario is typical for the “old” days. The 20-year cumulative incidence of radiation-induced cardiac toxicity is 15%-20% (Table, Figure).¹ Sitting with a patient about to begin chest radiation, the absolute risks are unknown but presumed to be less as treatment is delivered according to the modern techniques that you described in the question.

DH They’re so much better now, so this is less common.
JC With the shielding and breath-holding techniques and position changes, doing upright radiation rather than supine, and because the technology has improved both in the delivery of radiation and the technology in understanding where all the radiation is going, in today’s world, we can calculate pretty precisely how much radiation the heart actually receives. Ultimately, with the protective mechanisms that are in place going forward, the risks that I described for that survivor are probably exponentially less than what’s reported in the literature and what we see clinically. Radiation has become much, much safer. There is still probably some small risk of development of late changes, but I don’t think we know what that risk is today because the shielding and things we do to protect the heart have not yet been studied in the long term.

DH Of course, the patient is breathing and there’ll be some movement of the target. Some of the radiation techniques can follow the target despite the breathing?
JC Yes, definitely true. Radiation delivery is much more precise today. Not only has the delivery changed, but so has what we know about the location of potential arterial disease. For example, if you read any textbook, it says that for the coronaries, that it’s ostial and proximal disease of the left main, or the left anterior descending, or the right coronary artery. Today, somebody who gets chest/mediastinal radiation, for either breast cancer, lymphoma, or for a mediastinal tumor, the location of potential disease is more likely to mimic the location of classic coronary disease in the mid-portion of the left anterior descending artery rather than at the ostium. It’s going to be a different disease going forward.^2,3

With administration of the anthracyclines, we try to do whatever protective things we can do. There are some people who believe that continuous infusion is safer for the heart than bolus injection. It’s pretty controversial. Dexrazoxane, which is a chelating agent, has been shown to reduce cardiotoxicity, and using a lipophilic anthracycline preparation may also have less cardiac toxicity.

DH I have a population in which a lot of liposomal doxorubicin is used and I’ve given a lot and rarely if ever get cardiac toxicity. You see that as well?
JC Yes. There’s a significant financial difference between doxorubicin and liposomal doxorubicin; the latter is more expensive. From the standpoint of safety, and from the standpoint of if I ever needed doxorubicin, I would probably jump on that and ask for the liposomal preparation and/or dexrazoxane.

DH For trastuzumab, we are getting echo- cardiograms every 9 weeks. That seems awfully simple, but there’s a whole algorithm we follow for particular change in ejection fraction and watch the drug or stop the drug. Are we doing that correctly?
JC The first statement I would make about that is that there are too many women who need trastuzumab whose therapy has been prematurely stopped because of just looking at the ejection fractions. So, there has to be more to decision-making other than just the number of the ejection fraction. We’re pretty aggressive and tend to try to get women to get the full dose and whatever dose-effective dose they need, especially with curative intent in the adjuvant setting that we make decisions based not only on the ejection fraction.

We also have, I would say, a handful of our medical breast oncologists who do not follow the package insert. We don’t get ejection fractions every 3 cycles. We have substituted a little bit by following biomarkers so that we use N-terminal pro b-type natriuretic peptide (NT-proBNP) to monitor people, either with each cycle or every third cycle. The benefit of BNP is its negative predictive value. If it’s normal, it’s hard to have any clinically significant myocardial dysfunction.

What we’re going to see over – I would hope – the next year or two is that the recommendations about getting echocardiograms frequently will go away.
 

DH That would be welcome because in our electronic medical records, it’s 9 weeks, stop, do this, etc. How about a comment on infusional 5-FU and possibly its cousins, such as capecitabine, and any coronary issues?
JC Let me come back, just one more thing about trastuzumab. For metastatic disease, we do whatever is necessary to continue effective cancer therapy and in the absence of any cardiac symptoms or abnormal physical findings, we continue cancer treatment without any serial echocardiographic monitoring.

DH You think the NT-proBNP might be useful? I know that’s excreted by the kidneys, so that might rise in renal failure, but we can adjust for that.
JC The negative predictive value of having a normal BNP is helpful. I think what I wanted to say was that screening echocardiograms and looking at ejection fraction in low-risk populations probably is clearly not cost-effective. It probably never alters decision making. If you have a 30-year-old person with no cardiac risk factors and no past cardiac history who develops B-cell lymphoma and is going to get anthracycline-based chemotherapy, the likelihood of finding a reason not to give that therapy based on an echocardiogram is quite small. I would even go further and say close to zero. We’ve begun to look at this. There is literature that supports the concept. Also, that in low-risk people – if you can define the low-risk population in an accurate way – for lymphoma patients or women with breast cancer getting either anthracyclines, trastuzumab, or the other human epidermal growth factor receptor-2 (HER2)-directed therapies, there’s probably little yield to even getting a baseline study.

DH Very interesting. I would agree with you.
JC We’re going to talk about 5-FU, of course. The 5-FU thing has become a passion of mine. Over the last two to two-and-a- half years we have gotten very aggressive with treating coronary spasm that’s induced by the fluoropyrimidines. That’s 5-FU and capecitabine, the oral version.

There is an incidence that the literature says is less than 1%. It probably is somewhere between 3% and 5%. It’s a little bit more common than has been reported. The reason is the way that it presents has classically been described in the literature as different than what occurs in real life. It is a phenomenon. It’s the most common cardiac side effect. Sometimes it is large epicardial coronary artery spasm. Sometimes it’s small vessel spasm. You can have chest pain with no electrocardiographic changes or ECG changes without chest pain (so-called silent ischemia). The description doesn’t always sound like classic angina but symptoms are temporally related to getting the drug.

So, we’ve developed a protocol to treat documented spasm as an outpatient to be able to continue those drugs to their logical conclusion from an oncologic standpoint. In fact, we just submitted a manuscript to the American Journal of Cardiology describing our experience and the algorithm of how we treat people. We’re uniquely aggressive in re-challenging patients who’ve had spasm.
 

DH Finally, it occurred to me that we cause problems with radiation. We cause problems with chemotherapy and other infusions. Are there particular cancers that you think of or you’re called in to see that you worry about cardiac involvement by their location? What comes to mind are cases I’ve had in which there is pericardial involvement and tamponade or restrictive pericarditis.
JC We see metastatic disease to the pericardium with breast cancer, lung cancer, and lymphoma. Renal cell has an interesting predilection to go to the pericardium. We’ve seen in the last probably 6 months 2 cases of bladder cancer with pericardial metastases. When we reviewed the literature, we were only able to find 9 or 10 case reports. It’s rare, but it occurs.

Fluid in the pericardium with and without tamponade is increasingly common, and because we do a better job in treating complicated cancer, people successively can receive cycles of sequential chemotherapeutic regimens – they are living longer, their cancer can get more complicated and/or resistant and with it, there’s more time for metastatic disease to occur. Tamponade is a common phenomenon. We always say that at 4 o’clock on Friday we always see somebody who has tamponade. We see a lot of pericardial disease.

Then, another area of a concern is the tyrosine kinase inhibitors that can cause hypertension, which is very common. We’ve become pretty aggressive. The oncologists recognize the importance of being able to follow and treat blood pressures to allow patients to get these treatments. I guess we couldn’t end without talking about checkpoint inhibitors and the recent lay press flurry about reporting myocarditis.
 

DH I haven’t personally experienced that. How common is that, and how do we watch for it?
JC Personally, I’ve seen probably four or five people who were referred because of heart failure on checkpoint inhibitors. For each of them, there was historically something as a preexisting problem before the checkpoint inhibitor. It was coincident that with either fluid changes or blood pressure changes associated with the treatment that they had a flare-up of heart failure.

We have not seen, fortunately, the dynamics that were reported in the New England Journal of Medicine of three people with just rampant failure, incessant ventricular arrhythmias, and death.⁵ There’s probably some signal that may act as a cofactor. We’ve actually joined in a registry with Vanderbilt University in Nashville to try to understand this a little bit better.
 

DH Well, certainly with the proliferation of the checkpoint inhibitors, and so many different tumors, and so much widespread use, it looks like there is a small safety signal there but still yet to be defined. How common is that, and what should we watch for?
JC Actually, it’s serendipitous that yesterday I was walking to the parking lot with one of the nurse practitioners who takes care of the melanoma population. She said to me, “Now, do you think that we should be getting BNP levels on everybody who is getting a checkpoint inhibitor?”

I don’t think that we’re there. Just the awareness to ask the right questions when you see a patient and before starting ask, is this somebody who, in the absence of a checkpoint inhibitor, could be at risk for myocardial disease? Recognize that and use the cardiology and oncology community to work together and try to make sure that you do whatever cardioprotective things you can do and to monitor them a little bit more closely. I’m not sure that everybody who is going to start a checkpoint inhibitor needs a cardiac evaluation, doesn’t need an echocardiogram, and doesn’t need baseline biomarkers to decide if there’s a potential cardiotoxicity problem.
 

DH Well certainly, you’ve raised my awareness. It was not something that I had been thinking of with checkpoint inhibitors. Now, I certainly would if the patient has some comorbid illness that involves the heart, maybe think about it, wait to see how these reports develop, and what you and the registry do.
JC You’ve seen people who get this sort of immunologic reaction that they require steroids for fluid accumulation, rash, or other things that are in this constellation. I wouldn’t be surprised if that group might have some subclinical myocarditis that just gets better when they get treated for the other things.

We have actually been trying to get a quick look at the left ventricle when patients on checkpoint inhibitors present with systemic, noncardiac symptoms to see if there is a cardiac signal we are missing. We have a handheld portable echocardiogram device called a Vscan (General Electric Company, Fairfield, CT). It’s not much bigger than the larger cellphones that are available. We’ve been going to the bedside when people have the reaction and sticking the transducer on to get a feeling of what the ventricle looks like. There’s a lot that we don’t know. It’s a fertile ground for investigation.

DH Well, I couldn’t ask you to end on a higher note than covering the checkpoint inhibitors, which are so popular and so interesting and used everywhere. We’re still managing that whole concept. I want to thank you very much.
JC It was a great pleasure. Thank you.

DR CARVER [JC]

A typical example is a patient who had Hodgkin disease in his teens and received mediastinal mantle radiation. Fifteen to 25 years later, the patient has a pacemaker for heart block, coronary artery disease that requires a stent, and most recently has two valves replaced—so aortic and mitral valve replacement because of late radiation effects. This scenario is typical for the “old” days. The 20-year cumulative incidence of radiation-induced cardiac toxicity is 15%-20% (Table, Figure).¹ Sitting with a patient about to begin chest radiation, the absolute risks are unknown but presumed to be less as treatment is delivered according to the modern techniques that you described in the question.

DH They’re so much better now, so this is less common.
JC With the shielding and breath-holding techniques and position changes, doing upright radiation rather than supine, and because the technology has improved both in the delivery of radiation and the technology in understanding where all the radiation is going, in today’s world, we can calculate pretty precisely how much radiation the heart actually receives. Ultimately, with the protective mechanisms that are in place going forward, the risks that I described for that survivor are probably exponentially less than what’s reported in the literature and what we see clinically. Radiation has become much, much safer. There is still probably some small risk of development of late changes, but I don’t think we know what that risk is today because the shielding and things we do to protect the heart have not yet been studied in the long term.

DH Of course, the patient is breathing and there’ll be some movement of the target. Some of the radiation techniques can follow the target despite the breathing?
JC Yes, definitely true. Radiation delivery is much more precise today. Not only has the delivery changed, but so has what we know about the location of potential arterial disease. For example, if you read any textbook, it says that for the coronaries, that it’s ostial and proximal disease of the left main, or the left anterior descending, or the right coronary artery. Today, somebody who gets chest/mediastinal radiation, for either breast cancer, lymphoma, or for a mediastinal tumor, the location of potential disease is more likely to mimic the location of classic coronary disease in the mid-portion of the left anterior descending artery rather than at the ostium. It’s going to be a different disease going forward.^2,3

With administration of the anthracyclines, we try to do whatever protective things we can do. There are some people who believe that continuous infusion is safer for the heart than bolus injection. It’s pretty controversial. Dexrazoxane, which is a chelating agent, has been shown to reduce cardiotoxicity, and using a lipophilic anthracycline preparation may also have less cardiac toxicity.

DH I have a population in which a lot of liposomal doxorubicin is used and I’ve given a lot and rarely if ever get cardiac toxicity. You see that as well?
JC Yes. There’s a significant financial difference between doxorubicin and liposomal doxorubicin; the latter is more expensive. From the standpoint of safety, and from the standpoint of if I ever needed doxorubicin, I would probably jump on that and ask for the liposomal preparation and/or dexrazoxane.

DH For trastuzumab, we are getting echo- cardiograms every 9 weeks. That seems awfully simple, but there’s a whole algorithm we follow for particular change in ejection fraction and watch the drug or stop the drug. Are we doing that correctly?
JC The first statement I would make about that is that there are too many women who need trastuzumab whose therapy has been prematurely stopped because of just looking at the ejection fractions. So, there has to be more to decision-making other than just the number of the ejection fraction. We’re pretty aggressive and tend to try to get women to get the full dose and whatever dose-effective dose they need, especially with curative intent in the adjuvant setting that we make decisions based not only on the ejection fraction.

We also have, I would say, a handful of our medical breast oncologists who do not follow the package insert. We don’t get ejection fractions every 3 cycles. We have substituted a little bit by following biomarkers so that we use N-terminal pro b-type natriuretic peptide (NT-proBNP) to monitor people, either with each cycle or every third cycle. The benefit of BNP is its negative predictive value. If it’s normal, it’s hard to have any clinically significant myocardial dysfunction.

What we’re going to see over – I would hope – the next year or two is that the recommendations about getting echocardiograms frequently will go away.
 

DH That would be welcome because in our electronic medical records, it’s 9 weeks, stop, do this, etc. How about a comment on infusional 5-FU and possibly its cousins, such as capecitabine, and any coronary issues?
JC Let me come back, just one more thing about trastuzumab. For metastatic disease, we do whatever is necessary to continue effective cancer therapy and in the absence of any cardiac symptoms or abnormal physical findings, we continue cancer treatment without any serial echocardiographic monitoring.

DH You think the NT-proBNP might be useful? I know that’s excreted by the kidneys, so that might rise in renal failure, but we can adjust for that.
JC The negative predictive value of having a normal BNP is helpful. I think what I wanted to say was that screening echocardiograms and looking at ejection fraction in low-risk populations probably is clearly not cost-effective. It probably never alters decision making. If you have a 30-year-old person with no cardiac risk factors and no past cardiac history who develops B-cell lymphoma and is going to get anthracycline-based chemotherapy, the likelihood of finding a reason not to give that therapy based on an echocardiogram is quite small. I would even go further and say close to zero. We’ve begun to look at this. There is literature that supports the concept. Also, that in low-risk people – if you can define the low-risk population in an accurate way – for lymphoma patients or women with breast cancer getting either anthracyclines, trastuzumab, or the other human epidermal growth factor receptor-2 (HER2)-directed therapies, there’s probably little yield to even getting a baseline study.

DH Very interesting. I would agree with you.
JC We’re going to talk about 5-FU, of course. The 5-FU thing has become a passion of mine. Over the last two to two-and-a- half years we have gotten very aggressive with treating coronary spasm that’s induced by the fluoropyrimidines. That’s 5-FU and capecitabine, the oral version.

There is an incidence that the literature says is less than 1%. It probably is somewhere between 3% and 5%. It’s a little bit more common than has been reported. The reason is the way that it presents has classically been described in the literature as different than what occurs in real life. It is a phenomenon. It’s the most common cardiac side effect. Sometimes it is large epicardial coronary artery spasm. Sometimes it’s small vessel spasm. You can have chest pain with no electrocardiographic changes or ECG changes without chest pain (so-called silent ischemia). The description doesn’t always sound like classic angina but symptoms are temporally related to getting the drug.

So, we’ve developed a protocol to treat documented spasm as an outpatient to be able to continue those drugs to their logical conclusion from an oncologic standpoint. In fact, we just submitted a manuscript to the American Journal of Cardiology describing our experience and the algorithm of how we treat people. We’re uniquely aggressive in re-challenging patients who’ve had spasm.
 

DH Finally, it occurred to me that we cause problems with radiation. We cause problems with chemotherapy and other infusions. Are there particular cancers that you think of or you’re called in to see that you worry about cardiac involvement by their location? What comes to mind are cases I’ve had in which there is pericardial involvement and tamponade or restrictive pericarditis.
JC We see metastatic disease to the pericardium with breast cancer, lung cancer, and lymphoma. Renal cell has an interesting predilection to go to the pericardium. We’ve seen in the last probably 6 months 2 cases of bladder cancer with pericardial metastases. When we reviewed the literature, we were only able to find 9 or 10 case reports. It’s rare, but it occurs.

Fluid in the pericardium with and without tamponade is increasingly common, and because we do a better job in treating complicated cancer, people successively can receive cycles of sequential chemotherapeutic regimens – they are living longer, their cancer can get more complicated and/or resistant and with it, there’s more time for metastatic disease to occur. Tamponade is a common phenomenon. We always say that at 4 o’clock on Friday we always see somebody who has tamponade. We see a lot of pericardial disease.

Then, another area of a concern is the tyrosine kinase inhibitors that can cause hypertension, which is very common. We’ve become pretty aggressive. The oncologists recognize the importance of being able to follow and treat blood pressures to allow patients to get these treatments. I guess we couldn’t end without talking about checkpoint inhibitors and the recent lay press flurry about reporting myocarditis.
 

DH I haven’t personally experienced that. How common is that, and how do we watch for it?
JC Personally, I’ve seen probably four or five people who were referred because of heart failure on checkpoint inhibitors. For each of them, there was historically something as a preexisting problem before the checkpoint inhibitor. It was coincident that with either fluid changes or blood pressure changes associated with the treatment that they had a flare-up of heart failure.

We have not seen, fortunately, the dynamics that were reported in the New England Journal of Medicine of three people with just rampant failure, incessant ventricular arrhythmias, and death.⁵ There’s probably some signal that may act as a cofactor. We’ve actually joined in a registry with Vanderbilt University in Nashville to try to understand this a little bit better.
 

DH Well, certainly with the proliferation of the checkpoint inhibitors, and so many different tumors, and so much widespread use, it looks like there is a small safety signal there but still yet to be defined. How common is that, and what should we watch for?
JC Actually, it’s serendipitous that yesterday I was walking to the parking lot with one of the nurse practitioners who takes care of the melanoma population. She said to me, “Now, do you think that we should be getting BNP levels on everybody who is getting a checkpoint inhibitor?”

I don’t think that we’re there. Just the awareness to ask the right questions when you see a patient and before starting ask, is this somebody who, in the absence of a checkpoint inhibitor, could be at risk for myocardial disease? Recognize that and use the cardiology and oncology community to work together and try to make sure that you do whatever cardioprotective things you can do and to monitor them a little bit more closely. I’m not sure that everybody who is going to start a checkpoint inhibitor needs a cardiac evaluation, doesn’t need an echocardiogram, and doesn’t need baseline biomarkers to decide if there’s a potential cardiotoxicity problem.
 

DH Well certainly, you’ve raised my awareness. It was not something that I had been thinking of with checkpoint inhibitors. Now, I certainly would if the patient has some comorbid illness that involves the heart, maybe think about it, wait to see how these reports develop, and what you and the registry do.
JC You’ve seen people who get this sort of immunologic reaction that they require steroids for fluid accumulation, rash, or other things that are in this constellation. I wouldn’t be surprised if that group might have some subclinical myocarditis that just gets better when they get treated for the other things.

We have actually been trying to get a quick look at the left ventricle when patients on checkpoint inhibitors present with systemic, noncardiac symptoms to see if there is a cardiac signal we are missing. We have a handheld portable echocardiogram device called a Vscan (General Electric Company, Fairfield, CT). It’s not much bigger than the larger cellphones that are available. We’ve been going to the bedside when people have the reaction and sticking the transducer on to get a feeling of what the ventricle looks like. There’s a lot that we don’t know. It’s a fertile ground for investigation.

DH Well, I couldn’t ask you to end on a higher note than covering the checkpoint inhibitors, which are so popular and so interesting and used everywhere. We’re still managing that whole concept. I want to thank you very much.
JC It was a great pleasure. Thank you.

After cancer treatment, a new challenge emerges as patients negotiate reentry into their everyday lives. These patients often need multifaceted, simultaneous, and ongoing help with physical, emotional, and psychological issues. And they’re often dealing with a multiplicity of health care providers.

Researchers from University of Zurich and Centres for Addiction Medicine in Zurich, Switzerland, saw similarities between these needs and those of patients with chronic medical conditions. They hypothesized that case management—like that for chronic diseases—could work for cancer survivors perhaps even better than usual care. Among other duties, case managers can assess individual needs, identify barriers, ensure coordination among care providers, and perhaps most important, promote empowering self-management skills and self-efficacy. All of which could help cancer survivors cope with the long-term consequences of cancer and improve health-related quality of life (QOL).

Related: Putting the Focus on Quality of Life in Cancer Care

The researchers designed an intervention study in which 5 oncology nurse case managers met with 95 patients at least once a month for 3 months, then conducted telephone follow-ups for 9 months. Questionnaires measured health-related QOL at 12 months via the Functional Assessment of Cancer Therapy-General (FACT-G), self-efficacy, and concordance of received care with the Patient Assessment of Chronic Illness Care (PACIC).

Although the researchers’ study did not show a significant absolute difference between the groups in FACT-G after 12 months, all scores improved in the case management group compared with the usual care group. Overall, case management clearly boosted QOL and self-efficacy and aligned health care with the chronic care model.

Related: Quality of Supportive Care for Patients With Advanced Lung Cancer in the VHA

According to the researchers, their study is the first, to their knowledge, to examine the effect of case management on the QOL of early cancer survivors. Several factors help explain the intervention’s success: (1) The case managers provided important information on long-term symptoms and available services and therapies; (2) They offered a continuity of care when treatment appointments ceased and medical follow-up visits were less frequent; and (3) They offered support to cope with the psychological issues of the reentry phase.

All in all, the researchers say their findings show case management is a practical approach to bridging a “fragmented oncological health care system” and addressing the heterogenic needs of cancer survivors.

Source:

Scherz N, Bachmann-Mettler I, Chmiel C. BMC Cancer. 2017;17(1):223.

doi: 10.1186/s12885-017-3213-9.

After cancer treatment, a new challenge emerges as patients negotiate reentry into their everyday lives. These patients often need multifaceted, simultaneous, and ongoing help with physical, emotional, and psychological issues. And they’re often dealing with a multiplicity of health care providers.

Researchers from University of Zurich and Centres for Addiction Medicine in Zurich, Switzerland, saw similarities between these needs and those of patients with chronic medical conditions. They hypothesized that case management—like that for chronic diseases—could work for cancer survivors perhaps even better than usual care. Among other duties, case managers can assess individual needs, identify barriers, ensure coordination among care providers, and perhaps most important, promote empowering self-management skills and self-efficacy. All of which could help cancer survivors cope with the long-term consequences of cancer and improve health-related quality of life (QOL).

Related: Putting the Focus on Quality of Life in Cancer Care

The researchers designed an intervention study in which 5 oncology nurse case managers met with 95 patients at least once a month for 3 months, then conducted telephone follow-ups for 9 months. Questionnaires measured health-related QOL at 12 months via the Functional Assessment of Cancer Therapy-General (FACT-G), self-efficacy, and concordance of received care with the Patient Assessment of Chronic Illness Care (PACIC).

Although the researchers’ study did not show a significant absolute difference between the groups in FACT-G after 12 months, all scores improved in the case management group compared with the usual care group. Overall, case management clearly boosted QOL and self-efficacy and aligned health care with the chronic care model.

Related: Quality of Supportive Care for Patients With Advanced Lung Cancer in the VHA

According to the researchers, their study is the first, to their knowledge, to examine the effect of case management on the QOL of early cancer survivors. Several factors help explain the intervention’s success: (1) The case managers provided important information on long-term symptoms and available services and therapies; (2) They offered a continuity of care when treatment appointments ceased and medical follow-up visits were less frequent; and (3) They offered support to cope with the psychological issues of the reentry phase.

All in all, the researchers say their findings show case management is a practical approach to bridging a “fragmented oncological health care system” and addressing the heterogenic needs of cancer survivors.

Source:

Scherz N, Bachmann-Mettler I, Chmiel C. BMC Cancer. 2017;17(1):223.

doi: 10.1186/s12885-017-3213-9.

After cancer treatment, a new challenge emerges as patients negotiate reentry into their everyday lives. These patients often need multifaceted, simultaneous, and ongoing help with physical, emotional, and psychological issues. And they’re often dealing with a multiplicity of health care providers.

Researchers from University of Zurich and Centres for Addiction Medicine in Zurich, Switzerland, saw similarities between these needs and those of patients with chronic medical conditions. They hypothesized that case management—like that for chronic diseases—could work for cancer survivors perhaps even better than usual care. Among other duties, case managers can assess individual needs, identify barriers, ensure coordination among care providers, and perhaps most important, promote empowering self-management skills and self-efficacy. All of which could help cancer survivors cope with the long-term consequences of cancer and improve health-related quality of life (QOL).

Related: Putting the Focus on Quality of Life in Cancer Care

The researchers designed an intervention study in which 5 oncology nurse case managers met with 95 patients at least once a month for 3 months, then conducted telephone follow-ups for 9 months. Questionnaires measured health-related QOL at 12 months via the Functional Assessment of Cancer Therapy-General (FACT-G), self-efficacy, and concordance of received care with the Patient Assessment of Chronic Illness Care (PACIC).

Although the researchers’ study did not show a significant absolute difference between the groups in FACT-G after 12 months, all scores improved in the case management group compared with the usual care group. Overall, case management clearly boosted QOL and self-efficacy and aligned health care with the chronic care model.

Related: Quality of Supportive Care for Patients With Advanced Lung Cancer in the VHA

According to the researchers, their study is the first, to their knowledge, to examine the effect of case management on the QOL of early cancer survivors. Several factors help explain the intervention’s success: (1) The case managers provided important information on long-term symptoms and available services and therapies; (2) They offered a continuity of care when treatment appointments ceased and medical follow-up visits were less frequent; and (3) They offered support to cope with the psychological issues of the reentry phase.

All in all, the researchers say their findings show case management is a practical approach to bridging a “fragmented oncological health care system” and addressing the heterogenic needs of cancer survivors.

Source:

Scherz N, Bachmann-Mettler I, Chmiel C. BMC Cancer. 2017;17(1):223.

doi: 10.1186/s12885-017-3213-9.

Cancer drugs are becoming available at an unprecedented rate. In 2015 alone, the US Food and Drug Administration (FDA) approved 18 new agents.¹ Although many of those agents have adverse event profiles that are more favorable than those seen with conventional chemotherapy, nausea and vomiting still occur. In fact, nausea and vomiting continue to be ranked as among the most common and distressing of cancer symptoms.^2,3 In a 2004 study, Grunberg and colleagues reported that as many as 75% of health care providers misjudge the risk for chemotherapy-induced nausea and vomiting (CINV), even when prescribing cancer drugs that have been available for years,⁴ thus amplifying concerns that such risk assessment might be even worse when new cancer agents are prescribed for the first time.

In this study, we hypothesized that patients prescribed a new cancer drug, trifluridine-tipiracil, would be at risk for CINV because of poor guideline adherence on the part of health care providers. The correct matching of antiemetics to chemotherapy is important. Inadequate antiemetic prophylaxis predisposes to nausea and vomiting with dehydration and metabolic and electrolyte derangements – complications that can occur in up to one-third of patients who receive moderately or highly emetogenic chemotherapy and who have been reported to achieve poor symptom control.⁴ Over-prophylaxis also has drawbacks. For example, antiemetics are expensive and, at times, they can induce their own adverse events, such as lethargy, dyskinesia, constipation, headaches, hiccups, fatigue, and even cardiac arrhythmias.⁵ The best approach is to appropriately match the antiemetic to the chemotherapy. Indeed, adherence to evidence-based guidelines has yielded success in symptom control, but the guidelines work on the assumption that the emetogenic potential of new chemotherapy agents has been accurately determined and then disseminated to and acted upon by health care providers.^6,7 To our knowledge, no previous studies have tested that assumption, as we do in the present study.

Trifluridine-tipiracil was selected as the focus of this project and as illustrative of other newly approved chemotherapy agents for two reasons. First, it became available for routine prescribing in pretreated patients with metastatic colorectal cancer in the United States in September 2015.¹ That timing allowed us to analyze much of the early prescribing period, both during the 9 months before approval, when the drug was available on a compassionate-use basis at our institution, and the 3 months after approval. Second, trifluridine-tipiracil has classifiably low emetogenic potential, and mismatching of antiemetics tends to occur more often with low emetogenic chemotherapy.⁹ Trifluridine-tipiracil and placebo patients manifest rates of nausea at 48% and 24%, respectively, and rates of vomiting at 28% and 14%, respectively.⁸

Hence, the goal of this study was to explore whether a guideline-based prophylactic antiemetic regimen was appropriately matched to the new chemotherapy agent, trifluridine-tipiracil, to report whether such symptoms of nausea and vomiting are kept at bay, and to identify a potentially vulnerable interval – immediately after drug approval – when cancer patients may be at risk for CINV because of poor adherence to antiemetic guideline prescribing practices by health care providers.

Methods

Overview

The Mayo Clinic Institutional Review Board approved this study. We obtained the identifying information of all patients treated with trifluridine-tipiracil at our institution from the Mayo Clinic Specialty Pharmacy, which uses an electronic prescribing system that contributed to the comprehensiveness of the data set. Patients included those who had participated in a colorectal cancer compassionate-use program before the September 2015 approval of the drug and those who received the drug shortly after its approval. In essence, this retrospective, single-institution study included every patient who received trifluridine-tipiracil for metastatic colorectal cancer in 2015 (January through December); this approach enabled us to systematically report on early first-cycle prescribing practices 9 months before and 3 months after the drug’s approval in September of 2015.

Determination of guideline adherence

This project relied on the National Comprehensive Cancer Network (NCCN) Guidelines (v1.2015, behind paywall) because they had been updated in 2015 (and hence coincided with this project’s study dates) to incorporate recommendations specific to oral chemotherapy and because they seemed concordant with other guidelines.^10,11

Antiemetic prophylaxis for a specific patient was deemed guideline adherent if a version of the recommended NCCN antiemetic regimen had been prescribed during the first cycle of chemotherapy. This regimen consisted of metoclopramide, prochlorperazine, haloperidol, or a 5-hydroxytryptamine receptor antagonist. In contrast, if a patient had been prescribed a more aggressive or less aggressive regimen, such prescribing practices were deemed non–guideline adherent/aggressive (received more prophylaxis than called for) or non–guideline adherent/less aggressive (including no antiemetics), respectively. Again, medical record prescribing determined adherence.

Data reporting

The primary goal of this study was to report the percentage of patients who had been prescribed a first-cycle antiemetic prophylaxis regimen concordant with NCCN guidelines. Secondary goals included reporting the incidence of nausea and vomiting, the use of rescue antiemetics other than those prescribed up front, the need for an unplanned medical encounter to address nausea and vomiting, and change in antiemetic prescribing before the second chemotherapy cycle. Confidence intervals were calculated with JMP Pro 10.0.0. This study was too limited in sample size to assess sex-based differences in outcomes.

Results

Demographics

This report focuses on 44 patients who received first-cycle trifluridine-tipiracil during the first calendar year of the drug’s FDA approval. All patients had metastatic colorectal cancer and had previous exposures to other chemotherapy agents (Table 1). Of note, 28 patients (64%) had experienced CINV before starting trifluridine-tipiracil and all these patients had been heavily pretreated with multiple lines of chemotherapy.

Guideline adherence

Patients were most commonly prescribed prochlorperazine and ondansetron prophylaxis for CINV before the first chemotherapy cycle of trifluridine-tipiracil (Table 2): 15 patients were prescribed combination antiemetic therapy, typically two of the most commonly prescribed single agents with different mechanisms of action. Twenty-five patients (57%; 95% confidence interval (CI): 42%, 70%) were prescribed antiemetics in a manner consistent with guidelines; 15 (34%; 95% CI: 22%, 49%) were prescribed antiemetics in a non–guideline-adherent/more aggressive manner (received more prophylaxis than called for); and 4 (9%; 95% CI: 4%, 21%) were prescribed them in a non–guideline-adherent/less aggressive manner.

Clinical outcomes based on guideline adherence

In guideline-adherent patients, first-cycle nausea and vomiting occurred in 13 patients (52%) and 6 patients (24%), respectively, with 1 patient requiring an unscheduled clinic visit and another an emergency department visit and hospital admission – all for nausea and vomiting (Table 3). In non–guideline-adherent/more aggressive patients, those symptoms occurred in 5 patients (33%, nausea) and 4 patients (27%, vomiting), with 1 patient requiring a clinic visit and emergency department visit and another an emergency department visit – again, all for nausea and vomiting. In non–guideline-adherent/less aggressive patients, no nausea or vomiting was reported.

Discussion

This study examined adherence to antiemetic guidelines in the setting of a soon-to-be-approved or newly approved antineoplastic agent. As hypothesized, a substantial proportion of patients (43% in this study) were prescribed antiemetics in a nonadherent manner with respect to guidelines, thus identifying the period shortly before and after FDA approval as a particularly vulnerable interval with respect to antiemetic guideline adherence. It is possible that our institution’s practice of testing novel chemotherapy agents for the treatment of colorectal cancer prompted a heightened awareness of potential adverse events, leading to greater guideline adherence than might have occurred in other settings and resulting in judicious straying from guideline adherence only when appropriate.^12-14 Thus, these high rates of poor adherence may in fact represent an underestimate of what one might see in other clinical practices; and, similarly, these rates of symptom control might also be more favorable than those one might see in other clinical practices. To our knowledge, antiemetic prescribing practices with newer chemotherapy agents have not been explored before now, and our data underscore a clear need to do so – particularly during this limited interval when health care providers begin to prescribe new chemotherapy agents for the first time.

It is worth noting that despite the high rates of guideline nonadherence, rates of nausea and vomiting seemed to be comparable in patients prescribed antiemetics in a guideline-adherent manner and those prescribed antiemetics in a non–guideline-adherent/aggressive manner.A small number of patients in both the guideline-adherent and non–guideline-adherent/aggressive groups required rescue medications, unscheduled medical visits for nausea and vomiting, and additional antiemetics during the second cycle of chemotherapy. Of note,none of those interventions occurred in patients who were prescribed antiemetics in a non–guideline-adherent/less aggressive manner. These findings might reflect the fact that the patients had proven themselves to be at risk for nausea and vomiting with previous chemotherapy. Before they became candidates for trifluridine-tipiracil, patients had been heavily pretreated with other chemotherapy agents, most had experienced CINV, and many were therefore highly predisposed to nausea and vomiting. These observations underscore the fact that guidelines – even those that are well accepted and widely used – should be implemented in concert with good clinical judgment.^10,11 This study has shortcomings, most notably its small sample size. However, had we extended our study beyond 3 months of the FDA approval to include more patients, our findings would have reflected more experienced prescribing practices and we thereby would have deviated from our primary goal of assessing antiemetic prescribing practices with only recently-approved and available chemotherapy agents. In this context, this limited sample size aptly serves a primary role of capturing outcomes within a fleeting but critical interval of new drug availability.In summary, this study found a notable rate of poor guideline adherence when prescribing antiemetics for trifluridine-tipiracil, a new chemotherapy agent of low emetogenic potential. Although the resultant rates of nausea and vomiting suggest that good clinical judgment might have influenced whether or not guidelines were adhered to, these findings nonetheless underscore the need to assess adherence to antiemetic guidelines when new chemotherapy drugs become available and potentially to put in place institutional infrastructure rapidly to promote improved adherence. Such an assessment should be deliberate, formalized, and prompt within individual oncology clinics and cancer centers after a new cancer drug becomes available. In conjunction with clinical judgment, such measures might lead to improved symptom control.

Acknowledgment

This paper is based on a poster that was presented at the 2016 Palliative Care in Oncology Symposium, on September 10, 2016: Adherence to antiemetic guidelines with a newly approved chemotherapy agent, trifluridine-tipiracil (TAS-102): a single-institution study. Daniel Childs and Aminah Jatoi, Mayo Clinic, Rochester, MN. http://meetinglibrary.asco.org/record/136444/abstract. J Clin Oncol. 2016;34(suppl 26S):abstract 221.

Cancer drugs are becoming available at an unprecedented rate. In 2015 alone, the US Food and Drug Administration (FDA) approved 18 new agents.¹ Although many of those agents have adverse event profiles that are more favorable than those seen with conventional chemotherapy, nausea and vomiting still occur. In fact, nausea and vomiting continue to be ranked as among the most common and distressing of cancer symptoms.^2,3 In a 2004 study, Grunberg and colleagues reported that as many as 75% of health care providers misjudge the risk for chemotherapy-induced nausea and vomiting (CINV), even when prescribing cancer drugs that have been available for years,⁴ thus amplifying concerns that such risk assessment might be even worse when new cancer agents are prescribed for the first time.

In this study, we hypothesized that patients prescribed a new cancer drug, trifluridine-tipiracil, would be at risk for CINV because of poor guideline adherence on the part of health care providers. The correct matching of antiemetics to chemotherapy is important. Inadequate antiemetic prophylaxis predisposes to nausea and vomiting with dehydration and metabolic and electrolyte derangements – complications that can occur in up to one-third of patients who receive moderately or highly emetogenic chemotherapy and who have been reported to achieve poor symptom control.⁴ Over-prophylaxis also has drawbacks. For example, antiemetics are expensive and, at times, they can induce their own adverse events, such as lethargy, dyskinesia, constipation, headaches, hiccups, fatigue, and even cardiac arrhythmias.⁵ The best approach is to appropriately match the antiemetic to the chemotherapy. Indeed, adherence to evidence-based guidelines has yielded success in symptom control, but the guidelines work on the assumption that the emetogenic potential of new chemotherapy agents has been accurately determined and then disseminated to and acted upon by health care providers.^6,7 To our knowledge, no previous studies have tested that assumption, as we do in the present study.

Trifluridine-tipiracil was selected as the focus of this project and as illustrative of other newly approved chemotherapy agents for two reasons. First, it became available for routine prescribing in pretreated patients with metastatic colorectal cancer in the United States in September 2015.¹ That timing allowed us to analyze much of the early prescribing period, both during the 9 months before approval, when the drug was available on a compassionate-use basis at our institution, and the 3 months after approval. Second, trifluridine-tipiracil has classifiably low emetogenic potential, and mismatching of antiemetics tends to occur more often with low emetogenic chemotherapy.⁹ Trifluridine-tipiracil and placebo patients manifest rates of nausea at 48% and 24%, respectively, and rates of vomiting at 28% and 14%, respectively.⁸

Hence, the goal of this study was to explore whether a guideline-based prophylactic antiemetic regimen was appropriately matched to the new chemotherapy agent, trifluridine-tipiracil, to report whether such symptoms of nausea and vomiting are kept at bay, and to identify a potentially vulnerable interval – immediately after drug approval – when cancer patients may be at risk for CINV because of poor adherence to antiemetic guideline prescribing practices by health care providers.

Methods

Overview

The Mayo Clinic Institutional Review Board approved this study. We obtained the identifying information of all patients treated with trifluridine-tipiracil at our institution from the Mayo Clinic Specialty Pharmacy, which uses an electronic prescribing system that contributed to the comprehensiveness of the data set. Patients included those who had participated in a colorectal cancer compassionate-use program before the September 2015 approval of the drug and those who received the drug shortly after its approval. In essence, this retrospective, single-institution study included every patient who received trifluridine-tipiracil for metastatic colorectal cancer in 2015 (January through December); this approach enabled us to systematically report on early first-cycle prescribing practices 9 months before and 3 months after the drug’s approval in September of 2015.

Determination of guideline adherence

This project relied on the National Comprehensive Cancer Network (NCCN) Guidelines (v1.2015, behind paywall) because they had been updated in 2015 (and hence coincided with this project’s study dates) to incorporate recommendations specific to oral chemotherapy and because they seemed concordant with other guidelines.^10,11

Antiemetic prophylaxis for a specific patient was deemed guideline adherent if a version of the recommended NCCN antiemetic regimen had been prescribed during the first cycle of chemotherapy. This regimen consisted of metoclopramide, prochlorperazine, haloperidol, or a 5-hydroxytryptamine receptor antagonist. In contrast, if a patient had been prescribed a more aggressive or less aggressive regimen, such prescribing practices were deemed non–guideline adherent/aggressive (received more prophylaxis than called for) or non–guideline adherent/less aggressive (including no antiemetics), respectively. Again, medical record prescribing determined adherence.

Data reporting

The primary goal of this study was to report the percentage of patients who had been prescribed a first-cycle antiemetic prophylaxis regimen concordant with NCCN guidelines. Secondary goals included reporting the incidence of nausea and vomiting, the use of rescue antiemetics other than those prescribed up front, the need for an unplanned medical encounter to address nausea and vomiting, and change in antiemetic prescribing before the second chemotherapy cycle. Confidence intervals were calculated with JMP Pro 10.0.0. This study was too limited in sample size to assess sex-based differences in outcomes.

Results

Demographics

This report focuses on 44 patients who received first-cycle trifluridine-tipiracil during the first calendar year of the drug’s FDA approval. All patients had metastatic colorectal cancer and had previous exposures to other chemotherapy agents (Table 1). Of note, 28 patients (64%) had experienced CINV before starting trifluridine-tipiracil and all these patients had been heavily pretreated with multiple lines of chemotherapy.

Guideline adherence

Patients were most commonly prescribed prochlorperazine and ondansetron prophylaxis for CINV before the first chemotherapy cycle of trifluridine-tipiracil (Table 2): 15 patients were prescribed combination antiemetic therapy, typically two of the most commonly prescribed single agents with different mechanisms of action. Twenty-five patients (57%; 95% confidence interval (CI): 42%, 70%) were prescribed antiemetics in a manner consistent with guidelines; 15 (34%; 95% CI: 22%, 49%) were prescribed antiemetics in a non–guideline-adherent/more aggressive manner (received more prophylaxis than called for); and 4 (9%; 95% CI: 4%, 21%) were prescribed them in a non–guideline-adherent/less aggressive manner.

Clinical outcomes based on guideline adherence

In guideline-adherent patients, first-cycle nausea and vomiting occurred in 13 patients (52%) and 6 patients (24%), respectively, with 1 patient requiring an unscheduled clinic visit and another an emergency department visit and hospital admission – all for nausea and vomiting (Table 3). In non–guideline-adherent/more aggressive patients, those symptoms occurred in 5 patients (33%, nausea) and 4 patients (27%, vomiting), with 1 patient requiring a clinic visit and emergency department visit and another an emergency department visit – again, all for nausea and vomiting. In non–guideline-adherent/less aggressive patients, no nausea or vomiting was reported.

Discussion

This study examined adherence to antiemetic guidelines in the setting of a soon-to-be-approved or newly approved antineoplastic agent. As hypothesized, a substantial proportion of patients (43% in this study) were prescribed antiemetics in a nonadherent manner with respect to guidelines, thus identifying the period shortly before and after FDA approval as a particularly vulnerable interval with respect to antiemetic guideline adherence. It is possible that our institution’s practice of testing novel chemotherapy agents for the treatment of colorectal cancer prompted a heightened awareness of potential adverse events, leading to greater guideline adherence than might have occurred in other settings and resulting in judicious straying from guideline adherence only when appropriate.^12-14 Thus, these high rates of poor adherence may in fact represent an underestimate of what one might see in other clinical practices; and, similarly, these rates of symptom control might also be more favorable than those one might see in other clinical practices. To our knowledge, antiemetic prescribing practices with newer chemotherapy agents have not been explored before now, and our data underscore a clear need to do so – particularly during this limited interval when health care providers begin to prescribe new chemotherapy agents for the first time.

It is worth noting that despite the high rates of guideline nonadherence, rates of nausea and vomiting seemed to be comparable in patients prescribed antiemetics in a guideline-adherent manner and those prescribed antiemetics in a non–guideline-adherent/aggressive manner.A small number of patients in both the guideline-adherent and non–guideline-adherent/aggressive groups required rescue medications, unscheduled medical visits for nausea and vomiting, and additional antiemetics during the second cycle of chemotherapy. Of note,none of those interventions occurred in patients who were prescribed antiemetics in a non–guideline-adherent/less aggressive manner. These findings might reflect the fact that the patients had proven themselves to be at risk for nausea and vomiting with previous chemotherapy. Before they became candidates for trifluridine-tipiracil, patients had been heavily pretreated with other chemotherapy agents, most had experienced CINV, and many were therefore highly predisposed to nausea and vomiting. These observations underscore the fact that guidelines – even those that are well accepted and widely used – should be implemented in concert with good clinical judgment.^10,11 This study has shortcomings, most notably its small sample size. However, had we extended our study beyond 3 months of the FDA approval to include more patients, our findings would have reflected more experienced prescribing practices and we thereby would have deviated from our primary goal of assessing antiemetic prescribing practices with only recently-approved and available chemotherapy agents. In this context, this limited sample size aptly serves a primary role of capturing outcomes within a fleeting but critical interval of new drug availability.In summary, this study found a notable rate of poor guideline adherence when prescribing antiemetics for trifluridine-tipiracil, a new chemotherapy agent of low emetogenic potential. Although the resultant rates of nausea and vomiting suggest that good clinical judgment might have influenced whether or not guidelines were adhered to, these findings nonetheless underscore the need to assess adherence to antiemetic guidelines when new chemotherapy drugs become available and potentially to put in place institutional infrastructure rapidly to promote improved adherence. Such an assessment should be deliberate, formalized, and prompt within individual oncology clinics and cancer centers after a new cancer drug becomes available. In conjunction with clinical judgment, such measures might lead to improved symptom control.

Acknowledgment

This paper is based on a poster that was presented at the 2016 Palliative Care in Oncology Symposium, on September 10, 2016: Adherence to antiemetic guidelines with a newly approved chemotherapy agent, trifluridine-tipiracil (TAS-102): a single-institution study. Daniel Childs and Aminah Jatoi, Mayo Clinic, Rochester, MN. http://meetinglibrary.asco.org/record/136444/abstract. J Clin Oncol. 2016;34(suppl 26S):abstract 221.

Cancer drugs are becoming available at an unprecedented rate. In 2015 alone, the US Food and Drug Administration (FDA) approved 18 new agents.¹ Although many of those agents have adverse event profiles that are more favorable than those seen with conventional chemotherapy, nausea and vomiting still occur. In fact, nausea and vomiting continue to be ranked as among the most common and distressing of cancer symptoms.^2,3 In a 2004 study, Grunberg and colleagues reported that as many as 75% of health care providers misjudge the risk for chemotherapy-induced nausea and vomiting (CINV), even when prescribing cancer drugs that have been available for years,⁴ thus amplifying concerns that such risk assessment might be even worse when new cancer agents are prescribed for the first time.

In this study, we hypothesized that patients prescribed a new cancer drug, trifluridine-tipiracil, would be at risk for CINV because of poor guideline adherence on the part of health care providers. The correct matching of antiemetics to chemotherapy is important. Inadequate antiemetic prophylaxis predisposes to nausea and vomiting with dehydration and metabolic and electrolyte derangements – complications that can occur in up to one-third of patients who receive moderately or highly emetogenic chemotherapy and who have been reported to achieve poor symptom control.⁴ Over-prophylaxis also has drawbacks. For example, antiemetics are expensive and, at times, they can induce their own adverse events, such as lethargy, dyskinesia, constipation, headaches, hiccups, fatigue, and even cardiac arrhythmias.⁵ The best approach is to appropriately match the antiemetic to the chemotherapy. Indeed, adherence to evidence-based guidelines has yielded success in symptom control, but the guidelines work on the assumption that the emetogenic potential of new chemotherapy agents has been accurately determined and then disseminated to and acted upon by health care providers.^6,7 To our knowledge, no previous studies have tested that assumption, as we do in the present study.

Trifluridine-tipiracil was selected as the focus of this project and as illustrative of other newly approved chemotherapy agents for two reasons. First, it became available for routine prescribing in pretreated patients with metastatic colorectal cancer in the United States in September 2015.¹ That timing allowed us to analyze much of the early prescribing period, both during the 9 months before approval, when the drug was available on a compassionate-use basis at our institution, and the 3 months after approval. Second, trifluridine-tipiracil has classifiably low emetogenic potential, and mismatching of antiemetics tends to occur more often with low emetogenic chemotherapy.⁹ Trifluridine-tipiracil and placebo patients manifest rates of nausea at 48% and 24%, respectively, and rates of vomiting at 28% and 14%, respectively.⁸

Hence, the goal of this study was to explore whether a guideline-based prophylactic antiemetic regimen was appropriately matched to the new chemotherapy agent, trifluridine-tipiracil, to report whether such symptoms of nausea and vomiting are kept at bay, and to identify a potentially vulnerable interval – immediately after drug approval – when cancer patients may be at risk for CINV because of poor adherence to antiemetic guideline prescribing practices by health care providers.

Methods

Overview

The Mayo Clinic Institutional Review Board approved this study. We obtained the identifying information of all patients treated with trifluridine-tipiracil at our institution from the Mayo Clinic Specialty Pharmacy, which uses an electronic prescribing system that contributed to the comprehensiveness of the data set. Patients included those who had participated in a colorectal cancer compassionate-use program before the September 2015 approval of the drug and those who received the drug shortly after its approval. In essence, this retrospective, single-institution study included every patient who received trifluridine-tipiracil for metastatic colorectal cancer in 2015 (January through December); this approach enabled us to systematically report on early first-cycle prescribing practices 9 months before and 3 months after the drug’s approval in September of 2015.

Determination of guideline adherence

This project relied on the National Comprehensive Cancer Network (NCCN) Guidelines (v1.2015, behind paywall) because they had been updated in 2015 (and hence coincided with this project’s study dates) to incorporate recommendations specific to oral chemotherapy and because they seemed concordant with other guidelines.^10,11

Antiemetic prophylaxis for a specific patient was deemed guideline adherent if a version of the recommended NCCN antiemetic regimen had been prescribed during the first cycle of chemotherapy. This regimen consisted of metoclopramide, prochlorperazine, haloperidol, or a 5-hydroxytryptamine receptor antagonist. In contrast, if a patient had been prescribed a more aggressive or less aggressive regimen, such prescribing practices were deemed non–guideline adherent/aggressive (received more prophylaxis than called for) or non–guideline adherent/less aggressive (including no antiemetics), respectively. Again, medical record prescribing determined adherence.

Data reporting

The primary goal of this study was to report the percentage of patients who had been prescribed a first-cycle antiemetic prophylaxis regimen concordant with NCCN guidelines. Secondary goals included reporting the incidence of nausea and vomiting, the use of rescue antiemetics other than those prescribed up front, the need for an unplanned medical encounter to address nausea and vomiting, and change in antiemetic prescribing before the second chemotherapy cycle. Confidence intervals were calculated with JMP Pro 10.0.0. This study was too limited in sample size to assess sex-based differences in outcomes.

Results

Demographics

This report focuses on 44 patients who received first-cycle trifluridine-tipiracil during the first calendar year of the drug’s FDA approval. All patients had metastatic colorectal cancer and had previous exposures to other chemotherapy agents (Table 1). Of note, 28 patients (64%) had experienced CINV before starting trifluridine-tipiracil and all these patients had been heavily pretreated with multiple lines of chemotherapy.

Guideline adherence

Patients were most commonly prescribed prochlorperazine and ondansetron prophylaxis for CINV before the first chemotherapy cycle of trifluridine-tipiracil (Table 2): 15 patients were prescribed combination antiemetic therapy, typically two of the most commonly prescribed single agents with different mechanisms of action. Twenty-five patients (57%; 95% confidence interval (CI): 42%, 70%) were prescribed antiemetics in a manner consistent with guidelines; 15 (34%; 95% CI: 22%, 49%) were prescribed antiemetics in a non–guideline-adherent/more aggressive manner (received more prophylaxis than called for); and 4 (9%; 95% CI: 4%, 21%) were prescribed them in a non–guideline-adherent/less aggressive manner.

Clinical outcomes based on guideline adherence

In guideline-adherent patients, first-cycle nausea and vomiting occurred in 13 patients (52%) and 6 patients (24%), respectively, with 1 patient requiring an unscheduled clinic visit and another an emergency department visit and hospital admission – all for nausea and vomiting (Table 3). In non–guideline-adherent/more aggressive patients, those symptoms occurred in 5 patients (33%, nausea) and 4 patients (27%, vomiting), with 1 patient requiring a clinic visit and emergency department visit and another an emergency department visit – again, all for nausea and vomiting. In non–guideline-adherent/less aggressive patients, no nausea or vomiting was reported.

Discussion

This study examined adherence to antiemetic guidelines in the setting of a soon-to-be-approved or newly approved antineoplastic agent. As hypothesized, a substantial proportion of patients (43% in this study) were prescribed antiemetics in a nonadherent manner with respect to guidelines, thus identifying the period shortly before and after FDA approval as a particularly vulnerable interval with respect to antiemetic guideline adherence. It is possible that our institution’s practice of testing novel chemotherapy agents for the treatment of colorectal cancer prompted a heightened awareness of potential adverse events, leading to greater guideline adherence than might have occurred in other settings and resulting in judicious straying from guideline adherence only when appropriate.^12-14 Thus, these high rates of poor adherence may in fact represent an underestimate of what one might see in other clinical practices; and, similarly, these rates of symptom control might also be more favorable than those one might see in other clinical practices. To our knowledge, antiemetic prescribing practices with newer chemotherapy agents have not been explored before now, and our data underscore a clear need to do so – particularly during this limited interval when health care providers begin to prescribe new chemotherapy agents for the first time.

It is worth noting that despite the high rates of guideline nonadherence, rates of nausea and vomiting seemed to be comparable in patients prescribed antiemetics in a guideline-adherent manner and those prescribed antiemetics in a non–guideline-adherent/aggressive manner.A small number of patients in both the guideline-adherent and non–guideline-adherent/aggressive groups required rescue medications, unscheduled medical visits for nausea and vomiting, and additional antiemetics during the second cycle of chemotherapy. Of note,none of those interventions occurred in patients who were prescribed antiemetics in a non–guideline-adherent/less aggressive manner. These findings might reflect the fact that the patients had proven themselves to be at risk for nausea and vomiting with previous chemotherapy. Before they became candidates for trifluridine-tipiracil, patients had been heavily pretreated with other chemotherapy agents, most had experienced CINV, and many were therefore highly predisposed to nausea and vomiting. These observations underscore the fact that guidelines – even those that are well accepted and widely used – should be implemented in concert with good clinical judgment.^10,11 This study has shortcomings, most notably its small sample size. However, had we extended our study beyond 3 months of the FDA approval to include more patients, our findings would have reflected more experienced prescribing practices and we thereby would have deviated from our primary goal of assessing antiemetic prescribing practices with only recently-approved and available chemotherapy agents. In this context, this limited sample size aptly serves a primary role of capturing outcomes within a fleeting but critical interval of new drug availability.In summary, this study found a notable rate of poor guideline adherence when prescribing antiemetics for trifluridine-tipiracil, a new chemotherapy agent of low emetogenic potential. Although the resultant rates of nausea and vomiting suggest that good clinical judgment might have influenced whether or not guidelines were adhered to, these findings nonetheless underscore the need to assess adherence to antiemetic guidelines when new chemotherapy drugs become available and potentially to put in place institutional infrastructure rapidly to promote improved adherence. Such an assessment should be deliberate, formalized, and prompt within individual oncology clinics and cancer centers after a new cancer drug becomes available. In conjunction with clinical judgment, such measures might lead to improved symptom control.

Acknowledgment

This paper is based on a poster that was presented at the 2016 Palliative Care in Oncology Symposium, on September 10, 2016: Adherence to antiemetic guidelines with a newly approved chemotherapy agent, trifluridine-tipiracil (TAS-102): a single-institution study. Daniel Childs and Aminah Jatoi, Mayo Clinic, Rochester, MN. http://meetinglibrary.asco.org/record/136444/abstract. J Clin Oncol. 2016;34(suppl 26S):abstract 221.

Lung cancer is the leading cause of cancer death in the United States. It is estimated that there will be 222,500 new cases of lung cancer and 155,870 deaths from lung cancer in 2017. Non–small-cell lung carcinoma (NSCLC) accounts for 80%-85% of lung cancers, with adenocarcinoma being the most common histologic subtype. Other less common subtypes include squamous-cell carcinoma, large-cell carcinoma, and NSCLC that cannot be further classified.¹ Nearly 70% of patients present with locally advanced or metastatic disease at the time of diagnosis and are not candidates for surgical resection.² For that group of patients, the mainstay of treatment is platinum-based chemotherapy with or without radiation therapy. Patients who are chemotherapy naive often experience a modest response, however; durable remission is short lived, and the 5-year survival rate remains staggeringly low.³ Improved understanding of the molecular pathways that drive malignancy in NSCLC has led to the development of drugs that target specific molecular pathways.⁴ By definition, these driver mutations facilitate oncogenesis by conferring a selective advantage during clonal evolution.⁵ Moreover, agents targeting these pathways are extremely active and induce durable responses in many patients.^6,7,8

Predictive biomarkers in NSCLC include anaplastic lymphoma kinase (ALK) fusion oncogene and sensitizing epidermal growth factor receptor (EGFR) mutations. Mutations in the EGFR tyrosine kinase are observed in about 15%-20% of NSCLC adenocarcinomas in the United States and upward of 60% in Asian populations. They are also found more frequently in nonsmokers and women.⁶ The two most prevalent mutations in the EGFR tyrosine kinase domain are in-frame deletions of exon 19 and L858R substitution in exon 21, representing about 45% and 40% of mutations, respectively.⁹ Both mutations result in activation of the tyrosine kinase domain, and both are associated with sensitivity to the small-molecule tyrosine kinase inhibitors (TKIs), such as erlotinib, gefitinib, and afatinib.¹⁰ Other drug-sensitive mutations include point mutations at exon 21 (L861Q) and exon 18 (G719X).¹¹ Targeted therapy produces durable responses in the majority of patients.^12,13,14 Unfortunately, most patients develop acquired resistance to these therapies, which leads to disease progression.^4,15-17

ALK gene rearrangements, although less prevalent, are another important molecular target in NSCLC and are seen in 2%-7% of cases in the United States.⁷ As with EGFR mutations, these mutations are more prevalent in nonsmokers, and they are found more commonly in younger patients and in men.⁸

Identification of driver mutations early in the course of disease and acquired resistance mutations later are crucial for the optimal management of advanced NSCLC. DNA analysis using polymerase chain reaction (PCR) and next-generation sequencing is the preferred method for testing for EGFR mutations, and ALK rearrangements are generally tested either by flourescence in situ hybridization (FISH) or immunohistochemistry.^18,19 Newer blood-based assays have shown great promise, and clinicians may soon have the ability to monitor subtle genetic changes, identify resistance patterns, and change therapy when acquired resistance occurs.²⁰

The American College of Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology have proposed guidelines for molecular testing in lung cancer. It is recommended that all advanced squamous and nonsquamous cell lung cancers with an adenocarcinoma component should be tested for EGFR and ALK mutations independent of age, sex, ethnicity, or smoking history. In the setting of smaller lung cancer specimens (eg, from biopsies, cytology) where an adenocarcinoma component cannot be completely excluded, EGFR and ALK testing may be performed in cases showing squamous or small cell histology but clinical criteria (eg, young age, lack of smoking history) may be useful in selecting a subset of these samples for testing. Samples obtained through surgical resection, open biopsy, endoscopy, transthoracic needle biopsy, fine-needle aspiration, and thoracentesis are all considered suitable for testing, but large biopsy samples are generally preferred over small biopsy samples, cell-blocks, and cytology samples.²¹ Despite this recommendation, not all patients who are eligible for mutation analysis are tested. At our institution, preliminary observations suggested that the percentage of patients being tested and the prevalence of driver mutations were significantly lower compared with published data. The purpose of this study was to evaluate physician attitudes about molecular testing, and to determine the rate of testing, the effect of biopsy sample size on rate of testing, and the prevalence of driver mutations at our institution.

Methods

In this retrospective clinical study, we identified 206 cases of advanced nsNSCLC from the tumor registry (February 2011-February 2013). Registry data was obtained from three hospitals within our health network – two academic tertiary care centers, and one community-based hospital. The other hospitals in the network were excluded because their EHR systems were not integrated with the rest of the hospitals and/or there was a lack of registry data. The testing rates for driver mutations, prevalence of driver mutations, and the tissue procurement techniques were obtained from individual chart review. Surgical specimens, core biopsy samples, and large volume thoracentesis specimens were categorized as large biopsy samples, and samples obtained by fine-needle aspiration, bronchial washing, and bronchial brushing were considered small biopsy samples. We used a chi-square analysis to compare mutation testing rates between the large and small biopsy sample groups. The prevalence of driver mutations was determined, excluding unknown or inadequate samples.

EGFR analysis had been conducted at Integrated Oncology, using formalin-fixed, paraffin-embedded tissue. Genomic DNA was isolated, and EGFR mutation analysis was performed using SNaPShot multiplex PCR, primer extension assay for exons 18-21; samples with >4mm² and ≥50% tumor content were preferred. Macrodissection was used to enrich for tumor cells when samples had lower tumor cellularity and content. ALK rearrangements were tested in the hospital using the Vysis ALK Break Apart FISH probe kit (Abott Molecular Inc, Des Plaines, IL).

We conducted a web-based, 20-question survey about molecular profiling among 110 practitioners to gauge their knowledge and opinions about molecular testing. The practitioners included medical oncologists, thoracic surgeons, pulmonologists, and interventional radiologists. Each received an initial e-mail informing them of the study, inviting them to complete survey, and providing a link to it, and two reminder e-mails at biweekly intervals to maximize survey participation and responses. The questions were aimed at understanding the challenges surrounding molecular testing within our network. Apart from the questions gathering demographic information about the respondents, the questions were intended to highlight the disparities between guideline recommendations and physician practices; to gauge the perceived importance of molecular evaluation; to identify individual, subspecialty, and hospital-based challenges; and to assess physician attitudes toward alternatives to traditional tissue-based testing (Table 1, p. e150). Nineteen of the questions were structured as single or best answer, whereas Question 9, which was aimed at identifying system-based challenges, allowed for multiple answer selections.

Results

There were a total of 206 cases of advanced stage IIIb or IV nsNSCLC identified at three hospitals during 2011-2013. Of those 206 cases, 161 (78.2%) were recorded at the two large academic medical centers, and 45 (21.9%) were recorded at the smaller community-based hospital. Of the total, there were 145 (70.4%) large biopsy specimens and 61 (29.6%) small biopsy specimens. We found that 89 of the 206 cases (43.2 %) had been tested for EGFR mutations, and 49 (23.8%) had been tested for ALK rearrangements (Figure, A and C). In all, 70 (48.3%) large-sample biopsies and 19 (31.1%) small-sample biopsies were submitted for EGFR analysis (Figure, B), and 42 (29%) large-sample biopsies and 7 (11.5%) small-sample biopsies were tested for ALK rearrangements (Figure, D). Large-sample biopsies were more likely to be analyzed for EGFR mutations and ALK rearrangements, with the results reaching statistical significance (P = .023 and P = .007, respectively). Across all samples, a total of 7 EGFR mutations and 1 ALK rearrangement were identified, yielding a prevalence of 7.9% and 2% respectively (Figure, A and C).

The average age at diagnosis of the patients in the cases that were analyzed was 69.3 years. Most of the patients (83.9%) identified as white, 3.8% were African American, and 12.6% were in the Unknown category. Of the total number of patients, 11 were identified as never-smokers (5.3%), 50 (24.3%) had a 1-15 pack-year smoking history, 104 (50.5%) had a 16-45 pack-year smoking history, and 41 (19.9%) had a >45 pack-year smoking history.

In regard to the survey, 46 of the 110 physicians asked to participate in the survey responded, representing a response rate of 41.8% (range across medical specialties, 26%-45%, Table 4). Of those respondents, 38 (82.6%) indicated they believed molecular evaluation was a very important aspect of NSCLC care, with the remainder indicating it was somewhat important. 91.4% of the respondents who routinely ordered molecular testing agreed that stage IIIb or IV nsNSCLC should undergo molecular evaluation.

Discussion

The treatment of advanced nsNSCLC has evolved significantly over the past decade. Molecular profiling is now an essential part of initial evaluation, and larger-sample biopsies are needed to ensure accurate evaluation and appropriate treatment. The detection of EGFR and EML4-ALK driver mutations are associated with increased response to tyrosine kinase inhibitors and are associated with improvement in progression-free survival, patient quality of life, and even overall survival in some studies.^12,22,23,24 Early identification of these driver mutations is crucial, however, preliminary observation in our network suggested that a large percentage of patients with advanced nsNSCLC in were not being appropriately evaluated for those mutations. To evaluate our molecular profiling rates, we conducted a retrospective study and reviewed 3 years of registry data at 3 hospitals within our health system. Two of the hospitals included in our analysis were large tertiary academic centers, and one was a community hospital. Our findings confirmed that a large percentage of our patients who are eligible for molecular evaluation are not tested: 56.7% of cases were not tested for EGFR mutations, and 76.2% of cases were not tested for ALK rearrangements.

In a similar study, the Association for Community Cancer Centers conducted a project aimed at understanding the landscape and current challenges for molecular profiling in NSCLC. Eight institutions participated in the study, and baseline testing rates were analyzed. The findings demonstrated that high-volume institutions (treating >100 lung cancer patients a year tested 62% and 60% of advanced lung cancer patients for EGFR and EML4-ALK, respectively, and low-volume institutions (treating <100 lung cancer patients a year tested 52% and 47% for EGFR and EML4-ALK, respectively.^25,26 In a recent international physician self-reported survey, Spicer and colleagues found that EGFR testing was requested before first-line therapy in patients with stage IIIB or IV disease in 81% of cases, and mutation results were available before start of therapy in 77% of the cases.²⁷ Those percentages are relatively low, given that current guidelines recommend that molecular testing should be done for all patients with stage IIIB or IV nsNSCLC. This highlights the need for objective performance feedback so oncologists can make the necessary practice changes so that molecular testing is done before the start of therapy to ensure high-quality cancer care that will translate into better, cost-effective outcomes and improved patient quality of life.

Our study findings showed that the prevalence of EGFR and ALK mutations is substantially lower among the patients we treat in our network compared with other published data on prevalence. The reason for those low rates is not clear, but it is likely multifactorial. First, Western Pennsylvania, the region our network serves, has a large proportion of older adults – 17.3% of the population is older than 65 years (national average, 14.5%) and advanced age might have contributed to the lower EGFR and ALK rates measured in our study.²⁸ Second, the smoking rate in Pennsylvania is higher than the national average, 20%-24% compared with 18%, respectively.²⁹ Third, the air quality in Western Pennsylvania has historically been very poor as a result of the large steel and coal mining industries. Even though the air quality has improved in recent decades, the American Lung Association’s 2017 State of the Air report ranked Pittsburgh and surrounding areas in Western Pennsylvania among the top 25 most air polluted areas in the United States.³⁰ It is not certain whether air pollution and air quality have any impact on driver mutation rates, but the correlation with smoking, ethnicity, and geographic distribution highlight the need for further epidemiologic studies.

Biopsy sufficiency – getting an adequate amount of sample tissue during biopsy – is a known challenge to molecular profiling, and we found that biopsy sample size had an impact on the testing rates in a large percentage of our cases. To fully understand the impact of biopsy sufficiency, we conducted a subset analysis and compared the testing rates between our large and small biopsy samples. Our analysis showed that larger-sample biopsies were more likely to be tested for mutations than were smaller-sample biopsies (EGFR: P = .023; ALK: P = .007).

Those results suggest that larger-sample biopsies should be encouraged, but procedural risks, tumor location, and patient age and wishes need to be considered before tissue acquisition.²¹ Furthermore, clinicians who are responsible for tissue procurement need to be properly educated on the tissue sample requirements and the impact these results have on treatment decisions.³¹ Our institution, like many others, has adopted rapid onsite evaluation (ROSE) of biopsy samples, whereby a trained cytopathologist reviews sample adequacy at the time of tissue procurement. Although there is scant data directly comparing molecular testing success rates with and without the ROSE protocol, a meta-analysis conducted by Schmidt and colleagues concluded that ROSE improved the adequacy rate of fine-needle aspiration cytology by 12%.^32,33 Given that molecular profiling depends on both the absolute and relative amount of tumor cells present in the sample, the ROSE protocol likely enhances the procedural success rate and reduces the need for repeat and subsequent biopsies.

It is interesting to note that our data also demonstrated that we are obtaining large-sample biopsies in most of our patients (about 70%). However, we are still failing to test more than half of our cases for driver mutations (Figure, A and C). This strongly suggests there are additional factors beyond tissue adequacy that are contributing to our high failure rate. It is essential to understand the dynamics and system practices that influence testing rates if we are to improve the care and outcomes of our cancer patients. To better understand those barriers, we surveyed 110 practitioners (including medical oncologists, pulmonologists, thoracic surgeons, and interventional radiologists) about the molecular profiling process and their responses highlighted several important areas that deserve special attention (Tables 1, 4, 5).

In our institution, testing initiation is primarily the responsibility of the treating medical oncologist. This presents a challenge because there is often a significant delay between tissue acquisition, histologic confirmation, and oncologic review. Many institutions have adopted pathology-driven reflex testing to help overcome such delays. Automatic testing after pathologic confirmation streamlines the process, increases testing rates, and eliminates unnecessary delay between the time of diagnosis and the time of test ordering.³⁴ It also allows for the molecular and histologic diagnosis to be integrated into a single pathology report before therapy is initiated.

Another barrier to timely testing according to the respondents, was the CMS’s 14-day rule. The 14-day rule requires hospitals to wait 14 days after the patient is discharged for the lab to receive reimbursement for molecular testing and was frequently identified as a cause for significant delay in testing and having an impact on first-line treatment decisions.^35,36

Often clinicians will choose to defer testing until this time has elapsed to reduce the financial burden placed on the hospital but by that time, they might well have initiated treatment without knowing if the patient has a mutation. This is a significant challenge identified by many of our oncologists, and is a limitation to our analysis above as it is unclear what percentage of patients received follow up testing once care was established at an outside facility and once the 14-day time period had elapsed.

The data from our institution suggests there is discordance between physician attitudes and molecular testing practices. However, there are several limitations in our study. First, most of the survey respondents agreed that molecular testing is an important aspect of treating advanced lung cancer patients, but the retrospective nature of the study made it difficult to identify why testing was deferred or never conducted. Second, the absence of a centralized reporting system for molecular testing results at our institution, may have resulted in an overestimation of our testing failure rate in cases where results were not integrated our electronic medical record.

Third, the low survey response rate only allowed us to make generalizations regarding the conclusions, although it does provide a framework for future process improvements.

We believe the poor testing rates observed in our study are not isolated to our institution and reflect a significant challenge within the broader oncology community.²⁷ A system of best practices is essential for capturing this subset of patients who are never tested. There is agreement among oncologists that improving our current testing rates will require a multidisciplinary approach, a refined process for molecular evaluation, a push toward reflex testing, and standardization of biopsy techniques and tissue handling procedures. In our institution, we have initiated a Lean Six Sigma and PDSA (plan, do, study, act) initiative to improve our current molecular testing process. In addition, because obtaining larger-sample biopsies or additional biopsies is often not feasible for many of our advanced cancer patients, we have started using whole blood circulating tumor cells (CTC) and plasma ctDNA (cell-free circulating DNA) for molecular testing. Recent studies have shown high concordance (89%) between tissue biopsies and blood-based mutation testing, which will likely have a positive impact on the cancer care of our patients and help to capture a subset of patients who are not candidates for traditional biopsies.³⁷

Conclusions

Despite current guidelines for testing driver mutations in advanced nsNSCLC, a large segment of our patients are not being tested for those genetic aberrations. There are several barriers that continue to thwart the recommendation, including failure to integrate driver mutation testing into routine pathology practice (ie, reflex testing), insufficient tissue obtained from biopsy, and difficulty in obtaining tissue because of tumor location or risk of complications from the biopsy procedure. More important, these trends are not isolated to our institution and reflect a significant challenge within the oncology community. Our data show that for the purpose of driver mutation testing, larger-sample biopsies, such as surgical/core biopsies, are better than small-sample biopsies, such as needle aspiration. We have also demonstrated that the prevalence of driver mutations is lower in Western Pennsylvania, which is served by our network, than elsewhere in the United States.

Lung cancer is the leading cause of cancer death in the United States. It is estimated that there will be 222,500 new cases of lung cancer and 155,870 deaths from lung cancer in 2017. Non–small-cell lung carcinoma (NSCLC) accounts for 80%-85% of lung cancers, with adenocarcinoma being the most common histologic subtype. Other less common subtypes include squamous-cell carcinoma, large-cell carcinoma, and NSCLC that cannot be further classified.¹ Nearly 70% of patients present with locally advanced or metastatic disease at the time of diagnosis and are not candidates for surgical resection.² For that group of patients, the mainstay of treatment is platinum-based chemotherapy with or without radiation therapy. Patients who are chemotherapy naive often experience a modest response, however; durable remission is short lived, and the 5-year survival rate remains staggeringly low.³ Improved understanding of the molecular pathways that drive malignancy in NSCLC has led to the development of drugs that target specific molecular pathways.⁴ By definition, these driver mutations facilitate oncogenesis by conferring a selective advantage during clonal evolution.⁵ Moreover, agents targeting these pathways are extremely active and induce durable responses in many patients.^6,7,8

Predictive biomarkers in NSCLC include anaplastic lymphoma kinase (ALK) fusion oncogene and sensitizing epidermal growth factor receptor (EGFR) mutations. Mutations in the EGFR tyrosine kinase are observed in about 15%-20% of NSCLC adenocarcinomas in the United States and upward of 60% in Asian populations. They are also found more frequently in nonsmokers and women.⁶ The two most prevalent mutations in the EGFR tyrosine kinase domain are in-frame deletions of exon 19 and L858R substitution in exon 21, representing about 45% and 40% of mutations, respectively.⁹ Both mutations result in activation of the tyrosine kinase domain, and both are associated with sensitivity to the small-molecule tyrosine kinase inhibitors (TKIs), such as erlotinib, gefitinib, and afatinib.¹⁰ Other drug-sensitive mutations include point mutations at exon 21 (L861Q) and exon 18 (G719X).¹¹ Targeted therapy produces durable responses in the majority of patients.^12,13,14 Unfortunately, most patients develop acquired resistance to these therapies, which leads to disease progression.^4,15-17

ALK gene rearrangements, although less prevalent, are another important molecular target in NSCLC and are seen in 2%-7% of cases in the United States.⁷ As with EGFR mutations, these mutations are more prevalent in nonsmokers, and they are found more commonly in younger patients and in men.⁸

Identification of driver mutations early in the course of disease and acquired resistance mutations later are crucial for the optimal management of advanced NSCLC. DNA analysis using polymerase chain reaction (PCR) and next-generation sequencing is the preferred method for testing for EGFR mutations, and ALK rearrangements are generally tested either by flourescence in situ hybridization (FISH) or immunohistochemistry.^18,19 Newer blood-based assays have shown great promise, and clinicians may soon have the ability to monitor subtle genetic changes, identify resistance patterns, and change therapy when acquired resistance occurs.²⁰

The American College of Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology have proposed guidelines for molecular testing in lung cancer. It is recommended that all advanced squamous and nonsquamous cell lung cancers with an adenocarcinoma component should be tested for EGFR and ALK mutations independent of age, sex, ethnicity, or smoking history. In the setting of smaller lung cancer specimens (eg, from biopsies, cytology) where an adenocarcinoma component cannot be completely excluded, EGFR and ALK testing may be performed in cases showing squamous or small cell histology but clinical criteria (eg, young age, lack of smoking history) may be useful in selecting a subset of these samples for testing. Samples obtained through surgical resection, open biopsy, endoscopy, transthoracic needle biopsy, fine-needle aspiration, and thoracentesis are all considered suitable for testing, but large biopsy samples are generally preferred over small biopsy samples, cell-blocks, and cytology samples.²¹ Despite this recommendation, not all patients who are eligible for mutation analysis are tested. At our institution, preliminary observations suggested that the percentage of patients being tested and the prevalence of driver mutations were significantly lower compared with published data. The purpose of this study was to evaluate physician attitudes about molecular testing, and to determine the rate of testing, the effect of biopsy sample size on rate of testing, and the prevalence of driver mutations at our institution.

Methods

In this retrospective clinical study, we identified 206 cases of advanced nsNSCLC from the tumor registry (February 2011-February 2013). Registry data was obtained from three hospitals within our health network – two academic tertiary care centers, and one community-based hospital. The other hospitals in the network were excluded because their EHR systems were not integrated with the rest of the hospitals and/or there was a lack of registry data. The testing rates for driver mutations, prevalence of driver mutations, and the tissue procurement techniques were obtained from individual chart review. Surgical specimens, core biopsy samples, and large volume thoracentesis specimens were categorized as large biopsy samples, and samples obtained by fine-needle aspiration, bronchial washing, and bronchial brushing were considered small biopsy samples. We used a chi-square analysis to compare mutation testing rates between the large and small biopsy sample groups. The prevalence of driver mutations was determined, excluding unknown or inadequate samples.

EGFR analysis had been conducted at Integrated Oncology, using formalin-fixed, paraffin-embedded tissue. Genomic DNA was isolated, and EGFR mutation analysis was performed using SNaPShot multiplex PCR, primer extension assay for exons 18-21; samples with >4mm² and ≥50% tumor content were preferred. Macrodissection was used to enrich for tumor cells when samples had lower tumor cellularity and content. ALK rearrangements were tested in the hospital using the Vysis ALK Break Apart FISH probe kit (Abott Molecular Inc, Des Plaines, IL).

We conducted a web-based, 20-question survey about molecular profiling among 110 practitioners to gauge their knowledge and opinions about molecular testing. The practitioners included medical oncologists, thoracic surgeons, pulmonologists, and interventional radiologists. Each received an initial e-mail informing them of the study, inviting them to complete survey, and providing a link to it, and two reminder e-mails at biweekly intervals to maximize survey participation and responses. The questions were aimed at understanding the challenges surrounding molecular testing within our network. Apart from the questions gathering demographic information about the respondents, the questions were intended to highlight the disparities between guideline recommendations and physician practices; to gauge the perceived importance of molecular evaluation; to identify individual, subspecialty, and hospital-based challenges; and to assess physician attitudes toward alternatives to traditional tissue-based testing (Table 1, p. e150). Nineteen of the questions were structured as single or best answer, whereas Question 9, which was aimed at identifying system-based challenges, allowed for multiple answer selections.

Results

There were a total of 206 cases of advanced stage IIIb or IV nsNSCLC identified at three hospitals during 2011-2013. Of those 206 cases, 161 (78.2%) were recorded at the two large academic medical centers, and 45 (21.9%) were recorded at the smaller community-based hospital. Of the total, there were 145 (70.4%) large biopsy specimens and 61 (29.6%) small biopsy specimens. We found that 89 of the 206 cases (43.2 %) had been tested for EGFR mutations, and 49 (23.8%) had been tested for ALK rearrangements (Figure, A and C). In all, 70 (48.3%) large-sample biopsies and 19 (31.1%) small-sample biopsies were submitted for EGFR analysis (Figure, B), and 42 (29%) large-sample biopsies and 7 (11.5%) small-sample biopsies were tested for ALK rearrangements (Figure, D). Large-sample biopsies were more likely to be analyzed for EGFR mutations and ALK rearrangements, with the results reaching statistical significance (P = .023 and P = .007, respectively). Across all samples, a total of 7 EGFR mutations and 1 ALK rearrangement were identified, yielding a prevalence of 7.9% and 2% respectively (Figure, A and C).

The average age at diagnosis of the patients in the cases that were analyzed was 69.3 years. Most of the patients (83.9%) identified as white, 3.8% were African American, and 12.6% were in the Unknown category. Of the total number of patients, 11 were identified as never-smokers (5.3%), 50 (24.3%) had a 1-15 pack-year smoking history, 104 (50.5%) had a 16-45 pack-year smoking history, and 41 (19.9%) had a >45 pack-year smoking history.

In regard to the survey, 46 of the 110 physicians asked to participate in the survey responded, representing a response rate of 41.8% (range across medical specialties, 26%-45%, Table 4). Of those respondents, 38 (82.6%) indicated they believed molecular evaluation was a very important aspect of NSCLC care, with the remainder indicating it was somewhat important. 91.4% of the respondents who routinely ordered molecular testing agreed that stage IIIb or IV nsNSCLC should undergo molecular evaluation.

Discussion

The treatment of advanced nsNSCLC has evolved significantly over the past decade. Molecular profiling is now an essential part of initial evaluation, and larger-sample biopsies are needed to ensure accurate evaluation and appropriate treatment. The detection of EGFR and EML4-ALK driver mutations are associated with increased response to tyrosine kinase inhibitors and are associated with improvement in progression-free survival, patient quality of life, and even overall survival in some studies.^12,22,23,24 Early identification of these driver mutations is crucial, however, preliminary observation in our network suggested that a large percentage of patients with advanced nsNSCLC in were not being appropriately evaluated for those mutations. To evaluate our molecular profiling rates, we conducted a retrospective study and reviewed 3 years of registry data at 3 hospitals within our health system. Two of the hospitals included in our analysis were large tertiary academic centers, and one was a community hospital. Our findings confirmed that a large percentage of our patients who are eligible for molecular evaluation are not tested: 56.7% of cases were not tested for EGFR mutations, and 76.2% of cases were not tested for ALK rearrangements.

In a similar study, the Association for Community Cancer Centers conducted a project aimed at understanding the landscape and current challenges for molecular profiling in NSCLC. Eight institutions participated in the study, and baseline testing rates were analyzed. The findings demonstrated that high-volume institutions (treating >100 lung cancer patients a year tested 62% and 60% of advanced lung cancer patients for EGFR and EML4-ALK, respectively, and low-volume institutions (treating <100 lung cancer patients a year tested 52% and 47% for EGFR and EML4-ALK, respectively.^25,26 In a recent international physician self-reported survey, Spicer and colleagues found that EGFR testing was requested before first-line therapy in patients with stage IIIB or IV disease in 81% of cases, and mutation results were available before start of therapy in 77% of the cases.²⁷ Those percentages are relatively low, given that current guidelines recommend that molecular testing should be done for all patients with stage IIIB or IV nsNSCLC. This highlights the need for objective performance feedback so oncologists can make the necessary practice changes so that molecular testing is done before the start of therapy to ensure high-quality cancer care that will translate into better, cost-effective outcomes and improved patient quality of life.

Our study findings showed that the prevalence of EGFR and ALK mutations is substantially lower among the patients we treat in our network compared with other published data on prevalence. The reason for those low rates is not clear, but it is likely multifactorial. First, Western Pennsylvania, the region our network serves, has a large proportion of older adults – 17.3% of the population is older than 65 years (national average, 14.5%) and advanced age might have contributed to the lower EGFR and ALK rates measured in our study.²⁸ Second, the smoking rate in Pennsylvania is higher than the national average, 20%-24% compared with 18%, respectively.²⁹ Third, the air quality in Western Pennsylvania has historically been very poor as a result of the large steel and coal mining industries. Even though the air quality has improved in recent decades, the American Lung Association’s 2017 State of the Air report ranked Pittsburgh and surrounding areas in Western Pennsylvania among the top 25 most air polluted areas in the United States.³⁰ It is not certain whether air pollution and air quality have any impact on driver mutation rates, but the correlation with smoking, ethnicity, and geographic distribution highlight the need for further epidemiologic studies.

Biopsy sufficiency – getting an adequate amount of sample tissue during biopsy – is a known challenge to molecular profiling, and we found that biopsy sample size had an impact on the testing rates in a large percentage of our cases. To fully understand the impact of biopsy sufficiency, we conducted a subset analysis and compared the testing rates between our large and small biopsy samples. Our analysis showed that larger-sample biopsies were more likely to be tested for mutations than were smaller-sample biopsies (EGFR: P = .023; ALK: P = .007).

Those results suggest that larger-sample biopsies should be encouraged, but procedural risks, tumor location, and patient age and wishes need to be considered before tissue acquisition.²¹ Furthermore, clinicians who are responsible for tissue procurement need to be properly educated on the tissue sample requirements and the impact these results have on treatment decisions.³¹ Our institution, like many others, has adopted rapid onsite evaluation (ROSE) of biopsy samples, whereby a trained cytopathologist reviews sample adequacy at the time of tissue procurement. Although there is scant data directly comparing molecular testing success rates with and without the ROSE protocol, a meta-analysis conducted by Schmidt and colleagues concluded that ROSE improved the adequacy rate of fine-needle aspiration cytology by 12%.^32,33 Given that molecular profiling depends on both the absolute and relative amount of tumor cells present in the sample, the ROSE protocol likely enhances the procedural success rate and reduces the need for repeat and subsequent biopsies.

It is interesting to note that our data also demonstrated that we are obtaining large-sample biopsies in most of our patients (about 70%). However, we are still failing to test more than half of our cases for driver mutations (Figure, A and C). This strongly suggests there are additional factors beyond tissue adequacy that are contributing to our high failure rate. It is essential to understand the dynamics and system practices that influence testing rates if we are to improve the care and outcomes of our cancer patients. To better understand those barriers, we surveyed 110 practitioners (including medical oncologists, pulmonologists, thoracic surgeons, and interventional radiologists) about the molecular profiling process and their responses highlighted several important areas that deserve special attention (Tables 1, 4, 5).

In our institution, testing initiation is primarily the responsibility of the treating medical oncologist. This presents a challenge because there is often a significant delay between tissue acquisition, histologic confirmation, and oncologic review. Many institutions have adopted pathology-driven reflex testing to help overcome such delays. Automatic testing after pathologic confirmation streamlines the process, increases testing rates, and eliminates unnecessary delay between the time of diagnosis and the time of test ordering.³⁴ It also allows for the molecular and histologic diagnosis to be integrated into a single pathology report before therapy is initiated.

Another barrier to timely testing according to the respondents, was the CMS’s 14-day rule. The 14-day rule requires hospitals to wait 14 days after the patient is discharged for the lab to receive reimbursement for molecular testing and was frequently identified as a cause for significant delay in testing and having an impact on first-line treatment decisions.^35,36

Often clinicians will choose to defer testing until this time has elapsed to reduce the financial burden placed on the hospital but by that time, they might well have initiated treatment without knowing if the patient has a mutation. This is a significant challenge identified by many of our oncologists, and is a limitation to our analysis above as it is unclear what percentage of patients received follow up testing once care was established at an outside facility and once the 14-day time period had elapsed.

The data from our institution suggests there is discordance between physician attitudes and molecular testing practices. However, there are several limitations in our study. First, most of the survey respondents agreed that molecular testing is an important aspect of treating advanced lung cancer patients, but the retrospective nature of the study made it difficult to identify why testing was deferred or never conducted. Second, the absence of a centralized reporting system for molecular testing results at our institution, may have resulted in an overestimation of our testing failure rate in cases where results were not integrated our electronic medical record.

Third, the low survey response rate only allowed us to make generalizations regarding the conclusions, although it does provide a framework for future process improvements.

We believe the poor testing rates observed in our study are not isolated to our institution and reflect a significant challenge within the broader oncology community.²⁷ A system of best practices is essential for capturing this subset of patients who are never tested. There is agreement among oncologists that improving our current testing rates will require a multidisciplinary approach, a refined process for molecular evaluation, a push toward reflex testing, and standardization of biopsy techniques and tissue handling procedures. In our institution, we have initiated a Lean Six Sigma and PDSA (plan, do, study, act) initiative to improve our current molecular testing process. In addition, because obtaining larger-sample biopsies or additional biopsies is often not feasible for many of our advanced cancer patients, we have started using whole blood circulating tumor cells (CTC) and plasma ctDNA (cell-free circulating DNA) for molecular testing. Recent studies have shown high concordance (89%) between tissue biopsies and blood-based mutation testing, which will likely have a positive impact on the cancer care of our patients and help to capture a subset of patients who are not candidates for traditional biopsies.³⁷

Conclusions

Despite current guidelines for testing driver mutations in advanced nsNSCLC, a large segment of our patients are not being tested for those genetic aberrations. There are several barriers that continue to thwart the recommendation, including failure to integrate driver mutation testing into routine pathology practice (ie, reflex testing), insufficient tissue obtained from biopsy, and difficulty in obtaining tissue because of tumor location or risk of complications from the biopsy procedure. More important, these trends are not isolated to our institution and reflect a significant challenge within the oncology community. Our data show that for the purpose of driver mutation testing, larger-sample biopsies, such as surgical/core biopsies, are better than small-sample biopsies, such as needle aspiration. We have also demonstrated that the prevalence of driver mutations is lower in Western Pennsylvania, which is served by our network, than elsewhere in the United States.

Lung cancer is the leading cause of cancer death in the United States. It is estimated that there will be 222,500 new cases of lung cancer and 155,870 deaths from lung cancer in 2017. Non–small-cell lung carcinoma (NSCLC) accounts for 80%-85% of lung cancers, with adenocarcinoma being the most common histologic subtype. Other less common subtypes include squamous-cell carcinoma, large-cell carcinoma, and NSCLC that cannot be further classified.¹ Nearly 70% of patients present with locally advanced or metastatic disease at the time of diagnosis and are not candidates for surgical resection.² For that group of patients, the mainstay of treatment is platinum-based chemotherapy with or without radiation therapy. Patients who are chemotherapy naive often experience a modest response, however; durable remission is short lived, and the 5-year survival rate remains staggeringly low.³ Improved understanding of the molecular pathways that drive malignancy in NSCLC has led to the development of drugs that target specific molecular pathways.⁴ By definition, these driver mutations facilitate oncogenesis by conferring a selective advantage during clonal evolution.⁵ Moreover, agents targeting these pathways are extremely active and induce durable responses in many patients.^6,7,8

Predictive biomarkers in NSCLC include anaplastic lymphoma kinase (ALK) fusion oncogene and sensitizing epidermal growth factor receptor (EGFR) mutations. Mutations in the EGFR tyrosine kinase are observed in about 15%-20% of NSCLC adenocarcinomas in the United States and upward of 60% in Asian populations. They are also found more frequently in nonsmokers and women.⁶ The two most prevalent mutations in the EGFR tyrosine kinase domain are in-frame deletions of exon 19 and L858R substitution in exon 21, representing about 45% and 40% of mutations, respectively.⁹ Both mutations result in activation of the tyrosine kinase domain, and both are associated with sensitivity to the small-molecule tyrosine kinase inhibitors (TKIs), such as erlotinib, gefitinib, and afatinib.¹⁰ Other drug-sensitive mutations include point mutations at exon 21 (L861Q) and exon 18 (G719X).¹¹ Targeted therapy produces durable responses in the majority of patients.^12,13,14 Unfortunately, most patients develop acquired resistance to these therapies, which leads to disease progression.^4,15-17

ALK gene rearrangements, although less prevalent, are another important molecular target in NSCLC and are seen in 2%-7% of cases in the United States.⁷ As with EGFR mutations, these mutations are more prevalent in nonsmokers, and they are found more commonly in younger patients and in men.⁸

Identification of driver mutations early in the course of disease and acquired resistance mutations later are crucial for the optimal management of advanced NSCLC. DNA analysis using polymerase chain reaction (PCR) and next-generation sequencing is the preferred method for testing for EGFR mutations, and ALK rearrangements are generally tested either by flourescence in situ hybridization (FISH) or immunohistochemistry.^18,19 Newer blood-based assays have shown great promise, and clinicians may soon have the ability to monitor subtle genetic changes, identify resistance patterns, and change therapy when acquired resistance occurs.²⁰

The American College of Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology have proposed guidelines for molecular testing in lung cancer. It is recommended that all advanced squamous and nonsquamous cell lung cancers with an adenocarcinoma component should be tested for EGFR and ALK mutations independent of age, sex, ethnicity, or smoking history. In the setting of smaller lung cancer specimens (eg, from biopsies, cytology) where an adenocarcinoma component cannot be completely excluded, EGFR and ALK testing may be performed in cases showing squamous or small cell histology but clinical criteria (eg, young age, lack of smoking history) may be useful in selecting a subset of these samples for testing. Samples obtained through surgical resection, open biopsy, endoscopy, transthoracic needle biopsy, fine-needle aspiration, and thoracentesis are all considered suitable for testing, but large biopsy samples are generally preferred over small biopsy samples, cell-blocks, and cytology samples.²¹ Despite this recommendation, not all patients who are eligible for mutation analysis are tested. At our institution, preliminary observations suggested that the percentage of patients being tested and the prevalence of driver mutations were significantly lower compared with published data. The purpose of this study was to evaluate physician attitudes about molecular testing, and to determine the rate of testing, the effect of biopsy sample size on rate of testing, and the prevalence of driver mutations at our institution.

Methods

In this retrospective clinical study, we identified 206 cases of advanced nsNSCLC from the tumor registry (February 2011-February 2013). Registry data was obtained from three hospitals within our health network – two academic tertiary care centers, and one community-based hospital. The other hospitals in the network were excluded because their EHR systems were not integrated with the rest of the hospitals and/or there was a lack of registry data. The testing rates for driver mutations, prevalence of driver mutations, and the tissue procurement techniques were obtained from individual chart review. Surgical specimens, core biopsy samples, and large volume thoracentesis specimens were categorized as large biopsy samples, and samples obtained by fine-needle aspiration, bronchial washing, and bronchial brushing were considered small biopsy samples. We used a chi-square analysis to compare mutation testing rates between the large and small biopsy sample groups. The prevalence of driver mutations was determined, excluding unknown or inadequate samples.

EGFR analysis had been conducted at Integrated Oncology, using formalin-fixed, paraffin-embedded tissue. Genomic DNA was isolated, and EGFR mutation analysis was performed using SNaPShot multiplex PCR, primer extension assay for exons 18-21; samples with >4mm² and ≥50% tumor content were preferred. Macrodissection was used to enrich for tumor cells when samples had lower tumor cellularity and content. ALK rearrangements were tested in the hospital using the Vysis ALK Break Apart FISH probe kit (Abott Molecular Inc, Des Plaines, IL).

We conducted a web-based, 20-question survey about molecular profiling among 110 practitioners to gauge their knowledge and opinions about molecular testing. The practitioners included medical oncologists, thoracic surgeons, pulmonologists, and interventional radiologists. Each received an initial e-mail informing them of the study, inviting them to complete survey, and providing a link to it, and two reminder e-mails at biweekly intervals to maximize survey participation and responses. The questions were aimed at understanding the challenges surrounding molecular testing within our network. Apart from the questions gathering demographic information about the respondents, the questions were intended to highlight the disparities between guideline recommendations and physician practices; to gauge the perceived importance of molecular evaluation; to identify individual, subspecialty, and hospital-based challenges; and to assess physician attitudes toward alternatives to traditional tissue-based testing (Table 1, p. e150). Nineteen of the questions were structured as single or best answer, whereas Question 9, which was aimed at identifying system-based challenges, allowed for multiple answer selections.

Results

There were a total of 206 cases of advanced stage IIIb or IV nsNSCLC identified at three hospitals during 2011-2013. Of those 206 cases, 161 (78.2%) were recorded at the two large academic medical centers, and 45 (21.9%) were recorded at the smaller community-based hospital. Of the total, there were 145 (70.4%) large biopsy specimens and 61 (29.6%) small biopsy specimens. We found that 89 of the 206 cases (43.2 %) had been tested for EGFR mutations, and 49 (23.8%) had been tested for ALK rearrangements (Figure, A and C). In all, 70 (48.3%) large-sample biopsies and 19 (31.1%) small-sample biopsies were submitted for EGFR analysis (Figure, B), and 42 (29%) large-sample biopsies and 7 (11.5%) small-sample biopsies were tested for ALK rearrangements (Figure, D). Large-sample biopsies were more likely to be analyzed for EGFR mutations and ALK rearrangements, with the results reaching statistical significance (P = .023 and P = .007, respectively). Across all samples, a total of 7 EGFR mutations and 1 ALK rearrangement were identified, yielding a prevalence of 7.9% and 2% respectively (Figure, A and C).

The average age at diagnosis of the patients in the cases that were analyzed was 69.3 years. Most of the patients (83.9%) identified as white, 3.8% were African American, and 12.6% were in the Unknown category. Of the total number of patients, 11 were identified as never-smokers (5.3%), 50 (24.3%) had a 1-15 pack-year smoking history, 104 (50.5%) had a 16-45 pack-year smoking history, and 41 (19.9%) had a >45 pack-year smoking history.

In regard to the survey, 46 of the 110 physicians asked to participate in the survey responded, representing a response rate of 41.8% (range across medical specialties, 26%-45%, Table 4). Of those respondents, 38 (82.6%) indicated they believed molecular evaluation was a very important aspect of NSCLC care, with the remainder indicating it was somewhat important. 91.4% of the respondents who routinely ordered molecular testing agreed that stage IIIb or IV nsNSCLC should undergo molecular evaluation.

Discussion

The treatment of advanced nsNSCLC has evolved significantly over the past decade. Molecular profiling is now an essential part of initial evaluation, and larger-sample biopsies are needed to ensure accurate evaluation and appropriate treatment. The detection of EGFR and EML4-ALK driver mutations are associated with increased response to tyrosine kinase inhibitors and are associated with improvement in progression-free survival, patient quality of life, and even overall survival in some studies.^12,22,23,24 Early identification of these driver mutations is crucial, however, preliminary observation in our network suggested that a large percentage of patients with advanced nsNSCLC in were not being appropriately evaluated for those mutations. To evaluate our molecular profiling rates, we conducted a retrospective study and reviewed 3 years of registry data at 3 hospitals within our health system. Two of the hospitals included in our analysis were large tertiary academic centers, and one was a community hospital. Our findings confirmed that a large percentage of our patients who are eligible for molecular evaluation are not tested: 56.7% of cases were not tested for EGFR mutations, and 76.2% of cases were not tested for ALK rearrangements.

In a similar study, the Association for Community Cancer Centers conducted a project aimed at understanding the landscape and current challenges for molecular profiling in NSCLC. Eight institutions participated in the study, and baseline testing rates were analyzed. The findings demonstrated that high-volume institutions (treating >100 lung cancer patients a year tested 62% and 60% of advanced lung cancer patients for EGFR and EML4-ALK, respectively, and low-volume institutions (treating <100 lung cancer patients a year tested 52% and 47% for EGFR and EML4-ALK, respectively.^25,26 In a recent international physician self-reported survey, Spicer and colleagues found that EGFR testing was requested before first-line therapy in patients with stage IIIB or IV disease in 81% of cases, and mutation results were available before start of therapy in 77% of the cases.²⁷ Those percentages are relatively low, given that current guidelines recommend that molecular testing should be done for all patients with stage IIIB or IV nsNSCLC. This highlights the need for objective performance feedback so oncologists can make the necessary practice changes so that molecular testing is done before the start of therapy to ensure high-quality cancer care that will translate into better, cost-effective outcomes and improved patient quality of life.

Our study findings showed that the prevalence of EGFR and ALK mutations is substantially lower among the patients we treat in our network compared with other published data on prevalence. The reason for those low rates is not clear, but it is likely multifactorial. First, Western Pennsylvania, the region our network serves, has a large proportion of older adults – 17.3% of the population is older than 65 years (national average, 14.5%) and advanced age might have contributed to the lower EGFR and ALK rates measured in our study.²⁸ Second, the smoking rate in Pennsylvania is higher than the national average, 20%-24% compared with 18%, respectively.²⁹ Third, the air quality in Western Pennsylvania has historically been very poor as a result of the large steel and coal mining industries. Even though the air quality has improved in recent decades, the American Lung Association’s 2017 State of the Air report ranked Pittsburgh and surrounding areas in Western Pennsylvania among the top 25 most air polluted areas in the United States.³⁰ It is not certain whether air pollution and air quality have any impact on driver mutation rates, but the correlation with smoking, ethnicity, and geographic distribution highlight the need for further epidemiologic studies.

Biopsy sufficiency – getting an adequate amount of sample tissue during biopsy – is a known challenge to molecular profiling, and we found that biopsy sample size had an impact on the testing rates in a large percentage of our cases. To fully understand the impact of biopsy sufficiency, we conducted a subset analysis and compared the testing rates between our large and small biopsy samples. Our analysis showed that larger-sample biopsies were more likely to be tested for mutations than were smaller-sample biopsies (EGFR: P = .023; ALK: P = .007).

Those results suggest that larger-sample biopsies should be encouraged, but procedural risks, tumor location, and patient age and wishes need to be considered before tissue acquisition.²¹ Furthermore, clinicians who are responsible for tissue procurement need to be properly educated on the tissue sample requirements and the impact these results have on treatment decisions.³¹ Our institution, like many others, has adopted rapid onsite evaluation (ROSE) of biopsy samples, whereby a trained cytopathologist reviews sample adequacy at the time of tissue procurement. Although there is scant data directly comparing molecular testing success rates with and without the ROSE protocol, a meta-analysis conducted by Schmidt and colleagues concluded that ROSE improved the adequacy rate of fine-needle aspiration cytology by 12%.^32,33 Given that molecular profiling depends on both the absolute and relative amount of tumor cells present in the sample, the ROSE protocol likely enhances the procedural success rate and reduces the need for repeat and subsequent biopsies.

It is interesting to note that our data also demonstrated that we are obtaining large-sample biopsies in most of our patients (about 70%). However, we are still failing to test more than half of our cases for driver mutations (Figure, A and C). This strongly suggests there are additional factors beyond tissue adequacy that are contributing to our high failure rate. It is essential to understand the dynamics and system practices that influence testing rates if we are to improve the care and outcomes of our cancer patients. To better understand those barriers, we surveyed 110 practitioners (including medical oncologists, pulmonologists, thoracic surgeons, and interventional radiologists) about the molecular profiling process and their responses highlighted several important areas that deserve special attention (Tables 1, 4, 5).

In our institution, testing initiation is primarily the responsibility of the treating medical oncologist. This presents a challenge because there is often a significant delay between tissue acquisition, histologic confirmation, and oncologic review. Many institutions have adopted pathology-driven reflex testing to help overcome such delays. Automatic testing after pathologic confirmation streamlines the process, increases testing rates, and eliminates unnecessary delay between the time of diagnosis and the time of test ordering.³⁴ It also allows for the molecular and histologic diagnosis to be integrated into a single pathology report before therapy is initiated.

Another barrier to timely testing according to the respondents, was the CMS’s 14-day rule. The 14-day rule requires hospitals to wait 14 days after the patient is discharged for the lab to receive reimbursement for molecular testing and was frequently identified as a cause for significant delay in testing and having an impact on first-line treatment decisions.^35,36

Often clinicians will choose to defer testing until this time has elapsed to reduce the financial burden placed on the hospital but by that time, they might well have initiated treatment without knowing if the patient has a mutation. This is a significant challenge identified by many of our oncologists, and is a limitation to our analysis above as it is unclear what percentage of patients received follow up testing once care was established at an outside facility and once the 14-day time period had elapsed.

The data from our institution suggests there is discordance between physician attitudes and molecular testing practices. However, there are several limitations in our study. First, most of the survey respondents agreed that molecular testing is an important aspect of treating advanced lung cancer patients, but the retrospective nature of the study made it difficult to identify why testing was deferred or never conducted. Second, the absence of a centralized reporting system for molecular testing results at our institution, may have resulted in an overestimation of our testing failure rate in cases where results were not integrated our electronic medical record.

Third, the low survey response rate only allowed us to make generalizations regarding the conclusions, although it does provide a framework for future process improvements.

We believe the poor testing rates observed in our study are not isolated to our institution and reflect a significant challenge within the broader oncology community.²⁷ A system of best practices is essential for capturing this subset of patients who are never tested. There is agreement among oncologists that improving our current testing rates will require a multidisciplinary approach, a refined process for molecular evaluation, a push toward reflex testing, and standardization of biopsy techniques and tissue handling procedures. In our institution, we have initiated a Lean Six Sigma and PDSA (plan, do, study, act) initiative to improve our current molecular testing process. In addition, because obtaining larger-sample biopsies or additional biopsies is often not feasible for many of our advanced cancer patients, we have started using whole blood circulating tumor cells (CTC) and plasma ctDNA (cell-free circulating DNA) for molecular testing. Recent studies have shown high concordance (89%) between tissue biopsies and blood-based mutation testing, which will likely have a positive impact on the cancer care of our patients and help to capture a subset of patients who are not candidates for traditional biopsies.³⁷

Conclusions

Despite current guidelines for testing driver mutations in advanced nsNSCLC, a large segment of our patients are not being tested for those genetic aberrations. There are several barriers that continue to thwart the recommendation, including failure to integrate driver mutation testing into routine pathology practice (ie, reflex testing), insufficient tissue obtained from biopsy, and difficulty in obtaining tissue because of tumor location or risk of complications from the biopsy procedure. More important, these trends are not isolated to our institution and reflect a significant challenge within the oncology community. Our data show that for the purpose of driver mutation testing, larger-sample biopsies, such as surgical/core biopsies, are better than small-sample biopsies, such as needle aspiration. We have also demonstrated that the prevalence of driver mutations is lower in Western Pennsylvania, which is served by our network, than elsewhere in the United States.

Complex cancer treatments, limited personnel resources, and a growing number of cancer survivors are challenging cancer health care professionals’ abilities to provide comprehensive care. Cancer survivors have a range of needs that extend over the cancer care trajectory and that represent physical, psychological, social, and spiritual domains. Numerous studies have explored supportive care needs and recent systematic reviews have highlighted the supportive care needs related to cancer¹ and to specific cancer types, including prostate cancer,² breast cancer,³ gynecologic cancer,⁴ hematological cancer,⁵ and lung cancer.⁶ However, reviews are limited in that they do not always assess needs across the cancer trajectory or identify demographic or clinical variables that are associated with needs. These data are needed to focus survivorship program development in cancer centers in order to target populations most likely at risk for unmet needs, identify what salient concerns to address, and to appropriately schedule supportive care programs.

The importance of assessing the patient’s subjective view of his/her needs or concerns is well acknowledged as being fundamental to patient-centered care.⁷ Clinicians routinely assess needs in practice using a variety of screening tools. However, there needs to be a broader assessment of concerns and needs in a population of survivors with mixed cancer diagnoses, along with their appraisal of how well their needs were addressed by their health care team, to provide an overall identification of gaps in supportive care. The primary purpose of the present study was to prioritize survivors’ most salient physical, social, emotional, and spiritual concerns or needs; ascertain survivors’ perceived importance of those needs and the extent to which our institution, the University Hospitals Seidman Cancer Center, was attentive to those needs; and to identify who might be at risk for having greater concerns. The overall goal was to use the data to inform survivorship and supportive care program development.

Methods

Design, sample and setting

We used a cross-sectional design. Surveys were mailed once to a convenience sample of 2,750 adult patients who had been seen in follow-up during the previous 2 years (2010-2011) at all clinical sites of University Hospitals Seidman Cancer Center, a Midwestern National Cancer Institute-designated Comprehensive Cancer Center. Patients who had a noncancer diagnosis were excluded. The distribution list was screened for deceased individuals and those patients who had multiple visits during the time period. The project was reviewed and approved as nonresearch by the Case Western Reserve University Cancer Institutional Review Board.

Survey

An interdisciplinary team of clinicians, administrators, and researchers adapted the Mayo Clinic Cancer Center’s Cancer Survivors Survey of Needs⁸ to create a comprehensive survey for the cancer center. Input regarding the scope of the survey was sought from the Patient and Family Advisory Council of the cancer center. The survey, which was formatted for scanning purposes, consisted of 33 questions that were compiled into 4 sections. Sections 1 and 2 focused on demographic and treatment-related information, including use of community and hospital support services and preferences for follow-up care. In section 3, a quality-of-life framework was used to assess physical, social, emotional, and spiritual needs. Respondents were asked to rate their current level of concern for 19 physical effects, 10 social effects, 10 emotional effects, and 5 spiritual effects on a scale ranging from 0 (no concern) to 5 (extreme concern). In section 4, respondents were asked to indicate the importance of the cancer team addressing their physical, social, emotional, and spiritual needs. This was followed by their rating of the cancer team’s attention to their needs as Poor, Fair, Good, Excellent, or They did not ask about my needs. Respondents were asked about preferences for learning about physical, social, emotional, and spiritual effects. In addition to the 33 questions, there were 6 open-ended questions in which respondents were encouraged to share additional information about their needs, sources of support, and other concerns.

Procedures

Eligible respondents were mailed a cover letter explaining the survey from both the director and president of the cancer center, a survey, and a postage-paid return envelope. The option to respond to the survey by a telephone call to the director of the Office of Cancer Survivorship was offered in the cover letter.

Data analysis

Returned surveys were scanned into a Teleform database, verified, and exported into an SPSS data file. Data quality was checked by running frequency analyses and summarizing variables. Time-since-treatment responses were collapsed into 4 categories: on treatment, up to 2 years posttreatment, 2-5 years posttreatment, and more than 5 years posttreatment. Descriptive statistics were used to summarize demographic and medical characteristics of the respondents and to calculate the mean score for each concern for the total sample and then for each category of time since treatment. Because of the large number of respondents with breast cancer, the respondents were stratified into two groups, one of breast cancer the other of nonbreast cancer respondents. Then, the Mann-Whitney test was performed for each concern to examine differences between respondents with and without breast cancer.

To identify the most prevalent concerns, ratings for concerns were recoded into no concern (rated as 0), low concern (1 or 2), and moderate/high concern (3, 4, or 5). Since our interest was in the moderate and high concerns, the responses were dichotomized into moderate/high concerns and all other levels. Logistic regression models were then used to identify associations between a set of survivor characteristics or covariates (age, sex, living status, marital status, employment status, cancer type, and time since treatment) with the 12 most highly rated moderate/high concerns. All the analyses were performed using statistical software SPSS 20 and Stata 13.0

Results

Respondents

A total of 1,005 surveys were returned for a 37% response rate. Forty-two patients responded by telephone. The mean age of respondents was 64.9 years (range, 22-98; SD, 12.8). The typical respondent was female, white, and married (Table 1). Twenty-four percent of the respondents (n = 240) reported living alone. Although about 47% of respondents (n = 473) reported a breast cancer diagnosis, more than 17 cancers were identified, and 14% of respondents (n = 145) listed multiple diagnoses. About a third of respondents were receiving treatment when they completed the survey.

Just under half of the respondents (n = 498) reported using community resources for support and information about cancer, and 29.5% (n = 296) sought information on the internet during their cancer experience. The most commonly used community resources were The Gathering Place, a local organization offering free supportive programs and services to individuals with cancer and their families (n = 167), and the American Cancer Society (n = 138). Of the 496 respondents who reported accessing hospital resources, most (n = 322) said they used information that their health care team recommended. Other supportive options were used to a lesser degree: support groups (n = 92), chemotherapy and radiation therapy classes (n = 129), and supportive/educational programs offered by the cancer center (n = 27). Most of the respondents (n = 822, 88.6%) preferred to have their follow-up care remain with their cancer care team 1 year after treatments are completed. Almost two-thirds of respondents (n = 601, 64%) cited being seen at the cancer center for follow-up care as the most important factor in considering follow-up care.

Concerns
In determining whether the large proportion of respondents with breast cancer skewed the study results, it was determined that median scores differed significantly in only four concerns. Compared with respondents without breast cancer, respondents with breast cancer were more likely to have significantly lower scores for concerns related to fatigue (P <.001) and sexual issues/intimacy (P = .001). Respondents with breast cancer were more likely to have significantly higher scores than respondents without breast cancer for concerns related to genetic counseling (P = .001) and fear of developing a new cancer (P = .010).

Fears of the cancer returning and developing a new cancer were the two most prevalent concerns, identified by 51% (n = 486) and 47.5% (n = 459), respectively (Table 2). Physical concerns, rated as moderate/high concerns by at least 25% of the sample, were fatigue (n = 336, 34.8%), changes in [the] body after cancer (n = 323, 33.7%), trouble sleeping (n = 302, 31.0%), sexual issues/intimacy (n = 263, 28.0%), memory and concentration (n = 261, 26.7%), and weight changes (n = 248, 25.5%). The most prevalent moderate/high social concerns were related to finances (n = 265, 27.5%) and debt from medical bills (n = 232, 25.1%). Managing stress (n = 279, 29.2%) and difficult emotions (n = 244, 25.1%) were prevalent moderate/high emotional concerns. Spiritual concerns were less often rated as moderate/high concerns. Having a breast cancer diagnosis was not significantly related to the number of reported moderate to high concerns (P = 1.00).

Attention to needs

The health care teams were rated highly for their attention to the patients’ physical needs. Most respondents (n = 845, 92.4%) viewed the health care team’s attention their physical needs as important and 763 (77.6%) survivors rated the team’s attention to these needs as excellent. The importance of addressing emotional needs was affirmed by 723 (78.5%) respondents, and although 454 (46.8%) viewed the team’s attention to these needs as excellent, 119 (12.3%) reported that the health care team did not ask about emotional needs. In addition, 566 respondents (60%) viewed having the health care team address their social needs as important, and most (n = 715, 74.2%) rated the team’s attention to social needs as good or excellent. Yet, 162 (16.8%) respondents reported that team did not ask about their social needs. The health care team’s addressing of spiritual needs was viewed as important by 346 (37.5%) respondents and ratings for how well the team attended to spiritual needs were: 148 (15.6%) poor or fair, 204 (21.5%) good, and 150 (15.8%) excellent. However, 448 (47.2%) respondents reported that the health care team did not ask about their spiritual needs.
 

Discussion

The primary purpose of this project was to prioritize survivors’ most salient physical, social, emotional, and spiritual concerns or needs and to assess the perceived importance of these needs and the extent to which the cancer center staff were attentive to those needs. The overall goal of this assessment was to inform the development of survivorship and supportive care programs by highlighting common concerns, demographic and medical factors associated with specific concerns, and timing of moderate/high level concerns along the cancer trajectory. There were 3 main findings.

First, the results support the need for enhancing supportive care services to meet emotional concerns of survivors beyond the treatment phase. Similar to other studies,^8,9 emotional concerns ranked higher than all other concerns in this study with about 50% of the sample rating “fear the cancer will return” and “fear of developing a new cancer” as moderate/high concern. Although the odds of not having these emotional concerns improved up to 2 years posttreatment, these concerns are likely to resurface, as odds for survivors beyond 2 years were not significantly different from those receiving treatment. A recent systematic review reported that fear of cancer recurrence is experienced by about 73% of cancer survivors, with 49% reporting a moderate to high degree.¹⁰ It can have a chronic, stable trajectory for some survivors and is strongly associated with higher levels of anxiety, distress, and depression, and less global, emotional/mental, physical, role, social, and cognitive quality of life.¹⁰ In this sample, managing stress and difficult emotions were also rated as moderate/high concerns by at least 25% of the sample.

Second, the findings identified patients at risk for cancer-related concerns throughout the cancer trajectory. As demonstrated in other studies, younger age was associated with greater odds of having multiple greater moderate/high concerns.^11-13 Unemployment was the second most common demographic factor associated with multiple moderate/high concerns related to physical symptoms, finances and emotions. Similarly, identifying as black, Asian, American Indian/Alaskan Native, or other was also associated with greater odds of having numerous physical, financial, and emotional concerns. Women had greater concerns related to memory, sexual intimacy, coping with difficult emotions, and stress.

Third, the results helped to identify gaps in supportive care at our cancer center. Although spiritual concerns were not prevalent as being moderate/high, they were still viewed by about a third of survivors as being an important area for the health care team to address. Yet, consistent with other need assessments, spiritual concerns in this study were least often addressed by staff.¹ Assessment of spiritual care needs, screening for spiritual distress, and providing spiritual care are essential components of a clinician-patient relationship that supports healing.¹⁴ The importance of attending to spiritual care needs was underscored by a recent systematic review that found a positive association between overall spiritual well-being and quality of life in patients with cancer, with the meaning/peace factor consistently and positively associated with physical and mental health.¹⁵ Another identified gap was the health care team’s lack of attention to the patient’s social needs, which included concerns related to finances and debt from medical bills. In all, 46% of the respondents reported having financial concerns, with the odds of having moderate/high financial concerns being greatest during treatment to 2 years posttreatment. Attention to the financial burden of cancer patients is critical because the magnitude of cancer-related financial concerns is a significant, strong predictor of quality of life and adverse psychological issues such as depression, anxiety, and distress.^16,17

There were several program implications based on the results. A periodic audit of the concerns of survivors and their views on how well their needs were being met was a relatively low cost endeavor. Although the findings were consistent with the literature, the results, when shared with administrators and clinicians, were instrumental in effecting change because they represented the concerns of survivors at the cancer center. Another program directive, based on the results, was to extend the routine screening of patients’ needs during treatment to posttreatment survivorship. Patients who are young, unemployed, do not identify as white, and female warrant more thorough assessment of needs and concerns along the cancer trajectory. Integral to these screenings is the need for patient-centered communication, with discussion of how cancer is affecting the different domains of quality of life within the context of the patient’s life. Lastly, the results clearly indicated the need for additional training of health care providers on how to assess and address spiritual well-being in cancer survivors.

There were limitations to this study, including use of a nonvalidated survey and cross-sectional approach that limited our ability to explore how concerns might change over the trajectory. Also, it was not possible to clarify medical information of the respondents, such as cancer stage. Although the response rate of this study was not high, we are confident in the results because of the large sample size and the finding that the large proportion of respondents with breast cancer was not influential. Despite these limitations, this needs assessment of cancer survivors over the trajectory of care provided insight into the scope of their concerns, identified vulnerable groups of survivors, and highlighted gaps in addressing those concerns. A quality- of-life framework for assessing needs assured a comprehensive focus and generated practice changes to strengthen holistic, comprehensive oncology care.

Complex cancer treatments, limited personnel resources, and a growing number of cancer survivors are challenging cancer health care professionals’ abilities to provide comprehensive care. Cancer survivors have a range of needs that extend over the cancer care trajectory and that represent physical, psychological, social, and spiritual domains. Numerous studies have explored supportive care needs and recent systematic reviews have highlighted the supportive care needs related to cancer¹ and to specific cancer types, including prostate cancer,² breast cancer,³ gynecologic cancer,⁴ hematological cancer,⁵ and lung cancer.⁶ However, reviews are limited in that they do not always assess needs across the cancer trajectory or identify demographic or clinical variables that are associated with needs. These data are needed to focus survivorship program development in cancer centers in order to target populations most likely at risk for unmet needs, identify what salient concerns to address, and to appropriately schedule supportive care programs.

The importance of assessing the patient’s subjective view of his/her needs or concerns is well acknowledged as being fundamental to patient-centered care.⁷ Clinicians routinely assess needs in practice using a variety of screening tools. However, there needs to be a broader assessment of concerns and needs in a population of survivors with mixed cancer diagnoses, along with their appraisal of how well their needs were addressed by their health care team, to provide an overall identification of gaps in supportive care. The primary purpose of the present study was to prioritize survivors’ most salient physical, social, emotional, and spiritual concerns or needs; ascertain survivors’ perceived importance of those needs and the extent to which our institution, the University Hospitals Seidman Cancer Center, was attentive to those needs; and to identify who might be at risk for having greater concerns. The overall goal was to use the data to inform survivorship and supportive care program development.

Methods

Design, sample and setting

We used a cross-sectional design. Surveys were mailed once to a convenience sample of 2,750 adult patients who had been seen in follow-up during the previous 2 years (2010-2011) at all clinical sites of University Hospitals Seidman Cancer Center, a Midwestern National Cancer Institute-designated Comprehensive Cancer Center. Patients who had a noncancer diagnosis were excluded. The distribution list was screened for deceased individuals and those patients who had multiple visits during the time period. The project was reviewed and approved as nonresearch by the Case Western Reserve University Cancer Institutional Review Board.

Survey

An interdisciplinary team of clinicians, administrators, and researchers adapted the Mayo Clinic Cancer Center’s Cancer Survivors Survey of Needs⁸ to create a comprehensive survey for the cancer center. Input regarding the scope of the survey was sought from the Patient and Family Advisory Council of the cancer center. The survey, which was formatted for scanning purposes, consisted of 33 questions that were compiled into 4 sections. Sections 1 and 2 focused on demographic and treatment-related information, including use of community and hospital support services and preferences for follow-up care. In section 3, a quality-of-life framework was used to assess physical, social, emotional, and spiritual needs. Respondents were asked to rate their current level of concern for 19 physical effects, 10 social effects, 10 emotional effects, and 5 spiritual effects on a scale ranging from 0 (no concern) to 5 (extreme concern). In section 4, respondents were asked to indicate the importance of the cancer team addressing their physical, social, emotional, and spiritual needs. This was followed by their rating of the cancer team’s attention to their needs as Poor, Fair, Good, Excellent, or They did not ask about my needs. Respondents were asked about preferences for learning about physical, social, emotional, and spiritual effects. In addition to the 33 questions, there were 6 open-ended questions in which respondents were encouraged to share additional information about their needs, sources of support, and other concerns.

Procedures

Eligible respondents were mailed a cover letter explaining the survey from both the director and president of the cancer center, a survey, and a postage-paid return envelope. The option to respond to the survey by a telephone call to the director of the Office of Cancer Survivorship was offered in the cover letter.

Data analysis

Returned surveys were scanned into a Teleform database, verified, and exported into an SPSS data file. Data quality was checked by running frequency analyses and summarizing variables. Time-since-treatment responses were collapsed into 4 categories: on treatment, up to 2 years posttreatment, 2-5 years posttreatment, and more than 5 years posttreatment. Descriptive statistics were used to summarize demographic and medical characteristics of the respondents and to calculate the mean score for each concern for the total sample and then for each category of time since treatment. Because of the large number of respondents with breast cancer, the respondents were stratified into two groups, one of breast cancer the other of nonbreast cancer respondents. Then, the Mann-Whitney test was performed for each concern to examine differences between respondents with and without breast cancer.

To identify the most prevalent concerns, ratings for concerns were recoded into no concern (rated as 0), low concern (1 or 2), and moderate/high concern (3, 4, or 5). Since our interest was in the moderate and high concerns, the responses were dichotomized into moderate/high concerns and all other levels. Logistic regression models were then used to identify associations between a set of survivor characteristics or covariates (age, sex, living status, marital status, employment status, cancer type, and time since treatment) with the 12 most highly rated moderate/high concerns. All the analyses were performed using statistical software SPSS 20 and Stata 13.0

Results

Respondents

A total of 1,005 surveys were returned for a 37% response rate. Forty-two patients responded by telephone. The mean age of respondents was 64.9 years (range, 22-98; SD, 12.8). The typical respondent was female, white, and married (Table 1). Twenty-four percent of the respondents (n = 240) reported living alone. Although about 47% of respondents (n = 473) reported a breast cancer diagnosis, more than 17 cancers were identified, and 14% of respondents (n = 145) listed multiple diagnoses. About a third of respondents were receiving treatment when they completed the survey.

Just under half of the respondents (n = 498) reported using community resources for support and information about cancer, and 29.5% (n = 296) sought information on the internet during their cancer experience. The most commonly used community resources were The Gathering Place, a local organization offering free supportive programs and services to individuals with cancer and their families (n = 167), and the American Cancer Society (n = 138). Of the 496 respondents who reported accessing hospital resources, most (n = 322) said they used information that their health care team recommended. Other supportive options were used to a lesser degree: support groups (n = 92), chemotherapy and radiation therapy classes (n = 129), and supportive/educational programs offered by the cancer center (n = 27). Most of the respondents (n = 822, 88.6%) preferred to have their follow-up care remain with their cancer care team 1 year after treatments are completed. Almost two-thirds of respondents (n = 601, 64%) cited being seen at the cancer center for follow-up care as the most important factor in considering follow-up care.

Concerns
In determining whether the large proportion of respondents with breast cancer skewed the study results, it was determined that median scores differed significantly in only four concerns. Compared with respondents without breast cancer, respondents with breast cancer were more likely to have significantly lower scores for concerns related to fatigue (P <.001) and sexual issues/intimacy (P = .001). Respondents with breast cancer were more likely to have significantly higher scores than respondents without breast cancer for concerns related to genetic counseling (P = .001) and fear of developing a new cancer (P = .010).

Fears of the cancer returning and developing a new cancer were the two most prevalent concerns, identified by 51% (n = 486) and 47.5% (n = 459), respectively (Table 2). Physical concerns, rated as moderate/high concerns by at least 25% of the sample, were fatigue (n = 336, 34.8%), changes in [the] body after cancer (n = 323, 33.7%), trouble sleeping (n = 302, 31.0%), sexual issues/intimacy (n = 263, 28.0%), memory and concentration (n = 261, 26.7%), and weight changes (n = 248, 25.5%). The most prevalent moderate/high social concerns were related to finances (n = 265, 27.5%) and debt from medical bills (n = 232, 25.1%). Managing stress (n = 279, 29.2%) and difficult emotions (n = 244, 25.1%) were prevalent moderate/high emotional concerns. Spiritual concerns were less often rated as moderate/high concerns. Having a breast cancer diagnosis was not significantly related to the number of reported moderate to high concerns (P = 1.00).

Attention to needs

The health care teams were rated highly for their attention to the patients’ physical needs. Most respondents (n = 845, 92.4%) viewed the health care team’s attention their physical needs as important and 763 (77.6%) survivors rated the team’s attention to these needs as excellent. The importance of addressing emotional needs was affirmed by 723 (78.5%) respondents, and although 454 (46.8%) viewed the team’s attention to these needs as excellent, 119 (12.3%) reported that the health care team did not ask about emotional needs. In addition, 566 respondents (60%) viewed having the health care team address their social needs as important, and most (n = 715, 74.2%) rated the team’s attention to social needs as good or excellent. Yet, 162 (16.8%) respondents reported that team did not ask about their social needs. The health care team’s addressing of spiritual needs was viewed as important by 346 (37.5%) respondents and ratings for how well the team attended to spiritual needs were: 148 (15.6%) poor or fair, 204 (21.5%) good, and 150 (15.8%) excellent. However, 448 (47.2%) respondents reported that the health care team did not ask about their spiritual needs.
 

Discussion

The primary purpose of this project was to prioritize survivors’ most salient physical, social, emotional, and spiritual concerns or needs and to assess the perceived importance of these needs and the extent to which the cancer center staff were attentive to those needs. The overall goal of this assessment was to inform the development of survivorship and supportive care programs by highlighting common concerns, demographic and medical factors associated with specific concerns, and timing of moderate/high level concerns along the cancer trajectory. There were 3 main findings.

First, the results support the need for enhancing supportive care services to meet emotional concerns of survivors beyond the treatment phase. Similar to other studies,^8,9 emotional concerns ranked higher than all other concerns in this study with about 50% of the sample rating “fear the cancer will return” and “fear of developing a new cancer” as moderate/high concern. Although the odds of not having these emotional concerns improved up to 2 years posttreatment, these concerns are likely to resurface, as odds for survivors beyond 2 years were not significantly different from those receiving treatment. A recent systematic review reported that fear of cancer recurrence is experienced by about 73% of cancer survivors, with 49% reporting a moderate to high degree.¹⁰ It can have a chronic, stable trajectory for some survivors and is strongly associated with higher levels of anxiety, distress, and depression, and less global, emotional/mental, physical, role, social, and cognitive quality of life.¹⁰ In this sample, managing stress and difficult emotions were also rated as moderate/high concerns by at least 25% of the sample.

Second, the findings identified patients at risk for cancer-related concerns throughout the cancer trajectory. As demonstrated in other studies, younger age was associated with greater odds of having multiple greater moderate/high concerns.^11-13 Unemployment was the second most common demographic factor associated with multiple moderate/high concerns related to physical symptoms, finances and emotions. Similarly, identifying as black, Asian, American Indian/Alaskan Native, or other was also associated with greater odds of having numerous physical, financial, and emotional concerns. Women had greater concerns related to memory, sexual intimacy, coping with difficult emotions, and stress.

Third, the results helped to identify gaps in supportive care at our cancer center. Although spiritual concerns were not prevalent as being moderate/high, they were still viewed by about a third of survivors as being an important area for the health care team to address. Yet, consistent with other need assessments, spiritual concerns in this study were least often addressed by staff.¹ Assessment of spiritual care needs, screening for spiritual distress, and providing spiritual care are essential components of a clinician-patient relationship that supports healing.¹⁴ The importance of attending to spiritual care needs was underscored by a recent systematic review that found a positive association between overall spiritual well-being and quality of life in patients with cancer, with the meaning/peace factor consistently and positively associated with physical and mental health.¹⁵ Another identified gap was the health care team’s lack of attention to the patient’s social needs, which included concerns related to finances and debt from medical bills. In all, 46% of the respondents reported having financial concerns, with the odds of having moderate/high financial concerns being greatest during treatment to 2 years posttreatment. Attention to the financial burden of cancer patients is critical because the magnitude of cancer-related financial concerns is a significant, strong predictor of quality of life and adverse psychological issues such as depression, anxiety, and distress.^16,17

There were several program implications based on the results. A periodic audit of the concerns of survivors and their views on how well their needs were being met was a relatively low cost endeavor. Although the findings were consistent with the literature, the results, when shared with administrators and clinicians, were instrumental in effecting change because they represented the concerns of survivors at the cancer center. Another program directive, based on the results, was to extend the routine screening of patients’ needs during treatment to posttreatment survivorship. Patients who are young, unemployed, do not identify as white, and female warrant more thorough assessment of needs and concerns along the cancer trajectory. Integral to these screenings is the need for patient-centered communication, with discussion of how cancer is affecting the different domains of quality of life within the context of the patient’s life. Lastly, the results clearly indicated the need for additional training of health care providers on how to assess and address spiritual well-being in cancer survivors.

There were limitations to this study, including use of a nonvalidated survey and cross-sectional approach that limited our ability to explore how concerns might change over the trajectory. Also, it was not possible to clarify medical information of the respondents, such as cancer stage. Although the response rate of this study was not high, we are confident in the results because of the large sample size and the finding that the large proportion of respondents with breast cancer was not influential. Despite these limitations, this needs assessment of cancer survivors over the trajectory of care provided insight into the scope of their concerns, identified vulnerable groups of survivors, and highlighted gaps in addressing those concerns. A quality- of-life framework for assessing needs assured a comprehensive focus and generated practice changes to strengthen holistic, comprehensive oncology care.

Complex cancer treatments, limited personnel resources, and a growing number of cancer survivors are challenging cancer health care professionals’ abilities to provide comprehensive care. Cancer survivors have a range of needs that extend over the cancer care trajectory and that represent physical, psychological, social, and spiritual domains. Numerous studies have explored supportive care needs and recent systematic reviews have highlighted the supportive care needs related to cancer¹ and to specific cancer types, including prostate cancer,² breast cancer,³ gynecologic cancer,⁴ hematological cancer,⁵ and lung cancer.⁶ However, reviews are limited in that they do not always assess needs across the cancer trajectory or identify demographic or clinical variables that are associated with needs. These data are needed to focus survivorship program development in cancer centers in order to target populations most likely at risk for unmet needs, identify what salient concerns to address, and to appropriately schedule supportive care programs.

The importance of assessing the patient’s subjective view of his/her needs or concerns is well acknowledged as being fundamental to patient-centered care.⁷ Clinicians routinely assess needs in practice using a variety of screening tools. However, there needs to be a broader assessment of concerns and needs in a population of survivors with mixed cancer diagnoses, along with their appraisal of how well their needs were addressed by their health care team, to provide an overall identification of gaps in supportive care. The primary purpose of the present study was to prioritize survivors’ most salient physical, social, emotional, and spiritual concerns or needs; ascertain survivors’ perceived importance of those needs and the extent to which our institution, the University Hospitals Seidman Cancer Center, was attentive to those needs; and to identify who might be at risk for having greater concerns. The overall goal was to use the data to inform survivorship and supportive care program development.

Methods

Design, sample and setting

We used a cross-sectional design. Surveys were mailed once to a convenience sample of 2,750 adult patients who had been seen in follow-up during the previous 2 years (2010-2011) at all clinical sites of University Hospitals Seidman Cancer Center, a Midwestern National Cancer Institute-designated Comprehensive Cancer Center. Patients who had a noncancer diagnosis were excluded. The distribution list was screened for deceased individuals and those patients who had multiple visits during the time period. The project was reviewed and approved as nonresearch by the Case Western Reserve University Cancer Institutional Review Board.

Survey

An interdisciplinary team of clinicians, administrators, and researchers adapted the Mayo Clinic Cancer Center’s Cancer Survivors Survey of Needs⁸ to create a comprehensive survey for the cancer center. Input regarding the scope of the survey was sought from the Patient and Family Advisory Council of the cancer center. The survey, which was formatted for scanning purposes, consisted of 33 questions that were compiled into 4 sections. Sections 1 and 2 focused on demographic and treatment-related information, including use of community and hospital support services and preferences for follow-up care. In section 3, a quality-of-life framework was used to assess physical, social, emotional, and spiritual needs. Respondents were asked to rate their current level of concern for 19 physical effects, 10 social effects, 10 emotional effects, and 5 spiritual effects on a scale ranging from 0 (no concern) to 5 (extreme concern). In section 4, respondents were asked to indicate the importance of the cancer team addressing their physical, social, emotional, and spiritual needs. This was followed by their rating of the cancer team’s attention to their needs as Poor, Fair, Good, Excellent, or They did not ask about my needs. Respondents were asked about preferences for learning about physical, social, emotional, and spiritual effects. In addition to the 33 questions, there were 6 open-ended questions in which respondents were encouraged to share additional information about their needs, sources of support, and other concerns.

Procedures

Eligible respondents were mailed a cover letter explaining the survey from both the director and president of the cancer center, a survey, and a postage-paid return envelope. The option to respond to the survey by a telephone call to the director of the Office of Cancer Survivorship was offered in the cover letter.

Data analysis

Returned surveys were scanned into a Teleform database, verified, and exported into an SPSS data file. Data quality was checked by running frequency analyses and summarizing variables. Time-since-treatment responses were collapsed into 4 categories: on treatment, up to 2 years posttreatment, 2-5 years posttreatment, and more than 5 years posttreatment. Descriptive statistics were used to summarize demographic and medical characteristics of the respondents and to calculate the mean score for each concern for the total sample and then for each category of time since treatment. Because of the large number of respondents with breast cancer, the respondents were stratified into two groups, one of breast cancer the other of nonbreast cancer respondents. Then, the Mann-Whitney test was performed for each concern to examine differences between respondents with and without breast cancer.

To identify the most prevalent concerns, ratings for concerns were recoded into no concern (rated as 0), low concern (1 or 2), and moderate/high concern (3, 4, or 5). Since our interest was in the moderate and high concerns, the responses were dichotomized into moderate/high concerns and all other levels. Logistic regression models were then used to identify associations between a set of survivor characteristics or covariates (age, sex, living status, marital status, employment status, cancer type, and time since treatment) with the 12 most highly rated moderate/high concerns. All the analyses were performed using statistical software SPSS 20 and Stata 13.0

Results

Respondents

A total of 1,005 surveys were returned for a 37% response rate. Forty-two patients responded by telephone. The mean age of respondents was 64.9 years (range, 22-98; SD, 12.8). The typical respondent was female, white, and married (Table 1). Twenty-four percent of the respondents (n = 240) reported living alone. Although about 47% of respondents (n = 473) reported a breast cancer diagnosis, more than 17 cancers were identified, and 14% of respondents (n = 145) listed multiple diagnoses. About a third of respondents were receiving treatment when they completed the survey.

Just under half of the respondents (n = 498) reported using community resources for support and information about cancer, and 29.5% (n = 296) sought information on the internet during their cancer experience. The most commonly used community resources were The Gathering Place, a local organization offering free supportive programs and services to individuals with cancer and their families (n = 167), and the American Cancer Society (n = 138). Of the 496 respondents who reported accessing hospital resources, most (n = 322) said they used information that their health care team recommended. Other supportive options were used to a lesser degree: support groups (n = 92), chemotherapy and radiation therapy classes (n = 129), and supportive/educational programs offered by the cancer center (n = 27). Most of the respondents (n = 822, 88.6%) preferred to have their follow-up care remain with their cancer care team 1 year after treatments are completed. Almost two-thirds of respondents (n = 601, 64%) cited being seen at the cancer center for follow-up care as the most important factor in considering follow-up care.

Concerns
In determining whether the large proportion of respondents with breast cancer skewed the study results, it was determined that median scores differed significantly in only four concerns. Compared with respondents without breast cancer, respondents with breast cancer were more likely to have significantly lower scores for concerns related to fatigue (P <.001) and sexual issues/intimacy (P = .001). Respondents with breast cancer were more likely to have significantly higher scores than respondents without breast cancer for concerns related to genetic counseling (P = .001) and fear of developing a new cancer (P = .010).

Fears of the cancer returning and developing a new cancer were the two most prevalent concerns, identified by 51% (n = 486) and 47.5% (n = 459), respectively (Table 2). Physical concerns, rated as moderate/high concerns by at least 25% of the sample, were fatigue (n = 336, 34.8%), changes in [the] body after cancer (n = 323, 33.7%), trouble sleeping (n = 302, 31.0%), sexual issues/intimacy (n = 263, 28.0%), memory and concentration (n = 261, 26.7%), and weight changes (n = 248, 25.5%). The most prevalent moderate/high social concerns were related to finances (n = 265, 27.5%) and debt from medical bills (n = 232, 25.1%). Managing stress (n = 279, 29.2%) and difficult emotions (n = 244, 25.1%) were prevalent moderate/high emotional concerns. Spiritual concerns were less often rated as moderate/high concerns. Having a breast cancer diagnosis was not significantly related to the number of reported moderate to high concerns (P = 1.00).

Attention to needs

The health care teams were rated highly for their attention to the patients’ physical needs. Most respondents (n = 845, 92.4%) viewed the health care team’s attention their physical needs as important and 763 (77.6%) survivors rated the team’s attention to these needs as excellent. The importance of addressing emotional needs was affirmed by 723 (78.5%) respondents, and although 454 (46.8%) viewed the team’s attention to these needs as excellent, 119 (12.3%) reported that the health care team did not ask about emotional needs. In addition, 566 respondents (60%) viewed having the health care team address their social needs as important, and most (n = 715, 74.2%) rated the team’s attention to social needs as good or excellent. Yet, 162 (16.8%) respondents reported that team did not ask about their social needs. The health care team’s addressing of spiritual needs was viewed as important by 346 (37.5%) respondents and ratings for how well the team attended to spiritual needs were: 148 (15.6%) poor or fair, 204 (21.5%) good, and 150 (15.8%) excellent. However, 448 (47.2%) respondents reported that the health care team did not ask about their spiritual needs.
 

Discussion

The primary purpose of this project was to prioritize survivors’ most salient physical, social, emotional, and spiritual concerns or needs and to assess the perceived importance of these needs and the extent to which the cancer center staff were attentive to those needs. The overall goal of this assessment was to inform the development of survivorship and supportive care programs by highlighting common concerns, demographic and medical factors associated with specific concerns, and timing of moderate/high level concerns along the cancer trajectory. There were 3 main findings.

First, the results support the need for enhancing supportive care services to meet emotional concerns of survivors beyond the treatment phase. Similar to other studies,^8,9 emotional concerns ranked higher than all other concerns in this study with about 50% of the sample rating “fear the cancer will return” and “fear of developing a new cancer” as moderate/high concern. Although the odds of not having these emotional concerns improved up to 2 years posttreatment, these concerns are likely to resurface, as odds for survivors beyond 2 years were not significantly different from those receiving treatment. A recent systematic review reported that fear of cancer recurrence is experienced by about 73% of cancer survivors, with 49% reporting a moderate to high degree.¹⁰ It can have a chronic, stable trajectory for some survivors and is strongly associated with higher levels of anxiety, distress, and depression, and less global, emotional/mental, physical, role, social, and cognitive quality of life.¹⁰ In this sample, managing stress and difficult emotions were also rated as moderate/high concerns by at least 25% of the sample.

Second, the findings identified patients at risk for cancer-related concerns throughout the cancer trajectory. As demonstrated in other studies, younger age was associated with greater odds of having multiple greater moderate/high concerns.^11-13 Unemployment was the second most common demographic factor associated with multiple moderate/high concerns related to physical symptoms, finances and emotions. Similarly, identifying as black, Asian, American Indian/Alaskan Native, or other was also associated with greater odds of having numerous physical, financial, and emotional concerns. Women had greater concerns related to memory, sexual intimacy, coping with difficult emotions, and stress.

Third, the results helped to identify gaps in supportive care at our cancer center. Although spiritual concerns were not prevalent as being moderate/high, they were still viewed by about a third of survivors as being an important area for the health care team to address. Yet, consistent with other need assessments, spiritual concerns in this study were least often addressed by staff.¹ Assessment of spiritual care needs, screening for spiritual distress, and providing spiritual care are essential components of a clinician-patient relationship that supports healing.¹⁴ The importance of attending to spiritual care needs was underscored by a recent systematic review that found a positive association between overall spiritual well-being and quality of life in patients with cancer, with the meaning/peace factor consistently and positively associated with physical and mental health.¹⁵ Another identified gap was the health care team’s lack of attention to the patient’s social needs, which included concerns related to finances and debt from medical bills. In all, 46% of the respondents reported having financial concerns, with the odds of having moderate/high financial concerns being greatest during treatment to 2 years posttreatment. Attention to the financial burden of cancer patients is critical because the magnitude of cancer-related financial concerns is a significant, strong predictor of quality of life and adverse psychological issues such as depression, anxiety, and distress.^16,17

There were several program implications based on the results. A periodic audit of the concerns of survivors and their views on how well their needs were being met was a relatively low cost endeavor. Although the findings were consistent with the literature, the results, when shared with administrators and clinicians, were instrumental in effecting change because they represented the concerns of survivors at the cancer center. Another program directive, based on the results, was to extend the routine screening of patients’ needs during treatment to posttreatment survivorship. Patients who are young, unemployed, do not identify as white, and female warrant more thorough assessment of needs and concerns along the cancer trajectory. Integral to these screenings is the need for patient-centered communication, with discussion of how cancer is affecting the different domains of quality of life within the context of the patient’s life. Lastly, the results clearly indicated the need for additional training of health care providers on how to assess and address spiritual well-being in cancer survivors.

There were limitations to this study, including use of a nonvalidated survey and cross-sectional approach that limited our ability to explore how concerns might change over the trajectory. Also, it was not possible to clarify medical information of the respondents, such as cancer stage. Although the response rate of this study was not high, we are confident in the results because of the large sample size and the finding that the large proportion of respondents with breast cancer was not influential. Despite these limitations, this needs assessment of cancer survivors over the trajectory of care provided insight into the scope of their concerns, identified vulnerable groups of survivors, and highlighted gaps in addressing those concerns. A quality- of-life framework for assessing needs assured a comprehensive focus and generated practice changes to strengthen holistic, comprehensive oncology care.

Kaposi sarcoma is an angioproliferative tumor that is associated with human herpes virus-8 (HHV-8). Mucocutaneous disease is the most common site for manifestation of AIDS-related Kaposi sarcoma, commonly affecting the lower extremities, oral mucosa, face, and genitalia. Pleural effusions can occur in 36%-60% of patients with Kaposi sarcoma, and it has been documented that chylothorax is a rare, but plausible presentation in patients with Kaposi sarcoma.¹ We present here a case of bilateral chylothorax in a patient with AIDS-related Kaposi sarcoma.

Case presentation and summary

A 52-year-old MSM male with AIDS (CD4, <20 mm³; viral load, 58 copies/ml) presented to the emergency department with complaints of shortness of breath, productive cough, and diarrhea for 2 days prior to presentation. His medical history also included chronic obstructive pulmonary disease, coronary artery disease, and hyperlipidemia. The patient was not on HAART because of his history of noncompliance. The results of a chest X-ray and computed-tomography (CT) scan showed that the patient had bilateral pleural effusion and a spiculated 14-mm nodule in the left upper lobe.

The patient underwent ultrasound-guided placement of a 12-French left-sided chest catheter, and a milky white fluid was aspirated from the left pleural space. Laboratory analysis of the pleural fluid confirmed an exudate with an elevated triglyceride level of 120 mg/dL (chylous, >110 mg/dL) indicating chylothorax.

On close physical examination, the patient was found to have multiple irregular plaques on the back and lower extremities. As described by dermatology, there was a violaceous indurated plaque on the left axillae, violaceous indurated plaques with superficial scale grouped on the left midlateral back, and hyperpigmented lichenified plaques and papules on bilateral shins, with some with plate-like scale. Two punch biopsies were taken of the skin lesions, which confirmed Kaposi sarcoma, plaque stage from the lesion biopsied on the back, and patch stage from the lesion biopsied in the left axilla. Cytology of the pleural fluid was negative for malignant cells. On review by the radiologist of the CT scan of the chest, there was no indication of gross distention of the thoracic duct. Treatment options were offered to the patient, and the patient was considering options for chemotherapy and home hospice given his advanced disease state at the time of discharge.
 

Discussion

Chylothorax occurs with a thoracic duct obstruction, which results in leakage of lymphatic fluid into the pleural cavity. The two leading causes of chylothorax are trauma and malignancy, with lymphoma being the most common cause of chylothorax among those with malignancy.² Chylothorax, however, is a rare but documented complication of Kaposi sarcoma. Marais and colleagues reported the case of a 3-year-old HIV-positive patient with newly diagnosed Kaposi sarcoma who was found to have tumor infiltration in the thoracic duct leading to bilateral chylothorax.³ Maradona and colleagues described a 40-year-old man with AIDS-related Kaposi sarcoma who was found to have pleural and pericardial Kaposi sarcoma with chylothorax.⁴ Priest and colleagues wrote about a 32-year-old patient with AIDS with biopsy-proven Kaposi sarcoma who required multiple therapeutic thoracenteses for rapidly recurrent left chylothorax effusions.⁵

There are two leading discussions as to the pathophysiology of chylothorax that is related to Kaposi sarcoma: chylothorax developing secondary to metastatic disease or the development of chylothorax secondary to primary Kaposi sarcoma arising from the pleural region.⁶ One case report examined pleural and lung biopsies in a 34-year-old patient with AIDS-related Kaposi sarcoma that showed immunohistochemical staining that was suggestive of early-stage Kaposi sarcoma of lymphatic endothelial origin. The authors were attempting to illustrate that Kaposi sarcoma may have a stem-cell origin which can differentiate into lymph cells. Kontantinopoulos and colleagues postulated that in situ Kaposi sarcoma can arise from the lymphatic system with a resultant clinical presentation of chylothorax.⁷ The more mainstream thought however, is that chylothorax has been found to develop secondary to metastatic disease. The present case, therefore, illustrates an unusual presentation of cytology negative chylothorax in a patient with AIDS-related Kaposi sarcoma.

Kaposi sarcoma is an angioproliferative tumor that is associated with human herpes virus-8 (HHV-8). Mucocutaneous disease is the most common site for manifestation of AIDS-related Kaposi sarcoma, commonly affecting the lower extremities, oral mucosa, face, and genitalia. Pleural effusions can occur in 36%-60% of patients with Kaposi sarcoma, and it has been documented that chylothorax is a rare, but plausible presentation in patients with Kaposi sarcoma.¹ We present here a case of bilateral chylothorax in a patient with AIDS-related Kaposi sarcoma.

Case presentation and summary

A 52-year-old MSM male with AIDS (CD4, <20 mm³; viral load, 58 copies/ml) presented to the emergency department with complaints of shortness of breath, productive cough, and diarrhea for 2 days prior to presentation. His medical history also included chronic obstructive pulmonary disease, coronary artery disease, and hyperlipidemia. The patient was not on HAART because of his history of noncompliance. The results of a chest X-ray and computed-tomography (CT) scan showed that the patient had bilateral pleural effusion and a spiculated 14-mm nodule in the left upper lobe.

The patient underwent ultrasound-guided placement of a 12-French left-sided chest catheter, and a milky white fluid was aspirated from the left pleural space. Laboratory analysis of the pleural fluid confirmed an exudate with an elevated triglyceride level of 120 mg/dL (chylous, >110 mg/dL) indicating chylothorax.

On close physical examination, the patient was found to have multiple irregular plaques on the back and lower extremities. As described by dermatology, there was a violaceous indurated plaque on the left axillae, violaceous indurated plaques with superficial scale grouped on the left midlateral back, and hyperpigmented lichenified plaques and papules on bilateral shins, with some with plate-like scale. Two punch biopsies were taken of the skin lesions, which confirmed Kaposi sarcoma, plaque stage from the lesion biopsied on the back, and patch stage from the lesion biopsied in the left axilla. Cytology of the pleural fluid was negative for malignant cells. On review by the radiologist of the CT scan of the chest, there was no indication of gross distention of the thoracic duct. Treatment options were offered to the patient, and the patient was considering options for chemotherapy and home hospice given his advanced disease state at the time of discharge.
 

Discussion

Chylothorax occurs with a thoracic duct obstruction, which results in leakage of lymphatic fluid into the pleural cavity. The two leading causes of chylothorax are trauma and malignancy, with lymphoma being the most common cause of chylothorax among those with malignancy.² Chylothorax, however, is a rare but documented complication of Kaposi sarcoma. Marais and colleagues reported the case of a 3-year-old HIV-positive patient with newly diagnosed Kaposi sarcoma who was found to have tumor infiltration in the thoracic duct leading to bilateral chylothorax.³ Maradona and colleagues described a 40-year-old man with AIDS-related Kaposi sarcoma who was found to have pleural and pericardial Kaposi sarcoma with chylothorax.⁴ Priest and colleagues wrote about a 32-year-old patient with AIDS with biopsy-proven Kaposi sarcoma who required multiple therapeutic thoracenteses for rapidly recurrent left chylothorax effusions.⁵

There are two leading discussions as to the pathophysiology of chylothorax that is related to Kaposi sarcoma: chylothorax developing secondary to metastatic disease or the development of chylothorax secondary to primary Kaposi sarcoma arising from the pleural region.⁶ One case report examined pleural and lung biopsies in a 34-year-old patient with AIDS-related Kaposi sarcoma that showed immunohistochemical staining that was suggestive of early-stage Kaposi sarcoma of lymphatic endothelial origin. The authors were attempting to illustrate that Kaposi sarcoma may have a stem-cell origin which can differentiate into lymph cells. Kontantinopoulos and colleagues postulated that in situ Kaposi sarcoma can arise from the lymphatic system with a resultant clinical presentation of chylothorax.⁷ The more mainstream thought however, is that chylothorax has been found to develop secondary to metastatic disease. The present case, therefore, illustrates an unusual presentation of cytology negative chylothorax in a patient with AIDS-related Kaposi sarcoma.

Kaposi sarcoma is an angioproliferative tumor that is associated with human herpes virus-8 (HHV-8). Mucocutaneous disease is the most common site for manifestation of AIDS-related Kaposi sarcoma, commonly affecting the lower extremities, oral mucosa, face, and genitalia. Pleural effusions can occur in 36%-60% of patients with Kaposi sarcoma, and it has been documented that chylothorax is a rare, but plausible presentation in patients with Kaposi sarcoma.¹ We present here a case of bilateral chylothorax in a patient with AIDS-related Kaposi sarcoma.

Case presentation and summary

A 52-year-old MSM male with AIDS (CD4, <20 mm³; viral load, 58 copies/ml) presented to the emergency department with complaints of shortness of breath, productive cough, and diarrhea for 2 days prior to presentation. His medical history also included chronic obstructive pulmonary disease, coronary artery disease, and hyperlipidemia. The patient was not on HAART because of his history of noncompliance. The results of a chest X-ray and computed-tomography (CT) scan showed that the patient had bilateral pleural effusion and a spiculated 14-mm nodule in the left upper lobe.

The patient underwent ultrasound-guided placement of a 12-French left-sided chest catheter, and a milky white fluid was aspirated from the left pleural space. Laboratory analysis of the pleural fluid confirmed an exudate with an elevated triglyceride level of 120 mg/dL (chylous, >110 mg/dL) indicating chylothorax.

On close physical examination, the patient was found to have multiple irregular plaques on the back and lower extremities. As described by dermatology, there was a violaceous indurated plaque on the left axillae, violaceous indurated plaques with superficial scale grouped on the left midlateral back, and hyperpigmented lichenified plaques and papules on bilateral shins, with some with plate-like scale. Two punch biopsies were taken of the skin lesions, which confirmed Kaposi sarcoma, plaque stage from the lesion biopsied on the back, and patch stage from the lesion biopsied in the left axilla. Cytology of the pleural fluid was negative for malignant cells. On review by the radiologist of the CT scan of the chest, there was no indication of gross distention of the thoracic duct. Treatment options were offered to the patient, and the patient was considering options for chemotherapy and home hospice given his advanced disease state at the time of discharge.
 

Discussion

Chylothorax occurs with a thoracic duct obstruction, which results in leakage of lymphatic fluid into the pleural cavity. The two leading causes of chylothorax are trauma and malignancy, with lymphoma being the most common cause of chylothorax among those with malignancy.² Chylothorax, however, is a rare but documented complication of Kaposi sarcoma. Marais and colleagues reported the case of a 3-year-old HIV-positive patient with newly diagnosed Kaposi sarcoma who was found to have tumor infiltration in the thoracic duct leading to bilateral chylothorax.³ Maradona and colleagues described a 40-year-old man with AIDS-related Kaposi sarcoma who was found to have pleural and pericardial Kaposi sarcoma with chylothorax.⁴ Priest and colleagues wrote about a 32-year-old patient with AIDS with biopsy-proven Kaposi sarcoma who required multiple therapeutic thoracenteses for rapidly recurrent left chylothorax effusions.⁵

There are two leading discussions as to the pathophysiology of chylothorax that is related to Kaposi sarcoma: chylothorax developing secondary to metastatic disease or the development of chylothorax secondary to primary Kaposi sarcoma arising from the pleural region.⁶ One case report examined pleural and lung biopsies in a 34-year-old patient with AIDS-related Kaposi sarcoma that showed immunohistochemical staining that was suggestive of early-stage Kaposi sarcoma of lymphatic endothelial origin. The authors were attempting to illustrate that Kaposi sarcoma may have a stem-cell origin which can differentiate into lymph cells. Kontantinopoulos and colleagues postulated that in situ Kaposi sarcoma can arise from the lymphatic system with a resultant clinical presentation of chylothorax.⁷ The more mainstream thought however, is that chylothorax has been found to develop secondary to metastatic disease. The present case, therefore, illustrates an unusual presentation of cytology negative chylothorax in a patient with AIDS-related Kaposi sarcoma.

For years, this 33-year-old woman has had a firm, pea-sized nodule on her left upper back. It was never a problem until recently, when it suddenly enlarged and became red, swollen, and tender.

She was prescribed antibiotics (trimethoprim and sulfa) by a provider at her local urgent care center. Dubious of the diagnosis—carbuncle—she sought referral to dermatology.

The patient claims to be in otherwise excellent health, with no history of similar problems. She denies manual manipulation of the lesion.

EXAMINATION
The patient is afebrile and in no distress. On her upper left back is a round, cystic lesion measuring 3.5 cm. It appears swollen and red. The erythema, though impressive, is confined to
the area immediately around the margins. Palpation reveals increased warmth and modest tenderness. A central punctum can be seen in the center of the fluctuant lesion.

After a brief discussion of options, the lesion is incised and drained under sterile conditions with lidocaine and epinephrine. Cheesy, odoriferous material is expressed, effectively flattening the lesion.

What is the diagnosis?

When ruptured by trauma, epidermal cysts become inflamed and cheesy material leaks into deep tissues. This activates an immune response in which the body sends out white cells to clean up the leakage—what we call inflammation.

There are many types of cysts (eg, acne cysts, ganglion cysts, Bartholin gland cysts) but none resemble epidermal cysts. Providers often mistake epidermal cysts for carbuncles or boils and may prescribe oral or systemic antibiotics, or incise the cysts and pack the space. The truth is that inflamed epidermal cysts do not represent infection—hence the limited area of redness. By contrast, cellulitis or carbuncle would manifest with tenderness and blush of erythema over the entire area.

The fact that this lesion arose from a longstanding antecedent nodule is consistent with the diagnosis, as are the cheesy, odoriferous contents liberated by incision and drainage. Liberating the contents merely buys the patient relief from the pressure and pain, since the cyst wall is still present and will almost certainly fill up again. The ultimate solution is excision after the emptied cyst has had time to shrink back to its original size, which will minimize the scarring. There is no need to pack such cysts after incision and drainage, though they will continue to drain for a few days.

TAKE-HOME LEARNING POINTS

• Epidermal cysts are common, especially in oil-rich areas such as the face, back, chest, and neck.
• Epidermal cysts are often mistakenly called sebaceous cysts, but these are actually quite rare, containing clear sebum (oil) and no cheesy material.
• Even though such inflamed cysts are often mistaken for boils, carbuncles, and abscesses, they have nothing to do with bacteria or infection and therefore do not require antibiotics or packing after incision and drainage.
• For recurrent inflamed cysts, the treatment of choice is complete excision, done only after the cyst has shrunk to its smallest size.

For years, this 33-year-old woman has had a firm, pea-sized nodule on her left upper back. It was never a problem until recently, when it suddenly enlarged and became red, swollen, and tender.

She was prescribed antibiotics (trimethoprim and sulfa) by a provider at her local urgent care center. Dubious of the diagnosis—carbuncle—she sought referral to dermatology.

The patient claims to be in otherwise excellent health, with no history of similar problems. She denies manual manipulation of the lesion.

EXAMINATION
The patient is afebrile and in no distress. On her upper left back is a round, cystic lesion measuring 3.5 cm. It appears swollen and red. The erythema, though impressive, is confined to
the area immediately around the margins. Palpation reveals increased warmth and modest tenderness. A central punctum can be seen in the center of the fluctuant lesion.

After a brief discussion of options, the lesion is incised and drained under sterile conditions with lidocaine and epinephrine. Cheesy, odoriferous material is expressed, effectively flattening the lesion.

What is the diagnosis?

When ruptured by trauma, epidermal cysts become inflamed and cheesy material leaks into deep tissues. This activates an immune response in which the body sends out white cells to clean up the leakage—what we call inflammation.

There are many types of cysts (eg, acne cysts, ganglion cysts, Bartholin gland cysts) but none resemble epidermal cysts. Providers often mistake epidermal cysts for carbuncles or boils and may prescribe oral or systemic antibiotics, or incise the cysts and pack the space. The truth is that inflamed epidermal cysts do not represent infection—hence the limited area of redness. By contrast, cellulitis or carbuncle would manifest with tenderness and blush of erythema over the entire area.

The fact that this lesion arose from a longstanding antecedent nodule is consistent with the diagnosis, as are the cheesy, odoriferous contents liberated by incision and drainage. Liberating the contents merely buys the patient relief from the pressure and pain, since the cyst wall is still present and will almost certainly fill up again. The ultimate solution is excision after the emptied cyst has had time to shrink back to its original size, which will minimize the scarring. There is no need to pack such cysts after incision and drainage, though they will continue to drain for a few days.

TAKE-HOME LEARNING POINTS

• Epidermal cysts are common, especially in oil-rich areas such as the face, back, chest, and neck.
• Epidermal cysts are often mistakenly called sebaceous cysts, but these are actually quite rare, containing clear sebum (oil) and no cheesy material.
• Even though such inflamed cysts are often mistaken for boils, carbuncles, and abscesses, they have nothing to do with bacteria or infection and therefore do not require antibiotics or packing after incision and drainage.
• For recurrent inflamed cysts, the treatment of choice is complete excision, done only after the cyst has shrunk to its smallest size.

For years, this 33-year-old woman has had a firm, pea-sized nodule on her left upper back. It was never a problem until recently, when it suddenly enlarged and became red, swollen, and tender.

She was prescribed antibiotics (trimethoprim and sulfa) by a provider at her local urgent care center. Dubious of the diagnosis—carbuncle—she sought referral to dermatology.

The patient claims to be in otherwise excellent health, with no history of similar problems. She denies manual manipulation of the lesion.

EXAMINATION
The patient is afebrile and in no distress. On her upper left back is a round, cystic lesion measuring 3.5 cm. It appears swollen and red. The erythema, though impressive, is confined to
the area immediately around the margins. Palpation reveals increased warmth and modest tenderness. A central punctum can be seen in the center of the fluctuant lesion.

After a brief discussion of options, the lesion is incised and drained under sterile conditions with lidocaine and epinephrine. Cheesy, odoriferous material is expressed, effectively flattening the lesion.

What is the diagnosis?

When ruptured by trauma, epidermal cysts become inflamed and cheesy material leaks into deep tissues. This activates an immune response in which the body sends out white cells to clean up the leakage—what we call inflammation.

There are many types of cysts (eg, acne cysts, ganglion cysts, Bartholin gland cysts) but none resemble epidermal cysts. Providers often mistake epidermal cysts for carbuncles or boils and may prescribe oral or systemic antibiotics, or incise the cysts and pack the space. The truth is that inflamed epidermal cysts do not represent infection—hence the limited area of redness. By contrast, cellulitis or carbuncle would manifest with tenderness and blush of erythema over the entire area.

The fact that this lesion arose from a longstanding antecedent nodule is consistent with the diagnosis, as are the cheesy, odoriferous contents liberated by incision and drainage. Liberating the contents merely buys the patient relief from the pressure and pain, since the cyst wall is still present and will almost certainly fill up again. The ultimate solution is excision after the emptied cyst has had time to shrink back to its original size, which will minimize the scarring. There is no need to pack such cysts after incision and drainage, though they will continue to drain for a few days.

TAKE-HOME LEARNING POINTS

• Epidermal cysts are common, especially in oil-rich areas such as the face, back, chest, and neck.
• Epidermal cysts are often mistakenly called sebaceous cysts, but these are actually quite rare, containing clear sebum (oil) and no cheesy material.
• Even though such inflamed cysts are often mistaken for boils, carbuncles, and abscesses, they have nothing to do with bacteria or infection and therefore do not require antibiotics or packing after incision and drainage.
• For recurrent inflamed cysts, the treatment of choice is complete excision, done only after the cyst has shrunk to its smallest size.

We struggle daily to improve cancer care – to improve our therapeutic outcomes in cancer – as individual physicians and as researchers. We work collectively to disseminate information and collaborate, and there are welcome calls for open data sharing to accelerate progress.¹ We enroll patients on clinical trials, or we work in a basic science lab to discover mechanisms of carcinogenesis and potential therapeutic targets. We discuss “n of 1” trials and the “paradigm shift of precision oncology,” and we are optimistic about the future of cancer care.

Leaving the world of biology and clinical trials for a minute, we also can apply economic theory in our never-ending quest to improve cancer outcomes. One area of interest may be modern portfolio theory (MPT), which the economist Harry Markowitz introduced in an essay in 1952 and later won the Nobel Prize for his work.

We struggle daily to improve cancer care – to improve our therapeutic outcomes in cancer – as individual physicians and as researchers. We work collectively to disseminate information and collaborate, and there are welcome calls for open data sharing to accelerate progress.¹ We enroll patients on clinical trials, or we work in a basic science lab to discover mechanisms of carcinogenesis and potential therapeutic targets. We discuss “n of 1” trials and the “paradigm shift of precision oncology,” and we are optimistic about the future of cancer care.

Leaving the world of biology and clinical trials for a minute, we also can apply economic theory in our never-ending quest to improve cancer outcomes. One area of interest may be modern portfolio theory (MPT), which the economist Harry Markowitz introduced in an essay in 1952 and later won the Nobel Prize for his work.

We struggle daily to improve cancer care – to improve our therapeutic outcomes in cancer – as individual physicians and as researchers. We work collectively to disseminate information and collaborate, and there are welcome calls for open data sharing to accelerate progress.¹ We enroll patients on clinical trials, or we work in a basic science lab to discover mechanisms of carcinogenesis and potential therapeutic targets. We discuss “n of 1” trials and the “paradigm shift of precision oncology,” and we are optimistic about the future of cancer care.

Leaving the world of biology and clinical trials for a minute, we also can apply economic theory in our never-ending quest to improve cancer outcomes. One area of interest may be modern portfolio theory (MPT), which the economist Harry Markowitz introduced in an essay in 1952 and later won the Nobel Prize for his work.

Kaposi sarcoma is an AIDS-defining illness associated with human herpes virus-8 (HHV-8) co-infection. It was described in 1872 by the Hungarian dermatologist Mortiz Kaposi, and was an isolated and sporadic occurrence before the emergence of HIV infection and AIDS.¹ It was first affiliated as an AIDS-associated neoplasm in 1981.¹ Kaposi sarcoma is a systemic disease that can present with cutaneous lesions with or without internal involvement. There are four subtypes: Classic, African endemic, AIDS-related (CD4 count, <200), and Kaposi sarcoma in iatrogenically immunosuppressed patients. The disease has the propensity to manifest in the skin and gastro-intestinal and respiratory tracts, and osseous involvement is rarely encountered. We present here the case of an AIDS-positive man with generalized bone pain as a result of metastasis from Kaposi sarcoma. Our discussion includes the epidemiological, clinical, pathological, and radiological facets of AIDS-related Kaposi sarcoma, and the anomaly of osseous involvement.

Case presentation and summary

A 26-year-old African American man with a history of AIDS (CD4 count, 13 cells/mm³ [normal, 500-1,600 cells/mm³]) who was noncompliant with HAART (highly active antiretroviral therapy), presented to the emergency department in January 2016 with chest, abdominal, and back pain. His HAART regimen included darunavir 8 mL oral suspension daily, emtricitabine 4 mL oral suspension daily, and ritonavir 100 mg tab daily. A computed-tomography (CT) scan of the man’s abdomen revealed axillary, mediastinal, and abdominal lymphadenopathy, with splenomegaly and innumerable osseous lucent spinal lesions. A left axillary lymph node biopsy was positive for Kaposi sarcoma; pathology showed fascicles of spindle, oval- to round-shaped atypical cells positive for HHV-8 (granular nuclear staining), CD31, and CD34 (partial; Figure 1). Serum and urine protein electrophoresis showed no paraproteins.

He restarted his previous HAART regimen in March 2016, and was subsequently started on chemotherapy with liposomal doxorubicin (50 mg [20 mg/m²] in 250 ml D5W IV every 2 weeks) because of his extensive disease.² He completed 6 cycles by June 2016. However, he returned in July 2016 with worsening back pain. A repeat CT scan revealed significant improvement in the disseminated lymphadenopathy, but worsening osseous metastatic disease was seen in the lumbar, thoracic, and pelvic regions. A pelvic lytic lesion biopsy revealed Kaposi sarcoma; pathology showed spindle cells positive for CD34, CD31, and HHV-8 (Figure 2). The patient received palliative radiation to the spine, aiding in pain management and ambulatory dysfunction. He continued with his noncompliance with all medications and outpatient follow-ups, and succumbed to his disease burden.

Discussion

Kaposi sarcoma is a low-grade mesenchymal tumor that involves the blood and lymphatic vessels.³ Its association with AIDS was revealed in the early 1980s at the start of the HIV epidemic in the United States. In 1994, Chang and colleagues discovered the association between Karposi sarcoma and HHV-8 by isolating DNA fragments of HHV in Kaposi sarcoma tumors from AIDS patients.⁴ The mode of transmission of HHV-8 has not been fully decoded. It has been presumed that adult homosexual contact continues to be an important route of transmission, inferring a common route of infection. In 1990, the overall risk of developing Kaposi sarcoma in AIDS patients was 20,000 times greater than it was in the general population, and 300 times greater than in other immunosuppressed patients.⁵ This suggests an increase in incidence, in direct relation, with a decrease in the CD4 count.

Kaposi sarcoma can present with a range of clinical features, from negligible cutaneous lesions to a hastily progressing neoplasm. Involvement in the musculoskeletal system is infrequent, but encountered increasingly in the AIDS-related subtype. Moreover, it is recurrently observed in the African population.⁶ In one of the largest reviews to date exploring Kaposi sarcoma involving the musculoskeletal system, Caponetti and colleagues observed the greatest osseous involvement distinctly in patients with CD4 and T-cell counts below 100 cells/mm³.⁶

Kaposi sarcoma musculoskeletal involvement, specifically bone, is atypical. If it does occur, it usually manifests as a result of contiguous invasion from an adjacent nonosseous lesion. Caponetti and colleagues that isolated osseous Kaposi sarcoma lesions (with no overlying skin lesion) were found to be more likely to be associated with AIDS in the review by Caponetti and colleagues.⁶ As in our patient, it is also typically a manifestation of more widely disseminated disease.⁷

Most of the osseous lytic lesions in AIDS patients are located in the axial skeleton. Radiological features of musculoskeletal Kaposi sarcoma are variable. As observed by Caponetti and colleagues, Kaposi sarcoma lesions can appear as a periosteal reaction, cortical erosions, osteolysis, or osseous destruction, with irregular-shaped cortical erosions being most typical.⁶ Despite their osteolytic features, Kaposi sarcoma lesions are often not visualized by conventional radiography.⁶ The preferred imaging for identification of lytic bone changes is CT (Figure 3). Magnetic resonance imaging can also help distinguish marrow abnormalities as well as adjacent soft tissues masses. Radiologically, Kaposi sarcoma osseous lesions have parallel features to bacillary angiomatosis, tuberculosis, or lymphoma.⁸ Therefore, biopsy of the lesion is essential in establishing the diagnosis of Kaposi sarcoma.

Kaposi sarcoma is an AIDS-defining illness associated with human herpes virus-8 (HHV-8) co-infection. It was described in 1872 by the Hungarian dermatologist Mortiz Kaposi, and was an isolated and sporadic occurrence before the emergence of HIV infection and AIDS.¹ It was first affiliated as an AIDS-associated neoplasm in 1981.¹ Kaposi sarcoma is a systemic disease that can present with cutaneous lesions with or without internal involvement. There are four subtypes: Classic, African endemic, AIDS-related (CD4 count, <200), and Kaposi sarcoma in iatrogenically immunosuppressed patients. The disease has the propensity to manifest in the skin and gastro-intestinal and respiratory tracts, and osseous involvement is rarely encountered. We present here the case of an AIDS-positive man with generalized bone pain as a result of metastasis from Kaposi sarcoma. Our discussion includes the epidemiological, clinical, pathological, and radiological facets of AIDS-related Kaposi sarcoma, and the anomaly of osseous involvement.

Case presentation and summary

A 26-year-old African American man with a history of AIDS (CD4 count, 13 cells/mm³ [normal, 500-1,600 cells/mm³]) who was noncompliant with HAART (highly active antiretroviral therapy), presented to the emergency department in January 2016 with chest, abdominal, and back pain. His HAART regimen included darunavir 8 mL oral suspension daily, emtricitabine 4 mL oral suspension daily, and ritonavir 100 mg tab daily. A computed-tomography (CT) scan of the man’s abdomen revealed axillary, mediastinal, and abdominal lymphadenopathy, with splenomegaly and innumerable osseous lucent spinal lesions. A left axillary lymph node biopsy was positive for Kaposi sarcoma; pathology showed fascicles of spindle, oval- to round-shaped atypical cells positive for HHV-8 (granular nuclear staining), CD31, and CD34 (partial; Figure 1). Serum and urine protein electrophoresis showed no paraproteins.

He restarted his previous HAART regimen in March 2016, and was subsequently started on chemotherapy with liposomal doxorubicin (50 mg [20 mg/m²] in 250 ml D5W IV every 2 weeks) because of his extensive disease.² He completed 6 cycles by June 2016. However, he returned in July 2016 with worsening back pain. A repeat CT scan revealed significant improvement in the disseminated lymphadenopathy, but worsening osseous metastatic disease was seen in the lumbar, thoracic, and pelvic regions. A pelvic lytic lesion biopsy revealed Kaposi sarcoma; pathology showed spindle cells positive for CD34, CD31, and HHV-8 (Figure 2). The patient received palliative radiation to the spine, aiding in pain management and ambulatory dysfunction. He continued with his noncompliance with all medications and outpatient follow-ups, and succumbed to his disease burden.

Discussion

Kaposi sarcoma is a low-grade mesenchymal tumor that involves the blood and lymphatic vessels.³ Its association with AIDS was revealed in the early 1980s at the start of the HIV epidemic in the United States. In 1994, Chang and colleagues discovered the association between Karposi sarcoma and HHV-8 by isolating DNA fragments of HHV in Kaposi sarcoma tumors from AIDS patients.⁴ The mode of transmission of HHV-8 has not been fully decoded. It has been presumed that adult homosexual contact continues to be an important route of transmission, inferring a common route of infection. In 1990, the overall risk of developing Kaposi sarcoma in AIDS patients was 20,000 times greater than it was in the general population, and 300 times greater than in other immunosuppressed patients.⁵ This suggests an increase in incidence, in direct relation, with a decrease in the CD4 count.

Kaposi sarcoma can present with a range of clinical features, from negligible cutaneous lesions to a hastily progressing neoplasm. Involvement in the musculoskeletal system is infrequent, but encountered increasingly in the AIDS-related subtype. Moreover, it is recurrently observed in the African population.⁶ In one of the largest reviews to date exploring Kaposi sarcoma involving the musculoskeletal system, Caponetti and colleagues observed the greatest osseous involvement distinctly in patients with CD4 and T-cell counts below 100 cells/mm³.⁶

Kaposi sarcoma musculoskeletal involvement, specifically bone, is atypical. If it does occur, it usually manifests as a result of contiguous invasion from an adjacent nonosseous lesion. Caponetti and colleagues that isolated osseous Kaposi sarcoma lesions (with no overlying skin lesion) were found to be more likely to be associated with AIDS in the review by Caponetti and colleagues.⁶ As in our patient, it is also typically a manifestation of more widely disseminated disease.⁷

Most of the osseous lytic lesions in AIDS patients are located in the axial skeleton. Radiological features of musculoskeletal Kaposi sarcoma are variable. As observed by Caponetti and colleagues, Kaposi sarcoma lesions can appear as a periosteal reaction, cortical erosions, osteolysis, or osseous destruction, with irregular-shaped cortical erosions being most typical.⁶ Despite their osteolytic features, Kaposi sarcoma lesions are often not visualized by conventional radiography.⁶ The preferred imaging for identification of lytic bone changes is CT (Figure 3). Magnetic resonance imaging can also help distinguish marrow abnormalities as well as adjacent soft tissues masses. Radiologically, Kaposi sarcoma osseous lesions have parallel features to bacillary angiomatosis, tuberculosis, or lymphoma.⁸ Therefore, biopsy of the lesion is essential in establishing the diagnosis of Kaposi sarcoma.

Kaposi sarcoma is an AIDS-defining illness associated with human herpes virus-8 (HHV-8) co-infection. It was described in 1872 by the Hungarian dermatologist Mortiz Kaposi, and was an isolated and sporadic occurrence before the emergence of HIV infection and AIDS.¹ It was first affiliated as an AIDS-associated neoplasm in 1981.¹ Kaposi sarcoma is a systemic disease that can present with cutaneous lesions with or without internal involvement. There are four subtypes: Classic, African endemic, AIDS-related (CD4 count, <200), and Kaposi sarcoma in iatrogenically immunosuppressed patients. The disease has the propensity to manifest in the skin and gastro-intestinal and respiratory tracts, and osseous involvement is rarely encountered. We present here the case of an AIDS-positive man with generalized bone pain as a result of metastasis from Kaposi sarcoma. Our discussion includes the epidemiological, clinical, pathological, and radiological facets of AIDS-related Kaposi sarcoma, and the anomaly of osseous involvement.

Case presentation and summary

A 26-year-old African American man with a history of AIDS (CD4 count, 13 cells/mm³ [normal, 500-1,600 cells/mm³]) who was noncompliant with HAART (highly active antiretroviral therapy), presented to the emergency department in January 2016 with chest, abdominal, and back pain. His HAART regimen included darunavir 8 mL oral suspension daily, emtricitabine 4 mL oral suspension daily, and ritonavir 100 mg tab daily. A computed-tomography (CT) scan of the man’s abdomen revealed axillary, mediastinal, and abdominal lymphadenopathy, with splenomegaly and innumerable osseous lucent spinal lesions. A left axillary lymph node biopsy was positive for Kaposi sarcoma; pathology showed fascicles of spindle, oval- to round-shaped atypical cells positive for HHV-8 (granular nuclear staining), CD31, and CD34 (partial; Figure 1). Serum and urine protein electrophoresis showed no paraproteins.

He restarted his previous HAART regimen in March 2016, and was subsequently started on chemotherapy with liposomal doxorubicin (50 mg [20 mg/m²] in 250 ml D5W IV every 2 weeks) because of his extensive disease.² He completed 6 cycles by June 2016. However, he returned in July 2016 with worsening back pain. A repeat CT scan revealed significant improvement in the disseminated lymphadenopathy, but worsening osseous metastatic disease was seen in the lumbar, thoracic, and pelvic regions. A pelvic lytic lesion biopsy revealed Kaposi sarcoma; pathology showed spindle cells positive for CD34, CD31, and HHV-8 (Figure 2). The patient received palliative radiation to the spine, aiding in pain management and ambulatory dysfunction. He continued with his noncompliance with all medications and outpatient follow-ups, and succumbed to his disease burden.

Discussion

Kaposi sarcoma is a low-grade mesenchymal tumor that involves the blood and lymphatic vessels.³ Its association with AIDS was revealed in the early 1980s at the start of the HIV epidemic in the United States. In 1994, Chang and colleagues discovered the association between Karposi sarcoma and HHV-8 by isolating DNA fragments of HHV in Kaposi sarcoma tumors from AIDS patients.⁴ The mode of transmission of HHV-8 has not been fully decoded. It has been presumed that adult homosexual contact continues to be an important route of transmission, inferring a common route of infection. In 1990, the overall risk of developing Kaposi sarcoma in AIDS patients was 20,000 times greater than it was in the general population, and 300 times greater than in other immunosuppressed patients.⁵ This suggests an increase in incidence, in direct relation, with a decrease in the CD4 count.

Kaposi sarcoma can present with a range of clinical features, from negligible cutaneous lesions to a hastily progressing neoplasm. Involvement in the musculoskeletal system is infrequent, but encountered increasingly in the AIDS-related subtype. Moreover, it is recurrently observed in the African population.⁶ In one of the largest reviews to date exploring Kaposi sarcoma involving the musculoskeletal system, Caponetti and colleagues observed the greatest osseous involvement distinctly in patients with CD4 and T-cell counts below 100 cells/mm³.⁶

Kaposi sarcoma musculoskeletal involvement, specifically bone, is atypical. If it does occur, it usually manifests as a result of contiguous invasion from an adjacent nonosseous lesion. Caponetti and colleagues that isolated osseous Kaposi sarcoma lesions (with no overlying skin lesion) were found to be more likely to be associated with AIDS in the review by Caponetti and colleagues.⁶ As in our patient, it is also typically a manifestation of more widely disseminated disease.⁷

Most of the osseous lytic lesions in AIDS patients are located in the axial skeleton. Radiological features of musculoskeletal Kaposi sarcoma are variable. As observed by Caponetti and colleagues, Kaposi sarcoma lesions can appear as a periosteal reaction, cortical erosions, osteolysis, or osseous destruction, with irregular-shaped cortical erosions being most typical.⁶ Despite their osteolytic features, Kaposi sarcoma lesions are often not visualized by conventional radiography.⁶ The preferred imaging for identification of lytic bone changes is CT (Figure 3). Magnetic resonance imaging can also help distinguish marrow abnormalities as well as adjacent soft tissues masses. Radiologically, Kaposi sarcoma osseous lesions have parallel features to bacillary angiomatosis, tuberculosis, or lymphoma.⁸ Therefore, biopsy of the lesion is essential in establishing the diagnosis of Kaposi sarcoma.

Photo by Chad McNeeley

MADRID—Updated results of a phase 1/2 study suggest the T-cell product BPX-501 lowers the risks associated with haploidentical hematopoietic stem cell transplant (haplo-HSCT).

In this ongoing study, researchers are testing BPX-501 in pediatric patients undergoing haplo-HSCT to treat a range of hematologic disorders.

Patients treated thus far have experienced rapid engraftment and early hospital discharge, a low rate of acute graft-versus-host disease (GHVD), no extensive chronic GVHD, and a low rate of transplant-related mortality at 180 days.

“The combination of haploidentical transplantation and BPX-501 infusion is an effective strategy for children in need of an allograft lacking a compatible donor,” said study investigator Mattia Algeri, MD, of Ospedale Pediatrico Bambino Gesù in Rome, Italy.

Dr Algeri presented these results during the Presidential Symposium at the 22nd Congress of the European Hematology Association (EHA) as abstract S146.

The research was sponsored by Bellicum Pharmaceuticals, Inc., the company developing BPX-501.

About BPX-501

BPX-501 consists of genetically modified donor T cells incorporating the CaspaCIDe safety switch, which is designed to eliminate the T cells in the event of toxicity.

Rimiducid is used to activate the CaspaCIDe safety switch, which consists of the CID-binding domain coupled to the signaling domain of caspase-9, an enzyme that is part of the apoptotic pathway.

The goal of this therapy is to allow physicians to more safely perform haplo-HSCTs.

Patients

Dr Algeri and his colleagues have tested BPX-501 in 98 pediatric patients treated at centers in Europe and the US.

Fifty-nine patients had non-malignant conditions, including primary immune deficiency (n=26), thalassemia major (n=8), sickle cell disease (n=5), Diamond-Blackfan anemia (n=2), Swachman-Diamond syndrome (n=1), Fanconi anemia (n=9), hemophagocytic lymphohistiocytosis (n=6), aplastic anemia (n=1), and osteoporosis (n=1).

Thirty-nine patients had malignant conditions, including acute lymphoblastic leukemia (ALL, n=21), acute myeloid leukemia (AML, n=14), myelodysplastic syndromes (MDS, n=3), and non-Hodgkin lymphoma (NHL, n=1).

The patients received BPX-501 after an alpha/beta T-cell-depleted haplo-HSCT. All patients had at least 6 months of follow-up.

Overall results

Ninety-five percent of the patients engrafted (93/98), and the researchers said they observed rapid recovery of T cells, B cells, and immunoglobulins.

At 180 days, the incidence of transplant-related mortality was 5%, and there were no cases of post-transplant lymphoproliferative disorder.

The cumulative incidence of grade 2-4 acute GVHD was 14%. For patients with at least 1 year of follow-up, the cumulative incidence of chronic GVHD at 1 year was 3%.

Eleven patients received rimiducid—10 who had uncontrollable acute GVHD and 1 who developed late acute GVHD. In all of these patients, GVHD resolved and has not recurred.

There were no adverse events associated with BPX-501 or rimiducid.

European cohort

Dr Algeri presented more detailed data on the 61 patients treated at centers in Europe.

Fifteen of these patients had ALL, 10 had AML, 16 had primary immune deficiency, 7 had thalassemia major, 1 had sickle cell disease, 2 had Diamond-Blackfan anemia, 5 had Fanconi anemia, 4 had hemophagocytic lymphohistiocytosis, and 1 had osteoporosis.

Their median age was 4.8 (range, 0.25-17), and 56% were male. The patients received busulfan-based conditioning (41%), total body irradiation (36%), treosulfan-based conditioning (18%), and other conditioning (5%).

Ninety-five percent of the patients had a parent donor, and the other 5% had a sibling donor. The median donor age was 36 (range, 19-50).

The patients’ median time to neutrophil recovery was 15 days (range, 9-75), and their median time to platelet recovery was 10 days (range, 4-64). Their median time to discharge was 25 days (range, 14-122).

The cumulative incidence of acute grade 2-4 GVHD was 9.9%, and the cumulative incidence of acute grade 3-4 GVHD was 3.3%.

There were no cases of transplant-related mortality at 180 days and no cases of extensive chronic GVHD.

“These preliminary data compare favorably to previously published data on matched, unrelated donor transplantation,” Dr Algeri said. “And for this reason, an observational matched, unrelated donor study is being initiated to enable comparison of the safety and efficacy of haploidentical transplantation and BPX-501 infusion to the standard of care for patients without a matched sibling donor.”

Photo by Chad McNeeley

MADRID—Updated results of a phase 1/2 study suggest the T-cell product BPX-501 lowers the risks associated with haploidentical hematopoietic stem cell transplant (haplo-HSCT).

In this ongoing study, researchers are testing BPX-501 in pediatric patients undergoing haplo-HSCT to treat a range of hematologic disorders.

Patients treated thus far have experienced rapid engraftment and early hospital discharge, a low rate of acute graft-versus-host disease (GHVD), no extensive chronic GVHD, and a low rate of transplant-related mortality at 180 days.

“The combination of haploidentical transplantation and BPX-501 infusion is an effective strategy for children in need of an allograft lacking a compatible donor,” said study investigator Mattia Algeri, MD, of Ospedale Pediatrico Bambino Gesù in Rome, Italy.

Dr Algeri presented these results during the Presidential Symposium at the 22nd Congress of the European Hematology Association (EHA) as abstract S146.

The research was sponsored by Bellicum Pharmaceuticals, Inc., the company developing BPX-501.

About BPX-501

BPX-501 consists of genetically modified donor T cells incorporating the CaspaCIDe safety switch, which is designed to eliminate the T cells in the event of toxicity.

Rimiducid is used to activate the CaspaCIDe safety switch, which consists of the CID-binding domain coupled to the signaling domain of caspase-9, an enzyme that is part of the apoptotic pathway.

The goal of this therapy is to allow physicians to more safely perform haplo-HSCTs.

Patients

Dr Algeri and his colleagues have tested BPX-501 in 98 pediatric patients treated at centers in Europe and the US.

Fifty-nine patients had non-malignant conditions, including primary immune deficiency (n=26), thalassemia major (n=8), sickle cell disease (n=5), Diamond-Blackfan anemia (n=2), Swachman-Diamond syndrome (n=1), Fanconi anemia (n=9), hemophagocytic lymphohistiocytosis (n=6), aplastic anemia (n=1), and osteoporosis (n=1).

Thirty-nine patients had malignant conditions, including acute lymphoblastic leukemia (ALL, n=21), acute myeloid leukemia (AML, n=14), myelodysplastic syndromes (MDS, n=3), and non-Hodgkin lymphoma (NHL, n=1).

The patients received BPX-501 after an alpha/beta T-cell-depleted haplo-HSCT. All patients had at least 6 months of follow-up.

Overall results

Ninety-five percent of the patients engrafted (93/98), and the researchers said they observed rapid recovery of T cells, B cells, and immunoglobulins.

At 180 days, the incidence of transplant-related mortality was 5%, and there were no cases of post-transplant lymphoproliferative disorder.

The cumulative incidence of grade 2-4 acute GVHD was 14%. For patients with at least 1 year of follow-up, the cumulative incidence of chronic GVHD at 1 year was 3%.

Eleven patients received rimiducid—10 who had uncontrollable acute GVHD and 1 who developed late acute GVHD. In all of these patients, GVHD resolved and has not recurred.

There were no adverse events associated with BPX-501 or rimiducid.

European cohort

Dr Algeri presented more detailed data on the 61 patients treated at centers in Europe.

Fifteen of these patients had ALL, 10 had AML, 16 had primary immune deficiency, 7 had thalassemia major, 1 had sickle cell disease, 2 had Diamond-Blackfan anemia, 5 had Fanconi anemia, 4 had hemophagocytic lymphohistiocytosis, and 1 had osteoporosis.

Their median age was 4.8 (range, 0.25-17), and 56% were male. The patients received busulfan-based conditioning (41%), total body irradiation (36%), treosulfan-based conditioning (18%), and other conditioning (5%).

Ninety-five percent of the patients had a parent donor, and the other 5% had a sibling donor. The median donor age was 36 (range, 19-50).

The patients’ median time to neutrophil recovery was 15 days (range, 9-75), and their median time to platelet recovery was 10 days (range, 4-64). Their median time to discharge was 25 days (range, 14-122).

The cumulative incidence of acute grade 2-4 GVHD was 9.9%, and the cumulative incidence of acute grade 3-4 GVHD was 3.3%.

There were no cases of transplant-related mortality at 180 days and no cases of extensive chronic GVHD.

“These preliminary data compare favorably to previously published data on matched, unrelated donor transplantation,” Dr Algeri said. “And for this reason, an observational matched, unrelated donor study is being initiated to enable comparison of the safety and efficacy of haploidentical transplantation and BPX-501 infusion to the standard of care for patients without a matched sibling donor.”

Photo by Chad McNeeley

MADRID—Updated results of a phase 1/2 study suggest the T-cell product BPX-501 lowers the risks associated with haploidentical hematopoietic stem cell transplant (haplo-HSCT).

In this ongoing study, researchers are testing BPX-501 in pediatric patients undergoing haplo-HSCT to treat a range of hematologic disorders.

Patients treated thus far have experienced rapid engraftment and early hospital discharge, a low rate of acute graft-versus-host disease (GHVD), no extensive chronic GVHD, and a low rate of transplant-related mortality at 180 days.

“The combination of haploidentical transplantation and BPX-501 infusion is an effective strategy for children in need of an allograft lacking a compatible donor,” said study investigator Mattia Algeri, MD, of Ospedale Pediatrico Bambino Gesù in Rome, Italy.

Dr Algeri presented these results during the Presidential Symposium at the 22nd Congress of the European Hematology Association (EHA) as abstract S146.

The research was sponsored by Bellicum Pharmaceuticals, Inc., the company developing BPX-501.

About BPX-501

BPX-501 consists of genetically modified donor T cells incorporating the CaspaCIDe safety switch, which is designed to eliminate the T cells in the event of toxicity.

Rimiducid is used to activate the CaspaCIDe safety switch, which consists of the CID-binding domain coupled to the signaling domain of caspase-9, an enzyme that is part of the apoptotic pathway.

The goal of this therapy is to allow physicians to more safely perform haplo-HSCTs.

Patients

Dr Algeri and his colleagues have tested BPX-501 in 98 pediatric patients treated at centers in Europe and the US.

Fifty-nine patients had non-malignant conditions, including primary immune deficiency (n=26), thalassemia major (n=8), sickle cell disease (n=5), Diamond-Blackfan anemia (n=2), Swachman-Diamond syndrome (n=1), Fanconi anemia (n=9), hemophagocytic lymphohistiocytosis (n=6), aplastic anemia (n=1), and osteoporosis (n=1).

Thirty-nine patients had malignant conditions, including acute lymphoblastic leukemia (ALL, n=21), acute myeloid leukemia (AML, n=14), myelodysplastic syndromes (MDS, n=3), and non-Hodgkin lymphoma (NHL, n=1).

The patients received BPX-501 after an alpha/beta T-cell-depleted haplo-HSCT. All patients had at least 6 months of follow-up.

Overall results

Ninety-five percent of the patients engrafted (93/98), and the researchers said they observed rapid recovery of T cells, B cells, and immunoglobulins.

At 180 days, the incidence of transplant-related mortality was 5%, and there were no cases of post-transplant lymphoproliferative disorder.

The cumulative incidence of grade 2-4 acute GVHD was 14%. For patients with at least 1 year of follow-up, the cumulative incidence of chronic GVHD at 1 year was 3%.

Eleven patients received rimiducid—10 who had uncontrollable acute GVHD and 1 who developed late acute GVHD. In all of these patients, GVHD resolved and has not recurred.

There were no adverse events associated with BPX-501 or rimiducid.

European cohort

Dr Algeri presented more detailed data on the 61 patients treated at centers in Europe.

Fifteen of these patients had ALL, 10 had AML, 16 had primary immune deficiency, 7 had thalassemia major, 1 had sickle cell disease, 2 had Diamond-Blackfan anemia, 5 had Fanconi anemia, 4 had hemophagocytic lymphohistiocytosis, and 1 had osteoporosis.

Their median age was 4.8 (range, 0.25-17), and 56% were male. The patients received busulfan-based conditioning (41%), total body irradiation (36%), treosulfan-based conditioning (18%), and other conditioning (5%).

Ninety-five percent of the patients had a parent donor, and the other 5% had a sibling donor. The median donor age was 36 (range, 19-50).

The patients’ median time to neutrophil recovery was 15 days (range, 9-75), and their median time to platelet recovery was 10 days (range, 4-64). Their median time to discharge was 25 days (range, 14-122).

The cumulative incidence of acute grade 2-4 GVHD was 9.9%, and the cumulative incidence of acute grade 3-4 GVHD was 3.3%.

There were no cases of transplant-related mortality at 180 days and no cases of extensive chronic GVHD.

“These preliminary data compare favorably to previously published data on matched, unrelated donor transplantation,” Dr Algeri said. “And for this reason, an observational matched, unrelated donor study is being initiated to enable comparison of the safety and efficacy of haploidentical transplantation and BPX-501 infusion to the standard of care for patients without a matched sibling donor.”