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FDA approves first oral drug for NSCLC with EGFR Exon 20 insertion
The drug is limited to use in patients whose disease has progressed on or after platinum-based chemotherapy and who have had the EGFR Exon 20 insertion mutation detected on an FDA-approved test.
Mobocertinib is the first oral tyrosine kinase inhibitor (TKI) specifically designed to target these mutations, which are less common than the more predominant EGFR mutations in this lung cancer.
“EGFR Exon 20 insertion+ NSCLC is an underserved cancer that we have been unable to target effectively with traditional EGFR TKIs,” said Pasi Jänne, MD, PhD, of the Dana Farber Cancer Institute, Boston, in a press statement from the maker, Takeda.
“The approval of [mobocertinib] marks another important step forward that provides physicians and their patients with a new targeted oral therapy specifically designed for this patient population that has shown clinically meaningful and sustained responses,” Dr. Jänne added.
According to the company, EGFR Exon 20 insertion+ NSCLC makes up approximately 1%-2% of patients with NSCLC and is more common in Asian populations compared with Western populations.
The new approval is based on overall response rate (ORR) and duration of response (DoR) results from a phase 1/2 trial consisting of 114 patients with EGFR Exon 20 insertion+ NSCLC who received prior platinum-based therapy and were treated with the 160-mg dose.
Per an independent review committee, mobocertinib demonstrated a confirmed ORR of 28% and a median DoR of 17.5 months.
Median overall survival was 24 months and median progression-free survival was 7.3 months.
The FDA-approved next-generation sequencing (NGS) companion diagnostic for mobocertinib is Thermo Fisher Scientific’s Oncomine Dx Target Test, which identifies NSCLC patients with EGFR Exon 20 insertions.
“NGS testing is critical for these patients, as it can enable more accurate diagnoses compared to polymerase chain reaction (PCR) testing, which detects less than 50% of EGFR Exon 20 insertions,” according to the company.
Results from the phase 1/2 trial used in the FDA approval were presented at the 2021 American Society of Clinical Oncology Annual Meeting.
The most common adverse reactions (greater than 20%) were diarrhea, rash, nausea, stomatitis, vomiting, decreased appetite, paronychia, fatigue, dry skin, and musculoskeletal pain, according to the company.
The prescribing information includes a boxed warning for QTc prolongation and Torsades de Pointes, and warnings and precautions for interstitial lung disease/pneumonitis, cardiac toxicity, and diarrhea.
“Patients with EGFR Exon 20 insertion+ NSCLC have historically faced a unique set of challenges living with a very rare lung cancer that is not only underdiagnosed but also lacking targeted treatment options that can improve response rates,” said Marcia Horn, executive director, Exon 20 Group at the International Cancer Advocacy Network, in the press statement.
The FDA review was conducted under Project Orbis, an FDA initiative that enables concurrent submission and review of oncology products among international partners.
The new drug was also granted priority review and received breakthrough therapy, fast track, and orphan drug designations from the FDA.
A version of this article first appeared on Medscape.com.
The drug is limited to use in patients whose disease has progressed on or after platinum-based chemotherapy and who have had the EGFR Exon 20 insertion mutation detected on an FDA-approved test.
Mobocertinib is the first oral tyrosine kinase inhibitor (TKI) specifically designed to target these mutations, which are less common than the more predominant EGFR mutations in this lung cancer.
“EGFR Exon 20 insertion+ NSCLC is an underserved cancer that we have been unable to target effectively with traditional EGFR TKIs,” said Pasi Jänne, MD, PhD, of the Dana Farber Cancer Institute, Boston, in a press statement from the maker, Takeda.
“The approval of [mobocertinib] marks another important step forward that provides physicians and their patients with a new targeted oral therapy specifically designed for this patient population that has shown clinically meaningful and sustained responses,” Dr. Jänne added.
According to the company, EGFR Exon 20 insertion+ NSCLC makes up approximately 1%-2% of patients with NSCLC and is more common in Asian populations compared with Western populations.
The new approval is based on overall response rate (ORR) and duration of response (DoR) results from a phase 1/2 trial consisting of 114 patients with EGFR Exon 20 insertion+ NSCLC who received prior platinum-based therapy and were treated with the 160-mg dose.
Per an independent review committee, mobocertinib demonstrated a confirmed ORR of 28% and a median DoR of 17.5 months.
Median overall survival was 24 months and median progression-free survival was 7.3 months.
The FDA-approved next-generation sequencing (NGS) companion diagnostic for mobocertinib is Thermo Fisher Scientific’s Oncomine Dx Target Test, which identifies NSCLC patients with EGFR Exon 20 insertions.
“NGS testing is critical for these patients, as it can enable more accurate diagnoses compared to polymerase chain reaction (PCR) testing, which detects less than 50% of EGFR Exon 20 insertions,” according to the company.
Results from the phase 1/2 trial used in the FDA approval were presented at the 2021 American Society of Clinical Oncology Annual Meeting.
The most common adverse reactions (greater than 20%) were diarrhea, rash, nausea, stomatitis, vomiting, decreased appetite, paronychia, fatigue, dry skin, and musculoskeletal pain, according to the company.
The prescribing information includes a boxed warning for QTc prolongation and Torsades de Pointes, and warnings and precautions for interstitial lung disease/pneumonitis, cardiac toxicity, and diarrhea.
“Patients with EGFR Exon 20 insertion+ NSCLC have historically faced a unique set of challenges living with a very rare lung cancer that is not only underdiagnosed but also lacking targeted treatment options that can improve response rates,” said Marcia Horn, executive director, Exon 20 Group at the International Cancer Advocacy Network, in the press statement.
The FDA review was conducted under Project Orbis, an FDA initiative that enables concurrent submission and review of oncology products among international partners.
The new drug was also granted priority review and received breakthrough therapy, fast track, and orphan drug designations from the FDA.
A version of this article first appeared on Medscape.com.
The drug is limited to use in patients whose disease has progressed on or after platinum-based chemotherapy and who have had the EGFR Exon 20 insertion mutation detected on an FDA-approved test.
Mobocertinib is the first oral tyrosine kinase inhibitor (TKI) specifically designed to target these mutations, which are less common than the more predominant EGFR mutations in this lung cancer.
“EGFR Exon 20 insertion+ NSCLC is an underserved cancer that we have been unable to target effectively with traditional EGFR TKIs,” said Pasi Jänne, MD, PhD, of the Dana Farber Cancer Institute, Boston, in a press statement from the maker, Takeda.
“The approval of [mobocertinib] marks another important step forward that provides physicians and their patients with a new targeted oral therapy specifically designed for this patient population that has shown clinically meaningful and sustained responses,” Dr. Jänne added.
According to the company, EGFR Exon 20 insertion+ NSCLC makes up approximately 1%-2% of patients with NSCLC and is more common in Asian populations compared with Western populations.
The new approval is based on overall response rate (ORR) and duration of response (DoR) results from a phase 1/2 trial consisting of 114 patients with EGFR Exon 20 insertion+ NSCLC who received prior platinum-based therapy and were treated with the 160-mg dose.
Per an independent review committee, mobocertinib demonstrated a confirmed ORR of 28% and a median DoR of 17.5 months.
Median overall survival was 24 months and median progression-free survival was 7.3 months.
The FDA-approved next-generation sequencing (NGS) companion diagnostic for mobocertinib is Thermo Fisher Scientific’s Oncomine Dx Target Test, which identifies NSCLC patients with EGFR Exon 20 insertions.
“NGS testing is critical for these patients, as it can enable more accurate diagnoses compared to polymerase chain reaction (PCR) testing, which detects less than 50% of EGFR Exon 20 insertions,” according to the company.
Results from the phase 1/2 trial used in the FDA approval were presented at the 2021 American Society of Clinical Oncology Annual Meeting.
The most common adverse reactions (greater than 20%) were diarrhea, rash, nausea, stomatitis, vomiting, decreased appetite, paronychia, fatigue, dry skin, and musculoskeletal pain, according to the company.
The prescribing information includes a boxed warning for QTc prolongation and Torsades de Pointes, and warnings and precautions for interstitial lung disease/pneumonitis, cardiac toxicity, and diarrhea.
“Patients with EGFR Exon 20 insertion+ NSCLC have historically faced a unique set of challenges living with a very rare lung cancer that is not only underdiagnosed but also lacking targeted treatment options that can improve response rates,” said Marcia Horn, executive director, Exon 20 Group at the International Cancer Advocacy Network, in the press statement.
The FDA review was conducted under Project Orbis, an FDA initiative that enables concurrent submission and review of oncology products among international partners.
The new drug was also granted priority review and received breakthrough therapy, fast track, and orphan drug designations from the FDA.
A version of this article first appeared on Medscape.com.
Immunotherapy for cancer patients with poor PS needs a rethink
The findings have prompted an expert to argue against the use of immunotherapy for such patients, who may have little time left and very little chance of benefiting.
“It is quite clear from clinical practice that most patients with limited PS do very poorly and do not benefit from immune check point inhibitors (ICI),” Jason Luke, MD, UPMC Hillman Cancer Center and the University of Pittsburgh, said in an email.
“So, my strong opinion is that patients should not be getting an immunotherapy just because it might not cause as many side effects as chemotherapy,” he added.
“Instead of giving an immunotherapy with little chance of success, patients and families deserve to have a direct conversation about what realistic expectations [might be] and how we as the oncology community can support them to achieve whatever their personal goals are in the time that they have left,” he emphasized.
Dr. Luke was the lead author of an editorial in which he commented on the study. Both the study and the editorial were published online in JCO Oncology Practice.
Variety of cancers
The study was conducted by Mridula Krishnan, MD, Nebraska Medicine Fred and Pamela Buffett Cancer Center, Omaha, Nebraska, and colleagues.
The team reviewed 257 patients who had been treated with either a programmed cell death protein–1 inhibitor or programmed cell death–ligand-1 inhibitor for a variety of advanced cancers. The drugs included pembrolizumab (Keytruda), nivolumab (Opdivo), atezolizumab (Tecentique), durvalumab (Imfinzi), and avelumab (Bavencio).
Most of the patients (71%) had good PS, with an Eastern Cooperative Oncology Group (ECOG) PS of 0-1 on initiation of immunotherapy; 29% of patients had poor PS, with an ECOG PS of greater than or equal to 2.
“The primary outcome was OS stratified by ECOG PS 0-1 versus ≥2,” note the authors. Across all tumor types, OS was superior for patients in the ECOG 0-1 PS group, the investigators note. The median OS was 12.6 months, compared with only 3.1 months for patients in the ECOG greater than or equal to 2 group (P < .001).
Moreover, overall response rates for patients with a poor PS were low. Only 8%, or 6 of 75 patients with an ECOG PS of greater than or equal to 2, achieved an objective response by RECIST criteria.
This compared to an overall response rate of 23% for patients with an ECOG PS of 0-1, the investigators note (P = .005).
Interestingly, the hospice referral rate for patients with a poor PS (67%) was similar to that of patients with a PS of 1-2 (61.9%), Dr. Krishnan and colleagues observe.
Those with a poor PS were more like to die in-hospital (28.6%) than were patients with a good PS (15.1%; P = .035). The authors point out that it is well known that outcomes with chemotherapy are worse among patients who experience a decline in functional reserve, owing to increased susceptibility to toxicity and complications.
“Regardless of age, patients with ECOG PS >2 usually have poor tolerability to chemotherapy, and this correlates with worse survival outcome,” they emphasize. There is as yet no clear guidance regarding the impact of PS on ICI treatment response, although “there should be,” Dr. Luke believes.
“In a patient with declining performance status, especially ECOG PS 3-4 but potentially 2 as well, there is little likelihood that the functional and immune reserve of the patient will be adequate to mount a robust antitumor response,” he elaborated.
“It’s not impossible, but trying for it should not come at the expense of engaging about end-of-life care and maximizing the palliative opportunities that many only have a short window of time in which to pursue,” he added.
Again, Dr. Luke strongly believes that just giving an ICI without engaging in a frank conversation with the patient and their families – which happens all too often, he feels – is absolutely not the way to go when treating patients with a poor PS and little time left.
“Patients and families might be better served by having a more direct and frank conversation about what the likelihood [is] that ICI therapy will actually do,” Dr. Luke stressed.
In their editorial, Dr. Luke and colleagues write: “Overall, we as an oncology community need to improve our communication with patients regarding goals of care and end-of-life considerations as opposed to reflexive treatment initiation,” he writes.
“Our duty, first and foremost, should focus on the person sitting in front of us – taking a step back may be the best way to move forward with compassionate care,” they add.
The authors and editorialists have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The findings have prompted an expert to argue against the use of immunotherapy for such patients, who may have little time left and very little chance of benefiting.
“It is quite clear from clinical practice that most patients with limited PS do very poorly and do not benefit from immune check point inhibitors (ICI),” Jason Luke, MD, UPMC Hillman Cancer Center and the University of Pittsburgh, said in an email.
“So, my strong opinion is that patients should not be getting an immunotherapy just because it might not cause as many side effects as chemotherapy,” he added.
“Instead of giving an immunotherapy with little chance of success, patients and families deserve to have a direct conversation about what realistic expectations [might be] and how we as the oncology community can support them to achieve whatever their personal goals are in the time that they have left,” he emphasized.
Dr. Luke was the lead author of an editorial in which he commented on the study. Both the study and the editorial were published online in JCO Oncology Practice.
Variety of cancers
The study was conducted by Mridula Krishnan, MD, Nebraska Medicine Fred and Pamela Buffett Cancer Center, Omaha, Nebraska, and colleagues.
The team reviewed 257 patients who had been treated with either a programmed cell death protein–1 inhibitor or programmed cell death–ligand-1 inhibitor for a variety of advanced cancers. The drugs included pembrolizumab (Keytruda), nivolumab (Opdivo), atezolizumab (Tecentique), durvalumab (Imfinzi), and avelumab (Bavencio).
Most of the patients (71%) had good PS, with an Eastern Cooperative Oncology Group (ECOG) PS of 0-1 on initiation of immunotherapy; 29% of patients had poor PS, with an ECOG PS of greater than or equal to 2.
“The primary outcome was OS stratified by ECOG PS 0-1 versus ≥2,” note the authors. Across all tumor types, OS was superior for patients in the ECOG 0-1 PS group, the investigators note. The median OS was 12.6 months, compared with only 3.1 months for patients in the ECOG greater than or equal to 2 group (P < .001).
Moreover, overall response rates for patients with a poor PS were low. Only 8%, or 6 of 75 patients with an ECOG PS of greater than or equal to 2, achieved an objective response by RECIST criteria.
This compared to an overall response rate of 23% for patients with an ECOG PS of 0-1, the investigators note (P = .005).
Interestingly, the hospice referral rate for patients with a poor PS (67%) was similar to that of patients with a PS of 1-2 (61.9%), Dr. Krishnan and colleagues observe.
Those with a poor PS were more like to die in-hospital (28.6%) than were patients with a good PS (15.1%; P = .035). The authors point out that it is well known that outcomes with chemotherapy are worse among patients who experience a decline in functional reserve, owing to increased susceptibility to toxicity and complications.
“Regardless of age, patients with ECOG PS >2 usually have poor tolerability to chemotherapy, and this correlates with worse survival outcome,” they emphasize. There is as yet no clear guidance regarding the impact of PS on ICI treatment response, although “there should be,” Dr. Luke believes.
“In a patient with declining performance status, especially ECOG PS 3-4 but potentially 2 as well, there is little likelihood that the functional and immune reserve of the patient will be adequate to mount a robust antitumor response,” he elaborated.
“It’s not impossible, but trying for it should not come at the expense of engaging about end-of-life care and maximizing the palliative opportunities that many only have a short window of time in which to pursue,” he added.
Again, Dr. Luke strongly believes that just giving an ICI without engaging in a frank conversation with the patient and their families – which happens all too often, he feels – is absolutely not the way to go when treating patients with a poor PS and little time left.
“Patients and families might be better served by having a more direct and frank conversation about what the likelihood [is] that ICI therapy will actually do,” Dr. Luke stressed.
In their editorial, Dr. Luke and colleagues write: “Overall, we as an oncology community need to improve our communication with patients regarding goals of care and end-of-life considerations as opposed to reflexive treatment initiation,” he writes.
“Our duty, first and foremost, should focus on the person sitting in front of us – taking a step back may be the best way to move forward with compassionate care,” they add.
The authors and editorialists have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The findings have prompted an expert to argue against the use of immunotherapy for such patients, who may have little time left and very little chance of benefiting.
“It is quite clear from clinical practice that most patients with limited PS do very poorly and do not benefit from immune check point inhibitors (ICI),” Jason Luke, MD, UPMC Hillman Cancer Center and the University of Pittsburgh, said in an email.
“So, my strong opinion is that patients should not be getting an immunotherapy just because it might not cause as many side effects as chemotherapy,” he added.
“Instead of giving an immunotherapy with little chance of success, patients and families deserve to have a direct conversation about what realistic expectations [might be] and how we as the oncology community can support them to achieve whatever their personal goals are in the time that they have left,” he emphasized.
Dr. Luke was the lead author of an editorial in which he commented on the study. Both the study and the editorial were published online in JCO Oncology Practice.
Variety of cancers
The study was conducted by Mridula Krishnan, MD, Nebraska Medicine Fred and Pamela Buffett Cancer Center, Omaha, Nebraska, and colleagues.
The team reviewed 257 patients who had been treated with either a programmed cell death protein–1 inhibitor or programmed cell death–ligand-1 inhibitor for a variety of advanced cancers. The drugs included pembrolizumab (Keytruda), nivolumab (Opdivo), atezolizumab (Tecentique), durvalumab (Imfinzi), and avelumab (Bavencio).
Most of the patients (71%) had good PS, with an Eastern Cooperative Oncology Group (ECOG) PS of 0-1 on initiation of immunotherapy; 29% of patients had poor PS, with an ECOG PS of greater than or equal to 2.
“The primary outcome was OS stratified by ECOG PS 0-1 versus ≥2,” note the authors. Across all tumor types, OS was superior for patients in the ECOG 0-1 PS group, the investigators note. The median OS was 12.6 months, compared with only 3.1 months for patients in the ECOG greater than or equal to 2 group (P < .001).
Moreover, overall response rates for patients with a poor PS were low. Only 8%, or 6 of 75 patients with an ECOG PS of greater than or equal to 2, achieved an objective response by RECIST criteria.
This compared to an overall response rate of 23% for patients with an ECOG PS of 0-1, the investigators note (P = .005).
Interestingly, the hospice referral rate for patients with a poor PS (67%) was similar to that of patients with a PS of 1-2 (61.9%), Dr. Krishnan and colleagues observe.
Those with a poor PS were more like to die in-hospital (28.6%) than were patients with a good PS (15.1%; P = .035). The authors point out that it is well known that outcomes with chemotherapy are worse among patients who experience a decline in functional reserve, owing to increased susceptibility to toxicity and complications.
“Regardless of age, patients with ECOG PS >2 usually have poor tolerability to chemotherapy, and this correlates with worse survival outcome,” they emphasize. There is as yet no clear guidance regarding the impact of PS on ICI treatment response, although “there should be,” Dr. Luke believes.
“In a patient with declining performance status, especially ECOG PS 3-4 but potentially 2 as well, there is little likelihood that the functional and immune reserve of the patient will be adequate to mount a robust antitumor response,” he elaborated.
“It’s not impossible, but trying for it should not come at the expense of engaging about end-of-life care and maximizing the palliative opportunities that many only have a short window of time in which to pursue,” he added.
Again, Dr. Luke strongly believes that just giving an ICI without engaging in a frank conversation with the patient and their families – which happens all too often, he feels – is absolutely not the way to go when treating patients with a poor PS and little time left.
“Patients and families might be better served by having a more direct and frank conversation about what the likelihood [is] that ICI therapy will actually do,” Dr. Luke stressed.
In their editorial, Dr. Luke and colleagues write: “Overall, we as an oncology community need to improve our communication with patients regarding goals of care and end-of-life considerations as opposed to reflexive treatment initiation,” he writes.
“Our duty, first and foremost, should focus on the person sitting in front of us – taking a step back may be the best way to move forward with compassionate care,” they add.
The authors and editorialists have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Antibiotic use and colon cancer: More evidence of link
The latest data come from a Swedish population study. Investigators analyzed data from more than 40,000 colorectal cancer patients and 200,000 cancer-free control persons.
They found that moderate use of antibiotics increased the risk for proximal colon cancer by 9% and that very high antibiotic use increased the risk by 17%.
In contrast, the risk for rectal cancer was reduced by 4% with moderate use and 9% with very high use, but this association was confined to women.
Antibiotic use was categorized as no use (no reported use of antibiotics during the study period), low (use during a period of 1-10 days), moderate (11-60 days), high (61-180 days), and very high (>180 days).
The study, led by Sophia Harlid, PhD, department of radiation sciences, oncology, Umeå University, Sweden, was published online on Sept. 1 in the Journal of the National Cancer Institute.
The results complement findings from a recent study from Scotland, which found that a history of antibiotic use among individuals younger than 50 appeared to increase the risk of developing colon cancer but not rectal cancer by 49%.
The new data from Sweden “strengthen prior evidence and provide new insights into site-specific carcinogenesis as well as indirect support for the role of gut microbiota,” lead author Dr. Dr. Harlid commented in an interview.
“The positive associations between antibiotics use and proximal colon cancer began at the lowest level of antibiotics use, providing a potential justification for reducing antibiotics prescriptions in clinical practice,” she added.
In their article, the team suggests that the increased risk could be a result of antibiotics having a “disruptive effect” on the gut microbiome.
The finding of an increased risk for cancer in the proximal colon but not further along the alimentary tract “is consistent with a high microbial impact in the proximal colon and a decreasing concentration of short-chain fatty acids along the colon,” the authors comment.
This results “in higher bacterial activity, biofilm formation, and fermentation in the proximal compared with the distal colon and rectum.”
A further analysis showed that the use of quinolones and sulfonamides and/or trimethoprims was associated with an increased risk for proximal colon cancer, whereas use of nitrofurantoins, macrolides and/or lincosamides, and metronidazoles and/or tinidazoles was inversely associated with rectal cancer.
Details of the study findings
For their study, the team analyzed complete-population data from Swedish national registers for the period July 1, 2005 to Dec. 31, 2016.
They matched case patients who were diagnosed with colorectal cancer from Jan. 1, 2010 to Dec. 31, 2016 with cancer-free control persons in a 1:5 ratio. Data on antibiotic use were extracted from the Swedish Prescribed Drug Register.
Other variables, such as socioeconomic factors and health care utilization, were obtained from the Swedish Inpatient Register and the Longitudinal Integration Database for Health Insurance and Labor Market Studies.
The team identified 40,545 patients with colorectal cancer cases; there were 202,720 control persons. Just over half (52.9%) of the participants were men; the mean age at cancer diagnosis was 72 years. Among the cases, 36.4% were proximal colon cancers, 29.3% were distal colon cancers, and 33.0% rectal cancers.
Control patients were more likely to have been prescribed no antibiotics, at 22.4% versus 18.7% for case patients. Case patients were more likely than control persons to have used antibiotics for more than 2 months, at 20.8% versus 19.3% (P < .001).
Overall, antibiotic use was positively associated with colorectal cancer. In comparison with no use, the odds ratio for moderate use was 1.15; for very high use, it was 1.17 (P < .001 for trend).
Excluding all antibiotic use during the 2 years prior to a colorectal cancer diagnosis attenuated the association, such that it was no longer significant for very high use versus no antibiotic use.
Applying this cutoff to the remaining analyses, the team found that the dose-response relationship between antibiotic use and colorectal cancer was largely confined to proximal colon cancer, at an odds ratio of 1.09 for moderate use and 1.17 for very high use in comparison with no use (P < .001 for trend).
For distal colon cancer, the relationship was “close to null.”
There was a slight inverse relationship between rectal cancer and antibiotic use, at an odds rate of 0.96 for moderate use and 0.91 for very high use versus no use (P < .001 for trend). This association was found in women only, whereas the other associations were seen in both men and women.
The study was supported by the Lion’s Cancer Research Foundation, Umeå University, and Region Västerbotten. Dr. Harlid has disclosed no relevant financial relationships. Three coauthors report various relationships with industry, as noted in the original article.
A version of this article first appeared on Medscape.com.
The latest data come from a Swedish population study. Investigators analyzed data from more than 40,000 colorectal cancer patients and 200,000 cancer-free control persons.
They found that moderate use of antibiotics increased the risk for proximal colon cancer by 9% and that very high antibiotic use increased the risk by 17%.
In contrast, the risk for rectal cancer was reduced by 4% with moderate use and 9% with very high use, but this association was confined to women.
Antibiotic use was categorized as no use (no reported use of antibiotics during the study period), low (use during a period of 1-10 days), moderate (11-60 days), high (61-180 days), and very high (>180 days).
The study, led by Sophia Harlid, PhD, department of radiation sciences, oncology, Umeå University, Sweden, was published online on Sept. 1 in the Journal of the National Cancer Institute.
The results complement findings from a recent study from Scotland, which found that a history of antibiotic use among individuals younger than 50 appeared to increase the risk of developing colon cancer but not rectal cancer by 49%.
The new data from Sweden “strengthen prior evidence and provide new insights into site-specific carcinogenesis as well as indirect support for the role of gut microbiota,” lead author Dr. Dr. Harlid commented in an interview.
“The positive associations between antibiotics use and proximal colon cancer began at the lowest level of antibiotics use, providing a potential justification for reducing antibiotics prescriptions in clinical practice,” she added.
In their article, the team suggests that the increased risk could be a result of antibiotics having a “disruptive effect” on the gut microbiome.
The finding of an increased risk for cancer in the proximal colon but not further along the alimentary tract “is consistent with a high microbial impact in the proximal colon and a decreasing concentration of short-chain fatty acids along the colon,” the authors comment.
This results “in higher bacterial activity, biofilm formation, and fermentation in the proximal compared with the distal colon and rectum.”
A further analysis showed that the use of quinolones and sulfonamides and/or trimethoprims was associated with an increased risk for proximal colon cancer, whereas use of nitrofurantoins, macrolides and/or lincosamides, and metronidazoles and/or tinidazoles was inversely associated with rectal cancer.
Details of the study findings
For their study, the team analyzed complete-population data from Swedish national registers for the period July 1, 2005 to Dec. 31, 2016.
They matched case patients who were diagnosed with colorectal cancer from Jan. 1, 2010 to Dec. 31, 2016 with cancer-free control persons in a 1:5 ratio. Data on antibiotic use were extracted from the Swedish Prescribed Drug Register.
Other variables, such as socioeconomic factors and health care utilization, were obtained from the Swedish Inpatient Register and the Longitudinal Integration Database for Health Insurance and Labor Market Studies.
The team identified 40,545 patients with colorectal cancer cases; there were 202,720 control persons. Just over half (52.9%) of the participants were men; the mean age at cancer diagnosis was 72 years. Among the cases, 36.4% were proximal colon cancers, 29.3% were distal colon cancers, and 33.0% rectal cancers.
Control patients were more likely to have been prescribed no antibiotics, at 22.4% versus 18.7% for case patients. Case patients were more likely than control persons to have used antibiotics for more than 2 months, at 20.8% versus 19.3% (P < .001).
Overall, antibiotic use was positively associated with colorectal cancer. In comparison with no use, the odds ratio for moderate use was 1.15; for very high use, it was 1.17 (P < .001 for trend).
Excluding all antibiotic use during the 2 years prior to a colorectal cancer diagnosis attenuated the association, such that it was no longer significant for very high use versus no antibiotic use.
Applying this cutoff to the remaining analyses, the team found that the dose-response relationship between antibiotic use and colorectal cancer was largely confined to proximal colon cancer, at an odds ratio of 1.09 for moderate use and 1.17 for very high use in comparison with no use (P < .001 for trend).
For distal colon cancer, the relationship was “close to null.”
There was a slight inverse relationship between rectal cancer and antibiotic use, at an odds rate of 0.96 for moderate use and 0.91 for very high use versus no use (P < .001 for trend). This association was found in women only, whereas the other associations were seen in both men and women.
The study was supported by the Lion’s Cancer Research Foundation, Umeå University, and Region Västerbotten. Dr. Harlid has disclosed no relevant financial relationships. Three coauthors report various relationships with industry, as noted in the original article.
A version of this article first appeared on Medscape.com.
The latest data come from a Swedish population study. Investigators analyzed data from more than 40,000 colorectal cancer patients and 200,000 cancer-free control persons.
They found that moderate use of antibiotics increased the risk for proximal colon cancer by 9% and that very high antibiotic use increased the risk by 17%.
In contrast, the risk for rectal cancer was reduced by 4% with moderate use and 9% with very high use, but this association was confined to women.
Antibiotic use was categorized as no use (no reported use of antibiotics during the study period), low (use during a period of 1-10 days), moderate (11-60 days), high (61-180 days), and very high (>180 days).
The study, led by Sophia Harlid, PhD, department of radiation sciences, oncology, Umeå University, Sweden, was published online on Sept. 1 in the Journal of the National Cancer Institute.
The results complement findings from a recent study from Scotland, which found that a history of antibiotic use among individuals younger than 50 appeared to increase the risk of developing colon cancer but not rectal cancer by 49%.
The new data from Sweden “strengthen prior evidence and provide new insights into site-specific carcinogenesis as well as indirect support for the role of gut microbiota,” lead author Dr. Dr. Harlid commented in an interview.
“The positive associations between antibiotics use and proximal colon cancer began at the lowest level of antibiotics use, providing a potential justification for reducing antibiotics prescriptions in clinical practice,” she added.
In their article, the team suggests that the increased risk could be a result of antibiotics having a “disruptive effect” on the gut microbiome.
The finding of an increased risk for cancer in the proximal colon but not further along the alimentary tract “is consistent with a high microbial impact in the proximal colon and a decreasing concentration of short-chain fatty acids along the colon,” the authors comment.
This results “in higher bacterial activity, biofilm formation, and fermentation in the proximal compared with the distal colon and rectum.”
A further analysis showed that the use of quinolones and sulfonamides and/or trimethoprims was associated with an increased risk for proximal colon cancer, whereas use of nitrofurantoins, macrolides and/or lincosamides, and metronidazoles and/or tinidazoles was inversely associated with rectal cancer.
Details of the study findings
For their study, the team analyzed complete-population data from Swedish national registers for the period July 1, 2005 to Dec. 31, 2016.
They matched case patients who were diagnosed with colorectal cancer from Jan. 1, 2010 to Dec. 31, 2016 with cancer-free control persons in a 1:5 ratio. Data on antibiotic use were extracted from the Swedish Prescribed Drug Register.
Other variables, such as socioeconomic factors and health care utilization, were obtained from the Swedish Inpatient Register and the Longitudinal Integration Database for Health Insurance and Labor Market Studies.
The team identified 40,545 patients with colorectal cancer cases; there were 202,720 control persons. Just over half (52.9%) of the participants were men; the mean age at cancer diagnosis was 72 years. Among the cases, 36.4% were proximal colon cancers, 29.3% were distal colon cancers, and 33.0% rectal cancers.
Control patients were more likely to have been prescribed no antibiotics, at 22.4% versus 18.7% for case patients. Case patients were more likely than control persons to have used antibiotics for more than 2 months, at 20.8% versus 19.3% (P < .001).
Overall, antibiotic use was positively associated with colorectal cancer. In comparison with no use, the odds ratio for moderate use was 1.15; for very high use, it was 1.17 (P < .001 for trend).
Excluding all antibiotic use during the 2 years prior to a colorectal cancer diagnosis attenuated the association, such that it was no longer significant for very high use versus no antibiotic use.
Applying this cutoff to the remaining analyses, the team found that the dose-response relationship between antibiotic use and colorectal cancer was largely confined to proximal colon cancer, at an odds ratio of 1.09 for moderate use and 1.17 for very high use in comparison with no use (P < .001 for trend).
For distal colon cancer, the relationship was “close to null.”
There was a slight inverse relationship between rectal cancer and antibiotic use, at an odds rate of 0.96 for moderate use and 0.91 for very high use versus no use (P < .001 for trend). This association was found in women only, whereas the other associations were seen in both men and women.
The study was supported by the Lion’s Cancer Research Foundation, Umeå University, and Region Västerbotten. Dr. Harlid has disclosed no relevant financial relationships. Three coauthors report various relationships with industry, as noted in the original article.
A version of this article first appeared on Medscape.com.
Pandemic strategies to boost trial enrollment should stay
Although enrollment into lung cancer clinical trials fell during the early months of the COVID-19 pandemic, it increased after a number of mitigation strategies were introduced.
These strategies should now be maintained, say experts, in order to improve enrollment and access to trials and to ensure that trials are more pragmatic and streamlined.
These were the findings from a survey sent to 173 sites of clinical trials in 45 countries around the world. The findings were presented recently at the World Conference on Lung Cancer (WCLC) 2021. The meeting and the survey were organized by the International Association for the Study of Lung Cancer (IASLC).
Responses to the survey revealed that enrollment into lung cancer trials fell by 43% during the early months of the pandemic. Patients stopped attending clinics, and some trials were suspended.
Patients were less willing to visit clinical trial sites, and lockdown restrictions made travel difficult.
Organizers of clinical trials responded by implementing mitigation strategies, such as changing monitoring requirements, increasing use of telehealth, and using local non-study facilities for laboratory and radiology services.
These measures led to an increase in trial enrollment toward the end of 2020, the survey results show.
“The COVID-19 pandemic created many challenges [that led to] reductions in lung cancer clinical trial enrollment,” commented study presenter Matthew P. Smeltzer, PhD, from the Division of Epidemiology, Biostatistics, and Environmental Health, University of Memphis.
The employment of mitigation strategies allowed the removal of “barriers,” and although the pandemic “worsened, trial enrollment began to improve due in part to these strategies,” Dr. Smeltzer said.
Many of these measures were successful and should be maintained, he suggested. Strategies include allowing telehealth visits, performing testing at local laboratories, using local radiology services, mailing experimental agents “where possible,” and allowing flexibility in trial schedules.
This is a “very important” study, commented Marina Garassino, MD, professor of medicine, hematology, and oncology, the University of Chicago Medicine, in her discussion of the abstract.
Irrespective of the pandemic, the regulation and the bureaucracy of clinical trials hinder participation by patients and physicians, she said.
Many of the mitigation strategies highlighted by the survey were similar to recommendations on the conduct of clinical trials published by the American Society of Clinical Oncology during the pandemic. Those recommendations emphasize the use of telehealth and offsite strategies to help with patient monitoring, she noted.
The findings from the survey show that it is possible to conduct more “streamlined and pragmatic trials,” she said.
“More flexible approaches should be approved by the sponsors of clinical trials and global regulatory bodies,” she added.
However, she expressed concern that “with the telehealth visits, we can create some disparities.”
“We have to remember that lung cancer patients are sometimes a very old population, and they are not digitally evolved,” she commented.
Commenting on Twitter, Jennifer C. King, PhD, chief scientific officer at the GO2 Foundation for Lung Cancer, in Washington, D.C., agreed that many of the mitigation strategies identified in the study “are good for patients all of the time, not just during a pandemic.”
Impact on lung cancer clinical trials
The survey, which included 64 questions, was intended to assess the impact of the COVID pandemic on lung cancer clinical trials.
Most of the survey responses came from sites in Europe (37.6%); 21.4% came from Asia, 13.3% came from the United States, and 7.5% came from Canada.
The team found that enrollment into lung cancer trials declined by 43% in 2020 compared to 2019, at an incidence rate ratio of 0.57 (P = .0115).
The largest decreases in enrollment were between April and August 2020, Dr. Smeltzer noted. However, in the last quarter of 2020 (October to December), the differences in enrollment were significantly smaller (P = .0160), despite a marked increase in global COVID-19 cases per month, he added.
The most common challenges faced by clinical trial sites during the pandemic were the following: There were fewer eligible patients (cited by 67% of respondents); compliance protocol was worse (61%); trials were suspended (60%); there was a lack of research staff (48%); and there were institutional closures (39%).
Regarding patient-related challenges, 67% of sites cited less willingness to visit the site. Other challenges included less ability to travel (cited by 60%), reduced access to the trial site (52%), quarantining because of exposure to COVID-19 (40%), and SARS-CoV-2 infection (26%).
Concerns of patients included the following: Fear of SARS-CoV-2 infection, which was cited by 83%; travel restrictions (47%); securing transportation (38%); and access to the laboratory/radiology services (14%).
“Patient willingness to visit the site was a consistent barrier reported across Europe, the U.S., and Canada,” said Dr. Smeltzer, although the effect was smaller in North America, he added.
Regarding mitigation strategies that were employed during the pandemic to combat the challenges and concerns, the team found that the most common measure was the modification of monitoring requirements, used by 44% of sites.
This was followed by the use of telehealth visits (43% sites), the use of laboratories at non-study facilities ( 27%), and alterations to the number of required visits (25%).
Other mitigation strategies included use of mail-order medications, (24%), using radiology services at a non-study site (20%), and altering the trial schedules (19%).
The most effective mitigation strategies were felt to be those that allowed flexibility with respect to location. These measures included use of remote monitoring, remote diagnostics, telehealth visits, and modified symptom monitoring.
Effective strategies that increased flexibility in time were delayed visits, delayed assessments, and changes to the Institutional Review Board.
The study was funded by the IASLC, which received industry support to conduct the project. Dr. Smeltzer reported no relevant financial relationships. Dr. Garassino has relationships with AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Eli Lilly, Ignyta, Incyte, MedImmune, Mirati, MSD International, Novartis, Pfizer, Regeneron, Roche, Takeda, and Seattle Genetics.
A version of this article first appeared on Medscape.com.
Although enrollment into lung cancer clinical trials fell during the early months of the COVID-19 pandemic, it increased after a number of mitigation strategies were introduced.
These strategies should now be maintained, say experts, in order to improve enrollment and access to trials and to ensure that trials are more pragmatic and streamlined.
These were the findings from a survey sent to 173 sites of clinical trials in 45 countries around the world. The findings were presented recently at the World Conference on Lung Cancer (WCLC) 2021. The meeting and the survey were organized by the International Association for the Study of Lung Cancer (IASLC).
Responses to the survey revealed that enrollment into lung cancer trials fell by 43% during the early months of the pandemic. Patients stopped attending clinics, and some trials were suspended.
Patients were less willing to visit clinical trial sites, and lockdown restrictions made travel difficult.
Organizers of clinical trials responded by implementing mitigation strategies, such as changing monitoring requirements, increasing use of telehealth, and using local non-study facilities for laboratory and radiology services.
These measures led to an increase in trial enrollment toward the end of 2020, the survey results show.
“The COVID-19 pandemic created many challenges [that led to] reductions in lung cancer clinical trial enrollment,” commented study presenter Matthew P. Smeltzer, PhD, from the Division of Epidemiology, Biostatistics, and Environmental Health, University of Memphis.
The employment of mitigation strategies allowed the removal of “barriers,” and although the pandemic “worsened, trial enrollment began to improve due in part to these strategies,” Dr. Smeltzer said.
Many of these measures were successful and should be maintained, he suggested. Strategies include allowing telehealth visits, performing testing at local laboratories, using local radiology services, mailing experimental agents “where possible,” and allowing flexibility in trial schedules.
This is a “very important” study, commented Marina Garassino, MD, professor of medicine, hematology, and oncology, the University of Chicago Medicine, in her discussion of the abstract.
Irrespective of the pandemic, the regulation and the bureaucracy of clinical trials hinder participation by patients and physicians, she said.
Many of the mitigation strategies highlighted by the survey were similar to recommendations on the conduct of clinical trials published by the American Society of Clinical Oncology during the pandemic. Those recommendations emphasize the use of telehealth and offsite strategies to help with patient monitoring, she noted.
The findings from the survey show that it is possible to conduct more “streamlined and pragmatic trials,” she said.
“More flexible approaches should be approved by the sponsors of clinical trials and global regulatory bodies,” she added.
However, she expressed concern that “with the telehealth visits, we can create some disparities.”
“We have to remember that lung cancer patients are sometimes a very old population, and they are not digitally evolved,” she commented.
Commenting on Twitter, Jennifer C. King, PhD, chief scientific officer at the GO2 Foundation for Lung Cancer, in Washington, D.C., agreed that many of the mitigation strategies identified in the study “are good for patients all of the time, not just during a pandemic.”
Impact on lung cancer clinical trials
The survey, which included 64 questions, was intended to assess the impact of the COVID pandemic on lung cancer clinical trials.
Most of the survey responses came from sites in Europe (37.6%); 21.4% came from Asia, 13.3% came from the United States, and 7.5% came from Canada.
The team found that enrollment into lung cancer trials declined by 43% in 2020 compared to 2019, at an incidence rate ratio of 0.57 (P = .0115).
The largest decreases in enrollment were between April and August 2020, Dr. Smeltzer noted. However, in the last quarter of 2020 (October to December), the differences in enrollment were significantly smaller (P = .0160), despite a marked increase in global COVID-19 cases per month, he added.
The most common challenges faced by clinical trial sites during the pandemic were the following: There were fewer eligible patients (cited by 67% of respondents); compliance protocol was worse (61%); trials were suspended (60%); there was a lack of research staff (48%); and there were institutional closures (39%).
Regarding patient-related challenges, 67% of sites cited less willingness to visit the site. Other challenges included less ability to travel (cited by 60%), reduced access to the trial site (52%), quarantining because of exposure to COVID-19 (40%), and SARS-CoV-2 infection (26%).
Concerns of patients included the following: Fear of SARS-CoV-2 infection, which was cited by 83%; travel restrictions (47%); securing transportation (38%); and access to the laboratory/radiology services (14%).
“Patient willingness to visit the site was a consistent barrier reported across Europe, the U.S., and Canada,” said Dr. Smeltzer, although the effect was smaller in North America, he added.
Regarding mitigation strategies that were employed during the pandemic to combat the challenges and concerns, the team found that the most common measure was the modification of monitoring requirements, used by 44% of sites.
This was followed by the use of telehealth visits (43% sites), the use of laboratories at non-study facilities ( 27%), and alterations to the number of required visits (25%).
Other mitigation strategies included use of mail-order medications, (24%), using radiology services at a non-study site (20%), and altering the trial schedules (19%).
The most effective mitigation strategies were felt to be those that allowed flexibility with respect to location. These measures included use of remote monitoring, remote diagnostics, telehealth visits, and modified symptom monitoring.
Effective strategies that increased flexibility in time were delayed visits, delayed assessments, and changes to the Institutional Review Board.
The study was funded by the IASLC, which received industry support to conduct the project. Dr. Smeltzer reported no relevant financial relationships. Dr. Garassino has relationships with AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Eli Lilly, Ignyta, Incyte, MedImmune, Mirati, MSD International, Novartis, Pfizer, Regeneron, Roche, Takeda, and Seattle Genetics.
A version of this article first appeared on Medscape.com.
Although enrollment into lung cancer clinical trials fell during the early months of the COVID-19 pandemic, it increased after a number of mitigation strategies were introduced.
These strategies should now be maintained, say experts, in order to improve enrollment and access to trials and to ensure that trials are more pragmatic and streamlined.
These were the findings from a survey sent to 173 sites of clinical trials in 45 countries around the world. The findings were presented recently at the World Conference on Lung Cancer (WCLC) 2021. The meeting and the survey were organized by the International Association for the Study of Lung Cancer (IASLC).
Responses to the survey revealed that enrollment into lung cancer trials fell by 43% during the early months of the pandemic. Patients stopped attending clinics, and some trials were suspended.
Patients were less willing to visit clinical trial sites, and lockdown restrictions made travel difficult.
Organizers of clinical trials responded by implementing mitigation strategies, such as changing monitoring requirements, increasing use of telehealth, and using local non-study facilities for laboratory and radiology services.
These measures led to an increase in trial enrollment toward the end of 2020, the survey results show.
“The COVID-19 pandemic created many challenges [that led to] reductions in lung cancer clinical trial enrollment,” commented study presenter Matthew P. Smeltzer, PhD, from the Division of Epidemiology, Biostatistics, and Environmental Health, University of Memphis.
The employment of mitigation strategies allowed the removal of “barriers,” and although the pandemic “worsened, trial enrollment began to improve due in part to these strategies,” Dr. Smeltzer said.
Many of these measures were successful and should be maintained, he suggested. Strategies include allowing telehealth visits, performing testing at local laboratories, using local radiology services, mailing experimental agents “where possible,” and allowing flexibility in trial schedules.
This is a “very important” study, commented Marina Garassino, MD, professor of medicine, hematology, and oncology, the University of Chicago Medicine, in her discussion of the abstract.
Irrespective of the pandemic, the regulation and the bureaucracy of clinical trials hinder participation by patients and physicians, she said.
Many of the mitigation strategies highlighted by the survey were similar to recommendations on the conduct of clinical trials published by the American Society of Clinical Oncology during the pandemic. Those recommendations emphasize the use of telehealth and offsite strategies to help with patient monitoring, she noted.
The findings from the survey show that it is possible to conduct more “streamlined and pragmatic trials,” she said.
“More flexible approaches should be approved by the sponsors of clinical trials and global regulatory bodies,” she added.
However, she expressed concern that “with the telehealth visits, we can create some disparities.”
“We have to remember that lung cancer patients are sometimes a very old population, and they are not digitally evolved,” she commented.
Commenting on Twitter, Jennifer C. King, PhD, chief scientific officer at the GO2 Foundation for Lung Cancer, in Washington, D.C., agreed that many of the mitigation strategies identified in the study “are good for patients all of the time, not just during a pandemic.”
Impact on lung cancer clinical trials
The survey, which included 64 questions, was intended to assess the impact of the COVID pandemic on lung cancer clinical trials.
Most of the survey responses came from sites in Europe (37.6%); 21.4% came from Asia, 13.3% came from the United States, and 7.5% came from Canada.
The team found that enrollment into lung cancer trials declined by 43% in 2020 compared to 2019, at an incidence rate ratio of 0.57 (P = .0115).
The largest decreases in enrollment were between April and August 2020, Dr. Smeltzer noted. However, in the last quarter of 2020 (October to December), the differences in enrollment were significantly smaller (P = .0160), despite a marked increase in global COVID-19 cases per month, he added.
The most common challenges faced by clinical trial sites during the pandemic were the following: There were fewer eligible patients (cited by 67% of respondents); compliance protocol was worse (61%); trials were suspended (60%); there was a lack of research staff (48%); and there were institutional closures (39%).
Regarding patient-related challenges, 67% of sites cited less willingness to visit the site. Other challenges included less ability to travel (cited by 60%), reduced access to the trial site (52%), quarantining because of exposure to COVID-19 (40%), and SARS-CoV-2 infection (26%).
Concerns of patients included the following: Fear of SARS-CoV-2 infection, which was cited by 83%; travel restrictions (47%); securing transportation (38%); and access to the laboratory/radiology services (14%).
“Patient willingness to visit the site was a consistent barrier reported across Europe, the U.S., and Canada,” said Dr. Smeltzer, although the effect was smaller in North America, he added.
Regarding mitigation strategies that were employed during the pandemic to combat the challenges and concerns, the team found that the most common measure was the modification of monitoring requirements, used by 44% of sites.
This was followed by the use of telehealth visits (43% sites), the use of laboratories at non-study facilities ( 27%), and alterations to the number of required visits (25%).
Other mitigation strategies included use of mail-order medications, (24%), using radiology services at a non-study site (20%), and altering the trial schedules (19%).
The most effective mitigation strategies were felt to be those that allowed flexibility with respect to location. These measures included use of remote monitoring, remote diagnostics, telehealth visits, and modified symptom monitoring.
Effective strategies that increased flexibility in time were delayed visits, delayed assessments, and changes to the Institutional Review Board.
The study was funded by the IASLC, which received industry support to conduct the project. Dr. Smeltzer reported no relevant financial relationships. Dr. Garassino has relationships with AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Eli Lilly, Ignyta, Incyte, MedImmune, Mirati, MSD International, Novartis, Pfizer, Regeneron, Roche, Takeda, and Seattle Genetics.
A version of this article first appeared on Medscape.com.
Old saying about prostate cancer not true when it’s metastatic
.
The findings fill an information gap because, remarkably, “data are lacking” on causes of death among men whose prostate cancer has spread to other sites, say lead author Ahmed Elmehrath, MD, of Cairo University, Egypt, and colleagues.
“It was an important realization by our team that prostate cancer was the cause of death in 78% of patients,” said senior author Omar Alhalabi, MD, of University of Texas MD Anderson Cancer Center, Houston, in an email.
“Most patients with metastatic prostate cancer die from it, rather than other possible causes of death,” confirm Samuel Merriel, MSc, Tanimola Martins, PhD, and Sarah Bailey, PhD, University of Exeter, United Kingdom, in an accompanying editorial. The study was published last month in JAMA Network Open.
The findings represent the near opposite of a commonly held – and comforting – belief about early-stage disease: “You die with prostate cancer, not from it.”
That old saying is articulated in various ways, such as this from the Prostate Cancer Foundation: “We can confirm that there are those prostate cancers a man may die with and not of, while others are very aggressive.” The American Cancer Society says this: “Prostate cancer can be a serious disease, but most men diagnosed with prostate cancer do not die from it.”
However, these commonplace comments do not cover metastatic disease, which is what the authors of the new study decided to focus on.
The team used data from the Surveillance, Epidemiology, and End Results Program (SEER) database to gather a sample of 26,168 U.S. men who received a diagnosis of metastatic prostate cancer from January 2000 to December 2016. They then analyzed the data in 2020 and found that 16,732 men (64%) had died during the follow-up period.
The majority of these deaths (77.8%) were from prostate cancer, 5.5% were from other cancers, and 16.7% were from noncancer causes, including cardiovascular diseases, chronic obstructive pulmonary disease, and cerebrovascular diseases.
Senior author Dr. Alhalabi acknowledged a limitation in these findings – that the SEER database relies on causes of death extracted from death certificates. “Death certificates have limited granularity in terms of the details they can contain about the cause of death and also have reporting bias,” he said.
Most of the prostate cancer deaths (59%) occurred within 2 years. The 5-year overall survival rate in the study group was 26%.
The deadliness of metastatic disease “reinforces the need for innovations to promote early-stage diagnosis,” comment the editorialists. Striking a hopeful note, they also say that “new tests for prostate cancer detection may reduce the proportion of patients who receive a diagnosis at a late stage.”
Death from other causes
The mean age at metastatic prostate cancer diagnosis in the study was roughly 71 years. Most of the cohort was White (74.5%) and had a diagnosis of stage M1b metastatic prostate cancer (72.7%), which means the cancer had spread to the bones.
Among men in the cohort, the rates of death from septicemia, suicide, accidents, COPD, and cerebrovascular diseases were significantly increased compared with the general U.S. male population, the team observes.
Thus, the study authors were concerned with not only with death from metastatic prostate cancer but death from other causes.
That concern is rooted in the established fact that there is now improved survival among patients with prostate cancer in the U.S., including among men with advanced disease. “Patients tend to live long enough after a prostate cancer diagnosis for non–cancer-related comorbidities to be associated with their overall survival,” they write.
The editorialists agree: Prostate cancer “has a high long-term survival rate compared with almost all other cancer types and signals the need for greater holistic care for patients.”
As noted above, cardiovascular diseases were the most common cause of nonprostate cancer–related deaths in the new study.
As in the management of other cancers, there is concern among clinicians and researchers about the cardiotoxic effects of prostate cancer treatments.
The study authors point to a 2017 analysis that showed that men with prostate cancer and no prior cardiac disease had greater risk of heart failure after taking androgen deprivation therapy (ADT), a common treatment used when the disease recurs after definitive treatment. Another study suggested an association between cardiotoxic effects of ADT and myocardial infarction regardless of medical history in general.
The authors of the current study say that such findings highlight “the importance of multidisciplinary care for such patients and the role of primary care physicians in optimizing cardiovascular risk prevention and providing early referrals to cardiologists.”
Further, the team says that tailoring “ADT to each patient’s needs may be associated with improved survival, especially for patients with factors associated with cardiovascular disease.”
Who should lead the way in multidisciplinary care? “The answer probably is case-by-case,” said Dr. Alhalabi, adding that it might depend on the presence of underlying morbidities such as cardiovascular disease and COPD.
“It is also important for the oncologist (‘the gatekeeper’) to try to mitigate the potential metabolic effects of hormonal deprivation therapy such as weight gain, decreased muscle mass, hyperlipidemia, etc.,” he added.
The study had no specific funding. The study authors and editorialists have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
.
The findings fill an information gap because, remarkably, “data are lacking” on causes of death among men whose prostate cancer has spread to other sites, say lead author Ahmed Elmehrath, MD, of Cairo University, Egypt, and colleagues.
“It was an important realization by our team that prostate cancer was the cause of death in 78% of patients,” said senior author Omar Alhalabi, MD, of University of Texas MD Anderson Cancer Center, Houston, in an email.
“Most patients with metastatic prostate cancer die from it, rather than other possible causes of death,” confirm Samuel Merriel, MSc, Tanimola Martins, PhD, and Sarah Bailey, PhD, University of Exeter, United Kingdom, in an accompanying editorial. The study was published last month in JAMA Network Open.
The findings represent the near opposite of a commonly held – and comforting – belief about early-stage disease: “You die with prostate cancer, not from it.”
That old saying is articulated in various ways, such as this from the Prostate Cancer Foundation: “We can confirm that there are those prostate cancers a man may die with and not of, while others are very aggressive.” The American Cancer Society says this: “Prostate cancer can be a serious disease, but most men diagnosed with prostate cancer do not die from it.”
However, these commonplace comments do not cover metastatic disease, which is what the authors of the new study decided to focus on.
The team used data from the Surveillance, Epidemiology, and End Results Program (SEER) database to gather a sample of 26,168 U.S. men who received a diagnosis of metastatic prostate cancer from January 2000 to December 2016. They then analyzed the data in 2020 and found that 16,732 men (64%) had died during the follow-up period.
The majority of these deaths (77.8%) were from prostate cancer, 5.5% were from other cancers, and 16.7% were from noncancer causes, including cardiovascular diseases, chronic obstructive pulmonary disease, and cerebrovascular diseases.
Senior author Dr. Alhalabi acknowledged a limitation in these findings – that the SEER database relies on causes of death extracted from death certificates. “Death certificates have limited granularity in terms of the details they can contain about the cause of death and also have reporting bias,” he said.
Most of the prostate cancer deaths (59%) occurred within 2 years. The 5-year overall survival rate in the study group was 26%.
The deadliness of metastatic disease “reinforces the need for innovations to promote early-stage diagnosis,” comment the editorialists. Striking a hopeful note, they also say that “new tests for prostate cancer detection may reduce the proportion of patients who receive a diagnosis at a late stage.”
Death from other causes
The mean age at metastatic prostate cancer diagnosis in the study was roughly 71 years. Most of the cohort was White (74.5%) and had a diagnosis of stage M1b metastatic prostate cancer (72.7%), which means the cancer had spread to the bones.
Among men in the cohort, the rates of death from septicemia, suicide, accidents, COPD, and cerebrovascular diseases were significantly increased compared with the general U.S. male population, the team observes.
Thus, the study authors were concerned with not only with death from metastatic prostate cancer but death from other causes.
That concern is rooted in the established fact that there is now improved survival among patients with prostate cancer in the U.S., including among men with advanced disease. “Patients tend to live long enough after a prostate cancer diagnosis for non–cancer-related comorbidities to be associated with their overall survival,” they write.
The editorialists agree: Prostate cancer “has a high long-term survival rate compared with almost all other cancer types and signals the need for greater holistic care for patients.”
As noted above, cardiovascular diseases were the most common cause of nonprostate cancer–related deaths in the new study.
As in the management of other cancers, there is concern among clinicians and researchers about the cardiotoxic effects of prostate cancer treatments.
The study authors point to a 2017 analysis that showed that men with prostate cancer and no prior cardiac disease had greater risk of heart failure after taking androgen deprivation therapy (ADT), a common treatment used when the disease recurs after definitive treatment. Another study suggested an association between cardiotoxic effects of ADT and myocardial infarction regardless of medical history in general.
The authors of the current study say that such findings highlight “the importance of multidisciplinary care for such patients and the role of primary care physicians in optimizing cardiovascular risk prevention and providing early referrals to cardiologists.”
Further, the team says that tailoring “ADT to each patient’s needs may be associated with improved survival, especially for patients with factors associated with cardiovascular disease.”
Who should lead the way in multidisciplinary care? “The answer probably is case-by-case,” said Dr. Alhalabi, adding that it might depend on the presence of underlying morbidities such as cardiovascular disease and COPD.
“It is also important for the oncologist (‘the gatekeeper’) to try to mitigate the potential metabolic effects of hormonal deprivation therapy such as weight gain, decreased muscle mass, hyperlipidemia, etc.,” he added.
The study had no specific funding. The study authors and editorialists have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
.
The findings fill an information gap because, remarkably, “data are lacking” on causes of death among men whose prostate cancer has spread to other sites, say lead author Ahmed Elmehrath, MD, of Cairo University, Egypt, and colleagues.
“It was an important realization by our team that prostate cancer was the cause of death in 78% of patients,” said senior author Omar Alhalabi, MD, of University of Texas MD Anderson Cancer Center, Houston, in an email.
“Most patients with metastatic prostate cancer die from it, rather than other possible causes of death,” confirm Samuel Merriel, MSc, Tanimola Martins, PhD, and Sarah Bailey, PhD, University of Exeter, United Kingdom, in an accompanying editorial. The study was published last month in JAMA Network Open.
The findings represent the near opposite of a commonly held – and comforting – belief about early-stage disease: “You die with prostate cancer, not from it.”
That old saying is articulated in various ways, such as this from the Prostate Cancer Foundation: “We can confirm that there are those prostate cancers a man may die with and not of, while others are very aggressive.” The American Cancer Society says this: “Prostate cancer can be a serious disease, but most men diagnosed with prostate cancer do not die from it.”
However, these commonplace comments do not cover metastatic disease, which is what the authors of the new study decided to focus on.
The team used data from the Surveillance, Epidemiology, and End Results Program (SEER) database to gather a sample of 26,168 U.S. men who received a diagnosis of metastatic prostate cancer from January 2000 to December 2016. They then analyzed the data in 2020 and found that 16,732 men (64%) had died during the follow-up period.
The majority of these deaths (77.8%) were from prostate cancer, 5.5% were from other cancers, and 16.7% were from noncancer causes, including cardiovascular diseases, chronic obstructive pulmonary disease, and cerebrovascular diseases.
Senior author Dr. Alhalabi acknowledged a limitation in these findings – that the SEER database relies on causes of death extracted from death certificates. “Death certificates have limited granularity in terms of the details they can contain about the cause of death and also have reporting bias,” he said.
Most of the prostate cancer deaths (59%) occurred within 2 years. The 5-year overall survival rate in the study group was 26%.
The deadliness of metastatic disease “reinforces the need for innovations to promote early-stage diagnosis,” comment the editorialists. Striking a hopeful note, they also say that “new tests for prostate cancer detection may reduce the proportion of patients who receive a diagnosis at a late stage.”
Death from other causes
The mean age at metastatic prostate cancer diagnosis in the study was roughly 71 years. Most of the cohort was White (74.5%) and had a diagnosis of stage M1b metastatic prostate cancer (72.7%), which means the cancer had spread to the bones.
Among men in the cohort, the rates of death from septicemia, suicide, accidents, COPD, and cerebrovascular diseases were significantly increased compared with the general U.S. male population, the team observes.
Thus, the study authors were concerned with not only with death from metastatic prostate cancer but death from other causes.
That concern is rooted in the established fact that there is now improved survival among patients with prostate cancer in the U.S., including among men with advanced disease. “Patients tend to live long enough after a prostate cancer diagnosis for non–cancer-related comorbidities to be associated with their overall survival,” they write.
The editorialists agree: Prostate cancer “has a high long-term survival rate compared with almost all other cancer types and signals the need for greater holistic care for patients.”
As noted above, cardiovascular diseases were the most common cause of nonprostate cancer–related deaths in the new study.
As in the management of other cancers, there is concern among clinicians and researchers about the cardiotoxic effects of prostate cancer treatments.
The study authors point to a 2017 analysis that showed that men with prostate cancer and no prior cardiac disease had greater risk of heart failure after taking androgen deprivation therapy (ADT), a common treatment used when the disease recurs after definitive treatment. Another study suggested an association between cardiotoxic effects of ADT and myocardial infarction regardless of medical history in general.
The authors of the current study say that such findings highlight “the importance of multidisciplinary care for such patients and the role of primary care physicians in optimizing cardiovascular risk prevention and providing early referrals to cardiologists.”
Further, the team says that tailoring “ADT to each patient’s needs may be associated with improved survival, especially for patients with factors associated with cardiovascular disease.”
Who should lead the way in multidisciplinary care? “The answer probably is case-by-case,” said Dr. Alhalabi, adding that it might depend on the presence of underlying morbidities such as cardiovascular disease and COPD.
“It is also important for the oncologist (‘the gatekeeper’) to try to mitigate the potential metabolic effects of hormonal deprivation therapy such as weight gain, decreased muscle mass, hyperlipidemia, etc.,” he added.
The study had no specific funding. The study authors and editorialists have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
‘Dawn of a new era’ in the treatment of renal cell carcinoma
according to expert opinion.
The high hopes have been generated by results from the randomized, phase 3 KEYNOTE-564 trial, showing that monotherapy with pembrolizumab (Keytruda, Merck) was associated with significantly longer disease-free survival (DFS) after nephrectomy than placebo (77.3% vs. 68.1%, respectively). Median follow-up was 24 months.
The results come from the trial’s first interim analysis of data from 994 patients with clear-cell renal cell carcinoma (RCC) at high risk of recurrence.
For the pembrolizumab group, the estimated percentage alive at 24 months was 96.6%, compared with 93.5% in the placebo group (hazard ratio for death, 0.54), said Toni Choueiri, MD, of the Dana-Farber Cancer Institute, Boston, and colleagues.
However, grade 3 or higher adverse events (any cause) occurred at almost twice the rate in the pembrolizumab versus the placebo group (32.4% vs. 17.7%). The new study was published online Aug. 18, 2021, in the New England Journal of Medicine.
The study results were first presented at the 2021 American Society of Clinical Oncology annual meeting and described as likely to be practice changing in this setting, as reported by this news organization.
Currently, this patient population has “no options for adjuvant therapy to reduce the risk of recurrence that have high levels of supporting evidence,” observed the authors.
That’s about to change, as the trial results “herald the dawn of a new era in the treatment of renal cell carcinoma,” Rana McKay, MD, University of California San Diego Health, wrote in an accompanying editorial.
Multiple studies have investigated potential adjuvant therapies in RCC since the 1980s, she observed.
“For the first time, we now have an effective adjuvant immunotherapy option for patients with resected renal cell carcinoma at high risk of recurrence,” Dr. McKay said in an interview.
To date, the lack of clinically beneficial adjuvant therapy options in RCC has been “humbling,” Dr. Choueiri said in an interview. “We hope we can push the envelope further and get more patients with RCC some good options that make them live longer and better.”
Although the standard of care for patients diagnosed with locoregional RCC is partial or total nephrectomy, nearly half of patients eventually experience disease recurrence following surgery, Dr. Choueiri noted.
“No standard, globally approved adjuvant therapy options are currently available for this population,” he said. Clinical guidelines recommend patients at high risk of disease recurrence after surgery be entered into a clinical trial or undergo active surveillance.
Researchers will continue to follow the results for overall survival, a secondary endpoint. “The very early look suggests encouraging results [in overall survival] with an HR of 0.54,” Dr. Choueiri noted.
In the meantime, the prolongation of DFS represents a clear clinical benefit, said Dr. McKay, “given the magnitude of the increase” and “the limited incidence of toxic effects.”
KEYNOTE-564 will alter the adjuvant treatment landscape for RCC as a positive phase 3 trial of adjuvant immunotherapy for the disease, she added.
A number of earlier studies have investigated the use of adjuvant vascular endothelial growth factor–targeting agents in RCC. Only the 2016 Sunitinib Treatment of Renal Adjuvant Cancer (S-TRAC) trial showed improved DFS with sunitinib, compared with placebo (6.8 vs. 5.6 years). Subsequently, sunitinib was approved for adjuvant use in the United States. However, the S-TRAC trial also showed that sunitinib therapy was associated with an increased incidence of toxic effects and lower quality of life scores, and researchers did not observe any benefit in overall survival.
“Despite regulatory approval in the U.S., sunitinib is not approved for adjuvant use by the European Medicines Agency and has limited utilization in clinical practice given the low benefit-risk ratio,” Dr. McKay pointed out.
Study details
KEYNOTE-564 involved 996 patients with clear-cell RCC at high risk for recurrence after nephrectomy, with or without metastasectomy. They were randomly assigned in a 1:1 ratio to receive a 200-mg dose of adjuvant pembrolizumab or placebo given intravenously once every 3 weeks for up to 17 cycles for approximately 1 year.
The vast majority of patients enrolled in the study had localized disease with no evidence of metastases (M0) and intermediate to high or high risk of disease recurrence after partial or complete nephrectomy. However, 5.8% of patients in both the pembrolizumab and placebo groups had M1 NED (metastatic stage 1, no evidence of disease) status after nephrectomy and resection of metastatic lesions. These patients were also at intermediate to high or high risk of recurrence.
The benefit of pembrolizumab, compared with placebo, was maintained in this subgroup, said the investigators. “At this point, we continue to look at the data, but we know that there was a benefit for DFS in the population we included,” said Dr. Choueiri. “When we looked at several subgroups such as PD-L1 status, geography, gender, performance status, M0/M1, all HRs were less than 1 suggesting benefit from pembrolizumab over placebo.”
“Subset analyses by stage are going to be important to determine which group of patients will derive the most benefit,” asserted Dr. McKay. “While those with M1 NED appear to derive benefit with HR for DFS of 0.29, those with M1 NED comprise a small percentage of patient enrolled in the trial.”
Studies exploring tissue- and blood-based biomarkers, including circulating tumor DNA, will be key to identify patients at highest risk for recurrence or adjuvant treatment, Dr. McKay emphasized. “The adoption of adjuvant immune checkpoint inhibitors brings along new questions regarding patient selection, therapeutic use in patients with non–clear-cell renal cell carcinoma, and systemic treatment after recurrence during or after the receipt of adjuvant therapy.”
KEYNOTE-564 was funded by Merck. Multiple study authors including Dr. Choueiri have financial ties to the pharmaceutical industry, including Merck.
A version of this article first appeared on Medscape.com.
according to expert opinion.
The high hopes have been generated by results from the randomized, phase 3 KEYNOTE-564 trial, showing that monotherapy with pembrolizumab (Keytruda, Merck) was associated with significantly longer disease-free survival (DFS) after nephrectomy than placebo (77.3% vs. 68.1%, respectively). Median follow-up was 24 months.
The results come from the trial’s first interim analysis of data from 994 patients with clear-cell renal cell carcinoma (RCC) at high risk of recurrence.
For the pembrolizumab group, the estimated percentage alive at 24 months was 96.6%, compared with 93.5% in the placebo group (hazard ratio for death, 0.54), said Toni Choueiri, MD, of the Dana-Farber Cancer Institute, Boston, and colleagues.
However, grade 3 or higher adverse events (any cause) occurred at almost twice the rate in the pembrolizumab versus the placebo group (32.4% vs. 17.7%). The new study was published online Aug. 18, 2021, in the New England Journal of Medicine.
The study results were first presented at the 2021 American Society of Clinical Oncology annual meeting and described as likely to be practice changing in this setting, as reported by this news organization.
Currently, this patient population has “no options for adjuvant therapy to reduce the risk of recurrence that have high levels of supporting evidence,” observed the authors.
That’s about to change, as the trial results “herald the dawn of a new era in the treatment of renal cell carcinoma,” Rana McKay, MD, University of California San Diego Health, wrote in an accompanying editorial.
Multiple studies have investigated potential adjuvant therapies in RCC since the 1980s, she observed.
“For the first time, we now have an effective adjuvant immunotherapy option for patients with resected renal cell carcinoma at high risk of recurrence,” Dr. McKay said in an interview.
To date, the lack of clinically beneficial adjuvant therapy options in RCC has been “humbling,” Dr. Choueiri said in an interview. “We hope we can push the envelope further and get more patients with RCC some good options that make them live longer and better.”
Although the standard of care for patients diagnosed with locoregional RCC is partial or total nephrectomy, nearly half of patients eventually experience disease recurrence following surgery, Dr. Choueiri noted.
“No standard, globally approved adjuvant therapy options are currently available for this population,” he said. Clinical guidelines recommend patients at high risk of disease recurrence after surgery be entered into a clinical trial or undergo active surveillance.
Researchers will continue to follow the results for overall survival, a secondary endpoint. “The very early look suggests encouraging results [in overall survival] with an HR of 0.54,” Dr. Choueiri noted.
In the meantime, the prolongation of DFS represents a clear clinical benefit, said Dr. McKay, “given the magnitude of the increase” and “the limited incidence of toxic effects.”
KEYNOTE-564 will alter the adjuvant treatment landscape for RCC as a positive phase 3 trial of adjuvant immunotherapy for the disease, she added.
A number of earlier studies have investigated the use of adjuvant vascular endothelial growth factor–targeting agents in RCC. Only the 2016 Sunitinib Treatment of Renal Adjuvant Cancer (S-TRAC) trial showed improved DFS with sunitinib, compared with placebo (6.8 vs. 5.6 years). Subsequently, sunitinib was approved for adjuvant use in the United States. However, the S-TRAC trial also showed that sunitinib therapy was associated with an increased incidence of toxic effects and lower quality of life scores, and researchers did not observe any benefit in overall survival.
“Despite regulatory approval in the U.S., sunitinib is not approved for adjuvant use by the European Medicines Agency and has limited utilization in clinical practice given the low benefit-risk ratio,” Dr. McKay pointed out.
Study details
KEYNOTE-564 involved 996 patients with clear-cell RCC at high risk for recurrence after nephrectomy, with or without metastasectomy. They were randomly assigned in a 1:1 ratio to receive a 200-mg dose of adjuvant pembrolizumab or placebo given intravenously once every 3 weeks for up to 17 cycles for approximately 1 year.
The vast majority of patients enrolled in the study had localized disease with no evidence of metastases (M0) and intermediate to high or high risk of disease recurrence after partial or complete nephrectomy. However, 5.8% of patients in both the pembrolizumab and placebo groups had M1 NED (metastatic stage 1, no evidence of disease) status after nephrectomy and resection of metastatic lesions. These patients were also at intermediate to high or high risk of recurrence.
The benefit of pembrolizumab, compared with placebo, was maintained in this subgroup, said the investigators. “At this point, we continue to look at the data, but we know that there was a benefit for DFS in the population we included,” said Dr. Choueiri. “When we looked at several subgroups such as PD-L1 status, geography, gender, performance status, M0/M1, all HRs were less than 1 suggesting benefit from pembrolizumab over placebo.”
“Subset analyses by stage are going to be important to determine which group of patients will derive the most benefit,” asserted Dr. McKay. “While those with M1 NED appear to derive benefit with HR for DFS of 0.29, those with M1 NED comprise a small percentage of patient enrolled in the trial.”
Studies exploring tissue- and blood-based biomarkers, including circulating tumor DNA, will be key to identify patients at highest risk for recurrence or adjuvant treatment, Dr. McKay emphasized. “The adoption of adjuvant immune checkpoint inhibitors brings along new questions regarding patient selection, therapeutic use in patients with non–clear-cell renal cell carcinoma, and systemic treatment after recurrence during or after the receipt of adjuvant therapy.”
KEYNOTE-564 was funded by Merck. Multiple study authors including Dr. Choueiri have financial ties to the pharmaceutical industry, including Merck.
A version of this article first appeared on Medscape.com.
according to expert opinion.
The high hopes have been generated by results from the randomized, phase 3 KEYNOTE-564 trial, showing that monotherapy with pembrolizumab (Keytruda, Merck) was associated with significantly longer disease-free survival (DFS) after nephrectomy than placebo (77.3% vs. 68.1%, respectively). Median follow-up was 24 months.
The results come from the trial’s first interim analysis of data from 994 patients with clear-cell renal cell carcinoma (RCC) at high risk of recurrence.
For the pembrolizumab group, the estimated percentage alive at 24 months was 96.6%, compared with 93.5% in the placebo group (hazard ratio for death, 0.54), said Toni Choueiri, MD, of the Dana-Farber Cancer Institute, Boston, and colleagues.
However, grade 3 or higher adverse events (any cause) occurred at almost twice the rate in the pembrolizumab versus the placebo group (32.4% vs. 17.7%). The new study was published online Aug. 18, 2021, in the New England Journal of Medicine.
The study results were first presented at the 2021 American Society of Clinical Oncology annual meeting and described as likely to be practice changing in this setting, as reported by this news organization.
Currently, this patient population has “no options for adjuvant therapy to reduce the risk of recurrence that have high levels of supporting evidence,” observed the authors.
That’s about to change, as the trial results “herald the dawn of a new era in the treatment of renal cell carcinoma,” Rana McKay, MD, University of California San Diego Health, wrote in an accompanying editorial.
Multiple studies have investigated potential adjuvant therapies in RCC since the 1980s, she observed.
“For the first time, we now have an effective adjuvant immunotherapy option for patients with resected renal cell carcinoma at high risk of recurrence,” Dr. McKay said in an interview.
To date, the lack of clinically beneficial adjuvant therapy options in RCC has been “humbling,” Dr. Choueiri said in an interview. “We hope we can push the envelope further and get more patients with RCC some good options that make them live longer and better.”
Although the standard of care for patients diagnosed with locoregional RCC is partial or total nephrectomy, nearly half of patients eventually experience disease recurrence following surgery, Dr. Choueiri noted.
“No standard, globally approved adjuvant therapy options are currently available for this population,” he said. Clinical guidelines recommend patients at high risk of disease recurrence after surgery be entered into a clinical trial or undergo active surveillance.
Researchers will continue to follow the results for overall survival, a secondary endpoint. “The very early look suggests encouraging results [in overall survival] with an HR of 0.54,” Dr. Choueiri noted.
In the meantime, the prolongation of DFS represents a clear clinical benefit, said Dr. McKay, “given the magnitude of the increase” and “the limited incidence of toxic effects.”
KEYNOTE-564 will alter the adjuvant treatment landscape for RCC as a positive phase 3 trial of adjuvant immunotherapy for the disease, she added.
A number of earlier studies have investigated the use of adjuvant vascular endothelial growth factor–targeting agents in RCC. Only the 2016 Sunitinib Treatment of Renal Adjuvant Cancer (S-TRAC) trial showed improved DFS with sunitinib, compared with placebo (6.8 vs. 5.6 years). Subsequently, sunitinib was approved for adjuvant use in the United States. However, the S-TRAC trial also showed that sunitinib therapy was associated with an increased incidence of toxic effects and lower quality of life scores, and researchers did not observe any benefit in overall survival.
“Despite regulatory approval in the U.S., sunitinib is not approved for adjuvant use by the European Medicines Agency and has limited utilization in clinical practice given the low benefit-risk ratio,” Dr. McKay pointed out.
Study details
KEYNOTE-564 involved 996 patients with clear-cell RCC at high risk for recurrence after nephrectomy, with or without metastasectomy. They were randomly assigned in a 1:1 ratio to receive a 200-mg dose of adjuvant pembrolizumab or placebo given intravenously once every 3 weeks for up to 17 cycles for approximately 1 year.
The vast majority of patients enrolled in the study had localized disease with no evidence of metastases (M0) and intermediate to high or high risk of disease recurrence after partial or complete nephrectomy. However, 5.8% of patients in both the pembrolizumab and placebo groups had M1 NED (metastatic stage 1, no evidence of disease) status after nephrectomy and resection of metastatic lesions. These patients were also at intermediate to high or high risk of recurrence.
The benefit of pembrolizumab, compared with placebo, was maintained in this subgroup, said the investigators. “At this point, we continue to look at the data, but we know that there was a benefit for DFS in the population we included,” said Dr. Choueiri. “When we looked at several subgroups such as PD-L1 status, geography, gender, performance status, M0/M1, all HRs were less than 1 suggesting benefit from pembrolizumab over placebo.”
“Subset analyses by stage are going to be important to determine which group of patients will derive the most benefit,” asserted Dr. McKay. “While those with M1 NED appear to derive benefit with HR for DFS of 0.29, those with M1 NED comprise a small percentage of patient enrolled in the trial.”
Studies exploring tissue- and blood-based biomarkers, including circulating tumor DNA, will be key to identify patients at highest risk for recurrence or adjuvant treatment, Dr. McKay emphasized. “The adoption of adjuvant immune checkpoint inhibitors brings along new questions regarding patient selection, therapeutic use in patients with non–clear-cell renal cell carcinoma, and systemic treatment after recurrence during or after the receipt of adjuvant therapy.”
KEYNOTE-564 was funded by Merck. Multiple study authors including Dr. Choueiri have financial ties to the pharmaceutical industry, including Merck.
A version of this article first appeared on Medscape.com.
NCCN recommends third COVID-19 dose for patients with cancer
Experts at the National Comprehensive Cancer Network have now issued an updated recommendation for COVID-19 vaccination in people with cancer. The panel calls for these patients to be among the highest-priority group to be vaccinated against COVID-19 and to receive the newly approved third dose of vaccine.
The NCCN has recommended in February that all patients receiving active cancer treatment should receive a COVID-19 vaccine and should be prioritized for vaccination. In August, the FDA authorized a third dose of either the Pfizer or Moderna COVID-19 vaccines for people with compromised immune systems. Those eligible for a third dose include solid organ transplant recipients, those undergoing cancer treatments, and people with autoimmune diseases that suppress their immune systems
The new NCCN recommendations state that the following groups should be considered eligible for a third dose of the mRNA COVID-19 vaccine immediately, based on the latest decisions from the Food and Drug Administration and the Centers for Disease Control and Prevention:
- Patients with solid tumors (either new or recurring) receiving treatment within 1 year of their initial vaccine dose, regardless of their type of cancer therapy.
- Patients with active hematologic malignancies regardless of whether they are currently receiving cancer therapy.
- Anyone who received a stem cell transplant (SCT) or engineered cellular therapy (for example, chimeric antigen receptor T cells), especially within the past 2 years.
- Any recipients of allogeneic SCT on immunosuppressive therapy or with a history of graft-versus-host disease regardless of the time of transplant.
- Anyone with an additional immunosuppressive condition (for example, HIV) or being treated with immunosuppressive agents unrelated to their cancer therapy.
Cancer patients at high risk of complications
As previously reported by this news organization, infection with COVID-19 in people with cancer can severely impact survival. One study published in 2020 found that patients with both COVID-19 infection and progressing cancer had a fivefold increase in the risk of 30-day mortality, compared with COVID-19–positive cancer patients who were in remission or had no evidence of cancer.
Another study found that cancer type, stage, and recent treatment could affect outcomes of COVID-19 in patients with cancer. Patients with hematologic malignancies and metastatic cancers had higher risks of developing severe or critical COVID-19 symptoms, being admitted to the ICU, requiring ventilation, and dying. Conversely, those with nonmetastatic disease had outcomes that were comparable with persons without cancer and a COVID-19 infection. This study also found that having undergone recent surgery or receiving immunotherapy also put patients at a higher risk of poor outcomes, although patients with cancer who were treated with radiotherapy had outcomes similar to those of noncancer COVID-19 patients.
“COVID-19 can be very dangerous, especially for people living with cancer, which is why we’re so grateful for safe and effective vaccines that are saving lives,” Robert W. Carlson, MD, CEO of NCCN, said in a statement.
Right timing and location
The current NCCN update also recommends that individuals wait at least 4 weeks between the second and third doses, and those who are infected with COVID-19 after being vaccinated should wait until they have documented clearance of the virus before receiving a third dose.
It also recommends that people who live in the same household with immunocompromised individuals should also get a third dose once it becomes available, and that it is best to have a third dose of the same type of vaccine as the first two doses. However, a different mRNA vaccine is also acceptable.
Immunocompromised individuals should try to receive their third dose in a health care delivery setting, as opposed to a pharmacy or public vaccination clinic if possible, as it would limit their risk of exposure to the general population.
Steve Pergam, MD, MPH, associate professor, vaccine and infectious disease division, Fred Hutchinson Cancer Research Center, Seattle, commented that it is still necessary to take precautions, even after getting the booster dose.
“That means, even after a third dose of vaccine, we still recommend immunocompromised people, such as those undergoing cancer treatment, continue to be cautious, wear masks, and avoid large group gatherings, particularly around those who are unvaccinated,” said Dr. Pergam, who is also coleader of the NCCN COVID-19 Vaccination Advisory Committee. “All of us should do our part to reduce the spread of COVID-19 and get vaccinated to protect those around us from preventable suffering.”
A version of this article first appeared on Medscape.com.
Experts at the National Comprehensive Cancer Network have now issued an updated recommendation for COVID-19 vaccination in people with cancer. The panel calls for these patients to be among the highest-priority group to be vaccinated against COVID-19 and to receive the newly approved third dose of vaccine.
The NCCN has recommended in February that all patients receiving active cancer treatment should receive a COVID-19 vaccine and should be prioritized for vaccination. In August, the FDA authorized a third dose of either the Pfizer or Moderna COVID-19 vaccines for people with compromised immune systems. Those eligible for a third dose include solid organ transplant recipients, those undergoing cancer treatments, and people with autoimmune diseases that suppress their immune systems
The new NCCN recommendations state that the following groups should be considered eligible for a third dose of the mRNA COVID-19 vaccine immediately, based on the latest decisions from the Food and Drug Administration and the Centers for Disease Control and Prevention:
- Patients with solid tumors (either new or recurring) receiving treatment within 1 year of their initial vaccine dose, regardless of their type of cancer therapy.
- Patients with active hematologic malignancies regardless of whether they are currently receiving cancer therapy.
- Anyone who received a stem cell transplant (SCT) or engineered cellular therapy (for example, chimeric antigen receptor T cells), especially within the past 2 years.
- Any recipients of allogeneic SCT on immunosuppressive therapy or with a history of graft-versus-host disease regardless of the time of transplant.
- Anyone with an additional immunosuppressive condition (for example, HIV) or being treated with immunosuppressive agents unrelated to their cancer therapy.
Cancer patients at high risk of complications
As previously reported by this news organization, infection with COVID-19 in people with cancer can severely impact survival. One study published in 2020 found that patients with both COVID-19 infection and progressing cancer had a fivefold increase in the risk of 30-day mortality, compared with COVID-19–positive cancer patients who were in remission or had no evidence of cancer.
Another study found that cancer type, stage, and recent treatment could affect outcomes of COVID-19 in patients with cancer. Patients with hematologic malignancies and metastatic cancers had higher risks of developing severe or critical COVID-19 symptoms, being admitted to the ICU, requiring ventilation, and dying. Conversely, those with nonmetastatic disease had outcomes that were comparable with persons without cancer and a COVID-19 infection. This study also found that having undergone recent surgery or receiving immunotherapy also put patients at a higher risk of poor outcomes, although patients with cancer who were treated with radiotherapy had outcomes similar to those of noncancer COVID-19 patients.
“COVID-19 can be very dangerous, especially for people living with cancer, which is why we’re so grateful for safe and effective vaccines that are saving lives,” Robert W. Carlson, MD, CEO of NCCN, said in a statement.
Right timing and location
The current NCCN update also recommends that individuals wait at least 4 weeks between the second and third doses, and those who are infected with COVID-19 after being vaccinated should wait until they have documented clearance of the virus before receiving a third dose.
It also recommends that people who live in the same household with immunocompromised individuals should also get a third dose once it becomes available, and that it is best to have a third dose of the same type of vaccine as the first two doses. However, a different mRNA vaccine is also acceptable.
Immunocompromised individuals should try to receive their third dose in a health care delivery setting, as opposed to a pharmacy or public vaccination clinic if possible, as it would limit their risk of exposure to the general population.
Steve Pergam, MD, MPH, associate professor, vaccine and infectious disease division, Fred Hutchinson Cancer Research Center, Seattle, commented that it is still necessary to take precautions, even after getting the booster dose.
“That means, even after a third dose of vaccine, we still recommend immunocompromised people, such as those undergoing cancer treatment, continue to be cautious, wear masks, and avoid large group gatherings, particularly around those who are unvaccinated,” said Dr. Pergam, who is also coleader of the NCCN COVID-19 Vaccination Advisory Committee. “All of us should do our part to reduce the spread of COVID-19 and get vaccinated to protect those around us from preventable suffering.”
A version of this article first appeared on Medscape.com.
Experts at the National Comprehensive Cancer Network have now issued an updated recommendation for COVID-19 vaccination in people with cancer. The panel calls for these patients to be among the highest-priority group to be vaccinated against COVID-19 and to receive the newly approved third dose of vaccine.
The NCCN has recommended in February that all patients receiving active cancer treatment should receive a COVID-19 vaccine and should be prioritized for vaccination. In August, the FDA authorized a third dose of either the Pfizer or Moderna COVID-19 vaccines for people with compromised immune systems. Those eligible for a third dose include solid organ transplant recipients, those undergoing cancer treatments, and people with autoimmune diseases that suppress their immune systems
The new NCCN recommendations state that the following groups should be considered eligible for a third dose of the mRNA COVID-19 vaccine immediately, based on the latest decisions from the Food and Drug Administration and the Centers for Disease Control and Prevention:
- Patients with solid tumors (either new or recurring) receiving treatment within 1 year of their initial vaccine dose, regardless of their type of cancer therapy.
- Patients with active hematologic malignancies regardless of whether they are currently receiving cancer therapy.
- Anyone who received a stem cell transplant (SCT) or engineered cellular therapy (for example, chimeric antigen receptor T cells), especially within the past 2 years.
- Any recipients of allogeneic SCT on immunosuppressive therapy or with a history of graft-versus-host disease regardless of the time of transplant.
- Anyone with an additional immunosuppressive condition (for example, HIV) or being treated with immunosuppressive agents unrelated to their cancer therapy.
Cancer patients at high risk of complications
As previously reported by this news organization, infection with COVID-19 in people with cancer can severely impact survival. One study published in 2020 found that patients with both COVID-19 infection and progressing cancer had a fivefold increase in the risk of 30-day mortality, compared with COVID-19–positive cancer patients who were in remission or had no evidence of cancer.
Another study found that cancer type, stage, and recent treatment could affect outcomes of COVID-19 in patients with cancer. Patients with hematologic malignancies and metastatic cancers had higher risks of developing severe or critical COVID-19 symptoms, being admitted to the ICU, requiring ventilation, and dying. Conversely, those with nonmetastatic disease had outcomes that were comparable with persons without cancer and a COVID-19 infection. This study also found that having undergone recent surgery or receiving immunotherapy also put patients at a higher risk of poor outcomes, although patients with cancer who were treated with radiotherapy had outcomes similar to those of noncancer COVID-19 patients.
“COVID-19 can be very dangerous, especially for people living with cancer, which is why we’re so grateful for safe and effective vaccines that are saving lives,” Robert W. Carlson, MD, CEO of NCCN, said in a statement.
Right timing and location
The current NCCN update also recommends that individuals wait at least 4 weeks between the second and third doses, and those who are infected with COVID-19 after being vaccinated should wait until they have documented clearance of the virus before receiving a third dose.
It also recommends that people who live in the same household with immunocompromised individuals should also get a third dose once it becomes available, and that it is best to have a third dose of the same type of vaccine as the first two doses. However, a different mRNA vaccine is also acceptable.
Immunocompromised individuals should try to receive their third dose in a health care delivery setting, as opposed to a pharmacy or public vaccination clinic if possible, as it would limit their risk of exposure to the general population.
Steve Pergam, MD, MPH, associate professor, vaccine and infectious disease division, Fred Hutchinson Cancer Research Center, Seattle, commented that it is still necessary to take precautions, even after getting the booster dose.
“That means, even after a third dose of vaccine, we still recommend immunocompromised people, such as those undergoing cancer treatment, continue to be cautious, wear masks, and avoid large group gatherings, particularly around those who are unvaccinated,” said Dr. Pergam, who is also coleader of the NCCN COVID-19 Vaccination Advisory Committee. “All of us should do our part to reduce the spread of COVID-19 and get vaccinated to protect those around us from preventable suffering.”
A version of this article first appeared on Medscape.com.
Although inconclusive, CV safety study of cancer therapy attracts attention
The first global trial to compare the cardiovascular (CV) safety of two therapies for prostate cancer proved inconclusive because of inadequate enrollment and events, but the study is a harbinger of growth in the emerging specialty of cardio-oncology, according to experts.
“Many new cancer agents have extended patient survival, yet some of these agents have significant potential cardiovascular toxicity,” said Renato D. Lopes, MD, in presenting a study at the annual congress of the European Society of Cardiology.
In the context of improving survival in patients with or at risk for both cancer and cardiovascular disease, he suggested that the prostate cancer study he led could be “a model for interdisciplinary collaboration” needed to address the relative and sometimes competing risks of these disease states.
This point was seconded by several pioneers in cardio-oncology who participated in the discussion of the results of the trial, called PRONOUNCE.
“We know many drugs in oncology increase cardiovascular risk, so these are the types of trials we need,” according Thomas M. Suter, MD, who leads the cardio-oncology service at the University Hospital, Berne, Switzerland. He was the ESC-invited discussant for PRONOUNCE.
More than 100 centers in 12 countries involved
In PRONOUNCE, 545 patients with prostate cancer and established atherosclerotic cardiovascular disease were randomized to degarelix, a gonadotropin-releasing hormone antagonist, or leuprolide, a GnRH agonist. The patients were enrolled at 113 participating centers in 12 countries. All of the patients had an indication for an androgen-deprivation therapy (ADT).
In numerous previous studies, “ADT has been associated with higher CV morbidity and mortality, particularly in men with preexisting CV disease,” explained Dr. Lopes, but the relative cardiovascular safety of GnRH agonists relative to GnRH antagonists has been “controversial.”
The PRONOUNCE study was designed to resolve this issue, but the study was terminated early because of slow enrollment (not related to the COVID-19 pandemic). The planned enrollment was 900 patients.
In addition, the rate of major adverse cardiovascular events (MACE), defined as myocardial infarction, stroke, or death, was lower over the course of follow-up than anticipated in the study design.
No significant difference on primary endpoint
At the end of 12 months, MACE occurred in 11 (4.1%) of patients randomized to leuprolide and 15 (5.5%) of those randomized to degarelix. The greater hazard ratio for MACE in the degarelix group did not approach statistical significance (hazard ratio, 1.28; P = .53).
As a result, the question of the relative CV safety of these drugs “remains unresolved,” according to Dr. Lopes, professor of medicine at Duke University Medical Center, Durham, N.C.
This does not diminish the need to answer this question. In the addition to the fact that cancer is a malignancy primarily of advancing age when CV disease is prevalent – the mean age in this study was 73 years and 44% were over age 75 – it is often an indolent disease with long periods of survival, according to Dr. Lopes. About half of prostate cancer patients have concomitant CV disease, and about half will receive ADT at some point in their treatment.
In patients receiving ADT, leuprolide is far more commonly used than GnRH antagonists, which are offered in only about 4% of patients, according to data cited by Dr. Lopes. The underlying hypothesis of this study was that leuprolide is associated with greater CV risk, which might have been relevant to a risk-benefit calculation, if the hypothesis had been confirmed.
Cancer drugs can increase CV risk
Based on experimental data, “there is concern the leuprolide is involved in plaque destabilization,” said Dr. Lopes, but he noted that ADTs in general are associated with adverse metabolic changes, including increases in LDL cholesterol, insulin resistance, and body fat, all of which could be relevant to CV risk.
It is the improving rates of survival for prostate cancer as well for other types of cancer that have increased attention to the potential for cancer drugs to increase CV risk, another major cause of early mortality. For these competing risks, objective data are needed to evaluate a relative risk-to-benefit ratio for treatment choices.
This dilemma led the ESC to recently establish its Council on Cardio-Oncology, and many centers around the world are also creating interdisciplinary groups to guide treatment choices for patients with both diseases.
“You will certainly get a lot of referrals,” said Rudolf de Boer, MD, professor of translational cardiology, University Medical Center, Groningen, Netherlands. Basing his remark on his own experience starting a cardio-oncology clinic at his institution, he called this work challenging and agreed that the need for objective data is urgent.
“We need data to provide common ground on which to judge relative risks,” Dr. de Boer said. He also praised the PRONOUNCE investigators for their efforts even if the data failed to answer the question posed.
The PRONOUNCE results were published online in Circulation at the time of Dr. Lopes’s presentation.
The study received funding from Ferring Pharmaceuticals. Dr. Lopes reports financial relationships with Bristol-Myers Squibb, GlaxoSmithKline, Medtronic, Pfizer, and Sanofi. Dr. Suter reports financial relationships with Boehringer Ingelheim, GlaxoSmithKline, and Roche. Dr. de Boer reports financial relationships with AstraZeneca, Abbott, Bristol-Myers Squibb, Novartis, Novo Nordisk, and Roche.
The first global trial to compare the cardiovascular (CV) safety of two therapies for prostate cancer proved inconclusive because of inadequate enrollment and events, but the study is a harbinger of growth in the emerging specialty of cardio-oncology, according to experts.
“Many new cancer agents have extended patient survival, yet some of these agents have significant potential cardiovascular toxicity,” said Renato D. Lopes, MD, in presenting a study at the annual congress of the European Society of Cardiology.
In the context of improving survival in patients with or at risk for both cancer and cardiovascular disease, he suggested that the prostate cancer study he led could be “a model for interdisciplinary collaboration” needed to address the relative and sometimes competing risks of these disease states.
This point was seconded by several pioneers in cardio-oncology who participated in the discussion of the results of the trial, called PRONOUNCE.
“We know many drugs in oncology increase cardiovascular risk, so these are the types of trials we need,” according Thomas M. Suter, MD, who leads the cardio-oncology service at the University Hospital, Berne, Switzerland. He was the ESC-invited discussant for PRONOUNCE.
More than 100 centers in 12 countries involved
In PRONOUNCE, 545 patients with prostate cancer and established atherosclerotic cardiovascular disease were randomized to degarelix, a gonadotropin-releasing hormone antagonist, or leuprolide, a GnRH agonist. The patients were enrolled at 113 participating centers in 12 countries. All of the patients had an indication for an androgen-deprivation therapy (ADT).
In numerous previous studies, “ADT has been associated with higher CV morbidity and mortality, particularly in men with preexisting CV disease,” explained Dr. Lopes, but the relative cardiovascular safety of GnRH agonists relative to GnRH antagonists has been “controversial.”
The PRONOUNCE study was designed to resolve this issue, but the study was terminated early because of slow enrollment (not related to the COVID-19 pandemic). The planned enrollment was 900 patients.
In addition, the rate of major adverse cardiovascular events (MACE), defined as myocardial infarction, stroke, or death, was lower over the course of follow-up than anticipated in the study design.
No significant difference on primary endpoint
At the end of 12 months, MACE occurred in 11 (4.1%) of patients randomized to leuprolide and 15 (5.5%) of those randomized to degarelix. The greater hazard ratio for MACE in the degarelix group did not approach statistical significance (hazard ratio, 1.28; P = .53).
As a result, the question of the relative CV safety of these drugs “remains unresolved,” according to Dr. Lopes, professor of medicine at Duke University Medical Center, Durham, N.C.
This does not diminish the need to answer this question. In the addition to the fact that cancer is a malignancy primarily of advancing age when CV disease is prevalent – the mean age in this study was 73 years and 44% were over age 75 – it is often an indolent disease with long periods of survival, according to Dr. Lopes. About half of prostate cancer patients have concomitant CV disease, and about half will receive ADT at some point in their treatment.
In patients receiving ADT, leuprolide is far more commonly used than GnRH antagonists, which are offered in only about 4% of patients, according to data cited by Dr. Lopes. The underlying hypothesis of this study was that leuprolide is associated with greater CV risk, which might have been relevant to a risk-benefit calculation, if the hypothesis had been confirmed.
Cancer drugs can increase CV risk
Based on experimental data, “there is concern the leuprolide is involved in plaque destabilization,” said Dr. Lopes, but he noted that ADTs in general are associated with adverse metabolic changes, including increases in LDL cholesterol, insulin resistance, and body fat, all of which could be relevant to CV risk.
It is the improving rates of survival for prostate cancer as well for other types of cancer that have increased attention to the potential for cancer drugs to increase CV risk, another major cause of early mortality. For these competing risks, objective data are needed to evaluate a relative risk-to-benefit ratio for treatment choices.
This dilemma led the ESC to recently establish its Council on Cardio-Oncology, and many centers around the world are also creating interdisciplinary groups to guide treatment choices for patients with both diseases.
“You will certainly get a lot of referrals,” said Rudolf de Boer, MD, professor of translational cardiology, University Medical Center, Groningen, Netherlands. Basing his remark on his own experience starting a cardio-oncology clinic at his institution, he called this work challenging and agreed that the need for objective data is urgent.
“We need data to provide common ground on which to judge relative risks,” Dr. de Boer said. He also praised the PRONOUNCE investigators for their efforts even if the data failed to answer the question posed.
The PRONOUNCE results were published online in Circulation at the time of Dr. Lopes’s presentation.
The study received funding from Ferring Pharmaceuticals. Dr. Lopes reports financial relationships with Bristol-Myers Squibb, GlaxoSmithKline, Medtronic, Pfizer, and Sanofi. Dr. Suter reports financial relationships with Boehringer Ingelheim, GlaxoSmithKline, and Roche. Dr. de Boer reports financial relationships with AstraZeneca, Abbott, Bristol-Myers Squibb, Novartis, Novo Nordisk, and Roche.
The first global trial to compare the cardiovascular (CV) safety of two therapies for prostate cancer proved inconclusive because of inadequate enrollment and events, but the study is a harbinger of growth in the emerging specialty of cardio-oncology, according to experts.
“Many new cancer agents have extended patient survival, yet some of these agents have significant potential cardiovascular toxicity,” said Renato D. Lopes, MD, in presenting a study at the annual congress of the European Society of Cardiology.
In the context of improving survival in patients with or at risk for both cancer and cardiovascular disease, he suggested that the prostate cancer study he led could be “a model for interdisciplinary collaboration” needed to address the relative and sometimes competing risks of these disease states.
This point was seconded by several pioneers in cardio-oncology who participated in the discussion of the results of the trial, called PRONOUNCE.
“We know many drugs in oncology increase cardiovascular risk, so these are the types of trials we need,” according Thomas M. Suter, MD, who leads the cardio-oncology service at the University Hospital, Berne, Switzerland. He was the ESC-invited discussant for PRONOUNCE.
More than 100 centers in 12 countries involved
In PRONOUNCE, 545 patients with prostate cancer and established atherosclerotic cardiovascular disease were randomized to degarelix, a gonadotropin-releasing hormone antagonist, or leuprolide, a GnRH agonist. The patients were enrolled at 113 participating centers in 12 countries. All of the patients had an indication for an androgen-deprivation therapy (ADT).
In numerous previous studies, “ADT has been associated with higher CV morbidity and mortality, particularly in men with preexisting CV disease,” explained Dr. Lopes, but the relative cardiovascular safety of GnRH agonists relative to GnRH antagonists has been “controversial.”
The PRONOUNCE study was designed to resolve this issue, but the study was terminated early because of slow enrollment (not related to the COVID-19 pandemic). The planned enrollment was 900 patients.
In addition, the rate of major adverse cardiovascular events (MACE), defined as myocardial infarction, stroke, or death, was lower over the course of follow-up than anticipated in the study design.
No significant difference on primary endpoint
At the end of 12 months, MACE occurred in 11 (4.1%) of patients randomized to leuprolide and 15 (5.5%) of those randomized to degarelix. The greater hazard ratio for MACE in the degarelix group did not approach statistical significance (hazard ratio, 1.28; P = .53).
As a result, the question of the relative CV safety of these drugs “remains unresolved,” according to Dr. Lopes, professor of medicine at Duke University Medical Center, Durham, N.C.
This does not diminish the need to answer this question. In the addition to the fact that cancer is a malignancy primarily of advancing age when CV disease is prevalent – the mean age in this study was 73 years and 44% were over age 75 – it is often an indolent disease with long periods of survival, according to Dr. Lopes. About half of prostate cancer patients have concomitant CV disease, and about half will receive ADT at some point in their treatment.
In patients receiving ADT, leuprolide is far more commonly used than GnRH antagonists, which are offered in only about 4% of patients, according to data cited by Dr. Lopes. The underlying hypothesis of this study was that leuprolide is associated with greater CV risk, which might have been relevant to a risk-benefit calculation, if the hypothesis had been confirmed.
Cancer drugs can increase CV risk
Based on experimental data, “there is concern the leuprolide is involved in plaque destabilization,” said Dr. Lopes, but he noted that ADTs in general are associated with adverse metabolic changes, including increases in LDL cholesterol, insulin resistance, and body fat, all of which could be relevant to CV risk.
It is the improving rates of survival for prostate cancer as well for other types of cancer that have increased attention to the potential for cancer drugs to increase CV risk, another major cause of early mortality. For these competing risks, objective data are needed to evaluate a relative risk-to-benefit ratio for treatment choices.
This dilemma led the ESC to recently establish its Council on Cardio-Oncology, and many centers around the world are also creating interdisciplinary groups to guide treatment choices for patients with both diseases.
“You will certainly get a lot of referrals,” said Rudolf de Boer, MD, professor of translational cardiology, University Medical Center, Groningen, Netherlands. Basing his remark on his own experience starting a cardio-oncology clinic at his institution, he called this work challenging and agreed that the need for objective data is urgent.
“We need data to provide common ground on which to judge relative risks,” Dr. de Boer said. He also praised the PRONOUNCE investigators for their efforts even if the data failed to answer the question posed.
The PRONOUNCE results were published online in Circulation at the time of Dr. Lopes’s presentation.
The study received funding from Ferring Pharmaceuticals. Dr. Lopes reports financial relationships with Bristol-Myers Squibb, GlaxoSmithKline, Medtronic, Pfizer, and Sanofi. Dr. Suter reports financial relationships with Boehringer Ingelheim, GlaxoSmithKline, and Roche. Dr. de Boer reports financial relationships with AstraZeneca, Abbott, Bristol-Myers Squibb, Novartis, Novo Nordisk, and Roche.
FROM ESC 2021
Pandemic-related drops in breast cancer screening hit hardest among medically underserved
Breast cancer screening rates at community health centers (CHCs) in the United States declined during the pandemic, particularly among Black and uninsured individuals, based on a retrospective look at 32 sites.
Still, drops in screening were less dramatic than national declines previously reported, possibly because of the American Cancer Society–directed CHANGE program, which was simultaneously underway at the CHCs involved, reported lead author Stacey A. Fedewa, PhD, senior principal scientist at the ACS in Atlanta, and colleagues.
“This is one of the first studies to examine breast cancer screening rates during the pandemic specifically among clinics providing care to communities of color and lower income populations, a group with lower utilization of and greater barriers to [breast cancer] screening,” the investigators wrote in Cancer. “This is important because these populations have longstanding barriers to accessing care, lower breast screening rates, higher breast cancer mortality rates, and are especially vulnerable to health care disruptions.”
According to a previous analysis of electronic health records by Mast and Munoz del Rio, breast cancer screening rates in the United States dropped 94% in March/April 2020, when the COVID-19 pandemic was declared a national emergency. Although a recent follow-up report showed a rebound in breast cancer screening, the estimated rate remains 13% below average.
The present study evaluated data from 32 out of 1,385 CHCs in the United States. All centers were involved in the ACS-run CHANGE grant program, which funded the clinics for 2 years, during which time they implemented at least three evidence-based provider and client interventions, such as patient navigation or electronic medical record enhancements. The clinics reported breast cancer screening rates on a routine basis throughout the 2-year period, beginning August 2018.
Breast cancer screening rate was defined as the percentage of women aged 50-74 years who had a screening mammogram within the past 27 months, out of a total pool of women who had a medical visit within the past year. For 2018, 2019, and 2020, respectively, 142,207; 142,003; and 150,630 women had a medical visit. Screening rates were compared across years in either June or July. Findings were further characterized by demographic characteristics, urban/rural status, and clinic region.
From 2018 to 2019 breast cancer screening rates rose 18%, from 45.8% to 53.9%. This increase was followed by an 8% decline during the 2019-2020 period, from 53.9% to 49.6%.
The investigators estimated the number of missed mammograms and breast cancer diagnoses for two comparative, hypothetical scenarios: first, if the rising trend from 2018 to 2019 had continued through 2020, and second, if the rate had plateaued at 53.9%.
The rising trend model suggested that 47,517 fewer mammograms than normal were conducted during 2019-2020, resulting in 242 missed breast cancer diagnoses, of which 166 were invasive and 76 were ductal carcinoma in situ. The plateau model suggested that 6,477 fewer mammograms were conducted, leading to 33 missed diagnoses.
Compared with the 8% decline in screening overall, the rate among Black patients dropped 12%, while rates at clinics with a lower proportion of uninsured patients dropped an average of 15%. In contrast, clinics in the South did not have a significant reduction in screening, “possibly reflecting lower baseline rates or impact of stay-at-home orders,” the investigators wrote.
Dr. Fedewa and colleagues also noted that their findings were less dramatic than those reported by Mast and Munoz del Rio. They suggested that the CHANGE program may have softened the blow dealt by the pandemic.
“The CHANGE program–funded interventions – that were established before and continued through 2020 – may have mitigated the pandemic’s effects on breast cancer screening services among the 32 CHCs that were studied,” they wrote. “Further investigation of breast cancer screening rates among additional CHCs will further inform where targeted interventions (e.g., client reminders, education on return to screening) are most needed.”
According to Madeline Sutton, MD, assistant professor of obstetrics and gynecology at Morehouse School of Medicine, Atlanta, “Progress seen with the CHANGE program should be duplicated in other clinical venues based on improvements seen in numbers of mammograms and breast cancers detected.”
Still, Dr. Sutton noted that the racial/ethnic disparities remain cause for concern.
“This study has implications for persons served at CHCs, especially if breast cancer racial/ethnic disparities are unintentionally widened during this pandemic,” Dr. Sutton said in a written comment. “Policy-level changes that decrease BCSR [breast cancer screen rate] gaps for women are warranted.”
Ana Velázquez Mañana, MD, a medical oncology fellow at the University of California, San Francisco, suggested that the effects of the pandemic may have been even more pronounced among medically underserved patients in whom interventions to increase screening were not being conducted, as they were through the CHANGE program.
“One must wonder to what degree these interventions reduced the decline in screening mammography rates observed during the pandemic and to what degree could disparities in screening be magnified in community health centers with less resources,” Dr. Velázquez said in a written comment. “Therefore, understanding barriers to breast cancer screening among our specific health care systems is key to guide resource allocation and the development of evidence-based multilevel interventions that can address these barriers, and ultimately increase screening rates.”
Dr. Velázquez also noted that the study by Dr. Fedewa and colleagues may have missed drops in screening among vulnerable populations that occurred later in the pandemic and in geographic hotspots. In a recent JAMA Network Open study, Dr. Velázquez reported a 41% drop in breast cancer screening at a safety-net hospital in San Francisco during the first stay-at-home order, which lasted from Feb. 1, 2020 to May 31, 2020.
The Breast Health Equity CHANGE grant was funded by the National Football League in partnership with the American Cancer Society. The investigators reported employment by the American Cancer Society. Dr. Wehling and Dr. Wysocki disclosed grants from Pfizer unrelated to this research. Dr. Sutton and Dr. Velázquez disclosed no conflicts of interest.
Breast cancer screening rates at community health centers (CHCs) in the United States declined during the pandemic, particularly among Black and uninsured individuals, based on a retrospective look at 32 sites.
Still, drops in screening were less dramatic than national declines previously reported, possibly because of the American Cancer Society–directed CHANGE program, which was simultaneously underway at the CHCs involved, reported lead author Stacey A. Fedewa, PhD, senior principal scientist at the ACS in Atlanta, and colleagues.
“This is one of the first studies to examine breast cancer screening rates during the pandemic specifically among clinics providing care to communities of color and lower income populations, a group with lower utilization of and greater barriers to [breast cancer] screening,” the investigators wrote in Cancer. “This is important because these populations have longstanding barriers to accessing care, lower breast screening rates, higher breast cancer mortality rates, and are especially vulnerable to health care disruptions.”
According to a previous analysis of electronic health records by Mast and Munoz del Rio, breast cancer screening rates in the United States dropped 94% in March/April 2020, when the COVID-19 pandemic was declared a national emergency. Although a recent follow-up report showed a rebound in breast cancer screening, the estimated rate remains 13% below average.
The present study evaluated data from 32 out of 1,385 CHCs in the United States. All centers were involved in the ACS-run CHANGE grant program, which funded the clinics for 2 years, during which time they implemented at least three evidence-based provider and client interventions, such as patient navigation or electronic medical record enhancements. The clinics reported breast cancer screening rates on a routine basis throughout the 2-year period, beginning August 2018.
Breast cancer screening rate was defined as the percentage of women aged 50-74 years who had a screening mammogram within the past 27 months, out of a total pool of women who had a medical visit within the past year. For 2018, 2019, and 2020, respectively, 142,207; 142,003; and 150,630 women had a medical visit. Screening rates were compared across years in either June or July. Findings were further characterized by demographic characteristics, urban/rural status, and clinic region.
From 2018 to 2019 breast cancer screening rates rose 18%, from 45.8% to 53.9%. This increase was followed by an 8% decline during the 2019-2020 period, from 53.9% to 49.6%.
The investigators estimated the number of missed mammograms and breast cancer diagnoses for two comparative, hypothetical scenarios: first, if the rising trend from 2018 to 2019 had continued through 2020, and second, if the rate had plateaued at 53.9%.
The rising trend model suggested that 47,517 fewer mammograms than normal were conducted during 2019-2020, resulting in 242 missed breast cancer diagnoses, of which 166 were invasive and 76 were ductal carcinoma in situ. The plateau model suggested that 6,477 fewer mammograms were conducted, leading to 33 missed diagnoses.
Compared with the 8% decline in screening overall, the rate among Black patients dropped 12%, while rates at clinics with a lower proportion of uninsured patients dropped an average of 15%. In contrast, clinics in the South did not have a significant reduction in screening, “possibly reflecting lower baseline rates or impact of stay-at-home orders,” the investigators wrote.
Dr. Fedewa and colleagues also noted that their findings were less dramatic than those reported by Mast and Munoz del Rio. They suggested that the CHANGE program may have softened the blow dealt by the pandemic.
“The CHANGE program–funded interventions – that were established before and continued through 2020 – may have mitigated the pandemic’s effects on breast cancer screening services among the 32 CHCs that were studied,” they wrote. “Further investigation of breast cancer screening rates among additional CHCs will further inform where targeted interventions (e.g., client reminders, education on return to screening) are most needed.”
According to Madeline Sutton, MD, assistant professor of obstetrics and gynecology at Morehouse School of Medicine, Atlanta, “Progress seen with the CHANGE program should be duplicated in other clinical venues based on improvements seen in numbers of mammograms and breast cancers detected.”
Still, Dr. Sutton noted that the racial/ethnic disparities remain cause for concern.
“This study has implications for persons served at CHCs, especially if breast cancer racial/ethnic disparities are unintentionally widened during this pandemic,” Dr. Sutton said in a written comment. “Policy-level changes that decrease BCSR [breast cancer screen rate] gaps for women are warranted.”
Ana Velázquez Mañana, MD, a medical oncology fellow at the University of California, San Francisco, suggested that the effects of the pandemic may have been even more pronounced among medically underserved patients in whom interventions to increase screening were not being conducted, as they were through the CHANGE program.
“One must wonder to what degree these interventions reduced the decline in screening mammography rates observed during the pandemic and to what degree could disparities in screening be magnified in community health centers with less resources,” Dr. Velázquez said in a written comment. “Therefore, understanding barriers to breast cancer screening among our specific health care systems is key to guide resource allocation and the development of evidence-based multilevel interventions that can address these barriers, and ultimately increase screening rates.”
Dr. Velázquez also noted that the study by Dr. Fedewa and colleagues may have missed drops in screening among vulnerable populations that occurred later in the pandemic and in geographic hotspots. In a recent JAMA Network Open study, Dr. Velázquez reported a 41% drop in breast cancer screening at a safety-net hospital in San Francisco during the first stay-at-home order, which lasted from Feb. 1, 2020 to May 31, 2020.
The Breast Health Equity CHANGE grant was funded by the National Football League in partnership with the American Cancer Society. The investigators reported employment by the American Cancer Society. Dr. Wehling and Dr. Wysocki disclosed grants from Pfizer unrelated to this research. Dr. Sutton and Dr. Velázquez disclosed no conflicts of interest.
Breast cancer screening rates at community health centers (CHCs) in the United States declined during the pandemic, particularly among Black and uninsured individuals, based on a retrospective look at 32 sites.
Still, drops in screening were less dramatic than national declines previously reported, possibly because of the American Cancer Society–directed CHANGE program, which was simultaneously underway at the CHCs involved, reported lead author Stacey A. Fedewa, PhD, senior principal scientist at the ACS in Atlanta, and colleagues.
“This is one of the first studies to examine breast cancer screening rates during the pandemic specifically among clinics providing care to communities of color and lower income populations, a group with lower utilization of and greater barriers to [breast cancer] screening,” the investigators wrote in Cancer. “This is important because these populations have longstanding barriers to accessing care, lower breast screening rates, higher breast cancer mortality rates, and are especially vulnerable to health care disruptions.”
According to a previous analysis of electronic health records by Mast and Munoz del Rio, breast cancer screening rates in the United States dropped 94% in March/April 2020, when the COVID-19 pandemic was declared a national emergency. Although a recent follow-up report showed a rebound in breast cancer screening, the estimated rate remains 13% below average.
The present study evaluated data from 32 out of 1,385 CHCs in the United States. All centers were involved in the ACS-run CHANGE grant program, which funded the clinics for 2 years, during which time they implemented at least three evidence-based provider and client interventions, such as patient navigation or electronic medical record enhancements. The clinics reported breast cancer screening rates on a routine basis throughout the 2-year period, beginning August 2018.
Breast cancer screening rate was defined as the percentage of women aged 50-74 years who had a screening mammogram within the past 27 months, out of a total pool of women who had a medical visit within the past year. For 2018, 2019, and 2020, respectively, 142,207; 142,003; and 150,630 women had a medical visit. Screening rates were compared across years in either June or July. Findings were further characterized by demographic characteristics, urban/rural status, and clinic region.
From 2018 to 2019 breast cancer screening rates rose 18%, from 45.8% to 53.9%. This increase was followed by an 8% decline during the 2019-2020 period, from 53.9% to 49.6%.
The investigators estimated the number of missed mammograms and breast cancer diagnoses for two comparative, hypothetical scenarios: first, if the rising trend from 2018 to 2019 had continued through 2020, and second, if the rate had plateaued at 53.9%.
The rising trend model suggested that 47,517 fewer mammograms than normal were conducted during 2019-2020, resulting in 242 missed breast cancer diagnoses, of which 166 were invasive and 76 were ductal carcinoma in situ. The plateau model suggested that 6,477 fewer mammograms were conducted, leading to 33 missed diagnoses.
Compared with the 8% decline in screening overall, the rate among Black patients dropped 12%, while rates at clinics with a lower proportion of uninsured patients dropped an average of 15%. In contrast, clinics in the South did not have a significant reduction in screening, “possibly reflecting lower baseline rates or impact of stay-at-home orders,” the investigators wrote.
Dr. Fedewa and colleagues also noted that their findings were less dramatic than those reported by Mast and Munoz del Rio. They suggested that the CHANGE program may have softened the blow dealt by the pandemic.
“The CHANGE program–funded interventions – that were established before and continued through 2020 – may have mitigated the pandemic’s effects on breast cancer screening services among the 32 CHCs that were studied,” they wrote. “Further investigation of breast cancer screening rates among additional CHCs will further inform where targeted interventions (e.g., client reminders, education on return to screening) are most needed.”
According to Madeline Sutton, MD, assistant professor of obstetrics and gynecology at Morehouse School of Medicine, Atlanta, “Progress seen with the CHANGE program should be duplicated in other clinical venues based on improvements seen in numbers of mammograms and breast cancers detected.”
Still, Dr. Sutton noted that the racial/ethnic disparities remain cause for concern.
“This study has implications for persons served at CHCs, especially if breast cancer racial/ethnic disparities are unintentionally widened during this pandemic,” Dr. Sutton said in a written comment. “Policy-level changes that decrease BCSR [breast cancer screen rate] gaps for women are warranted.”
Ana Velázquez Mañana, MD, a medical oncology fellow at the University of California, San Francisco, suggested that the effects of the pandemic may have been even more pronounced among medically underserved patients in whom interventions to increase screening were not being conducted, as they were through the CHANGE program.
“One must wonder to what degree these interventions reduced the decline in screening mammography rates observed during the pandemic and to what degree could disparities in screening be magnified in community health centers with less resources,” Dr. Velázquez said in a written comment. “Therefore, understanding barriers to breast cancer screening among our specific health care systems is key to guide resource allocation and the development of evidence-based multilevel interventions that can address these barriers, and ultimately increase screening rates.”
Dr. Velázquez also noted that the study by Dr. Fedewa and colleagues may have missed drops in screening among vulnerable populations that occurred later in the pandemic and in geographic hotspots. In a recent JAMA Network Open study, Dr. Velázquez reported a 41% drop in breast cancer screening at a safety-net hospital in San Francisco during the first stay-at-home order, which lasted from Feb. 1, 2020 to May 31, 2020.
The Breast Health Equity CHANGE grant was funded by the National Football League in partnership with the American Cancer Society. The investigators reported employment by the American Cancer Society. Dr. Wehling and Dr. Wysocki disclosed grants from Pfizer unrelated to this research. Dr. Sutton and Dr. Velázquez disclosed no conflicts of interest.
FROM CANCER
Health-Related Quality of Life and Toxicity After Definitive High-Dose-Rate Brachytherapy Among Veterans With Prostate Cancer
Nearly 50,000 veterans are diagnosed with cancer within the Veterans Health Administration annually with prostate cancer (PC) being the most frequently diagnosed, accounting for 29% of all cancers diagnosed.1 The treatment of PC depends on the stage and risk group at presentation and patient preference. Men with early stage, localized PC can be managed with prostatectomy, radiation therapy, or active surveillance.2
Within the Veterans Health Administration, more patients are treated with radiation therapy than with radical prostatectomy.3 This is in contrast to the civil health system, where more patients are treated with radical prostatectomy than with radiation therapy.4,5 Radiation therapy for PC can be given externally with external beam radiation therapy or internally with brachytherapy (BT). BT is categorized by the rate at which the radiation dose is delivered and generally grouped as low-dose rate (LDR) or high-dose rate (HDR). LDRBT consists of permanently implanting radioactive seeds, which slowly deliver a radiation dose over an extended period. HDRBT consists of implanting catheters that allow delivery of a radioactive source to be placed temporarily in the prostate and removed after treatment. The utilization of HDRBT has become more common as treatment has evolved to consist of fewer, larger fractions in a shorter time, making it a convenient treatment option for men with PC.6 The veteran population has singular medical challenges. These patients differ from the general population and are often underrepresented in medical research and published studies.7 There are no studies exploring the treatment-associated toxicities from HDRBT treatment for PC specifically in the veteran population. The objective of this study is to report our findings regarding the veteran-reported and physician-graded toxicities associated with HDRBT as monotherapy in veterans treated through the US Department of Veterans Affairs (VA) for PC.
Methods
We performed a retrospective cohort study of a prospectively maintained, institutional review board-approved database of patients treated with HDRBT for PC. Veterans were seen in consultation at Edward Hines, Jr. VA Hospital (EHJVAH) in Hines, Illinois. This is the only VA hospital in Illinois that offers radiation therapy, so it acted as a tertiary center, receiving referrals from other, neighboring VA hospitals. If the veteran was deemed a good BT candidate and elected to proceed with HDRBT, HDR treatment was performed at a partnering academic institution equipped to provide HDRBT (Loyola University Medical Center).
We selected patients with National Cancer Center Network (NCCN) low- or intermediate-risk PC undergoing definitive HDRBT as monotherapy using 13.5 Gy x 2 fractions delivered over 2 implants that were 1 to 2 weeks apart. Patients who received androgen deprivation therapy (ADT) were excluded from this study. No patients received supplemental external beam radiation. Men with unfavorable intermediate risk PC were offered ADT and BT in accordance with NCCN guidelines. However, patients with unfavorable intermediate-risk PC who declined ADT or who were deemed poor ADT candidates due to comorbidities were treated with HDR as monotherapy and included in this study.8
HDR Treatment
Our HDRBT implant procedure and treatment planning details have been previously described.9 In brief, patients were implanted with between 17 and 22 catheters based on gland size under transrectal ultrasound guidance. After implantation, computed tomography and, when possible, magnetic resonance imaging of the prostate were obtained and registered for target delineation. The prostate was segmented, and an asymmetric planning target volume of 0 to 5 mm was created and extended to encompass the proximal seminal vesicles. The second fraction was given 1 to 2 weeks after initial treatment, based on patient, physician, and operating room availability.
Health-Related Quality of Life Assessment
Veteran-reported genitourinary (GU), gastrointestinal (GI), and sexual health-related quality of life (hrQOL) were assessed using the validated International Prostate Symptom Score (IPSS) and the Expanded Prostate Cancer Index Composite Short Form (EPIC-26) instruments.10,11 Baseline veteran-reported hrQOL scores in the GU, GI, and sexual domains were obtained prior to each veteran’s first HDR treatment. Veteran-reported hrQOL scores were assessed at each of the patient’s follow-up appointments. Physician-graded toxicity was assessed Common Terminology Criteria for Adverse Events (CTCAE) v 4.03 criteria.12 Physician-graded toxicity was assessed at each follow-up visit and reported as the highest grade reported during any follow-up examination.
Follow-up appointments typically occurred at 1 month, 3 months, 6 months, 12 months, and subsequently every 6 months after the second HDR treatment. Follow-up appointments were conducted in the radiation oncology department at EHJVAH.
Minimal Clinically Important Differences
To evaluate the veteran-reported hrQOL, we characterized statistically significant differences in IPSS or EPIC-26 scores over time as compared with baseline values as clinically important or not clinically important through the use of reported minimal clinically important difference (MCID) assessments.13-15 For the IPSS, we used reported data that showed a change of ≥ 3.0 points represented a clinically meaningful change in urinary function.14 For the EPIC-26 scores, we used reported data that showed a change of ≥ 6 points for urinary incontinence score, ≥ 5 points for urinary obstruction score, ≥ 4 points for bowel score, and ≥ 10 points for sexual score to represent an MCID.15
Statistical Analysis
Changes in veteran-reported hrQOL over time were compared using mixed linear effects models, with the time since the last BT implant serving as the fixed variable. Effects were deemed statistically significant if P < .05. If a statistically significant difference from baseline was found at any time point, additional evaluation was done to see if the numerical difference in the assessment led to an MCID as described above. IBM SPSS Statistics for Windows, version 25.0 was used for data analysis.
Results
Seventy-four veterans were included in the study. The median follow-up was 18 months (range 1-43). The demographic and oncologic specifics of the treated veterans are outlined in Table 1.
There was a significant increase in IPSS (P < .001) with reciprocal decline in EPIC-26 urinary incontinence (P = .008) and EPIC-26 urinary obstruction scores (P = .001) from baseline over time (Table 2 and Figure 1). At the 18-month follow-up assessment, there was no longer a significant difference in the EPIC-26 urinary obstruction score from baseline (88.7 vs 84.0, P = .31). The increases in IPSS at the 1-, 3-, and 6-month assessments met the criteria for MCID. The decrease in EPIC-26 urinary incontinence scores at the 1-, 3-, 6-, 12-, and 18-month assessments were found to be an MCID, as were the decrease in EPIC-26 urinary obstruction scores at the 1-, 3-, 6-, and 12-month assessments.
There was a significant decline in EPIC-26 bowel scores from baseline over time (P = .03). The decline in the EPIC-26 bowel hrQOL scores at the 1-, 3-, and 6-month follow-up assessment were significantly different from the baseline value. However, only the decrease seen at the 1-month assessment met criteria for MCID.
There was a significant decline in EPIC-26 sexual scores from baseline over time (P < .001). The decline in EPIC-26 sexual score noted at each follow-up compared with baseline was statistically significant. Each of these declines met criteria for an MCID.
The rate of grade 2 GU, GI, and sexual physician-graded toxicity was 65%, 5%, and 53%, respectively (Figure 2). There was a single incident of grade 3 GU toxicity, which was a urethral stricture. There were no reported grade 3 GI or sexual toxicities, nor were there grade 4 or 5 toxicities. There were 5 total incidents of acute urinary retention for a 6.8% rate overall.
Discussion
We performed a retrospective study of veterans with low- or intermediate-risk PC undergoing definitive HDR prostate BT as monotherapy. We found that veterans experienced immediate declines in GU, GI, and sexual hrQOL after treatment. However, each trended toward a return to baseline over time, with the EPIC-26 urinary obstruction and the EPIC-26 bowel scores showing no difference from the baseline value within 18 months and 12 months, respectively. The physician-reported toxicities were low, with only 1 incidence of grade 3 GU toxicity, no grade 3 GI or sexual toxicities, and no grade 4 or 5 toxicity. This suggests that HDRBT is a well-tolerated and safe, definitive treatment for veterans with localized PC.
In a series similar to ours, Gaudet and colleagues reported on their single institutional results of treating 30 low- or intermediate-risk PC patients with HDRBT as monotherapy.16 Patients included in their study were civilians from the general population, treated in a similar fashion to the veterans treated in our study. Each patient received 27 Gy in 2 fractions given over 2 implants. The authors collected patient-reported hrQOL results using the IPSS and EPIC questionnaires and found that 57% of patients treated experienced moderate-to-severe urinary symptoms at the 1-month assessment after implantation, with a rapid recovery toward baseline over time. In contrast, GI symptoms did not change from baseline, while sexual symptoms worsened after implantation and failed to return to baseline.
Our results mirror this experience, with similar rates of patient-reported hrQOL scores and physician-graded toxicities. Patients reported similar rates of decline in GU, GI, and sexual hrQOL after treatment. The patient-reported GU and GI hrQOL scores worsened immediately after treatment, with a return toward baseline over time. However, the patient-reported sexual hrQOL dropped after treatment and had a subtle trend toward a return to baseline. Our data show higher rates of maximum physician-graded GU toxicity rates of 23%, 65%, and 1% grade 1, 2, and 3, respectively. This is likely due in part to our prophylactic use of tamsulosin. Patients who continued tamsulosin after the implant out of preference were technically grade 2 based on CTCAE v5.0 criteria. GI and sexual toxicity were substantially lower with rates of 15% and 5% grade 1 and grade 2 bowel toxicity with no grade 3 events, and 15% and 52% grade 1 and grade 2 sexual toxicity, respectively.
Contreras and colleagues also reported on treating civilian patients with HDRBT as monotherapy for PC.17 They, too, found similar results as in our veteran study, with a rapid decline in GU, GI, and sexual hrQOL scores immediately after treatment. They also found a gradual return to baseline in the GU hrQOL scores. Contrary to our results, they reported a return to baseline in sexual hrQOL scores, while their patients did not report a return to baseline in the GI hrQOL scores.
Limitations
To the authors’ knowledge, there are no other studies exploring HDR prostate BT toxicity in a veteran-specific population, and our study is novel in addressing this question. One limitation of the study is the relatively short median follow-up time of 18 months. With this limitation, our data were not yet sufficiently mature to perform biochemical control or overall survival analyses. The next step in our study is to calculate these clinical endpoints from our data after longer follow-up.
An additional limitation to our study is the single institutional nature of the design. While veterans from neighboring VA hospitals were included in the study by way of referral and treatment at our center, the only VA hospital in the state to provide radiation therapy, our patient population remains limited. Further multi-institutional and prospective data are needed to validate our findings.
Conclusions
HDR prostate BT as monotherapy is feasible with a favorable veteran-reported hrQOL and physician-graded toxicity profile. Veterans should be educated about this treatment modality when considering the optimal treatment for their localized prostate cancer.
1. Zullig LL, Sims KJ, McNeil R, et al. Cancer incidence among patients of the U.S. Veterans Affairs health care system: 2010 update. Mil Med. 2017;182(7):e1883‐e1891. doi:10.7205/MILMED-D-16-00371
2. Skolarus TA, Hawley ST. Prostate cancer survivorship care in the Veterans Health Administration. Fed Pract. 2014;31(8):10‐17.
3. Nambudiri VE, Landrum MB, Lamont EB, et al. Understanding variation in primary prostate cancer treatment within the Veterans Health Administration. Urology. 2012;79(3):537‐545. doi:10.1016/j.urology.2011.11.013
4. Harlan LC, Potosky A, Gilliland FD, et al. Factors associated with initial therapy for clinically localized prostate cancer: prostate cancer outcomes study. J Natl Cancer Inst. 2001;93(24):1864-1871. doi:10.1093/jnci/93.24.1864
5. Burt LM, Shrieve DC, Tward JD. Factors influencing prostate cancer patterns of care: an analysis of treatment variation using the SEER database. Adv Radiat Oncol. 2018;3(2):170-180. doi:10.1016/j.adro.2017.12.008
6. Crook J, Marbán M, Batchelar D. HDR prostate brachytherapy. Semin Radiat Oncol. 2020;30(1):49‐60. doi:10.1016/j.semradonc.2019.08.003
7. Agha Z, Lofgren RP, VanRuiswyk JV, Layde PM. Are patients at Veterans Affairs medical centers sicker? A comparative analysis of health status and medical resource use. Arch Intern Med. 2000;160(21):3252-3257. doi: 10.1001/archinte.160.21.3252.
8. D’Amico AV, Chen MH, Renshaw AA, Loffredo M, Kantoff PW. Androgen suppression and radiation vs radiation alone for prostate cancer: a randomized trial. JAMA. 2008;299(3):289-295. doi:10.1001/jama.299.3.289
9. Solanki AA, Mysz ML, Patel R, et al. Transitioning from a low-dose-rate to a high-dose-rate prostate brachytherapy program: comparing initial dosimetry and improving workflow efficiency through targeted interventions. Adv Radiat Oncol. 2019;4(1):103-111. doi:10.1016/j.adro.2018.10.004
10. Barry MJ, Fowler FJ Jr, O’Leary MP, et al. The American Urological Association symptom index for benign prostatic hyperplasia. The Measurement Committee of the American Urological Association. J Urol. 1992;148(5):1549‐1564. doi:10.1016/s0022-5347(17)36966-5
11. Wei JT, Dunn RL, Litwin MS, Sandler HM, Sanda MG. Development and validation of the expanded prostate cancer index composite (EPIC) for comprehensive assessment of health-related quality of life in men with prostate cancer. Urology. 2000;56(6):899‐905. doi:10.1016/s0090-4295(00)00858-x
12. US Department of Health and Human Services. Common terminology criteria for adverse events (CTCAE). version 4.03. Updated June 14, 2010. Accessed June 15, 2021. https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf
13. McGlothlin AE, Lewis RJ. Minimal clinically important difference: defining what really matters to patients. JAMA. 2014;312(13):1342-1343. doi:10.1001/jama.2014.13128
14. Barry MJ, Williford WO, Chang Y, et al. Benign prostatic hyperplasia specific health status measures in clinical research: how much change in the American Urological Association Symptom Index and the Benign Prostatic Hyperplasia Impact Index is perceptible to patients? J Urol. 1995;154(5):1770-1774. doi:10.1016/S0022-5347(01)66780-6
15. Skolarus TA, Dunn RL, Sanda MG, et al. Minimally important difference for the Expanded Prostate Cancer Index Composite Short Form. Urology. 2015;85(1):101–105. doi:10.1016/j.urology.2014.08.044
16. Gaudet M, Pharand-Charbonneau M, Desrosiers MP, Wright D, Haddad A. Early toxicity and health-related quality of life results of high-dose-rate brachytherapy as monotherapy for low and intermediate-risk prostate cancer. Brachytherapy. 2018;17(3):524-529. doi:10.1016/j.brachy.2018.01.009
17. Contreras JA, Wilder RB, Mellon EA, Strom TJ, Fernandez DC, Biagioli MC. Quality of life after high-dose-rate brachytherapy monotherapy for prostate cancer. Int Braz J Urol. 2015;41(1):40-45. doi:10.1590/S1677-5538.IBJU.2015.01.07
Nearly 50,000 veterans are diagnosed with cancer within the Veterans Health Administration annually with prostate cancer (PC) being the most frequently diagnosed, accounting for 29% of all cancers diagnosed.1 The treatment of PC depends on the stage and risk group at presentation and patient preference. Men with early stage, localized PC can be managed with prostatectomy, radiation therapy, or active surveillance.2
Within the Veterans Health Administration, more patients are treated with radiation therapy than with radical prostatectomy.3 This is in contrast to the civil health system, where more patients are treated with radical prostatectomy than with radiation therapy.4,5 Radiation therapy for PC can be given externally with external beam radiation therapy or internally with brachytherapy (BT). BT is categorized by the rate at which the radiation dose is delivered and generally grouped as low-dose rate (LDR) or high-dose rate (HDR). LDRBT consists of permanently implanting radioactive seeds, which slowly deliver a radiation dose over an extended period. HDRBT consists of implanting catheters that allow delivery of a radioactive source to be placed temporarily in the prostate and removed after treatment. The utilization of HDRBT has become more common as treatment has evolved to consist of fewer, larger fractions in a shorter time, making it a convenient treatment option for men with PC.6 The veteran population has singular medical challenges. These patients differ from the general population and are often underrepresented in medical research and published studies.7 There are no studies exploring the treatment-associated toxicities from HDRBT treatment for PC specifically in the veteran population. The objective of this study is to report our findings regarding the veteran-reported and physician-graded toxicities associated with HDRBT as monotherapy in veterans treated through the US Department of Veterans Affairs (VA) for PC.
Methods
We performed a retrospective cohort study of a prospectively maintained, institutional review board-approved database of patients treated with HDRBT for PC. Veterans were seen in consultation at Edward Hines, Jr. VA Hospital (EHJVAH) in Hines, Illinois. This is the only VA hospital in Illinois that offers radiation therapy, so it acted as a tertiary center, receiving referrals from other, neighboring VA hospitals. If the veteran was deemed a good BT candidate and elected to proceed with HDRBT, HDR treatment was performed at a partnering academic institution equipped to provide HDRBT (Loyola University Medical Center).
We selected patients with National Cancer Center Network (NCCN) low- or intermediate-risk PC undergoing definitive HDRBT as monotherapy using 13.5 Gy x 2 fractions delivered over 2 implants that were 1 to 2 weeks apart. Patients who received androgen deprivation therapy (ADT) were excluded from this study. No patients received supplemental external beam radiation. Men with unfavorable intermediate risk PC were offered ADT and BT in accordance with NCCN guidelines. However, patients with unfavorable intermediate-risk PC who declined ADT or who were deemed poor ADT candidates due to comorbidities were treated with HDR as monotherapy and included in this study.8
HDR Treatment
Our HDRBT implant procedure and treatment planning details have been previously described.9 In brief, patients were implanted with between 17 and 22 catheters based on gland size under transrectal ultrasound guidance. After implantation, computed tomography and, when possible, magnetic resonance imaging of the prostate were obtained and registered for target delineation. The prostate was segmented, and an asymmetric planning target volume of 0 to 5 mm was created and extended to encompass the proximal seminal vesicles. The second fraction was given 1 to 2 weeks after initial treatment, based on patient, physician, and operating room availability.
Health-Related Quality of Life Assessment
Veteran-reported genitourinary (GU), gastrointestinal (GI), and sexual health-related quality of life (hrQOL) were assessed using the validated International Prostate Symptom Score (IPSS) and the Expanded Prostate Cancer Index Composite Short Form (EPIC-26) instruments.10,11 Baseline veteran-reported hrQOL scores in the GU, GI, and sexual domains were obtained prior to each veteran’s first HDR treatment. Veteran-reported hrQOL scores were assessed at each of the patient’s follow-up appointments. Physician-graded toxicity was assessed Common Terminology Criteria for Adverse Events (CTCAE) v 4.03 criteria.12 Physician-graded toxicity was assessed at each follow-up visit and reported as the highest grade reported during any follow-up examination.
Follow-up appointments typically occurred at 1 month, 3 months, 6 months, 12 months, and subsequently every 6 months after the second HDR treatment. Follow-up appointments were conducted in the radiation oncology department at EHJVAH.
Minimal Clinically Important Differences
To evaluate the veteran-reported hrQOL, we characterized statistically significant differences in IPSS or EPIC-26 scores over time as compared with baseline values as clinically important or not clinically important through the use of reported minimal clinically important difference (MCID) assessments.13-15 For the IPSS, we used reported data that showed a change of ≥ 3.0 points represented a clinically meaningful change in urinary function.14 For the EPIC-26 scores, we used reported data that showed a change of ≥ 6 points for urinary incontinence score, ≥ 5 points for urinary obstruction score, ≥ 4 points for bowel score, and ≥ 10 points for sexual score to represent an MCID.15
Statistical Analysis
Changes in veteran-reported hrQOL over time were compared using mixed linear effects models, with the time since the last BT implant serving as the fixed variable. Effects were deemed statistically significant if P < .05. If a statistically significant difference from baseline was found at any time point, additional evaluation was done to see if the numerical difference in the assessment led to an MCID as described above. IBM SPSS Statistics for Windows, version 25.0 was used for data analysis.
Results
Seventy-four veterans were included in the study. The median follow-up was 18 months (range 1-43). The demographic and oncologic specifics of the treated veterans are outlined in Table 1.
There was a significant increase in IPSS (P < .001) with reciprocal decline in EPIC-26 urinary incontinence (P = .008) and EPIC-26 urinary obstruction scores (P = .001) from baseline over time (Table 2 and Figure 1). At the 18-month follow-up assessment, there was no longer a significant difference in the EPIC-26 urinary obstruction score from baseline (88.7 vs 84.0, P = .31). The increases in IPSS at the 1-, 3-, and 6-month assessments met the criteria for MCID. The decrease in EPIC-26 urinary incontinence scores at the 1-, 3-, 6-, 12-, and 18-month assessments were found to be an MCID, as were the decrease in EPIC-26 urinary obstruction scores at the 1-, 3-, 6-, and 12-month assessments.
There was a significant decline in EPIC-26 bowel scores from baseline over time (P = .03). The decline in the EPIC-26 bowel hrQOL scores at the 1-, 3-, and 6-month follow-up assessment were significantly different from the baseline value. However, only the decrease seen at the 1-month assessment met criteria for MCID.
There was a significant decline in EPIC-26 sexual scores from baseline over time (P < .001). The decline in EPIC-26 sexual score noted at each follow-up compared with baseline was statistically significant. Each of these declines met criteria for an MCID.
The rate of grade 2 GU, GI, and sexual physician-graded toxicity was 65%, 5%, and 53%, respectively (Figure 2). There was a single incident of grade 3 GU toxicity, which was a urethral stricture. There were no reported grade 3 GI or sexual toxicities, nor were there grade 4 or 5 toxicities. There were 5 total incidents of acute urinary retention for a 6.8% rate overall.
Discussion
We performed a retrospective study of veterans with low- or intermediate-risk PC undergoing definitive HDR prostate BT as monotherapy. We found that veterans experienced immediate declines in GU, GI, and sexual hrQOL after treatment. However, each trended toward a return to baseline over time, with the EPIC-26 urinary obstruction and the EPIC-26 bowel scores showing no difference from the baseline value within 18 months and 12 months, respectively. The physician-reported toxicities were low, with only 1 incidence of grade 3 GU toxicity, no grade 3 GI or sexual toxicities, and no grade 4 or 5 toxicity. This suggests that HDRBT is a well-tolerated and safe, definitive treatment for veterans with localized PC.
In a series similar to ours, Gaudet and colleagues reported on their single institutional results of treating 30 low- or intermediate-risk PC patients with HDRBT as monotherapy.16 Patients included in their study were civilians from the general population, treated in a similar fashion to the veterans treated in our study. Each patient received 27 Gy in 2 fractions given over 2 implants. The authors collected patient-reported hrQOL results using the IPSS and EPIC questionnaires and found that 57% of patients treated experienced moderate-to-severe urinary symptoms at the 1-month assessment after implantation, with a rapid recovery toward baseline over time. In contrast, GI symptoms did not change from baseline, while sexual symptoms worsened after implantation and failed to return to baseline.
Our results mirror this experience, with similar rates of patient-reported hrQOL scores and physician-graded toxicities. Patients reported similar rates of decline in GU, GI, and sexual hrQOL after treatment. The patient-reported GU and GI hrQOL scores worsened immediately after treatment, with a return toward baseline over time. However, the patient-reported sexual hrQOL dropped after treatment and had a subtle trend toward a return to baseline. Our data show higher rates of maximum physician-graded GU toxicity rates of 23%, 65%, and 1% grade 1, 2, and 3, respectively. This is likely due in part to our prophylactic use of tamsulosin. Patients who continued tamsulosin after the implant out of preference were technically grade 2 based on CTCAE v5.0 criteria. GI and sexual toxicity were substantially lower with rates of 15% and 5% grade 1 and grade 2 bowel toxicity with no grade 3 events, and 15% and 52% grade 1 and grade 2 sexual toxicity, respectively.
Contreras and colleagues also reported on treating civilian patients with HDRBT as monotherapy for PC.17 They, too, found similar results as in our veteran study, with a rapid decline in GU, GI, and sexual hrQOL scores immediately after treatment. They also found a gradual return to baseline in the GU hrQOL scores. Contrary to our results, they reported a return to baseline in sexual hrQOL scores, while their patients did not report a return to baseline in the GI hrQOL scores.
Limitations
To the authors’ knowledge, there are no other studies exploring HDR prostate BT toxicity in a veteran-specific population, and our study is novel in addressing this question. One limitation of the study is the relatively short median follow-up time of 18 months. With this limitation, our data were not yet sufficiently mature to perform biochemical control or overall survival analyses. The next step in our study is to calculate these clinical endpoints from our data after longer follow-up.
An additional limitation to our study is the single institutional nature of the design. While veterans from neighboring VA hospitals were included in the study by way of referral and treatment at our center, the only VA hospital in the state to provide radiation therapy, our patient population remains limited. Further multi-institutional and prospective data are needed to validate our findings.
Conclusions
HDR prostate BT as monotherapy is feasible with a favorable veteran-reported hrQOL and physician-graded toxicity profile. Veterans should be educated about this treatment modality when considering the optimal treatment for their localized prostate cancer.
Nearly 50,000 veterans are diagnosed with cancer within the Veterans Health Administration annually with prostate cancer (PC) being the most frequently diagnosed, accounting for 29% of all cancers diagnosed.1 The treatment of PC depends on the stage and risk group at presentation and patient preference. Men with early stage, localized PC can be managed with prostatectomy, radiation therapy, or active surveillance.2
Within the Veterans Health Administration, more patients are treated with radiation therapy than with radical prostatectomy.3 This is in contrast to the civil health system, where more patients are treated with radical prostatectomy than with radiation therapy.4,5 Radiation therapy for PC can be given externally with external beam radiation therapy or internally with brachytherapy (BT). BT is categorized by the rate at which the radiation dose is delivered and generally grouped as low-dose rate (LDR) or high-dose rate (HDR). LDRBT consists of permanently implanting radioactive seeds, which slowly deliver a radiation dose over an extended period. HDRBT consists of implanting catheters that allow delivery of a radioactive source to be placed temporarily in the prostate and removed after treatment. The utilization of HDRBT has become more common as treatment has evolved to consist of fewer, larger fractions in a shorter time, making it a convenient treatment option for men with PC.6 The veteran population has singular medical challenges. These patients differ from the general population and are often underrepresented in medical research and published studies.7 There are no studies exploring the treatment-associated toxicities from HDRBT treatment for PC specifically in the veteran population. The objective of this study is to report our findings regarding the veteran-reported and physician-graded toxicities associated with HDRBT as monotherapy in veterans treated through the US Department of Veterans Affairs (VA) for PC.
Methods
We performed a retrospective cohort study of a prospectively maintained, institutional review board-approved database of patients treated with HDRBT for PC. Veterans were seen in consultation at Edward Hines, Jr. VA Hospital (EHJVAH) in Hines, Illinois. This is the only VA hospital in Illinois that offers radiation therapy, so it acted as a tertiary center, receiving referrals from other, neighboring VA hospitals. If the veteran was deemed a good BT candidate and elected to proceed with HDRBT, HDR treatment was performed at a partnering academic institution equipped to provide HDRBT (Loyola University Medical Center).
We selected patients with National Cancer Center Network (NCCN) low- or intermediate-risk PC undergoing definitive HDRBT as monotherapy using 13.5 Gy x 2 fractions delivered over 2 implants that were 1 to 2 weeks apart. Patients who received androgen deprivation therapy (ADT) were excluded from this study. No patients received supplemental external beam radiation. Men with unfavorable intermediate risk PC were offered ADT and BT in accordance with NCCN guidelines. However, patients with unfavorable intermediate-risk PC who declined ADT or who were deemed poor ADT candidates due to comorbidities were treated with HDR as monotherapy and included in this study.8
HDR Treatment
Our HDRBT implant procedure and treatment planning details have been previously described.9 In brief, patients were implanted with between 17 and 22 catheters based on gland size under transrectal ultrasound guidance. After implantation, computed tomography and, when possible, magnetic resonance imaging of the prostate were obtained and registered for target delineation. The prostate was segmented, and an asymmetric planning target volume of 0 to 5 mm was created and extended to encompass the proximal seminal vesicles. The second fraction was given 1 to 2 weeks after initial treatment, based on patient, physician, and operating room availability.
Health-Related Quality of Life Assessment
Veteran-reported genitourinary (GU), gastrointestinal (GI), and sexual health-related quality of life (hrQOL) were assessed using the validated International Prostate Symptom Score (IPSS) and the Expanded Prostate Cancer Index Composite Short Form (EPIC-26) instruments.10,11 Baseline veteran-reported hrQOL scores in the GU, GI, and sexual domains were obtained prior to each veteran’s first HDR treatment. Veteran-reported hrQOL scores were assessed at each of the patient’s follow-up appointments. Physician-graded toxicity was assessed Common Terminology Criteria for Adverse Events (CTCAE) v 4.03 criteria.12 Physician-graded toxicity was assessed at each follow-up visit and reported as the highest grade reported during any follow-up examination.
Follow-up appointments typically occurred at 1 month, 3 months, 6 months, 12 months, and subsequently every 6 months after the second HDR treatment. Follow-up appointments were conducted in the radiation oncology department at EHJVAH.
Minimal Clinically Important Differences
To evaluate the veteran-reported hrQOL, we characterized statistically significant differences in IPSS or EPIC-26 scores over time as compared with baseline values as clinically important or not clinically important through the use of reported minimal clinically important difference (MCID) assessments.13-15 For the IPSS, we used reported data that showed a change of ≥ 3.0 points represented a clinically meaningful change in urinary function.14 For the EPIC-26 scores, we used reported data that showed a change of ≥ 6 points for urinary incontinence score, ≥ 5 points for urinary obstruction score, ≥ 4 points for bowel score, and ≥ 10 points for sexual score to represent an MCID.15
Statistical Analysis
Changes in veteran-reported hrQOL over time were compared using mixed linear effects models, with the time since the last BT implant serving as the fixed variable. Effects were deemed statistically significant if P < .05. If a statistically significant difference from baseline was found at any time point, additional evaluation was done to see if the numerical difference in the assessment led to an MCID as described above. IBM SPSS Statistics for Windows, version 25.0 was used for data analysis.
Results
Seventy-four veterans were included in the study. The median follow-up was 18 months (range 1-43). The demographic and oncologic specifics of the treated veterans are outlined in Table 1.
There was a significant increase in IPSS (P < .001) with reciprocal decline in EPIC-26 urinary incontinence (P = .008) and EPIC-26 urinary obstruction scores (P = .001) from baseline over time (Table 2 and Figure 1). At the 18-month follow-up assessment, there was no longer a significant difference in the EPIC-26 urinary obstruction score from baseline (88.7 vs 84.0, P = .31). The increases in IPSS at the 1-, 3-, and 6-month assessments met the criteria for MCID. The decrease in EPIC-26 urinary incontinence scores at the 1-, 3-, 6-, 12-, and 18-month assessments were found to be an MCID, as were the decrease in EPIC-26 urinary obstruction scores at the 1-, 3-, 6-, and 12-month assessments.
There was a significant decline in EPIC-26 bowel scores from baseline over time (P = .03). The decline in the EPIC-26 bowel hrQOL scores at the 1-, 3-, and 6-month follow-up assessment were significantly different from the baseline value. However, only the decrease seen at the 1-month assessment met criteria for MCID.
There was a significant decline in EPIC-26 sexual scores from baseline over time (P < .001). The decline in EPIC-26 sexual score noted at each follow-up compared with baseline was statistically significant. Each of these declines met criteria for an MCID.
The rate of grade 2 GU, GI, and sexual physician-graded toxicity was 65%, 5%, and 53%, respectively (Figure 2). There was a single incident of grade 3 GU toxicity, which was a urethral stricture. There were no reported grade 3 GI or sexual toxicities, nor were there grade 4 or 5 toxicities. There were 5 total incidents of acute urinary retention for a 6.8% rate overall.
Discussion
We performed a retrospective study of veterans with low- or intermediate-risk PC undergoing definitive HDR prostate BT as monotherapy. We found that veterans experienced immediate declines in GU, GI, and sexual hrQOL after treatment. However, each trended toward a return to baseline over time, with the EPIC-26 urinary obstruction and the EPIC-26 bowel scores showing no difference from the baseline value within 18 months and 12 months, respectively. The physician-reported toxicities were low, with only 1 incidence of grade 3 GU toxicity, no grade 3 GI or sexual toxicities, and no grade 4 or 5 toxicity. This suggests that HDRBT is a well-tolerated and safe, definitive treatment for veterans with localized PC.
In a series similar to ours, Gaudet and colleagues reported on their single institutional results of treating 30 low- or intermediate-risk PC patients with HDRBT as monotherapy.16 Patients included in their study were civilians from the general population, treated in a similar fashion to the veterans treated in our study. Each patient received 27 Gy in 2 fractions given over 2 implants. The authors collected patient-reported hrQOL results using the IPSS and EPIC questionnaires and found that 57% of patients treated experienced moderate-to-severe urinary symptoms at the 1-month assessment after implantation, with a rapid recovery toward baseline over time. In contrast, GI symptoms did not change from baseline, while sexual symptoms worsened after implantation and failed to return to baseline.
Our results mirror this experience, with similar rates of patient-reported hrQOL scores and physician-graded toxicities. Patients reported similar rates of decline in GU, GI, and sexual hrQOL after treatment. The patient-reported GU and GI hrQOL scores worsened immediately after treatment, with a return toward baseline over time. However, the patient-reported sexual hrQOL dropped after treatment and had a subtle trend toward a return to baseline. Our data show higher rates of maximum physician-graded GU toxicity rates of 23%, 65%, and 1% grade 1, 2, and 3, respectively. This is likely due in part to our prophylactic use of tamsulosin. Patients who continued tamsulosin after the implant out of preference were technically grade 2 based on CTCAE v5.0 criteria. GI and sexual toxicity were substantially lower with rates of 15% and 5% grade 1 and grade 2 bowel toxicity with no grade 3 events, and 15% and 52% grade 1 and grade 2 sexual toxicity, respectively.
Contreras and colleagues also reported on treating civilian patients with HDRBT as monotherapy for PC.17 They, too, found similar results as in our veteran study, with a rapid decline in GU, GI, and sexual hrQOL scores immediately after treatment. They also found a gradual return to baseline in the GU hrQOL scores. Contrary to our results, they reported a return to baseline in sexual hrQOL scores, while their patients did not report a return to baseline in the GI hrQOL scores.
Limitations
To the authors’ knowledge, there are no other studies exploring HDR prostate BT toxicity in a veteran-specific population, and our study is novel in addressing this question. One limitation of the study is the relatively short median follow-up time of 18 months. With this limitation, our data were not yet sufficiently mature to perform biochemical control or overall survival analyses. The next step in our study is to calculate these clinical endpoints from our data after longer follow-up.
An additional limitation to our study is the single institutional nature of the design. While veterans from neighboring VA hospitals were included in the study by way of referral and treatment at our center, the only VA hospital in the state to provide radiation therapy, our patient population remains limited. Further multi-institutional and prospective data are needed to validate our findings.
Conclusions
HDR prostate BT as monotherapy is feasible with a favorable veteran-reported hrQOL and physician-graded toxicity profile. Veterans should be educated about this treatment modality when considering the optimal treatment for their localized prostate cancer.
1. Zullig LL, Sims KJ, McNeil R, et al. Cancer incidence among patients of the U.S. Veterans Affairs health care system: 2010 update. Mil Med. 2017;182(7):e1883‐e1891. doi:10.7205/MILMED-D-16-00371
2. Skolarus TA, Hawley ST. Prostate cancer survivorship care in the Veterans Health Administration. Fed Pract. 2014;31(8):10‐17.
3. Nambudiri VE, Landrum MB, Lamont EB, et al. Understanding variation in primary prostate cancer treatment within the Veterans Health Administration. Urology. 2012;79(3):537‐545. doi:10.1016/j.urology.2011.11.013
4. Harlan LC, Potosky A, Gilliland FD, et al. Factors associated with initial therapy for clinically localized prostate cancer: prostate cancer outcomes study. J Natl Cancer Inst. 2001;93(24):1864-1871. doi:10.1093/jnci/93.24.1864
5. Burt LM, Shrieve DC, Tward JD. Factors influencing prostate cancer patterns of care: an analysis of treatment variation using the SEER database. Adv Radiat Oncol. 2018;3(2):170-180. doi:10.1016/j.adro.2017.12.008
6. Crook J, Marbán M, Batchelar D. HDR prostate brachytherapy. Semin Radiat Oncol. 2020;30(1):49‐60. doi:10.1016/j.semradonc.2019.08.003
7. Agha Z, Lofgren RP, VanRuiswyk JV, Layde PM. Are patients at Veterans Affairs medical centers sicker? A comparative analysis of health status and medical resource use. Arch Intern Med. 2000;160(21):3252-3257. doi: 10.1001/archinte.160.21.3252.
8. D’Amico AV, Chen MH, Renshaw AA, Loffredo M, Kantoff PW. Androgen suppression and radiation vs radiation alone for prostate cancer: a randomized trial. JAMA. 2008;299(3):289-295. doi:10.1001/jama.299.3.289
9. Solanki AA, Mysz ML, Patel R, et al. Transitioning from a low-dose-rate to a high-dose-rate prostate brachytherapy program: comparing initial dosimetry and improving workflow efficiency through targeted interventions. Adv Radiat Oncol. 2019;4(1):103-111. doi:10.1016/j.adro.2018.10.004
10. Barry MJ, Fowler FJ Jr, O’Leary MP, et al. The American Urological Association symptom index for benign prostatic hyperplasia. The Measurement Committee of the American Urological Association. J Urol. 1992;148(5):1549‐1564. doi:10.1016/s0022-5347(17)36966-5
11. Wei JT, Dunn RL, Litwin MS, Sandler HM, Sanda MG. Development and validation of the expanded prostate cancer index composite (EPIC) for comprehensive assessment of health-related quality of life in men with prostate cancer. Urology. 2000;56(6):899‐905. doi:10.1016/s0090-4295(00)00858-x
12. US Department of Health and Human Services. Common terminology criteria for adverse events (CTCAE). version 4.03. Updated June 14, 2010. Accessed June 15, 2021. https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf
13. McGlothlin AE, Lewis RJ. Minimal clinically important difference: defining what really matters to patients. JAMA. 2014;312(13):1342-1343. doi:10.1001/jama.2014.13128
14. Barry MJ, Williford WO, Chang Y, et al. Benign prostatic hyperplasia specific health status measures in clinical research: how much change in the American Urological Association Symptom Index and the Benign Prostatic Hyperplasia Impact Index is perceptible to patients? J Urol. 1995;154(5):1770-1774. doi:10.1016/S0022-5347(01)66780-6
15. Skolarus TA, Dunn RL, Sanda MG, et al. Minimally important difference for the Expanded Prostate Cancer Index Composite Short Form. Urology. 2015;85(1):101–105. doi:10.1016/j.urology.2014.08.044
16. Gaudet M, Pharand-Charbonneau M, Desrosiers MP, Wright D, Haddad A. Early toxicity and health-related quality of life results of high-dose-rate brachytherapy as monotherapy for low and intermediate-risk prostate cancer. Brachytherapy. 2018;17(3):524-529. doi:10.1016/j.brachy.2018.01.009
17. Contreras JA, Wilder RB, Mellon EA, Strom TJ, Fernandez DC, Biagioli MC. Quality of life after high-dose-rate brachytherapy monotherapy for prostate cancer. Int Braz J Urol. 2015;41(1):40-45. doi:10.1590/S1677-5538.IBJU.2015.01.07
1. Zullig LL, Sims KJ, McNeil R, et al. Cancer incidence among patients of the U.S. Veterans Affairs health care system: 2010 update. Mil Med. 2017;182(7):e1883‐e1891. doi:10.7205/MILMED-D-16-00371
2. Skolarus TA, Hawley ST. Prostate cancer survivorship care in the Veterans Health Administration. Fed Pract. 2014;31(8):10‐17.
3. Nambudiri VE, Landrum MB, Lamont EB, et al. Understanding variation in primary prostate cancer treatment within the Veterans Health Administration. Urology. 2012;79(3):537‐545. doi:10.1016/j.urology.2011.11.013
4. Harlan LC, Potosky A, Gilliland FD, et al. Factors associated with initial therapy for clinically localized prostate cancer: prostate cancer outcomes study. J Natl Cancer Inst. 2001;93(24):1864-1871. doi:10.1093/jnci/93.24.1864
5. Burt LM, Shrieve DC, Tward JD. Factors influencing prostate cancer patterns of care: an analysis of treatment variation using the SEER database. Adv Radiat Oncol. 2018;3(2):170-180. doi:10.1016/j.adro.2017.12.008
6. Crook J, Marbán M, Batchelar D. HDR prostate brachytherapy. Semin Radiat Oncol. 2020;30(1):49‐60. doi:10.1016/j.semradonc.2019.08.003
7. Agha Z, Lofgren RP, VanRuiswyk JV, Layde PM. Are patients at Veterans Affairs medical centers sicker? A comparative analysis of health status and medical resource use. Arch Intern Med. 2000;160(21):3252-3257. doi: 10.1001/archinte.160.21.3252.
8. D’Amico AV, Chen MH, Renshaw AA, Loffredo M, Kantoff PW. Androgen suppression and radiation vs radiation alone for prostate cancer: a randomized trial. JAMA. 2008;299(3):289-295. doi:10.1001/jama.299.3.289
9. Solanki AA, Mysz ML, Patel R, et al. Transitioning from a low-dose-rate to a high-dose-rate prostate brachytherapy program: comparing initial dosimetry and improving workflow efficiency through targeted interventions. Adv Radiat Oncol. 2019;4(1):103-111. doi:10.1016/j.adro.2018.10.004
10. Barry MJ, Fowler FJ Jr, O’Leary MP, et al. The American Urological Association symptom index for benign prostatic hyperplasia. The Measurement Committee of the American Urological Association. J Urol. 1992;148(5):1549‐1564. doi:10.1016/s0022-5347(17)36966-5
11. Wei JT, Dunn RL, Litwin MS, Sandler HM, Sanda MG. Development and validation of the expanded prostate cancer index composite (EPIC) for comprehensive assessment of health-related quality of life in men with prostate cancer. Urology. 2000;56(6):899‐905. doi:10.1016/s0090-4295(00)00858-x
12. US Department of Health and Human Services. Common terminology criteria for adverse events (CTCAE). version 4.03. Updated June 14, 2010. Accessed June 15, 2021. https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf
13. McGlothlin AE, Lewis RJ. Minimal clinically important difference: defining what really matters to patients. JAMA. 2014;312(13):1342-1343. doi:10.1001/jama.2014.13128
14. Barry MJ, Williford WO, Chang Y, et al. Benign prostatic hyperplasia specific health status measures in clinical research: how much change in the American Urological Association Symptom Index and the Benign Prostatic Hyperplasia Impact Index is perceptible to patients? J Urol. 1995;154(5):1770-1774. doi:10.1016/S0022-5347(01)66780-6
15. Skolarus TA, Dunn RL, Sanda MG, et al. Minimally important difference for the Expanded Prostate Cancer Index Composite Short Form. Urology. 2015;85(1):101–105. doi:10.1016/j.urology.2014.08.044
16. Gaudet M, Pharand-Charbonneau M, Desrosiers MP, Wright D, Haddad A. Early toxicity and health-related quality of life results of high-dose-rate brachytherapy as monotherapy for low and intermediate-risk prostate cancer. Brachytherapy. 2018;17(3):524-529. doi:10.1016/j.brachy.2018.01.009
17. Contreras JA, Wilder RB, Mellon EA, Strom TJ, Fernandez DC, Biagioli MC. Quality of life after high-dose-rate brachytherapy monotherapy for prostate cancer. Int Braz J Urol. 2015;41(1):40-45. doi:10.1590/S1677-5538.IBJU.2015.01.07