General Surgery

The Food and Drug Administration is turning to doctors, dentists, and pharmacists to accomplish what some drug manufacturers won’t help it do.

In 2011, the agency recommended manufacturers cease marketing of acetaminophen/opioid combination products with more than 325 mg of acetaminophen per dose, in an effort to reduce the risk of severe liver injury. Not all manufacturers complied.

Now, the agency on Jan. 14 issued a MedWatch recommendation that health care providers refrain from prescribing combinations with larger acetaminophen doses. The recommendation goes further, urging pharmacists to contact prescribers when they receive a prescription for a combination product with more than 325 mg of acetaminophen per dose to discuss a substitute product with a lower acetaminophen dose.

"Inadvertent overdose from prescription combination drugs containing acetaminophen accounts for nearly half of all cases of acetaminophen-related liver failure in the United States, some of which result in liver transplant or death," the agency said, in a statement.

In the same 2011 notice, the FDA is requiring prescription acetaminophen combinations to carry a boxed warning on the potential for liver damage.

Acetaminophen-containing prescription combinations are among the most-prescribed pharmaceuticals in the United States, and include products such as Vicodin (acetaminophen/hydrocodone), Percocet (acetaminophen/oxycodone), and Tylenol with codeine.

The FDA has been examining acetaminophen since at least 2002. The recommendations of a joint meeting of several advisory committees in 2009 resulted in the 2011 policy changes and recommendations.

The agency now has sent letters to manufacturers that have not lowered the acetaminophen dose warning them that the FDA will withdraw approval of those products.

Physicians can report adverse events or side effects related to the use of acetaminophen products to the FDA’s MedWatch Safety Information and Adverse Event Reporting Program either online or at 800-332-1088.

[email protected]

On Twitter @aliciaault

The Food and Drug Administration is turning to doctors, dentists, and pharmacists to accomplish what some drug manufacturers won’t help it do.

In 2011, the agency recommended manufacturers cease marketing of acetaminophen/opioid combination products with more than 325 mg of acetaminophen per dose, in an effort to reduce the risk of severe liver injury. Not all manufacturers complied.

Now, the agency on Jan. 14 issued a MedWatch recommendation that health care providers refrain from prescribing combinations with larger acetaminophen doses. The recommendation goes further, urging pharmacists to contact prescribers when they receive a prescription for a combination product with more than 325 mg of acetaminophen per dose to discuss a substitute product with a lower acetaminophen dose.

"Inadvertent overdose from prescription combination drugs containing acetaminophen accounts for nearly half of all cases of acetaminophen-related liver failure in the United States, some of which result in liver transplant or death," the agency said, in a statement.

In the same 2011 notice, the FDA is requiring prescription acetaminophen combinations to carry a boxed warning on the potential for liver damage.

Acetaminophen-containing prescription combinations are among the most-prescribed pharmaceuticals in the United States, and include products such as Vicodin (acetaminophen/hydrocodone), Percocet (acetaminophen/oxycodone), and Tylenol with codeine.

The FDA has been examining acetaminophen since at least 2002. The recommendations of a joint meeting of several advisory committees in 2009 resulted in the 2011 policy changes and recommendations.

The agency now has sent letters to manufacturers that have not lowered the acetaminophen dose warning them that the FDA will withdraw approval of those products.

Physicians can report adverse events or side effects related to the use of acetaminophen products to the FDA’s MedWatch Safety Information and Adverse Event Reporting Program either online or at 800-332-1088.

[email protected]

On Twitter @aliciaault

The Food and Drug Administration is turning to doctors, dentists, and pharmacists to accomplish what some drug manufacturers won’t help it do.

In 2011, the agency recommended manufacturers cease marketing of acetaminophen/opioid combination products with more than 325 mg of acetaminophen per dose, in an effort to reduce the risk of severe liver injury. Not all manufacturers complied.

Now, the agency on Jan. 14 issued a MedWatch recommendation that health care providers refrain from prescribing combinations with larger acetaminophen doses. The recommendation goes further, urging pharmacists to contact prescribers when they receive a prescription for a combination product with more than 325 mg of acetaminophen per dose to discuss a substitute product with a lower acetaminophen dose.

"Inadvertent overdose from prescription combination drugs containing acetaminophen accounts for nearly half of all cases of acetaminophen-related liver failure in the United States, some of which result in liver transplant or death," the agency said, in a statement.

In the same 2011 notice, the FDA is requiring prescription acetaminophen combinations to carry a boxed warning on the potential for liver damage.

Acetaminophen-containing prescription combinations are among the most-prescribed pharmaceuticals in the United States, and include products such as Vicodin (acetaminophen/hydrocodone), Percocet (acetaminophen/oxycodone), and Tylenol with codeine.

The FDA has been examining acetaminophen since at least 2002. The recommendations of a joint meeting of several advisory committees in 2009 resulted in the 2011 policy changes and recommendations.

The agency now has sent letters to manufacturers that have not lowered the acetaminophen dose warning them that the FDA will withdraw approval of those products.

Physicians can report adverse events or side effects related to the use of acetaminophen products to the FDA’s MedWatch Safety Information and Adverse Event Reporting Program either online or at 800-332-1088.

[email protected]

On Twitter @aliciaault

WASHINGTON – Despite the recent attention given to considering obesity a disease, there are still many limitations to providing treatments for obesity and receiving adequate reimbursement for those treatments, Dr. Lee Kaplan said at a public workshop cosponsored by the Food and Drug Administration and the American Gastroenterological Association.

The American Medical Association resolution to recognize obesity as a disease in 2013 has no legal authority, and therefore does not represent as much progress as suggested by the media attention surrounding the announcement, said Dr. Kaplan, director of the Massachusetts General Hospital Weight Center, Boston.

The AMA resolution was preceded by the Internal Revenue Service’s determination that obesity could qualify as a medical deduction in 2007, and in 2008, the Obesity Society provided support for considering obesity as a medical disorder.

But despite these apparent signs of progress, limitations remain. Weight loss drugs are excluded under Medicare Part D coverage, and while Medicare has started coverage for nutritional counseling, only services provided in a primary care setting are covered, he pointed out. An estimated 1 of every 400 people with obesity in the United States has bariatric surgery every year, but 1 in 100-150 of every 400 meets the criteria for surgery, which "doesn’t sound like we are addressing the problem very seriously," he said.

One problem is that obesity, which has many causes, is lumped together "into one big group," raising the issue of whether treating obesity would require an investment that is so huge, "that even as a society we cannot make it."

A critical issue is how to define obesity, Dr. Kaplan said. A simple definition is excess fat accumulation that presents a risk to health, but this definition does not include ways of measuring excess fat. One measurement, body mass index, is a marker, not a definition of obesity.

A major barrier is the development of an effective therapy, he said, noting that other than gastric bands, there are no devices on the market to treat obesity, and the four drugs approved by the FDA have modest efficacy overall and are not widely used. Another major barrier is "provider utilization," getting the provider to prescribe treatments and obtain reimbursement for the costs of treatment.

"There is also a large gap between the relatively noninvasive treatments and the invasive, more effective therapies, which needs to be filled by midlevel therapies," he said. Those therapies should be gastrointestinal therapies almost exclusively, he added. The current treatment strategy is fairly simplistic: Patients are asked to change their lifestyle and when that does not work, the next step is to see a dietician, psychologist, or another professional to help with their lifestyle changes, followed by the addition of medication if that does not work. Surgery is broached in a small number of patients.

"Obesity is a disease whether we call it one or not, because it behaves like a disease," and there are implications to viewing it as a disease, he said. Therapy should be physiologically based, and the heterogeneity in the underlying causes of obesity, which explains the variable treatment responses, provides an opportunity to benefit selected subpopulations.

Considering the number of disorders that are associated with obesity, it is not surprising that treatment responses vary widely, Dr. Kaplan said. People with one defect may do better than others with gastric bypass, and some people may respond better than others to the approved combination of phentermine and topiramate (Qsymia) – as reflected in the ranges of response rates associated with these therapies, he pointed out.

The average excess weight loss with gastric bypass, the most effective therapy for obesity, is about 65%, but it can be as low as 20% in some people. With banding, some patients lose all or most of their excess weight, but most lose about 25%-30%, he said. Similarly, Dr. Kaplan found some patients responded well to treatment with sibutramine (which is no longer marketed), while others did not respond well; the same pattern was seen with lorcaserin.

"Whether you’re talking about a drug, a device, surgery, or lifestyle modifications, ... you see this very broad response," because there are subtypes of obesity, he said. Identifying the subgroups of patients that are highly responsive to any of these treatments could increase the success rate of the treatment, he noted.

[email protected]

WASHINGTON – Despite the recent attention given to considering obesity a disease, there are still many limitations to providing treatments for obesity and receiving adequate reimbursement for those treatments, Dr. Lee Kaplan said at a public workshop cosponsored by the Food and Drug Administration and the American Gastroenterological Association.

The American Medical Association resolution to recognize obesity as a disease in 2013 has no legal authority, and therefore does not represent as much progress as suggested by the media attention surrounding the announcement, said Dr. Kaplan, director of the Massachusetts General Hospital Weight Center, Boston.

The AMA resolution was preceded by the Internal Revenue Service’s determination that obesity could qualify as a medical deduction in 2007, and in 2008, the Obesity Society provided support for considering obesity as a medical disorder.

But despite these apparent signs of progress, limitations remain. Weight loss drugs are excluded under Medicare Part D coverage, and while Medicare has started coverage for nutritional counseling, only services provided in a primary care setting are covered, he pointed out. An estimated 1 of every 400 people with obesity in the United States has bariatric surgery every year, but 1 in 100-150 of every 400 meets the criteria for surgery, which "doesn’t sound like we are addressing the problem very seriously," he said.

One problem is that obesity, which has many causes, is lumped together "into one big group," raising the issue of whether treating obesity would require an investment that is so huge, "that even as a society we cannot make it."

A critical issue is how to define obesity, Dr. Kaplan said. A simple definition is excess fat accumulation that presents a risk to health, but this definition does not include ways of measuring excess fat. One measurement, body mass index, is a marker, not a definition of obesity.

A major barrier is the development of an effective therapy, he said, noting that other than gastric bands, there are no devices on the market to treat obesity, and the four drugs approved by the FDA have modest efficacy overall and are not widely used. Another major barrier is "provider utilization," getting the provider to prescribe treatments and obtain reimbursement for the costs of treatment.

"There is also a large gap between the relatively noninvasive treatments and the invasive, more effective therapies, which needs to be filled by midlevel therapies," he said. Those therapies should be gastrointestinal therapies almost exclusively, he added. The current treatment strategy is fairly simplistic: Patients are asked to change their lifestyle and when that does not work, the next step is to see a dietician, psychologist, or another professional to help with their lifestyle changes, followed by the addition of medication if that does not work. Surgery is broached in a small number of patients.

"Obesity is a disease whether we call it one or not, because it behaves like a disease," and there are implications to viewing it as a disease, he said. Therapy should be physiologically based, and the heterogeneity in the underlying causes of obesity, which explains the variable treatment responses, provides an opportunity to benefit selected subpopulations.

Considering the number of disorders that are associated with obesity, it is not surprising that treatment responses vary widely, Dr. Kaplan said. People with one defect may do better than others with gastric bypass, and some people may respond better than others to the approved combination of phentermine and topiramate (Qsymia) – as reflected in the ranges of response rates associated with these therapies, he pointed out.

The average excess weight loss with gastric bypass, the most effective therapy for obesity, is about 65%, but it can be as low as 20% in some people. With banding, some patients lose all or most of their excess weight, but most lose about 25%-30%, he said. Similarly, Dr. Kaplan found some patients responded well to treatment with sibutramine (which is no longer marketed), while others did not respond well; the same pattern was seen with lorcaserin.

"Whether you’re talking about a drug, a device, surgery, or lifestyle modifications, ... you see this very broad response," because there are subtypes of obesity, he said. Identifying the subgroups of patients that are highly responsive to any of these treatments could increase the success rate of the treatment, he noted.

[email protected]

WASHINGTON – Despite the recent attention given to considering obesity a disease, there are still many limitations to providing treatments for obesity and receiving adequate reimbursement for those treatments, Dr. Lee Kaplan said at a public workshop cosponsored by the Food and Drug Administration and the American Gastroenterological Association.

The American Medical Association resolution to recognize obesity as a disease in 2013 has no legal authority, and therefore does not represent as much progress as suggested by the media attention surrounding the announcement, said Dr. Kaplan, director of the Massachusetts General Hospital Weight Center, Boston.

The AMA resolution was preceded by the Internal Revenue Service’s determination that obesity could qualify as a medical deduction in 2007, and in 2008, the Obesity Society provided support for considering obesity as a medical disorder.

But despite these apparent signs of progress, limitations remain. Weight loss drugs are excluded under Medicare Part D coverage, and while Medicare has started coverage for nutritional counseling, only services provided in a primary care setting are covered, he pointed out. An estimated 1 of every 400 people with obesity in the United States has bariatric surgery every year, but 1 in 100-150 of every 400 meets the criteria for surgery, which "doesn’t sound like we are addressing the problem very seriously," he said.

One problem is that obesity, which has many causes, is lumped together "into one big group," raising the issue of whether treating obesity would require an investment that is so huge, "that even as a society we cannot make it."

A critical issue is how to define obesity, Dr. Kaplan said. A simple definition is excess fat accumulation that presents a risk to health, but this definition does not include ways of measuring excess fat. One measurement, body mass index, is a marker, not a definition of obesity.

A major barrier is the development of an effective therapy, he said, noting that other than gastric bands, there are no devices on the market to treat obesity, and the four drugs approved by the FDA have modest efficacy overall and are not widely used. Another major barrier is "provider utilization," getting the provider to prescribe treatments and obtain reimbursement for the costs of treatment.

"There is also a large gap between the relatively noninvasive treatments and the invasive, more effective therapies, which needs to be filled by midlevel therapies," he said. Those therapies should be gastrointestinal therapies almost exclusively, he added. The current treatment strategy is fairly simplistic: Patients are asked to change their lifestyle and when that does not work, the next step is to see a dietician, psychologist, or another professional to help with their lifestyle changes, followed by the addition of medication if that does not work. Surgery is broached in a small number of patients.

"Obesity is a disease whether we call it one or not, because it behaves like a disease," and there are implications to viewing it as a disease, he said. Therapy should be physiologically based, and the heterogeneity in the underlying causes of obesity, which explains the variable treatment responses, provides an opportunity to benefit selected subpopulations.

Considering the number of disorders that are associated with obesity, it is not surprising that treatment responses vary widely, Dr. Kaplan said. People with one defect may do better than others with gastric bypass, and some people may respond better than others to the approved combination of phentermine and topiramate (Qsymia) – as reflected in the ranges of response rates associated with these therapies, he pointed out.

The average excess weight loss with gastric bypass, the most effective therapy for obesity, is about 65%, but it can be as low as 20% in some people. With banding, some patients lose all or most of their excess weight, but most lose about 25%-30%, he said. Similarly, Dr. Kaplan found some patients responded well to treatment with sibutramine (which is no longer marketed), while others did not respond well; the same pattern was seen with lorcaserin.

"Whether you’re talking about a drug, a device, surgery, or lifestyle modifications, ... you see this very broad response," because there are subtypes of obesity, he said. Identifying the subgroups of patients that are highly responsive to any of these treatments could increase the success rate of the treatment, he noted.

[email protected]

SAN ANTONIO – Extracorporeal shock wave therapy shows early promise for limiting the often-vexing problem of lymphedema arising after axillary lymphadenectomy.

In the first 10 affected patients treated in an ongoing randomized, sham-controlled clinical trial, lymphedema, as measured by median whole-arm water displacement, dropped from 4,200 mL at baseline by 192.5 mL after 10 once-weekly extracorporeal shock wave (ECSW) sessions. Patients who received sham sessions had a 12.5-mL decline from baseline measures, Dr. Sara Imboden reported at the San Antonio Breast Cancer Symposium.

Quantitative CT measures indicated the mean total cross-sectional area of the most swollen part of the arm decreased by 3% in the ECSW group, compared with 1.4% in the control group, added Dr. Imboden of the University of Bern (Switzerland).

A mean of 22 axillary lymph nodes had been removed from the breast cancer patients in the study. The ECSW therapy was performed over the length of the edematous arm at an energy density of 0.25-0.69 mJ/mm² once per week for 10 weeks. The control group followed the same treatment schedule, but the shock waves were contained inside the probe during their sessions.

None of the patients had to interrupt ECSW therapy due to complications.

The researchers plan to expand the randomized trial to include 30 patients, and to augment the results with patient reports of symptoms based on questionnaires assessing body image and with extended follow-up to evaluate functioning and recurrences.

The likely mechanism of benefit in patients with lymphedema involves ECSW-induced stimulation of angiogenesis and lymphatic vessel regeneration. These results have been demonstrated in animal studies.

No medications have been shown effective in treating lymphedema. Conventional therapy entails repeated manual lymph drainage and compression bandages.

Dr. Imboden reported having no financial conflicts of interest with regard to this university-funded study.

[email protected]

SAN ANTONIO – Extracorporeal shock wave therapy shows early promise for limiting the often-vexing problem of lymphedema arising after axillary lymphadenectomy.

In the first 10 affected patients treated in an ongoing randomized, sham-controlled clinical trial, lymphedema, as measured by median whole-arm water displacement, dropped from 4,200 mL at baseline by 192.5 mL after 10 once-weekly extracorporeal shock wave (ECSW) sessions. Patients who received sham sessions had a 12.5-mL decline from baseline measures, Dr. Sara Imboden reported at the San Antonio Breast Cancer Symposium.

Quantitative CT measures indicated the mean total cross-sectional area of the most swollen part of the arm decreased by 3% in the ECSW group, compared with 1.4% in the control group, added Dr. Imboden of the University of Bern (Switzerland).

A mean of 22 axillary lymph nodes had been removed from the breast cancer patients in the study. The ECSW therapy was performed over the length of the edematous arm at an energy density of 0.25-0.69 mJ/mm² once per week for 10 weeks. The control group followed the same treatment schedule, but the shock waves were contained inside the probe during their sessions.

None of the patients had to interrupt ECSW therapy due to complications.

The researchers plan to expand the randomized trial to include 30 patients, and to augment the results with patient reports of symptoms based on questionnaires assessing body image and with extended follow-up to evaluate functioning and recurrences.

The likely mechanism of benefit in patients with lymphedema involves ECSW-induced stimulation of angiogenesis and lymphatic vessel regeneration. These results have been demonstrated in animal studies.

No medications have been shown effective in treating lymphedema. Conventional therapy entails repeated manual lymph drainage and compression bandages.

Dr. Imboden reported having no financial conflicts of interest with regard to this university-funded study.

[email protected]

SAN ANTONIO – Extracorporeal shock wave therapy shows early promise for limiting the often-vexing problem of lymphedema arising after axillary lymphadenectomy.

In the first 10 affected patients treated in an ongoing randomized, sham-controlled clinical trial, lymphedema, as measured by median whole-arm water displacement, dropped from 4,200 mL at baseline by 192.5 mL after 10 once-weekly extracorporeal shock wave (ECSW) sessions. Patients who received sham sessions had a 12.5-mL decline from baseline measures, Dr. Sara Imboden reported at the San Antonio Breast Cancer Symposium.

Quantitative CT measures indicated the mean total cross-sectional area of the most swollen part of the arm decreased by 3% in the ECSW group, compared with 1.4% in the control group, added Dr. Imboden of the University of Bern (Switzerland).

A mean of 22 axillary lymph nodes had been removed from the breast cancer patients in the study. The ECSW therapy was performed over the length of the edematous arm at an energy density of 0.25-0.69 mJ/mm² once per week for 10 weeks. The control group followed the same treatment schedule, but the shock waves were contained inside the probe during their sessions.

None of the patients had to interrupt ECSW therapy due to complications.

The researchers plan to expand the randomized trial to include 30 patients, and to augment the results with patient reports of symptoms based on questionnaires assessing body image and with extended follow-up to evaluate functioning and recurrences.

The likely mechanism of benefit in patients with lymphedema involves ECSW-induced stimulation of angiogenesis and lymphatic vessel regeneration. These results have been demonstrated in animal studies.

No medications have been shown effective in treating lymphedema. Conventional therapy entails repeated manual lymph drainage and compression bandages.

Dr. Imboden reported having no financial conflicts of interest with regard to this university-funded study.

[email protected]

DALLAS – Genotyping to guide the starting dosage of warfarin treatment showed no added value above tailoring treatment with a panel of clinical features in a randomized, controlled U.S. trial of more than 1,000 patients.

The resounding null result from adding genotype information should spell the end of this practice, said Dr. Stephen E. Kimmel, lead investigator for the study, and professor and director of cardiovascular epidemiology at the University of Pennsylvania in Philadelphia.

"Based on what we’ve seen, I don’t believe there is sufficient evidence to add genetic information on top of the available clinical algorithms," Dr. Kimmel said at the American Heart Association scientific sessions. "I don’t think we’ll see another genetics trial in warfarin treatment. I think this is it."

Good outcomes in the comparison group largely accounted for the failure of genotyping to significantly improve the percentage of time that patients’ international normalized ratios (INRs) were in the target range of 2.0-3.0. The amount of time in the therapeutic INR range (PTTR) averaged 45% in patients in the comparison arm during the first 4 weeks of warfarin treatment.

"When the comparison group does so well, it’s more difficult for genotyping to have an effect," said Dr. Elaine M. Hylek, professor of medicine and an anticoagulant specialist at Boston University.

That limitation, coupled with the shifting anticoagulant landscape, knock genotyping out of the picture, she agreed. "It will be difficult funding [another study of genotyping] with all the anticoagulant alternatives that are now out there" for preventing thrombosis in patients with atrial fibrillation or a recent venous thromboembolism.

Mitchel L. Zoler/Frontline Medical Communications

The Clarification of Optimal Anticoagulant through Genetics (COAG) trial enrolled 1,015 patients initiating warfarin therapy at 18 U.S. centers during September 2009 to April 2013. The study randomized patients to two different ways to calculate their warfarin dosage during the first 5 days of treatment. Half had their dosage calculated by a formula that took into account seven clinical and demographic factors, including age, race, smoking status, and body surface area. The others had their dosage calculated with the same formula and factors plus added information on the patient’s genotype for two genes that affect warfarin activity, CYP2C9 and VKORC1. Patients’ average age was 58 years; just over a quarter were African American.

During the first 4 weeks on treatment, the average PTTR was 45% in both arms of the study, the trial’s primary endpoint. Adding genotyping information led to a bigger improvement in the PTTR among the non–African American patients compared with those who were African American, but did not produce a significantly increased PTTR in the non–African American subgroup.

Dr. Munir Pirmohamed reported results from a similar study that enrolled 455 patients starting warfarin therapy at any of five centers in the United Kingdom and Sweden. The EU-Pharmacogenetics of Anticoagulant Therapy (EU-PACT) Warfarin study mainly differed from the COAG study by the background method used to calculate a starting warfarin dosage over the first 3 days of treatment. In EU-PACT, the warfarin dosage of all patients was adjusted for age but not for other factors. In the intervention arm, the starting dosages were adjusted for the status of the same two genes, CYP2C9 and VKORC1.

During the first 12 weeks after starting warfarin, the cumulative average PTTR was 67% in the patients whose dose was adjusted by genotype and 60% in patients who were not genotyped, a statistically significant difference for this study’s primary endpoint, reported Dr. Pirmohamed, professor and head of molecular and clinical pharmacology at the University of Liverpool, England.

Taken together, the findings of the two studies highlight that patients should not start warfarin treatment on a fixed dosage, said Dr. Patrick T. Ellinor, a cardiologist and arrhythmia specialist at Massachusetts General Hospital, Boston, and designated discussant for both reports at the meeting. The findings support use of a clinical algorithm that takes into account several clinical factors, he added.

Concurrently with the meeting, the reports were published online for COAG (N. Engl. J. Med. 2013 [doi:10.1056/NEJMoa1310669]) and for EU-PACT (N. Engl. J. Med. 2013 [doi:10.1056/NEJMoa1311386]).

The COAG and EU-PACT studies did not receive any direct commercial sponsorship. Dr. Kimmel has been a consultant to Pfizer and Janssen. Dr. Hylek has been a consultant or adviser to Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Johnson & Johnson, and Pfizer. Dr. Pirmohamed and Dr. Ellinor had no disclosures.

Warfarin on top despite competition

Warfarin remains the most widely used anticoagulant in the United States. Among patients with atrial fibrillation taking anticoagulation treatment, 72% used warfarin during the third quarter of 2013, data from a large registry show.

The new anticoagulants on the U.S. market – dabigatran (Pradaxa), apixaban (Eliquis), and rivaroxaban (Xarelto) – are gaining ground and widely acknowledged to be better, safer, and easier to manage. But warfarin clings to the market largely because of familiarity and low price, according to several experts.

Mitchel L. Zoler/Frontline Medical Communications

"There is no doubt that the new anticoagulants look better compared with warfarin, but the clinical fact is that it’s what you know versus what you don’t know, and warfarin has been used for 60 years," Dr. Kimmel said at the press conference.

"The new drugs perform better than warfarin does; they get patients to where they need to be more quickly, but warfarin has been around a long time. We know its interactions and risks, there is the ability to reverse its effect, and the cost to patients is a real issue. If the new anticoagulants were the same price as warfarin then I think you’d see a lot more patients get a new drug," Dr. Ellinor said in an interview.

Data on current U.S. uptake of the new oral anticoagulants came from the 148,320 unique patients with atrial fibrillation included during June to September of 2013 in the PINNACLE Registry database run by the American College of Cardiology. Among these patients, about 83,000 (56%) were on some anticoagulant treatment, and within this subgroup, 72% were on warfarin, 27% on a new anticoagulant, and the remainder on different treatment, said Dr. John Gordon Harold, ACC president and a cardiologist at Cedars-Sinai Heart Institute in Los Angeles.

"In my own practice the new anticoagulants are being used with increasing frequency, mainly driven by direct-to-consumer advertising," Dr. Harold said in an interview. "We have patients who are completely stable on warfarin. (They) come in because of a consumer ad and they ask if they should switch drugs. When patients are stable I don’t encourage them to switch, but we have a shared decision making conversation and go over the pros and cons, the cost, and the outcomes data. A lot of patients prefer to pay the difference" and switch to a new anticoagulant.

Dr. Harold said he also recommends that patients switch off warfarin if they have problems with compliance and variability in their international normalized ratio (INR).

"If you can keep a patient on warfarin in their INR target range 80% or more of the time then I wouldn’t change, but most patients on warfarin have a very hard time maintaining an INR of 2-3," said Dr. Mark S. Link, professor and codirector of the cardiac arrhythmia center at Tufts Medical Center, Boston. But he said cost is a major factor keeping many patients on warfarin.

The new anticoagulants "are better than warfarin, but we are often forced by insurers to start with the cheaper drug," Dr. Link said during the news conference.

The COAG and EU-PACT studies did not receive any direct commercial sponsorship. Dr. Kimmel has been a consultant to Pfizer and Janssen. Dr. Hylek has been a consultant or adviser to Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Johnson & Johnson, and Pfizer. Dr. Pirmohamed, Dr. Ellinor, Dr. Harold, and Dr. Link had no relevant disclosures.

[email protected]

On Twitter @mitchelzoler

DALLAS – Genotyping to guide the starting dosage of warfarin treatment showed no added value above tailoring treatment with a panel of clinical features in a randomized, controlled U.S. trial of more than 1,000 patients.

The resounding null result from adding genotype information should spell the end of this practice, said Dr. Stephen E. Kimmel, lead investigator for the study, and professor and director of cardiovascular epidemiology at the University of Pennsylvania in Philadelphia.

"Based on what we’ve seen, I don’t believe there is sufficient evidence to add genetic information on top of the available clinical algorithms," Dr. Kimmel said at the American Heart Association scientific sessions. "I don’t think we’ll see another genetics trial in warfarin treatment. I think this is it."

Good outcomes in the comparison group largely accounted for the failure of genotyping to significantly improve the percentage of time that patients’ international normalized ratios (INRs) were in the target range of 2.0-3.0. The amount of time in the therapeutic INR range (PTTR) averaged 45% in patients in the comparison arm during the first 4 weeks of warfarin treatment.

"When the comparison group does so well, it’s more difficult for genotyping to have an effect," said Dr. Elaine M. Hylek, professor of medicine and an anticoagulant specialist at Boston University.

That limitation, coupled with the shifting anticoagulant landscape, knock genotyping out of the picture, she agreed. "It will be difficult funding [another study of genotyping] with all the anticoagulant alternatives that are now out there" for preventing thrombosis in patients with atrial fibrillation or a recent venous thromboembolism.

Mitchel L. Zoler/Frontline Medical Communications

The Clarification of Optimal Anticoagulant through Genetics (COAG) trial enrolled 1,015 patients initiating warfarin therapy at 18 U.S. centers during September 2009 to April 2013. The study randomized patients to two different ways to calculate their warfarin dosage during the first 5 days of treatment. Half had their dosage calculated by a formula that took into account seven clinical and demographic factors, including age, race, smoking status, and body surface area. The others had their dosage calculated with the same formula and factors plus added information on the patient’s genotype for two genes that affect warfarin activity, CYP2C9 and VKORC1. Patients’ average age was 58 years; just over a quarter were African American.

During the first 4 weeks on treatment, the average PTTR was 45% in both arms of the study, the trial’s primary endpoint. Adding genotyping information led to a bigger improvement in the PTTR among the non–African American patients compared with those who were African American, but did not produce a significantly increased PTTR in the non–African American subgroup.

Dr. Munir Pirmohamed reported results from a similar study that enrolled 455 patients starting warfarin therapy at any of five centers in the United Kingdom and Sweden. The EU-Pharmacogenetics of Anticoagulant Therapy (EU-PACT) Warfarin study mainly differed from the COAG study by the background method used to calculate a starting warfarin dosage over the first 3 days of treatment. In EU-PACT, the warfarin dosage of all patients was adjusted for age but not for other factors. In the intervention arm, the starting dosages were adjusted for the status of the same two genes, CYP2C9 and VKORC1.

During the first 12 weeks after starting warfarin, the cumulative average PTTR was 67% in the patients whose dose was adjusted by genotype and 60% in patients who were not genotyped, a statistically significant difference for this study’s primary endpoint, reported Dr. Pirmohamed, professor and head of molecular and clinical pharmacology at the University of Liverpool, England.

Taken together, the findings of the two studies highlight that patients should not start warfarin treatment on a fixed dosage, said Dr. Patrick T. Ellinor, a cardiologist and arrhythmia specialist at Massachusetts General Hospital, Boston, and designated discussant for both reports at the meeting. The findings support use of a clinical algorithm that takes into account several clinical factors, he added.

Concurrently with the meeting, the reports were published online for COAG (N. Engl. J. Med. 2013 [doi:10.1056/NEJMoa1310669]) and for EU-PACT (N. Engl. J. Med. 2013 [doi:10.1056/NEJMoa1311386]).

The COAG and EU-PACT studies did not receive any direct commercial sponsorship. Dr. Kimmel has been a consultant to Pfizer and Janssen. Dr. Hylek has been a consultant or adviser to Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Johnson & Johnson, and Pfizer. Dr. Pirmohamed and Dr. Ellinor had no disclosures.

Warfarin on top despite competition

Warfarin remains the most widely used anticoagulant in the United States. Among patients with atrial fibrillation taking anticoagulation treatment, 72% used warfarin during the third quarter of 2013, data from a large registry show.

The new anticoagulants on the U.S. market – dabigatran (Pradaxa), apixaban (Eliquis), and rivaroxaban (Xarelto) – are gaining ground and widely acknowledged to be better, safer, and easier to manage. But warfarin clings to the market largely because of familiarity and low price, according to several experts.

Mitchel L. Zoler/Frontline Medical Communications

"There is no doubt that the new anticoagulants look better compared with warfarin, but the clinical fact is that it’s what you know versus what you don’t know, and warfarin has been used for 60 years," Dr. Kimmel said at the press conference.

"The new drugs perform better than warfarin does; they get patients to where they need to be more quickly, but warfarin has been around a long time. We know its interactions and risks, there is the ability to reverse its effect, and the cost to patients is a real issue. If the new anticoagulants were the same price as warfarin then I think you’d see a lot more patients get a new drug," Dr. Ellinor said in an interview.

Data on current U.S. uptake of the new oral anticoagulants came from the 148,320 unique patients with atrial fibrillation included during June to September of 2013 in the PINNACLE Registry database run by the American College of Cardiology. Among these patients, about 83,000 (56%) were on some anticoagulant treatment, and within this subgroup, 72% were on warfarin, 27% on a new anticoagulant, and the remainder on different treatment, said Dr. John Gordon Harold, ACC president and a cardiologist at Cedars-Sinai Heart Institute in Los Angeles.

"In my own practice the new anticoagulants are being used with increasing frequency, mainly driven by direct-to-consumer advertising," Dr. Harold said in an interview. "We have patients who are completely stable on warfarin. (They) come in because of a consumer ad and they ask if they should switch drugs. When patients are stable I don’t encourage them to switch, but we have a shared decision making conversation and go over the pros and cons, the cost, and the outcomes data. A lot of patients prefer to pay the difference" and switch to a new anticoagulant.

Dr. Harold said he also recommends that patients switch off warfarin if they have problems with compliance and variability in their international normalized ratio (INR).

"If you can keep a patient on warfarin in their INR target range 80% or more of the time then I wouldn’t change, but most patients on warfarin have a very hard time maintaining an INR of 2-3," said Dr. Mark S. Link, professor and codirector of the cardiac arrhythmia center at Tufts Medical Center, Boston. But he said cost is a major factor keeping many patients on warfarin.

The new anticoagulants "are better than warfarin, but we are often forced by insurers to start with the cheaper drug," Dr. Link said during the news conference.

The COAG and EU-PACT studies did not receive any direct commercial sponsorship. Dr. Kimmel has been a consultant to Pfizer and Janssen. Dr. Hylek has been a consultant or adviser to Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Johnson & Johnson, and Pfizer. Dr. Pirmohamed, Dr. Ellinor, Dr. Harold, and Dr. Link had no relevant disclosures.

[email protected]

On Twitter @mitchelzoler

DALLAS – Genotyping to guide the starting dosage of warfarin treatment showed no added value above tailoring treatment with a panel of clinical features in a randomized, controlled U.S. trial of more than 1,000 patients.

The resounding null result from adding genotype information should spell the end of this practice, said Dr. Stephen E. Kimmel, lead investigator for the study, and professor and director of cardiovascular epidemiology at the University of Pennsylvania in Philadelphia.

"Based on what we’ve seen, I don’t believe there is sufficient evidence to add genetic information on top of the available clinical algorithms," Dr. Kimmel said at the American Heart Association scientific sessions. "I don’t think we’ll see another genetics trial in warfarin treatment. I think this is it."

Good outcomes in the comparison group largely accounted for the failure of genotyping to significantly improve the percentage of time that patients’ international normalized ratios (INRs) were in the target range of 2.0-3.0. The amount of time in the therapeutic INR range (PTTR) averaged 45% in patients in the comparison arm during the first 4 weeks of warfarin treatment.

"When the comparison group does so well, it’s more difficult for genotyping to have an effect," said Dr. Elaine M. Hylek, professor of medicine and an anticoagulant specialist at Boston University.

That limitation, coupled with the shifting anticoagulant landscape, knock genotyping out of the picture, she agreed. "It will be difficult funding [another study of genotyping] with all the anticoagulant alternatives that are now out there" for preventing thrombosis in patients with atrial fibrillation or a recent venous thromboembolism.

Mitchel L. Zoler/Frontline Medical Communications

The Clarification of Optimal Anticoagulant through Genetics (COAG) trial enrolled 1,015 patients initiating warfarin therapy at 18 U.S. centers during September 2009 to April 2013. The study randomized patients to two different ways to calculate their warfarin dosage during the first 5 days of treatment. Half had their dosage calculated by a formula that took into account seven clinical and demographic factors, including age, race, smoking status, and body surface area. The others had their dosage calculated with the same formula and factors plus added information on the patient’s genotype for two genes that affect warfarin activity, CYP2C9 and VKORC1. Patients’ average age was 58 years; just over a quarter were African American.

During the first 4 weeks on treatment, the average PTTR was 45% in both arms of the study, the trial’s primary endpoint. Adding genotyping information led to a bigger improvement in the PTTR among the non–African American patients compared with those who were African American, but did not produce a significantly increased PTTR in the non–African American subgroup.

Dr. Munir Pirmohamed reported results from a similar study that enrolled 455 patients starting warfarin therapy at any of five centers in the United Kingdom and Sweden. The EU-Pharmacogenetics of Anticoagulant Therapy (EU-PACT) Warfarin study mainly differed from the COAG study by the background method used to calculate a starting warfarin dosage over the first 3 days of treatment. In EU-PACT, the warfarin dosage of all patients was adjusted for age but not for other factors. In the intervention arm, the starting dosages were adjusted for the status of the same two genes, CYP2C9 and VKORC1.

During the first 12 weeks after starting warfarin, the cumulative average PTTR was 67% in the patients whose dose was adjusted by genotype and 60% in patients who were not genotyped, a statistically significant difference for this study’s primary endpoint, reported Dr. Pirmohamed, professor and head of molecular and clinical pharmacology at the University of Liverpool, England.

Taken together, the findings of the two studies highlight that patients should not start warfarin treatment on a fixed dosage, said Dr. Patrick T. Ellinor, a cardiologist and arrhythmia specialist at Massachusetts General Hospital, Boston, and designated discussant for both reports at the meeting. The findings support use of a clinical algorithm that takes into account several clinical factors, he added.

Concurrently with the meeting, the reports were published online for COAG (N. Engl. J. Med. 2013 [doi:10.1056/NEJMoa1310669]) and for EU-PACT (N. Engl. J. Med. 2013 [doi:10.1056/NEJMoa1311386]).

The COAG and EU-PACT studies did not receive any direct commercial sponsorship. Dr. Kimmel has been a consultant to Pfizer and Janssen. Dr. Hylek has been a consultant or adviser to Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Johnson & Johnson, and Pfizer. Dr. Pirmohamed and Dr. Ellinor had no disclosures.

Warfarin on top despite competition

Warfarin remains the most widely used anticoagulant in the United States. Among patients with atrial fibrillation taking anticoagulation treatment, 72% used warfarin during the third quarter of 2013, data from a large registry show.

The new anticoagulants on the U.S. market – dabigatran (Pradaxa), apixaban (Eliquis), and rivaroxaban (Xarelto) – are gaining ground and widely acknowledged to be better, safer, and easier to manage. But warfarin clings to the market largely because of familiarity and low price, according to several experts.

Mitchel L. Zoler/Frontline Medical Communications

"There is no doubt that the new anticoagulants look better compared with warfarin, but the clinical fact is that it’s what you know versus what you don’t know, and warfarin has been used for 60 years," Dr. Kimmel said at the press conference.

"The new drugs perform better than warfarin does; they get patients to where they need to be more quickly, but warfarin has been around a long time. We know its interactions and risks, there is the ability to reverse its effect, and the cost to patients is a real issue. If the new anticoagulants were the same price as warfarin then I think you’d see a lot more patients get a new drug," Dr. Ellinor said in an interview.

Data on current U.S. uptake of the new oral anticoagulants came from the 148,320 unique patients with atrial fibrillation included during June to September of 2013 in the PINNACLE Registry database run by the American College of Cardiology. Among these patients, about 83,000 (56%) were on some anticoagulant treatment, and within this subgroup, 72% were on warfarin, 27% on a new anticoagulant, and the remainder on different treatment, said Dr. John Gordon Harold, ACC president and a cardiologist at Cedars-Sinai Heart Institute in Los Angeles.

"In my own practice the new anticoagulants are being used with increasing frequency, mainly driven by direct-to-consumer advertising," Dr. Harold said in an interview. "We have patients who are completely stable on warfarin. (They) come in because of a consumer ad and they ask if they should switch drugs. When patients are stable I don’t encourage them to switch, but we have a shared decision making conversation and go over the pros and cons, the cost, and the outcomes data. A lot of patients prefer to pay the difference" and switch to a new anticoagulant.

Dr. Harold said he also recommends that patients switch off warfarin if they have problems with compliance and variability in their international normalized ratio (INR).

"If you can keep a patient on warfarin in their INR target range 80% or more of the time then I wouldn’t change, but most patients on warfarin have a very hard time maintaining an INR of 2-3," said Dr. Mark S. Link, professor and codirector of the cardiac arrhythmia center at Tufts Medical Center, Boston. But he said cost is a major factor keeping many patients on warfarin.

The new anticoagulants "are better than warfarin, but we are often forced by insurers to start with the cheaper drug," Dr. Link said during the news conference.

The COAG and EU-PACT studies did not receive any direct commercial sponsorship. Dr. Kimmel has been a consultant to Pfizer and Janssen. Dr. Hylek has been a consultant or adviser to Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Johnson & Johnson, and Pfizer. Dr. Pirmohamed, Dr. Ellinor, Dr. Harold, and Dr. Link had no relevant disclosures.

[email protected]

On Twitter @mitchelzoler

SAN ANTONIO – Surgical removal of the primary tumor and affected lymph nodes afforded no overall survival benefit in women who had metastatic breast cancer at initial presentation, according to a pair of randomized trials presented at the San Antonio Breast Cancer Symposium.

In a first trial, conducted among 350 women in India who had responded to initial chemotherapy, about 20% of the women were still alive at 5 years regardless of whether they had surgery or just received more systemic therapy, first author Dr. Rajendra Badwe, director of the Tata Memorial Hospital in Mumbai, India, reported in a session and at a press briefing.

Superior locoregional control conferred by surgery was canceled out by a higher risk of progression in distant sites, lending support to more than 20-year-old preclinical data by Dr. Bernard Fisher and his colleagues suggesting that an intact primary suppresses growth of distant metastases (Cancer Res. 1989;49:1996-2001).

"Locoregional treatment of the primary tumor in women presenting with metastatic breast cancer did not result in any overall survival benefit and hence should not be offered as a routine practice," Dr. Badwe commented.

"The biological fallout of this study is that surgical removal of the primary tumor in these women appears to confer a growth advantage on distant metastases. ... This is the first time that we have evidence in human studies that locoregional treatment has a great kinetic effect on distant metastases," he added.

In a second trial, conducted among 293 women in Turkey with untreated de novo metastatic breast cancer, median estimated survival was statistically indistinguishable, at about 3.5 years, regardless of whether women had up-front surgery or simply systemic therapy, first author Dr. Atilla Soran reported in a session on behalf of the Turkish Federation of Societies for Breast Diseases.

Subgroup analyses suggested that surgery conferred a survival advantage among women with solitary bone metastases but a survival disadvantage among women with multiple liver or lung metastases.

The rate of locoregional progression was one-fifth as high with surgery as with systemic therapy.

"There was no statistically significant difference in overall survival at early follow-up, but we need longer follow-up," Dr. Soran commented. "There were potentially important subgroup differences."

The two trials have implications – both for other ongoing trials and for patient care – according to invited discussant Dr. Seema A. Khan, a professor of surgery and Bluhm Family Professor of Cancer Research at Northwestern University, Chicago, and a physician at the university’s Lynn Sage Breast Center.

"A large benefit of primary site local therapy seems unlikely based on the data we saw today," she maintained. "The assumptions we have used in our ongoing trial designs will need to be reassessed. Preplanned pooled analyses may yield sufficient power to detect smaller differences."

As for patient care, "it is pretty clear that at this point in time, we have to make sure that our patients understand that there is really no proven survival advantage to primary site local therapy," Dr. Khan said. "So I don’t think this treatment should be offered to patients with asymptomatic tumors unless they are participating in a clinical trial. There may be a local control advantage; we need to see more data on that."

Indian trial

Participants in the Indian trial, conducted between 2005 and 2013, were women with de novo metastatic breast cancer who had had a complete or partial response to anthracycline chemotherapy alone or with a taxane.

They were randomized evenly to receive locoregional therapy (lumpectomy or mastectomy with axillary lymph node dissection, plus radiation therapy to the chest wall or breast and lymph nodes) or no locoregional therapy as a control. Both groups received hormonal therapy if indicated.

In the control group, about 10% of women underwent a palliative mastectomy because of impending fungation or pain in the breast, as permitted by study protocol, according to Dr. Badwe.

The patients thus received contemporary therapy, he said, except that the 16% with HER2-positive disease did not receive the targeted agent trastuzumab (Herceptin).

Results showed that median overall survival was about 18 months, and the 5-year rate was 19.2% with locoregional therapy and 20.5% without it, a nonsignificant difference. "Uniformly, there was no difference at all in any subsets," Dr. Badwe reported.

The study had a one-sided superiority design, he noted. "We wouldn’t have been able to see a 2.5- or 3-month difference, or a 4% detriment" in overall survival.

The surgery group had a lower risk of local progression-free survival events (hazard ratio, 0.16; P = .00), but a higher risk of distant progression-free survival events (HR, 1.42; P = .01).

Several theories might explain why removal of the primary would accelerate growth of metastases, according to Dr. Badwe.

"The first and the foremost is that the act of surgery itself might elaborate some growth factors which might allow metastatic disease to grow. The second possibility, which was suggested by Dr. Fisher (Cancer Res. 1989;49:1996-2001) is that the primary tumor, which predates the onset of distant metastases, elaborates some inhibitory factors, and they are not there once the primary tumor is removed, bestowing autonomy of growth on the distant metastases," he explained. "And the third possibility is the act of surgery might induce some more metastatic processes by dissemination and create new disease."

Session attendee Dr. Steven Vogl, an oncologist in the Bronx, N.Y., said, "The ascertainment of disease progression requires disease that you can follow. A woman with bone-only metastases with her cancer in place, you can tell when her cancer is getting worse because the primary site or the axillary nodes are getting bigger. It’s much more difficult if you’ve taken those off and irradiated the chest wall. Have you looked at your data to see if that’s what was going on, why you had more distant metastases, because they couldn’t progress locally? This is a medical trial explanation that contradicts Fisher’s biologic hypothesis."

"There was a fixed time duration at which systemic investigations were performed to assess whether the distant metastases progressed," Dr. Badwe replied. If anything, the patients who did not have surgery had more assessments of their distant metastases, he said.

Dr. Tari A. King, a session attendee from the Memorial Sloan-Kettering Cancer Center, New York, noted that a lack of HER2 therapy in the trial may have had a large effect.

"We do have prospective registry data here [abstract 18-09, presented in a poster session] from a trial that we completed in the United States sponsored by the Translational Breast Cancer Research Consortium, and the patients in our study, whether they received surgery or not, their 2-year overall survival is far superior to what you’ve just showed us," she commented. "So I’m not sure that we can really apply your data to the modern targeted therapy regimens that we see in the United States."

Turkish trial

The Turkish trial, known as the MF07-01 trial, was conduced between 2008 and 2012 among treatment-naïve patients.

They were randomized evenly to receive either systemic therapy alone or surgery for the primary tumor (with or without axillary dissection) followed by radiation therapy if indicated, plus systemic therapy.

All patients received hormonal therapy as needed, and those with HER2-positive disease received trastuzumab.

With a median follow-up of 18 months, the median overall survival was 46 months with initial surgery and 42 months with initial systemic therapy, a nonsignificant difference, reported Dr. Soran, who disclosed no relevant conflicts of interest.

In unplanned subgroup analyses, the findings were similar for most subgroups of patients. However, surgery yielded superior survival in patients with solitary bone metastases (not reached vs. 42 months, P = .02) and inferior survival in patients having multiple liver or pulmonary metastases (16 months vs. not reached, P = .02).

The rate of locoregional progression was much lower with initial surgery than with initial systemic therapy (0.7% vs. 3.6%).

Dr. Soran emphasized that the trial’s planned median follow-up is 36 months, so the presented results are only preliminary. Quality of life and morbidity analyses are ongoing.

Dr. Badwe and Dr. Soran disclosed no relevant conflicts of interest.

SAN ANTONIO – Surgical removal of the primary tumor and affected lymph nodes afforded no overall survival benefit in women who had metastatic breast cancer at initial presentation, according to a pair of randomized trials presented at the San Antonio Breast Cancer Symposium.

In a first trial, conducted among 350 women in India who had responded to initial chemotherapy, about 20% of the women were still alive at 5 years regardless of whether they had surgery or just received more systemic therapy, first author Dr. Rajendra Badwe, director of the Tata Memorial Hospital in Mumbai, India, reported in a session and at a press briefing.

Superior locoregional control conferred by surgery was canceled out by a higher risk of progression in distant sites, lending support to more than 20-year-old preclinical data by Dr. Bernard Fisher and his colleagues suggesting that an intact primary suppresses growth of distant metastases (Cancer Res. 1989;49:1996-2001).

"Locoregional treatment of the primary tumor in women presenting with metastatic breast cancer did not result in any overall survival benefit and hence should not be offered as a routine practice," Dr. Badwe commented.

"The biological fallout of this study is that surgical removal of the primary tumor in these women appears to confer a growth advantage on distant metastases. ... This is the first time that we have evidence in human studies that locoregional treatment has a great kinetic effect on distant metastases," he added.

In a second trial, conducted among 293 women in Turkey with untreated de novo metastatic breast cancer, median estimated survival was statistically indistinguishable, at about 3.5 years, regardless of whether women had up-front surgery or simply systemic therapy, first author Dr. Atilla Soran reported in a session on behalf of the Turkish Federation of Societies for Breast Diseases.

Subgroup analyses suggested that surgery conferred a survival advantage among women with solitary bone metastases but a survival disadvantage among women with multiple liver or lung metastases.

The rate of locoregional progression was one-fifth as high with surgery as with systemic therapy.

"There was no statistically significant difference in overall survival at early follow-up, but we need longer follow-up," Dr. Soran commented. "There were potentially important subgroup differences."

The two trials have implications – both for other ongoing trials and for patient care – according to invited discussant Dr. Seema A. Khan, a professor of surgery and Bluhm Family Professor of Cancer Research at Northwestern University, Chicago, and a physician at the university’s Lynn Sage Breast Center.

"A large benefit of primary site local therapy seems unlikely based on the data we saw today," she maintained. "The assumptions we have used in our ongoing trial designs will need to be reassessed. Preplanned pooled analyses may yield sufficient power to detect smaller differences."

As for patient care, "it is pretty clear that at this point in time, we have to make sure that our patients understand that there is really no proven survival advantage to primary site local therapy," Dr. Khan said. "So I don’t think this treatment should be offered to patients with asymptomatic tumors unless they are participating in a clinical trial. There may be a local control advantage; we need to see more data on that."

Indian trial

Participants in the Indian trial, conducted between 2005 and 2013, were women with de novo metastatic breast cancer who had had a complete or partial response to anthracycline chemotherapy alone or with a taxane.

They were randomized evenly to receive locoregional therapy (lumpectomy or mastectomy with axillary lymph node dissection, plus radiation therapy to the chest wall or breast and lymph nodes) or no locoregional therapy as a control. Both groups received hormonal therapy if indicated.

In the control group, about 10% of women underwent a palliative mastectomy because of impending fungation or pain in the breast, as permitted by study protocol, according to Dr. Badwe.

The patients thus received contemporary therapy, he said, except that the 16% with HER2-positive disease did not receive the targeted agent trastuzumab (Herceptin).

Results showed that median overall survival was about 18 months, and the 5-year rate was 19.2% with locoregional therapy and 20.5% without it, a nonsignificant difference. "Uniformly, there was no difference at all in any subsets," Dr. Badwe reported.

The study had a one-sided superiority design, he noted. "We wouldn’t have been able to see a 2.5- or 3-month difference, or a 4% detriment" in overall survival.

The surgery group had a lower risk of local progression-free survival events (hazard ratio, 0.16; P = .00), but a higher risk of distant progression-free survival events (HR, 1.42; P = .01).

Several theories might explain why removal of the primary would accelerate growth of metastases, according to Dr. Badwe.

"The first and the foremost is that the act of surgery itself might elaborate some growth factors which might allow metastatic disease to grow. The second possibility, which was suggested by Dr. Fisher (Cancer Res. 1989;49:1996-2001) is that the primary tumor, which predates the onset of distant metastases, elaborates some inhibitory factors, and they are not there once the primary tumor is removed, bestowing autonomy of growth on the distant metastases," he explained. "And the third possibility is the act of surgery might induce some more metastatic processes by dissemination and create new disease."

Session attendee Dr. Steven Vogl, an oncologist in the Bronx, N.Y., said, "The ascertainment of disease progression requires disease that you can follow. A woman with bone-only metastases with her cancer in place, you can tell when her cancer is getting worse because the primary site or the axillary nodes are getting bigger. It’s much more difficult if you’ve taken those off and irradiated the chest wall. Have you looked at your data to see if that’s what was going on, why you had more distant metastases, because they couldn’t progress locally? This is a medical trial explanation that contradicts Fisher’s biologic hypothesis."

"There was a fixed time duration at which systemic investigations were performed to assess whether the distant metastases progressed," Dr. Badwe replied. If anything, the patients who did not have surgery had more assessments of their distant metastases, he said.

Dr. Tari A. King, a session attendee from the Memorial Sloan-Kettering Cancer Center, New York, noted that a lack of HER2 therapy in the trial may have had a large effect.

"We do have prospective registry data here [abstract 18-09, presented in a poster session] from a trial that we completed in the United States sponsored by the Translational Breast Cancer Research Consortium, and the patients in our study, whether they received surgery or not, their 2-year overall survival is far superior to what you’ve just showed us," she commented. "So I’m not sure that we can really apply your data to the modern targeted therapy regimens that we see in the United States."

Turkish trial

The Turkish trial, known as the MF07-01 trial, was conduced between 2008 and 2012 among treatment-naïve patients.

They were randomized evenly to receive either systemic therapy alone or surgery for the primary tumor (with or without axillary dissection) followed by radiation therapy if indicated, plus systemic therapy.

All patients received hormonal therapy as needed, and those with HER2-positive disease received trastuzumab.

With a median follow-up of 18 months, the median overall survival was 46 months with initial surgery and 42 months with initial systemic therapy, a nonsignificant difference, reported Dr. Soran, who disclosed no relevant conflicts of interest.

In unplanned subgroup analyses, the findings were similar for most subgroups of patients. However, surgery yielded superior survival in patients with solitary bone metastases (not reached vs. 42 months, P = .02) and inferior survival in patients having multiple liver or pulmonary metastases (16 months vs. not reached, P = .02).

The rate of locoregional progression was much lower with initial surgery than with initial systemic therapy (0.7% vs. 3.6%).

Dr. Soran emphasized that the trial’s planned median follow-up is 36 months, so the presented results are only preliminary. Quality of life and morbidity analyses are ongoing.

Dr. Badwe and Dr. Soran disclosed no relevant conflicts of interest.

SAN ANTONIO – Surgical removal of the primary tumor and affected lymph nodes afforded no overall survival benefit in women who had metastatic breast cancer at initial presentation, according to a pair of randomized trials presented at the San Antonio Breast Cancer Symposium.

In a first trial, conducted among 350 women in India who had responded to initial chemotherapy, about 20% of the women were still alive at 5 years regardless of whether they had surgery or just received more systemic therapy, first author Dr. Rajendra Badwe, director of the Tata Memorial Hospital in Mumbai, India, reported in a session and at a press briefing.

Superior locoregional control conferred by surgery was canceled out by a higher risk of progression in distant sites, lending support to more than 20-year-old preclinical data by Dr. Bernard Fisher and his colleagues suggesting that an intact primary suppresses growth of distant metastases (Cancer Res. 1989;49:1996-2001).

"Locoregional treatment of the primary tumor in women presenting with metastatic breast cancer did not result in any overall survival benefit and hence should not be offered as a routine practice," Dr. Badwe commented.

"The biological fallout of this study is that surgical removal of the primary tumor in these women appears to confer a growth advantage on distant metastases. ... This is the first time that we have evidence in human studies that locoregional treatment has a great kinetic effect on distant metastases," he added.

In a second trial, conducted among 293 women in Turkey with untreated de novo metastatic breast cancer, median estimated survival was statistically indistinguishable, at about 3.5 years, regardless of whether women had up-front surgery or simply systemic therapy, first author Dr. Atilla Soran reported in a session on behalf of the Turkish Federation of Societies for Breast Diseases.

Subgroup analyses suggested that surgery conferred a survival advantage among women with solitary bone metastases but a survival disadvantage among women with multiple liver or lung metastases.

The rate of locoregional progression was one-fifth as high with surgery as with systemic therapy.

"There was no statistically significant difference in overall survival at early follow-up, but we need longer follow-up," Dr. Soran commented. "There were potentially important subgroup differences."

The two trials have implications – both for other ongoing trials and for patient care – according to invited discussant Dr. Seema A. Khan, a professor of surgery and Bluhm Family Professor of Cancer Research at Northwestern University, Chicago, and a physician at the university’s Lynn Sage Breast Center.

"A large benefit of primary site local therapy seems unlikely based on the data we saw today," she maintained. "The assumptions we have used in our ongoing trial designs will need to be reassessed. Preplanned pooled analyses may yield sufficient power to detect smaller differences."

As for patient care, "it is pretty clear that at this point in time, we have to make sure that our patients understand that there is really no proven survival advantage to primary site local therapy," Dr. Khan said. "So I don’t think this treatment should be offered to patients with asymptomatic tumors unless they are participating in a clinical trial. There may be a local control advantage; we need to see more data on that."

Indian trial

Participants in the Indian trial, conducted between 2005 and 2013, were women with de novo metastatic breast cancer who had had a complete or partial response to anthracycline chemotherapy alone or with a taxane.

They were randomized evenly to receive locoregional therapy (lumpectomy or mastectomy with axillary lymph node dissection, plus radiation therapy to the chest wall or breast and lymph nodes) or no locoregional therapy as a control. Both groups received hormonal therapy if indicated.

In the control group, about 10% of women underwent a palliative mastectomy because of impending fungation or pain in the breast, as permitted by study protocol, according to Dr. Badwe.

The patients thus received contemporary therapy, he said, except that the 16% with HER2-positive disease did not receive the targeted agent trastuzumab (Herceptin).

Results showed that median overall survival was about 18 months, and the 5-year rate was 19.2% with locoregional therapy and 20.5% without it, a nonsignificant difference. "Uniformly, there was no difference at all in any subsets," Dr. Badwe reported.

The study had a one-sided superiority design, he noted. "We wouldn’t have been able to see a 2.5- or 3-month difference, or a 4% detriment" in overall survival.

The surgery group had a lower risk of local progression-free survival events (hazard ratio, 0.16; P = .00), but a higher risk of distant progression-free survival events (HR, 1.42; P = .01).

Several theories might explain why removal of the primary would accelerate growth of metastases, according to Dr. Badwe.

"The first and the foremost is that the act of surgery itself might elaborate some growth factors which might allow metastatic disease to grow. The second possibility, which was suggested by Dr. Fisher (Cancer Res. 1989;49:1996-2001) is that the primary tumor, which predates the onset of distant metastases, elaborates some inhibitory factors, and they are not there once the primary tumor is removed, bestowing autonomy of growth on the distant metastases," he explained. "And the third possibility is the act of surgery might induce some more metastatic processes by dissemination and create new disease."

Session attendee Dr. Steven Vogl, an oncologist in the Bronx, N.Y., said, "The ascertainment of disease progression requires disease that you can follow. A woman with bone-only metastases with her cancer in place, you can tell when her cancer is getting worse because the primary site or the axillary nodes are getting bigger. It’s much more difficult if you’ve taken those off and irradiated the chest wall. Have you looked at your data to see if that’s what was going on, why you had more distant metastases, because they couldn’t progress locally? This is a medical trial explanation that contradicts Fisher’s biologic hypothesis."

"There was a fixed time duration at which systemic investigations were performed to assess whether the distant metastases progressed," Dr. Badwe replied. If anything, the patients who did not have surgery had more assessments of their distant metastases, he said.

Dr. Tari A. King, a session attendee from the Memorial Sloan-Kettering Cancer Center, New York, noted that a lack of HER2 therapy in the trial may have had a large effect.

"We do have prospective registry data here [abstract 18-09, presented in a poster session] from a trial that we completed in the United States sponsored by the Translational Breast Cancer Research Consortium, and the patients in our study, whether they received surgery or not, their 2-year overall survival is far superior to what you’ve just showed us," she commented. "So I’m not sure that we can really apply your data to the modern targeted therapy regimens that we see in the United States."

Turkish trial

The Turkish trial, known as the MF07-01 trial, was conduced between 2008 and 2012 among treatment-naïve patients.

They were randomized evenly to receive either systemic therapy alone or surgery for the primary tumor (with or without axillary dissection) followed by radiation therapy if indicated, plus systemic therapy.

All patients received hormonal therapy as needed, and those with HER2-positive disease received trastuzumab.

With a median follow-up of 18 months, the median overall survival was 46 months with initial surgery and 42 months with initial systemic therapy, a nonsignificant difference, reported Dr. Soran, who disclosed no relevant conflicts of interest.

In unplanned subgroup analyses, the findings were similar for most subgroups of patients. However, surgery yielded superior survival in patients with solitary bone metastases (not reached vs. 42 months, P = .02) and inferior survival in patients having multiple liver or pulmonary metastases (16 months vs. not reached, P = .02).

The rate of locoregional progression was much lower with initial surgery than with initial systemic therapy (0.7% vs. 3.6%).

Dr. Soran emphasized that the trial’s planned median follow-up is 36 months, so the presented results are only preliminary. Quality of life and morbidity analyses are ongoing.

Dr. Badwe and Dr. Soran disclosed no relevant conflicts of interest.

SAN ANTONIO – Perineural injection of bupivacaine and dexamethasone was a simple and effective treatment for chronic neuropathic pain following mastectomy, based on results of a pilot study.

The effectiveness of this novel therapy strongly suggests the source of this common pain syndrome is damage to the T4 and T5 sensory nerves during surgery, rather than damage to the intercostobrachial nerve, as traditionally thought, according to Dr. Cathy J. Tang of the University of California, San Francisco.

The T4 and T5 sensory nerves come off the chest wall and enter the breast accompanied by a blood vessel. When these nerves are cut and cauterized during mastectomy, the resultant nerve damage can manifest as neuroma formation and neuropathic pain along the two dermatomes, she said at the San Antonio Breast Cancer Symposium.

Chronic postmastectomy breast pain is commonly referred to as postmastectomy pain syndrome. Published estimates of its incidence after mastectomy range from 20% to 68%. The pain can start in the immediate postoperative period, or onset can be delayed up to 6 months or more post mastectomy. The pain is typically experienced as a shooting or burning pain, with point tenderness. It persists well after the expected healing period.

The intervention involves identifying a patient’s points of maximum pain or tenderness, usually located laterally along the midaxillary line or at the inframammary fold directly below the nipple. These points are injected at the level of the chest wall. Each injection consists of 2 mL of an equal ratio of 0.5% bupivacaine plus 4 mg/mL of dexamethasone followed by a minute or two of massage to enhance infiltration of the area.

Dr. Tang reported on 19 patients who developed postmastectomy pain syndrome after either partial mastectomy, total mastectomy with immediate reconstruction, or lateral core biopsy in one case. A total of 29 points of maximum tenderness were identified and treated. All patients had pain relief within minutes, with point pain scores on a 0-10 scale falling from 8-9 to 0-1. Long-term pain relief was experienced after 17 of the 29 initial injections (59%) in 11 patients. Pain was resolved at another nine sites after a second injection. A third injection at one recalcitrant site led to long-term pain relief. Thus, perineural injections alleviated pain at 27 of 29 treated sites, or 93%, at a mean of 10.7 months of follow-up.

In light of how simple and safe this treatment is, Dr. Tang urged routine inquiry about postmastectomy neuropathic pain. Patients with postmastectomy pain often report an inability to lie on the affected side or to wear a bra.

The study also indicates the importance of careful dissection of the T4 and T5 sensory nerves during mastectomy in order to minimize the risk of postoperative neuroma formation.

Dr. Tang reported having no financial conflicts regarding this unfunded study.

[email protected]

SAN ANTONIO – Perineural injection of bupivacaine and dexamethasone was a simple and effective treatment for chronic neuropathic pain following mastectomy, based on results of a pilot study.

The effectiveness of this novel therapy strongly suggests the source of this common pain syndrome is damage to the T4 and T5 sensory nerves during surgery, rather than damage to the intercostobrachial nerve, as traditionally thought, according to Dr. Cathy J. Tang of the University of California, San Francisco.

The T4 and T5 sensory nerves come off the chest wall and enter the breast accompanied by a blood vessel. When these nerves are cut and cauterized during mastectomy, the resultant nerve damage can manifest as neuroma formation and neuropathic pain along the two dermatomes, she said at the San Antonio Breast Cancer Symposium.

Chronic postmastectomy breast pain is commonly referred to as postmastectomy pain syndrome. Published estimates of its incidence after mastectomy range from 20% to 68%. The pain can start in the immediate postoperative period, or onset can be delayed up to 6 months or more post mastectomy. The pain is typically experienced as a shooting or burning pain, with point tenderness. It persists well after the expected healing period.

The intervention involves identifying a patient’s points of maximum pain or tenderness, usually located laterally along the midaxillary line or at the inframammary fold directly below the nipple. These points are injected at the level of the chest wall. Each injection consists of 2 mL of an equal ratio of 0.5% bupivacaine plus 4 mg/mL of dexamethasone followed by a minute or two of massage to enhance infiltration of the area.

Dr. Tang reported on 19 patients who developed postmastectomy pain syndrome after either partial mastectomy, total mastectomy with immediate reconstruction, or lateral core biopsy in one case. A total of 29 points of maximum tenderness were identified and treated. All patients had pain relief within minutes, with point pain scores on a 0-10 scale falling from 8-9 to 0-1. Long-term pain relief was experienced after 17 of the 29 initial injections (59%) in 11 patients. Pain was resolved at another nine sites after a second injection. A third injection at one recalcitrant site led to long-term pain relief. Thus, perineural injections alleviated pain at 27 of 29 treated sites, or 93%, at a mean of 10.7 months of follow-up.

In light of how simple and safe this treatment is, Dr. Tang urged routine inquiry about postmastectomy neuropathic pain. Patients with postmastectomy pain often report an inability to lie on the affected side or to wear a bra.

The study also indicates the importance of careful dissection of the T4 and T5 sensory nerves during mastectomy in order to minimize the risk of postoperative neuroma formation.

Dr. Tang reported having no financial conflicts regarding this unfunded study.

[email protected]

SAN ANTONIO – Perineural injection of bupivacaine and dexamethasone was a simple and effective treatment for chronic neuropathic pain following mastectomy, based on results of a pilot study.

The effectiveness of this novel therapy strongly suggests the source of this common pain syndrome is damage to the T4 and T5 sensory nerves during surgery, rather than damage to the intercostobrachial nerve, as traditionally thought, according to Dr. Cathy J. Tang of the University of California, San Francisco.

The T4 and T5 sensory nerves come off the chest wall and enter the breast accompanied by a blood vessel. When these nerves are cut and cauterized during mastectomy, the resultant nerve damage can manifest as neuroma formation and neuropathic pain along the two dermatomes, she said at the San Antonio Breast Cancer Symposium.

Chronic postmastectomy breast pain is commonly referred to as postmastectomy pain syndrome. Published estimates of its incidence after mastectomy range from 20% to 68%. The pain can start in the immediate postoperative period, or onset can be delayed up to 6 months or more post mastectomy. The pain is typically experienced as a shooting or burning pain, with point tenderness. It persists well after the expected healing period.

The intervention involves identifying a patient’s points of maximum pain or tenderness, usually located laterally along the midaxillary line or at the inframammary fold directly below the nipple. These points are injected at the level of the chest wall. Each injection consists of 2 mL of an equal ratio of 0.5% bupivacaine plus 4 mg/mL of dexamethasone followed by a minute or two of massage to enhance infiltration of the area.

Dr. Tang reported on 19 patients who developed postmastectomy pain syndrome after either partial mastectomy, total mastectomy with immediate reconstruction, or lateral core biopsy in one case. A total of 29 points of maximum tenderness were identified and treated. All patients had pain relief within minutes, with point pain scores on a 0-10 scale falling from 8-9 to 0-1. Long-term pain relief was experienced after 17 of the 29 initial injections (59%) in 11 patients. Pain was resolved at another nine sites after a second injection. A third injection at one recalcitrant site led to long-term pain relief. Thus, perineural injections alleviated pain at 27 of 29 treated sites, or 93%, at a mean of 10.7 months of follow-up.

In light of how simple and safe this treatment is, Dr. Tang urged routine inquiry about postmastectomy neuropathic pain. Patients with postmastectomy pain often report an inability to lie on the affected side or to wear a bra.

The study also indicates the importance of careful dissection of the T4 and T5 sensory nerves during mastectomy in order to minimize the risk of postoperative neuroma formation.

Dr. Tang reported having no financial conflicts regarding this unfunded study.

[email protected]

WASHINGTON – The medical understanding of shock and trauma resuscitation has evolved over many decades. But cutting-edge research is revolutionizing the understanding of the mechanisms of trauma and will eventually have a profound impact on treatment models, according to Dr. Ronald V. Maier.

Dr. Maier, an ACS Fellow and the Jane and Donald D. Trunkey Professor and vice-chair of the department of surgery at the University of Washington, Seattle, delivered the Scudder Oration on Trauma during the American College of Surgeons Clinical Congress. He discussed the development of treatment models for trauma resuscitation in the 20th century, beginning with Cannon’s toxins theory of shock (Cannon WB. Traumatic Shock. New York: D. Appleton & Co; 1923), and continuing into the 1930s with Blalock’s pioneering work in developing the homeostasis theory of trauma treatment (Arch. Surg.1934;29:837-57) .

Many advancements in the theory of trauma came out of experiences on the battlefields of World War I, World War II, the Korean War, and the Vietnam War, he said.

The progression of ideas about treatment also evolved, beginning with a minimalist approach developed during World War I to the more interventionist models involving blood transfusion developed during the Korean War era, leading to a focus on crystalloid resuscitation and oxygen deficit that became prominent during the Vietnam War.

Dr. Maier traced the progression of interventionist strategies, each supplanted by new models based on improved understanding of the mechanism of trauma and a growing realization that many of the earlier approaches amounted to overtreatment with limited improvement in survival rates.

The recent paradigm is summed up as hypotensive resuscitation, meaning damage control and supporting blood pressure without reaching normotension, taking account of the natural coagulation process that occurs in the body in response to trauma.

"The goal is to recognize that if we try to chase interventions until they’ve completely corrected the system they impact, we will end up overtreating and having all the harmful effects of the treatment," Dr. Maier said.

Dr. Maier discussed the emerging "genomic storm" model of the mechanisms of trauma that zeros in on patterns of genetic expression. "In the overall genomic response of injured patients, there is a major change in the genomic activity. After a major injury, [the expression of] 80% of the genes change significantly." Damage to the immune system is evident, especially as reflected in down regulation of T-cell pathways and responses.

Dr. Maier’s research efforts have yielded new insight into the nature of that genomic shift. "What we were able to show is that in the patients who develop major complications vs. those who do not develop complications after severe injury, there is a limited number of genes that have a marked difference in reactivity." Sixty-four genes have been identified as having a bearing on the risk of complications.

The path to recovery involves a return of those patterns to a pre-trauma state. And the pursuit of a treatment model from this new understanding of the trauma mechanism means finding a way of predicting which patients will achieve that pre-trauma pattern and which will need intervention to prevent complicated outcomes.

The next step in this line of research will involve close scrutiny of individual responses to interventions, with a focus on timing and amounts. The details of the human body’s natural response to trauma are largely unknown, so this research will be expensive and time consuming, but according to Dr. Maier, necessary if progress is to be made in treatment models.

Dr. Maier described the emerging paradigm of trauma resuscitation in terms of chaos theory. Chaos theory in the context of trauma means that for the highly complex biological system that is the human body, small early perturbations can create significant changes in outcome. An example would be a small blood transfusion early in the treatment process of a trauma patient could have a profoundly positive impact on outcomes.

Dr. Maier argued that future treatment models will involve giving patients the correct treatment at the correct time and in the correct amounts based on the particular characteristics of the patient and the injury as determined by an understanding of their genetic response pattern and timing. "We have just been funded to develop a bedside test where, with a half cc of blood, we can test the 64 genes, and hopefully, by trending the responses ... we can predict patients who are going to have numerous, severe complications vs. those patients who will not," he said.

Despite the advances that have been made, Dr. Maier acknowledged the remaining challenges in transforming trauma resuscitation. "The holy grail is to be able to identify what patient needs what therapy. That is what we are still aspiring to find, and we have not achieved it yet."

Dr. Maier stated that he had no disclosures.

[email protected]

WASHINGTON – The medical understanding of shock and trauma resuscitation has evolved over many decades. But cutting-edge research is revolutionizing the understanding of the mechanisms of trauma and will eventually have a profound impact on treatment models, according to Dr. Ronald V. Maier.

Dr. Maier, an ACS Fellow and the Jane and Donald D. Trunkey Professor and vice-chair of the department of surgery at the University of Washington, Seattle, delivered the Scudder Oration on Trauma during the American College of Surgeons Clinical Congress. He discussed the development of treatment models for trauma resuscitation in the 20th century, beginning with Cannon’s toxins theory of shock (Cannon WB. Traumatic Shock. New York: D. Appleton & Co; 1923), and continuing into the 1930s with Blalock’s pioneering work in developing the homeostasis theory of trauma treatment (Arch. Surg.1934;29:837-57) .

Many advancements in the theory of trauma came out of experiences on the battlefields of World War I, World War II, the Korean War, and the Vietnam War, he said.

The progression of ideas about treatment also evolved, beginning with a minimalist approach developed during World War I to the more interventionist models involving blood transfusion developed during the Korean War era, leading to a focus on crystalloid resuscitation and oxygen deficit that became prominent during the Vietnam War.

Dr. Maier traced the progression of interventionist strategies, each supplanted by new models based on improved understanding of the mechanism of trauma and a growing realization that many of the earlier approaches amounted to overtreatment with limited improvement in survival rates.

The recent paradigm is summed up as hypotensive resuscitation, meaning damage control and supporting blood pressure without reaching normotension, taking account of the natural coagulation process that occurs in the body in response to trauma.

"The goal is to recognize that if we try to chase interventions until they’ve completely corrected the system they impact, we will end up overtreating and having all the harmful effects of the treatment," Dr. Maier said.

Dr. Maier discussed the emerging "genomic storm" model of the mechanisms of trauma that zeros in on patterns of genetic expression. "In the overall genomic response of injured patients, there is a major change in the genomic activity. After a major injury, [the expression of] 80% of the genes change significantly." Damage to the immune system is evident, especially as reflected in down regulation of T-cell pathways and responses.

Dr. Maier’s research efforts have yielded new insight into the nature of that genomic shift. "What we were able to show is that in the patients who develop major complications vs. those who do not develop complications after severe injury, there is a limited number of genes that have a marked difference in reactivity." Sixty-four genes have been identified as having a bearing on the risk of complications.

The path to recovery involves a return of those patterns to a pre-trauma state. And the pursuit of a treatment model from this new understanding of the trauma mechanism means finding a way of predicting which patients will achieve that pre-trauma pattern and which will need intervention to prevent complicated outcomes.

The next step in this line of research will involve close scrutiny of individual responses to interventions, with a focus on timing and amounts. The details of the human body’s natural response to trauma are largely unknown, so this research will be expensive and time consuming, but according to Dr. Maier, necessary if progress is to be made in treatment models.

Dr. Maier described the emerging paradigm of trauma resuscitation in terms of chaos theory. Chaos theory in the context of trauma means that for the highly complex biological system that is the human body, small early perturbations can create significant changes in outcome. An example would be a small blood transfusion early in the treatment process of a trauma patient could have a profoundly positive impact on outcomes.

Dr. Maier argued that future treatment models will involve giving patients the correct treatment at the correct time and in the correct amounts based on the particular characteristics of the patient and the injury as determined by an understanding of their genetic response pattern and timing. "We have just been funded to develop a bedside test where, with a half cc of blood, we can test the 64 genes, and hopefully, by trending the responses ... we can predict patients who are going to have numerous, severe complications vs. those patients who will not," he said.

Despite the advances that have been made, Dr. Maier acknowledged the remaining challenges in transforming trauma resuscitation. "The holy grail is to be able to identify what patient needs what therapy. That is what we are still aspiring to find, and we have not achieved it yet."

Dr. Maier stated that he had no disclosures.

[email protected]

WASHINGTON – The medical understanding of shock and trauma resuscitation has evolved over many decades. But cutting-edge research is revolutionizing the understanding of the mechanisms of trauma and will eventually have a profound impact on treatment models, according to Dr. Ronald V. Maier.

Dr. Maier, an ACS Fellow and the Jane and Donald D. Trunkey Professor and vice-chair of the department of surgery at the University of Washington, Seattle, delivered the Scudder Oration on Trauma during the American College of Surgeons Clinical Congress. He discussed the development of treatment models for trauma resuscitation in the 20th century, beginning with Cannon’s toxins theory of shock (Cannon WB. Traumatic Shock. New York: D. Appleton & Co; 1923), and continuing into the 1930s with Blalock’s pioneering work in developing the homeostasis theory of trauma treatment (Arch. Surg.1934;29:837-57) .

Many advancements in the theory of trauma came out of experiences on the battlefields of World War I, World War II, the Korean War, and the Vietnam War, he said.

The progression of ideas about treatment also evolved, beginning with a minimalist approach developed during World War I to the more interventionist models involving blood transfusion developed during the Korean War era, leading to a focus on crystalloid resuscitation and oxygen deficit that became prominent during the Vietnam War.

Dr. Maier traced the progression of interventionist strategies, each supplanted by new models based on improved understanding of the mechanism of trauma and a growing realization that many of the earlier approaches amounted to overtreatment with limited improvement in survival rates.

The recent paradigm is summed up as hypotensive resuscitation, meaning damage control and supporting blood pressure without reaching normotension, taking account of the natural coagulation process that occurs in the body in response to trauma.

"The goal is to recognize that if we try to chase interventions until they’ve completely corrected the system they impact, we will end up overtreating and having all the harmful effects of the treatment," Dr. Maier said.

Dr. Maier discussed the emerging "genomic storm" model of the mechanisms of trauma that zeros in on patterns of genetic expression. "In the overall genomic response of injured patients, there is a major change in the genomic activity. After a major injury, [the expression of] 80% of the genes change significantly." Damage to the immune system is evident, especially as reflected in down regulation of T-cell pathways and responses.

Dr. Maier’s research efforts have yielded new insight into the nature of that genomic shift. "What we were able to show is that in the patients who develop major complications vs. those who do not develop complications after severe injury, there is a limited number of genes that have a marked difference in reactivity." Sixty-four genes have been identified as having a bearing on the risk of complications.

The path to recovery involves a return of those patterns to a pre-trauma state. And the pursuit of a treatment model from this new understanding of the trauma mechanism means finding a way of predicting which patients will achieve that pre-trauma pattern and which will need intervention to prevent complicated outcomes.

The next step in this line of research will involve close scrutiny of individual responses to interventions, with a focus on timing and amounts. The details of the human body’s natural response to trauma are largely unknown, so this research will be expensive and time consuming, but according to Dr. Maier, necessary if progress is to be made in treatment models.

Dr. Maier described the emerging paradigm of trauma resuscitation in terms of chaos theory. Chaos theory in the context of trauma means that for the highly complex biological system that is the human body, small early perturbations can create significant changes in outcome. An example would be a small blood transfusion early in the treatment process of a trauma patient could have a profoundly positive impact on outcomes.

Dr. Maier argued that future treatment models will involve giving patients the correct treatment at the correct time and in the correct amounts based on the particular characteristics of the patient and the injury as determined by an understanding of their genetic response pattern and timing. "We have just been funded to develop a bedside test where, with a half cc of blood, we can test the 64 genes, and hopefully, by trending the responses ... we can predict patients who are going to have numerous, severe complications vs. those patients who will not," he said.

Despite the advances that have been made, Dr. Maier acknowledged the remaining challenges in transforming trauma resuscitation. "The holy grail is to be able to identify what patient needs what therapy. That is what we are still aspiring to find, and we have not achieved it yet."

Dr. Maier stated that he had no disclosures.

[email protected]

WASHINGTON – The political violence that plagued Northern Ireland for nearly 40 years has subsided, and the memories of those dark days in Belfast have begun to fade. But for Roy A. J. Spence, OBE, J.D., M.D., LL.D., FRCS, those years of treating trauma patients in the emergency room of the Royal Victoria Hospital in that city served as an important opportunity for learning and service.

Dr. Spence worked with a team of surgeons and other staff to treat thousands of victims of bombings, shootings, torture, kneecapping, and assault that happened in the context of clashes between two sides of a sectarian conflict and the British Army. Dr. Spence, who delivered the I.S. Ravdin Lecture in the Basic and Surgical Sciences during the annual clinical congress of the American College of Surgeons, discussed his experiences and lessons learned.

During the worst period of The Troubles, as the conflict is called, emergency room surgeons were treating what were essentially combat injuries in an urban hospital setting. The great majority of the injuries in Belfast occurred within 1 mile of the Royal Victoria Hospital and the Belfast City Hospital, "some at the door of the hospital, some within the hospital, and we even had one patient shot in a bed in the hospital," he said. One victim was killed in the presence of Dr. Spence in the ER.

Dr. Spence, now professor and head of the department of surgery, imaging, and perioperative medicine at Queen’s University of Belfast, stated that despite the at times overwhelming numbers of injured that flooded into the ER, 90% of patients were delivered to the ER within 30 minutes and 50% within 15 minutes. The staff developed systems to speed patients through the ER to treatment and surgery if needed. In 1972 alone, 20,000 individuals were injured in various ways, and most of these injuries occurred in Belfast.

In addition to a streamlined admission process, the surgeons developed their protocol based on lessons learned over the years.

"We had disaster plans, but, in truth, we almost never had a rehearsal. The rehearsals were for real. The rehearsals were occurring day by day."

It became clear in the early years of the conflict that, in most cases, patients were best served if the doctors stayed at the hospital to receive patients instead of rushing to the scene of a bombing or shooting. "We were almost a nuisance if we went to the scene, because there was often continuing gunfire, there were secondary explosions, and sometimes the bodies themselves were booby-trapped."

In addition, the system of handling large numbers of injured patients worked best if there was a senior surgeon and senior nurse at the door to triage patients. Those with minor injuries were taken to a separate room for treatment.

It was also important that one senior surgeon took charge of the situation and led the team. Surgeons discovered that in these crisis situations, x-raying patients could turn into a bottleneck in the treatment process, leading to dangerous delays, so at times surgery proceeded without imaging to save a patient’s life.

Dr. Spence said that the Royal Victoria distinguished itself in treating patients in the midst of a civil war by upholding the highest standards of care, documenting cases thoroughly, and treating all patients with the same level of care. Although the duty surgeons lived in the community, knew many of the victims, were aware of which group had carried out an attack, and even had family members killed in the conflict, Dr. Spence asserted that they maintained their professional standards and did not allow politics to deter them from their duties as physicians.

In the peak years of violence, the early 1970s to the early 1980s, two types of injuries – gunshot wounds to the head and kneecapping trauma – led to innovative treatment plans. The hospital established the standard of care for gunshot wounds to the head in that era, and also pioneered the use of vascular shunts to treat blast-injured limbs. The vascular shunt in particular was considered invaluable by Dr. Spence. This procedure reduced the number of amputations in cases of limb trauma from one-third to less than 10% and "allowed a very unhurried fracture reduction and external fixation."

Dr. Spence noted that general surgeons were valued in the ER because of their capacity to deal with a wide variety of injuries and because of the potentially fatal delays caused by waiting for a specialist. Although specialists were definitely needed and utilized in complex cases, most patients were treated by general surgeons. "I come from a generation that could do chest and abdominal surgery and amputations," said Dr. Spence.

Staff doctors were on call every other night and worked very long hours, a situation no longer allowed in U.K. hospitals. Surgeons worked "until the work was done" to care for all the injured and to maintain continuity of care. "There could be 100 injured people in the ER. You couldn’t just walk out at half past five."

In conclusion, Dr. Spence noted that the extended crisis of violence and trauma resulted in a close-knit "band of brothers, and occasionally, sisters" who worked in trying circumstances as colleagues. Many of those colleagues have left surgery or have died relatively young, and Dr. Spence intended his lecture to be a tribute to their service, dedication, and sacrifice in troubled times.

[email protected]

WASHINGTON – The political violence that plagued Northern Ireland for nearly 40 years has subsided, and the memories of those dark days in Belfast have begun to fade. But for Roy A. J. Spence, OBE, J.D., M.D., LL.D., FRCS, those years of treating trauma patients in the emergency room of the Royal Victoria Hospital in that city served as an important opportunity for learning and service.

Dr. Spence worked with a team of surgeons and other staff to treat thousands of victims of bombings, shootings, torture, kneecapping, and assault that happened in the context of clashes between two sides of a sectarian conflict and the British Army. Dr. Spence, who delivered the I.S. Ravdin Lecture in the Basic and Surgical Sciences during the annual clinical congress of the American College of Surgeons, discussed his experiences and lessons learned.

During the worst period of The Troubles, as the conflict is called, emergency room surgeons were treating what were essentially combat injuries in an urban hospital setting. The great majority of the injuries in Belfast occurred within 1 mile of the Royal Victoria Hospital and the Belfast City Hospital, "some at the door of the hospital, some within the hospital, and we even had one patient shot in a bed in the hospital," he said. One victim was killed in the presence of Dr. Spence in the ER.

Dr. Spence, now professor and head of the department of surgery, imaging, and perioperative medicine at Queen’s University of Belfast, stated that despite the at times overwhelming numbers of injured that flooded into the ER, 90% of patients were delivered to the ER within 30 minutes and 50% within 15 minutes. The staff developed systems to speed patients through the ER to treatment and surgery if needed. In 1972 alone, 20,000 individuals were injured in various ways, and most of these injuries occurred in Belfast.

In addition to a streamlined admission process, the surgeons developed their protocol based on lessons learned over the years.

"We had disaster plans, but, in truth, we almost never had a rehearsal. The rehearsals were for real. The rehearsals were occurring day by day."

It became clear in the early years of the conflict that, in most cases, patients were best served if the doctors stayed at the hospital to receive patients instead of rushing to the scene of a bombing or shooting. "We were almost a nuisance if we went to the scene, because there was often continuing gunfire, there were secondary explosions, and sometimes the bodies themselves were booby-trapped."

In addition, the system of handling large numbers of injured patients worked best if there was a senior surgeon and senior nurse at the door to triage patients. Those with minor injuries were taken to a separate room for treatment.

It was also important that one senior surgeon took charge of the situation and led the team. Surgeons discovered that in these crisis situations, x-raying patients could turn into a bottleneck in the treatment process, leading to dangerous delays, so at times surgery proceeded without imaging to save a patient’s life.

Dr. Spence said that the Royal Victoria distinguished itself in treating patients in the midst of a civil war by upholding the highest standards of care, documenting cases thoroughly, and treating all patients with the same level of care. Although the duty surgeons lived in the community, knew many of the victims, were aware of which group had carried out an attack, and even had family members killed in the conflict, Dr. Spence asserted that they maintained their professional standards and did not allow politics to deter them from their duties as physicians.

In the peak years of violence, the early 1970s to the early 1980s, two types of injuries – gunshot wounds to the head and kneecapping trauma – led to innovative treatment plans. The hospital established the standard of care for gunshot wounds to the head in that era, and also pioneered the use of vascular shunts to treat blast-injured limbs. The vascular shunt in particular was considered invaluable by Dr. Spence. This procedure reduced the number of amputations in cases of limb trauma from one-third to less than 10% and "allowed a very unhurried fracture reduction and external fixation."

Dr. Spence noted that general surgeons were valued in the ER because of their capacity to deal with a wide variety of injuries and because of the potentially fatal delays caused by waiting for a specialist. Although specialists were definitely needed and utilized in complex cases, most patients were treated by general surgeons. "I come from a generation that could do chest and abdominal surgery and amputations," said Dr. Spence.

Staff doctors were on call every other night and worked very long hours, a situation no longer allowed in U.K. hospitals. Surgeons worked "until the work was done" to care for all the injured and to maintain continuity of care. "There could be 100 injured people in the ER. You couldn’t just walk out at half past five."

In conclusion, Dr. Spence noted that the extended crisis of violence and trauma resulted in a close-knit "band of brothers, and occasionally, sisters" who worked in trying circumstances as colleagues. Many of those colleagues have left surgery or have died relatively young, and Dr. Spence intended his lecture to be a tribute to their service, dedication, and sacrifice in troubled times.

[email protected]

WASHINGTON – The political violence that plagued Northern Ireland for nearly 40 years has subsided, and the memories of those dark days in Belfast have begun to fade. But for Roy A. J. Spence, OBE, J.D., M.D., LL.D., FRCS, those years of treating trauma patients in the emergency room of the Royal Victoria Hospital in that city served as an important opportunity for learning and service.

Dr. Spence worked with a team of surgeons and other staff to treat thousands of victims of bombings, shootings, torture, kneecapping, and assault that happened in the context of clashes between two sides of a sectarian conflict and the British Army. Dr. Spence, who delivered the I.S. Ravdin Lecture in the Basic and Surgical Sciences during the annual clinical congress of the American College of Surgeons, discussed his experiences and lessons learned.

During the worst period of The Troubles, as the conflict is called, emergency room surgeons were treating what were essentially combat injuries in an urban hospital setting. The great majority of the injuries in Belfast occurred within 1 mile of the Royal Victoria Hospital and the Belfast City Hospital, "some at the door of the hospital, some within the hospital, and we even had one patient shot in a bed in the hospital," he said. One victim was killed in the presence of Dr. Spence in the ER.

Dr. Spence, now professor and head of the department of surgery, imaging, and perioperative medicine at Queen’s University of Belfast, stated that despite the at times overwhelming numbers of injured that flooded into the ER, 90% of patients were delivered to the ER within 30 minutes and 50% within 15 minutes. The staff developed systems to speed patients through the ER to treatment and surgery if needed. In 1972 alone, 20,000 individuals were injured in various ways, and most of these injuries occurred in Belfast.

In addition to a streamlined admission process, the surgeons developed their protocol based on lessons learned over the years.

"We had disaster plans, but, in truth, we almost never had a rehearsal. The rehearsals were for real. The rehearsals were occurring day by day."

It became clear in the early years of the conflict that, in most cases, patients were best served if the doctors stayed at the hospital to receive patients instead of rushing to the scene of a bombing or shooting. "We were almost a nuisance if we went to the scene, because there was often continuing gunfire, there were secondary explosions, and sometimes the bodies themselves were booby-trapped."

In addition, the system of handling large numbers of injured patients worked best if there was a senior surgeon and senior nurse at the door to triage patients. Those with minor injuries were taken to a separate room for treatment.

It was also important that one senior surgeon took charge of the situation and led the team. Surgeons discovered that in these crisis situations, x-raying patients could turn into a bottleneck in the treatment process, leading to dangerous delays, so at times surgery proceeded without imaging to save a patient’s life.

Dr. Spence said that the Royal Victoria distinguished itself in treating patients in the midst of a civil war by upholding the highest standards of care, documenting cases thoroughly, and treating all patients with the same level of care. Although the duty surgeons lived in the community, knew many of the victims, were aware of which group had carried out an attack, and even had family members killed in the conflict, Dr. Spence asserted that they maintained their professional standards and did not allow politics to deter them from their duties as physicians.

In the peak years of violence, the early 1970s to the early 1980s, two types of injuries – gunshot wounds to the head and kneecapping trauma – led to innovative treatment plans. The hospital established the standard of care for gunshot wounds to the head in that era, and also pioneered the use of vascular shunts to treat blast-injured limbs. The vascular shunt in particular was considered invaluable by Dr. Spence. This procedure reduced the number of amputations in cases of limb trauma from one-third to less than 10% and "allowed a very unhurried fracture reduction and external fixation."

Dr. Spence noted that general surgeons were valued in the ER because of their capacity to deal with a wide variety of injuries and because of the potentially fatal delays caused by waiting for a specialist. Although specialists were definitely needed and utilized in complex cases, most patients were treated by general surgeons. "I come from a generation that could do chest and abdominal surgery and amputations," said Dr. Spence.

Staff doctors were on call every other night and worked very long hours, a situation no longer allowed in U.K. hospitals. Surgeons worked "until the work was done" to care for all the injured and to maintain continuity of care. "There could be 100 injured people in the ER. You couldn’t just walk out at half past five."

In conclusion, Dr. Spence noted that the extended crisis of violence and trauma resulted in a close-knit "band of brothers, and occasionally, sisters" who worked in trying circumstances as colleagues. Many of those colleagues have left surgery or have died relatively young, and Dr. Spence intended his lecture to be a tribute to their service, dedication, and sacrifice in troubled times.

[email protected]

WASHINGTON – Years of research have taught us that when it comes to heath care delivery, there is no relationship between cost and quality, according to Dr. Glenn D. Steele, the president and CEO of Geisinger Health System. Dr. Steele delivered the 2013 Commission on Cancer Oncology Lecture at the annual clinical congress of the American College of Surgeons.

Geisinger Health System, based in Danville, Pa., is a renowned leader in transforming health care delivery through innovative multi-institution collaboration and an emphasis on consistent use of best practices and evidence-based medicine, he said. The goal over the past decade has been to reengineer complex medical care to improve quality and reduce costs. Dr. Steele asserted that these two goals are not mutually exclusive.

"We now believe that if you look at a patient cohort – whether it is hospital based or whether it’s ambulatory care – for folks with three, four, or five chronic diseases, you find that the population with the highest costs has also the least-quality health care ... more often than not, high cost equals a less-than-optimal outcome," he said.

At the heart of the reengineering concept is the recognition that many patients in conventional treatment situations end up with what Dr. Steele referred to as "unjustified variation" in the execution of the treatment. A noted study by Little et al. showed that only half of patients treated for lung cancer, for example, receive the recommended care (Ann. Thorac. Surg. 2005;80:2051-6). The Geisinger Health System tackled the problem of unwarranted variation in treatment and "road tested" a wide range of innovations involving standardization of treatment, electronic data gathering and tracking, and institutional culture change.

The ProvenCare model was developed to incorporate all the initiatives that had been researched and tested at Geisinger, and the model was first applied in 2005 to coronary artery bypass grafting (CABG). This application of ProvenCare showed that "an improvement model that embeds evidence-based medicine into the workflow, applies the principles of reliability science (standardization, error proofing, and failure mode redesign) to the care redesign process, employs effective data feedback strategies, and engages patients in their care results in the right care delivered 100% of the time with better patient outcomes" (CA: A Cancer Journal for Clinicians 2011;61:382-96). The model has since been applied to hip replacement surgery, percutaneous coronary intervention, and cataract surgery.

Dr. Steele gave an update on a recent ProvenCare project, a model for treatment of resectable non–small cell lung cancer. The project is a collaboration between Geisinger and the American College of Surgeons Commission on Cancer. The initial survey of lung cancer care revealed substantial room for improvement. The ProvenCare goals initially were to standardize care; build in redundancy to make sure all tasks are done; bundle related tasks; build teams, feedback protocols, and training models; move toward a multi-institutional collaboration; and achieve widespread change in institutional practices, protocol, and culture of care. The project involved an 18-month period of training and testing in the participating institutions.

Engagement of patients and a "very well-articulated set of expectations" were a critical part of the ProvenCare model. The challenge involved achieving 100% compliance across the many institutions

Geisinger has created an insurance company that has some role in controlling costs. Dr. Steele estimated that many resources spent in health care are wasted. "If we could figure out how to extract much of that 25%-30% of needless cost, we can redistribute it. ... Some of that redistribution would go to our bottom line and allow us to grow programs and make our balance sheet comfortable. ... Some of that value would go back to our insurance company and to the middle-size and small businesses that are buying our insurance premiums." This is where cost savings are reducing the cost of premiums and "giving some of that value back to consumers."

Dr. Steele said, "In most industries where you have reengineered whatever it is you are doing, you’ve got better outcomes on both the quality side and the cost side, and you are in heavy-duty competition in the consolidating market. What do you do? You lower your price. And you maintain your contribution margin. And you run your competition out of business. We don’t think that way in health care. But my bet is, in 5 years, we will think that way."

Ultimately, the drive to lower costs goes hand in hand with improving quality of care, he said. "If you believe that, and you are a professional driven to help your patients, you are much more enthusiastic about reengineering than simply working to keep costs down."

[email protected]

WASHINGTON – Years of research have taught us that when it comes to heath care delivery, there is no relationship between cost and quality, according to Dr. Glenn D. Steele, the president and CEO of Geisinger Health System. Dr. Steele delivered the 2013 Commission on Cancer Oncology Lecture at the annual clinical congress of the American College of Surgeons.

Geisinger Health System, based in Danville, Pa., is a renowned leader in transforming health care delivery through innovative multi-institution collaboration and an emphasis on consistent use of best practices and evidence-based medicine, he said. The goal over the past decade has been to reengineer complex medical care to improve quality and reduce costs. Dr. Steele asserted that these two goals are not mutually exclusive.

"We now believe that if you look at a patient cohort – whether it is hospital based or whether it’s ambulatory care – for folks with three, four, or five chronic diseases, you find that the population with the highest costs has also the least-quality health care ... more often than not, high cost equals a less-than-optimal outcome," he said.

At the heart of the reengineering concept is the recognition that many patients in conventional treatment situations end up with what Dr. Steele referred to as "unjustified variation" in the execution of the treatment. A noted study by Little et al. showed that only half of patients treated for lung cancer, for example, receive the recommended care (Ann. Thorac. Surg. 2005;80:2051-6). The Geisinger Health System tackled the problem of unwarranted variation in treatment and "road tested" a wide range of innovations involving standardization of treatment, electronic data gathering and tracking, and institutional culture change.

The ProvenCare model was developed to incorporate all the initiatives that had been researched and tested at Geisinger, and the model was first applied in 2005 to coronary artery bypass grafting (CABG). This application of ProvenCare showed that "an improvement model that embeds evidence-based medicine into the workflow, applies the principles of reliability science (standardization, error proofing, and failure mode redesign) to the care redesign process, employs effective data feedback strategies, and engages patients in their care results in the right care delivered 100% of the time with better patient outcomes" (CA: A Cancer Journal for Clinicians 2011;61:382-96). The model has since been applied to hip replacement surgery, percutaneous coronary intervention, and cataract surgery.

Dr. Steele gave an update on a recent ProvenCare project, a model for treatment of resectable non–small cell lung cancer. The project is a collaboration between Geisinger and the American College of Surgeons Commission on Cancer. The initial survey of lung cancer care revealed substantial room for improvement. The ProvenCare goals initially were to standardize care; build in redundancy to make sure all tasks are done; bundle related tasks; build teams, feedback protocols, and training models; move toward a multi-institutional collaboration; and achieve widespread change in institutional practices, protocol, and culture of care. The project involved an 18-month period of training and testing in the participating institutions.

Engagement of patients and a "very well-articulated set of expectations" were a critical part of the ProvenCare model. The challenge involved achieving 100% compliance across the many institutions

Geisinger has created an insurance company that has some role in controlling costs. Dr. Steele estimated that many resources spent in health care are wasted. "If we could figure out how to extract much of that 25%-30% of needless cost, we can redistribute it. ... Some of that redistribution would go to our bottom line and allow us to grow programs and make our balance sheet comfortable. ... Some of that value would go back to our insurance company and to the middle-size and small businesses that are buying our insurance premiums." This is where cost savings are reducing the cost of premiums and "giving some of that value back to consumers."

Dr. Steele said, "In most industries where you have reengineered whatever it is you are doing, you’ve got better outcomes on both the quality side and the cost side, and you are in heavy-duty competition in the consolidating market. What do you do? You lower your price. And you maintain your contribution margin. And you run your competition out of business. We don’t think that way in health care. But my bet is, in 5 years, we will think that way."

Ultimately, the drive to lower costs goes hand in hand with improving quality of care, he said. "If you believe that, and you are a professional driven to help your patients, you are much more enthusiastic about reengineering than simply working to keep costs down."

[email protected]

WASHINGTON – Years of research have taught us that when it comes to heath care delivery, there is no relationship between cost and quality, according to Dr. Glenn D. Steele, the president and CEO of Geisinger Health System. Dr. Steele delivered the 2013 Commission on Cancer Oncology Lecture at the annual clinical congress of the American College of Surgeons.

Geisinger Health System, based in Danville, Pa., is a renowned leader in transforming health care delivery through innovative multi-institution collaboration and an emphasis on consistent use of best practices and evidence-based medicine, he said. The goal over the past decade has been to reengineer complex medical care to improve quality and reduce costs. Dr. Steele asserted that these two goals are not mutually exclusive.

"We now believe that if you look at a patient cohort – whether it is hospital based or whether it’s ambulatory care – for folks with three, four, or five chronic diseases, you find that the population with the highest costs has also the least-quality health care ... more often than not, high cost equals a less-than-optimal outcome," he said.

At the heart of the reengineering concept is the recognition that many patients in conventional treatment situations end up with what Dr. Steele referred to as "unjustified variation" in the execution of the treatment. A noted study by Little et al. showed that only half of patients treated for lung cancer, for example, receive the recommended care (Ann. Thorac. Surg. 2005;80:2051-6). The Geisinger Health System tackled the problem of unwarranted variation in treatment and "road tested" a wide range of innovations involving standardization of treatment, electronic data gathering and tracking, and institutional culture change.

The ProvenCare model was developed to incorporate all the initiatives that had been researched and tested at Geisinger, and the model was first applied in 2005 to coronary artery bypass grafting (CABG). This application of ProvenCare showed that "an improvement model that embeds evidence-based medicine into the workflow, applies the principles of reliability science (standardization, error proofing, and failure mode redesign) to the care redesign process, employs effective data feedback strategies, and engages patients in their care results in the right care delivered 100% of the time with better patient outcomes" (CA: A Cancer Journal for Clinicians 2011;61:382-96). The model has since been applied to hip replacement surgery, percutaneous coronary intervention, and cataract surgery.

Dr. Steele gave an update on a recent ProvenCare project, a model for treatment of resectable non–small cell lung cancer. The project is a collaboration between Geisinger and the American College of Surgeons Commission on Cancer. The initial survey of lung cancer care revealed substantial room for improvement. The ProvenCare goals initially were to standardize care; build in redundancy to make sure all tasks are done; bundle related tasks; build teams, feedback protocols, and training models; move toward a multi-institutional collaboration; and achieve widespread change in institutional practices, protocol, and culture of care. The project involved an 18-month period of training and testing in the participating institutions.

Engagement of patients and a "very well-articulated set of expectations" were a critical part of the ProvenCare model. The challenge involved achieving 100% compliance across the many institutions

Geisinger has created an insurance company that has some role in controlling costs. Dr. Steele estimated that many resources spent in health care are wasted. "If we could figure out how to extract much of that 25%-30% of needless cost, we can redistribute it. ... Some of that redistribution would go to our bottom line and allow us to grow programs and make our balance sheet comfortable. ... Some of that value would go back to our insurance company and to the middle-size and small businesses that are buying our insurance premiums." This is where cost savings are reducing the cost of premiums and "giving some of that value back to consumers."

Dr. Steele said, "In most industries where you have reengineered whatever it is you are doing, you’ve got better outcomes on both the quality side and the cost side, and you are in heavy-duty competition in the consolidating market. What do you do? You lower your price. And you maintain your contribution margin. And you run your competition out of business. We don’t think that way in health care. But my bet is, in 5 years, we will think that way."

Ultimately, the drive to lower costs goes hand in hand with improving quality of care, he said. "If you believe that, and you are a professional driven to help your patients, you are much more enthusiastic about reengineering than simply working to keep costs down."

[email protected]

WASHINGTON – Technological innovation is transforming surgery at a rapid pace. The question, according to Dr. Mark Talamini, is how can surgeons prepare for and participate in that transformation.

Dr. Talamini delivered the Excelsior Surgical Society/Edward D. Churchill Lecture at the annual clinical congress of the American College of Surgeons. He discussed his own early interest in medical technology, the trends in technological change, and the complex issues that face surgeons in maintaining currency in training and working to develop new devices.

The most profound change in surgery in recent decades has been the insertion of high-tech devices between the surgeon and the patient. There is now most commonly a physical distance between the patient’s body and the surgeon’s hands, and "the majority of surgical procedures involve the surgeon looking at a screen." Surgical tasks of dissecting, controlling bleeding, and suturing in particular have been all but transformed by devices.

The drive to introduce new surgical devices has come up against the stringent approval process of the Food and Drug Administration and has led to public criticism of that process. Dr. Talamini, who chairs the surgery department at the State University of New York at Stony Brook, and who has worked with the FDA for more than 10 years in various capacities, argued that there must be a correct balance between innovation and regulation. "We’ve got to have both. We cannot just have instruments released to the public without understanding what the issues are regarding safety and effectiveness. For the FDA, that is the mantra: safety and effectiveness." He added, "They have a tough task to figure out the balance between getting new things to the market to benefit patients and yet maintaining overall public safety."

Dr. Talamini asserted that the growing number and complexity of surgical instruments mean that surgeons may be falling behind in their skills without realizing it. He illustrated his point by posing specific questions about the use of some recently introduced instruments and polling the audience on correct use. In response to the many wrong answers, he asserted that "we don’t know as much as we think we do about surgical technology."

To address this problem of maintaining currency and training on innovative devices, Dr. Talamini mentioned the Fundamental Use of Surgical Energy (FUSE) program created by the Society of American Gastrointestinal and Endoscopic Surgeons. FUSE is a web-based educational and testing program for all operating room participants, including surgeons.

Dr. Talamini is particularly proud of the Center for the Future of Surgery located at the University of California, San Diego, which he was instrumental in developing. This center has a research suite for doctors and scientists to collaborate on innovative devices; training suites for the latest in surgical, robotic, laparoscopic, and microscopic techniques; and simulated operating rooms and emergency departments.

Dr. Talamini reflected on the complex relationship between innovative surgeons and device development and manufacturing companies. He cautioned the audience to consider some principles when engaging in technology development with industry. First, there would be no technological innovation without collaboration between the medical device industry and surgeons. But development and training cannot be simply a means of selling equipment. Education and sales must be clearly differentiated. In addition, disclosure and transparency are fundamental to maintaining public trust.

Finally, Dr. Talamini argued that conflict of interest in this area cannot be eliminated, but it must be managed to foster innovation.

Dr. Talamini had no disclosures.

[email protected]

WASHINGTON – Technological innovation is transforming surgery at a rapid pace. The question, according to Dr. Mark Talamini, is how can surgeons prepare for and participate in that transformation.

Dr. Talamini delivered the Excelsior Surgical Society/Edward D. Churchill Lecture at the annual clinical congress of the American College of Surgeons. He discussed his own early interest in medical technology, the trends in technological change, and the complex issues that face surgeons in maintaining currency in training and working to develop new devices.

The most profound change in surgery in recent decades has been the insertion of high-tech devices between the surgeon and the patient. There is now most commonly a physical distance between the patient’s body and the surgeon’s hands, and "the majority of surgical procedures involve the surgeon looking at a screen." Surgical tasks of dissecting, controlling bleeding, and suturing in particular have been all but transformed by devices.

The drive to introduce new surgical devices has come up against the stringent approval process of the Food and Drug Administration and has led to public criticism of that process. Dr. Talamini, who chairs the surgery department at the State University of New York at Stony Brook, and who has worked with the FDA for more than 10 years in various capacities, argued that there must be a correct balance between innovation and regulation. "We’ve got to have both. We cannot just have instruments released to the public without understanding what the issues are regarding safety and effectiveness. For the FDA, that is the mantra: safety and effectiveness." He added, "They have a tough task to figure out the balance between getting new things to the market to benefit patients and yet maintaining overall public safety."

Dr. Talamini asserted that the growing number and complexity of surgical instruments mean that surgeons may be falling behind in their skills without realizing it. He illustrated his point by posing specific questions about the use of some recently introduced instruments and polling the audience on correct use. In response to the many wrong answers, he asserted that "we don’t know as much as we think we do about surgical technology."

To address this problem of maintaining currency and training on innovative devices, Dr. Talamini mentioned the Fundamental Use of Surgical Energy (FUSE) program created by the Society of American Gastrointestinal and Endoscopic Surgeons. FUSE is a web-based educational and testing program for all operating room participants, including surgeons.

Dr. Talamini is particularly proud of the Center for the Future of Surgery located at the University of California, San Diego, which he was instrumental in developing. This center has a research suite for doctors and scientists to collaborate on innovative devices; training suites for the latest in surgical, robotic, laparoscopic, and microscopic techniques; and simulated operating rooms and emergency departments.

Dr. Talamini reflected on the complex relationship between innovative surgeons and device development and manufacturing companies. He cautioned the audience to consider some principles when engaging in technology development with industry. First, there would be no technological innovation without collaboration between the medical device industry and surgeons. But development and training cannot be simply a means of selling equipment. Education and sales must be clearly differentiated. In addition, disclosure and transparency are fundamental to maintaining public trust.

Finally, Dr. Talamini argued that conflict of interest in this area cannot be eliminated, but it must be managed to foster innovation.

Dr. Talamini had no disclosures.

[email protected]

WASHINGTON – Technological innovation is transforming surgery at a rapid pace. The question, according to Dr. Mark Talamini, is how can surgeons prepare for and participate in that transformation.

Dr. Talamini delivered the Excelsior Surgical Society/Edward D. Churchill Lecture at the annual clinical congress of the American College of Surgeons. He discussed his own early interest in medical technology, the trends in technological change, and the complex issues that face surgeons in maintaining currency in training and working to develop new devices.

The most profound change in surgery in recent decades has been the insertion of high-tech devices between the surgeon and the patient. There is now most commonly a physical distance between the patient’s body and the surgeon’s hands, and "the majority of surgical procedures involve the surgeon looking at a screen." Surgical tasks of dissecting, controlling bleeding, and suturing in particular have been all but transformed by devices.

The drive to introduce new surgical devices has come up against the stringent approval process of the Food and Drug Administration and has led to public criticism of that process. Dr. Talamini, who chairs the surgery department at the State University of New York at Stony Brook, and who has worked with the FDA for more than 10 years in various capacities, argued that there must be a correct balance between innovation and regulation. "We’ve got to have both. We cannot just have instruments released to the public without understanding what the issues are regarding safety and effectiveness. For the FDA, that is the mantra: safety and effectiveness." He added, "They have a tough task to figure out the balance between getting new things to the market to benefit patients and yet maintaining overall public safety."

Dr. Talamini asserted that the growing number and complexity of surgical instruments mean that surgeons may be falling behind in their skills without realizing it. He illustrated his point by posing specific questions about the use of some recently introduced instruments and polling the audience on correct use. In response to the many wrong answers, he asserted that "we don’t know as much as we think we do about surgical technology."

To address this problem of maintaining currency and training on innovative devices, Dr. Talamini mentioned the Fundamental Use of Surgical Energy (FUSE) program created by the Society of American Gastrointestinal and Endoscopic Surgeons. FUSE is a web-based educational and testing program for all operating room participants, including surgeons.

Dr. Talamini is particularly proud of the Center for the Future of Surgery located at the University of California, San Diego, which he was instrumental in developing. This center has a research suite for doctors and scientists to collaborate on innovative devices; training suites for the latest in surgical, robotic, laparoscopic, and microscopic techniques; and simulated operating rooms and emergency departments.

Dr. Talamini reflected on the complex relationship between innovative surgeons and device development and manufacturing companies. He cautioned the audience to consider some principles when engaging in technology development with industry. First, there would be no technological innovation without collaboration between the medical device industry and surgeons. But development and training cannot be simply a means of selling equipment. Education and sales must be clearly differentiated. In addition, disclosure and transparency are fundamental to maintaining public trust.

Finally, Dr. Talamini argued that conflict of interest in this area cannot be eliminated, but it must be managed to foster innovation.

Dr. Talamini had no disclosures.

[email protected]