Susan London

SAN FRANCISCO – A new 86-gene signature may add to metabolic imaging in guiding early treatment decisions for esophagogastric junction cancer, researchers reported.

The leptin gene, among others, stood out as having the potential to become a clinically useful biomarker in analyses that were presented at the meeting.

Dr. Russell Petty of the University of Aberdeen (Scotland) and colleagues studied 182 patients with locally advanced or metastatic disease. The investigators performed FDG-PET (¹⁸fluorodeoxyglucose–positron emission tomography) imaging and CT imaging, as well as gene expression profiling, and immunohistochemistry of pretreatment tumor tissue.

Results showed that among a subgroup of 14 patients who had a PET metabolic response to the first cycle of neoadjuvant chemotherapy, a set of 86 genes in pretreatment tumor tissue distinguished those who had a radiologic response on CT after completing all cycles of that chemotherapy, compared with those who did not respond. In a variety of predictive models, this gene signature correctly predicted radiologic response in all cases.

"We have shown that gene expression profiling can subclassify FDG-PET metabolic responders into those patients that will and will not subsequently go on to have a [radiologic] response. We have also shown that combining molecular biomarkers and FDG-PET allows an optimization of response prediction," Dr. Petty said at a meeting on gastrointestinal cancer sponosored by the American Society of Clinical Oncology.

This is key, as PET alone has a poor positive predictive value in this setting, with only half of PET responders to neoadjuvant chemotherapy eventually showing a histopathologic response.

"While I suppose there is little doubt that if we used PET in this way to make treatment decisions, we would have a system that would be better than unstratified empirical treatment, what it still means is that quite significant proportions of our patients will go on to receive ineffective and intensely toxic therapy," he commented.

A subsequent gene enrichment and pathway analysis identified a half-dozen pathways that provided potential mechanistic explanations for the different tumor behavior.

"Within the pathways identified, the adipocytokine-signaling pathway immediately caught our attention because of the strong known [epidemiologic] link between obesity and body weight, and esophagogastric adenocarcinoma," Dr. Petty noted.

Additional analyses specifically fingered the leptin gene (among others) and showed that among PET responders, leptin expression was higher in radiologic nonresponders than in responders (P = .026).

Yet, immunohistochemistry in an independent group of 154 patients showed that strong leptin staining was also associated with better survival (P = .021), an association that held up in multivariate analysis (hazard ratio, 0.85; P = .04).

In stratified analyses, patients with leptin-positive tumors derived little survival benefit from neoadjuvant chemotherapy, whereas those with leptin-negative tumors fared considerably better if they received this therapy (indeed, about as well as the positive group).

"Leptin in particular may be a molecular biomarker that is useful to combine with PET," Dr. Petty commented.

"Leptin expression is associated with chemoresistance, but at the same time is also a favorable therapy-independent biomarker, so this combination of predictive and therapy-independent prognostic impacts mean that leptin has the potential to be a clinically useful biomarker."

"I really think that this is groundbreaking. ... The real future is here" when it comes to predicting treatment response in this cancer, as suggested by this study and others," session cochair Dr. Mark Krasna of the St. Joseph Medical Center in Towson, Md., commented in an interview.

"The question now is, are we ready for prime time to adopt that throughout?"

At present, more research is needed, according to Dr. Krasna, such as the ongoing validation of the 86-gene signature and from trials like CALGB (Cancer and Leukemia Group B) 80803 exploring response-adaptive treatment in this cancer.

"I think those are the important things we can do today. We are ready for that," he concluded.

Dr. Petty and Dr. Krasna reported that they had no relevant financial conflicts of interest.

SAN FRANCISCO – A new 86-gene signature may add to metabolic imaging in guiding early treatment decisions for esophagogastric junction cancer, researchers reported.

The leptin gene, among others, stood out as having the potential to become a clinically useful biomarker in analyses that were presented at the meeting.

Dr. Russell Petty of the University of Aberdeen (Scotland) and colleagues studied 182 patients with locally advanced or metastatic disease. The investigators performed FDG-PET (¹⁸fluorodeoxyglucose–positron emission tomography) imaging and CT imaging, as well as gene expression profiling, and immunohistochemistry of pretreatment tumor tissue.

Results showed that among a subgroup of 14 patients who had a PET metabolic response to the first cycle of neoadjuvant chemotherapy, a set of 86 genes in pretreatment tumor tissue distinguished those who had a radiologic response on CT after completing all cycles of that chemotherapy, compared with those who did not respond. In a variety of predictive models, this gene signature correctly predicted radiologic response in all cases.

"We have shown that gene expression profiling can subclassify FDG-PET metabolic responders into those patients that will and will not subsequently go on to have a [radiologic] response. We have also shown that combining molecular biomarkers and FDG-PET allows an optimization of response prediction," Dr. Petty said at a meeting on gastrointestinal cancer sponosored by the American Society of Clinical Oncology.

This is key, as PET alone has a poor positive predictive value in this setting, with only half of PET responders to neoadjuvant chemotherapy eventually showing a histopathologic response.

"While I suppose there is little doubt that if we used PET in this way to make treatment decisions, we would have a system that would be better than unstratified empirical treatment, what it still means is that quite significant proportions of our patients will go on to receive ineffective and intensely toxic therapy," he commented.

A subsequent gene enrichment and pathway analysis identified a half-dozen pathways that provided potential mechanistic explanations for the different tumor behavior.

"Within the pathways identified, the adipocytokine-signaling pathway immediately caught our attention because of the strong known [epidemiologic] link between obesity and body weight, and esophagogastric adenocarcinoma," Dr. Petty noted.

Additional analyses specifically fingered the leptin gene (among others) and showed that among PET responders, leptin expression was higher in radiologic nonresponders than in responders (P = .026).

Yet, immunohistochemistry in an independent group of 154 patients showed that strong leptin staining was also associated with better survival (P = .021), an association that held up in multivariate analysis (hazard ratio, 0.85; P = .04).

In stratified analyses, patients with leptin-positive tumors derived little survival benefit from neoadjuvant chemotherapy, whereas those with leptin-negative tumors fared considerably better if they received this therapy (indeed, about as well as the positive group).

"Leptin in particular may be a molecular biomarker that is useful to combine with PET," Dr. Petty commented.

"Leptin expression is associated with chemoresistance, but at the same time is also a favorable therapy-independent biomarker, so this combination of predictive and therapy-independent prognostic impacts mean that leptin has the potential to be a clinically useful biomarker."

"I really think that this is groundbreaking. ... The real future is here" when it comes to predicting treatment response in this cancer, as suggested by this study and others," session cochair Dr. Mark Krasna of the St. Joseph Medical Center in Towson, Md., commented in an interview.

"The question now is, are we ready for prime time to adopt that throughout?"

At present, more research is needed, according to Dr. Krasna, such as the ongoing validation of the 86-gene signature and from trials like CALGB (Cancer and Leukemia Group B) 80803 exploring response-adaptive treatment in this cancer.

"I think those are the important things we can do today. We are ready for that," he concluded.

Dr. Petty and Dr. Krasna reported that they had no relevant financial conflicts of interest.

SAN FRANCISCO – A new 86-gene signature may add to metabolic imaging in guiding early treatment decisions for esophagogastric junction cancer, researchers reported.

The leptin gene, among others, stood out as having the potential to become a clinically useful biomarker in analyses that were presented at the meeting.

Dr. Russell Petty of the University of Aberdeen (Scotland) and colleagues studied 182 patients with locally advanced or metastatic disease. The investigators performed FDG-PET (¹⁸fluorodeoxyglucose–positron emission tomography) imaging and CT imaging, as well as gene expression profiling, and immunohistochemistry of pretreatment tumor tissue.

Results showed that among a subgroup of 14 patients who had a PET metabolic response to the first cycle of neoadjuvant chemotherapy, a set of 86 genes in pretreatment tumor tissue distinguished those who had a radiologic response on CT after completing all cycles of that chemotherapy, compared with those who did not respond. In a variety of predictive models, this gene signature correctly predicted radiologic response in all cases.

"We have shown that gene expression profiling can subclassify FDG-PET metabolic responders into those patients that will and will not subsequently go on to have a [radiologic] response. We have also shown that combining molecular biomarkers and FDG-PET allows an optimization of response prediction," Dr. Petty said at a meeting on gastrointestinal cancer sponosored by the American Society of Clinical Oncology.

This is key, as PET alone has a poor positive predictive value in this setting, with only half of PET responders to neoadjuvant chemotherapy eventually showing a histopathologic response.

"While I suppose there is little doubt that if we used PET in this way to make treatment decisions, we would have a system that would be better than unstratified empirical treatment, what it still means is that quite significant proportions of our patients will go on to receive ineffective and intensely toxic therapy," he commented.

A subsequent gene enrichment and pathway analysis identified a half-dozen pathways that provided potential mechanistic explanations for the different tumor behavior.

"Within the pathways identified, the adipocytokine-signaling pathway immediately caught our attention because of the strong known [epidemiologic] link between obesity and body weight, and esophagogastric adenocarcinoma," Dr. Petty noted.

Additional analyses specifically fingered the leptin gene (among others) and showed that among PET responders, leptin expression was higher in radiologic nonresponders than in responders (P = .026).

Yet, immunohistochemistry in an independent group of 154 patients showed that strong leptin staining was also associated with better survival (P = .021), an association that held up in multivariate analysis (hazard ratio, 0.85; P = .04).

In stratified analyses, patients with leptin-positive tumors derived little survival benefit from neoadjuvant chemotherapy, whereas those with leptin-negative tumors fared considerably better if they received this therapy (indeed, about as well as the positive group).

"Leptin in particular may be a molecular biomarker that is useful to combine with PET," Dr. Petty commented.

"Leptin expression is associated with chemoresistance, but at the same time is also a favorable therapy-independent biomarker, so this combination of predictive and therapy-independent prognostic impacts mean that leptin has the potential to be a clinically useful biomarker."

"I really think that this is groundbreaking. ... The real future is here" when it comes to predicting treatment response in this cancer, as suggested by this study and others," session cochair Dr. Mark Krasna of the St. Joseph Medical Center in Towson, Md., commented in an interview.

"The question now is, are we ready for prime time to adopt that throughout?"

At present, more research is needed, according to Dr. Krasna, such as the ongoing validation of the 86-gene signature and from trials like CALGB (Cancer and Leukemia Group B) 80803 exploring response-adaptive treatment in this cancer.

"I think those are the important things we can do today. We are ready for that," he concluded.

Dr. Petty and Dr. Krasna reported that they had no relevant financial conflicts of interest.

SAN FRANCISCO – Despite disappointing results in an international randomized phase III trial, investigators are hoping a biomarker will help them to find a role for everolimus in advanced gastric cancer.

The oral mammalian target of rapamycin (mTOR) inhibitor appeared to have limited efficacy as second- or third-line therapy in the GRANITE-1 study of more than 650 patients.

Overall survival was statistically indistinguishable between patients given everolimus (Afinitor) and those given a placebo, each added to best supportive care. Statistically, progression-free survival was significantly better with everolimus, but the absolute benefit was small, just 0.3 months.

"This trial was negative," Dr. Eric Van Cutsem told attendees when he reported the results at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology. But the story did not end there.

"What is going to be crucial – and we hope to present at future meetings – is the biomarker analysis to show which are the patients who had the minor responses and had some activity," he added, with initial focus on biomarkers in the PI3 kinase/Akt/mTOR pathway.

The findings came on the heels of a phase II trial that suggested everolimus had promising efficacy in this hard-to-treat cancer (J. Clin. Oncol. 2010;28:1904-10). The PI3 kinase/Akt/mTOR pathway is a logical target in this disease, as it is dysregulated in 50%-60% of cases, according to Dr. Van Cutsem, an oncologist at University Hospital Gasthuisberg in Leuven, Belgium.

"The progression-free survival curve is somewhat provocative," said discussant Dr. David H. Ilson of the Memorial Sloan-Kettering Cancer Center in New York.

"We clearly need the study of biomarkers to identify the likely small subset of patients who may benefit from treatment with this agent," he said. "However, I would give a caveat here: This does not mean that we should mandate a biomarker up front in all of our new studies because we may miss detection of activity in all patients by mandating biomarkers up front."

Dr. Ilson noted that the magnitude of benefit may be important to taking everolimus forward in gastric cancer. "How high should the bar be set to consider developing new agents? Is a 1- to 2-month improvement in progression-free survival or overall survival enough of an adequate benchmark?" he questioned.

Patients were eligible for GRANITE-1 if they had advanced gastric cancer (or gastroesophageal junction cancer, provided the majority of the tumor was in the stomach) and had experienced progression after one or two lines of systemic chemotherapy.

In all, 656 patients were randomized 2:1 to everolimus 10 mg daily or placebo, each along with best supportive care. They had a median age of 62 years, and about 55% were from Asia. They were almost evenly split as far as having received one or two prior lines of chemotherapy.

The median duration of treatment was 7.1 weeks with everolimus and 6.4 weeks with placebo, Dr. Van Cutsem reported.

"The safety profile of everolimus was similar to that observed with everolimus in other cancers, with no new safety signals identified," he said. The rate of any grade 3 or 4 adverse event was 71% with everolimus and 54% with placebo, with the largest differences seen for certain gastrointestinal and hematologic adverse events.

Median overall survival, the trial’s primary end point, was 5.4 months with everolimus and 4.3 months with placebo, a nonsignificant difference. Subgroup analyses failed to identify any specific subgroup that had significant benefit.

Median progression-free survival was 1.7 months with everolimus and 1.4 months with placebo (hazard ratio, 0.66; P less than .0001). The overall response rate was 4.5% and 2.1%, respectively.

Dr. Van Cutsem disclosed that he receives research funding from Novartis. Dr. Ilson disclosed that he receives research funding from Bayer, BMS-ImClone, Roche-Genentech, and Sanofi-Aventis.

SAN FRANCISCO – Despite disappointing results in an international randomized phase III trial, investigators are hoping a biomarker will help them to find a role for everolimus in advanced gastric cancer.

The oral mammalian target of rapamycin (mTOR) inhibitor appeared to have limited efficacy as second- or third-line therapy in the GRANITE-1 study of more than 650 patients.

Overall survival was statistically indistinguishable between patients given everolimus (Afinitor) and those given a placebo, each added to best supportive care. Statistically, progression-free survival was significantly better with everolimus, but the absolute benefit was small, just 0.3 months.

"This trial was negative," Dr. Eric Van Cutsem told attendees when he reported the results at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology. But the story did not end there.

"What is going to be crucial – and we hope to present at future meetings – is the biomarker analysis to show which are the patients who had the minor responses and had some activity," he added, with initial focus on biomarkers in the PI3 kinase/Akt/mTOR pathway.

The findings came on the heels of a phase II trial that suggested everolimus had promising efficacy in this hard-to-treat cancer (J. Clin. Oncol. 2010;28:1904-10). The PI3 kinase/Akt/mTOR pathway is a logical target in this disease, as it is dysregulated in 50%-60% of cases, according to Dr. Van Cutsem, an oncologist at University Hospital Gasthuisberg in Leuven, Belgium.

"The progression-free survival curve is somewhat provocative," said discussant Dr. David H. Ilson of the Memorial Sloan-Kettering Cancer Center in New York.

"We clearly need the study of biomarkers to identify the likely small subset of patients who may benefit from treatment with this agent," he said. "However, I would give a caveat here: This does not mean that we should mandate a biomarker up front in all of our new studies because we may miss detection of activity in all patients by mandating biomarkers up front."

Dr. Ilson noted that the magnitude of benefit may be important to taking everolimus forward in gastric cancer. "How high should the bar be set to consider developing new agents? Is a 1- to 2-month improvement in progression-free survival or overall survival enough of an adequate benchmark?" he questioned.

Patients were eligible for GRANITE-1 if they had advanced gastric cancer (or gastroesophageal junction cancer, provided the majority of the tumor was in the stomach) and had experienced progression after one or two lines of systemic chemotherapy.

In all, 656 patients were randomized 2:1 to everolimus 10 mg daily or placebo, each along with best supportive care. They had a median age of 62 years, and about 55% were from Asia. They were almost evenly split as far as having received one or two prior lines of chemotherapy.

The median duration of treatment was 7.1 weeks with everolimus and 6.4 weeks with placebo, Dr. Van Cutsem reported.

"The safety profile of everolimus was similar to that observed with everolimus in other cancers, with no new safety signals identified," he said. The rate of any grade 3 or 4 adverse event was 71% with everolimus and 54% with placebo, with the largest differences seen for certain gastrointestinal and hematologic adverse events.

Median overall survival, the trial’s primary end point, was 5.4 months with everolimus and 4.3 months with placebo, a nonsignificant difference. Subgroup analyses failed to identify any specific subgroup that had significant benefit.

Median progression-free survival was 1.7 months with everolimus and 1.4 months with placebo (hazard ratio, 0.66; P less than .0001). The overall response rate was 4.5% and 2.1%, respectively.

Dr. Van Cutsem disclosed that he receives research funding from Novartis. Dr. Ilson disclosed that he receives research funding from Bayer, BMS-ImClone, Roche-Genentech, and Sanofi-Aventis.

SAN FRANCISCO – Despite disappointing results in an international randomized phase III trial, investigators are hoping a biomarker will help them to find a role for everolimus in advanced gastric cancer.

The oral mammalian target of rapamycin (mTOR) inhibitor appeared to have limited efficacy as second- or third-line therapy in the GRANITE-1 study of more than 650 patients.

Overall survival was statistically indistinguishable between patients given everolimus (Afinitor) and those given a placebo, each added to best supportive care. Statistically, progression-free survival was significantly better with everolimus, but the absolute benefit was small, just 0.3 months.

"This trial was negative," Dr. Eric Van Cutsem told attendees when he reported the results at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology. But the story did not end there.

"What is going to be crucial – and we hope to present at future meetings – is the biomarker analysis to show which are the patients who had the minor responses and had some activity," he added, with initial focus on biomarkers in the PI3 kinase/Akt/mTOR pathway.

The findings came on the heels of a phase II trial that suggested everolimus had promising efficacy in this hard-to-treat cancer (J. Clin. Oncol. 2010;28:1904-10). The PI3 kinase/Akt/mTOR pathway is a logical target in this disease, as it is dysregulated in 50%-60% of cases, according to Dr. Van Cutsem, an oncologist at University Hospital Gasthuisberg in Leuven, Belgium.

"The progression-free survival curve is somewhat provocative," said discussant Dr. David H. Ilson of the Memorial Sloan-Kettering Cancer Center in New York.

"We clearly need the study of biomarkers to identify the likely small subset of patients who may benefit from treatment with this agent," he said. "However, I would give a caveat here: This does not mean that we should mandate a biomarker up front in all of our new studies because we may miss detection of activity in all patients by mandating biomarkers up front."

Dr. Ilson noted that the magnitude of benefit may be important to taking everolimus forward in gastric cancer. "How high should the bar be set to consider developing new agents? Is a 1- to 2-month improvement in progression-free survival or overall survival enough of an adequate benchmark?" he questioned.

Patients were eligible for GRANITE-1 if they had advanced gastric cancer (or gastroesophageal junction cancer, provided the majority of the tumor was in the stomach) and had experienced progression after one or two lines of systemic chemotherapy.

In all, 656 patients were randomized 2:1 to everolimus 10 mg daily or placebo, each along with best supportive care. They had a median age of 62 years, and about 55% were from Asia. They were almost evenly split as far as having received one or two prior lines of chemotherapy.

The median duration of treatment was 7.1 weeks with everolimus and 6.4 weeks with placebo, Dr. Van Cutsem reported.

"The safety profile of everolimus was similar to that observed with everolimus in other cancers, with no new safety signals identified," he said. The rate of any grade 3 or 4 adverse event was 71% with everolimus and 54% with placebo, with the largest differences seen for certain gastrointestinal and hematologic adverse events.

Median overall survival, the trial’s primary end point, was 5.4 months with everolimus and 4.3 months with placebo, a nonsignificant difference. Subgroup analyses failed to identify any specific subgroup that had significant benefit.

Median progression-free survival was 1.7 months with everolimus and 1.4 months with placebo (hazard ratio, 0.66; P less than .0001). The overall response rate was 4.5% and 2.1%, respectively.

Dr. Van Cutsem disclosed that he receives research funding from Novartis. Dr. Ilson disclosed that he receives research funding from Bayer, BMS-ImClone, Roche-Genentech, and Sanofi-Aventis.

SAN FRANCISCO – The safety and efficacy profile of aspirin for preventing esophageal and other cancers is likely to limit its use to people at highest risk, said Dr. Janusz A. Jankowski in a presentation at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.

"The commonest question I’m asked is, ‘Should I now be taking low-dose aspirin?’," he said. "And my answer to that at this moment in time is indefatigably, no, you should not, unless you have a secondary risk factor," such as Barrett metaplasia or colon polyps (or a secondary cardiovascular risk factor).

Collectively, evidence suggests that taking aspirin reduces cancer risk by about one quarter, according to Dr. Jankowski; however, aspirin has to be taken for at least a decade to see clinically meaningful benefit (Lancet 2011;377:31-41). "Chemoprevention is a very, very long term goal here," he commented. "This is not about taking it for a few years and hoping to get a benefit – it’s 10 to 20 years. And that means that the side effect profile ... must be exceptionally low."

The risk of bleeding with aspirin is well known. Rates of any upper gastrointestinal bleeding and serious GI bleeding on the medication are about 4% and 2% per year, respectively, and aspirin particularly increases the risk of spontaneous GI bleeding after age 50 years. However, adding proton pump inhibitor (PPI) therapy largely attenuates the excess risk.

But new data have also implicated aspirin in the development of macular degeneration (Ophthalmology 2012;119:112-8). "That’s another thing that you may have to consider ... Could aspirin be causing something else, as well as preventing something?" said Dr. Jankowski, a visiting professor of GI oncology at the University of Oxford (U.K.) and the Honorary Sir James Black Professor at Barts and the London School of Medicine and Dentistry.

The authors of a recent analysis concluded that healthy people do not experience any significant reduction in either cardiovascular or cancer deaths when they take aspirin (Arch. Intern. Med. 2012;172:209-16), which "has kind of dashed our hopes for primary prevention," he said.

In the secondary prevention realm, the randomized Aspect trial (a phase III, randomized, study of aspirin and esomeprazole chemoprevention in Barrett’s metaplasia) is comparing lower- vs. higher-dose PPI therapy using esomeprazole. Each dosage level of esomeprazole is given with or without aspirin in about 2,500 patients with Barrett’s esophagus, which is thought to carry a 3%-5% lifetime risk of esophageal cancer.

In this trial, results for cancer and other clinical outcomes are not expected until 2019. But early endoscopic findings suggest that the added aspirin helps promote the appearance of new squamous epithelial islands in areas previously showing Barrett metaplasia, a promising surrogate end point, according to Dr. Jankowski.

At the same time, he cautioned against overreliance on aspirin, saying, "As good as aspirin is, ... it’s still not good enough because in fact we still don’t know who’s going to get a response, and we still think that the best response rate is probably only 20% in the population."

BADCAT (the Barrett’s Dysplasia and Cancer Task Force), which exhaustively reviews evidence on the topic, has identified aspirin effectiveness and responsiveness as an area of high priority for research. And because genetics have a major role here, the Chopin study (chemoprevention of premalignant intestinal neoplasia) is assessing genomewide associations in the development and prevention of esophageal cancer, including identification of aspirin-response genes.

Summing up the evidence on the use of aspirin to prevent esophageal and other cancers, Dr. Jankowski predicted, "In the next 2 years, there may very well be a recommendation that if you have secondary risk factors for cancer, like Barrett’s ... that you may be given aspirin therapy in addition to your proton pump inhibitor."

Only people in a fairly narrow age range will have net benefit, based on currently available data. "Aspirin is a wonderful agent. Having said that, there is no evidence whatsoever that even if you’ve got secondary risks factors for cardiac disease or cancer, you should take your aspirin before 55 years of age," he explained. And starting aspirin after age 75 years is not justified given the current human lifespan and the need for prolonged use to achieve benefit.

"The window of taking aspirin is between 55 and 75," he concluded, adding "while I am an enthusiast of aspirin ... it is only part of the jigsaw, and we still need even to answer that part."

Dr. Jankowski disclosed that he is a consultant to and receives research funding and honoraria from AstraZeneca.

SAN FRANCISCO – The safety and efficacy profile of aspirin for preventing esophageal and other cancers is likely to limit its use to people at highest risk, said Dr. Janusz A. Jankowski in a presentation at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.

"The commonest question I’m asked is, ‘Should I now be taking low-dose aspirin?’," he said. "And my answer to that at this moment in time is indefatigably, no, you should not, unless you have a secondary risk factor," such as Barrett metaplasia or colon polyps (or a secondary cardiovascular risk factor).

Collectively, evidence suggests that taking aspirin reduces cancer risk by about one quarter, according to Dr. Jankowski; however, aspirin has to be taken for at least a decade to see clinically meaningful benefit (Lancet 2011;377:31-41). "Chemoprevention is a very, very long term goal here," he commented. "This is not about taking it for a few years and hoping to get a benefit – it’s 10 to 20 years. And that means that the side effect profile ... must be exceptionally low."

The risk of bleeding with aspirin is well known. Rates of any upper gastrointestinal bleeding and serious GI bleeding on the medication are about 4% and 2% per year, respectively, and aspirin particularly increases the risk of spontaneous GI bleeding after age 50 years. However, adding proton pump inhibitor (PPI) therapy largely attenuates the excess risk.

But new data have also implicated aspirin in the development of macular degeneration (Ophthalmology 2012;119:112-8). "That’s another thing that you may have to consider ... Could aspirin be causing something else, as well as preventing something?" said Dr. Jankowski, a visiting professor of GI oncology at the University of Oxford (U.K.) and the Honorary Sir James Black Professor at Barts and the London School of Medicine and Dentistry.

The authors of a recent analysis concluded that healthy people do not experience any significant reduction in either cardiovascular or cancer deaths when they take aspirin (Arch. Intern. Med. 2012;172:209-16), which "has kind of dashed our hopes for primary prevention," he said.

In the secondary prevention realm, the randomized Aspect trial (a phase III, randomized, study of aspirin and esomeprazole chemoprevention in Barrett’s metaplasia) is comparing lower- vs. higher-dose PPI therapy using esomeprazole. Each dosage level of esomeprazole is given with or without aspirin in about 2,500 patients with Barrett’s esophagus, which is thought to carry a 3%-5% lifetime risk of esophageal cancer.

In this trial, results for cancer and other clinical outcomes are not expected until 2019. But early endoscopic findings suggest that the added aspirin helps promote the appearance of new squamous epithelial islands in areas previously showing Barrett metaplasia, a promising surrogate end point, according to Dr. Jankowski.

At the same time, he cautioned against overreliance on aspirin, saying, "As good as aspirin is, ... it’s still not good enough because in fact we still don’t know who’s going to get a response, and we still think that the best response rate is probably only 20% in the population."

BADCAT (the Barrett’s Dysplasia and Cancer Task Force), which exhaustively reviews evidence on the topic, has identified aspirin effectiveness and responsiveness as an area of high priority for research. And because genetics have a major role here, the Chopin study (chemoprevention of premalignant intestinal neoplasia) is assessing genomewide associations in the development and prevention of esophageal cancer, including identification of aspirin-response genes.

Summing up the evidence on the use of aspirin to prevent esophageal and other cancers, Dr. Jankowski predicted, "In the next 2 years, there may very well be a recommendation that if you have secondary risk factors for cancer, like Barrett’s ... that you may be given aspirin therapy in addition to your proton pump inhibitor."

Only people in a fairly narrow age range will have net benefit, based on currently available data. "Aspirin is a wonderful agent. Having said that, there is no evidence whatsoever that even if you’ve got secondary risks factors for cardiac disease or cancer, you should take your aspirin before 55 years of age," he explained. And starting aspirin after age 75 years is not justified given the current human lifespan and the need for prolonged use to achieve benefit.

"The window of taking aspirin is between 55 and 75," he concluded, adding "while I am an enthusiast of aspirin ... it is only part of the jigsaw, and we still need even to answer that part."

Dr. Jankowski disclosed that he is a consultant to and receives research funding and honoraria from AstraZeneca.

SAN FRANCISCO – The safety and efficacy profile of aspirin for preventing esophageal and other cancers is likely to limit its use to people at highest risk, said Dr. Janusz A. Jankowski in a presentation at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.

"The commonest question I’m asked is, ‘Should I now be taking low-dose aspirin?’," he said. "And my answer to that at this moment in time is indefatigably, no, you should not, unless you have a secondary risk factor," such as Barrett metaplasia or colon polyps (or a secondary cardiovascular risk factor).

Collectively, evidence suggests that taking aspirin reduces cancer risk by about one quarter, according to Dr. Jankowski; however, aspirin has to be taken for at least a decade to see clinically meaningful benefit (Lancet 2011;377:31-41). "Chemoprevention is a very, very long term goal here," he commented. "This is not about taking it for a few years and hoping to get a benefit – it’s 10 to 20 years. And that means that the side effect profile ... must be exceptionally low."

The risk of bleeding with aspirin is well known. Rates of any upper gastrointestinal bleeding and serious GI bleeding on the medication are about 4% and 2% per year, respectively, and aspirin particularly increases the risk of spontaneous GI bleeding after age 50 years. However, adding proton pump inhibitor (PPI) therapy largely attenuates the excess risk.

But new data have also implicated aspirin in the development of macular degeneration (Ophthalmology 2012;119:112-8). "That’s another thing that you may have to consider ... Could aspirin be causing something else, as well as preventing something?" said Dr. Jankowski, a visiting professor of GI oncology at the University of Oxford (U.K.) and the Honorary Sir James Black Professor at Barts and the London School of Medicine and Dentistry.

The authors of a recent analysis concluded that healthy people do not experience any significant reduction in either cardiovascular or cancer deaths when they take aspirin (Arch. Intern. Med. 2012;172:209-16), which "has kind of dashed our hopes for primary prevention," he said.

In the secondary prevention realm, the randomized Aspect trial (a phase III, randomized, study of aspirin and esomeprazole chemoprevention in Barrett’s metaplasia) is comparing lower- vs. higher-dose PPI therapy using esomeprazole. Each dosage level of esomeprazole is given with or without aspirin in about 2,500 patients with Barrett’s esophagus, which is thought to carry a 3%-5% lifetime risk of esophageal cancer.

In this trial, results for cancer and other clinical outcomes are not expected until 2019. But early endoscopic findings suggest that the added aspirin helps promote the appearance of new squamous epithelial islands in areas previously showing Barrett metaplasia, a promising surrogate end point, according to Dr. Jankowski.

At the same time, he cautioned against overreliance on aspirin, saying, "As good as aspirin is, ... it’s still not good enough because in fact we still don’t know who’s going to get a response, and we still think that the best response rate is probably only 20% in the population."

BADCAT (the Barrett’s Dysplasia and Cancer Task Force), which exhaustively reviews evidence on the topic, has identified aspirin effectiveness and responsiveness as an area of high priority for research. And because genetics have a major role here, the Chopin study (chemoprevention of premalignant intestinal neoplasia) is assessing genomewide associations in the development and prevention of esophageal cancer, including identification of aspirin-response genes.

Summing up the evidence on the use of aspirin to prevent esophageal and other cancers, Dr. Jankowski predicted, "In the next 2 years, there may very well be a recommendation that if you have secondary risk factors for cancer, like Barrett’s ... that you may be given aspirin therapy in addition to your proton pump inhibitor."

Only people in a fairly narrow age range will have net benefit, based on currently available data. "Aspirin is a wonderful agent. Having said that, there is no evidence whatsoever that even if you’ve got secondary risks factors for cardiac disease or cancer, you should take your aspirin before 55 years of age," he explained. And starting aspirin after age 75 years is not justified given the current human lifespan and the need for prolonged use to achieve benefit.

"The window of taking aspirin is between 55 and 75," he concluded, adding "while I am an enthusiast of aspirin ... it is only part of the jigsaw, and we still need even to answer that part."

Dr. Jankowski disclosed that he is a consultant to and receives research funding and honoraria from AstraZeneca.

SAN FRANCISCO – Tyrosine kinase inhibitors that target the vascular endothelial growth factor receptor increase the risk of a fatal adverse event in cancer patients, but the absolute rate is still low, investigators concluded from a meta-analysis of 10 randomized trials with a total of 4,679 patients.

Trial participants given sorafenib (Nexavar), sunitinib (Sutent), or pazopanib (Votrient) were more than twice as likely to die from an adverse event as were peers given control treatment, said lead investigator Dr. Christopher J. Richards of the Beth Israel Deaconess Medical Center in Boston. Yet, the rate was still less than 2%.

"Our analysis may underestimate the true incidence of fatal adverse events, as study patients may be healthier than the general population exposed to these drugs," he noted at the Genitourinary Cancers Symposium. But that said, "all three of the study drugs have been shown in various randomized controlled trials to improve clinical outcomes compared to traditional therapies."

Discussant Dr. Thomas E. Hutson of the Baylor Sammons Cancer Center in Dallas commented, "I feel confident that everyone or almost everyone in the room today would agree with me that our current therapy benefit outweighs the risk associated with the treatment."

Moreover, even among the new targeted agents, the 1.5% rate seen with the vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) in the meta-analysis "compares very favorably" with the rate of 2.9% seen previously with bevacizumab (Avastin), another VEGF-targeted therapy, in a similar analysis (JAMA 2011;305:487-94).

"Targeted therapies have real toxicities, and these toxicities include a low risk of death – a risk of death not much different than other therapies used for kidney and other cancer types," Dr. Hutson asserted. "If anything, this meta-analysis shows us that close monitoring is going to be essential for optimal use of these agents."

In the study, Dr. Richards and his colleagues identified 10 randomized controlled phase II or III trials in which patients received any of three VEGFR TKIs approved by the Food and Drug Administration for cancer treatment as of February 2011: sorafenib, sunitinib, or pazopanib. The control groups were usually treated with a placebo, but in some cases with chemotherapy or immunotherapy.

The enrolled patients had a variety of malignancies: renal cell carcinoma, hepatocellular carcinoma, melanoma, non–small cell lung cancer, breast cancer, and pancreatic neuroendocrine tumor. "All patients included in the studies had good performance status and had adequate baseline cardiac, hematologic, and renal function at the time of study entry," Dr. Richards pointed out.

In a pooled analysis, relative to control treatment, VEGFR TKI treatment was associated with a 2.23-fold increased risk of fatal adverse events (P = .02). But even so, the absolute rate of such events was just 1.5%, compared with 0.7% with the control treatment.

In stratified analyses, there was no significant difference in the relative risks across the three agents or the relative risks for renal cell carcinoma vs. other types of cancer.

The most common fatal adverse events in the trials overall (considering both control and VEGFR TKI arms) were hemorrhage (48% of the total), myocardial infarction (15%), and hepatic failure (10%). These events "occurred in both the placebo and control groups as well as study groups," Dr. Richards noted.

He acknowledged that limitations of the study included the fact that the analysis used study-level instead of patient-level data, which may have resulted in confounding, and that it did not have adequate power to detect differences between the three VEGFR TKIs, although they all have a similar mechanism of action.

The symposium was sponsored by the American Society of Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.

Dr. Richards disclosed that he had no relevant conflicts of interest. Dr. Hutson disclosed that he is a consultant to and receives honoraria from Bayer, Genentech, GlaxoSmithKline, Novartis, Onyx, Pfizer, and Wyeth, and that he receives research funding from GlaxoSmithKline, Pfizer, and Wyeth.

SAN FRANCISCO – Tyrosine kinase inhibitors that target the vascular endothelial growth factor receptor increase the risk of a fatal adverse event in cancer patients, but the absolute rate is still low, investigators concluded from a meta-analysis of 10 randomized trials with a total of 4,679 patients.

Trial participants given sorafenib (Nexavar), sunitinib (Sutent), or pazopanib (Votrient) were more than twice as likely to die from an adverse event as were peers given control treatment, said lead investigator Dr. Christopher J. Richards of the Beth Israel Deaconess Medical Center in Boston. Yet, the rate was still less than 2%.

"Our analysis may underestimate the true incidence of fatal adverse events, as study patients may be healthier than the general population exposed to these drugs," he noted at the Genitourinary Cancers Symposium. But that said, "all three of the study drugs have been shown in various randomized controlled trials to improve clinical outcomes compared to traditional therapies."

Discussant Dr. Thomas E. Hutson of the Baylor Sammons Cancer Center in Dallas commented, "I feel confident that everyone or almost everyone in the room today would agree with me that our current therapy benefit outweighs the risk associated with the treatment."

Moreover, even among the new targeted agents, the 1.5% rate seen with the vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) in the meta-analysis "compares very favorably" with the rate of 2.9% seen previously with bevacizumab (Avastin), another VEGF-targeted therapy, in a similar analysis (JAMA 2011;305:487-94).

"Targeted therapies have real toxicities, and these toxicities include a low risk of death – a risk of death not much different than other therapies used for kidney and other cancer types," Dr. Hutson asserted. "If anything, this meta-analysis shows us that close monitoring is going to be essential for optimal use of these agents."

In the study, Dr. Richards and his colleagues identified 10 randomized controlled phase II or III trials in which patients received any of three VEGFR TKIs approved by the Food and Drug Administration for cancer treatment as of February 2011: sorafenib, sunitinib, or pazopanib. The control groups were usually treated with a placebo, but in some cases with chemotherapy or immunotherapy.

The enrolled patients had a variety of malignancies: renal cell carcinoma, hepatocellular carcinoma, melanoma, non–small cell lung cancer, breast cancer, and pancreatic neuroendocrine tumor. "All patients included in the studies had good performance status and had adequate baseline cardiac, hematologic, and renal function at the time of study entry," Dr. Richards pointed out.

In a pooled analysis, relative to control treatment, VEGFR TKI treatment was associated with a 2.23-fold increased risk of fatal adverse events (P = .02). But even so, the absolute rate of such events was just 1.5%, compared with 0.7% with the control treatment.

In stratified analyses, there was no significant difference in the relative risks across the three agents or the relative risks for renal cell carcinoma vs. other types of cancer.

The most common fatal adverse events in the trials overall (considering both control and VEGFR TKI arms) were hemorrhage (48% of the total), myocardial infarction (15%), and hepatic failure (10%). These events "occurred in both the placebo and control groups as well as study groups," Dr. Richards noted.

He acknowledged that limitations of the study included the fact that the analysis used study-level instead of patient-level data, which may have resulted in confounding, and that it did not have adequate power to detect differences between the three VEGFR TKIs, although they all have a similar mechanism of action.

The symposium was sponsored by the American Society of Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.

Dr. Richards disclosed that he had no relevant conflicts of interest. Dr. Hutson disclosed that he is a consultant to and receives honoraria from Bayer, Genentech, GlaxoSmithKline, Novartis, Onyx, Pfizer, and Wyeth, and that he receives research funding from GlaxoSmithKline, Pfizer, and Wyeth.

SAN FRANCISCO – Tyrosine kinase inhibitors that target the vascular endothelial growth factor receptor increase the risk of a fatal adverse event in cancer patients, but the absolute rate is still low, investigators concluded from a meta-analysis of 10 randomized trials with a total of 4,679 patients.

Trial participants given sorafenib (Nexavar), sunitinib (Sutent), or pazopanib (Votrient) were more than twice as likely to die from an adverse event as were peers given control treatment, said lead investigator Dr. Christopher J. Richards of the Beth Israel Deaconess Medical Center in Boston. Yet, the rate was still less than 2%.

"Our analysis may underestimate the true incidence of fatal adverse events, as study patients may be healthier than the general population exposed to these drugs," he noted at the Genitourinary Cancers Symposium. But that said, "all three of the study drugs have been shown in various randomized controlled trials to improve clinical outcomes compared to traditional therapies."

Discussant Dr. Thomas E. Hutson of the Baylor Sammons Cancer Center in Dallas commented, "I feel confident that everyone or almost everyone in the room today would agree with me that our current therapy benefit outweighs the risk associated with the treatment."

Moreover, even among the new targeted agents, the 1.5% rate seen with the vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) in the meta-analysis "compares very favorably" with the rate of 2.9% seen previously with bevacizumab (Avastin), another VEGF-targeted therapy, in a similar analysis (JAMA 2011;305:487-94).

"Targeted therapies have real toxicities, and these toxicities include a low risk of death – a risk of death not much different than other therapies used for kidney and other cancer types," Dr. Hutson asserted. "If anything, this meta-analysis shows us that close monitoring is going to be essential for optimal use of these agents."

In the study, Dr. Richards and his colleagues identified 10 randomized controlled phase II or III trials in which patients received any of three VEGFR TKIs approved by the Food and Drug Administration for cancer treatment as of February 2011: sorafenib, sunitinib, or pazopanib. The control groups were usually treated with a placebo, but in some cases with chemotherapy or immunotherapy.

The enrolled patients had a variety of malignancies: renal cell carcinoma, hepatocellular carcinoma, melanoma, non–small cell lung cancer, breast cancer, and pancreatic neuroendocrine tumor. "All patients included in the studies had good performance status and had adequate baseline cardiac, hematologic, and renal function at the time of study entry," Dr. Richards pointed out.

In a pooled analysis, relative to control treatment, VEGFR TKI treatment was associated with a 2.23-fold increased risk of fatal adverse events (P = .02). But even so, the absolute rate of such events was just 1.5%, compared with 0.7% with the control treatment.

In stratified analyses, there was no significant difference in the relative risks across the three agents or the relative risks for renal cell carcinoma vs. other types of cancer.

The most common fatal adverse events in the trials overall (considering both control and VEGFR TKI arms) were hemorrhage (48% of the total), myocardial infarction (15%), and hepatic failure (10%). These events "occurred in both the placebo and control groups as well as study groups," Dr. Richards noted.

He acknowledged that limitations of the study included the fact that the analysis used study-level instead of patient-level data, which may have resulted in confounding, and that it did not have adequate power to detect differences between the three VEGFR TKIs, although they all have a similar mechanism of action.

The symposium was sponsored by the American Society of Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.

Dr. Richards disclosed that he had no relevant conflicts of interest. Dr. Hutson disclosed that he is a consultant to and receives honoraria from Bayer, Genentech, GlaxoSmithKline, Novartis, Onyx, Pfizer, and Wyeth, and that he receives research funding from GlaxoSmithKline, Pfizer, and Wyeth.

SAN FRANCISCO – Patients with gastrointestinal stromal tumors have a poorer prognosis if their primary tumor is located outside the gastrointestinal tract, researchers reported.

In an analysis of a U.S. population–based cohort of 2,591 patients who underwent surgery for gastrointestinal stromal tumors (GIST), 10% had primaries in the omentum, mesentery, retroperitoneum, or another location separate from the tubular gastrointestinal tract.

The 5-year overall survival rate for this group of patients with extragastrointestinal stromal tumors (EGIST) was 62%, which was significantly poorer than the 70% observed for those with primaries in the typical gastrointestinal tract location, mainly the stomach or small intestine.

Patients with primaries outside the gastrointestinal tract had larger tumors and more advanced stage, the study found. But even after adjustment for these potential confounders, extragastrointestinal location was still associated with a nearly 30% increase in the risk of death.

"The results of our study suggest that tumor location outside the gastrointestinal tract should be considered as an important variable, and risk stratification for prognosis should account for these rare GIST locations," said lead investigator Dr. Mary L. Guye, who presented the data at the gastrointestinal cancers symposium sponsored by the American Society of Clinical Oncology.

The reason for this poorer prognosis is unknown, said Dr. Guye, a surgical oncologist at the City of Hope National Medical Center in Duarte, Calif.

"It could be these are truly metastatic foci with an unidentified or unknown primary tumor, or they may simply be more aggressive tumors that arise de novo outside the gastrointestinal tract," she proposed, calling for further studies to investigate the tumor biology of these rare GIST tumors.

"Evaluation of histology, looking at tumor mitotic rate, and also mutational analyses may help to determine why extra-intestinal location confers a worse prognosis for GIST tumors," she said.

In an interview, Dr. Allan Pickens of Emory University in Atlanta, cochair of the scientific session in which the data were presented, said, "This was a great study [that further defined] the difference between the traditional GISTs that we treat more commonly and the ones that are outside of the gastrointestinal tract [and] have a worse prognosis."

Dr. Pickens agreed that molecular analyses will help better define how the two groups of tumors differ. "It would be interesting to see some of the microRNA information applied to those different tumors to see if it could predict those worse outcomes," he said.

Dr. Guye and her colleagues analyzed SEER (Surveillance, Epidemiology, and End Results) data for 1996-2008 to identify their study population with GIST, choosing the start year because that is when diagnosis of this tumor became more accurate, she explained.

Patients with primaries in and outside the gastrointestinal tract had similar age and racial distribution. But patients with EGIST were more likely to receive radiation therapy, to have tumors larger than 10 cm, and to have regional or distant disease.

Median overall survival was 120 months in the group with primaries in the gastrointestinal tract, and 105 months in the group with primaries in other locations (P = .002).

Additional analyses showed that location outside the gastrointestinal tract conferred a worse prognosis, even when tumors were matched for size and stage of disease, Dr. Guye reported. And the association stood up in multivariate analysis (P = .03).

However, "the SEER database does not include information on mitotic rate or information on systemic medical therapies," she noted. "Therefore, we were not able to include these factors in our analysis."

Dr. Guye and Dr. Pickens disclosed that they had no relevant conflicts of interest.

SAN FRANCISCO – Patients with gastrointestinal stromal tumors have a poorer prognosis if their primary tumor is located outside the gastrointestinal tract, researchers reported.

In an analysis of a U.S. population–based cohort of 2,591 patients who underwent surgery for gastrointestinal stromal tumors (GIST), 10% had primaries in the omentum, mesentery, retroperitoneum, or another location separate from the tubular gastrointestinal tract.

The 5-year overall survival rate for this group of patients with extragastrointestinal stromal tumors (EGIST) was 62%, which was significantly poorer than the 70% observed for those with primaries in the typical gastrointestinal tract location, mainly the stomach or small intestine.

Patients with primaries outside the gastrointestinal tract had larger tumors and more advanced stage, the study found. But even after adjustment for these potential confounders, extragastrointestinal location was still associated with a nearly 30% increase in the risk of death.

"The results of our study suggest that tumor location outside the gastrointestinal tract should be considered as an important variable, and risk stratification for prognosis should account for these rare GIST locations," said lead investigator Dr. Mary L. Guye, who presented the data at the gastrointestinal cancers symposium sponsored by the American Society of Clinical Oncology.

The reason for this poorer prognosis is unknown, said Dr. Guye, a surgical oncologist at the City of Hope National Medical Center in Duarte, Calif.

"It could be these are truly metastatic foci with an unidentified or unknown primary tumor, or they may simply be more aggressive tumors that arise de novo outside the gastrointestinal tract," she proposed, calling for further studies to investigate the tumor biology of these rare GIST tumors.

"Evaluation of histology, looking at tumor mitotic rate, and also mutational analyses may help to determine why extra-intestinal location confers a worse prognosis for GIST tumors," she said.

In an interview, Dr. Allan Pickens of Emory University in Atlanta, cochair of the scientific session in which the data were presented, said, "This was a great study [that further defined] the difference between the traditional GISTs that we treat more commonly and the ones that are outside of the gastrointestinal tract [and] have a worse prognosis."

Dr. Pickens agreed that molecular analyses will help better define how the two groups of tumors differ. "It would be interesting to see some of the microRNA information applied to those different tumors to see if it could predict those worse outcomes," he said.

Dr. Guye and her colleagues analyzed SEER (Surveillance, Epidemiology, and End Results) data for 1996-2008 to identify their study population with GIST, choosing the start year because that is when diagnosis of this tumor became more accurate, she explained.

Patients with primaries in and outside the gastrointestinal tract had similar age and racial distribution. But patients with EGIST were more likely to receive radiation therapy, to have tumors larger than 10 cm, and to have regional or distant disease.

Median overall survival was 120 months in the group with primaries in the gastrointestinal tract, and 105 months in the group with primaries in other locations (P = .002).

Additional analyses showed that location outside the gastrointestinal tract conferred a worse prognosis, even when tumors were matched for size and stage of disease, Dr. Guye reported. And the association stood up in multivariate analysis (P = .03).

However, "the SEER database does not include information on mitotic rate or information on systemic medical therapies," she noted. "Therefore, we were not able to include these factors in our analysis."

Dr. Guye and Dr. Pickens disclosed that they had no relevant conflicts of interest.

SAN FRANCISCO – Patients with gastrointestinal stromal tumors have a poorer prognosis if their primary tumor is located outside the gastrointestinal tract, researchers reported.

In an analysis of a U.S. population–based cohort of 2,591 patients who underwent surgery for gastrointestinal stromal tumors (GIST), 10% had primaries in the omentum, mesentery, retroperitoneum, or another location separate from the tubular gastrointestinal tract.

The 5-year overall survival rate for this group of patients with extragastrointestinal stromal tumors (EGIST) was 62%, which was significantly poorer than the 70% observed for those with primaries in the typical gastrointestinal tract location, mainly the stomach or small intestine.

Patients with primaries outside the gastrointestinal tract had larger tumors and more advanced stage, the study found. But even after adjustment for these potential confounders, extragastrointestinal location was still associated with a nearly 30% increase in the risk of death.

"The results of our study suggest that tumor location outside the gastrointestinal tract should be considered as an important variable, and risk stratification for prognosis should account for these rare GIST locations," said lead investigator Dr. Mary L. Guye, who presented the data at the gastrointestinal cancers symposium sponsored by the American Society of Clinical Oncology.

The reason for this poorer prognosis is unknown, said Dr. Guye, a surgical oncologist at the City of Hope National Medical Center in Duarte, Calif.

"It could be these are truly metastatic foci with an unidentified or unknown primary tumor, or they may simply be more aggressive tumors that arise de novo outside the gastrointestinal tract," she proposed, calling for further studies to investigate the tumor biology of these rare GIST tumors.

"Evaluation of histology, looking at tumor mitotic rate, and also mutational analyses may help to determine why extra-intestinal location confers a worse prognosis for GIST tumors," she said.

In an interview, Dr. Allan Pickens of Emory University in Atlanta, cochair of the scientific session in which the data were presented, said, "This was a great study [that further defined] the difference between the traditional GISTs that we treat more commonly and the ones that are outside of the gastrointestinal tract [and] have a worse prognosis."

Dr. Pickens agreed that molecular analyses will help better define how the two groups of tumors differ. "It would be interesting to see some of the microRNA information applied to those different tumors to see if it could predict those worse outcomes," he said.

Dr. Guye and her colleagues analyzed SEER (Surveillance, Epidemiology, and End Results) data for 1996-2008 to identify their study population with GIST, choosing the start year because that is when diagnosis of this tumor became more accurate, she explained.

Patients with primaries in and outside the gastrointestinal tract had similar age and racial distribution. But patients with EGIST were more likely to receive radiation therapy, to have tumors larger than 10 cm, and to have regional or distant disease.

Median overall survival was 120 months in the group with primaries in the gastrointestinal tract, and 105 months in the group with primaries in other locations (P = .002).

Additional analyses showed that location outside the gastrointestinal tract conferred a worse prognosis, even when tumors were matched for size and stage of disease, Dr. Guye reported. And the association stood up in multivariate analysis (P = .03).

However, "the SEER database does not include information on mitotic rate or information on systemic medical therapies," she noted. "Therefore, we were not able to include these factors in our analysis."

Dr. Guye and Dr. Pickens disclosed that they had no relevant conflicts of interest.

SAN FRANCISCO – Healthy middle-aged and older men who take vitamin E supplements have an increased risk of prostate cancer, although the risk takes some time to emerge, suggests an update of the randomized SELECT prevention trial.

At a median follow-up of 7 years – or 1.5 years after the trial had been closed early for futility and men had been told to stop taking supplements – those who had taken vitamin E had a significant 17% greater risk of prostate cancer than those who had taken a placebo. The risk had been increased, although not significantly so, at the time of trial closure.

Photo credit: Juanmonino/iStockphoto

In absolute terms, the elevated risk from taking vitamin E translated to 11 more cancers for every 1,000 men over a 7-year period, Dr. Eric A. Klein said at the Genitourinary Cancers Symposium.

The findings serve as a cautionary tale, he said. "Nutritional supplements are biologically active and may in fact be harmful, and importantly, the effect may continue after the intervention stops," Dr. Klein commented.

More than half of U.S. men over age 60 take vitamin E, with about one-quarter taking at least 400 IU daily (Ann. Intern. Med. 2005;143:116-20), the dose used in the trial. "Consumers should be skeptical about health claims for unregulated over-the-counter products in the absence of strong evidence of benefit from clinical trials," said Dr. Klein at the meeting, which was sponsored by the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.

In other updated results, men who took selenium with vitamin E and men who took selenium alone did not have any significant increase in the risk of prostate cancer. And baseline plasma levels of various tocopherols (forms of vitamin E) modified prostate cancer risk: Within the vitamin E group, for example, higher levels of alpha-tocopherol were protective, whereas higher levels of gamma-tocopherol were deleterious.

The obvious question now is, how does vitamin E increase prostate cancer risk? said Dr. Klein, who is chairman of the Glickman Urological and Kidney Institute at the Cleveland Clinic. Theories that have been advanced include the possibility that antioxidants become carcinogenic pro-oxidants at high doses; there may be interplay between the different types of tocopherols; high doses of vitamin E may inhibit absorption of other, protective fat-soluble vitamins; and genetic susceptibility may affect the actions of antioxidants. A related, as yet unanswered question is why adding selenium to vitamin E abolishes the excess risk.

"We need to sort all of this out," Dr. Klein said, pointing to the SELECT (Selenium and Vitamin E Cancer Prevention Trial) Biorepository, which contains a wealth of information about the men studied and is being offered as a resource. "I invite anybody in the scientific community to float a hypothesis. If it passes scientific muster, we will give you access to the Biorepository to help us answer [these questions]." More than a half dozen studies have already been approved, he said.

In SELECT, 35,533 healthy North American men aged 50 years or older if black or 55 years or older if of other races/ethnicities who had an average risk of prostate cancer were randomized to four groups: vitamin E (400 IU/day, all rac-alpha-tocopherol acetate), selenium (200 mcg/day from l-selenomethionine), the combination, or a placebo.

"It was recommended, but not required in this trial, unlike in the PCPT [Prostate Cancer Prevention Trial], that men be screened yearly with PSA and digital rectal exam," Dr. Klein noted. "One of the strengths of the trial is that the screening interval and the trigger for biopsy were not prescribed by the trial; they were left to local community standards at these 400-plus sites."

At the time that the trial was halted early, men in the vitamin E group had a marginally increased risk of prostate cancer compared with men in the placebo group (hazard ratio, 1.13; P = .06) (JAMA 2009;301:39-51). But with the additional follow-up, despite cessation of supplement use, the trend continued and became significant (hazard ratio, 1.17; P = .008) (JAMA 2011;306:1549-56).

"There was no difference in tumor aggressiveness across the four arms as assessed by tumor stage and grade," Dr. Klein reported. "And the increased risk of being diagnosed with prostate cancer in the vitamin E arm was not accounted for by more intense screening or an increasing rate of biopsy."

In the vitamin E group, the risk of prostate cancer generally decreased with each additional quintile of alpha-tocopherol at baseline. In contrast, within the selenium and combination groups, the risk increased with quintile, and within the placebo group, risk was unaffected.

The results were "somewhat opposite" for plasma gamma-tocopherol levels at baseline. In the vitamin E group, the risk generally increased with quintile. In contrast, within all the other groups, the risk decreased with quintile.

The findings have noteworthy implications for the design of clinical trials, said Dr. Klein.

"There were interactions between selenium and vitamin E with respect to risk, and a factorial design would not have captured that. So it’s important that these be powered to allow for these interactions to be tested for," he explained. "And maybe most importantly, for agents whose biology we don’t really understand and don’t really understand what the time line of the effect is, that postintervention follow-up is critical: If we had not continued to follow these men beyond the 5.5 years that they took the supplements, we would not have discovered [the elevated risk with vitamin E]".

Dr. Klein disclosed that he had no relevant conflicts of interest.

SAN FRANCISCO – Healthy middle-aged and older men who take vitamin E supplements have an increased risk of prostate cancer, although the risk takes some time to emerge, suggests an update of the randomized SELECT prevention trial.

At a median follow-up of 7 years – or 1.5 years after the trial had been closed early for futility and men had been told to stop taking supplements – those who had taken vitamin E had a significant 17% greater risk of prostate cancer than those who had taken a placebo. The risk had been increased, although not significantly so, at the time of trial closure.

Photo credit: Juanmonino/iStockphoto

In absolute terms, the elevated risk from taking vitamin E translated to 11 more cancers for every 1,000 men over a 7-year period, Dr. Eric A. Klein said at the Genitourinary Cancers Symposium.

The findings serve as a cautionary tale, he said. "Nutritional supplements are biologically active and may in fact be harmful, and importantly, the effect may continue after the intervention stops," Dr. Klein commented.

More than half of U.S. men over age 60 take vitamin E, with about one-quarter taking at least 400 IU daily (Ann. Intern. Med. 2005;143:116-20), the dose used in the trial. "Consumers should be skeptical about health claims for unregulated over-the-counter products in the absence of strong evidence of benefit from clinical trials," said Dr. Klein at the meeting, which was sponsored by the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.

In other updated results, men who took selenium with vitamin E and men who took selenium alone did not have any significant increase in the risk of prostate cancer. And baseline plasma levels of various tocopherols (forms of vitamin E) modified prostate cancer risk: Within the vitamin E group, for example, higher levels of alpha-tocopherol were protective, whereas higher levels of gamma-tocopherol were deleterious.

The obvious question now is, how does vitamin E increase prostate cancer risk? said Dr. Klein, who is chairman of the Glickman Urological and Kidney Institute at the Cleveland Clinic. Theories that have been advanced include the possibility that antioxidants become carcinogenic pro-oxidants at high doses; there may be interplay between the different types of tocopherols; high doses of vitamin E may inhibit absorption of other, protective fat-soluble vitamins; and genetic susceptibility may affect the actions of antioxidants. A related, as yet unanswered question is why adding selenium to vitamin E abolishes the excess risk.

"We need to sort all of this out," Dr. Klein said, pointing to the SELECT (Selenium and Vitamin E Cancer Prevention Trial) Biorepository, which contains a wealth of information about the men studied and is being offered as a resource. "I invite anybody in the scientific community to float a hypothesis. If it passes scientific muster, we will give you access to the Biorepository to help us answer [these questions]." More than a half dozen studies have already been approved, he said.

In SELECT, 35,533 healthy North American men aged 50 years or older if black or 55 years or older if of other races/ethnicities who had an average risk of prostate cancer were randomized to four groups: vitamin E (400 IU/day, all rac-alpha-tocopherol acetate), selenium (200 mcg/day from l-selenomethionine), the combination, or a placebo.

"It was recommended, but not required in this trial, unlike in the PCPT [Prostate Cancer Prevention Trial], that men be screened yearly with PSA and digital rectal exam," Dr. Klein noted. "One of the strengths of the trial is that the screening interval and the trigger for biopsy were not prescribed by the trial; they were left to local community standards at these 400-plus sites."

At the time that the trial was halted early, men in the vitamin E group had a marginally increased risk of prostate cancer compared with men in the placebo group (hazard ratio, 1.13; P = .06) (JAMA 2009;301:39-51). But with the additional follow-up, despite cessation of supplement use, the trend continued and became significant (hazard ratio, 1.17; P = .008) (JAMA 2011;306:1549-56).

"There was no difference in tumor aggressiveness across the four arms as assessed by tumor stage and grade," Dr. Klein reported. "And the increased risk of being diagnosed with prostate cancer in the vitamin E arm was not accounted for by more intense screening or an increasing rate of biopsy."

In the vitamin E group, the risk of prostate cancer generally decreased with each additional quintile of alpha-tocopherol at baseline. In contrast, within the selenium and combination groups, the risk increased with quintile, and within the placebo group, risk was unaffected.

The results were "somewhat opposite" for plasma gamma-tocopherol levels at baseline. In the vitamin E group, the risk generally increased with quintile. In contrast, within all the other groups, the risk decreased with quintile.

The findings have noteworthy implications for the design of clinical trials, said Dr. Klein.

"There were interactions between selenium and vitamin E with respect to risk, and a factorial design would not have captured that. So it’s important that these be powered to allow for these interactions to be tested for," he explained. "And maybe most importantly, for agents whose biology we don’t really understand and don’t really understand what the time line of the effect is, that postintervention follow-up is critical: If we had not continued to follow these men beyond the 5.5 years that they took the supplements, we would not have discovered [the elevated risk with vitamin E]".

Dr. Klein disclosed that he had no relevant conflicts of interest.

SAN FRANCISCO – Healthy middle-aged and older men who take vitamin E supplements have an increased risk of prostate cancer, although the risk takes some time to emerge, suggests an update of the randomized SELECT prevention trial.

At a median follow-up of 7 years – or 1.5 years after the trial had been closed early for futility and men had been told to stop taking supplements – those who had taken vitamin E had a significant 17% greater risk of prostate cancer than those who had taken a placebo. The risk had been increased, although not significantly so, at the time of trial closure.

Photo credit: Juanmonino/iStockphoto

In absolute terms, the elevated risk from taking vitamin E translated to 11 more cancers for every 1,000 men over a 7-year period, Dr. Eric A. Klein said at the Genitourinary Cancers Symposium.

The findings serve as a cautionary tale, he said. "Nutritional supplements are biologically active and may in fact be harmful, and importantly, the effect may continue after the intervention stops," Dr. Klein commented.

More than half of U.S. men over age 60 take vitamin E, with about one-quarter taking at least 400 IU daily (Ann. Intern. Med. 2005;143:116-20), the dose used in the trial. "Consumers should be skeptical about health claims for unregulated over-the-counter products in the absence of strong evidence of benefit from clinical trials," said Dr. Klein at the meeting, which was sponsored by the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.

In other updated results, men who took selenium with vitamin E and men who took selenium alone did not have any significant increase in the risk of prostate cancer. And baseline plasma levels of various tocopherols (forms of vitamin E) modified prostate cancer risk: Within the vitamin E group, for example, higher levels of alpha-tocopherol were protective, whereas higher levels of gamma-tocopherol were deleterious.

The obvious question now is, how does vitamin E increase prostate cancer risk? said Dr. Klein, who is chairman of the Glickman Urological and Kidney Institute at the Cleveland Clinic. Theories that have been advanced include the possibility that antioxidants become carcinogenic pro-oxidants at high doses; there may be interplay between the different types of tocopherols; high doses of vitamin E may inhibit absorption of other, protective fat-soluble vitamins; and genetic susceptibility may affect the actions of antioxidants. A related, as yet unanswered question is why adding selenium to vitamin E abolishes the excess risk.

"We need to sort all of this out," Dr. Klein said, pointing to the SELECT (Selenium and Vitamin E Cancer Prevention Trial) Biorepository, which contains a wealth of information about the men studied and is being offered as a resource. "I invite anybody in the scientific community to float a hypothesis. If it passes scientific muster, we will give you access to the Biorepository to help us answer [these questions]." More than a half dozen studies have already been approved, he said.

In SELECT, 35,533 healthy North American men aged 50 years or older if black or 55 years or older if of other races/ethnicities who had an average risk of prostate cancer were randomized to four groups: vitamin E (400 IU/day, all rac-alpha-tocopherol acetate), selenium (200 mcg/day from l-selenomethionine), the combination, or a placebo.

"It was recommended, but not required in this trial, unlike in the PCPT [Prostate Cancer Prevention Trial], that men be screened yearly with PSA and digital rectal exam," Dr. Klein noted. "One of the strengths of the trial is that the screening interval and the trigger for biopsy were not prescribed by the trial; they were left to local community standards at these 400-plus sites."

At the time that the trial was halted early, men in the vitamin E group had a marginally increased risk of prostate cancer compared with men in the placebo group (hazard ratio, 1.13; P = .06) (JAMA 2009;301:39-51). But with the additional follow-up, despite cessation of supplement use, the trend continued and became significant (hazard ratio, 1.17; P = .008) (JAMA 2011;306:1549-56).

"There was no difference in tumor aggressiveness across the four arms as assessed by tumor stage and grade," Dr. Klein reported. "And the increased risk of being diagnosed with prostate cancer in the vitamin E arm was not accounted for by more intense screening or an increasing rate of biopsy."

In the vitamin E group, the risk of prostate cancer generally decreased with each additional quintile of alpha-tocopherol at baseline. In contrast, within the selenium and combination groups, the risk increased with quintile, and within the placebo group, risk was unaffected.

The results were "somewhat opposite" for plasma gamma-tocopherol levels at baseline. In the vitamin E group, the risk generally increased with quintile. In contrast, within all the other groups, the risk decreased with quintile.

The findings have noteworthy implications for the design of clinical trials, said Dr. Klein.

"There were interactions between selenium and vitamin E with respect to risk, and a factorial design would not have captured that. So it’s important that these be powered to allow for these interactions to be tested for," he explained. "And maybe most importantly, for agents whose biology we don’t really understand and don’t really understand what the time line of the effect is, that postintervention follow-up is critical: If we had not continued to follow these men beyond the 5.5 years that they took the supplements, we would not have discovered [the elevated risk with vitamin E]".

Dr. Klein disclosed that he had no relevant conflicts of interest.

SAN FRANCISCO – A small proportion of patients with a lower-risk intraductal papillary mucinous neoplasm go on to develop pancreatic ductal adenocarcinoma in an entirely separate region of the gland, an outcome that raises questions about the surveillance strategy for these patients.

Dr. Jennifer LaFemina and her colleagues at the Memorial Sloan-Kettering Cancer Center, New York, retrospectively examined data for 158 patients who were seen at the center in 1989-2010 and who had intraductal papillary mucinous neoplasms (IPMNs) with favorable enough initial features that they were followed with radiographic surveillance for at least 6 months after diagnosis, instead of being taken right to surgery.

Five patients (3.2%) developed pancreatic cancer in a different part of the gland, she reported at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology. In all cases, the cancer was stage 2A or 2B at diagnosis and was resected with negative margins; however, with a median follow-up of just 1 year, three of the five patients have died.

Dr. LaFemina noted that several published studies have shown that IPMN represents a field defect of ductal instability, and although many have focused on the risk of developing malignancy in the IPMN cyst itself, "the risk of developing a cancer in a region of the pancreas separate from the target cyst that we are monitoring is poorly defined."

In her study, 97 of the 158 patients eventually underwent resection at a median of 16 months after IPMN diagnosis because of a worrisome change either in the IPMN target cyst or elsewhere in the pancreas (J. Clin. Oncol. 2012;30 [suppl 4]:abstract 152). "Five patients ultimately came to surgery not because of the target cyst but because of a ductal adenocarcinoma without IPMN that developed while we were watching them," Dr. LaFemina explained. (In all, 13 of the patients having resection were found to have cancer at the IPMN target cyst.)

In four of these five cases of a separate cancer, the IPMN that had been under surveillance was of the branched-duct subtype and was smaller, measuring no more than 1.6 cm. And in three cases, the time from diagnosis of the IPMN to diagnosis of the separate cancer was fairly short, just 16 months or less.

"Diagnostic, operative, and surveillance strategies should consider the cancer risk not only to the [IPMN] target cyst that we are presented with, but also to the entire gland," Dr. LaFemina recommended. Although the center has not changed its surveillance strategy for these patients, she said that this new information raises some concerns.

The findings also bring up the question of whether to recommend total pancreatectomy for patients who undergo resection, to be on the safe side. "At this point, we are not endorsing total pancreatectomy for a number of reasons," she said – notably because of the difficulty of predicting preoperatively what is actually going on in the gland.

A key question is to determine what is different about patients who develop an adenocarcinoma separate from the IPMN. "Can we identify them and watch them [more closely]? We don’t have that answer yet," Dr. LaFemina noted.

The study "has really thrown us a curve ball in terms of how we deal with these patients," commented session cochair Dr. Mitchell Posner, a surgical oncologist at the University of Chicago Medical Center.

"It’s scary, because the criteria we are using to decide not to operate on patients – which I think are appropriate – unfortunately aren’t definitively ruling out patients who will develop a pancreatic cancer in a relatively short period of time," he said in an interview. Furthermore, he noted, it’s tricky to decide whether to operate (because of the morbidity and mortality risks associated with a pancreatic resection) or to risk letting a patient develop a pancreatic cancer, knowing that an intervention potentially could have changed the outcome.

"So it is very frightening that we unfortunately don’t have the tools to identify patients accurately at this point. And we are detecting these lesions [IPMNs] at a very high frequency, so it’s a problem," Dr. Posner said. The lesions’ molecular signatures likely hold the key to identifying the bad actors, which may help target pancreatectomy to the patients who need it, he proposed.

Dr. LaFemina and Dr. Posner disclosed that they had no relevant conflicts of interest.

SAN FRANCISCO – A small proportion of patients with a lower-risk intraductal papillary mucinous neoplasm go on to develop pancreatic ductal adenocarcinoma in an entirely separate region of the gland, an outcome that raises questions about the surveillance strategy for these patients.

Dr. Jennifer LaFemina and her colleagues at the Memorial Sloan-Kettering Cancer Center, New York, retrospectively examined data for 158 patients who were seen at the center in 1989-2010 and who had intraductal papillary mucinous neoplasms (IPMNs) with favorable enough initial features that they were followed with radiographic surveillance for at least 6 months after diagnosis, instead of being taken right to surgery.

Five patients (3.2%) developed pancreatic cancer in a different part of the gland, she reported at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology. In all cases, the cancer was stage 2A or 2B at diagnosis and was resected with negative margins; however, with a median follow-up of just 1 year, three of the five patients have died.

Dr. LaFemina noted that several published studies have shown that IPMN represents a field defect of ductal instability, and although many have focused on the risk of developing malignancy in the IPMN cyst itself, "the risk of developing a cancer in a region of the pancreas separate from the target cyst that we are monitoring is poorly defined."

In her study, 97 of the 158 patients eventually underwent resection at a median of 16 months after IPMN diagnosis because of a worrisome change either in the IPMN target cyst or elsewhere in the pancreas (J. Clin. Oncol. 2012;30 [suppl 4]:abstract 152). "Five patients ultimately came to surgery not because of the target cyst but because of a ductal adenocarcinoma without IPMN that developed while we were watching them," Dr. LaFemina explained. (In all, 13 of the patients having resection were found to have cancer at the IPMN target cyst.)

In four of these five cases of a separate cancer, the IPMN that had been under surveillance was of the branched-duct subtype and was smaller, measuring no more than 1.6 cm. And in three cases, the time from diagnosis of the IPMN to diagnosis of the separate cancer was fairly short, just 16 months or less.

"Diagnostic, operative, and surveillance strategies should consider the cancer risk not only to the [IPMN] target cyst that we are presented with, but also to the entire gland," Dr. LaFemina recommended. Although the center has not changed its surveillance strategy for these patients, she said that this new information raises some concerns.

The findings also bring up the question of whether to recommend total pancreatectomy for patients who undergo resection, to be on the safe side. "At this point, we are not endorsing total pancreatectomy for a number of reasons," she said – notably because of the difficulty of predicting preoperatively what is actually going on in the gland.

A key question is to determine what is different about patients who develop an adenocarcinoma separate from the IPMN. "Can we identify them and watch them [more closely]? We don’t have that answer yet," Dr. LaFemina noted.

The study "has really thrown us a curve ball in terms of how we deal with these patients," commented session cochair Dr. Mitchell Posner, a surgical oncologist at the University of Chicago Medical Center.

"It’s scary, because the criteria we are using to decide not to operate on patients – which I think are appropriate – unfortunately aren’t definitively ruling out patients who will develop a pancreatic cancer in a relatively short period of time," he said in an interview. Furthermore, he noted, it’s tricky to decide whether to operate (because of the morbidity and mortality risks associated with a pancreatic resection) or to risk letting a patient develop a pancreatic cancer, knowing that an intervention potentially could have changed the outcome.

"So it is very frightening that we unfortunately don’t have the tools to identify patients accurately at this point. And we are detecting these lesions [IPMNs] at a very high frequency, so it’s a problem," Dr. Posner said. The lesions’ molecular signatures likely hold the key to identifying the bad actors, which may help target pancreatectomy to the patients who need it, he proposed.

Dr. LaFemina and Dr. Posner disclosed that they had no relevant conflicts of interest.

SAN FRANCISCO – A small proportion of patients with a lower-risk intraductal papillary mucinous neoplasm go on to develop pancreatic ductal adenocarcinoma in an entirely separate region of the gland, an outcome that raises questions about the surveillance strategy for these patients.

Dr. Jennifer LaFemina and her colleagues at the Memorial Sloan-Kettering Cancer Center, New York, retrospectively examined data for 158 patients who were seen at the center in 1989-2010 and who had intraductal papillary mucinous neoplasms (IPMNs) with favorable enough initial features that they were followed with radiographic surveillance for at least 6 months after diagnosis, instead of being taken right to surgery.

Five patients (3.2%) developed pancreatic cancer in a different part of the gland, she reported at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology. In all cases, the cancer was stage 2A or 2B at diagnosis and was resected with negative margins; however, with a median follow-up of just 1 year, three of the five patients have died.

Dr. LaFemina noted that several published studies have shown that IPMN represents a field defect of ductal instability, and although many have focused on the risk of developing malignancy in the IPMN cyst itself, "the risk of developing a cancer in a region of the pancreas separate from the target cyst that we are monitoring is poorly defined."

In her study, 97 of the 158 patients eventually underwent resection at a median of 16 months after IPMN diagnosis because of a worrisome change either in the IPMN target cyst or elsewhere in the pancreas (J. Clin. Oncol. 2012;30 [suppl 4]:abstract 152). "Five patients ultimately came to surgery not because of the target cyst but because of a ductal adenocarcinoma without IPMN that developed while we were watching them," Dr. LaFemina explained. (In all, 13 of the patients having resection were found to have cancer at the IPMN target cyst.)

In four of these five cases of a separate cancer, the IPMN that had been under surveillance was of the branched-duct subtype and was smaller, measuring no more than 1.6 cm. And in three cases, the time from diagnosis of the IPMN to diagnosis of the separate cancer was fairly short, just 16 months or less.

"Diagnostic, operative, and surveillance strategies should consider the cancer risk not only to the [IPMN] target cyst that we are presented with, but also to the entire gland," Dr. LaFemina recommended. Although the center has not changed its surveillance strategy for these patients, she said that this new information raises some concerns.

The findings also bring up the question of whether to recommend total pancreatectomy for patients who undergo resection, to be on the safe side. "At this point, we are not endorsing total pancreatectomy for a number of reasons," she said – notably because of the difficulty of predicting preoperatively what is actually going on in the gland.

A key question is to determine what is different about patients who develop an adenocarcinoma separate from the IPMN. "Can we identify them and watch them [more closely]? We don’t have that answer yet," Dr. LaFemina noted.

The study "has really thrown us a curve ball in terms of how we deal with these patients," commented session cochair Dr. Mitchell Posner, a surgical oncologist at the University of Chicago Medical Center.

"It’s scary, because the criteria we are using to decide not to operate on patients – which I think are appropriate – unfortunately aren’t definitively ruling out patients who will develop a pancreatic cancer in a relatively short period of time," he said in an interview. Furthermore, he noted, it’s tricky to decide whether to operate (because of the morbidity and mortality risks associated with a pancreatic resection) or to risk letting a patient develop a pancreatic cancer, knowing that an intervention potentially could have changed the outcome.

"So it is very frightening that we unfortunately don’t have the tools to identify patients accurately at this point. And we are detecting these lesions [IPMNs] at a very high frequency, so it’s a problem," Dr. Posner said. The lesions’ molecular signatures likely hold the key to identifying the bad actors, which may help target pancreatectomy to the patients who need it, he proposed.

Dr. LaFemina and Dr. Posner disclosed that they had no relevant conflicts of interest.

SAN FRANCISCO – Two new U.S. studies involving more than 150,000 older men with prostate cancer are likely to add to the intense debate about the optimal treatment for early disease, especially the various radiation therapy options.

One study suggests that the newer intensity-modulated radiation therapy (IMRT) is more effective and less toxic than the older conformal radiation therapy. But it found that proton therapy, which is even newer, not only wasn’t more effective than IMRT but also had higher bowel toxicity.

The second study suggests that external beam radiation therapy (EBRT) is more toxic than both prostatectomy and brachytherapy. Also, EBRT was at least twice as expensive.

Both studies used linked SEER (Surveillance, Epidemiology, and End Results) and Medicare data.

"We all love new technology, regardless of how much it costs," said Dr. Paul L. Nguyen in a discussion of both presentations at the Genitourinary Cancers Symposium. But third-party payers are increasingly seeking comparative effectiveness data to show that the benefits of newer therapies justify their higher expense.

"Whether you agree with the findings or not, these two provocative studies provide data that are going to shape the public’s thinking about the relative value of our treatments," added Dr. Nguyen of the Dana-Farber Cancer Institute in Boston.

"More work is needed from us as a field to generate the data [to prove] that our treatments are cost effective. And if we do not generate [these data], then third parties are going to increasingly dictate the treatments that we can and cannot offer."

IMRT Tops External RT Options

In the first study, Dr. Nathan C. Sheets and colleagues at the University of North Carolina at Chapel Hill analyzed data for 12,976 men who had localized prostate cancer and were diagnosed in 2002-2006. "We observed a rapid and nearly complete adoption of IMRT as the radiation treatment of choice for localized prostate cancer between 2002 and 2008," he noted.

Results using propensity adjustment (to try to compensate for factors that might have influenced treatment choice) showed that with a median follow-up of 4.5 years, IMRT was superior to conformal radiation therapy in terms of a lower rate of additional cancer treatment, which is a proxy for effectiveness (2.5 vs. 3.1 events per 100 person-years; P less than .001), and which he proposed might be related to the ability to increase the radiation dose given with IMRT.

Billing claims data indicated that IMRT also had lower rates of bowel toxicity (13.4 vs. 14.7 events; P less than .001) and hip fracture (0.8 vs. 1.0 events; P = .006), but a higher rate of erectile dysfunction (5.9 vs. 5.3 events; P = .006).

Proton Therapy Adds Cost, Toxicity

In an additional analysis of 1,638 men that compared proton therapy vs. IMRT – the largest series of proton therapy to date – the former was no more effective, as assessed from receipt of additional cancer treatments. Furthermore, it had a higher rate of bowel toxicity (17.8 vs. 12.2 events per 100 person-years; P less than .001), Dr. Sheets reported.

"This study supports the use of IMRT as the current standard radiation technique for prostate cancer. ... There is currently no clear evidence that proton therapy is better than IMRT," he concluded, adding that because of limitations of the data, the result for proton therapy is "hypothesis generating, but it is not in any way definitive."

The favorable findings for IMRT vs. conformal radiation therapy add to results of other studies to "support the use of IMRT despite its higher cost," according to Dr. Nguyen, the discussant. However, "this study raises doubts that protons are better than IMRT for prostate cancer."

"If you are a proponent of proton therapy, you should consider participating in the randomized trial of protons vs. IMRT that’s going to hopefully be opening later this year, ... or otherwise, commit to enrolling patients on the national prospective registry so that we can try to collect prospectively some of the data and make some of the adjustments, so we can see a little bit better what’s causing these differences," he recommended.

"In 2012, absent any data which has ever shown any clinical benefit for proton beam therapy over photon therapy, while the randomized trials are going on, how can we continue to pay what we pay for proton therapy?" Dr. Matthew R. Cooperberg of the University of California, San Francisco, asked during the comments period.

"Protons have a lot of promise, and there is a model now, maybe, of paying for this kind of therapy while we investigate it. So we want to pay for protons, but we want to learn something from every patient that is going to get proton therapy," Dr. Nguyen replied. "So I think that if we have that model where we try to enroll patients on trials, it’s worth it."

Dr. William U. Shipley, chair of the genitourinary oncology unit at the Massachusetts General Hospital in Boston, one of two institutions spearheading the randomized trial of protons vs. IMRT, noted the apparent reluctance of proton centers to participate.

"We are opening that trial, and we will be joined, surprisingly, by as many as 5 of the 25 centers in the United States. For some reason, the other 20 feel that they don’t want to test the protons," he commented. "But we are, and I assure you that it will give you whatever information we have."

Surgery and Brachytherapy Top EBRT

In the second study, Dr. Jay P. Ciezki of the Cleveland Clinic and colleagues, analyzed data for 137,427 men with prostate cancer of various stages diagnosed in 1991-2007 who received single-modality therapy.

The lengthy study period is important because patients are unlikely to die of prostate cancer, whereas morbidity may become problematic with time, he said. "It’s really of great interest to all of us who treat prostate cancer what happens after that 5-year mark."

With a median duration of follow-up of 5.9 years, the overall rate of toxicity requiring intervention, as determined from billing codes, was higher for men treated with EBRT (8.8%) than for their counterparts treated with prostatectomy (6.9%) or brachytherapy (3.7%). The most common gastrointestinal toxicity by far was rectal bleeding that required cauterization, whereas the most common genitourinary toxicity was urinary stricture requiring dilation.

The cumulative incidence of gastrointestinal and genitourinary toxicity with EBRT continued to rise over the 17-year period, whereas it generally plateaued for the other two modalities after the first 5 years. When the external beam group was stratified by radiation technique, the late rise in genitourinary toxicity seemed to be largely driven by IMRT.

EBRT was also the most expensive of the three modalities, Dr. Ciezki reported. When both the initial treatment and the treatment of any toxicity were considered, the mean total cost per patient per year was $6,412 – twice that for open prostatectomy, at $3,206, and more than twice that for brachytherapy, at $2,557 (P less than .0001).

Based on these data, "the long-term toxicity and cost per patient-year of the major prostate cancer treatment modalities [differ], with the external beam being the most toxic and the most costly," he commented.

Dr. Nguyen noted that it is unclear from the study whether EBRT should be abandoned for patients with low-risk disease, given factors such as potential confounding and the big improvement in the targeting of EBRT during the study period, so that the results might not reflect what is done today.

"Further prospective or randomized trials are needed to try to separate the effects of the treatment from the effects of patient selection," he concluded. "But if this study is confirmed in other large studies, this could provide a societal and clinical rationale to favor brachytherapy over external beam in men who qualify for both."

The symposium was sponsored by the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.

Dr. Sheets and Dr. Ciezki disclosed that they had no relevant conflicts of interest. Dr. Nguyen disclosed that he receives research funding from Varian.

SAN FRANCISCO – Two new U.S. studies involving more than 150,000 older men with prostate cancer are likely to add to the intense debate about the optimal treatment for early disease, especially the various radiation therapy options.

One study suggests that the newer intensity-modulated radiation therapy (IMRT) is more effective and less toxic than the older conformal radiation therapy. But it found that proton therapy, which is even newer, not only wasn’t more effective than IMRT but also had higher bowel toxicity.

The second study suggests that external beam radiation therapy (EBRT) is more toxic than both prostatectomy and brachytherapy. Also, EBRT was at least twice as expensive.

Both studies used linked SEER (Surveillance, Epidemiology, and End Results) and Medicare data.

"We all love new technology, regardless of how much it costs," said Dr. Paul L. Nguyen in a discussion of both presentations at the Genitourinary Cancers Symposium. But third-party payers are increasingly seeking comparative effectiveness data to show that the benefits of newer therapies justify their higher expense.

"Whether you agree with the findings or not, these two provocative studies provide data that are going to shape the public’s thinking about the relative value of our treatments," added Dr. Nguyen of the Dana-Farber Cancer Institute in Boston.

"More work is needed from us as a field to generate the data [to prove] that our treatments are cost effective. And if we do not generate [these data], then third parties are going to increasingly dictate the treatments that we can and cannot offer."

IMRT Tops External RT Options

In the first study, Dr. Nathan C. Sheets and colleagues at the University of North Carolina at Chapel Hill analyzed data for 12,976 men who had localized prostate cancer and were diagnosed in 2002-2006. "We observed a rapid and nearly complete adoption of IMRT as the radiation treatment of choice for localized prostate cancer between 2002 and 2008," he noted.

Results using propensity adjustment (to try to compensate for factors that might have influenced treatment choice) showed that with a median follow-up of 4.5 years, IMRT was superior to conformal radiation therapy in terms of a lower rate of additional cancer treatment, which is a proxy for effectiveness (2.5 vs. 3.1 events per 100 person-years; P less than .001), and which he proposed might be related to the ability to increase the radiation dose given with IMRT.

Billing claims data indicated that IMRT also had lower rates of bowel toxicity (13.4 vs. 14.7 events; P less than .001) and hip fracture (0.8 vs. 1.0 events; P = .006), but a higher rate of erectile dysfunction (5.9 vs. 5.3 events; P = .006).

Proton Therapy Adds Cost, Toxicity

In an additional analysis of 1,638 men that compared proton therapy vs. IMRT – the largest series of proton therapy to date – the former was no more effective, as assessed from receipt of additional cancer treatments. Furthermore, it had a higher rate of bowel toxicity (17.8 vs. 12.2 events per 100 person-years; P less than .001), Dr. Sheets reported.

"This study supports the use of IMRT as the current standard radiation technique for prostate cancer. ... There is currently no clear evidence that proton therapy is better than IMRT," he concluded, adding that because of limitations of the data, the result for proton therapy is "hypothesis generating, but it is not in any way definitive."

The favorable findings for IMRT vs. conformal radiation therapy add to results of other studies to "support the use of IMRT despite its higher cost," according to Dr. Nguyen, the discussant. However, "this study raises doubts that protons are better than IMRT for prostate cancer."

"If you are a proponent of proton therapy, you should consider participating in the randomized trial of protons vs. IMRT that’s going to hopefully be opening later this year, ... or otherwise, commit to enrolling patients on the national prospective registry so that we can try to collect prospectively some of the data and make some of the adjustments, so we can see a little bit better what’s causing these differences," he recommended.

"In 2012, absent any data which has ever shown any clinical benefit for proton beam therapy over photon therapy, while the randomized trials are going on, how can we continue to pay what we pay for proton therapy?" Dr. Matthew R. Cooperberg of the University of California, San Francisco, asked during the comments period.

"Protons have a lot of promise, and there is a model now, maybe, of paying for this kind of therapy while we investigate it. So we want to pay for protons, but we want to learn something from every patient that is going to get proton therapy," Dr. Nguyen replied. "So I think that if we have that model where we try to enroll patients on trials, it’s worth it."

Dr. William U. Shipley, chair of the genitourinary oncology unit at the Massachusetts General Hospital in Boston, one of two institutions spearheading the randomized trial of protons vs. IMRT, noted the apparent reluctance of proton centers to participate.

"We are opening that trial, and we will be joined, surprisingly, by as many as 5 of the 25 centers in the United States. For some reason, the other 20 feel that they don’t want to test the protons," he commented. "But we are, and I assure you that it will give you whatever information we have."

Surgery and Brachytherapy Top EBRT

In the second study, Dr. Jay P. Ciezki of the Cleveland Clinic and colleagues, analyzed data for 137,427 men with prostate cancer of various stages diagnosed in 1991-2007 who received single-modality therapy.

The lengthy study period is important because patients are unlikely to die of prostate cancer, whereas morbidity may become problematic with time, he said. "It’s really of great interest to all of us who treat prostate cancer what happens after that 5-year mark."

With a median duration of follow-up of 5.9 years, the overall rate of toxicity requiring intervention, as determined from billing codes, was higher for men treated with EBRT (8.8%) than for their counterparts treated with prostatectomy (6.9%) or brachytherapy (3.7%). The most common gastrointestinal toxicity by far was rectal bleeding that required cauterization, whereas the most common genitourinary toxicity was urinary stricture requiring dilation.

The cumulative incidence of gastrointestinal and genitourinary toxicity with EBRT continued to rise over the 17-year period, whereas it generally plateaued for the other two modalities after the first 5 years. When the external beam group was stratified by radiation technique, the late rise in genitourinary toxicity seemed to be largely driven by IMRT.

EBRT was also the most expensive of the three modalities, Dr. Ciezki reported. When both the initial treatment and the treatment of any toxicity were considered, the mean total cost per patient per year was $6,412 – twice that for open prostatectomy, at $3,206, and more than twice that for brachytherapy, at $2,557 (P less than .0001).

Based on these data, "the long-term toxicity and cost per patient-year of the major prostate cancer treatment modalities [differ], with the external beam being the most toxic and the most costly," he commented.

Dr. Nguyen noted that it is unclear from the study whether EBRT should be abandoned for patients with low-risk disease, given factors such as potential confounding and the big improvement in the targeting of EBRT during the study period, so that the results might not reflect what is done today.

"Further prospective or randomized trials are needed to try to separate the effects of the treatment from the effects of patient selection," he concluded. "But if this study is confirmed in other large studies, this could provide a societal and clinical rationale to favor brachytherapy over external beam in men who qualify for both."

The symposium was sponsored by the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.

Dr. Sheets and Dr. Ciezki disclosed that they had no relevant conflicts of interest. Dr. Nguyen disclosed that he receives research funding from Varian.

SAN FRANCISCO – Two new U.S. studies involving more than 150,000 older men with prostate cancer are likely to add to the intense debate about the optimal treatment for early disease, especially the various radiation therapy options.

One study suggests that the newer intensity-modulated radiation therapy (IMRT) is more effective and less toxic than the older conformal radiation therapy. But it found that proton therapy, which is even newer, not only wasn’t more effective than IMRT but also had higher bowel toxicity.

The second study suggests that external beam radiation therapy (EBRT) is more toxic than both prostatectomy and brachytherapy. Also, EBRT was at least twice as expensive.

Both studies used linked SEER (Surveillance, Epidemiology, and End Results) and Medicare data.

"We all love new technology, regardless of how much it costs," said Dr. Paul L. Nguyen in a discussion of both presentations at the Genitourinary Cancers Symposium. But third-party payers are increasingly seeking comparative effectiveness data to show that the benefits of newer therapies justify their higher expense.

"Whether you agree with the findings or not, these two provocative studies provide data that are going to shape the public’s thinking about the relative value of our treatments," added Dr. Nguyen of the Dana-Farber Cancer Institute in Boston.

"More work is needed from us as a field to generate the data [to prove] that our treatments are cost effective. And if we do not generate [these data], then third parties are going to increasingly dictate the treatments that we can and cannot offer."

IMRT Tops External RT Options

In the first study, Dr. Nathan C. Sheets and colleagues at the University of North Carolina at Chapel Hill analyzed data for 12,976 men who had localized prostate cancer and were diagnosed in 2002-2006. "We observed a rapid and nearly complete adoption of IMRT as the radiation treatment of choice for localized prostate cancer between 2002 and 2008," he noted.

Results using propensity adjustment (to try to compensate for factors that might have influenced treatment choice) showed that with a median follow-up of 4.5 years, IMRT was superior to conformal radiation therapy in terms of a lower rate of additional cancer treatment, which is a proxy for effectiveness (2.5 vs. 3.1 events per 100 person-years; P less than .001), and which he proposed might be related to the ability to increase the radiation dose given with IMRT.

Billing claims data indicated that IMRT also had lower rates of bowel toxicity (13.4 vs. 14.7 events; P less than .001) and hip fracture (0.8 vs. 1.0 events; P = .006), but a higher rate of erectile dysfunction (5.9 vs. 5.3 events; P = .006).

Proton Therapy Adds Cost, Toxicity

In an additional analysis of 1,638 men that compared proton therapy vs. IMRT – the largest series of proton therapy to date – the former was no more effective, as assessed from receipt of additional cancer treatments. Furthermore, it had a higher rate of bowel toxicity (17.8 vs. 12.2 events per 100 person-years; P less than .001), Dr. Sheets reported.

"This study supports the use of IMRT as the current standard radiation technique for prostate cancer. ... There is currently no clear evidence that proton therapy is better than IMRT," he concluded, adding that because of limitations of the data, the result for proton therapy is "hypothesis generating, but it is not in any way definitive."

The favorable findings for IMRT vs. conformal radiation therapy add to results of other studies to "support the use of IMRT despite its higher cost," according to Dr. Nguyen, the discussant. However, "this study raises doubts that protons are better than IMRT for prostate cancer."

"If you are a proponent of proton therapy, you should consider participating in the randomized trial of protons vs. IMRT that’s going to hopefully be opening later this year, ... or otherwise, commit to enrolling patients on the national prospective registry so that we can try to collect prospectively some of the data and make some of the adjustments, so we can see a little bit better what’s causing these differences," he recommended.

"In 2012, absent any data which has ever shown any clinical benefit for proton beam therapy over photon therapy, while the randomized trials are going on, how can we continue to pay what we pay for proton therapy?" Dr. Matthew R. Cooperberg of the University of California, San Francisco, asked during the comments period.

"Protons have a lot of promise, and there is a model now, maybe, of paying for this kind of therapy while we investigate it. So we want to pay for protons, but we want to learn something from every patient that is going to get proton therapy," Dr. Nguyen replied. "So I think that if we have that model where we try to enroll patients on trials, it’s worth it."

Dr. William U. Shipley, chair of the genitourinary oncology unit at the Massachusetts General Hospital in Boston, one of two institutions spearheading the randomized trial of protons vs. IMRT, noted the apparent reluctance of proton centers to participate.

"We are opening that trial, and we will be joined, surprisingly, by as many as 5 of the 25 centers in the United States. For some reason, the other 20 feel that they don’t want to test the protons," he commented. "But we are, and I assure you that it will give you whatever information we have."

Surgery and Brachytherapy Top EBRT

In the second study, Dr. Jay P. Ciezki of the Cleveland Clinic and colleagues, analyzed data for 137,427 men with prostate cancer of various stages diagnosed in 1991-2007 who received single-modality therapy.

The lengthy study period is important because patients are unlikely to die of prostate cancer, whereas morbidity may become problematic with time, he said. "It’s really of great interest to all of us who treat prostate cancer what happens after that 5-year mark."

With a median duration of follow-up of 5.9 years, the overall rate of toxicity requiring intervention, as determined from billing codes, was higher for men treated with EBRT (8.8%) than for their counterparts treated with prostatectomy (6.9%) or brachytherapy (3.7%). The most common gastrointestinal toxicity by far was rectal bleeding that required cauterization, whereas the most common genitourinary toxicity was urinary stricture requiring dilation.

The cumulative incidence of gastrointestinal and genitourinary toxicity with EBRT continued to rise over the 17-year period, whereas it generally plateaued for the other two modalities after the first 5 years. When the external beam group was stratified by radiation technique, the late rise in genitourinary toxicity seemed to be largely driven by IMRT.

EBRT was also the most expensive of the three modalities, Dr. Ciezki reported. When both the initial treatment and the treatment of any toxicity were considered, the mean total cost per patient per year was $6,412 – twice that for open prostatectomy, at $3,206, and more than twice that for brachytherapy, at $2,557 (P less than .0001).

Based on these data, "the long-term toxicity and cost per patient-year of the major prostate cancer treatment modalities [differ], with the external beam being the most toxic and the most costly," he commented.

Dr. Nguyen noted that it is unclear from the study whether EBRT should be abandoned for patients with low-risk disease, given factors such as potential confounding and the big improvement in the targeting of EBRT during the study period, so that the results might not reflect what is done today.

"Further prospective or randomized trials are needed to try to separate the effects of the treatment from the effects of patient selection," he concluded. "But if this study is confirmed in other large studies, this could provide a societal and clinical rationale to favor brachytherapy over external beam in men who qualify for both."

The symposium was sponsored by the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.

Dr. Sheets and Dr. Ciezki disclosed that they had no relevant conflicts of interest. Dr. Nguyen disclosed that he receives research funding from Varian.

SAN FRANCISCO – Everolimus is efficacious and safe for shrinking renal angiomyolipomas and reducing the formation of new ones in patients having the genetic disorder tuberous sclerosis complex or sporadic lymphangiomyomatosis, new data suggest.

More than 40% of the 118 patients enrolled in a randomized, phase III trial met criteria for tumor response when given everolimus, an oral inhibitor of the mammalian target of rapamycin (mTOR), researchers reported at the Genitourinary Cancers Symposium. In sharp contrast, none of those given a matching placebo did.

Everolimus could potentially provide the first effective pharmacologic option for treating angiomyolipomas, the surgical management of which is often frustrating, according to lead investigator Dr. John J. Bissler, a nephrologist at the Cincinnati Children’s Hospital Medical Center.

"These lesions can be multiple and bilateral, so surgical approaches can be problematic for this genetic disease. The lesions continue to pop up. You can remove a lesion ... and then you come back and have a lesion growing there that you thought you just took out. Maybe you did take the whole lesion out, but now you have incited another to begin to grow," he explained in an interview.

"So at the end of the day, having a drug therapy is just incredibly exciting," he commented.

The trial is also important in that it adds more evidence of benefit of this class of agents in tumors having dysregulated mTOR signaling, such as subependymal giant cell astrocytomas (SEGAs), for which everolimus is already an approved treatment, Dr. Bissler said at the meeting, which was sponsored by the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.

The drug was well tolerated, too, with adverse effects that were largely expected based on prior experience. "The only thing that we saw that was a little bit different and [that] we haven’t seen in other populations as much was ... a very small increase in amenorrhea," he said. "But we know that mTOR inhibition has effects on different sex hormones, so it’s not unexpected that you would see that, and we just need to keep track of that."

Angiomyolipomas are the most common renal manifestation of tuberous sclerosis complex. They are also seen in patients having lymphangiomyomatosis, a pulmonary condition occurring both in association with tuberous sclerosis complex and sporadically.

Of relevance to targeted therapy, mutations in the tuberous sclerosis complex genes TSC1 and TSC2 in these diseases lead to constitutive up-regulation of mTOR complex 1, resulting in excessive cell growth and proliferation.

The current trial, called EXIST-2, enrolled patients at least 18 years of age who had angiomyolipomas, and randomized them 2:1 to receive oral everolimus (Afinitor) at 10 mg once daily or placebo until tumor progression or unacceptable toxicity. Those in the latter group were allowed to cross over to everolimus if their disease progressed.

The investigators used central radiology review of serial kidney CT and MRI images to assess angiomyolipoma response, which required at least a one-half reduction in the sum of the volumes of all angiomyolipomas, no new tumors measuring 1 cm or larger, no increase in kidney volume of more than 20%, and no serious angiomyolipoma-related bleeding.

Patients were enrolled at 24 centers in 11 countries. Participants were about 32 years old on average, and two-thirds were female. Nearly all had tuberous sclerosis complex. A sizable proportion (39%) had previously had surgery or an invasive procedure, such as renal embolization, for their angiomyolipomas.

Trial results, reported in a poster session at the meeting, showed that with a median follow-up of 9.5 months, the angiomyolipoma response rate was 41.8% with everolimus and 0% with placebo (P less than .0001). Benefit was similar across patient subgroups stratified by sex, age, race, and use of enzyme-inducing antiepileptic drugs.

Additionally, patients in the everolimus group had a longer median time to angiomyolipoma progression (not reached vs. 11.4 months; hazard ratio, 0.08; P less than .0001) and were more likely to have a response of skin lesions as well (26% vs. 0%; P = .0002).

Everolimus was associated with higher (although still low) rates of grade 3 or 4 stomatitis/oral mucositis and cytopenia. Amenorrhea occurred in 14% of women in the everolimus group vs. 4% of their counterparts in the placebo group.

There was a single death in the study population, occurring in the everolimus arm and resulting from status epilepticus that was thought to be unrelated to the drug.

Dr. Bissler disclosed that he is a consultant to Gambro and receives honoraria and research funding from Novartis. The trial was sponsored by Novartis.

SAN FRANCISCO – Everolimus is efficacious and safe for shrinking renal angiomyolipomas and reducing the formation of new ones in patients having the genetic disorder tuberous sclerosis complex or sporadic lymphangiomyomatosis, new data suggest.

More than 40% of the 118 patients enrolled in a randomized, phase III trial met criteria for tumor response when given everolimus, an oral inhibitor of the mammalian target of rapamycin (mTOR), researchers reported at the Genitourinary Cancers Symposium. In sharp contrast, none of those given a matching placebo did.

Everolimus could potentially provide the first effective pharmacologic option for treating angiomyolipomas, the surgical management of which is often frustrating, according to lead investigator Dr. John J. Bissler, a nephrologist at the Cincinnati Children’s Hospital Medical Center.

"These lesions can be multiple and bilateral, so surgical approaches can be problematic for this genetic disease. The lesions continue to pop up. You can remove a lesion ... and then you come back and have a lesion growing there that you thought you just took out. Maybe you did take the whole lesion out, but now you have incited another to begin to grow," he explained in an interview.

"So at the end of the day, having a drug therapy is just incredibly exciting," he commented.

The trial is also important in that it adds more evidence of benefit of this class of agents in tumors having dysregulated mTOR signaling, such as subependymal giant cell astrocytomas (SEGAs), for which everolimus is already an approved treatment, Dr. Bissler said at the meeting, which was sponsored by the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.

The drug was well tolerated, too, with adverse effects that were largely expected based on prior experience. "The only thing that we saw that was a little bit different and [that] we haven’t seen in other populations as much was ... a very small increase in amenorrhea," he said. "But we know that mTOR inhibition has effects on different sex hormones, so it’s not unexpected that you would see that, and we just need to keep track of that."

Angiomyolipomas are the most common renal manifestation of tuberous sclerosis complex. They are also seen in patients having lymphangiomyomatosis, a pulmonary condition occurring both in association with tuberous sclerosis complex and sporadically.

Of relevance to targeted therapy, mutations in the tuberous sclerosis complex genes TSC1 and TSC2 in these diseases lead to constitutive up-regulation of mTOR complex 1, resulting in excessive cell growth and proliferation.

The current trial, called EXIST-2, enrolled patients at least 18 years of age who had angiomyolipomas, and randomized them 2:1 to receive oral everolimus (Afinitor) at 10 mg once daily or placebo until tumor progression or unacceptable toxicity. Those in the latter group were allowed to cross over to everolimus if their disease progressed.

The investigators used central radiology review of serial kidney CT and MRI images to assess angiomyolipoma response, which required at least a one-half reduction in the sum of the volumes of all angiomyolipomas, no new tumors measuring 1 cm or larger, no increase in kidney volume of more than 20%, and no serious angiomyolipoma-related bleeding.

Patients were enrolled at 24 centers in 11 countries. Participants were about 32 years old on average, and two-thirds were female. Nearly all had tuberous sclerosis complex. A sizable proportion (39%) had previously had surgery or an invasive procedure, such as renal embolization, for their angiomyolipomas.

Trial results, reported in a poster session at the meeting, showed that with a median follow-up of 9.5 months, the angiomyolipoma response rate was 41.8% with everolimus and 0% with placebo (P less than .0001). Benefit was similar across patient subgroups stratified by sex, age, race, and use of enzyme-inducing antiepileptic drugs.

Additionally, patients in the everolimus group had a longer median time to angiomyolipoma progression (not reached vs. 11.4 months; hazard ratio, 0.08; P less than .0001) and were more likely to have a response of skin lesions as well (26% vs. 0%; P = .0002).

Everolimus was associated with higher (although still low) rates of grade 3 or 4 stomatitis/oral mucositis and cytopenia. Amenorrhea occurred in 14% of women in the everolimus group vs. 4% of their counterparts in the placebo group.

There was a single death in the study population, occurring in the everolimus arm and resulting from status epilepticus that was thought to be unrelated to the drug.

Dr. Bissler disclosed that he is a consultant to Gambro and receives honoraria and research funding from Novartis. The trial was sponsored by Novartis.

SAN FRANCISCO – Everolimus is efficacious and safe for shrinking renal angiomyolipomas and reducing the formation of new ones in patients having the genetic disorder tuberous sclerosis complex or sporadic lymphangiomyomatosis, new data suggest.

More than 40% of the 118 patients enrolled in a randomized, phase III trial met criteria for tumor response when given everolimus, an oral inhibitor of the mammalian target of rapamycin (mTOR), researchers reported at the Genitourinary Cancers Symposium. In sharp contrast, none of those given a matching placebo did.

Everolimus could potentially provide the first effective pharmacologic option for treating angiomyolipomas, the surgical management of which is often frustrating, according to lead investigator Dr. John J. Bissler, a nephrologist at the Cincinnati Children’s Hospital Medical Center.

"These lesions can be multiple and bilateral, so surgical approaches can be problematic for this genetic disease. The lesions continue to pop up. You can remove a lesion ... and then you come back and have a lesion growing there that you thought you just took out. Maybe you did take the whole lesion out, but now you have incited another to begin to grow," he explained in an interview.

"So at the end of the day, having a drug therapy is just incredibly exciting," he commented.

The trial is also important in that it adds more evidence of benefit of this class of agents in tumors having dysregulated mTOR signaling, such as subependymal giant cell astrocytomas (SEGAs), for which everolimus is already an approved treatment, Dr. Bissler said at the meeting, which was sponsored by the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.

The drug was well tolerated, too, with adverse effects that were largely expected based on prior experience. "The only thing that we saw that was a little bit different and [that] we haven’t seen in other populations as much was ... a very small increase in amenorrhea," he said. "But we know that mTOR inhibition has effects on different sex hormones, so it’s not unexpected that you would see that, and we just need to keep track of that."

Angiomyolipomas are the most common renal manifestation of tuberous sclerosis complex. They are also seen in patients having lymphangiomyomatosis, a pulmonary condition occurring both in association with tuberous sclerosis complex and sporadically.

Of relevance to targeted therapy, mutations in the tuberous sclerosis complex genes TSC1 and TSC2 in these diseases lead to constitutive up-regulation of mTOR complex 1, resulting in excessive cell growth and proliferation.

The current trial, called EXIST-2, enrolled patients at least 18 years of age who had angiomyolipomas, and randomized them 2:1 to receive oral everolimus (Afinitor) at 10 mg once daily or placebo until tumor progression or unacceptable toxicity. Those in the latter group were allowed to cross over to everolimus if their disease progressed.

The investigators used central radiology review of serial kidney CT and MRI images to assess angiomyolipoma response, which required at least a one-half reduction in the sum of the volumes of all angiomyolipomas, no new tumors measuring 1 cm or larger, no increase in kidney volume of more than 20%, and no serious angiomyolipoma-related bleeding.

Patients were enrolled at 24 centers in 11 countries. Participants were about 32 years old on average, and two-thirds were female. Nearly all had tuberous sclerosis complex. A sizable proportion (39%) had previously had surgery or an invasive procedure, such as renal embolization, for their angiomyolipomas.

Trial results, reported in a poster session at the meeting, showed that with a median follow-up of 9.5 months, the angiomyolipoma response rate was 41.8% with everolimus and 0% with placebo (P less than .0001). Benefit was similar across patient subgroups stratified by sex, age, race, and use of enzyme-inducing antiepileptic drugs.

Additionally, patients in the everolimus group had a longer median time to angiomyolipoma progression (not reached vs. 11.4 months; hazard ratio, 0.08; P less than .0001) and were more likely to have a response of skin lesions as well (26% vs. 0%; P = .0002).

Everolimus was associated with higher (although still low) rates of grade 3 or 4 stomatitis/oral mucositis and cytopenia. Amenorrhea occurred in 14% of women in the everolimus group vs. 4% of their counterparts in the placebo group.

There was a single death in the study population, occurring in the everolimus arm and resulting from status epilepticus that was thought to be unrelated to the drug.

Dr. Bissler disclosed that he is a consultant to Gambro and receives honoraria and research funding from Novartis. The trial was sponsored by Novartis.

SAN FRANCISCO – Chronic kidney disease, even on the milder end of the spectrum, is an independent risk factor for urinary cancers and may therefore be useful for targeting screening, the results of a large observational study suggest.

In the study of nearly 1.2 million adults in the Kaiser Permanente Renal Registry, none of whom were on dialysis, the risks of urinary cancers increased in stepwise fashion with decreasing estimated glomerular filtration rate (GFR), Dr. William T. Lowrance reported at the Genitourinary Cancers Symposium.

After adjustments, patients having the lowest estimated GFRs had a more than 100% increase in the risk of renal cell cancer and a 35% increase in the risk of urothelial cancer. The risks of other types of cancers – breast, lung, prostate, and colorectal – and of cancer overall increased with decreasing estimated GFR in univariate analyses but not in multivariate analyses.

"We found an independent, graded increased risk of renal and urothelial cancer as you went to a lower estimated GFR, and this was especially true when your estimated GFR was less than 45 mL/min per 1.73 m2, in this large diverse population-based cohort," said Dr. Lowrance of the Huntsman Cancer Institute at the University of Utah, Salt Lake City.

"Estimated GFRs may play a role in identifying patients at higher risk for renal and urothelial malignancies," he added. "Certainly, prospective studies are needed to further assess any net clinical benefit of targeted cancer screening in these patients with CKD. And we also need to try and elucidate the etiology of this mechanism: Is there some underlying biological process that explains this association?"

"As far as I could determine on a literature search, this is the largest number of patients in a study to date," commented Thomas E. Hutson, D.O., Pharm.D., of the Baylor Sammons Cancer Center in Dallas, who was invited to discuss the study.

"We are used to screening patients with end-stage renal disease already, using renal ultrasounds, looking for renal tumors," he noted. This new study suggests that "GFR may play a role in identifying patients at higher risk, and therefore we may want to use that as a potential screening mechanism," a practice that should be studied prospectively, he agreed.

End-stage renal disease is a known risk factor for cancer, according to Dr. Lowrance. And previous studies have implicated CKD generally in cancer risk, "but they are somewhat limited by their size and their ability to control for important factors that may confound the association between CKD and cancer," he maintained.

The investigators studied adults aged 40 years or older who were in the Kaiser Permanente Renal Registry and had at least one outpatient, non–emergency department measurement of serum creatinine level between 2000 and 2008. Those who had cancer or a history of dialysis or renal transplantation were excluded.

Estimated GFR values within 3 months of cancer diagnosis and incident cancers in the first 2 years of follow-up were excluded from analysis to minimize the possibility of cancer affecting kidney function.

Results were based on 1.2 million patients with a median age of 55 years. A total of 76,809 cancers were diagnosed during a median follow-up of 5.3 years.

Univariate analyses showed increasing rates of various types of common cancers and of cancer overall with decreasing GFR, which was estimated with the CKD-Epi equation.

Multivariate analysis – adjusted for numerous potential confounders, such as proteinuria, comorbidities (including diabetes), smoking status, prescription medications taken, and health care use – showed that patients having an estimated GFR of 59 mL/min per 1.73 m² or lower had a significantly increased risk of renal cell cancer, and patients having an estimated GFR of 44 mL/min per 1.73 m² or lower had a significantly increased risk of urothelial cancer – both compared with their counterparts having an estimated GFR of 60 to 89 mL/min per 1.73 m².

Those with the poorest renal function – an estimated GFR of less than 30 mL/min per 1.73 m² – had a significant 2.09-fold increased risk of renal cell cancer and a significant 1.35-fold increased risk of urothelial cancer.

"A big concern [in such a study] is potential detection bias, meaning subjects with worse renal function may be followed more closely than those with normal renal function, and as a result, we are likely to diagnose more cancers in those patients," Dr. Lowrance acknowledged. However, analyses took into account numbers of outpatient visits and hospitalizations (although not specifically hematuria tests or imaging tests), reducing this possible source of bias.

The Genitourinary Cancers Symposium is sponsored by the American Society of Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.

Dr. Lowrance disclosed that he had no relevant conflicts of interest. Dr. Hutson disclosed that he is a consultant to and receives honoraria from Bayer, Genentech, GlaxoSmithKline, Novartis, Onyx, Pfizer, and Wyeth, and that he receives research funding from GlaxoSmithKline, Pfizer, and Wyeth.

SAN FRANCISCO – Chronic kidney disease, even on the milder end of the spectrum, is an independent risk factor for urinary cancers and may therefore be useful for targeting screening, the results of a large observational study suggest.

In the study of nearly 1.2 million adults in the Kaiser Permanente Renal Registry, none of whom were on dialysis, the risks of urinary cancers increased in stepwise fashion with decreasing estimated glomerular filtration rate (GFR), Dr. William T. Lowrance reported at the Genitourinary Cancers Symposium.

After adjustments, patients having the lowest estimated GFRs had a more than 100% increase in the risk of renal cell cancer and a 35% increase in the risk of urothelial cancer. The risks of other types of cancers – breast, lung, prostate, and colorectal – and of cancer overall increased with decreasing estimated GFR in univariate analyses but not in multivariate analyses.

"We found an independent, graded increased risk of renal and urothelial cancer as you went to a lower estimated GFR, and this was especially true when your estimated GFR was less than 45 mL/min per 1.73 m2, in this large diverse population-based cohort," said Dr. Lowrance of the Huntsman Cancer Institute at the University of Utah, Salt Lake City.

"Estimated GFRs may play a role in identifying patients at higher risk for renal and urothelial malignancies," he added. "Certainly, prospective studies are needed to further assess any net clinical benefit of targeted cancer screening in these patients with CKD. And we also need to try and elucidate the etiology of this mechanism: Is there some underlying biological process that explains this association?"

"As far as I could determine on a literature search, this is the largest number of patients in a study to date," commented Thomas E. Hutson, D.O., Pharm.D., of the Baylor Sammons Cancer Center in Dallas, who was invited to discuss the study.

"We are used to screening patients with end-stage renal disease already, using renal ultrasounds, looking for renal tumors," he noted. This new study suggests that "GFR may play a role in identifying patients at higher risk, and therefore we may want to use that as a potential screening mechanism," a practice that should be studied prospectively, he agreed.

End-stage renal disease is a known risk factor for cancer, according to Dr. Lowrance. And previous studies have implicated CKD generally in cancer risk, "but they are somewhat limited by their size and their ability to control for important factors that may confound the association between CKD and cancer," he maintained.

The investigators studied adults aged 40 years or older who were in the Kaiser Permanente Renal Registry and had at least one outpatient, non–emergency department measurement of serum creatinine level between 2000 and 2008. Those who had cancer or a history of dialysis or renal transplantation were excluded.

Estimated GFR values within 3 months of cancer diagnosis and incident cancers in the first 2 years of follow-up were excluded from analysis to minimize the possibility of cancer affecting kidney function.

Results were based on 1.2 million patients with a median age of 55 years. A total of 76,809 cancers were diagnosed during a median follow-up of 5.3 years.

Univariate analyses showed increasing rates of various types of common cancers and of cancer overall with decreasing GFR, which was estimated with the CKD-Epi equation.

Multivariate analysis – adjusted for numerous potential confounders, such as proteinuria, comorbidities (including diabetes), smoking status, prescription medications taken, and health care use – showed that patients having an estimated GFR of 59 mL/min per 1.73 m² or lower had a significantly increased risk of renal cell cancer, and patients having an estimated GFR of 44 mL/min per 1.73 m² or lower had a significantly increased risk of urothelial cancer – both compared with their counterparts having an estimated GFR of 60 to 89 mL/min per 1.73 m².

Those with the poorest renal function – an estimated GFR of less than 30 mL/min per 1.73 m² – had a significant 2.09-fold increased risk of renal cell cancer and a significant 1.35-fold increased risk of urothelial cancer.

"A big concern [in such a study] is potential detection bias, meaning subjects with worse renal function may be followed more closely than those with normal renal function, and as a result, we are likely to diagnose more cancers in those patients," Dr. Lowrance acknowledged. However, analyses took into account numbers of outpatient visits and hospitalizations (although not specifically hematuria tests or imaging tests), reducing this possible source of bias.

The Genitourinary Cancers Symposium is sponsored by the American Society of Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.

Dr. Lowrance disclosed that he had no relevant conflicts of interest. Dr. Hutson disclosed that he is a consultant to and receives honoraria from Bayer, Genentech, GlaxoSmithKline, Novartis, Onyx, Pfizer, and Wyeth, and that he receives research funding from GlaxoSmithKline, Pfizer, and Wyeth.

SAN FRANCISCO – Chronic kidney disease, even on the milder end of the spectrum, is an independent risk factor for urinary cancers and may therefore be useful for targeting screening, the results of a large observational study suggest.

In the study of nearly 1.2 million adults in the Kaiser Permanente Renal Registry, none of whom were on dialysis, the risks of urinary cancers increased in stepwise fashion with decreasing estimated glomerular filtration rate (GFR), Dr. William T. Lowrance reported at the Genitourinary Cancers Symposium.

After adjustments, patients having the lowest estimated GFRs had a more than 100% increase in the risk of renal cell cancer and a 35% increase in the risk of urothelial cancer. The risks of other types of cancers – breast, lung, prostate, and colorectal – and of cancer overall increased with decreasing estimated GFR in univariate analyses but not in multivariate analyses.

"We found an independent, graded increased risk of renal and urothelial cancer as you went to a lower estimated GFR, and this was especially true when your estimated GFR was less than 45 mL/min per 1.73 m2, in this large diverse population-based cohort," said Dr. Lowrance of the Huntsman Cancer Institute at the University of Utah, Salt Lake City.

"Estimated GFRs may play a role in identifying patients at higher risk for renal and urothelial malignancies," he added. "Certainly, prospective studies are needed to further assess any net clinical benefit of targeted cancer screening in these patients with CKD. And we also need to try and elucidate the etiology of this mechanism: Is there some underlying biological process that explains this association?"

"As far as I could determine on a literature search, this is the largest number of patients in a study to date," commented Thomas E. Hutson, D.O., Pharm.D., of the Baylor Sammons Cancer Center in Dallas, who was invited to discuss the study.

"We are used to screening patients with end-stage renal disease already, using renal ultrasounds, looking for renal tumors," he noted. This new study suggests that "GFR may play a role in identifying patients at higher risk, and therefore we may want to use that as a potential screening mechanism," a practice that should be studied prospectively, he agreed.

End-stage renal disease is a known risk factor for cancer, according to Dr. Lowrance. And previous studies have implicated CKD generally in cancer risk, "but they are somewhat limited by their size and their ability to control for important factors that may confound the association between CKD and cancer," he maintained.

The investigators studied adults aged 40 years or older who were in the Kaiser Permanente Renal Registry and had at least one outpatient, non–emergency department measurement of serum creatinine level between 2000 and 2008. Those who had cancer or a history of dialysis or renal transplantation were excluded.

Estimated GFR values within 3 months of cancer diagnosis and incident cancers in the first 2 years of follow-up were excluded from analysis to minimize the possibility of cancer affecting kidney function.

Results were based on 1.2 million patients with a median age of 55 years. A total of 76,809 cancers were diagnosed during a median follow-up of 5.3 years.

Univariate analyses showed increasing rates of various types of common cancers and of cancer overall with decreasing GFR, which was estimated with the CKD-Epi equation.

Multivariate analysis – adjusted for numerous potential confounders, such as proteinuria, comorbidities (including diabetes), smoking status, prescription medications taken, and health care use – showed that patients having an estimated GFR of 59 mL/min per 1.73 m² or lower had a significantly increased risk of renal cell cancer, and patients having an estimated GFR of 44 mL/min per 1.73 m² or lower had a significantly increased risk of urothelial cancer – both compared with their counterparts having an estimated GFR of 60 to 89 mL/min per 1.73 m².

Those with the poorest renal function – an estimated GFR of less than 30 mL/min per 1.73 m² – had a significant 2.09-fold increased risk of renal cell cancer and a significant 1.35-fold increased risk of urothelial cancer.

"A big concern [in such a study] is potential detection bias, meaning subjects with worse renal function may be followed more closely than those with normal renal function, and as a result, we are likely to diagnose more cancers in those patients," Dr. Lowrance acknowledged. However, analyses took into account numbers of outpatient visits and hospitalizations (although not specifically hematuria tests or imaging tests), reducing this possible source of bias.

The Genitourinary Cancers Symposium is sponsored by the American Society of Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.

Dr. Lowrance disclosed that he had no relevant conflicts of interest. Dr. Hutson disclosed that he is a consultant to and receives honoraria from Bayer, Genentech, GlaxoSmithKline, Novartis, Onyx, Pfizer, and Wyeth, and that he receives research funding from GlaxoSmithKline, Pfizer, and Wyeth.