Susan London

SEATTLE – Statin use was associated with protection against the development of Parkinson’s disease in a population-based historical cohort study of 94,308 middle-aged and older adults in Israel.

Statin users, who accounted for one-third of the cohort, had a 27% lower risk of Parkinson’s disease (PD), compared with nonusers, after accounting for potential confounders.

"Statins, in addition to lowering cholesterol levels and reducing cardiovascular risk, may have a protective effect on the incidence" of PD, lead investigator Dr. Amnon Lahad said at the annual meeting of the North American Primary Care Research Group.

PD, which is a central nervous system degenerative disease, "may react like other cardiovascular diseases in responding to statins," he said, speculating that ischemia plays a role in its pathogenesis, much as it does for dementia. "It is probably at the level of the microvasculature. We don’t really know how to test [for it], but it’s there."

About half a dozen studies have assessed the association between statins and PD in recent years, but their conclusions have been inconsistent. Most have found that statin use confers increased risk, with a subset suggesting that this association is mediated through cholesterol levels, making statins simply a confounder, according to Dr. Lahad, chairman of the department of family medicine at the Hebrew University of Jerusalem.

In the study, he and his colleagues searched the database of the largest health maintenance organization in Israel to identify all patients older than 45 years in a single administrative region during 2001-2007.

They excluded patients who had PD or took statins before the study period, used neuroleptic drugs at any time, changed health insurance, or did not have a record of LDL cholesterol values.

Statin use and chronic illnesses were also ascertained from the database. Family history on PD was not available, and body mass index was not used because it was inconsistently recorded, according to Dr. Lahad.

Analyses were based on 94,308 patients, he reported. The cohort was nearly equally divided by sex. About a fifth of patients had low socioeconomic status, as indicated in the database by the waiving of their copayment for prescriptions.

Substantial proportions of the cohort smoked (20%) and had diabetes (22%), hypertension (51%), or ischemic heart disease (19%), or had previously experienced a stroke (8%).

Some 32% of the patients were classified as statin users because they filled at least six monthly statin prescriptions during a 9-month period. The rest were classified as nonusers.

Overall, 1.1% of the cohort developed PD during the study period, as ascertained from their filling of at least two monthly prescriptions for an antiparkinsonian medication.

In a Cox regression analysis, the risk of PD was elevated for men compared with women (hazard ratio, 1.57; P less than .0001), for patients with low socioeconomic status compared with their better-off peers (HR, 1.33; P less than .0001), and for patients who had experienced a stroke compared with those who had not (HR, 1.96; P less than .0001).

"Surprisingly, the other diseases or conditions [hypertension, ischemic heart disease, diabetes, and smoking] were not related, even in a pretty big group," to PD, Dr. Lahad said. "The most surprising is smoking, which in the literature is connected."

LDL cholesterol level at baseline was not significantly associated with the risk of PD. However, there was a trend for an increased risk of PD with an LDL level greater than 100 mg/dL, as well as a lower risk of the disease in individuals with LDL levels greater than about 160 mg/dL.

When statin use was added to the analysis, statin users had about a one-fourth reduction in the risk of PD relative to nonusers (HR, 0.73; P = .001), and the other significant associations persisted.

However, when the investigators accounted for statin use, the individuals with the highest LDL cholesterol levels no longer had a reduced risk of the disease. "It probably was the effect that this group got statins much more often, so it did protect them," Dr. Lahad speculated. "And it showed, without the statin, purely the effect of the cholesterol."

The risk of PD fell with an increasing duration of statin use (as assessed from the number of prescriptions and months of use). But in this case, the association was weaker. "It was a trend; it wasn’t by itself significant," he noted.

"Of course, it’s not a randomized controlled trial," Dr. Lahad acknowledged, so it is possible that other factors explain the observed association. "But at least we don’t find the alarming finding of previous studies that show that statins are connected to an increase in morbidity."

Dr. Lahad reported that he had no relevant conflicts of interest.

SEATTLE – Statin use was associated with protection against the development of Parkinson’s disease in a population-based historical cohort study of 94,308 middle-aged and older adults in Israel.

Statin users, who accounted for one-third of the cohort, had a 27% lower risk of Parkinson’s disease (PD), compared with nonusers, after accounting for potential confounders.

"Statins, in addition to lowering cholesterol levels and reducing cardiovascular risk, may have a protective effect on the incidence" of PD, lead investigator Dr. Amnon Lahad said at the annual meeting of the North American Primary Care Research Group.

PD, which is a central nervous system degenerative disease, "may react like other cardiovascular diseases in responding to statins," he said, speculating that ischemia plays a role in its pathogenesis, much as it does for dementia. "It is probably at the level of the microvasculature. We don’t really know how to test [for it], but it’s there."

About half a dozen studies have assessed the association between statins and PD in recent years, but their conclusions have been inconsistent. Most have found that statin use confers increased risk, with a subset suggesting that this association is mediated through cholesterol levels, making statins simply a confounder, according to Dr. Lahad, chairman of the department of family medicine at the Hebrew University of Jerusalem.

In the study, he and his colleagues searched the database of the largest health maintenance organization in Israel to identify all patients older than 45 years in a single administrative region during 2001-2007.

They excluded patients who had PD or took statins before the study period, used neuroleptic drugs at any time, changed health insurance, or did not have a record of LDL cholesterol values.

Statin use and chronic illnesses were also ascertained from the database. Family history on PD was not available, and body mass index was not used because it was inconsistently recorded, according to Dr. Lahad.

Analyses were based on 94,308 patients, he reported. The cohort was nearly equally divided by sex. About a fifth of patients had low socioeconomic status, as indicated in the database by the waiving of their copayment for prescriptions.

Substantial proportions of the cohort smoked (20%) and had diabetes (22%), hypertension (51%), or ischemic heart disease (19%), or had previously experienced a stroke (8%).

Some 32% of the patients were classified as statin users because they filled at least six monthly statin prescriptions during a 9-month period. The rest were classified as nonusers.

Overall, 1.1% of the cohort developed PD during the study period, as ascertained from their filling of at least two monthly prescriptions for an antiparkinsonian medication.

In a Cox regression analysis, the risk of PD was elevated for men compared with women (hazard ratio, 1.57; P less than .0001), for patients with low socioeconomic status compared with their better-off peers (HR, 1.33; P less than .0001), and for patients who had experienced a stroke compared with those who had not (HR, 1.96; P less than .0001).

"Surprisingly, the other diseases or conditions [hypertension, ischemic heart disease, diabetes, and smoking] were not related, even in a pretty big group," to PD, Dr. Lahad said. "The most surprising is smoking, which in the literature is connected."

LDL cholesterol level at baseline was not significantly associated with the risk of PD. However, there was a trend for an increased risk of PD with an LDL level greater than 100 mg/dL, as well as a lower risk of the disease in individuals with LDL levels greater than about 160 mg/dL.

When statin use was added to the analysis, statin users had about a one-fourth reduction in the risk of PD relative to nonusers (HR, 0.73; P = .001), and the other significant associations persisted.

However, when the investigators accounted for statin use, the individuals with the highest LDL cholesterol levels no longer had a reduced risk of the disease. "It probably was the effect that this group got statins much more often, so it did protect them," Dr. Lahad speculated. "And it showed, without the statin, purely the effect of the cholesterol."

The risk of PD fell with an increasing duration of statin use (as assessed from the number of prescriptions and months of use). But in this case, the association was weaker. "It was a trend; it wasn’t by itself significant," he noted.

"Of course, it’s not a randomized controlled trial," Dr. Lahad acknowledged, so it is possible that other factors explain the observed association. "But at least we don’t find the alarming finding of previous studies that show that statins are connected to an increase in morbidity."

Dr. Lahad reported that he had no relevant conflicts of interest.

SEATTLE – Statin use was associated with protection against the development of Parkinson’s disease in a population-based historical cohort study of 94,308 middle-aged and older adults in Israel.

Statin users, who accounted for one-third of the cohort, had a 27% lower risk of Parkinson’s disease (PD), compared with nonusers, after accounting for potential confounders.

"Statins, in addition to lowering cholesterol levels and reducing cardiovascular risk, may have a protective effect on the incidence" of PD, lead investigator Dr. Amnon Lahad said at the annual meeting of the North American Primary Care Research Group.

PD, which is a central nervous system degenerative disease, "may react like other cardiovascular diseases in responding to statins," he said, speculating that ischemia plays a role in its pathogenesis, much as it does for dementia. "It is probably at the level of the microvasculature. We don’t really know how to test [for it], but it’s there."

About half a dozen studies have assessed the association between statins and PD in recent years, but their conclusions have been inconsistent. Most have found that statin use confers increased risk, with a subset suggesting that this association is mediated through cholesterol levels, making statins simply a confounder, according to Dr. Lahad, chairman of the department of family medicine at the Hebrew University of Jerusalem.

In the study, he and his colleagues searched the database of the largest health maintenance organization in Israel to identify all patients older than 45 years in a single administrative region during 2001-2007.

They excluded patients who had PD or took statins before the study period, used neuroleptic drugs at any time, changed health insurance, or did not have a record of LDL cholesterol values.

Statin use and chronic illnesses were also ascertained from the database. Family history on PD was not available, and body mass index was not used because it was inconsistently recorded, according to Dr. Lahad.

Analyses were based on 94,308 patients, he reported. The cohort was nearly equally divided by sex. About a fifth of patients had low socioeconomic status, as indicated in the database by the waiving of their copayment for prescriptions.

Substantial proportions of the cohort smoked (20%) and had diabetes (22%), hypertension (51%), or ischemic heart disease (19%), or had previously experienced a stroke (8%).

Some 32% of the patients were classified as statin users because they filled at least six monthly statin prescriptions during a 9-month period. The rest were classified as nonusers.

Overall, 1.1% of the cohort developed PD during the study period, as ascertained from their filling of at least two monthly prescriptions for an antiparkinsonian medication.

In a Cox regression analysis, the risk of PD was elevated for men compared with women (hazard ratio, 1.57; P less than .0001), for patients with low socioeconomic status compared with their better-off peers (HR, 1.33; P less than .0001), and for patients who had experienced a stroke compared with those who had not (HR, 1.96; P less than .0001).

"Surprisingly, the other diseases or conditions [hypertension, ischemic heart disease, diabetes, and smoking] were not related, even in a pretty big group," to PD, Dr. Lahad said. "The most surprising is smoking, which in the literature is connected."

LDL cholesterol level at baseline was not significantly associated with the risk of PD. However, there was a trend for an increased risk of PD with an LDL level greater than 100 mg/dL, as well as a lower risk of the disease in individuals with LDL levels greater than about 160 mg/dL.

When statin use was added to the analysis, statin users had about a one-fourth reduction in the risk of PD relative to nonusers (HR, 0.73; P = .001), and the other significant associations persisted.

However, when the investigators accounted for statin use, the individuals with the highest LDL cholesterol levels no longer had a reduced risk of the disease. "It probably was the effect that this group got statins much more often, so it did protect them," Dr. Lahad speculated. "And it showed, without the statin, purely the effect of the cholesterol."

The risk of PD fell with an increasing duration of statin use (as assessed from the number of prescriptions and months of use). But in this case, the association was weaker. "It was a trend; it wasn’t by itself significant," he noted.

"Of course, it’s not a randomized controlled trial," Dr. Lahad acknowledged, so it is possible that other factors explain the observed association. "But at least we don’t find the alarming finding of previous studies that show that statins are connected to an increase in morbidity."

Dr. Lahad reported that he had no relevant conflicts of interest.

SAN FRANCISCO – The FOLFOX4 regimen improved survival of patients with advanced hepatocellular carcinoma in a phase III trial conducted among nearly 400 patients in Asia and Southeast Asia.

Updated results showed that patients treated with FOLFOX4 had a 21% reduction in the risk of death, compared with their counterparts who were treated with doxorubicin. "The FOLFOX4 regimen [has] emerged as the first chemotherapy regimen to demonstrate prolonged survival in this population," commented lead investigator Dr. Sumitra Thongprasert, who reported the findings at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.

The 6.4-month median survival with FOLFOX4 was similar to the 6.5-month median survival seen with single-agent sorafenib (Nexavar) – the reference standard for HCC treatment – in a previous trial in a similar population (Lancet. Oncol. 2009;10:25-34), noted Dr. Thongprasert, an oncologist at the Chiang Mai (Thailand) University.

And the combination of sorafenib (a kinase inhibitor) with doxorubicin chemotherapy has shown greater benefit than doxorubicin alone (JAMA 2010;304:2154-60). Therefore, "our group concludes that further investigation of the combination of the FOLFOX4 regimen and sorafenib is warranted," she said.

Patients from mainland China, Taiwan, Korea, and Thailand were eligible for the trial if they had advanced and/or unresectable HCC and were cancer-treatment naive (except for surgery) or had experienced progression after previous adjuvant therapy completed at least a year earlier.

The patients were assigned in a 1:1 ratio to open-label treatment with the FOLFOX4 regimen (oxaliplatin plus 5-fluorouracil and leucovorin) given every 2 weeks, or with single-agent doxorubicin (50 mg/m2 IV) given every 3 weeks. Crossover was not permitted.

Doxorubicin was selected as the comparator agent "because this is a drug considered efficacious and [it] was a commonly used regimen in the region during the time of the study, which was 2006-2007, before the approval of sorafenib," Dr. Thongprasert explained.

The 371 patients were 49 years old on average, and 89% were men. Most (91%) had hepatitis B virus infection, and slightly more than half (54%) had cirrhosis. The majority had metastases (58%), Child-Pugh class A disease (88%), and a Barcelona Clinic Liver Cancer stage of C (80%).

The study’s prespecified final analysis, conducted after 266 deaths in the intent-to-treat population, showed a trend toward better median overall survival (the primary end point) among patients treated with FOLFOX4, compared with doxorubicin (6.40 vs. 4.97 months; hazard ratio, 0.79; P = .07). The benefit was significant in a post hoc analysis conducted after additional follow-up and 305 deaths (HR, 0.79; P = .04).

The FOLFOX4 group also fared better than the doxorubicin group in terms of median progression-free survival (2.93 vs. 1.77 months; P = .0002), response rate (8% vs. 3%; P = .02), and disease control rate (52% vs. 32%; P less than .0001).

The findings were similar in analyses that were restricted to the 279 Chinese patients, said Dr. Thongprasert. Overall and progression-free survival benefits were also seen in subgroups stratified by disease and patient characteristics as well as previous receipt of chemotherapy, except that there was little to no benefit of FOLFOX4 among patients with poorly differentiated (grade 3 or 4) tumors.

Patients in the FOLFOX4 group were more likely to experience grade 3 or higher adverse events (56% vs. 45%; P = .05). But rates of treatment discontinuation, serious adverse events, and death did not differ significantly.

Tolerability of FOLFOX4 was generally similar in patients with Child-Pugh class A and class B disease, according to Dr. Thongprasert. "However, the number of patients with Child[-Pugh class] B is quite small," she cautioned.

The trial, known as the EACH study, was supported by Sanofi-Aventis, manufacturer of oxaliplatin (Eloxatin), which is a component of the FOLFOX4 regimen. Dr. Thongprasert reported being a consultant to and receiving research funding from Sanofi-Aventis.

SAN FRANCISCO – The FOLFOX4 regimen improved survival of patients with advanced hepatocellular carcinoma in a phase III trial conducted among nearly 400 patients in Asia and Southeast Asia.

Updated results showed that patients treated with FOLFOX4 had a 21% reduction in the risk of death, compared with their counterparts who were treated with doxorubicin. "The FOLFOX4 regimen [has] emerged as the first chemotherapy regimen to demonstrate prolonged survival in this population," commented lead investigator Dr. Sumitra Thongprasert, who reported the findings at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.

The 6.4-month median survival with FOLFOX4 was similar to the 6.5-month median survival seen with single-agent sorafenib (Nexavar) – the reference standard for HCC treatment – in a previous trial in a similar population (Lancet. Oncol. 2009;10:25-34), noted Dr. Thongprasert, an oncologist at the Chiang Mai (Thailand) University.

And the combination of sorafenib (a kinase inhibitor) with doxorubicin chemotherapy has shown greater benefit than doxorubicin alone (JAMA 2010;304:2154-60). Therefore, "our group concludes that further investigation of the combination of the FOLFOX4 regimen and sorafenib is warranted," she said.

Patients from mainland China, Taiwan, Korea, and Thailand were eligible for the trial if they had advanced and/or unresectable HCC and were cancer-treatment naive (except for surgery) or had experienced progression after previous adjuvant therapy completed at least a year earlier.

The patients were assigned in a 1:1 ratio to open-label treatment with the FOLFOX4 regimen (oxaliplatin plus 5-fluorouracil and leucovorin) given every 2 weeks, or with single-agent doxorubicin (50 mg/m2 IV) given every 3 weeks. Crossover was not permitted.

Doxorubicin was selected as the comparator agent "because this is a drug considered efficacious and [it] was a commonly used regimen in the region during the time of the study, which was 2006-2007, before the approval of sorafenib," Dr. Thongprasert explained.

The 371 patients were 49 years old on average, and 89% were men. Most (91%) had hepatitis B virus infection, and slightly more than half (54%) had cirrhosis. The majority had metastases (58%), Child-Pugh class A disease (88%), and a Barcelona Clinic Liver Cancer stage of C (80%).

The study’s prespecified final analysis, conducted after 266 deaths in the intent-to-treat population, showed a trend toward better median overall survival (the primary end point) among patients treated with FOLFOX4, compared with doxorubicin (6.40 vs. 4.97 months; hazard ratio, 0.79; P = .07). The benefit was significant in a post hoc analysis conducted after additional follow-up and 305 deaths (HR, 0.79; P = .04).

The FOLFOX4 group also fared better than the doxorubicin group in terms of median progression-free survival (2.93 vs. 1.77 months; P = .0002), response rate (8% vs. 3%; P = .02), and disease control rate (52% vs. 32%; P less than .0001).

The findings were similar in analyses that were restricted to the 279 Chinese patients, said Dr. Thongprasert. Overall and progression-free survival benefits were also seen in subgroups stratified by disease and patient characteristics as well as previous receipt of chemotherapy, except that there was little to no benefit of FOLFOX4 among patients with poorly differentiated (grade 3 or 4) tumors.

Patients in the FOLFOX4 group were more likely to experience grade 3 or higher adverse events (56% vs. 45%; P = .05). But rates of treatment discontinuation, serious adverse events, and death did not differ significantly.

Tolerability of FOLFOX4 was generally similar in patients with Child-Pugh class A and class B disease, according to Dr. Thongprasert. "However, the number of patients with Child[-Pugh class] B is quite small," she cautioned.

The trial, known as the EACH study, was supported by Sanofi-Aventis, manufacturer of oxaliplatin (Eloxatin), which is a component of the FOLFOX4 regimen. Dr. Thongprasert reported being a consultant to and receiving research funding from Sanofi-Aventis.

SAN FRANCISCO – The FOLFOX4 regimen improved survival of patients with advanced hepatocellular carcinoma in a phase III trial conducted among nearly 400 patients in Asia and Southeast Asia.

Updated results showed that patients treated with FOLFOX4 had a 21% reduction in the risk of death, compared with their counterparts who were treated with doxorubicin. "The FOLFOX4 regimen [has] emerged as the first chemotherapy regimen to demonstrate prolonged survival in this population," commented lead investigator Dr. Sumitra Thongprasert, who reported the findings at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.

The 6.4-month median survival with FOLFOX4 was similar to the 6.5-month median survival seen with single-agent sorafenib (Nexavar) – the reference standard for HCC treatment – in a previous trial in a similar population (Lancet. Oncol. 2009;10:25-34), noted Dr. Thongprasert, an oncologist at the Chiang Mai (Thailand) University.

And the combination of sorafenib (a kinase inhibitor) with doxorubicin chemotherapy has shown greater benefit than doxorubicin alone (JAMA 2010;304:2154-60). Therefore, "our group concludes that further investigation of the combination of the FOLFOX4 regimen and sorafenib is warranted," she said.

Patients from mainland China, Taiwan, Korea, and Thailand were eligible for the trial if they had advanced and/or unresectable HCC and were cancer-treatment naive (except for surgery) or had experienced progression after previous adjuvant therapy completed at least a year earlier.

The patients were assigned in a 1:1 ratio to open-label treatment with the FOLFOX4 regimen (oxaliplatin plus 5-fluorouracil and leucovorin) given every 2 weeks, or with single-agent doxorubicin (50 mg/m2 IV) given every 3 weeks. Crossover was not permitted.

Doxorubicin was selected as the comparator agent "because this is a drug considered efficacious and [it] was a commonly used regimen in the region during the time of the study, which was 2006-2007, before the approval of sorafenib," Dr. Thongprasert explained.

The 371 patients were 49 years old on average, and 89% were men. Most (91%) had hepatitis B virus infection, and slightly more than half (54%) had cirrhosis. The majority had metastases (58%), Child-Pugh class A disease (88%), and a Barcelona Clinic Liver Cancer stage of C (80%).

The study’s prespecified final analysis, conducted after 266 deaths in the intent-to-treat population, showed a trend toward better median overall survival (the primary end point) among patients treated with FOLFOX4, compared with doxorubicin (6.40 vs. 4.97 months; hazard ratio, 0.79; P = .07). The benefit was significant in a post hoc analysis conducted after additional follow-up and 305 deaths (HR, 0.79; P = .04).

The FOLFOX4 group also fared better than the doxorubicin group in terms of median progression-free survival (2.93 vs. 1.77 months; P = .0002), response rate (8% vs. 3%; P = .02), and disease control rate (52% vs. 32%; P less than .0001).

The findings were similar in analyses that were restricted to the 279 Chinese patients, said Dr. Thongprasert. Overall and progression-free survival benefits were also seen in subgroups stratified by disease and patient characteristics as well as previous receipt of chemotherapy, except that there was little to no benefit of FOLFOX4 among patients with poorly differentiated (grade 3 or 4) tumors.

Patients in the FOLFOX4 group were more likely to experience grade 3 or higher adverse events (56% vs. 45%; P = .05). But rates of treatment discontinuation, serious adverse events, and death did not differ significantly.

Tolerability of FOLFOX4 was generally similar in patients with Child-Pugh class A and class B disease, according to Dr. Thongprasert. "However, the number of patients with Child[-Pugh class] B is quite small," she cautioned.

The trial, known as the EACH study, was supported by Sanofi-Aventis, manufacturer of oxaliplatin (Eloxatin), which is a component of the FOLFOX4 regimen. Dr. Thongprasert reported being a consultant to and receiving research funding from Sanofi-Aventis.

SAN FRANCISCO – A new diagnosis of diabetes may help identify older adults who will develop pancreatic cancer while there is still time for screening and early detection, researchers reported at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.

In an observational study of more than 20,000 older adults with pancreatic cancer, 10 antecedent diagnoses were found to be significantly associated with the cancer diagnosis.

Of these, a diagnosis of new-onset diabetes preceded the cancer diagnosis by the greatest amount of time – more than 2 years, on average – or potentially enough time to catch the cancer early with targeted screening. A diagnosis of abdominal pain was second, at 1.5 years.

Late diagnosis is a major contributor to the generally "dismal" survival of pancreatic cancer, lead investigator Dr. Elizaveta Ragulin-Coyne said in an interview.

"Colonoscopy screening works great, mammography works great. But those cancers are really a lot more common, so it makes sense to screen the whole population," she commented.

By contrast, pancreatic cancer is relatively uncommon, so population-based screening with current tests would generate many false positives. At present, only individuals from families having hereditary pancreatic cancers associated with certain mutations are screened.

The goal of the study was therefore to identify "the factors that can precede the diagnosis of pancreatic cancer, that sort of can act as red flags to identify that population at risk," she explained. "So we are trying to identify the risk-rich population of individuals who can benefit from potential future screening."

The investigators analyzed data from the Surveillance, Epidemiology, and End Results (SEER) database for the years 1991-2005 and the linked Medicare database for the years 1991-2007 to identify older adults with a diagnosis of pancreatic cancer and diagnoses preceding the cancer.

They evaluated 30 possible antecedent diagnoses for their association with the pancreatic cancer diagnosis, and narrowed it down to 10 that were significantly associated (P less than .05) in a stepwise logistic regression analysis: acute pancreatitis, chronic pancreatitis, cyst-pseudocyst, other pancreatic disease, bile duct obstruction, diabetes, weight loss, jaundice, abdominal pain, and hepatomegaly.

The 22,493 study patients were 77 years old on average; 55% were women and 86% were white, according to results reported in a poster session at the meeting.

The 10 antecedent diagnoses ranged in prevalence in this population from a low of 4% for hepatomegaly to a high of 76% for abdominal pain. A diagnosis of diabetes was seen in 45%.

In most cases, the median time between the antecedent diagnosis and the pancreatic cancer diagnosis was less than 3 months. The exceptions were abdominal pain, diagnosed a median of 18 months before the cancer, and diabetes, diagnosed a median of 28 months before the cancer.

The latter intervals are long enough to provide a window of opportunity for intervention, according to Dr. Ragulin-Coyne, a surgical resident and research fellow at the University of Massachusetts Medical Center in Worcester.

"It doesn’t make sense if you have preceding diagnoses within a month before, it doesn’t really make a difference," she explained. "But if it’s over 6 months or over a year, it is actually clinically significant because you can hypothesize that those people are potentially at an early stage and could have more interventions that give you a possibility of cure."

The average number of antecedent diagnoses decreased with increasing stage of pancreatic cancer at diagnosis, from 3.91 among patients with stage 0 disease to 2.04 among patients with stage IV disease.

This finding initially seemed counterintuitive, Dr. Ragulin-Coyne said. But perhaps patients having more advanced cancer at diagnosis have had less contact with the health care system in general, and therefore have fewer diagnoses on record.

In a logistic regression model among just the patients with an antecedent diabetes diagnosis, the odds of the gap between that diagnosis and the pancreatic cancer diagnosis being greater than 24 months were higher for nonwhite versus white patients; for patients aged 75-84 years or aged 85 years or older, compared with those aged 65-74 years; and for patients in the Midwest versus the Northeast.

The reason pancreatic cancer is diagnosed earlier in some patients and later in others is not yet clear, but it is likely multifactorial, according to Dr. Ragulin-Coyne.

"We can make guesses, whether it is socioeconomic or cultural or there is something else in play." For example, some patients may "tell the doctor about all their symptoms and get worked up early and get their doctors concerned more," she said. "But if they never come to the physician or they never mention what’s going on, they get diagnosed late."

In any case, identifying the reasons will be critical to moving all patients into the early diagnosis group. "I think that will ultimately be the best thing if, when they come, we can offer them treatments and cure and options, versus just saying, unfortunately, it’s too late," she commented.

The investigators have obtained the SEER data for all similar older adults without a pancreatic cancer diagnosis, and using a matched analysis, plan to develop and test a prediction nomogram using the information from their study. "Stay tuned for that," she advised.

"Screening for pancreatic cancer will be a great future tool," Dr. Ragulin-Coyne concluded, while also cautioning that there is still much work to be done before some type of population-based screening becomes a reality.

Dr. Ragulin-Coyne reported having no conflicts of interest related to the study.

SAN FRANCISCO – A new diagnosis of diabetes may help identify older adults who will develop pancreatic cancer while there is still time for screening and early detection, researchers reported at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.

In an observational study of more than 20,000 older adults with pancreatic cancer, 10 antecedent diagnoses were found to be significantly associated with the cancer diagnosis.

Of these, a diagnosis of new-onset diabetes preceded the cancer diagnosis by the greatest amount of time – more than 2 years, on average – or potentially enough time to catch the cancer early with targeted screening. A diagnosis of abdominal pain was second, at 1.5 years.

Late diagnosis is a major contributor to the generally "dismal" survival of pancreatic cancer, lead investigator Dr. Elizaveta Ragulin-Coyne said in an interview.

"Colonoscopy screening works great, mammography works great. But those cancers are really a lot more common, so it makes sense to screen the whole population," she commented.

By contrast, pancreatic cancer is relatively uncommon, so population-based screening with current tests would generate many false positives. At present, only individuals from families having hereditary pancreatic cancers associated with certain mutations are screened.

The goal of the study was therefore to identify "the factors that can precede the diagnosis of pancreatic cancer, that sort of can act as red flags to identify that population at risk," she explained. "So we are trying to identify the risk-rich population of individuals who can benefit from potential future screening."

The investigators analyzed data from the Surveillance, Epidemiology, and End Results (SEER) database for the years 1991-2005 and the linked Medicare database for the years 1991-2007 to identify older adults with a diagnosis of pancreatic cancer and diagnoses preceding the cancer.

They evaluated 30 possible antecedent diagnoses for their association with the pancreatic cancer diagnosis, and narrowed it down to 10 that were significantly associated (P less than .05) in a stepwise logistic regression analysis: acute pancreatitis, chronic pancreatitis, cyst-pseudocyst, other pancreatic disease, bile duct obstruction, diabetes, weight loss, jaundice, abdominal pain, and hepatomegaly.

The 22,493 study patients were 77 years old on average; 55% were women and 86% were white, according to results reported in a poster session at the meeting.

The 10 antecedent diagnoses ranged in prevalence in this population from a low of 4% for hepatomegaly to a high of 76% for abdominal pain. A diagnosis of diabetes was seen in 45%.

In most cases, the median time between the antecedent diagnosis and the pancreatic cancer diagnosis was less than 3 months. The exceptions were abdominal pain, diagnosed a median of 18 months before the cancer, and diabetes, diagnosed a median of 28 months before the cancer.

The latter intervals are long enough to provide a window of opportunity for intervention, according to Dr. Ragulin-Coyne, a surgical resident and research fellow at the University of Massachusetts Medical Center in Worcester.

"It doesn’t make sense if you have preceding diagnoses within a month before, it doesn’t really make a difference," she explained. "But if it’s over 6 months or over a year, it is actually clinically significant because you can hypothesize that those people are potentially at an early stage and could have more interventions that give you a possibility of cure."

The average number of antecedent diagnoses decreased with increasing stage of pancreatic cancer at diagnosis, from 3.91 among patients with stage 0 disease to 2.04 among patients with stage IV disease.

This finding initially seemed counterintuitive, Dr. Ragulin-Coyne said. But perhaps patients having more advanced cancer at diagnosis have had less contact with the health care system in general, and therefore have fewer diagnoses on record.

In a logistic regression model among just the patients with an antecedent diabetes diagnosis, the odds of the gap between that diagnosis and the pancreatic cancer diagnosis being greater than 24 months were higher for nonwhite versus white patients; for patients aged 75-84 years or aged 85 years or older, compared with those aged 65-74 years; and for patients in the Midwest versus the Northeast.

The reason pancreatic cancer is diagnosed earlier in some patients and later in others is not yet clear, but it is likely multifactorial, according to Dr. Ragulin-Coyne.

"We can make guesses, whether it is socioeconomic or cultural or there is something else in play." For example, some patients may "tell the doctor about all their symptoms and get worked up early and get their doctors concerned more," she said. "But if they never come to the physician or they never mention what’s going on, they get diagnosed late."

In any case, identifying the reasons will be critical to moving all patients into the early diagnosis group. "I think that will ultimately be the best thing if, when they come, we can offer them treatments and cure and options, versus just saying, unfortunately, it’s too late," she commented.

The investigators have obtained the SEER data for all similar older adults without a pancreatic cancer diagnosis, and using a matched analysis, plan to develop and test a prediction nomogram using the information from their study. "Stay tuned for that," she advised.

"Screening for pancreatic cancer will be a great future tool," Dr. Ragulin-Coyne concluded, while also cautioning that there is still much work to be done before some type of population-based screening becomes a reality.

Dr. Ragulin-Coyne reported having no conflicts of interest related to the study.

SAN FRANCISCO – A new diagnosis of diabetes may help identify older adults who will develop pancreatic cancer while there is still time for screening and early detection, researchers reported at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.

In an observational study of more than 20,000 older adults with pancreatic cancer, 10 antecedent diagnoses were found to be significantly associated with the cancer diagnosis.

Of these, a diagnosis of new-onset diabetes preceded the cancer diagnosis by the greatest amount of time – more than 2 years, on average – or potentially enough time to catch the cancer early with targeted screening. A diagnosis of abdominal pain was second, at 1.5 years.

Late diagnosis is a major contributor to the generally "dismal" survival of pancreatic cancer, lead investigator Dr. Elizaveta Ragulin-Coyne said in an interview.

"Colonoscopy screening works great, mammography works great. But those cancers are really a lot more common, so it makes sense to screen the whole population," she commented.

By contrast, pancreatic cancer is relatively uncommon, so population-based screening with current tests would generate many false positives. At present, only individuals from families having hereditary pancreatic cancers associated with certain mutations are screened.

The goal of the study was therefore to identify "the factors that can precede the diagnosis of pancreatic cancer, that sort of can act as red flags to identify that population at risk," she explained. "So we are trying to identify the risk-rich population of individuals who can benefit from potential future screening."

The investigators analyzed data from the Surveillance, Epidemiology, and End Results (SEER) database for the years 1991-2005 and the linked Medicare database for the years 1991-2007 to identify older adults with a diagnosis of pancreatic cancer and diagnoses preceding the cancer.

They evaluated 30 possible antecedent diagnoses for their association with the pancreatic cancer diagnosis, and narrowed it down to 10 that were significantly associated (P less than .05) in a stepwise logistic regression analysis: acute pancreatitis, chronic pancreatitis, cyst-pseudocyst, other pancreatic disease, bile duct obstruction, diabetes, weight loss, jaundice, abdominal pain, and hepatomegaly.

The 22,493 study patients were 77 years old on average; 55% were women and 86% were white, according to results reported in a poster session at the meeting.

The 10 antecedent diagnoses ranged in prevalence in this population from a low of 4% for hepatomegaly to a high of 76% for abdominal pain. A diagnosis of diabetes was seen in 45%.

In most cases, the median time between the antecedent diagnosis and the pancreatic cancer diagnosis was less than 3 months. The exceptions were abdominal pain, diagnosed a median of 18 months before the cancer, and diabetes, diagnosed a median of 28 months before the cancer.

The latter intervals are long enough to provide a window of opportunity for intervention, according to Dr. Ragulin-Coyne, a surgical resident and research fellow at the University of Massachusetts Medical Center in Worcester.

"It doesn’t make sense if you have preceding diagnoses within a month before, it doesn’t really make a difference," she explained. "But if it’s over 6 months or over a year, it is actually clinically significant because you can hypothesize that those people are potentially at an early stage and could have more interventions that give you a possibility of cure."

The average number of antecedent diagnoses decreased with increasing stage of pancreatic cancer at diagnosis, from 3.91 among patients with stage 0 disease to 2.04 among patients with stage IV disease.

This finding initially seemed counterintuitive, Dr. Ragulin-Coyne said. But perhaps patients having more advanced cancer at diagnosis have had less contact with the health care system in general, and therefore have fewer diagnoses on record.

In a logistic regression model among just the patients with an antecedent diabetes diagnosis, the odds of the gap between that diagnosis and the pancreatic cancer diagnosis being greater than 24 months were higher for nonwhite versus white patients; for patients aged 75-84 years or aged 85 years or older, compared with those aged 65-74 years; and for patients in the Midwest versus the Northeast.

The reason pancreatic cancer is diagnosed earlier in some patients and later in others is not yet clear, but it is likely multifactorial, according to Dr. Ragulin-Coyne.

"We can make guesses, whether it is socioeconomic or cultural or there is something else in play." For example, some patients may "tell the doctor about all their symptoms and get worked up early and get their doctors concerned more," she said. "But if they never come to the physician or they never mention what’s going on, they get diagnosed late."

In any case, identifying the reasons will be critical to moving all patients into the early diagnosis group. "I think that will ultimately be the best thing if, when they come, we can offer them treatments and cure and options, versus just saying, unfortunately, it’s too late," she commented.

The investigators have obtained the SEER data for all similar older adults without a pancreatic cancer diagnosis, and using a matched analysis, plan to develop and test a prediction nomogram using the information from their study. "Stay tuned for that," she advised.

"Screening for pancreatic cancer will be a great future tool," Dr. Ragulin-Coyne concluded, while also cautioning that there is still much work to be done before some type of population-based screening becomes a reality.

Dr. Ragulin-Coyne reported having no conflicts of interest related to the study.

SAN FRANCISCO – A new diagnosis of diabetes may help identify older adults who will develop pancreatic cancer while there is still time for screening and early detection, researchers reported at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.

In an observational study of more than 20,000 older adults with pancreatic cancer, 10 antecedent diagnoses were found to be significantly associated with the cancer diagnosis.

Of these, a diagnosis of new-onset diabetes preceded the cancer diagnosis by the greatest amount of time – more than 2 years, on average – or potentially enough time to catch the cancer early with targeted screening. A diagnosis of abdominal pain was second, at 1.5 years.

Late diagnosis is a major contributor to the generally "dismal" survival of pancreatic cancer, lead investigator Dr. Elizaveta Ragulin-Coyne said in an interview.

"Colonoscopy screening works great, mammography works great. But those cancers are really a lot more common, so it makes sense to screen the whole population," she commented.

By contrast, pancreatic cancer is relatively uncommon, so population-based screening with current tests would generate many false positives. At present, only individuals from families having hereditary pancreatic cancers associated with certain mutations are screened.

The goal of the study was therefore to identify "the factors that can precede the diagnosis of pancreatic cancer, that sort of can act as red flags to identify that population at risk," she explained. "So we are trying to identify the risk-rich population of individuals who can benefit from potential future screening."

The investigators analyzed data from the Surveillance, Epidemiology, and End Results (SEER) database for the years 1991-2005 and the linked Medicare database for the years 1991-2007 to identify older adults with a diagnosis of pancreatic cancer and diagnoses preceding the cancer.

They evaluated 30 possible antecedent diagnoses for their association with the pancreatic cancer diagnosis, and narrowed it down to 10 that were significantly associated (P less than .05) in a stepwise logistic regression analysis: acute pancreatitis, chronic pancreatitis, cyst-pseudocyst, other pancreatic disease, bile duct obstruction, diabetes, weight loss, jaundice, abdominal pain, and hepatomegaly.

The 22,493 study patients were 77 years old on average; 55% were women and 86% were white, according to results reported in a poster session at the meeting.

The 10 antecedent diagnoses ranged in prevalence in this population from a low of 4% for hepatomegaly to a high of 76% for abdominal pain. A diagnosis of diabetes was seen in 45%.

In most cases, the median time between the antecedent diagnosis and the pancreatic cancer diagnosis was less than 3 months. The exceptions were abdominal pain, diagnosed a median of 18 months before the cancer, and diabetes, diagnosed a median of 28 months before the cancer.

The latter intervals are long enough to provide a window of opportunity for intervention, according to Dr. Ragulin-Coyne, a surgical resident and research fellow at the University of Massachusetts Medical Center in Worcester.

"It doesn’t make sense if you have preceding diagnoses within a month before, it doesn’t really make a difference," she explained. "But if it’s over 6 months or over a year, it is actually clinically significant because you can hypothesize that those people are potentially at an early stage and could have more interventions that give you a possibility of cure."

The average number of antecedent diagnoses decreased with increasing stage of pancreatic cancer at diagnosis, from 3.91 among patients with stage 0 disease to 2.04 among patients with stage IV disease.

This finding initially seemed counterintuitive, Dr. Ragulin-Coyne said. But perhaps patients having more advanced cancer at diagnosis have had less contact with the health care system in general, and therefore have fewer diagnoses on record.

In a logistic regression model among just the patients with an antecedent diabetes diagnosis, the odds of the gap between that diagnosis and the pancreatic cancer diagnosis being greater than 24 months were higher for nonwhite versus white patients; for patients aged 75-84 years or aged 85 years or older, compared with those aged 65-74 years; and for patients in the Midwest versus the Northeast.

The reason pancreatic cancer is diagnosed earlier in some patients and later in others is not yet clear, but it is likely multifactorial, according to Dr. Ragulin-Coyne.

"We can make guesses, whether it is socioeconomic or cultural or there is something else in play." For example, some patients may "tell the doctor about all their symptoms and get worked up early and get their doctors concerned more," she said. "But if they never come to the physician or they never mention what’s going on, they get diagnosed late."

In any case, identifying the reasons will be critical to moving all patients into the early diagnosis group. "I think that will ultimately be the best thing if, when they come, we can offer them treatments and cure and options, versus just saying, unfortunately, it’s too late," she commented.

The investigators have obtained the SEER data for all similar older adults without a pancreatic cancer diagnosis, and using a matched analysis, plan to develop and test a prediction nomogram using the information from their study. "Stay tuned for that," she advised.

"Screening for pancreatic cancer will be a great future tool," Dr. Ragulin-Coyne concluded, while also cautioning that there is still much work to be done before some type of population-based screening becomes a reality.

Dr. Ragulin-Coyne reported having no conflicts of interest related to the study.

SAN FRANCISCO – A new diagnosis of diabetes may help identify older adults who will develop pancreatic cancer while there is still time for screening and early detection, researchers reported at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.

In an observational study of more than 20,000 older adults with pancreatic cancer, 10 antecedent diagnoses were found to be significantly associated with the cancer diagnosis.

Of these, a diagnosis of new-onset diabetes preceded the cancer diagnosis by the greatest amount of time – more than 2 years, on average – or potentially enough time to catch the cancer early with targeted screening. A diagnosis of abdominal pain was second, at 1.5 years.

Late diagnosis is a major contributor to the generally "dismal" survival of pancreatic cancer, lead investigator Dr. Elizaveta Ragulin-Coyne said in an interview.

"Colonoscopy screening works great, mammography works great. But those cancers are really a lot more common, so it makes sense to screen the whole population," she commented.

By contrast, pancreatic cancer is relatively uncommon, so population-based screening with current tests would generate many false positives. At present, only individuals from families having hereditary pancreatic cancers associated with certain mutations are screened.

The goal of the study was therefore to identify "the factors that can precede the diagnosis of pancreatic cancer, that sort of can act as red flags to identify that population at risk," she explained. "So we are trying to identify the risk-rich population of individuals who can benefit from potential future screening."

The investigators analyzed data from the Surveillance, Epidemiology, and End Results (SEER) database for the years 1991-2005 and the linked Medicare database for the years 1991-2007 to identify older adults with a diagnosis of pancreatic cancer and diagnoses preceding the cancer.

They evaluated 30 possible antecedent diagnoses for their association with the pancreatic cancer diagnosis, and narrowed it down to 10 that were significantly associated (P less than .05) in a stepwise logistic regression analysis: acute pancreatitis, chronic pancreatitis, cyst-pseudocyst, other pancreatic disease, bile duct obstruction, diabetes, weight loss, jaundice, abdominal pain, and hepatomegaly.

The 22,493 study patients were 77 years old on average; 55% were women and 86% were white, according to results reported in a poster session at the meeting.

The 10 antecedent diagnoses ranged in prevalence in this population from a low of 4% for hepatomegaly to a high of 76% for abdominal pain. A diagnosis of diabetes was seen in 45%.

In most cases, the median time between the antecedent diagnosis and the pancreatic cancer diagnosis was less than 3 months. The exceptions were abdominal pain, diagnosed a median of 18 months before the cancer, and diabetes, diagnosed a median of 28 months before the cancer.

The latter intervals are long enough to provide a window of opportunity for intervention, according to Dr. Ragulin-Coyne, a surgical resident and research fellow at the University of Massachusetts Medical Center in Worcester.

"It doesn’t make sense if you have preceding diagnoses within a month before, it doesn’t really make a difference," she explained. "But if it’s over 6 months or over a year, it is actually clinically significant because you can hypothesize that those people are potentially at an early stage and could have more interventions that give you a possibility of cure."

The average number of antecedent diagnoses decreased with increasing stage of pancreatic cancer at diagnosis, from 3.91 among patients with stage 0 disease to 2.04 among patients with stage IV disease.

This finding initially seemed counterintuitive, Dr. Ragulin-Coyne said. But perhaps patients having more advanced cancer at diagnosis have had less contact with the health care system in general, and therefore have fewer diagnoses on record.

In a logistic regression model among just the patients with an antecedent diabetes diagnosis, the odds of the gap between that diagnosis and the pancreatic cancer diagnosis being greater than 24 months were higher for nonwhite versus white patients; for patients aged 75-84 years or aged 85 years or older, compared with those aged 65-74 years; and for patients in the Midwest versus the Northeast.

The reason pancreatic cancer is diagnosed earlier in some patients and later in others is not yet clear, but it is likely multifactorial, according to Dr. Ragulin-Coyne.

"We can make guesses, whether it is socioeconomic or cultural or there is something else in play." For example, some patients may "tell the doctor about all their symptoms and get worked up early and get their doctors concerned more," she said. "But if they never come to the physician or they never mention what’s going on, they get diagnosed late."

In any case, identifying the reasons will be critical to moving all patients into the early diagnosis group. "I think that will ultimately be the best thing if, when they come, we can offer them treatments and cure and options, versus just saying, unfortunately, it’s too late," she commented.

The investigators have obtained the SEER data for all similar older adults without a pancreatic cancer diagnosis, and using a matched analysis, plan to develop and test a prediction nomogram using the information from their study. "Stay tuned for that," she advised.

"Screening for pancreatic cancer will be a great future tool," Dr. Ragulin-Coyne concluded, while also cautioning that there is still much work to be done before some type of population-based screening becomes a reality.

Dr. Ragulin-Coyne reported having no conflicts of interest related to the study.

SAN FRANCISCO – A new diagnosis of diabetes may help identify older adults who will develop pancreatic cancer while there is still time for screening and early detection, researchers reported at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.

In an observational study of more than 20,000 older adults with pancreatic cancer, 10 antecedent diagnoses were found to be significantly associated with the cancer diagnosis.

Of these, a diagnosis of new-onset diabetes preceded the cancer diagnosis by the greatest amount of time – more than 2 years, on average – or potentially enough time to catch the cancer early with targeted screening. A diagnosis of abdominal pain was second, at 1.5 years.

Late diagnosis is a major contributor to the generally "dismal" survival of pancreatic cancer, lead investigator Dr. Elizaveta Ragulin-Coyne said in an interview.

"Colonoscopy screening works great, mammography works great. But those cancers are really a lot more common, so it makes sense to screen the whole population," she commented.

By contrast, pancreatic cancer is relatively uncommon, so population-based screening with current tests would generate many false positives. At present, only individuals from families having hereditary pancreatic cancers associated with certain mutations are screened.

The goal of the study was therefore to identify "the factors that can precede the diagnosis of pancreatic cancer, that sort of can act as red flags to identify that population at risk," she explained. "So we are trying to identify the risk-rich population of individuals who can benefit from potential future screening."

The investigators analyzed data from the Surveillance, Epidemiology, and End Results (SEER) database for the years 1991-2005 and the linked Medicare database for the years 1991-2007 to identify older adults with a diagnosis of pancreatic cancer and diagnoses preceding the cancer.

They evaluated 30 possible antecedent diagnoses for their association with the pancreatic cancer diagnosis, and narrowed it down to 10 that were significantly associated (P less than .05) in a stepwise logistic regression analysis: acute pancreatitis, chronic pancreatitis, cyst-pseudocyst, other pancreatic disease, bile duct obstruction, diabetes, weight loss, jaundice, abdominal pain, and hepatomegaly.

The 22,493 study patients were 77 years old on average; 55% were women and 86% were white, according to results reported in a poster session at the meeting.

The 10 antecedent diagnoses ranged in prevalence in this population from a low of 4% for hepatomegaly to a high of 76% for abdominal pain. A diagnosis of diabetes was seen in 45%.

In most cases, the median time between the antecedent diagnosis and the pancreatic cancer diagnosis was less than 3 months. The exceptions were abdominal pain, diagnosed a median of 18 months before the cancer, and diabetes, diagnosed a median of 28 months before the cancer.

The latter intervals are long enough to provide a window of opportunity for intervention, according to Dr. Ragulin-Coyne, a surgical resident and research fellow at the University of Massachusetts Medical Center in Worcester.

"It doesn’t make sense if you have preceding diagnoses within a month before, it doesn’t really make a difference," she explained. "But if it’s over 6 months or over a year, it is actually clinically significant because you can hypothesize that those people are potentially at an early stage and could have more interventions that give you a possibility of cure."

The average number of antecedent diagnoses decreased with increasing stage of pancreatic cancer at diagnosis, from 3.91 among patients with stage 0 disease to 2.04 among patients with stage IV disease.

This finding initially seemed counterintuitive, Dr. Ragulin-Coyne said. But perhaps patients having more advanced cancer at diagnosis have had less contact with the health care system in general, and therefore have fewer diagnoses on record.

In a logistic regression model among just the patients with an antecedent diabetes diagnosis, the odds of the gap between that diagnosis and the pancreatic cancer diagnosis being greater than 24 months were higher for nonwhite versus white patients; for patients aged 75-84 years or aged 85 years or older, compared with those aged 65-74 years; and for patients in the Midwest versus the Northeast.

The reason pancreatic cancer is diagnosed earlier in some patients and later in others is not yet clear, but it is likely multifactorial, according to Dr. Ragulin-Coyne.

"We can make guesses, whether it is socioeconomic or cultural or there is something else in play." For example, some patients may "tell the doctor about all their symptoms and get worked up early and get their doctors concerned more," she said. "But if they never come to the physician or they never mention what’s going on, they get diagnosed late."

In any case, identifying the reasons will be critical to moving all patients into the early diagnosis group. "I think that will ultimately be the best thing if, when they come, we can offer them treatments and cure and options, versus just saying, unfortunately, it’s too late," she commented.

The investigators have obtained the SEER data for all similar older adults without a pancreatic cancer diagnosis, and using a matched analysis, plan to develop and test a prediction nomogram using the information from their study. "Stay tuned for that," she advised.

"Screening for pancreatic cancer will be a great future tool," Dr. Ragulin-Coyne concluded, while also cautioning that there is still much work to be done before some type of population-based screening becomes a reality.

Dr. Ragulin-Coyne reported having no conflicts of interest related to the study.

SAN FRANCISCO – Everolimus improves progression-free survival in all subgroups of patients with progressive advanced neuroendocrine tumors, and does so regardless of prior use of somatostatin analogs, according to updated results of the randomized RADIANT-2 and RADIANT-3 trials.

Both trials showed that the reduced risk of progression seen with everolimus in their study populations overall also was present to some extent in subgroups stratified by patient and disease characteristics, and by prior use of somatostatin analogs.

The updates were reported at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.

"There is a significant unmet medical need for patients with advanced NETs [neuroendocrine tumors]," asserted RADIANT-2 lead investigator Dr. James C. Yao of the department of gastrointestinal medical oncology at the University of Texas M.D. Anderson Cancer Center in Houston. In particular, "there are currently no drugs approved by the health authorities for the oncologic therapy of advanced carcinoid tumors."

RADIANT-2: Unselected NETs

The RADIANT-2 trial was conducted among 429 patients with progressive advanced NETs of diverse primary sites who had carcinoid syndrome. It compared everolimus (Afinitor) plus octreotide LAR (Sandostatin LAR, or long-acting release) with placebo plus octreotide LAR.

Everolimus, an inhibitor of the mammalian target of rapamycin (mTOR), is approved by the Food and Drug Administration for the treatment of certain subependymal giant cell astrocytomas and advanced renal cell carcinoma.

Octreotide LAR is a somatostatin analog approved for symptom control in patients with metastatic carcinoid tumors, a subset of NETs that cause secretory symptoms.

The trial found a 23% reduction in the risk of progression, as assessed by independent central review, with everolimus vs. placebo (hazard ratio [HR] 0.77, P = .026), but it fell just short of its predefined statistical boundary for significance (P = .0246), according to Dr. Yao.

Updated analyses showed that the benefit seen in the entire study population was also evident in subgroups stratified by patient and disease factors, and by prior treatment, although most of the hazard ratios overlapped unity.

About 80% of patients in both treatment groups had previously used long-acting somatostatin analogs. In exploratory analyses, everolimus was associated a reduced risk of progression in previous users (HR 0.81, P = .077) and in previous nonusers (HR 0.63, P = .054). "However, the absolute and relative benefits were perhaps greater among patients who have not had prior somatostatin [analog] exposure," he observed.

Dr. Yao also reported new analyses of the trial’s main results, showing that, when progression was assessed by local investigators instead of central reviewers, everolimus was associated with a 22% reduction in risk and the study met its statistical boundary (P = .018). The difference was due to 51 more events tallied by the local investigators vs. the central reviewers.

Additionally, the progression-free survival estimates for both treatment groups were longer with central review than with local investigator assessment. "These findings are actually hallmarks of informative censoring," he said. "The main source of informative censoring lies in the fact that patient management is based on investigator review, while the end point assessment is based on central review."

Issues arise when the local investigator calls progression before the central reviewer does. "In these cases, because of the crossover and change in therapy, the cases are censored. In fact, the central radiologist is effectively prevented from seeing the progression event," Dr. Yao explained. "This results in an inflation of PFS [progression-free survival] and reduced power in the study."

When the trial’s main analysis was repeated with correction for informative censoring, reduced power, and imbalances in randomization, the median progression-free survival was 13.8 months with everolimus and 8.3 months with placebo. That difference corresponds to a 40% reduction in risk and far exceeds the predefined boundary for significance (HR 0.60, P = .0014).

Commenting on the discrepancy between local and central review, discussant Dr. Mary F. Mulcahy said, "I think what this tells us ... is that progression-free survival may not be the right end point to be looking at when evaluating these diseases with secretory symptoms," because the symptoms may prompt investigators to switch treatment before radiographic progression occurs.

"So I think more so than these fancy calculations to try and rectify this, we need to maybe consider what our end point is for these very clinical syndromes that we see," she commented.

She called attention to the fact that the rate of discontinuation for progressive disease or adverse events was similarly high in the everolimus and placebo groups (70% and 75%), and median duration of treatment exposure was the same.

"So I have some concerns about the benefit of everolimus," said Dr. Mulcahy of the Robert H. Lurie Comprehensive Cancer Center in Chicago. "For the population studied, I think the benefit of everolimus with octreotide LAR is undefined. The activity of everolimus is demonstrated, but it’s associated with significant adverse events."

RADIANT-3: Pancreatic NET

The RADIANT-3 trial was conducted among 410 patients with progressive advanced pancreatic NET (pNET). It found a 65% reduction in the risk of progression with everolimus plus best supportive care, compared with placebo plus best supportive care (HR 0.35, P less than .0001).

Updated analyses showed that the benefit seen in the whole study population was also evident in subgroups stratified by patient and disease factors, and prior treatment, reported lead investigator Dr. Manisha H. Shah of the Ohio State University Comprehensive Cancer Center in Columbus.

"No matter how we slice the data based on different characteristics, we saw the significant benefit of everolimus compared to placebo," she commented. Some 50% of the patients had previously used somatostatin analogs, and 40% of patients used these agents concomitantly while in the trial.

In exploratory analyses, the progression-free survival benefit of everolimus was similar in subgroups of patients who had and had not previously used somatostatin analogs, and who did and did not use them concomitantly during the trial.

"Everolimus showed a consistent benefit in all subgroups regardless of presence or absence of somatostatin analog," commented Dr. Shah.

"RADIANT-3 is the largest randomized controlled trial ever completed in patients with progressive advanced pNET," she noted. "These data support the use of everolimus as the standard of care for patients with progressive advanced pNET."

In her discussion, Dr. Mulcahy noted that, in this trial, results were similar for central and local review. "That’s probably because these patients did not necessarily have the secretory symptoms of the patients in the RADIANT-2 study," she speculated.

The results are "strikingly similar" to those seen previously with the tyrosine kinase inhibitor sunitinib (Sutent) in patients with pNET. "We are seeing consistent results. How we are going to sequence these is something that needs to be further evaluated."

Her overall assessment of RADIANT-3 was more positive than that of RADIANT-2. "There is a significant and durable benefit of everolimus in previously treated [pNET] patients," she commented.

A variety of markers are being assessed in NET, including some associated with response to mTOR inhibitors, according to Dr. Mulcahy.

"This is hopefully the direction where we are going to be going, looking at these different prognostic and predictive markers, and assigning therapy and doing rationally designed clinical trials to find the best sequence of drugs," she concluded.

Novartis sponsored both trials. Dr. Yao and Dr. Shah reported being advisors to and receiving honoraria and research support from Novartis. Dr. Mulcahy did not report any relevant conflicts of interest.

SAN FRANCISCO – Everolimus improves progression-free survival in all subgroups of patients with progressive advanced neuroendocrine tumors, and does so regardless of prior use of somatostatin analogs, according to updated results of the randomized RADIANT-2 and RADIANT-3 trials.

Both trials showed that the reduced risk of progression seen with everolimus in their study populations overall also was present to some extent in subgroups stratified by patient and disease characteristics, and by prior use of somatostatin analogs.

The updates were reported at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.

"There is a significant unmet medical need for patients with advanced NETs [neuroendocrine tumors]," asserted RADIANT-2 lead investigator Dr. James C. Yao of the department of gastrointestinal medical oncology at the University of Texas M.D. Anderson Cancer Center in Houston. In particular, "there are currently no drugs approved by the health authorities for the oncologic therapy of advanced carcinoid tumors."

RADIANT-2: Unselected NETs

The RADIANT-2 trial was conducted among 429 patients with progressive advanced NETs of diverse primary sites who had carcinoid syndrome. It compared everolimus (Afinitor) plus octreotide LAR (Sandostatin LAR, or long-acting release) with placebo plus octreotide LAR.

Everolimus, an inhibitor of the mammalian target of rapamycin (mTOR), is approved by the Food and Drug Administration for the treatment of certain subependymal giant cell astrocytomas and advanced renal cell carcinoma.

Octreotide LAR is a somatostatin analog approved for symptom control in patients with metastatic carcinoid tumors, a subset of NETs that cause secretory symptoms.

The trial found a 23% reduction in the risk of progression, as assessed by independent central review, with everolimus vs. placebo (hazard ratio [HR] 0.77, P = .026), but it fell just short of its predefined statistical boundary for significance (P = .0246), according to Dr. Yao.

Updated analyses showed that the benefit seen in the entire study population was also evident in subgroups stratified by patient and disease factors, and by prior treatment, although most of the hazard ratios overlapped unity.

About 80% of patients in both treatment groups had previously used long-acting somatostatin analogs. In exploratory analyses, everolimus was associated a reduced risk of progression in previous users (HR 0.81, P = .077) and in previous nonusers (HR 0.63, P = .054). "However, the absolute and relative benefits were perhaps greater among patients who have not had prior somatostatin [analog] exposure," he observed.

Dr. Yao also reported new analyses of the trial’s main results, showing that, when progression was assessed by local investigators instead of central reviewers, everolimus was associated with a 22% reduction in risk and the study met its statistical boundary (P = .018). The difference was due to 51 more events tallied by the local investigators vs. the central reviewers.

Additionally, the progression-free survival estimates for both treatment groups were longer with central review than with local investigator assessment. "These findings are actually hallmarks of informative censoring," he said. "The main source of informative censoring lies in the fact that patient management is based on investigator review, while the end point assessment is based on central review."

Issues arise when the local investigator calls progression before the central reviewer does. "In these cases, because of the crossover and change in therapy, the cases are censored. In fact, the central radiologist is effectively prevented from seeing the progression event," Dr. Yao explained. "This results in an inflation of PFS [progression-free survival] and reduced power in the study."

When the trial’s main analysis was repeated with correction for informative censoring, reduced power, and imbalances in randomization, the median progression-free survival was 13.8 months with everolimus and 8.3 months with placebo. That difference corresponds to a 40% reduction in risk and far exceeds the predefined boundary for significance (HR 0.60, P = .0014).

Commenting on the discrepancy between local and central review, discussant Dr. Mary F. Mulcahy said, "I think what this tells us ... is that progression-free survival may not be the right end point to be looking at when evaluating these diseases with secretory symptoms," because the symptoms may prompt investigators to switch treatment before radiographic progression occurs.

"So I think more so than these fancy calculations to try and rectify this, we need to maybe consider what our end point is for these very clinical syndromes that we see," she commented.

She called attention to the fact that the rate of discontinuation for progressive disease or adverse events was similarly high in the everolimus and placebo groups (70% and 75%), and median duration of treatment exposure was the same.

"So I have some concerns about the benefit of everolimus," said Dr. Mulcahy of the Robert H. Lurie Comprehensive Cancer Center in Chicago. "For the population studied, I think the benefit of everolimus with octreotide LAR is undefined. The activity of everolimus is demonstrated, but it’s associated with significant adverse events."

RADIANT-3: Pancreatic NET

The RADIANT-3 trial was conducted among 410 patients with progressive advanced pancreatic NET (pNET). It found a 65% reduction in the risk of progression with everolimus plus best supportive care, compared with placebo plus best supportive care (HR 0.35, P less than .0001).

Updated analyses showed that the benefit seen in the whole study population was also evident in subgroups stratified by patient and disease factors, and prior treatment, reported lead investigator Dr. Manisha H. Shah of the Ohio State University Comprehensive Cancer Center in Columbus.

"No matter how we slice the data based on different characteristics, we saw the significant benefit of everolimus compared to placebo," she commented. Some 50% of the patients had previously used somatostatin analogs, and 40% of patients used these agents concomitantly while in the trial.

In exploratory analyses, the progression-free survival benefit of everolimus was similar in subgroups of patients who had and had not previously used somatostatin analogs, and who did and did not use them concomitantly during the trial.

"Everolimus showed a consistent benefit in all subgroups regardless of presence or absence of somatostatin analog," commented Dr. Shah.

"RADIANT-3 is the largest randomized controlled trial ever completed in patients with progressive advanced pNET," she noted. "These data support the use of everolimus as the standard of care for patients with progressive advanced pNET."

In her discussion, Dr. Mulcahy noted that, in this trial, results were similar for central and local review. "That’s probably because these patients did not necessarily have the secretory symptoms of the patients in the RADIANT-2 study," she speculated.

The results are "strikingly similar" to those seen previously with the tyrosine kinase inhibitor sunitinib (Sutent) in patients with pNET. "We are seeing consistent results. How we are going to sequence these is something that needs to be further evaluated."

Her overall assessment of RADIANT-3 was more positive than that of RADIANT-2. "There is a significant and durable benefit of everolimus in previously treated [pNET] patients," she commented.

A variety of markers are being assessed in NET, including some associated with response to mTOR inhibitors, according to Dr. Mulcahy.

"This is hopefully the direction where we are going to be going, looking at these different prognostic and predictive markers, and assigning therapy and doing rationally designed clinical trials to find the best sequence of drugs," she concluded.

Novartis sponsored both trials. Dr. Yao and Dr. Shah reported being advisors to and receiving honoraria and research support from Novartis. Dr. Mulcahy did not report any relevant conflicts of interest.

SAN FRANCISCO – Everolimus improves progression-free survival in all subgroups of patients with progressive advanced neuroendocrine tumors, and does so regardless of prior use of somatostatin analogs, according to updated results of the randomized RADIANT-2 and RADIANT-3 trials.

Both trials showed that the reduced risk of progression seen with everolimus in their study populations overall also was present to some extent in subgroups stratified by patient and disease characteristics, and by prior use of somatostatin analogs.

The updates were reported at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.

"There is a significant unmet medical need for patients with advanced NETs [neuroendocrine tumors]," asserted RADIANT-2 lead investigator Dr. James C. Yao of the department of gastrointestinal medical oncology at the University of Texas M.D. Anderson Cancer Center in Houston. In particular, "there are currently no drugs approved by the health authorities for the oncologic therapy of advanced carcinoid tumors."

RADIANT-2: Unselected NETs

The RADIANT-2 trial was conducted among 429 patients with progressive advanced NETs of diverse primary sites who had carcinoid syndrome. It compared everolimus (Afinitor) plus octreotide LAR (Sandostatin LAR, or long-acting release) with placebo plus octreotide LAR.

Everolimus, an inhibitor of the mammalian target of rapamycin (mTOR), is approved by the Food and Drug Administration for the treatment of certain subependymal giant cell astrocytomas and advanced renal cell carcinoma.

Octreotide LAR is a somatostatin analog approved for symptom control in patients with metastatic carcinoid tumors, a subset of NETs that cause secretory symptoms.

The trial found a 23% reduction in the risk of progression, as assessed by independent central review, with everolimus vs. placebo (hazard ratio [HR] 0.77, P = .026), but it fell just short of its predefined statistical boundary for significance (P = .0246), according to Dr. Yao.

Updated analyses showed that the benefit seen in the entire study population was also evident in subgroups stratified by patient and disease factors, and by prior treatment, although most of the hazard ratios overlapped unity.

About 80% of patients in both treatment groups had previously used long-acting somatostatin analogs. In exploratory analyses, everolimus was associated a reduced risk of progression in previous users (HR 0.81, P = .077) and in previous nonusers (HR 0.63, P = .054). "However, the absolute and relative benefits were perhaps greater among patients who have not had prior somatostatin [analog] exposure," he observed.

Dr. Yao also reported new analyses of the trial’s main results, showing that, when progression was assessed by local investigators instead of central reviewers, everolimus was associated with a 22% reduction in risk and the study met its statistical boundary (P = .018). The difference was due to 51 more events tallied by the local investigators vs. the central reviewers.

Additionally, the progression-free survival estimates for both treatment groups were longer with central review than with local investigator assessment. "These findings are actually hallmarks of informative censoring," he said. "The main source of informative censoring lies in the fact that patient management is based on investigator review, while the end point assessment is based on central review."

Issues arise when the local investigator calls progression before the central reviewer does. "In these cases, because of the crossover and change in therapy, the cases are censored. In fact, the central radiologist is effectively prevented from seeing the progression event," Dr. Yao explained. "This results in an inflation of PFS [progression-free survival] and reduced power in the study."

When the trial’s main analysis was repeated with correction for informative censoring, reduced power, and imbalances in randomization, the median progression-free survival was 13.8 months with everolimus and 8.3 months with placebo. That difference corresponds to a 40% reduction in risk and far exceeds the predefined boundary for significance (HR 0.60, P = .0014).

Commenting on the discrepancy between local and central review, discussant Dr. Mary F. Mulcahy said, "I think what this tells us ... is that progression-free survival may not be the right end point to be looking at when evaluating these diseases with secretory symptoms," because the symptoms may prompt investigators to switch treatment before radiographic progression occurs.

"So I think more so than these fancy calculations to try and rectify this, we need to maybe consider what our end point is for these very clinical syndromes that we see," she commented.

She called attention to the fact that the rate of discontinuation for progressive disease or adverse events was similarly high in the everolimus and placebo groups (70% and 75%), and median duration of treatment exposure was the same.

"So I have some concerns about the benefit of everolimus," said Dr. Mulcahy of the Robert H. Lurie Comprehensive Cancer Center in Chicago. "For the population studied, I think the benefit of everolimus with octreotide LAR is undefined. The activity of everolimus is demonstrated, but it’s associated with significant adverse events."

RADIANT-3: Pancreatic NET

The RADIANT-3 trial was conducted among 410 patients with progressive advanced pancreatic NET (pNET). It found a 65% reduction in the risk of progression with everolimus plus best supportive care, compared with placebo plus best supportive care (HR 0.35, P less than .0001).

Updated analyses showed that the benefit seen in the whole study population was also evident in subgroups stratified by patient and disease factors, and prior treatment, reported lead investigator Dr. Manisha H. Shah of the Ohio State University Comprehensive Cancer Center in Columbus.

"No matter how we slice the data based on different characteristics, we saw the significant benefit of everolimus compared to placebo," she commented. Some 50% of the patients had previously used somatostatin analogs, and 40% of patients used these agents concomitantly while in the trial.

In exploratory analyses, the progression-free survival benefit of everolimus was similar in subgroups of patients who had and had not previously used somatostatin analogs, and who did and did not use them concomitantly during the trial.

"Everolimus showed a consistent benefit in all subgroups regardless of presence or absence of somatostatin analog," commented Dr. Shah.

"RADIANT-3 is the largest randomized controlled trial ever completed in patients with progressive advanced pNET," she noted. "These data support the use of everolimus as the standard of care for patients with progressive advanced pNET."

In her discussion, Dr. Mulcahy noted that, in this trial, results were similar for central and local review. "That’s probably because these patients did not necessarily have the secretory symptoms of the patients in the RADIANT-2 study," she speculated.

The results are "strikingly similar" to those seen previously with the tyrosine kinase inhibitor sunitinib (Sutent) in patients with pNET. "We are seeing consistent results. How we are going to sequence these is something that needs to be further evaluated."

Her overall assessment of RADIANT-3 was more positive than that of RADIANT-2. "There is a significant and durable benefit of everolimus in previously treated [pNET] patients," she commented.

A variety of markers are being assessed in NET, including some associated with response to mTOR inhibitors, according to Dr. Mulcahy.

"This is hopefully the direction where we are going to be going, looking at these different prognostic and predictive markers, and assigning therapy and doing rationally designed clinical trials to find the best sequence of drugs," she concluded.

Novartis sponsored both trials. Dr. Yao and Dr. Shah reported being advisors to and receiving honoraria and research support from Novartis. Dr. Mulcahy did not report any relevant conflicts of interest.

SAN FRANCISCO – The length of time between surgery and the start of adjuvant chemotherapy may mean the difference between life and death for patients with colorectal cancer, researchers reported at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.

In a systematic review and meta-analysis of nine studies involving more than 14,000 patients, each 4-week delay in the start of adjuvant chemotherapy was associated with a 12% increase in the risk of death.

At the population level, such delays could translate to thousands of lives at risk in the United States annually, according to lead investigator Dr. James J. Biagi, an oncologist with the Cancer Research Institute at Queen’s University in Kingston, Ont.

"We believe the level of evidence from our study – with the knowledge that this relationship will not be subjected to prospective assessment – provides sufficient proof of an adverse association," he commented. "We think these results support that clinicians and jurisdictions should make efforts to optimize logistics that minimize time to adjuvant chemotherapy."

He noted that there are two common clinical assumptions regarding adjuvant chemotherapy for colorectal cancer: It should begin as soon as practical after surgery, and it may not offer any benefit when it’s started more than 3 months after surgery. However, "these assumptions have not been subjected to randomized trials, nor are they likely to be."

Dr. Biagi and colleagues searched the Medline database for the years 1975-2009 and also the online American Society of Clinical Oncology (ASCO) proceedings for the years 2007-2009 for studies of colorectal cancer reported in articles or in abstracts (to reduce the effect of publication bias) that assessed the association between time to initiation of adjuvant chemotherapy and patient outcomes.

To be included, the studies also had to adequately describe relevant prognostic factors and had to either have patient comparison groups similar on these factors or adjust for any imbalances in these factors.

The search identified nine studies with a total of 14,357 patients for analyses of overall survival, and five of the studies had data for analyses of disease-free survival.

Results of the meta-analysis showed that each 4-week delay in the initiation of chemotherapy after surgery was associated with a 12% increase in mortality risk (95% confidence interval, 9%-15%) and a 14% increase in recurrence risk as assessed from disease-free survival (95% CI, 9%-19%).

Both findings were essentially the same when the data were subjected to funnel plot analysis to assess for publication bias, according to Dr. Biagi.

To show the implications of these results at the patient level, he used the hypothetical case of a 65-year-old man in good general health with a T3N2 moderately differentiated colon cancer and 5-fluorouracil–based adjuvant chemotherapy.

This patient would have a 45% probability of being alive at 5 years if he did not receive the chemotherapy, but a 60% probability if he did, according to the "Adjuvant! Online" tool (www.adjuvantonline.com/index.jsp).

Assuming that this benefit depends on starting the chemotherapy 4 weeks after surgery, the patient’s survival probability would fall to 55% if chemotherapy were delayed until 8 weeks, and to 50% if it were delayed until 12 weeks.

At the population level, Dr. Biagi noted that an estimated 49,000 U.S. patients received a new diagnosis of stage III colorectal cancer in 2009, perhaps half of whom were eligible to start adjuvant chemotherapy at 4 weeks after surgery. Delaying chemotherapy to 8 weeks in this group alone would put 1,225 lives at risk, and delaying it to 12 weeks would put 2,450 lives at risk.

At the same time, study results also provided some reassurance when it comes to long delays in the start of chemotherapy, according to Dr. Biagi. For that hypothetical patient who has a 60% survival probability with adjuvant chemotherapy, study results suggested it would be 50% if the start of chemotherapy were delayed to 3 months – still better than the 45% expected without chemotherapy.

"This would suggest that there may be some benefit to adjuvant chemotherapy beyond that arbitrary 3-month window," he commented.

The study had its limitations, according to Dr. Biagi, such as "the inherent bias that a patient’s postoperative course may independently prolong wait time."

"Our results are based on trials from the era of fluoropyrimidine-alone therapy, in the era prior to oxaliplatin introduction," he further noted. "And of course, our results are based on nonrandomized and retrospective data."

The time to adjuvant chemotherapy is an issue that has implications for both trial design and overall patient treatment, according to discussant Dr. Johanna Bendell, an oncologist with the Sarah Cannon Research Institute in Nashville, Tenn.

"I think what we see from this study is that we need to start tracking this in clinical trials and control it better," she commented. "We also need to encourage – within health care systems, whether it be U.S.-based or other parts of the world – the importance of coordinated care," said Dr. Bendell. "We need to treat patients as quickly as possible after surgery."

Cosponsors of the symposium include the American Gastroenterological Association (AGA) Institute, ASCO, the American Society for Radiation Oncology, and the Society of Surgical Oncology.

Dr. Biagi reported that he had no relevant conflicts of interest. Dr. Bendell stated that she had no relevant disclosures.

SAN FRANCISCO – The length of time between surgery and the start of adjuvant chemotherapy may mean the difference between life and death for patients with colorectal cancer, researchers reported at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.

In a systematic review and meta-analysis of nine studies involving more than 14,000 patients, each 4-week delay in the start of adjuvant chemotherapy was associated with a 12% increase in the risk of death.

At the population level, such delays could translate to thousands of lives at risk in the United States annually, according to lead investigator Dr. James J. Biagi, an oncologist with the Cancer Research Institute at Queen’s University in Kingston, Ont.

"We believe the level of evidence from our study – with the knowledge that this relationship will not be subjected to prospective assessment – provides sufficient proof of an adverse association," he commented. "We think these results support that clinicians and jurisdictions should make efforts to optimize logistics that minimize time to adjuvant chemotherapy."

He noted that there are two common clinical assumptions regarding adjuvant chemotherapy for colorectal cancer: It should begin as soon as practical after surgery, and it may not offer any benefit when it’s started more than 3 months after surgery. However, "these assumptions have not been subjected to randomized trials, nor are they likely to be."

Dr. Biagi and colleagues searched the Medline database for the years 1975-2009 and also the online American Society of Clinical Oncology (ASCO) proceedings for the years 2007-2009 for studies of colorectal cancer reported in articles or in abstracts (to reduce the effect of publication bias) that assessed the association between time to initiation of adjuvant chemotherapy and patient outcomes.

To be included, the studies also had to adequately describe relevant prognostic factors and had to either have patient comparison groups similar on these factors or adjust for any imbalances in these factors.

The search identified nine studies with a total of 14,357 patients for analyses of overall survival, and five of the studies had data for analyses of disease-free survival.

Results of the meta-analysis showed that each 4-week delay in the initiation of chemotherapy after surgery was associated with a 12% increase in mortality risk (95% confidence interval, 9%-15%) and a 14% increase in recurrence risk as assessed from disease-free survival (95% CI, 9%-19%).

Both findings were essentially the same when the data were subjected to funnel plot analysis to assess for publication bias, according to Dr. Biagi.

To show the implications of these results at the patient level, he used the hypothetical case of a 65-year-old man in good general health with a T3N2 moderately differentiated colon cancer and 5-fluorouracil–based adjuvant chemotherapy.

This patient would have a 45% probability of being alive at 5 years if he did not receive the chemotherapy, but a 60% probability if he did, according to the "Adjuvant! Online" tool (www.adjuvantonline.com/index.jsp).

Assuming that this benefit depends on starting the chemotherapy 4 weeks after surgery, the patient’s survival probability would fall to 55% if chemotherapy were delayed until 8 weeks, and to 50% if it were delayed until 12 weeks.

At the population level, Dr. Biagi noted that an estimated 49,000 U.S. patients received a new diagnosis of stage III colorectal cancer in 2009, perhaps half of whom were eligible to start adjuvant chemotherapy at 4 weeks after surgery. Delaying chemotherapy to 8 weeks in this group alone would put 1,225 lives at risk, and delaying it to 12 weeks would put 2,450 lives at risk.

At the same time, study results also provided some reassurance when it comes to long delays in the start of chemotherapy, according to Dr. Biagi. For that hypothetical patient who has a 60% survival probability with adjuvant chemotherapy, study results suggested it would be 50% if the start of chemotherapy were delayed to 3 months – still better than the 45% expected without chemotherapy.

"This would suggest that there may be some benefit to adjuvant chemotherapy beyond that arbitrary 3-month window," he commented.

The study had its limitations, according to Dr. Biagi, such as "the inherent bias that a patient’s postoperative course may independently prolong wait time."

"Our results are based on trials from the era of fluoropyrimidine-alone therapy, in the era prior to oxaliplatin introduction," he further noted. "And of course, our results are based on nonrandomized and retrospective data."

The time to adjuvant chemotherapy is an issue that has implications for both trial design and overall patient treatment, according to discussant Dr. Johanna Bendell, an oncologist with the Sarah Cannon Research Institute in Nashville, Tenn.

"I think what we see from this study is that we need to start tracking this in clinical trials and control it better," she commented. "We also need to encourage – within health care systems, whether it be U.S.-based or other parts of the world – the importance of coordinated care," said Dr. Bendell. "We need to treat patients as quickly as possible after surgery."

Cosponsors of the symposium include the American Gastroenterological Association (AGA) Institute, ASCO, the American Society for Radiation Oncology, and the Society of Surgical Oncology.

Dr. Biagi reported that he had no relevant conflicts of interest. Dr. Bendell stated that she had no relevant disclosures.

SAN FRANCISCO – The length of time between surgery and the start of adjuvant chemotherapy may mean the difference between life and death for patients with colorectal cancer, researchers reported at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.

In a systematic review and meta-analysis of nine studies involving more than 14,000 patients, each 4-week delay in the start of adjuvant chemotherapy was associated with a 12% increase in the risk of death.

At the population level, such delays could translate to thousands of lives at risk in the United States annually, according to lead investigator Dr. James J. Biagi, an oncologist with the Cancer Research Institute at Queen’s University in Kingston, Ont.

"We believe the level of evidence from our study – with the knowledge that this relationship will not be subjected to prospective assessment – provides sufficient proof of an adverse association," he commented. "We think these results support that clinicians and jurisdictions should make efforts to optimize logistics that minimize time to adjuvant chemotherapy."

He noted that there are two common clinical assumptions regarding adjuvant chemotherapy for colorectal cancer: It should begin as soon as practical after surgery, and it may not offer any benefit when it’s started more than 3 months after surgery. However, "these assumptions have not been subjected to randomized trials, nor are they likely to be."

Dr. Biagi and colleagues searched the Medline database for the years 1975-2009 and also the online American Society of Clinical Oncology (ASCO) proceedings for the years 2007-2009 for studies of colorectal cancer reported in articles or in abstracts (to reduce the effect of publication bias) that assessed the association between time to initiation of adjuvant chemotherapy and patient outcomes.

To be included, the studies also had to adequately describe relevant prognostic factors and had to either have patient comparison groups similar on these factors or adjust for any imbalances in these factors.

The search identified nine studies with a total of 14,357 patients for analyses of overall survival, and five of the studies had data for analyses of disease-free survival.

Results of the meta-analysis showed that each 4-week delay in the initiation of chemotherapy after surgery was associated with a 12% increase in mortality risk (95% confidence interval, 9%-15%) and a 14% increase in recurrence risk as assessed from disease-free survival (95% CI, 9%-19%).

Both findings were essentially the same when the data were subjected to funnel plot analysis to assess for publication bias, according to Dr. Biagi.

To show the implications of these results at the patient level, he used the hypothetical case of a 65-year-old man in good general health with a T3N2 moderately differentiated colon cancer and 5-fluorouracil–based adjuvant chemotherapy.

This patient would have a 45% probability of being alive at 5 years if he did not receive the chemotherapy, but a 60% probability if he did, according to the "Adjuvant! Online" tool (www.adjuvantonline.com/index.jsp).

Assuming that this benefit depends on starting the chemotherapy 4 weeks after surgery, the patient’s survival probability would fall to 55% if chemotherapy were delayed until 8 weeks, and to 50% if it were delayed until 12 weeks.

At the population level, Dr. Biagi noted that an estimated 49,000 U.S. patients received a new diagnosis of stage III colorectal cancer in 2009, perhaps half of whom were eligible to start adjuvant chemotherapy at 4 weeks after surgery. Delaying chemotherapy to 8 weeks in this group alone would put 1,225 lives at risk, and delaying it to 12 weeks would put 2,450 lives at risk.

At the same time, study results also provided some reassurance when it comes to long delays in the start of chemotherapy, according to Dr. Biagi. For that hypothetical patient who has a 60% survival probability with adjuvant chemotherapy, study results suggested it would be 50% if the start of chemotherapy were delayed to 3 months – still better than the 45% expected without chemotherapy.

"This would suggest that there may be some benefit to adjuvant chemotherapy beyond that arbitrary 3-month window," he commented.

The study had its limitations, according to Dr. Biagi, such as "the inherent bias that a patient’s postoperative course may independently prolong wait time."

"Our results are based on trials from the era of fluoropyrimidine-alone therapy, in the era prior to oxaliplatin introduction," he further noted. "And of course, our results are based on nonrandomized and retrospective data."

The time to adjuvant chemotherapy is an issue that has implications for both trial design and overall patient treatment, according to discussant Dr. Johanna Bendell, an oncologist with the Sarah Cannon Research Institute in Nashville, Tenn.

"I think what we see from this study is that we need to start tracking this in clinical trials and control it better," she commented. "We also need to encourage – within health care systems, whether it be U.S.-based or other parts of the world – the importance of coordinated care," said Dr. Bendell. "We need to treat patients as quickly as possible after surgery."

Cosponsors of the symposium include the American Gastroenterological Association (AGA) Institute, ASCO, the American Society for Radiation Oncology, and the Society of Surgical Oncology.

Dr. Biagi reported that he had no relevant conflicts of interest. Dr. Bendell stated that she had no relevant disclosures.

SAN FRANCISCO – The length of time between surgery and the start of adjuvant chemotherapy may mean the difference between life and death for patients with colorectal cancer, researchers reported at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.

In a systematic review and meta-analysis of nine studies involving more than 14,000 patients, each 4-week delay in the start of adjuvant chemotherapy was associated with a 12% increase in the risk of death.

At the population level, such delays could translate to thousands of lives at risk in the United States annually, according to lead investigator Dr. James J. Biagi, an oncologist with the Cancer Research Institute at Queen’s University in Kingston, Ont.

"We believe the level of evidence from our study – with the knowledge that this relationship will not be subjected to prospective assessment – provides sufficient proof of an adverse association," he commented. "We think these results support that clinicians and jurisdictions should make efforts to optimize logistics that minimize time to adjuvant chemotherapy."

He noted that there are two common clinical assumptions regarding adjuvant chemotherapy for colorectal cancer: It should begin as soon as practical after surgery, and it may not offer any benefit when it’s started more than 3 months after surgery. However, "these assumptions have not been subjected to randomized trials, nor are they likely to be."

Dr. Biagi and colleagues searched the Medline database for the years 1975-2009 and also the online American Society of Clinical Oncology (ASCO) proceedings for the years 2007-2009 for studies of colorectal cancer reported in articles or in abstracts (to reduce the effect of publication bias) that assessed the association between time to initiation of adjuvant chemotherapy and patient outcomes.

To be included, the studies also had to adequately describe relevant prognostic factors and had to either have patient comparison groups similar on these factors or adjust for any imbalances in these factors.

The search identified nine studies with a total of 14,357 patients for analyses of overall survival, and five of the studies had data for analyses of disease-free survival.

Results of the meta-analysis showed that each 4-week delay in the initiation of chemotherapy after surgery was associated with a 12% increase in mortality risk (95% confidence interval, 9%-15%) and a 14% increase in recurrence risk as assessed from disease-free survival (95% CI, 9%-19%).

Both findings were essentially the same when the data were subjected to funnel plot analysis to assess for publication bias, according to Dr. Biagi.

To show the implications of these results at the patient level, he used the hypothetical case of a 65-year-old man in good general health with a T3N2 moderately differentiated colon cancer and 5-fluorouracil–based adjuvant chemotherapy.

This patient would have a 45% probability of being alive at 5 years if he did not receive the chemotherapy, but a 60% probability if he did, according to the "Adjuvant! Online" tool (www.adjuvantonline.com/index.jsp).

Assuming that this benefit depends on starting the chemotherapy 4 weeks after surgery, the patient’s survival probability would fall to 55% if chemotherapy were delayed until 8 weeks, and to 50% if it were delayed until 12 weeks.

At the population level, Dr. Biagi noted that an estimated 49,000 U.S. patients received a new diagnosis of stage III colorectal cancer in 2009, perhaps half of whom were eligible to start adjuvant chemotherapy at 4 weeks after surgery. Delaying chemotherapy to 8 weeks in this group alone would put 1,225 lives at risk, and delaying it to 12 weeks would put 2,450 lives at risk.

At the same time, study results also provided some reassurance when it comes to long delays in the start of chemotherapy, according to Dr. Biagi. For that hypothetical patient who has a 60% survival probability with adjuvant chemotherapy, study results suggested it would be 50% if the start of chemotherapy were delayed to 3 months – still better than the 45% expected without chemotherapy.

"This would suggest that there may be some benefit to adjuvant chemotherapy beyond that arbitrary 3-month window," he commented.

The study had its limitations, according to Dr. Biagi, such as "the inherent bias that a patient’s postoperative course may independently prolong wait time."

"Our results are based on trials from the era of fluoropyrimidine-alone therapy, in the era prior to oxaliplatin introduction," he further noted. "And of course, our results are based on nonrandomized and retrospective data."

The time to adjuvant chemotherapy is an issue that has implications for both trial design and overall patient treatment, according to discussant Dr. Johanna Bendell, an oncologist with the Sarah Cannon Research Institute in Nashville, Tenn.

"I think what we see from this study is that we need to start tracking this in clinical trials and control it better," she commented. "We also need to encourage – within health care systems, whether it be U.S.-based or other parts of the world – the importance of coordinated care," said Dr. Bendell. "We need to treat patients as quickly as possible after surgery."

Cosponsors of the symposium include the American Gastroenterological Association (AGA) Institute, ASCO, the American Society for Radiation Oncology, and the Society of Surgical Oncology.

Dr. Biagi reported that he had no relevant conflicts of interest. Dr. Bendell stated that she had no relevant disclosures.

SAN FRANCISCO – The length of time between surgery and the start of adjuvant chemotherapy may mean the difference between life and death for patients with colorectal cancer, researchers reported at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.

In a systematic review and meta-analysis of nine studies involving more than 14,000 patients, each 4-week delay in the start of adjuvant chemotherapy was associated with a 12% increase in the risk of death.

At the population level, such delays could translate to thousands of lives at risk in the United States annually, according to lead investigator Dr. James J. Biagi, an oncologist with the Cancer Research Institute at Queen’s University in Kingston, Ont.

"We believe the level of evidence from our study – with the knowledge that this relationship will not be subjected to prospective assessment – provides sufficient proof of an adverse association," he commented. "We think these results support that clinicians and jurisdictions should make efforts to optimize logistics that minimize time to adjuvant chemotherapy."

He noted that there are two common clinical assumptions regarding adjuvant chemotherapy for colorectal cancer: It should begin as soon as practical after surgery, and it may not offer any benefit when it’s started more than 3 months after surgery. However, "these assumptions have not been subjected to randomized trials, nor are they likely to be."

Dr. Biagi and colleagues searched the Medline database for the years 1975-2009 and also the online American Society of Clinical Oncology (ASCO) proceedings for the years 2007-2009 for studies of colorectal cancer reported in articles or in abstracts (to reduce the effect of publication bias) that assessed the association between time to initiation of adjuvant chemotherapy and patient outcomes.

To be included, the studies also had to adequately describe relevant prognostic factors and had to either have patient comparison groups similar on these factors or adjust for any imbalances in these factors.

The search identified nine studies with a total of 14,357 patients for analyses of overall survival, and five of the studies had data for analyses of disease-free survival.

Results of the meta-analysis showed that each 4-week delay in the initiation of chemotherapy after surgery was associated with a 12% increase in mortality risk (95% confidence interval, 9%-15%) and a 14% increase in recurrence risk as assessed from disease-free survival (95% CI, 9%-19%).

Both findings were essentially the same when the data were subjected to funnel plot analysis to assess for publication bias, according to Dr. Biagi.

To show the implications of these results at the patient level, he used the hypothetical case of a 65-year-old man in good general health with a T3N2 moderately differentiated colon cancer and 5-fluorouracil–based adjuvant chemotherapy.

This patient would have a 45% probability of being alive at 5 years if he did not receive the chemotherapy, but a 60% probability if he did, according to the "Adjuvant! Online" tool (www.adjuvantonline.com/index.jsp).

Assuming that this benefit depends on starting the chemotherapy 4 weeks after surgery, the patient’s survival probability would fall to 55% if chemotherapy were delayed until 8 weeks, and to 50% if it were delayed until 12 weeks.

At the population level, Dr. Biagi noted that an estimated 49,000 U.S. patients received a new diagnosis of stage III colorectal cancer in 2009, perhaps half of whom were eligible to start adjuvant chemotherapy at 4 weeks after surgery. Delaying chemotherapy to 8 weeks in this group alone would put 1,225 lives at risk, and delaying it to 12 weeks would put 2,450 lives at risk.

At the same time, study results also provided some reassurance when it comes to long delays in the start of chemotherapy, according to Dr. Biagi. For that hypothetical patient who has a 60% survival probability with adjuvant chemotherapy, study results suggested it would be 50% if the start of chemotherapy were delayed to 3 months – still better than the 45% expected without chemotherapy.

"This would suggest that there may be some benefit to adjuvant chemotherapy beyond that arbitrary 3-month window," he commented.

The study had its limitations, according to Dr. Biagi, such as "the inherent bias that a patient’s postoperative course may independently prolong wait time."

"Our results are based on trials from the era of fluoropyrimidine-alone therapy, in the era prior to oxaliplatin introduction," he further noted. "And of course, our results are based on nonrandomized and retrospective data."

The time to adjuvant chemotherapy is an issue that has implications for both trial design and overall patient treatment, according to discussant Dr. Johanna Bendell, an oncologist with the Sarah Cannon Research Institute in Nashville, Tenn.

"I think what we see from this study is that we need to start tracking this in clinical trials and control it better," she commented. "We also need to encourage – within health care systems, whether it be U.S.-based or other parts of the world – the importance of coordinated care," said Dr. Bendell. "We need to treat patients as quickly as possible after surgery."

Cosponsors of the symposium include the American Gastroenterological Association (AGA) Institute, ASCO, the American Society for Radiation Oncology, and the Society of Surgical Oncology.

Dr. Biagi reported that he had no relevant conflicts of interest. Dr. Bendell stated that she had no relevant disclosures.

SAN FRANCISCO – The length of time between surgery and the start of adjuvant chemotherapy may mean the difference between life and death for patients with colorectal cancer, researchers reported at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.

In a systematic review and meta-analysis of nine studies involving more than 14,000 patients, each 4-week delay in the start of adjuvant chemotherapy was associated with a 12% increase in the risk of death.

At the population level, such delays could translate to thousands of lives at risk in the United States annually, according to lead investigator Dr. James J. Biagi, an oncologist with the Cancer Research Institute at Queen’s University in Kingston, Ont.

"We believe the level of evidence from our study – with the knowledge that this relationship will not be subjected to prospective assessment – provides sufficient proof of an adverse association," he commented. "We think these results support that clinicians and jurisdictions should make efforts to optimize logistics that minimize time to adjuvant chemotherapy."

He noted that there are two common clinical assumptions regarding adjuvant chemotherapy for colorectal cancer: It should begin as soon as practical after surgery, and it may not offer any benefit when it’s started more than 3 months after surgery. However, "these assumptions have not been subjected to randomized trials, nor are they likely to be."

Dr. Biagi and colleagues searched the Medline database for the years 1975-2009 and also the online American Society of Clinical Oncology (ASCO) proceedings for the years 2007-2009 for studies of colorectal cancer reported in articles or in abstracts (to reduce the effect of publication bias) that assessed the association between time to initiation of adjuvant chemotherapy and patient outcomes.

To be included, the studies also had to adequately describe relevant prognostic factors and had to either have patient comparison groups similar on these factors or adjust for any imbalances in these factors.

The search identified nine studies with a total of 14,357 patients for analyses of overall survival, and five of the studies had data for analyses of disease-free survival.

Results of the meta-analysis showed that each 4-week delay in the initiation of chemotherapy after surgery was associated with a 12% increase in mortality risk (95% confidence interval, 9%-15%) and a 14% increase in recurrence risk as assessed from disease-free survival (95% CI, 9%-19%).

Both findings were essentially the same when the data were subjected to funnel plot analysis to assess for publication bias, according to Dr. Biagi.

To show the implications of these results at the patient level, he used the hypothetical case of a 65-year-old man in good general health with a T3N2 moderately differentiated colon cancer and 5-fluorouracil–based adjuvant chemotherapy.

This patient would have a 45% probability of being alive at 5 years if he did not receive the chemotherapy, but a 60% probability if he did, according to the "Adjuvant! Online" tool (www.adjuvantonline.com/index.jsp).

Assuming that this benefit depends on starting the chemotherapy 4 weeks after surgery, the patient’s survival probability would fall to 55% if chemotherapy were delayed until 8 weeks, and to 50% if it were delayed until 12 weeks.

At the population level, Dr. Biagi noted that an estimated 49,000 U.S. patients received a new diagnosis of stage III colorectal cancer in 2009, perhaps half of whom were eligible to start adjuvant chemotherapy at 4 weeks after surgery. Delaying chemotherapy to 8 weeks in this group alone would put 1,225 lives at risk, and delaying it to 12 weeks would put 2,450 lives at risk.

At the same time, study results also provided some reassurance when it comes to long delays in the start of chemotherapy, according to Dr. Biagi. For that hypothetical patient who has a 60% survival probability with adjuvant chemotherapy, study results suggested it would be 50% if the start of chemotherapy were delayed to 3 months – still better than the 45% expected without chemotherapy.

"This would suggest that there may be some benefit to adjuvant chemotherapy beyond that arbitrary 3-month window," he commented.

The study had its limitations, according to Dr. Biagi, such as "the inherent bias that a patient’s postoperative course may independently prolong wait time."

"Our results are based on trials from the era of fluoropyrimidine-alone therapy, in the era prior to oxaliplatin introduction," he further noted. "And of course, our results are based on nonrandomized and retrospective data."

The time to adjuvant chemotherapy is an issue that has implications for both trial design and overall patient treatment, according to discussant Dr. Johanna Bendell, an oncologist with the Sarah Cannon Research Institute in Nashville, Tenn.

"I think what we see from this study is that we need to start tracking this in clinical trials and control it better," she commented. "We also need to encourage – within health care systems, whether it be U.S.-based or other parts of the world – the importance of coordinated care," said Dr. Bendell. "We need to treat patients as quickly as possible after surgery."

Cosponsors of the symposium include the American Gastroenterological Association (AGA) Institute, ASCO, the American Society for Radiation Oncology, and the Society of Surgical Oncology.

Dr. Biagi reported that he had no relevant conflicts of interest. Dr. Bendell stated that she had no relevant disclosures.

SAN FRANCISCO – Pretreatment expression of ERCC1 in localized esophageal and gastroesophageal adenocarcinomas is a marker for outcomes among patients given trimodality therapy that includes oxaliplatin-based chemoradiation, investigators reported from a prospective study.

Fully 58% of the 55 patients studied from the Southwest Oncology Group (SWOG) S0356 trial had tumors expressing a high level of mRNA for ERCC1, a key gene in the repair of platinum- and radiation-induced DNA damage.

Compared with their counterparts whose tumors had low expression, these patients were nearly three times more likely to experience progression and more than twice as likely to die, according to results reported at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.

"ERCC1 mRNA level is a very promising pretreatment biomarker in patients with localized esophageal and gastroesophageal adenocarcinoma treated with trimodality treatment," asserted lead investigator Dr. Pierre O. Bohanes. "Based on these and published data, the SWOG is planning a prospective biomarker-driven clinical trial."

"In contrast to the growing number of predictive biomarkers for anticancer agents, there are no established biomarkers to select patients who will benefit most from chemoradiation," he noted. "Utilization of predictive biomarkers to select therapy should lead to higher cure rates."

The phase II trial, which was largely community based, enrolled patients with clinical stage II or III esophageal or gastroesophageal junction adenocarcinoma. They underwent tumor biopsy, then chemoradiation (oxaliplatin, 5-fluorouracil, and 45-Gy external beam radiation), then surgery, and finally more chemotherapy (oxaliplatin and 5-fluorouracil).

Response Genetics Inc., manufacturer of several biomarker assays, analyzed tumor ERCC1 mRNA expression for the 55 patients who had sufficient pretreatment tumor tissue. Laser-capture microdissection was used to ensure that only tumor cells were analyzed.

"ERCC1 has been shown to be a critical gene in DNA repair," Dr. Bohanes explained. "ERCC1 is involved in the nucleotide excision repair pathway, which recognizes and removes platinum-induced DNA adducts." Higher expression is associated with resistance to platinum compounds, including cisplatin, oxaliplatin, and carboplatin.

"Also more recently, ERCC1 has been shown to be involved in the double-strand break repair pathway, which repairs radiation-induced damage," he further observed.

Tumors were classified as having a high or low level of ERCC1 expression using a cutoff mRNA level of greater than 1.7 for high expression, as established in previous studies.

The 55 patients studied had a median age of 64 years. Most were men (93%) and white (94%), and had esophageal tumors (62%). One-fourth of them were found to have a pathological complete response at the time of surgery.

The median duration of follow-up was 36.8 months, reported Dr. Bohanes, a research fellow in medical oncology at the University of Southern California in Los Angeles.

Results showed that patients having high vs. low tumor expression of ERCC1 had a nearly tripled risk of progression (hazard ratio, 2.97; P = .006). The median duration of progression-free survival was 14.8 months for the former but was not reached for the latter. Corresponding 2-year rates of progression-free survival were 17% and 67%.

Similarly, patients with tumors having high vs. low expression of ERCC1 had a more than doubling of the risk of death (HR, 2.32; P = .047).The median duration of overall survival was 22.4 months for the former but was not reached for the latter. Corresponding 2-year rates of overall survival were 37% and 72%.

Expression of ERCC1 was not associated with pathological complete response. Also, expression of a host of other genes – XPD and RRM1 (associated with DNA repair), GSTP1 (associated with platinum detoxification), and TS, TP, and DPD (associated with 5-fluorouracil metabolism) – was not associated with any of the outcomes studied.

"Biomarker studies are feasible within cooperative groups," commented Dr. Bohanes, but adequate tissue was available for only 55 of 92 eligible patients. Hence, "future trials need to request additional endoscopic biopsies to allow for sufficient tumor tissue collection."

A study shortcoming was an inability to determine whether ERCC1 expression correlates with disease stage, he acknowledged. "The design of this study unfortunately did not require preoperative endoscopic ultrasound because it was thought that it would have hampered the recruitment of this trial," he said. "And often, in the community setting, endoscopic ultrasound is not available."

Also, the study could not determine whether ERCC1 expression is a prognostic marker. "We would need a control arm without platinum agent," he noted.

"I think that the patients with high expression are not benefiting from this treatment" and should be treated with alternative treatments, commented Dr. Heinz-Josef Lenz, senior investigator and chair of the gastrointestinal oncology program at the University of Southern California. "We have choices, and I think that would certainly be part of the new concept and design going forward."

He agreed with an attendee that recruiting patients with esophageal and gastroesophageal cancer to randomized trials has been difficult in the past and it might therefore take many years to obtain important biomarker data. But adaptive trial designs are addressing this issue.

"I think we are incorporating now more technologies with the design, which may be more flexible to adapt new findings so that we are not stuck for the next 3 or 5 years to a trial because of low accrual," he said.

Dr. Bohanes reported that he had no relevant conflicts of interest. Dr. Lenz reported having relationships with Response Genetics Inc. and with Sanofi-Aventis, manufacturer of oxaliplatin (Eloxatin).

SAN FRANCISCO – Pretreatment expression of ERCC1 in localized esophageal and gastroesophageal adenocarcinomas is a marker for outcomes among patients given trimodality therapy that includes oxaliplatin-based chemoradiation, investigators reported from a prospective study.

Fully 58% of the 55 patients studied from the Southwest Oncology Group (SWOG) S0356 trial had tumors expressing a high level of mRNA for ERCC1, a key gene in the repair of platinum- and radiation-induced DNA damage.

Compared with their counterparts whose tumors had low expression, these patients were nearly three times more likely to experience progression and more than twice as likely to die, according to results reported at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.

"ERCC1 mRNA level is a very promising pretreatment biomarker in patients with localized esophageal and gastroesophageal adenocarcinoma treated with trimodality treatment," asserted lead investigator Dr. Pierre O. Bohanes. "Based on these and published data, the SWOG is planning a prospective biomarker-driven clinical trial."

"In contrast to the growing number of predictive biomarkers for anticancer agents, there are no established biomarkers to select patients who will benefit most from chemoradiation," he noted. "Utilization of predictive biomarkers to select therapy should lead to higher cure rates."

The phase II trial, which was largely community based, enrolled patients with clinical stage II or III esophageal or gastroesophageal junction adenocarcinoma. They underwent tumor biopsy, then chemoradiation (oxaliplatin, 5-fluorouracil, and 45-Gy external beam radiation), then surgery, and finally more chemotherapy (oxaliplatin and 5-fluorouracil).

Response Genetics Inc., manufacturer of several biomarker assays, analyzed tumor ERCC1 mRNA expression for the 55 patients who had sufficient pretreatment tumor tissue. Laser-capture microdissection was used to ensure that only tumor cells were analyzed.

"ERCC1 has been shown to be a critical gene in DNA repair," Dr. Bohanes explained. "ERCC1 is involved in the nucleotide excision repair pathway, which recognizes and removes platinum-induced DNA adducts." Higher expression is associated with resistance to platinum compounds, including cisplatin, oxaliplatin, and carboplatin.

"Also more recently, ERCC1 has been shown to be involved in the double-strand break repair pathway, which repairs radiation-induced damage," he further observed.

Tumors were classified as having a high or low level of ERCC1 expression using a cutoff mRNA level of greater than 1.7 for high expression, as established in previous studies.

The 55 patients studied had a median age of 64 years. Most were men (93%) and white (94%), and had esophageal tumors (62%). One-fourth of them were found to have a pathological complete response at the time of surgery.

The median duration of follow-up was 36.8 months, reported Dr. Bohanes, a research fellow in medical oncology at the University of Southern California in Los Angeles.

Results showed that patients having high vs. low tumor expression of ERCC1 had a nearly tripled risk of progression (hazard ratio, 2.97; P = .006). The median duration of progression-free survival was 14.8 months for the former but was not reached for the latter. Corresponding 2-year rates of progression-free survival were 17% and 67%.

Similarly, patients with tumors having high vs. low expression of ERCC1 had a more than doubling of the risk of death (HR, 2.32; P = .047).The median duration of overall survival was 22.4 months for the former but was not reached for the latter. Corresponding 2-year rates of overall survival were 37% and 72%.

Expression of ERCC1 was not associated with pathological complete response. Also, expression of a host of other genes – XPD and RRM1 (associated with DNA repair), GSTP1 (associated with platinum detoxification), and TS, TP, and DPD (associated with 5-fluorouracil metabolism) – was not associated with any of the outcomes studied.

"Biomarker studies are feasible within cooperative groups," commented Dr. Bohanes, but adequate tissue was available for only 55 of 92 eligible patients. Hence, "future trials need to request additional endoscopic biopsies to allow for sufficient tumor tissue collection."

A study shortcoming was an inability to determine whether ERCC1 expression correlates with disease stage, he acknowledged. "The design of this study unfortunately did not require preoperative endoscopic ultrasound because it was thought that it would have hampered the recruitment of this trial," he said. "And often, in the community setting, endoscopic ultrasound is not available."

Also, the study could not determine whether ERCC1 expression is a prognostic marker. "We would need a control arm without platinum agent," he noted.

"I think that the patients with high expression are not benefiting from this treatment" and should be treated with alternative treatments, commented Dr. Heinz-Josef Lenz, senior investigator and chair of the gastrointestinal oncology program at the University of Southern California. "We have choices, and I think that would certainly be part of the new concept and design going forward."

He agreed with an attendee that recruiting patients with esophageal and gastroesophageal cancer to randomized trials has been difficult in the past and it might therefore take many years to obtain important biomarker data. But adaptive trial designs are addressing this issue.

"I think we are incorporating now more technologies with the design, which may be more flexible to adapt new findings so that we are not stuck for the next 3 or 5 years to a trial because of low accrual," he said.

Dr. Bohanes reported that he had no relevant conflicts of interest. Dr. Lenz reported having relationships with Response Genetics Inc. and with Sanofi-Aventis, manufacturer of oxaliplatin (Eloxatin).

SAN FRANCISCO – Pretreatment expression of ERCC1 in localized esophageal and gastroesophageal adenocarcinomas is a marker for outcomes among patients given trimodality therapy that includes oxaliplatin-based chemoradiation, investigators reported from a prospective study.

Fully 58% of the 55 patients studied from the Southwest Oncology Group (SWOG) S0356 trial had tumors expressing a high level of mRNA for ERCC1, a key gene in the repair of platinum- and radiation-induced DNA damage.

Compared with their counterparts whose tumors had low expression, these patients were nearly three times more likely to experience progression and more than twice as likely to die, according to results reported at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.

"ERCC1 mRNA level is a very promising pretreatment biomarker in patients with localized esophageal and gastroesophageal adenocarcinoma treated with trimodality treatment," asserted lead investigator Dr. Pierre O. Bohanes. "Based on these and published data, the SWOG is planning a prospective biomarker-driven clinical trial."

"In contrast to the growing number of predictive biomarkers for anticancer agents, there are no established biomarkers to select patients who will benefit most from chemoradiation," he noted. "Utilization of predictive biomarkers to select therapy should lead to higher cure rates."

The phase II trial, which was largely community based, enrolled patients with clinical stage II or III esophageal or gastroesophageal junction adenocarcinoma. They underwent tumor biopsy, then chemoradiation (oxaliplatin, 5-fluorouracil, and 45-Gy external beam radiation), then surgery, and finally more chemotherapy (oxaliplatin and 5-fluorouracil).

Response Genetics Inc., manufacturer of several biomarker assays, analyzed tumor ERCC1 mRNA expression for the 55 patients who had sufficient pretreatment tumor tissue. Laser-capture microdissection was used to ensure that only tumor cells were analyzed.

"ERCC1 has been shown to be a critical gene in DNA repair," Dr. Bohanes explained. "ERCC1 is involved in the nucleotide excision repair pathway, which recognizes and removes platinum-induced DNA adducts." Higher expression is associated with resistance to platinum compounds, including cisplatin, oxaliplatin, and carboplatin.

"Also more recently, ERCC1 has been shown to be involved in the double-strand break repair pathway, which repairs radiation-induced damage," he further observed.

Tumors were classified as having a high or low level of ERCC1 expression using a cutoff mRNA level of greater than 1.7 for high expression, as established in previous studies.

The 55 patients studied had a median age of 64 years. Most were men (93%) and white (94%), and had esophageal tumors (62%). One-fourth of them were found to have a pathological complete response at the time of surgery.

The median duration of follow-up was 36.8 months, reported Dr. Bohanes, a research fellow in medical oncology at the University of Southern California in Los Angeles.

Results showed that patients having high vs. low tumor expression of ERCC1 had a nearly tripled risk of progression (hazard ratio, 2.97; P = .006). The median duration of progression-free survival was 14.8 months for the former but was not reached for the latter. Corresponding 2-year rates of progression-free survival were 17% and 67%.

Similarly, patients with tumors having high vs. low expression of ERCC1 had a more than doubling of the risk of death (HR, 2.32; P = .047).The median duration of overall survival was 22.4 months for the former but was not reached for the latter. Corresponding 2-year rates of overall survival were 37% and 72%.

Expression of ERCC1 was not associated with pathological complete response. Also, expression of a host of other genes – XPD and RRM1 (associated with DNA repair), GSTP1 (associated with platinum detoxification), and TS, TP, and DPD (associated with 5-fluorouracil metabolism) – was not associated with any of the outcomes studied.

"Biomarker studies are feasible within cooperative groups," commented Dr. Bohanes, but adequate tissue was available for only 55 of 92 eligible patients. Hence, "future trials need to request additional endoscopic biopsies to allow for sufficient tumor tissue collection."

A study shortcoming was an inability to determine whether ERCC1 expression correlates with disease stage, he acknowledged. "The design of this study unfortunately did not require preoperative endoscopic ultrasound because it was thought that it would have hampered the recruitment of this trial," he said. "And often, in the community setting, endoscopic ultrasound is not available."

Also, the study could not determine whether ERCC1 expression is a prognostic marker. "We would need a control arm without platinum agent," he noted.

"I think that the patients with high expression are not benefiting from this treatment" and should be treated with alternative treatments, commented Dr. Heinz-Josef Lenz, senior investigator and chair of the gastrointestinal oncology program at the University of Southern California. "We have choices, and I think that would certainly be part of the new concept and design going forward."

He agreed with an attendee that recruiting patients with esophageal and gastroesophageal cancer to randomized trials has been difficult in the past and it might therefore take many years to obtain important biomarker data. But adaptive trial designs are addressing this issue.

"I think we are incorporating now more technologies with the design, which may be more flexible to adapt new findings so that we are not stuck for the next 3 or 5 years to a trial because of low accrual," he said.

Dr. Bohanes reported that he had no relevant conflicts of interest. Dr. Lenz reported having relationships with Response Genetics Inc. and with Sanofi-Aventis, manufacturer of oxaliplatin (Eloxatin).

SAN FRANCISCO – Pretreatment expression of ERCC1 in localized esophageal and gastroesophageal adenocarcinomas is a marker for outcomes among patients given trimodality therapy that includes oxaliplatin-based chemoradiation, investigators reported from a prospective study.

Fully 58% of the 55 patients studied from the Southwest Oncology Group (SWOG) S0356 trial had tumors expressing a high level of mRNA for ERCC1, a key gene in the repair of platinum- and radiation-induced DNA damage.

Compared with their counterparts whose tumors had low expression, these patients were nearly three times more likely to experience progression and more than twice as likely to die, according to results reported at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.

"ERCC1 mRNA level is a very promising pretreatment biomarker in patients with localized esophageal and gastroesophageal adenocarcinoma treated with trimodality treatment," asserted lead investigator Dr. Pierre O. Bohanes. "Based on these and published data, the SWOG is planning a prospective biomarker-driven clinical trial."

"In contrast to the growing number of predictive biomarkers for anticancer agents, there are no established biomarkers to select patients who will benefit most from chemoradiation," he noted. "Utilization of predictive biomarkers to select therapy should lead to higher cure rates."

The phase II trial, which was largely community based, enrolled patients with clinical stage II or III esophageal or gastroesophageal junction adenocarcinoma. They underwent tumor biopsy, then chemoradiation (oxaliplatin, 5-fluorouracil, and 45-Gy external beam radiation), then surgery, and finally more chemotherapy (oxaliplatin and 5-fluorouracil).

Response Genetics Inc., manufacturer of several biomarker assays, analyzed tumor ERCC1 mRNA expression for the 55 patients who had sufficient pretreatment tumor tissue. Laser-capture microdissection was used to ensure that only tumor cells were analyzed.

"ERCC1 has been shown to be a critical gene in DNA repair," Dr. Bohanes explained. "ERCC1 is involved in the nucleotide excision repair pathway, which recognizes and removes platinum-induced DNA adducts." Higher expression is associated with resistance to platinum compounds, including cisplatin, oxaliplatin, and carboplatin.

"Also more recently, ERCC1 has been shown to be involved in the double-strand break repair pathway, which repairs radiation-induced damage," he further observed.

Tumors were classified as having a high or low level of ERCC1 expression using a cutoff mRNA level of greater than 1.7 for high expression, as established in previous studies.

The 55 patients studied had a median age of 64 years. Most were men (93%) and white (94%), and had esophageal tumors (62%). One-fourth of them were found to have a pathological complete response at the time of surgery.

The median duration of follow-up was 36.8 months, reported Dr. Bohanes, a research fellow in medical oncology at the University of Southern California in Los Angeles.

Results showed that patients having high vs. low tumor expression of ERCC1 had a nearly tripled risk of progression (hazard ratio, 2.97; P = .006). The median duration of progression-free survival was 14.8 months for the former but was not reached for the latter. Corresponding 2-year rates of progression-free survival were 17% and 67%.

Similarly, patients with tumors having high vs. low expression of ERCC1 had a more than doubling of the risk of death (HR, 2.32; P = .047).The median duration of overall survival was 22.4 months for the former but was not reached for the latter. Corresponding 2-year rates of overall survival were 37% and 72%.

Expression of ERCC1 was not associated with pathological complete response. Also, expression of a host of other genes – XPD and RRM1 (associated with DNA repair), GSTP1 (associated with platinum detoxification), and TS, TP, and DPD (associated with 5-fluorouracil metabolism) – was not associated with any of the outcomes studied.

"Biomarker studies are feasible within cooperative groups," commented Dr. Bohanes, but adequate tissue was available for only 55 of 92 eligible patients. Hence, "future trials need to request additional endoscopic biopsies to allow for sufficient tumor tissue collection."

A study shortcoming was an inability to determine whether ERCC1 expression correlates with disease stage, he acknowledged. "The design of this study unfortunately did not require preoperative endoscopic ultrasound because it was thought that it would have hampered the recruitment of this trial," he said. "And often, in the community setting, endoscopic ultrasound is not available."

Also, the study could not determine whether ERCC1 expression is a prognostic marker. "We would need a control arm without platinum agent," he noted.

"I think that the patients with high expression are not benefiting from this treatment" and should be treated with alternative treatments, commented Dr. Heinz-Josef Lenz, senior investigator and chair of the gastrointestinal oncology program at the University of Southern California. "We have choices, and I think that would certainly be part of the new concept and design going forward."

He agreed with an attendee that recruiting patients with esophageal and gastroesophageal cancer to randomized trials has been difficult in the past and it might therefore take many years to obtain important biomarker data. But adaptive trial designs are addressing this issue.

"I think we are incorporating now more technologies with the design, which may be more flexible to adapt new findings so that we are not stuck for the next 3 or 5 years to a trial because of low accrual," he said.

Dr. Bohanes reported that he had no relevant conflicts of interest. Dr. Lenz reported having relationships with Response Genetics Inc. and with Sanofi-Aventis, manufacturer of oxaliplatin (Eloxatin).

SAN FRANCISCO – Pretreatment expression of ERCC1 in localized esophageal and gastroesophageal adenocarcinomas is a marker for outcomes among patients given trimodality therapy that includes oxaliplatin-based chemoradiation, investigators reported from a prospective study.

Fully 58% of the 55 patients studied from the Southwest Oncology Group (SWOG) S0356 trial had tumors expressing a high level of mRNA for ERCC1, a key gene in the repair of platinum- and radiation-induced DNA damage.

Compared with their counterparts whose tumors had low expression, these patients were nearly three times more likely to experience progression and more than twice as likely to die, according to results reported at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.

"ERCC1 mRNA level is a very promising pretreatment biomarker in patients with localized esophageal and gastroesophageal adenocarcinoma treated with trimodality treatment," asserted lead investigator Dr. Pierre O. Bohanes. "Based on these and published data, the SWOG is planning a prospective biomarker-driven clinical trial."

"In contrast to the growing number of predictive biomarkers for anticancer agents, there are no established biomarkers to select patients who will benefit most from chemoradiation," he noted. "Utilization of predictive biomarkers to select therapy should lead to higher cure rates."

The phase II trial, which was largely community based, enrolled patients with clinical stage II or III esophageal or gastroesophageal junction adenocarcinoma. They underwent tumor biopsy, then chemoradiation (oxaliplatin, 5-fluorouracil, and 45-Gy external beam radiation), then surgery, and finally more chemotherapy (oxaliplatin and 5-fluorouracil).

Response Genetics Inc., manufacturer of several biomarker assays, analyzed tumor ERCC1 mRNA expression for the 55 patients who had sufficient pretreatment tumor tissue. Laser-capture microdissection was used to ensure that only tumor cells were analyzed.

"ERCC1 has been shown to be a critical gene in DNA repair," Dr. Bohanes explained. "ERCC1 is involved in the nucleotide excision repair pathway, which recognizes and removes platinum-induced DNA adducts." Higher expression is associated with resistance to platinum compounds, including cisplatin, oxaliplatin, and carboplatin.

"Also more recently, ERCC1 has been shown to be involved in the double-strand break repair pathway, which repairs radiation-induced damage," he further observed.

Tumors were classified as having a high or low level of ERCC1 expression using a cutoff mRNA level of greater than 1.7 for high expression, as established in previous studies.

The 55 patients studied had a median age of 64 years. Most were men (93%) and white (94%), and had esophageal tumors (62%). One-fourth of them were found to have a pathological complete response at the time of surgery.

The median duration of follow-up was 36.8 months, reported Dr. Bohanes, a research fellow in medical oncology at the University of Southern California in Los Angeles.

Results showed that patients having high vs. low tumor expression of ERCC1 had a nearly tripled risk of progression (hazard ratio, 2.97; P = .006). The median duration of progression-free survival was 14.8 months for the former but was not reached for the latter. Corresponding 2-year rates of progression-free survival were 17% and 67%.

Similarly, patients with tumors having high vs. low expression of ERCC1 had a more than doubling of the risk of death (HR, 2.32; P = .047).The median duration of overall survival was 22.4 months for the former but was not reached for the latter. Corresponding 2-year rates of overall survival were 37% and 72%.

Expression of ERCC1 was not associated with pathological complete response. Also, expression of a host of other genes – XPD and RRM1 (associated with DNA repair), GSTP1 (associated with platinum detoxification), and TS, TP, and DPD (associated with 5-fluorouracil metabolism) – was not associated with any of the outcomes studied.

"Biomarker studies are feasible within cooperative groups," commented Dr. Bohanes, but adequate tissue was available for only 55 of 92 eligible patients. Hence, "future trials need to request additional endoscopic biopsies to allow for sufficient tumor tissue collection."

A study shortcoming was an inability to determine whether ERCC1 expression correlates with disease stage, he acknowledged. "The design of this study unfortunately did not require preoperative endoscopic ultrasound because it was thought that it would have hampered the recruitment of this trial," he said. "And often, in the community setting, endoscopic ultrasound is not available."

Also, the study could not determine whether ERCC1 expression is a prognostic marker. "We would need a control arm without platinum agent," he noted.

"I think that the patients with high expression are not benefiting from this treatment" and should be treated with alternative treatments, commented Dr. Heinz-Josef Lenz, senior investigator and chair of the gastrointestinal oncology program at the University of Southern California. "We have choices, and I think that would certainly be part of the new concept and design going forward."

He agreed with an attendee that recruiting patients with esophageal and gastroesophageal cancer to randomized trials has been difficult in the past and it might therefore take many years to obtain important biomarker data. But adaptive trial designs are addressing this issue.

"I think we are incorporating now more technologies with the design, which may be more flexible to adapt new findings so that we are not stuck for the next 3 or 5 years to a trial because of low accrual," he said.

Dr. Bohanes reported that he had no relevant conflicts of interest. Dr. Lenz reported having relationships with Response Genetics Inc. and with Sanofi-Aventis, manufacturer of oxaliplatin (Eloxatin).

SAN FRANCISCO – Pretreatment expression of ERCC1 in localized esophageal and gastroesophageal adenocarcinomas is a marker for outcomes among patients given trimodality therapy that includes oxaliplatin-based chemoradiation, investigators reported from a prospective study.

Fully 58% of the 55 patients studied from the Southwest Oncology Group (SWOG) S0356 trial had tumors expressing a high level of mRNA for ERCC1, a key gene in the repair of platinum- and radiation-induced DNA damage.

Compared with their counterparts whose tumors had low expression, these patients were nearly three times more likely to experience progression and more than twice as likely to die, according to results reported at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.

"ERCC1 mRNA level is a very promising pretreatment biomarker in patients with localized esophageal and gastroesophageal adenocarcinoma treated with trimodality treatment," asserted lead investigator Dr. Pierre O. Bohanes. "Based on these and published data, the SWOG is planning a prospective biomarker-driven clinical trial."

"In contrast to the growing number of predictive biomarkers for anticancer agents, there are no established biomarkers to select patients who will benefit most from chemoradiation," he noted. "Utilization of predictive biomarkers to select therapy should lead to higher cure rates."

The phase II trial, which was largely community based, enrolled patients with clinical stage II or III esophageal or gastroesophageal junction adenocarcinoma. They underwent tumor biopsy, then chemoradiation (oxaliplatin, 5-fluorouracil, and 45-Gy external beam radiation), then surgery, and finally more chemotherapy (oxaliplatin and 5-fluorouracil).

Response Genetics Inc., manufacturer of several biomarker assays, analyzed tumor ERCC1 mRNA expression for the 55 patients who had sufficient pretreatment tumor tissue. Laser-capture microdissection was used to ensure that only tumor cells were analyzed.

"ERCC1 has been shown to be a critical gene in DNA repair," Dr. Bohanes explained. "ERCC1 is involved in the nucleotide excision repair pathway, which recognizes and removes platinum-induced DNA adducts." Higher expression is associated with resistance to platinum compounds, including cisplatin, oxaliplatin, and carboplatin.

"Also more recently, ERCC1 has been shown to be involved in the double-strand break repair pathway, which repairs radiation-induced damage," he further observed.

Tumors were classified as having a high or low level of ERCC1 expression using a cutoff mRNA level of greater than 1.7 for high expression, as established in previous studies.

The 55 patients studied had a median age of 64 years. Most were men (93%) and white (94%), and had esophageal tumors (62%). One-fourth of them were found to have a pathological complete response at the time of surgery.

The median duration of follow-up was 36.8 months, reported Dr. Bohanes, a research fellow in medical oncology at the University of Southern California in Los Angeles.

Results showed that patients having high vs. low tumor expression of ERCC1 had a nearly tripled risk of progression (hazard ratio, 2.97; P = .006). The median duration of progression-free survival was 14.8 months for the former but was not reached for the latter. Corresponding 2-year rates of progression-free survival were 17% and 67%.

Similarly, patients with tumors having high vs. low expression of ERCC1 had a more than doubling of the risk of death (HR, 2.32; P = .047).The median duration of overall survival was 22.4 months for the former but was not reached for the latter. Corresponding 2-year rates of overall survival were 37% and 72%.

Expression of ERCC1 was not associated with pathological complete response. Also, expression of a host of other genes – XPD and RRM1 (associated with DNA repair), GSTP1 (associated with platinum detoxification), and TS, TP, and DPD (associated with 5-fluorouracil metabolism) – was not associated with any of the outcomes studied.

"Biomarker studies are feasible within cooperative groups," commented Dr. Bohanes, but adequate tissue was available for only 55 of 92 eligible patients. Hence, "future trials need to request additional endoscopic biopsies to allow for sufficient tumor tissue collection."

A study shortcoming was an inability to determine whether ERCC1 expression correlates with disease stage, he acknowledged. "The design of this study unfortunately did not require preoperative endoscopic ultrasound because it was thought that it would have hampered the recruitment of this trial," he said. "And often, in the community setting, endoscopic ultrasound is not available."

Also, the study could not determine whether ERCC1 expression is a prognostic marker. "We would need a control arm without platinum agent," he noted.

"I think that the patients with high expression are not benefiting from this treatment" and should be treated with alternative treatments, commented Dr. Heinz-Josef Lenz, senior investigator and chair of the gastrointestinal oncology program at the University of Southern California. "We have choices, and I think that would certainly be part of the new concept and design going forward."

He agreed with an attendee that recruiting patients with esophageal and gastroesophageal cancer to randomized trials has been difficult in the past and it might therefore take many years to obtain important biomarker data. But adaptive trial designs are addressing this issue.

"I think we are incorporating now more technologies with the design, which may be more flexible to adapt new findings so that we are not stuck for the next 3 or 5 years to a trial because of low accrual," he said.

Dr. Bohanes reported that he had no relevant conflicts of interest. Dr. Lenz reported having relationships with Response Genetics Inc. and with Sanofi-Aventis, manufacturer of oxaliplatin (Eloxatin).

SAN FRANCISCO – Combining monoclonal antibodies that target different cellular signaling pathways may improve antitumor activity in patients with metastatic colorectal cancer, according to the first results of an ongoing, randomized, phase II trial.

The combination of panitumumab (Vectibix, which targets the epidermal growth factor receptor [EGFR] and inhibits its downstream signaling) plus investigational rilotumumab (AMG-102, which targets hepatocyte growth factor [HGF] and inhibits downstream c-Met signaling) yielded a better objective response rate than did panitumumab alone (31% vs. 21%).

In contrast, the combination of panitumumab plus investigational ganitumab (AMG-479, which targets the insulinlike growth factor I receptor [IGF-IR] and inhibits downstream signaling through the PI3K/AKT and MAPK pathways) improved little on the rate that was seen with just panitumumab (22% vs. 21%).

"This is the first study to show promising evidence of the efficacy by an HGF inhibitor, rilotumumab, ... when combined with panitumumab in patients with pretreated metastatic colorectal cancer ... [of] KRAS wild type," lead investigator Dr. Eric Van Cutsem told attendees at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.

"Preclinical studies indeed have indicated that there is a complex interdependence between the HGF/c-Met and the IGF-IR and EGFR pathways," he noted, explaining the trial’s rationale. "Combinations of agents that block these receptors are being investigated for their potential to generate additive or synergistic anticancer effects."

To be eligible for the trial, patients had to have metastatic colorectal cancer with wild-type KRAS (because mutations in KRAS confer panitumumab resistance); progression during or after prior irinotecan- and/or oxaliplatin-based chemotherapy; a glycosylated hemoglobin level of 8% or less; a good performance status; and no previous EGFR, c-Met, or IGF-IR inhibitor therapy.

The patients were randomly assigned in nearly equal numbers to receive panitumumab (6 mg/kg every 2 weeks) in combination with placebo, with rilotumumab (10 mg/kg every 2 weeks), or with ganitumab (12 mg/kg every 2 weeks).

All three antibodies are manufactured by Amgen. Panitumumab is approved by the Food and Drug Administration for the treatment of EGFR-expressing metastatic colorectal cancer that has progressed during or after conventional chemotherapy. The other two antibodies are investigational.

The trial’s primary end point was the objective response rate as determined with modified RECIST (Response Evaluation Criteria in Solid Tumors). "It’s important to mention that all responses were required to be confirmed at least 4 weeks after response criteria were first met," noted Dr. Van Cutsem, head of digestive oncology at the University Hospital Gasthuisberg in Leuven, Belgium.

Median follow-up was 6.9 months, as of the data cutoff for the analyses reported. Some 58% of the 142 patients enrolled were men, and the average age was about 58 years. Nearly two-thirds had metastases in the liver plus other sites. About a third had received three or more prior lines of therapy.

All of the responses were partial ones. The median duration of response was 3.7 months with panitumumab alone, 5.1 months with panitumumab plus rilotumumab, and 3.7 months with panitumumab plus ganitumab. The corresponding values for the disease control rate (complete response, partial response, and stable disease) were 56%, 71%, and 61%.

The median duration of progression-free survival was 3.7 months with panitumumab. This compared with 5.2 months with panitumumab-rilotumumab and 5.3 months with panitumumab-ganitumab.

"In general, the safety and toxicity was acceptable in all three arms of this study," commented Dr. Van Cutsem. The overall rate of grade 3/4 adverse events was 52% with panitumumab alone and higher with panitumumab-rilotumumab (71%) and with panitumumab-ganitumab (63%).

Although the nature of these grade 3/4 events was generally similar across groups, the addition of rilotumumab to panitumumab increased the rate of rash (from 8% to 29%), and the addition of ganitumab to panitumumab increased the rate of hypomagnesemia (from 2% to 15%).

"We hope to report in future meetings and manuscripts further details and especially also analysis of biomarkers for response in serum and tissue samples that have been collected and that are underway," Dr. Van Cutsem concluded.

"I am very proud to say ... that we do have movement forward," said discussant Dr. Johanna C. Bendell, director of GI oncology research with the Sarah Cannon Research Institute in Nashville, Tenn. "Targeting the c-Met or HGF pathway in combination with anti-EGFR therapy looks promising for colorectal cancer in this small study."

Targeting both EGFR and Met signaling has been tapped with marked clinical benefit in patients with non–small cell lung cancer who have high Met expression (Ann. Oncol. 2010;21[suppl. 8]:viii7 [abstract LBA15]), she noted. But those whose tumors had low Met expression actually fared worse when they were given dual therapy than when they were given anti-EGFR therapy alone.

"We do await further progression-free survival data, but the early look looks quite interesting," concluded Dr. Bendell. "Also, we are very interested in the biomarker data that will be associated with this looking at whether or not – like we see in non–small cell lung cancer – if over–Met expression has some sort of effect on how patients do with colorectal cancer."

Amgen sponsored the trial. Dr. Van Cutsem reported receiving research funding from Amgen. Dr. Bendell reported having no relevant conflicts of interest.

SAN FRANCISCO – Combining monoclonal antibodies that target different cellular signaling pathways may improve antitumor activity in patients with metastatic colorectal cancer, according to the first results of an ongoing, randomized, phase II trial.

The combination of panitumumab (Vectibix, which targets the epidermal growth factor receptor [EGFR] and inhibits its downstream signaling) plus investigational rilotumumab (AMG-102, which targets hepatocyte growth factor [HGF] and inhibits downstream c-Met signaling) yielded a better objective response rate than did panitumumab alone (31% vs. 21%).

In contrast, the combination of panitumumab plus investigational ganitumab (AMG-479, which targets the insulinlike growth factor I receptor [IGF-IR] and inhibits downstream signaling through the PI3K/AKT and MAPK pathways) improved little on the rate that was seen with just panitumumab (22% vs. 21%).

"This is the first study to show promising evidence of the efficacy by an HGF inhibitor, rilotumumab, ... when combined with panitumumab in patients with pretreated metastatic colorectal cancer ... [of] KRAS wild type," lead investigator Dr. Eric Van Cutsem told attendees at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.

"Preclinical studies indeed have indicated that there is a complex interdependence between the HGF/c-Met and the IGF-IR and EGFR pathways," he noted, explaining the trial’s rationale. "Combinations of agents that block these receptors are being investigated for their potential to generate additive or synergistic anticancer effects."

To be eligible for the trial, patients had to have metastatic colorectal cancer with wild-type KRAS (because mutations in KRAS confer panitumumab resistance); progression during or after prior irinotecan- and/or oxaliplatin-based chemotherapy; a glycosylated hemoglobin level of 8% or less; a good performance status; and no previous EGFR, c-Met, or IGF-IR inhibitor therapy.

The patients were randomly assigned in nearly equal numbers to receive panitumumab (6 mg/kg every 2 weeks) in combination with placebo, with rilotumumab (10 mg/kg every 2 weeks), or with ganitumab (12 mg/kg every 2 weeks).

All three antibodies are manufactured by Amgen. Panitumumab is approved by the Food and Drug Administration for the treatment of EGFR-expressing metastatic colorectal cancer that has progressed during or after conventional chemotherapy. The other two antibodies are investigational.

The trial’s primary end point was the objective response rate as determined with modified RECIST (Response Evaluation Criteria in Solid Tumors). "It’s important to mention that all responses were required to be confirmed at least 4 weeks after response criteria were first met," noted Dr. Van Cutsem, head of digestive oncology at the University Hospital Gasthuisberg in Leuven, Belgium.

Median follow-up was 6.9 months, as of the data cutoff for the analyses reported. Some 58% of the 142 patients enrolled were men, and the average age was about 58 years. Nearly two-thirds had metastases in the liver plus other sites. About a third had received three or more prior lines of therapy.

All of the responses were partial ones. The median duration of response was 3.7 months with panitumumab alone, 5.1 months with panitumumab plus rilotumumab, and 3.7 months with panitumumab plus ganitumab. The corresponding values for the disease control rate (complete response, partial response, and stable disease) were 56%, 71%, and 61%.

The median duration of progression-free survival was 3.7 months with panitumumab. This compared with 5.2 months with panitumumab-rilotumumab and 5.3 months with panitumumab-ganitumab.

"In general, the safety and toxicity was acceptable in all three arms of this study," commented Dr. Van Cutsem. The overall rate of grade 3/4 adverse events was 52% with panitumumab alone and higher with panitumumab-rilotumumab (71%) and with panitumumab-ganitumab (63%).

Although the nature of these grade 3/4 events was generally similar across groups, the addition of rilotumumab to panitumumab increased the rate of rash (from 8% to 29%), and the addition of ganitumab to panitumumab increased the rate of hypomagnesemia (from 2% to 15%).

"We hope to report in future meetings and manuscripts further details and especially also analysis of biomarkers for response in serum and tissue samples that have been collected and that are underway," Dr. Van Cutsem concluded.

"I am very proud to say ... that we do have movement forward," said discussant Dr. Johanna C. Bendell, director of GI oncology research with the Sarah Cannon Research Institute in Nashville, Tenn. "Targeting the c-Met or HGF pathway in combination with anti-EGFR therapy looks promising for colorectal cancer in this small study."

Targeting both EGFR and Met signaling has been tapped with marked clinical benefit in patients with non–small cell lung cancer who have high Met expression (Ann. Oncol. 2010;21[suppl. 8]:viii7 [abstract LBA15]), she noted. But those whose tumors had low Met expression actually fared worse when they were given dual therapy than when they were given anti-EGFR therapy alone.

"We do await further progression-free survival data, but the early look looks quite interesting," concluded Dr. Bendell. "Also, we are very interested in the biomarker data that will be associated with this looking at whether or not – like we see in non–small cell lung cancer – if over–Met expression has some sort of effect on how patients do with colorectal cancer."

Amgen sponsored the trial. Dr. Van Cutsem reported receiving research funding from Amgen. Dr. Bendell reported having no relevant conflicts of interest.

SAN FRANCISCO – Combining monoclonal antibodies that target different cellular signaling pathways may improve antitumor activity in patients with metastatic colorectal cancer, according to the first results of an ongoing, randomized, phase II trial.

The combination of panitumumab (Vectibix, which targets the epidermal growth factor receptor [EGFR] and inhibits its downstream signaling) plus investigational rilotumumab (AMG-102, which targets hepatocyte growth factor [HGF] and inhibits downstream c-Met signaling) yielded a better objective response rate than did panitumumab alone (31% vs. 21%).

In contrast, the combination of panitumumab plus investigational ganitumab (AMG-479, which targets the insulinlike growth factor I receptor [IGF-IR] and inhibits downstream signaling through the PI3K/AKT and MAPK pathways) improved little on the rate that was seen with just panitumumab (22% vs. 21%).

"This is the first study to show promising evidence of the efficacy by an HGF inhibitor, rilotumumab, ... when combined with panitumumab in patients with pretreated metastatic colorectal cancer ... [of] KRAS wild type," lead investigator Dr. Eric Van Cutsem told attendees at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.

"Preclinical studies indeed have indicated that there is a complex interdependence between the HGF/c-Met and the IGF-IR and EGFR pathways," he noted, explaining the trial’s rationale. "Combinations of agents that block these receptors are being investigated for their potential to generate additive or synergistic anticancer effects."

To be eligible for the trial, patients had to have metastatic colorectal cancer with wild-type KRAS (because mutations in KRAS confer panitumumab resistance); progression during or after prior irinotecan- and/or oxaliplatin-based chemotherapy; a glycosylated hemoglobin level of 8% or less; a good performance status; and no previous EGFR, c-Met, or IGF-IR inhibitor therapy.

The patients were randomly assigned in nearly equal numbers to receive panitumumab (6 mg/kg every 2 weeks) in combination with placebo, with rilotumumab (10 mg/kg every 2 weeks), or with ganitumab (12 mg/kg every 2 weeks).

All three antibodies are manufactured by Amgen. Panitumumab is approved by the Food and Drug Administration for the treatment of EGFR-expressing metastatic colorectal cancer that has progressed during or after conventional chemotherapy. The other two antibodies are investigational.

The trial’s primary end point was the objective response rate as determined with modified RECIST (Response Evaluation Criteria in Solid Tumors). "It’s important to mention that all responses were required to be confirmed at least 4 weeks after response criteria were first met," noted Dr. Van Cutsem, head of digestive oncology at the University Hospital Gasthuisberg in Leuven, Belgium.

Median follow-up was 6.9 months, as of the data cutoff for the analyses reported. Some 58% of the 142 patients enrolled were men, and the average age was about 58 years. Nearly two-thirds had metastases in the liver plus other sites. About a third had received three or more prior lines of therapy.

All of the responses were partial ones. The median duration of response was 3.7 months with panitumumab alone, 5.1 months with panitumumab plus rilotumumab, and 3.7 months with panitumumab plus ganitumab. The corresponding values for the disease control rate (complete response, partial response, and stable disease) were 56%, 71%, and 61%.

The median duration of progression-free survival was 3.7 months with panitumumab. This compared with 5.2 months with panitumumab-rilotumumab and 5.3 months with panitumumab-ganitumab.

"In general, the safety and toxicity was acceptable in all three arms of this study," commented Dr. Van Cutsem. The overall rate of grade 3/4 adverse events was 52% with panitumumab alone and higher with panitumumab-rilotumumab (71%) and with panitumumab-ganitumab (63%).

Although the nature of these grade 3/4 events was generally similar across groups, the addition of rilotumumab to panitumumab increased the rate of rash (from 8% to 29%), and the addition of ganitumab to panitumumab increased the rate of hypomagnesemia (from 2% to 15%).

"We hope to report in future meetings and manuscripts further details and especially also analysis of biomarkers for response in serum and tissue samples that have been collected and that are underway," Dr. Van Cutsem concluded.

"I am very proud to say ... that we do have movement forward," said discussant Dr. Johanna C. Bendell, director of GI oncology research with the Sarah Cannon Research Institute in Nashville, Tenn. "Targeting the c-Met or HGF pathway in combination with anti-EGFR therapy looks promising for colorectal cancer in this small study."

Targeting both EGFR and Met signaling has been tapped with marked clinical benefit in patients with non–small cell lung cancer who have high Met expression (Ann. Oncol. 2010;21[suppl. 8]:viii7 [abstract LBA15]), she noted. But those whose tumors had low Met expression actually fared worse when they were given dual therapy than when they were given anti-EGFR therapy alone.

"We do await further progression-free survival data, but the early look looks quite interesting," concluded Dr. Bendell. "Also, we are very interested in the biomarker data that will be associated with this looking at whether or not – like we see in non–small cell lung cancer – if over–Met expression has some sort of effect on how patients do with colorectal cancer."

Amgen sponsored the trial. Dr. Van Cutsem reported receiving research funding from Amgen. Dr. Bendell reported having no relevant conflicts of interest.