Paul J. Catalano

Bevacizumab in Combination With Oxaliplatin, Fluorouracil, and Leucovorin (FOLFOX4) for Previously Treated Metastatic Colorectal Cancer: Results From the Eastern Cooperative Oncology Group Study E3200

PURPOSE Colorectal cancer is the second leading cause of cancer mortality in the United States. Antiangiogenic therapy with bevacizumab combined with chemotherapy improves survival in previously untreated metastatic colorectal cancer. This study was conducted to determine the effect of bevacizumab (at 10 mg/kg) on survival duration for oxaliplatin-based chemotherapy in patients with previously treated metastatic colorectal cancer. PATIENTS AND METHODS Eight hundred twenty-nine metastatic colorectal cancer patients previously treated with a fluoropyrimidine and irinotecan were randomly assigned to one of three treatment groups: oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) with bevacizumab; FOLFOX4 without bevacizumab; or bevacizumab alone. The primary end point was overall survival, with additional determinations of progression-free survival, response, and toxicity. RESULTS The median duration of survival for the group treated with FOLFOX4 and bevacizumab was 12.9 months compared with 10.8 months for the group treated with FOLFOX4 alone (corresponding hazard ratio for death = 0.75; P = .0011), and 10.2 months for those treated with bevacizumab alone. The median progression-free survival for the group treated with FOLFOX4 in combination with bevacizumab was 7.3 months, compared with 4.7 months for the group treated with FOLFOX4 alone (corresponding hazard ratio for progression = 0.61; P < .0001), and 2.7 months for those treated with bevacizumab alone. The corresponding overall response rates were 22.7%, 8.6%, and 3.3%, respectively (P < .0001 for FOLFOX4 with bevacizumab v FOLFOX4 comparison). Bevacizumab was associated with hypertension, bleeding, and vomiting. CONCLUSION The addition of bevacizumab to oxaliplatin, fluorouracil, and leucovorin improves survival duration for patients with previously treated metastatic colorectal.

Colon Cancer Survival Is Associated With Increasing Number of Lymph Nodes Analyzed: A Secondary Survey of Intergroup Trial INT-0089

PURPOSE To determine the relationship, in patients with adenocarcinoma of the colon, between survival and the number of lymph nodes analyzed from surgical specimens. PATIENTS AND METHODS Intergroup Trial INT-0089 is a mature trial of adjuvant chemotherapy for high-risk patients with stage II and stage III colon cancer. We performed a secondary analysis of this group with overall survival (OS) as the main end point. Cause-specific survival (CSS) and disease-free survival were secondary end points. Rates for these outcome measures were estimated using Kaplan-Meier methodology. Log-rank test was used to compare overall curves, and Cox proportional hazards regression was used to multivariately assess predictors of outcome. RESULTS The median number of lymph nodes removed at colectomy was 11 (range, one to 87). Of the 3411 assessable patients, 648 had no evidence of lymph node metastasis. Multivariate analyses were performed on the node-positive and node-negative groups separately to ascertain the effect of lymph node removal. Survival decreased with increasing number of lymph node involvement (P =.0001 for all three survival end points). After controlling for the number of nodes involved, survival increased as more nodes were analyzed (P =.0001 for all three end points). Even when no nodes were involved, OS and CSS improved as more lymph nodes were analyzed (P =.0005 and P =.007, respectively). CONCLUSION The number of lymph nodes analyzed for staging colon cancers is, itself, a prognostic variable on outcome. The impact of this variable is such that it may be an important variable to include in evaluating future trials.

Molecular predictors of survival after adjuvant chemotherapy for colon cancer

BACKGROUND Adjuvant chemotherapy improves survival among patients with stage III colon cancer, but no reliable molecular predictors of outcome have been identified. METHODS We evaluated loss of chromosomal material (also called loss of heterozygosity or allelic loss) from chromosomes 18q, 17p, and 8p; cellular levels of p53 and p21(WAF1/CIP1) proteins; and microsatellite instability as molecular markers. We analyzed tumor tissue from 460 patients with stage III and high-risk stage II colon cancer who had been treated with various combinations of adjuvant fluorouracil, leucovorin, and levamisole to determine the ability of these markers to predict survival. RESULTS Loss of heterozygosity at 18q was present in 155 of 319 cancers (49 percent). High levels of microsatellite instability were found in 62 of 298 tumors (21 percent), and 38 of these 62 tumors (61 percent) had a mutation of the gene for the type II receptor for transforming growth factor beta1 (TGF-beta1). Among patients with microsatellite-stable stage III cancer, five-year overall survival after fluorouracil-based chemotherapy was 74 percent in those whose cancer retained 18q alleles and 50 percent in those with loss of 18q alleles (relative risk of death with loss at 18q, 2.75; 95 percent confidence interval, 1.34 to 5.65; P=0.006). The five-year survival rate among patients whose cancer had high levels of microsatellite instability was 74 percent in the presence of a mutated gene for the type II receptor for TGF-beta1 and 46 percent if the tumor did not have this mutation (relative risk of death, 2.90; 95 percent confidence interval, 1.14 to 7.35; P=0.03). CONCLUSIONS Retention of 18q alleles in microsatellite-stable cancers and mutation of the gene for the type II receptor for TGF-beta1 in cancers with high levels of microsatellite instability point to a favorable outcome after adjuvant chemotherapy with fluorouracil-based regimens for stage III colon cancer.

Phase III Study of Gemcitabine in Combination With Fluorouracil Versus Gemcitabine Alone in Patients With Advanced Pancreatic Carcinoma: Eastern Cooperative Oncology Group Trial E2297

PURPOSE Gemcitabine is generally considered to constitute first-line therapy for pancreatic cancer. To determine whether the addition of fluorouracil (5-FU) improves on the results from single-agent gemcitabine, the Eastern Cooperative Oncology Group (ECOG) compared gemcitabine plus bolus 5-FU with gemcitabine alone for patients with advanced pancreatic carcinoma. PATIENTS AND METHODS This trial involved patients with biopsy-proven, advanced carcinoma of the pancreas not amenable to surgical resection. Patients were randomized to receive either gemcitabine alone (1,000 mg/m(2)/wk) weekly for 3 weeks of every 4 or to receive gemcitabine (1,000 mg/m(2)/wk) followed by 5-FU (600 mg/m(2)/wk) weekly on the same schedule. The primary end point of the trial was survival, with secondary end points of time to progression and response rate. RESULTS Of 327 patients enrolled over 18 months, 322 were eligible. Overall, the median survival was 5.4 months for gemcitabine alone and 6.7 months for gemcitabine plus 5-FU (P =.09). Progression-free survival for gemcitabine alone was 2.2 months, compared with 3.4 months for gemcitabine plus 5-FU (P =.022). Objective responses were uncommon and were observed in only 5.6% of patients treated with gemcitabine and 6.9% of patients treated with gemcitabine plus 5-FU. Most toxicities were hematologic or gastrointestinal; no significant differences were noted between the two treatment arms. CONCLUSION 5-FU, administered in conjunction with gemcitabine, did not improve the median survival of patients with advanced pancreatic carcinoma compared with single-agent gemcitabine. Further studies with other combinations of gemcitabine and 5-FU are not compelling, and clinical trial resources should address other combinations and novel agents.

Disease-Free Survival Versus Overall Survival As a Primary End Point for Adjuvant Colon Cancer Studies: Individual Patient Data From 20,898 Patients on 18 Randomized Trials

PURPOSE A traditional end point for colon adjuvant clinical trials is overall survival (OS), with 5 years demonstrating adequate follow-up. A shorter-term end point providing convincing evidence to allow treatment comparisons could significantly speed the translation of advances into practice. METHODS Individual patient data were pooled from 18 randomized phase III colon cancer adjuvant clinical trials. Trials included 43 arms, with a pooled sample size of 20,898 patients. The primary hypothesis was that disease-free survival (DFS), with 3 years of follow-up, is an appropriate primary end point to replace OS with 5 years of follow-up. RESULTS The recurrence rates for years 1 through 5 were 12%, 14%, 8%, 5%, and 3%, respectively. Median time from recurrence to death was 12 months. Eighty percent of recurrences were in the first 3 years; 91% of patients with recurrence by 3 years died before 5 years. Correlation between 3-year DFS and 5-year OS was 0.89. Comparing control versus experimental arms within each trial, the correlation between hazard ratios for DFS and OS was 0.92. Within-trial log-rank testing using both DFS and OS provided the same conclusion in 23 (92%) of 25 cases. Formal measures of surrogacy were satisfied. CONCLUSION In patients treated on phase III adjuvant colon clinical trials, DFS and OS are highly correlated, both within patients and across trials. These results suggest that DFS after 3 years of median follow-up is an appropriate end point for adjuvant colon cancer clinical trials of fluorouracil-based regimens, although marginally significant DFS improvements may not translate into significant OS benefits.

Colon Cancer Survival Is Associated With Decreasing Ratio of Metastatic to Examined Lymph Nodes

PURPOSE Colorectal cancer is the second leading cause of cancer deaths in the United States, with poor survival predicted by regional lymph node (LN) metastasis. The impact of LN ratio (LNR) on survival is unknown in this disease. PATIENTS AND METHODS We analyzed data from Intergroup trial 0089 of adjuvant chemotherapy for stage II and III patients with colon cancer, in which all patients received fluorouracil-based therapy. Survival was similar for all arms of the study, allowing us to evaluate all patients together. End points included overall survival (OS), cancer-specific survival (CSS), and disease-free survival (DFS). Multivariate analyses were performed on all patients and on groups according to LNR quartiles (LNR: < 0.05, 0.05 to 0.19, 0.2 to 0.39, and 0.4 to 1.0). Covariates included in the models were age, sex, tumor stage, grade, histology, number of positive LNs, number of LNs removed, and LNR. RESULTS The median age was 63.7 years, and the median number of LNs removed was 11. In the multivariate analysis, LNR was a significant factor for OS, DFS, and CSS in patients with 10 to 15 LN and more than 15 LN removed but not for patients with less than 10 LN removed. Using quartiles, LNR maintained its significance for all three end points when patients were grouped by node status. CONCLUSION After curative resection for colorectal cancer, the LNR is an important prognostic factor and should be used in stratification schemes for future clinical trials investigating adjuvant treatments.

Phase III, Randomized Study of Gemcitabine and Oxaliplatin Versus Gemcitabine (fixed-dose rate infusion) Compared With Gemcitabine (30-minute infusion) in Patients With Pancreatic Carcinoma E6201: A Trial of the Eastern Cooperative Oncology Group

PURPOSE Single-agent gemcitabine (GEM) is standard treatment of metastatic pancreatic cancer. Fixed-dose rate (FDR) GEM and GEM plus oxaliplatin have shown promise in early clinical trials. E6201 was designed to compare overall survival (OS) of standard weekly GEM 1,000 mg/m(2)/30 minutes versus GEM FDR 1,500 mg/m(2)/150 minutes or GEM 1,000 mg/m(2)/100 minutes/day 1 plus oxaliplatin 100 mg/m(2)/day 2 every 14 days (GEMOX). METHODS This trial included patients with metastatic or locally advanced pancreatic cancer, normal organ function, and performance status of 0 to 2. The study was designed to detect a 33% difference in median survival (hazard ratio [HR] < or = 0.75 for either of the experimental arms) with 81% power while maintaining a significance level of 2.5% in a two-sided test for each of the two primary comparisons. RESULTS Eight hundred thirty-two patients were enrolled. The median survival and 1-year survival were 4.9 months (95% CI, 4.5 to 5.6) and 16% for GEM, 6.2 months (95% CI, 5.4 to 6.9), and 21% for GEM FDR (HR, 0.83; stratified log-rank P = .04), and 5.7 months (95% CI, 4.9 to 6.5) and 21% for GEMOX (HR, 0.88; stratified log-rank P = .22). Neither of these differences met the prespecified criteria for significance. Survival was 9.2 months for patients with locally advanced disease, and 5.4 months for those with metastatic disease. Grade 3/4 neutropenia and thrombocytopenia were greatest with GEM FDR. GEMOX caused higher rates of nausea, vomiting, and neuropathy. CONCLUSION Neither GEM FDR nor GEMOX resulted in substantially improved survival or symptom benefit over standard GEM in patients with advanced pancreatic cancer.

Phase II/III Study of Doxorubicin With Fluorouracil Compared With Streptozocin With Fluorouracil or Dacarbazine in the Treatment of Advanced Carcinoid Tumors: Eastern Cooperative Oncology Group Study E1281

PURPOSE Optimal treatments for metastatic carcinoid tumor remain undefined, and the role of chemotherapy for symptomatic patients with progressive disease is uncertain. PATIENTS AND METHODS Two hundred forty-nine patients with advanced carcinoid tumors were randomized to either doxorubicin with fluorouracil (FU/DOX) or streptozocin with fluorouracil (FU/STZ). Patients crossed over to the dacarbazine (DTIC) treatment after disease progression following first-line treatment (either FU/DOX or FU/STZ), and 73 patients were assigned to one of these three treatments based on their previous treatment or on abnormal baseline cardiac or renal function. RESULTS In the randomized group, there was no difference between FU/DOX and FU/STZ in response rates (15.9% v 16%) and progression-free survival (4.5 v 5.3 months). FU/STZ (24.3 months) was superior to FU/DOX (15.7 months; P = .0267) in median survival. The response rate of crossover DTIC treatment was 8.2%, with a median survival of 11.9 months. Hematologic toxicities were the major treatment-related toxicities for both FU/DOX and FU/STZ, and mild to moderate renal toxicity was reported in 40 (34.8%) of 115 patients in the FU/STZ arm. CONCLUSION Response to all three treatment regimens were modest. FU/STZ improved survival compared with the doxorubicin-based regimen, suggesting that the combination should be considered to be an active regimen of therapy when chemotherapy is judged to be an option for selected patients with carcinoid tumors.

Impact of Diabetes Mellitus on Outcomes in Patients With Colon Cancer

PURPOSE To determine the influence of diabetes mellitus on long-term outcomes and treatment-related toxicity among patients with curatively resected colon cancer. PATIENTS AND METHODS This study was a cohort study within a large, randomized adjuvant chemotherapy trial of 3,759 patients with high-risk stage II and stage III colon cancer treated between 1988 and 1992 throughout the United States. In the cohort, 287 patients were identified as having diabetes mellitus. With a median follow-up of 9.4 years, we analyzed differences in overall survival (OS) and colon cancer recurrence as well as treatment-related toxicity between patients with diabetes and those without diabetes. RESULTS At 5 years, patients with diabetes mellitus, compared with patients without diabetes, experienced a significantly worse disease-free survival (DFS; 48% diabetics v 59% nondiabetics; P <.0001), OS (57% v 66%; P <.0001), and recurrence-free survival (RFS; 56% v 64%, P =.012). Median survival was 6.0 years and 11.3 years for diabetics and nondiabetics, respectively. Compared with patients without a history of diabetes, those with diabetes had a 42% increased risk of death from any cause (P <.0001) and 21% increased risk for recurrence (P =.05) after adjustment for other predictors of colon cancer outcome. Treatment-related toxicities were similar between the two groups, although patients with diabetes experienced an increase in treatment-related diarrhea. CONCLUSION Patients with diabetes mellitus and high-risk stage II and stage III colon cancer experienced a significantly higher rate of overall mortality and cancer recurrence, even after adjustment for other predictors of colon cancer outcome. These results underscore the need for further research to understand the mechanism that underlies this relation.

Phase III Study of Fluorouracil, Leucovorin, and Levamisole in High-Risk Stage II and III Colon Cancer: Final Report of Intergroup 0089

PURPOSE In 1990, fluorouracil (FU) plus levamisole for 1 year became standard adjuvant treatment for patients with high-risk stages II and III colon cancer. Intergroup (INT) 0089 assessed the relative contributions of leucovorin and levamisole in such patients. PATIENTS AND METHODS From 1988 to 1992, 3,794 patients were randomly assigned. Experimental treatment consisted of one of three chemotherapy regimens: the low-dose leucovorin plus FU (Mayo Clinic; LDLV) regimen, the high-dose leucovorin plus FU (Roswell Park; HDLV) regimen, and the low-dose leucovorin plus levamisole plus FU (LDLV plus LEV) regimen, each administered for 30 to 32 weeks. The control arm was levamisole plus FU (LEV) for 1 year. RESULTS After a median follow-up of 10 years, of 3,561 eligible patients, 1,691 (47%) have died and 1,330 (37%) have experienced disease recurrence; 137 (10%) of those experiencing recurrence are still alive. A total of 481 patients (13%) died without evidence of recurrence, and 1,723 (48%) are alive and disease free. Although there were toxicity differences among the four arms, none was statistically superior in disease-free or overall survival. CONCLUSION The 6- to 8-month regimens of LDLV and HDLV without levamisole used in this trial, rather than the previous standard regimen of 12 months of LEV, have become widely used. INT-0089 has long-term follow-up of the largest clinical trial of patients with high-risk colon cancer, documenting not only the durability of the treatment effects, but also the natural history of patients with high-risk colon cancer, and analyses of treatment based on age, race, and comorbid conditions such as obesity, diabetes, and second primary cancers.