Goldberg, Richard M.

Purpose The primary goal of this multicenter phase III trial was to determine whether overall survival (OS) of fluorouracil (FU) -refractory patients was noninferior when treated with second-line infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4; arm B) versus irinotecan (arm A). Cross-over to the other treatment on disease progression was mandated. Patients and Methods Patients who experienced treatment failure with one prior FU-based therapy and had not received prior irinotecan or oxaliplatin, either for metastatic disease or within 6 months of adjuvant FU therapy, were randomly assigned to arm A (irinotecan 350 or 300 mg/m2 every 3 weeks) or arm B (FOLFOX4). Results A total of 491 patients were randomly assigned (arm A, n = 245; arm B, n = 246); 288 (59%) had experienced treatment failure with FU for metastatic colorectal cancer. Two hundred twenty-seven patients (46%) received protocol-mandated third-line therapy (arm A, 43%; arm B, 57%). Median survival was 13.8 months (95% CI, 12.2 to 15.0 months) for initial treatment with FOLFOX4 and 14.3 months (95% CI, 12.0 to 15.9 months) for irinotecan (P = .38; hazard ratio = 0.92; 95% CI, 0.8 to 1.1). Response rates (RR; 28% v 15.5%; P = .0009) and time to progression (TTP; 6.2 v 4.4 months; P = .0009) were significantly superior with FOLFOX4. In the nonrandom subset of patients who crossed over, RR and TTP improvements with FOLFOX4 continued into third-line treatment. Irinotecan therapy was associated with more grade 3 nausea, vomiting, diarrhea, and febrile neutropenia; FOLFOX4 was associated with more neutropenia and paresthesias. Conclusion In patients who experienced treatment failure with front-line FU therapy, OS does not significantly differ whether second-line therapy begins with irinotecan or FOLFOX4. FOLFOX4 produces higher RR and longer TTP. Both arms had notable OS in patients who experienced treatment failure with first-line FU therapy.

PurposePerformance status (PS) is a prognostic factor in patients with metastatic colorectal cancer. Clinical trials typically enroll less than 10% of patients with a PS of 2 (PS2); thus, the benefit of systemic chemotherapy in PS2 patients is uncertain.Patients and MethodsIndividual data from 6,286 patients (509 PS2 patients) from nine clinical trials were used to compare treatment efficacy by PS. Progression-free survival (PFS), grade ≥ 3 adverse events, 60-day all-cause mortality, overall survival (OS), and response rate (RR) were explored in the full set of nine trials and in the five trials comparing first-line monotherapy with combination therapy.ResultsCompared with patients with PS of 0 or 1, PS2 patients had significantly higher rates of grade ≥ 3 nausea (8.5% v 16.4%, respectively; P < .0001) and vomiting (7.6% v 11.9%, respectively; P = .006) and 60-day all-cause mortality (2.8% v 12.0%, respectively; P < .0001). PS2 was prognostic for PFS (hazard ratio [HR] = 1.52; P < .0001; median PFS, 7.6 months for PS 0 or 1 v 4.9 months for PS2), OS (HR = 2.18; P < .0001; median OS, 17.3 months for PS 0 or 1 v 8.5 months for PS2), and RR (odds ratio = 0.61; P < .0001; 43.8% for PS 0 or 1 v 32.0% for PS2). The relative benefit and toxicity of experimental versus control treatment and monotherapy versus combination therapy were not different in PS 0 or 1 patients versus PS2 patients.ConclusionIn clinical trials, PS2 patients derive similar benefit from superior treatment as patients with PS of 0 to 1 but with an increased risk of toxicities and 12% 60-day mortality. Although current treatment provides benefit, new approaches are required to approach 1-year median survival for PS2 patients.

Purpose Limited data are available on the time course of treatment failures (recurrence and/or death), the nature and duration of adjuvant treatment benefit, and long-term recurrence rates in patients with resected stage II and III colon cancer. Methods The data set assembled by the Adjuvant Colon Cancer Endpoints Group, a collection of individual patient data from 18 trials and more than 20,800 patients testing fluorouracil-based adjuvant therapy in patients with stage II or III colon cancer, was analyzed. Results A significant overall survival (OS) benefit of adjuvant therapy was consistent over the 8-year follow-up period. The risk of recurrence in patients treated with adjuvant chemotherapy never exceeds that of control patients, signifying that adjuvant therapy cures some patients, as opposed to delaying recurrence. After 5 years, recurrence rates were less than 1.5% per year, and after 8 years, they were less than 0.5% per year. Significant disease-free survival (DFS) benefit from adjuvant chemotherapy was observed in the first 2 years. After 2 years, DFS rates in treated and control patients were not significantly different, and after 4 years, no trend toward benefit was demonstrated. This benefit was primarily driven by patients with stage III disease. Conclusion Adjuvant chemotherapy provides significant DFS benefit, primarily by reducing the recurrence rate, within the first 2 years of adjuvant therapy with some benefit in years 3 to 4, translating into long-term OS benefit. This reflects the curative role of chemotherapy in the adjuvant setting. After 5 years, recurrence rates in patients treated on clinical trials are low, and after 8 years, they are minimal; thus, long-term follow-up for recurrence is of little value.

Abstract Purpose: Insulin-like growth factor (IGF)-I and IGF-II stimulate neoplastic cell growth and inhibit apoptosis, whereas IGF-binding protein-3 (IGFBP-3) inhibits the bioavailability of IGF-I and has independent proapoptotic activity. We examined the influence of baseline plasma levels of IGF-I, IGF-II, IGFBP-3, and C-peptide on outcome among patients receiving first-line chemotherapy for metastatic colorectal cancer. Experimental Design: The plasma levels of IGF-I, IGF-II, IGFBP-3, and C-peptide as well as data on prognostic factors and body size were measured at baseline among 527 patients participating in a randomized trial of first-line chemotherapy for metastatic colorectal cancer. Results: Higher baseline plasma IGFBP-3 levels were associated with a significantly greater chemotherapy response rate (P = 0.03) after adjusting for other prognostic factors, whereas neither IGF-I nor IGF-II levels significantly predicted tumor response. Higher levels of IGF-I, IGF-II, and IGFBP-3 were all univariately associated with improved overall survival (P = 0.0001 for all). In a model that mutually adjusted for IGF-I and IGFBP-3, as well as other prognostic factors, increasing baseline-circulating IGFBP-3 was associated with a significantly longer time to tumor progression (P = 0.03), whereas circulating IGF-I was not associated with disease progression (P = 0.95). Levels of C-peptide were not associated with any measure of patient outcome. Conclusion: Among colorectal cancer patients receiving first-line chemotherapy, increasing levels of IGFBP-3, an endogenous antagonist to IGF-I, are associated with an improved objective treatment response and a prolonged time to cancer progression. The IGF pathway may represent an important target for future treatment strategies.

Purpose In this report, we update survival (OS) and time-to-progression (TTP) data for the Intergroup trial N9741 after a median 5 years of follow-up by using risk-stratified and prognostic factor analyses to determine if treatment outcomes differ in specific patient subgroups. Patients and Methods A total of 1,691 patients were randomly assigned to one of seven fluorouracil-, oxaliplatin-, and irinotecan-containing regimens. OS and TTP were calculated by treatment arm and baseline risk group (on the basis of WBC, performance status, number of sites of disease, and alkaline phosphatase). Multivariate prognostic factor analysis was used to assess clinical factors for their relationships to OS, TTP, response, and toxicity by using Cox and logistic regression models. Results The observed 5-year survival with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX) of 9.8% was better than with irinotecan plus bolus fluorouracil and leucovorin (IFL; 3.7%; P = .04) or with bolus irinotecan/oxaliplatin (IROX; 5.1%; P = .128). OS and TTP were significantly longer for FOLFOX (20.2 months and 8.9 months, respectively) than for IFL (14.6 months and 6.1 months, respectively; P < .001 for both) or for IROX (17.3 months and 6.7 months, respectively; P < .001 for both). OS differed by risk group: 20.7 months for low risk, 17.4 months for intermediate risk, and 9.4 months for high risk (P < .001). FOLFOX treatment was superior in all risk groups and was the most powerful prognostic factor for OS, TTP, response rate, and toxicity. Conclusion The 9.8% 5-year OS in patients with metastatic colorectal cancer who were treated with first-line FOLFOX sets a new benchmark. Neither baseline risk group nor any prognostic factor examined was predictive of treatment-specific outcome. However, treatment efficacy and patient longevity varied as a function of risk group.

Abstract Purpose: Colon tumors with defective DNA mismatch repair (dMMR) have a well-characterized phenotype and accounts for ∼15% to 20% of sporadic colon cancer as well as those colon cancer patients with Lynch syndrome. Although the presence of dMMR seems to be a favorable prognostic marker, data suggest that these patients do not respond as well to adjuvant chemotherapy. Experimental Design: In this study, we examined the prognostic significance of tumor MMR deficiency and the presence of a specific mutation in BRAF (V600E) in a group of patients (n = 533) who participated in a randomized prospective clinical trial through the North Central Cancer Treatment Group. Results: Tumors with dMMR were found to be associated with higher tumor grade (P = 0.001), proximal location (P &lt; 0.0001), and improved overall and disease-free survival (P = 0.05 and 0.04, respectively). Among all cases examined, evaluation of the BRAF V600E mutation status revealed no statistically significant differences in either disease-free or overall survival. Patients were then grouped into four categories for further analysis: dMMR/BRAF(−), dMMR/BRAF(+), pMMR/BRAF(−), and pMMR/BRAF(+). The dMMR/BRAF(−) group had a significantly improved overall survival (5-year overall survival of 100% versus 73%, P = 0.002) compared with all others. The remaining three groups had very similar survival outcomes. An additional cohort of tumors previously classified as having dMMR were also tested for the BRAF V600E alteration. Results remained significant (P = 0.006) when the two groups were combined for analysis. Conclusions: Overall, these data suggest that the underlying molecular etiology of those tumors having dMMR may influence the disease outcome in these patients.

Purpose This study was undertaken to examine five possible prognostic factors in patients with recurrent stage II and III colon cancer: time from randomization on an adjuvant therapy clinical trial to tumor recurrence (< 1 year, 1 to 2 years, 2 to 3 years, 3 to 4 years, > 4 years), initial stage (II v III), initial adjuvant treatment (fluorouracil [FU]-based v surgery alone), the era in which the patient entered an adjuvant therapy clinical trial (1978 to 1985, 1986 to 1992, 1993 to 1999), and patient age at recurrence. Methods The Adjuvant Colon Cancer End Points (ACCENT) data set was analyzed using univariate and multivariate Cox proportional hazards models, stratified by study. Results 5,722 (32.9%) of 17,381 patients experienced recurrence. Median survival following recurrence was 13.3 months. Time from randomization to recurrence was highly prognostic of survival following recurrence (P < .0001). Longer survival following recurrence was seen in patients with initial stage II versus III disease (P < .0001; 14.3% 6-year overall survival after recurrence in initial stage II patients), patients entered more recently onto trials (P < .0001), and patients initially treated with surgery alone versus FU adjuvant treatment (P = .0005). All relationships were maintained in multivariate models. Conclusion Time from initial treatment to recurrence and initial stage are important prognostic factors in patients with recurrent colon cancer. Survival following recurrence increased modestly from 1978 to 1999. Patients who had a recurrence following adjuvant therapy had poorer prognosis than those who progressed after surgery alone. These prognostic factors may be useful for clinical trial design and treatment decisions in patients with recurrent colon cancer.

Purpose In the phase III study AVF2107g, bevacizumab (BV) demonstrated a survival benefit when added to irinotecan, fluorouracil, and leucovorin (IFL) in first-line metastatic colorectal cancer (mCRC). In a parallel phase III study, Intergroup N9741, oxaliplatin plus fluorouracil and leucovorin (FOLFOX) also demonstrated a survival benefit compared with IFL. As these two superior therapies have differing mechanisms of action, we explored whether the improved survival associated with the superior therapy was dependent on tumor response. Patients and Methods For these retrospective, exploratory analyses, patients were defined as responders or nonresponders by whether complete or partial response was achieved with first-line therapy. Results Compared with IFL alone, BV plus IFL and FOLFOX each demonstrated statistically significant improvements in progression-free survival (PFS) and overall survival (OS) regardless of objective tumor response. BV-treated nonresponders had a hazard ratio (HR) of 0.63 (P = .0001) for PFS and 0.76 (P = .0188) for OS compared with IFL-treated nonresponders. FOLFOX-treated nonresponders had an HR of 0.75 (P = .0029) for PFS and 0.74 (P = .0030) for OS compared with IFL-treated nonresponders. Conclusion In both AVF2107g and N9741, objective response did not predict the magnitude of PFS or OS benefit from the superior therapy; nonresponders, despite a poorer prognosis than responders, achieved extended PFS and OS from BV plus IFL or FOLFOX compared with IFL. On the basis of these data, tumor response in metastatic colorectal cancer is not a necessary factor for a therapy to provide benefit to an individual patient.

Purpose The traditional end point for colon adjuvant clinical trials is overall survival (OS). We previously validated disease-free survival (DFS) after 3-year follow-up as an excellent predictor of 5-year OS results. Here we explore shorter term DFS and OS end points, as well as stage dependency. Methods Individual patient data from 18 phase III trials including 43 arms and 20,898 patients were pooled. Association measures included correlation of event rates within arms, correlation of hazard ratios (HRs) between arms, trial level significance comparisons (via log-rank testing), and a formal surrogacy model. Results DFS at earlier times was less accurate in predicting OS than 3-year DFS, but 2-year DFS remained a strong predictor. DFS with 1-year minimum follow-up demonstrated perfect negative predicted value; all trials negative at 1 year for DFS were negative for 5-year OS. OS with 3-year minimum follow-up was also an excellent predictor for 5-year OS; OS at earlier time points provided inaccurate prediction. The association between 3-year DFS and 5-year OS was greater for stage III patients; correlation of HR within trials was 0.92 (95% CI, 0.85 to 0.95) for stage III patients and 0.70 (95% CI, 0.44 to 0.80) for stage II patients. Conclusion DFS outcomes after 2- or 3-year median follow-up are excellent predictors of 5-year OS. DFS outcomes are appropriate for trials in which the majority of patients are stage III. DFS after 2- or 3-year median follow-up should be considered as the primary end point in future colon adjuvant trials.