Goldberg, Richard M.

Abstract Objective: Predictors of quality of life (QOL) in patients with metastatic colorectal cancer are lacking. The insulin-like growth factor (IGF) family of proteins is associated with QOL in noncancer populations. We sought to study whether these proteins are associated with QOL in patients with colorectal cancer. Method: We used a cohort of 526 patients with metastatic colorectal cancer treated with combination chemotherapy. Plasma samples of IGF-I, IGF-II, IGF binding protein-3, and C-peptide were collected before initiation of chemotherapy. QOL was measured by the uniscale instrument and the Symptom Distress Scale at baseline and throughout treatment. Results: Baseline plasma levels of IGF-I and IGF-II before initiation of chemotherapy were significantly associated with several important baseline QOL measures in patients with metastatic colorectal cancer. Patients with lower levels of IGF-I reported increased distress with regard to appearance, appetite, cough, and nausea intensity after adjustment for potential confounders. Similarly, decreased levels of IGF-II were predictive of worse quality related to appearance, appetite, fatigue, nausea frequency and intensity, pain frequency, and composite Symptom Distress Scale score. IGF binding protein-3 and C-peptide were not predictive of baseline QOL. Baseline biomarkers were not associated with subsequent changes in QOL during treatment. Higher body mass index was significantly associated with superior baseline QOL in several areas; nonetheless, the association of IGF-I and IGF-II with baseline QOL measures remained significant even after controlling for baseline body mass index. Conclusion: Baseline plasma IGF-I and IGF-II are significantly associated with symptom distress. Whether this association is simply reflective of patient nutritional status and/or disease burden or represents an independent biological effect of IGFs on QOL remains uncertain. Nonetheless, these data suggest that molecular biomarkers may be useful predictors of QOL in cancer patients.

Purpose Some patients with colon cancer have a high risk of local recurrence postoperatively. This trial was undertaken to determine whether radiation therapy added to an adjuvant chemotherapy regimen improves outcome in high-risk patients. Patients and Methods Patients with resected colon cancer with tumor adherence or invasion of surrounding structures, or with T3N1 or T3N2 tumors of the ascending or descending colon were randomly assigned to receive fluorouracil and levamisole therapy with or without radiation therapy. Patients who received chemotherapy and radiation therapy (chemoRT) received 45 to 50.4 Gy in 25 to 28 fractions beginning 28 days after starting chemotherapy. Patient enrollment was terminated because of slow accrual after 222 patients enrolled (original goal was 700 patients); 187 patients were assessable. Results Overall 5-year survival was 62% for chemotherapy patients and 58% for chemoRT patients (P > .50); 5-year disease-free survival was 51% for both groups (P > .50). Toxicity (≥ grade 3) occurred in 42% of chemotherapy patients and 54% of chemoRT patients (P = .04). Leukopenia (≥ grade 3) occurred in 10% of chemotherapy patients and 22% of chemoRT patients (P = .02). No significant difference in nonhematologic toxicity (≥ grade 3) was observed between chemoRT and chemotherapy patients (35% v 44%; P = .26). Conclusion Patients who received chemotherapy or chemoRT had similar overall survival and disease-free survival. Toxicity was higher among chemoRT patients. These results must be interpreted with caution because of the high number of ineligible patients and the limited power of the study to detect potentially meaningful differences.

Purpose Molecular studies of colon cancer have provided insights into pathogenesis, yet it is unclear how important these markers are in predicting prognosis. This study investigated the prognostic significance of TUNEL, bcl-2, p53, proliferation marker Ki-67 and DNA mismatch repair (MMR) status in patients with Dukes' stage B2 and C colorectal adenocarcinomas. Patients and Methods Tumor tissue from 366 patients (75% Dukes' C, 25% Dukes' B2) from four randomized North Central Cancer Treatment Group phase III surgical adjuvant trials were used. Eighty-one percent of patients received adjuvant treatment, which was primarily fluorouracil (FU) based (90%). Tumor location was predominantly (87%) the colon. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL), Ki-67, p53, bcl-2, and MMR were assayed using immunohistochemistry. Stage, grade, MMR, Ki-67, and previously determined flow cytometry markers (ploidy and S phase) were explored for associations with each other and with overall survival (OS) and disease-free survival (DFS). Results Univariately, stage B2, low grade, diploid, Ki-67 more than 27%, normal p53, and FU-based adjuvant treatment were significantly associated with improved OS and DFS (P < .05). After adjusting for stage, grade, and ploidy in multivariate analysis, Ki-67 remained significantly related to both OS and DFS (P < .01). Active FU-based adjuvant treatment was significant only for OS in this multivariate model. Neither bcl-2 nor TUNEL were significant. Conclusion This retrospective study indicates that Ki-67 and ploidy may have stronger prognostic impact on OS and DFS than other parameters investigated after adjusting for stage and tumor grade. Prospective studies to elucidate the mechanism and prognostic significance of these findings are necessary.

Purpose To determine survival and relapse rates by T and N stage and treatment method in five randomized phase III North American rectal adjuvant studies. Patients and Methods Data were pooled from 3,791 eligible patients enrolled onto North Central Cancer Treatment Group (NCCTG) 79-47-51, NCCTG 86-47-51, US Gastrointestinal Intergroup 0114, National Surgical Adjuvant Breast and Bowel Project (NSABP) R01, and NSABP R02. Surgery alone (S) was the treatment arm in 179 patients. The remaining patients received adjuvant treatment as follows: irradiation (RT) alone (n = 281), RT + fluorouracil (FU) ± semustine bolus chemotherapy (CT; n = 779), RT + protracted venous infusion CT (n = 325), RT + FU ± leucovorin or levamisole bolus CT (n = 1,695), or CT alone (n = 532). Five-year follow-up was available in 94% of surviving patients, and 8-year follow-up, in 62%. Results Overall (OS) and disease-free survival were dependent on TN stage, NT stage, and treatment method. Even among N2 patients, T substage influenced 5-year OS (T1-2, 67%; T3, 44%; T4, 37%; P < .001). Three risk groups of patients were defined: (1) intermediate (T1-2/N1, T3/N0), (2) moderately high (T1-2/N2, T3/N1, T4/N0), and (3) high (T3/N2, T4/N1, T4/N2). For intermediate-risk patients, those receiving S plus CT had 5-year OS rates of 85% (T1-2/N1) and 84% (T3/N0), which was similar to results with S plus RT plus CT (T1-2/N1, 78% to 83%; T3/N0, 74% to 80%). For moderately high-risk lesions, 5-year OS ranged from 43% to 70% with S plus CT, and 44% to 80% with S plus RT plus CT. For high-risk lesions, 5-year OS ranged from 25% to 45% with S plus CT, and 29% to 57% with S plus RT plus CT. Conclusion Different treatment strategies may be indicated for intermediate-risk versus moderately high- or high-risk patients based on differential survival rates and rates of relapse. Use of trimodality treatment for all patients with intermediate-risk lesions may be excessive, since S plus CT resulted in 5-year OS of approximately 85%; however, 5-year disease-free survival rates with S plus CT were 78% (T1-2/N1) and 69%(T3/N0), indicating room for improvement.

Purpose Although it is well-established that fluorouracil- (FU-) based adjuvant therapy improves survival for patients with resected high-risk colon cancer, the magnitude of adjuvant therapy benefit across specific subgroups and for individual patients has been uncertain. Patients and Methods Using a pooled data set of 3,302 patients with stage II and III colon cancer from seven randomized trials comparing FU + leucovorin or FU + levamisole to surgery alone, we performed an analysis based on a Cox proportional hazards regression model. Treatment, age, sex, tumor location, T stage, nodal status, and grade were tested for both prognostic and predictive significance. Model derived estimates of 5-year disease-free survival and overall survival (OS) for surgery alone and surgery plus FU-based therapy were calculated for a range of patient subsets. Results Nodal status, T stage, and grade were the only prognostic factors independently significant for both disease-free survival and OS. Age was significant only for OS. In a multivariate analysis, adjuvant therapy showed a beneficial treatment effect across all subsets. Treatment benefits were consistent across sex, location, age, T-stage, and grade. A significant stage by treatment interaction was present, with treatment benefiting stage III patients to a greater degree than stage II patients. Conclusion Patients with high-risk resected colon cancer obtain benefit from FU-based therapy across subsets of age, sex, location, T stage, nodal status, and grade. Model estimates of survival stratified by T stage, nodal status, grade, and age are available at http://www.mayoclinic.com/calcs . This information may improve patients' and physicians' understanding of the potential benefits of adjuvant therapy.

Purpose Fluorouracil (FU)-leucovorin (LV), irinotecan, and oxaliplatin administered alone or in combination have proven effective in the treatment of advanced colorectal cancer (CRC). Combination protocols using FU-LV with either irinotecan or oxaliplatin are currently regarded as standard first-line therapies in this disease. However, the importance of the availability of all three active cytotoxic agents, FU-LV, irinotecan, and oxaliplatin, on overall survival (OS) has not yet been evaluated. Materials and Methods We analyzed data from seven recently published phase III trials in advanced CRC to correlate the percentage of patients receiving second-line therapy and the percentage of patients receiving all three agents with the reported median OS, using a weighted analysis. Results The reported median OS is significantly correlated with the percentage of patients who received all three drugs in the course of their disease (P = .0008) but not with the percentage of patients who received any second-line therapy (P = .19). In addition, the use of combination protocols as first-line therapy was associated with a significant improvement in median survival of 3.5 months (95% CI, 1.27 to 5.73 months; P = .0083). Conclusion Our results support the strategy of making these three active drugs available to all patients with advanced CRC who are candidates for such therapy to maximize OS. In addition, our findings suggest that, with the availability of effective salvage options, OS should no longer be regarded as the most appropriate end point by which to assess the efficacy of a palliative first-line treatment in CRC.

Purpose Three agents with differing mechanisms of action are available for treatment of advanced colorectal cancer: fluorouracil, irinotecan, and oxaliplatin. In this study, we compared the activity and toxicity of three different two-drug combinations in patients with metastatic colorectal cancer who had not been treated previously for advanced disease. Patients and Methods Patients were concurrently randomly assigned to receive irinotecan and bolus fluorouracil plus leucovorin (IFL, control combination), oxaliplatin and infused fluorouracil plus leucovorin (FOLFOX), or irinotecan and oxaliplatin (IROX). The primary end point was time to progression, with secondary end points of response rate, survival time, and toxicity. Results A total of 795 patients were randomly assigned between May 1999 and April 2001. A median time to progression of 8.7 months, response rate of 45%, and median survival time of 19.5 months were observed for FOLFOX. These results were significantly superior to those observed for IFL for all end points (6.9 months, 31%, and 15.0 months, respectively) or for IROX (6.5 months, 35%, and 17.4 months, respectively) for time to progression and response. The FOLFOX regimen had significantly lower rates of severe nausea, vomiting, diarrhea, febrile neutropenia, and dehydration. Sensory neuropathy and neutropenia were more common with the regimens containing oxaliplatin. Conclusion The FOLFOX regimen of oxaliplatin and infused fluorouracil plus leucovorin was active and comparatively safe. It should be considered as a standard therapy for patients with advanced colorectal cancer.

Purpose: We sought to determine the maximum-tolerated dose (MTD) and evaluate the toxicities and clinical activity of two irinotecan (CPT-11), fluorouracil (FU), leucovorin (LV), and oxaliplatin schedules in patients with advanced solid tumors. Additionally, we investigated the effect of CPT-11 on oxaliplatin pharmacokinetics. Patients and Methods: Thirteen patients (cohort 1) received intravenous CPT-11 (infusion) and FU/LV (bolus) on days 1, 8, 15, and 22 and oxaliplatin (infusion) on days 1 and 15 every 6 weeks for a total 37 courses (median, three courses) at three dose levels. Twenty-two cohort 2 patients received intravenous CPT-11/oxaliplatin (infusion, day 1) and FU/LV (90-minute bolus infusion, days 2 to 5) every 3 weeks for a total of 122 courses (median, four courses) at three dose levels. Pharmacokinetic and neurotoxicity assessments were performed at the cohort 2 MTD. Results: Dose-limiting toxicity (DLT) seen in both cohorts at the starting dose required dose de-escalation. Cohort 1 DLT included diarrhea and neutropenia. In cohort 2, diarrhea, vomiting, dehydration, neutropenia, febrile neutropenia, and paresthesias were DLTs. Antitumor activity was seen in both cohorts. In cohort 2, the total platinum area under the curve of patients increased 17% in cycle 2 (P = .048), but objective neurotoxicity was not seen. Conclusion: The toxicities resulting from the addition of oxaliplatin to CPT-11/FU/LV are significant but manageable. The MTDs for the weekly schedule are CPT-11 (75 mg/m2), oxaliplatin (50 mg/m2), FU (320 mg/m2), and LV (20 mg/m2); and, for the 3-weekly schedule, the MTDs are CPT-11 (175 mg/m2), oxaliplatin (85 mg/m2), FU (240 mg/m2), and LV (20 mg/m2). Second-cycle platinum accumulation raises the possibility for enhanced cumulative neurotoxicity with CPT-11/oxaliplatin combinations.

PURPOSE: To evaluate quality of life (QOL) and tumor response after administration of an oral chemotherapy regimen in patients with previously untreated metastatic colorectal cancer. PATIENTS AND METHODS: Seventy-eight patients received a mean number of 5.8 cycles of therapy. QOL data were analyzed at baseline, after every two cycles of therapy, and at the time of treatment discontinuation. The Uniscale and the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire C30 were both utilized. RESULTS: The confirmed response rate was 26% (95% confidence interval [CI], 17% to 37%). Median survival was 11.3 months (95% CI, 9.6 to 15.1 months). Global QOL scores were unchanged over the course of therapy by either tool. Only the physical function subscale score had worsened at the end of therapy. In an analysis of responding patients, significant and durable improvements in both global QOL measures as well as select subscale scores were observed. Diarrhea and physical function QOL scores had declined at the time of treatment discontinuation. Patients who did not respond to therapy had preserved QOL scores when they were evaluated after two cycles of therapy. CONCLUSION: This oral treatment strategy preserved QOL in treated patients. Global QOL measures as well as several QOL subscale scores significantly improved in patients with a documented response to therapy. The profile of improved QOL components indicated that patient well-being was related to tumor response in specific and perceivable ways. Nonresponding patients reported preserved QOL during the first two cycles of therapy. QOL analysis was feasible and informative in this moderately sized multicenter phase II trial.