Findlay, B.

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.

Background Previous studies have established that higher baseline quality of life (QOL) scores are associated with improved survival in patients with metastatic colorectal cancer (mCRC). We examined the relationship between overall survival (OS) and baseline QOL. Patients and Methods A total of 1 247 patients with mCRC participating in N9741 (comparing bolus 5-FU/LV, irinotecan [IFL] vs infusional 5-FU/leucovorin [LV]/oxaliplatin [FOLFOX] vs. irinotecan/oxaliplatin [IROX]) provided data at baseline on overall QOL using a single-item linear analogue self-assessment (LASA) 0–100 point scale. The association of OS according to clinically deficient (defined as CD-QOL, score 0–50) vs not clinically deficient (nCD-QOL, score 51–100) baseline QOL scores was tested. A multivariable analysis using Cox proportional hazards modeling was performed to adjust for the effects of multiple baseline factors. An exploratory analysis was performed evaluating OS according to baseline QOL status among patients who did or did not receive second-line therapy. Results Baseline QOL was a strong predictor of OS for the whole cohort (CD-QOL vs nCD-QOL: 11.2 months vs 18.4 months, P < .0001), and in each arm IFL 12.4 vs 15.1 months, FOLFOX 11.1 months vs 20.6 months, and IROX 8.9 months vs 18.1 months. Baseline QOL was associated with baseline performance status (PS) ( P < .0001). After adjusting for PS and treatment arm, baseline QOL was still associated with OS ( P = .017). Conclusions Baseline QOL is an independent prognostic factor for OS in patients with mCRC. The demonstration that patient-assessed QOL and PS are independent prognostic indicators suggests that these assessments provide important complementary prognostic information.

3503 Background: The association between race & toxicity or response to systemic chemotherapy is poorly understood. We correlated relevent polymorphisms with toxicity & outcome data in AA & C patients (Pts) enrolled in N9741, a large randomized MCRC trial. Methods: Toxicity, response rate (RR), time to progression (TTP), overall survival (OS), & dose intensity (DI) were examined as a function of race in 1412 Pts enrolled on IFL, both full and reduced dose, FOLFOX, or IROX including 486 Pts with pharmacogenomic data. Accrual by race permitted comparison of C (n=1297) to AA (n=112). Results: C & AA were similar in disease extent, PS, gender, prior adjuvant treatment, and DI at cycles 1, 3, 6, or 12. The impact of race on RR, toxicity & the distribution of four relevent drug metabolism genotypes are in the table . AA had lower RR overall & in each treatment arm. Lower toxicity rates were seen in AA Pts, mainly due to less diarrhea, as measured by both CTC V2 & patient reported outcome data. These relationships were maintained in multivariate models adjusting for arm, age, gender, & PS. In these multivariate models, the odds ratio between RR and race was 1.72 (p=0.012) (29% AA vs 41% C) & for severe toxicity the odds ratio was 1.76 (p=0.006) (34% AA vs 48% C). Overall, race was not a significant predictor of TTP or OS (p > 0.50 for each). The hazard ratio comparing FOLFOX to IFL for C was 0.67 and for AA was 0.55. TTP for FOLFOX was superior to both IFL and IROX for both C & AA. Significant differences in pharmacogenetic variants were observed between C & AA, although the sample size for investigating the three-way combination of Rx, race, & pharmacogenomics is too small (36 AA) to draw definitive conclusions. Conclusions: It appears that AA have less toxicity & a lower RR than C when treated with standard MCRC regimens. Different frequencies of polymorphisms in genes relevent to drug metabolism may help explain these clinical differences. [Table: see text] [Table: see text]

4067 Background: N9741 randomized 1691 patients (pts) to seven 5FU, Ox and Iri containing regimens for MCRC. After 20.4 months median follow-up, FOLFOX and IROX improved time to progression (TTP) and overall survival (OS) compared to IFL. Here we update OS and TTP, and report an analysis of factors prognostic of pt outcome. Methods: 5 yr OS and TTP were calculated by Kaplan-Meier per treatment (rx) arm. Pt factors [rx arm, age, gender, prior adjuvant rx, body mass index (BMI), performance status (PS), number of disease sites (#sites), neutrophil count (ANC), hemoglobin, platelets, bilirubin, alkaline phosphatase (ALK), aspartate aminotransferase (AST)] were assessed for univariate association with OS, TTP, response rate (RR), and any grade =3 toxicity. Associated factors were included in multivariate Cox and logistic regression models. Results: After a median follow-up of 4.3 yrs, FOLFOX treated pts were more likely to live 5 yrs, 9.2% versus 5.4% for IROX (p=.016) and 3.8% for IFL (p<.001). Median TTP was also significantly longer in the FOLFOX arm, 9.2 mo vs 6.5 mo for IROX (p=<.001) and 6.0 mo for IFL (p=<.001). The prognostic model found higher PS, ANC and ALK, and more disease sites were prognostic of worse OS (see table ). Age = 70 was associated with poorer survival (HR death 1.33, p=.03), but not TTP, RR, or grade =3 toxicity. FOLFOX rx was the most powerful prognostic factor for TTP and OS. The odds of grade =3 toxicity were significantly higher in FOLFOX treated pts (OR 1.65, p<.001) and lower in men (OR .63, p<.001). No significant interactions between rx arm and pt factors were present, suggesting no factor examined is predictive of rx-specific outcome. Conclusions: 9% 5 yr OS in MCRC pts treated with first-line FOLFOX sets a new benchmark. We confirmed pre-rx PS, WBC, and ALK are prognostic for OS, though FOLFOX rx was the strongest prognostic factor. No factor was associated with differential outcome or toxicity by rx arm, thus these factors cannot be used to guide rx selection. [Table: see text] [Table: see text]

Purpose With three available chemotherapy drugs for advanced colorectal cancer (CRC), response rate (RR) and survival outcomes have improved with associated morbidity, accentuating the need for tools to select optimal individualized treatment. Pharmacogenetics identifies the likelihood of adverse events or response based on variants in genes involved in drug transport, metabolism, and cellular targets. Patients and Methods Germline DNA was extracted from 520 patients on the North American Gastrointestinal Intergroup N9741 study. Three study arms were evaluated: IFL (fluorouracil [FU] + irinotecan [IRN]), FOLFOX (FU + oxaliplatin), and IROX (IRN + oxaliplatin). Information on adverse events, response, and disease-free survival was available. Thirty-four variants in 15 candidate genes for analysis based on previous associations with adverse events or outcome were assessed. Genotyping was performed using pyrosequencing. Results All variants were polymorphic. The homozygous UGT1A1*28 allele observed in 9% of patients was associated with risk of grade 4 neutropenia in patients on IROX (55% v 15%; P = .002). Deletion in GSTM1 was associated with grade 4 neutropenia after FOLFOX (28% v 16%; P = .02). Patients with a homozygous variant genotype for GSTP1 were more likely to discontinue FOLFOX because of neurotoxicity (24% v 10%; P = .01). The presence of a CYP3A5 variant was significantly associated with RR on IFL (29% v 60%; P = .0074). Most previously published genotype-toxicity or -efficacy relationships were not validated in this study. Conclusion This study provides a platform to evaluate pharmacogenetic predictors of response or severe adverse events in advanced CRC. Pharmacogenetic studies can be conducted in multicenter trials, and our findings demonstrate that with continued research, clinical application is practical.

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.