Enrique Aranda

Prognostic Role of KRAS and BRAF in Stage II and III Resected Colon Cancer: Results of the Translational Study on the PETACC-3, EORTC 40993, SAKK 60-00 Trial

PURPOSE Mutations within the KRAS proto-oncogene have predictive value but are of uncertain prognostic value in the treatment of advanced colorectal cancer. We took advantage of PETACC-3, an adjuvant trial with 3,278 patients with stage II to III colon cancer, to evaluate the prognostic value of KRAS and BRAF tumor mutation status in this setting. PATIENTS AND METHODS Formalin-fixed paraffin-embedded tissue blocks (n = 1,564) were prospectively collected and DNA was extracted from tissue sections from 1,404 cases. Planned analysis of KRAS exon 2 and BRAF exon 15 mutations was performed by allele-specific real-time polymerase chain reaction. Survival analyses were based on univariate and multivariate proportional hazard regression models. RESULTS KRAS and BRAF tumor mutation rates were 37.0% and 7.9%, respectively, and were not significantly different according to tumor stage. In a multivariate analysis containing stage, tumor site, nodal status, sex, age, grade, and microsatellite instability (MSI) status, KRAS mutation was associated with grade (P = .0016), while BRAF mutation was significantly associated with female sex (P = .017), and highly significantly associated with right-sided tumors, older age, high grade, and MSI-high tumors (all P < 10(-4)). In univariate and multivariate analysis, KRAS mutations did not have a major prognostic value regarding relapse-free survival (RFS) or overall survival (OS). BRAF mutation was not prognostic for RFS, but was for OS, particularly in patients with MSI-low (MSI-L) and stable (MSI-S) tumors (hazard ratio, 2.2; 95% CI, 1.4 to 3.4; P = .0003). CONCLUSION In stage II-III colon cancer, the KRAS mutation status does not have major prognostic value. BRAF is prognostic for OS in MS-L/S tumors.

Randomized phase III trial comparing biweekly infusional fluorouracil/leucovorin alone or with irinotecan in the adjuvant treatment of stage III colon cancer: PETACC-3.

PURPOSE The primary objective of this randomized, multicenter, phase III trial was to investigate whether the addition of irinotecan to the de Gramont infusional fluorouracil (FU)/leucovorin (LV) adjuvant regimen (LV5FU2) would improve disease-free survival (DFS) in patients with stage III colon cancer. PATIENTS AND METHODS After curatively intentioned surgery, patients with stage II and III colon cancer were randomly allocated surgery to receive LV5FU2 (LV 200 mg/m(2) as a 2-hour infusion, followed by FU; as a 400 mg/m(2) bolus and then a 600 mg/m(2) continuous infusion over 22 hours, days 1 and 2, every 2 weeks for 12 cycles: de Gramont regimen) with or without irinotecan (180 mg/m(2) as a 30- to 90-minute infusion, day 1, every 2 weeks). In total, 260 (7.9%) of 3,278 patients received an alternative high-dose infusional FU/LV regimen (Arbeitsgemeinschaft Internische Onkologie regimen) with or without irinotecan. Results The principal efficacy analysis was based on 2,094 treated patients with stage III disease, randomly allocated in the LV5FU2 strata. After a median follow-up of 66.3 months, the 5-year DFS rate was 56.7% with irinotecan/LV5FU2 and 54.3% with LV5FU2 alone (primary end point: log-rank P = .106). Combining irinotecan with LV5FU2 did not significantly improve overall survival in this patient group compared with LV5FU2 alone (5-year rate 73.6% v 71.3%, respectively; log-rank P = .094). The addition of irinotecan to LV5FU2 was associated with an increased incidence of grade 3 to 4 GI events and neutropenia. CONCLUSION Irinotecan added to LV5FU2 as adjuvant therapy did not confer a statistically significant improvement in DFS or overall survival in patients with stage III colon cancer compared with LV5FU2 alone.

Phase III Study of Capecitabine Plus Oxaliplatin Compared With Continuous-Infusion Fluorouracil Plus Oxaliplatin As First-Line Therapy in Metastatic Colorectal Cancer: Final Report of the Spanish Cooperative Group for the Treatment of Digestive Tumors Trial

PURPOSE The aim of this phase III trial was to compare the efficacy and safety of capecitabine plus oxaliplatin (XELOX) versus Spanish-based continuous-infusion high-dose fluorouracil (FU) plus oxaliplatin (FUOX) regimens as first-line therapy for metastatic colorectal cancer (MCRC). PATIENTS AND METHODS A total of 348 patients were randomly assigned to receive XELOX (oral capecitabine 1,000 mg/m2 bid for 14 days plus oxaliplatin 130 mg/m2 on day 1 every 3 weeks) or FUOX (continuous-infusion FU 2,250 mg/m2 during 48 hours on days 1, 8, 15, 22, 29, and 36 plus oxaliplatin 85 mg/m2 on days 1, 15, and 29 every 6 weeks). RESULTS There were no significant differences in efficacy between XELOX and FUOX arms, which showed, respectively, median time to tumor progression (TTP; 8.9 v 9.5 months; P = .153); median overall survival (18.1 v 20.8 months; P = .145); and confirmed response rate (RR; 37% v 46%; P = .539). The safety profile of the two regimens was similar, although there were lower rates of grade 3/4 diarrhea (14% v 24%) and grade 1/2 stomatitis (28% v 43%), and higher rates of grade 1/2 hyperbilirubinemia (37% v 21%) and grade 1/2 hand-foot syndrome (14% v 5%) with XELOX versus FUOX, respectively. CONCLUSION This randomized study shows a similar TTP of XELOX compared with FUOX in the first-line treatment of MCRC, although there was a trend for slightly lower RR and survival. XELOX can be considered as an alternative to FUOX.

Randomized Phase 3 Trial of Fluorouracil, Epirubicin, and Cyclophosphamide Alone or Followed by Paclitaxel for Early Breast Cancer

BACKGROUND Taxanes are among the most active drugs for the treatment of metastatic breast cancer, and, as a consequence, they have also been studied in the adjuvant setting. METHODS After breast cancer surgery, women with lymph node-positive disease were randomly assigned to treatment with fluorouracil, epirubicin, and cyclophosphamide (FEC) or with FEC followed by weekly paclitaxel (FEC-P). The primary endpoint of study-5-year disease-free survival (DFS)-was assessed by Kaplan-Meier analysis. Secondary endpoints included overall survival and analysis of the prognostic and predictive value of clinical and molecular (hormone receptors by immunohistochemistry and HER2 by fluorescence in situ hybridization) markers. Associations and interactions were assessed with a multivariable Cox proportional hazards model for DFS for the following covariates: age, menopausal status, tumor size, lymph node status, type of chemotherapy, tumor size, positive lymph nodes, HER2 status, and hormone receptor status. All statistical tests were two-sided. RESULTS Among the 1246 eligible patients, estimated rates of DFS at 5 years were 78.5% in the FEC-P arm and 72.1% in the FEC arm (difference = 6.4%, 95% confidence interval [CI] = 1.6% to 11.2%; P = .006). FEC-P treatment was associated with a 23% reduction in the risk of relapse compared with FEC treatment (146 relapses in the 614 patients in the FEC-P arm vs 193 relapses in the 632 patients in the FEC arm, hazard ratio [HR] = 0.77, 95% CI = 0.62 to 0.95; P = .022) and a 22% reduction in the risk of death (73 and 95 deaths, respectively, HR = 0.78, 95% CI = 0.57 to 1.06; P = .110). Among the 928 patients for whom tumor samples were centrally analyzed, type of chemotherapy (FEC vs FEC-P) (P = .017), number of involved axillary lymph nodes (P < .001), tumor size (P = .020), hormone receptor status (P = .004), and HER2 status (P = .006) were all associated with DFS. We found no statistically significant interaction between HER2 status and paclitaxel treatment or between hormone receptor status and paclitaxel treatment. CONCLUSIONS Among patients with operable breast cancer, FEC-P treatment statistically significantly reduced the risk of relapse compared with FEC as adjuvant therapy.

Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with weekly high-dose 48-hour continuous-infusion fluorouracil for advanced colorectal cancer: A Spanish Cooperative Group for Gastrointestinal Tumor Therapy (TTD) study

PURPOSE The objective of this multicenter study was to compare the efficacy and toxicity profiles of a combination of 5-fluorouracil (5-FU) given by bolus injection together with intravenous leucovorin (LV) versus high-dose 5-FU in continuous infusion (CI) in the treatment of advanced colorectal cancer. PATIENTS AND METHODS A total of 306 patients were randomized to receive either 5-FU 425 mg/m2 given by bolus injection on days 1-5 plus intravenous (i.v.) LV 20 mg/m2 every four to five weeks or 5-FU 3.5 g/m2/week in a 48-hour CI. Therapy was continued until disease progression. Second-line chemotherapy was allowed in both arms. RESULTS The response rates in 306 patients with measurable lesions were 19.2% (modulated arm) and 30.3% (CI arm, P < 0.05). The median progression-free survival times were 23.5 weeks (modulated arm) and 25 weeks (CI arm, P = NS). Median survival times were 42.5 weeks (modulated arm) and 48 weeks (CI arm, P = NS). There were no significant differences in grade 3-4 toxicity profiles but if we consider all grades we observed more mucositis in the modulated arm and more hand-foot syndrome in the CI arm. CONCLUSIONS In terms of response rate, the continuous infusion regimen was more effective than the modulated regimen. There was no significant difference in survival and time to progression, and none in grade 3-4 toxicity.

Irinotecan in Combination With Fluorouracil in a 48-Hour Continuous Infusion As First-Line Chemotherapy for Elderly Patients With Metastatic Colorectal Cancer: A Spanish Cooperative Group for the Treatment of Digestive Tumors Study

PURPOSE Elderly patients constitute a subpopulation with special characteristics that differ from those of the nonelderly and have been underrepresented in clinical trials. This study was performed to determine the efficacy and safety of irinotecan (CPT-11) in combination with fluorouracil (FU) administered as a 48-hour continuous infusion twice a month in elderly patients. PATIENTS AND METHODS Patients > or = 72 years old with metastatic colorectal cancer, Eastern Cooperative Oncology Group performance status of 0 to 1, no geriatric syndromes, and no prior treatment were treated every 2 weeks with CPT-11 180 mg/m2 plus FU 3,000 mg/m2 in a 48-hour continuous infusion. RESULTS By intent-to-treat analysis, in 85 assessable patients, the objective response rate was 35% (95% CI, 25% to 46%), and stable disease was 33% (95% CI, 23% to 44%). Median time to progression was 8.0 months (95% CI, 6.0 to 10.0 months), and median overall survival time was 15.3 months (95% CI, 13.8 to 16.9 months). Toxicity was moderate. Grade 3 and 4 neutropenia, diarrhea, and asthenia were observed in 21%, 17%, and 13% of patients, respectively. Only one case of neutropenic fever occurred. There were two toxic deaths, one was a result of grade 4 diarrhea and acute kidney failure, and the other was a result of massive intestinal hemorrhage in the first cycle. The study of prognostic factors did not reveal any predictive factor of response. Response to treatment and baseline lactate dehydrogenase were the main factors conditioning progression-free and overall survival. CONCLUSION Twice a month continuous-infusion CPT-11 combined with FU is a valid therapeutic alternative for elderly patients in good general condition.

Circulating Tumor Cell Count Is a Prognostic Factor in Metastatic Colorectal Cancer Patients Receiving First-Line Chemotherapy Plus Bevacizumab: A Spanish Cooperative Group for the Treatment of Digestive Tumors Study

BACKGROUND The Maintenance in Colorectal Cancer trial was a phase III study to assess maintenance therapy with single-agent bevacizumab versus bevacizumab plus chemotherapy in patients with metastatic colorectal cancer. An ancillary study was conducted to evaluate the circulating tumor cell (CTC) count as a prognostic and/or predictive marker for efficacy endpoints. PATIENTS AND METHODS One hundred eighty patients were included. Blood samples were obtained at baseline and after three cycles. CTC enumeration was carried out using the CellSearch® System (Veridex LLC, Raritan, NJ). Computed tomography scans were performed at cycle 3 and 6 and every 12 weeks thereafter for tumor response assessment. RESULTS The median progression-free survival (PFS) interval for patients with a CTC count ≥3 at baseline was 7.8 months, versus the 12.0 months achieved by patients with a CTC count <3 (p = .0002). The median overall survival (OS) time was 17.7 months for patients with a CTC count ≥3, compared with 25.1 months for patients with a lower count (p = .0059). After three cycles, the median PFS interval for patients with a low CTC count was 10.8 months, significantly longer than the 7.5 months for patients with a high CTC count (p = .005). The median OS time for patients with a CTC count <3 was significantly longer than for patients with a CTC count ≥3, 25.1 months versus 16.2 months, respectively (p = .0095). CONCLUSIONS The CTC count is a strong prognostic factor for PFS and OS outcomes in metastatic colorectal cancer patients.

First-line single-agent cetuximab in elderly patients with metastatic colorectal cancer. A phase II clinical and molecular study of the Spanish group for digestive tumor therapy (TTD)

PURPOSE to evaluate the efficacy and safety of first-line single-agent cetuximab in fit elderly patients with metastatic colorectal cancer, as well as potential molecular predictive factors for efficacy. PATIENTS AND METHODS patients aged 70 or older with metastatic CRC without criteria for frailty and no prior treatment for advanced disease were treated with single-agent cetuximab 400mg/m(2) followed by weekly 250mg/m(2) until disease progression or unacceptable toxicity. RESULTS forty-one patients were included. Two patients achieved a complete response and 4 patients had a partial response for an overall response rate of 14.6%. Fifteen patients (36.6%) remained stable. Median time to progression was 2.9 months and median overall survival 11.1 months despite two-third of patients received chemotherapy at progression. Forty-five percent of EGFR gene copy number positive patients by FISH were progression-free at 12 weeks, in contrast with 12% of FISH negative patients (p=0.04). Grade 3 skin toxicity was reported in 5 patients (12.2%). Hypersensitivity infusion reactions were not reported and there were no toxic deaths. CONCLUSION cetuximab is a safe monoclonal antibody with moderate activity in first-line metastatic colorectal cancer, but the present study does not support the use of cetuximab as single-agent in first-line fit elderly patients with metastatic CRC.

First-Line Cetuximab Plus Capecitabine in Elderly Patients with Advanced Colorectal Cancer: Clinical Outcome and Subgroup Analysis According to KRAS Status from a Spanish TTD Group Study

UNLABELLED Single-agent cetuximab is safe and active in elderly patients with advanced colorectal cancer (CRC). A cetuximab-capecitabine combination has not previously been tested in elderly patients with advanced CRC. MATERIAL AND METHODS Sixty-six patients with advanced CRC were treated with cetuximab as a 400 mg/m2 i.v. infusion followed by 250 mg/m2 i.v. weekly plus capecitabine at a dose of 1,250 mg/m2 every 12 hours. After the inclusion of 27 patients, the protocol was amended for safety reasons, reducing the dose of capecitabine to 1,000 mg/m2 every 12 hours. Thirty-nine additional patients were treated with the reduced dose of capecitabine. RESULTS The overall response rate was 31.8%. KRAS status was determined in 58 patients (88%). Fourteen of 29 patients with wild-type KRAS tumors responded (48.3%; 95% confidence interval [CI], 29.4%-67.5%), compared with six of 29 patients with mutant KRAS tumors (20.7%; 95% CI, 8.0%-39.7%). The median progression-free survival (PFS) interval was 7.1 months. The median PFS interval for patients whose tumors were wild-type KRAS was significantly longer than for those with mutant KRAS tumors (8.4 months versus 6.0 months; p = .024). The high incidence of severe paronychia (29.6%) declined (7.7%) after capecitabine dose adjustment. CONCLUSIONS Cetuximab plus capecitabine at a dose of 1,000 mg/m2 every 12 hours may be an alternative to more aggressive regimens in elderly patients with advanced wild-type KRAS CRC.

Elderly patients with advanced colorectal cancer derive similar benefit without excessive toxicity after first-line chemotherapy with oxaliplatin-based combinations: Comparative outcomes from the 03-TTD-01 phase III study

PURPOSE Healthy elderly patients with metastatic colorectal cancer may benefit from chemotherapy as much as the younger population. This analysis compares the outcomes of first-line oxaliplatin plus fluoropyrimidines in elderly versus young patients. PATIENTS AND METHODS 348 patients were randomized to capecitabine 1000 mg/(m2 12 h), days 1-14 plus oxaliplatin 130 mg/m2 day 1, every 3 weeks or weekly infusional 5-FU 2250 mg/m2 over 48 h plus bimonthly oxaliplatin 85 mg/m2. We evaluated response rate, time to progression, overall survival and toxicity according to age. RESULTS ORR for elderly and young patients were 34.9% and 44.7%, respectively (p=0.081). Median TTP did not differ between the two groups: 8.3 months for patients > or =70 years and 9.6 months for those <70 years (p=0.114). Median OS was 16.8 months and 20.5 months for the > or =70 and <70 years groups, respectively (p=0.74). With XELOX, mild paresthesia and an increase in transaminase levels were more frequent for young patients, whereas grade 3/4 diarrhea was higher in those > or =70 years (25% vs. 8%, p=0.005). For FUOX, only paresthesia was significantly lower in patients > or =70 years (53% vs. 71%, p=0.032). CONCLUSION Elderly patients with MCRC benefit from first-line oxaliplatin-fluoropyrimidine combinations as much as younger patients, without increased toxicity.