Capecitabine and oxaliplatin in the preoperative multimodality treatment of rectal cancer: surgical end points from National Surgical Adjuvant Breast and Bowel Project trial R-04.

PURPOSE: The optimal chemotherapy regimen administered concurrently with preoperative radiation therapy (RT) for patients with rectal cancer is unknown. National Surgical Adjuvant Breast and Bowel Project trial R-04 compared four chemotherapy regimens administered concomitantly with RT. PATIENTS AND METHODS: Patients with clinical stage II or III rectal cancer who were undergoing preoperative RT (45 Gy in 25 fractions over 5 weeks plus a boost of 5.4 Gy to 10.8 Gy in three to six daily fractions) were randomly assigned to one of the following chemotherapy regimens: continuous intravenous infusional fluorouracil (CVI FU; 225 mg/m(2), 5 days per week), with or without intravenous oxaliplatin (50 mg/m(2) once per week for 5 weeks) or oral capecitabine (825 mg/m(2) twice per day, 5 days per week), with or without oxaliplatin (50 mg/m(2) once per week for 5 weeks). Before random assignment, the surgeon indicated whether the patient was eligible for sphincter-sparing surgery based on clinical staging. The surgical end points were complete pathologic response (pCR), sphincter-sparing surgery, and surgical downstaging (conversion to sphincter-sparing surgery). RESULTS: From September 2004 to August 2010, 1,608 patients were randomly assigned. No significant differences in the rates of pCR, sphincter-sparing surgery, or surgical downstaging were identified between the CVI FU and capecitabine regimens or between the two regimens with or without oxaliplatin. Patients treated with oxaliplatin experienced significantly more grade 3 or 4 diarrhea (P < .001). CONCLUSION: Administering capecitabine with preoperative RT achieved similar rates of pCR, sphincter-sparing surgery, and surgical downstaging compared with CVI FU. Adding oxaliplatin did not improve surgical outcomes but added significant toxicity. The definitive analysis of local tumor control, disease-free survival, and overall survival will be performed when the protocol-specified number of events has occurred.

Oxaliplatin as adjuvant therapy for colon cancer: updated results of NSABP C-07 trial, including survival and subset analyses.

PURPOSE: The National Surgical Adjuvant Breast and Bowel Project (NSABP) C-07 trial demonstrated that the addition of oxaliplatin to fluorouracil plus leucovorin (FULV) improved disease-free survival (DFS) in patients with stage II or III colon cancer. This analysis is the first publication of overall survival (OS) for the NSABP C-07 study. We updated DFS and examined both end points in clinically relevant patient subsets. PATIENTS AND METHODS: Other studies have identified patients age 70 or older and those with stage II disease as patient subsets in which oxaliplatin may not be effective. We investigated toxicity as a driver of divergent outcomes in these subsets. RESULTS: In all, 2,409 eligible patients with follow-up were randomly assigned to either FULV (FU 500 mg/m(2) by intravenous [IV] bolus weekly for 6 weeks; leucovorin 500 mg/m(2) IV weekly for 6 weeks of each 8-week cycle for three cycles) or FLOX (FULV plus oxaliplatin 85 mg/m(2) IV on days 1, 15, and 29 of each cycle). With 8 years median follow-up, OS was similar between treatment groups (hazard ratio [HR], 0.88; 95% CI, 0.75 to 1.02; P = .08). FLOX remained superior for DFS (HR, 0.82; 95% CI, 0.72 to 0.93; P = .002). The effect of oxaliplatin on OS did not differ by stage of disease (interaction P = .38 for OS; interaction P = 0.37 for DFS) but did vary by age for OS (younger than age 70 v 70+ interaction P = .039). There was a similar trend for DFS (interaction P = .073). Oxaliplatin significantly improved OS in patients younger than age 70 (HR, 0.80; 95% CI, 0.68 to 0.95; P = .013), but no positive effect was evident in older patients. CONCLUSION: Overall, the addition of oxaliplatin to FULV has not been proven to extend OS in this trial, but the DFS effect remained strong. Unplanned subset analyses suggest a significant OS effect of oxaliplatin in patients younger than age 70.

Phase III trial assessing bevacizumab in stages II and III carcinoma of the colon: results of NSABP protocol C-08.

PURPOSE: The National Surgical Adjuvant Breast and Bowel Project C-08 trial was designed to investigate the safety and efficacy of adding bevacizumab to modified FOLFOX6 (mFOLFOX6; ie, infusional/bolus fluorouracil, leucovorin, and oxaliplatin) for the adjuvant treatment of patients with stages II to III colon cancer. METHODS: Patients received mFOLFOX6 every 2 weeks for 26 weeks alone or modified as FOLFOX6 + bevacizumab (5 mg/kg every 2 weeks for 52 weeks [ie, experimental group]). The primary end point was disease-free survival (DFS). RESULTS: Among 2,672 analyzed patients, demographic factors were well balanced by treatment. With a median follow-up of 35.6 months, the addition of bevacizumab to mFOLFOX6 did not result in an overall significant increase in DFS (hazard ratio [HR], 0.89; 95% CI, 0.76 to 1.04; P = .15). The point estimates for 3-year DFS for the overall population were 77.4% and 75.5% for the experimental and control arms, respectively. For patients with stages II and III diseases, these same estimates were 87.4% and 84.7%, respectively, for stage II and 74.2% and 72.4%, respectively, for stage III. Exploratory analyses found that the effect of bevacizumab on DFS was different before and after a 15-month landmark (time-by-treatment interaction P value < .0001). Bevacizumab had a strong effect before the landmark (HR, 0.61; 95% CI, 0.48 to 0.78; P < .001) but no significant effect after (HR, 1.22; 95% CI, 0.98 to 1.52; P = .076). CONCLUSION: Bevacizumab for 1 year with mFOLFOX6 does not significantly prolong DFS in stages II and III colon cancer. However, a significant but transient effect during bevacizumab exposure was observed in the experimental arm. We postulate that this observation reflects a biologic effect during bevacizumab exposure. Given the lack of improvement in DFS, the use of bevacizumab cannot be recommended for use in the adjuvant treatment of patients with colon cancer.

Preoperative multimodality therapy improves disease-free survival in patients with carcinoma of the rectum: NSABP R-03.

PURPOSE: Although chemoradiotherapy plus resection is considered standard treatment for operable rectal carcinoma, the optimal time to administer this therapy is not clear. The NSABP R-03 (National Surgical Adjuvant Breast and Bowel Project R-03) trial compared neoadjuvant versus adjuvant chemoradiotherapy in the treatment of locally advanced rectal carcinoma. PATIENTS AND METHODS: Patients with clinical T3 or T4 or node-positive rectal cancer were randomly assigned to preoperative or postoperative chemoradiotherapy. Chemotherapy consisted of fluorouracil and leucovorin with 45 Gy in 25 fractions with a 5.40-Gy boost within the original margins of treatment. In the preoperative group, surgery was performed within 8 weeks after completion of radiotherapy. In the postoperative group, chemotherapy began after recovery from surgery but no later than 4 weeks after surgery. The primary end points were disease-free survival (DFS) and overall survival (OS). RESULTS: From August 1993 to June 1999, 267 patients were randomly assigned to NSABP R-03. The intended sample size was 900 patients. Excluding 11 ineligible and two eligible patients without follow-up data, the analysis used data on 123 patients randomly assigned to preoperative and 131 to postoperative chemoradiotherapy. Surviving patients were observed for a median of 8.4 years. The 5-year DFS for preoperative patients was 64.7% v 53.4% for postoperative patients (P = .011). The 5-year OS for preoperative patients was 74.5% v 65.6% for postoperative patients (P = .065). A complete pathologic response was achieved in 15% of preoperative patients. No preoperative patient with a complete pathologic response has had a recurrence. CONCLUSION: Preoperative chemoradiotherapy, compared with postoperative chemoradiotherapy, significantly improved DFS and showed a trend toward improved OS.

Initial safety report of NSABP C-08: A randomized phase III study of modified FOLFOX6 with or without bevacizumab for the adjuvant treatment of patients with stage II or III colon cancer.

PURPOSE: The National Surgical Adjuvant Breast and Bowel Project C-08 trial was designed to investigate the safety and effectiveness of adding bevacizumab to modified infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX) 6 regimen for the adjuvant treatment of patients with stage II or III colon cancer. We present safety information in advance of the planned analysis of efficacy. PATIENTS AND METHODS: Among 2,710 randomly assigned patients, demographic factors were balanced. Patients received modified FOLFOX6 every 2 weeks x 12 or modified FOLFOX6 plus bevacizumab (5 mg/kg every 2 weeks x 26, experimental group). RESULTS: Overall rates of grade 4 or 5 toxicities were nearly identical in the FOLFOX6 and FOLFOX6 plus bevacizumab arms (15.2% and 15.0%, respectively). Six-month mortality rates were 0.96% and 0.90% for the control and experimental groups, respectively. Grade 3+ toxicities that occurred more often in the experimental arm versus control arm included hypertension (12% v 1.8%, respectively), wound complications (abdominal incisional hernia or infusion port dehiscence/inflammation; 1.7% v 0.3%, respectively), pain (11.1% v 6.3%, respectively), and proteinuria (2.7% v 0.8%, respectively). Grade 2+ neuropathy was increased in the experimental arm versus the control arm (grade 2, 33% v 29%, respectively; grade 3, 16% v 14%, respectively; and grade 4, < 1% each). In the experimental arm versus control arm, significantly less thrombocytopenia (1.4% v 3.4%, respectively) and fewer allergic reactions (3.1% v 4.7%, respectively) were observed. Advanced age was associated with a significantly greater rate of grade 4 and 5 toxicities regardless of treatment. CONCLUSION: Bevacizumab with modified FOLFOX6 is well tolerated in the surgical adjuvant setting in these patients. No significant increase in GI perforation, hemorrhage, arterial or venous thrombotic events, or death with the addition of bevacizumab to modified FOLFOX6 has been observed. Follow-up for potential delayed adverse effects and efficacy is ongoing.

Neurotoxicity from oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: NSABP C-07.

PURPOSE: The randomized, multicenter, phase III protocol C-07 compared the efficacy of adjuvant bolus fluorouracil and leucovorin (FULV) versus FULV with oxaliplatin (FLOX) in stage II or III colon cancer. Definitive analysis revealed an increase in 4-year disease-free survival from 67.0% to 73.2% in favor of FLOX. This study compares neurotoxicity between the treatments. PATIENTS AND METHODS: Neurotoxicity was recorded for all patients using standard adverse event reporting. Patients at select institutions completed a neurotoxicity questionnaire through 18 months of follow-up. RESULTS: A total of 2,492 patients enrolled onto C-07 and 400 patients enrolled onto the patient-reported substudy. Mean patient-reported neurotoxicity was higher with oxaliplatin throughout the 18 months of study (P < .0001). During therapy, patients receiving oxaliplatin experienced significantly more hand/foot toxicity (eg, "quite a bit" of cold-induced hand/foot pain 26% FLOX v 2.6% FULV) and overall weakness (eg, moderate weakness in 27.4% FLOX v 16.2% FULV). At 18 months, hand neuropathy had diminished, but patients who received oxaliplatin experienced continued foot discomfort (eg, moderate foot numbness and tingling for 22.1% FLOX v 4.6% FULV). Observer-reported neurotoxicity was low grade and primarily neurosensory rather than neuromotor. Sixty-eight percent in the FLOX group v 8% in the FULV group had neurotoxicity at their first on-treatment assessment. Time to resolution was significantly longer for those receiving oxaliplatin, and continued beyond 2 years for more than 10% in the oxaliplatin group. CONCLUSION: Oxaliplatin causes significant neurotoxicity. It is experienced primarily in the hands during therapy and in the feet during follow-up. In a minority of patients the neurotoxicity is long lasting.

Oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: results from NSABP C-07.

PURPOSE: This phase III clinical trial evaluated the impact on disease-free survival (DFS) of adding oxaliplatin to bolus weekly fluorouracil (FU) combined with leucovorin as surgical adjuvant therapy for stage II and III colon cancer. PATIENTS AND METHODS: Patients who had undergone a potentially curative resection were randomly assigned to either FU 500 mg/m2 intravenous (IV) bolus weekly for 6 weeks plus leucovorin 500 mg/m2 IV weekly for 6 weeks during each 8-week cycle for three cycles (FULV), or the same FULV regimen with oxaliplatin 85 mg/m2 IV administered on weeks 1, 3, and 5 of each 8-week cycle for three cycles (FLOX). RESULTS: A total of 2,407 patients (96.6%) of the 2,492 patients randomly assigned were eligible. Median follow-up for patients still alive is 42.5 months. The hazard ratio (FLOX v FULV) is 0.80 (95% CI, 0.69 to 0.93), a 20% risk reduction in favor of FLOX (P < .004). The 3- and 4-year disease-free survival (DFS) rates were 71.8% and 67.0% for FULV and 76.1% and 73.2% for FLOX, respectively. Grade 3 neurosensory toxicity was noted in 8.2% of patients receiving FLOX and in 0.7% of those receiving FULV (P < .001). Hospitalization for diarrhea associated with bowel wall thickening occurred in 5.5% of the patients receiving FLOX and in 3.0% of the patients receiving FULV (P < .01). A total of 1.2% of patients died as a result of any cause within 60 days of receiving chemotherapy, with no significant difference between regimens. CONCLUSION: The addition of oxaliplatin to weekly FULV significantly improved DFS in patients with stage II and III colon cancer. FLOX can be recommended as an effective option in clinical practice.

Oral uracil and tegafur plus leucovorin compared with intravenous fluorouracil and leucovorin in stage II and III carcinoma of the colon: results from National Surgical Adjuvant Breast and Bowel Project Protocol C-06.

PURPOSE: The primary aim of this study was to compare the relative efficacy of oral uracil and tegafur (UFT) plus leucovorin (LV) with the efficacy of weekly intravenous fluorouracil (FU) plus LV in prolonging disease-free survival (DFS) and overall survival (OS) after primary surgery for colon carcinoma. PATIENTS AND METHODS: Between February 1997 and March 1999, 1,608 patients with stage II and III carcinoma of the colon were randomly assigned to receive either oral UFT+LV or intravenous FU+LV. RESULTS: Of the total patients, 47% had stage II colon cancer, and 53% had stage III colon cancer. Median follow-up time was 62.3 months. The estimated hazard ratio (HR) for OS of patients who received UFT+LV versus that of patients who received FU+LV was 1.014 (95% CI, 0.825 to 1.246). The estimated HR for DFS was 1.004 (95% CI, 0.847 to 1.190). Cox proportional hazards model analyses with regard to age (< 60 v > or = 60 years), stage, or number of involved nodes (none v one to three v > or = four nodes) revealed no interaction with OS or DFS. Toxicity was similar in the two groups. In the UFT+LV arm, 38.2% of patients experienced any grade 3 or 4 toxic event compared with 37.8% of patients in the FU+LV arm. Primary quality-of-life end points did not differ between the two regimens, although convenience of care analysis favored UFT+LV. CONCLUSION: UFT+LV achieved similar DFS and OS when compared with an intravenous, weekly, bolus FU+LV regimen. The two regimens were equitoxic and generally well tolerated.

Pemetrexed/oxaliplatin for first-line treatment of patients with advanced colorectal cancer: a phase II trial of the National Surgical Adjuvant Breast and Bowel Project Foundation Research Program.

BACKGROUND: Pemetrexed and oxaliplatin have clinical activity as single agents in colorectal cancer (response rates, 10%-17%). In this study, these drugs were used in combination as first-line therapy in a group of patients with metastatic colorectal cancer. PATIENTS AND METHODS: Fifty-four evaluable patients were to receive pemetrexed (500 mg/m2) with folic acid and vitamin B12 supplementation and oxaliplatin (120 mg/m2) every 21 days for 6 cycles or until disease progression occurred. Patients with stable or responding disease could continue therapy beyond 6 cycles at the discretion of the investigator. Eligibility criteria included a diagnosis of untreated metastatic adenocarcinoma of the colon or rectum, measurable disease, Zubrod performance status or=12 weeks life expectancy. RESULTS: The confirmed clinical response rate (primary endpoint) was 29.6% (95% confidence interval [CI], 18%-48.6%), with 1 complete response and 15 partial responses. Median time to progression was 5.3 months (95% CI, 3.9-6.3 months), and median survival was 12.3 months (95% CI, 8.6-17 months). Grade 3/4 nadir neutropenia occurred in 33.3% of patients, and 3 patients experienced grade 3 febrile neutropenia or infection associated with grade 3/4 neutropenia. Grade 3/4 nadir thrombocytopenia was seen in 11.1% of patients. Only 4% of the patients developed grade 3/4 neurotoxicity. CONCLUSION: This regimen of pemetrexed and oxaliplatin has activity in advanced colorectal cancer, and the toxicity profile suggests that escalation of the dose of pemetrexed in this combination may be possible.

Prognostic value of thymidylate synthase, Ki-67, and p53 in patients with Dukes' B and C colon cancer: a National Cancer Institute-National Surgical Adjuvant Breast and Bowel Project collaborative study.

PURPOSE: To define the value of thymidylate synthase (TS), Ki-67, and p53 as prognostic markers in patients with stage II and III colon carcinoma. PATIENTS AND METHODS: We retrospectively analyzed the prognostic value of TS, Ki-67, and p53 in 706 patients with Dukes' B (291 patients) or Dukes' C (415 patients) colon carcinoma who were treated with either surgery alone (275 patients) or surgery plus fluorouracil (FU)-leucovorin chemotherapy (431 patients) in National Surgical Adjuvant Breast and Bowel Project (NSABP) protocols C01-C04. All three markers were assayed using immunohistochemical techniques. RESULTS: Using 5 years of follow-up data, our retrospective analysis demonstrated an association between TS intensity (relapse-free survival [RFS]: risk ratio [RR] = 1.46, P =.01; overall survival [OS]: RR = 1.54, P =.002), Ki-67 (RFS: RR = 0.76, P =.05; OS: RR = 0.62, P =.001), and p53 (RFS: RR = 1.49, P =.01; OS: RR = 1.21, P =.18) for RFS and OS. High TS intensity levels and positive p53 staining were associated with a worse outcome. Tumors containing a high percentage of Ki-67-positive cells enjoyed an improved outcome compared with those patients whose tumors contained relatively few positive cells. An interaction with treatment was not identified for any of the markers. CONCLUSION: This retrospective investigation demonstrated that TS, Ki-67, and p53 staining each had significant prognostic value for patients with Dukes' B and C colon carcinoma. However, none of the markers could be used to clearly discern groups of individuals who would be predicted to derive greater or lesser benefit from the use of adjuvant chemotherapy.