A. Figer

Erlotinib Plus Gemcitabine Compared With Gemcitabine Alone in Patients With Advanced Pancreatic Cancer: A Phase III Trial of the National Cancer Institute of Canada Clinical Trials Group

PURPOSE Patients with advanced pancreatic cancer have a poor prognosis and there have been no improvements in survival since the introduction of gemcitabine in 1996. Pancreatic tumors often overexpress human epidermal growth factor receptor type 1 (HER1/EGFR) and this is associated with a worse prognosis. We studied the effects of adding the HER1/EGFR-targeted agent erlotinib to gemcitabine in patients with unresectable, locally advanced, or metastatic pancreatic cancer. PATIENTS AND METHODS Patients were randomly assigned 1:1 to receive standard gemcitabine plus erlotinib (100 or 150 mg/d orally) or gemcitabine plus placebo in a double-blind, international phase III trial. The primary end point was overall survival. RESULTS A total of 569 patients were randomly assigned. Overall survival based on an intent-to-treat analysis was significantly prolonged on the erlotinib/gemcitabine arm with a hazard ratio (HR) of 0.82 (95% CI, 0.69 to 0.99; P = .038, adjusted for stratification factors; median 6.24 months v 5.91 months). One-year survival was also greater with erlotinib plus gemcitabine (23% v 17%; P = .023). Progression-free survival was significantly longer with erlotinib plus gemcitabine with an estimated HR of 0.77 (95% CI, 0.64 to 0.92; P = .004). Objective response rates were not significantly different between the arms, although more patients on erlotinib had disease stabilization. There was a higher incidence of some adverse events with erlotinib plus gemcitabine, but most were grade 1 or 2. CONCLUSION To our knowledge, this randomized phase III trial is the first to demonstrate statistically significantly improved survival in advanced pancreatic cancer by adding any agent to gemcitabine. The recommended dose of erlotinib with gemcitabine for this indication is 100 mg/d.

Bevacizumab in Combination With Oxaliplatin-Based Chemotherapy As First-Line Therapy in Metastatic Colorectal Cancer: A Randomized Phase III Study

PURPOSE To evaluate the efficacy and safety of bevacizumab when added to first-line oxaliplatin-based chemotherapy (either capecitabine plus oxaliplatin [XELOX] or fluorouracil/folinic acid plus oxaliplatin [FOLFOX-4]) in patients with metastatic colorectal cancer (MCRC). PATIENTS AND METHODS Patients with MCRC were randomly assigned, in a 2 x 2 factorial design, to XELOX versus FOLFOX-4, and then to bevacizumab versus placebo. The primary end point was progression-free survival (PFS). RESULTS A total of 1,401 patients were randomly assigned in this 2 x 2 analysis. Median progression-free survival (PFS) was 9.4 months in the bevacizumab group and 8.0 months in the placebo group (hazard ratio [HR], 0.83; 97.5% CI, 0.72 to 0.95; P = .0023). Median overall survival was 21.3 months in the bevacizumab group and 19.9 months in the placebo group (HR, 0.89; 97.5% CI, 0.76 to 1.03; P = .077). Response rates were similar in both arms. Analysis of treatment withdrawals showed that, despite protocol allowance of treatment continuation until disease progression, only 29% and 47% of bevacizumab and placebo recipients, respectively, were treated until progression. The toxicity profile of bevacizumab was consistent with that documented in previous trials. CONCLUSION The addition of bevacizumab to oxaliplatin-based chemotherapy significantly improved PFS in this first-line trial in patients with MCRC. Overall survival differences did not reach statistical significance, and response rate was not improved by the addition of bevacizumab. Treatment continuation until disease progression may be necessary in order to optimize the contribution of bevacizumab to therapy.

OPTIMOX1: A Randomized Study of FOLFOX4 or FOLFOX7 With Oxaliplatin in a Stop-and-Go Fashion in Advanced Colorectal Cancer—A GERCOR Study

PURPOSE In metastatic colorectal cancer, a combination of leucovorin (LV) and fluorouracil (FU) with oxaliplatin (FOLFOX) 4 is a standard first-line regimen. The cumulative neurotoxicity of oxaliplatin often requires therapy to be stopped in patients who are still responding. This study evaluates a new strategy of intermittent oxaliplatin treatment that is based on FOLFOX7, a simplified leucovorin and fluorouracil regimen with high-dose oxaliplatin. PATIENTS AND METHODS Previously untreated patients were randomly assigned to either FOLFOX4 administered every 2 weeks until progression (arm A) or FOLFOX7 for six cycles, maintenance without oxaliplatin for 12 cycles, and reintroduction of FOLFOX7 (arm B). RESULTS Six hundred twenty patients were enrolled, including an exploratory cohort of 95 elderly or poor prognosis patients. Median progression-free survival and survival times were 9.0 and 19.3 months, respectively, in patients allocated to arm A compared with 8.7 and 21.2 months, respectively, in patients allocated to arm B (P = not significant). Response rates were 58.5% with arm A and 59.2% with arm B. National Cancer Institute Common Toxicity Criteria grade 3 or 4 toxicity was observed in 54.4% of the patients in arm A v 48.7% of patients in arm B. From cycle 7, fewer patients experienced grade 3 or 4 toxicity in arm B. Grade 3 sensory neuropathy was observed in 17.9% of the patients in arm A v 13.3% of patients in arm B (P = .12). In arm B, oxaliplatin was reintroduced in only 40.1% of the patients but achieved responses or stabilizations in 69.4% of these patients. CONCLUSION Oxaliplatin can be safely stopped after six cycles in a FOLFOX regimen. Further study is needed to fully evaluate oxaliplatin reintroduction.

Randomized Phase III Study of Capecitabine Plus Oxaliplatin Compared With Fluorouracil/Folinic Acid Plus Oxaliplatin As First-Line Therapy for Metastatic Colorectal Cancer

PURPOSE To evaluate whether capecitabine plus oxaliplatin (XELOX) is noninferior to fluorouracil. folinic acid, and oxaliplatin (FOLFOX-4) as first-line therapy in metastatic colorectal cancer (MCRC). PATIENTS AND METHODS The initial design of this trial was a randomized, two-arm, noninferiority, phase III comparison of XELOX versus FOLFOX-4. After patient accrual had begun, the trial design was amended in 2003 after bevacizumab phase III data became available. The resulting 2 x 2 factorial design randomly assigned patients to XELOX versus FOLFOX-4, and then to also receive either bevacizumab or placebo. We report here the results of the analysis of the XELOX versus FOLFOX-4 arms. The analysis of bevacizumab versus placebo with oxaliplatin-based chemotherapy is reported separately. The prespecified primary end point for the noninferiority analysis was progression-free survival. RESULTS The intent-to-treat population comprised 634 patients from the original two-arm portion of the study, plus an additional 1,400 patients after the start of the amended 2 x 2 design, for a total of 2,034 patients. The median PFS was 8.0 months in the pooled XELOX-containing arms versus 8.5 months in the FOLFOX-4-containing arms (hazard ratio [HR], 1.04; 97.5% CI, 0.93 to 1.16). The median overall survival was 19.8 months with XELOX versus 19.6 months with FOLFOX-4 (HR, 0.99; 97.5% CI, 0.88 to 1.12). FOLFOX-4 was associated with more grade 3/4 neutropenia/granulocytopenia and febrile neutropenia than XELOX, and XELOX with more grade 3 diarrhea and grade 3 hand-foot syndrome than FOLFOX-4. CONCLUSION XELOX is noninferior to FOLFOX-4 as a first-line treatment for MCRC, and may be considered as a routine treatment option for appropriate patients.

Edrecolomab alone or in combination with fluorouracil and folinic acid in the adjuvant treatment of stage III colon cancer: a randomised study

BACKGROUND Edrecolomab is a murine monoclonal antibody to the cell-surface glycoprotein 17-1A, which is expressed on epithelial tissues and on various carcinomas. Preliminary data suggested that it might be of use in the adjuvant treatment of patients with resected stage III colon cancer. We did a randomised trial in 27 countries to determine the effect of adding edrecolomab to the combination of fluorouracil and folinic acid in these patients. METHODS After surgery, 2761 patients were randomly assigned edrecolomab plus fluorouracil-folinic acid (combination therapy [n=912]); fluorouracil-folinic acid alone (chemotherapy [n=927]); or edrecolomab alone (edrecolomab monotherapy [n=922]). Patients were assessed for survival and disease recurrence after surgery. The primary endpoint tested the hypothesis that combination therapy improved overall survival relative to chemotherapy. The key secondary endpoint was to test whether edrecolomab monotherapy was non-inferior to chemotherapy in terms of disease-free survival. Analysis was by intention to treat. FINDINGS Median follow-up time was 26 months (IQR 20-36). 3-year overall survival on combination therapy was no different from that on chemotherapy (74.7% vs 76.1%, hazard ratio 0.94 [95% CI 0.76-1.15], p=0.53). Disease-free survival was significantly lower on edrecolomab monotherapy than on chemotherapy (53.0% vs 65.5%, 0.62 [0.53-0.73], p<0.0001). Hypersensitivity reactions occurred in 452 (25%) patients receiving edrecolomab, causing treatment discontinuation in 71 (4%). The addition of edrecolomab to chemotherapy did not increase neutropenia, diarrhoea, or mucositis. INTERPRETATION The addition of edrecolomab to fluorouracil and folinic acid in the adjuvant treatment of resected stage III colon cancer does not improve overall or disease-free survival, and edrecolomab monotherapy is associated with significantly shorter overall and disease-free survival than fluorouracil and folinic acid and is therefore an inferior treatment option. Edrecolomab is well tolerated and its addition to fluorouracil and folinic acid does not increase the toxicity of chemotherapy.

Phase III Trial of Capecitabine Plus Oxaliplatin As Adjuvant Therapy for Stage III Colon Cancer: A Planned Safety Analysis in 1,864 Patients

PURPOSE To report the results of a planned safety analysis from a phase III trial comparing capecitabine plus oxaliplatin (XELOX) with bolus fluorouracil/leucovorin (FU/LV) as adjuvant therapy for stage III colon cancer. PATIENTS AND METHODS Patients with stage III colon carcinoma were randomly assigned to receive either XELOX (intravenous oxaliplatin plus oral capecitabine; 3-week cycle for eight cycles) or standard intravenous bolus FU/LV administered as the Mayo Clinic (Mayo; Rochester, MN) or Roswell Park (RP; Buffalo, NY) regimen for a similar length of time. A total of 1,886 patients were randomly assigned. RESULTS The safety population comprised 1,864 patients, of whom 938 received XELOX and 926 received FU/LV. Most treatment-related adverse events (AEs) occurred at similar rates in both treatment arms. However, patients receiving XELOX experienced less all-grade diarrhea, alopecia, and more neurosensory toxicity, vomiting, and hand-foot syndrome than those patients receiving FU/LV. Compared with Mayo, XELOX showed fewer grade 3/4 hematologic AE and more grade 3/4 gastrointestinal AE. Compared with RP, XELOX showed less grade 3/4 gastrointestinal AE and more grade 3/4 hematologic AE. As expected grade 3/4 neurosensory toxicity and grade 3 hand-foot syndrome were higher with XELOX. Treatment-related mortality within 28 days from the last study dose was 0.6% in the XELOX group and 0.6% in the FU/LV group. CONCLUSION XELOX has a manageable tolerability profile in the adjuvant setting. Efficacy data will be available within the next 24 months.

XELOX vs FOLFOX-4 as first-line therapy for metastatic colorectal cancer: NO16966 updated results

Background:We report updated overall survival (OS) data from study NO16966, which compared capecitabine plus oxaliplatin (XELOX) vs 5-fluorouracil/folinic acid plus oxaliplatin (FOLFOX4) as first-line therapy in metastatic colorectal cancer.Methods:NO16966 was a randomised, two-arm, non-inferiority, phase III comparison of XELOX vs FOLFOX4, which was subsequently amended to a 2 × 2 factorial design with further randomisation to bevacizumab or placebo. A planned follow-up exploratory analysis of OS was performed.Results:The intent-to-treat (ITT) population comprised 2034 patients (two-arm portion, n=634; 2 × 2 factorial portion, n=1400). For the whole NO16966 study population, median OS was 19.8 months in the pooled XELOX/XELOX-placebo/XELOX-bevacizumab arms vs 19.5 months in the pooled FOLFOX4/FOLFOX4-placebo/FOLFOX4-bevacizumab arms (hazard ratio 0.95 (97.5% CI 0.85–1.06)). In the pooled XELOX/XELOX-placebo arms, median OS was 19.0 vs 18.9 months in the pooled FOLFOX4/FOLFOX4-placebo arms (hazard ratio 0.95 (97.5% CI 0.83–1.09)). FOLFOX4 was associated with more grade 3/4 neutropenia/granulocytopenia and febrile neutropenia than XELOX, and XELOX with more grade 3 diarrhoea and grade 3 hand-foot syndrome than FOLFOX4.Conclusion:Updated survival data from study NO16966 show that XELOX is similar to FOLFOX4, confirming the primary analysis of progression-free survival. XELOX can be considered as a routine first-line treatment option for patients with metastatic colorectal cancer.

Efficacy of FOLFIRI-3 (irinotecan D1,D3 combined with LV5-FU) or other irinotecan-based regimens in oxaliplatin-pretreated metastatic colorectal cancer in the GERCOR OPTIMOX1 study

BACKGROUND Second-line irinotecan-based chemotherapy is commonly used in metastatic colorectal cancers after first-line oxaliplatin-based chemotherapy. No standard schedule of irinotecan has been established in this situation. PATIENTS AND METHODS Metastatic colorectal cancer patients included in the OPTIMOX1 phase III study received first-line oxaliplatin-based chemotherapy (FOLFOX). No second line was defined in the protocol, but data concerning second line were prospectively registered. Inclusion criterion was patients receiving an irinotecan-based second-line chemotherapy. Second-line progression-free survival (PFS) and tumor response were evaluated according to type of irinotecan-based regimen administered. RESULTS A total of 342 patients received irinotecan-based chemotherapy as second-line chemotherapy: FOLFIRI-3 [n = 109, irinotecan 100 mg/m(2) days 1 and 3 combined with leucovorin (LV) 400 mg/m(2) day 1 and 46-h continuous 5-fluorouracil (5-FU) 2000 mg/m(2)], FOLFIRI-1 (n = 112, irinotecan 180 mg/m(2) day 1 combined with LV 400 mg/m(2) day 1, 5-FU bolus 400 mg/m(2) and 46-h continuous 5-FU 2400 mg/m(2)) and other various irinotecan-based regimens (n = 121). Median second-line PFS was 3.0 months (FOLFIRI-3: 3.7 months; FOLFIRI-1: 3.0 months; other regimens: 2.3 months). In multivariate analysis, FOLFIRI-3 regimen (relative risk 0.43, 95% confidence interval 0.28-0.68, P = 0.0003) and lactate deshydrogenase level at inclusion (P = 0.0006) in OPTIMOX1 were associated with a longer second-line PFS. CONCLUSION In unselected patients pretreated with oxaliplatin, PFS in second line appeared to be improved by FOLFIRI-3 regimen.

5-fluorouracil, folinic acid and oxaliplatin (FOLFOX) in very old patients with metastatic colorectal cancer

3571 Background: Pts with age over 75 years are usually excluded from randomised studies. OPTIMOX trial consisted in a phase III study for pts with conventional inclusion criteria (526 pts), comparing FOLFOX4 to FOLFOX7 x 6 cycles, followed simplified LV5FU2 x 12 cycles and FOLFOX7 reintroduction; and two exploratory studies in pts > 75 yrs (37 pts) and in pts with Alk Ph level > 3-time the UNV (63 pts), treated according to the same regimens. METHODS This report concerns the tolerance and the efficacy observed for the 37 pts aged 75 years or older. 20 pts were treated with FOLFOX4 (arm A), and 17 with FOLFOX7 - sLV5FU2 - FOLFOX7 (arm B). Characteristics of these pts were : PS 0/1-2=49/51%, LDH (normal / > normal / unknown) 51%/27%/22%, metastatic site (1/ > 1) 73/27%, alk phosp (nl/elevated/unknown) 59%/35%/6%. RESULTS 37 pts are evaluable for safety and 35 pts for response. Grade 3-4 toxicities (% of pts, arm A / arm B) were: neutrophils 55/24, platelets 5/0, hemoglobin 5/0, nausea-vomiting 0/12, diarrhea 5/6, neurotoxicity 20/24. Maximal toxicity per patient was grade 3-4 in 80% of arm A pts, and 59% of arm B pts. Response rate (intent-to-treat) was 59.4 % (arm A 65%; arm B 53%). Median PFS was 37 weeks (arm A 33 w; arm B 41 w) and median OS was 79 weeks (arm A 65w and arm B 90w). Moreover, in OPTIMOX study, age does not appear as a prognosis factor in a multivariate analysis. CONCLUSION These results indicate that efficacy is maintained with Folfox regimens in patients >75years. [Table: see text].

XELOX (capecitabine plus oxaliplatin), a safe and active first-line regimen for elderly patients with metastatic colorectal cancer (MCRC): Post-hoc analysis of a large phase II study

3555 Background: Tumor-activated capecitabine (Xeloda) has superior response rates and equivalent progression-free and overall survival compared with bolus 5-FU/LV in first-line MCRC, with favorable safety and fewer hospitalizations. This safety advantage is confirmed in the adjuvant setting, where improved safety is also seen in older patients. XELOX is safe and active in first-line MCRC and could also be suitable for older patients. METHODS In this post-hoc analysis of mature safety data in older vs younger patients, 96 patients with MCRC received first-line XELOX: oxaliplatin 130mg/m2 i.v. day 1 followed by oral capecitabine 1,000mg/m2 twice daily, evening day 1-morning day 15, every 3 weeks. All patients are evaluable: 64% male; median age 64 years (34-79); 52 younger patients (<65 years), 44 older patients (≥65 years); median KPS 100 (80-100). Primary tumor: 64% colon; 33% rectal; 3% both. Metastases: 54% >1 metastatic site; 77% liver, 38% lymph nodes, 32% lung. Prior adjuvant fluoropyrimidines: 28%. RESULTS Patients received a median nine cycles of XELOX. Safety profiles are similar in younger and older patients (table). The incidence of dose reductions and withdrawals for adverse events was similar. The activity of XELOX was also similar in both groups, response rates: 58% (95% CI, 43-71; younger) vs 52% (95% CI, 37-68; older). [Figure: see text] Conclusions: XELOX has a favorable safety profile with no clinically relevant differences between younger and older patients. Antitumor activity is preserved in older vs younger patients. These results imply that up-front dose reductions are not required when XELOX is prescribed in older patients. Ongoing phase II/III trials are prospectively evaluating XELOX in this population. [Table: see text].