VITAL phase 2 study: Upfront 5-fluorouracil, mitomycin-C, panitumumab and radiotherapy treatment in nonmetastatic squamous cell carcinomas of the anal canal (GEMCAD 09-02).

AIM: VITAL, a phase II single-arm study, aimed to evaluate efficacy and safety of panitumumab addition to 5-fluorouracil (5-FU), mitomycin-C (MMC) and radiotherapy (RT) in patients with localized squamous cell carcinoma of the anal canal (SCCAC). METHODS: Adult, treatment-naïve SCCAC patients (Stage T2-T4, any N, M0) and ECOG-PS ≤2, received panitumumab (6 mg/kg, day 1 and Q2W; 8 weeks), 5-FU (1000 mg/m2 /d, days 1-4 and 29-32), MMC (10 mg/m2 , days 1 and 29) and RT 45 Gy (1.8 Gy/fraction) to the primary tumor and mesorectal, iliac and inguinal lymph nodes, plus 10-15 Gy boost dose to the primary tumor and affected lymph nodes. The primary objective was disease free survival rate (DFS) at 3-years (expected 3-year DFS rate: 73.7 ± 12%). RESULTS: Fifty-eight patients (31 women; median age: 59 years; ECOG-PS 0-1:98%; TNM II [29%] (T2 or T3/N0/M0)/IIIA (T1-T3/N1/M0 or T4/N0/M0) [21%]/IIIB (T4/N1/M0 or any T/N2 or N3/M0) [47%]/nonevaluable [4%]) were included. The median follow-up was 45 months. The 3-year DFS rate was 61.1% (95% CI: 47.1, 72.4). The 3-year overall survival rate was 78.4% (95% CI: 65.1, 87.1). Eighteen patients (31.0%) required a colostomy within 2 years posttreatment. Grade 3-4 toxicities were experienced by 53 (91%) patients. Most common grade 3-4 treatment-related events were radiation skin injury (40%) and neutropenia (24%). No toxic deaths occurred. Improved efficacy in colostomy-free survival and complete response rate was observed in human papilloma virus positive patients. CONCLUSIONS: Panitumumab addition to MMC-5FU regimen in SCCAC patients increases toxicity and does not improve patients' outcomes. RT plus MMC-5FU remains the standard of care for localized SCCAC patients.

Oxaliplatin in combination with infusional 5-fluorouracil as first-line chemotherapy for elderly patients with metastatic colorectal cancer: a phase II study of the Spanish Cooperative Group for the Treatment of Digestive Tumors.

BACKGROUND: We previously reported a 35% overall response rate (ORR) with biweekly 5-fluorouracil (5-FU) continuous infusion (TTD [Spanish Cooperative Group for Digestive Tumour Therapy] schedule) plus irinotecan as first-line therapy in elderly patients with metastatic colorectal cancer (mCRC). The present study also was carried out in elderly patients to determine the efficacy and safety of the same 5-FU schedule plus oxaliplatin. PATIENTS AND METHODS: Patients (aged ≥72 years old) with mCRC, measurable disease, ECOG (Eastern Cooperative Oncology Group) ≤2, and no prior treatment were treated with oxaliplatin 85 mg/m(2) plus 5-FU 3000 mg/m(2) as a 48-hour infusion every 2 weeks. RESULTS: The study included 134 patients, of whom, 129 were eligible. The main comorbidities were hypertension (44%), diabetes (17%), and chronic obstructive pulmonary disease (11%). The ORR and disease control rate (ORR plus stable disease) were 52% and 80%, respectively. With a median follow-up of 14 months, the median progression-free survival and overall survival were 9.1 and 16.3 months, respectively. The most frequent grade 3/4 adverse events included neutropenia (16%), diarrhea (11%), and grade 3 neurotoxicity (18%). No correlation was found between efficacy or safety and comorbidities. CONCLUSIONS: To our knowledge, this is the largest phase II prospective study in elderly patients with mCRC. The observed efficacy and safety of this schedule compared favorably with those reported in this population, including regimens with monoclonal antibodies.

Addition of bevacizumab to XELOX induction therapy plus concomitant capecitabine-based chemoradiotherapy in magnetic resonance imaging-defined poor-prognosis locally advanced rectal cancer: the AVACROSS study.

BACKGROUND: Concomitant chemoradiotherapy followed by total mesorectal excision is standard treatment for locally advanced rectal cancer. This approach, however, focuses on local disease control and delays systemic treatment. Induction chemotherapy has the advantage of earlier administration of systemic therapy and may improve distant control. The objective of the current study was to assess the efficacy and toxicity of adding bevacizumab to induction chemotherapy followed by preoperative bevacizumab-based chemoradiotherapy in patients with locally advanced rectal cancer. PATIENTS AND METHODS: Eligible patients had high-risk rectal adenocarcinoma defined by magnetic resonance imaging criteria. Treatment consisted of four 21-day cycles of bevacizumab (7.5 mg/kg) and XELOX (capecitabine plus oxaliplatin), followed by concomitant radiotherapy (50.4 Gy) plus bevacizumab (5 mg/kg every 2 weeks) and capecitabine (825 mg/m2 twice daily on days 1-15). Surgery was scheduled for 6-8 weeks after chemoradiotherapy. The primary endpoint was pathologic complete response (pCR). RESULTS: Between July 2007 and July 2008, 47 patients were recruited. Among 45 patients who underwent surgery, pCR was achieved in 16 patients (36%; 95% confidence interval: 22.29%-51.27%), and an additional 17 patients (38%) had Dworak tumor regression grade 3. R0 resection was performed in 44 patients (98%). Most grade 3/4 adverse events occurred during the induction phase and included diarrhea (11%), asthenia (4%), neutropenia (6%), and thrombocytopenia (4%). Eleven patients (24%) required surgical reintervention. CONCLUSIONS: Addition of bevacizumab to induction chemotherapy and chemoradiotherapy is feasible, with impressive activity and manageable toxicity. However, caution is recommended regarding surgical complications.

Phase II study of irinotecan (CPT-11) administered every 2 weeks as treatment for patients with colorectal cancer resistant to previous treatment with 5-fluorouracil-based therapies: comparison of two different dose schedules (250 and 200 mg/m2) according to toxicity prognostic factors.

Our objective was to assess the antitumoral activity and toxicity of irinotecan (CPT-11) 60-min i.v. infusion every 2 weeks as second-line monotherapy of advanced colorectal cancer. Two doses were studied (250 and 200 mg/m) according to the risk of developing toxicity. Two groups of patients were studied: high-risk group (HR, 200 mg/m, n = 45; Karnofsky score 60-80% and/or the record of prior pelvic irradiation) and low-risk-group (LR, 250 mg/m, n = 51; Karnofsky score >80% and without prior pelvic irradiation). The mean number of cycles per patient was 7: 6.6 (HR group) and 8.3 (LR group). Median RDI was 0.96. The overall response rate was 8.9% [95% confidence interval (CI) 2.5-21.2%; HR group] and 15.7% (95% CI 7.0-28.5%; LR group), respectively. The LR group showed two complete responses and a higher percentage of stable disease (56.9 versus 33.3% in HR group). The median survival was 7.1 months (95% CI 5.2-8.9 months, HR group) and 11.7 months (95% CI 8.4-15.1 months, LR group). The median time to disease progression was 3.2 months (95% CI 1.0-5.4 months, HR group) and 5.3 months (95% CI 3.8-6.7 months, LR group). Both CPT-11 treatments were well tolerated. Grade 3/4 toxicity incidence was low, e.g. granulocytopenia (7% of patients in HR group and 9% in LR group) and delayed diarrhea (18% of patients in HR group and 14% in LR group). We conclude that the treatment of patients with the adjusted dose of CPT-11 according to prognostic factors for toxicity resulted in the improved toxicity profile, but showed poorer efficacy outcome. Therefore, the dose reduction in patients with low performance and treated with radiotherapy needs further investigation to provide some new insights on the benefit:risk ratio of such treatment.