Chronomodulated capecitabine and adjuvant radiation in intermediate-risk to high-risk rectal cancer: a phase II study.

OBJECTIVES: The aim of this study was to evaluate the feasibility and tolerability of capecitabine administration according to a specific time schedule, combined with adjuvant radiation therapy, in intermediate-risk to high-risk rectal cancer patients treated with an upfront surgery. The primary endpoint was the rate of grade 3 to 4 diarrhea during chemoradiation (CRT). MATERIALS AND METHODS: Stage II and III rectal cancer patients received, after total mesorectal excision, 2 cycles of XELOX regimen (oxaliplatin 130 mg/m(2) on day 1; capecitabine 1000 mg/m(2) bid on day 1 to 14, q21), followed by capecitabine (800 mg/m(2) bid daily; 20% dose at 12:00 AM and 80% dose at 12:00 PM) administered continuously during pelvic radiation (total 50.4 Gy in 28 fractions, 1.8 Gy daily dose between 2:00 and 4:00 PM). Four additional cycles of XELOX were administered after chemoradiotherapy. RESULTS: Fifty-one radically resected rectal cancer patients were enrolled. All, but one, cases were evaluated for safety of CRT. We reported a grade 3 and 4 diarrhea rate of 14% (7 of 50 patients), whereas no grade 3 and 4 leukopenia was observed. Grade 1 and 2 proctitis was observed in 26 (52%) cases, whereas grade 1 and 2 cystitis in 5 (10%) patients. Only 2 cases of grade 3 proctitis and cystitis were reported, respectively. The CRT phase was feasible and was completed by 43 (84%) patients. Three patients developed actinic enteritis 60 days after the end of the radiotherapy program. CONCLUSIONS: Capecitabine timetable administration combined with adjuvant radiation therapy of rectal cancer is well tolerated and feasible. Further investigation of this chronomodulated schedule in terms of efficacy is warranted in neoadjuvant setting.

Feasibility study of biweekly capecitabine, oxaliplatin, and irinotecan in patients with untreated advanced gastric cancer.

BACKGROUND: Capecitabine in combination with oxaliplatin and irinotecan (COI regimen) is active and well tolerated in metastatic colorectal cancer. Since there is no internationally adopted standard regimen, we have conducted a pilot study of COI in untreated advanced gastric cancer. METHODS: Patients received irinotecan, 180 mg/m2 infused over 90 min on day 1, followed by oxaliplatin, 85 mg/m2 in a 3-hr infusion on day 2, and capecitabine, 1000 mg/m2/day orally twice daily from days 2 to 6 of a biweekly schedule. Treatment was continued up to 8 cycles or until progression of disease occurred. Response (RECIST criteria) was assessed after the first three cycles and was to be confirmed at least 4 weeks following the first response. RESULTS: A total of 12 patients (5 men and 7 women) with a median age of 54 years (range, 42-65) was prospectively enrolled. Most of the patients (83%) had metastatic disease. Three complete responses, four partial responses and two disease stabilizations occurred in the intention-to-treat cohort, with an overall response rate of 58% (95% confidence interval, 28-85%). Median time to progressive disease and overall survival were 6.4 and 12 months, respectively. A total of 68 cycles was administered, with a median of 6 cycles per patient (range, 1-8). Grade 3 neutropenia occurred in two patients. The most common non-hematologic grade 3 toxicities were nausea (3 patients) and diarrhea 12 patients). CONCLUSIONS: These preliminary findings suggest that biweekly COI is a feasible and promising triplet for the first-line treatment of advanced gastric cancer. A large multi-institutional phase II study of the combination has already been planned in this setting.

Dose finding study of erlotinib combined to capecitabine and irinotecan in pretreated advanced colorectal cancer patients.

PURPOSE: This study evaluated the maximum tolerated dose (MTD) and the dose limiting toxicity (DLT) of erlotinib when combined to irinotecan and capecitabine in pre-treated metastatic colorectal cancer patients. METHODS: Five dose level combinations with irinotecan (from 180 to 240 mg/m(2), day 1, q21), capecitabine (1,500-2,000 mg/m(2) per day, days 2-15, q21) and erlotinib (50-150 mg per day, continuously) were planned. Patients were enrolled in cohorts of three, and evaluated for first cycle acute toxicity. RESULTS: Twenty-one patients were treated. In the first cohort, no DLT was reported, in the second: one DLT (G4 neutropenic fever associated with G3 cutaneous rash and mucositis); in the third dose level: two DLT (G3 diarrhea and G4 neutropenic fever). To confirm these results, other six patients were additionally included and no DLT was observed. CONCLUSIONS: The results documented that erlotinib at the dose of 100 mg per day, irinotecan 180 mg/m(2) and capecitabine 1,500 mg/m(2) per day for 14 days has an acceptable safety profile and appears suitable for further phase II studies.

Irinotecan, fluorouracil and folinic acid (FOLFIRI) as effective treatment combination for patients with advanced gastric cancer in poor clinical condition.

AIMS AND BACKGROUND: Irinotecan (CPT-11) has been tested as a single agent in several studies, and response rates of 18-23% have been reported in first-line gastric cancer therapy. In the present study we report the safety and efficacy results combining CPT-11 with 5-fluorouracil (5-FU) and folinic acid (FA). PATIENTS AND METHODS: Thirty consecutive patients with metastatic gastric cancer, considered in poor clinical condition, were treated with CPT-11 and 5-FU/FA according to the FOLFIRI regimen. All enrolled cases were evaluable for toxicity and drug activity. RESULTS: The main grade 3-4 toxicity (according to the NCI-CTC criteria) was neutropenia (16%, grade 4 in 1 patient); non-hematological grade 3 toxicity consisted mainly in vomiting and diarrhea reported in 1 patient. No treatment-related serious adverse events were observed. Response was obtained in 12 patients (40%), stable disease in 2 patients (7%), while progression was documented in 16 patients (53%). CONCLUSIONS: These results are very promising, and suggest that the combination of CPT-11 plus 5-FU/FA is active and well tolerated and can be considered as useful treatment in patients with metastatic gastric cancer in poor clinical condition.

Feasibility of sequential therapy with FOLFIRI followed by docetaxel/cisplatin in patients with radically resected gastric adenocarcinoma. A randomized phase III trial.

OBJECTIVE: Combination therapies of fluorouracil (FU) with irinotecan (CPT-11) and docetaxel plus cisplatin have been proven to be active in metastatic gastric cancer. In this paper, we present the results of a phase III trial in which these two combinations given sequentially were compared to mitomycin C (MMC) monochemotherapy in an adjuvant setting. METHODS: 169 patients with radically resected gastric cancer were randomized to receive CPT-11 (180 mg/m2 day 1), leucovorin (100 mg/m2 days 1-2), FU (400-600 mg/m2 days 1-2, q 14; for four cycles; FOLFIRI regimen), followed by docetaxel (85 mg/m2 day 1), cisplatin (75 mg/m2 day 1, q 21; for three cycles; arm A), or MMC (8 mg/m2 days 1-2 as 2-hour infusion, q 42; for four cycles; arm B). All patients had histologically confirmed gastric carcinoma with nodal positivity or pT3/4. A total of 166 patients (85 in arm A and 81 in arm B) were treated. Adjuvant treatment was completed in 76% of the patients in arm A and in 70% of the patients in arm B. The main grade 3/4 side effects recorded were neutropenia in 35%, with only 1 febrile patient, and diarrhea in 11% in arm A, and thrombocytopenia in 10% and neutropenia in 7% in arm B. The FOLFIRI regimen and docetaxel/cisplatin given in sequence was well tolerated and feasible in adjuvant setting. This sequence treatment currently represents the experimental arm of an ongoing multicenter trial.

Treatment of cancer-related anemia with epoetin alfa: a review.

Erythropoietin (EPO) is a hematopoietic growth hormone that regulates survival, proliferation, and differentiation of erythroid progenitor cells. A reduction in tissue oxygenation stimulates EPO production, through a complex feedback mechanism. Patients with cancer-related anemia have an inadequate EPO response that is further impaired by cancer treatments such as chemotherapy. Cancer-related anemia substantially impairs patient functioning and may contribute to poor treatment outcomes. A significant number of studies demonstrates that treatment of anemia in cancer patients using recombinant human EPO (rHuEPO, epoetin alfa) significantly increases haemoglobin (Hb) levels, reduces transfusion requirements, and improves quality of life, particularly by relieving fatigue. Recent data also show that epoetin alfa therapy may improve cognitive function in patients receiving chemotherapy. In addition, the correction of anemia may prolong survival by enhancing tumor oxygenation, thus increasing tumor sensitivity to chemotherapy or radiation. The indicated dose of epoetin alfa is 150-300 IU/kg three times per week, but it is commonly dosed at 40,000-60,000 IU once weekly based on trial data and extensive clinical use. Determining the timing of initiation of epoetin alfa is a clinical judgement; however, data suggest that patient functioning declines and the risk of transfusion increases when the Hb level falls under 12 g/dL.

Raltitrexed plus oxaliplatin in the treatment of metastatic colorectal cancer.

AIMS AND BACKGROUND: As raltitrexed and oxaliplatin (L-OHP) are both effective in the treatment of colorectal cancer but have different mechanisms of action, we studied the antitumoral activity and safety of their combined use in patients with advanced colorectal cancer. METHODS: A 15-min intravenous infusion of raltitrexed (2.5 mg/m2) and a 180-min infusion of oxaliplatin (100 mg/m2) were administered on day 1 every three weeks for a maximum of six cycles. RESULTS: The study involved 51 patients (27 males and 24 females) with a median age of 65 years (range, 43-78); 28 were aged > or = 65 years. The primary tumor site was the colon in 35 patients and the rectum in 16. Thirty-four patients had received prior chemotherapy: 20 as adjuvant treatment and 14 as pretreatment. The most frequent metastatic sites were liver (18 cases), lung (10 cases), liver + lung (8 cases) and lymph nodes (3 cases). Twenty-four patients completed the entire treatment plan. The most common toxicities were transaminitis (16 patients, grade 3-4), diarrhea (six patients, grade 3), nausea/vomiting (one patient, grade 4), and asthenia (one patient, grade 3). The treatment was stopped in one patient because of prolonged grade 4 transaminitis. The adverse event profile was similar in the patients aged > 65 years and < 65 years. Complete responses were observed in 2 patients, partial responses in 12, stable disease in 23, and progression in 8. CONCLUSIONS: The results of the study suggest that the raltitrexed plus oxaliplatin regimen is feasible and clinically active in advanced colorectal cancer.

Efficacy of treatment with irinotecan and oxaliplatin combination in FU-resistant metastatic colorectal cancer patients.

OBJECTIVES: As single agents, irinotecan and oxaliplatin are active in colorectal cancer after fluorouracil (FU)-containing regimen failure. Their synergistic activity and non-overlapping toxicity profile are well documented, but more data are needed to explore their exact sequence. The aim of this study was to evaluate the activity and tolerability of irinotecan followed by oxaliplatin in patients with FU-resistant colorectal cancer. METHODS: FU resistance was defined as disease progression during or within 6 months of discontinuing first-line or adjuvant FU/leucovorin chemotherapy. The study treatment consisted of irinotecan 150 mg/m(2) on days 1 and 8 followed by oxaliplatin 85 mg/m(2) on day 1 every 3 weeks. In order to improve the safety profile, we changed the schedule during the study to irinotecan 300 mg/m(2) on day 1 and oxaliplatin 85 mg/m(2) on day 2 every 3 weeks. RESULTS: Of 54 patients treated, the 45 patients with measurable disease were assessed in the efficacy analysis, whereas all patients receiving at least one cycle were evaluated in the safety analysis. Of the patients assessed for efficacy analysis, 19 cases received the first schedule and 26 patients received the second schedule. Twenty-two patients (49%) responded, 10 of the first schedule and 12 of the second schedule group. Stable disease was observed in 35% of all patients. The median response duration was 6.5 months (range 3-10), the median time to progression was 8 months (range 6-10), and the overall survival was 15 months (10-26+). The NCI-CTC grade 3 side effects documented in all of the treated patients were: nausea/vomiting (11%), diarrhea (18%), and neutropenia (7%); grade 4 diarrhea was observed in 2% of patients. CONCLUSION: The combination of irinotecan followed by oxaliplatin combination is well tolerated and highly active in FU-resistant metastatic colorectal cancer patients.