Phase II study of S-1 on alternate days plus bevacizumab in patients aged ≥ 75 years with metastatic colorectal cancer (J-SAVER)
BackgroundAlternate-day administration of S-1 is thought to reduce toxicities. This phase II study evaluated S-1 on alternate days combined with bevacizumab as first-line treatment for elderly patients with metastatic colorectal cancer.Patients and methodsEligible patients had histologically proven colorectal adenocarcinoma, measurable metastatic lesions, age ≥ 75 years, Eastern Cooperative Oncology Group performance status ≤ 1, no previous chemotherapy, and refused oxaliplatin- or irinotecan-containing regimens. Patients received 40 mg, 50 mg, or 60 mg (body surface area ≤ 1.25 m2, > 1.25 to ≤ 1.50 m2, or > 1.50 m2, respectively) of S-1 twice orally on Sunday, Monday, Wednesday, and Friday every week. Bevacizumab (7.5 mg/kg) was administered every 3 weeks. The primary endpoint was progression-free survival.ResultsOf 54 enrolled patients, 50 patients were evaluated for efficacy and 53 for safety. The median age was 79 years (range 75–88 years). The median progression-free survival was 8.1 months (95% confidence interval (CI) 6.7–9.5 months). The median overall survival was 23.1 months (95% CI 17.4–28.8 months). The response rate was 44% (95% CI 30.2–57.8%), and the disease control rate was 88% (95% CI 79.0–97.0%). Grade 3 or higher hematologic, non-hematologic, and bevacizumab-related adverse events occurred in 9%, 11%, and 25% of patients, respectively. The most common grade 3 and 4 treatment-related adverse events were hypertension (11%), nausea (6%), fatigue (6%), anemia (6%), and proteinuria (6%). Only 6 patients discontinued treatment due to adverse events.ConclusionS-1 on alternate days combined with bevacizumab showed better tolerability and comparable survival compared with the results of similar studies.
Bevacizumab is equally effective and no more toxic in elderly patients with advanced colorectal cancer: a subgroup analysis from the AGITG MAX trial: an international randomised controlled trial of Capecitabine, Bevacizumab and Mitomycin C.
BACKGROUND
In an ageing population, a greater proportion of geriatric patients will be considered for systemic chemotherapy. Colorectal cancer (CRC) is a common malignancy and will be a major health issue in geriatrics. We used the MAX population to investigate whether age affected the improved outcome found in CRC when bevacizumab is added to capecitabine chemotherapy.


PATIENTS AND METHODS
MAX, a three arm study of Capecitabine (C) versus CBevacizumab (CB) versus CBMitomycin C (CBM), found an improvement in progression-free survival (PFS), with addition of B [+/- mitomycin C (MMC)] to C. This analysis assesses the effect of adding B (+/- MMC) to C on PFS, overall survival (OS), response rate (RR), toxicity and dose intensity in geriatric patients (age ≥ 75 years).


RESULTS
Ninety-nine patients (21%) were aged 75-86 years. Baseline characteristics were well balanced. Eighty-eight per cent commenced C at the lower optional dose of 2000 mg/m(2)/day; days 1-14, q21 (61% for <75 years) and 88% were Eastern Cooperative Oncology Group 0-1. Co-morbidities were as expected in this population. The addition of B significantly improved PFS in geriatric patients(C 5.8 months versus CB 8.8 months, Hazard ratio (HR) 0.65 and C versus CBM 10.4 months HR 0.38). The interaction test for OS, RR and PFS revealed no impact of age. Dose intensity was maintained >90% in all patients. There were no major differences in toxicity patterns between age cohorts.


CONCLUSIONS
Addition of B to C significantly improved PFS in this geriatric population, with similar benefits to those aged <75 years. Treatment was well tolerated with no signal of increased toxicity (including thromboembolism) when compared with those aged <75 years.
Conceptual Changes in Cancer Chemotherapy: From an Oral Fluoropyrimidine Prodrug, UFT, to a Novel Oral Fluoropyrimidine Prodrug, S-1, and Low-Dose FP Therapy in Japan
The conventional concept in cancer chemotherapyconsiders that no efficacy can be attained withoutprovoking adverse reactions. We presented concretedescriptions based on a novel concept allowing us toemerge from the old one. Relief of adverse reactions,e.g., diarrhea, stomatitis, anorexia, and H&Fsyndrome, not only improves QOL of the patient butalso allows prolongation of the treatment periodwithout lowering patient compliance.We describe in this paper a therapeutic modality which is basedon SRC (self-rescuing concept)featuring dual activity, i.e., effect-enhancingactivity and adverse reaction-reducing activity.We present the theory and practice of S-1, anovel oral fluoropyrimidine anticancer agent designedto enhance anticancer activity and reducegastrointestinal toxicity through the deliberatecombination of the following components: an oralfluoropyrimidine agent tegafur; a DPD inhibitor (CDHP)which is more potent than uracil used in UFT; and anORTC inhibitor (Oxo) which localizes in thegastrointestinal tract. Furthermore, we refer tocombination therapy with 5-FU (CIV) and low-doseconsecutive CDDP in which CDDP was used as a modulatorof 5-FU and to the theory and practice of combinationtherapy with 5-FU (CVI) intermittent (Monday,Wednesday, and Friday) administration and low-doseCDDP consecutive administration in which a differencein cell cycle between gastrointestinal mucosal celland tumor cell or between bone marrow cell and tumorcell was utilized. We intend in future to combinethe abovementioned therapeutic modalities provokingless adverse reactions and being gentle to patientswith cancer in an effort to further increase theirlife expectancy.