Lessons learned: Difficulties in translating in vitro results into clinical practice are inevitable.Further efforts to verify the efficacy of alternative schedules of pemetrexed in solid tumors are encouraged.
Background: We investigated the cytotoxic activity of pemetrexed in combination with several drugs (gemcitabine, carboplatin, vinorelbine, and mitomycin C) using different exposure schedules in three colon cancer cell lines. The best results were obtained with the following schedule: a prolonged pemetrexed exposure followed by a 48-hour wash-out and then gemcitabine. This combination was then advanced to a phase II clinical trial.
Methods: Patients with metastatic colorectal cancer in progression after standard treatment were included in the study. Adequate bone marrow reserve, normal hepatic and renal function, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 were required. Treatment consisted of an 8-hour intravenous infusion of pemetrexed 150 mg/m2 on day 1 and a 30-minute intravenous infusion of gemcitabine 1,000 mg/m2 on day 3 of each cycle, repeated every 14 days.
Results: Fourteen patients were enrolled onto the study (first step). No objective responses were seen, and evidence of stable disease was observed in only one of the 12 evaluable patients. The most important grade 3-4 side effects were hematological toxicity (neutropenia 64.2%, thrombocytopenia 71.4%, anemia 28.7%), fatigue (50.0%), and stomatitis (21.5%). Median overall survival and time to progression were 5.8 months (95% confidence interval [CI]: 3.9-7.1) and 2.1 months (95% CI: 1.7-2.8), respectively.
Conclusion: The experimental pemetrexed-gemcitabine combination proved to be inactive and moderately toxic.
• 将体外结果转化为临床实践时, 遇到困难在所难免。
背景. 我们在3种结肠癌细胞系中考察了培美曲塞以不同给药方案与数种药物（吉西他滨、卡铂、长春瑞滨和丝裂霉素C）联用时的细胞毒活性。使用以下方案时获得了最佳结果：延长培美曲塞给药时间, 48小时洗脱期之后再给予吉西他滨。随后将这一联合用药方案推进至II期临床试验阶段。
方法. 本研究纳入了标准治疗后疾病进展的转移性结直肠癌患者。要求患者具有适当的骨髓储备、肝肾功能正常且美国东部肿瘤协作组（ECOG）体力状态评分为0‐2。治疗方案为在每个周期的第1天静脉输注培美曲塞150 mg/m2, 输注8小时, 并在第3天静脉输注吉西他滨1 000 mg/m2, 输注30分钟, 每14天为一个周期。
结果. 14例患者入组研究（第1步）。未观察到客观缓解, 12例可评价患者中仅有1例观察到疾病稳定证据。最重要的3‐4级副作用为血液学毒性（中性粒细胞减少症64.2%, 血小板减少症71.4%, 贫血28.7%）、疲乏（50.0%）和口腔炎（21.5%）。中位总生存期和至疾病进展时间分别为5.8个月[95%置信区间（CI）：3.9‐7.1]和2.1个月（95% CI：1.7‐2.8）。
结论. 本研究证明, 培美曲塞与吉西他滨的实验性联合治疗方案无效且具有中等毒性。
Trial registration: ClinicalTrials.gov NCT01909830.
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