Abratt R P, Sandler A, Crinò L, Steward W P, Shepherd F A, Green M R, Nguyen B, Peters G J
University of Cape Town, South Africa.
Semin Oncol. 1998 Aug;25(4 Suppl 9):35-43.
The scheduling of cytotoxic chemotherapy has important bearing on the toxicity and ability to deliver chemotherapy at or close to full dose. We report new data on the influence of different schedules of cisplatin and gemcitabine on toxicity and drug delivery in phase II studies of non-small cell lung cancer. Patients in six phase II studies had standard entry criteria for advanced non-small cell lung cancer. Whereas gemcitabine was given on days 1, 8, and 15 of a 28-day cycle in all these studies, the scheduling of cisplatin varied and was given either on day 1, day 2, day 15 (in two studies), or days 1, 8, and 15 (in two studies). The protocol dose per infusion for gemcitabine was 1,000 mg/m2 (five studies) and 1,500 mg/m2 (one study); for cisplatin, it was 100 mg/m2 when given once per cycle and 30 mg/m2 when given on days 1, 8, and 15. Similar dose reduction schedules were implemented in the event of grade 3 or higher drug toxicity for all studies except for the day 1 cisplatin study, in which the dose was omitted for grade 2 thrombocytopenia. Nonhematologic toxicity was very low. Hematologic toxicity was moderate, and in patients who developed grade 3 or 4 toxicity, there was no hemorrhage from thrombocytopenia and neutropenic sepsis was rare. The incidence of grade 3 or 4 thrombocytopenia with the day 1, day 2, day 15 (two studies combined), and days 1, 8, and 15 (two studies combined) cisplatin regimens was 50%, 52%, 26%, and 38%. The incidence of grade 3 or 4 neutropenia with these four regimens was 51%, 37%, 56%, and 49%, respectively. Although the hematologic toxicity might appear relatively similar, it represents the toxicity at the administered rather than the intended (protocol) dose, because drug delivery was reduced or omitted in the event of grade 3 or 4 toxicity. Differences between the schedules are revealed by analysis of the actual dosages delivered. The median dosage of gemcitabine per scheduled infusion was statistically higher with the day 15 cisplatin regimens (combined) compared with any of the other regimens treating at 1,000 mg/m2 (P < .003, z-score). The dose with the day 1, day 2, day 15, and days 1, 8, and 15 cisplatin regimens was 664, 829, 889, and 774 mg/m2, respectively. Both the percentages of cycles in which gemcitabine infusions were given at full dose and in which there were no omissions of gemcitabine infusions (including infusions with dose reductions) were statistically higher in the day 15 cisplatin regimen than with any of the other regimens (P < .0001, chi-square test). The percentage of cycles containing full-dose gemcitabine with the day 1, day 2, day 15, and days 1, 8, and 15 cisplatin regimens was 24%, 44%, 75%, and 46%, respectively. The percentage of cycles in which there were no omissions of gemcitabine infusions for the four regimens above was 32%, 55%, 83%, and 72%, respectively. Apart from the once-weekly regimen (days 1, 8, and 15) in which the protocol gemcitabine dose was 1,250 mg/m2, the day 15 cisplatin schedule allowed for the highest median concentration of gemcitabine. More importantly, the day 15 cisplatin schedule provided the longest duration of gemcitabine exposure, which is particularly important for its activity as gemcitabine is a phase-specific agent. The day 15 cisplatin schedule is associated with the best dose intensity and the longest median duration of exposure to gemcitabine, and best meets the goal of administering both agents at full doses in combination.
细胞毒性化疗的给药方案对毒性以及以全剂量或接近全剂量进行化疗的能力具有重要影响。我们报告了在非小细胞肺癌II期研究中，顺铂和吉西他滨不同给药方案对毒性和药物递送影响的新数据。六项II期研究中的患者均符合晚期非小细胞肺癌的标准入组标准。在所有这些研究中，吉西他滨均在28天周期的第1、8和15天给药，而顺铂的给药方案有所不同，分别在第1天、第2天、第15天（两项研究）或第1、8和15天（两项研究）给药。吉西他滨每次输注的方案剂量为1000mg/m²（五项研究）和1500mg/m²（一项研究）；顺铂在每个周期给药一次时为100mg/m²，在第1、8和15天给药时为30mg/m²。除第1天顺铂研究外，所有研究在出现3级或更高药物毒性时均实施了类似的剂量减少方案，在第1天顺铂研究中，2级血小板减少时省略剂量。非血液学毒性非常低。血液学毒性为中度，在出现3级或4级毒性的患者中，未发生血小板减少导致的出血，中性粒细胞减少性败血症也很少见。第1天、第2天、第15天（两项研究合并）和顺铂第1、8和15天（两项研究合并）给药方案的3级或4级血小板减少发生率分别为50%、52%、26%和38%。这四种方案的3级或4级中性粒细胞减少发生率分别为51%、37%、56%和49%。尽管血液学毒性可能看起来相对相似，但它代表的是给药剂量而非预期（方案）剂量下的毒性，因为在出现3级或4级毒性时药物递送会减少或省略。通过分析实际给药剂量可揭示给药方案之间的差异。与任何其他以1000mg/m²治疗的方案相比，第15天顺铂联合方案（合并）每次预定输注的吉西他滨中位剂量在统计学上更高（P <.003，z分数）。第1天、第2天、第15天和顺铂第1、8和15天给药方案的剂量分别为664、829、889和774mg/m²。在第15天顺铂给药方案中，吉西他滨全剂量输注的周期百分比以及无吉西他滨输注遗漏（包括减量输注）的周期百分比在统计学上均高于任何其他方案（P <.0001，卡方检验）。第1天、第2天、第15天和顺铂第1、8和15天给药方案中包含全剂量吉西他滨的周期百分比分别为24%、44%、75%和46%。上述四种方案中无吉西他滨输注遗漏的周期百分比分别为32%、55%、83%和72%。除了方案中吉西他滨剂量为每周一次（第1、8和15天）的1250mg/m²外，第15天顺铂给药方案允许吉西他滨的中位浓度最高。更重要的是，第15天顺铂给药方案提供了最长的吉西他滨暴露持续时间，这对其活性尤为重要，因为吉西他滨是一种时相特异性药物。第15天顺铂给药方案与最佳剂量强度和最长的吉西他滨中位暴露持续时间相关，并且最符合联合使用两种药物全剂量给药的目标。
