Martin C, Pollera C F
Lilly Research Centre, Windlesham, Surrey, UK.
Int J Clin Pharmacol Res. 1996;16(1):9-18.
Gemcitabine, a novel anticancer agent, has been shown to be active in several human solid tumours, including non-small cell lung cancer and pancreatic cancer. In addition, gemcitabine has been noted to have a particularly mild safety profile for such an active agent and is lacking some of the classical toxicities of oncolytics, i.e. alopecia, severe nausea and vomiting, and mucositis. Therefore, the safety data from 790 patients in 18 completed clinical studies were integrated to study its toxicity profile in more detail. In all of these studies gemcitabine was administered as a 30-minute intravenous infusion every week for three weeks followed by a week of rest (one cycle). This integrated database confirmed that gemcitabine is well tolerated. Its haematological toxicity was mild and short lasting. The low incidence of infection was correspondingly low. Transaminase elevations occurred frequently, but they were usually mild and rarely dose-limiting. Mild proteinuria and haematuria were seen but were rarely clinically significant. There was no evidence of cumulative hepatic or renal toxicity. Nausea and vomiting were mild, rarely dose-limiting and generally well controlled with standard antiemetics. Flu-like symptoms were experienced in a proportion of patients but were short-lasting. Where oedema or peripheral oedema were experienced, there was no evidence of any association with cardiac, hepatic or renal failure. Hair loss was rare. The integrated database was also analysed according to starting dose (800, 1000 or 1250 mg/m2) in a subset of 665 chemonaive patients to see whether an increased dose resulted in increased toxicity. In general, only small, clinically insignificant differences in toxicity were seen between the three dose groups. Although segmented neutrophil count appeared to increase as starting dose increased (grade 3 or 4, 19.4%, 23.2%, 28.3% respectively), this was not associated with an increased incidence of infection. In some cases, toxicity decreased with increasing dose but this may have been because of imbalances between the patient groups. These findings indicate that not only is gemcitabine well tolerated, but it also has a broad therapeutic index and the use of higher doses may be possible.
吉西他滨是一种新型抗癌药物，已被证明对多种人类实体瘤有效，包括非小细胞肺癌和胰腺癌。此外，人们注意到，作为一种活性药物，吉西他滨的安全性特别温和，没有一些溶瘤药物的典型毒性，即脱发、严重恶心和呕吐以及粘膜炎。因此，整合了18项已完成临床研究中790名患者的安全数据，以更详细地研究其毒性特征。在所有这些研究中，吉西他滨每周静脉输注30分钟，共三周，然后休息一周（一个周期）。这个综合数据库证实吉西他滨耐受性良好。其血液学毒性轻微且持续时间短。感染发生率相应较低。转氨酶升高经常发生，但通常较轻，很少有剂量限制作用。可见轻度蛋白尿和血尿，但在临床上很少有显著意义。没有累积肝毒性或肾毒性的证据。恶心和呕吐较轻，很少有剂量限制作用，一般用标准止吐药就能很好地控制。一部分患者出现流感样症状，但持续时间较短。出现水肿或外周性水肿的患者，没有证据表明与心、肝或肾衰竭有任何关联。脱发很少见。还对665名初治化疗患者的子集，根据起始剂量（800、1000或1250mg/m²）对综合数据库进行了分析，以观察剂量增加是否会导致毒性增加。总体而言，三个剂量组之间在毒性方面仅存在微小的、临床上无显著意义的差异。虽然随着起始剂量增加，分叶核中性粒细胞计数似乎也增加（3级或4级分别为19.4%、23.2%、28.3%），但这与感染发生率增加无关。在某些情况下，毒性随剂量增加而降低，但这可能是由于患者组之间的不平衡所致。这些发现表明，吉西他滨不仅耐受性良好，而且具有广泛的治疗指数，可能可以使用更高的剂量。
