Sikov W M, Safran H
Department of Medicine, The Miriam Hospital and the Brown University School of Medicine, Providence, RI 02906, USA.
Front Biosci. 1997 May 1;2:e21-7. doi: 10.2741/a222.
Many patients with cancer of the stomach or pancreas have locally advanced, unresectable disease at diagnosis or will develop an early local or regional recurrence despite potentially curative surgery. Effective local treatment could increase the proportion of patients able to undergo surgery and decrease locoregional recurrences, which should improve overall survival. External beam radiation (RT) by itself has little effect. Standard treatment, such as RT with concurrent administration of 5-fluorouracil-based chemotherapy as a radiation sensitizer, has, at best, a modest impact on locoregional recurrences and survival. The use of a more effective radiosensitizer might improve the efficacy of local treatment. Paclitaxel synchronizes cells at G2M, the phase of the cell cycle during which cells are most sensitive to the effects of ionizing radiation, and has been demonstrated to sensitize a variety of human cell lines to the effects of RT. In patients with locally advanced non-small cell lung cancer (NSCLC), the Brown University Oncology Group (BrUOG) has demonstrated a high response rate to low-dose weekly paclitaxel with concurrent RT. In addition, we demonstrated that the response to paclitaxel/RT was not affected by mutations in the p53 tumor suppressor gene. This suggested that paclitaxel/RT would be a rational treatment approach for other malignancies with a high frequency of p53 mutations, such as gastric and pancreatic cancers. We have completed a phase I study of weekly paclitaxel and concurrent radiation for locally advanced gastric and pancreatic cancers. The maximum tolerated dose of paclitaxel was 50mg/m2/week for six weeks with 50 Gray (Gy) abdominal radiation. The dose limiting toxicities were abdominal pain, nausea and anorexia. Preliminary response data from ongoing phase II studies suggest that preoperative paclitaxel/RT has substantial activity in patients with locally advanced gastric and pancreatic cancers, though whether this will translate into improved disease-free and overall survival in these patients is not known.
许多胃癌或胰腺癌患者在诊断时就已出现局部进展、无法切除的疾病，或者尽管接受了可能治愈性的手术，仍会出现早期局部或区域复发。有效的局部治疗可以增加能够接受手术的患者比例，并减少局部区域复发，这有望改善总体生存率。单纯的外照射放疗（RT）效果甚微。标准治疗，如将基于5-氟尿嘧啶的化疗作为放射增敏剂与放疗同时进行，对局部区域复发和生存率的影响至多也很有限。使用更有效的放射增敏剂可能会提高局部治疗的疗效。紫杉醇使细胞同步于G2M期，即细胞周期中对电离辐射作用最敏感的阶段，并且已被证明能使多种人类细胞系对放疗产生敏感性。在局部晚期非小细胞肺癌（NSCLC）患者中，布朗大学肿瘤学组（BrUOG）已证明低剂量每周一次的紫杉醇与同步放疗有较高的缓解率。此外，我们还证明对紫杉醇/放疗的反应不受p53肿瘤抑制基因突变的影响。这表明紫杉醇/放疗对于其他p53突变频率较高的恶性肿瘤，如胃癌和胰腺癌，将是一种合理的治疗方法。我们已经完成了一项针对局部晚期胃癌和胰腺癌的每周一次紫杉醇与同步放疗的I期研究。紫杉醇的最大耐受剂量为50mg/m²/周，共六周，同时进行50格雷（Gy）的腹部放疗。剂量限制性毒性为腹痛、恶心和厌食。正在进行的II期研究的初步缓解数据表明，术前紫杉醇/放疗在局部晚期胃癌和胰腺癌患者中有显著活性，不过这是否会转化为这些患者无病生存期和总体生存期的改善尚不清楚。
