Leyvraz S, Pasche P, Bauer J, Bernasconi S, Monnier P
Department of Ear, Nose, and Throat, and Radiotherapy, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
J Clin Oncol. 1994 Sep;12(9):1876-85. doi: 10.1200/JCO.1994.12.9.1876.
Treatment of locally advanced head and neck carcinoma by surgery and/or radiotherapy is associated with a high recurrence rate, poor survival, and, often, limitation in speech and swallowing functions. Because prolonged time of treatment might be detrimental for tumor control, we designed a study to develop a schedule of alternating radiotherapy and chemotherapy that should be administered over the shortest period of time and with the highest dose of radiotherapy as possible.
Following four successive steps of schedule modifications, regimens alternating split hyperfractionated radiotherapy (2.0 Gy/d times three over 30 to 40 days, to a total of 48 Gy to 60 Gy) and chemotherapy (cisplatin 80 to 100 mg/m2 and fluorouracil 1,000 mg/m2 by continuous infusion for 3 to 4 days, +/- vindesine 8 mg/m2 for two cycles) were administered in 91 patients with advanced squamous cell carcinoma of the head and neck. Adenectomy was performed for residual nodes and major surgery for progression only.
The overall response rate was 95.6% (95% confidence interval [CI], 89.1 to 98.8), with 69.2% complete and 26.4% partial responses. Among partial responders, two patients were converted into complete responders by resection of a residual node. With a median follow-up duration of 45 months, distant mestastases occurred in 18% and a second primary tumor in 7.7% of patients. The median overall survival (OS) and progression-free survival (PFS) durations were 24 months and 17 months, respectively. At 4 years, the survival rate was 40%. All of the locoregional recurrences occurred within the first 15 months, in 14% and 73% of the complete and partial responders, respectively. Mucositis was the dose-limiting toxicity, with a World Health Organization (WHO) grade III and IV rate of 81% at a 60-Gy dose of radiotherapy, compared with 65% at 48 Gy or 54 Gy, which precluded further dose escalation. Leukopenia was severe in the first two steps of treatment, with WHO grade IV toxicity occurring in 41% of patients; however, this decreased to 10% when vindesine was deleted from the chemotherapy regimen in the last two steps. Late toxicity in 29% of patients was not different from that expected with radiotherapy alone. Among patients with resectable tumors, a 64% rate of organ preservation was obtained.
We demonstrated that a full dose of hyperfractionated radiotherapy alternated with chemotherapy over 40 days could produce high antitumor activity. Mucositis was the dose-limiting toxicity, but this resolved completely within a median period of 6 weeks.
采用手术和/或放疗治疗局部晚期头颈癌，复发率高、生存率低，且常伴有言语和吞咽功能受限。由于延长治疗时间可能不利于肿瘤控制，我们设计了一项研究，以制定一种交替放疗和化疗的方案，该方案应在最短时间内给予尽可能高剂量的放疗。
经过四个连续的方案调整步骤，对91例晚期头颈鳞状细胞癌患者实施了交替分割超分割放疗（2.0 Gy/天，分三次，共30至40天，总量48 Gy至60 Gy）和化疗（顺铂80至100 mg/m²，氟尿嘧啶1000 mg/m²持续输注3至4天，两个周期可加用长春地辛8 mg/m²）的方案。仅对残留淋巴结进行腺切除术，对病情进展者进行大手术。
总缓解率为95.6%（95%置信区间[CI]，89.1至98.8），其中完全缓解率为69.2%，部分缓解率为26.4%。在部分缓解者中，两名患者通过切除残留淋巴结转变为完全缓解者。中位随访时间为45个月，18%的患者发生远处转移，7.7%的患者出现第二原发性肿瘤。中位总生存期（OS）和无进展生存期（PFS）分别为24个月和17个月。4年生存率为40%。所有局部区域复发均发生在最初15个月内，完全缓解者和部分缓解者的复发率分别为14%和73%。黏膜炎是剂量限制性毒性反应，放疗剂量为60 Gy时，世界卫生组织（WHO）Ⅲ级和Ⅳ级发生率为81%，而48 Gy或54 Gy时为65%，这使得无法进一步提高剂量。在前两个治疗步骤中白细胞减少严重，41%的患者出现WHO Ⅳ级毒性反应；然而，在最后两个步骤中化疗方案中删除长春地辛后，该发生率降至10%。29%患者的晚期毒性与单纯放疗预期的毒性无差异。在可切除肿瘤患者中，器官保留率为64%。
我们证明了在40天内交替给予全剂量超分割放疗和化疗可产生高抗肿瘤活性。黏膜炎是剂量限制性毒性反应，但在中位6周内可完全缓解。
