Weisman R A, Christen R, Los G, Jones V, Kerber C, Seagren S, Glassmeyer S, Orloff L A, Wong W, Kirmani S, Howell S
Department of Surgery, University of California, San Diego, San Diego Veterans Administration Medical Center, USA.
Otolaryngol Head Neck Surg. 1998 May;118(5):597-602. doi: 10.1177/019459989811800506.
Cis-platinum and 13-cis-retinoic acid have received much attention in the treatment of head and neck squamous cell cancer. Even though they have different mechanisms of action, little information is available on their interaction. This paper reviews experimental evidence for retinoic acid-cis-platinum synergy and presents toxicity data from patients with stage IV head and neck squamous cell cancer participating in a phase I trial combining 13-cis-retinoic acid and cis-platinum.
Patients were given 13-cis-retinoic acid orally daily for 7 days before and daily during high-dose (150 mg/m2 per week for 4 weeks) intraarterial cis-platinum treatment with concurrent radiation. Toxicity was scored with use of the cancer and leukemia group B scale.
In the phase I clinical trial, 15 patients were treated to determine a maximum tolerated dosage for 13-cis-retinoic acid of 20 mg/day. Grade 4 hematologic toxicity was dose limiting in 3 of 8 patients treated with 40 mg/day and in 1 patient treated with 60 mg/day. There were no deaths caused by toxicity; 12 of the 15 patients received all four weekly doses and the remaining 3 received three doses. Of 10 patients with fully evaluable data, all achieved a complete response at the primary site and 9 had a complete response in the neck. One patient had persistent neck disease after chemoradiation, and this tumor was removed with neck dissection.
13-Cis-retinoic acid and cis-platinum are strongly synergistic against head and neck squamous cell cancer in vitro. Pretreatment with retinoic acid results in stronger synergy than concurrent drug exposure alone. Preliminary clinical experience with combined retinoic acid and cis-platinum in a design that parallels the in vitro study indicates that toxicity is acceptable with 13-cis-retinoic acid dosages of 20 mg/day in a high-dose-intensity intraarterial chemoradiation regimen.
顺铂和13 - 顺式维甲酸在头颈部鳞状细胞癌的治疗中备受关注。尽管它们作用机制不同，但关于它们相互作用的信息却很少。本文综述了维甲酸 - 顺铂协同作用的实验证据，并展示了参与一项将13 - 顺式维甲酸与顺铂联合应用的I期试验的IV期头颈部鳞状细胞癌患者的毒性数据。
在高剂量（每周150 mg/m²，共4周）动脉内顺铂治疗并同步放疗前7天及治疗期间，患者每日口服13 - 顺式维甲酸，共7天。使用癌症与白血病B组标准对毒性进行评分。
在I期临床试验中，15例患者接受治疗以确定13 - 顺式维甲酸的最大耐受剂量为20 mg/天。在接受40 mg/天治疗的8例患者中有3例以及接受60 mg/天治疗的1例患者中，4级血液学毒性成为剂量限制因素。没有因毒性导致的死亡；15例患者中有12例接受了全部四个每周剂量，其余3例接受了三个剂量。在10例有完全可评估数据的患者中，所有患者在原发部位均达到完全缓解，9例在颈部达到完全缓解。1例患者在放化疗后颈部仍有病变，该肿瘤通过颈部清扫术切除。
13 - 顺式维甲酸和顺铂在体外对 头颈部鳞状细胞癌具有强烈的协同作用。维甲酸预处理比单独同时用药产生更强的协同作用。在一项与体外研究平行设计的维甲酸与顺铂联合应用的初步临床经验表明，在高剂量强度动脉内放化疗方案中，13 - 顺式维甲酸剂量为20 mg/天时毒性是可接受的。
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