Donaldson S S, Asmar L, Breneman J, Fryer C, Glicksman A S, Laurie F, Wharam M, Gehan E A
Department of Radiation Oncology, Stanford University Medical Center, CA 94305, USA.
Int J Radiat Oncol Biol Phys. 1995 Jul 15;32(4):903-11. doi: 10.1016/0360-3016(95)00151-n.
The Intergroup Rhabdomyosarcoma Study (IRS) Group initiated a pilot study (IRS IV-P) of hyperfractionated radiation (HF XRT) with chemotherapy to test the feasibility and toxicity of this combined modality approach in children with localized but nonresected (group III) and metastatic (group IV) rhabdomyosarcoma.
Using the linear quadratic equation, and an alpha/beta ratio of 10 Gy for acute reacting tumor effect and 3 Gy for late reacting normal tissue effect, a HF XRT protocol was developed giving a total radiation dose of 59.4 Gy, in 1.10 Gy fractions, twice daily at 6-8 h intervals. All patients received chemotherapy in addition to irradiation. The radiation scheme was calculated to increase the biologically effective dose to the tumor by 10% without increasing late effects, when compared to a conventional schedule of 50.4 Gy in 1.8 Gy daily fractions. This protocol also was predicted to cause an increase in acute normal tissue effects.
Four hundred forty-nine children age 21 years and younger were eligible for the hyperfractionated radiation study of whom 297 had Group III disease and 152 had Group IV disease. A total of 117 patients were excluded from the feasibility and toxicity analysis because of progressive disease or death prior to scheduled irradiation, surgical resection, major protocol violation, treatment with brachytherapy, or missing data. Thus, 332 children were evaluable for the HF XRT protocol. Twenty-eight of the 332 (8%) were given conventional radiation because of physician preference or young age. Twenty of the 332 (6%) were not irradiated because of young age, anesthesia, or transportation problems. All nonirradiated children were < or = 3 years of age. Thus, 284 children, 86% of the evaluable population, received HF XRT. The radiation dose, number of fractions, number of days, and interfractional interval were scored as appropriate in 93% of cases. Review of radiation portals revealed that in 230 of 284 cases (81%) the radiation fields were appropriate, as per protocol. Thus, the HF XRT was feasible treatment in a multiinstitutional study. Analysis of toxicity revealed that 152 of 204 (75%) of Group III and 52 of 80 (65%) of Group IV patients experienced severe or life-threatening toxicity, explained by the addition of chemotherapy with the radiation. The majority of this toxicity was hematopoietic. Observed organ toxicity, which was potentially explained by the radiation treatment, was greatest at the end of radiation, and improved at the 6-week and 3-month evaluation periods. There were no deaths attributed to radiation toxicity and no instance of toxicity that required alteration of the radiation protocol. Thus, the treatment was not associated with toxicity that was considered excessive or unusual.
The IRS IV-P study confirms that HF XRT combined with chemotherapy is both feasible and tolerable in children with rhabdomyosarcoma. A prospective randomized trial is underway to test its efficacy as compared to conventional radiation among children also receiving concurrent chemotherapy for rhabdomyosarcoma.
横纹肌肉瘤协作组（IRS）开展了一项超分割放疗（HF XRT）联合化疗的试点研究（IRS IV-P），以检验这种联合治疗方法对局限性但未切除（III组）和转移性（IV组）横纹肌肉瘤患儿的可行性和毒性。
利用线性二次方程，急性反应性肿瘤效应的α/β比值为10 Gy，晚期反应性正常组织效应的α/β比值为3 Gy，制定了一项HF XRT方案，总辐射剂量为59.4 Gy，每次分割剂量为1.10 Gy，每天两次，间隔6 - 8小时。所有患者除接受放疗外还接受化疗。与每天1.8 Gy常规分割方案给予50.4 Gy相比，该放疗方案经计算可使肿瘤的生物学有效剂量增加10%，同时不增加晚期效应。该方案预计也会使急性正常组织效应增加。
449名21岁及以下儿童符合超分割放疗研究条件，其中297例为III组疾病，152例为IV组疾病。共有117例患者因疾病进展、计划放疗前死亡、手术切除、严重违反方案、接受近距离放疗或数据缺失而被排除在可行性和毒性分析之外。因此，332名儿童可对HF XRT方案进行评估。332例中有28例（8%）因医生偏好或年龄小而接受常规放疗。332例中有20例（6%）因年龄小、麻醉或交通问题未接受放疗。所有未接受放疗的儿童年龄均≤3岁。因此，284名儿童，即可评估人群的86%，接受了HF XRT。在93%的病例中，辐射剂量、分割次数、天数和分割间隔均记录适当。对放疗野的审查显示，284例中有230例（81%）的放疗野符合方案要求。因此，HF XRT在多机构研究中是可行的治疗方法。毒性分析显示，III组204例中有152例（75%）、IV组80例中有52例（65%）出现严重或危及生命的毒性反应，这可归因于放疗联合化疗。这种毒性反应大多为血液系统毒性。观察到的可能由放疗引起的器官毒性在放疗结束时最为严重，在6周和3个月评估期有所改善。没有因放疗毒性导致的死亡，也没有需要改变放疗方案的毒性反应情况。因此，该治疗方法未出现被认为过度或异常的毒性反应。
IRS IV-P研究证实，HF XRT联合化疗对横纹肌肉瘤患儿既可行又可耐受。一项前瞻性随机试验正在进行，以检验其与常规放疗相比在同时接受横纹肌肉瘤化疗的儿童中的疗效。
