Dunst J, Ahrens S, Paulussen M, Rübe C, Winkelmann W, Zoubek A, Harms D, Jürgens H
Department of Radiotherapy, Martin-Luther-University Halle-Wittenberg, Halle, Germany.
Int J Radiat Oncol Biol Phys. 1998 Sep 1;42(2):379-84. doi: 10.1016/s0360-3016(98)00228-4.
During recent years, more intensified systemic and local treatment regimens have increased the 5-year survival figures in localized Ewing's sarcoma to more than 60%. There is, however, concern about the risk of second malignancies (SM) in long-term survivors. We have analyzed the second malignancies in patients treated in the German Ewing's Sarcoma Studies CESS 81 and CESS 86.
From January 1981 through June 1991, 674 patients were registered in the two sequential multicentric Ewing's sarcoma trials CESS 81 (recruitment period 1981-1985) and CESS 86 (1986-1991). The systemic treatment in both studies consisted of a four-drug-regimen (VACA = vincristine, actinomycin D, cyclophosphamide, and adriamycin; or VAIA = vincristine, actinomycin D, ifosfamide, and adriamycin) and a total number of four courses, each lasting nine weeks, was recommended by the protocol. Local therapy in curative patients was either complete surgery (n = 162), surgery plus postoperative radiotherapy with 36-46Gy (n = 274), or definitive radiotherapy with 46-60Gy (n = 212). The median follow-up at the time of this analysis was 5.1 years, the maximum follow-up 16.5 years.
The overall survival of all patients including metastatic patients was 55% after 5 years, 48% after 10 years, and 37% after 15 years. Eight out of 674 patients (1.2%) developed a SM. Five of these were acute myelogenic leukemias (n = 4) or MDS (n = 1), and three were sarcomas. The interval between diagnosis of Ewing's sarcoma and the diagnosis of the SM was 17-78 months for the four AMLs, 96 months for the MDS and 82-136 months for the three sarcomas. The cumulative risk of an SM was 0.7% after 5 years, 2.9% after 10 years, and 4.7% after 15 years. Out of five patients with AML/MDS, three died of rapid AML-progression, and two are living with disease. Local therapy (surgery vs. surgery plus postoperative irradiation vs. definitive radiotherapy) had no impact on the frequency of AML/MDS, but local therapy did influence the risk of secondary sarcomas. All three patients with secondary sarcomas had received radiotherapy; however, all three sarcomas were salvaged by subsequent treatment and are in clinical remission with a follow-up of 1 month, 4.3 years, and 7.5 years after the diagnosis of the secondary sarcoma. Thus far, SM contributed to less than 1 % (3/328) of all deaths in the CESS-studies.
The risk of leukemia after treatment for Ewing's sarcoma is probably in the range of 2%. The risk of solid tumors also seems to be low within the first 10 years after treatment and remains in the range of 5 % after 15 years. In the CESS-studies, less than 1% of all deaths within the first 10 years after diagnosis were caused by SM. Effective salvage therapy for secondary sarcomas is feasible.
近年来，更强化的全身和局部治疗方案已使局限性尤因肉瘤患者的5年生存率提高到60%以上。然而，长期存活者存在发生第二原发恶性肿瘤（SM）的风险，令人担忧。我们分析了在德国尤因肉瘤研究CESS 81和CESS 86中接受治疗的患者发生的第二原发恶性肿瘤。
从1981年1月至1991年6月，在两项连续的多中心尤因肉瘤试验CESS 81（招募期1981 - 1985年）和CESS 86（1986 - 1991年）中登记了674例患者。两项研究中的全身治疗均采用四药方案（VACA = 长春新碱、放线菌素D、环磷酰胺和阿霉素；或VAIA = 长春新碱、放线菌素D、异环磷酰胺和阿霉素），方案推荐共进行四个疗程，每个疗程持续9周。治愈性患者的局部治疗为完全手术（n = 162）、手术加术后36 - 46Gy放疗（n = 274）或46 - 60Gy根治性放疗（n = 212）。本次分析时的中位随访时间为5.1年，最长随访时间为16.5年。
包括转移性患者在内的所有患者5年总生存率为55%，10年为48%，15年为37%。674例患者中有8例（1.2%）发生了第二原发恶性肿瘤。其中5例为急性髓性白血病（n = 4）或骨髓增生异常综合征（MDS，n = 1），3例为肉瘤。4例急性髓性白血病患者从尤因肉瘤诊断到第二原发恶性肿瘤诊断的间隔时间为17 - 78个月，MDS患者为96个月，3例肉瘤患者为82 - 136个月。第二原发恶性肿瘤的累积风险5年后为0.7%，10年后为2.9%，15年后为4.7%。在5例急性髓性白血病/骨髓增生异常综合征患者中，3例死于急性髓性白血病快速进展，2例带病生存。局部治疗（手术、手术加术后放疗、根治性放疗）对急性髓性白血病/骨髓增生异常综合征的发生频率无影响，但局部治疗确实会影响继发肉瘤的风险。3例继发肉瘤患者均接受了放疗；然而，所有3例肉瘤均通过后续治疗挽救，在继发肉瘤诊断后1个月、4.3年和7.5年的随访中处于临床缓解状态。迄今为止，在CESS研究中，第二原发恶性肿瘤导致的死亡占所有死亡的比例不到1%（3/328）。
尤因肉瘤治疗后白血病的风险可能在2%左右。实体瘤的风险在治疗后的前10年内似乎也较低，15年后仍在5%左右。在CESS研究中，诊断后前10年内所有死亡中由第二原发恶性肿瘤导致的比例不到1%。继发肉瘤的有效挽救治疗是可行的。
