同步放化疗诱导后手术切除治疗侵袭性Ⅲ期胸腺肿瘤:前瞻性Ⅱ期临床研究

Surgical resection after neoadjuvant concurrent chemoradiotherapy for stage Ⅲ invasive thymic tumor: A phase Ⅱ prospective clinical trial

目的：分析侵袭性Ⅲ期胸腺肿瘤经诱导放化疗后的缓解率、手术彻底切除率（R0切除率）和远期生存率,以及无法手术切除的患者经巩固治疗后的远期生存率。方法：研究对象为经病理组织学活检及影像学检查明确为侵袭性Ⅲ期胸腺肿瘤的患者。诱导治疗方案为同步放化疗：放疗采用三维适形或调强放疗,剂量为40 Gy/20次;化疗采用多西他赛联合顺铂（多西他赛65 mg·m^-2·d^-1静脉滴注d 1,顺铂35 mg·m^-2·d^-1静脉滴注d 1～2）,于放疗第1天同时进行,如果患者可耐受,于第28天进行第2个疗程的诱导化疗。诱导放化疗结束后第3～4周对病情进行再评估：可手术切除的患者接受手术治疗,仍无法手术切除的患者继续完成根治剂量的放疗（总剂量为60 Gy/30次）。术后根据手术切除的彻底性以及病理诊断结果,给予适当的辅助放疗或化疗。结果：2008年11月—2013年10月,共有33例合格患者被纳入本研究。所有患者均完成了诱导放疗及至少1个疗程的化疗,其中19例患者完成2个疗程的同步化疗。33例患者中,1例在影像学上达到完全缓解（complete response,CR）,25例达到部分缓解（partial response,PR）,7例为疾病稳定（stable disease,SD）。诱导放化疗相关不良反应主要为中性粒细胞减少。在26例取得缓解的患者中,21例接受手术切除,术后7例（33%）的手术切除标本达到病理学CR。33例患者的3年总生存率为60%,手术组与未手术组的3年总生存率分别为50%和67%（P=0.78）,胸腺瘤与胸腺癌的3年总生存率分别为78%和52%（P=0.58）。治疗后失败的主要模式是远处转移。约43%（9/21）的胸腺癌患者发生远处转移。结论：同步放化疗作为侵袭性Ⅲ期胸腺肿瘤的一种诱导治疗手段,可以取得较高的缓解率,且绝大多数接受手术治疗的患者的肿瘤都能得到彻底的切除。对于高危型胸腺癌,建议采用以放化疗为主的综合治疗手段。胸腺癌的巩固化疗可选择更加广谱的化疗方案。

Obiective： To evaluate the response rate, complete resection rate （RO resection rate） and survival rate of patients with stage Ⅲ invasive thymic tumor who underwent surgery after neoadjuvant concurrent chemoradiotherapy, and to evaluate the survival rate of the patients with inoperable tumors after inductive chemoradiotherapy and receiving consolidation therapy thereafter. Methods： Patients with pathological biopsy-proved thymic tumors which were classified as invasive stage III by radiologic images were recruited in this study. The induction regimen included concurrent radiotherapy and 1-2 cycles of chemotherapy. The radiotherapy was delivered in three dimension conformal radiotherapy or intensity modulated radiotherapy at a dose of 40 Gy/20 fx from day 1. Meanwhile, the chemotherapy consisted of docetaxol （65 mg·m^-2·d^-1, d 1） and cisplatin （35 mg·m^-2·d^-1, d1-2）, which might be given for a second time on d 28 if judged endurable by patient＇s performance status. The tumors were re-evaluated 3-4 weeks after the end of inductive chemoradiotherapy. The operable tumors were removed by surgical resection, while those inoperable ones were irradiated to a definitive dose （total dose of 60 Gy/30 fx）. Post-operative adjuvant treatment including radiotherapy and chemotherapy was implemented individually according to the status of residual tumor and the pathologic type. Results： From November 2008 to October 2013, totally 33 eligible patients were included in this study. All patients completed inductive radiotherpy and at least one cycle of concurrent chemotherapy. Among them, 19 patients completed 2 cycles of concurrent chemotherapy. After induction therapy, by radiologic images, 1 patient achieved complete response （CR）, 25 patients achieved partial response （PR）, while the remaining 7 displayed stable disease （SD）. The main adverse effect of induction therapy was neutropenia. Of 26 patients achieving CR＋PR, 21 underwent surgical resection, among them, 7 （33%） showed pathologically CR （pCR） after the examination of resected specimen. The 3-year overall survival （OS） rate of 33 patients was 60%. The 3-year OS rates of surgical group and non-surgical group were 50% and 67%, respectively （P = 0.78）. For thymoma and thymic carcinoma, the 3-year OS rates were 78% and 52%, respectively （P = 0.58）. The failure pattern was mainly demonstrated as distant metastasis, about 43% （9/21 ） of the thymic carcinoma patients eventually developed distant metastasis. Conclusion： As an induction therapy, concurrent chemoradiotherapy can achieve a high response rate and most of the surgical candidates resulted in complete resection. For high-grade thymic carcinoma, chemoradiotherapy-based non-surgical modalities are recommended as major treatment. Wide-spectrum chemotherapy regimens should be adopted as consolidation treatment for thymic carcinoma.