Randomized Phase II Trial of Chemoradiotherapy Plus Induction or Consolidation Chemotherapy as Total Neoadjuvant Therapy for Locally Advanced Rectal Cancer: CAO/ARO/AIO-12.
Randomized Phase II Trial of Chemoradiotherapy Plus Induction or Consolidation Chemotherapy as Total Neoadjuvant Therapy for Locally Advanced Rectal Cancer: CAO/ARO/AIO-12.
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DOI：
10.1200/jco.19.00308
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发表时间：
2019-12-01
期刊：
影响因子：
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通讯作者：
Rodel, Claus
中科院分区：
文献类型：
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作者：
Fokas, Emmanouil;Allgauer, Michael;Rodel, Claus
目的：全新辅助治疗是直肠癌治疗的新模式。术前放化疗（CRT）和化疗的最佳计划仍有待确定。患者和方法：我们进行了一项多中心，随机，II期试验，采用优胜者设计，基于新辅助治疗后病理完全缓解（pCR）增加25%的假设，而术前CRT后标准的病理完全缓解（pCR）为15%。II期或III期直肠癌患者分为A组，在氟尿嘧啶/奥沙利铂CRT （50.4 Gy）前采用氟尿嘧啶、亚叶酸素和奥沙利铂诱导化疗3个周期，B组在CRT后进行巩固化疗。次要终点包括毒性、依从性和手术并发症。结果：在纳入的311例患者中，306例患者可评估（A组156例，B组150例）。B组与CRT相关的3级或4级毒性较低（37% vs 27%），对CRT的依从性较高（分别为91%、78%和76% vs 97%、87%和93%，A组和B组分别接受了全剂量放疗、联合氟尿嘧啶和联合奥沙利铂）；92%和85%分别完成了所有诱导/巩固化疗周期。B组CRT完成和手术之间的间隔较长（A组中位90天和45天），并没有增加手术发病率。在意向治疗人群中，A组的pCR率为17%，B组的pCR率为25%。因此，只有B组（P< 0.001），而A组（P = 0.210）不符合预先设定的统计假设。结论：与a组相比，前期CRT +化疗对CRT的依从性更好，但对化疗的依从性更差。长期随访将评估B组pCR改善是否转化为更好的肿瘤预后。
PURPOSE: Total neoadjuvant therapy is a new paradigm for rectal cancer treatment. Optimal scheduling of preoperative chemoradiotherapy (CRT) and chemotherapy remains to be established.PATIENTS AND METHODS: We conducted a multicenter, randomized, phase II trial using a pick-the-winner design on the basis of the hypothesis of an increased pathologic complete response (pCR) of 25% after total neoadjuvant therapy compared with standard 15% after preoperative CRT. Patients with stage II or III rectal cancer were assigned to group A for induction chemotherapy using three cycles of fluorouracil, leucovorin, and oxaliplatin before fluorouracil/oxaliplatin CRT (50.4 Gy) or to group B for consolidation chemotherapy after CRT. Secondary end points included toxicity, compliance, and surgical morbidity.RESULTS: Of the 311 patients enrolled, 306 patients were evaluable (156 in group A and 150 in group B). CRT-related grade 3 or 4 toxicity was lower (37% v 27%) and compliance with CRT higher in group B (91%, 78%, and 76% v 97%, 87%, and 93% received full-dose radiotherapy, concomitant fluorouracil, and concomitant oxaliplatin in groups A and B, respectively); 92% versus 85% completed all induction/consolidation chemotherapy cycles, respectively. The longer interval between completion of CRT and surgery in group B (median 90 v 45 days in group A) did not increase surgical morbidity. A pCR in the intention-to-treat population was achieved in 17% in group A and in 25% in group B. Thus, only group B (P< .001), but not group A (P = .210), fulfilled the predefined statistical hypothesis.CONCLUSION: Up-front CRT followed by chemotherapy resulted in better compliance with CRT but worse compliance with chemotherapy compared with group A. Long-term follow-up will assess whether improved pCR in group B translates to better oncologic outcome.