Wang et al. Radiation Oncology (2019) 14:215 https://doi.org/10.1186/s13014-019-1420-z RESEARCH Open Access Long-course neoadjuvant chemoradiotherapy with versus without a concomitant boost in locally advanced rectal cancer: a randomized, multicenter, phase II trial (FDRT-002) Jingwen Wang1,2†, Yun Guan3,4†, Weilie Gu1,5, Senxiang Yan6, Juying Zhou7, Dan Huang1,8, Tong Tong1,9, Chao Li10,11, Sanjun Cai1,5, Zhen Zhang1,2* and Ji Zhu1,2* Abstract Background: This study was designed to explore whether an intensified chemoradiotherapy (CRT) led to a better clinical outcome in locally advanced rectal cancer. Methods: Patients with stage II/III rectal cancer were randomly allocated to receive either pelvic intensity- modulated radiation therapy (IMRT) of 50 Gy/25Fx concurrently with capecitabine and oxaliplatin (Arm A), or pelvic radiation of 50 Gy/25Fx with a concomitant boost of 5 Gy to the primary lesion, followed by a cycle of XELOX 2 weeks after the end of CRT (Arm B). All patients were planned to receive a definitive operation 8 weeks after the completion of CRT and a total of six perioperative chemotherapy cycles of capecitabine and oxaliplatin regardless of pathological result. Pathological complete response (ypCR) was the primary endpoint. Results: From February 2010 to December 2011, 120 patients from three centers were enrolled in this study. Ninety- five percent patients completed a full-dose chemoradiotherapy as planning. Then 53 and 57 patients received a radical surgery, and 8 and 14 cases were confirmed as ypCR in two groups (P = 0.157). The other 10 patients failed to receive a definitive resection because of unresectable disease. Similar toxicities were observed between two groups and more incision healing delay were found in Arm B (3 vs.13, P = 0.011). No statistical differences were observed in local-regional control (P = 0.856), disease-free survival (P = 0.349) and overall survival (P = 0.553). Mesorectal fascia (MRF) involvement was an independent prognostic factor for survival in multivariate analysis. Conclusions: A concomitant boost to oxalipatin-combined preoperative chemoradiotherapy demonstrated a slightly higher pCR rate but delayed incision healing after surgery. The impact of MRF involvement on survival merits further investigations. Trial registration: NCT01064999 (ClinicalTrials.gov). Keywords: Rectal cancer, Neoadjuvant chemoradiotherapy, Intensity-modulated radiation therapy * Correspondence: [email protected]; [email protected] †Jingwen Wang and Yun Guan contributed equally to this work. 1Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China Full list of author information is available at the end of the article © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Wang et al. Radiation Oncology (2019) 14:215 Page 2 of 9 Introduction disorders. Informed consent must be obtained from With report of results from a series of large randomized every patient before randomization. The procedure of clinical trials comparing neoadjuvant pelvic radiotherapy random assignment was performed centrally at the (RT) alone versus RT plus concurrent 5-fluorouracil (5- Fudan University Shanghai Cancer Center. FU), the standard modality for stage II/III rectal cancer has shifted to preoperative chemoradiotherapy (CRT), Treatment schedule followed by total mesorectal excision (TME) and postop- The IMRT technique and tumor volumes definition has erative chemotherapy, which leads to preservation of been described in our previous trial [9]. For Arm A, the normal tissue, improvement of tumor regression and ex- planning dose to the PTV2 (pelvis) were 50 Gy in 25 cellent local control [1]. fractions, five times per week (Monday through Friday) The German CAO/ARO/AIO-94 study is the mile- over 5 weeks. For Arm B, the planning doses to the stone of preoperative CRT [2]. Patients who received PTV1 (primary tumor) and PTV2 were 55 Gy and 50 Gy preoperative RT in the study had superior local control in 25 fractions. Electronic portal imaging device (EPID) and reduced toxicity compared with patients in the post- films were used to verify the isocenter and positioning of operative group. Subsequently, the EORTC 22921 trial each patient for the anterior and lateral gantry positions. [3] and FFCD9203 trial [4] suggested 5-FU-based CRT Capecitabine and oxaliplatin were given in combin- resulted in a lower local recurrence rate compared with ation with pelvic radiotherapy. The concurrent chemo- long-course RT alone, in spite of similar long-term sur- therapy regimen was same in both Arms. Capecitabine vival. Furthermore, in EORTC 22921 trial, the ypT0–2 of 625 mg/m2 was given twice daily from Monday to Fri- group had a significant better OS and DFS than the day, and oxaliplatin was administered at a fix dose of 50 ypT3–4 group [5]. Similar results were also observed in mg/m2/week throughout the entire course of CRT. Two MDACC’s retrospective study, where tumor regression weeks after the end of CRT, one additional cycle of could be converted to a better long-term prognosis [6]. XELOX (capecitabine 1000 mg/m2 twice daily on day 1– Moreover, in a pooled analysis [7], it was reported that 14 and oxaliplatin 130 mg/m2 on day 1) was scheduled patients with pCR after CRT have better long-term out- for patients in Arm B (Fig. 1). come than do those without pCR (5-year crude DFS: After the completion of CRT, patients were planned to 83∙3% vs 65∙6%). Therefore, in some views, tumor down- undergo TME 8 weeks later, while the operation type, staging, especially pCR, was regarded as a goal in neoad- such as abdominal-perineal resection (APR) or low an- juvant treatment of locally advanced rectal cancer, which terior resection (LAR), and whether to perform a tem- motivated the combination of systemic chemotherapy porary colostomy, were left to the surgeon to decide. All and advanced RT technique in this approaches. patients were recommended to receive a total of six cy- In our center, previous phase II studies reported that cles of XELOX in perioperative period, regardless of oxaliplatin plus 5-FU-based CRT showed good tumor their pathological features. responses and tolerable toxicities [8–10]. Higher radi- ation dose was reported to contribute to tumor downsta- Treatment evaluation and follow-up ging in literatures [11–13]. Therefore, we designed this Baseline evaluation included a comprehensive medical randomized trial to explore whether a combined regi- history collection, digital examination, colonoscopy men of oxaliplatin-added chemoradiotherapy and a con- and biopsy, computed tomography (CT) scanning of comitant boost to the primary tumor would further lead chest and abdomen, and magnetic resonance imaging to a better clinical outcome. (MRI) of pelvis. Endorectal ultrasound (EUS) and posi- tron emission tomography (PET) were not routinely Patients and methods recommended. Patient eligibility Pathologic examination of surgical specimens was The main inclusion criteria of this study were as follows: performed in accordance with the American Joint (1) newly diagnosed rectal adenocarcinoma; (2) aged be- Committee on Cancer (AJCC, Version 7) [14]. If less tween 18 and 75 years old; (3) tumor located within 12 than 12 lymph nodes were found during standard cm from anal verge; (4) clinically staged T3–4 and/or examination for resected lymph nodes, two pathologists N+; (5) no evidence of distant metastases; (6) had Kar- needed to double check to verify the number of lymph nofsky Performance Status score of 60 or more; and (7) nodes. The tumor regression grade (TRG) after chemo- had adequate hematologic, renal and hepatic function. radiotherapy was recorded according to the AJCC TRG Patients were excluded if they had history of malignant system. TRG 0: Complete tumor response-no viable tumor but not including cured skin cancer or cervical cancer cells; TRG 1: Moderate response-single or small cancer in situ, had inflammatory bowel disease, ischemic groups of tumor cells; TRG 2: Minimal response- heart disease, peripheral neuropathy, or psychological residual cancer outgrown by fibrosis; TRG 3: Poor Wang et al. Radiation Oncology (2019) 14:215 Page 3 of 9 Fig. 1 Treatment schedules response-minimal or no tumor cells killed. PCR was de- Comparisons between two groups were performed using fined as the absence of viable tumor cells in the resec- χ2 tests for categorical variable. Survival curves were es- tion specimens including the primary tumor and lymph timated using the Kaplan-Meier method and compared nodes (ypT0N0), and near-pCR was defined as with Log-rank test. Cox proportional hazards regression ypT0N1a or TRG1 in our study. Those with a margin was used for univariate and multivariate modeling and of circumferential rectal margin (CRM) < 1 mm were for examining the prognostic significance of the variables marked in positive status [15]. identified in the model. P values of less than 0.05 were Acute toxicities were defined as toxicities occurred taken to indicate statistically significant differences. during the entire course of CRT and were evaluated weekly according to the National Cancer Institute Com- Results mon Toxicity Criteria (CTCAE 4.0). Follow-up was Baseline characteristics scheduled every 3 months during the first 2 years after From February 2010 to December 2011, 120 eligible pa- surgery, and then every 6 months over the next 3 years. tients in three centers (Fudan University Shanghai Cancer After 5 years, the frequency of follow-up was extended Center, Shanghai, China; The First Affiliated Hospital, to once each year.