Treatment Outcomes And Prognostic Factors Of Pathological Stage Ⅱ/Ⅲ Rectal Cancer Patients Treated With Radical Surgery Followed By Postoperative Chemoradiotherapy

Part I:Pathological stage Ⅱ/Ⅲ rectal cancer patients treated with radical surgery followed by concurrent capecitabine and radiotherapy:Long-term survival and treatment toxicitiesPurpose:The aim of this study is to evaluate long-term survival and treatment toxicities of pathological stage Ⅱ/Ⅲ rectal cancer patients treated with radical surgery followed by concurrent capecitabine and radiotherapy.Patients and methods:From January 2004 to December 2013,695 patients with pathologically confirmed pathological stage Ⅱ/Ⅲ rectal cancer were given radiotherapy (45-50.4 Gy/25-28 fractions) with concurrent 1600 mg/m2 capecitabine on days 1-14 and 22-35.Results:Grade 3 or 4 toxicities during concurrent chemoradiotherapy were.observed in 26.3%. Grade 3 long-term toxicities of 479 patients after concurrent chemoradiotherapy were observed in 15.4%.With a median follow-up time of 51.4(10.2-124.5) months, the 5-year overall survival (OS), disease-free survival (DFS), locoregional recurrence-free survival (LR-FS), and distant metastasis-free survival (DM-FS) were 85.0%,77.3%,95.0% and 79.4%, respectively. Multivariate Cox Regression analysis indicated that patients with stage ⅢA and Ⅱ had similar survival outcomes (5-year OS:90.8% vs.91.9%, HR 0.965, P= 0.955; DFS:92.8% vs.87.1%, HR 0.735, P= 0.563; DM-FS:95.8% vs.89.1%, HR 0.633, P = 0.454). Patients with stage ⅢB (ⅢB vs. Ⅱ,5-year OS:81.8% vs.91.9%, HR 2.402, P= 0.003; DFS:71.7% vs.87.1%, HR 2.740, P<0.001; DM-FS:72.4% vs.89.1%, HR 3.061, P < 0.001) and ⅢC (ⅢC vs. Ⅱ,5-year OS:69.3% vs.91.9%, HR 4.574, P< 0.001; DFS: 53.1% vs.87.1%, HR 4.115, P<0.001; DM-FS:59.0% vs.89.1%, HR 4.341, P< 0.001) had worse outcomes.Conclusions:Treatment-related toxicities were tolerable. The survival of pathological stage Ⅱ/Ⅲ rectal cancer patients treated with radical surgery followed by concurrent capecitabine and radiotherapy were excellent, and distant metastasis was the most commonly failure pattern.Part Ⅱ:Comparison of oxaliplatin and capecitabine versus capecitabine alone in stage Ⅱ/Ⅲ rectal cancer patients treated with postoperative chemoradiotherapyPurpose:The aim of this retrospective study was to compare the efficacy of capecitabine with or without oxaliplatin in the postoperative concurrent chemoradiation for stage Ⅱ/Ⅲ rectal cancer patients.Patients and methods:675 patients of stage Ⅱ/Ⅲ rectal cancer treated with postoperative concurrent chemoradiotherapy with capecitabine (CAP group, n= 427) or capecitabine and oxaliplatin (CAPOX group, n= 248) were analyzed. Radiotherapy (RT) was delivered to 45-50.4 Gy in 5 weeks. Capecitabine was given at median doses of 1600 or 1300 mg/m2 on Days 1-14 and 22-35 of RT. Oxaliplatin was administered at median dose of 60mg/m2 on Days 1,8,22 and 29.Results:The baseline characteristics between the two groups, such as age, distance from the anal verge, pN stage, TNM stage, differentiation, lymphovascular invasion, and metastatic lymph node ratio (LNR)>15% were not balanced (P<0.02). A propensity score matching method (1:1) was applied to balance the baseline characteristics and 248 patients in each group were derived. The interruption of radiotherapy due to acute toxicities was 4.0% and 9.3% respectively (P= 0.019). And the interruption of current chemotherapy was 8.5% and 22.2%, respectively (P< 0.001). Grade 3/4 toxicities occurred in 24.6% of patients in the CAP group vs.38.3% in the CAPOX group (P= 0.001). In the two 1groups, no statistically significant differences were found in terms of 5-year overall survival (OS.78.1% vs. 74.9%, P= 0.547), disease free survival (DFS,74.4% vs.67.9%, P= 0.292), locoregional recurrence-free survival (LR-FS,94.5% vs.92.8%, P= 0.484) and distant metastases-free survival (DM-FS,77.1% vs.70.9%, P= 0.364). In multivariate analysis, T4 (P= 0.017), lymphovascular invasion (P= 0.025), tumor nodules (P= 0.001) and LNR>15% (P< 0.001) were poor prognostic factors for DFS.Conclusions:Current oxaliplatin and capecitabine with radiotherapy applied to stage Ⅱ/Ⅲ rectal rancer patients postoperatively has higher rate of toxicities. However, there is no survival advantage over capecitabine alone and would not be recommended.Part Ⅲ:Preliminary analysis of postoperative chemoradiotherapy with capecitabine and oxaliplatin versus capecitabine alone for pathological stage Ⅱ and Ⅲ rectal cancer:A randomized multicenter phase III trialPurpose:The aim of this study is to evaluate acute toxicities and the preliminary results of a phase Ⅲ trial (NCT00714077) of postoperative concurrent capecitabine and radiotherapy with or without oxaliplatin for pathological stage Ⅱ/Ⅲ rectal cancer.Patients and methods:Patients with pathologically confirmed stage Ⅱ/Ⅲ rectal cancer were randomized to either radiotherapy (45-50.4 Gy/25-28 fractions) with concurrent 1600 mg/m2 capecitabine on days 1-14 and 22-35 (Cap-RT group) or with 1300 mg/m2 capecitabine on days 1-14 and 22-35 and 60 mg/m2 oxaliplatin on weeks 1,2,4, and 5 (Capox-RT group). The primary endpoint was 3-year disease-free survival rate (DFS); the secondary endpoints included overall survival rate (OS), cumulative incidence of local recurrence, cumulative incidence of distant recurrence, compliance, and safety.Results:492 patients were enrolled between January 1,2008, and July 30,2014.478 were evaluable. Baseline characteristics were balanced between the two groups. In the Capox-RT group,85.7% and 74.9% patients completed radiotherapy or concurrent chemotherapy on schedule, respectively, while 94.1% and 92.1% in the Cap-RT group finished full dose radiotherapy and chemotherapy, respectively. More grade 3-4 acute toxicity was observed in the Capox-RT group than those in the Cap-RT group (38.1% vs.29.2%, P= 0.041). The 3-year DFS rate was 73.9% in the Capox-RT group and 71.6% in the Cap-RT group (HR 0.92, P= 0.647), respectively. No statistically significant difference was observed in OS, cumulative incidence of local recurrence and distant recurrence between the two groups (P> 0.05). However, the Capox-RT group showed a lower cumulative incidence of local recurrence for patients with pathological stage III rectal cancer (9.4% vs.3.4%, P= 0.034).Conclusions:Inclusion of oxaliplatin in the capecitabine-based postoperative regimen may not improve disease-free survival but increase grade 3-4 acute toxicities for pathological stage Ⅱ and Ⅲ rectal cancer. Final report will be pending.Part IV:Pathological stage N2 rectal cancer patients might benefit from early adjuvant chemotherapy in the era of oxaliplatin-based adjuvant therapyPurpose:In this era of oxaliplatin-based adjuvant therapy, the optimal sequence in which chemoradiotherapy should be administered for pathological stage N2 rectal cancer is unknown. The aim of this study was to investigate this sequence.Patients and methods:In the primary adjuvant concurrent chemoradiotherapy (A-CRT) group (n= 71), postoperative concurrent chemoradiotherapy was administered before adjuvant chemotherapy. In the primary adjuvant chemotherapy (A-CT) group (n= 43), postoperative concurrent chemoradiotherapy was administered during or after adjuvant chemotherapy. Postoperative radiotherapy comprised 45-50.4 Gy in 25-28 fractions. Concurrent chemotherapy comprised two cycles of oral capecitabine (1600 mg/m2) on days 1-14 and 22-35. Patients receiving adjuvant chemotherapy with four or more cycles of XELOX (oxaliplatin plus capecitabine) or eight or more cycles of FOLFOX (fluorouracil, leucovorin, and oxaliplatin) were included.Results:Between June 2005 and December 2013, data for 114 qualified rectal cancer patients were analyzed. The percentages of patients in whom treatment failed in the A-CRT and A-CT groups were 33.8% and 16.3%, respectively (P= 0.042). More patients had distant metastasis in the A-CRT group than in the A-CT group (32.4% vs.14.3%, P= 0.028). Multivariate analysis indicated that the sequence in which chemoradiotherapy was administered (A-CT vs. A-CRT) was an independent prognostic factor for both estimated disease-free survival [hazard ratio (HR) 0.345,95% confidence interval (CI) 0.137-0.868, P = 0.024] and estimated distant metastasis-free survival (HR 0.366,95%CI 0.143-0.938, P= 0.036).Conclusions:In pathological stage N2 rectal cancer patients, administering adjuvant chemotherapy before chemoradiotherapy led to a lower rate of treatment failure, especially with respect to distant metastasis. Prescription of adjuvant chemotherapy as early as possible might benefit this cohort of patients in this era of oxaliplatin-based adjuvant therapy.