Prospective clinical study of capecitabine plus oxaliplatin concurrent chemoradiotherapy after radical resection of rectal cancer

Colorectal cancer (CRC) is the third most common malignancy and the fourth leading cause of cancer death in the world, there were approximately 1.4 million new cases and nearly 0.7 million deaths in 2012. At present, in many medium-to high Human Development Index (HDI) countries, especially in Eastern Europe, Asia and South America, the incidence of CRC incidence and mortality are increasing significantly [1, 2]. The number of newly added colorectal cancers in China is as high as 0.13–0.16 million cases each year. The prevalence of colorectal cancer in our country has reached as high as 46.8/100,000. Clinically, local advanced low rectal cancer is more common, accounting for 70–80% of patients with rectal cancer. NCCN clinical practice guidelines in Oncology (Rectal Cancer) [3] preferred recommendation is preoperative concurrent chemoradiotherapy (CRT) for locally advanced colorectal cancer (type I evidence), but concurrent adjuvant radiotherapy for postoperative locally advanced colorectal cancer without concurrent preoperative CRT remains the standard therapy. In recent years, with capecitabine, oxaliplatin in the treatment of advanced colorectal cancer made a breakthrough. Capecitabine and oxaliplatin are both active anticancer agents in the treatment of patients with advanced colorectal cancer. In a previous phase I/II trial, Bajeta et al. [4] demonstrated that capecitabine can safely replace 5-FU in combination with oxaliplatin and irinotecan with promising results in terms of activity. Up to now, there are five randomized clinical trial for preoperative capecitabine + oxaliplatin neoadjuvant concurrent CRT in rectal cancer [5‐10]. However, researches on adjuvant chemotherapy combined with radiotherapy after radical resection of rectal cancer have rarely been reported. For esophageal cancer patients treated by oxaliplatin 120 mg/m² intravenously on day 1, and capecitabine 1000 mg/m² orally twice daily on days 1–14 in a 21-day cycle of therapy, nausea and vomiting occurred in 51.6% of patients, leukopenia and diarrhea in 50%, stomatitis in 39.1%, polyneuropathy and hand-foot syndrome occurred in 37.5% of patients [11]. The purpose of this study was to investigate the safety and efficacy of combined chemotherapy of capecitabine-oxaliplatin and oxaliplatin alone when concurrent radiotherapy was performed in patients after radical resection of locally advanced rectal cancer.

All data are used SPSS17.0 statistical software package for data analysis. The categorical variables between 2 groups were compared using Chi square test; survival was analyzed by Kaplan–Meier method. Log-rank test was used to compare the survival rates of the two groups. P < 0.05 for the difference was statistically significant.

Rectal cancer has become one of the most common malignant tumors in our country. Its incidence is spirally increasing at a rate of 4.2%, far exceeding the international standard of 2%. They are characterized by late stage, high proportion of middle and low rectal cancers and simple surgical treatment is not satisfactory. Some patients with locally advanced rectal cancer underwent radical surgery without neoadjuvant therapy, for this part of patients, postoperative concurrent CRT and postoperative adjuvant chemotherapy is particularly important. The NCCN guidelines recommend [3] capecitabine or 5-fluorouracil chemoradiation as the standard protocol for postoperative treatment of type II/III rectal cancer (type I evidence). Compared with historical postoperative chemotherapy and radiotherapy, standard treatment of total mesorectal excision (TME) and neoadjuvant chemoradiation significantly improved the treatment of local rectal adenocarcinoma. Use of oxaliplatin with fluoropyrimidine therapy has provided survival benefit [18, 19]. Capecitabine is currently the only widely accepted oral 5-fluorouracil (5-FU) prodrug. It is mainly converted to 5-FU in human cancer cells and reduces toxicity. Compared with 5-FU infusion chemotherapy, the incidence of grade 3/4 myelotoxicity is significantly reduced [20]. Oxaliplatin mainly causes DNA damage, prevents the synthesis of DNA and RNA to exert cytotoxic effects, and leads to apoptosis of cancer cells [21]. In order to explore the efficacy and safety of concurrent CRT with capecitabine combined with oxaliplatin in patients with locally advanced rectal cancer, from January 2014 we conducted a phase III clinical trial of concurrent CRT with capecitabine + oxaliplatin or capecitabine after radical surgery for locally advanced rectal cancer, in order to provide safe and effective new program of concurrent CRT for patients with locally advanced rectal cancer after radical operation. This clinical study is one of few randomized studies investigating the use of oxaliplatin in capecitabine-based postoperative concurrent CRT in patients with locally advanced rectal cancer.,

Our research shows that 3-year disease-free survival (DFS), 3-year overall survival (OS), 3-year local recurrence, and 3-year distant metastasis were no significant difference between CAPE-OX-CRT group and control group (P > 0.05).

The addition of oxaliplatin increased the toxicity (the incidences of patients who were interrupted or stopped concurrent chemotherapy or radiotherapy were higher in CAPE-OX-CRT group than in control group). There was significant difference between the two groups in the rate of concurrent chemotherapy suspension (P < 0.05).

Hofheinz et al. [22] studied the effectiveness and safety of the capecitabine instead of fluorouracil in the treatment of locally advanced rectal cancer. Their study showed that capecitabine, compared to 5-fluorouracil groups, has no inferiority in 5-year OS; capecitabine can replace fluorouracil for preoperative or postoperative concurrent CRT in the treatment of locally advanced rectal cancer. The study also showed that capecitabine group had a lower distant metastasis rate (19% vs 28%, P = 0.04). In addition, the CAO/ARO/AIO-04 study [6] showed that the addition of oxaliplatin to fluorouracil-based concurrent CRT improved 3-year DFS in patients with locally advanced rectal cancer (71.2% vs 75.9%; P = 0.03). Our current findings and the study of preoperative concurrent chemoradiation published above indicated that weekly oxaliplatin did not increase 3-year DFS in capecitabine-based concurrent CRT. The reasons may be that the capecitabine is superior to fluorouracil in efficacy and it covers the benefit of oxaliplatin in DFS. However, the median follow-up time in both groups in this study was < 3 years, so the OS and DFS results in this study need further follow-up.

The ADORE and CAO/ARO/AIO-04 studies [5, 6] show that patients with rectal cancer can benefit from oxaliplatin-based adjuvant chemotherapy. In this study, 53.33% of patients in CAPE-OX-CRT group and 76.92% of patients in control group completed adjuvant chemotherapy (P = 0.063). More patients in control group received mFOLFOX6 regimen adjuvant chemotherapy. This may also hide the effectiveness of oxaliplatin in concurrent CRT. A number of preoperative radiotherapy and chemotherapy randomized study [5‐7] showed capecitabine monotherapy concurrent CRT in patients with grade 3–4 incidence of toxic reactions was 6.6–15.1%, while in the double-drug group (capecitabine + oxaliplatin), grade 3–4 toxicities were 15.4–36.7%. In our study, the incidence of grade 3 toxicities in group A was 13.33–23.33%, B was 7.69–11.54%, and there was no grade 4 toxicity in both groups. Regarding to the completion of postoperative adjuvant chemotherapy, the completion rate of adjuvant chemotherapy in CAPE-OX-CRT group was lower than that in control group (76.92% vs 53.33%, P > 0.05), but the difference was not statistically significant.

The completion rates of 8 cycles of adjuvant chemotherapy in both groups did not reach 80%, only 50% in CAPE-OX-CRT group, and it may be related to the addition of oxaliplatin during concurrent CRT, resulting in increased postoperative adjuvant chemotherapy toxicity. As more patients refused or interrupted systemic chemotherapy, it is difficult to complete adequate and full course of adjuvant chemotherapy. Whether will this increase the risk of distant metastasis of patients and affect long-term survival needs to be further observed. Future studies should expand the number of cases and longer follow-up.

Although these two methods are effective in the treatment of locally advanced rectal cancer after surgery, capecitabine combined with oxaliplatin chemotherapy regimen failed to further improve its efficacy. The capecitabine combined oxaliplatin therapy (CAPE-OC-CRT) did not increase the 3-year overall survival (OS) for patients after radical resection of rectal cancer, but increased hematological toxicity and non-hematological toxicity (grade 1–2). As a standard treatment for patients with locally advanced rectal cancer after radical treatment, it is recommended to use capecitabine combined with concurrent radiotherapy alone.