Total mesorectal excision with or without preoperative chemoradiotherapy for resectable mid/low rectal cancer: a long-term analysis of a prospective, single-center, randomized trial

Current clinical guidelines suggest that surgical resection still represents the most effective treatment measure for curing patients with mid/low rectal cancer [1, 2]. Total mesorectal excision (TME) has been recognized as the preferred surgical method for resectable rectal cancer, and it reduced locoregional recurrence rates to below 10% and improved cancer-free survival rates to over 70% [3, 4]. To further optimize local treatment, preoperative concurrent chemoradiotherapy (CCRT) consisting of fluoropyrimidine-based chemotherapy and concurrent radiotherapy has been widely performed before TME. Although local recurrence has been significantly reduced to < 7%, 5-year distant metastasis rates are still beyond 20% in mid/low rectal cancer patients after preoperative chemoradiotherapy (CCRT) followed by TME [5–7]. In addition, a certain proportion of patients experience CCRT-related adverse events, including leucopenia, thrombocytopenia, radiation proctitis, anastomotic leakage, and poor wound healing [8–10]. These adverse events can impair the quality of life, lead to great financial burden, and delay subsequent treatment, which might potentially translate into a reduced life expectancy in patients [11–13]. Given these suboptimal treatment outcomes, we considered the survival benefit of preoperative CCRT as questionable for patients with resectable mid/low rectal cancer.

To confirm the prognostic effect of CCRT, we completed a prospective, randomized phase II trial comparing TME with and without preoperative CCRT, both followed by postoperative adjuvant chemotherapy. The short-term results were reported in 2015, and the two groups had similar functional sphincter preservation rates and 3-year survival outcomes [14]. In the absence of a short-term survival benefit, prolongation of follow-up duration was necessary to observe late postoperative recurrences and survival events to obtain a more definite result. Here, we reported the long-term outcomes including local recurrence, distant metastasis, disease-free survival (DFS), and overall survival (OS) from the current trial after a median follow-up of 71 months.

The current study reveals that after a median follow-up of 69 months, preoperative CCRT followed by TME yields similar 5-year survival outcomes, including DFS, OS, cumulative local recurrence, and distant metastasis, to TME alone. These findings suggest that the widespread application of preoperative CCRT might not achieve expected survival benefits if high-quality TME surgery can be performed.

It is well known that compared with TME alone, preoperative radiotherapy improves local disease control for locally advanced rectal cancer, with a relative risk reduction of greater than 50% for postoperative local recurrence [15, 16]. However, our results showed that the 5-year cumulative rate of local recurrence was only slightly higher in the CCRT + TME group than in the TME group (6.3% vs. 5.0%, P = 0.681). Similarly, Williamson et al. [6] reported that preoperative CRT followed by surgery resulted in a higher 5-year local recurrence rate than did surgery alone for patients with stage II/III mid/low rectal cancer (6.5% vs. 0, P = 0.040). Because high-quality surgery resulted in a local recurrence rate of less than 5%, the significance of benefits from preoperative CCRT were difficult to determine for this selective cohort. Moreover, a trial involving TME conducted by the Dutch Colorectal Cancer Group (DCCG) has noted that the superiority of preoperative radiotherapy on local recurrence reduction was decreased from 70.7% at 2 years to 48.6% at 5 years during follow-up [15, 17]. Even after 12 years of follow-up, the rate of local recurrence was similar to that at 5 years after surgery, with 11% in the surgery-alone group and 9% in the radiotherapy + surgery group [18], indicating that the effect of radiotherapy on local recurrence control may be attenuated with time.

Consistent with our findings, previous clinical trials have demonstrated that distant metastasis rate was 3–6 times higher than the local recurrence rate in locally advanced rectal cancer, and metastasis remains the predominant reason for treatment failure [19–21], probably because of insufficient systemic control of micrometastasis by chemotherapy. To enhance systemic control, we added oxaliplatin to the capecitabine-based (XELOX) regimen for the CCRT + TME group, which has been shown to result in a significant increase in tumor response and to be well tolerated in Chinese locally advanced rectal cancer patients [22–24]. Although the CCRT + TME group achieved a 35.6% pathologic complete response (pCR) rate in our previous analysis [14], this treatment strategy failed to further reduce the distant metastasis rate relative to that in the TME group (3-year: 10.0% vs. 12.8%, P = 0.834; 5-year: 15.0% vs. 15.7%, P = 0.881). To the best of our knowledge, the value of adding oxaliplatin to the preoperative CCRT regimen for controlling distant metastasis remains unconfirmed [25–27]. Therefore, use of oxaliplatin may be debatable for these patients.

Thus far, accumulating evidence after long-term follow-up has revealed that preoperative CCRT had no significant effect on prolonging OS or DFS in patients with resectable rectal cancer [6, 28, 29]. In line with the 3-year survival outcomes of our patients [14], no significant differences were observed for the 5-year DFS and OS rates between the CCRT + TME and TME groups in the present study. It should be emphasized that perioperative chemotherapy with the XELOX regimen was recommended for all patients in the present study. Adjuvant chemotherapy with the XELOX regimen has been demonstrated to improve long-term survival in patients with resectable stage III colon cancer, with a potential effect on eliminating micrometastatic disease [30–32]. In the present study, both groups of patients received a median of 6 cycles of perioperative chemotherapy, and the completion rate of full course of therapy was comparable between the two groups (44.7% vs. 37.8%, P = 0.342). Based on these results, the efficacy of perioperative chemotherapy might outweigh the effect of CCRT on survival outcomes. Therefore, 6–8 cycles of perioperative chemotherapy with the XELOX regimen should be recommended for rectal cancer patients, irrespective of whether they undergo TME alone or in combination with CCRT, to minimize the risk of tumor recurrence.

Tumor pathologic stage has been widely confirmed as a prominent factor affecting survival outcomes in rectal cancer patients [33, 34]. In the present study, pN1–2 and pT3–4 were identified as the most important risk factors for 5-year DFS and OS rates, respectively, indicating that when high-quality surgery could be performed, the prognosis was not determined by preoperative treatment strategy but rather by tumor parameters. We also attempted to identify subgroups of patients with specific tumor features who would benefit from preoperative CCRT. Unfortunately, none of the subgroups of patients displayed significant improvements in 5-year survival outcomes after treatment with preoperative CCRT in the present study. The DCCG TME trial [17, 18] and a Swedish rectal cancer trial [35] have shown that the effects of preoperative radiotherapy were most convincing for patients with TNM stage III, mid/low rectal cancer without circumferential resection margin involvement. Because the high quality of TME and the systemic treatment with chemotherapy are likely to result in noticeable effects on survival, our trial was not able to capture the small but potential meaningful differences between the TME and CCRT + TME groups.

Some limitations of this study should be acknowledged. Because new diagnostic techniques, including MRI and ERUS, were not available at our center between 2008 and 2009, tumor staging was mostly based on CT scan examination, which explains the 62.8% and 41.5% staging accuracy for pT and pN stage, respectively [14]. This limitation might have caused a certain proportion of patients with stage I disease to be overtreated with preoperative CCRT, which might have led to the underestimation of the effect of preoperative CCRT. In addition, the recently identified high-risk parameters for rectal cancer such as threatened mesorectal fascia and extramural venous invasion were not evaluated by high-resolution MRI in the present study. These parameters might help to further optimize preoperative treatment strategies [36, 37]. Moreover, data on the molecular characteristics of tumors were not available for the patients in the present study. It has been shown that the expression of cyclooxygenase-2, vascular endothelial growth factor, and Raf kinase inhibitor protein and the mutational status of KRAS represent valuable molecular markers that can be used for predicting treatment outcomes in rectal cancer patients [38, 39]. Therefore, future studies should include the analysis of tumor molecular biomarkers.

Despite the increase in follow-up durations, there is still no conclusive effect of CCRT on survival outcomes. Our long-term data supported that a selective policy towards preoperative CCRT should be practiced for rectal cancer patients if high-quality TME surgery and aggressive chemotherapy were performed.