Local excision in mid-to-low rectal cancer patients who revealed clinically total or near-total regression after preoperative chemoradiotherapy; a proposed trial

In the treatment of rectal cancer, total mesorectal excision (TME) improves oncologic outcomes and adding preoperative chemo-radiotherapy (pre-CRT) to TME has been shown to effectively improve local control [1‐4]. For this reason, pre-CRT followed by TME is recommended for patients with locally advanced mid-to-low rectal cancer [5‐9]. However, significant complications are associated with TME, including anastomotic leak, sexual and urinary dysfunction, and frequent stool passage, on top of the peri-operative morbidity associated with all major surgery [10‐12]. In addition, abdominoperineal resection (APR) involves a permanent stoma and low anterior resection (LAR) often involves at least a temporary stoma [8, 12, 13]. The decision of a surgical strategy must take oncologic outcomes, postoperative complications, and quality of life into account.

For patients with favorable responses to pre-CRT, organ-preserving strategies such as local excision (LE) and watchful waiting are becoming more accepted [14‐19]. There has been some debate regarding the oncologic safety of LE following pre-CRT in advanced mid-to-low rectal cancer [14‐18]. LE following pre-CRT for advanced rectal cancer could be a particularly good option for patients showing a complete pathologic response and achieving tumor regression not only in the primary tumor but also in the mesorectal metastatic lymph nodes [20‐24]. Although the tumor regression grade (TRG) obtained using high-resolution rectal magnetic resonance imaging (mrTRG), as proposed by the MERCURY study group, correlated with the pathologic TRG [20, 21, 23, 24], mrTRG did not reflect the pathologic T status. A recent study from our institution showed that a status of mrTRG1 predicted a pathologic complete remission (pCR) with 60.6% accuracy and the projected completion TME rate of mrTRG1 was 25.6%. This results suggests that LE, compared with watchful wait, is more likely to result in pCR [25].

There have been several reports on the feasibility of performing LE following pre-CRT, most of which are focused on either clinical T2–3 rectal cancer or on cases of pCR [26‐28]. However, the oncologic safety of LE in patients with a pathologic early T status after pre-CRT has not been established [29]. Therefore, data on long term outcomes with respect to the pathologic status and the type of surgery in patients with locally advanced rectal cancer is needed.

Although pre-CRT followed by TME has become the standard treatment for patients with locally advanced rectal cancer, recent evidences suggests that organ-preserving strategies such as LE and watchful waiting can be used as an alternatively to TME in patients with a favorable response to pre-CRT without compromising oncologic outcomes and high rate of major LARS [14‐19, 31]. Numerous tools can be used to assess the tumor response after pre-CRT, including physical examination, endorectal ultrasound, endoscopy, and MRI. MR staging is currently considered one of the most useful methods of evaluating the response to pre-CRT [20, 24, 25]. However, the accuracy rate of mrTRG for predicting pCR is only approaximately 60% [25]. Considering that ypT status reflects the ypStage and that patients with pCR or ypT1N0M0 have a more favorable prognosis [29], accurate examination of tumor status is needed.

Recently, our institution reported a retrospective analysis demonstrating that oncologic outcomes of pre-CRT followed by LE were comparable to those of TME, even in patients with lymph node involvement [27]. A recent meta-analysis also suggested that there are no differences in local recurrence rates, disease-free survival, and overall survival between rectal cancer patients that received LE or TME [28]. In patients with early-stage rectal cancer, several studies found that LE did not compromise the oncologic outcome but did result in organ preservation [28]. Based on previous studies, if lymph nodes are positive after pre-CRT, patients are optimally treated with TME with regional lymph node clearance, in line with the current standard of treatment [29], but a patient that achieves a complete or near-complete response after pre-CRT can consider LE.

In terms of postoperative complications, only one patient (2.1%) in our previous study developed a postoperative complication (perianal fistula) that required prolonged hospitalization [27]. In a recent prospective study of LE in patients with T2 rectal cancer, surgery-related adverse events above grade 3 occurred in 16 patients (21%) and grade 1 or 2 complications occurred in 50 patients (65%) [26]. Although complications of LE after pre-CRT are generally less severe than complications of TME, the rate of overall complications including dehiscence of the rectal suture line resulted from anal pain are higher than TME after pre-CRT [26]. Based on the assumption that the oncologic outcomes of LE and TME are similar for patients with a favorable response (mrTRG 1 or 2) after pre-CRT, further prospective studies on surgical outcomes in LE after pre-CRT are needed.

Pre-CRT followed by LE causes minimal loss of anorectal function and quality of life, similar to watchful waiting [26]. TME results in postoperative loss of anorectal, urinary and sexual function, and also carries the risk of permanent stoma formation [10]. In mid-to-low advanced rectal cancer, the use of pre-CRT has decreased the rate of permanent stoma formation; however, in our recent study, approximately 30% of patients receiving TME after pre-CRT did develop a permanent stoma [27]. A recent prospective study suggested that pre-CRT followed by LE might be an alternative to TME for patients with rectal cancer who have a favorable response to pre-CRT or who seek organ preservation because the Fecal Incontinence Severity Index (FISI) score and the Functional Assessment of Cancer Therapy-Colorectal (FACT-C) scores did not substantially decrease after surgery [26].

Previous studies, even prospective studies for LE or watchful waiting, suffer from the lack of standardized selection criteria. Recently, the MECURY group convened multidisciplinary teams (MDT) to decide which patients should defer surgery and which patients should receive standard treatemtn after pre-CRT [22]. Our institution also reported that case discussions in MDT meetings resulted in altered clinical decisions in > 10% cases for advanced and recurrent colorectal cancer [32]. Based on this experience, in the current study, specialized faculty, including a colorectal surgeon, radiologist, medical oncologist, radiation oncologist, gastroenterologist, and pathologist, will select the study patients that show a favorable response after pre-CRT. The data on postoperative complications in LE and TME after pre-CRT collected through the current study will provide valuable information about the risk factors of LE after pre-CRT.

This prospective study has some weaknesses because this study will be performed based on the real practice in our institution. Recent studies insists that the interval between completion of pre-CRT and the assessment of tumor response is increased up to 12 weeks and this longer interval might increase the rate of pathologic CR [33, 34]. On the other hand, in this prospective study, TME is undertaken 6–8 weeks after the completion of pre-CRT according to the real practice in our institution. The schedule of restaging is designed within 2 weeks before surgery considering waiting time of MRI in our institution and minimizing dropouts, however, almost patients have restaged at 2 or 3 days before surgery on the real practice. About 10% of lymph node infiltration and the 15% of local recurrence in the ypT2 were worrisome for this study [27, 29, 35]. Nevertheless, recent reports showed the overall survival was not significantly different between the LE and TME groups [27, 36, 37]. The evidences of LE for ypT2 tumors are still lack, therefore, our study determines the effect of LE in ypT2 tumors on oncologic outcomes.