Predictive factors of disease-free survival after complete pathological response to neoadjuvant radiotherapy for rectal adenocarcinoma: retrospective case series

Currently, the standard treatment for mid-low locally advanced rectal cancer is neoadjuvant (chemo)-radiation therapy followed by curative surgical resection according to the guidelines of both the European Society of Medical Oncology (ESMO) and the National Comprehensive Cancer Network (NCCN) [1]. Most patients exhibit a substantial downstaging that may lead to complete pathological responses (CPRs) in 15 to 20% of cases, as defined by the absence of viable tumour cells after full pathologic examination of the resected specimen (ypT0N0), which is referred to as stage 0 disease [2]. These findings have helped many authors to reconsider the need for surgical resection after a CPR [3‐6]; however, no definitive surrogate of a CPR (clinical, biological or radiological) has been reported in the literature, and surgical resection remains the standard treatment.

Although many data suggest that patients with ypT0N0 status have better prognoses and improved survival and disease-free survival (DFS) compared to all other stages, few data are available regarding the details of oncological outcomes [7, 8]. Additionally, little is known about the specific prognostic factors for this subgroup of patients.

The aim of this study was to evaluate the long-term oncologic outcomes and predictive factors for DFS after a CPR of low rectal adenocarcinoma.

From January 2005 to December 2013, 694 consecutive patients underwent neoadjuvant treatment followed by TME in the 8 centres.

Of these, 84 (12.1%) patients achieved a CPR (ypT0N0). The mean age of these patients was 54.5 years (SD 12 years). The demographic details and treatment modalities are provided in Tables 1 and 2.

The 30-day mortality rate was 3.6%, and the global complication rate as defined by a Clavien-Dindo score (CD) ≥ IIIa was 14.3%. Perineal sepsis occurred in 16 patients (19%).

This study demonstrated that for patients with a CPR after neoadjuvant treatment followed by TME, the recurrence rate was 12.6%. Both poorly differentiated tumours and the occurrence of perineal sepsis were factors that independently predicted impaired DFS in this population with ORs of 9.23 and 13.51, respectively.

Patients who develop a CPR after neoadjuvant treatment exhibit better prognoses, a reduced propensity for local or distant recurrence and improved survival [4, 13, 14]. However, one study reported that even for ypT0N0M0 low rectal cancers, after a median follow-up of 48 months, 61 of 419 patients developed recurrences, which resulted in a five-year DFS of 83% [4].

A CPR after chemoradiation therapy reduces, but does not eradicate, the risks of local and distant metastases [4, 6, 7]. Additionally, there are no data regarding the predictive factors of impaired DFS in this specific population of patients with good prognoses who achieved a CPR for low rectal adenocarcinoma.

Growing evidence and accumulating data indicate that anastomotic leakage (perineal sepsis) affects not only the short- but also the long-term survival [15]. In a recent meta-analysis, anastomotic leakage was associated with a greater rate of local recurrence (HR 1.71; 95% CI 1.22–2.38) and a decrease in overall survival (HR 1.67; 95% CI 1.19–2.35) [16]. A major explanation of this finding is that tumour cells are exfoliated from the primary tumour and seed the intraluminal local resection environment [17]. When perineal sepsis occurs, these cells may find an adequate environment for implementation and growth that leads to pelvic recurrence. In vitro studies have demonstrated a multifactorial mechanism by which inflammatory responses of the postoperative peritoneum and/or pelvic sepsis may enhance local recurrence, and this mechanism involves a combination of the amplification of angiogenesis and stimulation of both the migration and invasion capacities of tumour cells [18]. This is a plausible theory in cases of CPR because no viable tumours are found in the resection specimens, leading us to believe that unique viable tumours are left in the perirectal (or extra-fascial) environment and may be reactivated by postoperative local inflammation.

Poor tumour differentiation is one of the best-known predictive factors of local and distant recurrence [18]. It is also a predictive factor of an incomplete response to neoadjuvant chemoradiotherapy [19]. However, it remains unclear how poorly differentiated tumours (especially the SRCC subtype) enable aggressive outcomes even after a CPR [20, 21]. Linosilva et al. reported a case with the presence of microscopic clinical carcinomatosis implants with a total mural tumour response [21]. This finding is a reminder of the strong potential for SRCCs in other locations and the high probability of recurrence, especially for peritoneal carcinomatosis [22, 23].

Another theory of local and distant recurrence after a CPR may be that the tumour is left behind in the patient during surgery [4]. Lateral pelvic lymph node (LPLN) involvement is associated with poorer survival and a high rate of locoregional recurrence [24‐26]. The management of this disease is completely different in Japan than in all other countries. In Western countries, LPLNs are considered metastatic and can only be managed by preoperative chemoradiotherapy combined with a standard TME, whereas in Japan, lateral pelvic lymph node dissection (LPLND) represents a standard regional lymphadenectomy. Akiyoshi et al. reported that preoperative CRT alone cannot eradicate LPLN involvement, but excellent local control and survival can be achieved with the combination of preoperative CRT and LPLND [27]. Because MRI before CRT seems to be useful for predicting LPLN metastases, extended lymphadenectomy may be indicated for selected patients with advanced low rectal cancer with preoperative cN status on a preoperative MRI [28] to avoid recurrence, even after a CPR.

Some limitations should be considered when interpreting our study results, including the retrospective multicenter study design, limited follow-up period, small size of the studied population and potential bias inherent in the data collection and analysis. We acknowledge that deficiencies in the perioperative evaluations may exist, such as the lack of systematic post-CRT MRI examinations, differences in radiotherapy protocols between centres, and difficulties in the pathological analysis of the specimens in cases in which no tumour was found. However, very specific attention was given to all specimens with a pCR, and they were reviewed by a second pathologist according to a standardized protocol.

To our knowledge, this is the first study to suggest that even in the group with the best prognoses and CPR after chemoradiotherapy for low rectal cancer, the occurrence of perineal sepsis and/or poor initial differentiation may be associated with impaired DFS.

Based on these findings, other options for the management of advanced low rectal cancer may be discussed, such as LPLND in patients with pre-treatment cN lPLN status on MRI results and the addition of oxaliplatin to fluorouracil-based neoadjuvant chemoradiotherapy and adjuvant chemotherapy to reduce the risks of both local and distant recurrences [29].

This study demonstrated that a CPR is associated with a 12.6% rate of recurrence and that perineal sepsis and histologically poor differentiation are associated with worse DFS times among patients with a CPR. Additional aggressive therapeutic options should be considered when these risk factors are present.