Adjuvant chemotherapy for rectal cancer with complete pathological response (pCR) may not be necessary: a pooled analysis of 5491 patients

Neo-adjuvant chemoradiotherapy (CRT) followed by radical surgery is the recommended optimal treatment for locally advanced rectal cancer [1], as the preoperative chemoradiotherapy could reduce recurrence and improve survival [2]. Similarly, post-operative adjuvant chemotherapy has an established role in patients with locally advanced rectal cancer for reducing the risk of recurrence and mortality up to 20–30% [3]. Then, is adjuvant chemotherapy necessary to the patients with complete response (pCR)? As once pCR has achieved, it will be followed with very low local recurrence, distant metastasis and improved long-term survival [4]. According to the present guidelines, adjuvant chemotherapy is offered as a standard treatment for all patients receiving CRT and the radical surgery, regardless of the postoperative pathological results. The NCCN recommended postoperative adjuvant chemotherapy for all patients undergoing preoperative chemoradiotherapy regardless of the final yield pathology, even pCR [5], while, the ESMO guidelines stated that “similar to the situation in colon cancer Stages III (and “high-risk” Stage II), adjuvant chemotherapy can be provided, even if the scientific support for sufficient effect is less” [6]. However, the various expert panels regarded definition of high risk differed slightly, generally including T4 tumor, poor differentiation, inadequate lymph node retrieval, the circumferential resection margin(CRM), extramural venous invasion (EMVI). Hence, no consensus was arrived on the basis of pCR in determining the necessity for adjuvant chemotherapy. Despite the widespread use of chemotherapy, solid evidence to support the benefits of adjuvant chemotherapy after pCR and radical excision is lacking [7]. What is more, several authors have demonstrated that pCR patients cannot benefit from the adjuvant chemotherapy after CRT and the curative resection [8‐10], however their studies showed characteristic of small size sample and selection bias. With these heterogeneous results and potential harmful effects about chemotherapy, we determined to assess the value of adjuvant chemotherapy after achievement of pCR following preoperative radiology and surgery in rectal cancer patients.

To our knowledge, this study is the first and largest study among Chinese population assessing the association between pCR and long-term prognosis. There are two main complementary findings highlighted in this study: 1) No association between improved OS and DFS and the reception of adjuvant chemotherapy after achievement of pCR; Meanwhile, the pretreatment factors of advanced T stage, positive EMVI and CRM remained no associated with worse outcomes in the context of a pCR. and 2) cumulative incidence of distant relapse surged rapidly on the 12 months and rose up to peak in the 36th month.

This current study is unique in comparing adjuvant chemotherapy against observation alone in context of pCR. In fact, previously there also existed some small sample size trials or sub-group analysis concerning to the role of adjuvant chemotherapy for patients with pCR. Consistently, those who received adjuvant chemotherapy had no survival benefits compared to those without adjuvant chemotherapy on rectal cancers with pCR [8]. Similarly, even during a median follow-up of 57 months, the 5y-DFS rates for patients in the chemo group and the no-chemo group were also comparable, showing no significant difference [9]. However, the retrospective design nature, small size sample and selection bias of those studies frequently were considered to be the potential drawbacks, hence, no consensus was arrived on the basis of pCR in determining the necessity for adjuvant chemotherapy.

Here a largest baseline balanced cohort demonstrated adjuvant chemotherapy had no overall and disease-free survival profit in pCR, which added more clear evidence on the no benefit of chemotherapy applied in pCR rectal cancers. The main reason was lied to accurate estimation for post-operative pathology, as final pathologic stage is most prognostic of oncologic outcomes in locally advanced rectal cancer patients after neo-adjuvant chemoradiotherapy [19]. It can be determined that most predictive of overall and disease-free survival was based on final pathologic T classification and N classification elements, while this applicability to the present pCR population in question is direct. Moreover, besides tumor response to preoperative therapy and final pathologic stage as strong predictors of survival, oncological outcome is most influenced by preoperative T stage and high-risk factors, such as EMVI and CRM [20, 21]. Then we stratified patients according to the clinical covariates, and identified the impact of adjuvant chemotherapy on survival in different subgroups. Similarly, there were no differences in survival with respect to positive for EMVI and CRM or not, no matter Mono or Combined Chemotherapy was administered. In addition, chemotherapy may be more effective in patients with poor prognosis, such as those with stage III or stage II with T3-4, just as the ADORE trial examining the role of oxaliplatin and leucovorin as chemotherapy for rectal cancer, it turned out that patients with final pathological stage III received improving survival but patients with stage I and II disease did not [22]. That is why we did not observe any survival profit in pCR when adding chemotherapy. Additionally, achievement of pCR seemed to have an excellent prognosis regardless of utilization of adjuvant chemotherapy, or the potential benefit of chemotherapy in patients with a pCR after neo-chemoradiation would appear to be small if it exists at all. The only way to prove the absence of such a small benefit must require a large sample size trial. That is why our study has been carried out here, as this pooled analysis covered not only 5491 patients with pCR in the whole world, but also the carefully followed patients at our single center. In total, the sample size more than 4000 pCR was enough to reach a power of consolidated conclusion, while, the benefit of adjuvant chemotherapy cannot be detected on the patients with pCR.

However, against our study, a potential advantage providing from adjuvant chemotherapy was demonstrated in three retrospective studies [14, 18, 23]. In fact, those studies were all based on the National Cancer Database (NCDB). Although the patients sample seemed very large, while, the surgical procedure was not clarified sufficiently, just demonstrating Partial proctectomy or Total proctectomy. However, others studies including our FUSCC data, which did not observe benefit of adjuvant chemotherapy in pCR, all performed TME. That may be the major reason accounting for the discrepancy. In another word, those patients from NCDB with pCR might undergo local resection, instead of TME, devoid of reginal lymph nodes resection. In addition, another explanation can be attributed to the fact that report only presented overall survival rather than DFS in their analyses, which allowed not cancer-related comorbidities to affect survival outcomes. Given that the tumor behavior is routinely evaluated by DFS, DFS is one of the most sensitive factors of the intended effects of biological characteristic. Unlike overall survival, DFS is less influenced by disparities in the treatment of relapse disease, management of comorbidity, and differential rates of death from competing causes irrelative to cancer. Additionally, the retrospective design and unbalanced baseline of that study may be considered to be other additional potential reasons.

Generally, approximately 80% of disease recurrences after radical surgery of colorectal cancer occurred within the first 2 years post-surgery [24, 25]. Nevertheless, it does not appear to be the case for achievement of pCR in our study. It inferred from some studies that about 80% of the recurrences occur within the first 4 years, which was postponed in patients with pCR [26]. That parallels the findings here, as among the cases developing distant disease relapse, relapse remained occur more than 3 years after the surgery. We therefore recommended the perspective that achievement of pCR require more prolonged close follow care [27].

Owing to insufficient data, we were unable to perform a subanalysis for different basic characters or concomitances, such as the lymph nodes retrieved and clinical TNM staging, which had important implication in the fates of outcome. Elsely, reporting bias is inherent in any retrospective database, so appropriate adjustment for potential confounders is performed to validate the effect of adjuvant chemotherapy. Although no heterogeneity in the pooling analysis was found in the present analysis, the results of a large-scale, dedicated, randomized controlled trials are awaited to determine the external validity of our findings.

Rectal cancer patients with pCR did not benefit from adjuvant chemotherapy after preoperative chemoradiotherapy and radical surgery, which supports the results of previous studies investigating the role of adjuvant chemotherapy in yield pathological stage. The value of adjuvant chemotherapy for pCR patients should be further determined in prospective randomized trials or large multicenter cohort studies, in addition, we recommended that achievement of pCR require more prolonged close follow care in case of distant metastasis.