Global variation in the long-term outcomes of ypT0 rectal cancers

https://doi.org/10.1016/j.ejso.2019.10.010Get rights and content

Abstract

Background

Colorectal cancer mortality presents world-wide variation. In rectal cancers presenting a complete/nearly-complete tumor response (ypT0/ypTis) following neoadjuvant treatment, the features correlated to nodal metastases and relapses still need to be defined.

Methods

An international cohort study enrolling ypT0/ypTis rectal cancers surgically treated from 2012 to 2017 was conducted. A propensity matching was used to balance nodal-positive and nodal-negative patients and statistical analyses were performed to investigate survivals, using a bootstrap model for internal validation. The features correlated with nodal metastasis were studied. Countries with participating centers were ranked using the World Bank (WBI), Human Development (HDI) and Global Gender Gap (GGG) indexes to compare survivals.

Results

680 ypT0/ypTis from 52 European, Australian, Indian and American Institutions were analyzed. Mean follow-up was of 30.4 months. 96.5% were treated with total mesorectal excision, 7.2% were nodal-positive and 8.8% relapsed. Distal cancers (HR 0.71 95%CI: 0.56-0.91) and nodal metastasis and nodal metastasis (HR 3.85 95%CI:1.12–13.19) correlated with worse DFS, whereas a younger age was of borderline significance (HR 0.95 95%CI:0.91–0.99). The bootstrap analysis validated the model on 5000 repetitions. A short-course radiotherapy (OR 0.18 95%CI:0.09–0.37) correlated with the occurrence of nodal metastasis. Those countries classified in the low/medium-WBI, medium-HDI and lower-GGG ranks documented worse DFS curves (respectively p < 0.0001, p < 0.0001 and p 0.0002). However, the clinical stages were similar and patients from medium-HDI countries received more adjuvant chemotherapy than the others (p < 0.0001).

Conclusion

Sub-groups at risk for relapses and nodal metastasis were identified. A global variation exists also when benchmarking a rectal cancer complete regression.

Introduction

Recent data from the Global Cancer Observatory (GLOBOCAN 2018), documented that colorectal cancer is still the third most frequent cancer and the second cause of cancer related mortality, however its incidence and mortality present a relevant world-wide variation [1,2].

Rectal cancers account for about 30% of colorectal cancers [3] and represent a field of relevant surgical, clinical and biological investigations. Over the last three decades the approach to rectal cancer radically changed: the improvements achieved lead to the introduction of total mesorectal excision (TME) and neoadjuvant (chemo)radiation treatments [4,5]. Nevertheless, the state-of-the art is continuously evolving as the effects of neoadjuvant treatments started to emerge in literature [6].

In particular, tumor down-staging following neoadjuvant treatment could result in a complete response, defined as clinical response (absence of residual primary tumor clinically detectable, cT0) or pathological response (absence of viable tumor cells within the rectal wall in the surgical specimen, ypT0) [7], occurring in about 10–20% of the patients who were treated with neoadjuvant therapy prior to surgery [8,9].

In this subset of patients, the improved survival outcomes [10,11] and the benefits of avoiding major surgical procedures, are encouraging a more conservative approach including watch and wait protocols [12,13] or a local excision of the residual tumor scar [14].

Despite the achievement of a complete response could be acknowledged as a milestone, a number of issues still need to be addressed, in particular in relation to the surgical strategy, the identification of factors correlated to relapses and tumor regression, and the incidence and impact of a residual nodal disease.

A pilot multicenter investigation was recently conducted in this field investigating the pattern of survivals of rectal cancer patients presenting a complete or nearly complete tumor response after neoadjuvant therapy. Patients were treated using local excision or TME in Italy and Spain and results were highly promising, in particular in disclosing differences in survivals between patients assessed as nodal negative (ypN0) or presenting residual nodal metastases (ypN+) [6].

On the other hand, significant differences are emerging concerning survivals of rectal cancers in different countries, surprising also when comparing Norther European countries [15]. The geographic discrepancies concerning surgical quality and access to surgical care are currently a prioritizing issue, as widely declared by the Lancet Commission on Global Surgery [16]. On this extent, the National Institute for Health Research (NIHR) Global Health Research Unit on Global Surgery is in the process of establishing research hubs in low- and middle-income countries; a four-stage modified Delphy study identified three priority areas for future research, including the access to surgery, surgical oncology and peri-operative surgical care. With respect to the second domain, the aim was to define a resource-weighted quality assurance framework for cancer surgery; the research questions included, among the others, the identification of quality indicators and the role of multidisciplinary team meeting (MDT) in delivering cancer care. Accordingly, it was agreed that “a global observational cohort study was needed to benchmark care pathways and outcomes in low-income against high-income countries. This study would capture data on patient pathways, including availability of diagnostic and therapeutic services, short-term surgical outcomes and longer-term cancer-specific outcomes”. Colorectal cancer was assessed as a top priority along with breast and gastric cancers [17].

This study focused on COmplete pathological ReSponse rectal CAncer (CORSiCA) and aimed to investigate if nodal metastases independently affected prognosis and the clinical variables correlated with the occurrence of pathologic nodes. In addition, the global variations in the outcomes of rectal cancers presenting a complete pathological response were studied.

Section snippets

Design

This retrospective cohort study was promoted by the European Society of Surgical Oncology (ESSO) Young Alumni Club (EYSAC). The project received approval by ESSO board and was registered on clinicaltrials.gov on November 2017 (ClinicalTrials.gov Identifier: NCT03351959). CORSiCA was publicized using ESSO network and social media and it was officially launched on December 1st, 2017 with a global call closing on March 2017. Actions were also taken by EYSAC steering committee members to spread the

Results

Between December and March 2017, 88 Institutions from all over the world registered in the study, however exclusively 52 of them (59.0%) performed as recruiting centers. About 93% of these 52 institutions were European, whereas non-European centers included Australia, India and Argentina, Fig. 1. Nine Institutions were also enrolled in the pilot investigation [6]. Mean age of the junior investigators was 32.9 ± 4.2 years whereas the seniors were about 15 years older (mean age 48.6 ± 8.9 years);

Discussion

The achievement of a complete pathologic response in the surgical specimen following neoadjuvant treatment is a benchmark of the progress made so far in rectal cancer treatment. Several manuscripts documented the benefits of complete response in terms of survival [6,10] and clinical research is moving forward to explore the benefits of an organ preservation.

This study identified a group of “ugly features” in patients treated with TME; in particular, patients with distal and nodal positive

Funding

None.

Declaration of competing interest

None of the authors has any potential financial conflict of interest related to this manuscript.

References (53)

  • R.C.H. Stijns et al.

    Advances in organ preserving strategies in rectal cancer patients

    Eur J Surg Oncol

    (2018)
  • M.R. Siddiqui et al.

    Interobserver agreement of radiologists assessing the response of rectal cancers to preoperative chemoradiation using the MRI tumour regression grading (mrTRG)

    Clin Radiol

    (2016)
  • F. Dossa et al.

    A watch-and-wait approach for locally advanced rectal cancer after a clinical complete response following neoadjuvant chemoradiation: a systematic review and meta-analysis

    Lancet Gastroenterol Hepatol

    (2017)
  • S.A. Chadi et al.

    Factors affecting local regrowth after watch and wait for patients with a clinical complete response following chemoradiotherapy in rectal cancer (InterCoRe consortium): an individual participant data meta-analysis

    Lancet Gastroenterol Hepatol

    (2018)
  • A.G. Renehan et al.

    Watch-and-wait approach versus surgical resection after chemoradiotherapy for patients with rectal cancer (the OnCoRe project): a propensity-score matched cohort analysis

    Lancet Oncol

    (2016)
  • M.J.M. van der Valk et al.

    Long-term outcomes of clinical complete responders after neoadjuvant treatment for rectal cancer in the International Watch & Wait Database (IWWD): an international multicentre registry study

    Lancet

    (2018)
  • M. den Dulk et al.

    Improved overall survival for patients with rectal cancer since 1990: the effects of TME surgery and pre-operative radiotherapy

    Eur J Cancer

    (2008)
  • C. Are et al.

    Variations in training of surgical oncologists: proposal for a global curriculum

    Eur J Surg Oncol

    (2016)
  • M. Babaei et al.

    Neoadjuvant therapy in rectal cancer patients with clinical stage II to III across European countries: variations and outcomes

    Clin Colorectal Cancer

    (2018)
  • R.L. Siegel et al.

    Cancer statistics

    CA Cancer J Clin

    (2016)
  • A. Habr-Gama et al.

    Operative versus nonoperative treatment for stage 0 distal rectal cancer following chemoradiation therapy: long-term results

    Ann Surg

    (2004)
  • E. Al-Sukhni et al.

    Predictors of pathologic complete response following neoadjuvant chemoradiotherapy for rectal cancer

    Ann Surg Oncol

    (2016)
  • 2017 European Society of Coloproctology (ESCP) collaborating group

    Evaluating the incidence of pathological complete response in current international rectal cancer practice: the barriers to widespread safe deferral of surgery

    Colorectal Dis

    (2018)
  • S.T. Martin et al.

    Systematic review and meta-analysis of outcomes following pathological complete response to neoadjuvant chemoradiotherapy for rectal cancer

    Br J Surg

    (2012)
  • Cited by (5)

    • Pathologic stage of ypT0N+ rectal cancers following neo-adjuvant treatment: clinical interpretation of an orphan status

      2022, Pathology Research and Practice
      Citation Excerpt :

      Patients with locally advanced non-metastatic rectal cancer usually undergo neoadjuvant treatment prior to surgical resection. Currently, approximately 14–23% of patients achieve a pathologic complete response,[1,2] however, approximately 8% of them still have nodal metastases in the surgical specimen (ypT0N+).[3,4]. Undoubtedly, patients presenting with a complete response have more favorable outcomes than others, but among those responding, the persistence of a nodal disease has been acknowledged as a major risk factor impairing prognosis.[5]

    This project was selected for presentation during the Scientific Symposium “Niall O'Higgins Award - Best Abstracts”, during the 38th Congress of the European Society of Surgical Oncology (ESSO 38), held in Budapest October 2018.

    View full text