Elsevier

The Lancet

Volume 391, Issue 10139, 23–29 June 2018, Pages 2537-2545
The Lancet

Articles
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

https://doi.org/10.1016/S0140-6736(18)31078-XGet rights and content

Summary

Background

The strategy of watch and wait (W&W) in patients with rectal cancer who achieve a complete clinical response (cCR) after neoadjuvant therapy is new and offers an opportunity for patients to avoid major resection surgery. However, evidence is based on small-to-moderate sized series from specialist centres. The International Watch & Wait Database (IWWD) aims to describe the outcome of the W&W strategy in a large-scale registry of pooled individual patient data. We report the results of a descriptive analysis after inclusion of more than 1000 patients in the registry.

Methods

Participating centres entered data in the registry through an online, highly secured, and encrypted research data server. Data included baseline characteristics, neoadjuvant therapy, imaging protocols, incidence of local regrowth and distant metastasis, and survival status. All patients with rectal cancer in whom the standard of care (total mesorectal excision surgery) was omitted after neoadjuvant therapy were eligible to be included in the IWWD. For the present analysis, we only selected patients with no signs of residual tumour at reassessment (a cCR). We analysed the proportion of patients with local regrowth, proportion of patients with distant metastases, 5-year overall survival, and 5-year disease-specific survival.

Findings

Between April 14, 2015, and June 30, 2017, we identified 1009 patients who received neoadjuvant treatment and were managed by W&W in the database from 47 participating institutes (15 countries). We included 880 (87%) patients with a cCR. Median follow-up time was 3·3 years (95% CI 3·1–3·6). The 2-year cumulative incidence of local regrowth was 25·2% (95% CI 22·2–28·5%), 88% of all local regrowth was diagnosed in the first 2 years, and 97% of local regrowth was located in the bowel wall. Distant metastasis were diagnosed in 71 (8%) of 880 patients. 5-year overall survival was 85% (95% CI 80·9–87·7%), and 5-year disease-specific survival was 94% (91–96%).

Interpretation

This dataset has the largest series of patients with rectal cancer treated with a W&W approach, consisting of approximately 50% data from previous cohort series and 50% unpublished data. Local regrowth occurs mostly in the first 2 years and in the bowel wall, emphasising the importance of endoscopic surveillance to ensure the option of deferred curative surgery. Local unsalvageable disease after W&W was rare.

Funding

European Registration of Cancer Care financed by European Society of Surgical Oncology, Champalimaud Foundation Lisbon, Bas Mulder Award granted by the Alpe d'Huzes Foundation and Dutch Cancer Society, and European Research Council Advanced Grant.

Introduction

The standard treatment for locally advanced rectal cancer is neoadjuvant (chemo)radiotherapy followed by major resection surgery, based on the principles of total mesorectal excision (TME).1 However, this strategy is associated with perioperative mortality of 1–2%, which increases with old age, frailty, and comorbidity.2, 3 Additionally, it can lead to temporary or permanent colostomy and serious long-term morbidity, such as urinary and sexual dysfunction in more than 60% of patients.4 Over the past two decades, focus has gradually shifted towards a more individualised approach, with the aim of improving long-term quality of life and functional outcomes. This approach has led to a growing interest in organ-preserving strategies in a strictly selected population.

The combination of neoadjuvant chemotherapy and radiotherapy has proven to be effective to downstage the primary tumour and it leads, in about 20% of patients, to complete disappearance of the tumour and tumour- positive lymph nodes—a pathological complete response (pCR), which is associated with favourable long-term outcomes compared with those without complete response.5, 6

Research in context

Evidence before this study

The watch and wait (W&W) strategy is gaining more attention as a treatment option for patients with rectal cancer with a clinical complete response after neoadjuvant therapy. Up to today, no evidence from randomised trials is available. Although several cohort studies and extensive reviews have been done, concerns remain about the oncological safety in patients who experience tumour regrowth. We did a PubMed search without date or language restrictions with the terms, “rectal neoplasms” as a major mesh term and the terms, “watchful waiting” (or variations, such as “watch-and wait” or “wait-and-see”) and “neoadjuvant therapy” for studies in human beings. The search yielded 110 hits, of which several were cohort studies and 33 were review articles published since 2004. The first report was published in 2004 by Habr-Gama and colleagues, and included 71 patients. Several reports from the Habr-Gama research group are now available, in which 5-year overall survival is reported ranging from 85·9% to 100%. The largest cohort study available is from the northwest of England cohort, and includes 129 patients. In this study, the outcomes of W&W patients were compared with patients who had surgery using a propensity matched cohort analysis. 34% of the patients developed local regrowth. Nonetheless, no differences were found in non-regrowth disease-free survival and overall survival (3-year overall survival was 96%). Other cohort studies report similar survival, though they are generally small, mostly retrospective, and the inclusion criteria are variable across studies. A meta-analysis was published by Dossa and colleagues. In this study, a pooled 2-year local regrowth rate of 15·7% was reported, ranging from 5% to 33% in the studies included in the meta-analysis. Although this meta-analysis found no survival benefit for surgical resection in patients with a clinical complete response, this conclusion was based on two studies only, including 48 patients on the W&W strategy.

Added value of this study

This is the first large registry-based study on international W&W strategies for patients with rectal cancer, consisting of pooled individual patient data of approximately 50% patients from previously published series and 50% unpublished data. Despite the heterogeneity, this study provides a reliable reflection of the real-world risks and benefits of W&W. Local regrowth was most frequently diagnosed in the first 2 years of follow-up and was located in the bowel wall in most patients. Nodal local tumour regrowth was very uncommon. This indicates that strict endoscopic surveillance in W&W protocols is essential and enables early detection followed by curative treatment. In this series, survival was excellent and the risk of local unsalvageable disease was small.

Implications of all the available evidence

This study provides a valuable insight into W&W strategies worldwide. However, further expansion of the network and prospective data collection are essential to learn more on long-term outcomes of W&W, including functional outcomes. The IWWD Consortium will focus on the development of uniform protocols for selection and follow-up of patients on the W&W strategy. All interested clinicians who perform organ-preserving strategies on patients with rectal cancer are welcome to join our network.

Since the first introduction of the watch and wait (W&W) strategy for patients with rectal cancer with a clinical complete response (cCR) after neoadjuvant chemoradiotherapy by Habr-Gama and colleagues,7 multiple cohort series8, 9, 10, 11 are now available in which surgery has been omitted. The diagnosis of a cCR based on the results of conventional imaging modalities does not perfectly correspond to a true complete response because local regrowth rates within 2 years of follow-up range from 7% to 33%.8, 12, 13 Despite the incidence of local tumour regrowth, the results so far are promising in terms of survival since most local regrowths are amenable to salvage resection.12

Several factors might have contributed to a limited adoption of such a strategy so far and its absence in most surgical oncology guidelines. Most available cohort series are small and have heterogeneous study populations and, therefore, are not adequate to define the individualised oncological risk. Furthermore, international consensus has not been reached on imaging strategies and timing to identify a cCR, or follow-up protocols for timely detection of tumour regrowth. Also, neoadjuvant treatment schedules and choice of chemotherapy and radiotherapy dosage are considerably variable across studies, subsequently resulting in a wide range of cCR rates (10–78%).9, 10 Finally, data on long-term survival, such as functional and quality-of-life results, are still scarce.

In this setting, more evidence supporting organ-preserving strategies is needed to implement W&W as a safe treatment option for selected cases. Randomised controlled trials for this indication are challenging for both practical and ethical reasons: patients are likely to prefer avoiding surgery, especially when they are facing permanent colostomy. The International Watch & Wait Database (IWWD) was established in February, 2014.14 This database was initiated by a collaboration of high-profile clinical experts, under the umbrella of the European Registration of Cancer Care and the Champalimaud Foundation Lisbon. The aim of this database is to collect all available data to expand knowledge on the benefits, risks, and oncological safety of organ-preserving strategies in rectal cancer. For the present study, the primary aim was to describe the pooled information after collection of patient data from more than 1000 patients in our network, which consists of data from previously published cohort series and about 50% of unpublished data from smaller W&W centres. Furthermore, we aimed to explore the local regrowth rate and survival in this population.

Section snippets

Study design

This was an international multicentre registry study. On April 14, 2015, the web-based database was opened for patient-data registry. Clinical experts on W&W strategies were invited to participate. Additionally, clinicians could join the network via our website or contact addresses. Participating centres agreed to enter information on all patients in their institute who had organ-preservation treatment after neoadjuvant therapy for rectal cancer, whether or not patients had been part of

Results

Between April 14, 2015, and June 30, 2017, 1009 patients were included in the database from 47 participating institutes and 15 countries (appendix). Of these, 880 patients had a cCR as defined by the criteria of participating institutes and were included for the present analysis, with a median follow-up time of 3·3 years (3·1–3·6; table 1). Other reasons for inclusion in the database but exclusion from this analysis were clinical near complete response or patient-related factors such as refusal

Discussion

This is the largest series of pooled individual data of patients with rectal cancer and a cCR after neoadjuvant therapy, treated with W&W. The main aim of this study was to provide insight in the W&W strategies worldwide and oncological outcome of W&W patients. The registry has collected data of more than 1000 patients, approximately 50% from published cohort studies and 50% of unpublished data.7, 8, 10, 11, 13, 16, 17

In the registry, 25% of patients with a cCR after neoadjuvant therapy and

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  • Cited by (0)

    Consortium listed in the appendix

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