Earlier this year the National Institute for Health and Care Excellence published new guidelines on the management of colorectal cancer which aims to improve quality of life and survival. [1] Input was sought from patients who were full members of the committee. The contributions from the members of the committee who were patients were highly valued. One of the most controversial topics proved to be on the best management of patients who achieve a clinical complete response (cCR)after neoadjuvant chemo/radiotherapy for rectal cancer.

Standard treatment for people with locally advanced rectal cancer is surgery which is undergone after neoadjuvant radiotherapy or chemoradiation. Perioperative mortality is around 1-2%, but rises with age, frailty index and the presence of co-morbidities. Around a quarter of those with low rectal cancer who undergo surgery end up with a permanent stoma. Histological examination of resected tissue shows that up to 1 in 5 specimens have no evidence of tumour, demonstrating a complete pathological response to the neoadjuvant treatment.

This suggests up to 20% of patients who undergo either neoadjuvant radiotherapy or chemoradiation for locally advanced rectal cancer may not require further surgery. The NICE committee therefore considered evidence for deferring surgery in patients who were fit to undergo it, but have achieved a complete response to neoadjuvant treatment. The key outcomes we deemed to be important were local and regional disease progression or recurrence; overall survival, and disease free survival and stoma avoidance rate. Potential prognostic factors identified were patient age and life expectancy, radiological staging, tumour pathology, and serological results of carcinoembryonic antigen (CEA).   

The committee looked at follow-up studies of randomised controlled trials and cohort studies with multiple regression analysis. Of 6919 titles and abstracts identified, no publication met the inclusion criteria for review. Evidence is absent because of the small number of people deferring surgery and lack of multiple regression analysis in the existing studies. Economic analysis demonstrated some benefit for deferral of surgery. [2] It was difficult to judge whether the quality of life gained from avoiding a stoma was greater than the anxiety related to the uncertainty of having to undergo regular endoscopic surveillance. The absolute difference in stoma rate between those for whom surgery was carried out promptly and those in whom  were deferred was low, only 26% (95% C.I. 13-39%) at 3 years in one observation study reporting outcomes for 129 patients with rectal cancer. [3] In the OnCoRe trial deferral of surgery was offered on the basis of a complete response on MRI, yet the 3 year actuarial local regrowth of tumours was 38% (95% C.I. 30-48%) reflecting the low sensitivity of MRI in predicting a complete response. Although most recurrences were treatable by surgery, the impact of deferring it on long term survival is unknown. 

In the face of limited evidence for deferral of surgery, the committee agreed that surgery after neoadjuvant treatment should be the gold standard. While acknowledging that, the lay representatives on the committee—both of whom had previously been treated for bowel cancer—found this challenging. 

Their key concerns were outcome and quality of life—and in particular the need for a stoma. They were keen that patients should be offered the option to defer surgery provided they were given a full explanation of the risks and benefits of this. However, the lack of data to guide safe patient selection for surveillance, the absence of a consistent and robust surveillance strategy, and no data on long-term outcomes and quality of life persuaded them that this course was not appropriate. In addition there was concern about variability of treatment options between different hospitals, the stress and anxiety associated with repeated surveillance visits, different definitions of “a complete response”, and different surveillance protocols.

There was also open discussion about further concerns including  perioperative morbidity and mortality as well as other reductions in quality of life related to the  likelihood of a permanent stoma,  associated with surgery versus deferral of surgery. 

The treatment choices people make are highly dependent on individual circumstances, priorities, and preferences.  These not only relate to the pros and cons of undergoing surgery, but also the level of family support people have, the distance from the hospital where surveillance is  performed and where a decision is being made by a family members on behalf of a patient who lacks capacity for decision making. Nevertheless, while the lay members of the NICE committee welcomed the idea of personalised medicine, and were attracted to the idea of offering patient choice about the decision to undergo surgery the ultimate consensus conclusion was that this should not appear in the final guideline recommendations

NICE recommendation on deferral of surgery:

• Offer surgery to people with rectal cancer (cT1-T2, cN1-N2, M0, or cT3-T4, any cN, M0) who have a resectable tumour. 
• Inform people with a complete clinical and radiological response to neoadjuvant treatment who wish to defer surgery that there is a risk of recurrence, and there are no prognostic factors to guide selection for deferral of surgery. For those who choose to defer, encourage their participation in a clinical trial and ensure that data is collected via a national registry. 

The committee acknowledged some people may choose to defer surgery, but concluded those who choose to defer, should be in the context of a clinical trial/national registry, to allow acquisition of critical data to inform future guidelines. 

Cindy Chew is a Radiologist, Honorary Clinical Associate Professor and Director of Imaging and Anatomy at University of Glasgow

Debby Lennard is a retired Senior Civil Servant who now participates as a lay member and patient representative in research for health and social care.

Julie Hepburn is Lead Lay Research Partner for Wales Cancer Research Centre and is involved in several cancer research groups.

Peter Hoskin is Professor in Oncology at University of Manchester and Clinical Oncologist at Mount Vernon Cancer Centre, Northwood UK.

Competing interests: None declared

References: 

1. National Institute for Health and Care Excellence (2020) Colorectal cancer. Available from https://www.nice.org.uk/guidance/ng151
2. Rao C1, Sun Myint A, Athanasiou T, Faiz O, Martin AP, Collins B, Smith FM. Avoiding Radical Surgery in Elderly Patients With Rectal Cancer Is Cost-Effective. Dis Colon Rectum. 2017 Jan;60(1):30-42.
3. Renehan AG, Malcomson L, Emsley R, Gollins S, Maw A, Myint AS 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 Feb;17(2):174-183. doi: 10.1016/S1470-2045(15)00467-2.

Acknowledgement :

The guideline referred to in this text was produced by the National Guideline Alliance (NGA) at the Royal College of Obstetricians and Gynaecologists (RCOG) for the National Institute for Health and Care Excellence (NICE). The views expressed in this text are those of the authors and not necessarily those of RCOG, NGA or NICE. 

Nathan Bromham, Senior Systematic Reviewer, was responsible for the systematic review and Matthew Prettyjohns reviewed the economic evaluations on this topic.

Guideline Committee Members (alphabetical):

Jay Bradbury, Michael Braun, Gemma Burgess, Cindy Chew, Justin Davies, Charlotte Dawson, Stephen Fenwick, Julie Hepburn, Peter Hoskin, Debby Lennard, Vivek Misra, Faheez Mohamed, Kevin Monahan, Richard Roope, Manuel Salto-Tellez, Michael Shackcloth, Baljit Singh and Ratan Verma

The members of the National Guideline Alliance technical team were (shown alphabetically): Offiong Ani, Ted Baker, Sabine Berendse, Lisa Boardman, Nathan Bromham, Louise Crathorne, Michaela Dijmarescu, Charlene Dixon, John Graham, James Hawkins, Maija Kallioinen, Agnesa Mehmeti, Alice Navein, Feima Ndoeka, Fionnuala O’Brien, Steve Pilling, Matthew Prettyjohns, Audrey Tan and Palida Teelucknavan.