Deferral of surgery in people having neoadjuvant therapy for rectal cancer
Evidence review C4
NICE Guideline, No. 151
Authors
National Guideline Alliance (UK).Deferral of surgery in people having neoadjuvant therapy for rectal cancer
This evidence review supports recommendations 1.3.4 to 1.3.5.
Review question
Which people having neoadjuvant radiotherapy or chemoradiotherapy for rectal cancer do not need surgery?
Introduction
People whose rectal cancer shows a complete clinical response to neoadjuvant therapy may choose to defer surgery, thereby avoiding the risk of surgical morbidity. However, despite having a complete clinical response some patients following such a watch and wait approach will experience locoregional recurrence or progression. This review question aimed to identify prognostic factors that predict recurrence and survival to better select people for watch and wait management.
Summary of protocol
Please see Table 1 for a summary of the population, prognostic factors, and outcomes (PPO) characteristics of this review.
Table 1
Summary of the protocol (PFO table).
For full details see the review protocol in appendix A
Methods and process
This evidence review was developed using the methods and process described in Developing NICE guidelines: the manual 2014. Methods specific to this review question are described in the review protocol in appendix A.
Declarations of interest were recorded according to NICE’s 2014 conflicts of interest policy until 31 March 2018. From 1 April 2018, declarations of interest were recorded according to NICE’s 2018 conflicts of interest policy. Those interests declared until April 2018 were reclassified according to NICE’s 2018 conflicts of interest policy (see Register of Interests).
Clinical evidence
Included studies
A systematic review of the clinical literature was conducted but no studies were identified which were applicable to this review question.
See the literature search strategy in appendix B and study selection flow chart in appendix C.
Excluded studies
No studies were identified which were applicable to this review question.
Summary of clinical studies included in the evidence review
No studies were identified which were applicable to this review question (and so there are no evidence tables in appendix D). No meta-analysis was undertaken for this review (and so there are no forest plots in appendix E).
Quality assessment of clinical outcomes included in the evidence review
No studies were identified which were applicable to this review question.
Economic evidence
Included studies
One relevant study was identified in a literature review of published cost-effectiveness analyses on this topic (Rao 2017; see appendix H and appendix I for summary and full evidence tables). The study considered the cost-effectiveness of watch and wait in comparison to radical surgery for patients with rectal cancer after a clinical complete response following chemoradiotherapy. The study considered three patient groups; 60 year old male cohort with no co-morbidities, 80 year old male cohort with no co-morbidities and 80 year old male cohort with significant co-morbidities.
The analysis was a cost-utility analysis measuring effectiveness in terms of quality adjusted life years (QALYs).
Excluded studies
A global search of economic evidence was undertaken for all review questions in this guideline. See Supplement 2 for further information.
Summary of studies included in the economic evidence review
The base case results of Rao 2017 suggest that watch and wait was found to be more effective and more costly than radical surgery in all modelled patient groups. The strategy was therefore dominant in all patient groups.
Uncertainty was assessed using deterministic and probabilistic sensitivity analysis. Results were found to be sensitive to relative recurrence rates after watch and wait (WW) and radical surgery as well as changes in the quality of life (QoL) reduction with radical surgery. It was also found that the model became sensitive to changes in perioperative mortality when the QoL benefit of WW was reduced. In probabilistic sensitivity analysis watch and wait was found to have a 74%, 85% and 90% probability of being cost-effective in the 60 year old male cohort, 80 year old male cohort with no co-morbidities and 80 year old male cohort with significant co-morbidities, respectively.
Despite being a UK study considering the NHS perspective, the study was considered to be only partially applicable. This is because it doesn’t directly address the review question posed in the guideline (but it is partially addressed by the different subgroups considered in the analysis). Whilst the study meets most of the requirements of an adequate economic evaluation (see Developing NICE guidelines: appendix H), it was deemed to have some potentially serious limitations. Most notably, a key aspect of the analysis is the QoL gain with watch and wait and this is based on QoL values from another disease area (prostate cancer).
Economic model
No economic modelling was undertaken for this review because the committee agreed that other topics were higher priorities for economic evaluation.
Evidence statements
Clinical evidence statements
No clinical evidence was identified which was applicable to this review question.
Economic evidence statements
One relevant study was identified in the literature review of published cost effectiveness analyses on this topic (Rao 2017). This was a cost utility study, partially applicable to the decision problem with potentially serious methodological limitations, comparing radical surgery to a ‘watch and wait’ strategy involving outpatient imaging and monitoring in male patients who had had a complete response to neoadjuvant therapy and were suitable for surgery for rectal cancer. ‘Watch and wait’ was the dominant intervention in all subgroups leading to a reduction in both costs (ranging from £6,274 to £8,095) and an increase in QALYs (ranging from 0.56 to 0.72). Probabilistic sensitivity analysis estimated the probability of ‘watch and wait’ being cost effective when QALYs are valued at £20,000 each, is over 74% for all sub-groups.
The committee’s discussion of the evidence
Interpreting the evidence
The outcomes that matter most
Locoregional progression or recurrence was a critical outcome because it typically leads to further treatment with associated treatment related adverse effects. Overall survival and disease free survival were also critical outcomes because a watch and wait strategy (with deferred surgery) would only be safe if it did not impact survival. Organ preservation rate was an important outcome because organ preservation avoids the morbidity and functional consequences of major surgery.
The quality of the evidence
No evidence was identified which was applicable to this review question.
Benefits and harms
Surgery is the gold standard treatment for rectal cancer. However, some people whose rectal cancer shows a complete clinical response to neoadjuvant therapy wish to defer surgery and opt for an organ preserving ‘watch and wait’ strategy instead. The committee acknowledged that while the watch and wait strategy avoids harms due to surgery around one third will experience local regrowth of their tumour and need salvage surgery. Any local regrowth needs to be detected and treated to avoid disease progression, however this involves a surveillance protocol with repeated examinations which may be inconvenient for some patients.
No evidence was identified on the prognostic factors which could predict recurrence or survival, therefore, there is no evidence to help identify groups of patients for whom deferral of surgery would or would not be appropriate. The committee also recognised the lack of agreed definition of complete clinical or radiological response bringing further uncertainty to who might be candidates for deferral of surgery. For these reasons the committee could not recommend deferral of surgery.
The committee agreed that if a person wishes to defer surgery, they should be informed that there is no evidence to help define for whom deferral might be appropriate and that there is a risk of recurrence. If a person still chooses to defer surgery, deferral should only happen in the context of a clinical trial or a national registry where patients are closely monitored in order to detect and treat any local regrowth of their tumour. Patients should be encouraged to enter a clinical trial (for example on going trials OPERA or TRIGGER) and data collection via a national registry should be ensured. This would generate evidence in the future to help define groups that might benefit from deferral of surgery.
Cost effectiveness and resource use
One relevant study was identified in the literature review of published cost effectiveness analyses on this topic (Rao 2017). This was a cost utility study comparing radial surgery to a ‘watch and wait’ strategy involving outpatient imaging and monitoring in male patients who had had a complete response to neoadjuvant therapy and were suitable for surgery for rectal cancer. Three different patient groups were considered - 60 year olds with no comorbidities, 80 year olds with no comorbidities and 80 year olds with significant comorbidities. The model was a decision tree and markov model informed by previous estimates from the literature. All costs were taken from NHS reference costs and the analysis took a NHS & PSS perspective.
‘Watch and wait’ was the dominant intervention in all subgroups leading to a reduction in both costs (ranging from £6,274 to £8,095) and an increase in QALYs (ranging from 0.56 to 0.72). Deterministic sensitivity analysis was conducted in two ways. Alternative scenarios to the base case were explored which involved applying National Comprehensive Cancer Network (NCCN) protocols for follow-up, correlated cost parameters or doubling all costs. Watch and wait remained dominant under all these alternate assumptions.
It was found that the results of the model were sensitive to relative recurrence rates after watch and wait and radical surgery as well as changes in the quality of life reduction with radical surgery. It was also found that the model became sensitive to changes in perioperative mortality when the quality of life benefit of ‘watch and wait’ was reduced. The model was not found to be sensitive to variations in baseline mortality and operative mortality or individual cost parameters. Probabilistic sensitivity analysis estimated the probability of ‘watch and wait’ being cost effective at a £20,000 per QALY threshold at over 74% for all sub-groups.
Despite being a recent UK cost effectiveness study it was deemed only partially applicable to the review questions as it did not directly address the review question posed in the guideline. The question was only partially addressed by the different subgroups considered. It was also deemed to have some potentially serious methodological limitations. Most notably, a key aspect of the analysis is the quality of life gain with ‘watch and wait’ and this is based on values from another disease area (prostate cancer).
The committee found the study to be of limited value in addressing the review question because it didn’t consider the patient factors which were of most interest.
Other factors the committee took into account
The committee were aware of an international registry of patients with rectal cancer managed by a watch and wait strategy after complete clinical response to neoadjuvant therapy. Only a multicentre project like this is likely to collect sufficient patient numbers to answer the question of who is best suited to a watch and wait strategy. Also ongoing trials such as OPERA and TRIGGER may generate evidence in the future on who is most suitable for deferral of surgery. For this reason they chose not to make a research recommendation for a new trial.
References
Rao 2017
Rao C, Sun Myint A, Athanasiou T, et al. (2017) Avoiding Radical Surgery in Elderly Patients With Rectal Cancer Is Cost-Effective. Diseases of the Colon and Rectum 60(1): 30–42 [PubMed: 27926555]
Appendices
Appendix A. Review protocol
Review protocol for review question: Which people having neoadjuvant radiotherapy or chemoradiotherapy for rectal cancer do not need surgery?
Appendix B. Literature search strategies
Appendix C. Clinical evidence study selection
Clinical study selection for review question: Which people having neoadjuvant radiotherapy or chemoradiotherapy for rectal cancer do not need surgery?
Appendix D. Clinical evidence tables
Clinical evidence tables for review question: Which people having neoadjuvant radiotherapy or chemoradiotherapy for rectal cancer do not need surgery?
No clinical evidence was identified which was applicable to this review question.
Appendix E. Forest plots
Forest plots for review question: Which people having neoadjuvant radiotherapy or chemoradiotherapy for rectal cancer do not need surgery?
No clinical evidence was identified which was applicable to this review question.
Appendix F. GRADE tables
GRADE tables for review question: Which people having neoadjuvant radiotherapy or chemoradiotherapy for rectal cancer do not need surgery?
No clinical evidence was identified which was applicable to this review question.
Appendix G. Economic evidence study selection
Economic evidence study selection for review question: Which people having neoadjuvant radiotherapy or chemoradiotherapy for rectal cancer do not need surgery?
A global search of economic evidence was undertaken for all review questions in this guideline. See Supplement 2 for further information.
Appendix H. Economic evidence tables
Economic evidence tables for review question: Which people having neoadjuvant radiotherapy or chemoradiotherapy for rectal cancer do not need surgery?
Appendix I. Economic evidence profiles
Economic evidence profiles for review question: Which people having neoadjuvant radiotherapy or chemoradiotherapy for rectal cancer do not need surgery?
Appendix J. Economic analysis
Economic evidence analysis for review question: Which people having neoadjuvant radiotherapy or chemoradiotherapy for rectal cancer do not need surgery?
No economic analysis was conducted for this review question.
Appendix K. Excluded studies
Excluded clinical studies for review question: Which people having neoadjuvant radiotherapy or chemoradiotherapy for rectal cancer do not need surgery?
Appendix L. Research recommendations
Research recommendations for review question: Which people having neoadjuvant radiotherapy or chemoradiotherapy for rectal cancer do not need surgery?
No research recommendations were made for this review question.
Final
Evidence reviews
Developed by the National Guideline Alliance part of the Royal College of Obstetricians and Gynaecologists
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