Low energy contact X‐ray brachytherapy for treatment of rectal cancer: a health technology appraisal by Health Technology Wales

Health Technology Wales sought to evaluate the clinical and cost‐effectiveness of contact X‐ray brachytherapy (CXB) for early‐stage rectal cancer.

adopted where intensive radiological, endoscopic and clinical surveillance aims to detect early signs of disease recurrence, facilitating timely TME surgery [4][5][6].This minimizes operative morbidity and mortality, delivers equivalent oncological outcomes and preserves bowel continuity [4,5,7].This is particularly important to patients who are reluctant to accept the risks associated with surgery, including a stoma, or who are unable to undergo surgery because of comorbidities.Almost half of patients have a stoma 18 months following TME surgery [8] and perioperative mortality, particularly in elderly comorbid demographic cohorts, is significant [9].If surgery is required, deferred TME can be performed with equivalent oncological outcomes to initial surgical management [10][11][12].
Unfortunately, in most cases external-beam chemoradiotherapy alone will not achieve a cCR [4,6] and following cCR the local regrowth rate is approximately 25%, necessitating TME surgery [5,6].Dose escalation to improve organ preservation rate has been advocated by several groups [13][14][15].50 kVp contact X-ray brachytherapy (CXB) boost has limited tissue penetration due to its low energy, and can be used to escalate the targeted dose of radiation directly to the tumour with minimal damage to surrounding tissues [16].CXB in combination with external-beam chemoradiotherapy appears to result in a higher cCR and lower regrowth rate [17][18][19].This article summarizes a recent health technology appraisal by Health Technology Wales (HTW), which sought to evaluate the clinical and cost-effectiveness of CXB and inform guidance on its use in Wales [20].

APPR AISAL ME THODS
Health Technology Wales is a national health technology assessment body working to improve the quality of health and social care by developing independent guidance for healthcare providers.HTW guidance is based on rapid evidence reviews, consideration of costeffectiveness and patient and public perspectives.The appraisal process has previously been described in detail [21] and a full description of the methodology and results of this appraisal have been published [20].The evidence review for this topic aimed to identify evidence comparing CXB boost against an external-beam radiotherapy boost or surgery for patients with early-stage rectal cancer, irrespective of their suitability for surgery.HTW undertook new cost-effectiveness modelling (Figure 1) to supplement economic evidence identified in the

F I G U R E 1
Cost-effectiveness model structure comprising a short-term decision tree of treatment response and surgical procedures, followed by a lifetime state transition (ST) model (shown in the insert) including incidence of local recurrence or regrowth after watch and wait based on the OPERA study.OPERA, Organ Preservation in Early Rectal Adenocarcinoma.

E VIDEN CE RE VIE W AND ECONOMIC ANALYS IS
The evidence review included all relevant studies published up to September 2023 and identified the Organ Preservation for Early Rectal Adenocarcinoma (OPERA) trial (NCT02505750) [22] as the only clinical study adhering to the appraisal protocol [20].OPERA is a European phase III multicentre randomized controlled trial in patients with T2-3, N0-1, M0 rectal cancer.It compared a 9 Gy boost of external-beam radiotherapy to a 90 Gy CXB boost either prior to (arm B1) or following (arm B2) chemoradiotherapy.Three-year follow-up data suggest that both cCR and organ preservation rates are better with CXB boost (arm B).Rates of surgery overall were lower with CXB, and there was no statistically significant difference in the rates of local recurrence, disease-free survival or overall survival.
Similarly, there was no difference in rates of early adverse events or in bowel function.Rectal bleeding was more common initially following CXB but had resolved by 3 years [22].
Health Technology Wales used the results of the OPERA study to estimate the cost-effectiveness of CXB compared with an external-beam boost from a UK National Health Service (NHS) perspective.The analysis suggested that CXB is cost effective, as part of a watch and wait strategy.The higher costs of CXB and increased surveillance were estimated to be partially offset by savings in surgery and stoma care, resulting in an incremental cost of £887 per person over a lifetime horizon.The delay or avoidance of surgery following CXB was estimated to provide an improvement of 0.2 quality-adjusted life years (QALYs) per person.The resulting incremental cost-effectiveness ratio (ICER) was £4463 per QALY gained.
Interventions with an ICER below £20 000 per QALY are commonly considered cost effective [23].
Decision models are vulnerable to uncertainty associated with model parameters.This was explored in sensitivity analysis.Costeffectiveness estimates were worst when higher costs of CXB, lower costs of stoma care or lower cCR rates following CXB were modelled.Estimates were best when the opposite was applied, or a reduced surveillance schedule was modelled.Scenario analyses showed that uncertainty in the cost of CXB led to uncertainty in cost-effectiveness estimates.However, the conclusions of the analysis did not change when the cost of CXB was estimated in different ways.Indeed, CXB was cost effective or dominant (both more effective and less costly) in all the scenarios modelled.In probabilistic sensitivity analysis, ICERs were below £20 000 per QALY in 91% of estimates, suggesting that CXB is highly likely to be cost effective compared with external-beam boost (Figure 2).People reported that getting a cancer diagnosis is difficult and can be life-altering.For patients diagnosed with rectal cancer, the most important outcome is survival and quality of life.For some patients, being told they need a stoma can be as difficult to hear and as harmful to their outlook on the future as the cancer diagnosis itself.Many patients react strongly to this news, believing that a stoma will prevent them from living a satisfying life, and leads some to refuse surgery.Patients advised that they would only accept surgery with consequent stoma if it truly was their only option.They discussed the importance of being supported to make the best decision for their own lives and not simply told about best practice.For some patients, CXB gave them the opportunity to treat their cancer without needing surgery, leading them to live a better quality of life than they believe they would otherwise have had.

PATIENT E XPERIENCE S AND PERSPEC TIVE S
Most respondents to the survey were not offered alternatives to surgery as part of their cancer treatment and reported that surgery had a significant impact on their quality of life.Individuals reported that having a stoma bag changed their sense of self, affected their daily activities and had a negative impact on their relationships and wellbeing.However, some reported that the stoma became 'a normal part of my life'.All respondents agreed that, where appropriate, patients should be given clear information to understand their condition and what alternatives are available.This is important for patients to maintain a sense of control and take part in decision making.They also noted that patients have a right to make choices that are best for them according to the outcomes they value most.

DISCUSS ION AND CON CLUS IONS
Patient testimonials emphasize the importance of patient choice and suggest there is a cohort of patients for whom the availability of organ-preserving approaches, that avoid permanent stoma, is very important.HTW's evidence review identified one randomized controlled trial that showed improved organ preservation for CXB boost compared with external-beam boost, without adverse oncological outcomes, for adults with T2-T3a,b, N0-1, M0 rectal cancer who are fit for surgery (Eastern Cooperative Oncology Group World Health Organization performance status 0-1).For these patients, costeffectiveness analysis indicates that CXB may also represent good value for money for the NHS as part of a watch and wait strategy.
There are limitations to these findings and considerations for their generalizability to routine clinical practice.For example, in current practice, the need for a CXB boost may be determined after reviewing initial response to chemoradiotherapy.This more selective approach may promote appropriate CXB use for patients who are most likely to benefit.The clinical and cost-effectiveness of CXB has not been demonstrated against external-beam boost for different patient groups, for example in more elderly or comorbid cohorts.The risk of surgical complications and mortality can be much higher for people who are older and have more comorbidities than those included in the OPERA study.The avoidance of TME could therefore be more beneficial in terms of survival and quality of life in clinical practice than the population included in the OPERA trial and the cost-effectiveness analysis.The use of CXB within a watch and wait strategy was not compared against a strategy of TME for all patients.Head-to-head comparisons of surgical and organ-preserving approaches are uncommon in trial settings.However, published observational data suggested that these approaches have comparable survival outcomes [12,24,25].Previous economic analyses suggest that watch and wait is cost effective compared with a strategy of initial TME surgery for all rectal cancer patients [26], and that watch and wait with CXB is cost effective compared with initial TME [27].Finally, the health-related quality of life associated with watch and wait and CXB has not been extensively studied [26].While HTW's costeffectiveness estimates were not sensitive to changes in modelled health state utility values, assumptions were made about quality of life following TME and organ preservation which introduce uncertainty to the study findings [20].
The HTW Appraisal Panel concluded that the clinical and costeffectiveness evidence supports the adoption of CXB boost in addition to chemoradiotherapy for patients with early rectal cancer who are suitable for surgery [20].HTW guidance does not cover patients who are unable to undergo surgery.However, guidance from the National Institute for Health and Care Excellence already recommends that the use of CXB in conjunction with externalbeam radiotherapy is safe and efficacious in this population [28].
Alongside existing consensus recommendations on the use of CXB in rectal cancer by the European Society for Therapeutic Radiology and Oncology [29], this guidance promotes wider access to CXB in Wales.
Due to the need for specialist equipment and clinical expertise in providing CXB, it is only available at present in four centres across the UK.CXB is not currently delivered in Wales which requires patients to travel to England for treatment.This leads to inequity of access depending on where people live and their ability to travel.If CXB treatment can be delivered in Wales, this would help to reduce inequity and may avoid delays to the delivery of care.Contact X-ray brachytherapy is a useful treatment option when surgical approaches to the management of early-stage rectal cancer are not suitable.When there is a choice between surgical and organ-preserving approaches, it is important to discuss all treatment options available with patients to enable them to make informed choices.International consensus provides guidance on the frequency of surveillance needed as part of watch and wait strategies [30].If the use of organ-preserving approaches continues to increase in the management of early-stage rectal cancer, robust and consistently applied surveillance programmes based on these guidelines are needed to support this.
review.Patient organizations were approached to contribute patient views, experiences and opinions on rectal cancer and treatment.HTW conducted a patient survey of the All-Wales Cancer Network with the support of Tenovus Cancer Care and patient testimonials were provided by the Papillon Patient Support group.

Five
people responded to the survey of the All-Wales Cancer Network and completed a questionnaire on experiences of rectal cancer diagnosis, surgery, stomas and CXB.The Papillon Patient Support group provided individually written accounts of patients' experiences of cancer diagnosis and accessing CXB.These stories described the experiences of patients who independently sought to have CXB with or without the support of their NHS clinicians and for whom CXB has been successful in treating their cancer.