Impact case study database

Anal cancer is diagnosed in over 4,300 patients per year in Europe and 8,600 in the United States and its incidence has increased by 75% in the last three decades. It is predominantly a pelvic disease with a relatively low rate of metastases, where successful local treatment to eradicate the disease and to prevent recurrence is of crucial importance to achieve long-term survival. The progressive improvement in radiotherapy technique, influenced by the findings from Sebag-Montefiore’s research, has led to substantial patient benefit by reducing severe acute treatment-related side effects, avoiding interruption in radiotherapy, ensuring the full dose delivery of radiotherapy and chemotherapy, resulting in high rates of locoregional control and overall survival.

The shrinking field radiotherapy approach was used in the Cancer Research UK ACT2 trial co-led by Sebag-Montefiore. It is the largest global phase III randomised anal cancer trial and recruited 940 patients between 2000 and 2008. 75% of patients completed planned radiotherapy and delays in treatment of 7 or more days occurred in 15% of patients. 3-year progression free survival was 71% and overall survival 83%, compared with 65% overall survival in ACT1. In 94/940 patients a delay in overall treatment beyond 42 days resulted in 78% 3-year overall survival.

As anal cancer is relatively uncommon and in the absence of detailed treatment guidelines, centres in the UK and internationally used the ACT2 radiotherapy protocol in their routine clinical practice and this remained the standard treatment approach for more than a decade.

Increased uptake of IMRT improves health outcomes

The UK adoption of IMRT is evidenced by a publication of a Royal College of Radiologists audit led by Sebag-Montefiore and colleagues [ A]. Performed between February and July 2015, 242 cases from 40/56 UK radiotherapy centres were analysed. This is the largest published prospective multicentre experience of IMRT in routine clinical practice. The UK IMRT protocol was used in 65% of cases, the remainder using the ACT2 protocol or a modified IMRT approach. Using IMRT the planned radiotherapy dose was delivered in 96% cases and radiotherapy interrupted in only 4% of cases, representing a substantial improvement compared with the ACT2 trial outcomes.

Overall, 41% of IMRT-treated patients experienced severe grade 3/4 toxicity. One-year survival was 94%. One-year patient reported outcome assessments of the IMRT treated patients found significant improvements in buttock pain, blood and mucous in stools, pain, constipation, appetite loss, and health anxiety compared to baseline. There was no evidence of clinically significant deteriorations at one year for diarrhoea, bowel frequency, and flatulence [ B, C].

IMRT has dramatically impacted on the lives of anal cancer patients internationally, resulting in substantial reductions in the acute toxicity of treatment and the avoidance of interruptions in radiotherapy treatment delivery that are associated with worse survival outcomes [ D, E, F].

Further evidence of implementation of IMRT in routine clinical practice in the English NHS is provided by the National Cancer Registration and Analysis Service, Public Health England. Prior to publication of the protocol IMRT was used in 13% of all anal cancer patients. This increased steadily to reach 78% by 2019 [ G].

Inclusion of IMRT in national and international guidelines

The national and international reach of the shrinking field technique and IMRT is evidenced through direct reference in national and international guideline documents.

The Association of Coloproctology Great Britain and Ireland (ACPGBI) guidelines [ H] for the management of cancer of the colon, rectum and anus state:

“Definitive CRT is the standard treatment for all anal cancers that are not amenable to local excision…and the minimum radiation dose for microscopic disease should be 40 Gy in 28 fractions over 5.5 weeks using IMRT or 30.6 Gy in 17 fractions over 3.5 weeks using the original ACT2 protocol.”

They further state: “IMRT should be considered for all patients in whom definitive CRT is intended, in order to reduce acute toxicity and possibly late toxicity. Standardization of radiotherapy volume outlining, planning and delivery should be based on published consensus guidelines…A UK consensus document for outlining, planning, dose objectives and constraints and dose delivery is available on-line at http://www.analimrtguidance.co.uk/. This consensus has taken into account the excellent results achieved in the ACT2 trial, together with a review of radiotherapy planning and dose delivered to patients in the trial and has resulted in an adaptation of the recommended dose prescription.”

The European Guidelines of the Medical Oncology, Surgical and Radiotherapy Organisations (ESMO-ESSO-ESTRO) guidelines [ I] cite the ACT2 dose and radiotherapy technique and provide it as an example regimen of curative CRT for anal cancer. The United States National Comprehensive Cancer Network (NCCN) guidelines for anal carcinoma [ J] cite the ACT2 trial outcomes, noting that “the absence of a planned treatment break in the ACT2 trial was considered to be at least partially responsible for the high colostomy-free survival rates observed in that study (74% at 3 years).”

The IMRT solution has been integrated into the CRUK-funded UK PLATO platform trial protocol, which aims to optimise radiotherapy dose for anal cancer patients with low-, intermediate- and high-risk disease. Sebag-Montefiore is Chief Investigator and has recruited over 400 patients to date in this uncommon disease. The trial platform includes three anal cancer trials (ACT) 3,4 and 5. The above IMRT technique is used to allow the ACT4 trial to test the benefit of de-escalation of radiotherapy dose in early stage disease and ACT5 trial to test the benefit of dose escalation in locally advanced disease.