Rational treatment selection for primary Merkel cell carcinoma: a rational MCC RCT comparing surgery and radiotherapy with parallel observational study
Steven, Neil M Pirrie, Sarah Jefferson-Hulme, Yolande Gaunt, Claire H Homer, Victoria
Steven, Neil M
Pirrie, Sarah
Jefferson-Hulme, Yolande
Gaunt, Claire H
Homer, Victoria
Affiliation
University Hospitals Birmingham NHS Foundation Trust; University of Birmingham
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Publication date
2025-12
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Abstract
Background: Merkel cell carcinoma is a rare locally invasive skin cancer of older people. Standard management for primary Merkel cell carcinoma is surgery and/or radiotherapy, with no standard of care or unity of practice, based on retrospective experience without randomised trials.
Objectives: Feasibility objectives were to determine whether Rational Compare was likely to deliver on its objectives to influence individual treatment decisions and clinical practice, and to determine operational adaptations to reduce variation between patients and in non-randomised components of the management pathway.
If the feasibility objectives were met, then the primary objective of the overall trial was to determine if surgery or radiotherapy as first definitive treatment for primary Merkel cell carcinoma results in better loco-regional disease control.
Design: Rational Merkel cell carcinoma was a multicentre, two-arm, randomised Phase III, adaptive trial with integrated feasibility phase (Rational Compare) plus observational study (Rational Review) designed to produce probabilities that wide local excision or radiotherapy as first treatment for primary Merkel cell carcinoma was at least as good or better than the other in terms of loco-regional control. In the observational protocol (Rational Review), definitive treatment was allocated by regional Specialist Skin Cancer Multidisciplinary Teams to maximise data on this rare cancer.
Setting: National Health Service hospitals with Specialist Skin Cancer Multidisciplinary Teams.
Participants: All patients with newly presenting histologically proven Merkel cell carcinoma considered for radical loco-regional control without distant metastases, capable to consent, were eligible for the trial. Randomisation occurred using a bespoke computer randomisation system developed by the Cancer Research UK Clinical Trials Unit employing a stratified minimisation method. Those with primary Merkel cell carcinoma that could be treated with margins of ≥ 1 cm by either surgery or radiotherapy for which the Specialist Skin Cancer Multidisciplinary Team was in equipoise were eligible for Rational Compare.
Interventions: Wide local excision or radiotherapy as first definitive treatment for primary Merkel cell carcinoma.
Main outcome measures: Time from randomisation to loco-regional treatment failure.
Rates of registration and randomisation.
Marginal excision and macroscopic disease at the time of definitive treatment.
Results: Sixty-four patients were recruited, of whom five were randomised. The trial did not meet its feasibility target for randomisation and closed.
The five randomised patients all underwent their allocated treatment (three radiotherapy and two surgery, one with adjuvant radiotherapy following surgery), and none experienced loco-regional failure. Twenty-six loco-regional failure events were reported in 59 observational patients (8 had radiotherapy, 27 had surgery, 18 had surgery with adjuvant radiotherapy, 5 had regional Merkel cell carcinoma without known primary and 1 unknown treatment). About a quarter of patients had macroscopic disease, and a majority likely had microscopic involvement at the primary site at the time of definitive treatment.
Conclusions: Both wide local excision and radiotherapy are offered as first treatment for primary Merkel cell carcinoma in UK practice, but it remains uncertain whether one should be prioritised.
Implications for health care: As Merkel cell carcinoma is a rare cancer, the challenge for healthcare systems has been that no specific management strategy currently exists. Merkel cell carcinoma requires a more definitive guideline with optimised referral pathways and interhospital working, which could accelerate and clarify treatments and thus allow better comparison and improvement of outcomes.
Limitations: Major logistic challenges meant randomisation targets were not met, so the trial closed without answering the primary objective.
Future work: The design and outcomes of Rational Merkel cell carcinoma will inform design of future studies for rare cancers. Readouts of circulating immune cells and analysis of the immune microenvironment in the Merkel cell carcinoma primary will be explored in relation to the clinical data set and outcomes.
Plain language summary
Merkel cell carcinoma is a skin cancer affecting only 250–300 people in the United Kingdom each year. Its rarity means clinicians advise patients on available treatments based on their experience of past cases rather than on the basis of evidence from past clinical trials.
Merkel cell carcinoma starts on the skin (known as the primary), grows quickly and often spreads to nearby lymph nodes in the neck, armpit or groin. It must be treated effectively or it quickly regrows. The primary Merkel cell carcinoma is removed by specialist surgeons who can remove the lesion with a good margin of healthy tissue and who can decide on the possibility of accurate staging. To get a good clearance, large areas of tissue may need to be removed. These patients often need specialist repair after surgery, as well as the consideration of sentinel node staging at the time of surgery, and then possibly radiotherapy. Some patients are instead treated by radiotherapy right away, reducing the need for repair, allowing delivery of radiotherapy sooner.
The Rational Merkel cell carcinoma trial was designed to fairly compare surgery or radiotherapy for primary Merkel cell carcinoma so the trial results could help patients and doctors make the best decision for treatment, taking into account other issues for that person, such as which bit of the body the Merkel cell carcinoma was on, their age and fitness, and preferences.
People with Merkel cell carcinoma are typically elderly and are referred to travel long distances to specialist centres. Treatment requires co-ordination between specialists. Unfortunately, we found that the trial was not feasible with only five patients entered. We recognised this risk of failure in advance and stopped the trial. The patients all underwent their allocated treatment (three had radiotherapy and two surgery, one with radiotherapy following surgery), and after 2 years, the Merkel cell carcinoma has not come back in these patients. However, it was not possible to say with certainty from these small numbers whether surgery or radiotherapy should be offered as the first treatment. An additional 59 patients, concurrently treated for Merkel cell carcinoma but not entered into the comparison, still contributed data on the patient, tumour, treatment and disease control. This meant the trial still collected useful data along with immune measurements and tumour samples from this rare group of patients for further study.
Information on the experience of running this trial and use of a novel trial design may help with design of future research to help people with rare cancers.
Citation
Steven NM, Pirrie S, Jefferson-Hulme Y, Gaunt CH, Homer V. Rational treatment selection for primary Merkel Cell Carcinoma: a Rational MCC RCT comparing surgery and radiotherapy with parallel observational study. Southampton (UK): National Institute for Health and Care Research; 2025 Dec.
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Article