Rational treatment selection for primary Merkel Cell Carcinoma: a Rational MCC RCT comparing surgery and radiotherapy with parallel observational study

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.

Study registration
This study is registered as ISRCTN16290169; Clinicaltrials.gov number NCT05253144.

Funding
This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation programme (NIHR award ref: 12/205/36) and is published in full in Efficacy and Mechanism Evaluation; Vol. 12, No. 12. See the NIHR Funding and Awards website for further award information.