Phase III RCTs needed to prove radiofrequency ablation is effective against colon liver metastases

Gianpaolo Carrafiello

Interventional radiologists must become involved in the multidisciplinary development of phase III randomised controlled trials (RCTs) to further assess the role of radiofrequency ablation in treating colorectal liver metastases. This view was expressed by Gianpaolo Carrafiello (Department of Diagnostic and Interventional Radiology, University of Milan, Italy), when he addressed the Cardiovascular and Interventional Radiological Society of Europe (CIRSE) at the annual congress (22–25 September, Lisbon, Portugal).

Speaking at a focus session outlining the lessons from the CLOCC (Chemotherapy and local ablation versus chemotherapy) trial, Carrafiello acknowledged that RCTs in interventional radiology are difficult to perform, but said they would help to persuade oncologists to work more closely with radiologists.

“We have many problems,” he says, elaborating: “The first one is that many of our procedures are operator dependent. The second one is we use different devices, and also the strategy is not always the same. And, we use different modalities of guidance, so maybe there are too many biases.”

Worldwide, one million people are diagnosed annually with colorectal cancer, up to 50% of whom will develop liver metastases. Only 10 to 15% will be able to undergo surgery, with five-year survival rates between 31% and 58% is carefully selected patients. For non-resectable disease, the standard treatment is systemic therapy, prolonging survival for about two years. Radiofrequency ablation (RFA) has been used to clear tumours from the liver, either alone or in combination with resection, but data on efficacy and survival were lacking until 2012, when the first results from the CLOCC trial became available. Longer-term findings were reported in 2017, and as a result, said Carrafiello, “radiofrequency considered from ESMO (the European Society for Medical Oncology), in addition to surgery, to eradicate visible metastases in liver sites.”

CLOCC was a phase II study of patients with unresectable colorectal liver metastases (CLM), randomised between RFA (with or without surgical resection) plus adjuvant systemic therapy (FOLFOX with or without bevacizumab) versus systemic therapy alone (FOLFOX with or without bevacizumab).

The trial was performed in 22 centres in Europe where 119 patients were randomised; 60 patients to the experimental arm, and 59 to the control arm. The primary endpoint of the first study was a 30-month overall survival rate higher than 38% in the combined modality arm, with secondary endpoints progression free survival, overall survival rate, and health-related quality of life.

By 2017, patients in the combined modality arm had a statistically significantly longer overall survival than patients in the systemic treatment arm, with three-, five-, and eight-year overall survival rates at 56.9%, 43.1%, and 35.9%, compared to 55.2%, 30.3%, and 8.9% in the control group.

Progression free survival was statistically significantly prolonged in the combined modality arm as compared with the systemic treatment arm, with three-, five-, and eight-year rates of 27.7%, 24.2%, and 22.3 in the experimental group, against 11.9%, 5.9%, and 2% in the systemic treatment arm.

But the study’s findings are limited by the fact that it was originally designed as a phase III trial which was downsized to a randomised phase II trial due to a smaller than planned sample size.

Carrafiello said at CIRSE: “A larger sample size would have offered better protection against possible risks of imbalances between treatment arms, and better reassurance of the external validity of the results. And although the effect of RFA on progression free survival was significant, the effect on overall survival is still lacking.”

Still, the legacy of CLOCC had been to enhance understanding of the combined treatment effects, Carrafiello said: “We have new technologies, we have new energy modalities of ablation, we have moved sometimes from radiofrequency to microwaves, and we have new imaging guidance systems. And we can also improve the effects of systemic therapy.”

A new direction for RFA is use in combination with immunotherapy. Carrafiello suggested two mechanisms that potentially have an impact on the efficacy of immunotherapy when used with radiofrequency: “There are mechanical changes in the tumour microenvironment and inflammatory mediated changes in immune-phenotypes. And the use of PD-1 [programmed cell death protein 1] and PD-1 blockade can boost the radiofrequency ablation immune response against tumours.”


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