Targeted therapy for metastatic melanoma may not need to be paused during radiotherapy as guidelines currently recommend, an expert has suggested.
Eastern Cooperative Oncology Group (ECOG) recommendations currently advise that BRAF inhibitors should be paused for three days before and after fractionated radiotherapy, and for one day either side of stereotactic radiotherapy due to potential toxicities.
However, in the decade since the guidelines were formulated, less toxic BRAF and MEK inhibitors have been developed and evidence indicates that their continuous dosing through radiotherapy results in better outcomes.
In an editorial in Clinical Oncology [link here], Dr Nicholas Rowell, a Consultant in Clinical Oncology at Maidstone and Tunbridge Wells NHS Trust, suggested that the three-day pause may not be necessary, “provided adequate attention is paid to minimising dose to adjacent normal tissues”.
Instead, “a pragmatic approach” would be to leave “a one-day [suspension] rule just for selected cases, which would help allay patients’ and clinicians’ concerns about longer treatment interruptions,” Dr Rowell wrote.
The ECOG consensus guidelines were published in 2016 in response to evidence that irradiation alongside the BRAF inhibitor vemurafenib resulted in significant risks of skin toxicities.
However, vemurafenib has since been superseded in metastatic melanoma care by less toxic targeted therapies, such as the BRAF inhibitors dabrafenib and encorafenib and the MEK inhibitor trametinib.
Recent systematic reviews have found that dabrafenib results in lower rates of all grade skin toxicity than vemurafenib (30% vs 45%) and less frequent UVA-related photosensitivity (3% vs 30%).
Another study reported that ten patients treated with dabrafenib and trametinib alongside radiotherapy experienced no grade 3 or 4 skin reactions, with all but one continuing the medication throughout irradiation.
Importantly, recent studies indicate that targeted therapy combined with radiotherapy can improve survival and local control for brain metastases in melanoma.
The editorial also highlighted three randomised trials in which intermittent dosing of BRAF-MEK inhibitors resulted in worse progression-free survival than continuous dosing, “pointing to a potential detrimental effect of suspending [targeted therapy] over a course of palliative radiotherapy measured in weeks”.
“Separate from the concerns of sensitisation of normal tissues, it remains possible that [targeted therapy] might actually increase the effectiveness of radiotherapy in terms of tumour control, the combination being more than just additive in effect,” Dr Rowell suggested.
However, he noted that “overall, evidence is limited on the actual level of risk where dabrafenib or encorafenib are continued without interruption, and therefore the extent to which treatment suspensions are helpful remains uncertain.”