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The effect of Carboplatin when given after DITC failure; enhanced clinical benefit of sequential therapy?

20th December 2022

The treatment for advanced or metastatic melanoma has dramatically changed in the past 10 years. Dacarbazine was the mainstay in chemotherapy for metastatic melanoma for over two decades before the advent of immunotherapy and BRAF inhibitors around 10 years ago.
The response rate for single agent dacarbazine was low at approximately 15-20% with a complete response rate <5% and despite dacarbazine being combined with other chemotherapeutic agents and immunomodulators like IL-2 of IFNg, the benefit for patients was negligible. Many other single agents have similar but slightly smaller impact on response rate than Dacarbazine. In large randomised multi-centre trials, combinations were shown to be no more effective than single agent Dacarbazine. Despite the advances in the field with immunotherapy there may be some role for chemotherapy in melanoma in a subset of patients. Following reports that there was no benefit in combining Dacarbazine and Carboplatin, compared to Dacarbazine alone, several clinicians started to use Carboplatin as the second line chemotherapy option in those patients who had failed Dacarbazine. Carboplatin was chosen as better tolerated compared to other standard chemotherapy agents and for the fact it showed some activity in melanoma as single agent. The appearance of some unexpectedly good responses to this sequential approach led to a multicentre audit of patients receiving Carboplatin as second-line. 112 patients with non-resectable metastatic melanoma from three Uk centres, who did not respond to first line, received Carboplatin and were included in the audit. Only 16 patients had the full course of planned six three weekly treatments, with three continuing beyond. The best response was one complete response, but eight partial responses were also observed, and 22 with achieved stable disease over three months, giving a 28% overall response, which is much higher than any first line response for Carboplatin reported previously. Surprisingly the majority of patients who benefited from second line Carboplatin did not have good prognostic factors and most were not expected to survive more than six months after first line treatment. The mechanism of action is unclear, but the sequential treatment may have an indirect effect on the micro environment or immune response. In vitro studies have shown that carboplatin can be an immune modulator and is therefore possible that that an immune effect may have occurred in the patients responding to treatment The one patient who is still alive and had a complete response also had a course of low dose Interleukin-2 after Carboplatin. The data of the audit suggest that sequential therapy with chemotherapy and other immunotherapies may yet have a role in the patients without a BRAF mutation and not responsive to standard immunotherapy.

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