Journal club: Presenter :- Dr. v.veeranath reddy.

Moderator :- Dr. G.Puranik. Professor Department of General surgery.

Topic: adjuvant therapies for malignant melanoma

BJS(August 2016 volume 103)

• The landscape of melanoma treatment changing rapidly, with the appearance of new adjuvant treatments.

• After initial excision of a melanoma, several strategies to reduce the risk of recurrence have been developed, all can be regarded as adjuvant therapies.

• 1st strategy was the development of wide local excision.

• Most current guidelines recommend a margin of 1 cm for thin melanomas(T1) and 2-3 cm for thicker lesions(T2-T4).

• 2nd risk-reducing surgical procedure is lymph node dissection.

• After the results of Multicentre Selective Lymphadenectomy Trial (MSLT), lymph node dissection was replaced by the sentinal node biopsy technique, with a completion lymph node dissection (CLND), If metastatic disease was present.

• 3rd adjuvant option is radiotherapy to lymph node basin.

• The Australian and New Zeland Melanoma Trials Group(ANZMTG), Trans-Tasman Radiation Oncology Group(TROG) showed that radiotherapy reduced the risk of lymph node recurrence in high risk patients, but had no effect on overall survival.

• Another adjuvant therapy is isolated limb perfusion (ILP)

• Loco regional treatments (surgery, radiation, and ILP) seem important in minimizing loco regional recurrences.

• There is, however, a lack of strong evidence that a larger margin, CLND, loco regional irradiation or ILP have a major impact on survival, underlining the importance of tumor biology rather than specific treatment modality.

• In recent years several new therapeutic options have emerged for stage IV melanoma.

• Targeted therapies with small molecules taken as oral agents (such as BRAF and mitogen-activated protein kinase inhibitors) or

• Immuno therapies with intravenously administered antibodies directed against specific check points interfering with T cells (such as cytotoxic t lymphocyte associated antigen (CTLA) 4 and programmed death (PD)1 inhibitors).

• These therapies have led to increased overall survival with a potential for long time survival benefits.

• These therapies now established as first line therapies, pushing back chemotherapy as a front line option.

• Both BRAF inhibitors in combination with MEK inhibitors and PD1 inhibitors have resulted in impressive survival for patients with tumours carrying a BRAF mutation.

• For BRAF wild type patients, PD-1 inhibitors are a reasonable first line therapy for the majority of the patiens.

• With the introduction of anti-PD-1 therapies for stage 4 disease, the overall survival rate has increased from 10-20 percent at 2 years in the chemotherapy era to 58 percent with anti –PD-1 therapy.

• Adjuvent therapy in stage 3 disease.

• There are a number of trials investigating the impact of BRAF inhibition as monotherapy (vemurafenib versus placebo) BRIM 8 trail and

• BRAF and MEK inhibition (dabrafenib+ trametinib

versus placebo; COMBI-AD trial.

• Similarly the data for the CTLA-4 inhibitor ipilimumab in high dose(10 mg/kg ) has also been challenged, because of the high rate of severe toxicity.

• In the study where median relapse free survival was the primary objective, this increased from 7 months in the placebo group to 26 months in the ipilimumab group at the expense of grade 3-4 toxicity rates of 42 % in this arm.

• Despite these concerns the US Food and Drug Administration approved ipilimumab in the adjuvant setting for patients with stage 3 disease in November 2015.

• Immune related toxicities have raised doubts about CTLA-4 inhibitors as appropriate adjuvant therapy, and much hope is now directed towards the two PD-1 inhibitors, nivolumab and pem brolizumab.

• These two have shown less toxicities in stage 4 trials.

• Adjuvant trials using PD-1 inhibitors were initiated last year.

• Nivolumab is being compared with high dose ipilimumab in high risk patients, including those with stage 3 and stage 4 tumours without evidence of macroscopic disease.

Thank you