- The document summarizes adjuvant therapies for malignant melanoma that have been presented by Dr. v.veeranath reddy and moderated by Dr. G.Puranik at a journal club meeting. - Traditional adjuvant therapies included wide local excision, lymph node dissection, and radiotherapy to lymph node basins. However, evidence for their impact on survival is lacking. - Recent therapies that have shown improved survival include targeted BRAF and MEK inhibitors for BRAF mutant tumors, and immuno therapies like anti-PD-1 inhibitors for BRAF wild type tumors. These are now established as first line therapies for stage 4 disease. - Ongoing adjuvant trials are investigating

1. Journal club:
Presenter :- Dr. v.veeranath reddy.
Moderator :- Dr. G.Puranik.
Professor
Department of General
surgery.

2. Topic: adjuvant therapies for
malignant melanoma
BJS(August 2016 volume 103)

3. • 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.

4. • 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).

5. • 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.

6. • 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.

7. • Another adjuvant therapy is isolated limb
perfusion (ILP)
• Loco regional treatments (surgery, radiation,
and ILP) seem important in minimizing loco
regional recurrences.

8. • 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.

9. • 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).

10. • 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.

11. • 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.

12. • 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.

13. • 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.

14. • 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.

15. • 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.

16. Thank you