Consulting fees and contracted research from: Bristol-Myers - PDF document

David Lawson, MD Sea Island August, 2014  Consulting fees and contracted research from:  Bristol-Myers Squibb, GlaxoSmithKline, Genentech, Merck, Merck, and Prometheus 1

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FOR THE MOST PART, SURGEONS ONLY OPERATE WHEN THEY THINK THEY HAVE A CHANCE TO CURE 3

 Group I: Complete metastectomy, time to recurrence (TTR) > 36 mos, solitary metastasis  Group II: Complete metastectomy, but TTR < 36 mos or multiple mets  Group III: Complete metastectomy, but TTR <36mos and multiple mets  Group IV: Incomplete metastectomy Leo, et al BJC 83:569, 2000 4

 Group I: 29%  Group II: 20%  Group III: 7%  Group IV: 0% Survival Curves Associated with Potentially Curative Resection, Palliative Resection, or Nonsurgical Intervention for Melanoma Metastatic to the GI Tract Ollila DW et al. Arch Surg 1996;131:975 5

Survival Curves after Potentially Curative Resection, Palliative Resection, or Nonsurgical Management of Adrenal Metastases of Metastatic Melanoma Haigh PI et al. Ann Surg Oncol 1999;6:633 6

M1a: Skin, soft tissue, and distant lymph nodes M1b: Pulmonary M1c: All other visceral sites Stage IV Median Survival Range (mos) 5-yr OS Range (%) M1a (n=728) 17 - 50 14 - 61 M1b (n=698) 14 - 28 14 - 50 M1c (n=395) 8 - 49 28 - 41 * Complete metastasectomy Median Survival post resection Year N Feun (MD Anderson) 1982 65 23 Overett (MSKCC) 1985 12 25 Wornom (U Ab) 1986 13 17 Markowitz (Mass Gen) 1991 72 24 Gadd (MSKCC) 1992 23 29 Wong (JWCI) 1993 36 24 Karakousis (Roswell) 1994 25 31 Barth (JWCI) 1995 281 15 Eton (MD Anderson) 1998 57 10 7

Median % 5 year Survival survival Year N (months) Harpole (Duke) 1992 98 20 20 Tafra (JWCI) 1995 106 18 27 La Hei (Sydney) 1996 83 19 22 Leo 2000 282 complete 19 22 Andrews (Moffitt) 2006 86 35 33 (estim) Peterson (Duke) 2007 249 complete 19 21 69 incomplete 11 13 Median % 5 year Survival survival Year N (months) Khadra 1990 56 10 2 Ihde 1991 32 symptomatic 6 0 Ricaniadis 1995 23 complete 28 28 (Roswell) Ollila (JWCI) 1996 46 49 41 Agrawal 1999 68 8.2 18 (MSKCC) 19 complete 14.9 38 8

Median % 5 survival year Year Site N (months) survival Pawlik 2006 Liver - dermal 24 23.6 0 Liver - ocular 16 29.4 20.5 Rose 2001 Liver 24 10 29 Branum 1991 Adrenal 8 59 50 Haigh 1999 Adrenal 18 complete 25.7 NS Oredsson 1990 Brain 40 8 15 Wronski 2000 Brain 76 incomplete 7 7 NS - not stated Site N* Median % estimated 2 % estimated 5 survival year survival year survival Skin, LN 281 15 29 + 3% 14 + 2% GI tract 91 11 28 + 5% 12 + 4% Lung 515 8 12 + 1% 4 + 1% Bone 81 6 9 + 3% 4 + 2% Liver 293 4 6 + 1% 2 + 1% Brain 260 4 8 + 2% 3 + 1% All sites 1521 7.5 14 + 1% 6 + 1% Patients with multiple sites classified by site with poorest prognosis Essner, R Surg Clin N Am 83(1):109 9

 1 29 mos  2 -3 16 mos  4 or more 14 mos Essner, et al Arch Surg 139:961, 2004 10

 Disease Free Interval (>3 yrs)  Performance Status  Possibly LDH (MMAIT)  Skill of the Surgeon  Difficulty of the Surgery 11

MMAIT-IV MMAIT-III DFS DFS DFS (%) DFS (%) BCG + Placebo BCG + Vaccine BCG + Vaccine BCG + Placebo Time (Months) Time (Months) OS OS BCG + Placebo OS (%) OS (%) BCG + Vaccine BCG + Placebo BCG + Vaccine Time (Months) Time (Months) Morton. ASCO . 2007 (abstr 8508). 12

 Median DFS (months) Vaccine 8.3 Placebo 7.2  DFS at 5 years Vaccine 27% Placebo 21%  P=0.418  Median Survival (months) Vaccine 32 Placebo 39  5 year Survival (%) Vaccine 40% Placebo 45%  P value not given 13

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Clearly, resection of metastases has been associated with long term survival. “our treatment of choice for metastases to a single anatomic site is surgical resection – if all disease can be removed.” (David Ollila and Donald Morton J Surg Onc 71(4):209, 1999) “Complete resection…has been the only form of treatment for metastatic disease that has been consistently associated with any actual 5-year survival and should be considered when appropriate.” (Peter Allen and Daniel Coit Ann Surg Onc 9(8):762, 2002) 17

 Surgery should be offered to virtually all patients with solitary melanoma metastases capable of undergoing the procedure with expectation of approximately 20% 5yr DFS and 10-15% 10 year survival  Surgery can be more selectively offered to other patients with stage IV melanoma based on above criteria  SRS for Brain  SBRT for extra-CNS  Ablation  Maybe even immunotherapy 18