title: Long-term survival in advanced melanoma patients using repeated therapies: successive immunomodulation improving the odds?
abstract: BACKGROUND
  Patients with advanced metastatic melanoma are often confronted with little prospect of medium- to longer-term survival by any currently available therapeutic means. However, most clinicians are aware of exceptional cases where survival defies the notion of futility. Prolonged survival from immunotherapies, including interleukin-2, vaccines and antibodies to cytotoxic lymphocyte antigen-4, and programmed death-1 receptor inhibitory monoclonal antibody, implies a role for immune system modulation. We aimed to identify cases where exceptional survival from advanced melanoma occurred prior to recent novel therapies to facilitate better understanding of this phenomenon.
  
  
  METHODS
  Cases of long-term survival of ≥3 years' duration (from diagnosis of metastatic disease) were identified from the database of one clinician; these cases were treated before the availability of newer immunotherapies, and they were documented and examined. A literature search for reported outcome measures from published studies using older and recent therapies for advanced melanoma was conducted to enable the comparison of data.
  
  
  RESULTS
  Eighteen cases were identified that identified survival of ≥3 years' duration from metastatic disease (12 American Joint Committee on Cancer [AJCC] Stage IV cases; six AJCC III cases) diagnosis. These were assessed and reported to detail the clinical course. Standard clinical prognostication methods predicted high risk of early mortality in those patients. No identifiable differences could be detected between these and other patients with similar patterns of disease. At evaluation, 17 patients (94%) had survived ≥5 years, and eleven patients (61%) had survived ≥10 years (range: 3-15 years). The median survival duration with metastatic disease was 11 years; 15 remained alive and three had died. Published studies of melanoma therapies were tabled for comparison.
  
  
  CONCLUSIONS
  The fact that 18 cases of exceptional survival in advanced melanoma were identified is remarkable in itself. Even with recent therapies, the factors for improved survival remain enigmatic; however, one apparent common denominator in most cases was the persistent use of repeated therapies to reduce tumor bulk, induce tumor necrosis, and/or cause immunostimulation. These cases are instructive, suggesting manipulation of an established, endogenous, existing immune response. These observations provide practical evidence that the course for any patient with advanced melanoma at the outset should be considered unpredictable, open to immunomanipulation, and thus not uniformly fatal. The findings were compared and interpreted with reported newer immunotherapeutic approaches.
authors.affiliation: Discipline of Surgery, Royal Adelaide Hospital, University of Adelaide, Adelaide, SA, Australia.
authors.forename: Brendon J
authors.initials: BJ
authors.lastname: Coventry
authors.affiliation: Discipline of Surgery, Royal Adelaide Hospital, University of Adelaide, Adelaide, SA, Australia.
authors.forename: Dominique
authors.initials: D
authors.lastname: Baume
authors.affiliation: Discipline of Surgery, Royal Adelaide Hospital, University of Adelaide, Adelaide, SA, Australia.
authors.forename: Carrie
authors.initials: C
authors.lastname: Lilly
keywords: advanced melanoma; clinical responses; immunotherapy; prolonged survival