Treatments for metastatic melanoma: Synthesis of evidence from randomized trials

University of Toronto, Toronto, Ontario, Canada
Cancer Treatment Reviews (Impact Factor: 6.47). 12/2007; 33(8):665-80. DOI: 10.1016/j.ctrv.2007.06.004
Source: PubMed

ABSTRACT Advanced melanomas (non-resectable Stage-III/IV) are fatal, with few effective treatments. It remains unclear if other drugs offer improvements over the standard, dacarbazine.
We quantified objective response rates (Complete+Partial response) of dacarbazine versus comparators for advanced cutaneous melanoma.
We retrieved all head-to-head randomized controlled trials involving dacarbazine and other drugs/combinations. Two reviewers searched MEDLINE (1966-Jan 2006), EMBASE (1980-2006), CINAHL (1982-2006) and Cochrane library, then compared results. Differences were resolved through consensus. Rates were combined using random effects meta-analysis. chi2 tested heterogeneity; points from Jadad's method were assessed to examine study quality.
We found 48 studies having 111 active treatment arms [24 with dacarbazine monotherapy (n=1390), 75 with dacarbazine combinations (n=4962), and 12 with non-dacarbazine treatments (n=783)] treating 7135 patients. Overall, study quality was poor. Response to dacarbazine monotherapy ranged between 5.3% and 28.0% (average 15.3%), OR=1.31, CI(95%): 1.06-1.61; N=3356. Partial responses comprised 73% of successes. Only adding interferons improved response rates (OR=1.69, CI(95%): 1.07-2.68, N=778) but survival duration was not significantly longer (P=0.32), and trials with larger sample sizes found lower success rates. All other treatments alone or in combination were ineffective P>0.05.
Dacarbazine generally produces poor outcomes. Adding other therapies offers minimal clinical advantages (possibly with interferons). In general, study quality was poor and sample sizes were small. This meta-analysis highlights the unmet need for effective treatment options for advanced melanoma.

Download full-text


Available from: Michiel E Hemels, Jun 30, 2015
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The discovery that BRAF is a driver oncogene in cancer, and complementary improvements in our understanding of the immune system have resulted in new targeted and immune-therapies for metastatic melanoma. Targeted therapies achieve impressive clinical results in carefully selected patients but the development of resistance seems inevitable in most cases. Conversely, immune-checkpoints inhibitors can achieve long-term remission and cures, but in a smaller proportion of patients, and biomarkers to predict which patients will respond are not available. Nevertheless, melanoma has led the evolution of cancer treatment from relatively nonspecific cytotoxic agents to highly selective therapies and here we review the lessons from this paradigm shift in treatment and the opportunities for further improvements in outcomes for melanoma patients.
    Molecular Oncology 08/2014; 8(6). DOI:10.1016/j.molonc.2014.07.027 · 5.94 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: We have previously reported a model for melanoma progression in which oscillation between melanoma cell phenotypes characterized by invasion or proliferation is fundamental to tumor heterogeneity and disease progression ADDIN EN.CITE ADDIN EN.CITE.DATA (Hoek et al., 2006). In this study we examine the possible role of hypoxia as one of the microenvironmental influences driving metastatic progression by promoting a switch from a proliferative to an invasive phenotype. Immunohistochemistry on primary human cutaneous melanoma biopsies showed intratumoral heterogeneity for cells expressing melanocytic markers, and a loss of these markers correlated to hypoxic regions. Furthermore, we show that the down-regulation of melanocytic markers is dependent on HIF1α, a known regulator of the hypoxic response. In vitro invasion assays showed that a hypoxic environment increases the invasiveness of proliferative melanoma cell cultures in a HIF1α-dependent manner. In contrast, invasive phenotype melanoma cells showed no increase in invasive potential upon exposure to hypoxia. Thus, exposure of proliferative melanoma cells to hypoxic microenvironments is sufficient, in a HIF1α-dependent manner, to down-regulate melanocytic marker expression and increase their invasive potential.Journal of Investigative Dermatology accepted article preview online, 8 March 2013; doi:10.1038/jid.2013.115.
    Journal of Investigative Dermatology 03/2013; 133(10). DOI:10.1038/jid.2013.115 · 6.37 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Dacarbazine (DTIC) is a cytotoxic drug widely used for melanoma treatment. However, the putative contribution of anticancer immune responses in the efficacy of DTIC has not been evaluated. By testing how DTIC affects host immune responses to cancer in a mouse model of melanoma, we unexpectedly found that both natural killer (NK) and CD8(+) T cells were indispensable for DTIC therapeutic effect. Although DTIC did not directly affect immune cells, it triggered the upregulation of NKG2D ligands on tumor cells, leading to NK cell activation and IFNγ secretion in mice and humans. NK cell-derived IFNγ subsequently favored upregulation of major histocompatibility complex class I molecules on tumor cells, rendering them sensitive to cytotoxic CD8(+) T cells. Accordingly, DTIC markedly enhanced cytotoxic T lymphocyte antigen 4 inhibition efficacy in vivo in an NK-dependent manner. These results underscore the immunogenic properties of DTIC and provide a rationale to combine DTIC with immunotherapeutic agents that relieve immunosuppression in vivo.Journal of Investigative Dermatology advance online publication, 6 September 2012; doi:10.1038/jid.2012.273.
    Journal of Investigative Dermatology 09/2012; 133(2). DOI:10.1038/jid.2012.273 · 6.37 Impact Factor