Treatments for metastatic melanoma: Synthesis of evidens from randomized trials
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.
Full-textDOI: · Available from: Michiel E Hemels, Sep 02, 2015
- SourceAvailable from: Maria Romina Girotti
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- "Temozolomide, an orally available DTIC analogue, did little to improve these responses (Middleton et al., 2000) and for the majority of patients durable responses remained elusive even when DTIC or temozolomide were combined with other drugs (Bhatia et al., 2009). A meta-analysis of 48 head-to-head clinical trials with DTIC revealed a weighted average objective response rate (mostly partial responses) of 15.3% for DTIC alone and no increase in survival or response rates with any combination, apart from IFN-a, which gave at best a modest improvement (Lui et al., 2007). A biochemotherapy (BCT) regimen of cisplatin, vinblastine and DTIC (CVD) with IFN-a and high-dose IL-2 did achieve response rates exceeding 50% in phase 2 trials, but at the price of substantial toxicity, preventing this therapy from becoming standard-of-care (Legha et al., 1996). "
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
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- "Clinically, the gold standard remains early detection, surgical resection, followed by bouts of chemo-or radiation therapy . Unfortunately, traditional chemo- and radiation therapy have also been reported to evoke resistance , . Moreover, the incidences of melanoma skin cancer continue to rise with the current status at 132,000 melanoma skin cancers occurring globally each year (World Health Organization http://www.who.int/uv/faq/skincancer/en/index1.html) "
ABSTRACT: Hypericin, an extract from St John's Wort (Hypericum perforatum L.), is a promising photosensitizer in the context of clinical photodynamic therapy due to its excellent photosensitizing properties and tumoritropic characteristics. Hypericin-PDT induced cytotoxicity elicits tumor cell death by various mechanisms including apoptosis, necrosis and autophagy-related cell death. However, limited reports on the efficacy of this photomedicine for the treatment of melanoma have been published. Melanoma is a highly aggressive tumor due to its metastasizing potential and resistance to conventional cancer therapies. The aim of this study was to investigate the response mechanisms of melanoma cells to hypericin-PDT in an in vitro tissue culture model. Hypericin was taken up by all melanoma cells and partially co-localized to the endoplasmic reticulum, mitochondria, lysosomes and melanosomes, but not the nucleus. Light activation of hypericin induced a rapid, extensive modification of the tubular mitochondrial network into a beaded appearance, loss of structural details of the endoplasmic reticulum and concomitant loss of hypericin co-localization. Surprisingly the opposite was found for lysosomal-related organelles, suggesting that the melanoma cells may be using these intracellular organelles for hypericin-PDT resistance. In line with this speculation we found an increase in cellular granularity, suggesting an increase in pigmentation levels in response to hypericin-PDT. Pigmentation in melanoma is related to a melanocyte-specific organelle, the melanosome, which has recently been implicated in drug trapping, chemotherapy and hypericin-PDT resistance. However, hypericin-PDT was effective in killing both unpigmented (A375 and 501mel) and pigmented (UCT Mel-1) melanoma cells by specific mechanisms involving the externalization of phosphatidylserines, cell shrinkage and loss of cell membrane integrity. In addition, this treatment resulted in extrinsic (A375) and intrinsic (UCT Mel-1) caspase-dependent apoptotic modes of cell death, as well as a caspase-independent apoptotic mode that did not involve apoptosis-inducing factor (501 mel). Further research is needed to shed more light on these mechanisms.PLoS ONE 07/2014; 9(7):e103762. DOI:10.1371/journal.pone.0103762 · 3.23 Impact Factor
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- "INTRODUCTION Melanoma is a growing public health burden because it is one of the few cancers still escalating in incidence (Jemal et al., 2009). Despite advances in understanding the molecular nature of melanoma in recent decades, few treatment options are available for metastatic melanoma that only marginally increase overall patient survival (Lui et al., 2007; Bollag et al., 2010; Hodi et al., 2010; Joseph et al., 2010; Chapman et al., 2011; Robert et al., 2011; Flaherty et al., 2012). One reason why melanoma is difficult to treat is its heterogeneity (Fidler, 1978). "
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