Long-term survival as a treatment benchmark in melanoma: latest results and clinical implications.
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ABSTRACT:
SUBMITTER: Grossmann KF
PROVIDER: S-EPMC4406913 | biostudies-literature | 2015 May
REPOSITORIES: biostudies-literature
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Project description:Melanoma treatment has been revolutionized over the past decade. Long-term results with immuno-oncology (I-O) agents and targeted therapies are providing evidence of durable survival for a substantial number of patients. These results have prompted consideration of how best to define long-term benefit and cure. Now more than ever, oncologists should be aware of the long-term outcomes demonstrated with these newer agents and their relevance to treatment decision-making. As the first tumor type for which I-O agents were approved, melanoma has served as a model for other diseases. Accordingly, discussions regarding the value and impact of long-term survival data in patients with melanoma may be relevant in the future to other tumor types. Current findings indicate that, depending on the treatment, over 50% of patients with melanoma may gain durable survival benefit. The best survival outcomes are generally observed in patients with favorable prognostic factors, particularly normal baseline lactate dehydrogenase and/or a low volume of disease. Survival curves from melanoma clinical studies show a plateau at 3 to 4 years, suggesting that patients who are alive at the 3-year landmark (especially in cases in which treatment had been stopped) will likely experience prolonged cancer remission. Quality-of-life and mixture-cure modeling data, as well as metrics such as treatment-free survival, are helping to define the value of this long-term survival. In this review, we describe the current treatment landscape for melanoma and discuss the long-term survival data with immunotherapies and targeted therapies, discussing how to best evaluate the value of long-term survival. We propose that some patients might be considered functionally cured if they have responded to treatment and remained treatment-free for at least 2 years without disease progression. Finally, we consider that, while there have been major advances in the treatment of melanoma in the past decade, there remains a need to improve outcomes for the patients with melanoma who do not experience durable survival.
| S-EPMC7549477 | biostudies-literature
Project description:This study aimed to identify prognostic factors in patients with metastatic uveal melanoma (UM) that were associated with long-term survival in a real-world setting. A total of 94 patients with metastatic UM were included from German skin cancer centers and the German national skin cancer registry (ADOReg). Data were analyzed for the response to treatment, progression-free survival, and overall survival (OS). Prognostic factors were explored with univariate Cox regression, log-rank, and χ2-tests. Identified factors were subsequently validated after the population was divided into two cohorts of short-term survival (< 2 years OS, cohort A, n = 50) and long-term survival (> 2 years OS, cohort B, n = 44). A poor ECOG performance status (hazard ratio [HR] 2.0, 95% confidence interval [CI] 1.0-3.9) and elevated serum LDH (HR 2.0, 95% CI 1.0-3.8) were associated with a poor OS, whereas a good response to immune checkpoint blockade (ICB, p < 0.001), radiation therapy (p < 0.001), or liver-directed treatments (p = 0.01) were associated with a prolonged OS. Long-term survivors (cohort B) showed a higher median number of organs affected by metastasis (p < 0.001), while patients with liver metastases only were more common in cohort A (40% vs. 9%; p = 0.002). A partial response to ICB was observed in 16% (12/73), being 21% (8/38) for combined ICB, 17% (1/6) for single CTLA4 inhibition, and 10% (3/29) for single PD1 inhibition. One complete response occurred in cohort B with combined ICB. We conclude that the response to ICB and the presence of extrahepatic disease were favorable prognostic factors for long-term survival.
| S-EPMC9123041 | biostudies-literature
Project description:PurposeThe long-term survival of uveal melanoma patients in the US is not known. We compared long-term survival estimates using relative survival, excess absolute risk (EAR), Kaplan-Meier (KM), and competing risk analyses.SettingPopulation based cohort study.Study populationPooled databases from Surveillance, Epidemiology, and End Results data (SEER, SEER-9+SEER-13+SEER-18).Main outcome measureOverall Survival (OS), Metastasis Free Survival (MFS) and relative survival, computed directly or estimated via a model fitted to excess mortality.ResultsThere were 10678 cases of uveal melanoma spanning a period of 42 years (1975-2016). The median age at diagnosis was 63 years (range 3-99). Over half the patients were still alive at the end of 2016 (53%, 5625). The KM estimates of MFS were 0.729 (0.719, 0.74), 0.648 (0.633, 0.663), and 0.616 (0.596, 0.636) at 10, 20, and 30 years, respectively. The cumulative probabilities of melanoma metastatic death at 10, 20 and 30 years were 0.241 (0.236, 0.245), 0.289 (0.283, 0.294), and 0.301 (0.295, 0.307). In the first 5 years since diagnosis of uveal melanoma, the proportion of deaths attributable to uveal melanoma were 1.3 with rapid fall after 10 years. Death due to melanoma were rare beyond 20 years. Relative survival (RS) plateaued to ~60% across 20 to 30 years. EAR parametric modeling yielded a survival probability of 57%.ConclusionsRelative survival methods can be used to estimate long term survival of uveal melanoma patients without knowing the exact cause of death. RS and EAR provide more realistic estimates as they compare the survival to that of a normal matched population. Death due to melanoma were rare beyond 20 years with normal life expectancy reached at 25 years after primary therapy.
| S-EPMC8130945 | biostudies-literature
Project description:Neuroendocrine tumors (NETs) are a heterogeneous class of diseases characterized by challenging management. Preclinical evidence shows that the PI3K/AKT/mTOR signaling pathway plays a central role in the pathogenesis and progression of NETs. Everolimus is a direct inhibitor of this pathway, and therefore this molecule appears to be a well-grounded strategy for the treatment of NETs, capable of changing clinical practice. The efficacy and safety of everolimus was demonstrated in the RADIANT trials. In this work, we comment on the results of the RADIANT trials, and other recent key evidence from fully published clinical trials on everolimus, and we discuss the current role of everolimus in the treatment of NETs.
| S-EPMC5349426 | biostudies-literature
Project description:Uveal melanoma (UM) is the most common primary intraocular tumor in adults. Up to 50% of UM patients will develop metastases. We present data of 175 metastatic UM patients diagnosed in the Netherlands between July 2012 and March 2018. In our cohort, elevated lactate dehydrogenase level (LDH) is an important factor associated with poorer survival (Hazard Ratio (HR) 9.0, 95% Confidence Interval (CI) 5.63-14.35), and the presence of liver metastases is negatively associated with survival (HR 2.09, 95%CI 1.07-4.08). We used data from the nation-wide Dutch Melanoma Treatment Registry (DMTR) providing a complete overview of the location of metastases at time of stage IV disease. In 154 (88%) patients, the liver was affected, and only 3 patients were reported to have brain metastases. In 63 (36%) patients, mutation analysis was performed, showing a GNA11 mutation in 28.6% and a GNAQ mutation in 49.2% of the analyzed patients. In the absence of standard care of treatment options, metastatic UM patients are often directed to clinical trials. Patients participating in clinical trials are often subject to selection and usually do not represent the entire metastatic UM population. By using our nation-wide cohort, we are able to describe real-life treatment choices made in metastatic UM patients and 1-year survival rates in selected groups of patients.
| S-EPMC6678641 | biostudies-literature
Project description:Melanoma has historically been considered a refractory disease with few if any options in the advanced/metastatic setting. Advances in both immune and genetically targeted treatment approaches have revolutionized the spectrum of treatment options for melanoma patients over the last several years. Recently, checkpoint inhibition has become a major focus in the immune-based therapy of cancer, especially melanoma. This concept involves inhibition of regulatory cell surface molecules which act normally to dampen or modulate T-cell activation. Cancer, including melanoma, takes advantage of this physiologic mechanism to turn off T-cell activation and prevent effective T-cell antitumor responses. Checkpoint inhibitors such as anti cytotoxic T-lymphocyte antigen 4 (anti-CTLA-4) and anti programmed death-1 (PD-1) can reverse this immune suppression and release T-cell activation. Nivolumab, a monoclonal antibody to the PD-1 receptor, promotes antitumor immunity by removing this key negative regulator of T-cell activation. In phase I/II studies, promising activity and safety have been observed and ongoing phase III trials are comparing nivolumab with other standard of care therapies (chemotherapy, ipilimumab). Efficacy may be even further increased when used in combination with ipilimumab (albeit with increased toxicity). In contrast to typical short-lived responses with cancer therapy in metastatic solid tumors, many responses induced by nivolumab appear durable. In this review, we discuss the evolution of immune therapy in melanoma leading to the development of nivolumab, the clinical experience with this agent, and its future development and clinical potential.
| S-EPMC4346215 | biostudies-literature
Project description:Melanoma is the deadliest skin cancer, whose morbidity and mortality indicators show an increasing trend worldwide. In addition to its great heterogeneity, melanoma has a high metastatic potential, resulting in very limited response to therapies currently available, which were restricted to surgery, radiotherapy and chemotherapy for many years. Advances in knowledge about the pathophysiological mechanisms of the disease have allowed the development of new therapeutic classes, such as immune checkpoint and small molecule kinase inhibitors. However, despite the incontestable progress in the quality of life and survival rates of the patients, effectiveness is still far from desired. Some adverse side effects and resistance mechanisms are the main barriers. Thus, the search for better options has resulted in many clinical trials that are now investigating new drugs and/or combinations. The low water solubility of drugs, low stability and rapid metabolism limit the clinical potential and therapeutic use of some compounds. Thus, the research of nanotechnology-based strategies is being explored as the basis for the broad application of different types of nanosystems in the treatment of melanoma. Future development focus on challenges understanding the mechanisms that make these nanosystems more effective.
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Project description:BACKGROUND:It remains unclear whether breast cancer subtypes are associated with clinical outcome in patients without any treatment including systemic and radiation therapy as an independent entity. Understanding the survival profiles among subtypes by treatment status could impact optimal selection of treatments. METHODS:Patients were diagnosed with invasive breast cancer from the community hospitals across four geographical regions of the United States. Expression of hormone receptor (HR) and HER2 in tumor specimens from 1169 patients was centrally determined by immunohistochemistry and fluorescence in situ; breast cancer was classified into HR+/HER2-, HR+/HER2+, triple-negative, and HER2+ subtypes. Overall survival (OS) at a median follow-up of about 15 years among subtypes in untreated patients and those with systemic treatments and radiotherapy was analyzed by Kaplan-Meier method and multivariable analysis adjusting for age, tumor size and grade, number of positive nodes, stage and breast cancer subtypes. RESULTS:Without treatment, breast cancer subtypes were not associated with OS (P = 0.983) and remained insignificant for prognosis by multivariable analysis after adjusting for confounders. This contrasted with a significant survival difference across the subtypes in patients with conventional therapies (P < 0.0001). Compared with HR+/HER2- subtype, triple-negative subtype (HR 1.5, 95% CI 1.11-2.04; P = 0.009) and HER2+ subtype (HR 2.18, 95% CI 1.48-3.28; P = 0.0001) were significantly associated with worse survival by multivariable analyses. CONCLUSION:Breast cancer subtypes are not associated with survival in untreated patient population and, in contrast, significantly associated with prognosis in patients with conventional therapy. The data provide evidence of treatment-associated differential outcomes among breast cancer subtypes.
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Project description:Treatment for cystic fibrosis (CF) has conventionally targeted downstream consequences of the defect such as mucus plugging and infection. More recently, significant advances have been made in treating the root cause of the disease, namely a defective CF transmembrane conductance regulator (CFTR) gene. This review summarizes current pulmonary treatment options and highlights advances in research and development of new therapies.
| S-EPMC4907071 | biostudies-literature
Project description:Over the past ten years, sorafenib, a multikinase inhibitor, has been the only systemic agent approved for first-line treatment of patients with unresectable hepatocellular carcinoma (HCC). Whereas only recently lenvatinib was shown to be noninferior to sorafenib, in terms of survival, all other agents previously tested failed to prove noninferiority (or superiority) when compared with sorafenib. Similarly, in a second-line setting, most investigational drugs have failed to provide better survival outcomes than placebo. However, in 2016, data from the RESORCE trial, a phase 3 study evaluating regorafenib in HCC patients who experience disease progression after first-line treatment with sorafenib, have shown a 2.8-month median survival benefit over placebo (10.6 versus 7.8 months). Overall, side-effects were in line with the known safety profile of regorafenib. More recently, the survival benefits of a sustained anti-angiogenic inhibition were demonstrated also with cabozantinib in the frame of the phase 3 CELESTIAL trial. As HCC seems to be an attractive target for immunotherapy, a phase 1/2 trial reported promising efficacy signals from nivolumab, and results of a larger phase 3 trial with another checkpoint inhibitor, namely, pembrolizumab, are still pending. After nearly a decade of a certain degree of stagnation, we are now witnessing a period of novel therapeutic advances with multikinase inhibitors and immunotherapy that will likely change the treatment scenario of HCC.
| S-EPMC6038776 | biostudies-literature