Asunto(s)
Anilidas , Carcinoma Hepatocelular , Ipilimumab , Neoplasias Hepáticas , Nivolumab , Piridinas , Humanos , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Nivolumab/farmacología , Nivolumab/uso terapéutico , Piridinas/farmacología , Piridinas/uso terapéutico , Anilidas/farmacología , Anilidas/uso terapéutico , Ipilimumab/uso terapéutico , Ipilimumab/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologíaRESUMEN
PURPOSE: Evaluate overall survival (OS), RAS, BRAF, and MSI frequencies in patients with metastatic colorectal cancer (mCRC), refractory to chemotherapy, and finally treated with cetuximab. METHODS: A retrospective cohort study to evaluate 211 mCRC patients with wild-type KRAS treated with cetuximab. BRAF V600E, KRAS, NRAS gene mutations, and MSI status were identified using PCR techniques in a population of pre-treated patients who were refractory to fluoropyrimidines, oxaliplatin, and irinotecan. In addition, we evaluated the mutation frequency of the BRAF and NRAS genes and the MSI status of this population. Uni- and multivariate analyses were performed for independent prognostic factors of OS. RESULTS: The median OS was 10.4 months, 6.6 months for patients with right and 11.5 months for left colon cancers (p = 0.02). The frequencies of mutations were BRAF at 3.9% (median OS of 4.9 months), NRAS at 3.38% (median OS of 6.9 months), and MSI-High status at 3.3% (median OS of 4.6 months). The OS, NRAS, and MSI frequencies were similar to those found in other studies that evaluated cetuximab in poly-treated patients and were associated with lower survival rates in univariate analyses. The frequency of BRAF mutations was lower than that found in previous studies. The only variable that remained significant for OS in the multivariate model was tumour laterality, with patients with right colon cancer presenting a worse prognosis (HR = 2.81). CONCLUSION: Although BRAF, NRAS mutations, and MSI-High status were associated with shorter OS in univariate analyses, only tumour laterality remained an independent prognostic factor in the multivariate analysis.
RESUMEN
Hepatocellular carcinoma often develops in the context of chronic liver disease. It is the sixth most frequently diagnosed cancer and the third most common cause of cancer-related mortality worldwide. Although the mainstay of therapy is surgical resection, most patients are not eligible because of liver dysfunction or tumor extent. Sorafenib was the first tyrosine kinase inhibitor that improved the overall survival of patients who failed to respond to local therapies or had advanced disease, and for many years, it was the only treatment approved for the first-line setting. However, in recent years, trials have demonstrated an improvement in survival with treatments based on immunotherapy and new targeting agents, thereby extending the treatment options. A phase III trial showed that a combination of immunotherapy and targeted therapy, including atezolizumab plus bevacizumab, improved survival in the first-line setting, and is now considered the new standard of care. Other agents and combinations are being tested, including the combination of nivolumab plus ipilimumab and tremelimumab plus durvalumab, and they reportedly have clinical benefits. The aim of this manuscript is to review the latest approved therapeutic options in first- and second-line settings for advanced HCC and discuss future perspectives.
RESUMEN
Advanced hepatocellular carcinoma is a prevalent and potentially aggressive disease. For more than a decade, treatment with sorafenib has been the only approved therapeutic approach. Moreover, no agent has been proven to prolong survival following the progression of disease after sorafenib treatment. However, in recent years, this scenario has changed substantially with several trials being conducted to examine the effects of immunotherapy and novel targeting agents. Several immune checkpoint inhibitors have shown promising results in early-stage clinical trials. Moreover, phase III trials with large cohorts have demonstrated remarkable improvement in survival with the use of new targeted therapies in second-line treatment. Treatment regimens involving the combination of two immune checkpoint inhibitors as well as immune checkpoint inhibitors and anti-angiogenic targeted therapies have shown potential to act synergistically in clinical trials. Recently, the combination of atezolizumab and bevacizumab evaluated in a phase III clinical trial has demonstrated survival superiority in the first-line treatment; it is the new considered standard of care. In this manuscript, we aimed to review the latest advances in the systemic treatment of advanced hepatocellular carcinoma focusing on immunotherapy and targeted therapies.
RESUMEN
IMPORTANCE: Chemotherapy may result in a detrimental effect on ovarian function and fertility in premenopausal women undergoing treatment for early-stage breast cancer (EBC). To minimize risk of harm to ovarian function and fertility for patients in this setting, careful considerations should be made. Gonadotropin-releasing hormone agonists (GnRHa) have been suggested as an alternative to prevent the loss of ovarian function due to exposure to cytotoxic agents, but GnRHa use for ovarian protection in EBC patients is not fully resolved. OBJECTIVE: To determine the effectiveness of GnRHa administered concurrently with chemotherapy for ovarian function preservation. DATA SOURCES: PubMed, SCOPUS, and Cochrane databases were searched for studies published between January 1975 and March 2015. The abstracts of the American Society of Clinical Oncology Annual Meeting between 1995 and 2014 and the San Antonio Breast Cancer Symposium between 2009 and 2014 were searched as well. STUDY SELECTION: Prospective, randomized, clinical trials addressing the role of ovarian suppression with GnRHa in preventing early ovarian dysfunction in premenopausal women undergoing treatment for EBC were selected. DATA EXTRACTION AND SYNTHESIS: Data extraction was performed independently by 2 authors. The methodology and the risk of bias were assessment based on the description of randomization method, withdrawals, and blinding process. MAIN OUTCOMES AND MEASURES: Rate of resumption of regular menses after a minimal follow-up period of 6 months following chemotherapy was used as a surrogate to assess the incidence of ovarian dysfunction. Additional secondary outcomes included hormone levels and number of pregnancies. Risk ratio estimates were calculated based on the number of evaluable patients. Analyses were conducted using a random effect model. RESULTS: Seven studies were included in this analysis, totaling 1047 randomized patients and 856 evaluable patients. The use of GnRHa was associated with a higher rate of recovery of regular menses after 6 months (odds ratio [OR], 2.41; 95% CI, 1.40-4.15; P = .002) and at least 12 months (OR, 1.85; 95% CI, 1.33-2.59; P < .001) following the last chemotherapy cycle. The use of GnRHa was also associated with a higher number of pregnancies (OR, 1.85; 95% CI, 1.02-3.36; P = .04), although this outcome was not uniformly reported and fertility or rate of pregnancy was not the primary outcome in any of the trials. CONCLUSIONS AND RELEVANCE: Gonadotropin-releasing hormone agonists given with chemotherapy was associated with increased rates of recovery of regular menses in this meta-analysis. Evidence was insufficient to assess outcomes related to GnRHa and ovarian function and fertility and needs further investigation.