Cardiovascular toxicity following sunitinib therapy in metastatic renal cell carcinoma: a multicenter analysis

BackgroundRecent data have shown that cardiotoxicity represents a potentially important side-effect in patients treated with sunitinib. We reviewed cardiac adverse events in patients with metastatic renal cell carcinoma (RCC) who underwent treatment with this agent.Patients and methodsThe medical records of 175 patients with metastatic RCC treated with sunitinib at eight Italian institutions were retrospectively reviewed. Alterations in left ventricular ejection fraction (LVEF) and blood pressure were evaluated. Patients with preexisting cardiac risk factors were specifically scrutinized for increased expression of cardiac changes.ResultsGrade 3 hypertension was seen in 17 patients (9.7%); in 12 of these 17, hypertension developed after receiving the third sunitinib cycle. Among these 17 patients, 12 (70.6%) also experienced left ventricular systolic (LVEF) dysfunction; in all, 33 of the 175 patients (18.9%) developed some degree of cardiac abnormality, of which 12 were classified as grade 3 LVEF dysfunction and/or congestive heart failure (CHF) (6.9%). Significant univariate associations for predictors of CHF were history of hypertension (P = 0.008), history of coronary heart disease (P = 0.0005) and prior treatment with an angiotensin-converting enzyme inhibitor (P = 0.04). Multivariate analysis suggested that a history of coronary artery disease [odds ratio (OR) 18, 95% confidence interval (CI) 4–160, P = 0.005] and hypertension (OR 3, 95% CI 1.5–80, P = 0.04) was the only significant independent predictors of CHF.ConclusionsPatients undergoing sunitinib, especially those with a previous history of hypertension and coronary heart disease, are at increased risk for cardiovascular events and should be monitored for exacerbations of their hypertension and for evidence of LVEF dysfunction during treatment.     

Nephrectomy in metastatic renal cell carcinoma

Opinion statement Patients presenting with metastatic renal cell carcinoma (RCC) face a dismal prognosis, with a median survival time of only 6 to 12 months and a 2-year survival rate of 10% to 20%. RCC is notoriously chemorefractory, and immunotherapy is associated with total response rates of less than 20% and complete response rates of less than 5%. Therefore, surgery has continued to play a prominent role in the management of patients with metastatic RCC. Recent randomized prospective trials suggest a survival advantage for cytoreductive nephrectomy, and some patients with advanced RCC may also achieve palliation. Patients with limited and resectable metastases should be considered for combined nephrectomy and metastasectomy. The other main option for patients with advanced RCC is systemic immunotherapy followed by assessment for surgical consolidation, but responses in the primary tumor are uncommon and results with this pathway have not been encouraging. Tumor embolization can be a valuable palliative adjunct for some patients with metastatic RCC. Cytoreductive nephrectomy represents the most aggressive pathway for patients with metastatic RCC. Although cytoreductive nephrectomy can extend survival by approximately 50% for many patients, it can be associated with morbidity and delay in administration of systemic therapy. Therefore, patient selection, taking into account performance status and sites and burden of disease, which are well-established prognostic factors for patients with metastatic RCC, is of paramount importance in managing this challenging group of patients.     

Interferon in metastatic renal cell carcinoma

Metastatic renal cell carcinoma (MRCC) represents an immunoresponsive malignancy in individual patients. Interferons (IFNs) have thus been broadly investigated in this cancer type, with the most commonly used being recombinant IFN-alpha. The average response rate is 15%, with a response duration of 4 to 6 months. Complete responses are rare (< or =5%), but may be long-lasting. Responses are seen predominantly in lung and lymph node metastases. Subcutaneous (SC) or intramuscular (IM) doses of 9 to 10 x 10(6) U/d or 9 to 18 x 10(6) U thrice weekly are most often used. Flu-like symptoms (fever, myalgia, asthenia) occur in almost all patients treated with IFN-alpha and may be dose-limiting. The combination of IFN-alpha with vinblastine is not superior to IFN monotherapy. Phase III studies have demonstrated a modest survival benefit for IFN-alpha therapy as compared with placebo-equivalent treatment, with a survival gain of 3 to 7 months. Predictive for beneficial outcome are an excellent performance status, low sedimentation rate, no weight loss, and long interval between initial diagnosis and start of IFN treatment. The significance of nephrectomy is currently being investigated in phase III studies. IFN-gamma has no major therapeutic role in MRCC. IFN-beta and "natural IFN" are equally effective as IFN-alpha. In conclusion, IFN-alpha represents the standard treatment in patients with MRCC who are candidates for systemic therapy. Any IFN-alpha-containing combination treatment is investigational (eg, with interleukins or retinoids).     

Sunitinib adverse events in metastatic renal cell carcinoma: a meta-analysis

Background

Sunitinib, a multi-targeted receptor tyrosine kinase inhibitor, has demonstrated survival benefit in patients with metastatic renal cell carcinoma (mRCC); however, significant adverse events (AEs) have been associated with its use. The significant variation in the reported incidences of AEs has prompted this meta-analysis to quantify the risk and explore associated predictors.

Methods

According to predefined selection criteria, a literature search identified 12 studies that were included in the analyses.

Results

The meta-analysis included 5,658 patients; 66 % patients had prior systemic therapy whereas the remaining patients (34 %) received sunitinib in the first-line setting. For any grade toxicity, skin rash, fatigue, diarrhea, and mucositis were the most frequently encountered events (81, 52, 45, and 33 %, respectively). Anemia, neutropenia, or thrombocytopenia of any grade occurred in more than one-third of patients, although grades 3 or 4 were less common. Any grade raised by liver enzymes or serum creatinine occurred in 40 and 44 % of patients, respectively. Meta-regression analyses showed that study size was inversely related to the risk of experiencing fatigue, diarrhea, mucositis, anemia, and thrombocytopenia. In particular, the incidence of AEs was higher when sunitinib was used in pretreated versus naive patients; however, there was no significant difference between the two groups concerning the incidence of laboratory abnormalities. We addressed the limitations of reporting AEs in clinical studies.

Conclusions

The present meta-analysis quantified sunitinib-associated AEs. The derived estimates would be similar to that to be expected from the use of sunitinib in community practice in unselected patients with metastatic renal cell carcinoma (mRCC).     

Immunotherapy of metastatic renal cell carcinoma

In 1992, high-dose bolus interleukin (IL)-2 was granted Food and Drug Administration approval based on its ability to produce durable complete responses in a small number of patients with metastatic renal cell carcinoma (RCC). However, the substantial toxicity and limited efficacy that is associated with IL-2 has narrowed its application to highly selected patients treated at specialized centers. In recent years, the relative merits of low- and high-dose cytokine regimens have been clarified by the results of 4 randomized trials. Taken together, these studies suggest that high-dose IV bolus IL-2 is superior in terms of response rate and possibly response quality to regimens that involve either low-dose IL-2 and interferon-alpha, intermediate- or low-dose IL-2 alone, or low-dose interferon-alpha alone. More significantly, investigations associated with these trials suggest that the potential exists for identifying predictors of response (or resistance) and limiting IL-2 therapy to those most likely to benefit. The Cytokine Working Group has launched the high-dose IL-2 "select" trial to determine, in a prospective fashion, if the predictive model proposed by Atkins et al. can identify a group of patients with advanced RCC who are significantly more likely to respond to high dose IL-2-based therapy ("good" risk) than a historical, unselected patient population. For patients unlikely to benefit from IL-2, are unable to receive it or who progress after IL-2, the emergence of molecularly targeted therapies offers hope for improved clinical outcome. As the list of effective therapies for metastatic RCC grows, improvements in patient selection and more "targeted" approaches will be required to optimize the benefits of cytokine therapy in metastatic RCC.     

Treatment of metastatic renal cell carcinoma

Purpose  To review the treatment of metastatic renal cell carcinoma (RCC), including the use of new targeted therapies. Methods  A search of MEDLINE (1966 to August 2008) and American Society of Clinical Oncology Meeting abstracts (2005 to May 2008) was preformed using the search terms bevacizumab, everolimus, interferon-alfa (IFN-α), interleukin-2 (IL-2), sorafenib, sunitinib, temsirolimus, and RCC. Articles most pertinent to the treatment of metastatic RCC are reviewed. Results  The treatment of metastatic RCC has undergone a paradigm shift over the past 5 years from biologic response modifiers to new targeted therapies. Historically, response rates for the biological response modifiers, aldesleukin (IL-2), and IFN-α were approximately 15%. Recently, three targeted agents, sorafenib, sunitinib, and temsirolimus have been approved for the treatment of RCC. Additionally, bevacizumab has been investigated and shown to increase progression free survival in RCC. IL-2 remains the only agent to induce complete, durable remissions; however, many patients are not eligible for this therapy. Newer agents (sorafenib, sunitinib, and temsirolimus) have shown to be superior to IFN-α or placebo and bevacizumab combined with IFN-α has shown activity when compared to IFN-α alone. Unlike IL-2, the greatest benefit obtained with targeted therapies is in achieving stable disease (SD). Despite their benefit, targeted therapies have never been compared with each other in clinical trials and choosing the most appropriate agent remains challenging. To date, the optimal sequence or combination of treatments has not been defined; however, everolimus has recently demonstrated activity in patients progressing on targeted therapy. Conclusions  IL-2 remains the most active regimen in inducing complete responses; however, its use is accompanied by substantial morbidity and is limited to those with a good performance status. Targeted therapies are also efficacious in the treatment of RCC, with the major benefit being induction of SD. Future research will better define the sequencing of therapies, as well as, explore the activity of novel combination regimens.     

Cytoreductive nephrectomy in metastatic renal cell carcinoma

Metastatic renal cell carcinoma is associated with a poor prognosis and a median survival time of only 6–12 months. However, the emergence of immunotherapies has rekindled interest in cytoreductive nephrectomy as a therapeutic option. Phase III randomized trials have demonstrated that cytoreductive nephrectomy significantly improves overall survival in selected patients with metastatic renal cell carcinoma treated with interferon immunotherapy. While cytokine-based immunotherapy may be considered the standard systemic therapy, clinical studies are ongoing to develop molecular biomarkers and new therapies with improved efficacy and tolerability. With further advances in our understanding of the pathogenesis, behavior and molecular biology of renal cell carcinoma, cytoreductive nephrectomy, in combination with molecular targeted therapies, may become the new standard of care for patients with metastatic renal cell carcinoma.     

VEGF-targeted therapy in metastatic renal cell carcinoma

PURPOSE: To review the biology of renal cell carcinoma (RCC) and the clinical results of vascular endothelial growth factor (VEGF) blockade in metastatic RCC. METHODS: A review of relevant published literature regarding VEGF, von Hippel-Lindau (VHL) gene inactivation, and VEGF overexpression in RCC was performed. Further, a review of the mechanism, toxicity, and clinical development of VEGF-targeted therapy in metastatic RCC was undertaken. RESULTS: VHL tumor suppressor gene inactivation is observed in the majority of clear cell RCC cases, leading to VEGF overexpression. Therapy with agents directed against the VEGF protein or the VEGF receptor have demonstrated initial clinical activity in metastatic RCC. CONCLUSIONS: Therapeutic targeting of VEGF in RCC has strong biologic rationale. Substantial clinical activity has been reported in initial clinical trials with VEGF-targeting agents. Further investigation is needed to optimally use these agents for maximal clinical benefit.     

Cytoreductive nephrectomy in metastatic renal cell carcinoma

Metastatic renal cell carcinoma is associated with a poor prognosis and a median survival time of only 6-12 months. However, the emergence of immunotherapies has rekindled interest in cytoreductive nephrectomy as a therapeutic option. Phase III randomized trials have demonstrated that cytoreductive nephrectomy significantly improves overall survival in selected patients with metastatic renal cell carcinoma treated with interferon immunotherapy. While cytokine-based immunotherapy may be considered the standard systemic therapy, clinical studies are ongoing to develop molecular biomarkers and new therapies with improved efficacy and tolerability. With further advances in our understanding of the pathogenesis, behavior and molecular biology of renal cell carcinoma, cytoreductive nephrectomy, in combination with molecular targeted therapies, may become the new standard of care for patients with metastatic renal cell carcinoma.     

Temsirolimus in VEGF-refractory metastatic renal cell carcinoma

Background: Temsirolimus is an i.v. administered inhibitor of mammalian target of rapamycin with activity in the first-line setting in poor-prognosis patients with metastatic renal cell carcinoma (RCC). The efficacy of this agent after failure of prior inhibitors of vascular endothelial growth factor (VEGF) is unknown.Methods: A retrospective review of patients with metastatic RCC treated at the Cleveland Clinic Taussig Cancer Institute and three regional cancer centers in Ontario, Canada, through the Torisel (temsirolimus) Compassionate Use Program was conducted. Demographic, toxicity and response data were collected.Results: A total of 87 patients with metastatic RCC were identified who had previously been treated with inhibitors of VEGF subsequently treated with temsirolimus. The majority of patients had either intermediate or poor-prognosis disease at baseline. Expected toxic effects including hyperglycemia and noninfectious pneumonitis were observed. The RECIST-defined objective response rate was 5% and the stable disease rate was 65%. The median time to progression (TTP) was 3.9 months (95% confidence interval 2.8–4.8 months), and median overall survival was 11.2 months.Conclusions: In a cohort of pre-treated intermediate to poor-prognosis patients with metastatic RCC, weekly i.v. temsirolimus is associated with predictable, but manageable toxicity, and a TTP approaching 4 months.     

Presurgical therapy in metastatic renal cell carcinoma

The standard approach for managing patients with metastatic renal cell carcinoma consists of a cytoreductive nephrectomy followed by immunotherapy, chemotherapy or a targeted agent. Optimal timing of surgery and systemic therapy is not known, and has not been researched. A number of questions arise. First, in the era of antivascular therapy, is cytoreductive nephrectomy a necessity? Second, is it possible that pretreatment with systemic therapy prior to cytoreductive nephrectomy improves surgical outcome and survival? Third, which agents are best suited for an integration of surgery with systemic therapy, both in the metastatic and the nonmetastatic setting? This review will address each of these questions and summarize ongoing trials that are designed to provide some of the answers.     

Signaling inhibitors in metastatic renal cell carcinoma

Renal cell carcinoma has made considerable progress in the past years, and new emerging strategies are coming almost every year since 2005. Development of targeted therapies in renal cell cancer is largely due to the fact that Von Hippel Lindau gene is often mutated in sporadic renal cell cancer. Von Hippel Lindau protein abnormalities lead to accumulation of hypoxia inducible factor-alpha, and activation of a series of gene, including vascular endothelial growth factor, and thus induce angiogenesis. Results from many recent studies with new agents, blocking the vascular endothelial growth factor pathway or the mammalian target of rapamycin pathway, have been recently reported and offer new strategic options for the patients with metastatic renal cell carcinoma. Sunitinib, sorafenib, and combination of bevacizumab and interferon improves progression free survival in either first or second line treatment of renal cell cancer and have been approved. Temsirolimus, a mammalian target of rapamycin inhibitor regulating hypoxia inducible factor-alpha, improves survival in renal cancer with poor risk features. Finally, everolimus improves progression free survival in patients who fail tyrosine kinase inhibitors. Overall, treatment of metastatic renal cell carcinoma is currently moving from the cytokine era to the targeted agent era. However, many questions still remain on the efficacy of combination treatments and on the best way to get complete remission, which is probably the best way to lead to cure of metastatic renal cell cancer in the future.     

Target therapy in metastatic renal cell carcinoma

Metastatic RCC with 38,000 new cases diagnosed in the United States every year is notoriously resistant to conventional chemotherapy and is almost invariably an incurable condition. New biologic drugs are beginning to break this resistance, reflecting in the registration of four innovative agents for treatment of advanced RCC in the last 2 years, bevacizumab, sorafenib, sunitinib and temsirolimus. Small-molecule multikinase inhibitors targeting VEGF receptors (sunitinib and sorafenib) can prolong time to progression and preserve quality of life when used in newly diagnosed or previously treated patients. The anti-VEGF antibody bevacizumab enhances response rate and prolongs disease control when added to interferon. Temsirolimus, mammalian target of rapamycin inhibitor, prolongs the survival duration of patients with poor-risk disease. In this review, we report pre-clinical data, data relative to registrative phase III trials, and guideline indications for an optimal use of these new agents that are revolutionising the management of metastatic Renal Cell Carcinoma.     

转移性肾细胞癌的靶向治疗研究进展

转移性肾细胞癌靶向治疗的药物包括VHL-低氧缺乏因子-血管内皮生长因子(VHL-HIF-VEGF)途径靶向药物舒尼替尼、索拉非尼、贝伐单抗、阿西替尼等和哺乳动物雷帕霉素靶蛋白(mTOR)抑制剂西罗莫司脂化物、依维莫司等.这些靶向药物在转移性肾细胞癌的治疗中取得了良好的效果,但是其不良反应需要引起足够的重视.在患者治疗方案上的选择以及对非透明肾细胞癌的治疗效果方面还需要进一步的研究.     

Targeting angiogenesis in metastatic renal cell carcinoma

Introduction: Renal cell carcinoma (RCC), and particularly its clear cell histological subtype, is commonly characterized by genetic alterations in the Von Hippel Lindau (VHL) tumor suppressor gene, leading to a typically exasperated angiogenesis. However, other biological and genetic peculiarities contribute to differentiate this malignancy from other solid tumors, including its immunogenicity.

Areas covered: This review focuses on the present and future role of antiangiogenic drugs, administered either alone (as it has been in the past few years), or in combination with other agents (e.g. immune checkpoint inhibitors), in the treatment of metastatic RCC.

Expert commentary: Due to its peculiar pathogenesis, it is unrealistic to expect to be able to get rid of antiangiogenic agents for the treatment of this disease; however, we do expect that combinations of VEGF/VEGFRs-targeting agents with immune checkpoint inhibitors will gradually replace antiangiogenic monotherapies as the standard of care, at least in the first line setting of metastatic RCC patients. Biomarkers discovery remains the highest priority in order to further improve the percentage of patients benefitting of our treatment.     

Sunitinib for metastatic renal cell carcinoma

Sunitinib is an orally available, multitargeted tyrosine kinase inhibitor licensed for the treatment of metastatic renal cell carcinoma. This article is an in-depth review of the mechanism of action of sunitinib, rationale for dose and schedule, toxicity and clinical efficacy. Other targeted therapies and treatment combinations for renal cell carcinoma are discussed. The use of sunitinib for other indications, biomarkers of response and future directions are explored.     

Prognostic factors of adult metastatic renal carcinoma: a multivariate analysis

In order to define the prognostic factors for metastatic renal carcinoma, we reviewed 134 patients who were treated from 1971 through 1986. Survival rates were 72, 45, and 25% at 6, 12, and 18 months, respectively. Seventeen variables were tested using the logrank test. Improved survival was correlated with normal performance status, and an absence of fever, weight loss, hepatic metastasis, and lung metastasis (or, if lung metastasis was present, less than 2 cm in diameter and limited to one site), a disease-free interval, sedimentation rate less than 100, and renal surgery. Four variables retained significant value in the multivariate analysis: hepatic metastasis, lung metastasis, disease-free interval, and a variable combining the sedimentation rate and the weight loss (SWRL). Predictive survival rates based on these variables were calculated from the Cox model. Six subgroups of patients were identified. The estimation of survival is clinically of value for future phase II trials of chemotherapy in patients with adult metastatic renal carcinoma.