pazopanib and temsirolimus

Several comparative randomised controlled trials (RCTs) have been performed including combinations of tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors since the publication of a Cochrane Review on targeted therapy for metastatic renal cell carcinoma (mRCC) in 2008. This review represents an update of that original review.. To assess the effects of targeted therapies for clear cell mRCC in patients naïve to systemic therapy.. We performed a comprehensive search with no restrictions on language or publication status. The date of the latest search was 18 June 2020.. We included randomised controlled trials, recruiting patients with clear cell mRCC naïve to previous systemic treatment. The index intervention was any TKI-based targeted therapy.. Two review authors independently assessed the included studies and extracted data for the primary outcomes: progression-free survival (PFS), overall survival (OS) and serious adverse events (SAEs); and the secondary outcomes: health-related quality of life (QoL), response rate and minor adverse events (AEs). We performed statistical analyses using a random-effects model and rated the certainty of evidence according to the GRADE approach.. We included 18 RCTs reporting on 11,590 participants randomised across 18 comparisons. This abstract focuses on the primary outcomes of select comparisons. 1. Pazopanib versus sunitinib Pazopanib may result in little to no difference in PFS as compared to sunitinib (hazard ratio (HR) 1.05, 95% confidence interval (CI) 0.90 to 1.23; 1 study, 1110 participants; low-certainty evidence). Based on the control event risk of 420 per 1000 in this trial at 12 months, this corresponds to 18 fewer participants experiencing PFS (95% CI 76 fewer to 38 more) per 1000 participants. Pazopanib may result in little to no difference in OS compared to sunitinib (HR 0.92, 95% CI 0.80 to 1.06; 1 study, 1110 participants; low-certainty evidence). Based on the control event risk of 550 per 1000 in this trial at 12 months, this corresponds to 27 more OSs (95% CI 19 fewer to 70 more) per 1000 participants. Pazopanib may result in little to no difference in SAEs as compared to sunitinib (risk ratio (RR) 1.01, 95% CI 0.94 to 1.09; 1 study, 1102 participants; low-certainty evidence). Based on the control event risk of 734 per 1000 in this trial, this corresponds to 7 more participants experiencing SAEs (95% CI 44 fewer to 66 more) per 1000 participants. 2. Sunitinib versus avelumab and axitinib Sunitinib probably reduces PFS as compared to avelumab plus axitinib (HR 1.45, 95% CI 1.17 to 1.80; 1 study, 886 participants; moderate-certainty evidence). Based on the control event risk of 550 per 1000 in this trial at 12 months, this corresponds to 130 fewer participants experiencing PFS (95% CI 209 fewer to 53 fewer) per 1000 participants. Sunitinib may result in little to no difference in OS (HR 1.28, 95% CI 0.92 to 1.79; 1 study, 886 participants; low-certainty evidence). Based on the control event risk of 890 per 1000 in this trial at 12 months, this would result in 29 fewer OSs (95% CI 78 fewer to 8 more) per 1000 participants. Sunitinib may result in little to no difference in SAEs (RR 1.01, 95% CI 0.93 to 1.10; 1 study, 873 participants; low-certainty evidence). Based on the control event risk of 705 per 1000 in this trial, this corresponds to 7 more SAEs (95% CI 49 fewer to 71 more) per 1000 participants.  3. Sunitinib versus pembrolizumab and axitinib Sunitinib probably reduces PFS as compared to pembrolizumab plus axitinib (HR 1.45, 95% CI 1.19 to 1.76; 1 study, 861 participants; moderate-certainty evidence). Based on the control event risk of 590 per 1000 in this trial at 12 mon. Based on the low to high certainty of evidence, several combinations of immune checkpoint inhibitors appear to be superior to single-agent targeted therapy in terms of PFS and OS, and with a favourable AE profile. Some single-agent targeted therapies demonstrated a similar or improved oncological outcome compared to others; minor differences were observed for AE within this group. The certainty of evidence was variable ranging from high to very low and all comparisons were based on single trials.

Topics: Adult; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Agents, Immunological; Axitinib; Bevacizumab; Bias; Carcinoma, Renal Cell; Everolimus; Humans; Indazoles; Ipilimumab; Kidney Neoplasms; Phenylurea Compounds; Progression-Free Survival; Protein Kinase Inhibitors; Pyrimidines; Quality of Life; Quinolines; Randomized Controlled Trials as Topic; Receptors, Vascular Endothelial Growth Factor; Sirolimus; Sorafenib; Sulfonamides; Sunitinib

Current systemic treatment of targeted therapies, namely the vascular endothelial growth factor-antibody (VEGF-AB), VEGF receptor tyrosine kinase inhibitor (TKI) and mammalian target of rapamycin (mTOR) inhibitors, have improved progression-free survival and replaced non-specific immunotherapy with cytokines in metastatic renal cell carcinoma (mRCC).. A panel of experts convened to review currently available phase 3 data for mRCC treatment of approved agents, in addition to available EAU guideline data for a collaborative review as the plurality of substances offers different options of first-, second- and third-line treatment with potential sequencing.. Sunitinib and pazopanib are approved treatments in first-line therapy for patients with favorable- or intermediate-risk clear cell RCC (ccRCC). Temsirolimus has proven benefit over interferon-alfa (IFN-α) in patients with non-clear cell RCC (non-ccRCC). In the second-line treatment TKIs or mTOR inhibitors are treatment choices. Therapy options after TKI failure consist of everolimus and axitinib. Available third-line options consist of everolimus and sorafenib. Recently, nivolumab, a programmed death-1 (PD1) checkpoint inhibitor, improved overall survival benefit compared to everolimus after failure of one or two VEGFR-targeted therapies, which is likely to become the first established checkpoint inhibitor in mRCC. Data for the sequencing of agents remain limited.. Despite the high level of evidence for first and second-line treatment in mRCC, data for third-line therapy are limited. Possible sequences include TKI-mTOR-TKI or TKI-TKI-mTOR with the upcoming checkpoint inhibitors in perspective, which might settle a new standard of care after previous TKI therapy.

Topics: Antibodies, Monoclonal; Antineoplastic Agents; Axitinib; Carcinoma, Renal Cell; Decision Trees; Everolimus; Humans; Imidazoles; Indazoles; Indoles; Niacinamide; Nivolumab; Phenylurea Compounds; Pyrimidines; Pyrroles; Sirolimus; Sorafenib; Sulfonamides; Sunitinib

While vascular endothelial growth factor-targeted therapy and mammalian target of rapamycin inhibition are effective strategies in treating clear cell renal cell carcinoma (ccRCC), the most effective therapeutic approach for patients with non-clear cell RCC (non-ccRCC) is unknown.. To systematically review relevant literature comparing the oncological outcomes and adverse events of different systemic therapies for patients with metastatic non-ccRCC.. Relevant databases including MEDLINE, Embase, and the Cochrane Library were searched up to March 24, 2016. Only comparative studies were included. Risk of bias and confounding assessments were performed. A meta-analysis was planned for and only performed if methodologically appropriate; otherwise, a narrative synthesis was undertaken.. The literature search identified 812 potential titles and abstracts. Five randomized controlled trials, recruiting a total of 365 patients, were included. Three studies compared sunitinib against everolimus, one of which reported the results for non-ccRCC as a subgroup rather than as an entire randomized cohort. Individually, the studies showed a trend towards favoring sunitinib in terms of overall survival and progression-free survival (PFS; Everolimus versus Sunitinib in Patients with Metastatic Non-clear Cell Renal Cell Carcinoma hazard ratio [HR]: 1.41, 80% confidence interval [CI] 1.03-1.92 and 1.41, 95% CI: 0.88-2.27, Evaluation in Metastatic Non-clear Cell Renal Cell Carcinoma HR: 1.16, 95% CI: 0.67-2.01, Efficacy and Safety Comparison of RAD001 Versus Sunitinib in the First-line and Second-line Treatment of Patients with Metastatic Renal Cell Carcinoma HR: 1.5, 95% CI: 0.9-2.8), but this trend did not reach statistical significance in any study. Meta-analysis was performed on two studies which solely recruited patients with non-ccRCC reporting on PFS, the results of which were inconclusive (HR: 1.30, 95% CI: 0.91-1.86). Sunitinib was associated with more Grade 3-4 adverse events than everolimus, although this was not statistically significant.. This systematic review and meta-analysis represent a robust summary of the evidence base for systemic treatment of metastatic non-ccRCC. The results show a trend towards favoring vascular endothelial growth factor-targeted therapy for PFS and overall survival compared with mammalian target of rapamycin inhibitors, although statistical significance was not reached. The relative benefits and harms of these treatments remain uncertain. Further research, either in the form of an individual patient data meta-analysis involving all relevant trials, or a randomized controlled trial with sufficient power to detect potential differences between treatments, is needed.. We examined the literature to determine the most effective treatments for advanced kidney cancer patients whose tumors are not of the clear cell subtype. The results suggest that a drug called sunitinib might be more effective than everolimus, but the statistics supporting this statement are not yet entirely reliable. Further research is required to clarify this unmet medical need.

Topics: Anilides; Antineoplastic Agents; Axitinib; Benzimidazoles; Bevacizumab; Carcinoma, Renal Cell; Comparative Effectiveness Research; Disease-Free Survival; Erlotinib Hydrochloride; Everolimus; Humans; Imidazoles; Indazoles; Indoles; Interferons; Interleukin-2; Kidney Neoplasms; Niacinamide; Phenylurea Compounds; Pyridines; Pyrimidines; Pyrroles; Pyrrolidinones; Quinolines; Quinolones; Sirolimus; Sorafenib; Sulfonamides; Sunitinib

Over the last few years, the most recent advances of the molecular mechanisms involved in renal cell carcinoma have led to the use of new drugs targeting VEGF, such as bevacizumab plus interferon, sorafenib, sunitinib, pazopanib, and axitinib, or the mTOR, such as temsirolimus and everolimus. The purpose of this review is to analyze the results of Phase III trial with these targeted agents, and on the management of the treatment and, in particular, when to start and to stop therapy and the use of alternative schedule of sunitinib. Recent developments in immunotherapy are also discussed.

Topics: Axitinib; Carcinoma, Renal Cell; Humans; Imidazoles; Indazoles; Indoles; Molecular Targeted Therapy; Niacinamide; Phenylurea Compounds; Pyrimidines; Pyrroles; Sirolimus; Sorafenib; Sulfonamides; Sunitinib; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factor A

In the recent years, a number of targeted therapies have been approved for first-line treatment of patients with metastatic renal cell carcinoma. A systematic review was conducted to assess the clinical efficacy, safety and effect of all first-line treatments evaluated to date on health-related quality of life (HRQoL). A systematic search of Embase, Cochrane and MEDLINE databases was performed to identify randomized controlled trials (1980-2015) evaluating any targeted therapy/immunotherapy against placebo or any other targeted intervention/immunotherapy in treatment-naive patients with metastatic renal cell carcinoma. Conference proceedings from major cancer congresses (2007-2015) were handsearched. Sixteen randomized controlled trials were identified, mostly phase III. Overall, targeted therapies were associated with either improved [sunitinib, bevacizumab+interferon α (IFNα) and temsirolimus] or comparable (sorafenib) progression-free survival (PFS) versus IFNα monotherapy. Sunitinib demonstrated comparable PFS and overall survival to pazopanib, comparable PFS to sorafenib and shorter PFS compared with bevacizumab+IFNα (although no conclusions were made with regard to superiority/inferiority). Compared with sorafenib, tivozanib demonstrated a significantly longer PFS, and both tivozanib and axitinib demonstrated higher response rates. Nintedanib demonstrated comparable PFS and overall survival to sunitinib in a phase II trial. Temsirolimus, sunitinib and sorafenib treatment led to better HRQoL versus IFNα; pazopanib was associated with better HRQoL versus sunitinib. No direct meta-analyses or indirect treatment comparison analysis were undertaken because of noncomparability of the trials. In general, targeted therapies demonstrated favourable clinical efficacy and improved HRQoL compared with IFNα monotherapy. The newer therapies, tivozanib and axitinib (but not nintedanib), appeared to exhibit greater clinical benefit (response rate) than older tyrosine kinase inhibitors.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Axitinib; Bevacizumab; Carcinoma, Renal Cell; Humans; Imidazoles; Indazoles; Indoles; Interferon-alpha; Kidney Neoplasms; Neoplasm Metastasis; Niacinamide; Phenylurea Compounds; Pyrimidines; Pyrroles; Quality of Life; Quinazolines; Quinolines; Randomized Controlled Trials as Topic; Sirolimus; Sorafenib; Sulfonamides; Sunitinib

Survival of patients with metastatic renal cell carcinoma (mRCC) has improved since the advent of targeted therapy. Approved agents include the multi-targeted tyrosine kinase inhibitors (TKIs) sunitinib, sorafenib, axitinib, pazopanib, cabozantinib, and lenvatinib (approved in combination with everolimus), the anti-VEGF monoclonal antibody bevacizumab, the mammalian target of rapamycin (mTOR) inhibitors everolimus and temsirolimus, and the programmed death-1 (PD-1) targeted immune checkpoint inhibitor nivolumab. The identification of predictive and prognostic factors of survival is increasing, and both clinical predictive factors and pathology-related prognostic factors are being evaluated. Serum-based biomarkers and certain histologic subtypes of RCC, as well as clinical factors such as dose intensity and the development of some class effect adverse events, have been identified as predictors of survival. Expression levels of microRNAs, expression of chemokine receptor 4, hypermethylation of certain genes, VEGF polymorphisms, and elevation of plasma fibrinogen or d-dimer have been shown to be prognostic indicators of survival. In the future, prognosis and treatment of patients with mRCC might be based on genomic classification, especially of the 4 most commonly mutated genes in RCC (VHL, PBRM1, BAP1, and SETD2). Median overall survival has improved for patients treated with a first-line targeted agent compared with survival of patients treated with first-line interferon-α, and results of clinical trials have shown a survival benefit of sequential treatment with targeted agents. Prognosis of patients with mRCC will likely improve with optimization and individualization of current sequential treatment with targeted agents.

Topics: Anilides; Antibodies, Monoclonal; Antineoplastic Agents; Axitinib; Bevacizumab; Biomarkers, Tumor; Carcinoma, Renal Cell; DNA-Binding Proteins; Everolimus; Gene Expression Regulation, Neoplastic; Histone-Lysine N-Methyltransferase; Humans; Imidazoles; Immunologic Factors; Indazoles; Indoles; Interferon-alpha; Kidney Neoplasms; MicroRNAs; Molecular Targeted Therapy; Mutation; Niacinamide; Nivolumab; Nuclear Proteins; Phenylurea Compounds; Precision Medicine; Prognosis; Pyridines; Pyrimidines; Pyrroles; Quinolines; Receptors, CCR4; Sirolimus; Sorafenib; Sulfonamides; Sunitinib; Transcription Factors; Tumor Suppressor Proteins; Ubiquitin Thiolesterase; Vascular Endothelial Growth Factor A; Von Hippel-Lindau Tumor Suppressor Protein

In the past 10 years, recent development of targeted therapy in metastatic renal cell carcinoma (mRCC) has provided a new hope and significantly enhanced the prognosis of the disease. Three class of targeted therapy were developed, including multi-targeted tyrosine kinase inhibitors (TKI), the mammalian target of rapamycin (mTOR) complex-1 kinase inhibitors, and the humanized antivascular endothelial growth factor (VEGF) monoclonal antibody. Hence, the objective of this article was to critically examine the current evidence of targeted therapy treatment for patients with mRCC. In the majority of trials evaluating targeted therapy, patients were stratified according to Memorial Sloan Kattering Cancer Center (MSKCC) risk model and the recommendation of targeted treatment based on risk features. In first-line setting (no previous treatment), sunitinib, pazopanib, or bevacizumab plus IFN-α were recommended as treatment options for patient with favorable- or intermediate- risk features and clear cell histology. Patients who progressed after previous cytokine therapy would have sorafenib or axitinib as treatment options. Clear-cell mRCC with favorable- or intermediate- risk features and failure with first-line TKI therapy might be treated with sorafenib, everolimus, temsirolimus or axitinib. However, the current evidence did not show the best treatment sequencing after first-line TKI failure. In patients with poor-risk clear-cell and non-clear cell mRCC, temsirolimus was the treatment option supported by phase III clinical trial. In addition, several new drugs, nowadays, are still being investigated and waiting for the result of phase II or III clinical trial, and this might change the standard therapy for mRCC in the future.

Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Axitinib; Bevacizumab; Carcinoma, Renal Cell; Everolimus; Humans; Imidazoles; Immunologic Factors; Indazoles; Indoles; Interferon-alpha; Kidney Neoplasms; Niacinamide; Phenylurea Compounds; Prognosis; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Sirolimus; Sorafenib; Sulfonamides; Sunitinib

Several 'lines of therapy' that utilize cytotoxic agents and are driven by platinum-free intervals are the current standard of care for patients with recurrent ovarian cancer. For patients with platinum-resistant disease, single agent chemotherapy (pegylated liposomal doxorubicin, topotecan, gemcitabine or weekly paclitaxel) is the standard of care. For patients with platinum-sensitive disease, combination chemotherapy (carboplatin plus paclitaxel, pegylated liposomal doxorubicin or gemcitabine) is the standard of care. In addition, antiangiogenic therapy using bevacizumab is an established option. Future directions could include 'lines of therapy' with biologic agents driven by specific biologic targets. Data from antiangiogenic agents (trebananib, pazopanib and cediranib), antifolate drugs (farletuzumab and vintafolide), poly(ADP-ribose) polymerase inhibitors (olaparib and veliparib), mTOR inhibitors (everolimus and temsirolimus) and immune editing agents (nivolumab) have been summarized in this review.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Carboplatin; Carcinoma, Ovarian Epithelial; Deoxycytidine; Doxorubicin; Everolimus; Female; Folic Acid; Gemcitabine; Humans; Indazoles; Neoplasm Recurrence, Local; Neoplasms, Glandular and Epithelial; Nivolumab; Ovarian Neoplasms; Paclitaxel; Phthalazines; Piperazines; Poly(ADP-ribose) Polymerase Inhibitors; Polyethylene Glycols; Pyrimidines; Quinazolines; Recombinant Fusion Proteins; Sirolimus; Sulfonamides; Topotecan; TOR Serine-Threonine Kinases; Vinca Alkaloids

A variety of therapeutic agents are currently available for the systemic treatment of metastatic renal cell carcinoma (mRCC). It was only when targeted treatment was developed in the past decade that a significant improvement was achieved in tumour therapy. This also led to the development of sequential treatment for mRCC.7 molecular targeted agents are available today (axitinib, bevacizumab/ IFNα, everolimus, pazopanib, sorafenib, sunitinib, and temsirolimus). Due to the individualisation of treatment it remains a challenge to choose the most appropriate drug in a given setting, with the choice being based on the knowledge of the relevant clinical data as well as individual patient parameters.During the recent past, efforts have been made to test different inhibitors or combinations without a major breakthrough. Instead, the development of novel specific immunotherapeutic approaches now heralds the next level of treatment in mRCC. The first significant trial results will be expected this year, and further trials for optimisation of treatment are warranted.

Topics: Antineoplastic Combined Chemotherapy Protocols; Axitinib; Bevacizumab; Carcinoma, Renal Cell; Disease Progression; Everolimus; Humans; Imidazoles; Immunotherapy; Indazoles; Indoles; Interferon-alpha; Kidney Neoplasms; Molecular Targeted Therapy; Niacinamide; Phenylurea Compounds; Prognosis; Pyrimidines; Pyrroles; Sirolimus; Sorafenib; Sulfonamides; Sunitinib; Survival Analysis

Synovial sarcoma is part of soft tissue sarcomas, an uncommon group of malignant tumors of mesenchymal origin. Unfortunately, a very limited number of useful drugs are active for most advanced synovial sarcoma. These tumors showed VEGF expression, and elevated serum VEGF levels correlate with higher histologic tumor grade. Inhibition of VEGFR was associated with tumor activity in preclinical models of synovial sarcoma and drugs such as sorafenib, pazopanib and bevacizumab have been employed in synovial sarcoma in monotherapy and in combination with chemotherapy. Other targets such as EGFR, HER2, IGFR-1R and mTOR have been exploited, but their inhibition by drugs such as gefitinib, trastuzumab, figitumumab, and temsirolimus, has not resulted in meaningful activity. Newer approaches include CXCR4 inhibition, immune-based therapies (NY-ESO-1), targeting epigenetic misregulation with HDAC inhibitors and targeting developmental pathways such Notch and Hedgehog. This review will summarize achievements and pitfalls of drugs against emerging therapeutic targets for synovial sarcoma.

Topics: Antibodies, Monoclonal; Antineoplastic Agents; Bevacizumab; Everolimus; Humans; Indazoles; Indoles; Molecular Targeted Therapy; Niacinamide; Phenylurea Compounds; Pyrimidines; Pyrroles; Receptors, Vascular Endothelial Growth Factor; Sarcoma; Sarcoma, Synovial; Sirolimus; Sorafenib; Sulfonamides; Sunitinib; TOR Serine-Threonine Kinases

With seven agents approved for renal cell carcinoma within the past few years, there has undoubtedly been progress in treating this disease. However, patients with poor-risk features remain a challenging and difficult-to-treat population, with the mTOR inhibitor, temsirolimus, the only agent approved in the first-line setting. Phase III trial data are still lacking VEGF-pathway inhibitors in patients with poor prognostic features. Poor-risk patients need to be considered as a heterogeneous population. Further understanding of biomarkers can lead to a better selection of patients who may benefit the most from treatment and improvements in prognosis. The presence of poor Karnofsky scores and liver or CNS disease may affect the outcome of these patients much more than other identified factors. This consideration may provide the rationale to further stratify poor-risk patients further subgroups destined to receive either cure or palliation.

Topics: Carcinoma, Renal Cell; Humans; Indazoles; Kidney Neoplasms; Molecular Targeted Therapy; Palliative Care; Protein Kinase Inhibitors; Pyrimidines; Receptors, Vascular Endothelial Growth Factor; Sirolimus; Sulfonamides; TOR Serine-Threonine Kinases

With the introduction of multiple new targeted agents for the treatment of metastatic renal cell carcinoma, specific attention must be given to toxicities induced by these agents.. Agents with activity on the same target can have different toxicities, which might lead the clinician to select or individualize therapies. However, some data also support the concept of maximal tolerated dose as a marker of efficacy. Specific elements of these data are summarized and discussed in the paper.. Toxicity management is pivotal in individualized cancer care. This papers outlines some of the principles related to disease and toxicity management.

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Dose-Response Relationship, Drug; Everolimus; Humans; Indazoles; Indoles; Kidney Neoplasms; Neoplasm Metastasis; Pyrimidines; Pyrroles; Randomized Controlled Trials as Topic; Receptors, Vascular Endothelial Growth Factor; Sirolimus; Sulfonamides; Sunitinib

The introduction of therapy targeting vascular endothelial growth factor (VEGF) and the mammalian target of rapomycin (mTOR) has significantly improved the outcome of patients with metastatic renal cancer. In this article a comprehensive overview of treatment choices for previously untreated patients with metastatic disease is given. Both established and emerging therapeutic options are discussed, as are prognostic factors predicting outcome.

Topics: Antibodies, Monoclonal, Humanized; Bevacizumab; Carcinoma, Renal Cell; Humans; Indazoles; Indoles; Kidney Neoplasms; Prognosis; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Sirolimus; Sulfonamides; Sunitinib

With the advent of targeted agents for the treatment of renal cell carcinoma (RCC), overall survival has improved, and patients are being treated continuously for increasingly long periods of time. This has raised challenges in the management of adverse events (AEs) associated with the six targeted agents approved in RCC-sorafenib, sunitinib, pazopanib, bevacizumab (in combination with interferon alpha), temsirolimus, and everolimus. Suggestions for monitoring and managing AEs have been published, but there are few consensus recommendations. In addition, there is a risk that patients will be subjected to multiple unnecessary investigations. In this review, we aimed to identify the level of supporting evidence for suggested AE management strategies to provide practical guidance on essential monitoring and management that should be undertaken when using targeted agents. Five databases were systematically searched for relevant English language articles (including American Society of Clinical Oncology abstracts) published between January 2007 and March 2011; European Society of Medical Oncology congress abstracts were hand searched. Strategies for AE management were summarized and categorized according to the level of recommendation. A total of 107 articles were identified that describe a large number of different investigations for monitoring AEs and interventions for AE management. We identify and summarize clear recommendations for the management of dermatologic, gastrointestinal, thyroid, cardiovascular, and other AEs, based predominantly on expert opinion. However, because the evidence for the suggested management strategies is largely anecdotal, there is a need for further systematic investigation of management strategies for AEs related to targeted therapies for RCC.

Topics: Anorexia; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Benzenesulfonates; Bevacizumab; Carcinoma, Renal Cell; Cardiovascular System; Drug Eruptions; Europe; Everolimus; Evidence-Based Medicine; Gastrointestinal Tract; Humans; Hypothyroidism; Indazoles; Indoles; Kidney Neoplasms; Molecular Targeted Therapy; Niacinamide; Phenylurea Compounds; Pneumonia; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyridines; Pyrimidines; Pyrroles; Sirolimus; Sorafenib; Sulfonamides; Sunitinib; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factor A; Weight Loss; Wound Healing

Therapeutic options in advanced renal-cell cancer have expanded through better understanding of molecular pathology and development of novel targeted therapeutics. Vascular endothelial growth factor, the key ligand of angiogenesis, has a major role in the progression of vascularized kidney tumors and this is the target molecule of modern medications. The three types of the mechanism of action of current therapies are: monoclonal antibodies blocking directly vascular endothelial growth factor ligand (bevacizumab), tyrosine-kinase inhibitors blocking vascular endothelial growth factor receptors (sorafenib, sunitinib, pazopanib) and inhibitors of the intracellular mTOR-kinase (temsirolimus, everolimus). Based on randomized studies, sunitinib, pazopanib or interferon-α-bevacizumab combination should be the first-line therapy in patients with good/moderate prognosis, while temsirolimus is recommended in those with poor prognosis. Following an ineffective cytokine therapy sorafenib or pazopanib are the second-line treatment. In case of tyrosine-kinase inhibitor inefficacy, current evidence favors everolimus. Patient outcome can further be improved by the involvement of more modern and effective target products.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Benzenesulfonates; Bevacizumab; Carcinoma, Renal Cell; Everolimus; Humans; Indazoles; Indoles; Kidney Neoplasms; Molecular Targeted Therapy; Neovascularization, Pathologic; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyridines; Pyrimidines; Pyrroles; Receptors, Vascular Endothelial Growth Factor; Sirolimus; Sorafenib; Sulfonamides; Sunitinib; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factor A

The median survival of patients with metastatic renal cell carcinoma (mRCC) increased from 10 to more than 40 months since the advent of targeted therapy. The transformation of mRCC from an initially lethal disease to a more favorable entity, albeit incurable, occurred with the transition from best supportive care, to cytokines, to finally sequential targeted therapies. Sunitinib and bevacizumab (level 1b) represent the first-line standard of care for patients with clear-cell mRCC vs temsirolimus (level 2) for those with high-risk features. Additionally, exploratory analyses of the temsirolimus data indicate important benefits for those with nonclear-cell mRCC histological subtypes. In second-line, everolimus proved its efficacy (level 1b). Nonetheless, sunitinib and sorafenib are also effective for nonclear-cell histological subtypes and after failure of other first-line treatment. The PFS benefits of first- and subsequent treatment-lines were confirmed in virtually all subgroup analyses. Potential survival benefits can be derived from cytoreductive nephrectomy (CNT), as was shown for cytokines in the general population, in sunitinib and bevacizumab-exposed patients. Phase III studies are ongoing to address the importance of CNT. This information is crucial to ensure timely delivery of a combination of medical and surgical therapies in this patient population.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Benzenesulfonates; Bevacizumab; Carcinoma, Renal Cell; Humans; Immunotherapy; Indazoles; Indoles; Interferons; Interleukin-2; Kidney Neoplasms; Neoplasm Metastasis; Nephrectomy; Niacinamide; Phenylurea Compounds; Pyridines; Pyrimidines; Pyrroles; Sirolimus; Sorafenib; Sulfonamides; Sunitinib

Over the last few years, targeted agents have assumed a predominant role in treatment of metastatic renal cell carcinoma (mRCC). Our aim is to discuss recent developments on this rapidly evolving topic.. Sunitinib represents front-line standard treatment for the good- and intermediate prognosis groups of patients with clear cell renal carcinoma. Bevacizumab/interferon and pazopanib have also been FDA-approved as first-line agents, while sorafenib has moved toward second-line and later therapy. Temsirolimus, an mTOR inhibitor, is recommended as front line therapy for patients in the poor-risk group and is the best front-line choice for patients with non-clear cell histology. Another mTOR inhibitor, everolimus, has shown clinical benefit post-tyrosine kinasis inhibitors failure in a phase III study and is considered the standard of care in this setting. Novel prognostic and efficacy markers might help to define most appropriate therapeutic strategy. Best sequence of use of these effective agents in mRCC patients remains up to the discretion of treating physician.. In light of the considerable advances in understanding the biology of mRCC, several new drugs have been recently developed, with an increasing number of treatment options. Several markers are under evaluation for diagnostic, prognostic and efficacy purposes. A treatment algorithm, based on the best scientific evidence produce so far, is presented and it will evolve as data from ongoing trials will be available.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Benzenesulfonates; Bevacizumab; Biomarkers, Tumor; Carcinoma, Renal Cell; Disease-Free Survival; Everolimus; Humans; Immunotherapy; Indazoles; Interferons; Kidney Neoplasms; Niacinamide; Phenylurea Compounds; Prognosis; Pyridines; Pyrimidines; Sirolimus; Sorafenib; Sulfonamides; TOR Serine-Threonine Kinases

The development of targeted molecules in renal carcinogenesis changed the therapeutic approaches of treatment for metastatic clear cell renal cell carcinoma. Four available drugs are currently available, i.e. bevacizumab, sunitinib, sorafenib and temsirolimus, but other molecules and combined therapy are under investigation. In this review we assess published reports of these targeted therapies and discuss the novel promising molecules targeting vascular endothelial growth factor and its receptors, the mammalian target of rapamycin and epithelial growth factor cascade.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Axitinib; Benzenesulfonates; Bevacizumab; Carcinoma, Renal Cell; Clinical Trials as Topic; Everolimus; Humans; Imidazoles; Indazoles; Indoles; Kidney Neoplasms; Neoplasm Metastasis; Niacinamide; Phenylurea Compounds; Pyridines; Pyrimidines; Pyrroles; Sirolimus; Sorafenib; Sulfonamides; Sunitinib; Vascular Endothelial Growth Factors

Treatment of advanced renal cell carcinoma (RCC) has undergone significant changes over the past 3 years after a long period of relative stagnation. A better understanding of the biology of the tumor led to the discovery of molecular targeted therapies resulting in significant improvement in outcome for this common malignancy.. A review of new drugs, both established and investigational, at present used in the treatment of RCC is provided in this article.. A comprehensive free-text search of all available published literature including but not limited to, Medline, Scopus, American Society of Clinical Oncology presentations, National Comprehensive Cancer Network guidelines and information available through other national and international scientific organizations was carried out during the preparation of this manuscript.. Targeted therapy in RCC is a prime example of successful translational research. Continuing clinical and preclinical research in drug development holds promise for further advances in this area.

Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Axitinib; Benzenesulfonates; Bevacizumab; Carcinoma, Renal Cell; Clinical Trials as Topic; Everolimus; Humans; Imidazoles; Indazoles; Indoles; Kidney Neoplasms; Niacinamide; Phenylurea Compounds; Pyridines; Pyrimidines; Pyrroles; Quinazolines; Sirolimus; Sorafenib; Sulfonamides; Sunitinib

Recent developments in the understanding of the molecular biology of renal cell carcinoma have led to the development of several biologic agents with different mechanisms of action. In 2005, promising results have been observed especially in second-line therapy following cytokine failures and in 2006 more mature data with regard to time to progression and overall survival should be available. This review, analyzing basic translational research principles, will summarize the available evidence with a glimpse of the future therapeutic approaches in renal cell carcinoma.. Vascular endothelial growth factor- and platelet-derived growth factor receptor-inhibiting drugs (SU11248, Bay 43-9006, Bevacizumab, AG-013736, etc.) report time to progression ranging between 4 and 9 months and variable benefits in overall survival. Confirmatory studies are ongoing regarding other novel treatments (CCI-779, Infliximab, PTK-787).. In renal cell carcinoma, there is a strong rationale for targeting multiple pathways and particularly angiogenesis. Vascular endothelial growth factor- and platelet-derived growth factor receptor-inhibiting drugs have been rapidly approved in the second-line setting and will soon be used as first-line therapy. In the next years, translational/clinical research will provide evidence for combination strategies to improve upon the results of the biologic agents and hopefully offer more hope to patients with renal cell carcinoma.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Axitinib; Benzenesulfonates; Bevacizumab; Carcinoma, Renal Cell; Erlotinib Hydrochloride; Humans; Imidazoles; Indazoles; Indoles; Kidney Neoplasms; Neoplasm Metastasis; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Pyridines; Pyrimidines; Pyrroles; Quinazolines; Sirolimus; Sorafenib; Sulfonamides; Sunitinib

Temsirolimus has level 1 evidence for initial treatment of poor-risk patients with advanced renal cell carcinoma (mRCC), but its efficacy has not been directly compared with an antiangiogenic tyrosine kinase inhibitor (vascular endothelial growth factor receptor tyrosine kinase inhibitor [VEGFR TKi]) in this setting.. To evaluate temsirolimus versus pazopanib as first-line therapy in patients with mRCC, predominant clear-cell features, and clinical characteristics of a poor prognosis.. A randomized (1:1) phase II trial in 69 treatment-naïve mRCC patients and with three or more predictors of short survival for temsirolimus was conducted during 2012-2017 in a single academic cancer center. Crossover to the alternative treatment upon discontinuation of the first-line agent was permitted.. Mechanistic target of rapamycin inhibitor temsirolimus and VEGFR TKi pazopanib.. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were overall survival (OS), objective response rate (ORR), safety, and patient-reported outcomes (PROs). Radiographic response was assessed by blinded radiologists. Efficacy outcomes were adjusted by prior nephrectomy status, prior interleukin-2 treatment, and the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) score.. Thirty-five patients received temsirolimus and 34 received pazopanib upfront; 72% overall had poor risk by IMDC. Median PFS in the first line was 2.7mo with temsirolimus and 5.2mo with pazopanib (adjusted hazard ratio [HR] 1.36, 95% confidence interval [CI] 0.84-2.22; p=0.210). Median OS was 7.1mo with temsirolimus and 11.9mo with pazopanib (adjusted HR 1.16, 95% CI 0.70-1.93; p=0.558), and ORRs were 5.9% and 21.2%, respectively (adjusted odds ratio 5.2, 95% CI 0.9-29.3; p=0.062). PRO measures favored pazopanib. Five patients discontinued first-line therapy due to adverse events.. Temsirolimus and pazopanib had modest activity in patients with poor-risk clear-cell mRCC, and therefore their use should be discouraged in this setting.. We evaluated outcomes of advanced renal cell carcinoma patients presenting with aggressive features when treated with temsirolimus or pazopanib as first-line therapy. Survival was <1yr for most, suggesting that more efficacious alternative treatments should be favored for these patients.

Topics: Adult; Aged; Aged, 80 and over; Carcinoma, Renal Cell; Female; Humans; Indazoles; Kidney Neoplasms; Male; Middle Aged; Neoplasm Staging; Prognosis; Pyrimidines; Risk Assessment; Single-Blind Method; Sirolimus; Sulfonamides

Vascular endothelial growth factor (VEGF) targeting represents the standard first-line therapy for metastatic renal-cell carcinoma (mRCC), while blocking the mammalian target of rapamycin (mTOR) is effective in relapsed disease. Since continuing blockade of VEGF may be of value, we studied the combination of bevacizumab with temsirolimus in mRCC patients relapsing after first-line treatment.. A prospective, phase II study of the combination of bevacizumab (10 mg/kg, every 2 weeks) with temsirolimus (25 mg weekly) in patients with mRCC who failed first-line anti-VEGF treatment. 6-month progression-free survival (PFS) rate was the primary end point. The association of VEGFa, VEGFR2, fibroblast growth factor (FGF) b, platelet-derived growth factor receptor (PDGFR) a and PDGFRb with prognostic factors and outcomes were also studied.. 39 patients were enrolled. First-line therapy included: sunitinib (n = 16), bevacizumab/interferon (n = 12), pazopanib (n = 10), sorafenib (n = 1). After a median follow-up of 37 months, 6-month PFS rate was 50.9% [95% confidence interval (CI) 33.8-65.7], median time to progression 6.8 months (95% CI 5.5-9.2) and median overall survival (OS) 18.2 months (95% CI 12.9-27.2). Objective response rate was 27%. The most common AEs were metabolic (33%), renal (8%) and gastrointestinal (GI) (7%). The most common grade 3-5 AEs were GI (18%), infections (14%) and metabolic (25%). Toxicity was the most frequent cause of treatment discontinuation (40%). FGFb levels were associated with OS.. In concert with recent data, our study confirms the efficacy of anti-VEGF/anti-mTOR combination in mRCC relapsing after anti-VEGF therapy. Toxicity was considerable leading to high rate of treatment discontinuations.. ClinicalTrials.gov: NCT01264341.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Biomarkers, Tumor; Carcinoma, Renal Cell; Humans; Indazoles; Kidney Neoplasms; Middle Aged; Neoplasm Recurrence, Local; Prospective Studies; Pyrimidines; Sirolimus; Sorafenib; Sulfonamides; Sunitinib; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factor A

The current treatment of metastatic renal cell carcinoma (mRCC) revolves around targeted agents, which have resulted in a median overall survival of 22 to 26 months in registration trials. However, the outcomes in a non-trial, real-world Indian population have not yet been evaluated.. The present study was a part of a prospective Clinical Trials Registry-India-registered study, the Kidney Cancer Registry, a prospectively maintained kidney cancer registry. The data of patients with a diagnosis of mRCC from February 2007 to August 2015 who were potential candidates for systemic therapy were extracted from the database and analyzed for treatment patterns and outcomes.. The data from 212 patients were eligible for analysis. Of these 212 patients, 204 (96.2%) received first-line systemic treatment with sunitinib (40.6%), sorafenib (37.7%), pazopanib (2.8%), temsirolimus (2.8%), or everolimus (1.9%). The risk status of 91% of the patients could be stratified using the Heng criteria into favorable (18.9%), intermediate (43.9%), and poor risk (28.3%) categories. The response rate, clinical benefit rate, median progression-free survival, and median overall survival with first-line targeted therapy were 22.5%, 60.7%, 7.09 months, and 12.87 months, respectively. The common adverse events seen included skin rash (31.7%), hypertension (29.4%), grade 3 hand-foot syndrome (27.4%), mucositis (26.4%), dyslipidemia (20%), and hyperglycemia (17.6%). Patients receiving second-line therapy (22.6%) had superior overall survival to patients who had not (16.46 vs. 10.67 months; P = .032).. The present registry-based study is the first, to the best of our knowledge, of its type from India and showed that the overall outcomes in this real-world cohort appear comparable to non-trial data worldwide. An increased incidence of metabolic adverse events that require monitoring during treatment was also found.

Topics: Adult; Aged; Antineoplastic Agents; Carcinoma, Renal Cell; Everolimus; Female; Humans; Indazoles; India; Indoles; Kidney Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Niacinamide; Phenylurea Compounds; Practice Patterns, Physicians'; Prospective Studies; Pyrimidines; Pyrroles; Retrospective Studies; Sirolimus; Sorafenib; Sulfonamides; Sunitinib; Survival Analysis; Tertiary Care Centers; Treatment Outcome; Young Adult

Inhibition of either vascular endothelial growth factor receptor or mammalian target of rapamycin (mTOR) signaling improves outcomes in patients with several advanced solid tumors. We conducted a phase I trial of temsirolimus with pazopanib to investigate the feasibility of simultaneous 'vertical inhibition' of vascular endothelial growth factor receptor and mTOR pathways. Patients with advanced solid tumors, no previous pazopanib or mTOR inhibitor, good performance status, and acceptable end-organ function were eligible. In a typical 3+3 escalation design starting at temsirolimus 15 mg by an intravenous infusion weekly and pazopanib 400 mg orally daily, we defined dose-limiting toxicity (DLT) as attributable grade 3 or higher nonhematologic adverse events in the first 28-day cycle and the maximum tolerable dose as the maximum dose level at which less than two patients experienced DLT. At the initial dose level, two patients had four DLTs (anorexia, fatigue, hyponatremia, and hypophosphatemia). After reduction to temsirolimus 10 mg intravenous infusion weekly and pazopanib 200 mg orally daily, one of three patients had DLT (fatigue) and the first patient in the subsequent expansion had dose-limiting hypophosphatemia. Attributable grade 3 or higher adverse events in more than one patient included leukopenia, neutropenia, fatigue, and hypophosphatemia. Tumor reduction not fulfilling the RECIST criteria for partial response was the best response in four of seven evaluable patients. The combination of temsirolimus and pazopanib was not feasible at clinically meaningful doses in this population because of constitutional and electrolyte disturbances.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Dose-Response Relationship, Drug; Female; Humans; Indazoles; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Staging; Neoplasms; Pyrimidines; Receptors, Vascular Endothelial Growth Factor; Sirolimus; Sulfonamides; TOR Serine-Threonine Kinases

Chromosomal rearrangements are common in clear cell renal cell carcinoma (ccRCC) and their roles in mediating sensitivity to tyrosine kinase inhibitors (TKIs) and mTOR inhibitors (mTORi) remain elusive.. We developed an in silico strategy by screening copy number variance (CNV) that was potentially related to TKI or mTORi sensitivity in ccRCC by reproducing the TCGA and GDSC datasets. Candidate genes should be both significantly prognostic and related to drug sensitivity or resistance, and were then validated in vitro.. ADCYAP1 loss and GNAS gain were associated with sensitivity and resistance and to Cabozantinib, respectively. ACRBP gain and CTBP1 loss were associated with sensitivity and resistance and to Pazopanib, respectively. CDKN2A loss and SULT1A3 gain were associated with sensitivity and resistance and to Temsirolimus, respectively. CCNE1 gain was associated with resistance to Axitinib and LRP10 loss was associated with resistance to Sunitinib. Mutivariate analysis showed ADCYAP1, GNAS, and CCNE1 remained independently prognostic when adjusted for the rest.. Here we show CNVs of several genes that are associated with sensitivity and resistance to commonly used TKIs and mTORi in ccRCC. Further validation and functional analyses are therefore needed.

Topics: Anilides; Antineoplastic Agents; Arylsulfotransferase; Axitinib; Carcinoma, Renal Cell; Carrier Proteins; Cell Line, Tumor; Chromogranins; Computer Simulation; Cyclin E; DNA Copy Number Variations; Drug Resistance, Neoplasm; GTP-Binding Protein alpha Subunits, Gs; Humans; Indazoles; Kidney Neoplasms; Oncogene Proteins; Pituitary Adenylate Cyclase-Activating Polypeptide; Protein Kinase Inhibitors; Pyridines; Pyrimidines; Sirolimus; Sulfonamides; Sunitinib

The objective of this study is to describe the use of targeted therapies for the treatment of advanced renal cell carcinoma (RCC) and overall survival (OS) among patients in clinical practice in the Veterans Health Administration (VHA).. A retrospective cohort of 286 patients from 24 VHA Medical Centers diagnosed with advanced clear cell RCC between Fiscal Year (FY) 2010 and FY2014 was followed through September 30, 2016. Among patients who received targeted therapy, we described the medications taken, duration of therapy, and overall survival. We also assessed the effect of the first therapy received on overall survival using Cox Proportional Hazards models.. There were 66 patients who did not receive therapy for their advanced RCC. Of the 220 treated patients, the mean (sd) number of medications received was 1.9 (1.1). The medications most commonly used first were sunitinib (61.8%), pazopanib (17.3%), and temsirolimus (10.9%). The median duration of first-line therapy was 86 days (interquartile range [IQR] 42, 210). Median total duration of therapy was 159 days (IQR 58, 397). 62.3% of patients had ≥ 1 dose of therapy held or reduced, mainly due to an adverse drug event (ADE). Median survival from the start of treatment to death was 1.08 years (IQR 0.80, 1.31). Finally, receipt of temsirolimus vs sunitinib (HR 1.95 [95%CI 1.09,3.47]) as the first targeted therapy was independently associated with an increased hazard of death.. Our analysis of targeted therapies for advanced RCC in VHA suggests duration of treatment is shorter in a real-world setting than in clinical trials, and dose reductions and ADEs are more common.

Topics: Aged; Antineoplastic Agents; Carcinoma, Renal Cell; Female; Humans; Indazoles; Kidney Neoplasms; Male; Middle Aged; Molecular Targeted Therapy; Pyrimidines; Retrospective Studies; Sirolimus; Sulfonamides; Sunitinib; Survival Analysis; Treatment Outcome; United States; United States Department of Veterans Affairs

To study the prevalence of hypogonadism in male patients with metastatic renal cell carcinoma (mRCC) starting with targeted therapies and the impact of the vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) sunitinib and pazopanib on the luteinizing hormone (LH)/testosterone (TT)-axis.. Male mRCC patients starting with targeted therapies were prospectively included in this study. TT- and LH-levels were sampled at start as well as during systemic therapy. Endpoints of the study were gonadal status (TT- and LH-levels) at start of targeted therapy and TT- and LH-evolution during targeted therapy.. Sixty-three patients were included in this study. At start of targeted therapy, 30% of patients were eugonadal and 48% had secondary hypogonadism. Decreased TT- and increased LH-levels were associated with inflammatory state and poor prognosis. During sunitinib therapy, TT-levels decreased with 32% (p = 0.004) and LH-levels with 14% (p = 0.03). TT-levels were 13% lower (p = 0.007) and LH-levels 15% lower (p = 0.004) on day 28 compared to day 1. In four patients, a dramatic TT decrease was observed shortly after starting sunitinib. In patients treated with pazopanib, no impact on TT- or LH-levels was observed.. Hypogonadism is a frequent finding in male mRCC-patients at start of targeted therapies. In contrast to pazopanib, during sunitinib therapy, TT- and LH-levels tend to decrease, leading to an increased incidence of secondary hypogonadism.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Renal Cell; Cross-Sectional Studies; Humans; Hypogonadism; Indazoles; Kidney Neoplasms; Luteinizing Hormone; Male; Middle Aged; Molecular Targeted Therapy; Prevalence; Prospective Studies; Protein Kinase Inhibitors; Pyrimidines; Sirolimus; Sulfonamides; Sunitinib; Testosterone; Vascular Endothelial Growth Factor A

Drug-induced nephrotic syndrome (NS) can be resolved by eliminating the causative agents. However, patients with metastatic cancer have not been previously reported to achieve complete recovery from anticancer drug-induced NS after discontinuation of treatment, because many patients die of cancer progression before NS is restored.. A 67-year-old man presented with edema of both lower extremities. He received pazopanib therapy for recurrent metastatic renal cell carcinoma (mRCC) for 17 months. Laboratory examinations revealed 7484.58 mg/day of 24-h urine protein, 434 mg/dL of serum cholesterol, and 2.9 g/dL of serum albumin. He was diagnosed with NS, and pazopanib treatment was discontinued. Four months later, he completely recovered from NS. He was then treated with temsirolimus and nivolumab sequentially for > 26 months. Pazopanib was re-introduced following disease progression, and demonstrated antitumor effects for 7 months without NS recurrence.. Pazopanib-induced NS can occur late in patients with mRCC, and its subsequent discontinuation can enable patients to completely recover from its adverse effects. Moreover, pazopanib treatment may be re-introduced without the recurrence of NS.

Topics: Aged; Amlodipine; Angiogenesis Inhibitors; Antihypertensive Agents; Antineoplastic Agents; Carcinoma, Renal Cell; Combined Modality Therapy; Diabetic Nephropathies; Dihydropyridines; Drug Substitution; Edema; Everolimus; Humans; Hypertension; Indazoles; Kidney Failure, Chronic; Lung Neoplasms; Male; Nephrotic Syndrome; Nivolumab; Pancreatic Neoplasms; Pancreaticoduodenectomy; Pneumonectomy; Protein Kinase Inhibitors; Pyrimidines; Sirolimus; Sulfonamides; Sunitinib

Mucositis is often experienced in metastatic renal cell carcinoma (mRCC) patients treated with targeted therapies. This might impair daily quality of life and lead to dose reduction, discontinuation, or treatment shift. We assessed the effect of folic acid to reduce mucositis.. Patients treated with systemic therapy for mRCC who developed Grade ≥2 mucositis according to Common Terminology Criteria for Adverse Events version 4.0 (CTCAE) received oral folic acid to reduce mucositis. The medical charts were retrospectively reviewed.. A total of 77 patients had Grade ≥2 mucositis during therapy with sunitinib (n = 29), pazopanib (n = 24), everolimus (n = 10), axitinib (n = 4), temsirolimus (n = 3), interleukin-2/interferon-α (n = 3), cabozantinib (n = 2), bevacizumab (n = 1), and nivolumab (n = 1). Given in doses of 1 to 5 mg daily, folic acid significantly reduced mucositis, mean CTCAE grade 0.88 (95% confidence interval [CI], 0.74-1.03) versus 2.38 (95% CI, 2.26-2.54; P < .0001). Stratified according to treatment, folic acid significantly reduced mucositis grade for sunitinib (0.97 [95% CI, 0.75-1.18] vs. 2.45 [95% CI, 2.23-2.67], P < .0001), pazopanib (0.96 [95% CI, 0.67-1.25] vs. 2.20 [2.03-2.38], P < .0001), everolimus (0.60 [95% CI, 0.10-1.10] vs. 2.60 [95% CI, 2.23-2.97], P < .0001), and other treatments (0.79 [95% CI, 0.38-1.19] vs. 2.36 [95% CI, 2.07-2.64], P < .0001). Of the 77 patients, 8 (10%) patients received dose reduction. Overall progression-free survival was 14 months and overall survival was 31 months.. Folic acid reduced mucositis in mRCC patients receiving systemic therapy. This finding needs prospective validation. A double-blind, placebo-controlled prospective evaluation of folic acid is ongoing (NCT03581773).

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Axitinib; Carcinoma, Renal Cell; Everolimus; Female; Folic Acid; Humans; Indazoles; Kidney Neoplasms; Male; Middle Aged; Mucositis; Neoplasm Metastasis; Pyrimidines; Retrospective Studies; Sirolimus; Sulfonamides; Sunitinib; Treatment Outcome

To identify predictors of prolonged or shortened progression-free survival (PFS) and overall survival (OS) among patients with metastatic renal cell carcinoma (mRCC) who received first-line targeted therapies.. This retrospective study included 146 patients with mRCC who were treated during 2007-2015. These patients were divided into a group with the worst response (WG), an expected group (EG), and a group with the best response (BG), based on their PFS (≤3 monthsnths, 3-18 monthsnths, and >18 monthsnths, respectively) and OS (<1 year, 1-3 years, and >3 years, respectively). To identify significant predictive factors, the BG and WG were compared to the EG using the Memorial Sloan Kettering Cancer Center and Heng risk models.. The overall PFS and OS were 9.3 months and 16.4 months, respectively. The median PFS for the WG (41.8 %), EG (45.9 %), and BG (12.3 %) were 2.7 months, 9.3 months, and 56.6 months, respectively, and the median OS for the WG (45.9 %), EG (35.6 %), and BG (18.5 %) were 5.5 months, 21.6 months, and 63.1 months, respectively; these outcomes were significantly different (p < 0.001). Nephrectomy (odds ratio [OR]: 7.15) was a significant predictor of PFS in the BG, and the significant predictors of OS in the BG were MSKCC intermediate risk (OR: 0.12), poor risk (OR: 0.04), and a disease-free interval of <1 year (OR: 0.23) (all, p < 0.05). Anemia (OR: 3.25) was a significant predictor of PFS in the WG, and the significant predictors of OS were age (OR: 1.05), anemia (OR: 4.13), lymphocytopenia (OR: 4.76), disease-free interval of <1 year (OR: 4.8), and synchronous metastasis (OR: 3.52) (all, p < 0.05).. We identified several significant predictors of unexpectedly good and poor response to first-line targeted therapy among patients with mRCC.

Topics: Aged; Antineoplastic Agents; Carcinoma, Renal Cell; Disease-Free Survival; Female; Humans; Indazoles; Indoles; Kidney Neoplasms; Male; Middle Aged; Molecular Targeted Therapy; Neoplasm Metastasis; Niacinamide; Phenylurea Compounds; Prognosis; Pyrimidines; Pyrroles; Retrospective Studies; Sirolimus; Sorafenib; Sulfonamides; Sunitinib; Survival Analysis; Treatment Outcome

Metastatic renal cell carcinoma (mRCC) develops in approximately 33% of all renal cancer patients. First line treatment of mRCC includes drugs such as sunitinib, temsirolimus and pazopanib, with overall survival now reaching up to 43,6months in patients with favorable-risk metastatic disease. Several side-effects in mRCC treatment, such as hypothyroidism, can be used as positive prognostic factors and indicate good response to therapy. Hypercholesterolemia and hypertriglyceridemia independent of hypothyroidism are reported as side-effects in temsirolimus treatment and recently in sunitinib treatment, but the exact mechanism and significance of the changes remains elusive. Most likely, metabolic changes are caused by inhibition of mechanistic target of rapamycin (mTOR), a positive target of tumor growth suppression, but also a regulator of iron homeostasis. There are no clinical studies reporting changes in iron and ferritin levels during mRCC biotherapy, but we hypothesize that inhibition of mTOR will also affect iron and ferritin levels. If both lipid and iron changes correlate, there is a high possibility that both changes are primarily caused by mTOR inhibition and the level of change should correlate with the inhibition of mTOR pathway and hence the efficacy of targeted treatment. We lastly hypothesize that mRCC biotherapy causes hypercholesterolemia with a possibly improved cholesterol profile due to increase HDL/LDL ratio, so statins might not have a role as supplementary treatment, whereas a sharp rise in triglyceride levels seems to be the primary target for additional therapy.

Topics: Animals; Antineoplastic Agents; Biomarkers, Tumor; Carcinoma, Renal Cell; Cholesterol; Ferritins; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Hypertriglyceridemia; Hypothyroidism; Indazoles; Indoles; Iron; Kidney Neoplasms; Lipids; Metabolome; Models, Theoretical; Neoplasm Metastasis; Prognosis; Pyrimidines; Pyrroles; Sirolimus; Sulfonamides; Sunitinib; TOR Serine-Threonine Kinases; Triglycerides

Clinical trials have demonstrated that pazopanib prolongs progression-free survival (PFS), with an acceptable safety profile, for patients with advanced renal cell carcinoma (aRCC). The efficacy of second-line mammalian target of rapamycin (mTOR) inhibitors in pazopanib-treated patients has also been evaluated in clinical trials; however, few studies have evaluated first-line pazopanib or second-line mTOR inhibitors in real-world settings. The present study evaluated the outcomes of first-line pazopanib, and pazopanib followed by mTOR inhibitors, in a community oncology setting.. The present study was a retrospective analysis of eligible patients in US Oncology's iKnowMed electronic health records database who had been treated for aRCC from November 1, 2009 to August 31, 2012. The patients received first-line therapy with pazopanib (cohort 1), followed by second-line therapy with either everolimus or temsirolimus (cohort 2). The key outcomes included overall survival (OS), PFS, adverse events (AEs), treatment patterns, and healthcare resource use.. The median OS in cohort 1 (n = 177) was 22 months, and the median PFS was 8.5 months. The most common AEs were fatigue (56%), diarrhea (52%), vomiting (44%), and nausea (40%). The median persistence was 151 days with pazopanib. The median OS in cohort 2 (n = 35) was 16 months; the median PFS was 5.7 months. The most common AEs were fatigue (51%) and nausea (34%). The median persistence was 93 days with everolimus and 49 days with temsirolimus.. The outcomes for the patients treated with first-line pazopanib in the community setting were consistent with those reported by previous prospective and retrospective studies. Although the second-line cohort was small, the results of mTOR inhibitors after pazopanib were also consistent with those of previous observations.

Topics: Adult; Aged; Angiogenesis Inhibitors; Carcinoma, Renal Cell; Community Networks; Electronic Health Records; Everolimus; Female; Humans; Indazoles; Kidney Neoplasms; Longitudinal Studies; Male; Middle Aged; Protein Kinase Inhibitors; Pyrimidines; Retrospective Studies; Sirolimus; Sulfonamides; Survival Analysis; TOR Serine-Threonine Kinases; Treatment Outcome; United States; Young Adult

Effective choice of anticancer drugs is important problem of modern medicine. We developed a method termed OncoFinder for the analysis of new type of biomarkers reflecting activation of intracellular signaling and metabolic molecular pathways. These biomarkers may be linked with the sensitivity to anticancer drugs. In this study, we compared the experimental data obtained in our laboratory and in the Genomics of Drug Sensitivity in Cancer (GDS) project for testing response to anticancer drugs and transcriptomes of various human cell lines. The microarray-based profiling of transcriptomes was performed for the cell lines before the addition of drugs to the medium, and experimental growth inhibition curves were built for each drug, featuring characteristic IC50 values. We assayed here four target drugs - Pazopanib, Sorafenib, Sunitinib and Temsirolimus, and 238 different cell lines, of which 11 were profiled in our laboratory and 227 - in GDS project. Using the OncoFinder-processed transcriptomic data on ~600 molecular pathways, we identified pathways showing significant correlation between pathway activation strength (PAS) and IC50 values for these drugs. Correlations reflect relationships between response to drug and pathway activation features. We intersected the results and found molecular pathways significantly correlated in both our assay and GDS project. For most of these pathways, we generated molecular models of their interaction with known molecular target(s) of the respective drugs. For the first time, our study uncovered mechanisms underlying cancer cell response to drugs at the high-throughput molecular interactomic level.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Survival; Computational Biology; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genomics; HeLa Cells; Hep G2 Cells; Humans; Indazoles; Indoles; Inhibitory Concentration 50; Jurkat Cells; MCF-7 Cells; Neoplasms; Niacinamide; Oligonucleotide Array Sequence Analysis; Phenylurea Compounds; Pyrimidines; Pyrroles; Sirolimus; Sorafenib; Sulfonamides; Sunitinib; Transcriptome

Although narrow eligibility criteria improve the internal validity of clinical trials, they may result in differences between study populations and real-world patients, threatening generalizability. Therefore, we evaluated whether patients treated for metastatic renal cell cancer (mRCC) in routine clinical practice are similar to those enrolled onto clinical trials.. In this cohort study, we compared baseline characteristics of patients with mRCC in phase III clinical trials of new targeted therapies and those in a retrospective registry composed of academic (Duke) and community (ACORN Network) practices.. A total of 438 registry patients received sunitinib, sorafenib, temsirolimus, or pazopanib (most commonly used agents) in first-line treatment. Registry patients receiving tyrosine kinase inhibitors (sunitinib, sorafenib, or pazopanib) were more likely to have poor-risk disease by Memorial Sloan Kettering Cancer Center criteria (poor, 7.4% v 2.9%; P < .001; favorable, 30.1% v 43.8%; P < .001) and to have impaired performance status (Eastern Cooperative Oncology Group > 1, 11.1% v 0.6%; P < .001). However, registry patients receiving temsirolimus were less likely to have poor-risk disease (poor, 10.2% v 69.4%; P < .001; favorable, 16.9% v 0%; P < .001). Thus, 39.0% of registry patients would have been excluded from the phase III clinical trial testing the drug they received.. Patients with mRCC treated with tyrosine kinase inhibitors in real-world clinical practice are sicker than those enrolled onto pivotal clinical trials, and more than one third are trial ineligible. Application of clinical trial findings to dissimilar populations may result in patient harm. Clinical research with more inclusive eligibility criteria is needed to appropriately guide real-world practice.

Topics: Aged; Antineoplastic Agents; Carcinoma, Renal Cell; Clinical Trials as Topic; Female; Humans; Indazoles; Indoles; Kaplan-Meier Estimate; Kidney Neoplasms; Male; Middle Aged; Niacinamide; Patients; Phenylurea Compounds; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Severity of Illness Index; Sirolimus; Sorafenib; Sulfonamides; Sunitinib

The SCAN genitourinary cancer workgroup aimed to develop Singapore Cancer Network (SCAN) clinical practice guidelines for systemic therapy of metastatic renal cell carcinoma (mRCC).. The workgroup utilised a modified ADAPTE process to calibrate high quality international evidence-based clinical practice guidelines to our local setting.. Six international guidelines were evaluated- those developed by the National Comprehensive Cancer Network (2014), the European Association for Urology (2013), the European Society of Medical Oncology (2012), the National Institute of Health and Clinical Excellence (2011), the Canadian Kidney Cancer Forum (2013) and the Asian Oncology Summit (2012). Recommendations on the first-, second- and third-line treatment for mRCC were developed.. These adapted guidelines form the SCAN Guidelines 2015 for systemic therapy of mRCC.

Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Axitinib; Bevacizumab; Carcinoma, Renal Cell; Everolimus; Humans; Imidazoles; Indazoles; Indoles; Interferon-alpha; Interleukin-2; Kidney Neoplasms; Nephrectomy; Niacinamide; Phenylurea Compounds; Pyrimidines; Pyrroles; Singapore; Sirolimus; Sorafenib; Sulfonamides; Sunitinib

Chemotherapy for collecting duct carcinoma (CDC) has demonstrated only limited efficacy in the advanced setting. The present study evaluated the activity of targeted therapies in metastatic CDC.. We evaluated a cohort of 384 consecutive patients with metastatic renal cell carcinoma (mRCC). The characteristics of patients with CDC were compared against those of the remaining cohort. All patients with CDC were treated with targeted therapies.. Thirteen patients with advanced CDC were referred to our Center (incidence: 3.4% of all mRCC). Median age was 57 and 62 years in the CDC and non-CDC groups, respectively. The overall disease control in the CDC population was 23%, and median overall survival was 4 (95% confidence interval(CI)=2.4-5.6) months. Three patients obtained a satisfying response (disease control lasting 6-33 months).. CDC has a poor prognosis compared to non-CDC renal cell carcinoma. Treatment for CDC represents a future challenge and targeted therapies may play a role in selected cases.

Topics: Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Antineoplastic Agents; Carcinoma, Renal Cell; Cohort Studies; Humans; Indazoles; Kidney Neoplasms; Middle Aged; Neovascularization, Pathologic; Niacinamide; Phenylurea Compounds; Pyrimidines; Sirolimus; Sorafenib; Sulfonamides

Patients with metastatic renal cell carcinoma (mRCC) in whom first-line therapies have failed might derive clinical benefit with sequential targeted agents. Limited data are available on the efficacy and toxicity of subsequent therapies after disease progression during pazopanib therapy.. Patients with mRCC who received subsequent systemic treatment after pazopanib treatment failure were identified across 7 institutions. Pazopanib was given as first-line therapy in 28 patients and after cytokines therapy in 7 patients. Clinical outcome and toxicity analyses of 2 sequential treatment options (anti-vascular endothelial growth factor [VEGF] or mammalian target of rapamycin inhibitor [mTORi]) is presented.. Subsequent therapy was anti-VEGF in 22 patients and mTORi in 13. One patient who received bevacizumab and temsirolimus combination was excluded. VEGF-targeted therapies included sorafenib (n = 10), sunitinib (n = 3), bevacizumab (n = 2), cediranib (n = 4) and cabozantinib (n = 3). Patients treated with mTORi received everolimus. Median progression-free survival was 5.6 months from the start of subsequent therapy with anti-VEGF and 2.4 months with mTORi (P = .009). Overall survival (OS) was not significantly different (P = .68). Clinical benefit (including partial response and stable disease) on subsequent therapy was observed in 15 patients (64%) and 4 patients (31%) of anti-VEGF- and everolimus-treated patients, respectively (P = .021).. In this retrospective study, targeting VEGF was an effective strategy after disease progression during pazopanib treatment, although OS was not different among patients treated with VEGF or mTORi.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma, Renal Cell; Everolimus; Female; Follow-Up Studies; Humans; Indazoles; Indoles; Kidney Neoplasms; Male; Middle Aged; Molecular Targeted Therapy; Neoplasm Staging; Niacinamide; Phenylurea Compounds; Prognosis; Pyrimidines; Pyrroles; Retrospective Studies; Sirolimus; Sorafenib; Sulfonamides; Sunitinib; Survival Rate; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factor A

We set out to identify Stearoyl-CoA desaturase 1 (SCD1) as a novel molecular target in clear cell renal cell carcinoma (ccRCC) and examine its role in tumor cell growth and viability in vitro and in vivo independently as well as in combination with current U.S. Food and Drug Administration (FDA)-approved regimens.. Patient normal and ccRCC tissue samples and cell lines were examined for SCD1 expression. Genetic knockdown models and targeted inhibition of SCD1 through use of a small molecule inhibitor, A939572, were analyzed for growth, apoptosis, and alterations in gene expression using gene array analysis. Therapeutic models of synergy were evaluated utilizing pharmacologic inhibition of SCD1 with the tyrosine kinase inhibitors (TKI) sunitinib and pazopanib, and the mTOR inhibitor temsirolimus.. Our studies identify increased SCD1 expression in all stages of ccRCC. Both genetic knockdown and pharmacologic inhibition of SCD1 decreased tumor cell proliferation and induced apoptosis in vitro and in vivo. Upon gene array, quantitative real-time PCR, and protein analysis of A939572-treated or SCD1 lentiviral knockdown samples, induction of endoplasmic reticulum stress response signaling was observed, providing mechanistic insight for SCD1 activity in ccRCC. Furthermore, combinatorial application of A939572 with temsirolimus synergistically inhibited tumor growth in vitro and in vivo.. Increased SCD1 expression supports ccRCC viability and therefore we propose it as a novel molecular target for therapy either independently or in combination with an mTOR inhibitor for patients whose disease cannot be remedied with surgical intervention, such as in cases of advanced or metastatic disease.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Cell Line, Tumor; Drug Synergism; Female; Gene Expression; Humans; Indazoles; Indoles; Kidney Neoplasms; Mice; Mice, Nude; Molecular Targeted Therapy; Pyrimidines; Pyrroles; Sirolimus; Stearoyl-CoA Desaturase; Sulfonamides; Sunitinib; Tumor Burden; Up-Regulation; Xenograft Model Antitumor Assays

To investigate the efficacy and safety of zoledronic acid (ZA) combined with targeted therapy (TT).. A retrospective study was performed in patients with metastatic renal cell carcinoma treated with ZA and TT.. Twenty-one patients received ZA and TT to prevent skeletal-related events and no pretherapy oral and maxillofacial (OM) examination (cohort A). Six patients (29%) developed osteonecrosis of the jaw (ONJ), which was observed only in patients receiving sunitinib and ZA. Sixteen patients received TT and ZA for hypercalcemia and no pretherapy OM examination (cohort B). In these patients, no ONJ was observed. Nine patients received ZA and TT and pretherapy OM examination (cohort C). One patient (11%) developed ONJ during sunitinib and ZA treatment. Mean skeletal morbidity rates were 0.8 for cohort A and 1.2 for cohort C. In the combined cohort (A plus C; n = 30), 47% developed skeletal-related events, 7% pathologic fracture, 7% medullary compression, and 37% progression of bone metastases. Patients who developed ONJ had a significantly improved median survival of 31.6 months compared with 14.5 months in patients without ONJ (P = .039).. The combination of ZA and TT resulted in high, clinically meaningful activity. ONJ may be exacerbated by concomitant ZA and sunitinib. Regular OM examinations before and during treatment are recommended.

Topics: Adult; Aged; Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Bevacizumab; Bisphosphonate-Associated Osteonecrosis of the Jaw; Bone Density Conservation Agents; Bone Neoplasms; Carcinoma, Renal Cell; Cohort Studies; Diphosphonates; Everolimus; Female; Follow-Up Studies; Fractures, Spontaneous; Humans; Imidazoles; Indazoles; Indoles; Interleukin-2; Kidney Neoplasms; Male; Middle Aged; Molecular Targeted Therapy; Niacinamide; Phenylurea Compounds; Pyrimidines; Pyrroles; Radiography, Panoramic; Retrospective Studies; Sirolimus; Sorafenib; Spinal Cord Compression; Sulfonamides; Sunitinib; Survival Rate; Zoledronic Acid

Limited information on real-world treatment patterns of targeted agents for metastatic renal cell carcinoma (mRCC) is available to inform their use in clinical practice.. This retrospective observational study used US claims data (from January 2007 to November 2010) to identify treatment patterns, including treatment duration and dosing, for molecular-targeted agents (sunitinib, sorafenib, pazopanib, bevacizumab, and temsirolimus) indicated in first-line management of advanced and/or mRCC. The study included adult patients with mRCC who were observable for ≥3 months after initiation of their first-line therapy with a targeted agent. Descriptive analyses were conducted for observed treatment patterns.. Of the 273 patients on first-line therapy identified and included in the sample, 235 patients were treated with sunitinib, 16 patients with sorafenib, and 15 patients with temsirolimus. Pazopanib and bevacizumab were excluded from the analysis due to the small sample size, n < 10. The median observed treatment durations were sunitinib 98 days, sorafenib 121 days, and temsirolimus 78 days. Approximately 76% (178/235) of patients who received sunitinib initiated therapy at the indicated dose of 50 mg; 65% of these patients were not observed filling a fourth prescription, whereas 23% maintained their starting dose and 12% experienced dose reduction at their 4+ fill. The mean starting dose for patients who initiated on sorafenib (n = 16) was 725 mg and for temsirolimus (n = 15) was 25 mg: their study samples were insufficient for further, meaningful dosing analyses.. Results of this study suggest that opportunities exist to improve treatment duration in clinical practice and to better understand influences on treatment and dose changes.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Bevacizumab; Carcinoma, Renal Cell; Cohort Studies; Female; Humans; Indazoles; Indoles; Kidney Neoplasms; Male; Middle Aged; Molecular Targeted Therapy; Neoplasm Metastasis; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Retrospective Studies; Sirolimus; Sorafenib; Sulfonamides; Sunitinib; United States

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma, Renal Cell; Disease-Free Survival; Everolimus; Humans; Indazoles; Indoles; Kidney Neoplasms; Niacinamide; Phenylurea Compounds; Pyrimidines; Pyrroles; Randomized Controlled Trials as Topic; Receptors, Vascular Endothelial Growth Factor; Sirolimus; Sorafenib; Sulfonamides; Sunitinib; TOR Serine-Threonine Kinases; Treatment Outcome

To provide an updated review of adverse events associated with sunitinib, pazopanib, bevacizumab, temsirolimus, axitinib, everolimus and sorafenib and their management.. We performed a PubMed and Cochrane-based review of side effects associated with the seven agents including product monographs to provide an outline of treatment measures aiming to reduce their toxicities. Subject and outcome of interest, design type, sample size, pertinence and quality, and detail of reporting were the indicators of manuscript quality.. All targeted therapies cause adverse events. Most adverse events may be prevented or tested before they escalate to severe levels.. Prevention, early recognition, and prompt management of side effects are of key importance and avoid unnecessary dose reductions, which may undermine treatment efficacy.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Axitinib; Bevacizumab; Carcinoma, Renal Cell; Everolimus; Humans; Imidazoles; Indazoles; Indoles; Kidney Neoplasms; Molecular Targeted Therapy; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Sirolimus; Sorafenib; Sulfonamides; Sunitinib

With the introduction of targeted drug therapies, a paradigm shift for the treatment of metastatic renal cell carcinoma has taken place. New compounds like sunitinib, sorafenib, bevacizumab and temsirolimus have become established as new therapeutic standards to replace the use of cytokines as standard therapy. Recently, these substances have been complemented by everolimus and pazopanib. An interdisciplinary consensus conference was held to discuss which criteria to consider when using these drugs (treatment sequence) and what questions remain unanswered based on the current study situation (open questions). Results from the 2009 conference provided the basis for the 2010 meeting. The results of the 2010 conference are presented as short theses.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Benzenesulfonates; Bevacizumab; Carcinoma, Renal Cell; Clinical Trials, Phase III as Topic; Combined Modality Therapy; Cooperative Behavior; Cytokines; Disease Progression; Everolimus; Evidence-Based Medicine; Humans; Indazoles; Indoles; Interdisciplinary Communication; Kidney Neoplasms; Molecular Targeted Therapy; Niacinamide; Patient Care Team; Phenylurea Compounds; Platelet-Derived Growth Factor; Pyridines; Pyrimidines; Pyrroles; Randomized Controlled Trials as Topic; Signal Transduction; Sirolimus; Sorafenib; Sulfonamides; Sunitinib; Survival Rate; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factor A

Several years ago, the oncologist was limited to a narrow scope of immunotherapeutic agents for the treatment of metastatic renal cell carcinoma (mRCC). Within the past 5 years, however, a total of 6 targeted agents have been approved for the treatment of this disease. The abundance of novel therapies has introduced a new dilemma for the oncologist--namely, how can one make evidence-based choices amongst available agents? Recently, two Phase III studies (AVOREN and Cancer and Leukemia Group B [CALGB] 90206) assessed the activity of 1st-line therapy with bevacizumab in combination with interferon-alfa (IFN-alfa) as compared to IFN-alfa alone. Both trials demonstrated a significant benefit in progression-free survival (PFS) with bevacizumab, with no benefit in overall survival (OS). Herein, the implications of these data are assessed in the context of data reported from other recent pivotal trials in mRCC. Methods to resolve areas of clinical equipoise in the treatment of mRCC (i.e., comparative trial designs and biomarker analyses) are also proposed.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Benzenesulfonates; Bevacizumab; Carcinoma, Renal Cell; Clinical Trials, Phase III as Topic; Disease-Free Survival; Humans; Indazoles; Indoles; Interferon-alpha; Kidney Neoplasms; Multicenter Studies as Topic; Niacinamide; Phenylurea Compounds; Pyridines; Pyrimidines; Pyrroles; Randomized Controlled Trials as Topic; Sirolimus; Sorafenib; Sulfonamides; Sunitinib; Survival Analysis