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Systemic therapy in metastatic renal cell carcinoma.
Bedke, J, Gauler, T, Grünwald, V, Hegele, A, Herrmann, E, Hinz, S, Janssen, J, Schmitz, S, Schostak, M, Tesch, H, et al
World journal of urology. 2017;(2):179-188
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Abstract
PURPOSE 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). METHODS 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. RESULTS 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. CONCLUSIONS 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.
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Primary hypothyroidism and isolated ACTH deficiency induced by nivolumab therapy: Case report and review.
Zeng, MF, Chen, LL, Ye, HY, Gong, W, Zhou, LN, Li, YM, Zhao, XL
Medicine. 2017;(44):e8426
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RATIONALE Nivolumab is a monoclonal IgG antibody blocking programmed death receptor-1 (PD1), leading to restoration of the natural T-cell-mediated immune response against the cancer cells. However, it also causes plenty of autoimmune-related adverse events, which often involves endocrine system. PATIENT CONCERNS A 54-year-old male with renal clear cell carcinoma was treated with nivolumab intravenously. Routine monitoring showed elevated thyroid-stimulating hormone and low free thyroxine after the 6th administration of nivolumab. After the 12th administration, he developed general fatigue, recurrent hypoglycemia, and relative hypotension. Laboratory tests showed low sodium, low morning cortisol without correspondence increase of corticotrophin (ACTH). Other pituitary hormones were normal. MRI showed no space-occupying lesions, but heterogeneous enhancement of the pituitary gland. DIAGNOSES Primary hypothyroidism and isolated ACTH deficiency. The etiologies were assumed to be nivolumab induced autoimmune lymphocytic thyroiditis and hypophysitis, respectively. INTERVENTIONS Hormone replacements with levothyroxine and acetate cortisone were given orally. Nivolumab was adjusted to lower dose and longer interval. OUTCOMES The patient felt good after adequate replacement. Nivolumab was returned to routine dose and interval six months later. And the metastasis was not obviously progressed during this time. LESSONS The present report provides the first detailed presentation of combined hypothyroidism and isolated ACTH deficiency induced by nivolumab. Adrenal deficiency often develops insidiously. We suggest routine monitoring of fasting blood-glucose, blood pressure and serum sodium as well as thyroid function during nivolumab and other cancer immunotherapies. When unexpected fatigue, hypoglycemia, hypotension or hyponatremia appeared, adrenal deficiency should be taken into consideration.
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The Therapeutic Aspects of the Endocannabinoid System (ECS) for Cancer and their Development: From Nature to Laboratory.
Khan, MI, Sobocińska, AA, Czarnecka, AM, Król, M, Botta, B, Szczylik, C
Current pharmaceutical design. 2016;(12):1756-66
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The endocannabinoid system (ECS) is a group of neuromodulatory lipids and their receptors, which are widely distributed in mammalian tissues. ECS regulates various cardiovascular, nervous, and immune system functions inside cells. In recent years, there has been a growing body of evidence for the use of synthetic and natural cannabinoids as potential anticancer agents. For instance, the CB1 and CB2 receptors are assumed to play an important role inside the endocannabinoid system. These receptors are abundantly expressed in the brain and fatty tissue of the human body. Despite recent developments in molecular biology, there is still a lack of knowledge about the distribution of CB1 and CB2 receptors in the human kidney and their role in kidney cancer. To address this gap, we explore and demonstrate the role of the endocannabinoid system in renal cell carcinoma (RCC). In this brief overview, we elucidate the therapeutic aspects of the endocannabinoid system for various cancers and explain how this system can be used for treating kidney cancer. Overall, this review provides new insights into cannabinoids' mechanisms of action in both in vivo and in vitro models, and focuses on recent discoveries in the field.
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Comparing comparators: a look at control arms in kidney cancer studies over the years.
Bracarda, S, Porta, C, Sisani, M, Marrocolo, F, Paglino, C, Hamzaj, A, D Buono, S, Sternberg, CN
British journal of cancer. 2015;(1):14-9
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In the past decade, an increasing number of frequently positive randomised clinical trials have been completed, allowing new consideration of the present therapeutic armamentarium for advanced renal cell carcinoma. These studies were predominantly designed to compare the experimental drugs with 1 of 2 active control arms: interferon alpha-2a or sorafenib. Different from expectations, the final results of some of these studies were not in line with the predictions, and the reasons have not been fully investigated. Consequently, there is a great need for careful analysis of the studies carried out so far, chiefly the role and validity of the control arms. In this regard, the examination of patient baseline characteristics and other factors of potential interest seems fundamental for a correct analysis of the results of these trials and consequent optimal use of the available targeted agents.
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The relationship between renal cell carcinoma and nuclear retinoid/rexinoid receptors.
Lenko, V, Bialesova, L, Macejova, D, Bujdak, P, Breza, J, Brtko, J
Biomedical papers of the Medical Faculty of the University Palacky, Olomouc, Czechoslovakia. 2013;(4):316-24
Abstract
BACKGROUND Renal cell carcinoma (RCC) is a urologic malignancy with a steady rise in incidence and high mortality rate. Between 60 to 70% of patients with renal cell carcinoma can only be cured with surgery but despite advances in early diagnostis, in around 20-30% of cases there is metastasis. For these patients, chemotherapy and radiotherapy are ineffective and hence the prognosis is poor. Retinoids are biologically active compounds of either natural or synthetic origin that are involved in complex physiological and developmental processes in many tissues including cell proliferation and activation of tumour suppression genes. This article reviews the role of retinoids and their cognate nuclear retinoid/rexinoid receptors in relation to renal cell carcinoma. METHODS A literature search using ScienceDirect and Medline with a focus on the relationship between renal cell carcinoma and nuclear retinoid/rexinoid receptors. RESULTS Use of retinoids/rexinoids in the treatment of locally advanced and metastatic RCC significantly prolongs median time of tumour progression and overall survival of patients. Combination therapy with other preparations has greater efficacy than treatment with retinoids alone. Patient survival can be predicted on the basis of the expression of different all-trans retinoic acid receptor (RAR) and 9-cis retinoic acid receptor (RXR) subtypes. CONCLUSIONS Since nuclear retinoid receptors play a crucial role as ligand-activated, DNA binding, trans-acting, transcription-modulating proteins involved in a general molecular mechanism responsible for transcriptional responses in target genes, retinoids might be an alternative approach for the treatment of renal cell carcinoma.
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Targeted therapies for the treatment of metastatic renal cell carcinoma: clinical evidence.
Hutson, TE
The oncologist. 2011;(Suppl 2):14-22
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Although systemic therapy for patients with metastatic renal cell carcinoma (mRCC) was once limited to the cytokines interleukin-2 and interferon (IFN)-α, in recent years several targeted therapies have become available for first- and second-line use. These include sorafenib, sunitinib, bevacizumab (plus IFN-α), temsirolimus, everolimus, and, most recently, pazopanib. This expanded list of treatment options arose from molecular biological research that revealed aberrant signal transduction activities in RCC, enabling the identification of specific molecular targets for therapy. Molecular-targeted therapies have better efficacy and tolerability than cytokine therapy, and many are administered orally. The superior outcomes achieved with molecular-targeted agents are prompting investigators to reconsider overall survival as a primary endpoint in clinical trials, given the inherent complications of a required long duration of follow-up, a required large population, and confounding caused by crossover trial designs or effects of subsequent therapy after progression on the agent of interest. In mRCC trials, progression-free survival has become a popular primary endpoint and has served as the basis of approval for several targeted therapies. In addition to the identification of new agents, current research is focused on the evaluation of combination therapy with targeted agents. As more information regarding mechanisms of disease and drug resistance becomes available, new targets, new targeted agents, and new combinations will be studied with the goal of providing maximal efficacy with minimal toxicity. This article reviews the clinical evidence supporting the benefits of targeted agents in mRCC treatment, discusses survival endpoints used in their pivotal clinical trials, and outlines future research directions.
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Beyond traditional outcomes: improving quality of life in patients with renal cell carcinoma.
Cella, D
The oncologist. 2011;(Suppl 2):23-31
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The introduction of molecular targeted therapies for patients with metastatic renal cell carcinoma has provided treatment options that are more efficacious and better tolerated than cytokine therapy, the previous standard of care. These advances have led to renewed efforts to define the health-related quality of life (HRQOL) impact of disease status stabilization or improvement versus that of treatment-associated adverse events. The distinct classes of targeted agents have unique AE profiles related to their specific targets; therefore, treatment considerations should include the patient's pretreatment HRQOL along with the known HRQOL effects of each drug. With more second- and third-line treatment options available for patients with metastatic renal cell carcinoma, HRQOL outcomes in earlier lines of therapy may guide treatment decisions for subsequent therapy, as poor HRQOL at therapy onset predicts poor survival. Both general and disease-specific instruments are used in clinical trials to reveal the impact of treatment on patient-reported outcomes. In this article, the common instruments used to assess HRQOL and the HRQOL outcomes observed in pivotal trials of targeted therapies are reviewed. Current data indicate that first-line therapy with sunitinib and first-line therapy in poor-prognosis patients with temsirolimus provide improved HRQOL compared with interferon-α. First- and second-line therapy with pazopanib and second-line therapy with everolimus and sorafenib maintained HRQOL levels similar to placebo, indicating that these agents do not worsen HRQOL. The HRQOL effects of bevacizumab plus IFN-α have not been reported. As new agents enter clinical investigation, HRQOL data can help determine their overall role in treatment.
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Treatment-associated adverse event management in the advanced renal cell carcinoma patient treated with targeted therapies.
Ravaud, A
The oncologist. 2011;(Suppl 2):32-44
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Targeted therapy for advanced renal cell carcinoma (RCC) has recently expanded the available treatment options for patients with these malignancies. The rapid introduction of novel treatment options into clinical practice within a relatively short time frame has created some new challenges pertaining to adverse event (AE) management in patients with advanced RCC. Accumulating safety data from the pivotal phase III clinical trials of the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab plus interferon, VEGF receptor tyrosine kinase inhibitors (sunitinib, sorafenib, and pazopanib), and mammalian target of rapamycin inhibitors (temsirolimus and everolimus) have served to characterize the toxicity profiles of these novel agents. Overall, it is evident that RCC-directed targeted therapy differs from immunotherapy and cytotoxic chemotherapy in terms of a number of unique nonhematologic AEs (some of which have not been traditionally encountered in oncology practice) and that there are distinctions within and across the various classes of agents with respect to the most prominent AEs and the risk for less common but serious complications. Although treatment-associated AEs are common, the majority of AEs reported during clinical trial experiences were grade 1 or 2 in severity and manageable with intervention in the form of supportive measures and/or dosage modification. Therefore, despite the relatively complex AE profiles of RCC-directed targeted therapy, patient education, consistent monitoring with a focus on early detection by health care providers (oncologists, general physicians, nurses), and the application of emerging AE management strategies may allow for prolonged treatment in most patients with advanced RCC.
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Vascular endothelial growth factor-targeted therapy in metastatic renal cell carcinoma.
Rini, BI
Cancer. 2009;(10 Suppl):2306-12
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Inactivation of the von Hippel-Lindau tumor suppressor gene in most sporadic renal cell carcinoma (RCC) tumors leads to a fundamental reliance on elements of this pathway, namely, the potent proangiogenic factor, vascular endothelial growth factor (VEGF). Thus, VEGF-targeted therapeutics have undergone extensive clinical testing in RCC. Approaches to bind circulating VEGF protein (eg, bevacizumab) and small molecule inhibitors of the receptor on which the VEGF ligand binds (eg, sunitinib, sorafenib, axitinib, and pazopanib) have been tested. Robust clinical effects have been observed, including high objective response rates, prolonged progression-free survival, and evidence of long overall survival for patients with metastatic RCC patients who are treated with these agents. Future directions include investigation of combination and sequenced therapy, elucidation of mechanisms of response and resistance, and exploration of the effect of these agents in other disease settings.
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[Interferon alpha and half-dose sorafenib is an effective treatment modality for interferon alpha-resistant metastatic renal cell carcinoma: a case report].
Furuya, N, Kamai, T, Tokui, N, Abe, H, Fukabori, Y, Yoshida, K
Hinyokika kiyo. Acta urologica Japonica. 2009;(6):323-6
Abstract
Metastatic renal cell carcinoma is notoriously resistant to chemotherapy and radiotherapy. Immunotherapy with interferon alpha is widely used for the disease, but its treatment effects are poor. A 69-year-old Japanese women presented with gross hematuria. Imaging studies revealed a left renal tumor, 12 cm in diameter, and multiple pulmonary and hepatic lesions. No abnormal laboratory data were observed other than anemia with Hb 9.2 g/dl. Performance status was 0. She underwent radial left nepherectomy. Pathological examination showed clear cell renal cell carcinoma with moderate histological differentiation (grade 2) and microscopic vessel invasion; pT3aN0M1 (Pul, Hep). Memorial Sloon-Kettering Cancer Center classification was an intermediate risk due to anemia. She received interferon alpha, 5 million IU three times per week, postoperatively. In three months, hepatic lesions rapidly progressed although there was no interval change of pulmonary lesions. Then, the patient received interferon alpha at the same dose as described above and half-dose sorafenib, 400 mg per day. Grade 2 hypertension was under control by calcium channel blocker and the hand-foot syndrome was not obvious. No other grade 3/4 drug-related adverse events were observed. In one month after combination therapy, not only pulmonary lesions but also hepatic lesions were smaller. She has received this combination therapy with stable disease for six months. Performance status was 1 with grade 1 fatigue. The doses of this regimen may be tolerable, and might be an available treatment option for interferon alpha-resistant advanced renal cancer.