Treatment Of Advanced Kidney Cancer Research Articles

Clinical Efficacy of PD-1 Inhibitors Plus Split-Course Radiotherapy in the First-Line Treatment of Advanced Kidney Cancer: A Randomized Controlled Trial.

Objective To assess the clinical efficacy of programmed death 1 (PD-1) inhibitors plus split-course radiotherapy in the first-line treatment of advanced kidney cancer. Methods In this prospective, randomized, single-blinded, controlled trial, 44 patients with advanced kidney cancer initially treated in our hospital from January 2017 to December 2018 were recruited. They were concurrently and randomly assigned at a ratio of 1 : 1 to the control group and the study group, with 22 cases in each group. The control group received PD-1 inhibitor nivolumab combined with ipilimumab, and the study group received split-course radiotherapy plus. The primary endpoint is clinical efficacy, and the secondary endpoints are progression-free survival (PFS), overall survival (OS), and adverse events (AEs). Results Nivolumab plus split-course radiotherapy was associated with an objective remission rate (ORR) of 59.09% versus nivolumab alone with an ORR of 27.27%. The median PFS was 21.5 months (95% CI: 14.1—NA) after single nivolumab therapy and 28.1 months (95% CI: 24.5—NA) after nivolumab plus split-course radiotherapy, with an HR of 1.875 (95% CI: 0.877–4.011). The median OS was 27.1 months (95% CI: 20.7—NA) after single nivolumab therapy and not reached after nivolumab plus split-course radiotherapy and an HR of 2.56 (95% CI: 1.081–6.06). Nivolumab was associated with significantly better OS plus split-course radiotherapy versus nivolumab alone. Conclusion Nivolumab plus split-course radiotherapy in patients with advanced renal cell carcinoma significantly improves ORR and prolongs overall survival with a good safety profile.

Updated European Association of Urology Guidelines on Renal Cell Carcinoma: Nivolumab plus Cabozantinib Joins Immune Checkpoint Inhibition Combination Therapies for Treatment-naïve Metastatic Clear-Cell Renal Cell Carcinoma

Longer follow-up and new trial data from phase 3 randomised controlled trials investigating immune checkpoint blockade (PD-1 or its ligand PD-L1) in advanced clear-cell renal cell carcinoma (RCC) have recently become available. The CheckMate 9ER trial demonstrated an improved progression-free survival (PFS) and overall survival (OS) benefit for the combination of cabozantinib plus nivolumab. A Keynote-426 update demonstrated an ongoing OS benefit for pembrolizumab plus axitinib in the intention-to-treat population, with a PFS benefit seen across all International Metastatic Database Consortium (IMDC) subgroups, while an update of CheckMate 214 confirmed the long-term benefit of ipilimumab plus nivolumab in IMDC intermediate and poor risk patients. The RCC Guidelines Panel continues to recommend these tyrosine kinase inhibitors + immunotherapy (IO) combination across IMDC risk groups in advanced first-line RCC and dual immunotherapy of ipilimumab and nivolumab in IMDC intermediate and poor risk. Patient summaryNew data from trials of immune checkpoint inhibitors for advanced kidney cancer confirm a survival benefit with the combination of cabozantinib plus nivolumab and pembrolizumab plus axitinib and ipilimumab plus nivolumab. These combination therapies are recommended as first-line treatment for advanced kidney cancer.

Multidisciplinary Management of Advanced Kidney Cancer

A number of therapeutic options are available for the treatment of advanced kidney cancer, including targeted therapy, immunotherapy, and nephrectomy. Choice of therapy for advanced kidney cancer is guided by risk stratification. Immunotherapy combinations are generally superior to vascular endothelial growth factor -based monotherapy, and overall survival rates continue to increase substantially. With new systemic therapy options, additional improvements have been noted in durable responses to treatment and in quality of life. Nephrectomy remains an important consideration in selected patients, particularly those with minimal burden of metastatic disease. Managing the adverse events of treatment of advanced kidney cancer requires close attention and multidisciplinary collaboration.

Adding Immunotherapy to Standard Treatment of Advanced Kidney Cancer

Adding Immunotherapy to Standard Treatment of Advanced Kidney Cancer

HPLC method development and validation for the estimation of Axitinib in rabbit plasma

A rapid, sensitive, and accurate high performance liquid chromatography for the determination of axitinibe (AN) in rabbit plasma is developed using crizotinibe as an internal standard (IS). Axitinibe is a tyrosine kinase inhibitor, used in the treatment of advanced kidney cancer, which works by slowing or stopping the growth of cancer cells. The chromatographic separation was performed on a Waters 2695, Kromosil (150 mm × 4.6 mm, 5 µm) column using a mobile phase containing buffer (pH 4.6) and acetonitrile in the ratio of 65:35 v/v with a flow rate of1 mL/min. The analyte and internal standard were extracted using liquid-liquid extraction with acetonitrile. The elution was detected by photo diode array detector at 320 nm.The total chromatographic runtime is 10.0 min with a retention time for axitinibe and IS of 5.685, and 3.606 min, respectively. The method was validated over a dynamic linear range of 0.002-0.2µg/mL for axitinibe with a correlation coefficient of r2 0.999.

Clinical outcome of patients who reduced sunitinib or pazopanib during first-line treatment for advanced kidney cancer

ObjectivesTo investigate the different outcomes in patients with metastatic renal cell carcinoma (mRCC) who receive a reduced first-line dose of sunitinib or pazopanib compared to those who continue at the standard dose. Patients and methodsAll the patients treated in 11 oncological centers in Italy for mRCC who started first-line treatment with sunitinib or pazopanib at the standard dose. Descriptive statistical tests were used to highlight differences among groups. Survival was estimated by the Kaplan-Meier method and compared across the groups using log-rank tests, the Cox proportional hazards model adjusted for statistically significant variables was also done. ResultsA total of 591 patients were included in the study. Of these, 45.7% received a reduced dose of sunitinib or pazopanib after a median treatment time of 3.6 months at the standard dose. The median overall survival in the patients who continued to receive the standard dose was 24.0 months compared to 49.4 months for those who received a reduced dose (hazard ratio = 1.80; 95% CI: 1.42–2.29; P<0.001).Only 45% of the patients received second-line therapy: 42.5% had an mTOR and 54.1% a tyrosine kinase inhibitor. Second-line overall survival was 19.8 and 11.8 months, respectively, in the patients who received, or did not, a reduced dose during first-line therapy (P = 0.007). ConclusionsToxicity-related dose reduction is a common event in mRCC patients who have started first-line therapy with either sunitinib or pazopanib. This is positively related to the outcomes of both first- and second-line therapy.

Révision de l’index thérapeutique des thérapies ciblées dans le cancer du rein : le mieux peut-il être l’ennemi du bien ? La toxicité peut-elle prédire l’efficacité ?

Since 2006, new treatments as targeted therapies (anti angiogenic and mTOR inhibitors) are prescribed in renal cell cancer. Toxicity of these treatments is well known by clinicians. Occurrence of these side effects has been associated with anti tumoral efficacy. High blood pressure, hypothyroïdie and hand foot syndrome were reported to be predictive of anti tumoral response. Fatigue and hyponatremia are still largely discussed. Moreover, non infectious pneumonia, which frequently occurs with mTOR inhibitors, is associated with clinical benefit. The main objective of treatment of advanced kidney cancer, specially renal cell cancer, is obtaining clinical benefit (stabilization and response) with a chronic evolution of the disease. This prolong exposure to drugs, according to their toxicity profile, often contributes to dose reduction, moreover interruption of treatment, potentially associated with a loss of control of disease. Thus, the adverse effects, described hereby, may be considered as « positive events », predicting efficacy, and thus looked for… Moreover, the sequential approach, with new drugs, emphasizes the need of defining the optimal sequence. Thus, because of the lack of molecular biomarkers to date, this predictives secondary effects may help for selecting the therapeutic strategy.

Carbonic Anhydrase 9 Expression Increases with Vascular Endothelial Growth Factor–Targeted Therapy and Is Predictive of Outcome in Metastatic Clear Cell Renal Cancer

BackgroundThere is a lack of biomarkers to predict outcome with targeted therapy in metastatic clear cell renal cancer (mccRCC). This may be because dynamic molecular changes occur with therapy. ObjectiveTo explore if dynamic, targeted-therapy-driven molecular changes correlate with mccRCC outcome. Design, setting, and participantsMultiple frozen samples from primary tumours were taken from sunitinib-naïve (n=22) and sunitinib-treated mccRCC patients (n=23) for protein analysis. A cohort (n=86) of paired, untreated and sunitinib/pazopanib-treated mccRCC samples was used for validation. Array comparative genomic hybridisation (CGH) analysis and RNA interference (RNAi) was used to support the findings. InterventionThree cycles of sunitinib 50mg (4 wk on, 2 wk off). Outcome measurements and statistical analysisReverse phase protein arrays (training set) and immunofluorescence automated quantitative analysis (validation set) assessed protein expression. Results and limitationsDifferential expression between sunitinib-naïve and treated samples was seen in 30 of 55 proteins (p<0.05 for each). The proteins B-cell CLL/lymphoma 2 (BCL2), mutL homolog 1 (MLH1), carbonic anhydrase 9 (CA9), and mechanistic target of rapamycin (mTOR) (serine/threonine kinase) had both increased intratumoural variance and significant differential expression with therapy. The validation cohort confirmed increased CA9 expression with therapy. Multivariate analysis showed high CA9 expression after treatment was associated with longer survival (hazard ratio: 0.48; 95% confidence interval, 0.26–0.87; p=0.02). Array CGH profiles revealed sunitinib was associated with significant CA9 region loss. RNAi CA9 silencing in two cell lines inhibited the antiproliferative effects of sunitinib. Shortcomings of the study include selection of a specific protein for analysis, and the specific time points at which the treated tissue was analysed. ConclusionsCA9 levels increase with targeted therapy in mccRCC. Lower CA9 levels are associated with a poor prognosis and possible resistance, as indicated by the validation cohort. Patient summaryDrug treatment of advanced kidney cancer alters molecular markers of treatment resistance. Measuring carbonic anhydrase 9 levels may be helpful in determining which patients benefit from therapy.

Les médicaments du cancer du rein

To describe drugs used in renal cell carcinoma. Pubmed search for efficacy, mode of action and side effects for each molecule. Additional data were searched from the French regulatory agencies websites (HAS and ANSM). Since 2007, a total of three different therapeutic classes in the management of metastatic renal cell carcinoma are available. These three classes are tyrosine kinase inhibitors with sunitinib and sorafenib, the anti-VEGF antibodies (bevacizumab which is associated with alpha interferon in the treatment of advanced kidney cancer) and mTOR inhibitors with temsirolimus and everolimus. These targeted therapies are a major progress in the treatment of patients with metastatic kidney cancer. The side effects encountered with these molecules are numerous but serious side effects are less than 5% of all reported side effects. A better understanding of molecular mechanisms has enabled the development of new therapies for the treatment of metastatic renal cell carcinoma. In the future, a personalized approach taking into account the biology of each tumor could be created to provide a more targeted treatment.

Clinical controlled trial of first-line treatment for advanced kidney cancer

To estimate the efficacies of different first-line treatments for advanced stage kidney cancer. For this observation controlled trial, a total of 82 cases with advanced stage kidney cancer from 2006 to 2011 were recruited. They were divided into 3 groups and accepted gemcitabine plus interleukin-2 (IL-2) (Group A), oxaliplatin plus capecitabine (Group B) or sorafenib alone (Group C). Among them, 76 patients had complete data. The overall response rates of A-C groups were 39.3% (11/28), 37.0% (10/27) and 38.1% (8/21) respectively. And there was no significant difference (χ(2) = 0.029, P = 0.986). And their progression-free survival (PFS) rates were 9.1 (95%CI: 7.9 - 10.3), 7.5(95%CI: 5.5 - 9.5) and 10.9 (95%CI: 10.5 - 11.3) months respectively. And there were significant differences (P = 0.013). Average daily treatment costs were 490, 498 and 501 Chinese yuan respectively. And there was no significant difference (P = 1.240). Because of toxicity, 2 and 3 cases withdrew in Groups A and B respectively. Gemcitabine plus IL-2 and oxaliplatin plus capecitabine have similar early efficacies and tolerance profiles for the patients who can not accept sorafenib as first-line treatment.

Sorafenib tosylate for advanced kidney cancer: lucky loser and magic box at the same time

Despite being the very first molecular targeted agents registered for the treatment of advanced kidney cancer (in the post-cytokines setting), Sorafenib seemed to lose its momentum as a credible first-line treatment option, when it proved not to be superior to Interferon within a randomized phase II trial...

Sorafenib tosylate for advanced kidney cancer: lucky loser and magic box at the same time

Despite being the very first molecular targeted agents registered for the treatment of advanced kidney cancer (in the post-cytokines setting), Sorafenib seemed to lose its momentum as a credible first-line treatment option, when it proved not to be superior to Interferon within a randomized phase II trial...

Sorafenib tosylate for advanced kidney cancer: lucky loser and magic box at the same time

Despite being the very first molecular targeted agents registered for the treatment of advanced kidney cancer (in the post-cytokines setting), Sorafenib seemed to lose its momentum as a credible first-line treatment option, when it proved not to be superior to Interferon within a randomized phase II trial...

Is Immunotherapy Re-Entering the Kidney Cancer Arena from the Back Door? Considerations from the Phase I/II Study of Siltuximab

Evaluation of: Rossi JF, Negrier S, James ND et al.: A Phase I/II study of siltuximab (CNTO 328), an anti-interleukin-6 monoclonal antibody, in metastatic renal cell cancer. Br. J. Cancer 103, 1154-1162 (2010). For years, immunotherapy was the mainstay of treatment for advanced kidney cancer. The recent development of molecularly targeted agents, and of antiangiogenic agents in particular, has completely changed this scenario, leaving immunotherapy with a minor role in treatment, if any. Recent insights in the mechanisms of resistance to these drugs suggest that the immune system could play a relevant role. In particular, IL-6 appears to cooperate with other growth factors in the recruitment of bone marrow-derived immune cells, ultimately leading to resistance to antiangiogenic agents. Furthermore, it is now clear that monoclonal antibodies actively interact with the immune system and show significant immune-modulating effects per se. Further translation research on this issue is much needed.

Uncovering Pandora’s vase: the growing problem of new toxicities from novel anticancer agents. The case of sorafenib and sunitinib

As newer, molecularly targeted, anticancer drugs are entering clinical practice, a wide array of previously unrecognised and ill defined side effects of these drugs are increasingly observed. Sorafenib and sunitinib are two of these novel agents, acting on tumour angiogenesis as well as on other key proliferative pathways; recently approved for the treatment of advanced kidney cancer, they may cause peculiar cutaneous, vascular and mucosal toxicities, including hand-foot skin reaction, skin rash, hypertension and GERD-like oesophagitis/gastritis. In this review, we shall deal with these poorly recognised, but sometimes extremely distressing, toxicities; pathophysiologic mechanisms will be discussed and suggestions for treatment of each toxicity will be proposed, based on the few pieces of evidence available and, especially, on our empirical experience.