Treatment Of Metastatic Renal Carcinoma Research Articles

Cost-Effectiveness Analysis of Treatment for Metastatic Renal Carcinoma in Romania.

Rationale: In recent years, the cost of several treatment options for renal cancer have been supported by the Romanian healthcare system for both first- and second-line therapies. First-line alternatives through real-life efficacy and amplitude of adverse reactions may influence the efficacy and costs of patients treated with second-line treatment.Objective: Estimation of the cost-effectiveness and cost-benefit ratio for first-line treatment alternatives: Sunitinib and Pazopanib from the payer’s perspective in the Romanian healthcare system.Methods and Results: We developed a Markov model to calculate the cost-effectiveness and cost-benefit ratio for 2 cohorts of patients using the results from the COMPARZ study for efficacy (progression-free survival, general survivability and quality of life) and safety and costs from national hospital databases. For an estimated population of 800 patients, Pazopanib has a quantified benefit of 7.19 years in progression-free survival, 11.71 life years gained and 8.97 years of quality-adjusted life-years compared to Sunitinib. The analysis is limited by the accuracy of the national data used and the transposition of general data on efficacy and safety at the local level.

In Vitro Antitumor Effects of AHR Ligands Aminoflavone (AFP 464) and Benzothiazole (5F 203) in Human Renal Carcinoma Cells.

We investigated activity and mechanism of action of two AhR ligand antitumor agents, AFP 464 and 5F 203 on human renal cancer cells, specifically examining their effects on cell cycle progression, apoptosis, and migration. TK-10, SN12C, Caki-1, and ACHN human renal cancer cell lines were treated with AFP 464 and 5F 203. We evaluated cytotoxicity by MTS assays, cell cycle arrest, and apoptosis by flow cytometry and corroborated a mechanism of action involving AhR signal transduction activation. Changes in migration properties by wound healing assays were investigated: 5F 203-sensitive cells show decreased migration after treatment, therefore, we measured c-Met phosphorylation by Western blot in these cells. A 5F 203 induced a decrease in cell viability which was more marked than AFP 464. This cytotoxicity was reduced after treatment with the AhR inhibitor α-NF for both compounds indicating AhR signaling activation plays a role in the mechanism of action. A 5F 203 is sequestered by TK-10 cells and induces CYP1A1 expression; 5F 203 potently inhibited migration of TK-10, Caki-1, and SN12C cells, and inhibited c-Met receptor phosphorylation in TK-10 cells. AhR ligand antitumor agents AFP 464 and 5F 203 represent potential new candidates for the treatment of renal cancer. A 5F 203 only inhibited migration of sensitive cells and c-Met receptor phosphorylation in TK-10 cells. c-Met receptor signal transduction is important in migration and metastasis. Therefore, we consider that 5F 203 offers potential for the treatment of metastatic renal carcinoma. J. Cell. Biochem. 118: 4526-4535, 2017. © 2017 Wiley Periodicals, Inc.

Hyponatremia and thrombocytopenia associated with sorafenib treatment for renal carcinoma: an alert of an adverse event

To date, the manufacturer of sorafenib has reported that the hyponatremia and thrombocytopenia associated with its use are generally moderate and tolerable and have resulted in no mortalities. In this article we describe a Japanese patient with severe hyponatremia and thrombocytopenia that were likely related to sorafenib treatment for metastatic renal carcinoma. Oncologists should be aware of hyponatremia and thrombocytopenia as an adverse effect related to this agent.

Preclinical efficacy data of MGN1601, a tumor vaccine comprising 4-fold gene-modified and irradiated allogeneic tumor cells in combination with a DNA-based immunomodulator for the treatment of metastatic renal carcinoma.

e15067 Background: MGN1601 is a cell-based tumor vaccine for the treatment of mRCC. MGN1601 consists of two active pharmaceutical ingredients. One consists of allogeneic, human tumor cells, derived from RCC tissue, and transfected in-vitro with four different MIDGE vectors for transient expression of human IL-7, GM-CSF, CD80 and CD154. The other ingredient is the DNA-based immunomodulator dSLIM-30L1, mainly a TLR-9 agonist. Methods: Murine tumor models were used to evaluate the efficacy of a murine homologue of MGN1601 (mMGN1601). mMGN1601 was set up from Renca cells and transfected with 4 different MIDGE vectors for transient expression of mouse IL-7, GM-CSF, CD80 and CD154. For tumor inoculation in syngenic BALB/c mice Renca cells were used. For efficacy of the vaccine in a prophylactic setting, mice were vaccinated with mMGN1601 and thereafter challenged with Renca cells. In therapeutic settings Balb/c mice first received naïve Renca cells and were subsequently vaccinated four times with different test items, either the complete mMGN1601 or one out of three lacking different components. To address the mode of action, modulations of the immune system were monitored in NMRI mice (allogeneic setting). Results: Prophylactic setting: None of the vaccinated mice showed tumor growth, whereas all of the tumor-bearing mice of the control group died due to the tumor growth. Efficacy evaluation in the therapeutic setting revealed, that the complete tumor vaccine clearly achieved the most pronounced effects in tumor reduction, showing a survival of 92%, compared to 25% survival in the control group. The incomplete derivatives led to less pronounced therapeutic efficacy. The immunomodulatory effects of mMGN1601 in allogeneic NMRI mice generated a more than 3-fold increase of the cytotoxic activity of spleen cells, an augmented T-cell proliferation (> 6-fold) and an increase of CD4+, CD8+ and CD86+ cells at the site of vaccination (up to 20-fold). Conclusions: The murine homologue of MGN1601 showed excellent antitumor efficacy and significant pharmacological effects in murine models. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration MOLOGEN AG MOLOGEN AG MOLOGEN AG

822. Preclinical Efficacy Data of MGN1601, a Tumor Vaccine Comprising 4-Fold Gene-Modified and Irradiated Allogeneic Tumor Cells in Combination with a DNA-Based Immunomodulator for the Treatment of Metastatic Renal Carcinoma

822. Preclinical Efficacy Data of MGN1601, a Tumor Vaccine Comprising 4-Fold Gene-Modified and Irradiated Allogeneic Tumor Cells in Combination with a DNA-Based Immunomodulator for the Treatment of Metastatic Renal Carcinoma

Temsirolimus for advanced renal cell carcinoma (RCC): Compassionate versus commercial use

16139 Background: Temsirolimus, a specific inhibitor of the mammalian target of rapamycin kinase, has been approved on May 31st, 2007 for treatment of metastatic renal carcinoma based on a study which showed improved survival compared to interferon among patients with metastatic renal cell carcinoma and poor risk features. Methods: In this single institution study, we have treated 15 patients (8 patients on compassionate use and 7 patients on commercial use). All patients had prior nephrectomy and received prior systemic immunotherapy and (or) chemotherapeutic agents (sutent, sorafenib, avastin, gemzar, HDIL2, interferon, AG 013736, Adriamycin). 93% of the patients had at least 3 of the 6 predictors of poor prognosis for RCC. Temsirolimus was administered as 25 mg I.V infusion weekly. The primary end point was overall survival. Results: Patients in commercial group of temsirolimus use had a better performance status and had received less number of prior systemic treatments and received more doses of temsirolimus and had a median survival of 4+ months still continuing (range 2 to 6+ months) compared to compassionate group with a median survival of 2.5 months (range 30 days to 8 months). 1 patient from each group had to discontinue the study due to the rapid progression of the disease. 1 patient from each group had stable disease for 18+ weeks still continuing. No lethal toxicities observed in these patients. Conclusion: Patients who received less number of prior systemic treatments received more doses of temsirolimus and had a prolonged survival. Baseline patient characteristics Patient Characteristics (M- Median, R- Range) Compassionate group (8) Commercial group (7) M/F 5/3 3/4 Age M 60 56 R 39-78 39-81 Time from Dx to Rx M 5 yrs 4 yrs R 3-24 yrs 2-16 yrs # Prior Rx # Cycles M 20 15 R 3–23 1-29 # Agents M 4 2 R 1-9 1-7 Performance status M 3 2 R 1-4 1-3 Median survival M 2.5 months 4+ months R 1-8 months 2-6+ months Time from last Rx to temsirolimus M 75 days 15 days R 15 days-2 yrs 10 days-1.5 yrs No. of temsirolimus doses M 7 8+ R 2-25 5-15+ Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Bayer, Genentech™ BioOncology, Novartis, Onyx, Pfizer Oncology, Wyeth Bayer, Novartis, Onyx, Pfizer Oncology, Wyeth Bayer, Genentech™ BioOncology, Novartis, Onyx, Pfizer Oncology, Wyeth

Interleukin-2 mutants with enhanced alpha-receptor subunit binding affinity.

Stimulation of T-cells by IL-2 has been exploited for treatment of metastatic renal carcinoma and melanoma. However, a narrow therapeutic window delimited by negligible stimulation of T-cells at low picomolar concentrations and undesirable stimulation of NK cells at nanomolar concentrations hampers IL-2-based therapies. We hypothesized that increasing the affinity of IL-2 for IL-2Ralpha may create a class of IL-2 mutants with increased biological potency as compared with wild-type IL-2. Towards this end, we have screened libraries of mutated IL-2 displayed on the surface of yeast and isolated mutants with a 15-30-fold improved affinity for the IL-2Ralpha subunit. These mutants do not exhibit appreciably altered bioactivity at 0.5-5 pM in steady-state bioassays, concentrations well below the IL-2Ralpha equilibrium binding constant for both the mutant and wild-type IL-2. A mutant was serendipitously identified that exhibited somewhat improved potency, perhaps via altered endocytic trafficking mechanisms described previously.

Interferon-α and survival in metastatic renal carcinoma: early results of a randomised controlled trial

BACKGROUND: Metastatic renal carcinoma has a 2-year survival of around 20% and is largely resistant to chemotherapy. The use of interferons in the treatment of metastatic renal carcinoma remains controversial. Although non-randomised studies suggest that biological therapy with interferons produces a small number of tumour responses, most clinicians judge such treatment to be ineffective. We have investigated the effect of treatment with interferon-alpha on survival in patients with metastatic renal carcinoma. METHODS: In a multicentre, randomised trial, patients with metastatic renal carcinoma were randomly assigned subcutaneous interferon-alpha (three doses--5 MU, 5 MU, 10 MU--for the first week, then 10 MU three times per week for a further 11 weeks; n=174) or oral medroxyprogesterone acetate (MPA; 300 mg once daily for 12 weeks; n=176). The primary endpoint was overall survival. Analysis was by intention to treat. The trial used a triangular sequential design for early termination as soon as results were conclusive. The trial was stopped in November, 1997, when data were available for 335 patients (167 interferon-alpha, 168 MPA). FINDINGS: A total of 111 patients have died in the interferon-alpha group, and 125 patients have died in the MPA group. There was a 28% reduction in the risk of death in the interferon-alpha group (hazard ratio 0.72 [95% CI 0.55-0.94], p=0.017). Interferon-alpha gave an improvement in 1-year survival of 12% (MPA 31% survival, interferon-alpha 43%), and an improvement in median survival of 2.5 months (MPA 6 months, interferon-alpha 8.5 months). INTERPRETATION: The benefit of treatment with interferon-alpha should be weighed against the drug's toxic effects. Combination regimens of biological therapy and chemotherapy should now be compared with interferon-alpha monotherapy in randomised controlled trials.

Cyclic Interferon Gamma Treatment of Patients with Metastatic Renal Carcinoma

The treatment of metastatic renal carcinoma is still unsatisfactory because of the lack of effective systemic therapy. In 14 patients with metastatic renal carcinoma an attempt was made to influence the course of the disease by administration of recombinant human interferon (rHu-IFN) gamma; 9 patients were evaluated after treatment. There was partial remission in 3 patients, stable disease in 2 and tumour progression in 4. The cyclic application of rHu-IFN at a dose of 0.25 mg/day for 8 days, with treatment-free intervals of 3 to 4 weeks, was tolerated well. Side effects consisted mainly of fever and leucocytopenia. From this small series it seems that cyclic IFN gamma treatment might be helpful in some cases of metastatic renal carcinoma.

Unexplained spontaneous regression and alpha-interferon as treatment for metastatic renal carcinoma.

A series of 73 patients with measurable metastatic disease referred to a tertiary referral centre for consideration for an experimental treatment protocol were entered into a surveillance protocol in order to establish the incidence of spontaneous regression. Initially, patients were taken off the study if metastases showed greater than 25% increase in products of bidimensional measurement but with increasing confidence patients went into therapy protocols only following the development of symptomatic progression. We observed 3 complete and 2 partial unexplained spontaneous regressions and a further 4 patients had prolonged stable disease for more than 12 months. A group of 21 patients on progression subsequently received treatment with alpha-interferon (Wellferon) as part of a multicentre study which included an additional 61 cases; 12 responded (3 surveillance relapse patients and 9 others). Patients with lung metastases only had the highest response rate (10/17 compared with 5 unexplained responses seen in 38 such patients on surveillance). These results confirm that alpha-interferon is active against metastatic renal carcinoma and that the responses are not totally explicable by spontaneous regression.

Principles of biotherapy and its application to the treatment of disseminated renal cancer.

Monoclonal antibody technology permits the preparation of tumor-specific immunoglobulin reagents that can be used directly in tumor therapy or that can be coupled to various chemotherapeutic drugs or toxins to aid in their delivery to the tumor site and thus enhance their therapeutic effectiveness. Additionally, recombinant DNA technology has facilitated the economic production of rare lymphokines (e.g., interleukin 2, interferon alpha and interferon gamma) or cytokines (tumor necrosis factor, lymphotoxin) that can either modulate the host immune response or kill tumor cells, respectively. These developments collectively have led to the development of a fourth modality for treatment of human cancers--biotherapy--as an addition to surgery, radiation, and chemotherapy modalities. This paper presents the rationale and emerging practice of the biotherapy of cancer and documents early clinical results, including the treatment of metastatic renal carcinoma at the Biological Therapy Institute.

Treatment of metastatic renal cell carcinoma with coumarin (1,2-benzopyrone) and cimetidine: a pilot study.

Forty-five patients with metastatic renal cell carcinoma were treated with coumarin (1,2-benzopyrone) and cimetidine. Patients received coumarin, 100 mg orally daily; cimetidine administration, 300 mg orally four times daily, was initiated on day 15 of therapy, and treatment with both drugs was continued until progression of disease. Three patients are too early to evaluate (on study less than or equal to 2 months with no change in tumor status). Objective responses (greater than or equal to 50% reduction in measurable disease) occurred in 14 of 42 evaluable patients (33.3%) (the 95% confidence interval based on this rate is +/- 14.3%), with three complete responses and 11 partial responses (PR). Complete responses lasted 9.5, 4+, and 9.5+ months. The median duration of response for the PR group was 5 months (range, 4 to 21+ months). Twelve patients experienced stabilization of disease ranging from 4 to 16.5+ months. No response was seen in 16 patients. There was no symptomatic, hematologic, or chemical (organ dysfunction) toxicity among the 45 patients treated. Coumarin and cimetidine appear to be safe and active agents in the treatment of metastatic renal carcinoma. Further studies are required to determine the optimal dose and scheduling of these agents.

Estramustine phosphate (Emcyt) as treatment for metastatic renal carcinoma

Sixteen patients completed an adequate trial of estramustine phosphate for the management of metastatic renal cell carcinoma. Although no patient showed a complete or partial response, 9 (56 per cent) had stabilization of disease for a median of 44 weeks. Toxicity was not severe, but intolerance to the drug may limit its widespread use.

The Role of Embolization and Nephrectomy in the Treatment of Metastatic Renal Carcinoma

The Role of Embolization and Nephrectomy in the Treatment of Metastatic Renal Carcinoma

Evaluation of chemotherapeutic agents in a new murine renal carcinoma model.

Vinblastine and 1-(2-chlorethyl)-3-cyclohexyl-1-nitrosourea (CCNU) were evaluated in a murine renal cell carcinoma model. Both drugs significantly decreased tumor weight and the percentage of distant metastases and very significantly prolonged the survival of tumor-bearing animals. Both also exhibited a dose-related effect. The therapeutic index of vinblastine was limited by signs of systemic toxicity, while the dosage of CCNU might have been limited by its tendency to suppress host immune response to tumor, based on observations of this renal tumor model. Vinblastine may prove clinically useful in early or prophylactic treatment of resected renal tumors, whereas CCNU may be very useful in prolonging survival of patients with renal tumors which have already metastasized. Therefore, both drugs, either alone or combined, may have clinical value in the treatment of metastatic renal carcinoma. Vinblastine may serve best as initial postsurgical treatment, with the addition of CCNU if metastatic disease is documented or progressive. The 3 response criteria evaluated by this model were tumor growth, tumor spread, and prolongation of survival. These seemed most clinically relevant and this model appeared to resemble closely the clinical situation of disseminated renal cell carcinoma in man.