Chemoresistance of renal cell carcinoma: 1986-1994

Multidrug resistance (MDR) in a variety of human tumors such as renal cell carcinoma (RCC) is thought to be caused by expression of the mdr1 gene and may be reversed by applying chemosensitizers such as Dexverapamil that inhibit the mdr1 gene product P-glycoprotein. On the basis of our preclinical analysis, we inititated a clinical (GCP) study with vinblastine (VBL), the most effective - if at all - chemotherapeutic agent; dexverapamil; and dexamethasone in patients with RCC. All patients had histologically proven RCC that was metastatic and progressive at study entry. The statistical design featured a preliminary study of two cycles of VBL alone followed by tumor evaluation. If no response was documented, with all patients thus serving as their own control, dexverapamil and dexamethasone were added for a minimum of three cycles of combination therapy. Having obtained institutional permission by the ethical review committee (MEC 124, 106-1993/12), we enrolled 24 patients on this protocol starting on May 3, 1993. In the preliminary study, 1 complete response (CR) was achieved with VBL alone, and myelotoxicity led to an adequate dose reduction from 2 mg/m2 VBL per day given as a 5-day continuous infusion (days 1-5) in 6/10 yet evaluable patients to 1.4 mg/m2 per day. In 8/11 yet evaluable patients, dexverapamil doses reached ≥3000 mg/day by 7-day oral uptake (days 0-6, supported by 20 mg dexamethasone given twice daily), which is significantly higher than those previously reported. The combination of VBL given at 1.4 mg/m2 per day plus, dexverapamil given at 3000 mg per day was felt to be safe and well tolerated. Nine patients were yet evaluable for response. One partial response and three minor responses were noted in this heavily pretreated study population. It appears that this innovative approach may have some activity in RCC and may eventually lead to a rational treatment modality. Careful evaluation in ongoing studies is warranted

Recurrence after radical prostatectomy for organ-confined prostate cancer

Background: Some patients from our radical prostatectomy (RPx) series with organ-confined (pT2) prostate cancer and negative surgical margins show a PSA (prostate specific antigen) relapse. Aim of the study was to analyze this cohort of patients that otherwise would have been considered to be cured. Patients and Methods: Since the introduction of PSA measurement in the follow-up after RPx, 475 pelvic lymph node dissections with subsequent RPx were performed in our department from 1988 to 1997. Of these, 227 were classified as pT2, 34 (15%) exhibited positive surgical margins, and 4 others were excluded due to an inadequate follow-up. Of the remaining 189 patients (study cohort), 19 (10%) developed a biochemical progression, defined as a minimum of 2 consecutive PSA measurements ≥ 0.1 ng/ml. Only in one of them a G3 tumor was present. Median follow-up was 19.1 months. Results: The Kaplan-Meier analysis of biochemical progression showed that after 1, 2 and 5 years, 95% (confidence interval (Cl) 91-99%), 91% (Cl 86-96%), and 77% (Cl 55-89%) of the patients were free of progression, respectively. This means that roughly one fourth of pT2 tumors will become progressive despite negative surgical margins. These 19 patients were subdivided into 4 groups: 1: biopsy-proven local recurrence (n = 2); 2: suspected local recurrence defined as slowly rising PSA ≤ 2 ng/ml, but negative biopsies (n = 12); 3: distant metastasis proven by radiologic imaging (n = 1); 4: suspected distant metastasis defined as rapidly rising PSA > 9 ng/ml without direct radiologic evidence (n = 4). Preoperatively all patients from groups 3 + 4 had negative bone scans and 4/5 had preoperative PSA values < 10 ng/ml. In total 7 patients with proven recurrence or with proven metastasis had positive biopsies. Conclusion: A pathological diagnosis of organ-confined prostate cancer (pT2) and a meticulous analysis of negative surgical margins do not exclude the occurrence of local relapses in 7% (14/189), and there is evidence for suspect hematogenic spread of PC cells in at least 2% (4/189) of patients

Costs of managing adverse events in the treatment of first-line metastatic renal cell carcinoma: Bevacizumab in combination with interferon-α2a compared with sunitinib

Background: Bevacizumab plus interferon-α2a (IFN) prolongs progression-free survival to>10 months, which is comparable with sunitinib as first-line treatment of metastatic renal cell carcinoma (RCC). The two regimens have different tolerability profiles; therefore, costs for managing adverse events may be an important factor in selecting therapy.Methods: Costs of managing adverse events affecting patients with metastatic RCC eligible for treatment with bevacizumab plus IFN or sunitinib were evaluated using a linear decision analytical model. Management costs were calculated from the published incidence of adverse events and health-care costs for treating adverse events in the United Kingdom, Germany, France and Italy.Results: Adverse event management costs were higher for sunitinib than for bevacizumab plus IFN. The average cost per patient for the management of grade 3-4 adverse events was markedly lower with bevacizumab plus IFN compared with sunitinib in the United Kingdom (\[euro]1475 vs \[euro]804), Germany (\[euro]1785 vs \[euro]1367), France (\[euro]2590 vs \[euro]1618) and Italy (\[euro]891 vs \[euro]402). The main cost drivers were lymphopaenia, neutropaenia, thrombocytopaenia, leucopaenia and fatigue/asthaenia for sunitinib; and proteinuria, fatigue/asthaenia, bleeding, anaemia and gastrointestinal perforation for bevacizumab plus IFN.Conclusion: The costs of managing adverse events are lower for bevacizumab plus IFN than for sunitinib. The potential for cost savings should be considered when selecting treatments for RCC

Dexverapamil to modulate vinblastine resistance in metastatic renal cell carcinoma

Multidrug resistance (MDR) in a variety of human tumours such as renal cell carcinoma (RCC) is thought to be caused by expression of the MDR1 gene and may be reversed by applying modern chemosensitisers such as dexverapamil, which inhibit the MDR1 gene product P-glycoprotein. This preliminary report gives information on a clinical study complying with good clinical practice regulations in patients with advanced RCC. The final evaluation is pending. Vinblastine, if anything the most effective chemotherapeutic agent (5-day continuous regimen), was combined with oral dexverapamil (6 times per day) as a chemosensitiser and dexamethasone to increase dexverapamil tolerance. All patients had histologically proven RCC, which was metastatic and progressive at study entry. The statistical design featured a pre-study regimen of two cycles of vinblastine alone followed by evaluation. If no response was documented, with all patients thus serving as their own control, dexverapamil and dexamethasone were added for three cycles of combination therapy. Having obtained institutional permission from the ethical review committee, we enrolled patients of whom 25 qualified for the combined-treatment arm; 13 patients finished the study, 5 patients failed to complete all treatment cycles (1 because of treatment-related toxicity, 3 for personal reasons, not related to treatment, 1 for tumour-related reasons) and 7 patients were at too early a stage for evaluation. Altogether, 61% of all patients tolerated a dose of dexverapamil of at least 2400 mg/day with peak serum levels reaching, in some cases, approximately 8 μM (the sum of dexverapamil plus nordexverapamil levels). WHO grade 3 and 4 toxicities were mainly myelosuppression (5/18). The combination of 1.4 mg m-2 day-1 vinblastine plus dexverapamil was generally felt to be safe and well tolerated. One partial response and 7 stable diseases were noted in this heavily pretreated study population. Four-hourly administration of dexverapamil in combination with dexamethasone plus escalation to the individually tolerated doses have permitted increases in serum levels of dexverapamil