Abstract: Although the number of men presenting with metastatic prostate cancer has decreased significantly over the last several years, the death rate for those men is essentially unchanged. Effective treatments have not existed for prostate cancer progressing after androgen deprivation therapy until recently. Docetaxel based chemotherapy has demonstrated to extend patient survival in two large randomized studies. These studies have provided the impetus to combine docetaxel with novel biologic drugs to further consolidate the gains in long-term outcome. With the arrival of new therapies such as epothilone analogues, small molecule receptor tyrosine kinase inhibitors, monoclonal antibodies, bone-targeted drugs, antisense oligonucleotides, antiangiogenics drugs and endothelin receptor antagonists, the future of prostate cancer therapy appears promising.
Abstract: BACKGROUND: We evaluated the possible use of prostate-specific antigen doubling time (PSA-DT) before chemotherapy initiation as a surrogate marker of survival in hormone-refractory prostate cancer (HRPC) patients. PATIENTS AND METHODS: Data from 250 consecutive metastatic HRPC patients treated with chemotherapy between February 2000 and November 2006 were retrospectively analysed. At least three PSA assays were required within 3 months before chemotherapy. PSA-DT was calculated as ln 2 divided by the slope of the log PSA line, and the difference between two log PSA levels was divided by the time interval. The primary endpoint was overall survival (OS). Survival rates according to PSA-DT were stratified on chemotherapy regimen. Multivariate Cox regression analysis was performed to isolate the impact of PSA-DT on OS, controlling for associate prognostic covariates. RESULTS: Patients received docetaxel- (82%) or mitoxantrone-based chemotherapy. The median PSA-DT was 45 days (range 4.7-1108 days). There were 174 deaths (70%). The median survival was 16.5 months (95% confidence interval [CI] = 12.5-20.5) and 26.4 months (95% CI = 20.3-32.4) for patients with a PSA-DT < 45 and >/=45 days, respectively. In the multivariate setting, the adjusted hazard ratio (HR) was 1.39 (95% CI = 1.03-1.89; P = 0.04), stratified by chemotherapy regimen. CONCLUSION: A short PSA-DT before onset of chemotherapy in HRPC patients was associated with an increased risk of death. This could be useful as a stratification parameter in trials with new drugs in a metastatic setting.
Abstract: Induction treatments in non-small cell lung cancer are usually discussed. Long-term survival after surgery and resecability are enhanced in locally advanced cancers. Morbidity and mortality observed after surgery limit the use of these treatments, despite they depend on many other factors: comorbidities in patient, smoking status, cancer staging, and type of surgery. Right pneumectomy enhances this risk more than left pneumectomy or other limited resections allowed by neoadjuvant treatments, especially in case of downstaging.
Abstract: Despite an increasing number of antiemetic drugs available, nausea and vomiting (NV) remain a central problem during chemotherapy. Acute and delayed NV benefit most often from the combination of classical antiemetic (such as metoclopramide or metopimazin), corticosteroids and 5HT3 inhibitors (setrons). Since 2006, a new class of antiemetics are available, the NK1 inhibitors (aprepitant), which improve the control of NV in combination with setrons and corticosteroids. Anticipatory NV must be treated with benzodiazepines. Other causes of NV must be discussed in those patients, such as gastro intestinal or metabolic disorders, cancer evolution such as occlusion, brain metastases. A global approach is necessary to improve the quality of life all along the courses of chemotherapy, including somatic and psychologic aspects.
Abstract: PURPOSE: Mitoxantrone-corticosteroid is currently the standard palliative treatment in hormone-refractory prostate cancer (HRPC) patients. Recent clinical trials documented the high activity of the docetaxel-estramustine combination. We conducted a randomized phase II study to evaluate prostate-specific antigen (PSA) response (primary end point) and safety of two docetaxel-estramustine-prednisone (DEP) regimens and mitoxantrone-prednisone (MP). PATIENTS AND METHODS: One hundred thirty metastatic HRPC patients were randomly assigned to receive docetaxel (70 mg/m2 on day 2 or 35 mg/m2 on days 2 and 9 of each 21-day cycle) and estramustine (280 mg p.o. tid on days 1 through 5 and 8 through 12) or mitoxantrone 12 mg/m2 every 3 weeks; all patients received prednisone (10 mg daily). RESULTS: One hundred twenty-seven patients were assessable for PSA response and safety. A > or = 50% PSA decline was found in a greater percentage of patients in the docetaxel arms (67% and 63%) compared with MP (18%; P = .0001). Median time to PSA progression was five times longer with DEP than with MP (8.8 and 9.3 v 1.7 months, respectively; P = .000001). Overall survival was better in the docetaxel arms (18.6 and 18.4 months) compared with the MP arm (13.4 months), but not significantly so (P = .3). Crossover rates differed significantly among treatment arms (16%, 10%, and 48% in arms A, B, and C, respectively; P = .00001). Treatment-related toxicities were mild and mainly hematologic. CONCLUSION: The results of this randomized phase II study showed significantly higher PSA decline < or = 50% and longer times to progression in HRPC patients receiving DEP-based chemotherapy than MP, and that DEP could be proposed in this setting.
Abstract: PURPOSE: Onycholysis and skin toxicity occur in approximately 30% of patients treated with docetaxel. We investigated the efficacy and safety of an Elasto-Gel (84400 APT Cedex, Akromed, France) frozen glove (FG) for the prevention of docetaxel-induced onycholysis and skin toxicity. PATIENTS AND METHODS: Patients receiving docetaxel 75 mg/m2 alone or in combination chemotherapy were eligible for this case-control study. Each patient wore an FG for a total of 90 minutes on the right hand. The left hand was not protected and acted as the control. Onycholysis and skin toxicity were assessed at each cycle by National Cancer Institute Common Toxicity Criteria and documented by photography. Wilcoxon matched-pairs rank test was used. RESULTS: Between August 2002 and September 2003, 45 patients were evaluated. Onycholysis and skin toxicity were significantly lower in the FG-protected hand compared with the control hand (P = .0001). Onycholysis was grade (G) 0 in 89% v 49% and G1 to 2 in 11% v 51% for the FG-protected hand and the control hand, respectively. Skin toxicity was G0 in 73% v 41% and G1 to 2 in 27% v 59% for the FG-protected and the control hand, respectively. Median time to nail and skin toxicity occurrence was not significantly different between the FG-protected and the control hand, respectively (106 v 58 days for nail toxicity; 57 v 58 days for skin toxicity). Five patients (11%) experienced discomfort due to cold intolerance. CONCLUSION: FG significantly reduces the nail and skin toxicity associated with docetaxel and provides a new tool in supportive care management to improve a patient's quality of life.
Abstract: OBJECTIVE: To report our preliminary experience with trastuzumab (Herceptin) in the management of metastatic transitional cell carcinoma of the urinary tract. PATIENTS AND METHODS: From november 2001 to august 2002, six patients received trastuzumab for metastatic transitional cell carcinoma of the bladder (n=5) or renal pelvic cancer (n=1). Trastuzumab was administered as a first-line therapy in 2 patients, a second-line therapy in 3, and a third-line therapy in 1. Each patient received a weekly intravenous administration of trastuzumab (initial dose of 4 mg/kg, followed by 2mg/kg for other courses). A total of 6 courses was given. In 4 patients, trastuzumab was administered in association with paclitaxel (175 mg/m2) and carboplatin (area under the curve of 6). One patient received the same combination of trastuzumab and paclitaxel, but without carboplatin. The remaining patient received only trastuzumab. RESULTS: The trastuzumab-based regimen achieved partial regression of metastases in all patients. Initial regression of metastases varied between 30% and 80%. The therapy was well tolerated. Treatment-related toxicity was moderate in all patients, except for one who experienced transient grade 4 neutropenia. Five patients died from cancer. The interval between trastuzumab initiation and patient death ranged from 8 to 22 months. The remaining patient was still alive 28 months after trastuzumab initiation. CONCLUSIONS: Our preliminary data suggest that trastuzumab-based therapy may be safe and effective in metastatic transitional cell carcinoma of the urinary tract. Prospective trials are needed to further investigate this therapeutic option.
Abstract: The study of mitotic transduction of the signal showed that overexpression of pAkt and reduction in pERK expression would be associated a biological relapse. For tumors T1-3 N0M0 at the high risk of local relapse after prostatectomy, an immediate radiotherapy compared with a differed radiotherapy (at the time of PSA relapse), showed a significant reduction in the rate of local relapse and an ameliorated progression free survival. The effectiveness of the docetaxel was confirmed in two phase III randomized clinical trials : TAX-327 with 3 arms compared docetaxel every 21 days, docetaxel every 7 days and mitoxantrone. All arms were prednisone-based. An increase in overall survival, PSA progression free survival, PSA response rate and a pain reduction were highlighted in the docetaxel arm every 21 days. Docetaxel obtained at the end of this study the marketing authorization in this indication and became the treatment of reference. The SWOG 99-16 study compared the docetaxel estramustine association with the same arm of reference, mitoxantrone and prednisone, with similar results. The addition of estramustine to the docetaxel seems to improve the PSA response rate and progression free survival, but with a greater embolic toxicity. The addition of an antiangiogenic agent, the thalidomide, to docetaxel, improves progression free survival and overall survival. PSA responses were observed with an inhibitor of the proteasome, the bortezomib, in monotherapy, contrary to the imatinib which in monotherapy didn't have any effectiveness. Studies in association with docetaxel are ongoing. Some biological responses were observed with a vaccine anti MUC-1 and must be confirmed on a greater series of patients. The docetaxel impact on localized disease is actually evaluated.
Abstract: PURPOSE: Collecting duct carcinoma (CDC) of the kidney is a rare variant that is associated with an extremely poor prognosis. We report our experience with this variety of cancer in the last 9 years. MATERIALS AND METHODS: From 1993 to 2002, 9 patients with CDC were treated at our institution. The diagnosis of CDC was made by a nephrectomy specimen in 8 cases and by renal biopsy in 1. Tumor characteristics, and patient treatment and outcome are reported. RESULTS: At presentation 1 T1N0M0, 1 T3N0M0, 3 T3N+M0 and 4 T3N+M+ tumors were seen. Mean followup was 13.6 months. Five patients received no complementary treatment. The patient with the T1N0M0 tumor remained free of disease 13 months after nephrectomy and the one with T3N0M0 tumor remained free of disease at 17 months. A patient with a T3N+M+ tumor experienced progression at 1 month, local recurrence at 17 months and was then lost to followup. The 2 other patients with T3N+M0 and T3N+M+ disease, respectively, progressed rapidly and were lost to followup after 5 months. One patient with a T3N+M0 neoplasm received immunotherapy and died after 24 months, while the other with T3N+M0 disease was treated with oral prednisolone and died after 5 months. Finally, 2 patients with T3N+M+ disease received chemotherapy, consisting of 1,250 mg/m2 gemcitabine on days 1 and 8, and 70 mg/m2 cisplatin on day 1. Each patient achieved an objective response after 3 chemotherapy cycles and remained disease-free 27 and 9 months after nephrectomy, respectively. CONCLUSIONS: CDC is an aggressive variety of kidney neoplasm that is often associated with nodal and visceral metastases at presentation. Our data suggest that combined gemcitabine and cisplatin chemotherapy may be the best therapeutic option for patients with this tumor.
Abstract: Various subpopulations of T lymphocytes-i.e. Type 1, Type 2, Tr1 T cells-play a major role in the homeostasis of the immune system and in the pathogenesis of many inflammatory and auto-immune diseases. At present, in the absence of specific surface markers, these T cells can only be reliably distinguished on the basis of their cytokine production profile. The Elispot assay detects cytokine-producing cells, but in most cases can detect only one secreted cytokine, which represents a major limitation of this technique. We have developed a Fluorospot assay to detect single cells that simultaneously produce multiple cytokines. The Fluorospot assay permits the detection of regulatory T cells with an immunosuppressive activity, identified by their coexpression of IL-10 and IFNgamma. Polarized type 1 and type 2 specific tetanus toxoid T cells are also directly detected using a dual color Fluorospot. This technique will therefore be useful for detailed analysis of T lymphocytes in various disease states in which an imbalance of T cell subpopulations is suspected, but will also provide a better characterization of polarized specific immune responses.
