Gwenaelle Gravis

The use of estramustine phosphate in the modern management of advanced prostate cancer.

What’s known on the subject? and What does the study add?

Anticancer Activity and Tolerance of Treatments Received Beyond Progression in Men Treated Upfront with Androgen Deprivation Therapy With or Without Docetaxel for Metastatic Castration-naïve Prostate Cancer in the GETUG-AFU 15 Phase 3 Trial

BACKGROUND Androgen deprivation therapy (ADT) plus docetaxel is the standard of care in fit men with metastatic castration-naive prostate cancer (mCNPC) following results from GETUG-AFU 15, CHAARTED, and STAMPEDE. No data are available on the efficacy of treatments used for metastatic castration-resistant prostate cancer (mCRPC) in men treated upfront with ADT plus docetaxel for mCNPC. OBJECTIVE To investigate the efficacy and tolerance of subsequent treatments in patients treated upfront with chemo-hormonal therapy for mCNPC. DESIGN, SETTING, AND PARTICIPANTS Retrospective data from the GETUG-AFU 15 phase 3 trial were collected for treatments received for mCRPC. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS For the first three lines of salvage treatment for mCRPC we investigated the biochemical progression-free survival, maximum prostate-specific antigen (PSA) decline, overall survival, and tolerance. RESULTS AND LIMITATIONS Overall, 245 patients received at least one treatment for mCRPC. For docetaxel used in first-line, a PSA decline ≥50% was observed in 25/66 (38%) and in 4/20 patients (20%) who had received upfront ADT alone and ADT plus docetaxel (p=0.14). The median biochemical progression-free survival was 6.0 mo (95% confidence interval: 3.6-7.7) and 4.1 mo (95% confidence interval: 1.3-4.9), respectively. For docetaxel used in first- or second-line, a PSA decline ≥50% was observed in 36/80 (45%) and in 4/29 patients (14%) who had received upfront ADT alone and ADT plus docetaxel (p=0.07). PSA declines ≥50% were observed with bicalutamide in 12/28 (43%) and 4/23 patients (17%) who had received upfront ADT alone and ADT plus docetaxel. Among men treated upfront with ADT plus docetaxel who received abiraterone or enzalutamide for mCRPC, 10/19 patients (53%) achieved a PSA decline ≥50%. Few grade 3-4 events occurred. Study limitations include the observational design and retrospective characteristics of this analysis, without standardized therapeutic salvage protocols, and the limited number of patients in some of the treatment subgroups. CONCLUSIONS Docetaxel rechallenge following progression to mCRPC after upfront ADT plus docetaxel for mCNPC was active only in a limited number of patients. Available data on abiraterone and enzalutamide support maintained efficacy in this setting. The lack of standardized therapeutic protocols for men developing mCRPC limits the comparability between patients. PATIENT SUMMARY Rechallenging docetaxel at castration-resistance was active only in a limited number of patients treated upfront with chemo-hormonal therapy for metastatic castration-naive prostate cancer. Anticancer activity was suggested with abiraterone or enzalutamide in this setting.

Prise en charge des cancers de la prostate métastatiques hormonosensibles (CPMHS)

The prostate cancer in its hormone-sensitive metastatic presentation is infrequent, it is either an initial presentation of the disease or an evolution after local treatment, without castration of the biological relapse. The surgical or biological castration remains the cornerstone of the treatment. The deadline of castration initiation and its modalities of administration, intermittent or continuous rest debated but consensual on the initiation is the appearance of the symptomatic disease. The chemotherapy by docetaxel in association with the castration increases significantly the survival of the patients having a high tumoral volume. The efficacy on the whole metastatic population requires additional analyses. Clinical prognostic factors as the bone localizations (axial or appendicular), the visceral involvement (liver, lung) are determining for the survival of these patients. Biological prognostic factors are in evaluation. Except the clodronate acid, which showed a survival improvement in the hormone-sensitive metastatic prostate cancer (HSMPC), the other treatments targeting the bone (zoledronic acid, rank-ligand inhibitor) demonstrated a benefit only in castrate resistant metastatic prostate cancer (MCRPC). The management of local disease lets suggest a benefit to at least symptomatic disease, but it requires to be estimated prospectively in clinical trials. The new hormonal treatments targeting the androgen receptor in CPMRC are in evaluation in CPMHS. The objective is to increase the survival and the quality of life of the CPMHS and to delay the evolution towards the castration resistant metastatic disease.

Transient detection of β-galactosidase activity in hematopoietic cells, following reinjection of retrovirally marked autologous blood progenitors in patients with breast or ovarian cancer receiving high-dose chemotherapy

Abstract Objective The aim of this report is to demonstrate the feasibility and safety of genetically modifying autologous human blood CD34 + cells in vitro, with a retroviral vector that encodes a marker gene. The fate of genetically modified cells and their progeny was followed in vivo, after reinfusion in patients treated with high-dose chemotherapy for poor-prognosis breast or ovarian carcinomas. Patients and Methods Six patients received genetically modified autologous peripheral blood progenitors, together with unmanipulated aphereses, following high-dose chemotherapy. CD34 + cells were immunoselected from aphereses, and retrovirally transduced by coculture with the retroviral vector producing cell line, to express a nuclear localized version of E. coli β-galactosidase, encoded by a defective Moloney-murine leukemia virus–derived retroviral vector. Cells were reinfused to the patients after myeloablation, without prior ex vivo selection. Results Five out of six patients showed the transient presence of low numbers of β-galactosidase + cells, as detected with an immunocytochemical assay, in the peripheral blood, during the first month following infusion. One patient had β-galactosidase + clonogenic progenitors in her marrow at two months after transplantation, including HPP-CFC; intriguingly, this patient had the lowest percentage of X-gal + cells in her graft. Patients experienced side effects that are often observed after high-dose chemotherapy. Conclusions Feasibility and safety of genetic modification of human hematopoietic stem and progenitor cells are demonstrated by this study. Ex vivo or in vivo selection is not mandatory, even in clinical situations where transduced cells have no survival advantage over wild-type cells; however, significant improvements in gene transfer technology are needed to achieve potentially useful levels of expression in such clinical situations.

Pharmaco-prévention et nutri-prévention des cancers de la prostate

In 2010, in France, 8,790 men died from prostate cancer despite a low and decreasing mortality rate. The individual risk/benefit ratio of prostate cancer screening is the focus of controversy and currently not in favor of a systematic screening program. Therefore, only prevention could reduce incidence, side effects of treatment and related mortality. Interestingly, prostate cancer prevention is also a field of controversy mainly about 5-alpha-reductase inhibitors. However, it could be expected that pharmaco- or diet-based prevention will be a huge tool for cancer control, even more for prostate cancer burden. This review comprehensively analyses which molecules or compounds could be used in preventive trials. With regard to pharmaco-prevention, three different kinds of drugs could be identified. First drugs, which aim at mainly or even solely reduce prostate cancer risk such as 5-alpha-reductase inhibitors and selective estrogen receptor modulators. Drugs, which aim at wider preventive impact such as: nonsteroidal anti-inflammatory drugs or difluoromethylornithine. Lastly, drugs for which reducing prostate cancer incidence is merely a side effect such as statins, metformin or histones desacetylase inhibitors. With regard to diet-based prevention, two main approaches could be identified: aliments and nutriments, on one hand, and vitamin and minerals, on the other. Interestingly if compounds reach experimental plausibility, natural foods or even global diet seem to have a higher impact. Lastly, besides assessment of efficacy, effectiveness required the critical step of compliance, which might actually be the weakest link of the prevention chain.

Three Cases of Severe Ulcerative Esophagitis Induced by SUTENT

IntroductionThe development of SUTENT® revolutionized the care of metastatic renal carcinoma and of non-operable GIST. The tolerance is quite good with mostly mild side effects grade 1 or 2.ObservationWe report the case of three severe esophagitis stage 4 responsible for digestive bleeding. Two patients were taking anti-coagulant that could worsen the bleeding, but none were taking either antiplatelet or non-steroidal anti-inflammatory or corticosteroid that could favour erosion or ulceration of the digestive mucosa. It seems that SUTENT® is responsible for the digestive bleeding.DiscussionCases of esophagitis induced by SUTENT® have already been reported but are rare and of mild severity. Our three cases of esophagitis are severe with SUTENT® treatment as only risk factor and worsened by anti-coagulant treatment for two patients. It might be of interest preventively to treat these patients with inhibitors of proton pump.