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Background: The Glass model developed in 2003 uses prognostic factors for noncastrate metastatic prostate cancer (NCMPC) to define subgroups with good, intermediate, and poor prognosis., Objective: To validate NCMPC risk groups in a more recently diagnosed population and to develop a more sensitive prognostic model., Design, Setting, and Participants: NCMPC patients were randomized to receive continuous androgen deprivation therapy (ADT) with or without docetaxel in the GETUG-15 phase 3 trial. Potential prognostic factors were recorded: age, performance status, Gleason score, hemoglobin (Hb), prostate-specific antigen, alkaline phosphatase (ALP), lactate dehydrogenase (LDH), metastatic localization, body mass index, and pain., Outcome Measurements and Statistical Analysis: These factors were used to develop a new prognostic model using a recursive partitioning method. Before analysis, the data were split into learning and validation sets. The outcome was overall survival (OS)., Results and Limitations: For the 385 patients included, those with good (49%), intermediate (29%), and poor (22%) prognosis had median OS of 69.0, 46.5 and 36.6 mo (p=0.001), and 5-yr survival estimates of 60.7%, 39.4%, and 32.1%, respectively (p=0.001). The most discriminatory variables in univariate analysis were ALP, pain intensity, Hb, LDH, and bone metastases. ALP was the strongest prognostic factor in discriminating patients with good or poor prognosis. In the learning set, median OS in patients with normal and abnormal ALP was 69.1 and 33.6 mo, and 5-yr survival estimates were 62.1% and 23.2%, respectively. The hazard ratio for ALP was 3.11 and 3.13 in the learning and validation sets, respectively. The discriminatory ability of ALP (concordance [C] index 0.64, 95% confidence interval [CI] 0.58-0.71) was superior to that of the Glass risk model (C-index 0.59, 95% CI 0.52-0.66). The study limitations include the limited number of patients and low values for the C-index., Conclusion: A new and simple prognostic model was developed for patients with NCMPC, underlying the role of normal or abnormal ALP., Patient Summary: We analyzed clinical and biological factors that could affect overall survival in noncastrate metastatic prostate cancer. We showed that normal or abnormal alkaline phosphatase at baseline might be useful in predicting survival., (Copyright © 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Androgen deprivation therapy is widely used in combination with radiotherapy for the treatment of prostate cancer. The knowledge of the biology of the androgen axis could help the radiation oncologist to combine both modalities in an efficient way. Moreover, new drugs have recently been approved and their role in combination with radiation needs pre-clinical and clinical studies. This review summarized the main data on the biology of androgen receptor and the potential implications for the physician. Mechanisms of interactions between androgen deprivation therapy and radiotherapy are also presented and discussed., (Copyright © 2015 Société française de radiothérapie oncologique (SFRO). Published by Elsevier SAS. All rights reserved.)

Advanced gastric cancer or gastro-oesophageal junction cancer after a failure of first line chemotherapy have poor outcome. Hereby, we present the first patient treated by radiotherapy with concurrent everolimus, a mTor inhibitor, for a reirradiation of metastasis invading left axillary, infraclavicular and supraclavicular lymph nodes in progression despite several lines of chemotherapy. After 6 months of follow-up, this association provided a satisfactory anti-tumor efficiency and tolerance. Nevertheless, clinical trials are needed in order to confirm this strategy for the treatment of gastric cancer metastasis., (Copyright © 2014 Société française de radiothérapie oncologique (SFRO). Published by Elsevier SAS. All rights reserved.)

Aim: To assess docetaxel-estramustine in patients with localised high-risk prostate cancer., Patients and Methods: After staging pelvic lymph node dissection, patients with high-risk prostate cancer randomly received androgen deprivation therapy (ADT) (3 years)+DE (4 cycles of docetaxel 70 mg/m(2)/3 weeks+estramustine 10mg/kg/dd1-5) or ADT alone. Local therapy was administered at 3 months., Results: Four hundred and thirteen patients were accrued: T3-T4 (67%), Gleason score ~8 (42%), PSA >20 ng/mL (59%), pN+ (29%). In the chemotherapy arm, 94% of patients received the planned four cycles of docetaxel. Local treatment consisted of radiotherapy in 358 patients (87%) (median dose 74 Gy in both arms). ADT was given for 36 months in both arms. A PSA response (PSA ~0.2 ng/mL after 3 months of treatment) was obtained in 34% and 15% in the ADT+DE arm and in the ADT arm, respectively (p<0.0001). Febrile neutropenia occurred in only 2%. Moderate to severe hot flashes occurred less often in the ADT+DE arm (2% versus 22%; p<0.001). There was no toxicity-related death, no secondary leukaemia, and no excess second cancers. Chemotherapy had a negative impact on quality of life (global health status, p = 0.01; fatigue, p = 0.003; role functioning, p = 0.003; social functioning, p = 0.006) at 3 months but this effect disappeared at 1 year., Conclusion: Docetaxel-estramustine can be combined safely with standard therapy in high-risk prostate cancer, with a promising PSA response rate and no negative impact on quality of life after 1 year. Long-term follow-up is required to assess the impact on relapse and survival., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: In the evolution of metastatic castration-resistant prostate cancer (mCRPC), patients present visceral metastases with or without neuroendocrine differentiation in 20% of cases., Patients and Methods: We assessed the efficacy and toxicity of a platinum-based chemotherapy regimen in mCRPC patients with either neuroendocrine differentiation defined by high serum levels of chromogranin A (CgA) and neuron-specific enolase (NSE) or visceral metastases. Patients received the combination of carboplatin and etoposide every 3 weeks. Efficacy end points included prostate-specific antigen (PSA) and neuroendocrine marker response, objective response and toxicity., Results: Of the 60 patients included from April 2005 to January 2008, 78.6% had bone metastases, 46.4% had lymph node involvement and 57.1% had liver and/or lung localizations. The objective response rate was 8.9% in the 46 patients with measurable disease. A neuroendocrine response was observed in 31% of cases for NSE and 7% for CgA. The PSA response rate was 8%. The most common grade 3-4 treatment-related toxic effects were neutropenia (65.5%), thrombocytopenia (32.7%) and anemia (27.3%). There was 7.2% febrile neutropenia, with one toxicity-related death. The median follow-up was 9.3 months [95% confidence interval (CI) 0.2-27.1] and the median overall survival 9.6 months (95% CI 8.7-12.7)., Conclusion: The benefit-risk ratio of this regimen seems unfavorable due to poor response and high toxicity.

Background: The endothelin-A receptor (ETAR) has been implicated in the progression of prostate cancer., Objectives: To investigate the safety and efficacy of the specific ETAR antagonist ZD4054 in patients with metastatic hormone-resistant prostate cancer (HRPC)., Design, Setting, and Participants: Double-blind, placebo-controlled, randomised, parallel-group, multicentre, phase 2 trial in patients attending cancer centres with HRPC and bone metastases who were pain free or mildly symptomatic for pain., Intervention: Patients were randomised to receive once-daily oral tablets of ZD4054 10 mg, or ZD4054 15 mg, or placebo., Measurements: The primary end point was time to progression, defined as clinical progression, requirement for opiate analgesia, objective progression of soft-tissue metastases, or death in the absence of progression. Secondary end points included overall survival, time to prostate-specific antigen (PSA) progression, and safety. Statistical significance was preset at 20%., Results and Limitations: A total of 312 patients were randomised (ZD4054 10 mg, n=107; ZD4054 15 mg, n=98; placebo, n=107). At the primary analysis, median time to progression was 3.6 mo, 4.0 mo, and 3.8 mo in the placebo, ZD4054 10 mg, and ZD4054 15 mg groups, respectively, with no statistically significant difference between ZD4054 groups and placebo (hazard ratio [HR] vs placebo for the ZD4054 10mg group: 0.88 [80% CI: 0.71-1.09]; HR vs placebo for the ZD4054 15 mg group: 0.83 [80% CI: 0.66-1.03]). However, a signal for prolonged overall survival was observed in the ZD4054 treatment groups versus placebo, based on 40 deaths. At a subsequent analysis after 118 deaths, this survival benefit was confirmed (HR vs placebo for the ZD4054 10 mg group, 0.55 [80% CI: 0.41-0.73], p=0.008; HR vs placebo for the ZD4054 15 mg group, 0.65 [80% CI: 0.49-0.86], p=0.052) but the differences in time to progression remained nonsignificant. Median overall survival was 17.3 mo, 24.5 mo, and 23.5 mo in the placebo group, the ZD4054 10 mg group, and the ZD4054 15 mg group, respectively. Discordance between results for time to progression and overall survival may be due to the sensitivity of the definition of progression. Adverse events were in line with the expected pharmacologic effects of an ETAR antagonist., Conclusions: The primary end point of time to progression was not achieved in this study, but an improvement was seen in overall survival in both active treatment arms. ZD4054 was well tolerated., Trial Registration: Clinicaltrials.gov NCT00090363.

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.

Specific treatments targeted toward oncogenes expressed in cancer cells are currently under development. Patients with urothelial carcinomas showing HER-2/ neu (human epidermal growth factor receptor 2) overexpression are candidates for such a specific treatment (trastuzumab). However, to be effective, this therapeutic approach requires an extremely reliable evaluation of HER-2/ neu status in tumors. In order to assess the status of expression of this gene and to optimize its assessment, we analyzed a series of 64 primary urothelial carcinomas using immunohistochemistry (IHC) with the CB11 monoclonal antibody coupled with fluorescent in situ hybridization (FISH) in 21 cases. Strong HER-2/ neu overexpression was detected using IHC in 15 of the 64 (23%) cases analyzed, and this rate rose to 33% for patients with metastases. HER-2/ neu overexpression, as revealed using IHC, is strongly associated (95%) with gene amplification assessed using FISH. Patients with urothelial carcinomas overexpressing HER-2/ neu using IHC are potential candidates for targeted chemotherapy.

We have previously reported an overall response rate of 41% and a median survival duration of 14 months in a series of 49 patients with metastatic or recurrent endometrial carcinoma treated by a combination of etoposide, 5-fluorouracil, and cisplatin. In order to increase response rate and survival duration, doxorubicin was added to this combination. From August 1992 to January 1996, 20 consecutive patients were treated with a monthly combination chemotherapy consisting of doxorubicin 30 mg/m2 i.v. Day 1, 5-fluorouracil 600 mg/m2 i.v. Days 1 to 3, etoposide 80 mg/m2 i.v. Days 1 to 3, and cisplatin 35 mg/m2 i.v. Days 1 to 3 (AFEP). All patients were evaluable for response and toxicity. Median age was 62 years (range 45-72). Two to eight cycles were delivered (median 5). Two of 20 patients had complete response and 7 of 20 had partial response. The objective response rate was 45% (CI 95%: 23-68%). The median survival duration was 17 months. The median progression-free survival was 8 months. Major toxic effect was myelosuppression: 75% of grade 3 and 4 leukopenia and 20% of grade 3 and 4 thrombocytopenia. Seven patients (35%) developed infection and 4 (20%) were hospitalized once or more for toxicity. These results indicate that AFEP is an effective combination therapy in metastatic endometrial carcinoma but its toxicity is unacceptable.

Forty-nine consecutive patients with metastatic or recurrent endometrial carcinoma were treated with a monthly combination chemotherapy consisting of VP 16-213 80 mg/m2 i.v. Days 1-3, 5-fluorouracil (5-FU) 600 mg/m2 i.v. Days 1-3, and cisplatin 35 mg/m2 i.v. Days 1-3. The objective response rate was 41% (95% CI, 27-54%) with 14.3% complete responses. The median survival duration was 14 months. The median response duration was 12 months. The estimated median survival for responders was 20 months. Three patients are still free of disease 5 years after treatment. The major toxic effects were myelosuppression (less than 25% of grade III and IV leucopenia, and 14% grade III and IV thrombocytopenia). Grade III peripheral neuropathy was observed in five patients. Cisplatin administration had to be stopped due to renal toxicity in six patients. No treatment-related deaths occurred. The combination of etoposide, 5 fluorouracil, and cisplatin is an effective regimen with an acceptable toxicity in patients with recurrent or metastatic endometrial carcinoma.

The authors undertook a study to test the feasibility and efficacy of doxorubicin (Dox) administered as continuous infusion (c.i.) in the treatment of advanced breast cancer patients. All patients were previously treated as first line chemiotherapy with bolus-administered Dox; then they received a second line treatment without Dox. Patients were eligible if they had advanced measurable breast cancer, resistant to first and second line chemotherapy regimens, and if previous Dox treatment had been performed more than one year before, and after ECG and cardiac echographic controls were performed. A dose of 4.5 mg/m2/day of Dox was planned for 10 consecutive days in c.i. through a central venous catheter, repeated at 28 day intervals, for a maximum of 10 cycles. Among the 71 patients, 56 received 3 or more treatment courses; 10 patients refused further therapy after the first cycle. Objective responses were achieved in 25 patients (35%), 3 complete and 22 partial remissions. Stabilization was obtained in 11 patients (16%). The median time to progression was 9.3 months. Obviously, haematological toxicity was the major problem; in the 71 patients, 376 courses were administered (mean number of courses per patient: 5.3): grade 4 neutropenia (WHO system) occurred in 2 patients, and grade 3 in 9 patients; while one patient died of gastric haemorrhage. Severe cardiac toxicity occurred in only one patient who died 24 hours after the beginning of therapy, with ECG lateral ischemia. Grade 4 stomatitis was observed in only one patient.(ABSTRACT TRUNCATED AT 250 WORDS)

223 inflammatory breast cancer patients were diagnosed at the Institut Curie between 1977 and 1987. Patients received chemotherapy and radiation treatment according to three consecutive randomised trials. Five- and 10- year survival rates were 41 and 32%, respectively. Disease-free interval rates were 25.5% at 5 years and 19% at 10 years. Parameters significantly linked with a pejorative prognosis in a multivariate analysis were: diffuse erythema, lymph node involvement, chest wall adherence, and age above 50 years. When therapeutic response parameters were included in the multivariate analysis, the five most important prognostic factors in order of significance were complete tumour regression after completion of induction treatment (at 8 months), complete regression of inflammatory symptoms after 3 months of neoadjuvant chemotherapy, limited erythema at presentation and, less significantly, complete regression of inflammatory symptoms at 8 months and tumour regression at 3 months. In conclusion, patients who achieved a rapid and complete remission had a better prognosis than patients who had an incomplete response to chemotherapy. High-dose chemotherapy and reversal or prevention of drug resistance will be evaluated in future trials. Detailed information on the biology of this disease should allow the design of new strategies aiming to improve patient management.

Between March 1985 and December 1987, 34 women who had advanced adenocarcinoma of the ovary with macroscopic residual disease entered in a phase II trial of chemotherapy. Treatment consisted of a 3-month induction with monthly ifosfamide combined with 5-fluorouracil and high-dose cisplatin, and a maintenance treatment with ifosfamide, 5-fluorouracil, cisplatin and hexamethylmelamine in monthly cycles. At the end of the treatment patients with complete remission were evaluated by surgery. Neurotoxicity was a limiting factor, and treatment had to be prematurely withdrawn in 10 patients. The above treatment was found to be effective with a 94 percent objective response rate, a 54-month median survival and a 51-month median relapse-free survival. Because of the neurotoxicity, a shorter therapy and the use of neuroprotective agents may be envisaged.