Comment on 'Anti-tumour activity of abiraterone and diethylstilboestrol when administered sequentially to men with castration-resistant prostate cancer'

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Dose intense chemotherapy in the management of poor prognosis and relapsed testicular cancer: experiences and controversies

INTRODUCTION: The treatment of poor prognosis chemotherapy naïve or relapsed testicular cancer is challenging. In poor prognosis treatment naïve disease, the outlook for patients with standard approaches utilising three weekly cisplatin based regimens, most commonly bleomycin, etoposide and cisplatin (BEP) is suboptimal, and one can expect more than half of patients to relapse or progress and need salvage treatment. Recent randomised studies have lent weight to the use of dose intensified treatments in these selected patient groups. In relapsed testicular cancer, post platinum based chemotherapy controversy exists as to the optimum relapse regimen as significant cure rates can be expected by re-treating with both conventional dose and high dose or dose intense regimens. AREAS COVERED: This review seeks to outline the evidence for alternative approaches beyond standard three weekly cisplatin based regimens in poor risk metastatic disease. It also explores the evidence available for selection between conventional dose and high dose strategies on relapse. EXPERT COMMENTARY: An overview of the data is presented to support personalising therapy selection in both poor risk and relapsed metastatic germ cell tumors

Shapes of free resolutions over a local ring

We classify the possible shapes of minimal free resolutions over a regular local ring. This illustrates the existence of free resolutions whose Betti numbers behave in surprisingly pathological ways. We also give an asymptotic characterization of the possible shapes of minimal free resolutions over hypersurface rings. Our key new technique uses asymptotic arguments to study formal Q-Betti sequences.Comment: 14 pages, 1 figure; v2: sections have been reorganized substantially and exposition has been streamline

The Use of Transdermal Estrogen in Castrate-resistant, Steroid-refractory Prostate Cancer

BACKGROUND: Androgen-deprivation therapy is the mainstay of treatment for metastatic prostate cancer. Corticosteroids and estrogens are also useful agents in castration-resistant prostate cancer (CRPC). However, oral estrogens are associated with thromboembolic events, which limits their use, and transdermal estrogens may offer a safer alternative. This study was carried out to determine the safety and effectiveness of transdermal estrogens in CRPC. PATIENTS AND METHODS: Forty-one patients with CRPC and steroid-resistant prostate cancer were eligible for this dose-escalation study of transdermal estradiol. A starting dose of 50 mcg/24 hours was applied and increased if prostate-specific antigen (PSA) rose > 5 ng/mL in steps to 300 mcg/24 hours. The primary endpoint was PSA response, and secondary outcomes included incidence of thromboembolic events and progression-free survival. Patients who progressed were offered diethylstilbestrol. RESULTS: Five (13%) of 40 patients had > 50% PSA reduction for at least 1 month at any transdermal estradiol dose. No venous-thromboembolic events were observed, and responses plateaued at 200 mcg/24 hours. A correlation between PSA response and rising sex hormone binding globulin was seen. Fifty percent of patients subsequently responded to low-dose diethylstilbestrol. CONCLUSION: Transdermal estradiol appears to be a low toxicity treatment option to control CRPC after failure of steroid therapy. Modulation of sex hormone binding globulin by transdermal estradiol may be one mechanism of action of estrogens on CRPC. Oral estrogens remain effective after the use of transdermal estradiol

Long-term outcomes with intensive induction chemotherapy (carboplatin, bleomycin, vincristine and cisplatin/bleomycin, etoposide and cisplatin) and standard bleomycin, etoposide and cisplatin in poor prognosis germ cell tumours: A randomised phase II trial (ISRCTN53643604).

Background Up to 50% of men with poor prognosis, non-seminoma germ cell tumours (GCTs) die with standard BEP (bleomycin, etoposide and cisplatin) chemotherapy. An intensive regimen, CBOP/BEP (carboplatin, bleomycin, vincristine and cisplatin/BEP), met response targets in a randomised, phase II trial (74% complete response or partial response marker negative, 90% confidence interval (CI) 61%-85%).Aim To assess long-term outcomes and late toxicity associated with CBOP/BEP.Methods Patients with poor prognosis extracranial GCT were randomised to 4xBEP or CBOP/BEP (2xCBOP, 2xBO, 3xBEP with 15,000iu of bleomycin). Low-dose, stabilising chemotherapy before entry was permitted. Response rates (primary outcome) were reported previously. Here, we report secondary outcomes: progression-free survival (PFS), overall survival (OS) and late toxicity. Prognostic factors and the impact of marker decline are assessed in exploratory analysis.Results Eighty-nine patients (43 CBOP/BEP) were randomised. After median 63 months follow-up, 3-year PFS is 55.7% (95% CI: 39.7%, 69.0%) for CBOP/BEP and 38.7% (95% CI: 24.7%, 52.4%) for BEP (hazard ratio [HR]: 0.59 (0.33, 1.06), p = 0.079). Three-year OS is 65.0% (48.8%, 77.2%) and 58.5% (43.0%, 71.2%), respectively (HR: 0.79 (0.41, 1.52), p = 0.49). Twelve-month toxicity was affected by subsequent treatments, with no clear differences between arms. Stabilising chemotherapy was associated with poorer PFS (HR: 2.09 (1.14, 3.81), p = 0.017), whereas unfavourable marker decline, in 60 (70%) patients, was not.Conclusion Although not powered for PFS, results for CBOP/BEP are promising. Impact on OS was less clear (and will be affected by subsequent therapy). Further study in an international phase III trial is warranted.Trial registration ISRCTN 53643604

Long-term outcomes with intensive induction chemotherapy (carboplatin, bleomycin, vincristine and cisplatin/bleomycin, etoposide and cisplatin) and standard bleomycin, etoposide and cisplatin in poor prognosis germ cell tumours: A randomised phase II trial (ISRCTN53643604)

BACKGROUND: Up to 50% of men with poor prognosis, non-seminoma germ cell tumours (GCTs) die with standard BEP (bleomycin, etoposide and cisplatin) chemotherapy. An intensive regimen, CBOP/BEP (carboplatin, bleomycin, vincristine and cisplatin/BEP), met response targets in a randomised, phase II trial (74% complete response or partial response marker negative, 90% confidence interval (CI) 61%-85%). AIM: To assess long-term outcomes and late toxicity associated with CBOP/BEP. METHODS: Patients with poor prognosis extracranial GCT were randomised to 4xBEP or CBOP/BEP (2xCBOP, 2xBO, 3xBEP with 15,000iu of bleomycin). Low-dose, stabilising chemotherapy before entry was permitted. Response rates (primary outcome) were reported previously. Here, we report secondary outcomes: progression-free survival (PFS), overall survival (OS) and late toxicity. Prognostic factors and the impact of marker decline are assessed in exploratory analysis. RESULTS: Eighty-nine patients (43 CBOP/BEP) were randomised. After median 63 months follow-up, 3-year PFS is 55.7% (95% CI: 39.7%, 69.0%) for CBOP/BEP and 38.7% (95% CI: 24.7%, 52.4%) for BEP (hazard ratio [HR]: 0.59 (0.33, 1.06), p = 0.079). Three-year OS is 65.0% (48.8%, 77.2%) and 58.5% (43.0%, 71.2%), respectively (HR: 0.79 (0.41, 1.52), p = 0.49). Twelve-month toxicity was affected by subsequent treatments, with no clear differences between arms. Stabilising chemotherapy was associated with poorer PFS (HR: 2.09 (1.14, 3.81), p = 0.017), whereas unfavourable marker decline, in 60 (70%) patients, was not. CONCLUSION: Although not powered for PFS, results for CBOP/BEP are promising. Impact on OS was less clear (and will be affected by subsequent therapy). Further study in an international phase III trial is warranted. TRIAL REGISTRATION: ISRCTN 53643604