A Single-arm Phase II Trial of Neoadjuvant Cabazitaxel and Cisplatin Chemotherapy for Muscle-Invasive Transitional Cell Carcinoma of the Urinary Bladder.

INTRODUCTION: Neoadjuvant cisplatin-based combination chemotherapy improves survival in muscle-invasive bladder cancer. However, response rates and survival remain suboptimal. We evaluated the efficacy, safety, and tolerability of cisplatin plus cabazitaxel. METHODS: A phase II single-arm trial was designed to recruit at least 26 evaluable patients. This would give 80% power to detect the primary endpoint, an objective response rate defined as a pathologic complete response plus partial response (pathologic downstaging), measured by pathologic staging at cystectomy (p0 = 0.35 and p1 = 0.60, α = 0.05). RESULTS: Objective response was seen in 15 of 26 evaluable patients (57.7%) and more than one- third of patients achieved a pathologic complete response (9/26; 34.6%). Seventy-eight percent of the patients (21/27) completed all cycles of treatment, with only 6.7% of the reported adverse events being graded 3 or 4. There were 6 treatment-related serious adverse event reported, but no suspected unexpected serious adverse reactions. In the patients who achieved an objective response, the median progression-free survival and overall survival were not reached (median follow-up of 41.5 months). In contrast, the median progression-free survival (7.2 months) and overall survival (16.9 months) were significantly worse (P = .001, log-rank) in patients who did not achieve an objective response. CONCLUSION: Cabazitaxel plus cisplatin for neoadjuvant treatment of muscle-invasive bladder cancer can be considered a well-tolerated and effective regimen before definitive therapy with higher rates (57.7%) of objective response, comparing favorably to that with of cisplatin/gemcitabine (23%-26%). These results warrant further evaluation in a phase III study.

A study of the clinical, treatment planning and dosimetric feasibility of dose painting in external beam radiotherapy of prostate cancer.

BACKGROUND AND PURPOSE: Radiotherapy dose painting is a promising technique which enables dose escalation to areas of higher tumour cell density within the prostate which are associated with radioresistance, known as dominant intraprostatic lesions (DILs). The aim of this study was to determine factors affecting the feasibility of radiotherapy dose painting in patients with high and intermediate risk prostate cancer. MATERIALS & METHODS: Twenty patients were recruited into the study for imaging using a 3 T magnetic resonance imaging (MRI) scanner. Identified DILs were outlined and the scan registered with the planning computed tomography (CT) dataset. Intensity-modulated plans were produced and evaluated to determine the effect of the organ-at-risk constraints on the dose that could be delivered to the DILs. Measurements were made to verify that the distribution could be safely delivered. RESULTS: MRI scans were obtained for nineteen patients. Fourteen patients had one to two DILs with ten overlapping the urethra and/or rectum. The target boost of 86 Gy was achieved in seven plans but was limited to 80 Gy for five patients whose boost volume overlapped or abutted the urethra. Dosimetric measurements gave a satisfactory gamma pass rate at 3%/3 mm. CONCLUSIONS: It was feasible to produce dose-painted plans for a boost of 86 Gy for approximately half the patients with DILs. The main limiting factor was the proximity of the urethra to the boost volumes. For a small proportion of patients, rigid registration between CT and MRI images was not adequate for planning purposes.

Corrigendum to "HDR Brachytherapy in the Management of High-Risk Prostate Cancer".

[This corrects the article DOI: 10.1155/2012/980841.].

Final quality of life and safety data for patients with metastatic castration-resistant prostate cancer treated with cabazitaxel in the UK Early Access Programme (EAP) (NCT01254279).

OBJECTIVE: To compile the safety profile and quality of life (QoL) data for patients with metastatic castration-resistant prostate cancer (mCRPC) treated with cabazitaxel in the UK Early Access Programme (UK EAP). PATIENTS AND METHODS: A total of 112 patients participated at 12 UK cancer centres. All had mCRPC with disease progression during or after docetaxel. Patients received cabazitaxel 25 mg/m(2) every 3 weeks with prednisolone 10 mg daily for up to 10 cycles. Safety assessments were performed before each cycle and QoL was recorded at alternate cycles using the EQ-5D-3L questionnaire and visual analogue scale (VAS). The safety profile was compiled after completion of the UK EAP and QoL measures were analysed to record trends. No formal statistical analysis was carried out. RESULTS: The incidences of neutropenic sepsis (6.3%), grade 3 and 4 diarrhoea (4.5%) and grade 3 and 4 cardiac toxicity (0%) were low. Neutropenic sepsis episodes, though low, occurred only in patients who did not receive prophylactic granulocyte-colony stimulating factor. There were trends towards improved VAS and EQ-5D-3L pain scores during treatment. CONCLUSIONS: The UK EAP experience indicates that cabazitaxel might improve QoL in mCRPC and represents an advance and a useful addition to the armamentarium of treatment for patients whose disease has progressed during or after docetaxel. In view of the potential toxicity, careful patient selection is important.

Second-line treatment options in metastatic castration-resistant prostate cancer: a comparison of key trials with recently approved agents.

Standard first-line treatment for metastatic castration-resistant prostate cancer (mCRPC) is docetaxel plus prednisone; however, patients will usually experience disease progression during or after docetaxel treatment due to inherent or acquired resistance. Before 2010, second-line options for mCRPC were limited. However, cabazitaxel, abiraterone acetate and enzalutamide have since been approved for patients with mCRPC whose disease has progressed during or after receiving docetaxel, based on the Phase III trials TROPIC, COU-AA-301 and AFFIRM. In all three trials, an overall survival benefit (primary endpoint) was seen in the experimental arm compared with the control arm: 15.1 vs. 12.7months for cabazitaxel plus prednisone compared with mitoxantrone plus prednisone in TROPIC (hazard ratio [HR] 0.70; P<0.0001); 14.8 vs. 10.9months for abiraterone acetateplus prednisone compared with placebo plus prednisone in COU-AA-301 (HR 0.65; P<0.001); and 18.4 vs. 13.6months for enzalutamide compared with placebo alone in AFFIRM (0.63; P<0.001). However, differences in patient populations, comparators, and selection and/or definition of secondary endpoints make it difficult to draw direct cross-trial comparisons. Radium-223 dichloride has also been approved for patients with mCRPC with metastases to bone but not other organs. To date, no comparative trials or sequencing studies with newer agents have been performed. Without such data, treatment decisions must be based on evaluation of the existing evidence. This commentary compares and contrasts study designs and key data from each of these Phase III trials, and also discusses recent and ongoing clinical trials with new agents in the first- and second-line settings in mCRPC.

Metastatic castrate-resistant prostate cancer: dawn of a new age of management.

What's known on the subject? and What does the study add? Metastatic castrate-resistant prostate cancer (mCRPC) was historically considered to be an aggressive disease resistant to conventional anticancer therapy. Within the last decade the outlook has changed beyond recognition; docetaxel chemotherapy is now firmly established as a well-tolerated treatment with significant survival benefits. Building on this, more recently there have been several landmark developments using various approaches in patients whose disease has progressed despite previous chemotherapy. Cabazitaxel chemotherapy offers survival and health-related quality of life (HRQL) improvements in this setting, as does the CYP inhibitor abiraterone acetate. Significant clinical benefits are also seen with novel radioisotope and immunotherapeutic approaches. There have been many developments in the management of this condition within the last 2 years, with several landmark studies showing new treatments that offer survival and HRQL benefits even in the setting of advanced disease, which has been heavily pretreated. This review article summarises these important developments and gives the reader an overview of current practice, recent changes and future directions. With current and forthcoming developments in the treatment of metastatic castrate-resistant prostate cancer (mCRPC) post-docetaxel, we are embarking on an age of potential 'chronic' management of this disease. It is hoped that the survival benefits associated with the various treatments, cytotoxic, hormonal and immunotherapeutic, will prove to be additive, providing a multimodal continuum of care. If so, it will be necessary to determine the optimal sequence and timing of the new treatments. One key factor in this regard is likely to be the patient's performance status and hence his eligibility for cytotoxic intervention. If chemotherapy is offered early in the post-docetaxel pathway, the patient may still be able to benefit from non-chemotherapeutic options subsequently. However, if this stage of management begins with a non-chemotherapeutic option, there is a risk that the patient's performance status will decline before he has an opportunity to benefit from chemotherapy. Further studies and ongoing clinical experience are likely to clarify this important issue, and help clinicians to maximise the survival of men with mCRPC post-docetaxel.

HDR Brachytherapy in the Management of High-Risk Prostate Cancer.

High-dose-rate (HDR) brachytherapy is used with increasing frequency for the treatment of prostate cancer. It is a technique which allows delivery of large individual fractions to the prostate without exposing adjacent normal tissues to unacceptable toxicity. This approach is particularly favourable in prostate cancer where tumours are highly sensitive to dose escalation and to increases in radiotherapy fraction size, due to the unique radiobiological behaviour of prostate cancers in contrast with other malignancies. In this paper we discuss the rationale and the increasing body of clinical evidence for the use of this technique in patients with high-risk prostate cancer, where it is combined with external beam radiotherapy. We highlight practical aspects of delivering treatment and discuss toxicity and limitations, with particular reference to current practice in the United Kingdom.