High‐grade prostate cancer and finasteride

Prostate cancer is the most common neoplasm in men. Encouraging results are emerging in prostate cancer risk reduction with 5α‐reductase (5AR) inhibitors. The Prostate Cancer Prevention Trial (PCPT) showed that prostate cancer risk is reduced by finasteride. However, there was an increase in the incidence of high‐grade prostate cancer with finasteride treatment vs placebo. The number of cases should have increased during the study in the finasteride group with the length of exposure to the drug. But, in fact the ratio between the two groups was lower during the fourth year. This therefore favours the hypothesis of a bias in the results. There are many hypotheses to explain the increase in the prevalence of high‐grade tumours with finasteride therapy. The effects of finasteride on prostate volume rather than on the tumour’s morphology and a selective inhibition of low‐grade cancers may have contributed to the increase the number of high‐grade cancers with finasteride in the PCPT. Despite the current trend to explain the increase of high‐grade tumours with finasteride therapy by a detection bias, other studies underline the potential role of low levels of dihydrotestosterone in the genesis of high‐grade tumours. In May 2008, a re‐analysis of the PCPT results showed a significant decrease of 30% in the overall risk of prostate cancer in the finasteride group vs the placebo group, but it also found a statistically non‐significant and less important increase of the prevalence of high‐grade cancers in the finasteride group. However, the 5AR isoenzyme type 1 is present at higher rates than type 2 in high‐grade cancers. Thus, finasteride is probably not the ideal drug to prevent high‐grade cancers.     

Carbon‐ion radiation therapy for prostate cancer

In 1994, carbon‐ion radiotherapy was started at the National Institute of Radiological Sciences using the Heavy‐Ion Medical Accelerator in Chiba. Between June 1995 and March 2000, two phase I/II dose escalation studies (protocols 9402 and 9703) of hypofractionated carbon‐ion radiotherapy for both early‐ and advance‐stage prostate cancer patients had been carried out to establish radiotherapy technique and to determine the optimal radiation dose. To validate the feasibility and efficacy of hypofractionated carbon‐ion radiotherapy, a phase II study (9904) was initiated in April 2000 using the shrinking field technique and the recommended dose fractionation (66 gray equivalents in 20 fractions over 5 weeks) obtained from the phase I/II studies, and was successfully completed in October 2003. The data from 175 patients in the phase II study showed the importance of an appropriate use of androgen deprivation therapy according to tumor risk group. Since November 2003, carbon‐ion radiotherapy for prostate cancer was approved as “Highly Advanced Medical Technology” from the Ministry of Health, Labor, and Welfare, and since then approximately 1100 patients have received carbon‐ion radiotherapy as of July 2011. In this review, we introduce our steps thorough three clinical trials carried out at National Institute of Radiological Sciences, and show the updated data of carbon‐ion radiotherapy obtained from approximately 1000 prostate cancer patients. In addition, our recent challenge and future direction will be also described.     

Phase II study of docetaxel re‐treatment in docetaxel‐pretreated castration‐resistant prostate cancer

Study Type – Therapy (cohort)
Level of Evidence 2b What’s known on the subject? and What does the study add? We show that (i) docetaxel re‐treatment, after a treatment‐free interval, preserves activity; (ii) the treatment is especially well tolerated in patients who were effectively pretreated with docetaxel; and (iii) it could be speculated that combining docetaxel with other agents in this setting might be safe and result in greater activity.

OBJECTIVE

To determine the activity and tolerability of docetaxel re‐treatment after first‐line therapy with docetaxel in castration‐resistant prostate cancer (CRPC).

PATIENTS AND METHODS

Between November 2005 and January 2009, 45 patients initially responding to docetaxel and then experiencing disease progression after a period of biochemical remission of at least 5 months were enrolled in a prospective multicenter study and re‐treated with docetaxel. The primary endpoint was the biochemical response (biochemical partial response defined as >50% prostate‐specific antigen [PSA] decline); secondary endpoints were objective response, toxicity, progression‐free survival (PFS) and overall survival (OS).

RESULTS

Partial PSA responses were observed in 11 patients (24.5%), 4 (25%) of whom also had an objective response. The treatment was well tolerated, with grade 1–2 neutropenia, thrombocytopenia, vomiting and peripheral neuropathy noted in 18 (40%), 11 (24.5%), 8 (17.8%), and 6 (13.3%) patients, respectively. The most common grade 3 toxicity was neutropenia, which was observed in 8 patients (17.8%). Median PFS was 5 months and median OS was 13 months.

CONCLUSIONS

Docetaxel re‐treatment preserves anti‐tumour activity and is well tolerated in a selected population of pretreated patients with CRPC. Further randomized trials are needed to confirm our preliminary results.