Radiotherapy for patients with localized hormone‐refractory prostate cancer: results of the Patterns of Care Study in Japan

OBJECTIVE

To evaluate the clinical results of radiotherapy (RT) for patients with regionally localized hormone‐refractory prostate carcinoma (HRPC).

PATIENTS AND METHODS

As part of a Patterns of Care Study in Japan, a nationwide survey was conducted of RT for patients with prostate adenocarcinoma. We reviewed the detailed information of 140 patients with regionally localized HRPC who received RT between 1996 and 1998, and between 1999 and 2001, in 117 randomly selected institutes in Japan. The median (range) age of the patients was 74 (51–94) years, and their tumours were defined as well (14), moderately (51) or poorly (54) differentiated, or of unknown differentiation (21). The median (range) interval between hormonal therapy (HT) and RT was 32.5 (1.1–168.4) months. Ninety‐five patients had T3‐4 tumours and 28 had regional lymph node metastases before treatment. The median (range) prostate‐specific antigen levels before the initial HT and before RT were 35.0 (1.5–276) and 10.0 (0.06–760.3) ng/mL, respectively. External beam RT was administered, with a median total dose of 66 Gy; 70 patients (50%) received pelvic irradiation.

RESULTS

At a median follow‐up of 20.7 months, the 5‐year overall and clinical progression‐free survival rates (95% confidence interval) were 48.1 (36–60)% and 36.7 (26–47)%, respectively. Although there were distant metastases in 46 patients, only six had local progression. There was late morbidity of grade ≥3 in six patients.

CONCLUSION

To the best of our knowledge, this study comprises the largest series of regionally localized HRPC treated with RT reported to date. RT might have a limited role for HRPC, because in most patients RT failed, with distant metastasis.     

Effects of local administration of interferon-beta on proliferation of retinal pigment epithelium in rabbit after laser photocoagulation

PURPOSE: To investigate whether local administration of interferon (IFN)-beta promotes proliferation of the retinal pigment epithelium (RPE) in vivo. METHODS: Following local injection of IFN-beta into the sub-Tenon space of rabbit eyes, the penetration of IFN-beta into various intraocular areas was determined by means of enzyme-linked immuno-adsorbent assay. Retinal lesions were produced by laser photocoagulation (PC), and IFN-beta (1 x 10(6) IU, 1 x 10(5) IU, or 1 x 10(4) IU) was administered into the sub-Tenon space. Physiological saline was substituted for IFN-beta in controls. The proliferation of RPE cells was inspected histopathologically. RESULTS: After IFN-beta administration, IFN-beta was found in all intraocular areas examined, with the highest concentration detected in the choroid. After PC, profuse proliferation of RPE cells began earlier in the rabbits that received the highest dose of IFN-beta than in the control rabbits; repair of the central part of the coagulated lesion in those rabbits was complete within 7 days after PC. In control rabbits, the histopathologic wound repair process proceeded more slowly and to a limited extent. Proliferation of RPE cells in the low and medium dose IFN-beta-treated rabbits was similar to that in the control rabbits. CONCLUSION: The present study demonstrates that repair of the PC-induced retinal lesions, particularly the proliferation of RPE cells, is promoted in vivo by local administration of IFN-beta.     

Radiation therapy for small-cell lung cancer: results of the 1995-1997 patterns of care process survey in Japan

The Patterns of Care Study (PCS) conducted a nationwide audit survey in order to establish the national practice process of radiation therapy for small-cell lung cancer (SCLC) and examined the influence of institutional stratification on the process of care in Japan. The PCS randomly sampled institutions and patients using a two-stage cluster method and surveyed the process of radiation therapy for 174 stage I-III SCLC patients according to the category of institution, stratified as follows: A1, academic institutions treating > or = 300 patients a year; A2, <300 patients; B1, non-academic institutions treating > or = 120 patients a year; and B2, <120 patients. Karnofsky performance status distributions showed significant variance by stratification of institutions (P=0.013). Patients treated on an outpatient basis accounted for 32% in A1, 23% in A2, 8% in B1, but only 5% in B2 (P=0.007). A photon energy > or = 10 MV was used for 87% of patients in A1, 69% in A2, 54% in B1 and 23% in B2 (P=0.001). Contralateral hilus was irradiated for 11% of patients in A1, 17% in A2, 29% in B1 and 3% in B2 (P=0.001). Field size reduction during the treatment course was done for 77% of patients in A1, 54% in A2, 60% in B1 and 42% in B2 (P=0.007). Ninety-two percent of patients received combined chemotherapy and radiation therapy, and the most frequently used drugs were etoposide (91%) and cisplatin (69%). The results of clinical studies on SCLC had favorably penetrated into the clinical practice. However, the stratification of institutions significantly affected the process of radiation therapy in Japan.     

Post launch studies

Evidence Based Medicine (EBM) is a growing concept in Japan as it is elsewhere. Central to improving the use of EBM is generation of data through well conducted controlled clinical studies. There are many problems associated with conduct of clinical studies after launch in Japan, and many initiatives are ongoing to improve the situation. Development of Clinical Research Coordinators (CRO) and central Data Management centers are key to improving the quality of clinical research in Japan. Currently Japan has an undeveloped legal system with regard to post-launch trials and off-label use of registered drugs. There is no reimbursement for off-label and various restrictions imposed on the recipients of the Ministry of Health, Labour and Welfare's (MHLW) funds. Maybe the biggest problem is the high cost of post-marketing studies sponsored by pharmaceutical manufacturers. A high quality system to support post launch clinical studies need a solid financial base. There is a need for a suitable review system for investigator initiated multi-centre studies, as the current IRB system is not sufficient. There are also challenges regarding the differences, perceived or real, in treatment practice and available registrations in Japan and in the West, causing problems in choosing suitable comparators and study designs. At the present time it is not clear whether investigator initiated trials will be acceptable for registration purposes in Japan. The agreed first priority is to build a suitable and strong infrastructure within the academic community to support researchers to investigate important questions with or without pharmaceutical company support. Despite all these issues, several groundbreaking projects are under way throughout Japan, in many different areas and by different collaborative groups, some with government support. In fact, researcher-initiated clinical trials achieved a rapid growth in Japan in the past year.     

Secreted and tumour targeted human carboxylesterase for activation of irinotecan

Irinotecan (CPT-11) is an anticancer agent for the treatment of colon cancer. CPT-11 can be considered as a prodrug, since it needs to be activated into the toxic drug SN-38 by the enzyme carboxylesterase. An approach to achieve tumour specific activation of CPT-11 is to transduce the cDNA encoding carboxylesterase into tumour cells. A secreted form of carboxylesterase may diffuse through a tumour mass and may activate CPT-11 extracellularly. This could enhance the antitumour efficacy by exerting a bystander effect on untransduced cells. In addition a secreted tumour-targeted form of carboxylesterase should prevent leakage of the enzyme from the site of the tumour into the circulation. We have constructed a secreted form of human liver carboxylesterase-2 by deletion of the cellular retention signal and by cloning the cDNA downstream of an Ig kappa leader sequence. The protein was secreted by transfected cells and showed both enzyme activity and efficient CPT-11 activation. To obtain a secreted, tumour-targeted form of carboxylesterase-2 the cDNA encoding the human scFv antibody C28 directed against the epithelial cell adhesion molecule EpCAM, was inserted between the leader sequence and carboxylesterase-2. This fusion protein showed CPT-11 activation and specific binding to EpCAM expressing cells. Importantly, in combination with CPT-11 both recombinant carboxylesterase proteins exerted strong antiproliferative effects on human colon cancer cells. They are, therefore, promising new tools for gene directed enzyme prodrug therapy approaches for the treatment of colon carcinoma with CPT-11.     

Monte Carlo calculation of depth doses for small field of CyberKnife

PURPOSE: A Monte Carlo (MC) model of CyberKnife was developed as a quality assurance tool. The percentage depth dose (%dd) was verified by using this model. MATERIALS AND METHODS: An MC model was developed with Electron Gamma Shower version 4 (EGS4) in two steps: (1) a model of the CyberKnife treatment head and (2) a model of the collimator and phantom. The bremsstrahlung spectrum was calculated using the first model, and this spectrum was then used to calculate %dds with the second model. The calculated %dds for a large field (60 mm diameter) and three small fields (30, 15, and 5 mm diameter) were compared with those measured with a diamond detector. RESULTS AND DISCUSSION: The MC-calculated and measured %dd-curves for the 60 mm diameter field were in excellent agreement (<1.85%), thus confirming the validity of the model. Discrepancies between the calculated and measured %dd-curves increased with decreasing field size, with considerable discrepancy (11.62%) for the 5 mm diameter field due to lateral electron disequilibrium. Accurate dose can be determined with MC even in small fields. CONCLUSION: The MC technique can provide reliable standard data for accurate dose delivery with high-technology radiotherapies using small beams.