Re: Results of a randomized trial of treatment modalities in patients with low or early­intermediate risk prostate cancer (PREFERE trial).

The authors of this "Letter to the Editors" express their major concern about selective and biased reporting in this paper.

Salvage ablative therapy in prostate cancer: international multidisciplinary consensus on trial design.

INTRODUCTION: Salvage ablative therapy (SAT) has been developed as a form of localized treatment for localized recurrence of prostate cancers following radiation therapy. To better address the utility of SAT, prospective clinical trials must address the aspects of accepted standards in the initial evaluation, treatment, follow-up, and outcomes in the oncology community. We undertook this study to achieve consensus on uniform standardized trial design for SAT trials. METHODS: A literature search was performed and an international multidisciplinary group of experts was identified. A questionnaire was constructed and sent out to 71 participants in 3 consecutive rounds according to the Delphi method. The project was concluded with a face-to-face meeting in which the results were reviewed and conclusions were formulated. RESULTS: Patients with recurrent disease after radiation therapy were considered candidates for a SAT trial using any ablation scenario performed with cryotherapy or high-intensity focused ultrasound. It is feasible to compare different sources of energy or to compare with historical data on salvage radical prostatectomy outcomes. The primary objective should be to assess the efficacy of the treatment for negative biopsy rate at 12 months. Secondary objectives should include safety parameters and quality-of-life assessment. Exclusion criteria should include evidence of local or distant metastases. The optimal biopsy strategy is image-guided targeted biopsies. Follow-up includes multiparametric magnetic resonance imaging, prostate-specific antigen level, and quality of life for at least 5 years. CONCLUSIONS: A multidisciplinary board from international experts reached consensus on trial design for SAT in prostate cancer and provides a standard for designing a feasible SAT trial.

Postimplantation analysis enables improvement of dose-volume histograms and reduction of toxicity for permanent seed implantation.

PURPOSE: To demonstrate how postimplantation analysis is useful for improving permanent seed implantation and reducing toxicity. PATIENTS AND METHODS: We evaluated 197 questionnaires completed by patients after permanent seed implantation (monotherapy between 1999 and 2003). For 70% of these patients, a computed tomography was available to perform postimplantation analysis. The index doses and volumes of the dose-volume histograms (DVHs) were determined and categorized with respect to the date of implantation. Differences in symptom scores relative to pretherapeutic status were analyzed with regard to follow-up times and DVH descriptors. Acute and subacute toxicities in a control group of 117 patients from an earlier study (June 1999 to September 2001) by Wust et al. (2004) were compared with a matched subgroup from this study equaling 110 patients treated between October 2001 and August 2003. RESULTS: Improved performance, identifying a characteristic time dependency of DVH parameters (after implantation) and toxicity scores, was demonstrated. Although coverage (volume covered by 100% of the prescription dose of the prostate) increased slightly, high-dose regions decreased with the growing experience of the users. Improvement in the DVH and a reduction of toxicities were found in the patient group implanted in the later period. A decline in symptoms with follow-up time counteracts this gain of experience and must be considered. Urinary and sexual discomfort was enhanced by dose heterogeneities (e.g., dose covering 10% of the prostate volume, volume covered by 200% of prescription dose). In contrast, rectal toxicities correlated with exposed rectal volumes, especially the rectal volume covered by 100% of the prescription dose. CONCLUSION: The typical side effects occurring after permanent seed implantation can be reduced by improving the dose distributions. An improvement in dose distributions and a reduction of toxicities were identified with elapsed time between 1999 and 2003.

Magnetic nanoparticles for interstitial thermotherapy--feasibility, tolerance and achieved temperatures.

BACKGROUND: The concept of magnetic fluid hyperthermia is clinically evaluated after development of the whole body magnetic field applicator MFH 300F and the magnetofluid MFL 082AS. This new system for localized thermotherapy is suitable either for hyperthermia or thermoablation. The magnetic fluid, composed of iron oxide nanoparticles dispersed in water, must be distributed in the tumour and is subsequently heated by exposing to an alternating magnetic field in the applicator. We performed a feasibility study with 22 patients suffering from heavily pretreated recurrences of different tumour entities, where hyperthermia in conjunction with irradiation and/or chemotherapy was an option. The potential to estimate (by post-implantation analyses) and to achieve (by improving the technique) a satisfactory temperature distribution was evaluated in dependency on the implantation technique. MATERIAL AND METHODS: Three implantation methods were established: Infiltration under CT fluoroscopy (group A), TRUS (transrectal ultrasound)--guided implantation with X-fluoroscopy (group B) and intra-operative infiltration under visual control (group C). In group A and B the distribution of the nanoparticles can be planned prior to implantation on the basis of three-dimensional image datasets. The specific absorption rates (SAR in W/kg) can be derived from the particle distribution imaged via CT together with the actual H-field strength (in kA/m). The temperature distribution in the tumour region is calculated using the bioheat-transfer equation assessing a mean perfusion value, which is determined by matching calculated temperatures to direct (invasive or endoluminal) temperature measurements in reference points in or near the target region. RESULTS: Instillation of the magnetic fluid and the thermotherapy treatments were tolerated without or with only moderate side effects, respectively. Using tolerable H-field-strengths of 3.0-6.0 kA/m in the pelvis, up to 7.5 kA/m in the thoracic and neck region and >10.0 kA/m for the head, we achieved SAR of 60-380 W/kg in the target leading to a 40 degrees C heat-coverage of 86%. However, the coverage with > or =42 degrees C is unsatisfactory at present (30% of the target volume in group A and only 0.2% in group B). CONCLUSION: Further improvement of the temperature distribution is required by refining the implantation techniques or simply by increasing the amount of nanofluid or elevation of the magnetic field strength. From the actual nanoparticle distribution and derived temperatures we can extrapolate, that already a moderate increase of the H-field by only 2 kA/m would significantly improve the 42 degrees C coverage towards 100% (98%). This illustrates the great potential of the nanofluid-based heating technology.

Clinical and physical determinants for toxicity of 125-I seed prostate brachytherapy.

BACKGROUND AND PURPOSE: To assess acute as well as long-term toxicity after permanent prostate seed implantation. To find predictive clinical or dosimetric factors for side effects in order to work out strategies for improvement. PATIENTS AND METHODS: A group of 174 patients with localised prostate cancer was treated with permanent seed implantation between 1999 and 2001, either alone (140 patients) or in combination with external radiotherapy (34 patients). For the majority (114/174, i.e. 66%) a CT was performed four weeks after implantation and analysed in the planning system VariSeed. In the postimplant analysis, dosimetric descriptors (doses, volumes) were determined for the prostate and rectum and compared with the intraoperative values. In addition, a questionnaire was sent to all patients to assess and quantify acute and chronic toxicity (urinary, rectal, sexual) and the impact on subjective acceptance and quality of life (return rate of questionnaires 83%). The derived score changes were correlated with clinical and dosimetric factors. RESULTS: In the mono-brachytherapy group 14% (16/140) required a bladder catheter, of them 8% (9/140) with a manifest urinary obstruction. Long-term rectal toxicity (<5%) and impairment of potency (<30%) are moderate and obviously below other treatment options. Urinary toxicity is dominant with an overall long-term dysuria up to 30% (at a mean observation interval of ten months), and a significant trend to decline with follow-up time. Conversely, the erectile function tends to deteriorate with follow-up time. Nevertheless, quality of life is not significantly reduced and acceptance is high. Our analysis suggests that the main factor for urinary toxicity and impaired erectile function is the dose load to larger portions of the prostate (D(50)>240 Gy), which appears to be attributed to unnecessarily high numbers of seeds (for a fixed activity per seed) and needles. The rectal toxicity is correlated with the high dose regions in the rectum (>/=145 Gy). Urinary toxicity is lower for combined-brachytherapy, while rectal toxicity and impairment of potency are slightly higher. CONCLUSIONS: Toxicity spectrum and quality of life after permanent seed implantation for early prostate cancer are acceptable for nearly all patients (98%). To further improve tolerance we should attempt to achieve a better dose homogeneity, i.e. by reducing D(50). Therefore, special attention should be given to D(50) during the real-time planning process. The necessity of more homogeneous dose distributions might imply a reduction of the activity per seed, e.g. from 0.7 mCi down to 0.6 mCi.

[Physical basics and clinical realization of interstitial brachytherapy of the prostate with iodine 125]. / Physikalische Grundlagen und klinische Durchführung der interstitiellen Brachytherapie der Prostata mit Jod-125.

BACKGROUND: Interstitial brachytherapy with I-125 seeds can be used for successful treatment of early stage prostate cancer. There is presented the technique of permanent transperineal implantation of I-125 seeds with intraoperative treatment planning which is suited for the treatment of prostate cancer up to the clinical stage of T2a. MATERIAL AND METHODS: Some weeks before the implantation of the seeds the prostate volume is determined using transrectal ultrasound (TRUS) so as to estimate the required number of I-125 seeds. At the outset of the treatment the prostate is stabilized by two perineally inserted needles. Subsequently there is carried out an ultrasound guided treatment planning that allows to optimize the distribution of the seeds within the prostate. In interstitial brachytherapy we use RAPID STRANDS((R)), i. e. the I-125 seeds are embedded in vicryl suture at distances of 1 cm. During implantation of the I-125 seeds the transversal placement of the applicator needles is controlled by TRUS and the cranio-caudal placement of the applicator needles is controlled using the fluoroscopic unit as well as TRUS. About 4 weeks after the implantation of the seeds there is carried out a postoperative computation of the dose distribution of the implant using CT imaging. RESULTS: The procedure possesses the advantage that ultrasound imaging, treatment planning and seed implantation are carried out with the prostate remaining in an unaltered position. During implantation the combined imaging of TRUS and fluoroscopy allows a safe placement of the seeds with in the prostate. CONCLUSION: The methods for the calculation of the actually attained dose distribution must still be optimized, because the postoperative examination of the individual results has so far been possible only with difficulties resulting from methodological inconveniences.