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Penile cancer (PeCa) is rare, and the survival of patients with advanced disease remains poor. A better understanding of where treatment fails could aid the development of new treatment strategies.To describe the disease course after pelvic lymph node (LN) treatment for PeCa.We retrospectively analysed 228 patients who underwent pelvic LN treatment with curative intent from 1969 to 2016. The main treatment modalities were neoadjuvant chemotherapy, chemoradiation, and pelvic LN dissection.In the case of multiple recurrence locations, the most distant location was taken and recorded as follows: local (penis), regional (inguinal and pelvic LN), and distant (any other location). A competing risk analysis was used to calculate the time to recurrence per location, and a Kaplan-Meier analysis was used for overall survival (OS).The median follow-up of the surviving patients was 79 mo. The reason for pelvic treatment was pelvic involvement on imaging (29%), two or more tumour-positive inguinal LNs (61%), or inguinal extranodal extension (52%). More than half of the patients (61%) developed a recurrence. The median recurrence-free survival was 11 mo. The distribution was local in 9%, regional in 27%, and distant in 64% of patients. The infield control rate of nonsystemically treated patients was 61% (113/184). From the start of pelvic treatment, the median OS was 17 mo (95% confidence interval 12-22). After regional or distant recurrence, all but one patient died of PeCa with median OS after a recurrence of 4.4 (regional) and 3.1 (distant) mo. This study is limited by its retrospective nature.The prognosis of PeCa patients treated on their pelvis who recur despite locoregional treatment is poor. The tendency for systemic spread emphasises the need for more effective systemic treatment strategies.In this report, we looked at the outcomes of penile cancer patients in an expert centre undergoing various treatments on their pelvis. We found that survival is poor after recurrence despite locoregional treatment. Therefore, better systemic treatments are necessary.

Highlights • PSA response to SABR is similar for PSMA-PET vs. choline-PET. • However, PSMA-PET results in longer PSA response duration than choline-PET. • PSMA-PET results in improved ADT-free survival compared with choline-PET., Background In patients with oligometastatic recurrent prostate cancer, standard treatment is androgen deprivation therapy (ADT). However, ADT has many potential side effects that may result in impaired quality of life. Early identification to select patients suitable for stereotactic ablative radiotherapy (SABR) is of utmost importance to prevent or delay start of ADT and its side effects. Because Prostate-Specific Membrane Antigen-11-Positron Emission Tomography (PSMA-11-PET) has a higher sensitivity than choline-PET, we hypothesise that PSMA-11-PET based SABR results in longer response duration and subsequent longer delay in starting ADT than choline-PET. Methods Patients with oligometastatic (≤4 metastases) recurrent prostate cancer (with no local recurrence) based on PSMA-11-PET or choline-PET treated with SABR from January 2012 until December 2017 were included. Primary endpoint was ADT-free survival. Secondary endpoints were Prostate Specific Antigen (PSA) response after SABR and time to PSA rise after SABR. Results Fifty patients (n = 40 PSMA-11-PET and n = 10 choline-PET) with in total 72 lesions were included. Median follow-up was 24.3 months. PSMA-11-PET enabled eligibility of patients with lower PSA levels than choline-PET (median 1.8 versus 4.2 ng/mL, p = 0.03). The PSMA-11-PET group had a significant longer PSA response duration (median 34.0 months (95% confidence interval (CI), 16.0–52.0) versus 14.7 months (95% CI 4.7–24.7), p = 0.004) with a subsequent longer ADT-free survival (median 32.7 months (95% CI, 20.8–44.5) versus 14.9 months (95% CI, 5.7–24.1), p = 0.01). Conclusions With PSMA-11-PET we are able to select patients with oligometastatic recurrent prostate cancer suitable for SABR in an earlier disease stage at lower PSA levels. PSMA-11-PET guided SABR resulted in a significant longer response duration and ADT-free survival compared with choline-PET and can therefore prevent or delay ADT related side effects.

Background: Oligometastatic prostate cancer (OMPC) is a heterogeneous disease state that is imperfectly understood, and its clinical implications are unclear. Objective: To determine the consensus of a Dutch multidisciplinary expert panel on biological aspects, treatment goals, and management of OMPC in daily clinical practice. Design, setting, and participants: The study comprised a modified Delphi method including an explorative survey with various statements and questions, followed by a consensus meeting to discuss and determine the agreement with revised statements and related items. The panel consisted of 34 Dutch representatives from urology, medical and radiation oncology, radiology, nuclear medicine, and basic research. Outcome measurements and statistical analysis: Agreement was determined with statements (five-point scale). Consensus was defined as ≥75% panel agreement with a statement. Results and limitations: Consensus existed for 56% of statements. The panel agreed that OMPC comprises a limited metastatic spread in the hormone-sensitive setting, in both the synchronous and the metachronous presentation. Limited metastatic spread was believed to involve three to five metastases and a maximum of two organs. Prostate-specific membrane antigen positron emission tomography/computed tomography scan was currently perceived as the most accurate diagnostic imaging modality. Although there was a consensus that targeted treatment of all metastases in OMPC will delay further dissemination of the disease, opinions on specific treatment regimens were divided. Panel outcomes were limited by the lack of scientific evidence on OMPC. Conclusions: A multidisciplinary panel reached a consensus that OMPC is a specific disease state requiring a tailored treatment approach. OMPC registries and clinical studies should focus on both the biology and the clinical parameters in relation to optimal treatment strategies in synchronous and metachronous OMPC. Patient summary: A group of Dutch medical specialists agreed that prostate cancer patients having few metastases may benefit from a new therapeutic approach. Clinical studies need to determine which treatment is best for each specific situation. A multidisciplinary panel reached consensus that oligometastatic prostate cancer (OMPC) is a specific disease state requiring a tailored treatment approach. OMPC registries and clinical studies should provide insight into the biology and clinical parameters in relation to optimal treatment strategies in synchronous and metachronous OMPC.

BACKGROUND AND PURPOSE: Radical cystectomy (RC) is considered standard treatment for muscle-invasive bladder cancer (BC) and high-risk non-muscle invasive BC. In selected cases, bladder-sparing treatment using brachytherapy can be offered. We examined the outcome after brachytherapy in comparison to RC in terms of survival, complications and bladder preservation in patients with cT1G3-T2N0M0 BC.MATERIALS AND METHODS: Between 1988 and 2016, 301 patients underwent brachytherapy in two centres. Overall survival (OS) and disease specific survival (DSS) after brachytherapy and RC were assessed using Kaplan-Meier curves. Cox proportional hazards modelling was used to determine variables associated with OS and DSS. Local recurrences, bladder preservation and salvage cystectomy (SC) after brachytherapy were reported. Complications after brachytherapy, RC and SC were compared using CTCAE criteria.RESULTS: Median follow-up was 9.6 years (95% confidence interval (CI): 8.8-10.4) after brachytherapy and 10.6 years (95% CI: 10.0-11.2) after RC. Five/10-year OS was 66%/49% after brachytherapy and 68%/53% after RC (p = 0.4). Five/10-year DSS was 73%/67% after brachytherapy and 75%/65% after RC (p = 0.8). Intravesical recurrence occurred in 58/259 brachytherapy patients after which salvage cystectomy was performed in 32 patients. In total, 84% of brachytherapy-treated patients preserved their bladder. The brachytherapy cohort experienced less high grade complications than the RC cohort (p = 0.02).CONCLUSION: In selected patients with solitary, ≤5 cm cT1G3-T2N0M0 bladder tumours brachytherapy is a bladder-sparing therapy with good survival outcome and with a favourable complication rate compared to RC.

Introduction Urachal adenocarcinoma (UrAC) is a rare malignancy arising from persistent urachal remnants, which can cause peritoneal metastases (PM). Currently, patients with this stage UrAC are considered beyond cure. Our objective is to report long-term oncological outcome after cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) for patients with PM of urachal adenocarcinoma (UrAC). Materials and methods We identified 55 patients with UrAC treated at our hospital between 1994 and 2017. Patients were staged with CT, bone scintigraphy and/or PET/CT. From 2001 on, cN0M0 patients underwent staging laparoscopy. Ten patients had PM and were treated with CRS/HIPEC; 35 showed no metastases and underwent local treatment; 10 had distant metastases and received palliative chemotherapy. Disease-specific survival (DSS) rates were estimated using the Kaplan-Meier method and log-rank tests. Postoperative complications represent a secondary outcome. Results The median follow-up was 96.8 months. Of the CRS/HIPEC patients, 5 (50%) developed a recurrence; 4 (40%) died of disease. The 2-yr and 5-yr DSS after CRS/HIPEC were 66.7% and 55.6%, respectively. DSS of the CRS/HIPEC patients did not significantly differ from DSS of patients without metastases who only underwent curative local treatment and was superior to patients with distant metastases (P = 0.012). The overall complication rate after CRS/HIPEC was 60%. Major complications (Clavien 3) constituted 20%. The study is limited by its retrospective nature and the small sample size. Conclusion CRS/HIPEC demonstrates satisfactory long-term oncological outcome for patients with PM of UrAC. It may be offered as a potentially curative treatment option for this group of patients.

Background: Robot-assisted laparoscopic (RAL) implantation of brachytherapy catheters (BTCs) can be a minimally invasive alternative to open retropubic implantation. Descriptions of the surgical technique and outcomes are sparse. Objective: To describe our technique and perioperative outcomes for RAL BTC implantation in urothelial carcinoma (UC) and urachal carcinoma (UraC). Design, setting and participants: Between June 2011 and May 2016, 26 patients with cN0M0 solitary T1G3 or T2G1-3 UC of ≤5. cm or cN0M0 UraC were scheduled for external beam radiotherapy (20. ×. 2. Gy), RAL BTC implantation, and pulsed-dose (29. ×. 1.04. Gy) or high-dose rate brachytherapy (10. ×. 2.50. Gy). Median follow-up was 12 mo (interquartile range 4-20). Surgical procedure: RAL BTC implantation with or without pelvic lymph node dissection and/or partial cystectomy. Measurements and statistical analysis: Perioperative data, complications, disease-free-survival (DFS), local recurrence-free survival (LRFS), and cystectomy-free survival (CFS) were evaluated as well as the feasibility of the technique. Results and limitations: BTC implantation was successful in 92% of the patients. Median hospitalisation was 5 d (interquartile range 4-7) and blood loss

Background. The efficacy of focal continuous low dose-rate brachytherapy (CLDR-BT) for prostate cancer requires that appropriate margins are applied to ensure robust target coverage. In this study we propose a method to establish such margins by emulating a focal treatment in patients treated with CLDR-BT to the entire gland.Material and methods. In 15 patients with localized prostate cancer, prostate volumes and dominant intra-prostatic lesions were delineated on pre-treatment magnetic resonance imaging (MRI). Delineations and MRI were registered to trans-rectal ultrasound images in the operating theater. The patients received CLDR-BT treatment to the total prostate volume. The implantation consisted of two parts: an experimental focal plan covering the dominant intra-prostatic lesion (F-GTV), followed by a plan containing additional seeds to achieve entire prostate coverage. Isodose surfaces were reconstructed using follow-up computed tomography (CT). The focal dose was emulated by reconstructing seeds from the focal plan only. The distance to agreement between planned and delivered isodose surfaces and F-GTV coverage was determined to calculate the margin required for robust treatment.Results. If patients had been treated only focally, the target volume would have been reduced from an average of 40.9 cm3 for the entire prostate to 5.8 cm3 for the focal plan. The D90 for the F-GTV in the focal plan was 195 ± 60 Gy, the V100 was 94% [range 71–100%]. The maximum distance (cd95) between the planned and delivered isodose contours was 0.48 cm.Conclusions. This study provides an estimate of 0.5 cm for the margin required for robust coverage of a focal target volume prior to actually implementing a focal treatment protocol.

Objectives: The pre-treatment risk of seminal vesicle (SV) invasion (SVI) from prostate cancer is currently based on nomograms which include clinical stage (cT), Gleason score (GS) and prostate-specific antigen (PSA). The aim of our study was to evaluate the staging accuracy of 3 T (3T) multi-parametric (mp) Magnetic Resonance Imaging (MRI) by comparing the imaging report of SVI with the tissue histopathology. The additional value in the existing prediction models and the role of radiologists' experience were also examined. Methods: After obtaining institutional review board approval, we retrospectively reviewed clinico-pathological data from 527 patients who underwent a robot-assisted radical prostatectomy (RARP) between January 2012 and March 2015. Preoperative prostate imaging with an endorectal 3T-mp-MRI was performed in all patients. Sequences consisted of an axial pre-contrast T1 sequence, three orthogonally-oriented T2 sequences, axial diffusion weighted and dynamic contrast-enhanced sequences. We considered SVI in case of low-signal intensity in the SV on T2-weighted sequences or apparent mass while diffusion-weighted and DCE sequences were used to confirm findings on T2. Whole-mount section pathology was performed in all patients. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of MRI (index test) for the prediction of histological SVI (reference standard) were calculated. We developed logistic multivariable regression models including: clinical variables (PSA, cT, percentage of involved cores/total cores, primary GS 4-5) and Partin table estimates. MRI results (negative/positive exam) were then added in the models and the multivariate modeling was reassessed. In order to assess the extent of SVI and the reason for mismatch with pathology an MRI-review from an expert genitourinary radiologist was performed in a subgroup of 379 patients. Results: A total of 54 patients (10%) were found to have SVI on RARP-histopathology. In the overall cohort sensitivity, specificity, PPV and NPV for SVI detection on MRI were 75.9%, 94.7%, 62% and 97% respectively. Based on our sub-analysis, the radiologist's expertise improved the accuracy demonstrating a sensitivity, specificity, PPV and NPV of 85.4%, 95.6%, 70.0% and 98.2%, respectively. In the multivariate analysis PSA (odds ratio [OR] 1.07, p = 0.008), primary GS 4 or 5 (OR 3.671, p= 0.007) and Partin estimates (OR 1.07, p = 0.023) were significant predictors of SVI. When MRI results were added to the analysis, a highly significant prediction of SVI was observed (OR 45.9, p

Background and purpose The reliability of post-implant dosimetry in the OR depends on the geometrical variability of implant and anatomy after the procedure. The purpose was to gain detailed information on seed displacement patterns in different sectors of the prostate. Materials and methods Of 33 patients with stranded seed implants the seed geometry and the dose distribution were compared between the situation in the OR just after the procedure, based on ultrasound images, and the situation after 1month, based on registered CT and MR images. Results There was a substantial displacement of ventral seeds of 3.8±2.5mm in caudal direction ( p p D 90 in the dorsal-caudal and ventral-caudal sectors increased with respectively 44±20Gy and 29±28Gy ( p p =0.008). Conclusions There were substantial changes in dose distribution 1month after the procedure, mainly due to implant and prostate shrinkage and displacement of ventral seed strands in caudal direction. When performing dynamic dosimetry or dosimetry at the end of the procedure the effect of these phenomena has to be taken into account when using stranded seeds.

Background and Purpose To investigate possible relationships between the dose to the sub-segments of the lower urinary tract and lower urinary tract symptoms (LUTS) after brachytherapy of the prostate. Materials and Methods This study involved 225 patients treated for prostate cancer with I-125 seeds. Post-implant dose-volume histograms of the prostate, urethra, bladder wall, bladder neck and external sphincter were determined. Endpoints were the mean and the maximum International Prostate Symptom Score (IPSS) during the first 3 months after the treatment. For binary analysis the patients were stratified in a group with enhanced LUTS and a group with non-enhanced LUTS. Results The dose to 0.5 cm 3 of the bladder neck ‘ D 0.5cc -blne’ ( p = 0.002 and p = 0.005), the prostate volume prior to treatment ‘ V pr -0’ ( p = 0.005 and p = 0.024) and the pre-treatment IPSS (both p D 0.5cc -blne ⩾ 175 Gy and a V pr -0 ⩾ 42 cm 3 , 68% suffered from enhanced LUTS, against just 30% of the other patients ( p Conclusions Pre-treatment IPSS, prostate volume and dose to the bladder neck are correlated with post-implant IPSS. A combination of a large prostate and a high dose to the bladder neck is highly predictive for enhanced early LUTS.

We assessed the prognostic significance of extranodal extension, defined as tumor extension through the lymph node capsule into the perinodal fibrous-adipose tissue, as well as several other risk factors in node positive penile cancer cases.We analyzed prospectively collected data on a consecutive series of 156 chemotherapy naïve patients with proven lymph node involvement who underwent therapeutic regional lymphadenectomy. Postoperative external radiotherapy was indicated when histopathological analysis revealed more tumor than 1 intranodal metastasis. We estimated cancer specific survival using the Kaplan-Meier method. Multivariate analysis was done according to the Cox proportional hazards model of factors statistically significant on univariate analysis.Adjuvant radiotherapy was done in 70 patients (45%). Median followup was 57.8 months. Overall 5-year cancer specific survival was 61%. Men with extranodal extension had significantly decreased 5-year cancer specific survival compared with men without it (42% vs 80%). Other prognostic variables on univariate analysis were bilateral metastatic involvement vs unilateral, 3 or greater unilateral metastatic inguinal nodes vs 2 or fewer, inguinal lymphadenectomy positive margin status vs negative status and pelvic lymph node involvement. Pathological T stage or differentiation grade were not significant predictors of outcome. On multivariate analysis extranodal extension and pelvic lymph node involvement remained associated with decreased cancer specific survival (HR 2.37 and 2.20, respectively).Metastatic inguinal lymph node extranodal extension and pelvic lymph node involvement are independent predictive parameters of cancer specific survival in patients with pathologically node positive penile carcinoma despite surgery with postoperative radiotherapy.

Purpose Reduction of the number of implantation needles for prostate brachytherapy will shorten the duration of implantation procedures and possibly reduce trauma-related morbidity. The purpose of this study was to investigate possibilities for the minimization of the number of needles and to investigate the consequences for the dose distribution. Methods and Materials A planning study for six different prostate volumes was performed. The number of needles was minimized by changing fixed 1 cm interseed spacing to free interseed spacing within the needles and by increasing the seed activity. Dose–volume parameters of prostate and organs at risk (OAR) bladder, rectum, and urethra were determined. For plans with different needle and seed configurations, the sensitivity for random seed placement inaccuracies was tested. Dose distributions of realized implants based on fixed ( n = 21) and free interseed spacing (n = 21) were compared. Results The average number of needles (±1 standard deviation) could be reduced from 18.8 ± 3.6 to 12.7 ± 2.9 (−33%) when changing from fixed interseed spacing to free interseed spacing and subsequently to 7.3 ± 1.0 (−42%) by increasing the seed strength from 0.57 U to 1.14 U. These needle reductions resulted in increased dose inhomogeneity within the prostate and increased sensitivity of dose–volume parameters of the OAR for random geometrical inaccuracies. Introduction of free interseed spacing in our clinic resulted in very satisfactory dose coverage of the prostate ( D 90 = 172 ± 17 Gy), while the average number of needles was reduced by 30%. Conclusions Substantial reduction of the number of implantation needles is possible without compromising adequate dose coverage of the prostate. However, the chance of an unpredicted high dose to the OAR increases as fewer needles are used.

Context After implantation of the prostate with I-125 or Pd-103 seeds, the majority of patients develop lower urinary tract symptoms (LUTS). There is not yet general agreement among practitioners on how to predict or prevent these symptoms. Objective To examine agreements and disagreements in relevant publications regarding severity, resolution and methods to predict and reduce LUTS after brachytherapy of the prostate. Evidence acquisition The database of the U.S. National Library of Medicine (PubMed) was searched for the terms "quality of life" and "urinary morbidity" in combination with either "prostate brachytherapy" or "prostate seed implants". Also relevant references of retrieved publications were reviewed. Papers reporting severity and resolution of post-implant urinary symptoms as well as papers analysing correlations between these symptoms and physical characteristics of the brachytherapy treatment were selected for the study. Evidence synthesis Post-implant LUTS vary from increased urinary voiding frequency to acute urinary retention (AUR) and are usually temporal phenomena. Prophylactic use of α-blockers significantly reduces the severity and resolution time of LUTS. There is reasonable agreement on the relation between prostate size and AUR. For other obstructive and irritative urinary symptoms there is less agreement about the predictors. The possible relation between dose to the urethra and LUTS is often investigated but there is no unambiguous evidence that there is any relation between both. Recently, high dose to small volumes of the bladder wall was identified as a predictor for LUTS. In a limited number of cases (1%–5%) persisting extreme symptoms have to be managed by means of a trans-urethral resection of the prostate (TURP). TURP procedures after brachytherapy, however, carry significant risk of inducing urinary incontinence. Conclusions Prophylactic use of α-blockers is required to reduce post-implant LUTS. Patients with large prostates carry a higher risk to develop AUR. Access needle puncturing and seed placements in the bladder wall have to be avoided.

There is growing concern that some cytotoxic regimens for cancer affect cognitive functioning. This study examined the prevalence of cognitive complaints and deficits in testicular cancer (TC) patients treated with the worldwide standard BEP (bleomycin, etoposide and cisplatin) chemotherapy.Seventy TC patients treated with BEP chemotherapy after surgery (S + CT) were examined with interviews and neuropsychological tests. These patients were compared with 57 TC patients treated with radiotherapy after surgery (S + RT) and with 55 TC patients that received surgery only (S). Patients were examined a median of 3 years after completion of treatment.Thirty two percent of the S + CT patients reported cognitive complaints compared with 32% of the S + RT patients and 27% of the S patients (p = 0.85). No differences in mean cognitive test performance were observed between the groups. On individual impairment scores, more S + CT patients showed cognitive dysfunction compared with S patients, but not compared with S + RT patients (S + CT versus S [p = 0.038, OR = 4.6, CI = 1.1-19.7], S + CT versus S + RT [p = 0.70, OR = 0.8, CI = 0.3-2.4] and S + RT versus S [p = 0.070, OR = 3.7, CI = 0.8-15.7). Cognitive complaints were not related to cognitive test performance, but to emotional distress and fatigue.Cognitive complaints are common among TC patients, independent of treatment modality. These complaints are related to emotional distress and fatigue and not to formal cognitive deficits. The finding of a small group of TC patients treated with chemotherapy exhibiting cognitive deficits should be confirmed in a prospective study before we can decide on its cause and relevance.

Purpose After prostate implantation, dose calculation is usually based on a single imaging session, assuming no geometrical changes occur during the months of dose accumulation. In this study, the effect of changes in anatomy and implant geometry on the dose distribution was investigated. Materials and methods One day, 1 month and 3 1 2 months after seed implantation, a combined TRUS-CT scan was made of 13 patients. Based on these scans changes in dose rate distribution were determined in prostate, urethra and bladder and a ‘geometry corrected' dose distribution was estimated. Results When based on the day-1 scan, parameters representing high dose volumes in prostate and urethra were largely underestimated: V150 of the prostate 18±10% and V120 of the urethra 47±32%. The dose to a 2cm 3 hotspot in the bladder wall (D2cc), however, was overestimated by 31±35%. Parameters based on scans 1 month post-implant or later were all within ±5% of geometry corrected values. Conclusion Values meant to indicate the adequacy of dose coverage of the prostate, V100 and D90, were not influenced by geometrical changes and were independent of the post-implant scan date. Other parameters representing high dose volumes changed strongly within the first month after implantation.

The radiotherapy panel met to develop international consensus about the optimal use of radiotherapy, alone or in combination with surgery and chemotherapy, in the radical treatment of patients with bladder cancer. A consensus meeting of experts in the treatment of bladder cancer was convened by the Société Internationale d'Urologie (SIU). The radiotherapy committee, which had international representation from 6 countries, performed a critical review of the English-language literature and developed evidence-based guidelines for the use of radiotherapy in the treatment of patients with bladder cancer. The strength of the evidence supporting each recommendation was ranked according to a 4-point scale. Consensus statements were developed that address (1) the effectiveness of radiotherapy in the treatment of bladder cancer, (2) the most appropriate patients for curative treatment with radiotherapy, (3) the optimal method of delivery of radiotherapy, (4) the best radiation prescription for treating bladder cancer, and (5) optimal management of the patient's condition after radiotherapy has been provided. Radiotherapy is effective treatment for selected patients with bladder cancer; it produces long-term disease control with preservation of normal bladder function. Modern radiotherapy treatment techniques offer the potential to improve cure rates and reduce adverse effects. All patients in whom the condition is newly diagnosed should be assessed in a multidisciplinary setting, where the relative merits of surgery, radiotherapy, and chemotherapy can be considered on an individual basis with the aim of optimizing overall outcomes.

Objective: To evaluate the long-term survival following brachytherapy and following cystectomy of patients with invasive bladder cancer treated in our institution. Patients and methods: Between 1988 and 2000 108 patients with solitary, organ confined T1–T2 invasive bladder cancer of ≤5cm were treated with a transurethral resection, and a course of external beam radiotherapy (30Gy) followed by 40Gy brachytherapy. The overall and disease specific survival rates of these patients are compared with those of 77 patients with T1–T2 invasive bladder cancer treated with cystectomy between 1988–2003. Results: The 5/10 year overall survival rates were 62%/50% after brachytherapy and 67%/58% after cystectomy ( p =0.67). The 5/10 year disease specific survival rates were 73%/67% after brachytherapy and 72%/72% after cystectomy ( p =0.28). When adjusted for age, multiplicity, T-stage, N-stage and grade, the 5/10 year overall survival rates were 65%/53% after brachytherapy and 62%/51% after cystectomy, respectively. The adjusted disease specific survival rates were 75%/70% after brachytherapy and 66%/66% after cystectomy. Conclusions: This study does not provide evidence regarding survival against the use of bladder preservation with brachytherapy for patients with solitary, T1–T2 invasive bladder cancer of ≤5cm diameter, seeking bladder-sparing alternatives to radical cystectomy.

To study dose-effect relations of prostate implants with I-125 seeds, accurate knowledge of the dose distribution in the prostate is essential. Commonly, a post-implant computed tomography (CT) scan is used to determine the geometry of the implant and to delineate the contours of the prostate. However, the delineation of the prostate on CT slices is very cumbersome due to poor contrast between the prostate capsule and surrounding tissues. Transrectal Ultrasound (TRUS) on the other hand offers good visualization of the prostate but poor visualization of the implanted seeds. The purpose of this study was to investigate the applicability of combining CT with 3D TRUS by means of image fusion. The advantage of fused TRUS-CT imaging is that both prostate contours and implanted seeds will be well visible. In our clinic, post-implant imaging was realized by simultaneously acquiring a TRUS scan and a CT scan. The TRUS transducer was inserted while the patient was on the CT couch and the CT scan was made directly after the TRUS scan, with the probe still in situ. With the TRUS transducer being visible on both TRUS and CT images, the geometrical relationship between both image sets could be defined by registration on the transducer. Having proven the applicability of simultaneous imaging, the accuracy of this registration method was investigated by additional registration on visible seeds, after preregistration on the transducer. In 4 out of 23 investigated cases an automatic grey value registration on seeds failed for each of the investigated cost functions, and in 2 cases for both cost functions, due to poor visibility of the seeds on the TRUS scan. The average deviations of the seed registration with respect to the transducer registration were negligible. However, in a few individual cases the deviations were significant and probably due to movement of the patient between TRUS and CT scan. In case of a registration on the transducer it is important to avoid patient movement in-between the TRUS and CT scan and to keep the time in-between the scans as short as possible. It can be concluded that fusion of a CT scan and a simultaneously made TRUS scan by means of a three-dimensional (3D) transducer is feasible and accurate when performing a registration on the transducer, if necessary, fine-tuned by a registration on seeds. These fused images are likely to be of great value for post-implant dose distribution evaluations.

Purpose To evaluate our long-term results of bladder preservation with brachytherapy in the treatment of bladder cancer. Methods and materials Between 1987 and 2000, 108 patients with T1-G3 and T2-T3a stages of bladder cancer were treated with a transurethral resection (TUR) and a course of external beam radiotherapy (30 Gy in 15 fractions) followed by brachytherapy (40 Gy). All tumors were solitary lesions with a diameter ≤5 cm. Median follow-up was 54 months (range, 1–178 months). Results The 5-year and 10-year overall survival rates were 62% and 50%, respectively. The 5-year and 10-year disease-specific survival rates were 73% and 67%, respectively. The actuarial local control rate was 73% at 5 and 73% at 10 years, respectively. The 5-year and 10-year disease-specific survival rates for patients with a preserved bladder were 68% and 59%, respectively. Of all long-term surviving patients, 90% preserved their native bladders. The treatment was well tolerated. Acute toxicity was mild. Two patients experienced serious late toxicity: 1 patient developed a persisting vesicocutaneous fistula and the other a stricture of the urethra and ureters. Conclusion For patients with solitary, organ confined invasive bladder cancer ≤5 cm, bladder preservation with brachytherapy is an excellent alternative to radical cystectomy and combined modality treatment.

OBJECTIVE To evaluate the long-term results of salvage cystectomy after interstitial radiotherapy (IRT) and external beam radiotherapy (EBRT) for transitional cell carcinoma, and to assess the morbidity and functional results of the different urinary diversions used. PATIENTS AND METHODS The records of 27 patients treated with salvage cystectomy in one institution between 1988 and 2003 were retrospectively analysed. RESULTS Salvage cystectomy was used after failure of IRT in 14 or EBRT in 13 patients, with a 3- and 5-year survival probability of 46% (95% confidence interval 26–65) and 33 (11–54)%. The 5-year overall survival after cystectomy was 54% after IRT and 14% after EBRT (P = 0.12). Tumour category, response to radiation, American Society of Anesthesiology score, and complete tumour resection had a significant influence on survival. Five of seven patients with incomplete resection died because of local disease, with a median survival of 5 months. There was clinical understaging after radiotherapy in 41% of patients. Nine patients had an orthotopic neobladder, with complete day- and night-time continence in eight and four, respectively. All patients but one had good voiding function. There were early complications in two and late complications in six patients (for Bricker, seven of 14 and none; for Indiana, none of four and two of four). The duration of hospitalization was not influenced by the type of diversion. Erectile function was maintained in four of six patients after a sexuality-preserving cystectomy and neobladder. CONCLUSIONS Salvage cystectomy can be performed with acceptable morbidity using any type of urinary diversion. Understaging after radiotherapy is common, but preoperative selection needs improving. A very significant factor for an adverse outcome and death from local tumour recurrence was incomplete resection, suggesting that salvage cystectomy should only be attempted if complete resection is probable.

The purpose of this study is to develop a model that quantifies in three dimensions changes in bladder shape due to changes in bladder and/or rectal volume. The new technique enables us to predict changes in bladder shape over a short period of time, based on known urinary inflow. Shortly prior to the treatment, the patient will be scanned using a cone beam CT scanner (x-ray volume imager) that is integrated with the linear accelerator. After (automated) delineation of the bladder, the model will be used to predict the short-term shape changes of the bladder for the time interval between image acquisition and dose delivery. The model was developed using multiple daily CT scans of the pelvic area of 19 patients. For each patient, the rigid bony structure in follow-up scans was matched to that of the planning CT scan, and the outer bladder and rectal wall were delineated. Each bladder wall was subdivided in 2500 domains. A fixed reference point inside the bladder was used to calculate for each bladder structure a "Mercator-like" 2D scalar map (similar to a height map of the globe), containing the distances from this reference point to each domain on the bladder wall. Subsequently, for all bladder shapes of a patient and for all domains on the wall individually, the distance to the reference point was fitted by a linear function of both bladder and rectal volume. The model uses an existing bladder structure to create a new structure via expansion (or contraction), until the expressed volume is reached. To evaluate the predictive power of the model, the jack-knife method was used. The errors in the fitting procedure depended on the part of the bladder and range from 0 to 0.5 cm (0.2 cm on average). It was found that a volume increase of 150 cc can lead to a displacement up to about 2.5 cm of the cranial part of the bladder. With the model, the uncertainty in the position of the bladder wall can be reduced down to a maximum value of about 0.5 cm in case the bladder volume increase is known. Furthermore, it was found that a change in rectal filling causes a shift of the bladder, while its shape is hardly influenced. In conclusion, we developed a model that describes the bladder shape and position as a function of the bladder volume and the rectal filling. The model accurately describes the complex shape of the bladder as it works on each domain of the bladder separately.

PURPOSE: To determine the efficacy and safety of a high-dose-rate (HDR) brachytherapy schedule in the treatment of bladder cancer and to investigate the impact of different values of repair half-times and alpha/beta ratios on the design of the HDR schedule.METHODS AND MATERIALS: Between 2000 and 2002, 40 patients with T1G3 and T2 bladder carcinoma were treated with 30 Gy external beam radiotherapy followed by interstitial HDR brachytherapy to a total dose of 32 Gy in 10 sessions of 3.2-Gy fractions in two fractions daily with a 6-h interfraction interval. The local control rate and toxicity were compared with a historical group of 108 patients treated with 30 Gy external beam radiotherapy followed by 40-Gy interstitial low-dose-rate (LDR) brachytherapy. The HDR schedule was designed to be biologically equivalent to the previously used LDR schedule with the linear-quadratic model, including incomplete mono-exponential repair.RESULTS: The local control rate at 2 years was 72% for HDR vs. 88% for LDR brachytherapy (p = 0.04). In the HDR group, 5 of 30 evaluable patients encountered serious late toxicity: 4 patients developed a contracted bladder with inadequate capacity (CONCLUSION: Local control of HDR brachytherapy for bladder cancer was disappointing and late toxicity unexpectedly high. The increase in late toxicity suggested a short repair half-time of 0.5-1 h for late-responding normal bladder tissue, which would not support HDR brachytherapy in the treatment of bladder cancer. The analysis demonstrated that the calculation of equivalent HDR schedules on the basis of the LDR schedules used in clinical practice might be hazardous.

Background and purpose We investigated the application of a differential target- and dose prescription concept for low-dose-rate prostate brachytherapy (LDR-BT), involving a re-distribution of dose according to risk of local failure and treatment-related morbidity. Material and methods Our study included 15 patients. Multi-parametric MRI was acquired prior to LDR-BT for gross tumor volume (GTV) delineation. Trans-rectal ultrasound (US) images were acquired during LDR-BT for prostate gland- (CTV Prostate ) and organs at risk delineation. The GTV contour was transferred to US images after US/MRI registration. An intermediate-risk target volume (CTV Prostate ) and a high-risk target volume (CTV HR =GTV+5mm margin) were defined. Two virtual dose plans were made: Plan risk-adapt consisted of a de-escalated dose of minimum 125Gy to the CTV Prostate and an escalated dose to 145–250Gy to the CTV HR ; Plan ref included the standard clinical dose of minimum 145Gy to the CTV Prostate . Dose-volume-histogram (DVH) parameters were expressed in equivalent 2Gy fractionation doses. Results The median D 90% to the GTV and CTV HR significantly increased by 44Gy and 17Gy, respectively when comparing Plan risk-adapt to Plan ref . The median D 10% and D 30% to the urethra significantly decreased by 9Gy and 11Gy, respectively and for bladder neck by 18Gy and 15Gy, respectively. The median rectal D 2.0cm 3 had a significant decrease of4Gy, while the median rectal D 0.1cm 3 showed an increase of 1Gy. Conclusions Our risk adaptive target- and dose prescription concept of prescribing a lower dose to the whole gland and an escalated dose to the GTV using LDR-BT seed planning was technically feasible and resulted in a significant dose-reduction to urethra and bladder neck.

Background and purpose : In a recent study on patients with transitional cell cancer of the bladder treated with curative radiotherapy following TUR-T, we demonstrated that a low apoptotic index and p53 positivity were associated with poor local control. The purpose of this study was to assess the prognostic significance of additional markers implicated in regulation of cell cycle and apoptosis. Patients and methods : Bcl-2, Bax and p21 positivity were detected immunohistochemically on paraffin-embedded pre-treatment biopsies from 83 patients with invasive transitional cell cancer (TCC) of the bladder, treated with radiotherapy. In addition, markers determined in an earlier analysis, i.e.: p53, apoptotic index, cyclin D1, retinoblastoma protein and Ki-67 were included in the multivariate analysis. A stepwise proportional hazard analysis was performed, adjusting for classic prognostic factors (T-stage, grade, multifocality and macroscopic completeness of the TUR). Positivity was defined as >10% of tumor cells staining positive for Bcl-2, Bax and p21, and >20% for p53. Results: Bcl-2 positivity was found in 63%, Bax was positive in 52% and p21 in 55% of cases. In the PH analysis Bcl-2 positivity was found to be related to poor local control (36 vs. 72% at 3 years; P =0.003), as well as to shorter disease-specific survival (74 vs. 94% at 3 years; P =0.017). Evidence for an adverse effect of p53 positivity was also found (local control: 32 vs. 69% at 3 years; P =0.037, disease-specific survival: 76 vs. 92% at 3 years; P =0.043). In an additional PH analysis, we found poor local control rates for bladder cancers with combined Bcl-2 and p53 positivity (17 vs. 65% at 3 years; P =0.0017), and lower disease specific survival (60 vs. 92%; P =0.0024), disease-free survival (7 vs.35%, P =0.0023) and overall survival (39 vs. 80%; P =0.0018). Conclusion : This study provides evidence for a poor outcome in patients treated with radiotherapy for TCC of the bladder expressing both Bcl-2 and p53. This relationship was found for local control and disease-free, disease-specific and overall survival.

Background and purpose : The three-dimensional (3D) dose distribution in combination with 3D anatomy of 13 patients treated for cervical carcinoma with intracavitary brachytherapy was analyzed. The aim of this study was to determine the correlation between a dose value obtained from the integral dose volume histogram (DVH) of the rectum and (a) the Nederlands Kanker Instituut (NKI) point of reference for the rectum dose ( R ) and (b) the highest dose to the frontal rectum wall in the transverse CT slice near the top of the vagina through point R . Results : The correlation between the DVH rectum dose value for 2 cm 3 in the highest dose region and the rectum dose at point R was poor (regression coefficient 0.50). On the contrary, however, the correlation between the DVH rectum dose value for 2 cm 3 in the highest dose region and the maximum rectum dose value in a transverse CT slice through point R was good (regression coefficient 0.90). Conclusions : The maximal rectum dose value obtained from a transverse CT slice near the top of the vagina through point R was found to be a more representative point for the rectal dose burden and might therefore show a good correlation with complications. The point of reference for the rectal dose ( R ) was found not to be a reliable estimation of the maximal dose in the rectum.

Purpose: A disadvantage of ovoid shields in a Fletcher-type applicator is that these shields cause artifacts on postimplant CT images. CT images, however, make it possible to calculate the dose distribution in the rectum and the bladder. To be able to estimate the possible advantage of having CT information over the use of ovoid shields without having CT information, we investigated the influence of shielding segments in a Fletcher-type Selectron-LDR applicator on the dose distribution in rectum and bladder. Methods and Materials: Contours of rectum and bladder were delineated on transaxial CT slices of 15 unshielded applications the volumes contained within these structures dose-volume histograms (DVHs) were calculated. In a similar way, DVHs of simulated shielded applications were calculated. The reduction, due to shielding, of the dose to the 2 cm 3 (D 2 ) and 5 cm 3 (D 5 ) volume of the cumulative DVHs of rectum and bladder, were determined. An isodose pattern in the sagittal plane through the center of each applicator was plotted to compare the location of the shielded area with the location of maximum dose in rectum and bladder in the unshielded situation. In two cases local dose reductions to the rectal wall were determined by calculating the dose in points at 10-mm intervals on the rectal contours. Results: For the rectum, the reduction of D 2 ranged from 0 to 11.1%, with an average of 5.0%; the reduction of D 5 ranged from 2.3 to 12.1%, with an average of 6.4%. The reduction of D 2 and D 5 for the bladder ranged from 0 to 11.9% and from 0 to 11.6%, with average values of 2.2 and 2.6%, respectively. In 8 out of 15 eases the rectal maximum dose was located inferior to the shielded area. In all cases except one the bladder maximum dose was located superior to the shielded area. Local dose reductions on the rectal wall can be as high as 30% or more in an optimally shielded area. Conclusions: Reductions of D 2 and D 5 to rectum and bladder due to shielding are rather small, because the shielded area does usually not coincide with the high dose region and even if it does, the shielded area is too small to result in large reductions of these values. Because local dose reductions vary largely, one should proceed with caution when calculating the dose in just one rectal or bladder reference point. Because large overall dose reductions cannot be achieved with shielding, it is safe to use an unshielded applicator when post implant CT images are used to realize optimized dose distributions.

Purpose of review To highlight recent developments in the selection of patients for bladder preservation and in the optimization of outcome after radiation. Recent findings Techniques in the delivery of radiation continue to improve. Increasing phase II evidence indicates that bladder preservation with multimodality approaches is safe and effective in selected patients. The list of molecular markers of bladder cancer with potential clinical relevance continues to extend. Summary Three studies on target delineation, set-up errors and organ motion during radiation show that radiation techniques can be improved considerably thereby reducing the risk of geographical miss. Two large studies with long follow-ups report excellent outcome after bladder preserving treatment strategies using concurrent chemotherapy and radiation. Results seem comparable with those reported for contemporary radical cystectomy. Molecular characterization of bladder cancer is rapidly expanding, but has up to now no established role in the selection or tailoring of treatment options for individual bladder cancer patients.

Squamous cell carcinoma of the penis is a rare disease in developed countries. Based on epidemiological data from the comprehensive cancer centers in the Netherlands, the age-adjusted incidence of penile cancer is estimated to be 1.5/100,000. Despite the fact that this disease is readily visible and easily accessible for both diagnostic and surgical interventions patients still present with advanced disease.

Among 118 patients with squamous cell carcinoma of the penis treated at our cancer institute between 1956 and 1989, we analyzed the accuracy of classification, using the tumor, nodes and metastasis system. We analyzed the role of lymphography, computerized tomography and fine needle aspiration cytology as additional staging procedures. The primary tumor (T category) was classified incorrectly in 26% of the cases. Overstaging was noted in 10% of the cases because of unsuspected infiltration and overstaging was noted in 16%. Overstaging occurred because of edema and infection masking the actual size and giving a misconception of infiltration, and also because of primary presentation as large exophytic tumors with no or minimal histopathological infiltration. When the regional lymph nodes were categorized simply as positive or negative 80% of the tumors were classified correctly and 20% incorrectly (13% were false positive and 7% were false negative). Regional lymph node invasion that escaped clinical examination was not detected by any imaging examination or fine needle aspiration cytology study. Positive findings were found only in patients with clinically suspected nodes. The classification of regional nodes by clinical examination only is hardly improved by additional imaging studies. Clinical decisions with respect to the management of regional lymph nodes should not be based on negative findings of lymphangiography, computerized tomography or fine needle aspiration cytology. In patients with proved metastasis additional imaging may be of some help in the detection of pelvic node invasion and the determination of the extent of involvement. We recommend lymphangiography as the examination of choice.

The value of cell kinetic measurements in head and neck tumors in predicting which patients will benefit from accelerated fractionation radiotherapy regimens is being tested in a multicenter European trial (EORTC trial 22851). This paper reports on the first analysis of the correlation of kinetics with outcome in this trial. A proportion of patients in both the accelerated arm (72 Gy in 5 weeks, 1.6Gy per fraction, 45 fractions) and the conventional arm (70–72 Gy in 7–8 weeks, 1.8–2.0 Gy per fraction, 35–40 fractions) were given an i.v. injection of 100 mg/m 2 IUdR (iododeoxyuridine) before treatment, and a tumor biopsy was taken several hours later. The potential doubling time of the tumor (T pot ) was obtained from a flow cytometric analysis of tumor cell nuclei using an anti-IUdR antibody. From a total of 260 patients entered in the trial, 53 have undergone kinetic analysis. Adequate IUdR labeling was seen in 47 patients (88.7%), from which the mean value for Tpot was found to be 4.5 ± 2.5 days (±S.D.). Of the IUdR labeled patients, 30 have now been followed up for at least 1 year, 17 with conventional and 13 with accelerated radiotherapy. These patients were split into those with fast and those with slowly growing tumors, the dividing line being the median T pot value of 4.6 days. After conventional 7-week radiotherapy, 2 of 6 patients with “fast” growing tumors obtained local control compared with 8 of 11 with “slow” growing tumors. A smaller difference in local control was seen been fast and slow tumors in the accelerated arm ( 5 9 vs. 3 4 ). These preliminary data support the hypothesis that patients with fast growing tumors do poorly with conventional radiotherapy and that pretreatment kinetic measurements can select patients at risk. The predictive power of the method must await the final analysis of trial results.

Purpose Lower urinary tract symptoms are frequently observed after I-125 seed implantation of the prostate. More knowledge about causes and predictors is necessary to be able to develop less toxic implantation techniques. The aim of this study was to identify implantation related factors that contribute to post-implant urinary morbidity. Materials and methods Analysed was a group of 72 patients that filled in a symptom score questionnaire before, 3 months and 6 months after implantation as well as a group of 15 patients that suffered from acute urinary retention. Several dose–volume parameters of prostate, urethra and bladder wall were determined based on a post-implant TRUS-CT scan. Results The dose to a 1cm 3 hotspot in the bladder wall (D1cc-bl) as well as the prostate volume were independently correlated with urinary morbidity symptom scores at 3 months ( p =0.006 and p =0.005, respectively) and at 6 months ( p =0.001 and p =0.015, respectively) after implantation. The number of implanted seeds and the D1cc-bl were significant discriminators ( p p =0.015, respectively) for either mild or severe early urinary morbidity. Conclusion Bladder hotspot dose appears to be an important dosimetric predictor for urinary morbidity both at 3 months and at 6 months after implantation. Other predictors are prostate volume, or equivalently, the number of implanted seeds.

We identified pathological parameters of inguinal lymph node involvement with the aim of predicting pelvic lymph node involvement and survival.A total of 308 patients with penile carcinoma and adequate followup were included in this study. The outcome of 102 patients who underwent lymphadenectomy for lymph node metastases was analyzed further. Histopathological characteristics of the regional lymph nodes were reviewed including unilateral or bilateral involvement, the number of involved nodes, pathological tumor grade of the involved nodes, and the presence of extracapsular growth.Tumor grade of the involved inguinal lymph nodes (OR 6.0, 95% CI 1.2-30.3) and the number of involved nodes (2 or less vs more than 2) (OR 12.1, 95% CI 3.0-48.1) were independent prognostic factors for pelvic lymph node involvement. Extracapsular growth (OR 2.3, 95% CI 1.1-4.8), bilateral inguinal involvement OR 3.4, 95% CI 1.2-9.4) and pelvic lymph node involvement (OR 3.1, 95% CI 1.4-6.6) were independent prognostic factors for disease specific survival.Patients with only 1 or 2 inguinal lymph nodes involved without extracapsular growth and no poorly differentiated tumor within these nodes are at low risk of pelvic lymph node involvement and have a good prognosis with a 5-year survival rate of approximately 90%. Pelvic lymph node dissection seems to be unnecessary in these cases.

Organ preservation has been in the forefront of modern cancer treatment for the last few decades. Conservative treatment is now standard of care for numerous malignancies including breast cancer, laryngeal cancer, anal cancer, and soft-tissue sarcomas of the extremities. For patients with muscle-invasive bladder cancer, radical cystectomy with a pelvic lymph node dissection is still considered the standard treatment. Certainly since orthotopic bladder substitution has become available, many urologists prefer early definitive therapy with continent urinary diversion. Lately also for the bladder, organ-preserving strategies have gained renewed interest. Bladder preservation to the patient means less surgery, no need for a urinary diversion, and the possibility of a normal sexual life. Modern sophisticated techniques for urinary diversion have not altered the fact that cystectomy is still associated with physical and psychological limitations. 1 The discussion of bladder-sparing strategies has mainly focused on combinations of cisplatin-containing chemotherapy and external beam radiotherapy (EBRT) after transurethral resection (TUR) of the bladder tumor. 2-5 . In the discussion, the option of treatment with brachytherapy after TUR and EBRT (further addressed as brachytherapy) seems to be largely overlooked. All reports addressing this approach consistently mention high cure rates (70 to 90%) with excellent maintenance of bladder function. 6-11 Regardless of this favorable outcome, brachytherapy for bladder cancer remains a seldom performed procedure, only performed in a few specialized centers, mainly in France and the Netherlands. Brachytherapy for bladder cancer was developed in the first half of the 20th century and existed as the permanent implantation of radon seeds or the temporary implant of radium/cobalt needles or iridium wires. 12-14 Although effective, this form of treatment resulted in radiation exposure to the medical and nursing staff. Patients had to be treated for several days in shielded rooms often far away from the wards with experienced staff. Moreover the implantation of radioactive needles caused urinary leakage and wound infections in many patients, resulting in a mean hospitalization of more than a month. 15 Therefore it is not surprising that the treatment of bladder cancer with brachytherapy became increasingly unpopular. However, since then substantial progress has been made. In the 1980s, after-loading techniques were introduced, which eliminated the radiation exposure to the staff and significantly reduced the complication rate. 7,8 In the 1990s, pulsed dose rate (PDR) and high-dose rate brachytherapy(HDR)machineswithasingleiridiumsourcebecame available. The introduction of these techniques in bladder cancer will reduce the treatment time and thus be a major step forward in treatment logistics. With the fractionated brachytherapy machines, 3D CT scan based planning software became available, allowing dose distribution optimization and integration of brachytherapy with external beam radiotherapy (EBRT) planning. With these improvements, brachytherapy for bladder cancer deserves a second chance.

Purpose: To determine whether the apoptotic index, the Ki67 index, and the expression of the p53, cyclin D1, and retinoblastoma genes correlate with local control, overall survival, and time to distant metastases in invasive bladder cancer treated with external beam radiation. Methods and Materials: Paraffin-embedded pretreatment biopsies from 83 patients with invasive transitional cell carcinoma of the bladder were scored morphologically for apoptosis and immunohistochemically for Ki67, p53, cyclin D1, and retinoblastoma gene expression. Survival analysis methods were used to assess overall survival, local control, and freedom from distant metastases. A multiple proportional hazard (PH) regression analysis was performed to study the prognostic value of the abovementioned biologic parameters (all divided into two categories, except Ki67) in addition to classical prognostic factors such as T stage, histologic grade, multifocality of the tumor, and completeness of transurethral resection. All patients were treated with external beam radiation as sole treatment. Median follow-up for the 19 patients still living was 7.5 years. Results: Apoptotic index varied from 0% to 3.4% with a mean of 0.8% and a median of 0.6%. Ki67 index varied from 0% to 60% with a mean of 14% and a median of 12%. P53 protein was detectable in 61% of the tumors. Overexpression of cyclin D1 was observed in 39% of the tumors and loss of retinoblastoma protein in 23% of the tumors. High Ki67 index was found to be significantly associated with p53 expression ( p = 0.04) and cyclin D1 overexpression ( p = 0.023). Cyclin D1 overexpression was found more often in Rb-positive tumors than in Rb-negative tumors ( p = 0.006). Other associations between the markers are less clear. Biologic markers were not correlated with T stage or grade. In the PH analysis local control was found to be significantly better for tumors with wild-type p53 ( p = 0.028). Also, tumors with an apoptotic index above the median value (0.6%) had a significantly better local control rate ( p = 0.035). Ki67 index ( p = 0.35), retinoblastoma gene expression ( p = 0.30) and cyclin D1 overexpression ( p = 0.61) were not found to have an additional predictive value regarding local tumor control. None of the tested biologic parameters were found to be associated with overall survival. Time to distant metastases was significantly shorter for tumors with high Ki67 index ( p = 0.01) and tumors with an apoptotic index less than median ( p = 0.009). Conclusions: The results of our study provide evidence for a prognostic value of p53 expression and apoptotic index with respect to the radiation response in bladder cancer in addition to more conventional prognosticators. The value of these parameters as a predictive assay for radiation response warrants confirmation in larger and prospective studies.

Eleven patients, ranging in age from 58 to 79 years and referred for 125I implantation because of localised prostatic carcinoma, were subjected to iliopelvic lymphoscintigraphy (IPL) prior to lymph node dissection. Scintigraphy was performed by perianal injection into the ischiorectal fossa of 0.2 ml 99mTc radio-labelled antimony sulphide colloid. The sensitivity of IPL was 100% and the specificity 13%, with a prevalence of positive nodes of 27%. It was concluded that IPL is not useful as a non-surgical method of detecting lymph node invasion in localised prostatic carcinoma because of the low specificity.

Purpose: To evaluate and eventually quantify a possible influence of tumor proliferation during the external radiation course on local control in muscle invasive bladder cancer. %Methods and Materials: The influence of total dose, overall treatment time, and treatment interruption has retrospectively been analyzed in a series of 379 patients with nonmetastasized, muscle-invasive transitional cell carcinoma of the urinary bladder. All patients received external beam radiotherapy at the Netherlands Cancer Institute between 1977 and 1990. Total dose varied between 50 and 75 Gy with a mean of 60.5 Gy and a median of 60.4 Gy. Overall treatment time varied between 20 and 270 days with a mean of 49 days and a median of 41 days. Number of fractions varied between 17 and 36 with a mean of 27 and a median of 26. Two hundred and fourty-four patients had a continuous radiation course, whereas 135 had an intended split course or an unintended treatment interruption. Median follow-up was 22 months for all patients and 82 months for the 30 patients still alive at last follow-up. A stepwise procedure using proportional hazard regression has been used to identify prognostic treatment factors with respect to local recurrence as sole first recurrence. Results: One hundred and thirty-six patients experienced a local recurrence and 120 of these occurred before regional or distant metastases. The actuarial local control rate was 40.3% at 5 years and 32.3% at 10 years. In a multivariate analysis total dose showed a significant association with local control ( p = 0.0039), however in a markedly nonlinear way. In fact only those patients treated with a dose below 57.5 Gy had a significant higher bladder relapse rate, whereas no difference in relapse rate was found among patients treated with doses above 57.5 Gy. This remained the case even after adjustment for overall treatment time and all significant tumor and patient characteristics. The Normalized Tumor Dose (NTD) (α/β = 10) and NTD (α/β = 15) were not significantly related to local control ( p = 0.96 and p = 0.053, respectively). Only weak evidence was found for an association between local control and overall treatment time ( p = 0.067). No difference in bladder relapse rate was found among patients treated with a continuous course and patients who had treatment interruptions ( p = 0.099). Neither the length of the interruption, nor the actual number of treatment days has a significant influence on local control ( p = 0.04 and p = 0.09, respectively). Conclusion: In contrast to two earlier, but smaller reports, in this study no significant effect of treatment prolongation on outcome after radiotherapy could be demonstrated and thus no support was found for an important role for tumor proliferation as the cause of treatment failure in muscle-invasive bladder cancer. Results of large-sized phase III trials will have to be awaited to show any benefit from reduction of the overall treatment time and to quantify the potential effect of tumor proliferation.1998 Elsevier Science Inc.

Purpose: To establish the shortest possible overall treatment time, with respect to acute and late toxicity, in which a radiation dose of 66 Gy in 2 Gy/fraction can be administered to the urinary bladder. Methods and Materials: In a stepwise fashion the overall treatment time of our routinely used conventional treatment schedule (66 Gy in 2 Gy/fraction in 6.5 weeks) was reduced to 5 weeks (Step 1) and then 4 weeks (Step 2). Shortening of the overall treatment time was obtained by giving two daily fractions during the last part of the treatment. The interfraction interval was a minimum of 6 h. Toxicity was scored according to a modified scheme of the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer. Fifteen patients received the 5-week schedule and 25 patients received the 4-week schedule. Results: Note that feasibility was very good for the 5-week schedule. No Grade ≥3 acute bowel or bladder toxicity was seen in these patients. Severe late complications did not occur. In the 4-week schedule, acute bladder toxicity was unaffected but acute bowel toxicity was considerably increased. Of the 25 patients, 16 suffered from Grade 3 toxicity, 3 from Grade 4, and 1 from Grade 5 toxicity. Actuarial analysis at 3 years showed a 31% incidence of Grade 4 late bladder complications. Conclusion: It is concluded that the 5-week schedule is well tolerated. In contrast, the 4-week schedule shows unacceptable acute bowel toxicity and an increased incidence of late bladder comlications ( p = 0.043).

OBJECTIVE To retrospectively analyse the efficacy and toxicity of conservative treatment for T1G3 and T2-3a bladder carcinoma and to compare the results with those obtained in a previous study using caesium implantation. PATIENTS AND METHODS Between 1987 and 1990 12 patients with high-grade T1 tumours and 28 with T2-3a tumours were treated using this combined approach. All tumours were solitary with a diameter not exceeding 5 cm. Treatment consisted of transurethral resection, a course of external irradiation (30 Gy in 15 fractions) to the whole pelvis and an implant procedure. RESULTS With a mean follow-up of 40 months (range 24-65) 31 patients remained free of disease and nine relapsed: three with distant metastases, two with bladder recurrence and four with combined bladder and distant relapse. Three patients showed tumour at the original site. The 5 years actuarial rate of local control was 84% with an overall 5 years actuarial survival of 86%. Early problems included bladder leakage, wound infection and psychological problems. Late complications in four patients, was transient ulceration at the implant side causing mild dysuria. CONCLUSIONS Implantation with iridium is equally effective as with caesium but has significantly fewer complications.