Search

CONTEXT: The primary lesion in penile cancer is managed by surgery or radiation. Surgical options include penile-sparing surgery, amputative surgery, laser excision, and Moh's micrographic surgery. Radiation is applied as external beam radiotherapy (EBRT) and brachytherapy. The treatment aims to completely remove the primary lesion and preserve a sufficient functional penile stump. OBJECTIVE: To assess whether the 5-yr recurrence-free rate and other outcomes, such as sexual function, quality of life, urination, and penile preserving length, vary between various treatment options. EVIDENCE ACQUISITION: The EMBASE, MEDLINE, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials (CENTRAL; Cochrane HTA, DARE, HEED), Google Scholar, and ClinicalTrials.gov were searched for publications from 1990 through May 2021. Randomized controlled trials, nonrandomized comparative studies (NRCSs), and case series (CSs) were included. EVIDENCE SYNTHESIS: The systematic review included 88 studies, involving 9578 men from 16 NRCSs and 72 CSs. The cumulative mean 5-yr recurrence-free rates were 82.0% for penile-sparing surgery, 83.9% for amputative surgery, 78.6% for brachytherapy, 55.2% for EBRT, 69.4% for lasers, and 88.2% for Moh's micrographic surgery, as reported from CSs, and 76.7% for penile-sparing surgery and 93.3% for amputative surgery, as reported from NRCSs. Penile surgery affects sexual function, but amputative surgery causes more appearance concerns. After brachytherapy, 25% of patients reported sexual dysfunction. Both penile-sparing surgery and amputative surgery affect all aspects of psychosocial well-being. CONCLUSIONS: Despite the poor quality of evidence, data suggest that penile-sparing surgery is not inferior to amputative surgery in terms of recurrence rates in selected patients. Based on the available information, however, broadly applicable recommendations cannot be made; appropriate patient selection accounts for the relative success of all the available methods. PATIENT SUMMARY: We reviewed the evidence of various techniques to treat penile tumor and assessed their effectiveness in oncologic control and their functional outcomes. Penile-sparing as well as amputative surgery is an effective treatment option, but amputative surgery has a negative impact on sexual function. Penile-sparing surgery and radiotherapy are associated with a higher risk of local recurrence, but preserve sexual function and quality of life better. Laser and Moh's micrographic surgery could be used for smaller lesions. ispartof: EUROPEAN UROLOGY OPEN SCIENCE vol:40 pages:58-94 ispartof: location:Netherlands status: published

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 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.

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.

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.

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.

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.

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.

Cell kinetic parameters in human tumours were determined by in vivo labelling with iododeoxyuridine (IUdR) followed by flow cytometric analysis of tumour biopsies after staining with a monoclonal antibody against IUdR-DNA. The purpose of this study was to determine the variation in these kinetic parameters from area to area within the same tumour. Each patient received a single i.v. injection of IUdR and the biopsy or operation specimen was taken several hours later. Multiple biopsies were taken or the operation specimen was cut into several pieces. Tumour material was stored in ethanol. Each piece was subsequently processed and stained for analysis separately. The duration of DNA synthesis (Ts), the labelling index (L.I., percent IUdR-labelled cells) and the potential doubling time (Tpot) were determined for each sample. The mean and standard deviation (variation between pieces) for each parameter was calculated for each tumour. The coefficient of variation (C.V.) provided the measure of intratumoural variation. Thirteen tumours were investigated, 6 of which were transitional cell carcinomas of the bladder and 7 of which were squamous cell carcinomas, mostly of the head and neck. Ts values ranged from 4.1 to 17.2 h (mean 9.5 h), L.I. values from 1.6 to 18.6% (mean 9.7%) and Tpot values from 2.3 to 15.1 days (mean 7.2 days). Mean C.V.s for Ts, L.I. and Tpot were 10, 24 and 27%, respectively. Most of the variation in Tpot (calculated from the other two parameters), came from the L.I., with Ts showing much less intratumoural variations. It is concluded that this kinetic method using low IUdR doses can be successfully applied in human tumours and has sufficient accuracy for predictive assay applications in which tumours need to be classified according to their proliferation rates. Further developments are required to distinguish normal and malignant cells flow cytometrically, particularly for diploid tumours.

Tumour cell kinetic parameters were determined in 80 patients by in viva labelling with Iododeoxyuridine followed by flow cytometric analysis of tumour biopsies after staining with a monoclonal antibody against IUdR-DNA. Approximately half of these patients were entered in an EORTC trial of accelerated fractionation in head and neck tumours. The aim is to test the predictive value o f the method for identification of those turnours in which repopulation during fractionated radiotherapy is likely to be of importance. An assessment was made both of the technical success of the method and of the kinetic parameters obtained. A single i.v. injection of 100 mg IUdR proved to be sufficient for labelling. In 88% of the cases sufficient fluorescence signal was obtained to estimate the DNA synthesis time (Ts), the labelling index (LI) and the potential doubling time (Tpot). In 63% of the tumours Tpot was less than 5 days. Large intertumoral variations were observed. The coi?fficiZnt of variations (CV) was 40.4% for Ts, 47% for LI and 57.3% for Tpot. Intratumoral variation was considerably less: CV values were 10.2% for Ts, 24.2% for LI and 26.6 for Tpot. No correlation was seen between Ts, LI and ploidy. Ts was not influenced by the labelling/biopsy time interval. Tpot was inversely correlated with 'LI, but with considerable scatter due to the contribution of a variable Ts. It is concluded that the method using low IUdR doses can be successfully applied iu human turnours. Its accuracy is sufficient for predictive assay applications in which tumours need to be classified according to their proliferation rates. Further developments are required to distinguish normal and malignant cells flow cytometrically, particularly for tumours with a less than tetraploid DNA content.