Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial.

BACKGROUND: Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. METHODS: RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. FINDINGS: Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61-69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1-10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688-1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4-82·5) in the no ADT group and 80·4% (76·6-83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. INTERPRETATION: Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population. FUNDING: Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society.

Docetaxel for Nonmetastatic Prostate Cancer: Long-Term Survival Outcomes in the STAMPEDE Randomized Controlled Trial.

BACKGROUND: STAMPEDE previously reported adding upfront docetaxel improved overall survival for prostate cancer patients starting long-term androgen deprivation therapy. We report long-term results for non-metastatic patients using, as primary outcome, metastatic progression-free survival (mPFS), an externally demonstrated surrogate for overall survival. METHODS: Standard of care (SOC) was androgen deprivation therapy with or without radical prostate radiotherapy. A total of 460 SOC and 230 SOC plus docetaxel were randomly assigned 2:1. Standard survival methods and intention to treat were used. Treatment effect estimates were summarized from adjusted Cox regression models, switching to restricted mean survival time if non-proportional hazards. mPFS (new metastases, skeletal-related events, or prostate cancer death) had 70% power (α = 0.05) for a hazard ratio (HR) of 0.70. Secondary outcome measures included overall survival, failure-free survival (FFS), and progression-free survival (PFS: mPFS, locoregional progression). RESULTS: Median follow-up was 6.5 years with 142 mPFS events on SOC (3 year and 54% increases over previous report). There was no good evidence of an advantage to SOC plus docetaxel on mPFS (HR = 0.89, 95% confidence interval [CI] = 0.66 to 1.19; P = .43); with 5-year mPFS 82% (95% CI = 78% to 87%) SOC plus docetaxel vs 77% (95% CI = 73% to 81%) SOC. Secondary outcomes showed evidence SOC plus docetaxel improved FFS (HR = 0.70, 95% CI = 0.55 to 0.88; P = .002) and PFS (nonproportional P = .03, restricted mean survival time difference = 5.8 months, 95% CI = 0.5 to 11.2; P = .03) but no good evidence of overall survival benefit (125 SOC deaths; HR = 0.88, 95% CI = 0.64 to 1.21; P = .44). There was no evidence SOC plus docetaxel increased late toxicity: post 1 year, 29% SOC and 30% SOC plus docetaxel grade 3-5 toxicity. CONCLUSIONS: There is robust evidence that SOC plus docetaxel improved FFS and PFS (previously shown to increase quality-adjusted life-years), without excess late toxicity, which did not translate into benefit for longer-term outcomes. This may influence patient management in individual cases.

Estimating the percentage of patients who might benefit from proton beam therapy instead of X-ray radiotherapy.

OBJECTIVES: High-energy Proton Beam Therapy (PBT) commenced in England in 2018 and NHS England commissions PBT for 1.5% of patients receiving radical radiotherapy. We sought expert opinion on the level of provision. METHODS: Invitations were sent to 41 colleagues working in PBT, most at one UK centre, to contribute by completing a spreadsheet. 39 responded: 23 (59%) completed the spreadsheet; 16 (41%) declined, arguing that clinical outcome data are lacking, but joined six additional site-specialist oncologists for two consensus meetings. The spreadsheet was pre-populated with incidence data from Cancer Research UK and radiotherapy use data from the National Cancer Registration and Analysis Service. 'Mechanisms of Benefit' of reduced growth impairment, reduced toxicity, dose escalation and reduced second cancer risk were examined. RESULTS: The most reliable figure for percentage of radical radiotherapy patients likely to benefit from PBT was that agreed by 95% of the 23 respondents at 4.3%, slightly larger than current provision. The median was 15% (range 4-92%) and consensus median 13%. The biggest estimated potential benefit was from reducing toxicity, median benefit to 15% (range 4-92%), followed by dose escalation median 3% (range 0 to 47%); consensus values were 12 and 3%. Reduced growth impairment and reduced second cancer risk were calculated to benefit 0.5% and 0.1%. CONCLUSIONS: The most secure estimate of percentage benefit was 4.3% but insufficient clinical outcome data exist for confident estimates. The study supports the NHS approach of using the evidence base and developing it through randomised trials, non-randomised studies and outcomes tracking. ADVANCES IN KNOWLEDGE: Less is known about the percentage of patients who may benefit from PBT than is generally acknowledged. Expert opinion varies widely. Insufficient clinical outcome data exist to provide robust estimates. Considerable further work is needed to address this, including international collaboration; much is already underway but will take time to provide mature data.

Multiple primary malignancies associated with a germline SMARCB1 pathogenic variant.

A 51-year old presented with a 6-month history of increasing pelvic/lower back pain with nocturnal waking and episodes of anorexia and vomiting. Examination revealed right torticollis and Horner's syndrome, and a large abdominal mass arising from the pelvis. Magnetic resonance and positron emission tomography imaging revealed (A) a 14 cm heterogeneous enhancing mass, abutting the left kidney with standardised uptake value max = 2.9, (B) a large heterogeneous enhancing pelvic mass (C) mesenteric adenopathy standardised uptake value max = 10.3 and (D) 6 cm right lung apex mass standardised uptake value max = 4.3. Computerised tomography-guided biopsy of lesion A was reported as neurofibroma with occasional atypia, lesion B a benign uterine leiomyoma and lesion C follicular lymphoma world health organisation Grade 2. Although she had been given the diagnosis of Neurofibromatosis Type-1 (NF1) 25-years previously following removal of an intradural extramedullary schwannoma she had no cutaneous stigmata of NF1. Genetic analysis of blood lymphocyte DNA identified a pathogenic variant in SMARCB1 confirming a diagnosis of schwannomatosis. Following 6-months chemotherapy for lymphoma, surgery was performed to remove lesion A. Histology revealed a malignant peripheral nerve sheath tumour with areas of low and high-grade change. An incidental, well-differentiated small bowel neuroendocrine carcinoma was also excised. Close surveillance continues with no recurrence after 6 years. This case study describes a novel finding of three separate synchronous primary malignancies in a patient with schwannomatosis and a proven SMARCB1 pathogenic variant.

Five-year outcomes after iodine-125 seed brachytherapy for low-risk prostate cancer at three cancer centres in the UK.

OBJECTIVE: To report the outcomes of >1000 men with low-risk prostate cancer treated with low-dose-rate (LDR) brachytherapy at three large UK cancer centres. PATIENTS AND METHODS: A total of 1038 patients with low-risk prostate cancer (prostate-specific antigen [PSA] ≤10 ng/mL, Gleason score 6, ≤T2b disease) were treated with LDR iodine 125 (I-125) brachytherapy between 2002 and 2007. Patients were treated at three UK centres. PSA and clinical follow-up was performed at each centre. Biochemical recurrence-free survival was reported for the cohort. RESULTS: The median (range) PSA follow-up for the whole group was 5 years (4 months to 9 years). A total of 79 patients had biochemical failure, defined by a rise in PSA level: 16 patients fulfilled the ASTRO definition of biochemical failure, 25 patients fulfilled the Phoenix definition and 38 patients fulfilled both definitions. The 5-year biochemical relapse-free survival (bRFS) rate was 94.1% by the ASTRO definition and 94.2% by the Phoenix definition. The absence of neoadjuvant hormone therapy was predictive of inferior biochemical control as defined by the Phoenix definition (P = 0.033). CONCLUSIONS: Our prospective multicentre series showed excellent bRFS with LDR I-125 brachytherapy for patients with low-risk prostate cancer. Further work is necessary to define the role of neoadjuvant androgen deprivation therapy in combination with brachytherapy.

Phase II study of conformal hypofractionated radiotherapy with concurrent gemcitabine in muscle-invasive bladder cancer.

PURPOSE: The aim of this prospective, phase II trial was to determine the response of muscle-invasive bladder cancer (MIBC) to concurrent chemoradiotherapy of weekly gemcitabine with 4 weeks of radiotherapy (RT; GemX). PATIENTS AND METHODS: Fifty patients with transitional cell carcinoma, stage T2-3, N0, M0 after transurethral resection and magnetic resonance imaging, were recruited. Gemcitabine was given intravenously at 100 mg/m(2) on days 1, 8, 15, and 22 of a 28-day RT schedule that delivered 52.5 Gy in 20 fractions. Chemotherapy was stopped for Radiation Therapy Oncology Group (RTOG) grade 3 bladder or bowel toxicity. The primary end points were tumor response, toxicity, and survival. RESULTS: All patients completed RT; 46 tolerated all four cycles of gemcitabine. Two patients stopped after two cycles, and two stopped after three cycles, because of bowel toxicity. Forty-seven patients had a post-treatment cystoscopy; 44 (88%) achieved a complete endoscopic response. At a median follow-up of 36 months (range, 15 to 62 months), 36 patients were alive, and 32 of these had a functional and intact bladder. Fourteen patients died; seven died as a result of metastatic MIBC, five died as a result of intercurrent disease, and two died as a result of treatment-associated deaths. Four patients underwent cystectomy; three because of recurrent disease and one because of toxicity. One patient required a bowel resection for late toxicity. By using Kaplan-Meier analyses, 3-year cancer-specific survival was 82%, and overall survival was 75%. CONCLUSION: Concurrent gemcitabine-based chemoradiotherapy (ie, GemX) produces a high response rate in MIBC and has durable local control and acceptable toxicity, which allows patients to preserve their own bladder. This treatment modality warrants additional investigation in a phase III setting.

Early prostate cancer--which treatment do men prefer and why?

STUDY TYPE: Preference (prospective cohort). LEVEL OF EVIDENCE: 1b. What's known on the subject? and What does the study add? In general the literature suggests that there is a need for improvement in aiding men diagnosed with early prostate cancer in their decision making about treatment options and that our understanding of this process is inadequate. There is limited data analyzing the reasons why these men decide between potentially curative or observational treatments and data evaluating patients' views before and after definitive therapy are scarce. This study begins the process of understanding the reasons underlying a patient's final treatment decision. Being a prospective study, it looks at the thought processes of these men before treatment during the time the decision is made. It also documents how satisfied patients are with their choice after their treatment and whether they would choose the same treatment again. OBJECTIVE: To identify the reasons for patients with localised prostate cancer choosing between treatments and the relationship of procedure type to patient satisfaction post-treatment. PATIENTS AND METHODS: 768 men with prostate cancer (stage T1/2, Gleason≤7, PSA<20 ug/L) chose between four treatments: radical prostatectomy, brachytherapy, conformal radiotherapy and active surveillance. Prior to choosing, patients were counselled by a urological surgeon, clinical (radiation) oncologist and uro-oncology specialist nurse. Pre-treatment reasons for choice were recorded. Post-treatment satisfaction was examined via postal questionnaire. RESULTS: Of the 768 patients, 305 (40%) chose surgery, 237 (31%) conformal beam radiotherapy, 165 (21%) brachytherapy and 61 (8%) active surveillance. Sixty percent of men who opted for radical prostatectomy were motivated by the need for physical removal of the cancer. Conformal radiotherapy was mainly chosen by patients who feared other treatments (n=63, 27%). Most men chose brachytherapy because it was more convenient for their lifestyle (n=64, 39%). Active surveillance was chosen by patients for more varied reasons. Post-treatment satisfaction was assessed in a subgroup who took part in the QOL aspect of this study. Of the respondents to the questionnaire, 212(87.6%) stated that they were satisfied/extremely satisfied with their choice and 171(92.9%) indicated they would choose the same treatment again. CONCLUSION: Men with early prostate cancer have clear reasons for making decisions about treatment. Overall, patients were satisfied with the treatment and indicated that despite different reasons for choosing treatment, they would make the same choice again.

Development of a patient-reported questionnaire for collecting toxicity data following prostate brachytherapy.

PURPOSE: To improve a questionnaire used to collect patient-reported outcomes from patients with early stage prostate cancer treated with brachytherapy. A secondary aim was to adapt the Late Effects of Normal Tissue (LENT) subjective toxicity questionnaire for use to collect Common Terminology Criteria for Adverse Events (CTCAE) data, the current preferred platform for assessing radiation toxicity. MATERIALS AND METHODS: Three hundred and seventy-seven patients were treated with permanent iodine-125 seed implant brachytherapy for early prostate cancer. Toxicity data were collected before and at nine time points post-treatment (0-36 months). Compliance rates for patients completing individual items and item-subsection correlation coefficients were calculated. A factor analysis was carried out to analyse responses to the questionnaire and identify less informative questions, which could be removed. Cronbach's α coefficient was used to measure reliability. RESULTS: Two thousand one hundred and eighty-eight questionnaires were analysed. There was poor compliance for questions specifically relating to operations and bowel medication. We found that the division of the questionnaire into subsections based on anatomical site was reasonable and that certain items could be safely removed. The high mean value for Cronbach's α across all questionnaires (0.752; 95% CI: 0.726-0.779) indicated that the questionnaire was reliable. Fifteen of the 44 questions were removed from the original questionnaires. Questions on urinary incontinence severity, management of urinary and bowel incontinence, effects of reduced flow of urine and the effects of symptoms on activity of daily living and change in sexual function were required to adapt the LENT subjective questionnaire for use to collect CTCAE data. CONCLUSIONS: A questionnaire, validated over 6 years to collect LENT subjective data were adapted and is a reliable approach for collecting CTCAE data after prostate brachytherapy.

Efficacy of data capture for patient-reported toxicity following radiotherapy for prostate or cervical cancer.

We investigated the efficacy of data capture of patient-reported toxicity following radiotherapy by comparing electronic and paper formats. Patient-reported toxicity questionnaires based on items from the NCI Common Terminology Criteria for Adverse Events (CTCAE) were created for patients receiving radiotherapy. Electronic and paper questionnaires had identical questions. Thirty seven gynaecological cancer and 40 prostate cancer patients completed questionnaires. Both questionnaire formats (electronic and paper) were completed by each patient at time points before and after radiotherapy. The average questionnaire and subsection scores for each format were compared directly and by using intra-class correlation (ICC) coefficients. The internal consistency/reliability was assessed by determining Cronbach's alpha coefficient. Patient preference for questionnaire format including clarity and ease-of-use was recorded. 324 questionnaires were collected as part of this study. A similar pattern of average subsection scores was found for the electronic and paper questionnaires. ICC coefficients for the mean overall questionnaire scores and subsection scores were high (>0.8). Cronbach's alpha was generally greater than 0.6, indicating that the reliability was high. Of the patients that responded, 27.3% preferred the electronic format, 25.7% preferred the paper format and 47% had no preference. The average time taken to complete a questionnaire was about 9 minutes for each format. The different questionnaire formats measured toxicity effects consistently and were reliable for both gynaecological cancer and prostate cancer patients. The survey indicated that patients found the questionnaires clear, easy to understand and straightforward to complete. Electronic data capture of patient-reported toxicity for CTCAE is feasible and acceptable.

Assessing the effect of a contouring protocol on postprostatectomy radiotherapy clinical target volumes and interphysician variation.

PURPOSE: To compare postprostatectomy clinical target volume (CTV) delineation before and after the introduction of a contouring protocol and to investigate its effect on interphysician variability METHODS AND MATERIALS: Six site-specialized radiation oncologists independently delineated a CTV on the computed tomography (CT) scans of 3 patients who had received postprostatectomy radiotherapy. At least 3 weeks later this was repeated, but with the physicians adhering to the contouring protocol from the Medical Research Council's Radiotherapy and Androgen Deprivation In Combination After Local Surgery (RADICALS) trial. The volumes obtained before and after the protocol were compared and the effect of the protocol on interphysician variability assessed. RESULTS: An increase in mean CTV for all patients of 40.7 to 53.9 cm(3) was noted as a result of observing the protocol, with individual increases in the mean CTV of 65%, 15%, and 24% for Patients 1, 2, and 3 respectively. A reduction in interphysician variability was noted when the protocol was used. CONCLUSIONS: Substantial interphysician variation in target volume delineation for postprostatectomy radiotherapy exists, which can be reduced by the use of a contouring protocol. The RADICALS contouring protocol increases the target volumes when compared with those volumes typically applied at our center. The effect of treating larger volumes on the therapeutic ratio and resultant toxicity should be carefully monitored, particularly if the same dose-response as documented in radical prostate radiotherapy applies to the adjuvant and salvage setting. Prostate cancer, Postprostatectomy, Radiotherapy, Target volume.

Hypofractionated intensity-modulated radiotherapy for carcinoma of the prostate: analysis of toxicity.

PURPOSE: Dose escalation for prostate cancer improves biological control but with a significant increase in late toxicity. Recent estimates of low alpha/beta ratio for prostate cancer suggest that hypofractionation may result in biological advantage. Intensity-modulated radiotherapy (IMRT) should enable dose escalation to the prostate while reducing toxicity to local organs. We report late toxicity data of a hypofractionated IMRT regime. METHODS AND MATERIALS: Eligible men had T2-3N0M0 adenocarcinoma prostate, and either Gleason score >or= 7 or prostate-specific antigen 20-50 ng/L. Patients received 57-60 Gy to prostate in 19-20 fractions using five-field IMRT. All received hormonal therapy for 3 months before radiotherapy to a maximum of 6 months. Toxicity was assessed 2 years postradiotherapy using the RTOG criteria, LENT/SOMA, and UCLA prostate index assessment tools. RESULTS: Acute toxicity was favorable with no RTOG Grade 3 or 4 toxicity. At 2 years, there was 4% Grade 2 bowel and 4.25% Grade 2 bladder toxicity. There was no Grade 3 or 4 bowel toxicity; one patient developed Grade 3 bladder toxicity. UCLA data showed a slight improvement in urinary function at 2 years compared with pretreatment. LENT/SOMA assessments demonstrated general worsening of bowel function at 2 years. Patients receiving 60 Gy were more likely to develop problems with bowel function than those receiving 57 Gy. CONCLUSIONS: These data demonstrate that hypofractionated radiotherapy using IMRT for prostate cancer is well tolerated with minimal late toxicity at 2 years posttreatment. Ongoing studies are looking at the efficacy of hypofractionated regimes with respect to biological control.

Analysis of prostate-specific antigen bounce after I(125) permanent seed implant for localised prostate cancer.

BACKGROUND AND PURPOSE: To report on the incidence of benign prostate-specific antigen bounce following permanent I(125) prostate brachytherapy, to describe the associations in our population and review the relationship of bounce to subsequent biochemical failure. MATERIALS AND METHODS: From February 2000 to May 2005, 374 patients with localised prostate cancer were treated with I(125) permanent prostate brachytherapy at a single institution. A prospectively collected database was used to identify cases of prostate-specific antigen (PSA) bounce, defined as a rise of 0.2 ng/ml above an initial PSA nadir with subsequent decline to or below that nadir without treatment. The patients who received neo-adjuvant or adjuvant hormone manipulation were excluded. Biochemical failure was determined using the both the ASTRO consensus definition and Phoenix (nadir +2 ng/mL) definition. RESULTS: Two hundred and five patients were identified with a median follow-up of 45 months (24-85). PSA bounce was noted in 79 (37%) men, occurring at a median of 14.8 months (1.7-40.6) following implant. The median peak PSA was 1.8 ng/ml (0.4-7.4) with a bounce magnitude of 0.91 ng/ml (0.2-5.8). When pre- and post-implant factors were assessed for association to bounce, only younger age was statistically significant (p=0.002). The threshold for biochemical failure as defined by the ASTRO consensus definition (1997) was met in 4 (5%) patients after experiencing bounce as opposed to 19 (15%) non-bounce patients (p=0.01). The threshold for Phoenix (nadir +2 ng/mL) was met in 6 (7.5%) patients following bounce versus 22 (17%) of non-bounce patients (p=0.003). Both definitions are prone to false positive calls during bounce. Median PSA velocity during the bounce was 0.08 ng/mL/month (0.02-0.98) and was statistically significantly lower than the median velocity prior to the Phoenix biochemical failure at 0.28 ng/mL/month (0.07-2.04) (p=0.0005). CONCLUSION: PSA bounce is a common finding in our population and is associated with a lower rate of subsequent biochemical failure. The noted differences in PSA velocity will require verification in a future analysis to reduce the influence of median follow-up on this finding. Patients should be advised of the potential of bounce in PSA follow-up after permanent I(125) prostate brachytherapy and physicians involved in follow-up of prostate brachytherapy patients should be aware of this phenomenon, allowing them to commit to appropriate PSA surveillance, avoiding the premature and inappropriate initiation of salvage therapy during PSA bounce.

Phase I study of conformal radiotherapy with concurrent gemcitabine in locally advanced bladder cancer.

PURPOSE: A prospective phase I trial was conducted to determine the maximal tolerated dose of gemcitabine given once weekly during hypofractionated conformal radiotherapy to patients with locally advanced transitional cell carcinoma of the bladder. Eight male patients, median age 69 years, with Stage T2 (n = 4) or T3 (n = 4) N0M0, were enrolled in cohorts of 3. Treatment comprised conformal radiotherapy (52.5 Gy in 20 fractions) within 4 weeks, with concurrent gemcitabine once weekly for four cycles. The weekly gemcitabine dose was escalated from 100 mg/m(2) in increments of 50 mg/m(2) per cohort. Dose-limiting toxicity was defined as any acute Radiation Therapy Oncology Group (RTOG) toxicity Grade 3 or greater arising in >1 of 3 patients in each cohort. Tumor response was assessed cystoscopically and radiologically at 3 months. RESULTS: All 8 patients completed radiotherapy, and 6 of 8 completed chemoradiotherapy. No acute toxicity greater than RTOG Grade 1 was seen with gemcitabine at 100 mg/m(2). Dose-limiting toxicity was observed at 150 mg/m(2) with Grade 3 toxicity seen in 2 of 2 patients (one bladder, one bowel). An additional 3 patients received 100 mg/m(2) with minimal toxicity. No hematologic toxicity was encountered. A complete response was seen in 7 (87.5%) of 8 patients, all of whom were disease free at a median follow-up of 19.5 months (range, 14-23 months). No late toxicity (greater than RTOG Grade 0) has been observed. CONCLUSION: The maximal tolerated dose for gemcitabine given once weekly with concurrent hypofractionated conformal bladder radiotherapy was 150 mg/m(2), with a maximal recommended dose of 100 mg/m(2). This dose regimen has now entered Phase II clinical trials.

Do differences in target volume definition in prostate cancer lead to clinically relevant differences in normal tissue toxicity?

PURPOSE: Many studies have described the quantitated differences between clinicians in target volume definition in prostate cancer. However, few studies have looked at the clinical effects of this. We aimed to assess the relevance and sequelae of such differences. METHODS AND MATERIALS: Five experienced radiation oncologists were given the clinical details of 5 patients with early-stage prostate cancer and asked to define the clinical target volume, consisting of the prostate and seminal vesicles (CTV1) and the prostate alone (CTV2), on specified planning CT scans of the pelvis. Planning target volumes (PTV1) were generated by automatic expansion of the CTV1 by a 1-cm margin. The PTV2 was defined as the CTV2. The rectum and bladder were defined by a single experienced clinician for each plan without knowledge of the involved clinician marking the CTVs. The Pinnacle planning system was used to generate the plans, using four-field conformal radiotherapy, to deliver 64 Gy in 32 fractions to the PTV1 followed by a boost of 10 Gy to the PTV2 (Medical Research Council RT01 trial protocol). Dose-volume histograms were generated for the whole bladder and rectum for each plan and the volume receiving a specific percentage of the dose (e.g., V(90)) calculated for 74 Gy, followed by estimates of normal tissue complication probabilities (NTCPs) for the bladder and rectum. RESULTS: Statistically significant differences were found in the CTV1 and CTV2 and, consequently, the PTV1 among the 5 clinicians (p < 0.0005). Most of the discrepancies occurred at the delineation of the prostatic apex and seminal vesicles, with the smallest variance noted at the rectum-prostate and bladder-prostate interfaces. No statistically significant differences were found among clinicians for the rectal V(90), V(85), V(80), V(70), or V(50) or for the bladder V(85), V(80), V(70), or V(50). A difference was noted among consultants for the bladder V(90) (p = 0.015), although no correlation was found between the bladder V(90) and the size of the outlined volumes. No statistically significant differences were found between the estimates of bladder (p = 0.1) and rectal (p = 0.09) NTCPs. CONCLUSION: The statistically significant difference in outlined volumes of the CTV1, CTV2, and PTV1 among the 5 clinicians is in keeping with the findings of previous studies. However, the interclinician variability did not result in clinically relevant outcomes with respect to the irradiated volume of rectum and bladder or NTCP. This may have been because the outlined areas in which interclinician differences were smallest (the rectal-prostate and prostate-bladder interfaces) are the areas that have the greatest effect on normal tissue toxicity. For the areas in which the interclinician correlation was lowest (the prostatic apex and distal seminal vesicles), the effects on normal tissue toxicity are smallest. The results of this study suggest that interclinician outlining differences in prostate cancer may have less clinical relevance than was previously thought.

Trans-perineal implantation of radio-opaque treatment verification markers into the prostate: an assessment of procedure related morbidity, patient acceptability and accuracy.

On-line imaging of prostate markers can be used to compensate for errors in radiation delivery. This study assessed the patient acceptability and morbidity associated with the trans-perineal route of implantation. A minority experienced acute pain or bleeding. Placement was accurate in all but one subject. An operator related learning curve exists. Although this is an invasive procedure most patients found it acceptable. Implementation for routine clinical practice is feasible.

Radiotherapy for muscle-invasive carcinoma of the bladder: results of a randomized trial comparing conventional whole bladder with dose-escalated partial bladder radiotherapy.

PURPOSE: To investigate whether delivering an increased radiation dose to the tumor-bearing region of the bladder alone would improve local disease control without increasing treatment toxicity. METHODS AND MATERIALS: A total of 149 patients with unifocal T2-T3N0M0 bladder carcinoma were randomized between whole bladder conformal radiotherapy (WBRT, 52.5 Gy in 20 fractions, n = 60) and partial bladder conformal RT (PBRT) to tumor alone with 1.5-cm margins within either 4 weeks (PBRT4, 57.5 Gy in 20 fractions, n = 44) or 3 weeks (PBRT3, 55 Gy in 16 fractions, n = 45). The response was assessed cystoscopically after 4 months. RESULTS: The 5-year overall and CFS rate was 58% and 47%, respectively, for the whole population. The CR rate was 75% for WBRT, 80% for PBRT4, and 71% for PBRT3 (p = 0.6), with a 5-year local control rate of 58%, 59%, and 34%, respectively (p = 0.18). Solitary new tumors arose within the bladder, outside the irradiated volume, in 6 (7%) of 89 patients who underwent PBRT. The 5-year overall survival and cystectomy-free survival rate was 61% and 49% for WBRT, 60% and 50% for PBRT4, and 51% and 41% for PBRT3 (p = 0.81 and p = 0.59). The treatment toxicity was mild and equivalent across the three trial arms. CONCLUSION: The reduction in treatment volume allowed delivery of an increased radiation dose without a reduction in local tumor control or the development of excess toxicity. However, this dose-escalated partial bladder approach did not result in significantly improved overall survival.

Hypofractionated conformal radiotherapy in carcinoma of the prostate: five-year outcome analysis.

PURPOSE: Recent publications have indicated that the alpha/beta ratios for carcinoma of the prostate are much lower than had originally been thought, suggesting that prostate cancer may be highly sensitive to fraction size. We have reviewed our unique experience of the use of 3.13 Gy fractions in a large cohort of men treated homogeneously in a single institute. MATERIALS AND METHODS: The outcome for 705 men with T1-T4, N0, M0 prostate cancer who received conformal radiotherapy between 1995 and 1998 at this center was analyzed. No patient received hormonal manipulation. Mean age was 68 years (range: 49-84 years). Median pretreatment PSA was 13 ng/mL (range: 0.6-270 ng/mL). Disease characteristics were as follows: Stage T1, 125 (18%); T2, 365 (52%); T3/4, 215 (30%); Gleason 2-6, 463 (66%); Gleason 7-10, 242 (34%); pretreatment PSA < or =10 ng/mL, 291 (41%); 10 to < or =20, 228 (32%); >20, 186 (27%). Median follow-up was 48 months (range: 1-82 months). Biochemical-free survival (bNED) was defined by the American Society for Therapeutic Radiology and Oncology consensus definition. Radiotherapy was delivered to a planning target volume (prostate plus all/base of the seminal vesicles dependent on risk criteria with a 1-cm margin) with a 4-field conformal technique to a dose of 50 Gy in 16 daily fractions over 22 days. RESULTS: The 5-year bNED survival was significantly associated (p < 0.001) with pretreatment PSA, stage, and Gleason score. Five-year bNED rates with respect to pretreatment characteristics were as follows: 73% (PSA < or =10), 52% (>10-20), 35% (>20), 64% (Stage T1/2), 38% (T3/4), 61% (Gleason score 2-6), and 46% (Gleason > or =7). When patients were grouped into good (Stage T1/2, PSA < or =10 ng/mL, and Gleason score <7) (n = 181), intermediate (1 raised value) (n = 247), or poor (2 or more raised values) (n = 277) prognostic groups, the bNED was, respectively, 82%, 56%, and 39%. Radiation Therapy Oncology Group Grade > or =2 bowel toxicity was 5% and bladder 9%. CONCLUSIONS: These data indicate that the delivery of a relatively low total dose using a hypofractionated regime results in similar tumor control and normal-tissue toxicity to 65-70 Gy delivered in 1.8-2 Gy fractions. These data suggest that this is an acceptable regime for good-prognosis patients. However, because of the evidence for a dose effect at doses above 70 Gy with "conventional fractionation," we are now treating intermediate- and poor-risk patients within a hypofractionated dose escalation trial to 60 Gy in 20 fractions using intensity- modulated radiotherapy.

Scoring of treatment-related late effects in prostate cancer.

BACKGROUND AND PURPOSE: To assess the correlation between different general and organ specific quality of life and morbidity scoring methods in a cohort of men treated with radical radiotherapy for prostate cancer. MATERIALS AND METHODS: Men who had been treated with radical radiotherapy (50 Gy in 16 fractions over 21 days) for localized prostate cancer more than 3 years previously and who had no evidence of recurrent disease were invited to take part in the study. A total of 101 of 135 invited patients agreed and completed LENT/SOMA, UCLA Prostate Cancer Index, and 36 item RAND Health survey questionnaires. RESULTS: The patients had comparable results with other published series with respect to the UCLA and SF-36 indices. There was significant correlation between the corresponding parts of the UCLA and LENT/SOMA scales (P<0.0005). However, for the same symptoms, a patient tended to score lower (worse) on the UCLA scale in comparison to LENT/SOMA. The relationship between the average LENT/SOMA score and maximum score was also not straightforward with each set of data revealing different information. CONCLUSIONS: The LENT/SOMA questions were, in the main, more wide-ranging and informative than the UCLA index. It is helpful to give both the overall and maximum LENT/SOMA scores to most efficiently use all of the data. There may need to be a further LENT/SOMA question to allow both symptoms of tenesmus and faecal urgency to be fully addressed.