Phase 3 Assessment of the Automated Bone Scan Index as a Prognostic Imaging Biomarker of Overall Survival in Men With Metastatic Castration-Resistant Prostate Cancer: A Secondary Analysis of a Randomized Clinical Trial.

Importance: Prostate cancer commonly metastasizes to bone, and bone metastases are associated with pathologic fractures, pain, and reduced survival. Bone disease is routinely visualized using the technetium Tc 99m (99mTc) bone scan; however, the standard interpretation of bone scan data relies on subjective manual assessment of counting metastatic lesion numbers. There is an unmet need for an objective and fully quantitative assessment of bone scan data. Objective: To clinically assess in a prospectively defined analysis plan of a clinical trial the automated Bone Scan Index (aBSI) as an independent prognostic determinant of overall survival (OS) in men with metastatic castration-resistant prostate cancer (mCRPC). Design, Setting, and Participants: This investigation was a prospectively planned analysis of the aBSI in a phase 3 multicenter randomized, double-blind, placebo-controlled clinical trial of tasquinimod (10TASQ10). Men with bone metastatic chemotherapy-naïve CRPC were recruited at 241 sites in 37 countries between March 2011 and August 2015. The statistical analysis plan to clinically evaluate the aBSI was prospectively defined and locked before unmasking of the 10TASQ10 study. The analysis of aBSI was conducted between May 25, 2016, and June 3, 2017. Main Outcomes and Measures: The associations of baseline aBSI with OS, radiographic progression-free survival (rPFS), time to symptomatic progression, and time to opiate use for cancer pain. Results: Of the total 1245 men enrolled, 721 were evaluable for the aBSI. The mean (SD) age (available for 719 men) was 70.6 (8.0) years (age range, 47-90 years). The aBSI population was representative of the total study population based on baseline characteristics. The aBSI (median, 1.07; range, 0-32.60) was significantly associated with OS (hazard ratio [HR], 1.20; 95% CI, 1.14-1.26; P < .001). The median OS by aBSI quartile (lowest to highest) was 34.7, 27.3, 21.7, and 13.3 months, respectively. The discriminative ability of the aBSI (C index, 0.63) in prognosticating OS was significantly higher than that of the manual lesion counting (C index, 0.60) (P = .03). In a multivariable survival model, a higher aBSI remained independently associated with OS (HR, 1.06; 95% CI, 1.01-1.11; P = .03). A higher aBSI was also independently associated with time to symptomatic progression (HR, 1.18; 95% CI, 1.13-1.23; P < .001) and time to opiate use for cancer pain (HR, 1.21; 95% CI, 1.14-1.30; P < .001). Conclusions and Relevance: To date, this investigation is the largest prospectively analyzed study to validate the aBSI as an independent prognostic imaging biomarker of survival in mCRPC. These data support the prognostic utility of the aBSI as an objective imaging biomarker in the design and eligibility of clinical trials of systemic therapies for patients with mCRPC. Trial Registration: ClinicalTrials.gov Identifier: NCT01234311.

Prospective assessment of urinary, gastrointestinal and sexual symptoms before, during and after image-guided volumetric modulated arc therapy for prostate cancer.

OBJECTIVE: The aim of this study was to prospectively assess the development of 24 urinary, gastrointestinal and sexual symptoms in patients with prostate cancer (PCa) during and after image-guided volumetric modulated arc therapy (IG-VMAT). MATERIAL AND METHODS: A total of 87 patients with PCa participated in this study. The patients were asked to complete a modified version of the Prostate Cancer Symptom Scale (PCSS) questionnaire before radiotherapy (RT) (baseline), at the start of RT, at the end of RT and 1 year after RT. Changes in symptoms at the start of RT, at the end of RT and 1 year after RT compared to baseline were analysed by a mixed model analysis of repeated measurements with the following covariates: age, comorbidity, smoking and androgen deprivation therapy (ADT). RESULTS: All urinary problems except for haematuria increased significantly at the end of RT compared to baseline. One year after RT, there was no longer any difference compared to baseline for any of the urinary symptoms. All gastrointestinal symptoms except for nausea increased significantly at the end of RT. One year after RT, patients also reported slightly higher degrees of stool frequency, bowel leakage, planning of toilet visits, flatulence, mucus, gastrointestinal bleeding and impact of gastrointestinal bother on daily activities compared to baseline. All sexual symptoms increased significantly at all times compared to baseline. The use of ADT was associated with worse sexual symptoms. CONCLUSIONS: IG-VMAT is a safe treatment for PCa, with few and mild changes in urinary and gastrointestinal symptoms 1 year after RT compared to baseline. Sexual symptoms deteriorated both during and after RT. The use of ADT was associated with worse sexual symptoms.

Late radiation effects to the rectum and anus after treatment for prostate cancer; validity of the LENT/SOMA score.

BACKGROUND: The Late Effects Normal Tissue/Subjective Objective Management Analytic (LENT/SOMA) system for grading of side effects after radiotherapy was proposed several years ago. Only a few studies have previously been performed on the validity of the LENT/SOMA. The aim of the present study was to validate the LENT/SOMA scoring system for recto-anal side effects after treatment for prostate cancer in a randomized trial. MATERIAL AND METHODS: A total of 875 patients with locally advanced prostate cancer were randomized to either hormonal treatment alone or hormonal treatment plus radiotherapy in the Scandinavian Prostate Cancer Group 7 (SPCG-7) study. At least three years after treatment was started, the 178 patients that were randomized at St. Olavs Hospital were approached. One hundred and three patients of these accepted inclusion. The side effects according to LENT/SOMA were graded by oncologist and nurse. In addition, side effects were graded according to the European Organisation for Research and Treatment of Cancer and the Radiation Therapy Oncology Group (EORTC/RTOG) toxicity scale and patient-reported health-related quality of life (HRQOL) questionnaires. Content/face validity, sensitivity and inter-rater reliability of the LENT/SOMA tables for rectum were analyzed. RESULTS: Content/face analysis of LENT/SOMA revealed serious problems. Significant correlations (Spearman's rho > 0.4) were found between three of 15 LENT/SOMA items and similar HRQOL items. LENT/SOMA score made it possible to detect significant differences between the two groups of patients (p < 0.001), EORTC/RTOG toxicity score did not (p = 0.138). Inter-rater reliability was acceptable. CONCLUSIONS: LENT/SOMA scoring system for recto-anal side effects after radiotherapy for prostate cancer displays serious difficulties in the present study. Replacement of LENT/SOMA tables for rectum by a combination of patient-reported HRQOL questionnaires, clinical examination and objective physiological measurements might be called for.

A systematic overview of radiation therapy effects in prostate cancer.

A systematic review of radiation therapy trials in prostate cancer has been performed according to principles adopted by the Swedish Council of Technology Assessment in Health Care (SBU). This synthesis of the literature is based on data from one meta-analysis, 30 randomized trials, many dealing with hormonal therapy, 55 prospective trials, and 210 retrospective studies. Totally the studies included 152,614 patients. There is a lack of properly controlled clinical trials in most important aspects of radiation therapy in prostate cancer. The conclusions reached can be summarized as follows: * There are no randomized studies that compare the outcome of surgery (radical prostatectomy) with either external beam radiotherapy or brachytherapy for patients with clinically localized low-risk prostate cancer. However, with the advent of widely accepted prognostic markers for prostate cancer (pre-treatment PSA, Gleason score, and T-stage), such comparisons have been made possible. There is substantial documentation from large single-institutional and multi-institutional series on patients with this disease category (PSA < 10, GS < or = 6, < or = T2b) showing that the outcome of external beam radiotherapy and brachytherapy is similar to those of surgery. * There is fairly strong evidence that patients with localized, intermediate risk, and high risk (pre-treatment PSA > or = 10 and/or GS > or = 7 and/or > T2) disease, i.e. patients normally not suited for surgery, benefit from higher than conventional total dose. No overall survival benefit has yet been shown. * Dose escalation to patients with intermediate-risk or high-risk disease can be performed with 3D conformal radiotherapy (photon or proton) boost, with Ir-192 high dose rate brachytherapy boost, or brachytherapy boost with permanent seed implantation. Despite an increased risk of urinary tract and/or rectal side effects, dose-escalated therapy can generally be safely delivered with all three techniques. * There is some evidence that 3D conformal radiotherapy results in reduced late rectal toxicity and acute anal toxicity compared with radiotherapy administered with non-conformal treatment volumes. * There is some evidence that postoperative external beam radiotherapy after radical prostatectomy in patients with pT3 disease prolongs biochemical disease-free survival and that the likelihood of achieving long-term DFS is higher when treatment is given in an adjuvant rather than a salvage setting. A breakpoint seems to exist around a PSA level of 1.0 ng/mL, above which the likelihood for eradication of the recurrence of cancer diminishes. * After prostatectomy, endocrine therapy prior to and during adjuvant radiotherapy may result in longer biochemical disease-free survival than if only adjuvant radiotherapy is given. No impact on overall survival has been shown. * There is fairly strong evidence that short-term endocrine therapy prior to and during radiotherapy results in increased disease-free survival, increased local control, reduced incidence of distant metastases, and reduced cause-specific mortality in patients with locally advanced disease. * There is some evidence that short-term endocrine therapy prior to and during radiotherapy results in increased overall survival in a subset (GS 2-6) of patients with locally advanced disease. * There is strong evidence that adjuvant endocrine treatment after curative radiotherapy results in improved local control, increased freedom from distant metastases, and increased disease-free survival in patients with loco-regionally advanced and/or high-risk disease. * There is moderately strong evidence that adjuvant endocrine treatment after radiotherapy results in longer overall survival compared with radiotherapy alone in patients with loco-regionally advanced disease.

A systematic overview of radiation therapy effects in urinary bladder cancer.

A systematic review of radiation therapy trials in several tumour types was performed by The Swedish Council of Technology Assessment in Health Care (SBU). The procedures for evaluation of the scientific literature are described separately (Acta Oncol 2003; 42: 357-365). This synthesis of the literature on radiation therapy for urinary bladder cancer is based on data from 3 meta-analyses and 33 randomized trials. The studies include 4333 patients. The results were compared with those of a similar overview from 1996 including 15,042 patients. The conclusions reached can be summarized as these points: There is moderate evidence for an overall survival benefit with preoperative radiotherapy followed by cystectomy compared to curative radiotherapy based on early studies (1964-1986). Since that time surgical as well as radiation techniques have developed considerably. Therefore, the conclusion may not be relevant to modern treatment of invasive urinary bladder carcinoma. There is only one small study reporting on curative radiotherapy where increased dose per fraction is compared with conventionally fractionated radiotherapy to the same total dose. Thus, no conclusions can be drawn concerning optimal fraction dose. A meta-analysis based on two studies on hyperfractionated radiotherapy gives moderate evidence of a survival benefit at 5 and 10 years and an increased local control rate compared with conventional fractionation. The documentation of local control and overall survival rate after split-course radiation treatment compared to continuous therapy is conflicting. No firm conclusions can be drawn. Four small and early studies have compared radiation treatment using neutrons with photon treatment. The reports favour therapy with photons with respect to overall treatment results. There is moderate evidence for this conclusion. There is fairly strong evidence in early studies that radiation treatment in combination with hyperbaric oxygen does not confer a treatment benefit compared to radiation in normal atmosphere. There is no indication of a treatment benefit with the addition of either hyperthermia or misonidazole. A large number of phase II studies, suggesting an increased possibility for bladder preservation with concomitant chemoradiotherapy compared to radiotherapy alone, have been reviewed in a previous SBU report on chemotherapy. Only one small randomized study has been reported where concomitant chemoradiotherapy with cisplatin is compared to radiation alone. No conclusion on the therapeutic benefit of combined treatment can be drawn. Large randomized studies are needed. There is some evidence that preoperative radiotherapy followed by cystectomy does not confer any significant survival benefit compared to cystectomy alone. There is moderate evidence that palliative radiotherapy of invasive bladder carcinoma can rapidly induce tumour-related symptom relief. There is moderate evidence that palliative hypofractionated radiotherapy, 3 fractions during one week, gives the same relief of symptoms as 10 fractions during 2 weeks.

Living with untreated localized prostate cancer: a qualitative analysis of patient narratives.

Few, if any, qualitative studies aimed at gaining an understanding of the experience of patients with prostate cancer have been done. The purpose of this study was to illuminate the meaning of being a patient living with untreated localized prostate cancer. Seven men with untreated localized prostate cancer were interviewed in their homes. The interviews were tape recorded and transcribed into text. The text was analyzed using a phenomenologic-hermeneutic approach inspired by Ricoeur's philosophy. The meaning of living with untreated localized prostate cancer could be interpreted as living life under a dark shadow. The disease was described as a threat to the patient's life. When living under this shadow, many of the men studied had an ambivalent wish both to share their experience with others and to be alone with their experiences of the disease. They believed that the disease had changed their lives, and their manhood was restricted by sexual dysfunctions and described as a burden. They used various coping strategies to manage this situation. Despite a positive relationship with their physicians, there is a risk that these patients will not be given the attention they need because of their good prognosis.