Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial.

BACKGROUND: Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. METHODS: RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous 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 add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), 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 metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. FINDINGS: Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60-69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0-10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612-0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6-75·7) in the short-course ADT group and 78·1% (74·2-81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. INTERPRETATION: Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. FUNDING: Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society.

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.

Management of Locally Recurrent Retroperitoneal Sarcoma in the Adult: An Updated Consensus Approach from the Transatlantic Australasian Retroperitoneal Sarcoma Working Group.

BACKGROUND: Surgery is the mainstay of treatment for retroperitoneal sarcoma (RPS), but local recurrence is common. Biologic behavior and recurrence patterns differ significantly among histologic types of RPS, with implications for management. The Transatlantic Australasian RPS Working Group (TARPSWG) published a consensus approach to primary RPS, and to complement this, one for recurrent RPS in 2016. Since then, additional studies have been published, and collaborative discussion is ongoing to address the clinical challenges of local recurrence in RPS. METHODS: An extensive literature search was performed, and the previous consensus statements for recurrent RPS were updated after review by TARPSWG members. The search included the most common RPS histologic types: liposarcoma, leiomyosarcoma, solitary fibrous tumor, undifferentiated pleomorphic sarcoma, and malignant peripheral nerve sheath tumor. RESULTS: Recurrent RPS management was evaluated from diagnosis to follow-up evaluation. For appropriately selected patients, resection is safe. Nomograms currently are available to help predict outcome after resection. These and other new findings have been combined with expert recommendations to provide 36 statements, each of which is attributed a level of evidence and grade of recommendation. In this updated document, more emphasis is placed on histologic type and clarification of the intent for surgical treatment, either curative or palliative. Overall, the fundamental tenet of optimal care for patients with recurrent RPS remains individualized treatment after multidisciplinary discussion by an experienced team with expertise in RPS. CONCLUSIONS: Updated consensus recommendations are provided to help guide decision-making for treatment of locally recurrent RPS and better selection of patients who would potentially benefit from surgery.

Radiation Oncology Fellowship: a Value-Based Assessment Among Graduates of a Mature Program.

The University of Toronto - Department of Radiation Oncology (UTDRO) has had a well-established Fellowship Program for over 20 years. An assessment of its graduates was conducted to evaluate training experience and perceived impact on professional development. Graduates of the UTDRO Fellowship Program between 1991 and 2015 were the focus of our review. Current employment status was collected using online tools. A study-specific web-based questionnaire was distributed to 263/293 graduates for whom active e-mails were identified; questions focused on training experience, and impact on career progression and academic productivity. As a surrogate measure for the impact of UTDRO Fellowship training, a comparison of current employment and scholarly activities of individuals who obtained their Fellow of the Royal College of Physicians of Canada (FRCPC) designation in Radiation Oncology between 2000 and 2012, with (n = 57) or without (n = 230) UTDRO Fellowship training, was conducted. Almost all UTDRO Fellowship graduates were employed as staff radiation oncologists (291/293), and most of those employed were associated with additional academic (130/293), research (53/293), or leadership (68/293) appointments. Thirty-eight percent (101/263) of alumni responded to the online survey. The top two reasons for completing the Fellowship were to gain specific clinical expertise and exposure to research opportunities. Respondents were very satisfied with their training experience, and the vast majority (99%) would recommend the program to others. Most (96%) felt that completing the Fellowship was beneficial to their career development. University of Toronto, Department of Radiation Oncology Fellowship alumni were more likely to hold university, research, and leadership appointments, and author significantly more publications than those with FRCPC designation without fellowship training from UTDRO. The UTDRO Fellowship Program has been successful since its inception, with the majority of graduates reporting positive training experiences, benefits to scholarly output, and professional development for their post-fellowship careers. Key features that would optimize the fellowship experience and its long-term impact on trainees were also identified.

Curability of patients with lymph node metastases from extremity soft-tissue sarcoma.

BACKGROUND: Lymph node metastases (LNM) rarely occur in adult extremity soft-tissue sarcoma (STS), affecting approximately 5% of patients. To the authors' knowledge, few studies to date have evaluated the prognosis and survival of patients with LNM. METHODS: A retrospective review was performed of a single-center, prospectively collected STS database. Demographic, treatment, and oncologic data for patients with STS of the extremity with LNM were obtained from clinical and radiographic records. RESULTS: Of 2689 patients with extremity STS, a total of 120 patients (4.5%) were diagnosed with LNM. LNM occurred most frequently among patients diagnosed with clear cell sarcoma (27.6%), epithelioid sarcoma (21.9%), rhabdomyosarcoma (17.3%), angiosarcoma (14.0%), and extraskeletal myxoid chondrosarcoma (9.3%). A total of 98 patients (81.7%) underwent LNM surgical resection. Patients with isolated LNM had a greater 5-year overall survival (57.3%) compared with patients with American Joint Committee on Cancer (AJCC) eighth edition stage IV STS with only systemic metastases (14.6%) or both LNM and systemic disease (0%; P < .0001). Patients with isolated LNM had an overall survival rate (52.9%) similar to that of patients with localized AJCC stage III tumors (ie, large, high-grade tumors) (49.3%) (P = .8). Patients with late, isolated, metachronous LNM had a 5-year overall survival rate (61.2%) that was similar to that of patients with isolated synchronous LNM at the time of presentation (53.6%) (P = .4). CONCLUSIONS: Many different types of STS develop LNM. Patients with extremity STS with isolated LNM should not be considered as having stage IV disease as they are according to the current AJCC eighth edition classification because they have significantly better survival than those with systemic metastases. Patients with isolated, late, metachronous LNM have a survival similar to that of patients with isolated synchronous LNM at the time of presentation. LAY SUMMARY: The results of the current study demonstrated that patients diagnosed with isolated lymph node metastases have a prognosis similar to that of patients diagnosed with localized American Joint Committee on Cancer stage III soft-tissue sarcomas, which also equates to a significantly better overall survival compared with patients with systemic metastases. Therefore, the authors recommend modifications to the most recent eighth edition of the American Joint Committee on Cancer staging system to clearly distinguish patients with isolated lymph node metastases to acknowledge their better prognosis compared with those with systemic metastases.

Designing a Rational Follow-Up Schedule for Patients with Extremity Soft Tissue Sarcoma.

PURPOSE: The risk of tumor recurrence after resection of soft tissue sarcoma (STS) necessitates surveillance in follow-up. The objective of this study was to determine the frequency/timing of metastasis and local recurrence following treatment for soft tissue sarcoma, and to use these data to justify an evidence-based follow-up schedule. METHODS: Utilizing a prospective database, a retrospective single center review was performed of all patients with minimum 2-year follow-up after resection of a localized extremity STS. Kaplan-Meier estimates were used to calculate the incidence of local recurrence and metastases on an annual basis for 10 years. RESULTS: We identified a total of 230 low-grade, 626 intermediate-grade and 940 high-grade extremity STS and a total of 721 events, 150 local recurrences and 571 metastases. Based on tumor size and grade, follow-up cohorts were developed that had similar metastatic risk. Using pre-determined thresholds for metastatic event, a follow-up schedule was established for each cohort. CONCLUSION: Based on our results we recommend that patients with small low-grade tumors undergo annual follow-up for 5 years following definitive local treatment. Patients with large low-grade tumors, small intermediate-grade and small high-grade tumors should have follow-up every 6 months for the first 2 years, then yearly to 10 years. Only patients with large intermediate- or high-grade tumors require follow-up every 3 months for the first 2 years, then every 6 months for years 3-5, followed by annually until 10 years.

International Multicenter Validation of an Intermediate Risk Subclassification of Prostate Cancer Managed with Radical Treatment without Hormone Therapy.

PURPOSE: The NCCN Guidelines® recently endorsed a subclassification of intermediate risk prostate cancer into favorable and unfavorable subgroups. However, this subclassification was developed in a treatment heterogeneous cohort. Thus, to our knowledge the natural history of androgen deprivation treatment naïve favorable and unfavorable intermediate risk prostate cancer cases remains unknown. MATERIALS AND METHODS: Groups at 3 academic centers pooled data on patients with intermediate risk prostate cancer treated with radical monotherapy (dose escalated external beam radiotherapy, brachytherapy or radical prostatectomy) without combined androgen deprivation treatment. We used the cumulative incidence with competing risk analysis to estimate biochemical recurrence, distant metastasis and prostate cancer specific mortality. RESULTS: A total of 2,550 men at intermediate risk were included in study, of whom 1,063 and 1,487 were at favorable and unfavorable risk, respectively. Of the men 1,149 underwent radical prostatectomy, 1,143 underwent dose escalated external beam radiotherapy and 258 underwent brachytherapy. Median followup after the different treatments ranged from 60.4 to 107.4 months. The 10-year cumulative incidence of distant metastasis in the favorable vs unfavorable risk groups was 0.2% (95% CI 0.2-0.2) vs 11.6% (95% CI 7.7-15.5) for radical prostatectomy (p <0.001), 2.8% (95% CI 0.8-4.8) vs 13.5% (95% CI 9.6-17.4) for dose escalated external beam radiotherapy (p <0.001) and 3.5% (95% CI 0-7.4) vs 10.2% (95% CI 4.3-16.1) for brachytherapy (p = 0.063). The 10-year rate of prostate cancer specific mortality in the favorable vs unfavorable risk groups was 0% (95% CI 0-0) vs 3.7% (95% CI 1.7-5.7) for radical prostatectomy (p = 0.016), 0.5% (95% CI 0.5-0.5) vs 5.6% (95% CI 3.6-7.6) for dose escalated external beam radiotherapy (p = 0.015) and 0% (95% CI 0-0) vs 2.5% (95% CI 0.5-4.5) for brachytherapy (p = 0.028). CONCLUSIONS: This multicenter international effort independently validates the prognostic value of the intermediate risk prostate cancer subclassification in androgen deprivation treatment naïve cases across all radical treatment modalities. It is unlikely that treatment intensification would meaningfully improve oncologic outcomes in men at favorable intermediate risk.

Unbiased data mining identifies cell cycle transcripts that predict non-indolent Gleason score 7 prostate cancer.

BACKGROUND: Patients with newly diagnosed non-metastatic prostate adenocarcinoma are typically classified as at low, intermediate, or high risk of disease progression using blood prostate-specific antigen concentration, tumour T category, and tumour pathological Gleason score. Classification is used to both predict clinical outcome and to inform initial management. However, significant heterogeneity is observed in outcome, particularly within the intermediate risk group, and there is an urgent need for additional markers to more accurately hone risk prediction. Recently developed web-based visualization and analysis tools have facilitated rapid interrogation of large transcriptome datasets, and querying broadly across multiple large datasets should identify predictors that are widely applicable. METHODS: We used camcAPP, cBioPortal, CRN, and NIH NCI GDC Data Portal to data mine publicly available large prostate cancer datasets. A test set of biomarkers was developed by identifying transcripts that had: 1) altered abundance in prostate cancer, 2) altered expression in patients with Gleason score 7 tumours and biochemical recurrence, 3) correlation of expression with time until biochemical recurrence across three datasets (Cambridge, Stockholm, MSKCC). Transcripts that met these criteria were then examined in a validation dataset (TCGA-PRAD) using univariate and multivariable models to predict biochemical recurrence in patients with Gleason score 7 tumours. RESULTS: Twenty transcripts met the test criteria, and 12 were validated in TCGA-PRAD Gleason score 7 patients. Ten of these transcripts remained prognostic in Gleason score 3 + 4 = 7, a sub-group of Gleason score 7 patients typically considered at a lower risk for poor outcome and often not targeted for aggressive management. All transcripts positively associated with recurrence encode or regulate mitosis and cell cycle-related proteins. The top performer was BUB1, one of four key MIR145-3P microRNA targets upregulated in hormone-sensitive as well as castration-resistant PCa. SRD5A2 converts testosterone to its more active form and was negatively associated with biochemical recurrence. CONCLUSIONS: Unbiased mining of large patient datasets identified 12 transcripts that independently predicted disease recurrence risk in Gleason score 7 prostate cancer. The mitosis and cell cycle proteins identified are also implicated in progression to castration-resistant prostate cancer, revealing a pivotal role for loss of cell cycle control in the latter.

Healthy Bones Study: can a prescription coupled with education improve bone health for patients receiving androgen deprivation therapy?-a before/after study.

PURPOSE: To evaluate the ability of a multimodal patient education initiative to improve adherence to healthy bone behaviors (HBBs) in men with prostate cancer receiving androgen deprivation therapy (ADT). METHODS: This was a pilot prospective, single-site, before-and-after clinical trial. The control arm (n = 51) received routine care. The intervention arm (n = 52) received multimodal HBB education which included a healthy bones prescription (BoneRx), focused face-to-face education with an oncology nurse or physician, and customized educational materials. The primary endpoints were feasibility of study methods and self-reported adherence to HBBs (vitamin D intake ≥ 1000 IU/day, calcium intake 1000-1500 mg/day, and exercise ≥ 150 min/week) at 3-month follow-up. Secondary endpoints included receipt of bone mineral density (BMD) testing. RESULTS: Patients were satisfied with the study intervention, found educational materials easy to understand, and felt that it increased their knowledge about osteoporosis. Although the intervention appeared to be associated with trends toward improved levels of vitamin D intake (adjusted odds ratio [OR] 1.8, 95% confidence interval [CI] 0.74-4.5), calcium intake (OR 1.5, 95% CI 0.63-3.4), and exercise (OR 1.7, 0.75-3.9) as compared to the control arm, none of these were statistically significant. Patients who received the study intervention were more likely to receive BMD testing (OR 3.3, 95% CI 1.3-8.8). CONCLUSIONS: Although a brief, tailored educational intervention was feasible to implement and improve BMD test utilization, it did not increase HBB participation. Larger, well-designed trials are needed to clarify the effect of patient education interventions on HBB adherence. TRIAL REGISTRATION: ClinicalTrials.gov ( NCT01973673 ).

Results of Resection for Recurrent or Residual Retroperitoneal Sarcoma After Failed Primary Treatment.

BACKGROUND: Local recurrence after resection of retroperitoneal sarcoma (RPS) is a common and difficult problem. Gross residual disease after incomplete resection is a particular challenge. The authors reviewed their experience with patients referred for management of recurrent or residual RPS. METHODS: Patients seen at the authors' center from 1996 to 2013 who had undergone resection at an outside institution were identified from a prospective database. Kaplan-Meier survival curves were generated and compared by log-rank analysis. RESULTS: A total of 45 patients were referred with recurrent (n = 33) or residual (n = 12) disease. Before initial surgery elsewhere, cross-sectional imaging (computed tomograpy/magnetic resonance imaging) had been obtained for 30 patients (67 %) and percutaneous biopsy for 8 patients (18 %). At referral to the authors' center, 15 patients were deemed inappropriate for resection, with a subsequent median overall survival (OS) period of 15 months. At the authors' center, 30 patients (22 with recurrent and 8 with residual disease) were resected. The majority received preoperative radiation (77 %). The postoperative mortality rate was 0 % in the recurrent group and 25 % (2/8) in the residual group (p = 0.015). Among the 30 resected patients, the median and 5-year OS was 53 months (50 %), and the OS was better in the recurrent group (median, 77 months) than in the residual group (median, 41 months (p = 0.027). The median time to local re-recurrence was 49 months in the recurrent group and 35 months in the residual group (p = 0.730). CONCLUSIONS: Durable disease control and prolonged survival may be achieved for selected patients with recurrent RPS. In this study, resection after previous grossly incomplete resection was associated with high postoperative mortality and inferior OS. The benefit of extensive surgery for these patients may be limited.

An Analysis of Tumor- and Surgery-Related Factors that Contribute to Inadvertent Positive Margins Following Soft Tissue Sarcoma Resection.

BACKGROUND: The risk of local recurrence (LR) after soft tissue sarcoma (STS) resection is higher in the setting of inadvertent positive margins (IPMs). This study assessed whether both tumor- and surgery-related factors contribute to IPMs, and whether tumor- versus surgery-related IPMs differ in LR or overall survival (OS). METHODS: Retrospective review of a tertiary center database identified patients with IPMs following STS resection between 1989 and 2014. Of 2234 resected STSs, 309 (13%) had positive margins; 89 (4%) were IPMs. Mean follow-up was 52 months, mean tumor size was 9.2 cm, and 55% were high grade. Cases were categorized as surgery-related (67, 75%) or tumor-related (22, 25%). RESULTS: There was a significant difference in positive margin location, with the deep margin commonly involved in surgery-related IPMs (55% vs. 9%; p < 0.001). Tissue type also differed (p = 0.01), with surgery-related IPMs frequently in muscle (33%), while tumor-related IPMs favored subcutaneous tissues (41%). STSs with surgery-related IPMs were larger (p = 0.01). Histologic subtypes differed (p = 0.02), with myxofibrosarcoma and undifferentiated pleomorphic sarcoma/malignant fibrous histiocytoma predominating in tumor-related IPMs (82%). The cumulative probability of LR after IPMs, with death as a competing risk, was 28% (95% confidence interval [CI] 18-35) at 5 years and 37% (95% CI 24-45) at 10 years. Mortality was 28% (95% CI 18-38) at 5 years and 38% (26-50) at 10 years. There was no difference in LR (p = 0.91) or OS (p = 0.44) between surgery- and tumor-related IPMS. CONCLUSIONS: IPMs after STS resection results in substantial LR risk. While demonstrating distinct surgery- and tumor-related contributions, there was no between-group difference in LR or OS. These results may aid in avoiding IPMs. LEVEL OF EVIDENCE: Therapeutic Level III, retrospective comparative study.

Clinical outcomes in breast angiosarcoma patients: A rare tumor with unique challenges.

BACKGROUND: Breast angiosarcoma (AS) accounts for less than 1% of all breast cancers. The goal of this study was to determine patient outcomes in radiation-associated angiosarcoma of the breast (RAAS) and sporadic AS. We evaluated patterns of recurrence and predictors of breast AS survival. METHODS: Patients with pathologically confirmed AS from 1994 to 2014 referred to Mount Sinai Hospital/Princess Margaret Cancer Centre were included. Primary outcome was overall survival (OS). Secondary outcomes were disease-free survival (DFS), clinicopathologic characteristics, patterns of recurrence and factors predictive of survival. Kaplan-Meier and log-rank tests were used for OS and DFS. RESULTS: Twenty-six patients were included: 6 with sporadic AS and 20 with RAAS. Median follow-up was 24 months. Five-year OS for RAAS and sporadic subgroups were 44% and 40%, respectively (P = ns). Five-year DFS for RAAS and sporadic subgroups were 23% and 20%, respectively (P = ns). Overall recurrence rate was 67% with median time to recurrence of 11 months. Age, tumor depth, margin status, and tumor size were not statistically significant predictive factors for OS and DFS. DISCUSSION: Breast AS is associated with poor survival and high recurrence rates. Prognosis may be mainly determined by its aggressive biology. Referral to tertiary care centers for multimodality treatment is recommended.

PMH 9907: Long-term outcomes of a randomized phase 3 study of short-term bicalutamide hormone therapy and dose-escalated external-beam radiation therapy for localized prostate cancer.

BACKGROUND: The role of hormone therapy (HT) with dose-escalated external-beam radiotherapy (DE-EBRT) in the treatment of intermediate-risk prostate cancer (IRPC) remains controversial. The authors report the long-term outcome of a phase 3 study of DE-EBRT with or without HT for patients with localized prostate cancer (LPC). METHODS: From 1999 to 2006, 252 of an intended 338 patients with LPC were randomized to receive DE-EBRT with or without 5 months of neoadjuvant and concurrent bicalutamide 150 mg once daily. The study was closed early because of contemporary concerns surrounding bicalutamide. The primary outcome was biochemical failure (BF) incidence, and the secondary endpoints were overall survival (OS), local control (LC), and quality of life. The BF and OS rates were estimated using the cumulative incidence function and Kaplan-Meier methods and were compared using the Gray test and the log-rank test. RESULTS: Eleven patients were excluded from analysis. Characteristics were well balanced in each treatment arm. Ninety-five percent of patients had IRPC. The prescribed dose increased from 75.6 grays (Gy) in 42 fractions to 78 Gy in 39 fractions over the period. At a median follow-up of 9.1 years, 98 BFs occurred, with no significant effect of HT versus no HT on the BF rate (40% vs 47%; P = .32), the OS rate (82% vs 86%; P = .37), the LC rate (52% vs 48 %; P = .32) or quality of life, in the patients who completed the questionnaires. Dose escalation to 75.6 Gy versus >75.6 Gy reduced the BF rate by 26% (P = .004). CONCLUSIONS: For patients who predominantly have IRPC, the addition of HT to DE-EBRT did not significantly affect BF, OS, or LC. Bicalutamide appeared to be well tolerated. The conclusions from the study are limited by incomplete recruitment. Cancer 2016;122:2595-603. © 2016 American Cancer Society.

Health-related quality of life following treatment for extremity soft tissue sarcoma.

BACKGROUND AND OBJECTIVES: The primary objective of this study was to estimate the change in health-related quality of life (HRQL) 1 year following treatment for extremity soft tissue sarcoma (STS), measured by the EQ-5D. Secondary objectives included determining clinical variables associated with HRQL at 1 year, estimating the proportion with a clinically important difference (CID) in HRQL, and evaluating variability within EQ-5D domains. METHODS: Patients over the age of 16 years, treated for a localized extremity STS, were included. The EQ-5D change score from pre-treatment to 1-year follow-up was determined. The association of clinical variables with EQ-5D scores was estimated using a linear regression model. The proportion of patients with a CID in HRQL score was determined. A vector analysis of the EQ-5D domains was undertaken. RESULTS: The mean EQ-5D change score was 0.02. Age, sex, disease status, and initial EQ-5D score were associated with EQ-5D score at 1 year. There was a CID improvement in 32% and a deterioration in 24%. The anxiety and depression domain demonstrated the most change between baseline and 1 year after treatment. CONCLUSION: Most patients maintain a high level of HRQL following treatment for extremity STS. J. Surg. Oncol. 2016;114:821-827. © 2016 2016 Wiley Periodicals, Inc.

The influence of time interval between preoperative radiation and surgical resection on the development of wound healing complications in extremity soft tissue sarcoma.

OBJECTIVE: The aim of this study was to determine the relationship of the time interval between completion of preoperative radiation therapy (RT) and surgical resection on wound complications (WCs) in extremity soft tissue sarcoma (STS). METHODS: Overall, 798 extremity STS patients were managed with preoperative RT and surgery from 1989 to 2013. WCs were defined as requiring secondary operations/invasive procedures for wound care, use of vacuum-assisted closure, prolonged dressing changes, or infection within 120 days of surgery. RESULTS: Mean tumor size was 8.8 cm. A total of 743 (93 %) tumors were primary presentations, 565 (71 %) patients had lower extremity tumors, and 238 patients (30 %) had a prior unplanned excision. Of 242 patients (30 %) who developed a WC, 206 (37 %) had lower extremity tumors and 36 (15 %) had upper extremity tumors. Mean time from RT completion to surgery was 41.3 (range 4-470) days; 42.0 (range 4-470) days for upper extremity cases, and 41.1 (range 4-109) days for lower extremity cases. Similarly, mean time interval for patients who developed a WC was 40.9 (range 4-100) days, and 41.5 (range 4-470) days for those who did not develop a WC (p = 0.69). Thirty-nine cases (5 %) had surgery within 3 weeks of RT; 15 (38 %) patients developed WCs versus 227 (30 %) patients who had their tumors excised after 3 weeks (p = 0.28). One hundred and twenty-nine (16 %) patients had surgery within 4 weeks, and 39 (30 %) patients developed WCs versus 203 (30 %) patients who had their tumors excised after 4 weeks (p = 1.0). A trend towards a higher rate of WCs was seen for those patients who had surgery after 6 weeks (28 % prior vs. 34 % after; p = 0.08). There was no difference in WCs with intensity-modulated RT (IMRT) versus non-IMRT cases (p = 0.6). CONCLUSION: The time interval between preoperative RT and surgical excision in extremity STS had minimal influence on the development of WCs. Four- or 5-week intervals showed equivalent complication rates between the two groups, suggesting an optimal interval to reduce potential WCs.

The effect of the setting of a positive surgical margin in soft tissue sarcoma.

BACKGROUND: The objectives of this study were to evaluate the risk of local recurrence and survival after soft tissue sarcoma (STS) resection with positive margins and to evaluate the safety of sparing adjacent critical structures. METHODS: One hundred sixty-nine patients with localized STS who had positive resection margins were identified from a prospective database. Patients who had positive margins were stratified into 3 groups, each representing a specific clinical scenario: critical structure positive margin (eg major nerve, vessel, or bone), tumor bed resection positive margin, and unexpected positive margin. The rates of local recurrence-free survival (LRFS) and cause-specific survival (CSS) were calculated and compared with relevant control patients who had negative margins after STS resection. RESULTS: After planned close dissection to preserve critical structures, the 5-year LRFS and CSS rates both depended on the quality of the surgical margins (97% and 80.3%, respectively, for those with negative margins vs 85.4% and 59.4%, respectively, for those with positive margins; P = .015 and P = .05, respectively). Negative margins achieved through resection of critical structures because of tumor invasion or encasement only slightly improved the 5-year rates of LRFS (91.2%) and CSS (63.6%; P = .8 and P = .9, respectively). The lowest 5-year LRFS and CSS rates were 63.4% and 59.2%, respectively, after an unexpected positive margin during primary surgery. CONCLUSIONS: After patients undergo resection of STS with positive margins, oncologic outcomes can be predicted based on the clinical context. Sparing adjacent critical structures in this setting is safe and contributes to improved functional outcomes.

Phase 2 study of preoperative image-guided intensity-modulated radiation therapy to reduce wound and combined modality morbidities in lower extremity soft tissue sarcoma.

BACKGROUND: This study sought to determine if preoperative image-guided intensity-modulated radiotherapy (IG-IMRT) can reduce morbidity, including wound complications, by minimizing dose to uninvolved tissues in adults with lower extremity soft tissue sarcoma. METHODS: The primary endpoint was the development of an acute wound complication (WC). IG-IMRT was used to conform volumes to avoid normal tissues (skin flaps for wound closure, bone, or other uninvolved soft tissues). From July 2005 to June 2009, 70 adults were enrolled; 59 were evaluable for the primary endpoint. Median tumor size was 9.5 cm; 55 tumors (93%) were high-grade and 58 (98%) were deep to fascia. RESULTS: Eighteen (30.5%) patients developed WCs. This was not statistically significantly different from the result of the National Cancer Institute of Canada SR2 trial (P = .2); however, primary closure technique was possible more often (55 of 59 patients [93.2%] versus 50 of 70 patients [71.4%]; P = .002), and secondary operations for WCs were somewhat reduced (6 of 18 patients [33%] versus 13 of 30 patients [43%]; P = .55). Moderate edema, skin, subcutaneous, and joint toxicity was present in 6 (11.1%), 1 (1.9%), 5 (9.3%), and 3 (5.6%) patients, respectively, but there were no bone fractures. Four local recurrences (6.8%, none near the flaps) occurred with median follow-up of 49 months. CONCLUSIONS: The 30.5% incidence of WCs was numerically lower than the 43% risk derived from the National Cancer Institute of Canada SR2 trial, but did not reach statistical significance. Preoperative IG-IMRT significantly diminished the need for tissue transfer. RT chronic morbidities and the need for subsequent secondary operations for WCs were lowered, although not significantly, whereas good limb function was maintained.

Effect of Brachytherapy With External Beam Radiation Therapy Versus Brachytherapy Alone for Intermediate-Risk Prostate Cancer: NRG Oncology RTOG 0232 Randomized Clinical Trial.

PURPOSE: To determine whether addition of external beam radiation therapy (EBRT) to brachytherapy (BT) (COMBO) compared with BT alone would improve 5-year freedom from progression (FFP) in intermediate-risk prostate cancer. METHODS: Men with prostate cancer stage cT1c-T2bN0M0, Gleason Score (GS) 2-6 and prostate-specific antigen (PSA) 10-20 or GS 7, and PSA < 10 were eligible. The COMBO arm was EBRT (45 Gy in 25 fractions) to prostate and seminal vesicles followed by BT prostate boost (110 Gy if 125-Iodine, 100 Gy if 103-Pd). BT arm was delivered to prostate only (145 Gy if 125-Iodine, 125 Gy if 103-Pd). The primary end point was FFP: PSA failure (American Society for Therapeutic Radiology and Oncology [ASTRO] or Phoenix definitions), local failure, distant failure, or death. RESULTS: Five hundred eighty-eight men were randomly assigned; 579 were eligible: 287 and 292 in COMBO and BT arms, respectively. The median age was 67 years; 89.1% had PSA < 10 ng/mL, 89.1% had GS 7, and 66.7% had T1 disease. There were no differences in FFP. The 5-year FFP-ASTRO was 85.6% (95% CI, 81.4 to 89.7) with COMBO compared with 82.7% (95% CI, 78.3 to 87.1) with BT (odds ratio [OR], 0.80; 95% CI, 0.51 to 1.26; Greenwood T P = .18). The 5-year FFP-Phoenix was 88.0% (95% CI, 84.2 to 91.9) with COMBO compared with 85.5% (95% CI, 81.3 to 89.6) with BT (OR, 0.80; 95% CI, 0.49 to 1.30; Greenwood T P = .19). There were no differences in the rates of genitourinary (GU) or GI acute toxicities. The 5-year cumulative incidence for late GU/GI grade 2+ toxicity is 42.8% (95% CI, 37.0 to 48.6) for COMBO compared with 25.8% (95% CI, 20.9 to 31.0) for BT (P < .0001). The 5-year cumulative incidence for late GU/GI grade 3+ toxicity is 8.2% (95% CI, 5.4 to 11.8) compared with 3.8% (95% CI, 2.0 to 6.5; P = .006). CONCLUSION: Compared with BT, COMBO did not improve FFP for prostate cancer but caused greater toxicity. BT alone can be considered as a standard treatment for men with intermediate-risk prostate cancer.

Local recurrence of localized soft tissue sarcoma: a new look at old predictors.

BACKGROUND: The objective of this study was to examine the effect of known predictors of local recurrence of soft tissue sarcoma in a competing risk setting. METHODS: The outcome of interest was the cumulative probability of local recurrence per category of relevant predictors, with death as a competing event. In total, 1668 patients with a localized soft tissue sarcoma of the extremity or trunk were included. RESULTS: Tumor size (hazard ratio, 3.3), depth (hazard ratio, 3.2), and histologic grade (hazard ratio, 4.5) were the variables that had the most effect on the risk of metastasis and, accordingly, were the most likely to induce competition. Surgical margins (hazard ratio, 3.3), histologic grade (hazard ratio, 2.1), presentation status (hazard ratio, 2.4), and tumor depth (hazard ratio, 1.5) were the variables that had the most effect on the risk of local recurrence. The 10-year cumulative probabilities of local recurrence were markedly different within categories for presentation status (P < .001) and surgical margin status (P < .001). However, because of the competing effect of death, there was little difference in the 10-year cumulative probabilities of local recurrence with regard to tumor depth (12% and 11.4% for deep and superficial tumors, respectively; P = .2), tumor size (10.6% and 13.3% for large and small tumors, respectively; P = .99), or histologic tumor grade (12.6%, 10.7%, and 11.1% for high, intermediate, and low-grade tumors, respectively; P = .17). CONCLUSIONS: Because of the competition between local recurrence and death, histologic tumor grade, tumor size, and tumor depth had little influence on the cumulative probability of local recurrence. The authors concluded that local management should be based on presentation status and surgical margins rather than other, previously acknowledged factors.