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.

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.

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.

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.

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.

Intermuscular extremity myxoid liposarcoma can be managed by marginal resection following neoadjuvant radiotherapy.

BACKGROUND: Compared with other soft tissue sarcomas, myxoid liposarcoma (MLS) occurs in younger patients, has a propensity for intermuscular locations and is highly radiosensitive. With pre-operative radiotherapy, intermuscular MLS demonstrates substantial volume reduction and can be easily separated from surrounding tissues during resection. However, it is unclear whether marginal excision of MLS is oncologically safe. This study aimed to assess the association between margins and survival in irradiated, intermuscular MLS. METHODS: The study identified 198 patients from seven sarcoma centres with a first presentation of localized, extremity, intermuscular MLS that received pre-operative radiotherapy and was diagnosed between 1990 and 2017. Patient and treatment characteristics, radiological and histological responses to neoadjuvant treatment and clinical surveillance were recorded. RESULTS: Margins were microscopically positive in 11% (n = 22), <1.0 mm in 15% (n = 29) and ≥1.0 mm in 72% (n = 143). There was no association between margin status and local recurrence-free, metastasis-free or overall survival. This finding held true even in patients at higher risk of worse overall survival based on multivariable analysis (% round cell≥5%, percentage ellipsoid tumour volume change ≤ -60.1%). CONCLUSION: Irradiated, extremity, intermuscular myxoid liposarcoma can safely undergo marginal resection without compromising oncologic control.

Long-term outcome of the treatment of high-risk tenosynovial giant cell tumor/pigmented villonodular synovitis with radiotherapy and surgery.

BACKGROUND: The treatment of diffuse tenosynovial giant cell tumor (TGCT) requires extensive surgical resection of the hypertrophic synovium and multiple soft tissue masses yet still may result in high rates of local failure. The authors of this report examined their experience in treating patients with advanced/multiply recurrent TGCT with a combination of surgery and external-beam radiotherapy. METHODS: Fifty patients who were treated for TGCT with radiotherapy and surgery from 1972 to 2006 were identified. Patient demographics, radiotherapy treatment parameters, surgical treatment, and oncologic and functional outcomes were evaluated. All patients had pathologic review at presentation and required at least 1 year follow-up. RESULTS: Forty-nine patients had diffuse TGCT with both intra-articular and extra-articular disease (1 had malignant TGCT). Twenty-eight patients (56%) were referred after at least 1 local recurrence. Thirty patients (60%) underwent at least 2 operations before radiotherapy. The mean dose of radiation delivered was 39.8 gray. At a mean follow-up of 94 months (range, 19-330 months), 47 patients (94%) had not developed a recurrence or had stable disease/signal characteristics on serial cross-sectional imaging (for those patients who had gross residual disease at the time of radiotherapy). Two patients required subsequent total hip arthroplasty because of progressive osteoarthritis, and there were 4 cases of avascular necrosis (only 1 post-treatment). Forty-one patients had good/excellent function. CONCLUSIONS: For patients with extensive or multiple local relapses or when surgery alone would result in a large burden of residual disease or major functional loss, the addition of moderate-dose adjuvant radiotherapy provided excellent local control while maintaining good function with low treatment-related morbidity.

Control charts for evaluation of quality of low-dose-rate brachytherapy for prostate cancer.

Purpose: Variations in dosimetric outcomes among patients treated with low-dose-rate brachytherapy for prostate cancer exist, even when implants are within dose constraints. Here, we used control charts to investigate reasons for intra-patient dosimetric variability. Material and methods: Univariate and multivariate control charts for prostate V100 (percentage of prostate volume that received 100% of prescribed radiation dose), D90 (radiation dose to 90% of prostate volume), and RV100 (rectal wall volume that received 100% of prescribed radiation dose) were generated for 212 consecutive prostate cancer patients implanted with iodine-125 (125I) radioactive seeds at the Princess Margaret Cancer Centre. Control limits were calculated based on the first fifty implants. Data points that were out of control were identified, and their pre-treatment and post-treatment dosimetric and clinical parameters were compared to data points that were in-control, using Student's t-test. Results: All implants were clinically acceptable. Twelve data points exceeded multivariate control limits. Ten of those points fell below the lower control limit of V100 control chart. Average prostate edema in the 10 out-of-control patients on both multivariate and V100 charts was 8.3%, as compared to 0.4% for in-control patients (p < 0.04). Two patients were observed to be out-of-control on multivariate control chart, but not on V100 control chart, and were found to have a reduction in prostate volume of 19.1% and 20.1% at one month after seed implant, compared to prostate volumes of pre-implantation evaluations. Conclusions: Control charts helped in identifying cases with out-of-control variability in post-plan prostate dosimetry. Post-treatment prostatic edema and contraction are important factors predicting variability in patients treated with 125I permanent seed brachytherapy.

Neoadjuvant Chemotherapy Before Bladder-Sparing Chemoradiotherapy in Patients With Nonmetastatic Muscle-Invasive Bladder Cancer.

BACKGROUND: Cisplatin-based neoadjuvant chemotherapy (NAC) before cystectomy improves survival in muscle-invasive urothelial bladder cancer (MIBC). The use of NAC before chemoradiation (CRT) has been limited, as these patients are often elderly, frail, and ineligible for cisplatin. However, the role of NAC in fit, cisplatin-eligible patients who opt for bladder preservation warrants further evaluation. PATIENTS AND METHODS: Patients with MIBC treated with NAC followed by CRT at the Princess Margaret and Durham Regional cancer centers from 2008 to 2017 were retrospectively reviewed. Gemcitabine-cisplatin NAC was given for 2 to 4 cycles, followed by reassessment for CRT. External-beam radiotherapy (60-66 Gy) over 6 weeks was given with concurrent weekly cisplatin at 40 mg/m2. Kaplan-Meier method was used for survival analyses. RESULTS: We identified 57 consecutive patients. Median age was 72 (range 45-87), and all had an Eastern Cooperative Oncology Group performance status of 0 (60%) or 1 (40%). Stage II disease (65%), stage III disease (25%), and regional nodal metastases (11%) were included. Most completed planned NAC (95%). All patients completed external-beam radiotherapy, and 84% completed at least 60% of the planned concurrent weekly cisplatin doses. Median (range) follow-up was 19.3 (4.8-96.1) months. Median overall survival (OS) was not reached. Two-year OS and disease-specific survival rates were 74% (95% confidence interval, 57.7-84.9) and 88% (95% confidence interval, 78.5-98.1), respectively. Two-year bladder-intact disease-free survival was 64%. Salvage cystectomy was performed in 14%. Distant relapse occurred in 11%, and 9% died of metastatic disease. OS was associated with baseline hydronephrosis and with bladder-intact disease-free survival with residual disease on cystoscopy. CONCLUSION: NAC followed by CRT can result in encouraging outcomes and tolerability in cisplatin-eligible patients.

Development of multiorgan finite element-based prostate deformation model enabling registration of endorectal coil magnetic resonance imaging for radiotherapy planning.

PURPOSE: Endorectal coil (ERC) magnetic resonance imaging (MRI) provides superior visualization of the prostate compared with computed tomography at the expense of deformation. This study aimed to develop a multiorgan finite element deformable method, Morfeus, to accurately co-register these images for radiotherapy planning. METHODS: Patients with prostate cancer underwent fiducial marker implantation and computed tomography simulation for radiotherapy planning. A series of axial MRI scans were acquired with and without an ERC. The prostate, bladder, rectum, and pubic bones were manually segmented and assigned linear elastic material properties. Morfeus mapped the surface of the bladder and rectum between two imaged states, calculating the deformation of the prostate through biomechanical properties. The accuracy of deformation was measured as fiducial marker error and residual surface deformation between the inferred and actual prostate. The deformation map was inverted to deform from 100 cm(3) to no coil. RESULTS: The data from 19 patients were analyzed. Significant prostate deformation occurred with the ERC (mean intrapatient range, 0.88 +/- 0.25 cm). The mean vector error in fiducial marker position (n = 57) was 0.22 +/- 0.09 cm, and the mean vector residual surface deformation (n = 19) was 0.15 +/- 0.06 cm for deformation from no coil to 100-cm(3) ERC, with an image vector resolution of 0.22 cm. Accurately deformed MRI scans improved soft-tissue resolution of the anatomy for radiotherapy planning. CONCLUSIONS: This method of multiorgan deformable registration enabled accurate co-registration of ERC-MRI scans with computed tomography treatment planning images. Superior structural detail was visible on ERC-MRI, which has potential for improving target delineation.

Radiation planning comparison for superficial tissue avoidance in radiotherapy for soft tissue sarcoma of the lower extremity.

PURPOSE: Three types of preoperative radiotherapy (RT) plans for extremity soft tissue sarcoma were compared to determine the amount of dose reduction possible to the planned surgical skin flaps required for tumor resection and wound closure, without compromising target coverage. METHODS AND MATERIALS: Twenty-four untreated patients with large, deep, lower extremity STS treated with preoperative RT and limb salvage surgery had their original conventional treatment plans re-created. The same clinical target volume was used for all three plans. The future surgical skin flaps were created virtually through contouring by the treating surgeon and regarded as an organ at risk. The original, conformal, and intensity-modulated RT (IMRT) plans were created to deliver 50 Gy in 25 fractions to the clinical target volume. Clinical target volume and organ-at-risk dose-volume histograms were calculated and the plans compared for conformality, target coverage, and dose sparing. RESULTS: The mean dose to the planned skin flaps was 42.62 Gy (range, 30.24-48.65 Gy) for the original plans compared with 40.12 Gy (range, 24.24-47.26 Gy) for the conformal plans and 26.71 Gy (range, 22.31-31.91 Gy) for the IMRT plans (p = 0.0008). An average of 86.4% (range, 53.2-97.4%) of the planned skin flaps received >or=30 Gy in the original plans compared with 83.4% (range, 36.2-96.2%) in the conformal plans and only 34.0% (range, 22.5-53.3%) in the IMRT plans (p = 0.0001). IMRT improved target conformality compared with the original and conformal plans (1.27, 2.34, and 1.76, respectively, p = 0.0001). CONCLUSION: In a retrospective review, preoperative IMRT substantially lowered the dose to the future surgical skin flaps, sparing a greater percentage of this structure's volume without compromising target (tumor) coverage.

Anatomic boundaries of the clinical target volume (prostate bed) after radical prostatectomy.

PURPOSE: We sought to derive and validate an interdisciplinary consensus definition for the anatomic boundaries of the postoperative clinical target volume (CTV, prostate bed). METHODS AND MATERIALS: Thirty one patients who had planned for radiotherapy after radical prostatectomy were enrolled and underwent computed tomography and magnetic resonance imaging (MRI) simulation prior to radiotherapy. Through an iterative process of consultation and discussion, an interdisciplinary consensus definition was derived based on a review of published data, patterns of local failure, surgical practice, and radiologic anatomy. In validation, we analyzed the distribution of surgical clips in reference to the consensus CTV and measured spatial uncertainties in delineating the CTV and vesicourethral anastomosis. Clinical radiotherapy plans were retrospectively evaluated against the consensus CTV (prostate bed). RESULTS: Anatomic boundaries of the consensus CTV (prostate bed) are described. Surgical clips (n = 339) were well distributed throughout the CTV. The vesicourethral anastomosis was accurately localized using central sagittal computed tomography reconstruction, with a mean +/- standard deviation uncertainty of 1.8 +/- 2.5 mm. Delineation uncertainties were small for both MRI and computed tomography (mean reproducibility, 0-3.8 mm; standard deviation, 1.0-2.3); they were most pronounced in the anteroposterior and superoinferior dimensions and at the superior/posterior-most aspect of the CTV. Retrospectively, the mean +/- standard deviation CTV (prostate bed) percentage of volume receiving 100% of prescribed dose was only 77% +/- 26%. CONCLUSIONS: We propose anatomic boundaries for the CTV (prostate bed) and present evidence supporting its validity. In the absence of gross recurrence, the role of MRI in delineating the CTV remains to be confirmed. The CTV is larger than historically practiced at our institution and should be encompassed by a microscopic tumoricidal dose.

Long-term outcome of radiation-based conservation therapy for invasive bladder cancer.

PURPOSE: To report the long-term results and examine factors associated with bladder preservation, risk of relapse, and survival in patients treated with radical radiotherapy for invasive bladder cancer. MATERIALS AND METHODS: Between 1986 and 1997, 340 patients with T1-T4 bladder cancer were treated at Princess Margaret Hospital and received radiotherapy alone, radiotherapy and concurrent cisplatin chemotherapy, or neoadjuvant chemotherapy followed by radiotherapy. Patients having complete response were followed with regular cystoscopy. Cystectomy was undertaken in suitable patients with persistent or locally recurrent disease. RESULTS: The median age of patients was 71 years, 13% had evidence of regional lymph node involvement, and 27% were medically unfit for radical cystectomy. A total of 247 patients received radiotherapy alone, 36 radiotherapy and concurrent cisplatin chemotherapy, and 57 neoadjuvant chemotherapy followed by radiotherapy. Complete response was obtained in 63.5% of patients overall, and median follow-up was 7.9 years. The 10-year overall survival, cause-specific survival, and local relapse-free rates were 19%, 35%, and 32%, respectively. In 131 patients with muscle-invasive disease confined to the bladder wall (T2N0M0), 10-year cause-specific survival (P = 0.02) and local relapse-free rates (P = 0.03) were 68% and 60% when carcinoma in situ was absent, and 47% and 28%, respectively, when present. In multivariable analysis, younger age, lower T category, and absence of carcinoma in situ were associated with a statistically significant improvement in survival and local control (P

Randomized Trial of a Hypofractionated Radiation Regimen for the Treatment of Localized Prostate Cancer.

Purpose Men with localized prostate cancer often are treated with external radiotherapy (RT) over 8 to 9 weeks. Hypofractionated RT is given over a shorter time with larger doses per treatment than standard RT. We hypothesized that hypofractionation versus conventional fractionation is similar in efficacy without increased toxicity. Patients and Methods We conducted a multicenter randomized noninferiority trial in intermediate-risk prostate cancer (T1 to 2a, Gleason score ≤ 6, and prostate-specific antigen [PSA] 10.1 to 20 ng/mL; T2b to 2c, Gleason ≤ 6, and PSA ≤ 20 ng/mL; or T1 to 2, Gleason = 7, and PSA ≤ 20 ng/mL). Patients were allocated to conventional RT of 78 Gy in 39 fractions over 8 weeks or to hypofractionated RT of 60 Gy in 20 fractions over 4 weeks. Androgen deprivation was not permitted with therapy. The primary outcome was biochemical-clinical failure (BCF) defined by any of the following: PSA failure (nadir + 2), hormonal intervention, clinical local or distant failure, or death as a result of prostate cancer. The noninferiority margin was 7.5% (hazard ratio, < 1.32). Results Median follow-up was 6.0 years. One hundred nine of 608 patients in the hypofractionated arm versus 117 of 598 in the standard arm experienced BCF. Most of the events were PSA failures. The 5-year BCF disease-free survival was 85% in both arms (hazard ratio [short v standard], 0.96; 90% CI, 0.77 to 1.2). Ten deaths as a result of prostate cancer occurred in the short arm and 12 in the standard arm. No significant differences were detected between arms for grade ≥ 3 late genitourinary and GI toxicity. Conclusion The hypofractionated RT regimen used in this trial was not inferior to conventional RT and was not associated with increased late toxicity. Hypofractionated RT is more convenient for patients and should be considered for intermediate-risk prostate cancer.

Testicular radiation for primary seminoma in a solitary testis.

Orchiectomy is the standard of care for patients with a second primary testicular tumor. We report a case of a man, with previous history of stage I left testicular germ cell tumor, who developed a contralateral seminoma and desired preservation of the remaining testis. Partial orchiectomy was not feasible due to tumor size and percutaneous needle biopsy revealed classical seminoma. He was treated with radiotherapy to the testis. Post treatment biopsy revealed no evidence of disease. At 32 months follow-up, he has not required androgen replacement. He has preservation of total testosterone level and libido.

Large retroperitoneal lymphadenopathy as a predictor of venous thromboembolism in patients with disseminated germ cell tumors treated with chemotherapy.

PURPOSE: Cisplatin-based chemotherapy, a mainstay of treatment for disseminated germ cell tumors (GCTs), is associated with venous thromboembolism (VTE). Many patients with disseminated GCTs have large retroperitoneal lymph node (RPLN) metastases that may cause venous stasis and increase the risk of VTE development. We hypothesized that there was an association between large RPLN and chemotherapy-associated VTE risk. PATIENTS AND METHODS: The training cohort was composed of patients with disseminated GCT receiving first-line chemotherapy at Princess Margaret Cancer Centre between January 2000 and December 2010. Large RPLN was defined as more than 5 cm in maximal axial diameter. The predictive and discriminatory accuracies of a model using large RPLN in predicting VTE were compared with high-risk Khorana score (≥ 3) using logistic regression and area under receiver operator characteristic curves (AUROCs). The model was externally validated in a cohort of patients treated at the London Health Sciences Centre. RESULTS: The training cohort comprised 216 patients, 21 (10%) of whom developed VTE during chemotherapy. VTE was associated with large RPLN (odds ratio [OR], 5.26; P = .001), high-risk Khorana score (OR, 11.8; P < .001), intermediate-/poor-risk disease (OR, 3.76; P = .005), and hospitalization during chemotherapy (OR, 4.24; P = .002). Large RPLN showed higher discriminatory accuracy than high-risk Khorana score (AUROC, 0.71 v 0.67, respectively). Superior discriminatory accuracy of large RPLN over high-risk Khorana score was validated in the London cohort (AUROC, 0.61 v 0.57, respectively). CONCLUSION: Large RPLN is associated with VTE in patients with disseminated GCT and provides higher discriminatory accuracy than high-risk Khorana score. Results should be validated in larger, prospective studies. Prophylactic anticoagulation may be considered in high-risk patients.

On-line aSi portal imaging of implanted fiducial markers for the reduction of interfraction error during conformal radiotherapy of prostate carcinoma.

PURPOSE: An on-line system to ensure accuracy of daily setup and therapy of the prostate has been implemented with no equipment modification required. We report results and accuracy of patient setup using this system. METHODS AND MATERIALS: Radiopaque fiducial markers were implanted into the prostate before radiation therapy. Lateral digitally reconstructed radiographs (DRRs) were obtained from planning CT data. Before each treatment fraction, a lateral amorphous silicon (aSi) portal image was acquired and the position of the fiducial markers was compared to the DRRs using chamfer matching. Couch translation only was used to account for marker position displacements, followed by a second lateral portal image to verify isocenter position. Residual displacement data for the aSi and previous portal film systems were compared. RESULTS: This analysis includes a total of 239 portal images during treatment in 17 patients. Initial prostate center of mass (COM) displacements in the superior, inferior, anterior, and posterior directions were a maximum of 7 mm, 9 mm, 10 mm and 11 mm respectively. After identification and correction, prostate COM displacements were <3 mm in all directions. The therapists found it simple to match markers 88% of the time using this system. Treatment delivery times were in the order of 9 min for patients requiring isocenter adjustment and 6 min for those who did not. CONCLUSIONS: This system is technically possible to implement and use as part of an on-line correction protocol and does not require a longer than standard daily appointment time at our center with the current action limit of 3 mm. The system is commercially available and is more efficient and user-friendly than portal film analysis. It provides the opportunity to identify and accommodate interfraction organ motion and may also permit the use of smaller margins during conformal prostate radiotherapy. Further integration of the system such as remote table control would improve efficiency.

Appropriate radiation volume for stage IIA/B testicular seminoma.

PURPOSE: Prophylactic left supraclavicular fossa irradiation has been suggested to reduce relapse rates in patients treated for Stage IIA/B testicular seminoma. To address this issue, we reviewed patterns of failure and treatment outcome in patients treated with radiation therapy at our institution. METHODS AND MATERIALS: Between 1981 and 1999, 79 men with Stage II seminoma (IIA, 49; IIB, 30) were treated with radiation therapy (RT) to the para-aortic and ipsilateral (+/- contralateral) pelvic lymph nodes (dose: 25-35 Gy). RESULTS: With a median follow-up of 8.5 years, the 5-year relapse-free rate was 91% (standard error: 3%), and 2 patients have died of seminoma, giving a 5-year cause-specific survival of 97%. A total of 7 patients have relapsed with 2 isolated to the left supraclavicular fossa. Five of 7 patients have been successfully salvaged. CONCLUSIONS: Prophylactic left supraclavicular fossa irradiation might have prevented relapse in 2 of 79 patients in Stage IIA/B seminoma. However, 97% of patients would have received unnecessary left neck RT, so we continue to recommend, as standard treatment, infradiaphragmatic RT only.

Mapping patterns of nodal metastases in seminoma: rethinking radiotherapy fields.

BACKGROUND AND PURPOSE: To analyze the location of metastatic lymph nodes in seminoma patients relative to vascular and bony anatomy and conventional radiation fields. MATERIALS AND METHODS: Cross-sectional scans of 90 seminoma patients with infradiaphragmatic adenopathy were analyzed. The position of each node respective to vascular anatomy was transferred to a standardized template. Conventional radiation fields were overlaid on the template and locations of metastatic nodes were assessed. RESULTS: One hundred and forty-five nodes were radiographically positive. Eighty-four percent, 9%, and 7% of nodes were located in the para-aortic, common iliac, and pelvic regions, respectively. Ninety-nine percent of nodes were within a 2.5 cm lateral and 2.1cm anterior expansion of the aorta inferior to T12/L1. No radiographically positive nodes were identified within the renal hilum or superior to L1 in left-sided seminomas. For right-sided seminomas, no radiographically positive nodes were superior to L2. Three percent of all radiographically positive nodes would have been located outside of conventional and modified fields. CONCLUSIONS: Infradiaphragmatic nodal metastases from a contemporary cohort of seminoma patients localized to a smaller area than is targeted by conventional radiation fields. Modified treatment fields based on vascular, rather than bony, anatomy are smaller and may allow for a significant decrease in normal tissue irradiation and toxicity.

The relationship between local recurrence and radiotherapy treatment volume for soft tissue sarcomas treated with external beam radiotherapy and function preservation surgery.

PURPOSE: To examine the geometric relationship between local recurrence (LR) and external beam radiotherapy (RT) volumes for soft-tissue sarcoma (STS) patients treated with function-preserving surgery and RT. METHODS AND MATERIALS: Sixty of 768 (7.8%) STS patients treated with combined therapy within our institution from 1990 through 2006 developed an LR. Thirty-two received preoperative RT, 16 postoperative RT, and 12 preoperative RT plus a postoperative boost. Treatment records, RT simulation images, and diagnostic MRI/CT data sets of the original and LR disease were retrospectively compared. For LR location analysis, three RT target volumes were defined according to the International Commission on Radiation Units and Measurements 29 as follows: (1) the gross tumor or operative bed; (2) the treatment volume (TV) extending 5 cm longitudinally beyond the tumor or operative bed unless protected by intact barriers to spread and at least 1-2 cm axially (the TV was enclosed by the isodose curve representing the prescribed target absorbed dose [TAD] and accounted for target/patient setup uncertainty and beam characteristics), and (3) the irradiated volume (IRV) that received at least 50% of the TAD, including the TV. LRs were categorized as developing in field within the TV, marginal (on the edge of the IRV), and out of field (occurring outside of the IRV). RESULTS: Forty-nine tumors relapsed in field (6.4% overall). Nine were out of field (1.1% overall), and 2 were marginal (0.3% overall). CONCLUSIONS: The majority of STS tumors recur in field, indicating that the incidence of LR may be affected more by differences in biologic and molecular characteristics rather than aberrations in RT dose or target volume coverage. In contrast, only two patients relapsed at the IRV boundary, suggesting that the risk of a marginal relapse is low when the TV is appropriately defined. These data support the accurate delivery of optimal RT volumes in the most precise way using advanced technology and image guidance.