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.

Prevalence and Risk Factors of QTc Prolongation in Prostate Cancer Patients Undergoing Brachytherapy.

QTc prolongation is linked to Torsade de Pointes, sudden cardiac death, and overall cardiovascular mortality. 754 prostate cancer patients undergoing brachytherapy were analyzed, prolonged QTc was defined as ≥450ms. A prolonged QTc was more frequent (10.1 vs. 5.1%, p = 0.040) in patients with high-risk cancer than in low to intermediate risk patients. The absolute QTc-time was correlated with age (r = 0.125), neutrophil count (r = 0.130) and negatively correlated with the testosterone level (r=-0.205). Treating physicians should be aware of this and monitor the QTc during ADT to possibly decrease cardiac morbidity/mortality in these patients who are more likely to require ADT.

The Clinical Significance of Bone Mineral Density Changes Following Long-Term Androgen Deprivation Therapy in Localized Prostate Cancer Patients.

PURPOSE: Long-term androgen deprivation therapy has been associated with decreased bone mineral density in men with prostate cancer. Some evidence suggests that there is no impact on fracture risk despite this bone mineral density loss. Our study aimed to quantify changes in bone mineral density in men with high risk prostate cancer on long-term androgen deprivation therapy and calcium and vitamin D supplementation. MATERIALS AND METHODS: Bone mineral density analysis was conducted for localized high risk prostate cancer patients enrolled in the phase III randomized trial PCS-V (Prostate Cancer Study 5), comparing conventional and hypofractionated radiation therapy. Patients received 28 months of luteinizing hormone-releasing hormone agonist and calcium and vitamin D supplementation (500 mg calcium BID+400 IU vitamin D3 BID). The areal density and T-scores (spine, femoral neck and total femur) at baseline and 30 months of followup were extracted, and the absolute change was calculated. Clinical bone density status (normal, osteopenia, osteoporosis) was monitored. RESULTS: The lumbar spine, femoral neck and total femoral bone mineral density were measured for 226, 231, and 173 patients, respectively. The mean percent change in bone mineral density was -2.65%, -2.76% and -4.27% for these respective sites (p <0.001 for all). The average decrease in bone mineral density across all sites was -3.2%, with no decline in bone mineral density category in most patients (83%). Eight patients (4%) became osteoporotic. CONCLUSIONS: Despite a mild decline in bone mineral density, the change in clinical bone mineral density category remained low with long-term androgen deprivation therapy. Consequently, calcium and vitamin D supplementation alone may suffice for most localized prostate cancer patients on long-term androgen deprivation therapy.

DEVIL, VAAD and vLSC constitute a spectrum of HPV-independent, p53-independent intra-epithelial neoplasia of the vulva.

AIMS: We aimed to characterise a large cohort of non-invasive, human papillomavirus (HPV) and p53-independent verruciform lesions, such as 'vulvar acanthosis with altered differentiation' (VAAD), 'differentiated exophytic vulvar intra-epithelial lesion' (DEVIL) and 'verruciform lichen simplex chronicus' (vLSC). METHODS AND RESULTS: From January 2008 to December 2020 we retrospectively identified 36 eligible patients with verruciform non-invasive lesions (n = 36) and collected clinical, histological and follow-up parameters. Verruciform non-invasive lesions occurred at a median age of 71 years, with a median follow-up of 33.5 months. Clinically, pruritus was only reported in patients with VAAD (n = 3, 21%). Lesion colour was significantly different across categories (P = 0.028). Apart from the histopathological criteria already known to distinguish these entities (hypogranulosis, epithelial pallor and low-magnification architecture), no other significant criteria were discovered and significant overlap was observed, particularly between VAAD and DEVIL. Patients with vLSC trended towards longer survival without recurrence compared to VAAD and DEVIL (P = 0.082), but showed comparable invasion-free survival interval (P = 0.782). Squamous cell carcinomas (SCC) associated with either VAAD, DEVIL or vLSC displayed similar clinical, histopathological and biological parameters. In non-invasive precursor lesions, stromal oedema was associated with invasion (P = 0.015) and remained so upon Cox regression analysis (P = 0.009). CONCLUSION: Our study of HPV and p53 independent non-invasive verruciform lesions of the vulva highlights significant clinical, histopathological and biological overlap between VAAD, DEVIL and vLSC, suggesting that these pre-invasive lesions should be viewed as a spectrum. We also show that stromal features such as oedema might play an import role in progression to invasion.

Oncologic outcomes in the era of modern radiation therapy using FIGO 2018 staging system for cervical cancer.

BACKGROUND: The recently published ASTRO cervical cancer guidelines recommend the use of modern radiotherapy. Imaging is now incorporated in the updated FIGO 2018 staging with a new stage IIIC. This study aims to evaluate the oncologic outcomes and predictors of survival using FIGO 2018 staging in a cohort of patients treated in an era of high-precision image-guided radiotherapy. METHODS: We performed a retrospective cohort study of 216 adult cervical cancer patients treated with definitive chemoradiotherapy between 2010 and 2018. Eligible patients had non-metastatic cervical cancer treated at a single academic institution. All patients had pre-treatment MRI and CT/PET. Treatment protocol consisted of external beam intensity-modulated radiotherapy and 3D image-guided brachytherapy. Kaplan-Meier curves were used for survival analysis. Multivariate cox proportional-hazards model was performed to identify potential prognostic factors. RESULTS: Median age at diagnosis was 50 and median BMI was 26.4 kg/m2. Median follow-up time was 44.3 months. Five-year overall survival (OS), disease-free survival and loco-regional disease-free survival rates were 76.8%, 68.5% and 82.6%, respectively. FIGO 2018 showed better OS discrimination compared to FIGO 2009 classification. OS was increasingly worse with positive pelvic and para-aortic nodes (p < 0.001). In a multivariate prediction model, performance status (p = 0.044) and FIGO 2018 classification (stage III p = 0.016; stage IVA p = 0.010) were predictors of mortality; FIGO 2018 classification (stage III p = 0.003; stage IVA p = 0.001) was a predictor of any recurrence; MRI tumor diameter (p ≤ 0.001) and nodal metastases (p = 0.024) were predictors of loco-regional recurrence. CONCLUSIONS: Integration of state-of-the-art imaging in cervical cancer staging and in radiotherapy planning leads to good loco-regional control rates, however distant recurrence remains an important issue. FIGO 2018 staging better reflects patient prognosis, highlighting the need for new treatment strategies for stage IIIC cervical cancer.

Neoadjuvant radiotherapy and brachytherapy in endometrial cancer with gross cervical involvement: a CHIRENDO research group study.

BACKGROUND: Historically, radical hysterectomy followed by adjuvant radiotherapy has been offered to patients with endometrial cancer who have gross cervical involvement; however, this approach is known to carry considerable morbidity. Neoadjuvant radiotherapy followed by extra-fascial hysterectomy has been proposed as an alternative treatment but has been poorly studied to date. OBJECTIVE: To evaluate the locoregional control rate associated with neoadjuvant radiotherapy followed by extra-fascial hysterectomy. METHODS: A retrospective cohort study of 30 patients with endometrial cancer with gross cervical involvement treated between May 2006 and January 2016 was performed. Eligible patients were those aged >18 years with non-metastatic endometrial adenocarcinoma and gross cervical disease treated with curative intent at the Centre hospitalier de l'Université de Montréal. Treatment protocol consisted of pelvic neoadjuvant radiotherapy and high-dose rate brachytherapy followed by extra-fascial hysterectomy. Kaplan-Meier curves were used for survival analysis. RESULTS: The median age was 60 (range 37-82) and median body mass index was 32 kg/m2 (range 16-55). Twenty-four (80%) patients were diagnosed with a positive cervical/endocervical biopsy. Clinical staging confirmed 36.7% (n=11) as stage II, 20% (n=6) stage IIIB, 30% (n=9) stage IIIC1, and 13.3% (n=4) stage IIIC2. Seventy-seven per cent (n=23) of patients had an endometrioid histology. Locally advanced disease was identified by imaging alone in six patients. Rates of parametrial, adnexal, vaginal, and nodal invasion were 10% (n=3), 6.7% (n=2), 13.3% (n=4), and 43.3% (n=13) at diagnosis, respectively. All patients completed pelvic radiotherapy (13.3% extended field) and 90% received brachytherapy. Twenty per cent (n=6) of surgeries were performed using minimal invasive technique. On surgical specimen, 63.3% (n=19) had complete cervical response, 90% (n=27) had negative margins, and 10% (n=3) had residual nodal involvement. Median follow-up time was 62 months (range 1-120). Six recurrences were identified; all except one involved distant failure, and two with locoregional failure. Five-year locoregional control rate, disease-free, overall, and disease-specific survival were 90.5%, 78.5%, 92.6%, and 96.2%, respectively. Two patients (6.7%) had grade 3+ acute radiation-related complications (all grade 3). Grade 3+ post-operative morbidity was noted in 2 (6.7%) patients. CONCLUSIONS: Neoadjuvant radiotherapy followed by extra-fascial hysterectomy offers good locoregional control with low treatment-related morbidity in patients with endometrial cancer with overt cervical involvement.

Pre-radiotherapy PSA progression is a negative prognostic factor in prostate cancer patients using 5­alpha-reductase inhibitors.

OBJECTIVE: To investigate the impact of 5­alpha-reductase inhibitor (5-ARI) use on radiotherapy outcomes for localized prostate cancer. PATIENTS AND METHODS: We included 203 patients on a 5-ARI from our institutional database comprising over 2500 patients who had been treated with either external beam radiotherapy (EBRT) or brachytherapy for localized prostate cancer. Patients received a 5-ARI for urinary symptoms or active surveillance. Cancer progressions at the time of definitive treatment were analyzed according to the following criteria: (a) progression of Gleason score or increase in cancer volume on biopsy, (b) first biopsy positive for cancer after being treated for urinary symptoms with a 5-ARI, and (c) prostate-specific antigen (PSA) progression with or without a previous cancer diagnosis. Biochemical failure (BF) was defined by the Phoenix definition. Log-rank test was used for survival analysis. RESULTS: At a median follow-up of 38.2 months (standard deviation 22.2 months), 10 (4.9%) patients experienced BF. Concerning prostate cancer progression criteria, 52% of men demonstrated none, 37% showed only one criterion, and 11% showed two. Using univariate analysis, PSA progression (p = 0.004) and appearance of a positive biopsy (p < 0.001) were significant predictive factors for BF, while Gleason progression (p = 0.3) was not. In multivariate analysis adjusted for cancer aggressiveness, rising PSA (hazard ratio, HR, 5.7; 95% confidence interval, CI, 1.1-28.8; p = 0.04) and the number of cancer progression factors (HR 2.9, 95% CI 1.2-7.0, p = 0.02) remained adverse risk factors. CONCLUSION: PSA progression experienced during 5­ARI treatment before radiotherapy is predictive of worse biochemical outcome. Such details should be considered when counseling men prior to radiation therapy.

External Beam Radiotherapy Affects Serum Testosterone in Patients With Localized Prostate Cancer.

BACKGROUND: Previous studies have examined testosterone levels after external beam radiation (EBRT) monotherapy, but since 2002 only sparse contemporary data have been reported. AIM: To examine testosterone kinetics in a large series of contemporary patients after EBRT. METHODS: The study was conducted in 425 patients who underwent definitive EBRT for localized prostate cancer from 2002 through 2014. Patients were enrolled in several phase II and III trials. Exclusion criteria were neoadjuvant or adjuvant androgen-deprivation therapy or missing data. Testosterone was recorded at baseline and then according to each study protocol (not mandatory in all protocols). Statistical analyses consisted of means and proportions, Kaplan-Meier plots, and logistic and Cox regression analyses. OUTCOMES: Testosterone kinetics after EBRT monotherapy and their influence on biochemical recurrence. RESULTS: Median follow-up of 248 assessable patients was 72 months. One hundred eighty-six patients (75.0%) showed a decrease in testosterone. Median time to first decrease was 6.4 months. Median percentage of decrease to the nadir was 30% and 112 (45.2%) developed biochemical hypogonadism (serum testosterone < 8 nmol/L). Of all patients with testosterone decrease, 117 (62.9%) recovered to at least 90% of baseline levels. Advanced age, increased body mass index, higher baseline testosterone level, and lower nadir level were associated with a lower chance of testosterone recovery. Subgroup analyses of 166 patients treated with intensity-modulated radiotherapy confirmed the results recorded for the entire cohort. In survival analyses, neither testosterone decrease nor recovery was predictive for biochemical recurrence. CLINICAL IMPLICATIONS: EBRT monotherapy influences testosterone kinetics, and although most patients will recover, approximately 45% will have biochemical hypogonadism. STRENGTHS AND LIMITATIONS: We report on the largest contemporary series of patients treated with EBRT monotherapy in whom testosterone kinetics were ascertained. Limitations are that testosterone follow-up was not uniform and the study lacked information on health-related quality-of-life data. CONCLUSION: Our findings indicate that up to 75% of patients will have a profound testosterone decrease, with up to a 40% increase in rates of biochemical hypogonadism, although the latter events will leave biochemical recurrence unaffected. Pompe RS, Karakrewicz PI, Zaffuto E, et al. External Beam Radiotherapy Affects Serum Testosterone in Patients With Localized Prostate Cancer. J Sex Med 2017;14:876-882.

Comparison of external beam radiotherapy versus permanent seed brachytherapy as monotherapy for intermediate-risk prostate cancer - a single center Canadian experience.

INTRODUCTION: We tested different classification systems in order to separate intermediate-risk prostate cancers into prognostic groups. We then examined which groups were most suited for either prostate seed brachytherapy (PB) or external beam radiotherapy (EBRT). MATERIALS AND METHODS: We selected patients with D'Amico intermediate-risk prostate cancer who were treated exclusively with either PB or EBRT. Patients were excluded if they had received androgen deprivation therapy in combination with EBRT or a follow up of < 30 months without recurrence. The Kaplan-Meier method was used to compare groups. RESULTS: Our sample consisted of 475 patients treated from July 2002-September 2013. Median follow up for patients without biochemical failure (BF) was 56 months (interquartile range 44-78); 222 patients (47%) were treated with PB exclusively (D90 interquartile range 145-176 Gy) and 253 (53%) with EBRT exclusively (dose interquartile range 76-80 Gy). The rate of BF was significantly lower in patients treated with PB (5.4%) than in patients treated with EBRT (14.2%) (p = 0.036, log-rank test). Upon univariate analysis, significant predictors of BF included the number of unfavorable intermediate-risk factors (0, 1, 2, 3) (p = 0.024) as well as the Cancer of the Prostate Risk Assessment (CAPRA) score (p = 0.002). After adjusting for the type of treatment, only the CAPRA score remained predictive (p = 0.025). For patients with a CAPRA score of 0-2, those with PB fared better than those treated with EBRT (p = 0.042). This difference disappeared in patients with a CAPRA score of 3-5 (p = 0.5). CONCLUSIONS: Using our current selection criteria for monotherapy, we found that PB or EBRT as monotherapy are equally effective treatment options for intermediate-risk prostate cancer.

Adjuvant Chemotherapy and Vaginal Vault Brachytherapy With or Without Pelvic Radiotherapy for Stage 1 Papillary Serous or Clear Cell Endometrial Cancer.

OBJECTIVE: The aim of this study was to assess and compare adjuvant chemotherapy followed by either high-dose-rate vaginal vault brachytherapy (VBT) alone or combined with pelvic external beam radiotherapy (EBRT) for International Federation of Gynaecology and Obstetrics stage 1 serous or clear cell (CC) endometrial cancer. METHODS: Between 2006 and 2012, 84 women with stage 1 serous or CC endometrial cancer were evaluated postoperatively for adjuvant treatment at our hospital. More than 80% of patients had pelvic lymphadenectomy. Patients declining or not completing adjuvant treatments were excluded. Twenty-five women received 4 to 6 cycles of carboplatin/paclitaxel followed by EBRT and VBT. Thirty-two women received 6 cycles of carboplatin/paclitaxel followed by VBT. Locoregional control and toxicities were assessed during follow-up. RESULTS: The 3-year disease-free survival and overall survival rates for the VBT group compared with the EBRT + VBT group were 88% versus 84%, P = 0.6, and 100% versus 94%, P = 0.6, respectively. Only 1 patient in the EBRT + VBT group developed a distant recurrence. One patient had grade 3 toxicity (chronic gastrointestinal [GI] toxicity) in the EBRT + VBT group. Acute grade 1-to-2 GI and grade 1 genitourinary (GU) toxicities were less frequent in the VBT group compared with the EBRT + VBT group (P = 0.008 and P = 0.019, respectively). Late GI and GU toxicities were comparable. Grade 1 vaginal toxicity was similar in both groups. No acute or late grade 2 GU or vaginal toxicities were reported. CONCLUSIONS: According to this study, VBT alone seems to be as effective as EBRT and VBT for stage 1 serous and CC endometrial cancer treated with surgery and adjuvant chemotherapy. Furthermore, less acute GI and GU toxicities were seen in the VBT group.

Vaginal epithelioid angiosarcoma: a potential pitfall in gynecologic pathology.

OBJECTIVE: Epithelioid angiosarcoma of the vagina is a rare variant that can easily be misdiagnosed considering the much higher frequency of epithelial neoplasms at that particular site. MATERIAL AND METHODS: We report the case of a 41-year-old gravida 2, para 1, aborta 1, with no prior history of irradiation, who consulted after the discovery of 3 lesions at the lower right portion of the vagina. RESULT: The lesion consisted of epithelioid cells with high-grade nuclei and prominent nucleoli. These cells expressed CD31, CD34, factor VIII, Fli-1, vimentin, smooth muscle actin, and WT-1. Keratin 8/18 was focally positive. They were immunonegative for keratin AE1/AE3, keratin 34ßE12, keratin 7, keratin 20, S100, HMB-45, myogenin, desmin, and human herpesvirus type 8. Polymerase chain reaction-based HPV viral search was also negative. CONCLUSIONS: A broad immunohistochemical panel including antibodies against vascular differentiation markers as well as various cytokeratins allows proper diagnosis of this unusual and aggressive entity.

Pan-Canadian Survey of Radiation Oncology Professional Involvement in Global Oncology Initiatives in Low- and Middle-Income Countries.

PURPOSE: Canadian radiation oncology professionals have a strong history of involvement in global oncology initiatives worldwide. This pan-Canadian survey-based study was conducted to determine the current level of engagement of Canadian radiation oncologists (ROs) and medical physicists (MPs) in global oncology initiatives and broaden the development of these activities. MATERIALS AND METHODS: This was a cross-sectional study. The survey was designed to characterize current levels of engagement of Canadian ROs and MPs in global oncology initiatives. The survey was open from March 2019 to April 2020. It was disseminated to all Canadian Association of Radiation Oncology and Canadian Organization of Medical Physicists members with two subsequent email reminders. RESULTS: Survey responses were received from 40 (93%) of the 43 Canadian cancer treatment centers that offer radiotherapy. At least one RO responded at 34 centers (79%) and one MP from 34 centers (79%) with some overlap. A response was received from a total of 93 participants, 47 ROs and 46 MPs. Of all survey participants, 58% reported some experience with global oncology. Nineteen percent of the participants surveyed were currently directly involved in short- or long-term projects, more than half of which have opportunity for additional staff involvement. The projects spanned 26 countries in South America, Africa, and Asia. Quality improvement and capacity building accounted for 27% and 20% of initiatives, respectively. The most common area of engagement was in direct treatment care, accounting for 56% of the projects. CONCLUSION: This study demonstrates the landscape of involvement of Canadian ROs and MPs in global oncology initiatives. The study also highlights areas of opportunity for broadening international participation and collaboration as it relates to global oncology for Canadian radiation oncology professionals.

Noninferiority of Hypofractionated vs Conventional Postprostatectomy Radiotherapy for Genitourinary and Gastrointestinal Symptoms: The NRG-GU003 Phase 3 Randomized Clinical Trial.

Importance: No prior trial has compared hypofractionated postprostatectomy radiotherapy (HYPORT) to conventionally fractionated postprostatectomy (COPORT) in patients primarily treated with prostatectomy. Objective: To determine if HYPORT is noninferior to COPORT for patient-reported genitourinary (GU) and gastrointestinal (GI) symptoms at 2 years. Design, Setting, and Participants: In this phase 3 randomized clinical trial, patients with a detectable prostate-specific antigen (PSA; ≥0.1 ng/mL) postprostatectomy with pT2/3pNX/0 disease or an undetectable PSA (<0.1 ng/mL) with either pT3 disease or pT2 disease with a positive surgical margin were recruited from 93 academic, community-based, and tertiary medical sites in the US and Canada. Between June 2017 and July 2018, a total of 296 patients were randomized. Data were analyzed in December 2020, with additional analyses occurring after as needed. Intervention: Patients were randomized to receive 62.5 Gy in 25 fractions (HYPORT) or 66.6 Gy in 37 fractions (COPORT). Main Outcomes and Measures: The coprimary end points were the 2-year change in score from baseline for the bowel and urinary domains of the Expanded Prostate Cancer Composite Index questionnaire. Secondary objectives were to compare between arms freedom from biochemical failure, time to progression, local failure, regional failure, salvage therapy, distant metastasis, prostate cancer-specific survival, overall survival, and adverse events. Results: Of the 296 patients randomized (median [range] age, 65 [44-81] years; 100% male), 144 received HYPORT and 152 received COPORT. At the end of RT, the mean GU change scores among those in the HYPORT and COPORT arms were neither clinically significant nor different in statistical significance and remained so at 6 and 12 months. The mean (SD) GI change scores for HYPORT and COPORT were both clinically significant and different in statistical significance at the end of RT (-15.52 [18.43] and -7.06 [12.78], respectively; P < .001). However, the clinically and statistically significant differences in HYPORT and COPORT mean GI change scores were resolved at 6 and 12 months. The 24-month differences in mean GU and GI change scores for HYPORT were noninferior to COPORT using noninferiority margins of -5 and -6, respectively, rejecting the null hypothesis of inferiority (mean [SD] GU score: HYPORT, -5.01 [15.10] and COPORT, -4.07 [14.67]; P = .005; mean [SD] GI score: HYPORT, -4.17 [10.97] and COPORT, -1.41 [8.32]; P = .02). With a median follow-up for censored patients of 2.1 years, there was no difference between HYPORT vs COPORT for biochemical failure, defined as a PSA of 0.4 ng/mL or higher and rising (2-year rate, 12% vs 8%; P = .28). Conclusions and Relevance: In this randomized clinical trial, HYPORT was associated with greater patient-reported GI toxic effects compared with COPORT at the completion of RT, but both groups recovered to baseline levels within 6 months. At 2 years, HYPORT was noninferior to COPORT in terms of patient-reported GU or GI toxic effects. HYPORT is a new acceptable practice standard for patients receiving postprostatectomy radiotherapy. Trial Registration: ClinicalTrials.gov Identifier: NCT03274687.

Hemoglobin level in cervical cancer: a surrogate for an infiltrative phenotype.

OBJECTIVE: Hemoglobin (Hb) is a prognostic factor in cervical cancer, but the underlying mechanisms remain unknown. In this study, we hypothesized that low Hb level, either before or during radiotherapy (RT), is a surrogate for a more infiltrative and therefore aggressive disease, with uterine corpus invasion and nodal metastases. METHODS AND MATERIALS: Prospectively collected data of patients with locally advanced cervical cancer treated with curative intent using chemoradiation at a tertiary academic center was reviewed. All eligible patients had a positron emission tomographic scan and pelvic magnetic resonance imaging. Hemoglobin levels before RT and Hb nadir during RT were collected from the medical record. RESULTS: The median follow-up for 263 eligible patients was 38.7 months. Ninety-six patients (36.5%) had both uterine corpus invasion and positron emission tomography-positive nodal disease (C+N+). Patients with pretreatment Hb level of less than 120 g/L were more likely to have C+N+ disease (47%) compared with patients with a high pretreatment Hb level (32%; P = 0.034). The 3-year disease-free survival and overall survival (OS) were significantly lower in the C+N+ group compared with the remaining patients (40.1% vs 76.1%, P < 0.001, and 59.7% vs 83.1%, P < 0.001, respectively). Patients with low Hb nadir were more likely to have a C+N+ disease (P < 0.001), and low Hb nadir during RT was significantly an indicator of a higher recurrence rate (P = 0.002) and lower OS (P < 0.001). In multifactor analysis, statistically significant prognostic factors for OS included histology, high-echelon nodal involvement, tumor volume on magnetic resonance imaging, C+N+ status, and Hb nadir during treatment. Pretreatment Hb level was not an independent prognostic factor. CONCLUSIONS: The combination of corpus invasion and nodal metastases is associated with lower Hb level and inferior prognosis. Because C+N+ state is related to tumor growth from early invasion to the time of presentation, it is unlikely that the correction of Hb level during treatment will have a major impact on outcome.

A Case of Radiation-Induced Aortitis in a Patient With Cervical Cancer.

Radiation-induced aortitis is a rare but potentially serious complication of radiotherapy. We report the case of a 46-year-old female with a history of cervical cancer who developed radiation-induced aortitis following two courses of concurrent chemoradiation. The patient was asymptomatic, and the condition was detected during a routine follow-up positron emission tomography (PET) scan. The patient was referred to rheumatology for differential diagnosis, which ruled out non-radiation-induced aortitis. The condition was managed conservatively, and a follow-up computed tomography (CT) scan showed resolution of the aortitis but the progression of aorto-iliac fibrosis. The patient was then started on prednisone, which led to a regression of the aorto-iliac vessel thickening.

Role of 18F-choline and 18F-fluorodeoxyglucose positron emission tomography in combination with magnetic resonance imaging in brachytherapy planning for locally advanced cervical cancer: A pilot study.

Background and purpose: This pilot study aims to describe the advantages of combining metabolic and anatomic imaging modalities in brachytherapy (BT) planning for locally advanced cervical cancer (LACC) and to evaluate the supplementary value of Fluoro(F)-Choline positron emission tomography/computed tomography (PET/CT) in comparison to 18F-fluorodeoxyglucose (FDG) in this setting. Materials and methods: A prospective cohort of six patients with LACC was included in this study. Each patient underwent BT planning CT scan, magnetic resonance imaging (MRI), and both FDG and F-Choline PET/CT scans on the same day, with BT applicators in place. Patients were treated according to the standard of care. Metabolic target volumes (TV) were generated retrospectively and compared with the anatomic volumes using Dice coefficients and absolute volume comparison. Results: The threshold at which the metabolic and anatomic volumes were the most concordant was found to be 35% maximum standardized uptake value (SUV max) for both PET/CT scans. Amongst the six patients in this cohort, three in the FDG cohort and four in the F-Choline cohort were found to have more than ten percent ratio of excess (increase) in their MRI gross tumor volumes (GTV) when incorporating the metabolic information from the PET/CT scans. However, no significant changes were needed in the high risk-clinical target volumes (CTVHR) for both PET tracers. Conclusions: FDG and F-Choline PET/CT scans can substantially modify the BT GTV on MRI, without affecting the CTVHR. F-Choline is potentially more informative than FDG in assessing residual TV, particularly in cases with significant post-radiation inflammatory changes.

Gastric-type adenocarcinoma of the endocervix: Potentially overcoming resistant behavior with surgery.

Objective: Gastric-type adenocarcinoma of the endocervix (GAS) is a rare form of human papillomavirus-independent cervical cancer commonly described as an insidious disease bearing a poor prognosis. Based on scarce data, uncertainty persists pertaining to its oncologic management. Method: All cases of well-differentiated GAS treated at our institution from 2010 to 2021 were reviewed. Clinical characteristics, diagnostic tests results and oncologic outcomes were recorded and analyzed. Kaplan-Meier curves and log rank test were performed to compare survival curves between patients with tumors confined to the cervix (group 1: up to stage IB3) versus locally advanced or metastatic (group 2: stages II to IV). Results: Cervical cytologies and biopsies yielded low detection rates (38 and 42% respectively) leading to 87% of patients with locally advanced or metastatic disease at diagnosis. Median overall survival (OS) was 40.0 ± 15.9 months with a clear dichotomy in survival when comparing patients with disease confined to the cervix to those with higher stages (respectively 59.0 vs 12.0 months, p = 0.047). None of the 5 patients initially managed with concurrent chemoradiotherapy (CCRT) responded to treatment but fortunately 3 of the latter achieved remission after surgery. Conclusion: Well-differentiated GAS did not show favorable response to chemotherapy and radiation. Surgical resection seems to be a cornerstone in the management of this disease, as all patients who achieved remission were treated with surgery, either upfront or after suboptimal response to CCRT. We suggest considering aggressive upfront surgery when feasible. If CCRT is selected to avoid upfront exenterative procedures, rapid evaluation of tumor response is recommended.

The Montreal split ring applicator: Towards highly adaptive gynecological brachytherapy using 3D-printed biocompatible patient-specific interstitial caps.

Purpose: The addition of interstitial (IS) needles to intra-cavitary (IC) brachytherapy applicators is associated with improved outcomes in locally advanced cervical cancers involving parametrial tumor extensions. The purpose of this work was to validate a clinical workflow involving 3D-printed caps for a commercial IC split ring applicator that enable using IS needle trajectories tailored to each treatment. Material and methods: A dedicated software module was developed in this work allowing users to design patient-specific IS caps without knowledge of computer-aided design (CAD) software. This software module was integrated to 3D Brachy, a commercial software developed by Adaptiiv Medical Technologies Inc. For validation of the workflow, CAD models of ground truth caps with five IS needle trajectories were designed with Fusion 360™, 3D-printed, assembled with a split ring applicator, and CT-scanned with radio-opaque markers. 3D Brachy was then applied to generate a replica based on trajectories reconstructed from the radio-opaque markers. A comparison between ground truth and replicated IS needle trajectories was done using intersection points with planes at the level of the cervix (z = 0 cm) and a representative needle depth (z = 3 cm). Results: Prototypes of interstitial caps 3D-printed in both BioMed Amber and BioMed Clear SLA resins were tested to be functional both pre- and post-sterilization for IS needles with obliquity angles ≤ 45°. Distance-to-agreement at z = 0 cm and 3 cm as well as deviations in pitch and yaw angles of the five IS needle trajectories were found to have mean values of 3.3 ±2.1 mm, 7.3 ±2.0 mm, 2.9° ±2.3°, and 7.0° ±7.0°, respectively. Conclusions: The clinical workflow for image-guided adaptive cervical cancer brachytherapy using the Montreal split ring applicator was validated.

PSMA-PET/CT-Guided Intensification of Radiation Therapy for Prostate Cancer (PSMAgRT): Findings of Detection Rate, Effect on Cancer Management, and Early Toxicity From a Phase 2 Randomized Controlled Trial.

PURPOSE: Prostate-specific membrane antigen (PSMA) ligand positron emission tomography (PET) is increasingly integrated in prostate cancer management because of its diagnostic performance. We sought to evaluate the effect of PSMA-PET/computed tomography (CT)-guided intensification of radiation therapy (PSMAgRT) on patient outcomes. Here, we report secondary trial endpoints including the rate of new lesion detection, effect on prostate cancer management, and treatment-related toxicities. METHODS AND MATERIALS: In this phase 2 cohort multiple randomized controlled trial across 2 institutions, men with prostate cancer planned for RT were randomly selected for PSMAgRT across 4 strata: oligometastatic, high risk (Cancer of the Prostate Risk Assessment ≥6 or cN1), salvage post-RT, and salvage postprostatectomy (RP). Primary endpoint was failure-free survival at 5 years, with analysis pending further follow-up. Secondary endpoints included new lesion detection yield of PSMA-PET/CT, acute and delayed toxicities, effect on prostate cancer management, and health-related quality-of-life outcomes. This trial is registered with ClinicalTrials.gov, identifier NCT03525288, companion to registry NCT03378856. RESULTS: Between May 2018 and February 2021, 262 patients were enrolled and randomized. Nine patients were later excluded (5 control, 4 PSMAgRT), leaving 253 patients for analysis (23 oligometastatic, 86 high risk, 16 salvage post-RT, and 128 salvage post-RP). New lesions were detected in 45.5% of oligometastatic, 39.5% of high risk, 14.3% of salvage post-RT, and 51.6% of salvage post-RP. Overall, PSMA-PET/CT led to intensification of RT in over half of patients (52.0%), with minimal intensification of systemic therapy (4.0%). With a median follow-up of 12.9 months, this intensification was associated with 3 attributable grade 3+ events (2.5% of patients undergoing PSMAgRT) but no difference in the rate of grade 2+ events attributable to RT compared with controls (43%, both arms). CONCLUSIONS: In this randomized trial, PSMA-PET/CT led to intensification of RT in more than half of patients. Longer follow-up is required to determine whether this intensification translates to effect on cancer control and long-term toxicity and health-related quality-of-life outcomes.