Prostate-Specific Membrane Antigen Positron Emission Tomography/Computed Tomography-Based Clinical Target Volume Delineation Guideline for Postprostatectomy Salvage Radiation Therapy: The PERYTON Guideline.

PURPOSE: Prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA PET/CT) scan is the standard imaging procedure for biochemical recurrent prostate cancer postprostatectomy because of its high detection rate at low serum prostate-specific antigen levels. However, existing guidelines for clinical target volume (CTV) in prostate bed salvage external beam radiation therapy (sEBRT) are primarily based on experience-based clinical consensus and have been validated using conventional imaging modalities. Therefore, this study aimed to optimize CTV definition in sEBRT by using PSMA PET/CT-detected local recurrences (LRs). METHODS AND MATERIALS: Patients with suspected LR on PSMA PET/CT postprostatectomy were retrospectively enrolled in 9 Dutch centers. Anonymized scans were centrally reviewed by an expert nuclear medicine physician. Each boundary of the CTV guideline from the Groupe Francophone de Radiothérapie en Urologie (GFRU) was evaluated and adapted to improve the accuracy and coverage of the area at risk of LR (CTV) on PSMA PET/CT. The proposed CTV adaptation was discussed with the radiation oncologists of the participating centers, and final consensus was reached. To assess reproducibility, the participating centers were asked to delineate 3 new cases according to the new PERYTON-CTV, and the submitted contours were evaluated using the Dice similarity coefficient (DSC). RESULTS: After central review, 93 LRs were identified on 83 PSMA PET/CTs. The proposed CTV definition improved the coverage of PSMA PET/CT-detected LRs from 67% to 96% compared with the GFRU-CTV, while reducing the GFRU-CTV by 25%. The new CTV was highly reproducible, with a mean DSC of 0.82 (range, 0.81-0.83). CONCLUSIONS: This study contributes to the optimization of CTV definition in postprostatectomy sEBRT by using the pattern of LR detected on PSMA PET/CT. The PERYTON-CTV is highly reproducible across the participating centers and ensures coverage of 96% LRs while reducing the GFRU-CTV by 25%.

Cosmetic Results and Side Effects of Accelerated Partial-Breast Irradiation Versus Whole-Breast Irradiation for Low-Risk Invasive Carcinoma of the Breast: The Randomized Phase III IRMA Trial.

PURPOSE: The results in terms of side effects vary among the published accelerated partial-breast irradiation (APBI) studies. Here, we report the 5-year results for cosmetic outcomes and toxicity of the IRMA trial. METHODS: We ran this randomized phase III trial in 35 centers. Women with stage I-IIA breast cancer treated with breast-conserving surgery, age ≥ 49 years, were randomly assigned 1:1 to receive either whole-breast irradiation (WBI) or external beam radiation therapy APBI (38.5 Gy/10 fraction twice daily). Patients and investigators were not masked to treatment allocation. The primary end point was ipsilateral breast tumor recurrence. We hereby present the analysis of the secondary outcomes, cosmesis, and normal tissue toxicity. All side effects were graded with the Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer Radiation Morbidity Scoring Schema. Analysis was performed with both intention-to-treat and as-treated approaches. RESULTS: Between March 2007 and March 2019, 3,309 patients were randomly assigned to 1,657 WBI and 1,652 APBI; 3,225 patients comprised the intention-to-treat population (1,623 WBI and 1,602 APBI). At a median follow-up of 5.6 (interquartile range, 4.0-8.4) years, adverse cosmesis in the APBI patients was higher than that in the WBI patients at 3 years (12.7% v 9.2%; P = .009) and at 5 years (14% v 9.8%; P = .012). Late soft tissue toxicity (grade ≥ 3: 2.8% APBI v 1% WBI, P < .0001) and late bone toxicity (grade ≥ 3: 1.1% APBI v 0% WBI, P < .0001) were significantly higher in the APBI arm. There were no significant differences in late skin and lung toxicities. CONCLUSION: External beam radiation therapy-APBI with a twice-daily IRMA schedule was associated with increased rates of late moderate soft tissue and bone toxicities, with a slight decrease in patient-reported cosmetic outcomes at 5 years when compared with WBI, although overall toxicity was in an acceptable range.

Side Effects 15 Years After Lymph Node Irradiation in Breast Cancer: Randomized EORTC Trial 22922/10925.

BACKGROUND: Uncertainty about the benefit-risk ratio of regional lymph node irradiation led to varying clinical protocols. We investigated long-term late side effects after internal mammary and medial supraclavicular (IM-MS) lymph node irradiation to improve shared decision making. METHODS: The multicenter European Organization for Research and Treatment of Cancer trial (ClinicalTrials.gov, NCT00002851) randomly assigned stage I-III breast cancer patients with involved axillary nodes and/or a medially located primary tumor. We analyzed late side effects both longitudinally at every follow-up and cross-sectionally at 5-year intervals. All statistical tests were 2-sided. RESULTS: Between 1996 and 2004, 46 departments from 13 countries accrued 4004 patients. Median follow-up was 15.7 years. Longitudinal follow-up data showed cumulative incidence rates at 15 years of 2.9% (95% confidence interval [CI] = 2.2% to 3.8%) vs 5.7% (95% CI = 4.7% to 6.9%) (P < .001) for lung fibrosis, 1.1% (95% CI = 0.7% to 1.7%) vs 1.9% (95% CI = 1.3% to 2.6%) (P = .07) for cardiac fibrosis, and 9.4% (95% CI = 8.0% to 10.8%) vs 11.1% (95% CI = 9.6% to 12.7%) (P = .04) for any cardiac disease when treated without or with IM-MS lymph node irradiation. There was no evidence for differences between left- and right-sided breast cancer (Wald χ2 test of treatment by breast side interaction, P = .33 and P = .35, for cardiac fibrosis and for any cardiac disease, respectively). The cumulative incidence probabilities of cross-sectionally reported side effects with a score of 2 or greater at 15 years were 0.1% (95% CI = 0.0% to 0.5%) vs 0.8% (95% CI = 0.4% to 1.4%) for pulmonary (P = .02), 1.8% (95% CI = 1.1% to 2.8%) vs 2.6% (95% CI = 1.8% to 3.7%) for cardiac (P = .15), and 0.0% (95% CI not evaluated) vs 0.1% (95% CI = 0.0% to 0.4%) for esophageal (P = .16), respectively. No difference was observed in the incidence of second malignancies, contralateral breast cancer, or cardiovascular deaths. CONCLUSIONS: The incidence of late pulmonary side effects was statistically significantly higher after IM-MS lymph node irradiation, as were some of the cardiac events, without a difference between left- and right-sided treatments. Absolute rates and differences were very low, without increased non-breast cancer-related mortality, even before introducing heart-sparing techniques.

Short Androgen Suppression and Radiation Dose Escalation in Prostate Cancer: 12-Year Results of EORTC Trial 22991 in Patients With Localized Intermediate-Risk Disease.

PURPOSE: The European Organisation for Research and Treatment of Cancer (EORTC) trial 22991 (NCT00021450) showed that 6 months of concomitant and adjuvant androgen suppression (AS) improves event- (EFS, Phoenix) and clinical disease-free survival (DFS) of intermediate- and high-risk localized prostatic carcinoma, treated by external-beam radiotherapy (EBRT) at 70-78 Gy. We report the long-term results in intermediate-risk patients treated with 74 or 78 Gy EBRT, as per current guidelines. PATIENT AND METHODS: Of 819 patients randomly assigned between EBRT or EBRT plus AS started on day 1 of EBRT, 481 entered with intermediate risk (International Union Against Cancer TNM 1997 cT1b-c or T2a with prostate-specific antigen (PSA) ≥ 10 ng/mL or Gleason ≤ 7 and PSA ≤ 20 ng/mL, N0M0) and had EBRT planned at 74 (342 patients, 71.1%) or 78 Gy (139 patients, 28.9%). We report the trial primary end point EFS, DFS, distant metastasis-free survival (DMFS), and overall survival (OS) by intention-to-treat stratified by EBRT dose at two-sided α = 5%. RESULTS: At a median follow-up of 12.2 years, 92 of 245 patients and 132 of 236 had EFS events in the EBRT plus AS and EBRT arm, respectively, mostly PSA relapse (48.7%) or death (45.1%). EBRT plus AS improved EFS and DFS (hazard ratio [HR] = 0.53; CI, 0.41 to 0.70; P < .001 and HR = 0.67; CI, 0.49 to 0.90; P = .008). At 10 years, DMFS was 79.3% (CI, 73.4 to 84.0) with EBRT plus AS and 72.7% (CI, 66.2 to 78.2) with EBRT (HR = 0.74; CI, 0.53 to 1.02; P = .065). With 140 deaths (EBRT plus AS: 64; EBRT: 76), 10-year OS was 80.0% (CI, 74.1 to 84.7) with EBRT plus AS and 74.3% (CI, 67.8 to 79.7) with EBRT, but not statistically significantly different (HR = 0.74; CI, 0.53 to 1.04; P = .082). CONCLUSION: Six months of concomitant and adjuvant AS statistically significantly improves EFS and DFS in intermediate-risk prostatic carcinoma, treated by irradiation at 74 or 78 Gy. The effects on OS and DMFS did not reach statistical significance.

Internal mammary and medial supraclavicular lymph node chain irradiation in stage I-III breast cancer (EORTC 22922/10925): 15-year results of a randomised, phase 3 trial.

BACKGROUND: 10-year results from several studies showed improved disease-free survival and distant metastasis-free survival, reduced breast cancer-related mortality, and variable effects on overall survival with the addition of partial or comprehensive regional lymph node irradiation after surgery in patients with breast cancer. We present the scheduled 15-year analysis of the European Organisation for Research and Treatment of Cancer (EORTC) 22922/10925 trial, which aims to investigate the impact on overall survival of elective internal mammary and medial supraclavicular (IM-MS) irradiation. METHODS: EORTC 22922/10925, a randomised, phase 3 trial done across 46 radiation oncology departments from 13 countries, included women up to 75 years of age with unilateral, histologically confirmed, stage I-III breast adenocarcinoma with involved axillary nodes or a central or medially located primary tumour. Surgery consisted of mastectomy or breast-conserving surgery and axillary staging. Patients were randomly assigned (1:1) centrally using minimisation to receive IM-MS irradiation at 50 Gy in 25 fractions (IM-MS irradiation group) or no IM-MS irradiation (control group). Stratification was done for institution, menopausal status, site of the primary tumour within the breast, type of breast and axillary surgery, and pathological T and N stage. Patients and investigators were not masked to treatment allocation. The primary endpoint was overall survival analysed according to the intention-to-treat principle. Secondary endpoints were disease-free survival, distant metastasis-free survival, breast cancer mortality, any breast cancer recurrence, and cause of death. Follow-up is ongoing for 20 years after randomisation. This study is registered with ClinicalTrials.gov, NCT00002851. FINDINGS: Between Aug 5, 1996, and Jan 13, 2004, we enrolled 4004 patients, of whom 2002 were randomly assigned to the IM-MS irradiation group and 2002 to the no IM-MS irradiation group. At a median follow-up of 15·7 years (IQR 14·0-17·6), 554 (27·7%) patients in the IM-MS irradiation group and 569 (28·4%) patients in the control group had died. Overall survival was 73·1% (95% CI 71·0-75·2) in the IM-MS irradiation group and 70·9% (68·6-72·9) in the control group (HR 0·95 [95% CI 0·84-1·06], p=0·36). Any breast cancer recurrence (24·5% [95% CI 22·5-26·6] vs 27·1% [25·1-29·2]; HR 0·87 [95% CI 0·77-0·98], p=0·024) and breast cancer mortality (16·0% [14·3-17·7] vs 19·8% [18·0-21·7]; 0·81 [0·70-0·94], p=0·0055) were lower in the IM-MS irradiation group than in the control group. No significant differences in the IM-MS irradiation group versus the control group were seen for disease-free survival (60·8% [95% CI 58·4-63·2] vs 59·9% [57·5-62·2]; HR 0·93 [95% CI 0·84-1·03], p=0·18), or distant metastasis-free survival (70·0% [67·7-72·2] vs 68·2% [65·9-70·3]; 0·93 [0·83-1·04], p=0·18). Causes of death between groups were similar. INTERPRETATION: The 15-year results show a significant reduction of breast cancer mortality and any breast cancer recurrence by IM-MS irradiation in stage I-III breast cancer. However, this is not converted to improved overall survival. FUNDING: US National Cancer Institute, Ligue Nationale contre le Cancer, and KWF Kankerbestrijding.

No long-term effects of hormonal therapy preceding brachytherapy on urinary function and health-related quality of life among prostate cancer patients.

OBJECTIVES: To prospectively investigate the influence of 3-month neoadjuvant hormonal therapy (NHT) before brachytherapy (BT) for low-risk prostate cancer (PCa) on urinary function and health-related quality of life (HRQL). METHODS: Between 2003 and 2008, 300 patients with PCa were treated with BT using (125)I stranded seeds, of whom 86 received 3-month NHT to downsize the prostate before treatment. Urinary complaints were measured on all occasions with the International Prostate Symptom Score (n = 134) and European Organization for Research and Treatment of Cancer-Quality of Life Questionnaire PR25 (EORTC-QLQ-PR25 questionnaire; n = 118) and HRQL with the EORTC-QLQ-C30 (n = 120) questionnaire. RESULTS: Post-BT, urinary function became worse over the first 6 weeks and then improved steadily, but did not return to baseline levels at 1 year. At baseline, the NHT group reported worse urinary function compared with the non-NHT group (P < .01). However, the post-BT improvement of urinary function was better in the NHT group at 3 months (P < .05). Global HRQL, physical, role and social functioning decreased over the first 3 months (P < .05) post-BT but returned to baseline levels within 1 year. Emotional function steadily improved over the 1-year follow-up period (P < .001). The NHT group reported better global HRQL, social and emotional functioning 1 year post-BT compared with baseline (P < 05). All results were adjusted for comorbidity. This is a single-center study with a follow-up of 1 year, thereby potentially limiting the general applicability of the results. CONCLUSIONS: Three months of NHT before BT might positively influence urinary function and HRQL up to 1 year post-BT. Therefore, PCa patients should not be dissuaded from considering NHT followed by BT because of prostate size.

Is sensorineural hearing loss a possible side effect of nasopharyngeal and parotid irradiation? A systematic review of the literature.

BACKGROUND AND PURPOSE: Little has been published about permanent hearing loss due to radiotherapy, thus making it a rather unknown phenomenon. Therefore, we performed a study of the literature over the last 20 years. MATERIALS AND METHODS: Sixteen relevant clinical studies were found, reporting mostly on nasopharyngeal or parotid gland treatments. Hearing loss was measured using a pure tone audiogram. Studies were assessed using a simple scoring list. Nine studies were used for further analysis. Data on the pure tone audiogram were pooled. RESULTS: Results showed that, especially in the higher frequencies (> or =4 kHz), loss can be measured. When data were pooled, in 42 +/- 3% of the patients a hearing loss was found of 10 dB or more at 4 kHz. Averaged over all measured frequencies the effect is less prominent but still statistically significant (18 +/- 2%). No significant difference between nasopharyngeal and parotid gland treatment was found (P < 0.05). CONCLUSION: Only a few studies, mostly concerning small patient numbers, have investigated hearing damage due to radiotherapy. So far there has been no consensus on the subject. However, in this systematic review we found a significant effect. Dose to the inner ear therefore deserves more attention, especially in dose escalation studies and inverse planning.