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Purpose: This trial examined if patients with ≤5 sites of oligoprogression benefit from the addition of SABR to standard of care (SOC) systemic therapy., Methods and Materials: We enrolled patients with 1 to 5 metastases progressing on systemic therapy, and after stratifying by type of systemic therapy (cytotoxic vs noncytotoxic), randomized 1:2 between continued SOC treatment versus SABR to all progressing lesions plus SOC. The trial was initially limited to non-small cell lung cancer but was expanded to include all nonhematologic malignancies to meet accrual goals. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), lesional control, quality of life, adverse events, and duration of systemic therapy postrandomization., Results: Ninety patients with 127 oligoprogressive metastases were enrolled across 8 Canadian institutions, with 59 randomized to SABR and 31 to SOC. The median age was 67 years, and 39 (43%) were women. The most common primary sites were lung (44%), genitourinary (23%), and breast (13%). Protocol adherence in the SOC arm was suboptimal, with 11 patients (35%) either receiving high-dose/ablative therapies (conflicting with trial protocol) or withdrawing from the study. The median follow-up was 31 months. There was no difference in PFS between arms (median PFS 8.4 months in the SABR arm vs 4.3 months in the SOC arm, but curves cross and 2-year PFS was 9% vs 24%, respectively; P = .91). The median OS was 31.2 months versus 27.4 months, respectively (P = .22). Lesional control was superior with SABR (70% vs 38%, respectively; P = .0015). There were 2 (3.4%) grade 3 and no grade 4/5 adverse events attributable to SABR., Conclusions: SABR was well-tolerated with superior lesional control but did not improve PFS or OS. Accrual to this study was difficult, and the results may have been impacted by an unwillingness to forgo ablative treatments on the SOC arm. (NCT02756793)., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: BIOEMBRACE was designed to study the impact of biomarkers in addition to clinicopathological factors on disease outcomes in patients treated with chemoradiation and magnetic resonance imaging (MRI)-guided brachytherapy (BT) for locally advanced cervical cancer in the EMBRACE study., Methods and Materials: Between 2018 and 2021, 8 EMBRACE-I sites contributed tumor tissue for the immunohistochemistry of p16, PD-L1, and L1CAM. These biomarkers and clinicopathological factors (International Federation of Gynecology and Obstetrics 2009 stage, nodal status, histology, and necrosis on MRI) were analyzed to predict poor response at BT (high-risk clinical target volume [HR-CTV] ≥ 40 cc) at BT) and 5-year local control, pelvic control, and disease-free survival. Interaction between p16, PD-L1, radiation therapy dose (HR-CTV D90), and disease outcomes was investigated. Univariable and multivariable analyses were performed., Results: Two hundred sixty-four patients were included. The median HR-CTV D90 was 89 Gy (86-95). P-16 positive status, PD-L1 > 1%, and L1CAM ≥ 10% was noted in 86.6%, 20.1%, and 17.8% of patients, respectively. P16 negative status (odds ratio, 2.0; 95% CI, 1.0-5.7; P = .04) and necrosis on MRI (odds ratio, 2.1; 95% CI, 1.1-4.3; P < .02) independently predicted for HR-CTV ≥ 40 cc, as did the International Federation of Gynecology and Obstetrics stage and tumor width >5 cm. PD-L1 > 1% was associated with reduced local (82% vs 94%; P = .02) and pelvic control (79% vs 89%; P = .02). HR-CTV D90 < 85 Gy was associated with inferior 5-year local control in p16-positive patients, especially if PD-L1 was coexpressed. On multivariable analysis, PD-L1 > 1% was the only independent factor for 5-year local control (hazard ratio, 3.3; P = .04) and L1CAM ≥ 50% for pelvic control (hazard ratio, 5.5; 95% CI, 1.3-23.3; P = .02)., Conclusions: P16 negative status and tumor necrosis on MRI are independently associated with poor response to chemoradiation, whereas PD-L1 > 1% and L1CAM ≥ 50% have an independent impact on local and pelvic control, suggesting an impact of biomarker expression on outcomes. Further validation is needed., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: A simple scoring system (T-score, TS) for integrating findings from clinical examination and magnetic resonance imaging (MRI) of the primary tumor at diagnosis has shown strong prognostic capability for predicting local control and survival in locally advanced cervical cancer treated with chemoradiation and MRI-guided brachytherapy (BT). The aim was to validate the performance of TS using the multicenter EMBRACE I study and to evaluate the prognostic implications of TS regression obtained during initial chemoradiation., Methods and Materials: EMBRACE I recruited 1416 patients, of whom 1318 were available for TS. Patients were treated with chemoradiation followed by MRI-guided BT. A ranked ordinal scale of 0 to 3 points was used to assess 8 anatomic locations typical for local invasion of cervical cancer. TS was calculated separately at diagnosis (TS D ) and at BT (TS BT ) by the sum of points obtained from the 8 locations at the 2 occasions., Results: Median TS D and TS BT was 5 and 4, respectively. TS regression was observed in 71% and was an explanatory variable for BT technique (intracavitary vs intracavitary/interstitial) and major dose-volume histogram parameters for BT, such as high-risk clinical target (CTV HR ), CTV HR D90 (minimal dose to 90% of the target volume), D2cm 3 bladder (minimal dose to the most exposed 2 cm 3 of the bladder), and D2cm 3 rectum. TS regression (TS BT ≤5) was associated with improved local control and survival and with less morbidity compared with patients with TS BT remaining high (>5) despite initial chemoradiation. TS regression was significant in multivariate analysis for both local control and survival when analyzed in consort with already established prognostic parameters related to the patient, disease, and treatment., Conclusions: TS was validated in a multicenter setting and proven to be a strong multidisciplinary platform for integration of clinical findings and imaging with the ability to quantitate local tumor regression and its prognostic implications regarding BT technique, dose-volume histogram parameters, local control, survival, and morbidity., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: Myocardial perfusion defects after breast radiation therapy (RT) correlate with volume of irradiated left ventricle (LV). We aimed to determine the relationship between myocardial perfusion, LV dosimetry, and grade ≥2 late cardiac events in patients with breast cancer undergoing adjuvant RT., Methods and Materials: A randomized study evaluated the benefit of inverse-planned intensity modulated radiation therapy over forward-planned intensity modulated radiation therapy for radiation toxicity in breast cancer. A secondary endpoint was evaluating cardiac perfusion by single-photon emission computed tomography done at baseline, 6 months, 1 year, 2 years, and 5 years post-RT. We used receiver operating curve and regression analysis to identify association between perfusion, radiation dose-volumes, and the risk of late cardiac events., Results: Of 181 patients who received adjuvant RT, 102 were patients with cancer in the left breast (called in this study the left-sided group) and 79 were patients with cancer in the right breast (called in this study the right-sided group). Median follow-up was 127 months (range, 19-160 months). A significant worsening of perfusion defects occurred after RT in the left-sided group, which improved by 1 year. Late cardiac events were found among 16 patients (17.2%) in the left-sided group and 4 patients (5.5%) in the right-sided group. Perfusion changes did not correlate with late cardiac events, but LV dose-volumes correlated with late cardiac events. Maintaining the LV volume receiving 5 Gy and 10 Gy to <42 cc and <38cc, respectively, can reduce the risk of radiation-related late cardiac events at 10 years to <5% over baseline., Conclusions: RT was associated with short-term perfusion defects that improved within 1 year and was not correlated with late cardiac events. The ventricular volumes receiving 5 Gy and 10 Gy were correlated with late cardiac events., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: This study aimed to evaluate patient- and treatment-related risk factors for late persistent fatigue within the prospective, multicenter EMBRACE-I study., Methods and Materials: Fatigue was prospectively assessed (Common Terminology Criteria for Adverse Events, version 3) at baseline and during regular follow up in 993 patients with locally advanced cervical cancer after treatment with chemoradiotherapy and magnetic resonance imaging-guided brachytherapy. Risk factors for baseline and late persistent fatigue were evaluated with multivariable logistic regression. Late persistent fatigue was defined when either grade ≥1 or ≥2 was scored in at least half of the follow ups., Results: The median follow-up time was 57 months. Baseline fatigue grade ≥1/≥2 (35.8%/6.3%, respectively) was associated with preexisting comorbidities, World Health Organization performance status, being underweight, severe pain, and tumor volume. Late persistent grade ≥1/≥2 fatigue (36.3%/5.8%, respectively) was associated with patient-related factors (baseline fatigue, younger age, obesity) along with the size of irradiated volumes and the level of radiation doses from external beam radiation therapy (EBRT) and brachytherapy (EBRT: V43Gy, V57Gy; EBRT + brachytherapy: V60Gy equivalent dose in 2-Gy fractions). Large-volume lymph node (LN) boost increased the risk for late persistent fatigue grade ≥2 by 18% and 5% in patients with and without baseline fatigue, respectively, compared with no LN boost. The risk for late persistent fatigue grade ≥1 increased by 7% and 4% with V43Gy <2000 cm³ versus >3000 cm³ in patients with and without baseline fatigue, respectively. Late persistent grade ≥1 fatigue occurred in 13% of patients without late persistent organ-related symptoms (gastrointestinal, genitourinary, and vaginal) versus 34% to 43%, 50% to 58%, and 73% in patients suffering from persistent symptoms involving 1, 2, or 3 organs, respectively., Conclusions: Late persistent fatigue occurs in a considerable number of patients after chemoradiotherapy, and is associated with patient-related factors, the size of volumes irradiated to intermediate and high EBRT and brachytherapy doses, and other persistent organ-related morbidity. These findings support the importance of ongoing efforts to better tailor the target dose and reduce irradiation of healthy tissue without compromising target coverage, using highly conformal EBRT and brachytherapy techniques., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: This report describes the persistence of late substantial treatment-related patient-reported symptoms (LAPERS) in the multi-institutional EMBRACE study on magnetic resonance image guided adaptive brachytherapy in locally advanced cervical cancer (LACC)., Methods and Materials: Patient-reported symptoms (European Organization for Research and Treatment of Cancer [EORTC]-C30/CX24) and physician-assessed morbidity (Common Terminology Criteria for Adverse Events [CTCAE], version 3.0) were assessed at baseline and regular timepoints during follow-up. Patients with sufficient EORTC follow-up (baseline and ≥3 late follow-up visits) were analyzed. LAPERS events were defined as the presence of substantial EORTC symptoms (quite a bit/very much) for at least half of the assessments (persistence) and progression beyond baseline condition (treatment-related). For each EORTC symptom, the ratio between LAPERS rates and crude incidence rates of substantial symptoms was calculated to represent the proportion of symptomatic patients with persisting symptoms. For 9 symptoms with a corresponding EORTC/CTCAE assessment, the overlap of LAPERS and severe morbidity events (grades 3-5) was evaluated., Results: Of 1047 patients with EORTC available, 741 had sufficient follow-up for the LAPERS analyses. The median follow-up was 59 months (interquartile range, 42-70 months). Across all symptoms, the proportion of patients with LAPERS events (LAPERS rates) was in median 4.6% (range, 0.0% vaginal bleeding to 20.4% tiredness). Urinary frequency, neuropathy, fatigue, insomnia, and menopausal symptoms revealed LAPERS rates of >10%. Vomiting, blood in stool, urinary pain/burning, and abnormal vaginal bleeding displayed LAPERS rates of <1%. A median of 19% of symptomatic patients (interquartile range, 8.0%-28.5%) showed persistent long-term symptoms (LAPERS events). In symptoms with a corresponding EORTC/CTCAE assessment, 12% of LAPERS events were accompanied by a severe CTCAE event., Conclusions: Within this large cohort of survivors of LACC, a subgroup of patients with persistent symptoms (LAPERS events) was identified. For symptoms with a corresponding EORTC/CTCAE assessment, the vast majority of LAPERS events occurred in patients without corresponding severe physician-assessed morbidity. These findings emphasize the importance of distinguishing between transient and persisting symptoms in the aftercare of LACC survivors., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: Prophylactic cranial irradiation (PCI) has a well-recognized role in the treatment of leukemia and small-cell lung cancer. Clinical utility has yet to be determined for breast cancer, where an emerging group at high risk of brain metastasis has fuelled consideration of PCI., Methods and Materials: In reviewing our experience with PCI as part of a complex protocol for advanced breast cancer, we present descriptive data on late central nervous system outcomes in those receiving PCI. After high-dose anthracycline-based induction chemotherapy, Stage IIIB/IV breast cancer responders underwent tandem autologous marrow transplantation. Those in continued remission were referred for PCI. Whole-brain radiotherapy was delivered by usual means, at 36 Gy in 20 fractions., Results: Twenty-four women, with median age 45 (28-61), were enrolled between 1995 and 1998. Disease was largely metastatic (79%), and 75% were previously exposed to chemotherapy or hormonotherapy. Ten patients received PCI, at a median of 13.4 (11.8-16.5) months from study entry. Six patients developed brain metastases, 2 despite PCI. Striking functional decline was documented in 3 patients (at 9 months, 4 years, and 5 years post-PCI), including one previously high-functioning woman requiring full care for posttreatment dementia., Conclusions: We present a series of advanced breast cancer patients treated prophylactically with whole-brain radiotherapy following an aggressive chemotherapy regimen. Although the therapeutic benefit of PCI is not ascertainable here, we describe brain metastases occurring despite PCI and serious long-term neurobehavioral sequelae in PCI-treated patients. Any further investigation of PCI in high-risk breast cancer will need to be approached with caution.