Identifying Patients Whose Symptoms Are Underrecognized During Treatment With Breast Radiotherapy.

Importance: Understanding whether physicians accurately detect symptoms in patients with breast cancer is important because recognition of symptoms facilitates supportive care, and clinical trials often rely on physician assessments using Common Toxicity Criteria for Adverse Events (CTCAE). Objective: To compare the patient-reported outcomes (PROs) of patients with breast cancer who received radiotherapy from January 1, 2012, to March 31, 2020, with physicians' CTCAE assessments to assess underrecognition of symptoms. Design, Setting, and Participants: This cohort study included a total of 29 practices enrolled in the Michigan Radiation Oncology Quality Consortium quality initiative. Of 13 725 patients with breast cancer who received treatment with radiotherapy after undergoing lumpectomy, 9941 patients (72.4%) completed at least 1 PRO questionnaire during treatment with radiotherapy and were evaluated for the study. Of these, 9868 patients (99.3%) were matched to physician CTCAE assessments that were completed within 3 days of the PRO questionnaires. Exposures: Patient and physician ratings of 4 symptoms (pain, pruritus, edema, and fatigue) were compared. Main Outcomes and Measures: We used multilevel multivariable logistic regression to evaluate factors associated with symptom underrecognition, hypothesizing that it would be more common in racial and ethnic minority groups. Results: Of 9941 patients, all were female, 1655 (16.6%) were Black, 7925 (79.7%) were White, and 361 (3.6%) had Other race and ethnicity (including American Indian/Alaska Native, Arab/Middle Eastern, and Asian), either as self-reported or as indicated in the electronic medical record. A total of 1595 (16.0%) were younger than 50 years, 2874 (28.9%) were age 50 to 59 years, 3353 (33.7%) were age 60 to 69 years, and 2119 (21.3%) were 70 years or older. Underrecognition of symptoms existed in 2094 of 6781 (30.9%) observations of patient-reported moderate/severe pain, 748 of 2039 observations (36.7%) of patient-reported frequent pruritus, 2309 of 4492 observations (51.4%) of patient-reported frequent edema, and 390 of 2079 observations (18.8%) of patient-reported substantial fatigue. Underrecognition of at least 1 symptom occurred at least once for 2933 of 5510 (53.2%) of those who reported at least 1 substantial symptom. Factors independently associated with underrecognition were younger age (younger than 50 years compared with 60-69 years: odds ratio [OR], 1.35; 95% CI, 1.14-1.59; P < .001; age 50-59 years compared with 60-69 years: OR, 1.19; 95% CI, 1.03-1.37; P = .02), race (Black individuals compared with White individuals: OR, 1.56; 95% CI 1.30-1.88; P < .001; individuals with Other race or ethnicity compared with White individuals: OR, 1.52; 95% CI, 1.12-2.07; P = .01), conventional fractionation (OR, 1.26; 95% CI, 1.10-1.45; P = .002), male physician sex (OR, 1.54; 95% CI, 1.20-1.99; P = .002), and 2-field radiotherapy (without a supraclavicular field) (OR, 0.80; 95% CI, 0.67-0.97; P = .02). Conclusions and Relevance: The results of this cohort study suggest that PRO collection may be essential for trials because relying on the CTCAE to detect adverse events may miss important symptoms. Moreover, since physicians in this study systematically missed substantial symptoms in certain patients, including younger patients and Black individuals or those of Other race and ethnicity, improving symptom detection may be a targetable mechanism to reduce disparities.

The Impact of Chemotherapy on Toxic Effects and Cosmetic Outcome in Patients Receiving Whole Breast Irradiation: An Analysis Within a Statewide Quality Consortium.

PURPOSE: We investigated whether the use of chemotherapy before whole breast irradiation (WBI) using either conventional fractionation (CWBI) or hypofractionation (HWBI) is associated with increased toxic effects or worse cosmetic outcome compared with WBI alone. METHODS AND MATERIALS: We identified 6754 patients who received WBI alone (without a third field covering the superior axillary and supraclavicular nodal regions) with data prospectively collected in a statewide consortium. We reported rates of 4 toxic effects: physician-reported acute moist desquamation, patient-reported acute moderate/severe breast pain, a composite acute toxic effect measure (including moist desquamation and either patient- or physician-reported moderate/significant breast pain), and physician-reported impaired cosmetic outcome at 1 year after WBI. Successive multivariable models were constructed to estimate the effect of chemotherapy on these outcomes. RESULTS: Rates of moist desquamation, patient-reported pain, composite acute toxic effects, and impaired cosmetic outcome were 23%, 34%, 42%, and 10% for 2859 patients receiving CWBI and 13%, 28%, 31%, and 11% for 3895 patients receiving HWBI. Receipt of chemotherapy before CWBI was not associated with higher rates of patient-reported pain, composite acute toxic effects, or impaired cosmetic outcome compared with CWBI without chemotherapy but was associated with more moist desquamation (odds ratio, 1.32 [1.07-1.63]; P = .01). Receipt of chemotherapy before HWBI was not associated with higher rates of any of the 4 toxic effects compared with HWBI alone. CONCLUSIONS: In this cohort, use of chemotherapy before WBI was generally well tolerated. CWBI with chemotherapy but not HWBI with chemotherapy was associated with higher rates of moist desquamation. Rates of acute breast pain and impaired cosmetic outcome at 1 year were comparable in patients receiving chemotherapy before either CWBI or HWBI. These data support the use of HWBI after chemotherapy.

Disease Control After Hypofractionation Versus Conventional Fractionation for Triple Negative Breast Cancer: Comparative Effectiveness in a Large Observational Cohort.

PURPOSE: Questions remain about whether moderately hypofractionated whole-breast irradiation is appropriate for patients with triple-negative breast cancer. METHODS AND MATERIALS: Using the prospective database of a multicenter, collaborative quality improvement consortium, we identified patients with node-negative, triple-negative breast cancer who received whole-breast irradiation with either moderate hypofractionation or conventional fractionation. Using inverse probability of treatment weighting (IPTW), we compared outcomes using the Kaplan-Meier product-limit estimation method with Cox regression models estimating the hazard ratio for time-to-event endpoints between groups. RESULTS: The sample included 538 patients treated at 18 centers in 1 state in the United States, of whom 307 received conventionally fractionated whole-breast irradiation and 231 received moderately hypofractionated whole-breast irradiation. The median follow-up time was 5.0 years (95% confidence interval [CI], 4.77-5.15 years). The 5-year IPTW estimates for freedom from local recurrence were 93.6% (95% CI, 87.8%-96.7%) in the moderate hypofractionation group and 94.4% (95% CI, 90.3%-96.8%) in the conventional fractionation group. The hazard ratio was 1.05 (95% CI, 0.51-2.17; P = .89). The 5-year IPTW estimates for recurrence-free survival were 87.8% (95% CI, 81.0%-92.4%) in the moderate hypofractionation group and 88.4% (95% CI 83.2%-92.1%) in the conventional fractionation group. The hazard ratio was 1.02 (95% CI, 0.62-1.67; P = .95). The 5-year IPTW estimates for overall survival were 96.6% (95% CI, 92.0%-98.5%) in the moderate hypofractionation group and 93.4% (95% CI, 88.7%-96.1%) in the conventional fractionation group. The hazard ratio was 0.65 (95% CI, 0.30-1.42; P = .28). CONCLUSIONS: Analysis of outcomes in this large observational cohort of patients with triple-negative, node-negative breast cancer treated with whole-breast irradiation revealed no differences by dose fractionation. This adds evidence to support the use of moderate hypofractionation in patients with triple-negative disease.

Toward Improving Patients' Experiences of Acute Toxicity From Breast Radiotherapy: Insights From the Analysis of Patient-Reported Outcomes in a Large Multicenter Cohort.

PURPOSE: Understanding acute toxicities after whole-breast radiotherapy is important to inform patients, guide treatment decisions, and target supportive care. We evaluated patient-reported outcomes prospectively collected from a cohort of patients with breast cancer. METHODS: We describe the maximal toxicity reported by 8,711 patients treated between 2012 and 2019 at 27 practices. Multivariable models identified characteristics associated with (1) breast pain, (2) bother from itching, stinging/burning, swelling, or hurting of the treated breast, and (3) fatigue within 7 days of completing whole-breast radiotherapy. RESULTS: Moderate or severe breast pain was reported by 3,233 (37.1%): 1,282 (28.9%) of those receiving hypofractionation and 1,951 (45.7%) of those receiving conventional fractionation. Frequent bother from at least one breast symptom was reported by 4,424 (50.8%): 1,833 (41.3%) after hypofractionation and 2,591 (60.7%) after conventional fractionation. Severe fatigue was reported by 2,008 (23.1%): 843 (19.0%) after hypofractionation and 1,165 (27.3%) after conventional fractionation. Among patients receiving hypofractionated radiotherapy, younger age (P < .001), higher body mass index (BMI; P < .001), Black (P < .001) or other race (P = .002), smoking status (P < .001), larger breast volume (P = .002), lack of chemotherapy receipt (P = .004), receipt of boost treatment (P < .001), and treatment at a nonteaching center predicted breast pain. Among patients receiving conventionally fractionated radiotherapy, younger age (P < .001), higher BMI (P = .003), Black (P < .001) or other race (P = .002), diabetes (P = .001), smoking status (P < .001), and larger breast volume (P < .001) predicted breast pain. CONCLUSION: In this large observational data set, substantial differences existed according to radiotherapy dose fractionation. Race-related differences in pain existed despite controlling for multiple other factors; additional research is needed to understand what drives these differences to target potentially modifiable factors. Intensifying supportive care may be appropriate for subgroups identified as being vulnerable to greater toxicity.

Cardiac Dose in Locally Advanced Lung Cancer: Results From a Statewide Consortium.

PURPOSE: The heart has been identified as a potential significant organ at risk in patients with locally advanced non-small cell lung cancer treated with radiation. Practice patterns and radiation dose delivered to the heart in routine practice in academic and community settings are unknown. METHODS AND MATERIALS: Between 2012 and 2017, 746 patients with stage III non-small cell lung cancer were treated with radiation within the statewide Michigan Radiation Oncology Quality Consortium (MROQC). Cardiac radiation dose was characterized, including mean and those exceeding historical or recently proposed Radiation Therapy Oncology Group and NRG Oncology constraints. Sites were surveyed to determine dose constraints used in practice. Patient-, anatomic-, and treatment-related associations with cardiac dose were analyzed using multivariable regression analysis and inverse probability weighting. RESULTS: Thirty-eight percent of patients had a left-sided primary, and 80% had N2 or N3 disease. Median prescription was 60 Gy (interquartile range, 60-66 Gy). Twenty-two percent of patients were prescribed 60 Gy in 2012, which increased to 62% by 2017 (P < .001). Median mean heart dose was 12 Gy (interquartile range, 5-19 Gy). The volume receiving 30 Gy (V30 Gy) exceeded 50% in 5% of patients, and V40 Gy was >35% in 3% of cases. No heart dose constraint was uniformly applied. Intensity modulated radiation therapy (IMRT) usage increased from 33% in 2012 to 86% in 2017 (P < .001) and was significantly associated with more complex cases (larger planning target volume, higher stage, and preexisting cardiac disease). In multivariable regression analysis, IMRT was associated with a lower percent of the heart receiving V30 Gy (absolute reduction = 3.0%; 95% confidence interval, 0.5%-5.4%) and V50 Gy (absolute reduction = 3.6%; 95% confidence interval, 2.4%-4.8%) but not mean dose. In inverse probability weighting analysis, IMRT was associated with 29% to 48% relative reduction in percent of the heart receiving V40-V60 Gy without increasing lung or esophageal dose or compromising planning target volume coverage. CONCLUSIONS: Within MROQC, historical cardiac constraints were met in most cases, yet 1 in 4 patients received a mean heart dose exceeding 20 Gy. Future work is required to standardize heart dose constraints and to develop treatment approaches that allow for constraints to be met without compromising other planning goals.

Recent Time Trends and Predictors of Heart Dose From Breast Radiation Therapy in a Large Quality Consortium of Radiation Oncology Practices.

PURPOSE: Limited data exist regarding the range of heart doses received in routine practice with radiation therapy (RT) for breast cancer in the United States today and the potential effect of the continual assessment of the cardiac dose on practice patterns. METHODS AND MATERIALS: From 2012 to 2015, 4688 patients with breast cancer treated with whole breast RT at 20 sites participating in a state-wide consortium were enrolled into a registry. The importance of limiting the cardiac dose has been emphasized in the consortium since 2012, and the mean heart dose (MHD) has been reported by each institution since 2014. The effects on the MHD were estimated for both conventional and accelerated fractionation using regression models, with technique (intensity modulated RT [IMRT] vs 3-dimensional conformal RT), deep inspiration breath hold use, patient position (supine vs prone), nodal RT (if delivered), and boost (yes vs no) as covariates. RESULTS: For left-sided breast cancer treated with conventional fractionation, the median MHD in 2012 was 2.19 Gy versus 1.65 Gy in 2015 (P<.001). The factors that significantly increased the MHD for conventional fractionation were increased separation relative to 22 cm (1.5%/1 cm), supraclavicular or infraclavicular nodal RT (17.1%), internal mammary nodal RT (40.7%), use of a boost (20.9%), treatment year before 2015 (7.7%), and use of IMRT (20.8%). For left-sided BC treated with accelerated fractionation, the median MHD in 2012 was 1.70 Gy versus 1.22 Gy in 2015 (P<.001). The factors that significantly increased the MHD for accelerated fractionation were separation (1.7%/1 cm), use of a boost (20.0%), year before 2015 (8.5%), and use of IMRT (19.2%). The factors for both conventional fractionation and accelerated fractionation that significantly reduced the MHD were the use of deep inspiration breath hold and prone positioning. CONCLUSIONS: The MHD for left-sided breast cancer decreased during a recent 4-year period, coincident with an increased focus on cardiac sparing in the radiation oncology community in general and a state-wide consortium specifically. These data suggest a positive effect of systematically monitoring the heart dose delivered.

Direct sagittal image registration and tumor delineation on sagittal magnetic resonance imaging sequences for image-guided brachytherapy of cervical cancer.

AIM: To test and evaluate direct sagittal-plane tumor delineation for MRI-based image-guided brachytherapy (IGBT) planning for patients with cervical cancer. MATERIALS AND METHODS: An image registration method based on the sagittal source MR images was developed and employed in ten patients with an indwelling ring/tandem applicator. The gross tumor volume (GTV) was delineated separately on the sagittal (GTV-S) and axial images (GTV-A). GTV conformity indices and dose-volume histogram analyses were compared among GTV-S and GTV-A (paired t-test). RESULTS: Image quality and delineation in the sagittal images was graded superior to the axial images. The ratio of common volume of the axial and sagittal volumes to that of the axial volume was 0.77 +/- (standard deviation) 0.2. The GTV-S mean volume (19.6 +/- 13.8 mL) was significantly larger than the GTV-A mean volume (10.3 +/- 7.3 mL, p=0.003). The GTV-S mean D99 (5.2 +/- 2.5 Gy) was significantly lower than the GTV-A mean D99 (6.9 +/- 2.7 Gy, p=0.013). The GTV-S mean D90 (6.8 +/- 2.8 Gy) was significantly lower than the GTV-A mean D90 (8.5 +/- 3.1 Gy, p=0.016). CONCLUSIONS: Registration of the sagittal source MRI and contouring the GTV directly on the sagittal images is feasible and practical for IGBT. Consistently larger sagittal GTVs may be explained by the better visualization and more continuous tumor topology in the sagittal plane, compared to the discrete oblique sectioning of the uterus/tumor and partial volume loss in the axial plane.

Radiotherapeutic and surgical management for newly diagnosed brain metastasis(es): An American Society for Radiation Oncology evidence-based guideline.

PURPOSE: To systematically review the evidence for the radiotherapeutic and surgical management of patients newly diagnosed with intraparenchymal brain metastases. METHODS AND MATERIALS: Key clinical questions to be addressed in this evidence-based Guideline were identified. Fully published randomized controlled trials dealing with the management of newly diagnosed intraparenchymal brain metastases were searched systematically and reviewed. The U.S. Preventative Services Task Force levels of evidence were used to classify various options of management. RESULTS: The choice of management in patients with newly diagnosed single or multiple brain metastases depends on estimated prognosis and the aims of treatment (survival, local treated lesion control, distant brain control, neurocognitive preservation). Single brain metastasis and good prognosis (expected survival 3 months or more): For a single brain metastasis larger than 3 to 4 cm and amenable to safe complete resection, whole brain radiotherapy (WBRT) and surgery (level 1) should be considered. Another alternative is surgery and radiosurgery/radiation boost to the resection cavity (level 3). For single metastasis less than 3 to 4 cm, radiosurgery alone or WBRT and radiosurgery or WBRT and surgery (all based on level 1 evidence) should be considered. Another alternative is surgery and radiosurgery or radiation boost to the resection cavity (level 3). For single brain metastasis (less than 3 to 4 cm) that is not resectable or incompletely resected, WBRT and radiosurgery, or radiosurgery alone should be considered (level 1). For nonresectable single brain metastasis (larger than 3 to 4 cm), WBRT should be considered (level 3). Multiple brain metastases and good prognosis (expected survival 3 months or more): For selected patients with multiple brain metastases (all less than 3 to 4 cm), radiosurgery alone, WBRT and radiosurgery, or WBRT alone should be considered, based on level 1 evidence. Safe resection of a brain metastasis or metastases causing significant mass effect and postoperative WBRT may also be considered (level 3). Patients with poor prognosis (expected survival less than 3 months): Patients with either single or multiple brain metastases with poor prognosis should be considered for palliative care with or without WBRT (level 3). It should be recognized, however, that there are limitations in the ability of physicians to accurately predict patient survival. Prognostic systems such as recursive partitioning analysis, and diagnosis-specific graded prognostic assessment may be helpful. CONCLUSIONS: Radiotherapeutic intervention (WBRT or radiosurgery) is associated with improved brain control. In selected patients with single brain metastasis, radiosurgery or surgery has been found to improve survival and locally treated metastasis control (compared with WBRT alone).

Lack of osteoradionecrosis of the mandible after intensity-modulated radiotherapy for head and neck cancer: likely contributions of both dental care and improved dose distributions.

PURPOSE: To assess the prevalence and dosimetric and clinical predictors of mandibular osteoradionecrosis (ORN) in patients with head and neck cancer who underwent a pretherapy dental evaluation and prophylactic treatment according to a uniform policy and were treated with intensity-modulated radiotherapy (IMRT). METHODS AND MATERIALS: Between 1996 and 2005, all patients with head-and-neck cancer treated with parotid gland-sparing IMRT in prospective studies underwent a dental examination and prophylactic treatment according to a uniform policy that included extractions of high-risk, periodontally involved, and nonrestorable teeth in parts of the mandible expected to receive high radiation doses, fluoride supplements, and the placement of guards aiming to reduce electron backscatter off metal teeth restorations. The IMRT plans included dose constraints for the maximal mandibular doses and reduced mean parotid gland and noninvolved oral cavity doses. A retrospective analysis of Grade 2 or worse (clinical) ORN was performed. RESULTS: A total of 176 patients had a minimal follow-up of 6 months. Of these, 31 (17%) had undergone teeth extractions before RT and 13 (7%) after RT. Of the 176 patients, 75% and 50% had received >or=65 Gy and >or=70 Gy to >or=1% of the mandibular volume, respectively. Falloff across the mandible characterized the dose distributions: the average gradient (in the axial plane containing the maximal mandibular dose) was 11 Gy (range, 1-27 Gy; median, 8 Gy). At a median follow-up of 34 months, no cases of ORN had developed (95% confidence interval, 0-2%). CONCLUSION: The use of a strict prophylactic dental care policy and IMRT resulted in no case of clinical ORN. In addition to the dosimetric advantages offered by IMRT, meticulous dental prophylactic care is likely an essential factor in reducing ORN risk.

Improving IMRT delivery efficiency using intensity limits during inverse planning.

Inverse planned intensity modulated radiotherapy (IMRT) fields can be highly modulated due to the large number of degrees of freedom involved in the inverse planning process. Additional modulation typically results in a more optimal plan, although the clinical rewards may be small or offset by additional delivery complexity and/or increased dose from transmission and leakage. Increasing modulation decreases delivery efficiency, and may lead to plans that are more sensitive to geometrical uncertainties. The purpose of this work is to assess the use of maximum intensity limits in inverse IMRT planning as a simple way to increase delivery efficiency without significantly affecting plan quality. Nine clinical cases (three each for brain, prostate, and head/neck) were used to evaluate advantages and disadvantages of limiting maximum intensity to increase delivery efficiency. IMRT plans were generated using in-house protocol-based constraints and objectives for the brain and head/neck, and RTOG 9406 dose volume objectives in the prostate. Each case was optimized at a series of maximum intensity ratios (the product of the maximum intensity and the number of beams divided by the prescribed dose to the target volume), and evaluated in terms of clinical metrics, dose-volume histograms, monitor units (MU) required per fraction (SMLC and DMLC delivery), and intensity map variation (a measure of the beam modulation). In each site tested, it was possible to reduce total monitor units by constraining the maximum allowed intensity without compromising the clinical acceptability of the plan. Monitor unit reductions up to 38% were observed for SMLC delivery, while reductions up to 29% were achieved for DMLC delivery. In general, complicated geometries saw a smaller reduction in monitor units for both delivery types, although DMLC delivery required significantly more monitor units in all cases. Constraining the maximum intensity in an inverse IMRT plan is a simple way to improve delivery efficiency without compromising plan objectives.