An Update on the Management of Bone Metastases.

PURPOSE OF REVIEW: Increasing life expectancy among patients with advanced cancer has placed a greater emphasis on optimizing pain control and quality of life. Concurrently, significant advancements in radiotherapy for bone metastases have permitted for dose escalation strategies such as stereotactic radiotherapy. This review aims to provide updated information on the management of bone metastases in light of these developments. RECENT FINDINGS: We reviewed recent studies regarding the role and details of external beam radiotherapy for bone metastases, with emphasis on differences by treatment site as well as intention (palliative versus ablative for oligometastases). Conventional palliative radiotherapy remains a mainstay of management. While stereotactic radiotherapy may augment durability of pain relief and even survival time, there are significant questions remaining regarding optimal dosing and patient selection. Radiotherapy for bone metastases continues to evolve, particularly with increasing use of stereotactic radiotherapy. Future studies are needed to clarify optimal dose, fractionation, modality, and patient selection criteria among different radiotherapy approaches.

Adjuvant treatment decisions among adults aged 65 years and older with early-stage hormone receptor positive breast cancer seen in a simple multidisciplinary clinic versus standard consultation.

INTRODUCTION: Randomized studies support de-escalation of adjuvant therapy for a target population of older adults ≥65 years with stage I, estrogen-receptor (ER) positive breast cancer after breast conserving surgery. We sought to evaluate the impact of a simplified multidisciplinary clinic (s-MDC) in this population by comparing treatment patterns and patient perceptions of adjuvant radiation therapy (RT) and hormone therapy (HT) between patients seen in s-MDC vs. standard consultations. MATERIALS AND METHODS: Medical records were retrospectively reviewed for patients in the above target population who underwent surgery between August 2020 and May 2022 at our institution. Two cohorts were included: (1) patients seen in s-MDC, and (2) patients seen in standard clinic separately by medical and radiation oncology (non-s-MDC cohort). The non-s-MDC patients declined, could not attend, and/or were not referred to the s-MDC. Patients in the s-MDC cohort were prospectively administered validated questionnaires to evaluate patient reported data including the Decision Autonomy Preference Scale (DAPS), e-Prognosis, and Medical Maximizing-Minimizing Scale (MMS). Chi square, t-tests, and non-parametric equivalents compared demographics, and logistic regression evaluated RT and HT use and survey score outcomes between cohorts. RESULTS: A total of 127 patients met inclusion criteria, with 33 s-MDC and 94 non-s-MDC patients. There was no difference between the cohorts in age, margin status, histology, grade, or focality. In the s-MDC cohort there were significantly more patients without sentinel lymph node biopsy (71.3% vs 42.4%, p = 0.003) and mean tumor size was smaller (0.69 vs. 0.96 cm, p < 0.003), and Charlson comborbidity index (CCI) was higher (5.21 vs 4.96, p = 0.038). There was no significant difference in receipt of RT (65% s-MDC vs 77% standard; odds ratio [OR] = 0.55, p = 0.189), HT (78% ss-MDC vs 72% standard; OR = 1.36, p = 0.513), or both (50% s-MDC vs 59% standard; OR = 0.7, p = 0.429). The s-MDC cohort was significantly more likely to undergo accelerated (vs. standard hypofractionated) RT (70% vs 39%; OR = 3.59, p = 0.020). In s-MDC patients with completed questionnaires (n = 33), all whose selected "mostly patient (n=6)" based decision making by DAPS chose RT while all "mostly doctor (n=1)" chose no RT. Based on e-Prognosis, there were lower odds of RT for increasing Schonberg score/ higher 10 yr mortality risk (OR 0.600, p = 0.048). MMS score ≥ 40 ("maximizer") was strongly linked with the use of RT (OR 18.57, p = 0.011). DISCUSSION: For adults ≥65 years with early stage, ER positive breast cancer, s-MDC participation was not significantly associated with lower use of adjuvant RT or HT versus standard consultation but was significantly associated with shorter RT courses. DAPS and MMS results indicate that patient treatment preference may be predictable, highlighting an opportunity to tailor consultation discussions and recommendations based on intrinsic patient preferences and individual goals.

Improving Quality Metrics in Radiation Oncology: Implementation of Pretreatment Peer Review for Stereotactic Body Radiation Therapy in Patients with Thoracic Cancer.

Purpose: Traditional peer reviews occur weekly, and can take place up to 1 week after the start of treatment. The American Society for Radiation Oncology peer-review white paper identified stereotactic body radiation therapy (SBRT) as a high priority for contour/plan review before the start of treatment, considering both the rapid-dose falloff and short treatment course. Yet, peer-review goals for SBRT must also balance physician time demands and the desire to avoid routine treatment delays that would occur in the setting of a 100% pretreatment (pre-Tx) review compliance requirement or prolonging the standard treatment planning timeline. Herein, we report on our pilot experience of a pre-Tx peer review of thoracic SBRT cases. Methods and Materials: From March 2020 to August 2021, patients undergoing thoracic SBRT were identified for pre-Tx review, and placed on a quality checklist. We implemented twice-weekly meetings for detailed pre-Tx review of organ-at-risk/target contours and dose constraints in the treatment planning system for SBRT cases. Our quality metric goal was to peer review ≥90% of SBRT cases before exceeding 25% of the dose delivered. We used a statistical process control chart with sigma limits (ie, standard deviations [SDs]) to access compliance rates with pre-Tx review implementation. Results: We identified 252 patients treated with SBRT to 294 lung nodules. When comparing pre-Tx review completion from initial rollout to full implementation, our rates improved from 19% to 79% (ie, from 1 sigma limit [SDs]) below to >2 sigma limits (SDs) above. Additionally, early completion of any form of contour/plan review (defined as any pre-Tx or standard review completed before exceeding 25% of the dose delivered) increased from 67% to 85% (March 2020-November 2020) to 76% to 94% (December 2020-August 2021). Conclusions: We successfully implemented a sustainable workflow for detailed pre-Tx contour/plan review for thoracic SBRT cases in the context of twice-weekly disease site-specific peer-review meetings. We reached our quality improvement objective to peer review ≥90% of SBRT cases before exceeding 25% of the dose delivered. This process was feasible to conduct in an integrated network of sites across our system.

Radiotherapy Deserts: The Impact of Race, Poverty, and the Rural-Urban Continuum on Density of Providers and the Use of Radiation Therapy in the US.

PURPOSE: Prior efforts to characterize disparities in radiation therapy access and receipt have not comprehensively investigated interplay between race, socioeconomic status, and geography relative to oncologic outcomes. This study sought to define these complex relationships at the US county level for prostate cancer (PC) and invasive breast (BC) cancer to build a tool that facilitates identification of "radiotherapy deserts"-regions with mismatch between radiation therapy resources and oncologic need. METHODS AND MATERIALS: An ecologic study model was constructed using national databases to evaluate 3,141 US counties. Radiation therapy resources and use densities were operationalized as physicians to persons at risk (PPR) and use to persons at risk (UPR): the number of attending radiation oncologists and Medicare beneficiaries per 100,000 persons at risk, respectively. Oncologic need was defined by "hot zone" counties with ≥2 standard deviations (SDs) above mean incidence and death rates. Univariable and multivariable logistic regressions examined links between PPR and UPR densities, epidemiologic variables, and hot zones for oncologic outcomes. Statistics are reported at a significance level of P < .05. RESULTS: The mean (SD) PPR and UPR densities were 2.1 (5.9) and 192.6 (557.6) for PC and 1.9 (5.3) and 174.4 (501.0) for BC, respectively. Counties with high PPR and UPR densities were predominately metropolitan (odds ratio [OR], 2.9-4.4), generally with a higher percentage of Black non-Hispanic constituents (OR, 1.5-2.3). Incidence and death rate hot zones were largely nonmetropolitan (OR, 0.3-0.6), generally with a higher percentage of Black non-Hispanic constituents (OR, 3.2-6.3). Lower PPR density was associated with death rate hot zones for both types of cancer (OR, 0.8-0.9); UPR density was generally not linked to oncologic outcomes on multivariable analysis. CONCLUSIONS: The study found that mismatch between oncologic need with PPR and UPR disproportionately affects nonmetropolitan communities with a higher percentage of Black non-Hispanic constituents. An interactive web platform (bit.ly/densitymaps) was developed to visualize "radiotherapy deserts" and drive targeted investigation of underlying barriers to care in areas of highest need, with the goal of reducing health inequities in this context.

Evaluation of the Clinical Utility of the Bone Metastases Ensemble Trees for Survival Decision Support Platform (BMETS-DSP): A Case-Based Pilot Assessment.

PURPOSE: The Bone Metastases Ensemble Trees for Survival Decision Support Platform (BMETS-DSP) provides patient-specific survival predictions and evidence-based recommendations to guide multidisciplinary management for symptomatic bone metastases. We assessed the clinical utility of the BMETS-DSP through a pilot prepost design in a simulated clinical environment. METHODS: Ten Radiation Oncology physicians reviewed 55 patient cases at two time points: without and then with the use of BMETS-DSP. Assessment included 12-month survival estimate, confidence in and likelihood of sharing estimates with patients, and recommendations for open surgery, systemic therapy, hospice referral, and radiotherapy (RT) regimen. Paired statistics compared pre- versus post-DSP outcomes. Reported statistical significance is P < .05. RESULTS: Pre- versus post-DSP, overestimation of true minus estimated survival time was significantly reduced (mean difference -2.1 [standard deviation 4.1] v -1 month [standard deviation 3.5]). Prediction accuracy was significantly improved at cut points of < 3 (72 v 79%), ≤ 6 (64 v 71%), and ≥ 12 months (70 v 81%). Median ratings of confidence in and likelihood of sharing prognosis significantly increased. Significantly greater concordance was seen in matching use of 1-fraction RT with the true survival < 3 months (70 v 76%) and < 10-fraction RT with the true survival < 12 months (55 v 62%) and appropriate use of open surgery (47% v 53%), without significant changes in selection of hospice referral or systemic therapy. CONCLUSION: This pilot study demonstrates that BMETS-DSP significantly improved physician survival estimation accuracy, prognostic confidence, likelihood of sharing prognosis, and use of prognosis-appropriate RT regimens in the care of symptomatic bone metastases, supporting future multi-institutional validation of the platform.

Risk of Malignant Transformation of Giant Cell Tumors of Bone Is 8 Times Lower with Megavoltage vs. Orthovoltage Radiation Therapy.

Background: The first-line treatment for most giant cell tumors (GCTs) of bone is surgical; radiotherapy (RT) is reserved for inoperable or refractory cases. While RT techniques have undergone a dramatic change over the past few decades, with the higher energy megavoltage RT replacing orthovoltage RT, concerns for high rates of malignant transformation following RT have limited its use. Evidence suggests a lower incidence of secondary malignancy after treatment with megavoltage compared with orthovoltage RT, but this has not been studied in GCTs. Our main purpose was to compare the incidence of malignant transformation of GCTB between patients treated with orthovoltage vs. megavoltage RT. Methods: A literature review was performed to identify studies reporting GCTBs treated with RT from 01/1900 through 12/2019. Studies that did not report RT modality or separate orthovoltage and megavoltage results were excluded. Included in the analysis were 6 patients from our institution. Primary outcome was the incidence of malignant transformation; secondary outcomes were time to transformation and incidence of local recurrence. Fisher's exact tests and independent sample t-tests were used, and significance was set at p < 0.05. Results: Twenty-two studies were included, which reported on 168 GCTBs treated with orthovoltage and 393 treated with megavoltage RT. Transformation incidence was 14% (n = 24) for orthovoltage and 1.8% (n = 7) for megavoltage RT, an 8-fold difference (odds ratio (OR) 9.1, 95% confidence interval (CI) 3.9-22, p < 0.001). Mean time to transformation was 8.7 years for orthovoltage and 11.2 years for megavoltage RT (p=0.28). Incidence of local recurrence was 38% (63/167) for orthovoltage and 17% (66/393) for megavoltage RT (OR 3.3, 95% CI 2.0-4.6, p < 0.001). Conclusions: The risk of developing a malignancy after RT of GCTB is 8 times lower with megavoltage than with orthovoltage. Malignant transformation with megavoltage, while not zero, is lower than that in historical series. Use of modern RT techniques in inoperable or refractory GCTB may be appropriate.

Integrating the Patient's Voice in Toxicity Reporting and Treatment Decisions for Breast Radiotherapy.

Breast cancer care is often defined by preference-sensitive decisions, in which no one choice clearly dominates, and the treatment approach is ideally guided by patient values and preferences. In this context, patients are vulnerable to suboptimal decision quality due to the number and complexity of choices. Arriving at a high-quality, patient-centered decision involves both an accurate understanding of the risks and benefits of treatment options, as well as concordance with the patient's preferences and values. These 2 objectives intersect at the informed consent discussion. In radiation oncology, informed consent has an added layer of complexity related to strong desire from patients to receive the most technologically advanced treatment, often out of balance with other rational considerations. These observations highlight challenges and opportunities unique to radiation oncology in improving communication and arriving at a high-quality decision.

Improving providers' survival estimates and selection of prognosis- and guidelines-appropriate treatment for patients with symptomatic bone metastases: Development of the Bone Metastases Ensemble Trees for Survival Decision Support Platform.

RATIONALE, AIMS AND OBJECTIVES: In the management of symptomatic bone metastases, current practice guidelines do not provide clear methodology for selecting palliative radiotherapy (RT) regimens based on specific patient and disease features. Decision support aids may offer an effective means for translating the complex data needed to render individualised treatment decisions, yet no such tools are available for use in this setting. Thus, we describe the development of the Bone Metastases Ensemble Trees for Survival-Decision Support Platform (BMETS-DSP), which aims to optimise selection of evidence-based, individualised palliative RT regimens. METHOD: The Ottawa Decision Support Framework was used as the theoretical basis for development of BMETS-DSP. First, we utilised stakeholder input and review of the literature to assess determinants underlying the provider decision. Based on this assessment and iterative stakeholder feedback, we developed the web-based, provider-facing BMETS-DSP. Consistent with the underlying theoretical framework, our design also included assessment of decision quality using the International Patient Decision Aids Standards (IPDAS) certification checklist. RESULTS: Stakeholder input and review of 54 evidence-based publications identified the following determinants of the provider decision: estimated prognosis, characteristics of the target symptomatic lesion and the primary cancer type, consideration of alternative interventions, access to patient-specific recommendations, and patient preferences. Based on these determinants, we developed the BMETS-DSP that (1) collects patient-specific data, (2) displays an individualised predicted survival curve, and (3) provides case-specific, evidence-based recommendations regarding RT, open surgery, systemic therapy, and hospice referral to aid in the decision-making process. The finalised tool met IPDAS quality requirements. Preliminary results of a pilot assessment suggest impact of clinical outcomes. CONCLUSIONS: We describe the successful development of a provider-facing decision support platform to aid in the provision of palliative RT in better alignment with patient and disease features. Impact of the BMETS-DSP on decision outcomes will be further assessed in a randomised, controlled study.

Incidence and Severity of Myelosuppression With Palbociclib After Palliative Bone Radiation in Advanced Breast Cancer: A Single Center Experience and Review of Literature.

BACKGROUND: Palbociclib is a cyclin-dependent kinase (CDK) 4/6 inhibitor with a primary toxicity of myelosuppression, especially neutropenia, due to cytostatic CDK6 inhibition on bone marrow. Preclinical studies suggest palbociclib may enhance radiation toxicity, but this was only evaluated in limited case series of palliative radiotherapy and not specific to radiation targeting bony metastases. PATIENTS AND METHODS: This was a single institution retrospective cohort study. We included female patients who initiated palbociclib for advanced breast cancer between 2015 and 2019. The primary exposure was receipt of palliative radiation to bony metastases within 1 year prior to starting palbociclib. The primary outcome was the incidence and severity of myelosuppression during cycle one. Secondary outcomes include treatment interruptions and cycle 2 dose reductions, with subgroup analysis of radiation timing, type, dose, and location. RESULTS: Of the 247 patients, 47 received radiation to bone metastases. Only absolute lymphocyte count (ALC) after cycle one of palbociclib was significantly lower in the group receiving radiation (median ALC 0.84 vs. 1.10 K/mm3, P < .001), with similar rates of neutropenia, anemia, and thrombocytopenia. Patients who received ≥10 fractions radiation were more likely to have cycle one interrupted than those receiving shorter radiation courses (42.9% vs. 11.1%, P = .03). No radiation characteristics were associated with other hematologic toxicities or dose reduction. CONCLUSION: Palliative bone radiation within 1 year prior to palbociclib initiation was associated with greater lymphopenia during the first cycle than patients unexposed to radiation, but not neutropenia, anemia, or thrombocytopenia that would modify treatment.

Treatment of Radiation-Associated Fractures: A Critical Analysis Review.

¼: Fractures that result from radiation-induced bone damage are a recognized adverse effect of radiation therapy (RT). ¼: The mechanisms of damage from RT are thought to be related to impaired vascularity, aberrations in osteoclast and osteoblast-mediated bone turnover, and compromise of cortical and trabecular microarchitecture. ¼: Treatment of radiation-associated fractures is challenging, with rates of delayed union and nonunion of >50%. ¼: Fracture management strategies, each with its own profile of risks and benefits, include prophylactic intramedullary nailing of long bones, open reduction and internal fixation with adjunctive iliac crest or vascularized fibular grafting, and endoprosthetic reconstruction.

External Validation of the Bone Metastases Ensemble Trees for Survival (BMETS) Machine Learning Model to Predict Survival in Patients With Symptomatic Bone Metastases.

PURPOSE: The Bone Metastases Ensemble Trees for Survival (BMETS) model uses a machine learning algorithm to estimate survival time following consultation for palliative radiation therapy for symptomatic bone metastases (SBM). BMETS was developed at a tertiary-care, academic medical center, but its validity and stability when applied to external data sets are unknown. PATIENTS AND METHODS: Patients treated with palliative radiation therapy for SBM from May 2013 to May 2016 at two hospital-based community radiation oncology clinics were included, and medical records were retrospectively reviewed to collect model covariates and survival time. The Kaplan-Meier method was used to estimate overall survival from consultation to death or last follow-up. Model discrimination was estimated using time-dependent area under the curve (tAUC), which was calculated using survival predictions from BMETS based on the initial training data set. RESULTS: A total of 216 sites of SBM were treated in 182 patients. Most common histologies were breast (27%), lung (23%), and prostate (23%). Compared with the BMETS training set, the external validation population was older (mean age, 67 v 62 years; P < .001), had more primary breast (27% v 19%; P = .03) and prostate cancer (20% v 12%; P = .01), and survived longer (median, 10.7 v 6.4 months). When the BMETS model was applied to the external data set, tAUC values at 3, 6, and 12 months were 0.82, 0.77, and 0.77, respectively. When refit with data from the combined training and external validation sets, tAUC remained > 0.79. CONCLUSION: BMETS maintained high discriminative ability when applied to an external validation set and when refit with new data, supporting its generalizability, stability, and the feasibility of dynamic modeling.

A multi-institutional phase 2 trial of stereotactic body radiotherapy in the treatment of bone metastases in pediatric and young adult patients with sarcoma.

BACKGROUND: Metastasectomy is standard of care for pediatric patients with metastatic sarcoma with limited disease. For patients with unresectable disease, stereotactic body radiotherapy (SBRT) may serve as an alternative. Herein, the authors report the results of a prospective, multi-institutional phase 2 trial of SBRT in children and young adults with metastatic sarcoma. METHODS: Patients aged >3 years and ≤40 years with unresected, osseous metastatic nonrhabdomyosarcoma sarcomas of soft tissue and bone were eligible. Patients received SBRT to a dose of 40 Gray (Gy) in 5 fractions. Local control (LC), progression-free survival (PFS), and overall survival (OS) were calculated using the Kaplan-Meier method. RESULTS: Fourteen patients with a median age of 17 years (range, 4-25 years) were treated to 37 distinct metastatic lesions. With a median follow-up of 6.8 months (30.5 months in surviving patients), the Kaplan-Meier patient-specific and lesion-specific LC rates at 6 months were 89% and 95%, respectively. The median PFS was 6 months and the median OS was 24 months. In a post hoc analysis, PFS (median, 9.3 months vs 3.7 months; log-rank P = .03) and OS (median not reached vs 12.7 months; log-rank P = .02) were improved when all known sites of metastatic disease were consolidated with SBRT compared with partial consolidation. SBRT was well tolerated, with 2 patients experiencing grade 3 toxicities. CONCLUSIONS: SBRT achieved high rates of LC in pediatric patients with inoperable metastatic nonrhabdomyosarcoma sarcomas of soft tissue and bone. These results suggest that the ability to achieve total consolidation of metastatic disease with SBRT is associated with improved PFS and OS.

Developing an Improved Statistical Approach for Survival Estimation in Bone Metastases Management: The Bone Metastases Ensemble Trees for Survival (BMETS) Model.

PURPOSE: To determine whether a machine learning approach optimizes survival estimation for patients with symptomatic bone metastases (SBM), we developed the Bone Metastases Ensemble Trees for Survival (BMETS) to predict survival using 27 prognostic covariates. To establish its relative clinical utility, we compared BMETS with 2 simpler Cox regression models used in this setting. METHODS AND MATERIALS: For 492 bone sites in 397 patients evaluated for palliative radiation therapy (RT) for SBM from January 2007 to January 2013, data for 27 clinical variables were collected. These covariates and the primary outcome of time from consultation to death were used to build BMETS using random survival forests. We then performed Cox regressions as per 2 validated models: Chow's 3-item (C-3) and Westhoff's 2-item (W-2) tools. Model performance was assessed using cross-validation procedures and measured by time-dependent area under the curve (tAUC) for all 3 models. For temporal validation, a separate data set comprised of 104 bone sites treated in 85 patients in 2018 was used to estimate tAUC from BMETS. RESULTS: Median survival was 6.4 months. Variable importance was greatest for performance status, blood cell counts, recent systemic therapy type, and receipt of concurrent nonbone palliative RT. tAUC at 3, 6, and 12 months was 0.83, 0.81, and 0.81, respectively, suggesting excellent discrimination of BMETS across postconsultation time points. BMETS outperformed simpler models at each time, with respective tAUC at each time of 0.78, 0.76, and 0.74 for the C-3 model and 0.80, 0.78, and 0.77 for the W-2 model. For the temporal validation set, respective tAUC was similarly high at 0.86, 0.82, and 0.78. CONCLUSIONS: For patients with SBM, BMETS improved survival predictions versus simpler traditional models. Model performance was maintained when applied to a temporal validation set. To facilitate clinical use, we developed a web platform for data entry and display of BMETS-predicted survival probabilities.