Development and validation of a recursive partitioning analysis-based pretreatment decision-making tool identifying ideal candidates for spine stereotactic body radiation therapy.

BACKGROUND: This study was aimed at developing and validating a decision-making tool predictive of overall survival (OS) for patients receiving stereotactic body radiation therapy (SBRT) for spinal metastases. METHODS: Three hundred sixty-one patients at one institution were used for the training set, and 182 at a second institution were used for external validation. Treatments most commonly involved one or three fractions of spine SBRT. Exclusion criteria included proton therapy and benign histologies. RESULTS: The final model consisted of the following variables and scores: Spinal Instability Neoplastic Score (SINS) ≥ 6 (1), time from primary diagnosis < 21 months (1), Eastern Cooperative Oncology Group (ECOG) performance status = 1 (1) or ECOG performance status > 1 (2), and >1 organ system involved (1). Each variable was an independent predictor of OS (p < .001), and each 1-point increase in the score was associated with a hazard ratio of 2.01 (95% confidence interval [CI], 1.79-2.25; p < .0001). The concordance value was 0.75 (95% CI, 0.71-0.78). The scores were discretized into three groups-favorable (score = 0-1), intermediate (score = 2), and poor survival (score = 3-5)-with 2-year OS rates of 84% (95% CI, 79%-90%), 46% (95% CI, 36%-59%), and 21% (95% CI, 14%-32%), respectively (p < .0001 for each). In the external validation set (182 patients), the score was also predictive of OS (p < .0001). Increasing SINS was predictive of decreased OS as a continuous variable (p < .0001). CONCLUSIONS: This novel score is proposed as a decision-making tool to help to optimize patient selection for spine SBRT. SINS may be an independent predictor of OS.

Pencil Beam Scanning Proton Therapy for Pregnant Patients With Brain and Head and Neck Cancers.

PURPOSE: When radiation therapy is medically necessary for pregnant patients, photon-based treatments (XRT) have traditionally been used, whereas proton radiation therapy (PRT) is avoided due to concerns about neutron dose. This retrospective study analyzes pregnant patients treated with XRT and models the equivalent dose that would have been delivered to the fetus with proton radiation compared with XRT. The purpose of this work is to provide a comprehensive analysis of pencil beam scanning proton therapy (PBS-PRT) for pregnant patients and to evaluate whether PBS-PRT should be the new standard of practice for treating pregnant patients with brain and head and neck cancers. METHODS AND MATERIALS: PBS-PRT plans were made for seven pregnant patients who received XRT: four treated for brain tumors and three for head and neck tumors. Measurements were performed with the patient plans using an anthropomorphic phantom and Wendi-2 meter placed at the phantom's abdomen. Patient-specific measurements were used to determine the total fetal equivalent dose from PBS-PRT compared with XRT. Imaging dose was also evaluated with a Fluke 451 dose meter. RESULTS: The average measured fetal equivalent dose, accounting for photons and neutrons, for the brain plans was 0.4 mSv for PBS-PRT and 7 mSv for XRT. For the head and neck plans, it was 6 mSv and 90 mSv for PBS-PRT and XRT, respectively. The PBS-PRT plans were preferred by the physicians for both tumor coverage and normal-tissue sparing. Daily imaging added between 0.05 and 1.5 mSv to the total dose. CONCLUSIONS: This retrospective study showed that when treating brain or head and neck cancers in pregnant patients, fetal equivalent dose is reduced by approximately a factor of 10 with PBS-PRT compared with XRT without making any compromises in treatment planning objectives. These results support a change of practice to using PBS-PRT as the new standard for treating pregnant patients with brain or head and neck tumors compared with XRT.

Assessment of minimum target dose as a predictor of local failure after spine SBRT.

OBJECTIVES: Metastasis-directed stereotactic body radiation therapy (SBRT) has demonstrated robust clinical benefits in carefully selected patients, improving local control and even overall survival (OS). We assess a large database to determine clinical and dosimetric predictors of local failure after spine SBRT. METHODS: Spine SBRT treatments with imaging follow-up were identified. Patients were treated with a simultaneous integrated boost technique using 1 or 3 fractions, delivering 20-24 Gy in 1 fraction to the gross tumor volume (GTV) and 16 Gy to the low dose volume (or 27-36 Gy and 21-24 Gy for 3 fraction treatments). Exclusions included: lack of imaging follow-up, proton therapy, and benign primary histologies. RESULTS: 522 eligible spine SBRT treatments (68 % single fraction) were identified in 377 unique patients. Patients had a median OS of 43.7 months (95 % confidence interval: 34.3-54.4). The cumulative incidence of local failure was 10.5 % (7.4-13.4) at 1 year and 16.3 % (12.6-19.9) at 2 years. Local control was maximized at 15.3 Gy minimum dose for single-fraction treatment (HR = 0.31, 95 % CI: 0.17 - 0.56, p < 0.0001) and confirmed via multivariable analyses. Cumulative incidence of local failure was 6.1 % (2.6-9.4) vs. 14.2 % (8.3-19.8) at 1 year using this cut-off, with comparable findings for minimum 14 Gy. Additionally, epidural and soft tissue involvement were predictive of local failure (HR = 1.77 and 2.30). CONCLUSIONS: Spine SBRT offers favorable local control; however, minimum dose to the GTV has a strong association with local control. Achieving GTV minimum dose of 14-15.3 Gy with single fraction SBRT is recommended whenever possible.

Development and validation of a unifying pre-treatment decision tool for intracranial and extracranial metastasis-directed radiotherapy.

Background: Though metastasis-directed therapy (MDT) has the potential to improve overall survival (OS), appropriate patient selection remains challenging. We aimed to develop a model predictive of OS to refine patient selection for clinical trials and MDT. Patients and methods: We assembled a multi-institutional cohort of patients treated with MDT (stereotactic body radiation therapy, radiosurgery, and whole brain radiation therapy). Candidate variables for recursive partitioning analysis were selected per prior studies: ECOG performance status, time from primary diagnosis, number of additional non-target organ systems involved (NOS), and intracranial metastases. Results: A database of 1,362 patients was assembled with 424 intracranial, 352 lung, and 607 spinal treatments (n=1,383). Treatments were split into training (TC) (70%, n=968) and internal validation (IVC) (30%, n=415) cohorts. The TC had median ECOG of 0 (interquartile range [IQR]: 0-1), NOS of 1 (IQR: 0-1), and OS of 18 months (IQR: 7-35). The resulting model components and weights were: ECOG = 0, 1, and > 1 (0, 1, and 2); 0, 1, and > 1 NOS (0, 1, and 2); and intracranial target (2), with lower scores indicating more favorable OS. The model demonstrated high concordance in the TC (0.72) and IVC (0.72). The score also demonstrated high concordance for each target site (spine, brain, and lung). Conclusion: This pre-treatment decision tool represents a unifying model for both intracranial and extracranial disease and identifies patients with the longest survival after MDT who may benefit most from aggressive local therapy. Carefully selected patients may benefit from MDT even in the presence of intracranial disease, and this model may help guide patient selection for MDT.

Development and Internal Validation of a Recursive Partitioning Analysis-Based Model Predictive of Pain Flare Incidence After Spine Stereotactic Body Radiation Therapy.

PURPOSE: Pain flares are a common acute toxic effect after stereotactic body radiation therapy (SBRT) for spine metastasis. We aimed to identify a subset of patients with the highest rate of pain flare after spine SBRT to optimize prophylactic corticosteroid administration. METHODS AND MATERIALS: The data set included 428 patients with 610 treatments. We defined pain flare as acute worsening of pain at the treatment site requiring new or higher dose therapy with corticosteroids, opiates, and/or hospitalization. Data were split into 70% training and 30% validation sets using a random number generator. After feature importance testing and generation of a correlation heatmap, feature extraction was performed via recursive partitioning analysis. RESULTS: We identified 125 total pain flares (20%). Five variables met significance (P < .02) for model inclusion: renal primary, soft tissue involvement, Bilsky >0, spinal instability neoplastic score >6, and gross tumor volume >8 cc. One point was assigned for each variable. The low-risk group (score = 0, n = 159) had pain flare rates of 7.0% and 13.6% in the training and validation sets; the intermediate-risk group (score = 1, n = 150) had rates of 14.0% and 16.3%; and the high-risk group (score >1, n = 301) had rates of 28.8% and 31.3%. Patients in the high-risk group had higher rates of flare (odds ratio, 3.50; 95% confidence interval, 2.06-5.92) and accumulated health care costs 3 and 6 months post-SBRT, relative to intermediate- and low-risk patients (P < .001). CONCLUSIONS: Our internally validated model identifies a high-risk group of patients more likely to develop a pain flare after spine SBRT, for whom prophylactic steroids may be considered. Evaluation in a clinical trial is warranted.

Development and Assessment of a Predictive Score for Vertebral Compression Fracture After Stereotactic Body Radiation Therapy for Spinal Metastases.

IMPORTANCE: Vertebral compression fracture (VCF) is a potential adverse effect following treatment with stereotactic body radiation therapy (SBRT) for spinal metastases. OBJECTIVE: To develop and assess a risk stratification model for VCF after SBRT. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study conducted at a high-volume referral center included 331 patients who had undergone 464 spine SBRT treatments from December 2007 through October 2019. Data analysis was conducted from November 1, 2020, to August 17, 2021. Exclusions included proton therapy, prior surgical intervention, vertebroplasty, or missing data. EXPOSURES: One and 3 fraction spine SBRT treatments were most commonly delivered. Single-fraction treatments generally involved prescribed doses of 16 to 24 Gy (median, 20 Gy; range, 16-30 Gy) to gross disease compared with multifraction treatment that delivered a median of 30 Gy (range, 21-50 Gy). MAIN OUTCOMES AND MEASURES: The VCF and radiography components of the spinal instability neoplastic score were determined by a radiologist. Recursive partitioning analysis was conducted using separate training (70%), internal validation (15%), and test (15%) sets. The log-rank test was the criterion for node splitting. RESULTS: Of the 331 participants, 88 were women (27%), and the mean (IQR) age was 63 (59-72) years. With a median follow-up of 21 months (IQR, 11-39 months), we identified 84 VCFs (18%), including 65 (77%) de novo and 19 (23%) progressive fractures. There was a median of 9 months (IQR, 3-21 months) to developing a VCF. From 15 candidate variables, 6 were identified using the backward selection method, feature importance testing, and a correlation heatmap. Four were selected via recursive partitioning analysis: epidural tumor extension, lumbar location, gross tumor volume of more than 10 cc, and a spinal instability neoplastic score of more than 6. One point was assigned to each variable, and the resulting multivariable Cox model had a concordance of 0.760. The hazard ratio per 1-point increase for VCF was 1.93 (95% CI, 1.62-2.30; P < .001). The cumulative incidence of VCF at 2 years (with death as a competing risk) was 6.7% (95% CI, 4.2%-10.7%) for low-risk (score, 0-1; 273 [58.3%]), 17.0% (95% CI, 10.8%-26.7%) for intermediate-risk (score, 2; 99 [21.3%]), and 35.4% (95% CI, 26.7%-46.9%) for high-risk cases (score, 3-4; 92 [19.8%]) (P < .001). Similar results were observed for freedom from VCF using stratification. CONCLUSIONS AND RELEVANCE: The results of this cohort study identify a subgroup of patients with high risk for VCF following treatment with SBRT who may potentially benefit from undergoing prophylactic spinal stabilization or vertebroplasty.