Metastatic site radiation therapy for Ewing sarcoma and rhabdomyosarcoma: Consensus guidelines from the National Pediatric Cancer Foundation.

BACKGROUND: Despite the urgent need for improved outcomes in patients with metastatic Ewing sarcoma (EWS) and rhabdomyosarcoma (RMS), it is unknown how to best approach metastatic site radiation therapy for these patients and whether such treatment provides a significant oncologic benefit that outweighs the toxicities. METHODS: We gathered a panel of pediatric radiation oncologists from academic hospitals to identify and discuss current controversies regarding the role of radiation in the management of metastatic EWS and RMS. The panel reviewed existing clinical data and ongoing trials to address five key questions: 1) the role of whole lung irradiation (WLI) in treating lung metastases 2) number of metastatic sites warranting radiotherapy and the radicality of such an approach; 3) radiation techniques, including stereotactic body radiation therapy (SBRT); 4) the timing of metastatic-site radiation therapy; and 5) the utility of metastatic site radiation therapy for relapsed metastatic disease. RESULTS: After a review of existing data, consensus recommendations were developed to support the decision-making process in metastatic-site irradiation with the goal of improving long-term disease control. Patients with pulmonary metastases should receive WLI. In patients with limited (<8 sites) metastatic disease, a comprehensive approach should be taken to treat all sites of metastatic disease diagnosed at presentation. SBRT should be considered as a preferred treatment technique. The timing of metastatic-site treatment should coincide with the end of systemic therapy. However, if there is a dosimetric advantage or improved compliance, concurrent treatment with the primary site may be preferred. CONCLUSIONS: A consensus guideline was established to address several critical questions regarding the role of radiation in the treatment of metastatic EWS and RMS. The study highlights the existing controversies, provides a structured approach, and underscores the need for future studies to further evaluate the therapeutic ratio of metastatic-site directed therapy.

Whole Lung Irradiation in Rhabdomyosarcoma With Lung Metastases: A Report From the Soft Tissue Sarcoma Committee of the Children's Oncology Group.

PURPOSE: Patients with rhabdomyosarcoma with metastatic disease have a poor prognosis despite therapy intensification. The aim of this study was to investigate the efficacy of whole lung irradiation (WLI) in patients with rhabdomyosarcoma and lung metastases. METHODS: Patients with rhabdomyosarcoma with lung metastases enrolled on four Children's Oncology Group protocols (D9802, D9803, ARST08P1, ARST0431) were retrospectively reviewed. Event-free survival (EFS) and overall survival (OS) were compared between patients who received and did not receive WLI. RESULTS: In 143 patients with rhabdomyosarcoma with lung metastases, 65 patients (45.5%) received WLI and 78 patients (54.5%) did not receive WLI despite protocol requirements. The 5-year EFS was 38.3% (95% CI, 24.8 to 51.8) in patients who received WLI and 25.2% (95% CI, 13.8 to 36.6) in patients who did not receive WLI (P = .0496). The 5-year OS was 45.5% (95% CI, 31.8 to 59.3) in patients who received WLI and 32.4% (95% CI, 20.4 to 44.4) in patients who did not receive WLI (P = .08). In exploratory subgroup analyses, the benefit of WLI on EFS and OS was significant in patients 10 years and older. Other clinical factors associated with EFS on univariable analysis included age, histology FOXO1 fusion status, number of metastatic sites, location of metastatic sites, and Oberlin Score. CONCLUSION: WLI is associated with improved EFS in patients with rhabdomyosarcoma with lung metastases. These results highlight the potential importance of WLI and need for more stringent protocol compliance for administering WLI.

Children and young adults with newly diagnosed rhabdomyosarcoma metastatic to bone treated on Children's Oncology Group studies.

BACKGROUND: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. Despite bone metastases being present in 5% of patients at diagnosis, there are limited studies examining these outcomes. We sought to define the prognostic factors, clinical courses, and outcomes of children treated on Children's Oncology Group (COG) clinical trials with RMS metastatic to bone at diagnosis. METHODS: We performed a retrospective analysis of patients diagnosed with bone metastatic RMS enrolled on COG RMS clinical trials (D9802, D9803, ARST0431, or ARST08P1) between 1997 and 2013. RESULTS: RMS metastatic to bone was identified in 154 patients at a median age of 14.9 years at diagnosis. Fifty-eight percent of patients were male, 90% had metastases at additional sites, 74% had alveolar histology, and extremity was the most common primary site (31%). Eighty-six percent of patients (n = 133) received radiation therapy. The 3- and 5-year event-free survival (EFS) was 15.4% and 14.5%, respectively. The 3- and 5-year overall survival (OS) was 30.4% and 18.0%, respectively. We identified alveolar histology, FOXO1 fusion presence, unfavorable primary location, higher Oberlin score, and lack of radiation as poor prognostic characteristics for both EFS and OS in univariate analysis. Lack of radiation was not significant when excluding patients with events prior to 20 weeks. CONCLUSIONS: This study is the largest analysis of patients with bone metastatic RMS, and defines the poor overall outcomes and negative prognostic factors for these patients. They may be eligible for therapy deintensification for improved quality of life or pursuit of novel treatments/approaches, which are desperately needed.

Impact of Targeted Systemic Therapy and Radiotherapy on Patients Undergoing Spine Surgery for Metastatic Renal Cell Carcinoma.

BACKGROUND: In patients undergoing spine surgery for renal cell carcinoma (RCC), we sought to: (1) describe patterns of postoperative targeted systemic therapy and radiotherapy (RT), (2) compare perioperative outcomes among those treated with targeted systemic therapy to those without, and (3) evaluate the impact of targeted systemic therapy and/or RT on overall survival (OS) and local recurrence (LR). METHODS: A single-institution, retrospective cohort study of patients undergoing spine surgery for metastatic RCC from 2010 to 2021 was undertaken. Treatment groups were RT alone, targeted systemic therapy alone, dual therapy consisting of RT and targeted systemic therapy, and neither therapy. Multivariable Cox regression controlled for age, race, sex, insurance, and preoperative targeted systemic therapy. RESULTS: Forty-nine patients underwent spine surgery for RCC. Postoperatively, 4 patients (8%) received RT alone, 19 (38.8%) targeted systemic therapy alone, 12 (24.5%) dual therapy, and 13 (28.6%) neither. All groups were similar in demographics, preoperative Karnofsky Performance Score (P = 0.372), tumor size (P = 0.413), readmissions (P = 0.884), complications (P = 0.272), Karnofsky Performance Score (P = 0.466), and Modified McCormick Scale (P = 0.980) at last follow-up. Higher 1-year survival was found in dual therapy (83.3%) compared with other therapies. OS was significantly longer in patients with dual therapy compared with other therapies (log-rank; P = 0.010). Multivariate Cox regression (HR = 0.08, 95% CI = 0.02-0.31, P < 0.001) showed longer OS in dual therapy compared with other therapies. Seven patients (14.3%) experienced LR, and a similar time to LR was found between groups (log-rank; P = 0.190). CONCLUSION: In patients undergoing metastatic spine surgery for RCC, postoperative dual therapy demonstrated significantly higher 1-year survival and OS compared with other therapies. CLINICAL RELEVANCE: Multidisciplinary management of metastatic RCC is necessary to ensure timely implementation of targeted systemic therapy and RT to improve outcomes.

Dosimetric Advantage of Combined IMRT for Whole Lung and Abdomen Irradiation for Wilms Tumor.

Purpose: In patients with Wilms tumor with lung metastases, a cardiac-sparing intensity modulated radiation therapy (CS-IMRT) technique is increasingly being adopted for whole lung irradiation. However, the standard technique for flank and whole abdomen radiation remains 2-dimensional anterioposterior (AP), and overlap at the junction between the whole lung CS-IMRT and abdominal AP fields can result in overdose to normal organs. Here, we compared the dosimetry of patients who received whole lung irradiation and flank or abdominal radiation therapy with CS-IMRT with AP abdominal field (IMRT-AP) versus CS-IMRT with IMRT abdominal field (combined IMRT). Methods and Materials: We retrospectively reviewed the radiation plans of 2 patients with Wilms tumor who received CS-IMRT and flank or whole abdomen irradiation with a combined IMRT approach. Comparison IMRT-AP plans were generated with equivalent target coverage of 95% receiving the prescribed dose. Maximum doses to normal organs were compared at the junctional overlap. Results: Overlap at the junction between CS-IMRT and abdominal fields resulted in a significantly lower dose with combined IMRT plans compared with IMRT-AP plan. Differences in maximum doses (in cGy) to normal organs between combined IMRT versus IMRT-AP plans were most significant in the vertebral body (patient 1 = 1277 vs 2065; patient 2 = 1334 vs 2287), lungs (patient 1 = 1298 vs 2081; patient 2 = 1234 vs 1820), spinal cord (patient 1 = 1235 vs 1975; patient 2 = 1345 vs 2253), stomach (patient 1 = 1264 vs 1977; patient 2 = 1118 vs 2062), and liver (patient 1 = 1297 vs 1889; patient 2 = 1334 vs 2237). Conclusions: The combined IMRT approach for Wilms patients who require whole lung and abdomen irradiation can provide more uniform dose distribution in the junction area and significantly lower doses to normal organs at the junctional overlap.

Obstacles to receiving postoperative radiation therapy following separation surgery for metastatic spine disease.

OBJECTIVE: Obtaining timely postoperative radiotherapy (RT) following separation surgery is critical to avoid local recurrence of disease yet can be a challenge due to scheduling conflicts, insurance denials, and travel arrangements. In patients undergoing metastatic spine surgery for spinal cord compression, the authors sought to: 1) report the rate of postoperative RT, 2) describe reasons for patients not receiving postoperative RT, and 3) investigate factors that may predict whether a patient receives postoperative RT. METHODS: A single-center retrospective case series was undertaken of all patients who underwent metastatic spine surgery for extradural disease between January 2010 and January 2021. Inclusion criteria were patients with intermediate or radioresistant tumors with evidence of spinal cord compression who underwent surgery. The primary outcome was the occurrence of RT within 3 months following surgery. Multivariable logistic regression analysis was performed controlling for age, BMI, race, total number of decompressed levels, tumor size, other organ metastasis, and preoperative RT or chemotherapy to predict patients receiving postoperative RT. RESULTS: Of 239 patients undergoing spine surgery for metastatic disease, 113 (47.3%) received postoperative RT while 126 (52.7%) did not. In the postoperative RT group, 24 (21.2%) received stereotactic body radiation therapy while 89 (78.8%) received conventional external-beam radiation therapy. The most common reasons for patients not receiving postoperative RT included death or transfer to hospice (31.0%), RT not being recommended by radiation oncology (30.2%), and loss to follow-up (23.8%). On critical review with the radiation oncology department, the authors estimated that 101 of 126 (80.2%) patients who did not receive postoperative RT were potential candidates for postoperative RT. Patients who received postoperative RT had more documented inpatient (48.7% vs 32.5%, p < 0.001) and outpatient (100.0% vs 65.1%, p < 0.001) radiation oncology consultations than those who did not. Additionally, patients who received postoperative RT had a higher rate of postoperative chemotherapy (53.1% vs 25.4%, p < 0.001), while patients who did not receive postoperative RT had a higher rate of preoperative RT (7.1% vs 31.0%, p < 0.001). Multivariable analysis confirmed that patients who received preoperative RT had lower odds of undergoing postoperative RT (OR 0.14, 95% CI 0.06-0.34; p < 0.001), and patients who underwent postoperative chemotherapy had higher odds of undergoing postoperative RT (OR 3.83, 95% CI 2.05-7.17; p < 0.001). CONCLUSIONS: In the current study reflecting real-world care of patients with metastatic spine disease after undergoing separation surgery, 47% of patients did not receive postoperative RT, and 80% of those patients were potential candidates for postoperative RT. Radiation oncology consultation and postoperative chemotherapy were significantly associated with receiving postoperative RT, whereas preoperative RT was significantly associated with not receiving postoperative RT. The lack of timely postoperative RT highlights a potential gap in metastatic spine tumor care and underscores the necessity for prompt radiation oncology consultation and effective planning.

Earlier Radiation Is Associated with Improved 1-Year Survival After Metastatic Spine Tumor Surgery.

OBJECTIVE: In patients undergoing metastatic spine surgery, we sought to 1) report time to postoperative radiation therapy (RT), 2) describe the predictive factors of time to postoperative RT, and 3) determine if earlier postoperative RT is associated with improved local recurrence (LR) and overall survival (OS). METHODS: A single-center retrospective cohort study was undertaken of all patients undergoing spine surgery for extradural metastatic disease and receiving RT within 3 months postoperatively between January 2010 and January 2021. Time to postoperative RT was dichotomized at <1 month versus 1-3 months. The primary outcomes were LR, OS, and 1-year survival. Secondary outcomes were wound complication, Karnofsky Performance Status, and modified McCormick Scale (MMS) score. Regression analyses controlled for age, body mass index, tumor size, preoperative RT, preoperative/postoperative chemotherapy, and type of RT. RESULTS: Of 76 patients undergoing spinal metastasis surgery and receiving postoperative RT within 3 months, 34 (44.7%) received RT within 1 month and 42 (55.2%) within 1-3 months. Patients with larger tumor size (ß = -3.58; 95% confidence interval [CI], -6.59 to -0.57; P = 0.021) or new neurologic deficits (ß = -16.21; 95% CI, -32.21 to -0.210; P = 0.047) had a shorter time to RT. No significant association was found between time to RT and LR or OS on multivariable logistic/Cox regression. However, patients who received RT between 1 and 3 months had a lower odds of 1-year survival compared with those receiving RT within 1 month (odds ratio, 0.18; 95% CI, 0.04-0.74; P = 0.022). Receiving RT within 1 month versus 1-3 months was not associated with wound complications (7.1% vs. 2.9%; P = 0.556) (odds ratio, 4.40; 95% CI, 0.40-118.0; P = 0.266) or Karnofsky Performance Status/modified McCormick Scale score. CONCLUSIONS: Spine surgeons, oncologists, and radiation oncologists should make every effort to start RT within 1 month to improve 1-year survival after metastatic spine tumor surgery.

Optimization of the flip angles of narrow-band editing pulses in J-difference edited MRS of lactate at 3T.

PURPOSE: Application of highly selective editing RF pulses provides a means of minimizing co-editing of contaminants in J-difference MRS (MEGA), but it causes reduction in editing yield. We examined the flip angles (FAs) of narrow-band editing pulses to maximize the lactate edited signal with minimal co-editing of threonine. METHODS: The effect of editing-pulse FA on the editing performance was examined, with numerical and phantom analyses, for bandwidths of 17.6-300 Hz in MEGA-PRESS editing of lactate at 3T. The FA and envelope of 46 ms Gaussian editing pulses were tailored to maximize the lactate edited signal at 1.3 ppm and minimize co-editing of threonine. The optimized editing-pulse FA MEGA scheme was tested in brain tumor patients. RESULTS: Simulation and phantom data indicated that the optimum FA of MEGA editing pulses is progressively larger than 180° as the editing-pulse bandwidth decreases. For 46 ms long 17.6 Hz bandwidth Gaussian pulses and other given sequence parameters, the lactate edited signal was maximum at the first and second editing-pulse FAs of 241° and 249°, respectively. The edit-on and difference-edited lactate peak areas of the optimized FA MEGA were greater by 43% and 25% compared to the 180°-FA MEGA, respectively. In-vivo data confirmed the simulation and phantom results. The lesions of the brain tumor patients showed elevated lactate and physiological levels of threonine. CONCLUSION: The lactate MEGA editing yield is significantly increased with editing-pulse FA much larger than 180° when the editing-pulse bandwidth is comparable to the lactate quartet frequency width.

Prognosis of children and young adults with newly diagnosed rhabdomyosarcoma metastatic to bone marrow treated on Children's Oncology Group studies.

BACKGROUND: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. Metastatic disease occurs in 16% of all RMS cases and has a poor prognosis. There are limited studies examining the outcomes specific to patients with RMS metastatic to bone marrow despite an incidence of 6% at diagnosis. Our study aims to document the outcomes, prognostic factors, and clinical courses of children presenting with RMS metastatic to bone marrow treated on Children's Oncology Group (COG) cooperative trials. METHODS: We performed a retrospective analysis of the patients diagnosed with RMS metastatic to bone marrow between 1997 and 2013 enrolled on one of four COG RMS clinical trials of D9802, D9803, ARST0431, and ARST08P1. RESULTS: We identified 179 cases with RMS metastatic to bone marrow. Patients had a median age of 14.8 years, 58% were male, predominantly alveolar histology (76%), extremity was the most common primary site (32%), and 87% had metastatic disease to additional sites; 83% (n = 149) received radiation as a treatment modality. The 3- and 5-year event-free survival was 9.4% and 8.2%, respectively. The 3- and 5-year overall survival was 26.1% and 12.6%, respectively. Age ≥10 years, alveolar histology, FOXO1 fusion presence, unfavorable primary location, higher Oberlin score, and lack of radiation were identified as poor prognostic/predictive characteristics. CONCLUSIONS: This study represents the largest analysis of RMS metastatic to bone marrow, defining the poor prognostic outcome for these patients. These patients may be eligible for therapy deintensification or early pursuit of novel treatments/approaches that are desperately needed.

Does Low-Grade Versus High-Grade Bilsky Score Influence Local Recurrence and Overall Survival in Metastatic Spine Tumor Surgery?

BACKGROUND AND OBJECTIVES: Spinal cord compression caused by spinal tumors is measured using the epidural spinal cord compression scale, also known as the Bilsky score. Whether Bilsky score predicts short-/long-term outcomes remains unknown. The objectives were to determine the correlation of Bilsky score 0-1 vs 2-3 with regards to (1) preoperative presentation, (2) perioperative variables, and (3) long-term outcomes. METHODS: A single-center, retrospective evaluation of a cohort of patients undergoing metastatic spine surgery was performed between 01/2010 and 01/2021. Multivariable logistic/linear/Cox regression were performed controlling for age, body mass index, race, total decompressed levels, tumor size, other organ metastases, and postoperative radiotherapy/chemotherapy. RESULTS: Of 343 patients with extradural spinal metastasis, 92 (26.8%) were Bilsky 0-1 and 251 (73.2%) were Bilsky 2-3. Preoperatively, patients with Bilsky 2-3 lesions were older ( P = .008), presented more with sensory deficits ( P = .029), and had worse preoperative Karnofsky Performance Scale (KPS) ( P = .002). Perioperatively, Bilsky 2-3 patients had more decompressed levels ( P = .005) and transpedicular decompression ( P < .001), with similar operative time ( P = .071) and blood loss ( P = .502). Although not statistically significant, patients with Bilsky 2-3 had more intraoperative neuromonitoring changes ( P = .412). Although rates of complications ( P = .442) and neurological deficit ( P = .852) were similar between groups, patients with Bilsky 2-3 lesions had a longer length of stay ( P = .007) and were discharged home less frequently ( P < .001). No difference was found in 90-day readmissions ( P = .607) and reoperation ( P = .510) Long-term: LR ( P =.100) and time to LR (log-rank; P =0.532) were not significantly different between Bilsky 0-1 and Bilsky 2-3 lesions. However, patients with Bilsky 2-3 lesions had worse postoperative KPS ( P < .001), worse modified McCormick scale score ( P = .003), shorter overall survival (OS) (log-rank; P < .001), and worse survival at 1 year ( P = .012). Bilsky 2-3 lesions were associated with shorter OS on multivariable Cox regression (hazard ratio = 1.78, 95% CI = 1.27-2.49, P < .001), with no significant impact on time to LR (hazard ratio = 0.73, 95% CI = 0.37-1.44, P = .359). CONCLUSION: Bilsky 2-3 lesions were associated with longer length of stay, more nonhome discharge, worse postoperative KPS/modified McCormick scale score, shorter OS, and reduced survival at 1 year. Higher-grade Bilsky score lesions appear to be at a higher risk for worse outcomes. Efforts should be made to identify metastatic spine patients before they reach the point of severe spinal cord compression..

Management and outcomes of chest wall rhabdomyosarcoma: A report from the Children's Oncology Group Soft Tissue Sarcoma Committee.

INTRODUCTION: Rhabdomyosarcoma (RMS) of the chest wall presents unique management challenges and local control considerations. The benefit of complete excision is uncertain and must be weighed against potential surgical morbidity. Our aim was to assess factors, including local control modality, associated with clinical outcomes in children with chest wall RMS. METHODS: Forty-four children with RMS of the chest wall from low-, intermediate-, and high-risk Children's Oncology Group studies were reviewed. Predictors of local failure-free survival (FFS), event-free survival (EFS), and overall survival (OS) were assessed, including clinical characteristics and staging, primary tumor anatomic locations, and local control modalities. Survival was assessed by Kaplan-Meier analysis and the log-rank test. RESULTS: Tumors were localized in 25 (57%) and metastatic in 19 (43%), and they involved the intercostal region (52%) or superficial muscle alone (36%). Clinical group was I (18%), II (14%), III (25%), and IV (43%), and ultimately 19 (43%) patients had surgical resection (upfront or delayed), including 10 R0 resections. Five-year local FFS, EFS, and OS were 72.1%, 49.3%, and 58.5%, respectively. Univariate factors associated with local FFS included age, International Rhabdomyosarcoma Study (IRS) group, extent of surgical excision, tumor size, superficial tumor location, and presence of regional or metastatic disease. Other than tumor size, the same factors were associated with EFS and OS. CONCLUSIONS: Chest wall RMS has variable presentation and outcome. Local control is a significant contributor to EFS and OS. Complete surgical excision, whether upfront or after induction chemotherapy, is usually only possible for smaller tumors confined to the superficial musculature but is associated with improved outcomes. While overall outcomes remain poor for patients with initially metastatic tumors, regardless of local control modality, complete excision may be beneficial for patients with localized tumors if it can be achieved without excess morbidity.

Rhabdomyosarcoma with isolated lung metastases: A report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group.

BACKGROUND: To determine outcomes of children with rhabdomyosarcoma (RMS) with isolated lung metastases. METHODS: Data were analyzed for 428 patients with metastatic RMS treated on COG protocols. Categorical variables were compared using Chi-square or Fisher's exact tests. Event-free survival (EFS) and overall survival (OS) were estimated using Kaplan-Meier method and compared using the log-rank test. RESULTS: Compared with patients with other metastatic sites (n = 373), patients with lung-only metastases (n = 55) were more likely to be <10 years of age, have embryonal histology (embryonal rhabdomyosarcoma), have N0 disease, and less likely to have primary extremity tumors. Lung-only patients had significantly better survival outcomes than patients with all other sites of metastatic disease (p < .0001) with 5-year EFS of 48.1 versus 18.8% and 5-year OS of 64.1 versus 26.9%. Patients with lung-only metastases, and those with a single extrapulmonary site of metastasis, had better survival compared with patients with two or more sites of metastatic disease (p < .0001). In patients with ERMS and lung-only metastases, there was no significant difference in survival between patients ≥10 years and 1-9 years (5-year EFS: 58.3 vs. 68.2%, 5-year OS: 66.7 vs. 67.7%). CONCLUSIONS: With aggressive treatment, patients with ERMS and lung-only metastatic disease have superior EFS and OS compared with patients with other sites of metastatic disease, even when older than 10 years of age. Consideration should be given to including patients ≥10 years with ERMS and lung-only metastases in the same group as those <10 years in future risk stratification algorithms.

Unplanned Readmission Is Associated With Decreased Overall Survival and Performance After Metastatic Spine Surgery.

STUDY DESIGN: Retrospective case-control study. OBJECTIVE: In a cohort of patients undergoing metastatic spine surgery, we sought to: (1) identify risk factors associated with unplanned readmission, and (2) determine the impact of an unplanned readmission on long-term outcomes. SUMMARY OF BACKGROUND DATA: Factors affecting readmission after metastatic spine surgery remain relatively unexplored. MATERIALS AND METHODS: A single-center, retrospective, case-control study was undertaken of patients undergoing spine surgery for extradural metastatic disease between 02/2010 and 01/2021. The primary outcome was 3-month unplanned readmission. Preoperative, perioperative, and tumor-specific variables were collected. Multivariable Cox regression was performed, controlling for tumor size, other organ metastasis, and preoperative/postoperative radiotherapy/chemotherapy. RESULTS: A total of 357 patients underwent surgery for spinal metastases with a mean follow-up of 538.7±648.6 days. Unplanned readmission within 3 months of surgery occurred in 64/357 (21.9%) patients, 37 (57.8%) were medical, 27 (42.2%) surgical, and 21 (77.7%) were related to their spine surgery. No significant differences were found regarding demographics and preoperative variables, except for insurance, where most readmitted patients had private insurance compared with nonreadmitted patients ( P =0.021). No significant difference was found in preoperative radiotherapy/chemotherapy. Regarding perioperative exposure variables, readmitted patients had a higher rate of postoperative complications (68.8% vs. 24.2%, P <0.001) and worse postoperative Karnofsky Performance Score ( P =0.021) and Modified McCormick Scale ( P =0.015) at the time of first follow-up. On multivariate logistic regression, postoperative complications were associated with increased readmissions (odds ratio=1.38, 95% CI=1.25-1.52, P <0.001). Regarding the impact of unplanned readmission on long-term tumor control, unplanned readmission was associated with shorter time to local recurrence (log-rank; P =0.029) and reduced overall survival (OS) (log-rank; P <0.001). On multivariate Cox regression, other organ metastasis [hazard ratio (HR)=1.48, 95% CI=1.13-1.93, P =0.004] and 3-month readmission (HR=1.75, 95% CI=1.28-2.39, P <0.001) were associated with worsened OS, with no impact on LR. Postoperative chemotherapy was significantly associated with longer OS (HR=0.59, 95% CI=0.45-0.77, P <0.001). CONCLUSIONS: Postoperative complications were associated with unplanned readmission following metastatic spine surgery. Furthermore, 3-month unplanned readmission was associated with a shorter time to local recurrence and decreased OS. These results help surgeons understand the drivers of readmissions and the impact of readmissions on patient outcomes. LEVEL OF EVIDENCE: 3.

Unplanned Readmission After Surgery for Cervical Spine Metastases.

OBJECTIVE: Patients undergoing surgery for cervical spine metastases are at risk for unplanned readmission due to comorbidities and chemotherapy/radiation. Our objectives were to: 1) report the incidence of unplanned readmission, 2) identify risk factors associated with unplanned readmission, and 3) determine the impact of an unplanned readmission on long-term outcomes. METHODS: A single-center, retrospective, case-control study was undertaken of patients undergoing cervical spine surgery for metastatic disease between 02/2010 and 01/2021. The primary outcome of interest was unplanned readmission within 6 months. Survival analysis was performed for overall survival (OS) and local recurrence (LR). RESULTS: A total of 61 patients underwent cervical spine surgery for metastatic disease with the following approaches: 11 (18.0%) anterior, 28 (45.9%) posterior, and 22 (36.1%) combined. Mean age was 60.9 ± 11.2 years and 38 (62.3%) were males. A total of 9/61 (14.8%) patients had an unplanned readmission, 3 for surgical reasons and 6 for medical reasons. No difference was found in demographics, preoperative Karnofsky Performance Scale (P = 0.992), motor strength (P = 0.477), or comorbidities (P = 0.213) between readmitted patients versus not. Readmitted patients had a higher rate of preoperative radiation (P = 0.009). No statistical differences were found in operative time (P = 0.893), estimated blood loss (P = 0.676), length of stay (P = 0.720), discharge disposition (P = 0.279), and operative approach (P = 0.450). Furthermore, no difference was found regarding complications (P = 0.463), postoperative Karnofsky Performance Scale (P = 0.535), and postoperative Modified McCormick Scale (P = 0.586). Lastly, unplanned readmissions were not associated with OS (log-rank; P = 0.094) or LR (log-rank; P = 0.110). CONCLUSIONS: In patients undergoing cervical spine metastasis surgery, readmission occurred in 15% of patients, 33% for surgical reasons, and 67% for medical reasons. Preoperative radiotherapy was associated with an increased rate of unplanned readmissions, yet readmission had no association with OS or LR.

Adjuvant Radiation after Primary Resection of Atypical Lipomatous Tumors of the Extremity Reduces Local Recurrence but Increases Complications: A Multicenter Evaluation.

Background: Radiation after resection of an atypical lipomatous tumor (ALT) is controversial. This study evaluates local control and complications after the first resection of ALTs of the extremity with or without adjuvant radiation. Methods: A dual institution, retrospective review of patients treated from 1995 to 2020 with first-time resection of an ALT in the extremity was performed. In total, 102 patients underwent adjuvant radiation (XRT group) and 68 patients were treated with surgery alone (no-XRT group). The median follow-up time was 4.6 years (interquartile range (IQR) 2.0-7.3 years). The median radiation dose was 60 Gy (IQR 55-66 Gy). Univariable and multivariable analyses evaluated the association of patient, tumor, and treatment variables with recurrence and complications. Kaplan-Meier analysis evaluated local recurrence-free survival (LRFS) and time to complication. Results: The overall incidence of local recurrence was 1% (1/102) in the XRT group and 24% (16/68) in the no-XRT group (p < 0.001). The median time-to-recurrence was 8.2 years (IQR 6.5-10.5 years). In the XRT and the no-XRT groups, 5-yr LRFS was 98% and 92% (p=0.21) and 10-yr LRFS was 98% and 41% (p < 0.001), respectively. The absence of radiation (HR = 23.63, 95% CI (3.09-180.48); p < 0.001) and R2 surgical resection margins (HR = 11.04, 95% CI (2.07-59.03); p < 0.001) incurred a 23-fold and 11-fold increased risk of local recurrence, respectively, while tumor size, depth, location, and neurovascular involvement were not found to be independent predictors of recurrence. The complication rate was 37% (38/102) in the XRT group and 10% (7/68) in the no-XRT group (p < 0.001). Eight patients (8/102, 8%) required surgical management for complication in the XRT group compared with two patients (2/68, 3%) in the no-XRT group (p=0.10). Higher radiation dose had a modest correlation with increased severity of complication (ρ=0.24; p=0.02). Conclusions: Adjuvant radiation after first-time resection of an ALT of the extremity was associated with a significantly reduced risk of local recurrence but a three-fold increase in complication rate. These data support a 10-year follow-up for these patients and inform a notable clinical trade-off if considering adjuvant radiation for this tumor with recurrent potential.

Genomic Analyses for Predictors of Response to Chemoradiation in Stage III Non-Small Cell Lung Cancer.

BACKGROUND: Radiation with platinum-based chemotherapy is the standard of care for unresectable stage III non-small cell lung cancer (NSCLC). Despite aggressive treatment, progression-free survival and overall survival remain poor. It is unclear whether any tumor genetic mutations are associated with response to chemoradiation therapy. METHODS: We retrospectively reviewed clinical outcomes of patients with stage III NSCLC treated with definitive radiation who had undergone tumor molecular profiling through a next-generation DNA sequencing platform. Cox proportional hazards model was used to investigate associations between clinical outcomes and genetic mutations detected by next-generation sequencing. RESULTS: 110 patients were identified with stage III NSCLC and underwent definitive radiation between 2013 and 2017 and tumor molecular profiling. Concurrent or sequential chemotherapy was given in 104 patients (95%). Unbiased genomic analyses revealed a significant association between AKT2 mutations and decreased local-regional tumor control and overall survival (hazard ratios [HR] 12.5 and 13.7, P = .003 and P = .003, respectively). Analyses restricted to loss-of-function mutations identified KMT2C and KMT2D deleterious mutations as negative prognostic factors for overall survival (HR 13.4 and 7.0, P < .001 and P < .001, respectively). Deleterious mutations in a panel of 38 DNA damage response and repair pathway genes were associated with improved local-regional control (HR 0.32, P = .049). CONCLUSIONS: This study coupled multiplexed targeted sequencing with clinical outcome and identified mutations in AKT2, KMT2C, and KMT2D as negative predictors of local-regional control and survival, and deleterious mutations in damage response and repair pathway genes were associated with improved local-regional disease control after chemoradiation therapy. These findings will require validation in a larger cohort of patients with prospectively collected and detailed clinical information.

Socioeconomic inequality and omission of adjuvant radiation therapy in high-risk, early-stage endometrial cancer.

OBJECTIVE: Gaps in access to appropriate cancer care, and associated cancer mortality, have widened across socioeconomic groups. We examined whether demographic and socioeconomic factors influenced receipt of adjuvant radiation therapy (RT) in patients with high-risk, early-stage endometrial cancer. METHODS: A retrospective study cohort was selected from 349,404 endometrial carcinoma patients from the National Cancer Database in whom adjuvant RT would be recommended per national guidelines. The study included surgically treated patients with endometrioid endometrial cancer with one of the following criteria: 1) FIGO 2009 stage IB, grade 1/2 disease, age ≥ 60 years; 2) stage IB, grade 3 disease; or 3) stage II disease. Logistic regression analysis was performed to identify factors associated with omission of adjuvant RT. Association between adjuvant RT, covariables, and overall survival (OS) was assessed with multivariable Cox proportional hazards models. RESULTS: 19,594 patients were eligible for analysis; 47% did not receive adjuvant RT. Omission of adjuvant RT was more prevalent among African-American, Hispanic, and Asian compared to non-Hispanic white patients (OR 0.79, 95%CI: 0.69-0.91; OR 0.75, 95%CI: 0.64-0.87; OR 0.75, 95%CI: 0.60-0.94, respectively). Lower median household income of patient's area of residence, lack of health insurance, treatment at non-academic hospitals, farther distance to treatment facilities, and residence in metropolitan counties were associated with omission of adjuvant RT. Such omission was independently associated with worse OS (HR1.43, p < 0.001). CONCLUSION: Adjuvant RT is omitted in 47% of patients with early-stage, high-risk endometrial cancer, which is associated with poor access to appropriate, high-quality care and worse outcome.

Reduced-dose craniospinal irradiation for central nervous system relapsed neuroblastoma.

PURPOSE: In patients with high-risk neuroblastoma, there is an increased recognition of relapse in the central nervous system (CNS). Craniospinal irradiation (CSI) has been an effective treatment but carries significant long-term complications. It is unclear whether reducing the CSI dose from 21 to 18 Gy can achieve similar CNS tumor control. PATIENTS AND METHODS: A retrospective review of pediatric patients with CNS-relapsed neuroblastoma treated with CSI and boost to parenchymal lesions between 2003 and 2019 was performed. The goal was to assess CNS control comparing 18 Gy and 21 Gy regimens. RESULTS: Ninety-four patients with CNS-relapsed neuroblastoma were treated with CSI followed by intraventricular compartmental radioimmunotherapy. Median age at the time of CNS disease was 4 years (range 1-13 years). Forty-one patients (44%) received 21 Gy CSI prior to an institutional decision to lower the dose; 53 patients (56%) received 18 Gy CSI. Seventy-nine patients (84%) received additional boosts. With a median follow up of 4.1 years for surviving patients, 2-year CNS relapse-free survival was 74% for 18 Gy group versus 77% for 21 Gy group, and 5-year CNS relapse-free survival was 66% for 18 Gy versus 72% for 21 Gy group, respectively (P = .40). Five-year overall survival rate was 43% in 18 Gy group versus 47% in 21 Gy group (P = .72). CONCLUSION: For patients with CNS-relapsed neuroblastoma, CNS disease control is comparable between 18 Gy and 21 Gy CSI dose regimens, in conjunction with radioimmunotherapy and CNS penetrating chemotherapy. More than 65% of the patients remain CNS disease free after 5 years. The findings support 18 Gy as the new standard CSI dose for CNS-relapsed neuroblastoma.

Combining Radiation with Immunotherapy: The University of Pennsylvania Experience.

Immune checkpoint inhibitors have shown remarkable clinical benefit across a variety of cancer types. However, the majority of patients do not respond or develop relapse after therapy. Radiation can favorably modulate the immune system and enhance tumor antigen recognition and rejection. Thus, the combination of radiation and immune checkpoint blockade (ICB) has been recognized as a promising strategy to improve tumor response and broaden the clinical utility of immunotherapy. In this review, we highlight the preclinical and clinical experience at our institution aimed at understanding and promoting the immunostimulatory effect of radiation. We discuss the rationale, design, results, and lessons from our clinical trials in combining radiation with anti-CTLA4 and/or anti-PD-1 therapy. In parallel, our studies to understand the resistance mechanism to radiation and ICB have converged on interferon (IFN) signaling as a key regulatory pathway. Persistent IFN-γ signaling impairs anti-tumor immune responses which can be reversed by using JAK inhibitor to disrupt the IFN signaling. Lastly we discuss remaining challenges, ongoing studies, and future directions in combining radiation with immunotherapy.