Outcomes following proton therapy for Ewing sarcoma of the cranium and skull base.

PURPOSE: Despite the dosimetric advantages of proton therapy, little data exist on patients who receive proton therapy for Ewing sarcoma of the cranium and skull base. This study reports local disease control and toxicity in such patients. MATERIALS/METHODS: We reviewed 25 patients (≤21 years old) with nonmetastatic Ewing sarcoma of the cranium and skull base treated between 2008 and 2018. Treatment toxicity was graded per the Common Terminology Criteria for Adverse Events v4.0. The Kaplan-Meier product limit method provided estimates of disease control and survival. RESULTS: Median patient age was 5.9 years (range, 1-21.7). Tumor subsites included the skull base (48%), non-skull-base calvarial bones (28%), paranasal sinuses (20%), and nasal cavity (4%). All patients underwent multiagent alkylator- and anthracycline-based chemotherapy; 16% underwent gross total resection (GTR) before radiation. Clinical target volume (CTV) 1 received 45 GyRBE and CTV2 received 50.4 GyRBE following GTR or 54-55.8 GyRBE following biopsy or subtotal resection. Median follow-up was 3.7 years (range, 0.26-8.3); no patients were lost. The 4-year local control, disease-free survival, and overall survival rates were 96%, 86%, and 92%, respectively. Two patients experienced in-field recurrences. One patient experienced bilateral conductive hearing loss requiring aids, two patients developed intracranial vasculopathy, and 6 patients required hormone replacement therapy for neuroendocrine deficits. None developed a secondary malignancy. CONCLUSION: Proton therapy is associated with a favorable therapeutic ratio in children with large Ewing tumors of the cranium and skull base. Despite its high conformality, we observed excellent local control and no marginal recurrences. Treatment dosimetry predicts limited long-term neurocognitive and neuroendocrine side effects.

Proton therapy following induction chemotherapy for pediatric and adolescent nasopharyngeal carcinoma.

PURPOSE: In children treated for nasopharyngeal carcinoma, proton therapy and postchemotherapy target volumes can reduce the radiation dose to developing tissue in the brain and the skull base region. We analyzed outcomes in children with nasopharyngeal carcinoma treated with induction chemotherapy followed by moderate-dose proton therapy. METHODS/MATERIALS: Seventeen patients with nonmetastatic nonkeratinizing undifferentiated/poorly differentiated nasopharyngeal carcinoma underwent double-scattered proton therapy between 2011 and 2017. Median age was 15.3 years (range, 7-21). The American Joint Committee on Cancer T and N stage distribution included the following: T1, one patient; T2, five patients; T3, two patients; and T4, nine patients; and N1, six patients; N2, nine patients; and N3, two patients. Median radiation dose to the primary target volume and enlarged lymph nodes was 61.2 Gy (range, 59.4-61.2). Uninvolved cervical nodes received 45 Gy (range, 45-46.8). All radiation was delivered at 1.8 Gy/fraction daily using sequential plans. In 11 patients, photon-based intensity-modulated radiotherapy was used for elective neck irradiation to optimize dose homogeneity and improve target conformity. All patients received induction chemotherapy; all but one received concurrent chemotherapy. Five received adjuvant beta-interferon therapy. RESULTS: Median follow-up was 3.0 years (range, 1.6-7.9). No patients were lost to follow-up. Overall survival, progression-free survival, and local control rates were 100%. Fifteen patients developed mucositis requiring enteral feeding (n = 14) or total parenteral nutrition (n = 1) during radiotherapy. Serious late side effects included cataract (n = 1), esophageal stenosis requiring dilation (n = 1), sensorineural hearing loss requiring aids (n = 1), and hormone deficiency (n = 5, including three with isolated hypothyroidism). CONCLUSION: Following induction chemotherapy, moderate-dose proton therapy can potentially reduce toxicity in the brain and skull base region without compromising disease control. However, further follow-up is needed to fully characterize and evaluate any reduction in long-term complications.

45 GyRBE for group III orbital embryonal rhabdomyosarcoma.

Purpose: Despite widespread concerns of radiotherapy toxicity in children with head and neck tumors, recent Children's Oncology Group (COG) findings suggest that the use of 45 Gy results in an unacceptably high rate of local recurrences in patients with low-risk orbital rhabdomyosarcoma. We therefore evaluated outcomes in our pediatric patients who received 45 GyRBE using proton therapy. Material and methods: To assess disease control and toxicity, we reviewed the medical records of 30 children (≤21 years old) with COG stage 1, group III embryonal orbital rhabdomyosarcoma enrolled on a prospective outcome study and treated with proton therapy between 2007 and 2018. Results: Median age at the time of radiation was 4.8 years old. Twenty-one and nine patients received ifosfamide- and cyclophosphamide-based chemotherapy according to their respective cooperative group regimens. Median duration between the start of induction chemotherapy and radiation was 12 weeks. Two patients had a complete response to induction chemotherapy and two had stable disease. Twenty-six patients had a partial response to induction chemotherapy, with a median volume reduction of 66%. With a median follow-up of 4.0 years (range, 0.5-9.5 years), we observed 1 local failure 6 months following treatment in a patient who had a partial response to cyclosphophomide-based induction chemotherapy. The 5-year local control, progression-free survival, and overall survival rates were 97%, 97%, and 100%, respectively. Serious late toxicities included 18 patients with cataracts, 4 with exposure keratoconjunctivitis resulting in permanently reduced visual acuity, and 1 with chronic sinusitis. Conclusion: 45 GyRBE offers effective local control for most patients with group III orbital rhabdomyosarcoma. The delivery of proton therapy to the postinduction tumor volume plus a small margin can mitigate early- and intermediate-term toxicity, but side effects still occur and long-term data are needed to demonstrate the dosimetric advantage of proton therapy.

Prognostic Factors of Oligometastasis After Stereotactic Body Radiotherapy: The Real-World Utility of the European Society for Radiotherapy and Oncology/European Organisation for Research and Treatment of Cancer Classification.

AIM: The efficacy of local therapy for oligometastatic disease (OMD) remains unclear. This study aimed to evaluate the prognostic utility of the classification system for OMD and explore which groups may benefit from stereotactic body radiation therapy (SBRT). METHODS: This single-center retrospective study included 45 patients (52 sites) with solid tumors and 1-3 extracranial oligometastases who underwent SBRT for all metastases at our institution between January 2018 and December 2021. OMD states were classified based on the European Society for Radiotherapy and Oncology (ESTRO) and the European Organisation for Research and Treatment of Cancer (EORTC) classification system. Local control (LC), overall survival (OS), and progression-free survival (PFS) for each group were analyzed using the Kaplan-Meier method. Acute and late adverse events (AEs) were evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. RESULTS: The median follow-up period was 14 months (range: 0-48 months). The numbers of patients in the de novo (first diagnosis of OMD), repeat (previous history of OMD), and induced (previous history of polymetastatic disease) OMD groups were 15, 17, and 13, respectively. The LC rates at one year for the entire, de novo, repeat, and induced cohorts were 87.2%, 87.5%, 90.2%, and 83.9%, respectively (p=0.80). The one-year PFS rates for each group were 35.0%, 56.7%, and 29.9%, respectively (p=0.58). The one-year OS rates for each group were 80.0%, 86.2%, and 80.8%, respectively (p=0.50). Grade 2 or 3 AEs occurred in five patients (10.4%). No grade 4 or 5 AEs were observed. CONCLUSIONS: SBRT is safe and highly effective for local control. Patients with repeat OMD demonstrated a trend of longer PFS, suggesting that this subgroup may benefit from local therapy at metastatic sites.

Uptake of ultra-hypofractionated radiation therapy following breast-conserving surgery among patients with early-stage breast cancer: a multi-institutional questionnaire survey.

BACKGROUND: In patients with early-stage breast cancer following breast surgery, ultra-hypofractionated (UHF) breast/chest wall radiation therapy (RT) has been shown to be non-inferior to a moderate-hypofractionated (MHF) regimen, with a minimal risk of breast induration, in the FAST-Forward trial, and UHF is now becoming the standard regimen in Europe. Herein, we aimed to investigate Japanese patients' attitudes toward the UHF regimen. METHODS: A questionnaire-based survey was conducted at 13 RT centers in nine prefectures across Japan. All patients underwent breast-conserving surgery, followed by either conventional fractionation (2 Gy/fr) or MHF (2.66 Gy/fr) whole-breast irradiation (WBI) with or without a tumor bed boost. The questionnaire consisted of 13 questions mainly addressing quality-of-life during RT. Key questions included an 11-point scale (0-10) for rating the patients' enthusiasm for the UHF regimen and prioritization of the following treatment-related effects: treatment efficacy, acute/late adverse effects, physical/emotional/financial burden, and breast cosmesis. The patient and treatment characteristics were assessed by a physician. RESULTS: In total, 247 questionnaires were administered between November 2022 and June 2023. The age distribution was as follows: < 50:50 s:60 s: ≥ 70 = 59 (24%):76 (30%):63 (26%):49 (20%). Sixty-nine percent of patients rated their enthusiasm for the UHF regimen at ≥ 6 out of 10 points (45% rated 10/10). Treatment efficacy was the highest priority for most patients (89%), whereas breast cosmesis the lowest priority (53%). CONCLUSIONS: Patients' enthusiasm for UHF-WBI was observed across the cohort. These results could motivate researchers and clinicians to introduce UHF regimens in clinical practice.

Multi-institutional prospective observational study of radiotherapy for metastatic bone tumor.

Purpose of this study is to evaluate patient characteristics, treatments and outcomes in bone metastasis radiotherapy practice. Patients for whom radiotherapy for bone metastasis was planned at 26 institutions in Japan between December 2020 and March 2021 were consecutively registered in this prospective, observational study. Study measures included patient characteristics, pain relief, skeletal-related events (SREs), overall survival and incidence of radiation-related adverse events. Pain was evaluated using a numerical rating scale (NRS) from 0 to 10. Irradiated dose was analyzed by the biologically effective dose (BED) assuming α/ß = 10. Overall, 232 patients were registered; 224 patients and 302 lesions were fully analyzed. Eastern Cooperative Oncology Group Performance Status was 0/1/2/3/4 in 23%/38%/22%/13%/4%; 59% of patients had spinal metastases and 84% had painful lesions (NRS ≥ 2). BED was <20 Gy (in 27%), 20-30 Gy (24%), 30-40 Gy (36%) and ≥ 40 Gy (13%); 9% of patients were treated by stereotactic body radiotherapy. Grade 3 adverse events occurred in 4% and no grade 4-5 toxicity was reported. Pain relief was achieved in 52% at 2 months. BED is not related to pain relief. The cumulative incidence of SREs was 6.5% (95% confidence interval (CI) 3.1-9.9) at 6 months; no factors were significantly associated with SREs. With spinal lesions, 18% of patients were not ambulatory at baseline and 50% of evaluable patients in this group could walk at 2 months. The 6-month overall survival rate was 70.2% (95% CI 64.2-76.9%). In conclusion, we report real-world details of radiotherapy in bone metastasis.

Reduced Risk of Lymphedema With Intensity-modulated Radiation Therapy Compared With 3-dimensional Conformal Radiation Therapy in Patients With Cervical Cancer Who Received Postoperative Pelvic Radiation Therapy.

OBJECTIVES: To compare the long-term adverse events of intensity-modulated radiation therapy (IMRT) with those of 3-dimensional conformal radiation therapy (3D-CRT) in patients with intermediate-risk and high-risk uterine cervical cancer who underwent postoperative pelvic radiation therapy (PORT). METHODS: We reviewed the medical records of 177 patients with cervical cancer who underwent radical surgery and PORT. IMRT and 3D-CRT were administered to 93 and 84 patients, respectively. Follow-up and toxicity assessments were then carried out. RESULTS: The median follow-up period was 63 months (range: 3 to 177). There was a significant difference in the follow-up period between the IMRT and 3D-CRT cohorts (median: 59 vs. 112 mo, P <0.0001). The crude incidences of acute grade 2+ and grade 3+ gastrointestinal toxicities were significantly lower with IMRT than with 3D-CRT (22.6% vs. 48.1%, P =0.002, and 3.2% vs. 11.1%, P =0.04, respectively). The Kaplan-Meier estimates of late toxicities revealed that IMRT significantly reduced grade 2+ genitourinary (GU) toxicity and lower-extremity lymphedema ([LEL] requiring intervention) compared with 3D-CRT ([6.8% vs. 15.2% at 5-year, P =0.048] and [3.1% vs. 14.6% at 5-year, P =0.0029], respectively). IMRT was the only significant predictor of reducing LEL risk. CONCLUSIONS: The risks of acute gastrointestinal toxicity, late GU toxicity, and LEL from PORT for cervical cancer were reduced by IMRT. Lower inguinal doses may have contributed to a lower risk of developing LEL, which should be validated in future studies.

Factors associated with quality of life in patients receiving palliative radiotherapy for bone metastases: a secondary cross-sectional analysis of data from a prospective multicenter observational study.

OBJECTIVE: To identify factors significantly associated with quality of life (QOL) and determine if these associations are strong enough to predict certain aspects of QOL without measuring them. METHODS: We conducted an exploratory secondary analysis of baseline data of 224 patients (enrolled between December 2020 and March 2021) from a previously published prospective observational study on radiotherapy for bone metastases at 26 centres. Using univariable linear regression, we assessed the association between patient/treatment factors and QOL scale scores as measured by the European Organization for Research and Treatment of Cancer (EORTC) QOL Questionnaire Core 15-Palliative (QLQ-C15-PAL) and the EORTC QOL Questionnaire Bone Metastases module (QLQ-BM22). RESULTS: Age and sex were not significantly associated with QOL. Worse performance status, higher pain scores, and opioid and single-fraction use were significantly associated with most QOL scales; these four factors were associated with worse global QOL, worse functioning status, and more severe symptoms. The coefficients of determination for most QOL scales were less than 0.2, indicating that most of the variability in QOL scores was not explained by any of the explanatory variables. CONCLUSION: Performance status, pain intensity, and opioid and single-fraction use were significantly associated with most QOL scales. However, the associations were not strong enough to estimate QOL. ADVANCES IN KNOWLEDGE: To date, the association between treatment factors and QOL in patients with bone metastases has not been fully studied. We identified the factors that were significantly associated with QOL and found that these associations were not strong enough to predict QOL.

Income and Employment of Patients at the Start of and During Follow-up After Palliative Radiation Therapy for Bone Metastasis.

Purpose: The aim of this study was to understand the income and employment status of patients at the start of and during follow-up after palliative radiation therapy for bone metastasis. Methods and Materials: From December 2020 to March 2021, a prospective multi-institutional observational study was conducted to investigate income and employment of patients at the start of administration of radiation therapy for bone metastasis and at 2 and 6 months after treatment. Of 333 patients referred to radiation therapy for bone metastasis, 101 were not registered, mainly because of their poor general condition, and another 8 were excluded from the follow-up analysis owing to ineligibility. Results: In 224 patients analyzed, 108 had retired for reasons unrelated to cancer, 43 had retired for reasons related to cancer, 31 were taking leave, and 2 had lost their jobs at the time of registration. The number of patients who were in the working group was 40 (30 with no change in income and 10 with decreased income) at registration, 35 at 2 months, and 24 at 6 months. Younger patients (P = 0), patients with better performance status (P = 0), patients who were ambulatory (P = .008), and patients with lower scores on a numerical rating scale of pain (P = 0) were significantly more likely to be in the working group at registration. There were 9 patients who experienced improvements in their working status or income at least once in the follow-up after radiation therapy. Conclusions: The majority of patients with bone metastasis were not working at the start of or after radiation therapy, but the number of patients who were working was not negligible. Radiation oncologists should be aware of the working status of patients and provide appropriate support for each patient. The benefit of radiation therapy to support patients continuing their work and returning to work should be investigated further in prospective studies.

CT-based image-guided brachytherapy in uterine cervical cancer: Effect of tumor dose and volume on local control.

BACKGROUND AND PURPOSE: To determine the optimal primary tumor dose for cervical cancer treatment using computed tomography (CT)-based image-guided brachytherapy (IGBT). MATERIALS AND METHODS: We retrospectively reviewed 171 patients with cervical cancer who underwent both external beam radiation therapy (EBRT) and IGBT between May 2015 and December 2019. Majority of EBRT plan included central shielding technique. CT-based IGBT was performed weekly a median of three times. Magnetic resonance imaging preceded the first and third session of IGBT for target delineation. RESULTS: The median age of the patients was 64 years (range: 30-91 years). The median follow-up time for living patients was 43 months (range: 6-76 months). The 3-year local control rates according to the International Federation of Gynecology and Obstetrics (FIGO, 2008) stages were 89%, 100%, 92%, 89%, 78%, and 100% for stages IB, IIA, IIB, IIIA, IIIB, and IVA, respectively. The median EBRT dose to the central pelvis and parametrium/pelvic wall was 41.4 Gy and 50.4 Gy, respectively. Patients who received a cumulative 2 Gy equivalent dose (EQD2) (α/ß = 10 Gy) of high-risk clinical target volume (HR CTV) D90% ≥ 75 Gy achieved a long-term local control rate of 93%, compared with 80% in those who received <75 Gy (p = 0.02). CONCLUSION: This is one of the largest CT-based IGBT series examining the treatment of cervical cancer based on the tumor dose-volume relationship. An HR CTV D90% ≥75 Gy was significantly associated with favorable local control in this study.

Long-term Outcomes from Proton Therapy for Sinonasal Cancers.

PURPOSE: To report long-term disease control, survival, and toxicity after proton therapy for sinonasal cancer. PATIENTS AND METHODS: We reviewed 143 cases of adults with nonmetastatic sinonasal cancers treated with primary (18%; n = 26) or adjuvant (82%; n = 117) proton therapy. The most common histologies were squamous cell carcinoma (29%; n = 42), olfactory neuroblastoma (23%; n = 33), and adenoid cystic carcinoma (16%; n = 23). Patients had predominantly advanced-stage disease (T3, 24%, n = 35; T4, 66%, n = 94) and high-grade histology (52%; n = 74). Surgery included endoscopic resection alone (50%) with craniotomy (10%) or open resection (40%), and 31% had gross disease present at radiotherapy. Most (91%) received high-dose (median, 73.6 Gy radiobiological equivalent [GyRBE]; 84% >70 GyRBE) passive-scatter proton therapy using accelerated hyperfractionation (1.2 GyRBE twice daily) and concurrent chemotherapy (70%). Univariate and multivariate models assessed prognostic factors. Grade 3+ toxicities were recorded per Common Terminology Criteria, version 4. Median follow-up was 3.4 years (range, 0.1-12.5 years) overall and 4.9 years (range, 0.9-12.5 years) for living patients. RESULTS: The 5-year outcomes were as follows: local control (LC), 80%; neck control, 96%; local-regional control, 78%; freedom from distant metastases, 71%; and disease-free survival, 62%; cause-specific survival, 64%; and overall survival, 59%. Surgery improved LC, but only with gross total resection (5-year LC 87% versus subtotal resection 62.9%, and biopsy alone 55% (P < 0.001). Gross residual disease was the only significant prognostic factor for local-regional control on multivariate analysis. High-grade, T4, and local recurrence were associated with decreased overall survival. Late (G3+) toxicity occurred in 22% (32 of 143), including central nervous system necrosis and vision loss in 6% (9 of 143) and 3.5% (5 of 143), respectively. CONCLUSION: Proton therapy after gross-total resection provides excellent long-term LC in patients with locally advanced, high-grade sinonasal cancer. Moreover, LC remains strongly associated with long-term survival. With gross disease, about 60% of patients had long-term LC with proton therapy and induction or concurrent chemotherapy.

Clinical PET/CT utilization during the COVID-19 pandemic: initial experience at Yale University.

OBJECTIVE: To determine temporal changes in PET/CT utilization during the COVID-19 pandemic and examine the impact of epidemiologic, demographic and oncologic factors on PET/CT utilization. METHODS: Clinical PET-CT utilization between 1 January 2020 and 15 June 2020 at a tertiary academic center was assessed using change-point-detection (CPD) analysis. COVID-19 epidemiologic trend was obtained from Connecticut Department of Public Health records. Demographic and oncologic data were gathered from electronic medical records and PET-CT scans by four reviewers in consensus. RESULTS: A total of 1685 cases were reviewed. CPD analysis identified five distinct phases of PET-CT utilization during COVID-19, with a sharp decline and a gradual recovery. There was a 62.5% decline in case volumes at the nadir. These changes correlated with COVID-19 epidemiologic changes in the state of Connecticut, with a negative correlation between COVID-19 cases and PET-CT utilization (τ = -0.54; P value < 0.001). Statistically significant differences in age, race, cancer type and current and prior scan positivity were observed in these five phases. A greater percentage of young patients and minorities were scanned during the pandemic relative to baseline. PET/CT scanning was less impacted for hematologic malignancies than for solid cancers, with less profound decline and better recovery. DISCUSSION: PET-CT cancer imaging was vulnerable to the COVID-19 pandemic at our institution. Epidemiologic, demographic and oncologic factors affected PET-CT utilization.

Outcomes of Stereotactic Radiosurgery and Immunotherapy in Renal Cell Carcinoma Patients With Brain Metastases.

OBJECTIVE: The impact of immunotherapy and stereotactic radiosurgery (SRS) in treatment of brain metastases (BM) from renal cell carcinoma (RCC) has not been well investigated. MATERIALS AND METHODS: Forty-eight patients with 372 RCC BM were treated with SRS and divided into those ever treated with immunotherapy versus those who never received immunotherapy. Survival and local control (LC) outcomes were studied. χ2 and Mann-Whitney U tests compared categorical and continuous variables, respectively. Kaplan-Meier curves were used to estimate survival and log-rank test was used to compare survival between groups. RESULTS: Immunotherapy and nonimmunotherapy groups contained 29 and 19 patients, respectively. Median follow-up was 23.1 months (range, 6 to 93.8 mo). Demographic and treatment variables were similar except median prescribed margin dose was significantly lower in immunotherapy group (20 vs. 22 Gy, P<0.0001). Median overall survival (OS) was 27.2 months (immunotherapy) and 14.9 months (nonimmunotherapy), P=0.14. Furthermore, patients treated with immune checkpoint inhibitor (ICI) had even better median OS compared with those who never received ICI (33 vs. 16.7 mo, P=0.03). Factors associated with improved LC were use of ICI (P=0.002) and lesion size <1000 mm3 (P=0.046). There was no difference in incidence of radiation necrosis between the 2 groups (P=0.67). CONCLUSIONS: Patients with RCC BM undergoing SRS can experience prolonged survival when treated with ICI. Equally effective LC of BM was achieved when treated with immunotherapy using a 2 Gy decrease in SRS dose without increasing the risk of central nervous system toxicity.

Re-evaluation of prophylactic cranial irradiation in limited-stage small cell lung cancer: a propensity score matched analysis.

We attempted to re-evaluate the efficacy of prophylactic cranial irradiation (PCI) in limited-stage small cell lung cancer (LS-SCLC) with more recent data. A total of 179 patients with LS-SCLC received radical thoracic radiotherapy and chemotherapy at our institution between 1998 and 2018. One hundred twenty-eight patients who achieved complete response (CR), good partial response (PR), and PR without progression for at least for one year after initial therapy were enrolled in this study. These patients were divided into a PCI group (group A, n = 43), and a non-PCI group (group B, n = 85). Survival outcomes were retrospectively evaluated. Because several background factors differed significantly between groups A and B, propensity score (PS) matching was performed as 1:1 match of the two groups. Finally, we analyzed 64 patients (group A/B = 32/32). Median follow-up periods were 53 and 31 months in groups A and B, respectively. There were no significant differences between the groups' backgrounds. Two-year overall survival (OS) rates were 77% in group A and 62% in group B (p = 0.224). Two-year brain metastasis free survival (BMFS) rates were 85% in group A and 57% in group B (p = 0.008). The number of patients who underwent a brain imaging test for confirmation of no brain metastasis (BM) after radical thoracic radiotherapy and chemotherapy (before PCI) was 84 (group A/B = 32/52). A PS matched analysis for cases of pre-PCI brain imaging group, two-year OS rates for group A/B were 73/59% (p = 0.446). Two-year BMFS rates for group A/B were 91/52% (p = 0.021). Retrospectively, PS matched analysis revealed that adding PCI to LS-SCLC patients who achieved good thoracic control significantly improved BMFS, but OS did not improve.

Treatment Outcomes After Proton Therapy for Ewing Sarcoma of the Pelvis.

PURPOSE: Ewing sarcoma of the pelvis is associated with inferior local control compared with those arising from other primary sites. Despite its increased use, outcome data for treatment with proton therapy remain limited. We report 3-year disease control and toxicity in pediatric patients treated with proton therapy. METHODS AND MATERIALS: Thirty-five patients aged ≤21 years (median, 14 years) with nonmetastatic pelvic Ewing sarcoma received proton therapy and chemotherapy between 2010 and 2018. Overall survival and tumor control rates were calculated using the Kaplan-Meier method. A log-rank test assessed significance between strata of prognostic factors. Significant toxicity was reported per the Common Terminology Criteria for Adverse Events, version 4.0. RESULTS: Most patients received definitive radiation (n = 26; median dose 55.8 Gy relative biological effectiveness [RBE]; range, 54.0-64.8), 7 received preoperative radiation (50.4 Gy RBE), and 2 received postoperative radiation (45 Gy RBE and 54 Gy RBE). The median primary tumor size was 10.5 cm. With a median follow-up of 3 years (range, 0.3-9.0 years), the 3-year overall survival, progression-free survival, and local control rates were 83% (95% confidence interval [CI], 65%-93%), 64% (95% CI, 45%-79%), and 92% (95% CI, 74%-98%), respectively. There was no association between local control, progression-free survival, or overall survival and tumor size, patient age, radiation dose, or definitive versus pre-/postoperative radiation therapy. Median time to progression was 1 year (range, 0.1-1.9 years). All patients with large tumors (≥8 cm) who underwent definitive proton therapy with a higher dose (≥59.4 Gy RBE) remained free from tumor recurrence (n = 5). Five patients experienced grade ≥2 subacute/late toxicity, all of whom were treated with combined surgery and radiation. CONCLUSIONS: Definitive proton therapy offers local control comparable to photon therapy in pediatric patients with pelvic Ewing sarcoma. These data lend preliminary support to radiation dose escalation without significant toxicity, which may contribute to the favorable outcomes. Combined surgery and radiation therapy, particularly preoperative radiation, is associated with postoperative complications, but not survival, compared with radiation alone.

Dose-Effect Analysis of Early Changes in Orbital Bone Morphology After Radiation Therapy for Rhabdomyosarcoma.

PURPOSE: In survivors of orbital embryonal rhabdomyosarcoma (ERMS), late effects include facial deformation and asymmetry. We sought to quantify orbital asymmetry in ERMS survivors and characterize the dose effect of radiation to the orbital bones. METHODS AND MATERIALS: We evaluated the most recent follow-up magnetic resonance imaging (MRI) in 17 children (≤21 years old) with stage 1 group III orbital ERMS treated with proton therapy between 2007 and 2018. For all patients, the orbital socket volumes were calculated and compared with the contralateral, unirradiated orbital socket. Patient age, orbital tumor quadrant, and the radiation dose delivered to the major orbital bones (maxillary, frontal, and zygomatic bones) were recorded and correlated with the orbital socket volume difference. RESULTS: The mean age at diagnosis was 5.4 years old (range, 1.1-9.7 years). All patients received a prescription dose of 45 GyRBE. The mean time interval between radiation and MRI was 2.9 years (range, 0.8-3.2 years). The mean age at most recent MRI was 8.4 years (range, 2.3-12.9 years). In 16 of 17 patients, the volume of the ipsilateral orbit was significantly smaller than the contralateral orbit on follow-up MRI (P ≤ .0001). In one patient with nonviable tumor in situ, the irradiated orbit was larger. The volume difference increased with follow-up time and did not correlate with age at treatment or age at MRI. A dose >40 GyRBE to all bones of the orbital rim was associated with a significant decrease in orbital volume (P < .05), but an isolated dose of >40 GyRBE to either the frontal, maxillary, or zygomatic bone was not. CONCLUSIONS: Despite the dosimetric precision of proton therapy, orbital asymmetry will develop after >40 GyRBE to multiple bones of the orbital rim. These data may be used to guide treatment planning and counsel patients on expected cosmesis.

Outcomes Following Proton Therapy for Group III Pelvic Rhabdomyosarcoma.

PURPOSE: This study aimed to report on the institutional outcomes after proton therapy for pelvic rhabdomyosarcoma (RMS). METHODS AND MATERIALS: Thirty-one children (≤21 years old) with group III pelvic RMS were enrolled on a prospective outcome study and treated between 2007 and 2018. Patients with vaginal/cervical RMS were excluded. The median age was 2.6 years. Twenty-four patients had embryonal RMS. At diagnosis, the median tumor volume was 185 cm3 and the median maximum diameter was 9.4 cm. Seven patients had N1 disease. Nineteen and 12 patients received European Pediatric Soft Tissue Sarcoma Study Group- and Children's Oncology Group-based chemotherapy, respectively. Fourteen patients underwent resection of the primary tumor after induction chemotherapy, including 6 patients who had a total cystectomy. The median radiation dose was 50.4 Gy relative biological effectiveness. RESULTS: With a median follow-up of 4.2 years, the 5-year local control, progression-free survival, and overall survival rates were 83%, 80%, and 84%, respectively. Patients <3 years old had better local control (100% vs 68%; P = .02), and patients with embryonal histology had better survival (96% vs 54%; P = .02). No other factors were significantly associated with disease control or survival. Specifically, no statistically significant difference was observed in local control, progression-free survival, or overall survival when comparing patients who underwent biopsy versus gross total resection (75% vs 93%, 68% vs 93%, 75% vs 93%, respectively). Excluding patients who underwent cystectomy, urinary toxicity was limited to 2 patients with nocturnal enuresis. Exploratory surgery to address a persistent mass or thickened bladder wall after radiation was the most common source of serious toxicity. CONCLUSIONS: This cohort of young children with large pelvic tumors treated with proton therapy demonstrates similar local control with less toxicity than historic reports. Functional bladder preservation is possible in most patients. Exploratory biopsy in the 18 months after radiation should be approached with caution.

Patterns of Failure in Parameningeal Alveolar Rhabdomyosarcoma.

PURPOSE: To determine patterns of failure, clinical outcomes, and prognostic factors among pediatric patients treated with radiation therapy for parameningeal alveolar rhabdomyosarcoma. METHODS AND MATERIALS: We evaluated clinical and treatment planning records of patients aged ≤21 years with parameningeal alveolar rhabdomyosarcoma treated with definitive or adjuvant radiation therapy at our institution. The Kaplan-Meier product limit method assessed disease control and survival; the log-rank test was used to evaluate prognostic impact. RESULTS: We identified 24 patients with a median age of 3.5 years (range, 1-20) treated between 2009 and 2016. The median follow-up was 2.4 years for all (range, 0.3-5.6) and 3.2 years for living patients (range, 0.7-5.6). Most patients had group III (96%), node-negative (67%), positive FOX fusion status (63%) disease, and intracranial extension (54%). The paranasal sinus was the most common subsite (29%). All patients were treated with concurrent chemotherapy and proton radiation therapy with a median dose of 50.4 Gy relative biological effectiveness (range, 41.4-59.4) at a median 13 weeks after induction chemotherapy (range, 3-25). The 3-year local control, regional control, disease-free survival, and overall survival rates were 66%, 94%, 40%, and 58%, respectively. Median time to any failure was 0.5 years (range, 0.2-2.1). N1 disease and intracranial extension (ICE) portended inferior overall survival (P = .002 and .02, respectively). Female sex portended better local control (P = .05). All 7 patients with distant metastases as the first site of recurrence had central nervous system metastases. Age <4 years, absence of ICE, N0 disease, and primary tumor <5 cm were associated with a statistically significant improvement in freedom from distant metastases. CONCLUSIONS: Although regional nodal failures were rare, in-field local recurrences and leptomeiningeal progression in those with ICE suggest the need for modification of local and central nervous system therapies.

Pattern of recurrence after CyberKnife stereotactic body radiotherapy for peripheral early non-small cell lung cancer.

BACKGROUND: The treatment efficacy after CyberKnife stereotactic body radiotherapy (SBRT) have not been adequately addressed. The purpose of this study was to investigate pattern of recurrence according to irradiation field after CyberKnife SBRT for early-stage non-small cell lung cancer (NSCLC). METHODS: This retrospective study included patients with peripheral cT1/2N0M0 NSCLC that was treated with SBRT using a CyberKnife between May 2013 and March 2016 at single institute and followed up by more than two imaging examinations. Both operable and inoperable patients were included. Overall survival (OS) and progression-free survival (PFS) curves were estimated using the Kaplan-Meier method with 95% confidence intervals (CI). Cumulative incidence curves of recurrence were calculated and compared using the Gray's test. RESULTS: Total 71 patients were included and analyzed in this study. The median follow-up period for surviving patients was 34 months (range, 7-64 months). The 2-year OS and PFS rate were 93% (95% CI: 83-97%) and 77% (95% CI: 65-86%), respectively. The 2-year cumulative incidence rate of infield recurrence and out-of-field recurrence were 6% (95% CI: 2-14%) and 17% (95% CI: 9-27%), respectively. Gross tumor volume (GTV) ≥9 mL and diagnosis-to-treatment interval (DTI) ≥90 days were significantly associated with infield recurrence (P<0.001 and P=0.007), and epidermal growth factor receptor (EGFR) mutation was significantly associated with out-of-field recurrence (P=0.014). CONCLUSIONS: Treatment efficacy after CyberKnife SBRT for peripheral early-stage NSCLC was identical to previous conventional linac-based SBRT reports. With short follow-up period, it was found that GTV and DTI were the significant predictive factor of infield recurrence, and EGFR mutation was the significant predictive factor of out-of-field recurrence.

Outcomes Following Proton Therapy for Pediatric Low-Grade Glioma.

PURPOSE: Dosimetric studies show that proton therapy can reduce the low/intermediate radiation dose to uninvolved tissue in children with low-grade glioma (LGG). For this reason, LGG is the fourth most common pediatric tumor treated with proton therapy, yet clinical outcome data on efficacy and toxicity are limited. METHODS AND MATERIALS: We reviewed the medical records of 174 children (≤21 years old) with nonmetastatic LGG enrolled on a prospective protocol and treated with proton therapy between 2007 and 2017. We assessed clinical outcomes and toxicity and analyzed patient, tumor, and treatment-related variables. RESULTS: The median age was 10.2 years (range, 2-21). Fifty-eight percent of tumors were World Health Organization grade 1 and 30% were grade 2; 12% were diagnosed on imaging characteristics alone. The most common histology was pilocytic astrocytoma (47%). The most common tumor subsites were diencephalon/optic pathway (52%), caudal brainstem (16%), and cerebellum (13%). Forty-two percent received chemotherapy before radiation therapy. The median follow-up was 4.4 years. The 5-year actuarial rates of local control, progression-free survival, and overall survival were 85% (95% confidence interval [CI], 78%-90%), 84% (95% CI, 77%-89%), and 92% (95% CI, 85%-95%), respectively. On univariate analysis, brainstem/spinal cord tumor location (62% vs 90% elsewhere) and dose <54 GyRBE (67% vs 91% for 54 GyRBE) were associated with inferior local control (P < .01 for both). Twenty-two patients (12.6%) experienced acute nausea or vomiting requiring ondansetron; 2 patients (1.1%) required corticosteroids. Serious toxicities (4% of patients) included brainstem necrosis requiring corticosteroids (n = 2), symptomatic vasculopathy (n = 2), radiation retinopathy (n = 1), epilepsy (n = 1), and death from radiation-induced high-grade glioma (n = 1). Thirty-nine patients (22%) developed new-onset central hormone deficiency. Pseudoprogression was observed in 32.1%. CONCLUSIONS: Compared with modern photon series, proton therapy reduces the radiation dose to developing brain tissue, diminishing acute toxicities without compromising disease control.