Radiotherapy for Atypical Teratoid/Rhabdoid Tumor (ATRT) on the Pediatric Proton/Photon Consortium Registry (PPCR).

PURPOSE: Atypical teratoid/rhabdoid tumors (ATRT) of the central nervous system (CNS) are rare tumors with a poor prognosis and variable use of either focal or craniospinal (CSI) radiotherapy (RT). Outcomes on the prospective Pediatric Proton/Photon Consortium Registry (PPCR) were evaluated according to RT delivered. METHODS: Pediatric patients receiving RT were prospectively enrolled on PPCR to collect initial patient, disease, and treatment factors as well as provide follow-up for patient outcomes. All ATRT patients with evaluable data were included. Kaplan-Meier analyses with log-rank p-values and cox proportional hazards regression were performed. RESULTS: The PPCR ATRT cohort includes 68 evaluable ATRT patients (median age 2.6 years, range 0.71-15.40) from 2012 to 2021. Median follow-up was 40.8 months (range 3.4-107.7). Treatment included surgery (65% initial gross total resection or GTR), chemotherapy (60% with myeloablative therapy including stem cell rescue) and RT. For patients with M0 stage (n = 60), 50 (83%) had focal RT and 10 (17%) had CSI. Among patients with M + stage (n = 8), 3 had focal RT and 5 had CSI. Four-year overall survival (OS, n = 68) was 56% with no differences observed between M0 and M + stage patients (p = 0.848). Local Control (LC) at 4 years did not show a difference for lower primary dose (50-53.9 Gy) compared to ≥ 54 Gy (73.3% vs 74.7%, p = 0.83). For patients with M0 disease, four-year OS for focal RT was 54.6% and for CSI was 60% (Hazard Ratio 1.04, p = 0.95. Four-year event free survival (EFS) among M0 patients for focal RT was 45.6% and for CSI was 60% (Hazard Ratio 0.71, p = 0.519). For all patients, the 4-year OS comparing focal RT with CSI was 54.4% vs 60% respectively (p = 0.944), and the 4-year EFS for focal RT or CSI was 42.8% vs 51.4% respectively (p = 0.610). CONCLUSION: The PPCR ATRT cohort found no differences in outcomes according to receipt of either higher primary dose or larger RT field (CSI). However, most patients were M0 and received focal RT. A lower primary dose (50.4 Gy), regardless of patient age, is appealing for further study as part of multi-modality therapy.

Palliative radiotherapy for children: Symptom response and treatment-associated toxicity according to radiation therapy dose and fractionation.

BACKGROUND/OBJECTIVES: Radiotherapy is an effective palliative treatment in advanced cancer. Shorter palliative treatment courses are recommended for adults, though pediatric data addressing treatment efficacy and toxicity according to radiation therapy (RT) dose and fractionation are limited. DESIGN/METHODS: Total 213 patients aged 21 years or younger receiving 422 palliative radiotherapy treatment courses from 2003 to 2016 were included. Symptom response and treatment-associated toxicity were recorded and analyzed in relationship to demographic and treatment variables. RESULTS: Common diagnoses included sarcoma (32.5%), neuroblastoma (24.9%), leukemia/lymphoma (14.9%), and central nervous system tumors (10.9%). The most common indication for treatment was pain (46.7%). Patients received a median of 10 fractions, 2.5 Gy dose per fraction, and 21 Gy total dose. Number of RT fractions was five or less in 166 (39.3%), six to 10 fractions in 117 (27.2%), and 10 or more fractions in 139 (32.9%) of courses. Complete or partial pain relief was achieved in 85% (151 of 178 evaluable patients), including 77.8% receiving five or less fractions and 89.6% receiving more than five fractions. Highest toxicity was grade 1 in 159 (38.9%), grade 2 in 26 (6.4%), and grade 3 in two (0.5%) treatments. On multivariable analysis, RT delivered 30 or more days from death (OR 12.13, 95% CI: 2.13-69.2, p = .005) and no adjuvant chemotherapy (OR 0.14, 95% CI: 0.03-0.54, p = .005) were significantly associated with pain response, and five or less fractions were significantly associated with lower toxicity (OR 0.24, 95% CI: 0.06-0.97, p = .045). CONCLUSIONS: Palliative RT courses of five or less fractions result in high rates of pain control and are associated with low toxicity in pediatric patients with cancer.

Intellectual functioning among case-matched cohorts of children treated with proton or photon radiation for standard-risk medulloblastoma.

BACKGROUND: Proton therapy may reduce cognitive deficits after radiotherapy among brain tumor survivors, although current data are limited to retrospective comparisons between historical cohorts. The authors compared intelligence quotient scores within a case-matched cohort of children with medulloblastoma treated with proton radiation (PRT) or photon radiation (XRT) over the same time period. METHODS: Among 88 consecutive patients with standard-risk medulloblastoma treated with PRT or XRT at 2 institutions from 2000 to 2009, 50 were matched 1:1 (25 with PRT and 25 with XRT) according to age, gender, date of diagnosis, histology, radiation boost, and craniospinal irradiation dose. One-way analyses of variance were performed to compare the Full-Scale Intelligence Quotient (FSIQ) and associated index scores between the 2 cohorts. RESULTS: Neurocognitive data were available for 37 survivors (17 with PRT and 20 with XRT) from the matched cohort. The mean age was 8.5 years (SD, 4.14 years). The median follow-up was 5.3 years (range, 1.0-11.4 years) and 4.6 years (range, 1.1-11.2 years) for the PRT and XRT cohorts, respectively (P = .193). Patients treated with PRT had significantly higher mean FSIQ (99.6 vs 86.2; P = .021), verbal (105.2 vs 88.6; P = .010), and nonverbal scores (103.1 vs 88.9; P = .011) than the XRT-treated cohort. Differences in processing speed (82.9 vs 77.2; P = .331) and working memory (97.0 vs 92.7; P = .388) were not statistically significant. CONCLUSIONS: Radiotherapy-associated cognitive effects appear to be more attenuated after proton therapy. Comprehensive prospective studies are needed to appropriately evaluate the neurocognitive advantages of proton therapy.

Osteosarcoma.

Osteosarcoma is a rare tumor that requires complex multidisciplinary management. This paper reviews the general management and standard radiotherapy guidelines for osteosarcoma in both North America and Europe in a joined effort between the Children's Oncology Group and International Society of Pediatric Oncology. Standard treatment involves multiagent induction chemotherapy followed by surgical resection for local tumor control and consolidation local control to metastatic sites. Radiotherapy is reserved for cases with a marginal or incomplete resection or for definitive treatment in the case of unresectable disease. We present supporting data for the role of chemotherapy, surgery, and radiation therapy.

Adjuvant chemoradiation for high-grade cardiac leiomyosarcoma in a child: Case report and review of literature.

A 13-year-old healthy girl presented with dizziness and palpitations, found to have a left atrial mass. An 8-cm tumor was removed en bloc. Pathology confirmed grade 3 leiomyosarcoma with multifocal positive margins. She received adjuvant ifosfamide and doxorubicin, followed by concurrent proton radiotherapy and ifosfamide. Radiotherapy included 66 Gy (RBE) in 33 fractions to the operative bed. Prospectively graded toxicities included Grade 2 esophagitis and Grade 1 anorexia, dermatitis, and fatigue. She completed six cycles of ifosfamide. Two years post operation, she had no evidence of disease, intermittent palpitations with normal cardiac function, and no other cardiopulmonary or esophageal symptoms.

Ewing sarcoma.

Ewing sarcoma is a rare tumor that requires complex multidisciplinary management. This report describes the general management and standard radiotherapy guidelines in both North America (Children's Oncology Group) and Europe (International Society of Pediatric Oncology). Standard treatment involves multiagent induction chemotherapy followed by local treatment with surgery, definitive radiation, or a combination of surgery and radiation followed by additional chemotherapy and consolidation local treatment to metastatic sites. The data supporting the role of chemotherapy, surgery, and radiation and specific radiation therapy guidelines are presented.

Optimal timing of chemoradiotherapy after surgical resection of glioblastoma: Stratification by validated prognostic classification.

BACKGROUND: Previous studies examining the time to initiate chemoradiation (CRT) after surgical resection of glioblastoma have been conflicting. To better define the effect that the timing of adjuvant treatment may have on outcomes, the authors examined patients within the National Cancer Database (NCDB) stratified by a validated prognostic classification system. METHODS: Patients with glioblastoma in the NCDB who underwent surgery and CRT from 2004 through 2013 were analyzed. Radiation Therapy Oncology Group recursive partitioning analysis (RPA) class (III, IV, V) was extrapolated for the cohort. Time intervals were grouped weekly, with weeks 4 to 5 serving as the reference category for analyses. Kaplan-Meier analysis, log-rank testing, and multivariate (MVA) Cox proportional hazards regression were performed. RESULTS: In total, 30,414 patients were included. RPA classes III, IV, and V contained 5250, 20,855, and 4309 patients, respectively. On MVA, no time point after week 5 was associated with a change in overall survival for the entire cohort or for any RPA class subgroup. The periods of weeks 0 to 1 (hazard ratio [HR], 1.18; 95% CI, 1.02-1.36), >1 to 2 (HR, 1.23; 95% CI, 1.16-1.31), and >2 to 3 (HR, 1.11; 95% CI, 1.07-1.15) demonstrated slightly worse overall survival (all P < .03). The detriment to early initiation was consistent across each RPA class subgroup. CONCLUSIONS: The current data provide insight into the optimal timing of CRT in patients with glioblastoma and describe RPA class-specific outcomes. In general, short delays beyond 5 weeks did not negatively affect outcomes, whereas early initiation before 3 weeks may be detrimental.

Outcomes of whole-brain radiation with simultaneous in-field boost (SIB) for the treatment of brain metastases.

PURPOSE: Prospective studies have demonstrated increased local control with the addition of a radiosurgery (SRS) boost to whole-brain irradiation (WBRT) in patients with brain metastases. However, the clinical application of SRS boost can be limited by several factors, including tumor size, numbers of lesions, and high cost of care. Here, we investigate the use of WBRT with a simultaneous integrated boost (SIB) to visible lesions in patients with brain metastases. MATERIALS: From 2011 to 2016, patients were prospectively enrolled and prescribed a dose of 25 or 37.5 Gray (Gy) WBRT with a SIB dose of 45 or 52.5 Gy to the gross lesions in 10 or 15 fractions, respectively. All plans were optimized for dose coverage of the whole brain and lesions using volumetric arc therapy (VMAT). Comprehensive neurocognitive and quality of life assessments were conducted at baseline and at follow-up. RESULTS: Thirteen patients were treated on this protocol. The 1-year local control rates were 92% at the patient level, and 98.6% at the lesion level. The overall 1-year intracranial control was 46%. Patients had no significant declines in Mini-Mental State Examination (MMSE), Hopkins Verbal Learning Test-Revised (HVLT-R), and Medical Outcomes Study (MOS) Cognitive Functional status scores pre- and post-treatment. CONCLUSION: WBRT with SIB to gross lesions using VMAT planning appears to be safe and effective in the treatment of brain metastases without significant cognitive decline. This treatment strategy should be considered in those patients with a high number of metastases or ones not amenable for radiosurgery. CLINICAL TRIAL REGISTRATION CODE: NCT01218542.

Reduced-volume tumor-bed boost is not associated with inferior local control and survival outcomes in high-risk medulloblastoma.

BACKGROUND: Radiotherapy boost to the entire posterior fossa (PF) is standard of care for high-risk (H-R) medulloblastoma patients; the utility of tumor bed (TB)-only boost is unclear. The purpose of this study was to examine the impact of PF versus TB boost volume on tumor control and survival in the H-R medulloblastoma population. METHODS: Single-institution records for patients with H-R medulloblastoma were reviewed. The median craniospinal irradiation dose was 36 Gy (range, 23.4-45 Gy), and boost doses to either PF or TB were 54 to 55.8 Gy. PF (local) failures were scored as in-field, marginal (between 80% and 95% isodose lines), or distant. Kaplan-Meier methods and Cox proportional hazards were used to assess the impact of radiation boost technique on local control (LC) and survival endpoints. RESULTS: Thirty-two patients with H-R medulloblastoma were treated between 1990 and 2015, with a median follow-up length of 5.12 years. Twenty-two patients received PF boost, and 10 received TB boost. Patient and disease characteristic were comparable between groups. A total of 11 PF failures occurred, including 3 isolated LFs (2 in the PF and 1 in the TB group). Most PF failures were in-field: three of four in the TB group and six of seven in the PF group; the remainder were marginal failures. TB boost was not associated with inferior LC (hazard ratio [HR] 0.86, log-rank P = 0.81) or overall survival (HR 1.40, P = 0.56) compared with PF boost. CONCLUSION: Reduced-volume radiotherapy boost to the TB does not appear to compromise LC or survival in patients with H-R medulloblastoma; it may reduce the risk of ototoxicity.

Is less more? Comparing chemotherapy alone with chemotherapy and radiation for high-risk grade 2 glioma: An analysis of the National Cancer Data Base.

BACKGROUND: The addition of chemotherapy to adjuvant radiotherapy (chemotherapy and radiation therapy [CRT]) improves overall survival (OS) for patients with high-risk grade 2 gliomas; however, the impact of chemotherapy alone (CA) is unknown. This study compares the OS of patients with high-risk grade 2 gliomas treated with CA versus CRT. METHODS: Patients with high-risk grade 2 gliomas (subtotal resection or age ≥ 40 years) with oligodendrogliomas, astrocytomas, or mixed tumors were identified with the National Cancer Data Base. Patients were grouped into CA and CRT cohorts. Univariate analyses and multivariate analyses (MVAs) were performed. Propensity score (PS) matching was also implemented. The Kaplan-Meier method was used to analyze OS. RESULTS: A total of 1054 patients with high-risk grade 2 gliomas were identified: 496 (47.1%) received CA, and 558 (52.9%) received CRT. Patients treated with CA were more likely (all P values < .05) to have oligodendroglioma histology (65.5% vs 34.2%), exhibit a 1p/19q codeletion (22.8% vs 7.5%), be younger (median age, 47.0 vs 48.0 years), and receive treatment at an academic facility (65.2% vs 50.3%). The treatment type was not a significant predictor for OS (P = .125) according to the MVA; a tumor size > 6 cm, astrocytoma histology, and older age were predictors for worse OS (all P values < .05). After 1:1 PS matching (n = 331 for each cohort), no OS difference was seen (P = .696) between the CA and CRT cohorts at 5 (69.3% vs 67.4%) and 8 years (52.8% vs 56.7%). CONCLUSIONS: No long-term OS difference was seen in patients with high-risk grade 2 gliomas treated with CA versus CRT. These findings are hypothesis-generating, and prospective clinical trials comparing these treatment paradigms are warranted. Cancer 2018;124:1169-78. © 2017 American Cancer Society.

Long-term toxic effects of proton radiotherapy for paediatric medulloblastoma: a phase 2 single-arm study.

BACKGROUND: Compared with traditional photon radiotherapy, proton radiotherapy irradiates less normal tissue and might improve health outcomes associated with photon radiotherapy by reducing toxic effects to normal tissue. We did a trial to assess late complications, acute side-effects, and survival associated with proton radiotherapy in children with medulloblastoma. METHODS: In this non-randomised, open-label, single-centre, phase 2 trial, we enrolled patients aged 3-21 years who had medulloblastoma. Patients had craniospinal irradiation of 18-36 Gy radiobiological equivalents (GyRBE) delivered at 1·8 GyRBE per fraction followed by a boost dose. The primary outcome was cumulative incidence of ototoxicity at 3 years, graded with the Pediatric Oncology Group ototoxicity scale (0-4), in the intention-to-treat population. Secondary outcomes were neuroendocrine toxic effects and neurocognitive toxic effects, assessed by intention-to-treat. This study is registered at ClinicalTrials.gov, number NCT00105560. FINDINGS: We enrolled 59 patients from May 20, 2003, to Dec 10, 2009: 39 with standard-risk disease, six with intermediate-risk disease, and 14 with high-risk disease. 59 patients received chemotherapy. Median follow-up of survivors was 7·0 years (IQR 5·2-8·6). All patients received the intended doses of proton radiotherapy. The median craniospinal irradiation dose was 23·4 GyRBE (IQR 23·4-27·0) and median boost dose was 54·0 GyRBE (IQR 54·0-54·0). Four (9%) of 45 evaluable patients had grade 3-4 ototoxicity according to Pediatric Oncology Group ototoxicity scale in both ears at follow-up, and three (7%) of 45 patients developed grade 3-4 ototoxicity in one ear, although one later reverted to grade 2. The cumulative incidence of grade 3-4 hearing loss at 3 years was 12% (95% CI 4-25). At 5 years, it was 16% (95% CI 6-29). Pediatric Oncology Group hearing ototoxicity score at a follow-up of 5·0 years (IQR 2·9-6·4) was the same as at baseline or improved by 1 point in 34 (35%) of 98 ears, worsened by 1 point in 21 (21%), worsened by 2 points in 35 (36%), worsened by 3 points in six (6%), and worsened by 4 points in two (2%). Full Scale Intelligence Quotient decreased by 1·5 points (95% CI 0·9-2·1) per year after median follow-up up of 5·2 years (IQR 2·6-6·4), driven by decrements in processing speed and verbal comprehension index. Perceptual reasoning index and working memory did not change significantly. Cumulative incidence of any neuroendocrine deficit at 5 years was 55% (95% CI 41-67), with growth hormone deficit being most common. We recorded no cardiac, pulmonary, or gastrointestinal late toxic effects. 3-year progression-free survival was 83% (95% CI 71-90) for all patients. In post-hoc analyses, 5-year progression-free survival was 80% (95% CI 67-88) and 5-year overall survival was 83% (95% CI 70-90). INTERPRETATION: Proton radiotherapy resulted in acceptable toxicity and had similar survival outcomes to those noted with conventional radiotherapy, suggesting that the use of the treatment may be an alternative to photon-based treatments. FUNDING: US National Cancer Institute and Massachusetts General Hospital.

Benefit of adjuvant radiotherapy after breast-conserving therapy among elderly women with T1-T2N0 estrogen receptor-negative breast cancer.

BACKGROUND: The purpose of the current study was to evaluate the impact of radiotherapy (RT) among women aged ≥ 70 years with T1-2N0 estrogen receptor (ER)-negative breast cancer using Surveillance, Epidemiology, and End Results (SEER)-Medicare-linked data. METHODS: The study included 3432 women, 2850 of whom received and 582 of whom did not receive RT after breast-conserving surgery. Outcomes were estimated by the cumulative incidence method and compared with the Gray test. The Fine and Gray subdistribution hazard regression models were used to assess the impact of RT and other variables. RESULTS: Women who received RT were more commonly aged <75 years (42% vs 16%), had T1 tumors (78% vs 65%), ductal carcinoma histology (91% vs 88%), a Charlson-Deyo Comorbidity Index of 0 (41% vs 25%), and had received chemotherapy (29% vs 12%). The 5-year cumulative incidence of mastectomy and breast cancer-specific death for patients who received versus those did not receive adjuvant RT was 4.9% and 8.3% versus 10.8% and 24.1%, respectively (P<.001). On multivariable analysis, the omission of RT was found to be an independent predictor of an increased risk of mastectomy (hazard ratio, 2.33; 95% confidence interval, 1.56-3.49). Among women aged ≥ 80 years or with T1N0 tumors, the mastectomy incidence with or without receipt of RT was 3.4% vs. 6.9%, and 5.3% vs 7.7%, respectively. CONCLUSIONS: The use of adjuvant RT after breast-conserving surgery in older women with T1-2N0 estrogen receptor-negative breast cancer is associated with a reduced incidence of future mastectomy and breast cancer death. The magnitude of benefit may be small for women aged ≥80 years or those with T1 tumors. Cancer 2016;122:3059-3068. © 2016 American Cancer Society.

Hypofractionated radiosurgery has a better safety profile than single fraction radiosurgery for large resected brain metastases.

The purpose of this study is to compare the safety and efficacy of single fraction radiosurgery (SFR) with hypofractionated radiosurgery (HR) for the adjuvant treatment of large, surgically resected brain metastases. Seventy-five patients with 76 resection cavities ≥ 3 cm received 15 Gray (Gy) × 1 SFR (n = 40) or 5-8 Gy × 3-5 HR (n = 36). Cumulative incidence of local failure (LF) and radiation necrosis (RN) was estimated accounting for death as a competing risk and compared with Gray's test. The effect of multiple covariates was evaluated with the Fine-Gray proportional hazards model. The most common HR dose-fractionation schedules were 6 Gy × 5 (44%), 7-8 Gy × 3 (36%), and 6 Gy × 4 (8%). The median follow-up was 11 months (range 2-71). HR patients had larger median resection cavity volumes (24.0 vs. 13.3 cc, p < 0.001), planning target volumes (PTV) (37.7 vs. 20.5 cc, p < 0.001), and cavity to PTV expansion margins (2 vs. 1.5 mm, p = 0.002) than SFR patients. Cumulative incidence of LF (95% CI) at 6 and 12-months for HR versus SFR was 18.9% (0.07-0.34) versus 15.9% (0.06-0.29), and 25.6% (0.12-0.42) versus 27.2% (0.14-0.42), p = 0.80. Cumulative incidence of RN (95% CI) at 6 and 12 months for HR vs. SFR was 3.3% (0.00-0.15) versus 10.7% (0.03-0.23), and 10.3% (0.02-0.25) versus 19.2% (0.08-0.34), p = 0.28. On multivariable analysis, SFR was significantly associated with an increased risk of RN, with a HR of 3.81 (95% CI 1.04-13.93, p = 0.043). Hypofractionated radiosurgery may be the more favorable treatment approach for radiosurgery of cavities 3-4 cm in size and greater.

Local recurrence patterns in breast cancer patients treated with oncoplastic reduction mammaplasty and radiotherapy.

BACKGROUND: The purpose of this study was to describe the incidence and location of ipsilateral breast tumor recurrence (IBTR) among breast cancer patients treated with oncoplastic reduction mammoplasty (ORM) and radiotherapy (RT). METHODS: The medical records of 86 consecutive women with ductal carcinoma in situ (DCIS) (n = 11) or invasive carcinoma of the breast (n = 75) treated with ORM at Emory University between January 1994 and December 2010 were reviewed. RESULTS: Following ORM, prolonged wound healing or surgical complications led to delay of adjuvant chemotherapy or RT in 11 patients. Surgical clips were found outside the primary tumor breast quadrant in 43 % of the patients with available RT planning CT images. When the clips were found outside the primary tumor quadrant, the RT boost was more frequently delivered outside versus inside the primary tumor quadrant (67 vs. 33 %, p < 0.001). After a median follow-up period of 4.5 years (range 0.1-17.9), 6 patients developed an IBTR and only 1 IBTR occurred outside the primary tumor quadrant. The 5-year ipsilateral breast tumor control rates were 91 % (95 % CI 0.82-0.99) and 93 % (95 % CI 0.90-0.97) for patients with DCIS and invasive carcinoma, respectively. CONCLUSIONS: The use of ORM yields acceptable rates of IBTR. ORM may displace breast tissue and surgical clips to breast quadrants outside of the original tumor location, but the majority of IBTRs still occur in the original tumor quadrant. This area remains at highest risk of in-breast recurrence in women treated with ORM irrespective of surgical clip location.

Quantitative dosimetry for yttrium-90 radionuclide therapy: tumor dose predicts fluorodeoxyglucose positron emission tomography response in hepatic metastatic melanoma.

PURPOSE: To assess a new method for generating patient-specific volumetric dose calculations and analyze the relationship between tumor dose and positron emission tomography (PET) response after radioembolization of hepatic melanoma metastases. METHODS AND MATERIALS: Yttrium-90 ((90)Y) bremsstrahlung single photon emission computed tomography (SPECT)/computed tomography (CT) acquired after (90)Y radioembolization was convolved with published (90)Y Monte Carlo estimated dose deposition kernels to create a three-dimensional dose distribution. Dose-volume histograms were calculated for tumor volumes manually defined from magnetic resonance imaging or PET/CT imaging. Tumor response was assessed by absolute reduction in maximum standardized uptake value (SUV(max)) and total lesion glycolysis (TLG). RESULTS: Seven patients with 30 tumors treated with (90)Y for hepatic metastatic melanoma with available (90)Y SPECT/CT and PET/CT before and after treatment were identified for analysis. The median (range) for minimum, mean, and maximum dose per tumor volume was 16.9 Gy (5.7-43.5 Gy), 28.6 Gy (13.8-65.6 Gy) and 36.6 Gy (20-124 Gy), respectively. Response was assessed by fluorodeoxyglucose PET/CT at a median time after treatment of 2.8 months (range, 1.2-7.9 months). Mean tumor dose (P = .03) and the percentage of tumor volume receiving ≥ 50 Gy (P < .01) significantly predicted for decrease in tumor SUV(max), whereas maximum tumor dose predicted for decrease in tumor TLG (P < .01). CONCLUSIONS: Volumetric dose calculations showed a statistically significant association with metabolic tumor response. The significant dose-response relationship points to the clinical utility of patient-specific absorbed dose calculations for radionuclide therapy.

Primary Diffuse Leptomeningeal Melanomatosis in a Child with Extracranial Metastasis: Case Report.

Primary meningeal melanomatosis is an extremely rare tumor with very few documented responses to treatment. A 3-year-old male with a complex past medical history, including prematurity and shunted hydrocephalus, was diagnosed with primary meningeal melanomatosis with peritoneal implants. Molecular testing revealed an NRAS Q61R mutation. The patient received proton craniospinal radiation followed by immunotherapy with nivolumab (1 mg/kg) and ipilimumab (3 mg/kg) IV every 3 weeks and, upon progression, he was switched to a higher dose of nivolumab (3 mg/kg IV every 2 weeks) and binimetinib (24 mg/m2/dose, twice a day). The patient had significant improvement of CNS disease with radiation therapy and initial immunotherapy but progression of extracranial metastatic peritoneal and abdominal disease. Radiation was not administered to the whole abdomen. After two cycles of nivolumab and treatment with the MEK inhibitor binimetinib, he had radiographic and clinical improvement in abdominal metastasis and ascitis. He ultimately died from RSV infection, Klebsiella sepsis, and subdural hemorrhage without evidence of tumor progression. This is the first report of a child with primary meningeal melanomatosis with extracranial metastatic disease with response to a combination of radiation, immunotherapy and MEK inhibitor therapy.

Initial experience and patient tolerance of proton stereotactic body radiotherapy.

Purpose: To review our initial experience with proton-based SBRT to evaluate the planning outcomes and initial patient tolerance of treatment. Patients and methods: From Sep. 2019 to Dec. 2020, 52 patients were treated with proton SBRT to 62 lesions. Fractionation varied by indication and site with a median of 5 fractions and median fractional dose of 8 Gy. Planning outcomes, including plan heterogeneity, conformity, and PTV volume receiving 100% of the prescription dose (PTV V100%) were evaluated. Acute toxicities were prospectively recorded, and patient reported outcomes were assessed prior to and at completion of treatment using the MD Anderson Symptom Inventory (MDASI) and EQ-5D5L visual analogue score (VAS). Results: All treated patients completed their course of proton-based SBRT. The mean conformity index was 1.05 (range 0.51-1.48). R50% values were comparable to ideal photon parameters. PTV V100% was 89.9% on average (40.44% - 99.76%). 5 patients (10%) required plan modification due to setup or tumor changes. No patients developed a new grade 3 or greater toxicity during treatment. Comparing pretreatment to end of treatment timepoints, there was a significant improvement in the mean VAS (65 to 75, p = 0.014), with no significant change in the mean MDASI symptom (1.7, 1.8; p = 0.79) or interference (2.3, 2.4; p = 0.452) scores. Conclusion: Proton-based SBRT can achieve dosimetric goals required by major clinical photon trials. It was well-tolerated with no decrement in patient reported outcomes and a mean 10-point improvement in VAS at the conclusion of SBRT. Further follow-up is necessary for tumor control and late effects analysis.

Indoximod-based chemo-immunotherapy for pediatric brain tumors: A first-in-children phase I trial.

BACKGROUND: Recurrent brain tumors are the leading cause of cancer death in children. Indoleamine 2,3-dioxygenase (IDO) is a targetable metabolic checkpoint that, in preclinical models, inhibits anti-tumor immunity following chemotherapy. METHODS: We conducted a phase I trial (NCT02502708) of the oral IDO-pathway inhibitor indoximod in children with recurrent brain tumors or newly diagnosed diffuse intrinsic pontine glioma (DIPG). Separate dose-finding arms were performed for indoximod in combination with oral temozolomide (200 mg/m2/day x 5 days in 28-day cycles), or with palliative conformal radiation. Blood samples were collected at baseline and monthly for single-cell RNA-sequencing with paired single-cell T cell receptor sequencing. RESULTS: Eighty-one patients were treated with indoximod-based combination therapy. Median follow-up was 52 months (range 39-77 months). Maximum tolerated dose was not reached, and the pediatric dose of indoximod was determined as 19.2 mg/kg/dose, twice daily. Median overall survival was 13.3 months (n = 68, range 0.2-62.7) for all patients with recurrent disease and 14.4 months (n = 13, range 4.7-29.7) for DIPG. The subset of n = 26 patients who showed evidence of objective response (even a partial or mixed response) had over 3-fold longer median OS (25.2 months, range 5.4-61.9, p = 0.006) compared to n = 37 nonresponders (7.3 months, range 0.2-62.7). Four patients remain free of active disease longer than 36 months. Single-cell sequencing confirmed emergence of new circulating CD8 T cell clonotypes with late effector phenotype. CONCLUSIONS: Indoximod was well tolerated and could be safely combined with chemotherapy and radiation. Encouraging preliminary evidence of efficacy supports advancing to Phase II/III trials for pediatric brain tumors.

Radiation therapy target volume reduction in pediatric rhabdomyosarcoma: implications for patterns of disease recurrence and overall survival.

BACKGROUND: The use of radiation therapy (RT) "cone-down" boost to reduce high-dose treatment volumes according to tumor response to induction chemotherapy in patients with pediatric rhabdomyosarcoma (RMS) may reduce treatment morbidity, yet the impact on tumor control is unknown. METHODS: Fifty-five children, including 18 (33%) with parameningeal (PM) RMS and 37 (67%) with non-PM RMS, who received definitive treatment with chemotherapy and RT from April 2000 through January 2010 were retrospectively reviewed. RESULTS: In total, 28 patients (51%) received a cone-down boost. The high-dose boost volume was reduced by a median of 56% of the initial target volume (range, 5%-91%). The median time to initiating RT was 3 weeks for patients with PM RMS and 16 weeks for patients with non-PM RMS (P < .001). After a median follow-up of 41 months, local failure occurred in 5 patients (9%), including 2 patients who received a cone-down boost, and there were no marginal failures. Twelve patients (67%) with PM RMS had intracranial tumor extension. In this subgroup, 4 patients (30%) who received a cone-down boost and had ≥ 3 weeks between chemotherapy and RT initiation experienced leptomeningeal failure as their first site of disease progression, and a delayed time to RT initiation was associated with decreased survival (P = .055) CONCLUSIONS: A cone-down boost allowed for significant reductions in high-dose RT treatment volume while maintaining excellent tumor control in most patients. However, in the subset of patients with PM RMS and intracranial tumor extension, early RT initiation and wider margin RT to cover adjacent areas at high risk for meningeal extension may be more important for adequate disease control.