The NIH pediatric/young adult chordoma clinic and natural history study: Making advances in a very rare tumor.

BACKGROUND: Chordomas are rare tumors arising from the skull base and spine, with approximately 20 pediatric chordoma cases in the Unitedn States per year. The natural history and optimal treatment of pediatric chordomas, especially poorly differentiated and dedifferentiated subtypes, is incompletely understood. Herein, we present findings from our first National Cancer Institute (NCI) chordoma clinic and a retrospective analysis of published cases of pediatric poorly differentiated chordomas (PDC) and dedifferentiated chordomas (DC). METHODS: Patients less than 40 years old with chordoma were enrolled on the NCI Natural History and Biospecimens Acquisitions Study for Children and Adults with Rare Solid Tumors protocol (NCT03739827). Chordoma experts reviewed patient records, evaluated patients, and provided treatment recommendations. Patient-reported outcomes, biospecimens, and volumetric tumor analyses were collected. A literature review for pediatric PDC and DC was conducted. RESULTS: Twelve patients (median age: 14 years) attended the clinic, including four patients with active disease and three patients with PDC responsive to systemic therapy. Consensus treatment, management, and recommendations were provided to patients. Literature review returned 45 pediatric cases of PDC or DC with variable treatments and outcomes. CONCLUSIONS: A multidisciplinary expert clinic was feasible and successful in improving understanding of pediatric chordoma. While multimodal approaches have all been employed, treatment for PDC has been inconsistent and a recommended standardized treatment approach has not been defined. Centralized efforts, inclusive of specialized chordoma-focused clinics, natural history studies, and prospective analyses will help in the standardization of care for this challenging disease.

Clinical outcomes of head and neck adenoid cystic carcinoma patients treated with pencil beam-scanning proton therapy.

OBJECTIVE: The aim of this study was to evaluate the outcome of patients with head and neck adenoid cystic carcinoma (ACC) treated using pencil beam scanning proton therapy (PBS PT) at our institution. MATERIALS AND METHODS: Thirty-five patients who underwent treatment with PBS PT for ACC between 2001 and 2017 were included. Local control (LC), distant control (DC), progression-free survival (PFS), overall survival (OS) and their prognostic factors were evaluated. Adverse effects were prospectively assessed. RESULTS: The median patient follow-up was 30 months. Prior to PT, 26 patients (74.3%) underwent surgery with R0/R1/R2 outcome in 5, 13 and 8 cases, respectively. Nine patients (25.7%) presented with inoperable disease. The 2-year LC, DC, PFS and OS was 92.2%, 77.8%, 74.3% and 88.8%, respectively. LC was influenced by patient age (p = 0.002) with a significant difference between local and distant failure (median 61.3 vs. 42.3 years, p = 0.005). Tumor T stage was a significant risk factor for PFS (p = 0.045) and tumor prognostic group affected OS (p = 0.049). No significant survival advantage for operable vs. inoperable disease could be identified. The acute and late grade 3 toxicity rates were 14.3% and 6.1%, respectively. No acute or late grade 4/5 toxicities were observed. CONCLUSIONS: PBS PT is an effective and safe treatment for patients with head & neck ACC in both definitive and adjuvant setting. Distant metastases are the main pattern of failure. Age, tumor stage and clinical stage had a significant negative impact on LC, OS and PFS.

Defining Clinical Indications of Proton Beam Therapy at National Level in the Kingdom of Saudi Arabia.

The Saudi Particle Therapy Centre (SPTC) is establishing proton beam therapy (PBT) services within Kingdom of Saudi Arabia (KSA). Thus, national guidelines for the pertinent draft, and recommendations of PBT for cancer patients are utmost important. Saudi Particle Therapy Centre invited a panel of expert radiation oncologists practicing within KSA to formulate national clinical practice guidelines for the referral, absolute and relative indications and dose/fractionation for PBT. After identifying the key clinical questions, ample search through PubMed, EMBASE, and various search drives was accomplished for appropriate meta-analyses, clinical trials, case-control, and case series studies, and case reports. Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach was incorporated to formulate various recommendations. Saudi Particle Therapy Centre expert panel recommended PBT as utter modality for ocular tumors, base of skull/spine tumors, hepatocellular carcinoma, all pediatric central nervous system (CNS) malignancies, para-nasal sinuses/nasal cavity tumors and for re-irradiation of all sites aimed for cure. However, PBT may be contemplated, as a relative indication if no other parallel option is available, or when photon therapy plans exceed the dose constraints for critical structures.  Further, panel did not recommend routine PBT for other sites beyond clinical trials. However, individual oncology patients can be considered for PBT after a multidisciplinary approach and expert's opinion.

Long-Term Outcomes and Prognostic Factors After Pencil-Beam Scanning Proton Radiation Therapy for Spinal Chordomas: A Large, Single-Institution Cohort.

PURPOSE: To evaluate the efficacy and safety of high-dose pencil-beam scanning proton therapy (PBS-PT) in the adjuvant treatment of spinal chordomas. METHODS AND MATERIALS: Between 1997 and 2015, 100 patients with spinal chordomas (median age, 56 years; range, 25-81 years) were treated with adjuvant PBS-PT at the Paul Scherrer Institute: cervical (n = 46), thoracic (n = 4), lumbar (n = 12), and sacral (n = 38). The majority (88%) received PBS-PT alone rather than combined photon-proton therapy. The median radiation therapy dose prescribed was 74 Gy (relative biological effectiveness [RBE]) (range, 59.4-77 Gy [RBE]). Thirty-nine patients (39%) had undergone surgical stabilization, primarily with titanium hardware, before radiation therapy. RESULTS: With a median follow-up of 65 months (range, 13-175 months), 5-year local control, disease control, and overall survival rates were 63% (95% confidence interval [CI] 57.7-68.7%; median, 103 months), 57% (95% CI 50.9-62.1%; median, 82 months), and 81% (95% CI 76.8-85.6%; median, 157 months), respectively. On univariate and multivariate analyses, the presence of surgical stabilization was highly prognostic for worsened outcomes. Multivariate analysis also revealed the extent of treatment volumes and presence of gross residual disease to be important in predicting outcomes. High-grade (grade ≥3) toxicities were rare in both the acute (8%) and late (6%) settings. CONCLUSION: For spinal chordomas, PBS-PT remains a highly effective and safe method for delivery of dose-escalated adjuvant radiation therapy. The presence of metallic surgical stabilization prognosticates for worsened outcomes. Further investigation is warranted to characterize ideal treatment volumes and effect of surgical stabilization on therapy for these challenging tumors.

Dramatic Response of a Large Sacral Chordoma to Intensity Modulated Proton Beam Therapy.

Sacral chordomas are slow-growing, indolent, and locally invasive tumors that typically present with pain and neurologic dysfunction. Wide en-bloc surgical excision is the primary treatment, but achieving adequate margins is difficult and surgery is often associated with significant morbidity. Adjuvant radiation therapy (RT) is utilized to decrease the risk of local recurrence or as definitive treatment for nonsurgical candidates. Although chordomas are considered to be relatively radioresistant tumors, several studies have demonstrated tumor response to high-dose proton therapy. Here, we present a patient with a large sacral chordoma who underwent definitive treatment with intensity-modulated proton therapy (IMPT).

Excellent Pathologic Response and Atypical Clinical Course of High-Grade Extremity Sarcoma to Neoadjuvant Pencil Beam Scanning Proton Therapy.

Neoadjuvant radiation therapy, followed by definitive surgical resection, remains the standard of care for resectable high-grade and unresectable soft tissue sarcomas. Proton therapy offers the promise of highly conformal dose distributions with improved sparing of neighboring normal tissues as compared with conformal and intensity modulated photon techniques. It is unclear whether proton therapy may offer an improved tumoral response, especially with dose escalation, in this relatively radio-insensitive tumor type. We, herein, present a patient with an excellent pathologic response to preoperative pencil beam scanning proton therapy despite a complex treatment course.

Systematic assessment of clinical outcomes and toxicities of proton radiotherapy for reirradiation.

Reirradiation (reRT) for locoregional recurrences poses unique challenges and risks; re-treatment using proton beam radiotherapy (PBT) could prove advantageous. Assessing clinical outcomes and toxicity profiles, this systematic review comprehensively evaluated available evidence regarding PBT reRT. Fourteen original investigations across central nervous system (CNS) (n=6), head/neck (H&N) (n=4), lung (n=2), and gastrointestinal (n=2) malignancies were analyzed. PBT for recurrent uveal melanoma achieved 5-year eye retention of 55%; for chordomas, reRT afforded a 2-year local control and overall survival (OS) of 85% and 80%, respectively. Multiple PBT reRT studies for adult gliomas illustrate no grade ≥3 toxicities. Two pediatric CNS tumor studies demonstrated the safety and efficacy of reRT, with one total grade 3 toxicity and achievement of longer-term OS. PBT for H&N malignancies shows appropriate local/locoregional control and favorable toxicity profiles versus historical photon-based methods, including low (9-10%) rates of feeding tube placement. PBT for recurrent lung cancer can achieve favorable survival with expected toxicities/complications of reRT, especially with concurrent chemotherapy and centrally located recurrences. Lastly, PBT reRT in gastrointestinal malignancies induced very few high-grade complications. Hence, based on the limited existing data, PBT is a notably safe reRT modality for effective salvage of recurrent disease. Institutional experiences must continue to be reported: dosimetric correlations, late toxicities, and advanced PBT techniques.

Clinical and Radiologic Outcomes in Adults and Children Treated with Pencil-Beam Scanning Proton Therapy for Low-Grade Glioma.

PURPOSE: We assessed clinical and radiologic outcomes in adults and children with low-grade glioma (LGG) of the brain treated with pencil-beam scanning (PBS) proton therapy (PT). MATERIALS AND METHODS: Between 1997 and 2014, 28 patients were treated with PBS PT, 20 (71%) of whom were younger than 18 years. Median age at start of PT was 12.3 years (range, 2.2-53.0 years). Nine patients (32%) underwent at least a subtotal resection; 12 (43%) underwent biopsy; and 7 (25%) were diagnosed radiographically. Twelve patients (43%) had grade II and 9 (32%) had grade I gliomas. Eleven patients (39%) received chemotherapy before PT. A median dose of 54 Gy (relative biologic effectiveness) was administered. Radiologic response to PT was determined using the Response Evaluation Criteria in Solid Tumors (RECIST). Eight domains of quality of life (QoL) for 16 pediatric patients were assessed prospectively by patients' parents using the pediatric QoL proxy questionnaire. Progression-free survival and overall survival (OS) were estimated by the Kaplan-Meier method. Median follow-up was 42.1 months for living patients. RESULTS: Ten patients (36%) developed local, clinical failure. Three patients (11%) died, all of tumor progression. Radiographic tumor response by RECIST was evaluable in 11 patients: 9 (82%) with stable disease, 1 (9%) with partial response, and 1 (9%) with complete response to PT. Three-year OS and progression-free survival were 83.4% and 56.0%, respectively. No ≥ grade III acute toxicities were observed. Grade III, late radiation necrosis developed in 1 patient (4%). No appreciable change in pediatric QoL proxy scores in children was noted in any of the 8 domains at any time point. CONCLUSION: Treatment with PBS PT is effective for LGG, with minimal acute toxicity and, in children, no appreciable decline in QoL. More patients and longer follow-up are needed to determine the long-term efficacy and toxicity of PT for LGG.

Effect of Anatomic Changes on Pencil Beam Scanned Proton Dose Distributions for Cranial and Extracranial Tumors.

PURPOSE: To estimate the frequency and impact of anatomic changes on the delivered dose in pencil beam scanning proton therapy, to assess the need for repeat CT scanning and adaptive replanning. METHODS AND MATERIALS: A total of 730 patients treated at Paul Scherrer Institut between 2007 and 2014 were included in this study, for which the number of patients who had control CT scans and who were replanned as a result of anatomic changes was analyzed. For those that were replanned, the nominal dose distributions (originally optimized on the planning CT scan) were recalculated on the replanning CT scan and differences evaluated using standard dose metrics for planning target volumes and clinical target volumes and organs at risk (OARs). RESULTS: Control CT studies were acquired for 244 patients (33.5%), and replanning was deemed clinically necessary for 40 (16%) of these (5.5% of the total cohort). The OARs and target dose differences between the nominal and recalculated dose distributions were found to be strongly dependent on the subgroup of patients. Nevertheless, dose differences were found to be ≤ 5% for 88% of all analyzed OARs, and planning target volume/clinical target volume V95% was reduced by ≤5% in 87%/90% of cases. CONCLUSIONS: Despite anatomic variations, clinically delivered plans have been found to be robust to anatomic changes, with replanning being deemed necessary in only a small number of cases. However, because the dosimetric effect of such changes can be quite large for some cases, they have to be monitored and evaluated on an individual basis.

Tumour control and Quality of Life in children with rhabdomyosarcoma treated with pencil beam scanning proton therapy.

PURPOSE: To assess clinical outcomes in children with rhabdomyosarcoma (RMS) treated with pencil beam scanning (PBS) proton therapy (PT). METHODS AND MATERIALS: Eighty-three RMS (embryonal, n=74; 89%) patients treated between January 2000 and December 2014 were included. The median age was 4.5years (range, 0.8-15.5). All patients received systemic chemotherapy according to prospective protocols. Patients had low-, intermediate-, and high-risk disease in 24%, 63%, and 13% of cases, respectively. The median total dose delivered was 54Gy(RBE) (range, 41.4-64.8). RESULTS: After a median follow-up time of 55.5 months (range, 0.9-126.3), local failure occurred in 16 patients. The 5-year local-control survival rate was 78.5% [95% confidence interval (CI), 69.5-88.5%]. Significant predictors for local failure were group/stage, tumour location, and size. Fourteen patients (16%) died, all from tumour progression. The 5-year overall survival was 80.6% (95%CI, 71.8-90.0%). The 5-year incidence of grade 3 non-ocular late toxicity was 3.6% (95%CI, 1-12%). No grade 4-5 late toxicities were observed. One radiation-induced malignancy was observed (1.2%). The Quality of Life (QoL) scores increased significantly after PT compared to baseline values. CONCLUSIONS: PBS PT led to excellent outcome in children with RMS. Late non-ocular toxicity was minimal and QoL good.

Long term outcomes of patients with skull-base low-grade chondrosarcoma and chordoma patients treated with pencil beam scanning proton therapy.

PURPOSE: To evaluate the long term tumor control and toxicity of skull base tumors treated with pencil beam scanning proton therapy (PT). MATERIALS AND METHODS: PT was delivered to 151 (68%) and 71 (32%) chordoma and chondrosarcoma (ChSa) patients, respectively. Mean age of patients was 40.8±18.4years and the male to female ratio was 0.53. The postoperative tumor was abutting the brainstem or optic apparatus in 71 (32.0%) patients. The postoperative mean gross tumor volume (GTV) was 35.7±29.1cm(3). The delivered mean PT dose was 72.5±2.2GyRBE. RESULTS: After a mean follow-up of 50 (range, 4-176) months, 35 local (15.8%) failures were observed between 10.9 and 85.4months. The estimated 7-year LC rate for chordoma (70.9%; CI95% 61.5-81.8) was significantly lower compared to the LC rate for ChSa patients (93.6%; 95%CI 87.8-99.9; P=0.014). The estimated 7-year distant metastasis-free- and overall survival rate was 91.6% (95%CI 91.6-98.6) and 81.7% (95%CI 74.7-89.5), respectively. On multivariate analysis, optic apparatus and/or brainstem compression, histology and GTV were independent prognostic factors for LC and OS. The 7-year high grade toxicity-free survival was 87.2 (95%CI 82.4-92.3). CONCLUSIONS: PBS PT is an effective treatment for skull base tumors with acceptable late toxicity. Optic apparatus and/or brainstem compression, histology and GTV allow independent prediction of the risk of local failure and death in skull base tumor patients.

Evaluation of Robustness to Setup and Range Uncertainties for Head and Neck Patients Treated With Pencil Beam Scanning Proton Therapy.

PURPOSE: To evaluate the robustness of head and neck plans for treatment with intensity modulated proton therapy to range and setup errors, and to establish robustness parameters for the planning of future head and neck treatments. METHODS AND MATERIALS: Ten patients previously treated were evaluated in terms of robustness to range and setup errors. Error bar dose distributions were generated for each plan, from which several metrics were extracted and used to define a robustness database of acceptable parameters over all analyzed plans. The patients were treated in sequentially delivered series, and plans were evaluated for both the first series and for the combined error over the whole treatment. To demonstrate the application of such a database in the head and neck, for 1 patient, an alternative treatment plan was generated using a simultaneous integrated boost (SIB) approach and plans of differing numbers of fields. RESULTS: The robustness database for the treatment of head and neck patients is presented. In an example case, comparison of single and multiple field plans against the database show clear improvements in robustness by using multiple fields. A comparison of sequentially delivered series and an SIB approach for this patient show both to be of comparable robustness, although the SIB approach shows a slightly greater sensitivity to uncertainties. CONCLUSIONS: A robustness database was created for the treatment of head and neck patients with intensity modulated proton therapy based on previous clinical experience. This will allow the identification of future plans that may benefit from alternative planning approaches to improve robustness.

Long-term outcomes and prognostic factors of skull-base chondrosarcoma patients treated with pencil-beam scanning proton therapy at the Paul Scherrer Institute.

BACKGROUND: Skull-base chondrosarcoma (ChSa) is a rare disease, and the prognostication of this disease entity is ill defined. METHODS: We assessed the long-term local control (LC) results, overall survival (OS), and prognostic factors of skull-base ChSa patients treated with pencil beam scanning proton therapy (PBS PT). Seventy-seven (male, 35; 46%) patients with histologically confirmed ChSa were treated at the Paul Scherrer Institute. Median age was 38.9 years (range, 10.2-70.0y). Median delivered dose was 70.0 GyRBE (range, 64.0-76.0 GyRBE). LC, OS, and toxicity-free survival (TFS) rates were calculated using the Kaplan Meier method. RESULTS: After a mean follow-up of 69.2 months (range, 4.6-190.8 mo), 6 local (7.8%) failures were observed, 2 of which were late failures. Five (6.5%) patients died. The actuarial 8-year LC and OS were 89.7% and 93.5%, respectively. Tumor volume > 25 cm(3) (P = .02), brainstem/optic apparatus compression at the time of PT (P = .04) and age >30 years (P = .08) were associated with lower rates of LC. High-grade (≥3) radiation-induced toxicity was observed in 6 (7.8%) patients. The 8-year high-grade TFS was 90.8%. A higher rate of high-grade toxicity was observed for older patients (P = .073), those with larger tumor volume (P = .069), and those treated with 5 weekly fractions (P = .069). CONCLUSIONS: This is the largest PT series reporting the outcome of patients with low-grade ChSa of the skull base treated with PBS only. Our data indicate that protons are both safe and effective. Tumor volume, brainstem/optic apparatus compression, and age were prognosticators of local failures.

Tumor control and QoL outcomes of very young children with atypical teratoid/rhabdoid tumor treated with focal only chemo-radiation therapy using pencil beam scanning proton therapy.

The aim of this analysis was to assess the early clinical results of pencil beam scanning proton therapy (PT) in the treatment of young children with non-metastatic atypical teratoid/rhabdoid tumor (ATRT) of the CNS. Fifteen children (male, n = 8, 53 %) were treated with PT between May 2008 and January 2013. Mean age at diagnosis was 17.4 ± 7.0 months. The localization was infratentorial in 9 (60 %) patients. Gross total resection of the primary tumors was achieved in 7 (47 %) patients. The dose administered focally under sedation was 54 Gy (RBE). After a median follow-up of 33.4 months (range 9.7-69.2), 3 (20 %), 4 (27 %) and 2 (13 %) patients presented with local failure (LF), distant brain failure (DBF) and spinal failure (SF), respectively. Six patients died, all of tumor progression. The 2-year overall- and progression-free survival was 64.6 and 66.0 %. Tumor location (supratentorial) and the extent of surgical resection (non-gross total resection) were negative prognostic factors for both OS and PFS. PT was well tolerated. No grade >2 acute toxicity was observed. The estimated 2-year toxicity-free survival was 90 %. As assessed by the PedsQoL proxy, no decrease in QoL was observed after PT. We conclude that PBS PT is an effective treatment for young children with ATRT. After PT, with or without concomitant chemotherapy, two third of the patients survived >2 years. Acute toxicity was manageable. Longer follow-up and larger numbers of patients are needed to assess long-term outcomes and treatment-induced toxicity.

Radiation therapy for mucosal melanoma of the head and neck.

OBJECTIVES: The aim of this study was to evaluate the long-term effectiveness and complications of radiotherapy (RT) in the treatment of patients with mucosal melanomas of the head and neck. MATERIALS AND METHODS: The medical records of 21 patients treated with definitive or postoperative (RT) between 1974 and 2011 at the University of Florida Department of Radiation Oncology in Gainesville, FL, and the University of Florida Proton Therapy Institute in Jacksonville, FL, were retrospectively reviewed under an Institutional Review Board-approved protocol. Primary sites included nasal cavity, oropharynx, and paranasal sinuses. Sixteen patients (76%) received surgery and postoperative RT and 5 patients (24%) received RT alone. Seventeen patients received photon RT alone, whereas 4 patients received combined photon-based and proton-based RT. Median follow-up for all patients was 1.05 years (range, 0.36 to 12.97 y); median follow-up for survivors was 2.2 years (range 0.9 to 13.0 y). RESULTS: The 5-year outcomes were: local control, 79%; regional control, 85%; local-regional control, 65%; distant metastasis-free survival, 20%; cause-specific survival, 22%; and overall survival, 22%. Three patients (14%) experienced severe complications including bilateral blindness and skin necrosis. CONCLUSIONS: Definitive or postoperative RT for mucosal melanoma of the head and neck yields fairly good local-regional control of disease. The prognosis for patients treated with definitive RT is less promising than for those who receive surgery and postoperative RT.

Proton therapy for skull base chordomas: an outcome study from the university of Florida proton therapy institute.

Objectives Skull base chordoma is a rare, locally aggressive tumor located adjacent to critical structures. Gross total resection is difficult to achieve, and proton therapy has the conformal advantage of delivering a high postoperative dose to the tumor bed. We present our experience using proton therapy to treat 33 patients with skull base chordomas. Design Retrospective outcomes study. Setting University of Florida Proton Therapy Institute; 2007 to 2011. Participants A total of 33 patients with skull base chordomas received postoperative three-dimensional conformal proton therapy. The patients were 79% male and 6% diabetic; 27% had received a gross total resection. Main Outcome Measures The gross tumor/tumor bed received a dose between 77.4 CGE and 79.4 CGE. Local control and overall survival were tracked, and radiation toxicity was assessed using a modified Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer Late Radiation Morbidity Scoring Scheme. Results Median follow-up for all patients was 21 months. Local control and overall survival rates at 2 years were 86% and 92%, respectively. Grade 2 toxicity was observed in 18% of our cohort in the form of unilateral hearing loss partially corrected with a hearing aid. No grade 2 or higher optic or brainstem toxicities were observed. Conclusions Proton therapy is an effective treatment modality for skull base chordomas.

Radiotherapy for sinonasal undifferentiated carcinoma.

PURPOSE: To evaluate the long-term effectiveness of radiotherapy (RT) in the treatment of sinonasal undifferentiated carcinoma (SNUC). MATERIALS AND METHODS: The medical records of 23 patients treated with definitive or postoperative RT between 1992 and 2010 at the University of Florida were retrospectively reviewed. Fifteen patients (65%) received primary surgery and postoperative RT. Radiation doses ranged from 59.0 to 74.8 Gy (median, 70.2 Gy). The median follow-up time for all patients was 3.0 years (range, 0.9-19.9), and for living patients was 7.7 years (range, 2.5-19.9). RESULTS: The actuarial 5-year survival outcomes were as follows: progression-free survival, 42%; cause-specific survival, 43%; and overall survival, 32%. Actuarial 5-year disease control rates were as follows: local control (infield or marginal), 74%; local-regional control (excluding leptomeningeal spread), 58%, regional control 78%, freedom from leptomeningeal recurrence, 72%, and distant metastasis-free survival, 73%. Five of the 8 (62.5%) patients treated with definitive RT died with disease, and 6 of the 15 patients (40%) treated with primary surgery and postoperative RT died with disease. Three patients (13%) experienced severe complications including unilateral eye removal, osteoradionecrosis of the maxilla requiring hyperbaric oxygen and surgery, and brain necrosis. One patient died due to an infected bone graft and brain abscess. CONCLUSIONS: A multimodal approach is best when treating SNUC patients. The prognosis for patients treated with definitive RT ± chemotherapy is less promising than for those who receive surgery and postoperative RT ± chemotherapy. Severe complications occur in about 17% of patients due to the high dose of RT alone or combined with surgery required for acceptable disease control.

Differential sensitivity of choroidal endothelial, retinal ganglion, and retinal pigment epithelial cells in vitro to proton radiation.

PURPOSE: To evaluate the differential sensitivity of choroidal endothelial, retinal pigment epithelial, and retinal ganglion cells to escalating doses of proton beam radiation and to establish a safe dose range for the management of choroidal neovascularization associated with age-related macular degeneration (AMD). DESIGN: Laboratory investigation. METHODS: Proliferating simian choroidal endothelial cells (RF/6A), differentiated rat retinal ganglion cells (RGC-5), and serum-starved human retinal pigment epithelial cells (ARPE-19) were exposed to 2, 4, 8, and 12 cobalt gray equivalent of proton beam radiation and cell viability was quantified on day 9. Reactive oxygen species levels were analyzed. RESULTS: Significant decline of choroidal endothelial cell viability was noted as dose escalated from 4 to 8 cobalt gray equivalent with maximum effect observed at 12 cobalt gray equivalent. RGC-5 and ARPE-19 cell count decreased to 95% and 62.7% at 8 cobalt gray equivalent, respectively. Sub-analysis between 4 and 8 cobalt gray equivalent radiation revealed significant decrease in choroidal endothelial cell viability (43.1% at 7 cobalt gray equivalent and 32.3% at 8 cobalt gray equivalent of radiation). Correspondingly, RGC-5 and ARPE-19 cells did not show decrease in cell count or viability. Reactive oxygen species levels significantly increased in radiation-treated choroidal endothelial cells (8.3%-11.9%). CONCLUSIONS: At 6-8 cobalt gray equivalent proton beam radiation, retinal ganglion and retinal pigment epithelial cells are preserved while choroidal endothelial cells are completely inhibited. This dosage offers optimum therapeutic safety window for treatment using proton beam radiation for exudative AMD.

Response to sunitinib in combination with proton beam radiation in a patient with chondrosarcoma: a case report.

INTRODUCTION: Chondrosarcoma is well-known to be primarily resistant to conventional radiation and chemotherapy. CASE PRESENTATION: We present the case of a 32-year-old Caucasian man with clear cell chondrosarcoma who presented with symptomatic recurrence in his pelvis and metastases to his skull and lungs. Our patient underwent systemic therapy with sunitinib and then consolidation with proton beam radiation to his symptomatic site. He achieved complete symptomatic relief with a significantly improved performance status and had an almost complete and durable metabolic response on fluorine-18-fluorodeoxyglucose positron emission tomography. CONCLUSIONS: Our findings have important clinical implications and suggest novel clinical trials for this difficult to treat disease.

Evaluation of proton beam radiation sensitivity of proliferating choroidal endothelial and retinal ganglion cells with clonogenic assay.

CONTEXT: Proton beam therapy offers the advantage of precise delivery with limited damage to the healthy tissue and is being tested in the management of exudative age-related macular degeneration (AMD). However, the dosages tested are empirical and not based on preclinical studies. OBJECTIVE: In this study we evaluated the effects of varying doses of proton beam radiation on choroidal endothelial cells (CECs) and retinal ganglion cells (RGCs) using clonogenic assay to determine differential sensitivity. MATERIALS AND METHODS: Each cell type has different efficiency to replicate (plating efficiency (PE)). PE of CEC (RF/6A) and RGC (RGC-5) grown in culture flasks was determined by plating 250 cells each (without any treatment) and counting the number of colonies after 13 days. Radiation induced sensitivity was determined by exposing the semi-confluent RF/6A and RGC-5 cells to proton beam at the doses of 0 (control), 2, 4, 8 and 12 cobalt gray equivalent (CGE). The ability of the cells to repair and replicate to form colonies were analyzed 13 days after radiation with crystal violet stain and the survival ratio was calculated. The significance of survival was analyzed using ANOVA (Graphpad Instat.3). RESULTS: The PE of CEC and RGC was 12.96 ± 0.29% and 40.7 ± 1.48%, respectively. A survival ratio of CEC at 2, 4, 8 and 12 CGE proton radiation was 66.0 ± 8.6%, 44.3 ± 6.5%, 7.6 ± 0.3% and 1.14 ± 0.06% on exposure to 2, 4, 8 and 12 CGE proton radiation, respectively, p < 0.01). Survival ratio of RGC was 71.1 ± 22.4% (p = 0.05), 40.2 ± 7.9%, 8.89 ± 2.6% and 0.78 ± 0.31% at 2, 4, 8 and 12 CGE dosages (p < 0.001). DISCUSSION: CEC showed dose-dependent decrease in survival rate with values attaining significance at all radiation dosages. In contrast, RGC was comparatively radio resistant and were able to replicate at lower doses and sensitive at higher doses after proton beam radiation. CONCLUSION: Since CECs proliferate during neovascularization, this clonogenic assay is a useful assay to assess the sensitivity of CEC to radiation. This study identified that CEC were more sensitive to proton beam radiation than RGC at all doses. This may provide a therapeutic window for administration of proton beam radiation in the management of AMD.