Receiving Proton Therapy Research Articles

Proton therapy delivery method affects dose-averaged linear energy transfer in patients

The dosimetric advantages of proton therapy have led to its rapid proliferation in recent decades. This has been accompanied by a shift in technology from older units that deliver protons by passive scattering (PS) to newer units that increasingly use pencil-beam scanning (PBS). The biologic effectiveness of proton physical dose purportedly rises with increasing dose-weighted average linear energy transfer (LETD). The objective of this study was to determine the extent to which proton delivery methods affect LETD. We calculated LETD from simple, dosimetrically matched, and clinical treatment plans with TOPAS Monte-Carlo transport code. Simple treatment plans comprised single fields of PS and PBS protons in a water phantom. We performed simulations of matched and clinical treatment plans by using the treatment and anatomic data obtained from a cohort of children with craniopharyngioma who previously received PS or PBS proton therapy. We compared the distributions of LETD from PS and PBS delivery methods in clinically relevant ROIs. Wilcoxon signed-rank tests comparing single fields in water revealed that the LETD values from PBS were significantly greater than those from PS inside and outside the targeted volume (p < 0.01). Statistical tests comparing LETD-volume histograms from matched and clinical treatment plans showed that LETD was generally greater for PBS treatment plans than for PS treatment plans (p < 0.05). In conclusion, the proton delivery method affects LETD both inside and outside of the target volume. These findings suggest that PBS is more biologically effective than PS. Given the rapid expansion of PBS proton therapy, future studies are needed to confirm the applicability of treatment evaluation methods developed for PS proton therapy to those for modern PBS treatments to ensure their safety and effectiveness for the growing population of patients receiving proton therapy. This study uses data from two clinical trials: NCT01419067 and NCT02792582.

Distinct imaging patterns of pseudoprogression in glioma patients following proton versus photon radiation therapy

Criteria by the Radiologic Assessment in Neuro-Oncology (RANO) group outline the diagnosis of pseudoprogression (Ps) after photon therapy for gliomas based on timing and location. We noted that patients receiving proton therapy manifested radiographic changes that appear different than Ps after photon therapy, which could be interpreted as tumor progression. In this study, we retrospectively reviewed MR imaging after proton or photon radiation for gliomas. We propose criteria to characterize proton pseudoprogression (ProPs) as distinct from Ps seen after photons. Post-treatment MR imaging, clinical and pathological data of low grade glioma patients were reviewed. Overall, 57 patients receiving protons were reviewed for the presence of ProPs, and 43 patients receiving photons were reviewed for any equivalent imaging changes. Data collected included the location and timing of the new enhancement, tumor grade, molecular subtype, chemotherapy received, and clinical symptoms. Fourteen patients (24.6%) had new enhancement following radiation therapy that was unique to treatment with protons. The mean time to development of the ProPs was 15.4months (7-27months). We established the following criteria to characterize ProPs: located at the distal end of the proton beam; resolves without tumor-directed therapy; and subjectively multifocal, patchy, and small (< 1cm). In the group receiving photons, none had changes that met our criteria for ProPs. Patients who receive protons have unique imaging changes after radiation therapy. ProPs could be mistaken for tumor progression, but typically resolves on follow up. Further studies are needed to understand the radiobiology and pathophysiology underlying these imaging changes.

Head-and-neck organs-at-risk auto-delineation using dual pyramid networks for CBCT-guided adaptive radiotherapy

Organ-at-risk (OAR) delineation is a key step for cone-beam CT (CBCT) based adaptive radiotherapy planning that can be a time-consuming, labor-intensive, and subject-to-variability process. We aim to develop a fully automated approach aided by synthetic MRI for rapid and accurate CBCT multi-organ contouring in head-and-neck (HN) cancer patients. MRI has superb soft-tissue contrasts, while CBCT offers bony-structure contrasts. Using the complementary information provided by MRI and CBCT is expected to enable accurate multi-organ segmentation in HN cancer patients. In our proposed method, MR images are firstly synthesized using a pre-trained cycle-consistent generative adversarial network given CBCT. The features of CBCT and synthetic MRI (sMRI) are then extracted using dual pyramid networks for final delineation of organs. CBCT images and their corresponding manual contours were used as pairs to train and test the proposed model. Quantitative metrics including Dice similarity coefficient (DSC), Hausdorff distance 95% (HD95), mean surface distance, and residual mean square distance (RMS) were used to evaluate the proposed method. The proposed method was evaluated on a cohort of 65 HN cancer patients. CBCT images were collected from those patients who received proton therapy. Overall, DSC values of 0.87 ± 0.03, 0.79 ± 0.10/0.79 ± 0.11, 0.89 ± 0.08/0.89 ± 0.07, 0.90 ± 0.08, 0.75 ± 0.06/0.77 ± 0.06, 0.86 ± 0.13, 0.66 ± 0.14, 0.78 ± 0.05/0.77 ± 0.04, 0.96 ± 0.04, 0.89 ± 0.04/0.89 ± 0.04, 0.83 ± 0.02, and 0.84 ± 0.07 for commonly used OARs for treatment planning including brain stem, left/right cochlea, left/right eye, larynx, left/right lens, mandible, optic chiasm, left/right optic nerve, oral cavity, left/right parotid, pharynx, and spinal cord, respectively, were achieved. This study provides a rapid and accurate OAR auto-delineation approach, which can be used for adaptive radiation therapy.

Promising long-term results with proton therapy for localized prostate cancer.

The value of proton therapy in managing prostate cancer is not yet defined. A recent study has reported promising long-term results for patients with localized prostate cancer who received proton therapy. However, results from ongoing clinical trials are required before determining the role of proton therapy for this indication.

Proton Therapy for Pediatric Ependymoma: Mature Results From a Bicentric Study

To report the long-term efficacy and toxicity of proton therapy for pediatric ependymoma. Between 2000 and 2019, 386 children with nonmetastatic grade 2/3 intracranial ependymoma received proton therapy at 1 of 2 academic institutions. Median age at treatment was 3.8 years (range, 0.7-21.3); 56% were male. Most (72%) tumors were in the posterior fossa and classified as World Health Organization grade 3 (65%). Eighty-five percent had a gross total or near total tumor resection before radiation therapy; 30% received chemotherapy. Median radiation dose was 55.8 Gy relative biologic effectiveness (RBE) (range, 50.4-59.4). Median follow-up was 5.0 years (range, 0.4-16.7). The 7-year local control, progression-free survival, and overall survival rates were 77.0% (95% confidence interval [CI], 71.9%-81.5%), 63.8% (95% CI, 58.0%-68.8%), and 82.2% (95% CI, 77.2%-86.3%), respectively. Subtotal resection was associated with inferior local control (59% vs 80%; P < .005), progression-free survival (48% vs 66%; P < .001), and overall survival (70% vs 84%; P < .05). Male sex was associated with inferior progression-free (60% vs 69%; P < .05) and overall survival (76% vs 89%; P < .05). Posterior fossa tumor site was also associated with inferior progression-free (59% vs 74%; P < .05) and overall survival (79% vs 89%; P < .01). Twenty-one patients (5.4%) required hearing aids; of these, 13 received cisplatin, including the 3 with bilateral hearing loss. Forty-five patients (11.7%) required hormone replacement, typically growth hormone (38/45). The cumulative incidence of grade 2+ brain stem toxicity was 4% and occurred more often in patients who received >54 GyRBE. Two patients (0.5%) died of brain stem necrosis. The second-malignancy rate was 0.8%. Proton therapy offers disease control commensurate with modern photon therapy without unexpected toxicity. The high rate of long-term survival justifies efforts to reduce radiation exposure in this young population. Independent of radiation modality, this large series confirms extent of resection as the most important modifiable factor for survival.

RONC-24. PROTON THERAPY FOR PEDIATRIC EPENDYMOMA: MATURE OUTCOMES FROM THE UNIVERSITY OF FLORIDA AND MASSACHUSETTS GENERAL HOSPITAL

OBJECTIVEReport long-term efficacy and toxicity of proton therapy for pediatric ependymoma.MATERIALS AND METHODSBetween 2000–2017, 318 children with nonmetastatic grade II/III intracranial ependymoma received proton therapy at Massachusetts General Hospital and the University of Florida. Median age was 3.5 years (range, 0.7–21.3 years); 56% were male. Most (69%) tumors were in the posterior fossa and classified as WHO grade III (64%). Eighty-four percent had a gross total or near total tumor resection before radiotherapy and 30% received chemotherapy. Median radiation dose was 55.8 CGE (range, 50.4–59.4 CGE).RESULTSMedian follow-up was 6 years (range, 0.6–19.2 years). Seven-year local control, progression-free survival, and overall survival rates were 77.1% (95% CI 71.7–81.7%), 64.4% (95% CI 58.6–69.8%), and 82% (76.9–86.2%), respectively. Subtotal resection was associated with inferior local control (60% vs 80%; p<0.01), progression-free survival (49% vs 67%; p<0.01), and overall survival (69% vs 84%; p<0.05). Male gender was associated with inferior progression-free (59% vs 71%; p<0.01) and overall survival (77% vs 89%; p<0.05). Twenty patients (6.2%) require hearing aids; of these, 12/20 received cisplatin. Grade 3+ brainstem toxicity rate was 1.6% and more common in patients who received >54 CGE. The rate of second malignancy was 0.9%.CONCLUSIONProton therapy offers commensurate disease control to modern photon therapy without unexpected toxicity. The high rate of long-term survival justifies efforts to reduce radiation exposure in this young population with brain tumors. Independent of modality, this large series confirms extent of resection as the most important modifiable factor for survival.

RONC-32. LOCAL CONTROL FOLLOWING PROTON THERAPY FOR PEDIATRIC CHORDOMA

BACKGROUNDDue to the location and high dose required for disease control, pediatric chordomas are theoretically well-suited for treatment with proton therapy, but their low incidence limits the clinical outcome data available in the literature. METHODS AND MATERIALS: Between 2008 and 2019, 29 patients with a median age of 14.8 years (range, 3.8–21.8) received proton therapy for non-metastatic chordoma at a single institution. Twenty-four tumors arose in the clivus/cervical spine region and 5 in the lumbosacral spine. Twenty-six tumors demonstrated well-differentiated histology and 3 were dedifferentiated or not otherwise specified (NOS). Approximately half of the tumors underwent specialized testing: 14 were brachyury-positive and 10 retained INI-1. Seventeen patients had gross disease at the time of radiation. The median radiation dose was 73.8 GyRBE.RESULTSWith a median follow-up of 4.3 years (range, 1.0–10.7), the 5-year estimates of local control, progression-free survival, and overall survival rates were 85%, 82%, and 86%, respectively. Excluding 3 patients with dedifferentiated/NOS chordoma, the 5-year local control, progression-free survival, and overall survival rates were 92%, 92%, and 91%, respectively. Serious toxicities included 3 patients with hardware failure or related infection requiring revision surgery, 2 patients with hormone deficiency, and 2 patients with Eustachian tube dysfunction causing chronic otitis media.CONCLUSIONIn pediatric patients with chordoma, proton therapy is associated with a low risk of serious toxicity and high efficacy, particularly in well-differentiated tumors. Complete resection may be unnecessary for local control and destabilizing operations requiring instrumentation may result in additional complications following therapy.

Machine Learning Nomogram to Predict Breast Reconstruction Complications with and without Radiation

The lack of consensus about integrating Postmastectomy Radiotherapy (PMRT) and breast reconstruction has led to wide variability in reconstruction options: Autologous (AR), Single stage direct-implant (DTI) and two stages expander/implant (TE/I), as well as in PMRT techniques: use of electrons chest wall boost (CWB) and proton therapy. We use machine learning models to provide interactive nomogram tool similar to adjuvant online tool. This nomogram predicts personalized reconstruction complications with and without PMRT to guide different treatment types decisions. From 1997-2017, 1,618 patients undergoing mastectomy and breast reconstruction for their primary tumor were analyzed. Reconstruction approaches included pure AR flaps, DTI and TE/I. PMRT was delivered either with 3D conformal photon or proton therapy. Complication endpoints were defined based upon surgical reintervention operative notes as infection/necrosis requiring debridement. For implant-based patients we studied capsular contracture requiring capsulotomy, absolute reconstruction failure (removal of expander/or implant without salvage reconstruction) and overall failure (removal of permanent implant with and without salvage reconstruction). For each complication endpoint, LASSO penalized regression was used to select the subset of predictors associated with the smallest prediction error from 10-fold cross validation. Candidate predictors included demographics, pathology, surgery, systemic therapy and PMRT details. Nomograms were built using the machine selected predictors. Median follow-up was 6.6 years. Among 1,618 patients,23% had AR, 39% with DTI, 37%TE/I, 47%with PMRT, 22% had neoadjuvant chemotherapy, 43% had adjuvant chemotherapy alone. Among 758 patients with PMRT, 8.3% received proton therapy, 43% received CWB with electrons and 48% without CWB. 75% of patients with TE/I had PMRT before the exchange surgery to implant. The following predictors for infection/necrosis were significant: periareolar incisions, CWB, higher BMI, smoking, TE/I reconstruction (p<0.05 for all). The model achieved an AUC of 73%. For capsular contracture, machine selected the following predictors: menopause, smoking, diabetes, radiation types, number of lymph node sampled, chemotherapy, reconstruction type, type of mesh and location of surgical incisions. Preliminary results showed protons significantly increased capsular contracture risk (OR 4.7, p = 0.003) as well as CWB (OR 2.3, p = 0.02) compared to those with no PMRT, and Alloderm mesh significantly reduced contracture risk (p<0.01). Similar models were built and validated for reconstruction failure and different clinical scenarios will be provided. Nomograms were developed to predict the personalized anticipated risk for breast reconstruction complications based on demographics and different treatment approaches. This tool can be used in guiding treatment and patient counseling.

Phase II Study Of Proton Radiation Therapy For Lower Grade Gliomas

To evaluate the role of proton therapy in the management of patients with lower grade gliomas in regard to progression free survival (PFS) and treatment toxicity WHO 2007 grade II glioma patients and IDH mutant grade III glioma patients indicated for radiation therapy were enrolled in a prospective single arm trial of involved field proton therapy receiving a dose of 54 Gy (RBE) in 30 fractions if grade II, and 59.4 Gy (RBE) in 33 fractions if grade III. No prior cranial irradiation was permitted. Comprehensive baseline and regular post treatment evaluations of neuroendocrine function, neurocognitive functions, quality of life (QOL), and PFS were performed. Among 60 patients (median age 40.8 years) who received proton therapy, 28 (47%) were men, and 39 (65%) were WHO Grade II. Forty-one patients (68%) were treated at initial diagnosis and 19 (32%) patients were treated at the time of progression. Primary tumor locations were frontal (32; 53%), temporal (10; 17%), parietal (7; 12%), and occipital (1; 2%) lobes, thalamus (1; 2%), and 9 patients (15%) with tumor involving temporal lobe and one or more adjacent lobes. All patients tolerated the delivery of proton therapy without difficulty. Median follow-up after proton therapy was 3.1 years among 47 progression-free patients with ongoing follow-up. Progression-free survival at 5-years was 71%. 5-year PFS for grade II gliomas (n = 39) was 67% and for favorable grade III (n = 21) was 78%. New endocrine dysfunction was detected in 3 patients (5%). The axes affected were thyroid (2%), testosterone (4% of men), and cortisol (2%). The mean pituitary doses for patients with new endocrine dysfunction were 0 Gy, 21.0 Gy, and 0 Gy, respectively. Of the 34 patients with at-risk pituitary (mean dose >0 Gy), the median pituitary mean dose was 14.58 Gy (range: 0.01 – 48.29 Gy). There was one grade 4 case of central nervous system necrosis (2%) which was biopsy proven; there were no grade 3 toxicities. The most common grade 2 toxicities were fatigue (15%), dermatitis (5%), and headache (3%). QOL assessment by FACT-Brain showed modest improvement at 2 years follow-up (n = 46) with mean increase of 3.5 in total score from baseline, but the mean score returned to baseline level at 4 years (n = 20). Early results demonstrate that lower grade glioma patients tolerate proton therapy with very few toxicities. There were minimal neuroendocrine deficiencies and no evidence for early decline in QOL which may be partially attributable to limited integral dose to the brain and pituitary by use of proton therapy. Neurocognitive function is yet to be reported. PFS is equivalent to that of photon-based therapy.

The Role of Socioeconomic Status (SES) in Disease Outcomes in Pediatric Cancer Patients Receiving Proton Therapy

Social factors are known to play a critical role in disease burden and socioeconomic status (SES) has been associated with several health conditions and outcomes. There is strong evidence that SES plays an important role in the incidence, morbidity and mortality of cancer within the adult population, but the impact of SES within the pediatric cancer population is still under debate due to conflicting results. Here we use the large multicenter Pediatric Proton/Photon Consortium Registry (PPCR) to investigate how SES can affect disease control and other outcomes in patients treated for pediatric cancers at proton therapy centers across the United States. All patients were enrolled in the PPCR from October 2012 – August 2015 and received radiation. Home addresses, progression free survival (PFS) and overall survival (OS) were extracted from the PPCR for socioeconomic analysis. Their zip code (ZC) and census tract (CT), two different enumeration areas, were established using their home address and zip code, if provided. CT is much smaller than ZC. The American Community Survey from the US Bureau of Labor Statistics was used to extract median income, attainment of high school diploma, and percentage of population below the poverty line for the enumeration area corresponding to the patient’s address and zip code. All data was analyzed using SAS. Two-sided hypothesis testing was used, where p-value < 0.05 was considered significant. Correlation between data at ZC and CT level was assessed using Spearman and Pearson correlations. 876 patients with pediatric cancer were enrolled in the PPCR during this time. International patients and those with no address were excluded, leaving 637 patients for analysis. Mean median income was $67,639 at ZC level and $70,906 at CT level. Mean rate of high school graduation was 89.0% at ZC level and 89.1% at CT level. Mean rate below poverty line was 12.3% at ZC level and 11.7% at CT level. There was no significant difference between data obtained at ZC and CT levels for all metrics. No significant difference was found in OS or PFS (p-value 0.49 and 0.65) as a function of median income, or by poverty status (p-value 0.94 and 0.88). There is no significant difference in OS or PFS with attainment of high school diploma (p-value 0.51 and 0.65). Within the population of patients with pediatric cancer treated with proton therapy, population socioeconomic factors including median income, attainment of high school diplomas and rate of poverty have not been shown to significantly impact OS or PFS. Importantly, results do not vary when taken at two different enumeration areas.Tabled 1Abstract 2958; TableMeasureZC levelCT levelCorrelationsMean95% CIMean95% CIPearsonSpearmanMedian Income ($)67,63911,691.71 – 123,586.0670,9065,143.25 – 136,368.550.8550.838High school graduation (%)89.0272.95 – 10089.0870.63 – 1000.8540.821Rate below poverty (%)12.330 – 30.7811.740 – 32.160.730.776 Open table in a new tab

Median Household Income Remains Strongly Associated With Integrative Therapy Utilization During Radiation Treatment Despite Program Subsidization

Prior studies have shown that demographic factors, including income, are associated with usage of integrative therapies. We hypothesize that such factors may also impact integrative therapy utilization by patients actively undergoing cancer therapy. Data was collected prospectively on 1059 patients receiving proton therapy at a single institution between 2/2018 and 6/2019. During this time period, all patients were offered an optional no-cost, on-site integrative health consultation followed by subsidized therapeutic modalities including group yoga, oncology massage, acupuncture, etc. Participation in the integrative wellness (IW) program, demographics, and treatment plans were recorded in real time for each patient in their individual electronic medical records. In this analysis, data regarding median household income (determined by zip code-based data from the 2017 inflation-adjusted national census), race, gender, cancer primary site, primary vs re-irradiation, concurrent chemotherapy, and curative vs palliative intent of treatment was obtained from these records. Multivariate logistic regression was used to investigate differences between patients who elected to participate or forego participation in the IW program. Median incomes were grouped into quartiles (<$61,819; $61,819- $78,900; $78,900-$101,081; >$101,081) and evaluated as $20,000 units. Of the 1059 patients who received proton treatment, 298 (28%) utilized some component of the IW program. Based on multivariate analysis, these patients were more likely to be younger (p = 0.028), have genitourinary cancers (p = 0.002), and have higher incomes (p = 0.027). Patients were 11% more likely to participate in the IW program for every $20,000 increase in median income (OR = 1.11 CI 95% 1.01-1.22). Differences in race, gender, prior radiation treatment, concurrent chemotherapy administration, and intent of treatment were not significantly different between participants and non-participants. Despite subsidization of the IW program, lower income patients were significantly less likely to pursue IW modalities. Future analyses should explore possible barriers to participation for low income individuals such as transportation challenges, opportunity costs for employed patients, patient perception of integrative therapies, or marketing of such programs as optional versus expected components of cancer therapy.

Have We Underestimated the Risk of Radiation-induced Esophagitis in Non-Small Cell Lung Cancer Patients Receiving Proton Therapy Using Constant RBE?

Have We Underestimated the Risk of Radiation-induced Esophagitis in Non-Small Cell Lung Cancer Patients Receiving Proton Therapy Using Constant RBE?

Proton Therapy for Pediatric Ependymoma: Mature Results from a Multi-Center Study

Report long-term efficacy and toxicity of proton therapy for pediatric ependymoma. Between 2000 and 2017, 318 children with nonmetastatic grade II/III intracranial ependymoma received proton therapy at two academic institutions. Median age was 3.5 years (range, 0.7-21.3 years); 56% were male. Most (69%) tumors were in the posterior fossa and classified as WHO grade III (64%). Eighty-four percent had a gross total or near total tumor resection before radiotherapy and 30% received chemotherapy. Median radiation dose was 55.8 CGE (range, 50.4-59.4 CGE). The Kaplan-Meier product limit method estimated freedom from time-dependent endpoints, and the log-rank test statistic estimated the level of statistical significance between strata of selected prognostic factors. Median follow-up was 6 years (range, 0.6-19.2 years). Seven-year local control, progression-free survival, and overall survival rates were 77.1% (95% CI 71.7-81.7%), 64.4% (95% CI 58.6-69.8%), and 82% (95% CI 76.9-86.2%), respectively. Subtotal resection was associated with inferior local control (60% vs 80%; p<0.01), progression-free survival (49% vs 67%; p<0.01), and overall survival (69% vs 84%; p<0.05). Male gender was associated with inferior progression-free (59% vs 71%; p<0.01) and overall survival (77% vs 89%; p<0.05). Twenty patients (6.2%) required hearing aids; of these, 12/20 received cisplatin, including all three cases with bilateral hearing loss. 44 patients (13.8%) required hormone replacement, most commonly growth hormone (37/44). Grade 3+ brainstem toxicity rate was 1.6% and more often in patients who received >54 CGE. Two patients (0.6%) died of brainstem necrosis. The rate of second malignancy was 0.9%. Proton therapy offers commensurate disease control to modern photon therapy without unexpected toxicity. The high rate of long-term survival justifies efforts to reduce radiation exposure in this young population with brain tumors. Independent of radiation modality, this large series confirms extent of resection as the most important modifiable factor for survival. The pronounced gender disparity in survival deserves greater attention.

Feasibility of Deep Inspiratory Breath Hold in Pediatric Patients Receiving Proton Therapy for Hodgkin Lymphoma Patients to Decrease Radiation Dose to Organs at Risk

Radiation therapy plays an important role in the combined modality treatment of Hodgkin lymphoma (HL) in pediatric patients. Given the excellent oncologic outcomes following therapy, late toxicities from radiation therapy, such as cardiovascular disease and second malignancy, are a major concern. Deep Inspiratory Breath Hold (DIBH) has been used in adult patients to minimize normal tissue radiation exposure. Our institution has developed a pathway to use DIBH in pediatric patients with HL involving the mediastinum and hilum in an effort to reduce dose to nearby tissues and organs at risk (OARs). From 12/2016-11/2018, 19 consecutive pediatric patients with HL received pencil beam scanning proton therapy to the mediastinum and other subsites. All patients first underwent DIBH and 5-point mask education with a nurse navigator prior to consultation, met with child life specialists prior to DIBH training and 5-point mask creation, and then underwent actual DIBH CT simulation. Patients who underwent DIBH CT simulation had treatment volumes and OARs contoured on a breath hold scan for treatment planning and on a free breathing 4D scan (FBS) for volumetric comparative analysis. All 19 patients were successfully simulated with DIBH; no patient was unable to tolerate simulation with 5-point mask and DIBH. The median age was 17 (range 9-21). Male: female ratio was 8:11. Patients had Stage II (n = 9), III (5), and IV (5) nodular sclerosing HL. Sites of treatment included neck (N), supraclavicular fossa (Sc), and mediastinum (M) in 9, Sc, M, and hila (H) in 3, Sc, M, and axilla (A) in 3, Sc and M in 2, and Sc, M, N, H, and A in 2. Sixteen patients received a total dose of 21Gy, the remaining three patients received 30Gy for residual FDG avid disease. All but 2 patients completed their radiation course using daily DIBH. One patient stopped treatment early due to disease progression, and the other patient was unable to tolerate DIBH during daily treatment. Compared to volumes on FBS, ITV volumes were an average of 242cm3 smaller using DIBH (p = 0.02). There was less ITV volume intersecting the left anterior descending artery (14.2cm3 vs 24.5 cm3, p = 0.02), left ventricle (32.1cm3 vs 54.5 cm3, p = 0.02), aorta (12.2cm3 vs 29.5 cm3, p = 0.02), and lung (67.2cm3 vs 98.5 cm3, p = 0.02) using DIBH compared to FBS. DIBH is feasible in a pediatric patient population with support of multidisciplinary education and coaching, and has the potential to optimize the therapeutic ratio in patients with Hodgkin lymphoma. Reductions in dose to OARs may allow for reduced long term toxicity risk following radiation therapy, and this approach should be considered for select pediatric patients receiving radiation therapy to the mediastinum.

Patterns Of Failure For Adolescent And Young Adult Hodgkin Lymphoma Patients Treated With Radiotherapy In The Modern Era: A Multi-Institution Review

The treatment of adolescent and young adults (AYA) with classical Hodgkin lymphoma (cHL) can be challenging given the significant differences in treatment approaches for the pediatric and adult populations. We aimed to assess outcomes in this population across three institutions to evaluate patterns of and predictive factors for failure following treatment including radiotherapy. After institutional review board approval at all institutions, we included 91 consecutive patients with stage I or II cHL treated with radiotherapy as part of their initial course of treatment at one of three institutions between July 2008 and December 2017. We excluded patients with less than 3 months of follow-up. Demographic and treatment variables were abstracted from patient medical records. In- versus out-of-field relapses were determined at the discretion of the treating physician. Kaplan-Meier survival analyses were performed to determine differences in disease-free survival (DFS) and overall survival (OS). We included 91 patients; the cohort was predominately female (64%) and had a relatively even age distribution (<18: 26%; 18 - <30: 37%; ≥30: 36%); most patients had stage II disease (87%). The majority of patients were treated with typical adult doses in excess of 30 Gy (59%). Total dose ranged from 15 - 45 Gy. A total of 63% of patients had unfavorable-risk disease. There was an even balance by treatment modality with 53% of patients receiving proton therapy and the remainder receiving photon therapy. With a median follow-up of 2.6 years, the overall 2-year progression-free survival rate (PFS) was 89%. Of the 12 patients who experienced progression after RT, 4 occurred out-of-field only, 2 occurred in-field only, and 6 experienced progression both in- and out-of-field. There were no significant differences in 2-year PFS among AYA patients by radiotherapy dose received (≥30 Gy, 91%; <30 Gy, 86%; p = 0.82). Likewise, there was no difference in 2-year PFS among patients who received either proton or photon therapy (proton, 94%; photon, 83%; p = 0.07). Patients with favorable- and unfavorable-risk disease had similar outcomes (2-year DFS 94% vs 86%, p = 0.27). AYA patients with early-stage cHL experience excellent outcomes after treatment regimens including radiotherapy regardless of dose used. Proton therapy appears to be associated with no reduction in disease control relative to photon therapy in this population. Further research in optimally delineating patients who best tolerate lower radiotherapy doses and require more advanced modalities such as proton therapy is needed.

171: The Role of Socioeconomic Status (Ses) in Disease Outcomes in Pediatric Cancer Patients Receiving Proton Therapy

171: The Role of Socioeconomic Status (Ses) in Disease Outcomes in Pediatric Cancer Patients Receiving Proton Therapy

Treatment Outcomes After Proton Therapy for Ewing Sarcoma of the Pelvis

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. 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. 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. 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.

Three-Year Results of a Prospective Statewide Insurance Coverage Pilot for Proton Therapy: Stakeholder Collaboration Improves Patient Access to Care.

Proton therapy is increasingly prescribed, given its potential to improve outcomes; however, prior authorization remains a barrier to access and is associated with frequent denials and treatment delays. We sought to determine whether appropriate access to proton therapy could ensure timely care without overuse or increased costs. Our large academic cancer center collaborated with a statewide self-funded employer (n = 186,000 enrollees) on an insurance coverage pilot, incorporating a value-based analysis and ensuring preauthorization for appropriate indications. Coverage was ensured for prospective trials and five evidence-supported anatomic sites. Enrollment initiated in 2016 and continued for 3 years. Primary end points were use, authorization time, and cost of care, with case-matched comparison of total charges at 1 month pretreatment through 6 months posttreatment. Thirty-two patients were approved over 3 years, with only 22 actually receiving proton therapy, versus a predicted use by 120 patients (P < .01). Median follow-up was 20.1 months, and average authorization time decreased from 17 days to < 1 day (P < .01), significantly enhancing patient access. During this time, 25 patients who met pilot eligibility were instead treated with photons; and 17 patients with > 6 months of follow-up were case matched by treatment site to 17 patients receiving proton therapy, with no significant differences in sex, age, performance status, stage, histology, indication, prescribed fractions, or chemotherapy. Total medical costs (including radiation therapy [RT] and non-RT charges) for patients treated with PBT were lower than expected (a cost increase initially was expected), with no significant difference in total average charges (P = .82), in the context of overall ancillary care use. This coverage pilot demonstrated that appropriate access to proton therapy does not necessitate overuse or significantly increase comprehensive medical costs. Objective evidence-based coverage polices ensure appropriate patient selection. Stakeholder collaboration can streamline patient access while reducing administrative burden.

End-of-Range Radiobiological Effect on Rib Fractures in Patients Receiving Proton Therapy for Breast Cancer

A prospective trial of proton therapy for breast cancer revealed an increased rib fracture rate of 7%, which is higher than the expected rate based on the literature on photon therapies. We aim to evaluate the hypothesis that the increased relative biological effectiveness (RBE) at the distal edge of proton beams is the cause. We combined the cohort from the prospective clinical trial and a retrospective cohort from a database. Monte Carlo simulations were performed to recalculate the physical dose and dose-averaged linear energy transfer (LETd). The first 10 ribs and fracture areas in patients with fractures were contoured and deformably registered. The LETd-weighted dose was used as a surrogate for biological effectiveness and compared with the conventional fixed RBE of 1.1. Dose to 0.5 cm3 of the ribs (D0.5) was selected to analyze the dose-response relationship using logistic regression. We chose an alpha/beta ratio of 3 to calculate the biological effective dose in Gy3(RBE). Thirteen of 203 patients in the cohorts exhibited a total of 25 fractures. The LETd in fractured areas is increased (6.1 ± 2.0 keV/μm, mean ± standard deviation), suggesting possible end-of-range radiobiological effects with increased RBE. The D0.5 of the fractured ribs is 80.3 ± 9.4 Gy3(RBE) with a generic factor of 1.1 and is relatively low compared with historical photon results. On the other hand, the D0.5 of the fractured ribs is 100.0 ± 12.5 Gy3(RBE) using the LETd-based model with a dose-response curve that is more consistent with historical photon data. The increased rib fracture rate seen in our trial is probably associated with the increased LETd and RBE at the distal edge of proton beams. This phenomenon warrants further investigation and possible integration of LETd into treatment planning and optimization in proton therapy.

Temporal Lobe Necrosis in Head and Neck Cancer Patients after Proton Therapy to the Skull Base.

Purpose:To demonstrate temporal lobe necrosis (TLN) rate and clinical/dose-volume factors associated with TLN in radiation-naïve patients with head and neck cancer treated with proton therapy where the field of radiation involved the skull base.Materials and Methods:Medical records and dosimetric data for radiation-naïve patients with head and neck cancer receiving proton therapy to the skull base were retrospectively reviewed. Patients with <3 months of follow-up, receiving <45 GyRBE or nonconventional fractionation, and/or no follow-up magnetic resonance imaging (MRI) were excluded. TLN was determined using MRI and graded using Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Clinical (gender, age, comorbidities, concurrent chemotherapy, smoking, radiation techniques) and dose-volume parameters were analyzed for TLN correlation. The receiver operating characteristic curve and area under the curve (AUC) were performed to determine the cutoff points of significant dose-volume parameters.Results:Between 2013 and 2019, 234 patients were included. The median follow-up time was 22.5 months (range = 3.2–69.3). Overall TLN rates of any grade, ≥ grade 2, and ≥ grade 3 were 5.6% (N = 13), 2.1%, and 0.9%, respectively. The estimated 2-year TLN rate was 4.6%, and the 2-year rate of any brain necrosis was 6.8%. The median time to TLN was 20.9 months from proton completion. Absolute volume receiving 40, 50, 60, and 70 GyRBE (absolute volume [aV]); mean and maximum dose received by the temporal lobe; and dose to the 0.5, 1, and 2 cm3 volume receiving the maximum dose (D0.5cm3, D1cm3, and D2cm3, respectively) of the temporal lobe were associated with greater TLN risk while clinical parameters showed no correlation. Among volume parameters, aV50 gave maximum AUC (0.921), and D2cm3 gave the highest AUC (0.935) among dose parameters. The 11-cm3 cutoff value for aV50 and 62 GyRBE for D2cm3 showed maximum specificity and sensitivity.Conclusion:The estimated 2-year TLN rate was 4.6% with a low rate of toxicities ≥grade 3; aV50 ≤11 cm3, D2cm3 ≤62 GyRBE and other cutoff values are suggested as constraints in proton therapy planning to minimize the risk of any grade TLN. Patients whose temporal lobe(s) unavoidably receive higher doses than these thresholds should be carefully followed with MRI after proton therapy.