Clinical outcomes and toxicities of 100 patients treated with proton therapy for chordoma on the proton collaborative group prospective registry.

BACKGROUND: We present efficacy and toxicity outcomes among patients with chordoma treated on the Proton Collaborative Group prospective registry. METHODS: Consecutive chordoma patients treated between 2010-2018 were evaluated. One hundred fifty patients were identified, 100 had adequate follow-up information. Locations included base of skull (61%), spine (23%), and sacrum (16%). Patients had a performance status of ECOG 0-1 (82%) and median age of 58 years. Eighty-five percent of patients underwent surgical resection. The median proton RT dose was 74 Gy (RBE) (range 21-86 Gy (RBE)) using passive scatter proton RT (PS-PBT) (13%), uniform scanning proton RT (US-PBT) (54%) and pencil beam scanning proton RT (PBS-PBT) (33%). Rates of local control (LC), progression-free survival (PFS), overall survival (OS) and acute and late toxicities were assessed. RESULTS: 2/3-year LC, PFS, and OS rates are 97%/94%, 89%/74%, and 89%/83%, respectively. LC did not differ based on surgical resection (p = 0.61), though this is likely limited by most patients having undergone a prior resection. Eight patients experienced acute grade 3 toxicities, most commonly pain (n = 3), radiation dermatitis (n = 2), fatigue (n = 1), insomnia (n = 1) and dizziness (n = 1). No grade ≥ 4 acute toxicities were reported. No grade ≥ 3 late toxicities were reported, and most common grade 2 toxicities were fatigue (n = 5), headache (n = 2), CNS necrosis (n = 1), and pain (n = 1). CONCLUSIONS: In our series, PBT achieved excellent safety and efficacy outcomes with very low rates of treatment failure. CNS necrosis is exceedingly low (<1%) despite the high doses of PBT delivered. Further maturation of data and larger patient numbers are necessary to optimize therapy in chordoma.

Dosimetry and Acute Toxicity Profile of Patients With Esophageal Cancer Treated With Proton Beam Radiation Therapy: Outcomes From the Proton Collaborative Group REG001-09 Trial.

PURPOSE: Concurrent chemoradiation plays an integral role in the treatment of esophageal cancer. Proton beam radiation therapy has the potential to spare adjacent critical organs, improving toxicity profiles and potentially improving clinical outcomes. METHODS AND MATERIALS: We evaluated the REG001-09 registry for patients undergoing proton radiation therapy for esophageal cancer. Demographic, clinicopathologic, toxicity, and dosimetry information were compiled. RESULTS: We identified 155 patients treated at 10 institutions between 2010 and 2019. One hundred twenty (77%) had adenocarcinoma and 34 (22%) had squamous cell carcinoma. One hundred thirty-seven (88%) received concurrent chemotherapy. The median delivered dose was 50.51 Gy-equivalent (GyE; range, 41.4-70.1). Grade ≥3 toxicities occurred in 22 (14%) of patients and were most commonly dysphagia (6%), esophagitis (4%), anorexia (4%), and nausea (2%). There were no episodes of grade ≥4 lymphopenia and no grade 5 toxicities. The average mean heart, lung, and liver doses and average maximum spinal cord dose were 10.0 GyE, 4.8 GyE, 3.8 GyE, and 34.2 GyE, respectively. For gastroesophageal junction tumors, 8% of patients developed acute grade ≥3 toxicity and the mean heart, liver, right kidney, and left kidney doses were 10.5 GyE, 3.9 GyE, 0.4 GyE, and 4.9 GyE, respectively. Gastroesophageal junction location was protective against development of grade ≥3 toxicity on univariate (P = .0009) and multivariate (P = .004) analysis. CONCLUSIONS: Proton beam radiation therapy affords excellent dosimetric parameters and low toxicity in patients with esophageal cancer treated with curative intent. Prospective trials are underway investigating the comparative benefit of proton-based therapy.

Optimization of Field Design in the Treatment of Rectal Cancer with Intensity Modulated Proton Beam Radiation Therapy: How Many Fields Are Needed to Account for Rectal Distension Uncertainty?

PURPOSE: Preoperative chemoradiation represents the standard of care in patients with locally advanced rectal cancer. Robustness is often compromised in the setting of proton beam therapy owing to the sensitivity of proton particles to tissue heterogeneity, such as with intestinal gas. The ideal beam arrangement to mitigate the anatomic uncertainty caused by intestinal gas is not well defined. METHODS AND MATERIALS: We developed pencil beam scanning plans using (1) 1-beam posteroanterior (PA) plans, (2) 2-beam with right and left posterior oblique (RPO and LPO) plans, (3) 3-beam with PA and opposed lateral plans, and (4) 5-beam with PA, RPO, LPO, and opposed lateral plans. We created 12 plans with robustness optimization and ran a total of 60 plan evaluations for varying degrees of intestinal gas distension to evaluate which plans would maintain clinical goals to the greatest degree. RESULTS: A single PA beam resulted in considerable loss of target coverage to the clinical target volume prescribed 50 Gy (volume receiving 100% of the prescribed dose [V100%] < 90%) with rectal distension ≥3 cm in diameter in the short axis. In contrast, the other field designs maintained coverage with up to 5 cm of distension. On plans generated based on a 5-cm distended rectum with air medium, the 1-beam, 3-beam, and 5-beam arrangements resulted in loss of target coverage (V100% < 90%) with rectal contraction ≤3 cm, whereas the 2-beam arrangement maintained coverage to as low as 2 cm. On plans generated based on a 3-cm distension of the rectum, both the 2-beam and 3-beam arrangements maintained V100% > 90% even with collapsed rectum to as low as 1 cm, simulating a patient treatment scenario without any rectal gas. CONCLUSIONS: A single PA beam should be avoided when using proton beam therapy for rectal cancer. RPO/LPO and PA/opposed lateral arrangements may both be considered; RPO/LPO is favored to reduce integral dose and avoid beams traversing the hips. In patients for whom the plan CT has rectal distension of ≥3 cm, resimulation or strategies to reduce intestinal gas should be strongly considered.

Proton Therapy for Skull-Base Chordomas and Chondrosarcomas: Initial Results From the Beaumont Proton Therapy Center.

  Background:Skull-base chordomas and chondrosarcomas are rare tumors that arise directly adjacent to important critical structures. Appropriate management consists of maximal safe resection followed by postoperative dose-escalated radiation therapy. Proton beam therapy is often employed in this context to maximize the sparing of organs at risk, such as the brainstem and optic apparatus. METHODS: This is a single-institutional experience treating skull-base chordomas and chondrosarcomas with postoperative pencil beam scanning proton therapy. We employed a simultaneous integrated boost to the gross tumor volume (GTV) for increased conformality. Demographic, clinicopathologic, toxicity, and dosimetry information were collected. Toxicity was assessed according to Common Terminology Criteria for Adverse Events (CTCAE), v. 4.0. RESULTS: Between 2017 and 2020, 13 patients were treated with postoperative proton therapy. There were 10 patients with chordoma (77%) and three with chondrosarcoma (23%). A gross total resection was achieved in six (60%) patients with chordoma and one patient with chondrosarcoma (33%). Nine patients (69%) received postoperative therapy, whereas four (31%) received treatment at recurrence/progression following re-excision. The median dose to the GTV was 72.4 cobalt-Gray equivalents (range, 70.0 to 75.8). The mean GTV was 3.4 cc (range, 0.2-38.7). There were no grade 3 or greater toxicities. One patient developed grade 2 temporal lobe necrosis. At 10.7 months' median follow-up (range, 2.1-30.6), the rates of local control and overall survival were 100%. CONCLUSIONS: Proton beam therapy with pencil beam scanning and simultaneous integrated boost to the GTV affords excellent early local control with the suggestion of low morbidity. This method deserves consideration as an optimal method for limiting dose to adjacent organs at risk and delivering clinically effective doses to the treatment volume.

Linear Energy Transfer Incorporated Spot-Scanning Proton Arc Therapy Optimization: A Feasibility Study.

PURPOSE: To integrate dose-averaged linear energy transfer (LETd) into spot-scanning proton arc therapy (SPArc) optimization and to explore its feasibility and potential clinical benefits. METHODS: An open-source proton planning platform (OpenREGGUI) has been modified to incorporate LETd into optimization for both SPArc and multi-beam intensity-modulated proton therapy (IMPT) treatment planning. SPArc and multi-beam IMPT plans with different beam configurations for a prostate patient were generated to investigate the feasibility of LETd-based optimization using SPArc in terms of spatial LETd distribution and plan delivery efficiency. One liver and one brain case were studied to further evaluate the advantages of SPArc over multi-beam IMPT. RESULTS: With similar dose distributions, the efficacy of spatially optimizing LETd distributions improves with increasing number of beams. Compared with multi-beam IMPT plans, SPArc plans show substantial improvement in LETd distributions while maintaining similar delivery efficiency. Specifically, for the liver case, the average LETd in the GTV was increased by 124% for the SPArc plan, and only 9.6% for the 2-beam IMPT plan compared with the 2-beam non-LETd optimized IMPT plan. In case of LET optimization for the brain case, the SPArc plan could effectively increase the average LETd in the CTV and decrease the values in the critical structures while smaller improvement was observed in 3-beam IMPT plans. CONCLUSION: This work demonstrates the feasibility and significant advantages of using SPArc for LETd-based optimization, which could maximize the LETd distribution wherever is desired inside the target and averts the high LETd away from the adjacent critical organs-at-risk.

Hidradenocarcinoma of the Abdominal Wall Treated With Wide Surgical Excision and Adjuvant Radiotherapy.

Hidradenocarcinomas are rare malignant sweat gland tumors that typically arise in the head and neck area. To the best of our knowledge, this is the only reported instance of hidradenocarcinoma of the abdominal wall as well as the first case arising from a region of prior trauma. A 72-year-old female presented with a left abdominal wall lesion, which she had first noticed after an injury to the area. Initially, the lesion remained stable in size, after which it became mildly pruritic, progressive in size, and expressive of a clear, non-odorous discharge. Imaging demonstrated a heterogeneous cystic density. Surgical pathology revealed a malignant dermal adnexal neoplasm composed of pleomorphic polygonal cells and focal intracytoplasmic lumina lined by eosinophilic cuticles, as well as areas of ductal differentiation, apocrine differentiation, and mucinous metaplasia. Surgical excision of the mass was performed, followed by adjuvant external beam radiotherapy (EBRT). The patient had no long-term toxicities or clinical evidence of local disease recurrence as of one year post-surgery and six months post-EBRT. Early diagnosis and treatment are essential to improving outcomes in patients with hidradenocarcinomas. Frequent follow-up is equally important, as these tumors have high recurrence rates.

Perivascular Epithelioid Cell Tumor of the Buttock Region.

Perivascular epithelioid cell neoplasms, also known as PEComas, are a group of rare mesenchymal tumors that have a perivascular distribution and have no known counterpart to normal cells. The PEComa grouping includes angiomyolipomas, lymphangioleiomyomatoses, clear cell (sugar) tumors at extrapulmonary and intrapulmonary sites, clear cell myomelanocytic tumor of the falciform ligament/ligamentum teres among others. These rare tumors most commonly arise in the uterus. Here, we present an unusual case of malignant PEComa arising in the buttock region.

A population-based analysis of chemoradiation versus radiation alone in the definitive treatment of patients with stage I-II squamous cell carcinoma of the anus.

BACKGROUND: The optimal management of patients with stage I-II squamous cell carcinoma (SCC) of the anus is controversial. The current study evaluates the efficacy of combined chemotherapy and radiation therapy (CRT) versus radiation therapy (RT) alone in the treatment of these patients using the Surveillance, Epidemiology, and End Results (SEER) registries. METHODS: SEER 18 Custom Data registries were queried for patients with stage I-II SCC of the anus. Univariate analysis (UVA) and multivariable analysis (MVA) using Kaplan-Meier and Cox proportional hazards regression modeling were performed. Propensity-score matched analysis with inverse probability of treatment weighting (IPTW) was used to account for indication bias. RESULTS: A total of 4,288 patients with stage I-II disease were identified, of whom 3,982 (93%) underwent CRT and 306 (7%) underwent RT. Median follow-up was 42 months. Approximately 30.8% had T1 disease and 69.2% had T2-T3 disease. The IPTW-adjusted 5-year overall survival (OS) was 76.7%, with no significant differences between the CRT and RT groups (77% vs. 73.5%, P=0.33). On multivariate IPTW-adjusted analysis, the lack of association between CRT use and OS was upheld (HR, 0.84, 95% CI, 0.65-1.08, P=0.2). On subgroup analyses, 5-year OS was 86% with CRT (n=1,216) and 84.2% with RT (n=103) (P=0.74) in stage I (T1N0) patients, while 5-year OS was 72.8% with CRT (n=2,766) and 66.4% with RT (n=203) (P=0.13) in stage II (T2-3N0) patients. CRT was associated with improved median OS in stage II patients (119 months vs. not reached, P=0.04). CONCLUSIONS: The current study suggests that omission of concurrent chemotherapy is not associated with inferior OS in patients with stage I SCC of the anus. However, combined chemoradiation was superior to radiation alone in patients with stage II disease. Prospective evidence is needed to optimize clinical decision-making in this patient population.

Ethical Allocation of Proton Therapy and the Insurance Review Process.

PURPOSE: The purpose of this study was to delineate a scoring system to maximize the ethical allocation of proton beam therapy (PBT) and determine what factors are associated with receipt of PBT, including the role of specific insurance providers. METHODS AND MATERIALS: Our scoring system was developed in collaboration with a multidisciplinary panel of experts. Patients submitted for PBT consideration were assigned a score by committee at a weekly peer-reviewed session at a time when our center was operating at capacity. Univariate analysis and multivariable analysis of initial and final insurance response were performed. RESULTS: One hundred ninety-seven patients were prospectively reviewed. Ninety-three percent of patients with Medicaid coverage, 88% of patients with Medicare, and 78% of patients with private insurance were ultimately approved for PBT. Median time to final insurance response was 12 days (interquartile range, 9-18 days) for patients who were ultimately denied PBT coverage. Having primary provider C (odds ratio [OR], 14; 95% confidence interval [CI], 1.20-1.96; P = .033) or third party providers A (OR, 4.22; 95% CI, 1.71-10.9; P = .002) or B (OR, 5.28; 95% CI, 1.56-17.2; P = .006) was significantly associated with final insurance denial for PBT on univariate analysis. Total score (OR, 0.79; 95% CI, 0.67-0.90; P = .002) and having coverage through third party provider A (OR, 24.2; 95% CI, 9.51-68.9; P < .001) were associated with final insurance response on multivariable analysis. CONCLUSIONS: Our scoring system was significantly associated with receipt of proton beam therapy. Certain insurance providers are less likely to approve PBT for patients, all else being equal. Such a scoring system could be implemented effectively at other PBT facilities, and additional work is needed in ensuring patients with the most to gain from PBT will be approved by their insurance providers.

Rectal cancer in young patients: incidence and outcome disparities.

BACKGROUND: There is an alarming rise in incidence among young patients with rectal cancer. The National Cancer Database (NCDB) and Surveillance, Epidemiology, and End Results Analysis (SEER) databases may help identify population level disparities in incidence and cancer-related outcomes. METHODS: A total of 197,178 patients within the SEER 18 registry and 221,886 patients from the NCDB database with rectal cancer were evaluated in this retrospective cohort study. The analyzed cohort consisted of young (<50), white or African American patients. Indication bias was mitigated by conducting inverse probability of treatment weighted analysis using binary logistic regression modeling to determine propensity score for being white or African American. RESULTS: A total of 6,144 young patients were identified from the SEER 18 registry and a total of 17,819 young patients were identified from the NCDB. From 1990 to 2016, there was a significant change in rectal cancer incidence, with a steadily increasing APC of 3.06 (P<0.05). The was no overall change in age-adjusted APC among young African American patients (APC 0.00, P=1); however, there was a significant increase among young white patients (APC 2.97, P<0.05). There was an increased incidence for both stage III and IV among young rectal cancer patients, with an age-adjusted APC of 5.35 and 3.83, respectively (P<0.05). After propensity score matching and inverse probability of treatment weighting, young African Americans had worse overall survival in both the NCDB and SEER (HR 1.1-1.3, P<0.05) databases. This disparity was also seen for cancer-specific survival (HR 1.5, P=0.002). CONCLUSIONS: The current study adds to the growing body of literature demonstrating an alarming increase in incidence of rectal cancer among young patients. Moreover, the incidence appears to be increasing particularly among young white patients and driven by stage III disease.

Hypofractionated proton beam radiotherapy in patients with unresectable liver tumors: multi-institutional prospective results from the Proton Collaborative Group.

BACKGROUND: Recent advances in radiotherapy techniques have allowed ablative doses to be safely delivered to inoperable liver tumors. In this setting, proton beam radiotherapy (PBT) provides the means to escalate radiation dose to the target volume while sparing the uninvolved liver. This study evaluated the safety and efficacy of hypofractionated PBT for liver tumors, predominantly hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). METHODS: We evaluated the prospective registry of the Proton Collaborative Group for patients undergoing definitive PBT for liver tumors. Demographic, clinicopathologic, toxicity, and dosimetry information were compiled. RESULTS: To date, 63 patients have been treated at 9 institutions between 2013 and 2019. Thirty (48%) had HCC and 25 (40%) had ICC. The median dose and biological equivalent dose (BED) delivered was 58.05 GyE (range 32.5-75) and 80.5 GyE (range 53.6-100), respectively. The median mean liver BED was 13.9 GyE. Three (4.8%) patients experienced at least one grade ≥ 3 toxicity. With median follow-up of 5.1 months (range 0.1-40.8), the local control (LC) rate at 1 year was 91.2% for HCC and 90.9% for ICC. The 1-year LC was significantly higher (95.7%) for patients receiving BED greater than 75.2 GyE than for patients receiving BED of 75.2 GyE or lower (84.6%, p = 0.029). The overall survival rate at 1 year was 65.6% for HCC and 81.8% for ICC. CONCLUSIONS: Hypofractionated PBT results in excellent LC, sparing of the uninvolved liver, and low toxicity, even in the setting of dose-escalation. Higher dose correlates with improved LC, highlighting the importance of PBT especially in patients with recurrent or bulky disease.

Feasibility study: spot-scanning proton arc therapy (SPArc) for left-sided whole breast radiotherapy.

BACKGROUND: This study investigated the feasibility and potential clinical benefit of utilizing a new proton treatment technique: Spot-scanning proton arc (SPArc) therapy for left-sided whole breast radiotherapy (WBRT) to further reduce radiation dose to healthy tissue and mitigate the probability of normal tissue complications compared to conventional intensity modulated proton therapy (IMPT). METHODS: Eight patients diagnosed with left-sided breast cancer and treated with breast-preserving surgery followed by whole breast irradiation without regional nodal irradiation were included in this retrospective planning. Two proton treatment plans were generated for each patient: vertical intensity-modulated proton therapy used for clinical treatment (vIMPT, gantry angle 10°-30°) and SPArc for comparison purpose. Both SPArc and vIMPT plans were optimized using the robust optimization of ± 3.5% range and 5 mm setup uncertainties. Root-mean-square deviation dose (RMSD) volume histograms were used for plan robustness evaluation. All dosimetric results were evaluated based on dose-volume histograms (DVH), and the interplay effect was evaluated based on the accumulation of single-fraction 4D dynamic dose on CT50. The treatment beam delivery time was simulated based on a gantry rotation with energy-layer-switching-time (ELST) from 0.2 to 5 s. RESULTS: The average D1 to the heart and LAD were reduced to 53.63 cGy and 82.25 cGy compared with vIMPT 110.38 cGy (p = 0.001) and 170.38 cGy (p = 0.001), respectively. The average V5Gy and V20Gy of ipsilateral lung was reduced to 16.77% and 3.07% compared to vIMPT 25.56% (p = 0.001) and 4.68% (p = 0.003). Skin3mm mean and maximum dose were reduced to 3999.38 cGy and 4395.63 cGy compared to vIMPT 4104.25 cGy (p = 0.039) and 4411.63 cGy (p = 0.043), respectively. A significant relative risk reduction (RNTCP = NTCPSPArc/NTCPvIMPT) for organs at risk (OARs) was obtained with SPArc ranging from 0.61 to 0.86 depending on the clinical endpoint. The RMSD volume histogram (RVH) analysis shows SPArc provided better plan robustness in OARs sparing, including the heart, LAD, ipsilateral lung, and skin. The average estimated treatment beam delivery times were comparable to vIMPT plans when the ELST is about 0.5 s. CONCLUSION: SPArc technique can further reduce dose delivered to OARs and the probability of normal tissue complications in patients treated for left-sided WBRT.

A novel energy sequence optimization algorithm for efficient spot-scanning proton arc (SPArc) treatment delivery.

BACKGROUND: Spot-scanning proton arc therapy (SPArc) has been proposed to improve dosimetric outcome and to simplify treatment workflow. To efficiently deliver a SPArc plan, it's crucial to minimize the number of energy layer switches (ELS) a sending because of the magnetic hysteresis effect. In this study, we introduced a new SPArc energy sequence optimization algorithm (SPArc_seq) to reduce ascended ELS and to investigate its impact on the beam delivery time (BDT). METHOD AND MATERIALS: An iterative energy layer sorting and re-distribution mechanism following the direction of the gantry rotation was implemented in the original SPArc algorithm (SPArc_orig). Five disease sites, including prostate, lung, brain, head neck cancer (HNC) and breast cancer were selected to evaluate this new algorithm. Dose-volume histogram (DVH) and plan robustness were used to assess the plan quality for both SPArc_seq and SPArc_orig plans. The BDT evaluations were analyzed through two methods: 1. fixed gantry angle delivery (BDTfixed) and 2. An in-house dynamic arc scanning controller simulation which considered of gantry rotation speed, acceleration and deceleration (BDTarc). RESULTS: With a similar total number of energy layers, SPArc_seq plans provided a similar nominal plan quality and plan robustness compared to SPArc_orig plans. SPArc_seq significantly reduced the number of ascended ELS by 83% (19 vs.115), 70% (16 vs. 64), 82% (19 vs. 104), 80% (19 vs. 94) and 70% (9 vs. 30), which effectively shortened the BDTfixed by 65% (386 vs. 1091 s), 61% (235 vs. 609 s), 64% (336 vs. 928 s), 48% (787 vs.1521 s) and 25% (384 vs. 511 s) and shortened BDTarc by 54% (522 vs.1128 s), 52% (310 vs.645 s), 53% (443 vs. 951 s), 49% (803 vs.1583 s) and 26% (398 vs. 534 s) in prostate, lung, brain, HNC and breast cancer, respectively. CONCLUSIONS: The SPArc_seq optimization algorithm could effectively reduce the BDT compared to the original SPArc algorithm. The improved efficiency of the SPArc_seq algorithm has the potential to increase patient throughput, thereby reducing the operation cost of proton therapy.

Patterns of care and outcomes for adjuvant treatment of pT3N0 rectal cancer using the National Cancer Database.

BACKGROUND: The standard of care in locally advanced rectal cancer is preoperative chemoradiation followed by surgical resection. However, the optimal treatment paradigm is currently controversial for patients with pathological T3N0 (pT3N0) in the era of total mesorectal excision (TME). Given the paucity of data, we conducted an analysis using the National Cancer Database (NCDB) to identify patterns of care and outcomes. METHODS: We utilized the NCDB to identify 7,836 non-metastatic, pT3N0 rectal cancer patients who did not receive neoadjuvant therapy from 2004-2014. Univariate and multivariable analysis for factors affecting treatment selection were completed using logistic regression. Overall survival (OS) analyses were completed using Cox regression modeling, incorporating propensity scores with inverse probability of treatment weighting (IPTW) and conditional landmark analysis. RESULTS: There was a significant improvement in OS in patients receiving adjuvant chemotherapy (P<0.01) or radiotherapy (RT) with chemotherapy (P<0.01) vs. observation alone. There was no significant difference between RT vs. observation (P=0.54) and chemotherapy vs. chemotherapy with RT cohorts (P=0.15). Multivariable analysis showed age, gender, race, insurance status, income, Charlson-Deyo Comorbidity Condition (CDCC) score, facility location, grade, surgical margin, RT, and chemotherapy to be statistically significant predictors of OS. After correcting for indication and immortal time biases, chemotherapy, with or without RT, improved OS compared with observation [hazard ratio (HR) 0.48, P<0.001]. This benefit was maintained in the margin negative cohort. CONCLUSIONS: Practice patterns vary in the management of pT3N0 rectal cancer patients. This analysis suggests that the use of adjuvant therapy, particularly adjuvant chemotherapy with or without RT, appears to improve OS.

Improve the dosimetric outcome in bilateral head and neck cancer (HNC) treatment using spot-scanning proton arc (SPArc) therapy: a feasibility study.

BACKGROUND: To explore the dosimetric improvement, delivery efficiency, and plan robustness for bilateral head and neck cancer (HNC) treatment utilizing a novel proton therapy technique - the spot-scanning proton arc (SPArc) therapy. METHODS: We evaluated fourteen bilateral HNC patients retrospectively. Both SPArc and 3-field Intensity Modulated Proton Therapy (IMPT) plans were generated for each patient using the same robust optimization parameters. The prescription doses were 70Gy (relative biological effectiveness (RBE) for CTV_high and 60Gy[RBE] for CTV_low. Clinically significant dosimetric parameters were extracted and compared. Root-mean-square deviation dose (RMSDs) Volume Histogram(RVH) was used to evaluate the plan robustness. Total treatment delivery time was estimated based on the machine parameters. RESULTS: The SPArc plan was able to provide equivalent or better robust target coverage while showed significant dosimetric improvements over IMPT in most of the organs at risk (OARs). More specifically, it reduced the mean dose of the ipsilateral parotid, contralateral parotid, and oral cavity by 25.8%(p = 0.001), 20.8%(p = 0.001) and 20.3%(p = 0.001) respectively compared to IMPT. This technique reduced D1 (the maximum dose covering 1% volume of a structure) of cord and brain stem by 20.8% (p = 0.009) and 10.7% (p = 0.048), respectively. SPArc also reduced the average integral dose by 17.2%(p = 0.001) and external V3Gy (the volume received 3Gy[RBE]) by 8.3%(p = 0.008) as well. RVH analysis showed that the SPArc plans reduced the dose uncertainties in most OARs compared to IMPT, such as cord: 1.1 ± 0.4Gy[RBE] vs 0.7 ± 0.3Gy[RBE](p = 0.001), brain stem: 0.9 ± 0.7Gy[RBE] vs 0.7 ± 0.7Gy[RBE](p = 0.019), contralateral parotid: 2.5 ± 0.5Gy[RBE] vs 2.2 ± 0.6Gy[RBE](p = 0.022) and ipsilateral parotid: 3.1 ± 0.7Gy[RBE] vs 2.8 ± 0.6Gy[RBE](p = 0.004) respectively. The average total estimated treatment delivery time were 283.4 ± 56.2 s, 469.2 ± 62.0 s and 1294.9 ± 106.7 s based on energy-layer-switching-time (ELST) of 0.1 s, 1 s, and 5 s respectively for SPArc plans, compared to the respective values of 328.0 ± 47.6 s(p = 0.002), 434.1 ± 52.0 s(p = 0.002), and 901.7 ± 74.8 s(p = 0.001) for 3-field IMPT plans. The potential clinical benefit of utilizing SPArc will lead to a decrease in the mean probability of salivary flow dysfunction by 31.3%(p = 0.001) compared with IMPT. CONCLUSIONS: SPArc could significantly spare OARs while providing a similar or better robust target coverage compared with IMPT in the treatment of bilateral HNC. In the modern proton system with ELST less than 0.5 s, SPArc could potentially be implemented in the routine clinic with a practical, achievable treatment delivery efficiency.

A Patients-Based Statistical Model of Radiotherapy Dose Distribution in Nasopharyngeal Cancer.

PURPOSE: To develop a patients-based statistical model of dose distribution among patients with nasopharyngeal cancer (NPC). METHODS AND MATERIALS: The dose distributions of 75 patients with NPC were acquired and preprocessed to generate a dose-template library. Subsequently, the dominant modes of dose distribution were extracted using principal component analysis (PCA). Leave-one-out cross-validation (LOOCV) was performed for evaluation. Residual reconstruction errors between the doses reconstructed using different dominating eigenvectors and the planned dose distribution were calculated to investigate the convergence characteristics. Three-dimensional Gamma analysis was performed to investigate the accuracy of dose reconstruction. RESULTS: The first 29 components contained 90% of the variance in dose distribution, and 45 components accounted for more than 95% of the variance on average. The residual error of the LOOCV model for the cumulative sum of components over all patients decreased from 8.16 to 4.79 Gy when 1 to 74 components were included in the LOOCV model. The 3-dimensional Gamma analysis results implied that the PCA model was capable of dose distribution reconstruction, and the accuracy was especially satisfactory in the high-dose area. CONCLUSIONS: A PCA-based model of dose distribution variations in patients with NPC was developed, and its accuracy was determined. This model could serve as a predictor of 3-dimensional dose distribution.

18F-FDG PET Predicts Hematologic Toxicity in Patients with Locally Advanced Anal Cancer Treated With Chemoradiation.

PURPOSE: Hematologic toxicity (HT) during chemoradiation therapy (CRT) for anal cancer can lead to treatment breaks that compromise efficacy. We hypothesized that CRT-induced HT correlates with changes in active bone marrow (ABM) characterized by pre-/post-CRT positron emission tomography (PET)/computed tomography. METHODS AND MATERIALS: Data from 36 patients with anal cancer who were treated with 18F-fluorodeoxyglucose PET/computed tomography scans 2 weeks before and 6 to 16 weeks after CRT were analyzed. Complete blood counts with differential within 2 weeks from, weekly during, and 2 week after treatment were obtained. HT was defined as baseline complete blood count change to nadir and posttreatment recovery. Total bone marrow was segmented into 2 subregions: lumbosacral (LS) pelvis (L5 vertebrae, sacrum, and coccyx) and lower pelvis (LP) (ilium, femoral head/neck, and greater and lesser trochanter). PET ABM was characterized as the volume having standard uptake value (SUV) greater than the mean uptake of unirradiated extrapelvic bone marrow. PET variables of pre-/post-CRT and HT predictors were analyzed by linear regression. RESULTS: Average pelvic ABM was significantly reduced from 52% to 41% in pre- to post-CRT PET scans for all patients (P = .0012). Regional analysis indicated significant post-CRT reduction of LS-ABM (P < .0001) and LP-ABM (P = .006). Linear regression analysis identified post-CRT SUVmean, differential ΔSUVmean, and ΔABM as correlating significantly with pre- and posttreatment HT. ΔWBC linearly correlated with ΔABM of LS and LP pelvis (P = .033 and P = .028, respectively). Dosimetrically, ABM was sensitive to higher radiation doses (>50 Gy) in terms of acute hematologic ΔWBC (P = .021) and ΔANC(P = .028). HT increased with increasing volume of ABM receiving 40 Gy. The results also suggest that ABM V40 Gy ≤ 20% to 25% may significantly reduce the risk of HT. CONCLUSIONS: HT was significantly associated with ΔABM in patients with anal cancer who were treated with CRT. LS-ABM was a robust surrogate for evaluating CRT-induced HT. Our results suggest implementation of ABM dosimetric constraints, V40 Gy ≤ 20-25%, may significantly reduce HT and lead to decreased treatment delays associated with clinical outcomes.

Amelioration of Mucositis in Proton Therapy of Fanconi Anemia Fanca-/- Mice by JP4-039.

BACKGROUND/AIM: We tested JP4-039, a GS-nitroxide radiation damage mitigator in proton therapy of Fanconi anemia (FA) mice. MATERIALS AND METHODS: Fanca-/- and Fanca+/+ bone marrow stromal cells were pre-treated with JP4-039 and irradiated with either protons or photons (0-10 GyRBE) followed by clonogenic survival and ß-Galactosidase senescence analysis. Fanca-/- and Fanca+/+ mice were pretreated with JP4-039 for 10 min prior to oropharyngeal irradiation with either protons or photons (0 or 30 GyRBE) followed by sacrifice and measurement of oral cavity ulceration, distant hematopoietic suppression, and real-time polymerase chain reaction analysis. RESULTS: JP4-039 reduced oral cavity ulceration in Fanca-/- mice, transcripts Nfkb, Ap1, Sp1, and Nrf2, and proton therapy induced distant marrow suppression. CONCLUSION: JP4-039 protected Fanca-/- and Fanca+/+ cells and mouse oral cavity from both proton and photon radiation.

Trimodality therapy for atypical teratoid/rhabdoid tumor is associated with improved overall survival: A surveillance, epidemiology, and end results analysis.

BACKGROUND: Atypical teratoid/rhabdoid tumors (AT/RTs) are rare aggressive central nervous system tumors. The use of radiation therapy (RT) remains controversial, especially for patients younger than three years of age. The purpose of the current investigation is to robustly analyze the impact of RT among pediatric AT/RT patients using the Surveillance, Epidemiology, and End Results (SEER) database. METHODS: SEER 18 Custom Data registries were queried for AT/RT (ICD-0-3 9508/3). A total of 190 pediatric AT/RT patients were identified, of whom 102 underwent surgery + chemotherapy and 88 underwent trimodality therapy. Univariate and multivariable analyses using Kaplan-Meier and Cox proportional hazards regression modeling were performed. Propensity-score matched analysis with inverse probability of treatment weighting was performed to account for indication bias. The landmark method was used to account for immortal time bias. RESULTS: The majority of patients were <3 years old (75.8%). Patients <3 were more likely to be treated without RT as compared with older patients (62% vs 38%). Doubly robust MVA identified distant disease as a negative prognostic factor (HR 2.1, P = 0.003), whereas trimodality therapy was strongly protective (HR 0.39, P < 0.001). Infants (<1), toddlers (1-2), and older children (3+) all benefited from trimodality therapy, with largest benefit for infants (HR 0.34, P = 0.02) and toddlers (HR 0.31, P < 0.001). CONCLUSION: The current study provides further evidence that trimodality therapy improves clinical outcomes among patients with AT/RT. This finding was most pronounced for younger patients; therefore, further studies are needed to confirm this finding in this vulnerable population.

The first prototype of spot-scanning proton arc treatment delivery.

PURPOSE: We report the first prototype of spot-scanning arc treatment (SPArc) delivery on a clinical proton beam therapy machine and evaluate its delivery accuracy and efficiency. METHODS AND MATERIALS: A new module called Proton Dynamic Arc Delivery (PDAD) was developed to allow simultaneously delivering spot-scanning proton beam treatments while rotating the gantry on an IBA Proteus®One proton machine. A series of measurements was performed to validate the basic beam characteristics. Subsequently, patient specific quality assurance (QA) of a brain SPArc plan was performed. Total SPArc treatment delivery time was also recorded and compared to the clinically delivered intensity modulated proton therapy (IMPT) treatment time. Finally, the log file of the SPArc plan was analyzed and processed to reconstruct the actual delivered dose. RESULTS: All the basic beam characteristics were confirmed in the PDAD mode, similar as those measured using fixed gantry deliveries in clinical mode. The brain SPArc plan with similar or superior plan quality was delivered in 4 mins compared to total 11 mins for the clinical treatment of the three-field IMPT plan. The patient QA result showed a good agreement between the measured and calculated dose distributions with the gamma index of 98.6% (3%/3 mm). The analysis of the log file confirmed the accuracy of the SPArc plan delivery, with the gamma index of 98.3% (1%/1 mm) between reconstructed and the planned doses. CONCLUSION: The first prototype of dynamic proton arc delivery on a clinical proton therapy system was successfully performed. The measurements and simulations demonstrated the feasibility of SPArc treatment within the clinical requirements.