Gy Relative Biological Effectiveness Research Articles

Proton therapy for intracranial meningioma: a single-institution retrospective analysis of efficacy, survival and toxicity outcomes.

To report the outcomes of a large series of intracranial meningiomas (IMs) submitted to proton therapy (PT) with curative intent. We conducted a retrospective analysis on all consecutive IM patients treated between 2014 and 2021. The median PT prescription dose was 55.8Gy relative biological effectiveness (RBE) and 66 GyRBE for benign/radiologically diagnosed and atypical/anaplastic IMs, respectively. Local recurrence-free survival (LRFS), distant recurrence-free survival (DRFS), overall survival (OS), and radionecrosis-free survival (RNFS) were evaluated with the Kaplan-Meier method. Univariable analysis was performed to identify potential prognostic factors for clinical outcomes. Toxicity was reported according to the latest Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Overall, 167 patients were included. With a median follow-up of 41 months (range, 6-99), twelve patients (7%) developed tumor local recurrence after a median time of 39 months. The 5-year LRFS was 88% for the entire cohort, with a significant difference between benign/radiologically diagnosed and atypical/anaplastic IMs (98% vs. 47%, p < 0.001); this significant difference was maintained also for the 5-year OS and the 5-year DRFS rates. Patients aged ≤ 56 years reported significantly better outcomes, whereas lower prescription doses and skull base location were associated with better RNFS rates. Two patients experienced G3 acute toxicities (1.2%), and three patients G3 late toxicities (1.8%). There were no G4-G5 adverse events. PT proved to be effective with an acceptable toxicity profile. To the best of our knowledge this is one of the largest series including IM patients submitted to PT.

Outcomes of definitive carbon-ion radiotherapy for cT1bN0M0 esophageal squamous cell carcinoma.

A recent phase I/II study determined the optimal dose of definitive carbon-ion radiotherapy (CIRT) for cT1bN0M0 esophageal cancer. This study aimed to further confirm the efficacy and feasibility of the recommended dose fractionation of CIRT with long-term follow-up results in a larger sample size. This single center retrospective study evaluated patients with cT1bN0M0 esophageal squamous cell carcinoma treated with the recommended dose fractionation of 50.4Gy relative biological effectiveness in 12 fractions, between 2012 and 2022. Thirty-eight patients underwent CIRT at our hospital. Although eight (21.1%) patients were older than 80years, 15 (39.5%) had high surgical risk, and seven (18.4%) were at high risk for chemotherapy, all patients underwent CIRT as scheduled. Grade 3 esophagitis occurred in eight (21.1%) patients and grade 3 pneumonia in one (2.6%) patient in this study, but no grade 4 adverse events occurred. The only grade 3 late adverse event was pneumonia in one patient (2.6%). The 5-year overall survival rate, local control rate, and disease-free survival rates were 76.6% (95% CI, 90.9-62.4), 74.9% (95% CI, 90.7-59.0), and 66.4% (95% CI, 83.3-49.5), respectively. Additionally, post CIRT recurrence was as follows: seven (18.4%) patients had recurrence in another part of the esophagus, three (7.9%) in the primary site, three (7.9%) in lymph nodes outside the irradiated area, and one (2.6%) patient had liver metastasis. Our study demonstrates that CIRT using the recommended dose fractionation is feasible and effective for cT1bN0M0 esophageal squamous cell carcinoma.

Long-term survival outcomes and quality of life of image-guided proton therapy for operable stage I non-small cell lung cancer: A phase 2 study

Background and purposeThis study evaluated long-term efficacy, safety, and changes in quality of life (QOL) of patients after image-guided proton therapy (IGPT) for operable stage I non-small cell lung cancer (NSCLC). Materials and methodsThis single-institutional prospective phase 2 study enrolled patients with operable histologically confirmed stage IA or IB NSCLC (7th edition of UICC). The prescribed dose was 66 Gy relative biological effectiveness equivalents (GyRBE) in 10 fractions for peripheral lesions, or 72.6 GyRBE in 22 fractions for central lesions. The primary endpoint was the 3-year overall survival (OS). The secondary endpoints included disease control, toxicity, and changes in QOL score. ResultsWe enrolled 43 patients (median age: 68 years; range, 47–79 years) between July 2013 to January 2021, of whom 41 (95 %) had peripheral lesions and 27 (63 %) were stage IA. OS, local control, and progression-free survival rates were 95 % (95 % CI: 83–99), 95 % (82–99), and 86 % (72–94), respectively, at 3 years, and 83 % (66–92), 95 % (82–99), and 77 % (60–88), respectively, at 7 years. Four patients (9 %) developed grade 2, and one patient (2 %) developed grade 3 radiation pneumonitis. No other grade 3 or higher adverse events were observed. In the QOL analysis, global QOL remained favorable; however, approximately 40 % of patients reported dyspnea at 3 and 24 months. ConclusionOur findings suggest that IGPT provides effective disease control and survival in operable stage I NSCLC, particularly for peripheral lesions. Moreover, toxicity associated with IGPT was minimal, and patients reported favorable QOL.

Spot-scanning proton therapy for early breast cancer in free breathing versus deep inspiration breath-hold.

Proton therapy for breast cancer is usually given in free breathing (FB). With the use of deep inspiration breath-hold (DIBH) technique, the location of the heart is displaced inferiorly, away from the internal mammary nodes and, thus, the dose to the heart can potentially be reduced. The aim of this study was to explore the potential benefit of proton therapy in DIBH compared to FB for highly selected patients to reduce exposure of the heart and other organs at risk. We aimed at creating proton plans with delivery times feasible with treatment in DIBH. Sixteen patients with left-sided breast cancer receiving loco-regional proton therapy were included. The FB and DIBH plans were created for each patient using spot-scanning proton therapy with 2-3 fields, robust and single field optimization. For the DIBH plans, minimum monitor unit per spot and spot spacing were increased to reduce treatment delivery time. All plans complied with target coverage constraints. The median mean heart dose was statistically significant reduced from 1.1 to 0.6 Gy relative biological effectiveness (RBE) by applying DIBH. No statistical significant difference was seen for mean dose and V17Gy RBE to the ipsilateral lung. The median treatment delivery time for the DIBH plans was reduced by 27% compared to the FB plans without compromising the plan quality. The median absolute reduction in dose to the heart was limited. Proton treatment in DIBH may only be relevant for a subset of these patients with the largest reduction in heart exposure.

Prospective Analysis of Radiation-Induced Contrast Enhancement and Health-Related Quality of Life After Proton Therapy for Central Nervous System and Skull Base Tumors

Intracerebral radiation-induced contrast enhancement (RICE) can occur after photon as well as proton beam therapy (PBT). This study evaluated the incidence, characteristics, and risk factors of RICE after PBT delivered to, or in direct proximity to, the brain and its effect on health-related quality of life (HRQoL). Four hundred twenty-one patients treated with pencil beam scanning PBT between 2017 and 2021 were included. Follow-up included clinical evaluation and contrast-enhanced magnetic resonance imaging at 3, 6, and 12 months after treatment completion and annually thereafter. RICE was graded according to Common Terminology Criteria for Adverse Events version 4, and HRQoL parameters were assessed via European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30 questionnaires. The median follow-up was 24 months (range, 6-54), and median dose to 1% relative volume of noninvolved central nervous system (D1%CNS) was 54.3 Gy relative biologic effectiveness (RBE; range, 30-76 Gy RBE). The cumulative RICE incidence was 15% (n = 63), of which 10.5% (n = 44) were grade 1, 3.1% (n = 13) were grade 2, and 1.4% (n = 6) were grade 3. No grade 4 or 5 events were observed. Twenty-six of 63 RICE (41.3%) had resolved at the latest follow-up. The median onset after PBT and duration of RICE in patients in whom the lesions resolved were 11.8 and 9.0 months, respectively. On multivariable analysis, D1%CNS > 57.6 Gy RBE, previous in-field radiation, and diabetes mellitus were identified as significant risk factors for RICE development. Previous radiation was the only factor influencing the risk of symptomatic RICE. After PBT, general HRQoL parameters were not compromised. In a matched cohort analysis of 54/50 patients with and without RICE, no differences in global health score or functional and symptom scales were seen. The overall incidence of clinically relevant RICE after PBT is very low and has no significant negative effect on long-term patient QoL.

Curative carbon ion radiotherapy in a head and neck mucosal melanoma series: Facing the future within multidisciplinarity

PurposeTo evaluate efficacy and toxicity of carbon ion radiotherapy (CIRT) in locally advanced head and neck mucosal melanoma (HNMM) patients treated at our Institute. Materials and MethodsBetween June 2013 and June 2020, 40 HNMM patients were treated with CIRT. Prescription dose was 65.6-68.8 Gy relative biological effectiveness [RBE] in 16 fractions. Twelve (30%) patients received only biopsy, 28 (70%) surgical resection before CIRT. Immunotherapy was administered before and/or after CIRT in 45% of patients, mainly for distant progression (89%). ResultsMedian follow-up was 18 months. 2-year Local Relapse Free Survival (LRFS), Overall Survival (OS), Progression Free Survival (PFS) and Distant Metastasis Free Survival (DMFS) were 84.5%, 58.6%, 33.2% and 37.3%, respectively. At univariate analysis, LRFS was significantly better for non-recurrent status, < 2 surgeries before CIRT and treatment started < 9 months from the initial diagnosis, with no significant differences for operated versus unresected patients. After relapse, immunotherapy provided longer median OS (17 months vs 3.6, p-value<0.001). Late toxicity ≥ G3 (graded with CTCAE 5.0 scale) was reported in 10% of patients. ConclusionCIRT in advanced HNMM patients is safe and locally effective. Prospective trials are warranted to assess the role of targeted/immune- systemic therapy to improve OS.

Combined Photon and Carbon Ion Radiation Therapy for Sinonasal Malignancies: Results of the HIT–SNT Prospective Phase 2 Trial

Radiation treatment of sinonasal malignancies is a challenging task due to proximity to critical structures of the head and neck and skull base. Local tumor control is highly dose-dependent, but dose application is limited due to accompanying toxicity and dose constraints. To evaluate the toxicity and efficacy of combined radiation treatment with intensity-modulated radiation therapy (IMRT) and carbon ion boost, we conducted a prospective phase 2 IMRT-Heidelberg Ion-Beam Therapy Sinonasal Tumors (HIT-SNT) trial. Between 2011 and 2019, we treated 35 patients with histologically proven, incompletely resected or inoperable adeno- (51%) or squamous cell carcinoma (49%) of the paranasal sinuses with combined IMRT (50 Gy) and carbon ion boost (24 Gy relative biologic effectiveness) to a total dose of 74 Gy. Acute mucositis Common Terminology Criteria for Adverse Events (CTCAE) grade 3 occurred in 12% of patients (n = 4) and was accompanied by odynophagia CTCAE grade 3. Except for 1 case of grade 3 weight loss, no other acute high-grade toxicity (grade 3-4) was observed. In a small patient cohort of 15 patients eligible for long-term follow-up we have seen no high-grade (grade ≥3) long-term side effects 2 years after radiation therapy. None of these patients suffered from therapy-associated vision or hearing loss. Secondary endpoints were 2-year overall survival, 2-year local progression-free survival, 2-year progression-free survival, and 2-year metastases-free survival with 79.4%, 61.8%, 61.8%, and 64.8%, respectively. To our knowledge, this is the first prospective data on toxicity and outcome of bimodal radiation therapy for the rare entity of sinonasal malignancies. Our study shows a low rate of CTCAE-reported acute toxicity with reasonable tumor control and survival rates after bimodal radiation therapy, which therefore remains a therapy approach to be further evaluated.

Estimating Potential Benefits of Online Adaptive Proton Therapy for Head-and-Neck Cancer: A Retrospective Study

Proton therapy is highly sensitive to anatomical changes and setup variations in head-and-neck (HN) treatments. To address this issue, proton centers often acquire patient CT images weekly to monitor patient anatomical changes during the treatment course and perform offline plan adaptation when needed. However, offline adaptation cannot fully account for daily setup variations or the anatomical changes occurring with high frequency. There are a few groups endeavoring to develop advanced technologies to enable online adaptive proton therapy (APT). However, the necessity of online APT remains controversial, as it is unknown that whether online APT will significantly improve treatment quality and outcomes compared to offline APT. The purpose of this study is to estimate the clinical potential of online APT in the management of HN cancers in relation to the current offline APT. Our retrospective study was conducted with four HN patients (35 fractions per patient), who had been treated with intensity modulated proton therapy and had offline adaptation once or twice during their treatment courses. Synthetic CT (sCT) images were generated from 140 daily CBCT images for us to recalculate the dose of the treatment plan in patient's actual treatment anatomy for each treatment fraction and adapt the plan when warranted. These adaptations were assumed to be performed online before treatment delivery to mimic an online APT course. Accumulative doses were calculated for both courses using the CBCT-based sCT images of every fraction for us to compare the target coverage, organ at risk (OAR) sparing, tumor control probability (TCP) and normal tissue complication probability (NTCP). An in-house script was developed to semi-automate this process in a commercial treatment planning system to facilitate our study. All patients would benefit from online APT to different extents. For the first patient, with OAR doses comparable to the actual offline course, the retrospective online APT course improved dose coverages of the three CTVs from 95.2%, 98.64% and 89.53% to 98.88%, 99.81%, 98.97%, which would lead to a 4.52% improvement in TCP. Similarly, online APT would yield a 2.66% improvement in TCP for the second patient. For the third patient, with comparable CTV dose coverages, the mean doses of right parotid and oral cavity were decreased from 29.52 Gy relative biological effectiveness (RBE) and 41.89 Gy RBE to 22.16 Gy RBE and 34.61 Gy RBE, leading to a reduce of 1.67% and 3.40% in NTCP. The mean dose of right parotid was decreased from 21.71 Gy RBE to 19.37 Gy RBE for the last patient, leading to a reduce of 0.73% in NTCP. Our results showed that online APT could better maintain the treatment plan quality than offline APT for all the four patients, despite their significant anatomical changes. Future investigation will focus on collecting more patient data to obtain statistically significant results and help identify the patients to whom the online APT will be of most benefit.

Carbon-ion radiotherapy for inoperable upper tract ureteral cancer.

This study aimed to report initial results of hypofractionated carbon-ion radiotherapy (C-ion RT) for inoperable upper tract ureteral cancer. Retrospective chart review was performed for five consecutive patients with medically inoperable ureter cancer that was treated with radical C-ion RT between December 2013 and December 2014. The median age of the patients was 80 years (range, 68-84 years). The reasons for inoperability were advanced age, post-contralateral nephrectomy, alcoholic cirrhosis, both advanced age and contralateral renal function degeneracy, and pneumonia. The median size of tumor was 2.8cm (range, 2.2-4.0cm). Diagnostic imaging did not identify lymph node metastases or distant metastases in any case. All patients underwent C-ion RT (52.8Gy relative biological effectiveness; 12 fractions in 3weeks). The clinical target volume encompassed the growth tumor volume with a 5-mm margin bilaterally; there was a 40-mm margin craniocaudally but the clinical target volume did not encompass the whole ureter. Within a median follow-up time of 32.9 months (range, 24-36 months), two patients died and three remained alive. Neither local recurrence nor regional lymph node metastases were observed. Secondary bladder tumor was observed in four patients, and one patient had a liver metastasis. Grade 1 hematuria was observed in two patients, and Grade 3 pyelonephritis was observed in one patient as acute toxicity. Ureteral obstruction was observed in two patients. C-ion RT might be a useful treatment option for inoperable ureter cancer.

Acute genitourinary toxicity of pencil beam scanning proton therapy for localized prostate cancer: utility of the transition zone index and average urinary flow rate in predicting acute urinary retention.

The purpose of this study was to evaluate the incidence of acute genitourinary toxicities in patients undergoing pencil beam scanning proton therapy for prostate cancer and investigate predictive factors associated with acute urinary retention. A total of 227 patients treated between 2018 and 2021 were divided into the normo-fractionated proton therapy group (n=107) and the moderately hypo-fractionated proton therapy group (n=120), with prescribed doses of 76-78Gy relative biological effectiveness in 38-39 fractions and 60-63Gy relative biological effectiveness in 20-21 fractions, respectively. Uroflowmetry parameters and the transition zone index were prospectively evaluated. Forty-five patients (42%) in the normo-fractionated proton therapy and 33 (28%) in the moderately hypo-fractionated proton therapy developed acute grade 2 genitourinary toxicities (P=0.02). The most common acute genitourinary toxicity was acute urinary retention. Thirty-nine patients (36%) treated with normo-fractionated proton therapy and 27 (23%) treated with moderately hypo-fractionated proton therapy developed grade 2 acute urinary retention (P=0.02). No patients developed grade≥3 toxicity. Univariate analysis showed the transition zone index, prostate volume, international prostate symptom score, voided volume, maximum flow rate and average flow rate were associated with grade 2 acute urinary retention. Multivariate analysis in both groups revealed the transition zone index (P=0.025 and 0.029) and average flow rate (P=0.039 and 0.044) were predictors of grade 2 acute urinary retention. The incidence of acute genitourinary toxicities was lower in the moderately hypo-fractionated proton therapy compared with the normo-fractionated proton therapy. Lower pretreatment average flow rate and a higher transition zone index were useful predictors of grade 2 acute urinary retention.

Initial Quality of Life and Toxicity Analysis of a Randomized Phase 3 Study of Moderately Hypofractionated Radiation Therapy With or Without Androgen Suppression for Intermediate-Risk Adenocarcinoma of the Prostate: PCG GU003

Our objective was to report the quality of life (QoL) analysis and toxicity in patients with intermediate-risk prostate cancer treated with or without androgen deprivation therapy (ADT) in Proton Collaborative Group (PCG) GU003. Between 2012 and 2019, patients with intermediate-risk prostate cancer were enrolled. Patients were randomized to receive moderately hypofractionated proton beam therapy (PBT) to 70 Gy relative biologic effectiveness in 28 fractions to the prostate with or without 6 months of ADT. Expanded Prostate Cancer Index Composite, Short-Form 12, and the American Urological Association Symptom Index instruments were given at baseline and 3, 6, 12, 18, and 24 months after PBT. Toxicities were assessed according to Common Terminology Criteria for Adverse Events (version 4). One hundred ten patients were randomized to PBT either with 6 months of ADT (n=55) or without ADT (n=55). The median follow-up was 32.4 months (range, 5.5-84.6). On average, 101 out of 110 (92%) patients filled out baseline QoL and patient-reported outcome surveys. The compliance was 84%, 82%, 64%, and 42% at 3, 6, 12, and 24 months, respectively. Baseline median American Urological Association Symptom Index was comparable between arms (6 [11%] ADT vs 5 [9%] no ADT, P=.359). Acute and late grade 2+ genitourinary and gastrointestinal toxicity were similar between arms. The ADT arm experienced a QoL decline of mean scores in the sexual (-16.1, P < .001) and hormonal (-6.3, P < .001) domains, with the largest time-specific hormonal differences at 3 (-13.8, P < .001) and 6 (-11.2, P < .001) months. The hormonal QoL domain returned to baseline 6 months after therapy. There was a trend to baseline in sexual function 6 months after completion of ADT. After 6 months of ADT, sexual and hormonal domains returned to baseline 6 months after completion of treatment for men with intermediate-risk prostate cancer.

Intensity modulated proton therapy for early-stage glottic cancer: high-precision approach to laryngeal function preservation with exceptional treatment tolerability

BackgroundDue to the increasing expertise in transoral laser surgery and image-guided radiation therapy, treatment outcomes have recently improved in patients with early-stage glottic cancer. The objective of the current study was to evaluate intensity-modulated proton therapy (IMPT) as novel treatment option.MethodsA total of 15 patients with T1-2N0 glottic squamous cell carcinoma, treated between 2017 and 2020, were evaluated. Toxicity was recorded according to the Common Terminology Criteria for Adverse Events (CTCAE) v4.03.ResultsThe majority were T1a/b tumors (66.7%) and no patient had lymph node or distant metastases. The median total dose was 70 Gy relative biological effectiveness (RBE) (range 66–70 Gy RBE). The one- and two-year OS and metastases-free survival were 100%. One patient developed local failure and received salvage laryngectomy. No higher-grade acute or late toxicity was reported. The mean number of CTCAE grade I and II overall toxicity events per patient was 4.1 (95%-[confidence interval] CI 3.1–5.3) and 1.0 (95%-CI 0.5–1.5).ConclusionHigh-precision proton therapy of T1-2N0 glottic cancer resulted in exceptional treatment tolerability with high rates of laryngeal function preservation and promising oncological outcome. IMPT has the potential to become a standard treatment option for patients with early-stage laryngeal cancer.

Carbon-ion radiotherapy boost with standard dose proton radiation for incomplete-resected high-grade glioma: a phase 1 study

To investigate the maximal tolerated dose (MTD) of a carbon-ion radiotherapy (CIRT) boost prior to standard dose proton radiotherapy (PRT) for newly diagnosed glioblastoma (GBM) and anaplastic astrocytoma (AA) patients with residual lesion after resection. In total, 18 patients with high-grade glioma (HGG) (16 with GBM and 2 with AA) were enrolled in a prospective 3×3 design phase 1 trial. We investigated four dose-levels of CIRT boost [9 (starting level), 12, 15, and 18 Gy relative biological effectiveness (RBE)] delivered in three equal fractions prior to the standard dose PRT (60 Gy RBE in 30 fractions). Concurrent temozolomide (TMZ) was not provided during the CIRT boost but was initiated on the first day of PRT. Acute and late toxicities were scored based on the Common Terminology Criteria for Adverse Events (CTCAE, v 4.03). Dose-limiting toxicities (DLTs) were defined as radiation-induced severe toxicities (≥ grade 3). With a median follow-up of 17.9 months, no severe (≥ grade 3) acute or late toxicities were observed in patients treated with the first three dose levels (CIRT boost doses of 9, 12, 15 Gy RBE). Severe late toxicity (grade 3 radiation necrosis) was observed in the first patient treated with the 18 Gy RBE CIRT boost level. Therefore, this trial was terminated and the MTD of the induction CIRT boost was determined at 15 Gy RBE in 3 fractions. At the time of this analysis, both patients with AA were alive without disease progression. The progression-free survival (PFS) and overall survival (OS) for GBM at 12 months were 50.6% and 78.6%, respectively. Particle beam radiotherapy consisting of a CIRT boost of 15 Gy RBE (in 3 fractions) following standard dose PRT (60 Gy RBE in 30 fractions), and used in conjunction with TMZ, is safe and potentially effective for patients with HGG.

Retrospective Analysis of Proton Beam Therapy for Postoperative Locally Recurrent Rectal Cancer

<h3>Purpose/Objective(s)</h3> The outcomes of postoperative locally recurrent rectal cancer (PLRRC) are unsatisfactory in the multimodal treatment era. We retrospectively analyzed the outcomes of proton beam therapy (PBT) for PLRRC at our institution. <h3>Materials/Methods</h3> We included 79 PBT-treated PLRRC patients between December 2008 to December 2019. We excluded patients with prior history of salvage surgery, radiotherapy, or distant metastasis before PBT, and those treated with postoperative adjuvant PBT. We included patients who had history of chemotherapy. We estimated the overall survival (OS), disease-free survival (DFS), and local control (LC) using the Kaplan–Meier method. The prognostic factor for each outcome was verified using a Cox proportional hazards model. <h3>Results</h3> We enrolled 23 patients. The median follow-up time was 36.8 months. The median age was 64 (range, 34–83) years. The median time from surgery to recurrence was 18.1 months. Twenty patients (87%) had adenocarcinoma, two had carcinoid, and one had neuroendocrine carcinoma. The postoperative recurrent sites were presacral (12 patients), pelvic side wall (seven patients), and anastomoses (four patients). The median recurrent tumor size was 37 (range, 16–130) mm. The median maximum standardized uptake value (SUV_max) of Fluorine-18-fluorodeoxyglucose-positron emission tomography/computed tomography (18^F-FDG-PET/CT) before PBT was 7.4. Twenty-one patients (91%) received PBT alone. The median total dose was 72.6 (range, 60–87) Gy relative biological effectiveness. The treatment response was stratified by initial imaging (median, two months) after PBT. Of 23 patients, 16 (70%) received 18^F-FDG-PET/CT for initial imaging modality. Eleven patients had complete response (CR), eight had partial response, two had stable disease, and two had progressive disease. Eleven patients (48%) had lumbar or anal pain before PBT and had symptomatic pain improvement after PBT. Three- and five-year OS, DFS, and LC were 71.5%/43.3%, 37.3%/37.3%, and 54.5%/46.7%, respectively. The SUV_max of 18^F-FDG-PET/CT before PBT (cut-off value:10) showed significant difference for OS (<i>P</i>=0.0135), DFS (<i>P</i>=0.047), and LC (<i>P</i>=0.0239). The patients who achieved CR after PBT had significantly better LC compared with those with non-CR (HR 4.71, 95% CI 1.18–18.65, <i>P</i>=0.0177). Elderly patients (≧65 years) had significantly better LC and DFS. The patients with pain before PBT and larger tumor (≧30 mm) also had significantly lower DFS. Of 23 patients, 12 (52%) had further local recurrence after PBT. One patient developed grade 2 acute radiation dermatitis. Grade 4 late gastrointestinal toxicity (perforation) was recorded in three patients, two of which were associated with reirradiation for further local recurrence after PBT. <h3>Conclusion</h3> The outcomes of PBT for PLRRC are better than those of conventional photon therapy, and are comparable with those of surgery. 18^F-FDG-PET/CT before/after PBT correctly reflected the treatment effect and prognosis.

Reirradiation with Proton Therapy for Recurrent Malignancies of the Esophagus and Gastroesophageal Junction: Results of the Proton Collaborative Group Multi-Institutional Prospective Registry Trial

<h3>Purpose/Objective(s)</h3> Salvage treatment options for locoregional recurrences of esophageal/gastroesophageal junction (GEJ) cancers previously treated with radiation therapy are limited. Photon reirradiation, which has historically been employed as one such modality in these cases, is associated with high toxicity rates. Proton therapy provides superior normal tissue sparing and may permit safer dose escalation during reirradiation. However, there are limited current data on proton reirradiation. Thus, we sought to evaluate patient outcomes and toxicities after proton reirradiation for recurrent esophageal/GEJ cancers. <h3>Materials/Methods</h3> The Proton Collaborative Group prospective, multi-institutional registry was queried for patients with recurrent esophageal/GEJ cancers retreated with proton therapy. All patients included in this analysis received prior photon radiotherapy, either in the definitive or adjuvant setting. Baseline demographics, treatment details, outcomes, and acute toxicities (CTCAEv4.0) were evaluated. Local control (LC) and overall survival (OS) were estimated using the Kaplan-Meier method, with the time to event determined from the start of reirradiation for LC and the time from first recurrence for OS. <h3>Results</h3> Thirty-one patients retreated between May 2012 and October 2020 were analyzed. The median age was 68 years (range 40-87 years), and most were male (74%) and non-Hispanic Caucasian (81%) with adenocarcinoma (55%). The initial stages of their cancers were as follows: T1 6%, T2 10%, T3 77%, unknown 6%; N0 29%, N+ 67%, unknown 3%; stage I 0%, IIA 3%, IIB 23%, IIIA 29%, IV 10%, unknown 35%. During their first course of radiation therapy, they received a median of 49.5 Gy (10.8-66.0 Gy) in 6-33 fractions. Additionally, 71% received concurrent chemotherapy and 35% underwent resection. The median time to recurrence was 22.1 months (3.7–134.1 months). Proton reirradiation was primarily delivered using uniform scanning/passive scattering (n=18) or pencil beam scanning (n=12) to a median dose of 46.17 Gy relative biological effectiveness (RBE) (25.2 – 72.1 Gy(RBE)) in 12- fractions, given daily or twice daily, and 71% (n=22) received concurrent chemotherapy. Median follow-up from reirradiation completion was 9.2 months (0-63.3). OS at 6 and 12 months were 93.5% and 60.1%, respectively, and LC at 6 and 12 months were 80.5% and 69.0%, respectively. Grade 3 acute toxicities occurred in 13% (anorexia=1; dyspnea=1; dysphagia=1; cough=1; esophagitis=2) and grade 2 in 45% (most commonly, fatigue=7). No grade 4 or 5 acute events occurred. Additionally, zero patients developed an esophageal fistula or stricture, or experienced esophageal necrosis. <h3>Conclusion</h3> In this multi-institutional cohort, proton reirradiation for locoregionally recurrent esophageal/GEJ cancers resulted in high rates of early local control with acceptable acute toxicities. Longer follow-up to assess for late adverse events and additional prospective investigations are warranted.

A phase II trial of hypofractionated high-dose proton beam therapy for unresectable liver metastases

Background and purposeProton beam therapy (PBT) is an effective treatment option for primary malignant liver disease. However, evidence regarding liver metastasis is insufficient. We aimed to investigate the efficacy and safety of hypofractionated high-dose PBT in the treatment of metastatic liver disease. Materials and methodsFrom January 2019 to January 2021, patients with unresectable liver metastases were enrolled. For PBT, the dose schemes of 60 Gy relative biological effectiveness (GyRBE) in 5 fractions (fx) (biologically effective dose [BED] 132 GyE) or 70 GyRBE in 10 fx (BED 119 GyE) were used. Either a passive scattered beam or pencil beam scanning (PBS)-based intensity-modulated proton therapy (IMPT) was performed with proper respiratory management. The primary endpoint of the study was 6-month freedom from local progression (FFLP) rate; and the Kaplan–Meier method was used to calculate the FFLP and survival rates. ResultsOf the 49 liver metastases in 46 patients, the colorectum accounted for 60% of the primary cancer sites, followed by the gastrointestinal organs and pancreas/biliary tract. Forty patients presented only 1 liver metastasis, while the other 6 patients had 2 to 4 metastases. The Six-month FFLP rate was 95.2%. The 1-year FFLP rate in patients with <3 cm liver metastasis was 87.4%, while that was 74.1% in patients with > 3 cm group (p = 0.087). With regard to systemic treatment, the 1-year FFLP rate after PBT was better (94.1%) than that without systemic treatment (75.8%; p = 0.051). Regarding PBT-related toxicity, one patient developed a grade 2 gastric ulcer, while none of the patients developed grade ≥3 toxicities. ConclusionsHypofractionated PBT with a BED > 100 GyRBE for liver metastasis is safe and effective, given the high rate of 6-month FFLP without grade ≥3 treatment-related toxicities. However, further improvements are required for larger tumors and/or those without prior systemic therapy.

Novel Carbon Ion and Proton Partial Irradiation of Recurrent Unresectable Bulky Tumors (Particle-PATHY): Early Indication of Effectiveness and Safety.

Simple SummaryWe present the early results of a novel partial bulky-tumor irradiation using carbon ions and protons. This approach explores the radiation-induced bystander and abscopal effects in patients with recurrent unresectable bulky tumors who failed previous state-of-the-art treatments including radio-chemotherapy. Early tumor response, symptom relief and minimal toxicity suggest that the partial bulky-tumor irradiation was an effective, safe and well tolerated treatment. Abscopal effects elucidate an immunogenic pathway contribution.Background: We present the early results of a novel partial bulky-tumor irradiation using particles for patients with recurrent unresectable bulky tumors who failed previous state-of-the-art treatments. Methods: First, eleven consecutive patients were treated from March 2020 until December 2021. The targeted Bystander Tumor Volume (BTV) was created by subtracting 1 cm from Gross Tumor Volume (GTV) surface. It reflected approximately 30% of the central GTV volume and was irradiated with 30–45 Gy RBE (Relative Biological Effectiveness) in three consecutive fractions. The Peritumoral Immune Microenvironment (PIM) surrounding the GTV, containing nearby tissues, blood-lymphatic vessels and lymph nodes, was considered an organ at risk (OAR) and protected by highly conservative constraints. Results: With the median follow up of 6.3 months, overall survival was 64% with a median survival of 6.7 months; 46% of patients were progression-free. The average tumor volume regression was 61% from the initial size. The symptom control rate was 91%, with an average increase of the Karnofsky Index of 20%. The abscopal effect has been observed in 60% of patients. Conclusions: Partial bulky-tumor irradiation is an effective, safe and well tolerated treatment for patients with unresectable recurrent bulky disease. Abscopal effects elucidate an immunogenic pathway contribution. Extensive tumor shrinkage in some patients might permit definitive treatment—otherwise previously impossible.

Influence of photon, proton and carbon ion irradiation on differentiation, maturation and functionality of dendritic cells.

While the primary purpose of radiotherapy (RT) is the elimination of cancer cells by inducing DNA-damage, considerable evidence emerges that anti-neoplastic effects extend beyond mere tumor cell killing. These secondary effects are based on activation of dendritic cells (DCs) via induction of antitumoral immune reactions. However, there is an ongoing debate whether or not irradiation of the DCs themselves may negatively affect their maturation and functionality. Human monocytes were irradiated with different absorbed doses (1 × 15 Gy relative biological effectiveness (RBE), 5 × 2 Gy (RBE), 1 × 0.5 Gy (RBE)) with photons, protons and carbon ions. Differentiation and maturation of DCs were assessed by staining of corresponding cell surface molecules and functional analysis of irradiated DCs was based on in vitro analysis of phagocytosis, migration and IL-12 secretion. Irradiation of CD14-positive DCs did not alter surface phenotypes of immature DCs and mature DCs. Not only differentiation, but also functionality of immature DCs regarding phagocytosis, migration and IL-12 secretion capacity was not negatively influenced through RT with photons, protons or carbon ions as well as with different dose levels. After proton irradiation migratory capacity of immature DCs was increased. Our experiments reveal that phenotypic maturation of DCs remains unchanged after RT with different fractionations and after irradiation with particle therapy. Unaffected functionality (phagocytosis, migration and cytokine secretion) after RT of DCs indicated possible persistent potential for inducing adaptive immune response. Additional effects on the immunogenic potential of DCs will be investigated by further functional assays.

Pre- and Posttherapy Risk Factors for Vasculopathy in Pediatric Patients With Craniopharyngioma Treated With Surgery and Proton Radiation Therapy

Vasculopathy (VAS) is a significant complication associated with radiation therapy in patients treated for brain tumors. We studied the type, location, severity, timing, and resolution of VAS in children with craniopharyngioma treated with proton radiation therapy (PRT) and evaluated predictors of stenosis (STN) using a novel patient and imaging-based modeling approach. Children with craniopharyngioma (n=94) were treated with 54 Gy relative biological effectiveness PRT in a clinical trial, NCT01419067. We evaluated VAS type, location, severity, and resolution. VAS events were segmented and related to their location, operative corridor, PRT dose, and vascular territory to facilitate mixed effect logistic regression modeling of spatial predictors of STN events. Forty-five (47.9%) patients had 111 instances of confirmed VAS (pre-PRT n=37, 33.3%). The median time to post-PRT VAS was 3.41 years (95% confidence interval, 1.86-6.11). STN events were observed post-PRT in 23.4% (n=22) of patients. Post-PRT VAS was detected by cerebral angiogram in 9.6% (n=9), severe in 4.3% (n=4), and compensated on perfusion in 2.1% (n=2). Revascularization was required for 5 (5.3%) patients. Postsurgical, pre-PRT VAS, and PRT dose to unperturbed vessels were predictive of STN. The effect of PRT on STN was negligible within the surgical corridor. VAS often precedes PRT and was the strongest predictor of post-PRT STN. The adverse effect of PRT on STN was only apparent in unperturbed vasculature beyond the operative corridor.

Dose-volume comparison of intensity modulated proton therapy and volumetric modulated arc therapy for cervical esophageal cancer.

Proton therapy for cervical esophageal cancer has many issues to be considered, such as the physiological curvature of the spine and the large range change from the neck to the trunk. We clarified the dosimetric characteristics of intensity modulated proton therapy (IMPT) for cervical esophageal cancer by comparing with volumetric modulated arc therapy (VMAT). Ten patients with cervical esophageal cancer were retrospectively planned for VMAT, 2-field IMPT (2F-IMPT), and 3-field IMPT (3F-IMPT). All plans were optimized to reach clinically acceptable levels. For planning target volume (PTV) coverage, 95% of the PTV should be covered by 95% of the prescription dose, unless the spinal cord limit is violated. The organs at risk included the lung, spinal cord, larynx, skin, and whole body. The prescription dose was 60 Gy relative biological effectiveness (RBE) in 30 fractions to the PTV. We compared the results according to dose-volume metrics. Significant dose reductions were achieved at lung doses, especially at low dose volumes of 20 Gy RBE or less in IMPT plans compared with VMAT plans (p < 0.05). Although the spinal cord PRV was below the tolerance level, the results were also significantly higher in VMAT plans than in IMPT plans (p < 0.001). Spinal cord PRV Dmean was significantly higher in 3F-IMPT than in 2F-IMPT (p < 0.001). In addition, it was confirmed that the integral whole body dose can be dramatically reduced in IMPT plans compared with VMAT plans. Both of 2F-IMPT and 3F-IMPT could effectively reduce spinal cord dose, as well as low integral whole body dose to a certain extent, while maintaining similar target coverage compared to VMAT. IMPT could be a promising treatment technique for patients with cervical esophageal cancer.