Acute toxicities after proton beam therapy following breast-conserving surgery for breast cancer: Multi-institutional prospective PCG registry analysis.

We investigated adverse events (AEs) and clinical outcomes for proton beam therapy (PBT) after breast-conserving surgery (BCS) for breast cancer. From 2012 to 2016, 82 patients received PBT in the prospective multi-institutional Proton Collaborative Group registry. AEs were recorded prospectively at each institution. Median follow-up was 8.1 months. Median dose was 50.4 Gy in 28 fractions. Most patients received a lumpectomy bed boost (90%) and regional nodal irradiation (RNI)(83%). Six patients (7.3%) experienced grade 3 AEs (5 with dermatitis, 5 with breast pain). Body mass index (BMI) was associated with grade 3 dermatitis (P = .015). Fifty-eight patients (70.7%) experienced grade ≥2 dermatitis. PBT including RNI after BCS is well-tolerated. Elevated BMI is associated with grade 3 dermatitis.

Proton beam therapy reirradiation for breast cancer: Multi-institutional prospective PCG registry analysis.

To investigate adverse events (AEs, CTCAE v4.0) and clinical outcomes for proton beam therapy (PBT) reirradiation (reRT) for breast cancer. From 2011 to 2016, 50 patients received PBT reRT for breast cancer in the prospective Proton Collaborative Group (PCG) registry. Acute AEs occurred within 180 days from start of reRT. Late AEs began or persisted beyond 180 days. Fisher's exact and Mann-Whitney rank-sum tests were utilized. Kaplan-Meier methods were used to estimate overall survival (OS) and local recurrence-free survival (LFRS). Median follow-up was 12.7 months (0-41.8). Median prior RT dose was 60 Gy (10-96.7). Median reRT dose was 55.1 Gy (45.1-76.3). Median cumulative dose was 110.6 Gy (70.6-156.8). Median interval between RT courses was 103.8 months (5.5-430.8). ReRT included regional nodes in 84% (66% internal mammary node [IMN]). Surgery included the following: 44% mastectomy, 22% wide local excision, 6% lumpectomy, 2% reduction mammoplasty, and 26% no surgery. Grade 3 AEs were experienced by 16% of patients (10% acute, 8% late) and were associated with body mass index (BMI) > 30 kg/m2 (P = 0.04), bilateral recurrence (P = 0.02), and bilateral reRT (P = 0.004). All grade 3 AEs occurred in patients receiving IMN reRT (P = 0.08). At 1 year, LRFS was 93%, and OS was 97%. Patients with gross disease at time of PBT trended toward worse 1-year LRFS (100% without vs. 84% with, P = 0.06). PBT reRT is well tolerated with favorable local control. BMI > 30, bilateral disease, and IMN reRT were associated with grade 3 AEs. Toxicity was acceptable despite median cumulative dose > 110 Gy.

Commissioning of the world's first compact pencil-beam scanning proton therapy system.

This paper summarizes clinical commissioning of the world's first commercial, clinically utilized installation of a compact, image-guided, pencil-beam scanning, intensity-modulated proton therapy system, the IBA Proteus® ONE, at the Willis-Knighton Cancer Center (WKCC) in Shreveport, LA. The Proteus® ONE is a single-room, compact-gantry system employing a cyclotron-generated proton beam with image guidance via cone-beam CT as well as stereoscopic orthogonal and oblique planar kV imaging. Coupling 220° of gantry rotation with a 6D robotic couch capable of in plane patient rotations of over 180° degrees allows for 360° of treatment access. Along with general machine characterization, system commissioning required: (a) characterization and calibration of the proton beam, (b) treatment planning system commissioning including CT-to-density curve determination, (c) image guidance system commissioning, and (d) safety verification (interlocks and radiation survey). System readiness for patient treatment was validated by irradiating calibration TLDs as well as prostate, head, and lung phantoms from the Imaging and Radiation Oncology Core (IROC), Houston. These results confirmed safe and accurate machine functionality suitable for patient treatment. WKCC also successfully completed an on-site dosimetry review by an independent team of IROC physicists that corroborated accurate Proteus® ONE dosimetry.

Predicting the Effect of Proton Beam Therapy Technology on Pulmonary Toxicities for Patients With Locally Advanced Lung Cancer Enrolled in the Proton Collaborative Group Prospective Clinical Trial.

PURPOSE: This study aimed to predict the probability of grade ≥2 pneumonitis or dyspnea within 12 months of receiving conventionally fractionated or mildly hypofractionated proton beam therapy for locally advanced lung cancer using machine learning. METHODS AND MATERIALS: Demographic and treatment characteristics were analyzed for 965 consecutive patients treated for lung cancer with conventionally fractionated or mildly hypofractionated (2.2-3 Gy/fraction) proton beam therapy across 12 institutions. Three machine learning models (gradient boosting, additive tree, and logistic regression with lasso regularization) were implemented to predict Common Terminology Criteria for Adverse Events version 4 grade ≥2 pulmonary toxicities using double 10-fold cross-validation for parameter hyper-tuning without leak of information. Balanced accuracy and area under the curve were calculated, and 95% confidence intervals were obtained using bootstrap sampling. RESULTS: The median age of the patients was 70 years (range, 20-97), and they had predominantly stage IIIA or IIIB disease. They received a median dose of 60 Gy in 2 Gy/fraction, and 46.4% received concurrent chemotherapy. In total, 250 (25.9%) had grade ≥2 pulmonary toxicity. The probability of pulmonary toxicity was 0.08 for patients treated with pencil beam scanning and 0.34 for those treated with other techniques (P = 8.97e-13). Use of abdominal compression and breath hold were highly significant predictors of less toxicity (P = 2.88e-08). Higher total radiation delivered dose (P = .0182) and higher average dose to the ipsilateral lung (P = .0035) increased the likelihood of pulmonary toxicities. The gradient boosting model performed the best of the models tested, and when demographic and dosimetric features were combined, the area under the curve and balanced accuracy were 0.75 ± 0.02 and 0.67 ± 0.02, respectively. After analyzing performance versus the number of data points used for training, we observed that accuracy was limited by the number of observations. CONCLUSIONS: In the largest analysis of prospectively enrolled patients with lung cancer assessing pulmonary toxicities from proton therapy to date, advanced machine learning methods revealed that pencil beam scanning, abdominal compression, and lower normal lung doses can lead to significantly lower probability of developing grade ≥2 pneumonitis or dyspnea.

Validation of Patient-Reported Outcomes in Patients With Nonmetastatic Breast Cancer Receiving Comprehensive Nodal Irradiation in the RadComp Trial.

PURPOSE: Our purpose was to evaluate the measurement properties of patient-reported outcome (PRO) measures used in the ongoing RadComp pragmatic randomized clinical trial (PRCT). METHODS AND MATERIALS: The deidentified and blinded data set included 774 English-speaking female participants who completed their 6-month posttreatment assessment. Eleven PRO measures were evaluated, including the Trial Outcome Index from the Functional Assessment of Cancer Therapy-Breast (FACT-B), Satisfaction with Breast Cosmetic Outcomes, the BREAST-Q, and selected Patient-Reported Outcomes Measurement Information System (PROMIS) measures. PROs were measured at 3 timepoints: baseline, completion of radiation therapy (RT), and 6 months post-RT. Ten variables were used as validity anchors. Pearson or Spearman correlations were calculated between PROs and convergent validity indicators. Mean PRO differences between clinically distinct categories were compared with analysis of variance methods (known-groups validity). PRO change scores were mapped to change in other variables (sensitivity to change). RESULTS: Most correlations between PROs and validity indicators were large (≥0.5). Mean score for Satisfaction with Breast Cosmetic Outcomes was higher (better) for those with a lumpectomy compared with those with a mastectomy (P < .001). Mean scores for the FACT-B Trial Outcome Index and for PROMIS Fatigue and Ability to Participate in Social Roles and Activities were better for those with good baseline performance status compared with those with poorer baseline performance status (P < .05). At completion of RT and post-RT, mean scores for Satisfaction with Breast Cosmetic Outcomes and BREAST-Q Radiation were significantly different (P < .001) across categories for all Functional Assessment of Chronic Illness Therapy -Treatment Satisfaction - General items. There were medium-sized correlations between change scores for FACT-B Trial Outcome Index, Fatigue, Anxiety, and Ability to Participate in Social Roles and change scores in the Visual Analog Scale. CONCLUSIONS: For patients with nonmetastatic breast cancer receiving radiation in the RadComp PRCT, our findings demonstrate high reliability and validity for important PRO measures, supporting their psychometric strength and usefulness to reflect the effect of RT on health-related quality of life.

Clinical Outcomes After Proton Beam Therapy for Locally Advanced Non-Small Cell Lung Cancer: Analysis of a Multi-institutional Prospective Registry.

PURPOSE: For most disease sites, level 1 evidence is lacking for proton beam therapy (PBT). By identifying target populations that would benefit most from PBT, prospective registries could overcome many of the challenges in clinical trial enrollment. Herein, we report clinical outcomes of patients treated with PBT for locally advanced non-small cell lung cancer (LA-NSCLC). METHODS AND MATERIALS: Data were obtained from the multi-institutional prospective database of the Proton Collaborative Group (PCG). Inclusion criteria of our study were stage III de novo or recurrent LA-NSCLC, use of PBT, and availability of follow-up data. Overall survival (OS) time was calculated from the start of treatment until death or last follow-up. Kaplan-Meier curves were generated for groups of interest and compared with log-rank tests. Cox regression modeling was used to evaluate the multivariate association between selected covariates and OS. RESULTS: A total of 195 patients were included in the analysis. PBT was given with a median equivalent dose in 2 Gy fractions (EQD2) of 63.8 Gy (relative biological effectiveness). Pencil beam scanning was used in 20% of treatments. Treatment-related grade 3 adverse events were rare: 1 pneumonitis, 2 dermatitis, and 3 esophagitis. No grade 4 events were reported. Two cardiac-related grade 5 events occurred in patients with multiple risk factors. The median follow-up time for living patients was 37.1 months and the median OS was 19.0 months. On multivariate analysis, good performance status (hazard ratio, 0.27; [95% confidence interval, 0.15-0.46]; P < .0001), pencil beam scanning use (0.55; [0.31-0.97]; P = .04), and increased EQD2 (0.80; [0.71-0.90] - per 10 Gy increase; P = .0002) were associated with decreased mortality. CONCLUSIONS: PBT appears to yield low rates of adverse events with an OS similar to other retrospective studies on PBT for LA-NSCLC. PBS use and increased EQD2 can potentially improve OS.

TomoTherapy stereotactic body radiation therapy (SBRT) for the salvage treatment of locally recurrent esophageal adenocarcinoma following trimodality therapy: a case report.

Esophageal cancer patients with local recurrence after chemoradiation and surgery (trimodality therapy) have limited palliative treatment options. We present a case of local recurrence successfully palliated using TomoTherapy stereotactic body radiation therapy (SBRT). The patient was a 58-year-old man with distal esophageal adenocarcinoma initially treated with trimodality therapy. Symptomatic local recurrence developed 4 years later. Using TomoTherapy SBRT successful palliation was achieved with 3500 cGy in 7 fractions given every other weekday. He remained free of local recurrence without requiring further local therapies, eventually succumbing to metastatic disease 11 months after radiation. Presently there are no reported cases of malignant esophageal obstruction treated with SBRT. Radiosurgery is increasingly used in extracranial sites such as the liver, lung and spine. Reirradiation was convenient and well tolerated by our patient and the response durable. Palliation of local recurrence in esophageal cancer initially treated with trimodality therapy can be achieved using SBRT and is a reasonable option in appropriately selected patients. Further studies are needed to clarify its role in this and other body sites.

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.

Selection of Mediastinal Lymphoma Patients for Proton Therapy Within the Proton Collaborative Group Registry: Concordance With the ILROG Guidelines.

PURPOSE: As patients with mediastinal lymphoma are typically young with curable disease, advanced radiation techniques such as proton therapy are often considered to minimize subacute and late toxicity. However, it is unclear which mediastinal lymphoma patients are treated with proton therapy. Within a prospective, multi-institutional proton registry, we characterized mediastinal lymphoma patients treated with proton therapy and assessed concordance with consensus recommendations published in 2018 by the International Lymphoma Radiation Oncology Group (ILROG). METHODS: Eligible patients included those with lymphoma of the mediastinum treated exclusively with proton therapy for whom digital imaging and communications in medicine (DICOM) treatment data were available for review. Given the challenge with reliably visualizing the left mainstem coronary artery, the inferior-most aspect of the left pulmonary artery (PA) was used as a surrogate. Extent of disease was characterized as upper mediastinum (above level of left PA), middle mediastinum (below left PA but at or above level of T8), or low mediastinum (below T8). RESULTS: Between November 2012 and April 2019, 56 patients were treated and met inclusion criteria. Patients treated with proton therapy were young (median, 24 y; range: 12 to 88), with over half being female (55%). Patients were most commonly treated at initial diagnosis (86%) and had Hodgkin lymphoma (79%). Most patients (96%) had mediastinal disease that extended down to the level of the heart: 48% had middle and 48% had low mediastinal involvement. Nearly all patients (96%) met the ILROG consensus recommendations: 95% had lower mediastinal disease, 46% were young females, and 9% were heavily pretreated. Heart (mean) and lung dose (mean, V5, V20) were significantly associated with lowest extent of mediastinal disease. CONCLUSIONS: Mediastinal lymphoma patients treated with proton therapy are typically young with lower mediastinal involvement. Within a prospective, multi-institutional proton registry, nearly all treated patients fit the ILROG consensus recommendations regarding which mediastinal lymphoma patients may most benefit from proton therapy.

Risk of Pneumonitis and Outcomes After Mediastinal Proton Therapy for Relapsed/Refractory Lymphoma: A PTCOG and PCG Collaboration.

PURPOSE: Despite high response rates, there has been reluctance to use radiation therapy for patients with relapsed/refractory (r/r) Hodgkin (HL) or aggressive non-Hodgkin lymphoma (NHL) given concerns for subacute and late toxicities. Symptomatic pneumonitis, a subacute toxicity, has an incidence of 17% to 24% (≥grade 2) even with intensity modulated radiation therapy. Proton therapy (PT), which has no exit radiation dose, is associated with a lower dose to lung compared with other radiation techniques. As risk of radiation pneumonitis is associated with lung dose, we evaluated whether pneumonitis rates are lower with PT. METHODS AND MATERIALS: Within an international, multi-institutional cohort, we retrospectively evaluated the incidence and grade of radiation pneumonitis (National Cancer Institute Common Terminology Criteria for Adverse Events v4) among patients with r/r HL or NHL treated with PT. RESULTS: A total of 85 patients with r/r lymphoma (66% HL, 34% NHL; 46% primary chemorefractory) received thoracic PT from 2009 to 2017 in the consolidation (45%) or salvage (54%) setting. Median dose was 36 Gy(RBE). Before PT, patients underwent a median of 1 salvage systemic therapy (range, 0-4); 40% received PT within 4 months of transplant. With a median follow-up of 26.3 months among living patients, 11 patients developed symptomatic (grade 2) pneumonitis (12.8%). No grade 3 or higher pneumonitis was observed. Dose to lung, including mean lung dose, lung V5, and V20, significantly predicted risk of symptomatic pneumonitis, but not receipt of brentuximab, history of bleomycin toxicity, sex, or peritransplant radiation. CONCLUSIONS: PT for relapsed/refractory lymphoma was associated with favorable rates of pneumonitis compared with historical controls. We confirm that among patients treated with PT, pneumonitis risk is associated with mean lung and lung V20 dose. These findings highlight how advancements in radiation delivery may improve the therapeutic ratio for patients with relapsed/refractory lymphoma. PT may be considered as a treatment modality for patients with relapsed/refractory lymphoma in the consolidation or salvage setting.

Subungual squamous cell carcinoma: radiation therapy as an alternative to amputation and review of the literature.

We report the outcomes of three patients who were treated with external beam radiotherapy as an alternative to distal phalanx amputation for subungual squamous cell carcinomas between December 2004 and September 2006. The patients' ages ranged from 46 to 83 years and the median follow-up time was 48 months (range: 36-52 months). As of the current date, the three patients show no signs of recurrence following a course of external beam radiotherapy. Complete function of the treated digit was obtained in all three patients. Irradiation should be considered as an alternative modality choice in the treatment of subungual squamous cell carcinoma in lieu of distal phalanx amputation.

Technical Note: 4D cone-beam CT reconstruction from sparse-view CBCT data for daily motion assessment in pencil beam scanned proton therapy (PBS-PT).

PURPOSE: The number of pencil beam scanned proton therapy (PBS-PT) facilities equipped with cone-beam computed tomography (CBCT) imaging treating thoracic indications is constantly rising. To enable daily internal motion monitoring during PBS-PT treatments of thoracic tumors, we assess the performance of Motion-Aware RecOnstructiOn method using Spatial and Temporal Regularization (MA-ROOSTER) four-dimensional CBCT (4DCBCT) reconstruction for sparse-view CBCT data and a realistic data set of patients treated with proton therapy. METHODS: Daily CBCT projection data for nine non-small cell lung cancer (NSCLC) patients and one SCLC patient were acquired at a proton gantry system (IBA Proteus® One). Four-dimensional CBCT images were reconstructed applying the MA-ROOSTER and the conventional phase-correlated Feldkamp-Davis-Kress (PC-FDK) method. Image quality was assessed by visual inspection, contrast-to-noise ratio (CNR), signal-to-noise ratio (SNR), and the structural similarity index measure (SSIM). Furthermore, gross tumor volume (GTV) centroid motion amplitudes were evaluated. RESULTS: Image quality for the 4DCBCT reconstructions using MA-ROOSTER was superior to the PC-FDK reconstructions and close to FDK images (median CNR: 1.23 [PC-FDK], 1.98 [MA-ROOSTER], and 1.98 [FDK]; median SNR: 2.56 [PC-FDK], 4.76 [MA-ROOSTER], and 5.02 [FDK]; median SSIM: 0.18 [PC-FDK vs FDK], 0.31 [MA-ROOSTER vs FDK]). The improved image quality of MA-ROOSTER facilitated GTV contour warping and realistic motion monitoring for most of the reconstructions. CONCLUSION: MA-ROOSTER based 4DCBCTs performed well in terms of image quality and appear to be promising for daily internal motion monitoring in PBS-PT treatments of (N)SCLC patients.

Treatment interruptions affect biochemical failure rates in prostate cancer patients treated with proton beam therapy: Report from the multi-institutional proton collaborative group registry.

INTRODUCTION: To date, no studies examining the effect of treatment interruptions (TI) with proton beam therapy (PBT) have been published. The goal of our study was to determine the predictors of TI amongst patients with prostate cancer (PCa) treated with PBT and to determine whether TI are associated with biochemical failure (BF). We hypothesized that any correlation between TI and biochemical control would be more pronounced in high risk groups. METHODS: Data for 4278 patients with PCa was obtained from the prospectively collected Proton Collaborative Group (PCG) data registry. Univariate and multivariate logistic regression analysis (MVA) was used to model possible predictors of BF. A subset analysis was performed for high risk patients treated with ADT and PBT. Finally, propensity score (PS) analysis was performed to account for any indication bias caused by lack of randomization. RESULTS: Total treatment duration (OR, 1.05 [1.04-1.06]; p < 0.001) increased the likelihood of TI on MVA. TI did not have a statistically significant correlation with BF (OR, 1.44 [0.86-2.39]; p = 0.162) amongst PS matched patients. However, on subset analyses of high risk group patients with PS matching, there was a trend towards worse BF in patients with TI (OR 3.85; 95%CI (0.96-15.44); p = 0.057). CONCLUSION: In the first analysis of its kind, the results suggest that TI in high risk PCa patients treated with PBT and ADT have worse BF rates. Interventions such as increased patient education, proper maintenance of proton facilities, and decreasing total treatment duration with alternative fractionation schedules may help avoid the unintended negative effects on tumor control due to TI. However, future analyses on a larger patient population is needed.

Patient reported outcomes following proton pencil beam scanning vs. passive scatter/uniform scanning for localized prostate cancer: Secondary analysis of PCG 001-09.

BACKGROUND: Although pencil beam scanning (PBS) is the most conformal method for proton beam therapy (PBT) delivery, it is unknown if outcomes differ compared to treatment with passive scatter/uniform scanning (PS/US). This analysis compares patient reported outcomes (PRO) changes following PBS and PS/US for prostate cancer (PC) in a prospective multicenter registry study. METHODS: We evaluated PROs with the Expanded Prostate Cancer Index Composite (EPIC) instrument for men with localized PC enrolled in PCG 001-09 (NCT01255748). PROs were assessed at baseline and through 12 months of follow-up. We compared mean changes in EPIC scores, as well as the proportions of men experiencing a one- and two-fold minimally important difference (MID) in domain scores, between PBS and PS/US. Multivariate analyses (MVAs) were performed to further evaluate the association between proton modality and PRO changes. RESULTS: Three-hundred-and-four men completed EPIC at baseline; 72 received PBS and 232 received PS/US. The average quality-of-life (QOL) declines from baseline through 12 months did not significantly differ between the two groups. The proportion of men reporting a 1-MID decline at 12 months for PBS and PS/US was 34.3% and 27.4%, respectively, for urinary QOL (P = 0.27); 40. 1% and 40.9% for bowel QOL (P = 0.36); and 30. 1% and 36.6% for sexual QOL (P = 0.94). Corresponding 2-MID declines for PBS and PS/US were observed in 26.9% and 13.2% of men for urinary QOL (P = 0.01), 35.3% and 29.1% for bowel QOL (P = 0.33); and 16.4% and 18.1% for sexual QOL (P = 0.76). The association between proton modality and 2-MID changes in urinary QOL at 12-months remained significant on MVA (P = 0.007). CONCLUSIONS: The results of this analysis show differences between PBS and PS/US with regards to two-fold MID changes in urinary function at 12 months, but no differences for average score declines over time. Future studies evaluating PRO measures between the two PBT modalities are warranted.

Proton beam therapy delivered using pencil beam scanning vs. passive scattering/uniform scanning for localized prostate cancer: Comparative toxicity analysis of PCG 001-09.

BACKGROUND AND PURPOSE: Patient-level benefits of proton beam therapy (PBT) relative to photon therapy for prostate cancer (PC) continue to be the focus of debate. Although trials comparing the two modalities are underway, most are being conducted using "conventional" PBT (passive scattering/uniform scanning [PS/US]) rather than pencil beam scanning (PBS). The dosimetric benefits of PBS are well-known, but comparative data are limited. This analysis compares PBS toxicity rates with those of PS/US in a prospective multicenter registry. METHODS: We evaluated acute/late gastrointestinal (GI) and genitourinary (GU) toxicity rates for men with low-to-intermediate risk PC enrolled in PCG 001-09. Acute toxicities with the two techniques were compared using χ2 tests, and the cumulative incidence methods for late toxicity. Multivariable analyses (MVAs) for acute toxicity were performed using logistic regression, and cox proportional hazards models for late toxicity. RESULTS: Patients were treated using PS/US (n = 1105) or PBS (n = 238). Acute grade ≥2 GI toxicity in PBS did not significantly differ from that with PS/US (2.9% and 2.1%, respectively; P = 0.47). Acute grade ≥2 GU toxicity was significantly higher with PBS (21.9% and 15.1%; P < 0.01). In MVA, PBS was significantly associated with increased acute grade ≥2 GU toxicity (RR = 1.57, p < 0.001). Late grade ≥2 GI and GU toxicities did not differ significantly between groups. CONCLUSIONS: This is the first multi-institutional comparative effectiveness evaluation of PBT techniques in PC. Differences in acute GU toxicity warrant further evaluation, and highlight the urgent need for prospective data using PBT.

Sodium sulfide selectively induces oxidative stress, DNA damage, and mitochondrial dysfunction and radiosensitizes glioblastoma (GBM) cells.

Glioblastoma (GBM) has a poor prognosis despite intensive treatment with surgery and chemoradiotherapy. Previous studies using dose-escalated radiotherapy have demonstrated improved survival; however, increased rates of radionecrosis have limited its use. Development of radiosensitizers could improve patient outcome. In the present study, we report the use of sodium sulfide (Na2S), a hydrogen sulfide (H2S) donor, to selectively kill GBM cells (T98G and U87) while sparing normal human cerebral microvascular endothelial cells (hCMEC/D3). Na2S also decreased mitochondrial respiration, increased oxidative stress and induced γH2AX foci and oxidative base damage in GBM cells. Since Na2S did not significantly alter T98G capacity to perform non-homologous end-joining or base excision repair, it is possible that GBM cell killing could be attributed to increased damage induction due to enhanced reactive oxygen species production. Interestingly, Na2S enhanced mitochondrial respiration, produced a more reducing environment and did not induce high levels of DNA damage in hCMEC/D3. Taken together, this data suggests involvement of mitochondrial respiration in Na2S toxicity in GBM cells. The fact that survival of LN-18 GBM cells lacking mitochondrial DNA (ρ0) was not altered by Na2S whereas the survival of LN-18 ρ+ cells was compromised supports this conclusion. When cells were treated with Na2S and photon or proton radiation, GBM cell killing was enhanced, which opens the possibility of H2S being a radiosensitizer. Therefore, this study provides the first evidence that H2S donors could be used in GBM therapy to potentiate radiation-induced killing.

Effect of Radiation Therapy on Survival in Hodgkin's Lymphoma: A SEER Data Analysis.

BACKGROUND/AIM: Hodgkin's Lymphoma (HL) is curable in up to 80% of patients due, in part, to simultaneous advances in chemotherapy regimens as well as radiation therapy planning and delivery. Concerns regarding the historical use of large-field radiotherapy on overall survival have been published. In this study, we performed a Surveillance, epidemiology, and end results (SEER) data analysis to evaluate the impact of patients and treatments related factors on survival in HL. PATIENTS AND METHODS: Data from 39,700 adult patients registered in the SEER data with diagnosis of HL, between 1983-2011 and follow-up through 2012 were analyzed. Impact of patient demographics (sex, age, race, ethnicity, year of diagnosis, family income, education, unemployment, poverty level and stage of disease) and treatment characteristics (delivery of radiotherapy) on survival were evaluated via multivariate analysis. RESULTS: Median age was 36 years. Most patients were Ann Arbor Stage II (39%) at diagnosis with the remainder distributed evenly between the remaining stages (I, III, IV: 19-21%). In multivariate analysis, after adjusting for secondary predictor variables including stage of disease, Radiation therapy (RT) was a statistically significant predictor of overall survival from HL (HR=0.72, (95% CI=0.68-0.75). At follow up of more than 25 years, Kaplan-Meier analysis showed that RT improved survival for all patients, irrespective of stage. Factors associated with worse survival included older age, male sex, extra nodal disease, advanced stage, African-American race, and non-Hispanic ethnicity. CONCLUSION: Radiation therapy improved survival in patients with all stages of HL. Demographic and disease factors associated with worse survival in this study may be related to particular patterns of care and warrant additional study.

Treatment planning comparison of IMPT, VMAT and 4π radiotherapy for prostate cases.

BACKGROUND: Intensity-modulated proton therapy (IMPT), non-coplanar 4π intensity-modulated radiation therapy (IMRT), and volumetric-modulated arc therapy (VMAT) represent the most advanced treatment methods based on heavy ion and X-rays, respectively. Here we compare their performance for prostate cancer treatment. METHODS: Ten prostate patients were planned using IMPT with robustness optimization, VMAT, and 4π to an initial dose of 54 Gy to a clinical target volume (CTV) that encompassed the prostate and seminal vesicles, then a boost prescription dose of 25.2 Gy to the prostate for a total dose of 79.2 Gy. The IMPT plans utilized two coplanar, oblique scanning beams 10° posterior of the lateral beam positions. Range uncertainties were taken into consideration in the IMPT plans. VMAT plans used two full, coplanar arcs to ensure sufficient PTV coverage. 4π plans were created by inversely selecting and optimizing 30 beams from 1162 candidate non-coplanar beams using a greedy column generation algorithm. CTV doses, bladder and rectum dose volumes (V40, V45, V60, V65, V70, V75, and V80), R100, R50, R10, and CTV homogeneity index (D95/D5) were evaluated. RESULTS: Compared to IMPT, 4π resulted in lower anterior rectal wall mean dose as well as lower rectum V40, V45, V60, V65, V70, and V75. Due to the opposing beam arrangement, IMPT resulted in significantly (p < 0.05) greater femoral head doses. However, IMPT plans had significantly lower bladder, rectum, and anterior rectal wall max dose. IMPT doses were also significantly more homogeneous than 4π and VMAT doses. CONCLUSION: Compared to the VMAT and 4π plans, IMPT treatment plans are superior in CTV homogeneity and maximum point organ-at-risk (OAR) doses with the exception of femur heads. IMPT is inferior in rectum and bladder volumes receiving intermediate to high doses, particularly to the 4π plans, but significantly reduced low dose spillage and integral dose, which are correlated to secondary cancer for patients with expected long survival. The dosimetric benefits of 4π plans over VMAT are consistent with the previous publication.

Comparison of stereotactic body radiation therapy for biopsy-proven versus radiographically diagnosed early-stage non-small lung cancer: a single-institution experience.

INTRODUCTION: Histological confirmation of non-small cell lung cancer (NSCLC) is often required before patients are offered stereotactic body radiation therapy (SBRT) as a treatment option. Many patients, however, are unsuitable to undergo a biopsy procedure because of comorbidity. Our objective is to compare the outcomes of patients with biopsy-proven (BxPr) or clinically/radiographically diagnosed (RadDx) early-stage NSCLC treated with SBRT. METHODS: Records of 88 patients treated with SBRT at a single institution were reviewed. Sixty-five patients had BxPr early-stage NSCLC. Twenty-three patients were RadDx with early-stage NSCLC based on an FDG-avid chest nodule on PET scan, serial sequential CT-findings compatible with NSCLC, and consensus of a multidisciplinary team. Outcomes of patients with BxPr and RadDx NSCLC were evaluated in regard to local control, regional lymph node metastasis-free and distant metastasis-free rates, and overall survival using Kaplan-Meier survival curves. RESULTS: Median follow-up for all patients was 29 months (range, 4-82 months). Cumulative local progression-free rate after 3 years for the BxPr group was 93.1% (95% confidence interval [CI], 85.2%-97.6%) and 94.10% (95% CI, 73.2%-97.6%) for the RadDx group (p = 0.98). No differences regarding regional lymph node metastasis-free and distant metastasis-free rates by subgroup were observed. The overall 3-year survival rate for the BxPr group was 59.9% (95% CI, 44.8%-68.2%) and 58.9% (95% CI, 40.1%-77.8%) for the RadDx group (p = 0.46). CONCLUSIONS: SBRT is a practical treatment modality for patients with RadDx early-stage NSCLC. Outcomes of patients RadDx with NSCLC mirror the results of patients treated with BxPr disease.

Stereotactic radiotherapy using tomotherapy for early-stage non-small cell lung carcinoma: analysis of intrafraction tumour motion.

INTRODUCTION: Intrafraction tumour motion in helical tomotherapy was investigated by comparing pre- and mid-fraction CT scans in patients with early non-small cell lung carcinoma (NSCLC) to assess the efficacy of a 7-mm margin around gross tumour volumes (GTVs) in stereotactic body radiation therapy (SBRT). METHODS: Thirty patients with early-stage NSCLC received SBRT in four or five fractions for a total of 141 treatments. A slow positron emission tomography/CT scan was fused with the simulation CT to determine the GTV. A planning target volume was created by placing an isotropic margin of 7 mm around the GTV. Data were retrospectively analyzed to assess translational tumour positional changes along the x, y and z axes and vector changes in millimeters from the pretreatment megavoltage (MV)-CT to the mid-fraction MV-CT. RESULTS: Average movements for all 141 treatment days along the x, y and z axes were 0.5 ± 2.3, -0.3 ± 3.0 and 0.9 ± 3.0 mm, respectively. Average movements for each patient along the x, y and z axes were 0.5 ± 1.5, -0.2 ± 2.0 and 0.9 ± 1.9 mm, respectively. Average vector displacement was 4.3 ± 2.4 mm for all treatment days and 4.2 ± 1.7 mm for each patient. Of 141 treatments, 137 (97.2%) fell within 7.0 mm in all axes. CONCLUSION: The addition of a 7-mm margin to the GTV for patients receiving SBRT for NSCLC using tomotherapy is adequate to account for tumour movement. Mid-fraction CT scans proved to be valuable in assessing intrafraction tumour motion.