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.
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.
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.
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.
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.
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.
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 (Na
S), a hydrogen sulfide (H
S) donor, to selectively kill GBM cells (T98G and U87) while sparing normal human cerebral microvascular endothelial cells (hCMEC/D3). Na
S also decreased mitochondrial respiration, increased oxidative stress and induced γH2AX foci and oxidative base damage in GBM cells. Since Na
S 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, Na
S 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 Na
S toxicity in GBM cells. The fact that survival of LN-18 GBM cells lacking mitochondrial DNA (ρ
) was not altered by Na
S whereas the survival of LN-18 ρ
cells was compromised supports this conclusion. When cells were treated with Na
S and photon or proton radiation, GBM cell killing was enhanced, which opens the possibility of H
S being a radiosensitizer. Therefore, this study provides the first evidence that H
S donors could be used in GBM therapy to potentiate radiation-induced killing.
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.
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.
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.
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.
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).
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.
•Benefits of proton beam therapy for treatment of prostate cancer are unknown.•Data comparing pencil beam vs. passive scatter/uniform scanning protons are limited.•Significant differences in acute ...toxicity between proton modalities were observed.•Future studies evaluating differences between the two proton modalities are needed.
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.
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.
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.
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.
•Data comparing PROs with pencil beam and passive scattering are lacking.•We performed a comparison of EPIC domain scores for prostate cancer patients.•Results were sensitive to the methods used to ...compare PROs.•Future studies are needed to prospectively compare PROs following protons.
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 (PROs) following PBS and PS/US for prostate cancer (PC) in a prospective multicenter registry study.
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.
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).
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.
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