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Simple Summary: While the definition of the prostate bed clinical target volume (CTV) has been proposed in consensus guidelines, various PTV expansions have been proposed. Depending on the institution, isotropic or non-isotropic expansions on the prostate bed CTV may be considered. This is a preliminary study evaluating PTV margin reduction accounting for inter-fractional uncertainties using high quality iCBCT image guidance. This analysis revealed that 2 mm and 4 mm margins may be considered for margin expansion with and without an endorectal balloon. Purpose: Planning target volume (PTV) expansion for post-prostatectomy radiotherapy is typically ≥5 mm. Recent clinical trials have proved the feasibility of a reduced margin of 2–3 mm for treatments on MRI-linac. We aim to study the minimum PTV margin needed using iterative cone-beam CT (iCBCT) as image guidance on conventional linacs. Materials/Methods: Fourteen patients who received post-prostatectomy irradiation (8 with an endorectal balloon and 6 without a balloon) were included in this study. Treatment was delivered with volumetric modulated radiation therapy (VMAT). Fractional dose delivery was evaluated in 165 treatment fractions. The bladder, rectal wall, femoral heads, and prostate bed clinical tumor volume (CTV) were contoured and verified on daily iCBCT. PTV margins (0 mm, 2 mm, and 4 mm) were evaluated on daily iCBCT. CTV coverage and OAR dose parameters were assessed with each PTV margin. Results: CTV D100% was underdosed with a 0 mm margin in 32% of fractions in comparison with 2 mm (6%) and 4 mm (6%) PTV margin (p ≤ 0.001). CTV D95% > 95% was met in 93–94% fractions for all PTV expansions. CTV D95% > 95% was achieved in more patients with an endorectal balloon than those without: 0 mm—90/91 (99%) vs. 63/74 (85%); 2 mm—90/91 (99%) vs. 65/75 (87%); 4 mm—90/90 (100%) vs. 63/73 (86%). There was no difference in absolute median change in CTV D95% (0.32%) for 0-, 2-, and 4 mm margins. The maximum dose remained under 108% for 100% (0 mm), 97% (2 mm), and 98% (4 mm) of images. Rectal wall maximum dose remained under 108% for 100% (0 mm), 100% (2 mm), and 98% (4 mm) of images. Conclusions: With high-quality iCBCT image guidance, PTV margin accounting for inter-fractional uncertainties can be safely reduced for post-prostatectomy radiotherapy. For fractionated radiotherapy, an isotropic expansion of 2 mm and 4 mm may be considered for margin expansion with and without the endorectal balloon. Future application for margin reduction needs to be further evaluated and considered with the advent of shorter post-prostatectomy radiation courses. [ABSTRACT FROM AUTHOR]

Simple Summary: Organs at risk (OARs) management (rectum and bladder) is evaluated in patients receiving post-prostatectomy radiation. The role of full bladder instruction and the use of the endorectal balloon is evaluated. The efficacy of this practice was based on daily image and dose delivery using high-quality iterative cone-beam CT (iCBCT). The analysis revealed that a minimal bladder contour can be generated and followed to ensure sufficient bladder sparing. An endorectal balloon is not needed for sufficient target coverage or OAR sparing. Purpose: Post-operative prostate cancer patients are treated with full bladder instruction and the use of an endorectal balloon (ERB). We reassessed the efficacy of this practice based on daily image guidance and dose delivery using high-quality iterative reconstructed cone-beam CT (iCBCT). Methods: Fractional dose delivery was calculated on daily iCBCT for 314 fractions from 14 post-operative prostate patients (8 with and 6 without ERB) treated with volumetric modulated radiotherapy (VMAT). All patients were positioned using novel iCBCT during image guidance. The bladder, rectal wall, femoral heads, and prostate bed clinical tumor volume (CTV) were contoured and verified on daily iCBCT. The dose-volume parameters of the contoured organs at risk (OAR) and CTV coverage were assessed for the clinical impact of daily bladder volume variations and the use of ERB. Minimum bladder volume was studied, and a straightforward bladder instruction was explored for easy clinical adoption. Results: A "minimum bladder" contour, the overlap between the original bladder contour and a 15 mm anterior and superior expansion from prostate bed PTV, was confirmed to be effective in identifying cases that might fail a bladder constraint of V65% <60%. The average difference between the maximum and minimum bladder volumes for each patient was 277.1 mL. The daily bladder volumes varied from 62.4 to 590.7 mL and ranged from 29 to 286% of the corresponding planning bladder volume. The bladder constraint of V65% <60% was met in almost all fractions (98%). CTVs (D90%, D95%, and D98%) remained well-covered regardless of the absolute bladder volume daily variation or the presence of the endorectal balloon. Patients with an endorectal balloon showed smaller variation but a higher average maximum rectal wall dose (D0.03mL: 104.3% of the prescription) compared to patients without (103.3%). Conclusions: A "minimum bladder" contour was determined that can be easily generated and followed to ensure sufficient bladder sparing. Further analysis and validation are needed to confirm the utility of the minimal bladder contour. Accurate dose delivery can be achieved for prostate bed target coverage and OAR sparing with or without the use of ERB. [ABSTRACT FROM AUTHOR]

Purpose: We proposed a novel tool-a dose linear energy transfer (LET)-volume histogram (DLVH)-and performed an exploratory study to investigate rectal bleeding in prostate cancer treated with intensity modulated proton therapy.Methods and Materials: The DLVH was constructed with dose and LET as 2 axes, and the normalized volume of the structure was contoured in the dose-LET plane as isovolume lines. We defined the DLVH index, DLv%(d,l) (ie, v% of the structure) to have a dose of ≥d Gy and an LET of ≥l keV/μm, similar to the dose-volume histogram index Dv%. Nine patients with prostate cancer with rectal bleeding (Common Terminology Criteria for Adverse Events grade ≥2) were included as the adverse event group, and 48 patients with no complications were considered the control group. A P value map was constructed by comparison of the DLVH indices of all patients between the 2 groups using the Mann-Whitney U test. Dose-LET volume constraints (DLVCs) were derived based on the P value map with a manual selection procedure facilitated by Spearman's correlation tests. The obtained DLVCs were further cross-validated using a multivariate support vector machine (SVM)-based normal tissue complication probability (NTCP) model with an independent testing data set composed of 8 adverse event and 13 control patients.Results: We extracted 2 DLVC constraints. One DLVC was obtained, Vdose/LETboundary:2.5keVμmat 75 Gy to 3.2keVμmat8.65Gy <1.27% (DLVC1), revealing a high LET volume effect. The second DLVC, V(72.2Gy,0keVμm) < 2.23% (DVLC2), revealed a high dose volume effect. The SVM-based NTCP model with 2 DLVCs provided slightly superior performance than using dose only, with an area under the curve of 0.798 versus 0.779 for the testing data set.Conclusions: Our results demonstrated the importance of rectal "hot spots" in both high LET (DLVC1) and high dose (DLVC2) in inducing rectal bleeding. The SVM-based NTCP model confirmed the derived DLVCs as good predictors for rectal bleeding when intensity modulated proton therapy is used to treat prostate cancer. [ABSTRACT FROM AUTHOR]

Introduction: Proton beam therapy (PBT) reduces normal organ dose compared to intensity-modulated radiation therapy (IMRT) for patients with major salivary gland tumors. It is not known whether this dosimetric advantage is clinically meaningful for reducing acute toxicity. Methods: We evaluated treatment parameters and acute toxicity outcomes of patients with major salivary gland cancers enrolled on the Proton Collaborative Group REG001-09 trial (NCT01255748). Results: One-hundred and five patients with a median age of 61 years were included. The majority had parotid (N = 90) versus submandibular gland (N = 15) tumors. The patients were treated across seven institutions in the United States between 2010 and 2017, most commonly in the postoperative setting (70.5%) although a minority were treated definitively (29.5%). Median PBT dose was 66.5 GyE in 33 fractions; only one patient was prescribed less than 50 GyE. Chemotherapy was given concurrently to 20%. Median follow-up was 14.3 months. Acute grade 2 or higher toxicity included nausea (1.5%), dysgeusia (4.8%), xerostomia (7.6%), mucositis (10.5%) and dysphagia (10.5%). Conclusions: PBT should be strongly considered when ipsilateral radiation therapy is indicated for major salivary gland cancer based on a considerably lower incidence of acute grade 2 or higher toxicity in this analysis compared to historical IMRT outcomes. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: Thymic malignancies (TM) are rare tumors with long-term survivorship, causing concerns for radiotherapy-related late side effects. Proton therapy (PT) reduces the radiation dose to organs at risk, potentially decreasing long-term toxicities while preserving disease control. We report patterns-of-care and early clinical outcomes after PT for thymoma and thymic carcinoma. Methods: Between January 2008 and March 2017, 30 patients with TMs enrolled on one of two IRB-approved prospective protocols and received postoperative or definitive PT. Clinical outcomes, pathology, treatment dose, toxicities, and follow-up information were analyzed. Results: Twenty-two thymoma patients with a median age of 52.1 years (range, 23–72) received a median RT dose of 54 Gy (RBE) (range, 45–70) either postoperatively (91%) or definitively (9%); 23% received adjuvant chemotherapy. Among eight thymic carcinoma patients, the median age was 65.5 years (range, 38-88) and median RT dose was 60 Gy (RBE) (range, 42–70) delivered postoperatively (75%) or definitively (25%); 50% received chemotherapy. Median follow-up for all patients was 13 months (range, 2–59 months). Five patients relapsed, one locally (3%). Three patients died of disease progression, including two thymomas and one thymic carcinoma patient; a fourth died of intercurrent disease. One patient with thymic carcinoma and 1 with thymoma are alive with disease. No patients treated with PT for their initial disease (de novo) experienced grade ≥3 toxicities. The most common grade 2 toxicities were dermatitis (37%), cough (13%), and esophagitis (10%). Conclusion: Adjuvant and definitive PT are being used in the treatment of TMs. Early results of the largest such cohort reported to date demonstrates an acceptable rate of recurrence with a favorable toxicity profile. Longer follow-up and a larger patient cohort are needed to confirm these findings. [ABSTRACT FROM AUTHOR]

The article presents a study that reports proton beam therapy (PBT) for breast angiosarcoma from prospective proton collaborative group (PCG) registry. It mentions that patients received postmastectomy PBT to the chest wall after mastectomy for angiosarcoma. It informs that aggressive surgery and chemotherapy may improve outcomes.

Purpose: To compare dose distributions in targeted tissues (prostate, seminal vesicles, pelvic regional nodes) and nontargeted tissues in the pelvis with intensity-modulated radiotherapy (IMRT) and forward-planned, double-scattered, three-dimensional proton radiotherapy (3D-PRT). Methods and Materials: IMRT, IMRT followed by a prostate 3D-PRT boost (IMRT/3D-PRT), and 3D-PRT plans were created for 5 high-risk prostate cancer patients (n = 15 plans). A 78-CGE/Gy dose was prescribed to the prostate and proximal seminal vesicles and a 46-CGE/Gy was prescribed to the pelvic nodes. Various dosimetric endpoints were compared. Results: Target coverage of the prostate and nodal planning target volumes was adequate for all three plans. Compared with the IMRT and IMRT/3D-PRT plans, the 3D-PRT plans reduced the mean dose to the rectum, rectal wall, bladder, bladder wall, small bowel, and pelvis. The relative benefit of 3D-PRT (vs IMRT) at reducing the rectum and rectal wall V5-V40 was 53% to 71% (p < 0.05). For the bladder and bladder wall, the relative benefit for V5 to V40 CGE/Gy was 40% to 63% (p < 0.05). The relative benefit for reducing the volume of small bowel irradiated from 5 to 30 CGE/Gy in the 3D-PRT ranged from 62% to 69% (p < 0.05). Use of 3D-PRT did not produce the typical low-dose “bath” of radiation to the pelvis seen with IMRT. Femoral head doses were higher for the 3D-PRT. Conclusions: Use of 3D-PRT significantly reduced the dose to normal tissues in the pelvis while maintaining adequate target coverage compared with IMRT or IMRT/3D-PRT. When treating the prostate, seminal vesicles, and pelvic lymph nodes in prostate cancer, proton therapy may improve the therapeutic ratio beyond what is possible with IMRT. [Copyright &y& Elsevier]

Purpose: To determine the influence of magnetic-resonance-imaging (MRI)–vs. computed-tomography (CT)–based prostate and normal structure delineation on the dose to the target and organs at risk during proton therapy. Methods and Materials: Fourteen patients were simulated in the supine position using both CT and T2 MRI. The prostate, rectum, and bladder were delineated on both imaging modalities. The planning target volume (PTV) was generated from the delineated prostates with a 5-mm axial and 8-mm superior and inferior margin. Two plans were generated and analyzed for each patient: an MRI plan based on the MRI-delineated PTV, and a CT plan based on the CT-delineated PTV. Doses of 78 Gy equivalents (GE) were prescribed to the PTV. Results: Doses to normal structures were lower when MRI was used to delineate the rectum and bladder compared with CT: bladder V50 was 15.3% lower (p = 0.04), and rectum V50 was 23.9% lower (p = 0.003). Poor agreement on the definition of the prostate apex was seen between CT and MRI (p = 0.007). The CT-defined prostate apex was within 2 mm of the apex on MRI only 35.7% of the time. Coverage of the MRI-delineated PTV was significantly decreased with the CT-based plan: the minimum dose to the PTV was reduced by 43% (p < 0.001), and the PTV V99% was reduced by 11% (p < 0.001). Conclusions: Using MRI to delineate the prostate results in more accurate target definition and a smaller target volume compared with CT, allowing for improved target coverage and decreased doses to critical normal structures. [Copyright &y& Elsevier]

Purpose: We propose linear energy transfer (LET)-guided robust optimization in intensity modulated proton therapy for head and neck cancer. This method simultaneously considers LET and physical dose distributions of tumors and organs at risk (OARs) with uncertainties.Methods and Materials: Fourteen patients with head and neck cancer were included in this retrospective study. Cord, brain stem, brain, and oral cavity were considered. Two algorithms, voxel-wise worst-case robust optimization and LET-guided robust optimization (LETRO), were used to generate intensity modulated proton therapy plans for each patient. The latter method directly optimized LET distributions rather than indirectly as in previous methods. LET-volume histograms (LETVHs) were generated, and high LET was redistributed from nearby OARs to tumors in a user-defined way via LET-volume constraints. Dose-volume histogram indices, such as clinical target volume (CTV) D98% and D2%-D98%, cord Dmax, brain stem Dmax, brain Dmax, and oral cavity Dmean, were calculated. Plan robustness was quantified using the worst-case analysis method. LETVH indices analogous to dose-volume histogram indices were used to characterize LET distributions. The Wilcoxon signed rank test was performed to measure statistical significance.Results: In the nominal scenario, LETRO provided higher LET distributions in the CTV (unit: keV/μm; CTV LET98%: 1.18 vs 1.08, LETRO vs RO, P = .0031) while preserving comparable physical dose and plan robustness. LETRO achieved significantly reduced LET distributions in the cord, brain stem, and oral cavity compared with RO (cord LETmax: 7.20 vs 8.20, P = .0010; brain stem LETmax: 10.95 vs 12.05, P = .0007; oral cavity LETmean: 2.11 vs 3.12, P = .0052) and had comparable physical dose and plan robustness in all OARs. In the worst-case scenario, LETRO achieved significantly higher LETmean in the CTV, reduced LETmax in the brain, and was comparable to other LETVH indices (CTV LETmean: 3.26 vs 3.35, P = .0012; brain LETmax: 24.80 vs 22.00, P = .0016).Conclusions: LETRO robustly optimized LET and physical dose distributions simultaneously. It redistributed high LET from OARs to targets with slightly modified physical dose and plan robustness. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to compare the impact of uncertainties and interplay on 3-dimensional (3D) and 4D robustly optimized intensity modulated proton therapy (IMPT) plans for lung cancer in an exploratory methodology study.Methods and Materials: IMPT plans were created for 11 nonrandomly selected non-small cell lung cancer (NSCLC) cases: 3D robustly optimized plans on average CTs with internal gross tumor volume density overridden to irradiate internal target volume, and 4D robustly optimized plans on 4D computed tomography (CT) to irradiate clinical target volume (CTV). Regular fractionation (66 Gy [relative biological effectiveness; RBE] in 33 fractions) was considered. In 4D optimization, the CTV of individual phases received nonuniform doses to achieve a uniform cumulative dose. The root-mean-square dose-volume histograms (RVH) measured the sensitivity of the dose to uncertainties, and the areas under the RVH curve (AUCs) were used to evaluate plan robustness. Dose evaluation software modeled time-dependent spot delivery to incorporate interplay effect with randomized starting phases of each field per fraction. Dose-volume histogram (DVH) indices comparing CTV coverage, homogeneity, and normal tissue sparing were evaluated using Wilcoxon signed rank test.Results: 4D robust optimization plans led to smaller AUC for CTV (14.26 vs 18.61, respectively; P=.001), better CTV coverage (Gy [RBE]) (D95% CTV: 60.6 vs 55.2, respectively; P=.001), and better CTV homogeneity (D5%-D95% CTV: 10.3 vs 17.7, respectively; P=.002) in the face of uncertainties. With interplay effect considered, 4D robust optimization produced plans with better target coverage (D95% CTV: 64.5 vs 63.8, respectively; P=.0068), comparable target homogeneity, and comparable normal tissue protection. The benefits from 4D robust optimization were most obvious for the 2 typical stage III lung cancer patients.Conclusions: Our exploratory methodology study showed that, compared to 3D robust optimization, 4D robust optimization produced significantly more robust and interplay-effect-resistant plans for targets with comparable dose distributions for normal tissues. A further study with a larger and more realistic patient population is warranted to generalize the conclusions. [ABSTRACT FROM AUTHOR]