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.

Electronic patient-reported outcomes and toxicities during radiotherapy for head-and-neck cancer.

PURPOSE: To characterize quality of life (QOL) using real-time, electronic patient-reported outcomes (ePROs) and to evaluate adverse events (AEs) and supportive care during head-and-neck radiotherapy (RT) and concurrent chemoradiotherapy (CCRT). METHODS: Sixty-five patients undergoing head-and-neck RT completed electronic, real-time, 12-item linear analog self-assessments (LASA) at baseline, before biweekly appointments, and at the last week of RT. Changes in QOL domains between time points were calculated. Clinical data were collected from the institutional medical record. AEs were recorded at the same time points as the LASA and graded. RESULTS: During head-and-neck RT, most patients had clinically meaningful decreases in all QOL domains except level of support, financial concerns, and legal concerns. QOL domains with the most prevalent, clinically meaningful decreases were fatigue (75.4% of patients; 95% CI, 62.9-84.9%), social activity (70.8%; 95% CI, 58.0-81.1%), and overall QOL (70.8%; 95% CI, 58.0-81.1%). All patients had grade 2 AEs; 35.4% had grade 3 (50.0%, CCRT; 12.0%, RT; P = .002). Weight loss averaged 5.5 kg (6.9 kg, CCRT; 2.8 kg, RT; P < .001). Intravenous hydration was needed in 52.3% (77.5%, CCRT; 12.0%, RT; P < .001); feeding tube placement 40.0% (57.5%, CCRT; 12.0%, RT; P = .001); emergency department visits without hospitalization, 10.8%; and emergent hospitalization, 27.7% (37.5%, CCRT; 12.0%, RT; P = .04). CONCLUSIONS: Head-and-neck RT, particularly CCRT, negatively impacts patients' overall QOL, social activity, and fatigue, with frequent grade 3 AEs, weight loss, intravenous hydration, feeding tube placement, ED visits, and hospitalization. Real-time ePROs allow providers to monitor QOL at multiple time points during RT, potentially allowing early intervention to improve QOL and mitigate AEs.

Proton therapy for isolated local regional recurrence of breast cancer after mastectomy alone.

Purpose/Objectives: To assess adverse events (AEs) and disease-specific outcomes after proton therapy for isolated local-regional recurrence (LRR) of breast cancer after mastectomy without prior radiotherapy (RT). Materials/Methods: Patients were identified from a multi-institutional prospective registry and included if diagnosed with invasive breast cancer, initially underwent mastectomy without adjuvant RT, experienced an LRR, and subsequently underwent salvage treatment, including proton therapy. Follow-up and cancer outcomes were measured from the date of RT completion. Results: Nineteen patients were included. Seventeen patients were treated with proton therapy to the chest wall and comprehensive regional lymphatics (17/19, 90%). Maximum grade AE was grade 2 in 13 (69%) patients and grade 3 in 4 (21%) patients. All patients with grade 3 AE received > 60 GyE (p=0.04, Spearman correlation coefficient=0.5). At the last follow-up, 90% of patients were alive with no LRR or distant recurrence. Conclusions: For breast cancer patients with isolated LRR after initial mastectomy without adjuvant RT, proton therapy is well-tolerated in the salvage setting with excellent loco-regional control. All grade 3 AEs occurred in patients receiving > 60 GyE.

Using Novel Statistical Techniques to Accurately Determine the Predictive Dose Range in a Study of Overall Survival after Definitive Radiotherapy for Stage III Non-Small Cell Lung Cancer in Association with Heart Dose.

PURPOSE: Recent studies of radiotherapy (RT) for stage III non-small-cell lung cancer (NSCLC) have associated high dose to the heart with cardiac toxicity and decreased overall survival (OS). We used advanced statistical techniques to account for correlations between dosimetric variables and more accurately determine the range of heart doses which are associated with reduced OS in patients receiving RT for stage III NSCLC. METHODS: From 2006 to 2013, 119 patients with stage III NSCLC received definitive RT at our institution. OS data was obtained from institutional tumor registry. We used multivariate Cox model to determine patient specific covariates predictive for reduced overall survival. We examined age, prescription dose, mean lung dose, lung V20, RT technique, stage, chemotherapy, tumor laterality, tumor volume, and tumor site as candidate covariates. We subsequently used novel statistical techniques within multivariate Cox model to systematically search the whole heart dose-volume histogram (DVH) for dose parameters associated with OS. RESULTS: Patients were followed until death or 2.5 to 81.2 months (median 30.4 months) in those alive at last follow up. On multivariate analysis of whole heart DVH, the dose of 51 Gy was identified as a threshold dose above which the dose volume relationship becomes predictive for OS. We identified V55Gy (percentage of the whole heart volume receiving at least 55 Gy) as the best single DVH index which can be used to set treatment optimization constraints (Hazard Ratio = 1.044 per 1% increase in heart volume exposed to at least 55 Gy, P = 0.03). Additional characteristics correlated with OS on multivariate analysis were age, stage (IIIA/IIIB), and administration of chemotherapy. CONCLUSION: Doses above 51 Gy, applied to small volumes of the heart, are associated with worse OS in stage III NSCLC patients treated with definitive RT. Higher stage, older age and lack of chemotherapy were also associated with reduced OS.

Patient-reported quality-of-life outcomes in relation to provider-assessed adverse events during head and neck radiotherapy.

PURPOSE: To assess the relationship between patient-reported quality-of-life (QOL) outcomes and provider-assessed adverse events (AEs) during head-and-neck (H&N) radiotherapy (RT). METHODS: Sixty-five patients undergoing H&N RT prospectively completed 12-domain linear analogue self-assessments (LASA) at baseline, before biweekly appointments, and at last week of RT. At the same time points, provider-assessed AEs were graded using Common Terminology Criteria for Adverse Events v4.0. LASA scores were stratified by maximum-grade AE and analyzed using Kruskal-Wallis methodology. Agreement between LASA scores and maximum-grade AE was assessed using Bland-Altman analysis. RESULTS: Patient-reported QOL outcomes showed clinically meaningful decreases in most domains, predominantly fatigue (77.8% of patients), social activity (75.4%), and overall QOL (74.2%). Provider-assessed AEs showed 100% grade 2 AE, 35.4% grade 3 AE, and 3.1% grade 4 AE. At baseline, patients with higher grade AEs reported worse physical well-being (WB) (P = .04). At week 1, the following QOL domains were worse for patients with higher grade AEs: overall QOL (P = .03), mental WB (P = .02), and physical WB (P = .03). Bland-Altman analysis showed that QOL scores were relatively worse than AE burden at baseline and relatively better at RT completion. CONCLUSIONS: Worse QOL was associated with higher-grade AEs at baseline and early in RT. The impact of AEs on QOL appears to lessen with time. Patient-reported QOL outcomes and provider-assessed AEs provide complementary information.

The fibroblast growth factor-inducible 14 receptor is highly expressed in HER2-positive breast tumors and regulates breast cancer cell invasive capacity.

Genomic characterization is beginning to define a molecular taxonomy for breast cancer; however, the molecular basis of invasion and metastasis remains poorly understood. We report a pivotal role for the fibroblast growth factor-inducible 14 (Fn14) receptor in this process. We examined whether Fn14 and its ligand tumor necrosis factor-like weak inducer of apoptosis (TWEAK) were expressed in breast tumors and whether deregulation of Fn14 levels affected malignant behavior of breast cancer cell lines. Analysis of TWEAK and Fn14 in publicly available gene expression data indicated that high Fn14 expression levels significantly correlated with several poor prognostic indicators (P < 0.05). Fn14 expression was highest in the HER2-positive/estrogen receptor-negative (HER2(+)/ER(-)) intrinsic subtype (P = 0.0008). An association between Fn14 and HER2 expression in breast tumors was confirmed by immunohistochemistry. Fn14 levels were elevated in invasive, ER(-) breast cancer cell lines. Overexpression of Fn14 in weakly invasive MCF7 and T47D cells resulted in a marked induction of invasion and activation of nuclear factor-kappaB (NF-kappaB) signaling. Ectopic expression of Fn14tCT, a Fn14 deletion mutant that cannot activate NF-kappaB signaling, was not able to induce invasion. Moreover, ectopic expression of Fn14tCT in highly invasive MDA-MB-231 cells reduced their invasive capability. RNA interference-mediated inhibition of Fn14 expression in both MDA-MB-231 and MDA-MB-436 cells reduced invasion. Expression profiling of the Fn14-depleted cells revealed deregulation of NF-kappaB activity. Our findings support a role for Fn14-mediated NF-kappaB pathway activation in breast tumor invasion and metastasis.

Initial results of a randomized phase III trial of high dose image guided radiation with or without androgen deprivation therapy for intermediate-risk prostate cancer.

BACKGROUND: Prior randomized studies have shown a survival benefit using combined androgen deprivation therapy (ADT) and radiation therapy for intermediate-risk prostate cancer. However, these studies either used low doses of radiation (66.6 Gy to isocenter) or imaged guidance was not available. This study reports the initial differences for high dose image guided radiation with or without ADT. METHODS: From 2012 to 2014, 56 patients were treated with and 60 patients without 6 months of ADT (N = 116) in our phase III randomized trial for intermediate-risk prostate cancer. The primary endpoints of the current analysis are Expanded Prostate Cancer Index Composite (EPIC) scores, International Prostate Symptom Score (IPSS) scores, and bowel or urinary adverse events (AEs, graded using CTCAE v4) with and without ADT. Treatment consisted of 81 Gy in 45 treatments (tx) or 100 Gy Pd-103 implant followed by 45 Gy in 25 tx with or without ADT. Cone-beam fiducial-based guidance was done. Statistical analysis included Fisher's exact test, chi-square test, and ANCOVA. RESULTS: Median follow-up for both groups was 2.6 years. Acute or chronic urinary and acute or chronic bowel toxicities were similar with or without ADT (acute urinary: 16 vs 25 G0-1, 39 vs 35 G2 and 1 vs 0 G3, p = 0.17; chronic urinary: 40 vs 45 G1 and 16 vs 15 G2 toxicities, p = 0.68; acute bowel: 56 vs 59 G1 and 0 vs 1 G2 toxicities, p = 0.99; chronic bowel: 56 vs 59 G1 and 0 vs 1 G2 toxicities, p = 0.99). One patient had grade 3 urinary AE (1/116 or 0.8%). No patient had grade 3 bowel AE. With the use of ADT, a temporary decline in the EPIC sexual (p = 0.004) and hormonal scores (p = 0.02) were seen for the first 3 to 6 months after the completion of radiation, but the scores recovered by 12 months. Brachytherapy plus external beam radiation was compared to external beam radiation alone; brachytherapy EPIC urinary irritative scores were temporarily lower at 3 months, 76 vs. 84 (p = 0.006), had higher IPSS scores at 3 months, 15 vs 12 (p = 0.01), and had increased acute urinary AEs (p<0.001). No difference in failures were seen with or without ADT or associated with the use of brachytherapy. SIGNIFICANCE: Low toxicity and minimal temporary bother as measured by EPIC and IPSS were seen in both arms. ADT was well-tolerated and associated with temporary changes.

Initial toxicity, quality-of-life outcomes, and dosimetric impact in a randomized phase 3 trial of hypofractionated versus standard fractionated proton therapy for low-risk prostate cancer.

PURPOSE: Randomized evidence for extreme hypofractionation in prostate cancer is lacking. We aimed to identify differences in toxicity and quality-of-life outcomes between standard fractionation and extreme hypofractionated radiation in a phase 3 randomized trial. METHODS AND MATERIALS: We analyzed the results of the first 75 patients in our phase 3 trial, comparing 38 Gy relative biologic effectiveness (RBE) in 5 fractions (n = 46) versus 79.2 Gy RBE in 44 fractions (n = 29). Patients received proton radiation using fiducials and daily image guidance. We evaluated American Urological Association Symptom Index (AUASI), adverse events (AEs), and Expanded Prostate Index Composite (EPIC) domains. The primary endpoint of this interim analysis was the cumulative incidence of grade 2 (G2) or higher AEs. The randomized patient allocation scheme was a 2:1 ratio favoring the 38 Gy RBE arm. RESULTS: The median follow-up was 36 months; 30% of patients reached 48-month follow-up. AUASI scores differed <5 points (4.4 vs 8.6; P = .002) at 1 year, favoring the 79.2 Gy arm. Differences in AUASI were not significant at ≥18 months. EPIC urinary symptoms favored the 79.2 Gy arm at 1 year (92.3 vs 84.5; P = .009) and 18 months (92.3 vs 85.3; P = .03); bother scores were not significant at other time points. Cumulative ≥G2 genitourinary toxicity was similar between the 79.2 Gy and 38 Gy arms (34.5% vs 30.4%; P = .80). We found no differences in the EPIC domains of bowel symptoms, sexual symptoms, or bowel ≥G2 toxicities. Bladder V80 (79.2 Gy arm; P = .04) and V39 (38 Gy arm; P = .05) were predictive for cumulative G2 genitourinary AEs. CONCLUSIONS: Low AE rates were seen in both study arms. Early temporary differences in genitourinary scores disappeared over time. Bladder constraints were associated with genitourinary AEs.

Radiation and the heart: systematic review of dosimetry and cardiac endpoints.

INTRODUCTION: Recent trials in radiotherapy have associated heart dose and survival, inadequately explained by the existing literature for radiation-related late cardiac effects.  Authors aimed to review the recent literature on cardiac dosimetry and survival/cardiac endpoints. Areas covered: Systematic review of the literature in the past 10 years (2008-2017) was performed to identify manuscripts reporting both cardiac dosimetry and survival/cardiac endpoints.  Authors identified 64 manuscripts for inclusion, covering pediatrics, breast cancer, lung cancer, gastrointestinal diseases (primarily esophageal cancer), and adult lymphoma. Expert commentary: In the first years after radiotherapy, high doses (>40 Gy) to small volumes of the heart are associated with decreased survival from an unknown cause.  In the long-term, mean heart dose is associated with a small increased absolute risk of cardiac death.  For coronary disease, relative risk increases roughly 10% per Gy mean heart dose, augmented by age and cardiac risk factors.  For valvular disease and heart failure, doses >15 Gy substantially increase risk, augmented by anthracyclines.  Arrhythmias after radiotherapy are poorly described but may account for the association between upper heart dose and survival.  Symptomatic pericardial effusion typically occurs with doses >40 Gy.  Close follow-up and mitigation of cardiovascular risk factors are necessary after thoracic radiotherapy.

Choosing wisely after publication of level I evidence in breast cancer radiotherapy.

BACKGROUND: Recent trials in early-stage breast cancer support hypofractionated whole-breast radiotherapy (WBRT) as part of breast-conserving therapy (BCT). Evidence also suggests that radiotherapy (RT) omission may be reasonable for some patients over 70 years. Among radiation-delivery techniques, intensity-modulated RT (IMRT) is more expensive than 3-dimensional conformal RT (3DCRT). Based on this evidence, in 2013, the American Society for Radiation Oncology (ASTRO) recommended hypofractionated schedules for women aged ≥50 years with early-stage breast cancer and avoiding routine use of IMRT for WBRT. To assess response to level I evidence and adherence to ASTRO recommendations, we evaluated the pattern of RT use for early-stage breast cancer at our National Comprehensive Cancer Network institution from 2006 to 2008 and 2011 to 2013 and compared the results with national trends. METHODS: Data from a prospective database were extracted to include patients treated with BCT, aged ≥50 years, with histologic findings of invasive ductal carcinoma, stage T1-T2N0M0, estrogen receptor-positive, and HER2 normal. We retrospectively reviewed the medical records and estimated costs based on 2016 Hospital Outpatient Prospective Payment System (technical fees) and Medicare Physician Fee Schedule (professional fees). RESULTS: Among 55 cases from 2006 to 2008, treatment regimens were 11% hypofractionated, 69% traditional schedule, and 20% RT omission (29% of patients were aged >70 years). Among 83 cases from 2011 to 2013, treatment regimens were 54% hypofractionated, 19% traditional schedule, and 27% RT omission (48% of patients were aged >70 years). 3DCRT was used for all WBRT treatments. Direct medical cost estimates were as follows: 15 fractions 3DCRT, $7,197.87; 15 fractions IMRT, $11,232.33; 25 fractions 3DCRT, $9,731.39; and 25 fractions IMRT, $16,877.45. CONCLUSION: Despite apparent resistance to shorter radiation schedules in the United States, we demonstrate that rapid practice change in response to level I evidence is feasible. Wider adoption of evidence-based guidelines in early-stage breast cancer may substantially lower health care costs and improve convenience for patients without sacrificing oncologic outcomes.

Tissue Expanders and Proton Beam Radiotherapy: What You Need to Know.

Proton beam radiotherapy (PBR) has gained acceptance for the treatment of breast cancer because of unique beam characteristics that allow superior dose distributions with optimal dose to the target and limited collateral damage to adjacent normal tissue, especially to the heart and lungs. To determine the compatibility of breast tissue expanders (TEs) with PBR, we evaluated the structural and dosimetric properties of 2 ex vivo models: 1 model with internal struts and another model without an internal structure. Although the struts appeared to have minimal impact, we found that the metal TE port alters PBR dynamics, which may increase proton beam range uncertainty. Therefore, submuscular TE placement may be preferable to subcutaneous TE placement to reduce the interaction of the TE and proton beam. This will reduce range uncertainty and allow for more ideal radiation dose distribution.

Impact of intravenous contrast enhancement phase on target definition for hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (IHC): Observations from patients enrolled on a prospective phase 2 trial.

BACKGROUND: The safety and efficacy of radiation therapy for hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (IHC) depend on accurate definition of gross tumor volume (GTV), but GTV often varies between phases of multiphasic computed tomography (CT) imaging. METHODS: We contoured GTVs on arterial, portal venous, and delayed phases of multiphasic CT scans for 32 patients treated on an institutional review board-approved prospective trial of proton therapy for primary liver tumors and determined which phase provided optimal GTV visualization. We assessed agreement between individual phase GTVs to determine if GTV for each phase was encompassed in a 5-mm expansion of either the smallest or the best-visualized GTV. RESULTS: There were 19 HCC lesions and 14 IHC lesions. HCC lesions were best identified on the arterial phase in 42% (n = 8), portal venous phase in 32% (n = 6), and delayed phase in 26% (n = 5). IHC lesions were best identified on portal venous phase in 64% (n = 9) and the arterial phase in 29% (n = 4), with 1 case equally visualized on arterial and portal venous phases. In all 33 lesions, a 5-mm expansion around the smallest GTV failed to cover GTVs defined on other available phases. A 5-mm expansion around the best-visualized GTV provided satisfactory coverage of all available phases' GTVs in 6/18 HCC cases and 2/9 IHC cases. CONCLUSIONS: Variability between GTVs on multiphasic CT scans could not be overcome with a 5-mm expansion of either the smallest GTV or the best-visualized GTV. Assessment of all available intravenous contrast phases is essential to accurately define the GTV.

Therapeutic intervention for chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS): a systematic review and meta-analysis.

BACKGROUND: Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) has been treated with several different interventions with limited success. This meta-analysis aims to review all trials reporting on therapeutic intervention for CP/CPPS using the National Institutes of Health-Chronic Prostatitis Symptom Index (NIH-CPSI). METHODS: We searched Medline, PubMed, the Cochrane Pain, Palliative & Supportive Care Trials, the Cochrane Register of Controlled Trials, CINAHL, ClinicalTrials.gov, and the NIDDK website between 1947 and December 31, 2011 without language or study type restrictions. All RCTs for CP/CPPS lasting at least 6 weeks, with a minimum of 10 participants per arm, and using the NIH-CPSI score, the criterion standard for CP/CPPS, as an outcome measure were included. Data was extracted from each study by two independent reviewers. Gillbraith and I-squared plots were used for heterogeneity testing and Eggers and Peters methods for publication bias. Quality was assessed using a component approach and meta-regression was used to analyze sources of heterogeneity. RESULTS: Mepartricin, percutaneous tibial nerve stimulation (PTNS), and triple therapy comprised of doxazosin + ibuprofen + thiocolchicoside (DIT) resulted in clinically and statistically significant reduction in NIH-CPSI total score. The same agents and aerobic exercise resulted in clinically and statistically significant NIH-CPSI pain domain score reduction. Acupuncture, DIT, and PTNS were found to produce statistically and clinically significant reductions in the NIH-CPSI voiding domain. A statistically significant placebo effect was found for all outcomes and time analysis showed that efficacy of all treatments increased over time. Alpha-blockers, antibiotics, and combinations of the two failed to show statistically or clinically significant NIH-CPSI reductions. CONCLUSION: Results from this meta-analysis reflect our current inability to effectively manage CP/CPPS. Clinicians and researchers must consider placebo effect and treatment efficacy over time and design studies creatively so we can more fully elucidate the etiology and role of therapeutic intervention in CP/CPPS.