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

Purpose: Treatment options for recurrent esophageal cancer (EC) previously treated with radiation therapy (RT) are limited. Reirradiation (reRT) with proton beam therapy (PBT) can offer lower toxicities by limiting doses to surrounding tissues. In this study, we present the first multi-institutional series reporting on toxicities and outcomes after reRT for locoregionally recurrent EC with PBT. Methods and Materials: Analysis of the prospective, multicenter, Proton Collaborative Group registry of patients with recurrent EC who had previously received photon-based RT and underwent PBT reRT was performed. Patient/tumor characteristics, treatment details, outcomes, and toxicities were collected. Local control (LC), distant metastasis-free survival (DMFS), and overall survival (OS) were estimated using the Kaplan-Meier method. Event time was determined from reRT start. Results: Between 2012 and 2020, 31 patients received reRT via uniform scanning/passive scattering (61.3%) or pencil beam scanning (38.7%) PBT at 7 institutions. Median prior RT, PBT reRT, and cumulative doses were 50.4 Gy (range, 37.5-110.4), 48.6 Gy (relative biological effectiveness) (25.2-72.1), and 99.9 Gy (79.1-182.5), respectively. Of these patients, 12.9% had 2 prior RT courses, and 67.7% received PBT with concurrent chemotherapy. Median follow-up was 7.2 months (0.9-64.7). Post-PBT, there were 16.7% locoregional only, 11.1% distant only, and 16.7% locoregional and distant recurrences. Six-month LC, DMFS, and OS were 80.5%, 83.4%, and 69.1%, respectively. One-year LC, DMFS, and OS were 67.1%, 83.4%, and 27%, respectively. Acute grade ≥3 toxicities occurred in 23% of patients, with 1 acute grade 5 toxicity secondary to esophageal hemorrhage, unclear if related to reRT or disease progression. No grade ≥3 late toxicities were reported. Conclusions: In the largest report to date of PBT for reRT in patients with recurrent EC, we observed acceptable acute toxicities and encouraging rates of disease control. However, these findings are limited by the poor prognoses of these patients, who are at high risk of mortality. Further research is needed to better assess the long-term benefits and toxicities of PBT in this specific patient population.

Proton Therapy With Concurrent Chemotherapy for Thoracic Esophageal Cancer: Toxicity, Disease Control, and Survival Outcomes.

Purpose: When treating esophageal cancer with radiation therapy, it is critical to limit the dose to surrounding structures, such as the lung and/or heart, as much as possible. Proton radiation therapy allows a reduced radiation dose to both the heart and lungs, potentially reducing the risk of cardiopulmonary toxicity. Here, we report disease control, survival, and toxicity outcomes among patients with esophageal cancer treated with proton radiation therapy and concurrent chemotherapy (chemoradiation therapy; CRT) with or without surgery. Materials and Methods: We enrolled 17 patients with thoracic esophageal carcinoma on a prospective registry between 2010 and 2021. Patients received proton therapy to a median dose of 50.4-GyRBE (range, 50.4-64.8) in 1.8-Gy fractions.Acute and late toxicities were graded per the Common Terminology Criteria for Adverse Events, version 4.0 (US National Cancer Institute, Bethesda, Maryland). In addition, disease control, patterns of failure, and survival outcomes were collected. Results: Nine patients received preoperative CRT, and 8 received definitive CRT. Overall, 88% of patients had adenocarcinoma, and 12% had squamous cell carcinoma. With a median follow-up of 2.1 years (range, 0.5-9.4), the 3-year local progression-free, disease-free, and overall survival rates were 85%, 66%, and 55%, respectively. Two patients (1 with adenocarcinoma and 1 with squamous cell carcinoma) recurred at the primary site after refusing surgery after a complete clinical response to CRT. The most common acute nonhematologic and hematologic toxicities, respectively, were grades 1 to 3 esophagitis and grades 1 to 4 leukopenia, both affecting 82% of patients. No acute cardiopulmonary toxicities were observed in the absence of surgical resection. Reagarding surgical complications, 3 postoperative cardiopulmonary complications occurred as follows: 1 grade 1 pleural effusion, 1 grade 3 pleural effusion, and 1 grade 2 anastomotic leak. Two severe late CRT toxicities occurred: 1 grade 5 tracheoesophageal fistula and 1 grade 3 esophageal stenosis requiring a feeding tube. Conclusion: Proton radiation therapy is a safe, effective treatment for esophageal cancer with increasing evidence supporting its role in reducing cardiopulmonary toxicity.

Patterns-of-care disparities among uninsured versus insured patients with anorectal carcinoma referred for radiotherapy at an Urban Safety-Net Hospital.

Background: To compare patterns-of-care and clinical outcomes among uninsured versus insured patients (IPs) with anorectal malignancies referred for radiotherapy at an urban safety-net hospital. This topic is important because uninsured patients (UPs) in the US often have limited access to health care, which can result in worse health outcomes. Methods: We reviewed the medical records of 59 patients with biopsy-proven, non-metastatic anal and rectal cancers who received curative-intent primary or neoadjuvant/adjuvant radiotherapy between May 2002 and August 2012. Data regarding patient and disease characteristics, weight loss, insurance status at symptom onset, date of first therapeutic intervention, and survival status at last follow-up, were collected and analyzed. Results: The percentage of IPs presenting with T4 tumors was 7% versus 40% among the uninsured (P=0.005). The median interval between first symptom onset and diagnosis date was 89 (range, 0-1,428) days for IPs and 221 (range, 0-1,576) days for UPs (P=0.01). The median interval between first symptom onset and treatment initiation was 172 (range, 9-1,498) days for IPs and 302 (range, 35-1,624 days) days for UPs (P=0.01). The 5-year overall survival rate was 59% for the entire cohort, 62% for the insured patients, and 55% for the uninsured patients (P=0.76). Conclusions: Differences in health insurance status demonstrated various disparities in patterns-of-care, including significant delay in diagnosis, more advanced-stage disease at presentation, and treatment initiation delays among UPs. Nevertheless, overall survival at 5 years was not statistically significant between the insured and the uninsured.

Dose-escalated proton therapy with elective nodal irradiation and concomitant chemotherapy for unresectable, borderline resectable, or medically inoperable pancreatic cancer: a phase II trial.

Background: To report outcomes of a phase II single-institution trial of dose-escalated proton radiotherapy with elective nodal irradiation (ENI) and concomitant chemotherapy for patients with unresectable, borderline resectable, or medically inoperable pancreatic adenocarcinoma. Methods: Patients received 40.5 GyRBE in 18 fractions to the gross disease and elective nodal volumes followed by 22.5 GyRBE as a 10-fraction boost to the gross disease for a cumulative dose of 63 GyRBE over 28 fractions. Oral capecitabine (1,000 mg taken orally twice daily) was given on radiation treatment days. The primary objective of this study was to improve the proportion surviving to at least 1 year from the historical rate of 50% to 75%. Secondary objectives included assessing gastrointestinal (GI) toxicity and weight loss during treatment, and evaluating the safety of subsequent surgical resection. This single-institution study was closed to accrual early after the opening of the multicenter PAN009-18 trial by the Proton Collaborative Group (PCG), which follows a similar protocol. Results: At enrollment, 10 (67%) patients had unresectable disease, 3 (20%) had borderline-resectable disease, and 2 (13%) refused surgery. All 15 patients successfully completed radiation therapy as prescribed. With regard to toxicity, a single patient experienced grade 3 nausea requiring cessation of capecitabine, which ultimately resolved by treatment completion. The median percentage weight loss during treatment was -3.0% (range, -9.6% to +12.0%). Two (13%) initially borderline patients ultimately underwent R0 resection: their total operating room times were 267 and 410 minutes, and blood loss was 700 and 400 mL, respectively. Neither patient experienced intraoperative or postoperative complications. Both were discharged on postoperative day 6. The median follow-up was 0.93 years (range, 0.21 to 2.14 years). The 1-year overall survival (OS) rate was 47%. Three enrolled patients are currently alive: 2 with no evidence of disease and 1 with stable disease. Conclusions: The primary objective of 1-year OS of 75% was not reached. Proton therapy was well-tolerated. Patients undergoing surgery did not experience operative or perioperative complications, suggesting that patients with borderline resectable or even resectable disease may benefit from neoadjuvant proton therapy. The PCG will test this premise as patients accrue to the multicenter PAN009-18 trial. Trial Registration: NCT02598349.

Chemoradiation with Hypofractionated Proton Therapy in Stage II-III Non-Small Cell Lung Cancer: A Proton Collaborative Group Phase 2 Trial.

PURPOSE: Hypofractionated radiation therapy has been safely implemented in the treatment of early-stage non-small cell lung cancer (NSCLC) but not locally advanced NSCLC owing to prohibitive toxicities with photon therapy. Proton therapy, however, may allow for safe delivery of hypofractionated radiation therapy. We sought to determine whether hypofractionated proton therapy with concurrent chemotherapy improves overall survival. METHODS AND MATERIALS: The Proton Collaborative Group conducted a phase 1/2 single-arm nonrandomized prospective multicenter trial from 2013 through 2018. We received consent from 32 patients, of whom 28 were eligible for on-study treatment. Patients had stage II or III unresectable NSCLC (based on the 7th edition of the American Joint Committee on Cancer's staging manual) and received hypofractionated proton therapy at 2.5 to 4 Gy per fraction to a total 60 Gy with concurrent platin-based doublet chemotherapy. The primary outcome was 1-year overall survival comparable to the 62% reported for the Radiation Therapy Oncology Group (RTOG) 9410 trial. RESULTS: The trial closed early owing to slow accrual, in part, from a competing trial, RTOG 1308. Median patient age was 70 years (range, 50-86 years). Patients were predominantly male (n = 20), White (n = 23), and prior smokers (n = 27). Most had stage III NSCLC (n = 22), 50% of whom had adenocarcinoma. After a median follow-up of 31 months, the 1- and 3-year overall survival rates were 89% and 49%, respectively, and progression-free survival rates were 58% and 32%, respectively. No acute grade ≥3 esophagitis occurred. Only 14% developed a grade ≥3 radiation-related pulmonary toxic effect. CONCLUSIONS: Hypofractionated proton therapy delivered at 2.5 to 3.53 Gy per fraction to a total 60 Gy with concurrent chemotherapy provides promising survival, and additional examination through larger studies may be warranted.

Insurance Approval for Definitive Proton Therapy for Prostate Cancer.

PURPOSE: To determine factors that influence insurance approval for definitive proton therapy (PT) for prostate cancer. MATERIALS AND METHODS: Between 2014 and 2018, 1592 insured patients with localized prostate cancer were evaluated and recommended to undergo definitive PT; 547 patients (34.4%) had commercial insurance, whereas 1045 patients (65.6%) had Medicare/Medicaid. Of those with Medicare, 164 patients (15.7%) had Medicare alone; 677 (64.8%) had supplemental plans; and 204 (19.5%) had secondary commercial insurance. Insurance that "covered" PT for prostate cancer implied that it was an indication designated in the coverage policy. "Not covered" means that the insurance policy did not list prostate cancer as an indication for PT. Of all 1592 patients, 1263 (79.3%) belonged to plans that covered PT per policy. However, approval for PT was still required via medical review for 619 patients (38.9%), comparative dosimetry for 56 patients (3.5%), peer-to-peer discussion for 234 patients (14.7%), and administrative law judge hearings for 3 patients (<0.1%). Multivariate analyses of factors affecting approval were conducted, including risk group (low/intermediate versus high), insurance type (commercial versus Medicare/Medicaid), whether PT was included as a covered benefit under the plan (covered versus not covered), and time period (2014-16 versus 2017 versus 2018). RESULTS: On multivariate analysis, factors affecting PT approval for prostate treatment included coverage of PT per policy (97.1% had approval with insurance that covered PT versus 48.6% whose insurance did not cover PT; P < .001); insurance type (32.5% had approval with commercial insurance versus 97.4% with Medicare; P < .001); and time, with 877/987 patients (88.9%) approved between 2014 and 2016, 255/312 patients (81.7%) approved during 2017, and 255/293 patients (87.0%) approved thereafter (P = .02). Clinical factors, including risk group, had no bearing on insurance approval (P = .44). CONCLUSION: Proton insurance approval for prostate cancer has decreased, is most influenced by the type of insurance a patient belongs to, and is unrelated to clinical factors (risk group) in this study. More work is needed to help navigate appropriate access to care and to assist patients seeking definitive PT for prostate cancer treatment.

Hypofractionated Proton Therapy with Concurrent Chemotherapy for Locally Advanced Non-Small Cell Lung Cancer: A Phase 1 Trial from the University of Florida and Proton Collaborative Group.

PURPOSE: We report the safety data from the first multicenter phase 1 trial investigating the use of hypofractionated proton therapy with concurrent chemotherapy for patients with stage II or III non-small cell lung cancer. METHODS AND MATERIALS: From 2013 through 2018, patients with newly diagnosed stage II or III non-small cell lung cancer were enrolled in a multicenter phase 1 clinical trial evaluating concurrent chemotherapy with increasing dose-per-fraction proton therapy. This was a stepwise 5 + 2 dose-intensification protocol with the following dose arms: (1) 2.5 GyRBE per fraction to 60 GyRBE; (2) 3.0 GyRBE per fraction to 60 GyRBE; (3) 3.53 GyRBE per fraction to 60.01 GyRBE; and (4) 4.0 GyRBE per fraction to 60 GyRBE. A dose arm was considered tolerable if no radiation therapy-attributable severe adverse event (SAE) occurred within 90 days of treatment among 5 patients enrolled on the arm or if 1 SAE occurred among 7 patients enrolled. Dose constraints to the heart, brachial plexus, and spinal cord were more conservative at higher doses per fraction. RESULTS: The study closed early because of slow accrual and competing enrollment in NRG 1308 before accrual was met, with no maximum tolerated dose identified. Eighteen patients were treated, including 5 patients on arms 1 and 2, 7 patients on arm 3, and 1 patient on arm 4. Two SAEs occurred among 7 patients treated at 3.53 GyRBE per fraction; however, per outside expert review, both were attributed to chemotherapy and unrelated to radiation therapy. CONCLUSIONS: Hypofractionated proton therapy delivered at 2.5 to 3.53 GyRBE per fraction to a dose of 60 GyRBE with concurrent chemotherapy has an acceptable toxicity profile. Further exploration of this regimen is warranted on a phase 2 clinical trial.

Proton beam radiotherapy for pancreas cancer.

Pancreatic carcinoma is a challenging malignancy to manage with a very poor prognosis. Despite continued difficulties in its management, there have been incremental improvements in outcomes over the past several decades. Achieving the best oncologic outcomes requires a multimodality approach including surgery, chemotherapy, and radiotherapy. Proton radiotherapy enables the delivery of high-dose radiotherapy to the tumor or resection bed while sparing nearby critical organs. Due to their unique physical properties, protons can deliver radiotherapy dose distributions that are not achievable with photons (X-rays) even with advanced photon delivery techniques (e.g., intensity-modulated radiotherapy). Improved dose distributions can lead to reduced treatment toxicity and enable treatment intensification. As better chemotherapy regimens lead to better systemic disease control, it will become increasingly important that local-regional control is achieved. This will in part be accomplished by combining better radiotherapy with more active chemotherapies. Proton radiotherapy provides an excellent means for achieving this.

Impact of unfavorable factors on outcomes among inoperable stage II-IV Nonsmall cell lung cancer patients treated with proton therapy.

PURPOSE: To investigate the impact of unfavorable risk factors among patients with locally advanced nonsmall cell lung cancer (LA-NSCLC) treated with proton therapy (PT). MATERIAL AND METHODS: From May 2008 through July 2015, 90 consecutive patients with unresectable stage II-IV (oligometastatic) NSCLC were treated with PT. Unfavorable factors including age ≥80 years, stage IV, weight loss >10% in 3 months, performance status (PS) ≥2, FEV1 < 1.0 or O2 dependency, prior lung cancer, prior lung surgery, prior 2nd cancer in the past 3 years, and prior chest irradiation were evaluated. All patients received standard fractionation of 1.8-2 Gy(RBE) (median dose, 70 Gy[RBE]). Overall survival (OS) and progression-free survival (PFS) were calculated with the Kaplan-Meier method. The impact of unfavorable factors was analyzed in Cox regression models. RESULTS: Twenty-six percent were favorable-risk, while 42%, 22%, and 10% had 1-, 2-, or ≥3 unfavorable factors. The 2-year OS was 52% and 45% (p = .8522), and 2-year PFS was 21% and 44% (p = .0207), for favorable and unfavorable risk patients, respectively. Among patients with stage III-IV, only PS ≥2 adversely impacted OS (p = .0015). CONCLUSION: Most patients treated with PT for LA-NSCLC have unfavorable risk factors. These patients had similar outcomes to favorable-risk patients. Enrollment in future clinical trials may improve if eligibility is less restrictive.

Pencil beam scanning versus passively scattered proton therapy for unresectable pancreatic cancer.

BACKGROUND: With an increasing number of proton centers capable of delivering pencil beam scanning (PBS), understanding the dosimetric differences in PBS compared to passively scattered proton therapy (PSPT) for pancreatic cancer is of interest. METHODS: Optimized PBS plans were retrospectively generated for 11 patients with locally advanced pancreatic cancer previously treated with PSPT to 59.4 Gy on a prospective trial. The primary tumor was targeted without elective nodal coverage. The same treatment couch, target coverage and normal tissue dose objectives were used for all plans. A Wilcoxon t-test was performed to compare various dosimetric points between the two plans for each patient. RESULTS: All target volume coverage goals were met in all PBS and passive scattering (PS) plans, except for the planning target volume (PTV) coverage goal (V100% >95%) which was not met in one PS plan (range, 81.8-98.9%). PBS was associated with a lower median relative dose (102.4% vs. 103.8%) to 10% of the PTV (P=0.001). PBS plans had a lower median duodenal V59.4 Gy (37.4% vs. 40.4%; P=0.014), lower small bowel median V59.4 Gy (0.11% vs. 0.37%; P=0.012), lower stomach median V59.4 Gy (0.01% vs. 0.1%; P=0.023), and lower median dose to 0.1 cc of the spinal cord {35.0 vs. 38.7 Gy [relative biological effectiveness (RBE)]; P=0.001}. Liver dose was higher in PBS plans for median V5 Gy (24.1% vs. 20.2%; P=0.032), V20 Gy (3.2% vs. 2.8%; P=0.010), and V25 Gy (2.6% vs. 2.2%; P=0.019). There was no difference in kidney dose between PBS and PS plans. CONCLUSIONS: Proton therapy for locally advanced pancreatic cancer using PBS was not clearly associated with clinically meaningful reductions in normal tissue dose compared to PS. Some statistically significant improvements in PTV coverage were achieved using PBS. PBS may offer improved conformality for the treatment of irregular targets, and further evaluation of PBS and PS incorporating elective nodal irradiation should be considered.

Long-term outcomes following proton therapy for prostate cancer in young men with a focus on sexual health.

BACKGROUND: We investigated long-term outcomes for men ≤60 years old treated with proton therapy (PT). METHODS: Of 254 men ≤60 years old were treated with proton therapy alone for prostate cancer. Risk stratification included 56% with low-, 42% with intermediate- and 2% with high-risk disease. Patients received 76-82 Gy at 2 Gy/fraction or 70-72.5 Gy at 2.5 Gy/fraction. Before treatment and every 6-12 months for 5 years, patients were evaluated by a physician, answered health-related quality of life surveys, including the EPIC, IIEF and IPSS, and had PSA evaluated. RESULTS: Median follow-up for the cohort was 7.1 years; 7-year biochemical-free survival was 97.8%. Eight men (one high-risk; five intermediate-risk and two low-risk) experienced biochemical progression, including one who died of disease 9 years after treatment. Potency (erections firm enough for sexual intercourse) was 90% at baseline and declined to 72% at the first-year follow-up, but declined to only 67% at 5 years. Only 2% of patients developed urinary incontinence requiring pads. The bowel habits mean score declined from a baseline of 96 to 88 at 1 year, which improved over the following years to 93 at 5 years. CONCLUSIONS: Young men with prostate cancer continue to have excellent results with respect to 7-year biochemical control and 5-year erectile function, without clinically significant urinary incontinence 5 years after proton therapy. Comparative effectiveness studies of proton therapy with surgery and IMRT are needed.

Race Does Not Affect Tumor Control, Adverse Effects, or Quality of Life after Proton Therapy.

PURPOSE: To compare 5-year biochemical control, toxicity, and patient-reported quality of life (QOL) outcomes for African American and White patients treated with proton therapy (PT) for prostate cancer. MATERIALS AND METHODS: We reviewed the medical records of 1,066 men with clinically localized prostate cancer. Patients were treated with definitive PT between 2006 and 2010. Patients received a median radiation dose of 78 Gy (RBE) with conventional fractionation (1.8- 2 Gy [RBE] per fraction). Sixty-eight (6.4%) men self-identified as African American and 998 (93.6%) self-identified as White. Five-year rates of biochemical control, grade 3 genitourinary and gastrointestinal toxicity, and patient-reported QOL are reported and compared between African American and White patients. RESULTS: Median biochemical follow-up was 5.0 years for both African American and White patients. Median follow-up for toxicity was 5.0 and 5.2 years, respectively. On multivariate analysis, race was not a significant predictor for 5-year freedom from biochemical failure (HR 0.8, p=0.55). No significant association was found between race and grade 3 genitourinary toxicity on multivariate analysis at 5 years (HR 2.5, p=0.10). Patient-reported QOL using median EPIC bowel, urinary incontinence, and irritative summaries scores were not significantly different between the groups. African Americans had higher median sexual summary scores at 2 years than White patients (75 vs. 54, p=0.01) but by 5+ years, the sexual summary scores were no longer significantly different (63 vs. 53, p=0.35). CONCLUSION: With a median follow-up of 5 years, there were no racial disparities in biochemical control, grade 3 toxicity, or patient-reported QOL after PT for prostate cancer.

Sperm preservation and neutron contamination following proton therapy for prostate cancer study.

BACKGROUND: The present study investigates the impact of scatter dose radiation to the testis on ejaculate and sperm counts from treatment of prostate cancer with passive-scatter proton therapy. MATERIAL AND METHODS: From March 2010 to November 2014, 20 men with low- or intermediate-risk prostate cancer enrolled in an IRB-approved protocol and provided a semen sample prior to passive-scatter proton therapy and 6-12 months following treatment. Men were excluded if they had high-risk prostate cancer, received androgen deprivation therapy, were on alpha blockers (due to retrograde ejaculation) prior to treatment, had baseline sperm count <1 million, or were unable to produce a pre-treatment sample or could not provide a follow-up specimen. Sperm counts of 0 were considered azoospermia and <15 million/ml were classified as oligospermia. RESULTS: Four patients were unable to provide a sufficient quantity of semen for analysis. Among the 16 remaining patients, only one was found to have oligospermia (7 million/ml). There was a statistically significant reduction in semen volume (median, 0.5 ml) and increase in pH (median 0.5). Although not statistically significant, there appeared to be a decline in sperm concentration (median, 16 million/ml), total sperm count (median, 98.5 million), normal morphology (median, 9%), and rapid progressive motility (median, 9.5%). DISCUSSION: Men did not have azoospermia 6-12 months following passive-scatter proton therapy indicating minimal scatter radiation to the testis during treatment. Changes in semen quantity and consistency may occur due to prostate irradiation, which could impact future fertility and/or sexual activity.

Proton Therapy as Salvage Treatment for Local Relapse of Prostate Cancer Following Cryosurgery or High-Intensity Focused Ultrasound.

PURPOSE: Local recurrence of prostate cancer after cryosurgery (CS) and high-intensity focused ultrasound (HIFU) is an emerging problem for which optimal management is unknown. Proton therapy (PT) may offer advantages over other local therapeutic options. This article reviews a single institution's experience using PT for salvage of local recurrent disease after HIFU or CS. METHODS AND MATERIALS: We reviewed the medical records of 21 consecutive patients treated with salvage PT following a local recurrence of prostate cancer after CS (n=12) or HIFU (n=9) between January 2007 and July 2014. Patients were treated to a median dose of 74 Gy(relative biological effectiveness [RBE]; range: 74-82 Gy[RBE]) and 8 patients received androgen deprivation therapy with radiation therapy. Patients were evaluated for quality of life (QOL) by using the Expanded Prostate Index Composite questionnaire and toxicity by using Common Terminology Criteria for Adverse Events, version 3.0, weekly during treatment, every 6 months for 2 years after treatment, and then annually. RESULTS: Median follow-up was 37 months (range: 6-95 months). The 3-year biochemical progression-free survival (bPFS) rate was 77%. The 3-year grade 3 toxicity rate was 17%; however, 2 of these patients had pre-existing grade 3 GU toxicities from their HIFU/CRYO prior to PT. At 1 year, bowel summary, urinary incontinence, and urinary obstructive QOL scores declined, but only the bowel QOL score at 12 months met the minimally important difference threshold. CONCLUSIONS: PT achieved a high rate of bPFS with acceptable toxicity and minimal changes in QOL scores compared with baseline pre-PT functions. Although most patients have done fairly well, the study size is small, follow-up is short, and early results suggest that outcomes with PT for salvage after HIFU or CS failure are inferior to outcomes with PT given in the de novo setting with respect to disease control, toxicity, and QOL.

A Phase 2 Trial of Concurrent Chemotherapy and Proton Therapy for Stage III Non-Small Cell Lung Cancer: Results and Reflections Following Early Closure of a Single-Institution Study.

PURPOSE: Proton therapy has been shown to reduce radiation dose to organs at risk (OAR) and could be used to safely escalate the radiation dose. We analyzed outcomes in a group of phase 2 study patients treated with dose-escalated proton therapy with concurrent chemotherapy for stage 3 non-small cell lung cancer (NSCLC). METHODS AND MATERIALS: From 2009 through 2013, LU02, a phase 2 trial of proton therapy delivering 74 to 80 Gy at 2 Gy/fraction with concurrent chemotherapy for stage 3 NSCLC, was opened to accrual at our institution. Due to slow accrual and competing trials, the study was closed after just 14 patients (stage IIIA, 9 patients; stage IIIB, 5 patients) were accrued over 4 years. During that same time period, 55 additional stage III patients were treated with high-dose proton therapy, including 7 in multi-institutional proton clinical trials, 4 not enrolled due to physician preference, and 44 who were ineligible based on strict entry criteria. An unknown number of patients were ineligible for enrollment due to insurance coverage issues and thus were treated with photon radiation. Median follow-up of surviving patients was 52 months. RESULTS: Two-year overall survival and progression-free survival rates were 57% and 25%, respectively. Median lengths of overall survival and progression-free survival were 33 months and 14 months, respectively. There were no acute grade 3 toxicities related to proton therapy. Late grade 3 gastrointestinal toxicity and pulmonary toxicity each occurred in 1 patient. CONCLUSIONS: Dose-escalated proton therapy with concurrent chemotherapy was well tolerated with encouraging results among a small cohort of patients. Unfortunately, single-institution proton studies may be difficult to accrue and consideration for pragmatic and/or multicenter trial design should be considered when developing future proton clinical trials.

Does Race Influence Health-related Quality of Life and Toxicity Following Proton Therapy for Prostate Cancer?

OBJECTIVE: This matched-paired analysis explores disparities in health-related quality of life (QOL) and common toxicities between African American (AA) and white patients following proton therapy for prostate cancer at our institution. MATERIALS AND METHODS: A total of 1536 men with clinically localized prostate cancer were treated from 2006 to 2009 with definitive proton therapy to a median dose of 78 Gy +/- androgen deprivation therapy. A cohort of 92 consecutively treated AA men was matched to a cohort of 92 white men on the basis of National Comprehensive Cancer Network risk category and age. The 2 groups were compared with regard to comorbidities, demographics, and treatment regimen. Differences in genitourinary and gastrointestinal (GI) toxicity according to the Common Terminology Criteria for Adverse Events scale and QOL data from the Expanded Prostate Index Composite 26-question questionnaire were reported. RESULTS: Median follow-up was 2.1 years. Baseline patient and treatment characteristics were similar between the 2 groups with the exception of prostate-specific antigen ≥10 (32% for AAs vs. 20% for whites; P=0.068) and use of androgen deprivation therapy (26% for AAs vs. 21% for whites; P=0.38). No difference in Expanded Prostate Index Composite 26-question sexual summary, urinary incontinence, urinary obstruction, or bowel summary scores was detected between the 2 groups, nor was there a difference in grade 2 or higher GI toxicity (P=0.45). AAs had a statistically nonsignificant higher absolute incidence of late grade 3 genitourinary toxicity (4.4% vs. 0%; P=0.12). CONCLUSIONS: After 2 years, there were no disparities in health-related QOL, physician-reported Common Terminology Criteria for Adverse Events GI toxicity, or biochemical relapse. Longer follow-up is needed to confirm these findings.

Patient-Reported Quality of Life in Men with Transurethral Resection of the Prostate Undergoing Proton Therapy for Management of Prostate Cancer.

PURPOSE: We report on quality of life (QOL) and early toxicity among men with prostate cancer who underwent transurethral resection of the prostate (TURP) before proton therapy. MATERIALS AND METHODS: Between 2006 and 2010, 1,289 patients were treated definitively with proton therapy for prostate cancer at our institution and enrolled on a prospective outcomes-tracking protocol. Ninety-six of the men had received a TURP before proton therapy, while 1,193 men had not. Baseline comorbidities, medications, expanded prostate index composite (EPIC) score, international prostate symptom score (IPSS), and CTCAE vs.3 toxicity assessment were collected prospectively. The Kaplan-Meier product limit method was used to estimate freedom from toxicity. RESULTS: Men who had TURP before proton therapy had lower baseline EPIC scores for urinary incontinence, bowel summary, and sexual summary compared with the non-TURP group, but no significant difference in urinary obstructive score was observed. After controlling for baseline scores, there was no significant difference in bowel summary or sexual summary scores between the two groups over time. There were, however, differences for urinary irritation/obstruction scores and urinary incontinence scores favoring those patients who did not have a TURP-like procedure. Toxicity assessment showed that the 2-year and 5-year rates of grade 3 genitourinary toxicity in the pretreatment TURP group were 12.3% and 17.2%, respectively. CONCLUSIONS: Pretreatment TURP was associated with both a high incidence of physician-assessed toxicity and inferior patient-reported QOL scores both before and after proton therapy treatment. Studies investigating QOL and toxicity after specific prostate cancer therapies should stratify patients by pretreatment TURP. Longer follow-up is needed to confirm if these differences ever resolve.

Proton therapy for pancreatic cancer.

Radiotherapy is commonly offered to patients with pancreatic malignancies although its ultimate utility is compromised since the pancreas is surrounded by exquisitely radiosensitive normal tissues, such as the duodenum, stomach, jejunum, liver, and kidneys. Proton radiotherapy can be used to create dose distributions that conform to tumor targets with significant normal tissue sparing. Because of this, protons appear to represent a superior modality for radiotherapy delivery to patients with unresectable tumors and those receiving postoperative radiotherapy. A particularly exciting opportunity for protons also exists for patients with resectable and marginally resectable disease. In this paper, we review the current literature on proton therapy for pancreatic cancer and discuss scenarios wherein the improvement in the therapeutic index with protons may have the potential to change the management paradigm for this malignancy.

Rectal toxicity after proton therapy for prostate cancer: an analysis of outcomes of prospective studies conducted at the university of Florida Proton Therapy Institute.

PURPOSE: Study goals were to characterize gastrointestinal effects of proton therapy (PT) in a large cohort of patients treated for prostate cancer, identify factors associated with rectal bleeding (RB), and compare RB between patients receiving investigational protocols versus those in outcome-tracking protocols. METHODS AND MATERIALS: A total of 1285 consecutive patients were treated with PT between August 2006 and May 2010. Potential pre-existing clinical and treatment-related risk factors for rectal toxicity were recorded. Common Terminology Criteria for Adverse Events version 3.0 was used to score toxicity. RESULTS: Transient RB was the predominant grade 2 or higher (GR2+) toxicity after PT, accounting for 95% of gastrointestinal events. GR1 RB occurred in 217 patients (16.9%), GR2 RB in 187 patients (14.5%), and GR3 in 11 (0.9%) patients. There were no GR4 or GR5 events. Univariate analyses showed correlations between GR2+ RB and anticoagulation therapy (P=.008) and rectal and rectal wall dose-volume histogram (DVH) parameters (P<.001). On multivariate analysis, anticoagulation therapy (P=.0034), relative volume of rectum receiving 75 Gy (V75; P=.0102), and relative rectal wall V75 (P=.0017) were significant predictors for G2+ RB. Patients treated with investigational protocols had toxicity rates similar to those receiving outcome-tracking protocols. CONCLUSIONS: PT was associated with a low rate of GR2+ gastrointestinal toxicity, predominantly transient RB, which was highly correlated with anticoagulation and rectal DVH parameters. Techniques that limit rectal exposure should be used when possible.