Hypofractionated Proton Therapy Research Articles

Five- and seven-year outcomes for image-guided moderately accelerated hypofractionated proton therapy for prostate cancer

Background To report 5- and 7-year outcomes after image-guided moderately accelerated hypofractionated proton therapy (AHPT) for prostate cancer. Material and methods We reviewed the first 582 prostate cancer patients enrolled on prospective outcomes tracking trial and treated with double-scattered moderately AHPT between 2008 and 2015. 269 patients had low-risk (LR) and 313 had intermediate-risk (IR) disease, including 149 with favorable intermediate-risk (FIR) and 164 with unfavorable intermediate-risk (UIR) disease. LR patients received a median 70.0GyRBE (2.5GyRBE/fraction) and IR patients received a median of 72.5 GyRBE. Seventeen patients (UIR, n = 12) received androgen deprivation therapy (ADT) for a median of 6 months. Toxicities were graded per the CTCAE, v4.0, and patient-reported quality-of-life data were reviewed. Results Median follow-up was 8.0 years (0.9–12.2). The 5- and 7-year rates of freedom from biochemical progression (FFBP) overall and in the LR and IR subsets, respectively, were 96.8/95.2%, 98.8/98.8%, and 95.0/91.9%. For the FIR and UIR subsets, they were 97.2/95.2% and 93.1/88.8%. Actuarial 5- and 7-year rates of late CTCAE, v4.0, grade 2 gastrointestinal (GI), grade 3 GI, and grade 3 genitourinary (GU) toxicities were 9.9%/11.2%, 1.4/1.4% and 1.3/2.1%, respectively. No grade ≥4 GI or GU toxicities occurred. The mean (standard deviation, SD) IPSS and EPIC Composite bowel function and bother scores were 7 (SD = 5), 97 (SD = 7), and 94 (SD = 6), respectively at baseline, 7 (SD = 5), 92 (SD = 13), and 92 (SD = 9) at the 5-year follow-up, and 7 (SD = 5), 93 (SD = 12), and 92 (SD = 10) at the 7-year follow-up. Conclusion Image-guided AHPT 5- and 7-year outcomes show high efficacy, minimal physician-assessed toxicity, and excellent patient-reported outcomes in this cohort.

Updated Toxicity and Quality-of-Life Outcomes From a Randomized Phase III Trial of Extreme Hypofractionated vs. Standard Fractionated Proton Therapy for Low-Risk Prostate Cancer

<h3>Purpose/Objective(s)</h3> We present an interim analysis of toxicity and quality-of-life (QOL) from a randomized phase III trial of extreme hypofractionated versus standard hypofractionated proton therapy for low-risk prostate cancer. <h3>Materials/Methods</h3> From 2011-2020, low-risk prostate cancer patients were randomized in a 1:2 fashion to standard fractionation (79.2 Gy [RBE] in 44 fractions, Arm A) versus extreme hypofractionation (38 Gy [RBE] in 5 fractions, Arm B) proton therapy. Patients were excluded if they had an American Urological Association Symptom Index (AUASI) > 17. Toxicity was defined according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 and adjusted for pre-treatment toxicities. Patients completed Expanded Prostate Cancer Index Composite + (EPIC), Short Form 12 (SF) and AUASI surveys at baseline and 3, 6, 12, 18, 24 and 36 months. <h3>Results</h3> Forty-six patients were included in Arm A and 84 patients in Arm B. Median follow-up was 50 months. The majority of patients were clinical T1c (89% Arm A, 84.5% Arm B, <i>P</i> = 0.86) and a PSA > 4-10 (80.4% Arm A, 78.6% Arm B, <i>P</i> = 1.00). For both groups, median AUASI was 5 (range 0-14). Four patients (1 Arm A, 3 Arm B) had died at the time of last follow-up, none related to their prostate cancer or treatment. Between the two arms, no significant differences were noted in acute treatment-related genitourinary (GU) or gastrointestinal (GI) toxicities: acute GU grade ≥ 2 (0% Arm A, 5% Arm B), GU grade ≥ 3 (0% each arm), GI grade ≥ 2 (0% Arm A, 2% Arm B), grade ≥ 3 (0% each arm). Similarly, no significant differences were noted in late treatment-related GU or GI toxicities: late GU grade ≥ 2 (26% Arm A, 33% Arm B), GU grade ≥ 3 (2% Arm A, 1% Arm B), GI grade ≥ 2 (13% Arm A, 19% Arm B), GI grade ≥ 3 (0% each arm). When analyzing QOL by arm and timepoints, only EPIC Overall scores at 36 months were clinically significantly different (> MID) between the two arms with Arm B having improved scores (+29.62 points, <i>P</i> = 0.02). Other QOL domains (EPIC Urinary, EPIC Bowel, AUASI) were not clinically significantly different between the two arms across timepoints. <h3>Conclusion</h3> In a phase III randomized controlled trial comparing extreme hypofractionation to standard fractionation for the treatment of prostate cancer, no significant differences for treatment-related acute or late, grade ≥ 2 or ≥ 3, toxicity were found for GU or GI toxicities. Additionally, improved EPIC Overall scores at 36 months were found in patients treated with extreme hypofractionation. This trial was registered with Western IRB 20101536, and NCT01230866.

Acute toxicity and patient-reported symptom score after conventional versus moderately hypofractionated proton therapy for prostate cancer.

IntroductionTo confirm the feasibility of hypofractionated proton beam therapy (PBT), we compared the acute adverse event rates and International Prostate Symptom Score (IPSS) in prostate cancer patients treated with hypofractionated versus conventionally fractionated (2.0 Gy relative biological effectiveness (RBE)/fraction) PBT.MethodsWe reviewed 289 patients with prostate cancer, of whom 73, 100, and 116 patients were treated with 2.0, 2.5, and 3.0 Gy (RBE)/fraction, respectively. The endpoints were acute genitourinary and gastrointestinal toxicities and the IPSS, evaluated up to 6 months after PBT initiation.ResultsNo significant differences were found in acute toxicity rates or the IPSS among the fractionation schedules. Diabetes mellitus, age, and androgen deprivation therapy were not identified as factors associated with the IPSS.ConclusionThere were no significant differences in adverse events or quality of life among the three fractionation schedules early after PBT.

Reirradiation with Hypofractionated Proton Therapy for Recurrent Lung Cancer

Proton therapy has been explored in treating locoregionally recurrent lung cancer to decrease toxicity in previously irradiated tissue given the sharp dose gradient achievable with charged particle therapy. However, experience with proton reirradiation (reRT) is limited, dose fractionation is variable, and fatal radiation-related toxicity has been reported. Here we report our single institution experience with efficacy and safety of patients treated with a moderately hypofractionated proton regimen for lung cancer reRT. Thirty-one patients received hypofractionated proton therapy for recurrent lung cancer from 10/2012 to 06/2019. Prior courses of thoracic radiation were delivered using conventionally fractionated radiation therapy (median 60 Gy/30 fx, BED10 = 72 Gy) in 56% patients and hypofractionated/stereotactic body radiotherapy (median BED10 = 100 Gy) in 28% patients. One patient received two prior courses of thoracic radiation. Median time from prior radiation to proton reRT was 19.4 months. Proton reRT was prescribed to 60 Gy (RBE) in 15 fractions in the majority (73%) of cases with a range of 2.5-4 Gy (RBE) per fraction (BED10 = 53.1-84 Gy). Twenty-five patients (80.1%) received proton reRT with direct dose overlap with initial thoracic radiation. Median tumor volume treated was 36.7 cm3 (range 2.76-270.6 cm3). Median PTV V95% coverage was 96% (range 63-100%). At median follow-up of 6.3 months (range 1.4-49 months), 7 patients (22.6%) developed local recurrence, 4 (12.9%) experienced regional recurrences and 3 (9.7%) developed distant metastasis. Median lung V20 Gy and V5 Gy were 6.6% (0.7-42.9%) and 12.3% (1.2-79.6%), respectively. Median mean heart dose was 0.07 Gy (0.0-57.1 Gy). Median esophageal V40 Gy and Dmax were 0.0% (0.0-31.0%) and 13.0 Gy (0.0-64.0 Gy), respectively. There was 1 episode of grade 3 pneumonitis within 1 month of completion of reirradiation and no grade 3-5 late toxicity. There were no treatment-related deaths; 19 patients died from other causes during follow-up period. Reirradiation with moderately hypofractionated proton therapy for locoregionally recurrent lung cancer is well tolerated with low rates of toxicity in this cohort of patients, the majority of whom had dose overlap with prior thoracic radiation. Disease control rates are comparable to previously published data. These promising results warrant prospective studies to establish the role of moderately hypofractionated proton reRT for treating recurrent lung cancer.

Image-Guided Hypofractionated Proton Therapy in the Management of Centrally Located Early-Stage Non-Small Cell Lung Cancer

Image-Guided Hypofractionated Proton Therapy in the Management of Centrally Located Early-Stage Non-Small Cell Lung Cancer

Five-year Outcomes for Moderately Accelerated Hypofractionated Proton Therapy for Prostate Cancer

To report 5-year outcomes of a prospective trial of image-guided moderately accelerated hypofractionated proton therapy (AHPT) for prostate cancer. This is a retrospective review of the outcomes of the first 586 consecutive prostate cancer patients who were enrolled on an IRB-approved outcome tracking trial between 2008 and 2015, and treated with double-scattered moderately AHPT. There were 275 low-risk (LR) and 311 intermediate-risk (IR) patients, including 161 favorable intermediate-risk (FIR) and 150 unfavorable-risk (UIR) patients. LR patients were treated with 2.5 GyRBE per fraction to a median of 70.0 GyRBE (range, 64.4 to 72.5 GyRBE) and IR patients to a median of 72.5 GyRBE (range 67.5 to 72.5 GyRBE). Nineteen patients (13 with UIR disease) received androgen deprivation therapy (ADT) for a median of 6 months (range, 2 to 15 months). No patient had SpaceOAR placement. Toxicities were graded prospectively according to Common Terminology Criteria for Adverse Events (CTCAE), version 3.0, and prospectively or retrospectively for versions 4.0 and 5.0. Patient-reported quality of life data were reviewed. Median follow-up was 6.6 years (range, 0.6 to 11.4). The 5-year rates of freedom from biochemical and clinical disease progression (FFBCP) were 96.9%, 98.4%, and 95.6% in the overall group, and LR and IR subsets, respectively. The five-year rates of FFBCP were 98.7% and 92.0% for the FIR and UIR subsets. ADT was not associated with improvement in FFBCP for patients with UIR disease on univariate analysis (p = 0.2827). Actuarial 5-year rates of late radiation-related CTCAE versions 3.0, 4.0, and 5.0 grade 2 gastrointestinal (GI) toxicities, with medical intervention defined as inclusive of any prescription medication, were 9.4%, 10.1% and 10.1%. The corresponding grade 3 GI toxicities were 1.0%, 1.0%, and 1.0%, and grade 3 genitourinary (GU) toxicities were 1.4%, 0.9% and 0.9% respectively. Grade 3 GI toxicity was significantly related to Absolute Rectal Volume receiving 70 GyRBE (Rec V70) (p = 0.0218). The optimal cut point for Rec V70 was 6.9 cc with a 5-year risk of grade 3 GI toxicity with <6.9cc of 0% (95% CI: n/a) and with >6.9 of 3.1% (95% CI: 1.4%-6.7%). There were no grade 4 or higher GI or GU toxicities. The mean and standard deviation of the International Prostate Symptom Score, and Expanded Prostate Cancer Index Composite bowel function and bother were 6 (SD = 5), 97 (SD = 7), and 94 (SD = 6), respectively at baseline, and 6 (SD = 6), 92 (SD = 13) and 92 (SD = 9) at the 5-year follow-up. Image-guided moderately AHPT 5-year outcomes show high efficacy, minimal physician-assessed toxicity, and excellent patient-reported outcomes in this cohort of patients. These results are comparable to the 5-year results of our prospective trials of conventionally fractionated proton therapy for patients with LR and IR prostate cancer.

Good long-term visual outcomes of parapapillary choroidal melanoma patients treated with proton therapy: a comparative study

PurposeTo evaluate why small- and certain medium-sized parapapillary choroidal melanoma (pcM) patients treated with hypo-fractionated proton therapy (PT) retain excellent long-term visual acuity (VA) and assess the negative predictive factors for retaining good vision (≤ 0.2 logMAR (≥ 0.6 decimal) after 5 years.MethodsThis single-center, retrospective, comparative study recruited consecutive pcM patients that were treated with PT. Between 1984 and 2005, 609 patients received a total of 60 CGE, of whom 310 met the following inclusion criteria: posterior tumor border ≤ 2.5 mm from the optic disc, largest tumor diameter ≤ 17.9 mm, tumor thickness ≤ 5.2 mm and available follow-up data for at least 5 years.ResultsMean follow-up was 120.8 ± 48.8 months (54.0–295.0). Out of 310 patients, 64 (21%) maintained a VA ≤ 0.2 logMAR (≥ 0.6 decimal) for at least 5 years following PT and were allocated to the “good visual outcome” (GVO) group, while the remaining 246 (79%) constituted the “poor visual outcome” (PVO) group, subdivided into 70 (22%) with a VA of 0.3–1.0 logMAR (0.1–0.5 decimal) and 157 (57%) patients with a VA > 1.0 logMAR (< 0.1 decimal). On multivariate analysis, older age (P = 0.04), tumor localization ≤ 0.5 mm to the fovea (P < 0.03), volume of the optic disc and macula receiving 50% of dose (30 CGE) (P = 0.02 and P < 0.001, respectively) were independent negative predictors of GVO.ConclusionsOf 310 small- to medium-sized pcM patients successfully treated with PT, 21% retained a VA ≤ 0.2 logMAR (≥ 0.6 decimal) for at least 5 years. Strongest negative predictive factor for retaining good long-term vision was the volume of the macula irradiated with at least 30 Gy.

Image-Guided Hypofractionated Proton Therapy in Early-Stage Non-Small Cell Lung Cancer: A Phase 2 Study.

PurposeDue to the excellent outcomes with image-guided stereotactic body radiotherapy for patients with early-stage non–small cell lung cancer (NSCLC) and the low treatment-related toxicities using proton therapy (PT), we investigated treatment outcomes and toxicities when delivering hypofractionated PT.Materials and MethodsBetween 2009 and 2018, 22 patients with T1 to T2 N0M0 NSCLC (45% T1, 55% T2) received image-guided hypofractionated PT. The median age at diagnosis was 72 years (range, 58-90). Patients underwent 4-dimensional computed tomography simulation following fiducial marker placement, and daily image guidance was performed. Nine patients (41%) were treated with 48 GyRBE in 4 fractions for peripheral lesions, and 13 patients (59%) were treated with 60 GyRBE in 10 fractions for central lesions. Patients were assessed for CTCAEv4 toxicities with computed tomography imaging for tumor assessment. The primary endpoint was grade 3 to 5 toxicity at 1 year.ResultsThe median follow-up for all patients was 3.5 years (range, 0.2-8.8 years). The overall survival rates at 3 and 5 years were 81% and 49%, respectively. Cause-specific survival rates at 3 and 5 years were 100% and 75%, respectively. The 3-year local, regional, and distant control rates were 86%, 85%, and 95%, respectively. Four patients experienced in-field recurrences between 18 and 45 months after treatment. One patient (5%) developed a late grade 3 bronchial stricture requiring hospitalization and stent.ConclusionImage-guided hypofractionated PT for early-stage NSCLC provides promising local control and long-term survival with a low likelihood of toxicity. Regional nodal and distant relapses remain a problem.

Image-guided hypofractionated double-scattering proton therapy in the management of centrally-located early-stage non-small cell lung cancer

Background The treatment of centrally-located early-stage non-small cell lung cancer (NSCLC) with image-guided stereotactic body radiotherapy (SBRT) is challenging due to the proximity of critical normal structures to the tumor target. The purpose of this study was to report the results of our experience in treating centrally-located early-stage NSCLC with hypofractionated proton therapy (PT). Material and methods Between 2009 and 2018, 23 patients with T1–T2N0M0 NSCLC (T1, 46%; T2, 54%) were treated with image-guided hypofractionated double-scattering PT. The median age at the time of treatment was 74 years (range, 58–88). Patients underwent 4-dimensional computed tomography (CT) simulation following fiducial marker placement, and daily image guidance was performed. All patients were treated with 60 GyRBE in 10 fractions. Patients were assessed for CTCAEv4 toxicities weekly during treatment, and at regular follow-up intervals with CT imaging for tumor assessment. Overall survival, cause-specific survival, local control, regional control, and metastases-free survival were evaluated using cumulative incidence with competing risks. Results Median follow-up for all patients was 3.2 years (range, 0.2–9.2 years). Overall survival rates at 3 and 5 years were 81% and 50% (95% CI, 27–79%), respectively. Cause-specific survival rates at 3 and 5 years were 81% and 71% (95% CI, 46–92%). The 3-year local, regional, and distant control rates were 90%, 81%, and 87%, respectively. Three patients (13%) experienced local recurrences as their first recurrence, at a median time of 28 months from completion of radiation (range, 18–61 months). Two patients (9%) experienced late grade 3 toxicities, including 1 patient who developed a bronchial stricture that required stent placement. Conclusion Image-guided hypofractionated PT for centrally-located early-stage NSCLC provides excellent local control with low rates of grade ≥3 toxicities. For tumors in sensitive locations, PT may provide safer treatment than photon-based treatments due to its dosimetric advantages.

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

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. 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. 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. 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.

Intensity-modulated proton therapy using dose-painting pencil beam scanning for high-risk hepatocellular carcinoma.

558 Background: High rates of local control are achievable with hypofractionated proton therapy with passive techniques for hepatocellular carcinoma (HCC), but may have limitations when tumors are adjacent to organs-at-risk (OARs), which may result in tumor underdosage and lead to inferior local control. We present the first reported series of HCC patients treated with pencil beam scanning (PBS) intensity-modulated proton therapy (IMPT) using a simultaneous-integrated boost and protection (SIB/SIP) technique to escalate tumor dose while protecting adjacent OARs. Methods: Twenty-five HCC patients were treated between 2015-2019 with a 15-fraction regimen using IMPT SIB/SIP. SIB/SIP dose levels generally ranged from 36.0-67.5 GyRBE to minimize dose to OARs at their respective dose-limiting thresholds (e.g. luminal gastrointestinal organs, chest wall). Radiation-induced liver disease (RILD) was defined by a Child-Pugh (CP) score increase of 2 or greater and/or any RTOG grade 3 enzyme elevation. Other toxicities were graded by CTCAEv5.0. Overall survival (OS), progression-free survival (PFS), and local control were calculated using the Kaplan-Meier method. Results: Patients most commonly had BCLC stage B or C disease (84%) and CP-A (80%) and ALBI grade 2 (60%) liver function. Median gross tumor volume (GTV) size and volume were 12.3 cm (range 2.17-20.57) and 461 cc (range 4.68-2439), and 32% had gross vascular invasion. Median mean and minimum dose delivered to the gross tumor volume (GTV) was 64.0 GyRBE (EQD2 76.1, BED 91.3, range 54.3-69.6) and 45.1 GyRBE (EQD2 48.9, BED 58.7, range 33.4-67.7), respectively. Median mean dose to liver minus GTV was 15.0 GyRBE (range, 8.2-19.6). 1-year OS, PFS, and local control were 66%, 32%, and 84%, respectively. No isolated local failures occurred. Two patients experienced RILD with no RILD-related deaths. Two grade 3 non-GI toxicities occurred: 1 rib fracture and 1 pneumonitis. No acute or late GI grade ≥2 occurred. Conclusions: In our series of HCC patients with large tumors near OARs, IMPT SIB/SIP allows for tumor dose escalation while sparing of OARs and results in favorable local control and acceptable toxicities.

Proceedings to the 6th Annual Conference of the Particle Therapy Cooperative Group North America (PTCOG-NA): 14-16 October 2019, Hosted by Miami Cancer Institute, part of Baptist Health South Florida, Miami, FL, USA.

Proceedings to the 6th Annual Conference of the Particle Therapy Cooperative Group North America (PTCOG-NA): 14-16 October 2019, Hosted by Miami Cancer Institute, part of Baptist Health South Florida, Miami, FL, USA.

A Phase II trial of Hypofractionated Proton Therapy in Prostate Cancer: 3-year Physician and Patient Reported Outcomes

To investigate the role of hypofractionated proton beam therapy (HFPBT) in men with localized prostate cancer. Men with localized prostate carcinoma were treated with HFPBT on this prospective phase II trial. All patients were treated with a total dose of 55.5Gy for 15 fractions with 3.7Gy per fractions. Patients completed Expanded Prostate Cancer Index Composite (EPIC) questionnaire at baseline and every 6-12 months after HFPBT. Using modified Radiation Therapy Oncology Group scoring, acute and chronic gastrointestinal (GI) and genitourinary (GU) toxicities were determined and scored. The cumulative incidence (CI) rates were estimated using the method of Kaplan and Meier. EPIC scores were compared between baseline and a specific time point using the paired t tests. A clinically significant change from baseline for an EPIC domain score is defined as ½ the baseline standard deviation for that domain. In total 210 patients were enrolled on this Phase II trial from Oct, 2013 to Jan, 2019 out of which 181 patients were included in the analysis. 29 patients were excluded due to: patients withdrew consents (n=19), patients have not started treatment yet (n=10). Mean age was 66 years. Median follow-up was 2.6 years with max of 5 years. 50.8% patients received androgen deprivation therapy with a mean of 4 months. At 3 year follow-up, there were no grade 3 or higher acute and chronic GU or GI adverse events reported. Acute grade 2 GU and GI toxicity occurred in 15.0% and 4.8% patients respectively. The CI rates of chronic grade 2 GU toxicity at 1, 2 and 3 years were 9.0%, 12.4%, and 14.41%. The CI rates of chronic grade 2 GI toxicity at 1, 2 and 3 years were 2.7%, 3.6%, 4.6%. Acute Grade 2 GU toxicity were hesitancy (6.3%), dysuria (4.4%), frequency (1.9%), urgency (0.6 %). Chronic Grade 2 GU toxicity were frequency (6.3%), nocturia (5.7%), dysuria (1.7 %), urgency (1.7%) and hematuria (1.7%). Acute Grade 2 GI toxicity was diarrhea (4.8%) and chronic Grade 2 GI toxicity was bleeding (5.3%) and diarrhea (1.3%). At 3 year follow-up, 95% of patients reported no use of pads for incontinence. The EPIC mean score of bowel function at baseline was 93.9 and at 36 months was 90.8. The mean score of sexual function at baseline was 34.9 and at 36 months was 39.4. The mean score of urinary function at baseline was 95 and at 36 months was 91. At baseline, 73 patients (40.3%) reported erections firm enough for intercourse. Of those 73 pts, 26 reached 36 months follow-up and 15 (58%) among them reported erections firm enough for intercourse. At 3 years, HFPBT in men with localized prostate cancer treated with 55.5Gy in 15 fractions generated no Grade 3, 4 or 5 acute or chronic GI/GU toxicities. Patent reported urinary, bowel and erectile function, demonstrates no clinically significant difference. However sexual potency declined while overall patient satisfaction remained high.

UF-Pcg Phase II Study of Hypofractionated Proton Therapy with Concurrent Chemotherapy for Stage II-III NSCLC

UF-Pcg Phase II Study of Hypofractionated Proton Therapy with Concurrent Chemotherapy for Stage II-III NSCLC

High efficacy of hypofractionated proton therapy with 4 fractions of 5 Gy as a boost to 50 Gy photon therapy for localized prostate cancer

PurposeWe report the outcome of hypofractionated proton boost as an alternative to high dose-rate brachytherapy boost, aimed at an equivalent dose exceeding 86 Gy in 2 Gy fractions, for patients with localized prostate cancer and all risk groups. MethodsProton boost of 20 Gy given in 4 daily fractions to the prostate was followed after a one-week rest by photon therapy to 50 Gy in 2 Gy fractions. Outcomes are presented per risk group according to both NCCN and ISUP classifications. Advanced imaging was performed for adequate staging, and at an early stage of rising PSA, to identify the relapse site. Endpoints were PSA relapse-free-, locoregional relapse-free-, and distant metastasis-free- survival. Prostate cancer-specific-, metastasis-free-, and overall survival were also estimated. Genitourinary (GU) and gastrointestinal (GI) toxicity were based on patients‘ questionnaires and physicians‘ records. ResultsWe treated 531 patients between 2002 and 2015; 504 had localized disease. The cohort included 180 patients with T3/T4 disease (36%). The majority of the 50% with high-/very high-risk disease received ADT, 9–24 months; 92 had adjuvant pelvic node treatment. Median follow-up was 113 months (43–193). For low-, intermediate-, high-, and very high-risk patients, the 5-year PSA relapse-free survival was 100%, 94%, 82%, and 72%, respectively. Prolonged ADT improved biochemical control and nodal treatment regional control. The NCCN classification had higher predictive discrimination than the ISUP classification. The 5-year prevalence grade 3+ was 2% for GU and 0% for GI toxicity in pre-treatment symptom-free patients, and not worsened by nodal treatment. ConclusionDose escalation with hypofractionated proton boost was as effective as reported with high dose-rate brachytherapy boost, and the GU and GI toxicity profile was very similar. The proton boost was also appropriate for patients with larger prostate volume, higher T-stage, and high-risk disease encompassing elective regional node photon therapy.

Four-Year Outcomes From a Prospective Phase II Clinical Trial of Moderately Hypofractionated Proton Therapy for Localized Prostate Cancer

Moderately hypofractionated radiation therapy represents an effective treatmentfor localized prostate cancer (PC). Although large randomized trials have reported the efficacy of photon-based hypofractionated therapy, hypofractionated proton therapy (HFPT) has not been extensively studied. This study was performed to determine the clinical and patient-reported outcomes for patients with PC treated with HFPT. Between 2010 and 2017, 184 men were enrolled on a trial of 70 Gy in 28 fractions of HFPT for low- to intermediate-risk PC. Acute and late toxicity was evaluated using National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Patient-reported outcomes were measured by International Prostate Symptom Score, International Index of Erectile Function Questionnaire, and Expanded Prostate Cancer Index Composite scores. Median follow-up was 49.2 months. Enrolled patients had low-risk (n = 18), favorable intermediate-risk (n = 78), and unfavorable intermediate-risk (n = 88) PC. Four-year rates of biochemical-clinical failure-free survival were 93.5% (95% confidence interval, 89%-98%), 94.4% (89%-100%), 92.5% (86%-100%), and 93.8% (88%-100%) in the overall group and the low-risk, favorable intermediate-risk, and unfavorable intermediate-risk cohorts, respectively (log-rank P > .4). The incidence of acute grade 2 or higher gastrointestinal (GI) and urologic toxicities were 3.8% and 12.5%, respectively. The 4-year incidence of late grade 2 or higher urologic and GI toxicity was 7.6% (4%-13%) and 13.6% (9%-20%), respectively. One late grade 3 GI toxicity was reported. All late toxicities were transient. Patient-reported International Prostate Symptom, International Index of Erectile Function, and Expanded Prostate Cancer Index Composite scores had no significant long-term changes after completion of HFPT (Supplementary Table 1, available at https://doi.org/10.1016/j.ijrobp.2019.05.069). HFPT is associated with low rates of toxicity and does not appear to negatively affect 4-year patient reported urinary and bowel health. Further comparative analyses are warranted to better understand differences between proton and photon HFRT.

Hypofractionated Proton Therapy in Early Prostate Cancer: Results of a Phase I/II Trial at Loma Linda University.

To determine whether a hypofractionated proton therapy regimen will control early-stage disease and maintain low rates of side effects similar to results obtained using standard-fraction proton therapy at our institution. A cohort of 146 patients with low-risk prostate cancer according to National Comprehensive Cancer Network guidelines (Gleason score <7, prostate-specific antigen [PSA] <10, tumor stage of T1-T2a) received 60 Gy (cobalt Gy equivalent) of proton therapy (20 fractions of 3.0 Gy per fraction) in 4 weeks, a dose biologically equivalent to standard fractionation (44-45 fractions of 1.8 Gy to a total of 79.2 to 81 Gy in 0 weeks). Patients were evaluated at least weekly during treatment, at which time documentation of treatment tolerance and acute reactions was obtained. Follow-up visits were conducted every 3 months for the first 1 years, every 6 months for the next 3 years, then annually. Follow-up visits consisted of history and physical examination, PSA measurements, and evaluation of toxicity. The median follow-up time was 42 months (range, 3-96 months). Acute grade 2 urinary toxicity occurred in 16% (20/120) of the patients; acute grade 2 or higher gastrointestinal toxicity was seen in 1.7% (2/120). At 9 months, 1 patient had late grade 3 urinary toxicity, which resolved by 12 months; no grade 3 gastrointestinal toxicities occurred. The 3-year biochemical survival rate was 99.3% (144/145). The median time to PSA nadir was 30 months. Hypofractionated proton therapy of 60 Gy in 20 fractions was safe and effective for patients with low-risk prostate cancer.

Effect of Irradiation Time on Biological Effectiveness and Tumor Control Probability in Proton Therapy

The biological effectiveness of proton beams may decrease with irradiation time because of sublethal damage repair (SLDR). The purpose of this study is to systematically evaluate this effect in hypofractionated proton therapy for various target sizes, depths, and prescribed doses per fraction. Plans with a single spread-out Bragg peak beam were created using a constant relative biological effectiveness (RBE) of 1.1 to cover targets of 6 different sizes located at 3 different depths in water. Biological doses of 2, 3, 5, 10, and 20 Gy (RBE) were prescribed to the targets. First, to investigate the depth variation of the biological effectiveness, the biological dose in instantaneous irradiation was recalculated based on the microdosimetric kinetic model. SLDR was then taken into account in the microdosimetric kinetic model during treatments to obtain the irradiation time-dependent biological effectiveness for irradiation time T of 5 to 60 minutes and beam interruption time τ of 0 to 60 minutes. The tumor control probabilities were calculated for single-fraction proton therapy fields of different Ts and τs, and the curative doses were evaluated at a tumor control probability of 90%. The biological effectiveness decreased with longer T and τ and higher prescribed dose. The maximum decrease in the biological effectiveness was 21% with a 20 Gy (RBE) prescribed dose. In single-fraction proton therapy, the curative dose increased linearly by approximately 33% to 35% with the increase of T from 0 to 60 minutes. The biological effectiveness varies largely with T and τ because of SLDR during treatments. This effect was pronounced for high prescribed doses per fraction. Thus, the effect of SLDR needs to be considered in hypofractionated and single-fraction proton therapies in relation to size and depth of the target.

Inter-patient variations of radiation-induced normal-tissue changes in Gd-EOB-DTPA-enhanced hepatic MRI scans during fractionated proton therapy

Background and purposePrevious MRI studies have shown a substantial decrease in normal-tissue uptake of a hepatobiliary-directed contrast agent 6–9 weeks after liver irradiation. In this prospective clinical study, we investigated whether this effect is detectable during the course of proton therapy. Material and methodsGd-EOB-DTPA enhanced MRI was performed twice during hypo-fractionated proton therapy of liver lesions in 9 patients (plus two patients with only one scan available). Dose-correlated signal changes were qualitatively scored based on difference images from the two scans. We evaluated the correlation between the MRI signal change with the planned dose map. The GTV was excluded from all analyses. In addition, were examined timing, irradiated liver volume, changes in liver function parameters as well as circulating biomarkers of inflammation. ResultsStrong, moderate or no dose-correlated signal changes were detected for 2, 3 and 5 patients, respectively. Qualitative scoring was consistent with the quantitative dose to signal change correlation. In an exploratory analysis, the strongest correlation was found between the qualitative scoring and pretreatment IL-6 concentration. For all patients, a clear dose-correlated signal decrease was seen in late follow-up scans. ConclusionRadiation-induced effects can be detected with Gd-EOB-DTPA enhanced MRI in a subgroup of patients within a few days after proton irradiation. The reason for the large inter-patient variations is not yet understood and will require validation in larger studies.

PO-0972 Intrafraction prostate motion effects with or without ERB in highly hypofractionated proton therapy

PO-0972 Intrafraction prostate motion effects with or without ERB in highly hypofractionated proton therapy