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.

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.

Minimal toxicity after proton beam therapy for prostate and pelvic nodal irradiation: results from the proton collaborative group REG001-09 trial.

BACKGROUND: Proton beam therapy (PBT) reduces normal organ dose compared to intensity modulated radiation therapy (IMXT) for prostate cancer patients who receive pelvic radiation therapy. It is not known whether this dosimetric advantage results in less gastrointestinal (GI) and genitourinary (GU) toxicity than would be expected from IMXT. MATERIAL AND METHODS: We evaluated treatment parameters and toxicity outcomes for non-metastatic prostate cancer patients who received pelvic radiation therapy and enrolled on the PCG REG001-09 trial. Patients who received X-ray therapy and/or brachytherapy were excluded. Of 3210 total enrolled prostate cancer patients, 85 received prostate and pelvic radiation therapy exclusively with PBT. Most had clinically and radiographically negative lymph nodes although 6 had pelvic nodal disease and one also had para-aortic involvement. Pelvic radiation therapy was delivered using either 2 fields (opposed laterals) or 3 fields (opposed laterals and a posterior beam). Median pelvic dose was 46.9 GyE (range 39.7-56) in 25 fractions (range 24-30). Median boost dose to the prostate +/- seminal vesicles was 30 GyE (range 20-41.4) in 16 fractions (range 10-24). RESULTS: Median follow-up was 14.5 months (range 2.8-49.2). Acute grade 1, 2, and 3 GI toxicity rates were 16.4, 2.4, 0%, respectively. Acute grade 1, 2, and 3 GU toxicity rates were 60, 34.1, 0%, respectively. CONCLUSIONS: Prostate cancer patients who receive pelvic radiation therapy using PBT experience significantly less acute GI toxicity than is expected using IMXT. Further investigation is warranted to confirm whether this favorable acute GI toxicity profile is related to small bowel sparing from PBT.

A Case Study: Proton Therapy for Male Breast Cancer with Previous Irradiation.

This is a case report of a male patient with previous radiation for a thymic carcinoma (20 years ago) who presented with a left breast cancer. He underwent a partial mastectomy followed by proton radiation therapy with a dose of 5040 cGy to the whole breast in 28 fractions with simultaneous boost to 5800 cGy to the lumpectomy cavity. Proton beam therapy was used instead of conventional photon radiation therapy to spare the heart and lung and to avoid any previously irradiated areas. This study describes the technique and comparative dosimetry for this case.

ACR Appropriateness Criteria® external-beam radiation therapy treatment planning for clinically localized prostate cancer.

Image-based radiation treatment planning and localization have contributed to better targeting of the prostate and sparing of normal tissues. Guidelines are needed to address radiation dose delivery, including patient setup and immobilization, target volume definition, treatment planning, treatment delivery methods, and target localization. Guidelines for external-beam radiation treatment planning have been updated and are presented here. The use of appropriate doses, simulation techniques, and verification of field setup are essential for the accurate delivery of radiation therapy. The ACR Appropriateness Criteria(®) are evidence-based guidelines for specific clinical conditions that are reviewed every 2 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances in which evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.

Comparison of high-dose proton radiotherapy and brachytherapy in localized prostate cancer: a case-matched analysis.

PURPOSE: To report a case-matched analysis comparing high-dose external-beam radiation (EBRT) for prostate cancer delivered on Proton Radiation Oncology Group (PROG) 95-09, a randomized trial, with permanent prostate brachytherapy over the same era. METHODS: From 1996 to 1999, 196 patients were accrued to the high-dose arm (79.2 Gray equivalent (GyE) using photons and protons) of PROG 95-09 at the Massachusetts General Hospital and Loma Linda University Medical Center. Entry criteria specified T1-2 and prostate-specific antigen ≤ 15 ng/mL. When Gleason score >7 was excluded, 177 men were left for case matching. At Massachusetts General Hospital, 203 similar patients were treated by a single brachytherapist from 1997 to 2002. Minimum follow-up was 3 years. Case matching, based on T stage, Gleason score, prostate-specific antigen, and age resulted in 141 matches (282 patients). Median follow-up was 8.6 and 7.4 years for EBRT and brachytherapy, respectively. The primary endpoint was biochemical failure (BF). RESULTS: Using the Phoenix definition, the 8-year BF rates were 7.7% and 16.1% for EBRT and brachytherapy, respectively (p = 0.42). A stratified analysis was performed by risk group. In the EBRT group, 113 and 28 patients were low and intermediate risk, respectively. In the brachytherapy group, 118 and 23 were. When stratified by risk group, the BF rates were similar by either technique. CONCLUSIONS: High-dose EBRT and brachytherapy result in similar BF rates for men with localized prostate cancer. Comparative quality-of-life and cost-effectiveness studies are warranted.

ACR Appropriateness Criteria® definitive external beam irradiation in stage T1 and T2 prostate cancer.

PURPOSE: : External beam radiation therapy is a standard of care treatment for men who present with clinically localized (T1-T2) prostate cancer. The purpose of this review was to provide clarification on the appropriateness criteria and management considerations for the treatment of prostate cancer with external beam radiation therapy. METHODS: : A panel consisting of physicians with expertise on prostate cancer was assembled and provided with a number of clinical scenarios for consensus treatment and management guidelines. Prostate cancer patient vignettes were presented along with specific management recommendations based on an extensive review of the modern external beam radiotherapy literature. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 2 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer reviewed journals and the application of a well established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances, where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. RESULTS: : Modern external beam radiation therapy series demonstrate favorable biochemical control rates for patients with localized prostate cancer. Morbidity profiles are also favorable and it is clear that this is enhanced by modern techniques like 3-dimensional conformal radiation therapy and intensity-modulated radiation therapy. An active area of investigation is evaluating the use of hypofractionated dosing. CONCLUSIONS: : Continued investigation to refine patient selection, external beam radiation technology application, and alternative dosing schedules should result in further improvements in biochemical outcome and decreased morbidity with external beam radiation treatment for localized prostate cancer.

American College of Radiology Appropriateness Criteria permanent source brachytherapy for prostate cancer.

PURPOSE: Permanent prostate brachytherapy has emerged as a standard of care treatment for approximately 50,000 men annually who present with clinically localized prostate cancer. The purpose of this review was to provide clarification on the appropriateness criteria and management considerations for the treatment of prostate cancer with permanent prostate brachytherapy. METHODS: Panel members with expertise on prostate cancer were assembled and provided several clinical scenarios for consensus treatment and management guidelines. Prostate cancer patient vignettes were presented along with specific management recommendations based on an extensive review of the modern brachytherapy literature. The brachytherapy topic development and review consists of two parts which require extensive participation by the expert panel. The American College of Radiology (ACR) Appropriateness Criteria (AC) are derived from a multidisciplinary panel of experts from both the academic and private practice settings. The first activity is a review of the current literature with development of an evidence table, referenced narrative, and ratings table of treatments. The second activity is the consensus-building process using a modified Delphi technique via an anonymous voting process. RESULTS: Most brachytherapy series have demonstrated favorable morbidity profiles and durable biochemical control rates for patients with low-, intermediate-, and high-risk features. However, as brachytherapy followups have matured, it has become increasingly apparent that efficacy and morbidity are highly dependent on implant quality. CONCLUSION: Continued attempts to refine patient selection, brachytherapy treatment planning philosophy, technique, and postimplant management should result in further improvements in biochemical outcome and decreased brachytherapy-related morbidity.

ACR appropriateness criteria postradical prostatectomy irradiation in prostate cancer.

The role of postradical prostatectomy radiation therapy continues to evolve under the influence of new clinical data. In particular, 2 recently published or updated randomized trials have prompted a reevaluation of its utility in the adjuvant and salvage setting. The Southwest Oncology Group 8794 trial randomized 473 patients with stage T3a-T3b disease to adjuvant radiotherapy versus observation. With a median follow-up of 12.7 years, this trial demonstrates an improvement in metastasis-free (93/214 vs. 114/211, P = 0.016) and overall survival (88 vs. 110 deaths, P = 0.023) favoring adjuvant radiotherapy. The European Organization for Research and Treatment of Cancer 22911 study of 972 patients with at least 1 "high risk" feature at surgery (extracapsular extension, positive surgical margins, seminal vesicle involvement) randomized to immediate adjuvant radiotherapy (60 Gy) versus observation. The freedom from biochemical failure at 5 years was 53% in the observation alone group versus 74% in the adjuvant radiotherapy group (P < 0.0001). This review summarizes the current evidence-based literature supporting the use of postradical prostatectomy radiation therapy in various common clinical settings and will serve to illustrate the appropriateness of postoperative radiotherapy by reviewing its implementation in a variety of commonly occurring clinical scenarios. It is intended to serve both as a guideline for the practicing radiation oncologist and a resource for further learning.

Acute and late toxicity after dose escalation to 82 GyE using conformal proton radiation for localized prostate cancer: initial report of American College of Radiology Phase II study 03-12.

PURPOSE: Several randomized trials have shown a benefit of dose escalation to 78 to 79 Gy for men treated with external radiation for localized prostate cancer. Single-institution data suggest a benefit with even higher doses. American College of Radiology 03-12 is a Phase II trial testing the safety and efficacy of 82 GyE (Gray equivalent) delivered with conformal proton radiation. METHODS AND MATERIALS: From 2003-2006, 85 men with localized prostate cancer were accrued to American College of Radiology 03-12. Eighty-four were eligible for analysis. They were treated with conformal proton radiation alone to a total dose of 82 GyE. The study was designed to test whether the rate of 18-month Grade 3+ late toxicity was greater than 10%. RESULTS: The median follow-up was 31.6 months. Regarding treatment-related acute toxicity, there were 39 Grade 1 cases (46%), 19 Grade 2 cases (23%) and 2 Grade 3 cases (2%). Regarding genitourinary/gastrointestinal toxicity, there were 42 Grade 1 cases (50%), 12 Grade 2 cases (14%) and 1 Grade 3 case (1%). Regarding late toxicity, there were 28 Grade 1 cases (33%), 22 Grade 2 cases (26%), 6 Grade 3 cases (7%), and 1 Grade 4 case (1%). The late genitourinary/gastrointestinal rates were the same. The estimated rate of Grade 3+ late toxicity at 18 months was 6.08%. CONCLUSIONS: Although not free of late toxicity, 82 GyE at 2 GyE per fraction delivered with conformal proton radiation did not exceed the late morbidity target tested in this trial. There was sufficient morbidity, however, that this may be the maximal dose that can be delivered safely with this technique and fractionation.

Randomized trial comparing conventional-dose with high-dose conformal radiation therapy in early-stage adenocarcinoma of the prostate: long-term results from proton radiation oncology group/american college of radiology 95-09.

PURPOSE To test the hypothesis that increasing radiation dose delivered to men with early-stage prostate cancer improves clinical outcomes. PATIENTS AND METHODS Men with T1b-T2b prostate cancer and prostate-specific antigen /= 3 genitourinary toxicity, and 1% of patients in the high-dose arm experienced late grade >/= 3 GI toxicity. CONCLUSION This randomized controlled trial shows superior long-term cancer control for men with localized prostate cancer receiving high-dose versus conventional-dose radiation. This was achieved without an increase in grade >/= 3 late urinary or rectal morbidity.

Patient tolerance of rectal balloons in conformal radiation treatment of prostate cancer.

PURPOSE: To evaluate patient tolerance of intrarectal balloons used during conformal prostate irradiation. METHODS AND MATERIALS: A retrospective analysis was performed on 3,561 patients who underwent conformal radiation for prostate cancer. Therapy consisted of proton irradiation of the prostate and seminal vesicles and X-ray treatment of the pelvis when warranted. The number of treatments in which the balloon was tolerated was recorded. Results were stratified according to method of irradiation (protons alone vs. combined proton/X-ray) and method of planning (2D vs. 3D planning of X-ray fields in patients undergoing combination treatment). RESULTS: Of all the patients evaluated, 3,474 (97.6%) tolerated the balloon throughout treatment; 87 (2.4%) declined the balloon for 1 or more treatments and tolerated the balloon for 85.5% of their treatments. Chi-square analysis revealed a significant tolerance advantage in those who received protons alone compared with combination treatment (99.5% vs. 95.7%; p < 0.001). In patients undergoing combination treatment, chi-square analysis did not reveal significant tolerance differences in patients undergoing 3D vs. 2D planning for pelvic X-ray fields (95.74% vs. 95.72%; p = 0.990). CONCLUSIONS: Intrarectal balloons are well tolerated over a course of conformal prostate irradiation.

Comparison of conventional-dose vs high-dose conformal radiation therapy in clinically localized adenocarcinoma of the prostate: a randomized controlled trial.

CONTEXT: Clinically localized prostate cancer is very prevalent among US men, but recurrence after treatment with conventional radiation therapy is common. OBJECTIVE: To evaluate the hypothesis that increasing the radiation dose delivered to men with clinically localized prostate cancer improves disease outcome. DESIGN, SETTING, AND PATIENTS: Randomized controlled trial of 393 patients with stage T1b through T2b prostate cancer and prostate-specific antigen (PSA) levels less than 15 ng/mL randomized between January 1996 and December 1999 and treated at 2 US academic institutions. Median age was 67 years and median PSA level was 6.3 ng/mL. Median follow-up was 5.5 (range, 1.2-8.2) years. INTERVENTION: Patients were randomized to receive external beam radiation to a total dose of either 70.2 Gy (conventional dose) or 79.2 Gy (high dose). This was delivered using a combination of conformal photon and proton beams. MAIN OUTCOME MEASURE: Increasing PSA level (ie, biochemical failure) 5 years after treatment. RESULTS: The proportions of men free from biochemical failure at 5 years were 78.8% [corrected] (95% confidence interval, 73.1%-84.6%) [corrected] for conventional-dose and 91.3% [corrected] (95% confidence interval, 87.2%-95.4%) [corrected] for high-dose therapy (P<.001), a 59% [corrected] reduction in the risk of failure. The advantage to high-dose therapy was statistically significant [corrected] in both the low-risk subgroup [corrected] (risk reduction, 84% [P<.001]) [corrected] There has been no significant difference in overall survival rates between the treatment groups. Only 1% of patients receiving conventional-dose and 2% receiving high-dose radiation experienced acute urinary or rectal morbidity of Radiation Therapy Oncology Group (RTOG) grade 3 or greater. So far, only 2% and 1%, respectively, have experienced late morbidity of RTOG grade 3 or greater. CONCLUSIONS: Men with clinically localized prostate cancer have a lower risk of biochemical failure if they receive high-dose rather than conventional-dose conformal radiation. This advantage was achieved without any associated increase in RTOG grade 3 acute or late urinary or rectal morbidity.

Influence of patient age on biochemical freedom from disease in patients undergoing conformal proton radiotherapy of organ-confined prostate cancer.

OBJECTIVES: To examine a large, single-institution series of patients to test the perception among clinicians that radiotherapy is preferred for "older" patients and surgery should be indicated for "younger" men. Both radiotherapy and surgery are used to control prostate cancer, and both yield similar results in terms of long-term biochemical disease-free (bNED) survival. METHODS: The bNED survival results from more than 1000 patients treated solely with conformal radiotherapy were analyzed to determine whether a difference in outcome supervened for patients younger than 60 years of age versus older patients. RESULTS: No statistically significant difference in bNED survival was found, in terms of patient age. Statistically significant predictors of outcome included pretreatment prostate-specific antigen level, clinical stage at diagnosis, and Gleason score. CONCLUSIONS: Patient age younger than 60 years versus older than 60 years at treatment did not influence bNED survival significantly. Patient age at treatment should not be used in and of itself to recommend one type of treatment over another.

Proton therapy for prostate cancer: the initial Loma Linda University experience.

PURPOSE: We analyzed results of conformal proton radiation therapy for localized prostate cancer, with emphasis on biochemical freedom from relapse. METHODS AND MATERIALS: Analyses were performed for 1255 patients treated between October 1991 and December 1997. Outcomes were measured on primarily in terms of biochemical relapse and toxicity. RESULTS: The overall biochemical disease-free survival rate was 73%, and was 90% in patients with initial PSA