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PURPOSE: Late cardiac complications from thoracic radiation of patients with Hodgkin lymphoma are of great concern. The authors investigated whether cardiac biomarkers could identify patients with early cardiac damage from thoracic radiation. MATERIALS AND METHODS: Following completion of anthracycline-based chemotherapy, 14 patients with stage I-IIIA mediastinal Hodgkin lymphoma were enrolled on an IRB-approved prospective trial and agreed to serum evaluation of troponin, CK-MB, and BNP before beginning radiation, after completing radiation, and every 3 to 6 months for 5 years, during follow-up or until relapse. RESULTS: Among the 14 patients, median follow-up for the entire cohort was 5 years. No evidence in abnormal values in troponin or CK-MB was observed among the patient cohort. BNP levels demonstrated statistically significant higher values at various follow-up time points. Higher levels of BNP were observed among patients receiving higher anthracycline doses (>250 mg), but not among patients with higher mean heart radiation doses. CONCLUSIONS: In the first 5 years after treatment, no rise in CK-MB or troponin was identified. BNP levels significantly increased following treatment, with larger increases among patients who received higher doses of anthracyclines. Further investigation is warranted.

The aim of this article is to discuss the current role of radiotherapy (RT) for early-stage Hodgkin's lymphoma (HL) in the context of risk-adapted and response-adapted treatment strategy, and describe changes in RT technical approach.In low-risk patients, RT could be omitted but, at the price of a lower progression-free survival, and its role is still debated. Ongoing trials are combining new agents with chemotherapy alone or response-adapted combined modality therapy, and results are awaited. Modern RT incorporates lower doses and smaller fields, together with the implementation of sophisticated delivery techniques aimed to reducing the dose to critical structures such as the heart. The role of RT for early-stage HL is still under debate, and new combinations are emerging; an individualized approach should be recommended, considering all RT technical opportunities to minimize toxicity while maintaining efficacy.

Purpose: To report 5-year outcomes of a prospective trial of image-guided accelerated hypofractionated proton therapy (AHPT) for prostate cancer. Patients and methods: 215 prostate cancer patients accrued to a prospective institutional review board-approved trial of 70Gy(RBE) in 28 fractions for low-risk disease (n = 120) and 72.5Gy(RBE) in 29 fractions for intermediate-risk disease (n = 95). This trial excluded patients with prostate volumes of ≥60 cm3 or International Prostate Symptom Scores (IPSS) of ≥15, patients on anticoagulants or alpha-blockers, and patients in whom dose-constraint goals for organs at risk (OAR) could not be met. Toxicities were graded prospectively according to Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. This trial can be found on ClinicalTrials.gov (NCT00693238). Results: Median follow-up was 5.2 years. Five-year rates of freedom from biochemical and clinical disease progression were 95.9%, 98.3%, and 92.7% in the overall group and the low- and intermediate-risk subsets, respectively. Actuarial 5-year rates of late radiation-related CTCAE v3.0 grade 3 or higher gastrointestinal and urologic toxicities were 0.5% and 1.7%, respectively. Median IPSS before treatment and at 4+ years after treatment were 6 and 5 for low-risk patients and 4 and 6 for intermediate-risk patients. Conclusions: Image-guided AHPT 5-year outcomes show high efficacy and minimal physician-assessed toxicity in selected patients. These results are comparable to the 5-year results of our prospective trials of standard fractionated proton therapy for patients with low-risk and intermediate-risk prostate cancer. Longer follow-up and a larger cohort are necessary to confirm these findings.

International harmonization of staging evaluation and response criteria is needed for childhood, adolescence, and young adulthood Hodgkin lymphoma. Two Hodgkin lymphoma protocols from cooperative trials in Europe and North America were compared for areas in need of harmonization, and an evidence-based approach is currently underway to harmonize staging and response evaluations with a goal to enhance comparisons, expedite identification of effective therapies, and aid in the approval process for new agents by regulatory agencies.

Purpose: Hodgkin lymphoma (HL) survivors are susceptible to long-term side effects from definitive treatment with combination chemotherapy and radiation therapy (RT). Because late effects from RT correlate to radiation treatment volume, stage III/IV pediatric HL requiring large radiation fields are at greater risk for late complications. This study investigates the dosimetric impact of proton therapy (PT) to spare the organs at risk (OARs) in stage III and IV HL. Patients and Methods: From October 2011 through January 2014, 7 pediatric patients with stage III or IV HL involving both supradiaphragmatic and infradiaphragmatic underwent treatment planning with 3-dimensional conformal radiation therapy (3DCRT), intensity-modulated radiation therapy (IMRT), and PT to a dose of 21 Gy after ABVE-PC chemotherapy. Plans were normalized to meet treatment parameters including target coverage and dose to OARs. Results: All 7 patients were treated with PT. PT had the lowest integral body dose (101 J; range, 5...

This work describes the clinical implementation of a beam-specific planning treatment volume (bsPTV) calculation for lung cancer proton therapy and its integration into the treatment planning process. Uncertainties incorporated in the calculation of the bsPTV included setup errors, machine delivery variability, breathing effects, inherent proton range uncertainties and combinations of the above. Margins were added for translational and rotational setup errors and breathing motion variability during the course of treatment as well as for their effect on proton range of each treatment field. The effect of breathing motion and deformation on the proton range was calculated from 4D computed tomography data. Range uncertainties were considered taking into account the individual voxel HU uncertainty along each proton beamlet. Beam-specific treatment volumes generated for 12 patients were used: a) as planning targets, b) for routine plan evaluation, c) to aid beam angle selection and d) to create beam-specific margins for organs at risk to insure sparing. The alternative planning technique based on the bsPTVs produced similar target coverage as the conventional proton plans while better sparing the surrounding tissues. Conventional proton plans were evaluated by comparing the dose distributions per beam with the corresponding bsPTV. The bsPTV volume as a function of beam angle revealed some unexpected sources of uncertainty and could help the planner choose more robust beams. Beam-specific planning volume for the spinal cord was used for dose distribution shaping to ensure organ sparing laterally and distally to the beam.

Purpose To report 5-year clinical outcomes of 3 prospective trials of image-guided proton therapy for prostate cancer. Methods and Materials A total of 211 prostate cancer patients (89 low-risk, 82 intermediate-risk, and 40 high-risk) were treated in institutional review board-approved trials of 78 cobalt gray equivalent (CGE) in 39 fractions for low-risk disease, 78 to 82 CGE for intermediate-risk disease, and 78 CGE with concomitant docetaxel therapy followed by androgen deprivation therapy for high-risk disease. Toxicities were graded according to Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. Median follow-up was 5.2 years. Results Five-year rates of biochemical and clinical freedom from disease progression were 99%, 99%, and 76% in low-, intermediate-, and high-risk patients, respectively. Actuarial 5-year rates of late CTCAE, version 3.0 (or version 4.0) grade 3 gastrointestinal and urologic toxicity were 1.0% (0.5%) and 5.4% (1.0%), respectively. Median pretreatment scores and International Prostate Symptom Scores at >4 years posttreatment were 8 and 7, 6 and 6, and 9 and 8, respectively, among the low-, intermediate-, and high-risk patients. There were no significant changes between median pretreatment summary scores and Expanded Prostate Cancer Index Composite scores at >4 years for bowel, urinary irritative and/or obstructive, and urinary continence. Conclusions Five-year clinical outcomes with image-guided proton therapy included extremely high efficacy, minimal physician-assessed toxicity, and excellent patient-reported outcomes. Further follow-up and a larger patient experience are necessary to confirm these favorable outcomes.

Pediatric Hodgkin lymphoma is a highly curable malignancy and potential long-term effects of therapy need to be considered in optimizing clinical care. An expert panel was convened to reach consensus on the most appropriate approach to evaluation and treatment of pediatric Hodgkin lymphoma. 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. Four clinical variants were developed to assess common clinical scenarios and render recommendations for evaluation and treatment approaches to pediatric Hodgkin lymphoma. We provide a summary of the literature as well as numerical ratings with commentary. By combining available data in published literature and expert medical opinion, we present a consensus to the approach for management of pediatric Hodgkin lymphoma. Pediatr Blood Cancer 2014;61:1305–1312. © 2014 American College of Radiology.

BACKGROUND Data continue to emerge on the relative merits of different treatment modalities for prostate cancer. The objective of this study was to compare patient-reported quality-of-life (QOL) outcomes after proton therapy (PT) and intensity-modulated radiation therapy (IMRT) for prostate cancer. METHODS A comparison was performed of prospectively collected QOL data using the Expanded Prostate Cancer Index Composite (EPIC) questionnaire. QOL data were collected during the first 2 years after treatment for men who received PT and IMRT. PT was delivered to 1243 men at a single center at doses from 76 grays (Gy) to 82 Gy. IMRT was delivered to 204 men who were included in the Prostate Cancer Outcomes and Satisfaction with Treatment Quality Assessment (PROSTQA) study in doses from 75.6 Gy to 79.4 Gy. The Wilcoxon rank-sum test was used to compare EPIC outcomes by modality using baseline-adjusted scores at different time points. Individual questions were assessed by converting to binary outcomes and testing with generalized estimating equations. RESULTS No differences were observed in summary score changes for bowel, urinary incontinence, urinary irritative/obstructive, and sexual domains between the 2 cohorts. However, more men who received IMRT reported moderate/big problems with rectal urgency (P = 0.02) and frequent bowel movements (P = 0.05) than men who received PT. CONCLUSIONS There were no differences in QOL summary scores between the IMRT and PT cohorts during early follow-up (up to 2-years). Response to individual questions suggests possible differences in specific bowel symptoms between the 2 cohorts. These outcomes highlight the need for further comparative studies of PT and IMRT. Cancer 2014;120:1076–1082. © 2013 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.

To the Editor: This opposing views article highlights some of the fundamental differences in how radiation oncologists view the burgeoning (but not new) application of proton beam therapy (PBT) to treat prostate cancer. Hoppe et al articulate the respective arguments of the so-called proton and photon “camps” that have emerged within our specialty. These camps predictably fall along the lines of whether one practices at a center with PBT, and the financial differences between the 2 technologies are the key driver of the debate. Frankly none of us would be arguing against a product or device that delivers less unwanted radiation while maintaining (if not increasing) dose to the targetdif the cost is comparable to the alternatives. But it is different with prostate cancer. Excellent and affordable alternatives do exist, including brachytherapy, which is cheaper and more conformal than PBT and intensity modulated radiation therapy (IMRT). Those who use PBT should ask the important clinical questions, test them, and be given the time and resources to do so. Those who use only photon based techniques should, in turn, support these efforts, recognizing that IMRT was not held to the same standard when it was widely adopted over older and cheaper conventional techniques. Rather than recapitulating conflicting interpretations of the same methodologically flawed study, 1,2 as is done here, the radiation oncology community could look to patient level data on prospectively collected toxicity and quality of life outcomes for a disease as prevalent as prostate cancer. 3 In the spirit of incorporating patient reported outcomes Hoppe and Bryant suggest that the retrospectively observed 6% to 8% difference in bowel quality of life as measured by EPIC (Expanded Prostate Cancer Index Composite) is not only statistically significant, but also clinically relevant. 4 Sandler references the currently open randomized trial of IMRT vs proton therapy in prostate cancer, which has a primary end point of 2-year patient reported bowel quality of life (using EPIC). While this study will examine whether the retrospectively observed difference in bowel quality of life is statistically significant in a phase III setting, will it answer the question of whether it is clinically meaningful? If we do not see a difference for this specific end point, the trial will be negative. But will we truly feel that we answered the question of which is better? The media and payers certainly will, and frankly in many cases they have already decided that cheaper is better, period. The tide against PBT due to its generally greater costs is a foregone conclusion in many parts of the country but we have not afforded it the opportunity to prove itself. The institutional studies that have been reported to date generally all used passive scatter technique, an increasingly outdated and suboptimal form of proton beam delivery. We need to compare the “best” PBT techniques (ie pencil beam scanning) to the best IMRT. This comparison will require patience as centers work to responsibly deploy such capabilities. 5 While time is a rare luxury in the world of “do more with less,” it is necessary if we really want to test the various hypotheses described by the authors. Although there is multidirectional pressure to produce and report trial results quickly, doing so in prostate cancer can give a limited view of a disease with a long natural history involving patients who are at risk for late toxicities and relapses. As Sandler notes, the proton debate in prostate cancer carries great economic importance. But the comparative effectiveness challenges inherent to prostate cancer hopefully will not translate to a general disregard of PBT for other cancers. As a genitourinary radiation oncologist who uses PBT and photon based IMRT, I would like us to focus our efforts on investigating the promise of

Adjuvant androgen deprivation therapy (ADT) improves outcomes of patients receiving definitive radiotherapy (RT) for local-regionally advanced prostate cancer. However, patients in most randomized trials had more advanced disease than observed in many practices and were treated with suboptimal RT doses. Although data are conflicting, long-term ADT likely has adverse side-effects in patients with comorbidities. We recommend 6 months of ADT monotherapy with gonadotropin-releasing hormone agonist and RT for patients with high-risk prostate cancer (≥T2c, Gleason Score 8 to 10, and/or prostate-specific antigen ≥20 ng/mL) with minimal or no comorbidities. Adjuvant ADT for unfavorable intermediate-risk patients with a Gleason Score of 4+3=7 is also reasonable.

In this case report, we present the history and treatment of a 70-year-old man with synchronous bilateral non-small-cell lung cancers with proton-beam radiation. Surgical treatment was not feasible and optimized photon intensity-modulated radiotherapy (IMRT) to the primary tumors would have resulted in unacceptably high normal-tissue exposures. Proton-beam radiation enabled radiation dose escalation and concurrent chemotherapy while maintaining normal-tissue tolerance.

Background. To assess genitourinary (GU) function and toxicity in patients treated with image-guided proton therapy (PT) for early- and intermediate-risk prostate cancer and to analyze the impact of pretreatment urinary obstructive symptoms on urinary function after PT. Material and methods. Two prospective trials accrued 171 prostate cancer patients from August 2006 to September 2007. Low-risk patients received 78 cobalt gray equivalent (CGE) in 39 fractions and intermediate-risk patients received 78–82 CGE. Median follow-up was five years. The International Prostate Symptom Score (IPSS) and GU toxicities (per CTCAE v3.0 and v4.0) were documented prospectively. Results. Five transient GU events were scored Gr 3 per CTCAE v4.0, for a cumulative late GU toxicity rate of 2.9% at five years. There were no Gr 4 or 5 events. On multivariate analysis (MVA), the only factor predictive of Gr 2 + GU toxicity was pretreatment GU symptom management (p = 0.0058). Patients with pretreatment IPSS of 15–25 had a decline (clinical improvement) in median IPSS from 18 before treatment to 10 at their 60-month follow-up. At last follow-up, 18 (54.5%) patients had a > 5-point decline, 14 (42.5%) remained stable, and two patients (3%) had a > 5-point rise (deterioration) in IPSS. Patients with IPSS < 15 had a stable median IPSS of 6 before treatment and at 60 months. Conclusion. Urologic toxicity at five years with image-guided PT has been uncommon and transient. Patients with pretreatment IPSS of < 15 had stable urinary function five years after PT, but patients with 15–25 showed substantial improvement (decline) in median IPSS, a finding not explained by initiation or dose adjustment of alpha blockers. This suggests that PT provides a minimally toxic and effective treatment for low and intermediate prostate cancer patients, including those with significant pretreatment GU dysfunction (IPSS 15–25).

To review treatment toxicity for patients with pancreatic and ampullary cancer treated with proton therapy at our institution.From March 2009 through April 2012, 22 patients were treated with proton therapy and concomitant capecitabine (1000 mg PO twice daily) for resected (n = 5); marginally resectable (n = 5); and unresectable/inoperable (n = 12) biopsy-proven pancreatic and ampullary adenocarcinoma. Two patients with unresectable disease were excluded from the analysis for reasons unrelated to treatment. Proton doses ranged from 50.40 cobalt gray equivalent (CGE) to 59.40 CGE.Median follow-up for all patients was 11 (range 5-36) months. No patient demonstrated any grade 3 toxicity during treatment or during the follow-up period. Grade 2 gastrointestinal toxicities occurred in three patients, consisting of vomiting (n = 3); and diarrhea (n = 2). Median weight loss during treatment was 1.3 kg (1.75% of body weight). Chemotherapy was well-tolerated with a median 99% of the prescribed doses delivered. Percentage weight loss was reduced (p = 0.0390) and grade 2 gastrointestinal toxicity was eliminated (p = 0.0009) in patients treated with plans that avoided anterior and left lateral fields which were associated with reduced small bowel and gastric exposure.Proton therapy may allow for significant sparing of the small bowel and stomach and is associated with a low rate of gastrointestinal toxicity. Although long-term follow-up will be needed to assess efficacy, we believe that the favorable toxicity profile associated with proton therapy may allow for radiotherapy dose escalation, chemotherapy intensification, and possibly increased acceptance of preoperative radiotherapy for patients with resectable or marginally resectable disease.

Background. Concurrent chemoradiotherapy (CRT) is the standard of care in patients with limited-stage small cell lung cancer (SCLC). Treatment with conventional x-ray therapy (XRT) is associated with high toxicity rates, particularly acute grade 3 � esophagitis and pneumonitis. We present outcomes for the fi rst known series of limited-stage SCLC patients treated with proton therapy and a dosimetric comparison of lung and esophageal doses with intensity-modulated radiation therapy (IMRT). Material and methods. Six patients were treated: fi ve concurrently and one sequentially. Five patients received 60 ‐ 66 CGE in 30‐34 fractions once daily and one patient received 45 CGE in 30 fractions twice daily. All six patients received prophylactic cranial irradiation. Common Terminology Criteria for Adverse Events, v3.0, was used to grade toxicity. IMRT plans were also generated and compared with proton plans. Results. The median follow-up was 12.0 months. The one-year overall and progression-free survival rates were 83% and 66%, respectively. There were no cases of acute grade 3 � esophagitis or acute grade 2 � pneumonitis, and no other acute grade 3 � non-hematological toxicities were seen. One patient with a history of pulmonary fi brosis and atrial fi brillation developed worsening symptoms four months after treatment requiring oxygen. Three patients died: two of progressive disease and one after a fall; the latter patient was disease-free at 36 months after treatment. Another patient recurred and is alive, while two patients remain disease-free at 12 months of follow-up. Proton therapy proved superior to IMRT across all esophageal and lung dose volume points. Conclusion. In this small series of SCLC patients treated with proton therapy with radical intent, treatment was well tolerated with no cases of acute grade 3 � esophagitis or acute grade 2 � pneumonitis. Dosimetric comparison showed better sparing of lung and esophagus with proton therapy. Proton therapy merits further investigation as a method of reducing the toxicity of CRT.

Proton therapy (PT) for prostate cancer reduces rectal and bladder dose, but increases dose to the femoral necks. We assessed the risk of hip fracture and pain in men treated with PT for prostate cancer.From 2006 to 2008, 382 men were treated for prostate cancer and evaluated at six-month intervals after PT for toxicities at University of Florida Proton Therapy Institute (UFPTI). The WHO Fracture Risk Assessment Tool (FRAX) generated annual hip-fracture risk for the cohort. The WHO FRAX tool was utilized to generate the expected number of patients with hip fractures and the observed-to-expected ratio; confidence intervals and p-value were generated with the mid-P exact test. Univariate analysis of hip pain as a function of several prognostic factors was accomplished with Fisher's exact test.Median follow-up was four years (range, 0.1-5.5 years). Per FRAX, 3.02 patients were expected to develop a hip fracture without PT. Three PT patients actually developed fractures for a rate of 0.21 fractures per 100 person-years of follow-up. There was an observed-expected ratio of 0.99 (p-value not significant). Forty-eight patients (13%) reported new pain in the hip during follow-up; three required prescription analgesics.PT for prostate cancer did not increase hip-fractures in the first four years after PT compared to expected rates in untreated men.

Follicular lymphoma is the second most common non-Hodgkin lymphoma histology diagnosed and the most common of the indolent histologies. Radiotherapy remains an important treatment modality for patients with follicular lymphoma. Among patients with early-stage disease, definitive treatment with radiotherapy remains the standard of care to doses of 24–30 Gy using involved-site radiotherapy. For patients with advanced disease, low-dose radiotherapy (2 Gy/fraction × two fractions) remains an excellent palliative treatment with durable control for approximately 18 months. Utilizing two different clinical scenarios, this chapter discusses epidemiology, staging, and treatment options and provides an in-depth overview of the radiotherapy treatment field design and plan evaluation for follicular lymphoma.

These guidelines review the historical evolution of treatment for early-stage Hodgkin lymphoma (HL) with current standards that rely on prognostic factors to risk stratify and direct current treatment schemes that includes differentiation of favorable and unfavorable presentations. The major clinical trials for unfavorable early-stage HL are reviewed. Patients in this heterogenous subgroup of classic HL are best managed with sequential chemotherapy and radiotherapy. The role of imaging response assessment as a means to modify therapy is a strategy under investigation. Tailoring the radiation treatment volume and radiation dose prescription along with selective use of modern conformal techniques is expected to help reduce long-term toxicities. Many patients are well served receiving involved-site radiotherapy to 30 Gy after appropriate systemic therapy intensity; but, there are nuances for which some variations in the chemotherapy and radiotherapy specifics are appropriately individualized. Following a discussion of the current evidence-based treatment algorithms, several different example cases are reviewed to help physicians make appropriate treatment decisions. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 3 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.

We present a case of an adolescent male with relapsed Hodgkin lymphoma involving the mediastinum two years following chemotherapy without radiotherapy. The patient was treated with second-line chemotherapy followed by high-dose chemotherapy and autologous stem cell transplant and then presented for evaluation of consolidative involved-field proton therapy (PT). Comparative treatment plans were developed with three-dimensional X-ray radiotherapy (3DXRT) and PT. PT substantially reduced the dose to the lungs, heart, esophagus, and total body compared with 3DXRT, resulting in treatment with PT. PT should reduce the risk of late side effects compared with 3DXRT, including secondary malignancies and cardiovascular disease.

PURPOSE: To determine the incidence of a bacterial urinary tract infection (UTI) necessitating hospitalization after transrectal placement of fiducial markers prior to proton radiotherapy (RT) for prostate cancer. MATERIALS AND METHODS: Six hundred sixty six patients returning for follow up after proton RT consented to participate in this institutional review board (IRB) approved study. Patients were queried whether they required hospitalization within 1 month of transrectal placement of fiducial markers. Patients were treated with proton RT between August 2006 and December 2014. Median International Prostate Symptom Score (IPSS) was 7. Sixty four patients (9.6%) had diabetes, 9 patients (1.4%) had chronic obstructive pulmonary disease, 6 patients (0.9%) had prior bladder surgery, 7 patients (1.1%) had a transurethral prostatectomy within 3 months, and 549 patients (82.4%) had a course of antibiotics within 6 months. Fifty five patients (8.3%) were taking tamsulosin, 16 patients (2.4%) were taking finasteride, and 62 patients (9.3%) were taking saw palmetto. The interval between the most recent prostate biopsy prior to fiducial placement and fiducial marker placement was less than 6 months in 609 patients (91.4%). No patient had a prior recent rectal culture. RESULTS: Ten patients (1.5%) developed a bacterial UTI necessitating hospitalization after transrectal placement of fiducial markers. A bacterial UTI occurred in 3 (0.7%) of 440 patients treated from 2006 to 2012 and in 7 (3.1%) of 226 patients treated from 2013 to 2014. Univariate analysis of potential association of a bacterial UTI with the following parameters revealed: IPSS less than or greater than the median (p=0.3400), diabetes (p=0.6099), tamsulosin (p=0.9999), saw palmetto (p=0.0093), interval between prostate biopsy and placement of fiducials (p=0.9999), year of treatment (p=0.0363), and antibiotics within 6 months (p=0.2233). A bacterial UTI was observed in 4 (6.5%) of 62 patients who were taking saw palmetto versus 6 (1.0%) of 604 patients who were not taking this medication. The incidence of a bacterial UTI between 2006 and 2012 was 3 (0.7%) of 440 patients and from 2013 to 2014 was 7 (3.1%) of 226 patients. Multivariate analysis revealed that the likelihood of a bacterial UTI was increased in patients taking saw palmetto (p=0.0044) and those treated in 2013-2014 (p=0.0303). CONCLUSION: The incidence of a bacterial UTI requiring hospitalization after transrectal placement of fiducial markers prior to proton RT was 1.5% and was impacted by taking saw palmetto and year of treatment. Patients treated during 2013 and 2014 had a significantly higher risk of a bacterial UTI requiring hospitalization.

Purpose We investigated the dosimetric impact of proton therapy (PT) on various cardiac subunits in patients with Hodgkin lymphoma (HL). Methods and Materials From June 2009 through December 2010, 13 patients were enrolled on an institutional review board-approved protocol for consolidative involved-node radiotherapy (INRT) for HL. Three separate treatment plans were developed prospectively by using three-dimensional conformal radiotherapy (3DCRT), intensity-modulated radiotherapy (IMRT), and PT. Cardiac subunits were retrospectively contoured on the 11 patients with intravenous-contrast simulation scans, and the doses were calculated for all treatment plans. A Wilcoxon paired test was performed to evaluate the statistical significance ( p Results The mean heart doses were 21 Gy, 12 Gy, and 8 Gy (relative biologic effectiveness [RBE]) with 3DCRT, IMRT, and PT, respectively. Compared with 3DCRT and IMRT, PT reduced the mean doses to the left and right atria; the left and right ventricles; the aortic, mitral, and tricuspid valves; and the left anterior descending, left circumflex, and right circumflex coronary arteries. Conclusions Compared with 3DCRT and IMRT, PT reduced the radiation doses to all major cardiac subunits. Limiting the doses to these structures should translate into lower rates of cardiac toxicities.

Purpose: To analyze prostate intrafraction motion using both non-gas-release (NGR) and gas-release (GR) rectal balloons and to evaluate the ability of GR rectal balloons to reduce prostate intrafraction motion. Methods: Twenty-nine patients with NGR rectal balloons and 29 patients with GR balloons were randomly selected from prostate patients treated with proton therapy at University of Florida Proton Therapy Institute (Jacksonville, FL). Their pretreatment and post-treatment orthogonal radiographs were analyzed, and both pretreatment setup residual error and intrafraction-motion data were obtained. Population histograms of intrafraction motion were plotted for both types of balloons. Population planning target-volume (PTV) margins were calculated with the van Herk formula of 2.5{Sigma}+ 0.7{sigma} to account for setup residual errors and intrafraction motion errors. Results: Pretreatment and post-treatment radiographs indicated that the use of gas-release rectal balloons reduced prostate intrafraction motion along superior-inferior (SI) and anterior-posterior (AP) directions. Similar patient setup residual errors were exhibited for both types of balloons. Gas-release rectal balloons resulted in PTV margin reductions from 3.9 to 2.8 mm in the SI direction, 3.1 to 1.8 mm in the AP direction, and an increase from 1.9 to 2.1 mm in the left-right direction. Conclusions: Prostate intrafraction motion is an important uncertainty source inmore » radiotherapy after image-guided patient setup with online corrections. Compared to non-gas-release rectal balloons, gas-release balloons can reduce prostate intrafraction motion in the SI and AP directions caused by gas buildup.« less

To determine the potential role for adjuvant proton-based radiotherapy (PT) for resected pancreatic head cancer.Between June 2008 and November 2008, 8 consecutive patients with resected pancreatic head cancers underwent optimized intensity-modulated radiotherapy (IMRT) treatment planning. IMRT plans used between 10 and 18 fields and delivered 45 Gy to the initial planning target volume (PTV) and a 5.4 Gy boost to a reduced PTV. PTVs were defined according to the Radiation Therapy Oncology Group 9704 radiotherapy guidelines. Ninety-five percent of PTVs received 100% of the target dose and 100% of the PTVs received 95% of the target dose. Normal tissue constraints were as follows: right kidney V18 Gy to70%; left kidney V18 Gy to30%; small bowel/stomach V20 Gy to50%, V45 Gy to15%, V50 Gy to10%, and V54 Gy to5%; liver V30 Gy to60%; and spinal cord maximum to 46 Gy. Optimized two- to three-field three-dimensional conformal proton plans were retrospectively generated on the same patients. The team generating the proton plans was blinded to the dose distributions achieved by the IMRT plans. The IMRT and proton plans were then compared. A Wilcoxon paired t-test was performed to compare various dosimetric points between the two plans for each patient.All proton plans met all normal tissue constraints and were isoeffective with the corresponding IMRT plans in terms of PTV coverage. The proton plans offered significantly reduced normal-tissue exposure over the IMRT plans with respect to the following: median small bowel V20 Gy, 15.4% with protons versus 47.0% with IMRT (p = 0.0156); median gastric V20 Gy, 2.3% with protons versus 20.0% with IMRT (p = 0.0313); and median right kidney V18 Gy, 27.3% with protons versus 50.5% with IMRT (p = 0.0156).By reducing small bowel and stomach exposure, protons have the potential to reduce the acute and late toxicities of postoperative chemoradiation in this setting.

Purpose To compare the dose reduction to organs at risk (OARs) with proton therapy (PT) versus three-dimensional conformal radiotherapy (3D-CRT) and intensity-modulated radiotherapy (IMRT) in patients with mediastinal Hodgkin lymphoma (HL) enrolled on a Phase II study of involved-node radiotherapy (INRT). Methods and Materials Between June 2009 and October 2010, 10 patients were enrolled on a University of Florida institutional review board–approved protocol for de novo "classical" Stage IA-IIIB HL with mediastinal (bulky or nonbulky) involvement after chemotherapy. INRT was planned per European Organization for Research and Treatment of Cancer guidelines. Three separate optimized plans were developed for each patient: 3D-CRT, IMRT, and PT. The primary end point was a 50% reduction in the body V4 with PT compared with 3D-CRT or IMRT. Results The median relative reduction with PT in the primary end point, body V4, was 51% compared with 3D-CRT ( p = 0.0098) and 59% compared with IMRT ( p = 0.0020), thus all patients were offered treatment with PT. PT provided the lowest mean dose to the heart, lungs, and breasts for all 10 patients compared with either 3D-CRT or IMRT. The median difference in the OAR mean dose reduction with PT compared with 3D-CRT were 10.4 Gy/CGE for heart; 5.5 Gy/CGE for lung; 0.9 Gy/CGE for breast; 8.3 Gy/CGE for esophagus; and 4.1 Gy/CGE for thyroid. The median differences for mean OAR dose reduction for PT compared with IMRT were 4.3 Gy/CGE for heart, 3.1 Gy/CGE for lung, 1.4 Gy/CGE for breast, 2.8 Gy/CGE for esophagus, and 2.7 Gy/CGE for thyroid. Conclusions All 10 patients benefitted from dose reductions to OARs with PT compared with either 3D-CRT or IMRT. It is anticipated that these reductions in dose to OAR will translate into lower rates of late complications, but long-term follow-up on this Phase II INRT study is needed.

Objectives: Evaluate the dosimetric impact of selective/elective nodal treatment with dose-escalated radiotherapy for regionally advanced non-small-cell lung cancer (NSCLC) using proton therapy (PT) or intensity-modulated radiotherapy (IMRT). Methods: Five consecutive patients with regionally advanced NSCLC underwent treatment planning for high-dose involved-field (IF) treatment (positron emission tomography-positive gross disease) with or without selective/elective nodal irradiation, defined as the extended field (EF). Four treatment plans were developed for each patient: i) IMRT to treat IF to 74 Gy (IFrT); ii) IMRT to treat high-risk nodes to 44 Gy and IF to 74 Gy (EFrT); iii) PT to treat IF to 74CGE (IFpT); and iv) PT to treat high-risk nodes to 44CGE and IF to 74CGE (EFpT). High-risk nodes were defined as mediastinal, hilar, and supraclavicular lymph node stations adjacent to foci of PET-positive gross disease. The IMRT and PT plans were isoeffective. Dose to organs at risk (OARs), including the lung, esophagus, heart and spinal cord, were evaluated. Results: The average IF clinical target volume (CTV) was 397 cc (344–428), while the average EF CTV was 642 cc (530–753 cc). Comparing IMRT with PT, mean lung dose reduced 3.4 Gy/CGE and 3.7 Gy/CGE; lung V20 reduced 4% and 5% for EF and IF, respectively. Conclusions: Selective/elective nodal irradiation with protons reduces normal-lung exposure compared to selective/elective nodal irradiation with IMRT.

Purpose To compare the efficacy and toxicity of external-beam radiotherapy (EBRT) to sites of bulky lymphadenopathy in patients with chemotherapy-refractory low-grade non-Hodgkin's lymphoma (NHL) immediately before receiving Bexxar (tositumomab and 131 I) vs. in patients receiving Bexxar alone for nonbulky disease. Methods and Materials Nineteen patients with chemotherapy-refractory NHL were treated with Bexxar at our institution (University of Florida, Gainesville, FL) from 2005 to 2008. Seventeen patients had Grade 1–2 follicular lymphoma. Ten patients received a median of 20 Gy in 10 fractions to the areas of clinical involvement, immediately followed by Bexxar (EBRT + Bexxar); 9 patients received Bexxar alone. The median tumor sizes before EBRT + Bexxar and Bexxar alone were 4.8 cm and 3.3 cm, respectively. All 5 patients with a tumor diameter >5 cm were treated with EBRT + Bexxar. A univariate analysis of prognostic factors for progression-free survival (PFS) was performed. Results The median follow-up was 2.3 years for all patients and 3.1 years for 12 patients alive at last follow-up. Of all patients, 79% had a partial or complete response; 4 of the 8 responders in the EBRT + Bexxar group achieved a durable response of over 2 years, including 3 of the 5 with tumors >5 cm. Three of 9 patients treated with Bexxar alone achieved a durable response over 2 years. Actuarial estimates of 3-year overall survival and PFS for EBRT + Bexxar and Bexxar alone were 69% and 38% and 62% and 33%, respectively. The median time to recurrence after EBRT + Bexxar and Bexxar alone was 9 months. Having fewer than 4 involved lymph-node regions was associated with superior PFS at 3 years (63% vs. 18%). There was no Grade 4 or 5 complications. Conclusions Adding EBRT immediately before Bexxar produced PFS equivalent to that with Bexxar alone, despite bulkier disease. Hematologic toxicity was not worsened. EBRT combined with Bexxar adds a safe and effective therapeutic treatment for managing recurrent low-grade follicular NHL.

Erectile dysfunction (ED) is a critical health-related quality of life (HRQoL) outcome in men treated for prostate cancer and has been associated with depression and significant distress.1, 2 Many effective treatment options are available to men with prostate cancer, including surgery, external-beam radiotherapy (EBRT), and brachytherapy, and some men select treatment based on perceived side effect profiles, frequently focusing on urinary incontinence and ED. Several studies have investigated and compared HRQoL factors following various treatments for prostate cancer.3-6 These studies have consistently found a more significant decline in ED following surgery than after EBRT. The median age of patients receiving surgery is typically significantly lower than that of patients who receive EBRT; in addition, the EBRT population also includes less healthy men who are not candidates for surgery.3, 6 Thus, reported ED outcomes following EBRT are generally based on an older, less healthy cohort with lower baseline sexual function and may not reflect outcomes attainable with EBRT in a younger, healthier population of patients with prostate cancer. Proton therapy (PT) is a highly conformal radiotherapy modality that delivers much less radiation dose to nontargeted normal tissues, such as the bladder and rectum, than conventional radiation therapy. Moreover, comparative dosimetry studies have documented lower doses to nontargeted tissues with PT compared with intensity-modulated radiotherapy,7 providing a rationale for the very low rates of genitourinary and rectal toxicity that have been observed in clinical studies8 and the expectation of a lower rate of second malignancy in younger men with prostate cancer.8-10 Although patient-reported ED and urinary incontinence following PT have been studied,11, 12 none have investigated outcomes using the more commonly used Expanded Prostate Cancer Index Composite (EPIC) questionnaire, which can easily be compared with outcomes after other prostate cancer treatments. Furthermore, no study has evaluated ED in a cohort of young men treated with EBRT, where interactions from medical comorbidities are less likely to influence ED outcomes and for whom baseline sexual function would be similar to “typical” surgical patients. This study investigates patient-reported HRQoL outcomes (with an emphasis on sexual outcomes) through use of the EPIC questionnaire in a young cohort of patients (≤60 years old) who received definitive treatment with PT alone.

Purpose To report early outcomes with image-guided proton therapy for prostate cancer. Methods and Materials We accrued 211 prostate cancer patients on prospective Institutional Review Board-approved trials of 78 cobalt gray equivalent (CGE) in 39 fractions for low–risk disease, dose escalation from 78 to 82 CGE for intermediate-risk disease, and 78 CGE with concomitant docetaxel followed by androgen deprivation for high-risk disease. Minimum follow-up was 2 years. Results One intermediate-risk patient and 2 high-risk patients had disease progression. Pretreatment genitourinary (GU) symptom management was required in 38% of patients. A cumulative 88 (42%) patients required posttreatment GU symptom management. Four transient Grade 3 GU toxicities occurred, all among patients requiring pretreatment GU symptom management. Multivariate analysis showed correlation between posttreatment GU 2+ symptoms and pretreatment GU symptom management (p (p = 0.0048). Only 1 Grade 3+ gastrointestinal (GI) symptom occurred. The prevalence of Grade 2+ GI symptoms was 0 (0%), 10 (5%), 12 (6%), and 8 (4%) at 6, 12, 18, and 24 months, with a cumulative incidence of 20 (10%) patients at 2 years after proton therapy. Univariate and multivariate analyses showed significant correlation between Grade 2+ rectal bleeding and proctitis and the percentage of rectal wall (rectum) receiving doses ranging from 40 CGE (10 CGE) to 80 CGE. Conclusions Early outcomes with image-guided proton therapy suggest high efficacy and minimal toxicity with only 1.9% Grade 3 GU symptoms and

Purpose Stereotactic body radiotherapy (SBRT) has gained popularity in the treatment of early-stage non-small-cell lung cancer (NSCLC) because of its ability to deliver conformal radiation doses to small targets. However, photon-based SBRT (xSBRT) is associated with significant grade 3+ toxicities. In this study, we compare xSBRT treatment plans with proton-based SBRT (pSBRT) to determine whether dose to normal structures could be reduced if SBRT was delivered with protons. Materials and methods Eight patients with medically inoperable, peripherally located stage I NSCLC were treated with xSBRT to 48Gy in 4 12-Gy fractions. These patients were retrospectively re-planned using the same treatment volumes with 3-dimensional conformal double-scatter proton therapy. A Wilcoxon paired test compared dosimetric parameters between the plans for each patient. Results Compared with xSBRT there was a dosimetric improvement with pSBRT for these volumes: lung V5 (median difference [MD]=10.4%, p =0.01); V10 (MD=6.4%, p =0.01); V20 (MD=2.1%, p =0.01); V40 (MD=1.5%, p =0.05); and mean lung dose (MD=2.17Gy, p =0.01). There were also benefits ( p = Conclusions In a dosimetric comparison between photon and proton-based SBRT, protons resulted in lower doses to critical organs at risk and a smaller volume of non-targeted normal lung exposed to radiation (V5, V10, V20, and V40). The clinical significance and relevance of these dosimetric improvements remain unknown.

Purpose We examined the rate of acute skin toxicity within a prospectively managed database of patients treated for early-stage non–small-cell lung cancer (NSCLC) and investigated factors that might predict skin toxicity. Methods From May 2006 through January 2008, 50 patients with Stage I NSCLC were treated at Memorial Sloan-Kettering Cancer Center with 60 Gy in three fractions or 44–48 Gy in four fractions. Patients were treated with multiple coplanar beams (3–7, median 4) with a 6 MV linac using intensity-modulated radiotherapy (IMRT) and dynamic multileaf collimation. Toxicity grading was performed and based on the National Cancer Institute Common Terminology Criteria for Adverse Effects. Factors associated with Grade 2 or higher acute skin reactions were calculated by Fisher's exact test. Results After a minimum 3 months of follow-up, 19 patients (38%) developed Grade 1, 4 patients (8%) Grade 2, 2 patients (4%) Grade 3, and 1 patient Grade 4 acute skin toxicity. Factors associated with Grade 2 or higher acute skin toxicity included using only 3 beams (p = 0.0007), distance from the tumor to the posterior chest wall skin of less than 5 cm (p = 0.006), and a maximum skin dose of 50% or higher of the prescribed dose (p = 0.02). Conclusions SBRT can be associated with significant skin toxicity. One must consider the skin dose when evaluating the treatment plan and consider the bolus effect of immobilization devices.

Purpose To analyze the recent experience of patients with adenoid cystic carcinoma treated with radiation therapy at Memorial Sloan-Kettering Cancer Center. Methods and Materials From 1990 to 2004, a total of 59 patients with a diagnosis of primary adenoid cystic carcinoma of the head and neck received radiation therapy at our institution. The subsite distribution was oral cavity, 28% ( n = 17); paranasal sinuses, 22% ( n = 13); parotid, 14% ( n = 8); submandibular, 14% ( n = 8); oropharynx, 10% ( n = 6); sublingual, 3% ( n = 2); nasopharynx, 3% ( n = 2); and other, 5% ( n = 3). T Stage distribution was T1, 34% ( n = 20); T2, 19% ( n = 11); T3, 14% ( n = 8); and T4, 34% ( n = 20). Twenty-nine percent of patients ( n = 17) were treated with intensity-modulated radiation therapy; 25% ( n =15), with three-dimensional conformal therapy, and the remainder, with conventional techniques. Ninety percent ( n = 53) of patients received treatment including the base of skull. Results Median follow-up for surviving patients was 5.9 years. Five-year and 10-year rates of local control and distant metastases–free survival were 91%/81% and 81%/49%, respectively. Five-year and 10-year rates of disease-free and overall survival were 76%/40% and 87%/65%, respectively. On univariate analysis, stage T4 ( p = 0.004) and gross/clinical nerve involvement ( p = 0.002) were associated with decreased progression free survival, whereas stage T4 and lymph node involvement were associated with decreased overall survival ( p = 0.046 and p Conclusions Radiation therapy in combination with surgery produces excellent rates of local control, although distant metastases account for a high proportion of failures. Routine treatment to the base of skull reduces the significance of histologic perineural invasion, but major nerve involvement remains an adverse prognostic factor.

Our aim was to review Memorial Sloan-Kettering Cancer Center's experience with postoperative intensity-modulated radiotherapy (IMRT) for paranasal sinus, nasal cavity, and lacrimal gland cancer and report dosimetric measures, toxicity, and outcomes.Between September 2000 and June 2006, 37 patients with paranasal sinus, nasal cavity, or lacrimal gland cancer underwent postoperative IMRT. Median values were as follows: prescription dose, 60 Gy (range, 50-70); PTV(D95), 99% (range, 79-101%); optic nerve Dmax, 53 Gy (range, 2-54); optic chiasm Dmax, 51Gy (range, 2-55). Acute and late toxicities were scored by Radiation Therapy Oncology Group morbidity criteria.Median follow-up was 28 months. Two-year local progression-free and overall survivals were 75% and 80%. No early- or late-grade 3/4 radiation-induced ophthalmologic toxicity occurred.Preliminary results show that adjuvant IMRT in these patients is feasible, allowed for excellent planning target volume (PTV) coverage, and minimized dose delivered to optic structures. Longer follow-up is warranted to assess the extent of late effects and outcomes.

The management of diffuse large B-cell lymphoma depends on the initial diagnosis including molecular and immunophenotypic characteristics, Ann Arbor staging, and International Prognostic Index (IPI score). Treatment approaches with different chemotherapy regimens used is discussed in detail. The role of radiation as a consolidation is discussed including: (1) the prerituximab randomized trials that challenged the role of radiation, (2) recent prospective studies (UNFOLDER/RICOVER-60), and (3) retrospective studies; the last 2 showed a potential benefit of radiation both for early and advanced stage. The document also discusses the role of positron emission tomography/computed tomography for predicting outcome and potentially guiding therapy. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 3 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.

Radiation dose escalation has been shown to improve local control and survival in patients with non-small cell lung cancer in some studies, but randomized data have not supported this premise, possibly owing to adverse effects. Because of the physical characteristics of the Bragg peak, proton therapy (PT) delivers minimal exit dose distal to the target volume, resulting in better sparing of normal tissues in comparison to photon-based radiation therapy. This is particularly important for lung cancer given the proximity of the lung, heart, esophagus, major airways, large blood vessels, and spinal cord. However, PT is associated with more uncertainty because of the finite range of the proton beam and motion for thoracic cancers. PT is more costly than traditional photon therapy but may reduce side effects and toxicity-related hospitalization, which has its own associated cost. The cost of PT is decreasing over time because of reduced prices for the building, machine, maintenance, and overhead, as well as newer, shorter treatment programs. PT is improving rapidly as more research is performed particularly with the implementation of 4-dimensional computed tomography-based motion management and intensity modulated PT. Given these controversies, there is much debate in the oncology community about which patients with lung cancer benefit significantly from PT. The Particle Therapy Co-operative Group (PTCOG) Thoracic Subcommittee task group intends to address the issues of PT indications, advantages and limitations, cost-effectiveness, technology improvement, clinical trials, and future research directions. This consensus report can be used to guide clinical practice and indications for PT, insurance approval, and clinical or translational research directions.