Oren Cahlon

Long-Term Results of Conformal Radiotherapy for Prostate Cancer: Impact of Dose Escalation on Biochemical Tumor Control and Distant Metastases-Free Survival Outcomes

PURPOSE To report prostate-specific antigen (PSA) relapse-free survival and distant metastases-free survival (DMFS) outcomes for patients with clinically localized prostate cancer treated with high-dose conformal radiotherapy. METHODS AND MATERIALS Between 1988 and 2004, a total of 2,047 patients with clinically localized prostate cancer were treated with three-dimensional conformal radiotherapy or intensity-modulated radiotherapy. Prescribed dose levels ranged from 66-86.4 Gy. Median follow-up was 6.6 years (range, 3-18 years). RESULTS Although no differences were noted among low-risk patients for the various dose groups, significant improvements were observed with higher doses for patients with intermediate- and high-risk features. In patients with intermediate-risk features, multivariate analysis showed that radiation dose was an important predictor for improved PSA relapse-free survival (p < 0.0001) and improved DMFS (p = 0.04). In patients with high-risk features, multivariate analysis showed that the following variables predict for improved PSA relapse-free survival: dose (p < 0.0001); age (p = 0.0005), and neoadjuvant-concurrent androgen deprivation therapy (ADT; p = 0.01). In this risk group, only higher radiation dose was an important predictor for improved DMFS (p = 0.04). CONCLUSIONS High radiation dose levels were associated with improved biochemical tumor control and decreased risk of distant metastases. For high-risk patients, despite the delivery of high radiation dose levels, the use of ADT conferred an additional benefit for improved tumor control outcomes. We observed a benefit for ADT in high-risk patients who received higher doses.

Ultra-High Dose (86.4 Gy) IMRT for Localized Prostate Cancer: Toxicity and Biochemical Outcomes

PURPOSE To report toxicity and preliminary biochemical outcomes with high-dose intensity-modulated radiation therapy (IMRT) to a dose of 86.4 Gy for localized prostate cancer. METHODS AND MATERIALS Between August 1997 and March 2004, 478 patients were treated with 86.4 Gy using a 5- to 7-field IMRT technique. To adhere to normal tissue constraints, the mean D95 and V100 for the planning target volume were 83 Gy and 87%, respectively. Toxicity data were scored according to the Common Terminology Criteria for Adverse Events Version 3.0. Freedom from biochemical relapse was calculated. The median follow-up was 53 months. RESULTS Thirty-seven patients (8%) experienced acute Grade 2 gastrointestinal (GI) toxicity. There was no acute Grade 3 or 4 GI toxicity. One hundred and five patients (22%) experienced acute Grade 2 genitourinary (GU) toxicity and three patients (0.6%) had Grade 3 GU toxicity. There was no acute Grade 4 GU toxicity. Sixteen patients (3%) developed late Grade 2 GI toxicity and two patients (<1%) developed late Grade 3 GI toxicity. Sixty patients (13%) had late Grade 2 GU toxicity and 12 (<3%) experienced late Grade 3 GU toxicity. The 5-year actuarial PSA relapse-free survival according to the nadir plus 2 ng/mL definition was 98%, 85% and 70% for the low, intermediate, and high risk NCCN prognostic groups. CONCLUSION This report represents the largest data set of patients treated to ultra-high radiation dose levels of 86.4 Gy using IMRT for localized prostate cancer. Our findings indicate that this treatment is well tolerated and the early excellent biochemical control rates are encouraging.

Comparison of PSA Relapse Free Survival in Patients Treated with Ultra-high Dose IMRT versus Combination HDR Brachytherapy and IMRT

PURPOSE We report on a retrospective comparison of biochemical outcomes using an ultra-high dose of conventionally fractionated intensity-modulated radiation therapy (IMRT) vs. a lower dose of IMRT combined with high-dose-rate (HDR) brachytherapy to increase the biologically effective dose of IMRT. METHODS Patients received IMRT of 86.4Gy (n=470) or HDR brachytherapy (21Gy in three fractions) followed by IMRT of 50.4Gy (n=160). Prostate-specific antigen (PSA) relapse was defined as PSA nadir+2. Median followup was 53 months for IMRT alone and 47 months for HDR. RESULTS The 5-year actuarial PSA relapse-free survival (PRFS) for HDR plus IMRT vs. ultra-high-dose IMRT were 100% vs. 98%, 98% vs. 84%, and 93% vs. 71%, for National Comprehensive Cancer Network low- (p=0.71), intermediate- (p<0.001), and high-risk (p=0.23) groups, respectively. Treatment (p=0.0006), T stage (p<0.0001), Gleason score (p<0.0001), pretreatment PSA (p=0.0037), risk group (p<0.0001), and lack of androgen-deprivation therapy (p=0.0005) were significantly associated with improved PRFS on univariate analysis. HDR plus IMRT vs. ultra-high-dose IMRT (p=0.0012, hazard ratio [HR]=0.184); age (p=0.0222, HR=0.965); and risk group (p<0.0001, HR=2.683) were associated with improved PRFS on multivariate analysis. CONCLUSION Dose escalation of IMRT by adding HDR brachytherapy provided improved PRFS in the treatment of prostate cancer compared with ultra-high-dose IMRT, independent of risk group on multivariate analysis, with the most significant benefit for intermediate-risk patients.

A postoperative nomogram for local recurrence risk in extremity soft tissue sarcomas after limb-sparing surgery without adjuvant radiation.

Purpose: To develop a nomogram based on clinicopathologic factors to quantify the risk of local recurrence (LR) after limb-sparing surgery without adjuvant radiation (RT). Methods: Review of our prospective sarcoma database identified 684 patients with primary, nonmetastatic, extremity STS treated with limb-sparing surgery alone between June 1982 and December 2006. No patient received adjuvant radiation or chemotherapy. Age, sex, grade, depth, size, site, margin status and histology were analyzed for prognostic significance with respect to local recurrence rates using Grays test. Variables which were significant in univariate analysis at the 0.05 level were entered into a multivariate competing risk regression model. On the basis of the multivariate analysis, a nomogram for predicting the 3- and 5-year risk of LR was developed using R libraries cmprsk and QHScrnomo. Concordance index (C-index) was calculated to evaluate the discriminatory power of the prognostic model. Results: With a median follow-up of 58 months for censored patients (73 months for all patients), the overall 3- and 5-year actuarial local recurrence rates were 11% and 13%, respectively. Factors included in the nomogram were age (⩽50 vs. >50), size (⩽5 vs. >5 cm), margin status (negative vs. positive), grade (low vs. high), and histology (atypical lipomatous tumor/well differentiated liposarcoma vs. other). The STS nomogram predicted the local recurrence rate with a C-index of 0.73. Conclusions: A nomogram for extremity STS that includes age, size, margin status, grade of tumor, and histology predicts the 3- and 5-year risk of local recurrence after limb-sparing surgery in the absence of adjuvant RT.

Proton beam radiation therapy results in significantly reduced toxicity compared with intensity-modulated radiation therapy for head and neck tumors that require ipsilateral radiation

BACKGROUND As proton beam radiation therapy (PBRT) may allow greater normal tissue sparing when compared with intensity-modulated radiation therapy (IMRT), we compared the dosimetry and treatment-related toxicities between patients treated to the ipsilateral head and neck with either PBRT or IMRT. METHODS Between 01/2011 and 03/2014, 41 consecutive patients underwent ipsilateral irradiation for major salivary gland cancer or cutaneous squamous cell carcinoma. The availability of PBRT, during this period, resulted in an immediate shift in practice from IMRT to PBRT, without any change in target delineation. Acute toxicities were assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. RESULTS Twenty-three (56.1%) patients were treated with IMRT and 18 (43.9%) with PBRT. The groups were balanced in terms of baseline, treatment, and target volume characteristics. IMRT plans had a greater median maximum brainstem (29.7 Gy vs. 0.62 Gy (RBE), ​P < 0.001), maximum spinal cord (36.3 Gy vs. 1.88 Gy (RBE), ​P < 0.001), mean oral cavity (20.6 Gy vs. 0.94 Gy (RBE), ​P < 0.001), mean contralateral parotid (1.4 Gy vs. 0.0 Gy (RBE), P<0.001), and mean contralateral submandibular (4.1 Gy vs. 0.0 Gy (RBE), ​P < 0.001) dose when compared to PBRT plans. PBRT had significantly lower rates of grade 2 or greater acute dysgeusia (5.6% vs. 65.2%, P<0.001), mucositis (16.7% vs. 52.2%, P=0.019), and nausea (11.1% vs. 56.5%, P=0.003). CONCLUSIONS The unique properties of PBRT allow greater normal tissue sparing without sacrificing target coverage when irradiating the ipsilateral head and neck. This dosimetric advantage seemingly translates into lower rates of acute treatment-related toxicity.

Long‐term outcomes in extremity soft tissue sarcoma after a pathologically negative re‐resection and without radiotherapy

The purpose was to define the rate of local recurrence (LR) and identify prognostic factors for LR in patients with extremity soft‐tissue sarcoma (STS) treated with limb‐sparing surgery and a pathologically negative re‐resection specimen without radiotherapy (RT).

Proton Beam Reirradiation for Recurrent Head and Neck Cancer: Multi-institutional Report on Feasibility and Early Outcomes

PURPOSE Reirradiation therapy (re-RT) is the only potentially curative treatment option for patients with locally recurrent head and neck cancer (HNC). Given the significant morbidity with head and neck re-RT, interest in proton beam radiation therapy (PBRT) has increased. We report the first multi-institutional clinical experience using curative-intent PBRT for re-RT in recurrent HNC. METHODS AND MATERIALS A retrospective analysis of ongoing prospective data registries from 2 hybrid community practice and academic proton centers was conducted. Patients with recurrent HNC who underwent at least 1 prior course of definitive-intent external beam radiation therapy (RT) were included. Acute and late toxicities were assessed with the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 and the Radiation Therapy Oncology Group late radiation morbidity scoring system, respectively. The cumulative incidence of locoregional failure was calculated with death as a competing risk. The actuarial 12-month freedom-from-distant metastasis and overall survival rates were calculated with the Kaplan-Meier method. RESULTS Ninety-two consecutive patients were treated with curative-intent re-RT with PBRT between 2011 and 2014. Median follow-up among surviving patients was 13.3 months and among all patients was 10.4 months. The median time between last RT and PBRT was 34.4 months. There were 76 patients with 1 prior RT course and 16 with 2 or more courses. The median PBRT dose was 60.6 Gy (relative biological effectiveness, [RBE]). Eighty-five percent of patients underwent prior HNC RT for an oropharynx primary, and 39% underwent salvage surgery before re-RT. The cumulative incidence of locoregional failure at 12 months, with death as a competing risk, was 25.1%. The actuarial 12-month freedom-from-distant metastasis and overall survival rates were 84.0% and 65.2%, respectively. Acute toxicities of grade 3 or greater included mucositis (9.9%), dysphagia (9.1%), esophagitis (9.1%), and dermatitis (3.3%). There was 1 death during PBRT due to disease progression. Grade 3 or greater late skin and dysphagia toxicities were noted in 6 patients (8.7%) and 4 patients (7.1%), respectively. Two patients had grade 5 toxicity due to treatment-related bleeding. CONCLUSIONS Proton beam re-RT of the head and neck can provide effective tumor control with acceptable acute and late toxicity profiles likely because of the decreased dose to the surrounding normal, albeit previously irradiated, tissue, although longer follow-up is needed to confirm these findings.

Early toxicity in patients treated with postoperative proton therapy for locally advanced breast cancer.

PURPOSE To report dosimetry and early toxicity data in breast cancer patients treated with postoperative proton radiation therapy. METHODS AND MATERIALS From March 2013 to April 2014, 30 patients with nonmetastatic breast cancer and no history of prior radiation were treated with proton therapy at a single proton center. Patient characteristics and dosimetry were obtained through chart review. Patients were seen weekly while on treatment, at 1 month after radiation therapy completion, and at 3- to 6-month intervals thereafter. Toxicity was scored using Common Terminology Criteria for Adverse Events version 4.0. Frequencies of toxicities were tabulated. RESULTS Median dose delivered was 50.4 Gy (relative biological equivalent [RBE]) in 5 weeks. Target volumes included the breast/chest wall and regional lymph nodes including the internal mammary lymph nodes (in 93%). No patients required a treatment break. Among patients with >3 months of follow-up (n=28), grade 2 dermatitis occurred in 20 patients (71.4%), with 8 (28.6%) experiencing moist desquamation. Grade 2 esophagitis occurred in 8 patients (28.6%). Grade 3 reconstructive complications occurred in 1 patient. The median planning target volume V95 was 96.43% (range, 79.39%-99.60%). The median mean heart dose was 0.88 Gy (RBE) [range, 0.01-3.20 Gy (RBE)] for all patients, and 1.00 Gy (RBE) among patients with left-sided tumors. The median V20 of the ipsilateral lung was 16.50% (range, 6.1%-30.3%). The median contralateral lung V5 was 0.34% (range, 0%-5.30%). The median maximal point dose to the esophagus was 45.65 Gy (RBE) [range, 0-65.4 Gy (RBE)]. The median contralateral breast mean dose was 0.29 Gy (RBE) [range, 0.03-3.50 Gy (RBE)]. CONCLUSIONS Postoperative proton therapy is well tolerated, with acceptable rates of skin toxicity. Proton therapy favorably spares normal tissue without compromising target coverage. Further follow-up is necessary to assess for clinical outcomes and cardiopulmonary toxicities.

Pediatric Proton Therapy: Patterns of Care across the United States

Abstract Purpose: Children are particularly prone to the late side effects of normal tissue irradiation. For this reason, pediatric solid tumors are a commonly cited indication for proton therapy worldwide. The aim of this survey was to assess pediatric patterns of care across proton centers in the United States. Patients and Methods: A survey was developed and distributed annually to each clinical proton therapy facility in the United States in operation during the years of 2010, 2011, and 2012. Anonymized patient information including age range, tumor site, and diagnosis were collected annually for each patient 18 years old or younger treated between January 1, 2010 and December 31, 2012. Results: There was a 100% response rate from the United States proton therapy centers in operation for each year surveyed. All facilities treated at least 1 pediatric patient each year. A total of 694 pediatric patients were treated in 2012, an increase from 613 patients in 2011 and 465 patients in 2010. Fifty-seven pe...

Exponential Increase in Relative Biological Effectiveness Along Distal Edge of a Proton Bragg Peak as Measured by Deoxyribonucleic Acid Double-Strand Breaks

PURPOSE To quantify the relative biological effectiveness (RBE) of the distal edge of the proton Bragg peak, using an in vitro assay of DNA double-strand breaks (DSBs). METHODS AND MATERIALS U2OS cells were irradiated within the plateau of a spread-out Bragg peak and at each millimeter position along the distal edge using a custom slide holder, allowing for simultaneous measurement of physical dose. A reference radiation signal was generated using photons. The DNA DSBs at 3 hours (to assess for early damage) and at 24 hours (to assess for residual damage and repair) after irradiation were measured using the γH2AX assay and quantified via flow cytometry. Results were confirmed with clonogenic survival assays. A detailed map of the RBE as a function of depth along the Bragg peak was generated using γH2AX measurements as a biological endpoint. RESULTS At 3 hours after irradiation, DNA DSBs were higher with protons at every point along the distal edge compared with samples irradiated with photons to similar doses. This effect was even more pronounced after 24 hours, indicating that the impact of DNA repair is less after proton irradiation relative to photons. The RBE demonstrated an exponential increase as a function of depth and was measured to be as high as 4.0 after 3 hours and as high as 6.0 after 24 hours. When the RBE-corrected dose was plotted as a function of depth, the peak effective dose was extended 2-3 mm beyond what would be expected with physical measurement. CONCLUSIONS We generated a highly comprehensive map of the RBE of the distal edge of the Bragg peak, using a direct assay of DNA DSBs in vitro. Our data show that the RBE of the distal edge increases with depth and is significantly higher than previously reported estimates.