Randomized Trial of Hypofractionated, Dose-Escalated, Intensity-Modulated Radiation Therapy (IMRT) Versus Conventionally Fractionated IMRT for Localized Prostate Cancer.

PURPOSE: Hypofractionated radiotherapy delivers larger daily doses of radiation and may increase the biologically effective dose delivered to the prostate. We conducted a randomized trial testing the hypothesis that dose-escalated, moderately hypofractionated intensity-modulated radiation therapy (HIMRT) improves prostate cancer control compared with conventionally fractionated IMRT (CIMRT) for men with localized prostate cancer. PATIENTS AND METHODS: Men were randomly assigned to 75.6 Gy in 1.8-Gy fractions delivered over 8.4 weeks (CIMRT) or 72 Gy in 2.4 Gy fractions delivered over 6 weeks (HIMRT, biologically equivalent to 85 Gy in 1.8-Gy fractions assuming prostate cancer α-to-ß ratio of 1.5). Failure was defined as prostate-specific antigen (PSA) failure (nadir plus 2 ng/mL) or initiation of salvage therapy. Modified Radiation Therapy Oncology Group criteria were used to grade late (≥ 90 days after completion of radiotherapy) GI and genitourinary toxicity. RESULTS: Most of the 206 men (72%) had cT1, Gleason score 6 or 7 (99%), and PSA level ≤ 10 ng/mL (90%) disease. Androgen deprivation therapy was received by 24%. With a median follow-up of 8.5 years, men treated with HIMRT experienced fewer treatment failures (n = 10) than men treated with CIMRT (n = 21; P = .036). The 8-year failure rate was 10.7% (95% CI, 5.8% to 19.1%) with HIMRT and 15.4% (95% CI, 9.1% to 25.4%) with CIMRT. There was no difference in overall survival ( P = .39). There was a nonsignificant increase in late grade 2 or 3 GI toxicity with HIMRT (8-year 5.0% v 12.6%; P = .08). However, GI toxicity was only 8.6% when rectal volume receiving 65 Gy of HIMRT was ≤ 15%. Late genitourinary toxicity was similar ( P = .84). There was no grade 4 toxicity. CONCLUSION: The results of this randomized trial demonstrate superior cancer control for men with localized prostate cancer who receive dose-escalated moderately hypofractionation radiotherapy while shortening treatment duration.

Prognostic Factors as a Function of Disease-free Interval After Definitive (Chemo)radiation for Non-Small Cell Lung Cancer Using Conditional Survival Analysis.

PURPOSE: We analyzed overall and disease-free survival (OS and DFS) after definitive (chemo)radiation for stage III non-small cell lung cancer with 2 statistical methods: Kaplan-Meier (KM) analysis, with diagnosis as index date, and conditional survival (CS) analysis, with a variety of disease-free index dates, and determined whether prognostic factors varied based on the reference date. MATERIALS AND METHODS: All 651 patients analyzed received definitive (chemo)radiotherapy for stage III non-small cell lung cancer in November 1998 to December 2010 at a single institution; all had Karnofsky performance status scores ≥60 and received ≥60 Gy. OS and DFS were first calculated with the KM method, and then CS was used to calculate 2 outcomes: OS conditioned on DFS time (OS|DFS) and DFS conditioned on DFS time (DFS|DFS). Factors predicting OS and DFS conditioned on 1-, 2-, and 3-year DFS were sought in univariate and multivariate analyses. RESULTS: KM analysis produced 1-, 2-, and 3-year DFS rates of 48%, 30%, and 26%; OS rates were 64%, 41%, and 29%. By CS analysis, both OS|DFS and DFS|DFS showed an increase in 5-year OS after 6 months, and CS after 30 months approached 100%. On multivariate analyses, age and concurrent chemoradiation predicted OS|DFS; age, smoking history, tumor histology, disease stage, and radiation dose predicted DFS|DFS. CONCLUSIONS: CS analysis showed that the probability of long-term survival increases sharply after 6 months with no evidence of disease; factors predicting survival differed based on the method and endpoint used.

Patient-reported Urinary, Bowel, and Sexual Function After Hypofractionated Intensity-modulated Radiation Therapy for Prostate Cancer: Results From a Randomized Trial.

OBJECTIVES: Hypofractionated prostate radiotherapy may increase biologically effective dose delivered while shortening treatment duration, but information on patient-reported urinary, bowel, and sexual function after dose-escalated hypofractionated radiotherapy is limited. We report patient-reported outcomes (PROs) from a randomized trial comparing hypofractionated and conventional prostate radiotherapy. METHODS: Men with localized prostate cancer were enrolled in a trial that randomized men to either conventionally fractionated intensity-modulated radiation therapy (CIMRT, 75.6 Gy in 1.8 Gy fractions) or to dose-escalated hypofractionated IMRT (HIMRT, 72 Gy in 2.4 Gy fractions). Questionnaires assessing urinary, bowel, and sexual function were completed pretreatment and at 2, 3, 4, and 5 years after treatment. RESULTS: Of 203 eligible patients, 185 were evaluable for PROs. A total of 173 completed the pretreatment questionnaire (82 CIMRT, 91 HIMRT) and 102 completed the 2-year questionnaire (46 CIMRT, 56 HIMRT). Patients who completed PROs were similar to those who did not complete PROs (all P>0.05). Patient characteristics, clinical characteristics, and baseline symptoms were well balanced between the treatment arms (all P>0.05). There was no difference in patient-reported bowel (urgency, control, frequency, or blood per rectum), urinary (dysuria, hematuria, nocturia, leakage), or sexual symptoms (erections firm enough for intercourse) between treatment arms at 2, 3, 4, and 5 years after treatment (all P>0.01). Concordance between physician-assessed toxicity and PROs varied across urinary and bowel domains. DISCUSSION: We did not detect an increase in patient-reported urinary, bowel, and sexual symptom burden after dose-escalated intensity-modulated prostate radiation therapy using a moderate hypofractionation regimen (72 Gy in 2.4 Gy fractions) compared with conventionally fractionated radiation.

Sparing of normal tissues with volumetric arc radiation therapy for glioblastoma: single institution clinical experience.

BACKGROUND: Patients with glioblastoma multiforme (GBM) require radiotherapy as part of definitive management. Our institution has adopted the use of volumetric arc therapy (VMAT) due to superior sparing of the adjacent organs at risk (OARs) compared to intensity modulated radiation therapy (IMRT). Here we report our clinical experience by analyzing target coverage and sparing of OARs for 90 clinical treatment plans. METHODS: VMAT and IMRT patient cohorts comprising 45 patients each were included in this study. For all patients, the planning target volume (PTV) received 50 Gy in 30 fractions, and the simultaneous integrated boost PTV received 60 Gy. The characteristics of the two patient cohorts were examined for similarity. The doses to target volumes and OARs, including brain, brainstem, hippocampi, optic nerves, eyes, and cochleae were then compared using statistical analysis. Target coverage and normal tissue sparing for six patients with both clinical IMRT and VMAT plans were analyzed. RESULTS: PTV coverage of at least 95% was achieved for all plans, and the median mean dose to the boost PTV differed by only 0.1 Gy between the IMRT and VMAT plans. Superior sparing of the brainstem was found with VMAT, with a median difference in mean dose being 9.4 Gy. The ipsilateral cochlear mean dose was lower by 19.7 Gy, and the contralateral cochlea was lower by 9.5 Gy. The total treatment time was reduced by 5 min. The difference in the ipsilateral hippocampal D100% was 12 Gy, though this is not statistically significant (P = 0.03). CONCLUSIONS: VMAT for GBM patients can provide similar target coverage, superior sparing of the brainstem and cochleae, and be delivered in a shorter period of time compared with IMRT. The shorter treatment time may improve clinical efficiency and the quality of the treatment experience. Based on institutional clinical experience, use of VMAT for the treatment of GBMs appears to offer no inferiority in comparison to IMRT and may offer distinct advantages, especially for patients who may require re-irradiation.

The Pulmonary Fibrosis Associated MUC5B Promoter Polymorphism Is Prognostic of the Overall Survival in Patients with Non-Small Cell Lung Cancer (NSCLC) Receiving Definitive Radiotherapy.

BACKGROUND: MUC5B is glycoprotein secreted by bronchial glands. A promoter variant in MUC5B, rs35705950, was previously found to be strongly associated with the incidence of idiopathic pulmonary fibrosis (IPF) and also the overall survival (OS) of such patients. Patients with IPF and patients with radiation pneumonitis (RP) have the similar pathologic process and clinical symptoms. However, the role of rs35705950 in patients receiving thoracic radiotherapy remains unclear. PATIENTS AND METHODS: In total, 664 patients with NSCLC receiving definitive radiotherapy (total dose ≥60 Gy) were included in our study. RP was scored via the Common Terminology Criteria for Adverse Events v3.0. OS was the second end point. MUC5B rs35705950 was genotyped, and Kaplan-Meier and Cox regression analyses were used to evaluate associations between MUC5B rs35705950 and the risk of RP or OS. RESULTS: The median patient age was 66 years (range 35-88); most (488 [73.2%]) had stage III of the disease. Until the last follow-up, 250 patients developed grade≥2 RP, 82 patients developed grade≥3 RP, and 440 patients died. The median mean lung dose was 17.9 Gy (range 0.15-32.74). No statistically significant associations were observed between genotypes of MUC5B rs35705950 and the incidence of RP≥grade 2 either in univariate analysis (hazard ratio [HR] 1.009, 95% confidence interval [CI] 0.728-1.399, P=.958) or in multivariate analysis (HR 0.921, 95% CI 0.645-1.315, P=.65). Similar results were also observed for RP≥grade 3, while TT/GT genotypes in MUC5B were significantly associated with poor OS in both univariate analysis (HR 1.287, 95% CI 1.009-1.640, P=.042) and multivariate analysis (HR 1.561, 95% CI 1.193-2.042, P=.001). CONCLUSION: MUC5B promoter polymorphism could be prognostic of the OS among NSCLC patients receiving definitive radiotherapy, although no significant associations were found with the risk of RP.

Factors associated with regional recurrence after lymph node dissection for penile squamous cell carcinoma.

OBJECTIVE: To identify factors associated with regional recurrence after lymph node dissection (LND) for squamous cell carcinoma (SCC) to determine which patients might benefit from adjuvant therapy. PATIENTS AND METHODS: Men who underwent LND for penile SCC from 1977 to 2014 were identified from an institutional database. Kaplan-Meier curves estimated recurrence-free survival (RFS) calculated from the date of LND. Cox regression models evaluated the association between RFS and patient and tumour characteristics. RESULTS: In all, 182 men who underwent LND for penile SCC were identified. The median patient age was 62 years and the median follow-up was 4.2 years. After LND 34 men had regional recurrence, of which 24 developed isolated regional recurrences without distant metastasis. The median RFS was 5.7 months, and the 3-year RFS rate was 70%. On univariate analysis, lymphovascular invasion, clinical and pathological nodal stage, pathological inguinal laterality, pelvic nodal involvement, lymph node density ≥5.2%, ≥3 pathologically involved lymph nodes, and extranodal extension (ENE) were associated with worse RFS (all P < 0.05). On multivariate analysis, clinical N3 disease [adjusted hazard ratio (AHR)] 3.53, 95% confidence interval (CI) 1.68-7.45; P = 0.001), ≥3 pathologically involved lymph nodes (AHR 3.78, 95% CI 2.12-6.65; P < 0.001), and ENE (AHR 3.32, 95% CI 1.93-5.76; P < 0.001) were associated with worse RFS. The 3-year RFS for patients with cN0, cN1, cN2, and cN3 disease was 91.7%, 64.5%, 54.7%, and 38.3%, respectively. For men with ≥3 involved nodes, the 3-year RFS was 17% vs 82.4% in men with <3 involved nodes. The 3-year RFS was 29.7% in men with ENE and 85.7% in men without ENE. CONCLUSION: The presence of clinical N3 disease, ≥3 pathologically involved lymph nodes, and ENE was associated with worse RFS. As regional recurrence portends a dismal prognosis with few salvage options, adjuvant therapies should be developed for men with the aforementioned adverse factors.

The Influence of Age and Comorbidity on the Benefit of Adding Androgen Deprivation to Dose-escalated Radiation in Men With Intermediate-risk Prostate Cancer.

OBJECTIVE: Androgen deprivation therapy (ADT) can improve outcomes for men with intermediate-risk prostate cancer (IR-PrCa) receiving external-beam radiotherapy (EBRT). Older men and men with significant comorbidity may be more susceptible to the harms of ADT, therefore we aimed to determine whether these men benefit from ADT. METHODS: The adult comorbidity evaluation-27 index categorized severity of comorbidity in 636 men treated for IR-PrCa with dose-escalated EBRT (>75 Gy). The cohort was dichotomized at median age of 70. Multivariate Cox proportional hazard analysis evaluated the association of ADT with failure-free survival (FFS) for each age and comorbidity subgroup. RESULTS: A total of 48% of men were 70 years and above. After adjustment for tumor characteristics, the addition of ADT to EBRT was associated with improved FFS for both men below 70 years of age (adjusted hazard ratio [AHR] 0.44; 95% confidence interval [CI], 0.19-0.99; P=0.046) and men 70 years and above (AHR 0.23; 95% CI, 0.06-0.91; P=0.035). ADT improved FFS for men below 70 years who had no or mild comorbidity (AHR 0.25; 95% CI, 0.09-0.73; P=0.011) but not for men below 70 years who had moderate or severe comorbidity (AHR 1.62; 95% CI, 0.35-7.49; P=0.537). Similarly, in men 70 years and above, there was a trend for improved FFS with ADT in healthy men (AHR 0.10; 95% CI, 0.01-1.08; P=0.058) but not in men with moderate to severe comorbidity (AHR 0.38; 95% CI, 0.06-2.56; P=0.318). CONCLUSIONS: The addition of ADT to dose-escalated EBRT can improve outcomes for both younger and older men with IR-PrCa. This benefit was more pronounced in healthy men.

Merkel cell carcinoma of the head and neck: Favorable outcomes with radiotherapy.

BACKGROUND: The purpose of this study was to report the outcomes of patients with Merkel cell carcinoma (MCC) of the head and neck using a radiation-based treatment approach. METHODS: We reviewed records of 106 consecutive patients with MCC of the head and neck treated with radiation therapy (RT) at our institution between 1988 and 2011. The Kaplan-Meier method was used to estimate outcomes and hazard ratios (HRs) were calculated. RESULTS: The 5-year actuarial local and regional control rates were 96% and 96%, respectively. There were no regional recurrences in 22 patients treated with RT to gross nodal disease without neck dissection. The 5-year cause-specific survival rate was 76%. Lymphadenopathy at presentation impacted distant metastatic-free survival outcomes (p < .001). Treatment was well tolerated with only 5 patients having grade ≥3 toxicities. CONCLUSION: For MCC of the head and neck, a management strategy that includes RT offers excellent locoregional control. Gross nodal disease can be successfully treated with RT. © 2015 Wiley Periodicals, Inc. Head Neck 38: E452-E458, 2016.

Survival and toxicity following sequential multimodality treatment including whole abdominopelvic radiotherapy for patients with desmoplastic small round cell tumor.

BACKGROUND AND PURPOSE: Desmoplastic small round cell tumor (DSRCT) is a rare, aggressive malignancy. We report survival rates and toxicity associated with sequential multimodality treatment including whole abdominopelvic radiation therapy (WART). MATERIAL AND METHODS: Medical records of 32 patients with DSRCT treated at our institution were reviewed. Patients underwent chemotherapy, cytoreductive surgery with hyperthermic intraperitoneal chemoperfusion (HIPEC), followed by WART with intensity-modulated radiation or volumetric-modulated arc therapy. RESULTS: Median overall survival (OS) was 60months. After 18months of follow-up, 20 patients (62.5%) had disease recurrence and median disease-free survival (DFS) was 10months. Median time to extrahepatic abdominal failure was 19.4months. Factors affecting time to local progression included liver metastases at diagnosis, and an interval of greater than 5.6months between diagnosis and HIPEC or greater than 2.1months between HIPEC and WART. None of these factors altered OS. Grade 3 or higher toxicities occurred in 84% of patients. CONCLUSIONS: WART following chemotherapy, surgical cytoreduction and HIPEC is an aggressive treatment for DSRCT patients and can result in severe side effects. Our median OS of 5years is favorable compared to prior studies, despite a median DFS of only 10months, which may be due to improved salvage therapies.

Long-term outcomes after proton therapy, with concurrent chemotherapy, for stage II-III inoperable non-small cell lung cancer.

PURPOSE: We report long-term disease control, survival, and toxicity for patients with locally advanced non-small cell lung cancer prospectively treated with concurrent proton therapy and chemotherapy on a nonrandomized case-only observational study. METHODS: All patients received passive-scatter proton therapy, planned with 4D-CT-based simulation; all received proton therapy concurrent with weekly chemotherapy. Endpoints were local and distant control, disease-free survival (DFS), and overall survival (OS). RESULTS: The 134 patients (21 stage II, 113 stage III; median age 69 years) had a median gross tumor volume (GTV) of 70 cm(3) (range, 5-753 cm(3)); 77 patients (57%) received 74 Gy(RBE), and 57 (42%) received 60-72 Gy(RBE) (range, 60-74.1 Gy(RBE)). At a median follow-up time of 4.7 years, median OS times were 40.4 months (stage II) and 30.4 months (stage III). Five-year DFS rates were 17.3% (stage II) and 18.0% (stage III). OS, DFS, and local and distant control rates at 5 years did not differ by disease stage. Age and GTV were related to OS and DFS. Toxicity was tolerable, with 1 grade 4 esophagitis and 16 grade 3 events (2 pneumonitis, 6 esophagitis, 8 dermatitis). CONCLUSION: This report of outcomes after proton therapy for 134 patients indicated that this regimen produced excellent OS with tolerable toxicity.

Mesenchymal stem cells mediate the clinical phenotype of inflammatory breast cancer in a preclinical model.

INTRODUCTION: Inflammatory breast cancer (IBC) is an aggressive type of breast cancer, characterized by very rapid progression, enlargement of the breast, skin edema causing an orange peel appearance (peau d'orange), erythema, thickening, and dermal lymphatic invasion. It is characterized by E-cadherin overexpression in the primary and metastatic disease, but to date no robust molecular features that specifically identify IBC have been reported. Further, models that recapitulate all of these clinical findings are limited and as a result no studies have demonstrated modulation of these clinical features as opposed to simply tumor cell growth. METHODS: Hypothesizing the clinical presentation of IBC may be mediated in part by the microenvironment, we examined the effect of co-injection of IBC xenografts with mesenchymal stem/stromal cells (MSCs). RESULTS: MSCs co-injection significantly increased the clinical features of skin invasion and metastasis in the SUM149 xenograft model. Primary tumors co-injected with MSCs expressed higher phospho-epidermal growth factor receptor (p-EGFR) and promoted metastasis development after tumor resection, effects that were abrogated by treatment with the epidermal growth factor receptor (EGFR) inhibitor, erlotinib. E-cadherin expression was maintained in primary tumor xenografts with MSCs co-injection compared to control and erlotinib treatment dramatically decreased this expression in control and MSCs co-injected tumors. Tumor samples from patients demonstrate correlation between stromal and tumor p-EGFR staining only in IBC tumors. CONCLUSIONS: Our findings demonstrate that the IBC clinical phenotype is promoted by signaling from the microenvironment perhaps in addition to tumor cell drivers.

Use of simultaneous radiation boost achieves high control rates in patients with non-small-cell lung cancer who are not candidates for surgery or conventional chemoradiation.

BACKGROUND: Intensity-modulated radiation therapy (IMRT) with a simultaneous integrated boost (SIB) has improved the local disease control at a variety of anatomic sites. However, little is known about its use in lung cancer, especially in the context of shorter treatment schedules (hypofractionation). We analyzed the feasibility, toxicity, and patterns of failure of this approach for patients with non-small-cell lung cancer (NSCLC) who were not candidates for surgery or standard concurrent chemoradiation therapy. PATIENTS AND METHODS: We retrospectively identified 71 patients with NSCLC who received IMRT+SIB in 15 fractions to ≥ 52.5 Gy from January 2007 to February 2013. Toxicity and local control were evaluated for all patients. RESULTS: Of the 71 patients, 11 (16%) had stage I to II NSCLC, 15 (21%) stage III, and 45 (63%) stage IV. The esophagitis rate was grade 0 to 1 in 55%, grade 2 in 39%, and grade ≥ 3 in 6%. One patient developed a bronchoesophageal fistula 6 months after radiation. The pneumonitis rate was grade 0 to 1 in 93%, grade 2 in 6%, and grade 3 in 1%. At the time of analysis, 17 (24%) patients had local failure at a median of 5.2 months (range, < 1-16.1) after treatment. All but 1 failure occurred within the higher dose region. CONCLUSION: Hypofractionated IMRT+SIB is a viable option for some patients with NSCLC, with little high-grade toxicity overall. Nearly all local failures occurred within the higher dose region, implying strong radioresistance or some other mechanism for recurrence in a subgroup of patients.

Incidental receipt of cardiac medications and survival outcomes among patients with stage III non-small-cell lung cancer after definitive radiotherapy.

BACKGROUND: Preclinical and epidemiologic studies suggest that receipt of some cardiac medications such as angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), ß-blockers, or aspirin may have antiproliferative effects in several types of cancer. The aim of this study was to estimate survival outcomes in patients receiving incidental cardiac medications during treatment for lung cancer, and to compare outcomes with those patients not receiving these medications. PATIENTS AND METHODS: We retrospectively reviewed 673 patients who had received definitive radiotherapy for stage III non-small-cell lung cancer (NSCLC). Cox proportional hazard models were used to assess associations between receipt of ACEIs, ARBs, ß-blockers, or aspirin and locoregional progression-free survival (LRPFS), distant metastasis-free survival (DMFS), disease-free survival (DFS), and overall survival (OS). RESULTS: Multivariate analyses showed that ACEI receipt was associated with poorer LRPFS but had no effect on DMFS, DFS, or OS. Aspirin receipt was associated only with improved DMFS, and ß-blocker receipt was associated with improved DMFS, DFS, and OS. CONCLUSION: Incidental receipt of ACEIs was associated with a higher prevalence of local failure, whereas receipt of either ß-blockers or aspirin had protective effects on survival outcomes in this large group of patients with lung cancer. This finding warrants further clinical and preclinical exploration, as it may have important implications for treating patients with lung cancer who are also receiving cardiac medications.

Serum inflammatory miRNAs predict radiation esophagitis in patients receiving definitive radiochemotherapy for non-small cell lung cancer.

BACKGROUND AND PURPOSE: MicroRNAs (miRNAs) are small, highly conserved non-coding RNAs that regulate many biological processes. We sought to investigate whether three serum miRNAs related to immunity or inflammation were associated with esophagitis induced by chemoradiation therapy (CRT) for non-small cell lung cancer (NSCLC). MATERIAL AND METHODS: We measured serum miR-155, miR-221 and miR-21, before and during week 1-2 of CRT for 101 NSCLC patients by real-time PCR. Associations between miRNA and severe radiation-induced esophageal toxicity (RIET) were analyzed by logistic regression. RESULTS: We found that patients with stage IIIB-IV disease, higher mean esophagus dose or esophageal V50 had higher rates of severe RIET. Furthermore, high levels of miR-155 and miR-221 at week 1-2 of CRT were also risk factors for severe RIET (miR-155: OR=1.53, 95% CI: 1.04-2.25, P=0.03; miR-221: OR=2.07, 95% CI: 1.17-3.64, P=0.012). In addition, the fold change of miR-221 was also predictive of severe RIET (OR=1.18, 95% CI: 1.02-1.37, P=0.026). However, pretreatment miRNAs was not predictive of severe RIET. CONCLUSIONS: High serum miR-155 and miR-221 during the first 2 weeks of CRT were associated with the development of severe RIET, suggesting that these miRNAs may be useful as an early surrogate for this form of toxicity.

Current clinical presentation and treatment of localized prostate cancer in the United States.

PURPOSE: SEER recently released patient Gleason scores at biopsy/transurethral resection of the prostate. For the first time this permits accurate assessment of prostate cancer presentation and treatment according to clinical factors at diagnosis. MATERIALS AND METHODS: We used the SEER database to identify men diagnosed with localized prostate cancer in 2010 who were assigned NCCN(®) risk based on clinical factors. We identified sociodemographic factors associated with high risk disease and analyzed the impact of these factors along with NCCN risk on local treatment. RESULTS: Of the 42,403 men identified disease was high, intermediate and low risk in 38%, 40% and 22%, respectively. On multivariate analysis patients who were older, nonwhite, unmarried or living in a county with a higher poverty rate were more likely to be diagnosed with high risk disease (each p <0.05). Of the 38,634 men in whom prostate cancer was the first malignancy 23% underwent no local treatment, 40% were treated with prostatectomy, 36% received radiation therapy and 1% underwent local tumor destruction, predominantly cryotherapy. On multivariate analysis patients who were older, black, unmarried or living in a county with a higher poverty rate, or who had low risk disease were less likely to receive local treatment (each p <0.05). CONCLUSIONS: Our analysis provides information on the current clinical presentation and treatment of localized prostate cancer in the United States. Nonwhite and older men living in a county with a higher poverty rate were more likely to be diagnosed with high risk disease and less likely to receive local treatment.

Risk of late toxicity in men receiving dose-escalated hypofractionated intensity modulated prostate radiation therapy: results from a randomized trial.

OBJECTIVE: To report late toxicity outcomes from a randomized trial comparing conventional and hypofractionated prostate radiation therapy and to identify dosimetric and clinical parameters associated with late toxicity after hypofractionated treatment. METHODS AND MATERIALS: Men with localized prostate cancer were enrolled in a trial that randomized men to either conventionally fractionated intensity modulated radiation therapy (CIMRT, 75.6 Gy in 1.8-Gy fractions) or to dose-escalated hypofractionated IMRT (HIMRT, 72 Gy in 2.4-Gy fractions). Late (≥90 days after completion of radiation therapy) genitourinary (GU) and gastrointestinal (GI) toxicity were prospectively evaluated and scored according to modified Radiation Therapy Oncology Group criteria. RESULTS: 101 men received CIMRT and 102 men received HIMRT. The median age was 68, and the median follow-up time was 6.0 years. Twenty-eight percent had low-risk, 71% had intermediate-risk, and 1% had high-risk disease. There was no difference in late GU toxicity in men treated with CIMRT and HIMRT. The actuarial 5-year grade ≥2 GU toxicity was 16.5% after CIMRT and 15.8% after HIMRT (P=.97). There was a nonsignificant numeric increase in late GI toxicity in men treated with HIMRT compared with men treated with CIMRT. The actuarial 5-year grade ≥2 GI toxicity was 5.1% after CIMRT and 10.0% after HIMRT (P=.11). In men receiving HIMRT, the proportion of rectum receiving 36.9 Gy, 46.2 Gy, 64.6 Gy, and 73.9 Gy was associated with the development of late GI toxicity (P<.05). The 5-year actuarial grade ≥2 GI toxicity was 27.3% in men with R64.6Gy ≥ 20% but only 6.0% in men with R64.6Gy < 20% (P=.016). CONCLUSIONS: Dose-escalated IMRT using a moderate hypofractionation regimen (72 Gy in 2.4-Gy fractions) can be delivered safely with limited grade 2 or 3 late toxicity. Minimizing the proportion of rectum that receives moderate and high dose decreases the risk of late rectal toxicity after this hypofractionation regimen.

Acute phase response before treatment predicts radiation esophagitis in non-small cell lung cancer.

BACKGROUND AND PURPOSE: Radiation esophagitis (RE) represents an inflammatory reaction to radiation therapy (RT). We hypothesized that aspects of the physiologic acute phase response (APR) predicts RE. MATERIAL AND METHODS: We retrospectively analyzed 285 patients with non-small cell lung cancer (NSCLC) treated with definitive radiation. The primary analysis was the association of pretreatment lab values reflective of the APR with symptomatic (grade ⩾ 2) RE. Univariate and multivariate odds ratios (ORs) were calculated to test associations of clinical and pretreatment lab values with RE. Optimal cutpoints and multivariable risk stratification groupings were determined via recursive partitioning analysis. RESULTS: Pretreatment platelet counts were higher and hemoglobin levels lower in patients who developed RE (P<0.05). Based on these two pre-treatment risk factors, an APR score was defined as 0 (no risk factors), 1 (either risk factor), or 2 (both risk factors). APR score was significantly associated with RE in both univariate (OR = 2.3 for each point, 95% confidence interval [CI] 1.5-3.4, P = 0.001) and multivariate (OR = 2.1, 95% CI 1.3-3.4, P = 0.002) analyses. CONCLUSIONS: The APR score may represent a novel metric to predict RE. However, pending validation in an independent dataset, caution is advised when interpreting these results given their retrospective and thus exploratory nature.

Association between white blood cell count following radiation therapy with radiation pneumonitis in non-small cell lung cancer.

PURPOSE: Radiation pneumonitis (RP) is an inflammatory response to radiation therapy (RT). We assessed the association between RP and white blood cell (WBC) count, an established metric of systemic inflammation, after RT for non-small cell lung cancer. METHODS AND MATERIALS: We retrospectively analyzed 366 patients with non-small cell lung cancer who received ≥60 Gy as definitive therapy. The primary endpoint was whether WBC count after RT (defined as 2 weeks through 3 months after RT completion) was associated with grade ≥3 or grade ≥2 RP. Median lung volume receiving ≥20 Gy (V20) was 31%, and post-RT WBC counts ranged from 1.7 to 21.2 × 10(3) WBCs/µL. Odds ratios (ORs) associating clinical variables and post-RT WBC counts with RP were calculated via logistic regression. A recursive-partitioning algorithm was used to define optimal post-RT WBC count cut points. RESULTS: Post-RT WBC counts were significantly higher in patients with grade ≥3 RP than without (P<.05). Optimal cut points for post-RT WBC count were found to be 7.4 and 8.0 × 10(3)/µL for grade ≥3 and ≥2 RP, respectively. Univariate analysis revealed significant associations between post-RT WBC count and grade ≥3 (n=46, OR=2.6, 95% confidence interval [CI] 1.4‒4.9, P=.003) and grade ≥2 RP (n=164, OR=2.0, 95% CI 1.2‒3.4, P=.01). This association held in a stepwise multivariate regression. Of note, V20 was found to be significantly associated with grade ≥2 RP (OR=2.2, 95% CI 1.2‒3.4, P=.01) and trended toward significance for grade ≥3 RP (OR=1.9, 95% CI 1.0-3.5, P=.06). CONCLUSIONS: Post-RT WBC counts were significantly and independently associated with RP and have potential utility as a diagnostic or predictive marker for this toxicity.

Do angiotensin-converting enzyme inhibitors reduce the risk of symptomatic radiation pneumonitis in patients with non-small cell lung cancer after definitive radiation therapy? Analysis of a single-institution database.

PURPOSE: Preclinical studies have suggested that angiotensin-converting enzyme inhibitors (ACEIs) can mitigate radiation-induced lung injury. We sought here to investigate possible associations between ACEI use and the risk of symptomatic radiation pneumonitis (RP) among patients undergoing radiation therapy (RT) for non-small cell lung cancer (NSCLC). METHODS AND MATERIALS: We retrospectively identified patients who received definitive radiation therapy for stages I to III NSCLC between 2004 and 2010 at a single tertiary cancer center. Patients must have received a radiation dose of at least 60 Gy for a single primary lung tumor and have had imaging and dosimetric data available for analysis. RP was quantified according to Common Terminology Criteria for Adverse Events, version 3.0. A Cox proportional hazard model was used to assess potential associations between ACEI use and risk of symptomatic RP. RESULTS: Of 413 patients analyzed, 65 were using ACEIs during RT. In univariate analysis, the rate of RP grade ≥2 seemed lower in ACEI users than in nonusers (34% vs 46%), but this apparent difference was not statistically significant (P=.06). In multivariate analysis of all patients, ACEI use was not associated with the risk of symptomatic RP (hazard ratio [HR] = 0.66; P=.07) after adjustment for sex, smoking status, mean lung dose (MLD), and concurrent carboplatin and paclitaxel chemotherapy. Subgroup analysis showed that ACEI use did have a protective effect from RP grade ≥2 among patients who received a low (≤20-Gy) MLD (P<.01) or were male (P=.04). CONCLUSIONS: A trend toward reduction in symptomatic RP among patients taking ACEIs during RT for NSCLC was not statistically significant on univariate or multivariate analyses, although certain subgroups may benefit from use (ie, male patients and those receiving low MLD). The evidence at this point is insufficient to establish whether the use of ACEIs does or does not reduce the risk of RP.

Long-term outcomes for men with high-risk prostate cancer treated definitively with external beam radiotherapy with or without androgen deprivation.

BACKGROUND: Men with high-risk prostate cancer are often thought to have very poor outcomes in terms of disease control and survival even after definitive treatment. However, results after external beam radiotherapy have improved significantly through dose escalation and the use of androgen deprivation therapy (ADT). This report describes long-term findings after low-dose (< 75.6 Gy) or high-dose (≥ 75.6 Gy) external beam radiation, with or without ADT. METHODS: This analysis included 741 men with high-risk prostate cancer (clinical classification ≥ T3, Gleason score ≥ 8, or prostate-specific antigen level ≥ 20 ng/mL) treated with external beam radiotherapy at a single tertiary institution from 1987 through 2004. The radiation dose ranged from 60 to 79.3 Gy (median, 70 Gy); 295 men had received ADT for ≥ 2 years, and the median follow-up time was 8.3 years. RESULTS: The 5- and 10-year actuarial overall survival rates were significantly better for men treated with the higher radiation dose (no ADT plus ≥ 75.6 Gy, 87.3% and 72.0%, respectively; and ADT plus ≥ 75.6 Gy, 92.3% and 72%, respectively) (P = .0035). The corresponding 5- and 10-year biochemical failure-free survival rates were significantly better for patients treated with both ADT and higher radiation dose (82% and 77%, P < .0001). At 5 years, men who had not received ADT and had received radiation dose < 75.6 Gy had higher clinical local failure rates than those given ADT and radiation dose ≥ 75.6 Gy (24.2% versus 0%, P < .0001). The 10-year symptomatic local failure rate was only 2% for all patients. CONCLUSIONS: Contrary to lingering historical perceptions, treatment of high-risk prostate cancer with modern, high-dose, external beam radiotherapy and ADT can produce better biochemical, clinical, and survival outcomes over those from previous eras. Specifically, symptomatic local failure is uncommon, and few men die of prostate cancer even 10 or more years after treatment.