Faculty Bibliography

PURPOSE:To assess the long-term quality of life (QoL) outcomes from a phase 3 trial comparing 2 modes of intensity modulated radiation therapy (IMRT): conventional IMRT (CIMRT) versus hypofractionated IMRT (HIMRT) in patients with localized prostate cancer. METHODS AND MATERIALS:Between 2002 and 2006, 303 men with low-risk to high-risk prostate cancer were randomized to 76 Gy in 38 fractions (CIMRT) versus 70.2 Gy in 26 fractions (HIMRT). QoL was compared by use of the Expanded Prostate Cancer Index Composite (EPIC), the International Prostate Symptom Score (IPSS), and EuroQoL (EQ5D) questionnaires. The primary outcome of the QoL analysis was a minimum clinically important difference defined as a 0.5 standard deviation change from baseline for each respective QoL parameter. Treatment effects were evaluated with the use of logistic mixed effects regression models. RESULTS:A total of 286, 299, and 218 patients had baseline EPIC, IPSS, or EQ5D data available and were included in the analysis. Overall, there was no statistically significant difference between the 2 treatment arms in terms of EPIC, IPSS, or EQ5D scores over time, although there was a trend toward lower EPIC urinary incontinence scores in the HIMRT arm. More patients in the HIMRT arm had a lower EPIC urinary incontinence score relative to baseline versus patients in the CIMRT arm with long-term follow-up. On multivariable analysis, there was no association between radiation fractionation scheme and any QoL parameter. When other clinical factors were examined, lymph node radiation was associated with worse EPIC hormonal scores versus patients receiving no lymph node radiation. In general, QoL outcomes were generally stable over time, with the exception of EPIC hormonal and EQ5D scores. CONCLUSIONS:In this randomized prospective study, there were stable QoL changes in patients receiving HIMRT or CIMRT. Our results add to the growing body of literature suggesting that HIMRT may be an acceptable treatment modality in clinically localized prostate cancer.

BACKGROUND:The long natural history of prostate cancer (CaP) limits comparisons of efficacy between radical prostatectomy (RP) and external beam radiotherapy (EBRT), since patients treated years ago received treatments considered suboptimal by modern standards (particularly with regards to androgen deprivation therapy [ADT] and radiotherapy dose-escalation]. Gleason score (GS) 9-10 CaP is particularly aggressive, and clinically-relevant endpoints occur early, facilitating meaningful comparisons. OBJECTIVE:To compare outcomes of patients with GS 9-10 CaP following EBRT, extremely-dose escalated radiotherapy (as exemplified by EBRT+brachytherapy [EBRT+BT]), and RP. DESIGN, SETTING, PARTICIPANTS:Retrospective analysis of 487 patients with biopsy GS 9-10 CaP treated between 2000 and 2013 (230 with EBRT, 87 with EBRT+BT, and 170 with RP). Most radiotherapy patients received ADT and dose-escalated radiotherapy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:Kaplan-Meier analysis and multivariate Cox regression estimated and compared 5-yr and 10-yr rates of distant metastasis-free survival, cancer-specific survival (CSS), and overall survival (OS). RESULTS AND LIMITATIONS:The median follow-up was 4.6 yr. Local salvage and systemic salvage were performed more frequently in RP patients (49.0% and 30.1%) when compared with either EBRT patients (0.9% and 19.7%) or EBRT+BT patients (1.2% and 16.1%, p<0.0001). Five-yr and 10-yr distant metastasis-free survival rates were significantly higher with EBRT+BT (94.6% and 89.8%) than with EBRT (78.7% and 66.7%, p=0.0005) or RP (79.1% and 61.5%, p<0.0001). The 5-yr and 10-yr CSS and OS rates were similar across all three cohorts. CONCLUSIONS:Radiotherapy and RP provide equivalent CSS and OS. Extremely dose-escalated radiotherapy with ADT in particular offers improved systemic control when compared with either EBRT or RP. These data suggest that extremely dose-escalated radiotherapy with ADT might be the optimal upfront treatment for patients with biopsy GS 9-10 CaP. PATIENT SUMMARY:While some prostate cancers are slow-growing requiring many years, sometimes decades, of follow-up in order to compare between radiation and surgery, high-risk and very aggressive cancers follow a much shorter time course allowing such comparisons to be made and updated as treatments, especially radiation, rapidly evolve. We showed that radiation-based treatments and surgery, with contemporary standards, offer equivalent survival for patients with very aggressive cancers (defined as Gleason score 9-10). Extremely-dose escalated radiotherapy with short-course androgen deprivation therapy offered the least risk of developing metastases, and equivalent long term survival.

INTRODUCTION:Our study sought to characterize the presentation, local management and outcomes of invasive cervical cancer with regard to patient insurance status. METHODS:We queried the NCI-SEER database for invasive cervical cancer cases in patients aged 18-64 from 2007 to 2011. We analyzed clinical and socioeconomic data with regard insurance status (insured, Medicaid, or uninsured). We tested for associations between patient insurance status and treatment with definitive surgery for FIGO IA2-IB1 patients, and treatment with suboptimal radiation therapy (RT) for FIGO IB2-IVA patients (other than combination external beam and brachytherapy). We evaluated overall and cause specific survival according to insurance status. RESULTS:11,714 cases were analyzed: 60% insured, 31% Medicaid, and 9% uninsured. FIGO III/IV stage at presentation was more frequent with Medicaid (40%) and uninsured (42%) compared to insured patients (28%) (p<0.001). For FIGO IA2-IB1 patients, receipt of definitive surgery was inversely associated with uninsured status (OR [95%CI]=0.65 [0.47-0.90], p<0.001) in univariable analysis; however the relationship lost significance after multivariable adjustment. For FIGO IB2-IVA patients, the use of suboptimal RT was associated with uninsured status (OR [95%CI]=1.33 [1.07-1.65], p=0.011) in adjusted analyses. Among all patients, overall mortality was increased with Medicaid (HR [95%CI]=1.16 [1.05-1.28], p=0.003) and uninsured status (HR [95%CI]=1.17 [1.01-1.34], p=0.031) in multivariable analysis. Cancer specific mortality survival trended towards significance in multivariable analyses for both Medicaid (HR [95%CI]=1.11 [1.00-1.24] and uninsured status (HR [95%CI]=1.14 [0.98-1.33]). CONCLUSIONS:Disparities in cervical cancer treatment with regard to insurance status are apparent in a recent cohort of American patients. Later stage at presentation and differences in management partially account for the inferior prognostic outcomes associated with Medicaid and uninsured status.

We review radiation therapy (RT) options available for prostate cancer, including external beam (EBRT; with conventional fractionation, hypofractionation, stereotactic body RT [SBRT]) and brachytherapy (BT), with an emphasis on the outcomes, toxicities, and contraindications for therapies. PICOS/PRISMA methods were used to identify published English-language comparative studies on PubMed (from 1980 to 2015) that included men treated on prospective studies with a primary endpoint of patient outcomes, with ⩾70 patients, and ⩾5year median follow up. Twenty-six studies met inclusion criteria; of these, 16 used EBRT, and 10 used BT. Long-term freedom from biochemical failure (FFBF) rates were roughly equivalent between conventional and hypofractionated RT with intensity modulation (evidence level 1B), with 10-year FFBF rates of 45-90%, 40-60%, and 20-50% (for low-, intermediate-, and high-risk groups, respectively). SBRT had promising rates of BF, with shorter follow-up (5-year FFBF of >90% for low-risk patients). Similarly, BT (5-year FFBF for low-, intermediate-, and high-risk patients have generally been >85%, 69-97%, 63-80%, respectively) and BT+EBRT were appropriate in select patients (evidence level 1B). Differences in overall survival, distant metastasis, and cancer specific mortality (5-year rates: 82-97%, 1-14%, 0-8%, respectively) have not been detected in randomized trials of dose escalation or in studies comparing RT modalities. Studies did not use patient-reported outcomes, through Grade 3-4 toxicities were rare (<5%) among all modalities. There was limited evidence available to compare proton therapy to other modalities. The treatment decision for a man is usually based on his risk group, ability to tolerate the procedure, convenience for the patient, and the anticipated impact on quality of life. To further personalize therapy, future trials should report (1) race; (2) medical comorbidities; (3) psychiatric comorbidities; (4) insurance status; (5) education status; (6) marital status; (7) income; (8) sexual orientation; and (9) facility-related characteristics.

OBJECTIVES:The purpose of this study was to assess the trends in use of clinical diagnosis and its impact on treatment outcomes in patients receiving radiation therapy for early-stage lung cancer. METHODS:The Surveillance, Epidemiology, and End Results registry was queried from 2004 to 2012 for patients at least 18 years old in whom stage I (clinical stage T1a-T2a) lung cancer had been diagnosed and who underwent radiation therapy alone. Trends in diagnostic confirmation patterns were characterized. A Cox proportional hazards model was used to assess overall survival, and competing risk regression analysis was used to assess cancer-specific survival (CSS). RESULTS:A total of 7050 patients were included; the disease of 6399 of them (90.8%) was pathologically diagnosed and that of 651 (9.2%) was clinically diagnosed. There was no significant change in the utilization of clinical versus pathologic diagnosis (p = 0.172) over time. Patients with T1 disease (p < 0.001), tumors 0 to 1.9 cm in size (p < 0.001), and upper lobe tumors (p = 0.004) were more likely to have been clinically diagnosed. On multivariable analysis, clinical diagnosis was associated with an improved CSS (hazard ratio [HR] = 0.82, 95% confidence interval [CI]: 0.71-0.96) but was not associated with an improved overall survival (HR = 1.01, 95% CI: 0.90-1.13). When stratified by T stage, patients whose disease had been clinically diagnosed as stage T1a had an improved CSS (HR = 0.75, 95% CI: 0.58-0.96, p = 0.022). There was a trend toward improved CSS in patients with clinical stage T1b tumors (HR = 0.74, 95% CI: 0.55-1.00, p = 0.052). CONCLUSIONS:The improved CSS in patients with a clinical diagnosis suggests treatment of benign disease, particularly in smaller tumors. Prudent patient selection is needed to reduce the potential for overtreatment.

OBJECTIVES:The purpose of this study was to examine the impact of adjuvant radiation on overall survival (OS) and cancer specific survival (CSS) in patients with lymph node (LN) positive endometrial cancer. METHODS:We analyzed all women diagnosed with FIGO stage IIIC endometrial adenocarcinoma in the Surveillance, Epidemiology, and End Results database from 2004 to 2012 (n=2177). Patients not undergoing surgery or with missing treatment information were excluded. Chi-squared tests were used to compare predictors of treatment received. Cox proportional hazards model and Kaplan-Meier method were used to assess OS and CSS. RESULTS:The median age was 60 (27-84) and the median follow-up was 31months (2-107). Adjuvant radiation was administered to 1248 (60.3%) patients. A total of 1363 (65.9%) patients had pelvic LN involvement while 658 (31.8%) had para-aortic involvement. The 3-year actuarial OS for patients with and without radiation was 80.5% and 67.6%, respectively (p<0.001). The 3-year actuarial CSS for patients with and without radiation was 83.4% and 73%, respectively (p<0.001). On multivariable analysis, receipt of radiotherapy remained associated with OS (HR 0.61 95% CI 0.51-0.74) and CSS (HR 0.65, 95% CI 0.53-0.80). After propensity matching, radiotherapy continued to be associated with an improved OS (HR 0.65 95% CI 0.54-0.78) and CSS (HR 0.65 95% CI 0.53-0.81). The addition of brachytherapy was not associated with OS or CSS. CONCLUSIONS:In this large population registry analysis, adjuvant radiation was associated with improved OS and CSS in patients with LN positive endometrial cancer. Prospective data is needed to confirm these findings.

PURPOSE/OBJECTIVE:This study was undertaken to identify parameters associated with hematologic toxicity or chemotherapy dose modification in patients undergoing concurrent chemoradiation (CRT) with gemcitabine for localized pancreatic cancer. METHODS AND MATERIALS/METHODS:We reviewed patients with localized pancreatic cancer undergoing CRT between 2006 and 2012. Exclusion criteria included receipt of nongemcitabine therapy, chemotherapy before CRT, or abnormal baseline hematologic indices. The T11-L3 vertebrae were contoured as bone marrow region at risk. Linear and logistic regression models were used to test associations between dosimetric parameters and gemcitabine dose modification or hematologic toxicity during or within 3 months following CRT. Receiver operator curves were generated to identify threshold doses for hematologic toxicity. RESULTS:Forty-nine patients were included. During CRT, the maximum thoracolumbar dose was associated with grade 2+ neutropenia during CRT (P = .017) and the volume receiving 5 Gy (V5) was associated with grade 2+ leukopenia (P = .041). Post-CRT, thoracolumbar mean dose (P = .015), V5 (P = .01), and V10 (P = .012) were associated with increased grade 2+ neutropenia. On multivariable analysis, the thoracolumbar maximum dose (P = .045) and V5 (P = .045) were associated with grade 2+ neutropenia and grade 2+ leukopenia during CRT, respectively. Post-CRT, the mean dose (P = .046), V5 (P = .019), and V10 (P = .037) were associated with increased grade 2+ neutropenia. A maximum dose of 48.02 Gy and V5 of 57.6% were identified as predictors of toxicity during CRT. A V5 of 56.6%, V10 of 47.05%, and mean dose of 11.67 Gy were identified as predictors of post-CRT hematologic toxicity. Post-CRT, there was a trend toward increased dose modifications with increased V5 (P = .065). CONCLUSIONS:In our dataset, the thoracolumbar mean dose, maximum dose, V5, and V10 correlated with hematologic toxicity during CRT and post-CRT in patients with localized pancreatic cancer. Because of the high rates of distant failure and importance of systemic therapy in these patients, this may be an important consideration during treatment planning.

PURPOSE/OBJECTIVE:There are limited data regarding clinical and treatment factors associated with radiation pneumonitis (RP) in patients receiving taxane-based trimodality therapy for esophageal cancer. The purpose of this study was to identify predictors of RP in patients undergoing trimodality therapy. METHODS AND MATERIALS/METHODS:test and Mann-Whitney U test. Multivariable regression was used to assess the relationship between grade 2+ RP and clinical/dosimetric factors. Receiver operator curves were generated to identify threshold doses for RP. RESULTS:A total of 139 patients were included; 19 (13.7%) patients experienced grade 2+ RP. Patients with upper/middle thoracic tumors (P = .038) and receiving higher radiation doses (P = .038) were more likely to develop grade 2+ RP. There was no association between taxane-based therapy and grade 2+ RP (P = .728). The percent volume of lung receiving 5 Gy (V5; P < .001), 10 Gy (P < .001), 20 Gy (V20; P < .001), and 30 Gy (P < .001) was associated with an increased risk of grade 2+ RP. On multivariable regression, the lung V5 (odds ratio, 1.101; 95% confidence interval, 1.1014-1.195) and V20 (odds ratio, 1.149; 95% confidence interval, 1.1015-1.301) remained associated with grade 2+ RP. A V5 ≤65% and V20 ≤25% were identified as optimal thresholds for increased grade 2+ RP. CONCLUSIONS:Dosimetric parameters are strong predictors of symptomatic RP in patients undergoing trimodality therapy for esophageal cancer. Mitigating the risk of RP in these patients should be an important consideration during treatment planning.

PURPOSE:To assess the impact of radiation treatment time (RTT) in head and neck cancers on overall survival (OS) in the era of chemoradiation. METHODS AND MATERIALS:tests to identify predictors of RTT. The Kaplan-Meier method was used to compare OS among groups. Cox proportional hazards model was used for OS analysis in patients with known comorbidity status. RESULTS:19,531 patients were included; 12,987 (67%) had a standard RTT, 4,369 (34%) had an accelerated RTT, and 2,165 (11%) had a prolonged RTT. On multivariable analysis, accelerated RTT (hazard ratio [HR] 0.84; 95% confidence interval [CI] 0.73-0.97) was associated with an improved OS, and prolonged RTT (HR 1.25; 95% CI 1.14-1.37) was associated with a worse OS relative to standard RTT. When the 9,200 (47%) patients receiving definitive concurrent chemoradiation were examined, prolonged RTT (HR 1.29; 95% CI 1.11-1.50) was associated with a worse OS relative to standard RTT, whereas there was no significant association between accelerated RTT and OS (HR 0.76; 95% CI 0.57-1.01). CONCLUSION:Prolonged RTT is associated with worse OS in patients receiving radiation therapy for head and neck cancer, even in the setting of chemoradiation. Expeditious completion of radiation should continue to be a quality metric for the management of head and neck malignancies.

BACKGROUND:The purpose of the study was to identify the effect of final surgical margin (SM) status and re-excision on outcomes in patients with ductal carcinoma in situ (DCIS) who underwent breast conservation therapy (BCT). PATIENTS AND METHODS:The study population consisted of women diagnosed with DCIS who underwent BCT between 1989 and 2014. All women received adjuvant whole breast radiation and a boost. The primary end point was local control (LC). Final SMs were defined according to margin width: negative SM was defined as > 2 mm, close SM was defined as > 0 to ≤ 2 mm, and a positive SM was defined as tumor on ink. The Cox proportional hazards model was used to determine predictors of outcomes on multivariable analysis. Actuarial incidence of LC was estimated using the Kaplan-Meier method. RESULTS:A total of 498 patients were included; 400 patients had a final negative SM, 87 had a close SM, and 11 had a positive SM. A total of 172 patients received adjuvant hormonal therapy, 265 patients required ≥ 1 re-excision. Patients with positive or close SMs were more likely to receive a radiation dose > 60 Gy (P < .001) and undergo re-excision (P < .01). The 10-year LC rates were not significantly different between patients with a negative (93.5%), close (91.8%), or positive (100%) SM (P = .57). There was no difference in LC in patients who underwent re-excision for initial close or positive SMs (P = .55). CONCLUSION:This single-institution experience showed that risks of local recurrence remain poorly characterized. Re-excision and whole breast radiation with boost resulted in excellent LC for women with DCIS. Trials aimed at personalized deintensified local therapy are warranted.