Faculty Bibliography

PURPOSE: The management of superficial primary and recurrent esophageal cancer (EC) in medically inoperable patients is complex. Endoluminal high-dose-rate (HDR) brachytherapy has shown mixed results in terms of toxicity and local control. In this study, we examined the outcomes and toxicities in a set of patients with superficial primary and recurrent EC treated with a consistent HDR technique. METHODS AND MATERIALS: Between 8/2008 and 7/2011, 14 patients were treated with HDR intraluminal brachytherapy, 10 (71.4%) with recurrent disease, and 4 (28.6%) with previously unirradiated lesions. Patients received three weekly fractions to a median dose of 12 Gy (range, 10-15 Gy); dose was prescribed to 7-mm median depth with mucosal dose limited to 8-10 Gy using a 12-14-mm applicator. RESULTS: Median followup was 15.4 months. Overall freedom from failure (OFFF) and overall survival (OS) at 18 months were 30.8% (95% confidence interval [CI]: 5.2, 56.4) and 72.7% (95% CI: 45.3, 100), respectively. For patients with recurrent disease, OFFF and OS at 18 months were 11.1% (95% CI: 0, 32.1) and 55.6% (95% CI: 15.4, 95.8), respectively. For patients with previously unirradiated disease, OFFF and OS at 18 months were 75.0% (95% CI: 31.6, 100) and 100.0%, respectively. Eight (57.1%) patients had Grade 1 acute adverse effects; 6 (42.9%) patients had chronic Grade 1 adverse effects; 1 (7.1%) patient developed Grade 2 stricture. Grade 3 tracheoesophageal fistula occurred in 1 (7.1%) patient. One patient died before completion of treatment of unrelated causes. CONCLUSIONS: HDR endoluminal brachytherapy is a well-tolerated treatment for superficial primary and recurrent EC in medically inoperable patients.

PURPOSE/OBJECTIVE:To determine whether the response to neoadjuvant androgen deprivation therapy (ADT) defined by a decline in prostate-specific antigen (PSA) to nadir values is associated with improved survival outcomes after external beam radiation therapy (EBRT) for prostate cancer. METHODS AND MATERIALS/METHODS:One thousand forty-five patients with localized prostate cancer were treated with definitive EBRT in conjunction with neoadjuvant and concurrent ADT. A 6-month course of ADT was used (3 months during the neoadjuvant phase and 2 to 3 months concurrently with EBRT). The median EBRT prescription dose was 81 Gy using a conformal-based technique. The median follow-up time was 8.5 years. RESULTS:The 10-year PSA relapse-free survival outcome among patients with pre-radiation therapy PSA nadirs of ≤0.3 ng/mL was 74.3%, compared with 57.7% for patients with higher PSA nadir values (P<.001). The 10-year distant metastases-free survival outcome among patients with pre-radiation therapy PSA nadirs of ≤0.3 ng/mL was 86.1%, compared with 78.6% for patients with higher PSA nadir values (P=.004). In a competing-risk analysis, prostate cancer-related deaths were also significantly reduced among patients with pre-radiation therapy PSA nadirs of <0.3 ng/mL compared with higher values (7.8% compared with 13.7%; P=.009). Multivariable analysis demonstrated that the pre-EBRT PSA nadir value was a significant predictor of long-term biochemical tumor control, distant metastases-free survival, and cause-specific survival outcomes. CONCLUSIONS:Pre-radiation therapy nadir PSA values of ≤0.3 ng/mL after neoadjuvant ADT were associated with improved long-term biochemical tumor control, reduction in distant metastases, and prostate cancer-related death. Patients with higher nadir values may require alternative adjuvant therapies to improve outcomes.

OBJECTIVE:To report long-term outcomes of men ≤60 years treated with brachytherapy (BT) for low- and intermediate-risk prostate cancer. PATIENTS AND METHODS/METHODS:Of 1655 patients treated with BT for clinically localized prostate cancer between January 1998 and May 2008 at Memorial Sloan-Kettering Cancer Center, 236 patients with National Comprehensive Cancer Network low- (n = 178) or intermediate-risk (n = 58) prostate cancer were ≤60 years old with a 3-year minimum follow-up, and represent the subjects of this report. Brachytherapy was given either as monotherapy (n = 169) or with external beam radiation therapy (EBRT; n = 67). Forty-four patients (19%) received neoadjuvant cytoreductive hormone therapy. The 'nadir+2' definition was used for prostate-specific antigen (PSA) recurrence. Common Terminology Criteria for Acute Events (CTCAE) v 3.0 was used to grade genitourinary (GU) and gastrointestinal (GI) toxicity. Potency was defined as the ability to obtain an erection suitable for intercourse or an International Index of Erectile Function score ≥ 22. The Kaplan-Meier method and Cox regression were used for statistical analysis. The median follow-up was 83 months. RESULTS:The 8-year PSA relapse-free survival (RFS), cancer-specific and overall survival rates for the entire cohort were 96, 99 and 96%, respectively. For patients with low-risk disease, the 8-year PSA RFS rate was 97% and for intermediate-risk patients it was 94% (P = 0.34). There was no difference in PSA RFS between BT alone and combined therapy (P = 0.17). Late grade ≥ 2 GU and GI toxicity was 14 and 3%, respectively. Of 150 patients potent before treatment, 76 (51%) were potent at last follow-up, with 50/76 (66%) using no medication. There was no significant difference in post-treatment potency between BT alone and BT with EBRT (P = 0.74). CONCLUSIONS:Brachytherapy provides patients aged ≤ 60 years with low- and intermediate-risk prostate cancer with excellent outcomes and has a low risk of significant long-term GU or GI morbidity. Erectile function is preserved in >50% of patients and the majority do not require erectile dysfunction medication.

PURPOSE/OBJECTIVE:To analyze the effect of primary Gleason (pG) grade among a large cohort of Gleason 7 prostate cancer patients treated with external beam radiation therapy (EBRT). METHODS AND MATERIALS/METHODS:From May 1989 to January 2011, 1190 Gleason 7 patients with localized prostate cancer were treated with EBRT at a single institution. Of these patients, 613 had a Gleason 7 with a minimum of a sextant biopsy with nonfragmented cores and full biopsy core details available, including number of cores of cancer involved, percentage individual core involvement, location of disease, bilaterality, and presence of perineural invasion. Median follow-up was 6 years (range, 1-16 years). The prognostic implication for the following outcomes was analyzed: biochemical recurrence-free survival (bRFS), distant metastasis-free survival (DMFS), and prostate cancer-specific mortality (PCSM). RESULTS:The 8-year bRFS rate for pG3 versus pG4 was 77.6% versus 61.3% (P<.0001), DMFS was 96.8% versus 84.3% (P<.0001), and PCSM was 3.7% versus 8.1% (P=.002). On multivariate analysis, pG4 predicted for significantly worse outcome in all parameters. Location of disease (apex, base, mid-gland), perineural involvement, maximum individual core involvement, and the number of Gleason 3+3, 3+4, or 4+3 cores did not predict for distant metastases. CONCLUSIONS:Primary Gleason grade 4 independently predicts for worse bRFS, DMFS, and PCSM among Gleason 7 patients. Using complete core information can allow clinicians to utilize pG grade as a prognostic factor, despite not having the full pathologic details from a prostatectomy specimen. Future staging and risk grouping should investigate the incorporation of primary Gleason grade when complete biopsy core information is used.

BACKGROUND:In vitro data and early clinical results suggest that metformin has desirable antineoplastic effects and has a theoretical benefit on castration-resistant prostate cancer (CRPC). OBJECTIVE:To determine whether the use of metformin would be associated with improved clinical outcomes and a reduction in the development of CRPC. DESIGN, SETTING, AND PARTICIPANTS/METHODS:Data from 2901 consecutive patients (157 metformin, 162 diabetic non-metformin, and 2582 nondiabetic) with localized prostate cancer treated with external-beam radiation therapy from 1992 to 2008 were collected from a single institution in the United States. INTERVENTION/METHODS:Use of metformin in localized prostate cancer. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS/METHODS:Univariate and multivariate regression models utilizing k-sample, Fine and Gray, Cox regression, log-rank, and Kaplan-Meier methods to assess prostate-specific antigen-recurrence-free survival (PSA-RFS), distant metastases-free survival (DMFS), prostate cancer-specific mortality (PCSM), overall survival (OS), and development of CRPC. RESULTS AND LIMITATIONS/CONCLUSIONS:With a median follow-up of 8.7 yr, the 10-yr actuarial rates for metformin, diabetic non-metformin, and nondiabetic patients for PCSM were 2.7%, 21.9%, and 8.2% (log-rank p ≤ 0.001), respectively. Metformin use independently predicted (correcting for PSA, T stage, Gleason score, age, diabetic status, and androgen-deprivation therapy use) improvement in all outcomes compared with the diabetic non-metformin group; PSA-RFS (hazard ratio [HR]: 1.99 [1.24-3.18]; p=0.004), DMFS (adjusted HR: 3.68 [1.78-7.62]; p<0.001), and PCSM (HR: 5.15 [1.53-17.35]; p=0.008). Metformin use was also independently associated with a decrease in the development of CRPC in patients experiencing biochemical failure compared with diabetic non-metformin patients (odds ratio: 14.81 [1.83-119.89]; p=0.01). The retrospective study design was the primary limitation of the study. CONCLUSIONS:To our knowledge, our results are the first clinical data to indicate that metformin use may improve PSA-RFS, DMFS, PCSM, OS, and reduce the development of CRPC in prostate cancer patients. Further validation of metformin's potential benefits is warranted.

PURPOSE/OBJECTIVE:We investigated the benefit of short-term androgen-deprivation therapy (ADT) in patients with intermediate-risk prostate cancer (PC) receiving dose-escalated external beam radiation therapy. METHODS AND MATERIALS/METHODS:The present retrospective study comprised 710 intermediate-risk PC patients receiving external beam radiation therapy with doses of ≥81 Gy at a single institution from 1992 to 2005, including 357 patients receiving neoadjuvant and concurrent ADT. Prostate-specific antigen recurrence-free survival (PSA-RFS) and distant metastasis (DM) were compared using the Kaplan-Meier method and Cox proportional hazards models. PC-specific mortality (PCSM) was assessed using competing-risks analysis. RESULTS:The median follow-up was 7.9 years. Despite being more likely to have higher PSA levels, Gleason score 4 + 3 = 7, multiple National Comprehensive Cancer Network intermediate-risk factors, and older age (P≤.001 for all comparisons), patients receiving ADT had improved PSA-RFS (hazard ratio [HR], 0.598; 95% confidence interval [CI], 0.435-0.841; P=.003), DM (HR, 0.424; 95% CI, 0.219-0.819; P=.011), and PCSM (HR, 0.380; 95% CI, 0.157-0.921; P=.032) on univariate analysis. Using multivariate analysis, ADT was an even stronger predictor of improved PSA-RFS (adjusted HR [AHR], 0.516; 95% CI, 0.360-0.739; P<.001), DM (AHR, 0.347; 95% CI, 0.176-0.685; P=.002), and PCSM (AHR, 0.297; 95% CI, 0.128-0.685; P=.004). Gleason score 4 + 3 = 7 and ≥50% positive biopsy cores were other independent predictors of PCSM. CONCLUSIONS:Short-term ADT improves PSA-RFS, DM, and PCSM in patients with intermediate-risk PC undergoing dose-escalated external beam radiation therapy.

PURPOSE/OBJECTIVE:To report long-term survival and toxicity outcomes with the use of high-dose intensity modulated radiation therapy (IMRT) to 86.4 Gy for patients with localized prostate cancer. METHODS AND MATERIALS/METHODS:Between August 1997 and December 2008, 1002 patients were treated to a dose of 86.4 Gy using a 5-7 field IMRT technique. Patients were stratified by prognostic risk group based on National Comprehensive Cancer Network risk classification criteria. A total of 587 patients (59%) were treated with neoadjuvant and concurrent androgen deprivation therapy. The median follow-up for the entire cohort was 5.5 years (range, 1-14 years). RESULTS:For low-, intermediate-, and high-risk groups, 7-year biochemical relapse-free survival outcomes were 98.8%, 85.6%, and 67.9%, respectively (P<.001), and distant metastasis-free survival rates were 99.4%, 94.1%, and 82.0% (P<.001), respectively. On multivariate analysis, T stage (P<.001), Gleason score (P<.001), and >50% of initial biopsy positive core (P=.001) were predictive for distant mestastases. No prostate cancer-related deaths were observed in the low-risk group. The 7-year prostate cancer-specific mortality (PCSM) rates, using competing risk analysis for intermediate- and high-risk groups, were 3.3% and 8.1%, respectively (P=.008). On multivariate analysis, Gleason score (P=.004), percentage of biopsy core positivity (P=.003), and T-stage (P=.033) were predictive for PCSM. Actuarial 7-year grade 2 or higher late gastrointestinal and genitourinary toxicities were 4.4% and 21.1%, respectively. Late grade 3 gastrointestinal and genitourinary toxicity was experienced by 7 patients (0.7%) and 22 patients (2.2%), respectively. Of the 427 men with full potency at baseline, 317 men (74%) retained sexual function at time of last follow-up. CONCLUSIONS:This study represents the largest cohort of patients treated with high-dose radiation to 86.4 Gy, using IMRT for localized prostate cancer, with the longest follow-up to date. Our findings indicate that this treatment results in excellent clinical outcomes with acceptable toxicity.

PURPOSE:To test the feasibility of using proposed quality indicators to assess radiotherapy quality in prostate cancer management based on a 2007 stratified random survey of treating academic and non-academic US institutions. METHODS AND MATERIALS:414 patients with clinically localized prostate cancer treated with external beam radiotherapy (EBRT) or brachytherapy were selected from 45 institutions. Indicators used as specific measurable clinical performance measures to represent surrogates for quality of radiotherapy delivery included established measures, such as the use of prescription doses ≥75 Gy for intermediate- and high-risk EBRT patients and androgen-deprivation therapy (ADT) in conjunction with EBRT for patients with high-risk disease, and emerging measures, including daily target localization (image-guidance) to correct for organ motion for EBRT patients. RESULTS:167 patients (47%) were treated with 6 MV photons, 31 (9%) were treated with 10 MV, 65 (18%) received 15 MV, and the remaining 90 (26%) 16-23 MV. For intermediate- plus high-risk patients (n=181), 78% were treated to ≥75 Gy. Among favorable-risk patients, 72% were treated to ≥75 Gy. Among high-risk EBRT patients, 60 (87%) were treated with ADT in conjunction with EBRT and 13% (n=9) with radiotherapy alone. Among low- and intermediate-risk patients, 10% and 42%, respectively, were treated with ADT plus EBRT. For 24% of EBRT patients (85/354), weekly electronic portal imaging was obtained as verification films without daily target localization and the remaining 76% were treated with daily localization of the target using various methods. CONCLUSIONS:Adherence to defined quality indicators was observed in a majority of patients. ≈90% of high-risk patients are treated with ADT plus EBRT and ≈80% of intermediate- and high-risk patients receive prescription doses >=75 Gy, consistent with the published results of randomized trials.

PURPOSE/OBJECTIVE:To report long-term outcomes of high-dose-rate (HDR) intraoperative radiotherapy (IORT) at the time of radical resection for recurrent head-and-neck cancer and determine potential prognostic factors. METHODS AND MATERIALS/METHODS:Between 7/1998 and 11/2011, 57 patients with recurrent head-and-neck cancer underwent radical resection with curative intent and single-fraction IORT to 59 sites using a Harrison-Anderson-Mick applicator with remotely after-loaded (192)Ir HDR brachytherapy. RESULTS:One- and 3-year in-field progression-free survival (IFPFS) was 67% and 57%, respectively. In a multivariate model, IORT dose >15Gy (hazard ratio [HR] = 0.11; p = 0.02), and prerecurrence disease-free interval >12 months (HR = 0.29; p = 0.04) independently predicted for superior IFPFS; nodal extracapsular extension (HR = 4.62; p = 0.003) predicted for inferior IFPFS. Three-year overall survival (OS) was 50% vs. 32% in those achieving in-field control vs. those not achieving in-field control (p = 0.04). Grade 3+ toxicity occurred in 37% and was unrelated to IORT dose. CONCLUSIONS:HDR-IORT combined with radical surgical resection is associated with durable IFPFS and long-term overall survival in select patients with acceptable treatment-related morbidity. IORT dose >15Gy should be used to increase the likelihood of disease control. The ability to achieve in-field local control in this poor prognostic cohort was associated with improved survival outcomes.