Faculty Bibliography

PURPOSE/OBJECTIVE:To investigate whether pretreatment endorectal magnetic resonance imaging (MRI) findings can predict biochemical relapse in patients with clinically localized prostate cancer treated with external beam radiation therapy (EBRT). METHODS AND MATERIALS/METHODS:Between January 2000 and January 2002, 224 patients (median age, 69 years; age range, 45-82 years) with biopsy-proven prostate cancer underwent endorectal MRI before high-dose (≥81Gy) EBRT. The value of multiple clinical and MRI variables in predicting prostate-specific antigen (PSA) relapse at 5 years was determined by use of univariate and multivariate stepwise Cox regression. Clinical variables included pretreatment PSA, clinical T stage, Gleason score, use of neoadjuvant hormonal therapy, and radiation dose. Magnetic resonance imaging variables, derived from retrospective consensus readings by two radiologists, were used to measure intraprostatic and extraprostatic tumor burden. RESULTS:After a median follow-up of 67 months, PSA relapse developed in 37 patients (16.5%). The significant predictors of PSA relapse on univariate analysis were pretreatment PSA, clinical T stage, and multiple MRI variables, including MRI TN stage score; extracapsular extension (ECE) status; number of sextants involved by ECE, all lesions, or index (dominant) lesion; apical involvement; and diameter and volume of index lesion. Pretreatment PSA and ECE status were the only significant independent predictors on multivariate analysis (p < 0.05 for both). Extracapsular extension status was associated with the highest hazard ratio, 3.04; 5-year PSA relapse rates were 7% for no ECE, 20% for unilateral ECE, and 48% for bilateral ECE. CONCLUSIONS:Magnetic resonance imaging findings can be used to predict post-EBRT PSA relapse, with ECE status on MRI and pretreatment PSA being significant independent predictors of this endpoint.

OBJECTIVE:To determine if the location and number of positive surgical margins (PSMs) after radical prostatectomy (RP) are associated with recurrence after salvage external beam radiation therapy (sEBRT). PATIENTS AND METHODS/METHODS:We retrospectively reviewed the medical records of 60 patients with PSMs who underwent three-dimensional conformal sEBRT for biochemical recurrence (BCR) or clinically detected local recurrence after RP between 1996 and 2007. PSMs were categorized as present or absent at three locations, and patients were classified as having either one or more than one PSM. BCR after RP was defined as a prostate-specific antigen (PSA) level of ≥ 0.1 ng/mL. BCR after sEBRT was defined as a serum PSA level of ≥ 0.1 ng/mL above the PSA nadir after sEBRT. RESULTS:In all, 24 (40%) patients had more than one PSM. Overall, the most common location of a PSM was the posterior prostate with 40 (66%) patients having a positive posterior margin. The location of PSMs was not significantly associated with secondary BCR (global P= 0.8). There was a borderline result between the number of PSMs and BCR: men with more than one PSM were less likely to recur compared with those with only one PSM (hazard ratio 0.42; P= 0.067). CONCLUSIONS:This is the first study to specifically analyse location and number of PSMs as prognostic factors for men who undergo sEBRT. There was no evidence to suggest that the location of a PSM predicted secondary BCR. Further research is needed to determine whether the number of PSMs is an important predictor of BCR after sEBRT.

OBJECTIVES/OBJECTIVE:To evaluate the use of real-time kilovoltage cone-beam computed tomography (CBCT) during prostate brachytherapy for intraoperative dosimetric assessment and correcting deficient dose regions. METHODS:A total of 20 patients were evaluated intraoperatively with a mobile CBCT unit immediately after implantation while still anesthetized. The source detector system was enclosed in a circular CT-like geometry with a bore that accommodates patients in the lithotomy position. After seed deposition, the CBCT scans were obtained. The dosimetry was evaluated and compared with the standard postimplantation CT-based assessment. In 8 patients, the deposited seeds were localized in the intraoperative CBCT frame of reference and registered to the intraoperative transrectal ultrasound images. With this information, a second intraoperative plan was generated to ascertain whether additional seeds were needed to achieve the planned prescription dose. The final dosimetry was compared with the postimplantation scan assessment. RESULTS:The mean differences between the dosimetric parameters from the intraoperative CBCT and postimplant CT scans were < .5% for percentage of volume receiving 100% of the prescription dose, minimal dose received by 90% of the prostate, and percentage of volume receiving 150% of the prescription dose. The minimal dose received by 5% (maximal dose) of the urethra differed by 8% on average and for the rectum an average difference of approximately 18% was observed. After fusion of the implanted seed coordinates from the intraoperative CBCT scans to the intraoperative transrectal ultrasound images, the dosimetric outcomes were not significantly different from the postimplantation CT dosimetric results. CONCLUSIONS:Intraoperative CT-based dosimetric evaluation of prostate permanent seed implantation before anesthesia reversal is feasible and might avert misadministration of dose delivery. The dosimetric measurements using the intraoperative CBCT scans were dependable and correlated well with the postimplant diagnostic CT findings.

PURPOSE/OBJECTIVE: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/CONCLUSIONS: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.

PURPOSE/OBJECTIVE:Assess the importance of overall time (OT) and dose for biochemical failure (BF) after external-beam radiotherapy of prostate cancer in a retrospective analysis of a nine-institution database with 4839 patients. PATIENTS AND METHODS/METHODS:Relevant baseline factors (T stage, Gleason score, initial PSA) were available for 4338 men. Cox models were used to estimate the effects of dose and OT corrected for baseline factors, treatment year, institution and interactions, and differences in post-treatment PSA-measurement intervals. After exclusion of very short and long intervals, patient numbers were 1445 events/3426 at risk (endpoint all BFs), and 1177 events/3354 at risk (endpoint exclusion of BFs that were likely distant failures). Separate analyses were carried out by risk group for men who received <70 Gy and > or = 70 Gy. RESULTS:Neither dose nor OT was significant when the analysis was restricted to doses <70 Gy, while for patients treated to 70 Gy or higher there were significant influences of both dose and OT on outcome in low- and intermediate-risk patients. These effects were quantified as a relative increase after 5 years followup of 6% in BFs for a 1-week increase in OT, a relative decrease of 15% in BFs for a 6-Gy increase in dose, and a dose equivalent of proliferation of 0.24 Gy/day. As the dose per fraction was nearly constant, the data contain no information on the alpha/beta ratio. CONCLUSION/CONCLUSIONS:The results show that OT and dose are significant determinants of outcome of radiotherapy in low- and intermediate-risk patients treated to 70 Gy or higher, and suggest that meaningful improvements in outcome may be targeted by modest increases in total dose and decreases in OT.

OBJECTIVES: To present our single-institution experience with postoperative radiotherapy for mucosal melanoma of the head and neck. METHODS: Between 1992 and 2007, 27 patients with mucosal melanoma of the head and neck underwent surgical resection followed by postoperative radiotherapy. Median age was 68 years (range: 45-89 years). Sites included were sinonasal in 24 patients, oral cavity in 2, and oropharynx in 1. All but 2 patients had stage I disease. Twenty-two patients received hypofractionated radiation. Radiation techniques were intensity-modulated radiation therapy in 13, 3-dimensional conformal in 4, and conventional in 10. RESULTS: The median follow-up for living patients was 45 months (range: 24-122 months). The 3- and 5-year estimates of local progression-free, loco-regional progression-free, distant metastasis-free, and overall survival were: 47% and 35%; 34% and 22%; 30% and 24%; and 40% and 33%, respectively. Median time to local failure and distant metastasis was 32 and 14 months, respectively. Acute toxicities included 19% with grade 2 or higher mucositis. No late complications related to the optic structures were seen. CONCLUSIONS: Modern radiotherapeutic techniques including intensity-modulated radiation therapy appear feasible and well-tolerated in the postoperative treatment of head and neck mucosal melanoma. Unusual or serious late complications have not been observed despite extensive use of hypofractionated regimens. However, rates of local and distant failure remain high.

PURPOSE: Increased prostate cancer risk has been reported for BRCA mutation carriers, but BRCA-associated clinicopathologic features have not been clearly defined. EXPERIMENTAL DESIGN: We determined BRCA mutation prevalence in 832 Ashkenazi Jewish men diagnosed with localized prostate cancer between 1988 and 2007 and 454 Ashkenazi Jewish controls and compared clinical outcome measures among 26 BRCA mutation carriers and 806 noncarriers. Kruskal-Wallis tests were used to compare age of diagnosis and Gleason score, and logistic regression models were used to determine associations between carrier status, prostate cancer risk, and Gleason score. Hazard ratios (HR) for clinical end points were estimated using Cox proportional hazards models. RESULTS: BRCA2 mutations were associated with a 3-fold risk of prostate cancer [odds ratio, 3.18; 95% confidence interval (95% CI), 1.52-6.66; P = 0.002] and presented with more poorly differentiated (Gleason score > or =7) tumors (85% versus 57%; P = 0.0002) compared with non-BRCA-associated prostate cancer. BRCA1 mutations conferred no increased risk. After 7,254 person-years of follow-up, and adjusting for clinical stage, prostate-specific antigen, Gleason score, and treatment, BRCA2 and BRCA1 mutation carriers had a higher risk of recurrence [HR (95% CI), 2.41 (1.23-4.75) and 4.32 (1.31-13.62), respectively] and prostate cancer-specific death [HR (95% CI), 5.48 (2.03-14.79) and 5.16 (1.09-24.53), respectively] than noncarriers. CONCLUSIONS: BRCA2 mutation carriers had an increased risk of prostate cancer and a higher histologic grade, and BRCA1 or BRCA2 mutations were associated with a more aggressive clinical course. These results may have implications for tailoring clinical management of this subset of hereditary prostate cancer

PURPOSE/OBJECTIVE:To develop an optimization method using volumetric modulated arc therapy (VMAT) and evaluate VMAT plans relative to the standard intensity-modulated radiotherapy (IMRT) approach in prostate cancer. METHODS AND MATERIALS/METHODS:A single gantry rotation was modeled using 177 equispaced beams. Multileaf collimator apertures and dose rates were optimized with respect to gantry angle subject to dose-volume-based objectives. Our VMAT implementation used conjugate gradient descent to optimize dose rate, and stochastic sampling to find optimal multileaf collimator leaf positions. A treatment planning study of 11 prostate cancer patients with a prescription dose of 86.4 Gy was performed to compare VMAT with a standard five-field IMRT approach. Plan evaluation statistics included the percentage of planning target volume (PTV) receiving 95% of prescribed dose (V95), dose to 95% of PTV (D95), mean PTV dose, tumor control probability, and dosimetric endpoints of normal organs, whereas monitor unit (MU) and delivery time were used to assess delivery efficiency. RESULTS:Patient-averaged PTV V95, D95, mean dose, and tumor control probability in VMAT plans were 96%, 82.6 Gy, 88.5 Gy, and 0.920, respectively, vs. 97%, 84.0 Gy, 88.9 Gy, and 0.929 in IMRT plans. All critical structure dose requirements were met. The VMAT plans presented better rectal wall sparing, with a reduction of 1.5% in normal tissue complication probability. An advantage of VMAT plans was that the average number of MUs (290 MU) was less than for IMRT plans (642 MU). CONCLUSION/CONCLUSIONS:The VMAT technique can reduce beam on time by up to 55% while maintaining dosimetric quality comparable to that of the standard IMRT approach.

PURPOSE/OBJECTIVE:We assessed the effect of radical prostatectomy (RP) and external beam radiotherapy (EBRT) on distant metastases (DM) rates in patients with localized prostate cancer treated with RP or EBRT at a single specialized cancer center. PATIENTS AND METHODS/METHODS:Patients with clinical stages T1c-T3b prostate cancer were treated with intensity-modulated EBRT (> or = 81 Gy) or RP. Both cohorts included patients treated with salvage radiotherapy or androgen-deprivation therapy for biochemical failure. Salvage therapy for patients with RP was delivered a median of 13 months after biochemical failure compared with 69 months for EBRT patients. DM was compared controlling for patient age, clinical stage, serum prostate-specific antigen level, biopsy Gleason score, and year of treatment. RESULTS:The 8-year probability of freedom from metastatic progression was 97% for RP patients and 93% for EBRT patients. After adjustment for case mix, surgery was associated with a reduced risk of metastasis (hazard ratio, 0.35; 95% CI, 0.19 to 0.65; P < .001). Results were similar for prostate cancer-specific mortality (hazard ratio, 0.32; 95% CI, 0.13 to 0.80; P = .015). Rates of metastatic progression were similar for favorable-risk disease (1.9% difference in 8-year metastasis-free survival), somewhat reduced for intermediate-risk disease (3.3%), and more substantially reduced in unfavorable-risk disease (7.8% in 8-year metastatic progression). CONCLUSION/CONCLUSIONS:Metastatic progression is infrequent in men with low-risk prostate cancer treated with either RP or EBRT. RP patients with higher-risk disease treated had a lower risk of metastatic progression and prostate cancer-specific death than EBRT patients. These results may be confounded by differences in the use and timing of salvage therapy.

PURPOSE/OBJECTIVE:To report the use of high-dose-rate intraoperative radiation therapy (HDR-IORT) for recurrent head-and-neck cancer (HNC) at a single institution. METHODS AND MATERIALS/METHODS:Between July 1998 and February 2007, 34 patients with recurrent HNC received 38 HDR-IORT treatments using a Harrison-Anderson-Mick applicator with Iridium-192. A single fraction (median, 15 Gy; range, 10-20 Gy) was delivered intraoperatively after surgical resection to the region considered at risk for close or positive margins. In all patients, the target region was previously treated with external beam radiation therapy (median dose, 63 Gy; range, 24-74 Gy). The 1- and 2-year estimates for in-field local progression-free survival (LPFS), locoregional progression-free survival (LRPFS), distant metastases-free survival (DMFS), and overall survival (OS) were calculated. RESULTS:With a median follow-up for surviving patients of 23 months (range, 6-54 months), 8 patients (24%) are alive and without evidence of disease. The 1- and 2-year LPFS rates are 66% and 56%, respectively, with 13 (34%) in-field recurrences. The 1- and 2-year DMFS rates are 81% and 62%, respectively, with 10 patients (29%) developing distant failure. The 1- and 2-year OS rates are 73% and 55%, respectively, with a median time to OS of 24 months. Severe complications included cellulitis (5 patients), fistula or wound complications (3 patients), osteoradionecrosis (1 patient), and radiation-induced trigeminal neuralgia (1 patient). CONCLUSIONS:HDR-IORT has shown encouraging local control outcomes in patients with recurrent HNC with acceptable rates of treatment-related morbidity. Longer follow-up with a larger cohort of patients is needed to fully assess the benefit of this procedure.