Faculty Bibliography

PURPOSE/OBJECTIVE:To investigate the effects of androgen-deprivation therapy (ADT) on MRI parameters and evaluate their associations with treatment response measures. MATERIALS AND METHODS/METHODS:The study included 30 men with histopathologically confirmed prostate cancer who underwent MRI before and after initiation of ADT. Thirty-four tumours were volumetrically assessed on DW-MRI (n = 32) and DCE-MRI (n = 18), along with regions of interest in benign prostatic tissue, to calculate apparent diffusion coefficient (ADC) and transfer constant (K(trans)) values. Changes in MRI parameters and correlations with clinical parameters (change in prostate-specific antigen [PSA], treatment duration, PSA nadir) were assessed. RESULTS:Prostate volume and PSA values decreased significantly with therapy (p < 0.001). ADC values increased significantly in tumours and decreased in benign prostatic tissue (p < 0.05). Relative changes in ADC and absolute post-therapeutic ADC values differed significantly between tumour and benign tissue (p < 0.001). K(trans) decreased significantly only in tumours (p < 0.001); relative K(trans) changes and post-therapeutic values were not significantly different between tumour and benign tissue. The relative change in tumour ADC correlated significantly with PSA decrease. No changes were associated with treatment duration or PSA nadir. CONCLUSIONS:Multi-parametric MRI shows significant measurable changes in tumour and benign prostate caused by ADT and may help in monitoring treatment response. KEY POINTS/CONCLUSIONS:• Androgen-deprivation therapy caused changes of ADC, K (trans) in tumour and benign prostate. • Prostate volume and PSA values decreased significantly with therapy. • ADC values may be helpful for monitoring treatment response.

BACKGROUND:Although intensity-modulated radiotherapy (IMRT) is a standard of care for many head and neck cancers, its use for carotid-sparing (CS) therapy in early-stage laryngeal carcinoma is controversial. METHODS:330 consecutive patients with early-stage laryngeal carcinoma were treated from 1/1989 to 5/2011, including 282 conventional radiotherapy (CRT) and 48 CS-IMRT patients. The median follow-up was 43 (CS-IMRT) and 66 (CRT) months. RESULTS:There was no difference in local failure rates comparing patients undergoing CS-IMRT with CRT, with 3-year local control rates of 88% vs. 89%, respectively (p=0.938). Using a 1cm circumferential margin, the average dose to the left and right carotid arteries was 48.3 and 47.9 Gy, respectively. 88% of locoregional recurrences involved the ipsilateral true vocal cord, including all local recurrences in the IMRT group. CONCLUSIONS:These results warrant further prospective evaluation of CS-IMRT for early-stage glottic larynx cancer.

BACKGROUND:We evaluated outcomes of intraoperative radiotherapy delivered with focal high-dose-rate (HDR) brachytherapy [intraoperative radiotherapy (IORT)] in the management of locally recurrent (LR) and locally advanced (LA) primary T4 colorectal carcinoma (CRC). LR CRC or LA primary disease is a clinical challenge due to the difficulty in obtaining negative margins after radical surgery and the high risk of subsequent recurrence. Few data exist on long-term outcomes of patients treated with surgery and HDR-IORT for LR or LA primary CRC. METHODS:Three hundred CRC patients underwent HDR-IORT to the pelvis with gross surgical resection during November 1992-December 2007. Median follow-up for surviving patients was 53 (range 5-216) months. Eighty-eight patients (29 %) were treated for LA primary and 212 (71 %) LR disease. HDR-IORT was delivered using an iridium-192 remote afterloader and a Harrison-Anderson-Mick applicator. Median IORT dose was 1,500 (range 1,000-2,000) cGy. RESULTS:Five-year overall survival probability was 49 %. Positive margin status was associated with inferior overall survival and disease-free survival. Competing-risks analysis for time to local failure and distant metastases identified a 5-year cumulative incidence of local failure and distant metastases of 33 and 47 %, respectively. Five-year cumulative incidence of local failure was 22 % for the LA group and 38 % in the LR group. Five-year probability of disease-free survival was 48 and 31 % for LA and LR patients, respectively, and 5-year probability of overall survival was 56 and 45 % for LA and LR patients, respectively. CONCLUSIONS:HDR-IORT combined with resection results in encouraging local control rates with acceptable toxicity for patients with locally aggressive CRC.

BACKGROUND:The management of biochemical failure (BF) following external beam radiotherapy (EBRT) for prostate cancer is controversial, due to both the heterogeneous disease course following a BF and a lack of clinical trials in this setting. OBJECTIVE:We sought to characterize the natural history and predictors of outcome for patients experiencing BF in a large cohort of men with localized prostate cancer undergoing definitive dose-escalated EBRT. DESIGN, SETTING, AND PARTICIPANTS/METHODS:This retrospective analysis included 2694 patients with localized prostate cancer treated with EBRT at a large academic center. Of these, 609 experienced BF, defined as prostate-specific antigen (PSA) nadir + 2 ng/ml. The median follow-up was 83 mo for all patients and 122 mo for BF patients. INTERVENTION(S)/METHODS:All patients received EBRT at doses of 75.6-86.4 Gy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS/METHODS:The primary objective of this study was to determine predictors of distant progression at the time of BF. Cox proportional hazards models were used in univariate and multivariate analyses of distant metastases (DM), and a competing risks method was used to analyze prostate cancer-specific mortality (PCSM). RESULTS AND LIMITATIONS/CONCLUSIONS:From the date of BF, the median times to DM and PCSM mortality were 5.4 yr and 10.5 yr, respectively. Shorter posttreatment PSA doubling time, a higher initial clinical tumor stage, a higher pretreatment Gleason score, and a shorter interval from the end of radiotherapy to BF were independent predictors for clinical progression following BF. Patients with two of these risk factors had a significantly higher incidence of DM and PCSM following BF than those with zero or one risk factor. The main limitations of this study are its retrospective nature and heterogeneous salvage interventions. CONCLUSIONS:Clinical and pathologic factors can help identify patients at high risk of clinical progression following BF. PATIENT SUMMARY/RESULTS:In this report, we look at predictors of outcome for patients with prostate cancer recurrence, as determined by prostate-specific antigen (PSA) levels, following radiation treatment. We found that the approximate median times to distant metastasis and death from prostate cancer for patients in this situation were 5 yr and 10 yr, respectively. Furthermore, we found that patients with a rapid increase in PSA levels following treatment, a short time to PSA recurrence, invasion of extraprostatic organs, or a high Gleason score had worse outcomes.

PURPOSE/OBJECTIVE:To compare the potential benefits of continuous monitoring of prostate position and intervention (CMI) using 2-mm displacement thresholds during stereotactic body radiation therapy (SBRT) treatment to those of a conventional image-guided procedure involving single localization prior to treatment. METHODS AND MATERIALS/METHODS:Eighty-nine patients accrued to a prostate SBRT dose escalation protocol were implanted with radiofrequency transponder beacons. The planning target volume (PTV) margin was 5 mm in all directions, except for 3 mm in the posterior direction. The prostate was kept within 2 mm of its planned position by the therapists halting dose delivery and, if necessary, correcting the couch position. We computed the number, type, and time required for interventions and where the prostate would have been during dose delivery had there been, instead, a single image-guided setup procedure prior to each treatment. Distributions of prostate displacements were computed as a function of time. RESULTS:After the initial setup, 1.7 interventions per fraction were required, with a concomitant increase in time for dose delivery of approximately 65 seconds. Small systematic drifts in prostate position in the posterior and inferior directions were observed in the study patients. Without CMI, intrafractional motion would have resulted in approximately 10% of patients having a delivered dose that did not meet our clinical coverage requirement, that is, a PTV D95 of >90%. The posterior PTV margin required for 95% of the dose to be delivered with the target positioned within the PTV was computed as a function of time. The margin necessary was found to increase by 2 mm every 5 minutes, starting from the time of the imaging procedure. CONCLUSIONS:CMI using a tight 2-mm displacement threshold was not only feasible but was found to deliver superior PTV coverage compared with the conventional image-guided procedure in the SBRT setting.

BACKGROUND:Castration-resistant prostate cancer (CRPC) is a near uniformly fatal form of prostate cancer; however, information on time to development and predictors for progression to CRPC is limited. We report a detailed longitudinal study for development of CRPC in men initially treated with external beam radiotherapy (EBRT). METHODS:During 1991-2008, 2,478 patients with clinically localized prostate cancer were treated with dose-escalated EBRT at a single institution. The primary objective was to determine predictors of CRPC among men who failed definitive EBRT and progressed to salvage androgen-deprivation therapy (ADT). CRPC was defined as castrate levels of testosterone (<50 ng/dl) with progressive biochemical or radiographic disease. RESULTS:For the entire cohort (n = 2,478), the 10-year cumulative incidence rate for developing CRPC was 9.9%. For those that progressed to salvage ADT (n = 362), the 7-year cumulative incidence rates for developing CRPC from time of salvage ADT was 33.7%. Amongst this cohort, multivariable analysis demonstrated that PSA doubling-time (continuous; hazard ratio [HR], 0.98 [0.97-0.99], P < 0.001), higher Gleason score (HR, 1.96 [1.12-3.43]; P = 0.034), and duration of ADT at time of EBRT (continuous; HR, 1.02 [1.01-1.03]; P = 0.007) were associated with development of CRPC. CONCLUSIONS:This represents the first report of predictors of CRPC for patients treated with modern dose-escalated EBRT. We demonstrate that among the minority of patients not initially cured after EBRT, those treated with longer-course ADT have higher rates of resistance to the re-introduction of ADT. Future trials will need to test this subgroup with more aggressive or alternative forms of salvage therapies.

PURPOSE/OBJECTIVE:Small cell carcinoma of the urinary bladder (SCCB) is rare. We report our experience using definitive external beam radiation therapy (EBRT) as part of multimodality management of SCCB. METHODS AND MATERIALS/METHODS:Nineteen patients with locoregional SCCB were treated at our institution with EBRT between January 1994 and September 2012. Five patients had radiographic nodal disease. Eighteen patients received neoadjuvant (17/19; 89%) or concurrent (11/19: 58%) platinum-based chemotherapy. Acute (<90 days) and late (>90 days) toxicity was recorded using Common Terminology Criteria for Adverse Events, version 4. The Kaplan-Meier method was used for survival analysis and a log-rank test used to compare subsets of patients. RESULTS:Median follow-up was 26 months. Three patients had in-bladder recurrence (2-year local recurrence, 25%), 2 being noninvasive and successfully managed with transurethral resection and the third being invasive but managed with chemotherapy alone due to simultaneous distant metastases. No patient underwent salvage cystectomy. Six patients had recurrence distantly (2-year distant recurrence, 40%), predominantly bone metastases (n = 3). No patients developed brain metastases. Actuarial 2-year disease-free and overall survival was 51% and 78%, respectively. The 2-year distant metastasis-free survival for node-negative and node-positive patients was 76% and 26%, respectively (P = .04). The 2-year incidence of distant metastases for patients receiving ≥4 cycles of doublet chemotherapy was 27%, compared with 75% with less chemotherapy (P = .01). The incidence of grade ≥2 acute and late genitourinary or gastrointestinal toxicity was 69% and 7%, respectively. CONCLUSIONS:Definitive chemoradiation for locoregional SCCB is well tolerated, with encouraging local control and overall survival at 2 years.