Faculty Bibliography

PURPOSE/OBJECTIVE:To assess radiotherapy (RT)-induced changes in the urethra and periurethral tissues after treatment for prostate cancer (PCa). METHODS AND MATERIALS/METHODS:This retrospective study included 108 men (median age, 64 years; range, 43-87 years) who received external-beam radiotherapy (EBRT) and/or brachytherapy for PCa and underwent endorectal-coil MRI of the prostate within 180 days before RT and a median of 20 months (range, 2-62 months) after RT. On all MRIs, two readers independently measured the urethral length (UL) and graded the margin definition (MD) of the urethral wall and the signal intensities (SIs) of the urethral wall and pelvic muscles on 4-point scales. RESULTS:The mean urethral length decreased significantly from pre- to post-RT MRI (from 15.2 to 12.6mm and from 14.4 to 12.9 mm for readers 1 and 2, respectively; both p-values <0.0001). Brachytherapy resulted in greater urethral shortening than EBRT. After RT, SI in the urethral wall increased in 57% (62/108) and 35% (38/108) of patients (readers 1 and 2, respectively). The frequency and magnitude of SI increase in pelvic muscles depended on muscle location. In the obturator internus muscle, SI increased more often after EBRT than after brachytherapy, while in the periurethral levator ani muscle SI increased more often after brachytherapy than after EBRT. CONCLUSION/CONCLUSIONS:After RT for PCa, MRI shows urethral shortening and increased SI of the urethral wall and pelvic muscles in substantial percentages of patients.

BACKGROUND:Treatment-related toxicity and quality of life (QoL) considerations are important when counseling patients with localized prostate cancer (PCa). OBJECTIVE:To determine the incidence and longitudinal pattern of late genitourinary (GU) toxicity and QoL after high-dose, intensity-modulated radiotherapy (IMRT). DESIGN, SETTING, AND PARTICIPANTS/METHODS:A total of 268 patients with localized PCa were treated between June 2004 and December 2008 at a tertiary referral center. Median follow-up was 5 yr (range: 3-7.7 yr). INTERVENTION/METHODS:Patients underwent IMRT to a total dose of 86.4Gy; 50% of patients underwent neoadjuvant and concurrent androgen-deprivation therapy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS/METHODS:Patients were evaluated with the prospectively obtained International Prostate Symptom Score (IPSS) questionnaire. GU toxicity was also scored using the Common Terminology Criteria for Adverse Events (CTCAE) v.4.0; toxicity events were defined as increase over baseline. Differences in increases in IPSS sums and QoL index between baseline IPSS sum and QoL index groups were analyzed using the Kruskal-Wallis and Mann-Whitney tests. Univariate and multivariate Cox regression models were applied. RESULTS AND LIMITATIONS/CONCLUSIONS:The overall median IPSS sum increase during follow-up was 3 and was less pronounced among patients with severe baseline symptoms compared with those with mild baseline symptoms (median increase: 0 vs 4; p<0.0001). Overall QoL index was unchanged after IMRT but appeared to improve in patients with dissatisfied baseline QoL compared with satisfied baseline QoL (p<0.0001). Fifty-five (20%) and 2 (1%) patients developed grade 2 and 3 late GU toxicities, respectively; however, in 28 of 57 patients (49%), toxicity resolved during follow-up. Even though the IPSS data were prospectively obtained, most patients were not treated within a prospective protocol. CONCLUSIONS:Late GU toxicity after high-dose IMRT was mild; severe, late GU toxicity was rare. Changes in IPSS sum and QoL index were dependent on the baseline GU function, which might be useful for future patient counseling.

BACKGROUND:The management of intermediate-risk prostate cancer (PCa) is controversial, in part due to the heterogeneous nature of patients falling within this classification. OBJECTIVE:We propose a new risk stratification system for intermediate-risk PCa to aid in prognosis and therapeutic decision making. DESIGN, SETTING, AND PARTICIPANTS/METHODS:Between 1992 and 2007, 1024 patients with National Comprehensive Cancer Network intermediate-risk PCa and complete biopsy information were treated with definitive external-beam radiation therapy (EBRT) utilizing doses ≥ 81 Gy. Unfavorable intermediate-risk (UIR) PCa was defined as any intermediate-risk patient with a primary Gleason pattern of 4, percentage of positive biopsy cores (PPBC) ≥ 50%, or multiple intermediate-risk factors (IRFs; cT2b-c, prostate-specific antigen [PSA] 10-20, or Gleason score 7). INTERVENTION/METHODS:All patients received EBRT with ≥ 81 Gy with or without neoadjuvant and concurrent androgen-deprivation therapy (ADT). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS/METHODS:Univariate and multivariate analyses were performed using a Cox proportional hazards model for PSA recurrence-free survival (PSA-RFS) and distant metastasis (DM). PCa-specific mortality (PCSM) was analyzed using a competing-risk method. RESULTS AND LIMITATIONS/CONCLUSIONS:Median follow-up was 71 mo. Primary Gleason pattern 4 (hazard ratio [HR]: 3.26; p<0.0001), PPBC ≥ 50% (HR: 2.72; p=0.0007), and multiple IRFs (HR: 2.20; p=0.008) all were significant predictors of increased DM in multivariate analyses. Primary Gleason pattern 4 (HR: 5.23; p<0.0001) and PPBC ≥ 50% (HR: 4.08; p=0.002) but not multiple IRFs (HR: 1.74; p=0.21) independently predicted for increased PCSM. Patients with UIR disease had inferior PSA-RFS (HR: 2.37; p<0.0001), DM (HR: 4.34; p=0.0003), and PCSM (HR: 7.39; p=0.007) compared with those with favorable intermediate-risk disease, despite being more likely to receive neoadjuvant ADT. Short follow-up and retrospective study design are the primary limitations. CONCLUSIONS:Intermediate-risk PCa is a heterogeneous collection of diseases that can be separated into favorable and unfavorable subsets. These groups likely will benefit from divergent therapeutic paradigms.

There have been significant improvements in the radiotherapeutic management of patients with high risk prostate cancer. Randomized trials have clearly demonstrated improved outcomes with the combination of radiotherapy in conjunction with androgen deprivation. While these trials have utilized low doses of radiotherapy in the range of 70 Gy, recent studies have suggested that significant benefits of combined androgen deprivation therapy with dose escalated radiotherapy are also observed. The use of high radiation dose levels in the setting of high risk prostate cancer is important, and strategies which combine external beam radiotherapy with a brachytherapy boost may provide an opportunity for even greater intensification of the radiation dose to the prostate target. Systemic therapies, second generation anti-androgen therapy and novel targeted agents integrated with radiotherapy will open up new vistas and challenges for further improved outcomes in patients with high-risk disease.

To develop an optimization algorithm for volumetric modulated arc therapy which incorporates an electromagnetic tracking (EMT) guided gating strategy and is robust to residual intra-fractional motion uncertainties. In a computer simulation, intra-fractional motion traces from prior treatments with EMT were converted to a probability distribution function (PDF), truncated using a patient specific action volume that encloses allowed deviations from the planned position, and renormalized to yield a new PDF with EMT-gated interventions. In lieu of a conventional planning target volume (PTV), multiple instances of clinical target volume (CTV) and organs at risk (OARs) were replicated and displaced to extreme positions inside the action volume representing possible delivery scenarios. When optimizing the volumetric modulated arc therapy plan, doses to the CTV and OARs were calculated as a sum of doses to the replicas weighted by the PDF to account for motion. A treatment plan meeting the clinical constraints was produced and compared to the counterpart conventional margin (PTV) plan. EMT traces from a separate testing database served to simulate motion during gated delivery. Dosimetric end points extracted from dose accumulations for each motion trace were utilized to evaluate potential clinical benefit. Five prostate cases from a hypofractionated protocol (42.5 Gy in 5 fractions) were retrospectively investigated. The patient specific gating window resulted in tight anterior and inferior action levels (~1 mm) to protect rectal wall and bladder wall, and resulted in an average of four beam interruptions per fraction in the simulation. The robust-optimized plans achieved the same average CTV D95 coverage of 40.5 Gy as the PTV-optimized plans, but with reduced patient-averaged rectum wall D1cc by 2.2 Gy (range 0.7 to 4.7 Gy) and bladder wall mean dose by 2.9 Gy (range 2.0 to 3.4 Gy). Integration of an intra-fractional motion management strategy into the robust optimization process is feasible and may yield improved OAR sparing compared to the standard margin approach.

UNLABELLED:We demonstrate that the androgen receptor (AR) regulates a transcriptional program of DNA repair genes that promotes prostate cancer radioresistance, providing a potential mechanism by which androgen deprivation therapy synergizes with ionizing radiation. Using a model of castration-resistant prostate cancer, we show that second-generation antiandrogen therapy results in downregulation of DNA repair genes. Next, we demonstrate that primary prostate cancers display a significant spectrum of AR transcriptional output, which correlates with expression of a set of DNA repair genes. Using RNA-seq and ChIP-seq, we define which of these DNA repair genes are both induced by androgen and represent direct AR targets. We establish that prostate cancer cells treated with ionizing radiation plus androgen demonstrate enhanced DNA repair and decreased DNA damage and furthermore that antiandrogen treatment causes increased DNA damage and decreased clonogenic survival. Finally, we demonstrate that antiandrogen treatment results in decreased classical nonhomologous end-joining. SIGNIFICANCE/CONCLUSIONS:We demonstrate that the AR regulates a network of DNA repair genes, providing a potential mechanism by which androgen deprivation synergizes with radiotherapy for prostate cancer.

Traditionally, patients treated with chemoradiotherapy for node-positive oropharyngeal squamous cell carcinoma (N+ OPSCC) have undergone a planned neck dissection (ND) after treatment. Recently, negative post-treatment positron-emission tomography (PET)/computed tomography (CT) imaging has been found to have a high negative predictive value for the presence of residual disease in the neck. Here, we present the first comprehensive analysis of a large, uniform cohort of N+ OPSCC patients achieving a PET/CT-based complete response (CR) after chemoradiotherapy, and undergoing observation, rather than ND. From 2002 to 2009, 302 patients with N+ OPSCC treated with 70 Gy intensity-modulated radiation therapy and concurrent chemotherapy underwent post-treatment clinical assessment including PET/CT. CR was defined as no evidence of disease on clinical examination and post-treatment PET/CT. ND was reserved for patients with <CR on either PET/CT, clinical examination, or other imaging. 260 patients (86.1%) had clinical and radiographic CRs, and underwent neck observation (rate of regional control, 97.7%; 5-year overall survival, 79.8%). The four observed patients experiencing neck recurrence had initial staging of N1 (n = 2), N2b (n = 1), and N2c (n = 1). Three of four were successfully surgically salvaged. There was no association between N stage and rate of neck recurrence (p = 0.74). 52 and 25% of patients undergoing ND had viable tumor in the neck after positive and negative PET/CT, respectively. We conclude that patients achieving CRs after chemoradiation, based on clinical and PET/CT assessment, have a high probability of regional control, with a 2.3% regional failure rate, and may be safely observed without planned ND.

PURPOSE/OBJECTIVE:To compare diagnostic accuracy of T2-weighted magnetic resonance (MR) imaging with that of multiparametric (MP) MR imaging combining T2-weighted imaging with diffusion-weighted (DW) MR imaging, dynamic contrast material-enhanced (DCE) MR imaging, or both in the detection of locally recurrent prostate cancer (PCa) after radiation therapy (RT). MATERIALS AND METHODS/METHODS:This retrospective HIPAA-compliant study was approved by the institutional review board; informed consent was waived. Fifty-three men (median age, 70 years) suspected of having post-RT recurrence of PCa underwent MP MR imaging, including DW and DCE sequences, within 6 months after biopsy. Two readers independently evaluated the likelihood of PCa with a five-point scale for T2-weighted imaging alone, T2-weighted imaging with DW imaging, T2-weighted imaging with DCE imaging, and T2-weighted imaging with DW and DCE imaging, with at least a 4-week interval between evaluations. Areas under the receiver operating characteristic curve (AUC) were calculated. Interreader agreement was assessed, and quantitative parameters (apparent diffusion coefficient [ADC], volume transfer constant [K(trans)], and rate constant [k(ep)]) were assessed at sextant- and patient-based levels with generalized estimating equations and the Wilcoxon rank sum test, respectively. RESULTS:At biopsy, recurrence was present in 35 (66%) of 53 patients. In detection of recurrent PCa, T2-weighted imaging with DW imaging yielded higher AUCs (reader 1, 0.79-0.86; reader 2, 0.75-0.81) than T2-weighted imaging alone (reader 1, 0.63-0.67; reader 2, 0.46-0.49 [P ≤ .014 for all]). DCE sequences did not contribute significant incremental value to T2-weighted imaging with DW imaging (reader 1, P > .99; reader 2, P = .35). Interreader agreement was higher for combinations of MP MR imaging than for T2-weighted imaging alone (κ = 0.34-0.63 vs κ = 0.17-0.20). Medians of quantitative parameters differed significantly (P < .0001 to P = .0233) between benign tissue and PCa (ADC, 1.64 × 10(-3) mm(2)/sec vs 1.13 × 10(-3) mm(2)/sec; K(trans), 0.16 min(-1) vs 0.33 min(-1); k(ep), 0.36 min(-1) vs 0.62 min(-1)). CONCLUSION/CONCLUSIONS:MP MR imaging has greater accuracy in the detection of recurrent PCa after RT than T2-weighted imaging alone, with no additional benefit if DCE is added to T2-weighted imaging and DW imaging.