M.C. Abramowitz

Contemporary Update of a Multi-Institutional Predictive Nomogram for Salvage Radiotherapy After Radical Prostatectomy

PURPOSE We aimed to update a previously published, multi-institutional nomogram of outcomes for salvage radiotherapy (SRT) following radical prostatectomy (RP) for prostate cancer, including patients treated in the contemporary era. METHODS Individual data from node-negative patients with a detectable post-RP prostate-specific antigen (PSA) treated with SRT with or without concurrent androgen-deprivation therapy (ADT) were obtained from 10 academic institutions. Freedom from biochemical failure (FFBF) and distant metastases (DM) rates were estimated, and predictive nomograms were generated. RESULTS Overall, 2,460 patients with a median follow-up of 5 years were included; 599 patients (24%) had a Gleason score (GS) ≤ 6, 1,387 (56%) had a GS of 7, 244 (10%) had a GS of 8, and 230 (9%) had a GS of 9 to 10. There were 1,370 patients (56%) with extraprostatic extension (EPE), 452 (18%) with seminal vesicle invasion (SVI), 1,434 (58%) with positive surgical margins, and 390 (16%) who received ADT (median, 6 months). The median pre-SRT PSA was 0.5 ng/mL (interquartile range, 0.3 to 1.1). The 5-yr FFBF rate was 56% overall, 71% for those with a pre-SRT PSA level of 0.01 to 0.2 ng/mL (n = 441), 63% for those with a PSA of 0.21 to 0.50 ng/mL (n = 822), 54% for those with a PSA of 0.51 to 1.0 ng/mL (n = 533), 43% for those with a PSA of 1.01 to 2.0 ng/mL (n = 341), and 37% for those with a PSA > 2.0 ng/mL (n = 323); P < .001. On multivariable analysis, pre-SRT PSA, GS, EPE, SVI, surgical margins, ADT use, and SRT dose were associated with FFBF. Pre-SRT PSA, GS, SVI, surgical margins, and ADT use were associated with DM, whereas EPE and SRT dose were not. The nomogram concordance indices were 0.68 (FFBF) and 0.74 (DM). CONCLUSION Early SRT at low PSA levels after RP is associated with improved FFBF and DM rates. Contemporary nomograms can estimate individual patient outcomes after SRT in the modern era.

Association of multiparametric MRI quantitative imaging features with prostate cancer gene expression in MRI-targeted prostate biopsies

Standard clinicopathological variables are inadequate for optimal management of prostate cancer patients. While genomic classifiers have improved patient risk classification, the multifocality and heterogeneity of prostate cancer can confound pre-treatment assessment. The objective was to investigate the association of multiparametric (mp)MRI quantitative features with prostate cancer risk gene expression profiles in mpMRI-guided biopsies tissues. Global gene expression profiles were generated from 17 mpMRI-directed diagnostic prostate biopsies using an Affimetrix platform. Spatially distinct imaging areas (‘habitats’) were identified on MRI/3D-Ultrasound fusion. Radiomic features were extracted from biopsy regions and normal appearing tissues. We correlated 49 radiomic features with three clinically available gene signatures associated with adverse outcome. The signatures contain genes that are over-expressed in aggressive prostate cancers and genes that are under-expressed in aggressive prostate cancers. There were significant correlations between these genes and quantitative imaging features, indicating the presence of prostate cancer prognostic signal in the radiomic features. Strong associations were also found between the radiomic features and significantly expressed genes. Gene ontology analysis identified specific radiomic features associated with immune/inflammatory response, metabolism, cell and biological adhesion. To our knowledge, this is the first study to correlate radiogenomic parameters with prostate cancer in men with MRI-guided biopsy.

Patient-reported quality of life after stereotactic body radiation therapy versus moderate hypofractionation for clinically localized prostate cancer

BACKGROUND AND PURPOSE Evaluate changes in bowel, urinary and sexual patient-reported quality of life following treatment with moderately hypofractionated radiotherapy (<5Gray/fraction) or stereotactic body radiation therapy (SBRT;5-10Gray/fraction) for prostate cancer. MATERIALS AND METHODS In a pooled multi-institutional analysis of men treated with moderate hypofractionation or SBRT, we compared minimally detectable difference in bowel, urinary and sexual quality of life at 1 and 2years using chi-squared analysis and logistic regression. RESULTS 378 men received moderate hypofractionation compared to 534 men who received SBRT. After 1year, patients receiving moderate hypofractionation were more likely to experience worsening in bowel symptoms (39.5%) compared to SBRT (32.5%; p=.06), with a larger difference at 2years (37.4% versus 25.3%, p=.002). Similarly, patients receiving moderate fractionation had worsening urinary symptom score compared to patients who underwent SBRT at 1 and 2years (34.7% versus 23.1%, p<.001; and 32.8% versus 14.0%, p<.001). There was no difference in sexual symptom score at 1 or 2years. After adjusting for age and cancer characteristics, patients receiving SBRT were less likely to experience worsening urinary symptom scores at 2years (odds ratio: 0.24[95%CI: 0.07-0.79]). CONCLUSIONS Patients who received SBRT or moderate hypofractionation have similar patient-reported change in bowel and sexual symptoms, although there was worse change in urinary symptoms for patients receiving moderate hypofractionation.

Comparison Between Adjuvant and Early-Salvage Postprostatectomy Radiotherapy for Prostate Cancer With Adverse Pathological Features

Importance Prostate cancer with adverse pathological features (ie, pT3 and/or positive margins) after prostatectomy may be managed with adjuvant radiotherapy (ART) or surveillance followed by early-salvage radiotherapy (ESRT) for biochemical recurrence. The optimal timing of postoperative radiotherapy is unclear. Objective To compare the clinical outcomes of postoperative ART and ESRT administered to patients with prostate cancer with adverse pathological features. Design, Setting, and Participants This multi-institutional, propensity score–matched cohort study involved 1566 consecutive patients who underwent postprostatectomy ART or ESRT at 10 US academic medical centers between January 1, 1987, and December 31, 2013. Propensity score 1-to-1 matching was used to account for covariates potentially associated with treatment selection. Data were collected from January 1 to September 30, 2016. Data analysis was conducted from October 1, 2016, to October 21, 2017. Main Outcomes and Measures Freedom from postirradiation biochemical failure, freedom from distant metastases, and overall survival. All outcomes were measured from date of surgery to address lead-time bias. Results Of 1566 patients, 1195 with prostate-specific antigen levels of 0.1 to 0.5 ng/mL received ESRT and 371 patients with prostate-specific antigen levels lower than 0.1 ng/mL received ART. The median age (interquartile range) was 60 (55-65) years. After propensity score matching, the median (interquartile range) follow-up after surgery was similar between the ESRT and ART groups (73.3 [44.9-106.6] months vs 65.8 [40-107] months; P = .22). Adjuvant RT, compared with ESRT, was associated with higher freedom from biochemical failure (12-year actuarial rates: 69% [95% CI, 60%-76%] vs 43% [95% CI, 35%-51%]; effect size, 26%), freedom from distant metastases (95% [95% CI, 90%-97%] vs 85% [95% CI, 76%-90%]; effect size, 10%), and overall survival (91% [95% CI, 84%-95%] vs 79% [95% CI, 69%-86%]; effect size, 12%). Adjuvant RT, lower Gleason score and T stage, nodal irradiation, and postoperative androgen deprivation therapy were favorable prognostic features on multivariate analysis for biochemical failure. Sensitivity analysis demonstrated that the decreased risk of biochemical failure associated with ART remained significant unless more than 56% of patients in the ART group were cured by surgery alone. This threshold is greater than the estimated 12-year freedom from biochemical failure rate of 33% to 52% after radical prostatectomy alone, as determined by a contemporary dynamic nomogram. Conclusions and Relevance Adjuvant RT, compared with ESRT, was associated with reduced biochemical recurrence, distant metastases, and death for high-risk patients, pending prospective validation. These findings suggest that a greater proportion of patients with prostate cancer who have adverse pathological features may benefit from postprostatectomy ART rather than surveillance followed by ESRT.

Head and neck second primary cancer rates in the human papillomavirus era: A population‐based analysis

Patients with head and neck cancer are at high risk for second primary malignancies. Human papillomavirus (HPV)‐driven tumors are generally high‐grade oropharyngeal cancers. We analyzed the incidence of second primary malignancy of the head and neck in patients with primary squamous cell carcinoma (SCC) of the head and neck and temporal trends in the HPV era.

Concurrent radiotherapy with carboplatin and cetuximab for the treatment of medically compromised patients with locoregionally advanced head and neck squamous cell carcinoma

Background: Cetuximab (Cx) + radiation therapy (RT) is well-tolerated and has improved survival in patients (pts) with locoregionally advanced head and neck squamous cell carcinomas (LA-HNSCC). However, its efficacy when compared to HD-DDP + RT has been questioned. At our institution, low-dose weekly carboplatin is added to Cx + RT for patients unsuitable for HD-DDP. Methods: We reviewed records of 16 patients with LA-HNSCC treated with definitive Cx + carboplatin + RT at the University of Miami from 2007 to 2011. Median follow-up was 24 months (range: 1–69 months). Results: Median age: 71.5 years (range: 57–90 years); 15 male, 1 female. ECOG PS 0 = 15, 1 = 1. TNM staging was: T1 = 1, T2 = 5, T3 = 8, T4 = 2; N stage: N0 = 8, N1 = 5, N2a = 2, N2b = 1. All patients received weekly carboplatin (AUC 1.5–2), Cx given conventionally and daily conventionally fractionated RT. Median total weeks of concurrent systemic therapy = 7 (range: 3–8 weeks). RT was delivered to a median total dose of 70 Gy (range 30–74 Gy). Of the 15 evaluable patients, there were: 12 CR, 2 PR, and 1 PD. There were three local in-field failures, two regional failures, and three distant failures. At last follow-up, 8/15 patients remained with NED. Three-year locoregional recurrence was 28.3% (95% CI: 7.7–53.9%). Mean percentage of weight loss was 14% (range: 6–26%). Two patients required systemic therapy dose reduction. Three patients experienced a treatment delay and three did not finish RT as planned including a patient who received only 30 Gy due to death secondary to MI during treatment. Conclusion: In this small retrospective series, carboplatin/Cx/RT was well-tolerated and efficacious in patients unsuitable for HD-DDP having LA-HNSCC. Acute toxicities were similar to Cx + RT, likely due to the non-overlapping toxicity profiles of the two systemic agents. We hypothesize that the addition of a well-tolerated cytotoxic chemotherapy agent may improve the therapeutic ratio of Cx + RT in patients who are poor candidates for more aggressive therapies and warrants evaluation in a prospective manner.

Weighing the Addition of Androgen Suppression Therapy to Radiotherapy Dose Escalation for Intermediate-Risk Prostate Cancer

Men with intermediate-risk prostate cancer have a number of treatment options. These include external-beam radiation therapy (EBRT) alone and EBRT combined with short-term androgen suppression therapy (AST), among others such as brachytherapy and prostatectomy. When EBRT is the selected primary treatment option, short-term AST for 4 to 6 months should be strongly considered because the data supporting its use are overwhelmingly positive. The Harvard study reported by D’Amico et al and the Radiation Therapy Oncology Group (RTOG; now part of NRG Oncology) trial 9408 reported by Jones et al both randomly assigned intermediate-risk men between EBRT alone or EBRT plus 6 or 4 months of short-term AST beginning 2 months prior to the start of EBRT; both showed a survival benefit in the short-term AST arms. In addition, there is no evidence that shortterm AST longer than 4 months confers additional benefit in patients with intermediate-risk prostate cancer. In the RTOG 9910 trial, Pisansky et al compared 4months of short-termASTwith 9months of intermediate-term AST (7 months of neoadjuvant and 2 months of concurrent AST with EBRT) in 1,579 men who were randomly assigned to treatment. These investigators found no difference in the primary end point of cause-specific survival or in other end points, including biochemical-based end points. All of these trials involved relatively low total doses of EBRT, termed standard-dose EBRT, of 66 to 70 Gy in standard fractionation of 1.8 to 2.0 Gy per day. Level I evidence supports the use of 4 months of AST with standard doses of EBRT for men with intermediate-risk prostate cancer. In the article accompanying this editorial, the results of European Organisation for Research and Treatment of Cancer (EORTC) trial 22991 are described by Bolla et al. Approximately 75% of the 819 men were at intermediate risk and 25% were high risk. The study adds to our body of knowledge concerning the efficacy of short-term AST plus EBRT, showing a significant and substantial improvement in the primary end point of biochemical disease-free survival when 6 months of short-term AST was combined with institution-selected total EBRT doses of 70 (n 5 200), 74 (n 5 416), or 78 (n 5 197) Gy. The overall biochemical disease-free 5-year survival rates were 83% for those with AST versus 70% for those without AST. The 10-year survival rates appear to be more pronounced, with further separation of the curves. A statistically significant benefit from ASTwas also seen in clinical disease-free survival. As expected, at this juncture in a predominantly intermediate-risk cohort, there was no difference in overall survival (OS). The study relates well to prior randomized trials on this topic. Dose-escalated EBRT has been shown in several studies to improve biochemical freedom from failure in patients with intermediateto high-risk prostate cancer. However, the impact of adding AST to EBRTon cause-specific and overall survival has been much more consistent and pronounced. With long-term follow up in an MD Anderson Cancer Center dose-escalation study comparing 70 Gy to 78 Gy (no AST was used), patients with intermediate(levels of prostate-specific androgen . 10 ng/mL) or high-risk disease experienced longer survival; however, patient numbers were small in this subgroup analysis. Preliminarily, Michalski et al described an interim analysis of the RTOG 0126 dose-escalation trial comparing 70.2 Gy with 79.2 Gy. With a median follow up of 76 months and 329 events (in 1,532 men who were randomly assigned) at the interim analysis (715 events were planned for the final definitive analysis), there was no difference in OS, the planned primary end point. Notably, there was a robust reduction in biochemical failure in the higher-dose arm. The interim analysis was reported because the OS end point crossed the futility boundary. In contrast, in virtually every phase III trial comparing EBRT alone to EBRT plus AST, a cause-specific or overall survival benefit has been seen over time. Although dose escalation has become the standard for men with intermediate-risk prostate cancer, the addition of AST is a powerful adjunct. An interesting aspect of EORTC-22991 is the dose-escalation component. The balance between the use of AST and radiation dose is a topic of much interest. However, as the investigators point out, this is an exploratory subgroup analysis. At each dose level, the benefit of AST was maintained; yet, in the multivariable analyses described, no significant interaction was found with EBRT dose. There are a number of questions related to the combination of radiotherapy and AST, including: (1) whether there is a benefit from adding AST to dose-escalated EBRT (dose escalated EBRT 6 AST), which seems to be the case in EORTC-22991; and (2) whether EBRT dose escalation improves results when AST is given (standard dose EBRT 1 AST v dose-escalated EBRT 1 AST), which was not statistically significant in the EORTC-22991 heterogeneity analysis. In

Automatic Detection and Quantitative DCE-MRI Scoring of Prostate Cancer Aggressiveness

Purpose To develop a robust and clinically applicable automated method for analyzing Dynamic Contrast Enhanced (DCE-) MRI of the prostate as a guide for targeted biopsies and treatments. Materials and methods An unsupervised pattern recognition (PR) method was used to analyze prostate DCE-MRI from 71 sequential radiotherapy patients. Identified regions of interest (ROIs) with increased perfusion were assigned either to the peripheral (PZ) or transition zone (TZ). Six quantitative features, associated with the washin and washout part of the weighted average DCE curve from the ROI, were calculated. The associations between the assigned DCE-scores and Gleason Score (GS) were investigated. A heatmap of tumor aggressiveness covering the entire prostate was generated and validated with histopathology from MRI-ultrasound fused (MRI-US) targeted biopsies. Results The volumes of the PR-identified ROI’s were significantly correlated with the highest GS from the biopsy session for each patient. Following normalization (and only after normalization) with gluteus maximus muscle’s DCE signal, the quantitative features in PZ were significantly correlated with GS. These correlations straightened in subset of patients with available MRI-US biopsies when GS from the individual biopsies were used. Area under the receiver operating characteristics curve for discrimination between indolent vs aggressive cancer for the significant quantitative features reached 0.88–0.95. When DCE-scores were calculated in normal appearing tissues, the features were highly discriminative for cancer vs no cancer both in PZ and TZ. The generated heatmap of tumor aggressiveness coincided with the location and GS of the MRI-US biopsies. Conclusion A quantitative approach for DCE-MRI analysis was developed. The resultant map of aggressiveness correlated well with tumor location and GS and is applicable for integration in radiotherapy/radiology imaging software for clinical translation.

Multi-institutional Evaluation of Elective Nodal Irradiation and/or Androgen Deprivation Therapy with Postprostatectomy Salvage Radiotherapy for Prostate Cancer

BACKGROUND Outcomes with postprostatectomy salvage radiation therapy (SRT) are not ideal. Little evidence exists regarding potential benefits of adding whole pelvic radiation therapy (WPRT) alone or in combination with androgen deprivation therapy (ADT). OBJECTIVE To explore whether WPRT and/or ADT added to prostate bed radiation therapy (PBRT) improves freedom from biochemical failure (FFBF) or distant metastases (DM). DESIGN, SETTING, AND PARTICIPANTS A database was compiled from 10 academic institutions of patients with postprostatectomy prostate-specific antigen (PSA) >0.01 ng/ml; pT1-4, Nx/0, cM0; and Gleason score (GS) ≥7 treated between 1987 and 2013. Median follow-up was 51 mo. INTERVENTIONS WPRT and/or ADT in addition to PBRT. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSES FFBF and DM were calculated using cumulative incidence estimation. Multivariable analysis (MVA) utilized cumulative incidence regression. RESULTS AND LIMITATION Median pre-SRT PSA was 0.5 ng/ml for 1861 patients. Median follow-up for patients not experiencing biochemical failure (BF) was 55 mo. MVA showed increased BF for PBRT versus WPRT (hazard ratio [HR] 1.82, p<0.001) and no ADT versus ADT (HR 1.70, p<0.001). WPRT was associated with a 5-yr FFBF of 62% versus 49% (p<0.001) for PBRT. ADT use was associated with improved 5-yr FFBF (55% vs 50%, p=0.012). No significant differences in DM cumulative incidence were found. CONCLUSIONS For patients with GS ≥7 receiving SRT, clinicians should weigh FFBF benefits of WPRT and ADT against toxicities. Future studies should explore the impact of WPRT on quality of life, clinical progression, and overall survival. PATIENT SUMMARY We evaluated patients with prostate cancer treated with radiation after surgery to remove the prostate. Both radiation to the pelvic lymph nodes and suppression of testosterone lowered the chance of increasing prostate-specific antigen (a marker for cancer returning).

Ethnicity and Clinical Outcomes in Head and Neck Cancer: an Analysis of the SEER Database

BackgroundWe evaluated the differences within various ethnic groups diagnosed with head and neck cancer in the USA with a specific focus on the clinical outcomes of patients of Hispanic ethnicity.Material/MethodsWe used the Surveillance, Epidemiology, and End Results (SEER) database to examine the clinical outcomes of patients with head and neck cancer by ethnicity, region of origin, place of birth, treatment modality, primary location, age, gender, and SEER tumor stage.ResultsFor all patients, African American race conferred the worst prognosis for head and neck cancer (1.41; CI 1.361–1.454), while non-US born Hispanics had the best prognosis (0.74; 0.684–0.804). US born Hispanics (0.86; CI 0.823–0.892) had a significantly better prognosis than Whites (ref.).ConclusionThe Hispanic population appears to have a better prognosis compared to their Caucasian peers while both do better than Blacks across all stages and in local and regional disease subsets. Furthermore, non-US born Hispanics had a better prognosis than US born Hispanics. The cause of this disparity is unclear and warrants further investigation.