Precision patient education using a "flipped classroom" approach.

OBJECTIVES: To improve patient education delivered over telemedicine by using a "flipped classroom"-inspired approach. METHODS: A "flipped classroom" is an education strategy used to engage active learning by sending students home with lecture material and reserving classroom time for collaborative learning. To adapt this approach for use in radiation oncology patient education, three pieces of written education material were created: introduction to radiation oncology, treatment planning scan, and treatment delivery. An automated system was created to deliver precisely timed emails at three time points ahead of appointments. Appointment time was then used for collaborative learning with our staff. As a primary endpoint, email engagement metrics were tracked via the automated system. Secondarily, enrolled patients were surveyed to assess level of understanding (before vs. after intervention), anxiety (before vs. after intervention), and satisfaction. Additionally, email delivery timing, clarity, relevance, and patient support were evaluated. Data analyses test the impact of active learning against our existing education approaches. RESULTS: Overall, 77.1% of the emails were opened, and of those, patients accessed 72.2% of the education material. Patients re-read the education material 4.6 times on average. Active learning increased patient understanding regarding the purpose of the treatment planning scan (p = 0.031) and increased patient understanding of what to expect during daily radiation treatments (p = 0.0078). Patients reported reduced anxiety (p = 0.031) and high scores for satisfaction, timing, clarity, relevance, and overall support. CONCLUSIONS: Patient engagement with the education material was high, and they continued to access it many times. Active learning enhances patient comprehension of complex treatment information leading to decreased anxiety. Furthermore, this technique can be incorporated into existing telemedicine with basic technology.

A model combining age, equivalent uniform dose and IL-8 may predict radiation esophagitis in patients with non-small cell lung cancer.

BACKGROUND AND PURPOSE: To study whether cytokine markers may improve predictive accuracy of radiation esophagitis (RE) in non-small cell lung cancer (NSCLC) patients. MATERIALS AND METHODS: A total of 129 patients with stage I-III NSCLC treated with radiotherapy (RT) from prospective studies were included. Thirty inflammatory cytokines were measured in platelet-poor plasma samples. Logistic regression was performed to evaluate the risk factors of RE. Stepwise Akaike information criterion (AIC) and likelihood ratio test were used to assess model predictions. RESULTS: Forty-nine of 129 patients (38.0%) developed grade ≥2 RE. Univariate analysis showed that age, stage, concurrent chemotherapy, and eight dosimetric parameters were significantly associated with grade ≥2 RE (p < 0.05). IL-4, IL-5, IL-8, IL-13, IL-15, IL-1α, TGFα and eotaxin were also associated with grade ≥2 RE (p < 0.1). Age, esophagus generalized equivalent uniform dose (EUD), and baseline IL-8 were independently associated grade ≥2 RE. The combination of these three factors had significantly higher predictive power than any single factor alone. Addition of IL-8 to toxicity model significantly improves RE predictive accuracy (p = 0.019). CONCLUSIONS: Combining baseline level of IL-8, age and esophagus EUD may predict RE more accurately. Refinement of this model with larger sample sizes and validation from multicenter database are warranted.

Neoadjuvant twice daily chemoradiotherapy for esophageal cancer: Treatment-related mortality and long-term outcomes.

OBJECTIVE: Because of the short potential doubling time of esophageal cancer, there is a theoretical benefit to using an accelerated radiation treatment schedule. This study evaluates outcomes and treatment-related mortality and morbidity of patients treated with neoadjuvant hyperfractionated accelerated chemoradiation for resectable esophageal cancer. METHODS AND MATERIALS: Outcomes from 250 consecutive patients with resectable esophageal cancer treated with preoperative hyperfractionated accelerated chemoradiotherapy (45 Gy in 30 twice-daily fractions over 3 weeks) followed by planned transhiatal esophagectomy were analyzed. Grade 3 or greater treatment related toxicity, surgical complications, and treatment-related mortality were determined. Additionally, available surgical specimens were graded for pathological response to chemoradiation. Overall survival (OS) and locoregional control were calculated using the Kaplan-Meier method. The log rank test was used to determine statistical significance. RESULTS: Median follow-up was 59 months for surviving patients; 87% of patients had adenocarcinoma and 13% had squamous cell carcinoma. Eleven percent of patients did not have surgery because of the development of metastases, declining performance status, or refusal. Twenty-seven patients were found to have unresectable and/or metastatic disease at the time of surgery. Overall, 10 of 223 operated patients died within 3 months, resulting in a perioperative mortality rate of 4%. Median OS was 28.4 months (95% confidence interval, 22.3-35.6 months) for all patients and 35.1 months (95% confidence interval, 27.4-47 months) for patients who underwent esophagectomy. There were 32 isolated locoregional failures with a 3-year locoregional control rate of 83%. Of 129 patients who had independent pathology review, 29% had complete response to treatment. This group had a median OS of 98.9 months and 3-year OS of 74%. CONCLUSION: Neoadjuvant twice-daily chemoradiation for esophageal cancer is a safe and effective alternative to daily fractionation with low treatment-related mortality and long-term outcomes similar to standard fractionation courses.

Plasma Levels of IL-8 and TGF-ß1 Predict Radiation-Induced Lung Toxicity in Non-Small Cell Lung Cancer: A Validation Study.

PURPOSE AND OBJECTIVES: We previously reported that the combination of mean lung dose (MLD) and inflammatory cytokines interleukin-8 (IL-8) and transforming growth factor-ß1 (TGF-ß1) may provide a more accurate model for radiation-induced lung toxicity (RILT) prediction in 58 patients with non-small cell lung cancer (NSCLC). This study is to validate the previous findings with new patients and to explore new models with more cytokines. METHODS AND MATERIALS: One hundred forty-two patients with stage I-III NSCLC treated with definitive radiation therapy (RT) from prospective studies were included. Sixty-five new patients were used to validate previous findings, and all 142 patients were used to explore new models. Thirty inflammatory cytokines were measured in plasma samples before RT and 2 weeks and 4 weeks during RT (pre, 2w, 4w). Grade ≥2 RILT was defined as grade 2, and higher radiation pneumonitis or symptomatic pulmonary fibrosis was the primary endpoint. Logistic regression was performed to evaluate the risk factors of RILT. The area under the curve (AUC) for the receiver operating characteristic curves was used for model assessment. RESULTS: Sixteen of 65 patients (24.6%) experienced RILT2. Lower pre IL-8 and higher TGF-ß1 2w/pre ratio were associated with higher risk of RILT2. The AUC increased to 0.73 by combining MLD, pre IL-8, and TGF-ß1 2w/pre ratio compared with 0.61 by MLD alone to predict RILT. In all 142 patients, 29 patients (20.4%) experienced grade ≥2 RILT. Among the 30 cytokines measured, only IL-8 and TGF-ß1 were significantly associated with the risk of RILT2. MLD, pre IL-8 level, and TGF-ß1 2w/pre ratio were included in the final predictive model. The AUC increased to 0.76 by combining MLD, pre IL-8, and TGF-ß1 2w/pre ratio compared with 0.62 by MLD alone. CONCLUSIONS: We validated that a combination of mean lung dose, pre IL-8 level, and TGF-ß1 2w/pre ratio provided a more accurate model to predict the risk of RILT2 compared with MLD alone.

Influence of human papillomavirus on the clinical presentation of oropharyngeal carcinoma in the United States.

OBJECTIVE: Much of what is known about the significance of human papillomavirus (HPV) in oropharyngeal squamous cell carcinoma is derived from single-institution retrospective studies, post hoc analyses of tissue specimens from clinical trials, and tissue bank studies with a small sample size. The objective of this study is to investigate the impact of HPV on the frequency and clinical presentation of oropharyngeal carcinoma in a large, national sample with information from patients who underwent HPV testing. STUDY DESIGN: Retrospective, cross-sectional study. METHODS: We identified a comprehensive national sample of 8,359 patients with oropharyngeal carcinoma and known HPV status diagnosed between 2010 and 2011 within the National Cancer Database. Multivariable logistic regression was used to assess correlates of patient and tumor characteristics on HPV status. RESULTS: Among patients with oropharyngeal carcinoma, the frequency of HPV-related squamous cell carcinoma in the United States was 65.4%. HPV-related oropharyngeal carcinoma was associated with younger age, male sex, and white race (P < 0.001). Advanced primary tumor stage was associated with HPV-negative disease (P < 0.001), whereas increasing nodal burden was associated with HPV-positive disease (P < 0.001). Despite less-advanced nodal disease, HPV-negative tumors were associated with a higher likelihood of metastasis at presentation (P < 0.001). CONCLUSION: HPV now accounts for the majority of newly diagnosed oropharyngeal carcinoma in the United States and is associated with a distinct clinical profile, supporting efforts to re-evaluate the staging and treatment paradigm for HPV-associated oropharyngeal cancer. LEVEL OF EVIDENCE: 4. Laryngoscope, 127:2270-2278, 2017.

Priority-driven plan optimization in locally advanced lung patients based on perfusion SPECT imaging.

PURPOSE: Limits on mean lung dose (MLD) allow for individualization of radiation doses at safe levels for patients with lung tumors. However, MLD does not account for individual differences in the extent or spatial distribution of pulmonary dysfunction among patients, which leads to toxicity variability at the same MLD. We investigated dose rearrangement to minimize the radiation dose to the functional lung as assessed by perfusion single photon emission computed tomography (SPECT) and maximize the target coverage to maintain conventional normal tissue limits. METHODS AND MATERIALS: Retrospective plans were optimized for 15 patients with locally advanced non-small cell lung cancer who were enrolled in a prospective imaging trial. A staged, priority-based optimization system was used. The baseline priorities were to meet physical MLD and other dose constraints for organs at risk, and to maximize the target generalized equivalent uniform dose (gEUD). To determine the benefit of dose rearrangement with perfusion SPECT, plans were reoptimized to minimize the generalized equivalent uniform functional dose (gEUfD) to the lung as the subsequent priority. RESULTS: When only physical MLD is minimized, lung gEUfD was 12.6 ± 4.9 Gy (6.3-21.7 Gy). When the dose is rearranged to minimize gEUfD directly in the optimization objective function, 10 of 15 cases showed a decrease in lung gEUfD of >20% (lung gEUfD mean 9.9 ± 4.3 Gy, range 2.1-16.2 Gy) while maintaining equivalent planning target volume coverage. Although all dose-limiting constraints remained unviolated, the dose rearrangement resulted in slight gEUD increases to the cord (5.4 ± 3.9 Gy), esophagus (3.0 ± 3.7 Gy), and heart (2.3 ± 2.6 Gy). CONCLUSIONS: Priority-driven optimization in conjunction with perfusion SPECT permits image guided spatial dose redistribution within the lung and allows for a reduced dose to the functional lung without compromising target coverage or exceeding conventional limits for organs at risk.

Matted nodes: High distant-metastasis risk and a potential indication for intensification of systemic therapy in human papillomavirus-related oropharyngeal cancer.

BACKGROUND: The purpose of this study was to determine whether matted nodes uniquely identify patients with human papillomavirus (HPV)-positive oropharyngeal cancer at disproportionately high distant failure risk who may benefit from intensified systemic therapy. METHODS: One hundred seventy-eight patients with stage III/IV HPV-positive oropharyngeal cancer who completed definitive chemoradiotherapy were stratified by risk group (low-risk = T1-3/N0-2c/<10 pack-years; intermediate-risk = T1-3/N0-2c/≥10 pack-years; and high-risk = T4 or N3). Prognostic impact of matted nodes was assessed. RESULTS: At the 52-month median follow-up, event rates with and without matted nodes were: locoregional failure: 23.3% versus 12.8% (p = .16), distant failure: 50.0% versus 1.4% (p < .01), any failure: 73.3% versus 14.2% (p < .01); cause-specific mortality: 56.7% versus 5.4% (p < .01), and death: 56.7% versus 13.5% (p < .01). In multivariate analyses, including risk group and individual risk factors, matted nodes were the strongest predictor for all endpoints except locoregional failure. Among patients without matted nodes, risk-group discriminated locoregional failure (at 3 years: low-risk = 2.0%; intermediate-risk = 14.4%; and high-risk = 24.2%; p < .01), but not distant failure (low-risk = 0.0%; intermediate-risk = 2.1%; and high-risk = 3.8%; p = .53). CONCLUSION: Matted nodes portended dramatically increased distant failure and death risks in HPV-positive oropharyngeal cancer, identifying a candidate population for consideration of chemo-intensification. © 2015 Wiley Periodicals, Inc. Head Neck 38: E805-E814, 2016.

Outcomes After Stereotactic Body Radiotherapy or Radiofrequency Ablation for Hepatocellular Carcinoma.

PURPOSE: Data guiding selection of nonsurgical treatment of hepatocellular carcinoma (HCC) are lacking. We therefore compared outcomes between stereotactic body radiotherapy (SBRT) and radiofrequency ablation (RFA) for HCC. PATIENTS AND METHODS: From 2004 to 2012, 224 patients with inoperable, nonmetastatic HCC underwent RFA (n = 161) to 249 tumors or image-guided SBRT (n = 63) to 83 tumors. We applied inverse probability of treatment weighting to adjust for imbalances in treatment assignment. Freedom from local progression (FFLP) and toxicity were retrospectively analyzed. RESULTS: RFA and SBRT groups were similar with respect to number of lesions treated per patient, type of underlying liver disease, and tumor size (median, 1.8 v 2.2 cm in maximum diameter; P = .14). However, the SBRT group had lower pretreatment Child-Pugh scores (P = .003), higher pretreatment alpha-fetoprotein levels (P = .04), and a greater number of prior liver-directed treatments (P < .001). One- and 2-year FFLP for tumors treated with RFA were 83.6% and 80.2% v 97.4% and 83.8% for SBRT. Increasing tumor size predicted for FFLP in patients treated with RFA (hazard ratio [HR], 1.54 per cm; P = .006), but not with SBRT (HR, 1.21 per cm; P = .617). For tumors ≥ 2 cm, there was decreased FFLP for RFA compared with SBRT (HR, 3.35; P = .025). Acute grade 3+ complications occurred after 11% and 5% of RFA and SBRT treatments, respectively (P = .31). Overall survival 1 and 2 years after treatment was 70% and 53% after RFA and 74% and 46% after SBRT. CONCLUSION: Both RFA and SBRT are effective local treatment options for inoperable HCC. Although these data are retrospective, SBRT appears to be a reasonable first-line treatment of inoperable, larger HCC.

Long-term quality of life after swallowing and salivary-sparing chemo-intensity modulated radiation therapy in survivors of human papillomavirus-related oropharyngeal cancer.

PURPOSE: To evaluate long-term health-related quality of life (HRQOL) in 2 prospective studies of chemo-intensity modulated radiation therapy (chemo-IMRT) for oropharyngeal cancer (OPC). METHODS AND MATERIALS: Of 93 patients with stage III/IV OPC treated on prospective studies of swallowing and salivary organ-sparing chemo-IMRT, 69 were eligible for long-term HRQOL assessment. Three validated patient-reported instruments, the Head and Neck QOL (HNQOL) questionnaire, the University of Washington quality of life (UWQOL) questionnaire, and the Xerostomia Questionnaire (XQ), previously administered from baseline through 2 years in the parent studies, were readministered at long-term follow-up, along with the Short-Form 36. Long-term changes in HRQOL from before treatment and 2 years were evaluated. RESULTS: Forty patients (58%) with a median follow-up of 6.5 years participated, 39 of whom (97.5%) had confirmed human papillomavirus-positive OPC. Long term, no clinically significant worsening was detected in mean HRQOL scores compared with 2 years, with stable or improved HRQOL from before treatment in nearly all domains. "Moderate" or greater severity problems were uncommon, reported by 5% of patients for eating, 5% for swallowing, and 2.5% and 5% by HNQOL and UWQOL summary scores, respectively. Freedom from percutaneous endoscopic gastrostomy tube dependence and stricture dilation beyond 2 years was 97.5% and 95%, respectively. Eleven percent and 14% of patients reported "moderate" or "severe" long-term worsening in HNQOL Pain and Overall Bother domains, respectively, which were associated with mean dose to the cervical esophagus, larynx, and pharyngeal constrictors. CONCLUSIONS: At more than 6 years' median follow-up, OPC patients treated with swallowing and salivary organ-sparing chemo-IMRT reported stable or improved HRQOL in nearly all domains compared with both before treatment and 2-year follow-up. New late toxicity after 2 years was uncommon. Further emphasis on sparing the swallowing organs may yield additional HRQOL gains for long-term OPC survivors.

Wide Variation in the Diffusion of a New Technology: Practice-Based Trends in Intensity-Modulated Radiation Therapy (IMRT) Use in the State of Michigan, With Implications for IMRT Use Nationally.

PURPOSE: To characterize the adoption and variation of intensity-modulated radiation therapy (IMRT) use in the state of Michigan. METHODS: As a certificate-of-need state, Michigan requires every radiation oncology facility to report the number of external-beam and IMRT treatments delivered annually. We examined the percentage of treatments delivered using IMRT across centers from 2005 to 2012. We constructed a repeated-measures longitudinal linear regression model to evaluate bivariable and multiple variable associations with IMRT use. RESULTS: The median proportion of treatments delivered with IMRT rose from 16% in 2005 to 42% in 2012. All treatment centers in the state of Michigan possessed the capacity to deliver IMRT as of 2009. The fraction of treatments delivered with IMRT varied between 23% and 96% (standard deviation, 19%) in the lowest- and highest-use centers in 2012. Higher IMRT use was significantly associated with freestanding facilities and year of treatment, with a trend toward higher IMRT use in academic centers and low-volume facilities. CONCLUSION: IMRT use grew significantly across the state of Michigan over time, with four-fold variability among centers, which was related to facility characteristics. These data provide no indication of an ideal or appropriate level of IMRT use. Rather, the wide variation in IMRT use among centers indicates a lack of consensus regarding the situations in which IMRT provides significant clinical benefit. This supports further research and interventions to ensure that patients receive appropriate care, regardless of where they are treated.

Treatment planning for SBRT using automated field delivery: A case study.

Stereotactic body radiation therapy (SBRT) treatment planning and delivery can be accomplished using a variety of techniques that achieve highly conformal dose distributions. Herein, we describe a template-based automated treatment field approach that enables rapid delivery of more than 20 coplanar fields. A case study is presented to demonstrate how modest adaptations to traditional SBRT planning can be implemented to take clinical advantage of this technology. Treatment was planned for a left-sided lung lesion adjacent to the chest wall using 25 coplanar treatment fields spaced at 11° intervals. The plan spares the contralateral lung and is in compliance with the conformality standards set forth in Radiation Therapy and Oncology Group protocol 0915, and the dose tolerances found in the report of the American Association of Physicists in Medicine Task Group 101. Using a standard template, treatment planning was accomplished in less than 20 minutes, and each 10Gy fraction was delivered in approximately 5.4 minutes. For those centers equipped with linear accelerators capable of automated treatment field delivery, the use of more than 20 coplanar fields is a viable SBRT planning approach and yields excellent conformality and quality combined with rapid planning and treatment delivery. Although the case study discusses a laterally located lung lesion, this technique can be applied to centrally located tumors with similar results.

Human papillomavirus-related oropharyngeal cancer: HPV and p16 status in the recurrent versus parent tumor.

BACKGROUND: Although typically associated with a favorable prognosis, a minority of human papillomavirus (HPV)-related (+) oropharyngeal cancers recur after chemoradiation. We postulated that a minor HPV-negative tumor subfraction may be responsible for recurrences of HPV+ oropharyngeal cancer. METHODS: Paired untreated primary and recurrent tumor specimens were identified for 37 patients with oropharyngeal cancer who received definitive chemoradiotherapy at our institution. Concordance in HPV/p16 expression between primary and recurrent tumors was assessed. RESULTS: Among 31 patients with HPV+/p16+ primary tumors, 30 (97%) retained evidence of both HPV and p16 expression at recurrence (27 HPV+/p16+; 3 HPV+/p16-partial). One (3%) initially HPV+/p16+ patient developed an HPV-negative/p16-negative lung squamous cell carcinoma (SCC), representing either a discordant oropharyngeal cancer metastasis or second primary tumor. CONCLUSION: HPV-related oropharyngeal cancers retain HPV+/p16+ expression at recurrence. Our results fail to provide evidence that a minor HPV-negative tumor subfraction is responsible for biologically aggressive behavior of HPV+ oropharyngeal cancer that recurs after chemoradiation.

Estimating functional liver reserve following hepatic irradiation: adaptive normal tissue response models.

PURPOSE: To estimate the limit of functional liver reserve for safe application of hepatic irradiation using changes in indocyanine green, an established assay of liver function. MATERIALS AND METHODS: From 2005 to 2011, 60 patients undergoing hepatic irradiation were enrolled in a prospective study assessing the plasma retention fraction of indocyanine green at 15-min (ICG-R15) prior to, during (at 60% of planned dose), and after radiotherapy (RT). The limit of functional liver reserve was estimated from the damage fraction of functional liver (DFL) post-RT [1-(ICG-R15pre-RT/ICG-R15post-RT)] where no toxicity was observed using a beta distribution function. RESULTS: Of 48 evaluable patients, 3 (6%) developed RILD, all within 2.5 months of completing RT. The mean ICG-R15 for non-RILD patients pre-RT, during-RT and 1-month post-RT was 20.3%(SE 2.6), 22.0%(3.0), and 27.5%(2.8), and for RILD patients was 6.3%(4.3), 10.8%(2.7), and 47.6%(8.8). RILD was observed at post-RT damage fractions of ≥78%. Both DFL assessed by during-RT ICG and MLD predicted for DFL post-RT (p<0.0001). Limiting the post-RT DFL to 50%, predicted a 99% probability of a true complication rate <15%. CONCLUSION: The DFL as assessed by changes in ICG during treatment serves as an early indicator of a patient's tolerance to hepatic irradiation.

Refining risk stratification for locoregional failure after chemoradiotherapy in human papillomavirus-associated oropharyngeal cancer.

BACKGROUND: To determine whether the addition of molecular and imaging biomarkers to established clinical risk factors could help predict locoregional failure (LRF) after chemoradiation in human papillomavirus (HPV)-related (+) oropharyngeal cancer (OPC) and improve patient selection for locoregional treatment de-intensification. METHODS: HPV status was determined for 198 consecutive patients with stage III/IV OPC treated with definitive chemoradiation from 5/2003 to 10/2010. The impact of pre-therapy epidermal growth factor receptor (EGFR) overexpression; imaging biomarkers including primary tumor and nodal maximum standardized uptake values on FDG-PET, gross tumor volumes, and matted nodes; and clinical factors on LRF (including residual disease at adjuvant neck dissection) was assessed. RESULTS: Primary tumors were HPV+ in 184 patients and HPV-negative in 14. EGFR overexpression was related to HPV-negative status and was univariately associated with LRF in the overall population, but was neither retained in the multivariate model after adjustment for HPV status, nor associated with LRF in HPV+ patients. Similarly, imaging biomarkers were univariately associated with LRF, but correlated with T-stage and/or N-stage and did not remain predictive in HPV+ patients after adjustment for T4- and N3-stages, which were the only significant predictors of LRF on multivariate analysis. Among HPV+ patients with non-T4- or N3-stages, only minimal smoking was associated with decreased LRF. CONCLUSIONS: The prognostic impact of EGFR overexpression and imaging biomarkers on LRF was predominantly related to their association with HPV-negative status and T- or N-stage, respectively. Among HPV+ OPC patients treated with uniform chemoradiation, only T4-stage, N3-stage, and smoking contributed to risk-stratification for LRF.

Nonendemic HPV-positive nasopharyngeal carcinoma: association with poor prognosis.

PURPOSE: To investigate the relationship between human papillomavirus (HPV) and Epstein-Barr virus (EBV) in nonendemic nasopharyngeal carcinoma (NPC) and assess the prognostic implications of viral status. METHODS AND MATERIALS: Paraffin-embedded tumor specimens from 62 patients with primary NPC diagnosed between 1985 and 2011 were analyzed for EBV and high-risk HPV. EBV status was determined by the use of in situ hybridization for EBV encoded RNA. HPV status was assessed with p16 immunohistochemistry and multiplex polymerase chain reaction MassArray for determination of HPV type. Proportional hazards models were used to compare the risk of death among patients as stratified by viral status. RESULTS: Of 61 evaluable tumors, 26 (43%) were EBV-positive/HPV-negative, 18 (30%) were HPV-positive/EBV-negative, and 17 (28%) were EBV/HPV-negative. EBV and HPV infection was mutually exclusive. HPV positivity was significantly correlated with World Health Organization grade 2 tumors, older age, and smoking (all P<.001). The racial distribution of the study population was 74% white, 15% African American, and 11% Asian/Middle Eastern. Among HPV-positive patients, 94% were white. At a median follow-up time of 7 years, HPV-positive and EBV/HPV-negative tumors exhibited worse outcomes than did EBV-positive tumors, including decreased overall survival (hazard ratio [HR] 2.98, P=.01; and HR 3.89, P=.002), progression-free survival (HR 2.55, P=.02; and HR 4.04, P<.001), and locoregional control (HR 4.01, P=.03; and HR 6.87, P=.001). CONCLUSION: In our Midwestern population, high-risk HPV infection may play an etiologic role in the development of nonendemic, EBV-negative NPC. Compared with EBV-positive NPC, HPV-positive and EBV/HPV-negative NPC are associated with worse outcomes. A larger confirmatory study is needed to validate these findings.

Dose to the inferior rectum is strongly associated with patient reported bowel quality of life after radiation therapy for prostate cancer.

PURPOSE: To evaluate rectal dose and post-treatment patient-reported bowel quality of life (QOL) following radiation therapy for prostate cancer. METHODS: Patient-reported QOL was measured at baseline and 2-years via the expanded prostate cancer index composite (EPIC) for 90 patients. Linear regression modeling was performed using the baseline score for the QUANTEC normal tissue complication probability model and dose volume histogram (DVH) parameters for the whole and segmented rectum (superior, middle, and inferior). RESULTS: At 2-years the mean summary score declined from a baseline of 96.0-91.8. The median volume of rectum treated to ≥70 Gy (V70) was 11.7% for the whole rectum and 7.0%, 24.4%, and 1.3% for the inferior, middle, and superior rectum, respectively. Mean dose to the whole and inferior rectum correlated with declines in bowel QOL while dose to the mid and superior rectum did not. Low (V25-V40), intermediate (V50-V60) and high (V70-V80) doses to the inferior rectum influenced bleeding, incontinence, urgency, and overall bowel problems. Only the highest dose (V80) to the mid-rectum correlated with rectal bleeding and overall bowel problems. CONCLUSIONS: Segmental DVH analysis of the rectum reveals associations between bowel QOL and inferior rectal dose that could significantly influence radiation planning and prognostic models.

Reliability of post-chemoradiotherapy F-18-FDG PET/CT for prediction of locoregional failure in human papillomavirus-associated oropharyngeal cancer.

OBJECTIVES: Although widely adopted, the accuracy of post-chemoradiotherapy (CRT) 18F-fluorodeoxygluocose positron emission tomography/computed tomography (PET/CT) for predicting locoregional failure (LRF) in human papillomavirus-related (HPV+) oropharyngeal cancer (OPC) remains poorly characterized. We assessed the predictive value of 3-month PET/CT response for LRF in this population. MATERIALS AND METHODS: 101 consecutive patients with stage III-IV HPV+ OPC who underwent definitive CRT with pre-treatment and 3-month post-CRT PET/CT at our institution from 3/2005-3/2011 were included. 3-month PET/CT response was re-classified as complete-response (CR), near-CR, or incomplete-response (

High-risk human papillomavirus detection in oropharyngeal, nasopharyngeal, and oral cavity cancers: comparison of multiple methods.

IMPORTANCE: Human papillomaviruses are now recognized as an etiologic factor in a growing subset of head and neck cancers and have critical prognostic importance that affects therapeutic decision making. There is no universally accepted gold standard for high-risk HPV (hrHPV) assessment in formalin-fixed, paraffin-embedded (FFPE) tissue specimens, nor is there a clear understanding of the frequency or role of hrHPV in sites other than oropharynx. OBJECTIVE: To determine the optimal assessment of hrHPV in FFPE head and neck tumor tissue specimens. DESIGN, SETTING, PARTICIPANTS: In the setting of a large Midwestern referral center, assessment of hrHPV by p16 immunohistochemical staining, in situ hybridization, and polymerase chain reaction (PCR)-MassArray (PCR-MA), with L1 PGMY-PCR and sequencing to resolve method discordance, was conducted for 338 FFPE oropharyngeal, nasopharyngeal, and oral cavity tumor tissue specimens. Relative sensitivity and specificity were compared to develop a standard optimal test protocol. Tissue specimens were collected from 338 patients with head and neck cancer treated during the period 2001 through 2011 in the departments of Otolaryngology, Radiation Oncology, and Medical Oncology. INTERVENTION: Patients received standard therapy. MAIN OUTCOMES AND MEASURES: Optimal hrHPV identification, detection, and activity in head and neck cancers. RESULTS: Using combined PCR-MA with L1 PGMY-PCR and sequencing for conclusive results, we found PCR-MA to have 99.5% sensitivity and 100% specificity, p16 to have 94.2% sensitivity and 85.5% specificity, and in situ hybridization to have 82.9% sensitivity and 81.0% specificity. Among HPV-positive tumors, HPV16 was most frequently detected, but 10 non-HPV16 types accounted for 6% to 50% of tumors, depending on the site. Overall, 86% of oropharynx, 50% of nasopharynx, and 26% of oral cavity tumors were positive for hrHPV. CONCLUSIONS AND RELEVANCE: PCR-MA has a low DNA (5 ng) requirement effective for testing small tissue samples; high throughput; and rapid identification of HPV types, with high sensitivity and specificity. PCR-MA together with p16INK4a provided accurate assessment of HPV presence, type, and activity and was determined to be the best approach for HPV testing in FFPE head and neck tumor tissue specimens.

Stereotactic body radiation therapy for primary and metastatic liver tumors.

OBJECTIVES: The full potential of stereotactic body radiation therapy (SBRT), in the treatment of unresectable intrahepatic malignancies, has yet to be realized as our experience is still limited. Thus, we evaluated SBRT outcomes for primary and metastatic liver tumors, with the goal of identifying factors that may aid in optimization of therapy. METHODS: From 2005 to 2010, 62 patients with 106 primary and metastatic liver tumors were treated with SBRT to a median biologic effective dose (BED) of 100 Gy (42.6-180). The majority of patients received either three (47%) or five fractions (48%). Median gross tumor volume (GTV) was 8.8 cm(3) (0.2-222.4). RESULTS: With a median follow-up of 18 months (0.46-46.8), freedom from local progression (FFLP) was observed in 97 of 106 treated tumors, with 1- and 2-year FFLP rates of 93% and 82%. Median overall survival (OS) for all patients was 25.2 months, with 1- and 2-year OS of 81% and 52%. Neither BED nor GTV significantly predicted for FFLP. Local failure was associated with a higher risk of death [hazard ratio (HR) = 5.1, P = .0007]. One Child-Pugh Class B patient developed radiation-induced liver disease. There were no other significant toxicities. CONCLUSIONS: SBRT provides excellent local control for both primary and metastatic liver lesions with minimal toxicity. Future studies should focus on appropriate selection of patients and on careful assessment of liver function to maximize both the safety and efficacy of treatment.

The addition of low-dose-rate brachytherapy and androgen-deprivation therapy decreases biochemical failure and prostate cancer death compared with dose-escalated external-beam radiation therapy for high-risk prostate cancer.

BACKGROUND: The objective of this study was to determine whether the addition of low-dose-rate brachytherapy or androgen-deprivation therapy (ADT) improves clinical outcome in patients with high-risk prostate cancer (HiRPCa) who received dose-escalated radiotherapy (RT). METHODS: Between 1995 and 2010, 958 patients with HiRPCa were treated at Schiffler Cancer Center (n = 484) or at the University of Michigan (n = 474) by receiving either dose-escalated external-beam RT (EBRT) (n = 510; minimum prescription dose, 75 grays [Gy]; median dose, 78 Gy) or combined-modality RT (CMRT) consisting of (103) Pd implants (n = 369) or (125) I implants (n = 79) both with pelvic irradiation (median prescription dose, 45 Gy). The cumulative incidences of biochemical failure (BF) and prostate cancer-specific mortality (PCSM) were estimated by using the Kaplan-Meier method and Fine and Gray regression analysis. RESULTS: The median follow-up was 63.2 months (interquartile range, 35.4-99.0 months), and 250 patients were followed for >8 years. Compared with CMRT, patients who received EBRT had higher prostate-specific antigen levels, higher tumor classification, lower Gleason sum, and more frequent receipt of ADT for a longer duration. The 8-year incidence BF and PCSM among patients who received EBRT was 40% (standard error, 38%-44%) and 13% (standard error, 11%-15%) compared with 14% (standard error, 12%-16%; P < .0001) and 7% (standard error 6%-9%; P = .003) among patients who received CMRT. On multivariate analysis, the hazard ratios (HRs) for BF and PCSM were 0.35 (95% confidence interval [CI], 0.23-0.52; P < .0001) and 0.41 (95% CI, 0.23-0.75; P < .003), favoring CMRT. Increasing duration of ADT predicted decreased BF (P = .04) and PCSM (P = .001), which was greatest with long-term ADT (BF: HR, 0.33; P < .0001; 95% CI, 0.21-0.52; PCSM: HR, 0.30; P = .001; 95% CI, 0.15-0.6) even in the subgroup that received CMRT. CONCLUSIONS: In this retrospective comparison, both low-dose-rate brachytherapy boost and ADT were associated with decreased risks of BF and PCSM compared with EBRT.