David D. Wilson

p16 Not a Prognostic Marker for Hypopharyngeal Squamous Cell Carcinoma

OBJECTIVE To investigate the prognostic significance of p16 in patients with hypopharyngeal squamous cell carcinoma (HPSCC) and to evaluate the relationship between p16 and human papillomavirus (HPV). Unlike in oropharyngeal SCC (OPSCC), the prognostic significance of p16 in HPSCC and its association with HPV is unclear. DESIGN Retrospective medical chart review. SETTING University tertiary referral center. PATIENTS A total of 27 patients with HPSCC treated with definitive radiation therapy between 2002 and 2011 whose tissue was available for immunohistochemical analysis. INTERVENTIONS Twenty-two patients were treated with chemoradiation, and 5 with radiation alone. All tumor biopsy specimens were analyzed for p16 and, when sufficient tissue was available, for HPV DNA. MAIN OUTCOME MEASURES Overall survival (OS), locoregional control (LRC), disease-free survival (DFS), and laryngoesophageal dysfunction-free survival (LEDFS) were analyzed according to p16 status. RESULTS Findings for p16 were positive in 9 tumors and negative in 18 tumors. Median follow-up was 29.3 months. There was no significant difference in OS, LRC, DFS, or LEDFS for patients with p16-positive vs p16-negative tumors. Only 1 of the 19 tumors tested for HPV was found to be HPV positive. When used as a test for HPV, p16 had a positive predictive value of 17%. CONCLUSIONS In contrast to OPSCC, p16 expression in patients with HPSCC had a low positive predictive value for HPV and did not predict improved OS, LRC, DFS, or LEDFS. Thus, for HPSCC, p16 is not a prognostic biomarker. Caution must be taken when extrapolating the prognostic significance of p16 in patients with OPSCC to patients with head and neck SCC of other subsites.

p16, Cyclin D1, and HIF-1α Predict Outcomes of Patients with Oropharyngeal Squamous Cell Carcinoma Treated with Definitive Intensity-Modulated Radiation Therapy

We evaluated a panel of 8 immunohistochemical biomarkers as predictors of clinical response to definitive intensity-modulated radiotherapy in patients with oropharyngeal squamous cell carcinoma (OPSCC). 106 patients with OPSCC were treated to a total dose of 66–70 Gy and retrospectively analyzed for locoregional control (LRC), disease-free survival (DFS), and overall survival (OS). All tumors had p16 immunohistochemical staining, and 101 tumors also had epidermal growth factor receptor (EGFR) staining. 53% of the patients had sufficient archived pathologic specimens for incorporation into a tissue microarray for immunohistochemical analysis for cyclophilin B, cyclin D1, p21, hypoxia-inducible factor-1α (HIF-1α), carbonic anhydrase, and major vault protein. Median followup was 27.2 months. 66% of the tumors were p16 positive, and 34% were p16 negative. On univariate analysis, the following correlations were statistically significant: p16 positive staining with higher LRC (P = 0.005) and longer DFS (P < 0.001); cyclin D1 positive staining with lower LRC (P = 0.033) and shorter DFS (P = 0.002); HIF-1α positive staining with shorter DFS (P = 0.039). On multivariate analysis, p16 was the only significant independent predictor of DFS (P = 0.023). After immunohistochemical examination of a panel of 8 biomarkers, our study could only verify p16 as an independent prognostic factor in OPSCC.

Treatment‐related complications of radiation therapy after radical prostatectomy: comparative effectiveness of intensity‐modulated versus conformal radiation therapy

Intensity‐modulated radiation therapy (IMRT) is frequently utilized after prostatectomy without strong evidence for an improvement in outcomes compared to conformal radiation therapy (RT). We analyzed a large group of patients treated with RT after radical prostatectomy (RP) to compare complications after IMRT and CRT. The Surveillance, Epidemiology and End Results (SEER)‐Medicare database was queried to identify male Medicare beneficiaries aged 66 years or older who underwent prostatectomy with 1+ adverse pathologic features and received postprostatectomy RT between 1995 and 2007. Chi‐square test was used to compare baseline characteristics between the treatment groups. First complication events, based upon administrative procedure or diagnosis codes occurring >1 year after start of RT, were compared for IMRT versus CRT groups. Propensity score adjustment was performed to adjust for potential confounders. Multivariable Cox proportional hazards models of time to first complication were performed. A total of 1686 patients were identified who received RT after RP (IMRT = 634, CRT = 1052). Patients treated with IMRT were more likely to be diagnosed after 2004 (P < 0.001), have minimally invasive prostatectomy (P < 0.001) and have positive margins (P = 0.019). IMRT use increased over time. After propensity score adjustment, IMRT was associated with lower rate of gastrointestinal (GI) complications, and higher rate of genitourinary‐incontinence complications, compared to CRT. The observed outcomes after IMRT must be considered when determining the optimal approach for postprostatectomy RT and warrant additional study.

Prognostic Significance of p16 and Its Relationship With Human Papillomavirus in Pharyngeal Squamous Cell Carcinomas

IMPORTANCE The prognostic significance of p16 in squamous cell carcinoma (SCC) of the hypopharynx (HP) and nasopharynx (NP) and relationship between human papillomavirus (HPV) and p16 is unclear. OBJECTIVES To evaluate the prognostic significance of p16 in pharyngeal subsites (oropharynx [OP], HP, and NP) and assess the relationship between HPV and p16 in the HP and NP. DESIGN, SETTING, AND PARTICIPANTS Retrospective medical record review of 172 patients with SCC of the pharynx treated with definitive radiation therapy from 2002 to 2013 at a university tertiary referral center, with tissue available for immunohistochemical analysis. The median follow-up was 30.1 months. INTERVENTIONS A total of 118 patients were treated with chemoradiation, and 54 patients were treated with radiation alone. Immunohistochemical analysis for p16 was performed for all tumors. Hypopharynx and NP tumors were tested for HPV using in situ hybridization, and NP tumors were tested for Epstein-Barr virus. MAIN OUTCOMES AND MEASURES Overall survival, locoregional control, and disease-free survival were analyzed according to p16, HPV, and Epstein-Barr virus status. RESULTS Thirty-two patients had HP SCC, 127 had OP SCC, and 13 had NP SCC. p16 Was positive in the HP (34%), OP (66%), and NP (46%). Prevalence of HPV was 14% in the HP and 50% in the NP. As a test for HPV, p16 had a positive predictive value of 38% (HP) and 67% (NP) and a negative predictive value of 100% in HP and NP tumors. p16 Status was a significant predictor of all clinical outcomes for patients with OP SCC (P<.001), but not for patients with HP or NP SCC. Patients with Epstein-Barr virus- or HPV-associated NP SCC had improved clinical outcomes. CONCLUSIONS AND RELEVANCE p16 Was not associated with improved outcomes in patients with HP or NP SCC. The positive predictive value of p16 as a test for HPV is too low for p16 testing alone in the HP and NP. However, p16 negativity is sufficient to rule out HPV. As a research approach, we recommend p16 immunohistochemistry as a screening test for HPV in NP SCC and HP SCC followed by confirmatory HPV in situ hybridization when p16 positive.

SU-D-105-06: A Novel QA Process Based On Monte Carlo 2nd Check and Dose Reconstruction From Machine Log File On TomoTherapy

PURPOSE To develop a QA process that combines the pre-treatment plan verification with post-treatment delivery verification. Individual source of error such as dose calculator, MLC, and gantry angle can be isolated and analyzed. METHODS A Monte-Carlo (MC) package, TomoPen, has been modified for pre-treatment plan verification. During TomoTherapy treatment, information such as ion chamber measured output, gantry and couch position, and MVCT exit-detectors fluence are recorded into a log file (rawdata). The log file is retrieved after each treatment and information about the treatment delivery is extracted. MLC movement is obtained through analysis of the exit-detector fluence. The actual delivery information is fed into MC dose calculation to evaluate the overall impact. 255 treatment deliveries in 38 patient plans were analyzed with this process. RESULTS The average percent difference from the MC 2nd check on planned dose was -1.2%. MLC errors have strong correlation with plans. On average, MLC errors were 0.1+/-2.2%, which will produce negligible error. However, error as big as 1.7+/-0.8% was observed. It is also observed that the MLC errors did not have big variations day-to-day for the same patient plan. The LINAC output has been a big source of error. On average, the output dropped by 0.8% during each treatment, and varies day to day as target degrades. The output error for all treatment during a 7 month span has been 1.3+/-1.1%. MC reconstructed dose is found to correlated with the mean MLC and output errors. The log file analysis can be completed in less than 30 seconds and the MC calculation took 2-4 minutes. CONCLUSION We have developed a QA process capable of detecting errors from the planning to treatment delivery for TomoTherapy. The advantage over the existing phantom based QA method is that it provides more information about discrepancies in planning and delivery. This study is supported in part by UVa George Amorino Pilot Grant.

Patterns of Distant Failure and Second Primary Cancers in Patients with Oropharyngeal Squamous Cell Carcinoma: Implications for Surveillance Methodology

Background: We analyzed the pattern of distant metastasis (DM) and secondary primary cancers (SPC) in patients with oropharyngeal squamous cell carcinoma (OPSCC) to develop surveillance guidelines. Methods: A retrospective review of 177 patients with OPSCC treated with intensity modulated radiation therapy ± chemotherapy between 2002 and 2012 was performed to characterize the rate, pattern, and timing of DM and SPC. Results: Sixteen patients (9.0%) developed DM and 9 patients (5.1%) developed a SPC. Overall, 24/177 patients (13.6%) developed a DM and/or SPC for a total of 27 events. 92.6% (25/27) of events were detectable on physical exam and/or chest CT. p16+ patients developed DM later than p16- tumors (23.4 months versus 8.7 months). Conclusions: Chest CT with physical examination detects the majority of DM and SPC in patients with OPSCC and would provide effective surveillance in these patients. A risk adapted surveillance strategy is proposed.

Review of Postoperative and Elective Nodal Irradiation in Head and Neck Cancer

Abstract: Radiotherapy plays a critical role in the nodal management of patients with head and neck cancer. The indications, dose fractionation schedules, and results of postoperative radiation therapy (PORT) and elec-tive nodal management (ENI) in various head and neck cancers are reviewed and summarized with common themes identified. Keywords: Elective irradiation, head and neck cancer, lymph nodes, postoperative irradiation, skin cancer. INTRODUCTION Cancers in the head and neck region commonly spread to regional cervical, retropharyngeal and parotid lymph nodes in a predictable pattern. Man-agement of nodal disease is dependent on primary tumor histology and location, extent of primary and nodal disease, surgical resectability of nodal disease and medical operability of the patient. In patients treated with upfront surgical resection of nodal disease, PORT is commonly utilized to re-duce the risk of regional recurrence. Elective nodal irradiation of draining nodal stations has been shown to reduce regional recurrence as well. For example, in mucosal squamous cell carcinomas of the head and neck large prospective, randomized trials have been conducted to define the role for postoperative nodal irradiation and chemotherapy [1,2] and data has existed supporting ENI for at least forty years [3]. The National Comprehensive Cancer Network (NCCN) provides updated con-sensus guidelines for PORT and ENI for common cancers of the head and neck region and these guidelines are a valuable resource for clinicians that provide a national standard for radiation treatment [4-7].