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Background: The p16/CDKN2A protein is being explored as an independent prognostic marker in laryngeal cancer, with studies suggesting that p16-positive patients may have a better prognosis. While its role is well-established in oropharyngeal squamous cell carcinoma (OPSCC) related to HPV, ongoing research indicates its potential prognostic value in laryngeal cancer, even in HPV-negative cases., Methods: In this study, we investigated the association between survival outcomes and p16 expression in a cohort of 310 laryngeal cancer patients from the Cancer Genome Atlas (TCGA) Program and the University of Maryland Medical Center (UMMC)., Results: In the TCGA cohort, patients with high p16 protein expression had a significantly higher probability of disease-free survival (DFS) at 89%, compared to 51% in the low p16 protein group (p = 0.0266). Additionally, the mean relative p16 protein expression decreased significantly with advancing TNM stage, measured at 1.116 for stage II, 1.075 for stage III, and 0.6204 for stage IV (p = 0.7871 for stage II vs. stage III, p = 0.0065 for stage III vs. stage IV, p = 0.0031 for stage I vs. stage IV). Protein expression for p16 also correlated with CDKN2A retention/deletion status (p = 0.0077), where the DFS was higher in patients with retained CDKN2A than those with deleted CDKN2A (p = 0.0187). Multivariate analysis of the UMMC and TCGA cohorts revealed that both an increase in the patient's age and higher T stage significantly increased the risk of mortality (p = 0.05, p = 0.01, respectively)., Conclusion: While this study observes trends suggesting that low p16 protein expression is associated with longer DFS and advanced TNM stage in laryngeal cancer, the multivariate analysis did not establish p16 as an independent prognostic factor. These findings suggest that while p16 may have a biological role in tumor progression, its utility as a standalone prognostic marker in clinical outcomes requires further validation., (© 2024 Wiley Periodicals LLC.)

Purpose: Single vocal cord irradiation (SVCI) is a promising technique to maintain excellent oncologic control and potentially improve upon toxicities for treatment of early-stage glottic squamous cell carcinomas. We sought to investigate whether pencil beam scanning (PBS) proton therapy could improve upon the already favorable dose gradients demonstrated with volumetric modulated arc therapy (VMAT) SVCI., Patients and Methods: A 64-year-old gentleman was treated in our department with 6X-flattening filter-free VMAT SVCI to 58.08 Gy in 16 fractions for a T1a well-differentiated squamous cell carcinoma of the left true vocal cord and tolerated it well with good local control. Comparative PBS plans were created in Raystation for the Varian ProBeam with clinical target volume (CTVs) generated to mimic the prescription target volume extent of the VMAT planning target volumes when accounting for PBS plan robustness (±3 mm translational shifts, 3.5% density perturbation). A 3-field single-field optimization plan was selected as dosimetrically preferable. Dosimetric variables were compared., Results: Several organs at risk doses improved with PBS, including the maximum and mean dose to ipsilateral carotids, maximum and mean dose to contralateral carotid, maximum dose to the spinal cord, maximum and mean dose to inferior constrictor/cricopharyngeus, maximum and mean dose to the uninvolved vocal cord, and mean dose to the thyroid gland. There are tradeoffs in skin dose depending on location relative to the target-with the highest and lowest isodoses extending more into the skin with the VMAT plan but with the moderate isodose lines covering a wider area with the PBS plan, but we deemed it tolerable regardless., Conclusion: SVCI is a promising strategy for maintaining the oncologic effectiveness of whole-larynx photon radiation while potentially improving upon the historic toxicity profile. The favorable dose distribution with PBS with respect to organs at risk dosimetry for PBS may allow for further improvements upon VMAT SVCI strategies. Clinical implementation of PBS SVCI may be considered., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Matthew J. Ferris, MD, reports a relationship with Maryland Proton Treatment Center that includes employment. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Surveillance for survivors of head and neck cancer (HNC) is focused on early detection of recurrent or second primary malignancies. After initial restaging confirms disease-free status, the use of surveillance imaging for asymptomatic patients with HNC is controversial. Our objective was to comprehensively review literature pertaining to imaging and biomarker surveillance of asymptomatic patients treated for head and neck squamous cell carcinoma and to convene a multidisciplinary expert panel to provide appropriate use criteria for surveillance in representative clinical scenarios. The evidence base for the appropriate use criteria was gathered through a librarian-mediated search of literature published from 1990 to 2022 focused on surveillance imaging and circulating tumor-specific DNA for nonmetastatic head and neck squamous cell carcinoma using MEDLINE (Ovid), Embase, Web of Science Core Collection, and the Cochrane Central Register of Controlled Trials. The systematic review was reported according to PRISMA guidelines. Using the modified Delphi process, the expert panel voted on appropriate use criteria, providing recommendations for appropriate use of surveillance imaging and human papillomavirus (HPV) circulating tumor DNA. Of 5178 studies identified, 80 met inclusion criteria (5 meta-analyses/systematic reviews, 1 randomized control trial, 1 post hoc analysis, 25 prospective, and 48 retrospective cohort studies [with ≥50 patients]), reporting on 27,525 patients. No large, randomized, prospective trials examined whether asymptomatic patients who receive surveillance imaging or HPV circulating tumor DNA monitoring benefit from earlier detection of recurrence or second primary tumors in terms of disease-specific or quality-of-life outcomes. In the absence of prospective data, surveillance imaging for HNC survivors should rely on individualized recurrence-risk assessment accounting for initial disease staging, HPV disease status, and tobacco use history. There is an emerging surveillance role for circulating tumor biomarkers., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Periodic quality assurance CTs (QACTs) are routine in proton beam therapy. In this study, we tested whether the necessity for a QACT could be determined by evaluating the change in beam path length (BPL) on daily cone-beam CT (CBCT)., Patients and Methods: In this Institutional Review Board-approved study, we retrospectively analyzed 959 CBCT images from 78 patients with sarcomas treated with proton pencil-beam scanning. Plans on 17 QACTs out of a total of 243 were clinically determined to be replanned for various reasons. Daily CBCTs were retrospectively analyzed by automatic ray-tracing of each beam from the isocenter to the skin surface along the central axis. A script was developed for this purpose. Patterns of change in BPL on CBCT images were compared to those from adaptive planning using weekly QACTs., Results: Sixteen of the 17 adaptive replans showed BPL changes ≥4 mm for at least 1 of the beams on 3 consecutive CBCT sessions. Similarly, 43 of 63 nonadaptively planned patients had BPL changes <4 mm for all of the beams. A new QACT criterium of a BPL change of any beam ≥4 mm on 3 consecutive CBCT sessions resulted in a sensitivity of 94.1% and a specificity of 68.3%. Had the BPL change been used as the QACT predictor, a total of 37 QACTs would have been performed rather than 243 QACTs in clinical practice., Conclusion: The use of BPL changes on CBCT images represented a significant reduction (85%) in total QACT burden while maintaining treatment quality and accuracy. QACT can be performed only when it is needed, but not in a periodic manner. The benefits of reducing QACT frequency include reducing imaging dose and optimizing patient time and staff resources., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Objectives: We sought to describe outcomes for locally advanced cutaneous squamous cell carcinoma (SCC) involving the parotid treated with volumetric modulated arc therapy (VMAT) versus pencil beam scanning proton beam therapy (PBT)., Materials and Methods: Patients were gathered from 2016 to 2022 from 5 sites of a large academic RT department; included patients were treated with RT and had parotid involvement by: direct extension of a cutaneous primary, parotid regional spread from a previously or contemporaneously resected but geographically separate cutaneous primary, or else primary parotid SCC (with a cutaneous primary ostensibly occult). Acute toxicities were provider-reported (CTCAE v5.0) and graded at each on treatment visit. Statistical analyses were conducted., Results: Median follow-up was 12.9 months (1.3 - 72.8); 67 patients were included. Positive margins/extranodal extension were present in 34 cases; gross disease in 17. RT types: 39 (58.2 %) VMAT and 28 (41.8 %) PBT. Concurrent systemic therapy was delivered in 10 (14.9 %) patients. There were 17 treatment failures (25.4 %), median time of 168 days. Pathologically positive neck nodes were associated with locoregional recurrence (p = 0.015). Oral cavity, pharyngeal constrictor, and contralateral parotid doses were all significantly lower for PBT. Median weight change was -3.8 kg (-14.1 - 5.1) for VMAT and -3 kg (-16.8 - 3) for PBT (p = 0.013). Lower rates of ≥ grade 1 xerostomia (p = 0.002) and ≥ grade 1 dysguesia (p < 0.001) were demonstrated with PBT., Conclusions: Cutaneous SCC involving the parotid can be an aggressive clinical entity despite modern multimodal therapy. PBT offers significantly lower dose to organs at risk compared to VMAT, which seemingly yields diminished acute toxicities., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Purpose: Noncoplanar plans (NCPs) are commonly used for proton treatment of bilateral head and neck (HN) malignancies. NCP requires additional verification setup imaging between beams to correct residual errors of robotic couch motion, which increases imaging dose and total treatment time. This study compared the quality and robustness of NCPs with those of coplanar plans (CPs)., Methods and Materials: Under an IRB-approved study, CPs were created retrospectively for 10 bilateral HN patients previously treated with NCPs maintaining identical beam geometry of the original plan but excluding couch rotations. Plan robustness to the inter-fractional variation (IV) of both plans was evaluated through the Dose Volume Histograms (DVH) of weekly quality assurance CT (QACT) sets (39 total). In addition, delivery efficiency for both plans was compared using total treatment time (TTT) and beam-on time (BOT)., Results: No significant differences in plan quality were observed in terms of clinical target volume (CTV) coverage (D95) or organ-at-risk (OAR) doses (p > 0.4 for all CTVs and OARs). No significant advantage of NCPs in the robustness to IV was found over CP, either. Changes in D95 of QA plans showed a linear correlation (slope = 1.006, R 2  > 0.99) between NCP and CP for three CTV data points (CTV1, CTV2, and CTV3) in each QA plan (117 data points for 39 QA plans). NCPs showed significantly higher beam delivery time than CPs for TTT (539 ± 50 vs. 897 ± 142 s; p < 0.001); however, no significant differences were observed for BOT., Conclusion: NCPs are not more robust to IV than CPs when treating bilateral HN tumors with pencil-beam scanning proton beams. CPs showed plan quality and robustness similar to NCPs while reduced treatment time (∼6 min). This suggests that CPs may be a more efficient planning technique for bilateral HN cancer proton therapy., (© 2023 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

Objectives: Given emerging data suggesting that uncertainty in the relative biologic effectiveness at the distal end of the Bragg peak results in increased mucosal injury in patients with oropharynx cancer receiving adjuvant proton therapy, we evaluated the results of post-treatment positron emission tomography-computed tomography (PET/CT) in patients with p16-positive oropharynx cancer (p16+OPC) treated with definitive intensity-modulated proton therapy (IMPT)., Material and Methods: A retrospective cohort study of patients with p16+OPC treated with definitive IMPT between 2016 and 2022 was performed at a single institution. Patients with PET/CT scans within 6 months following completion of IMPT were included in the study. Positive post-treatment scans were defined by a maximum standard uptake values (SUVmax) >4.0 or a <65% reduction in SUVmax in either the primary tumor or lymph node. The Fisher's exact test was used to evaluate factors associated with positive post-treatment PET/ CT values., Results: Sixty-two patients were included for analysis. Median follow-up was 21 months (range: 3-71 months) with a median time to post-treatment PET/CT of 3 months (range: 2-6 months). Median post-treatment SUVmax of the primary disease and nodal disease was 0 (mean: 0.8, range: 0-7.7) and 0 (mean: 0.7, range: 0-9.5), respectively. Median post-treatment percent reduction in SUVmax for the primary site and lymph node was 100% (mean: 94%, range: 31.3-100%) and 100% (mean: 89%, range: 23-100%), respectively. Eleven patients had a positive post-treatment PET/CT with one biopsy-proven recurrence. Negative and positive predictive values (NPV and PPV) were 98% and 9.1%, respectively. There were no factors associated with positive post-treatment PET/CT., Conclusion: Similar to patients treated with photon-based radiation therapy, post-treatment PET/CT has a high NPV for patients with p16+OPC treated with definitive proton therapy and should be used to guide patient management. Additional patients and more events are needed to confirm the PPV of a post-treatment PET/CT in this favorable patient cohort., Competing Interests: There are no conflicts of interest., (© 2023 Published by Scientific Scholar on behalf of Journal of Clinical Imaging Science.)

Primary radiation therapy using interstitial brachytherapy (IBT) provides excellent local tumor control for early-stage squamous cell carcinoma of the lip. Technical aspects of treatment are important to optimize outcomes. In this report, we discuss patient selection criteria, procedural details, and dosimetric considerations for performing IBT for cancers of the lip. Catheters are inserted across the length of tumor entering and exiting approximately 5 mm beyond the palpable tumor extent. A custom mouthpiece is fabricated to facilitate normal tissue sparing. Patients undergo computed tomography imaging, the gross tumor volume is contoured based on physical examination and computed tomography findings, and an individualized brachytherapy plan is generated with the goals of achieving gross tumor volume D90% ≥ 90% and minimizing V150%. Ten patients with primary (n = 8) or recurrent (n = 2) cancers of the lip who received high-dose-rate lip IBT using 2.0- to 2.5-week treatment regimens are described (median prescription: 47.6 Gy in 14 fractions of 3.4 Gy). Local tumor control was 100%. There were no cases of acute grade ≥4 or late grade ≥2 toxicity, and cosmesis scores were graded as good to excellent in all patients. IBT represents an excellent treatment option for patients with lip squamous cell carcinoma. With careful attention to technical considerations furthered described in the present report, high rates of tumor control, low rates of toxicity, and favorable esthetic and functional outcomes can be achieved with IBT for lip cancer., (Copyright © 2023 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Background: To determine if the extent of high-dose gross tumor volume (GTV) to clinical target volume (CTV) expansion is associated with local control in patients with p16-positive oropharynx cancer (p16+ OPC) treated with definitive intensity modulated proton therapy (IMPT)., Methods: We performed a retrospective analysis of patients with p16+ OPC treated with IMPT at a single institution between 2016 and 2021. Patients with a pre-treatment PET-CT and restaging PET-CT within 4 months following completion of IMPT were analyzed., Results: Sixty patients were included for analysis with a median follow-up of 17 months. The median GTV to CTV expansion was 5 mm (IQR: 2 mm). Thirty-three percent of patients (20 of 60) did not have a GTV to CTV expansion. There was one local failure within the expansion group (3%)., Conclusion: Excellent local control was achieved using IMPT for p16+ OPC independent of GTV expansion. IMPT with minimal target expansions represent a potential harm-minimization technique for p16-positive oropharynx cancer., (© 2023 Wiley Periodicals LLC.)

Background: To evaluate disease control, toxicities, and variables associated with clinical outcomes for patients with head and neck squamous cell carcinoma and clinical N3 disease (HNSCC N3) treated with definitive chemoradiation therapy., Methods: We performed a retrospective review of patients with HNSCC N3 treated at two high-volume academic centers between 1996 and 2019., Results: We identified 85 patients with a median follow-up of 2.8 years. Five-year overall survival, regional control, and freedom from distant metastases rates were 38%, 80%, and 80%, respectively. Severe complications were identified in 19% of patients., Conclusions: Favorable regional control is achievable with definitive chemoradiation therapy for patients with HNSCC N3 disease. Distant metastases are a common pattern of failure and should be a focus of prospective study., (© 2023 Wiley Periodicals LLC.)

Objectives: To survey academic and community physician preferences regarding the virtual multidisciplinary tumor board (MTB) for further improvement and expansion., Study Design: This anonymous 14-question survey was sent to individuals that participated in the head and neck virtual MTBs. The survey was sent via email beginning August 3, 2021, through October 5, 2021., Setting: The University of Maryland Medical Center and regional practices in the state of Maryland., Methods: Survey responses were recorded and presented as percentages. Subset analysis was performed to obtain frequency distributions by facility and provider type., Results: There were 50 survey responses obtained with a response rate of 56%. Survey participants included 11 surgeons (22%), 19 radiation oncologists (38%), and 8 medical oncologists (16%), amongst others. More than 96% of participants found the virtual MTB to be useful when discussing complex cases and impactful to future patient care. A majority of respondents perceived a reduction in time to adjuvant care (64%). Community and academic physician responses strongly agreed that the virtual MTB improved communication (82% vs 73%), provided patient-specific information for cancer care (82% vs 73%), and improved access to other specialties (66% vs 64%). Academic physicians, more so than community physicians, strongly agreed that the virtual MTB improves access to clinical trial enrollment (64% vs 29%) and can be useful in obtaining CME (64% vs 55%)., Conclusion: Academic and community physicians view the virtual MTB favorably. This platform can be adapted regionally and further expanded to improve communication between physicians and improve multidisciplinary care for patients., Competing Interests: The authors declare that there are no conflicts of interest., (© 2023 The Authors. OTO Open published by Wiley Periodicals LLC on behalf of American Academy of Otolaryngology–Head and Neck Surgery Foundation.)

Purpose: Treatment planning for head-and-neck (H&N) cancer, in particular oropharynx, nasopharynx, and paranasal sinus cases, at our center requires noncoplanar proton beams due to the complexity of the anatomy and target location. Targeting accuracy for all beams is carefully evaluated by using image guidance before delivering proton beam therapy (PBT). In this study, we analyzed couch shifts to evaluate whether imaging is required before delivering each field with different couch angles., Methods: After the Institutional Review Board approval, a retrospective analysis was performed on data from 28 H&N patients treated with PBT. Each plan was made with two-to-three noncoplanar and two-to-three coplanar fields. Cone-beam computed tomography and orthogonal kilovoltage (kV) images were acquired for setup and before delivering each field, respectively. The Cartesian (longitudinal, vertical, and lateral) and angular (pitch and roll) shifts for each field were recorded from the treatment summary on the first two fractions and every subsequent fifth fraction. A net magnitude of the three-dimensional (3D) shift in Cartesian coordinates was calculated, and a 3D vector was created from the 6 degrees of freedom coordinates for transforming couch shifts in the system coordinate to the beam's-eye view., Results: A total of 3219 Cartesian and 2146 angular shift values were recorded for 28 patients. Of the Cartesian shifts, 2069 were zero (64.3%), and 1150 (35.7%) were nonzero (range, -7 to 11 mm). Of the angular shifts, 1034 (48.2%) were zero, and 1112 (51.8%) were nonzero (range, -3.0° to 3.2°). For 17 patients, the couch shifts increased toward the end of the treatment course. We also found that patients with higher body mass index (BMI) presented increased net couch shifts (p < 0.001). With BMI < 27, all overall net shift averages were <2 mm, and overall maximum net shifts were <6 mm., Conclusions: These results confirm the need for orthogonal kV imaging before delivering each field of H&N PBT at our center, where a couch rotation is involved., (© 2022 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, LLC on behalf of The American Association of Physicists in Medicine.)

Objective: The objective of this study was to examine tumor response with positron emission tomography (PET)/magnetic resonance imaging (MRI) during chemoradiotherapy as a predictor of outcome in patients with p16-positive oropharynx cancer., Materials and Methods: Patients with p16-positive oropharynx cancer were treated with chemoradiotherapy. Low-risk (LR) disease was defined as T1-T3 and N0-2b and ≤10 pack-years and intermediate-risk (IR) disease as T4 or N2c-3 or >10 pack-years. Patients underwent a PET/MRI scan pretreatment and at fraction 10. Change in value of imaging means were analyzed by analysis of variance. K-means clustering with Euclidean distance functions were used for patient clustering. Silhouette width was used to determine the optimal number of clusters. Linear regression was performed on all radiographic metrics using patient and disease characteristics., Results: Twenty-four patients were enrolled with 7 LR and 11 IR patients available for analysis. Pretreatment imaging characteristics between LR and IR patients were similar. Patients with LR disease exhibited a larger reduction in maximum standardized uptake value (SUV) compared with IR patients (P<0.05). Cluster analysis defined 2 cohorts that exhibited a similar intratreatment response. Cluster 1 contained 7 of 7 LR patients and 8 of 11 IR patients. Cluster 2 contained 3 of 11 IR patients. Cluster 2 exhibited significant differences compared with cluster 1 in the change in primary tumor peak SUV and largest lymph node median SUV., Conclusions: We identified that IR p16-positive oropharynx cancers exhibit heterogeneity in their PET/MRI response to chemoradiotherapy. These data support further study of intratreatment imaging response as a potential mechanism to identify patients with IR oropharynx cancer suitable for treatment deintensification., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Chemoradiation for head and neck cancer is associated with a variety of early and late complications. Toxicities may affect the aero-digestive tract (mucositis, salivary gland injury), regional osseous and cartilaginous structures (osteoradionecrosis (ORN) and chondronecrosis), vasculature (progressive radiation vasculopathy and carotid blow out syndromes), and neural structures (optic neuritis, myelitis, and brain injury). These may be difficult to distinguish from tumor recurrence on imaging, and may necessitate the use of advanced MRI and molecular imaging techniques to reach the correct diagnosis. Secondary radiation-induced malignancies include thyroid cancer and a variety of sarcomas that may manifest several years after treatment. Checkpoint inhibitors can cause a variety of adverse immune events, including autoimmune hypophysitis and encephalitis., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: To define the location of the initial contralateral lymph node (LN) metastasis in patients with oropharynx cancer., Methods: The location of the LN centroids from patients with oropharynx cancer and a single radiographically positive contralateral LN was defined. A clinical target volume (CTV) inclusive of all LN centroids was created, and its impact on dose to organs at risk was assessed., Results: We identified 55 patients of which 49/55 had a single contralateral LN in level IIA, 4/55 in level III, 1/55 in level IIB, and 1/55 in the retropharynx. Mean radiation dose to the contralateral parotid gland was 15.1 and 21.0 Gy, (p <0.001) using the modeled high-risk elective CTV and a consensus CTV, respectively., Conclusions: We present a systematic approach for identifying the contralateral nodal regions at highest risk of harboring subclinical disease in patients with oropharynx cancer that warrants prospective clinical study., (© 2021 Wiley Periodicals LLC.)

Background: To evaluate disease control, toxicities, and dose to dysphagia/aspiration risk structures (DARS) using a direct gross tumor volume (GTV 70Gy ) to planning target volume expansion (dPTV 70Gy ) for patients with squamous cell carcinoma of the larynx (LSCC)., Methods: A retrospective review was performed on patients with LSCC treated between 2003 and 2018. Clinical outcomes, toxicities, and dosimetric data were analyzed., Results: Seventy-three patients were identified. Overall survival at 5-years was 57.8%. Five-year local and regional control was 79.8% and 88.2%, respectively. Distant metastatic-only failure was 2.7%. Eighty percent of failures were 95% contained within the dPTV 70Gy . Mean dose and the volume of DARS receiving 70 Gy was significantly lower for dPTV 70Gy compared to a consensus-defined PTV 70Gy ., Discussion: Judicious reduction in high-dose target volumes can preserve high tumor control rates while reducing dose to normal surrounding structures underscoring the potential benefit of this approach in enabling local therapy intensification to improve locoregional control., (© 2020 Wiley Periodicals, Inc.)

Objective: In the context of the opioid epidemic, there is value in examining the use of opioids in specific cancer patient cohorts. We analyzed opioid use in patients undergoing adjuvant therapy for oral cavity cancer to define the incidence of new persistent use beyond 3 months., Study Design: Retrospective., Setting: Comprehensive academic cancer center., Subjects and Methods: We performed a retrospective IRB-approved analysis of opioid use in patients who received adjuvant radiotherapy with or with concurrent systemic therapy for surgically resected oral cavity cancer between 2003 and 2016. Factors associated with opioid use were evaluated by Chi-square test and one-way ANOVA. The Kaplan-Meier method was used to estimate overall survival., Results: Of 77 identified patients, 10 (13%) patients received opioid prescriptions at 3 months or greater following completion of radiotherapy. Patients who were opioid naive prior to surgery required significantly fewer opioid prescriptions than intermittent or chronic opioid users. No specific factors were associated with new persistent opioid use., Conclusions: Patients undergoing surgery and adjuvant radiotherapy for oral cavity cancer who required opioids for cancer treatment related pain are at minimal risk for new dependency. Judicious pain management should be applied for patients with a history of prior opioid use. Larger patient cohorts will be needed to identify patient, disease, and treatment characteristics associated with new persistent use given its limited incidence.

Purpose: To evaluate clinical outcomes and patterns of failure using a direct gross tumor volume to planning target volume expansion in patients with p16-positive oropharyngeal squamous cell carcinoma., Methods and Materials: We performed a retrospective review of patients with p16-positive oropharyngeal squamous cell carcinomas treated between 2002 and 2017 with primary radiotherapy with or without concurrent systemic therapy. Patient and disease characteristics associated with disease control and clinical outcomes were analyzed by Cox proportional hazards regression and Kaplan-Meier analyses. Imaging at the time of first failure was used to categorize failure patterns., Results: We identified 134 patients with a median follow-up of 56.2 months (range 8.2-160.2 months). Local and regional control at 5 years was 91.5% (95% CI: 86.8-96.4%), and 90.8% (95% CI: 85.6-96.2%), respectively. Of the 14 locoregional failures, there were 10 in-field (Type A), 3 marginal (Type B), and 1 geographic (Type E). Age >70 years (HR 5.42; 95% CI: 1.87-15.68) and T4 versus T1-3 (HR 4.09; 95% CI: 1.01-2.65) were associated with increased rates of locoregional failure on multivariate analysis. The rate of gastrostomy tube retention at one year was 6.0% (range 2.8-12.7%)., Conclusions: Management of patients with p16-positive oropharyngeal squamous cell carcinoma using definitive radiotherapy and a high-dose planning target volume created without a gross tumor volume to clinical tumor volume expansion resulted in high locoregional control with the vast majority of failures occurring within the high-dose field. These data warrant prospective evaluation of this technique as a therapy de-intensification approach., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objective We evaluated the ability of the American Joint Committee on Cancer (AJCC) seventh edition staging system to prognosticate the overall survival of patients with human papillomavirus (HPV)-positive laryngeal squamous cell carcinoma. Study Design Retrospective analysis. Setting National Cancer Database. Subjects and Methods Patients diagnosed with laryngeal squamous cell carcinoma who were treated with curative intent were identified in the National Cancer Database. Multivariate analysis was utilized to determine factors correlated with overall survival in the HPV-negative and HPV-positive cohorts. Unadjusted and propensity score-weighted Kaplan-Meier estimation was used to determine overall survival of HPV-negative and HPV-positive patients across AJCC stage groupings. Results We identified 3238 patients with laryngeal squamous cell carcinoma, of which 2812 were HPV negative and 426 were HPV positive. Overall survival adjusted for age, sex, and comorbidity status confirmed significant differences among all consecutive stage groupings (I vs II, P < .001; II vs III, P < .05; III vs IVA, P < .001; IVA vs IVB, P < .05) in the HPV-negative cohort, whereas only stages IVAs and IVB ( P < .01) exhibited a significant difference in overall survival for HPV-positive patients. Conclusion The current AJCC staging system does not accurately distinguish risk of mortality for patients with HPV-positive disease. These data support the consideration of HPV status in estimating prognosis as well as clinical trial design and clinical decision making for patients with laryngeal squamous cell carcinoma.

Objectives: Human papillomavirus (HPV) status is a favorable prognostic marker for patients with oropharyngeal squamous cell carcinoma (OPSCC) and non-metastatic head and neck non-OPSCC. We evaluated the impact of HPV status on overall survival (OS) for patients with Stage IVC non-OPSCC., Materials and Methods: Patients diagnosed with Stage IVC non-OPSCC and known HPV status between 2010-2013 were identified in the National Cancer Database. Univariate and multivariate analyses were performed to determine factors associated with OS. Propensity score-weighted Kaplan-Meier estimation was used to adjust for confounders in OS analyses. Multiple imputation method was used for sensitivity analysis., Results: We identified 708 patients with Stage IVC non-OPSCC with 30% being HPV-positive. Unadjusted median survival was 10.3 months for HPV-negative patients and 21.4 months for HPV-positive patients (p<0.0001). Age ≥ 65 and tumor diameter were associated with worse OS (p<0.05) while treatment versus no treatment and HPV-positive status were associated with improved OS on multivariate analysis (p<0.001). Adjusted median survival for patients with HPV-negative and HPV-positive disease was 11.1 months and 23.8 months, respectively (p<0.001). On unadjusted subgroup analysis, patients with HPV-positive oral cavity disease exhibited improved outcomes (p<0.0001) while HPV-positive hypopharynx (p<0.06) and larynx (p<0.12) patients exhibited a trend for improved OS compared to HPV-negative patients. The survival advantage associated with HPV positivity was maintained on sensitivity analysis (p<0.01)., Conclusion: These data demonstrate a clinically meaningful association between HPV status and OS in patients with non-OSPCC presenting with Stage IVC disease. In the absence of randomized data, these findings support active consideration of HPV status in clinical decision making, clinical trial design, and patient counseling regarding prognosis.

Importance: Radiotherapy (RT)-based organ preservation approaches for patients with advanced laryngeal cancer have been established stepwise through prospective randomized clinical trials. However, broad adoption of these approaches has stimulated discussion about long-term results challenging their applicability in a heterogeneous patient population, most recently for patients with T3 disease., Objective: To define outcomes in patients with clinical T3N0M0 glottic laryngeal cancer treated with definitive surgical and RT-based approaches., Design, Setting, and Participants: This retrospective cohort study included patients treated from January 1, 2004, through December 31, 2013, with a median follow-up time of 58 months (range, 0-126.6 months) in the National Cancer Database. Of the 4003 patients with T3N0M0 disease, 2622 received definitive therapy defined by the study protocol. Data were obtained from the clinical oncology database sourced from hospital registry data that are collected from more than 1500 Commission on Cancer-accredited facilities. Data were analyzed from September 14, 2016, through April 24, 2017., Interventions: Radiotherapy, chemoradiotherapy, surgery, surgery and RT, or surgery and chemoradiotherapy., Main Outcomes and Measures: Five-year overall survival (OS)., Results: A total of 2622 patients (2251 men [85.9%] and 371 women [14.1%]; median age, 64 years [range, 19-90 years]) were included in the analytic cohort. In the overall patient cohort, the adjusted 5-year survival probability was 53%. No statistical differences were observed between the primary surgery (53%; 95% CI, 48%-57%) and primary RT (54%; 95% CI, 52%-57%) cohorts. In multivariate analysis, patient factors associated with decreased OS included age (hazard ratio [HR], 1.04; 95% CI, 1.03-1.04), insurance status (HR, 1.26; 95% CI, 1.06-1.50), and increasing comorbidity (HR, 1.20; 95% CI, 1.02-1.42)., Conclusions and Relevance: Current management of T3N0M0 glottic laryngeal cancer relies largely on RT-based organ preservation approaches. The present study substantiates randomized clinical trial data supporting the use of RT-based organ preservation approaches for patients with T3N0M0 glottic laryngeal cancer without compromising OS.

Background: There is a paucity of data regarding head and neck squamous cell carcinomas (HNSCCs) and N3 nodal disease., Methods: Retrospective analysis of patients with N3 HNSCC identified in the National Cancer Database (NCDB) was performed., Results: We identified 4867 patients with N3 HNSCC treated with primary surgery or chemoradiotherapy (CRT). Propensity-adjusted median survival was 54.2 and 44.8 months for surgery and CRT, respectively (P = .06). Oropharyngeal primary subsite demonstrated a survival advantage with surgery versus CRT with propensity-adjusted median survivals of 86.0 and 61.9 months, respectively (P < .05)., Conclusion: Management of N3 HNSCC relies largely on CRT. Patients with N3 nodal disease with nonoropharyngeal primary tumors exhibit 5-year overall survival approaching 30% independent of initial treatment modality. Patients with oropharyngeal primaries exhibit improved outcomes with surgery largely influenced by the human papillomavirus (HPV)-negative subset. These data represent the most comprehensive analysis of N3 HNSCC outcomes and serves as a foundation for future research and clinical management., (© 2017 Wiley Periodicals, Inc.)

Purpose: We examined overall survival in a large cohort of patients with human papillomavirus (HPV)-positive and HPV-negative non-oropharyngeal squamous cell carcinoma of the head and neck (non-OPSCC)., Methods: Patients diagnosed with non-OPSCC and known HPV status were identified in the National Cancer Database (NCDB). Multivariate logistic regression was applied to examine factors associated with HPV status. Multivariate analysis was utilized to determine factors correlated with overall survival. Propensity score-weighted Kaplan-Meier estimation was used to adjust for confounders in survival analyses. Multiple imputation method was used for sensitivity analysis., Results: We identified 19,993 non-OPSCC patients with 5070 being positive for HPV in the NCDB. Median follow-up was 23.5 months. HPV-positive patients were more commonly male, white, with a lower comorbidity index score, presenting with T-stage <2, and N-stage ≥1. Unadjusted 3-year overall survival was 62% and 80% for HPV-negative and HPV-positive patients, respectively (p < 0.0001). On multivariate analysis, mortality was reduced for HPV-positive patients with early stage (HR = 0.68) and locally advanced disease (HR = 0.46). Adjusted 3-year overall survival was 65% for HPV-negative and 76% for HPV-positive patients (p < 0.0001). The survival advantage of HPV was maintained in all subsites and robust on sensitivity analysis., Conclusions: Patients with HPV-positive non-OPSCC exhibit similar characteristics as HPV-positive OPSCC. Overall survival was significantly higher for patients with HPV-positive versus HPV-negative non-OPSCC. These data reveal that HPV-positive non-OPSCC represent a favorable cohort that warrants recognition in the design of future clinical trial investigation.

Purpose/objective(s): To evaluate treatment trends and overall survival of patients with small cell carcinoma of the head and neck region., Materials/methods: Patients from 2004 to 2012 were identified from the National Cancer Database. Patient demographics and overall survival were analyzed. Multivariable analysis was used to identify predictors of survival., Results: Among 347,252 head and neck patients a total of 1042 (0.3%) patients with small cell carcinoma were identified. 17% of patients were diagnosed as stage I/II, 61% as stage III/IVA/IVB and 22% as stage IVC disease. The distribution by anatomic site was 9% oral cavity, 12% oropharynx, 35% larynx, 4% hypopharynx, 10% nasopharynx and 30% nasal cavity and paranasal sinuses. The median overall survival by anatomical site was 20.8months for oral cavity, 23.7months for oropharynx, 17.9months for larynx/hypopharynx, 15.1months for nasopharynx and 36.4months for nasal cavity primary tumors. On multivariable analysis across stage, patients with nasal cavity and paranasal sinuses tumors had the best survival and patients with nasopharynx primaries had the worst survival. In stage I/II patients, type of treatment delivered resulted in no overall survival difference (p=0.78). In patients with locally advanced disease, there was no difference in survival between those treated with combined surgery, radiotherapy and chemotherapy compared to those treated only with radiotherapy and chemotherapy (p=0.46). The addition of radiotherapy to chemotherapy in the metastatic setting did not result in improved survival (p=0.14)., Conclusions: Small cell carcinoma of the head and neck is a rare malignancy with a poor prognosis. The addition of surgery to radiotherapy and chemotherapy did not improve survival in patients with locally advanced disease., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: The present study evaluated clinical outcomes for patients with head and neck squamous cell carcinoma presenting with N3 nodal disease., Methods: A retrospective analysis of N3 head and neck squamous cell carcinoma patients was performed. Pearson chi-square and Wilcoxon signed-rank tests were used to analyze patient demographics, disease characteristics, and treatment variables. Survival was evaluated using Kaplan-Meier curves with the log-rank test. Univariate analysis using Cox proportional hazards models was used to define factors associated with overall survival. Patient and tumor characteristics associated with treatment assignments were analyzed by univariate multinomial logistic regression., Results: We identified 36 patients with radiographically-defined N3 disease. For the entire cohort, median follow-up was 23.6 (range 2.8-135.0) months, and overall survival was 60% at 2 years and 30% at 5 years. Overall survival was similar between patients receiving primary surgery, radiotherapy, or chemoradiotherapy ( p = 0.10). Primary, regional, and distant control at 5 years was 71%, 66%, and 53%, respectively. There was a trend towards improved regional control with primary surgery ( p = 0.07). Planned neck dissection following primary chemoradiotherapy did not improve regional control ( p = 0.55). Patients with p16-positive tumors exhibited improved overall ( p = 0.05) and metastatic recurrence-free survival ( p < 0.05). There were no factors predictive of treatment assignment nor factors associated with overall survival, local and regional control, or distant metastases free-survival on univariate analysis., Conclusions: Patients with N3 head and neck squamous cell carcinoma exhibit 5-year overall survival rates of approximately 30% regardless of treatment modality. Planned neck dissection does not improve regional control in patients undergoing definitive chemoradiotherapy. p16-positive patients represent a favorable cohort. Distant failure comprises the major failure pattern and should be the focus of future studies in improving the outcome of this patient cohort., Competing Interests: Competing interests The authors declare that they have no competing interests.

Background: Concurrent chemoradiation is the standard of care in non-operable stage III non-small-cell lung cancer (NSCLC). Data have suggested a benefit of dose escalation; however, results from the randomized dose-escalation trial RTOG 0617 revealed a lower survival rate with high-dose radiation. To evaluate the impact of dose escalation on overall survival (OS) in stage III NSCLC treated with chemoradiotherapy outside the controlled setting of a randomized trial, we carried out an observational, population-based investigation of the National Cancer Database (NCDB)., Patients and Methods: A total of 33 566 patients with stage III NSCLC treated with chemoradiation from 2004 to 2012 and radiation doses between 59.4 and 85 Gy were included. The primary end point was OS, with median survival calculated via Kaplan-Meier. Univariate, multivariable and propensity-score matching analyses were carried out., Results: Patients were stratified by dose with median OS of: 18.8, 19.8 and 21.6 months for cohorts receiving 59.4-60, 61-69 and ≥70 Gy, respectively (P < 0.001). Granular dose analyses were carried out demonstrating increased OS with increasing radiation dose: median survival of 18.8, 21.1, 22.0 and 21.0 months for 59.4-60, 66, 70 and ≥71 Gy, respectively. While 66, 70 and ≥71 Gy resulted in increased OS in comparison with 59.4-60 Gy, no significant difference in OS was observed when comparing 66 with ≥71 Gy (P = 0.38)., Conclusions: Dose escalation above 60 Gy was associated with improved OS in this cohort of stage III NSCLC patients treated with chemoradiotherapy. A plateau of benefit was observed, with no additional improvement in OS with increased dose (≥71 Gy) compared with 66-70 Gy. With evidence suggesting worse OS and quality of life with increased dose, these data support investigation of the role of intermediate-dose radiation, and in the absence of randomized evidence, may be leveraged to justify utilization of intermediate-dose radiation., (© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

To compare the roles of intensity-modulated radiation therapy (IMRT) and volumetric- modulated arc therapy (VMAT) therapy as compared to simple and complex 3-dimensional chemoradiotherpy (3DCRT) planning for resectable and borderline resectable pancreatic cancer. In all, 12 patients who received postoperative radiotherapy (8) or neoadjuvant concurrent chemoradiotherapy (4) were evaluated retrospectively. Radiotherapy planning was performed for 4 treatment techniques: simple 4-field box, complex 5-field 3DCRT, 5 to 6-field IMRT, and single-arc VMAT. All volumes were approved by a single observer in accordance with Radiation Therapy Oncology Group (RTOG) Pancreas Contouring Atlas. Plans included tumor/tumor bed and regional lymph nodes to 45Gy; with tumor/tumor bed boosted to 50.4Gy, at least 95% of planning target volume (PTV) received the prescription dose. Dose-volume histograms (DVH) for multiple end points, treatment planning, and delivery time were assessed. Complex 3DCRT, IMRT, and VMAT plans significantly (p < 0.05) decreased mean kidney dose, mean liver dose, liver (V30, V35), stomach (D10%), stomach (V45), mean right kidney dose, and right kidney (V15) as compared with the simple 4-field plans that are most commonly reported in the literature. IMRT plans resulted in decreased mean liver dose, liver (V35), and left kidney (V15, V18, V20). VMAT plans decreased small bowel (D10%, D15%), small bowel (V35, V45), stomach (D10%, D15%), stomach (V35, V45), mean liver dose, liver (V35), left kidney (V15, V18, V20), and right kidney (V18, V20). VMAT plans significantly decreased small bowel (D10%, D15%), left kidney (V20), and stomach (V45) as compared with IMRT plans. Treatment planning and delivery times were most efficient for simple 4-field box and VMAT. Excluding patient setup and imaging, average treatment delivery was within 10minutes for simple and complex 3DCRT, IMRT, and VMAT treatments. This article shows significant improvements in 3D plan performance with complex planning over the more frequently compared 3- or 4-field simple 3D planning techniques. VMAT plans continue to demonstrate potential for the most organ sparing. However, further studies are required to identify if dosimetric benefits associated with inverse optimized planning can be translated into clinical benefits and if these treatment techniques are value-added therapies for this group of patients with cancer., (Published by Elsevier Inc.)

Purpose: Sparing the hippocampus during whole brain radiation therapy (WBRT) offers potential neurocognitive benefits. However, previously reported intensity modulated radiation therapy (IMRT) plans use multiple noncoplanar beams for treatment delivery. An optimized coplanar IMRT template for hippocampal-sparing WBRT would assist in clinical workflow and minimize resource utilization. In this study, we sought to determine the optimal patient position to facilitate coplanar treatment planning and delivery of hippocampal-sparing WBRT using IMRT., Methods and Materials: A variable angle, inclined board was utilized for patient positioning. An anthropomorphic phantom underwent computed tomography simulation at various head angles. The IMRT goals were designed to achieve target coverage of the brain while maintaining hippocampal dose-volume constraints designed to conform to the Radiation Therapy Oncology Group 0933 protocol. Optimal head angle was then verified using data from 8 patients comparing coplanar and noncoplanar WBRT IMRT plans., Results: Hippocampal, hippocampal avoidance region, and whole brain mean volumes were 1.1 cm(3), 12.5 cm(3), and 1185.1 cm(3), respectively. The hippocampal avoidance region occupied 1.1% of the whole brain planning volume. For the 30-degree head angle, a 7-field coplanar IMRT plan was generated, sparing the hippocampus to a maximum dose of 14.7 Gy; D100% of the hippocampus was 7.4 Gy and mean hippocampal dose was 9.3 Gy. In comparison, for flat head positioning the hippocampal Dmax was 22.9 Gy with a D100% of 9.2 Gy and mean dose of 11.7 Gy. Target coverage and dose homogeneity was comparable with previously published noncoplanar IMRT plans., Conclusions: Compared with conventional supine positioning, an inclined head board at 30 degrees optimizes coplanar whole brain IMRT treatment planning. Clinically acceptable hippocampal-sparing WBRT dosimetry can be obtained using a simplified coplanar plan at a 30-degree head angle, thus obviating the need for complex and time consuming noncoplanar IMRT plans.

Gene expression is a dynamic and coordinated process coupling transcription with pre-mRNA processing. This regulation enables tissue-specific transcription factors to induce expression of specific transcripts that are subsequently amplified by alternative splicing allowing for increased proteome complexity and functional diversity. The intestine-specific transcription factor CDX2 regulates development and maintenance of the intestinal epithelium by inducing expression of genes characteristic of the mature enterocyte phenotype. Here, sequence analysis of CDX2 mRNA from colonic mucosa-derived tissues revealed an alternatively spliced transcript (CDX2/AS) that encodes a protein with a truncated homeodomain and a novel carboxy-terminal domain enriched in serine and arginine residues (RS domain). CDX2 and CDX2/AS exhibited distinct nuclear expression patterns with minimal areas of co-localization. CDX2/AS did not activate the CDX2-dependent promoter of guanylyl cyclase C nor inhibit transcriptional activity of CDX2. Unlike CDX2, CDX2/AS co-localized with the putative splicing factors ASF/SF2 and SC35. CDX2/AS altered splicing patterns of CD44v5 and Tra2-β1 minigenes in Lovo colon cancer cells independent of CDX2 expression. These data demonstrate unique dual functions of the CDX2 gene enabling it to regulate gene expression through both transcription (CDX2) and pre-mRNA processing (CDX2/AS).

Here we present the Transcription Factor Encyclopedia (TFe), a new web-based compendium of mini review articles on transcription factors (TFs) that is founded on the principles of open access and collaboration. Our consortium of over 100 researchers has collectively contributed over 130 mini review articles on pertinent human, mouse and rat TFs. Notable features of the TFe website include a high-quality PDF generator and web API for programmatic data retrieval. TFe aims to rapidly educate scientists about the TFs they encounter through the delivery of succinct summaries written and vetted by experts in the field. TFe is available at http://www.cisreg.ca/tfe.

Purpose: Guanylyl cyclase C (GCC), a receptor for bacterial diarrheagenic enterotoxins, may be a prognostic and predictive marker to detect occult micrometastases in patients undergoing staging for colorectal cancer. However, quantification of GCC expression in tissues by the quantitative reverse transcription-PCR (qRT-PCR) has not undergone analytic and clinicopathologic validation., Experimental Design: A technique to quantify GCC mRNA in tissues employing RT-PCR was developed and validated employing external calibration standards of RNA complementary to GCC., Results: GCC qRT-PCR exhibited reaction efficiencies >92%, coefficients of variations <5%, linearity >6 orders of magnitude, and a limit of quantification of >25 copies of GCC cRNA. This assay confirmed that GCC mRNA was overexpressed by colorectal tumors from 41 patients, which correlated with increased GCC protein quantified by immunohistochemistry. Analyses obtained with 164 lymph nodes from patients free of cancer and 15 nodes harboring metastases established a threshold for metastatic disease of approximately 200 GCC mRNA copies/mug total RNA, with a sensitivity of 93% and specificity of 97%. GCC mRNA above that threshold was detected in 76 of 367 (approximately 21%) nodes free of disease by histopathology from 6 of 23 (26%) patients, suggesting the presence of occult micrometastases., Conclusions: Quantifying GCC mRNA in tissues by RT-PCR employing external calibration standards is analytically robust and reproducible, with high clinicopathologic sensitivity and specificity. This validated assay is being applied to approximately 10,000 lymph nodes in a prospective trial to define the sensitivity of GCC qRT-PCR for staging patients with colorectal cancer.

Purpose: The current paradigm suggests that the homeodomain transcription factor Cdx2, which directs the development and maintenance of the intestinal epithelium, is a tumor suppressor in the colon and rectum. Although a cardinal property of tumor suppressors is their inactivation during carcinogenesis, the expression of Cdx2 in colorectal tumors has not been compared with that in normal mucosa. Here, Cdx2 expression and function was quantified in tumors and matched normal mucosa from patients with colorectal cancer., Experimental Design: Cdx2 expression was quantified by reverse transcription-PCR, immunoblot analysis, and immunohistochemistry. Transcriptional activity was explored by quantifying expression of an endogenous downstream target of Cdx2, guanylyl cyclase C (GCC), in tissues by quantitative reverse transcription-PCR and expression of exogenous Cdx2-specific luciferase promoter constructs in epithelial cells isolated from tumors and normal mucosa., Results: Most (>80%) colorectal tumors overexpressed Cdx2 mRNA and protein compared with normal mucosa, with median fold increases of 3.6 and 1.4, respectively (P<0.002). Concomitantly, immunohistochemistry revealed elevated levels of Cdx2 in nuclei of tumor cells compared with normal epithelial cells. Further, tumors exhibited increased expression of GCC compared with normal mucosa. Moreover, cells isolated from tumors overexpressed a Cdx2-specific luciferase promoter construct compared with normal mucosal cells., Conclusion: These observations show, for the first time, the structural and functional overexpression of Cdx2 by human colorectal tumors compared with matched normal mucosa. They suggest that loss of Cdx2 expression or transcriptional activity is an infrequent event during tumorigenesis, which does not contribute to molecular mechanisms underlying initiation and progression of most colorectal tumors.