Oral Oncology

Machine learning to predict occult nodal metastasis in early oral squamous cell carcinoma Publication date: May 2019 Source: Oral Oncology, Volume 92 Author(s): Andrés M. Bur, Andrew Holcomb, Sara Goodwin, Janet Woodroof, Omar Karadaghy, Yelizaveta Shnayder, Kiran Kakarala, Jason Brant, Matthew Shew Abstract Objectives To develop and validate an algorithm to predict occult nodal metastasis in clinically node negative oral cavity squamous cell carcinoma (OCSCC) using machine learning. To compare algorithm performance to a model based on tumor depth of invasion (DOI). Materials and methods Patients who underwent primary tumor extirpation and elective neck dissection from 2007 to 2013 for clinical T1-2N0 OCSCC were identified from the National Cancer Database (NCDB). Multiple machine learning algorithms were developed to predict pathologic nodal metastasis using clinicopathologic data from 782 patients. The algorithm was internally validated using test data from 654 patients in NCDB and was then externally validated using data from 71 patients treated at a single academic institution. Performance was measured using area under the receiver operating characteristic (ROC) curve (AUC). Machine learning and DOI model performance were compared using Delong's test for two correlated ROC curves. Results The best classification performance was achieved with a decision forest algorithm (AUC = 0.840). When applied to the single-institution data, the predictive performance of machine learning exceeded that of the DOI model (AUC = 0.657, p = 0.007). Compared to the DOI model, machine learning reduced the number of neck dissections recommended while simultaneously improving sensitivity and specificity. Conclusion Machine learning improves prediction of pathologic nodal metastasis in patients with clinical T1-2N0 OCSCC compared to methods based on DOI. Improved predictive algorithms are needed to ensure that patients with occult nodal disease are adequately treated while avoiding the cost and morbidity of neck dissection in patients without pathologic nodal disease.

Electrochemotherapy as palliative treatment in patients with advanced head and neck tumours: Outcome analysis in 93 patients treated in a single institution Publication date: May 2019 Source: Oral Oncology, Volume 92 Author(s): Francesco Longo, Francesco Perri, Ettore Pavone, Corrado Aversa, Maria Grazia Maglione, Agostino Guida, Massimo Montano, Salvatore Villano, Antonio Daponte, Francesco Caponigro, Franco Ionna Abstract Purpose To describe outcomes of Electrochemotherapy as palliative treatment in patients with advanced head and neck (H&N) tumours. Methods Ninety-three patients (120 treatment sessions) with H&N recurrent and/or metastatic neoplasm were treated. Treatment response was assessed 4 weeks after ECT with clinical examination and two months after the first evaluation with a CT scan of the H&N for deep lesions evaluation. The grade of bleeding and pain before, at the end of treatment and one week after ECT were evaluated. Results Five percent of complete responses, 40% of partial responses were registered. Disease progression was seen in 20% of patients after the first ECT procedure, the remaining 34% of patients experienced stable disease. A good control of pain and bleeding was obtained, especially in patients with moderate symptoms before the treatment. No toxicities related to ECT were seen. Conclusions ECT is an interesting antitumoral therapy in advanced chemo and radio-refractory H&N neoplasms. ECT is able to reduce frequent symptoms, such as pain and bleeding, improving quality of life without damage to healthy tissue and with limited side effects. Moreover, ECT reduces hospitalization time and may contribute to an overall reduction in healthcare costs associated with advanced H&N cancers care.

Reducing radiotherapy target volume expansion for patients with HPV-associated oropharyngeal cancer Publication date: May 2019 Source: Oral Oncology, Volume 92 Author(s): Adam R. Burr, Paul M. Harari, Huaising C. Ko, Justine Y. Bruce, Randall J. Kimple, Matthew E. Witek Abstract 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.

FDG PET/CT for metastatic squamous cell carcinoma of unknown primary of the head and neck Publication date: May 2019 Source: Oral Oncology, Volume 92 Author(s): Yiyan Liu Abstract Objective The role of FDG PET/CT is uncertain in squamous cell carcinoma of unknown primary (SCCUP). Published data are limited by heterogeneity of pathology, varied diagnostic criteria, and small sample size. Materials/methods This retrospective study was conducted in 40 patients who had FDG PET/CT for SCCUP. Prior to PET/CT, patients had underwent standard clinical evaluations including flexible rhinolaryngoscopy. The majority of the patients had anatomic imaging. All subjects had histopathological investigations, and follow-up data after PET/CT. Results FDG PET/CT detected the primary in 16 of 40 patients (40%), and the most common locations of the primary were in the base of the tongue, palatine tonsil, and hypopharynx. There were 10 false positive and 6 false negative PET/CT scans. There was no difference in the mean SUVs of the suspected primary lesions between true and false positive groups. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and overall accuracy of FDG PET/CT for SCCUP in this patient cohort were 72.7% (16/22), 44.4% (8/18), 61.5% (16/26), 57.1% (8/14), and 60% (24/40), respectively. The tonsil was the site with the most false positive and false negative findings. Conclusions FDG PET/CT might be an effective single shot of whole-body imaging for detection of the primary in SCCUP. Low specificity remained the most notable weakness of FDG-PET in work-up for SCCUP. In addition to varied physiologic uptake or inflammatory related uptake in the common locations of the primary, the image indication bias might be another significant contributor of high false positive rate.

Effect of local treatment for metastasis and its sequence with chemotherapy on prognosis of post-treatment metastatic nasopharyngeal carcinoma patients Publication date: May 2019 Source: Oral Oncology, Volume 92 Author(s): Yu-Jing Liang, Xue-Song Sun, Zhen-Chong Yang, Qing-Nan Tang, Shan-Shan Guo, Li-Ting Liu, Hao-Jun Xie, Sai-Lan Liu, Jin-Jie Yan, Xiao-Yun Li, Qiu-Yan Chen, Hai-Qiang Mai Abstract Background Distant metastasis after chemoradiotherapy remains the leading cause of death in NPC patients. But the effect of local treatment for metastatic sites and its sequence with chemotherapy on prognosis of them are poorly documented. Methods 448 post-treatment metastatic NPC patients were included in our retrospective study. And Cox regression and log-rank tests were applied to investigate the association between topical treatment and its sequence with chemotherapy and survival using the propensity score method (PSM) to adjust for gender, age, Tumor stage, Node stage, metastatic sites, diabetes and smoking with a 1:2 matching protocol. Results The 3-year OS was significantly higher in patients who received local treatment of distant metastasis compared with patients who did not (48.8% vs 33.8%, P = 0.001) in primary cohort. PSM identified 120 patients in the cohort with local treatment and 240 in that without and similar survival benefits were observed for the local treatment (3-year OS: 36.2% versus 48.8%, P = 0.011). Subgroup analyses indicated that there was no significant survival difference in patients with different treatment sequence. Conclusions In conclusion, post-treatment metastatic NPC patients could be beneficial from local treatment for metastasis but its sequence with palliative chemotherapy does not affect overall survival.

Significant association of PD-L1 expression with human papillomavirus positivity and its prognostic impact in oropharyngeal cancer Publication date: May 2019 Source: Oral Oncology, Volume 92 Author(s): Angela M. Hong, Peter Ferguson, Tristan Dodds, Deanna Jones, Mengbo Li, Jean Yang, Richard A Scolyer Abstract Background The programmed death pathway plays a role in persistent human papillomavirus (HPV) infection as well as in resistance to immune elimination during malignant progression. In this study, we examined PD-L1 expression by immunohistochemistry and tumour infiltrating lymphocytes (TIL) in 214 patients with oropharyngeal squamous cell cancer (OPSCC) to assess its clinical significance. Results HPV-positive OPSCC were significantly more likely to express PD-L1 than HPV-negative OPSCC (85.2% vs 57.1%, p < 0.05). PD-L1 staining was more likely to be associated with TILs in HPV-positive OPSCC (67.9% vs 49.6%, p = 0.01). Relative to those patients with HPV-positive/PD-L1-positive OPSCC, patients with HPV negative/PD-L1 negative OPSCC were 6.4 times more likely to develop a local recurrence, 5.8 times more likely to develop an event and 6.5 times more likely to die. Within the HPV positive cases, PD-L1 expression also significantly impacted on the outcomes with PD-L1 negative cases more likely to develop a locoregional recurrence (HR 4.16), to have an event (HR 2.5) and to die (HR 3.16). Evidence of an interaction between HPV status and PD-L1 expression was found for overall survival (p < 0.005). Conclusion Our findings suggested that different immune profiles in oropharyngeal cancer by HPV status and the effect of HPV on the outcomes is modified by PD-L1 expression.

Prognostic factors associated with achieving total oral diet after glossectomy with microvascular free tissue transfer reconstruction Publication date: May 2019 Source: Oral Oncology, Volume 92 Author(s): Diane W. Chen, Tao Wang, Jonathan Shey-Sen Ni, Vlad C. Sandulache, Evan M. Graboyes, Mitchell Worley, Joshua D. Hornig, Judith M. Skoner, Terry A. Day, Andrew T. Huang Abstract Objective Primary surgery followed by adjuvant therapy is the current standard of care in the multidisciplinary management of squamous cell carcinoma (SCC) of the oral tongue. Additionally, salvage glossectomy is used to treat recurrent base of tongue SCC. Microvascular free tissue transfer reconstruction (MVFTT) is utilized to maximize functional outcomes such as swallowing. We sought to identify prognostic factors related to achievement of a total oral diet in patients that underwent glossectomy with MVFTT. Methods Retrospective review at a tertiary care center from 2010 to 2015. Results 200 patients (69% male, mean age 60 years) met inclusion criteria. Extent of glossectomy was categorized as partial or hemiglossectomy (39%), tongue base resection with or without hemi-oral glossectomy (23%), composite resection with mandibulectomy (18%), and subtotal or total glossectomy (21%). Flap success rate was 96%. Median follow-up time was 14  months. A total oral diet was achieved by 49% of patients with median time to achievement of 31  days (IQR 9-209). Multivariate analysis identified body mass index  < 25 kg/m2, prior radiation therapy, adjuvant chemoradiation, and resection requiring subtotal or total glossectomy or concurrent mandibulectomy as independent risk factors for worse total oral diet achievement. Conclusion Swallowing dysfunction represents a significant morbidity following glossectomy in the treatment of SCC. High BMI, smaller resection fields, and absence of prior radiation therapy or adjuvant chemoradiotherapy correlated with improved likelihood of obtaining a total oral diet. Patients should be appropriately counseled of this risk with emphasis placed on aggressive swallow rehabilitation in the post- treatment setting.

Intra-operative point-of-procedure delineation of oral cancer margins using optical coherence tomography Publication date: May 2019 Source: Oral Oncology, Volume 92 Author(s): Sumsum P. Sunny, Sagar Agarwal, Bonney Lee James, Emon Heidari, Anjana Muralidharan, Vishal Yadav, Vijay Pillai, Vivek Shetty, Zhongping Chen, Naveen Hedne, Petra Wilder-Smith, Amritha Suresh, Moni Abraham Kuriakose Abstract Objectives Surgical margin status is a significant determinant of treatment outcome in oral cancer. Negative surgical margins can decrease the loco-regional recurrence by five-fold. The current standard of care of intraoperative clinical examination supplemented by histological frozen section, can result in a risk of positive margins from 5 to 17 percent. In this study, we attempted to assess the utility of intraoperative optical coherence tomography (OCT) imaging with automated diagnostic algorithm to improve on the current method of clinical evaluation of surgical margin in oral cancer. Materials and methods We have used a modified handheld OCT device with automated algorithm based diagnostic platform for imaging. Intraoperatively, images of 125 sites were captured from multiple zones around the tumor of oral cancer patients (n = 14) and compared with the clinical and pathologic diagnosis. Results OCT showed sensitivity and specificity of 100%, equivalent to histological diagnosis (kappa, ĸ = 0.922), in detection of malignancy within tumor and tumor margin areas. In comparison, for dysplastic lesions, OCT-based detection showed a sensitivity of 92.5% and specificity of 68.8% and a moderate concordance with histopathology diagnosis (ĸ = 0.59). Additionally, the OCT scores could significantly differentiate squamous cell carcinoma (SCC) from dysplastic lesions (mild/moderate/severe; p ≤ 0.005) as well as the latter from the non-dysplastic lesions (p ≤ 0.05). Conclusion The current challenges associated with clinical examination-based margin assessment could be improved with intra-operative OCT imaging. OCT is capable of identifying microscopic tumor at the surgical margins and demonstrated the feasibility of mapping of field cancerization around the tumor.

Development of a cytology-based multivariate analytical risk index for oral cancer Publication date: May 2019 Source: Oral Oncology, Volume 92 Author(s): Timothy J. Abram, Pierre N. Floriano, Robert James, A. Ross Kerr, Martin H. Thornhill, Spencer W. Redding, Nadarajah Vigneswaran, Rameez Raja, Michael P. McRae, John T. McDevitt Abstract Objectives The diagnosis and management of oral cavity cancers are often complicated by the uncertainty of which patients will undergo malignant transformation, obligating close surveillance over time. However, serial biopsies are undesirable, highly invasive, and subject to inherent issues with poor inter-pathologist agreement and unpredictability as a surrogate for malignant transformation and clinical outcomes. The goal of this study was to develop and evaluate a Multivariate Analytical Risk Index for Oral Cancer (MARIO) with potential to provide non-invasive, sensitive, and quantitative risk assessments for monitoring lesion progression. Materials and methods A series of predictive models were developed and validated using previously recorded single-cell data from oral cytology samples resulting in a "continuous risk score". Model development consisted of: (1) training base classification models for each diagnostic class pair, (2) pairwise coupling to obtain diagnostic class probabilities, and (3) a weighted aggregation resulting in a continuous MARIO. Results and conclusions Diagnostic accuracy based on optimized cut-points for the test dataset ranged from 76.0% for Benign, to 82.4% for Dysplastic, 89.6% for Malignant, and 97.6% for Normal controls for an overall MARIO accuracy of 72.8%. Furthermore, a strong positive relationship with diagnostic severity was demonstrated (Pearson's coefficient = 0.805 for test dataset) as well as the ability of the MARIO to respond to subtle changes in cell composition. The development of a continuous MARIO for PMOL is presented, resulting in a sensitive, accurate, and non-invasive method with potential for enabling monitoring disease progression, recurrence, and the need for therapeutic intervention of these lesions.

Risk of prolonged opioid use among cancer patients undergoing curative intent radiation therapy for head and neck malignancies Publication date: May 2019 Source: Oral Oncology, Volume 92 Author(s): William H. Smith, Ian Luskin, Lucas Resende Salgado, Bethann M. Scarborough, Jung-Yi Lin, Umut Özbek, Brett A. Miles, Vishal Gupta, Richard L. Bakst Abstract Objective Patients undergoing radiation treatment (RT) for head and neck malignancies often suffer significant disease- and treatment-related pain requiring opioids for effective management. However, the prevalence and associated risk factors of prolonged opioid use in this population remain poorly characterized. We sought to quantify the rate of prolonged opioid use among opioid naïve patients receiving curative-intent RT for head and neck malignancies and to identify associated risk factors. Methods We retrospectively identified patients who had undergone RT for head and neck malignancies at our institution between Jan 2011 and Sept 2017. Our primary endpoint was persistent opioid use 6-months following completion of RT. Patients were included if they were opioid-naïve, underwent curative intent RT, had adequate follow-up, and did not have residual or recurrent disease within our follow-up period. Univariable and multivariable logistic regression was utilized to identify risk factors for prolonged opioid use. Results We identified 311 patients meeting our inclusion criteria; 40 (12.9%) continued to use opioids 6-months following RT. Univariable analysis found current smoking, alcohol abuse, RT dose, treatment to the bilateral necks, induction chemotherapy, concurrent chemotherapy, PEG tube, daily milligram morphine equivalents, and adjuvant analgesic medication use to be positively associated with prolonged opioid use; prior surgery was negatively associated with prolonged opioid use. Delivery of induction chemotherapy (OR 2.86, CI (95%) 1.32–6.21) and alcohol abuse (OR 3.75, CI (95%) 1.66–8.47) remained statistically significant on multivariable analysis. Conclusion The prevalence of prolonged opioid use in previously opioid naïve patients undergoing curative intent head and neck RT was just under 13%. Patients with history of alcohol abuse and those who undergo induction chemotherapy were most at risk.