Oral Oncology

Management of recurrent and metastatic oral cavity cancer: Raising the bar a step higher Publication date: February 2020 Source: Oral Oncology, Volume 101 Author(s): Petr Szturz, Jan B. Vermorken Abstract In recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M-SCCHN), the armamentarium of systemic anti-cancer modalities continues to grow in parallel with innovations in and better integration of local approaches. The backbone of cytotoxic chemotherapy remains cisplatin with 5-fluorouracil or a taxane. In contrast to cisplatin, the tumoricidal activity of carboplatin monotherapy is debatable. Adding the epidermal growth factor receptor (EGFR) inhibitor cetuximab to a platinum/5-fluorouracil doublet (the so-called EXTREME regimen) produced a statistically but also clinically significant improvement of survival and became thus the standard first-line palliative treatment in adequately fit patients. Interestingly, three large randomized trials (EXTREME, SPECTRUM, and ZALUTE) evaluating different anti-EGFR monoclonal antibodies (cetuximab, panitumumab, and zalutumumab, respectively) demonstrated preferential anti-tumour efficacy in patients with primary cancer in the oral cavity. Modern immunotherapy with immunomodulating antibodies, dubbed immune checkpoint inhibitors, such as anti-programmed cell death protein-1 (anti-PD-1) inhibitors nivolumab and pembrolizumab, showed unprecedented activity in one first-line (KEYNOTE-048) and several second-line trials (CheckMate-141, KEYNOTE-012, KEYNOTE-055, and KEYNOTE-040). In a minority of also heavily-pretreated patients, these agents generate long-lasting responses without the typical chemotherapy-related toxicity, however, at a price of a low overall response rate, rare but potentially life-threatening immune-related adverse events, the risk of hyperprogression, and high costs. In oligometastatic disease, emerging data indicate long-term benefit with locally ablative techniques including metastasectomy and stereotactic radiotherapy of pulmonary but also hepatic and other distant lesions. In the frame of highly-individualized cancer care, a particularly intriguing approach is a combination of systemic and local therapies.

The efficacy of chemotherapy in survival of stage II nasopharyngeal carcinoma Publication date: February 2020 Source: Oral Oncology, Volume 101 Author(s): Xin-Bin Pan, Ling Li, Song Qu, Long Chen, Shi-Xiong Liang, Xiao-Dong Zhu Abstract Purpose Chemotherapy use remains controversial for stage II nasopharyngeal carcinoma (NPC). This retrospective study was conducted to identify whether chemoradiotherapy was associated with better survival compared to radiotherapy. Materials and methods The Surveillance, Epidemiology, and End Results (SEER) database was queried for stage II NPC patients between 2004 and 2015. Patients were divided into radiotherapy and chemoradiotherapy groups. Overall survival (OS) and cancer-specific survival (CSS) were examined using the Kaplan-Meier method, Cox proportional hazards models, and propensity score matching analyses. Results This study examined 908 patients, including 102 receiving radiotherapy and 806 receiving chemoradiotherapy. Chemoradiotherapy was associated with 5-year OS (78.01% vs. 75.12%; p = 0.22) and CSS (78.92% vs. 78.26%; p = 0.40) rates comparable to those of radiotherapy. Propensity score matching analyses demonstrated similar OS (HR: 0.63, 95% CI: 0.36–-1.10; p = 0.10) and CSS (HR: 0.77, 95% CI: 0.41–1.48; p = 0.44) rates with radiotherapy. Age >60 years and non-Asian patients were associated with worse survival. Conclusion This study revealed that chemoradiotherapy showed similar survivals to stage II NPC patients compared with radiotherapy. Due to the limitations of SEER database, further studies should be performed to verify the results.

Neck management in patients with olfactory neuroblastoma Publication date: February 2020 Source: Oral Oncology, Volume 101 Author(s): Xinmao Song, Chuang Huang, Shengzi Wang, Li Yan, Jie Wang, Yi Li Abstract Objective Optimal neck management in patients with olfactory neuroblastoma (ONB), a rare malignancy, remains uncertain. This study aimed to analyse patterns of cervical lymph node metastases and corresponding clinical outcomes and to investigate the value of elective neck irradiation (ENI) in this population. Methods and materials This study retrospectively reviewed clinical records, imaging findings, nodal metastasis features and treatment data of 217 patients with ONB treated at our hospital during 1991–2019. Univariate and multivariate analyses were used to assess the influence of cervical lymph node involvement on treatment outcomes. Survival and regional failure rates were compared between patients with or without ENI. Results Thirty-two patients (14.7%) presented initially with cervical lymph node metastases, most frequently at levels II (10.6%, 23/217) and VIIa (5.5%, 12/217). Patients with and without cervical node metastasis differed significantly in overall (OS) (41.9% vs. 86.1%, p < 0.001), progression-free (PFS) (41.9% vs. 84.8%, p < 0.001), regional failure-free (45.9% vs. 89%, p < 0.001) and distant metastasis-free survival (41.5% vs. 86.1%, p < 0.001). Cervical lymph involvement was an independent factor affecting poor OS (hazard ratio, 0.184, 95% confidence interval, 0.078–0.436, p < 0.001) and PFS (hazard ratio, 0.198, 95% confidence interval, 0.088–0.445, p < 0.001). Moreover, 43.8% patients (95/217) underwent ENI, which significantly reduced the incidence of regional recurrence from 10.7% to 3.2% (χ2 = 4.396, p = 0.036) but did not significantly affect other survival outcomes. Regional failures could be resolved using salvage treatment. Conclusions Our findings indicate the importance of systematic therapy for patients with initial cervical lymph node metastases. ENI is not recommended for N0 disease.

Assessing the validity of EQ-5D-5L in people with head & neck cancer: Does a generic quality of life measure perform as well as a disease-specific measure in a patient population? Publication date: February 2020 Source: Oral Oncology, Volume 101 Author(s): A. Davies, A. Waylen, S. Leary, S. Thomas, M. Pring, B. Janssen, R. Beynon, S. Lang, S. Schimansky, K. Hurley, A. Ness Abstract Background Head and neck cancer (HNC) is an important cause of morbidity and mortality globally. Radical treatment methods may result in facial disfigurement and/or functional difficulties with subsequent adverse impacts on health-related quality of life (HRQoL). Guidelines suggest that HRQoL should be measured repeatedly throughout treatment to enable refined treatment protocols and tailored follow-up support but questionnaires are often long and burdensome. We compared condition-specific and generic metrics to assess HRQoL for people with this condition. Methods We used data from the prospective Head and Neck 5000 clinical cohort study - 5511 participants with a new diagnosis of HNC between 2011 and 2014. HRQoL data were collected at baseline from 2065 people who completed both the condition-specific EORTC-QLQ-C30 and the shorter, generic EQ-5D-5L questionnaires. Results There was strong evidence of association between comparable scales on each questionnaire at baseline: higher levels of functioning and lower levels of reported symptoms assessed with EQ-5D-5L were associated with lower EORTC-QLQ-C30 symptom scores. A moderate relationship (0.61) was found between overall QoL in the EQ-5D-5L index and self-perceived health (EQ VAS). Conclusions HRQoL data collected from the generic EQ-5D-5L and cancer-specific EORTC-QLQ-C30 questionnaires are comparable at baseline for people diagnosed with HNC. This would allow a reduced burden of data collection but the EQ-5D-5L may not be sensitive to some condition-specific symptoms. Clinicians and researchers must clarify their aims and outcomes of interest before choosing their HRQoL measures. Further work is required to examine the ability to detect change in these measures over time.

The future of robotic surgery in otolaryngology – head and neck surgery Publication date: February 2020 Source: Oral Oncology, Volume 101 Author(s): Akina Tamaki, James W. Rocco, Enver Ozer Abstract Robotic surgery for management of head and neck pathologies has only been in practice for little more than a decade. Since then, there has been a rapid development in the field of transoral robotic surgery (TORS) and robotic surgery in otolaryngology. TORS has emerged as a tool in the treatment of both malignant and benign oropharyngeal, hypopharyngeal, and laryngeal disease. TORS is also a critical component of ongoing clinical trials seeking to improve the treatment of oropharyngeal squamous cell carcinoma. In addition, it’s application has expanded to treatment of obstructive sleep apnea, thyroid and parathyroid disease, and skull base pathologies. This review will provide an overview of the current application of robotics in otolaryngology as well as highlight the developing robotic platforms and technologies, and future of the field.

Validation and characterisation of prognostically significant PD-L1+ immune cells in HPV+ oropharyngeal squamous cell carcinoma Publication date: February 2020 Source: Oral Oncology, Volume 101 Author(s): Richard J. Young, Mathias Bressel, Sandro Porceddu, Janez Cernelc, Peter Savas, Howard Liu, Damien Urban, Alesha A. Thai, Caroline Cooper, Tsien Fua, Paul Neeson, Danny Rischin, Benjamin Solomon Abstract We previously showed in human papillomavirus positive oropharyngeal squamous cell carcinoma (HPV+OPSCC) that the presence of intratumoral (IT) PD-L1+ immune cells (ICs) or CD8+ infiltrating ICs are of prognostic value. Here we report the prognostic significance of these immune biomarkers in an independent validation cohort of 177 HPV+OPSCC patients. IT and stromal (S) localisation of PD-L1+ and CD8+ ICs were scored. High abundance (≥5%) of PD-L1+ IT ICs was found in 51/167 patients (30.5%) and was associated with improved overall survival (OS) (HR, 0.21; 95% CI, 0.05–0.91; P = 0. 012) validating our previous results. High abundance (≥30%) of CD8+ IT or S ICs, found in 77/167 patients (46.1%) provided a HR of 0.45 for OS however the confidence interval was wide (95% CI 0.16–1.25, p = 0.105). Multiplex immunohistochemistry revealed CD68+ macrophages and CD3+CD8+ T cells to be the most common ICs expressing PD-L1. Gene expression analysis showed tumors with high abundance of PD-L1+ IT ICs exhibit gene signatures associated with responses to PD1 or PD-L1 inhibitors pembrolizumab and atezolizumab. These data support the role of immune biomarkers such as PD-L1+ ICs to identify subgroups of HPV+OPSCC patients with an excellent outcome that may be suitable for trials evaluating de-intensification of therapy.

Prognostic efficacy of extensive invasion of primary tumor volume for T3-4 nasopharyngeal carcinoma receiving intensity-modulated radiotherapy Publication date: January 2020 Source: Oral Oncology, Volume 100 Author(s): Fen Xue, Dan Ou, Xiaomin Ou, Xin Zhou, Chaosu Hu, Xiayun He Abstract Objectives This study aimed to explore the prognostic value of extensive invasion of primary tumor volume for local control in patients with T3-4 NPC receiving intensity-modulated radiotherapy (IMRT). Materials and methods Between January 2009 and December 2015, initial volume of GTV-P, the confined and extensive invasion part of GTV-P (GTV-C and GTV-E) were obtained from 159 prospectively enrolled non-metastatic T3-4 NPC patients. GTV-E included the tumor with infiltration of bony structures at skull base, cervical vertebra, paranasal sinuses or with intracranial extension. GTV-C was calculated by the subtraction of GTV-E from GTV-P. The effects of tumor volume levels on local control rate (LC) were evaluated by Kaplan-Meier method and multivariate analysis. Results GTV-P (P = 0.015) and GTV-E (P = 0.001) were significantly correlated with local failure, while GTV-C (P = 0.494) was not. Then optimal cut-off values of GTV-P (43 mL) and GTV-E (22 mL) were determined by receiver operating characteristic curve analysis. Patients with small (<22 mL) GTV-E achieved better 5-year LC rate than those with large (≥22 mL) GTV-E (96.3% vs.76.1%, P < 0.001), but no significant difference was found between patients with small (<43 mL) and large (≥43 mL) GTV-P (95.9% vs. 85.5%, P = 0.094). Multivariate analysis also demonstrated large (≥22 mL) GTV-E to be an independent unfavorable prognostic factor for LC (hazard ratio [HR], 3.805; 95% CI, 1.100–13.166; P = 0.035). Conclusion GTV-E is an independent prognostic factor for LC in T3-4 NPC and may further assist in the optimization of treatment strategies.

Management of the neck in oral cancers Publication date: January 2020 Source: Oral Oncology, Volume 100 Author(s): Gouri Pantvaidya, Karthik Rao, Anil D'Cruz Abstract Oral cavity cancers are treated by surgery with or without adjuvant therapy. Being the most important prognostic factor, neck node management is an important aspect of treating oral cancers. There are numerous areas of debate in the management of the node-negative and node-positive neck. In an attempt to answer these questions, a large volume of literature has been generated over the last few decades. This review article describes the current evidence and approach considerations for the management of cervical nodes in patients with oral cavity cancers.

Prediction of survival of HPV16-negative, p16-negative oral cavity cancer patients using a 13-gene signature: A multicenter study using FFPE samples Publication date: January 2020 Source: Oral Oncology, Volume 100 Author(s): Chu Chen, Pawadee Lohavanichbutr, Yuzheng Zhang, John R. Houck, Melissa P. Upton, Behnoush Abedi-Ardekani, Antonio Agudo, Wolfgang Ahrens, Laia Alemany, Devasena Anantharaman, David I. Conway, Neal D. Futran, Ivana Holcatova, Kathrin Günther, Bo T. Hansen, Claire M. Healy, Doha Itani, Kristina Kjaerheim, Marcus M. Monroe, Peter J. Thomson Abstract Objectives To test the performance of an oral cancer prognostic 13-gene signature for the prediction of survival of patients diagnosed with HPV-negative and p16-negative oral cavity cancer. Materials and Methods Diagnostic formalin-fixed paraffin-embedded oral cavity cancer tumor samples were obtained from the Fred Hutchinson Cancer Research Center/University of Washington, University of Calgary, University of Michigan, University of Utah, and seven ARCAGE study centers coordinated by the International Agency of Research on Cancer. RNA from 638 Human Papillomavirus (HPV)-negative and p16-negative samples was analyzed for the 13 genes using a NanoString assay. Ridge-penalized Cox regressions were applied to samples randomly split into discovery and validation sets to build models and evaluate the performance of the 13-gene signature in predicting 2-year oral cavity cancer-specific survival overall and separately for patients with early and late stage disease. Results Among AJCC stage I/II patients, including the 13-gene signature in the model resulted in substantial improvement in the prediction of 2-year oral cavity cancer-specific survival. For models containing age and sex with and without the 13-gene signature score, the areas under the Receiver Operating Characteristic Curve (AUC) and partial AUC were 0.700 vs. 0.537 (p < 0.001), and 0.046 vs. 0.018 (p < 0.001), respectively. Improvement in predicting prognosis for AJCC stage III/IV disease also was observed, but to a lesser extent. Conclusions If confirmed using tumor samples from a larger number of early stage oral cavity cancer patients, the 13-gene signature may inform personalized treatment of early stage HPV-negative and p16-negative oral cavity cancer patients.

Increased risk of head and neck cancer in Agent Orange exposed Vietnam Era veterans Publication date: January 2020 Source: Oral Oncology, Volume 100 Author(s): Alia Mowery, Michael Conlin, Daniel Clayburgh Abstract Importance United States military personnel during the Vietnam Era were potentially exposed to Agent Orange, a known carcinogen. The link between Agent Orange and head and neck cancers is largely unknown; laryngeal cancer is currently the only subsite with sufficient evidence of an Agent Orange association. Objective We aim to determine the relationship between Agent Orange exposure and the incidence of head and neck cancers in Vietnam Era veterans as well as any relationship with head and neck cancer survival. Materials and methods The present study utilizes the Veterans Affairs Corporate Data Warehouse (VA CDW) to identify Vietnam Era veterans, their Agent Orange exposure status, limited demographic data, presence of head and neck cancer, and survival data. Results Of 8,877,971 Vietnam Era veterans, 22% self-reported exposure to Agent Orange, and 54,717 had a diagnosis of head and neck cancer. Agent Orange exposure significantly predicted upper aerodigestive tract carcinoma, with a relative risk (RR) of 1.10. On subsite analysis, Agent Orange exposure (as well as race, gender, and substance use) was significantly associated with oropharyngeal (RR 1.16), nasopharyngeal (RR 1.22), laryngeal (1.11), and thyroid (1.24) cancers. Agent Orange exposure was associated with improved 10-year overall survival in upper aerodigestive tract cancer patients. Conclusions and Relevance Self-reported Agent Orange exposure correlated with increased risks of oropharyngeal, nasopharyngeal, laryngeal, and thyroid cancers, and predicted improved survival in upper aerodigestive tract cancer patients. These findings broaden our understanding of the risks of Agent Orange exposure.