Therapeutic Advances and Challenges for the Management of HPV-Associated Oropharyngeal Cancer.

The use of conventional chemotherapy in conjunction with targeted and immunotherapy drugs has emerged as an option to limit the severity of side effects in patients diagnosed with head and neck cancer (HNC), particularly oropharyngeal cancer (OPC). OPC prevalence has increased exponentially in the past 30 years due to the prevalence of human papillomavirus (HPV) infection. This study reports a comprehensive review of clinical trials registered in public databases and reported in the literature (PubMed/Medline, Scopus, and ISI web of science databases). Of the 55 clinical trials identified, the majority (83.3%) were conducted after 2015, of which 77.7% were performed in the United States alone. Eight drugs have been approved by the FDA for HNC, including both generic and commercial forms: bleomycin sulfate, cetuximab (Erbitux), docetaxel (Taxotere), hydroxyurea (Hydrea), pembrolizumab (Keytruda), loqtorzi (Toripalimab-tpzi), methotrexate sodium (Trexall), and nivolumab (Opdivo). The most common drugs to treat HPV-associated OPC under these clinical trials and implemented as well for HPV-negative HNC include cisplatin, nivolumab, cetuximab, paclitaxel, pembrolizumab, 5-fluorouracil, and docetaxel. Few studies have highlighted the necessity for new drugs specifically tailored to patients with HPV-associated OPC, where molecular mechanisms and clinical prognosis are distinct from HPV-negative tumors. In this context, we identified most mutated genes found in HPV-associated OPC that can represent potential targets for drug development. These include TP53, PIK3CA, PTEN, NOTCH1, RB1, FAT1, FBXW7, HRAS, KRAS, and CDKN2A.

Loss of Independence in Older Adults With Operable Oral Cavity Cancer: A Retrospective Cohort Study.

OBJECTIVE: To ascertain the effect of curative-intent surgery on loss of independence (LOI) in patients with oral cavity squamous cell carcinoma (OCSCC). STUDY DESIGN: Retrospective observational study of patients diagnosed from 2014 to 2021. SETTING: Single tertiary care academic center. Patients having undergone curative-intent surgical treatment for OCSCC from 2014 to 2021 in the cancer registry. METHODS: LOI as the primary outcome was measured based on a combination of decrease in activities of daily living (ADLs) and/or decline in mobility during treatment. Descriptive statistics were used to compare baseline demographics and multivariable logistic regression was used to assess the association between LOI and perioperative variables of interest. RESULTS: Of the 180 patients included in this study, 139 (79%) were fully independent in ADLs/instrumental ADLs prior to surgery. The average age of the cohort was 74 with 49% males. Thirty-seven (21%) experienced a decline in mobility or increased care needs following surgery, and 18 (10%) experienced an independent decline in functional status. Increasing age, osseous flap reconstruction, high Charlson Comorbidity Index, and major postoperative adverse events were associated with LOI. Fifty-five percent of patients with LOI had recovered to baseline within 7 months from surgery. LOI was associated with poor treatment tolerance (odds ratio: 4.77, 95% confidence interval: 1.87-12.2) while adjusting for multiple confounders. CONCLUSION: LOI is common in older adults undergoing curative-intent surgery for OCSCC and associated with poor treatment tolerance.

Rethinking treatment paradigms: Neoadjuvant therapy and de-escalation strategies in HPV-positive head and neck cancer.

Head and neck cancer (HNC) is the 6th most common cancer across the world, with a particular increase in HNC associated with human papilloma virus (HPV) among younger populations. Historically, the standard treatment for this disease consisted of combined surgery and radiotherapy or curative platinum-based concurrent chemoradiotherapy, with associated long term and late toxicities. However, HPV-positive HNC is recognized as a unique cancer subtype, typically with improved clinical outcomes. As such, treatment de-escalation strategies have been widely researched to mitigate the adverse effects associated with the current standard of care without compromising efficacy. These strategies include treatment de-escalation, such as novel surgical techniques, alternative radiation technologies, radiation dose and volume reduction, as well as neoadjuvant chemotherapies, immunotherapies, and combined therapies. Although these therapies show great promise, many of them are still under investigation due to hesitation surrounding their widespread implementation. The objective of this review is to summarize the most recent progress in de-escalation strategies and neoadjuvant therapies designed for HPV-positive HNC. While specific treatments may require additional research before being widely adopted, encouraging results from recent studies have highlighted the advantages of neoadjuvant chemotherapy and immunotherapy, as well as radiation and surgical de-escalation approaches in managing HPV-positive HNC.

Sarcopenia predicts short-term treatment-related toxicity in patients undergoing curative-intent therapy for head and neck cancer: A systematic review and meta-analysis.

Sarcopenia is an increasingly recognized biomarker associated with poorer outcomes. The objective of this study was to ascertain the effect of sarcopenia on treatment tolerance and short-term toxicity in head and neck cancer (HNC). A systematic review was performed using multiple databases. An inverse-variation, random-effects model was used to perform the meta-analysis to evaluate the effect of sarcopenia on severe treatment toxicity and poor treatment tolerance. Sixteen observational studies, including 3187 patients with HNC, were analyzed. The combined odds ratio (OR) for severe treatment toxicity and tolerance was 2.22 (95%CI 1.50-3.29) and 1.40 (95%CI 0.84-2.32), respectively. The effect of sarcopenia on short-term severe treatment toxicity was similar with upfront surgery (OR 2.03, 95%CI 1.22-3.37) and definitive radiotherapy (OR 2.24, 95%CI 1.18-4.27) Patients with sarcopenia are more than twice as likely to suffer a short-term treatment-related toxicity when undergoing curative-intent HNC treatment.

Quality of Life After Neoadjuvant Chemotherapy and Transoral Robotic Surgery for Oropharynx Cancer.

Importance: Efforts are underway to deintensified treatment protocols for patients with human papillomavirus virus-associated oropharyngeal squamous cell carcinoma (HPV-OPSCC) to achieve similar excellent oncologic outcomes while reducing treatment-related adverse effects. Transoral robotic surgery (TORS) as primary treatment often requires adjuvant therapy due to the high incidence of nodal metastasis. Treatment with neoadjuvant chemotherapy followed by TORS and neck dissection (NECTORS), reserving radiation therapy for salvage, yields excellent oncologic outcomes. Objective: To assess patient-reported quality of life (QOL) and functional outcomes among patients with HPV-OPSCC who undergo NECTORS. Design, Settings, and Participants: This was a multicenter prospective cohort study of patients with HPV-OPSCC treated with the NECTORS protocol in 2017 to 2022. Consecutive patients with stage III or IVa HPV-OPSCC treated with NECTORS in 2017 to 2022 who had completed the primary QOL questionnaire at baseline and at least once during the 24-month follow-up period were included. Ninety-four patients were eligible, and 67 were included in the analyses. Outcome Measures: QOL questionnaires at baseline, and at month 1, 3, 6, 12, 18, and 24 posttreatment. Global score on the 30-item European Organization for Research and Treatment of Cancer Core quality of life questionnaire (EORTC QLQ-C30) was the primary outcome; the head and neck extension module (EORTC QLQ-HN35); the MD Anderson Dysphagia Inventory for dysphagia-related QOL; and the Decision Regret Scale were also used. Paired t tests assessed change between the baseline and 12- or 24-month patient-reported outcomes. Results: Among the study population of 67 patients (median [range] age, 63 [58-67] years; 54 [80.6%] male) with HPV-OPSCC, the most frequent cancer subsites were palatine tonsil (41 [61%]) and base of tongue (26 [39%]); none required adjuvant RT. Global QOL at 24 months improved compared with baseline (mean difference, 9.49; 95% CI, 2.45 to 16.53). All EORTC QLQ-C30 functional scores returned to baseline or improved within 3 to 6 months posttreatment and remained stable at 24 months. EORTC QLQ-HN35 symptom scale scores improved or were stable at 24 months. The MD Anderson Dysphagia Inventory scores demonstrated no significant difference between baseline and month 12 for global scores (mean difference, 6.15; 95% CI, -4.18 to 16.49) and composite scores (mean difference, 2.73; 95% CI, -1.62 to 7.09). Median (range) score on the Decision Regret Scale was 5 of 100 (0-30), representing mild overall regret. Conclusion and Relevance: The findings of this multicenter cohort study indicate that use of the NECTORS protocol is associated with excellent QOL outcomes. QOL measures returned to baseline levels or were better than baseline, which represents positive outcomes for patients with HPV-OPSCC who undergo this treatment regimen.

Long-read sequencing of oropharyngeal squamous cell carcinoma tumors reveal diverse patterns of high-risk Human Papillomavirus integration.

Introduction: In North America and in most European countries, Human Papillomavirus (HPV) is responsible for over 70% of oropharyngeal squamous cell carcinomas. The burden of OPSCC, in high-income countries, has been steadily increasing over the past 20 years. As a result, in the USA and in the UK, the burden of HPV-related oropharyngeal squamous cell carcinoma in men has now surpassed that of cervical cancer in women. However, the oncogenic impact of high-risk HPV integration in oropharyngeal squamous cell carcinomas hasn't been extensively studied. The present study aimed to explore the patterns of HPV integration in oropharyngeal squamous cell carcinomas and to assess the feasibility and reliability of long-read sequencing technology in detecting viral integration events in oropharyngeal head and neck cancers. Methods: A cohort of eight HPV-positive OPSCC pre-treatment patient tumors (four males and four females), were selected. All patients received a p16INK4A positive OPSCC diagnosis and were treated at the McGill University Health Centre, a quaternary center in Montreal. A minimum of 20mg of tumor tissue was used for DNA extraction. Extracted DNA was subjected to Nanopore long-read sequencing to detect and analyze for the presence of high-risk HPV sequences. PCR and Sanger sequencing experiments were performed to confirm Nanopore long-read sequencing readings. Results: Nanopore long-read sequencing showed that seven out of eight patient samples displayed either integrated or episomal high-risk HPV sequences. Out of these seven samples, four displayed verifiable integration events upon bioinformatic analysis. Integration confirmation experiments were designed for all four samples using PCR-based methods. Sanger sequencing was also performed. Four distinct HPV integration patterns were identified: concatemer chromosomal integration in a single chromosome, bi-chromosomal concatemer integration, single chromosome complete integration and bi-chromosomal complete integration. HPV concatemer integration also proved more common than full HPV integration events. Conclusion and relevance: Long-read sequencing technologies can be effectively used to assess HPV integration patterns in OPSCC tumors. Clinically, more research should be conducted on the prognostication value of high-risk HPV integration in OPSCC tumors using long-read sequencing technology.

Genetic predisposition to depression and inflammation impacts symptom burden and survival in patients with head and neck cancer: A longitudinal study.

OBJECTIVE: The primary purpose of this study was to investigate the contribution of genetic predispositions to depression and inflammation, as measured through polygenic risk scores, on symptom burden (physical and psychological) in patients with head and neck cancer in the immediate post-treatment period (i.e., at three months post-diagnosis), as well as on 3-, 6-, 12-, 24- and 36-month survival. METHODS: Prospective longitudinal study of 223 adults (72 % participation) newly diagnosed with a first occurrence of primary head and neck cancer, paired with genetic data (Illumina PsychArray), validated psychometric measures, Structured Clinical Interviews for DSM Disorders (SCID-I), and medical chart reviews. RESULTS: Symptom burden at 3 months was predicted by (R2 adj. = 0.38, p < 0.001): a baseline SCID-I Anxiety Disorder (b = 1.69, B = 0.23, 95%CI = 0.43-2.94; p = 0.009), baseline levels of HADS anxiety (b = 0.20, B = 0.29, 95%CI = 0.07-0.34; p = 0.003), the polygenic risk score (PRS) for depression (b = 0.66, B = 0.18, 95%CI = 0.003-1.32; p = 0.049), and cumulated dose of radiotherapy (b = 0.002, B = 0.46, 95%CI = 0.001-0.003; p < 0.001). When controlling for factors known to be associated with cancer survival, patients with a higher PRS associated with depression and inflammation, respectively, presented higher risk of death within 36 months (b = 1.75, Exp(B) = 5.75, 95%CI = 1.55-21.27, p = 0.009 and b = 0.14, Exp(B) = 1.15, 95%CI = 1.01-1.30, p = 0.03). CONCLUSIONS: Our results outline three potential pathways of symptom burden in patients with head and neck cancer: a genetic predisposition towards depression; an initial anxiety disorder upon being diagnosed with cancer or high levels of anxiety upon diagnosis; and a dose-related response to radiotherapy. One may want to investigate early interventions in these areas to alleviate symptom burden in patients faced with a life-threatening disease, as well as consider targeting genetic predisposition towards depression and inflammation implicated in survival. The high prevalence of distress in patients with head and neck cancer is an opportunity to study genetic predispositions, which could potentially be broadly generalized to other cancers and diseases.

Prioritization of head and neck cancer patient care during the COVID-19 pandemic: a retrospective cohort study.

BACKGROUND: The COVID-19 pandemic placed considerable strain on the healthcare system, leading to the re-allocation of resources and implementation of new practice guidelines. The objective of this study is to assess the impact of COVID-19 guideline modifications on head and neck cancer (HNC) care at two tertiary care centers in Canada. METHODS: A retrospective cohort study was conducted. HNC patients seen at two tertiary care centers before and after the onset of the COVID-19 pandemic (pre-pandemic: July 1st, 2019, to February 29th, 2020; pandemic: March 1st, 2020, to October 31st, 2020) were included. The pre-pandemic and pandemic cohorts were compared according to patient and tumor characteristics, duration of HNC workup, and treatment type and duration. Mean differences in cancer care wait times, including time to diagnosis, tumor board, and treatment as well as total treatment package time and postoperative hospital stay were compared between cohorts. Univariate and multivariate analyses were used to compare characteristics and outcomes between cohorts. RESULTS: Pre-pandemic (n = 132) and pandemic (n = 133) patients did not differ significantly in sex, age, habits, or tumor characteristics. The percentage of patients who received surgery only, chemo/radiotherapy (CXRT) only, and surgery plus adjuvant CXRT did not differ significantly between cohorts. Pandemic patients experienced a significant time reduction compared to pre-pandemic patients with regards to the date first seen by a HNC service until start of treatment ([Formula: see text] = 48.7 and 76.6 days respectively; p = .0001), the date first seen by a HNC service until first presentation at tumor board ([Formula: see text] = 25.1 and 38 days respectively; p = .001), mean total package time for patients who received surgery only ([Formula: see text] = 3.7 and 9.0 days respectively; p = .017), and mean total package time for patients who received surgery plus adjuvant CXRT ([Formula: see text] = 80.2 and 112.7 days respectively; p = .035). CONCLUSION: The time to treatment was significantly reduced during the COVID-19 pandemic as compared to pre-pandemic. This transparent model of patient-centered operative-room prioritization can serve as a model for improving resource allocation and efficiency of HNC care during emergency and non-emergency scenarios.

Response to Neoadjuvant Targeted Therapy in Operable Head and Neck Cancer Confers Survival Benefit.

PURPOSE: Neoadjuvant targeted therapy provides a brief, preoperative window of opportunity that can be exploited to individualize cancer care based on treatment response. We investigated whether response to neoadjuvant therapy during the preoperative window confers survival benefit in patients with operable head and neck squamous cell carcinoma (HNSCC). PATIENTS AND METHODS: A pooled analysis of treatment-naïve patients with operable HNSCC enrolled in one of three clinical trials from 2009 to 2020 (NCT00779389, NCT01218048, NCT02473731). Neoadjuvant regimens consisted of EGFR inhibitors (n = 83) or anti-ErbB3 antibody therapy (n = 9) within 28 days of surgery. Clinical to pathologic stage migration was compared with disease-free survival (DFS) and overall survival (OS) while adjusting for confounding factors using multivariable Cox regression. Circulating tumor markers validated in other solid tumor models were analyzed. RESULTS: 92 of 118 patients were analyzed; all patients underwent surgery following neoadjuvant therapy. Clinical to pathologic downstaging was more frequent in patients undergoing neoadjuvant targeted therapy compared with control cohort (P = 0.048). Patients with pathologic downstage migration had the highest OS [89.5%; 95% confidence interval (CI), 75.7-100] compared with those with no stage change (58%; 95% CI, 46.2-69.8) or upstage (40%; 95% CI, 9.6-70.4; P = 0.003). Downstage migration remained a positive prognostic factor for OS (HR, 0.22; 95% CI, 0.05-0.90) while adjusting for measured confounders. Downstage migration correlated with decreased circulating tumor markers, SOX17 and TAC1 (P = 0.0078). CONCLUSIONS: Brief neoadjuvant therapy achieved pathologic downstaging in a subset of patients and was associated with significantly better DFS and OS as well as decreased circulating methylated SOX17 and TAC1.

Development and validation of the modified index of fragility in head and neck cancer surgery.

BACKGROUND: This study aims to develop and validate, a clinically useful modified index of fragility (mIFG) to identify patients at risk of fragility and to predict postoperative adverse events. METHOD: An observational study was performed using the American College of Surgeons National Surgical Quality Improvement Program database, from 2006 to 2018. All patients undergoing nonemergency head and neck cancer surgery were included. A seven-item index (mIFG) was developed using variables associated with frailty, cachexia, and sarcopenia, drawn from the literature (weight loss, low body mass index, dyspnea, diabetes, serum albumin, hematocrit, and creatinine). Multivariable logistic regression was used to model the association between mIFG, postoperative adverse events and death. A validation cohort was then used to ascertain the diagnostic accuracy of the mIFG. RESULTS: A total of 23,438 cases were included (16,407 in the derivation group and 7031 in the validation group). There was a total of 4273 postoperative major adverse events (AE) and deaths, 1023 postoperative pulmonary complications and 1721 wound complications. Using the derivation cohort, the 7-item mIFG was independently associated with death, major AEs, pulmonary and wound complications, when controlling for significant covariates. The mIFG predicted death and major adverse events using the validation cohort with an accuracy of 0.70 (95% CI: 0.63-0.76) and 0.64 (95% CI: 0.63-0.66), respectively. The mIFG outperformed the modified Frailty index. CONCLUSION: The modified index of fragility is a reliable and easily accessible tool to predict risk of postoperative adverse events and death in patients undergoing head and neck cancer surgery.

Percutaneous Tracheostomy With a Demistifier Canopy in the COVID-19 Era: A Safe Technique in the Intensive Care Unit.

BACKGROUND: Endoscopic percutaneous tracheostomy (PT) is a safe technique that is performed frequently by otolaryngologists and intensivists. New challenges have been identified in order to maintain the safety of this procedure during the COVID-19 pandemic. A novel approach, using a modified demistifier canopy, was developed during the first wave of the pandemic and implemented for 17 consecutive percutaneous tracheostomies in order to enhance procedural safety. METHODS: A protocol was developed after performing a literature review of tracheostomy in COVID-19 patients. A multidisciplinary tracheostomy team was established, including the departments of otolaryngology, critical care, and respiratory therapy. Simulation was performed prior to each PT, and postoperative debriefings were done. RESULTS: A protocol and technical description of PT using a modified demistifier canopy covering was written and video documented. Data were collected on 17 patients who underwent this procedure safely in our tertiary care hospital. There were no procedure-related complications, and no evidence of COVID-19 transmission to any member of the health care team during the study period. CONCLUSION: As patients continue to recover from COVID-19, their need for tracheostomy will increase. The technique described provides a safe, multidisciplinary method of performing PT in COVID-19 patients.

Dealing with the Vicissitudes and Abject Consequences of Head and Neck Cancer: A Vital Role for Psycho-Oncology.

Patients with head and neck cancer face important life-altering effects in appearance and function, affecting distress and quality of life and requiring the involvement of a multidisciplinary team. Psycho-oncology makes an important contribution to the field, as head and neck cancers carry a huge adaptational toll. To illustrate the value of this discipline, we report two cases of patients with advanced head and neck cancer for which the treatment-related body changes were of major significance. A commentary by the treating surgeons and psycho-oncologists precedes a general discussion about the clinical management of such patients. The article outlines strategies to address health literacy, doctor-patient communication, treatment decision-making, and emotional distress; placing the person at the center of oncological care. It calls for the broad application of principles of psychological first aid by healthcare professionals in oncology.

Biopsychosocial Markers of Body Image Concerns in Patients with Head and Neck Cancer: A Prospective Longitudinal Study.

(1) Background: Patients and survivors of head and neck cancer (HNC) are at a high risk of developing body image concerns. Despite the prevalence of body image concerns in patients with HNC, there is a lack of longitudinal research exploring the wide array of its associated determinants. The current longitudinal study examined the determinants and longitudinal course of body image dissatisfaction in patients with HNC. (2) Methods: Patients participated in Structured Clinical Interviews and self-administered questionnaires at four time-points: (T1) upon cancer diagnosis, (T2) at 3 months post-diagnosis, (T3) at 6 months post-diagnosis, and (T4) at 12 months post-diagnosis. They also underwent a disfigurement rating on an objective scale. (3) Results: Two hundred and twenty-four patients participated in our study. Fourteen percent to twenty-eight percent of patients reported at least moderate body image concerns across time points, with the lowest rates at baseline and the highest at 3 months (T1). It was found that patients more predisposed to developing higher levels of body image concerns presented physical markers (i.e., advanced cancer stage, lower physical functioning, higher disfigurement), psychosocial markers (i.e., higher depression, higher anxiety, and higher levels of coping with denial), and health disparities (i.e., younger age, female sex, French language, and marital status, with divorced and widowers most affected). (4) Conclusions: The findings of this study highlight the multifaceted nature of body image concerns in patients with HNC and its biopsychosocial determinants. Clinicians should pay specific attention to these biopsychosocial markers in their clinics to predict high levels of body image concerns and tailor communication/refer for support accordingly.

Application of the Milan system for reporting salivary gland cytopathology using cell blocks.

The Milan system for reporting salivary gland cytopathology (MSRSGC) is a novel standardized classification tool for salivary gland cytology specimens based on the use of direct smears. Formalin-fixed paraffin-embedded (FFPE) cell blocks facilitate the use of ancillary studies, leading to improved diagnostic accuracy. However, the application of the MSRSGC with only cell blocks has not been well established. Consecutive cohort of all parotid gland cytology specimens between 01/01/2018 and 30/06/2021 was performed. All cytology specimens were processed into cell blocks only. Cytologic diagnoses were classified prospectively according to the MSRSGC categories. The risk of malignancy (ROM) for each diagnostic category and the diagnostic performance were calculated. A total of 230 FNA samples from 221 patients were identified, including 47% and 78.4% with surgical or clinical follow-up, respectively. The ROMs based on surgical follow-up for the non-diagnostic, non-neoplastic, AUS, neoplasm: benign, SUMP, SFM and malignant categories were 21.4%,0%,50%,0%,30%,100% and 100%, respectively. The ROMs based on the clinical follow-up for these categories were 7.3%,0%,37.3%,0%,27.3%,100% and 100%, respectively. Following surgical excision, all Milan IVa category samples were confirmed as benign, and all Milan V and VI category samples were confirmed as malignant. This study validates the application of the MSRSGC with the sole use of FFPE cell blocks. The diagnostic accuracy of MSRSGC is high and compares favorably to other institutions using traditional cytology assessment methods. Furthermore, FNA results using this technique enabled to provide optimal patient management based on the ROM of the different Milan system categories.

Historical Perspective: How the Discovery of HPV Virus Led to the Utilization of a Robot.

The treatment of oropharyngeal cancer has undergone many paradigms shifts in recent decades. First considered a surgical disease, improvements in radiotherapy led to its popularization in the 1990s. Subsequently, the discovery of the human papillomavirus (HPV) in the pathogenesis of oropharyngeal cancer, as well as the increase in HPV-associated oropharynx cancer incidence, have prompted a reevaluation of its management. Its sensitivity to standard treatment with a favorable prognosis compared to non HPV-associated oropharyngeal cancer led to a focus on minimizing treatment toxicity. Advances in radiation and surgical techniques, including the use of transoral robotic surgery, gave the rationale to ongoing de-escalation clinical trials in HPV-associated oropharynx cancer.