Multiphasic exercise prehabilitation for patients undergoing surgery for head and neck cancer: a hybrid effectiveness-implementation study protocol.

Head and neck cancer (HNC) treatment often consists of major surgery followed by adjuvant therapy, which can result in treatment-related side effects, decreased physical function, and diminished quality of life. Perioperative nutrition interventions and early mobilization improve recovery after HNC treatment. However, there are few studies on prehabilitation that include exercise within the HNC surgical care pathway. We have designed a multiphasic exercise prehabilitation intervention for HNC patients undergoing surgical resection with free flap reconstruction. We will use a hybrid effectiveness-implementation study design guided by the RE-AIM framework to address the following objectives: (1) to evaluate intervention benefits through physical function and patient-reported outcome assessments; (2) to determine the safety and feasibility of the prehabilitation intervention; (3) to evaluate the implementation of exercise within the HNC surgical care pathway; and (4) to establish a post-operative screening and referral pathway to exercise oncology resources. The results of this study will provide evidence for the benefits and costs of a multiphasic exercise prehabilitation intervention embedded within the HNC surgical care pathway. This paper describes the study protocol design, multiphasic exercise prehabilitation intervention, planned analyses, and dissemination of findings. Trial registration: https://clinicaltrials.gov/NCT04598087.

Treatment de-escalation for HPV-associated oropharyngeal squamous cell carcinoma with radiotherapy vs. trans-oral surgery (ORATOR2): study protocol for a randomized phase II trial.

BACKGROUND: Patients with human papillomavirus-positive (HPV+) oropharyngeal squamous cell carcinoma (OPC) have substantially better treatment response and overall survival (OS) than patients with HPV-negative disease. Treatment options for HPV+ OPC can involve either a primary radiotherapy (RT) approach (± concomitant chemotherapy) or a primary surgical approach (± adjuvant radiation) with transoral surgery (TOS). These two treatment paradigms have different spectrums of toxicity. The goals of this study are to assess the OS of two de-escalation approaches (primary radiotherapy and primary TOS) compared to historical control, and to compare survival, toxicity and quality of life (QOL) profiles between the two approaches. METHODS: This is a multicenter phase II study randomizing one hundred and forty patients with T1-2 N0-2 HPV+ OPC in a 1:1 ratio between de-escalated primary radiotherapy (60 Gy) ± concomitant chemotherapy and TOS ± de-escalated adjuvant radiotherapy (50-60 Gy based on risk factors). Patients will be stratified based on smoking status (< 10 vs. ≥ 10 pack-years). The primary endpoint is OS of each arm compared to historical control; we hypothesize that a 2-year OS of 85% or greater will be achieved. Secondary endpoints include progression free survival, QOL and toxicity. DISCUSSION: This study will provide an assessment of two de-escalation approaches to the treatment of HPV+ OPC on oncologic outcomes, QOL and toxicity. Results will inform the design of future definitive phase III trials. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT03210103. Date of registration: July 6, 2017, Current version: 1.3 on March 15, 2019.

The Association of Ethnicity and Oncologic Outcomes for Oral Cavity Squamous Cell Carcinoma (OSCC).

(1) Background: To compare oncologic outcomes of South Asian (SA) patients treated for oral squamous cell carcinoma (OSCC) to the general population. (2) Methods: Adult patients who underwent surgical resection of OSCC +/- adjuvant treatment between 2009 and 2022 (N = 697) at a regional cancer centre in Canada were included. SA patients, identified using a validated method, were compared to non-SA patients. Kaplan-Meier methods were used to compare the primary outcomes, disease-specific survival (DSS) and recurrence-free survival (RFS) across baseline univariate characteristics, including betel nut consumption. Median follow-up time was 36.4 months. Cox proportional hazard models were used to identify independent predictors of survival with significance set at p < 0.05. (3) Results: SA patients (9% of cohort, N = 64) were significantly younger and had lower rates of smoking and alcohol consumption compared to non-SA patients (p < 0.05). SA patients had a two-fold higher risk of recurrence and significantly worse disease-specific survival, even after adjusting for stage and high-risk features [RFS: HR 2.01 (1.28-3.14), DSS: HR 1.79 (1.12-2.88)]. The consumption of betel nut was not associated with outcomes. (4) Conclusions: SA patients had significantly worse oncologic outcomes, even after controlling for known predictors of poor prognosis. These findings are novel and can inform personalized treatment decisions and influence public health policies when managing patients with different ethnic backgrounds.

Osteocutaneous free tissue transplantation for mandibular osteoradionecrosis.

OBJECTIVE: To describe the success rate, complications, and functional outcomes of patients who are treated with osteocutaneous free tissue transplantation for grade 4 mandibular osteoradionecrosis (ORN). DESIGN: Retrospective case series. SETTING: Tertiary care academic medical center. PATIENTS: Twelve patients (8 males, 4 females; mean age, 57.6 years) with grade 4 mandibular ORN. Three patients (25%) had a history of primary radiotherapy, two (17%) had previous concurrent chemoradiation, and seven (58%) had undergone postoperative adjuvant radiotherapy. Ten patients (83%) had previous major ablative surgery to treat the primary tumor and five (50%) had been reconstructed with a free tissue transplant prior to the onset of ORN. INTERVENTIONS: All patients underwent reconstruction with an osteocutaneous free tissue transplant for grade 4 mandibular ORN between 1999 and 2006. MAIN OUTCOME MEASURES: Successful treatment of mandibular ORN; major, minor, and late complications; gastrostomy tube (G-tube) dependence; speech and swallowing scores. RESULTS: Grade 4 mandibular ORN was successfully treated in eight (73%) evaluable patients. One patient (8%) died of a second primary tumor before the 12-month assessment. Eight patients (67%) had a major complication, three (25%) had a minor complication, and nine (75%) had a late complication. Three of the five G-tube- dependent patients prior to mandibular reconstruction were able to discontinue the use of their G-tube. Seven of the eight successfully treated patients maintained their nutrition by mouth. Median "range of liquids" score was 6/6 (range, 4 to 6). Median "range of solids" score was 4/6 (range, 3 to 6). Median "understandability of speech" score was 4/5 (range, 2 to 5). CONCLUSIONS: Grade 4 mandibular ORN was treated successfully with an osteocutaneous free tissue transfer in eight evaluable patients (73%). In successfully treated patients, median speech/swallowing scores were highly functional, but the remaining radiated soft tissue resulted in higher local wound complications and a modified diet.

NCBP2 and TFRC are novel prognostic biomarkers in oral squamous cell carcinoma.

There are few prognostic biomarkers and targeted therapeutics currently in use for the clinical management of oral squamous cell carcinoma (OSCC) and patient outcomes remain poor in this disease. A majority of mutations in OSCC are loss-of-function events in tumour suppressor genes that are refractory to conventional modes of targeting. Interestingly, the chromosomal segment 3q22-3q29 is amplified in many epithelial cancers, including OSCC. We hypothesized that some of the 468 genes located on 3q22-3q29 might be drivers of oral carcinogenesis and could be exploited as potential prognostic biomarkers and therapeutic targets. Our integrative analysis of copy number variation (CNV), gene expression and clinical data from The Cancer Genome Atlas (TCGA), identified two candidate genes: NCBP2, TFRC, whose expression positively correlates with worse overall survival (OS) in HPV-negative OSCC patients. Expression of NCBP2 and TFRC is significantly higher in tumour cells compared to most normal human tissues. High NCBP2 and TFRC protein abundance is associated with worse overall, disease-specific survival, and progression-free interval in an in-house cohort of HPV-negative OSCC patients. Finally, due to a lack of evidence for the role of NCBP2 in carcinogenesis, we tested if modulating NCBP2 levels in human OSCC cell lines affected their carcinogenic behaviour. We found that NCBP2 depletion reduced OSCC cell proliferation, migration, and invasion. Differential expression analysis revealed the upregulation of several tumour-promoting genes in patients with high NCBP2 expression. We thus propose both NCBP2 and TFRC as novel prognostic and potentially therapeutic biomarkers for HPV-negative OSCC.

Identifying Factors of Operative Efficiency in Head and Neck Free Flap Reconstruction.

Importance: Head and neck oncological resection and reconstruction is a complex process that requires multidisciplinary collaboration and prolonged operative time. Numerous factors are associated with operative time, including a surgeon's experience, team familiarity, and the use of new technologies. It is paramount to evaluate the contribution of these factors and modalities on operative time to facilitate broad adoption of the most effective modalities and reduce complications associated with prolonged operative time. Objective: To examine the association of head and neck cancer resection and reconstruction interventions with operative time. Design, Setting, and Participants: This large cohort study included all patients who underwent head and neck oncologic resection and free flap-based reconstruction in Calgary (Alberta, Canada) between January 1, 2007, and March 31, 2020. Data were analyzed between November 2021 and May2022. Interventions: The interventions that were implemented in the program were classified into team-based strategies and the introduction of new technology. Team-based strategies included introducing a standardized operative team, treatment centralization in a single institution, and introducing a microsurgery fellowship program. New technologies included use of venous coupler anastomosis and virtual surgical planning. Main Outcomes and Measures: The primary outcome was mean operative time difference before and after the implementation of each modality. Secondary outcomes included returns to the operating room within 30 days, reasons for reoperation, returns to the emergency department or readmissions to hospital within 30 days, and 2-year and 5-year disease-specific survival. Multivariate regression analyses were performed to examine the association of each modality with operative time. Results: A total of 578 patients (179 women [30.9%]; mean [SD] age, 60.8 [12.9] years) undergoing 590 procedures met inclusion criteria. During the study period, operative time progressively decreased and reached a 32% reduction during the final years of the study. A significant reduction was observed in mean operative time following the introduction of each intervention. However, a multivariate analysis revealed that team-based strategies, including the use of a standardized nursing team, treatment centralization, and a fellowship program, were significantly associated with a reduction in operative time. Conclusions: The results of this cohort study suggest that among patients with head and neck cancer, use of team-based strategies was associated with significant decreases in operative time without an increase in complications.

Spatial transcriptomics reveals distinct and conserved tumor core and edge architectures that predict survival and targeted therapy response.

The spatial organization of the tumor microenvironment has a profound impact on biology and therapy response. Here, we perform an integrative single-cell and spatial transcriptomic analysis on HPV-negative oral squamous cell carcinoma (OSCC) to comprehensively characterize malignant cells in tumor core (TC) and leading edge (LE) transcriptional architectures. We show that the TC and LE are characterized by unique transcriptional profiles, neighboring cellular compositions, and ligand-receptor interactions. We demonstrate that the gene expression profile associated with the LE is conserved across different cancers while the TC is tissue specific, highlighting common mechanisms underlying tumor progression and invasion. Additionally, we find our LE gene signature is associated with worse clinical outcomes while TC gene signature is associated with improved prognosis across multiple cancer types. Finally, using an in silico modeling approach, we describe spatially-regulated patterns of cell development in OSCC that are predictably associated with drug response. Our work provides pan-cancer insights into TC and LE biology and interactive spatial atlases ( http://www.pboselab.ca/spatial_OSCC/ ; http://www.pboselab.ca/dynamo_OSCC/ ) that can be foundational for developing novel targeted therapies.

Oncologic Significance of Therapeutic Delays in Patients With Oral Cavity Cancer.

Importance: Oral cavity cancer often requires multidisciplinary management, subjecting patients to complex therapeutic trajectories. Prolonged treatment intervals in oral cavity cancer have been associated with poor oncological outcomes, but there has yet to be a study investigating treatment times in Canada. Objective: To report treatment delays for patients with oral cavity cancer in Canada and evaluate the outcomes of treatment delays on overall survival. Design, Setting, and Participants: This multicenter cohort study was performed at 8 Canadian academic centers from 2005 to 2019. Participants were patients with oral cavity cancer who underwent surgery and adjuvant radiation therapy. Analysis was performed in January 2023. Main Outcomes and Measures: Treatment intervals evaluated were surgery to initiation of postoperative radiation therapy interval (S-PORT) and radiation therapy interval (RTI). The exposure variables were prolonged intervals, respectively defined as index S-PORT greater than 42 days and RTI greater than 46 days. Patient demographics, Charlson Comorbidity Index, smoking status, alcohol status, and cancer staging were also considered. Univariate (log rank and Kaplan-Meier) and multivariate (Cox regression) analyses were performed to determine associations with overall survival (OS). Results: Overall, 1368 patients were included; median (IQR) age at diagnosis was 61 (54-70) years, and 896 (65%) were men. Median (IQR) S-PORT was 56 (46-68) days, with 1093 (80%) patients waiting greater than 42 days, and median (IQR) RTI was 43 (41-47) days, with 353 (26%) patients having treatment time interval greater than 46 days. There were variations in treatment time intervals between institutions for S-PORT (institution with longest vs shortest median S-PORT, 64 days vs 48 days; η2 = 0.023) and RTI (institution with longest vs shortest median RTI, 44 days vs 40 days; η2 = 0.022). Median follow-up was 34 months. The 3-year OS was 68%. In univariate analysis, patients with prolonged S-PORT had worse survival at 3 years (66% vs 77%; odds ratio 1.75; 95% CI, 1.27-2.42), whereas prolonged RTI (67% vs 69%; odds ratio 1.06; 95% CI, 0.81-1.38) was not associated with OS. Other factors associated with OS were age, Charlson Comorbidity Index, alcohol status, T category, N category, and institution. In the multivariate model, prolonged S-PORT remained independently associated with OS (hazard ratio, 1.39; 95% CI, 1.07-1.80). Conclusions and Relevance: In this multicenter cohort study of patients with oral cavity cancer requiring multimodal therapy, initiation of radiation therapy within 42 days from surgery was associated with improved survival. However, in Canada, only a minority completed S-PORT within the recommended time, whereas most had an appropriate RTI. An interinstitution variation existed in terms of treatment time intervals. Institutions should aim to identify reasons for delays in their respective centers, and efforts and resources should be directed toward achieving timely completion of S-PORT.

Bax expression measured by AQUAnalysis is an independent prognostic marker in oral squamous cell carcinoma.

BACKGROUND: Resistance to apoptosis is a hallmark of cancer and proteins regulating apoptosis have been proposed as prognostic markers in several malignancies. However, the prognostic impact of apoptotic markers has not been consistently demonstrated in oral squamous cell carcinoma (OSCC). This inconsistency in reported associations between apoptotic proteins and prognosis can be partly attributed to the intrinsic low resolution and misclassification associated with manual, semi-quantitative methods of biomarker expression measurement. The aim of this study was to examine the association between apoptosis-regulating proteins and clinical outcomes in oral squamous cell carcinoma (OSCC) using the quantitative fluorescence immunohistochemistry (IHC) based AQUAnalysis technique. METHODS: Sixty-nine OSCC patients diagnosed between 1998-2005 in Calgary, Alberta, Canada were included in the study. Clinical data were obtained from the Alberta Cancer Registry and chart review. Tissue microarrays (TMAs) were assembled from triplicate cores of formalin-fixed paraffin embedded pre-treatment tumour tissue. Bax, Bcl-2 and Bcl-XL protein expression was quantified using fluorescent IHC and AQUA technology in normal oral cavity squamous epithelium (OCSE) and OSCC tumour samples. Survival was analyzed using Kaplan-Meier plots and the Cox proportional hazard model. RESULTS: Bax expression was predominantly nuclear in OCSE and almost exclusively cytoplasmic in OSCC. No similar differences in localization were observed for Bcl-2 or Bcl-XL. Only Bax expression associated with disease-specific survival (DSS), with 5-year survival estimates of 85.7% for high Bax versus 50.3% for low Bax (p = 0.006), in univariate analysis. High Bax expression was also significantly associated with elevated Ki67 expression, indicating that increased proliferation might lead to an improved response to radiotherapy in patients with elevated Bax expression. In multivariate analyses, Bax protein expression remained an independent predictor of DSS in OSCC [HR 0.241 (0.078-0.745), p = 0.013]. CONCLUSIONS: The AQUA technique used in our study eliminates observer bias and provides reliable and reproducible estimates for biomarker expression. AQUA also provides essential measures of quality control that cannot be achieved with manual biomarker scoring techniques. Our results support the use of Bax protein expression as a prognostic marker in conjunction with other clinico-pathological variables when designing personalized treatment strategies for OSCC patients.

TRK Inhibition with Entrectinib in Metastatic Salivary Secretory Carcinoma (SC): A Case Report.

NTRK gene fusions are rare oncogenic driver mutations that can be found in a broad range of neoplasms. In secretory carcinoma (SC), ETV6-NTRK3 gene fusion is seen in a majority of the cases and represents a druggable target for patients with advanced disease in the absence of a currently accepted standard of care. In our case, we describe a patient with recurrent, metastatic SC treated with first line entrectinib with clinically meaningful, durable ongoing response after 49 months. The patient experienced grade 1 fatigue, dysgeusia, skin sensitivity, arthralgias, an increase in serum creatinine, and weight-gain as well as grade 2 hypotension which resolved after a dose reduction. Entrectinib is a well-tolerated treatment with the potential for durable responses and TRK inhibition should be considered the standard of care in SC and other NTRK gene fusion-positive advanced neoplasms without acceptable alternative treatment options.

Cost-effectiveness analysis of molecular testing for cytologically indeterminate thyroid nodules.

BACKGROUND: Thyroid nodules affect up to 65% of the population. Although fine needle aspirate (FNA) cytology is the gold standard for diagnosis, 15-30% of results are indeterminate. Molecular testing may aid in the diagnosis of nodules and potentially reduce unnecessary surgery. However, these tests are associated with significant costs. The objective of this study was to evaluate the cost-effectiveness of Afirma, a commercially available molecular test, in cytologically indeterminate thyroid nodules. METHODS: The base case was a solitary thyroid nodule with no additional high-risk features and an indeterminate FNA. Decision tree analysis was performed from the single payer perspective with a 1-year time horizon. Costing data were collected through micro-costing methodology. A probabilistic sensitivity analysis was performed. The primary outcome was the incremental cost effectiveness ratio (ICER) of cost per thyroid surgery avoided. RESULTS: Over 1 year, mean cost estimates were $8176.28 with 0.58 effectiveness for the molecular testing strategy and $6016.83 with 0.07 effectiveness for current standard management. The ICER was $4234.22 per surgery avoided. At a willingness-to-pay (WTP) threshold of $5000 per surgery avoided, molecular testing is cost-effective with 63% certainty. CONCLUSION: This cost-effectiveness analysis suggests utilizing Afirma for indeterminate solitary thyroid nodules is a cost-effective strategy for avoiding unnecessary thyroid surgery. With a $5000 WTP threshold, molecular testing has a 63% chance of being the more cost-effective strategy. The cost effectiveness varies based on the cost of the molecular test and the value of Afirma for patients with indeterminate thyroid nodules depends on the WTP threshold to avoid unnecessary thyroid surgery.

The feasibility of patient-reported outcomes, physical function, and mobilization in the care pathway for head and neck cancer surgical patients.

BACKGROUND: Head and neck cancer (HNC) patients are an understudied population whose treatment often includes surgery, causing a wide range of side effects. Exercise prehabilitation is a promising tool to optimize patient outcomes and may confer additional benefits as a prehabilitation tool. The primary objective of this study was to assess the feasibility of measuring patient-reported outcomes (PROs), physical function, and in-hospital mobilization across the HNC surgical timeline in advance of a future prehabilitation trial. The secondary objective was to examine potential changes in these outcomes across the surgical timeline. METHODS: HNC patients scheduled to undergo oncologic resection with free-flap reconstruction completed assessments of PROs and physical function at three timepoints across the surgical timeline (baseline, in-hospital, and postsurgical/outpatient). Mobilization was measured during the in-hospital period. The feasibility of recruitment and measurement completion was tracked, as were changes in both PROs and physical function. RESULTS: Of 48 eligible patients, 16 enrolled (recruitment rate of 33%). The baseline and in-hospital PROs were completed by 88% of participants, while the outpatient assessments were completed by 81% of participants. The baseline and in-hospital assessment of physical function were completed by 56% of participants, and 38% completed the outpatient assessment. Measuring in-hospital mobilization was completed for 63% of participants. CONCLUSION: Measuring PROs and in-hospital mobilization is feasible across the surgical timeline in HNC; however, the in-person assessment of physical function prior to surgery was not feasible. A multidisciplinary collaboration between exercise specialists and clinicians supported the development of new clinical workflows in HNC surgical care that will aid in the implementation of a future prehabilitation trial for this patient population.

The Prospective Implementation of the 2015 ATA Guidelines and Modified ATA Recurrence Risk Stratification System for Treatment of Differentiated Thyroid Cancer in a Canadian Tertiary Care Referral Setting.

Objective: To present clinical outcomes of the prospective implementation of the 2015 American Thyroid Association (ATA) guidelines for the management of thyroid nodules and differentiated thyroid cancer (DTC) using the modified ATA recurrence risk (RR) stratification system. Methods: We prospectively analyzed 612 patients with DTC treated between April 2017 and December 2021 in Calgary, Alberta. Each patient was prospectively assigned a modified ATA RR and American Joint Committee Cancer 8th edition stage. Initial risk stratification and consideration of the 2015 ATA guidelines guided surgical management as well as the indication for and dose of radioiodine (RAI) and other adjuvant therapies. Patients were assessed for their response to treatment (RTT) at 2-years postoperatively. Results: There were 479 patients who had 2-year follow-up data and were included in the study. Of these patients, there were 253 (53%) low-, 129 (27%) intermediate-, and 97 (20%) high-RR patients. Of these, 227 patients (47%) underwent total thyroidectomy (TTX) plus RAI, 178 (37%) underwent TTX only, and 74 (16%) underwent lobectomy. The RTT at 2 years was excellent for 89% (66) of patients with lobectomy, 84% (149) for TTX only, and 53% (121) for TTX plus RAI. Among 253 patients who were deemed low RR, 85% (216) had excellent RTT, 13% (32) indeterminate RTT, 2% (4) biochemical incomplete RTT, and 1 patient had structural incomplete RTT. The intermediate RR group had the following RTT outcomes: 64% (83) excellent, 23% (30) indeterminate, 6% (7) biochemical incomplete, and 7% (9) structural incomplete. The high RR group had the worst RTT outcomes, with 38% (37) excellent, 19% (18) indeterminate, 10% (10) biochemical incomplete, and 33% (32) structural incomplete RTT. Conclusions: The 2015 ATA RR stratification system is useful for predicting disease status at 2-year post-treatment in patients with DTC. The 2015 ATA guidelines and modified ATA RR stratification treatment recommendations may reduce thyroid cancer overtreatment by including lobectomy as a definitive treatment option for low-risk thyroid cancers and selective use of RAI for intermediate and high-risk patients.

A Qualitative Study of Patient and Healthcare Provider Perspectives on Building Multiphasic Exercise Prehabilitation into the Surgical Care Pathway for Head and Neck Cancer.

Head and neck cancer (HNC) surgical patients experience a high symptom burden. Multiphasic exercise prehabilitation has the potential to improve patient outcomes, and to implement it into the care pathway, the perspectives of patients and healthcare providers (HCPs) must be considered. The purpose of this study was thus to gather feedback from HNC surgical patients and HCPs on building exercise into the standard HNC surgical care pathway. Methods: Semi-structured interviews were conducted with patients and HCPs as part of a feasibility study assessing patient-reported outcomes, physical function, and in-hospital mobilization. Interview questions included satisfaction with study recruitment, assessment completion, impact on clinical workflow (HCPs), and perceptions of a future multiphasic exercise prehabilitation program. This study followed an interpretive description methodology. Results: Ten patients and ten HCPs participated in this study. Four themes were identified: (1) acceptability and necessity of assessments, (2) the value of exercise, (3) the components of an ideal exercise program, and (4) factors to support implementation. Conclusion: These findings highlight the value of exercise across the HNC surgical timeline from both the patient and the HCP perspective. Results have informed the implementation of a multiphasic exercise prehabilitation trial in HNC surgical patients.

Assessment of Toxic Effects and Survival in Treatment Deescalation With Radiotherapy vs Transoral Surgery for HPV-Associated Oropharyngeal Squamous Cell Carcinoma: The ORATOR2 Phase 2 Randomized Clinical Trial.

Importance: The optimal approach for treatment deescalation in human papillomavirus (HPV)-related oropharyngeal squamous cell carcinomas (OPSCCs) is unknown. Objective: To assess a primary radiotherapy (RT) approach vs a primary transoral surgical (TOS) approach in treatment deescalation for HPV-related OPSCC. Design, Setting, and Participants: This international, multicenter, open-label parallel-group phase 2 randomized clinical trial was conducted at 9 tertiary academic cancer centers in Canada and Australia and enrolled patients with T1-T2N0-2 p16-positive OPSCC between February 13, 2018, and November 17, 2020. Patients had up to 3 years of follow-up. Interventions: Primary RT (consisting of 60 Gy of RT with concurrent weekly cisplatin in node-positive patients) vs TOS and neck dissection (ND) (with adjuvant reduced-dose RT depending on pathologic findings). Main Outcomes and Measures: The primary end point was overall survival (OS) compared with a historical control. Secondary end points included progression-free survival (PFS), quality of life, and toxic effects. Results: Overall, 61 patients were randomized (30 [49.2%] in the RT arm and 31 [50.8%] in the TOS and ND arm; median [IQR] age, 61.9 [57.2-67.9] years; 8 women [13.6%] and 51 men [86.4%]; 31 [50.8%] never smoked). The trial began in February 2018, and accrual was halted in November 2020 because of excessive toxic effects in the TOS and ND arm. Median follow-up was 17 months (IQR, 15-20 months). For the OS end point, there were 3 death events, all in the TOS and ND arm, including the 2 treatment-related deaths (0.7 and 4.3 months after randomization, respectively) and 1 of myocardial infarction at 8.5 months. There were 4 events for the PFS end point, also all in the TOS and ND arm, which included the 3 mortality events and 1 local recurrence. Thus, the OS and PFS data remained immature. Grade 2 to 5 toxic effects occurred in 20 patients (67%) in the RT arm and 22 (71%) in the TOS and ND arm. Mean (SD) MD Anderson Dysphagia Inventory scores at 1 year were similar between arms (85.7 [15.6] and 84.7 [14.5], respectively). Conclusions and Relevance: In this randomized clinical trial, TOS was associated with an unacceptable risk of grade 5 toxic effects, but patients in both trial arms achieved good swallowing outcomes at 1 year. Long-term follow-up is required to assess OS and PFS outcomes. Trial Registration: Clinicaltrials.gov Identifier: NCT03210103.

Are there opportunities to improve care as patients transition through the cancer care continuum? A scoping review protocol.

INTRODUCTION: Transitions in Care (TiC) are vulnerable periods in care delivery associated with adverse events, increased cost and decreased patient satisfaction. Patients with cancer encounter many transitions during their care journey due to improved survival rates and the complexity of treatment. Collectively, improving TiC is particularly important among patients with cancer. The objective of this scoping review is to synthesise and map the existing literature regarding TiC among patients with cancer in order to explore opportunities to improve TiC among patients with cancer. METHODS AND ANALYSIS: This scoping review will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analysis-Scoping Review Extension and the Joanna Briggs Institute methodology. The PubMed cancer filter and underlying search strategy will be tailored to each database (Embase, Cochrane, CINAHL and PsycINFO) and combined with search terms for TiC. Grey literature and references of included studies will be searched. The search will include studies published from database inception until 9 February 2020. Quantitative and qualitative studies will be included if they describe transitions between any type of healthcare provider or institution among patients with cancer. Descriptive statistics will summarise study characteristics and quantitative data of included studies. Qualitative data will be synthesised using thematic analysis. ETHICS AND DISSEMINATION: Our objective is to synthesise and map the existing evidence; therefore, ethical approval is not required. Evidence gaps around TiC will inform a programme of research aimed to improve high-risk transitions among patients with cancer. The findings of this scoping review will be published in a peer-reviewed journal and widely presented at academic conferences. More importantly, decision makers and patients will be provided a summary of the findings, along with data from a companion study, to prioritise TiC in need of interventions to improve continuity of care for patients with cancer.

The impact of close surgical margins on recurrence in oral squamous cell carcinoma.

BACKGROUND: Close margins influence treatment and outcome in patients with oral squamous cell carcinoma (OSCC). This study evaluates 187 cases of surgically treated OSCC regarding the impact of close margins on recurrence-free survival (RFS) and disease-specific survival (DSS). METHODS: Predictors of worsened outcome were identified using Kaplan-Meier analysis and multivariate Cox regression analysis. RESULTS: Tumour size [HR:1.70(0.95-3.08)], nodal status [HR:2.15(1.00-4.64)], presence of extracapsular spread (ECS) [HR:6.36(2.41-16.74)] and smoking history [HR:2.87(1.19-6.86)] were associated with worsened RFS. Similar factors were associated with worsened DSS. Close margins did not influence RFS or DSS. CONCLUSIONS: While most conventional risk factors for OSCC conferred a worsened outcome, close margins did not. One explanation for this would be that close margins (< 5 mm) are equivalent to clear margins and the cutoff definition for a close margin should be re-evaluated. Lack of standardized pathology could also reduce accuracy of reporting of close surgical margins.

Chronic opioid use following surgery for head and neck cancer patients undergoing free flap reconstruction.

BACKGROUND: Physician opioid-prescribing patterns have significant impacts on the current opioid crisis. Patients who use opioids in the postoperative period are at risk of developing chronic postoperative opioid use. This study determined the rate of chronic postoperative opioid use among head and neck cancer patients undergoing primary surgery with free-flap reconstruction. Additionally, this study identified major risk factors associated with the development of chronic postoperative opioid use. METHODS: A retrospective chart review was performed for all adults (age ≥ 18 years) undergoing primary head and neck surgical resection with free-flap reconstruction between January 2008 and December 2015. Patients were identified from a prospectively collected database, Otobase™. Data from the provincial drug insurance program were used to capture drug dispensing information to determine chronic opioid use at 3- and 12-months postoperatively. Data extracted from Otobase™ included patient demographics, social habits, clinical stage, pathological stage, type of surgery, and adjuvant treatment. RESULTS: The total cohort was comprised of 212 patients. Chronic opioid use at 3- and 12- months postoperatively was observed in 136 (64%) and 116 (55%) patients, respectively. Of the 212 patients, 85 patients (40%) were identified as preoperative opioid users and 127 were opioid naïve (60%). Of the 85 patients who were preoperative opioid users, 70 (82%) and 63 (77%) patients continued to use opioids 3- and 12-months postoperatively, respectively. The proportion of opioid-naïve patients who were using opioids at 3- and 12-months postoperatively was 52% (66 patients) and 42% (53 patients), respectively. Identified risk factors included preoperative opioid use, prior tobacco use, advanced pathologic T-stage, and adjuvant treatment. CONCLUSIONS: Among head and neck cancer patients that have undergone major resection with free-flap reconstruction, the prevalence of chronic postoperative opioid users was considerable. Identified risk factors included preoperative opioid use, prior tobacco use, tumor stage, and adjuvant treatment.

Efficacy of Multimodal Analgesia for Postoperative Pain Management in Head and Neck Cancer Patients.

Postoperative opioid use has been linked to the subsequent development of opioid dependency. Multimodal analgesia (MMA) can reduce the use of opioids in the postoperative period, but MMA has not been well-studied after major head and neck surgery. Our goal is to explore the association between MMA and postoperative opioid use and pain control in patients undergoing major head and neck surgery. We performed a retrospective study in adult (age ≥ 18 years) patients undergoing primary head and neck cancer resection with free-flap reconstruction. All patients were treated using an established care pathway. The baseline group was treated between January 2015-December 2015 (n = 41), prior to the implementation of MMA, and were compared to an MMA-treated cohort treated between December 2017-June 2019 (n = 97). The primary outcome was the proportion of opioids prescribed and oral morphine equivalents (OMEs) consumed during the hospitalization. The secondary outcome was pain control. We found that the post-MMA group consumed fewer opioids in the postoperative period compared to the pre-MMA group. Prior to post-operative day (POD) 6, pain control was better in the post-MMA group; however, the pain control lines intersect on POD 6 and the pre-MMA group appeared to have better pain control from PODs 7-10. In conclusion, our data suggest MMA is an effective method of pain control and opioid reduction in patients undergoing surgery for head and neck cancer with free flap reconstruction. MMA use was associated with a significant decrease in the quantity of opioids consumed postoperatively. The MMA protocol was associated with improved pain management early in the postoperative course. Finally, the MMA protocol is a feasible method of pain control and may reduce the adverse side effects associated with opioid use.

From Pathways to Practice: Impact of Implementing Mobilization Recommendations in Head and Neck Cancer Surgery with Free Flap Reconstruction.

One of the foundational elements of enhanced recovery after surgery (ERAS) guidelines is early postoperative mobilization. For patients undergoing head and neck cancer (HNC) surgery with free flap reconstruction, the ERAS guideline recommends patients be mobilized within 24 h postoperatively. The objective of this study was to evaluate compliance with the ERAS recommendation for early postoperative mobilization in 445 consecutive patients who underwent HNC surgery in the Calgary Head and Neck Enhanced Recovery Program. This retrospective analysis found that recommendation compliance increased by 10% despite a more aggressive target for mobilization (from 48 to 24 h). This resulted in a decrease in postoperative mobilization time and a stark increase in the proportion of patients mobilized within 24 h (from 10% to 64%). There was a significant relationship between compliance with recommended care and time to postoperative mobilization (Spearman's rho = -0.80; p < 0.001). Hospital length of stay was reduced by a median of 2 days, from 12 (1QR = 9-16) to 10 (1QR = 8-14) days (z = 3.82; p < 0.001) in patients who received guideline-concordant care. Engaging the clinical team and changing the order set to support clinical decision-making resulted in increased adherence to guideline-recommended care for patients undergoing major HNC surgery with free flap reconstruction.