A Protocol for a Pan-Canadian Prospective Observational Study on Active Surveillance or Surgery for Very Low Risk Papillary Thyroid Cancer

BackgroundThe traditional management of papillary thyroid cancer (PTC) is thyroidectomy (total or partial removal of the thyroid). Active surveillance (AS) may be considered as an alternative option for small, low risk PTC. AS involves close follow-up (including regularly scheduled clinical and radiological assessments), with the intention of intervening with surgery for disease progression or patient preference.MethodsThis is a protocol for a prospective, observational, long-term follow-up multi-centre Canadian cohort study. Consenting eligible adults with small, low risk PTC (< 2cm in maximal diameter, confined to the thyroid, and not immediately adjacent to critical structures in the neck) are offered the choice of AS or surgery for management of PTC. Patient participants are free to choose either option (AS or surgery) and the disease management course is thus not assigned by the investigators. Surgery is provided as usual care by a surgeon in an institution of the patient’s choice. Our primary objective is to determine the rate of ‘failure’ of disease management in respective AS and surgical arms as defined by: i) AS arm – surgery for progression of PTC, and ii) surgical arm - surgery or other treatment for disease persistence or progression after completing initial treatment. Secondary outcomes include long-term thyroid oncologic and treatment outcomes, as well as patient-reported outcomes.DiscussionThe results from this study will provide long-term clinical and patient reported outcome evidence regarding active surveillance or immediate surgery for management of small, low risk PTC. This will inform future clinical trials in disease management of small, low risk papillary thyroid cancer.Registration detailsThis prospective observational cohort study is registered on clinicaltrials.gov (NCT04624477), but it should not be considered a clinical trial as there is no assigned intervention and patients are free to choose either AS or surgery

Reconstruction of medium-size defects of the oral cavity: radial forearm free flap vs facial artery musculo-mucosal flap

Abstract Background The radial forearm free flap (RFFF) is the most commonly used flap for defects of the oral cavity. The facial artery musculomucosal (FAMM) is a safe and effective method to reconstruct medium sized defects of the oral cavity. No comparison exists between the FAMM flap and RFFF. Methods 1) Retrospective chart review from 2007 to 2016. 2) Cost difference analysis. Results Thirteen FAMM flap cases and 18 RFFF met inclusion criteria. The FAMM flap showed a tendency to lower rates of return to the operating room (p = 0.065) as well as lower rates of complications not requiring return to the OR with 1 complication in 1 patient as opposed to 10 patients with 15 complications (p = 0.008). Also, FAMM flap had shorter operative times compared to the RFFF group (7.2HR and 8.9 HR respectively, p = 0.002). The average operative room related costs for a FAMM flap were 6510 CAD vs 10,703 CAD for RFFF (p  0.05). Conclusion The FAMM flap can be used for reconstruction of medium-size defects of the oral cavity with functional outcomes similar to the RFFF while decreasing the associated costs and morbidity. Graphical Abstrac

Free versus pedicled flaps for reconstruction of head and neck cancer defects: a systematic review

Abstract Objective The present review focuses on comparative studies of reconstruction with free flaps (FF) versus pedicled flaps (PF) after oncologic resection. Method A systematic review was developed in compliance with PRISMA guidelines and performed using the Pubmed, Medline, EMBASE, Amed and Biosis databases. Results A total of 30 articles were included. FF are associated with a longer operative time, a higher cost and a higher incidence of postoperative revisions compared to PF. FF are associated with a longer stay at the intensive care unit than the supraclavicular artery island flap (SCAIF) and with a more extended hospital stay compared to the submental island flap (SMIF). FF are associated with fewer infections and necrosis compared to the pectoralis major myocutaneous flap (PMMF). Conclusion The comparison of both type of flaps is limited by the inherent design of the studies included. In sum, FF seem superior to the PMMF for several outcomes. SMIF and SCAIF compare favorably to FF for some specific indications achieving similar outcomes at a lower cost

Single Nucleotide Polymorphism rs6942067 Is a Risk Factor in Young and in Non-Smoking Patients with HPV Negative Head and Neck Squamous Cell Carcinoma

Genetic factors behind the increasing incidence of human papillomavirus (HPV) negative head and neck squamous cell carcinoma (HNSCC) in young non-smokers are suspected, but have not been identified. Recently, rs6942067, a single nucleotide polymorphism (SNP) located upstream of the DCBLD1 gene, was found associated with non-smoking lung adenocarcinoma. To validate if this SNP is also implicated in HNSCC, participants of The Cancer Genome Atlas HNSCC cohort were investigated for rs6942067 status, associated DCBLD1 expression, and clinical characteristics. Occurrence of the rs6942067 GG genotype is significantly higher in young and in HPV negative non-smoking HNSCC than in other HNSCC. Additionally, rs6942067 GG is associated with higher DCBLD1 expression in HNSCC and patients with high DCBLD1 expression have a worse overall survival at three years, both in univariate and multivariate analysis. Furthermore, high DCBLD1 expression is associated with activation of the integrin signaling pathway and its phosphorylation with EGFR and MET. Collectively, these findings suggest that DCBLD1 plays a critical role in HNSCC and demonstrate an association between rs6942067 and clinical characteristics of young age and HPV negative non-smoking status in HNSCC patients

Prevalence of K-RAS Codons 12 and 13 Mutations in Locally Advanced Head and Neck Squamous Cell Carcinoma and Impact on Clinical Outcomes

Background. RAS gene mutations have an impact on treatment response and overall prognosis for certain types of cancer. Objectives. To determine the prevalence and impact of K-RAS codons 12 and 13 mutations in patients with locally advanced HNSCC treated with primary or adjuvant chemo-radiation. Methods. 428 consecutive patients were treated with chemo-radiation therapy and followed for a median of 37 months. From these, 199 paraffin embedded biopsy or surgical specimens were retrieved. DNA was isolated and analyzed for K-RAS mutational status. Results. DNA extraction was successful in 197 samples. Of the 197 specimens, 3.5% presented K-RAS codon 12 mutations. For mutated cases and non-mutated cases, complete initial response to chemoradiation therapy was 71 and 73% (P=0.32). LRC was respectively 32 and 83% (P=0.03), DFS was 27 and 68% (P=0.12), distant metastasis-free survival was 100 and 81% (P=0.30) and OS was 57 and 65% (P=0.14) at three years. K-Ras codon 13 analysis revealed no mutation. Conclusion. K-RAS codon 12 mutational status, although not associated with a difference in response rate, may influence the failure pattern and the type of therapy offered to patients with HNSCC. Our study did not reveal any mutation of K-RAS codon 13

Medial Mandibulotomies: Is there sufficient space in the midline to allow a mandibulotomy without compromising the dentition?

Abstract Objectives The objective of this study was to determine the frequency of complications in median and paramedian mandibulotomies. In addition, the interdental space in the median and paramedian region was calculated. Study design Retrospective study. Setting Tertiary care center. Methods A retrospective chart review was performed for all cases where a mandibulotomy was performed from 2002 to 2010. 117 charts (61 paramedian and 56 median) were identified. We included data on complications, which fell in the following 2 categories: plate and dental complications. For our second objective, we evaluated 40 different patients with base of tongue or tonsillar cancer treated with intensity modulated radiation therapy (IMRT). The interdental space between the lateral incisors and the canines was electronically calculated on the digital Panorex images. Main outcome measures Dental and plate complications were evaluated. We also assessed interdental space. Results Patient characteristics were not significantly different. The median group had significantly more dental complications (p=0.0375, RD=0.19 and 95% CI (0.0139-0.3661)). The paramedian group had significantly more plate complications (p=0.0375, RD=0.082 and 95% CI (0.0131-0.1508). The distance between the central incisors was significantly less than the distance between the lateral incisors and canines both at the crestal and apical levels (p=0.0086 and p<0.001). Conclusions There are significantly more dental complications in the median approach. There were significantly more plate complications in the paramedian group. In addition, there is significantly less space in the between the median region as compared to the paramedian region. This is the first study that documents the advantage of the paramedian approach for dental complications

Phase I/II trial of Durvalumab plus Tremelimumab and stereotactic body radiotherapy for metastatic head and neck carcinoma

Abstract Background The efficacy of immunotherapy targeting the PD-1/PD-L1 pathway has previously been demonstrated in metastatic head and neck squamous cell carcinoma (HNSCC). Stereotactic Body Radiotherapy (SBRT) aims at ablating metastatic lesions and may play a synergistic role with immunotherapy. The purpose of this study is to assess the safety and efficacy of triple treatment combination (TTC) consisting of the administration of durvalumab and tremelimumab in combination with SBRT in metastatic HNSCC. Method This is a phase I/II single arm study that will include 35 patients with 2–10 extracranial metastatic lesions. Patients will receive durvalumab (1500 mg IV every 4 weeks (Q4W)) and tremelimumab (75 mg IV Q4W for a total of 4 doses) until progression, unacceptable toxicity or patient withdrawal. SBRT to 2–5 metastases will be administered between cycles 2 and 3 of immunotherapy. The safety of the treatment combination will be evaluated through assessment of TTC-related toxicities, defined as grade 3–5 toxicities based on Common Terminology Criteria for Adverse Events (v 4.03), occurring within 6 weeks from SBRT start, and that are definitely, probably or possibly related to the combination of all treatments. We hypothesize that dual targeting of PD-L1 and CTLA-4 pathways combined with SBRT will lead to < 35% grade 3–5 acute toxicities related to TTC. Progression free survival (PFS) will be the primary endpoint of the phase II portion of this study and will be assessed with radiological exams every 8 weeks using the RECIST version 1.1 criteria. Discussion The combination of synergistic dual checkpoints inhibition along with ablative radiation may significantly potentiate the local and systemic disease control. This study constitutes the first clinical trial combining effects of SBRT with dual checkpoint blockade with durvalumab and tremelimumab in the treatment of metastatic HNSCC. If positive, this study would lead to a phase III trial testing this treatment combination against standard of care in metastatic HNSCC. Trial registration NCT03283605. Registration date: September 14, 2017; version 1