Swallowing Outcomes Following Primary Surgical Resection And

Swallowing Outcomes Following Primary Surgical Resection and Primary Free Flap Reconstruction for Oral and Oropharyngeal Squamous Cell Carcinomas: A Systematic Review of Quantitative Evidence

Stephen Shih-Teng Kao Master of Clinical Science Joanna Briggs Institute Faculty of Health Sciences The University of Adelaide Australia

October 2015

Abstract

Background Dysphagia is still a treatment related morbidity as organ preservation does not always translate into function preservation despite advances in treatment modalities. The purpose of this systematic review is to review the swallowing outcomes of patients with oral or oropharyngeal squamous cell carcinoma following primary surgery with primary free flap reconstruction with or without adjuvant therapy.

Objectives The objective of this systematic review is to investigate swallowing outcomes following primary surgical resection and free flap reconstruction for the treatment of patients with oral and oropharyngeal squamous cell carcinoma. Dysphagia was evaluated with the use of objective investigations (Videofluoroscopic swallowing studies, Fibreoptic endoscopic evaluations of swallowing, Manometry, Gastrostomy dependency, Tracheostomy dependency) and subjective questionnaires (MD Anderson Dysphagia Inventory, University of Washington Quality of Life Questionnaire, Functional Oral Intake Score).

Inclusion criteria This review considered studies which included patients with oral or oropharyngeal squamous cell carcinoma treated with primary surgical resection and primary surgical reconstruction with or without adjuvant therapy. Swallowing evaluation was conducted at six months or greater after curative therapy. Objective outcome measures included gastrostomy dependency, tracheostomy dependency, penetration-aspiration rates, oral and pharyngeal transit times or pharyngeal pressure readings measured with either videofluoroscopic swallowing studies or fibreoptic endoscopic evaluations of swallowing or manometry. Subjective outcomes were measured with the MD Anderson Dysphagia inventory, University Washington Quality of Life Questionnaire or Functional Oral Intake Scale.

Methods A comprehensive search strategy was undertaken across MEDLINE, CINAHL, Embase, and Scopus. Papers retrieved were assessed by two independent reviewers regarding study design, study population, interventions, outcome measures, results and conclusions for each article. Data extracted and analyzed for descriptive studies and findings presented in narrative form.

Results 15 studies were included in the systematic review, which consisted of eight cohort studies and seven cases series. Postoperative radiotherapy was associated with worse swallowing outcomes. Swallowing outcomes following the use of radial forearm free flap and anterolateral thigh flap were inconclusive. Resections of the oropharynx demonstrated poorer swallowing outcomes compared with oral cavity resections.

Conclusion Radiotherapy has been demonstrated to be detrimental to swallowing function following surgical resection and primary free flap reconstruction. Furthermore, swallowing function was shown to improve with the use of free flap reconstruction compared with primary closure for large tumor resections. From these results, a protocol for the identification of patients at low or high risk of developing dysphagia has been proposed. There is, however, a lack of high quality primary research regarding swallowing outcomes following primary surgery with primary free flap reconstruction for oral and oropharyngeal squamous cell carcinoma.

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Acknowledgements

I would like to thank my supervisors, Dr Micah Peters and Dr Eng Ooi for their guidance, feedback and support in completing the Thesis.

I would also like to acknowledge Maureen Bell, research librarian, for helping me develop a comprehensive search strategy and Dr Sabapathy Krishnan my secondary reviewer.

I would like to thank Doris, Huei-Jong and Wen-I for their unconditional love and support. Furthermore, I would like to thank my four sisters (Jennifer, Alice, Rebecca and Vanessa) for their ongoing support.

Table of Contents

CHAPTER 1: INTRODUCTION ...... 1

1.1. CONTEXT OF THE REVIEW ...... 1

1.2. EPIDEMIOLOGY OF THE ORAL AND OROPHARYNGEAL SQUAMOUS CELL CARCINOMA... 1

1.3. ANATOMY OF THE ORAL CAVITY AND OROPHARYNX...... 1

1.4. PHYSIOLOGY OF SWALLOWING ...... 2

1.5. PATHOLOGY OF DYSPHAGIA ...... 3

1.6. TNM CLASSIFICATION ...... 4

1.7. TREATMENT MODALITIES ...... 5

1.8. SWALLOWING EVALUATIONS ...... 7

1.9. OVERVIEW OF THE SCIENCE OF EVIDENCE SYNTHESIS ...... 11

1.11 REVIEW OBJECTIVE ...... 17

1.12. REVIEW QUESTION ...... 17

1.13. INCLUSION CRITERIA ...... 17

1.13.1. TYPES OF PARTICIPANTS ...... 17

1.13.2. TYPES OF INTERVENTIONS ...... 18

1.13.3. OUTCOMES ...... 18

1.13.4. TYPES OF STUDIES ...... 18

CHAPTER 2: METHODS...... 19

2.1. SEARCH STRATEGY ...... 19

2.2. STUDY SELECTION ...... 19

2.3. CRITICAL APPRAISAL ...... 20

2.4. DATA EXTRACTION ...... 20

2.5. DATA SYNTHESIS ...... 21

CHAPTER 3: RESULTS ...... 22

3.1. SEARCH RESULTS ...... 22

3.2. ASSESSMENT OF METHODOLOGICAL QUALITY ...... 24

3.3. DESCRIPTION OF INCLUDED STUDIES ...... 26

CHAPTER 4: DISCUSSION ...... 35

4.1. OVERVIEW OF FINDINGS ...... 35

4.2. LIMITATIONS TO THE STUDY ...... 40

4.3. IMPLICATIONS FOR PRACTICE ...... 40

4.4. IMPLICATIONS FOR RESEARCH...... 41

4.5. CONCLUSION ...... 42

REFERENCES ...... 43

APPENDIX I: SEARCH STRATEGY ...... 50

APPENDIX II: CRITICAL APPRAISAL INSTRUMENTS ...... 54

APPENDIX III: DATA EXTRACTION INSTRUMENTS ...... 57

APPENDIX IV: AUTHORS CONTACTED ...... 58

APPENDIX V: INCLUDED STUDIES ...... 59

APPENDIX VI: EXCLUDED STUDIES ON FULL TEXT REVIEW ...... 62

APPENDIX VII: DYSPHAGIA RISK STRATIFICATION TOOL ...... 70

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Chapter 1: Introduction

1.1. Context of the review Treatment modalities for oral and oropharyngeal squamous cell carcinoma (SCC) have significantly progressed over recent years, with treatments now aimed at organ preservation and quality of life as well as survival. Dysphagia is still a treatment related morbidity as organ preservation does not always translate into function preservation despite advances in treatment modalities. As swallowing function is an integral part of a patient's quality of life following cancer treatment, it is of great importance that this issue is thoroughly reviewed. The purpose of this systematic review is to review the swallowing outcomes of patients with oral or oropharyngeal squamous cell carcinoma following primary surgery with primary free flap reconstruction with or without adjuvant therapy. This systematic review strives to identify and synthesize high quality evidence, with the goal of proposing recommendations for clinical practice and directing future research.

1.2. Epidemiology of the oral and oropharyngeal squamous cell carcinoma There are approximately 264,000 cases of oral-cavity malignancies and 136,000 cases of pharyngeal malignancies diagnosed annually worldwide.2-9 The etiology of oral and oropharyngeal SCC has been strongly linked to smoking and alcohol use.10, 11 Recently, the human papilloma virus (HPV) has been linked to the development and rise in incidence of oropharyngeal SCC. Patients with HPV-positive disease are typically younger, non-smokers and have a favorable prognosis for long-term survival, compared with their HPV-negative counter parts.12 Therefore treatment regimes have shifted toward organ preservation techniques with the goal of improving functional outcomes such as swallowing.

1.3. Anatomy of the oral cavity and oropharynx The oral cavity extends from the vermillion border of the lips and extends to the palatoglossal arches. It is enclosed superiorly by the hard palate and inferiorly by the muscles of the floor of mouth. The palatoglossal arches serve as the boundary between the oral cavity and oropharynx (Figure 1). The oropharynx extends from the lower border of the soft palate to the upper border of the epiglottis, including the base of tongue. The posterior and lateral walls of the oropharynx are formed by the pharyngeal constrictors. Anatomically, malignancies in the oral cavity can extend into the oropharynx, or vice versa, thus it is important to investigate malignancies of both regions as treatment of both sites adversely effect swallowing.

The oral cavity and oropharynx are lined by mucous membranes moistened by saliva secreted by the major and minor salivary glands.13 Three paired major salivary glands include the parotid, submandibular and sublingual glands. The parotid gland is located between the posterior mandibular ramus and mastoid process of temporal bone. Serous secretions enter the oral cavity via the Stensen duct. The submandibular glands lie superior to the digastric muscles and drain a mixture of serous fluid and mucus into the oral cavity via the Wharton duct. Lastly, the sublingual gland is located anterior to the submandibular gland, inferior to the oral tongue. It drains mainly mucus via the Wharton duct into the floor of mouth. Minor salivary glands are located within the submucosa throughout the oral cavity and oropharynx. Saliva produced from these glands play a large role in the lubrication of the oral cavity and oropharynx to assist in swallowing.14

Figure 1. Anatomy of the oral cavity and oropharynx15

(Used with the permission from Elsevier Limited, Oxford, UK)

1.4. Physiology of swallowing Swallowing is a complex process where food is transported from the oral cavity to the stomach. The process of swallowing is commonly divided into oral, pharyngeal and esophageal stages according to the location of the bolus.16 During the oral phase, the tongue contracts against

2 the hard palate, acting as a propulsion mechanism transporting the bolus toward the oropharynx. Sufficient force must be generated by the tongue to drive the food bolus posteriorly. Resections of the oral tongue causing loss of tongue length and projection, impairs bolus formation.17 Furthermore, fixation of the oral tongue to the floor of mouth decreases tongue elevation, thus impairing the bolus being pushed against the roof of the mouth.18, 19 The pharyngeal phase consists of soft palate elevation, which prevents nasal regurgitation, pharyngeal wall contraction and sequential contractions of the pharyngeal constrictors. The oropharynx sphincteric closure maintains the posterior oral and oropharyngeal pressure wave to propulse the bolus forwards in the upper aerodigestive tract. Sufficient sensation and flexibility of the pharynx in conjunction with adequate lubrication with saliva aids the process of swallowing. During this phase the vocal cords seal the glottis, the larynx is displaced anterior-superiorly and the epiglottis seals the laryngeal vestibule. This process prevents aspiration and directs the food into the esophagus through the upper esophageal sphincter. Finally, the bolus is transported to the stomach via peristalsis of the esophagus.

1.5. Pathology of dysphagia Dysphagia, or difficulty swallowing, is a devastating consequence of treatment that effects up to 50% of head and neck cancer survivors.20 Swallowing impairment following treatment of head and neck malignancy occurs depending on the treatment modality and structures involved.

Surgical resections involving the oral cavity or oropharynx can significantly affect swallowing function, due to removal of fundamental structures involved in swallowing. Studies have shown resections involving the oral tongue, floor of mouth or hypoglossal nerve result in difficulty chewing and initiating swallowing.21 As previously stated, resections involving the oral tongue results in difficulty of bolus formation and propulsion through the oral cavity. The base of tongue plays a vital role in initiating swallowing and propelling the bolus through the pharynx, thus any resection involving the tongue base will result in reduced pressure generation causing delayed initiation of swallow and pharyngeal stasis resulting in aspiration.22 Studies have demonstrated increased tongue base resection to be associated with poorer swallowing outcomes.7, 19

Radiotherapy is associated with a range of short and long term side effects. Mucositis is seen in 30 to 60% of patients receiving radiation therapy to the head and neck region.23 Stomatitis (superficial ulcers) and mucositis are associated with odynophagia and decreased oral intake.24 Xerostomia, or dry mouth, secondary to salivary gland hypofunction is a common

3 sequela following radiotherapy.25 Saliva has antimicrobial properties and plays an integral role in formation of food bolus and lubrication of the oral cavity, orophayngeal and upper esophageal mucosa.26 Thus, xerostomia is associated with increased rates of oral infection, dental caries, difficulty speaking and swallowing.27 Intensity modulated radiotherapy has shown to be effective in delivering the full dose of radiation to the tumor site with decreased exposure to surrounding healthy tissues, such as salivary glands.28 Muscular fibrosis, is a feared late effect of radiation therapy, causing decreased range of motion of pharyngeal structures resulting in increased risk of aspiration. Decreased laryngeal elevation, tongue base to pharyngeal wall contraction and cricopharyngeal sphincter opening have been observed following radiotherapy.29 Trismus, or limited mouth opening, occurs following radiotherapy due to loss of function and range of motion secondary to damage and fibrosis to the muscles of mastication.30 Reduced mastication leads to poor bolus organization with increased residue, resulting in increased risk of aspiration and increased bolus transit times.

Chemotherapeutic agents are typically used in conjunction with radiotherapy, and are associated with a range of adverse side effects. Nausea and vomiting is commonly observed with chemotherapy with associated anorexia and weight loss. The incidence of mucositis increases to greater than 90% when chemotherapy is utilized in conjunction with radiotherapy.23 Radiotherapy-induced mucositis is due to a reactive inflammatory process of the mucous membranes and chemotherapeutic agents cause direct toxicity to the epithelium.31 Thus, the addition of chemotherapy introduces systemic toxicity and thus exacerbates local tissue reactions, such as mucositis. Combinations of these symptoms have a cumulative effect on dysphagia, leading to insufficient nutritional intake, increased rates of aspiration and adversely affecting quality of life.

1.6. TNM classification Head and neck cancers are staged according to the International Union Against Cancer (UICC) TNM Classification of Malignant Tumors Edition 7 or American Joint Committee on Cancer (AJCC) Staging System Edition 7 (Table 1).32, 33 Components of both these systems include: tumor size (T), regional lymph node spread (N) and distant metastasis (M). The goal of the TNM staging system is to assist in planning treatment and aid in prognosis.34 Important factors not taken into account by the TNM classification system that have a significant impact on prognosis include biological factors (i.e. p16 status) and smoking history.35 Thus patient factors along with TNM classification must be utilized together to formulate a treatment plan. Early stage (I/II) and advanced stage (III/IV) malignancies will have immensely different treatment regimes ranging from single modality treatment, multiple modality treatment to

4 palliation. Depending on the treatment modality utilized, functional outcomes will vary greatly.36 Patients undergoing treatment aimed at palliation are more likely to have worsening dysphagia as treatment would be focused on comfort. Therefore, it is paramount to compare the swallowing outcomes of varying treatment regimes with malignancies of similar stage.

Table 1. Stage Grouping for all Head and Neck Sites Except the Nasopharynx and Thyroid Stage Group T Stage N Stage M Stage 0 Tis N0 M0 I T1 N0 M0 II T2 N0 M0 III T3 N0 M0 T1 N1 M0 T2 N1 M0 T3 N1 M0 IVa T4a N0 M0 T4a N1 M0 T1 N2 M0 T2 N2 M0 T3 N2 M0 T4a N2 M0 IVb T4b Any N M0 Any T N3 M0 IVc Any T Any N M1 Tis: Tumor in situ; T: Tumor; N: Node; M: Metastases (Adapted from AJCC Cancer Staging Manual, Seventh Edition (2010) published by Springer- Verlag New York, www.springeronline.com)37

1.7. Treatment modalities The prognosis from head and neck cancer is improving with treatment protocols utilizing surgery, radiotherapy, and chemotherapy. Early cancers (Stage I and II) may be treated with single modality treatment and advanced cancers (Stage III and IV) are treated with sequential combinations of therapy to enhance survival outcomes.38 The combination of chemoradiotherapy has been shown to improve survival outcomes; however, it is associated with increased long-term toxicity.39 The utilization of surgery in advanced stage malignancy to remove the primary cancer whilst preserving function is a difficult task, as it traditionally involves mandibulotomies and defects within the head and neck.7, 40 Surgery is typically the primary treatment for oral cancers, however, there remains controversy regarding the place of surgery for oropharyngeal malignancies.41 Step-wise increases in access requirements ranging from pharyngotomies to extensive mandibular and maxillary resections as a result of increasing size of the primary lesion, thus greatly affecting swallowing outcomes.42, 43 These

5 extensive procedures are required when primary radiotherapy with or without chemotherapy are unlikely to cure the patient. In these cases, the best option is surgical resection in conjunction with adjuvant therapy.44

De-escalation of therapy is a concept currently being investigated to assess whether it is able to reduce toxicity in the short- and long-term without compromising oncological cure.41 In patients treated with primary chemoradiotherapy, there should be a reduction in total dose to areas unaffected by cancer as well as adjacent salivary tissue and pharyngeal muscles.45 For patients treated with primary surgery, the aim is to avoid adjuvant therapy where possible, with reduction of dosimetry of radiation to avoid chemotherapy.38

Recent advances in treatment modalities, such as transoral robotic surgery (TORS) and intensity modulated radiotherapy (IMRT) have been developed to improve functional outcomes post-treatment without compromising oncological benefit.46 Transoral robotic surgery allows for more accurate dissection, improved visualization with the ability to navigate around corners with decreased postoperative complications.47 Intensity modulated radiotherapy was developed to minimize radiation dosage to normal tissue, without compromising clinical outcomes. Studies have found decreased rates of trismus compared to conventional radiotherapy.39 Hutcheson et al published a systematic review demonstrating lower rates of gastrostomy utilization in patients with oropharyngeal SCC treated with primary TORS compared with definitive IMRT.48 Conversely, de Almeida and colleagues found similar oncological and functional outcomes following treatment of early oropharyngeal cancer with TORS or IMRT.46 Despite these advances, swallowing dysfunction is still a regular occurrence post-treatment.

Surgical reconstruction techniques with the use of free vascularized flaps allows for improvement in functional and cosmetic outcomes.49 There has been a paradigm shift toward reestablishing normal function and appearance, in addition to reliable wound closure.50 This is evidenced by studies transferring free flaps with their associated nerves, allowing for additional sensory and motor function.51 Free flaps are typically harvested with their associated blood vessels from a range of various sites, the most commonly utilized soft tissue donor sites include the radial forearm and anterolateral thigh. The harvested flaps are employed to fill in surgical defects to improve tongue bulk and contraction power following glossectomy and restore continuity between the oral cavity and esophagus for pharyngeal defects. Primary reconstructions performed at the time of resection allows for rapid restoration of anatomy and function, with decreased potential for muscular atrophy and fibrosis associated

6 with delayed reconstruction, whereas secondary reconstructions are performed as a separate procedure following resection. 52

1.8. Swallowing evaluations Gastrostomy tubes are typically inserted in head and neck cancer patients to assist in maintaining nutritional status during treatment. Due to the devastating effects of dysphagia, it is common practice in many institutions to insert gastrostomy tubes prior to treatment to prevent malnutrition secondary to dysphagia. Studies have shown patients with no oral intake after two weeks are associated with worse swallowing outcomes, potentially due to deconditioning and disuse atrophy of pharyngeal muscles.43 Dependence on gastrostomy feeds to maintain adequate nutrition affects 10-25% of these patients with dysphagia.53 There is currently no consensus on the definition of long-term gastrostomy dependence, however, articles have correlated swallowing dysfunction present six months after curative therapy to be highly predictive of life-long dysphagia with up to 38% of patients requiring permanent gastrostomy tubes.54-58

Tracheostomies are typically required for airway management and protection following open resections of oral and oropharyngeal cancers, particularly with free flap reconstructions. Potential life threatening complications following surgery include airway occlusion and aspiration, of which tracheostomies are a life-saving adjunct.4 The utilization of tracheostomy tubes has been associated with dysphagia and aspiration, likely due to alteration of oropharyngeal anatomical structures and preventing laryngeal elevation with swallowing.59 Due to the minimally invasive approach of TORS for oropharyngeal SCC, tracheostomy insertion can be avoided in greater than 70% of TORS cases, regardless of adjuvant therapy.60, 61 Tracheostomy dependence therefore is an important aspect to consider when investigating swallowing outcomes following treatment of oral and oropharyngeal SCC. Apart from malnutrition and poor general health, secondary to dysphagia, survivors also report a decreased quality of life.62 Therefore, it is vital to assess the impact of swallowing function, objectively and subjectively in this population of individuals.

There are objective and subjective assessments used in assessing dysphagia (Table 2). However, due to the complexity and multi-factorial processes involved in dysphagia, there is currently no gold standard approach to the assessment of dysphagia. The governance of limited clinical resources also plays a role in the selection of swallowing investigations required for each patient. Depending on the progress of their swallowing proficiency following treatment, investigations are tailored to their needs. Objective assessments currently utilized

7 include videofluoroscopic swallowing studies (VFSS), fibreoptic endoscopic evaluation of swallowing (FEES) and manometry. VFSS allows for a functional evaluation of swallowing by visualization and analysis of events that occur during a swallow. It involves swallowing a barium paste and radiologically tracking its movements through the alimentary tract. Through this process, investigators are able to measure and review the movements of various anatomical structures and track bolus transit times during the phases of swallowing. Additionally, post-radiation stricture formation can be identified and subsequently managed with dilatation therapy. FEES involves using a flexible nasoendoscope transnasally for real- time visualization of laryngeal and pharyngeal structures. Food or liquid boluses can be given to assist in visualization of bolus residue after the pharyngeal phase of swallowing. This procedure can be completed by the patient's bedside with nil exposure to radiation. The combination of a bedside assessment with direct observation, allows for prediction of optimum food consistency to avoid aspiration. The penetration-aspiration-scale (PAS) is an 8-point scale commonly used in conjunction with VFSS and FEES to assist in quantifying severity of aspiration. Kelly et al63 published results showing PAS to be perceived more severely in FEES than from VFSS, however, the likelihood of aspiration pneumonia requires further investigation. Manometry allows for quantitative evaluation of impedance and pressures secondary to pharyngeal contraction and upper esophageal sphincter relaxation. It allows of identification of abnormal pressure peaks or troughs and failure of peristaltic function. Pressure flow analysis using manometry and impedance measures are an emerging research tool to investigate swallowing disorders.64, 65

Table 2. Summary of Objective Swallowing Assessments Evaluation Method Items Assessed Advantages Disadvantages Videofluoroscopic  Visualization of  Non-invasive  Radiation exposure Swallowing Study bolus flow procedure  Requires (VFSS)66  Bolus transit time  Reproducible fluoroscopy suite  Structural movement  Can assess the of related anatomical pharyngeal and structures esophageal phase  Presence and timing of aspiration Functional Endoscopic  Testing laryngeal  Bedside examination  Discomfort, gagging Evaluation of Swallowing sensitivity  Easy to perform  Adverse reactions to (FEES)67  Static and dynamic  Well tolerated topical anesthetics evaluation of  Economical  Operator dependent structures in the  Can only assess upper airways post pharyngeal  Presence of swallowing aspiration Manometry68  Upper esophageal  No radiation  Specialized and sphincter relaxation exposure experienced staff  Pharyngeal  Adverse reactions to peristalsis topical anesthetics  Intrabolus pressure

Subjective assessments include quality of life and functionality questionnaires. Quality of life questionnaires consist of emotional and physical functioning in conjunction with the patient’s perception of their own functional state (Table 3). The MD Anderson Dysphagia inventory (MDADI) was the first validated and reliable self-administered quality of life questionnaire designed specifically for evaluating dysphagia in patients with head and neck cancer.69 MDADI consists of four subscales: global, emotional, functional and physical with a total score ranging from 0-100, higher scores indicating higher quality of life. The University of Washington Quality of Life Questionnaire (UW-QoL) is another validated self-administered quality of life and function questionnaire designed specifically for head and neck cancer patients.70-72 Items assessed in this questionnaire include: pain, appearance, activity, recreation, swallowing, chewing, speech, shoulder, taste, saliva, mood and anxiety with each domain scored between 0-100. The questionnaire focuses on the patients’ current health and quality of life within the past seven days. Both these questionnaires are quick and simple for patients to use and have been widely utilized by clinicians worldwide. The Functional Oral Intake Scale (FOIS) is an objective and validated 7-point functionality questionnaire used to assess a patient's oral intake ability.73 Score of one implies the patient is nil by mouth, and seven represents total

9 oral diet with nil restriction. Due to differing measures utilized between these subjective assessments, they are not directly comparable with each other.

Table 3. Subjective Questionnaires Questionnaire Domains Assessed MD Anderson Dysphagia Inventory Global (MDADI) Emotional Functional Physical University of Washington Quality of Life Pain Questionnaire (UW-QoL) Appearance Activity Recreation Swallowing Chewing Speech Shoulder Taste Saliva Mood Anxiety Functional Oral Intake Scale (FOIS)73 1 - Nothing by mouth 2 - Tube dependent with minimal attempts of food or liquid 3 - Tube dependent with consistent oral intake or food or liquid 4 - Total oral diet of a single consistency 5 - Total oral diet with multiple consistencies, but requiring special preparation or compensations 6 - Total oral diet with multiple consistencies without special preparation, but with specific food limitations 7 - Total oral diet with no restrictions

The treatment modalities for oral and oropharyngeal SCC has dramatically progressed over recent years, with treatments now aimed at organ preservation. Despite these new advances, dysphagia is still a common and devastating side effect as organ preservation does not always translate into function preservation. There is currently no standardized approach to the assessment of swallowing dysfunction, which causes difficulty in drawing conclusions from the current available literature. The purpose of this systematic review is to review the subjective and objective swallowing outcomes of patients with oral or oropharyngeal SCC following primary surgery with primary free flap reconstruction with or without adjuvant therapy.

Lam and colleagues published a systematic review focusing on speech and swallowing outcomes following tongue cancer surgery and free flap reconstruction.74 They included patients with intraoral tongue and base of tongue SCC. They demonstrated preoperative dysphagia was related to tumor volume, and resection of such tumors were less likely to recover from normal swallowing. Furthermore, partial glossectomy without tip resection, floor of mouth or base of tongue resection may not have better swallowing outcomes with free flap reconstruction compared with primary closure. It was shown that immediate reconstruction of the tongue was associated with poor swallowing and speech outcomes in the early postoperative phase, however, function improved to preoperative level at one-year post- treatment. Dziegielewski published a brief systematic review on gastrostomy dependency rates six to twelve months following total glossectomy with free flap reconstruction.75 They found twelve-month gastrostomy dependency rate was 24%. Due to the brevity of the systematic review, no further information was able to be extracted. This systematic review will focus on swallowing outcomes following treatment of squamous cell carcinomas in all sub- sites of the oral cavity and oropharynx. It is important to consider all sub-sites of the oral cavity and oropharynx as both sites are anatomically related with dysphagia. A preliminary search of the JBI Database of Systematic Reviews & Implementation Reports, Cochrane Database of Systematic Reviews, Medline, Embase and CINAHL on 26/03/2015 found no systematic review protocols or reports that investigate swallowing outcomes following free flap reconstruction in both oral-cavity and oropharynx SCC.76

1.9. Overview of the science of evidence synthesis Improvement in survival outcomes from advancements in treatment modalities has led to a focus on functional outcomes, such as swallowing. Dysphagia is a common occurrence following the treatment of head and neck cancer with great impacts on the quality of life of these patients. Therefore, it is of great importance that swallowing outcomes are reviewed following treatment to assist in monitoring and management of post-treatment dysphagia. Despite, previous systematic reviews focusing on swallowing outcomes following surgical resection and primary free flap reconstruction of tongue malignancies, none have focused on all sub-sites of the oral cavity and oropharynx.74, 75 This systematic review is vital to gain further insight into the effects of post-treatment dysphagia. It addresses this important post-treatment consequence by using a comprehensive search strategy to locate the evidence, assessment of the quality of the primary research, and synthesizing the findings extracted from the best available evidence on this topic. The aim of this systematic review is to provide evidence useful in clinical practice, and allow for better counselling of patients pre- and post-treatment of their oral or oropharyngeal SCC. Ideally, the evidence from this systematic review will inform

11 healthcare policy makers and support the standardization in the evaluation of swallowing outcomes.

Systematic reviews are considered the cornerstone of medical research as they have a reproducible and rigorous approach to identifying relevant studies with the best available evidence.77 There are numerous publications investigating functional outcomes following treatment of oral and oropharyngeal SCC, however, initial searches revealed a lack of placebo controlled randomized controlled trials (RCTs) available in this area due to ethical concerns with randomizing people with cancer to receive placebo treatment. Publications on this topic are typically conducted in single institutions and report on cohort or case-series studies. As with RCTs, these study designs also range in methodological quality. When conducted well, RCTs are generally considered to be of a higher level of evidence than cohort and case series studies. While the strength of evidence available is considered generally less robust and prone to greater bias than the evidence of high-quality RCTs, in the absence of RCTs, the best available evidence is likely to be found in papers reporting the results of cohort and case series studies.78 A systematic review was chosen as the best method of synthesizing the evidence from the published literature for use in evidence-based healthcare. Evidence-based healthcare emphasizes that clinical practice should be directed by the best available evidence.79 Sackett and his colleagues have defined evidence-based healthcare as decisions made regarding the care of individual patients to be based on the current best evidence, with the integration of individual clinical expertise with best available external clinical evidence from systematic research.80 Systematic reviews utilize a predefined methodology stipulated in a peer reviewed and published a-priori protocol to systematically and comprehensively locate, collect and appraise, extract data from, and synthesize the evidence from the most relevant and highest quality studies.77 The strict methodology pre-defined in the protocol aims to limit bias, thus synthesizing valid and reliable results. This is achieved with the development of an a-priori protocol consisting of the review question, inclusion and exclusion criteria with a predefined methodology. The protocol allows for study transparency and reduces author and study selection bias.81 Systematic reviews are becoming increasingly important in clinical practice as they allow clinicians to maintain up to date knowledge on their specialty, assist in production of clinical guidelines, provide evidence for policy makers to review risks, benefits and harms of interventions, and guide direction for new research.82 Systematic reviews, however, are limited by the quality of included studies. Therefore, strict critical appraisal is required to eliminate low quality studies that have the potential to bias the results. The ultimate goals of systematic reviews are to provide evidence to assist in implementing evidence-based- practice by promoting practices that are efficacious and eliminating those that are harmful and ineffective as well as to direct future research.82

Systematic reviews can be classified into qualitative or quantitative reviews depending on the question posed and the type of evidence extracted. Quantitative methodology was developed from the study of natural and social sciences and has formed the basis of traditional scientific methods.83 Quantitative evidence involves the collection of numerical data to establish cause and effect relationships between two or more variables with the use of statistical models.83 The advantage of quantitative evidence is due to its validity and reliability, in other words, studies with the same study population, study design and measurement outcomes should consistently yield the same results.83, 84 It is due to these characteristics of quantitative methodology that favors its application in surgical research.85 This type of methodology allows for hypotheses to be tested while minimizing bias when analyzing a group of studies with similar methodologies in a systematic review.86 In the case of this systematic review, the swallowing effects of patients with oral or oropharyngeal SCC following surgery and adjuvant therapies will be reviewed.

This systematic review utilized the Joanna Briggs Institute (JBI) systematic review method and followed a structured process to achieve synthesized findings from the included studies. The JBI systematic review method corresponds with the PRISMA statement which encourages transparent reporting of systematic reviews.1 Rigorous and reproducible methodologies with clear and transparent reporting are techniques utilized in systematic reviews to assist in synthesis of results with minimal bias and increased validity.1

The development of an a-priori protocol is a fundamental step in conducting a thorough systematic review. The research protocol provides a framework for the proposed study to improve rigor, transparency, and reduce study selection bias.81 It consists of a detailed background with a clear research question, justification of the proposed study, clear inclusion and exclusion criteria and a proposed methodology.83 Due to the retrospective nature of systematic reviews, it is important to establish and document these aspects in advance to reduce potential for author bias and study duplication.87 The Cochrane Collaboration and Joanna Briggs Institute both have a peer-review process for all protocols prior to the initiation of systematic reviews.83 The peer-review process for protocols allows for expert opinion on the proposed study, and gives authors the opportunity to incorporate changes prior to undertaking the systematic review.88 Furthermore, the protocol for this systematic review was developed and presented to a panel of experts in the field in July 2015. The panel meeting provided an opportunity for clarification of various aspects of the protocol and discussion regarding the topic. The publication of the systematic review protocol promotes transparency and allows for peer review of the planned methods.88 Deviations from the protocol should be

13 clearly rationalized with judgement on the effects on bias.87 It is vital to document these changes, as post hoc changes are highly susceptible to bias. There were no post hoc changes to the systematic review protocol.

A clear and well documented list of inclusion and exclusion criteria are key components of a systematic review protocol.83 These criteria should be established during the development of the protocol to reduce the potential of author bias. Explicit inclusion and exclusion criteria with clear rationale are required to capture studies relevant to the review objective.87 This is exceptionally important as precise selection criteria assists in narrowing down pertinent studies, as it reduces the amount of subjective decisions regarding inclusion and exclusion, thus increasing reproducibility of the study.83, 87 Significant aspects of the inclusion criteria include types of participants, types of interventions, outcomes of interest, and types of studies. 83 Population of interest should be clearly defined with patients included having similar stages of malignancy and surgical resection techniques to decrease the potential for known or unknown confounding biases. Furthermore, outcomes of interest should be clearly defined including time of evaluation. As there is no gold standard to the assessment of dysphagia, this systematic review utilized validated objective and subjective assessments which was clearly described in the protocol. 76 Additionally, study selection is an important aspect to consider prior to undertaking the systematic review as not all topics will have high quality evidence available. Randomized control trials are considered the highest level of evidence source of experimental research as the randomization and blinding process aims to reduce selection and confounding biases.89 Despite these advantages of randomized controlled trials they are not appropriate for all study types. Such as in this topic, the highest level of evidence available are cohort studies and case-series. Regardless of study design, all identified studies need to undergo further critical appraisal to review their methodological quality.

A detailed and comprehensive search strategy is required to identify all relevant studies. This aspect of the systematic review decreases the potential for study selection bias when compared with traditional literature reviews. Regardless of outcomes, all published and non- published literature are considered for inclusion, thus decreasing potential for selection and publication bias.83 A preliminary search is utilized to identify important key words and index terms to the research topic. Once identified, the thorough search strategy is applied across all included databases. The reference lists of identified studies are further searched for any missed literature. Upon inception of the systematic review search strategy, the research librarian was consulted for further advice. Research librarians are vital to the process of consolidating a comprehensive search strategy due to their expertise and experience in database searches.90, 91 The goal of a comprehensive search strategy is to identify all relevant

14 articles for review, as missed research leads to biased and incomplete conclusions. 92 Furthermore, search strategies should be included in the systematic review to increase transparency for readers. 1 Firstly, this allows the readers to gauge the quality of the search strategy. Secondly, it allows the search to be reproducible for when the review requires future updating.93

The titles and abstracts from the studies identified from the comprehensive search of all the included databases are individually reviewed against the inclusion and exclusion criteria set in the a-prior protocol.83 Furthermore, the full text screening occurs for studies that meet the inclusion criteria at the title and abstracts stage. Authors should be contacted where details are unclear. This thorough process of study selection is required as it brings together literature that is specific to the review question.83, 87 Thus, conclusions drawn from the systematic review will be focused and specific to the review question.91 Once the studies that meet all inclusion criteria are identified, they undergo the process of critical appraisal of methodological quality.

The quality of the systematic reviews are dependent on the quality of included studies, thus critical appraisal is integral to the process. Critical appraisal of methodology is a practice of systematically examining literature for the presence of bias and thus the validity of its results.83 Studies with poor methodological quality can greatly distort the overall data, and thus should be excluded from the review. Critical appraisal is crucial as it allows the reviewers to distinguish the best available evidence from the vast collection of literature available.93 In the JBI approach, the critical appraisal process involves two independent reviewers, who have undergone the JBI Comprehensive Review training, and the utilization of the JBI Critical Appraisal Instruments (Appendix II).83 The JBI Critical Appraisal Instruments (Appendix II) vary depending on the type of study, as differing types of studies have unique aspects that have the potential to increase or decrease bias.83 Two trained independent reviewers along with the standardized appraisal instruments are required in this process to reduce author bias and increase reproducibility of the critical appraisal process.83, 94, 95 The use the JBI critical appraisal instrument allows for a thorough and standardized approach to critical appraisal, as well as transparency of the procedure.83, 87, 96 The depth of information and minimum requirements in the methodology must be determined and discussed between reviewers prior to conduction of independent critical appraisal, as this further decreases the potential for selection biases.83, 96 Only if the systematic review consists of the best available evidence, will it be able to facilitate evidence-based health care.80

Once the relevant studies that have met all inclusion criteria and passed the critical appraisal process for methodological quality, they are included in the systematic review for data

15 extraction. Data extraction is an important step that involves the collection of data and information relevant to the review objective from the included studies. The results from surgical quantitative studies were typically derived from calculations with the use of statistical models. Depending on the research question, the results were presented within summary tables or Kaplan-Meier curves with associated statistically significant p-values. Ideally, the data presented should not only provide the numerical results, but also statistical and clinical significance to better increase transparency. When all the pertinent data was collected, it was able to be synthesized into meaningful results in the form of a meta-analysis or narrative summary.

When similar studies are collated together in a systematic review, the results can be combined to form a meaningful meta-analysis. The goal for a meta-analysis is to increase the overall sample size, thus improving the statistical power of the analysis and precision of the treatment effects.97 The synthesis of a meta-analysis depends on the quality and heterogeneity of the included studies.83 If there is a large variation in characteristics in the included studies, combining data would yield invalid results. The main outcomes from a meta-analysis are the measure of effect, confidence interval and degree of heterogeneity.83 Included studies were weighted depending on which studies provided the most relevant information, as they were likely to provide results closer to the “true effect”.82 Forest plots are commonly utilized to summarize the findings of a meta-analysis.82, 91 This graphical demonstration allows for comparison of results from individual studies as well as the overall outcome. Forest plots which show studies with varying results may demonstrate elements of heterogeneity.82, 98 Alternatively, heterogeneity can be quantified by a calculation developed by Higgins et al.98 In situations where heterogeneity is present, the studies should not be combined for meta- analysis. In circumstances, where meta-analyses are not a valid option, narrative summaries are employed. This process synthesizes the study findings into conclusions that represent credible opinion. Outcomes predetermined from the a-priori protocol drive the focus of the narrative review. Although the data cannot be combined, as in a meta-analysis, the narrative review provides a broad overview of relevant information from the included studies. The validity of these findings is therefore dependent on the quality of the included studies. A protocol driven method of analysis that is transparent allows synthesis of quantitative findings with the research findings utilized as a useful method for transmission of information to be used in clinical practice.

This systematic review aims to identify the best available evidence examining the swallowing outcomes of patients with oral or oropharyngeal SCC treated with primary surgery and primary free flap reconstruction. Systematic review methodology was chosen for this research

16 question due to its rigorous and reproducible approach to the identification of the best evidence available. Ultimately, this review aimed to synthesize evidence-based research with the goal of translating the results into recommendations for clinical practice and direct future research.99

1.11 Review objective The objective of this systematic review is to investigate swallowing outcomes following primary surgical resection and free flap reconstruction for the treatment of patients with oral and oropharyngeal squamous cell carcinoma.

1.12. Review question What are the swallowing outcomes of primary surgical resection with primary free flap reconstruction with or without adjuvant therapy for the treatment of oral or oropharyngeal squamous cell carcinoma?

1.13. Inclusion criteria 1.13.1. Types of participants The review sought to include studies with participants aged 18 years of age or older with a histological diagnosis of oral or oropharyngeal squamous cell carcinoma. To be eligible for inclusion, patients must have received a histological diagnosis of malignancy and have received treatment aimed at curative intent with locoregional control at time of swallowing evaluation. Locoregional control at the time of swallowing evaluation is critical as swallowing outcomes at this time are recognized to be representative of swallowing function that is not impaired by the primary cancer.100

Exclusion criteria include patients with mandibular or maxillary involvement requiring osseous free flap reconstruction, distant metastasis at diagnosis, presence of other malignancies, and diagnosis of dementia, stroke or neurological disease prior to treatment. Osseous free flap reconstructions are typically associated with larger primary resections, thus effecting swallowing outcomes. Dementia, stroke and neurological diseases have potential to cause dysphagia, and thus will be excluded. Patients with distant metastases and other malignancies will likely undergo aggressively treatment therapies potentially affecting quality of life scores and swallowing outcomes.

1.13.2. Types of interventions This review will consider the following interventions:  Primary surgery with primary free flap reconstruction alone  Primary surgery with primary free flap reconstruction with adjuvant therapies  Swallowing outcomes with use of radial forearm free flaps following primary surgical resection with or without adjuvant therapy  Swallowing outcomes with use of anterolateral thigh flaps following primary surgical resection with or without adjuvant therapy

1.13.3. Outcomes The outcomes of interest for this review are related to dysphagia. Evaluation of dysphagia will be measured at six months, as articles have correlated swallowing dysfunction present six months after curative therapy to be highly predictive of life-long dysphagia.54, 55 To be included, studies must have measured dysphagia outcomes objectively with either gastrostomy dependency, tracheostomy dependency, penetration-aspiration rates, oral and pharyngeal transit times or pharyngeal pressure readings. These outcomes are to be identified with either Videofluoroscopic Swallowing Studies (VFSS), Fibreoptic Endoscopic Evaluations of Swallowing (FEES) or manometry. Subjective outcomes were measured with the MD Anderson Dysphagia Inventory (MDADI), University of Washington Quality of Life Questionnaire (UW-QOL) or Functional Oral Intake Scale (FOIS).

1.13.4. Types of studies This review sought to include both experimental and epidemiological study designs including randomized controlled trials, non-randomized controlled trials, quasi-experimental, before and after studies, prospective and retrospective cohort studies, case control studies, and analytical cross sectional studies. Due to the nature of this topic, there are currently no published randomised controlled trials due to ethical concerns. Thus in the absence of randomized controlled trials and quasi-experimental studies, the included studies consisted of cohort studies and case-series.

Chapter 2: Methods

2.1. Search strategy The search strategy aimed to find both published and unpublished studies. A three-step search strategy was utilized in this review. An initial limited search of MEDLINE and CINAHL using the terms "oropharynx squamous cell carcinoma", "oral cavity squamous cell carcinoma", "dysphagia" and "primary free flap reconstruction." The results from this initial search were reviewed for relevant articles. Relevant articles were retrieved to identify further keywords and index terms. These identified keywords and index terms were subsequently applied across all included databases. Once all relevant keywords and index terms were identified, assistance from a research librarian was sought to aid in producing a detailed and comprehensive search strategy for each database (Appendix I).

A second search using all identified keywords and index terms was undertaken across all included databases. The search strategy was designed to capture and retrieve all research articles relevant to the research question. Thirdly, the reference list of all selected studies and articles was searched for additional studies that had not been previously identified in the search. No further papers were found. Studies with human participants published in English were considered for inclusion in this review. Studies published from the inception of the included databases to 26/03/2015 were considered for inclusion in this review.

The initial terms searched to identify the number of relevant studies consisted of “oropharyngeal squamous cell carcinoma”, “oral cavity squamous cell carcinoma”, “dysphagia” and “primary free flap reconstruction.” The inclusion of Medical Subject Headings (MeSH) in PubMed, CINAHL Subheadings in CINAHL and EMTREE in Embase were utilized to increase the sensitivity of the search strategy. Unpublished studies were searched using the same search terms as above, in conjunction with MeSH terms. The search terms were used across the following medical databases:

MEDLINE (PubMed), CINAHL, Embase, and Scopus. Grey literature was sought through Cochrane Central Register of Controlled Trials (CENTRAL), MedNar and ProQuest.

2.2. Study Selection This systematic review aimed to identify studies in which swallowing outcomes were the primary or additional outcome. All identified studies were entered and sorted in EndnoteTM, into groups based on the database the study was extracted from. Duplicate studies were then

19 removed from the list of studies with assistance from an automated scan conducted in EndnoteTM. The titles and abstracts of all identified studies were screened and assessed according to the inclusion and exclusion criteria. Studies that were unclear in their title or abstracts, regarding inclusion and exclusion criteria, full text was retrieved for further analysis. Studies that underwent full text screening were organized into subgroups depending on the reason for exclusion.

2.3. Critical Appraisal Critical appraisal of the fifteen identified qualitative studies was performed by two independent reviewers, both post-graduate course candidates, for methodological validity prior to inclusion in the review using standardized critical appraisal instruments from the Joanna Briggs Institute Meta-Analysis of Statistics Assessment and Review Instrument (JBI-MAStARI) (Appendix II).

During the critical appraisal process, it was identified that confounding biases were present among all included studies. These confounding factors included malignancies of varying stages or sub-sites, different surgical access techniques and differing extent of resection. Strategies of reducing confounding bias include randomization, restriction, matching or multivariate analysis.101 Multivariate analysis is an effective method for stratifying known confounding factors, however, this was only present in five of the included studies.3, 4, 6-8 Due to the included studies consisting cohort and case-series studies with small population numbers, unknown confounding factors are thus difficult to reduce.

Prior to the critical appraisal the two reviewers agreed to a list of guidelines to resolve potential issues or disagreements. Prospective studies with ten patients or less conducted at a single institution were classified as case-series. Any disagreements that arose between the reviewers regarding methodological assessment criteria or the inclusion/ exclusion of studies were resolved through discussion.

2.4. Data extraction Data was extracted from papers included in the review using the standardized data extraction tool from JBI-MAStARI (Appendix III). The data extracted included population, resection technique, type of flap utilized, site of malignancy, malignancy stage, adjuvant therapy, outcome measures and time of evaluation. Extracted data from the included studies were collected and summarized in Appendix V. If relevant data was missing or incomplete in the located studies, where feasible, the authors were contacted directly with the request to provide

20 this information (Appendix IV). The study was excluded when the required data could not be provided.

Of the contacted authors, Hartl et al102 and Longo et al17 both provided raw data for further analysis. With this additional information, both studies were included in this review.

2.5. Data synthesis Quantitative data was planned to be pooled into a statistical meta-analysis using JBI- MAStARI. This however, was not possible due to the heterogeneity between included studies. The heterogeneity consisted of differing surgical resection techniques, utilization of differing flaps, malignancies of varying stages and sub-sites. Thus the findings were presented in narrative form including tables and figures to aid in data presentation and interpretation.

Studies were grouped into patients treated with surgery alone or primary surgery with adjuvant therapies. Additionally, swallowing outcomes with the use of radial forearm free flap were compared with anterolateral thigh flap. Swallowing outcomes between oral-cavity squamous cell carcinoma were compared with oropharyngeal squamous cell carcinoma. The effect of differing surgical access technique was not reviewed, as it is known invasive mandibulotomies have worse swallowing outcomes compared with transoral approaches.47

Chapter 3: Results

This chapter presents the findings of the systematic review, details of the search results, study selection, assessment of methodological quality and a detailed description of included studies. The results of swallowing outcomes are presented according to the type of swallowing evaluation used.

3.1. Search results As shown in figure 2 the search identified a total of 699 studies in English. Following removal of duplicates, 420 studies remained for screening. The titles and abstracts were reviewed against the inclusion criteria to determine their relevance to the review question and objectives. Through this process, 270 studies were excluded, leaving 150 studies which were retrieved in full text for detailed examination. Of the 150 full text articles, 135 studies were excluded as they did not fully meet the inclusion criteria resulting in the selection of 15 for critical appraisal (Appendix V). The reasons for the exclusion of each of the 135 studies are provided in Appendix VI. No studies were excluded after assessment of methodological quality, which is discussed in the next section. Fifteen studies were included in the systematic review, of which eight were cohort studies and seven cases series. These search results have been summarized in the following Preferred Reporting Items for Systematic reviews and Meta- Analyses (PRISMA) flow diagram (Figure 2).

Records identified through database searching, English only

n = 699

Identification Records after duplicates removed Duplicates excluded n = 420 n = 279

Full text retrieved for detailed examination Records excluded after n = 150 review of title and abstract n = 270

Screening

Studies Assessed for methodological quality Full-text articles excluded, n = 15 with reasons

n = 135

Reasons:

Eligibility Studies Included in this review Incorrect population n = 15 n = 44

Incorrect study design n = 2

Incorrect outcome

Cohort Studies Case-Series n = 43 n = 8 n = 7 Follow up <6/12

n = 16 Included

Non- Free Flap/Osseous Flap n = 21

Poster n = 9

Figure 2. PRISMA Flow diagram illustrating the process of including and excluding studies from the systematic review.1 Number of studies found and retrieved

3.2. Assessment of methodological quality Following the screening and review of the full text, 15 studies underwent independent critical appraisal by two reviewers trained in the use of JBI-MAStARI (Appendix III). Eight cohort studies and seven case-series were reviewed. Any disagreements were resolved by discussion. All fifteen studies were included in this systematic review.

Cohort Studies: Methodological quality was similar across all 8 cohort studies included in this review. Question 4, regarding confounding bias was answered “yes” in 5 of the included studies as they had performed multivariate analyses in an attempt to reduce confounding biases.3, 4, 6-8 Confounding factors such as varying surgical access techniques, cancer stages and sub-sites occurred across all studies. Surgical heterogeneity is a common occurrence in surgical studies, and therefore is a difficult bias to avoid.103, 104 However, due to small the numbers present in included studies with no randomization present, unknown confounding biases could not be controlled.

Two studies7, 18 answered "no" to question 2, regarding similarity in stage of disease. These studies included patients with varying T-stages with swallowing outcome results combined together. This further added confounding bias to the studies. This is another common occurrence in many surgical studies, due to small population numbers present. Both publications otherwise had sound methodology, and thus were included in the systematic review.7, 18

Question 7 regarding outcomes of patients who withdrew from the study was typically answered with "no" or "not applicable". "Not applicable" was answered in studies where no patients withdrew, and "no" was answered as patients were excluded if they failed to be evaluated.

Table 4. Results of critical appraisal of cohort studies. Study Q1 Q2 Q3 Q4 Q5 Q6 Q7 Q8 Q9 Borggreven3 Y Y Y Y Y Y N Y Y Chien4 Y Y Y Y Y Y N Y Y Farace5 Y Y Y N Y Y N Y Y Keiner18 Y N Y N Y Y N/A Y Y Longo17 Y Y Y N Y Y N/A Y Y O'Connell6 Y Y Y Y Y Y N/A Y Y Rieger7 Y N Y Y Y Y N Y Y Seikaly8 Y Y Y Y Y Y N/A Y Y % 100 25 100 63 100 100 0 100 100 Y = Yes, N = No, N/A = Not applicable, U/C = Unclear

JBI Critical Appraisal Checklist for Comparable Cohort/Case Control Q1. Is sample representative of patients in the population as a whole? Q2. Are the patients at a similar point in the course of their condition/illness? Q3. Has bias been minimized in relation to selection of cases and of controls? Q4. Are confounding factors identified and strategies to deal with them stated? Q5. Are outcomes assessed using objective criteria? Q6. Was follow up carried over a sufficient time period? Q7. Were the outcomes of people who withdrew described and included in the analysis? Q8. Were outcomes measured in a reliable way? Q9. Was appropriate statistical analysis used?

Case-series Studies: All patients selected for these studies were consecutive patients treated at a single institution. Prospective studies with ten patients or less conducted at a single institution were classified as case-series. Similar to the cohort studies, the same confounding factors were present and thus question 3 was answered "no". Although sufficient descriptions of the groups were present, five of the included studies made no comparisons and thus questions 5 was answered not applicable.102, 105-108 None of the patients excluded from the studies were included in the analysis, thus question 7 was answered not applicable. Hsiao109 compared swallowing outcomes between RFFF reconstruction with primary closure, with sufficient descriptions of both groups. The primary closure group was excluded from the review process as it met exclusion criteria. Li108 was the only included study not to describe in detail their surgical technique, thus it is unclear if surgical access was achieved through a mandibulotomy or peroral approach.

Table 5. Results of critical appraisal of case-series. Study Q1 Q2 Q3 Q4 Q5 Q6 Q7 Q8 Q9 Haddock105 Y Y N Y N/A Y N/A Y Y Hartl102 Y Y N Y N/A Y N/A Y Y Hsiao109 Y Y N Y Y Y N/A Y Y Li108 Y Y N Y N/A Y N/A Y Y Moerman106 Y Y N Y N/A Y N/A Y Y Shin9 Y Y N Y Y Y N/A Y Y Winter107 Y Y N Y N/A Y N/A Y Y % 100 100 0 100 29 100 0 100 100 Y = Yes, N = No, N/A = Not applicable, U/C = Unclear

JBI Critical Appraisal Checklist of Descriptive/Case Series Q1. Was study based on a random or pseudorandom sample? Q2. Were the criteria for inclusion in the sample clearly defined? Q3. Were confounding factors identified and strategies to deal with them stated? Q4. Were outcomes assessed using objective criteria? Q5. If comparisons are being made, was there sufficient descriptions of the groups? Q6. Was follow up carried out over a sufficient time period? Q7. Were the outcomes of the people who withdrew described and included in the analysis? Q8. Were outcomes measured in a reliable way? Q9. Was appropriate statistical analysis used?

3.3. Description of included studies Eight cohort studies and seven case series were included in this review. All articles were published between 2000 and 2013. Three studies were completed in Canada6-8, two in Taiwan4, 109 and Italy5, 17 and one in United States of America105, Netherlands3, France102, Germany18, United Kingdom107, South Korea9, China108 and Belgium106.

The age of all patients included ranged between 23 and 87 with mean of 61, with all studies having similar age range. 79% of all patients included were males, which is typically seen in all head and neck malignancies110.

Follow up period for studies ranged between 6 and 93 months following curative surgery. The vast majority of swallowing evaluation occurred within 12 months of treatment in all studies.

Heterogeneity present in the included studies include differing surgical access technique, stages of malignancy, sub-sites of malignancy and varying and sizes of resection. Due to the heterogeneity of the studies included in this review, pooled data was deemed unlikely to yield

26 statistically valid results. Thus a narrative summary and discussion was chosen to highlight the analysis.

Three of the included studies utilized subjective methods to assess swallowing outcomes9, 107, 108, with the remaining 12 studies focusing on objective methods of assessment.3-8, 17, 18, 102, 105, 106, 109 Subjective evaluation included the self-administered MD Anderson Dysphagia Inventory (MDADI) and University of Washington Quality of Life (UW-QoL).9, 107 Six studies utilized gastrostomy dependency and seven studies utilized tracheostomy dependency as a measure of swallowing assessment.4, 6-8, 17, 18, 102, 105, 106 Five studies employed bolus transit time measured with VFSS in the assessment of swallowing.3, 5, 7, 17, 109 Nine studies reviewed the presence of aspiration via VFSS or FEES in the evaluation of swallowing.3-8, 18, 102, 105 The results of the swallowing outcomes are presented below, with a summary of included studies in Appendix V.

Subjective Assessments Three case-series evaluated swallowing outcomes with the use of subjective questionnaires.9, 107, 108 Shin found postoperative radiotherapy was associated with poorer MDADI scores (Table 6).9 Li and Winter both utilized the UW-QoL to review swallowing outcomes following surgery with adjuvant therapy (Table 6).107, 108 Furthermore, Li found cancer of the tongue and floor of mouth had poorer swallowing outcomes than buccal tumors.108 Six patients were excluded from the Winter study as one patient underwent primary closure, and five patients underwent supraglottic laryngectomies. All studies found postoperative radiotherapy or chemotherapy was also associated with more tongue shrinkage and decreased coordinated tongue movements. Furthermore, subcutaneous fibrosis, mucosal oedema, trismus and xerostomia secondary to radiotherapy had a cumulative effective on swallowing outcomes.9, 107

Table 6. MDADI Scores Study Site Population Stage Flap Treatment Evaluation MDADI MDADI Regime Time Score Score (Months) Surgery Surgery + RT only Shin9 Oral 31 T1, T2 RFFF S + RT 21-91 80.5 +/- 64.77 +/- tongue 10.9 16.34 RFFF: Radial forearm free flap; S: Surgery; RT: Radiotherapy

Table 7. UW-QoL Scores

Study Site Population Stage Flap Treatment Evaluation UW-QoL Regime Time Score (Months) Li108 Oral Tongue, 51 T1, T2, ALTF S + CRT 12-84 49 FOM, Gum, T3, T4 Buccal mucosa Winter107 BOT 6 III, IV RFFF, RMF S + RT 9-56 63.33 BOT: Base of tongue; RFFF: Radial forearm free flap; RMF: Rectus myocutaneous flap; S: Surgery; RT: Radiotherapy

Seven cohort studies and two case series reviewed the presence of aspiration as an outcome of dysphagia (Table 8).3-8, 18, 102, 105 Three studies identified aspiration with the use of flexible nasoendoscopy.5, 18, 102 The remaining six studies utilized VFSS in the evaluation of aspiration.3, 4, 6-8, 105 Three of these studies used varying consistencies of food (liquid, pudding, cookie) with their VFSS, however, found not all patients were able to tolerate all consistencies. 3, 7, 8 Penetration aspiration scale (PAS) was utilized in two studies, where penetration was

28 defined as a score of 2-5 and aspiration was defined as 6-8.3, 7 Swallowing outcome was negatively correlated with percentage of oral tongue or BOT resected. Patients treated with near total glossectomy had greater chances of achieving improved swallowing outcome compared with total glossectomy.4 There was minimal change in incidence of aspiration at six and twelve months following curative surgery.3, 7 Nil significant difference in aspiration rates between flaps utilized, although RFFF was by far the most common. Aspiration detected on VFSS or FEES lead to gastrostomy or tracheostomy dependency in some patients.4, 6-8, 102

Objective Assessments Aspiration Table 8. Summary of Aspiration Study Site Population Stage Free Treatment Aspiration Aspiration Aspiration Flap Regime @ Preop @ 6/12 @ 12/12 Borggreven3 Oral tongue, 54 II, III, IV RFFF S + RT - L-18 (34%) L-14 (25%) FOM, BOT, Tonsil, Soft palate Chien4 Oral tongue, 29 T3, T4 RFFF, S + CRT - - 9 (31%) BOT ALTF Farace5 Oral cavity 20 T2, T3 ALTF, S - 0 (0%) - RFFF Haddock105 Oral tongue 8 III, IV VRAM S + RT - - 0 (0%) Hartl102 Oral tongue, 5 IV RFFF, S + RT - - 2 (40%) BOT LDF, RMF Keiner18 Oral 49 T2, T3, RFFF S + RT - - 0 (0%) T4 Oropharynx 101 T2, T3, RFFF S + RT - - 0 (0%) T4 O’Connell6 BOT, Lateral 36 III, IV RFFF S+ CRT - - P-1(3%) pharyngeal wall, Soft palate Rieger7 BOT, Lateral 32 T1, T2, RFFF S + CRT L-0 (0%) L-5 (21%) L-4 (21%) pharyngeal T3, T3 P-0(0%) P-4 (17%) P-1 (19%) wall, Soft palate Seikaly8 BOT, Lateral 18 III, IV RFFF S + RT - - L-3 (17%) pharyngeal P-2 (11%) wall, Soft palate FOM: Floor of mouth; BOT: Base of tongue; ALTF: Anterolateral thigh flap; RFFF: Radial forearm free flap; VRAM: Vertical rectus abdominus myocutaneous flap; LDF: Latissiumus dorsi flap; RMF: Rectus myocutaneous flap; S: Surgery; RT: Radiotherapy; CRT: Chemoradiotherapy; L: Liquid; P: Pudding

Four cohort studies and three case-series reviewed gastrostomy dependency (Table 9).4, 6-8, 102, 105, 107 All patients in included studies had late stage malignancies with reconstructions utilizing various flaps. Patients requiring gastrostomy feeds at time of evaluation was secondary to significant aspiration.4, 6-8, 102 Chien found nil significant difference in success of oral feeding among RFFF and ALTF.4

Gastrostomy Tube Dependency Table 9: Summary of Gastrostomy Dependency Study Malignancy Population Stage Flap Treatment Evaluation Gastrostomy Site Regime Time (Months) Chien4 Oral tongue, 29 T3, T4 RFFF, ALTF S + CRT 12 3 (10%) BOT Haddock105 Oral tongue 8 III, IV VRAM S + RT 12 0 (0%) Hartl102 Oral tongue, 5 IV RFFF, LDF, RMF S + RT 24 1 (20%) BOT O’Connell6 BOT, Lateral 36 III, IV RFFF S+ RT 12 4 (11%) pharyngeal wall, Soft palate Rieger7 BOT, Lateral 32 T1, T2, T3, T4 RFFF S + CRT 6 - 12 3 (9%) pharyngeal wall, Soft palate Seikaly8 BOT, Lateral 18 III, IV RFFF S + RT 6 - 9 1 (6%) pharyngeal wall, Soft palate Winter107 BOT 6 III, IV RFFF, RMF S + RT 9 - 56 0 (0%) BOT: Base of tongue; RFFF: Radial forearm free flap; ALTF: Anterolateral thigh flap; VRAM: Vertical rectus abdominus myocutaneous flap; LDF: Latissiumus dorsi flap; RMF: Rectus myocutaneous flap; S: Surgery; RT: Radiotherapy; CRT: Chemoradiotherapy

Five cohort studies and two prospective case-series reviewed tracheostomy dependency as a swallowing outcome (Table 10). Six of the included studies mentioned routine preoperative insertion of tracheostomies.4, 6, 7, 17, 105, 106 Five studies found all their patients to be decannulated prior to their evaluation at least 6 months following curative surgery.6, 7, 17, 105, 106 Two studies had patients requiring tracheostomy at time of evaluation, both who had resections involving the oropharynx, primarily for pulmonary toileting.4, 18

Tracheostomy Dependency Table 10: Summary of Tracheostomy Dependency Study Malignancy Population Stage Flap Treatment Evaluation Tracheostomy Site Regime Time (Months) Chien4 Oral tongue, 29 T3, T4 RFFF, S + CRT 12 1 (3%) BOT ALTF Haddock105 Oral tongue 8 III, IV VRAM S 12 0 (0%) Keiner18 Oral cavity 49 T2, RFFF S + RT 8-15 0 (0%) T3, T4 Oropharynx 101 T2, RFFF S + RT 8-15 1 (2.9%) T3, T4 Longo17 Oral tongue 13 T3, T4 ALTF S + RT 6-18 0 (0%) Moerman106 Tonsil, Soft 4 T2, T3 RFFF S+ RT 8-21 0 (0%) palate, Lateral pharyngeal wall O’Connell6 BOT, Lateral 36 III, IV RFFF S + RT 12 0 (0%) pharyngeal wall, Soft palate Rieger7 BOT, Lateral 32 T1, RFFF S + CRT 6 – 12 0 (0%) pharyngeal T2, wall, Soft T3, T4 palate BOT: Base of tongue; RFFF: Radial forearm free flap; ALTF: Anterolateral thigh flap; VRAM: Vertical rectus abdominus myocutaneous flap; S: Surgery; RT: Radiotherapy; CRT: Chemoradiotherapy

Four cohort studies and one case-series reviewed bolus transit time via VFSS as an evaluation method of dysphagia (Table 11).3, 5, 7, 17, 109 One study utilized pudding in the evaluation of OTT and PTT,7 whereas two studies used liquid consistency in their evaluation of OTT and PTT.3, 109 Minimal difference between OTT at six and 12 months following treatment was found.3, 7 Addition of chemotherapy to the regime was associated with increased transit time.7, 109 Farace measured OTT with nasoendoscopy and varying consistencies of food, and thus transit time measurement was different other included studies.5

Oral and pharyngeal transit time Table 11: Summary of oral and pharyngeal transit time Study Site Population Stage Flap Treatment OT OTT OTT PTT PTT PTT Regime T @ @ @ @ @ @ 12 Pre 6/12 12/12 Preo 6/12 /12 op (s) (s) p (s) (s) (s) (s) Borggreven3 Oral tongue, 54 II, III, IV RFFF S + RT - 0.56 0.52 - 1.04 1.09 FOM, BOT, +/- +/- +/- +/- Tonsil, Soft 0.38 0.48 0.41 0.48 Palate Farace5 Oral cavity 20 T2, T3 RFFF Unclear - <10 - - - - ALTF Hsiao109 Oral tongue 4 T2, T3 RFFF S + CRT - - 1.21 - - - Longo17 Oral tongue 13 T3, T4 ALTF S + RT - - 0.79 - - - Rieger7 BOT, Lateral 32 T1, T2, RFFF S + CRT 0.8 1.16 1.24 0.94 1.27 1.96 pharyngeal T3, T4 0 +/- +/- +/- +/- +/- wall, Soft +/- 1.43 1.20 0.47 1.00 2.14 palate 1.0 1 FOM: Floor of mouth; BOT: Base of tongue; RFFF: Radial forearm free flap; ALTF: Anterolateral thigh flap; S: Surgery; RT: Radiotherapy; CRT: Chemoradiotherapy; OT: Oral transit time; PTT: Pharyngeal transit time

None of the studies included in this review evaluated swallowing outcomes utilizing manometry or functional oral intake scale.

Surgery alone Vs. Surgery and Adjuvant Therapy Shin was the only study to directly compare the MDADI scores of patients treated with surgery alone against surgery with adjuvant therapy. They found postoperative RT to be associated with poorer MDADI scores.9 They inferred tongue shrinkage following radiotherapy resulted in decreased coordinated tongue movements, thus impairing swallowing efficiency. The studies published by Winter and Li consisted of patients treated predominately with surgery and adjuvant therapy.107, 108 Although there was no direct comparison regarding the effects of postoperative RT, they both correlated postoperative RT with lower UW-QoL scores. Farace was the only study to include patients treated with primary surgery alone, and found no patients suffered from with aspiration at six months (Table 8).5 As they employed nasoendoscopy for the measurement of OTT, results were not comparable to the other included studies. Although the majority of included studies did not directly investigate the effects of postoperative RT, poorer swallowing outcomes were inferred to be secondary to RT. 18, 102

Radial Forearm Free Flap Vs. Anterolateral Thig Flap Radial forearm free flaps were utilized in 12 of the included studies.3-8, 18, 102, 106, 109 Chien found improved muscular function with the thin pliable RFFF due to its smaller bulk compared with the ALTF. However, overall they found no significant difference between the various flaps4 Five of the included studies solely utilized the RFFF and found its thin pliable attributes allow it to integrate well with the oral cavity and oropharynx, thus leading to improved swallowing outcomes. 3, 7, 8, 18, 106 Farace compared the RFFF and ALTF in the reconstruction of oral defects and found no significant differences regarding functional outcomes.5 They suggested the use of ALTF for intraoral reconstructions due to decreased donor site morbidity. Longo also favored the ALTF due to lower donor site morbidity with reliable revascularization without sacrificing the radial artery.17 They found the only drawback of the ALTF to be the large amount of bulk potentially affecting movement of the neotongue, however, thinning was achievable with careful dissection of the suprafascial plane.

Oral Cavity Vs. Oropharynx Oropharyngeal resections lead to worse swallowing outcomes compared with oral cavity. Resections of the soft palate in combination with the BOT had the most swallowing complications including penetration and aspiration. 3 Resections of the soft palate, tongue base, pharyngeal walls typically required reconstruction to decrease risk of strictures. 18 Tongue and FOM had poorer outcomes compared to buccal region. 108 Tracheostomy dependency occurred in two patients in the included studies, of which both underwent resections involving their oropharynx (Table 10).4, 18

Chapter 4: Discussion

4.1. Overview of findings Treatment modalities for oral and oropharyngeal squamous cell carcinomas have improved oncological outcomes over recent years, with goals now aimed at improving functional outcomes, such as swallowing. Numerous studies have investigated swallowing outcomes following treatment of head and neck cancers. However, due to the complexity and multitude of processes involved in deglutition, there is currently no standardized approach to the assessment of swallowing. Postoperative deglutition function is a vital aspect in a patient's quality of life, and thus a thorough and systematic approach must be applied in the evaluation of these patients.

This systematic review sought to retrieve and synthesize the best available evidence on the swallowing function of patients with oral or oropharyngeal squamous cell carcinoma treated with primary surgery with primary free flap reconstruction with or without adjuvant therapy. A total of eight cohort studies3-8, 17, 18 and seven case-series9, 102, 105-109 met the inclusion criteria and methodological quality, were included in this review. There was a large variation in methodological design and reporting of results in the included studies. Despite the lack of high quality randomized data currently available, the included studies are a representative sample of the current available literature. Large amounts of heterogeneity existed between these published studies, thus causing difficulty in pooling of results for meta-analysis. The studies included in this review evaluated patients with squamous cell carcinoma of varying sub-sites of the oral cavity and oropharynx. The swallowing outcomes of varying sub-sites were typically combined together due to the small population numbers available. This lead to decreased validity in studies as differing sub-sites contributed to deglutition more than others. The included studies also consisted of patients with varying stages of disease, ranging from T1 to T4 and stage II to IV. This factor further added to the confounding biases commonly present in surgical studies, as it is well established patients requiring larger resections will have poorer swallowing outcomes.7, 111 In addition, differing surgical access techniques such as mandibulotomies and peroral access have vastly different swallowing outcomes. Invasive mandibulotomies involve disruption of the oral and pharyngeal anatomy and physiology, typically leading to poorer outcomes. Lastly, preferences between surgeons and institutions played a large role in functional outcomes. Therefore, findings in this study were presented in narrative form due to the heterogeneity present in this review.

The included studies in this review have associated a dose-dependent relationship between postoperative radiotherapy and worsening swallowing function. Shin was the only article to specifically review this relationship, and found a significant decrease in MDADI score following radiotherapy.9 Shin attributed this worsening swallowing function to excessive reconstructed tissue shrinkage secondary to RT.9 Furthermore, two studies found no improvement in swallowing function between six and twelve months following surgery and adjuvant RT.3, 7 Their findings were similar to the results from Pauloski, who also found minimal improvement in swallowing function after RT.112 These findings suggest decreased healing ability in combination with fibrosis, causing impaired swallowing function at six months following RT. In addition, late complications of RT consisting of subcutaneous fibrosis, trismus and salivary gland dysfunction all have a cumulative and detrimental impact on swallowing function. Although this study did not focus specifically on these complications, the presence of these effects is evidenced by prolonged gastrostomy dependency and increased transit times. The findings from this review are further supported by other published reviews demonstrating improved swallowing outcomes with surgery alone compared with surgery and adjuvant CRT.46, 48 Moncrieff et al found evidence to support the use of primary surgery alone for the treatment of T1 and T2 oropharyngeal SCC, thus avoiding the side effects of adjuvant RT.38 They recommended postoperative RT for local control of high-risk primaries or regional control of bulky cervical metastases. Despite the great debate regarding optimal treatment of oral and oropharyngeal SCC, the above findings demonstrate a potential for primary surgery-alone for a select group of patients, thus sparing the effects of RT for these patients. Evidence from this systematic review support the development of a protocol for the identification of patients at high and low risk of developing post-treatment swallowing dysfunction. Furthermore, these stratified patients should be monitored closely with a standardized swallowing protocol. This proposed protocol will lead to improved understanding of dysphagia and better counseling for patients preoperatively.

Currently published literature show promising results encouraging the use of swallowing exercises to decrease the incidence of post-treatment dysphagia.113, 114 115-117 Scherpenhuizen found statistically significant increased interincisal opening in patients who utilized jaw- mobilizing device compared with no exercise.113 Furthermore, two randomized control trials have found swallowing exercise programs associated with superior muscle maintenance and functional swallowing ability.114, 115 MRI studies in the Carnaby-Mann study demonstrated maintenance of muscle characteristics following swallowing exercises.115 They proposed the “pharyngocise” protocol may be associated with decreased inflammatory changes following treatment with CRT. Furthermore, Carroll and Kulbersh found pre-treatment swallowing exercises to be correlated with improved swallowing function post-CRT.116, 117 These results

36 show promising results for the use of swallowing exercises pre- and during treatment for patients undergoing CRT. These results, however, need to be validated with further research.

Microvascular free flap reconstructions have been employed in the reconstruction of surgical defects as they allow for wider resection margins and are able to improve swallowing outcomes by restoring tissue bulk.18, 118, 119 Hsiao found primary closure of the defect resulted in a small mobile tongue which lacked volume and lead to ineffective deglutition.119 Flap selection is dependent on the size and location of the defect, however, donor site morbidity must be taken into account. Donor sites are associated with the potential of increased pain, delayed wound healing and unsightly scars. All these factors need to be taken into account prior to surgical resection and reconstruction. The majority of the cases included in this study utilized RFFF, however, a small number of studies also employed the ALTF, RMF, VRAM and LDF in their reconstructions. Farace and Longo suggested the use of the ALTF for reconstruction, due to lower rates of donor site morbidity.5, 17 These findings are supported by published literature favoring the use of ALTF due to its versatility, presence of abundant perforating vessels and bulk for head and neck reconstructions.120 Systematic review published by Lam, similarly found difficulty in concluding the ideal free flap for optimal functional outcomes.74 Due to the heterogeneity involved in the studies, there is no clear consensus on the efficacy of RFFF over ALTF for the reconstruction of oral or oropharyngeal defects. Graft choice is largely dependent on the defect size as well as surgeon preference.

Compared with primary closure, microvascular reconstruction has been demonstrated to improve deglutition.119 Hsiao was able to demonstrate the additional bulk was necessary to close the dead space in the oral cavity, and allow for sufficient tongue to soft palate contraction.109 Keiner recommended primary closure only for T1 tumors, as opposition of adjacent mucosa in larger resections is not always possible.18 They also found scar tissue formation, particularly in the oropharynx, lead to narrowing of the digestive tract. McConnel found small resections of the oral or base of tongue demonstrated nil improvement in swallowing efficiency between primary closure and flap repair.121 In larger resections, free flaps have demonstrated versatility in being able to repair surgical defects without tethering the tongue to surrounding structures.122, 123 Despite advances in microvascular reconstruction, some studies demonstrated pharyngeal bolus transit time to be increased with no recovery to preoperative function.3, 124 Lam found when tumor resection was limited to either oral tongue or BOT, good functional outcome can be obtained through immediate free flap reconstruction.74

Due to the complexity of swallowing and lack of standardization in its assessment, this systematic review chose a combination of validated objective and subjective assessments to evaluate swallowing function. Aspiration was noted to be a commonly utilized measure of dysphagia among studies, with its detection via VFSS or nasoendoscopy. Penetration- aspiration scale is a validated tool in quantifying the severity of penetration or aspiration, which was only utilized in two studies.3, 7 The rate of aspiration was variable among studies, as differing consistencies of food boluses were employed. The presence of aspiration is an important factor to consider with regards to dysphagia, as it has the potential to lead to life- threatening lower respiratory tract infections. The presence of persistent aspiration and dysphagia results in the insertion of gastrostomy tubes and tracheostomies in some patients. However, the presence of pneumonia was not utilized as an outcome of dysphagia as there is great difficulty in ascertaining if the infection was secondary to aspiration or another cause.

Gastrostomy tubes were employed when there was a persistence of aspiration, severe odynophagia, dysphagia or unable to maintain adequate nutrition. The included studies showed a low rate of gastrostomy dependency, with removal typically prior to 12 months following surgery. Other published systematic reviews similarly found variable rates of gastrostomy dependency, ranging up to 75%.75 Haddock et al105 was the only study to prophylactically insert gastrostomy tubes prior to treatment. Prophylactic gastrostomy tube placement is practiced in some institutions with the goal of maintaining nutrition, avoiding interruptions in treatment and improving tolerance and response to CRT.125-127 However, studies have associated early gastrostomy tube insertion to be associated with long term dysphagia and decreased quality of life, likely secondary to disuse muscle atrophy and fibrosis.43, 128 Swallowing exercises have been employed in the treatment regime to reduce the effects of CRT, with promising results. 114, 115 The presence of gastrostomy tubes as a marker for dysphagia may be influenced by other factors, such as anxiety or lack of education involved with the use of gastrostomy tubes.129 Therefore, it is important to utilize gastrostomy dependency in conjunction with other assessment tools.

Tracheostomy dependency is not a commonly utilized measure of dysphagia in current literature. It, however, plays a large role in swallowing function due to its potential to distort pharyngeal anatomy and physiology when in situ. Tracheostomies are commonly conducted in head and neck cancer cases involving large resections, as it allows for a definitive airway. This was mentioned in six of the included studies.4, 6, 7, 17, 105, 106 Tracheostomy dependency was low and occurred only in patients who underwent oropharyngeal resections, due to recurrent aspiration or need for frequent pulmonary toileting. Thus tracheostomy dependency is not only a marker for dysphagia, but is also a source of dysphagia. Despite the majority of

38 included studies in this systematic review performing mandibulotomies, the tracheostomy dependency rates were similar to rates following transoral robotic surgery.48

Bolus transit time is an effective and versatile method of evaluating swallowing function. The included studies measured a combination of oral, oropharyngeal and pharyngeal transit times. Despite the lack of standardization in the measurement of bolus transit time, all studies based their procedure on the study published by Lazarus and colleagues.130 The consistency used varied between liquid and pudding in included studies, thus causing great difficulty in drawing conclusions from the results. Due to its use in conjunction the VFSS, the movement of anatomical structures can be assessed during the same procedure. However, due to the vastly differing measures of movement in pharyngeal structures available, this was not used in the review.

Manometry is a gold standard for the assessment of esophageal motility disorders, however, is technically demanding and requires experienced and specialized staff. Manometry is typically used in the investigation of dysphagia, however, is only performed when diagnosis has not been achieved with other forms of investigations. The complexity of this procedure causes difficulty in access to this form of investigation, thus it is the likely reason none of the included studies utilized manometry as an evaluation method of swallowing function. However, studies have demonstrated the important role of impedance manometry as an alternative non-radiological method in the assessment of oropharyngeal swallowing disorders.131

Subjective questionnaires are integral to the evaluation of dysphagia in patients following cancer therapy. It provides clinicians with important information regarding the patient's perception of their physical and emotional state. Therefore, it is extremely important to combine both objective and subjective methods for a more holistic management regime. The MD Anderson Dysphagia Inventory (MDADI) and University Washington Quality of Life Questionnaire (UW-QoL) have both been validated for use in head and neck cancer patients. The included studies that utilized subjective questionnaires showed similar scores among the patients treated. Interestingly, Kendall and colleagues demonstrated a lack of correlation in quality of life and physiological functioning.132 It is important to consider the questionnaires measure the patient's emotional response to their disease and different aspects of their life. This association between objective and subjective evaluations require further research.

Swallowing evaluation is an integral component in the management of patients following treatment of head and neck malignancy. Due to the complexity of dysphagia, there is not a

39 standardized protocol for post-treatment swallowing evaluation. A wide range of assessment tools is currently available to clinicians, ranging from subjective questionnaires to bedside nasoendoscopy to videofluoroscopy in the radiology suites. Despite these advances in assessments available, there is a lack of published literature investigating swallowing in a standardized manner. There is a need for a well-designed prospective longitudinal cohort study to assist furthering our knowledge on post-treatment swallowing outcomes. VFSS and FEES should be utilized routinely in the evaluation of dysphagia, as they are able to provide large amounts of information regarding deglutition. Detection of aspiration is paramount in decreasing rates of aspiration pneumonia, thus improving quality of life. Ideally, the evaluation of aspiration with the use of the validated penetration-aspiration scale allows quantitative grading. Due to the late toxicities following the CRT, more studies are required to evaluate long term swallowing outcomes greater than one to two years. Studies should aim to include both objective investigations with subjective questionnaires for a more holistic approach. A standardized protocol for the measurement of transit time and movement of pharyngeal structures should be developed and validated, thus allowing for in-depth investigation of changes following treatment with CRT.

4.2. Limitations to the study The search strategy for this systematic review was limited to studies published in English. Therefore, studies published in languages other than English may have added to the findings in this review. Furthermore, there was a lack of high quality studies due to the nature of the topic. Improvements in methodology and reporting of data is required for future studies. Primary studies should include clearly documented inclusion and exclusion criteria with surgical resection and reconstruction techniques clearly described. Patients with malignancies of similar stage should be grouped together. Additionally, results from swallowing evaluations should be clearly documented.

4.3. Implications for practice This review included studies of varying methodological quality by the critical appraisal process. Due to the nature of this topic, high quality evidence is currently limited. Interpretation of the findings provide credible evidence useful in clinical practice with the potential to produce useful strategies in identifying patients at high risk of developing dysphagia post-treatment, and in turn have appropriate swallowing evaluations and follow up. A number of recommendations for practice have been developed based upon the results of this review which have been graded using the JBI approach. Grades of Recommendation are used to assist healthcare professionals when implementing evidence into practice.

The JBI Levels of Evidence and Grades of Recommendations is based on the JBI "FAME Model" of feasibility, appropriateness, meaningfulness and effectiveness.133 Grade A recommendations are considered "strong" recommendations, whereas, Grade B recommendations, are considered "weak" recommendations for a health management strategy. Due to the quality of included studies and current available literature, the recommendations from this review are Grade B.

Based upon the findings from this systematic review, it can be recommended that patients receiving treatment for their oral and oropharyngeal squamous cell carcinoma are identified early by using a validated screening protocol that stratifies patients into low and high risk of developing post-treatment dysphagia. A draft protocol for dysphagia risk stratification for the assessment of patients diagnosed with oral and oropharyngeal squamous cell carcinomas was developed (Appendix VII). Such a protocol will also be able to be used to facilitate counselling for patients with regard to their likelihood of experiencing post-treatment dysphagia. The proposed protocol contains the following recommendations for practice:  Low risk patients with early stage malignancy (T1 and T2) with no evidence of regional or distant metastases, may benefit with less dysphagia from surgery-alone without radiotherapy to the primary tumor. (Grade B)  Larger resections involving combinations of the BOT, oral tongue and soft palate with the addition of RT following resection would be deemed higher risk to be associated with long- term dysphagia. (Grade B)  Preoperatively, all patients require evaluation with FEES and subjective questionnaires. (Grade B)  Postoperatively, patients should be closely monitored with quality of life questionnaires and routine FEES to evaluate for aspiration, with use the aspiration-penetration scale. (grade B)  Patients deemed higher risk will require closer monitoring with the use of VFSS pre- and postoperatively. (Grade B)

4.4. Implications for research There was a lack of high level evidence in the area of swallowing outcomes following primary surgery and primary free flap reconstruction. Due to ethical concerns, no high quality randomized control trials have been published. The only available literature on this topic are cohort and case-series studies. These studies require clearly defined inclusion and exclusion criteria with detailed descriptions of surgical techniques and adjuvant therapies involved.

Furthermore, different stages and sub-sites of cancer must ideally be stratified separately to decrease confounding factors. All these elements must be addressed to produce a high quality study. A standardized protocol of swallowing function is required, consisting of both objective and subjective assessments. Subjective assessments such as the MDADI and UW-QoL are both validated questionnaires that should be routinely utilized. These subjective findings should be utilized with findings from objective investigations for a holistic approach. The reporting of these outcomes must be standardized and detailed for it to be used in a meta- analysis. The use of the dysphagia risk stratification protocol is recommended to be used in clinical practice. Patients stratified into the low and high risk groups should be followed prospectively, monitored with both objective and subjective swallowing evaluations. The long term outcomes of these patients should be documented clearly, and will assist in validating the effectiveness of this protocol. A prospective multi-centered approach would be a preferred method of performing a high quality study.

4.5. Conclusion Swallowing function is a fundamental component in the management of patients following treatment of head and neck malignancy. Due to the intricacy of swallowing, there is yet to be a standardized protocol for post-treatment dysphagia evaluation. A vast array of objective and subjective assessment tools are currently available, however, there is still a lack of published literature investigating swallowing in a standardized manner.

This systematic review has retrieved and collated the best available evidence in the literature on swallowing outcomes following primary surgical resection with primary free flap reconstruction. Results have found that postoperative radiotherapy has been demonstrated to adversely affect swallowing outcomes. Furthermore, there is currently no consensus regarding swallowing outcomes between the use of radial forearm free flaps and anterolateral thigh flaps, both appear to be efficacious. Lastly, primary free flap reconstruction has been demonstrated to have improved swallowing outcomes compared with primary closure.

There is a need for a well-designed prospective longitudinal cohort study to assist furthering our knowledge on post-treatment swallowing outcomes. Furthermore, long term studies are required to review late toxicities following CRT. Studies should aim to combine both objective investigations with subjective questionnaires for a more holistic approach. A standardized protocol for identifying low and high risk patients with corresponding swallowing evaluations has been proposed.

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Appendix I: Search Strategy

The following PubMed logic grid was adapted and utilized for all included databases searched, with search limits consisting of only English and Human studies. Oral or Oropharyngeal SCC Dysphagia Primary Free Flap Reconstruction deglutition oropharyngeal neoplasms[mh] OR disorders[mh:noexp] OR surgical flaps[mh] OR deglutition disorder*[tw] oropharyngeal neoplasm*[tw] OR OR free tissue flaps[mh] OR oropharyngeal squamous cell carcinoma*[tw] OR dysphagi*[tw] OR surgical flap*[tw] OR oropharyngeal SCC[tw] OR swallow*[tw] OR tissue flap*[tw] OR oropharyngeal cancer*[tw] OR deglutition[tw] free flap*[tw] OR oropharyngeal carcinoma[tw] OR tissue graft*[tw] OR oropharyngeal tumo*[tw] OR microvascular reconstruction*[tw] OR oropharynx cancer*[tw] OR microsurgical free flap[tw] OR oropharynx neoplasm*[tw] OR recontruct*[tw] oropharynx carcinoma*[tw] OR oropharynx tumo*[tw] OR oropharynx squamous cell carcinoma*[tw] OR oropharynx SCC[tw] OR mouth neoplasms[mh] OR mouth neoplasm*[tw] OR mouth cancer*[tw] OR mouth carcinoma*[tw] OR mouth tumo*[tw] OR mouth SCC[tw] OR mouth squamous cell carcinoma*[tw] OR oral neoplasm*[tw] OR oral cancer*[tw] OR oral carcinoma*[tw] OR oral tumo*[tw] OR

oral SCC[tw] OR oral squamous cell carcinoma*[tw] OR oral cavity neoplasm*[tw] OR oral cavity cancer*[tw] OR oral cavity carcinoma*[tw] OR oral cavity tumo*[tw] OR oral cavity SCC[tw] OR oral cavity squamous cell carcinoma*[tw] OR intraoral neoplasm*[tw] OR intraoral cancer*[tw] OR intraoral carcinoma*[tw] OR intraoral tumo*[tw] OR intraoral SCC[tw] OR intraoral squamous cell carcinoma*[tw]

Pubmed searched 26/03/2015 => 241 - Search limits: English, Humans (((oropharyngeal neoplasms[mh] OR oropharyngeal neoplasm*[tw] OR oropharyngeal squamous cell carcinoma*[tw] OR oropharyngeal SCC[tw] OR oropharyngeal cancer*[tw] OR oropharyngeal carcinoma[tw] OR oropharyngeal tumo*[tw] OR oropharynx cancer*[tw] OR oropharynx neoplasm*[tw] OR oropharynx carcinoma*[tw] OR oropharynx tumo*[tw] OR oropharynx squamous cell carcinoma*[tw] OR oropharynx SCC[tw] OR mouth neoplasms[mh] OR mouth neoplasm*[tw] OR mouth cancer*[tw] OR mouth carcinoma*[tw] OR mouth tumo*[tw] OR mouth SCC[tw] OR mouth squamous cell carcinoma*[tw] OR oral neoplasm*[tw] OR oral cancer*[tw] OR oral carcinoma*[tw] OR oral tumo*[tw] OR oral SCC[tw] OR oral squamous cell carcinoma*[tw] OR oral cavity neoplasm*[tw] OR oral cavity cancer*[tw] OR oral cavity carcinoma*[tw] OR oral cavity tumo*[tw] OR oral cavity SCC[tw] OR oral cavity squamous cell carcinoma*[tw] OR intraoral neoplasm*[tw] OR intraoral cancer*[tw] OR intraoral carcinoma*[tw] OR intraoral tumo*[tw] OR intraoral SCC[tw] OR intraoral squamous cell carcinoma*[tw])) AND (deglutition disorders[mh:noexp] OR deglutition disorder*[tw] OR dysphagi*[tw] OR swallow*[tw] OR deglutition[tw])) AND (surgical flaps[mh] OR free tissue flaps[mh] OR surgical flap*[tw] OR tissue flap*[tw] OR free flap*[tw] OR tissue graft*[tw] OR microvascular reconstruction*[tw] OR microsurgical free flap[tw] OR recontruct*[tw])

Embase searched 26/03/2015 => 120 - Search limits: English, Humans (oropharynx tumor'/syn OR 'oropharynx tumor'/exp OR 'oropharynx cancer':ab,ti OR 'oropharynx cancers':ab,ti OR 'oropharynx carcinoma':ab,ti OR 'oropharynx carcinomas':ab,ti OR 'oropharynx neoplasm':ab,ti OR 'oropharynx neoplasms':ab,ti OR 'oropharynx tumor':ab,ti OR 'oropharynx tumors':ab,ti OR 'oropharynx tumour':ab,ti OR 'oropharynx tumours':ab,ti OR 'oropharynx squamous cell carcinoma':ab,ti OR 'oropharynx squamous cell carcinomas':ab,ti OR 'oropharynx scc':ab,ti OR 'oropharyngeal cancer':ab,ti OR 'oropharyngeal cancers':ab,ti OR 'oropharyngeal carcinoma':ab,ti OR 'oropharyngeal carcinomas':ab,ti OR 'oropharyngeal neoplasm':ab,ti OR 'oropharyngeal neoplasms':ab,ti OR 'oropharyngeal tumor':ab,ti OR 'oropharyngeal tumors':ab,ti OR 'oropharyngeal tumour':ab,ti OR 'oropharyngeal tumours':ab,ti OR 'oropharyngeal squamous cell carcinoma':ab,ti OR 'oropharyngeal squamous cell carcinomas':ab,ti OR 'oropharyngeal scc':ab,ti OR 'mouth tumor'/syn OR 'mouth tumor'/exp OR 'mouth tumour':ab,ti OR 'mouth tumours':ab,ti OR 'mouth tumor':ab,ti OR 'mouth tumors':ab,ti OR 'mouth neoplasm':ab,ti OR 'mouth neoplasms':ab,ti OR 'mouth cancer':ab,ti OR 'mouth cancers':ab,ti OR 'mouth carcinoma':ab,ti OR 'mouth carcinomas':ab,ti OR 'mouth scc':ab,ti OR 'mouth squamous cell carcinoma':ab,ti OR 'mouth squamous cell carcinomas':ab,ti OR 'oral tumour':ab,ti OR 'oral tumours':ab,ti OR 'oral tumor':ab,ti OR 'oral tumors':ab,ti OR 'oral neoplasm':ab,ti OR 'oral neoplasms':ab,ti OR 'oral cancer':ab,ti OR 'oral cancers':ab,ti OR 'oral carcinoma':ab,ti OR 'oral carcinomas':ab,ti OR 'oral scc':ab,ti OR 'oral squamous cell carcinoma':ab,ti OR 'oral squamous cell carcinomas':ab,ti OR 'oral cavity tumour':ab,ti OR 'oral cavity tumours':ab,ti OR 'oral cavity tumor':ab,ti OR 'oral cavity tumors':ab,ti OR 'oral cavity neoplasm':ab,ti OR 'oral cavity neoplasms':ab,ti OR 'oral cavity cancer':ab,ti OR 'oral cavity cancers':ab,ti OR 'oral cavity carcinoma':ab,ti OR 'oral cavity carcinomas':ab,ti OR 'oral cavity scc':ab,ti OR 'oral cavity squamous cell carcinoma':ab,ti OR 'oral cavity squamous cell carcinomas':ab,ti OR 'intraoral tumour':ab,ti OR 'intraoral tumours':ab,ti OR 'intraoral tumor':ab,ti OR 'intraoral tumors':ab,ti OR 'intraoral neoplasm':ab,ti OR 'intraoral neoplasms':ab,ti OR 'intraoral cancer':ab,ti OR 'intraoral cancers':ab,ti OR 'intraoral carcinoma':ab,ti OR 'intraoral carcinomas':ab,ti OR 'intraoral scc':ab,ti OR 'intraoral squamous cell carcinoma':ab,ti OR 'intraoral squamous cell carcinomas':ab,ti) AND (dysphagi*:de,ab,ti OR 'deglutition disorder':ab,ti OR 'deglutition disorders':ab,ti OR swallow*:ab,ti OR deglutition:ab,ti) AND ('free tissue graft':de,ab,ti OR 'free tissue graft'/syn OR 'surgical flap':ab,ti OR 'surgical flaps':ab,ti OR 'free flap':ab,ti OR 'free flaps':ab,ti OR 'tissue graft':ab,ti OR 'tissue grafts':ab,ti OR 'tissue flap':ab,ti OR 'tissue flaps':ab,ti OR 'microvascular

52 reconstruction':ab,ti OR 'microsurgical free flap':ab,ti OR 'microsurgical free flaps':ab,ti OR recontruct:de,ab,ti)

CINAHL Searched 26/03/2015 =>12 - Search limits: English, Humans (MH pharyngeal squamous cell carcinoma* OR AB oropharyngeal squamous cell carcinoma* OR TI oropharyngeal neoplasm* OR AB oropharyngeal neoplasm* OR TI oropharyngeal cancer* OR AB oropharyngeal cancer* OR TI oropharyngeal carcinoma* OR AB oropharyngeal carcinoma* OR TI oropharyngeal tumo* OR AB oropharyngeal tumo* OR TI oropharynx SCC OR AB oropharynx SCC OR TI oropharynx squamous cell carcinoma* OR AB oropharynx squamous cell carcinoma* OR TI oropharynx neoplasm* OR AB oropharynx neoplasm* OR TI oropharynx cancer* OR AB oropharynx cancer* OR TI oropharynx carcinoma* OR AB oropharynx carcinoma* OR TI oropharynx tumo* OR AB oropharynx tumo* MH mouth neoplasms OR TI mouth neoplas* OR AB mouth neoplas* OR TI mouth cancer* OR AB mouth cancer* OR TI mouth carcinoma* OR AB mouth carcinoma* OR TI mouth tumo* OR AB mouth tumo* OR TI mouth SCC OR AB mouth SCC OR TI mouth squamous cell carcinoma* OR AB mouth squamous cell carcinoma* OR TI oral neoplas* OR AB oral neoplas* OR TI oral cancer* OR AB oral cancer* OR TI oral carcinoma* OR AB oral carcinoma* OR TI oral tumo* OR AB oral tumo* OR TI oral SCC OR AB oral SCC OR TI oral squamous cell carcinoma* OR AB oral squamous cell carcinoma* OR TI oral cavity neoplas* OR AB oral cavity neoplas* OR TI oral cavity cancer* OR AB oral cavity cancer* OR TI oral cavity carcinoma* OR AB oral cavity carcinoma* OR TI oral cavity tumo* OR AB oral cavity tumo* OR TI oral cavity SCC OR AB oral cavity SCC OR TI oral cavity squamous cell carcinoma* OR AB oral cavity squamous cell carcinoma* OR TI intraoral neoplas* OR AB intraoral neoplas* OR TI intraoral cancer* OR AB intraoral cancer* OR TI intraoral carcinoma* OR AB intraoral carcinoma* OR TI intraoral tumo* OR AB intraoral tumo* OR TI intraoral SCC OR AB intraoral SCC OR TI intraoral squamous cell carcinoma* OR AB intraoral squamous cell carcinoma* ) AND ( MH deglutition disorder OR TI deglutition disorder* OR AB deglutition disorder* OR TI swallow* OR AB swallow* OR TI deglutition OR AB deglutition OR TI dysphagi* OR AB dysphagi* ) AND ( MH surgical flaps OR TI sugical flap* OR AB surgical flap* OR TI free tissue flap* OR AB free tissue flap* OR TI tissue flap* OR AB tissue flap* OR TI free flap* OR AB free flap* OR TI tissue graft* OR AB tissue graft* OR TI microvascular reconstruction* OR AB microvascular reconstruction* OR TI microsurgical free flap* OR microsurgical free flap* OR TI recontruct* OR AB recontruct* )

Appendix II: Critical Appraisal Instruments

Appendix III: Data Extraction Instruments

Appendix IV: Authors Contacted

Archontaki M, Athanasiou A, Stavrianos SD, Korkolis DP, Faratzis G, Papadopoulou F, et al. Functional results of speech and swallowing after oral microvascular free flap reconstruction. Eur Arch Otorhinolaryngol. 2010;267(11):1771-7. Barata LF, De Carvalho GB, Carrara-De Angelis E, De Faria JCM, Kowalski LP. Swallowing, speech and quality of life in patients undergoing resection of soft palate. Eur Arch Otorhinolaryngol. 2013;270(1):305-12. Brown JS, Rogers SN, Lowe D. A comparison of tongue and soft palate squamous cell carcinoma treated by primary surgery in terms of survival and quality of life outcomes. Int J Oral Maxillofac Surg. 2006;35(3):208-14. Brown L, Rieger JM, Harris J, Seikaly H. A longitudinal study of functional outcomes after surgical resection and microvascular reconstruction for oral cancer: tongue mobility and swallowing function. Journal of Oral & Maxillofacial Surgery (02782391). 2010;68(11):2690-700. Gabr EM, Kobayashi MR, Salibian AH, Armstrong WB, Sundine M, Calvert JW, et al. Oromandibular reconstruction with vascularized free flaps: A review of 50 cases. Microsurgery. 2004;24(5):374-7. Gabr EM, Kobayashi MR, Salibian AH, Armstrong WB, Sundine M, Calvert JW, et al. Role of ulnar forearm free flap in oromandibular reconstruction. Microsurgery. 2004;24(4):285-8. Kalavrezos N, Cotrufo S, Govender R, Rogers P, Pirgousis P, Balasundram S, et al. Factors affecting swallow outcome following treatment for advanced oral and oropharyngeal malignancies. Head Neck. 2014;36(1):47-54. Li W, Li R, Safdar J, Huang S, Xu Z, Tan X, et al. Modified visor approach applied to total or subtotal glossectomy and reconstruction: avoidance of lip splitting and mandibulotomy and cutting off mental nerve. Tumour Biol. 2014;35(8):7847-52. Lv M, Shen Y, Li J, Zhang C, Zhu H, Sun J. Immediate reconstruction of soft palate defects after ablative surgery and evaluation of postoperative function: an analysis of 45 consecutive patients. J Oral Maxillofac Surg. 2014;72(7):1397-406. Markkanen-Leppanen M, Isotalo E, Makitie AA, Rorarius E, Asko-Seljavaara S, Pessi T, et al. Swallowing after free-flap reconstruction in patients with oral and pharyngeal cancer. Oral Oncol. 2006;42(5):501-9. Navach V, Zurlo V, Calabrese L, Massaro MA, Bruschini R, Giugliano G, et al. Total glossectomy with preservation of the larynx: oncological and functional results. Br J Oral Maxillofac Surg. 2013;51(3):217-23. Pierre CS, Dassonville O, Chamorey E, Poissonnet G, Riss JC, Ettaiche M, et al. Long-term functional outcomes and quality of life after oncologic surgery and microvascular reconstruction in patients with oral or oropharyngeal cancer. ActaOtolaryngol. 2014;134(10):1086-93. Vega C, Leon X, Cervelli D, Pons G, Lopez S, Fernandez M, et al. Total or subtotal glossectomy with microsurgical reconstruction: functional and oncological results. Microsurgery. 2011;31(7):517-23. Villaret AB, Cappiello J, Piazza C, Pedruzzi B, Nicolai P. Quality of life in patients treated for cancer of the oral cavity requiring reconstruction: a prospective study. ActaOtorhinolaryngol Ital. 2008;28(3):120-5. Zafereo ME, Weber RS, Lewin JS, Roberts DB, Hanasono MM. Complications and functional outcomes following complex oropharyngeal reconstruction. Head Neck. 2010;32(8):1003-11. Zuydam AC, Lowe D, Brown JS, Vaughan ED, Rogers SN. Predictors of speech and swallowing function following primary surgery for oral and oropharyngeal cancer. ClinOtolaryngol. 2005;30(5):428-37.

Appendix V: Included Studies

Time of Outcome Adjuvant Author Method Population Site Stage Type of Resection Flap Assessment Measures Therapy (Months) Paramedian mandibular Oral tongue, Oral and swing for access Prospective FOM, BOT, II, III, pharyngeal Borggreven3 54 Composite resection with RFFF 6, 12 RT Cohort Tonsil, Soft IV transit time microvascular soft tissue palate Aspiration (PAS) transfer Tracheostomy Dependency Prospective Oral tongue, Partial or total glossectomy RFFF Chien4 29 T3, T4 G-tube 12 CRT Cohort BOT via mandibulotomy ALTF Dependency Aspiration Intraoral soft tissue ablation: Prospective RFFF Farace5 20 Oral cavity T2, T3 Hemiglossectomy, anterior Aspiration 6 Unclear Cohort ALTF pavement ablation Tracheostomy Dependency Retrospective Haddock105 8 Oral tongue III, IV Subtotal or total glossectomy VRAM G-tube 12 RT Case-series Dependency Aspiration RFFF Prospective Oral tongue, Hartl102 5 IV Subtotal or total glossectomy LDF Aspiration 18-83 RT Case-series BOT RMF

Prospective Hemiglossectomy + Hsiao109 4 Oral tongue T2, T3 RFFF Oral transit time 6 CRT Case-series Mandibulotomy

Tumor resection through Tracheostomy Prospective Oral cavity, T2, T3, Keiner18 150 transoral or lateral RFFF Dependency 8-15 RT Cohort Oropharynx T4 pharyngotomy approach Aspiration Oral tongue, Retrospective T1, T2, Li108 51 FOM, Gum, Unclear ALTF UW-QoL 12-84 CRT Case-series T3, T4 Buccal mucosa Anterior total mobile tongue Oral transit time Prospective Longo17 13 Oral tongue T3, T4 resection, subtotal tongue ALTF Tracheostomy 18 RT Cohort resection dependency Tonsil, Soft Prospective WLE of lateral pharyngeal Tracheostomy Moerman106 4 palate, Lateral T2, T3 RFFF 8-21 RT Case-series wall, RMT, Soft palate Dependency pharyngeal wall Tracheostomy BOT, Lateral Lip-splitting incision and Dependency Prospective O'Connell6 20 pharyngeal III, IV presymphyseal RFFF G-tube 12 CRT Cohort wall, Soft palate mandibulotomy dependency Aspiration (PAS) Tracheostomy Dependency G-tube BOT, Lateral Lip-splitting incision and Prospective T1, T2, dependency Preoperatively, Rieger7 32 pharyngeal presymphyseal RFFF CRT Cohort T3, T4 Aspiration (PAS) 1, 6 , 12 wall, Soft palate mandibulotomy Oral and pharyngeal transit time BOT, Lateral Oropharynx resection, lip split G-tube Prospective Seikaly8 18 pharyngeal III, IV incision and parasymphyseal RFFF dependency 1, 6, 9, 12 RT Cohort wall, Soft palate mandibulotomy Aspiration

Partial glossectomy Retrospective performed through peroral Shin9 31 Oral tongue T1, T2 RFFF MDADI 21-91 RT Case-series approach, pull through or paramedian mandibulotomy Resection of tongue base Prospective RFFF, Winter107 6 BOT III, IV with mandibulotomy, per oral UW-QOL 9-56 RT Case-series RMF resection or lingual release BOT: Base of tongue; FOM: Floor of mouth; RMT: Retromolar trigone; WLE: Wide local excision; RFFF: Radial forearm free flap; ALFT: Anterolateral thigh flap; VRAM: Vertical rectus abodminus myocutaneous flap; LDF: Latissimus dorsi flap; RMF: rectus myocutaenous flap; G-tube: Gastrostomy tube; MDADI: MD Anderson Dysphagia Inventory; UW-QOL: University of Washington Quality of Life Questionnaire; S: Surgery; RT: Radiotherapy; CRT: Chemoradiotherapy

Appendix VI: Excluded Studies on Full Text Review

Reason: Follow up Less than 6/12 Butler CE, Lewin JS. Reconstruction of large composite oromandibulomaxillary defects with free vertical rectus abdominismyocutaneous flaps. PlastReconstr Surg. 2004;113(2):499-507. Chepeha DB, Sacco AG, Erickson VR, Lyden T, Haxer M, Moyer J, et al. Oropharyngoplasty with template-based reconstruction of oropharynx defects. Arch Otolaryngol Head Neck Surg. 2009;135(9):887-94. Hara I, Gellrich NC, Duker J, Schon R, Nilius M, Fakler O, et al. Evaluation of swallowing function after intraoral soft tissue reconstruction with microvascular free flaps. Int J Oral Maxillofac Surg. 2003;32(6):593-9. Joo YH, Hwang SH, Park JO, Cho KJ, Kim MS. Functional outcome after partial glossectomy with reconstruction using radial forearm free flap. AurisNasus Larynx. 2013;40(3):303-7. Leymarie N, Karsenti G, Sarfati B, Rimareix F, Kolb F. Modification of flap design for total mobile tongue reconstruction using a sensitive antero-lateral thigh flap. J PlastReconstrAesthet Surg. 2012;65(7):e169-74. McConnel FMS, Logemann JA, Rademaker AW, Pauloski BR, Baker SR, Lewin J, et al. Surgical variables affecting postoperative swallowing efficiency in oral cancer patients: A pilot study. Laryngoscope [Internet]. 1994; 104(1 i):[87-90 pp.]. Available from: http://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/154/CN-00188154/frame.html. McConnel FMS, Pauloski BR, Logemann JA, Rademaker AW, Colangelo L, Shedd D, et al. Functional results of primary closure vs flaps in oropharyngeal reconstruction: A prospective study of speech and swallowing. Arch Otolaryngol Head Neck Surg. 1998;124(6):625-30. Panchal J, Potterton AJ, Scanlon E, McLean NR. An objective assessment of speech and swallowing following free flap reconstruction for oral cavity cancers. Br J Plast Surg. 1996;49(6):363-9. Pauloski BR, Rademaker AW, Logemann JA, McConnel FMS, Heiser MA, Cardinale S, et al. Surgical variables affecting swallowing in patients treated for oral/oropharyngeal cancer. Head Neck. 2004;26(7):625-36. Pazardzhikliev DD, Shipkov CD, Yovchev IP, Khater RH, Kamishev IS. Functional reconstruction of subtotal glossectomy defects with radial forearm free flap: case report and review of literature. Folia Med (Plovdiv). 2012;54(2):60-5. Schache AG, Lieger O, Rogers P, Kelly A, Newman L, Kalavrezos N. Predictors of swallowing outcome in patients treated with surgery and radiotherapy for advanced oral and oropharyngeal cancer. Oral Oncol. 2009;45(9):803-8. Sinha UK, Young P, Hurvitz K, Crockett DM. Functional outcomes following palatal reconstruction with a folded radial forearm free flap. Ear Nose Throat J. 2004;83(1):45-8. Skoner JM, Andersen PE, Cohen JI, Holland JJ, Hansen E, Wax MK. Swallowing function and tracheotomy dependence after combined-modality treatment including free tissue transfer for advanced-stage oropharyngeal cancer. Laryngoscope. 2003;113(8):1294-8. Tsue TT, Desyatnikova SS, Deleyiannis FW, Futran ND, Stack BC, Weymuller EA, et al. Comparison of cost and function in reconstruction of the posterior oral cavity and oropharynx: free vspedicled soft tissue transfer (Structured abstract). Archives of Otolaryngology Head and Neck Surgery [Internet].

1997; 123(7):[731-7 pp.]. Available from: http://onlinelibrary.wiley.com/o/cochrane/cleed/articles/NHSEED-21997001038/frame.html

Uwiera T, Seikaly H, Rieger J, Chau J, Harris JR. Functional outcomes after hemiglossectomy and reconstruction with a bilobed radial forearm free flap. J Otolaryngol. 2004;33(6):356-9. Vigili MG, Bozza F, Bellussi C, Cerro P, Palma O, Pompei S. Use of microvascular free flaps for base of the tongue reconstructions: Functional evaluation by videofluoroscopy. MedecineBiologieEnvironnement. 1997;25(2):163-7.

Reason: Non-FF/Osseous FF Barata LF, De Carvalho GB, Carrara-De Angelis E, De Faria JCM, Kowalski LP. Swallowing, speech and quality of life in patients undergoing resection of soft palate. Eur Arch Otorhinolaryngol. 2013;270(1):305-12. Brown JS, Rogers SN, Lowe D. A comparison of tongue and soft palate squamous cell carcinoma treated by primary surgery in terms of survival and quality of life outcomes. Int J Oral Maxillofac Surg. 2006;35(3):208-14. Cheng N, Shou B, Zheng M, Huang A. Microneurovascular transfer of the tensor fascia latamusculocutaneous flap for reconstruction of the tongue. Ann Plast Surg. 1994;33(2):136-41. Gehanno P, Guedon C, Barry B, Depondt J, Kebaili C. Advanced carcinoma of the tongue: total glossectomy without total laryngectomy. Review of 80 cases. Laryngoscope. 1992;102(12 Pt 1):1369-71. Inoue T, Nagata M, Yukawa H, Ogura M, Fujisawa T, Miyamoto M, et al. Evaluation of postoperative function in patients undergoing reconstruction following resection of superior and lateral oropharyngeal cancer: long-term outcomes of reconstruction with the Gehanno method. Int J Oral Maxillofac Surg. 2012;41(1):9-16. Kobayashi W, Kobayashi M, Hirota W, Kado K, Fukui R, Sato H, et al. Reconstruction of the floor of the mouth using free jejunal grafts. Asian Journal of Oral and Maxillofacial Surgery. 2002;14(4):190- 6. Lv M, Shen Y, Li J, Zhang C, Zhu H, Sun J. Immediate reconstruction of soft palate defects after ablative surgery and evaluation of postoperative function: an analysis of 45 consecutive patients. J Oral Maxillofac Surg. 2014;72(7):1397-406. Mowry SE, Ho A, Lotempio MM, Sadeghi A, Blackwell KE, Wang MB. Quality of life in advanced oropharyngeal carcinoma after chemoradiation versus surgery and radiation. Laryngoscope. 2006;116(9):1589-93. Pierre CS, Dassonville O, Chamorey E, Poissonnet G, Riss JC, Ettaiche M, et al. Long-term functional outcomes and quality of life after oncologic surgery and microvascular reconstruction in patients with oral or oropharyngeal cancer. ActaOtolaryngol. 2014;134(10):1086-93. Robertson MS, Robinson JM, Horsfall RM. A technique of tongue reconstruction following near-total glossectomy. J Laryngol Otol. 1987;101(3):260-5. Rogers SN, Lowe D, Yueh B, WeymullerJr EA. The physical function and social-emotional function subscales of the University of Washington quality of life questionnaire. Arch Otolaryngol Head Neck Surg. 2010;136(4):352-7. Salibian AH, Allison GR, Armstrong WB, Krugman ME, Strelzow VV, Kelly T, et al. Functional hemitongue reconstruction with the microvascular ulnar forearm flap. PlastReconstr Surg. 1999;104(3):654-60.

Su WF, Chen SG, Sheng H. Speech and swallowing function after reconstruction with a radial forearm free flap or a pectoralis major flap for tongue cancer. J Formos Med Assoc. 2002;101(7):472-7. Sultan MR, Coleman JJ, 3rd. Oncologic and functional considerations of total glossectomy. Am J Surg. 1989;158(4):297-302. Tiwari R, Karim AB, Greven AJ, Snow GB. Total glossectomy with laryngeal preservation. Arch Otolaryngol Head Neck Surg. 1993;119(9):945-9. Tiwari R, Snow GB. Role of myocutaneous flaps in reconstruction of the head and neck. J Laryngol Otol. 1983;97(5):441-58. Urade M, Igarashi T, Sugi M, Matsuya T, Fukuda T. Functional recovery of swallowing, speech, and taste in an oral cancer patient with subtotal glossectomy. J Oral Maxillofac Surg. 1987;45(3):282-5. Urken ML, Buchbinder D, Weinberg H, Vickery C, Sheiner A, Parker R, et al. Functional evaluation following microvascularoromandibular reconstruction of the oral cancer patient: A comparative study of reconstructed and nonreconstructed patients. Laryngoscope. 1991;101(9):935-50. Villaret AB, Cappiello J, Piazza C, Pedruzzi B, Nicolai P. Quality of life in patients treated for cancer of the oral cavity requiring reconstruction: a prospective study. ActaOtorhinolaryngol Ital. 2008;28(3):120-5. Yang ZH, Zhang DM, Chen WL, Wang YY, Fan S. Reconstruction of through-and-through oral cavity defects with folded extended vertical lower trapezius island myocutaneous flap. Br J Oral Maxillofac Surg. 2013;51(8):731-5. Zafereo ME, Weber RS, Lewin JS, Roberts DB, Hanasono MM. Complications and functional outcomes following complex oropharyngeal reconstruction. Head Neck. 2010;32(8):1003-11.

Reason: Incorrect Outcome Ahmad NA, Margaret L. Anterolateral thigh free flap in reconstruction of Oral cavity malignancy: Ummc experience. Journal of Health and Translational Medicine. 2008;11(1):33-6. Airoldi M, Garzaro M, Raimondo L, Pecorari G, Giordano C, Varetto A, et al. Functional and psychological evaluation after flap reconstruction plus radiotherapy in oral cancer. Head Neck. 2011;33(4):458-68. Antohi N, Tibirna G, Suharski I, Huian C, Nae S, Stan V, et al. Gastro-omental free flap in oro/hypopharyngeal reconstruction after enlarged ablative surgery for advanced stage cancer. Chirurgia (Bucur). 2013;108(4):503-8. Biglioli F, Brusati R. The folded radial forearm flap in soft-palate and tonsillary fossa reconstruction: technical note. Int J Oral Maxillofac Surg. 2008;37(1):76-81. Brown JS, Zuydam AC, Jones DC, Rogers SN, Vaughan ED. Functional outcome in soft palate reconstruction using a radial forearm free flap in conjunction with a superiorly based pharyngeal flap. Head Neck. 1997;19(6):524-34. Brown L, Rieger JM, Harris J, Seikaly H. A longitudinal study of functional outcomes after surgical resection and microvascular reconstruction for oral cancer: tongue mobility and swallowing function. Journal of Oral & Maxillofacial Surgery (02782391). 2010;68(11):2690-700. Bruschi S, Fraccalvieri M, Bussi M, Cavalot A, Ferrero V, Fava R. Reconstruction of the oral cavity and pharynx with microsurgical flaps after oncological ablation: Our clinical experience. RivistaItaliana di ChirurgiaPlastica. 2002;34(1-2):47-52. Bussu F, Salgarello M, Adesi LB, Rigante M, Parrilla C, Guidi ML, et al. Oral cavity defect reconstruction using anterolateral thigh free flaps. B-ent. 2011;7(1):19-25. Checcoli E, Bianchini C, Ciorba A, Candiani M, Riberti C, Pelucchi S, et al. Reconstructive head and neck surgery: oncological and functional results. Tumori. 2013;99(4):493-9.

Chen F, Liu J, Lv D, Wang L, Liu Y. Reconstruction of the oropharynx with free posterior tibial flap after tonsillar cancer extirpation. J Oral Maxillofac Surg. 2014;72(10):2083-91. Chen WL, Yang ZH, Li JS, Huang ZQ. Reconstruction of the tongue using an extended vertical lower trapezius island myocutaneous flap after removal of advanced tongue cancer. Br J Oral Maxillofac Surg. 2008;46(5):379-82. Cigna E, Rizzo MI, Greco A, De Virgilio A, Palmieri A, Maruccia M, et al. RetromolarTrigone Reconstructive Surgery: Prospective Comparative Analysis Between Free Flaps. Ann SurgOncol. 2014;22(1):272-8. Cipriani R, Contedini F, Caliceti U, Cavina C. Three-dimensional reconstruction of the oral cavity using the free anterolateral thigh flap. PlastReconstr Surg. 2002;109(1):53-7. de Almeida JR, Park RC, Villanueva NL, Miles BA, Teng MS, Genden EM. Reconstructive algorithm and classification system for transoraloropharyngeal defects. Head Neck. 2014;36(7):934-41. de Vicente JC, de Villalaín L, Peña I. Microvascular free tissue transfer for tongue reconstruction after hemiglossectomy: a functional assessment of radial forearm versus anterolateral thigh flap. Journal of Oral & Maxillofacial Surgery (02782391). 2008;66(11):2270-5. Duflo S, Lief F, Paris J, Giovanni A, Thibeault S, Zanaret M. Microvascular radial forearm fasciocutaneous free flap in hard palate reconstruction. Eur J SurgOncol. 2005;31(7):784-91. Elsherbiny M, Mebed A, Mebed H. Microvascular radial forearm fasciocutaneous free flap for palatomaxillary reconstruction following malignant tumor resection. J Egypt NatlCanc Inst. 2008;20(1):90-7. Engel H, Huang JJ, Lin CY, Lam W, Kao HK, Gazyakan E, et al. A strategic approach for tongue reconstruction to achieve predictable and improved functional and aesthetic outcomes. PlastReconstr Surg. 2010;126(6):1967-77. Gende G. The use of a forehead flap to reconstruct the soft and hard palate after cancer excision. P N G Med J. 2011;54(1-2):59-62. Guerin-Lebailly C, Mallet Y, Lambour V, Fournier C, El Bedoui S, Ton Van J, et al. Functional and sensitive outcomes after tongue reconstruction: about a series of 30 patients. Oral Oncol. 2012;48(3):272-7. Hara I, Gellrich NC, Duker J, Schon R, Fakler O, Smelzeisen R, et al. Swallowing and speech function after intraoral soft tissue reconstruction with lateral upper arm free flap and radial forearm free flap. Br J Oral Maxillofac Surg. 2003;41(3):161-9. Hsiao HT, Leu YS, Lin CC. Primary closure versus radial forearm flap reconstruction after hemiglossectomy: functional assessment of swallowing and speech. Ann Plast Surg. 2002;49(6):612- 6. Hsiao HT, Leu YS, Lin CC. Tongue reconstruction with free radial forearm flap after hemiglossectomy: a functional assessment. J ReconstrMicrosurg. 2003;19(3):137-42. Hsiao HT, Leu YS, Liu CJ, Tung KY, Lin CC. Radial forearm versus anterolateral thigh flap reconstruction after hemiglossectomy: functional assessment of swallowing and speech. J ReconstrMicrosurg. 2008;24(2):85-8. Kang HG, Park MC, Lim H, Kim JH, Lee IJ. Modified folding radial forearm flap in soft palate and tonsillar fossa reconstruction. J Craniofac Surg. 2013;24(2):458-60. Ko AB, Lavertu P, Rezaee RP. Double bilobed radial forearm free flap for anterior tongue and floor- of-mouth reconstruction. Ear Nose Throat J. 2010;89(4):177-9. Koshima I, Hosoda M, Moriguchi T, Kawada S. New multilobe "accordion" flaps for three-dimensional reconstruction of wide, full-thickness defects in the oral floor. Ann Plast Surg. 2000;45(2):187-92.

LaFerriere KA, Sessions DG, Thawley SE, Wood BG, Ogura JH. Composite resection and reconstruction for oral cavity and oropharynx cancer. A functional approach. Arch Otolaryngol. 1980;106(2):103-10. Lew DH, Choi EC, Tark KC. Standardization of flap design for oropharyngeal reconstruction after cancer ablation surgery. Yonsei Med J. 2003;44(6):1078-82. Longo B, Ferri G, Fiorillo A, Rubino C, Santanelli F. Bilobed perforator free flaps for combined hemitongue and floor-of-the-mouth defects. J PlastReconstrAesthet Surg. 2013;66(11):1464-9. McCombe D, Lyons B, Winkler R, Morrison W. Speech and swallowing following radial forearm flap reconstruction of major soft palate defects. Br J Plast Surg. 2005;58(3):306-11. McConnel FM, Teichgraeber JF, Adler RK. A comparison of three methods of oral reconstruction. Arch Otolaryngol Head Neck Surg. 1987;113(5):496-500. Roh TS, Lee WJ, Choi EC, Koh YW, Lew DH. Radial forearm-palmarislongustenocutaneous free flap; implication in the repair of the moderate-sized postoncologic soft palate defect. Head Neck. 2009;31(9):1220-7. Salibian AH, Allison GR, Krugman ME, Strelzow VV, Brugman JJ, Rappaport I, et al. Reconstruction of the base of the tongue with the microvascular ulnar forearm flap: a functional assessment. PlastReconstr Surg. 1995;96(5):1081-9; discussion 90-1. Schliephake H, Jamil MU. Impact of intraoral soft-tissue reconstruction on the development of quality of life after ablative surgery in patients with oral cancer. PlastReconstr Surg. 2002;109(2):421-30; discussion 31-2. Schliephake H, Ruffert K, Schneller T. Prospective study of the quality of life of cancer patients after intraoral tumor surgery. J Oral Maxillofac Surg. 1996;54(6):664-9; discussion 9-70. Sharma M, Iyer S, Kuriakose MA, Vijayaraghavan S, Arun P, Sudhir VR, et al. Functional reconstruction of near total glossectomy defects using composite gastro omental-dynamic gracilis flaps. J PlastReconstrAesthet Surg. 2009;62(10):1277-80. Stern JR, Keller AJ, Wenig BL. Evaluation of reconstructive techniques of oropharyngeal defects. Ann Plast Surg. 1989;22(4):332-6. Su WF, Hsia YJ, Chang YC, Chen SG, Sheng H. Functional comparison after reconstruction with a radial forearm free flap or a pectoralis major flap for cancer of the tongue. Otolaryngol Head Neck Surg. 2003;128(3):412-8. Tai SR, Won JL, Eun CC, Yoon WK, Dae HL. Radial forearm-palmarislongustenocutaneous free flap; implication in the repair of the moderate-sized postoncologic soft palate defect. Head Neck. 2009;31(9):1220-7. Tarsitano A, Vietti MV, Cipriani R, Marchetti C. Functional results of microvascular reconstruction after hemiglossectomy: free anterolateral thigh flap versus free forearm flap. ActaOtorhinolaryngol Ital. 2013;33(6):374-9. Tiwari RM, van Ardenne A, Leemans CR, Quak JJ, Tobi H, Mehta DM, et al. Advanced squamous cell carcinoma of the base of the tongue treated with surgery and post-operative radiotherapy. Eur J SurgOncol. 2000;26(6):556-60. Yokoo S, Komori T, Furudoi S, Shibuya Y, Umeda M, Ichinose A, et al. Indications for vascularized free rectus abdominismusculocutaneous flap in oromandibular region in terms of efficiency of anterior rectus sheath. Microsurgery. 2003;23(2):96-102.

Reason: Incorrect Population Anain SA, Yetman RJ. The fate of intraoral free muscle flaps: is skin necessary? PlastReconstr Surg. 1993;91(6):1027-31.

Archontaki M, Athanasiou A, Stavrianos SD, Korkolis DP, Faratzis G, Papadopoulou F, et al. Functional results of speech and swallowing after oral microvascular free flap reconstruction. Eur Arch Otorhinolaryngol. 2010;267(11):1771-7. Bianchi B, Ferri A, Ferrari S, Copelli C, Boni P, Baj A, et al. Reconstruction of lateral through and through oro-mandibular defects following oncological resections. Microsurgery. 2010;30(7):517-25. Bianchi B, Ferri A, Ferrari S, Copelli C, Boni P, Sesenna E. Reconstruction of anterior through and through oromandibular defects following oncological resections. Microsurgery. 2010;30(2):97-104. Bodin IK, Lind MG, Arnander C. Free radial forearm flap reconstruction in surgery of the oral cavity and pharynx: surgical complications, impairment of speech and swallowing. ClinOtolaryngol Allied Sci. 1994;19(1):28-34. Caliceti U, Piccin O, Sgarzani R, Negosanti L, Fernandez IJ, Nebiaj A, et al. Surgical strategies based on standard templates for microsurgical reconstruction of oral cavity and oropharynx soft tissue: a 20 years' experience. Microsurgery. 2013;33(2):90-104. Chepeha DB, Teknos TN, Shargorodsky J, Sacco AG, Lyden T, Prince ME, et al. Rectangle tongue template for reconstruction of the hemiglossectomy defect. Arch Otolaryngol Head Neck Surg. 2008;134(9):993-8. Cocks HC, Kumar BN, Das Gupta AR, Simms MH. Free jejunal patch flaps in oral and oropharyngeal reconstruction. J Laryngol Otol. 1999;113(7):680-2. Furia CL, Carrara-de Angelis E, Martins NM, Barros AP, Carneiro B, Kowalski LP. Video fluoroscopic evaluation after glossectomy. Arch Otolaryngol Head Neck Surg. 2000;126(3):378-83. Gabr EM, Kobayashi MR, Salibian AH, Armstrong WB, Sundine M, Calvert JW, et al. Role of ulnar forearm free flap in oromandibular reconstruction. Microsurgery. 2004;24(4):285-8. Gabr EM, Kobayashi MR, Salibian AH, Armstrong WB, Sundine M, Calvert JW, et al. Oromandibular reconstruction with vascularized free flaps: A review of 50 cases. Microsurgery. 2004;24(5):374-7. Gellrich NC, Kwon TG, Lauer G, Fakler O, Gutwald R, Otten JE, et al. The lateral upper arm free flap for intraoral reconstruction. Int J Oral Maxillofac Surg. 2000;29(2):104-11. Guerin-Lebailly C, Mallet Y, Lambour V, Fournier C, El Bedoui S, Ton Van J, et al. Functional and sensitive outcomes after tongue reconstruction: about a series of 30 patients. Oral Oncol. 2012;48(3):272-7. Hartl DM, Kolb F, Bretagne E, Bidault F, Sigal R. Cine-MRI swallowing evaluation after tongue reconstruction. Eur J Radiol. 2010;73(1):108-13. Haughey BH. Tongue reconstruction: concepts and practice. Laryngoscope. 1993;103(10):1132-41. Haughey BH, Taylor SM, Fuller D. Fasciocutaneous flap reconstruction of the tongue and floor of mouth: outcomes and techniques. Arch Otolaryngol Head Neck Surg. 2002;128(12):1388-95. Julieron M, Kolb F, Schwaab G, Luboinski B. Reconstruction of the posterior pharyngeal wall after tumoral resection sparing the larynx. MedecineBiologieEnvironnement. 1997;25(2):149-53. Kalavrezos N, Cotrufo S, Govender R, Rogers P, Pirgousis P, Balasundram S, et al. Factors affecting swallow outcome following treatment for advanced oral and oropharyngeal malignancies. Head Neck. 2014;36(1):47-54. Kimata Y, Uchiyama K, Ebihara S, Saikawa M, Hayashi R, Haneda T, et al. Postoperative complications and functional results after total glossectomy with microvascular reconstruction. PlastReconstr Surg. 2000;106(5):1028-35. Lazarus C, Husaini H, Jacobson A, Mojica J, Anand S, Urken M. Tongue strength, functional outcomes and quality of life after oral cancer surgery. Dysphagia. 2012;27(4):602. Li W, Li R, Safdar J, Huang S, Xu Z, Tan X, et al. Modified visor approach applied to total or subtotal glossectomy and reconstruction: avoidance of lip splitting and mandibulotomy and cutting off mental nerve. Tumour Biol. 2014;35(8):7847-52.

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Yu P. Reinnervated anterolateral thigh flap for tongue reconstruction. Head Neck. 2004;26(12):1038- 44. Yun IS, Lee DW, Lee WJ, Lew DH, Choi EC, Rah DK. Correlation of neotongue volume changes with functional outcomes after long-term follow-up of total glossectomy. J Craniofac Surg. 2010;21(1):111- 6. Zuydam AC, Lowe D, Brown JS, Vaughan ED, Rogers SN. Predictors of speech and swallowing function following primary surgery for oral and oropharyngeal cancer. ClinOtolaryngol. 2005;30(5):428-37. Zuydam AC, Rogers SN, Brown JS, Vaughan ED, Magennis P. Swallowing rehabilitation after oropharyngeal resection for squamous cell carcinoma. Br J Oral Maxillofac Surg. 2000;38(5):513-8.

Reason: Incorrect Study Design Dziegielewski PT, Ho ML, Rieger J, Singh P, Langille M, Harris JR, et al. Total glossectomy with laryngeal preservation and free flap reconstruction: objective functional outcomes and systematic review of the literature. Laryngoscope. 2013;123(1):140-5. Lam L, Samman N. Speech and swallowing following tongue cancer surgery and free flap reconstruction--a systematic review. Oral Oncol. 2013;49(6):507-24.

Reason: Poster Presentation Haddock NT, DeLacure MD, Saadeh PB. Less is more: VRAM inset modification in glossectomy reconstruction. PlastReconstr Surg. 2008;122(2):70e-2e. Shin YS, Kim WS, Lee HS, Hong HJ, Kim SH, Koh YW, et al. Radiation deteriorates functional outcome after glossectomy. Otolaryngology - Head and Neck Surgery. 2011;145:177-8. Bussu F, Almadori G, Parrilla C, Salgarello M, BaroneAdesi L, Micciche F, et al. Evolution of the surgical approach to oral squamous cell carcinoma in a single institution. Decisive impact of the improvement of the reconstructive techniques evaluated on a series of 106 patients between 2004 and 2009. RadiotherOncol. 2011;98:S29. Cho YH, Song CM, Ji YB, Tae K. Functional outcomes after oral tongue cancer surgery: Determination of optimal reconstruction method. Oral Oncol. 2013;49:S82. Dedivitis RA. Long term cosmetic and functional results of reconstruction using myocutaneous and free flaps. Oral Oncol. 2011;47:S20. O'Connell DA, Reiger J, Dziegielewski PT, Tang JL, Wolfaardt J, Harris JR, et al. Effect of lingual and hypoglossal nerve reconstruction on swallowing function in head and neck surgery: Prospective functional outcomes study. Journal of Otolaryngology - Head and Neck Surgery. 2009;38(2):246-54.

Ryuichi Hayashi MD. Surgical treatment for advanced tongue cancer. Oral Oncol. 2011;47:S16. Shenoy AM, Krishna A, Shenoy P, Premalatha, Rahul, Sharath. Challenges in rehabilitation after sub-total and total glossectomy with laryngeal preservation. Oral Oncol. 2011;47:S20. Shockley R, Johnston B, Netterville JL, Rohde SL. Survival and functional outcomes following total glossectomy. Otolaryngology - Head and Neck Surgery (United States). 2013;149(2):P197.

Appendix VII: Dysphagia Risk Stratification Tool

Dysphagia Risk Stratification Tool

Low Risk Patients High Risk Patients  Early Stage (T1 and T2)  Late Stage (T3 and T4)  No evidence of regional or distant  Resections involving metastases combinations of the BOT,  No postoperative CRT oral tongue or soft palate  Postoperative CRT  Swallowing exercises pre- during treatment

Pre-operative Evaluations Pre-operative Evaluations  Subjective Quality of Life  Subjective Quality of Life Questionnaires (MDADI, UW-QoL) Questionnaires (MDADI, UW-QoL)  FEES with PAS  FEES with PAS  VFSS

Post-operative Evaluations  Subjective Quality of Life Post-operative Evaluations Questionnaires (MDADI, UW-QoL)  Subjective Quality of Life  FEES with PAS Questionnaires (MDADI, UW-QoL)  FEES with PAS  VFSS Every 6 months

CRT: Chemoradiotherapy, MDADI: MD Anderson Dysphagia Inventory, UW-QoL: University of Washington Quality of Life Questionnaire, FEES: Fibreoptic endoscopic evaluations of swallowing, VFSS: Videofluoroscopy swallowing study, PAS: Penetration-aspiration scale