i

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

ii

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.

iii

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.

iv

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.

v

vi

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

vii

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

1

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.

2

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

3

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

4

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

5

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

6

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

7

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

8

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

9

Table 2. Summary of Objective Swallowing Assessments

Evaluation Method Items Assessed Advantages Disadvantages

Videofluoroscopic

Swallowing Study

(VFSS)66

Visualization of

bolus flow

Bolus transit time

Structural movement

of related anatomical

structures

Presence and timing

of aspiration

Non-invasive

procedure

Reproducible

Can assess the

pharyngeal and

esophageal phase

Radiation exposure

Requires

fluoroscopy suite

Functional Endoscopic

Evaluation of Swallowing

(FEES)67

Testing laryngeal

sensitivity

Static and dynamic

evaluation of

structures in the

upper airways

Presence of

aspiration

Bedside examination

Easy to perform

Well tolerated

Economical

Discomfort, gagging

Adverse reactions to

topical anesthetics

Operator dependent

Can only assess

post pharyngeal

swallowing

Manometry68 Upper esophageal

sphincter relaxation

Pharyngeal

peristalsis

Intrabolus pressure

No radiation

exposure

Specialized and

experienced staff

Adverse reactions to

topical anesthetics

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

10

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

(MDADI)

Global

Emotional

Functional

Physical

University of Washington Quality of Life

Questionnaire (UW-QoL)

Pain

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.

11

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

12

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

13

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

14

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

15

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

16

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

17

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.

18

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.

19

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

20

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

21

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

22

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).

23

Figure 2. PRISMA Flow diagram illustrating the process of including and excluding studies

from the systematic review.1 Number of studies found and retrieved

Iden

tifi

cati

on

S

cree

nin

g

Incl

ud

ed

Elig

ibili

ty

Full text retrieved for detailed examination n = 150

Full-text articles excluded, with reasons

n = 135

Reasons:

Incorrect population

n = 44

Incorrect study design n = 2

Incorrect outcome

n = 43

Follow up <6/12 n = 16

Non- Free Flap/Osseous Flap

n = 21

Poster n = 9

Studies Assessed for methodological quality n = 15

Cohort Studies n = 8

Records identified through database searching, English only

n = 699

Records after duplicates removed n = 420

Duplicates excluded n = 279

Studies Included in this review

n = 15

Records excluded after review of title and abstract

n = 270

Case-Series n = 7

24

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.

25

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 per-

oral approach.

26

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

27

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.

28

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

RFFF: Radial forearm free flap; S: Surgery; RT: Radiotherapy

Table 7. UW-QoL Scores

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

Study Site Population Stage Flap Treatment

Regime

Evaluation

Time

(Months)

MDADI

Score

Surgery

only

MDADI

Score

Surgery + RT

Shin9 Oral

tongue

31 T1, T2 RFFF S + RT 21-91 80.5 +/-

10.9

64.77 +/-

16.34

Study Site Population Stage Flap Treatment

Regime

Evaluation

Time

(Months)

UW-QoL

Score

Li108 Oral Tongue,

FOM, Gum,

Buccal

mucosa

51 T1, T2,

T3, T4

ALTF S + CRT 12-84 49

Winter107 BOT 6 III, IV RFFF, RMF S + RT 9-56 63.33

29

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

30

Objective Assessments

Aspiration

Table 8. Summary of Aspiration

Study Site Population Stage Free

Flap

Treatment

Regime

Aspiration

@ Preop

Aspiration

@ 6/12

Aspiration

@ 12/12

Borggreven3 Oral tongue,

FOM, BOT,

Tonsil, Soft

palate

54 II, III, IV RFFF S + RT - L-18 (34%) L-14 (25%)

Chien4 Oral tongue,

BOT

29 T3, T4 RFFF,

ALTF

S + CRT - - 9 (31%)

Farace5 Oral cavity 20 T2, T3 ALTF,

RFFF

S - 0 (0%) -

Haddock105 Oral tongue 8 III, IV VRAM S + RT - - 0 (0%)

Hartl102 Oral tongue,

BOT

5 IV RFFF,

LDF,

RMF

S + RT - - 2 (40%)

Keiner18 Oral 49 T2, T3,

T4

RFFF S + RT - - 0 (0%)

Oropharynx 101 T2, T3,

T4

RFFF S + RT - - 0 (0%)

O’Connell6 BOT, Lateral

pharyngeal

wall, Soft

palate

36 III, IV RFFF S+ CRT - - P-1(3%)

Rieger7 BOT, Lateral

pharyngeal

wall, Soft

palate

32 T1, T2,

T3, T3

RFFF S + CRT L-0 (0%)

P-0(0%)

L-5 (21%)

P-4 (17%)

L-4 (21%)

P-1 (19%)

Seikaly8 BOT, Lateral

pharyngeal

wall, Soft

palate

18 III, IV RFFF S + RT - - L-3 (17%)

P-2 (11%)

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

31

Gastrostomy Tube Dependency

Table 9: Summary of Gastrostomy Dependency

Study Malignancy

Site

Population Stage Flap Treatment

Regime

Evaluation

Time

(Months)

Gastrostomy

Chien4 Oral tongue,

BOT

29 T3, T4 RFFF, ALTF S + CRT 12 3 (10%)

Haddock105 Oral tongue 8 III, IV VRAM S + RT 12 0 (0%)

Hartl102 Oral tongue,

BOT

5 IV RFFF, LDF, RMF S + RT 24 1 (20%)

O’Connell6 BOT, Lateral

pharyngeal

wall, Soft

palate

36 III, IV RFFF S+ RT 12 4 (11%)

Rieger7 BOT, Lateral

pharyngeal

wall, Soft

palate

32 T1, T2, T3, T4 RFFF S + CRT 6 - 12 3 (9%)

Seikaly8 BOT, Lateral

pharyngeal

wall, Soft

palate

18 III, IV RFFF S + RT 6 - 9 1 (6%)

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

32

Tracheostomy Dependency

Table 10: Summary of Tracheostomy Dependency

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

Study Malignancy

Site

Population Stage Flap Treatment

Regime

Evaluation

Time

(Months)

Tracheostomy

Chien4 Oral tongue,

BOT

29 T3, T4 RFFF,

ALTF

S + CRT 12 1 (3%)

Haddock105 Oral tongue 8 III, IV VRAM S 12 0 (0%)

Keiner18 Oral cavity 49 T2,

T3, T4

RFFF S + RT 8-15 0 (0%)

Oropharynx 101 T2,

T3, T4

RFFF S + RT 8-15 1 (2.9%)

Longo17 Oral tongue 13 T3, T4 ALTF S + RT 6-18 0 (0%)

Moerman106 Tonsil, Soft

palate, Lateral

pharyngeal

wall

4 T2, T3 RFFF S+ RT 8-21 0 (0%)

O’Connell6 BOT, Lateral

pharyngeal

wall, Soft

palate

36 III, IV RFFF S + RT 12 0 (0%)

Rieger7 BOT, Lateral

pharyngeal

wall, Soft

palate

32 T1,

T2,

T3, T4

RFFF S + CRT 6 – 12 0 (0%)

33

Oral and pharyngeal transit time

Table 11: Summary of oral and pharyngeal transit time

Study Site Population Stage Flap Treatment

Regime

OT

T @

Pre

op

(s)

OTT

@

6/12

(s)

OTT

@

12/12

(s)

PTT

@

Preo

p (s)

PTT

@

6/12

(s)

PTT

@ 12

/12

(s)

Borggreven3 Oral tongue,

FOM, BOT,

Tonsil, Soft

Palate

54 II, III, IV RFFF S + RT - 0.56

+/-

0.38

0.52

+/-

0.48

- 1.04

+/-

0.41

1.09

+/-

0.48

Farace5 Oral cavity 20 T2, T3 RFFF

ALTF

Unclear - <10 - - - -

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

pharyngeal

wall, Soft

palate

32 T1, T2,

T3, T4

RFFF S + CRT 0.8

0

+/-

1.0

1

1.16

+/-

1.43

1.24

+/-

1.20

0.94

+/-

0.47

1.27

+/-

1.00

1.96

+/-

2.14

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

34

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

35

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.

36

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

37

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

38

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

39

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

40

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.

41

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.

42

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.

43

References

1. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. Ann Intern Med. 2009;151(4):264-9.

2. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, DM P. GLOBOCAN 2008 v2, cancer incidence and mortality worldwide: IARC cancerbase No. 10 Lyon (France): International Agency for Research on Cancer 2010.

3. Borggreven PA, Verdonck-De Leeuw IM, Rinkel RN, Langendijk JA, Roos JC, David EFL, et al. Swallowing after major surgery of the oral cavity or oropharynx: A prospective and longitudinal assessment of patients treated by microvascular soft tissue reconstruction. Head Neck. 2007;29(7):638-47.

4. Chien CY, Su CY, Hwang CF, Chuang HC, Jeng SF, Chen YC. Ablation of advanced tongue or base of tongue cancer and reconstruction with free flap: functional outcomes. Eur J Surg Oncol. 2006;32(3):353-7.

5. Farace F, Fois VE, Manconi A, Puddu A, Stomeo F, Tullio A, et al. Free anterolateral thigh flap versus free forearm flap: Functional results in oral reconstruction. J Plast Reconstr Aesthet Surg. 2007;60(6):583-7.

6. O'Connell DA, Rieger J, Harris JR, Dziegielewski P, Zalmanowitz J, Sytsanko A, et al. Swallowing function in patients with base of tongue cancers treated with primary surgery and reconstructed with a modified radial forearm free flap. Arch Otolaryngol Head Neck Surg. 2008;134(8):857-64.

7. Rieger JM, Zalmanowitz JG, Li SY, Sytsanko A, Harris J, Williams D, et al. Functional outcomes after surgical reconstruction of the base of tongue using the radial forearm free flap in patients with oropharyngeal carcinoma. Head Neck. 2007;29(11):1024-32.

8. Seikaly H, Rieger J, Wolfaardt J, Moysa G, Harris J, Jha N. Functional outcomes after primary oropharyngeal cancer resection and reconstruction with the radial forearm free flap. Laryngoscope. 2003;113(5):897-904.

9. Shin YS, Kim WS, Koh YW, Hong HJ, Lee SY, Choi EC. Radiotherapy deteriorates post-operative functional outcome after partial glossectomy with free flap reconstruction. Oral Oncol. 2011;47:S31-S2.

10. Huber MA, Tantiwongkosi B. Oral and oropharyngeal cancer. Med Clin North Am. 2014;98(6):1299-321.

11. Hashibe M, Sturgis EM. Epidemiology of oral-cavity and oropharyngeal carcinomas: controlling a tobacco epidemic while a human papillomavirus epidemic emerges. Otolaryngol Clin North Am. 2013;46(4):507-20.

12. Gillison ML. Human papillomavirus-related diseases: oropharynx cancers and potential implications for adolescent HPV vaccination. J Adolesc Health. 2008;43(4 Suppl):S52-60.

13. Amano O, Mizobe K, Bando Y, Sakiyama K. Anatomy and Histology of Rodent and Human Major Salivary Glands: —Overview of the Japan Salivary Gland Society-Sponsored Workshop—. Acta Histochemica et Cytochemica. 2012;45(5):241-50.

14. Holmberg KV, Hoffman MP. Anatomy, biogenesis, and regeneration of salivary glands. Monogr Oral Sci. 2014;24:1-13.

15. Drake RL, Vogl AW, Mitchell AWM, H. G. Gray's anatomy for students. Philadelphia, PA: Churchill Livingstone; 2010.

16. Matsuo K, Palmer JB. Anatomy and physiology of feeding and swallowing: normal and abnormal. Phys Med Rehabil Clin N Am. 2008;19(4):691-707, vii.

17. Longo B, Pagnoni M, Ferri G, Morello R, Santanelli F. The mushroom-shaped anterolateral thigh perforator flap for subtotal tongue reconstruction. Plast Reconstr Surg. 2013;132(3):656-65.

18. Keiner S, Bootz F, Flisek J, Fuchs M. Reconstructive surgery after tumor resection in the oral cavity and oropharynx. Onkologie. 2000;23(3):240-4.

44

19. McConnel FM, 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.

20. Nguyen NP, Sallah S, Karlsson U, Antoine JE. Combined chemotherapy and radiation therapy for head and neck malignancies: quality of life issues. Cancer. 2002;94(4):1131-41.

21. Pauloski BR, Logemann JA, Fox JC, Colangelo LA. Biomechanical analysis of the pharyngeal swallow in postsurgical patients with anterior tongue and floor of mouth resection and distal flap reconstruction. J Speech Hear Res. 1995;38(1):110-23.

22. Gaziano JE. Evaluation and management of oropharyngeal Dysphagia in head and neck cancer. Cancer Control. 2002;9(5):400-9.

23. Naidu MUR, Ramana GV, Rani PU, Mohan IK, Suman A, Roy P. Chemotherapy-Induced and/or Radiation Therapy-Induced Oral Mucositis—Complicating the Treatment of Cancer. Neoplasia (New York, NY). 2004;6(5):423-31.

24. Arcuri MR, Schneider RL. The physiological effects of radiotherapy on oral tissue. J Prosthodont. 1992;1(1):37-41.

25. Vissink A, Jansma J, Spijkervet FK, Burlage FR, Coppes RP. Oral sequelae of head and neck radiotherapy. Crit Rev Oral Biol Med. 2003;14(3):199-212.

26. Jensen SB, Pedersen AM, Vissink A, Andersen E, Brown CG, Davies AN, et al. A systematic review of salivary gland hypofunction and xerostomia induced by cancer therapies: prevalence, severity and impact on quality of life. Support Care Cancer. 2010;18(8):1039-60.

27. Chambers MS, Garden AS, Kies MS, Martin JW. Radiation-induced xerostomia in patients with head and neck cancer: pathogenesis, impact on quality of life, and management. Head Neck. 2004;26(9):796-807.

28. Dysphagia Section OCSGMAoSCiCISoOO, Raber-Durlacher JE, Brennan MT, Verdonck-de Leeuw IM, Gibson RJ, Eilers JG, et al. Swallowing dysfunction in cancer patients. Support Care Cancer. 2012;20(3):433-43.

29. 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.

30. Bensadoun RJ, Riesenbeck D, Lockhart PB, Elting LS, Spijkervet FK, Brennan MT, et al. A systematic review of trismus induced by cancer therapies in head and neck cancer patients. Support Care Cancer. 2010;18(8):1033-8.

31. Nagarajan K. Chemo-radiotherapy induced oral mucositis during IMRT for head and neck cancer - An assessment. Med Oral Patol Oral Cir Bucal. 2015;20(3):e273-e7.

32. International Union Against Cancer (UICC). TNM Classification of Malignant Tumours. 7th ed. Sobin LH, Gospodarowicz MK, Wittekind C, editors. Oxford: Wiley-Blackwell 2009. 336 p.

33. Edge SB, Compton CC. The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol. 2010;17(6):1471-4.

34. Webber C, Gospodarowicz M, Sobin LH, Wittekind C, Greene FL, Mason MD, et al. Improving the TNM classification: findings from a 10-year continuous literature review. Int J Cancer. 2014;135(2):371-8.

35. Ang KK, Harris J, Wheeler R, Weber R, Rosenthal DI, Nguyen-Tan PF, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med. 2010;363(1):24-35.

36. Weinstein GS, O'Malley BW, Jr., Cohen MA, Quon H. Transoral robotic surgery for advanced oropharyngeal carcinoma. Arch Otolaryngol Head Neck Surg. 2010;136(11):1079-85.

37. Patel SG, Shah JP. TNM staging of cancers of the head and neck: striving for uniformity among diversity. CA Cancer J Clin. 2005;55(4):242-58; quiz 61-2, 64.

45

38. Moncrieff M, Sandilla J, Clark J, Clifford A, Shannon K, Gao K, et al. Outcomes of primary surgical treatment of T1 and T2 carcinomas of the oropharynx. Laryngoscope. 2009;119(2):307-11.

39. Givens DJ, Karnell LH, Gupta AK, Clamon GH, Pagedar NA, Chang KE, et al. Adverse events associated with concurrent chemoradiation therapy in patients with head and neck cancer. Arch Otolaryngol Head Neck Surg. 2009;135(12):1209-17.

40. Moose BD, Kelly MD, Levine PA, Constable WC, Cantrell RW, Larner JM. Definitive radiotherapy for T1 and T2 squamous cell carcinoma of the tonsil. Head Neck. 1995;17(4):334-8.

41. Gourin CG, Johnson JT. A contemporary review of indications for primary surgical care of patients with squamous cell carcinoma of the head and neck. Laryngoscope. 2009;119(11):2124-34.

42. Garden AS, Dong L, Morrison WH, Stugis EM, Glisson BS, Frank SJ, et al. Patterns of disease recurrence following treatment of oropharyngeal cancer with intensity modulated radiation therapy. Int J Radiat Oncol Biol Phys. 2013;85(4):941-7.

43. Gillespie MB, Brodsky MB, Day TA LF, B. M-H. Swallowing-related quality of life after head and neck cancer treatment. Laryngoscope. 2004;114(8):1362-7.

44. Bernier J, Domenge C, Ozsahin M, Matuszewska K, Lefebvre JL, Greiner RH, et al. Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med. 2004;350(19):1945-52.

45. Frowen JJ, Perry AR. Swallowing outcomes after radiotherapy for head and neck cancer: a systematic review. Head Neck. 2006;28(10):932-44.

46. de Almeida JR, Byrd JK, Wu R, Stucken CL, Duvvuri U, Goldstein DP, et al. A systematic review of transoral robotic surgery and radiotherapy for early oropharynx cancer: a systematic review. Laryngoscope. 2014;124(9):2096-102.

47. Duek I, Billan S, Amit M, Gil Z. Transoral Robotic Surgery in the HPV Era. Rambam Maimonides Med J. 2014;5(2):e0010.

48. Hutcheson KA, Holsinger FC, Kupferman ME, Lewin JS. Functional outcomes after TORS for oropharyngeal cancer: a systematic review. Eur Arch Otorhinolaryngol. 2015;272(2):463-71.

49. Chim H, Salgado CJ, Seselgyte R, Wei F-C, Mardini S. Principles of Head and Neck Reconstruction: An Algorithm to Guide Flap Selection. Semin Plast Surg. 2010;24(2):148-54.

50. Hanasono MM. Reconstructive Surgery for Head and Neck Cancer Patients. Advances in Medicine. 2014;2014:795483.

51. 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.

52. Urken ML, Buchbinder D, Costantino PD, Sinha U, Okay D, Lawson W, et al. Oromandibular reconstruction using microvascular composite flaps: report of 210 cases. Arch Otolaryngol Head Neck Surg. 1998;124(1):46-55.

53. Hutcheson KA, Lewin JS, Barringer DA, Lisec A, Gunn GB, Moore MW, et al. Late dysphagia after radiotherapy-based treatment of head and neck cancer. Cancer. 2012;118(23):5793-9.

54. Dijkstra PU, Huisman PM, Roodenburg JL. Criteria for trismus in head and neck oncology. Int J Oral Maxillofac Surg. 2006;35(4):337-42.

55. Langendijk JA, Doornaert P, Rietveld DH, Verdonck-de Leeuw IM, Leemans CR, Slotman BJ. A predictive model for swallowing dysfunction after curative radiotherapy in head and neck cancer. Radiother Oncol. 2009;90(2):189-95.

56. Rusthoven KE, Raben D, Ballonoff A, Kane M, Song JI, Chen C. Effect of radiation techniques in treatment of oropharynx cancer. Laryngoscope. 2008;118(4):635-9.

57. Lawson JD, Otto K, Chen A, Shin DM, Davis L, Johnstone PA. Concurrent platinum-based chemotherapy and simultaneous modulated accelerated radiation therapy for locally advanced squamous cell carcinoma of the tongue base. Head Neck. 2008;30(3):327-35.

46

58. de Arruda FF, Puri DR, Zhung J, Narayana A, Wolden S, Hunt M, et al. Intensity-modulated radiation therapy for the treatment of oropharyngeal carcinoma: the Memorial Sloan-Kettering Cancer Center experience. Int J Radiat Oncol Biol Phys. 2006;64(2):363-73.

59. Suiter DM, McCullough GH, Powell PW. Effects of cuff deflation and one-way tracheostomy speaking valve placement on swallow physiology. Dysphagia. 2003;18(4):284-92.

60. Sinclair CF, McColloch NL, Carroll WR, Rosenthal EL, Desmond RA, Magnuson JS. Patient-perceived and objective functional outcomes following transoral robotic surgery for early oropharyngeal carcinoma. Arch Otolaryngol Head Neck Surg. 2011;137(11):1112-6.

61. Moore EJ, Olsen KD, Kasperbauer JL. Transoral robotic surgery for oropharyngeal squamous cell carcinoma: a prospective study of feasibility and functional outcomes. Laryngoscope. 2009;119(11):2156-64.

62. Payakachat N, Ounpraseuth S, Suen JY. Late complications and long-term quality of life for survivors (>5 years) with history of head and neck cancer. Head Neck. 2013;35(6):819-25.

63. Kelly AM, Drinnan MJ, Leslie P. Assessing penetration and aspiration: how do videofluoroscopy and fiberoptic endoscopic evaluation of swallowing compare? Laryngoscope. 2007;117(10):1723-7.

64. Omari T, Tack J, Rommel N. Impedance as an adjunct to manometric testing to investigate symptoms of dysphagia: What it has failed to do and what it may tell us in the future. United European Gastroenterol J. 2014;2(5):355-66.

65. Omari TI, Dejaeger E, Van Beckevoort D, Goeleven A, De Cock P, Hoffman I, et al. A novel method for the nonradiological assessment of ineffective swallowing. Am J Gastroenterol. 2011;106(10):1796-802.

66. Martin-Harris B, Jones B. The Videofluorographic Swallowing Study. Phys Med Rehabil Clin N Am. 2008;19(4):769-85.

67. Nacci A, Ursino F, La Vela R, Matteucci F, Mallardi V, Fattori B. Fiberoptic endoscopic evaluation of swallowing (FEES): proposal for informed consent. Acta Otorhinolaryngol Ital. 2008;28(4):206-11.

68. Bhatia SJ, Shah C. How to Perform and Interpret Upper Esophageal Sphincter Manometry. J Neurogastroenterol Motil. 2013;19(1):99-103.

69. Chen AY, Frankowski R, Bishop-Leone J, Hebert T, Leyk S, Lewin J, et al. The development and validation of a dysphagia-specific quality-of-life questionnaire for patients with head and neck cancer: the M. D. Anderson dysphagia inventory. Arch Otolaryngol Head Neck Surg. 2001;127(7):870-6.

70. McHorney CA, Bricker DE, Kramer AE, Rosenbek JC, Robbins J, Chignell KA, et al. The SWAL-QOL outcomes tool for oropharyngeal dysphagia in adults: I. Conceptual foundation and item development. Dysphagia. 2000;15(3):115-21.

71. McHorney CA, Bricker DE, Robbins J, Kramer AE, Rosenbek JC, Chignell KA. The SWAL-QOL outcomes tool for oropharyngeal dysphagia in adults: II. Item reduction and preliminary scaling. Dysphagia. 2000;15(3):122-33.

72. McHorney CA, Robbins J, Lomax K, Rosenbek JC, Chignell K, Kramer AE, et al. The SWAL-QOL and SWAL-CARE outcomes tool for oropharyngeal dysphagia in adults: III. Documentation of reliability and validity. Dysphagia. 2002;17(2):97-114.

73. Crary MA, Mann GD, Groher ME. Initial psychometric assessment of a functional oral intake scale for dysphagia in stroke patients. Arch Phys Med Rehabil. 2005;86(8):1516-20.

74. 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.

75. 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.

47

76. Kao SS, Ooi EH, Peters MDJ. Swallowing outcomes following primary surgical resection and primary free flap reconstruction for oral and oropharyngeal squamous cell carcinomas: a systematic review protocol. JBI Database of System Rev Implement Rep. 2015;13(8):120-34.

77. Burns PB, Rohrich RJ, Chung KC. The Levels of Evidence and their role in Evidence-Based Medicine. Plast Reconstr Surg. 2011;128(1):305-10.

78. Shadish W, Cook T, Campbell T. Experimental and quasi-experimental designs for generalized causal inference. Boston Houghton Mifflin Company 2001.

79. Pearson A, Wiechula R, Court A, Lockwood C. The JBI model of evidence-based healthcare. International journal of evidence-based healthcare. 2005;3(8):207-15.

80. Sackett DL, Rosenberg WMC, Gray JAM, Haynes RB, Richardson WS. Evidence based medicine: what it is and what it isn't. BMJ. 1996;312(7023):71-2.

81. Silagy CA, Middleton P, Hopewell S. Publishing protocols of systematic reviews: comparing what was done to what was planned. JAMA. 2002;287(21):2831-4.

82. Akobeng AK. Understanding systematic reviews and meta-analysis. Arch Dis Child. 2005;90(8):845-8.

83. The Joanna Briggs Institute. Joanna Briggs Institute Reviewers' Manual: 2014 edition. Adelaide, Australia The Joanna Briggs Institute 2014.

84. Greenhalgh T. How to read a paper. Statistics for the non-statistician. I: Different types of data need different statistical tests. BMJ. 1997;315(7104):364-6.

85. Higgs J, Titchen A. Research and knowledge. Physiotherapy. 1998;84(2):72-80. 86. Greenhalgh T. How to read a paper. Statistics for the non-statistician. II: "Significant"

relations and their pitfalls. BMJ. 1997;315(7105):422-5. 87. Green S, Higgins JPT. Preparing a Cochrane Review. Cochrane Handbook for

Systematic Reviews of Interventions: John Wiley & Sons, Ltd; 2008. p. 11-30. 88. Eysenbach G. Peer Review and Publication of Research Protocols and Proposals: A

Role for Open Access Journals. J Med Internet Res. 2004;6(3):e37. 89. Schulz KF, Grimes DA. Blinding in randomised trials: hiding who got what. Lancet.

2002;359(9307):696-700. 90. Harris MR. The librarian's roles in the systematic review process: a case study. J Med

Libr Assoc. 2005;93(1):81-7. 91. Uman LS. Systematic Reviews and Meta-Analyses. Journal of the Canadian Academy

of Child and Adolescent Psychiatry. 2011;20(1):57-9. 92. Yoshii A, Plaut DA, McGraw KA, Anderson MJ, Wellik KE. Analysis of the reporting of

search strategies in Cochrane systematic reviews. Journal of the Medical Library Association : JMLA. 2009;97(1):21-9.

93. Cook DJ, Mulrow CD, Haynes RB. Systematic Reviews: Synthesis of Best Evidence for Clinical Decisions. Ann Intern Med. 1997;126(5):376-80.

94. Fakhry N, Michel J, Colavolpe C, Varoquaux A, Dessi P, Giovanni A. Screening for distant metastases before salvage surgery in patients with recurrent head and neck squamous cell carcinoma: A retrospective case series comparing thoraco-abdominal CT, positron emission tomography and abdominal ultrasound. Clinical Otolaryngology. 2012;37(3):197-206.

95. Pearson A, Field J, Jordan Z. Evidence Synthesis: The Systematic Review. Evidence-Based Clinical Practice in Nursing and Health Care: Blackwell Publishing Ltd.; 2009. p. 52-71.

96. Katrak P, Bialocerkowski AE, Massy-Westropp N, Kumar S, Grimmer KA. A systematic review of the content of critical appraisal tools. BMC Med Res Methodol. 2004;4:22.

97. Koch WM. Head and neck surgery in the era of organ preservation therapy. Seminars in oncology. 2000;27(4):5-12.

98. Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ : British Medical Journal. 2003;327(7414):557-60.

99. Bernier L, Archambault J, Vigneault E, Fortin A. Regional outcome in N2-N3 patients with head and neck carcinoma in function of FDG PET/CT results. International Journal of Radiation Oncology Biology Physics. 2013;87(2):S441.

48

100. 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. Acta Otolaryngol. 2014;134(10):1086-93.

101. Pourhoseingholi MA, Baghestani AR, Vahedi M. How to control confounding effects by statistical analysis. Gastroenterology and Hepatology From Bed to Bench. 2012;5(2):79-83.

102. Hartl DM, Dauchy S, Escande C, Bretagne E, Janot F, Kolb F. Quality of life after free-flap tongue reconstruction. J Laryngol Otol. 2009;123(5):550-4.

103. Brown MB. Control groups appropriate for surgical interventions: ethical and practical issues. Gastroenterology. 2004;126, Supplement 1:S164-S8.

104. Walter CJ, Dumville JC, Hewitt CE, Moore KC, Torgerson DJ, Drew PJ, et al. The quality of trials in operative surgery. Ann Surg. 2007;246(6):1104-9.

105. Haddock NT, DeLacure MD, Saadeh PB. Functional reconstruction of glossectomy defects: the vertical rectus abdominus myocutaneous neotongue. J Reconstr Microsurg. 2008;24(5):343-50.

106. Moerman M, Vermeersch H, Van Lierde K, Fahimi H, Van Cauwenberge P. Refinement of the free radial forearm flap reconstructive technique after resection of large oropharyngeal malignancies with excellent functional results. Head Neck. 2003;25(9):772-7.

107. Winter SCA, Cassell O, Corbridge RJ, Goodacre T, Cox GJ. Quality of life following resection, free flap reconstruction and postoperative external beam radiotherapy for squamous cell carcinoma of the base of tongue. Clin Otolaryngol Allied Sci. 2004;29(3):274-8.

108. Li W, Yang Y, Xu Z, Liu F, Cheng Y, Xu L, et al. Assessment of quality of life of patients with oral cavity cancer who have had defects reconstructed with free anterolateral thigh perforator flaps. Br J Oral Maxillofac Surg. 2013;51(6):497-501.

109. Hsiao HT, Leu YS, Chang SH, Lee JT. Swallowing function in patients who underwent hemiglossectomy: comparison of primary closure and free radial forearm flap reconstruction with videofluoroscopy. Ann Plast Surg. 2003;50(5):450-5.

110. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65(1):5-29.

111. Smith JE, Suh JD, Erman A, Nabili V, Chhetri DK, Blackwell KE. Risk factors predicting aspiration after free flap reconstruction of oral cavity and oropharyngeal defects. Arch Otolaryngol Head Neck Surg. 2008;134(11):1205-8.

112. Pauloski BR, Logemann JA, Rademaker AW, McConnel FM, Stein D, Beery Q, et al. Speech and swallowing function after oral and oropharyngeal resections: one-year follow-up. Head Neck. 1994;16(4):313-22.

113. Scherpenhuizen A, van Waes AM, Janssen LM, Van Cann EM, Stegeman I. The effect of exercise therapy in head and neck cancer patients in the treatment of radiotherapy-induced trismus: A systematic review. Oral Oncol. 2015;51(8):745-50.

114. Kotz T, Federman AD, Kao J, Milman L, Packer S, Lopez-Prieto C, et al. Prophylactic swallowing exercises in patients with head and neck cancer undergoing chemoradiation: a randomized trial. Arch Otolaryngol Head Neck Surg. 2012;138(4):376-82.

115. Carnaby-Mann G, Crary MA, Schmalfuss I, Amdur R. "Pharyngocise": randomized controlled trial of preventative exercises to maintain muscle structure and swallowing function during head-and-neck chemoradiotherapy. Int J Radiat Oncol Biol Phys. 2012;83(1):210-9.

116. Carroll WR, Locher JL, Canon CL, Bohannon IA, McColloch NL, Magnuson JS. Pretreatment swallowing exercises improve swallow function after chemoradiation. Laryngoscope. 2008;118(1):39-43.

117. Kulbersh BD, Rosenthal EL, McGrew BM, Duncan RD, McColloch NL, Carroll WR, et al. Pretreatment, preoperative swallowing exercises may improve dysphagia quality of life. Laryngoscope. 2006;116(6):883-6.

49

118. Smith GI, Brennan PA, Scott PJ, Ilankovan V. Outcome after radial forearm, gastro-omental, and jejunal free flaps in oral and oropharyngeal reconstruction. Br J Oral Maxillofac Surg. 2002;40(4):330-3.

119. 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.

120. Xu Z, Zhao XP, Yan TL, Wang M, Wang L, Wu HJ, et al. A 10-year retrospective study of free anterolateral thigh flap application in 872 head and neck tumour cases. Int J Oral Maxillofac Surg. 2015;44(9):1088-94.

121. 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.

122. 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.

123. 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. Plast Reconstr Surg. 1995;96(5):1081-9; discussion 90-1.

124. 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.

125. Wopken K, Bijl HP, van der Schaaf A, Christianen ME, Chouvalova O, Oosting SF, et al. Development and validation of a prediction model for tube feeding dependence after curative (chemo-) radiation in head and neck cancer. PLoS One. 2014;9(4):e94879.

126. Lee JH, Machtay M, Unger LD, Weinstein GS, Weber RS, Chalian AA, et al. Prophylactic gastrostomy tubes in patients undergoing intensive irradiation for cancer of the head and neck. Arch Otolaryngol Head Neck Surg. 1998;124(8):871-5.

127. Scolapio JS, Spangler PR, Romano MM, McLaughlin MP, Salassa JR. Prophylactic placement of gastrostomy feeding tubes before radiotherapy in patients with head and neck cancer: is it worthwhile? J Clin Gastroenterol. 2001;33(3):215-7.

128. Cheng SS, Terrell JE, Bradford CR, Ronis DL, Fowler KE, Prince ME, et al. Variables associated with feeding tube placement in head and neck cancer. Arch Otolaryngol Head Neck Surg. 2006;132(6):655-61.

129. Shaw SM, Flowers H, O'Sullivan B, Hope A, Liu LW, Martino R. The effect of prophylactic percutaneous endoscopic gastrostomy (PEG) tube placement on swallowing and swallow-related outcomes in patients undergoing radiotherapy for head and neck cancer: a systematic review. Dysphagia. 2015;30(2):152-75.

130. Lazarus CL, Logemann JA, Pauloski BR, Rademaker AW, Larson CR, Mittal BB, et al. Swallowing and tongue function following treatment for oral and oropharyngeal cancer. J Speech Lang Hear Res. 2000;43(4):1011-23.

131. Holloway RH. Combined impedance-manometry for the evaluation of esophageal disorders. Current opinion in gastroenterology. 2014;30(4):422-7.

132. Kendall KA, Kosek SR, Tanner K. Quality-of-life scores compared to objective measures of swallowing after oropharyngeal chemoradiation. Laryngoscope. 2014;124(3):682-7.

133. Ferrari S, Copelli C, Bianchi B, Ferri A, Sesenna E. The Bozola flap in oral cavity reconstruction. Oral Oncol. 2012;48(4):379-82.

50

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

oropharyngeal neoplasms[mh] OR

deglutition

disorders[mh:noexp] OR surgical flaps[mh] OR

oropharyngeal neoplasm*[tw] OR

deglutition disorder*[tw]

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

51

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])

52

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

53

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* )

54

Appendix II: Critical Appraisal Instruments

55

56

57

Appendix III: Data Extraction Instruments

58

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.

59

Appendix V: Included Studies

Author Method Population Site Stage Type of Resection Flap Outcome

Measures

Time of

Assessment

(Months)

Adjuvant

Therapy

Borggreven3 Prospective

Cohort 54

Oral tongue,

FOM, BOT,

Tonsil, Soft

palate

II, III,

IV

Paramedian mandibular

swing for access

Composite resection with

microvascular soft tissue

transfer

RFFF

Oral and

pharyngeal

transit time

Aspiration (PAS)

6, 12 RT

Chien4 Prospective

Cohort 29

Oral tongue,

BOT T3, T4

Partial or total glossectomy

via mandibulotomy

RFFF

ALTF

Tracheostomy

Dependency

G-tube

Dependency

Aspiration

12 CRT

Farace5 Prospective

Cohort 20 Oral cavity T2, T3

Intraoral soft tissue ablation:

Hemiglossectomy, anterior

pavement ablation

RFFF

ALTF Aspiration 6 Unclear

Haddock105 Retrospective

Case-series 8 Oral tongue III, IV Subtotal or total glossectomy VRAM

Tracheostomy

Dependency

G-tube

Dependency

Aspiration

12 RT

Hartl102 Prospective

Case-series 5

Oral tongue,

BOT IV Subtotal or total glossectomy

RFFF

LDF

RMF

Aspiration 18-83 RT

Hsiao109 Prospective

Case-series 4 Oral tongue T2, T3

Hemiglossectomy +

Mandibulotomy RFFF Oral transit time 6 CRT

60

Keiner18 Prospective

Cohort 150

Oral cavity,

Oropharynx

T2, T3,

T4

Tumor resection through

transoral or lateral

pharyngotomy approach

RFFF

Tracheostomy

Dependency

Aspiration

8-15 RT

Li108 Retrospective

Case-series 51

Oral tongue,

FOM, Gum,

Buccal mucosa

T1, T2,

T3, T4 Unclear ALTF UW-QoL 12-84 CRT

Longo17 Prospective

Cohort 13 Oral tongue T3, T4

Anterior total mobile tongue

resection, subtotal tongue

resection

ALTF

Oral transit time

Tracheostomy

dependency

18 RT

Moerman106 Prospective

Case-series 4

Tonsil, Soft

palate, Lateral

pharyngeal wall

T2, T3 WLE of lateral pharyngeal

wall, RMT, Soft palate RFFF

Tracheostomy

Dependency 8-21 RT

O'Connell6 Prospective

Cohort 20

BOT, Lateral

pharyngeal

wall, Soft palate

III, IV

Lip-splitting incision and

presymphyseal

mandibulotomy

RFFF

Tracheostomy

Dependency

G-tube

dependency

Aspiration (PAS)

12 CRT

Rieger7 Prospective

Cohort 32

BOT, Lateral

pharyngeal

wall, Soft palate

T1, T2,

T3, T4

Lip-splitting incision and

presymphyseal

mandibulotomy

RFFF

Tracheostomy

Dependency

G-tube

dependency

Aspiration (PAS)

Oral and

pharyngeal

transit time

Preoperatively,

1, 6 , 12 CRT

Seikaly8 Prospective

Cohort 18

BOT, Lateral

pharyngeal

wall, Soft palate

III, IV

Oropharynx resection, lip split

incision and parasymphyseal

mandibulotomy

RFFF

G-tube

dependency

Aspiration

1, 6, 9, 12 RT

61

Shin9 Retrospective

Case-series 31 Oral tongue T1, T2

Partial glossectomy

performed through peroral

approach, pull through or

paramedian mandibulotomy

RFFF MDADI 21-91 RT

Winter107 Prospective

Case-series 6 BOT III, IV

Resection of tongue base

with mandibulotomy, per oral

resection or lingual release

RFFF,

RMF UW-QOL 9-56 RT

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

62

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].

63

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.

64

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.

65

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.

66

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.

67

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 oro-

pharyngeal 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.

68

Lidman D, Niklasson M. Survival and function in patients with tumours of the head and neck operated

on and reconstructed with free flaps. Scand J PlastReconstrSurg Hand Surg. 2008;42(2):77-85.

López-Arcas JM, Arias J, Morán MJ, Navarro I, Pingarrón L, Chamorro M, et al. The Deep Inferior

Epigastric Artery Perforator (DIEAP) Flap for Total Glossectomy Reconstruction. Journal of Oral &

Maxillofacial Surgery (02782391). 2012;70(3):740-7.

Lyos AT, Evans GRD, Perez D, Schusterman MA. Tongue reconstruction: Outcomes with the rectus

abdominis flap. PlastReconstr Surg. 1999;103(2):442-9.

Mah SM, Durham JS, Anderson DW, Irvine RA, Chow C, Fache JS, et al. Functional results in oral

cavity reconstruction using reinnervated versus nonreinnervated free fasciocutaneous grafts. J

Otolaryngol. 1996;25(2):75-81.

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.

Matloub HS, Larson DL, Kuhn JC, Yousif NJ, Sanger JR. Lateral arm free flap in oral cavity

reconstruction: A functional evaluation. Head Neck. 1989;11(3):205-11.

Mosahebi A, Chaudhry A, McCarthy CM, Disa JJ, Mehrara BJ, Pusic AL, et al. Reconstruction of

extensive composite posterolateral mandibular defects using nonosseous free tissue transfer.

PlastReconstr Surg. 2009;124(5):1571-7.

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.

Paydarfar JA, Patel UA. Submental island pedicled flap vs radial forearm free flap for oral

reconstruction: comparison of outcomes. Arch Otolaryngol Head Neck Surg. 2011;137(1):82-7.

Seikaly H, Rieger J, O'Connell D, Ansari K, Alqahtani K, Harris J. Beavertail modification of the radial

forearm free flap in base of tongue reconstruction: technique and functional outcomes. Head Neck.

2009;31(2):213-9.

Seikaly H, Rieger J, Zalmanowitz J, Tang JL, Alkahtani K, Ansari K, et al. Functional soft palate

reconstruction: a comprehensive surgical approach. Head Neck. 2008;30(12):1615-23.

Smith GI, Brennan PA, Scott PJ, Ilankovan V. Outcome after radial forearm, gastro-omental, and

jejunal free flaps in oral and oropharyngeal reconstruction. Br J Oral Maxillofac Surg. 2002;40(4):330-

3.

Song XM, Ye JH, Yuan Y, Zhang SY, Jiang HB, Wu YN. Radial forearm free flap for reconstruction of

a large defect after radical ablation of carcinoma of the tongue and floor of the mouth: some new

modifications. ORL J OtorhinolaryngolRelat Spec. 2010;72(2):106-12.

Steinhart H, Iro H. Carcinoma of the posterior pharyngeal wall - Larynx preservation with the radial

forearm flap or transoral resection. Radiology and Oncology. 1997;31(2):190-1.

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.

Wagner JD, Coleman JJ, 3rd, Weisberger E, Righi PD, Radpour S, McGarvey S, et al. Predictive

factors for functional recovery after free tissue transfer oromandibular reconstruction. Am J Surg.

1998;176(5):430-5.

Weber RS, Ohlms L, Bowman J, Jacob R, Goepfert H. Functional results after total or near total

glossectomy with laryngeal preservation. Arch Otolaryngol Head Neck Surg. 1991;117(5):512-5.

Yagi S, Kamei Y, Nakayama B, Toriyama K, Torii S. A new design for free flap reconstruction of the

tongue and oropharynx. J ReconstrMicrosurg. 2008;24(3):211-9.

Yanai C, Kikutani T, Adachi M, Thoren H, Suzuki M, Iizuka T. Functional outcome after total and

subtotal glossectomy with free flap reconstruction. Head Neck. 2008;30(7):909-18.

69

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 oro-

pharyngeal 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.

70

Appendix VII: Dysphagia Risk Stratification Tool

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

Low Risk Patients

Early Stage (T1 and T2)

No evidence of regional or distant

metastases

No postoperative CRT

High Risk Patients

Late Stage (T3 and T4)

Resections involving

combinations of the BOT,

oral tongue or soft palate

Postoperative CRT

Swallowing exercises pre-

during treatment

Pre-operative Evaluations

Subjective Quality of Life

Questionnaires (MDADI, UW-QoL)

FEES with PAS

Post-operative Evaluations

Subjective Quality of Life

Questionnaires (MDADI, UW-QoL)

FEES with PAS

Post-operative Evaluations

Subjective Quality of Life

Questionnaires (MDADI, UW-QoL)

FEES with PAS

VFSS Every 6 months

Pre-operative Evaluations

Subjective Quality of Life

Questionnaires (MDADI, UW-QoL)

FEES with PAS

VFSS

Dysphagia Risk Stratification Tool