Swallowing outcomes following primary surgical resection and primary free flap reconstruction for oral and oropharyngeal squamous cell carcinomas: a systematic review protocol

Abstract

Review question / objective 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? 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. More specifically, the objectives are to evaluate dysphagia following primary surgical resection with or without adjuvant therapy with the use of objective investigations (videofluoroscopy, fiberoptic endoscopic evaluations of swallowing, manometry, gastrostomy dependency and tracheostomy dependency) and subjective questionnaires (MD Anderson Dysphagia Inventory, University of Washington Quality of Life Questionnaire and Functional Oral Intake Score). Background There are approximately 264,000 cases of oral-cavity malignancies and 136,000 cases of pharyngeal malignancies diagnosed annually worldwide.1 The oral cavity begins at the vermillion border of the lips and extends to the junction of hard and soft palate and circumvallate papilla of the tongue. The anterior tonsillar pillars serve as the boundary between the oral cavity and oropharynx. The oropharynx is made up of the posterior and lateral pharyngeal walls, tonsillar regions, base of tongue and soft palate. The etiology of oral and oropharyngeal squamous cell carcinoma (OPSCC) has been strongly linked to the intensity and duration of smoking and alcohol use.2,3 Recently, the human papilloma virus (HPV) has been linked to the development and rise in incidence of OPSCC.4 Patients with HPV-positive disease are typically younger, non-smokers and have a favorable prognosis for long-term survival, compared with their HPV-negative counterparts.5 Therefore treatment regimens have shifted toward organ preservation techniques with the goal of improving functional outcomes such as swallowing. 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 7.6,7 Components of both these systems include: local tumor growth (T), regional lymph node spread (N) and distant metastasize (M). The goal of the TNM staging system is to assist in planning treatment and aid in prognosis.8 Early stage (I/II) and advanced stage (III/IV) malignancies will have immensely different treatment regimens ranging from single modality treatment, multiple modality treatment to palliation. Depending on the treatment modality utilized, functional outcomes will vary greatly.9 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 regimens with malignancies of a similar stage. The prognosis from head and neck cancer is improving with treatment protocols utilizing surgery, radiotherapy and chemotherapy. The combination of chemoradiotherapy has been shown to improve survival outcomes; however, it is associated with increased long-term toxicity.10 The utilization of surgery to maintain disease control, in advanced stage malignancy, whilst preserving function, is a difficult task, as it typically involves mandibulotomies and defects within the head and neck.11,12 Surgical reconstruction techniques with the use of free vascularized flaps allows for improvement in functional and cosmetic outcomes.13 Free flaps can be transferred with their associated nerves, allowing for additional sensory and motor function.14 Commonly used soft tissue donor sites include the radial forearm and anterolateral thigh graft. Primary reconstructions are performed at the time of resection, whereas secondary reconstructions are performed as a separate procedure following resection. Primary reconstruction is typically utilized for head and neck cancer patients as it allows for rapid restoration of anatomy and function, with decreased potential for muscular atrophy and fibrosis associated with delayed reconstruction.15 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.16 Transoral robotic surgery allows for more accurate dissection, improved visualization with the ability to navigate around corners with decreased postoperative complications.17 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.10 Despite these advances, swallowing dysfunction is still a regular occurrence post-treatment. 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.18 During the oral phase, the tongue contracts against the hard palate transporting the bolus toward the oropharynx. The pharyngeal phase consists of soft palate elevation, which prevents nasal regurgitation, pharyngeal wall contraction and sequential contractions of the pharyngeal constrictors. 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. Dysphagia, or difficulty swallowing, is a devastating consequence of treatment that affects up to 50% of head and neck cancer survivors.19 It is common practice in many institutions to insert gastrostomy tubes prior to treatment to prevent malnutrition secondary to dysphagia. Studies have shown that patients with no oral intake after two weeks are associated with worse swallowing outcomes, potentially due to deconditioning and disuse atrophy of pharyngeal muscles.20 Dependence on gastrostomy feeds to maintain adequate nutrition affects 10–25% of these patients with dysphagia.21 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 with a high prediction of life-long dysphagia, with up to 38% of patients requiring permanent gastrostomy tubes.22–26 Tracheostomies are typically required for airway management following open resections of oral and oropharyngeal cancers. The utilization of tracheostomy tubes has been associated with dysphagia and aspiration, likely due to compression and alteration of oropharyngeal anatomical structures.27 Due to the minimally invasive approach of TORS for OPSCC, tracheostomy insertion can be avoided in greater than 70% of TORS cases, regardless of adjuvant therapy.28,29 Tracheostomy dependence therefore is an important aspect to consider when investigating swallowing outcomes following treatment of oral and OPSCC. Apart from malnutrition and poor general health, secondary to dysphagia, survivors also report a decreased quality of life.30 Therefore, it is vital to assess the impact of swallowing function, objectively and subjectively, in this population of individuals. Due to the complexity and multi-factorial processes involved in dysphagia, there is currently no gold standard approach to the assessment of dysphagia. There are objective and subjective assessments. Commonly used objective assessments currently include videofluoroscopy swallowing studies (VFSS), fiberoptic endoscopic evaluation of swallowing (FEES) and manometry. Videofluoroscopy swallowing studies allow 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. Fiberoptic endoscopic evaluation of swallowing involves flexible nasoendoscope transnasally for real-time visualization of laryngeal and pharyngeal structures. Food or liquid boluses can be given to assist in visualization of the pharyngeal phase of swallowing. This procedure can be completed by the bedside with nil exposure to radiation. 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 al.31 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 pressures secondary to pharyngeal contraction and upper esophageal sphincter relaxation. Pressure flow analysis using manometry and impedance measures are an emerging research tool used to investigate swallowing disorders.32,33 Subjective assessments using quality of life questionnaires consist of emotional and physical functioning in conjunction with the patient's perception of their own functional state. The MD Anderson Dysphagia Inventory (MDADI) and University of Washington Quality of Life Questionnaire (UW-QOL) have both been developed specifically and validated for head and neck cancer patients.34–37 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 tool used to assess a patient's oral intake ability.38 The understanding of oral and OPSCC treatment modalities 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 translate into function preservation. There is currently no standardized approach to the assessment of swallowing dysfunction, which causes difficulty in drawing conclusions from current available literature. Various objective and subjective methods of assessment should be combined to assist in a more holistic practice. 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. Lam and colleagues published a systematic review focusing on speech and swallowing outcomes following tongue cancer surgery and free flap reconstruction.39 They included patients with intraoral tongue and base of tongue squamous cell carcinoma. 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. 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 dysphagia is a potential complication following resection of any of these regions. A preliminary search of the JBI Database of Systematic Reviews and Implementation Reports, the Cochrane Library, MEDLINE, Embase and CINAHL found no systematic review protocols or review reports that investigate swallowing outcomes following free flap reconstruction in both oral-cavity and oropharynx squamous cell carcinoma. Inclusion criteria Types of participants The participants of interest for the review will be patients of 18 years of age or older with a histological diagnosis of oral or oropharyngeal squamous cell carcinoma. Histological diagnosis of malignancy is required to confirm the presence of malignancy. Treatment must be aimed at curative intent, with locoregional control at the time of swallowing evaluation, as swallowing outcomes at this time would be likely representative of swallowing function that is not impaired by the primary cancer.40 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 affecting swallowing outcomes. Dementia, stroke and neurological diseases have potential to cause dysphagia, and thus will be excluded. Patients with distant metastasize and other malignancies will likely undergo aggressive treatment therapies potentially affecting quality of life scores and swallowing outcomes. Types of Interventions This review will consider with 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 Swallowing outcomes with use of anterolateral thigh flaps. 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 a high prediction of life-long dysphagia.22,23 Dysphagia will be measured objectively with either Videofluoroscopy Swallowing Studies (VFSS), Fiberoptic Endoscopic Evaluations of Swallowing (FEES), manometry, gastrostomy and tracheostomy dependency or subjectively with MD Anderson Dysphagia Inventory (MDADI), University of Washington Quality of Life Questionnaire (UW-QOL) or Functional Oral Intake Scale (FOIS). Types of studies This review will consider 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 randomized controlled trials due to ethical concerns. Thus in the absence of randomized controlled trials and quasi-experimental studies, other studies will be considered for review. Search strategy The search strategy will aim to find both published and unpublished studies. A three-step search strategy will be utilized in this review. An initial limited search of MEDLINE and CINAHL will be undertaken followed by an analysis of the text words contained in the title and abstract, and of the index terms used to describe the article. A second search using all identified keywords and index terms will then be undertaken across all included databases. Thirdly, the reference list of all identified reports and articles will be searched for additional studies. Studies published in English will be considered for inclusion in this review. The databases to be searched include: MEDLINE (PubMed), CINAHL, Embase and Scopus. Grey literature will be searched through Cochrane Central Register of Controlled Trials (CENTRAL), MedNar and ProQuest. The initial search strategy that will be used when searching the MEDLINE (PubMed) database includes: 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 OR microvascular reconstruction*[tw] OR microsurgical free flap[tw] OR reconstruct*[tw] Assessment of methodological quality Papers selected for retrieval will be assessed by two independent reviewers 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 I). Any disagreements that arise between the reviewers will be resolved through discussion, or with a third reviewer. Data extraction Data will be extracted from papers included in the review using the standardized data extraction tool from JBI-MAStARI (Appendix II). The data extracted will include specific details about the interventions, populations, study methods and outcomes of significance to the review question and specific objectives. If relevant data is missing or incomplete in the located studies, where feasible, the authors will be contacted directly with the request to provide this information. In the event the required data cannot be provided, the study will be excluded. Data synthesis Quantitative data will, where possible, be pooled in statistical meta-analysis using JBI-MAStARI. All results will be subject to double data entry. Effect sizes expressed as relative risk and odds ratio for categorical data and weighted mean differences for continuous data and their 95% confidence intervals will be calculated for analysis. A random effects model will be used and heterogeneity will be assessed statistically using the standard Chi-square. Where statistical pooling is not possible the findings will be presented in narrative form including tables and figures to aid in data presentation where appropriate. Due the heterogeneity of the studies included in this review, pooled data may not yield statistically valid results. Thus narrative summary and discussion will be required to highlight the analysis. Studies will be grouped into patients treated with surgery alone or primary surgery with adjuvant therapies. Additionally, swallowing outcomes with the use of radial forearm free flap will be compared with anterolateral thigh flap. Swallowing outcomes between oral-cavity squamous cell carcinoma will be compared with oropharyngeal squamous cell carcinoma. Conflicts of interest The authors declare no conflicts of interest. Acknowledgements The authors acknowledge University of Adelaide Librarian Maureen Bell for her input and feedback regarding the search strategy.