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1 CADTH RAPID RESPONSE REPORT: SYSTEMATIC REVIEW Treatments for Locally Advanced Oropharyngeal Cancer: A Systematic Review of Clinical Effectiveness and Cost- Effectiveness Service Line: Rapid Response Service Version: 1.0 Publication Date: Month XX, 2017 Report Length: 79 Pages

2 Authors: First name Last name, First name Last name Cite As: Title. Ottawa: CADTH; yyyy mmm. (CADTH rapid response report: systematic review). Acknowledgments: ISSN: (online) Disclaimer: The information in this document is intended to help Canadian health care decision-makers, health care professionals, health systems leaders, and policy-makers make well-informed decisions and thereby improve the quality of health care services. While patients and others may access this document, the document is made available for informational purposes only and no representations or warranties are made with respect to its fitness for any particular purpose. The information in this document should not be used as a substitute for professional medical advice or as a substitute for the application of clinical judgment in respect of the care of a particular patient or other professional judgment in any decision-making process. The Canadian Agency for Drugs and Technologies in Health (CADTH) does not endorse any information, drugs, therapies, treatments, products, processes, or services. While care has been taken to ensure that the information prepared by CADTH in this document is accurate, complete, and up-to-date as at the applicable date the material was first published by CADTH, CADTH does not make any guarantees to that effect. CADTH does not guarantee and is not responsible for the quality, currency, propriety, accuracy, or reasonableness of any statements, information, or conclusions contained in any third-party materials used in preparing this document. The views and opinions of third parties published in this document do not necessarily state or reflect those of CADTH. CADTH is not responsible for any errors, omissions, injury, loss, or damage arising from or relating to the use (or misuse) of any information, statements, or conclusions contained in or implied by the contents of this document or any of the source materials. This document may contain links to third-party websites. CADTH does not have control over the content of such sites. Use of third-party sites is governed by the third-party website owners own terms and conditions set out for such sites. CADTH does not make any guarantee with respect to any information contained on such third-party sites and CADTH is not responsible for any injury, loss, or damage suffered as a result of using such third-party sites. CADTH has no responsibility for the collection, use, and disclosure of personal information by third-party sites. Subject to the aforementioned limitations, the views expressed herein are those of CADTH and do not necessarily represent the views of Canada s federal, provincial, or territorial governments or any third party supplier of information. This document is prepared and intended for use in the context of the Canadian health care system. The use of this document outside of Canada is done so at the user s own risk. This disclaimer and any questions or matters of any nature arising from or relating to the content or use (or misuse) of this document will be governed by and interpreted in accordance with the laws of the Province of Ontario and the laws of Canada applicable therein, and all proceedings shall be subject to the exclusive jurisdiction of the courts of the Province of Ontario, Canada. The copyright and other intellectual property rights in this document are owned by CADTH and its licensors. These rights are protected by the Canadian Copyright Act and other national and international laws and agreements. Users are permitted to make copies of this document for non-commercial purposes only, provided it is not modified when reproduced and appropriate credit is given to CADTH and its licensors. About CADTH: CADTH is an independent, not-for-profit organization responsible for providing Canada s health care decision-makers with objective evidence to help make informed decisions about the optimal use of drugs, medical devices, diagnostics, and procedures in our health care system. Funding: CADTH receives funding from Canada s federal, provincial, and territorial governments, with the exception of Quebec. SYSTEMATIC REVIEW Treatments for Locally Advanced Oropharyngeal Cancer DRAFT for consultation 2

3 Table of Contents Table of Contents... 3 Executive Summary... 4 Abbreviations... 7 Context and Policy Issues... 8 Research Questions... 9 Methods... 9 Summary of Evidence Discussion Conclusions and Implications for Decision or Policy Making APPENDIX 1: Literature search strategy APPENDIX 2: Flow chart of included studies APPENDIX 3: List of included Studies APPENDIX 4: List of Excluded Studies APPENDIX 5: Study Characteristics APPENDIX 6: Patient Characteristics APPENDIX 7: Critical Appraisal APPENDIX 8: Clinical Data APPENDIX 9: Economic data SYSTEMATIC REVIEW Treatments for Locally Advanced Oropharyngeal Cancer DRAFT for consultation 3

4 Executive Summary The Issue Oropharyngeal cancer, a subset of head and neck cancer, is associated with human papillomavirus (HPV) infection and alcohol or tobacco use. It is the 13 th most common diagnosed cancer and the 15 th most common cause of cancer death for adults in Canada. Treatment strategies for locally advanced oropharyngeal cancer include primary surgery with or without adjuvant chemoradiotherapy (CRT) or primary concurrent CRT with or without salvage surgery. Surgery is usually performed as open surgery, or with recent advances in minimally invasive techniques, namely Transoral Robotic Surgery (TORS) and Trans Oral Laser Microsurgery (TLM). In light of the morbidity associated with open surgical approaches to excise tumors of the oropharynx, non-surgical treatments with or without salvage surgery have, in most Canadian centres, become the mainstay of treatment. Chemotherapy options usually consist of platinum-based drugs (e.g. single-agent cisplatin) or cetuximab in the concurrent CRT setting, and cisplatin in the adjuvant setting. Radiotherapy includes conventional radiotherapy or intensity-modulated radiotherapy (IMRT) that delivers a precise radiation dosage to the tumor while sparing surrounding structures. Altered fractionation schedules have been explored, including accelerated fractionation that reduces the total treatment time and hyper-fractionation that involves daily administration of two reduced-dose fractions. The superiority of initial surgery or initial concurrent CRT for the treatment of oropharyngeal cancer in terms of oncologic and functional outcomes, toxicities, complications, and quality of life outcomes are not apparent. Likewise, the cost-effectiveness of the two regimens is unclear. Objectives This systematic review aims to compare the clinical effectiveness of primary surgical therapy (with or without adjuvant radiation or CRT) versus primary CRT (with or without salvage surgery) for adults with locally advanced oropharyngeal cancer. Cost effectiveness of the two treatment strategies will also be examined. Methods This review is based on protocol developed a priori. Published and unpublished literature describing studies that actively compare both treatment strategies and cost studies were identified through systematic searches of multiple databases and resources. The outcomes investigated were oncologic and functional outcomes, toxicities and complications of treatments, quality of life, and cost- SYSTEMATIC REVIEW Treatments for Locally Advanced Oropharyngeal Cancer DRAFT for consultation 4

5 effectiveness. Two reviewers independently screened the titles and abstracts of all citations retrieved from the literature search and ordered the full text of articles based on the selection criteria. The reviewers independently reviewed the full text of the selected articles and compared the independently chosen included/excluded studies. Data were extracted independently by reviewers and any disagreements were resolved through discussion until consensus was reached. The quality of clinical studies and cost evaluations was assessed using the Downs and Black and Drummond checklists. Due to heterogeneity in studies and patients characteristics, meta-analyses were not performed. A narrative summary of the included study findings was instead constructed. Results Clinical review No randomized controlled trials (RCTs) were identified through the literature search. This systematic review of 14head-to-head observational studies revealed three main findings. First, oncologic outcomes between primary surgery and primary concurrent CRT after 5 years, showed inconsistent results across studies and a lack of consistent statistical significance between the outcome differences. Data from one study suggested that a primary surgery plus adjuvant CRT approach resulted in a higher disease-specific survival (DSS) rate than concurrent CRT with or without salvage surgery after five years in patients with p16-negative cancers and in smokers. Data from one study found similar overall survival (OS) rates between the two treatment strategies for high-risk patients, but a significantly higher survival rate with a primary CRT strategy for low/intermediate risk patients after five years. Functional outcomes after one year seemed to favour concurrent CRT over open surgery in one study, but seemed to favour surgery over concurrent CRT when TLM or TORS was the surgical approach in another study. There were no statistically significant differences between the two treatment strategies for the most common complications such as acute dermatitis, mucositis, chronic swallowing difficulty, dry mouth and trismus after over four years of follow-up, but there were statistically more CRT patients than surgery patients who experienced hematological toxicities and pharyngitis during treatment. Reported quality of life scores for physical and social functions were favourable in the CRT group compared to surgery, after a median follow-up time of 56 months. Data from studies with shorter follow-up times suggested similar quality of life between the groups after two years and TLM or TORS led to better swallowing outcomes after one year. Second, subgroup analyses showed that the type of surgery (i.e., open or transoral [TORS or TLM] approach) did not change the oncologic outcomes when compared to concurrent CRT.Third, the quality of current evidence is weak due to the heterogeneous nature of the included observational studies where selection bias is probable, preventing a solid comparison between the two treatment options. Future large controlled trials are needed to strengthen the evidence. Economic review SYSTEMATIC REVIEW Treatments for Locally Advanced Oropharyngeal Cancer DRAFT for consultation 5

6 No Canadian cost-effectiveness studies were identified. The literature search identified one US cost-effectiveness study that compared TORS to primary CRT based on a base-case of a non-smoking 65- year old man with HPV-positive locally advanced oropharyngeal squamous cell carcinoma. The study found that the recurrence rate was the determining factor for the cost-effectiveness of the treatment options, with concurrent CRT to be the dominant strategy. Primary CRT dominated TORS in almost every situation, except when the recurrence risk after CRT was high or the risk after TORS was very low. Conclusions Our review provides evidence that oncologic outcomes between primary surgery and primary concurrent CRT for locally advanced oropharyngeal cancer were similar after five years of follow-up, even though one study may suggest a higher disease-specific survival rate with surgery in patients with p16-negative cancers and in smokers, while overall survival rates may favour CRT in intermediate/low risk patients. The type of surgical (i.e., open or transoral [TORS or TLM]) approach did not seem to change the oncologic outcomes compared to concurrent CRT. Limited evidence on functional outcomes after one year seemed to favour surgery over concurrent CRT when TLM or TORS was the surgical approach. The most common complications were similar after over four years of follow-up, but a larger number of CRT patients may experience hematological toxicities and pharyngitis during treatment compared to surgery. Quality of life outcomes favoured CRT compared to surgery in general, but TLM or TORS led to better swallowing outcomes after one year. Primary CRT may be the cost-effective therapy for patients with p16- positive locally advanced oropharyngeal cancer under most circumstances, with recurrence rates being the determining factor. The results from the clinical review must be interpreted with caution given the heterogeneity of the included studies and the absence of RCTs which prevented a pooled estimate of the clinical outcomes. The outcomes analyzed are reflective of relatively short-term follow-up times that have been reported to date. Until long-term data becomes available, no further conclusions can be drawn beyond those previously outlined. Large RCTs with long-term follow-up times are necessary to provide robust evidence. The generalizability of the costeffectiveness study results to a Canadian context may not be strong since the costs of the intervention was based on one American jurisdiction and analyses was not based on a large volume of data on which to estimate clinical efficacy and harms of treatment strategies. SYSTEMATIC REVIEW Treatments for Locally Advanced Oropharyngeal Cancer DRAFT for consultation 6

7 Abbreviations CT Chemotherapy CRT Chemoradiotherapy DFS Disease-free survival DMFS Distant metastasis-free survival DSS Disease-specific survival EORTC-QLQ European Organization Research and Treatment of Cancer QoL Questionnaires GY Gray (unit) HNSCC Head and neck squamous cell carcinoma HPV Human papillomavirus HR Hazard ratio ICER Incremental cost-effectiveness ratio IMRT Intensity-modulated radiation therapy LRC Local-regional control LRR Local-regional recurrence LRRFS Loco-regional recurrence-free survival MDADI MD Anderson Dysphagia Inventory N Regional lymph nodes NA Not applicable Not reported OS Overall survival p16 Tumor suppressor protein PFS Progression-free survival PORT Post-operative radiotherapy PSS Performance status scale QALY Quality-adjusted life years QoL Quality of life RCT Randomized controlled trial RFS Recurrence-free survival RT Radiotherapy SS Statistical significance T Primary tumor TLM Transoral laser microsurgery TORS Transoral robotic surgery US United States UW-QoL University of Washington quality of life WST Water swallow test SYSTEMATIC REVIEW Treatments for Locally Advanced Oropharyngeal Cancer DRAFT for consultation 7

8 Context and Policy Issues Introduction Head and neck squamous cell carcinoma (HNSCC) encompasses multiple sites of origin, including the oral cavity, oropharynx, and larynx, with diverse drivers of carcinogenesis and clinical outcomes. Oropharyngeal cancer, the subset of HNSCC that originates in the oropharynx, is associated with human papillomavirus (HPV) infection (often detected with protein p16 expression status), alcohol or tobacco use, and is the 13 th most common diagnosed cancer and the 15 th most common cause of cancer death for adults in Canada. 1 It is estimated that in 2015, 4,400 Canadians (2900 men and 1450 women) were diagnosed with HNSCC, and 1,200 Canadians would die of the disease. 2-5 In 2010, 210 Canadians (170 men and 40 women) were diagnosed with oropharyngeal cancer. 6 Oropharyngeal cancer is defined as locally advanced when the cancer is in clinical stage III, Iva or IVb (i.e., tumour stage T3-4a plus lymph nodes stage 0-1; or any tumour stage plus lymph nodes stage 2-3). 7 In light of the morbidity associated with open surgical approaches to excise tumors of the oropharynx, non-surgical treatments have, in most centres, become the mainstay of treatment. A 2003 trial by Adelstein et al., 8 established concurrent cisplatin and conventional fractionation radiotherapy as the standard of care over radiotherapy alone, with a13% improvement in three-year survival. Of the population of HNSCC patients included in this study, 59% had oropharyngeal cancer. More recently, another radiosensitizing agent, cetuximab, has been made available in Canada as an alternative to cisplatin as part of concurrent chemoradiotherapy for HNSCC. 9 With some exceptions, namely the open surgical experience in Alberta (particularly Edmonton), most locally advanced oropharynx malignancies have been treated with either radiation or concurrent chemoradiation therapy (CRT) with or without salvage surgery. In 2015, an Alberta Health Clinical Practice Guideline on oropharyngeal treatment recommended either surgery followed by radiotherapy or chemotherapy, or concurrent CRT for locally advanced oropharyngeal cancer. 10 The chemotherapy options recommended by the guideline are single-agent cisplatin or cetuximab in the concurrent CRT setting, and cisplatin in the adjuvant setting. 10 Intensity-modulated radiotherapy that delivers precise radiation doses to the tumor while sparing surrounding structures is the accepted standard of care (the recommended radiation dose is Gy when part of concurrent CRT setting, or Gy when following surgery in the adjuvant setting). 10 Altered fractionation schedules have been explored, including accelerated fractionation that reduces the total treatment time and hyper-fractionation that involves daily administration of two reduced-dose fractions. Relatively recent advances in minimally invasive techniques, transoral robotic surgery (TORS) and transoral laser microsurgery (TLM), are being incorporated as favourable options for early stage oropharyngeal cancer For oropharyngeal cancer that is at a more advanced stage, treatment with these minimally invasive techniques is still associated with functional impairment. For residual or recurrent oropharynx cancer, the more traditional open surgical approach via SYSTEMATIC REVIEW Treatments for Locally Advanced Oropharyngeal Cancer DRAFT for consultation 8

9 mandibulotomy or lateral pharyngotomy is used. In these cases, microvascular reconstruction of the subsequent defect is almost universally required. Issues The superiority of primary surgery or primary CRT in the treatment of locally advanced oropharyngeal cancer in terms of oncologic and functional outcomes, toxicities, complications, and quality of life are not apparent. The cost-effectiveness of the two regimens is likewise unclear. Objectives This systematic review aims to compare the clinical effectiveness of primary surgical therapy (with or without adjuvant radiation and chemotherapy) versus primary CRT (with or without salvage surgery) for adults with locally advanced oropharyngeal cancer. Cost effectiveness of the two treatment strategies will also be examined. Research Questions 1. What is the comparative clinical effectiveness of primary surgery (with or without adjuvant radiotherapy and chemotherapy) versus primary CRT (with or without salvage surgery) for the treatment of adults with a diagnosis of locally advanced oropharyngeal cancer? 2. What is the cost-effectiveness of primary surgery (with or without adjuvant radiotherapy and chemotherapy) for the treatment of adults with a diagnosis of locally advanced oropharyngeal cancer? 3. What is the cost-effectiveness of primary CRT(with or without salvage surgery) for the treatment of adults with a diagnosis of locally advanced oropharyngeal cancer? Methods This review is based on protocol developed a priori. 14 Literature Search Strategy A limited literature search was conducted on key resources including PubMed, OVID, The Cochrane Library, University of York Centre for Reviews and Dissemination (CRD) databases, Canadian and major international health technology agencies, as well as a focused Internet search. Filters were applied to limit the retrieval to health technology assessments, systematic reviews, and meta-analyses, randomized controlled trials, non-randomized studies, and economic studies. Where possible, retrieval was limited to the human population. The search was also limited to English language documents published between January 1, 2001 and September 8, See Appendix 1 for the detailed search strategy. Selection Criteria and Methods Two reviewers independently screened the titles and abstracts of all citations retrieved from the literature search and, based on the selection criteria (Table1),ordered the full text of any articles that SYSTEMATIC REVIEW Treatments for Locally Advanced Oropharyngeal Cancer DRAFT for consultation 9

10 Table 1: Selection Criteria Population appeared to meet those criteria. The reviewers independently reviewed the full text of the selected articles, applied the selection criteria, and compared the independently chosen included/excluded studies. Disagreements were resolved through discussion until consensus was reached. Duplicate publications of the same study were excluded unless they provide additional outcome information of interest. The study selection process is presented in a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow chart in Appendix 2. Adult patients (aged 18 years) with biopsy proven primary locally advanced oropharyngeal carcinoma (American Joint Committee on Cancer stage III, IVa, or IVb) Intervention Comparator Outcomes Concurrent primary chemoradiotherapy (with or without salvage surgery)* Primary surgery (with or without adjuvant radiotherapy and chemotherapy) Oncologic outcomes Overall survival, recurrence-free survival, local-regional control (LRC, freedom from local progression) Functional outcomes Rate of percutaneous feeding tube dependence at 2 years, rate of tracheostomy dependence at 2 years Quality of life outcomes Quality of life, anxiety, recreation, pain, saliva, dry mouth, swallowing, taste and speech measured with a standardized scale Toxicities Mortality rates due to chemotherapy-induced neutropenia, rates of skin and mucosal toxicity, osteoradionecrosis, soft tissue necrosis, cerebellar necrosis, xerostomia Complications Fistula formation, postoperative hemorrhage, hematoma formation, surgical site infections, pneumonia Cost-effectiveness outcomes Cost of primary surgery +/- adjuvant radiotherapy +/- adjuvant chemotherapy Cost of primary chemoradiotherapy +/- salvage surgery All specific related costs Quality-adjusted life years (QALY) Incremental cost-effectiveness ratio (ICER) Study design Randomized controlled trials (RCTs), non-randomized studies with a comparator group, cost studies *any chemoradiotherapy regimen or surgical approach reported in publications in the last 15 years was considered for inclusion Exclusion Criteria Studies were excluded when they did not meet the selection criteria or presented preliminary results in abstract form. Duplicate publications, narrative reviews, case studies, and editorials were excluded. Studies with mixed populations were excluded if results for patients with locally advanced oropharyngeal cancer were not reported separately. SYSTEMATIC REVIEW Treatments for Locally Advanced Oropharyngeal Cancer DRAFT for consultation 10

11 Data Extraction A data extraction form for the review was designed a priori to document and tabulate relevant study characteristics. Data were extracted independently by two reviewers and any disagreements were resolved through discussion until consensus was reached. While it was planned to contact study authors in case of missing or unclear data, this was not necessary. A calibration exercise (data from a sample of studies were extracted independently by each reviewer and compared, before all studies were extracted) was conducted to ensure consistency in data extraction. Critical Appraisal of Individual Studies The quality of clinical studies and cost evaluations was assessed using the Downs and Black 15 and Drummond 16 checklists, respectively. Quality assessments were completed by the lead researcher and verified by the second researcher. Any disagreements were resolved through discussion until consensus was reached. Studies were not excluded based on methodological assessments, but assessments were used to explain any potential differences across study results. Data Analysis and Synthesis Methods Tables were created to summarize quantitative findings for each outcome listed in Table 1. Data was synthesized separately for each question, by outcome. Head-to-head trials between the two treatment strategies were included. Randomized controlled trials (RCTs) were not found from our literature search. Due to the high level of heterogeneity in the study and patient characteristics, meta-analyses were not performed. A narrative summary of the included study findings was instead constructed. Planned subgroup analyses based on use of additional treatments (i.e. surgery alone or surgery with adjuvant chemo or radiotherapy; primary CRT with or without salvage surgery), surgical approach (open, TORS or TLM), chemotherapy agent (cisplatin or cetuximab), and based on patient characteristics such as HPV status, smoking habit and alcohol use were performed when sufficient data were available. For the economic review, costs and cost-effectiveness outcomes of primary surgery with or without adjuvant CRT, and of primary CRT with or without salvage surgery from the available evidence were summarized, and reported narratively and in tables. Summary of Evidence Quantity of Research Available A total of 772 citations were identified in the literature search. Following screening of titles and abstracts, 719 citations were excluded and 53 potentially relevant reports from the electronic search were retrieved for full-text review. No potentially relevant publications were retrieved from the grey literature search. Of these 53 potentially relevant articles, 38 publications were excluded for various reasons, while 15 publications (14 clinical studies and one economic evaluation) met the SYSTEMATIC REVIEW Treatments for Locally Advanced Oropharyngeal Cancer DRAFT for consultation 11

12 inclusion criteria and were included in this report. Appendix 2 describes the PRISMA flowchart of the study selection. A list of included and excluded studies, with reasons for exclusion, is provided for each research question in Appendices 3 and 4. Summary of Patient and Study Characteristics Details of the individual study characteristics are provided in Appendix 5. Study Design Fourteen non-randomized studies were identified regarding the comparative clinical effectiveness of primary surgery versus primary CRT for locally advanced oropharyngeal cancer. Six studies were prospective, seven studies were retrospective, and one study 30 was cross-sectional. Specifically, four studies 18-20,31 were prospective cohort studies, one study 22 was a prospective case series compared to a historical cohort, one study 21 was a prospective observational pre and post study compared to a historical cohort, seven studies were retrospective cohort studies. One economic evaluation 32 was identified regarding the costeffectiveness of primary surgery versus primary CRT. The study 32 had a cost-effectiveness analysis and a Markov model was designed. Country of Origin Of the fourteen studies, three studies 18,22,30 were conducted in Italy, two studies 19,31 were conducted in Canada, three studies 20,23,24 were conducted in the United States, one study 21 was conducted in the United Kingdom, one study 25 was conducted in Australia, one study 26 was conducted in Japan, two studies 27,29 were conducted in South Korea, and one study 28 was conducted in Taiwan. The economic evaluation 32 was conducted in the United States. The analysis was performed from the payer perspective with a 10-year time horizon. Patient Population Additional detail of the patient characteristics in the included studies is provided in Appendix 6. All of the studies included patients with locally advanced oropharyngeal cancer. Two of the studies 18,20 had all patients with oropharyngeal squamous cell carcinoma, but they provided separate data for locally advanced oropharyngeal squamous cell carcinoma. Six studies reported patients HPV status, 20,21,23-25,31 and five studies reported smoking habits. 20,24,26,27,31 One study reported separate data on patients with HPV status and smoking habits. 31 While eight studies had patients in treatment groups with different demographics such as age, gender, or risk profile, six studies 22,24,26,28,30,31 reported that there was no statistically significant differences in patient demographics or comorbidities between the intervention groups. One study reported a different radiation dose used between the treatment groups. 29 SYSTEMATIC REVIEW Treatments for Locally Advanced Oropharyngeal Cancer DRAFT for consultation 12

13 The economic evaluation 32 designed a Markov model to simulate the clinical history of non-smoking 65-year-old with T1-2, N2a-b, HPVpositive oropharyngeal squamous cell carcinoma. Interventions All fifteen studies used concurrent CRT as their intervention. All studies used cisplatin or other platinum-based drugs for chemotherapy. In addition to platinum-based drugs, three studies used 5- fluouracil, 22,29,30 one study used cetuximab and tirapazamine, 18 one study used 5-fluouracil, doxorubicin and taxanes, 19 and one study used mitomycin C. 21 For radiotherapy, either a conventional approach or IMRT were used in all studies, but details or dose were not specified in eight studies ,23,26-29 Comparator Among the 14 included clinical studies, the surgical approach was open surgery in four studies, 19,25,27,28 open surgery or transoral surgery in six studies, 22,23,26,29-31 transoral laser microsurgery (TLM) in one study, 21 transoral robotic surgery (TORS) in one study, 20 TLM or TORS in one study, 24 and the specific approach was not reported in one study. 18 Eight studies had post-operative radiotherapy (PORT) as adjuvant therapy, 18,22,25-30 and six studies had PORT or CRT as adjuvant therapy ,23,24,31 The economic evaluation study used TORS as the surgical approach, and PORT or CRT as adjuvant therapy. 32 All studies used cisplatin or other platinum-based drugs for chemotherapy. For radiotherapy, conventional approach or IMRT were used in all studies, but details or dose were not specified in eight studies ,23,26-29 Outcomes Thirteen studies reported on oncologic, functional, toxicity and complication outcomes, in which seven studies reported oncologic outcomes after 5 years follow-up 19,20,25-28,31 and the remaining six studies reported outcomes less than 5 years follow-up ,29,30 Four studies 18,24,29,30 reported quality of life outcomes. The costeffectiveness evaluation reported costs, and cost per quality-adjusted life years (QALYs). The analysis was performed from the payer perspective with a 10-year time horizon. Cost and quality-adjusted life years (QALYs) were discounted at an annual rate of 3%. The Markov model was based on a base-case of a non-smoking 65-year old man with T1-2, N2, HPV-positive oropharyngeal squamous cell carcinoma. Summary of Critical Appraisal All included clinical studies were non-rcts, with the potential bias in patient selection. Due to the nature of the interventions, blinding was not possible in the included studies. Hypotheses were described, the method of selection from the source population was described, main outcomes, interventions, patient characteristics, and main findings were clearly described, and estimates of random variability and actual probability values were provided in most studies ,26-31 Patients and treatment options were representative of the condition under study. Among the trials reporting oncologic outcomes, only one study had clear definitions of clinical endpoints. 28 The lack of clinical endpoint SYSTEMATIC REVIEW Treatments for Locally Advanced Oropharyngeal Cancer DRAFT for consultation 13

14 definitions may lead to variability in the observed results both within and between studies. There was imbalance in patient demographics between the treatment groups in eight studies despite attempts to correct for baseline imbalance, with six 22,24,26,28,30,31 studies reporting that there was no statistically significant differences between the groups. It was unclear in all studies whether there was sufficient power to detect a clinically important effect as studies did not report power calculations to determine an appropriate sample size Loss to follow-up not clearly described in eight studies ,24-28 The cost-effectiveness study 32 based cost calculations on the Chicago region 2015 Medicare payment schedule. Medicare payments vary across the country, influencing the relative cost-effectiveness of the two treatment strategies. The utility data were extracted from one study that favored surgery, thus presenting a potential bias towards surgery. The Markov model was based on a base-case of a non-smoking 65- year old man with T1-2, N2, HPV-positive oropharyngeal squamous cell carcinoma. The 10-year time horizon seems appropriate. All relevant costs were considered. Appropriate sensitivity analyses were done. The generalizability of the results may not be strong since the costs of the intervention varies across jurisdictions, and analyses was not based on large volume of data on which to estimate clinical efficacy and harms of treatment strategies. Details of the quality appraisal of individual included studies are provided in Appendix 7. Summary of Findings Clinical Review The literature search identified 14 observational studies comparing clinical outcomes between primary surgery and primary concurrent CRT in patients with locally advanced oropharyngeal cancer. A narrative synthesis was completed, with a focus on the outcomes reported after the longest follow-up time (5 years for oncologic outcomes, and 1 year for functional outcomes). Details of the clinical findings in the included studies are provided in Appendix 8. Clinical findings comparing surgery (all types) and concurrent CRT is listed in Table 2, and subgroup analyses between open surgery and concurrent CRT, and between TLM/TORS and concurrent CRT is listed in Tables 3 and 4, respectively. Appendix 8, Tables A9 and A10 provide the individual study findings according to outcome. Oncologic and Functional Outcomes As elaborated below, in general, oncologic outcomes between the two treatment strategies after 5 years were similar. There were inconsistencies in findings among studies and lack of consistent statistically significant differences between outcomes. When patients were stratified by risk factors such as HPV status and smoking habits, data from one study suggested that a primary surgery plus adjuvant CRT approach offered higher disease-specific survival (DSS) rate than concurrent CRT with or without salvage surgery in patients with p16- negative cancers, and in smokers. Data from one study found similar overall survival (OS) rates between the two treatment strategies for high-risk patients but significantly higher survival rate with CRT SYSTEMATIC REVIEW Treatments for Locally Advanced Oropharyngeal Cancer DRAFT for consultation 14

15 strategy for intermediate/low risk patients. Data on oncologic outcomes with follow-up times less than 5 years mostly showed non-statistically significant differences between the two treatment strategies. Limited evidence on functional outcomes after 1 year follow-up seems to favour concurrent CRT over open surgery, but appear to favour surgery over concurrent CRT when transoral laser microsurgery (TLM) or transoral robotic surgery (TORS) was the surgical approach. Oncologic Outcomes after 5 years Follow-Up Three prospective cohort studies 19,20,31 and four retrospective chart reviews, compared five-year oncologic outcomes between surgery and concurrent CRT in patients with locally advanced oropharyngeal cancer. Examination of study details in terms of patient demographics or treatment did not show a clear pattern to explain the differences in outcomes between studies. For DSS, surgery lead to greater survival rate in three studies, 19,20,31 and lower rate in one study; 28 statistical significance was found in two studies, 19,31 and differences were not significant in two studies. 20,28 When patients were stratified by p16 (HPV status) and smoking status, data from one study 31 on 200 patients found that surgery (transoral or open) plus adjuvant CRT was associated with statistically significantly higher DSS for p16-negative patients (72.0% vs. 37.1%) and for smokers (76.9% vs. 47.5%) as compared to CRT. When patients were further stratified into subsets, smokers with p16-positive cancers (n = 81) had statistically significantly higher survival rate with surgery than with CRT (85.4% vs 66.2%). Differences between the two strategies for p16-positive non-smokers (n = 35), p16-negative smokers (n = 65), and p16-negative non-smokers (n = 19) were not statistically significant. For overall survival (OS), findings were mixed among studies, with surgery leading to a greater survival rate than CRT in three studies, 19,20,31 and smaller rate in four studies; statistical significance was found in three studies 19,25,31 and not significant in the rest. There was no clear pattern with regards to the characteristics of studies that demonstrated statistically significant differences and those that did not. Data from one study 31 showed that p16-negative smokers had statistically significantly higher survival rate with surgery than with CRT (43.1% vs 20.8%). Differences between the two strategies for the other subsets such as p16-positive non-smokers, p16-positive smokers and p16-negative non-smokers were not statistically significant. Data from one study that stratified patients into high-, intermediate- and lowrisk groups 25 found similar survival rates between the two treatment strategies for high-risk patients but a statistically significant higher rate with CRT for intermediate/low risk patients (HR 4.46; 95% CI ). For disease-free survival (DFS), surgery lead to greater survival rate in onestudy, 28 and lower rate in one study 27 ; the difference was not statistically significant in both studies. For local-regional control (LRC), surgery led to a greater control rate in one study, 28 and a lower rate in one study; 20 the difference was not statistically significant in both SYSTEMATIC REVIEW Treatments for Locally Advanced Oropharyngeal Cancer DRAFT for consultation 15

16 studies. For locoregional recurrence rate (LRR), surgery led to more patients with locoregional recurrence than CRT in one study, 27 and fewer patients in one study. 26 Statistical significance was not reported in either study. For locoregional recurrence-free survival (LRRFS), data from one study suggested surgery led to a lower survival rate than CRT 27 the difference was not statistically significant. For progressionfree survival (PFS), data from one study showed surgery lead to a lower survival rate than CRT; 26 the difference was not statistically significant. For distant metastasis-free survival (DMFS), surgery lead to greater survival rate in one study, 28 and a lower rate in one study; 27 the difference was not statistically significant in both studies. Oncologic Outcomes after less than 5 years Follow-Up Five studies reported oncologic outcomes after less than 5 years of follow-up. 19,22,23,29,30 DSS, OS, DFS and PFS were found not statistically significantly different between surgery (transoral or open) and concurrent CRT in four trials with follow-up times from 2 to 4 years, 22,23,29,30 while one trial found open surgery significantly reduced the likelihood of DSS and OS after 2 years follow-up. 19 Functional Outcomes Two retrospective cohort studies 24,26 and one observational pre and post study 21 compared functional outcomes between surgery and concurrent CRT in patients with locally advanced oropharyngeal cancer with up to one year follow-up. At completion of treatment, surgery lead to greater gastrostomy tube dependence rate than CRT in the study in which the surgery approach was mostly open surgery, 26 and a lower rate of dependence in the study in which transoral laser microsurgery (TLM) or transoral robotic surgery (TORS) were the surgical approaches. 24 At one year, surgery lead to a lower gastrostomy tube dependence rate (3% vs 10%), and lower esophageal stricture rate (0% vs 7%) than CRT when TLM or TORS were used. 24 The differences in both studies in tube dependence rates were statistically significant. A pre and post observational study 21 found that fewer patients undergoing TLM (76%) reported swallowing problems after treatment than those undergoing CRT (92%) (in this study, the majority of patients in the TLM group were HPV-positive, but testing was not done in the CRT group). Change in MD Anderson Dysphagia Inventory score (MDADI) between pre-treatment and 3 months post-treatment was greater for CRT than for TLM (effect size not reported); the difference was statistically significant. Table 2: Surgery (all types) vs CRT Outcome Surgery + Adjuvant RT/CRT CRT +/- Salvage surgery Notes Oncologic outcomes (at 5 years [range]) OS 52.9% to 86% 19,20,25-28, % to Surgery led to a 88.9% 19,20,25-28,31 greater overall survival rate in 3 studies, 19,20,31 and Statistical Significance between Surgery and CRT SS was demonstrated in 3 studies 19,25,31 and not SS in the remaining SYSTEMATIC REVIEW Treatments for Locally Advanced Oropharyngeal Cancer DRAFT for consultation 16

17 lower rate in the 4 20,26-28 remaining DSS 62.9% to 91% 19,20,28, % to 78% 19,20,28,31 Surgery led to a greater diseasespecific survival rate in 3 studies, 19,20,31 and a lower rate in the remaining 1 28 DFS 53.7% to 79.5% 27,28 48% to 84.2% 27,28 Surgery led to a greater diseasefree survival rate in 1 study, 28 and a lower rate in the remaining 1 27 LRR 9.2% to 25.8% 26,27 8.1% to 28.0% 26,27 Surgery led to more patients with locoregional recurrence than CRT in 1 study, 27 and fewer patients in 1 study. 26 LRC 59.2% to 81% 20, % to 91.0% 20,28 Surgery led to a greater control rate in 1 study, 28 and a lower rate in the remaining 1 20 LRRFS 88.4% % 27 Surgery led to a lower recurrencefree survival rate than CRT PFS 51.0% % 26 Surgery led to a lower progressionfree survival rate than CRT DMFS 88.9% to 90.7% 27, % to 92.3% 27,28 Surgery led to a greater distant metastasis-free survival rate in 1 study, 28 and smaller rate in the remaining 1 27 Functional outcomes Gastrostomy tube dependence rate At completion of PORT: 13% 24 to 25.8% 26 At 1 year: 3% 24 At completion of CRT: 11% 26 to 29% 24 At 1 year: 10% 24 At completion of treatment, surgery led to a greater gastrostomy tube dependence rate in 1 study, 26 and smaller rate in the remaining SS was demonstrated in 2 studies, 19,31 and not SS in the remaining 2 20,28 No SS was demonstrated SS values not reported No SS was demonstrated No SS was demonstrated No SS was demonstrated No SS was demonstrated SS was demonstrated Esophageal stricture rate At 1 year, surgery lead to a lower dependence rate than CRT 24 At 1 year: 0% 24 At 1 year: 7% 24 At 1 year, surgery led to a lower esophageal stricture rate than CRT. SS value not reported SYSTEMATIC REVIEW Treatments for Locally Advanced Oropharyngeal Cancer DRAFT for consultation 17

18 Swallowing function At 3 months, compared to baseline Based on MDADI, 16/21 patients (76%) reported more swallowing problems after treatment 21 At 3 months, compared to baseline Based on MDADI, 24/26 patients (92%) reported more swallowing problems after treatment 21 Surgery led to a reduced chance of swallowing problems than CRT after treatment SS was demonstrated Change in MDADI score between baseline and 3 months was greater for CRT than for surgery CRT = concurrent chemoradiotherapy; DFS = disease-free survival rate; DSS = disease-specific survival rate; DMFS = distant metastasis-free survival rate; LRC =locoregional control rate; LRR =localregional recurrence; LRRFS =locoregional recurrence-free survival rate; MDADI = MD Anderson Dysphagya Inventory; OS = overall survival rate; PFS = progression-free survival rate; PORT = post-operative radiotherapy; SS = statistical significance Toxicity Outcomes and Complications A retrospective cohort study examining the role of primary surgery in 82 patients with resectable stage III/IV tonsillar carcinoma 28 found no statistically significant differences in radiotherapy-related toxicity between open surgery plus adjuvant radiotherapy and concurrent CRT after a median follow-up time of 39 months, with the most common acute and late toxicity being radiation mucositis (54.5% in the surgery group; 80% in CRT group), dry mouth (77.3% in surgery group; 80% in CRT group), and neck fibrosis(54.5% in surgery group; 32% in CRT group). A retrospective cohort study compared open surgery plus adjuvant radiotherapy to concurrent CRT in 114 patients with locally advanced tonsillar carcinoma after a median follow-up time of 58 months in the surgery group and 44 months in the CRT group. 27 More CRT patients than surgery patients experienced grade 3 (or higher) hematological toxicities (leucopenia and neutropenia) (17 CRT patients; 4 surgery patients) and grade 2 pharyngitis during treatment (46 CRT patients; 49 surgery patients); the differences were statistically significant. Acute dermatitis, mucositis, chronic swallowing difficulty, dry mouth and trismus were most common complications, but there was no statistically significant difference between the two treatment strategies. Quality of Life Reported quality of life scores for physical and social functions were favourable in the CRT group compared to surgery, after a median follow-up time of 56 months. Data from studies with shorter follow-up times suggested similar quality of life between the groups after two years and TLM or TORS led to better swallowing outcomes after one year. Long-term quality of life was evaluated in a cross-sectional study of 57 patients with locally advanced cancer who underwent surgery (transoral, open, or both) plus adjuvant radiotherapy or concurrent CRT. 30 After a median follow-up time of 56 months, the scores for physical and social functions were favourable in the CRT group (differences were statistically significant) using the European SYSTEMATIC REVIEW Treatments for Locally Advanced Oropharyngeal Cancer DRAFT for consultation 18

19 Organization Research and Treatment of Cancer QoLC30 Questionnaires (EORTC-QLQ-C30). Differences in other domains such as role, emotional and cognitive functioning were not statistically significant between the two groups. The global quality of life score of the EORTC was statistically higher in the CRT group. Surgical patients showed statistically greater problems (higher scores) with pain, fatigue, swallowing, social eating and social contact. Patients in CRT group reported statistically higher problems with open mouth, dry mouth, teeth, and sticky saliva, using the EORTC-QLQ-H&N35 questionnaire. In a retrospective cohort study comparing quality of life of patients with locally advanced oropharynx carcinoma undergoing transoral laser microsurgery (TLM) or transoral robotic surgery (TORS) plus adjuvant radiotherapy and concurrent CRT. 24 After 1 year follow-up, there was no statistically significant difference in any of the University of Washington Quality of Life (UW-QOL) domains, except for the swallowing outcome when the outcomes statistically favoured TLM or TORS. A prospective study compared the quality of life outcomes of 96 patients with all-stage oropharyngeal cancer undergoing surgery (type of surgery not specified) plus adjuvant radiotherapy or concurrent CRT. 18 Based on the EORTC QLQ H&N35 module, both groups reported the greatest deterioration in the head and neck module at 3 months. In stage III/IV patients, a higher proportion of patients receiving surgery plus adjuvant radiotherapy experienced clinically significant deterioration in more domains compared to CRT patients at 3 months; however, by 12 months this trend had reversed in outcomes such as dry mouth, coughing, feeling ill, sexuality, teeth, and speech, when higher proportions of CRT patients reported clinically significant deterioration. A retrospective chart review compared the quality of life outcomes of 42 patients with locally advanced tonsillar carcinoma undergoing surgery (open or transoral) plus adjuvant radiotherapy or concurrent CRT. 29 Based on the EORTC QLQ C30, the scores for global health status was similar between the two groups after 2 years of follow-up. Patients in the surgery group reported statistically higher scores for cognitive and social function, but significantly lower scores for insomnia. Based on the EORTC QLQ H&N35module, there were no statistically different scores between the two groups. Subgroup Analyses Data was available for subgroup analyses on different surgical approaches (open surgery, TORS or TLM) and is reported in Tables 3 and 4.Subgroup analyses showed that the type of surgery, open or transoral (TORS or TLM), does not change the oncologic outcomes compared to concurrent CRT. Oncologic outcomes between the two treatment strategies after five years were similar, with inconsistent findings among studies and lack of consistent statistical significance between outcome differences. Functional outcomes seem to favour TLM or TORS after one year follow-up. SYSTEMATIC REVIEW Treatments for Locally Advanced Oropharyngeal Cancer DRAFT for consultation 19