Intervention Protocol

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Minimally invasive surgery versus radiotherapy/chemoradiotherapy for early-stage oropharyngeal carcinoma

  1. James Howard1,*,
  2. Liam Masterson1,
  3. Raghav C Dwivedi1,
  4. Faruque Riffat2,
  5. Richard Benson3,
  6. Sarah Jefferies4,
  7. Piyush Jani1,
  8. James R Tysome4,
  9. Chris Nutting5

Editorial Group: Cochrane Ear, Nose and Throat Disorders Group

Published Online: 20 FEB 2014

DOI: 10.1002/14651858.CD010963


How to Cite

Howard J, Masterson L, Dwivedi RC, Riffat F, Benson R, Jefferies S, Jani P, Tysome JR, Nutting C. Minimally invasive surgery versus radiotherapy/chemoradiotherapy for early-stage oropharyngeal carcinoma (Protocol). Cochrane Database of Systematic Reviews 2014, Issue 2. Art. No.: CD010963. DOI: 10.1002/14651858.CD010963.

Author Information

  1. 1

    Cambridge University Hospitals NHS Foundation Trust, ENT Department, Cambridge, UK

  2. 2

    University of Sydney, Westmead Hospital, Sydney, Australia

  3. 3

    Addenbrooke's Hospital, Oncology Centre, Cambridge, UK

  4. 4

    Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK

  5. 5

    Royal Marsden Hospital, Head and Neck Unit, London, UK

*James Howard, ENT Department, Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge, CB2 0QQ, UK. j.howard@doctors.org.uk.

Publication History

  1. Publication Status: New
  2. Published Online: 20 FEB 2014

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Background

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support
 

Description of the condition

Approximately 600,000 cases of head and neck squamous cell carcinoma (HNSCC) are diagnosed each year, making it the sixth most common cancer worldwide (Ramqvist 2010). Oropharyngeal squamous cell carcinoma (OPSCC) constitutes approximately 10% of all HNSCC and its epidemiology is noted to have changed worldwide. In developed countries, the incidence of OPSCC is steadily rising, particularly in younger age males (Chaturvedi 2011).

Human papillomavirus (HPV) is a major carcinogen, with an estimated 4.8% of total worldwide cancers in 2008 linked to the virus (de Martel 2012). The association between high-risk (carcinogenic) HPV and oropharyngeal cancer is now evident from data collected by independent controlled studies. The virus now fulfils epidemiological criteria for disease causality, especially in non-smokers (Sudhoff 2011). A recent meta-analysis of the world literature demonstrated that the proportion of oropharyngeal squamous cell carcinoma caused by HPV has increased from 40.5% in studies recruiting before the year 2000 to 72.2% in studies reporting after 2005 (Mehanna 2012). It is of interest to note that this group of patients has significantly improved rates of both overall survival and disease-free survival compared to HPV-negative tumour groups (Ang 2010; Fakhry 2008). Indeed the presence or absence of HPV with regard to the tumour may have a greater impact on five-year survival than T-stage or nodal status alone (Haughey 2011).

Risk factors for oral HPV infection include a history of orogenital sexual practice, a large number of sexual partners and first intercourse at an early age. The same factors also reflect changes in modern society and combine to increase the cumulative effect of HPV infection in OPSCC (Chung 2009). HPV-associated OPSCC behaves differently from the other, more common type, which affects an older age group and is normally associated with smoking and alcohol. Virus-associated disease often presents with a small primary in the oropharynx combined with a metastatic cystic deposit in the neck and this entails a higher stage at presentation for the majority of patients (Ang 2010; Evans 2010).

 

Description of the intervention

Over the last 20 years management of oropharyngeal cancer has changed dramatically. In 2002, Parsons et al published a review of 51 studies of patients with OPSCC who were treated with surgery with or without radiation therapy or primary radiation therapy without neck dissection (Parsons 2002). The cumulative five-year survival was 47% for patients undergoing primary surgical resection with or without neck dissection, and 43% for those undergoing primary radiation therapy with or without neck dissection. However, the severe complication rate was 23% in the primary surgical group and only 6% in the primary radiation group. This led to the conclusion that non-operative therapy was superior to operative therapy for OPSCC of all stages. More recently, a large meta-analysis of 17,346 HNSCC patients that compared primary radiotherapy with chemoradiotherapy provided updated results. The study concluded an absolute survival benefit of 6.5% after five years in patients treated with concurrent chemoradiotherapy (Pignon 2009).

As the biological differences in viral/non-viral associated OPSCC are further elaborated, radical change in most therapeutic interventions has taken place. With regard to radiotherapy, intensity modulation and computerised planning have been introduced in addition to external beam therapy. In surgery, the focus has shifted to the use of minimally invasive procedures such as transoral laser microsurgery or transoral robotic surgery. These techniques have the potential to improve organ preservation and function, decrease postoperative complications, reduce the length of hospital stay, improve quality of life and ameliorate the economic burden of treatment. Additionally, with regards to control of lymphatic spread, neck dissections have become more selective (resulting in the removal of fewer normal structures and therefore lower morbidity); we plan to address this in a subgroup analysis in this review (Adelstein 2012).

Current management, following the US National Comprehensive Cancer Network (NCCN 2013) and British Association of Otorhinolaryngology, Head and Neck Surgery (BAHNO 2011) guidelines for T1, N0-2 oropharyngeal tumours, is either definitive radiotherapy (with or without salvage surgery) or primary surgery (with or without ipsilateral or bilateral neck dissection). Post surgery, if there is extracapsular spread or a positive margin not amenable to re-resection, the patient should have adjuvant chemoradiotherapy. If there are other adverse features (pT3-4 primary, N2-3 nodal disease, nodal disease in levels IV or V, perineural invasion or vascular embolism) patients should at least have radiotherapy with consideration of chemoradiotherapy. For T2 lesions the current guidance is for patients to receive induction chemotherapy prior to radiotherapy or to receive chemoradiotherapy.

The extent of neck dissection depends on the staging. In the case of N0 lesions a selective neck dissection of at least levels II-IV is recommended. In N1-N2a-c cases a selective to comprehensive neck dissection is recommended. The NCCN guidelines state: "In general, patients undergoing selective neck dissection should not have clinical nodal disease; however, selective neck dissection may prevent morbidity in patients with nodal disease and may be appropriate in certain patients with N1-N2 disease".

Transoral approach, minimally invasive surgery poses several challenges in relation to haemostasis, illumination and tissue manipulation. In particular, transoral laser surgery is limited by a 'line of sight' where the lens of the microscope, used for visualisation, is distant from the patient. The CO2 laser is also not ideally suited to haemostasis, sometimes requiring alternation of the laser with diathermy or surgical clips. The long manipulators can further restrict the surgeon. Piecemeal removal may be required to facilitate the minimally invasive approach, which goes against the traditional tenets of en-bloc removal to preserve the specimen for the histopathologist and in order to prevent seeding of the tumour. Data published by several units have provided evidence that challenges this latter point (Christiansen 2006; Haughey 2011).

Robotic surgery has now emerged to overcome some of the limitations of laser surgery and further expand the minimally invasive surgery portfolio. The advantages offered to the surgeon include a three-dimensional view, 360° robotic arm movement (in restricted spaces with precision of movement), hand tremor filtration and lack of muscle fatigue. Line of sight restrictions can be avoided as the tip of endoscope is near the resection tissue and angled instruments can be used (Genden 2012).

 

How the intervention might work

In the 1980s, Wolfgang Steiner pioneered the transoral use of lasers to resect tumours of the upper aerodigestive tract (Steiner 1988). Subsequent publications have confirmed that survival using these transoral laser techniques is at least as good as with primary radiotherapy/chemoradiotherapy, whilst long-term swallowing function is significantly enhanced (Haughey 2011; Rich 2011).

The published literature suggests that survival outcomes are similar for OPSCC treated by either transoral laser microsurgery or lip split mandibulotomy (Jackel 2007). One recent clinical trial comparing both modalities had too few patients in each group to make a valid comparison with respect to survival, but suggested a benefit of transoral laser microsurgery for other parameters such as tracheostomy rate, time to decannulation, mode of feeding, length of hospital stay and cost (Williams 2013).

Most tertiary head and neck ENT departments will already possess or have access to a CO2 laser, given its use in the larynx, and its limitations are well recognised. However, the expertise required for its use in resection of OPSCC is less widespread. Nevertheless, given the possibilities in terms of patient outcomes its use can only increase (Grant 2009).

In recent years, additional evidence of enhanced functional outcome following transoral tumour resection has been provided by the early proponents of transoral robotic surgery (Lawson 2011; Moore 2009; Weinstein 2012). The da Vinci Surgical Robot (Intuitive Surgical Incorporated, CA, USA) has been utilised for almost all surgical procedures performed in the head and neck region (Weinstein 2012). The system comprises three components: (a) a high-definition visual display unit, (b) a surgical control platform that is distant from the patient, and (c) a robotic platform adjacent to the patient. The surgeon can remotely operate the robot using EndoWrist technology, which offers several advantages in terms of tremor filtration, three-dimensional visualisation and wristed instrumentation. The surgical platform allows control of robot manipulators that normally consist of a camera arm (providing true stereoscopic, high-definition images) and two 8 mm or 5 mm handling arms.

Lack of haptic feedback, extra space and time allocation are common limitations that are likely to improve in the near future with advancing technology. The cost of installation is approximately GBP 1 million along with a GBP 70,000 to 80,000 yearly maintenance fee and GBP 150 to 500 per case due to disposable instrumentation. This high price restricts acquisition to larger teaching hospital settings where the cost can be shared with urology, general surgery and cardiothoracic departments (Weinstein 2007).

 

Why it is important to do this review

The oropharynx plays an essential role in swallowing, speech and protecting the airway as it is situated at the bifurcation of the respiratory and digestive tract (Dwivedi 2009). Treatment modalities are heavily influenced by the aim of reducing the risk of functional disability where possible.

Early-stage tumours arising from the tonsil or base of the tongue region (T1 or T2) can be a technical challenge to excise and may necessitate a trans-cervical or mandibulotomy approach. Radiotherapy or chemoradiotherapy are alternative primary treatments and will often be given as adjuvant treatment if complete surgical clearance cannot be obtained. Open surgery and radiotherapy/chemoradiotherapy both have drawbacks in terms of cost, overall survival and patient quality of life (Haigentz 2009; Machtay 2008). This latter point has become more important because HPV-associated OPSCC affects a younger patient cohort who may have to carry the burden of treatment-related morbidity for a much longer period of time (Quon 2013).

Advanced technology has now made it possible to completely resect a primary oropharyngeal tumour using transoral, minimal access surgery. Lasers can be used to resect tumours under microscopic guidance and three-dimensional images of the back of the mouth enable robotically guided instruments to dissect tumours free from surrounding tissues. So far, observational studies suggest that these approaches may have an advantage by improving patient quality of life and functional outcome, and reducing the need for adjuvant chemoradiotherapy (Leonhardt 2012; Moore 2013). Furthermore, the use of transoral laser microsurgery or transoral robotic surgery for the primary site may permit a lower radiation dose to the neck (60 Gy rather than 70 Gy), with a concomitant reduction in radiation-related morbidity. This has raised the potential option of 'de-escalation therapy' in the case of HPV-related OPSCC (Masterson 2014; Moore 2009; Moore 2013). The potential benefits of this are apparent when one considers the well-established relationship between the radiation dose to the constrictor muscles and long-term swallowing difficulties: patients in whom more than 78% of their cricopharyngeus inlet receives over 60 Gy have a 50% risk of developing a stricture (Chen 2010).

 

Objectives

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support

To assess the efficacy of transoral robotic surgery or transoral laser microsurgery for early-stage (T1-2, N0-2) oropharyngeal carcinoma in comparison to radiotherapy/chemoradiotherapy.

 

Methods

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support
 

Criteria for considering studies for this review

 

Types of studies

Randomised controlled clinical trials.

 

Types of participants

Patients with carcinoma in the oropharynx subsite will be included (as defined by the World Health Organization classification C09, C10). Oral cavity (C01-C02, C03, C04, C05-C06), hypopharynx (C13), nasopharynx (C11) and larynx (C32) lesions will be excluded (WHO 2000).

Cancers will be primary squamous cell carcinomas arising from the oropharyngeal mucosa. The tumour will be classified as T1-T2 with or without nodal disease and with no evidence of distant metastatic spread. A significant proportion of patients are expected to be HPV16-positive. 

 

Types of interventions

 

Intervention

Transoral, minimally invasive surgery with or without adjuvant radiotherapy or adjuvant chemoradiotherapy.

 

Control

Primary radiotherapy with or without induction or concurrent chemotherapy for the tumour. The treatments received and compared will be of curative intent and patients will not have undergone prior intervention, other than diagnostic biopsy.

 

Types of outcome measures

 

Primary outcomes

  • Overall survival/total mortality (disease-related mortality will also be studied if possible)
  • Locoregional control
  • Disease-free survival
  • Progression-free survival or time to recurrence

All outcomes measured at two, three and five years after diagnosis.

 

Secondary outcomes

  • Quality of life
  • Harms associated with treatment
  • Patient satisfaction
  • Xerostomia score

 

Search methods for identification of studies

 

Electronic searches

We will search the following databases from their inception for published, unpublished and ongoing trials: the Cochrane Ear, Nose and Throat Disorders Group Trials Register; the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, current issue); PubMed; EMBASE; CINAHL; PsycINFO; LILACS; KoreaMed; IndMed; PakMediNet; CAB Abstracts; Web of Science; ISRCTN; ClinicalTrials.gov; ICTRP; Google Scholar and Google.

We will model subject strategies for databases on the search strategy designed for CENTRAL (Appendix 1). Where appropriate, we will combine subject strategies with adaptations of the highly sensitive search strategy designed by The Cochrane Collaboration for identifying randomised controlled trials and controlled clinical trials (as described in theCochrane Handbook for Systematic Reviews of Interventions Version 5.1.0, Box 6.4.b. (Handbook 2011)).

 

Searching other resources

We will scan the reference lists of identified publications for additional trials and contact trial authors where necessary. In addition, we will search PubMed, TRIPdatabase, The Cochrane Library and Google to retrieve existing systematic reviews relevant to this systematic review, so that we can scan their reference lists for additional trials. We will search for conference abstracts using the Cochrane Ear, Nose and Throat Disorders Group Trials Register.

 

Data collection and analysis

 

Selection of studies

Three authors (JH, LM and RD) will independently screen the results of the search to identify studies which broadly meet the inclusion criteria. We will assess studies selected for full-text review independently against predefined inclusion criteria. Any conflict will be resolved by referral to a senior author.

 

Data extraction and management

Three review authors (JH, LM and RD) will independently extract data using a specially designed data extraction form. We will pilot the data extraction forms on several papers and modify them as required before use. We will discuss any disagreements in full and consult a senior review author where necessary. If required, we will contact the authors for clarification or missing information.

For each trial we will record the following data.

  • Year of publication, country of origin and source of study funding.
  • Details of the participants, including demographic characteristics and criteria for inclusion and exclusion.
  • Details of the type of intervention, timing and duration.
  • Details of quality of life after treatment (EORTC QLQ-HN35 or equivalent questionnaire) (Singer 2013).
  • Details of treatment-related morbidity, categorised as acute (less than 90 days after treatment) or late (more than 90 days) and classified according to the Common Terminology Criteria for Adverse Events (CTCAE 2009).
  • Details of all other outcomes reported, including method of assessment and time intervals.
  • HPV status for each patient established by displaying p16 activity (a surrogate marker of viral activity) utilising immunohistochemistry and, if positive, confirmed by polymerase chain reaction or DNA/RNA in situ hybridisation (Schache 2011; Westra 2009).

 

Assessment of risk of bias in included studies

JH, LM and RD will undertake assessment of the risk of bias of the included trials independently, with the following taken into consideration, as guided by theCochrane Handbook for Systematic Reviews of Interventions (Handbook 2011):

  • sequence generation;
  • allocation concealment;
  • blinding;
  • incomplete outcome data;
  • selective outcome reporting; and
  • other sources of bias.

We will use the Cochrane 'Risk of bias' tool in RevMan 5.2 (RevMan 2012), which involves describing each of these domains as reported in the trial and then assigning a judgement about the adequacy of each entry: 'low', 'high' or 'unclear' risk of bias.

 

Assessment of heterogeneity

We plan to assess heterogeneity by inspecting the overlap of confidence intervals for the results of individual studies. We will utilise horizontal lines depicting these graphically. We plan to conduct formal assessment of heterogeneity using the Chi² test (with a significance level of α = 0.1 in view of the low power of this test) and the I² statistic (75% or more indicates a considerable level of inconsistency), both available in RevMan 5.2 (RevMan 2012).

 

Data synthesis

We plan to extract data from the included studies and enter the data into RevMan 5.2 for statistical analysis. In the event of incomplete data, we intend to contact the study authors to obtain further information. We will seek statistical advice where necessary. We will approach survival and disease recurrence in one of two ways depending on the data available. This may include analysis of the proportion surviving at two, three and five years as dichotomous outcomes or hazard ratios for comparison in meta-analysis. Secondary outcomes will be restricted to assessment of validated questionnaires (where appropriate). If the data provided are in the form of means and standard deviations, we intend to display the effects on outcomes as standardised mean differences (SMD) with 95% confidence intervals (CIs) and using an intention-to-treat analysis. If hazard ratios are not quoted in studies, we plan to calculate them from available summary statistics such as observed events, expected events, variance, confidence intervals, P values or survival curves (Parmar 1998).

 

Subgroup analysis and investigation of heterogeneity

We intend to assess clinical heterogeneity by examining the types of participants, interventions and outcomes in each study. We will attempt a meta-analysis if studies are available with similar comparisons and report the same outcome measures. If appropriate, we intend to calculate pooled estimates using a random-effects model (Handbook 2011) as there is likely to be significant statistical or clinical heterogeneity (an I² value > 50%, as specified in the Cochrane Handbook for Systematic Reviews of Interventions).

If the data provided are in the form of means and standard deviations, we intend to display the effects on outcomes as standardised mean differences (SMD) with 95% CIs and using an intention-to-treat analysis.

Furthermore, if the subgroups show a clinically relevant difference we will report them separately using a fixed-effect model (Handbook 2011).

 

Sensitivity analysis

We will consider a sensitivity analysis to compare fixed and random-effects estimates. We also plan to undertake a sensitivity analysis to examine the effects of allocation concealment, randomisation, quality of follow-up and blind outcome assessment (if appropriate).

 

Acknowledgements

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support

We acknowledge the very helpful contributions made by the editorial team of the Cochrane ENT Disorders Group.

 

Appendices

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support
 

Appendix 1. CENTRAL search strategy

#1 MeSH descriptor: [Oropharyngeal Neoplasms] explode all trees
#2 MeSH descriptor: [Head and Neck Neoplasms] this term only
#3 MeSH descriptor: [Otorhinolaryngologic Neoplasms] explode all trees
#4 MeSH descriptor: [Neoplasms] explode all trees
#5 cancer* or carcinoma* or neoplas* or tumor* or tumour* or malignan* or SCC*
#6 #4 or #5
#7 MeSH descriptor: [Oropharynx] explode all trees
#8 oropharyn* or mesopharyn* or tonsil* or "head and neck" or "head neck" or "head-neck" or "head-and-neck" or tongue
#9 #7 or #8
#10 #6 and #9
#11 HNSCC or SCCHN or OP-SCC or OPSCC or OPC or SCCOP
#12 #1 or #2 or #3 or #10 or #11
#13 MeSH descriptor: [Surgical Procedures, Operative] explode all trees
#14 surg* or operat* or microsurg* or resect* or dissect* or microdissect* or excis or microresect*
#15 #13 or #14
#16 #12 and #15
#17 MeSH descriptor: [Head and Neck Neoplasms] this term only and with qualifiers: [Surgery - SU]
#18 MeSH descriptor: [Otorhinolaryngologic Neoplasms] explode all trees and with qualifiers: [Surgery - SU]
#19 MeSH descriptor: [Oropharyngeal Neoplasms] explode all trees and with qualifiers: [Surgery - SU]
#20 #16 or #17 or #18 or #19
#21 (minimal* and invasive) or transoral* or trans-oral* or "trans oral*" or TORS or TOLS or (minimal* and access) or TLM or ORATOR or TOVANS or "video assist*" or video-assist* or "computer guid*" or computer-guid* or laser or robot* or TOL
#22 MeSH descriptor: [Robotics] explode all trees
#23 MeSH descriptor: [Laser Therapy] this term only1
#24 MeSH descriptor: [Microsurgery] explode all trees
#25 MeSH descriptor: [Surgical Procedures, Minimally Invasive] this term only
#26 MeSH descriptor: [Lasers] explode all trees
#27 #21 or #22 or #23 or #24 or #25 or #26
#28 #20 and #27

 

Contributions of authors

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support

James Howard (JH): protocol draft, search strategy development, acquiring trial copies, trial selection, data extraction, data analysis, data interpretation, review draft and future review update.

Liam Masterson (LM): protocol draft, search strategy development, acquiring of trial copies, trial selection, data extraction, data analysis, data interpretation, review draft and future review update.

Raghav C Dwivedi (RCD): protocol draft, search strategy development, acquiring trial copies, trial selection, data extraction, data analysis, data interpretation, review draft and future review update.

Faruque Riffat (FR): protocol draft, data interpretation, review draft and future review update.

James Tysome (JT): protocol draft, data interpretation, review draft and future review update.

Richard Benson (RB): protocol draft, data interpretation, review draft and future review update.

Sarah Jefferies (SJ): protocol draft, data interpretation, review draft and future review update.

Piyush Jani (PJ): protocol draft, data interpretation, review draft and future review update.

Christopher Nutting (CN): protocol draft, data interpretation, review draft and future review update.

 

Declarations of interest

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support

None known.

 

Sources of support

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support
 

Internal sources

  • NIHR Cambridge Biomedical Research Centre, UK.

 

External sources

  • No sources of support supplied

References

Additional references

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Acknowledgements
  7. Appendices
  8. Contributions of authors
  9. Declarations of interest
  10. Sources of support
  11. Additional references
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