Title: Surgical Trials in Head & Neck Oncology: Renaissance and Revolution? Richard J Shaw MD FDS FRCS(OMFS)* Professor of Head and Neck Surgery Department of Molecular and Clinical Cancer Medicine The University of Liverpool Cancer Research Centre Roy Castle Building, 200 London Road Liverpool, L3 9TA Tel: 0151 794 8884, Fax: 0151 706 5798 [email protected] F Christopher Holsinger MD PhD FACS Professor of Otolaryngology / Head & Neck Surgery Stanford University School of Medicine 291 Campus Drive Rm LK3C02 Li Ka Shing Building, 3rd floor Dean's Office, MC 5216 Stanford, CA 94305-5101 (650) 723-4000 [email protected] Vinidh Paleri MS FRCS (CSiG) FRCS(ORL-HNS) Consultant Head & Neck and Thyroid Surgeon & Hon Clinical Senior Lecturer Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust +44 (0) 191 213 7630 [email protected] Mererid Evans PhD FRCR Consultant Clinical Oncologist, Velindre Cancer Centre, Velindre Road, Whitchurch, Cardiff, UK CF14 2TL 029 2061 5888 Ext 6160 [email protected] Catrin Tudur-Smith PhD Reader in Biostatistics, Institute of Translational Medicine, University of Liverpool Duncan Building, Daulby Street, Liverpool.UK [email protected] Robert L. Ferris, MD, PhD, FACS, Professor, Vice-Chair for Clinical Operations Chief, Division of Head and Neck Surgery Departments of Otolaryngology, Radiation Oncology, and Immunology Co-Leader, Cancer Immunology Program University of Pittsburgh Cancer Institute. Eye and Ear Institute, Suite 500 200 Lothrop St. Pittsburgh, PA 15213 Phone: 412-647-4654 Patient Office: 412-647-2100 [email protected] *corresponding author Keywords: Clinical trials, Head & neck surgery, evidence based medicine, head & neck squamous cell carcinoma Short title: Surgical Trials in Head & Neck Oncology
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as an ‘Accepted Article’, doi: 10.1002/hed.23846
Head & Neck
Page 2 of 9
Clinical trials for patients with head & neck cancer have been dominated by non-surgical interventions with the overwhelming majority of high impact publications in the fields of radiotherapy, chemotherapy and novel agents. The predictable result of this is that the evidence base largely ignores one important intervention, namely surgery. The ‘shifting sands’ of changing demographics, changing aetiology, new techniques and economic pressures in head and neck cancer threaten to marginalise treatments that are not formally and rigorously evaluated. In particular, the epidemic of Human Papillomavirus mediated oropharynx cancer challenges all those involved, including surgeons, to carefully evaluate the role of various modalities in the context of clinical trials. In contrast to the evident weakness of the evidence base, the field of head & neck surgery has advanced enormously, with transoral endoscopic head and neck surgery (eHNS) using either robotics(1) or the CO2 laser(2), sentinel node biopsy (3) and technical refinement in microvascular reconstruction(4-6). These cumulative advances now usher in a new era of personalised surgery. There is a risk that these treatments may not be widely adopted unless they have well conducted clinical trials supporting their introduction and rightly so. The surgical community must demonstrate their effectiveness in well-conducted clinical trials, protocols and registration studies to effect changes in clinical practice. Concomitant chemoradiotherapy is associated with significant toxicities(7, 8) and recent attempts to increase its efficacy by the use of induction chemotherapy (9, 10) and concurrent Cetuximab(11) have had limited success. Thus there is renewed interest in surgery and in combining minimally invasive surgery with modern radiotherapy techniques. The recognition that nonsurgical therapies have reached their limit of intensification, with potentially devastating, permanent long term morbidity or without appreciable benefit despite combination or sequential approaches, has led to re-evaluation of the potential role of oncologic resection which takes advantage of novel technologies and natural orifice access and approaches. Recently, head and neck surgeons have become increasingly pro-active in driving clinical trials. Completed, open or funded surgical trials in head and neck oncology conducted in the USA or UK are included in Table 1. The UK trials have been stimulated by the formation of the National Cancer Research Institute (NCRI) Head & Neck Clinical Studies Group, which includes a Surgery and Localised Therapies subgroup. The NCRI was formed in 2001 with the aim of increasing clinical trials activity in oncology. The dramatic John Wiley & Sons, Inc.
Page 3 of 9
Head & Neck
success, increasing recruitment 4-fold to 17% of the incident cancer population treated by the National Health Service (12), has revealed a relative paucity of surgically driven research(13). The Head and Neck Clinical Studies Group is one of three NCRI tumour site groups that have adopted the idea of a surgical subgroup; its constituents are 7 surgeons and, to maintain balance and appropriate expertise, also a pathologist, a clinical oncologist (ME) and a trials methodologist (CTS). Additionally, the relevant surgical associations (ENT-UK & British Association of Oral & Maxillofacial Surgeons) have funded two fellowship positions for surgical trainees within the Clinical Studies Group, thus mentoring a new generation of leaders in surgical research in the head and neck specialties. The renaissance of surgeon investigation regarding transoral surgery was stimulated by the advent of novel technologies, after several decades of equipoise and acceptance of clinical investigation into nonsurgical therapies. In the USA, the National Cancer Institute sponsored a Clinical Trials Planning Meeting on the Transoral Resection of Pharynx Cancer in 2011(14). A multidisciplinary team of more than 50 oncologists and critical partners in speech therapy, statistics, economics came to the consensus that further investigation of transoral surgery for oropharyngeal cancer was an important priority for the co-operative groups. Two Phase II trials were designed to explore the potential of eHNS: ECOG 3311 and RTOG1221, both opened in 2013. ECOG3311 examines the role of transoral eHNS to reduce toxicity in patients with good prognosis HPV-associated OPC, while RTOG1221 explores the role of surgery to intensify locoregional therapy with upfront surgery in poorer prognosis HPV-negative OPC. Parallel trials (PATHOS for good prognosis HPVassociated OPC and COMPARE for poorer-prognosis HPV-negative OPC) have recently been funded in the UK and will open to recruitment in 2015. The successful establishment of surgical trials in head and neck cancer on both sides of the Atlantic emphasises the important role surgeons can play by taking an active role in collaborative research groups. It is important to recognise the career pathway in academic head & neck surgery, not only in basic and translational laboratory research, but also in the field of clinical trials. In comparison to drug trials, where pharmaceutical or industrial sponsorship and funding may be available, surgical interventions may be less well supported. It is therefore vitally important to build a cadre of surgeons capable of driving academically led studies. Doubtless, surgical studies present particular challenges to trial design and methodology. It is John Wiley & Sons, Inc.
Head & Neck
more difficult to blind patients or investigators or use placebo arms when compared with drug trials. Often endpoints other than survival and recurrence are proposed that lack proven validity and make power calculations difficult. Establishing the concept of equipoise for an individual, rather than amongst a cohort of surgeons requires careful discussion and education. Introducing a positive view of clinical trials is vital to shifting the culture of the relevant H&N surgical specialties. It is likely that a culture where clinical uncertainty is tolerated (and even encouraged!) will foster a more positive attitude to surgical trials(15).It is important that surgeons have access to, and engage with clinical trials units who have relevant expertise. Where enrolment has been slower than the predicted trajectory, the barriers to recruitment have been systematically explored(16) and lessons learned. In contrast to non-surgical oncology specialties, clinical trials methodology is currently not prominent in the syllabus of surgical trainees. Several changes in the surgical training system are required to facilitate the trend for increased surgical participation in research, and to increase exposure of trainees in statistics, trial design and a culture of clinical investigation. Clinician-scientists in the past 20 years have generally been employed in laboratory studies, studying mechanisms of disease and biomarkers of clinical outcome to selected novel therapeutics. However, recent dedication to higher training in clinical and cost effectiveness research methods and study design has created a new generation of surgical investigators, focused on addressing clinically and societally relevant questions regarding treatment selection, surveillance, and multimodality therapy. In the UK, a head & neck trials methodology residential workshop was recently funded by the Medical Research Council and attended by 20 head & neck surgical trainees. Several new trial ideas and methodological discussions emerged. Recent surgical trial funding applications have challenged the applicants to specify how the surgeons will be trained and credentialed in new surgical techniques and how uniform standards of surgery will be maintained in the trial. Previously, the regulatory authorities (FDA & MHRA) have been largely focussed on drug studies and hence have little to offer, but this is an area of vital importance. As an exemplar of good practice, head and neck radiotherapy research has undergone a revolution in the last decade. It is known that poor quality radiotherapy reduces survival (by 20%) & locoregional control (by 24%) rates in head and neck squamous cell cancer (17). Intensity Modulated Radiotherapy (IMRT) has John Wiley & Sons, Inc.
Page 4 of 9
Page 5 of 9
Head & Neck
further reduced margins for error and increased the need to standardise practice. As a consequence, radiotherapy quality assurance (RT-QA) has become embedded in clinical trial protocols, helping to minimise variations and ensure that clinical trial outcomes reflect differences in randomisation schedules rather than departures from trial protocols. Trial RT-QA includes pre-trial and on-trial QA where outlines of ‘test case’ and trial patients are centrally reviewed against gold standard. Departmental inspections and credentialing may also be carried out prior to study opening. RT-QA for all clinical trials in the UK is funded by the Department of Health and managed centrally by a multi professional UK RTTQA group. Engagement with RT-QA has also been seen to provide benefits that extend beyond individual clinical trials to routine clinical practice, supporting the widespread implementation of innovations in radiotherapy and development of consensus standards. There are lessons here for surgical researchers. Although a hard copy of the operation may not be easily available as in radiotherapy, the need for agreed protocol, training, inspection and transparency are emerging as well as centralised pathology review. Clinical trials in head and neck surgery require new standards and unprecedented collaboration across institutions. For instance, for ECOG3311 and RTOG1221, surgeon credentialing for both trials was harmonized, with the support of the NCI, to identify qualified and experienced surgeons using a standardized approach in eHNS. Principal investigators and a working group of surgeons review all surgeon credentials, including de-identified paired operative notes and pathology reports for ten patients. As an example, ECOG 3311 and RTOG 1221 designed a novel approach to surgeon credentialing. For candidate surgeons with credentials that meet standard outlined below, surgeons were approved. Applicant surgical investigators specify the number of transoral oncologic resections required for credentialing (n=20) and evaluated in detail the operative notes/pathology reports of 10 of these cases by a multi-centre credentialing committee of experts, representing NCI, ECOG and RTOG. Not all applicants met the initial criteria and these have been encouraged to resubmit when appropriate cases warrant their accrual to these trials. Furthermore, the Working Group for Transoral eHNS will continue to provide guidance for ongoing quality assurance and assessment of serious adverse events, during these trials. In addition to the credentialing process for accrual onto ECOG 3311/RTOG 1221, ongoing surgical quality assurance has been set up, whereby a surgeon investigator must maintain less than 10% positive margins or grade III/IV bleeding (requiring a return to the operating room for control) to retain status as accruing to the trial. Similar John Wiley & Sons, Inc.
Head & Neck
arrangements for surgical credentialing and QA will be put in place for upcoming UK surgical trials for OPC, including PATHOS. In summary, it is vital to introduce surgical innovation in context of formal protocols or trials to ensure safety of future patients. In developing surgical credentialing for the current cohort of studies there is a clear opportunity to harmonise international efforts, which will foster future collaborative efforts. These goals require a shift in our training paradigm, from learning past and current techniques, to advancing the field through life-long learning and surgical investigation. These tenets are analogously part of training in clinical and medical oncology, where trial design is emphasized and critical thinking promoted. The benefits to the field include seamless academic transitions during a faculty career to design and incorporate prospective studies into daily surgical practice. Novel technologies, efficacy, QOL, function and cost effectiveness research must grow out of early inculcation of the culture of investigation, beginning with trials design, statistics, scientific method, and critical interpretation of clinical trial results, resulting in a greater evidence– based foundation for academic surgery and more rationale evolution of surgical therapy.
John Wiley & Sons, Inc.
Page 6 of 9
Page 7 of 9
Head & Neck
References 1.
White HN, Frederick J, Zimmerman T, Carroll WR, Magnuson JS. Learning curve for transoral
robotic surgery: a 4-year analysis. JAMA otolaryngology-- head & neck surgery 2013;139(6):564-7. 2.
Ambrosch P. The role of laser microsurgery in the treatment of laryngeal cancer. Current opinion in
otolaryngology & head and neck surgery 2007;15(2):82-8. 3.
Civantos FJ, Zitsch RP, Schuller DE, et al. Sentinel lymph node biopsy accurately stages the regional
lymph nodes for T1-T2 oral squamous cell carcinomas: results of a prospective multi-institutional trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2010;28(8):1395-400. 4.
Bak M, Jacobson AS, Buchbinder D, Urken ML. Contemporary reconstruction of the mandible. Oral
oncology 2010;46(2):71-6. 5.
Brown JS, Shaw RJ. Reconstruction of the maxilla and midface: introducing a new classification.
The lancet oncology 2010;11(10):1001-8. 6.
Delaere PR, Vander Poorten V, Vanclooster C, Goeleven A, Hermans R. Results of larynx
preservation surgery for advanced laryngeal cancer through tracheal autotransplantation. Archives of otolaryngology--head & neck surgery 2000;126(10):1207-15. 7.
Forastiere AA, Zhang Q, Weber RS, et al. Long-term results of RTOG 91-11: a comparison of three
nonsurgical treatment strategies to preserve the larynx in patients with locally advanced larynx cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2013;31(7):84552. 8.
Machtay M, Moughan J, Trotti A, et al. Factors associated with severe late toxicity after concurrent
chemoradiation for locally advanced head and neck cancer: an RTOG analysis. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2008;26(21):3582-9. 9.
Cohen EE. DeCIDE: A phase III randomized trial of docetaxel (D), cisplatin (P), 5-fluorouracil (F)
(TPF) induction chemotherapy (IC) in patients with N2/N3 locally advanced squamous cell carcinoma of the head and neck (SCCHN). In; 2012. p. ASCO abstract. 10.
Haddad R, O'Neill A, Rabinowits G, et al. Induction chemotherapy followed by concurrent
chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally John Wiley & Sons, Inc.
Head & Neck
advanced head and neck cancer (PARADIGM): a randomised phase 3 trial. The lancet oncology 2013;14(3):257-64. 11.
Ang K. RTOG 0522: a randomized phase III trial of concurrent accelerated radiation and cisplatin
versus concurrent accelerated radiation, cisplatin, and cetuximab [followed by surgery for selected patients] for Stage III and IV head and neck carcinomas. Clinical advances in hematology & oncology : H&O 2007;5(2):79-81. 12.
Cameron D, Stead M, Lester N, et al. Research-intensive cancer care in the NHS in the UK. Annals
of oncology : official journal of the European Society for Medical Oncology / ESMO 2011;22 Suppl 7:vii29-vii35. 13.
Macdougal J. Challenges and opportunities in surgical cancer research in the UK. In: National
Cancer Research Institute; 2012. 14.
Adelstein DJ, Ridge JA, Brizel DM, et al. Transoral resection of pharyngeal cancer: summary of a
National Cancer Institute Head and Neck Cancer Steering Committee Clinical Trials Planning Meeting, November 6-7, 2011, Arlington, Virginia. Head & neck 2012;34(12):1681-703. 15.
Treasure T, Morton D. GRIST: Growing Recruitment in Interventional and Surgical Trials. Journal
of the Royal Society of Medicine 2012;105(4):140-1. 16.
Kaur G, Hutchison I, Mehanna H, Williamson P, Shaw R, Tudur Smith C. Barriers to recruitment for
surgical trials in head and neck oncology: a survey of trial investigators. BMJ open 2013;3(4). 17.
Peters LJ, O'Sullivan B, Giralt J, et al. Critical impact of radiotherapy protocol compliance and
quality in the treatment of advanced head and neck cancer: results from TROG 02.02. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2010;28(18):2996-3001.
John Wiley & Sons, Inc.
Page 8 of 9
Page 9 of 9
Head & Neck
Table 1. Surgical head and neck cancer trials in the UK & USA Trial Name
Country
Complete / Open / Funded
Clinical question
SEND
UK
Open
Elective neck dissection in early OSCC
ISRCTN65018995
PET in CRT response & need for surgery
ISRCTN13735240
HBO in prevention of ORN after surgery
ISRCTN39634732
HBO as adjunct to surgery in treatment of ORN
NCT00760682 ISRCTN03712770
PETNeck
HOPON
UK
UK + Denmark
DAHANCA21
Denmark + UK
PATHOS
UK
COMPARE
ECOG 3311
RTOG 1221
UK
USA
USA
Complete
Open
Open
Funded
Funded
Open
Open
Z0360 USA
Complete
Adjuvant treatment after surgery for HPV+ oropharynx SCC
Surgery as option for CRT in oropharynx SCC
De-Intensified adjuvant radiotherapy after surgery for HPV+ oropharynx SCC
RCT comparing transoral endoscopic H&N surery to chemoRT
ISRCTN or CTN identifier
Not yet assigned
Not yet assigned
NCT01898494
NCT01953952
Validation of accuracy of SLNB vs END NCT00042926
LIHNCS
ADEPT
TUBE
UK
USA
UK
Complete
Open
Funded
Lugols iodine as adjunct for surgical margins
ISRCTN03712770
De-escalation as an adjunct to laser surgery for HPV+ oropharynx cancer
NCT01687413
Gastrostomy vs reactive nasogastric feeding during chemoradiation
Not yet assigned
John Wiley & Sons, Inc.
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as an ‘Accepted Article’, doi: 10.1002/hed.23846
Head & Neck
Page 2 of 9
Clinical trials for patients with head & neck cancer have been dominated by non-surgical interventions with the overwhelming majority of high impact publications in the fields of radiotherapy, chemotherapy and novel agents. The predictable result of this is that the evidence base largely ignores one important intervention, namely surgery. The ‘shifting sands’ of changing demographics, changing aetiology, new techniques and economic pressures in head and neck cancer threaten to marginalise treatments that are not formally and rigorously evaluated. In particular, the epidemic of Human Papillomavirus mediated oropharynx cancer challenges all those involved, including surgeons, to carefully evaluate the role of various modalities in the context of clinical trials. In contrast to the evident weakness of the evidence base, the field of head & neck surgery has advanced enormously, with transoral endoscopic head and neck surgery (eHNS) using either robotics(1) or the CO2 laser(2), sentinel node biopsy (3) and technical refinement in microvascular reconstruction(4-6). These cumulative advances now usher in a new era of personalised surgery. There is a risk that these treatments may not be widely adopted unless they have well conducted clinical trials supporting their introduction and rightly so. The surgical community must demonstrate their effectiveness in well-conducted clinical trials, protocols and registration studies to effect changes in clinical practice. Concomitant chemoradiotherapy is associated with significant toxicities(7, 8) and recent attempts to increase its efficacy by the use of induction chemotherapy (9, 10) and concurrent Cetuximab(11) have had limited success. Thus there is renewed interest in surgery and in combining minimally invasive surgery with modern radiotherapy techniques. The recognition that nonsurgical therapies have reached their limit of intensification, with potentially devastating, permanent long term morbidity or without appreciable benefit despite combination or sequential approaches, has led to re-evaluation of the potential role of oncologic resection which takes advantage of novel technologies and natural orifice access and approaches. Recently, head and neck surgeons have become increasingly pro-active in driving clinical trials. Completed, open or funded surgical trials in head and neck oncology conducted in the USA or UK are included in Table 1. The UK trials have been stimulated by the formation of the National Cancer Research Institute (NCRI) Head & Neck Clinical Studies Group, which includes a Surgery and Localised Therapies subgroup. The NCRI was formed in 2001 with the aim of increasing clinical trials activity in oncology. The dramatic John Wiley & Sons, Inc.
Page 3 of 9
Head & Neck
success, increasing recruitment 4-fold to 17% of the incident cancer population treated by the National Health Service (12), has revealed a relative paucity of surgically driven research(13). The Head and Neck Clinical Studies Group is one of three NCRI tumour site groups that have adopted the idea of a surgical subgroup; its constituents are 7 surgeons and, to maintain balance and appropriate expertise, also a pathologist, a clinical oncologist (ME) and a trials methodologist (CTS). Additionally, the relevant surgical associations (ENT-UK & British Association of Oral & Maxillofacial Surgeons) have funded two fellowship positions for surgical trainees within the Clinical Studies Group, thus mentoring a new generation of leaders in surgical research in the head and neck specialties. The renaissance of surgeon investigation regarding transoral surgery was stimulated by the advent of novel technologies, after several decades of equipoise and acceptance of clinical investigation into nonsurgical therapies. In the USA, the National Cancer Institute sponsored a Clinical Trials Planning Meeting on the Transoral Resection of Pharynx Cancer in 2011(14). A multidisciplinary team of more than 50 oncologists and critical partners in speech therapy, statistics, economics came to the consensus that further investigation of transoral surgery for oropharyngeal cancer was an important priority for the co-operative groups. Two Phase II trials were designed to explore the potential of eHNS: ECOG 3311 and RTOG1221, both opened in 2013. ECOG3311 examines the role of transoral eHNS to reduce toxicity in patients with good prognosis HPV-associated OPC, while RTOG1221 explores the role of surgery to intensify locoregional therapy with upfront surgery in poorer prognosis HPV-negative OPC. Parallel trials (PATHOS for good prognosis HPVassociated OPC and COMPARE for poorer-prognosis HPV-negative OPC) have recently been funded in the UK and will open to recruitment in 2015. The successful establishment of surgical trials in head and neck cancer on both sides of the Atlantic emphasises the important role surgeons can play by taking an active role in collaborative research groups. It is important to recognise the career pathway in academic head & neck surgery, not only in basic and translational laboratory research, but also in the field of clinical trials. In comparison to drug trials, where pharmaceutical or industrial sponsorship and funding may be available, surgical interventions may be less well supported. It is therefore vitally important to build a cadre of surgeons capable of driving academically led studies. Doubtless, surgical studies present particular challenges to trial design and methodology. It is John Wiley & Sons, Inc.
Head & Neck
more difficult to blind patients or investigators or use placebo arms when compared with drug trials. Often endpoints other than survival and recurrence are proposed that lack proven validity and make power calculations difficult. Establishing the concept of equipoise for an individual, rather than amongst a cohort of surgeons requires careful discussion and education. Introducing a positive view of clinical trials is vital to shifting the culture of the relevant H&N surgical specialties. It is likely that a culture where clinical uncertainty is tolerated (and even encouraged!) will foster a more positive attitude to surgical trials(15).It is important that surgeons have access to, and engage with clinical trials units who have relevant expertise. Where enrolment has been slower than the predicted trajectory, the barriers to recruitment have been systematically explored(16) and lessons learned. In contrast to non-surgical oncology specialties, clinical trials methodology is currently not prominent in the syllabus of surgical trainees. Several changes in the surgical training system are required to facilitate the trend for increased surgical participation in research, and to increase exposure of trainees in statistics, trial design and a culture of clinical investigation. Clinician-scientists in the past 20 years have generally been employed in laboratory studies, studying mechanisms of disease and biomarkers of clinical outcome to selected novel therapeutics. However, recent dedication to higher training in clinical and cost effectiveness research methods and study design has created a new generation of surgical investigators, focused on addressing clinically and societally relevant questions regarding treatment selection, surveillance, and multimodality therapy. In the UK, a head & neck trials methodology residential workshop was recently funded by the Medical Research Council and attended by 20 head & neck surgical trainees. Several new trial ideas and methodological discussions emerged. Recent surgical trial funding applications have challenged the applicants to specify how the surgeons will be trained and credentialed in new surgical techniques and how uniform standards of surgery will be maintained in the trial. Previously, the regulatory authorities (FDA & MHRA) have been largely focussed on drug studies and hence have little to offer, but this is an area of vital importance. As an exemplar of good practice, head and neck radiotherapy research has undergone a revolution in the last decade. It is known that poor quality radiotherapy reduces survival (by 20%) & locoregional control (by 24%) rates in head and neck squamous cell cancer (17). Intensity Modulated Radiotherapy (IMRT) has John Wiley & Sons, Inc.
Page 4 of 9
Page 5 of 9
Head & Neck
further reduced margins for error and increased the need to standardise practice. As a consequence, radiotherapy quality assurance (RT-QA) has become embedded in clinical trial protocols, helping to minimise variations and ensure that clinical trial outcomes reflect differences in randomisation schedules rather than departures from trial protocols. Trial RT-QA includes pre-trial and on-trial QA where outlines of ‘test case’ and trial patients are centrally reviewed against gold standard. Departmental inspections and credentialing may also be carried out prior to study opening. RT-QA for all clinical trials in the UK is funded by the Department of Health and managed centrally by a multi professional UK RTTQA group. Engagement with RT-QA has also been seen to provide benefits that extend beyond individual clinical trials to routine clinical practice, supporting the widespread implementation of innovations in radiotherapy and development of consensus standards. There are lessons here for surgical researchers. Although a hard copy of the operation may not be easily available as in radiotherapy, the need for agreed protocol, training, inspection and transparency are emerging as well as centralised pathology review. Clinical trials in head and neck surgery require new standards and unprecedented collaboration across institutions. For instance, for ECOG3311 and RTOG1221, surgeon credentialing for both trials was harmonized, with the support of the NCI, to identify qualified and experienced surgeons using a standardized approach in eHNS. Principal investigators and a working group of surgeons review all surgeon credentials, including de-identified paired operative notes and pathology reports for ten patients. As an example, ECOG 3311 and RTOG 1221 designed a novel approach to surgeon credentialing. For candidate surgeons with credentials that meet standard outlined below, surgeons were approved. Applicant surgical investigators specify the number of transoral oncologic resections required for credentialing (n=20) and evaluated in detail the operative notes/pathology reports of 10 of these cases by a multi-centre credentialing committee of experts, representing NCI, ECOG and RTOG. Not all applicants met the initial criteria and these have been encouraged to resubmit when appropriate cases warrant their accrual to these trials. Furthermore, the Working Group for Transoral eHNS will continue to provide guidance for ongoing quality assurance and assessment of serious adverse events, during these trials. In addition to the credentialing process for accrual onto ECOG 3311/RTOG 1221, ongoing surgical quality assurance has been set up, whereby a surgeon investigator must maintain less than 10% positive margins or grade III/IV bleeding (requiring a return to the operating room for control) to retain status as accruing to the trial. Similar John Wiley & Sons, Inc.
Head & Neck
arrangements for surgical credentialing and QA will be put in place for upcoming UK surgical trials for OPC, including PATHOS. In summary, it is vital to introduce surgical innovation in context of formal protocols or trials to ensure safety of future patients. In developing surgical credentialing for the current cohort of studies there is a clear opportunity to harmonise international efforts, which will foster future collaborative efforts. These goals require a shift in our training paradigm, from learning past and current techniques, to advancing the field through life-long learning and surgical investigation. These tenets are analogously part of training in clinical and medical oncology, where trial design is emphasized and critical thinking promoted. The benefits to the field include seamless academic transitions during a faculty career to design and incorporate prospective studies into daily surgical practice. Novel technologies, efficacy, QOL, function and cost effectiveness research must grow out of early inculcation of the culture of investigation, beginning with trials design, statistics, scientific method, and critical interpretation of clinical trial results, resulting in a greater evidence– based foundation for academic surgery and more rationale evolution of surgical therapy.
John Wiley & Sons, Inc.
Page 6 of 9
Page 7 of 9
Head & Neck
References 1.
White HN, Frederick J, Zimmerman T, Carroll WR, Magnuson JS. Learning curve for transoral
robotic surgery: a 4-year analysis. JAMA otolaryngology-- head & neck surgery 2013;139(6):564-7. 2.
Ambrosch P. The role of laser microsurgery in the treatment of laryngeal cancer. Current opinion in
otolaryngology & head and neck surgery 2007;15(2):82-8. 3.
Civantos FJ, Zitsch RP, Schuller DE, et al. Sentinel lymph node biopsy accurately stages the regional
lymph nodes for T1-T2 oral squamous cell carcinomas: results of a prospective multi-institutional trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2010;28(8):1395-400. 4.
Bak M, Jacobson AS, Buchbinder D, Urken ML. Contemporary reconstruction of the mandible. Oral
oncology 2010;46(2):71-6. 5.
Brown JS, Shaw RJ. Reconstruction of the maxilla and midface: introducing a new classification.
The lancet oncology 2010;11(10):1001-8. 6.
Delaere PR, Vander Poorten V, Vanclooster C, Goeleven A, Hermans R. Results of larynx
preservation surgery for advanced laryngeal cancer through tracheal autotransplantation. Archives of otolaryngology--head & neck surgery 2000;126(10):1207-15. 7.
Forastiere AA, Zhang Q, Weber RS, et al. Long-term results of RTOG 91-11: a comparison of three
nonsurgical treatment strategies to preserve the larynx in patients with locally advanced larynx cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2013;31(7):84552. 8.
Machtay M, Moughan J, Trotti A, et al. Factors associated with severe late toxicity after concurrent
chemoradiation for locally advanced head and neck cancer: an RTOG analysis. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2008;26(21):3582-9. 9.
Cohen EE. DeCIDE: A phase III randomized trial of docetaxel (D), cisplatin (P), 5-fluorouracil (F)
(TPF) induction chemotherapy (IC) in patients with N2/N3 locally advanced squamous cell carcinoma of the head and neck (SCCHN). In; 2012. p. ASCO abstract. 10.
Haddad R, O'Neill A, Rabinowits G, et al. Induction chemotherapy followed by concurrent
chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally John Wiley & Sons, Inc.
Head & Neck
advanced head and neck cancer (PARADIGM): a randomised phase 3 trial. The lancet oncology 2013;14(3):257-64. 11.
Ang K. RTOG 0522: a randomized phase III trial of concurrent accelerated radiation and cisplatin
versus concurrent accelerated radiation, cisplatin, and cetuximab [followed by surgery for selected patients] for Stage III and IV head and neck carcinomas. Clinical advances in hematology & oncology : H&O 2007;5(2):79-81. 12.
Cameron D, Stead M, Lester N, et al. Research-intensive cancer care in the NHS in the UK. Annals
of oncology : official journal of the European Society for Medical Oncology / ESMO 2011;22 Suppl 7:vii29-vii35. 13.
Macdougal J. Challenges and opportunities in surgical cancer research in the UK. In: National
Cancer Research Institute; 2012. 14.
Adelstein DJ, Ridge JA, Brizel DM, et al. Transoral resection of pharyngeal cancer: summary of a
National Cancer Institute Head and Neck Cancer Steering Committee Clinical Trials Planning Meeting, November 6-7, 2011, Arlington, Virginia. Head & neck 2012;34(12):1681-703. 15.
Treasure T, Morton D. GRIST: Growing Recruitment in Interventional and Surgical Trials. Journal
of the Royal Society of Medicine 2012;105(4):140-1. 16.
Kaur G, Hutchison I, Mehanna H, Williamson P, Shaw R, Tudur Smith C. Barriers to recruitment for
surgical trials in head and neck oncology: a survey of trial investigators. BMJ open 2013;3(4). 17.
Peters LJ, O'Sullivan B, Giralt J, et al. Critical impact of radiotherapy protocol compliance and
quality in the treatment of advanced head and neck cancer: results from TROG 02.02. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2010;28(18):2996-3001.
John Wiley & Sons, Inc.
Page 8 of 9
Page 9 of 9
Head & Neck
Table 1. Surgical head and neck cancer trials in the UK & USA Trial Name
Country
Complete / Open / Funded
Clinical question
SEND
UK
Open
Elective neck dissection in early OSCC
ISRCTN65018995
PET in CRT response & need for surgery
ISRCTN13735240
HBO in prevention of ORN after surgery
ISRCTN39634732
HBO as adjunct to surgery in treatment of ORN
NCT00760682 ISRCTN03712770
PETNeck
HOPON
UK
UK + Denmark
DAHANCA21
Denmark + UK
PATHOS
UK
COMPARE
ECOG 3311
RTOG 1221
UK
USA
USA
Complete
Open
Open
Funded
Funded
Open
Open
Z0360 USA
Complete
Adjuvant treatment after surgery for HPV+ oropharynx SCC
Surgery as option for CRT in oropharynx SCC
De-Intensified adjuvant radiotherapy after surgery for HPV+ oropharynx SCC
RCT comparing transoral endoscopic H&N surery to chemoRT
ISRCTN or CTN identifier
Not yet assigned
Not yet assigned
NCT01898494
NCT01953952
Validation of accuracy of SLNB vs END NCT00042926
LIHNCS
ADEPT
TUBE
UK
USA
UK
Complete
Open
Funded
Lugols iodine as adjunct for surgical margins
ISRCTN03712770
De-escalation as an adjunct to laser surgery for HPV+ oropharynx cancer
NCT01687413
Gastrostomy vs reactive nasogastric feeding during chemoradiation
Not yet assigned
John Wiley & Sons, Inc.
![[Quality assurance in head and neck surgical oncology].](/assets/img/hold.png)
