- Email: [email protected]
Surgical trials in head & neck cancer – Are you serious?
Oral Oncology 49 (2013) 843–844
Contents lists available at SciVerse ScienceDirect
Oral Oncology journal homepage: www.elsevier.com/locate/oraloncology
Editorial
Surgical trials in head & neck cancer – Are you serious?
Although around half of curative impact of cancer treatment is attributed to surgery, surgical studies receive only 2.8% of UK cancer funding [1]. There has been a historical lack of surgical engagement with existing research infrastructure and a failure to tap into the huge resources available [2]. As a result, the evidence base in surgical management of head and neck cancer is doubtless weaker than that for drugs and radiotherapy, with resultant uncertainty between surgical and non-surgical approaches and also between different surgical methods. Surgeons usually co-ordinate aspects of clinical care for all stages of head and neck cancer, from diagnosis, to treatment, surveillance and, potentially, recurrence. As such, it is clear that lack of surgical engagement with clinical research can weaken not only surgical trials, but undermine multidisciplinary efforts to improve treatment through diagnostic, translational and non-surgical cancer research. Surgeons are often under-represented in clinical research in the UK when compared with other medical professionals [3]. However, it appears in the last few years, several initiatives are emerging, with head and neck surgeons leading several influential randomised trials. In the UK this step change in activity has been achieved through the National Cancer Research Network, where the Clinical Studies Groups for each cancer site develop portfolios and are encouraged to form surgically led sub-groups. The emergence and success of surgical studies has tracked the overall head and neck portfolio. The overall portfolio has developed to now include 33 studies recruiting 2517 patients in the UK during 2012. The first 3 surgical studies (SEND, HOPON, PETNECK) have recruited patients steadily, with over 860 patients now randomised between them. A further cohort of surgical trials have also now been funded, and over 1500 patients have been randomised since 2008. Recently, we have reached a new milestone, with PET NECK completing recruitment of 560 patients, making it the largest head and neck surgical trial to be completed to date. In the US, two new surgical trials for minimal access surgery of the oropharynx have been advanced through ECOG and RTOG. Further a recent multimodality trial has successfully completed in Shanghai, exploring the role of induction chemotherapy in the surgical management of oral cavity cancer [4]. One of the problems in surgical oncology trials is that surgical trials often present discrete methodological issues i.e. surgical trials are hard to design [5]. Exactly how to quality assure the delivery of surgery in a trials setting is not clear, although credentialing and enhanced training, pathology second-reporting, and intra-operative photos are possible. Comparable issues of quality assurance in H&N radiotherapy have successfully evolved with the advent of IMRT (Intensity Modulated Radiotherapy). Further, 1368-8375/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.oraloncology.2013.06.004
surgical teams are often less well trained in research methods and there often lacks a critical mass of surgeons with enthusiasm to randomise their patients. In the UK, we have addressed these issues in number of ways including trials roadshows and workshops. We have set up a national fellowship programme in clinical trials for otorhinolaryngologists and maxillofacial surgeons, where the fellows spend a year working on current clinical trials, mentored by an experienced surgical triallist affiliated to an established clinical trials unit. We also have gained funding from the Medical Research Council and North West Surgical Trials Centre to run a new 2-day head and neck surgical trials methodology course for senior surgical residents and fellows on the academic track. The first course will run in 2013 and inform future efforts. We trust that these integrated initiatives will seed a new generation of more research-savvy surgeons but highlight the need for education in clinical research as part of all surgical training programmes. Understanding that surgical trials often lag in terms of patient accrual rates, we have recently explored barriers to recruitment in the first three first three head and neck cancer surgery trials within the UK National Institute for Health Research (NIHR) portfolio [6]. The commonest and most serious problems were that patients refused consent, however we do know that this will often reflect a lack of equipoise on behalf of the surgical investigator rather than an underlying unwillingness from patients [7]. The majority of cancer patients are receptive to RCT participation [8]. However, enthusiasm to recruit patients is stronger amongst medical than surgical oncologists [9]. Other commonly identified barriers we identified were lack of research experience in the clinical team, inadequate time or resources in the clinic for trial administration [6]. As head and neck cancers are not common, and randomised trials often focus on specific indications and sub-sets within diagnoses (in particular HPV positive/ negative), one of the major methodological issues is the lack of adequately powered studies, and consequently a requirement for international collaborations. This is difficult, but not insurmountable. The barriers include proper arrangements for funding, data ownership, trial oversight committees, pharmacovigilance, sponsorship and non-negligent indemnity insurance. These issues can, however, be addressed through patience and persistence, for example with the recent opening of the Danish DAHANCA-21 trial on the treatment of mandibular osteoradionecrosis recruiting in several European countries. Often the funding issues can be solved if each nation seeks funding for their own recruitment as, evidently, many of these trials are academically-led, non-commercial interests. We would call on the competent international bodies (such as the major head and neck journals and associations) to actively
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Editorial / Oral Oncology 49 (2013) 843–844
promote future development in the international promotion of surgical trials for head and neck cancer. References [1] UK National Cancer Research Institute; 2012.. [2] Treasure T, Morton D. GRIST: growing recruitment in interventional and surgical trials. J Roy Soc Med 2012;105(4):140–1. [3] Royal College of Surgeons of England. . [4] Zhong LP, Zhang CP, Ren GX, Guo W, William Jr WN, Sun J, et al. Randomized phase III trial of induction chemotherapy with docetaxel, cisplatin, and fluorouracil followed by surgery versus up-front surgery in locally advanced resectable oral squamous cell carcinoma. J Clinical Oncol: Official J Am Soc Clinical Oncol 2013;31(6):744–51. [5] Blazeby JM. Recruiting patients into randomized clinical trials in surgery. British J Surg 2012;99(3):307–8. [6] 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). [7] Mills N, Donovan JL, Wade J, Hamdy FC, Neal DE, Lane JA. Exploring treatment preferences facilitated recruitment to randomized controlled trials. J Clinical Epidemiol 2011;64(10):1127–36.
[8] Jenkins V, Farewell D, Batt L, Maughan T, Branston L, Langridge C, et al. The attitudes of 1066 patients with cancer towards participation in randomised clinical trials. British J Cancer 2010;103(12):1801–7. [9] Ford E, Jenkins V, Fallowfield L, Stuart N, Farewell D, Farewell V. Clinicians’ attitudes towards clinical trials of cancer therapy. British J Cancer 2011;104(10):1535–43.
Richard Shaw Mersey Head & Neck Oncology Research Group, Liverpool CR-UK Centre, Department of Molecular & Clinical Cancer Medicine, University of Liverpool, 5th Floor Duncan Bldg., Daulby St., Liverpool L69 3GA, UK Tel.: +44 151 529 5290 E-mail address: [email protected] Hisham Mehanna Institute of Head and Neck Studies and Education, School of Cancer Sciences, University of Birmingham, Birmingham B15 2TT, UK E-mail address: [email protected] Available online 28 June 2013
Contents lists available at SciVerse ScienceDirect
Oral Oncology journal homepage: www.elsevier.com/locate/oraloncology
Editorial
Surgical trials in head & neck cancer – Are you serious?
Although around half of curative impact of cancer treatment is attributed to surgery, surgical studies receive only 2.8% of UK cancer funding [1]. There has been a historical lack of surgical engagement with existing research infrastructure and a failure to tap into the huge resources available [2]. As a result, the evidence base in surgical management of head and neck cancer is doubtless weaker than that for drugs and radiotherapy, with resultant uncertainty between surgical and non-surgical approaches and also between different surgical methods. Surgeons usually co-ordinate aspects of clinical care for all stages of head and neck cancer, from diagnosis, to treatment, surveillance and, potentially, recurrence. As such, it is clear that lack of surgical engagement with clinical research can weaken not only surgical trials, but undermine multidisciplinary efforts to improve treatment through diagnostic, translational and non-surgical cancer research. Surgeons are often under-represented in clinical research in the UK when compared with other medical professionals [3]. However, it appears in the last few years, several initiatives are emerging, with head and neck surgeons leading several influential randomised trials. In the UK this step change in activity has been achieved through the National Cancer Research Network, where the Clinical Studies Groups for each cancer site develop portfolios and are encouraged to form surgically led sub-groups. The emergence and success of surgical studies has tracked the overall head and neck portfolio. The overall portfolio has developed to now include 33 studies recruiting 2517 patients in the UK during 2012. The first 3 surgical studies (SEND, HOPON, PETNECK) have recruited patients steadily, with over 860 patients now randomised between them. A further cohort of surgical trials have also now been funded, and over 1500 patients have been randomised since 2008. Recently, we have reached a new milestone, with PET NECK completing recruitment of 560 patients, making it the largest head and neck surgical trial to be completed to date. In the US, two new surgical trials for minimal access surgery of the oropharynx have been advanced through ECOG and RTOG. Further a recent multimodality trial has successfully completed in Shanghai, exploring the role of induction chemotherapy in the surgical management of oral cavity cancer [4]. One of the problems in surgical oncology trials is that surgical trials often present discrete methodological issues i.e. surgical trials are hard to design [5]. Exactly how to quality assure the delivery of surgery in a trials setting is not clear, although credentialing and enhanced training, pathology second-reporting, and intra-operative photos are possible. Comparable issues of quality assurance in H&N radiotherapy have successfully evolved with the advent of IMRT (Intensity Modulated Radiotherapy). Further, 1368-8375/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.oraloncology.2013.06.004
surgical teams are often less well trained in research methods and there often lacks a critical mass of surgeons with enthusiasm to randomise their patients. In the UK, we have addressed these issues in number of ways including trials roadshows and workshops. We have set up a national fellowship programme in clinical trials for otorhinolaryngologists and maxillofacial surgeons, where the fellows spend a year working on current clinical trials, mentored by an experienced surgical triallist affiliated to an established clinical trials unit. We also have gained funding from the Medical Research Council and North West Surgical Trials Centre to run a new 2-day head and neck surgical trials methodology course for senior surgical residents and fellows on the academic track. The first course will run in 2013 and inform future efforts. We trust that these integrated initiatives will seed a new generation of more research-savvy surgeons but highlight the need for education in clinical research as part of all surgical training programmes. Understanding that surgical trials often lag in terms of patient accrual rates, we have recently explored barriers to recruitment in the first three first three head and neck cancer surgery trials within the UK National Institute for Health Research (NIHR) portfolio [6]. The commonest and most serious problems were that patients refused consent, however we do know that this will often reflect a lack of equipoise on behalf of the surgical investigator rather than an underlying unwillingness from patients [7]. The majority of cancer patients are receptive to RCT participation [8]. However, enthusiasm to recruit patients is stronger amongst medical than surgical oncologists [9]. Other commonly identified barriers we identified were lack of research experience in the clinical team, inadequate time or resources in the clinic for trial administration [6]. As head and neck cancers are not common, and randomised trials often focus on specific indications and sub-sets within diagnoses (in particular HPV positive/ negative), one of the major methodological issues is the lack of adequately powered studies, and consequently a requirement for international collaborations. This is difficult, but not insurmountable. The barriers include proper arrangements for funding, data ownership, trial oversight committees, pharmacovigilance, sponsorship and non-negligent indemnity insurance. These issues can, however, be addressed through patience and persistence, for example with the recent opening of the Danish DAHANCA-21 trial on the treatment of mandibular osteoradionecrosis recruiting in several European countries. Often the funding issues can be solved if each nation seeks funding for their own recruitment as, evidently, many of these trials are academically-led, non-commercial interests. We would call on the competent international bodies (such as the major head and neck journals and associations) to actively
844
Editorial / Oral Oncology 49 (2013) 843–844
promote future development in the international promotion of surgical trials for head and neck cancer. References [1] UK National Cancer Research Institute; 2012.
[8] Jenkins V, Farewell D, Batt L, Maughan T, Branston L, Langridge C, et al. The attitudes of 1066 patients with cancer towards participation in randomised clinical trials. British J Cancer 2010;103(12):1801–7. [9] Ford E, Jenkins V, Fallowfield L, Stuart N, Farewell D, Farewell V. Clinicians’ attitudes towards clinical trials of cancer therapy. British J Cancer 2011;104(10):1535–43.
Richard Shaw Mersey Head & Neck Oncology Research Group, Liverpool CR-UK Centre, Department of Molecular & Clinical Cancer Medicine, University of Liverpool, 5th Floor Duncan Bldg., Daulby St., Liverpool L69 3GA, UK Tel.: +44 151 529 5290 E-mail address: [email protected] Hisham Mehanna Institute of Head and Neck Studies and Education, School of Cancer Sciences, University of Birmingham, Birmingham B15 2TT, UK E-mail address: [email protected] Available online 28 June 2013