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Feasibility RCT of definitive chemoradiotherapy or chemotherapy and surgery for oesophageal squamous cell cancer

Feasibility RCT of definitive chemoradiotherapy or chemotherapy and surgery for oesophageal... FULL PAPER British Journal of Cancer (2014) 111, 234–240 | doi: 10.1038/bjc.2014.313 Keywords: oesophageal cancer; surgery; chemoradiotherapy; pilot RCT; qualitative methods Feasibility RCT of definitive chemoradiotherapy or chemotherapy and surgery for oesophageal squamous cell cancer ,1,2 1,2 1 1 1 3 2 4 J M Blazeby , S Strong , J L Donovan , C Wilson , W Hollingworth , T Crosby , J Nicklin , S J Falk , 2 2 2 2 2,5 6 1 C P Barham , A D Hollowood , C G Streets , D Titcomb , R Krysztopik , S M Griffin and S T Brookes 1 2 Centre of Surgical Research, School of Social and Community Medicine, University of Bristol, Bristol BS8 2PS, UK; Division of Surgery, Head & Neck, University Hospitals Bristol NHS Foundation Trust, Bristol BS2 8HW, UK; Velindre NHS Trust, Unit 2 Charnwood Court, Cardiff CF14 2TL, UK; Bristol Haematology and Oncology Centre, University Hospitals Bristol NHS Foundation 5 6 Trust, Bristol BS8 2PS, UK; Royal United Hospital Bath, Bath, BA1 3NG, UK and Northern Oesophagogastric Unit, Royal Victoria Infirmary, Queen Victoria Road, Newcastle upon Tyne NE1 4LP, UK Background: The optimal treatment for localised oesophageal squamous cell carcinoma (SCC) is uncertain. We assessed the feasibility of an RCT comparing neoadjuvant treatment and surgery with definitive chemoradiotherapy. Methods: A feasibility RCT in three centres examined incident patients and reasons for ineligibility using multi-disciplinary team meeting records. Eligible patients were offered participation in the RCT with integrated qualitative research involving audio- recorded recruitment appointments and interviews with patients to inform recruitment training for staff. Results: Of 375 patients with oesophageal SCC, 42 (11.2%) were eligible. Reasons for eligibility varied between centres, with significantly differing proportions of patients excluded because of total tumour length (P¼ 0.002). Analyses of audio-recordings and patient interviews showed that recruiters had challenges articulating the trial design in simple terms, balancing treatment arms and explaining the need for randomisation. Before analyses of the qualitative data and recruiter training no patients were randomised. Following training in one centre 5 of 16 eligible patients were randomised. Conclusions: An RCT of surgical vs non-surgical treatment for SCC of the oesophagus is not feasible in the UK alone because of the low number of incident eligible patients. A trial comparing diverse treatment approaches may be possible with investment to support the recruitment process. The optimal treatment for localised squamous cell carcinoma interventions are associated with significant toxicities, morbidity, (SCC) of the oesophagus remains controversial and international risk of procedural-related death and detrimental impact on practice includes surgery with or without neoadjuvant treatment or short- and longer-term health-related quality of life (HRQL) an entirely non-surgical approach with definitive chemoradio- (Parameswaran et al, 2008; Hirst et al, 2011; National Oesophago- therapy (Allum et al, 2009, 2010; Stahl et al, 2010). In the UK 2013 Gastric Cancer Audit, 2012). Comparative data are limited as national audit of new patients with localised oesophageal SCC, 50% previous early trials struggled to recruit and were closed early, and received surgical treatment (alone or with neoadjuvant therapy) more recent trials have included different criteria and interventions and 48% had definitive chemoradiotherapy (National Oesophago- (Urba et al, 2001; Burmeister et al, 2005; Chiu et al, 2005; Stahl Gastric Cancer Audit, 2013). Five-year survival rates of 40% have et al, 2005; Bedenne et al, 2007; Teoh et al, 2013). In one trial, all been achieved with both treatments in single-centre studies but patients received neoadjuvant chemoradiotherapy and those *Correspondence: Professor JM Blazeby; E-mail: J.M.Blazeby@bristol.ac.uk Received 26 January 2014; revised 25 April 2014; accepted 12 May 2014; published online 12 June 2014 & 2014 Cancer Research UK. All rights reserved 0007 – 0920/14 234 www.bjcancer.com | DOI:10.1038/bjc.2014.313 Feasibility RCT of surgery and chemoradiation for oesophageal squamous cell cancer BRITISH JOURNAL OF CANCER responding were then randomised to surgery or chemoradiotherapy. summarised, documenting incident patients, numbers eligible for Survival rates were shown to be similar but extrapolation of the trial, reasons for ineligibility and final recommended results is limited owing to the inclusion only of patients responding treatments. to chemoradiotherapy (Bedenne et al, 2007). Another was powered to determine equivalence (15% margin) of surgical and non- (ii) Pilot RCT with integrated qualitative research. A pilot RCT surgical treatments and randomised 172 patients to induction was set up to assess acceptance of randomisation and to chemotherapy followed by chemoradiotherapy or surgery (Stahl understand clinician and patient treatment preferences. Eligibility et al, 2005). Overall survival was equivalent between treatments, criteria included, aged 18 years or older, histologically confirmed however, the equivalence margin might be considered too broad to oesophageal SCC, sufficient performance status and fitness to exclude a clinically important difference. The third more recent undergo surgery or definitive chemoradiotherapy, tumour staged trial randomised 81 patients to surgery alone or definitive between T2N0M0 and T4N1M0 (where the T4 tumour involved chemoradiotherapy, finding no difference in overall survival or the diaphragmatic crura or mediastinal pleura only), and a total HRQL at 2 or 5 years (Chiu et al, 2005; Teoh et al, 2013). The primary tumour and node length of o10 cm (Sobin and magnitude of difference between the two treatments required to Wittekind, 2002). Patients were excluded with concomitant or conclude superiority was never reported by the authors as no past malignancy within 5 years (except for basal cell carcinoma or sample size calculation was provided. In the UK since the OEO2 SCC of the skin or in situ carcinoma of the cervix), tumour within study, which included both adenocarcinoma and SSC, standard 2 cm of cricopharyngeus, tumour including 42 cm of gastric wall treatment for oesophageal cancer has been chemotherapy and or previous treatment that compromised the ability to deliver surgery or definitive chemoradiotherapy (National Oesophago- definitive chemoradiotherapy or surgery. Staging was performed Gastric Cancer Audit, 2012), and only more recently the Neoscope with endoscopic ultrasound (EUS), computed tomography of the trial (Gwynne et al, 2011) has opened that aims to compare chest and abdomen, positron emission tomography when available strategies for preoperative chemoradiotherapy before surgery. and staging laparoscopy and bronchoscopy in selected patients. All There was therefore a lack of high-quality evidence comparing centres measured tumour length on EUS and total length included surgical and non-surgical treatments of localised oesophageal SCC a measure of the primary tumour and submucosal disease meaning that treatment decision-making is currently based on and lymphadenopathy assessed with standard local criteria clinician or patient preferences and a trial is needed. (Davies et al, 2012). Trials of surgical and non-surgical treatments can be difficult to conduct and recruit into because of the diverse nature of Integrated qualitative research to optimise trial recruitment. treatments (Cook, 2009). In the UK, these difficulties were Qualitative research methods were integrated into the pilot RCT to overcome in the ProtecT trial that successfully randomised 1500 optimise challenges with recruitment. Eligible patients at identified men between radical surgery, radiotherapy or active monitoring for MDT meetings were sent information sheets and invited to clinic localised prostate cancer (Donovan et al, 2002). The ProtecT study where the appointment was audio-recorded. Consultations took used detailed screening logs to record patient eligibility and place in the usual hospital setting (Donovan et al, 2009). Patients qualitative methods (audio-recordings of consultations, recruiter underwent surgical consultations before meeting the oncologists. and patient interviews) to improve recruitment. Subsequent work Once the patient had made a decision about their preferred by Donovan and colleagues has further demonstrated how treatment option or randomisation, they were invited to take part qualitative research can improve trial conduct, information in a semi-structured interview at home so they could provide provision and rates of informed consent (Donovan et al, 2009; detailed feedback on the surgery and oncology appointments, their Paramasivan et al, 2011; Donovan et al, 2014). Although these understanding of the trial design, the treatment arms, the methods have been applied to other settings, it is unknown acceptability of randomisation, preferences and their treatment whether it is possible to successfully recruit into a trial of surgical decision. and non-surgical treatment for oesophageal cancer where the Audio-recordings and interview data were transcribed verbatim treatment-related morbidities are high, long-term outcomes are and analysed using techniques of constant comparison to under- poor and the impact on HRQL significant. This study, therefore, stand how the study was being presented and discussed with aimed to determine the feasibility of a main trial of chemotherapy patients (Glaser, 1998). Targeted conversation analysis was used to and surgery vs definitive chemoradiotherapy for localised oeso- identify problematic aspects of the clinical interaction (Donovan, phageal SCC. et al, 2002). The study planned to discuss findings within each centre with individual recruiters and in group training. Group training was based on analysis of the audio recordings (JLD, SS and CW). Standard thematic methods of qualitative data analysis were MATERIALS AND METHODS used to identify key findings that were then presented to surgeons, oncologists and nurses in the recruiting team with illustrative The study included three parts, (i) monitoring multi-disciplinary quotes to promote discussion of ‘good’ and ‘not so good’ team (MDT) meetings to determine the number of incident eligible information provision. Full details of this process are described participants with localised oesophageal SCC and final treatment elsewhere and have been integrated into several RCTs (Donovan received, (ii) undertaking a pilot RCT with integrated qualitative et al, 2014). research to establish whether recruitment was possible and (iii) development of core information sets for surgeons Trial treatments. Induction chemotherapy was given as 21 days of and oncologists to use to explain the two treatments. Parts (i) and either cisplatin 80 mg m by intravenous infusion on days 1 and (ii) are reported here. 5 followed by fluorouracil 1 g m per day as a continuous (i) Determination of incident numbers of eligible participants intravenous infusion for four days or cisplatin 80 mg m by for a main trial. Multi-disciplinary team meeting records from intravenous infusion on day 1 and capecitabine 625 mg m orally three specialist centres were studied to capture the number of new twice daily continuously. In the surgical arm, two- or three-phase patients with localised oesophageal SCC potentially eligible for oesophagectomies were performed as an open, laparoscopically this trial. Two of the MDT meetings considered all referrals and assisted or with a totally minimally invasive approach with a two- the third only considered patients without metastatic disease field lymphadenectomy. These are described in detail elsewhere suitable for radical treatment. Multi-disciplinary team data were (Blazeby et al, 2011). www.bjcancer.com | DOI:10.1038/bjc.2014.313 235 BRITISH JOURNAL OF CANCER Feasibility RCT of surgery and chemoradiation for oesophageal squamous cell cancer Induction chemotherapy before chemoradiotherapy consisted of months of recruitment. Eligible patients were predominantly two cycles of 21 days with either cisplatin 80 mg m by women 27(64.3%) (Table 1). intravenous infusion on day 1 and 5-fluorouracil 1 g m per (i) Determination of incident numbers of eligible trial patients day by continuous intravenous infusion for four days starting on for a main trial. The percentage of eligible patients ranged from 2  2 day 1 (i.e., total cycle dose¼4gm ) or cisplatin 80 mg m to be 6.0% to 14.7% across centres. Further investigation into reasons for by intravenous infusion on day 1 and capecitabine 625 mg m ineligibility showed that as expected about a third of patients orally twice daily within 30 min of food, starting in the evening of were not eligible because of metastatic disease and another quarter day 1 and finishing on the morning of day 43. The chemotherapy were ineligible because of frailty (this was lower as expected in the component of the definitive chemoradiotherapy was identical to centre that only discussed patients selected for radical treatment). the induction chemotherapy regimen above continued for a further There were unexpected differences between centres, however, in two cycles (i.e., from day 43 to day 84). Radiotherapy was started terms of the percentage of patients categorised ineligible because on day 43 and delivered in a single phase: 50 Gy in 25 fractions. the total tumour and node length exceeding 10 cm, with 27/147 (18.4%), 4/47 (8.5%) and 8/139 (5.8%) of patients in centres Outcome assessment and sample size. When eligible patients 1, 2 and 3, respectively, being classified as ineligible for that consented to randomisation, treatment allocation was determined reasons, P¼ 0.002 (Table 2). by an automated randomisation web-based system. The proportion of eligible patients consenting to randomisation was examined and (ii) Pilot RCT with integrated qualitative research. In total, 26 treatments recommended for eligible but non-randomised patients paired audio-recordings (7 from centre 1, 0 from centre 2 and 19 noted. The purpose of this feasibility study was to establish from centre 3) of surgery and oncology appointments were potential rates of eligible patients and of those, the percentage analysed alongside 14 in-depth patient interviews. Centres 1 and 2 consenting to randomisation. Hence, eligibility and randomisation did not randomise any patients and centre 3 randomised five rates were the primary outcomes for this study and were calculated patients. Feedback meetings to improve consultations were separately for each centre and overall. Differences between centres undertaken in centres 1 and 3. In centre 1 following feedback, were examined using Chi-square tests. The pilot RCT assessed the no eligible patients were identified before the end of the study, feasibility of data collection including toxicity, surgical morbidity preventing analyses of the impact of feedback and training. In and HRQL (EORTC QLQ-C30 and QLQ-OG25) data (Aaronson centre 3, before feedback no one had consented to randomisation et al, 1993; Lagergren et al, 2007). It was not the intention of this (of 8 eligible patients) but following feedback, 5 of the next 16 study to examine the comparative effectiveness of the two eligible patients consented to randomisation (Table 1). This treatments, hence no formal sample size calculation was indicates the positive impact on recruitment of training and performed. North Somerset and South Bristol Research Ethics feedback from the qualitative study. Committee (09/H0106/69) approved this study. Analyses of the final treatment received for eligible but non- randomised patients in centre 1 showed a preference for surgery (Table 2), whereas the proportions of eligible but non-randomised RESULTS patients in centres 2 and 3 were similar for surgery and definitive chemoradiotherapy. Centres recruited for different lengths of time between April 2010 The qualitative research identified three issues hindering and March 2013 (for a total of 82 centre months) during which 375 recruitment. Recruiters had difficulties in (a) articulating the trial patients with oesophageal SCC were discussed in 331 MDT design in simple terms; (b) balancing treatment arms, in particular, meetings. Only 42 (11%) were considered eligible (Figure 1); this describing the effect of radiotherapy on the tumour; (c) explaining equates to just one eligible patient identified for every two centre the selection of treatment by randomisation. Difficulties explaining the trial design identified in the early recruitment appointments occurred because recruiters presented patients with the two Number of patients different treatment options (chemotherapy and surgery or screened N =375 chemo-radiotherapy) without mentioning the trial. As a result, patients thought they had to make a choice between these two treatment options. Other patients reported not understanding what Ineligible taking part in the trial actually meant. In many appointments, the N =333 trial was presented as a third option, only suitable for those who could not make a decision about their preferred treatment (Figure 2 provides illustrative quotes). This limited the number Eligible N =42 of patients who considered taking part in the study. Many patients who declined to take part in the study expressed a strong preference, either for or against surgery. Patients Declined intuitively understood that surgery ‘removes’ or ‘cuts out’ the randomisation N =37 tumour, but were uncertain about the action of radiotherapy on the cancer. Recruitment appointments were reviewed to examine how consultants talked about surgery and radiotherapy. In early Randomised recruitment appointments, several surgeons unintentionally N =5 expressed a preference for surgery. Following training, surgeons were able to use balancing statements to convey the strengths and limitations of both treatment options and to explain the effect of radiotherapy on the tumour (Figure 3 provides illustrative quotes). N =2 Interview data showed that the majority of patients did not like N =3 Induction chemotherapy Induction chemotherapy the idea of a computer allocating their treatment and they did not and definitive and oesophagectomy understand the need for randomisation. Early recordings showed chemoradiotherapy consultants were reluctant to explain the rationale for randomisa- Figure 1. Flow diagram of recruitment into the pilot RCT. tion. Training was provided to help consultants explain 236 www.bjcancer.com | DOI:10.1038/bjc.2014.313 Feasibility RCT of surgery and chemoradiation for oesophageal squamous cell cancer BRITISH JOURNAL OF CANCER Table 1. Eligible patient details and final treatment received Centre 1, N¼ 15 Centre 2, N¼ 3 Centre 3, N¼ 24 Total, N¼ 42 Mean age, years (range) 67 (48–76) 61 (55–69) 68 (41–77) 65 (41–78) Female, n (%) 10 (66.7) 3 (100) 14 (58.3) 27 (64.3) Tumour stage I 002 2 IIa 127 10 IIb 2 0 14 16 III 13 1 1 15 Randomised into pilot RCT, n (%) 0 0 5 (20.8) 5 (11.9) Treatment received by eligible but non-randomised patients, n (%) Chemotherapy & surgery 8 (53.3) 1 (25.0) 7 (43.7) 16 (43.2) Surgery alone 1 (6.7) 0 (0.0) 0 (0.0) 1 (2.7) Definitive chemoradiotherapy 6 (40.0) 2 (50.0) 9 (47.4) 17 (45.9) Stent 0 (0.0) 0 (0.0) 2 (10.5) 2 (5.4) Unknown 0 (0.0) 0 (0.0) 1 (5.2) 1 (2.7) Abbreviation: RCT¼ randomised controlled trial. Table 2. Numbers of incident patients with oesophageal SCC eligible for the trials, reasons for ineligibility and final treatment received by centres Centre 1, N (%) Centre 2, N (%) Centre 3, N (%) Total, N (%) Incident oesophageal SCC discussed at MDT 162 50 163 375 Eligible for the pilot RCT 15 (9.3) 3 (6.0) 24 (14.7) 42 (11.2) Reasons for ineligibility (n (%) of those not eligible) Metastatic disease 44 (29.9) 15 (31.9) 44 (31.7) 103 (30.9) Unfit for radical treatment 43 (29.3) 9 (19.1) 41 (29.5) 93 (27.9) Total tumour length 410 cm 27 (18.4) 4 (8.5) 8 (5.8) 39 (11.7) T4 disease (aorta/pericardium) 14 (9.5) 8 (17.0) 16 (11.5) 38 (11.4) Tumour o2 cm cricopharyngeus 4 (2.7) 1 (2.1) 6 (4.3) 11(3.3) Previous malignancy 7 (4.8) 3 (6.4) 3 (2.2) 13 (3.9) Recurrent disease 3 (2.0) 3 (6.4) 5 (4.0) 11 (3.3) Other 5 (3.4) 4 (8.5) 16 (11.5) 25 (7.5) Abbreviation: MDT¼ multi-disciplinary team; RCT¼ randomised controlled trial; SCC¼ squamous cell carcinoma. Only patients suitable for radical treatment referred to this centre and MDT. randomisation, significantly improving patient understanding and differences were seen between the centres in terms of the reasons acceptance of the study (Figure 3 provides illustrative quotes). for ineligibility. Initially, no eligible patients consented to All participating patients completed HRQL outcome measures randomisation. In one centre where the qualitative research was at the required time points. Other outcomes were reviewed at clinic effectively applied and feedback meetings undertaken some 5 of the appointments to 6 months after randomisation. 16 patients were randomised providing an indication that recruitment was possible with appropriate support. Despite the successful randomisation in one centre this study has shown that a DISCUSSION full trial comparing a surgical and non-surgical approach for oesophageal SCC is not feasible in the UK alone because of This paper describes feasibility work to establish whether a main insufficient eligible patients. It does, however, show that recruit- trial comparing a surgical and non-surgical approach for ment difficulties are often multi-factorial and a range of methods is oesophageal SCC is possible. It integrated specific methodological needed to identify and address them. It also shows how investment techniques to optimise recruitment because of the well-recognised with qualitative research in a trial can support surgeons and challenges enroling patients in trials comparing diverse treatment oncologists to recruit and this method has promising implications options and to help surgeons with this unfamiliar process. The for other settings. study scrutinised MDT records for eligible patients, carefully The methods used to examine incident patients via MDT documenting reasons for ineligibility and it used qualitative meetings were found to be practical and useful in providing research methods to understand how the trial was discussed by accurate information to inform whether a main trial is possible. surgeons and oncologists and to allow feedback and training. It was Others have explored the role of MDT records to optimise trial found that 11% of all patients with oesophageal SCC were eligible recruitment and demonstrated that these provide an excellent for the trial, which in this study equated to just one patient every resource to identify eligible patients into oncology trials (McNair two months that a centre was open for recruitment. Notable et al, 2008). It is recommended, therefore, that this approach is www.bjcancer.com | DOI:10.1038/bjc.2014.313 237 BRITISH JOURNAL OF CANCER Feasibility RCT of surgery and chemoradiation for oesophageal squamous cell cancer used more widely. Analysing reasons for ineligibility for the trial Example quotes before training: also provided useful data. It showed how centres differently used Surgeon 1: “If you can’t decide, go into the trial.” local staging investigations to assess tumour lengths and trial Surgeon 2: “If you say that you were happy to go into the trial at this point, you say, ‘I don’t know which way to go –I’ll go into a trial’, your name is drawn out of a hat as eligibility. For example, centre 1 found a larger proportion of to which of those two options you get –as you could have either of the two options ineligible patients due to disease length than the other centres anyway.” because of the interpretation of the EUS data. In a main trial more Patient (79 yr old male, not consented, surgery preference): “I’m not quite with that detailed guidance for assessing the tumour length and trial word trial at the moment ‘cause if you’re gonna try something then you do something eligibility is recommended. differently, so what’s different? (ctd...) This word trial to me seems to be a completely wrong word. It’s not a trial, it’s actually what you’re gonna get. It’s the actual Other trials have integrated qualitative research methods to treatment, isn’t it?” optimise recruitment by audio-recording consultations, analysing Training points: Consultants were asked to replace the word trial with ‘study’ and to data and providing training and feedback to surgeons (Donovan use the study to frame discussion of the treatment options. et al, 2002; Lewin et al, 2009; Paramasivan et al, 2011; Donovan Example quote post training: et al, 2014). To achieve this, however, it is necessary to ensure Surgeon 3: “.... there are different types of treatment for the cancer you have. that audio-recordings are undertaken and returned from the You can have chemotherapy and radiotherapy. You can have chemotherapy and surgery. And the difficulty we have as experts is that we don’t know which one of participating centres. Difficulties in obtaining audio-recordings those treatments is best, so we’ve started this study...now what I wanted to talk from clinical centres identified in this study have been to you about today is whether or not you would consider going into the experienced in another trial of a surgical and non-surgical study...you don’t have to, it’s completely voluntary.” treatment for bladder cancer (Paramasivan et al, 2011). The Figure 2. Example quotes to show the difficulties that surgeons had reasons for lack of audio-recording consultations and transfer of in explaining the study design and the improvements made after data may be related to logistical issues. There is evidence that training. there is a general reluctance among recruiters to be audio- Example quotes about unbalanced information provision: Surgeon 4: “I don’t think these things are set in stone but if we were going to make a list of treatments starting with which one is most likely to cure my cancer then it’s probably gonna be chemotherapy followed by surgery. If we do anything less it won’t cure your cancer... and the cancer will eventually kill you.” Surgeon 5: “There is evidence that having chemotherapy and radiotherapy without an operation may also be able to treat the tumour.” Oncologist 1: “There are two treatments for your complaint...either an operationwhere they cut it away or radiotherapy, and chemotherapy where we treat people with x-ray treatment and drugs.” Training points: Consultants were asked to use balancing statements to compare the advantages and disadvantages of both treatments and to describe the action of the radiotherapy, as being able to “destroy” or “kill” the cancer cells. Example quotes post training: Surgeon 4: “We have a treatment that could involve chemotherapy and then an operation to cut it out and we have a treatment that involved chemotherapy and radiation, and our previous experience of patients is that we know that both of those work and as best we can tell, both of them seem to work equally effectively in curing your cancer.” Surgeon 3: “We give radiotherapy to kill off the cancer cells that maybe there.” Example quotes of difficulties explaining randomisation: Surgeon 1: “If you’re not sure of one, we recommend that the decision about which treatment you have is made by a process called randomisation so rather than me, you or Dr (Surname) deciding, a computer decides and then you’re allocated to one of those two, and then, you have got a good chance of having the best treatment because you don’t know what’s the best treatment. You’ve got a fifty/fifty chance of having the best treatment. In other words, you don’t decide - the computer decides for you.” Example quotes showing patient difficulties to understand/accept randomisation Patient (77 yr old male, non-randomised, chemo-radiotherapy preference): “[Consultant X] said they put all the information they’ve got – how old I am and what - where it is into a computer, and then the computer shoots out a result which is the best way to go. No, I don’t think that I’d want to be at the mercy of a computer. I wouldn’t accept any of that... you see were not computer oriented. We haven’t got one in our house.” Patient (71 yr old female, non-randomised, surgery preference): “Why can’t they follow people up, whatever option they choose? I don’t want a computer to take over my life, make decisions. When I made the choice – right or wrong, I’ve made it and it’s me that’s made it.” Training points: Consultants were asked to avoid using the word computer and explain the rationale for randomisation Example quotes post training: Oncologist 1: “The study decides whether you have the radiotherapy or the surgery and the reason we have to do that is that the problem is that say we see 10 patients in a row and we say well quite like - the surgeon says well I quite like the look at that one for an operation, they’re the right, size, shape and age then that puts in what’s called bias into the study. So it has to be done on what’s called a random allocation where if you like the study decides rather than we do because otherwise we put bias in it. So if you look at previous studies for example where they’ve done that the patients operated on tend to be young and fit and the people who have the radiotherapy tend to be older andless fit.” Surgeon 4: “the way of approaching any study would be to allocate the treatment to you, to randomise you to one or the other options and that is done as part of the study itself.... we obviously monitor you as you go through everything, looking at you, the effects of the treatment and see how you are, hopefully at the end of all of this, with enough people we will answer the question as to which one would appear the better option.. So that’s the basis of the study itself. If people, if some people don’t want to enter into the study then obviously we’ve got to still think about you and how we would treat you and we’re still then left with the same two options.” Figure 3. Example quotes to show the difficulties consultants had in balancing the treatment groups and explaining randomisation, and how the improvements were demonstrated after training. 238 www.bjcancer.com | DOI:10.1038/bjc.2014.313 Feasibility RCT of surgery and chemoradiation for oesophageal squamous cell cancer BRITISH JOURNAL OF CANCER recorded (Donovan et al, 2014) and this was also found in this possible in the UK alone and would require an international effort. trial. In centres where this was not challenged, recording was not The integration of qualitative research methods with accompany- undertaken (centre 2), but when the recording was undertaken by ing feedback can improve recruitment into trials with very different the PI and strongly encouraged, it became a routine (centre 3). treatment interventions and should be routinely incorporated. These experiences emphasise the need for better training of clinicians before participation in trials and strong support and ACKNOWLEDGEMENTS trial leadership during the study itself. Recent evidence suggests that there are some generic lessons that can be learned from previous qualitative research integrated This article summarises independent research funded by the with trials, such as the need to support recruiters in explaining National Institute for Health Research (NIHR) under its Research aspects of trial design including randomisation and equipoise, and for Patient Benefit (RfPB) Program (Grant reference PB-PG-0807– the need to explore the basis of apparent preferences; but also that 14131). there are likely to be some issues specific to the particular trial that are likely to require the dedicated qualitative research (Donovan AUTHORS CONTRIBUTIONS et al, 2014). As more of this research is conducted, it is also possible that clinicians exposed to the training may acquire recruitment skills that will be transferable to other trials. Other JMB, STB, JLD, WH, TC and SMG designed the study with methods to improve trial recruitment could involve holding joint contributions to its adaptation during delivery of the trial from SS, clinics with surgeons and oncologists together or changing the CW, SJF, CPB, ADH, CGS, DT, RK and JN. Participation in order in which patients meet each specialist (Paramasivan et al, recruitment, delivery of interventions and audio-recordings were 2011). These approaches may be interesting to explore in future undertaken by CPB, ADH, RK, CGS, DT, JMB, TC, JN and SMG. work. There has also been an initiative promoted by the Royal SS, CW and JLD analysed and interpreted the qualitative data. The College of Surgeons of England for surgical trainees to be involved first draft of the paper was written by JMB. All authors contributed and recruit into trials in surgery, which has had promising early to the final version. JMB is the guarantor of the study. results (Bhangu et al, 2013). Few trials have directly compared surgical vs non-surgical treatment for oesophageal cancer, although two RCTs randomised DISCLAIMER patients following neoadjuvant chemoradiotherapy to consolida- tion chemoradiotherapy or surgery (Stahl et al, 2005; Bedenne et al, The views expressed in this publication are those of the author(s) 2007). The original trials of radical surgical and non-surgical and not necessarily those of the NHS, the NIHR or the Department approaches initiated some time ago were stopped because of poor of Health. recruitment (Urba et al, 2001; Burmeister et al, 2005) and the more recent Chinese trial did not report a sample size calculation recruiting only 80 patients (Chiu et al, 2005; Teoh et al, 2013). 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A full trial comparing surgery with definitive Chiu PW, Chan A, Leung SF, Leong HT, Kwong KH, Li MK, Au-Yeung AC, chemoradiotherapy for oesophageal SCC alone, however, is not Chung SC, Ng EK (2005) Multicenter prospective randomized trial www.bjcancer.com | DOI:10.1038/bjc.2014.313 239 BRITISH JOURNAL OF CANCER Feasibility RCT of surgery and chemoradiation for oesophageal squamous cell cancer comparing standard esophagectomy with chemoradiotherapy for McNair AG, Choh CT, Metcalfe C, Littlejohns D, Barham CP, Hollowood A, treatment of squamous esophageal cancer: early results from the Chinese Falk SJ, Blazeby JM (2008) Maximising recruitment into randomised University Research Group for Esophageal Cancer (CURE). J Gastrointest controlled trials: the role of multidisciplinary cancer teams. Eur J Cancer Surg 9: 794–802. 44: 2623–2626. 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NEngl Quality of Life Groups (2007) Clinical and psychometric validation JMed 366: 2074–2084. of a questionnaire module, the EORTC QLQ-OG25, to assess health- related quality of life in patients with cancer of the oesophagus, the oesophago-gastric junction and the stomach. Eur J Cancer 43: This work is published under the standard license to publish agree- 2066–2073. ment. After 12 months the work will become freely available and Lewin S, Glenton C, Oxman AD (2009) Use of qualitative methods alongside the license terms will switch to a Creative Commons Attribution- randomised controlled trials of complex healthcare interventions. BMJ 339: b3496. NonCommercial-Share Alike 3.0 Unported License. 240 www.bjcancer.com | DOI:10.1038/bjc.2014.313 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png British Journal of Cancer Springer Journals

Feasibility RCT of definitive chemoradiotherapy or chemotherapy and surgery for oesophageal squamous cell cancer

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Springer Journals
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Copyright © 2014 by The Author(s)
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Biomedicine; Biomedicine, general; Cancer Research; Epidemiology; Molecular Medicine; Oncology; Drug Resistance
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0007-0920
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10.1038/bjc.2014.313
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Abstract

FULL PAPER British Journal of Cancer (2014) 111, 234–240 | doi: 10.1038/bjc.2014.313 Keywords: oesophageal cancer; surgery; chemoradiotherapy; pilot RCT; qualitative methods Feasibility RCT of definitive chemoradiotherapy or chemotherapy and surgery for oesophageal squamous cell cancer ,1,2 1,2 1 1 1 3 2 4 J M Blazeby , S Strong , J L Donovan , C Wilson , W Hollingworth , T Crosby , J Nicklin , S J Falk , 2 2 2 2 2,5 6 1 C P Barham , A D Hollowood , C G Streets , D Titcomb , R Krysztopik , S M Griffin and S T Brookes 1 2 Centre of Surgical Research, School of Social and Community Medicine, University of Bristol, Bristol BS8 2PS, UK; Division of Surgery, Head & Neck, University Hospitals Bristol NHS Foundation Trust, Bristol BS2 8HW, UK; Velindre NHS Trust, Unit 2 Charnwood Court, Cardiff CF14 2TL, UK; Bristol Haematology and Oncology Centre, University Hospitals Bristol NHS Foundation 5 6 Trust, Bristol BS8 2PS, UK; Royal United Hospital Bath, Bath, BA1 3NG, UK and Northern Oesophagogastric Unit, Royal Victoria Infirmary, Queen Victoria Road, Newcastle upon Tyne NE1 4LP, UK Background: The optimal treatment for localised oesophageal squamous cell carcinoma (SCC) is uncertain. We assessed the feasibility of an RCT comparing neoadjuvant treatment and surgery with definitive chemoradiotherapy. Methods: A feasibility RCT in three centres examined incident patients and reasons for ineligibility using multi-disciplinary team meeting records. Eligible patients were offered participation in the RCT with integrated qualitative research involving audio- recorded recruitment appointments and interviews with patients to inform recruitment training for staff. Results: Of 375 patients with oesophageal SCC, 42 (11.2%) were eligible. Reasons for eligibility varied between centres, with significantly differing proportions of patients excluded because of total tumour length (P¼ 0.002). Analyses of audio-recordings and patient interviews showed that recruiters had challenges articulating the trial design in simple terms, balancing treatment arms and explaining the need for randomisation. Before analyses of the qualitative data and recruiter training no patients were randomised. Following training in one centre 5 of 16 eligible patients were randomised. Conclusions: An RCT of surgical vs non-surgical treatment for SCC of the oesophagus is not feasible in the UK alone because of the low number of incident eligible patients. A trial comparing diverse treatment approaches may be possible with investment to support the recruitment process. The optimal treatment for localised squamous cell carcinoma interventions are associated with significant toxicities, morbidity, (SCC) of the oesophagus remains controversial and international risk of procedural-related death and detrimental impact on practice includes surgery with or without neoadjuvant treatment or short- and longer-term health-related quality of life (HRQL) an entirely non-surgical approach with definitive chemoradio- (Parameswaran et al, 2008; Hirst et al, 2011; National Oesophago- therapy (Allum et al, 2009, 2010; Stahl et al, 2010). In the UK 2013 Gastric Cancer Audit, 2012). Comparative data are limited as national audit of new patients with localised oesophageal SCC, 50% previous early trials struggled to recruit and were closed early, and received surgical treatment (alone or with neoadjuvant therapy) more recent trials have included different criteria and interventions and 48% had definitive chemoradiotherapy (National Oesophago- (Urba et al, 2001; Burmeister et al, 2005; Chiu et al, 2005; Stahl Gastric Cancer Audit, 2013). Five-year survival rates of 40% have et al, 2005; Bedenne et al, 2007; Teoh et al, 2013). In one trial, all been achieved with both treatments in single-centre studies but patients received neoadjuvant chemoradiotherapy and those *Correspondence: Professor JM Blazeby; E-mail: J.M.Blazeby@bristol.ac.uk Received 26 January 2014; revised 25 April 2014; accepted 12 May 2014; published online 12 June 2014 & 2014 Cancer Research UK. All rights reserved 0007 – 0920/14 234 www.bjcancer.com | DOI:10.1038/bjc.2014.313 Feasibility RCT of surgery and chemoradiation for oesophageal squamous cell cancer BRITISH JOURNAL OF CANCER responding were then randomised to surgery or chemoradiotherapy. summarised, documenting incident patients, numbers eligible for Survival rates were shown to be similar but extrapolation of the trial, reasons for ineligibility and final recommended results is limited owing to the inclusion only of patients responding treatments. to chemoradiotherapy (Bedenne et al, 2007). Another was powered to determine equivalence (15% margin) of surgical and non- (ii) Pilot RCT with integrated qualitative research. A pilot RCT surgical treatments and randomised 172 patients to induction was set up to assess acceptance of randomisation and to chemotherapy followed by chemoradiotherapy or surgery (Stahl understand clinician and patient treatment preferences. Eligibility et al, 2005). Overall survival was equivalent between treatments, criteria included, aged 18 years or older, histologically confirmed however, the equivalence margin might be considered too broad to oesophageal SCC, sufficient performance status and fitness to exclude a clinically important difference. The third more recent undergo surgery or definitive chemoradiotherapy, tumour staged trial randomised 81 patients to surgery alone or definitive between T2N0M0 and T4N1M0 (where the T4 tumour involved chemoradiotherapy, finding no difference in overall survival or the diaphragmatic crura or mediastinal pleura only), and a total HRQL at 2 or 5 years (Chiu et al, 2005; Teoh et al, 2013). The primary tumour and node length of o10 cm (Sobin and magnitude of difference between the two treatments required to Wittekind, 2002). Patients were excluded with concomitant or conclude superiority was never reported by the authors as no past malignancy within 5 years (except for basal cell carcinoma or sample size calculation was provided. In the UK since the OEO2 SCC of the skin or in situ carcinoma of the cervix), tumour within study, which included both adenocarcinoma and SSC, standard 2 cm of cricopharyngeus, tumour including 42 cm of gastric wall treatment for oesophageal cancer has been chemotherapy and or previous treatment that compromised the ability to deliver surgery or definitive chemoradiotherapy (National Oesophago- definitive chemoradiotherapy or surgery. Staging was performed Gastric Cancer Audit, 2012), and only more recently the Neoscope with endoscopic ultrasound (EUS), computed tomography of the trial (Gwynne et al, 2011) has opened that aims to compare chest and abdomen, positron emission tomography when available strategies for preoperative chemoradiotherapy before surgery. and staging laparoscopy and bronchoscopy in selected patients. All There was therefore a lack of high-quality evidence comparing centres measured tumour length on EUS and total length included surgical and non-surgical treatments of localised oesophageal SCC a measure of the primary tumour and submucosal disease meaning that treatment decision-making is currently based on and lymphadenopathy assessed with standard local criteria clinician or patient preferences and a trial is needed. (Davies et al, 2012). Trials of surgical and non-surgical treatments can be difficult to conduct and recruit into because of the diverse nature of Integrated qualitative research to optimise trial recruitment. treatments (Cook, 2009). In the UK, these difficulties were Qualitative research methods were integrated into the pilot RCT to overcome in the ProtecT trial that successfully randomised 1500 optimise challenges with recruitment. Eligible patients at identified men between radical surgery, radiotherapy or active monitoring for MDT meetings were sent information sheets and invited to clinic localised prostate cancer (Donovan et al, 2002). The ProtecT study where the appointment was audio-recorded. Consultations took used detailed screening logs to record patient eligibility and place in the usual hospital setting (Donovan et al, 2009). Patients qualitative methods (audio-recordings of consultations, recruiter underwent surgical consultations before meeting the oncologists. and patient interviews) to improve recruitment. Subsequent work Once the patient had made a decision about their preferred by Donovan and colleagues has further demonstrated how treatment option or randomisation, they were invited to take part qualitative research can improve trial conduct, information in a semi-structured interview at home so they could provide provision and rates of informed consent (Donovan et al, 2009; detailed feedback on the surgery and oncology appointments, their Paramasivan et al, 2011; Donovan et al, 2014). Although these understanding of the trial design, the treatment arms, the methods have been applied to other settings, it is unknown acceptability of randomisation, preferences and their treatment whether it is possible to successfully recruit into a trial of surgical decision. and non-surgical treatment for oesophageal cancer where the Audio-recordings and interview data were transcribed verbatim treatment-related morbidities are high, long-term outcomes are and analysed using techniques of constant comparison to under- poor and the impact on HRQL significant. This study, therefore, stand how the study was being presented and discussed with aimed to determine the feasibility of a main trial of chemotherapy patients (Glaser, 1998). Targeted conversation analysis was used to and surgery vs definitive chemoradiotherapy for localised oeso- identify problematic aspects of the clinical interaction (Donovan, phageal SCC. et al, 2002). The study planned to discuss findings within each centre with individual recruiters and in group training. Group training was based on analysis of the audio recordings (JLD, SS and CW). Standard thematic methods of qualitative data analysis were MATERIALS AND METHODS used to identify key findings that were then presented to surgeons, oncologists and nurses in the recruiting team with illustrative The study included three parts, (i) monitoring multi-disciplinary quotes to promote discussion of ‘good’ and ‘not so good’ team (MDT) meetings to determine the number of incident eligible information provision. Full details of this process are described participants with localised oesophageal SCC and final treatment elsewhere and have been integrated into several RCTs (Donovan received, (ii) undertaking a pilot RCT with integrated qualitative et al, 2014). research to establish whether recruitment was possible and (iii) development of core information sets for surgeons Trial treatments. Induction chemotherapy was given as 21 days of and oncologists to use to explain the two treatments. Parts (i) and either cisplatin 80 mg m by intravenous infusion on days 1 and (ii) are reported here. 5 followed by fluorouracil 1 g m per day as a continuous (i) Determination of incident numbers of eligible participants intravenous infusion for four days or cisplatin 80 mg m by for a main trial. Multi-disciplinary team meeting records from intravenous infusion on day 1 and capecitabine 625 mg m orally three specialist centres were studied to capture the number of new twice daily continuously. In the surgical arm, two- or three-phase patients with localised oesophageal SCC potentially eligible for oesophagectomies were performed as an open, laparoscopically this trial. Two of the MDT meetings considered all referrals and assisted or with a totally minimally invasive approach with a two- the third only considered patients without metastatic disease field lymphadenectomy. These are described in detail elsewhere suitable for radical treatment. Multi-disciplinary team data were (Blazeby et al, 2011). www.bjcancer.com | DOI:10.1038/bjc.2014.313 235 BRITISH JOURNAL OF CANCER Feasibility RCT of surgery and chemoradiation for oesophageal squamous cell cancer Induction chemotherapy before chemoradiotherapy consisted of months of recruitment. Eligible patients were predominantly two cycles of 21 days with either cisplatin 80 mg m by women 27(64.3%) (Table 1). intravenous infusion on day 1 and 5-fluorouracil 1 g m per (i) Determination of incident numbers of eligible trial patients day by continuous intravenous infusion for four days starting on for a main trial. The percentage of eligible patients ranged from 2  2 day 1 (i.e., total cycle dose¼4gm ) or cisplatin 80 mg m to be 6.0% to 14.7% across centres. Further investigation into reasons for by intravenous infusion on day 1 and capecitabine 625 mg m ineligibility showed that as expected about a third of patients orally twice daily within 30 min of food, starting in the evening of were not eligible because of metastatic disease and another quarter day 1 and finishing on the morning of day 43. The chemotherapy were ineligible because of frailty (this was lower as expected in the component of the definitive chemoradiotherapy was identical to centre that only discussed patients selected for radical treatment). the induction chemotherapy regimen above continued for a further There were unexpected differences between centres, however, in two cycles (i.e., from day 43 to day 84). Radiotherapy was started terms of the percentage of patients categorised ineligible because on day 43 and delivered in a single phase: 50 Gy in 25 fractions. the total tumour and node length exceeding 10 cm, with 27/147 (18.4%), 4/47 (8.5%) and 8/139 (5.8%) of patients in centres Outcome assessment and sample size. When eligible patients 1, 2 and 3, respectively, being classified as ineligible for that consented to randomisation, treatment allocation was determined reasons, P¼ 0.002 (Table 2). by an automated randomisation web-based system. The proportion of eligible patients consenting to randomisation was examined and (ii) Pilot RCT with integrated qualitative research. In total, 26 treatments recommended for eligible but non-randomised patients paired audio-recordings (7 from centre 1, 0 from centre 2 and 19 noted. The purpose of this feasibility study was to establish from centre 3) of surgery and oncology appointments were potential rates of eligible patients and of those, the percentage analysed alongside 14 in-depth patient interviews. Centres 1 and 2 consenting to randomisation. Hence, eligibility and randomisation did not randomise any patients and centre 3 randomised five rates were the primary outcomes for this study and were calculated patients. Feedback meetings to improve consultations were separately for each centre and overall. Differences between centres undertaken in centres 1 and 3. In centre 1 following feedback, were examined using Chi-square tests. The pilot RCT assessed the no eligible patients were identified before the end of the study, feasibility of data collection including toxicity, surgical morbidity preventing analyses of the impact of feedback and training. In and HRQL (EORTC QLQ-C30 and QLQ-OG25) data (Aaronson centre 3, before feedback no one had consented to randomisation et al, 1993; Lagergren et al, 2007). It was not the intention of this (of 8 eligible patients) but following feedback, 5 of the next 16 study to examine the comparative effectiveness of the two eligible patients consented to randomisation (Table 1). This treatments, hence no formal sample size calculation was indicates the positive impact on recruitment of training and performed. North Somerset and South Bristol Research Ethics feedback from the qualitative study. Committee (09/H0106/69) approved this study. Analyses of the final treatment received for eligible but non- randomised patients in centre 1 showed a preference for surgery (Table 2), whereas the proportions of eligible but non-randomised RESULTS patients in centres 2 and 3 were similar for surgery and definitive chemoradiotherapy. Centres recruited for different lengths of time between April 2010 The qualitative research identified three issues hindering and March 2013 (for a total of 82 centre months) during which 375 recruitment. Recruiters had difficulties in (a) articulating the trial patients with oesophageal SCC were discussed in 331 MDT design in simple terms; (b) balancing treatment arms, in particular, meetings. Only 42 (11%) were considered eligible (Figure 1); this describing the effect of radiotherapy on the tumour; (c) explaining equates to just one eligible patient identified for every two centre the selection of treatment by randomisation. Difficulties explaining the trial design identified in the early recruitment appointments occurred because recruiters presented patients with the two Number of patients different treatment options (chemotherapy and surgery or screened N =375 chemo-radiotherapy) without mentioning the trial. As a result, patients thought they had to make a choice between these two treatment options. Other patients reported not understanding what Ineligible taking part in the trial actually meant. In many appointments, the N =333 trial was presented as a third option, only suitable for those who could not make a decision about their preferred treatment (Figure 2 provides illustrative quotes). This limited the number Eligible N =42 of patients who considered taking part in the study. Many patients who declined to take part in the study expressed a strong preference, either for or against surgery. Patients Declined intuitively understood that surgery ‘removes’ or ‘cuts out’ the randomisation N =37 tumour, but were uncertain about the action of radiotherapy on the cancer. Recruitment appointments were reviewed to examine how consultants talked about surgery and radiotherapy. In early Randomised recruitment appointments, several surgeons unintentionally N =5 expressed a preference for surgery. Following training, surgeons were able to use balancing statements to convey the strengths and limitations of both treatment options and to explain the effect of radiotherapy on the tumour (Figure 3 provides illustrative quotes). N =2 Interview data showed that the majority of patients did not like N =3 Induction chemotherapy Induction chemotherapy the idea of a computer allocating their treatment and they did not and definitive and oesophagectomy understand the need for randomisation. Early recordings showed chemoradiotherapy consultants were reluctant to explain the rationale for randomisa- Figure 1. Flow diagram of recruitment into the pilot RCT. tion. Training was provided to help consultants explain 236 www.bjcancer.com | DOI:10.1038/bjc.2014.313 Feasibility RCT of surgery and chemoradiation for oesophageal squamous cell cancer BRITISH JOURNAL OF CANCER Table 1. Eligible patient details and final treatment received Centre 1, N¼ 15 Centre 2, N¼ 3 Centre 3, N¼ 24 Total, N¼ 42 Mean age, years (range) 67 (48–76) 61 (55–69) 68 (41–77) 65 (41–78) Female, n (%) 10 (66.7) 3 (100) 14 (58.3) 27 (64.3) Tumour stage I 002 2 IIa 127 10 IIb 2 0 14 16 III 13 1 1 15 Randomised into pilot RCT, n (%) 0 0 5 (20.8) 5 (11.9) Treatment received by eligible but non-randomised patients, n (%) Chemotherapy & surgery 8 (53.3) 1 (25.0) 7 (43.7) 16 (43.2) Surgery alone 1 (6.7) 0 (0.0) 0 (0.0) 1 (2.7) Definitive chemoradiotherapy 6 (40.0) 2 (50.0) 9 (47.4) 17 (45.9) Stent 0 (0.0) 0 (0.0) 2 (10.5) 2 (5.4) Unknown 0 (0.0) 0 (0.0) 1 (5.2) 1 (2.7) Abbreviation: RCT¼ randomised controlled trial. Table 2. Numbers of incident patients with oesophageal SCC eligible for the trials, reasons for ineligibility and final treatment received by centres Centre 1, N (%) Centre 2, N (%) Centre 3, N (%) Total, N (%) Incident oesophageal SCC discussed at MDT 162 50 163 375 Eligible for the pilot RCT 15 (9.3) 3 (6.0) 24 (14.7) 42 (11.2) Reasons for ineligibility (n (%) of those not eligible) Metastatic disease 44 (29.9) 15 (31.9) 44 (31.7) 103 (30.9) Unfit for radical treatment 43 (29.3) 9 (19.1) 41 (29.5) 93 (27.9) Total tumour length 410 cm 27 (18.4) 4 (8.5) 8 (5.8) 39 (11.7) T4 disease (aorta/pericardium) 14 (9.5) 8 (17.0) 16 (11.5) 38 (11.4) Tumour o2 cm cricopharyngeus 4 (2.7) 1 (2.1) 6 (4.3) 11(3.3) Previous malignancy 7 (4.8) 3 (6.4) 3 (2.2) 13 (3.9) Recurrent disease 3 (2.0) 3 (6.4) 5 (4.0) 11 (3.3) Other 5 (3.4) 4 (8.5) 16 (11.5) 25 (7.5) Abbreviation: MDT¼ multi-disciplinary team; RCT¼ randomised controlled trial; SCC¼ squamous cell carcinoma. Only patients suitable for radical treatment referred to this centre and MDT. randomisation, significantly improving patient understanding and differences were seen between the centres in terms of the reasons acceptance of the study (Figure 3 provides illustrative quotes). for ineligibility. Initially, no eligible patients consented to All participating patients completed HRQL outcome measures randomisation. In one centre where the qualitative research was at the required time points. Other outcomes were reviewed at clinic effectively applied and feedback meetings undertaken some 5 of the appointments to 6 months after randomisation. 16 patients were randomised providing an indication that recruitment was possible with appropriate support. Despite the successful randomisation in one centre this study has shown that a DISCUSSION full trial comparing a surgical and non-surgical approach for oesophageal SCC is not feasible in the UK alone because of This paper describes feasibility work to establish whether a main insufficient eligible patients. It does, however, show that recruit- trial comparing a surgical and non-surgical approach for ment difficulties are often multi-factorial and a range of methods is oesophageal SCC is possible. It integrated specific methodological needed to identify and address them. It also shows how investment techniques to optimise recruitment because of the well-recognised with qualitative research in a trial can support surgeons and challenges enroling patients in trials comparing diverse treatment oncologists to recruit and this method has promising implications options and to help surgeons with this unfamiliar process. The for other settings. study scrutinised MDT records for eligible patients, carefully The methods used to examine incident patients via MDT documenting reasons for ineligibility and it used qualitative meetings were found to be practical and useful in providing research methods to understand how the trial was discussed by accurate information to inform whether a main trial is possible. surgeons and oncologists and to allow feedback and training. It was Others have explored the role of MDT records to optimise trial found that 11% of all patients with oesophageal SCC were eligible recruitment and demonstrated that these provide an excellent for the trial, which in this study equated to just one patient every resource to identify eligible patients into oncology trials (McNair two months that a centre was open for recruitment. Notable et al, 2008). It is recommended, therefore, that this approach is www.bjcancer.com | DOI:10.1038/bjc.2014.313 237 BRITISH JOURNAL OF CANCER Feasibility RCT of surgery and chemoradiation for oesophageal squamous cell cancer used more widely. Analysing reasons for ineligibility for the trial Example quotes before training: also provided useful data. It showed how centres differently used Surgeon 1: “If you can’t decide, go into the trial.” local staging investigations to assess tumour lengths and trial Surgeon 2: “If you say that you were happy to go into the trial at this point, you say, ‘I don’t know which way to go –I’ll go into a trial’, your name is drawn out of a hat as eligibility. For example, centre 1 found a larger proportion of to which of those two options you get –as you could have either of the two options ineligible patients due to disease length than the other centres anyway.” because of the interpretation of the EUS data. In a main trial more Patient (79 yr old male, not consented, surgery preference): “I’m not quite with that detailed guidance for assessing the tumour length and trial word trial at the moment ‘cause if you’re gonna try something then you do something eligibility is recommended. differently, so what’s different? (ctd...) This word trial to me seems to be a completely wrong word. It’s not a trial, it’s actually what you’re gonna get. It’s the actual Other trials have integrated qualitative research methods to treatment, isn’t it?” optimise recruitment by audio-recording consultations, analysing Training points: Consultants were asked to replace the word trial with ‘study’ and to data and providing training and feedback to surgeons (Donovan use the study to frame discussion of the treatment options. et al, 2002; Lewin et al, 2009; Paramasivan et al, 2011; Donovan Example quote post training: et al, 2014). To achieve this, however, it is necessary to ensure Surgeon 3: “.... there are different types of treatment for the cancer you have. that audio-recordings are undertaken and returned from the You can have chemotherapy and radiotherapy. You can have chemotherapy and surgery. And the difficulty we have as experts is that we don’t know which one of participating centres. Difficulties in obtaining audio-recordings those treatments is best, so we’ve started this study...now what I wanted to talk from clinical centres identified in this study have been to you about today is whether or not you would consider going into the experienced in another trial of a surgical and non-surgical study...you don’t have to, it’s completely voluntary.” treatment for bladder cancer (Paramasivan et al, 2011). The Figure 2. Example quotes to show the difficulties that surgeons had reasons for lack of audio-recording consultations and transfer of in explaining the study design and the improvements made after data may be related to logistical issues. There is evidence that training. there is a general reluctance among recruiters to be audio- Example quotes about unbalanced information provision: Surgeon 4: “I don’t think these things are set in stone but if we were going to make a list of treatments starting with which one is most likely to cure my cancer then it’s probably gonna be chemotherapy followed by surgery. If we do anything less it won’t cure your cancer... and the cancer will eventually kill you.” Surgeon 5: “There is evidence that having chemotherapy and radiotherapy without an operation may also be able to treat the tumour.” Oncologist 1: “There are two treatments for your complaint...either an operationwhere they cut it away or radiotherapy, and chemotherapy where we treat people with x-ray treatment and drugs.” Training points: Consultants were asked to use balancing statements to compare the advantages and disadvantages of both treatments and to describe the action of the radiotherapy, as being able to “destroy” or “kill” the cancer cells. Example quotes post training: Surgeon 4: “We have a treatment that could involve chemotherapy and then an operation to cut it out and we have a treatment that involved chemotherapy and radiation, and our previous experience of patients is that we know that both of those work and as best we can tell, both of them seem to work equally effectively in curing your cancer.” Surgeon 3: “We give radiotherapy to kill off the cancer cells that maybe there.” Example quotes of difficulties explaining randomisation: Surgeon 1: “If you’re not sure of one, we recommend that the decision about which treatment you have is made by a process called randomisation so rather than me, you or Dr (Surname) deciding, a computer decides and then you’re allocated to one of those two, and then, you have got a good chance of having the best treatment because you don’t know what’s the best treatment. You’ve got a fifty/fifty chance of having the best treatment. In other words, you don’t decide - the computer decides for you.” Example quotes showing patient difficulties to understand/accept randomisation Patient (77 yr old male, non-randomised, chemo-radiotherapy preference): “[Consultant X] said they put all the information they’ve got – how old I am and what - where it is into a computer, and then the computer shoots out a result which is the best way to go. No, I don’t think that I’d want to be at the mercy of a computer. I wouldn’t accept any of that... you see were not computer oriented. We haven’t got one in our house.” Patient (71 yr old female, non-randomised, surgery preference): “Why can’t they follow people up, whatever option they choose? I don’t want a computer to take over my life, make decisions. When I made the choice – right or wrong, I’ve made it and it’s me that’s made it.” Training points: Consultants were asked to avoid using the word computer and explain the rationale for randomisation Example quotes post training: Oncologist 1: “The study decides whether you have the radiotherapy or the surgery and the reason we have to do that is that the problem is that say we see 10 patients in a row and we say well quite like - the surgeon says well I quite like the look at that one for an operation, they’re the right, size, shape and age then that puts in what’s called bias into the study. So it has to be done on what’s called a random allocation where if you like the study decides rather than we do because otherwise we put bias in it. So if you look at previous studies for example where they’ve done that the patients operated on tend to be young and fit and the people who have the radiotherapy tend to be older andless fit.” Surgeon 4: “the way of approaching any study would be to allocate the treatment to you, to randomise you to one or the other options and that is done as part of the study itself.... we obviously monitor you as you go through everything, looking at you, the effects of the treatment and see how you are, hopefully at the end of all of this, with enough people we will answer the question as to which one would appear the better option.. So that’s the basis of the study itself. If people, if some people don’t want to enter into the study then obviously we’ve got to still think about you and how we would treat you and we’re still then left with the same two options.” Figure 3. Example quotes to show the difficulties consultants had in balancing the treatment groups and explaining randomisation, and how the improvements were demonstrated after training. 238 www.bjcancer.com | DOI:10.1038/bjc.2014.313 Feasibility RCT of surgery and chemoradiation for oesophageal squamous cell cancer BRITISH JOURNAL OF CANCER recorded (Donovan et al, 2014) and this was also found in this possible in the UK alone and would require an international effort. trial. In centres where this was not challenged, recording was not The integration of qualitative research methods with accompany- undertaken (centre 2), but when the recording was undertaken by ing feedback can improve recruitment into trials with very different the PI and strongly encouraged, it became a routine (centre 3). treatment interventions and should be routinely incorporated. These experiences emphasise the need for better training of clinicians before participation in trials and strong support and ACKNOWLEDGEMENTS trial leadership during the study itself. Recent evidence suggests that there are some generic lessons that can be learned from previous qualitative research integrated This article summarises independent research funded by the with trials, such as the need to support recruiters in explaining National Institute for Health Research (NIHR) under its Research aspects of trial design including randomisation and equipoise, and for Patient Benefit (RfPB) Program (Grant reference PB-PG-0807– the need to explore the basis of apparent preferences; but also that 14131). there are likely to be some issues specific to the particular trial that are likely to require the dedicated qualitative research (Donovan AUTHORS CONTRIBUTIONS et al, 2014). As more of this research is conducted, it is also possible that clinicians exposed to the training may acquire recruitment skills that will be transferable to other trials. Other JMB, STB, JLD, WH, TC and SMG designed the study with methods to improve trial recruitment could involve holding joint contributions to its adaptation during delivery of the trial from SS, clinics with surgeons and oncologists together or changing the CW, SJF, CPB, ADH, CGS, DT, RK and JN. Participation in order in which patients meet each specialist (Paramasivan et al, recruitment, delivery of interventions and audio-recordings were 2011). These approaches may be interesting to explore in future undertaken by CPB, ADH, RK, CGS, DT, JMB, TC, JN and SMG. work. There has also been an initiative promoted by the Royal SS, CW and JLD analysed and interpreted the qualitative data. The College of Surgeons of England for surgical trainees to be involved first draft of the paper was written by JMB. All authors contributed and recruit into trials in surgery, which has had promising early to the final version. JMB is the guarantor of the study. results (Bhangu et al, 2013). Few trials have directly compared surgical vs non-surgical treatment for oesophageal cancer, although two RCTs randomised DISCLAIMER patients following neoadjuvant chemoradiotherapy to consolida- tion chemoradiotherapy or surgery (Stahl et al, 2005; Bedenne et al, The views expressed in this publication are those of the author(s) 2007). The original trials of radical surgical and non-surgical and not necessarily those of the NHS, the NIHR or the Department approaches initiated some time ago were stopped because of poor of Health. recruitment (Urba et al, 2001; Burmeister et al, 2005) and the more recent Chinese trial did not report a sample size calculation recruiting only 80 patients (Chiu et al, 2005; Teoh et al, 2013). 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British Journal of CancerSpringer Journals

Published: Jun 12, 2014

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