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E. Neugebauer, H. Troidl", W. Spangenberger*, A. Dietrich, R . Lefering and The Cholecystectomy Study Group Biochemical and Experimental Division and *Surgical Clinic, 2nd Department of Surgery, University of Cologne, Germany Correspondence to: Dr E. Neugebauer, Biochemical and Experimental Division, 2nd Department of Surgery, University of Cologne, Ostmerheimer Str. 200, D-5000 Cologne 91, Germany

Convent ionaI versus lapa roscopic cholecystectomy and the randomized cont ro I led t r iaI W e considered using a randomized trial to assess the value of laparoscopic cholecystectomy in the treatment of symptomatic gallstones. The pros and cons for the timing of such a trial were in favour of not beginning the trial until surgeons learned to use the new procedure safely and effectively, and until key endpoints and outcome indices could be identified and assessed using valid measures. Instead an observational study was implemented to monitor the learning curve of surgeons as they mastered the laparoscopic equipment andprocedures, and to assess the responses of the patients to the procedure. In theJi:rst 100 patients, the procedure proved to be as safe and feasible to use as conventional surgery, and there were strong benefits in terms of quicker recovery of the patients with less pain, discomfort, and a reduced length of hospital stay. The responses of the surgeons and the patients to the new procedure now place ethical constraints on the planning of a randomized controlled trial. Currently, comprehensive surveillance and monitoring of laparoscopic cholecystectomy is the only realistic method with which to assess the impact of this new technology in our clinic.

Cholelithiasis is one of the most common diseases in Western European countries, with a prevalence between 5 and 22 per cent'-', and cholecystectomy has been the accepted method of treating patients with symptomatic gallstones. The purpose of cholecystectomy is the relief of symptoms and disability and the prevention of mortality. Although the mortality rate of the operation (overall less than 0.1 per cent but up to 10 per cent if elderly patients are operated on for complications caused by gallstone^^^'^^' ') and the rate of complications following cholecystectomy are low, most patients still experience difficulty because of postoperative ileus, pain, discomfort, disability and long convalescence. This has led to the development of a number of alternatives, including dissolution of gallstones with cholelitholytic drugs", extracorporal shock-wave lithotripsy with o r without adjuvant bile acid dissolution1z,13and various techniques of laparoscopic cholecystectomy10~'4.L5~L6. Laparoscopic cholecystectomy is the most promising new technique for the treatment of cholelithiasis in terms of reduction in postoperative morbidity and length of convalescence. However, as correctly pointed out in two recent -one entitled 'The laparoscopic evolution - walk carefully before we run' - the authors asked for a controlled evaluation of the new technique. They suggested prospective randomized controlled trials to define the indications for the laparoscopic approach and to confirm its benefits when compared with the standard operation of open cholecystectomy. When we started doing laparoscopic cholecystectomies in Cologne in October 1989, we intended to set up a prospective randomized trial after confirmation of the feasibility and safety of the new procedure in our hands. The protocol had to meet all accepted criteria for assessment including safety, applicability, benefit for the patient and the surgeon, efficacy and cost-benefit effectiveness, because it is no longer acceptable o r tolerable to describe the clinical significance of technologies in terms of case studies or empirical judgements''. In setting up the protocol, however, we were confronted with several basic problems which had to be solved before starting a trial. The purpose of this paper is to point out some of these problems and to present our solutions for debate.

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When is it appropriateto carry out a randomized controlled trial? After the introduction of laparoscopic cholecystectomy in our clinic in October 1989, the timing of a possible randomized controlled trial for its comparison with the well established conventional cholecystectomy was discussed repeatedly. Examining the literature to learn through the example provided by other innovations in surgery (i.e. shunt surgery for portal hypertensionzO.zl, coronary artery bypass g r a f t i ~ ~ g ' ~ . ~ ~ . ~ ~ , jejunocolic and jejunoileal bypass surgeryz5, or total hip replacementz6)it became obvious that the timing of randomized trials was and still is a highly controversial issue. Some people insist that clinical trials must be done as early as possible in the evaluation of new therapies" whereas others have argued against them, especially in surgeryz8. There is, however, unanimous agreement that a new treatment should be introduced in a manner that allows prompt and reliable evaluation of its efficacy and safety. The question is: how to do this promptly and reliably?

Pro: initiate a randomized controlled trial as early as possible Chalmersz7 has made an especially strong case for randomizing the first patient to receive a new drug, procedure or operation and has provided a number of compelling arguments against 'pilot trials'. The concept stems from recognition of the influence of pilot trials in postponing or eliminating a definitive therapeutic trial. If one considers for example the disorderly history of shunting procedures for portal hypertension, decades were wasted by the failure to introduce, standardize, and carry out randomized controlled trials from the beginningz9. Increasing and unrestricted use of a new operation such as laparoscopic cholecystectomy increases the uncertainty about its value. In the absence of an explicit and detailed experimental protocol, institutions and surgeons are apt to vary considerably their selection of patients and choice of operative technique as well as their criteria for subsequent evaluation. Purists even state that it is scientifically and ethically inexcusable not to undertake randomized controlled trials as soon as possible.

0007-1323/91/020148-05

6 1991 Butterworth-Heinemann

Ltd

Conventional versus laparoscopic cholecystectomy: E. Neugebauer et al.

Con: do not initiate a randomized controlled trial as early as possible There are strong arguments for not randomizing the first patient in the evolutionary phase of a new operation, especially if the new operation requires training as is the case for laparoscopic cholecystectomy. Few general surgeons have any experience in using a video monitor to watch instruments inserted through holes in the abdomen. In contrast to medical trials, which are almost independent of any special skill, the results of surgical trials vary according to the skill and experience of the surgeon. Sometimes proper information on the feasibility of a trial is lacking3’. Before conducting a trial, the investigator needs to have the necessary knowledge and tools. He or she must have information about the safety of the intervention and the endpoints to assess, and must have validated techniques to conduct the assessment. Another aspect of timing is the consideration of the relative stability of the intervention. An early randomized trial can be rendered obsolete by advances in surgical technique. As laparoscopic cholecystectomy is a completely new approach in gallbladder disease, improvements in the operative technique and surgical skills, as well as a constant development of surgical instruments, can be expected within a short time. A good example to support this argument, and one which was widely discussed in literature, was the randomized study of coronary artery bypass surgery, the Veterans Administration trialz4. This trial did not have the expected impact on coronary surgery because it was criticized for poor early operative results and lack of relevance to current experience, not for fundamental flaws in the design3’. Surgical journals contain a number of examples of innovations which would not have stood a chance of adoption if they had been immediately subjected to a randomized trial. Langenbuch published the first account of cholecystectomy in

188232, having taken the utmost care, including care in the selection of the first patient. To quote Van der Linden”: ‘In spite of this and in spite of the fact that the operation was successful, he engendered much criticism among his p e e d 3 . Fortunately, Langenbuch did not randomize his first patient, neither did he run a trial. Such a trial, performed by surgeons unfamiliar with a procedure which requires careful training and thorough knowledge of biliary tract anatomy would have given a very unfair picture of an operation, the value of which cannot be doubted’.

After weighing the pros and cons for the timing of a randomized controlled trial of ‘conventional uersus laparoscopic cholecystectomy’ we were in favour of not starting such a trial from the very beginning. Instead, consensus was obtained first to initiate a careful observational study of the new procedure in parallel with a study of conventional cholecystectomy using the same detailed and standardized protocol. This observational study was intended to be replaced by a randomized controlled trial after demonstration of safety and feasibility. The purpose of the observational study was to audit outcome by prognostic factors such as age, sex, diagnostic categories and severity of the condition and to identify the therapeutic uncertainty justifying a randomized controlled trial. Furthermore all factors contributing to the ‘learning curve’ had to reach an acceptable degree of variation or plateau which was unlikely to change greatly. We published our description of the outcome of laparoscopic cholecystectomy in 100 patients comprising this observational study‘ and a summary is given in Table I. The Cholecystectomy Study Group is now meeting again to discuss the results and the prerequisites to be fulfilled before switching over to a more advanced assessment, ideally a randomized controlled trial, to allow reliable evaluation of the benefits and limitations of the new laparoscopic technique.

Table 1 Laparoscopic cholecystectomy: demographic data, characteristics and major endpoints estimated in the observational study on the first 100 patients operated on from October 1989 lo May1990 (from Spangenberger et a1.16) ~

Demographic data Total number of patients (n) Sex (n) Male Female Age (years) Weight (kg) History of biliary tract symptoms (years) Cholelithiasis Pain Colic Severity of biliary tract symptoms (classification scale according to McSherry et Grade 0 (n) Grade + (n) Grade + + (n) Severity of condition (ASA classification) ASAI (n) ASAII (n) ASAIII ( n )

Major endpoints estimated 100

18 82 45 (25-78)* 64 (41-130)* 2 (0-27)* 1 (0-20)* 0.5 (0-27)*

12 65 23 29 55 16

Mortality (number of patients) Complications during operation Iatrogenic leak from bile duct Complications after operation ‘Major’ Ileus ( n ) Peritonitis ( n ) ‘Minor’ Thrombophlebitis ( n ) Wound discharge ( n ) Haematoma ( n ) Time of operation (min) Patient 1-50 Patient 51-100 Time of hospitalization (days) Preoperative Postoperative Pain intensity (VAS scale) 1st postoperative day 2nd postoperative day 3rd postoperative day Discharge Nausea ( n ) Day of operation 1st postoperative day 2nd postoperative day 3rd postoperative day Vomiting (n) Day of operation 1st postoperative day 2nd and 3rd postoperative days

0 1

I 1 1 10 1

120 (60-240)* 90 (30-210)* 2 (1-9)* 3 (1-15)* 33 23 10 7

51 24 8 1 22 6 0

* Median (range); ASA, American Society of Anaesthesiologists

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Can a randomized controlled trial really be performed? In focusing attention on procedures with which to evaluate the efficacy of a feasible new operation or to compare its efficacy with that of competing operations there is a choice of approach ranging from case series with or without historical controls to a randomized controlled trial. Among investigators there is unanimous agreement that a properly planned and executed randomized controlled trial is the best available method for evaluating alternative treatments including surgical operations. Surgeons have had considerable difficulties in learning to put aside judgements based on experience or tradition and it was Goligher who set up the first randomized controlled trial in surgery (comparing vagotomy with gastroenterostomy or antrectomy with subtotal gastrectomy in the elective treatment of duodenal ulcer)34.This report spurred surgeons all over the world to conduct randomized controlled trials but it is still true that most clinical research in surgery relies on comparisons with historical or contemporary non-random controls35. New operations may be more difficult to evaluate than new Furthermore, recent developments in the application of ethical principles coupled with problems of selective enrolment of patients have clearly restricted the use of randomized controlled trials as clinical research tool^^^.^'. This also applies to our intended randomized controlled comparison of conventional as opposed to laparoscopic cholecystectomy. The two basic problems, namely ‘the selection bias problem’ and ‘the ethical problem’ will now be discussed. The selection bias problem One of the prerequisites of a trial is that a sufficient number of patients can be recruited within a reasonable period of time so that there is a high likelihood of detecting a significant difference in event rate between the groups. The study population as a subset of the general population requires specification of criteria for eligibility. These criteria must relate to safety and study design. To fulfill these prerequisites only those patients should be enrolled who are considered suitable for both operations. Our eligibility criteria in the present context were to be: age > 18 years, elective operation on patients with a history of symptomatic cholelithiasis (severity according to McSherry3’), of symptoms scale 0 to + ultrasonographic confirmation of gallstones, no signs of infection or cholestasis clinically or by assessment of laboratory data, and patients classified as ASA 1-111 according to the American Society of Anaesthesiologists. In a retrospective audit of patients operated on in our clinic in the year before starting laparoscopic cholecystectomy, we found that only 70 patients fulfilled these criteria. This number was considered far too small to start a randomized controlled trial. However, the very high public interest in laparoscopic cholecystectomy and the publicity surrounding our clinic following reports of the first successful operations in Germany led to a rapid increase in the number of eligible patients with gallbladder symptoms in our clinic. The patients were no longer recruited only from the area around Cologne but came from elsewhere in Germany and Europe. The potential advantage of this increased recruitment of patients, namely that it would enable us to run a trial, was diminished by the fact that all these patients wanted only the new ‘minor’ invasive technique that they had heard about. The change in recruitment pattern led to our collecting a highly selected group of patients not comparable with the historical ‘control’ cholelithiasis patients in our clinic. Of the 100 patients who had laparoscopic cholecystectomy’6 77 were classified as grade 0 to (McSherry3’), a grading which applied to only about 10 per cent of the patients who were operated on for gallstones previously. Furthermore, after the introduction of the laparoscopic technique in October 1989 no patient was denied the new operation on the basis of the eligibility criteria outlined above. The reason was not only to get more experience with the new technique but (and much more importantly) that the parallel analysis of the endpoints of postoperative pain, nausea,

+

+

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convalescence and in-hospital stay were strongly in favour of the new technique. Our ‘historical experience’ was not, however, based on a well documented database using the new endpoints. To run a trial under these circumstances brought us to the next problem, the ethical problem. The ethical problem People have debated the ethics of clinical trials for as long as they have been undertaken. The fundamental ethical justification for a randomized controlled trial is that neither the patient nor the surgeon will have a preference for one arm over another; ignorance of the respective merits of the two techniques is essential. It is quite wrong for surgeons to engage in a randomized controlled trial unless they are convinced that the answers to the questions being addressed are truly unknown. No trial is justified unless it is scientifically sound and the need for any study should be subject to evaluation using available information3’. When a new technique is introduced there is only scanty information available. It was therefore one of the aims of our observational study to identify the field of therapeutic uncertainty justifying a randomized controlled trial. The first two of the three basic ethical principles (respect for persons, beneficence and justice) consonant with the major traditions of Western countries as identified in the Belmont Report4’ have to be considered. According to the principle of autonomy, patients have the right to make their own decision about treatment. Application of this principle to clinical research translates into informed consent41. Informed consent requires full disclosure of the available information regarding the potential benefit and harm of any procedure. Despite the fact that patients were informed that only preliminary information was available for the new laparoscopic technique and that there was a great deal of medical uncertainty, it proved impossible to translate this to the patients at a time of enthusiasm for the new technique. Patients were strongly in favour of it because of the smaller scar, diminished postoperative pain, shorter hospital stay and the more rapid physical recovery. Accepting the ethical principle of autonomy means that randomized controlled trials have become obsolete for alternative treatments that are of concern to the patients. The intended randomized controlled trial then joins other obsolete controlled trials such as comparisons of partial mastectomy and total mastectomy or colonic anastomosis with or without colostomy, as outlined recently by Oettinger and Beger37. The second principle (beneficence) is. directly relevant to the ethics of evidence. It is unethical to use a powerful therapeutic procedure without sound assessment of risks and benefits. To meet this principle the safety of the laparoscopic technique was carefully evaluated. All the patients in the observational study (Table 1)were discussed separately in open conference with members of the Cholecystectomy Study Group, other surgeons from the clinic and invited guests. There was unanimous agreement that the new technique, in the selected group of patients operated on, was as safe as the conventional technique in the hands of surgeons with specific experience. In our clinic only three surgeons were involved in all of the 100 operations. There were no deaths and the only three major complications occurred early in the series and were considered avoidable. An iatrogenic injury to the common bile duct resulted in one patient undergoing a mini-laparotomy with conventional cholecystectomy and T tube drainage. Two further complications occurred postoperatively which made laparotomy necessary; one 44-year-old woman with an initially uneventful postoperative course returned 4 weeks later with a subacute small bowel obstruction. Laparotomy revealed that the small bowel serosa had been sutured to the abdominal wall. One other patient developed an acute abdomen on the first postoperative day. Laparotomy revealed early peritonitis with positive bacteriological culture (Escherickia coli). After

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treatment all three patients were discharged from hospital and there have been no further complications to date. The benefits of laparoscopic cholecystectomy as compared with conventional cholecystectomy were evaluated from published data, historical data from our clinic and the personal experience of the senior surgeons. This revealed a strong benefit for the new technique with regard to all endpoints concerned with patients’ discomfort and disability (postoperative pain intensity, nausea, vomiting. convalescence) as well as duration of hospital stay. There was a consensus that a randomized controlled trial was not justified at this time in patients similar to those enrolled in the observational study. The group was aware that this decision was based on insufficient information about the results of the conventional technique. Nevertheless, the fundamental ethical justification for a randomized trial that the participating surgeons should have no preference for one arm over another - was not fulfilled.

-

Where do we go from here? Ethical restraints and resistance by patients and surgeons to allowing the choice of operation for symptomatic gallstones to be decided by chance mean that we have to consider alternatives to randomized clinical trials. A system of comprehensive surveillance seems to be the only realistic alternative at a time when the laparoscopic procedure is spreading like ‘wi1dfi1-e’~’. Continuing surveillance should be maintained at a level which will allow long term evaluation of both the new and the old techniques. Such surveillance should be carried out at the minimum level necessary. For this purpose, an extensive (as many institutions as possible) computer based databank is versatile and appropriate. We therefore strongly support the most recent initiative of the Society of American Gastrointestinal Endoscopic Surgeons who set up the International Retrospective and Prospective Multi-Institutional Laparoscopic Cholecystectomy Study (study co-ordinators: G. Berci and J. Sackier), It is the responsibility of all participants to report complete, accurate, and honest audit of outcomes in order to make this assessment tool reliable. This database will then reveal the value of the new laparoscopic technique in comparison with alternative treatments and will answer questions of therapeutic uncertainty which may justify randomized controlled trials in the future. To justify a randomized controlled trial in conditions where uncertainty is recognized requires extensive discussion of all prerequisites outlined above. The discussion in our Cholecystectomy Study Group revealed that it will never be easy to run such a trial in this field. O n the basis of current knowledge and experience our group reached a consensus that the efficacy of the laparoscopic technique is most questionable for patients with acute cholecystitis evidenced by tenderness in the right abdomen, fever and leucocytosis ( + + + according to M ~ S h e r r y ~Despite ~). the fact that the study protocol for a randomized controlled trial in this group of patients had been approved by an independent ethics committee at our university we are at present unable to perform the trial. The reason is that our operation facilities are totally blocked by patients with symptomatic cholelithiasis awaiting elective laparoscopic operation. We are therefore unable to enrol a sufficient number of eligible patients in our clinic alone. A multicentre trial is currently not possible because of lack of experience with the laparoscopic techique in otherwise suitable surgical clinics. Two further problems are connected with the fact that the two treatment arms (laparoscopic versus conventional cholecystectomy) can be distinguished by the patients involved. As the trial proceeds it is unavoidable that impressions about results will be conveyed to new patients entering the trial. These impressions will interfere decisively with further randomization and the assessment of results as judged by the patient. The bias in the assessment of the results is considerable as most of the relevant endpoints, such as pain relief and fatigue, will rely only on patients’ evaluation.

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Conclusions Laparoscopic cholecystectomy is a considerable advance in the treatment of gallbladder disease. Many consider that all hopes for a critical assessment of the procedure have to all intents and purposes disappeared. We d o not share this opinion but hope that the time will come again to perform randomized controlled trials in specific subsets of patients with gallstone disease. Moreover, future trials comparing laparoscopic cholecystectomy with alternative medical therapies, in particular extracorporeal shock-wave lithotripsy, or trials comparing lithotripsy plus postponed laparoscopic cholecystectomy with early laparoscopic cholecystectomy in high risk patients with gallstone disease will further reveal its value. The safe application of the laparoscopic technique will also renew old controversies regarding the treatment of asymptomatic gallstones in the near future.

Acknowledgements We wish to acknowledge with thanks the constructive discussions of Professor Jack Williams, University of Toronto (Canada), Professor Sharon Wood-Dauphinee, McGill University, Montreal (Canada), Professor Matthias Rothmund, Philipps University, Marburg (Germany), Professor Alan Pollock, Scarborough Hospital, North Yorkshire ( U K ) and all colleagues of the 2nd Department of Surgery at the University of Cologne. Members of the Cholecystectomy Study Group are: B. Bouillon, E. Eypasch, W. Juchem, J. Klein, A. Koch, U. Leistikow, A. Paul, B. Ure (Surgical Clinic, 2nd Department of Surgery, University of Cologne); M . Doehn, M . Matuszczak (Department of Anaesthesiology, Stadt. Krankenanstalten Koln-Merheim); B. Well (Biochemical and Experimental Division, University of Cologne); and W. Winkelmann (Medical Clinic, 2nd Department of Medicine, University of Cologne).

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Paper accepted 1 October 1990

Br. J. Surg., Vol. 78, No. 2, February1991

Conventional versus laparoscopic cholecystectomy and the randomized controlled trial. Cholecystectomy Study Group.

We considered using a randomized trial to assess the value of laparoscopic cholecystectomy in the treatment of symptomatic gallstones. The pros and co...
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