CANCER CONTROVERSIESClinical Trials Confirm But Don’t Innovate—Con

David J. Girling, MD*

Randomised clinical trials became an essential part ofclinical research in the 1940s. They have led to manyimportant innovations in treatment in all areas of medi-cine, not least in oncology. Those of us involved in clini-cal research are aware, however, that the ways we areconstrained to publish our results can create a misleadingimpression. The standard structure of a clinical scientificarticle—introduction, patients and methods, results, dis-cussion—and the way it is written can all too often givethe impression that clinical research is more inductivethan innovative. This constraint can conceal the explor-atory nature of hypotheses that are being tested and ourgenuine uncertainty about the likely outcomes of a ran-domised trial at the time it is planned. It also obscures thesense of discovery that can prevail as we conduct the trialand analyse the results. I therefore make my case againstthis motion on the basis of the way clinical researchhappens in practice, using a number of examples fromour own and others’ research. These examples comemainly, but not exclusively, from the field of oncology.

Small cell lung cancer (SCLC) is highly sensitive tochemotherapy. In the 1970s, however, there was genuineuncertainty and disagreement within the medical com-munity about whether chemotherapy had a role in thetreatment of SCLC. The drug combinations then in usewere considered highly toxic, and toxicity was not aswell controlled as it is today. Some clinicians were con-vinced that those using chemotherapy could be killing asmany patients as they were helping and were probablycuring none. The view was also expressed at the time thateven if a minor survival benefit could be demonstrated, itwould not justify the toxicity. In contrast, other clinicianswere enthusiastic advocates of chemotherapy in the lightof their own experiences.

We therefore conducted a multicentre randomised trialcomparing multidrug chemotherapy versus selective pal-liative treatment, in which supportive care, radiotherapy,and minimal single-drug chemotherapy could be given asand when required to control symptoms. We made thecomparison in terms of survival, adverse reactions, andquality of life, recognising the importance of all theseendpoints [1]. The trial showed that with immediate mul-tidrug chemotherapy, there was a large survival benefit (adoubling of median survival), better control of metasta-ses, acceptable toxicity, and better quality of life in terms

of clinicians’ assessments of breathlessness, level of ac-tivity, and overall condition. The important issue here isthat this trial was not simply confirming what everyonethought to be the case before it was conducted. If that hadbeen so, its ethics could have been questioned and wewould certainly not have been able to enlist the level ofcollaboration that we achieved. This was one of a numberof trials that established the role of chemotherapy in themanagement of SCLC and led to major changes in clini-cal practice.

It was followed by trials that established the appropri-ate duration of chemotherapy. But these, again, were nottrials that simply confirmed previous prejudices. Therewas no way of knowing in advance what the best dura-tion would be. Indeed, the level of genuine uncertainty isevident from the wide range of durations that was stud-ied, from 3 to 14 courses of chemotherapy at intervals of3 weeks, and even then, some clinicians were suggestingbefore the trials were conducted that chemotherapyshould be continued indefinitely in patients who werestill considered to be responding. These trials showedthat six courses were sufficient and fewer for patientswith poor performance status in whom the primary aimsof chemotherapy were palliative.

The first placebo-controlled, randomised trial of zid-ovudine in patients with advanced AIDS-related complex(ARC) or AIDS showed that with zidovudine there wassignificant reduction in mortality and in the frequency ofopportunistic infections [2]. The important question thenarose whether zidovudine might have a role in the man-agement of HIV-infected people who were well andsymptom-free. The dilemma was real. If the drug were tobe given early in the course of infection, it might delaydisease progression and so improve survival, and it mighteven abort the infection altogether in its earliest stages.Alternatively, it might have no beneficial effects at thisstage. It might, in contrast, serve as a constant reminder

Medical Research Council Cancer Trials Office, Cambridge, UnitedKingdom

*Correspondence to: David J. Girling, M.D., Medical ResearchCouncil Cancer Trials Office, 5 Shaftesbury Rd., Cambridge CB22BW, UK.

Received 19 May 1998; Accepted 5 June 1998

Medical and Pediatric Oncology 31:522–524 (1998)

© 1998 Wiley-Liss, Inc.

of a person’s HIV-positive status and cause unacceptabletoxicity, substantially worsening quality of life. More-over, it might also induce viral resistance, thereby mak-ing further use of the drug ineffective, once ARC orAIDS had supervened. The toxicity of zidovudine in pa-tients with AIDS was already well documented and couldbe life-threatening. Which was the better policy?

The Concorde trial: a randomised, double-blind, pla-cebo-controlled trial comparing immediate versus de-ferred zidovudine in people with symptom-free HIV in-fection was conducted to answer the better policy ques-tion [3]. At the time it was planned, it attracted vigorouscriticism from some quarters on the basis that its double-blind, placebo-controlled design was unethical (now thatzidovudine was known to be active against HIV), that itcontravened the 1964 Declaration of Helsinki, and thatwhen a patient’s treatment was chosen at random, thephysician was abandoning personal responsibility to thepatient. The critics lost sight of the genuine uncertaintyabout the better treatment policy. They assumed that zid-ovudine must be beneficial whenever it was given in thecourse of HIV infection. They made the fundamentalerror of supposing that the Concorde trial was simplyconfirmatory in character. In any event, affected peoplewere eager to join the trial, which accrued 1,749 subjectsin 3 years. The results showed that, contrary to the preju-dices of some, the early use of zidovudine wasnot ben-eficial. There was no statistically significant difference inclinical outcome between the two treatment policies de-spite the large difference in the amount of zidovudinereceived by the two patient groups and the fact that thenumber (347) of clinical endpoints (AIDS and death) waslarger than the sum of those in all other published trialsin early HIV infection at the time. Six participants expe-rienced life-threatening adverse events, five while receiv-ing zidovudine, one while receiving placebo. These re-sults were, for some, counterintuitive.

It is not uncommon for the results of a randomisedtrial to be counterintuitive, for a trial to be the very op-posite of confirmatory in character. This is because theuncontrolled and biased evidence on which all too manyclinical decisions are based leads to misleading and er-roneous conclusions. A few examples of counterintuitiveresults follow.

In the 1960s and early 1970s, the hope was that thelong-term administration of alkylating agents followingsurgical resection of nonsmall cell lung cancer wouldimprove survival. A meta-analysis of five randomisedtrials involving 2,145 patients designed to answer thisquestion showed that surgery alone was the better treat-ment policy, postoperative chemotherapy being associ-ated with a 15%increasein the risk of death [4].

In the Veterans Administration’s first large ran-domised trial of the treatment of cancer of the prostate,2,314 patients were randomised: those with stages I and

II disease to radical prostatectomy (RP), plus either pla-cebo (P) or 5 mg daily of diethylstilboestrol (DES); thosewith stages III and IV to P or DES alone or with orchi-dectomy [5]. Much against expectations, DES in a dailydose of 5 mg did not improve survival because of anexcess hazard of cardiovascular death.

In the late 1980s and early 1990s, single-drug oraletoposide daily for 5 or more days in 3-week cycles wasbeing increasingly used as palliative chemotherapy forSCLC on the basis of reports of its efficacy and relativelylow toxicity in nonrandomised studies. Intake to the firstrandomised trial comparing oral etoposide versus stan-dard intravenous multidrug chemotherapy had to bestopped prematurely. This followed the recommendationof an independent Data Monitoring and Ethics Commit-tee, when 370 of the planned intake of 450 patients hadbeen randomised. A planned interim analysis had shownthat oral etoposide was associated with a higher risk ofhematologic toxicity, lower response rates, and worsesurvival [6]. This trial was confirmatory only in the senseof confirming the imprudence of giving new treatmentregimens without their having been reliably assessed ininnovative randomised trials.

Innovative analyses of collated data from randomisedtrials have contributed greatly to knowledge of, for ex-ample, prognostic factors, survival expectations, acuteand long-term toxicity risks, and rare adverse effects oftreatment. They have also led to improved and clinicallymore relevant staging definitions. In no sense are suchanalyses and trials-associated research merely confirma-tory. On the contrary, they contribute substantially tonew knowledge and better understanding.

Randomised trials also need to be innovative in theirmethodology. For example, we increasingly appreciatethe value of comparing quality of life (QL) between treat-ment groups. A number of well-validated QL instrumentsare available, but big questions remain about when toapply them, how to define QL endpoints, and how best toanalyse and present the data collected. The assessment ofpalliation, for example, is an essential component ofmany treatment comparisons. Yet there is no consensuson its precise definition. As well as relief of symptoms,this could embrace time to onset, duration, and degree ofsymptom control and prevention. Using data from a largerandomised trial, we have, therefore, investigated differ-ent methods of defining and analysing palliation [7]. Wefound that not only the degree, but even the direction ofbetween-treatment differences could vary with the meth-ods used. There is nothing ‘‘confirmatory’’ here; indeed,the findings emphasise the need for innovation to reachagreed definitions to be specified in published reports.

Of course, there are circumstances in which it is de-sirable to conduct a genuinely confirmatory randomisedtrial (a trial designed to assess whether a treatment effectseen in a previous randomised trial is real and important)

Cancer Controversies—Con 523

[8]. These include differences in the interpretation ofresults of a randomised trial. Such can arise from differ-ences in prior beliefs about the efficacy of the treatmentsunder comparison and prior skepticism about the clinicalworth of a treatment in question. Such differences are notuncommon after publication of a single trial, unless thetrial is very large. That they exist at all confounds anynotion that clinical trials are in general no more thanconfirmatory.

In conclusion, properly designed, clinically relevant,randomised trials can be highly innovative. They andassociated research lead to reliable comparisons betweentreatment policies, accurate assessments of the size ofdifferences, and important changes in clinical practicefrom which patients benefit. They have come a long wayfrom coin-tossing randomisation and simple comparisonsof proportions to be sophisticated research instrumentsrequiring highly specialised methodologic, statistical,and computing expertise. It is essential that the clinicalcommunity appreciate their value and importance.

REFERENCES

1. Medical Research Council Lung Cancer Working Party: Survival,adverse reactions and quality of life during combination chemo-

therapy compared with selective palliative treatment for small-celllung cancer. Resp Med 83:51–58, 1989.

2. Fischl MA, Richman DD, Grieco MH, Gottlieb MS, VolberdingPA, Laskin OL, Leedom JM, Groopman JE, Mildvan D, SchooleyRT, Jackson GG, Durack DT, King D, and the AZT CollaborativeWorking Group: The efficacy of azidothymidine (AZT) in thetreatment of participants with AIDS and AIDS-related complex: Adouble-blind, placebo-controlled trial. N Engl J Med 317:185–191, 1987.

3. Concorde Coordinating Committee: Concorde: MRC/ANRS ran-domised double-blind controlled trial of immediate and deferredzidovudine in symptom-free HIV infection. Lancet 343:871–881,1994.

4. Non-small Cell Lung Cancer Collaborative Group: Chemotherapyfor non-small cell lung cancer: A meta-analysis using updated dataon individual patients from 52 randomised clinical trials. Br MedJ 311:899–909, 1995.

5. Byar DP: The Veterans Administration Cooperative UrologicalResearch Group’s studies of cancer of the prostate. Cancer 32:1126–1130, 1973.

6. Medical Research Council Lung Cancer Working Party: Compari-son of oral etoposide and standard intravenous multidrug chemo-therapy for small-cell lung cancer: A stopped multicentre ran-domised trial. Lancet 348:563–566, 1996.

7. Stephens R, Hopwood P: Response to palliative treatment: the casefor a standard definition. Psycho-Oncology 5:13, abstract 41, 1996.

8. Parmar MKB, Ungerleider RS, Simon R: Assessing whether toperform a confirmatory randomized clinical trial. J Natl CancerInst 88:1645–1651, 1996.

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