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The Genitourinary (GU) Cancer Committee of the Southwestern Oncology Group (SWOG) has achieved repeated successes in conducting prospective studies of prostate cancer. This article is a summary of recently completed and current trials in prostate cancer and, as such, represents an intriguing snapshot of priorities in prostate cancer clinical trials in 1997.
The Genitourinary (GU) Cancer Committee of the Southwestern OncologyGroup (SWOG) has
achieved repeated successes in conducting prospective studies of prostatecancer. This article is a summary of recently completed and current trialsin prostate cancer and, as such, represents an intriguing snapshot of prioritiesin prostate cancer clinical trials in 1997.
Bilateral Orchiectomy With or Without Flutamide
The most provocative recent trial, and one which can be anticipatedto reverberate for decades through the prostate cancer literature, is therecently analyzed comparison of bilateral orchiectomy with or without flutamide(Eulexin) for D2 prostate cancer. This trial is of landmark importance.It represents the 27th randomized prospective trial of total androgen blockadecompared to monotherapy performed since 1979. It is unique because of itslarge size (about 1,300 patients).
Few clinical questions in all of medicine have been subjected to somany prospective clinical trials as that of combination vs monotherapyfor advanced prostate cancer. Ironically, the results of these numeroustrials are contradictory. In 1995, the Prostate Cancer Trialists CooperativeGroup (PCTCG) subjected 22 of these trials published up to 1994 to a meta-analysis.Although there was a trend toward a benefit of total androgen blockade,it was not significant at 95% confidence limits. This threw substantialdoubt on the benefit of total androgen blockade.
This meta-analysis has been criticized. In particular, many of the trialstudies were of relatively poor quality, and a number were unpublished.For a number of these trials, there was no data regarding such importantissues as concealment of randomization, (ie, the effectiveness of blinding)patient selection, and adequacy of follow-up. A sensitivity analysis, whichranked the published studies according to their quality, demonstrated thata benefit of total androgen blockade was demonstrated if the least welldone studies were excluded from the meta-analysis.
Thus, controversy continues to rage over the benefit of total androgenblockade. The limitations of meta-analysis are well known. Meta-analysisis retrospective and subject to bias. Methodologists agree that there isno substitute for a large, well-done, randomized trial. Therefore, theresults of the SWOG trial have been anticipated with eagerness. It washoped that this trial would provide the final proof for the benefit (orlack thereof) of total androgen blockade.
The trial, in fact, demonstrated a lack of benefit for the additionof flutamide to bilateral orchiectomy. This raises a difficult question.The earlier SWOG trial showed a clear benefit of flutamide plus daily leuprolide(Lupron) injection compared to leuprolide alone. Both trials were largeand carefully carried out. Both trials seem conclusive.
How does one explain the different outcomes? There are several possibilities.It is likely that at least part of the benefit of total androgen blockadeis due to blocking of the flare effect. This benefit would not be seenwith orchiectomy. In addition, it may be that compliance with daily luteinizinghormone-releasing hormone (LHRH) injections was poor. If so, it is possiblethat patients who frequently missed injections would have frequent minorspikes in testosterone. In that case, the use of flutamide would have blockedthe repeated "mini-flares," and thus produced a durable survivalbenefit. This would not be an issue in patients on long-term depot LHRHanalog.
These studies have contributed enormously to the quality of evidencerelating to the treatment of metastatic disease. It is safe to say thatthe magnitude of the effect of total androgen blockade is small; when orchiectomyis used, that effect appears to be negligible.
Unfortunately, some issues remain unresolved. What is the significanceof the finding in the LHRH-flutamide study of an increased benefit in thepatients with minimal metastatic disease? Does this mean there is a subsetof patients who might benefit after all? Can these individuals be identifiedusing genetic markers, for example?
What if flutamide had been stopped once biochemical progression occurred?What about biochemical failure following initial radical therapy, the mostcommon current indication for the initiation of therapy? All of these questionswill require further studies.
Intermittent vs Continuous Androgen Therapy
The second study reviewed, SWOG 9346, compares intermittent androgendeprivation (IAD) to continuous therapy. Intermittent androgen ablation,first reported in 1986, offers undisputed benefits relative to qualityof life (QOL) during the interval off treatment. Such therapy also mayhave potential benefits in terms of time to androgen independence and survival.Moreover, intermittent androgen deprivation reduces cost compared to continuousmedical castration.
The difficulty this trial has encountered is due to the stage migrationeffect of prostate-specific antigen (PSA) screening and monitoring. Thenumber of newly diagnosed cases of stage D2 prostate cancer has droppeddramatically. In addition, patients who do not respond to radical therapytend to be treated when their PSA rises, and therefore, are not candidatesfor a study of hormonally naive D2 disease.
Interestingly, the Medical Research Council (MRC) recently publishedthe results of a trial of immediate vs deferred treatment for advancedprostate cancer. This was a randomized study of 938 patients with locallyadvanced or asymptomatic metastatic disease. Both overall and disease-specificsurvival were improved in the immediate-treatment group.
Based on the MRC trial and general international trends, one can expectthat patients will be treated progressively earlier with androgen ablation.Therefore, the appeal of intermittent androgen suppression for patientswho have biochemical relapse is compelling. The SWOG 9346 trial will bean important contribution to our understanding of intermittent androgensuppression.
Adjuvant Radiotherapy vs Observation
The SWOG 8794 study of adjuvant radiotherapy vs observation followingradical prostatectomy in patients with positive margins represents a tremendousaccomplishment. This study addressed a mounting demographic problem, ie,the management of the patient with positive margins after radical prostatectomy.Phase 2 trials have suggested improved rates of local control in patientswho receive adjuvant radiation.[5,6] In the absence of a comparative trial,no conclusions could be reached about the impact of this therapy on disease-specificsurvival. The SWOG trial was broad-based, and included the National CancerInstitute of Canada and other cooperative groups.
The study nearly closed for lack of accrual on several occasions. Aconcerted effort by senior trial investigators to promote and publicizethe trial, and to bring in contributors throughout North America, resultedin its eventual successful accrual.
This study, perhaps more than any other, illustrates the importanceof cooperative clinical trials groups in furthering our ability to practiceevidence-based medicine. This trial was hard to sell to patients. It requireda concerted effort on the part of hundreds of physicians. The per-casefunding for the trial was small. The motivation to accrue came largelyfrom a desire by participants to answer this important scientific question.The results of this trial (to which accrual closed in December 1996) willhave a major effect on the management of patients with positive margins.
This willingness to tackle the compelling but difficult scientific questionalso characterizes the Prostate Cancer Prevention Trial (PCPT) and theProstate Intervention Versus Observation Trial (PIVOT). Regardless of theiroutcome, these trials will influence our understanding of prostate cancerand patient management for decades and possibly centuries to come.
The ability of the cooperative clinical trials groups to fund largedifficult trials like the adjuvant radiation trial has been traditionallybased on the funds provided by simpler pharmaceutical company-funded trials.Increasingly, these simpler trials are being funded outside of the cooperativeclinical trials group infrastructure. One sincerely hopes that the SWOG8794 adjuvant radiation trial will serve as an example to funding agenciesof the importance of maintaining organizations that are willing and ableto tackle the tough scientific questions in oncology, whether or not theyare of interest to the pharmaceutical industry.
The GU Global Group
Another noteworthy SWOG accomplishment is the development of the GUGlobal Group. This group has facilitated the development of intergrouptrials in a number of areas. The members of the global group representthousands of clinicians with an interest in accruing patients into clinicaltrials. These physicians, in turn, have access to hundreds of thousandsof patients who could potentially be accrued. The potential is enormous.The Global GU Group was instrumental in spearheading the intergroup collaborationthat resulted in the successful completion of the adjuvant radiation trialfor positive margins.
We are in the era of evidence-based medicine. SWOG represents a modelfor clinical trials that has been very successful. SWOG trials have addressed,and ultimately will answer, some of the most vexing questions in urologiconcology. As is often the case with good trials, some of the SWOG trialshave raised more questions than they have answered.
Given the prevalence of prostate cancer, and the societal costs, thereis no excuse for not carrying out large randomized trials to address thefundamental questions that clinicians face. Most physicians who care forpatients with prostate cancer are tired of telling patients, "We don'tknow the answer to that question," in response to most specific inquiries.The uncertainty has gone on long enough. It is time to get some answers.This will require a great deal of resources and the efficient functioningof large cooperative clinical trials groups, of which SWOG is emblematic.
1. Prostate Cancer Trialists Cooperative Group: Maximum androgen blockadein advanced prostate cancer. An overview of 22 randomized trials with 3283deaths in 5710 patients. Lancet 346:265-269, 1995.
2. Klotz LH, Newman T, and the OCTRF Practice Guidelines DevelopmentGroup: Does maximal androgen blockade improve survival? A sensitivity analysisof the evidence. Can J Urology 3(3):246-250, 1996.
3 Klotz LH, Herr H, Morse M, Whitmore W: Intermittent endocrine therapyfor advanced cancer. Cancer 58:2546-2550, 1986.
4. The Medical Research Council Prostate Cancer Working Party InvestigatorsGroup: Immediate versus deferred treatment for advanced prostatic cancerinitial results of the Medical Research Council Trial. Br J Urol l997,79, 235-246.
5. Gibbons RP, Cole BS, et al: Adjuvant radio