surEORTC-GU group - history and outcome of trials
TheEORTCGUgroupwasformedinAugust1976bymerginga French speaking group and a British bladder cancer group headed by Michele Pavone Macaluso and Philip Smith. Richard Sylvester, a young statistician joined the EORTC Headquarters one year earlier and was involved in the GU group from its beginning.
In those early days it was much easier to do clinical studies, a few enthusiastic urologists were sitting together over the weekend and developed an idea for a clinical study and aftertheweekendthe protocol was written and soon the inclusion of patients could be started. At that time the EORTC Headquarters had only 8 employees and about 25 trials were recruiting patients. However, trials were oftenunderpowered,becauseunrealisticallylargetreatment differencesweresoughtandclinicaltrialmethodology was at its infancy.
In the past more than 30 years more than 90 phase II and III trials have been performed in all areas of genito-urinary cancers, but what have we learned from the results of these trials and what has changed clinical urological practice?
Testis cancer is not a very common entity and form the early beginning a close collaboration was started between the EORTC and MRC to treat all patients as much as possible within the framework of a clinical trial. Due to this initiative it is now possible to offerthebesttherapyforlow-riskandintermediatedisease with the least chance of toxicity. For the high risk patient still improvement is possible.
In case of a non-seminoma testis it was demonstrated that in the good risk group patients 4 course of BEP are more effectivethat4 courses of EP , but this resulted in more pulmonary- and neurotoxicity (EORTC 30824). In a subsequent trials it was demonstrated that cisplatin could not be replaced by carboplatin (EORTC 30896) and that BEP could be given in three cycles, with an improved Quality of Life and in a three days schedule (EORTC 30941) . In the intermediate risk group patients 4 cycles of BEP was as effectiveas4cyclesofVIP,attheexpenseofmore hematological toxicity if VIP was given (EORTC 30873). For the poor risk group patients no treatment differencewasfound between 4 course of BEP and 4 courses of alternating BEP/PVB, but the latter scheme had more hematological and neurological toxicity (EORTC 30824). In the poor risk patients still improvement in treatment outcome is necessary, but this can only be accomplished if more intensive chemotherapy is given and it was shown that especially in these cases treatment outcome is better if this treatment is given in high volume hospitals (EORTC 30895).
Renal cell cancer
In localized renal cell cancer (RCC) it was demonstrated that lymph node dissection did not result in an increased morbidity, the incidence of positive nodes was very low and no differencesin efficacywereobserved.(EORTC30881).Forsmallrenaltumors (<5 cm) partial nephrectomy a slightly increased morbidity was observed compared to radical nephrectomy, the efficacyresults are still awaited (EORTC 30904). In case of metastatic RCC it was shown that combination of nephrectomy with interferon- alpha treatment was superior compared to interferon-alpha alone and these results were confirmedbyasimilarPhaseIIIstudy of the SWOG (EORTC 30947). Interferon- alpha treatment is effectivetreatmentinmRCCalthoughthebenefitforthepatient is still marginal. In EORTC 30951 interferon-alpha was compared to interferon-alpha plus 13-cis-retinoic acid and the combination resulted in an improved progression-free and overall survival rate with only moderate increase in non-hematological side effects.
In the seventies it was shown that DES and Estracyt resulted in comparable activity in metastatic and locally advanced prostate cancer, but cardiovascular (DES) and gastro-intestinal (Estracyt) toxicity was considerable. Theconceptofcombinedandrogen deprivation (CAB) was explored in two differentstudies.Using Buserelin no advantage was obsereved in trial EORTC 30843, but the combination of Zoladex plus flutamideshowedasignificantlylongersurvival,timetoprogressionandprogression- free survival (EORTC 30853). Thedifferencescouldbeexplained by an imbalance in prognostic factors in the two studies and a later meta-analysis showed only a small significantbenefitfor CAB, but this was too small to recommend CAB for all metastatic prostate cancer patients.
Several trials were done in Castration Resistant Prostate Cancer (CRPC), but the addition of chemotherapy was not beneficialforthe patients (orchidectomy versus orchidectomy plus Mitomycin C [EORTC 30893], Mitomycin C versus Estracyt [EORTC 30865]). A trial with an oral platinum was closed prematurely but an improvement in progression-free survival was observed (EORTC 30972). In patients with lymph node positive disease a non-significantincreaseinriskofdeathwasobserved,butthesedata have to interpreted with caution, because the trial was underpowered (EORTC 30846). Just recently the outcome of deferred treatment versus immediate hormonal treatment in patients that are not candidates for treatment with curative intent have been published (EORTC 30891). A significant23%increasein risk of death in the deferred treatment arm was found, however, no increase in prostate cancer death or symptom-free surEORTC vival could be demonstrated. Patients in the deferred arm with a PSA doubling time of <12 months had a 3-fold increase in the risk of death.
Several studies have been done in close collaboration with the EORTC radiotherapy group. In patients that underwent a radical prostatectomy, but were found to have pT3, positive margins or seminal vesicle invasion, the addition of adjuvant radiotherapy resulted in an improvement of biochemical progression-free survival and clinical progression-free survival, for survival the follow-up is too short. (EORTC 22911). For patients presenting with locally advanced disease, the addition of 3 years of hormonal therapy to external beam radiotherapy showed a significant improvement in disease-free survival, overall survival and disease-specificsurvival.
Advanced bladder cancer
EORTC trial 30894, which evaluated the role of neo-adjuvant chemotherapy (CMV) in combination with surgery and/or radiotherapy, a significantincreaseof6%in3yearsurvivalwasfound with a follow-up of 5 years. Theroleofadjuvanttherapywas also evaluated in a randomized setting, unfortunately this trial recently had to be closed because of poor recruitment (EORTC 30994). Since comparable trials were done in Italy and Spain, a combined analysis is explored.
Non-muscle invasive bladder cancer (NMIBC)
It has been demonstrated that there was no differenceinactivitybetween the differentintravesicalchemotherapyagents.Ifintravesical chemotherapy is given it should be started early, because the total duration of instillation can be shortened to 6 months. (EORTC 30831/30832). AfterhavingdefinedriskgroupsforNMIBC that were based on the results of the past trials, all further studies were developed on evaluation of treatment concepts in the three risk groups. In the good prognosis group, the majority of the patients presenting with NMIBC, one immediate post TUR bladder instillation with a chemotherapeutic agent decreased the recurrence rate by nearly 50% and is considered now standard treatment. (EORTC 30863). In order to reduce the side effectsofintravesicalBCGtreatment,INHwasaddedinEORTCtrial 30911 randomizing intermediate- and high-risk patients. No decrease in side effectswasfound,butintheINHarmmoretransient liver function disturbances were identified.Inthesametrial it was found that the recurrence, distant metastases and death rates for the BCG arms were lower compared to the Epirubicin arm, however no differenceintimetoprogressionwasseen. In patients with Carcinoma in Situ (CIS) BCG maintenance treatment was better compared to Epirubicin maintenance regarding duration of complete response, for progression the follow-up is too short (EORTC 30906). A meta-analysis showed that BCG instillations when given as a form of maintenance could delay or prevent progression (27% reduction in the odds of progression). A second meta-analysis comparing chemotherapy and BCG in patients with CIS demonstrated a significant reduction in the risk of short-term and long-term treatment failure in favour of BCG-treated patients.
Based on the results of Phase III studies in patients with NMIBC, risk tables for recurrence and for progression were developed. By introducing prior recurrence rate, number of tumours, tumour diameter, T-category, grade and presence of CIS, the probability of recurrence and progression can be calculated and help the urologist in counseling the patient for adjuvant therapy and follow up.
Other issues that could be extracted from the EORTC studies concerned the question of performing routine random biopsies and the large variability in the three-months recurrence rate. It was found that random biopsies were only necessary in case of high grade urine cytology. Thethree-monthsrecurrencerateinthe trials evaluated was as high as 40% depending on the number of tumours present at the initial TUR. Thisobservationledto initiatives to investigate methods to improve the complete resection of the bladder tumour(s).
In the past years the EORTC-GU group has made a considerable contribution to improve treatment of patients with urological cancers. However, there were also trials that were not finalizedor not started due to several reasons, e.g. comparing radical prostatectomy and external beam radiation in localized prostate cancer, immediate versus expectant management of patients presenting with a rising PSA following treatment with curative intent, and comparing surgical trials in muscle invasive bladder cancer comparing differentformsofdiversion.Anewobstaclein executing clinical trials are the rules imposed by the EU legislation. Theadministrativeburdenhasincreasedtremendouslyand the fact that all medication (also registered drugs) should be provided for free within the framework of a clinical study has prevented the initiation of academic trials. New trials to be initiated within the EORTC GU group are: - a collaborative, double blind trial with the MRC comparing Sorafenib with placebo in patients with resected primary RCC at intermediate- to high-risk of relapse (SORCE/EORTC 30072), - a randomized Phase III trial comparing presurgical sunitinib followed by nephrectomy and sunitinib versus nephrectomy followed by sunitinib in patients with synchronous metastatic renal cell carcinoma (EORTC 30073), - a randomized Phase II trial in patients with advanced urothelial tract cancer (T3b,T4/N+/M+) of Gemcitabine and Cisplatin with Sorafenib or placebo (EORTC 33071), -a quality control study for TUR of bladder tumours, and ?a randomized trial comparing adjuvant radiotherapy plus or minus hormonal therapy in patients with pT3 or margin positive disease following radical prostatectomy (EORTC 30041).
TheEORTCneedsmotivatedandactivecolleaguesfromalloverEurope in order to design and execute studies that address the clinical questions in uro-oncology. TheadvantagesoftheEORTC-GU group are its independency and the multidisciplinary composition of the group and if you want more information you can visit the EORTC website (www.eortc.be).