This is actually a study that was conducted in Egypt, the principle investigator is Dr Mohamed Zaghloul who unfortunately wasn’t able to come to present our work. We collaborated with him on the analysis of the project and this is a study that’s really a question of adjuvant therapy following radical cystectomy for bladder cancer. The background for this study is that in Egypt there was an earlier randomised trial performed in the ‘80s that showed not only a significant local failure benefit but also a significant overall survival benefit for the use of adjuvant radiation. So in Egypt, and really nowhere else in the world, adjuvant radiation has become the standard of care for patients who are at high risk for local failure following cystectomy.
The trial that we’re presenting today is a trial in which Dr Zaghloul tested the standard of care arm, adjuvant radiation, to sequential adjuvant radiation and chemotherapy to see if there was a benefit to adding chemotherapy. The question of adjuvant chemotherapy in bladder cancer is a controversial one; his hypothesis was that the addition of chemo would actually improve disease free survival. Now, the question that he was posing is very interesting in Egypt but not so interesting in the rest of the world so he recognised that and decided to add a third arm for chemotherapy alone and this would allow him to see if there was any benefit for radiation with or without chemo compared to chemotherapy alone. So the primary endpoint, as I said, was disease free survival; secondary endpoints were local failure free survival, distant metastasis free survival, overall survival and toxicity. He enrolled patients who were treated with radical cystectomy at the NCI in Egypt with negative margins and these patients all had excellent performance status, they were less than 70 years of age, good renal function etc., and they had to have one of three factors that would put them at higher risk for local failure. So a very advanced pathologic T stage as well as positive nodal involvement or grade 3 tumour, so that was his selection criteria.
After surgery they were randomised to one of the two initial arms, so adjuvant radiation alone or adjuvant chemotherapy and radiation. The adjuvant radiation was given 45Gy twice daily over three weeks. The adjuvant chemo and radiation arm was actually a sandwich approach: two cycles of gem-cis, adjuvant radiation and then two more cycles of adjuvant chemo, gem-cis. Then later, several years after the trial had already begun enrolling they added the chemo alone arm which was four cycles of gem-cis. So in the combined treatment arm and in the chemo alone it’s the same number of cycles of chemotherapy.
The majority of the patients did have urothelial cell histology which is the dominant form in the rest of the world but 41% did have squamous cell. There was a median follow-up of 19 months on the study. First I think I’ll talk about the initial randomisation, so that’s the chemo-radiation versus the radiation alone. There the primary endpoint was disease free survival and there was not a statistically significant difference. The difference, however, did favour the combined arm versus radiation alone. We saw that for the other endpoints as well: distant metastasis free survival, local recurrence free survival and overall survival. The difference for overall survival was fairly large and was 14% difference but again not statistically significant. So interesting but certainly nothing that would change practice.
In many ways the second randomisation is more interesting, certainly in Europe and in America. There there was actually a trend towards a disease free survival benefit when you looked at the combined arm versus chemo alone with a 12% improvement in disease free survival with the addition of radiation to chemotherapy. There was also a statistically significant and very dramatic improvement in local recurrence free survival with either of the radiation arms compared to chemotherapy alone. That was very interesting. Distant metastasis free survival there was essentially no difference, overall survival there was no significant difference but again there was a difference that was pretty strong in favour of the combined modality arm versus chemotherapy alone; the magnitude of the difference was 14%.
So the trial had some limitations, so a third arm was added later as a weighted accrual and that unbalanced some of the baseline characteristics. In addition, the study doesn’t have sufficient sample size to really detect a clinically meaningful difference. Lastly there’s a lot of heterogeneity in the patients on the study, so 41% had squamous cell, in most of the world the vast majority of patients have urothelial cell. So it’s unclear how generalizable the results are but I should point out that the results for the subset who had urothelial cell carcinoma, the main type we see in this country, the results mirrored those of the entire cohort. So I still think there’s some interesting results here.
The trend towards a disease free survival benefit is also intriguing. We can’t make any definitive conclusions based on this study but it certainly warrants further investigation on some of the actively enrolling or the trials in development looking at the question of adjuvant radiation, many of whom would be in patients who are also getting neoadjuvant chemo. The NRG has an actively accruing trial, NRG-GU001, looking at the question of adjuvant radiation, and co-operative groups in France, the UK and India are also in the process of developing trials. So we think that those trials will hopefully answer the question but this trial provides us with some very interesting and intriguing results that suggest that this is a treatment where there may be benefit.