SWOG S1011 was conceived, we probably started working on it in earnest in 2010. So there was, you can call it dogma, but accepted practice by many of us who had trained with Don Skinner at USC and we taught our trainees as well that for patients with curable, predominantly urothelial, muscle-invasive bladder cancer that a bilateral pelvic lymphadenectomy was standard of care, results in a low local recurrence rate, identifies most patients with pathologic positive nodes but that that dissection really should be taken up, so to speak, in an extended template at least up to the bifurcation of the aorta. So defined anatomically and very precise.
At the time there was no level 1 evidence to really support it and when you looked at other organ site cancers there were similar trials that had been done which did not show a benefit and at least in one, the gastric trial reported from Japan in The New England Journal of Medicine, showed that there may be more harm, so to speak, more toxicity associated with it. So in SWOG Ian Thompson is our Chair of the GU Committee, Ian said we should do this trial and I said, ‘Great, I’m in.’
The trial asks the basic, fundamental question that in patients undergoing radical cystectomy does an extended node dissection provide improved disease free and overall survival compared to a bilateral standard node dissection. A couple of unique aspects to the trial are that this was a limited institution trial – a selected group of urologic surgeons who met certain specifications of doing 30 cystectomies a year, the hospital 50 a year over three years. All the surgeons were credentialled by submitting op & path reports from five cases, videos or photos, most of them were photos, and in 27 centres.
So a patient gets registered and then the cystectomy starts and the first thing we do is an exploration to rule out metastatic disease outside the true pelvis. Then they could get randomised to either standard plus extended or standard alone. We registered 659 patients, we had the expected amount of patients that were ineligible. We’re now at six years follow-up and we’re reporting both the primary endpoint of disease free survival and the secondary endpoint of overall survival. The bottom line is there was no benefit to the extended node dissection with either of those oncologic endpoints, clearly establishing a bilateral standard node dissection as the standard of care.
There was some increased toxicity in the patients that underwent the extended arm, predominantly grade 3 anaemia, urinary tract infections, a little higher rate of sepsis, a higher rate of postoperative ileus. There was an increase in mortality, all cause mortality, independent of whether it was attributable to the surgery or not. Those numbers were all well within what’s accepted for both 30-day and 90-day mortality rates.
How can these results impact the treatment of muscle-invasive urothelial cancer in the future?
There is no longer a need to do a more extensive node dissection as long as you do your exploration and verify that there is no concern for metastatic disease outside the true pelvis. So we can lay that to rest.
Now there are some really interesting questions about treatment intensification, de-intensification, this is happening a lot in not just GU cancer but other cancers. So can we use biomarkers? There will be a lot of translational medicine research that goes along with this trial. We’ve got about 350-400 tumour samples that we’re going to do full sequencing. We’re developing, we can apply molecular subtypes to try to identify maybe who should have treatment intensification, maybe undergo an extended node dissection, and those that are going to benefit or potentially just be cured with surgery alone. ctDNA may have a role in this pre-surgery.
I do want to mention that there was a similar trial conducted in Germany that showed something quite similar – no benefit to progression free or overall survival. They do have some long-term data that suggests there may be a benefit to cancer-specific survival. But the bottom line is that you have now got two large randomised phase III trials that essentially, in my opinion, have closed the book at this point.