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Dr. Alicia Morgans: Hi, my name is Alicia Morgans, and I am a GU Medical Oncologist at Northwestern University. I am delighted to have with me here today, Dr. Toni Choueiri who is the Director of the Lank Center for GU Oncology at the Dana Farber Cancer Institute, as well as a Professor of Medicine at Harvard Medical School, and a good friend of mine. Thanks so much for joining us here today, Toni.

Dr. Toni Choueiri: Thank you for having me, it's a pleasure to be on Urotoday.

Dr. Alicia Morgans: In RCC, there was a major trial just reported at ASCO this year, a plenary at ASCO, which is a big, big deal. And I know you have a lot of thoughts on the CARMENA trial, and I'm wondering if you could share your thoughts on that study, and how it may have impacted the field in your practice. 

Dr. Toni Choueiri: Yeah, so, this trial took us by surprise. And it’s still taking us by surprise, because the paradigm based on two studies in the interferon area, one in the US, one in Europe, when patient presents with metastatic renal cell cancer, if they can go to surgery, really and there is no major operative risks, and they're in relatively good shape, you should take the kidney. That's the paradigm of cytoreductive nephrectomy, that actually stayed for years, and years, and years. That, interestingly, is not applicable to other solid tumors. So it's not applicable to breast cancer, to prostate cancer. You know more than me, that there are ongoing trials, but doesn't seem to be applicable, doesn't seem to be applicable to pancreatic cancer and others. But, we stuck with it in kidney cancer, and that was the paradigm. 

And actually, in the era of target therapy that started around 2006, when we accumulated data, a board from national databases, or from institutional databases, or from multi-center data-bases, and looked at them, knowing the caveat of non-randomized studies, but we did our best and we adjusted for all the clinical characteristics that could play a role in imbalances between a group. We also found that from the IMDC data base, the NCDB and other, we found that removing the kidney also results in a survival benefit. 

So, the story was somewhat established, and then the CARMENA came, applaud the French were getting the study done that we could never get done in the United States. They pushed through, and they were able to accrue 450 patients in eight years, September 2009 to September 2017, took eight years. Mostly French, although I believe some patients were accrued outside France. They were supposed to accrue more than the 450 patients, but I think they stopped at 450. This was a non-inferiority trial, where patients see a Urologist and perhaps also an Oncologist and get randomized to remove the kidney and get sunitinib, or get sunitinib without removing the kidney, and with it being a non-inferiority again study. And interesting enough, sunitinib alone, without taking the kidney out was not inferior to the sequence of nephrectomy followed by sunitinib. 

It's a well-conducted study, of course we can always say whatever we want about that study, but if you look at different subgroup analyses, the trend, the curve you look at favored sunitinib alone, even if it wasn't statistically significant because with 450 you can't do many subgroups and look at them and be sure that what's going is really. But there isn't hint of evidence that taking the kidney out in any of the subgroup is way superior than keeping the kidney in. 

Of course, the study some of the nihilistic views is that the study anyhow included 44 percent of patients with poor risks, and these patients, we would not anyhow consider for surgery. Well, my view is these are patients yes, this is certainly up to the Urologist seeing the patients, but these are patients in general despite some of them are called poor risk by MSKCC risk group. These are patients with ECOG performance 0 and 1, so from a performance status perspective, these should be a surgical candidate. Then if you look at the tumor burden that was actually measured on the study, in terms of looking at the tumor size of the kidney, looking at the total burden in the kidney and outside the kidney, looking at the number of metastatic sites, those are all poor man's way to look at the burden overall and how much metastatic disease and quantify it. 

Well, guess what? There was no major difference between both groups, the nephrectomy sunitinib or the sunitinib only, so the authors did their best. They looked also at the fact that of course there are some patients, Alicia, that were supposed to get nephrectomy end up not getting nephrectomy, and those patients that end up not getting sunitinib, so this was an intent to treat analyses. But when you look at the non-intent to treat, at what patients received effectively, even with that, there was no trend favoring removing the kidney, so this is a strong message that people have to be careful in revisiting cytoreductive nephrectomy. Now of course, if the disease burden outside the kidney is minimal and a lot of it could be removed anyhow, the patient could become NED, that's a different issue. And we hope that patients with small metastatic disease burden, at least could be considered for cytoreductive nephrectomy, and possibly metastasectomy, even in this situation. But again, this is a very, very, very important study. 

It remains to be seen how it's going to be accepted, the results, and what the Urologists are going to do. There's a lot of practices and surgeons that when you ask them, their practice has been not to take the patient to the OR if they have a significant disease burden, but are too sick. So some people may be doing it already, but at least, here you have some prospective data to back that. 

Dr. Alicia Morgans: So, thank you for reviewing that, and I think that that really just is the perfect reflection of the way that kidney cancer physicians, whether they're Urologists or Medical Oncologists are really thinking about trying to match the right treatment to the right patient. The revisiting old standards to make sure that they hold up in new eras with new treatments, which are coming fast and furious in renal cell cancer, and I commend you and your group for participating in those. And I thank you so much for talking with us today because really matching the right patient with the right treatment, limiting overexposure to treatments for extended periods of time, patient selection, these are all things that you guys are working on, and I just appreciate your time in sharing your thoughts with us today, and also your message, that we can't stop right now where we are. We can't rest on our laurels and say we have enough treatments, that this work needs to continue to happen, and we're making progress in RCC. So thank you for your time today Dr. Choueiri.

Dr. Toni Choueiri: Absolutely. Thank you for having me. Thank you, Urotoday, and thank you Alicia.