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A review of select trials in colorectal cancer from ESMO 2017

Interview with Axel Grothey

‘Filmed by PracticeUpdate with permission for inclusion on Advances in Gastrointestinal Cancer. More information and additional ESMO coverage can be found at www.practiceupdate.com

Interview transcript

Dr. Caudle: Welcome to PracticeUpdate. I’m your host, Dr. Jennifer Caudle, and joining me, today, is Dr. Axel Grothey. Dr. Grothey, welcome to the program.

Dr. Grothey: Thanks for having me.

Dr. Caudle: Well, we’re excited that you’re here, so, let’s jump in. So, the IDEA collaboration data really caught a lot of attention, at ASCO, back in June. Now that you’re a few months removed, and we’re at ESMO, what’s your reaction to the oncology community’s impression of your data, and are reactions different in the US compared to Europe, or the rest of the world?

Dr. Grothey: Yeah, great question. So, let me frame, first of all, what IDEA actually stands for, the International Duration Evaluation of Adjuvant Therapy in colon cancer. So, since 2004, the standard of care, in the adjuvant management of stage III lymph node positive colon cancer, was to give six months, 12 cycles, of FOLFOX or eight cycles of CAPOX, capecitabine and oxaliplatin, and you know, we know that we could improve survival for patients, with a delta of about 4.4% at 6 years, so with the addition of oxaliplatin for the old standard, 5-FU, but it also inflicted damage on patients. I mean, oxaliplatin is a drug that causes neurotoxicity, and some of the neurotoxicity doesn’t go away when patients stop their treatment, so the survivors of adjuvant treatment live with the impairment of sensory neuropathy for the rest of their lives, and that is something, which, of course, as a passionate oncologist, it’s not what we like to accept, so the question is, can we shorten the duration of adjuvant therapy without taking away benefit, and that is, actually, a noninferiority trial design, so when you talk about, you want to give a framework of running a clinical trial, with an adequate number of patients, making sure that we’re not compromising efficacy, when we shorten the duration of treatment and taking away side effects.

So, this is what, about 10 years ago, sparked the formation of this international collaboration. We figured out that there was not going to be a, let’s say, commercial sponsor supporting the idea of shorter duration of treatment, it had to be an academic collaboration, and in order to run an international trial, where we calculate, we need about 10,500 patients, we allowed every country to run their own trial, in the same way, the preplan pulled analysis of all patient data, so we had six phase 3 trials initiated over the next decade, you know, when we started this, and each trial randomized patients with stage III colon cancer, with three months of treatment versus 6 months of treatment using FOLFOX, 5-FU-based therapy or CAPOX, capecitabine-based therapy at their discretion. There was no randomization of treatments, and we, eventually, included 12,834 patients, and we set a noninferiority margin with a hazard ratio of 1.12. What does it mean? We’re allowing to have an upper limit of, so probability to comprise the efficacy by about 12%, but you really wanted to shoot for almost equality.

Dr. Caudle: Right.

Dr. Grothey: Okay. So, at ASCO, we presented the data of the overall patient population, and first of all, we saw that the neurotoxicity, the side effects that we were really interested in, was down to a third, when we cut the duration of treatment by half, and there were really no long-term toxicities, as documented in the trials. Now the question is, did we need the noninferiority margin, and we didn’t. We crossed the noninferiority margin by 1.17 instead of 1.12, for the overall patient population. Now we could have said, you know, that’s it, and the trial is negative, everyone needs six months of treatment, but that’s not true because, you know, the 12,834 patients are not all alike. We have two different treatment regimens, we have CAPOX and FOLFOX, we have high risk patients, low risk patients, a lot of lymph nodes involved, few lymph nodes involved, different countries involved, men and women, younger and older.

So, now we had time to dig into this data a little bit more, and these are some updates and different perception that we’ll present here, at ESMO, actually, tomorrow, and so there are two messages that came up. Number one, CAPOX, the capecitabine and oxaliplatin combination, with the oral agents of the IV, is non-inferior in the whole group when we used three months compared to six months, so if you like CAPOX, if you use CAPOX in your country, like in the UK, in Italy, in Japan, you’re fine. You can get away with three months, period. The difference between CAPOX and FOLFOX is how the _____ (4:54), the most important chemotherapy component is delivered, if capecitabine and oxaliplatin gets delivered daily for 2 weeks on, 1 week off, and FOLFOX is 2 days on, 2 weeks off, so it’s a shorter duration. The continuous administration of this chemotherapy allows us to give shorter duration of therapy. In addition, when you have a low risk cancer, let’s say only up to three lymph nodes involved, not more than three lymph nodes involved, you can get away with 3 months too, whether you use CAPOX or you use FOLFOX, so now we have a regimen based assessment and a risk based assessment. 

Now, in the US, CAPOX is not commonly used, and the data with FOLFOX was not impressive for the three months versus six months comparison. So, there was a lot of pushback, in all the data, inconclusive, whatever, we’ll see discussion tomorrow, here, in the European environment, where I believe we are much more in favor of shortening the duration of therapy and using capecitabine and oxaliplatin. My clinical practice, at Mayo Clinic, since then, we have had time for about six months, to look at the data. We have switched to capecitabine and oxaliplatin for the majority of patients. It’s a pill chemotherapy, patients don’t need a port, they don’t need a pump, they get away with four IV infusions of oxaliplatin, peripherally. It’s three months of treatment, and you’ll see the data, tomorrow, from a health economic perspective, just for the European environment. Timon, who will be discussing calculated, that annually will save about half a billion dollars in healthcare costs by switching from FOLFOX to CAPOX and shorten duration from 6 months to three months. I have a lot of ideas of how we can spend this money in a better way, so I do believe this is practice changing, and we’re saving patients toxicities, so it will be interesting to see the discussion tomorrow, and if you’re interested in, and everyone who has a chance to go to the ESMO webcast, because we’ll actually discuss real patient cases, scenarios, and ask the panel of experts, what do you do with the data they will present of these 12,834 patient collaboration, international collaboration, and they really give guidelines based on the individual patients.

Dr. Caudle: Right, which I think is really quite fascinating and interesting where you’re, sort of, breaking down the data but you’re also talking about how region, country, individual patient characteristics, all of these things really matter, and it’s not just a 20,000-foot view, you really have to break it down and look at the individual components.

Dr. Grothey: Yeah, and you can easily see that, with this database, of really well followed patients, almost 13 thousand patients conducted anywhere from the United States, Canada, to Japan, and we’ll get a lot of information, out there, in the future, a lot of these patients have annotated biomarkers, have annotated circulating tumor DNA data, etc, so this is all coming down for future analysis, so this academic collaboration, where we just will give the, you know, basic data, right now, will be a treasure trove, you know, to really provide us with more information, which can, then, influence our treatment practice.

Dr. Caudle: Right. Absolutely. It’s actually quite fascinating. Dr. Axel Grothey, thank you, so much, for joining us today.

Dr. Grothey: Thanks for having me.

Dr. Caudle: And thank you for tuning in to PracticeUpdate.


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