Practice Update | Onology

CONFERENCE COVERAGE 16

New standard of care for low risk stage 3 colorectal cancer? Interview with Axel Grothey MD

threshold. We had 12,800 patients to work with, and then we were able to dive into these subgroups that you just mentioned because just from a rational perspective, do patients with a lower risk of tumor recur- rence, early stage disease, really need the same amount of treatment as higher risk tumors? The answer is no. About 60% of patients have what we identified as low- risk – T1, 2, 3, N1, so not more than 3 lymph nodes involved. Those patients would make up about 60% of the whole cohort, they really do not need more than 3 months of therapy. For the higher-risk group of patients – T4 and/or N2s, so more lymph node involved and with larger and more penetrating tum- ors – some patients will still get away with 3 months of therapy. But we can discuss with patients, is it worthwhile for a statis- tical risk reduction of let’s say 1.5% in 3 years to push for more chemotherapy, when patients might have already experi- enced neurotoxicity, nausea, vomiting, etc? So, I think what we are able to do now is really individualize treatments, which ties into all this precision medicine, but not with a biomarker, but with more data available to really engage patients in the discussion. How much is it worth it for you? You know, this might depend...might be different for older patients, younger patients, different socio-economic status, etc. There are a lot of factors that we can now take into account, but I think the message, the one message that we agreed upon, which was very clear, lower-risk tumors 60% should not receive more than 3 months of treatment. Dr Haffizulla: I like that you mentioned about the multiple variables with each patient, and knowing that you’re personalizing care and treatment options. Dr Grothey: Absolutely. We finally have a way to really base our interaction on data. If the patient asks me, “If I stop now, how much does it mean for my cancer to come back

Dr Farzanna Haffizulla speaks with Dr Grothey, Professor of Oncology at the Mayo School of Medicine in Minnesota, on results of the pooled analysis of six Phase 3 trials investigating 3 vs 6 months of adjuvant oxaliplatin-based therapy for patients with stage 3 colon cancer.

Dr Haffizulla: The perspective pooled anal- ysis of six phase 3 trials investigating the duration of adjuvant oxaliplatin-based ther- apy, 3 versus 6 months for patients with stage 3 colon cancer, appears to define a new standard of care for patients with low- risk stage 3 colon cancer. Can you describe this particular trial further and any implica- tions for clinical practice? Dr Grothey: First of all, the reason why we ran this trial was to decrease toxicity for patients with oxaliplatin-based adjuvant therapy. It’s frustrating for clinicians and for patients to go through 6 months of treatment and be stuck with persistent neuropathy, which can be life changing; it affects patients for the rest of their life because that’s really the main side effect of oxaliplatin-based therapy – cumulative neuropathy. So, the longer we treat, the more neuropathy we see in severity and persistence. Now, the question of can you shorten the duration of treatment without sacrificing the efficacy, that’s a question that needs to be addressed in a non-inferiority study design. Meaning you need large num- bers of patients; we actually calculated we needed 10,500 patients. Not a single country can pull that off in terms of run- ning a clinical trial to get 10,500 patients randomized to 3 or 6 months of therapy. We needed an international collaboration. Fortunately, this clinical question “can we get away with shorter duration of ther- apy?” was a worldwide question because everyone struggles with these toxicities that are inflicted in the worldwide standard of 6 months of therapy. Dan Sargent, who is a statistician at Mayo Clinic and myself, went to groups around the world and said “would you like to start a study? Would you like to join in this endeavor?” And six Phase 3 trials were started. Eventually we had a pooled analysis, a pre-planned pooled individual patient data analysis of 12,834 patients, which is by far the largest endeavor ever conducted. It’s important to realize this could only be

pulled off with public funding, philanthropy, because which company would investigate shorter duration of their therapy? That is something where we needed an interna- tional academic effort. And we presented the data here at ASCO. Dr Haffizulla: That’s an excellent example of global work, coming together. Dr Grothey: Global work and also identify- ing a need, and then really making things happen. It’s a very nice and collaborative interaction. Dr Haffizulla: Given the results of that particu- lar study, is there any low-risk colon cancer patient who you would treat with more than 3 months of FOLFOX? Dr Grothey: Let me recap some of the results because, first of all, we did show that neu- rotoxicity and toxicities in general were lower, and that’s not unexpected. You give less chemotherapy, you have less toxic- ity. That’s the benefit that patients have. How much would they have to sacrifice in terms of anti-tumor efficacy? When you look at 3-year disease-free survival, which is one of the hallmarks of efficacy assess- ment for all patients combined, the sacrifice was 0.9% in disease-free survival. Unfortunately, for the study purpose, it did not meet our non-inferiority criteria, which were very strict, probably too strict; it crossed the kind of pre-planned analysis

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