Maintenance Therapy in the Treatment of Metastatic Colorectal Cancer

Axel Grothey, MD

As part of our coverage of the European Society for Medical Oncology (ESMO) World Congress on Gastrointestinal Cancer held July 1 to 4 in Barcelona, today we are speaking with Axel Grothey, MD, professor of oncology at Mayo Clinic, Rochester, Minnesota. At this year’s meeting, Dr. Grothey will be participating in an education session discussing whether or not to use maintenance therapy in the setting of metastatic colorectal cancer.

  -Interviewed by Leah Lawrence 

Cancer Network: Dr. Grothey, thank you for taking the time to speak with us today.

Dr. Grothey: Thank you for having me.

Cancer Network: You are participating in a session discussing the use of maintenance therapy vs stop-and-go therapy for patients with metastatic colorectal cancer. Can you first tell us, what patient might qualify for the use of maintenance treatment in this setting and what is the goal of that therapy?

Dr. Grothey: Unfortunately, for most patients with metastatic colorectal cancer the goal of treatment is not cure. For some patients with liver-limited or lung-limited disease we try to cure with surgical intervention and chemotherapy, but for the vast majority of patients, unfortunately, the goal is palliation, meaning extending their lives and maintaining their quality of life.

We have various different treatment regimens or agents that can, from the medical oncology perspective, delay the onset of symptoms quite a bit with systemic chemotherapy with or without the inclusion of targeted agents. The goal is really to delay tumor progression using the least amount of treatment necessary to control the disease. This is exactly what I tell my patients. I tell them I want to keep you around as long as possible, maintaining your quality of life as long as possible, using the least amount of treatment necessary to control your disease. I think, particularly when we use agents like oxaliplatin in first-line therapy or second-line therapy where we have some cumulative toxicity, the idea of using the induction chemotherapy phase, pushing the cancer back, decreasing tumor load and potentially tumor-related symptoms, and then keeping the disease controlled by using a maintenance therapy approach, some kind of chemo-lite approach using agents that do not have cumulative toxicities and are pretty well tolerated, I think that makes a lot of sense from a biologic perspective.

Cancer Network: Would these patients continue on cytotoxic treatments or are more targeted therapies typically employed? What evidence is there for the efficacy of this approach?

Dr. Grothey: A lot of patients receive combination chemotherapy with fluoropyrimidines, oxaliplatin or irinotecan, and bevacizumab, for instance, as first-line therapy, or if they are RAS wild type, a monoclonal antibody against the EGFR receptor. When we use a maintenance therapy approach, the critical issue is that these agents should still be effective in controlling the disease, but on the other hand, should not have a lot of cumulative toxicities. They should be well-tolerated.

A combination of a fluoropyrimidine plus bevacizumab, meaning capecitabine as an oral fluoropyrimidine or IV chemotherapy with 5-fluorouracil plus bevacizumab, has shown to be quite active even without the addition of oxaliplatin and irinotecan as first-line therapy and does not have any cumulative toxicities. We have seen several phase III studies that looked at the efficacy of a fluoropyrimidine plus bevacizumab as maintenance therapy. Most prominently was the so-called CAIRO 3 study, which was published in Lancet just this year, which showed that with use of low-dose capecitabine continuously administered plus bevacizumab every 3 weeks compared with a chemotherapy-free interval, the time to tumor progression was doubled, meaning it was clear that the low-dose maintenance therapy approach with a fluoropyrimidine plus bevacizumab was quite active in delaying tumor progression and can be considered as one of the standard maintenance therapies.

Cancer Network: In the session at the Congress, you are representing the use of maintenance therapy, but what might be the argument against maintenance therapy and for a more stop-and-go treatment approach?

Dr. Grothey: First of all, when you look at the overall survival outcomes, we have not yet seen clear proof that maintenance therapy can improve overall survival in a statistically significant manner. We have seen incremental improvements in overall survival and I strongly believe that what you lose early on, you cannot make up in the end. Particularly in the CAIRO 3 study, we still saw a difference in overall survival of about 3.5 months median, which was not statistically significant. If you just look at statistical significance and you say, “Show me if maintenance therapy has improved overall survival,” that has not happened yet.

On the other hand, of course, any treatment is more expensive than no treatment. Particularly when we use antibodies against VEGF, like bevacizumab, we do have cost factors, or financial toxicity.

I strongly believe that not every patient needs maintenance therapy. There are some patients with low-volume smoldering disease where we probably don’t need any treatment, but should keep a close eye on patients and reinitiate treatment when needed.

I consider a maintenance therapy approach as one of our tools that we have, and we need to adjust our tool kit and what we use according to the needs of patients. This is really the hallmark of individualized therapy.

Cancer Network: What factors should oncologists consider when trying to decide if a patient with metastatic disease should be given maintenance treatment?

Dr. Grothey: It does depend on the overall volume of disease, as well as whether the patient had a response to treatment in the induction phase, but also how aggressive the cancer is. Some patients might not be controlled with maintenance therapy. The tumors might be too aggressive, like BRAF-mutant tumors, which show very aggressive behavior. A fluoropyrimidine plus bevacizumab would not be able to control the disease.

On the other hand, if patients who had a good response to first-line therapy, if their tumor is well-controlled and they are asymptomatic from their disease, but there is still the concern that if we take any treatment away the tumor might flare up, those are the perfect patients for maintenance therapy, particularly if they are willing to take the treatment on a longer-term basis. The idea of an oral chemotherapy, an oral cytotoxic agent like capecitabine, plus an IV drug like bevacizumab every 3 weeks can be attractive to patients in terms of convenience and not interfering with their quality of life and what they like to do with their life in this palliative setting.

Cancer Network:Thank you so much for giving us this great summary of the current status of maintenance therapy in patients with metastatic colorectal cancer.

Dr. Grothey: You’re welcome.