Metronomic Chemotherapy for Patients With Breast Cancer

Hyman Muss, MD, Lineberger Comprehensive Cancer Center at the University of North Carolina, Chapel Hill, NC, discusses the use of metronomic chemotherapy for patients with breast cancer.

Dr Muss covered the potential risks with this course of treatment, the best agents to use, and how metronomic chemotherapy compares to traditional forms of chemotherapy.

Transcript:

I'm Hyman Muss. I'm a professor of medicine at the University of North Carolina School of Medicine, and I'm a member of the Department of Medicine and the Lineberger Comprehensive Cancer Center.

What is metronomic chemotherapy and how does it differ from more traditional forms of chemotherapy?

Metronomic chemotherapy involves using smaller doses of chemotherapy frequently at shorter intervals, to try to achieve the same or similar benefits as more standard regimens, but with much less toxicity. Like the metronome on the piano in the old days that went back, forth, tick-tock. This is smaller doses, smaller intervals, but less toxicity.

What are the best agents to use in metronomic chemotherapy for breast cancers?

In breast cancer, one of the original studies of metronomic chemotherapy used very low doses of oral cyclophosphamide, 50 mg tablets, and methotrexate, which was given in very small doses twice a week. The so-called CM regimen was developed by the Italians. They had very good responses with almost no toxicity. At these doses of oral agents, you almost saw no myelosuppression, nausea, vomiting, or any other problems. In the progression-free intervals that lasted months, patients could take this treatment at home. It required minimal monitoring and they had very good response rates. These were frequently older patients who had already been through several other chemotherapy agents.

More recently, there have been studies with lower doses of liposomal doxorubicin given every 2 weeks. There have also been studies with lower doses of eribulin given several weeks in a row and 1 week off, and there have been studies with lower doses of capecitabine, all orally. It appears that the progression-free survival in these studies is usually similar to some of the earlier studies using the higher doses. Whether this is patient selection is uncertain.

These treatments are worth a try in people who are wary of taking any higher doses of chemo, or where you've had a long discussion about perhaps the fact that chemotherapy is not likely to be helpful to them in the future, but they want to try something. You as the clinician don't want to make them sick or put them through any other major toxicity, so these are nice things that can be considered and presented in a discussion.

Can metronomic chemotherapy be combined with other treatment modalities?

That’s a great question. Traditionally we haven't done it. It's interesting because weekly paclitaxel is, in a way, a metronomic approach. We used to give it every 3 weeks in bigger doses, and we found that in clinical trials and metastatic disease that the weekly dose was better. It had a better response rate, and patients did better with this, in at least 2 big trials, one by Andy Seidman years ago.

In metronomic chemotherapy now, we use taxanes and things with other agents. As far as things like liposomal doxirubicin or eribulin or the CM regimen, there have been some studies with other agents, but they don't seem to have added much. The question might suggest that to me, if you're considering other biologics or other agents that are potentially more toxic, you might as well use the better-defined regimens because there's a very limited experience here.

In the future, studies like that might be interesting, especially for patients who are a little bit frailer. All our clinical trials are usually done on Olympic athletes regardless of age, performance statuses of 0 to 1, very healthy people. I suspect that many of the patients we see don't have performance statuses of 0 to 1. Many have other issues, other symptoms, other comorbidities, and don't always fit the defining initial clinical trial eligibility criteria. Considering the safety of metronomic chemotherapy, combining with other agents upfront might be worth a try, worth a few phase 2 studies, just to make sure it really doesn't appear to have a much poorer outcome.

What are the risks vs benefits of metronomic chemotherapy?

I think when you're doing this, you're giving it to people who were sick. You have breast cancer patients; they've usually been through multiple treatments. They're coming to end-of-life in many instances. The worst thing you want to do is make them sicker. The benefits are that these drugs really have limited side effects. They have some, and you've got to be careful, but that's the major thing. You don't want to add insult to injury in a patient that's already sick, no hope for cure certainly, and then add an agent which causes more neuropathy or nausea and vomiting, et cetera. So that's a downside.

I think using them upfront, which has not been extensively tried, then you're concerned with whether they are going to be as efficacious as the standard treatments. You would need some form of comparative trial for that to make sure you're not low-balling patients who might do much better on standard treatments. It’s unlikely we'll see a lot of those trials. They'd be difficult to do and require a lot of patients. They'd certainly be of interest to practicing clinicians who are always interested in maintaining response and minimizing toxicity. We have a whole movement today on lesser aggressive treatments in many settings to maintain the same response. I think here and now would be a little premature to offer these regimens earlier on, because they might be inferior.

For providers treating patients with metronomic chemotherapy, what are some key things to remember?

I think there are several options you have. The thing to remember is that these patients are frequently sick. You and your team need to make sure that they're not having any undue side effects with the treatment and that it's not adding another major financial burden to them. I suspect that these treatments are not going to do that, but it's hard for clinicians. I've been doing this a long time. I never know what the costs are for the average patient. It's a whole other area of medicine and support as part of the big healthcare systems we work in. We're frequently not aware of that, but it's important to bring up, to make sure that that's not going to be an issue.

I think you give it a try. If people are not doing well or moving on, it may bring you a little easier into the discussion of end-of-life care and whether you want to provide supportive care alone for the patient. There's always something you can do to help the patient, but it may not be more treatment. I think it may make those discussions a little bit easier to get into than they can be, because you've already tried something a little bit gentler, and the disease has moved on and gotten worse. They’re sicker, and they have a greater volume of malignant spread. I think it can be helpful for all those reasons.