Metronomic Chemotherapy Represents Late Treatment Option for Some Patients With Metastatic Breast Cancer

Hyman B. Muss, MD

Patients with metastatic breast cancer may reach a point in their treatment where traditional therapies, and even newer agents, will not offer enough benefit to warrant their use. However, metronomic chemotherapy—the use of low-dose chemotherapy over a long period—could represent an option for some patients without negatively affecting quality of life, according to Hyman B. Muss, MD.

“There comes a time for many patients with metastatic disease, no matter where they’ve begun, that they get to a point where it’s not likely any treatments are going to be extremely effective,” Muss explained. “Some exciting new therapies…don’t apply to all patients, and as good as they are, there will be a time where in most of the patients, they stop working. In this context, you might want to do something [with metronomic chemotherapy].”

In an interview with OncLive^®, Muss discussed key highlights from his upcoming presentation at the 40th Annual Miami Breast Cancer Conference^®, including the potential benefits of metronomic chemotherapy and which patients with metastatic breast cancer could be candidates, as well as how to approach end-of-life conversations and decisions for patients. Muss is the Mary Jones Hudson Distinguished Professor of Geriatric Oncology, Division of Oncology, at the University of North Carolina (UNC) Lineberger School of Medicine, and director of the Geriatric Oncology Program at UNC-Chapel Hill in Chapel Hill.

Could you expand on metronomic chemotherapy and when this option could be considered for patients with metastatic breast cancer?

I’m very excited to participate [in the Miami Breast Cancer Conference], and this year, I’ve been asked to speak at the plenary [session] about metronomic chemotherapy and end-of-life care in patients with metastatic breast cancer.

When we use the term metronomic, we are using smaller doses of [chemotherapy] on a more constant basis. The idea is that by doing that, you reduce toxicity, but you maintain a similar or minimally poor result as far as shrinking a tumor or achieving palliation, which is your goal. I’m going to talk about [metronomic chemotherapy], when to use it, [as well as] philosophy of life and when it’s time to stop all treatment, which is extremely hard for patients, doctors, and nurses.

Patients frequently want to try something. However, you don’t want to give them a drug that you know is not likely to work [and] that can be very toxic. There are several studies of patients who have been moderately to heavily treated, [and] giving them small doses of chemotherapy. Specifically, drugs like capecitabine, which we use orally very frequently in breast cancer, but in lower doses. You can [use] liposomal doxorubicin, which is commonly used in smaller metronomic doses. You can do it with eribulin in smaller doses.

In these studies, the toxicity rates were low [and] responses were very good. Perhaps [responses] are as good as giving full doses, but those are studies that haven’t been done. [Metronomic chemotherapy] gives a little hope to the patient and to the doctor that we can help them out physically, as well as spiritually, and shrink the tumor for a while and improve quality of life.

This is a concept that’s been used [for some time], although it’s not homeopathic medicine. [Homeopathic medicine] is giving very tiny doses of medicine with no benefit. These are tested drugs, they are effective in breast cancer, and there are clinically published data supporting their use.

What factors can help determine whether metronomic chemotherapy is an appropriate approach for a given patient?

I like to say that there are [different] types of patients, and they overlap. There are [patients] who have been treated with numerous therapies, [such as] endocrine therapies for hormone receptor–positive [disease] or anti-HER2 therapies for HER2-positive [disease], or chemotherapy for triple-negative [disease]. They’ve had extensive treatment, and they are coming to the end of the line for treatments that are likely to give them a good, prolonged progression-free survival [PFS]. In those patients, these strategies [with metronomic chemotherapy] can be helpful.

There are [patients] who say…they don’t want to do any more chemotherapy. You never tell a patient there’s nothing more you can do to help. There’s always something you can do to help another human being, patient or not. [However], it may come to a point where chemotherapy is likely to be futile, low value, and the patient says they have had enough and [prefer] hospice or palliative care.

There’s another group [of patients] in the middle where you discuss the pros and cons to treatment. If they feel it’s worth a try with not too many adverse effects, they might do it. Then there are patients who will, to their last breath, want to try something. There is no right or wrong [answer], and we’re all going to encounter all of these [types of] patients.

Irrespective of what you might think, as a doctor, an advanced practitioner, or a nurse, it is the patient’s decision. You need to provide them with [the] best information, and if a patient asks [about what you would do in their situation], I think you should tell them what you think you would do. I believe you should do your best to pick what you would do, and that’s where your judgment, experience, and practice style all come into effect, which can be helpful.

Your presentation will look at providing hope for patients with breast cancer. Why is that important?

If you look at a [clinical trial], there is always a tail on a [survival] curve. There is always someone at the end of that PFS or overall survival curve, and you always hope it’s [your] patient. When you frame your treatment, how do you present treatment options to patients? You need to be honest, to say that the average patient on this treatment usually does well for a [certain amount of] time. Then, if it’s honest, you can say there is a small percentage of patients—whom you can’t identify up front with any precision—who may do well for long periods…and no one can tell whether that’s your patient.

A small probability of benefit maintains some hope. If that patient is sophisticated and [looks at the available data], you can show them and explain that some [individuals] are doing well, and it could be [them]. I believe that’s OK to do. I hate this concept now of becoming an efficient doctor; I want to be a good doctor. I want to explain things to patients, and it takes time to do it and answer questions.

If you feel it’s futile [for a certain patient] who is very sick, has a terrible performance status, they’re not getting out of bed, and they’re in pain, that discussion is much more difficult, [to say that a treatment is] not going to help. Some patients may still want to try, and that gets into your ethics and style.

Most hospices do not allow you to give chemotherapy in midst of hospice, which is OK, although we could fix a little bit of that to be more flexible. That said, your job is to make that transition into dying of the disease as smooth as possible. There are ways of doing that [by] working with families and patients. There is a wonderful end-of-life letter where patients annotate all the things in their life, [persons] and things they want to remember. It’s hard to do, but in a way, it’s a catharsis for many [patients]. It’s not for everybody. Some patients never do it, as they can never accept it, but it [can be] very helpful.

How do you approach end-of-life care with patients?

The process of dealing with bad news [includes] denial, anger, bargaining, depression, [and] acceptance. That algorithm is helpful to think about, but I don’t believe it ever works that way. Usually you don’t see too [much] denial these days, but you still [see] it [where a patient will say,] “How could this happen to me?”

Then, there’s anger. “Why did it happen to me?” Then there’s bargaining. “If I do this or that, maybe if I don’t step on the cracks on the sidewalk, the tumor will shrink a little bit.” You have depression, when [everything] finally hits a patient.

I’m not sure we all accept it. We get to a place where we know what’s going on, and [a patient] will say they can handle it. In my experience, very few [individuals] do that with any end-of-life situation. It’s all mixed in. It’s bargaining one day, it’s acceptance the next, and it’s anger the next day. That’s being human. Those are helpful constructs.

However, [individuals] are too complicated. It is much more complicated for very sick [patients]. Giving bad news is never a one-off. We teach [delivering bad news] in medical school, and it’s good, but it’s never a one-off. For some [persons], you need to stop the discussion abruptly because they are panicked. [Others] are very logical and you can go through it, but it’s such a mix. Everybody’s different, and despite 50 years of being in oncology and practicing, I still rehearse [end-of-life discussions], and I’m still surprised by some of the answers I get in these discussions with patients.

What are the indicators that a patient is approaching end-of-life?

As you get more experienced, you know that when a patient has extensive metastases in several organs of the body, a slight growth of that tumor is going to cause liver failure or respiratory failure.

Today we’re very good at [managing] pain. Years ago, we worried about cancer pain, and even with this terrible opioid crisis we have, I don’t believe it has affected treatment [for patients with cancer]. I don’t believe that’s a big issue with oncologists or palliative care patients.

There is an e-prognosis calculator on the internet open to everybody, and they have a hospice-type calculator for [patients] who are critically ill, not just with cancer but with anything. You can use it, but I believe most doctors get experience, and they know when we’re approaching days to weeks to sometimes months [remaining].

Patients will try to pin you down [on the exact amount of time they have left]. You pick a median, but you are careful to explain that it has tremendous variability. You could be very sick within a few weeks, or we may see you in a year and you’ll be very similar. We know from a lot of human and animal data that cancers don’t grow linearly. They can plateau off. There’s a lot we don’t know, so doctors should be aware of that uncertainty and not be too precise, but they need to be realistic.

If you have a sick patient [approaching end of life], you need to tell them they are very sick and if there is anything they need to do, they need to do it now. They need to get their affairs in order, have a durable health care power of attorney, and must have a will. They’ll save their family a lot of stress later. If there is some relative or friend they would like to make amends with, they need to do that now. They need to involve caregivers in this whole process.

My wife, Loretta Muss, RN, BA, of UNC Lineberger Comprehensive Cancer Center, is a superb leader of caregiver support teams and groups. It is a tragedy to die alone, and most [individuals] don’t do it. But getting the caregivers, family, kids, and friends involved is a crucial thing.

How can physicians incorporate metronomic chemotherapy and these end-of-life decisions into clinical practice?

Use your best clinical judgment to determine where the patient is [regarding their disease and treatment]. If there is a patient who really would like you to do something, and you feel it’s ethical to try it based on some of the data, you can consider metronomic chemotherapy. Of course, it can be associated with some toxicity, which is usually modest. In many of those patients, they are already having major symptoms from their cancer itself, so the add-on of these toxicities is frequently very minimal, but they’re real. That might offer the patient some hope and you a little peace of mind. However, the patient and their family’s perspective on this [will inform this decision].

At a time where you really feel everything is futile, it’s good to have that honest [discussion], and some patients are going to turn you down. They’re going to ask [whether] you are giving up on them. We’re human, and it varies. Then you’ll have to decide what you want to do.

One of the metronomic therapies is oral cyclophosphamide and methotrexate, which hardly causes any toxicity. I don’t think [using that regimen] is unethical; if the patient thinks maybe these pills will help them, I don’t think that’s so bad. Maybe the ethicist would feel [differently], but I don’t think that that’s so bad.