Chemotherapy in the management of metastatic breast cancer

Single agents versus combinations

For the patient with more indolent disease, particularly the patient with a long disease-free interval who may have had sequential hormonal therapy and is now hormone therapy refractory, I use sequential single-agent chemotherapy. Many of my patients receive capecitabine as the first chemotherapy in this situation because it’s orally administered, does not cause alopecia and is extremely well tolerated. It is similar to taking a hormone pill. I also use capecitabine in combination with trastuzumab in patients with HER2-positive tumors, and I’ve had patients on that combination for years with bone, lung and lymph node involvement. These patients keep their hair. They come in every three weeks, and the palliation from this can last for years and is extraordinary.

— Joanne L Blum, MD, PhD

Clinical trials with capecitabine

In the mid 1990s, we studied capecitabine in patients with metastatic disease who had previously received taxane therapy, and we conducted the pivotal Phase II trial that led to the FDA approval of capecitabine (Blum 1999). In the pivotal trial, most of the 162 patients had previously received anthracycline therapy, and more than 60 percent benefited from capecitabine. The response rate was 20 percent, and an additional 40 percent of patients experienced stable disease. The tolerability of this oral agent was impressive with no alopecia or myelosuppression.

We also participated in the Phase III metastatic trial comparing docetaxel with or without capecitabine, and survival was approximately three months longer in patients who received the combination (O’Shaughnessy 2002). This important trial led to the current US Oncology trial of capecitabine in the adjuvant setting, which evaluates AC followed by docetaxel with or without capecitabine for patients with node-positive or high-risk, node-negative disease.

We also did a study that combined capecitabine with paclitaxel, and the regimen was extremely well tolerated. The side effects were those we expected from paclitaxel — alopecia, fluid retention, Grade I neuropathy and skin and nail changes (Blum 2004). Capecitabine didn’t seem to add much to the toxicity, and the clinical benefit was extraordinary (1.3). We had some patients on this therapy for one to two years. Since we have seen such long, durable responses with such minimal side effects, I’m very impressed with the paclitaxel/capecitabine combination.

— Joanne L Blum, MD, PhD

Benefits of capecitabine

We have been using capecitabine earlier in the treatment algorithm for patients with metastatic disease, partly because of its convenience. We can initially start the patient on it, see her every three weeks for a couple of cycles to make sure she is doing okay, and then spread her visits out from there. As time goes on, the patient may just come in every four or five months like any patient who comes in on a regular basis without metastatic disease.

Another benefit is that capecitabine doesn’t cause alopecia. That is a great advantage. People don’t know the patient is being treated, and she doesn’t look like she is receiving chemotherapy, so she is able to go on with her life without everybody asking, “How are you feeling?”

— Barbara Thompson, RN

An important advantage of capecitabine is being able to stop therapy and adjust the dose if the patient experiences side effects. If I prescribe IV chemotherapy to a patient and she experiences side effects that are worse than expected, I’m rather limited in my options. All I can do is support her until the symptoms resolve and then adjust the dose for the next cycle. That is not what happens with capecitabine because the patient receives it slowly over two weeks. If the side effects start building up, we can stop the treatment and adjust the dose in the first cycle to limit problems. This can provide comfort to patients who are squeamish about toxicity or who have had a bad experience with it.

— Kathy D Miller, MD

I’ve been impressed with capecitabine. It’s user friendly for the patients, doesn’t generally cause hair loss and as you work with it, it becomes easy for the nurses and physicians to manage the patient. It allows for a lot of flexibility, and we can do a lot with scheduling to fit a patient’s lifestyle. We’ve seen lots of good responses to capecitabine.

— Anita Rush-Taylor, RN, CCRC

Management of capecitabine-related side effects

The key to safely using all chemotherapies is patient education. That is much more driven and dependent on nurses than it is on oncologists. My nurses spend a lot more time focusing on education than I do. This is particularly important with an agent like capecitabine. We know that even when calculating the capecitabine dose based on body surface area, approximately one fourth of all women will develop hand-foot syndrome, mucositis or diarrhea that will require them to stop taking their pills before they finish the first 14 days of therapy.

Therefore, patients need to clearly understand what side effects to look for and what they should do to manage them. My nurses specifically tell patients receiving capecitabine, “If you notice these side effects, stop taking the drug and call us.” We talk to them about three things. The main one is hand-foot syndrome. Redness doesn’t bother me, even if it is bright red and looks bad. However, if the hands and feet are becoming uncomfortable and sore, then that’s a trigger that the patient needs to stop taking the drug.

Other side effects that we discuss are mucositis and diarrhea, although I believe those are less often reasons to stop. A little diarrhea doesn’t bother me, but if a patient is having more than two or three bowel movements a day, particularly diarrhea, that can become a serious, life-threatening problem. For mucositis, our instructions are similar to those we provide for hand-foot syndrome. If the mouth is a little red or feels rough, that’s not a major issue. However, if it is becoming sore or is sore when the patient eats spicy things or drinks soda, then it is time to stop taking the drug. For the majority of patients who follow our directions and contact us when they are having problems, I really believe that capecitabine has a minimal impact on their quality of life.

— Kathy D Miller, MD

With capecitabine, teaching the patient up front when to call us and when to stop the drug is important. Our whole life we’ve been told, “Take all of your medicine.” However, with capecitabine, this is the one time the patient doesn’t necessarily need to take all of her medicine. For the most part, if I can convince my patients not to take their capecitabine when they start having side effects, they do fine with it. We can simply adjust their dose, and they can continue.

Occasionally, you will have a person who doesn’t listen and then develops hand-foot syndrome or severe diarrhea. I have more trouble with those two side effects than anything else. Therefore, we tell our patients to stop the drug and call us if they have more than four to six stools in a 24-hour period or numbness, tingling or burning on the soles of their feet or the palms of their hands. For the majority of patients, if they stop capecitabine when they truly start to experience those symptoms, within 48 hours the side effects will go away and we can restart the drug at a reduced dose.

— Barbara Thompson, RN

Nanoparticle albumin-bound (nab) paclitaxel (Abraxane™)

Nab paclitaxel is an albumin-formulated, cremophor-free paclitaxel preparation that enters cells via a specific albumin receptor — the gp60 receptor — that leads to high intracellular concentrations of paclitaxel. In animal models of breast, lung, prostate and ovarian cancer, this agent demonstrated marked suppression of tumor growth compared to paclitaxel.

I believe nab paclitaxel is more active than paclitaxel based on the randomized trials (O’Shaughnessy 2003; [1.4]). In cross-study comparisons of nab paclitaxel versus docetaxel, each given every three weeks, the response rates were similar — in the 30 percent range. However, docetaxel in the metastatic setting, whether given weekly or every three weeks, is toxic because of side effects like asthenia, fluid retention and neutropenia. It’s also difficult to administer for long periods of time. Docetaxel can be administered in the adjuvant setting, in which treatment is short term, but I believe nab paclitaxel is better tolerated.

— Joanne L Blum, MD, PhD

Benefits of nab paclitaxel

Nab paclitaxel is a very nice option for many reasons. In the randomized trial, it was shown to be more effective than paclitaxel given on an every three-week schedule (O’Shaughnessy 2003). While it did cause a bit more neuropathy in the trial, it also resulted in less myelosuppression.

I believe the biggest advantage for patients is that the drug does not require steroid administration or premedication. Many of my patients hate steroids more than virtually anything else I prescribe to them. Nab paclitaxel is also infused over 30 minutes. For working women or those with dependent children at home, being able to receive chemotherapy in 30 minutes instead of three hours is a big time saver. I think sometimes we underestimate how much time out of patients’ lives the logistics of therapy can take.

— Kathy D Miller, MD

It is an extraordinary advantage to be able to avoid dexamethasone. Patients dislike weekly dexamethasone — it gets them “jazzed up,” causes insomnia and weight gain, has significant immunologic effects and may contribute to osteopenia and osteoporosis. In addition, a hypersensitivity reaction is a frightening experience for a patient. These reactions can be catastrophic and, if severe, may preclude further taxanes. I believe we underestimate the negative impact of dexamethasone on patients and should avoid using it.

— Joanne L Blum, MD, PhD