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. 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, studying AC followed by docetaxel with or without capecitabine for patients with node-positive or high-risk, node-negative disease.

In our ongoing US Oncology adjuvant trial, we had to reduce the capecitabine dose after approximately the first 90 patients, but I’ve put many patients on this trial and the regimen is well tolerated.

US Oncology trial of capecitabine/paclitaxel in metastatic disease

We are currently investigating capecitabine 1,650 mg/m² total daily dose for 14 days with paclitaxel 80 mg/m² on days one and eight of a three-week cycle in patients with metastatic breast cancer. The regimen has been extremely well tolerated and the side effects have been those we expected from paclitaxel — alopecia, fluid retention, Grade I neuropathy, skin and nail changes — but capecitabine doesn’t seem to add much to the toxicity and the clinical benefit is extraordinary. We have had some patients on this trial for one to two years.

In the taxane-naïve subset, we found this regimen to be exceedingly effective and well tolerated (2.1). We’ve seen long, durable responses with capecitabine/ paclitaxel, and it is more tolerable than capecitabine/docetaxel. Capecitabine has also been combined with vinorelbine, which is another well-tolerated regimen.

Chemotherapy for metastatic disease

I decide whether a patient should receive combination chemotherapy or sequential single agents based on the burden and pace of the disease. So, for example, women with quite a bit of visceral involvement — particularly liver involvement — may need combination therapy.

For the patient with much 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 agents. 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.

For patients with ER-positive, HER2-positive disease, I often utilize trastuzumab combined with endocrine therapy — for example, an aromatase inhibitor — with excellent benefit.

Clinical trials of nanoparticle paclitaxel

Nanoparticle paclitaxel is an albumin-formulated, cremophor-free, paclitaxel preparation that enters cells via a specific albumin receptor — the gp60 receptor — which 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 or the control animals.

We conducted a Phase II study with nanoparticle paclitaxel at 100 mg/m² weekly times three, followed by a week off therapy, in 106 patients with taxane-refractory, metastatic breast cancer (Blum 2004). The response rate was 15 percent and another 15 percent experienced stable disease, so the overall clinical benefit was 30 percent. Almost all of the patients received the full dose, and the side effect profile was extremely favorable with only one and four percent of patients experiencing Grade IV neutropenia and sensory neuropathy, respectively. This regimen proved to be active in this taxane-refractory group of patients and was extremely well tolerated. These results are favorable compared to prior studies of weekly paclitaxel at 80 mg/m².

Nanoparticle paclitaxel compared to other taxanes

I believe nanoparticle paclitaxel is more active than paclitaxel based on the randomized trials. In cross-study comparisons of nanoparticle 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, and it’s difficult to administer for long periods of time. One can give docetaxel in the adjuvant setting, where treatment is short-term, but I believe nanoparticle paclitaxel is better tolerated.

If nanoparticle paclitaxel were available today, I would probably use it in lieu of other taxanes in the metastatic setting. I don’t use single-agent docetaxel in this setting, but I would certainly use nanoparticle paclitaxel in lieu of weekly paclitaxel. I would like to see more data on combinations with this agent to learn more about the toxicity profiles before using it in a combination off protocol.

Avoiding premedication with nanoparticle paclitaxel

In the Phase I, II and III clinical trials, nanoparticle paclitaxel was administered over 30 minutes without premedication — such as dexamethasone or antihistamines — and it did not require G-CSF support. 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.

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Dr Blum is Director of the Hereditary Cancer Risk Program and Research Site Leader at Baylor- Charles A Sammons Cancer Center in Dallas, Texas.