DR JOANNE L BLUM: I decide whether a patient should receive combination chemotherapy or sequential single agents based on the burden and pace of the disease. 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.

DR NANCY E DAVIDSON: Many times in metastatic disease, we use all of the available therapies, so what we’re really deciding on is the order — what to start with. Many patients make that decision based on their personal values.

I find many of my older patients are attracted to capecitabine because it is an oral agent. Some of my younger patients think of intravenous therapy as more aggressive, and they prefer that strategy. However, this perception is based on gut reaction rather than reality. I am a big fan of capecitabine. Maybe it comes from being a “hormonal therapy person” who prefers pills to begin with because I use capecitabine a lot for salvage chemotherapy in women who’ve already had an anthracycline and a taxane for metastatic disease.

In oncology, we tend to remember our successes, but I have seen several impressive responses with capecitabine in dire circumstances. I have had women on capecitabine for a considerable period of time with relatively good quality of life.

DR DICKLER: Positive data exist for several combinations, including capecitabine/docetaxel and paclitaxel/ gemcitabine. The doxorubicin/docetaxel combination improved response rate but didn’t improve overall survival, and George Sledge demonstrated that sequential therapy was as good as combination treatment in terms of overall survival, so I tend to use sequential single agents for the vast majority of my patients.

In a patient who is chemotherapy naïve and needs a rapid response, I would consider an anthracycline-based combination regimen. It would probably be doxorubicin/docetaxel, but it could also be doxorubicin/paclitaxel. If a patient had dose-dense AC/paclitaxel in the adjuvant setting, I’d be very interested in incorporating a gemcitabine-based combination or a capecitabine- based combination.

I use a lot of capecitabine. I believe it’s a great drug and is generally well tolerated when given at nonpackage-insert doses. For the patient who’s had adjuvant AC T, I frequently use capecitabine or vinorelbine as first-line therapy. For someone who’s chemotherapy-naïve, my first choice would probably be weekly paclitaxel followed by either vinorelbine or capecitabine. I don’t use early-line doxorubicin up front very often in my asymptomatic patients, because I think it causes a lot of fatigue and alopecia. Weekly paclitaxel also results in alopecia, but I prefer to use weekly paclitaxel more than doxorubicin in the metastatic setting.

DR TRIPATHY: When we have many chemotherapy drugs that, as single agents, provide response rates that overlap with each other, it shouldn’t be looked at as a conundrum but rather as an opportunity to individualize therapy based on the side-effect profiles. I’m starting to use drugs with less toxicity first, because we generally see the longest duration of response with the drug we use first. We might as well have that long period of time be the one with the least toxicity. Utilizing an agent that does not result in hair loss should be considered, if that’s important to the patient. Or, in the patient with pre-existing neuropathy from diabetes or prior chemotherapy, avoidance of an agent with neurotoxicity is important.

For me, the single most important factor is what treatment the patient has previously received. If a patient has progressed on an adjuvant taxane, I’m more likely to use a nontaxane drug. Although, granted, you can see responses to docetaxel and nanoparticle albuminbound (nab ) paclitaxel upon progression with the original paclitaxel formulation.

I usually consider patients progressing after AC and a taxane as being anthracycline and taxane refractory, but if a long period has passed (ie, two or more years) since the adjuvant therapy, one could certainly retry a taxane. Nanoparticle paclitaxel or a weekly regimen of the original paclitaxel formulation would be attractive choices. However, I’m generally treating these patients as anthracycline and taxane refractory, and I’m using capecitabine. Not only is capecitabine FDA approved for that indication, it seems to have among the higher response rates in the anthracycline- and taxane-refractory group of patients. Alternatives to capecitabine would include vinorelbine and gemcitabine. I believe combinations of these drugs are also something to consider.

We’re so geared toward thinking of single agents, but combinations do have a role, particularly for more symptomatic patients. It’s hard to know which combination wins out. Data exist on combinations of vinorelbine/ capecitabine, gemcitabine/vinorelbine and gemcitabine/capecitabine.

Clinical use of bevacizumab: Implications of the results from E2100

DR SLEDGE: Bevacizumab ought to be considered for use along with taxanebased therapy as front-line therapy for patients with metastatic breast cancer. I certainly would not argue with those who suggest we need safety data for bevacizumab in combination with docetaxel or nab paclitaxel. However, much of our preclinical testing was with docetaxel, and I would expect docetaxel to work well with bevacizumab.

I would not be surprised if nanoparticle taxane therapy would also work well. In fact, the nanoparticle taxanes have — as a possible mechanism of action — an effect on endothelial cells. We might see some synergistic activity there also. I’m not aware of any safety data for nab paclitaxel in combination with bevacizumab, but I suspect it would be safe. I would not have a problem with someone using the combination, and I would not expect any unusual toxicity.

DR WINER: I believe the results of ECOG-E2100 are impressive enough that, in the absence of a contraindication to bevacizumab, I would use it in a first-line setting, optimally in combination with paclitaxel as administered in the study. I doubt that the interaction is specific between paclitaxel and bevacizumab, although I’m well aware that when given with capecitabine in more advanced disease, bevacizumab seemed to be less active. However, I believe that’s probably related to the setting rather than the drug.

Nanoparticle paclitaxel compared to other taxanes

The superior efficacy, favorable safety profile, and greater patient convenience of ABI-007 [nanoparticle paclitaxel] make this novel albumin-bound paclitaxel an important advance in the treatment of patients with MBC [metastatic breast cancer]. ABI-007 warrants further investigation, using additional dosing regimens (eg, weekly) and in combination with other treatment modalities, as front-line treatment of breast cancer and other solid tumors.

— William J Gradishar, MD et al.
J Clin Oncol 2005;23(31);7794-803.

DR BLUM: 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. I don’t use single-agent docetaxel in the metastatic setting, and I would use nanoparticle paclitaxel in lieu of weekly paclitaxel. I would like to see more data on combinations with nanoparticle paclitaxel to learn more about the toxicity profiles before using it in a combination off protocol.

DR TRIPATHY: A weekly regimen of the original paclitaxel formulation would have been my choice in the past. Now that we have data with nab paclitaxel, I think that’s a reasonab le option also. From the data, nab paclitaxel may be preferable. It outperformed the original paclitaxel formulation when administered every three weeks.

A weekly regimen also seems to outperform an every three-week regimen of the original paclitaxel formulation, and I’m left wondering which is the best drug to use. For patients who prefer an every three-week schedule, I believe nab paclitaxel is the way to go. Otherwise, it’s a toss-up between every three-week nab paclitaxel and a weekly regimen of the original paclitaxel formulation. I don’t believe there’s a way to compare the two. CALGB is planning to conduct a head-to-head trial comparing weekly regimens of nab paclitaxel and the original paclitaxel formulation.

Phase III trial of docetaxel versus paclitaxel

This is the first clinical trial to compare directly the taxanes docetaxel and paclitaxel as monotherapy for patients with advanced breast cancer. Using US Food and Drug Administrationapproved doses and schedules for each agent, this Phase III study has demonstrated that docetaxel is superior to paclitaxel in TTP (5.7 vs 3.6 months; p <.0001), response duration (7.5 vs 4.6 months; p = .01), and OS (15.4 vs 12.7 months; p = .03). The overall response rate was also greater with docetaxel (32% vs 25%; p = .10). The survival advantage for docetaxel was observed despite the increased incidence of toxicities leading to dose reductions and treatment withdrawal, and the slightly greater use of salvage treatment in patients randomly assigned to paclitaxel. The results of this study are consistent with those reported for previous Phase III studies of singleagent docetaxel and paclitaxel...

— Stephen E Jones, MD et al.
J Clin Oncol 2005;23(24):5542-51.

Dosing of bevacizumab

DR SLEDGE: The dose we choose is based on our Phase I/II dosing in patients with breast cancer. Colon and lung cancer had different paths based on randomized Phase II trials conducted in those diseases. I don’t know what represents the right dose of bevacizumab.

We know 20 mg/kg is too much because of the dose-limiting toxicity of migraines. In the Phase I trials, once we got past approximately one mg/kg, all circulating, free VEGF was bound. So somewhere in between one and 20 mg/ kg is the right dose. We used 10 mg/kg in E2100. In the Phase I/II breast cancer trial, we looked at doses of three mg/kg, 10 mg/kg and 20 mg/kg. Even though the numbers were small, we had a sense that when we went from three to 10 mg/ kg, the responses were more brisk, and we saw relatively more patient benefit.

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