Miami Breast Cancer Conference Tumor Panel Discussion

DR BURSTEIN: The exciting thing about ECOG-E2100 was it really established a principle that anti-angiogenic therapy can be effective in advanced breast cancer. We had the results from the previous trial of anthracycline- and taxane-treated patients who were randomly assigned to capecitabine with or without bevacizumab, and in that study it was hard to see much significant clinical benefit.

It was always hard to square that result with the data that were seen in colorectal cancer. It’s not clear that one is such a vascular-driven tumor and the other would not be. So, from a conceptual point of view, the ECOG-E2100 really opens up a whole new area for us to try and exploit to help take better care of cancer patients, and that’s why I think it’s a very compelling study. It really gives us something tremendous to build upon.

Meet The Professors 2005 (3)

DR O’SHAUGNESSY: It’s not too surprising that E2100 was a positive trial because as a single agent, it has activity. It also had activity in the capecitabine randomized Phase III trial. That was a late-line population, and it’s difficult to change the median of anything when only a small percentage of patients benefited.

I guess the number one thing I want to see are some interesting exploratory subset analyses. For example, is the benefit of bevacizumab going to be largely seen in the higher-grade tumors, such as ER-negative, PR-negative or perhaps HER2-positive tumors?

What about indolent disease? You might have patients with some indolent biology, so I need to see the data. However, this sounds like a real advance for select patients for whom you believe it will be safe to administer bevacizumab.

Breast Cancer Update 2006 (4)

DR KATHY D MILLER: In the design of ECOG-E2100, we allowed patients who had received a taxane-containing adjuvant regimen to enroll as long as their disease-free interval was at least 12 months. We did that for pragmatic reasons because the taxanes were being used more frequently in the adjuvant setting. We thought it would be reasonable to consider re-treating those patients if their disease-free interval was at least a year.

Approximately 18 percent of our patients had received a taxane-containing regimen. Their hazard ratio was 0.38, which was the best hazard ratio of all of the clinically based subsets. For those patients, that translated into an improvement not from six to 11 months but from four to just more than 12 months in median progression-free survival.

We talked about whether we should have a crossover in ECOG-E2100, and we decided not to for a couple of practical reasons. One was that it would have made the trial a lot more complicated and expensive. Also, our primary endpoint was progression-free survival, so having a crossover would not have contributed to our primary endpoint.

Breast Cancer Update 2005 (7)

DR WINER: I believe the results of ECOG-E2100 are impressive enough that, in the absence of a contraindication to bevacizumab, I would now 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. I believe that’s probably related to the setting rather than the drug.

Breast Cancer Update 2005 (6)

DR SLEDGE: As a result of the previous toxicity seen in the lung cancer trial, we had very stringent criteria for discontinuing E2100 if we saw an excess number of patients developing Grade IV hypertension or bleeding. When the trial was initiated, the National Cancer Institute had significant concerns about patient safety as a result of the initial experience with bevacizumab in lung cancer.

Fortunately, early analyses demonstrated that was not an issue in breast cancer. The side effects were relatively minimal. Predominantly, we saw mild to moderate increases in blood pressure, which is readily handled from a clinical standpoint. Of course, we’ll have to be careful with the hypertension as we move bevacizumab into the adjuvant setting. We also saw a low incidence of serious bleeding. Overall, bevacizumab was a nontoxic addition to chemotherapy.

Breast Cancer Update 2006 (4)

DR MILLER: Adding bevacizumab increases the risk of arterial thrombotic events, although to a very modest degree. We know a little about the risk factors in that the risk seems to be preferentially borne out in patients who are older than age 65 or those who have had previous arterial thrombotic events, particularly MI, TIA or stroke.

No reports associate cardiomyopathy or congestive heart failure with bevacizumab in any of the trials that either did not use concurrent anthracyclines or were in patient populations who would not have been previously treated with anthracyclines. So this is an issue specific to patients with breast cancer, sarcoma or leukemia, for which anthracyclines are used.

In the randomized bevacizumab/capecitabine trial, two patients had congestive heart failure or cardiomyopathy in the capecitabine-alone group compared to seven in the capecitabine with bevacizumab group. That sounds like an increase, but the overall event rate was so low that, statistically, those numbers were not different.

In ECOG-E2100, we didn’t see any sign of congestive heart failure when comparing the two groups. In Sandy Swain’s 21-patient experience, which is the only breast cancer trial that has used an anthracycline and bevacizumab concurrently, none of the patients had clinical congestive heart failure, but two of them showed a decrease in their ejection fraction to less than 40 percent.

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Breast Cancer Update — Think Tank Issue 1, 2006

DR WINER: Three issues have led people to be less enthusiastic about bevacizumab use in first-line metastatic breast cancer. One is that the E2100 data apply to a large subset of patients. They would be happier if it were targeted to a smaller specific subset of patients. The second is that they are less enthusiastic and unsure of what to do with the capecitabine trial. And the third and very real issue is the cost.

Breast Cancer Update — Think Tank Issue 1, 2006

DR SLEDGE: From a quality-of-life standpoint, those of us who have used bevacizumab have found it an incredibly easy drug for patients. The toxicity is truly trivial compared to every single chemotherapeutic agent in the therapeutic armamentarium. So it’s not had any major negative effect on any significant percentage of patients in terms of quality of life and increase in toxicity.

However, these are the issues regarding bevacizumab extension: First, safety of prolonged exposure to bevacizumab; second, response to second-line combination therapy with bevacizumab; third, issues surrounding resistance to antiangiogenic therapy; and then, finally, the cost of therapy.

Breast Cancer Update 2006 (4)

DR MILLER: One of the trials that we activated shortly after we had the results from ECOG-E2100 was a Phase II trial known as XCaliBr, which uses the capecitabine/bevacizumab combination from the earlier Phase III trial but as first-line therapy for patients with metastatic disease. It’s essentially the ECOG-E2100 patient population using the regimen from the capecitabine/bevacizumab trial. We thought that was a reasonable trial because we had ample safety data with the combination, and we knew that adding bevacizumab to capecitabine improved the response rates.

It potentially will provide patients in that first-line chemotherapy setting another option and one that would be oral and wouldn’t cause alopecia, if we see similar response rates and progression-free survival in a decent-sized Phase II study.

Our trial with refractory patients found a doubling of response rates. We have data that strongly suggest this would be active. What we don’t know is whether we’ll have the same response rate and progression-free survival as with the paclitaxel-based regimen. I believe that would be an important piece of data clinically to allow people greater flexibility in their first-line regimen of chemotherapy with bevacizumab.

Breast Cancer Update 2006 (3)

DR GRADISHAR: I still believe that capecitabine is a good up-front agent to use in metastatic disease for many patients, and that hasn’t changed with the bevacizumab data. However, the data that emerge from the XCaliBr study may provide justification for using capecitabine with bevacizumab, assuming the data are positive and comparable to what we saw in the E2100 study.

Capecitabine is comparable to our most active chemotherapy drugs, but I don’t view any drug as the best agent in a particular situation. I would use capecitabine for patients with minimal visceral disease such as small liver metastases, but docetaxel or nanoparticle albumin- bound (nab) paclitaxel would be fine as well. It’s a judgment call that you make with each patient depending on her preferences.

Miller KD et al. Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol 2005;23(4):792-9.

The addition of bevacizumab to capecitabine clearly increased response rates, whether assessed by the IRF or the investigators, without significantly adding to the overall toxicity of the treatment regimen.

Despite improvement in ORR, the duration of the responses was short with respect to PFS, and the proportion of long-term responders was similar in the two groups.

Burstein HJ et al. Metronomic chemotherapy with and without bevacizumab for advanced breast cancer: A randomized phase II study. San Antonio Breast Cancer Symposium 2005;Abstract 4.

Metronomic chemotherapy administered to this patient population using low dose oral cyclophosphamide and methotrexate had minimal clinical activity by itself. In combination with metronomic chemotherapy and bevacizumab, there was a higher clinical activity rate noted in women with advanced breast cancer.

We believe the combination therapy is reasonably well tolerated and lacks many of the acute side effects of chemotherapy. We are in the process of performing correlative studies of VEGF levels and circulating endothelial cells to both understand the mechanism of action of these treatments and to try and identify patients who might selectively benefit, and we believe that further investigation of this treatment option is warranted.

To that end, we have activated a study at Dana-Farber, Indiana University, and UCSF, in which patients who have residual invasive breast cancer after receiving neoadjuvant chemotherapy will be assigned to treatment cohorts where they will receive one year of bevacizumab or one year of bevacizumab with six months of metronomic chemotherapy in a group of women who by some of the definition have resistance to traditional chemotherapy.

Breast Cancer Update 2005 (8)

DR VICENTE VALERO: There are two combination regimens that have proved to be superior to single-agent taxane therapy for metastatic disease. One is gemcitabine with paclitaxel, which was compared to paclitaxel alone. The data were presented at ASCO, showing an improvement in time to progression and preliminary evidence of an increase in overall survival.

The other study compared docetaxel with capecitabine to docetaxel alone and also showed a time to progression and overall survival advantage.

Based on the evidence, both of these combinations are reasonable for first-line chemotherapy of metastatic disease. However, in some patients, sequential chemotherapy is our preference.

I tend to use more sequential single-agent chemotherapy, but I believe the role of combination chemotherapy in some instances is well documented by the two studies I just mentioned.

For women who have symptomatic breast cancer with visceral involvement, it is essential to have a response to alleviate the symptoms and improve their quality of life. For those patients, despite the enhancement of the adverse events, I strongly consider combination chemotherapy.

Eniu A et al. Weekly administration of docetaxel and paclitaxel in metastatic or advanced breast cancer. Oncologist 2005;10(9):665-85.

Optimizing the dose and schedule of taxane therapy to maximize antitumor activity while maintaining a favorable toxicity profile remains an important goal in MBC. Weekly, rather than the standard every three weeks, dosing of docetaxel and paclitaxel at lower doses is one way to provide an efficacious method of drug delivery while maintaining a favorable toxicity profile.

Various studies support weekly taxane dosing as an active regimen in MBC, even in heavily pretreated, refractory disease and in elderly patients or those with poor performance status. Importantly, this regimen is associated with a low incidence of severe hematologic toxicities and acute nonhematologic toxicities.

Jones SE et al. Randomized phase III study of docetaxel compared with paclitaxel in metastatic breast cancer. J Clin Oncol 2005;23(24):5542-51.

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 Administration-approved doses and schedules for each agent, this phase III study has demonstrated that docetaxel is superior to paclitaxel in TTP (5.7 v 3.6 months; P <.0001), response duration (7.5 v 4.6 months; P <.01), and OS (15.4 v 12.7 months; P <.03).

The overall response rate was also greater with docetaxel (32% v 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 single-agent docetaxel and paclitaxel.

Ghersi D et al. A systematic review of taxane-containing regimens for metastatic breast cancer. Br J Cancer 2005;93(3):293-301.

We compared the results of randomized trials comparing taxane-containing chemotherapy regimens with regimens not containing a taxane in women with metastatic breast cancer. The specialized register of the Cochrane Breast Cancer Group was searched in March 2004. Eligibility was assessed and data extracted from eligible studies by two reviewers. Hazard ratios (HR) were derived for time-to-event outcomes, and a fixed-effect model was used for meta-analysis. Tumor response rates were analyzed as dichotomous variables.

Of 21 eligible trials, 16 had published some results and 12 data on overall survival. An estimated 2621 deaths among 3643 women suggest a significant difference in overall survival in favor of taxane-containing regimens (HR 0.93, 95% confidence interval (CI) 0.86-1.00, P=0.05). The treatment effect on survival was similar if only trials of first-line chemotherapy were included, although not statistically significant.

There appeared to be an advantage for taxanes in time to progression (HR 0.92, 95% CI 0.85-0.99, P=0.02) and overall response (odds ratio (OR) 1.34, 95% CI 1.18-1.52, P<0.001). There was significant heterogeneity across the trials (P<0.001), partly because of the varying efficacy of the comparator regimens. Taxane-containing regimens improved overall survival in women with metastatic breast cancer. Taxane-containing regimens are more effective than some, but not all, nontaxane-containing regimens.

Breast Cancer Update 2006 (3)

DR GRADISHAR: In terms of first-line taxanes in the metastatic setting, the data are still more abundant with both paclitaxel and docetaxel than with nab paclitaxel, so if basing a decision on the length of experience, those agents have been around for a longer time.

However, I see no reason to believe that nab paclitaxel will prove inferior to those drugs with more data. I believe nab paclitaxel will compare favorably, if not prove to be superior.

When you examine clinical trials that have evaluated docetaxel or paclitaxel in similar patient populations with metastatic disease, the indirect evidence shows the activity of nab paclitaxel to be comparable to docetaxel. These agents may have similar antitumor effects, so one should consider other factors, including toxicities, patient convenience and cost.

If nab paclitaxel can offer the same antitumor effect as docetaxel and paclitaxel along with advantages in terms of lack of pre-medication and shorter infusion time, whether or not it would become the preferred agent is an important question. When you think of busy office practices, the throughput of patients and convenience to patients are important. An upside to nab paclitaxel clearly is the shorter infusion time and the lack of need for pre-medication.

As for the higher acquisition cost of nab paclitaxel, economic analyses suggest that some of the downstream expenses related to administering paclitaxel or docetaxel — specifically the costs of pre-medications and antibiotics or growth factors to manage the neutropenias or cytopenias — result in a net savings with the use of nab paclitaxel.

Although we need more information, I believe we shouldn’t necessarily be put off by the up-front cost; we should take into account the whole package of managing the patient’s treatment.

Smith I. Goals of treatment for patients with metastatic breast cancer. Semin Oncol 2006;33(1 Suppl 2):2-5.

The key goal in the treatment of metastatic breast cancer is to prolong survival, with an emphasis on restricting treatment-related toxicity as much as possible. Despite the plethora of treatment modalities available in metastatic breast cancer, significant survival differences are relatively uncommon. Symptom relief and quality of life are other important, clinically validated measurement instruments.

Symptom relief in particular is not used as widely used as it could be, in contrast to lung cancer where it has been proven clinically informative. Finally, time to disease progression is an increasingly used primary endpoint in comparing treatments for metastatic breast cancer; this measure includes both patients who achieve an objective response, and those whose disease may be stabilized with treatment.

Special Edition BCU: Proceedings from Two Medical Oncology Educational Forums, 2005

DR RAVDIN: Capecitabine has some attractive features. In terms of toxicity and response, I view it as something that bridges the gap between hormonal therapy and intravenous chemotherapy. Particularly when dosed a bit lower than the package insert dose, it’s tolerable for most patients, and they don’t experience nausea, vomiting or hair loss, almost as if they were receiving an endocrine agent. It’s an oral agent — we don’t have to put in a line — so it’s easier for patients to accept. I think all those features make it an attractive agent.

Actually, I’m surprised that it isn’t more commonly used in the community because I think it’s one of those agents that is generally tolerated with repeated use. With a lot of other agents, patients begin to get tired when you get in six cycles.

Breast Cancer Update 2005 (8)

DR VALERO: When using capecitabine in patients with a good performance status who are not heavily pretreated, I use 2,000 mg/m² daily in two divided doses for 14 of 21 days.

After two cycles of therapy, I will consider escalating the dose if the patient has no toxicity. For patients with a poor performance status, for whom I’m going to consider capecitabine as a second- or third-line therapy — patients who are fragile — I may use 1,750 mg/m² daily.

We recently published in the Annals of Oncology about our experience at MD Anderson with different doses of capecitabine. We believe that a lower dose is preferable, although the FDA-approved dose is 2,500 mg/m².

I believe this publication confirms what we do in the clinic. When you have a Phase II study in several locations, but you select people out and monitor them very closely, capecitabine can be administered at a higher dose.

I could deliver capecitabine at 2,500 mg/m² daily, but it needs close monitoring with a patient who is able to follow closely with her oncologist.

In the clinical trials, as soon as the patients start to develop early signs of mucositis, diarrhea or hand-foot syndrome, capecitabine is stopped immediately.

Then the patient reports to the oncologist or the research nurse for instructions. Then you restart the capecitabine, and you may restart it at a lower dose. So it needs some close monitoring.

In general, most patients at the end of the day receive an average dose of around 2,000 mg/m² daily as a single agent. In some patients, I also use even lower doses — 1,500 mg/m² daily.

The bottom line is that the evidence that a lower dose is efficacious is just not there. Our study is one of the first that provides information, but it was not a prospective study to assess response and time to progression in a well-designed Phase II fashion.

Hennessy BT et al. Lower dose capecitabine has a more favorable therapeutic index in metastatic breast cancer: Retrospective analysis of patients treated at MD Anderson Cancer Center and a review of capecitabine toxicity in the literature. Ann Oncol 2005;16(8):1289-96.

We retrospectively reviewed the records of 141 consecutive patients with metastatic breast cancer identified from pharmacy records as receiving capecitabine outside of a clinical trial between May 1998 and February 1999...

It is apparent that the toxic effects associated with capecitabine therapy at 2,500 mg/m²/day cause morbidity in a relatively high proportion of patients, necessitating frequent dose reduction. This is consistent with our experience. Since the most important goal of the treatment of metastatic breast cancer is symptom palliation, therapy associated with considerable morbidity defeats the purpose. Reduction of the capecitabine dose has been shown to improve drug tolerability in most cases.

Moreover, retrospective analysis of many of the capecitabine trials has found that dose reduction for adverse events related to capecitabine did not have an impact on efficacy of the drug. This is supported by our data. In our experience, the mean tolerated dose of capecitabine is 2,040 mg/m²/day. Thus, it seems appropriate to use the drug at a lower starting dose, perhaps 2,000 mg/m²/day in two divided doses.

Bajetta E et al. Safety and efficacy of two different doses of capecitabine in the treatment of advanced breast cancer in older women. J Clin Oncol 2005;23(10):2155-61.

To the best of our knowledge, this is the first report specifically dealing with the use of capecitabine in an elderly population with breast cancer...

Overall, efficacy of the two starting doses was similar to that reported in a previous trial, in which first-line monotherapy with capecitabine at the dose of 2,500 mg/m²/d resulted in an objective response rate of 30% in 61 women aged 55 years and older. This study has shown in a large series that oral capecitabine is well tolerated and effective in older women with advanced breast cancer. Older patients may frequently exhibit diminished capacity to eliminate drugs, resulting in unusual sensitivity to standard dosing regimens.

In light of this, the overall results of the study suggest that although the dose groups are small and nonrandomized, the capecitabine dose of 1,000 mg/m2 twice daily merits consideration as “standard” for women aged 70 years and older who are candidates to cytotoxic therapy for metastatic breast cancer and do not have severely impaired renal function.

Meet The Professors 2005 (3)

DR O’SHAUGHNESSY: I have been impressed with the combination of a taxane and capecitabine in patients with the bone and liver metastases.

I think the capecitabine dose of 825 mg/m² BID, 14 days on and seven days off, is now pretty well established for combination therapy. I will usually treat for six or seven cycles with the combination, stop the taxane and keep going with capecitabine. The duration of response that I have seen with some patients has been remarkable. That is not to say that you wouldn’t have seen the same if you had used sequential therapy, but the duration of responses in a number of patients is impressive, and it’s gratifying.

In the JCO an Italian group reported a Phase II first-line metastatic trial of capecitabine in patients with a mean age of 73. Patients were started on capecitabine at 1,250 mg/m² BID. Two deaths occurred, so they reduced the dose to 1,000 mg/m². The report included about 40 patients treated with 1,250 mg/m² and another 43 patients treated with 1,000 mg/m². In the trial, they observed an acceptably low rate of Grade III toxicities with the lower dose in less than 10 percent of patients. In both cohorts, the response rate was 35 percent, which is pretty impressive, and another third of patients treated with 1,000 mg/m2 had stable disease for more than six months. That is getting remarkably high.

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Meet The Professors 2005 (3)

DR HUDIS: I don’t harbor a firm belief that the order of single agents matters as much as people believe it does. For patients reluctant to receive chemotherapy for reasons that are largely emotional, capecitabine allows them to make that transition and say to themselves, “I’m not getting intravenous therapy. It’s not so bad.”

The fact that capecitabine is as active as many of the intravenous therapies that we routinely use makes this sort of a silly point, but it is one that people buy into.

So if I have a patient who is reluctant to start intravenous therapy, I will look toward capecitabine.

If I have an older patient, to tell you the truth, it cuts both ways. The truth is that capecitabine does bring up compliance and safety issues related to self-administration. It’s not crystal clear to me that it’s always safe for or better for a person to take medication at home. Sometimes you have a little more control over them if you can administer intravenous therapy and withhold it when you should.

Breast Cancer Update 2005 (5)

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 have 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.

Breast Cancer Update 2005 (9)

DR VOGEL: In postmenopausal patients, when I use hormonal therapy in metastatic disease, for the most part, I generally start with an aromatase inhibitor. There are nine lines of hormonal therapy for postmenopausal women, and there is no tried and true sequence — we don’t have any consensus on a true hormonal cascade. In some women hormones can be manipulated for years. I’ve had patients on hormonal therapy for 10 or 12 years before ever reaching cytotoxic chemotherapy.

Breast Cancer Update 2005 (4)

DR GRADISHAR: If you evaluate most of the available data with endocrine agents in the metastatic setting — tamoxifen, steroidal or nonsteroidal aromatase inhibitors or fulvestrant — the question that comes up is whether one sequence enhances patient outcome more than another. This becomes important because if you can demonstrate that one sequence enhances the time to disease progression, it may be built on over time so that overall outcome is improved.

In theory, simply having an improvement in recurrence or progression of metastatic disease impacts quality of life. Patients now typically receive a nonsteroidal aromatase inhibitor — anastrozole or letrozole — as the first treatment.

The question then becomes, if patients progress on one of those agents, what would be the next best therapy? Should it be the steroidal aromatase inhibitor exemestane, or should it be fulvestrant?

Indirect data evaluating the sequence of a nonsteroidal aromatase inhibitor to fulvestrant suggest that 25 to 30 percent of patients may benefit with that approach. An important issue is whether fulvestrant at 250 mg is optimal.

Some of the data suggest that the dose is really on the low end of the curve where you might expect the optimal response rate. Some strategies have evaluated quickly increasing serum levels of fulvestrant, including administering loading doses of 500 mg and within two weeks administering another 250 mg and then proceeding to the monthly schedule. Those strategies are based on mathematical modeling that has shown an ability to achieve steady-state levels much more quickly and consequently achieve a biologically relevant dose of drug circulating much faster.

Patterns of Care 2005 (1)

DR JONES: Generally, patients are either going to relapse on tamoxifen or after adjuvant tamoxifen. In that setting and in the fulvestrant versus anastrozole clinical trials, evidence exists that a proportion of women have a longer response to fulvestrant than to anastrozole when given right after tamoxifen. I‘ve had patients with long responses to fulvestrant.

I prefer fulvestrant to an aromatase inhibitor after tamoxifen because approximately 20 percent of patients have long responses with it in this setting. However, 99 percent of oncologists will choose an aromatase inhibitor after tamoxifen. Fulvestrant is generally being used as third-line therapy.

Despite Trials 20 and 21, most physicians start with anastrozole rather than fulvestrant because of the way the data have been presented. We are just beginning to see patients who have been treated with two or three years of adjuvant anastrozole and then relapsed.

Currently, there are few data on treatment options in this setting. It’s somewhat of a “dealer’s choice” because there are no hard and fast rules. There are multiple options including fulvestrant, exemestane and even tamoxifen — if the patient hasn’t seen it — because it’s obviously still a useful drug. So the sequence is going to be all over the map for most folks.

Patterns of Care 2005 (1)

DR BURSTEIN: Previously, patients received tamoxifen in the adjuvant setting, so we would use an aromatase inhibitor as front-line therapy in the metastatic setting. Fulvestrant was used second line, or we could use megestrol acetate, but for many women fulvestrant has a more convenient side-effect profile.

Now that more women receive aromatase inhibitors in the adjuvant setting, we’re using tamoxifen or fulvestrant as first-line treatment in the metastatic setting.

Breast Cancer Update 2005 (5)

DR DEBU TRIPATHY: In the up-front study, tamoxifen and fulvestrant were essentially equivalent. As second-line therapy, fulvestrant seemed to perform equally as well as anastrozole. At this point in time, the sequencing and timing for fulvestrant are unclear. I think it’s reasonable to use the drug — maybe not up front, but as second- or third-line therapy.

This is when you might consider the patient’s preferences in terms of an intramuscular or an oral drug. A recent study of 261 women with metastatic breast cancer demonstrated that about one third preferred a monthly intramuscular injection. I’ve always assumed that oral drugs were preferable, if they were equally effective. Therefore, I was surprised to see that many patients preferred an intramuscular injection. I need to query my patients more when I start evaluating these options.

Patterns of Care 2005 (1)

DR JOANNE L BLUM: In my experience, patients tolerate the fulvestrant injections just fine. We have randomized data comparing fulvestrant versus anastrozole in patients who have already received tamoxifen, but the optimal sequence for using fulvestrant is still undetermined. In choosing between an aromatase inhibitor and fulvestrant, I ask my patients whether they prefer an injection or a pill. If they have transportation problems, then I use an oral agent.

However, for the Medicare population, these drugs are very expensive. If the patient does not have adequate insurance coverage and can’t afford them, a monthly injection may be better. Compliance is also an issue to be considered when choosing between a daily oral agent and a monthly injection.

Special Edition BCU: Proceedings from Two Medical Oncology Educational Forums, 2005

DR OSBORNE: Two clinical trials were conducted comparing fulvestrant versus anastrozole for second-line therapy in patients who had received tamoxifen in the adjuvant or metastatic setting. One study was conducted in North America and the other in Europe and the rest of the world. The data from both trials were similar. The complete response rate was slightly higher with fulvestrant, whereas the partial and objective response rates were similar.

In terms of stable disease and clinical benefit, fulvestrant was a tiny bit better than anastrozole. In one of the trials, duration of response favored fulvestrant, but by and large, the drugs were similar.

How does fulvestrant compare with tamoxifen in the front-line setting? All the preclinical data suggested that fulvestrant would be significantly better than tamoxifen, so a trial was conducted comparing these two endocrine agents. In the receptor-positive group, fulvestrant and tamoxifen were similar in response and time to treatment failure, but overall, tamoxifen looked slightly better in some of the parameters.

Breast Cancer Update 2005 (8)

DR VALERO: Our approach in the institution is to use an aromatase inhibitor up front and then fulvestrant as second-line therapy. Fulvestrant is approved for patients who have failed tamoxifen, so you can use one agent or the other.

In the palliative setting, I believe you can use it either way. Fulvestrant has been shown to be as effective as anastrozole and tamoxifen. I use them in sequence. I don’t believe there is any information that one sequence is better than the other. I use an aromatase inhibitor, and then I use fulvestrant as a second-line therapy.

Breast Cancer Update 2005 (8)

DR BUDD: I tend to use an aromatase inhibitor first and then use fulvestrant. One could build a rationale for using an alternative sequence, but I believe the data for aromatase inhibitors are strong.

When trying to decide between fulvestrant and an aromatase inhibitor for a postmenopausal patient who has relapsed on adjuvant tamoxifen, I believe ease of administration and the magnitude of the information are key. We have trials with each one of these agents that indicate, in one way or another, that the aromatase inhibitors are an optimal treatment. Granted, anastrozole and fulvestrant appear to be equivalent in that situation. So fulvestrant is also a reasonable choice.

I believe most, but not all, patients would still rather take a pill than have an intramuscular injection. Many of these patients are coming back to the clinic on a monthly basis for a bisphosphonate, so some of the practical advantages of a pill may not pertain for all patients.

Breast Cancer Update 2006 (3)

DR JOHN FR ROBERTSON: The SoFEA trial compares exemestane to fulvestrant following another aromatase inhibitor. The EFECT study is also testing exemestane versus fulvestrant following another aromatase inhibitor. That study has finished recruiting and is now in the follow-up phase, so the results should be reported in the foreseeable future.

With the SoFEA trial, I hope we see an improvement by combining the two treatments, though I suspect we may have answers to that question before the SoFEA trial results are reported, in that metastatic studies often take a bit longer to run. A couple of ongoing studies are also combining therapies, and they may report sooner.

The SWOG-S0226 trial is comparing fulvestrant with anastrozole to anastrozole alone, so we may see whether the combination is better than a single-agent aromatase inhibitor, and that will be an interesting result.

Breast Cancer Update 2004 (6)

DR MITCHELL DOWSETT: EFECT is an American and European study that randomly assigns patients who have failed therapy with a nonsteroidal aromatase inhibitor to fulvestrant or exemestane.

Our own study, SoFEA, is slightly different from EFECT because it is based on the observation that the addition of small amounts of estrogen to cells that have been estrogen deprived for a long time reduces the effectiveness of fulvestrant. That scenario equates to the withdrawal of a nonsteroidal aromatase inhibitor and the addition of fulvestrant.

Hence, the third arm of our trial includes a nonsteroidal aromatase inhibitor and fulvestrant. I predict fulvestrant alone will probably be better than exemestane, and fulvestrant with anastrozole will be better than fulvestrant alone.

Breast Cancer Update 2005 (9)

DR VOGEL: In terms of efficacy, fulvestrant seems to be equivalent to anastrozole. Based on data published this year in Cancer, there seems to be no difference in overall survival in the randomized trials of anastrozole versus fulvestrant.

Fulvestrant is a good drug and a viable alternative to aromatase inhibitors in patients who have disease progression on tamoxifen. We do have to contend with the randomized trial of fulvestrant versus tamoxifen, where we expected a strongly beneficial effect for fulvestrant over tamoxifen, which was not forthcoming. There were some subsets where fulvestrant appeared to be better, but the overall results were about the same.

Breast Cancer Update 2005 (8)

DR VALERO: At MD Anderson we use a loading dose of fulvestrant. We administer 500 milligrams on day one and 250 milligrams on day 15 and day 29, and then monthly. Many of the key investigators in the early development of the drug believe it is important to attain steady state. As you know, there are no randomized data for the loading approach.

Currently, it is FDA approved at 250 milligrams monthly and is reimbursed by Medicare at that dose. With all of those caveats, I believe — and I don’t know if this is my bias — the loading approach is reasonable.

Meet The Professors 2005 (6)

DR AMAN U BUZDAR: Data suggest that if you use the package insert dose of fulvestrant, which is 250 mg every four weeks, it takes about two to three months to get a steady-state therapeutic level. So we give a 500-mg loading dose, and then in another two weeks we give another 250 mg, and then treat every four weeks.

This is being evaluated in a prospective study because an important question is whether we are losing some patients before we get to the therapeutic level and the disease is progressing because patients do not have enough drug in their system.

Breast Cancer Update — Think Tank Issue 1, 2006

DR ROBERTSON: There is evidence supporting a loading dose of fulvestrant. First, tamoxifen reaches a steady state at two weeks, whereas fulvestrant can take up to four or five months to reach a steady state.

Another issue, which I believe makes people slightly uncomfortable, is that in the second-line study, fulvestrant was just as good as anastrozole after tamoxifen.

The first-line study, however, had two problems. Although it was a randomized study, 10 percent more people were assigned to fulvestrant than tamoxifen.

In addition, in the intention-to-treat population, the time-to-progression curve for the initial fulvestrant arm drops down much more quickly than the curve for tamoxifen, and then, after the first six months, it runs parallel to tamoxifen. It makes one think that perhaps the drug is not on board in that first six months.

The question is, why would you see this in the first-line and not the second-line setting? You could argue that some of those patients in the second-line setting may be having a tamoxifen withdrawal effect while the fulvestrant levels are going up.

Breast Cancer Update 2005 (8)

DR VOGEL: Although we think that may be utilizing the best dosing schedule for fulvestrant, we won’t know unless we do a pharmacokinetic study and a large study to show that the doses are equally effective. I’m not sure if we’re going to be seeing a dosing study large enough to determine efficacy. You can look at the pharmacokinetics in a smaller study, but I don’t know if we’re going to see efficacy differences.

Fulvestrant is a good drug that has minimal toxicity. We don’t even encounter much in the way of buttock pain with a five-cc injection. We’re also not seeing the degree of joint discomfort that we see with the aromatase inhibitors.

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