Newsletter #80–Feb./Mar. 2004
Something Old, Something New: Refinements of Existing Treatments
by Musa Mayer
Note: The names and numbers in brackets refer to abstracts available on www.sabcs.org. Click on “Abstracts Online 2003,” login as a guest, and search by author.
If this year’s San Antonio Breast Cancer Symposium was short on new drugs, it was long on refinements of existing treatments, which always comprise the bulk of the clinical research presented at the conference.
New drugs are FDA approved on the basis of minimal data on safety and efficacy. Clarity about how best to use a new drug comes from the many trials done in the years following its approval. Further refinements with regard to combining, sequencing, scheduling and dosing may not make the headlines, but they often make a real, if incremental, difference in the clinic.
Of course, not all such studies ask and answer meaningful research questions. Advocates are often justifiably skeptical about the host of seemingly pointless clinical trials that combine chemotherapies in advanced breast cancer. Too often, new formulations of drugs that have lost patent protection represent attempts on the part of drug companies to maintain their profits and offer little to patients to justify their high costs.
New formulations of older effective drugs with problematic side effects can, however, represent a real step forward, if they offer less toxicity or are more effective. Abraxane® (ABI-007) looks as if it will be one such example.
The old drug in question is Taxol® (paclitaxel), which because of solubility problems has usually been administered dissolved in a castor-oil derivative called Cremophor®. Having to take steroid premedication and antihistamines to prevent serious hypersensitivity reactions to Cremophor has been a constant complaint among patients on Taxol, especially those on weekly regimens for metastatic breast cancer. Cremophor has also contributed to bone marrow suppression and neural toxicity. In Abraxane, the Taxol is broken up into tiny “nanoparticles,” coated with albumin, a natural “transport” substance in the body. This patented NAB process may also be adaptable for other chemotherapy drugs, like Taxotere®, (docetaxel).
In a randomized Phase III trial presented in San Antonio comparing Abraxane with Taxol in 454 metastatic breast cancer patients, the newer formulation produced significantly higher response rates and longer time to disease progression. [O’Shaughnessy 44] There was, however, greater peripheral neuropathy at the somewhat larger Taxol doses the Abraxane formulation permitted, but the neuropathy resolved more quickly than it did with Taxol. Surprisingly, blood counts generally were better with Abraxane, despite the increased dose. Once this drug is FDA approved—said to be likely early in 2004—we’ll have to see how much of a struggle insurance coverage presents, especially for Medicare patients.
Taxol and Taxotere the taxane chemotherapies, played a role in a number of other studies worthy of mention. Edith Perez, of the Mayo Clinic, Jacksonville, compared two different schedules of Taxol, Carboplatin® and Herceptin® in a randomized Phase II study as first-line treatment in 96 metastatic breast cancer patients with HER2-positive tumors, and found that delivering this combination therapy every week was both less toxic and more effective than the usual every-three-weeks regimen. [Perez 216]
This study adds to other favorable results that have been mounting for years, both in adjuvant and metastatic treatment, which generally support more frequent administration of both single agent and combination chemotherapy regimens, usually referred to as “dose dense.”
In a study of adjuvant treatment, done in Italy with 1,214 primary node-positive and high-risk node negative breast cancer patients, the women were randomized to receive standard FEC (the “E” is epirubicin, used in some other countries instead of Adriamycin®) every three weeks, vs. FEC every two weeks, with Neupogen® support. [Venturini 12] After nearly 7 years of follow-up, a modest but not statistically significant benefit of the two-week regimen was found for the entire group. Patients under 50 showed the most benefit, while patients over 60 did worse with the accelerated regimen.
One widely held theory is that the dose-dense effect is related to angiogenesis, because both the tumor and its blood supply are thought to be targeted by more frequent doses. Many chemotherapy and other drugs have been shown to decrease the blood supply in tumors. So-called “metronomic” studies using frequent low doses of angiogenesis inhibitors have been initiated to look at whether tumor growth can be controlled in this way.
A 1,500-woman trial by the Breast Cancer International Research Group (BCIRG) looked at four-year disease-free and overall survival in node-positive primary breast cancer patients who had been randomized to receive adjuvant chemotherapy consisting of either FAC or TAC, in which Taxotere substitutes for 5-FU, along with Adriamycin and Cytoxan®. [Martin 43] Both disease-free and overall survival were significantly improved by the Taxotere in TAC. This finding offers further confirmation to the established benefit of adding one of the taxane drugs to the standard AC regimen for patients with node-positive cancers. However, the Taxotere combination caused more moderate to serious (Grade 3 and 4) hematological toxicities, like febrile neutropenia, for which support with Neupogen or Neulasta® may be needed.
In a drug company sponsored trial, Taxotere (docetaxel) offered a longer time to disease progression over Taxol (paclitaxel) in metastatic breast cancer patients who took these drugs on a 3-weekly regimen, but at the expense of greater toxicities. Given the potential impact of the sometimes severe side-effects on quality of life, an increase of two months in time to disease progression with the Taxotere may not offer enough to most women with metastatic breast cancer, at least in the relatively high doses used in this regimen. [Jones 10] Weekly administration of both Taxol and Taxotere is seen as less toxic, and at some hospitals, doctors are studying alternate weekly dosing of the two taxane drugs, in an effort to reduce toxicities still further.
What’s New in Hormonal Treatments?
In an Italian study, 426 postmenopausal patients with node-positive, ER+ breast cancers who had been taking tamoxifen for two to three years were randomized to either continue on tamoxifen, or to switch to Arimidex® (anastrozole) for the remainder of five years. After two years of follow-up, patients who switched to Arimidex had one third the number of recurrences, and there were fewer deaths as well. [Boccardo 3] While the short-term results of a single study like this may not influence a widespread change in clinical practice, this trial’s findings add meaningfully to the results of other similar larger trials that have examined aromatase inhibitors as adjuvant treatment.
Of particular interest were the findings of the recently halted MA-17 trial, a much larger study of 5,187 patients in which Femara® (letrozole) was found to further reduce recurrence in postmenopausal women with node-positive ER+ breast cancer who had already completed five years of tamoxifen. In this year’s San Antonio meeting, updated quality-of-life results were presented from this study. [Goss 42] Most frequently reported side effects involved pain in muscles and joints (myalgia, arthralgia), mild hot flashes, and increases in osteoporosis. It should be emphasized that optimal length of dosage with Femara, as well as its long-term safety, have yet to be established. As with other treatments, those patients most likely to benefit from additional Femara after five years of tamoxifen are those at most at risk of recurrence.
The ATAC trial, which has been news for three years at the San Antonio meeting, reported some provocative new findings. This 9,000-woman trial, comparing Arimidex with tamoxifen as adjuvant therapy, has generally found that Arimidex prevented more recurrences. While most attention has been paid to the estrogen receptor, the activity of the progesterone receptor (PgR) was also measured in these patients, as it is routinely in breast cancers. The new results of a sub-group analysis [Dowsett 4] indicate that most of the benefit of Arimidex over tamoxifen was found in the 16% of patients with ER-positive, PgR-negative tumors. This finding, if it holds up over time, may help patients in making their treatment decisions.
Every year, it seems, at least one European study demonstrates that hormonal treatments are equivalent to chemotherapy in ER-positive breast cancers in pre- and peri-menopausal women. This year, a German study in premenopausal patients with node-positive ER-positive cancers showed the same benefits from an LHRH-analogue (similar to Lupron® or Zoladex® here in the US, which shut down ovarian function) administered every three months for two years as it did for CMF chemotherapy. [Untch 40] In the US, however, CA (Cytoxan, Adriamycin) has generally replaced CMF (Cytoxan, Methotrexate®, 5-FU) as standard chemotherapy in recent years because of slightly better results, perhaps in part because HER2-positive cancers respond better to CA.
Research on other methods for predicting recurrence that don’t rely on genomic analysis has been moving forward. Several studies examined data on the use of Ki-67, a promising marker of cell proliferation. Data suggesting bone marrow status may turn out to be a good marker of recurrence for invasive breast cancer has been accumulating, but studies have often been too small for definitive conclusions. German researchers pooled the data from 4,200 patients in eight previous studies of bone marrow status as a prognostic factor, to examine the impact of occult cancer cells in bone marrow, often called micrometastases, as a predictor of survival at 10 years. [Braun 7] While pooling data from smaller studies may offer more statistical power, this method of analysis is considered less reliable than that of a larger prospective study. That said, in this study, the presence of cancer cells in bone marrow was indeed found to be an independent predictor of overall survival, especially for patients who had not received adjuvant treatment.
A small Dutch study examined the prognostic value of micrometastases in sentinel node biopsies of 66 patients diagnosed with ductal carcinoma in situ. [Wijsman 9] After 3-10 years, all women in this study with DCIS only remained free of disease without adjuvant therapy. The authors concluded that full axillary lymph node dissection was not necessary for DCIS patients when micrometastases are found in the sentinel node.
Musa Mayer is a 14-year survivor and the author of four books including, most recently, After Breast Cancer: Answers to the Questions You’re Afraid to Ask (O’Reilly, 2003). She provides information and support for women with metastatic breast cancer daily at www.bclist.org and www.bcmets.org.