This superb review by Drs. Kimmick and Muss clearly and concisely summarizes the literature on the prevention and treatment of breast cancer in "older" women.
In their discussions of prevention, the authors acknowledge the limitations in the literature created by the relative lack of accrual of older women into clinical trials. Nonetheless, they provide a clear discussion and comparison of the three major tamoxifen(Drug information on tamoxifen) (Nolvadex) prevention trials, while continually emphasizing the need for clinical trials (and the particular need to enroll older women in such trials). Although Drs. Kimmick and Muss emphasize the value of enrolling in the Study of Tamoxifen and Raloxifene(Drug information on raloxifene) (STAR) trial, they also provide valuable suggestions for those who choose not to participate.
Adjuvant Therapeutic Options for Older Women
One of the greatest values of this article lies in its concise summary of the complexities of the trialists’ 1998 overview of adjuvant systemic therapy. In Tables 3 through 5, the authors again provide practicing oncologists with valuable tools for counseling older women on adjuvant therapeutic options. In particular, data in Table 3 indicate that the long-term adjuvant chemotherapy benefits in reducing the risk of recurrence in older women appear to be only one-half to one-third the benefit in younger women. Thus, while it is clear that chemotherapy does add to the benefits of tamoxifen in hormone-receptor-positive older patients, the magnitude of that additional benefit is modest.
In contrast to the in-depth discussion in the sections on prevention and adjuvant therapy, the section on metastatic disease relies more heavily on references to other review articles for more specific recommendations. I agree completely with the author’s strategy for the treatment of metastatic disease in older women (as summarized in Table 7) but would like to have seen more specific recommendations for choosing among the chemotherapeutic agents. Also, we are poised on the verge of a paradigm shift in hormonal therapy, and this would have been worth a few sentences of discussion.
Emerging Hormonal Therapies
Tamoxifen has long dominated the field of hormonal management of metastatic breast cancer, but this is likely to change very soon. Controlled randomized trials now suggest that anastrozole(Drug information on anastrozole) (Arimidex) is at least as good or better than tamoxifen in terms of response rates, time to progression, and toxicity. Moreover, letrozole(Drug information on letrozole) (Femara) even more convincingly shows statistically significant benefits compared with tamoxifen, both in metastatic and locally advanced breast cancer. In addition, exemestane(Drug information on exemestane) (Aromasin) also appeared to show superiority over tamoxifen in a smaller pilot trial. Thus, I would predict that by the end of 2001 there will be more widespread use of the aromatase inhibitors and inactivators as first-line hormonal therapy for metastatic breast cancer.
Because results in the adjuvant setting frequently mirror those in metastatic disease, ongoing adjuvant trials, when mature, may also demonstrate the superiority of the aromatase inhibitors over tamoxifen in early-stage breast cancer. Even while this paradigm shift is occurring, still other selective estrogen-receptor modulators (SERMs) and selective estrogen-receptor downregulators (SERDs) such as fulvestrant (Faslodex) are also challenging for positions in the hormonal therapeutic cascade.
The authors mention the different cytotoxic compounds available for palliation but do not provide guidance in choosing among them. I generally agree with the use of sequential single agents as opposed to combination chemotherapy in the palliative setting, and largely chose among the available drugs on the basis of their toxicity profiles. It is likely that many of these single agents will produce antitumor responses in 30% to 40% of women as first-line therapy and 20% as second-line therapy, with selected studies showing meaningful palliative benefit for their use as third-line options and beyond.
Among the anthracyclines and anthraquinones, some have better toxicity profiles than others. Weekly doxorubicin(Drug information on doxorubicin) at doses of 15 to 20 mg/m2 is well tolerated except for alopecia and the possible need for a venous access device. Mitoxantrone(Drug information on mitoxantrone) (Novantrone) is also active and well tolerated but without those disadvantages.
The liposomal doxorubicin preparations are also attractive alternatives, although they raise an interesting paradox. The best studied of the liposomal compounds in breast cancer patients, TLC D-99 appears to show equivalence to doxorubicin with less toxicity.[8-11] Unfortunately, the drug has not yet been approved by the Food and Drug Administration (FDA) for this indication.
Conversely, while pivotal comparison trials against conventional doxorubicin have yet to be completed, the FDA-approved formulation of liposomal doxorubicin (Doxil) can now be used for metastatic breast cancer. Although most of the trials of liposomal doxorubicin in breast cancer have shown the drug to produce inordinate toxicities (such as palmar-plantar erythrodysesthesias and stomatitis), either the doses used in these studies were too high or the intervals between doses were too short. In my experience, a dose of 40 mg/m2 every 4 weeks is well tolerated and has produced clinical benefit in a number of older women.[12-14] If that dose produces toxicity, increasing the interval between doses will result in better tolerance. My colleagues and I are about to initiate a first-line trial of liposomal doxorubicin at this dose in older women with metastatic breast cancer.
Another excellent drug has also been associated with dosing problems. Capecitabine(Drug information on capecitabine) (Xeloda), at the package insert dose of 2,510 mg/m2/d for 14 days, more frequently than not causes undue toxicity especially in older women. Others have published more tolerable doses,[15,16] but these have not been endorsed either by the manufacturer or the FDA because of the absence of data from prospectively designed phase II or III trials at lower doses. Nevertheless, many major US oncologists specializing in breast cancer routinely employ much lower starting doses under the assumption that these lower doses can still be effective. In clinical practice, my routine starting dosage using the same schedule cited earlier is usually 2 to 2.5 g/d (ie, not mg/m2) as a total dose.
The taxanes, paclitaxel(Drug information on paclitaxel) (Taxol) and docetaxel (Taxotere), are also reasonably well-tolerated single agents, especially when given on a weekly basis. Weekly paclitaxel at 80 mg/m2/wk has produced a 25% response rate when used as a single agent in first-line therapy for metastatic disease. This response rate is similar to the published 25% to 30% rate for paclitaxel when given by a 3- or 24-hour infusion every 3 weeks in phase III trials.[18-20] The regimen is generally well tolerated and associated with minimal myelosuppression (but also with alopecia and neuropathy after more prolonged use).
Similarly, docetaxel(Drug information on docetaxel) is better tolerated on a weekly schedule at 35 mg/m2/wk (usually given 3 out of 4 weeks) than when administered more intermittently. This agent induces alopecia and asthenia and is further compromised by the need for pre- and postadministration of corticosteroids to prevent allergic reactions and minimize fluid retention with prolonged use. Just how much dexamethasone(Drug information on dexamethasone) is needed with each dose remains controversial.
The Other Available Agents
As mentioned in the article, vinorelbine (Navelbine) has been studied specifically in older women, producing a credible response rate of 38%. Aside from neutropenia, the major problem associated with use of this drug is arm pain caused by peripheral administration. Vinorelbine is best administered through a venous access device, which, in itself, can be another disadvantage of this otherwise excellent palliative drug. If the new oral vinorelbine preparation is as active as the parenteral form, with a similar toxicity profile, it could emerge as an important drug over the next few years.
Gemcitabine (Gemzar) is another well-tolerated drug with significant activity in breast cancer. Anecdotally, in the absence of many large-scale trials, it may be slightly less effective than many of the agents discussed above.
Trastuzumab (Herceptin) also has an excellent side effect profile for patients with HER2/neu gene amplification. Of critical importance in the use of trastuzumab(Drug information on trastuzumab) is choosing the appropriate patient for treatment. The published response rate is only 26% for trastuzumab as a first-line single agent in women whose degree of HER2 expression is 2+ and 3+ (as determined by immunohistochemistry). However, selecting patients with 3+ overexpression and including stable disease for more than 6 months as a surrogate for response improves clinical benefit to 47%. Combining traztusumab with weekly paclitaxel or vinorelbine may increase this figure to nearly 70%, still with only modest toxicity.[21-23]
How then does one choose among these palliative single agents? Capecitabine can be given orally, and mitoxantrone and liposomal doxorubicin are generally given on a more intermittent schedule than the taxanes, gemcitabine(Drug information on gemcitabine), and vinorelbine (which are best tolerated and administered on a weekly basis). In addition to choosing on the basis of route or schedule of administration, one can factor in the differing toxicity profiles such as alopecia, neuropathy, myelosuppression, or the need for a venous access device when selecting the most appropriate drug for an older woman. Of course, I, too, fully endorse the concept of clinical trials specifically geared to older women and, as mentioned, our next phase II trial will study liposomal doxorubicin in this population.
In conclusion, Drs. Kimmick and Muss have provided an important addition to the literature pertaining to the treatment of breast cancer in older women. It should be required reading for all oncologists.