Systemic Therapy for Older Women With Breast Cancer
Systemic Therapy for Older Women With Breast Cancer
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 (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 (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 (Arimidex) is at least as good or better than tamoxifen in terms of response rates, time to progression, and toxicity. Moreover, letrozole (Femara) even more convincingly shows statistically significant benefits compared with tamoxifen, both in metastatic and locally advanced breast cancer. In addition, 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 at doses of 15 to 20 mg/m2 is well tolerated except for alopecia and the possible need for a venous access device. 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 (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 (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 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 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 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, 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.
1. Bonneterre J, Thurlimann B, Robertson JFR, et al: Anastrozole vs tamoxifen as first-line therapy for advanced breast cancer in 668 post-menopausal women: Results of the tamoxifen or Arimidex randomized group efficacy and tolerability study. J Clin Oncol 8:3748-3757, 2000.
2. Nabholtz JM, Buzdar A, Pollak M, et al: Anastrozole is superior to tamoxifen as first-line therapy for advanced breast cancer in post-menopausal women: Results of a North American multicenter randomized trial. J Clin Oncol 18:3758-3767, 2000.
3. Mouridsen H, Perez-Carrion R, Becquart D, et al: Letrozole (Femara) vs tamoxifen: Preliminary data of a first-line clinical trial in post-menopausal women with locally advanced or metastatic breast cancer (abstract 220). Eur J Cancer 36(5):S-88, 2000.
4. Paepke S, Apffelstaedt J, Eremin J, et al: Neoadjuvant treatment of post-menopausal breast cancer patients with letrozole (Femara): A randomized study vs tamoxifen (abstract 179). Eur J Cancer 36(5):S-76, 2000.
5. Paridaens R, Dirix L, Lohrisch C, et al: Promising activity and safety of exemestane as first-line hormonal therapy in metastatic breast cancer patients: Final results of an EORTC randomized phase II trial (abstract 167). Breast Cancer Res Treat 64(1):52, 2000.
6. Baselga J: Randomized double-blind phase II study of a selective estrogen receptor modulator LY 353381 in patients with locally advanced or metastatic breast cancer (abstract 25). Breast Cancer Res Treat 57(1):31, 1999.
7. Howell A, Osborne K, Morris, et al: ICI 182, 780 (Faslodex): Development of a novel "pure" antiestrogen. Cancer 89:817-825, 2000.
8. Erdkamp F, Chan S, Davidson N, et al: Phase III study of TLC D-99 (liposome-encapsulated doxorubicin) plus cyclophosphamide vs epirubicin plus cyclophosphamide in patients with metastatic breast cancer (abstract 459). Proc Am Soc Clin Oncol 18:121a, 1999.
9. Shapiro CL, Ervin T, Welles L, et al: Phase II trial of high-dose liposome-encapsulated doxorubicin with granulocyte colony-stimulating factor in metastatic breast cancer. J Clin Oncol 17:1435-1441, 1999.
10. Valero V, Buzdar A, Theriault RL, et al: Phase II trial of liposome-encapsulated doxorubicin, cyclophosphamide, and fluorouracil as first-line therapy in patients with metastatic breast cancer. J Clin Oncol 17:1425-1434, 1999.
11. Batist G, Harris L, Azarnia N, et al: Improved therapeutic index of TLC-99 (liposomal-encapsulated doxorubicin) compared to free doxorubicin in first-line treatment of metastatic breast cancer in patients who had received prior adjuvant doxorubicin (abstract 405). Proc Am Soc Clin Oncol 19:105a, 2000.
12. Ransom MR, Carmichael J, Byrne O, et al: Treatment of advanced breast cancer with sterically stabilized liposomal doxorubicin: Results of a multicenter phase II trial. J Clin Oncol 15:3185-3191, 1997.
13. Lyass O, Uziely B, Ben-Yosef R, et al: Correlation of toxicity with pharmacokinetics of pegylated liposomal doxorubicin (Doxil) in metastatic breast carcinoma. Cancer 89:1037-1047, 2000.
14. Safra T, Muggia F, Jeffers S, et al: Pegylated liposomal doxorubicin (Doxil): Reduced clinical cardiotoxicity in patients reaching or exceeding cumulative doses of 500 mg/m2. Ann Oncol 11:1029-1033, 2000.
15. O’Shaughnessy J, Blum J: A retrospective evaluation of the impact of dose reduction in patients treated with Xeloda (capecitabine) (abstract 400). Proc Am Soc Clin Oncol 19:104a, 2000.
16. Michaud LB, Gauthier MA, Wojoylo JR, et al: Improved therapeutic index with lower-dose capecitabine in metastatic breast cancer patients (abstract 402). Proc Am Soc Clin Oncol 19:104a, 2000.
17. Perez E, Irwin DH, Patel R, et al: A large phase II trial of paclitaxel administered as a weekly one-hour infusion in patients with metastatic breast cancer (abstract 480). Proc Am Soc Clin Oncol 18:126a, 1999.
18. Bishop J, Dewar J, Toner GC, et al: Initial paclitaxel improves outcome compared with CMFP combination chemotherapy as front-line therapy in untreated metastatic breast cancer. J Clin Oncol 17:2355-2364, 1999.
19. Sledge GW, Neuberg D, Ingle J, et al: Phase III trial of doxorubicin vs paclitaxel vs doxorubicin + paclitaxel as first-line therapy for metastatic breast cancer: An intergroup trial (abstract 2). Proc Am Soc Clin Oncol 16:1a, 1997.
20. Gamucci T, Piccart M, Bruning P, et al: An EORTC crossover trial comparing single-agent Taxol and doxorubicin as first- and second-line chemotherapy in advanced breast cancer (abstract 539). Proc Am Soc Clin Oncol 16:154a, 1997.
21. Vogel CL, Cobleigh M, Tripathy D, et al: First-line, non-hormonal treatment of women with Her 2 overexpressing metastatic breast cancer with Herceptin (trastuzumab, humanized anti-Her 2 antibody) (abstract 275). Proc Am Soc Clin Oncol 19:71a, 2000.
22. Seidman A, Fornier M, Esteva F, et al: Final report. Weekly Herceptin and Taxol for metastatic breast cancer: Analysis of efficacy by Her-2 immunophenotype (immunohistochemistry) and gene amplification (fluorescent in-situ hybridization) (abstract 319). Proc Am Soc Clin Oncol 19:83a, 2000.
23. Burstein HJ, Kuter I, Richardson PG, et al: Herceptin and vinorelbine for Her 2 positive metastatic breast cancer: A phase II study (abstract 392). Proc Am Soc Clin Oncol 19:102a, 2000.