Systemic Therapy for Older Women With Breast Cancer

March 1, 2001

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.

This superb review by Drs. Kimmick andMuss clearly and concisely summarizes the literature on the prevention andtreatment of breast cancer in "older" women.

In their discussions of prevention, the authors acknowledge thelimitations in the literature created by the relative lack of accrual of olderwomen into clinical trials. Nonetheless, they provide a clear discussion andcomparison of the three major tamoxifen (Nolvadex) prevention trials, whilecontinually emphasizing the need for clinical trials (and the particular need toenroll older women in such trials). Although Drs. Kimmick and Muss emphasize thevalue of enrolling in the Study of Tamoxifen and Raloxifene (STAR) trial, theyalso 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 concisesummary of the complexities of the trialists’ 1998 overview of adjuvantsystemic therapy. In Tables 3 through 5, the authors again providepracticing oncologists with valuable tools for counseling older women onadjuvant therapeutic options. In particular, data in Table 3 indicatethat the long-term adjuvant chemotherapy benefits in reducing the risk ofrecurrence in older women appear to be only one-half to one-third the benefit inyounger women. Thus, while it is clear that chemotherapy does add to thebenefits of tamoxifen in hormone-receptor-positive older patients, themagnitude of that additional benefit is modest.

In contrast to the in-depth discussion in the sections onprevention and adjuvant therapy, the section on metastatic disease relies moreheavily on references to other review articles for more specificrecommendations. I agree completely with the author’s strategy for thetreatment of metastatic disease in older women (as summarized in Table 7)but would like to have seen more specific recommendations for choosing among thechemotherapeutic agents. Also, we are poised on the verge of a paradigm shift inhormonal therapy, and this would have been worth a few sentences of discussion.

Emerging Hormonal Therapies

Tamoxifen has long dominated the field of hormonal management ofmetastatic breast cancer, but this is likely to change very soon. Controlledrandomized trials now suggest that anastrozole (Arimidex) is at least as good[1]or better[2] than tamoxifen in terms of response rates, time to progression, andtoxicity. Moreover, letrozole (Femara) even more convincingly showsstatistically significant benefits compared with tamoxifen, both inmetastatic[3] and locally advanced[4] breast cancer. In addition, exemestane(Aromasin) also appeared to show superiority over tamoxifen in a smaller pilottrial.[5] Thus, I would predict that by the end of 2001 there will be morewidespread use of the aromatase inhibitors and inactivators as first-linehormonal therapy for metastatic breast cancer.

Because results in the adjuvant setting frequently mirror thosein metastatic disease, ongoing adjuvant trials, when mature, may alsodemonstrate the superiority of the aromatase inhibitors over tamoxifen inearly-stage breast cancer. Even while this paradigm shift is occurring, stillother selective estrogen-receptor modulators (SERMs)[6] and selectiveestrogen-receptor downregulators (SERDs) such as fulvestrant (Faslodex) are alsochallenging for positions in the hormonal therapeutic cascade.[7]

Cytotoxic Options

The authors mention the different cytotoxic compounds availablefor palliation but do not provide guidance in choosing among them. I generallyagree with the use of sequential single agents as opposed to combinationchemotherapy in the palliative setting, and largely chose among the availabledrugs on the basis of their toxicity profiles. It is likely that many of thesesingle agents will produce antitumor responses in 30% to 40% of women asfirst-line therapy and 20% as second-line therapy, with selected studies showingmeaningful palliative benefit for their use as third-line options and beyond.

Among the anthracyclines and anthraquinones, some have bettertoxicity profiles than others. Weekly doxorubicin at doses of 15 to 20 mg/m2is well tolerated except for alopecia and the possible need for a venous accessdevice. Mitoxantrone (Novantrone) is also active and well tolerated but withoutthose disadvantages.

The liposomal doxorubicin preparations are also attractivealternatives, although they raise an interesting paradox. The best studied ofthe liposomal compounds in breast cancer patients, TLC D-99 appears to showequivalence to doxorubicin with less toxicity.[8-11] Unfortunately, the drug hasnot yet been approved by the Food and Drug Administration (FDA) for thisindication.

Conversely, while pivotal comparison trials against conventionaldoxorubicin have yet to be completed, the FDA-approved formulation of liposomaldoxorubicin (Doxil) can now be used for metastatic breast cancer. Although mostof the trials of liposomal doxorubicin in breast cancer have shown the drug toproduce inordinate toxicities (such as palmar-plantar erythrodysesthesias andstomatitis), either the doses used in these studies were too high or theintervals between doses were too short. In my experience, a dose of 40 mg/m2every 4 weeks is well tolerated and has produced clinical benefit in a number ofolder women.[12-14] If that dose produces toxicity, increasing the intervalbetween doses will result in better tolerance. My colleagues and I are about toinitiate a first-line trial of liposomal doxorubicin at this dose in older womenwith metastatic breast cancer.

Another excellent drug has also been associated with dosingproblems. Capecitabine (Xeloda), at the package insert dose of 2,510 mg/m2/dfor 14 days, more frequently than not causes undue toxicity especially in olderwomen. Others have published more tolerable doses,[15,16] but these have notbeen endorsed either by the manufacturer or the FDA because of the absence ofdata from prospectively designed phase II or III trials at lower doses.Nevertheless, many major US oncologists specializing in breast cancer routinelyemploy much lower starting doses under the assumption that these lower doses canstill be effective. In clinical practice, my routine starting dosage using thesame schedule cited earlier is usually 2 to 2.5 g/d (ie, not mg/m2)as a total dose.

The Taxanes

The taxanes, paclitaxel (Taxol) and docetaxel (Taxotere), arealso reasonably well-tolerated single agents, especially when given on a weeklybasis. Weekly paclitaxel at 80 mg/m2/wk hasproduced a 25% response rate when used as a single agent in first-line therapyfor metastatic disease.[17] 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 weeksin phase III trials.[18-20] The regimen is generally well tolerated andassociated with minimal myelosuppression (but also with alopecia and neuropathyafter more prolonged use).

Similarly, docetaxel is better tolerated on a weekly schedule at35 mg/m2/wk (usually given 3 out of 4 weeks)than when administered more intermittently. This agent induces alopecia andasthenia and is further compromised by the need for pre- and postadministrationof corticosteroids to prevent allergic reactions and minimize fluid retentionwith prolonged use. Just how much dexamethasone is needed with each dose remainscontroversial.

The Other Available Agents

As mentioned in the article, vinorelbine (Navelbine) has beenstudied specifically in older women, producing a credible response rate of 38%.Aside from neutropenia, the major problem associated with use of this drug isarm pain caused by peripheral administration. Vinorelbine is best administeredthrough a venous access device, which, in itself, can be another disadvantage ofthis otherwise excellent palliative drug. If the new oral vinorelbinepreparation is as active as the parenteral form, with a similar toxicityprofile, it could emerge as an important drug over the next few years.

Gemcitabine (Gemzar) is another well-tolerated drug withsignificant activity in breast cancer. Anecdotally, in the absence of manylarge-scale trials, it may be slightly less effective than many of the agentsdiscussed above.

Trastuzumab (Herceptin) also has an excellent side effectprofile for patients with HER2/neu gene amplification. Of criticalimportance in the use of trastuzumab is choosing the appropriate patient fortreatment. The published response rate is only 26% for trastuzumab as afirst-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 asurrogate for response improves clinical benefit to 47%. Combining traztusumabwith weekly paclitaxel or vinorelbine may increase this figure to nearly 70%,still with only modest toxicity.[21-23]

Conclusions

How then does one choose among these palliative single agents?Capecitabine can be given orally, and mitoxantrone and liposomal doxorubicin aregenerally 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, onecan factor in the differing toxicity profiles such as alopecia, neuropathy,myelosuppression, or the need for a venous access device when selecting the mostappropriate drug for an older woman. Of course, I, too, fully endorse theconcept 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 importantaddition to the literature pertaining to the treatment of breast cancer in olderwomen. It should be required reading for all oncologists.

References:

1. Bonneterre J, Thurlimann B, Robertson JFR, et al: Anastrozolevs tamoxifen as first-line therapy for advanced breast cancer in 668post-menopausal women: Results of the tamoxifen or Arimidex randomized groupefficacy and tolerability study. J Clin Oncol 8:3748-3757, 2000.

2. Nabholtz JM, Buzdar A, Pollak M, et al: Anastrozole issuperior to tamoxifen as first-line therapy for advanced breast cancer inpost-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 inpost-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: Neoadjuvanttreatment of post-menopausal breast cancer patients with letrozole (Femara): Arandomized study vs tamoxifen (abstract 179). Eur J Cancer 36(5):S-76, 2000.

5. Paridaens R, Dirix L, Lohrisch C, et al: Promising activityand safety of exemestane as first-line hormonal therapy in metastatic breastcancer patients: Final results of an EORTC randomized phase II trial (abstract167). Breast Cancer Res Treat 64(1):52, 2000.

6. Baselga J: Randomized double-blind phase II study of aselective estrogen receptor modulator LY 353381 in patients with locallyadvanced or metastatic breast cancer (abstract 25). Breast Cancer Res Treat57(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 TLCD-99 (liposome-encapsulated doxorubicin) plus cyclophosphamide vs epirubicinplus 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 ofhigh-dose liposome-encapsulated doxorubicin with granulocyte colony-stimulatingfactor in metastatic breast cancer. J Clin Oncol 17:1435-1441, 1999.

10. Valero V, Buzdar A, Theriault RL, et al: Phase II trial ofliposome-encapsulated doxorubicin, cyclophosphamide, and fluorouracil asfirst-line therapy in patients with metastatic breast cancer. J Clin Oncol17:1425-1434, 1999.

11. Batist G, Harris L, Azarnia N, et al: Improved therapeuticindex of TLC-99 (liposomal-encapsulated doxorubicin) compared to freedoxorubicin in first-line treatment of metastatic breast cancer in patients whohad received prior adjuvant doxorubicin (abstract 405). Proc Am Soc Clin Oncol19:105a, 2000.

12. Ransom MR, Carmichael J, Byrne O, et al: Treatment ofadvanced breast cancer with sterically stabilized liposomal doxorubicin: Resultsof a multicenter phase II trial. J Clin Oncol 15:3185-3191, 1997.

13. Lyass O, Uziely B, Ben-Yosef R, et al: Correlation oftoxicity with pharmacokinetics of pegylated liposomal doxorubicin (Doxil) inmetastatic breast carcinoma. Cancer 89:1037-1047, 2000.

14. Safra T, Muggia F, Jeffers S, et al: Pegylated liposomaldoxorubicin (Doxil): Reduced clinical cardiotoxicity in patients reaching orexceeding cumulative doses of 500 mg/m2. AnnOncol 11:1029-1033, 2000.

15. O’Shaughnessy J, Blum J: A retrospective evaluation of theimpact 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: Improvedtherapeutic index with lower-dose capecitabine in metastatic breast cancerpatients (abstract 402). Proc Am Soc Clin Oncol 19:104a, 2000.

17. Perez E, Irwin DH, Patel R, et al: A large phase II trial ofpaclitaxel administered as a weekly one-hour infusion in patients withmetastatic breast cancer (abstract 480). Proc Am Soc Clin Oncol 18:126a, 1999.

18. Bishop J, Dewar J, Toner GC, et al: Initial paclitaxelimproves outcome compared with CMFP combination chemotherapy as front-linetherapy in untreated metastatic breast cancer. J Clin Oncol 17:2355-2364, 1999.

19. Sledge GW, Neuberg D, Ingle J, et al: Phase III trial ofdoxorubicin vs paclitaxel vs doxorubicin + paclitaxel as first-line therapy formetastatic breast cancer: An intergroup trial (abstract 2). Proc Am Soc ClinOncol 16:1a, 1997.

20. Gamucci T, Piccart M, Bruning P, et al: An EORTC crossovertrial comparing single-agent Taxol and doxorubicin as first- and second-linechemotherapy in advanced breast cancer (abstract 539). Proc Am Soc Clin Oncol16:154a, 1997.

21. Vogel CL, Cobleigh M, Tripathy D, et al: First-line,non-hormonal treatment of women with Her 2 overexpressing metastatic breastcancer with Herceptin (trastuzumab, humanized anti-Her 2 antibody) (abstract275). Proc Am Soc Clin Oncol 19:71a, 2000.

22. Seidman A, Fornier M, Esteva F, et al: Final report. WeeklyHerceptin and Taxol for metastatic breast cancer: Analysis of efficacy by Her-2immunophenotype (immunohistochemistry) and gene amplification (fluorescentin-situ hybridization) (abstract 319). Proc Am Soc Clin Oncol 19:83a, 2000.

23. Burstein HJ, Kuter I, Richardson PG, et al: Herceptin andvinorelbine for Her 2 positive metastatic breast cancer: A phase II study(abstract 392). Proc Am Soc Clin Oncol 19:102a, 2000.