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Paradigm Shift in Adjuvant Treatment of Receptor Positive Premenopausal Breast Cancer Patients? Not Yet!

Akdeniz University Division of Medical Oncology, Antalya, Turkey

To the Editor:

We read with great interest the two articles and the editorial in the December 15, 2002 issue of the Journal of Clinical Oncology, concerning adjuvant hormonal treatment of breast cancer.^1–3 In both studies, the authors compared a "standard" cyclophosphamide, methotrexate fluorouracil– (CMF-) only treatment arm with goserelin¹ or goserelin plus tamoxifen.² According to Jonat et al,¹ "goserelin offers an effective, well-tolerated alternative to CMF chemotherapy in the management of premenopausal patients with ER- [estrogen receptor–] positive and node-positive early breast cancer." According to Jakesz et al,² "complete endocrine blockade with goserelin and tamoxifen is superior to standard chemotherapy in premenopausal women with hormone-responsive stage I and II breast cancer." In the editorial commenting on these two studies, Kathleen Pritchard asked, "Is it time for another paradigm shift?"³

If this question is asked in the context of the previously mentioned studies, the answer might be, "Not yet." Let us repeat what we all know. First, anthracycline-containing regimens yield superior results, both for recurrence-free survival (absolute difference at 5 years, 3.2%) and overall survival (absolute difference at 5 years, 2.7%).⁴ In both the Jonat et al and Jakesz et al studies, the control arm was patients receiving CMF. We know that 4 months of doxorubicin and cyclophosphamide is clearly equivalent to 6 months of CMF⁵; however, we also know that there are regimens that are clearly superior to CMF^6,7 that have been defined in previously reported studies.⁸

Second, tamoxifen was associated with a highly significant improvement in recurrence-free survival (absolute difference at 10 years, 14.9%–15.2%) and in overall survival (absolute difference at 10 years, 5.5%–10.9%) in ER-positive women.⁹ In the article by Jonat et al¹ and in the accompanying editorial,³ it was acknowledged that there were only 177 women with ER-positive disease who were randomly selected to chemotherapy, or to chemotherapy plus tamoxifen in the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) overview. According to the Jonat et al and the accompanying editorial, although widely used in practice, not enough data were available to support the addition of tamoxifen after standard chemotherapy in premenopausal patients, and this argument was used as a justification for lack of tamoxifen use in the control groups. However, both in the recently published studies, as well as in all other studies cited in the editorial that compared ovarian ablation with chemotherapy (mostly with CMF), the chemotherapy plus tamoxifen regimen is apparently lacking. So "177" is better than "zero," and as a general rule, absence of proof does not mean proof of absence. On the other side, Jakesz et al,² in addressing the choice of treatment in the control arm, stated that when Austrian Breast and Colorectal Cancer Study Group Trial 5 was launched in 1990, the data of the EBCTGG overview were largely unknown; therefore, CMF-only, the chemotherapeutic regimen of choice at that time, was chosen. However, knowing the data at present, we do not accept CMF without tamoxifen as a "standard" in this group, and so we can not come to the same conclusion of Jakesz et al, who reported that "complete endocrine blockade with goserelin and tamoxifen is superior to standard chemotherapy in premenopausal woman with hormone responsive stage I and II breast cancer". We still do not know what is the "best standard" chemotherapy for lymph node–positive, ER-positive premenopausal breast cancer; however, we absolutely know what is not. CMF without tamoxifen is clearly not a sufficient treatment in this group of patients. Studies with a control arm of anthracycline-based chemotherapy plus tamoxifen are definitely and urgently needed in order that the conclusions of Jakesz et al be better received.

After reading the results of these two trials, we draw a conclusion that is different from those reported. Ovarian ablation with goserelin is equivalent to CMF without tamoxifen, and goserelin plus tamoxifen is more effective than CMF without tamoxifen. If one has a premenopausal patient with ER-positive, lymph node–positive breast cancer, goserelin plus tamoxifen is a good alternative to treating her with intravenous CMF without tamoxifen while achieving the same results. Is there anyone who would treat such a patient with CMF only?

REFERENCES

1. Jonat W, Kaufmann M, Sauerbrei W, et al: Goserelin versus cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy in premenopausal patients with node-positive breast cancer: The Zoladex Early Breast Cancer Research Association study. J Clin Oncol 20:4628–4635, 2002[Abstract/Free Full Text]

2. Jakesz R, Hausmaninger H, Kubista E, et al: Randomized adjuvant trial of tamoxifen and goserelin versus cyclophosphamide, methotrexate, and fluorouracil: Evidence for the superiority of treatment with endocrine blockade in premenopausal patients with hormone-responsive breast cancer—Austrian Breast and Colorectal Cancer Study Group Trial 5. J Clin Oncol 20:4621–4627, 2002[Abstract/Free Full Text]

3. Pritchard KI. Adjuvant therapy for premenopausal women with breast cancer: Is it time for another paradigm shift? J Clin Oncol 20:4611–4614, 2002[Free Full Text]

4. Polychemotherapy for early breast cancer: An overview of the randomized trials—Early Breast Cancer Trialists’ Collaborative Group. Lancet 352:930–942, 1998[CrossRef][Medline]

5. Fisher B, Brown AM, Dimitrov NV, et al: Two months of doxorubicin-cyclophosphamide with and without interval reinduction therapy compared with 6 months of cyclophosphamide, methotrexate, and fluorouracil in positive-node breast cancer patients with tamoxifen-nonresponsive tumors: Results from the National Surgical Adjuvant Breast and Bowel Project B-15. J Clin Oncol 8:1483–1496, 1990[Abstract]

6. Levine MN, Bramwell VH, Pritchard KI, et al: A randomized trial of cyclophosphamide, epirubicin, fluorouracil chemotherapy compared with cyclophosphamide, methotrexate, fluorouracil in premenopausal women with node-positive breast cancer. J Clin Oncol 16:2651–2658, 1998[Abstract]

7. Coombes RC, Bliss JM, Wils J, et al: Adjuvant cyclophosphamide, methotrexate and fluorouracil versus fluorouracil, epirubicin and cyclophosphamide chemotherapy in premenopausal women with axillary node-positive operable breast cancer: Results of a randomized trial. J Clin Oncol 14:35–45, 1996[Abstract]

8. Nabholtz J-M, Pienkowski T, Mackey J, et al: Phase III trial comparing TAC (docetaxel, doxorubicin, cyclophosphamide) with FAC (5-fluorouracil, doxorubicin, cyclophosphamide) in the adjuvant treatment of node positive breast cancer (BC) patients: Interim analysis of the BCIRG 001 study. Proc Am Soc Clin Oncol 21: 36a, 2002 (abstr 141)

9. Tamoxifen for early breast cancer: An overview of the randomised trials: Early Breast Cancer Trialists’ Collaborative Group. Lancet 351:1451–1467, 1998 [CrossRef][Medline]

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This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Samur, M. Articles by Bozcuk, H. S. Search for Related Content PubMed PubMed Citation Articles by Samur, M. Articles by Bozcuk, H. S. Social Bookmarking                            What's this?