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Letter to the Editor

OB/GYN June 2003

Misunderstood Findings?

To The Editor:

I read with great interest Dr Birge’s response to question 3 in your January 2003 issue (Birge SJ. The faculty speaks: questions & answers. The Female Patient. 2003;28(2 suppl):21). I have a few comments. First, the statement that Dr Fisher¹ found a doubling of the occurrence of breast cancer in an additional 5 years is not what I read. “Through 7 years after reassignment to either placebo or continued tamoxifen, a slight advantage was observed in patients who discontinued tamoxifen relative to those who continued to receive it: DFS = 82% vs 78%, RFS = 94% vs 91%.” Where is the 80% increase in mortality? Next Birge states that Jordan² gave raloxifene to women who had been on tamoxifen. My reading of Jordan and O’Regan’s³ work was that they used breast cancer cells inserted into mice and then gave the mice estrogen to stimulate growth followed by tamoxifen and raloxifene. Hardly an evidence-based meaningful study. To glibly state that raloxifene taken for the long term may increase a woman’s risk of breast cancer is at best a premature and at worst criminal.

Kenneth A. Baer, MD
Miami, Fla

References

1. Fisher B, Dignam J, Bryant J, et al. Five versus more than five years of tamoxifen therapy for breast cancer patients with negative lymph nodes and estrogen receptor-positive tumors. J Nat Cancer Inst. 1988;88: 1529-1542.
2. Jordan VC, Gapstur S, Morrow S. Selective estrogen receptor modulation and reduction in risk of breast cancer, osteoporosis, and coronary heart disease. J Nat Cancer Inst. 2001;93(19):1449-1457.
3. O’Regan RM, Gajdos C, Dardes RC, et al. Effects of raloxifene after tamoxifen on breast and endometrial tumor growth in athymic mice. J Natl Cancer Inst. 2002 Feb 20;94(4):274-83
   

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The Author Responds

The remarks of Dr Baer are appreciated. However, after reviewing the article by Fisher et al,¹ I was unable to find the statement quoted. It would appear that Dr Baer intended to quote the statement on page 1,535 of the Fisher article: “through 4 years following the second randomization (to either placebo or additional 5 years of tamoxifen), the DFS (disease free survival) of patients who switched from tamoxifen to placebo was 92% compared to 86% for those who continued to receive tamoxifen (P=0.003).” The authors go on to state (p 1535-1536) that the “average annual recurrence rate per 1,000 patients among the tamoxifen-treated women in the second randomization was 35.4, for those who received the placebo, it was 19.3.” With respect to mortality, Fisher et al indicate on page 1,537 that those treated with tamoxifen for an additional 5 years experienced 25 deaths compared to 14 deaths in the placebo group—a 79% (to be more exact) increase in mortality with the continuation of tamoxifen. I would not characterize these differences as “slight.”

With respect to raloxifene’s effects on breast cancer, Jordan et al,² page 1,454, write: “Tamoxifen-stimulated breast cancer is well recognized (in patients) and provides the rationale for stopping tamoxifen therapy at 5 years. Raloxifene has been shown to promote the growth of tamoxifen-stimulated tumors in the laboratory raising concern about its use (clinically).” The US Preventive Services Task Force has recommended that both tamoxifen and raloxifene not be used to prevent breast cancer in women at average risk of breast cancer and expressed concerns about their use in high risk patients.³

I agree with Dr Baer that we should practice evidenced-based medicine. Unfortunately, the only evidence that we have to guide us is that long-term raloxifene therapy may increase the incidence of and mortality from breast cancer.

Stanley J. Birge, MD
Washington University School of Medicine
St. Louis, Mo

References

1. Fisher B, Dignam J, Bryant J, et al. Five versus more than five years of tamoxifen therapy for breast cancer patients with negative lymph nodes and estrogen receptor positive tumors. J Natl Cancer Inst. 1996;88: 1529-1542.
2. Jordan VC, Gapstur S, Morrow M. Selective estrogen receptor modulation and reduction in risk of breast cancer, osteoporosis, and coronary heart disease. J Natl Cancer Inst. 2001;93:1449-1457.
3. US Preventive Services Task Force. Chemoprevention of breast cancer: Recommendations and rationale. Ann Internal Med. 2002;137:56-58.

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Wrong Ring Cited

To The Editor:

Your March article regarding new contraceptive methods is greatly appreciated.¹ However, I must correct one point. In the section regarding NuvaRing (etonogestrel/ethinyl estradiol vaginal ring), it was stated that many users experience nausea during the first cycle of use and that this side effect can be avoided by soaking the ring in water overnight prior to its first use.

This information pertains not to NuvaRing, but to an unrelated, investigational contraceptive vaginal ring that releases ethinyl estradiol along with a different progestin, norethindrone acetate.² With NuvaRing, the incidence of nausea is low. In the Phase III clinical trials, the incidence of drug-related nausea was only 3.2% and users were not instructed to soak their rings prior to use.³

The vaginal route of administration allows for a continuous release of the lowest daily dose of ethinyl estradiol in combined hormonal contraception. These characteristics of NuvaRing are reflected in its low incidence (see above) of estrogen-related side effects. The fact, moreover, that NuvaRing can be removed from its packaging and inserted in the vagina without any additional manipulations makes it user friendly and convenient.

Nancy J. Alexander, PhD
Director, Contraception & Andriol Medical Affairs
Organon Pharmaceuticals
USA Inc.

References

1. Paladine H. What’s new in contraception. The Female Patient. 2003;28: 20-24.
2. Weisberg E, Fraser IS, Lacarra M, Mishell DR Jr, Jackanicz T. Effect of different insertion regimens on side effects with a combination contraceptive vaginal ring. Contraception. 1997; 56:233-239.
3. Dieben TOM, Roumen FJME, Apter D. Efficacy, cycle control, and user acceptability of a novel combined contraceptive vaginal ring. Obstet Gynecol. 2002;100:585-593.

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