Ovarian Protection during Breast-Cancer Adjuvant Chemotherapy

Jonathan Frazier, PharmD Candidate 2015, Mercer University College of Pharmacy

Ovarian failure is often times a daunting concern for women of childbearing age with breast cancer due chemotherapy treatments being notorious for affecting menstrual status and fertility among premenopausal women diagnosed with breast cancer. Premenopausal women who undergo chemotherapy treatment for breast cancer may develop amenorrhea, the absence of menstruation, which can result in the potential loss of fertility, problems with sexual functioning, onset of menopausal symptoms, and exposure to the long-term health risk of early menopause.1

For some patients, these concerns can influence their treatment choices despite potential survival benefits. According to a self-complete questionnaire developed by the European Organization for Research and Treatment of Cancer (EORTC) Breast Cancer Group and the EORTC Quality of Life Department, out of 400 patients, 32 patients (8.2%) would refuse treatment (chemotherapy) if it meant if would reduce their fertility.2

Title: Goserelin for Ovarian Protection during Breast Cancer Adjuvant Chemotherapy3
Design Phase 3, international, randomized study; 257 participants
Objective To evaluate whether administration of the GnRH agonist goserelin with chemotherapy would reduce the rate of ovarian failure after adjuvant or neoadjuvant treatment of hormone-receptor-negative breast cancer
Study groups Two groups: chemotherapy alone and chemotherapy plus goserelin
Methods Patients were randomly assigned, in a 1:1 ratio, to standard adjuvant or neoadjuvant chemotherapy +/-goserelin 3.6 mg subcutaneously every four weeks beginning one week before the initial chemotherapy dose and was continued to within two weeks before or after the final chemotherapy dose. Randomization was stratified according to age (<40 versus 40 to 49 years) and chemotherapy regimen (3-4 cycles versus 6-8 cycles and anthracycline-based versus nonanthracycline-based).
Duration February 2004 to January 22, 2014
Primary Outcome Measure Rate of ovarian failure between the two treatment groups.
*Ovarian failure was defined as amenorrhea for the preceding six months and follicle stimulating hormone (FSH) levels in the post-menopausal range at two years. Patients who became pregnant were considered not to have ovarian failure.
Baseline Characteristics Chemotherapy alone (N=113): mean age 38.7 years
Chemotherapy regimen:
3-4 cycles; anthracycline-based 22 (19%), nonanthracycline-based 7 (6%)
6-8 cycles; anthracycline-based 80 (71%), nonanthracycline-based therapy 4 (4%)
Stages of cancer: stage I 32 (28%), stage II 52 (46%), stage IIIA 29 (26%), unknown 0
HER2 status: positive 19 (17%), negative 93 (83%), unknown 1 (1%)

Chemotherapy plus goserelin (N=105): mean age 37.6 years
Chemotherapy regimen:
3-4 cycles; anthracycline-based 24 (23%), nonanthracycline-based 5 (5%)
6-8 cycles; anthracycline-based 72 (69%), nonanthracycline-based 4 (4%)
Stages of cancer: stage I 23 (22%), stage II 55 (52%), stage IIIA 25 (24%) unknown 2 (2%)
HER2 status: positive 13 (13%), negative 90 (87%), unknown 2 (2%)

Results Ovarian failure:
A total of 15 of 69 (22%) patients in the chemotherapy alone group and 5 of 66 (8%) in the chemotherapy plus goserelin had protocol defined ovarian failure – odds ratio, 0.30l 95% CI, 0.09 to 0.97; one-side p=0.02, two-sided p=0.04.
Adverse Events Common Adverse Events: Chemotherapy alone: diarrhea 2, fatigue 1, hot flashes 17, irregular menses 2, degrease in libido 6, agitation 5, anxiety 4, depression 3, joint paint 2, muscle pain 2, headache 2, sweating 7, vaginal dryness 9
Chemotherapy plus goserelin: diarrhea 0, fatigue 2, hot flashes 33, irregular menses 7, degrease in libido 9, agitation 6, anxiety 9, depression 9, joint paint 0, muscle pain 1, headache 12, sweating 10, vaginal dryness 12
Serious Adverse Events: chemotherapy plus goserelin: thromboembolism 1
Percentage that Discontinued due to Adverse Evens: N/A
Study Author Conclusions Based on the results of the study, the authors concluded that the administration of a GnRH agonist during the course of chemotherapy protects ovarian function.

Patients suffering from breast cancer have enough going on in their lives without having to worry about the ability to start a family. The results of this study show that the use of a GnRH agonist for ovarian protection can help to decrease the burden that patients carry and save potential lives that would refuse treatment based on potential infertilely risk.

References
1. Partridge AH, Ruddy KJ. Fertility and adjuvant treatment in young women with breast cancer. Breast. 2007;16 Suppl 2:S175-81.
2. Senkus E, Gomez H, Dirix L, et al. Attitudes of young patients with breast cancer toward fertility loss related to adjuvant systemic therapies. EORTC study 10002 BIG 3-98. Psychooncology. 2014;23(2):173-82.
3. Moore HC, Unger JM, Phillips KA, et al. Goserelin for ovarian protection during breast-cancer adjuvant chemotherapy. N Engl J Med. 2015;372(10):923-32.

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