Ovarian Function in Premenopausal Women Treated With Adjuvant Chemotherapy for Breast Cancer

REVIEW ARTICLE Ovarian Function in Premenopausal Women Treated With Adjuvant Chemotherapy for Breast Cancer By Jos6 Bines, Denise M. Oleske, and Melo...
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REVIEW ARTICLE

Ovarian Function in Premenopausal Women Treated With Adjuvant Chemotherapy for Breast Cancer By Jos6 Bines, Denise M. Oleske, and Melody A. Cobleigh Purpose: Adjuvant chemotherapy for breast cancer causes significant changes in ovarian function. More young women survive breast cancer than ever before and they are at risk of the sequelae of early menopause. We attempted to (1) define menopausal status in the setting of adjuvant chemotherapy; (2) define chemotherapy-related amenorrhea (CRA); (3) document rates of permanent amenorrhea, temporary amenorrhea, and oligomenorrhea among different regimens; and (4) analyze variables that influence ovarian function. Design: We reviewed reports of the effects of adjuvant chemoWerapy for breast cancer on ovarian function in premenopausal women. We searched Medline and Cancerlit from 1966 to 1995 on the following terms: breast neoplasms; chemotherapy, adjuvant; menstruation disorders; premature menopause; and amenorrhea. Further references were obtained from reports retrieved in the initial search.

Results: A uniform definition of menopause and CRA is lacking. The wide range of CRA rates reported in adjuvant chemotherapy trials is a result, at least in part, of this problem. The average CRA rate reported in regimens based on cyclophosphamide, methotrexate, and fluorouracil (CMF) is 68% (95%confidence interval [CI], 66% to 70%), with a range of 20% to 100%. CRA incidence varies with age, cytotoxic agent, and cumulative dose. Conclusion: Ovarian damage is the most significant long-term sequela of adjuvant chemotherapy in premenopausal breast cancer survivors. We suggest a common definition of the following important terms: menopausal status, CRA (early and late), temporary CRA, and oligomenorrhea in the setting of adjuvant treatment. With uniform definitions in place, regimens can be more precisely compared with respect to this important complication. J Clin Oncol 14:1718-1729. C 1996 by American Society of Clinical Oncology.

REAST CANCER is the most common malignancy among women, predicted to affect approximately 184,000 individuals in the United States in 1995. It is the second most common cause of cancer death in women, with an estimated 46,000 deaths in the same year. 1 Adjuvant chemotherapy prolongs disease-free survival and overall survival of patients with breast cancer.2 At the same time, it has been shown that cytotoxic drugs can cause premature menopause."3 Seven percent of breast cancer occurs by the age of 408 and nearly 25% of all women diagnosed with breast cancer are premenopausal.8 10 These women are more likely to be concerned about preservation of ovarian function. Premature menopause is associated with a wide array of problems that include the following: (1) vasomotor-hot flashes and night sweats; (2) psychosocial--mood swings and disrupted sleep; (3) genitourinary -atrophic vaginitis, dyspareunia, dysuria, and urinary frequency;

(4) skeletal-osteoporosis with resultant fractures; (5) cardiovascular disease (CVD)"; and (6) infertility. The beneficial effects of hormone replacement therapy (HRT) are well documented. The Food and Drug Administration (FDA) has approved HRT for the following indications: relief of vasomotor symptoms, vulvar and vaginal atrophy, and osteoporosis. HRT is contraindicated in breast cancer survivors, according to the FDA, so an understanding of the impact of various chemotherapy regimens on ovarian function is important.1 2 We reviewed reports of the effects of adjuvant chemotherapy for breast cancer on ovarian function in premenopausal women. We searched Medline and Cancerlit from 1966 to 1994 on the following terms: breast neoplasms; chemotherapy, adjuvant; menstruation disorders; premature menopause; and amenorrhea. Further references were obtained from reports retrieved in the initial search. We reported the most recent update when studies were published at different follow-up times. We attempted to (1) define menopausal status in the setting of adjuvant chemotherapy; (2) define chemotherapy-related amenorrhea (CRA); (3) document permanent and temporary amenorrhea and oligomenorrhea rates among different regimens; and (4) analyze variables that influence ovarian function.

From the Departmentsof Internal Medicine and Preventive Medicine, Division of Hematology/Oncology, Rush-Presbyterian-St Luke's Medical Center, Chicago, IL. Submitted July 28, 1995; accepted December 27, 1995. Address reprint requests to Melody A. Cobleigh, MD, Department of Internal Medicine, Division of Hematology/Oncology, Section of Medical Oncology, Rush-Presbyterian-StLuke's Medical Center, Suite 821, Professional Bldg 1, 1725 W Harrison, Chicago, IL 60612. © 1996 by American Society of Clinical Oncology. 0732-183X/96/1405-0042$3.00/0

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DEFINITIONS Terminology differed from one study to another. The relevant terms include definitions of menopausal status and amenorrhea.

Journal of Clinical Oncology, Vol 14, No 5 (May), 1996: pp 1718-1729

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ADJUVANT CHEMOTHERAPY FOR BREAST CANCER Menopausal Status

1719 Table 2. Incidence of Amenorrhea in Control Groups

The pituitary gland and the ovary function in a feedback fashion. In normal menstruating women, folliclestimulating hormone (FSH), produced by the pituitary, stimulates the follicular granulosa cells in the ovaries to develop. In turn, the ovary produces estradiol, which causes feedback inhibition of the pituitary and results in FSH levels less than 10 mlU/mL. In ovarian failure or menopause, the ovary is depleted of follicles and there is no feedback inhibition. FSH levels increase to greater than 10 mIU/mL. The hormone profile observed in premenopausal women treated with adjuvant chemotherapy who develop CRA is consistent with primary ovarian failure.13 The World Health Organization (WHO) defines menopause as follows. (1) Menopause is the permanent cessation of menstruation that results from loss of ovarian follicular activity. (2) Perimenopause corresponds to the period before the menopause and at least the first year after the menopause. (3) Postmenopause dates from the menopause, although it cannot be determined until a period of 12 months of spontaneous amenorrhea has occurred.14 The American College of Obstetricians and Gynecologists (ACOG) offers no definitions of these terms. The average age of menopause in the United States is between 50 and 52 years. 111,15 This age has not changed in many years, as opposed to a decline in the age of menarche. Premature menopause or premature ovarian failure corresponds to the cessation of menses before the age of 40 years.16,17 Table 1 lists the cumulative rates of natural menopause according to age groups and serves as a baseline for further comparison.t 8 We found that few reports described spontaneous amenorrhea rates in control subjects (Table 2). Rates varied from 4% to 6% in the younger age group and from 19% to 26% in women > 40 years. The high rate reported by Valagussa et a124 may be explained by longer followup time. The original trials of the National Surgical Adjuvant Breast and Bowel Project (NSABP), Eastern Cooperative Oncology Group (ECOG), and the Milan group showed Table 1. Cumulative Rates of Natural Menopause by Age Groups Age Group (years)

% Natural Menopause

25-29 30-34 35-39 40-44 45-49 50-54 55-58

0 0 1 4 25 73 98

Data from MacMahon and Worcester."

First Author

No. of Patients

Median Age at Onset of Amenorrhea (years)

BrinckertO 2 Goldhirsch " 2 Koyoma ' 22 Fisher 23 Padmanabhan 24 Valagussa

125 199 21 37 39 14

NA NA NA NA 52 50

% Amenorrhea (no. of patients in trial)

< 40 Years

Ž

4(24) 6(52)

40 Years

19(101) 26(147) 10 3 13 50

Abbreviation: NA, not available.

differences in outcome associated with age and presumably menopause. Therefore, subsequent trials have stratified patients according to menopausal status.2 5 The NSABP used age to define menopausal status. Premenopausal women were defined as those < 49 years of age.26 Other groups attempted to define menopausal status based on more physiologic events. Bianco et a127 defined patients as premenopausal if their last menstrual period was within 6 weeks of the beginning of treatment. The Milan group,28 ECOG,2 9 and Guy's/Manchester group30 defined premenopausal women as those who had had a menstrual period within 12 months of diagnosis. The last two groups also included in their definition women younger than 50 (52 according to ECOG) who had undergone prior hysterectomy. Reyno et a131 defined premenopausal women as those who reported a menstrual cycle in the 3 months before randomization and six or more periods in the preceding year. Boccardo et a132 considered postmenopausal those women with -- 2 years of amenorrhea or those older than 55 if they had undergone hysterectomy. Toma et a133 defined perimenopausal as the presence of "menstrual irregularities in the last year." The Danish Breast Cancer Cooperative Group (DBCCG) defined premenopausal and perimenopausal women as those with less than 5 years of spontaneous amenorrhea.34 The Ludwig Breast Cancer Study Group (LBCSG) included perimenopausal and premenopausal under the same definition for women with at least one of the following criteria: normal menstruation, amenorrhea for less than 1 year, biochemical evidence of ovarian function, amenorrhea for 1 to 3 years in patients younger than 52 years, or hysterectomy without bilateral oophorectomy for patients younger than 56 years of age.35 Amenorrhea The ACOG defines amenorrhea as the absence or cessation of menstrual flow. Secondary amenorrhea is characterized by 3 months of amenorrhea in a woman who

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BINES, OLESKE, AND COBLEIGH

has previously been menstruating.36 Others require 6 months of amenorrhea. 37 The definition of CRA varied among different studies (Table 3). Some investigators had a clear definition for CRA, while others analyzed their data at a certain time interval. Most used a minimum of 3 months, while ECOG defined amenorrhea as cessation of menstrual activity for 12 months. The definition of interval from beginning chemotherapy to cessation of menstruation also varied. MECHANISM OF CHEMOTHERAPY-RELATED AMENORRHEA Ovarian failure can be divided into the following two types: (1) primary or hypergonadotropic hypogonadism, and (2) secondary or hypogonadotropic hypogonadism. Cytotoxic agents induce primary ovarian failure. Breast cancer per se does not cause changes in ovarian function.4 3' 4 4 After treatment with cytotoxic agents, the ovaries show a spectrum of injury that ranges from a decreased number of secondary follicles to absent follicles with ovarian fibrosis. In many cases, histologic sections appear identical to those seen in postmenopausal 45

ovaries.

-52

Ovarian histology correlates well with studies that show low estradiol and high FSH and luteinizing hormone (LH) levels.2 ' Pituitary and adrenal function remain unchanged if regimens do not contain glucocorticoids or tamoxifen, which supports the notion that gonadal failure in women who undergo adjuvant chemotherapy for breast cancer is a result of primary failure.3 5""-5 The clinical consequences of drug-induced ovarian damage include oligomenorrhea, amenorrhea, and the sequelae of menopause.5 6 Jordan et a154 reported gonadotrophins in the postmenopausal range among amenorrheic women within 6 months of the beginning of chemotherapy. The values remained constant after treatment was Table 3. Definition of CRA According to Different Investigators Definition of CRA First Author

Bonadonna 39 LBCSG

Duration (months)

38

3 -3

Interval (months)

During treatment 9 from beginning of treatment

Padmanabhan 40 Brincker 4 Tormey " 2 Bianco Dowsett42 6

Mehta 3 Reyno '

30

Permanent 3 12 3 NA NA NA

ý 12 NA NA 3 from end of treatment - 2 from beginning of treatment During treatment During treatment

stopped. In summary, CRA can be used as a crude measure of ovarian failure. CHEMOTHERAPY-RELATED AMENORRHEA The first study of systemic adjuvant chemotherapy for breast cancer showed cessation of menses in 40% of the patients treated with thiotepa as opposed to 3% of the control group.26 Various chemotherapeutic regimens have been in use since the late 1960s, but reports on the incidence of CRA have been erratic. A recent review reported only 15 of 40 studies with information on the effects of adjuvant chemotherapy on ovarian function in premenopausal women.57 The reported incidence of CRA ranges from 0% to 100% among different chemotherapy regimens. Most data were collected at 12 months after the beginning of treatment. The average percentage of CRA in regimens based on cyclophosphamide, methotrexate, and fluorouracil (CMF) given for at least 3 months is 68% (95% confidence interval [CI], 66% to 70%), with a range of 20% to 100% (Table 4). This wide range can be attributed to the following variations in experimental design: (1) definition of amenorrhea; (2) definition of menopausal status; (3) age distribution; (4) therapeutic regimen (drug, dose, duration, and route of administration); and (5) population characteristics. It is of note that most of these clinical trials involved treatment for - 12 months and thus cannot necessarily be generalized to the briefer regimens used today. EFFECT OF AGE ON THE INCIDENCE OF CHEMOTHERAPY-RELATED AMENORRHEA The average age of menopause in the United States is between 50 and 52 years.'""' The median age of women who became amenorrheic following adjuvant chemotherapy varied from 38 to 46 years and the median age of women who continued to menstruate regularly ranged from 33 to 35 years (Table 5). The risk of gonadal damage was directly related to the age of the patient. Patients older than 40 years experienced a consistently higher rate of amenorrhea when compared with those < 40 years (Table 6). Rates varied from 21% to 71% in the younger age group and from 49% to 100% in the older group. The average percentage of CRA for CMF-based treatments (for at least 3 months) was 40% (95% CI, 36% to 44%) and 76% (95% CI, 74% to 78%) for younger and older groups, respectively. No patients under 30 years of age treated with a doxorubicin-containing regimen for 6 to 24 months stopped menstruating, compared with 33% of those between 30 and 39 years, 96% between 40 and 49 years, and 100% of those older than 50 years.5 9 Dnistrian et al 7 reported

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Table 4. Incidence of CRA

First Author

Treatment

Fisher26 Koyama21

Rose

TSPA C MMC 5-FU L-PAM CMFV L-PAM L-PAM + 5-FU L-PAM Doxo-containing chemotherapy regimen CMF

3

Fisher

22

58

Rubens 59 Hortobagyi 60 Tancini Rose

4

CMF CMFP CMFPT CMF CMF + lev CMF CMFP C CMF CMF CMF CMF + Epi CMF+ Epi+ T CMF CMFP CMFP CMF CMF CMFP CMFPT CMF CMF- T A + CMF CMF/A CMF LMF CMF CMF CMF + A CMF CMFP CMFVP CMF CMFVP + AT CMFVP CMF - Pr M to F CMF AC CMF

7

Dnistrian 35

LBCSG § Brincker'9, Beex et a161 55 Murugesan Boccardo32 Goldhirsch'2 62

IBCSG § 63 Richards 64 Tormey

Bianco

27

65

Buzzoni

Dowsett•

2

6

Mehta MoliterniM Toma33¶

67

Zambetti 31 Reyno

68

SCTBG 69 Cobleigh 70 Bonadonno 71 Cobleigh

Average % CRA for CMF-based regimens

Duration of Treatment (months)*

Total Follow-Up (months)

< 1 3-14 40 years instead of < 40 and - 40 years. randomized trial. Abbreviations: IV, intravenously; PO, orally; d, day; qd, every day.

"tThis study was not a

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(141) (104) (113) (60) (52) (74) (69) 66 (172) 60(172) 34 (53) 69 (35) 65 (108) 85(113) 55 (42) 83 (53)

(400) (283) (286) (86) (89) (240) (252)

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ADJUVANT CHEMOTHERAPY FOR BREAST CANCER months following the cessation of menses for at least 3 months. The Milan group defined reversible amenorrhea as cessation of menses for a period of 3 to 6 months.24 Some studies found no reversibility, while others reported temporary amenorrhea rates as high as 56% (Table 10). Age was important: 0% to 11% of women older than 40 years resumed regular menses as opposed to 39% to 55% of those younger than 40. Little information is available regarding time to reversibility. Bianco et a127 reported women who resumed their periods from 4 to 29 months after treatment. 27 OLIGOMENORRHEA

Table 10. Incidence of Temporary CRA % Temporary CRA (no. of patients in trial)

2

Koyama " Hortobagyis* 6 Tancini ot 2

Bonadonna "t 9 LBCSG 13P 2 Goldhirsch 0• 27 Bionco f Koyama21 22 Fisher 62 IBCSG + 33 Toma t

3

Reyno ' Valagussa

24

Treatment (duration in months)

< 40 Years

-

40 Years

C (3-14) Doxo-containing regimen (6-24) CMF (6) CMF (12) CMF (12) CMF t P (12) CMF (6) CMF (6) CMF t T (9) MMC (5 1) L-PAM _ 5 FU (24) CMFP (12) CMF (9) CMFP (9) CMFVP (9) CMFVP + AT (3) CMFVP (9) CMF ± A (12)

40 (5) 50 (NA) 22 (60) 27 (52) 39 (32) 55(113) 18 (103) 12(67)

0(13) Few (NA) 8 (86) 2 (89) 5 (46) 11 (286) NA (NA) 8 (154)

13(15) 0 (96) 16 (134) 0 (147) 15 (95) 2 (494)

*Hortobagyi et al treated 64 patients but did not provide the number of patients in each age group. authors divided the age groups into those s 40 and > 40 years instead of < 40 and 2 40 years. tPerimenopausal women were also included in these analyses.

"tThese

First Author Fisher 3 Rose

22

Bonadonna"s 4 Rose

Delrio

53

Boccardo Dowsett Toma

Oligomenorrhea is a reduction in the frequency of menses: the interval must be longer than 40 days, but shorter than 6 months.37 Boccardo et a132 and Delrio et a153 referred to oligomenorrhea as irregular menstrual activity. Dowsett and Richer42 defined oligomenorrhea as elongation of normal periodicity, while Fisher et al 22 considered oligomenorrhea as some alteration in the usual menstrual pattern. The oligomenorrhea rate varies from 0% to 50%, and the average rate for CMF-based regimens is 10% (95% CI, 7.4% to 12.6%) (Table 11). Ravdin et al86 showed evidence of ovarian function in nine of 14 patients with irregular menses after treatment with adjuvant chemotherapy and tamoxifen. Dnistrian et al7 reported menstrual irregularity associated with low

First Author

Table 11. Incidence of Oligomenorrhea

32

2

33

Treatment (duration in months)

No. of % Oligomenorrhea Patients in Trial < 40 Years 40 Years

L-PAM - 5FU (24) L-PAM (NA) CMFV (NA) CMF (12) CMF (10) CMFP (10) CMFPT (0) CMF (9) CMFT (9) CMF + Epi (10) CMF + Epi + T (10) CMF (6) LMF(6) CMF (10-12) CMFP (10-12) CMFPT (10-12)

Average % oligomenorrhea for CMF-based regimens

96 16

24

7 13

90 15 10 13 25 25 81 77 10 5

9 7 10 0 12 8 7 7 50 20

147

7

493

10% (95% CI, 7%-13%)

*These authors divided the age groups into those - 40 and > 40 years instead of < 40 and ý- 40 years.

estradiol and concomitant increase in gonadotrophins without reaching postmenopausal levels. Dowsett and Richer42 found similar results and discouraged measurement of gonadotrophins, at this stage, for assessment of ovarian function. It is not known what percentage of patients with oligomenorrhea will develop permanent amenorrhea and what percentage will resume normal periodicity. We cannot predict the outcome of this subgroup of patients from the information available. DISCUSSION Rare but important long-term sequelae from adjuvant chemotherapy in breast cancer include secondary malignancies and cardiac toxicity.87 These pale in comparison to the high rates of CRA and their impact on the health of large numbers of women. It is therefore unfortunate that the majority of clinical trials we reviewed did not report the incidence of CRA. Cardiovascular disease is the number one cause of mortality in American women and results in 500,000 deaths per year.88 Most studies have found an increased risk of cardiovascular disease in women with early menopause.8 Likewise, osteoporosis is a major cause of morbidity, with 250,000 hip fractures per year resulting in 40,000 deaths. Menopausal symptoms diminish quality of life (QOL) in this population.90 HRT ameliorates these problems, but is not approved by the FDA for breast cancer survivors. 12 After almost 40 years of adjuvant trials, little attention has been paid to the mechanisms, rates, variables, and consequences of gonadal damage. This review of the liter-

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ature found important observations that are summarized here. The CRA rate varies from 0% to 100%. This wide range results from different definitions of populations at risk for CRA, age distribution of patients, and chemotherapeutic regimens. Age, cytotoxic agents, and cumulative dose of cyclophosphamide influence the incidence of CRA. There is no conclusive evidence that duration of treatment, doseintensity, schedule, or administration route are independent variables. Age and incidence of CRA are inversely related. The average incidence of CRA for CMF-based regimens is 40% for women < 40 years and 76% for those older than 40. Age is inversely correlated with time to CRA, cumulative dose required to produce CRA, and incidence of temporary amenorrhea. This might be explained by the lower number of follicles and the resulting increased susceptibility to ovarian failure in older women. The mean age at onset of CRA varies from 38 to 46 years of age as opposed to 50 to 52 years, the average age of menopause of women in North America.' 1.15 The median time to CRA varies from 6 to 16 months in the younger age group and from 2 to 4 months among older women. Cyclophosphamide is the drug most commonly implicated in CRA. 45-52,78 The antimetabolites do not seem to cause significant gonadal dysfunction; the role of anthracyclines and taxanes are still undetermined. No conclusions can be drawn in relation to the effects of drugs in combination. CRA is mediated through primary ovarian failure.3-5,53-55 Gonadal damage is progressive and not an abrupt process. Reversibility and oligomenorrhea can be explained by partial suppression of ovarian function through impairment of follicular maturation rather than follicular destruction. Reversibility varies from 0% to 56% among the total number of women. When divided by age groups, CRA is reversible in 22% to 56% of younger women and in 0% to 11% of older patients. Reversal of CRA can occur as long as 29 months after treatment. The incidence of oligomenorrhea ranges from 0% to 50%. The average incidence of oligomenorrhea in patients treated with CMF-based regimens is 10%. With so many definitions of menopause and CRA, it is no wonder that the reported rates vary, even for the same chemotherapy regimen. For uniformity, we suggest the following definitions for clinical trial design and reporting. These definitions apply to breast cancer survivors who do not receive HRT.

Table 12. Some Ongoing or Proposed Trials of Ovarian Ablation in Premenopausal Breast Cancer Study

Patients

Treatment

IBCSG VIII

Node-negative any ER or PR

Intergroup 0101

Node-positive ER or PR positive

Scottish/Guy's

Node-positive any ER or PR Node-positive any ER or PR Operable any ER or PR

German Vietnam

Intergroup 0142

Node-negative ER or PR positive

Swedish/Danish

Node-positive ER positive Operable any ER or PR

United Kingdom

CMF x 6 Goserelin x 2y CMF x 6 - goserelin x 1 /2 y CAF x 6 CAF x 6 -• goserelin x 5ys CAF x 6 - goserelin + tamoxifen x 5y CMF x 6 - P Ovarian ablation + P CMF x 6 Goserelin x 2y Placebo x 5y Oophorectomy + tamoxifen x 5y Tamoxifen x 5y Tamoxifen x 5y + ovarian ablation CMF x 9 Radiation ablation Observation Tamoxifen x 2y Goserelin x 2y Tamoxifen + goserelin x 2y

9

NOTE. Reprinted with permission. Abbreviations: ER, estrogen receptor; PR, progesteron receptor; y, years.

(1) Cessation of menses defines menopause rather than age. Exclude women who have had a hysterectomy from ovarian function analysis. They have a higher rate of premature ovarian failure and one cannot evaluate their gonadal activity clinically." Premenopausal women are those who had their last menstrual period within 12 months from diagnosis. Postmenopausal women had their last menstrual period more than 12 months from diagnosis. (2) CRA is - 6 months without menstrual periods in a patient who was premenopausal at diagnosis. Early CRA begins within 1 year of starting chemotherapy. Late CRA begins more than 1 year after starting chemotherapy if a woman is less than 50 when CRA occurs. (3) Temporary CRA (or reversible CRA) is the reappearance of regular menstruation after CRA has occurred. (4) Oligomenorrhea is anything other than regular menstrual cycles, CRA or temporary CRA.

We present the following proposals. (1) Investigators should report CRA rates according to age groups. The traditional cutoff points of less than 40 versus '40 years are satisfactory for small trials. Larger trials should divide patients into smaller cohorts, ie, by decade. (2) Investigators should report the median age of CRA and the median age at menopause of the general population from which the study group was obtained. If the study includes a control group, the menopausal status of controls should be reported. (3) Trialists should monitor patients until death and should report the age at which menopause occurred and the cause of

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ADJUVANT CHEMOTHERAPY FOR BREAST CANCER death. It is only through long-term follow-up data that we can learn the rate of premature menopause, a potentially fatal complication of adjuvant treatment of premenopausal women. In conclusion, the effect of ovarian ablation on survival from breast cancer remains controversial. It is possible that the action of adjuvant chemotherapy in premenopausal women is mediated in part through chemical castration. A deeper discussion of this topic is beyond the scope of this review. Ongoing clinical trials address this fundamental question (Table 12).91 Even if ovarian ablation proves beneficial, there will be women who wish to preserve their ovarian function. We cannot answer many of the questions they ask. Which combination of drugs is least toxic to the ovaries? Is there a combination of drugs that provides equal relapse-free

survival and has a lower CRA rate? Does tamoxifen, when added to chemotherapy, affect the CRA rate? How long should contraception be used after CRA occurs? Do the benefits of adjuvant treatment outweigh the consequences of early menopause, especially in a node-negative population? After 30 years of adjuvant chemotherapy trials, our understanding of the impact of chemotherapy on ovarian function remains surprisingly limited. More women survive breast cancer now than ever before."' It is possible that early mediated gains in survival, especially of nodenegative women, may be overshadowed by higher allcause mortality, related to premature menopause. We are obliged to study this important toxicity of our treatment in a consistent and prospective fashion.

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