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VARIAN ABLATION is the oldest form of systemic treatment for breast cancer. Its use as a palliative treatment for advanced breast cancer was first described by a Scottish surgeon, G.T. Beatson, in 1896.1 Its application as an adjuvant therapy was proposed at about the same time in Germany by Schinzinger (reviewed in Clarke)2 and reiterated again by Taylor in 1939.3 The first randomized trial of ovarian ablation in the adjuvant setting was begun in 1948.4 Over the past 100 years a number of case series, retrospective reviews, and clinical trials have addressed the utility of ovarian ablation as adjuvant therapy for breast

0

From the Division of Hematology and Oncology, The University of North Carolina at Chapel Hill, Chapel Hill, NC; and the Johns Hopkins Oncology Center, The JohnsHopkins Uniwrsity School of Medicine, Baltimore, MD. Address reprint requeststo Nancy Davidson, MD, Johns Hopkins Oncology Center, 1650 Orleans St, Room 409, Baltimore, MD 21231. Copyright 0 2001 by W.B. Saunders Company 0093-7754/01/2804-0002$35.00/O doi:10.1053/sonc.2001.26143 322

for

Breast

Cancer

E. Davidson

cancer. Most of these studies are small and many have methodologic flaws in that they either were not randomized or used randomization procedures now thought to be inadequate. The largest collected body of information on this subject is the Early Breast Cancer Trialists’ Collaborative Group’s (EBCTCG) overview analysis, which is discussed below. The 15-year follow-up results from the overview were published in 1996.5 These and earlier versions of the results are responsible in part for recent resurgence of interest in this modality, which has been further revitalized by the development of luteinizing hormone-releasing hormone (LHRH) agonists, which cause a medical ovarian ablation, and by the suggestion that the benefit from adjuvant cytotoxic chemotherapy seen in premenopausal women may be largely due to its induction of premature ovarian failure in more than 50% of these women.6,7 This article reviews the existing data on the use of ovarian ablation in the adjuvant treatment of breast cancer as well as the yet-unanswered questions and ongoing trials. METHODS

OF OVARIAN

ABLATION

Surgical Oo@orectomy Surgical oophorectomy as described by Beatson’ is the oldest method of ovarian ablation for the treatment of breast cancer. The advantage of surgical ovarian ablation is that it causes an immediate and permanent drop in the production of serum estradiol. However, early studies reported a procedure-related mortality rate as high as 4.5% among women with metastatic breast cancer.8,9 More recently, surgical oophorectomy has been performed laparoscopically with lower mortality and morbidity and shorter hospital stay. Interestingly, in a recent series of 25 women with breast cancer who underwent therapeutic laparoscopoic oophorectomy, unexpected ovarian micrometastases were found in 32% of patients (12 of 44 ovaries removed). Nevertheless, none of the patients with incidentally detected ovarian micrometastases went on to develop abdominal wall metastases with a mean follow-up of 38 months.1° Seminars in Oncology, Vol 28, No 4 (August),

200 I: pp 322-33

I

OVARIAN

ABLATION

Radiation-Induced

CANCER

323

Ablation

drug withdrawal might stimulate any latent tumor cells) of this method. Side effects from LHRH agonists include injection site reactions, tumor flare, and menopausal symptoms such as hot flashes (50%). Other more rare effects include nausea, hypotension, insomnia, migraine, myalgia, bony pain, and breast fullness.13J6

FOR BREAST

Ovarian

Beginning in the 1920s many studies of ovarian ablation used radiation-induced ablation. Trials investigating radiation-induced ablation used doses ranging from 450 cGy in one fraction to 1,000 to 2,000 cGy over five to six fractions5j11 Advantages to this method of ovarian ablation are ease and safety of outpatient administration. Disadvantages are that achievement of castrate levels of estradiol may be slower and potentially incomplete or reversible. Although it is used in Western Europe and Canada, this technique is not widely employed in the United States for the treatment of breast cancer. l2 Medical

Ovarian

Suppression

Over the past 20 years, several LHRH analogs (goserelin, leuprolide, buserelin, triptorelin) have been developed and studied as treatment for breast cancer. One of these, goserelin acetate implant (Zoladex; AstraZeneca Phamaceuticals, Wilmington, DE), has been approved by the Food and Drug Administration for the treatment of advanced breast cancer in pre- or perimenopausal women.13 Although there is some in vitro evidence that LHRH analogs may have direct cytotoxic effects,14 a phase II clinical trial of goserelin in postmenopausal women with metastatic breast cancer showed very little benefit.15 Thus, the main mechanism of action of these agonists is thought to be indirect, by suppression of serum estradiol levels. Circulating gonadotropins produced by the pituitary stimulate ovarian production of estrogen. Gonadotropin production is stimulated by the pulsatile release of LHRH from the hypothalamus. LHRH analogs are thought to act by binding pituitary gonadotropin-releasing hormone (GnRH) receptors more avidly than native LHRH, thereby causing receptor downregulation, internalization, and degradation. Thus, after an initial surge, continuous treatment with LHRH agonists paradoxically suppresses the secretion of serum gonadotropins, and thereby reduces serum estradiol to castrate levels. In premenopausal women, therefore, chronic treatment with an LHRH agonist is a medical method of ovarian ablation.iz,iJ It is also the only completely reversible form of ovarian ablation, which may be seen as an advantage (preservation of fertility in breast cancer survivors) or as a disadvantage (estrogen resurgence after

Comparisonof the Methods of Ovarian

Ablation

The relative efficacy of surgical oophorectomy, radiation-induced ablation, and medical castration as treatments for breast cancer is not well defined. Large randomized trials comparing these methods with regard to efficacy and quality of life would ideally be useful, but are not likely to be performed. They are apparently equally effective by indirect comparisons. Indeed, in many trials of ovarian ablation, surgical oophorectomy and radiation-induced ablation have been presumed to be equivalent. For example, the EBCTCG overview analysis combines patients treated with these two modalities, assuming equivalence of effects. However, as noted earlier, there are data to suggest that ovarian ablation may be incomplete following radiation, depending on dose, schedule, and age of the patient. For example, Nissen-Meyer and colleagues found that 13% of women treated with radiation resumed menses at a later date.lTJs Clearly, incomplete ablation by radiation might modify the long-term efficacy of this modality in breast cancer treatment. How medical castration compares to older methods of ovarian ablation as treatment for breast cancer is also unclear. When LHRH analogs have been used to treat premenopausal women with metastatic breast cancer, response rates of 31% to 63% have been reported, with higher response rates in women with hormone receptorpositive tumors. These results are similar to those with surgical ablationi+ Two prospective trials comparing use of LHRH agonists to the other methods of ovarian ablation in the palliative treatment of metastatic breast cancer have been performed. The larger of these two is an Intergroup trial that randomized 136 premenopausal women with estrogen receptor (ER)-positive metastatic breast cancer to receive goserelin or surgical oophorectomy as first-line therapy for metastatic disease. This study found no significant differences in failure-free survival or overall survival between the two treatment groups.

324

DEES AND

Of note, the study was closed early due to insufficient accrual, and therefore lacked power to detect a small difference between the groups.20 Another prospective study randomized 85 preor perimenopausal women with metastatic breast cancer to receive surgical or radiation-induced oophorectomy with or without tamoxifen versus goserelin with or without tamoxifen. In this 2 X 2 factorial design study there were no significant differences in response, progression-free survival, or overall survival between patients who underwent surgical or radiation-induced ovarian ablation and those treated with goserelin. However, there was a trend toward improved response and survival in the patients treated with oophorectomy, and the small size of the trial may have prevented detection of a small but meaningful difference. There was evidence of an interaction between the effect of tamoxifen and method of ovarian ablation, such that tamoxifen seemed to increase the activity of goserelin, whereas it appeared to decrease the results with oophorectomy. Unfortunately, the ER status of the tumor was unknown for many of the participants. The percentage of tumors which were ER-unknown was unequal among treatment arms, and far greater in the oophorectomy arms than the goserelin arms. This disparity makes it difficult to interpret the results. This trial was also terminated prematurely because of low accrual.*l It is unclear whether these results from trials of LHRH agonists in the metastatic setting can be extrapolated to their use in the adjuvant setting. In the trials described above, goserelin was given until disease progression or patient withdrawal, whereas in the adjuvant setting, duration is arbitrarily assigned. It seems likely that the duration of therapy with goserelin might affect the efficacy of medical castration as adjuvant therapy, particularly in young women who might regain ovarian function when the LHRH analog is discontinued. Neither the optimal duration of this therapy in the adjuvant setting, nor the impact of goserelin duration on its comparability to surgical oophorectomy has been defined. Chemotherapy-Induced

Ouatian

Failure

Cytotoxic chemotherapy causes ovarian ablation or dysfunction in a significant number of premenopausal women receiving adjuvant therapy for breast cancer. The risk of treatment-induced

DAVIDSON

ovarian failure increases with increasing age at the time of treatment and increasing dose. Approximately 30% to 40% of breast cancer patients under age 40 and 70% to 90% over age 40 will develop permanent ovarian failure following chemotherapy.z2~23 The rate of chemotherapy induced amenorrhea is 10% to 33% after one cycle of cyclophosphamide/ methotrexate/fluorouracil (CMF), 33% to 81% after six cycles, and 61% to 95% after 12 cycles.23 This chemotherapy-induced ablation may be an underappreciated mechanism of action of chemotherapy. Numerous retrospective reviews have addressed this question and give conflicting results. Several studies have found that induction of amenorrhea did not correlate with improved diseasefree survival, whereas others have demonstrated that chemotherapy-induced amenorrhea was associated with lower recurrence and mortality rates.*4 The high rate of chemotherapy-induced ovarian failure in premenopausal women and the suggestion that it may be one mechanism of benefit from adjuvant chemotherapy has led to resurgence of interest in ovarian ablation as a modality of adjuvant therapy. REVIEW

OF THE

OVERVIEW

ANALYSIS

Numerous clinical trials of ovarian ablation as adjuvant therapy for breast cancer have been performed. Unfortunately, their interpretation is often fraught with a number of problems. Most of the trials were small in size, and patient eligibility was often defined by age not menopausal status. Hormone receptor status of the primary tumor was often unspecified. A number of these trials used randomization procedures that are now regarded as inadequate. Finally, there is inherent difficulty in performing randomized trials of dramatically different therapies (eg, surgical oophorectomy e, medical therapy). The largest collected body of data regarding the use of ovarian ablation in the adjuvant setting is the EBCTCG systematic overview.5,25,26 This meta-analysis used data from 12 trials considered to be properly randomized, which began before 1980. They assessed the utility of ovarian ablation by surgical or radiotherapeutic methods. The results of the 20.year overview have been completed. The most recently published analysis presents the 15year follow-up results for 2,102 women under age 50 at randomization.5 The results of this overview analysis are depicted in

OVARIAN

ABLATION

Tabte

1. IS-Year Analysis

Patients

FOR

BREAST

Results

of the

of Ovarian

325

CANCER

EBCTCC

Overview

Ablations

DiseaseFree

OVWdl

Survival

Survival (“/-)

w

All Ovarian Control

ablation

Node-negative Ovarian ablation Control Node-positive Ovarian ablation Control

45.0 39.0 75.4

66.5 37.4 24.0

P < ,001

P = .Ol

P < .Ol

52.4 46.1

76.6 70.9 4 1.7 29.2

P = ,001

P=

.Ol

P < ,001

Table 1, and show a significant improvement in disease-free survival (DFS) and overall survival for women who underwent ovarian ablation in the adjuvant setting compared to those who did not. In women under age 50, the 15year recurrencefree survival rate was 45% among those randomized to ovarian ablation and 39% among those who were not. Similarly, the overall survival at 15 years was 52.4% among women treated with ovarian ablation and 46.1% among those who were not. Of note, five of the trials used to compile the overview analysis included routine adjuvant cytotoxic chemotherapy, whereas the rest of the trials did not. Since cytotoxic chemotherapy may produce amenorrhea in more than 50% of women undergoing adjuvant therapy for breast cancer, ovarian ablation might be expected to have a greater proportional effect in women who did not receive cytotoxic therapy compared with those who did. Subgroup analysis by presence or absence of concomitant chemotherapy showed that the proportional improvement in DFS in women who were treated with ovarian ablation and chemotherapy was smaller than in those who received ovarian ablation alone as their adjuvant treatment (10% v 25%). However, this difference was not statistically significant. Similarly, the proportional improvement in overall survival due to ovarian ablation was smaller in women who also received cytotoxic therapy than in those who did not (8% v 24%), and again the difference was not significant. The numbers of women in each group of this

subgroup analysis are too small to draw any firm conclusion regarding the way chemotherapy may modify the impact of ovarian ablation. The trials analyzed in the EBCTCG overview did not select patients by steroid receptor status. ER status of tumors was available for four of the trials (-750 patients). Among the group of patients whose tumors were known to be ER-negative, there was no difference in DFS or overall survival between those treated with ovarian ablation plus chemotherapy versus those treated with chemotherapy alone. By contrast, among patients whose tumors were known to be ER-positive, ablation plus chemotherapy was associated with higher DFS and overall survival than chemotherapy alone. These differences were not statistically significant. The impact of nodal status on the effect of ovarian ablation was also assessed by subgroup analysis using only the group of women who did not receive cytotoxic chemotherapy. The beneficial effect of ovarian ablation was seen both in node-positive and node-negative subgroups, although the number of events in these subgroups is too small for reliable estimation.5 Although the most recent overview analysis of this topic focused on women under 50 years of age (and therefore presumed to be premenopausal), it included some data on the use of ovarian ablation in older women. This modality was not found to be beneficial for older women. There were 1,354 women over age 50 when randomized. No significant differences were observed in recurrence-free or overall survival between patients who received adjuvant ovarian ablation and those who did not. In sum, the met:a-analysis suggests that ovarian ablation is an effective method of adjuvant therapy for premenopausal women, probably as effective for node-positive tumors as for nodenegative, and probably more effective for ERpositive than ER-negative tumors. Indirect comparisons suggest that the benefit from ovarian ablation is comparable to the benefit from cytotoxic chemotherapy in the adjuvant setting. However, many questions remain to be answered. For example, the relative contributions of ovarian ablation and chemotherapy in the adjuvant treatment of premenopausal women have not been determined. Second, the value of combined ovarian ablation and chemotherapy is not known. Third, the effects of LHRH agonists

326

DEES AND

Patients

Study Ovarian

oblation

N

Treatment

Node(+)

Sweden

332 732

Stage II, ER(+)

OA*

+ p

CMF

+ p

OA CMF

ZEBRA

Node(+) oblation

1,640

Node(+),

II

Equivalent

27

Equivalent

28

X 9

Goserelin

X 2 yr

CMF

X 6 cycles

ER or PgR(+)

1,504

CAF

x

CAF

X 6 + goserelin

X 5 yr

327

Node(+)

CAF

X 6 + goserelin

+ Tam X 5 yr

6 cycles

DFS equivalent

in ER(+)

OS equivalent

DFS better

Oophorectomy

w/Tam,

+ CMFp

CMFp IBCSG

References

29,30

+ chemotherapy

Intergroup

IBCSG

Results

Y chemotherapy

Scottish

Ovarian

Comparison

DAVIDSON

VIII

Node(-)

Italian

1,200

92

ER(+)

2,500

Stage I-II

better

for <40

Equivalent,

trend

yr in favor

32

of OA for ER(+)

Goserelin

X 2 yr

Ongoing

CMF

X 6 cycles

CMF

X 6 + goserelin

29,34

X 1.5 yr

Fa-CMF

Equivalent,

Fa-CMF CRC

31

?goserelin

+ goserelin

Goserelin

X 2 yr

DFS greater

Tam X 2 yr Goserelin

underpowered

35

X 2 yr for goserelin,

36

OS equivalent

+ Tam X 2 yr

Observation Ovarian

oblation

+ tamoxfin

ABCSG

Stage I-II

1,045

Goserelin CMF

GROCTA

Node(+),

ER(+)

235

Goserelin CMF

FASG 06

Node

(+),

ER(+)

333

X 3 yr + Tam X 5 yr

DFS better

X 6

therapy, + Tam

for endocrine

37

OS equivalent

Equivalent

38

DFS and OS equivalent

39

Equivalent,

40

X 6 cycles

Triptorelin

X 3 yr + Tam

FEC X 6 France

Node(+),

ER(+)

162

OA*

+ Tam

underpowered

FAC Intergroup

Node(-),

ER or PgR(+)

OA OA

Vietnamese

Closed

Oophorectomy

Premenopausal

+ Tam

DFS, OS longer

Observation Abbreviations:

OA,

ovarian

ablation;

phamide/doxorubicin/fluorouracil IBCSG,

International

(CAF);

Breast

Cancer

Study

CMF,

adjuvant

cyclophosphamide/methotrexate/fluorouracil;

Tam, tamoxifen; Group;

ABCSG,

for poor

accrual

+ Tam

p, prednisolone;

FEC, flourouracil/epirubicin/cyclophosphamide; Austrian

Breast

Cancer

Study Group;

41

Fa, farmarubicin; CRC,

GROCTA,

with

treatment

Italian

Cancer Breast

FAC, Research

Cancer

cyclophosCampaign;

Adjuvant

Study

Group. * By surgery

or pelvic

radiation.

(either alone or with chemotherapy) have not been compared to those of other endocrine therapies, like tamoxifen. Finally, the role of combined endocrine therapy with ovarian ablation and tamoxifen-a so-called total estrogen blockade-has not been assessed definitively. A variety of newer and ongoing trials including more than 6,000 patients in aggregate may answer some of these questions. Several of these trials are outlined below and in Table 2.

RECENT Ovarian

Ablation

AND

ONGOING

TRIALS

Versus Chemotherapy

In 1980, the Scottish Cancer Trials Breast Group began a study that sought to compare ovarian ablation to chemotherapy as adjuvant therapy for breast cancer. Three hundred thirty-two premenopausal women with node-positive breast cancer were randomized after mastectomy or breastconserving therapy to undergo ovarian ablation

OVARIAN

ABLATION

FOR BREAST

327

CANCER

(by surgery or pelvic radiation) or receive CMF chemotherapy, each with or without 5 years of prednisolone. With a median follow-up of 6 years, no differences in event-free survival or overall survival were found. However, subgroup analysis by hormone receptor status revealed that the relative benefits of chemotherapy and ovarian ablation may differ depending on ER content of the tumor. Specifically, among women with low-ER tumors, a trend toward improved event-free survival was noted in those who received chemotherapy. Conversely, a trend toward improved eventfree survival was seen in women with high-ER tumors who were treated with ovarian ablation.27 A second trial compared ovarian ablation to nine cycles of intravenous CMF in 732 women with node-positive or T3 tumors. DFS and overall survival were equivalent between the two treatment arms. Sixty-eight percent of patients receiving CMF became amenorrheic2s The Zoladex Early Breast Cancer Research Association (ZEBRA) trial was designed to compare the treatment outcomes and tolerability of chemical ovarian ablation and cytotoxic chemotherapy. This trial included 1,640 premenopausal patients with node-positive tumors. After mastectomy or breast-conserving therapy, participants were randomized to adjuvant therapy with goserelin for 2 years or six cycles of classical CMF. Preliminary results were presented at the Annual San Antonio Breast Cancer Symposium in December 2000.29,30 In patients with ER-positive tumors, DFS was equivalent between the two treatment arms. By contrast, and not surprisingly, among patients with ER-negative tumors (25% of total), those treated with CMF had significantly greater DFS. Overall survival data are not yet mature. Hypothesis-generating subgroup analyses suggest that patients treated with CMF who become amenorrheic following therapy may have longer DFS. However, in women treated with goserelin, there seems to be no difference in DFS between those who remain amenorrheic and those who do not. Two thirds of patients regained menses by 1 year following completion of goserelin, whereas 80% of women treated with CMF in this study remained amenorrheic at 3 years. Goserelin may therefore be a preferable treatment alternative for breast cancer patients wishing to preserve fertility without compromising DFS. Furthermore, bone mineral den-

sity partially recovers following the completion of treatment with goserelin, but not CMF. Together, these trials suggest that oophorectomy and CMF chemotherapy have similar efficacy in women with node-positive, ER-positive breast cancer. Furthermore, the benefit from adjuvant CMF may be mediated in part by its induction of premature ovarian failure.

Ovuriun Ablation Plus Chemotherapy Several trials evaluated the benefit of combining ovarian ablation with adjuvant chemotherapy. For example, a United States Intergroup trial was designed to assess the benefit of adding goserelin or tamoxifen plus goserelin to standard adjuvant chemotherapy. More than 1,500 premenopausal patients with node-positive, steroid receptor-positive breast cancer were randomized to receive six cycles of cyclophosphamide/doxorubicin/fluorouracil (CAF) versus six cycles of CAF followed by goserelin for 5 years versus six cycles of CAF followed by goserelin and tamoxifen for 5 years. Recruitment for this trial is complete and preliminary results reveal that the addition of goserelin to CAF did not improve DFS. However, the addition of tamoxifen to CAF plus goserelin was associated with improvement. As yet, no difference in overall survival among the three arms has been observed, but longer follow-up is needed.31 Exploratory subset analysis found that for patients under age 40 years at time of entry, the addition of goserelin significantly increased 5-year DFS. For those 40 or older, no difference in DFS was associated with the addition of goserelin; however, the addition of tamoxifen did improve DFS. Post hoc analysis of 1,000 patients who had estrogen levels assessed showed th,at the benefit of goserelin was limited to women who retained premenopausal levels of estrogen following treatment with CAF.31 The International Breast Cancer Study Group (IBCSG) trial II compared outcome in premenopausal node-positive women treated with oophorectomy prior to chemotherapy (CMF + prednisone) and those treated with adjuvant chemotherapy only. Data from this analysis of 327 patients were included in the EBCTCG overview. No difference in DFS or overall survival was found between the groups. However, among the 107 women with receptor-positive tumors, there was a trend toward improved survival in those who underwent oophorectomy in addition to chemotherapy.jz

DEES AND

A retrospective analysis of 3,700 pre- and perimenopausal women who were treated in this and three other IBCSG trials of various adjuvant CMF regimens found that younger patients (~35 years) had shorter DFS and overall survival times than did older patients (>35 years). Furthermore, ERpositive status was an unfavorable prognostic factor in younger women in contrast to the older patients. The patient population with the highest risk of relapse and death consisted of women under age 35 who had receptor-positive tumors and did not experience amenorrhea following CMF chemotherapy. The authors argue that chemotherapy alone is inadequate for this subgroup and the addition of endocrine therapy such as oophorectomy should be strongly considered.33 IBCSG Trial VIII is evaluating whether the combination of adjuvant chemotherapy followed by goserelin can improve outcome compared with either modality alone in the treatment of premenopausal women with node-negative breast cancer. After surgery, patients are randomized to receive goserelin for 2 years or six cycles of CMF or six cycles of CMF followed by goserelin for 1.5 years. The target sample size is 1,200 and recruitment began in 1990.29s34 In a small Italian trial, 92 premenopausal patients with receptor-positive breast cancer were randomized to receive adjuvant chemotherapy (farmarubicin and CMF) followed by either goserelin for 2 years or observation. No differences in DFS or overall survival were seen in this underpowered trial.35 A European trial led by the Cancer Research Campaign (CRC) has investigated the potential benefits of adding goserelin, tamoxifen, or the combination after standard unspecified adjuvant chemotherapy. Approximately 2,500 premenopausal women with stage I or II breast cancer have been enrolled. After standard local therapy and adjuvant chemotherapy, patients were randomized to goserelin for 2 years, tamoxifen for 2 years, the combination for 2 years, or observation. Adjuvant chemotherapy was used in selected patients dependent on the standard at the participating institution. At a median follow-up of 4 years, event-free survival was significantly greater in the patients receiving goserelin. The benefit was largest in patients who were ER-positive and somewhat less among those receiving concomitant tamoxifen or chemotherapy. Overall survival was not signifi-

DAVIDSON

cantly different in the patients who received goserelin.36 Taken together, the completed trials have shown no definite increase in survival associated with adding ovarian ablation to chemotherapy. However, the available data suggest there may be subgroups who benefit from the addition of ovarian ablation, such as young women with ER-positive tumors who do not develop amenorrhea following chemotherapy. Ongoing studies may further clarify this question.

Several trials have evaluated the combination of ovarian ablation and tamoxifen. This approach is of particular interest as comparative studies of tamoxifen and ovarian ablation show that both are effective palliative treatments in advanced breast cancer. Further, a crossover effect is seen, that is, women whose disease initially responds to ovarian ablation may again respond to tamoxifen at time of progression and vice versa. Thus, the two modalities may have complementary mechanisms of action and combined therapy might therefore be superior in theory. Recently, the Austrian Breast Cancer Study Group (ABCSG) presented preliminary results of a trial comparing combined endocrine therapy with tamoxifen and goserelin to six cycles of adjuvant CMF in 1,045 premenopausal women with hormone receptor-positive early-stage breast cancer. At a median follow-up of 42 months, women receiving the combined hormonal therapy had significantly longer DFS. However, there was no significant difference in overall survival between the groups. Among patients randomized to CMF, those who became amenorrheic following chemotherapy had significantly longer DFS and overall survival than those who did not.37 The Italian Breast Cancer Adjuvant Study Group (GROCTA) trial randomized 244 pre- or perimenopausal women with node-positive, receptor-positive tumors to receive six cycles of classical CMF or ovarian ablation (either surgical oophorectomy, ovarian irradiation, or monthly goserelin for 2 years) plus tamoxifen for 5 years. With a median follow-up of 76 months, there is no significant difference between the two groups with respect to DFS or overall survival. Among patients treated with ovarian ablation there was no difference in the outcome of patients treated with gos-

OVARIAN

ABLATION

FOR BREAST

329

CANCER

erelin compared to oophorectomy or ovarian radiation. Of note, among patients treated with chemotherapy, those who became amenorrheic had longer overall survival, even after adjusting for age (relative risk of death, 0.41; P = .08).x* Two small trials have compared anthacyclinebased chemotherapy to a combined endocrine therapy approach. The first, a French trial (FASG 06), compared combined hormonal therapy with tamoxifen and triptorelin for 3 years to adjuvant chemotherapy with fluorouracil/epirubicin/cyclophosphamide (FEC). A total of 333 premenopausal women were randomized and, at 54 months median follow-up, the DFS rate is 92% in the group receiving hormonal therapy and 81% in the chemotherapy-treated groups. Overall survival was 97% in the combined hormonal therapy arm and 82% in the chemotherapy arm. These differences did not reach statistical significance.39 Another small trial in France compared adjuvant chemotherapy with fluorouracil/doxorubicin/ cyclophosphamide (FAC) to ovarian ablation (by surgery or radiotherapy) plus tamoxifen in 162 premenopausal women with node-positive, receptor-positive breast cancer. After adjusting for number of positive nodes, no difference was seen in DFS between the treatment groups. There was a trend toward improved overall survival for the women receiving total estrogen blockade, which did not reach statistical significance. This trial was stopped prematurely due to poor accrual.40 Two other trials are investigating combination hormonal therapy in the absence of chemotherapy. An Intergroup trial is comparing tamoxifen to ovarian ablation plus tamoxifen in premenopausal women with node-negative, receptor-positive tumors less than 3 cm in size. This trial has been closed due to poor accrual and the emerging evidence of benefit from chemotherapy in this population. Three hundred forty-five patients were enrolled and results are not yet available. A study of 709 premenopausal women in Vietnam who were randomized to oophorectomy plus tamoxifen given in the adjuvant setting versus the same given at the time of relapse has recently been presented. With median follow-up of 3 years, there is significantly longer DFS and OS in the adjuvant therapy arm. However, given the trial design, it is impossible to separate the relative benefit of oophorectomy from that of tamoxifen.41 In summary, two completed trials have shown

improved DFS with combined endocrine therapy, but there was no difference in overall survival. Three studies comparing combined endocrine therapy to chemotherapy in node-positive, ERpositive patients have shown no difference in DFS or overall survival. Again, the possibility of specific subgroups that may benefit most from a combined endocrine approach needs further exploration. LONG-TERM OVARIAN

MORBIDITY ABLATION

OF

A greater understanding of the cardiac and skeletal effects of hypoestrogenic states has prompted increased discussion about hormone-replacement therapy in healthy women. There is also ongoing discussion about the relative benefits of hormonereplacement therapy in breast cancer survivors.42 In this context, a renewed interest in the use of ovarian ablation as adjuvant therapy for breast cancer must consider the potential long-term morbidity of this therapy. Ideally, ongoing trials comparing ovarian ablation to other modalities should include cause-specific mortality end points. The EBCTCG overview analysis addressed the question of cause-specific mortality and found no difference in vascular deaths, other non-breastcancer deaths, or all non-breast-cancer deaths between women allocated to ovarian ablation and those who were not.5 These results are reassuring. However, it is possible that combination endocrine approaches may address these concerns more fully. For example, Bilimoria and Jordan have suggested that an optimal strategy would include ovarian ablation followed by long-term tamoxifen. Tamoxifen would provide the beneficial effects of lowering serum lipids and maintaining bone density in premenopausal women who had undergone ovarian ablation, as well as potentially blocking effects of any estrogen produced by adrenal steroidogenesis in these women.6 Several ongoing trials are investigating this combination. In addition, new selective estrogen receptor modulators (SERMs) may also be employed in this way. CONCLUSION Ovarian ablation has been used as a form of treatment for premenopausal women with breast cancer for more than 100 years. Randomized trials of this modality in the adjuvant setting have been performed for over 50 years. Several methods of

330

DEES AND

ovarian ablation are available including surgery, radiotherapy, and chronic use of LHRH analogs. Fifteen-year follow-up from the EBCTCG Overview analysis shows that use of ovarian ablation as an adjuvant treatment for premenopausal women correlates with improved DFS and overall survival. The benefit from ovarian ablation is seen across nodal subsets, but appears greater in women whose tumors are ER-positive. The proportional benefit seems higher for women who did not also receive chemotherapy. However, this analysis was too small to make definitive conclusions about which subgroups may benefit most from ovarian ablation. Preliminary results from some newer and ongoing trials suggest that women with ERepositive tumors may have greater benefit from ovarian ablation or ovarian ablation plus chemotherapy than from chemotherapy alone.z7J* However, several recent trials have found no difference?J”J5 Exploratory subgroup analyses from some of these studies suggest that certain groups, such as young women who retain premenopausal estrogen levels following completion of chemotherapy, may benefit most from the addition of ovarian ablation. Much of the data is preliminary and published only in abstract form. However, expert panels at both the International Conference on Adjuvant Therapy of Primary Breast Cancer in St Gallen, Switzerland, and the Consensus Development Conference held at the National Institutes of Health, have reviewed the existing data and concluded that ovarian ablation is an acceptable alternative for the treatment of selected premenopausal women with ER-positive tumors.43~44 The optimal use of ovarian ablation alone and in combination with other forms of adjuvant therapy remains unclear, as does definition of the particular patient groups who may gain the most from this therapy. Other issues that remain include the relative benefit of the three methods of ovarian ablation, the necessary duration of therapy with LHRH agonists, and the long-term morbidity of ovarian ablation in breast cancer survivors.

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