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Journal of Clinical Oncology, Vol 18, Issue 4 (February), 2000: 734
© 2000 American Society for Clinical Oncology

Value of Estrogenic Recruitment Before Chemotherapy: First Randomized Trial in Primary Breast Cancer

By M. Bontenbal, W. L. J. van Putten, J. Th. M. Burghouts, M. G. A. Baggen, G. J. Ras, W. F. Stiegelis{dagger}, M. Beudeker, J. Th. P. Janssen, J. J. Braun, G. H. M. van der Linden, P. C. van der Velden, A. N. van Geel, P. Helle, M. Leisink, J. A. Foekens, J. G. M. Klijn

From the Departments of Medical Oncology, Statistics, Surgery, and Radiotherapy, Rotterdam Cancer Institute (Daniel den Hoed Kliniek), University Hospital Rotterdam; Ikazia Hospital; and Sint Clara Hospital, Rotterdam; Bosch Medicenter, ’s-Hertogenbosch; Ignatius Hospital, Breda; Hospital Walcheren, Vlissingen; Sint Franciscus Hospital, Roosendaal; Schieland Hospital, Schiedam; Drechtsteden Hospital, Refaja Location, Dordrecht; and St Het van Weel-Bethesda Hospital, Dirksland, the Netherlands.
{dagger}Deceased.

Address reprint requests to M. Bontenbal, MD, PhD, Rotterdam Cancer Institute (Daniel den Hoed Kliniek), University Hospital Rotterdam, PO Box 5201, 3008 AE Rotterdam, the Netherlands; email bom{at}onch.azr.nl


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
PURPOSE: Several preclinical studies showed that short-term pretreatment of breast cancer cells with estrogens can increase the antitumor efficacy of different cytotoxic drugs. Some early clinical studies in patients with advanced breast cancer did seem to support these findings. Therefore, the efficacy of estrogenic recruitment followed by chemotherapy was compared with that of chemotherapy alone in a randomized phase III study in women with lymph node–positive primary breast cancer.

PATIENTS AND METHODS: Three hundred twenty-eight patients with stage II/IIIA breast cancer who were younger than 66 years of age were randomly allocated to chemotherapy with fluorouracil, doxorubicin, and cyclophosphamide (FAC) or FAC plus pretreatment with ethinyl estradiol (EE2). FAC (500, 50, and 500 mg/m2, respectively) was administered intravenously once every 4 weeks for four cycles. EE2 (0.5 mg) was administered orally, both 24 hours and immediately preceding FAC chemotherapy.

RESULTS: Patient and tumor characteristics and chemotherapy dosages were comparable in both treatment groups. Of 318 assessable patients, with a median follow-up of 6.8 years, 177 patients had a relapse and 127 died. No significant differences were observed between the two treatment groups with respect to relapse-free, local recurrence–free, and overall survival according to univariate and multivariate analyses adjusted for age, menopausal status, tumor size, grade, number of positive nodes, and steroid-receptor status. The power for the detection of an increase of 50% in the median relapse-free survival was 80%.

CONCLUSION: Estrogenic recruitment of breast cancer cells before FAC chemotherapy did not influence the efficacy of adjuvant chemotherapy in stage II/IIIA breast cancer patients after a follow-up of 6.8 years.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
ALTHOUGH BOTH adjuvant endocrine therapy and adjuvant chemotherapy significantly improve the disease-free and overall survival of patients with primary breast cancer, the absolute benefit is limited.1,2 Alternative treatment modalities are therefore desirable. We and others have shown that in vitro, estrogens or other steroids may induce the semisynchronous recruitment of a population of quiescent breast cancer cells into the cell cycle.3-5 Possibly these actively proliferating cells are more prone to the cytotoxic effects of chemotherapeutic agents.4,6-10

It thus may be that, in addition to the beneficial long-term effects of chemotherapy-induced castration,11 the relatively good results of adjuvant chemotherapy in premenopausal women can partly be explained by the natural priming of the breast cancer cells at the time of chemotherapy as a result of increased estradiol levels during the menstrual cycle. The negative effects of the antiestrogen tamoxifen on the efficacy of concomitantly administered chemotherapy in some premenopausal women may support this hypothesis.12,13

Priming of cancer cells by estrogens seemed to be promising in phase II studies of patients with metastatic or locally advanced breast cancer, as evidenced by the relatively high objective and complete response rates (65% to 75% and 22% to 47%, respectively).14-16 Furthermore, Lippman et al15 noted a longer duration of response with improved survival in subgroups of patients. Based on the here described laboratory and clinical studies, we initiated a randomized trial to study the efficacy of estrogenic recruitment before adjuvant chemotherapy in patients with primary breast cancer.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Eligibility Criteria
Women were eligible for this study if they had resectable primary breast cancer with at least one histologically verified positive axillary lymph node, a pathologic staging classification of T1-T3aN+M0 (American Joint Committee on Cancer staging system), and had been treated with radical mastectomy. Adjuvant chemotherapy had to be initiated within 15 days after surgery. Oral contraceptives should have been stopped at least 2 weeks before the start of chemotherapy. Exclusion criteria included the following: a Karnofsky performance status of less than 80, a WBC count of less than 3.5 x 109/L or a platelet count of less than 100 x 109/L, an abnormal liver or renal function (bilirubin > 30 µmol/L, gamma-glutamyltransferase [{gamma}-GT] > 30 IU/L; serum creatinine > 120 µmol/L), bilateral breast cancer, previous treatment for breast cancer or other neoplasms (except for adequately treated basal cell carcinoma or stage 0-I squamous cell carcinoma of the uterine cervix), current pregnancy or lactation, congestive heart failure or myocardial infarction less than 6 months before diagnosis of breast cancer, and rapidly progressive fatal illness other than carcinoma. All subjects gave informed consent, and the study was approved by the Dutch Cancer Society (Study KWF-CKVO 85-09).

Prestudy Screening and Follow-Up
Before entry onto the trial, all women were subjected to a history and physical examination, a chest x-ray, a mammogram, and a bone scan. Laboratory investigations included hemoglobin level, WBC count, platelet count, liver function tests (bilirubin, alkaline phosphatase, AST, ALT, lactate dehydrogenase, and {gamma}-GT) and renal function tests (urea, creatinine). Tumor specimens were assayed for estrogen receptor (ER) and progesterone receptor (PgR) levels by ligand-binding assay or enzyme immunoassay, as previously described.17 After treatment the subjects were followed every 6 months for 5 years and yearly thereafter. Each follow-up visit included a history and physical examination. Chest x-ray, mammography, complete blood cell count, and chemistry profile were performed annually.

Therapy Regimens
Four cycles of fluorouracil 500 mg/m2, doxorubicin 50 mg/m2, and cyclophosphamide 500 mg/m2 (the FAC regimen) were administered intravenously once every 4 weeks starting within 15 days after surgery. For subjects in the estrogenic recruitment group, each chemotherapy cycle was preceded by the oral administration of two doses of 0.5 mg ethinyl estradiol (EE2), 24 hours before and again at the time of administration of the FAC chemotherapy. The 4-week interval between the chemotherapy cycles was used to prevent cytopenia-related postponement of chemotherapy in a substantial number of patients who had received estrogen treatment the day before. The dose of 0.5 mg EE2 (at least 10 times greater than dosages used in contraceptive pills) was chosen to ensure increased plasma estrogen levels in both pre- and postmenopausal women. Short-term administration of physiologic or pharmacologic dosages of estrogen have been shown to increase the proliferation indices in endometrium, breast, and breast cancer.18-21 Adjuvant chemotherapy was started within 2 weeks after surgery because it had been demonstrated in some initial trials that early chemotherapy before radiotherapy resulted in longer relapse-free survival as compared with delayed chemotherapy.22,23 During the first chemotherapy cycle, the total dose of cyclophosphamide was divided equally over the first 5 days of therapy because it had been shown in some experimental studies that the labeling index of local and distant tumor foci increased after extirpation of the primary tumor.24,25 Subsequent chemotherapy cycles were postponed for 1 or 2 weeks if at the time of scheduled retreatment the WBC count was less than 3 x 109/L and/or the platelet count was less than 100 x 109/L. The FAC doses were adjusted when, after 2 weeks of postponement, no full hematologic recovery had been achieved. The patient then received one half of the doses of all three agents when the WBC count was between 2.0 and 3.0 x 109/L and/or the platelet count was between 75 and 100 x 109/L, whereas the subject went off study when the WBC count was less than 2 x 109/L and/or the platelet count was less than 75 x 109/L.

Radiotherapy
Radiotherapy to the chest wall, and incidentally also to the axillary nodes, was administered if there was tumor within 1 cm of the resection margins. Radiation was started after the four cycles of chemotherapy. The total dose of administered radiation was 46 Gy.

Statistical Methods
Relapse-free and overall survival were primary end points for the study. The trial was designed to detect an increase of 50% in the median relapse-free survival, with a power of 90% at a 5% significance level. To that end, 210 events needed to be observed and our target accrual was 432 patients. We expected to accrue this number of patients over 4 years. In fact, the accrual rate of the trial was lower than expected, and the trial was therefore closed after 6.5 years when 328 patients had been entered onto the study. Although fewer events were observed (n = 181), the power for the detection of an increase of 50% in the median relapse-free survival was still reasonable at 80%. Actuarial survival probabilities and curves were determined using the Kaplan-Meier method. For relapse-free survival analysis, subjects were considered to have failed treatment at relapse or at death and were censored at the date of last contact if alive without relapse.

For distant metastasis–free or local recurrence–free survival analyses, subjects were censored at the last follow-up appointment or at death without recurrence. Differences in relapse-free or overall survival between groups and associations between continuous covariates and failures rates were analyzed and tested using the Cox proportional hazards model. Differences in relapse-free or overall survival between the two treatment groups were tested with and without adjustment for prognostic factors.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient and Tumor Characteristics
Sixteen institutions (located in the southwest of the Netherlands) participated in the study, each contributing between two and 80 patients. Between October 1985 and May 1992, 328 patients were randomized to FAC adjuvant chemotherapy or FAC preceded by estrogenic recruitment (162 and 166 patients, respectively). Nine patients were found to be ineligible, five of whom were on FAC therapy and four of whom were on FAC plus EE2 treatment. Reasons for ineligibility were lumpectomy without mastectomy in three patients, pT4 tumor in three patients, distant metastases in two patients, and continuation of oral contraceptives therapy in one patient. One patient was not assessable because cyclophosphamide, methotrexate, and fluorouracil chemotherapy was administered instead of FAC. The analysis has been restricted to the 318 eligible and assessable patients. The two treatment groups were comparable with respect to patient and tumor characteristics (Table 1). There were a few (but not significantly) more subjects with PgR-negative tumors in the FAC + EE2 treatment group. The mean number of lymph nodes examined was 13 (range, two to 31 nodes), and the mean number of positive nodes was five (range, one to 28 nodes). The median duration of follow-up for subjects who are still alive is 6.8 years (range, 3 to 11 years).


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  		Table 1. Patient and Tumor Characteristics
 
Treatment Characteristics
The treatment was started at day 12 ± 3 (mean ± SD) after surgery. The mean dose administered for each of the three chemotherapeutic drugs varied between 97.8% and 99.1%, without significant differences between the two treatment groups. The side effects of the FAC chemotherapy were as expected for this well-known regimen. Treatment was well tolerated, and there were no toxicity-related hospital admissions nor treatment-related deaths.

Seventy-four women received adjuvant radiotherapy (38 in the FAC + EE2 and 36 in the FAC treatment groups, respectively). Radiotherapy was directed to the regional lymph nodes in 15 women and to the chest wall in 72 women. Of the latter group, only six of the 72 women (8%) experienced a chest wall relapse in contrast to 38 of 246 women (15%) who had not been treated with radiotherapy. Overall, these 72 women had a significantly (P = .02) poorer survival because of unfavorable tumor characteristics.

Relapse-free and Overall Survival
One hundred seventy-seven patients experienced a relapse, 123 of whom died (Table 2). Four additional patients died without documented relapse. No significant differences between the two treatment groups were observed with respect to the local recurrence–free and distant metastasis–free period (P = .96 and .76, respectively), nor with respect to relapse-free and overall survival (P = .66 and .72, respectively). The 5-year survival data for these four parameters are listed in Table 3. There were also no significant differences in the type of disease recurrences (Table 2). The survival curves for both treatment groups are nearly completely superimposable for all four parameters used (Fig 1).


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  		Table 2. Events
 

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  		Table 3. Actuarial 5-Year Probabilities and Relative Hazard Rates
 


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  		Fig 1. Relapse-free and overall survival and local recurrence–free and distant metastasis–free period by treatment group (——, FAC + EE2; - - -, FAC).

 
Overall, women with an ER/PgR-positive tumor tended to have a slightly better relapse-free survival rate at 5 years of follow-up compared with other patients (51% and 46%, respectively). When the analysis is restricted to these ER/PgR-positive patients, no significant differences between the two treatment groups were observed with respect to the 5-year relapse-free survival (EE2 + FAC, 52%; FAC, 49%).

Clinical Prognostic Factors
The prognostic value of various subject and tumor characteristics on 8-year actuarial relapse-free survival are indicated in Fig 2 and Table 4. As expected, large tumor size, large number of positive nodes, and negative ER or PgR status predicted a worse prognosis. There was no significant association between menopausal status or age and relapse-free or overall survival, although women younger than 40 years tended to have more early relapses (Fig 2) and a higher death rate, ie, an 8-year overall survival of 46% versus 60% and 56% in the other two age groups. Subjects with an ER-positive tumor had a lower relapse rate in the first 3 years of follow-up but a higher relapse rate after longer follow-up (Fig 2), resulting in the absence of a difference at 8 years.



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  		Fig 2. Relapse-free survival according to age, ER status, tumor size, differentiation grade, percentage of positive nodes, and number of positive nodes.

 

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  		Table 4. Impact of Prognostic Factors on Relapse-Free Survival
 
A multivariate analysis of these prognostic factors did not reveal a significant difference between the two treatment groups with respect to relapse-free survival or overall survival (P = .95 and .40, respectively). The prognostic value of the number versus that of the percentage of positive lymph nodes on the clinical outcome was addressed using three subgroups for each parameter. Patients were grouped according to the number of positive nodes: one to three positive nodes, four to 10 positive nodes, and more than 10 positive nodes (165, 118, and 33 patients, respectively). Using the percentage of positive nodes, patients were grouped accordingly: less than 40% positive nodes, 41% to 80% positive nodes, and more than 80% positive nodes (203, 61, and 39 patients, respectively). Both parameters were highly significantly associated with relapse rate, but the percentage of positive nodes showed even a more powerful prognostic value than the number of positive nodes (P = 5 x 10-11 and 1 x 10-6, respectively).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The concept of hormonal priming before chemotherapy is not new. However, at the time when we started our study, the role of estrogenic recruitment of breast cancer cells before chemotherapy was unclear. Several laboratory studies had demonstrated that short-term pretreatment of tumor cells with estrogens can increase the antitumor efficacy of cytotoxic drugs.4,6-10,26-30 Investigators have demonstrated an increase in proliferation in locally advanced tumors after several days of estrogen treatment.18,21,31,32 However, this procedure of estrogenic recruitment of tumor cells before chemotherapy did not seem to uniformly increase the proliferation fraction or improve response rates to subsequent chemotherapy.33 Nevertheless, some of the phase II studies that applied the principle of estrogenic recruitment therapy in locally advanced (Table 5) and metastatic disease (Table 6) initially showed relatively high (complete) response rates.14,16,21,32-37 Subsequently, a number of randomized studies in women with locally advanced or metastatic disease using different estrogen recruitment strategies and chemotherapy regimens were completed (Tables 5 and 6).15,38-44 Most studies of patients with advanced disease did not find differences in response rate and/or (progression-free) survival between the patient groups.


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  		Table 5. Clinical Trials of Hormonal Recruitment Strategies in Locally Advanced Breast Cancer
 

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  		Table 6. Clinical Trials of Hormonal Recruitment Strategies in Metastatic Breast Cancer
 
The possible reasons for these disappointing results in locally advanced and metastatic disease can be the application of suboptimal estrogen recruitment regimens, prior drug resistance, and, especially, tumor heterogeneity. In this adjuvant study, applying the principle of estrogenic recruitment therapy, we also found no additional benefit of such hormonal manipulation in earlier stage patients. Lack of benefit, in addition to the reasons mentioned above, might be caused by estrogen-induced resistance at the molecularlevel. In rat pituitary cells, estradiol induced the multidrug resistance protein leading to drug efflux, a mechanism that can protect the cells from the lethal effects of chemotherapy.45 Estrogens may also impede chemotherapy-induced apoptosis.46

Another explanation for the absence of a significant effect might be that our study is underpowered. The study had been designed for the detection of a rather large effect, eg, a 50% increase in the median relapse-free survival, which corresponds roughly with an absolute increase in 5-year relapse-free survival from approximately 50% to 63%. Moreover, the target accrual number of patients was not reached because of a low accrual rate, and, despite longer follow-up, fewer events (n = 181) have been observed than is required (n = 210) by the power calculations. Nevertheless, the power for the detection of an increase of 50% in the median relapse-free survival was still reasonable at 80%. However, a reduction or increase of the true 5-year probability of relapse by estrogenic stimulation of approximately 7% to 8% cannot be totally excluded. For the detection of effects of this size or even smaller (perhaps 5% benefit), much larger studies that include more than 2,000 to 3,000 patients would be required. Such studies—or a meta-analysis of similar randomized studies with sufficient numbers of patients and events—are required before definitive conclusions can be drawn.

In conclusion, we did not find that estrogenic recruitment with EE2 before FAC chemotherapy improved relapse-free or overall survival in women with node-positive, stage II and III breast cancer. This supports the findings of other randomized studies in more advanced stages of the disease.


   ACKNOWLEDGMENTS
 
Supported by the Dutch Cancer Society (study KWF-CKVO 85-09).

We thank P.J. van Assendelft, K.J. Roozendaal, Th.M. Dekkers, P.J.J. Leeuwerik, A.J. van der Hoorn, W.H. Ezendonk, and C.M.A. Geers for their contributions, M. Schutte for her comments, and F. Smits for typing the manuscript.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
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Submitted October 28, 1998; accepted October 28, 1999.




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