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© 2000 American Society for Clinical Oncology Activity of Exemestane in Metastatic Breast Cancer After Failure of Nonsteroidal Aromatase Inhibitors: A Phase II TrialFrom the Department of Oncology, Haukeland University Hospital, Bergen, Norway; Istituto Nazionale Tumori and Pharmacia & Upjohn, Milan, Italy; Peter MacCallum Cancer Institute, East Melbourne, Victoria, Australia; Centre Rene Huguenin, St Cloud, France; Marin Oncology Associates Inc, Greenbrae, CA; Instituto A.H. Roffo, Buenos Aires, Argentina; the Netherlands Cancer Institute, Amsterdam, the Netherlands; and Pharmacia & Upjohn, Kalamazoo, MI. Address reprint requests to Per Eystein Lønning, MD, Department of Oncology, Haukeland University Hospital, Bergen, N-5021, Norway; email plon{at}haukeland.no
PURPOSE: To evaluate the antitumor activity and toxicity of a new steroidal aromatase inactivator, exemestane, in postmenopausal women with metastatic breast cancer who had progressive disease (PD) after treatment with a nonsteroidal aromatase inhibitor. PATIENTS AND METHODS: In this phase II trial, eligible patients were treated with exemestane 25 mg daily (n = 241) followed, at the time PD was determined, by exemestane 100 mg daily (n = 58). RESULTS: On the basis of the intent-to-treat analysis by independent review, exemestane 25 mg produced objective responses in 6.6% of patients (95% confidence interval [CI], 3.8% to 10.6%) and overall success (complete response + partial response + no change for 24 weeks or longer) in 24.3% (95% CI, 19.0% to 30.2%). The median durations of objective response and overall success were 58.4 weeks (95% CI, 49.7 to 71.1 weeks) and 37.0 weeks (95% CI, 35.0 to 39.4 weeks), respectively. Increasing the dose of exemestane to 100 mg upon the development of PD produced one partial response (1.7%; 95% CI, 0.0% to 9.2%). Both dosages were well tolerated and were discontinued because of adverse events in only 1.7% of patients. CONCLUSION: Exemestane 25 mg once daily seems to be an attractive alternative to chemotherapy for the treatment of patients with metastatic breast cancer after multiple hormonal therapies have failed.
ENDOCRINE THERAPY is the treatment of choice for advanced breast cancer in postmenopausal patients with estrogen receptor–positive tumors and slowly progressive disease (PD).1,2 Tamoxifen is usually administered as first-line therapy,3 and progestins or aromatase inhibitors are used as second-line therapy.1,2 Importantly, exposure to endocrine treatment does not seem to hamper later response to chemotherapy.4 Because the goal of treating metastatic breast cancer is palliative,1 minimally toxic alternatives are needed to produce clinical benefit, as measured by the ability to ameliorate clinical symptoms, to maintain acceptable performance status and quality of life, and to delay the need for chemotherapy. Exemestane (Aromasin; Pharmacia & Upjohn, Milan, Italy) is a new, steroidal, irreversible aromatase inactivator that is distinguished from nonsteroidal aromatase inhibitors by its chemical configuration and mechanism of action. Most steroidal aromatase inhibitors are derivatives of androstenedione,5 the main substrate for the aromatase enzyme in postmenopausal women.6 In contrast to nonsteroidal aromatase inhibitors, which bind reversibly to the cytochrome P450 (heme) moiety of the aromatase enzyme, steroidal aromatase inactivators are false substrates that bind irreversibly to the substrate binding site of the aromatase enzyme, causing its inactivation.7,8 Consequently, exemestane is considered to be an aromatase inactivator, rather than an inhibitor. The results of recent studies revealed that another steroidal aromatase inactivator, formestane, causes tumor regression in patients with breast cancer that is resistant to aminoglutethimide.9,10 Exemestane, unlike formestane, can be administered orally and is a more potent enzyme inactivator in vivo.11,12 The protocol in the study presented here was designed as a phase II study to evaluate the antitumor activity of exemestane in postmenopausal patients with metastatic breast cancer who had experienced a primary or acquired failure of aminoglutethimide or one of the novel, potent nonsteroidal aromatase inhibitors of the triazole class. We also evaluated the extent of serum estrogen suppression and the toxicity of exemestane.
Study Design This study was designed as an open-label, uncontrolled, two-part, multinational clinical trial with the participation of 75 centers in 16 countries. Initially, patients received exemestane 25 mg daily, the dose being used in clinical development on the basis of previous endocrine and toxicity data.13 At the time of disease progression, patients who were considered candidates for further endocrine therapy were offered dose escalation to exemestane 100 mg daily. The primary study objectives were to evaluate the antitumor activity and toxicity of the usual dose of exemestane, 25 mg daily. The secondary objectives were to evaluate the extent of estrogen suppression, compared with that in previous treatments, the relationship between antitumor activity and subjective response treatment, and the antitumor activity of exemestane dose escalation at the time of progression.
Patient Population The exclusion criteria were as follows: prior therapy with a steroidal aromatase inactivator or more than one nonsteroidal aromatase inhibitor(s); more than one prior chemotherapy regimen for metastatic disease or high-dose chemotherapy with stem-cell rescue; low probability of response to hormonal therapy because of inflammatory breast cancer, rapidly progressive disease, brain or leptomeningeal metastases, or extensive visceral metastases; chemotherapy-induced amenorrhea for less than 2 years and age less than 60 years; and previous or concomitant malignancies other than adequately treated skin cancer or in situ carcinoma of the uterine cervix. All patients gave written or oral witnessed informed consent according to local regulations.
Drug Administration
Assessments Compulsory baseline tumor assessments consisted of a physical examination, chest x-rays, liver ultrasound or computed tomography scan, and total body skeletal scintigram. If the scintigram revealed focal increased uptake, the affected area was evaluated by x-rays, computed tomography scan, or magnetic resonance imaging. Antitumor response was determined according to modified World Health Organization criteria. CR was defined as the disappearance of all known lesions without any new lesions. PR was defined as at least a 50% decrease in the sum of the product of the perpendicular diameters of all measurable lesions, without any new lesions or progression of existing lesions. Objective responses (ie, CR + PR) had to be confirmed by a second assessment performed 4 weeks or longer after the first assessment. PD was defined by a 25% or greater increase in the size (products of the diameters) of one or more lesions, the appearance of any new lesions, or the requirement for radiotherapy, surgery, or other antitumor treatment for palliation of symptomatic lesions after 8 or more weeks of therapy. NC was defined as a less than 50% decrease or a less than 25% increase in measurable disease without any new lesions, the stabilization of assessable disease for 8 or more weeks without any new lesions, or failure to meet the criteria for CR, PR, or PD. Each case determined by the investigator to be an objective response or NC for 24 or more weeks was reviewed by an independent panel composed of one oncologist and one radiologist. In the event of controversy, the case was brought to a peer-review committee, which consisted of two oncologists and two radiologists. Standard definitions were used to determine the duration of objective response, time to progression, time to treatment failure, and time to death (survival). To evaluate whether any effect of exemestane could be due to enhanced estrogen suppression after treatment with the previous nonsteroidal aromatase inhibitor, serum estrone (E1), estradiol (E2), and estrone sulfate (E1S) levels were measured just before treatment with the previous nonsteroidal aromatase inhibitor was terminated. Subsequent samples were obtained just before treatment with exemestane 25 mg daily was commenced; after weeks 8, 16, 24, 36, and 48 on therapy; and at the time therapy was discontinued (PD). After dose escalation, estrogen levels were measured only at week 8 of treatment with exemestane 100 mg. Samples were assayed by a procedure consisting of solid-phase extraction and high-performance liquid chromatography purification followed by specific radioimmunoassay by the Pharmacology Department at Pharmacia & Upjohn (Nerviano, Italy).13 The detection limits of the assay were 2.6, 6.7, and 22 pmol/L for E2, E1, and E1S, respectively. Subjective status was evaluated at baseline and at each visit as performance status, tumor-related signs and symptoms (TRSSs), and quality of life. Performance status was assessed by the ECOG scale. An overall pain score was calculated on a 15-point scale.15 TRSSs other than pain were graded according to National Cancer Institute Common Toxicity Criteria (NCI CTC). For all TRSSs, the average severity grade over the previous week was recorded. Quality of life was measured by the European Organization for Research and Treatment of Cancer QLQ-C30 quality-of-life questionnaire.16 Toxicity assessments consisted of physical examination, monitoring of hematology and blood chemistry, urinalysis, and ECG. Severity was graded by NCI CTC.
Statistical Analysis Response rates and their 95% confidence intervals (95% CIs) were calculated. Kaplan-Meier methods were used to analyze the duration of objective response and overall success, TTP, TTF, and survival. Serum estrogen (E1, E2, and E1S) levels were summarized for each visit in terms of geometric mean and 95% CIs. In the subset of patients for whom estrogen determinations were available both within 1 day after discontinuation of previous nonsteroidal aromatase inhibitor therapy and after 8 weeks of exemestane 25 mg, a statistical comparison was performed by the Wilcoxon matched-pairs signed-ranks test. Furthermore, the estrogen levels at these visits in the two subsets of patients (ie, on previous aminoglutethimide versus other nonsteroidal aromatase inhibitors) were compared by the Wilcoxon rank sum test.
For subjective response, descriptive statistics were provided for each multi-item scale and single-item measure comprising the QLQ-C30. Overall pain score was calculated as the sum of physician-assessed pain score, analgesic consumption score, and performance status. On-treatment changes in TRSS were summarized according to best tumor response. A total score was calculated at each visit by summing up the worst NCI CTC grade of each TRSS, and the relevant score was compared with baseline. The association between the best tumor response and evolution trend in TRSS was evaluated by the Adverse events were coded by World Health Organization Adverse Reaction Terminology and described in terms of severity and most-likely cause. Laboratory results were graded according to NCI CTC classification whenever possible.
Patient Population Between April 1995 and October 1997, 242 patients were enrolled onto the study. One patient was withdrawn before starting treatment because her postmenopausal status was not confirmed. There were no major differences in demographic or pretreatment characteristics between the subsets after failure of previous aminoglutethimide versus other aromatase inhibitors (Table 1). Bisphosphonates were used by a total of 27 patients during treatment with exemestane. Of these 27, 18 continued the therapy that was initiated before study enrollment. Bisphosphonate therapy was initiated during the study in nine patients, seven of whom received them at only one study visit and one of whom received them at two study visits. The remaining patient received a bisphosphonate from week 8 through week 40.
The median duration of follow-up was 37 weeks (range, 2 to 137 weeks), and the median duration of treatment with exemestane 25 mg daily was 16 weeks (range, 1 to 113 weeks). Eleven patients (4.5% of total) were still being treated at the cutoff date for analysis. The reasons for discontinuation were PD (n = 213 [88.0% of total]), death (n = 7), patient refusal (n = 5), toxicity/adverse event (n = 4), increased serum tumor markers (n = 1), and patient noncompliance (n = 1). Forty-three patients (17.8% of total) did not complete the first 8 weeks of treatment because of PD (n = 35 [81.4% of early withdrawals]), toxicity/adverse event (n = 3), patient refusal (n = 3), and death (n = 2). Fifty-nine patients were eligible for dose escalation to 100 mg of exemestane daily, but one patient withdrew consent before receiving treatment. Among the 58 treated patients, the median duration of follow-up was 52 weeks (range, 3 to 130 weeks), and the median duration of treatment was 10 weeks (range, 2 to 74 weeks). The reasons for discontinuation were PD (n = 57 [96.6% of total]), toxicity/adverse event (n = 1), and patient refusal (n = 1). Sixteen patients did not complete the first 8 weeks of treatment because of PD (n = 15 [93.8% of early withdrawals]) and toxicity/adverse event (n = 1).
Efficacy
Responses were observed across a broad range of underlying disease characteristics and other prognostic factors that might have impacted the efficacy of exemestane 25 mg daily (Table 3). The objective response and overall success rates were 25.0% and 50.0%, respectively, if the predominate disease site was soft tissue only; 6.3% and 24.1% for bone disease with or without soft tissue; and 2.3% and 18.0% for visceral disease with or without other sites. The objective response and overall success rates were 8.1% and 27.2%, respectively, for patients whose prior nonsteroidal aromatase inhibitor was aminoglutethimide only; the corresponding rates were 4.8% and 20.0%, respectively, for those who had received other nonsteroidal aromatase inhibitors.
Median survival could not be estimated because there were only 88 deaths (36.5%) at the time of analysis. Figure 1 shows the survival curves for patients who did and did not respond to treatment.
Dose escalation of exemestane to 100 mg after PD at 25 mg daily produced one PR, for an objective response rate of 1.7% (95% CI, 0.0% to 9.2%). An additional six patients had long-term disease stabilization, for an overall success rate of 12.1% (95% CI, 5.0% to 23.3%). The median durations of objective response and overall success were 50.0 weeks (95% CI, not estimable) and 37.0 weeks (95% CI, 26.7 to 50.0 weeks), respectively. Median survival could not be estimated because there were only 25 deaths (43.1%) at the time of analysis.
Estrogen Suppression
Compared with values obtained just before previous therapy was terminated, treatment with exemestane 25 mg for 8 weeks further suppressed mean serum E2, E1, and E1S levels to 3.1, 12.3, and 106 pmol/L, respectively, in patients previously exposed to aminoglutethimide (P < .0001; Table 4). In contrast, mean estrogen levels were similar during treatment with exemestane, compared with those obtained just before treatment with other nonsteroidal aromatase inhibitors was terminated (P > .2; Table 4). In both groups, treatment with exemestane maintained estrogen suppression up to at least 48 weeks (Fig 2), with no evidence of an escape phenomenon, even in patients with PD. Furthermore, E2 levels were below the detection limit of the assay in at least 53% of patients during the entire study period.
Eight weeks of treatment with exemestane 100 mg did not further suppress mean serum E2, E1, and E1S levels (Fig 2).
Subjective Response
Toxicity
Five patients were withdrawn from the study because of adverse events during treatment with exemestane 25 mg daily (n = 4 [1.7%]) or 100 mg daily (n = 1 [1.7%]). These adverse events were not related to treatment in three patients. The two treatment-related adverse events were reversible after treatment with exemestane was discontinued and consisted of one case each of grade 2 nausea and grade 3 confusion during treatment with exemestane 25 and exemestane 100 mg, respectively. The percentage of patients with abnormal laboratory test results remained essentially constant for all parameters throughout the study for both doses of exemestane. Grade 4 abnormalities were sporadic and consisted primarily of lymphocytopenia (6.0% for both doses of exemestane) and increased gamma-glutamyl transferase levels (2.8% for exemestane 25 mg only). The only grade 4 laboratory abnormality that was related to the study drug was an increased gamma-glutamyl transferase level during week 8 of treatment with exemestane 25 mg in a patient who developed massive PD in the bone immediately after the visit in which the increased transferase level was noted; no further laboratory assessments were carried out in this patient. Clinically relevant abnormalities of non–CTC-graded parameters were also infrequent and primarily consisted of variations in blood electrolyte levels.
This study demonstrates the safety and antitumor activity of third- or fourth-line therapy with exemestane 25 mg once daily in postmenopausal patients with metastatic breast cancer following PD after treatment with nonsteroidal aromatase inhibitors. Exemestane produced objective responses in 6.6% of treated patients, including 8.1% and 4.8% of patients after failure of treatment with aminoglutethimide and other nonsteroidal aromatase inhibitors, respectively. In view of the palliative goal of treatment in this setting,1 it is reasonable to consider disease stabilization (ie, NC for 24 weeks or longer) as a clinical outcome. The 24.3% overall success rate (CR + PR + NC for 24 weeks or longer) suggests that a meaningful percentage of patients in our study benefited from treatment with exemestane 25 mg daily. Notably, the duration of objective response (median, 58 weeks) as well as overall success (median, 37 weeks) was substantial. The finding that exemestane was more active in patients with soft tissue disease only (50%) concurs with observations in patients treated with nonsteroidal aromatase inhibitors such as anastrozole17 and letrozole.18 It should be noted, however, that exemestane also had some activity when the predominant disease site was the viscera. These efficacy results are noteworthy because unfavorable characteristics were prevalent in our patients. Ninety-eight percent of our patients received exemestane as third- or fourth-line hormonal treatment, and 51% had previously received chemotherapy. Half had viscera as the predominant disease site, and one third did not benefit from therapy with a nonsteroidal aromatase inhibitor. In general, these patients had been offered chemotherapy at this stage. Considering the limited value of second- and third-line chemotherapy in patients with metastatic breast cancer,19–21 the benefits obtained by the addition of an additional endocrine regimen are clinically significant. The literature on third- and fourth-line hormonal therapy is limited. Although there are several reports that anecdotally mention response to third-line endocrine therapy, we are aware of only four studies that specifically evaluate response to third-line hormonal therapy.9,22–24 Objective response rates ranged from 18% to 26%; however, only two studies23,24 required confirmation of response at a second visit and only Thürlimann et al24 required confirmation by independent review. Interestingly, only 10% of 263 patients had objective responses to second-line anastrozole 1 mg in a large, well-designed phase III study, which included response documentation on two occasions (but not independent review) and intent-to-treat analysis.17,25 These observations underscore the importance of considering study design and response criteria when comparing results from different studies. Interestingly, exemestane was associated with responses in patients who had not responded to prior hormonal therapy (Table 3). It should be noted that the correlation between response to previous and subsequent therapy is generally based on experience with the transition from first- to second-line therapy, and we do not have similar evidence regarding the predictive value of previous responses to third- and fourth-line therapy. The clinical efficacy observed in the study presented here suggests a lack of cross-resistance between exemestane and nonsteroidal aromatase inhibitors. One possible explanation is that exemestane is more potent than aminoglutethimide, on the basis of the in vivo inhibition of aromatase12,26 and the suppression of plasma estrogen levels reported in this and other studies.13,27 Consistent with this hypothesis, Thürlimann et al24 reported that third-line exemestane 200 mg produced objective response and overall success rates of 26% (95% CI, 16% to 37%) and 39% (95% CI, 28% to 50%), respectively. We are reluctant to attribute this potentially higher response rate to differences in dose because of the lack of benefit from increasing the dose in our study. The patient population seemed to be similar to ours; however, the sample size was smaller (n = 80), women who had failed treatment with other nonsteroidal aromatase inhibitors were excluded, and a higher percentage of patients had soft tissue disease (22%). Interestingly, the upper limits of the confidence interval for the objective response rate in the subset that had failed previous treatment with aminoglutethimide 500 mg in our study (95% CI, 4.1% to 14.0%) approached the lower limits in the study by Thürlimann et al. Better aromatase inhibition and plasma estrogen suppression could explain the responses to exemestane after treatment failure with aminoglutethimide, but this hypothesis does not explain the responses to exemestane after treatment failure with the novel, potent nonsteroidal aromatase inhibitors. Other studies revealed that the degree of total body aromatase inhibition was similar for exemestane (97.9%),12 compared with anastrozole (96%)28 and letrozole (98.9%).29 Furthermore, exemestane did not further suppress circulating estrogens in patients who had previously been exposed to other nonsteroidal aromatase inhibitors in the study presented here. Therefore, the activity of exemestane in this subset must be due to some other effect. One possibility is the differences in pharmacologic effects on intratumor aromatase or in local pharmacokinetic profiles between the drugs. Alternatively, exemestane could also be working through a hormonal mechanism in addition to aromatase inhibition, such as local stimulation of the androgen receptor within the breast tissue. Contrary to exemestane itself, which has no androgenic activity,5 the 17-hydroxyexemestane metabolite, which is formed by reduction of the 17-oxo group via 17-beta-hydroxysteroid dehydrogenase, has weak androgenic activity,13 which could contribute to antitumor activity. However, when exemestane is administered at its regular dose of 25 mg daily, systemic activity of the 17-hydroxyexemestane metabolite is minor, as determined by only minor influence on circulating sex-hormone binding globulin concentrations.13 In all conditions, exemestane maintained estrogen suppression for at least up to 48 weeks, even when patients developed PD. This finding suggests that PD was not due to a loss of estrogen-suppressing activity of exemestane but to other mechanisms at the tumor level. The 100-mg dose maintained, but did not further suppress, estrogen levels compared with the 25-mg dose, which is consistent with the results of previous studies which showed that maximal suppression occurs at a daily dose of 25 mg.13,30 It is not surprising that exemestane was not associated with improved quality-of-life parameters because at baseline, patients had a low pain score (median score, 13), and 89% of patients had an ECOG performance status of 0 or 1. Importantly, treatment was not associated with deterioration of subjective parameters, which could be considered to be clinically relevant in patients who are candidates for third- or fourth-line hormonal therapy. Both doses of exemestane were well tolerated in our study. Most treatment-related adverse events were of mild to moderate severity and did not interfere with treatment. The three most frequent drug-related adverse events were nausea, fatigue, and hot flushes; however, each of these events occurred in only 7.5% to 10.8% of patients. In conclusion, our findings suggest a lack of complete cross-resistance between nonsteroidal aromatase inhibitors and steroidal aromatase inactivators, which seems to have clinical implications. Exemestane 25 mg once daily seems to be an attractive alternative to chemotherapy for the treatment of patients with metastatic breast cancer after failure of multiple hormonal therapies, especially for those patients with predominantly soft tissue disease.
We thank all of the principal investigators, especially those not named as authors (see below), and our coinvestigators, especially G.B. Anker from Haukeland University Hospital, Bergen, Norway, and Martin Muller from the Netherlands Cancer Institute, Amsterdam, the Netherlands. ARGENTINA: Dr D. Campos, Hospital de San Isidro, Buenos Aires; Dr C. Delfino, Hosp. Priv de la Comunidad, Mar del Plata, Buenos Aires; Dr L.E. Fein, Ctro. Oncol. de Rosario, Rosario Santa Fe; Dr R. Wainstein, Hospital Pasadas, Haedo Buenos Aires; and Dr S. Zunino, Inst. Priv. de Radioterapia, Nueva Cordoba. AUSTRALIA: Prof P.G. Gill, Royal Adelaide Hospital, Adelaide, South Australia; and Dr M.D. Green, Royal Melborne Hospital, Parkville, Victoria. AUSTRIA: Dr W. Scheithauer, I. Med. Univ. Klinik, Vienna. BELGIUM: Dr D. Becquart, A.Z. Middelheim, Antwerpen; Dr J.L. Canon, Clinique Notre Dame, Charleroi; Dr L. Dirix, St Augustinusziekenuis, Antwerpen; Prof J. De Grève, A.Z. VUB, Brussels; Dr C. Focan, C.H. St Joseph/Espérance, Liège; Prof J. Longueville, Cliniques Univer. St Luc, Brussels; Dr F. Maisin, Clinique Ste Elisabeth, Namur; Dr J. Michel, Hôpital de Tivoli, La Louviere; Prof R. Paridaens, U.Z. Gasthuisberg, Leuven; Prof M. Piccart, Institut J. Bordet, Brussels; Dr A. Prové, UZ Antwerpen, Edegem; Prof J.P. Van Belle, U.Z. Gent, Gent; and Dr H. Wassenaar, St Vincentiusziekenhuis, Antwerpen. Denmark: Dr J. Andersen, AarhusKommunehospital, Aarhus C. FRANCE: Dr G. Auclerc, Hôpital Salpetriere, Paris; Dr J. Bonneterre, Centre Oscar Lambert, Lille; Prof P. Chollet, C.A.C. Jean Perrin, Clermont-Ferrand; Dr T. Delozier, Centre Francois Baclesse, Caen; Dr E. Garcia Giralt, Institut Curie, Paris; Dr J.P. Guastalla, Centre Leon Berard, Lyon; and Dr H. Roche, Centre Claudius Regaud, Toulouse. GERMANY: Dr Engelhardt, Med Universitätsklinik Freiburg, Freiburg; Dr Marschner, Oncologic Practice Tumor Center, Freiburg; and Prof H. Wilke, Universitätsklinikum Essen Zentrum für Tumorforschung, Essen. ISRAEL: Dr H. Lurie, Institute of Oncology, Belinson Medical Center. NETHERLANDS: Dr L.V.A.M. Beex, Academisch Ziekenhuis St Radboud, Nijmegen; Dr F.L.G. Erdkamp, Maaslandziekenhuis Sittard, Sittard; Dr M.A. Nooy, Academisch Ziekenhuis Leiden, Leiden; Dr J.W.R. Nortier, Diakonessenhuis, Afdeling Inwendige Geneeskunde, Utrecht; Dr A. van Bochove, St Ziekenhuis "De Heel," Afdeling Inwendige Geneeskunde, Zaandam; Dr J.B. Vermorken, Academisch Ziekenuis VU, Afdeling Inwendige Geneeskunde, Amsterdam; and Dr J. Wals, Ziekenhuis de Wever en Gregorius, Brunssum. NORWAY: Dr R. Telhaug, Regionsykehuset i, Trondheim. RUSSIA: Prof M. Gershanovich and Prof N.N. Petrov Research Institute of Oncology, St Petersburg. SOUTH AFRICA: Prof W.R. Bezwoda, Johannesburg General Hospital, Department of Oncology, Parktown; Prof L. Goedhals, National Hospital, Bloemfontein; Prof J.P. Jordaan, Addington Hospital, Durban; and Dr D.A. Vorobiof, Sandton Oncology Center, Johannesburg. SWITZERLAND: Dr J.K. Thürlimann, Kantonsspital St Gallen, St Gallen. UNITED KINGDOM: Dr P. Barrett-Lee, Velindre Hospital, Cardiff; Dr M.B. McIllmurray, Royal Lancaster Infirmary, Lancaster; Prof R.D. Rubens, ICRF Department of Clinical Oncology, Guy’s Hospital, London; and Dr A. Stewart, Christie Hospital and Holt Radium Hospital, Manchester. UNITED STATES: Dr R.F. Berris, Colorado Cancer Research Program Inc, Denver, CO; Dr A. Buzdar, The University of Texas M.D. Anderson Cancer Center, Houston, TX; Dr N.V. Dimitrov, Michigan State University, Department of Medicine, East Lansing, MI; Dr M. Greenhawt, South Florida Oncology-Hematology, Aventura, FL; Dr J. Gutheil, Clinical Oncology Research, Sharp HealthCare, Sidney Kimmel Cancer Center, San Diego, CA; Dr E. Krill, Mount Sinai Comprehensive Cancer Center, Miami Beach, FL; Dr J. Kugler, Oncology/Hematology Associates, Peoria, IL; Dr J.A. Mailliard, Creighton Cancer Center, Omaha, NE; Dr D. Merkel, Evanston Hospital, Evanston, IL; Dr M.W. Meshad, The Cancer Center at Providence Hospital, Mobile, AL; Dr H. Muss, Fletcher Allen Health Center, Burlington, VT; Dr D.C. Osborn, Western Washington Cancer Center, Olympia, WA; Dr E.P. Winer and Dr L. Parker, Dana-Farber Cancer Institute, Boston, MA; Dr D. Prager, University of California, Los Angeles Division of Hematology/Oncology Cancer Therapy Development Programs, Los Angeles, CA; Dr L. Sutton, Duke University Medical Center, Durham, NC; Dr K. Tkaczuk, Marlene and Stewart Greenebaum Cancer Center, University of Maryland, Baltimore, MD; Dr N. Valente, University of California, San Francisco, Division of Hematology/Oncology, San Francisco, CA; and Dr C.L. Vogel, Columbia Cancer Research Network of Florida, Plantation, FL.
Supported by a grant (protocol no. EXE-017) from Pharmacia & Upjohn, Milan, Italy. We thank our colleagues from Pharmacia & Upjohn, including Antonello Abbattista (data management and analysis), Alessandra Consonni, Silvana Lanzalone, Ornella Mariani, and Marsha Royer (study and data management); Maria Luisa Bonanomi and Paola di Nicolò (data management); Jolanda Paolini (serious adverse events management); Giorgio Ornati (pharmacodynamic assays); and Gabriella Piscitelli (previous clinical program director). We also thank Cindy W. Hamilton for her assistance during the preparation of the manuscript.
Preliminary findings of this study have previously been published in abstract form (Lønning PE, Bajetta E, Murray R, et al: A phase II study of exemestane (EXE) in metastatic breast cancer (MBC) patients failing nonsteroidal aromatase inhibitors (ns-AIs). Breast Cancer Res Treat 50:304, 1998 [abstr 435]).
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ABSTRACT
INTRODUCTION
.10 was to be tested against the alternative P1 
.20, assuming a significance level of alpha = 0.05 and a power of 1 - beta = 0.80. Approximately 200 patients were to be accrued to provide at least 83 assessable patients in each of these two groups. After dose escalation to exemestane 100 mg daily, accrual was stopped if no objective response was recorded among the first 11 patients. 
2 test with 4 df. 
