This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Boccardo, F. Articles by Mustacchi, G. Search for Related Content PubMed PubMed Citation Articles by Boccardo, F. Articles by Mustacchi, G. Social Bookmarking                            What's this?

Sequential Tamoxifen and Aminoglutethimide Versus Tamoxifen Alone in the Adjuvant Treatment of Postmenopausal Breast Cancer Patients: Results of an Italian Cooperative Study

From the Professorial Unit of Medical Oncology, Biostatistics Unit, University and National Cancer Research Institute; and Department of Medical Oncology, Ospedali Galliera, Genoa; Institute of Oncology, University of Messina, Messina; Department of Clinical Oncology, University of Sassari, Sassari; Department of Oncology, Umberto I Hospital, Lugo di Romagna; Department of Radiochemotherapy, San Raffaele H Scientific Institute, Milan; Department of Medicine, General Hospital, Saronno; and Oncologic Center, University of Trieste, Trieste, Italy.

Address reprint request to Francesco Boccardo, MD, Professorial Unit of Medical Oncology, University and National Cancer Research Institute, Largo R Benzi 10, 16132 Genoa, Italy; email: boccardo{at}hp380.ist.unige.it

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
PURPOSE: To determine whether switching patients from tamoxifen to antiaromatase treatment would prevent some of the relapses or deaths that we assume would occur if tamoxifen were continued.

PATIENTS AND METHODS: Three hundred eighty postmenopausal breast cancer patients receiving adjuvant tamoxifen treatment for 3 years were randomized to either continue tamoxifen for 2 more years or to switch to low-dose aminoglutethimide (250 mg daily) for 2 years.

RESULTS: At a median follow-up of 61 months (range, 5 to 94 months), 59 events occurred in the tamoxifen group, and 55 occurred in the aminoglutethimide group. More treatment failures at distant sites, such as viscera (P = .02), were observed in the tamoxifen group. Although no differences in disease-free survival between the two groups have emerged so far, a significant trend favors aminoglutethimide in overall survival (P = .005) and breast cancer–specific survival (P = .06). Even if more patients in the antiaromatase group complained of drug-related side effects and more of them discontinued treatment (P = .0001), the number of cardiovascular events and, in general, of life-threatening adverse events was higher in the tamoxifen arm.

CONCLUSION: Switching patients from tamoxifen to aminoglutethimide treatment resulted in comparable event-free survival, but longer overall survival was achieved in patients who were switched to aminoglutethimide as compared with those who continued to receive tamoxifen. Should these preliminary results be confirmed by larger studies with a similar design, which are now testing the effectiveness of the new, more active, and tolerable aromatase inhibitors, sequencing tamoxifen with an aromatase inhibitor could become a preferable alternative to tamoxifen alone in early breast cancer patients.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
TAMOXIFEN IS an established treatment for postmenopausal women with early breast cancer and in particular for women with estrogen receptor (ER)–positive tumors.¹ The most recent overview confirmed that even 1 or 2 years of tamoxifen treatment can significantly reduce the risk of relapse and death for these women and that the clinical benefits increase as tamoxifen administration is prolonged.² However, the same overview also confirmed that prolonging tamoxifen administration leads to an increased risk for endometrial cancer.² Although no increase in breast cancer–unrelated mortality emerged from the overview data,² uterine cancer represents an undoubtedly life-threatening complication associated with tamoxifen therapy.^3,4 Moreover, several trials have shown that other life-threatening complications, including thromboembolic events and stroke,^5,6 might be associated with tamoxifen use. Our aim was to develop a new strategy that could minimize the hazards associated with long-term antiestrogenic treatment and could improve treatment effectiveness. Switching patients who are being treated with tamoxifen to a different hormonal treatment before the onset of tamoxifen resistance or tamoxifen-dependent tumor growth seems logical. This should be pursued especially if the alternative treatment is devoid of the side effects tamoxifen has on the endometrium and on blood clotting as well as any obvious cross-resistance with this drug. Aminoglutethimide was chosen for the following reasons: it was a common therapeutic option for patients with metastatic disease who did not respond to front-line treatment with tamoxifen and had proven to be beneficial to a significant number of such patients⁷; it represented the only aromatase inhibitor to have been successfully tested in the adjuvant setting with an acceptable level of safety⁸; and it was the only aromatase inhibitor available to our group at the time this trial was conceived.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Postmenopausal women with histologically proven ER-positive (defined as tissue containing 10 fmol of cytosolic ER protein or positive immunostaining of 10% tumor cells with specific anti-ER monoclonal antibodies) or undetermined tumors who had already been receiving tamoxifen for an average of 3 years were eligible for this study. Patients were admitted regardless of nodal status, tumor grade, or primary treatment of their disease (including adjuvant chemotherapy) provided that tumor relapse could be ruled out by clinical examination, mammography, chest x-ray, bone scan (and bone x-rays when necessary), and liver sonography. We required tumor marker (carcinoembryonic antigen and carcinoma-associated glycoprotein 15-3) levels as well as blood counts and biochemical tests to be within the normal range. Postmenopause was defined by the absence of regular menses for more than 12 months. Patients with regular menses at the time of tumor diagnosis were also eligible provided they had become postmenopausal according to the previous definition by the time of randomization. This occurred more commonly in patients that had previously been treated with adjuvant chemotherapy.

Assigned Treatment and Method of Randomization
Randomization was carried out by telephone at a central office in the National Cancer Research Institute of Genoa, Italy, and was based on random number tables. Treatment assignment was split equally into blocks of varying sizes, and specific lists of randomization were available for each participating center. The clinicians did not know which treatment would be assigned until the patient identifiers had been recorded centrally. None of the patients who had been assigned to treatment were subsequently withdrawn from the study.

Patients were randomly allocated to either continue tamoxifen at the same daily dose as before for 2 more years or to be treated for a comparable period of time with aminoglutethimide. To improve compliance to adjuvant treatment with this aromatase inhibitor, a low dose (ie, 250 mg daily) was selected for this trial. This dose required no corticosteroid supplementation and seemed to yield comparable results compared with the higher doses commonly used in patients with metastatic disease.⁹ We allowed patients who might have been potentially suitable for the trial but who had not yet completed 3 years of treatment with tamoxifen to register with the central office.

Efficacy and Tolerability Assessment
All the randomized patients were followed-up at regular intervals. Clinical examinations, blood counts, and biochemical tests (including carcinoembryonic antigen and carcinoma-associated glycoprotein 15-3) were carried out every 3 months for the first 2 years after randomization and then every 6 months afterward. Adverse events were recorded during each visit and scored according to World Health Organization criteria.¹⁰ Chest x-rays and mammography were repeated yearly. All the other examinations, including bone scan and liver sonography, were repeated when required. The status of any patient who did not come to her examination was contacted by telephone to confirm she was still alive.

Ethical Approval
All patients signed an informed consent form. Approval by the local ethics committee was also obtained by each participating center.

Statistical Analysis
The percentage of patients who experienced event-free survival (EFS) or overall survival was computed by the Kaplan-Meier estimate.¹¹ The events used to calculate EFS included first local recurrence of disease, regional and distant metastases, ipsilateral breast tumor relapse after lumpectomy, occurrence of tumor in the contralateral breast, occurrence of second primary tumors, and death as a result of causes other than breast cancer. Death from all causes was included in the analysis of overall survival. The statistical significance of the differences between treatments was determined by the log-rank test.^12,13 All P values were derived from two-sided test for significance. The ² test or Fisher’s exact test was used to compare groups with respect to the incidence of side effects and distribution of events.

Sample Size
It was estimated that 685 patients, recruited over 5 years, would ensure a power of 80% (with an alpha error equal to 5%) to detect a 7% difference in the 5-year survival rate in favor of the patients assigned to aminoglutethimide, which assumes a 5-year survival rate of 78% for the patients who continue tamoxifen. This difference implied that switching to aminoglutethimide would decrease the annual 5% death rate assumed for the patients who continue tamoxifen by approximately one third.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
This trial failed to recruit the number of patients that was originally planned, which was mainly because of the following reasons: the higher incidence of acute side effects that occurred in patients who had switched to aminoglutethimide was not only the cause of a higher discontinuation rate observed in those patients, but it also discouraged some of the participating centers from continuing recruitment. In 1998, anastrozole, a third-generation aromatase inhibitor, which was expected to be more potent and better tolerated than aminoglutethimide,¹⁴ became available to our group. Therefore, participating centers agreed it might be more appropriate to stop patient recruitment onto the present trial and to start up a new trial with anastrozole, adopting a comparable study design to allow us to pool the data of the two studies.

Six hundred sixty-two patients were centrally registered, and 380 were randomized between September 1992 and January 1998. At the time of analysis, median time on the study was 61 months (range, 5 to 94 months), and 114 events, including 45 deaths, had occurred. The two groups did not differ significantly for age, tumor size and grade, number of involved nodes, receptor status, treatment of primary tumor, percentage who received prior chemotherapy, and previous time on tamoxifen (Table 1). There were 59 events in the tamoxifen group, including seven second primaries and 10 breast cancer–unrelated deaths, and 55 events in the aminoglutethimide group, including 11 second primaries and two breast cancer–unrelated deaths. Tables 2 and 3 provide details about tumor relapse, second primaries, and causes of death. Patients in the tamoxifen group experienced more treatment failures at distant sites, namely in the viscera (the latter difference is statistically significant, P = .02). By contrast, patients who switched to aminoglutethimide experienced more local-regional treatment failures and, as a consequence, more treatment failures in the soft tissues. There were no major differences between the two groups regarding the number of second primaries. However, five patients in the aminoglutethimide group developed carcinoma in the contralateral breast, as compared with two in the tamoxifen group. One patient per group developed endometrial carcinoma. A greater number of both breast cancer–related deaths and breast cancer–unrelated deaths occurred in the tamoxifen group. Most of the breast cancer–unrelated deaths that occurred in the tamoxifen group were cardiovascular. There was no difference in EFS between the groups (Fig 1). However, there was a trend in favor of patients who had switched to aminoglutethimide relative to both overall (P = .005) and breast cancer–specific survival (P = .06) (Fig 2A and B). Treatment-related side effects were more common in the patients who had switched to aminoglutethimide. In particular, significantly more patients in this group complained of gastrointestinal symptoms (P = .003), skin symptoms (P = .0001), and fatigue (P = .02), and a significantly higher number of patients had to discontinue the assigned treatment because of acute side effects (14% v 4%, P = .0001) (Fig 3). However, serious adverse events (ie, life-threatening events and events that required hospitalization) were more common in patients who continued tamoxifen (Table 4).

View larger version (12K): [in this window] [in a new window]   Fig 1. EFS curves. Abbreviations: pts, patients; Obs, observed; TAM, tamoxifen; AG, aminoglutethimide.

View larger version (15K): [in this window] [in a new window]   Fig 2. (A) Overall and (B) breast cancer–specific survival curves.

View larger version (38K): [in this window] [in a new window]   Fig 3. Incidence of side effects (any degree) according to assigned treatment. TMX, tamoxifen.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

Indeed, if we simply look at EFS, there do not seem to be any major advantages in switching patients from tamoxifen to aminoglutethimide. In fact, a comparable number of events occurred among the patients who continued to receive tamoxifen and those assigned to aminoglutethimide, although side effects were more common in the latter group. As a matter of fact, even at the low dose used in this trial, aminoglutethimide showed poor tolerability, and a considerable proportion of patients discontinued treatment. Even though the number of subjects involved in the study was too small to allow for statistical comparison, it would, however, seem that switching patients from tamoxifen to aminoglutethimide does not reduce the incidence of second primaries, endometrial cancer in particular. However, there was only one case of endometrial cancer diagnosed per group. Aminoglutethimide is less effective in preventing contralateral breast cancer; five cancers developed in the contralateral breast in the women who had switched to aminoglutethimide, as compared with two cancers in the women who had continued tamoxifen. However, patients who had switched to aminoglutethimide survived significantly longer than those who continued tamoxifen. This seems to be an effect of the assigned treatment both on breast cancer–unrelated and on breast cancer–related mortality. With regard to the former effect, it is noteworthy that 10 patients in the tamoxifen group died in the absence of proven disease progression, as compared with just two patients in the aminoglutethimide group. Eight of the deaths that occurred in the tamoxifen group were the result of cardiovascular causes. In particular, two of them were caused by stroke, one was caused by pulmonary emboli, and two were caused by myocardial infarction. Cardiac failure was the cause of death in the other three patients. Why so many more cardiovascular deaths occurred in patients who continued tamoxifen is not clear.

The size of this trial and the number of events that have occurred so far are relatively small. Therefore, we cannot rule out that the results observed might be because of chance or confounding factors, such as those that are commonly associated with increased risk of cardiovascular mortality (ie, ischemic disease, hypertension, blood clotting alterations, and so on). Unfortunately, these factors were not recorded properly for several patients, nor were they available for the present analysis. Although previous cardiac or thromboembolic disease was a cause for ineligibility in our trial, it might well be that previous thromboembolic or cardiac events had been missed, especially in the older patients (50% of the patients enrolled onto our trial were 65 years of age or older), and that by chance these events might have occurred more frequently in the patients who continued tamoxifen. Therefore, evidence from our study regarding this aspect should be considered with extreme caution. However, the three strokes (two of which were fatal) and the one fatal pulmonary embolism that occurred in the patients on tamoxifen likely represent a genuine consequence of continuing tamoxifen treatment in those women. Although no obvious increase in coronary heart disease was recorded among tamoxifen users in previous adjuvant studies,^6,15,16 some recent findings from a National Surgical Adjuvant Breast and Bowel Project trial showed that thromboembolic events as well as stroke occur more frequently in tamoxifen users, namely in older patients, and might represent a cause of death for some of them.¹⁷ Moreover, a higher incidence of thromboembolic events was reported among tamoxifen users in two recent trials that compared tamoxifen with anastrozole, a nonsteroidal aromatase inhibitor, in patients with advanced breast cancer.^18,19

The second result to emerge from our trial is that switching patients to aminoglutethimide leads to a reduced risk of dying of breast cancer. In fact, there were 19 breast cancer–related deaths among the women who continued tamoxifen, as compared with 10 breast cancer–related deaths among those who were switched to aminoglutethimide, although a comparable number of women experienced relapse in both groups. Because there were no obvious differences in patients or disease characteristics before randomization in patients who experienced relapse (data not shown) nor in the treatment type they received on relapse, it could be hypothesized that the lower mortality rate we observed in the patients assigned to aminoglutethimide (Fig 4) might well be related to the effect of the assigned treatment on the relapse pattern. Indeed, median time to relapse was shorter for patients receiving tamoxifen (22 months v 28 months for the patients who had switched to aminoglutethimide), and more of them experienced relapse at distant sites and in the viscera. Previous trials with aminoglutethimide^20-22 and more recent trials that compared new aromatase inhibitors with tamoxifen in the front-line treatment of metastatic breast cancer have shown at least comparable results.^18,19,23,24 However, in some of these trials, longer progression-free and/or overall survival^18,19,24 or greater efficacy of antiaromatase treatment at specific disease sites, such as bone metastasis,²¹ was evident. Different therapeutic activity relative to the disease site also emerged from the trials that compared some new aromatase inhibitors to megestrol acetate in patients who did not respond to front-line treatment with tamoxifen.^25,26

View larger version (12K): [in this window] [in a new window]   Fig 4. Survival of patients who experience relapse, from time of relapse.

In conclusion, switching patients from tamoxifen to aminoglutethimide treatment resulted in comparable EFS but longer overall survival. Improvement in survival seems to be related both to the increased breast cancer–unrelated mortality we observed in patients receiving tamoxifen and to the better outcome of patients who experience relapse among those who switched to aminoglutethimide. Should these preliminary results be confirmed by our new study with anastrozole and by larger studies with a similar design, which are also testing the effectiveness of the new, more active, and tolerable aromatase inhibitors,²⁷ sequencing tamoxifen with an aromatase inhibitor could become a preferable alternative to tamoxifen alone in early breast cancer patients.

	APPENDIX

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Participating Members of the Italian Breast Cancer Adjuvant Study Group are as follows:A. Dalla Mola and G. Porcile (Ospedale S. Lazzaro, Alba); S. Iacobelli and L. Irtelli (Università degli Studi, Chieti); D. Amoroso, F. Boccardo, and A. Rubagotti (Università degli Studi e Istituto Nazionale per la Ricerca sul Cancro); R. Rosso (Istituto Nazionale per la Ricerca sul Cancro); C. Caroti and L. Gallo (E.O. Ospedali Galliera, Genova); G. Cruciani and E. Montanari (Ospedale Umberto I, Lugo); S. Banducci (Ospedale Civile, Merate); M. Mesiti and D. Romeo (Policlinico Universitario G. Martino, Messina); D. Aldrighetti, A. Bolognesi, and E. Villa (Istituto Scientifico S. Raffaele, Milano); B. Agostara, A. Russo, and A. Traina (Ospedale Oncologico M. Ascoli, Palermo); L. Galletto (Ospedale Generale E. Agnelli, Pinerolo); M. Sassi (Ospedale Spallanzani, Reggio Emilia); D. Guarneri (Ospedale Civile, Sanremo); G. Burani and D. Schieppati (Ospedale Generale Provinciale, Saronno); M.G. Alicicco and A. Farris (Università degli Studi, Sassari); F. Brema and G. Pastorino (Ospedale S. Paolo Valloria, Savona); F. Buzzi (Ospedale S. Maria, Terni); P. Sismondi (Università di Torino, Ospedale Mauriziano); F. Genta (Ospedale S. Anna, Torino); M. Mansutti, M. Muggia, and G. Mustacchi (Centro Oncologico M. Lovenati, Trieste); P. Marsilio (Ospedale S. Maria Misericordia, Udine, Italy).

	ACKNOWLEDGMENTS

 
Supported in part by grant nos. 92.02298, 93.022275, 94.01242, 95.00473, and 96.00670 PF 39 from the Italian National Research Council Project ACRO.

We thank Alessia Fossati for her secretarial assistance, Simona Barozzi for data management, and Valerie Perricone for reviewing the English format.

	NOTES

 
Presented in part at the Thirty-Sixth Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, May 20-23, 2000.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
1. Forbes JF: The control of breast cancer: The role of tamoxifen. Semin Oncol 24: SI-5–SI-19, 1997 (suppl 1)

2. Early Breast Cancer Trialists’ Collaborative Group: Adjuvant tamoxifen in early breast cancer: An overview of the randomised trials. Lancet 351: 1451-1467, 1998[Medline]

3. Mignotte H, Lasset C, Bonadonna V, et al: Iatrogenic risk of endometrial carcinoma after treatment for breast cancer in a large French case-control study. Int J Cancer 76: 325-330, 1998[Medline]

4. Bergman L, Beelen MLR, Gallee MPW, et al: Risk and prognosis of endometrial cancer after tamoxifen for breast cancer. Lancet 356: 881-887, 2000[Medline]

5. Jaiyesimi IA, Budzar AV, Decker DA, et al: Use of tamoxifen for breast cancer. J Clin Oncol 13: 513-529, 1995[Abstract/Free Full Text]

6. McDonald C, Alexander FE, Whyte BW, et al: Cardiac and vascular morbidity in women receiving adjuvant tamoxifen for breast cancer in a randomised trial. BMJ 311: 977-980, 1995[Abstract/Free Full Text]

7. Smith IE, Fitzharris BM, Mckinna JA, et al: Aminoglutethimide in the treatment of metastatic breast carcinoma. Lancet 2: 646-649, 1978[Medline]

8. Coombes RC, Powles TJ, Easton D, et al: Adjuvant aminoglutethimide therapy for postmenopausal patients with primary breast cancer. Cancer Res 47: 2496-2499, 1987

9. Bruning PF, Bonfrer JM, Hart AA, et al: Low-dose aminoglutethimide without hydrocortisone for the treatment of advanced postmenopausal breast cancer. Eur J Cancer Clin Oncol 25: 369-376, 1989[Medline]

10. Miller AB, Hoogstraten B, Staquet M, et al: Reporting results of cancer treatment. Cancer 47: 207-214, 1981[Medline]

11. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53: 457-481, 1958

12. Peto R, Pike MC, Armitage P, et al: Design and analysis of randomised clinical trials requiring prolonged observation of each patient: I. Introduction and design. Br J Cancer 34: 585-612, 1976[Medline]

13. Peto R, Pike MC, Armitage P, et al: Design and analysis of randomised clinical trials requiring prolonged observation of each patient: II. Analysis and examples. Br J Cancer 35: 1-39, 1977[Medline]

14. Geisler J, King N, Dowsett M, et al: Influence of anastrozole (Arimidex), a selective, non-steroidal aromatase inhibitor, on in vivo aromatisation and plasma oestrogen levels in postmenopausal women with breast cancer. Br J Cancer 74: 1286-1291, 1996[Medline]

15. Rutqvist LE, Mattsson A: Cardiac and thromboembolic morbidity among postmenopausal women with early stage breast cancer in a randomized trial of adjuvant tamoxifen. J Natl Cancer Inst 85: 1398-1406, 1993[Abstract/Free Full Text]

16. Costantino JP, Kuller LH, Ives DG, et al: Coronary heart disease mortality and adjuvant tamoxifen therapy. J Natl Cancer Inst 89: 776-782, 1997[Abstract/Free Full Text]

17. Dignam JJ, Fisher B: Occurrence of stroke with tamoxifen in NSABP B-24. Lancet 355: 848, 2000 (letter)[Medline]

18. Bonneterre J, Thurlimann B, Robertson JFR, et al: Anastrozole versus tamoxifen as first-line therapy for advanced breast cancer in 668 postmenopausal women: Results of the Tamoxifen or Arimidex Randomized Group Efficacy and Tolerability study. J Clin Oncol 18: 3748-3757, 2000[Abstract/Free Full Text]

19. Nabholtz JM, Budzar A, Pollak M, et al: Anastrozole is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: Results of a North American Multicenter Randomized Trial. J Clin Oncol 18: 3758-3767, 2000[Abstract/Free Full Text]

20. Lipton A, Harvey HA, Santen RJ, et al: Randomized trial of aminoglutethimide versus tamoxifen in metastatic breast cancer. Cancer Res 42: S3434-S3436, 1982 (suppl 8)

21. Smith IE, Harris AL, Morgan M, et al: Tamoxifen versus aminoglutethimide versus tamoxifen combined with aminoglutethimide in the treatment of advanced breast carcinoma. Cancer Res 42: S3430-S3433, 1982 (suppl 8)

22. Gale KE, Andersen JW, Tormey DC, et al: Hormonal treatment for metastatic breast cancer: An Eastern Cooperative Oncology Group Phase III trial comparing aminoglutethimide to tamoxifen. Cancer 73: 354-361, 1994[Medline]

23. Milla-Santos A, Milla L, Rallo L, et al: Anastrozole vs. tamoxifen in hormone-dependent advanced breast cancer: A phase II randomized trial. Breast Cancer Res Treat 64: 54, 2000 (abstr 173)

24. Mouridsen H, Gershanovich M, Sun Y, et al: Superior efficacy of letrozole versus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: Results of a phase III study of the International Letrozole Breast Cancer Group. J Clin Oncol 19: 2596-2606, 2001[Abstract/Free Full Text]

25. Dombernowsky P, Smith I, Falkson G, et al: Letrozole, a new oral aromatase inhibitor for advanced breast cancer: Double-blind randomized trial showing a dose effect and improved efficacy and tolerability compared with megestrol acetate. J Clin Oncol 16: 453-461, 1998[Abstract]

26. Kaufmann M, Bajetta E, Dirix LY, et al: Exemestane is superior to megestrol acetate after tamoxifen failure in postmenopausal women with advanced breast cancer: Results of a phase III randomized double-blind trial—The Exemestane Study Group. J Clin Oncol 18: 1399-1411, 2000[Abstract/Free Full Text]

27. Baum M: Use of aromatase inhibitors in the adjuvant treatment of breast cancer. Endocr Relat Cancer 6: 231-234, 1999[Abstract]

Submitted March 9, 2001; accepted June 26, 2001.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				K. Gibson and C. L O'Bryant Screening and management of osteoporosis in breast cancer patients on aromatase inhibitors Journal of Oncology Pharmacy Practice, September 1, 2008; 14(3): 139 - 145. [Abstract] [PDF]

				F. Boccardo and A. Rubagotti In Reply: J. Clin. Oncol., December 20, 2005; 23(36): 9437 - 9439. [Full Text] [PDF]

				A. Goldhirsch, J. H. Glick, R. D. Gelber, A. S. Coates, B. Thurlimann, H.-J. Senn, and and Panel Members Meeting Highlights: International Expert Consensus on the Primary Therapy of Early Breast Cancer 2005 Ann. Onc., October 1, 2005; 16(10): 1569 - 1583. [Abstract] [Full Text] [PDF]

				F. Boccardo, A. Rubagotti, M. Puntoni, P. Guglielmini, D. Amoroso, A. Fini, G. Paladini, M. Mesiti, D. Romeo, M. Rinaldini, et al. Switching to Anastrozole Versus Continued Tamoxifen Treatment of Early Breast Cancer: Preliminary Results of the Italian Tamoxifen Anastrozole Trial J. Clin. Oncol., August 1, 2005; 23(22): 5138 - 5147. [Abstract] [Full Text] [PDF]

				R. Kudachadkar and R. M. O'Regan Aromatase Inhibitors as Adjuvant Therapy for Postmenopausal Patients With Early Stage Breast Cancer CA Cancer J Clin, May 1, 2005; 55(3): 145 - 163. [Abstract] [Full Text] [PDF]

				L. B. Michaud Adjuvant use of aromatase inhibitors in postmenopausal women with breast cancer Am. J. Health Syst. Pharm., February 1, 2005; 62(3): 266 - 273. [Abstract] [Full Text] [PDF]

				I. E. Smith and M. Dowsett Aromatase Inhibitors in Breast Cancer N. Engl. J. Med., June 12, 2003; 348(24): 2431 - 2442. [Full Text] [PDF]

				M. Schmid, R. Jakesz, H. Samonigg, E. Kubista, M. Gnant, C. Menzel, M. Seifert, K. Haider, S. Taucher, B. Mlineritsch, et al. Randomized Trial of Tamoxifen Versus Tamoxifen Plus Aminoglutethimide as Adjuvant Treatment in Postmenopausal Breast Cancer Patients With Hormone Receptor-Positive Disease: Austrian Breast and Colorectal Cancer Study Group Trial 6 J. Clin. Oncol., March 15, 2003; 21(6): 984 - 990. [Abstract] [Full Text] [PDF]

				J. A. Ligibel and E. P. Winer Clinical Differences among the Aromatase Inhibitors Clin. Cancer Res., January 1, 2003; 9(1): 473s - 479s. [Abstract] [Full Text]

				J. N. Ingle Adjuvant Endocrine Therapy in Postmenopausal Breast Cancer Clin. Cancer Res., January 1, 2003; 9(1): 480s - 485s. [Abstract] [Full Text]

				E. P. Winer, C. Hudis, H. J. Burstein, R. T. Chlebowski, J. N. Ingle, S. B. Edge, E. P. Mamounas, J. Gralow, L. J. Goldstein, K. I. Pritchard, et al. American Society of Clinical Oncology Technology Assessment on the Use of Aromatase Inhibitors as Adjuvant Therapy for Women With Hormone Receptor-Positive Breast Cancer: Status Report 2002 J. Clin. Oncol., August 1, 2002; 20(15): 3317 - 3327. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Boccardo, F. Articles by Mustacchi, G. Search for Related Content PubMed PubMed Citation Articles by Boccardo, F. Articles by Mustacchi, G. Social Bookmarking                            What's this?