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Clinical Trials |
Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905 [J. N. I., V. J. S., C. L. L.,]; Carle Cancer Center Community Clinical Oncology Program (CCOP), Urbana, Illinois 61801 [P. A. J.]; Duluth CCOP, Duluth, Minnesota 55805 [J. E. K.]; Missouri Valley Cancer Consortium, Omaha, Nebraska 68131 [J. A. M.]; Scottsdale CCOP, Scottsdale, Arizona 85259-5404 [R. H. W.]; Mayo Clinic Jacksonville, Jacksonville, Florida 32224 [E. A. P.]; Robert H. Lurie Comprehensive Cancer Center, Northwestern University Medical School, Chicago, Illinois 60611 [V. C. J.]; and Royal Marsden Hospital, London SW3 6JJ, United Kingdom [M. D.]
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Estrogens are considered the primary mitogens for breast cancer cells. From the standpoint of treating breast cancer, TAM is considered an antiestrogen because the mechanism of action is viewed primarily as competition with E2 for the ER in the nucleus of the cancer cell. The major source of this estrogen in the postmenopausal or castrated woman is the adrenal cortex, which secretes precursors of E1 and E2. Androstenedione is the major precursor of these estrogens and undergoes aromatization in peripheral tissues and in some breast cancers to E1, which is subsequently reduced to E2.
AG is a first-generation aromatase inhibitor and has been shown to have antitumor activity in postmenopausal women with metastatic breast cancer, with one review of 929 patients showing an overall response rate of 32% (2) . AG has effects in addition to aromatase inhibition that include the inhibition of cholesterol side chain cleavage enzymes necessitating cortisol supplementation. The main reason AG did not achieve widespread popularity was its potential for substantial toxicity, primarily lethargy and skin rash.
There are several compelling reasons to combine an antiestrogen with an aromatase inhibitor. Both agents have been shown to have antitumor activity as single agents but have different mechanisms of action. It is possible that their different mechanisms of action would be complementary, with the aromatase inhibitor decreasing the estrogen level and thus allowing TAM to function more effectively as a competitive inhibitor with E2. In addition, previous clinical trials have demonstrated that these two classes of agents are not entirely cross-resistant (2) .
Several clinical trials have examined the concept of combining TAM with the aromatase inhibitor AG without demonstrating a significantly improved clinical outcome (3 , 4) . Lien et al. (5) studied pharmacokinetic interactions between TAM and AG and found that AG markedly reduced serum concentrations of TAM and its major metabolites. They postulated that this reduced bioavailability of TAM and its metabolites could explain why combination therapy did not result in higher response rates than TAM lone.
Letrozole (CGS 20267) is a novel nonsteroidal benzhydroltriazole derivative that has been shown in animal studies to be a highly selective and potent competitive aromatase inhibitor (6) . Iveson et al. (7) have summarized the relative potency data for letrozole and AG. In vitro, using microsomal preparations of human placental aromatase, letrozole was 165 times as potent as AG; and, in an in vivo assay of androstenedione-induced uterine hypertrophy, letrozole was 4 orders of magnitude more potent. Letrozole also differs from AG in its selectivity. The inhibition of aldosterone occurred at concentrations 14,000 times greater than that required for inhibition of estrogen production, and the difference for inhibition of corticosterone was even greater. Thus, letrozole is a highly selective aromatase inhibitor.
Dowsett et al. (8) evaluated letrozole in postmenopausal women with breast cancer and found a >98% aromatase inhibition at a daily dose of 2.5 mg. After 6 weeks of treatment, the mean suppression of E1 was 80.8%, and that of E2 was 68.1%.
Letrozole has been evaluated in the clinic in a randomized double-blind trial comparing it to megestrol acetate. Dombernowsky et al. (9) found that letrozole (2.5 mg daily) was significantly superior to megestrol acetate in terms of overall objective response rate (P = 0.04), duration of response (P = 0.02), and TTF (P = 0.04). In addition, letrozole was found to be significantly better tolerated than megestrol acetate.
On the basis of the preclinical and clinical data, letrozole was considered an ideal agent to use in the re-examination of the concept of combining an antiestrogen with an aromatase inhibitor. In further support of this choice are the data from a prospective randomized trial in postmenopausal women with advanced breast cancer showing that letrozole was superior to AG in terms of time to progression, TTF, and overall survival and was associated with fewer adverse events (10) . However, given the previous findings by Lien et al. (5) of pharmacokinetic interactions between TAM and AG, it was considered crucial to determine whether any such interactions exist between TAM and letrozole. To address this issue, the following Phase II trial was conducted in which patients received TAM for 6 weeks to achieve steady-state concentrations, and then letrozole was added with subsequent evaluation for impact on TAM levels.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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60 years with a prior hysterectomy without oophorectomy and FSH in postmenopausal range; or (d) prior oophorectomy. ER and/or PgR had to be positive or not obtained. Hormone receptor positivity was defined as 
10 fmol/mg cytosol protein if a ligand-binding assay was used or as defined by institutional standards in the case of immunohistochemical methodology. Patients were required to have measurable or evaluable disease. Measurable disease was defined as bidimensionally measurable except in the case of hepatomegaly due to metastatic disease, in which case linear measurements of 5 cm below a costal margin in the midclavicular line or xiphoid were acceptable. The minimum acceptable size of a measurable indicator lesion depended on the method of measurement. The minimum acceptable size was 1.0 cm for physical exam or chest radiograph and 3.0 cm for computed tomography scan, magnetic resonance imaging scan, or sonogram. Evaluable disease was disease that was assessable, but not measurable, and documentable on radiographs (e.g., mediastinal masses, pleural-based masses, or lytic bone metastasis) or photographs (e.g., soft tissue or skin metastasis). Specifically not evaluable were third-space fluid accumulations and blastic osseous metastasis. Patients could not have received any prior additive hormonal therapy for metastatic disease. Prior adjuvant therapy with TAM was permissible, provided that at least 6 months had elapsed from discontinuation of TAM to identification of recurrent disease. Patients could not have received prior therapy with any recognized aromatase inhibitor or undergone adrenalectomy or hypophysectomy. More than one prior chemotherapy for metastatic disease was not allowed, and patients could have received chemotherapy in the adjuvant setting. The ECOG performance score must have been 0, 1, or 2. Patients with brain metastases, hepatic metastases estimated to involve more than one-third of the liver, and pulmonary lymphangitic spread were not eligible. The following laboratory values were required: (a) leukocyte count > 2,000/µl; (b) platelet count > 75,000/µl; (c) serum calcium < 10% above the ULIN; (d) total bilirubin < 0.8 mg/dl above the ULIN; and (e) creatinine < 1 mg/dl above the ULIN.
Studies obtained before entry onto protocol included a medical history; physical examination with assessment of indicator lesion(s); hemoglobin, leukocyte, and platelet counts; sodium, potassium; calcium; glucose; phosphorus; alkaline phosphatase; serum glutamic oxaloacetic transaminase; total bilirubin; creatinine; and chest radiograph. This trial was performed after approval by local institutional review boards in accordance with assurances filed with and approved by the United States Department of Health and Human Services. Written informed consent was provided by each patient before entry on study.
After registration, patients were treated with TAM (20 mg, p.o.) each morning (at 8–10 a.m.), and then, after 6 weeks, letrozole (supplied as Femara by Novartis Pharmaceuticals Corp., East Hanover, NJ; 2.5 mg, p.o.) each morning (at 8–10 a.m.) was added. After initiation of therapy, patients were assessed at 6, 12, 18, and 24 weeks and every 3 months thereafter. Megestrol acetate was not permitted for treatment of hot flashes.
Treatment was to be continued if the status of the patient was stable or better, and no unacceptable toxicity had occurred. For both measurable and evaluable disease, a CR was defined as the disappearance of all evidence of tumor. For measurable disease, a PR was defined as at least a 50% reduction in the product of the largest perpendicular diameters of indicator lesions or, in the case of palpable hepatomegaly, a 30% reduction in the sum of linear measurements of the liver below both costal margins in the midclavicular line and the xiphoid. For measurable disease, progression was defined as: (a) a new lesion; (b) at least a 25% increase in indicator lesions compared with pretreatment status in patients not achieving a CR or PR; or (c) in patients achieving a PR, an increase in indicator lesion from its smallest measurement of at least 50% of the decrease in size between the pretreatment measurements and the smallest measurements at the point of maximum tumor reduction. For evaluable disease, a response that was less than a CR was termed a Reg and was defined as a definite decrease in tumor that could be documented by radiographs, other imaging modalities, or photographs. Progression for evaluable disease was defined as: (a) a new lesion; (b) a definite increase in indicator lesion compared to its pretreatment size if a patient failed to achieve a Reg; and (c) a definite increase in indicator lesion compared with the smallest size while on study if a patient achieved a Reg. Stable disease was defined as failure to qualify for CR, PR, Reg, or progression. An additional criterion for progression was significant clinical deterioration that could not be attributed to treatment or to other medical conditions, such as weight loss of >5% of body weight, worsening of tumor-related symptoms, or a decline in ECOG performance score of more than 1.
A patient was considered to have achieved an objective response if she maintained a CR, PR, or Reg on two consecutive evaluations at least 6 weeks apart. An exact binomial CI was constructed for the true proportion of objective responses.
TTF was defined as time from registration to removal from study due to disease progression, toxicity, refusal, or death without documented progression. Time to progression was defined as time from registration to progression or death unless there was clear evidence that the patient had not progressed at the time of death. Survival was defined as the time from registration to death. Time-to-event distributions were estimated by the Kaplan-Meier method (11) .
Blood specimens were to be obtained before treatment and at weeks 6, 12, 18, and 24 for assays of E2, E1, E1S, SHBG, LH, and FSH. Blood samples were obtained in the morning, preferably between 7 and 8 a.m., before the patient took that day’s TAM ± letrozole. These assays were performed by M. D. using the methods reported previously (12)
. The Wilcoxon signed rank test was used to assess whether the percentage changes from pretreatment levels at weeks 6, 12, 18, and 24 were different from zero. Because of multiple testing for each assay, a Bonferroni correction was made, and a two-sided P 0.0125 was considered significant.
To examine for any effect of letrozole on the levels of TAM and two important metabolites, N-desmethyl-TAM and 4-hydroxy-TAM, blood was obtained at 6, 12, 18, and 24 weeks. Blood samples for these analyses were obtained at the same time as for the endocrinological studies noted above, i.e., before that day’s medication. These assays were performed by V. C. J. using methods reported previously (13) . The primary end point of interest was the difference in TAM and its metabolites after the addition of letrozole for 18 weeks. For each of the assay results at weeks 12, 18, and 24, three graphs were constructed: (a) the assay result at that week was plotted against the assay result at week 6; (b) the difference between the assay result at that week and the assay result at week 6 was plotted against the assay result at week 6; and (c) the percentage change from the assay result at week 6 was plotted against the assay result at week 6. The resulting plots indicated a high degree of variability in the difference between the assay result at a particular week and the assay result at week 6 and no tendency toward the size of the difference to depend upon the patient’s level at 6 weeks.
The assumptions under which the sample size for this trial was determined failed to hold; namely, the variability in the difference between the assay result at week 24 and the assay result at week 6 was much higher than anticipated. Thus, there is little power to detect all but large differences. For each assay, a 95% CI for the mean difference between a patient’s level at week 24 and the patient’s level at week 6 was constructed. One data point at week 24 appeared to be an outlier. Upon investigation, it was unclear whether the patient followed instructions not to take her TAM and letrozole until after her blood draw. Her data are indicated by an asterisk in the plots but are not included in the construction of the CIs.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. All patients were ER positive, >50% had a disease-free interval of more than 5 years, 29% had received prior TAM, and 59% had received no prior chemotherapy.
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display paired data for each patient showing the correlation of week 6 levels (before the addition of letrozole) and week 24 levels (18 weeks after the addition of letrozole), which was the primary comparison specified in the protocol. Twenty-three patients were still on study at week 24, and 18 (75%) of these patients had blood samples available. One patient was excluded when examining TAM and its two metabolites because it was suspected that she failed to follow instructions not to take TAM or letrozole before her blood draw. The 95% CI for the mean difference between an individual’s level at week 24 and an individual’s level at week 6 was -34 to 15 for TAM, -35 to 45 for N-desmethyl-TAM, and -1 to 2 for 4-hydroxy-TAM. Considered in terms of percentage change, the median change in week 24 levels from week 6 levels was 2.6% (range, -59 to 99%) for TAM, 4.7% (range, -51 to 94%) for N-desmethyl-TAM, and 40% (range, -71 to 350%) for 4-hydroxy-TAM. Fig. 4
displays the percentage change in TAM, N-desmethyl-TAM, and 4-hydroxy-TAM levels from the week 6 level to levels observed at 6, 12, and 18 weeks after the addition of letrozole. No substantial difference was observed in the median percentage change in TAM or either of its metabolites after the addition of letrozole at the three time points examined. However, at each of these time points, a large variability was evident in the percentage change from the week 6 level for each assay. The SD of the percentage change from the week 6 level to levels at weeks 12, 18 and 24 for TAM were 39%, 39%, and 42%, respectively. For N-desmethyl-TAM, the corresponding values were 29%, 35%, and 37%, respectively, and for 4-hydroxy-TAM, the corresponding values were 63%, 98%, and 98%, respectively.
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display each parameter as the percentage change from baseline (pretreatment) level at each time point for all of the assessable patients. All patients experienced a substantial reduction in E2 after the addition of letrozole for 6 weeks, with a median percentage decrease of 88.5% (range, 73.7–95.2%) that was maintained for the additional 12 weeks of testing (Fig. 5)
. E1 levels showed a similar decrease after the addition of letrozole for 6 weeks, with a median percentage decrease of 81.4% (range, 44.4–91.5%) that was maintained for the additional 12 weeks of testing (Fig. 6)
. There was a tendency for E1S levels after 6 weeks of TAM alone to be higher than pretreatment levels (median increase, 39.5%), but significant reductions occurred after the addition of letrozole (median reduction, 96.3%; range, 92.0–98.9%) for 6 weeks, and this reduction was maintained (Fig. 7)
. SHBG levels were significantly higher (median increase, 65.5%; range, -1.2 to 172.4%) than pretreatment levels after 6 weeks of TAM alone (P < 0.001) and remained significantly higher than pretreatment levels after the addition of letrozole for 6, 12, and 18 weeks (all P < 0.001). LH levels were significantly lower than pretreatment levels after 6 weeks of TAM alone but were not found to be significantly lower after the addition of letrozole. FSH levels were significantly lower after 6 weeks of TAM alone (P < 0.001) and remained so after the addition of letrozole (all P 0.002).
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. The overall objective response rate was 17.6% (95% CI, 6.8–34.5%).
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Two of the 34 patients have died. The 1-year survival rate was estimated to be 92% (95% CI, 81–100%).
The toxicities observed are given in Table 3
. Hot flashes were the most common toxicity and occurred in 44% of patients.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The primary goal of our clinical trial was to examine for pharmacokinetic interactions between TAM and letrozole in terms of the levels of TAM and two of its major metabolites, N-desmethyl-TAM and 4-hydroxy-TAM. There was substantial interpatient variability in the levels of TAM and its two metabolites achieved after 6 weeks of TAM alone. The median TAM level in our study was 107 ng/ml, with a range of 24–317 ng/ml, which is of the order of that reported by Langen-Fahey et al. (14) , i.e., a mean level of 148 ng/ml with a range of 8–574 ng/ml in 35 patients who had received TAM for at least 2 years. Also consistent with our findings were those of Lønning et al. (15) , who identified a mean TAM level of 125.3 ng/ml with a 95% CI of 63.8–246.1 ng/ml in 32 postmenopausal women who received TAM for 3–12 months (median, 6 months). The levels of N-desmethyl-TAM and 4-hydroxy-TAM were comparable to those reported previously (14 , 15) . The substantial variability between patients in terms of TAM and its two metabolites raises questions as to whether a standard dose of TAM is appropriate or optimal for all patients.
With the addition of letrozole to TAM, a substantial amount of variability was observed in the degree to which TAM, N-desmethyl-TAM, and 4-hydroxy-TAM were perturbed. However, the variability was generally consistent at 6, 12, and 18 weeks after the addition of letrozole, and there was no indication of a systematic decrease in TAM or in either of the two metabolites.
Patients were evaluated for the degree of aromatase inhibition as indicated by E2, E1, E1S, and SHBG. During periods up to 18 weeks after the addition of letrozole to TAM, there were substantial reductions in E2, E1, and E1S that were consistent with those seen in earlier studies of letrozole alone (12 , 16) . An increase in E1S with TAM alone has been described previously (15) . Whatever the mechanism of this effect, it clearly did not antagonize the suppressive effects of letrozole on E1S or the other estrogens.
The increase in SHBG levels during the 6 weeks of treatment with TAM alone was expected because this effect has been described previously (17) . The persistence of this effect was consistent with the observation that letrozole alone does not affect SHBG levels (7) and with the earlier finding that SHBG levels are increased during combination hormonal therapy with TAM plus AG (18) . Similarly, LH levels are known to be suppressed by TAM in postmenopausal women (19) , and this decrease was also identified with the combination of TAM plus AG (18) . Decreases in FSH were noted in these two earlier studies (18 , 19) and observed in the present study.
Dowsett et al. (16) performed an evaluation of the pharmacokinetic interaction between letrozole and TAM in which patients received letrozole (2.5 mg daily) for 6 weeks, followed by the addition of TAM at a dose of 20 mg daily. Letrozole pharmacokinetics were based on plasma samples taken 1 day before the addition of TAM and after 6 weeks of receiving both agents. Letrozole AUC decreased by an average of 30.6% (+ 17.9%, SD), with the reduction being seen in 9 of the 10 patients. The range of the AUC reduction was from -5% to +59.4% and was >30% in seven patients. The authors noted that the reduced plasma levels of letrozole corresponded to estimated daily doses of 1.5–2 mg.
The overall objective response rate in the current study was 17.6%, with a 95% CI of 6.8–34.5%. This level of response is lower than we saw in a randomized trial in which 159 patients receiving TAM alone demonstrated a 38% objective response rate (20) . The median time to progression for TAM plus letrozole was 7.6 months, which is shorter than the level of 11 months in the trial noted above (20) . These outcome measures for TAM plus letrozole are disappointing but may simply be due to the patients entered. Of note with respect to using both TAM and letrozole concurrently is recent data from preclinical studies from Brodie et al. (21) using an intratumoral aromatase model. This model uses MCF-7 cells stably transfected with the aromatase gene, which are inoculated into ovariectomized nude mice. The combination of TAM plus letrozole was found to be more effective than TAM alone in terms of antitumor effect. However, they also found letrozole to be significantly more effective than TAM and found no indication that the combination of TAM plus letrozole was more effective than letrozole alone. Validation of applicability to the clinical setting of findings from preclinical models such as this would be of great value in developing future clinical research.
The TAM plus letrozole regimen was well tolerated. There were no apparent unusual toxicities or untoward reactions observed.
In summary, there was no indication of a systematic decrease in TAM, N-desmethyl-TAM, or 4-hydroxy-TAM after the addition of letrozole. The variability in the percentage change in TAM and that of the two metabolites was substantial but generally consistent, and the median percentage changes were close to zero for most of the determinations. Thus, there was no evidence for a substantial detrimental impact of letrozole on TAM as had been observed with AG (5) . The level of estrogen suppression induced by letrozole was substantial despite the concomitant administration of TAM. The level of antitumor benefit for TAM plus letrozole was less than expected, but this represents experience from a single and relatively small Phase II study. The value of combination hormonal therapy involving TAM plus letrozole remains to be established.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 This study was conducted as a collaborative trial of the North Central Cancer Treatment Group and Mayo Clinic and was supported in part by USPHS Grants CA-25224, CA-37404, CA-35195, CA-52352, CA-35269, CA-35448, CA-63849, CA-35113, CA-60276, and CA-35103 from the National Cancer Institute, United States Department of Health and Human Services. This study was presented in part at "Aromatase and Its Inhibitors: New Biology and Clinical Perspectives," a conference held in Prague, The Czech Republic on September 4, 1998. Additional participating institutions include the following: Quain and Ramstad Clinic, Bismarck, North Dakota (Dr. Delano M. Pfeifle); CentraCare Clinic, St. Cloud, Minnesota (Dr. Harold E. Windschitl); Sioux Community Cancer Consortium, Sioux Falls, South Dakota (Dr. Loren K. Tschetter); Geisinger Clinic and Medical Center Community Clinical Oncology Program (CCOP), Danville, Pennsylvania (Dr. Suresh Nair); Illinois Oncology Research Association CCOP, Peoria, Illinois (Dr. John W. Kugler). 
2 To whom requests for reprints should be addressed, at Mayo Clinic, 200 First Street SW, Rochester, MN 55905. Phone: (507) 284-8432; Fax: (507) 284-1803; E-mail: ingle.james{at}mayo.edu
3 The abbreviations used are: TAM, tamoxifen; E2, estradiol; E1, estrone; E1S, estrone sulfate; SHBG, sex hormone-binding globulin; CI, confidence interval; AG, aminoglutethimide; FSH, follicle-stimulating hormone; ER, estrogen receptor; PgR, progesterone receptor; ECOG, Eastern Cooperative Oncology Group; ULIN, upper limit of institutional normal; CR, complete response; PR, partial response; Reg, regression; TTF, time to treatment failure; LH, luteinizing hormone; AUC, area under the curve.
Received 12/28/98; revised 3/15/99; accepted 4/ 1/99.
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