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High-dose estrogen as salvage hormonal therapy for highly refractory metastatic breast cancer: A retrospective chart review
Clinical Therapeutics/Volume 31, Theme Issue, 2009
Brief Report
High-Dose Estrogen as Salvage Hormonal Therapy for Highly Refractory Metastatic Breast Cancer: A Retrospective Chart Review Reshma L. Mahtani, DO1; Alisha Stein, RNC, BSN, OCN2; and Charles L. Vogel, MD, FACP1 1Boca
Raton Comprehensive Cancer Center, Boca Raton, Florida; and 2The Cancer Research Network, Inc., Boca Raton, Florida ABSTRACT Background: High-dose estrogens (HDEs) are an efficacious but widely overlooked treatment option for patients with metastatic breast cancer (MBC). This is due in part to the introduction of tamoxifen in the 1970s, which was proven to be equivalent in efficacy and associated with fewer adverse events (AEs). Objective: The aim of this study was to report our experience with the use of HDE in postmenopausal women with advanced breast cancer. Methods: Local institutional review board approval was obtained to conduct a retrospective chart review of patients with MBC treated with HDEs at the Boca Raton Comprehensive Cancer Center, Boca Raton, Florida, from 2001 through March 2009. Demographic information, response rates, and tolerability profiles were collected. Results: Of the 426 patients with MBC identified, we found 26 patients with MBC who were prescribed HDEs as a treatment in any line of therapy for advanced breast cancer. The median age at the start of HDE therapy was 59 years (range, 42–92 years). Three of the 26 patients (11.5%) were human epidermal growth factor receptor 2–positive determined via fluorescent in situ hybridization analysis. With the exception of 1 patient who had received no prior systemic treatment for metastatic disease, all patients received multiple lines of treatment (both chemotherapy and hormonal treatments) in the advanced setting (median, 7 lines; range, 0–12) prior to the initiation of HDE. Five of 20 patients (25%) with measurable metastatic disease (visceral and/or soft tissue metastases) had objective antitumor responses defined as either a partial response (PR) or a complete response (CR). Four additional patients (20%) had prolonged stable disease (SD) for ≥6 months. Three of 6 patients (50%) 2009
with nonmeasurable metastatic disease (bone-only) had prolonged SD for ≥6 months. Clinical benefit rate (defined as CR + PR + SD ≥6 months) for all patients was 46% (12/26), with a median duration of 10 months. Overall median progression-free survival for the 26 subjects was 5 months. Median survival from the start of HDE was 17 months (range, 3–54 months). AEs included fluid retention (8 [31%]), vaginal bleeding (7 [27%]), and nausea (4 [15%]). Two patients discontinued therapy after 1 month. Three of the remaining 24 patients discontinued estrogen therapy due to AEs. Conclusions: This retrospective chart review details our facility’s experience with the use of HDE in patients with advanced breast cancer, most of whom had received multiple prior treatments. Our data suggest that this treatment is another option for heavilytreated patients in whom further endocrine manipulation might still be appropriate. (Clin Ther. 2009;31 [Theme Issue]:2371–2378 © 2009 Excerpta Medica Inc. Key words: metastatic breast cancer, hormonal therapy, salvage treatment, estrogen treatment.
INTRODUCTION Although the mechanism(s) versial, the use of high-dose fective treatment option in (MBC) has been recognized
of action remain controestrogen (HDE) as an efmetastatic breast cancer for many years. In 1944,
Data in this manuscript were presented at the 31st Annual San Antonio Breast Cancer Symposium, December 10–14, 2008, San Antonio, Texas. Accepted for publication September 24, 2009. doi:10.1016/j.clinthera.2009.11.002 0149-2918/$ - see front matter © 2009 Excerpta Medica Inc. All rights reserved.
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Clinical Therapeutics Sir Alexander Haddow published his “apparently paradoxical” observation that estrogens can both stimulate and retard growth of breast tumors.1 In the years that followed, other clinicians such as Kennedy et al2 in 1957 and Stoll3 in 1973 continued to note the efficacy of HDE, making it the endocrine treatment of choice in postmenopausal women with advanced breast cancer. This was the case until the introduction of tamoxifen in the 1970s, at which time the use of HDEs decreased. This was largely due to the improved tolerability profile that was associated with tamoxifen. Several studies have suggested the equivalent efficacy of tamoxifen and estrogen therapy. In 1971, Cole et al4 reported the first clinical trial of tamoxifen in 46 women with advanced or recurrent breast cancer. These findings were compared with a similar trial (unpublished) in which women received diethylstilbestrol (DES)—a synthetic estrogen—or an androgen. The authors concluded that efficacy was similar but tamoxifen had a lower incidence of “troublesome side effects.” Patients treated with tamoxifen reported hot flashes, gastrointestinal intolerance, edema, vaginal bleeding, tumor pain, vaginal pruritus, and lassitude. These adverse events (AEs) were not graded but were deemed “mild” and required discontinuation of the drug on only 2 occasions (4%) (1 for intolerable hot flashes and 1 for nausea and vomiting). Ingle et al published results from a randomized clinical trial comparing tamoxifen with DES in 143 postmenopausal women in 19815 and provided updated results in 2002.6 Mature survival data were available for the updated analysis, as 95% of the 143 patients had died. There was no significant difference between the 2 agents in terms of response rates or time to progression. However, survival was significantly better for those women initially treated with DES (adjusted P = 0.039) than for those treated with tamoxifen, with median survival of 3.0 and 2.4 years, respectively, and 5-year survival rates of 35% and 16%. Twelve percent of patients discontinued treatment with DES because of AEs. These AEs included gastrointestinal intolerance (4 patients), congestive heart failure (3), thrombophlebitis (1), and refractory lower-extremity edema with superficial ulcerations (1). Nausea and emesis were found with tamoxifen, but in no patient were they severe enough to warrant discontinuation of the drug. In fact, patients who received tamoxifen had a lower incidence of all AEs reported, with the exception of hot flushes (29% vs 3%) and leukopenia 2372
(15% vs 2%). In a randomized trial, Gockerman et al7 also compared tamoxifen and DES in 115 postmenopausal patients with MBC who were hormone receptor– positive or –unknown and found similar complete response (CR) rates (2% for both groups), partial responses (PR) (4% vs 8% respectively), disease stability (78% vs 73%), median time to disease progression (5 vs 6 months), and median survival (34 vs 35 months) with both agents. In an update of their randomized trial, Peethambaram et al8 reported their results with 151 postmenopausal women with progressive MBC and no prior hormonal therapy who were treated with either DES or tamoxifen. The overall response rate (PR + CR) was 42% for DES and 33% for tamoxifen (P = NS). The duration of response for DES was 11.8 versus 9.9 months for tamoxifen (P = NS). Progressionfree survival was not found to be significantly different between DES and tamoxifen. Median survival was significantly improved for DES versus tamoxifen (3.0 vs 2.4 years, respectively; P = 0.039). Resistance to endocrine agents invariably develops during the course of long-term treatment.9 The sequential use of hormonal therapy in advanced breast cancer is associated with diminishing response rates, and therefore, any further hormonal therapy that has the potential to induce a response is an attractive option for the appropriate patient. In the current retrospective review, we report our experience with the use of HDE in postmenopausal women with advanced breast cancer, the majority of whom had previously progressed on multiple lines of treatment.
MATERIALS AND METHODS After local institutional review board (Boca Raton Community Hospital) approval, medical records for patients with MBC treated in our practice (Boca Raton Comprehensive Cancer Center, Boca Raton, Florida) from 2001 through March 2009 were reviewed. Patients with advanced breast cancer who had received HDE during any line of therapy were identified. Consent was waived based on the fact that all data presented are in aggregate. Health Insurance Portability and Accountability Act guidelines were followed to protect patient information. Baseline evaluation included physical examination, complete blood count, complete metabolic profile, and levels of lactate dehydrogenase, carcinoembryonic antigen, and cancer antigen 27.29. In general, bone scans and computed tomography scans of the chest, abdomen, and pelvis Volume 31 Theme Issue
R.L. Mahtani et al. or a positron emission tomography scan were performed at baseline. Patients were evaluated at 4- to 8-week intervals by physical exam and blood work similar to baseline. Repeat imaging was performed at 8- to 12-week intervals or earlier if symptoms warranted. Severity of AEs was graded using National Cancer Institute Common Terminology Criteria (grade 1 = mild; grade 2 = moderate; grade 3 = severe; grade 4 = life-threatening or disabling; and grade 5 = death).10 Patients were considered to have had CR if there was complete disappearance of all areas of preexisting metastatic disease. This included normalization of bone scans and radiographs in patients with concomitant bone (nonmeasurable) disease in addition to measurable metastatic disease. PR was defined as a ≥50% reduction in the sum of the diameters of selected measurable sites ≥1 cm. Stable disease (SD) was defined as ≤49% reduction in the sum of the diameters of selected measurable sites ≥1 cm or no change in prior nonmeasurable sites of disease without any evidence of new lesions. Overall response rate included all patients with CR and PR divided by all evaluated patients. Clinical benefit rate was defined as CR + PR + SD for ≥6 months among the entire cohort.
RESULTS Patients A total of 426 patients with MBC were treated at our facility during the review period; of these, 26 patients with advanced breast cancer received HDE during treatment. Twenty-four patients were evaluable for response (measurable disease) or clinical benefit (measurable and evaluable disease). However, all 26 patients were included in the efficacy analysis. The first 2 admitted patients were administered DES 5 mg TID (15 mg/d) prepared by a compounding pharmacy (Francks Pharmacy, Ocala, Florida). Twenty-two patients received estradiol 10 mg TID (30 mg total administered as 2-mg tablets) and the 2 most recently treated patients received estradiol 2 mg TID (6 mg/d), based on data recently presented by Ellis et al.11 All patients were encouraged to take enteric-coated aspirin 81 mg/d. The patients’ demographic and clinical characteristics are shown in Table I. All 26 patients were female (median age [at the time of estrogen therapy], 59 years; range, 42–92 years). Estrogen-receptor status was known for 24 of 26 patients (92%); of the 2 (8%) that were unknown, 1 had a prior PR to hormonal therapy 2009
Table I. Demographic and clinical characteristics of patients with metastatic breast cancer who received high-dose estrogens as a treatment (N = 26). Characteristic
Value
Age, median (range), y At initial diagnosis At start of estrogen
46 (29–78) 59 (42–92)
Estrogen receptor status, no. (%) Positive Negative Unknown
24 (92) 0 2 (8)*
HER-2 status, no. (%) Positive Negative
3 (12)† 24 (88)
Disease measurability, no. (%) Bidimensionally measurable‡ Bone only
20 (77) 6 (23)
Metastatic sites, median (range) Dominant metastatic site, no. (%) Visceral Liver Lung Liver and lung Bone Soft tissue
2 (1–3) 17 (65) 12 (71) 2 (12) 3 (18) 8 (31) 1 (4)
Prior treatment lines, median (range) Hormonal 4 (1–7) Chemotherapy 3 (0–7) Total prior systemic treatments 7 (0–12) DDFI from definitive surgery, no. (%) ≤24 Months 7 (27) >24 Months 19 (73) Time from recurrence to use of estrogen therapy, median (range), mo
57 (1–132)
HER-2 = human epidermal growth factor receptor 2; DDFI = distant disease-free interval. * One patient had a long disease-free interval of 8 years and the other had a partial response to prior hormonal therapy. † All 3 patients received concomitant trastuzumab after failure of 2, 9, and 9 trastuzumab-based regimens, respectively; 1 of these 3 patients had a partial response to estrogen with trastuzumab. ‡ Visceral and soft tissue metastases.
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Clinical Therapeutics and 1 had an 8-year disease-free interval. Three of the 26 patients (11.5%) were human epidermal growth factor receptor 2 (HER-2) positive; all 3 patients received concomitant trastuzumab and estradiol treatment. The majority (20 [77%]) of patients had measurable metastatic disease, while the remainder (6 [23%]) had bone-only disease. The dominant metastatic site was visceral in 17 patients (65%), bone in 8 (31%), and soft tissue in 1 (4%). Most patients (25 [96%]) had received multiple lines of therapy in the metastatic setting with a median of 4 prior hormonal agents (range, 1–7) and 3 prior chemotherapies (range, 0–7), for a total of 7 total prior systemic therapies (range, 0–12). Individual patient data are presented in Table II. All patients completed estradiol therapy as of March 2009; therefore, all data are complete and updated as of that date.
Effectiveness Of the 26 patients identified, 2 (8%) (1 with boneonly disease and 1 with measurable disease) discontinued treatment after 1 month due to AEs. Efficacy data for all 26 patients are detailed in Table III. Of the 20 patients with measurable disease, CR was observed in 1 patient (5%) with biopsy-proven liver metastases, PR was observed in 4 (20%), and SD for ≥6 months was observed in 4 (20%); the remaining 11 (55%) had disease progression. Of the 6 patients with boneonly disease, 3 (50%) remained on estrogens for ≥6 months. The clinical benefit rate (CR + PR + SD ≥6 months) of all 26 patients was 46%. When only considering evaluable patients, the clinical benefit rate was 50%. The median time to progression for all 26 patients was 5 months (range, 1–22 months); 14 patients died by study end. The median survival from the start of estrogen therapy was 17 months (range, 3–54 months). Of the 2 patients who were administered DES 15 mg/d (5 mg TID), 1 was HER-2 positive and received concomitant trastuzumab. She experienced progression of disease after 5 months. The other patient treated with DES had SD for 9 months. Therapy was discontinued due to suspected disease progression by tumor-marker elevation and grade 1 AEs. This patient then had an estrogen-withdrawal response with tumor-marker decrease lasting an additional 12 months. Of the 2 patients who were administered estradiol 6 mg/d (2 mg TID), 1 had SD for 7 months, and the other had SD for 9 months. The 3 patients who were HER-2 positive and received concomitant trastuzumab treatment ex2374
perienced disease progression after 3, 5, and 12 months, respectively. Finally, of the remaining 18 patients who received estradiol 30 mg/d, 1 had a CR lasting 22 months, 3 had PR (5, 8, and 19 months), 4 had SD ≥6 months (8, 12, 13, and 20 months), and the remainder experienced disease progression at a median of 2 months (range, 2–5 months).
Tolerability In addition to the 2 patients who discontinued after 1 month due to AEs (1 for grade 2 vaginal bleeding and 1 for grade 2 nausea), 3 more patients (13%) discontinued due to AEs at later time points. One had grade 2 vaginal bleeding and the second discontinued due to grade 2 nausea. The third patient discontinued treatment because of grade 2 vaginal bleeding after experiencing a >19-month response of symptomatic pulmonary metastases. She also had significant fluid retention that responded to dose reduction from 30 to 6 mg, allowing for 16 additional months of therapy after her initial response at 3 months. A fourth patient encountered a serious complication of treatment (deep vein thrombosis) and discontinued treatment. However, this patient was not considered off study due to an AE because she was, at the same time, determined to have disease progression after 3 months of treatment. The majority of AEs were deemed to be grade 1 and included nausea, fluid retention, vaginal bleeding, fatigue, and pruritus. All AEs are detailed in Table IV. Anecdotally, 2 patients volunteered information that estrogen therapy was associated with increased libido.
DISCUSSION The use of HDE in the treatment of MBC dates back many years. However, several recently completed studies support its continued use. LØnning et al,12 in a Phase II study, reported the use of DES in women with heavily pretreated MBC (91% [29/32] of patients had ≥3 prior endocrine regimens and 62% had also received chemotherapy). These authors reported an objective response rate of 31% (10/32) with a median duration of 50 weeks (range, 30–124+ weeks). Two additional patients had SD for ≥6 months, for a clinical benefit rate of 38% (12/32). Median time to progression was 18 weeks and median time to failure was 16.5 weeks. Nineteen percent of patients discontinued treatment due to AEs. Some of these AEs were directly attributed to DES administration, including bleeding, vaginal discharge, and mastalgia (not graded). For Volume 31 Theme Issue
2009
Table II. Individual data in study patients with metastatic breast cancer who received high-dose estrogens as a treatment (N = 26).
Patient Number 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26
Age at Start of Estrogen, y 46 56 82 49 58 59 82 92 42 63 61 52 46 69 54 82 60 55 64 69 67 71 80 58 44 53
DDFI, mo
Estrogen Receptor Status
62 59 84 120 24 32 39 36 48 180 84 0 0 0 149 60 151 84 20 216 112 0 264 68 0 138
+ + + + + + + + NA + + + + + + + NA + + + + + + + + +
HER-2 Status
Metastatic Sites, No.
Measurable Disease
Prior H/C/T
No. of Mo. From First Relapse to Start of Estrogen
– + – – – – – + – – – – – – – – + – – – – – – – – –
2 3 2 2 1 1 1 1 1 1 1 2 3 1 3 3 3 2 2 2 2 1 1 1 3 2
Yes Yes Yes Yes No Yes Yes Yes Yes No Yes Yes Yes No Yes Yes Yes No Yes Yes Yes No Yes No Yes Yes
4/4/8 3/3/6 0/2/2 2/2/4 4/4/8 0/4/4 0/6/6 4/6/10 3/6/9 4/4/8 0/0/0 5/5/10 1/4/5 1/4/5 5/4/9 5/3/8 7/4/11 0/7/7 0/2/2 3/4/7 5/7/12 0/2/2 3/4/7 0/3/3 3/5/8 0/3/3
48 86 36 34 45 4 119 132 108 45 1 89 56 49 72 60 72 104 47 52 114 33 79 46 90 48
Time on Estrogens, mo 8 5 19 5 1 22 13 3 2 20 8 3 3 2 9 2 12 12 5 3 2 5 1 7 9 2
Best Response PR PD PR PD OFF CR† SD PD PD SD SD PD PD PD SD‡§ PD PR SD PR PD PD PD OFF SD SD PD
Survival From Start of Estrogen, mo 27* 47 24* 11 19 48* 27 15 23* 39* 28 11 21* 13* 93* 16 15* 54 20* 24 27 17 16 13* 13* 3 R.L. Mahtani et al.
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DDFI = distant disease-free interval; HER-2 = human epidermal growth factor receptor 2; H/C/T = hormonal therapies/chemotherapies/total systemic therapies; PR = partial response; PD = progressive disease; OFF = off treatment after 1 month but included in efficacy evaluation; CR = complete response; NA = not available; SD = stable disease ≥6 months. * Alive at study end (March 2009). † Rechallenged with estradiol at 6 mg/d without response. ‡ Patient also had a 12-month estrogen withdrawal response (21 months control on estrogen and withdrawal). § Rechallenged after intervening therapies with estradiol at 6 mg/d and progressed after 2 months.
Clinical Therapeutics
Table III. Clinical benefit and response rates in patients with metastatic breast cancer who received high-dose estrogens as a treatment (N = 26). Data are number (%) of patients unless otherwise specified. Response
Value
Measurable disease (n = 20) CR 1 (5) PR 4 (20) SD 4 (20) PD 11 (55) Objective response rate (CR + PR) 5 (25) Bone-only disease (n = 6) Disease control ≥6 mo 3 (50) Disease control ≤6 mo 0 PD 3 (50) Total clinical benefit (CR + PR + SD) 12 (46) Median TTP, mo (n = 26) 5 Median time of response or clinical benefit, mo (n = 12) 27 CR = complete response; PR = partial response; SD = stable disease ≥6 months; PD = progressive disease; TTP = time to progression.
others, systemic adverse effects were reported but the authors commented that these might have been associated with other causes. These included nausea, diarrhea, abdominal bloating, arthralgia, dizziness, and lethargy. Massidda et al13 reported an objective response rate in 50% of patients treated with HDE. Interestingly, the only AEs reported in that study were dose-related cholestatic liver abnormalities. In a study by Beex et al,14 63 postmenopausal women with advanced breast cancer were randomized to receive either tamoxifen or HDEs. The authors reported similar response rates (33% vs 31%), median duration of response (12 vs 11 months), and median overall survival (31 vs 25 months) in both treatment groups. One patient treated with HDEs experienced hepatic impairment and discontinued treatment. Finally, Agrawal et al15 reported a clinical benefit rate of 33%, median duration of response of 10 months (range, 7–36 months), and timeto-treatment failure of 4 months (range, 0.5–36 months) in 12 patients treated with HDEs as third- to seventh-line endocrine therapy. One patient in this study discontinued treatment due to hepatorenal syndrome, which developed within 2 weeks of initiating treatment. In the current retrospective chart review, we report, for those patients with measurable disease, an objective response rate of 25% and prolonged SD of 20%. When including the patients with bone-only disease
Table IV. Adverse events (AEs) experienced by patients with metastatic breast cancer who received high-dose estrogens as a treatment (N = 26). All data are number (%). AE Fluid retention Vaginal bleeding Fatigue Nausea Pruritus Venous thromboembolism
Grade 1*
Grade 2*
Grade 3*
7 (27) 5 (19) 3 (12) 3 (12) 2 (8) –
1 (4)† 2 (8)†‡ – 2 (8)§] – –
– – – – – 1 (4)¶
* National Cancer Institute Common Terminology Criteria (grade 1 = mild; grade 2 = moderate; grade 3 = severe; grade 4 = life-threatening or disabling; grade 5 = death).10 † Patient dose reduced from 30 to 6 mg estradiol per day because of fluid retention, but discontinued after 2 years for grade 2 vaginal bleeding. ‡ One of 2 patients with grade 2 vaginal bleeding discontinued after 1 month of therapy but was included in the efficacy analysis. § One of 2 patients with grade 2 nausea discontinued after 1 month of therapy but was included in the efficacy analysis. ] One patient discontinued due to toxicity after 1 month but was included in the efficacy analysis. ¶ Patient off study at 3 months for disease progression concomitant with deep vein thrombosis.
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Volume 31 Theme Issue
R.L. Mahtani et al. who had SD for ≥6 months, the clinical benefit rate was 46%. These values are similar to the published literature.12–15 HDEs are not tolerated by all patients and this is illustrated by the fact that 3 patients (12%) in our study discontinued therapy because of AEs. This rate of discontinuation is also similar to rates published in previous studies12,14,15 In contrast, in a randomized study comparing tamoxifen and 2 separate doses of toremifene, 1.4% (3/215) discontinued tamoxifen due to AEs.16 Some clinicians advocate a stepwise escalation of the estrogen dose over a period of a few weeks to help ameliorate the AEs associated with HDE therapy.6 The mechanism(s) by which HDEs induce antitumor response are poorly understood. Several animal and in vitro studies provide insights into possible mechanisms by which tumors initially become resistant to endocrine therapy. An in vitro study by Masamura et al17 found that deprivation of MCF-7 cells of estrogen in tissue culture medium for periods of 1 to 6 months (long-term estrogen deprivation) resulted in estrogen hypersensitivity. These cells replicated at a concentration of 10–15 to 10–14 mol/L, but at a concentration of 10–10 replication was inhibited. In contrast, wild-type MCF-7 cells replicated maximally at 10–10 mol/L and required much higher doses for inhibition. Therefore, the authors found that the dose–response curve to estrogen shifted to the left in the estrogen-deprived cell line. The authors hypothesized that the response observed to subsequent endocrine therapy was related to increased sensitivity to estradiol. Similarly, Yao et al18 reported tumor regression in response to estradiol in tamoxifen-treated athymic mice serially transplanted with MCF-7TAM and MT2 tumor lines. After an initial response to estradiol, both cell lines regrew, but then again demonstrated a response to tamoxifen. Finally, Song et al19 reported apoptosis by high concentrations of estrogen in estrogen-deprived cell lines. The data suggested that only the estrogen-deprived cell line expressed Fas protein. The authors hypothesized that the mechanism of estrogen-induced tumor response in postmenopausal women is through activation of Fas-mediated apoptosis. These laboratory observations have a clinical correlate. Estrogen deprivation in the laboratory is akin to the use of third-generation aromatase inhibitors. The optimal subsequent dose of HDE is not known, but observed physiologic levels have been used to guide dosing. Physiologically, 1 mg of estradiol simulates 2009
levels of estrogen that are observed at the beginning of the menstrual cycle. At a dose of 6 mg, midmenstrual cycle or preovulatory levels are achieved. The 30-mg dose is more typical of the first trimester of pregnancy. Therefore, this was considered the “standard” therapeutic dose and was used in the studies cited thus far that included estradiol, with some using DES at 15 mg/d in divided doses.5,7,8 The majority of patients in our study also received this dose. As is to be expected, higher doses are associated with greater toxicity. To identify a lower dose that might be equally efficacious but less toxic, Ellis et al11 studied a lower midcycle dose (6 mg) of estradiol in the treatment of postmenopausal advanced breast cancer. Patients who had received treatment with an aromatase inhibitor in the advanced disease setting and experienced ≥24 weeks of progression-free survival were eligible. Postmenopausal women with systemic or unresectable local relapse after taking adjuvant aromatase inhibitor therapy for ≥2 years were also eligible. Patients were randomized to receive either 30 mg (10 mg TID) or 6 mg (2 mg TID) of estradiol. The clinical benefit rate in the higherand lower-dose estradiol arms was very similar (28% vs 29%, respectively). AEs deemed to be grade 3 or higher were significantly more common with the 30-mg dose compared with the 6-mg dose and included significantly more grade 3 nausea (16% vs 0%) and fluid retention (13% vs 0%). Interestingly, a patient who developed a venous thromboembolism that was thought to be study drug–related was treated with the lower dose of estradiol. If a patient experienced a response or SD, but then developed progressive disease, retreatment was conducted with an aromatase inhibitor (on which the cancer had originally progressed). Three of 66 patients (5%) were retreated with an aromatase inhibitor after progression on estradiol. One achieved SD and the other 2 had PR. Due to the fact that our study was a retrospective chart review, there are inherent limitations. The number of patients was small and this was an uncontrolled, nonrandomized study. In these types of reviews, investigator bias might play a role in the interpretation of the results. In addition, not all patients received the same dose of estradiol, with a few even receiving DES.
CONCLUSIONS Our experience treating a small number of patients with HDE suggests that this treatment option may still be effective in this group of patients. Half of our 2377
Clinical Therapeutics patients had received up to 7 forms of treatment, indicating that responses can be seen in heavily pretreated women. Despite the limitations discussed, our findings suggest the need to further explore the use of HDE to clarify optimal dosing and mechanism(s) of action that may translate into new therapeutic options.
ACKNOWLEDGMENTS There was no industry involvement in the design, conduct, analysis, or publication of this study. The authors have indicated that they have no conflicts of interest regarding the content of this article.
REFERENCES 1. Haddow A, Watkinson JM, Paterson E, Koller PC. Influence of synthetic oestrogens upon advanced malignant disease. BMJ. 1944;2:393–398. 2. Kennedy BJ, Kelly RM, White G, Nathanson IT. Surgery as an adjunct to hormone therapy of breast cancer. Cancer. 1957;10:1055–1075. 3. Stoll BA. Responses to repeated doses of stilboesterol. BMJ. 1973;3:446–450. 4. Cole MP, Jones CT, Todd ID. A new anti-oestrogenic agent in late breast cancer. An early clinical appraisal of ICI46474. Br J Cancer. 1971;25:270–275. 5. Ingle JN, Ahmann DL, Green SJ, et al. Randomized clinical trial of diethylstilbestrol versus tamoxifen in postmenopausal women with advanced breast cancer. N Engl J Med. 1981;304:16–21. 6. Ingle JN. Estrogen as therapy for breast cancer. Breast Cancer Res. 2002;4:133–136. 7. Gockerman JP, Spremulli EN, Raney M, Logan T. Randomized comparison of tamoxifen versus diethylstilbestrol in estrogen receptor-positive or -unknown metastatic breast cancer: A Southeastern Cancer Study Group trial. Cancer Treat Rep. 1986;70:1199–1203. 8. Peethambaram PP, Ingle JN, Suman VJ, et al. Randomized trial of diethylstilbestrol vs. tamoxifen in postmenopausal women with advanced breast cancer. An updated analysis. Breast Cancer Res Treat. 1999;54:117–122.
9. Hayes DF, Henderson IC, Shapiro CL. Treatment of metastatic breast cancer: Present and future prospects. Semin Oncol. 1995;22(Suppl 5):5–19; discussion 19–21. 10. National Cancer Institute Common Terminology Criteria for Adverse Events, v3.0 (CTCAE). http://ctep.cancer. gov/protocolDevelopment/electronic_applications/docs/ ctcaev3.pdf. Accessed October 15, 2009. 11. Ellis MJ, Gao F, Dehdashti F, et al. Lower-dose vs highdose oral estradiol therapy of hormone receptor-positive, aromatase inhibitor-resistant advanced breast cancer: A phase 2 randomized study. JAMA. 2009;302:774-780. 12. Lønning PE, Taylor PD, Anker G, et al. High-dose estrogen treatment in postmenopausal breast cancer patients heavily exposed to endocrine therapy. Breast Cancer Res Treat. 2001;67:111–116. 13. Massidda B, Mascia V, Broccia G, et al. Estrogen therapy of advanced breast cancer [in Italian]. Minerva Med. 1977; 68:2509–2516. 14. Beex L, Pieters G, Smals A, et al. Tamoxifen versus ethinyl estradiol in the treatment of postmenopausal women with advanced breast cancer. Cancer Treat Rep. 1981;65: 179–185. 15. Agrawal A, Robertson JF, Cheung KL. Efficacy and tolerability of high dose “ethinylestradiol” in post-menopausal advanced breast cancer patients heavily pre-treated with endocrine agents. World J Surg Oncol. 2006;4:44. 16. Hayes DF, Van Zyl JA, Hacking A, et al. Randomized comparison of tamoxifen and two separate doses of toremifene in postmenopausal patients with metastatic breast cancer. J Clin Oncol. 1995;13:2556–2566. 17. Masamura S, Santner SJ, Heitjan DF, Santen RJ. Estrogen deprivation causes estradiol hypersensitivity in human breast cancer cells. J Clin Endocrinol Metab. 1995;80:2918– 2925. 18. Yao K, Lee ES, Bentrem DJ, et al. Antitumor action of physiological estradiol on tamoxifen-stimulated breast tumors grown in athymic mice. Clin Cancer Res. 2000;6: 2028–2036. 19. Song RX, Mor G, Naftolin F, et al. Effect of long-term estrogen deprivation on apoptotic responses of breast cancer cells to 17beta-estradiol. J Natl Cancer Inst. 2001;93: 1714–1723.
Address correspondence to: Reshma L. Mahtani, DO, Boca Raton Comprehensive Cancer Center, 21020 State Road 7, Boca Raton, FL 33428. E-mail: [email protected] 2378
Volume 31 Theme Issue
Brief Report
High-Dose Estrogen as Salvage Hormonal Therapy for Highly Refractory Metastatic Breast Cancer: A Retrospective Chart Review Reshma L. Mahtani, DO1; Alisha Stein, RNC, BSN, OCN2; and Charles L. Vogel, MD, FACP1 1Boca
Raton Comprehensive Cancer Center, Boca Raton, Florida; and 2The Cancer Research Network, Inc., Boca Raton, Florida ABSTRACT Background: High-dose estrogens (HDEs) are an efficacious but widely overlooked treatment option for patients with metastatic breast cancer (MBC). This is due in part to the introduction of tamoxifen in the 1970s, which was proven to be equivalent in efficacy and associated with fewer adverse events (AEs). Objective: The aim of this study was to report our experience with the use of HDE in postmenopausal women with advanced breast cancer. Methods: Local institutional review board approval was obtained to conduct a retrospective chart review of patients with MBC treated with HDEs at the Boca Raton Comprehensive Cancer Center, Boca Raton, Florida, from 2001 through March 2009. Demographic information, response rates, and tolerability profiles were collected. Results: Of the 426 patients with MBC identified, we found 26 patients with MBC who were prescribed HDEs as a treatment in any line of therapy for advanced breast cancer. The median age at the start of HDE therapy was 59 years (range, 42–92 years). Three of the 26 patients (11.5%) were human epidermal growth factor receptor 2–positive determined via fluorescent in situ hybridization analysis. With the exception of 1 patient who had received no prior systemic treatment for metastatic disease, all patients received multiple lines of treatment (both chemotherapy and hormonal treatments) in the advanced setting (median, 7 lines; range, 0–12) prior to the initiation of HDE. Five of 20 patients (25%) with measurable metastatic disease (visceral and/or soft tissue metastases) had objective antitumor responses defined as either a partial response (PR) or a complete response (CR). Four additional patients (20%) had prolonged stable disease (SD) for ≥6 months. Three of 6 patients (50%) 2009
with nonmeasurable metastatic disease (bone-only) had prolonged SD for ≥6 months. Clinical benefit rate (defined as CR + PR + SD ≥6 months) for all patients was 46% (12/26), with a median duration of 10 months. Overall median progression-free survival for the 26 subjects was 5 months. Median survival from the start of HDE was 17 months (range, 3–54 months). AEs included fluid retention (8 [31%]), vaginal bleeding (7 [27%]), and nausea (4 [15%]). Two patients discontinued therapy after 1 month. Three of the remaining 24 patients discontinued estrogen therapy due to AEs. Conclusions: This retrospective chart review details our facility’s experience with the use of HDE in patients with advanced breast cancer, most of whom had received multiple prior treatments. Our data suggest that this treatment is another option for heavilytreated patients in whom further endocrine manipulation might still be appropriate. (Clin Ther. 2009;31 [Theme Issue]:2371–2378 © 2009 Excerpta Medica Inc. Key words: metastatic breast cancer, hormonal therapy, salvage treatment, estrogen treatment.
INTRODUCTION Although the mechanism(s) versial, the use of high-dose fective treatment option in (MBC) has been recognized
of action remain controestrogen (HDE) as an efmetastatic breast cancer for many years. In 1944,
Data in this manuscript were presented at the 31st Annual San Antonio Breast Cancer Symposium, December 10–14, 2008, San Antonio, Texas. Accepted for publication September 24, 2009. doi:10.1016/j.clinthera.2009.11.002 0149-2918/$ - see front matter © 2009 Excerpta Medica Inc. All rights reserved.
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Clinical Therapeutics Sir Alexander Haddow published his “apparently paradoxical” observation that estrogens can both stimulate and retard growth of breast tumors.1 In the years that followed, other clinicians such as Kennedy et al2 in 1957 and Stoll3 in 1973 continued to note the efficacy of HDE, making it the endocrine treatment of choice in postmenopausal women with advanced breast cancer. This was the case until the introduction of tamoxifen in the 1970s, at which time the use of HDEs decreased. This was largely due to the improved tolerability profile that was associated with tamoxifen. Several studies have suggested the equivalent efficacy of tamoxifen and estrogen therapy. In 1971, Cole et al4 reported the first clinical trial of tamoxifen in 46 women with advanced or recurrent breast cancer. These findings were compared with a similar trial (unpublished) in which women received diethylstilbestrol (DES)—a synthetic estrogen—or an androgen. The authors concluded that efficacy was similar but tamoxifen had a lower incidence of “troublesome side effects.” Patients treated with tamoxifen reported hot flashes, gastrointestinal intolerance, edema, vaginal bleeding, tumor pain, vaginal pruritus, and lassitude. These adverse events (AEs) were not graded but were deemed “mild” and required discontinuation of the drug on only 2 occasions (4%) (1 for intolerable hot flashes and 1 for nausea and vomiting). Ingle et al published results from a randomized clinical trial comparing tamoxifen with DES in 143 postmenopausal women in 19815 and provided updated results in 2002.6 Mature survival data were available for the updated analysis, as 95% of the 143 patients had died. There was no significant difference between the 2 agents in terms of response rates or time to progression. However, survival was significantly better for those women initially treated with DES (adjusted P = 0.039) than for those treated with tamoxifen, with median survival of 3.0 and 2.4 years, respectively, and 5-year survival rates of 35% and 16%. Twelve percent of patients discontinued treatment with DES because of AEs. These AEs included gastrointestinal intolerance (4 patients), congestive heart failure (3), thrombophlebitis (1), and refractory lower-extremity edema with superficial ulcerations (1). Nausea and emesis were found with tamoxifen, but in no patient were they severe enough to warrant discontinuation of the drug. In fact, patients who received tamoxifen had a lower incidence of all AEs reported, with the exception of hot flushes (29% vs 3%) and leukopenia 2372
(15% vs 2%). In a randomized trial, Gockerman et al7 also compared tamoxifen and DES in 115 postmenopausal patients with MBC who were hormone receptor– positive or –unknown and found similar complete response (CR) rates (2% for both groups), partial responses (PR) (4% vs 8% respectively), disease stability (78% vs 73%), median time to disease progression (5 vs 6 months), and median survival (34 vs 35 months) with both agents. In an update of their randomized trial, Peethambaram et al8 reported their results with 151 postmenopausal women with progressive MBC and no prior hormonal therapy who were treated with either DES or tamoxifen. The overall response rate (PR + CR) was 42% for DES and 33% for tamoxifen (P = NS). The duration of response for DES was 11.8 versus 9.9 months for tamoxifen (P = NS). Progressionfree survival was not found to be significantly different between DES and tamoxifen. Median survival was significantly improved for DES versus tamoxifen (3.0 vs 2.4 years, respectively; P = 0.039). Resistance to endocrine agents invariably develops during the course of long-term treatment.9 The sequential use of hormonal therapy in advanced breast cancer is associated with diminishing response rates, and therefore, any further hormonal therapy that has the potential to induce a response is an attractive option for the appropriate patient. In the current retrospective review, we report our experience with the use of HDE in postmenopausal women with advanced breast cancer, the majority of whom had previously progressed on multiple lines of treatment.
MATERIALS AND METHODS After local institutional review board (Boca Raton Community Hospital) approval, medical records for patients with MBC treated in our practice (Boca Raton Comprehensive Cancer Center, Boca Raton, Florida) from 2001 through March 2009 were reviewed. Patients with advanced breast cancer who had received HDE during any line of therapy were identified. Consent was waived based on the fact that all data presented are in aggregate. Health Insurance Portability and Accountability Act guidelines were followed to protect patient information. Baseline evaluation included physical examination, complete blood count, complete metabolic profile, and levels of lactate dehydrogenase, carcinoembryonic antigen, and cancer antigen 27.29. In general, bone scans and computed tomography scans of the chest, abdomen, and pelvis Volume 31 Theme Issue
R.L. Mahtani et al. or a positron emission tomography scan were performed at baseline. Patients were evaluated at 4- to 8-week intervals by physical exam and blood work similar to baseline. Repeat imaging was performed at 8- to 12-week intervals or earlier if symptoms warranted. Severity of AEs was graded using National Cancer Institute Common Terminology Criteria (grade 1 = mild; grade 2 = moderate; grade 3 = severe; grade 4 = life-threatening or disabling; and grade 5 = death).10 Patients were considered to have had CR if there was complete disappearance of all areas of preexisting metastatic disease. This included normalization of bone scans and radiographs in patients with concomitant bone (nonmeasurable) disease in addition to measurable metastatic disease. PR was defined as a ≥50% reduction in the sum of the diameters of selected measurable sites ≥1 cm. Stable disease (SD) was defined as ≤49% reduction in the sum of the diameters of selected measurable sites ≥1 cm or no change in prior nonmeasurable sites of disease without any evidence of new lesions. Overall response rate included all patients with CR and PR divided by all evaluated patients. Clinical benefit rate was defined as CR + PR + SD for ≥6 months among the entire cohort.
RESULTS Patients A total of 426 patients with MBC were treated at our facility during the review period; of these, 26 patients with advanced breast cancer received HDE during treatment. Twenty-four patients were evaluable for response (measurable disease) or clinical benefit (measurable and evaluable disease). However, all 26 patients were included in the efficacy analysis. The first 2 admitted patients were administered DES 5 mg TID (15 mg/d) prepared by a compounding pharmacy (Francks Pharmacy, Ocala, Florida). Twenty-two patients received estradiol 10 mg TID (30 mg total administered as 2-mg tablets) and the 2 most recently treated patients received estradiol 2 mg TID (6 mg/d), based on data recently presented by Ellis et al.11 All patients were encouraged to take enteric-coated aspirin 81 mg/d. The patients’ demographic and clinical characteristics are shown in Table I. All 26 patients were female (median age [at the time of estrogen therapy], 59 years; range, 42–92 years). Estrogen-receptor status was known for 24 of 26 patients (92%); of the 2 (8%) that were unknown, 1 had a prior PR to hormonal therapy 2009
Table I. Demographic and clinical characteristics of patients with metastatic breast cancer who received high-dose estrogens as a treatment (N = 26). Characteristic
Value
Age, median (range), y At initial diagnosis At start of estrogen
46 (29–78) 59 (42–92)
Estrogen receptor status, no. (%) Positive Negative Unknown
24 (92) 0 2 (8)*
HER-2 status, no. (%) Positive Negative
3 (12)† 24 (88)
Disease measurability, no. (%) Bidimensionally measurable‡ Bone only
20 (77) 6 (23)
Metastatic sites, median (range) Dominant metastatic site, no. (%) Visceral Liver Lung Liver and lung Bone Soft tissue
2 (1–3) 17 (65) 12 (71) 2 (12) 3 (18) 8 (31) 1 (4)
Prior treatment lines, median (range) Hormonal 4 (1–7) Chemotherapy 3 (0–7) Total prior systemic treatments 7 (0–12) DDFI from definitive surgery, no. (%) ≤24 Months 7 (27) >24 Months 19 (73) Time from recurrence to use of estrogen therapy, median (range), mo
57 (1–132)
HER-2 = human epidermal growth factor receptor 2; DDFI = distant disease-free interval. * One patient had a long disease-free interval of 8 years and the other had a partial response to prior hormonal therapy. † All 3 patients received concomitant trastuzumab after failure of 2, 9, and 9 trastuzumab-based regimens, respectively; 1 of these 3 patients had a partial response to estrogen with trastuzumab. ‡ Visceral and soft tissue metastases.
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Clinical Therapeutics and 1 had an 8-year disease-free interval. Three of the 26 patients (11.5%) were human epidermal growth factor receptor 2 (HER-2) positive; all 3 patients received concomitant trastuzumab and estradiol treatment. The majority (20 [77%]) of patients had measurable metastatic disease, while the remainder (6 [23%]) had bone-only disease. The dominant metastatic site was visceral in 17 patients (65%), bone in 8 (31%), and soft tissue in 1 (4%). Most patients (25 [96%]) had received multiple lines of therapy in the metastatic setting with a median of 4 prior hormonal agents (range, 1–7) and 3 prior chemotherapies (range, 0–7), for a total of 7 total prior systemic therapies (range, 0–12). Individual patient data are presented in Table II. All patients completed estradiol therapy as of March 2009; therefore, all data are complete and updated as of that date.
Effectiveness Of the 26 patients identified, 2 (8%) (1 with boneonly disease and 1 with measurable disease) discontinued treatment after 1 month due to AEs. Efficacy data for all 26 patients are detailed in Table III. Of the 20 patients with measurable disease, CR was observed in 1 patient (5%) with biopsy-proven liver metastases, PR was observed in 4 (20%), and SD for ≥6 months was observed in 4 (20%); the remaining 11 (55%) had disease progression. Of the 6 patients with boneonly disease, 3 (50%) remained on estrogens for ≥6 months. The clinical benefit rate (CR + PR + SD ≥6 months) of all 26 patients was 46%. When only considering evaluable patients, the clinical benefit rate was 50%. The median time to progression for all 26 patients was 5 months (range, 1–22 months); 14 patients died by study end. The median survival from the start of estrogen therapy was 17 months (range, 3–54 months). Of the 2 patients who were administered DES 15 mg/d (5 mg TID), 1 was HER-2 positive and received concomitant trastuzumab. She experienced progression of disease after 5 months. The other patient treated with DES had SD for 9 months. Therapy was discontinued due to suspected disease progression by tumor-marker elevation and grade 1 AEs. This patient then had an estrogen-withdrawal response with tumor-marker decrease lasting an additional 12 months. Of the 2 patients who were administered estradiol 6 mg/d (2 mg TID), 1 had SD for 7 months, and the other had SD for 9 months. The 3 patients who were HER-2 positive and received concomitant trastuzumab treatment ex2374
perienced disease progression after 3, 5, and 12 months, respectively. Finally, of the remaining 18 patients who received estradiol 30 mg/d, 1 had a CR lasting 22 months, 3 had PR (5, 8, and 19 months), 4 had SD ≥6 months (8, 12, 13, and 20 months), and the remainder experienced disease progression at a median of 2 months (range, 2–5 months).
Tolerability In addition to the 2 patients who discontinued after 1 month due to AEs (1 for grade 2 vaginal bleeding and 1 for grade 2 nausea), 3 more patients (13%) discontinued due to AEs at later time points. One had grade 2 vaginal bleeding and the second discontinued due to grade 2 nausea. The third patient discontinued treatment because of grade 2 vaginal bleeding after experiencing a >19-month response of symptomatic pulmonary metastases. She also had significant fluid retention that responded to dose reduction from 30 to 6 mg, allowing for 16 additional months of therapy after her initial response at 3 months. A fourth patient encountered a serious complication of treatment (deep vein thrombosis) and discontinued treatment. However, this patient was not considered off study due to an AE because she was, at the same time, determined to have disease progression after 3 months of treatment. The majority of AEs were deemed to be grade 1 and included nausea, fluid retention, vaginal bleeding, fatigue, and pruritus. All AEs are detailed in Table IV. Anecdotally, 2 patients volunteered information that estrogen therapy was associated with increased libido.
DISCUSSION The use of HDE in the treatment of MBC dates back many years. However, several recently completed studies support its continued use. LØnning et al,12 in a Phase II study, reported the use of DES in women with heavily pretreated MBC (91% [29/32] of patients had ≥3 prior endocrine regimens and 62% had also received chemotherapy). These authors reported an objective response rate of 31% (10/32) with a median duration of 50 weeks (range, 30–124+ weeks). Two additional patients had SD for ≥6 months, for a clinical benefit rate of 38% (12/32). Median time to progression was 18 weeks and median time to failure was 16.5 weeks. Nineteen percent of patients discontinued treatment due to AEs. Some of these AEs were directly attributed to DES administration, including bleeding, vaginal discharge, and mastalgia (not graded). For Volume 31 Theme Issue
2009
Table II. Individual data in study patients with metastatic breast cancer who received high-dose estrogens as a treatment (N = 26).
Patient Number 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26
Age at Start of Estrogen, y 46 56 82 49 58 59 82 92 42 63 61 52 46 69 54 82 60 55 64 69 67 71 80 58 44 53
DDFI, mo
Estrogen Receptor Status
62 59 84 120 24 32 39 36 48 180 84 0 0 0 149 60 151 84 20 216 112 0 264 68 0 138
+ + + + + + + + NA + + + + + + + NA + + + + + + + + +
HER-2 Status
Metastatic Sites, No.
Measurable Disease
Prior H/C/T
No. of Mo. From First Relapse to Start of Estrogen
– + – – – – – + – – – – – – – – + – – – – – – – – –
2 3 2 2 1 1 1 1 1 1 1 2 3 1 3 3 3 2 2 2 2 1 1 1 3 2
Yes Yes Yes Yes No Yes Yes Yes Yes No Yes Yes Yes No Yes Yes Yes No Yes Yes Yes No Yes No Yes Yes
4/4/8 3/3/6 0/2/2 2/2/4 4/4/8 0/4/4 0/6/6 4/6/10 3/6/9 4/4/8 0/0/0 5/5/10 1/4/5 1/4/5 5/4/9 5/3/8 7/4/11 0/7/7 0/2/2 3/4/7 5/7/12 0/2/2 3/4/7 0/3/3 3/5/8 0/3/3
48 86 36 34 45 4 119 132 108 45 1 89 56 49 72 60 72 104 47 52 114 33 79 46 90 48
Time on Estrogens, mo 8 5 19 5 1 22 13 3 2 20 8 3 3 2 9 2 12 12 5 3 2 5 1 7 9 2
Best Response PR PD PR PD OFF CR† SD PD PD SD SD PD PD PD SD‡§ PD PR SD PR PD PD PD OFF SD SD PD
Survival From Start of Estrogen, mo 27* 47 24* 11 19 48* 27 15 23* 39* 28 11 21* 13* 93* 16 15* 54 20* 24 27 17 16 13* 13* 3 R.L. Mahtani et al.
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DDFI = distant disease-free interval; HER-2 = human epidermal growth factor receptor 2; H/C/T = hormonal therapies/chemotherapies/total systemic therapies; PR = partial response; PD = progressive disease; OFF = off treatment after 1 month but included in efficacy evaluation; CR = complete response; NA = not available; SD = stable disease ≥6 months. * Alive at study end (March 2009). † Rechallenged with estradiol at 6 mg/d without response. ‡ Patient also had a 12-month estrogen withdrawal response (21 months control on estrogen and withdrawal). § Rechallenged after intervening therapies with estradiol at 6 mg/d and progressed after 2 months.
Clinical Therapeutics
Table III. Clinical benefit and response rates in patients with metastatic breast cancer who received high-dose estrogens as a treatment (N = 26). Data are number (%) of patients unless otherwise specified. Response
Value
Measurable disease (n = 20) CR 1 (5) PR 4 (20) SD 4 (20) PD 11 (55) Objective response rate (CR + PR) 5 (25) Bone-only disease (n = 6) Disease control ≥6 mo 3 (50) Disease control ≤6 mo 0 PD 3 (50) Total clinical benefit (CR + PR + SD) 12 (46) Median TTP, mo (n = 26) 5 Median time of response or clinical benefit, mo (n = 12) 27 CR = complete response; PR = partial response; SD = stable disease ≥6 months; PD = progressive disease; TTP = time to progression.
others, systemic adverse effects were reported but the authors commented that these might have been associated with other causes. These included nausea, diarrhea, abdominal bloating, arthralgia, dizziness, and lethargy. Massidda et al13 reported an objective response rate in 50% of patients treated with HDE. Interestingly, the only AEs reported in that study were dose-related cholestatic liver abnormalities. In a study by Beex et al,14 63 postmenopausal women with advanced breast cancer were randomized to receive either tamoxifen or HDEs. The authors reported similar response rates (33% vs 31%), median duration of response (12 vs 11 months), and median overall survival (31 vs 25 months) in both treatment groups. One patient treated with HDEs experienced hepatic impairment and discontinued treatment. Finally, Agrawal et al15 reported a clinical benefit rate of 33%, median duration of response of 10 months (range, 7–36 months), and timeto-treatment failure of 4 months (range, 0.5–36 months) in 12 patients treated with HDEs as third- to seventh-line endocrine therapy. One patient in this study discontinued treatment due to hepatorenal syndrome, which developed within 2 weeks of initiating treatment. In the current retrospective chart review, we report, for those patients with measurable disease, an objective response rate of 25% and prolonged SD of 20%. When including the patients with bone-only disease
Table IV. Adverse events (AEs) experienced by patients with metastatic breast cancer who received high-dose estrogens as a treatment (N = 26). All data are number (%). AE Fluid retention Vaginal bleeding Fatigue Nausea Pruritus Venous thromboembolism
Grade 1*
Grade 2*
Grade 3*
7 (27) 5 (19) 3 (12) 3 (12) 2 (8) –
1 (4)† 2 (8)†‡ – 2 (8)§] – –
– – – – – 1 (4)¶
* National Cancer Institute Common Terminology Criteria (grade 1 = mild; grade 2 = moderate; grade 3 = severe; grade 4 = life-threatening or disabling; grade 5 = death).10 † Patient dose reduced from 30 to 6 mg estradiol per day because of fluid retention, but discontinued after 2 years for grade 2 vaginal bleeding. ‡ One of 2 patients with grade 2 vaginal bleeding discontinued after 1 month of therapy but was included in the efficacy analysis. § One of 2 patients with grade 2 nausea discontinued after 1 month of therapy but was included in the efficacy analysis. ] One patient discontinued due to toxicity after 1 month but was included in the efficacy analysis. ¶ Patient off study at 3 months for disease progression concomitant with deep vein thrombosis.
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R.L. Mahtani et al. who had SD for ≥6 months, the clinical benefit rate was 46%. These values are similar to the published literature.12–15 HDEs are not tolerated by all patients and this is illustrated by the fact that 3 patients (12%) in our study discontinued therapy because of AEs. This rate of discontinuation is also similar to rates published in previous studies12,14,15 In contrast, in a randomized study comparing tamoxifen and 2 separate doses of toremifene, 1.4% (3/215) discontinued tamoxifen due to AEs.16 Some clinicians advocate a stepwise escalation of the estrogen dose over a period of a few weeks to help ameliorate the AEs associated with HDE therapy.6 The mechanism(s) by which HDEs induce antitumor response are poorly understood. Several animal and in vitro studies provide insights into possible mechanisms by which tumors initially become resistant to endocrine therapy. An in vitro study by Masamura et al17 found that deprivation of MCF-7 cells of estrogen in tissue culture medium for periods of 1 to 6 months (long-term estrogen deprivation) resulted in estrogen hypersensitivity. These cells replicated at a concentration of 10–15 to 10–14 mol/L, but at a concentration of 10–10 replication was inhibited. In contrast, wild-type MCF-7 cells replicated maximally at 10–10 mol/L and required much higher doses for inhibition. Therefore, the authors found that the dose–response curve to estrogen shifted to the left in the estrogen-deprived cell line. The authors hypothesized that the response observed to subsequent endocrine therapy was related to increased sensitivity to estradiol. Similarly, Yao et al18 reported tumor regression in response to estradiol in tamoxifen-treated athymic mice serially transplanted with MCF-7TAM and MT2 tumor lines. After an initial response to estradiol, both cell lines regrew, but then again demonstrated a response to tamoxifen. Finally, Song et al19 reported apoptosis by high concentrations of estrogen in estrogen-deprived cell lines. The data suggested that only the estrogen-deprived cell line expressed Fas protein. The authors hypothesized that the mechanism of estrogen-induced tumor response in postmenopausal women is through activation of Fas-mediated apoptosis. These laboratory observations have a clinical correlate. Estrogen deprivation in the laboratory is akin to the use of third-generation aromatase inhibitors. The optimal subsequent dose of HDE is not known, but observed physiologic levels have been used to guide dosing. Physiologically, 1 mg of estradiol simulates 2009
levels of estrogen that are observed at the beginning of the menstrual cycle. At a dose of 6 mg, midmenstrual cycle or preovulatory levels are achieved. The 30-mg dose is more typical of the first trimester of pregnancy. Therefore, this was considered the “standard” therapeutic dose and was used in the studies cited thus far that included estradiol, with some using DES at 15 mg/d in divided doses.5,7,8 The majority of patients in our study also received this dose. As is to be expected, higher doses are associated with greater toxicity. To identify a lower dose that might be equally efficacious but less toxic, Ellis et al11 studied a lower midcycle dose (6 mg) of estradiol in the treatment of postmenopausal advanced breast cancer. Patients who had received treatment with an aromatase inhibitor in the advanced disease setting and experienced ≥24 weeks of progression-free survival were eligible. Postmenopausal women with systemic or unresectable local relapse after taking adjuvant aromatase inhibitor therapy for ≥2 years were also eligible. Patients were randomized to receive either 30 mg (10 mg TID) or 6 mg (2 mg TID) of estradiol. The clinical benefit rate in the higherand lower-dose estradiol arms was very similar (28% vs 29%, respectively). AEs deemed to be grade 3 or higher were significantly more common with the 30-mg dose compared with the 6-mg dose and included significantly more grade 3 nausea (16% vs 0%) and fluid retention (13% vs 0%). Interestingly, a patient who developed a venous thromboembolism that was thought to be study drug–related was treated with the lower dose of estradiol. If a patient experienced a response or SD, but then developed progressive disease, retreatment was conducted with an aromatase inhibitor (on which the cancer had originally progressed). Three of 66 patients (5%) were retreated with an aromatase inhibitor after progression on estradiol. One achieved SD and the other 2 had PR. Due to the fact that our study was a retrospective chart review, there are inherent limitations. The number of patients was small and this was an uncontrolled, nonrandomized study. In these types of reviews, investigator bias might play a role in the interpretation of the results. In addition, not all patients received the same dose of estradiol, with a few even receiving DES.
CONCLUSIONS Our experience treating a small number of patients with HDE suggests that this treatment option may still be effective in this group of patients. Half of our 2377
Clinical Therapeutics patients had received up to 7 forms of treatment, indicating that responses can be seen in heavily pretreated women. Despite the limitations discussed, our findings suggest the need to further explore the use of HDE to clarify optimal dosing and mechanism(s) of action that may translate into new therapeutic options.
ACKNOWLEDGMENTS There was no industry involvement in the design, conduct, analysis, or publication of this study. The authors have indicated that they have no conflicts of interest regarding the content of this article.
REFERENCES 1. Haddow A, Watkinson JM, Paterson E, Koller PC. Influence of synthetic oestrogens upon advanced malignant disease. BMJ. 1944;2:393–398. 2. Kennedy BJ, Kelly RM, White G, Nathanson IT. Surgery as an adjunct to hormone therapy of breast cancer. Cancer. 1957;10:1055–1075. 3. Stoll BA. Responses to repeated doses of stilboesterol. BMJ. 1973;3:446–450. 4. Cole MP, Jones CT, Todd ID. A new anti-oestrogenic agent in late breast cancer. An early clinical appraisal of ICI46474. Br J Cancer. 1971;25:270–275. 5. Ingle JN, Ahmann DL, Green SJ, et al. Randomized clinical trial of diethylstilbestrol versus tamoxifen in postmenopausal women with advanced breast cancer. N Engl J Med. 1981;304:16–21. 6. Ingle JN. Estrogen as therapy for breast cancer. Breast Cancer Res. 2002;4:133–136. 7. Gockerman JP, Spremulli EN, Raney M, Logan T. Randomized comparison of tamoxifen versus diethylstilbestrol in estrogen receptor-positive or -unknown metastatic breast cancer: A Southeastern Cancer Study Group trial. Cancer Treat Rep. 1986;70:1199–1203. 8. Peethambaram PP, Ingle JN, Suman VJ, et al. Randomized trial of diethylstilbestrol vs. tamoxifen in postmenopausal women with advanced breast cancer. An updated analysis. Breast Cancer Res Treat. 1999;54:117–122.
9. Hayes DF, Henderson IC, Shapiro CL. Treatment of metastatic breast cancer: Present and future prospects. Semin Oncol. 1995;22(Suppl 5):5–19; discussion 19–21. 10. National Cancer Institute Common Terminology Criteria for Adverse Events, v3.0 (CTCAE). http://ctep.cancer. gov/protocolDevelopment/electronic_applications/docs/ ctcaev3.pdf. Accessed October 15, 2009. 11. Ellis MJ, Gao F, Dehdashti F, et al. Lower-dose vs highdose oral estradiol therapy of hormone receptor-positive, aromatase inhibitor-resistant advanced breast cancer: A phase 2 randomized study. JAMA. 2009;302:774-780. 12. Lønning PE, Taylor PD, Anker G, et al. High-dose estrogen treatment in postmenopausal breast cancer patients heavily exposed to endocrine therapy. Breast Cancer Res Treat. 2001;67:111–116. 13. Massidda B, Mascia V, Broccia G, et al. Estrogen therapy of advanced breast cancer [in Italian]. Minerva Med. 1977; 68:2509–2516. 14. Beex L, Pieters G, Smals A, et al. Tamoxifen versus ethinyl estradiol in the treatment of postmenopausal women with advanced breast cancer. Cancer Treat Rep. 1981;65: 179–185. 15. Agrawal A, Robertson JF, Cheung KL. Efficacy and tolerability of high dose “ethinylestradiol” in post-menopausal advanced breast cancer patients heavily pre-treated with endocrine agents. World J Surg Oncol. 2006;4:44. 16. Hayes DF, Van Zyl JA, Hacking A, et al. Randomized comparison of tamoxifen and two separate doses of toremifene in postmenopausal patients with metastatic breast cancer. J Clin Oncol. 1995;13:2556–2566. 17. Masamura S, Santner SJ, Heitjan DF, Santen RJ. Estrogen deprivation causes estradiol hypersensitivity in human breast cancer cells. J Clin Endocrinol Metab. 1995;80:2918– 2925. 18. Yao K, Lee ES, Bentrem DJ, et al. Antitumor action of physiological estradiol on tamoxifen-stimulated breast tumors grown in athymic mice. Clin Cancer Res. 2000;6: 2028–2036. 19. Song RX, Mor G, Naftolin F, et al. Effect of long-term estrogen deprivation on apoptotic responses of breast cancer cells to 17beta-estradiol. J Natl Cancer Inst. 2001;93: 1714–1723.
Address correspondence to: Reshma L. Mahtani, DO, Boca Raton Comprehensive Cancer Center, 21020 State Road 7, Boca Raton, FL 33428. E-mail: [email protected] 2378
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