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A phase II study of fulvestrant in the treatment of multiply-recurrent epithelial ovarian cancer
Gynecologic Oncology 113 (2009) 205–209
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Gynecologic Oncology j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / y g y n o
A phase II study of fulvestrant in the treatment of multiply-recurrent epithelial ovarian cancer Peter A. Argenta ⁎, Sajeena G. Thomas, Patricia L. Judson, Levi S. Downs Jr., Melissa A. Geller, Linda F. Carson, Amy L. Jonson, Rahel Ghebre Division of Gynecologic Oncology, Department of Obstetrics, Gynecology, and Women's Health, University of Minnesota, MMC 395, 420 Delaware St. SE, Minneapolis MN, 55455, USA
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Article history: Received 3 December 2008 Available online 23 February 2009 Keywords: Ovarian cancer Faslodex Fulvestrant Estrogen Phase II Estrogen receptor
a b s t r a c t Objective. The goal of treating recurrent ovarian cancer is disease control while minimizing toxicity. Fulvestrant, a novel estrogen receptor (ER) antagonist, has proven clinically beneficial and well-tolerated in treating recurrent breast cancer. Ovarian cancer often expresses ER and may respond to anti-estrogen therapy. We evaluated fulvestrant in women with recurrent ovarian or primary peritoneal cancer. Methods. Patients with ER-positive, multiply recurrent ovarian or primary peritoneal carcinoma and either measurable disease according to RECIST criteria or an abnormal and rising CA-125 were eligible for enrollment. Treatment consisted of single agent fulvestrant, 500 mg IM on Day 1, 250 mg IM on Day 15, and 250 mg IM on Day 29 and every 28 days thereafter until either intolerance or disease progression. Disease response was assessed by monthly physical exams and CA-125 levels as well as CT scans bimonthly. The primary endpoint was clinical benefit (CB = complete response (CR) + partial response (PR) + stable disease (SD)) at 90 days. Results. Thirty-one women were enrolled and 26 women (median age of 61) met inclusion criteria and received at least one dose. Patients had received a median of 5 prior chemotherapeutic regimens (range: 2– 13). We observed one CR (4%), one PR (4%), and 9 patients with SD (35%) using modified-Rustin criteria (CA125 level). Using modified-RECIST criteria 13 patients (50%) achieved SD. The median time to disease progression was 62 days (mean 86 days). Grade 1 toxicity included headache (1 patient) and bromidrosis (2 patients). Conclusions. Fulvestrant is well-tolerated and efficacious. Objective response rates are low, but disease stabilization was common. © 2009 Elsevier Inc. All rights reserved.
Introduction Despite improvements in the delivery of cytotoxic chemotherapy, most patients with advanced ovarian cancer relapse and ultimately experience progressive disease [1]. Repeated courses of salvage therapy can induce remission in a minority of patients, but these regimens are generally characterized by increasingly short progression-free intervals and often accumulating toxicity, highlighting the need for novel approaches to treating recurrent disease [2,3]. Biologic therapies, which modify tumor biology with or without cytotoxicity, have been used successfully in selected breast (tamoxifen [4], her2/neu inhibition [5,6]) endometrial (progestin therapy [7]) and gastrointestinal stromal cancers (c-kit inhibition [8]), among others. Initial efforts in the biologic treatment of ovarian cancer, including tamoxifen, trastuzumab, and imatinib mesylate have met with mixed results [9–11]. However, recent successes with anti-VEGF antibodies and aromatase inhibition suggest that subsets of ovarian ⁎ Corresponding author. Fax: +1 612 626 0665. E-mail address: [email protected] (P.A. Argenta). 0090-8258/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2009.01.012
cancer may be susceptible to biologic therapy [12,13]. Further, Walker et al. suggest that in the case of anti-estrogen therapy, response may be predictable based on tumor protein expression profiles [14]. Though estrogen has long been known to be an ovarian cancer growth factor in vitro, an increasing body of evidence now suggests that estrogen plays an integral role in both the development and propagation of some ovarian cancers [15]. A recent metanalysis of studies of estrogen-base hormone replacement therapy demonstrated a statistical increase in the incidence of epithelial ovarian cancer among women taking hormone replacement therapy [16]. Silva et al. have also demonstrated that even short exposure to any of multiple estrogens is capable of inducing neoplastic changes, cystadenomas and papillary excrescences in the ovaries in a mammalian model [17]. Inhibition of estrogen production via blockade of either the aromatase or sulfatase pathways has proven therapeutic in breast cancer [18,19]. Similarly, mitigation of estrogen function at the level of the receptor is effective and well tolerated in beast cancer [20]. Among estrogen function inhibitors (aromatase, sulfatase, and pure estrogen receptor antagonists), only letrozole has been tested in ovarian cancer.
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Fulvestrant, a novel estrogen receptor (ER) antagonist devoid of agonist properties, is beneficial in some women with breast cancer even after heavy pretreatment [21]. Fulvestrant is a 17-β estradiol derivative, substituted with an alkyl chain at the 7-α position, giving it a binding affinity similar to estradiol [22]. It is available as an intramuscular injection, and has been used in a variety of schedules. In preliminary studies, steady-state ER blockade could be achieved with minimal toxicity in 28 days using a loading-dose strategy of intramuscular injections [23]. This study was conducted to determine the efficacy and toxicity profile, including effects on bone mineral turnover, of fulvestrant in the treatment of recurrent ovarian cancer. Methods After obtaining approval from the Institutional Review Board and the Cancer Protocol Review Committee of the University of Minnesota, we conducted a single institution phase II study of fulvestrant in the treatment of multiply recurrent ovarian cancer. All subjects signed informed consent prior to study enrollment. Patients were eligible if they had all of the following: histologicallyproven estrogen receptor-positive, recurrent or persistent ovarian carcinoma; received at least 2 previous cytotoxic regimens (with at least one containing a platinum agent); measurable disease according to RECIST criteria or a CA-125 that was rising and either above 35 U/ml on 2 evaluations at least 2 weeks apart, or below 35 with a progressive rise of N200%; adequate organ function within 14 days of study entry defined by platelets above 50 × 109/L, serum creatinine ≥2.5 mg/dL, INR ≤ 1.6, bilirubin ≤ 1.5× upper limit of institutional normal, aspartate aminotransferase (AST) and alkaline phosphatase ≤3× the upper limit of institutional normal; age ≥18 years; Gynecologic Oncology Group (GOG) performance status 0–3; undergone surgical castration or were on adequate birth control; not received previous hormonal therapy, chemotherapy or radiation within 3 weeks of enrollment, and had willingly signed an informed consent. Exclusion criteria were intentionally limited to broaden the applicability of our findings, but included: pregnancy or active lactation, history of a bleeding event (disseminated intravascular coagulation or clotting factor deficiency) or long term anti-coagulation, AST or alanine aminotransferase (ALT) ≥2.5× the upper limit of institutional normal in the absence of liver metastasis or ≥5× the upper limit of institutional normal in the presence of liver metastasis, sensitivity to the active or inactive excipients of fulvestrant (castor oil or mannitol). There was no limit to number of previous chemotherapy regimens allowed. Prior to enrollment estrogen receptor analysis of the primary tumor via immunohistochemistry was performed; only patients with no staining were excluded. At study enrollment, each patient gave a medical history and underwent a physical examination. Performance status, quality of life (FACT-O), assessment of disease (either CT or CA125 depending on entry criteria), hematologic and blood chemistry analysis including B-hCG where appropriate, and measurement of bone turnover markers (N-telopeptide and serum skeletal-specific alkaline phosphatase) were performed serially during the study.
Our institution is a large, metropolitan academic center that generally treats about 100 patients with newly diagnosed ovarian cancer annually, with between 10 and 30% of all patients being enrolled in clinical trials. There were no trials open to competitive accrual during the duration of this study. Treatment protocol Patients were given fulvestrant as an intramuscular injection as follows: a “loading dose” of 500 mg IM on day 1, followed by a “booster dose” of 250 mg IM on day 15, and then “maintenance dosing” of 250 mg IM every 28 days beginning on day 29 and continuing until disease progression, patient intolerance, or medically-indicated discontinuation by the treating physician. Self-administration of ibuprofen or acetaminophen was allowed for injection site pain, but no concurrent chemotherapy or hormonal therapy was allowed. No dose modifications or treatment delays were allowed. Physical examination, toxicity assessment, performance status, and serum laboratory values were performed prior to day 1 of each cycle and at the conclusion of the study. Disease assessment and chest X-ray or CT were performed every other cycle (q8 weeks). The FACT-O was administered every third cycle (q12 weeks) and at the conclusion of treatment. Bone turnover markers were assessed before treatment and at 1, 3, and 6 months. ER status was determined by immunohistochemistry and evaluated by pathologists independent of this study; any estrogen receptor detection was considered sufficient for inclusion. The primary study endpoint was 90-day clinical benefit (CB) defined as the sum of complete response (CR), partial response (PR), and stable disease (SD). Responses were evaluated by modified RECIST criteria and by modified Rustin Criteria (Table 1) [24,25]. For overall assessment of clinical benefit the worse of the two measures was used (ie a patient with stable disease by RECIST criteria and progressive disease by Rustin criteria was considered progressive disease). Secondary endpoints included establishing the time to termination of treatment for any cause (TTT), and determine the toxicity profile in this population classified according to the National Cancer Institute's Common Terminology Criteria for adverse events V3.0. Correlative endpoints included assessing the impact of this regimen on quality of life using the Functional Assessment of Cancer Therapy — Ovarian cancer (FACT-O), and the effect on bone mineral turnover as measured by changes in the urine N-telopeptide and serum skeletal specific alkaline phosphatase. Statistical consideration The pre-determined primary endpoint was clinical benefit over 90 days. The target accrual was 27 patients over 48 months. The sample size calculation was based on the Simon method using a minimax design [26]. A two step enrollment with early stopping rules for low observed response rates (RR = clinical benefit), selecting 5% as an unacceptably low RR and 20% as “clinically significant;” and setting the alpha at 0.05 and power at 0.8. Based on these calculations, early
Table 1 Response definitions
RECISTa Modified Rustin
Partial response
Complete response
Progressive disease
≥ 30% decrease in the sum of all target lesions (longest diameters) ≥ 50% decrease in serum CA-125 level from 2 initially elevated samplesb
Disappearance of all target lesions
≥ 20% increase in the sum of all target lesions (longest diameter) or any new lesions CA-125 2× ULN on 2 occasions (if previously normalized) OR CA-125 2× nadir on 2 occasions (if elevated at initiation of treatment)
Normalization of serum CA-125 level from 2 initially elevated samplesb
ULN; upper limit of normal. a Patients without measurable disease were considered ineligible for complete or partial response, but were considered to have stable disease (SD) if no new or worsening lesions were detected during study period. b Requires confirmatory sample at least 28 days from response determinant.
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stopping would have occurred if no responses were observed in the first 13 patients. Secondary endpoints included time to treament termination (TTT), quality of life analysis, toxicity assessment. Analysis of the markers of bone mineral turnover was by unpaired ttest assuming unequal varience. Results Due to higher than anticipated ER prevalence among consented patients (91%), 29 eligible women were enrolled between July, 2007 to April, 2008, after approval from the Institutional Review Board of the University of Minnesota. Patient characteristics are listed in Table 2. Generally the patients were heavily pre-treated, with the median number of previous regimens being 5 (range 2–13). The median TTT for the antecedent therapy was 16 weeks (range 2– 39 weeks). Twenty-six patients received at least one treatment and were included in the analysis. The median number of injections received was 3 (range 1–11), and the indications for termination of treatment are listed in Table 3. At 90 days of treatment we observed one complete response (4%), one partial response (4%), and 9 patients with stable disease (35%) using modified-Rustin criteria (CA-125 level). Nine of 25 evaluable patients (36%) experienced at least a transitory drop in CA-125. Using modified-RECIST criteria 13 patients (50%) achieved stable disease at 90 days, while 13 experienced PD. Clinical benefit at 90 days, using the “worst response” for each patient was observed in 8 (31%) of patients (all SD). The median progression-free survival was 62 days (mean 86 days). The median overall survival is not yet met. The median time to treatment termination (TTT) was also 62 days, though the mean (93 days) was skewed higher by 2 patients who remain on treatment (253 and 373 days) despite meeting progression endpoints owing to the absence of symptoms despite rising CA-125 in one patient, and intolerance of previous cytotoxic chemotherapy in the other. The treatment was very well tolerated, with no grade 3 or 4 toxicities. Observed toxicity included headache, grade 1 (1 patient, 4%) and bromidrosis (alternation in body odor), grade 1 (2 patients, 8%). The median quality of life score (FACT-O) at baseline was 86.7. After 3 and 6 treatments the median scores were not significantly reduced at 84.3 (p = .68) and 81 (p = .78) respectively, indicating no significant detriment to quality of life experienced by these women. Fulvestrant administration was not associated with any statistical impact on the markers of bone turnover (Fig. 1). Median (range) serum bone-specific alkaline phosphatase levels were 14.0 (6.9–23.5) U/L at baseline; 16.1 (7.1–26.5) U/L at 1 month of treatment (p = .23); 18.5 (8.3–25.5) U/L at 3 months (p = .48); 16.2 (13.8–29.2) U/L at 6 months (p = .23). Median (range) urinary N-telopeptide levels were
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Table 3 Reasons for discontinuation of therapy N (%) Intolerance Rise in CA-125 N200% of baseline/nadir Clinical progression Radiologic progression Multiple modalities Still on therapy
0 12 (46%) 4 (15%) 2 (8%) 5 (19%) 3 (12%)
50 (8–184) BCE/mM at baseline; 49 (11–117) BCE/mM at 1 month of treatment (p = .98); 43 (18–115) BCE/mM at 3 months (p = .51); 46 (42–91) BCE/mM at 6 months (p = .84). Discussion Fulvestrant, delivered using the loading dose strategy, is well tolerated and appears to provide some benefit even in the setting of multiply recurrent disease. Objective response rates are low, but disease stabilization was common albeit short-lived. Implicit in any discussion of treatment options for patients with recurrent ovarian cancer is the tradeoff between benefit and toxicity in the setting where cure is rare. To date few drugs have demonstrated significant activity in the third and fourth lines, and clinical decisions are frequently based on toxicity profiles as much as therapeutic potential. Despite the grim overall prognosis however, many patients continue to maintain high performance status and seek treatment for years. This desire of patients for low toxicity therapies is reflected in the short accrual time of this study, under half of that predicted by previous, cytotoxic trials with similar design at our institution. Fulvestrant, now being increasingly used in breast cancer, has multiple unique properties that make it well-suited to treatment of heavily pretreated patients. Primary among these is the absence of marrow toxicity, which typically limits the tolerability of many cytotoxic therapies. It is easy to administer, has a favorable monthly dosing schedule, and does not require intravenous access or interval assessment of the neutrophil count or hemoglobin. There are few
Table 2 Patient characteristics Age (years) median (range) Race Caucasian Previous chemotherapy regimens: median (range) Performance status (GOG): median (range) Stage at diagnosis I II III IV Histology Serous Endometrioid Clear cell Other Grade 2 3
61 (43–95) 100% 5 (2–13) 1 (0–2) 1 2 20 3
(4%) (8%) (77%) (12%)
16 4 1 5
(62%) (15%) (4%) (19%)
4 (15%) 22 (85%)
Fig. 1. Markers of bone mineral turnover. (A) Urinary N-telopeptide. (B) Serum bonespecific alkaline phosphatase.
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lingering toxicities, and our quality of life analysis confirms previously published data that the drug does not appear to impair QOL [27]. Our data also demonstrates relative stability of the markers of bone mineral turnover, which may prove to be a relative advantage over currently available aromatase inhibitors which have been associated with accelerated bone loss. Lastly, unlike tamoxifen which exhibits weak estrogen activity in the uterus, fulvestrant has no ER agonistic properties and is currently being evaluated by the Gynecologic Oncology Group as a treatment for endometrial cancer. Why blockade of ER is therapeutic in the multiply recurrent ovarian cancer setting when other hormonal therapies have had mixed results in more favorable settings remains unclear. There is increasing evidence, however, that estrogen may play a key role in both the development and propagation of ovarian cancer despite the fact that most women will be diagnosed well into the menopausal years. Sasano et al. suggest that estrogen produced intratumorally through the conversion of inactive precursors, may act locally to enhance tumor growth [28]. This “intracrinology” would be unaffected by centrally acting agents, and may explain why studies of GnRH agonists have generally demonstrated minimal or no activity [29,30]. Intratumoral estrogen production could also potentially blunt the effect of systemic aromatase or sulfatase inhibitors, possibly accounting for mixed results observed in patients treated with letrozole or other aromatase inhibitors. Our group and others have demonstrated that the enzymes required for intratumoral conversion of estrogen precursors to estrogen and for conversion of low potency estrogens to high potency estrogens exist in a majority of ovarian cancers [31,32]. A corollary to this hypothesis is that loss of ER, typically associated with a poorer prognosis, may be a later event in tumorigenesis/progression, either as a cause or effect of local estrogen activity [33,34]. Another possible explanation for failure of some anti-estrogen strategies is that compensatory activation of alternate estrogenic pathways may compensate for blockade of either the aromatase or sulfatase pathway. This would explain the observation that STX 64 (667 Coumate), a novel sulfatase inhibitor is effective in breast cancer patients who have ceased responding to aromatase inhibitors [19]. This hypothesis would also explain why blockade of the estrogen receptor, a downstream event may still be therapeutic after other failed endocrine therapies. Interestingly, both of these observations suggest that multimodal therapy may be synergistic. The use of fulvestrant in selected populations remains understudied. Multiple prospective and retrospective studies in breast cancer have included ER-negative patients, but subset analysis of this population is reported in only one to date [35,36]. Interestingly Neven et al., in reporting the compassionate use experience with fulvestrant observed CB in a similar proportion of ER-positive and ER-negative patients [35]. Though histologic grade was generally not included in the breast cancer analyses, it may be a relevant predictor in gynecologic malignancies. Unfortunately no patients with low grade histology, who might be expected to have the most favorable responses, were enrolled in this study. This subgroup however may merit directed inclusion in follow-up trials. The primary end-point of this study, clinical benefit, is arguably a weakness of the study, especially as relatively few patients exhibited objective responses. However, there is little evidence that objective responses correlate to prolonged over-all or even disease-free survival in the recurrent setting. Since most patients will go on to subsequent therapy, we feel that clinical benefit – effectively the time that a patient does not require cytotoxic therapy – is perhaps the most relevant endpoint. The concept of clinical benefit has been adopted in the breast cancer literature for similar reasons, and may be particularly appropriate for the evaluation of biologic therapies, where objective response may be the exception, even among highly active drugs. QOL and TTT data obtained confirms that CB time was not gained at a cost to quality of life or at the expense of unanticipated toxicity. Despite this we observed 35% of patients met the 90 day TTT.
This preliminary study supports the use of fulvestrant in the setting of multiply recurrent ovarian cancer and further investigation of fulvestrant in the adjuvant setting. We would suggest that to maximize the potential of this drug it may be better used earlier in the therapeutic armamentarium and perhaps best as long-term consolidation therapy after primary remission. We would further propose the study of combining anti-estrogen therapies to most effectively block end organ activity. Conflict of interest statement The authors declare that there are no conflicts, financial or otherwise, with regard to this manuscript.
Acknowledgement Support for this investigator-initiated trial was provided by AstraZeneca Pharmaceuticals. References [1] Armstrong DK, Bundy B, Wenzel L, Huang HQ, Baergen R, Lele S, et al, Gyncologic Oncology Group. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med 2006;354(1):34–43. [2] McGuire WP, Hoskins WJ, Brady MF, Kucera PR, Partridge EE, Look KY, et al. Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med 1996;334(1):1–6. [3] Piccart MJ, Bertelsen K, James K, Cassidy J, Mangioni C, Simonsen E, et al. Randomized intergroup trial of cisplatin-paclitaxel versus cisplatin-cyclophosphamide in women with advanced epithelial ovarian cancer: three-year results. J Natl Cancer Inst 2000;92(9):699–708. [4] Fisher B, Redmond C, Brown A, Fisher ER, Wolmark N, Bowman D, et al. Adjuvant chemotherapy with and without tamoxifen in the treatment of primary breast cancer: 5-year results from the National Surgical Adjuvant Breast and Bowel Project trial. J Clin Oncol 1986;4(4):459–71. [5] Untch M, Gelber RD, Jackisch C, Procter M, Baselga J, Bell R, et al, HERA Study Team. Estimating the magnitude of trastuzumab effects within patient subgroups in the HERA trial. Ann Oncol 2008;19(6):1090–6. [6] Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG, Pienkowski T, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 2006; 355(26):2733–43. [7] Fiorica JV, Brunetto VL, Hanjani P, Lentz SS, Mannel R, Andersen W, Gynecologic Oncology Group study. Phase II trial of alternating courses of megestrol acetate and tamoxifen in advanced endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol 2004;92(1):10–4. [8] Demetri GD, von Mehren M, Blanke CD, Van den Abbeele AD, Eisenberg B, Roberts PJ, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 2002;347(7):472–80. [9] Markman M, Iseminger KA, Hatch KD, Creasman WT, Barnes W, Dubeshter B. Tamoxifen in platinum-refractory ovarian cancer: a Gynecologic Oncology Group ancillary report. Gynecol Oncol 1996;62(1):4–6. [10] Bookman MA, Darcy KM, Clarke-Pearson D, Boothby RA, Horowitz IR. Evaluation of monoclonal humanized anti-HER2 antibody, trastuzumab, in patients with recurrent or refractory ovarian or primary peritoneal carcinoma with overexpression of HER2: a phase II trial of the Gynecologic Oncology Group. J Clin Oncol 2003;21(2):283–90. [11] Alberts DS, Liu PY, Wilczynski SP, Jang A, Moon J, Ward JH, et al. Phase II trial of imatinib mesylate in recurrent, biomarker positive, ovarian cancer (Southwest Oncology Group Protocol S0211). Int J Gynecol Cancer 2007;17(4):784–8. [12] Burger RA, Sill MW, Monk BJ, Greer BE, Sorosky JI. Phase II trial of bevacizumab in persistent or recurrent epithelial ovarian cancer or primary peritoneal cancer: a Gynecologic Oncology Group study. J Clin Oncol 2007;25(33):5165–71. [13] Smyth JF, Gourley C, Walker G, MacKean MJ, Stevenson A, Williams AR, et al. Antiestrogen therapy is active in selected ovarian cancer cases: the use of letrozole in estrogen receptor-positive patients. Clin Cancer Res 2007;13(12):3617–22. [14] Walker G, MacLeod K, Williams AR, Cameron DA, Smyth JF, Langdon SP. Estrogenregulated gene expression predicts response to endocrine therapy in patients with ovarian cancer. Gynecol Oncol 2007;106(3):461–8. [15] O'Donnell AJ, Macleod KG, Burns DJ, Smyth JF, Langdon SP. Estrogen receptor-alpha mediates gene expression changes and growth response in ovarian cancer cells exposed to estrogen. Endocr Relat Cancer 2005;12(4):851–66. [16] Zhou B, Sun Q, Cong R, Gu H, Tang N, Yang L, et al. Hormone replacement therapy and ovarian cancer risk: a meta-analysis. Gynecol Oncol 2008;108(3):641–51. [17] Silva EG, Tornos C, Deavers M, Kaisman K, Gray K, Gershenson D. Induction of epithelial neoplasms in the ovaries of guinea pigs by estrogenic stimulation. Gynecol Oncol 1998;71(2):240–6. [18] Breast International Group (BIG) 1–98 Collaborative GroupThürlimann B, Keshaviah A, Coates AS, Mouridsen H, Mauriac L, Forbes JF, et al. A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med 2005;353(26):2747–57. [19] Stanway SJ, Purohit A, Woo LW, Sufi S, Vigushin D, Ward R, et al. Phase I study of STX 64 (667 Coumate) in breast cancer patients: the first study of a steroid sulfatase inhibitor. Clin Cancer Res 2006;12(5):1585–92.
P.A. Argenta et al. / Gynecologic Oncology 113 (2009) 205–209 [20] Chia S, Gradishar W, Mauriac L, Bines J, Amant F, Federico M, et al. Double-blind, randomized placebo controlled trial of fulvestrant compared with exemestane after prior nonsteroidal aromatase inhibitor therapy in postmenopausal women with hormone receptor-positive, advanced breast cancer: results from EFECT. J Clin Oncol 2008;26(10):1664–70. [21] Neven P, Paridaens R, Pelgrims G, Martens M, Bols A, Goeminne JC, et al. Fulvestrant (Faslodextrade mark) in advanced breast cancer: clinical experience from a Belgian cooperative study. Breast Cancer Res Treat 2008;109(1):59–65. [22] Wakeling AE, Dukes M, Bowler J. A potent pure antiestrogen with clinical potential. Cancer Res 1991;51:3867–73. [23] Robertson JF, Harrison MP. Equivalent single-dose pharmacokinetics of two different dosing methods of prolonged-release fulvestrant (‘Faslodex’) in postmenopausal women with advanced breast cancer. Cancer Chemother Pharmacol 2003;52(4):346–8. [24] Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000;92(3): 205–16. [25] Guppy AE, Rustin GJS. CA125 response: can it replace the traditional response criteria in ovarian cancer? The Oncologist 2002;7:437–43. [26] Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials 1989;10:1–10. [27] Mlineritsch B, Psenak O, Mayer P, Moik M, Namberger K, Hauser-Kronberger C. Fulvestrant (‘Faslodex’) in heavily pretreated postmenopausal patients with advanced breast cancer: single centre clinical experience from the compassionate use programme. Breast Cancer Res Treat 2007;106(1):105–12. [28] Sasano H, Suzuki T, Miki Y, Moriya T. Intracrinology of estrogens and androgens in breast carcinoma. J Steroid Biochem Mol Biol 2008;108(3–5):181–5.
209
[29] du BA, Meier W, Lück HJ, Emon G, Moebus V, Schroeder W. Chemotherapy versus hormonal treatment in platinum- and paclitaxel-refractory ovarian cancer: a randomised trial of the German Arbeitsgemeinschaft Gynaekologische Onkologie (AGO) Study Group Ovarian Cancer. Ann Oncol 2002;13(2):251–7. [30] Duffaud F, van der Burg ME, Namer M, Vergote I, Willemse PHB, ten Bokkel Huinink W. D-TRP-6-LHRH (Triptorelin) is not effective in ovarian carcinoma: an EORTC Gynaecological Cancer Co-operative Group study. Anticancer Drugs 2001; 12(2):159–62. [31] Chura, JC, Ryu, HS, Simard, M, Poirrer, D, Tremblay, Y, Brooker, DC, Blomquist, CH, Argenta PA Steroid-converting enzymes in human ovarian cancers. Mol Cell Endocrinol. In press. [32] Chura, JC, Blomquist, CH, Ryu, HS, Argenta PA. estrone sulfatase activity in patients with advanced ovarian cancer. Gynecol Oncol 2009;112(1)(Jan):205–9. [33] García-Velasco A, Mendiola C, Sánchez-Muñoz A, Ballestín C, Colomer R, Cortés-Funes H. Prognostic value of hormonal receptors, p53, ki67 and HER2/ neu expression in epithelial ovarian carcinoma. Clin Transl Oncol 2008;10(6): 367–71. [34] Høgdall EV, Christensen L, Høgdall CK, Blaakaer J, Gayther S, Jacobs IJ. Prognostic value of estrogen receptor and progesterone receptor tumor expression in Danish ovarian cancer patients: from the ‘MALOVA’ ovarian cancer study. Oncol Rep 2007;18(5):1051–9. [35] Neven P, Paridaens R, Pelgrims G, Martens M, Bols A, et al. Fulvestrant (Faslodex) in advanced breast cancer: clinical experience from a Belgian cooperative study. Breast Cancer Res Treat 2008;109:59–65. [36] Osborne CK, Pippen J, Jones SE, Parker M, Ellis S, et al. Double-blind, randomized trial comparing the efficacy and tolerability of fulvestrant versus anastrozole in postmenopausal women with advanced breast cancer progressing on prior endocrine therapy: results of a North American trial. J Clin Oncol 2002;20: 3386–95.
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Gynecologic Oncology j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / y g y n o
A phase II study of fulvestrant in the treatment of multiply-recurrent epithelial ovarian cancer Peter A. Argenta ⁎, Sajeena G. Thomas, Patricia L. Judson, Levi S. Downs Jr., Melissa A. Geller, Linda F. Carson, Amy L. Jonson, Rahel Ghebre Division of Gynecologic Oncology, Department of Obstetrics, Gynecology, and Women's Health, University of Minnesota, MMC 395, 420 Delaware St. SE, Minneapolis MN, 55455, USA
a r t i c l e
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Article history: Received 3 December 2008 Available online 23 February 2009 Keywords: Ovarian cancer Faslodex Fulvestrant Estrogen Phase II Estrogen receptor
a b s t r a c t Objective. The goal of treating recurrent ovarian cancer is disease control while minimizing toxicity. Fulvestrant, a novel estrogen receptor (ER) antagonist, has proven clinically beneficial and well-tolerated in treating recurrent breast cancer. Ovarian cancer often expresses ER and may respond to anti-estrogen therapy. We evaluated fulvestrant in women with recurrent ovarian or primary peritoneal cancer. Methods. Patients with ER-positive, multiply recurrent ovarian or primary peritoneal carcinoma and either measurable disease according to RECIST criteria or an abnormal and rising CA-125 were eligible for enrollment. Treatment consisted of single agent fulvestrant, 500 mg IM on Day 1, 250 mg IM on Day 15, and 250 mg IM on Day 29 and every 28 days thereafter until either intolerance or disease progression. Disease response was assessed by monthly physical exams and CA-125 levels as well as CT scans bimonthly. The primary endpoint was clinical benefit (CB = complete response (CR) + partial response (PR) + stable disease (SD)) at 90 days. Results. Thirty-one women were enrolled and 26 women (median age of 61) met inclusion criteria and received at least one dose. Patients had received a median of 5 prior chemotherapeutic regimens (range: 2– 13). We observed one CR (4%), one PR (4%), and 9 patients with SD (35%) using modified-Rustin criteria (CA125 level). Using modified-RECIST criteria 13 patients (50%) achieved SD. The median time to disease progression was 62 days (mean 86 days). Grade 1 toxicity included headache (1 patient) and bromidrosis (2 patients). Conclusions. Fulvestrant is well-tolerated and efficacious. Objective response rates are low, but disease stabilization was common. © 2009 Elsevier Inc. All rights reserved.
Introduction Despite improvements in the delivery of cytotoxic chemotherapy, most patients with advanced ovarian cancer relapse and ultimately experience progressive disease [1]. Repeated courses of salvage therapy can induce remission in a minority of patients, but these regimens are generally characterized by increasingly short progression-free intervals and often accumulating toxicity, highlighting the need for novel approaches to treating recurrent disease [2,3]. Biologic therapies, which modify tumor biology with or without cytotoxicity, have been used successfully in selected breast (tamoxifen [4], her2/neu inhibition [5,6]) endometrial (progestin therapy [7]) and gastrointestinal stromal cancers (c-kit inhibition [8]), among others. Initial efforts in the biologic treatment of ovarian cancer, including tamoxifen, trastuzumab, and imatinib mesylate have met with mixed results [9–11]. However, recent successes with anti-VEGF antibodies and aromatase inhibition suggest that subsets of ovarian ⁎ Corresponding author. Fax: +1 612 626 0665. E-mail address: [email protected] (P.A. Argenta). 0090-8258/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2009.01.012
cancer may be susceptible to biologic therapy [12,13]. Further, Walker et al. suggest that in the case of anti-estrogen therapy, response may be predictable based on tumor protein expression profiles [14]. Though estrogen has long been known to be an ovarian cancer growth factor in vitro, an increasing body of evidence now suggests that estrogen plays an integral role in both the development and propagation of some ovarian cancers [15]. A recent metanalysis of studies of estrogen-base hormone replacement therapy demonstrated a statistical increase in the incidence of epithelial ovarian cancer among women taking hormone replacement therapy [16]. Silva et al. have also demonstrated that even short exposure to any of multiple estrogens is capable of inducing neoplastic changes, cystadenomas and papillary excrescences in the ovaries in a mammalian model [17]. Inhibition of estrogen production via blockade of either the aromatase or sulfatase pathways has proven therapeutic in breast cancer [18,19]. Similarly, mitigation of estrogen function at the level of the receptor is effective and well tolerated in beast cancer [20]. Among estrogen function inhibitors (aromatase, sulfatase, and pure estrogen receptor antagonists), only letrozole has been tested in ovarian cancer.
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Fulvestrant, a novel estrogen receptor (ER) antagonist devoid of agonist properties, is beneficial in some women with breast cancer even after heavy pretreatment [21]. Fulvestrant is a 17-β estradiol derivative, substituted with an alkyl chain at the 7-α position, giving it a binding affinity similar to estradiol [22]. It is available as an intramuscular injection, and has been used in a variety of schedules. In preliminary studies, steady-state ER blockade could be achieved with minimal toxicity in 28 days using a loading-dose strategy of intramuscular injections [23]. This study was conducted to determine the efficacy and toxicity profile, including effects on bone mineral turnover, of fulvestrant in the treatment of recurrent ovarian cancer. Methods After obtaining approval from the Institutional Review Board and the Cancer Protocol Review Committee of the University of Minnesota, we conducted a single institution phase II study of fulvestrant in the treatment of multiply recurrent ovarian cancer. All subjects signed informed consent prior to study enrollment. Patients were eligible if they had all of the following: histologicallyproven estrogen receptor-positive, recurrent or persistent ovarian carcinoma; received at least 2 previous cytotoxic regimens (with at least one containing a platinum agent); measurable disease according to RECIST criteria or a CA-125 that was rising and either above 35 U/ml on 2 evaluations at least 2 weeks apart, or below 35 with a progressive rise of N200%; adequate organ function within 14 days of study entry defined by platelets above 50 × 109/L, serum creatinine ≥2.5 mg/dL, INR ≤ 1.6, bilirubin ≤ 1.5× upper limit of institutional normal, aspartate aminotransferase (AST) and alkaline phosphatase ≤3× the upper limit of institutional normal; age ≥18 years; Gynecologic Oncology Group (GOG) performance status 0–3; undergone surgical castration or were on adequate birth control; not received previous hormonal therapy, chemotherapy or radiation within 3 weeks of enrollment, and had willingly signed an informed consent. Exclusion criteria were intentionally limited to broaden the applicability of our findings, but included: pregnancy or active lactation, history of a bleeding event (disseminated intravascular coagulation or clotting factor deficiency) or long term anti-coagulation, AST or alanine aminotransferase (ALT) ≥2.5× the upper limit of institutional normal in the absence of liver metastasis or ≥5× the upper limit of institutional normal in the presence of liver metastasis, sensitivity to the active or inactive excipients of fulvestrant (castor oil or mannitol). There was no limit to number of previous chemotherapy regimens allowed. Prior to enrollment estrogen receptor analysis of the primary tumor via immunohistochemistry was performed; only patients with no staining were excluded. At study enrollment, each patient gave a medical history and underwent a physical examination. Performance status, quality of life (FACT-O), assessment of disease (either CT or CA125 depending on entry criteria), hematologic and blood chemistry analysis including B-hCG where appropriate, and measurement of bone turnover markers (N-telopeptide and serum skeletal-specific alkaline phosphatase) were performed serially during the study.
Our institution is a large, metropolitan academic center that generally treats about 100 patients with newly diagnosed ovarian cancer annually, with between 10 and 30% of all patients being enrolled in clinical trials. There were no trials open to competitive accrual during the duration of this study. Treatment protocol Patients were given fulvestrant as an intramuscular injection as follows: a “loading dose” of 500 mg IM on day 1, followed by a “booster dose” of 250 mg IM on day 15, and then “maintenance dosing” of 250 mg IM every 28 days beginning on day 29 and continuing until disease progression, patient intolerance, or medically-indicated discontinuation by the treating physician. Self-administration of ibuprofen or acetaminophen was allowed for injection site pain, but no concurrent chemotherapy or hormonal therapy was allowed. No dose modifications or treatment delays were allowed. Physical examination, toxicity assessment, performance status, and serum laboratory values were performed prior to day 1 of each cycle and at the conclusion of the study. Disease assessment and chest X-ray or CT were performed every other cycle (q8 weeks). The FACT-O was administered every third cycle (q12 weeks) and at the conclusion of treatment. Bone turnover markers were assessed before treatment and at 1, 3, and 6 months. ER status was determined by immunohistochemistry and evaluated by pathologists independent of this study; any estrogen receptor detection was considered sufficient for inclusion. The primary study endpoint was 90-day clinical benefit (CB) defined as the sum of complete response (CR), partial response (PR), and stable disease (SD). Responses were evaluated by modified RECIST criteria and by modified Rustin Criteria (Table 1) [24,25]. For overall assessment of clinical benefit the worse of the two measures was used (ie a patient with stable disease by RECIST criteria and progressive disease by Rustin criteria was considered progressive disease). Secondary endpoints included establishing the time to termination of treatment for any cause (TTT), and determine the toxicity profile in this population classified according to the National Cancer Institute's Common Terminology Criteria for adverse events V3.0. Correlative endpoints included assessing the impact of this regimen on quality of life using the Functional Assessment of Cancer Therapy — Ovarian cancer (FACT-O), and the effect on bone mineral turnover as measured by changes in the urine N-telopeptide and serum skeletal specific alkaline phosphatase. Statistical consideration The pre-determined primary endpoint was clinical benefit over 90 days. The target accrual was 27 patients over 48 months. The sample size calculation was based on the Simon method using a minimax design [26]. A two step enrollment with early stopping rules for low observed response rates (RR = clinical benefit), selecting 5% as an unacceptably low RR and 20% as “clinically significant;” and setting the alpha at 0.05 and power at 0.8. Based on these calculations, early
Table 1 Response definitions
RECISTa Modified Rustin
Partial response
Complete response
Progressive disease
≥ 30% decrease in the sum of all target lesions (longest diameters) ≥ 50% decrease in serum CA-125 level from 2 initially elevated samplesb
Disappearance of all target lesions
≥ 20% increase in the sum of all target lesions (longest diameter) or any new lesions CA-125 2× ULN on 2 occasions (if previously normalized) OR CA-125 2× nadir on 2 occasions (if elevated at initiation of treatment)
Normalization of serum CA-125 level from 2 initially elevated samplesb
ULN; upper limit of normal. a Patients without measurable disease were considered ineligible for complete or partial response, but were considered to have stable disease (SD) if no new or worsening lesions were detected during study period. b Requires confirmatory sample at least 28 days from response determinant.
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stopping would have occurred if no responses were observed in the first 13 patients. Secondary endpoints included time to treament termination (TTT), quality of life analysis, toxicity assessment. Analysis of the markers of bone mineral turnover was by unpaired ttest assuming unequal varience. Results Due to higher than anticipated ER prevalence among consented patients (91%), 29 eligible women were enrolled between July, 2007 to April, 2008, after approval from the Institutional Review Board of the University of Minnesota. Patient characteristics are listed in Table 2. Generally the patients were heavily pre-treated, with the median number of previous regimens being 5 (range 2–13). The median TTT for the antecedent therapy was 16 weeks (range 2– 39 weeks). Twenty-six patients received at least one treatment and were included in the analysis. The median number of injections received was 3 (range 1–11), and the indications for termination of treatment are listed in Table 3. At 90 days of treatment we observed one complete response (4%), one partial response (4%), and 9 patients with stable disease (35%) using modified-Rustin criteria (CA-125 level). Nine of 25 evaluable patients (36%) experienced at least a transitory drop in CA-125. Using modified-RECIST criteria 13 patients (50%) achieved stable disease at 90 days, while 13 experienced PD. Clinical benefit at 90 days, using the “worst response” for each patient was observed in 8 (31%) of patients (all SD). The median progression-free survival was 62 days (mean 86 days). The median overall survival is not yet met. The median time to treatment termination (TTT) was also 62 days, though the mean (93 days) was skewed higher by 2 patients who remain on treatment (253 and 373 days) despite meeting progression endpoints owing to the absence of symptoms despite rising CA-125 in one patient, and intolerance of previous cytotoxic chemotherapy in the other. The treatment was very well tolerated, with no grade 3 or 4 toxicities. Observed toxicity included headache, grade 1 (1 patient, 4%) and bromidrosis (alternation in body odor), grade 1 (2 patients, 8%). The median quality of life score (FACT-O) at baseline was 86.7. After 3 and 6 treatments the median scores were not significantly reduced at 84.3 (p = .68) and 81 (p = .78) respectively, indicating no significant detriment to quality of life experienced by these women. Fulvestrant administration was not associated with any statistical impact on the markers of bone turnover (Fig. 1). Median (range) serum bone-specific alkaline phosphatase levels were 14.0 (6.9–23.5) U/L at baseline; 16.1 (7.1–26.5) U/L at 1 month of treatment (p = .23); 18.5 (8.3–25.5) U/L at 3 months (p = .48); 16.2 (13.8–29.2) U/L at 6 months (p = .23). Median (range) urinary N-telopeptide levels were
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Table 3 Reasons for discontinuation of therapy N (%) Intolerance Rise in CA-125 N200% of baseline/nadir Clinical progression Radiologic progression Multiple modalities Still on therapy
0 12 (46%) 4 (15%) 2 (8%) 5 (19%) 3 (12%)
50 (8–184) BCE/mM at baseline; 49 (11–117) BCE/mM at 1 month of treatment (p = .98); 43 (18–115) BCE/mM at 3 months (p = .51); 46 (42–91) BCE/mM at 6 months (p = .84). Discussion Fulvestrant, delivered using the loading dose strategy, is well tolerated and appears to provide some benefit even in the setting of multiply recurrent disease. Objective response rates are low, but disease stabilization was common albeit short-lived. Implicit in any discussion of treatment options for patients with recurrent ovarian cancer is the tradeoff between benefit and toxicity in the setting where cure is rare. To date few drugs have demonstrated significant activity in the third and fourth lines, and clinical decisions are frequently based on toxicity profiles as much as therapeutic potential. Despite the grim overall prognosis however, many patients continue to maintain high performance status and seek treatment for years. This desire of patients for low toxicity therapies is reflected in the short accrual time of this study, under half of that predicted by previous, cytotoxic trials with similar design at our institution. Fulvestrant, now being increasingly used in breast cancer, has multiple unique properties that make it well-suited to treatment of heavily pretreated patients. Primary among these is the absence of marrow toxicity, which typically limits the tolerability of many cytotoxic therapies. It is easy to administer, has a favorable monthly dosing schedule, and does not require intravenous access or interval assessment of the neutrophil count or hemoglobin. There are few
Table 2 Patient characteristics Age (years) median (range) Race Caucasian Previous chemotherapy regimens: median (range) Performance status (GOG): median (range) Stage at diagnosis I II III IV Histology Serous Endometrioid Clear cell Other Grade 2 3
61 (43–95) 100% 5 (2–13) 1 (0–2) 1 2 20 3
(4%) (8%) (77%) (12%)
16 4 1 5
(62%) (15%) (4%) (19%)
4 (15%) 22 (85%)
Fig. 1. Markers of bone mineral turnover. (A) Urinary N-telopeptide. (B) Serum bonespecific alkaline phosphatase.
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lingering toxicities, and our quality of life analysis confirms previously published data that the drug does not appear to impair QOL [27]. Our data also demonstrates relative stability of the markers of bone mineral turnover, which may prove to be a relative advantage over currently available aromatase inhibitors which have been associated with accelerated bone loss. Lastly, unlike tamoxifen which exhibits weak estrogen activity in the uterus, fulvestrant has no ER agonistic properties and is currently being evaluated by the Gynecologic Oncology Group as a treatment for endometrial cancer. Why blockade of ER is therapeutic in the multiply recurrent ovarian cancer setting when other hormonal therapies have had mixed results in more favorable settings remains unclear. There is increasing evidence, however, that estrogen may play a key role in both the development and propagation of ovarian cancer despite the fact that most women will be diagnosed well into the menopausal years. Sasano et al. suggest that estrogen produced intratumorally through the conversion of inactive precursors, may act locally to enhance tumor growth [28]. This “intracrinology” would be unaffected by centrally acting agents, and may explain why studies of GnRH agonists have generally demonstrated minimal or no activity [29,30]. Intratumoral estrogen production could also potentially blunt the effect of systemic aromatase or sulfatase inhibitors, possibly accounting for mixed results observed in patients treated with letrozole or other aromatase inhibitors. Our group and others have demonstrated that the enzymes required for intratumoral conversion of estrogen precursors to estrogen and for conversion of low potency estrogens to high potency estrogens exist in a majority of ovarian cancers [31,32]. A corollary to this hypothesis is that loss of ER, typically associated with a poorer prognosis, may be a later event in tumorigenesis/progression, either as a cause or effect of local estrogen activity [33,34]. Another possible explanation for failure of some anti-estrogen strategies is that compensatory activation of alternate estrogenic pathways may compensate for blockade of either the aromatase or sulfatase pathway. This would explain the observation that STX 64 (667 Coumate), a novel sulfatase inhibitor is effective in breast cancer patients who have ceased responding to aromatase inhibitors [19]. This hypothesis would also explain why blockade of the estrogen receptor, a downstream event may still be therapeutic after other failed endocrine therapies. Interestingly, both of these observations suggest that multimodal therapy may be synergistic. The use of fulvestrant in selected populations remains understudied. Multiple prospective and retrospective studies in breast cancer have included ER-negative patients, but subset analysis of this population is reported in only one to date [35,36]. Interestingly Neven et al., in reporting the compassionate use experience with fulvestrant observed CB in a similar proportion of ER-positive and ER-negative patients [35]. Though histologic grade was generally not included in the breast cancer analyses, it may be a relevant predictor in gynecologic malignancies. Unfortunately no patients with low grade histology, who might be expected to have the most favorable responses, were enrolled in this study. This subgroup however may merit directed inclusion in follow-up trials. The primary end-point of this study, clinical benefit, is arguably a weakness of the study, especially as relatively few patients exhibited objective responses. However, there is little evidence that objective responses correlate to prolonged over-all or even disease-free survival in the recurrent setting. Since most patients will go on to subsequent therapy, we feel that clinical benefit – effectively the time that a patient does not require cytotoxic therapy – is perhaps the most relevant endpoint. The concept of clinical benefit has been adopted in the breast cancer literature for similar reasons, and may be particularly appropriate for the evaluation of biologic therapies, where objective response may be the exception, even among highly active drugs. QOL and TTT data obtained confirms that CB time was not gained at a cost to quality of life or at the expense of unanticipated toxicity. Despite this we observed 35% of patients met the 90 day TTT.
This preliminary study supports the use of fulvestrant in the setting of multiply recurrent ovarian cancer and further investigation of fulvestrant in the adjuvant setting. We would suggest that to maximize the potential of this drug it may be better used earlier in the therapeutic armamentarium and perhaps best as long-term consolidation therapy after primary remission. We would further propose the study of combining anti-estrogen therapies to most effectively block end organ activity. Conflict of interest statement The authors declare that there are no conflicts, financial or otherwise, with regard to this manuscript.
Acknowledgement Support for this investigator-initiated trial was provided by AstraZeneca Pharmaceuticals. References [1] Armstrong DK, Bundy B, Wenzel L, Huang HQ, Baergen R, Lele S, et al, Gyncologic Oncology Group. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med 2006;354(1):34–43. [2] McGuire WP, Hoskins WJ, Brady MF, Kucera PR, Partridge EE, Look KY, et al. Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med 1996;334(1):1–6. [3] Piccart MJ, Bertelsen K, James K, Cassidy J, Mangioni C, Simonsen E, et al. Randomized intergroup trial of cisplatin-paclitaxel versus cisplatin-cyclophosphamide in women with advanced epithelial ovarian cancer: three-year results. J Natl Cancer Inst 2000;92(9):699–708. [4] Fisher B, Redmond C, Brown A, Fisher ER, Wolmark N, Bowman D, et al. Adjuvant chemotherapy with and without tamoxifen in the treatment of primary breast cancer: 5-year results from the National Surgical Adjuvant Breast and Bowel Project trial. J Clin Oncol 1986;4(4):459–71. [5] Untch M, Gelber RD, Jackisch C, Procter M, Baselga J, Bell R, et al, HERA Study Team. Estimating the magnitude of trastuzumab effects within patient subgroups in the HERA trial. Ann Oncol 2008;19(6):1090–6. [6] Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG, Pienkowski T, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 2006; 355(26):2733–43. [7] Fiorica JV, Brunetto VL, Hanjani P, Lentz SS, Mannel R, Andersen W, Gynecologic Oncology Group study. Phase II trial of alternating courses of megestrol acetate and tamoxifen in advanced endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol 2004;92(1):10–4. [8] Demetri GD, von Mehren M, Blanke CD, Van den Abbeele AD, Eisenberg B, Roberts PJ, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 2002;347(7):472–80. [9] Markman M, Iseminger KA, Hatch KD, Creasman WT, Barnes W, Dubeshter B. Tamoxifen in platinum-refractory ovarian cancer: a Gynecologic Oncology Group ancillary report. Gynecol Oncol 1996;62(1):4–6. [10] Bookman MA, Darcy KM, Clarke-Pearson D, Boothby RA, Horowitz IR. Evaluation of monoclonal humanized anti-HER2 antibody, trastuzumab, in patients with recurrent or refractory ovarian or primary peritoneal carcinoma with overexpression of HER2: a phase II trial of the Gynecologic Oncology Group. J Clin Oncol 2003;21(2):283–90. [11] Alberts DS, Liu PY, Wilczynski SP, Jang A, Moon J, Ward JH, et al. Phase II trial of imatinib mesylate in recurrent, biomarker positive, ovarian cancer (Southwest Oncology Group Protocol S0211). Int J Gynecol Cancer 2007;17(4):784–8. [12] Burger RA, Sill MW, Monk BJ, Greer BE, Sorosky JI. Phase II trial of bevacizumab in persistent or recurrent epithelial ovarian cancer or primary peritoneal cancer: a Gynecologic Oncology Group study. J Clin Oncol 2007;25(33):5165–71. [13] Smyth JF, Gourley C, Walker G, MacKean MJ, Stevenson A, Williams AR, et al. Antiestrogen therapy is active in selected ovarian cancer cases: the use of letrozole in estrogen receptor-positive patients. Clin Cancer Res 2007;13(12):3617–22. [14] Walker G, MacLeod K, Williams AR, Cameron DA, Smyth JF, Langdon SP. Estrogenregulated gene expression predicts response to endocrine therapy in patients with ovarian cancer. Gynecol Oncol 2007;106(3):461–8. [15] O'Donnell AJ, Macleod KG, Burns DJ, Smyth JF, Langdon SP. Estrogen receptor-alpha mediates gene expression changes and growth response in ovarian cancer cells exposed to estrogen. Endocr Relat Cancer 2005;12(4):851–66. [16] Zhou B, Sun Q, Cong R, Gu H, Tang N, Yang L, et al. Hormone replacement therapy and ovarian cancer risk: a meta-analysis. Gynecol Oncol 2008;108(3):641–51. [17] Silva EG, Tornos C, Deavers M, Kaisman K, Gray K, Gershenson D. Induction of epithelial neoplasms in the ovaries of guinea pigs by estrogenic stimulation. Gynecol Oncol 1998;71(2):240–6. [18] Breast International Group (BIG) 1–98 Collaborative GroupThürlimann B, Keshaviah A, Coates AS, Mouridsen H, Mauriac L, Forbes JF, et al. A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med 2005;353(26):2747–57. [19] Stanway SJ, Purohit A, Woo LW, Sufi S, Vigushin D, Ward R, et al. Phase I study of STX 64 (667 Coumate) in breast cancer patients: the first study of a steroid sulfatase inhibitor. Clin Cancer Res 2006;12(5):1585–92.
P.A. Argenta et al. / Gynecologic Oncology 113 (2009) 205–209 [20] Chia S, Gradishar W, Mauriac L, Bines J, Amant F, Federico M, et al. Double-blind, randomized placebo controlled trial of fulvestrant compared with exemestane after prior nonsteroidal aromatase inhibitor therapy in postmenopausal women with hormone receptor-positive, advanced breast cancer: results from EFECT. J Clin Oncol 2008;26(10):1664–70. [21] Neven P, Paridaens R, Pelgrims G, Martens M, Bols A, Goeminne JC, et al. Fulvestrant (Faslodextrade mark) in advanced breast cancer: clinical experience from a Belgian cooperative study. Breast Cancer Res Treat 2008;109(1):59–65. [22] Wakeling AE, Dukes M, Bowler J. A potent pure antiestrogen with clinical potential. Cancer Res 1991;51:3867–73. [23] Robertson JF, Harrison MP. Equivalent single-dose pharmacokinetics of two different dosing methods of prolonged-release fulvestrant (‘Faslodex’) in postmenopausal women with advanced breast cancer. Cancer Chemother Pharmacol 2003;52(4):346–8. [24] Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000;92(3): 205–16. [25] Guppy AE, Rustin GJS. CA125 response: can it replace the traditional response criteria in ovarian cancer? The Oncologist 2002;7:437–43. [26] Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials 1989;10:1–10. [27] Mlineritsch B, Psenak O, Mayer P, Moik M, Namberger K, Hauser-Kronberger C. Fulvestrant (‘Faslodex’) in heavily pretreated postmenopausal patients with advanced breast cancer: single centre clinical experience from the compassionate use programme. Breast Cancer Res Treat 2007;106(1):105–12. [28] Sasano H, Suzuki T, Miki Y, Moriya T. Intracrinology of estrogens and androgens in breast carcinoma. J Steroid Biochem Mol Biol 2008;108(3–5):181–5.
209
[29] du BA, Meier W, Lück HJ, Emon G, Moebus V, Schroeder W. Chemotherapy versus hormonal treatment in platinum- and paclitaxel-refractory ovarian cancer: a randomised trial of the German Arbeitsgemeinschaft Gynaekologische Onkologie (AGO) Study Group Ovarian Cancer. Ann Oncol 2002;13(2):251–7. [30] Duffaud F, van der Burg ME, Namer M, Vergote I, Willemse PHB, ten Bokkel Huinink W. D-TRP-6-LHRH (Triptorelin) is not effective in ovarian carcinoma: an EORTC Gynaecological Cancer Co-operative Group study. Anticancer Drugs 2001; 12(2):159–62. [31] Chura, JC, Ryu, HS, Simard, M, Poirrer, D, Tremblay, Y, Brooker, DC, Blomquist, CH, Argenta PA Steroid-converting enzymes in human ovarian cancers. Mol Cell Endocrinol. In press. [32] Chura, JC, Blomquist, CH, Ryu, HS, Argenta PA. estrone sulfatase activity in patients with advanced ovarian cancer. Gynecol Oncol 2009;112(1)(Jan):205–9. [33] García-Velasco A, Mendiola C, Sánchez-Muñoz A, Ballestín C, Colomer R, Cortés-Funes H. Prognostic value of hormonal receptors, p53, ki67 and HER2/ neu expression in epithelial ovarian carcinoma. Clin Transl Oncol 2008;10(6): 367–71. [34] Høgdall EV, Christensen L, Høgdall CK, Blaakaer J, Gayther S, Jacobs IJ. Prognostic value of estrogen receptor and progesterone receptor tumor expression in Danish ovarian cancer patients: from the ‘MALOVA’ ovarian cancer study. Oncol Rep 2007;18(5):1051–9. [35] Neven P, Paridaens R, Pelgrims G, Martens M, Bols A, et al. Fulvestrant (Faslodex) in advanced breast cancer: clinical experience from a Belgian cooperative study. Breast Cancer Res Treat 2008;109:59–65. [36] Osborne CK, Pippen J, Jones SE, Parker M, Ellis S, et al. Double-blind, randomized trial comparing the efficacy and tolerability of fulvestrant versus anastrozole in postmenopausal women with advanced breast cancer progressing on prior endocrine therapy: results of a North American trial. J Clin Oncol 2002;20: 3386–95.