- Email: [email protected]
Efficacy of letrozole in the treatment of recurrent platinum- and taxane-resistant high-grade cancer of the ovary or peritoneum
Available online at www.sciencedirect.com
Gynecologic Oncology 110 (2008) 56 – 59 www.elsevier.com/locate/ygyno
Efficacy of letrozole in the treatment of recurrent platinum- and taxane-resistant high-grade cancer of the ovary or peritoneum B Pedro T. Ramirez a,⁎, Kathleen M. Schmeler a , Michael R. Milam a , Brian M. Slomovitz c , Judith A. Smith a , John J. Kavanagh a , Michael Deavers b , Charles Levenback a , Robert L. Coleman a , David M. Gershenson a a
c
Department of Gynecologic Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA b Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA Department of Obstetrics and Gynecology, Cornell Weill Medical College, New York Presbyterian Hospital, New York, NY, USA Received 13 February 2008 Available online 5 May 2008
Abstract Objective. To evaluate the efficacy and safety of letrozole in patients with recurrent platinum- and taxane-resistant estrogen receptor-positive (ER+) high-grade cancer of the ovary or peritoneum. Methods. A single-institution, phase II study was performed in women with recurrent ER+ epithelial carcinoma of the ovary or peritoneum. All patients had measurable disease. Letrozole was administered at a dose of 2.5 mg orally once daily until disease progression or toxicity occurred. Results. Thirty-three patients were enrolled. The median age was 63 years (range, 38 to 83 years). Twenty-three patients (74%) had received three or more prior chemotherapy regimens. The 31 patients evaluable for response received a total of 81 cycles (4 weeks/cycle) of therapy (range, 1 to 14 cycles/patient). The median treatment duration was 8 weeks (range, 4 to 52 weeks). None of the patients had a complete response (CR), 1 (3%) had a partial response (PR), and 7 (23%) had stable disease (SD). The median duration of clinical benefit (SD and PR) was 9 weeks (range, 7 to 46 weeks). The median follow-up for all patients was 25 weeks. All patients were evaluable for toxicity. The most common adverse effects were fatigue (36%) and diaphoresis (21%). No grade 3 or 4 toxicities were reported, and no patients discontinued treatment owing to adverse effects. Eighteen patients (58%) went on to receive additional therapy with other agents. Conclusion. In patients with ER-positive, platinum- and taxane-resistant high-grade ovarian and primary peritoneal cancer treated with letrozole, 26% derived a clinical benefit (SD and PR). © 2008 Elsevier Inc. All rights reserved. Keywords: Letrozole; Resistant ovarian and peritoneal cancer
Introduction In 2007, an estimated 22,430 new cases of ovarian cancer will be diagnosed, and approximately 15,280 women will die of this disease [1]. Although the objective response rate associated with initial standard platinum- and taxane-based chemotherapy is nearly B
This research was supported by an Investigator Initiated Research Proposal from Novartis Pharmaceutical. ⁎ Corresponding author. Department of Gynecologic Oncology, Unit 1362, The University of Texas M. D. Anderson Cancer Center, P.O. Box 301439, Houston, TX 77230-1439, USA. Fax: +1 713 792 7586. E-mail address: [email protected] (P.T. Ramirez). 0090-8258/$ - see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2008.03.014
70% in patients with advanced disease, the majority of patients with advanced ovarian cancer will have relapses and ultimately die from progressive disease that is not responsive to chemotherapy. Furthermore, patients often suffer significant morbidity secondary to the toxicity of agents used to treat recurrent disease, resulting in a decline in the patients' quality of life. Epithelial ovarian carcinomas express a number of hormonal receptors, including estrogen (67% of tumors) and progesterone (47%) [2]. Preclinical models have shown that ovarian cancer cells that express high levels of estrogen receptors are stimulated or inhibited by estrogens and antiestrogens [3–5]. Therefore, a number of investigators have evaluated hormonal therapy in
P.T. Ramirez et al. / Gynecologic Oncology 110 (2008) 56–59
patients with ovarian cancer. Agents studied in the setting of advanced or recurrent ovarian cancer include antiestrogens, progestins, androgens, gonadotropin-releasing hormone agonists, and aromatase inhibitors. In a previously reported study from the Gynecologic Oncology Group, Markman et al. [6] evaluated 102 patients with platinum-resistant ovarian cancer who were treated with tamoxifen. The authors found that tamoxifen offered an objective response rate of 13% with a median duration of response of 4.4 months. Previous studies have shown the aromatase inhibitor, letrozole, to have clinical activity with minimal side effects in women with recurrent ovarian cancer. [7,8] The objective of this study was to evaluate the efficacy and safety of the aromatase inhibitor letrozole in patients with platinum- and taxane-resistant, ER-positive highgrade cancer of the ovary or peritoneum. Materials and methods This single-institution, phase II study was conducted with the approval of the Institutional Review Board at The University of Texas M. D. Anderson Cancer Center. Patients were eligible for the study if they met the following criteria: 1) histologically documented, advanced or metastatic high-grade epithelial carcinoma of the ovary or peritoneum that was considered platinum- and taxaneresistant (defined as progression of disease during platinum and taxane chemotherapy, recurrence of disease within 6 months of completing initial platinum and taxane chemotherapy, or failure to achieve a complete response [i.e., persistent macroscopic disease] after six cycles of platinum and taxane chemotherapy); 2) tumor documented to be ER-positive by immunohistochemistry; 3) measurable disease by response evaluation criteria in solid tumors (RECIST); 4) Zubrod performance status of ≤2; 5) an expected survival of 3 months or longer; and 6) adequate hematologic, cardiac, renal, and hepatic function (absolute neutrophil count ≥ 1500 ells/μL; platelet count≥ 100,000 cells/μL; no documented myocardial infarction within 6 months; no documented unstable angina, congestive heart failure, or uncontrolled hypertension; serum creatinine ≤ 1.5 mg/dL; and total bilirubin, alanine transaminase, and alkaline phosphatase b 1.5 times normal). All patients provided informed consent indicating that they were aware of the investigational nature of the study. Patients were excluded from the study if they had any of the following: 1) tumor of low grade or low malignant potential; 2) incomplete recovery from the toxicity of previous chemotherapy, radiation therapy, or immunologic therapy; 3) history of other malignancy, with the exception of nonmelanoma skin cancer or carcinoma in situ of the cervix, unless in complete remission and off all therapy for that disease for a minimum of 5 years; 4) previously documented human immunodeficiency virus infection; 5) uncontrolled intercurrent disease such as ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia; 6) any medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with study participation; 7) known allergies to letrozole; and 8) prior therapy with letrozole. Patients were not allowed to undergo concurrent treatment with other anticancer agents while participating in this study. Patients were treated with letrozole at a dose of 2.5 mg orally once daily until disease progression or toxicity occurred. No dose adjustments were planned. One cycle was defined as four weeks of treatment. The scheduled follow-up consisted of a physical examination, including a pelvic examination, and a serum CA 125 measurement every 28 days for the first 4 months or as clinically indicated. Thereafter, patients with stable or responding disease were evaluated every 12 weeks. All patients kept a drug administration diary, which was reviewed after each cycle of therapy to verify compliance. Lesions were measured by CT scan or by pelvic examination. CT scans were performed after cycle 2 and 4 then every 3 months. A complete response was defined as the disappearance of all target lesions and no evidence of new lesions documented during two consecutive disease assessments at least 4 weeks apart. Normalization of the serum CA 125 level, if elevated at baseline, was also required. A partial response was defined as at least a 30% decrease in the sum of the longest dimensions of all target lesions. Disease progression was defined as at least a 20% increase in the sum of the longest dimensions of target lesions. Stable disease was defined as any condition not meeting the above criteria. Response
57
Table 1 Patient and disease characteristics Characteristic Age Median Range Ethnicity Caucasian African–American Hispanic Histology Adenocarcinoma Mixed carcinoma Serous carcinoma Prior therapy Surgery Chemotherapy Hormonal therapy Immunotherapy Radiation therapy
Number of patients (%) 63 38–83 27 (82) 3 (9) 3 (9) 1 (3) 3 (9) 29 (88) 33 (100) 33 (100) 5 (15) 3 (9) 1 (3)
duration was measured from the time of response (not the beginning of treatment) until there was evidence of disease progression. Immunohistochemical staining was performed on formalin-fixed, paraffinembedded tissue sections using the avidin–biotin–peroxidase complex method in a Dako AutoStainer (Carpinteria, CA). The primary monoclonal antibody used was the 6F11 to estrogen receptor (Novocastra, Newcastle-upon-Tyne, UK; dilution, 1:50). To enhance the immunostaining, a heat induced epitope retrieval procedure was performed using a Black and Decker vegetable steamer (Shelton, CT). Briefly, deparaffinized sections were placed in a thermoresistant container filled with Tris-EDTA buffer (pH 8.0), steamed for 45 min, then cooled for 20 min before immunostaining. The antigen–antibody reaction was visualized using 3 V, 3-diaminobenzidine as chromogen. To verify the specificity of the antibody, known positive and negative tissues were used as controls. The percentage of tumor cells staining was recorded. Immunohistochemical staining was performed prospectively in patients in whom this study had not been previously performed. A Simon's optimal two-stage design was used in this study [7]. A response rate of 20% or better was established as the criterion of objective response (complete or partial response) by which further studies would be of interest. If no responses were noted among the first 15 patients, then the study would be stopped early. If there was at least 1 responder among the first 15 patients, an additional 16 patients would be enrolled. If there were at least 4 responders among these first 31 patients, then an additional 52 patients would be enrolled and evaluated.
Results A total of 33 patients were entered in this study. Twenty nine patients (88%) had ovarian cancer and 4 patients (12%) had primary peritoneal cancer. Thirty-one patients (94%) were evaluable for response and toxicity, and 2 (6%) were evaluable for toxicity only. These two patients were not evaluable for response because they did not complete a full cycle of therapy. The median age at enrollment was 63 years (range, 38 to 83). Demographics and prior chemotherapy regimens are summarized in Table 1. A total of 31 patients (94%) were previously treated with more than one cycle of chemotherapy. Twenty-three patients (74%) had received three or more prior chemotherapy regimens. A total of 5 patients had received hormonal therapy. Four patients were previously treated with tamoxifen and one patient had been previously treated with tamoxifen and anastrozole. The total number of letrozole cycles administered was 81 (range, 1 to 14 cycles/patient). The median treatment duration
58
P.T. Ramirez et al. / Gynecologic Oncology 110 (2008) 56–59
Table 2 Response to therapy Response
Number of patients (%)
Complete response Partial response Stable disease Progressive disease Not evaluable
0 (0) 1 (3) 7 (23) 23 (74) 2 (6)
was 8 weeks (range, 4 to 52 weeks). There were no patients with a complete response. One patient (3%) had a partial response in the first accrual cohort, opening the second stage. The duration of this partial response was 16 weeks. Seven patients (23%) had stable disease. The median duration of stable disease for these patients was 8 weeks (range, 7 to 46 weeks). Response to therapy is shown on Table 2. There was no statistically significant difference in the median number of prior chemotherapy regimens between the patients who derived a clinical benefit (2.5 prior treatments) versus those who did not derive a clinical benefit (4 prior treatments) (p = 0.051). A total of 23 patients (74%) had disease progression. The median duration of clinical benefit (stable disease or complete or partial response) was 9 weeks (range, 2 to 29 weeks). The median follow-up for the entire cohort of patients was 25 weeks. Twenty patients went on to receive additional chemotherapy (liposomal doxorubicin, gemcitabine, topotecan, and capecitabine). Three patients went on to receive other hormonal therapies. Six patients went on to hospice care and the treatment for the remaining four patients is unknown. Median survival for those patient who derived a clinical benefit (partial response and stable disease) was 10.9 months (4.9–27 months) compared to 5.6 months (1.6– 38.4) for nonresponders (p = 0.27). A total of 10 (30%) patients went on to undergo treatment on clinical trials after completing therapy with letrozole. The most common adverse effects were fatigue (36%) and diaphoresis (21%). No grade 3 or 4 toxicities were reported, and no patient discontinued treatment due to adverse effects. Two patients stopped therapy soon after enrolling on the trial. One patient was admitted two weeks into therapy with bowel obstruction and elected to undergo no further treatment and hospice care. The second patient had rapid progression of disease and went on to hospice care. Discussion In our study, we found that patients with platinum- and taxane-resistant, ER-positive recurrent high-grade ovarian and primary peritoneal cancer had a low response rate to letrozole. However, twenty-six percent of patients derived a clinical benefit from this therapy by achieving either a partial response or stable disease. In addition, over half of the patients entered in the study went on to receive additional chemotherapy once progression of disease was documented. The utility of the aromatase inhibitor letrozole in the setting of advanced ovarian cancer has been previously reported. Papadimitriou et al. [8] performed a phase II trial of oral letrozole (2.5 mg once daily) in 27 women with recurrent epithelial ovarian cancer. In
this cohort, 67% of patients were considered platinum sensitive and only 22% of patients had received more than two prior chemotherapy regimens. In this same study, 75% of patients had ER-positive tumors and 25% had PR-positive tumors. Among the 21 patients with measurable disease who were evaluable for response, the overall objective response rate was 15%, with one complete and two partial responses. Among the patients evaluable for a CA 125 response, the CA 125 response rate was 15%. This was defined as at least a 50% decrease in CA 125 level following two levels which were elevated. An additional five patients (18%) had stable CA 125 levels, defined as b 50% rise in CA 125 level for at least three months. Letrozole treatment was generally well tolerated in this cohort. The authors concluded that letrozole has clinical activity and only limited toxicity in patients with relapsed ovarian cancer. The higher response rate reported in this study compared with the current study is most likely due to the majority of patients being platinum sensitive and not heavily pretreated with other chemotherapy regimens. In our study, all patients were platinum and taxane resistant and 74% had received N3 previous chemotherapy regimens. Bowman et al. [9] performed an open-label, phase II trial using letrozole (2.5 mg once daily) at the time of CA 125 relapse in 60 patients with ovarian cancer. Fifty percent of patients had received only one previous chemotherapy regimen. Information was not provided regarding platinum or taxane sensitivity status; however, 50% of patients were enrolled more than two years following their diagnosis. There were no complete or partial responses, but 10 patients (17%) had stable disease for at least 12 weeks. The median time to progression was 35 weeks. CA 125 responses were evaluable in 54 patients. A partial CA 125 response was noted in 5 patients (8%), and the CA 125 level remained stable in an additional 14 patients (23%). Biologic markers of response were also evaluated. Tumors from patients with stable disease had significantly higher ER and PR values compared with tumors from patients with progressive disease. Interestingly, a CA 125 response was associated with higher ER, lower erbB2, and higher epidermal growth factor receptor expression. The authors concluded that letrozole could produce disease stabilization and partial response by CA 125 levels, and that the response was associated with higher levels of tumor ER expression. More recently, Smyth et al. [10] reported a phase II study of letrozole 2.5 mg daily in previously treated ER-positive ovarian cancer patients with a rising CA 125. The primary end point was a response according to CA 125 and response evaluation criteria in solid tumors (RECIST) criteria. In that study, of the 42 patients evaluable for CA 125 response, 7 (17%) had a response (decrease of N 50%), and 11 (26%) patients had not progressed (doubling of CA 125) following 6 months on treatment. Of 33 patients evaluable for radiological response, 3 (9%) had a partial remission, and 14 (42%) had stable disease at 12 weeks. Eleven patients (26%) had a PFS of N6 months. It should be noted that 52% of the patients included in that study were considered platinum sensitive. Currently, objective responses are defined as complete or partial responses. However, there is also a benefit in achieving stable disease, particularly if the treatment has low toxicity and does not adversely affect the patient's quality of life. Gronlund et al. [11]
P.T. Ramirez et al. / Gynecologic Oncology 110 (2008) 56–59
evaluated the significance of stabilization of tumor size in secondline chemotherapy as an indicator of survival in patients with ovarian cancer. In a multivariate analysis of survival, stable disease was found to be an independent prognostic factor for survival and the death hazard ratio was 0.37 (stable disease versus progressive disease; 95% CI:0.16–0.86; p= 0.02). In addition, the difference in survival between patients with stable disease and partial response was not statistically significant (p = 0.09). The authors concluded that because recurrent and refractory ovarian carcinomas are considered as incurable diseases, stabilization of tumor burden should be considered as a reasonable treatment outcome in the salvage clinical setting. In our study, we found that 26% of patients with recurrent platinum- and taxane-resistant high-grade ovarian and primary peritoneal cancer gained a clinical benefit from taking oral letrozole–stable disease in seven and a partial response in one–with minimal toxicity. These results suggest that oral letrozole may be useful in the setting of recurrent disease when other chemotherapeutic options have been exhausted or in patients who wish to take time off from chemotherapy. Conflict of interest statement The authors declare that they have no conflicts of interest to disclose.
Acknowledgment The authors would like to gratefully acknowledge Donna Branham for her assistance in the recruitment and follow-up of this research project.
59
References [1] American Cancer Society: cancer statistics. http://www.acs.org. [2] Rao BR, Slotman BJ. Endocrine role in ovarian cancer. Endocr Relat Cancer 1996;3:309–26. [3] Langdon SP, Hawkes MM, Lawrie SS, et al. Oestrogen receptor expression and the effects of oestrogen and tamoxifen on the growth of human ovarian carcinoma cell lines. Br J Cancer 1990;62:213–6. [4] Langdon SP, Crew AJ, Ritchie AA, et al. Growth inhibition of oestrogen receptor-positive human ovarian carcinoma by anti-oestrogens in vitro and in a xenograft model. Eur J Cancer 1994;30A:682–6. [5] O'Donnell AJM, MacLeod KG, Burns DJ, et al. Estrogen receptor α mediates gene expression changes and growth response in ovarian cancer cells exposed to estrogen. Endocr Relat Cancer 2005;12:851–66. [6] Markman M, Iseminger KA, Hatch KD, et al. Tamoxifen in platinum-refractory ovarian cancer. A Gynecologic Oncology Group ancillary report. Gynecol Oncol 1996;62:4–6. [7] Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials 1988;10:1–10. [8] Papadimitriou CA, Markaki S, Siapkaras J, et al. Hormonal therapy with letrozole for relapsed epithelial ovarian cancer. Long term results of a phase II study. Oncology 2004;66:112–7. [9] Bowman A, Gabra H, Langdon SP, et al. CA125 response is associated with estrogen receptor expression in a phase II trial of letrozole in ovarian cancer: identification of an endocrine-sensitive subgroup. Clin Cancer Res 2002;8:2233–9. [10] Smyth JF, Gourley C, Walker G, et al. Antiestrogen therapy is active in selected ovarian cancer cases: the use of letrozole in estrogen-receptor positive patients. Clin Cancer Res 2007;13:3617–22. [11] Gronlund B, Hogdall C, Christensen IJ, et al. Is stabilization of disease a useful indicator for survival in second-line treatment of ovarian carcinoma pre-treated with paclitaxel-platinum? Gynecol Oncol 2004;94:409–15.
Gynecologic Oncology 110 (2008) 56 – 59 www.elsevier.com/locate/ygyno
Efficacy of letrozole in the treatment of recurrent platinum- and taxane-resistant high-grade cancer of the ovary or peritoneum B Pedro T. Ramirez a,⁎, Kathleen M. Schmeler a , Michael R. Milam a , Brian M. Slomovitz c , Judith A. Smith a , John J. Kavanagh a , Michael Deavers b , Charles Levenback a , Robert L. Coleman a , David M. Gershenson a a
c
Department of Gynecologic Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA b Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA Department of Obstetrics and Gynecology, Cornell Weill Medical College, New York Presbyterian Hospital, New York, NY, USA Received 13 February 2008 Available online 5 May 2008
Abstract Objective. To evaluate the efficacy and safety of letrozole in patients with recurrent platinum- and taxane-resistant estrogen receptor-positive (ER+) high-grade cancer of the ovary or peritoneum. Methods. A single-institution, phase II study was performed in women with recurrent ER+ epithelial carcinoma of the ovary or peritoneum. All patients had measurable disease. Letrozole was administered at a dose of 2.5 mg orally once daily until disease progression or toxicity occurred. Results. Thirty-three patients were enrolled. The median age was 63 years (range, 38 to 83 years). Twenty-three patients (74%) had received three or more prior chemotherapy regimens. The 31 patients evaluable for response received a total of 81 cycles (4 weeks/cycle) of therapy (range, 1 to 14 cycles/patient). The median treatment duration was 8 weeks (range, 4 to 52 weeks). None of the patients had a complete response (CR), 1 (3%) had a partial response (PR), and 7 (23%) had stable disease (SD). The median duration of clinical benefit (SD and PR) was 9 weeks (range, 7 to 46 weeks). The median follow-up for all patients was 25 weeks. All patients were evaluable for toxicity. The most common adverse effects were fatigue (36%) and diaphoresis (21%). No grade 3 or 4 toxicities were reported, and no patients discontinued treatment owing to adverse effects. Eighteen patients (58%) went on to receive additional therapy with other agents. Conclusion. In patients with ER-positive, platinum- and taxane-resistant high-grade ovarian and primary peritoneal cancer treated with letrozole, 26% derived a clinical benefit (SD and PR). © 2008 Elsevier Inc. All rights reserved. Keywords: Letrozole; Resistant ovarian and peritoneal cancer
Introduction In 2007, an estimated 22,430 new cases of ovarian cancer will be diagnosed, and approximately 15,280 women will die of this disease [1]. Although the objective response rate associated with initial standard platinum- and taxane-based chemotherapy is nearly B
This research was supported by an Investigator Initiated Research Proposal from Novartis Pharmaceutical. ⁎ Corresponding author. Department of Gynecologic Oncology, Unit 1362, The University of Texas M. D. Anderson Cancer Center, P.O. Box 301439, Houston, TX 77230-1439, USA. Fax: +1 713 792 7586. E-mail address: [email protected] (P.T. Ramirez). 0090-8258/$ - see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2008.03.014
70% in patients with advanced disease, the majority of patients with advanced ovarian cancer will have relapses and ultimately die from progressive disease that is not responsive to chemotherapy. Furthermore, patients often suffer significant morbidity secondary to the toxicity of agents used to treat recurrent disease, resulting in a decline in the patients' quality of life. Epithelial ovarian carcinomas express a number of hormonal receptors, including estrogen (67% of tumors) and progesterone (47%) [2]. Preclinical models have shown that ovarian cancer cells that express high levels of estrogen receptors are stimulated or inhibited by estrogens and antiestrogens [3–5]. Therefore, a number of investigators have evaluated hormonal therapy in
P.T. Ramirez et al. / Gynecologic Oncology 110 (2008) 56–59
patients with ovarian cancer. Agents studied in the setting of advanced or recurrent ovarian cancer include antiestrogens, progestins, androgens, gonadotropin-releasing hormone agonists, and aromatase inhibitors. In a previously reported study from the Gynecologic Oncology Group, Markman et al. [6] evaluated 102 patients with platinum-resistant ovarian cancer who were treated with tamoxifen. The authors found that tamoxifen offered an objective response rate of 13% with a median duration of response of 4.4 months. Previous studies have shown the aromatase inhibitor, letrozole, to have clinical activity with minimal side effects in women with recurrent ovarian cancer. [7,8] The objective of this study was to evaluate the efficacy and safety of the aromatase inhibitor letrozole in patients with platinum- and taxane-resistant, ER-positive highgrade cancer of the ovary or peritoneum. Materials and methods This single-institution, phase II study was conducted with the approval of the Institutional Review Board at The University of Texas M. D. Anderson Cancer Center. Patients were eligible for the study if they met the following criteria: 1) histologically documented, advanced or metastatic high-grade epithelial carcinoma of the ovary or peritoneum that was considered platinum- and taxaneresistant (defined as progression of disease during platinum and taxane chemotherapy, recurrence of disease within 6 months of completing initial platinum and taxane chemotherapy, or failure to achieve a complete response [i.e., persistent macroscopic disease] after six cycles of platinum and taxane chemotherapy); 2) tumor documented to be ER-positive by immunohistochemistry; 3) measurable disease by response evaluation criteria in solid tumors (RECIST); 4) Zubrod performance status of ≤2; 5) an expected survival of 3 months or longer; and 6) adequate hematologic, cardiac, renal, and hepatic function (absolute neutrophil count ≥ 1500 ells/μL; platelet count≥ 100,000 cells/μL; no documented myocardial infarction within 6 months; no documented unstable angina, congestive heart failure, or uncontrolled hypertension; serum creatinine ≤ 1.5 mg/dL; and total bilirubin, alanine transaminase, and alkaline phosphatase b 1.5 times normal). All patients provided informed consent indicating that they were aware of the investigational nature of the study. Patients were excluded from the study if they had any of the following: 1) tumor of low grade or low malignant potential; 2) incomplete recovery from the toxicity of previous chemotherapy, radiation therapy, or immunologic therapy; 3) history of other malignancy, with the exception of nonmelanoma skin cancer or carcinoma in situ of the cervix, unless in complete remission and off all therapy for that disease for a minimum of 5 years; 4) previously documented human immunodeficiency virus infection; 5) uncontrolled intercurrent disease such as ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia; 6) any medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with study participation; 7) known allergies to letrozole; and 8) prior therapy with letrozole. Patients were not allowed to undergo concurrent treatment with other anticancer agents while participating in this study. Patients were treated with letrozole at a dose of 2.5 mg orally once daily until disease progression or toxicity occurred. No dose adjustments were planned. One cycle was defined as four weeks of treatment. The scheduled follow-up consisted of a physical examination, including a pelvic examination, and a serum CA 125 measurement every 28 days for the first 4 months or as clinically indicated. Thereafter, patients with stable or responding disease were evaluated every 12 weeks. All patients kept a drug administration diary, which was reviewed after each cycle of therapy to verify compliance. Lesions were measured by CT scan or by pelvic examination. CT scans were performed after cycle 2 and 4 then every 3 months. A complete response was defined as the disappearance of all target lesions and no evidence of new lesions documented during two consecutive disease assessments at least 4 weeks apart. Normalization of the serum CA 125 level, if elevated at baseline, was also required. A partial response was defined as at least a 30% decrease in the sum of the longest dimensions of all target lesions. Disease progression was defined as at least a 20% increase in the sum of the longest dimensions of target lesions. Stable disease was defined as any condition not meeting the above criteria. Response
57
Table 1 Patient and disease characteristics Characteristic Age Median Range Ethnicity Caucasian African–American Hispanic Histology Adenocarcinoma Mixed carcinoma Serous carcinoma Prior therapy Surgery Chemotherapy Hormonal therapy Immunotherapy Radiation therapy
Number of patients (%) 63 38–83 27 (82) 3 (9) 3 (9) 1 (3) 3 (9) 29 (88) 33 (100) 33 (100) 5 (15) 3 (9) 1 (3)
duration was measured from the time of response (not the beginning of treatment) until there was evidence of disease progression. Immunohistochemical staining was performed on formalin-fixed, paraffinembedded tissue sections using the avidin–biotin–peroxidase complex method in a Dako AutoStainer (Carpinteria, CA). The primary monoclonal antibody used was the 6F11 to estrogen receptor (Novocastra, Newcastle-upon-Tyne, UK; dilution, 1:50). To enhance the immunostaining, a heat induced epitope retrieval procedure was performed using a Black and Decker vegetable steamer (Shelton, CT). Briefly, deparaffinized sections were placed in a thermoresistant container filled with Tris-EDTA buffer (pH 8.0), steamed for 45 min, then cooled for 20 min before immunostaining. The antigen–antibody reaction was visualized using 3 V, 3-diaminobenzidine as chromogen. To verify the specificity of the antibody, known positive and negative tissues were used as controls. The percentage of tumor cells staining was recorded. Immunohistochemical staining was performed prospectively in patients in whom this study had not been previously performed. A Simon's optimal two-stage design was used in this study [7]. A response rate of 20% or better was established as the criterion of objective response (complete or partial response) by which further studies would be of interest. If no responses were noted among the first 15 patients, then the study would be stopped early. If there was at least 1 responder among the first 15 patients, an additional 16 patients would be enrolled. If there were at least 4 responders among these first 31 patients, then an additional 52 patients would be enrolled and evaluated.
Results A total of 33 patients were entered in this study. Twenty nine patients (88%) had ovarian cancer and 4 patients (12%) had primary peritoneal cancer. Thirty-one patients (94%) were evaluable for response and toxicity, and 2 (6%) were evaluable for toxicity only. These two patients were not evaluable for response because they did not complete a full cycle of therapy. The median age at enrollment was 63 years (range, 38 to 83). Demographics and prior chemotherapy regimens are summarized in Table 1. A total of 31 patients (94%) were previously treated with more than one cycle of chemotherapy. Twenty-three patients (74%) had received three or more prior chemotherapy regimens. A total of 5 patients had received hormonal therapy. Four patients were previously treated with tamoxifen and one patient had been previously treated with tamoxifen and anastrozole. The total number of letrozole cycles administered was 81 (range, 1 to 14 cycles/patient). The median treatment duration
58
P.T. Ramirez et al. / Gynecologic Oncology 110 (2008) 56–59
Table 2 Response to therapy Response
Number of patients (%)
Complete response Partial response Stable disease Progressive disease Not evaluable
0 (0) 1 (3) 7 (23) 23 (74) 2 (6)
was 8 weeks (range, 4 to 52 weeks). There were no patients with a complete response. One patient (3%) had a partial response in the first accrual cohort, opening the second stage. The duration of this partial response was 16 weeks. Seven patients (23%) had stable disease. The median duration of stable disease for these patients was 8 weeks (range, 7 to 46 weeks). Response to therapy is shown on Table 2. There was no statistically significant difference in the median number of prior chemotherapy regimens between the patients who derived a clinical benefit (2.5 prior treatments) versus those who did not derive a clinical benefit (4 prior treatments) (p = 0.051). A total of 23 patients (74%) had disease progression. The median duration of clinical benefit (stable disease or complete or partial response) was 9 weeks (range, 2 to 29 weeks). The median follow-up for the entire cohort of patients was 25 weeks. Twenty patients went on to receive additional chemotherapy (liposomal doxorubicin, gemcitabine, topotecan, and capecitabine). Three patients went on to receive other hormonal therapies. Six patients went on to hospice care and the treatment for the remaining four patients is unknown. Median survival for those patient who derived a clinical benefit (partial response and stable disease) was 10.9 months (4.9–27 months) compared to 5.6 months (1.6– 38.4) for nonresponders (p = 0.27). A total of 10 (30%) patients went on to undergo treatment on clinical trials after completing therapy with letrozole. The most common adverse effects were fatigue (36%) and diaphoresis (21%). No grade 3 or 4 toxicities were reported, and no patient discontinued treatment due to adverse effects. Two patients stopped therapy soon after enrolling on the trial. One patient was admitted two weeks into therapy with bowel obstruction and elected to undergo no further treatment and hospice care. The second patient had rapid progression of disease and went on to hospice care. Discussion In our study, we found that patients with platinum- and taxane-resistant, ER-positive recurrent high-grade ovarian and primary peritoneal cancer had a low response rate to letrozole. However, twenty-six percent of patients derived a clinical benefit from this therapy by achieving either a partial response or stable disease. In addition, over half of the patients entered in the study went on to receive additional chemotherapy once progression of disease was documented. The utility of the aromatase inhibitor letrozole in the setting of advanced ovarian cancer has been previously reported. Papadimitriou et al. [8] performed a phase II trial of oral letrozole (2.5 mg once daily) in 27 women with recurrent epithelial ovarian cancer. In
this cohort, 67% of patients were considered platinum sensitive and only 22% of patients had received more than two prior chemotherapy regimens. In this same study, 75% of patients had ER-positive tumors and 25% had PR-positive tumors. Among the 21 patients with measurable disease who were evaluable for response, the overall objective response rate was 15%, with one complete and two partial responses. Among the patients evaluable for a CA 125 response, the CA 125 response rate was 15%. This was defined as at least a 50% decrease in CA 125 level following two levels which were elevated. An additional five patients (18%) had stable CA 125 levels, defined as b 50% rise in CA 125 level for at least three months. Letrozole treatment was generally well tolerated in this cohort. The authors concluded that letrozole has clinical activity and only limited toxicity in patients with relapsed ovarian cancer. The higher response rate reported in this study compared with the current study is most likely due to the majority of patients being platinum sensitive and not heavily pretreated with other chemotherapy regimens. In our study, all patients were platinum and taxane resistant and 74% had received N3 previous chemotherapy regimens. Bowman et al. [9] performed an open-label, phase II trial using letrozole (2.5 mg once daily) at the time of CA 125 relapse in 60 patients with ovarian cancer. Fifty percent of patients had received only one previous chemotherapy regimen. Information was not provided regarding platinum or taxane sensitivity status; however, 50% of patients were enrolled more than two years following their diagnosis. There were no complete or partial responses, but 10 patients (17%) had stable disease for at least 12 weeks. The median time to progression was 35 weeks. CA 125 responses were evaluable in 54 patients. A partial CA 125 response was noted in 5 patients (8%), and the CA 125 level remained stable in an additional 14 patients (23%). Biologic markers of response were also evaluated. Tumors from patients with stable disease had significantly higher ER and PR values compared with tumors from patients with progressive disease. Interestingly, a CA 125 response was associated with higher ER, lower erbB2, and higher epidermal growth factor receptor expression. The authors concluded that letrozole could produce disease stabilization and partial response by CA 125 levels, and that the response was associated with higher levels of tumor ER expression. More recently, Smyth et al. [10] reported a phase II study of letrozole 2.5 mg daily in previously treated ER-positive ovarian cancer patients with a rising CA 125. The primary end point was a response according to CA 125 and response evaluation criteria in solid tumors (RECIST) criteria. In that study, of the 42 patients evaluable for CA 125 response, 7 (17%) had a response (decrease of N 50%), and 11 (26%) patients had not progressed (doubling of CA 125) following 6 months on treatment. Of 33 patients evaluable for radiological response, 3 (9%) had a partial remission, and 14 (42%) had stable disease at 12 weeks. Eleven patients (26%) had a PFS of N6 months. It should be noted that 52% of the patients included in that study were considered platinum sensitive. Currently, objective responses are defined as complete or partial responses. However, there is also a benefit in achieving stable disease, particularly if the treatment has low toxicity and does not adversely affect the patient's quality of life. Gronlund et al. [11]
P.T. Ramirez et al. / Gynecologic Oncology 110 (2008) 56–59
evaluated the significance of stabilization of tumor size in secondline chemotherapy as an indicator of survival in patients with ovarian cancer. In a multivariate analysis of survival, stable disease was found to be an independent prognostic factor for survival and the death hazard ratio was 0.37 (stable disease versus progressive disease; 95% CI:0.16–0.86; p= 0.02). In addition, the difference in survival between patients with stable disease and partial response was not statistically significant (p = 0.09). The authors concluded that because recurrent and refractory ovarian carcinomas are considered as incurable diseases, stabilization of tumor burden should be considered as a reasonable treatment outcome in the salvage clinical setting. In our study, we found that 26% of patients with recurrent platinum- and taxane-resistant high-grade ovarian and primary peritoneal cancer gained a clinical benefit from taking oral letrozole–stable disease in seven and a partial response in one–with minimal toxicity. These results suggest that oral letrozole may be useful in the setting of recurrent disease when other chemotherapeutic options have been exhausted or in patients who wish to take time off from chemotherapy. Conflict of interest statement The authors declare that they have no conflicts of interest to disclose.
Acknowledgment The authors would like to gratefully acknowledge Donna Branham for her assistance in the recruitment and follow-up of this research project.
59
References [1] American Cancer Society: cancer statistics. http://www.acs.org. [2] Rao BR, Slotman BJ. Endocrine role in ovarian cancer. Endocr Relat Cancer 1996;3:309–26. [3] Langdon SP, Hawkes MM, Lawrie SS, et al. Oestrogen receptor expression and the effects of oestrogen and tamoxifen on the growth of human ovarian carcinoma cell lines. Br J Cancer 1990;62:213–6. [4] Langdon SP, Crew AJ, Ritchie AA, et al. Growth inhibition of oestrogen receptor-positive human ovarian carcinoma by anti-oestrogens in vitro and in a xenograft model. Eur J Cancer 1994;30A:682–6. [5] O'Donnell AJM, MacLeod KG, Burns DJ, et al. Estrogen receptor α mediates gene expression changes and growth response in ovarian cancer cells exposed to estrogen. Endocr Relat Cancer 2005;12:851–66. [6] Markman M, Iseminger KA, Hatch KD, et al. Tamoxifen in platinum-refractory ovarian cancer. A Gynecologic Oncology Group ancillary report. Gynecol Oncol 1996;62:4–6. [7] Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials 1988;10:1–10. [8] Papadimitriou CA, Markaki S, Siapkaras J, et al. Hormonal therapy with letrozole for relapsed epithelial ovarian cancer. Long term results of a phase II study. Oncology 2004;66:112–7. [9] Bowman A, Gabra H, Langdon SP, et al. CA125 response is associated with estrogen receptor expression in a phase II trial of letrozole in ovarian cancer: identification of an endocrine-sensitive subgroup. Clin Cancer Res 2002;8:2233–9. [10] Smyth JF, Gourley C, Walker G, et al. Antiestrogen therapy is active in selected ovarian cancer cases: the use of letrozole in estrogen-receptor positive patients. Clin Cancer Res 2007;13:3617–22. [11] Gronlund B, Hogdall C, Christensen IJ, et al. Is stabilization of disease a useful indicator for survival in second-line treatment of ovarian carcinoma pre-treated with paclitaxel-platinum? Gynecol Oncol 2004;94:409–15.