SUMMARY
Hormonal therapy for adjuvant treatment of ovarian cancer may provide a low toxicity option in some patients with refractory disease. A 53 year-old patient with stage IIIC papillary serous ovarian cancer previously treated with multiple chemotherapy regimens with platinum-resistant disease was treated with antiestrogen therapy for 28 months before requiring reinstitution of cytotoxic chemotherapy. Hormonal therapy may be effective in a subset of epithelial ovarian cancer patients with endocrine sensitivity and should be considered in the treatment of platinum-resistant patients.
Keywords: Ovarian Neoplasms, Antineoplastic Agents, Hormonal, Selective Estrogen Receptor Modulators, Tamoxifen, Aromatase
INTRODUCTION
There has been a modest improvement in the five-year overall survival rate of epithelial ovarian cancer (EOC) from about 37% in 1975 to 45% in 2002 (1). Factors contributing to this improvement include aggressive debulking and the introduction of platinum compounds and taxanes (2,3).
Despite these improvements, most patients will relapse and develop refractory disease. Thus, the goal of second-line chemotherapy is palliation. Considerations in the choice of second-line therapy should include response to therapy and treatment related toxicity. Hormonal therapies are an attractive option owing to their limited toxicity profile and ease of administration (4). We present a patient with advanced ovarian cancer who had stable disease on hormonal therapy for 28 months.
CASE
A 53-year-old woman presented with a two-week history of abdominal bloating. Pelvic examination revealed a 2-3 cm right adnexal mass. A CT scan confirmed the mass and showed abdominal and pelvic ascites. Serum CA-125 was elevated at 3050 U/ml (normal 0-35 U/ml). The patient underwent optimal debulking including total abdominal hysterectomy, bilateral salpingoophorectomy, omentectomy and lymph node sampling. Pathology demonstrated stage IIIC grade 2 papillary serous adenocarcinoma involving the omentum and peritoneal surfaces.
Following surgery, the patient was treated with seven cycles of postoperative intravenous (IV) carboplatin and paclitaxel. CA-125 decreased but did not normalize (nadir = 66) in the setting of a negative physical exam. A peritoneal catheter was placed for purposes of intraperitoneal (IP) chemotherapy at which time persistent disease was documented histological during the second-look surgery. She was given one cycle of IV cisplatin 65 mg/m2 on day 1 and IV etoposide 90 mg/m2 on days 1 through 3, while healing from the second-look surgery. Subsequently, she received five cycles of IP carboplatin 300 mg/m2 on day 1 and IV etoposide 90 mg/m2 on days 1 through 3 as second-line, took two months off from chemotherapy, and then received one cycle of IP carboplatin and two cycles of IP carboplatin and IV etoposide at the above doses. CA-125 increased from 27 to 54, so she received five cycles of single agent IV paclitaxel 185 mg/m2 as third-line therapy. CA-125 decreased to 24 at the completion of paclitaxel. CT scans and pelvic exam always remained negative, and she had no symptoms of her disease. Because hormone receptors on her original tumor were determined to be positive for both estrogen and progesterone, she started with tamoxifen 20 mg per day. After one month of being on tamoxifen, her CA-125 had fallen to 14. Three months later, it rose to 27. Tamoxifen dose was doubled to 40 mg per day. Her CA-125 remained stable for eight months, when it rose to 45. Tamoxifen was discontinued, and anastrozole 1 mg per day was prescribed. Five months later, CA-125 had decreased to 19.
While on anastrozole, her CA-125 gradually rose to 96 over the course of six months. Anastrozole was discontinued, and a monthly dose of fulvestrant 250 mg intramuscularly was initiated. CA-125 fell to 68 and stayed in that range for about 5 months, when it rose to 106, and CT scan showed new development of enlarged retroperitoneal nodes. After 28 months of stable disease on hormonal measures, she required reinstitution of platinum-based chemotherapy. The patient had either a transient or no response to single agent carboplatin, carboplatin and taxol, carboplatin and etoposide, doxorubucin, gemcitabine, avastin, and finally cytoxan and avastin. She died of complications secondary to bowel obstruction.
DISCUSSION
In platinum-resistant patients, there are a number of cytotoxic agents that have activity based on retrospective studies and phase II trials with objective response rates varying from 5 to 25%, and the duration of these responses lasting less than 8 months. An additional 35 to 50% of patients may maintain stable disease. The main advantage of using hormonal therapy among second-line therapy options is its limited toxicity profile and ease of administration, making it a suitable option for patients who are unable to tolerate or do not desire to continue cytotoxic chemotherapy due to side effects or comorbidities contraindicating the use of cytotoxic agents (4). In this patient, despite rising CA-125 levels after ultimately developing resistance to tamoxifen, the subsequent use of anastrozole and fulvestrant still resulted in stable disease. Thus, resistance to one hormonal therapy does not preclude trial of another. One explanation is the differing mechanisms of actions of each of these agents. Tamoxifen and fulvestrant bind to estrogen receptors. Tamoxifen has some agonist activity whereas fulvestrant does not. Anastrozole is an aromatase inhibitor that blocks the peripheral conversion of androgens to estrogen, thereby decreasing the total amount of estrogen in the body.
Tamoxifen is the most studied of the three agents. In a large prospective study, patients with recurrent or persistent disease (platinum-sensitive and resistant) given tamoxifen 20 mg per day after first-line chemotherapy, a 17% objective response was observed (5). Analysis limited to platinum-resistant patients showed an overall response rate (of 13% (6). Tamoxifen does not appear to improve responses in combination with cytotoxic agents (7,8). Clinical studies using letrozole have shown conflicting results. One study showed an objective response of 15%; the other showed no objective responses (9,10). Fulvestrant 500mg IM on day 1, 15, and 250mg IM on day 28 and monthly thereafter has been studied in patients with recurrent EOC. Objective response rates were 8% with another 35% achieving stable disease (11). Other options for hormonal therapy include gonadotropin analogs, progesterones, and androgens. A review of published papers on the use of tamoxifen alone or in combination with other agents, aromatase inhibitors, and fulvestrant in recurrent EOC is shown in Tablea 1-5. Of published studies that likely had overlapping patients, the study with a higher number of patients or analysis of the overall data (versus a subpopulation) were included. Other factors thought to affect response to therapy include dosage and receptor status. Higher doses of tamoxifen in breast cancer have not been shown to be more effective and may even be more toxic (12-14). Dose escalation in uterine cancer has shown similar results (15). There are no data comparing dose responses of tamoxifen or other antiestrogen therapy in ovarian cancer. Varying doses (20mg to 160mg) and regimens of tamoxifen have been used. Estrogen and progesterone receptors are thought to play a role in the development of EOC and their presence would be expected to correlate with response to hormonal therapy in ovarian cancer as in breast cancer. However, the role that receptor status plays in the response to hormonal therapy in ovarian cancer remains unclear and should not necessarily influence treatment choices. A few trials suggest that response to tamoxifen may be related to hormone receptor status (5,16,17), but no studies have been specifically designed to examine this effect.
Table 1.
Review of published literature on the use of tamoxifen alone in epithelial ovarian cancer
| Study and Year | Type of study | N | Median number of prior regimens | Tamoxifen dose | CR (%) | PR (%) | SD (%) | PD (%) | Median PFS mos (range) | Median OS mos (range) | |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Schwartz 1982 (18) | Phase II | 13 | 2(1-4) | 10mg BID to 40mg QID | 0 | 1(7.6) | 4(30.7) | 8(61.5) | NA | NA | |
| Shirey1985 (19) | Phase II | 23 | NA | 10mg to 20mg BID | 0 | 0 | 19(82.6) | 4(17.4) | 4.3(2-11.8) | not reached | |
| Slevin 1986 (20) | Phase II | 22 | 2(1-5) | 10mg to 20mg BID | 0 | 1(4.5) | 0 | 21(9.5) | 1.4(0.75-3) | 3.5(0.75-12) | |
| Weiner 1987 (16) | Phase II | 31 | 3 | 40mg QD for 7 days f/b 10mg BID | 1(3.2) | 2(6.4) | 6(19.3) | 22(70.9) | 14(3-23) | responders 16, nonresponders 7 | |
| Osborne 1988 (22) | Phase II | 51 | NA | 100mg/m2 in 4 divided doses over 24 h and then 20mg BID | 0 | 1(1.9) | 0 | 50(98.0) | 2 | 4(1-16) | |
| Hatch 1991 (5) | Phase II | 105 | 1 | 20mg PO BID | 10(9.5) | 8(7.6) | 40(38.0) | 47(44.7) | NA | NA | |
| Ahlgren 1993 (22) | Phase II | 29 | NA | 40mg PO BID for 30 days then 20mg BID | 2(6.8) | 3(10.3) | NA | NA | 1.9 | 6.1 | |
| Jager 1995 (23) | Phase II | 37 | 1-2 | 30mg QD | 0 | 0 | 2(5.4) | 31(83.7) | NA | 6.5 | |
| Van der Vange 1995 (24) | Phase II | 10 | NA | 20mg PO BID | 0 | 1 (10.0) | 1 (10.0) | 4 (40.0) | NA | 4.8 (0.4-17) | 2 early deaths and 2 NA |
| Van der Velden 1995 (25) | Phase II | 30 | 1-3 | 20mg PO BID | 2(6.6) | 0 | 10(33.3) | 18(60.0) | NA | NA | |
| Marth 1997 (26) | Phase II | 65 | Majority 1-2 | 30mg or 40mg QD | 2(3.0) | 2(3.0) | 50(75.7) | 11(16.6) | 11.5 (mean) (4-30) in patients with stable disease | 3.8 | |
| Markman 2004 (27) | Retrospective | 56 | NA | 20mg or 40mg PO QD | NA | NA | NA | NA | 3 (1-30) | NA | |
| Karagol 2007 (28) | Retrospective | 29 | NA | 20mg BID | 1 (3.4) | 2 (6.9) | 6 (20.6) | 20 (68.9) | 4 | 15 |
CR: complete response; PR: partial response; SD: stable disease; PD: progressive isease; PFS: progression free survival; OS: overall survival; ER: estrogen receptor; NA: data not available in this study; f/b: followed by.
Table 5.
Review of the use of fulvestrant in epithelial ovarian cancer
| FULVESTRANT | N | Median number of previous regimens (range) | Fulvestrant dose | CR (%) | PR (%) | SD (%) | PD (%) | Median PFS mos (range) | Median OS mos (range) | Notes | |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Argenta 2009 (11) | Phase II | 26 | 5(2-13) | 500mg IM on Day 1, 250mg IM on Day 15, and 250mg IM on Day 29 repeated every 28 days | 1(3.8) | 1(3.8) | 9(34.6) | 15(57.7) | 2.1 | not reached | modified Rustin criteria |
| Argenta 2009 (11) | 0 | 0 | 13(50%) | 13(50%) | RECIST criteria |
Our patient had one of the longest remissions reported to hormonal therapy. Hormonal therapy may have some activity in a subset of EOC patients with endocrine sensitivity. It should be considered in patients unable to tolerate cytotoxic chemotherapy or in the palliative setting as most of the literature focuses on patients with refractory or progressive disease. Further studies are needed to better characterize the role of hormonal therapy in ovarian cancer.
Table 2.
Review of published literature on the use of tamoxifen in combination with other hormonal agents in epithelial ovarian cancer
| Study and year | N | Median number of previous regimens | Tamoxifen dose | Other Agent Dose | CR (%) | PR (%) | SD (%) | PD (%) | Median PFS mos (range) | Median OS mos (range) | |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Belinson 1987 (29) | Phase II | 19 | 1-2 | 20mg QD | 160mg MPA | 0 | 0 | 10(52.6) | 9(47.3) | NA | NA |
| Jakobsen 1987 (30) | Phase II | 26 | NA | 10mg TID for 14 days | 400mg MPA BID for 14 days after tamoxifen | 0 | 0 | 7(26.9) | 19(73.0) | NA | NA |
|
| |||||||||||
| Hasan 2005 (31) | Phase II | 26 | 3 (1-8) | 20mg PO QD | Goserelin 3.6mg SC monthly | 1 (3.8) | 2 (7.7) | 10 (38.5) | NA | 4 | 36 |
CR: complete response; PR: partial response; SD: stable disease; PD: progressive disease; PFS: progression free survival; OS: overall survival; ER: estrogen receptor; NA: data not available in this study.
Table 3.
Review of published literature on the use of tamoxifen in combination with cytotoxic chemotherapy in epithelial ovarian cancer
| Paper and year | N | Median number of previous regimens (range) | Tamoxifen dose | Cytotoxic chemo dose | CR (%) | PR (%) | SD (%) | PD (%) | Median PFS mos (range) | Median OS mos (range) | |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Schwartz 1989 (8) | Prospective Randomized | 49 | 0 | 10mg BID only to ER positive patients | Cisplatin 50mg/m2 and doxorubicin 50mgm2 | NA | NA | NA | NA | NA | 30.6 |
| Millward 1992 (32) | Phase II | 11 | NA | 160mg BID for 6 days | Etoposide (dose NA) on days 4,5,6. | 0 | 1(9.0) | 3(27.2) | 7(63.6) | NA | NA |
| Benedetti Panici 2001 (33) | Phase II | 50 | Majority 1 prior, but 2 or more also included | 80mg QD for 30 days f/b 40mg QD | 100mg/m2 cisplatin or 400mg/m2 carboplatin q21 days | 15(30.0) | 10(20.0) | 12(24.0) | 13(26.0) | 8.5 (3-42) | 23 (3-48) measurable disease 19 platinum resistant 20 |
| Markman 2004 (7) | Retrospective | 14 | 80mg QD for first cycle then reduced to 40mg QD | Carboplatin AUC 5 q21 days | 0 | 0 | NA | NA | 2 (1-5) | NA | |
| Wagner 2007 (34) | Phase II | 49 | 2 (2-8) | 40mg QD | Gefitinib 500mg PO QD | 0 | 0 | 16 (28.6) | 33 (58.9) | 2 | 8.4 |
CR: complete response; PR: partial response; SD: stable disease; PD: progressive disease; PFS: progression free survival; OS: overall survival; ER: estrogen receptor; NA: data not available in this study; f/b: followed by.
Table 4.
Review of the published literature on the use of aromatase inhibitors in epithelial ovarian cancer
| Paper and year | N | Median number of previous regimens | Letrozole or anastrozole dose | CR (%) | PR (%) | SD (%) | PD (%) | Median PFS mos (range) | Median OS mos (range) | Comments | |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Bowman 2002 (9) | Phase II | 50 | Majority 1, but 2, 3-5 also included | Letrozole 2.5mg QD | 0 | 0 | 10(20.0) | 40(80.0) | 8.8 | 14(1-35) | |
| Papadimitriou 2004 (10) | Phase II | 27 | Majority 1, but 2, and 3 or more also included | Letrozole 2.5mg QD | 1(4) | 3(11.1) | 5(18.5) | 18(66.6) | 2.6(1.2-33.6) | 26.7(2.4-44.2) | |
| Smyth 2007 (35) | Phase II | 42 | Majority 1, but 2 and 3 or more also included | Letrozole 2.5mg QD | 0 | 3(7.1) | 14(42) | NA | NA | NA | ER positive patients only |
| del Carmen 2003 (36) | Phase II | 53 | NA | Anastrozole 1mg QD | 0 | 1 | 42 | NA | 2.8 | NA |
CR: complete response; PR: partial response; SD: stable disease; PD: progressive disease; PFS: progression free survival; OS: overall survival; ER: estrogen receptor; NA: data not available in this study.
Footnotes
Conflict of interest We declare no conflicts
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