Topotecan in Platinum- and Paclitaxel-Resistant Ovarian Cancer

GYNECOLOGIC ONCOLOGY ARTICLE NO.

66, 480–486 (1997)

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Topotecan in Platinum- and Paclitaxel-Resistant Ovarian Cancer1 Elizabeth M. Swisher, M.D., David G. Mutch, M.D., Janet S. Rader, M.D., Alaa Elbendary, M.D., and Thomas J. Herzog, M.D. Washington University School of Medicine, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, St. Louis, Missouri 63110 Received March 18, 1997

Objective: The purpose of this study was to define the response rate and toxicity of topotecan in patients with ovarian cancer resistant to first-line therapy. Methods: Twenty patients with advanced or recurrent ovarian cancer were enrolled in a phase I/II protocol, and an additional 16 patients were treated following protocol closure at Washington University Medical Center. The starting dose of topotecan was 1.25 mg/m2/day given intravenously over 30 min for 5 consecutive days. Patients were eligible for response evaluation if they completed more than one cycle of topotecan. All patients were evaluated for toxicity. Results: Of 28 patients eligible for response evaluation, 26 were resistant to both platinum and paclitaxel prior to treatment with topotecan. There were four partial responders and no complete responders for a total response rate of 14% (95% confidence interval: 4 to 33%). All responders had exhibited primary resistance to both platinum and paclitaxel. Myelotoxicity was the major toxicity, with 92% of patients experiencing Gynecologic Oncology Group (GOG) grade 3 or 4 neutropenia and 67% experiencing GOG grade 3 or 4 thrombocytopenia. Other toxicity was minimal and easily managed. Fifty percent of patients receiving more than one cycle of topotecan tolerated a dose equal or greater to the starting dose. Conclusions: Topotecan exhibits activity in patients with ovarian cancer resistant to both platinum and paclitaxel. Further study is warranted in less heavily pretreated patients and in combination with other chemotherapeutic agents. q 1997 Academic Press

INTRODUCTION

Ovarian cancer has the highest mortality rate among gynecologic malignancies in developed countries. Most women present with advanced disease and require a combination of surgery and chemotherapy. The combination of a platinum compound with paclitaxel became common first-line chemotherapy for ovarian cancer following a phase III study demonstrating that paclitaxel and cisplatin increased progressionfree and overall survival compared to cisplatin and cyclo1 SmithKline Beecham, Inc., provided full financial support for treatment of the 20 protocol patients and provided topotecan without charge on a compassionate use basis to the other 16 patients included in this study.

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MATERIALS AND METHODS

A total of 36 patients with persistent or recurrent epithelial ovarian cancer were begun on topotecan treatment between February 1995 and October 1996 at Washington University Medical Center. The first 20 patients were enrolled in a phase I/II protocol to evaluate the toxicity and

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phosphamide in stage IV and suboptimally resected stage III patients [1]. While response rates are high (60 to 80%), most women ultimately recur and require further treatment [2]. In patients with platinum-sensitive disease, retreatment with platinum offers a 30 to 70% response rate, which improves with increased length of time since last treatment [3]. Most patients eventually develop platinum resistance, and salvage chemotherapy in this group is much less effective than first-line therapy [4]. A subset of ovarian cancer patients have recurrent or persistent disease that is resistant to paclitaxel as well as to platinum. Rates of response to salvage chemotherapy in this group are unknown. Chemotherapeutics with novel mechanisms of action are attractive agents to test against these multiply resistant tumors. The DNA topoisomerase I inhibitors derived from camptothecin represent a unique class of chemotherapeutic agents with the potential for a different spectrum of activity. Camptothecin, a derivative of the Chinese tree Camptotheca acuminata, was discovered in the 1950’s. Despite some promising responses, early trials were abandoned because of severe and unpredictable toxicity consisting of myelosuppression, diarrhea, and hemorrhagic cystitis [5, 6]. Topotecan is a water-soluble analog of camptothecin with better bioavailability and less gastrointestinal toxicity. Phase I studies of topotecan have demonstrated acceptable toxicity and activity in a diverse group of human tumors including acute leukemia, small cell lung, non-small cell lung, esophageal, and colorectal cancer as well as ovarian cancer [5, 7, 8]. This report details our experience with the efficacy and toxicity of a 5-day infusion of topotecan at Washington University in 36 patients with ovarian cancer resistant to both platinum and paclitaxel.

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the response rate of topotecan in patients with solid tumors refractory to standard therapies. The institutional review board of the cancer center at Washington University had approved the protocol, and all patients gave informed consent prior to participation. An additional 16 patients received topotecan following protocol closure on a compassionate use basis or after FDA approval of topotecan for refractory ovarian cancer in May 1996. All patients had persistent or recurrent ovarian cancer with measurable disease and/or an elevated serum CA-125 level. Additional treatment criteria used for all patients included a greater than 4-week interval from last chemotherapy treatment or surgery, white blood cell (WBC) count greater than 3500/mm3, granulocyte count greater or equal to 1500/mm3, platelet count greater or equal to 100,000/mm3, creatinine less than or equal to 1.5 mg/dL, serum bilirubin less than or equal to 2.0 mg/dL, serum SGOT, SGPT, and alkaline phosphatase less than or equal to two times the upper limit of normal if liver metastases were absent or less than or equal to five times the upper limit of normal if liver metastases were present by computed tomography. Only protocol patients were required to have an Eastern Cooperative Oncology Group performance status less than or equal to 2. Platinum resistance was defined as an incomplete response to treatment with a platinum compound, progression of disease while on treatment with a platinum compound, or relapse within 6 months of treatment. Primary platinum resistance was defined as those patients who demonstrated platinum resistance in their initial treatment with a platinum compound. Resistance to paclitaxel was similarly defined. Topotecan was administered as an intravenous infusion at an initial dose of 1.25 mg/m2/day over 30 min for 5 sequential days and was repeated every 21 days. The initial two infusions were given at Washington University Medical Center and, if well tolerated, the remaining infusions were given at home with nursing assistance. Patients had complete blood counts weekly and complete chemistry panels every 3 weeks. Blood counts were repeated every other day for grade 3 or 4 toxicity. Toxicity was graded by standard Gynecologic Oncology Group (GOG) criteria. The dose was reduced by 0.25 mg/m2/day for grade 4 neutropenia associated with a fever or infection or lasting greater than 7 days, absolute neutrophil count less than 1000/mm 3 lasting beyond Day 21 of the treatment regimen, platelet count below 25,000/mm3, or other grade 3 or 4 toxicity (excluding grade 3 nausea). Following one dose reduction, granulocyte colony stimulating factor (GCSF) could be administered, if needed, to avoid a second dose reduction. Chemotherapy was delayed if the platelet count was less than 100,000/mm3 or if the granulocyte count was less than 1500/mm3. Topotecan could be continued in patients with a response or stable disease until demonstration of progression. All patients had serum CA-125 measurements prior to

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each cycle. Patients on protocol underwent pertinent radiological studies for evaluation of tumor response after every second cycle. The patients treated outside protocol had other diagnostic studies at the discretion of the treating physician. Patients had to complete at least two cycles of topotecan to be considered eligible for response evaluation. In patients with measurable disease the following definitions were used: a complete response (CR) was disappearance of all measurable disease for at least 4 weeks, a partial response (PR) was a greater than or equal to 50% reduction in the product of the perpendicular diameters of all lesions without appearance of new lesions, progressive disease (PD) consisted of a greater than or equal to 50% increase in the product of the perpendicular diameters of the tumor lesions or the appearance of new lesions, and stable disease (SD) was a less than PR without progressive disease for at least 3 weeks. For patients with nonmeasurable disease, a partial response was defined by the criteria established by Rustin et al. [9, 10]: a 50% decrease in the CA-125 level in two samples, confirmed by a fourth sample, or a 75% decrease in serum125 over three samples. In both cases the final sample must be at least 28 days after the first. Progressive disease was defined as increasing CA-125 over three samples with concomitant increasing disease-related symptoms or an increase in CA-125 over four samples without a change in symptoms. Duration of response was measured from the time of maximal response until disease progression. Progression-free interval was measured from initiation of topotecan until disease progression. Survival was measured from the time of initiation of topotecan treatment to death. Statistical analysis consisted of life table analysis using the Kaplan–Meier method. Ninety-five percent confidence intervals (CI) were defined in standard fashion. RESULTS

The 36 women were treated with a median of three cycles of topotecan (range 1 to 20). Follow-up was available on all patients. Eight patients received only one course and were ineligible for response data. Six of these eight died before receiving a second course, one postponed treatment to receive intracavitary radiation, and one had severe and prolonged hematological toxicity and was changed to another chemotherapy agent. These eight patients were included in toxicity evaluation and survival data. A total of 143 cycles of topotecan were given. A summary of clinical characteristics is given in Table 1. The median age at treatment was 59.5 years (range 42 to 74) and median performance status was 0 (range 0 to 3). Twenty-eight patients (80%) had tumors of papillary serous histology and 20 (62.5%) were histologic grade 3. Twenty-nine patients (80.5%) had stage III disease, and all were surgically staged. Twenty-two patients (62.8%) were optimally debulked to less than 2 cm residual volume, and 13 were suboptimally debulked at initial surgery.

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TABLE 1 Patient Characteristics No. with measurable disease No. with nonmeasurable disease Age Median Range FIGO stage I II III IV Histology Papillary serous Endometrioid Clear cell Undifferentiated Unspecified Initial tumor grade Low malignant potential 1 2 3 Unspecified Primary surgery Optimally debulked Suboptimally debulked Unspecified Performance status 0 1 2 3

31 5 59.5 42–74 1 5 29 1 28 3 2 2 1 1 1 10 20 4 22 13 1 19 8 8 1

Twenty-three of the 28 assessable patients had measurable disease, and the remaining five had elevated CA-125 levels. Table 2 summarizes the previous chemotherapeutic treatment of assessable patients. The median number of prior courses of chemotherapy was 3 (range 1 to 7). All patients had received both paclitaxel and a platinum compound during previous treatment, and all patients had received platinum as a component of their first chemotherapy regimen. The median treatment-free interval was 2.0 months (range 1 to 14). Three patients had treatment-free intervals longer than 6 months (9, 10, and 14 months); 2 had evidence of disease progression within 6 months of completing their last chemotherapy course but postponed further treatment for personal reasons. The patient with a treatment-free interval of 14 months had been last treated with palliative radiotherapy and exhibited a prolonged response before progressing. Of 28 assessable patients, 27 were platinum-resistant at the time of topotecan treatment and 26 were paclitaxel-resistant. The tumors from these patients had exhibited primary platinum sensitivity in 12 cases and primary platinum resistance in 16 cases. One patient was potentially platinumsensitive but declined retreatment with a platinum compound following a severe allergic reaction to carboplatin. This same

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patient was also one of the two paclitaxel-sensitive patients. Regarding response to their first chemotherapy, 17 patients (60.7%) achieved a clinical CR. Five of these had secondlook laparotomies; one of which was negative and four of which were positive for pathologic evidence of disease. Six patients (21.4%) had a PR, while three (10.7%) had SD, and two (7.1%) had PD with their first course of chemotherapy. The major toxicity with topotecan treatment was myelosuppression and the majority of patients exhibited grade 3 or 4 neutropenia and/or thrombocytopenia. Hematological toxicity is summarized in Fig. 1. Thirty-three (91.6%) patients experienced GOG grade 3 or 4 neutropenia, and 24 (66.7%) experienced GOG grade 3 or 4 thrombocytopenia. The median granulocyte nadir was 1000/mm3 (range 0 to 25,000), and median platelet nadir was 69,000/mm3 (range 3000 to 755,000). The median duration of grade 3 or 4 neutropenia or thrombocytopenia was 5 days (range 1 to 21) and 4 days (range 1 to 19), respectively. Significant anemia was also common; 23 patients (65.7%) experienced GOG grade 3 or 4 anemia, and 32 of 36 patients (88.9%) were transfused with packed red cells at least once during treatment. Myelotoxicity was not cumulative over time, and once a tolerable dose was achieved, further dose adjustment was rarely needed. Febrile neutropenia requiring hospital admission was experienced by 15 patients (41.7%) and complicated 11.8% of the topotecan cycles administered. Four patients had documented bacteremia. Other toxicity was minimal and easily managed. Gastrointestinal side effects were minimal; 8.3% of patients had mild to moderate nausea or vomiting requiring antiemetics. Patients exhibited mucositis (2.7%) and mild diarrhea (3.3%). Mild to moderate fatigue was the most common complaint

TABLE 2 Previous Treatment of Assessable Patients No. of prior chemotherapy regimens Median Range Treatment-free interval Median (months) Range (months) Response to first chemotherapy regimen Complete response Partial response No response Platinum sensitivity Primarily resistant Primarily sensitive Resistant at time of topotecan treatment Sensitive at time of topotecan treatment Paclitaxel sensitivity Primarily resistant Primarily sensitive Resistant at time of topotecan treatment Sensitive at time of topotecan treatment

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3 1–7 2.0 1–14 17 6 5 16 12 27 1 23 5 26 2

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FIG. 1. topotecan.

Graph depicting maximum GOG grade toxicity for thrombocytopenia and for neutropenia experienced by all 36 patients treated with

of 75% of patients and improved only partially with transfusion for anemia. There were no cases of maculopapular puritic exanthema. There was no reported cardiovascular, neurologic, or genitourinary toxicity. One possible treatment-related death occurred in a 68year-old patient referred with progressive persistent stage IIIC disease after having failed both paclitaxel and cisplatin. She received one cycle of topotecan. Within 1 week of initiation of topotecan treatment, she was admitted and hospitalized for 4 days with neutropenic fever. She was discharged with an improving WBC count on GCSF and resolution of fever but expired 4 days later. No autopsy was performed. All treatment delays except one and all dose reductions were secondary to hematological toxicity. Of 28 patients receiving multiple cycles of topotecan, 11 remained on the initial dose of 1.25 mg/m2/day. Three patients tolerated a dose increase to 1.5 mg/m2/day resulting in a total of 14 patients (50%) who were able to tolerate a dose equal to or greater than the target dose of 1.25 mg/m2/day without factor support. Ten patients (35.7%) required a dose reduction to 1.0 mg/m2/day. Four patients (14.3%) required further dose reductions; three received 1.0 mg/m2/day for 4 days, and one received 1.25 mg/m2/day for 3 days. GCSF was used to avoid further dose reductions or treatment delays in eight patients (28.6%). There were 28 patients who received two or more cycles of topotecan and were eligible for response evaluation. Response to topotecan is summarized in Table 3. There were

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no CRs and four PRs for a total response rate of 14.3% (95% CI: 4 to 33%). There were 13 patients (36.1%) with SD and 11 (30.5%) with PD. Of those 23 patients with measurable disease, there were three partial responses (13.0%, 95% CI: 3 to 34%). The one patient with nonmeasurable disease who had a PR to topotecan had a pretreatment CA-125 level of 245 U/ml which decreased to 102 U/ml (58% decrease) after four cycles and was maintained for an additional two cycles before increasing and finally surpassing pretreatment levels after seven cycles. For those with a PR or SD the median progression-free interval was 5 months (range 3 to 20). The median time to response was 3 months. All four patients with a PR had stage IIIC disease and had demonstrated primary platinum and paclitaxel resistance. During their first chemotherapy course, two patients achieved a PR and two patients had a clinical CR but exhibited progressive disease within 1 and 5 months of finishing treatment, respectively. These four patients did not represent any particularly favorable prognostic subgroup (i.e., optimal debulking, lower grade, etc.). One patient with stable disease received 20 cycles of topotecan without progression and elected to discontinue treatment despite minimal toxicity because of the apparent stability of her disease. Three months after discontinuation of topotecan, she manifested progressive disease and was started on vinorelbine chemotherapy. Of 36 patients, 21 are alive with disease and 15 have died

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TABLE 3 Response to Topotecan in 28 Assessable Patients Response duration (months) Response

No. of patients

% of patients

95% CI (%)

CR PR SD PD

0 4 13 11

0 14 46 39

0–10 4–34 27–66 22–59

Progression-free interval (months)

Median

Range

Median

Range

4.5

3–6

7.5 4

4–9 3–17

Note. CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; CI, confidence interval.

of their disease including the one possible treatment-related death. Median survival from initiation of treatment in assessable patients was 6.0 months (range 3 to 23/). Kaplan– Meier life table analysis demonstrates the survival of assessable patients in Fig. 2. Of the 21 living patients, seven remain on topotecan treatment, including one who continues to have a partial response to treatment and six with stable disease. DISCUSSION

Topotecan is a derivative of camptothecin, an inhibitor of topoisomerase I, and is the first of this unique class of chemotherapeutic agents to undergo extensive clinical testing in ovarian cancer. Our patients were heavily pretreated, and nearly all patients had failed both paclitaxel and platinum chemotherapy. The response rate of 14% agrees with the response rates noted in other recent phase II trials of topotecan in refractory ovarian cancer [11, 12]. Both the M.D. Anderson trial [12] and the multicenter European trial [11], however, excluded patients previously exposed to taxanes.

FIG. 2.

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As has been noted in other phase I and II studies of topotecan, the significant and dose-limiting toxicity was myelosuppression, while other toxicity was minimal and easily managed. Neutropenia was common and severe with 60% of patients experiencing grade 4 neutropenia. While GCSF was effective in decreasing the need for further dose reductions, dose escalation will require thrombopoietic factors [13]. The rapid development of anemia, observed in our patients, has been noted in phase I studies and was specific to the 5-day infusion of topotecan [8]. Those patients who experienced minimal myelotoxicity initially with topotecan did not demonstrate cumulative myelosuppression over prolonged courses. We observed no cases of maculopapular pruritic exanthema in contrast to Kudelka et al., who observed a 20% incidence of this toxicity. Fatigue was common, but other nonhematological toxicity was rare. Our patients tolerated home infusion of topotecan in all cases. Due to stratification with resultant small subgroups, analysis of prognostic factors was not possible; however, review of those patients who achieved a PR with topotecan revealed that all responders demonstrated primary resis-

Kaplan–Meier survival curve in months for all 36 patients treated with topotecan.

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tance to both platinum and paclitaxel. This finding suggests that response to topotecan may be independent of platinum and paclitaxel sensitivity. It is reassuring that we found the same response rate in our paclitaxel-resistant patients as that noted in both the M. D. Anderson study (14%) and the European trial (16%), which both excluded patients previously treated with taxanes. Gordon et al. has also reported a 13.4% response rate to topotecan in ovarian cancer after failure of platinum and paclitaxel [14]. The similar response rates between all these trials despite the variation in chemoresistance may be evidence for a lack of cross-resistance between paclitaxel and topotecan. Resistance to topotecan may be mediated via different mechanisms of action than those for paclitaxel and platinum resistance. Indeed, in experiments with human tumor cell lines, expression of the mdr-1 gene, important in taxane resistance, does not seem to be involved in resistance to the camptothecin analogue CPT-11 [15]. Instead, mechanisms unique to CPT-11 pharmacology and topoisomerase I inhibition were identified in CPT-11-resistant cell lines [15 – 17]. Comparisons between salvage chemotherapies in ovarian cancer require a strict definition of the subgroup studied [18]. Many phase II studies of salvage therapy in ovarian cancer have not distinguished platinum exposure from platinum resistance, making interpretation of response rates difficult [19, 20]. We noted a response rate for topotecan of 14% with a short median progression-free interval of 5 months. This response rate and duration is similar to that observed for a number of other agents used as salvage chemotherapy in platinum-resistant ovarian cancer including hexamethylmelamine, ifosfamide, etoposide, and gemcitabine [21–25]. Because paclitaxel is now being used as initial treatment in ovarian cancer, it becomes important to define the activity of salvage chemotherapies in taxane-resistant patients. A recent trial by Fleming et al. [26] noted no responses for continuous infusion etoposide and doxorubicin with bolus cyclophosphamide in 15 patients resistant to platinum and previously treated with taxanes. The response rate of 14% for topotecan may or may not be superior to other salvage therapies whose activity in patients resistant to both paclitaxel and platinum is unknown. A high proportion of patients remained with stable disease, and one patient remained on a prolonged course of topotecan (20 cycles) with an excellent quality of life. The advent of oral therapy of camptothecin analogues, currently in phase I trials, will further facilitate such long-term therapy in patients with stable disease. Topotecan is an active agent in this heavily pretreated group of ovarian cancer patients. The optimal schedule and route for topotecan treatment remain to be defined. The 5day infusion appears to be the most active in phase I studies of those tested, but longer infusions may be more active yet [6]. As topotecan shows activity in platinum- and taxane-

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resistant patients, it may be useful as first-line therapy in combination with these agents. Studies of topotecan in combination with other agents are needed as well as studies in less heavily pretreated patients. ACKNOWLEDGMENTS The authors thank Margeruite Boyd for invaluable assistance and the oncology nurses Judy Parham, Meg Clarke, and Susan Temple for their dedicated patient care and organized data management.

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