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Clinical Cancer Research Vol. 10, 6080-6085, September 15, 2004
© 2004 American Association for Cancer Research

Clinical Trials

Sequential Intraperitoneal Topotecan and Oral Etoposide Chemotherapy in Recurrent Platinum-Resistant Ovarian Carcinoma

Results of a Phase II Trial

Anil K. Sood1, Richard Lush2, John P. Geisler3, Mark S. Shahin3, Linda Sanders3, Dan Sullivan2, Richard E. Buller3 and Joel I. Sorosky3

1 Department of Gynecologic Oncology, University of Texas, M. D. Anderson Cancer Center, Houston, Texas; 2 H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida; and 3 Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics, Iowa City, Iowa


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Purpose: The purpose is to investigate the safety and efficacy of i.p. topotecan and oral etoposide as salvage treatment for patients with platinum-resistant ovarian or primary peritoneal cancer.

Experimental Design: Patients were treated with i.p. topotecan initial dose, 1 mg/m2 on days 1 to 5, followed by oral etoposide 100 mg on days 6 to 9 of a 28-day cycle for six cycles. Dose reduction of topotecan was used for severe bone marrow suppression. Peritoneal (topotecan) and plasma (topotecan and etoposide) levels were assessed at multiple time points using high-pressure liquid chromatography.

Results: Twenty-two patients (mean age, 61 years) with a median of 1.5 prior treatments were enrolled. Etoposide peak plasma concentrations ranged from 1.9 to 6.9 µg/mL (mean, 3.6 µg/mL). Topotecan plasma levels rose with increasing peritoneal concentration and were detectable within 1 hour but tended to decrease rapidly to below detectable levels within 24 hours. The peak plasma concentration of topotecan was 12.82 ± 8.55 µg/mL with a plasma half-life of 6.17 ± 2.75 hours. A total of 104 cycles was administered; 14 patients (64%) completed all six planned cycles. All patients were evaluable for toxicity, and 21 patients were evaluable for response. The most common grade 4 toxicities were neutropenia and thrombocytopenia in eight and four patients (36 and 18%), respectively. There were no treatment-related deaths. The overall response rate was 38% [complete response, three (14%); partial response, five (24%)]. Seven patients had stable disease and six progressed while on treatment.

Conclusions: The combination of i.p. topotecan and oral etoposide is an active and well-tolerated regimen in platinum-resistant ovarian carcinoma. Additional studies investigating topotecan in combination with etoposide are warranted.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Ovarian cancer remains the most common cause of death from gynecologic malignancies. Most patients present with advanced-stage disease and are usually treated with cytoreductive surgery followed by paclitaxel- and platinum-based chemotherapy (1) . The majority of newly diagnosed patients respond to first-line chemotherapy. However, despite the initial surgical and chemotherapy treatments, most patients develop recurrent disease, and long-term survival rates remain dismal. Several agents have demonstrated activity after failure of paclitaxel-containing regimens (2, 3, 4) . However, response rates are only in the 10 to 30% range and have generally been of modest duration. Typically, response rates are even lower for those who are refractory to front-line chemotherapy or who develop recurrent disease within 6 months of completing chemotherapy. In this setting, chemotherapeutic agents with novel mechanisms of action or better combinations are needed.

Topotecan, a water-soluble semisynthetic analogue of the alkaloid antitumor agent camptothecin, is a topoisomerase I inhibitor that was first isolated from Camptotheca acuminata, a deciduous tree in South China (5) . Phase I studies determined a maximum-tolerated dose of 1.5 mg/m2/day administered as a 30-minute i.v. infusion on days 1 through 5 of a 21-day cycle (6) . Intravenous topotecan administered with the 5-day regimen is currently approved for the treatment of patients with relapsed ovarian cancer. There are limited data on the use of i.p. topotecan. Plaxe et al. (7) treated 17 patients with recurrent ovarian cancer with i.p. topotecan and reported a substantial increase in drug exposure for the peritoneal cavity without compromising systemic exposure. Similarly, Hofstra et al. (8) reported that i.p. topotecan was well tolerated with a mean peritoneal/plasma area under the curve (AUC) ratio of 54 for total topotecan.

Etoposide is a semisynthetic derivative of the podophyllotoxins. The antitumor activity of single-agent etoposide in patients with relapsed ovarian cancer has been investigated in several small phase II studies. The largest and most recent trial by Rose et al. (3) demonstrated that oral etoposide (50 mg/m2/day) has antitumor activity in both platinum-sensitive and -resistant patients. However, single-agent etoposide is not yet approved for the treatment of patients with relapsed ovarian cancer. Additional studies are investigating the use of oral etoposide in combination with other agents in this patient population.

Topoisomerases are classified on the basis of their mechanism of action—topoisomerase I breaks one strand of double-stranded DNA, allowing the remaining intact strand to pass through the break, thereby affecting DNA relaxation. Topoisomerase II catalyzes transient double-strand breaks and the passage of double-stranded DNA in an ATP-dependent reaction (9 , 10) . It has been suggested that sequential topoisomerase I and topoisomerase II inhibition may be the optimal combination of these agents. Whitacre et al. (11) used an in vivo colon cancer model to demonstrate that inhibition of topoisomerase I resulted in a compensatory increase in topoisomerase II{alpha} levels, which rendered the xenografts more sensitive to subsequent etoposide exposure. The sequential regimen was associated with the best tumor response compared with simultaneous administration of topotecan and etoposide or etoposide injection administered 5 days after the last dose of topotecan.

On the basis of the available preclinical data regarding sequential treatment with topoisomerase inhibitors, we conducted a single-center, open-label, noncomparative study to characterize the tolerability and efficacy of sequential i.p. topotecan followed by etoposide.


   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Eligibility.
This protocol was reviewed by the Institutional Review Board at the University of Iowa and received written unconditional approval before enrolling patients. An informed consent form was reviewed by all patients, discussed with their physicians, and signed before initiating treatment. Eligibility requirements for patients entering this study included having progressive disease during or within 6 months of being treated with platinum-based chemotherapy and having more than or equal to one lesion that was bidimensionally measurable by computed tomography, magnetic resonance imaging, ultrasound, radiograph, or physical examination. Other inclusion criteria included ≥4 weeks since prior surgery, hormonal therapy, radiotherapy, or chemotherapy; age ≥ 18 years; life expectancy of >6 months; Gynecologic Oncology Group performance status of ≤2; adequate bone marrow function (absolute neutrophil count > 1.5 x 109 cells/L, platelets > 100 x 109/L); normal liver function (total bilirubin ≤ 2 and aspartate and alanine aminotransferase < 3x the upper limit of normal); and normal renal function (creatinine/blood, urea, nitrogen < 3x the upper limit of normal). Patients with uncontrolled infection, history of HIV, prior abdominal radiation, prior treatment with topoisomerase inhibitors, or more than two prior chemotherapy regimens were not eligible for the study.

Treatment Schedule.
An i.p. catheter was inserted before initiating treatment on the protocol. Intraperitoneal topotecan (1 mg/m2) was administered over 30 minutes on days 1 through 5, and oral etoposide (100 mg) was administered on days 6 through 9 of a 28-day cycle. Treatment was repeated for a total of six cycles if the following criteria were met: hemoglobin ≥ 9 g/dL (transfusion allowed as needed); neutrophils ≥ 1.5 x 109 cells/L; and platelets ≥ 100 x 109/L.

A dose reduction of topotecan in a 0.25-mg/m2/day increment was required if any of the following toxicities occurred: grade 4 neutropenia, more than or equal to grade 3 thrombocytopenia or gastrointestinal toxicity, or more than or equal to grade 3 of any other toxicity, except anemia or alopecia. The minimum allowed topotecan dose was 0.75 mg/m2/day, and if there was more than a 3-week delay at this dose level, the patient was withdrawn from the protocol. Dose escalation of i.p. topotecan in 0.25 mg/m2/day increments was allowed for the next course if the patient had no toxicity more than grade 1 during the previous course. The maximum allowed topotecan dose was 1.5 mg/m2/day.

Patients continued with therapy until completing 6 cycles, experiencing disease progression, or toxicity occurred, as listed above. Patients with a complete or partial response (CR or PR) were allowed to continue with treatment at the discretion of the investigator until disease progression.

Drug Assay.
Plasma samples for etoposide were obtained before dosing and at 1, 2, 4, and 24 hours after a dose. The samples were immediately placed on ice and then centrifuged at 5000 rpm for 3 minutes at 4°C. The plasma was transferred to two microfuge tubes and frozen at –80°C until analysis. Etoposide levels were measured using high-performance liquid chromatography as described previously (12 , 13) .

Plasma samples for topotecan were obtained before chemotherapy administration and at 0.5, 1.0, 1.5, 3.5, 5.5, and 23.5 hours from the end of the infusion. Topotecan peritoneal fluid levels were obtained at the end of the 30-minute i.p. infusion and at 1.0, 3.5, and 23.5 hours from the end of the infusion. Additionally, a single blood and peritoneal fluid level of topotecan was obtained on days 3 and 5, immediately before starting the i.p. topotecan on those days. The samples were immediately placed on ice and then centrifuged at 5000 rpm for 3 minutes at 4°C. Separate duplicate aliquots of these samples were prepared with either acidified methanol or pure methanol and stored at –80°C until analysis. Topotecan total plasma concentrations were measured with a modified isocratic high-performance liquid chromatography assay using fluorescence detection (14 , 15) . Topotecan total concentrations were measured by adding 20 µL of 20% phosphoric acid to 400 µL of the methanolic solution. Excitation and emission wavelengths were 320 and 540 nm, respectively, and the retention time for topotecan was 7 minutes. The lower limit of quantitation was 0.5 ng/mL.

Pharmacokinetic Analysis.
The pharmacokinetic analysis of topotecan was performed using maximum a posteriori Bayesian estimation in ADAPT II pharmacokinetic and pharmacodynamic systems analysis software (16) . A two-compartment linear model was fit to topotecan total-plasma concentration-time data, and population priors were obtained from Zamboni et al. (17) Individual parameters were used to estimate the central volume of distribution and distributional and total body clearance. The i.p. dose of topotecan administered to the patient was bloused into a separate compartment and allowed to absorb into the central compartment. The AUC for etoposide was estimated using the limited sampling method as described by Gentili et al. (13) . Estimates for the etoposide terminal and elimination rate were obtained using the 6- and 24-hour plasma concentration. The AUC0-inf was interpolated to infinity using standard methods. Estimates for the apparent oral etoposide clearance were obtained by dividing the administered dose by the estimated AUC.

Safety Assessment.
Before each cycle of chemotherapy, a complete blood count with differential, platelet count, serum electrolytes, liver function tests, serum creatinine, and cancer antigen 125 was obtained for each patient. Complete blood cell counts with differentials and platelets were also evaluated weekly. Patients who received one or more courses of chemotherapy were considered evaluable for adverse effects regardless of subsequent survival. All toxicity was assessed before each cycle and graded according to the National Cancer Institute Common Toxicity Criteria (18) .

Efficacy Assessment.
Patients who received one or more cycles of chemotherapy and lived for ≥4 weeks were considered evaluable for response. Tumor measurements were repeated before cycles 3 and 5 and 4 weeks after completing treatment. Response was classified as follows: complete response is the disappearance of all gross evidence of disease for ≥4 weeks; partial response is ≥50% reduction in the bidimensional tumor measurement; progressive disease is a ≥50% increase or the appearance of any new lesions; and stable disease is any condition not meeting the above criteria.

Time to response and time to progression were measured in weeks from the first dose of chemotherapy to a documented response (complete response or partial response) or to documented progression. Duration of response was measured from the time of initial documented response to the first evidence of disease progression. Survival was measured from the first dose of chemotherapy on this regimen to death. Follow-up data were obtained every 3 months from the date of withdrawal to assess response duration and time to progression for patients who had not progressed before withdrawal and to assess survival for all patients.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient Baseline Characteristics and Disposition.
A total of 22 patients was enrolled in this trial, and all patients were evaluable for toxicity (Table 1)Citation . Twenty-one patients were evaluable for response. One patient dropped out of the study after one cycle because of excessive fatigue. All patients had received prior first-line therapy containing platinum and paclitaxel. Three patients also received recombinant adenoviral p53 gene replacement therapy (SCH58500) in conjunction with primary chemotherapy (19) . Six patients had received gemcitabine as prior second-line chemotherapy, and 3 patients had been treated with oregovomab before enrolling in this protocol. Fourteen patients had platinum-resistant disease (developed recurrent disease within 6 months of completing primary therapy), and 8 patients had platinum-refractory disease (no response to first-line platinum-based regimen). A total of 104 cycles of chemotherapy was administered to 22 patients, and 14 patients completed all 6 cycles of chemotherapy. The mean number of cycles per patient was 4.7 (range, 1 to 6 cycles). The chemotherapy dose was escalated after cycle 1 as planned in 10 patients. Three patients required dose reductions. Delays beyond day 28 were experienced by 6 patients (27%) and occurred in 21 cycles (20%). Complete follow-up data were available for all patients on this protocol.


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  		Table 1 Patient demographics and baseline disease characteristics

 
Pharmacokinetics.
Pharmacokinetics was assessed in all 22 patients, but only 17 data sets contained sufficient data to provide reliable pharmacokinetic parameter estimates (Table 2)Citation . Three patients who had received gene therapy were excluded because of turbid ascites, fibrotic tissue, and substantially lower peritoneal permeability, similar to the effects of radiation therapy. Two patients did not have enough data points to be included in the analysis. Etoposide peak-plasma concentrations ranged from 1.9 to 6.9 µg/mL (mean, 3.6 µg/mL). Topotecan was detectable in the plasma within 1 hour of peritoneal instillation. At 1 hour, the mean ratio of peritoneal to plasma topotecan concentration was 92 (range, 15 to 430). Plasma topotecan concentrations rose with increasing peritoneal concentrations but tended to decrease rapidly. The mean peak plasma concentration of topotecan was 12.82 ± 8.55 µg/mL, with a half-life of 6.17 ± 2.75 hours. Most plasma samples obtained 23 hours after dosing contained undetectable amounts of topotecan (<0.5 ng/mL). The mean ± SD pharmacokinetic parameter estimates for etoposide half-life, AUC, and clearance were 7.84 ± 2.32 hours, 37.40 ± 2.86 mg x hour/L, and 2.69 ± 0.19 L/hour, respectively.


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  		Table 2 Serum pharmacokinetics parameters of i.p. topotecan (N = 17)

 
Hematologic Toxicity.
The frequency of hematologic toxicity in patients and number of cycles are reported in Table 3Citation . The most common severe (grade 4) hematologic toxicity was neutropenia, which occurred in 36% of patients and in 14% of chemotherapy cycles. Grade 3 or 4 neutropenia occurred in 68% of patients and in 34% of chemotherapy cycles. Febrile neutropenia requiring hospital admission was experienced by four patients (18%) and complicated six (6%) of the chemotherapy cycles administered. Granulocyte-colony stimulating factor was used in four patients (18%) during 15 cycles (14%). Grade 3 or 4 thrombocytopenia was detected in 36% of patients and occurred during 14% of the chemotherapy cycles. Two (9%) patients required platelet transfusions during two cycles (2%). Grade 3 or 4 anemia was detected in 45% of patients and occurred in 12% of all chemotherapy cycles. Red blood cell transfusions were administered to six patients (27%) during 10 cycles (10%). There were no treatment-related deaths on this protocol.


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  		Table 3 Hematologic toxicity

 
Nonhematologic Toxicity.
Nonhematologic adverse events of any grade were reported in 19 patients (86%) in 85 of 104 cycles (82%) of chemotherapy (Table 4)Citation . The most common nonhematologic toxicity was nausea, which occurred in 68% of patients and in 54% of cycles; however, most patients had only grade 1 or 2 nausea, which was controllable with antiemetics. Twenty-three percent and 9% of patients experienced grades 1/2 and 3 vomiting, respectively. Diarrhea was infrequent and mild on this regimen. Sixty-eight percent of patients complained of fatigue during 47% of the cycles; however, most patients had only grade 1 or 2 symptoms.


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  		Table 4 Nonhematologic toxicity

 
The safety of the sequential intraperitoneal topotecan and oral etoposide regimen is further supported by surgical evidence. Two patients underwent an exploratory laparotomy remote from the administration of i.p. topotecan, and minimal adhesions were found. There was no clinical evidence of chemical peritonitis during or after i.p. topotecan.

Antitumor Activity.
Twenty-one patients were considered evaluable for response. The overall response rate for patients treated on this protocol was 38%, including three (14%) patients with a complete response and five patients (24%) with a partial response (Table 5)Citation . Seven patients (33%) had stable disease on chemotherapy and six progressed while on treatment. Among patients with platinum-resistant disease, the overall response rate was 46% compared with 25% for those with platinum-refractory disease. The mean duration of response in the eight patients with a complete response or partial response was 43.2 weeks (range, 18.2 to 73.8 weeks). The mean time to response was 12 weeks (range, 8 to 16 weeks).


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  		Table 5 Antitumor response

 
At the time of analysis, 15 patients had died from recurrent or persistent disease. The mean survival after starting treatment on this regimen for all patients was 66.1 weeks (median, 54.8 weeks) based on Kaplan-Meier analysis (Fig. 1)Citation .



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  		Fig. 1. Overall survival in patients with relapsed ovarian cancer treated with i.p. topotecan and oral etoposide. Kaplan-Meier estimate of overall survival for all patients.

 

   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Advanced epithelial ovarian cancer is a highly chemosensitive tumor with response rates of 70 to 80% to first-line chemotherapy (20, 21, 22, 23) . However, most patients eventually develop recurrent disease and die of disease progression (1 , 24) . Emergence of chemotherapy resistance is a significant clinical problem in the treatment of patients with ovarian cancer. Response rates of most chemotherapy agents after developing platinum resistance remain unacceptable, and novel combinations or therapeutic drugs are needed (25) .

Both topoisomerase I and II inhibitors have activity as single agents in patients with ovarian cancer (3 , 26 , 27) . In a randomized phase III study in the second-line setting, topotecan produced an overall response rate of 21% and was active in patients with platinum-resistant or -refractory disease (28) . In patients with platinum- and paclitaxel-resistant ovarian carcinoma, topotecan produced a 14% response rate (27) . In a recent phase III study, Gordon et al. (29) reported overall response rates of 31% for patients with platinum-sensitive disease, 18% for patients with platinum-resistant disease, and 8.8% for platinum-refractory disease. Single-agent etoposide is also active in the second-line treatment of platinum-sensitive and platinum-resistant ovarian cancer (3 , 30) . In phase II testing, prolonged oral etoposide produced overall response rates of 34% in patients with platinum-sensitive disease and 27% in patients with platinum-resistant disease (3) . Likewise, Kuhn et al. (30) reported an overall response rate of 22% in both platinum-sensitive and platinum-resistant patients.

Topotecan and etoposide target the two major classes of enzymes involved in regulating DNA topology within the cell; therefore, their combination could be highly active. In preclinical studies of these agents, drug schedule and sequence were critical determinants of antitumor activity (11 , 31) . Combination of topotecan with a topoisomerase II inhibitor produced maximal cytotoxicity with prolonged exposure to topotecan (32) . Therefore, Hammond et al. (33) treated 50 patients with solid neoplasms with topotecan via 72-hour continuous infusion on days 1 through 3, followed by etoposide on days 8 through 10. Responses were seen in only three patients. However, the length of topotecan exposure and the timing between treatments might not have been optimal. Indeed, the studies of Whitacre et al. (11) in a human cancer xenograft mouse model suggest that the treatment interval between topotecan and etoposide critically affects antitumor activity. Simultaneous drug administration resulted in cytotoxic antagonism. However, pretreatment with topotecan inhibited topoisomerase I, resulting in a compensatory increase in intratumoral topoisomerase II{alpha} and potentiation of the antitumor effect of subsequent etoposide treatment. Five days after the last dose of topotecan, topoisomerase II{alpha} levels declined and the original responsiveness of the xenograft to etoposide was restored.

Increasing dose intensity does not appear to lead to improved response rates with i.v. topotecan (34) , but increasing the duration of exposure to >24 hours appears to have higher efficacy in ovarian cancer (35 , 36) . Prolonged topotecan exposure is achieved with the standard 5-day i.v. regimen, which is associated with noncumulative and reversible hematologic toxicity. However, the tolerability of this regimen may be lower in patients with poor performance status, advanced age, or comorbidities. Alternative dosing regimens and pathways of administration that have better tolerability while maintaining prolonged exposure have been investigated (7 , 8 , 26 , 37 , 38) . In two phase I, pharmacokinetic studies (7 , 8) , i.p. instillation allowed for prolonged exposure to topotecan with reduced hematologic toxicity. The only grade 4 toxicities, leukopenia and neutropenia, occurred in <10 and <15% of all treatment cycles, respectively. This is consistent with studies of i.p. administration of other cytotoxic agents (39) .

In the current study, i.p. topotecan was well tolerated and active. The hematologic toxicity of i.p. topotecan compared favorably with that of single-agent topotecan administered via 24-hour i.v. infusion (36) . With continuous-infusion topotecan, grade 4 neutropenia occurred in 86% of patients, compared with only 36% in this trial. Furthermore, consistent with the profile of i.v. topotecan, nonhematologic toxicities associated with intraperitoneal topotecan were generally mild and manageable with supportive care. There was no clinical evidence of chemical peritonitis in our study, which is consistent with other reports of i.p. topotecan administration (7) .

We used i.p. delivery because of its potential to increase the duration of drug exposure and lower toxicity (7) . Indeed, the pharmacokinetic parameters of i.p. topotecan in this combination therapy trial were consistent with those reported in earlier studies where i.p. instillation increased the apparent availability of active plasma topotecan (7 , 8) . In turn, topotecan may have potentiated the antitumor activity of the subsequent etoposide treatment. Indeed, the overall response rate in this trial that enrolled patients with platinum-resistant or -refractory ovarian cancer was 38%, compared with the reported response rate of only 7% for 24-hour continuous-infusion topotecan in patients with platinum-sensitive disease (36) . An alternative for combining these two drugs might include a lower dose of systemically delivered topotecan.

In summary, the sequential combination of i.p. topotecan and oral etoposide is an active regimen in patients with platinum-resistant ovarian carcinoma.


   FOOTNOTES
 
Grant support: A grant from GlaxoSmithKline and NIH Grant CA82533.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: R. Buller is currently at GlaxoSmithKline, Collegeville, Pennsylvania.

Requests for reprints: Anil K. Sood, Department of Gynecologic Oncology, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 440, Houston, TX 77030. Phone: (713) 745-5266; Fax: (713) 792-7586; E-mail: asood{at}mdanderson.org

Received 3/25/04; revised 4/30/04; accepted 5/17/04.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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M. T. Tomicic, M. Christmann, and B. Kaina
Topotecan-Triggered Degradation of Topoisomerase I Is p53-Dependent and Impacts Cell Survival
Cancer Res., October 1, 2005; 65(19): 8920 - 8926.
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