Despite initial high response rates to platinum-taxane-containing, first-line chemotherapy, the majority of patients with advanced ovarian carcinoma will develop recurrent disease.1 Many single cytotoxic agents have documented activity in recurrent ovarian carcinoma; however, response rates generally have been low and of short duration because of emerging tumor clones that are resistant to the monotherapy regimen used.2 Combining several anticancer drugs, thus, may circumvent resistance and halt progression.3
Topotecan, a water-soluble semisynthetic analogue of the plant alkaloid camptothecin, has been studied extensively in the treatment of ovarian carcinoma. In recurrent ovarian carcinoma, numerous Phase II studies of topotecan examining different doses, infusion times, drug administration, and schedules have been published that demonstrated response rates ranging from 12% to 33%.4, 5 The U.S. Food and Drug Administration (FDA)-approved dose of topotecan for patients with recurrent ovarian carcinoma (1.5 mg/m2 per day for 5 days every 3 weeks) has been used in randomized trials and in clinical practice.5
Etoposide is a semisynthetic glucosidic derivate of podophyllotoxin.6 The efficacy of intravenous etoposide in recurrent ovarian carcinoma has been studied in Phase II trials, in which the response rate has been on the order of 8–22%.7, 8 Sequential treatment with intravenous topotecan and intravenous etoposide has been evaluated clinically in several tumors, such as small cell lung carcinoma, nonsmall cell lung carcinoma, and leukemia.9, 10 However, severe neutropenia was frequent; furthermore, a schedule of repetitive daily drug infusions and hospital admissions may be inconvenient for many patients. The oral formulation of etoposide may increase patient compliance and quality of life.
The objectives of the current study were to determine the maximum tolerable dose (MTD), toxicity, efficacy, and feasibility of a sequential regimen of fixed-dose topotecan (1.00 mg/m2 per day) and increasing doses of oral etoposide in patients with recurrent ovarian carcinoma.
MATERIALS AND METHODS
This was a multicenter, open-label study that was planned as a Phase I–II study. In the Phase I study, we planned a dose-escalation scheme to identify the MTD, and the planned Phase II dose was determined as one dose level below the MTD. The study protocol and consent form were approved by the Ethics Committees for the participating hospitals and the National Health Authorities in Denmark, Sweden, and Finland, respectively. The study was conducted in accordance with the principles of Good Clinical Practice and the Declaration of Helsinki. Written informed consent to participate in the trial was obtained from each patient. The protocol was activated in March, 2000, and the data base was closed for analyses in January, 2004.
Eligible patients had a histologic diagnosis of epithelial ovarian carcinoma and either 1) treatment failure or recurrent disease < 12 months after platinum-taxane-containing, first-line chemotherapy (primary failure) or 2) treatment failure or recurrent disease > 12 months after platinum-based, first-line chemotherapy and then received taxane-based, second-line chemotherapy and developed recurrent disease again < 12 months after end of the second-line chemotherapy (secondary failure). Inclusion criteria were 1) age 18–75 years; 2) an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2; 3) life expectancy ≥ 3 months; 4) at least 1 tumor lesion measuring ≥ 2 cm in greatest dimension (as defined by imaging methods: computed tomography [CT] scan, magnetic resonance image, ultrasonography, or chest X-ray) or elevated CA125 levels (> 70 U/mL; Phase II study only); 5) adequate bone marrow function (white blood cell count [(WBC] ≥ 3.0 × 109, absolute neutrophil count [ANC] ≥ 1.5 × 109, platelets ≥ 100 × 109, and hemoglobin > 6.0 mmol/L); 6) adequate liver function (alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase levels ≤ 2 times the upper limit of the normal range in patients with no liver metastases and ≤ 3 times the normal range in patients with liver metastases present); 7) adequate renal function (serum creatinine ≤ 150 μ150 μmol/L); 8) no concomitant malignancies with the exception of basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix; and 9) informed consent.
Topotecan (Hycamtin®; SmithKline Beecham) was supplied in vials containing topotecan HCl, equivalent to 4 mg of free base. Inactive ingredients are mannitol (48 mg) and tartaric acid (20 mg). Prior to injection, the drug was reconstituted with 4 mL of sterile water and diluted with 100 mL of sterile water. Etoposide (Vepesid®; Bristol Myers-Squibb) was supplied as soft gelatin capsules of 25 mg, 50 mg, or 100 mg. All patients received topotecan at a dose of 1.00 mg/m2 per day, which was administered intravenously over 30 minutes daily for 5 consecutive days (Days 1–5). Topotecan was followed by oral etoposide using the fixed-interval dose-escalation schedule depicted in Table 1. Treatment was administered in a 28-day schedule.
Table 1. Dose-Escalation Scheme
Toxicities were graded using the National Cancer Institute Expanded Common Toxicity Criteria (CTC).11 The next treatment course began on schedule provided the following criteria were met by Day 28 of the previous treatment course: hemoglobin > 6.0 mmol/L, ANC > 1.5 × 109, and platelets > 100 × 109.
In patients who had inadequate recovery or nonhematologic toxicity CTC Grade ≥ 3 (excluding alopecia), the next treatment course was postponed until the toxicity had resolved for a maximum of 14 days or the patient was withdrawn from the study. Dose-limiting toxicity (DLT) was defined as any of the following events during the first 2 cycles of treatment: 1) Grade 4 neutropenia that lasted > 1 week; 2) either neutropenic fever 38.5 °C that lasted > 24 hours or sepsis, 3) Grade 4 thrombocytopenia that lasted > 1 week, 4) thrombocytopenia with bleeding that required transfusion, or 5) Grade ≥ 3 nonhematologic toxicity (except alopecia).
The MTD was planned as the highest dose that could be administered safely to a patient and that produced tolerable, manageable, and reversible toxicity. The MTD was declared as the highest dose level in which DLT occurred in two or more of six patients during therapy at that dose level. The final MTD was to be defined by the investigators based on clinical judgment.
A conventional dose-escalation design was applied. Three patients were entered at each dose level. Toxicity was assessed after three patients had completed two cycles of treatment. If none of three patients had toxicity, then dose escalation was continued. If one of three patients had DLT, then three more patients were included. If one more instance of DLT was observed at that level (two of six patients overall), then dose escalation was stopped, and the next six patients were treated at the previous dose level. If, at this level, no more than two DLTs occurred in six patients, then this dose level represented the dose recommended for the subsequent Phase II trial using this schedule of administration. Patients were planned to receive subsequent courses of therapy until disease progression or until unacceptable toxicity occurred. For patients with stable disease, six courses would be provided (after stable disease was determined).
The baseline evaluation included a complete medical history, including continuing toxicity from previous chemotherapy. Before each cycle, the following parameters were recorded: complete physical examination, including nonhematologic toxicity, performance status, and blood chemistry (including liver and renal function tests and CA125). Complete blood counts were repeated on Days 1, 5, 12, 15, and 21 in each cycle. Tumor measurements by imaging methods were performed at baseline and at every third cycle thereafter. The same imaging modality was to be used throughout the series. After the end of treatment, the patients were seen at the outpatient clinic every 3 months, and the same parameters that were recorded before each treatment cycle were recorded once again. Moreover, CT scans and chest X-rays were performed, as indicated.
Patients were evaluable for toxicity after the completion of one course. Patients were assessable for therapy efficacy if they completed at least 3 courses (imaging-based response criteria) or 1 course (CA125 response criteria) of treatment, respectively. In the original protocol, we planned to use the WHO tumor response criteria12 for response evaluation in patients with assessable disease by imaging criteria. Therefore, it was planned that only patients who had at least 1 measurable (bidimensional) lesion that measured ≥ 2 cm would be enrolled in the Phase II study. Due to the advent of the Response Evaluation Criteria in Solid Tumors (RECIST),13 those criteria were instead used for the response evaluation. Briefly, a complete response according to RECIST is defined as the disappearance of all target lesions. A partial response is defined as a decrease ≥ 30% in the baseline sum of the greatest dimensions of the target lesions. A nonresponse is defined as a decrease < 30% or an increase in the baseline sum of the greatest dimensions. Patients with solid tumors assessed by CT-scan (> 10 mm) or by ultrasonography (> 20 mm) were categorized with measurable disease. Nonmeasurable disease was defined as lesions that measured < 10 mm on a CT scan or < 20 mm on ultrasonography. Nonmeasurable disease included cystic lesions and ascites as well as patients who had a response assessment that was performed using different imaging techniques. In patients who had elevated levels of CA125 (> 70 U/mL), a response was defined as a reduction ≥ 50% in the pretreatment CA125 level. All case report forms were reviewed at the Clinical Research Unit at the Finsen Data Center, Rigshospitalet by a physician (B.G.), and all responses were evaluated by a physician (B.G.) and by the study coordinator (S.A.E.).
Between June, 2000 and October, 2002, 31 patients were enrolled in the Phase I study. The patient characteristics are summarized in Table 2. The median age was 61.5 years (range, 35.9–75.3 years). The median body surface area was 1.76 m2 (range 1.47–2.20 m2). Three patients went off the study before they completed the first cycle because of ileus (1 patient) or refusal (2 patients), leaving 28 patients who were assessable for toxicity.
Table 2. Patient Characteristics (n = 31 patients)
|FIGO stage|| || |
|Histology|| || |
| Clear cell||1||6|
|Grade of differentiation|| || |
| Well differentiated||2||7|
| Moderately differentiated||4||13|
| Poorly differentiated||15||48|
|Ascites|| || |
|Baseline performance status|| || |
All patients (n = 28 patients) had been pretreated with platinum and taxane-containing chemotherapy. Seventeen patients (61%) had primary failure, and 11 patients (39%) had secondary failure. The median treatment-free interval, which was defined as the time between the end of the previous chemotherapy regimen and the start of topotecan-etoposide, was 4.4 months (range, 0.5–11.9 months). The patients received a median of 5 cycles (range, 2–12 cycles) of topotecan-etoposide, and a total of 159 cycles were administered.
The Phase I study was carried out as follows: No DLTs were registered at Dose Level 1a. At the next dose level (2a), a DLT (Grade 4 neutropenia) was noted, and 3 more patients were included without any DLTs. No DLTs were observed at Dose Level 3a. At Dose Level 4a, DLT (Grade 4 neutropenia, neutropenic fever/sepsis) was registered in 2 of 4 patients; and, according to the protocol, the dose level was reduced. At Dose Level 3b, DLT (neutropenic fever/sepsis) was observed in 1 patient. However, severe nonmyeloid toxicity (Grade 3 fatigue) was observed in late cycles (Cycles 6 and 12) in another patient at Dose Level 3b. Therefore, the investigators decided to reduce the dose further. At Dose Level 2b, DLT (Grade 4 neutropenia, neutropenic fever/sepsis) was observed in 2 of 7 patients, and the Phase I study was stopped without reaching any conclusion about the MTD. Thus, the highest administered dose was intravenous topotecan at 1.0 mg/m2 on Days 1–5 and oral etoposide at 75 mg per day on Days 6–19. Because no MTD was reached, a recommended dose could not be determined, and the investigators decided to refrain from including patients in the planned Phase II trial. However, the 28 patients were followed, according to protocol, until they developed disease progression; then, the patients were given either antineoplastic, third-line treatment or supportive care.
Of 159 administered cycles, 4 cycles were obstructed either because etoposide was administered at the wrong dose (1 patient) or because etoposide treatment was aborted during treatment because of tonsillitis (1 patient), trauma (1 patient), or progression of tumor-related symptoms (1 patient). Hence, in total, 155 cycles were evaluable for toxicity. The main DLTs were Grade 4 neutropenia that lasted for > 1 week and neutropenic fever/sepsis. The overall hematologic toxicity is depicted in Table 3. The main hematologic toxicity was neutropenia. Neutropenia grade 4 that lasted for > 1 week and sepsis were noticed in 4 cycles (3%) and 3 cycles (2%), respectively, and these events were observed at every dose level. More than 50% of the incidents of Grade 4 neutropenia or neutropenic fever/sepsis (4 of 7 incidents) occurred during the first cycle of treatment. Prolonged neutropenia, which caused a delay in the onset on the subsequent cycle, was registered in 8 cycles (5%). Delay in the start of a treatment cycle for reasons other than myelotoxicity (e.g., deep venous thrombosis, cardiac problems, pneumonia) was noticed in 4 cycles (3%). Grade 4 thrombocytopenia that lasted for > 1 week was not registered in any cycle. Grade 4 anemia was rare (1%). Nonhematologic toxicity generally was mild. The main Grade 3 nonhematologic toxicity was fatigue, which was noted overall in 3 cycles (2%). None of the patients who experienced Grade 3 nonhematologic toxicity had lasting toxicity from previous treatment. One patient developed acute myeloid leukemia 9.7 months after the completion of 12 cycles of topotecan-etoposide. Chromosome analysis revealed the translocation t(9:11). No treatment-related deaths occurred.
Table 3. Overall Hematologic Toxicity (28 patients, 155 cycles)
Among 28 patients in the Phase I study, 23 patients had measurable disease according to RECIST. Of these, 16 patients completed at least 3 cycles of topotecan-etoposide; thus, these patients were assessable for response evaluation. Two patients obtained a complete response (13%), and 4 patients obtained a partial response (25%) (Table 4). Twenty-two of 28 patients had evaluable disease (CA125 > 70 U/mL) and completed at least 1 cycle. In these patients, a response (50% reduction) was obtained in 9 patients (41%) (Table 4). Overall responders included patients with either measurable disease (response); or nonmeasurable disease and evaluable disease (response). The overall response rate was 32% (95% confidence interval, 15.9–52.3%). Seven of 9 responding patients (78%) had primary failure with a median treatment-free interval of 5.6 months (range, 2.9–9.6 months). For responders, the progression-free interval, which was defined as the time from the start of topotecan-etoposide to disease progression, was a median of 8.0 months (range, 5.1–23.8 months). The progression-free interval for nonresponders was a median of 3.8 months (range, 1.8–14.1 months).
Table 4. Response
|1||1a||S||+|| ||+|| || |
|2||1a||S||+|| ||+||+|| |
|3||1a||P||+|| ||+|| || |
|4||2a||P||+|| ||+||+|| |
|6||2a||P||+|| ||+|| || |
|8||2a||S||+|| ||−|| || |
|9||2a||S||+|| ||−|| || |
|10||3a||P||+|| ||+|| || |
|13||4a||S||−|| ||+|| || |
|14||4a||S||+|| ||−|| || |
|15||4a||S||−|| ||+|| || |
|16||4a||S||−|| ||+|| || |
|18||3b||S||+|| ||+|| || |
|20||3b||P||+|| ||−|| || |
|21||3b||P||+|| ||+||+|| |
|23||2b||P||+|| ||+|| || |
|24||2b||P||+|| ||−|| || |
|25||2b||P||+|| ||+|| || |
|26||2b||P||+|| ||+|| || |
The combination of topoisomerase I and II inhibitors is a potentially attractive treatment modality in patients with recurrent ovarian carcinoma. Topoisomerase I and II both are enzymes that bind to supercoiled DNA, forming a cleavable complex that relaxes the torsion strain introduced ahead of the moving replication fork. Through DNA breakage, strand passage, and relegation of the cleaved DNA, the enzymes allow replication and repair to take place.3, 5, 6 The two topoisomerase enzymes are related functionally, and it has been demonstrated that the inhibition of one enzyme is associated both with a compensatory up-regulation in the expression of the other enzyme and with increased sensitivity to inhibitors of the other enzyme.3 Based on a mechanical rationale, the combination of topotecan (a topoisomerase I inhibitor) and etoposide (a topoisomerase II inhibitor), thus, may cause additive or synergistic actions in the clinical management of malignant diseases. Topoisomerase I inhibitors are unique in that they do not cause cytotoxicity by depleting the product of their target enzymes but by freezing the cleavable complex, resulting in single-stranded DNA breakage and apoptosis.14 Therefore, drug activity is proportional directly to the target enzyme level rather than inversely proportional to the target enzyme level, which is the case for many other cytotoxic enzyme inhibitors. Topoisomerase I activity is not linked to proliferation rate, and similar enzyme activities can be detected in slowly proliferating or quiescent cells. Thus, topotecan has the potential for activity against human solid tumors that tend to proliferate slowly and that generally are refractory to most of the established antitumor drugs.
Preclinical studies have demonstrated an additive effect when topoisomerase I and II inhibitors are administered sequentially with topoisomerase I inhibitors before topoisomerase II inhibitors, whereas the effects on cytotoxicity when topoisomerase I and II inhibitors are administered concurrently are conflicting.3, 6 Clinical studies of the sequential combination of topotecan and etoposide generally have yielded limited evidence of improved efficacy over the individual agents when used as monotherapies. Moreover, the combination seems to have translated into added myelotoxicity, and the combination regimen appears to have more impact on normal tissue toxicity than on antitumor efficacy.3
The continuous problems regarding toxicity of the sequential topotecan-etoposide combination are highlighted by the results from the current study. In a series of patients with recurrent ovarian carcinoma, the MTD could not be determined using a conventional dose-finding Phase I design because of unpredictable toxicity: DLT was found at each dose level except the starting dose level. Potential explanations for the unpredictable toxicity include 1) biochemical interaction between the two drugs, 2) pharmacokinetic problems related to the oral administration of etoposide, or 3) factors related to the biology of recurrent ovarian carcinoma.
Sequential treatment with intravenous topotecan plus intravenous etoposide has been evaluated clinically in several tumors, such as small cell lung carcinoma,10 nonsmall cell lung carcinoma,10 or leukemia.9 In a Phase I study of patients with various solid tumors, Hammond et al. established an MTD of topotecan (0.7 mg/m2 per day as a 72-hour, intravenous infusion on Days 1–3) and etoposide (75 mg/m2 per Day as a 2-hour, intravenous infusion on Days 8–10) in heavily treated patients.15 In another Phase I study of patients with small cell or nonsmall cell lung carcinoma by Huisman et al., the MTD was reached at a dose of topotecan 1.0 mg/m2 per day (given over 30 minutes on Days 1–3) and etoposide 75 mg/m2 per day (given over 1 hour on Days 4–6).10 Conversely, in a Phase I study of patients with myeloid leukemia, Crump et al. found the DLT at the first dose level of topotecan 1.5 mg/m2 per day (as a continuous infusion on Days 1–5) and etoposide 100 mg/m2 per day (bolus on Days 6–8), and those authors judged that further dose escalation was not feasible. It is noteworthy that high doses of topotecan and etoposide were selected for Dose Level 1.9 The results from those dose-finding, Phase I studies indicate a correlation between toxicity and the dose levels of the agents and indicate that the unpredictable toxicity in the current study was caused by factors other than biochemical interaction between the two agents.
The bioavailability of a cytotoxic drug is dependent on pharmacokinetic factors, such as drug absorption, metabolism, and elimination. It is known that drug absorption is fairly variable from patient to patient, leading to major interindividual variations in the systemic exposure (area under the concentration time curve [AUC]) of the drug, even if the same oral dose is administered.5, 6 Early clinical studies of oral etoposide found that 1) the bioavailability ranged from 32% to 57% when a 200–400 mg oral dose was administered; 2) the percentage of etoposide absorption decreased with increasing doses of oral etoposide; and 3) considerable variation in bioavailability when repeated doses of oral etoposide were administered to the same patients.6 The pharmacokinetics of oral etoposide may be altered by the combined administration with topotecan. Because the therapeutic index of etoposide is narrow, major variations in plasma level and exposure time potentially may explain the unpredictable DLT found in the current study. A Phase I study of sequential topotecan and oral etoposide was presented first by Herben et al.16 In that study of patients with solid tumors, unacceptable DLTs were encountered at Dose Level 4, and the MTD was settled at topotecan 1.0 mg/m2 per day (for 30 minutes on Days 1–5) and etoposide 40 mg/m2 per day (on Days 6–12) at 4-week intervals. Pharmacokinetic analyses revealed that the topotecan AUC correlated with the percentage decrease in the WBC (r2 = 0.70) and the ANC (r2 = 0.65), whereas the etoposide AUC was not related significantly to hematologic toxicity. In a Phase I study of patients with small cell lung carcinoma, Mok et al. found DLT at Dose Level 3, and the MTD was defined as topotecan 0.75 mg/m2 per day (on Days 1–5) and etoposide 100 mg per day (on Days 6–12) every 3 weeks.17 That study did not include pharmacokinetic parameters. Although clinical studies of sequential topotecan-oral etoposide are few, the theory of variable absorption of oral etoposide as an explanation for the erratic DLT in our study seems less plausible.
The erratic DLT potentially may have been due to conditions that are specific to ovarian carcinoma. The tumor-specific bioavailability of etoposide has been demonstrated for other tumor types. In a Phase I study, Desoize et al. found extremely low bioavailability of oral etoposide in patients with advanced head and neck carcinoma.18 However, the design of the current study did not provide an explanation for the erratic DLT observed. One limitation of our study was the lack of information regarding the bioavailability of the two agents, because this may have explained whether the toxicity was related to the AUC of topotecan or the AUC of etoposide.
To our knowledge, this is the first study to examine the impact of sequential topotecan-oral etoposide in patients with ovarian carcinoma pretreated with platinum-taxane. Reviewing the feasibility of the topotecan-etoposide combination, it has been suggested previously that the degree of normal tissue toxicity prevents the delivery of sufficient doses to enhance the response rate over the monotherapy regimens.3 This finding was supported by the current study, in which 1 patient at Dose Level 1a experienced both severe nonhematologic toxicity (Cycle 5; Grade 3 fatigue) and hematologic toxicity (Cycle 9, Grade 4 neutropenia) toxicity. The main DLTs were Grade 4 neutropenia that lasted > 1 week and neutropenic fever/sepsis. Overall, Grade 4 neutropenia was noted in 3% of cycles and in 14% of patients (Table 3). The Grade 4 neutropenia was noncumulative and was not dose-dependent, and the main clinical problem was that the events of Grade 4 neutropenia were unpredictable and were not related to the dose level. Grade 4 Neutropenia was complicated with sepsis in 2% of cycles and in 11% of patients (Table 3). The toxicity of the single agents in the treatment of recurrent ovarian carcinoma has been evaluated previously. In a recent study, Gronlund et al. reviewed the experience with intravenous topotecan 1.0 mg/m2 per day on Days 1–5 in a series of 56 patients with recurrent ovarian carcinoma.19 Neutropenic sepsis was noted in 1 patient (0.4% of cycles, 2% of patients). Oral etoposide used as a single agent has been studied in several Phase II trials; and, in a large study by Rose et al., neutropenic sepsis was noted in 2% of patients.20 Although comparison of toxicity frequencies preferably should be made in randomized studies, the results indicate that the addition of oral etoposide to topotecan does cause some unfavorable interaction in toxicities. One patient developed acute myeloid leukemia during the observational period. It is known that etoposide carries a risk of secondary myelodysplasia and acute leukemia, and the risk is related to the duration of therapy and the cumulative dose.6 The patient (patient 27) was treated at Dose Level 2 and received a cumulative etoposide dose of 8400 mg administered over 12 cycles.
A question is whether the topotecan plus oral etoposide combination in different doses may be worth pursuing. It is noteworthy that the starting dose of topotecan (1.0 mg/m2 on Days 1–5) is a well established dose from other studies of topotecan as monotherapy in patients with recurrent ovarian carcinoma.19, 21 Similarly, the starting dose of oral etoposide (50 mg per day) has been used in several studies of combination chemotherapy in patients with recurrent ovarian carcinoma.22, 23 Therefore, a potential increased feasibility using other starting doses seems less possible, and future studies should focus on combinations of topoisomerase I and II inhibitors other than intravenous topotecan and oral etoposide.
Although the planned Phase II trial was cancelled, the patients from the Phase I trial were assessable for response evaluation. The overall response rate was 32%. This favorable response rate is in agreement with a study by Guastalla et al., who observed a response rate of 19% using a schedule of topotecan (1.0 mg/m2 per day on Days 1–5) and etoposide (50 mg per day on Days 6–12) in heavily pretreated patients.24 The treatment-free interval is a strong predictive factor for response in the recurrent clinical setting.25 It is noteworthy that 7 of 9 responding patients (78%) had primary failure with a relatively short median treatment-free interval of 5.6 months (range, 2.9–9.6 months). In comparison, some Phase II studies that included the combination of oral etoposide and other agents in patients with chemoresistant, recurrent ovarian carcinoma have been published recently. The combinations included, as the other agent, liposomal doxorubicin,22 ifosfamide,26 or cisplatin,23, 27 and very encouraging response rates ranging from 26% to 46% were observed.
In conclusion, a sequential regimen of intravenous topotecan and oral etoposide is not recommended for future trials in patients with recurrent ovarian carcinoma because of unpredictable hematologic toxicity. However, the attractive response rate highlights the potential additive effect of topoisomerase I and II inhibitors. Orally administration of etoposide may enhance patient compliance in the salvage setting, and future studies should focus on etoposide combinations other than with topotecan.