Topotecan (9-dimethylaminomethyl-10-hydroxycampthothecin) is a new topoisomerase I inhibitor with promising efficacy in the treatment of patients with small cell lung carcinoma (SCLC). Combination with a topoisomerase II inhibitor may potentate the therapeutic effect of topotecan, although there has been conflicting preclinical information on the combination. The objectives of this study were to establish the maximum tolerated dose and to determine the efficacy of the sequential combination of intravenous topotecan and oral etoposide in the treatment of patients with SCLC.
Patients with histologically confirmed, limited or extensive stage SCLC were eligible. The dose escalation scheme of three cohorts (six patients per cohort) started at intravenous topotecan 0.5 mg/m2 per day for 5 days and oral etoposide 50 mg twice daily for 7 days (21-day cycles). Subsequent dose levels involved escalation of topotecan to 0.75 mg/m2 per day and 1.0 mg/m2 per day for 5 days. A Phase II study was conducted at one dose level below the maximum tolerated dose. The authors alternated the drug sequence with each consecutive cycle and compared the hematologic toxicity between the two sequences.
Thirty-six patients (21 patients with limited disease and 15 patients with extensive disease) received a total of 173 courses of sequential combination chemotherapy (topotecan → etoposide, 88 courses; etoposide → topotecan, 85 courses). The authors identified dose levels for the Phase II study as follows: topotecan, 0.75 mg/m2 per day for 5 days; and etoposide, 50 mg twice daily for 7 days. The dose-limiting toxicity was neutropenia. At this dose level, the incidence of Grade 3–4 neutropenia and the incidence of Grade 3–4 thrombocytopenia were 25% and 10.9%, respectively. Two patients died from neutropenic sepsis. There was no significant difference in hematologic toxicities between the two sequences. Complete and partial response rates were 5.6% and 55.6%, respectively (limited disease, 9.5% and 66.75%; extensive disease, 0% and 40%, respectively). The median progression free survival was 31.9 weeks (limited disease, 36.1 weeks; extensive disease, 28.9 weeks; 95% confidence interval, 25.6–36.0 weeks), and the median overall survival was 52.4 weeks (limited disease, 54.9 weeks; extensive disease, 30.1 weeks; 95% confidence interval, 39.6–57.7 weeks).
Topotecan (9-dimethylaminomethyl-10-hydroxycampthothecin), a hydrophilic, semisynthetic analog of camptothecin, is a topoisomerase I inhibitor that is active in the treatment of chemotherapy-naïve and chemotherapy-sensitive patients with recurrent small cell lung carcinoma (SCLC).1, 2 Schiller et al. treated 48 chemotherapy-naïve patients with extensive SCLC with topotecan at 2 mg/m2 per day for 5 days and reported a response rate of 39% and a median survival of 10 months. Second-line therapy for patients with chemotherapy-sensitive disease (durable response to first line therapy of at least 3 months) consisted of single-agent topotecan at a dose of 1.5 mg/m2 per day, and patients achieved a response rate of 19–37%.3, 4 Primary toxicity was myelosuppression. Single-agent topotecan was as effective as the combination of cyclophosphamide, doxorubicin, and vincristine in a randomized Phase III study of patients with recurrent, chemotherapy-sensitive disease (response rates, 24.3% and 17.3%, respectively).5 Thus, current evidence supports the activity of single-agent topotecan in the treatment of patients with SCLC. The issue is how best to incorporate this new drug into combination therapy.
Etoposide, which is a topoisomerease II inhibitor with established clinical efficacy, is part of the standard regimen for the treatment of patients with SCLC.6 Its oral version (Vepesid; Bristol-Myers Squibb, Syracuse, NY) provides a safe and convenient alternative method of administration. Oral etoposide can attain tumor response in patients with either chemotherapy naïve or recurrent SCLC, although its role as single-agent therapy is limited due to the lack of a survival benefit compared with combination chemotherapy.7, 8 Combining etoposide with a topoisomerase I inhibitor potentially may increase the cytotoxic effect. Both topoisomerase inhibitors bond covalently between the enzyme and DNA and form a cleavable complex that causes permanent DNA strand break and cell death. Given the overlap function of the two topoismerases and the established role of each drug as single-agent therapy for patients with SCLC,2, 6, 7 it may be appropriate to combine topotecan with etoposide. However, results from preclinical studies on this combination are conflicting. The simultaneous administration of topoisomerase I and II inhibitors in cell line studies was antagonistic,9, 10 whereas sequential administration was synergistic in action.11, 12 The sequence of administration also may be significant. Bonner and Kozelsky reported a higher level of synergistic interaction when topoisomerase I inhibitor was followed by topoisomerase II inhibitor (T → E).13 This phenomenon may be explained by the compensatory up-regulation of topoisomerase II in cells with the inactivation of topoisomerase I, resulting in enhanced cytotoxicity of the topoisomerase II inhibitor.14
Early clinical studies on the sequential combination of topotecan and etoposide in the treatment of patients with leukemia and advanced solid tumors were based on the hypothesis described above, although the results generally were disappointing.15–19 This lack of antitumor activity may be explained either by the sequence of administration or by the tumor cell type selected. In a Phase II study, patients with lung carcinoma were treated with a continuous infusion of topotecan on Days 1–3 followed by oral etoposide on Days 7–9.17 No synergism was noted, perhaps because of the prolonged delay between administrations of the two topoisomerase inhibitors, especially if topoisomerase II up-regulation induced by topoisomerase I inhibition is short-lived. The sequence of administration was compared in a randomized Phase I–II study of patients with recurrent leukemia. Vey et al.16 observed that the antileukemic effect was insufficient with either sequence of administration, but mucositis was more common with the T → E sequence. Therefore, it may be logical to study the effect of sequential administration on a tumor cell type, such as SCLC, in which topotecan has established activity.
Clinical information on the combination of topotecan and etoposide in the treatment of patients with SCLC is limited. An ongoing trial has adopted the sequential combination of daily topotecan infusion followed by daily etoposide infusion and recently has established the dose for a planned Phase II study.20 Gervais et al. reported remarkable antitumor activity in their randomized Phase II study in patients with extensive SCLC; however, significant hematologic toxicity was associated with simultaneous intravenous infusion of topotecan and etoposide.21
Based on the hypothesis of topoisomerase II up-regulation, the T → E sequence should be more cytotoxic than the reverse sequence (E → T). However, there are no published clinical data to test this hypothesis. The objectives of the current study were to establish the maximum tolerated dose (MTD) and to study the efficacy of the sequential combination of intravenous topotecan and oral etoposide in the treatment of patients with SCLC. We also evaluated the differences in toxicity between the two sequences of administration.
MATERIALS AND METHODS
This was a single-center, open-label, nonrandomized, Phase I–II study. In the Phase I study, we used a dose-escalation scheme to identify the MTD and continued to a Phase II study at one dose level below the MTD. The study protocol and consent form were approved by the Ethics Committee of the Chinese University of Hong Kong. We conducted the study in accordance with principles of good clinical practice and obtained informed consent from all enrolled patients. The protocol was activated in May, 1997, and the data base was frozen for analysis in June, 2001.
Patients with histologically proven, limited or extensive, SCLC were eligible for the study with the following inclusion criteria: 1) age 18–75 years; 2) Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2; 3) bidimensionally measurable disease; 4) no prior exposure to chemotherapy or radiation; 5) life expectancy ≥ 3 months; 6) no central nervous system (CNS) metastasis on presentation; 7) adequate bone marrow function (hemoglobulin > 10 g/mL, leukocyte count > 4000/mL, and platelet count > 100,000/mL), renal function (serum creatine < 1.5 × the upper limit of normal [ULN]), and hepatic function (bilirubin < 2 × ULN, alkaline phosphatase < 3 × ULN, transaminase < 3 × ULN, and prothrombin time < 1.5 × ULN); 8) no active infection or other life-threatening medical condition; 9) absence of other malignancy in the last 5 years; 10) mentally competent; 11) compliant with oral medication schedule; 12) informed consent.
Topotecan (Hycamtin; SmithKline Beecham Pharmaceuticals, Philadelphia, PA) was supplied in vials containing 4 mg of drug as a lyophilized formulation. Prior to injection, the drug was reconstituted with 4 mL of sterile water and diluted with 100 mL 5% dextrose solution for intravenous infusion over 30 minutes. Oral etoposide (Vepesid; Bristrol-Myers Squibb, Princeton, NJ) was supplied as 50 mg capsule for ingestion at home. Patients were advised not to eat within 1 hour before and after ingestion of the capsule. We monitored the oral etoposide consumption with self-administered drug-compliance forms. All unused capsules were returned to the investigator during clinic visits.
Because there was little information on the toxicity of this sequential combination, and because both drugs were known to be myelotoxic, we designed a dose-escalation scheme involving 3 cohorts of patients starting at Dose Level 1 with topotecan 0.5 mg/m2 per day for 5 days and oral etoposide 50 mg twice daily for 7 days (21-day cycles). We fixed the dosage of oral etoposide and escalated the dose of topotecan for the second and third cohorts to 0.75 mg/m2 per day and 1.0 mg/m2 per day, respectively. The MTD was defined as the dose level at which > 25% of courses led to the following toxicity (World Health Organization [WHO] recommendations for acute toxicity evaluation): 1) Grade 3 or 4 neutropenia for > 7 days; 2) neutropenic sepsis; 3) Grade 4 thrombocytopenia; 4) Grade 3–4 nonhematologic toxicity; and 5) any chemotherapy-induced, serious, adverse event requiring hospitalization. Once the MTD was reached, the Phase II trial continued at one dose lower. At this dose level, individual patients underwent a dose reduction of topotecan by 25% for Grade 3–4 hematologic toxicity. There was no dose reduction for nonhematologic toxicity. At all dose levels, treatment could be deferred for 1 week if bone marrow recovery was insufficient.
All patients with limited disease were considered for mediastinal and prophylactic cranial irradiation if their pulmonary function and performance status were sufficient. Patients who had disease progression or developed recurrent disease were treated with salvage therapy (cisplatin 75 mg/m2 on Day 1 and intravenous etoposide 100 mg/m2 on Days 1–3 [EP]; cyclophosphamide 1000 mg/m2 on Day 1, doxorubicin 50 mg/m2 on Day 1, and vincristine 1.4 mg/m2 on Day 1 [CAV]; or carboplatin at a dose 5 × the area under the concentration time curve on Day 1 and intravenous etoposide 100 mg/m2 on Days 1–3 [CE]) if their clinical condition allowed it. Palliative radiotherapy was administered for symptom control as appropriate.
The first, third, and fifth patients at each dose level started the first cycle with topotecan followed by oral etoposide (T → E), and the sequence was alternated in subsequent cycles. The second, fourth, and sixth patients started the first course with oral etoposide followed by topotecan (E → T). Thereafter, the drug sequence was alternated with each successive course. With this regimen, the intravenous topotecan infusions always were started on Monday and completed by Friday. Oral etoposide was ingested at home twice daily.
At the time of enrollment, all patients had a complete blood count, renal and liver function tests, serum calcium, prothrombin time, blood glucose, hepatitis B serology, creatinine clearance, electrocardiograph, and chest radiograph. Computed tomography (CT) scans of the brain, thorax, and abdomen were taken within 4 weeks of the first treatment. Complete blood counts were repeated on Days 1, 8, and 15 of each cycle. Renal and liver function was measured on Days 1 and 15. Chemotherapy was deferred for 1 week if patients suffered Grade 3 toxicity on Day 21. A chest radiograph was repeated after each cycle. If the tumor was measurable by CT scan, then the scan would be repeated after the second, forth, and sixth cycles. A response had to be confirmed with repeated imaging at least 4 weeks apart. Complete remission (CR) was defined as the complete disappearance of all measurable and evaluable disease. A partial response (PR) was defined as a reduction by 50% in the sum of the dimensions of bidimensional, measurable disease on CT scan. Patients who had an increase ≥ 25% in tumor size or who developed new sites of metastasis were classified with disease progression.
Toxicity was classified according to WHO recommendations for acute toxicity evaluation. Overall survival was defined as the time from enrollment to death from any cause. The time to disease progression was the duration from the first treatment to the day of confirmed disease progression or recurrence. All patients were followed until death or until they were lost to follow-up.
The primary end point in this study was tumor response rate. Only chemotherapy-naïve patients were recruited in this study. Assuming that the target activity level was 80% and that the lower actual level was 60%, we calculated a sample size, according to the Simon minimax design, of 36 patients (α = 0.10, β = 0.10). The response rate, progression free survival, and overall survival (stratified by disease stage) were calculated according to the intention-to-treat principle. A generalized estimating equation (GEE) approach was used to model the incidence of toxicities with respect to method of treatment, dose level, and the two drug sequences. The model assumes a symmetry correlation structure for repeated measurements on each cycle within patients. This assumption is validated by comparing the results with models using unstructured correlation that came to the same conclusion. Time-to-event data were analyzed by using the Kaplan–Meier method. A 95% confidence interval (95%CI) for the median survival was determined using the method by Brookmeyer and Crowley.22 Calculations of the median time to response and the median duration of response were performed on the subset of patients who had responded to treatment. A Cox regression model was used to assess the association of baseline prognostic factors with overall survival.
Between October, 1997 and February, 2000, 36 consecutive patients were enrolled on the study (21 patients with limited disease and 15 patients with extensive disease). Eight additional patients (all males) were screened for enrollment during this period but were excluded for different reasons, including age, concurrent medical illness, poor performance status, and refusal to participate. Almost all patients (97%) were male. The patient characteristics are summarized in Table 1. Most enrolled patients (91.7%) had a good performance status (ECOG 0 or 1).
Table 1. Patient Characteristics
ECOG: Eastern Cooperative Oncology Group.
No. of patients
ECOG performance status (0:1:2)
In total, 173 courses of sequential chemotherapy were administered. Six patients completed 22 courses (3.7 courses per patient) at Dose Level 1. Less than 25% of courses reached MTD criteria, although one patient died from severe pneumonia shortly after the first cycle. Treatment was deferred in two courses at Dose Level 1. The first cohort of six patients at Dose Level 2 did not reach the MTD, although one patient died from neutropenic sepsis. We decided to treat a second cohort of 6 patients at this dose level to ensure acceptable myelotoxicity before we proceeded to Dose Level 3, and, again, the MTD was not reached in a total of 12 patients. Seven patients started chemotherapy at Dose Level 3 and completed 23 courses (3.3 courses per patient). Myelosuppression was the dose-limiting toxicity, resulting in 4 patients requiring dose reductions, and 15 courses were deferred. Over 50% of courses were associated with Grade 3–4 neutropenia. Thus, we defined MTD at Dose Level 3 and continue treating patients at Dose Level 2 for the rest of the accruals. A total of 23 patients (15 patients with limited disease and 8 patients with extensive disease), including the 2 cohorts of 6 patients each, completed 128 courses of therapy (83 patients with limited disease and 45 patients with extensive disease) at Dose Level 2 (5.5 courses per patient). Mediastinal radiation was given to 10 patients with limited disease but was withheld from other patients because of poor lung function and patient refusal. Two patients with limited disease received prophylactic cranial irradiation.
Disease Response and Survival
We observed tumor response at all three dose levels (Table 2). The overall CR and PR rates for all patients were 5.6% and 55.6%, respectively. Half of the patients at Dose Level 1 responded. One patient was not evaluable because of premature septic death after the first cycle of chemotherapy. The response rates at Dose Levels 2 and 3 were 60.8% and 71.4%, respectively. The response rate in patients who had limited disease was significantly greater compared with patients who had extensive disease (76.2% vs. 40% respectively; P = 0.032). The median follow-up was 90.5 weeks (range, 2–172 weeks). Only seven patients, all with limited disease at the time of initial presentation, were alive at the time of data analysis. The median progression free survival was 31.9 weeks (36.1 weeks for patients with limited disease and 28.9 weeks for patients with extensive disease; 95%CI, 25.6–36 weeks), and the median overall survival was 52.4 weeks (54.9 weeks for patients with limited disease and 30.1 weeks for patients with extensive disease; 95%CI, 39.6–57.7 weeks) (Fig. 1). Patients with limited disease had 1-year and 2-year survival rates of 65.1% and 12.5%, respectively, compared with 28.5% and 0% for patients with extensive disease. Disease stage and ECOG performance status were significant prognostic factors for survival (P = 0.036 and P = 0.05, respectively), whereas dose level and patient age were not significant prognostic factors (P = 0.8 and P = 0.98, respectively).
Bone marrow suppression was the major toxicity (Table 3). Grade 3–4 neutropenia occurred in 4.5%, 25.0%, and 47.8% of courses at Dose Levels 1–3, respectively. Three patients had febrile neutropenia that required hospitalization, and two of these patients died from sepsis that was related directly to chemotherapy. Thrombocytopenia was relatively uncommon (WHO Grade 3–4 toxicity at Dose Levels 1–3 were 13.6%, 10.9%, and 9.1%, respectively). Platelet transfusion was required in one patient, and none of the patients had a major hemorrhagic event. Three patients had Grade 4 anemia that required blood transfusion. The GEE model also showed significant increases in Grade 3–4 thrombocytopenia (P = 0.041) and neutropenia (P = 0.029) with increasing dose levels. Nonhematologic toxic was negligible (Table 4). Alopecia was common among patients on Dose Levels 2 and 3. Most patients only suffered from Grade 1 nausea and emesis, requiring the use of oral antiemetics. Mild-to-moderate mucositis occurred in 28.9% of all courses. None of the patients were hospitalized for nonhematologic toxicity related to the combination chemotherapy.
Table 3. Hematologic Toxicity per Course: World Health Organization Recommendation for Acute Toxicity Evaluation
Salvage chemotherapy was given to 16 patients for disease progression or recurrence (2 patients received CAV, 10 patients received EP, and 4 patients received CE). Four patients attained a PR (one patient with limited disease and three patients with extensive disease), and six patients had stable disease (three patients with limited disease and three patients with extensive disease) on salvage chemotherapy. Fourteen patients received palliative radiation on disease progression at the following sites: bone in 2 patients, CNS in 1 patient, chest in 10 patients, and soft tissue in 1 patient.
Sequence of Administration
Eighty-eight courses of chemotherapy were given in the T → E sequence, and 85 courses were given in the E → T sequence. Bone marrow toxicity of the two sequences is compared in Table 5. There was no significant difference between the sequences of administration. In the GEE model, patients who received the T → E sequence had borderline significantly more Grade 3–4 neutropenia compared with patients who received the reverse sequence (P = 0.049). No other hematologic toxicities were significant with respect to the sequence of administration.
Table 5. Hematologic Toxicity by Sequence of Chemotherapy with Topotecan and Etoposide (No. of courses)
Toxicity grade (%)
HB: hemoglobulin; LC: leukocyte count; PLT: platelets; ANC; absolute neutrophil count; T → E: topotecan followed by oral etoposide; E → T: oral etoposide followed by topotecan.
T → E
E → T
T → E
E → T
T → E
E → T
T → E
E → T
To our knowledge,this report is the one of the first clinical studies on sequential administration of topoisomerase I and II inhibitors in the treatment of patients with SCLC. We have shown that the sequential combination of intravenous topotecan infusion at a dose of 0.75 mg/m2 per day for 5 days followed by oral etoposide at a dose of 50.0 mg twice daily for 7 days is active and well tolerated. Tumor response rates for this combination appear to be similar to single-agent topotecan infusion at a dose of 2.0 mg/m2 per day for patients with extensive SCLC but are inferior to the response rates achieved with standard combination regimens.23 In contrast, a response rate of 76.2% for patients with limited disease is not inferior to the rates achieved with standard regimens, although it does not represent a significant improvement. However, a median survival of 12 months for patients with limited disease appears to be inferior to the standard median duration reported in some of the major randomized studies that used cisplatin-based combination chemotherapy and thoracic radiation.24–26 Future developments of this combination should focus on patients with extensive disease, and particularly on patients with poor tolerance to cisplatin. This sequential combination therapy may attain tumor response and survival prolongation in this group of patients with less toxicity and greater convenience.
Although single-agent oral etoposide is not an adequate therapy for patients with SCLC, the role of combination oral cytotoxic therapy remains to be defined.8, 27 Based on our results with intravenous topotecan, an oral regimen with topotecan and etoposide is feasible for future investigation. Oral topotecan at a dose of 2.3 mg/m2 per day for 5 days is equivalent to intravenous administration of the same drug at dose of 1.5 mg/m2 per day.28 von Pawel et al. found that oral topotecan was similar to intravenous topotecan in efficacy in patients with recurrent, chemotherapy-sensitive SCLC. For first-line therapy in patients with extensive SCLC, oral topotecan attained a response rate of 30% and a median survival of 8.7 months.29 In light of the established efficacy, toxicity profile, and convenient schedule, there are potential advantages with a sequential combination of oral topotecan and etoposide for the treatment of elderly patients with extensive SCLC.
Gervais et al. treated 41 patients with extensive SCLC with intravenous topotecan at a dose of 0.75 mg/m2 per day together with intravenous etoposide at a dose of 60 mg/m2 per day for 5 days and reported a response rate of 61%.21 Dose intensities of this concurrent regimen and our sequential regimen at Dose Level 2 are equal (assuming that the bioavailability of oral etoposide is ≈ 50–60%).30, 31 The response rate achieved in 23 patients who were treated at this dose level by sequential combination appeared similar to the response rate achieved with concurrent therapy. This finding contradicts the preclinical evidence that showed a lack of synergism in cell line studies with concurrent exposure to topoisomerase I and II inhibitors.8–11 Short of a randomized, comparative study, we should consider the clinical efficacy of concurrent and sequential administration of topoisomerase I and II inhibitors to be equal.
We did not observe obvious synergism between these two topoisomerase inhibitors in our clinical study. This combination, as limited by myelosuppression at the MTD of topotecan, attained a tumor response rate similar to the response rate achieved with single-agent topotecan.2 It has been hypothesized that there is a synergistic interaction between topoisomerase I and II inhibitors that can be explained by the up-regulation of topoisomerase II by the inhibition of topoisomerase I. If this hypotheses is correct, then we would expect to see more cytotoxicity with the T → E sequence of administration and less cytotoxicity with the reverse schedule. However, adopting hematologic toxicity as a surrogate marker of cytotoxicity, the two sequences of administration appear equally toxic. Hammond et al. measured in vivo topoisomerase levels prior to and immediately after intravenous infusion of topotecan in six patients with advanced solid tumors and detected topoisomerase II up-regulation in only one sample.18 Huisman et al. adopted a similar design of alternate drug sequence in their Phase I study of intravenous topotecan and etoposide. They treated 19 patients with lung carcinoma (7 patients with SCLC, 11 patients with nonsmall cell lung carcinoma, and 1 patient with mesothelioma) and stopped dose escalation at their third dose level (topotecan 1 mg/m2 per day for 3 days and etoposide 100 mg/m2 per day for 3 days) because of severe myelosuppression.32 Consistent with our findings, they observed no difference in hematologic toxicity between the sequences of administration. Febrile neutropenia, the dose-limiting toxicity, occurred in both the T → E sequence and the E → T sequence. Therefore, the hypothesis of topoisomerase II up-regulation as an explanation for their synergism remains unsubstantiated.
In conclusion, the sequential combination of intravenous topotecan followed by oral etoposide, or the reverse sequence, is an active combination regimen for the treatment of patients with SCLC. The mild toxicity profile and convenient administration schedule may facilitate the development of oral combination therapy for patients with extensive SCLC and poor tolerance to cisplatin. We recommend a regimen of oral topotecan 1.2 mg/m2 per day (equivalent to intravenous topotecan at 0.75 mg/m2 per day) for 5 days followed sequentially by oral etoposide 50 mg twice daily for 7 days for future Phase II studies.