Topotecan has demonstrated activity in ovarian carcinomas. In order to increase the tumour response rate and to define the maximum tolerated dose (MTD) of topotecan, we decided to develop a high-dose phase I regimen supported by stem cell support. High-doses schedules using a 1-day single administration have MTDs of 10.5 (24 h continuous infusion (CI)) or 22.5 mg/m2 (30 min infusion). Five-day CI induces grade IV mucositis at high doses (MTD<12 mg/m2). We chose to administer topotecan in a 5-day schedule with a 30 min daily infusion. Patients were scheduled to receive one cycle of therapy. The first dose level was 4.0 mg/m2/day × 5 days. Limiting toxicities were defined as toxic death, grade IV non-haematopoietic or haematopoietic toxicity >6 weeks. From August 1998 to April 2002, 49 patients were included. Forty-three patients have completed one course and 15 have received two cycles. One patient treated at level 7 mg/m2/day died of sepsis. Median duration of grade IV neutropenia was 9 days. Two episodes of grade IV diarrhoea were observed at level 9.5 mg/m2/day. Pharmacokinetic data were linear within the dose range of 4–9.0 mg/m2/day. The MTD was reached at 9 mg/m2/day × 5 days.
The prognosis of ovarian cancers (OC) remains poor. Despite the progress achieved in the 1990s, enabling the achievement of clinical complete response (CR) rates of 50% and histological CR rates of 25%, the majority of patients will relapse and die.1, 2 The outlook is particularly poor in patients presenting with residual macroscopic disease after initial chemotherapy (CT), or whose disease progresses during CT or relapses after a short treatment-free interval following platin-based therapy, or whose initial disease is stage IV.3 For patients whose disease is resistant to platinum salts, the efficacy of new drugs that are non-cross-resistant with those previously used should be tested. Treatment intensification followed by autologous haematopoietic stem cell transplantation (AHSCT) has been an experimental approach to optimize the induction and/or consolidation treatments. Topotecan (topotecan hydrochloride, Hycamtin®, Laboratoire GlaxoSmithKline, Marly le Roi, France), which has demonstrated activity in second-line treatment of OC, is associated mainly with haematopoietic toxicity and seems to be a good candidate for dose-intensification studies.4, 5 Its key pharmacokinetic characteristics may support its use: linear relationship between AUC and dose, no evidence of accumulation when the drug is administered as a 30 min infusion on 5 consecutive days, elimination half-life of the order of 3 h even at high doses, necessity for dose adjustment according to renal function, but less according to hepatic function.6, 7, 8
In view of these data, we decided to develop a phase I protocol of high-dose chemotherapy (HDCT) using single agent topotecan at increasing doses, supported by AHSCT and granulocyte colony-stimulating factor (G-CSF) in poor-prognosis OC patients. The aim was to define its maximum tolerated dose (MTD) as a single agent, administered as a 30 min bolus infusion for 5 days. We herein report the definitive results of this phase I study, the so-called ITOV 01 protocol.
Materials and methods
Patient selection, eligibility requirements, inclusion and non-inclusion criteria
Inclusion criteria were as follows: histologically proven ovarian, fallopian tube or primary peritoneal carcinoma, age between 18 and 65 years, ECOG performance index ⩽2, creatinine clearance ⩾60 ml/min, bilirubin <1.25 normal value, transaminases and alkaline phosphatases <2 normal values (three times if hepatic metastases were present), normal cardiac function, normal blood count and, negative viral serologies. Patients were enrolled either after a single line of CT including a platinum salt (cisplatin or carboplatin) and a taxane if they had experienced progressive or stable disease on CT, or had macroscopically positive second look, initial stage FIGO IV disease, or relapse before 6 months after the end of the initial treatment, or relapse after two lines of CT including a platinum salt and a taxane, and with a first relapse occurring more than 6 months after the end of the initial treatment and whose disease was primarily or secondarily refractory to a second-line treatment with a platinum salt and/or a taxane. As it was a phase I study to determine the MTD of topotecan, measurable disease was not required. Patients had to have signed an informed consent.
Exclusion criteria were as follows: expected survival <3 months, previous pelvic radiotherapy, previous treatment with topoisomerase I inhibitors, intestinal occlusion, grade ⩾2 platinum-induced neuropathy, clinical evidence of cerebral metastases, serious psychiatric disease, uncontrolled serious infection, previous HDCT or more than two lines of prior CT.
The primary end point of this phase I study was to define the MTD after one cycle of single-agent topotecan. To achieve this aim, the dose-limiting toxicities (DLT) were defined as follows: grade IV non-haematological toxicity (life-threatening infection, exfoliating dermatitis, grade IV diarrhoea, renal, cardiac, neurological, pulmonary toxicities, increase in serum bilirubin level to three times normal, increase in transaminases to 20 times normal, absence of haematological recovery at 6 weeks (PMN<1 × 109/l or platelets <50 × 109/l)) and therapy-related death. Deaths due to toxicity, unacceptable toxicities, and interruption after the mobilization protocol, whatever the reason was, were considered as treatment failures. Thus, the MTD was defined as the dose immediately below that at which unacceptable toxicity occurred.
Secondary end points included the pharmacokinetic behaviour of HD topotecan, the response to therapy according to the Rustin criteria,9 the duration of response and the overall survival from the first day of topotecan treatment using the Kaplan–Meier method,10 and finally the extra-haematopoietic toxicities according to the NCI criteria.11
Pre-enrolment assessment and survey of the therapeutic sequence
Pre-enrolment assessment should comprise the following elements: physical examination, abdominal/pelvic CT scan, chest X-ray, CA 125 assay, assessment of major vital functions, search for foci of infection and viral status. During the post-mobilization and pre-intensification phases, assessment consisted in physical examination, CA 125 assay and radiological assessment at the discretion of the investigator to evaluate any effect of mobilization therapy on the progression of the disease.
The study was continuously monitored for potential adverse events and disease-related or treatment-related signs and symptoms. During the HDCT sequence, all potential extra-haematopoietic toxicity criteria were carefully explored, mainly cutaneous, gastrointestinal and perianal mucositis. Haematological recovery was assessed by at least three CBC/week. Long-term assessment was performed at 1-month post HD therapy, then every 3 months during 1 year and every 6 months during the following 2 years or until disease progression.
Mobilization of haematopoietic stem cells
Patients were scheduled to receive for mobilization one cycle of cyclophosphamide (CPM), 3 g/m2, supported by G-CSF (filgrastime), 5 μg/kg/day, from D+6 up to the time of aphaeresis. The required concentration of CD34+ cells was at least 3 × 106 cells/kg of body weight, that is, the minimum required for one graft. However, considering that a second course of HDCT with AHSCT could be proposed, a rate of 6 × 106 CD34+ cells/kg of body weight was the aim of the aphaeresis. In case of harvest failure, a new attempt of mobilization using double-dose G-CSF for 5 days from steady state was proposed to the patient.
High-dose chemotherapy and dose escalation of topotecan
The study was conducted according to the protocol, and the dose levels were evaluated according to the following scheme: the first and the second doses tested were respectively 4 mg/m2/day × 5 days and 5 mg/m2/day × 5 days, and the subsequent doses were increased in increments of 0.5 mg/m2/day. The interval between enrolment of the last patient at a given dose level and enrolment of the first patient at the next level above was 6 weeks starting from the first day of topotecan. Three patients had to have received treatment and be evaluable for toxicity at each dose level before escalation to the next dose level was considered. If any patient experienced a DLT, three additional patients had to be enrolled at the same dose level without experiencing DLT before escalation was allowed. If two patients experienced a DLT at the same dose level, dose escalation had to be stopped and this level would be the MTD. One additional patient was to be enrolled in the event of failure of haematopoietic stem cell harvest or non-evaluability of a patient for toxicity. If one patient failed to show haematological recovery at 4 weeks, enrolment of the following patient was to be delayed until 6 weeks had elapsed.
High-dose chemotherapy and supportive care
Topotecan was administered from day 1 to 5, as a 30 min infusion after dilution to a final concentration of 25–50 μg/ml. The haematopoietic stem cells harvested were reinjected on day 7. Granulocyte colony-stimulating factor had been administered from day 8 up to haematological recovery (PMN⩾2.5 × 109/l). Anti-emetics, antibiotics, red blood cells and platelets transfusions were used as required.
Post-intensification treatment was decided in each case according to the efficacy and toxicity of the first HD cycle: continuation of topotecan at conventional doses, administration of a second intensification with topotecan at the same or at lower dose level in case of previous toxicity (according to the judgement of each investigator and the agreement of the patient), re-introduction of topotecan or other therapeutic agents only in the event of relapse, best supportive care or simple ‘wait-and-see’ attitude. Patients whose disease did not respond to the first HD cycle were not proposed for a second one. If a second high-dose topotecan at the same dose level or at the immediately lower dose level was performed, survival was calculated from the time of administration of the first HD cycle, and the extra-haematopoietic toxicities observed during this second cycle were not used for the determination of the MTD of topotecan.
Pharmacokinetic parameters were planned to be studied in all patients on days 1 and 2. It was planned to make the following blood sampling, on a 1.5 ml sample collected in a heparinized tube (lithium heparinate), drawn peripherally or via the central catheter after a 5 ml purge. The chronology of the sample was (T0=start of infusion) as follows: on Day 1: T0, T15 and T25 (min), and T1, T2, T4, T8 and T24 (h): and on day 2: T0, T15 and T25 (min), and T1, T2, T4, T8, T24 and T48 (h). Samples were immediately dispatched in ice to the laboratory. The samples were centrifuged and the plasma was stored at −25°C until analysis. Total plasma topotecan concentrations were assayed using a high-performance liquid chromatography with fluorescence detection.12 Topotecan pharmacokinetic parameters were obtained using Micropharm software (S Urien, CRH-Inserm, St-Cloud, France).
Characteristics of the patients
(Tables 1 and 2) This phase I study was performed in four institutions between August 1998 and April 2002. Analysis was performed on December 2004. Forty-nine patients were enrolled in this phase I study. Characteristics of the population and the status of the disease at the time of inclusion are summarized in Tables 1 and 2.
The median number of CD34+ cells collected per graft was 5 × 106 CD34+/kg of body weight (range: 2.45–21.5). Six patients (12%) failed to be harvested. Except chemotherapy-induced neutropenia and/or febrile aplasia, no particular toxicities were observed during this phase of treatment.
Treatment, extrahaematopoietic toxicities, toxic deaths and determination of the MTD
Forty-three patients could be treated with HD topotecan. The number of patients treated at each dose level is summarized in Table 3. Toxicity and MTD were evaluated only after the first HD topotecan cycle. One sepsis-related death unfortunately occurred on day 12 of the first course of treatment at a dose level of 7 mg/m2/day × 5 days. No other DLTs were observed in the five other patients treated at this dose. Two episodes of grade IV diarrhoea were observed at 9.5 mg/m2/day × 5 days. As one of these two episodes was only notified after a delay (retrospectively upgraded from grade III to grade IV), three patients were treated in the subsequent dose level, set up at 10 mg/m2/day × 5 days. In these last 3 patients treated, no major toxic side effects were observed. However, this phase I trial was closed and the MTD was consequently established at 9.0 mg/m2/day × 5 days. Other extra-haematopoietic grade III–IV toxicities consisted mainly cutaneous toxicity (grade III maculopapular eruption) in one patient and vomiting in 10 patients. Eight patients experienced fever during the administration of topotecan. The fever was characterized by its intensity (up to 40°C), occurring each evening during the 5-day course of topotecan. This symptom was successfully prevented later by the administration of 5 mg of dexchlorpheniramin.
The median number duration of PMN<0.5 × 109/l was 9 days (range: 4–12 days) and that of grade IV thrombocytopenia was 2 days (range: 0–7 days).
Subsequent therapy, response to therapy and survival
Following the first HD cycle, subsequent therapy consisted in a second HD cycle of topotecan for 15 patients (35%): 13 patients (30%) received a second cycle at the same dose level and two (5%) received a second course at the immediately lower dose level. No toxic death occurred during the second HD cycle. The other patients received conventional courses of topotecan (five patients), other or various conventional CT regimens (seven patients), or best supportive care (15 patients).
Five patients were not assessable for response: three patients who were grafted in CR, one who died from toxic side effects on day 12 and one for whom a ‘wait and see’ attitude without any evaluation was observed as requested by the patient. For the 38 evaluable patients, 10 (26%) achieved a clinical CR with a median duration of 6 months (range: 2–50+ months). One of these CR was surgically confirmed. Eight patients (21%) achieved a PR with a median duration of 4.8 months (range: 1–9 months). Thirteen patients (34%) were considered to have stable disease, and seven patients clearly failed to have any response to HDCT.
Survival, which remains an unusual end point for a phase I study was determined from the date of the HD cycle for the forty three patients who completed their HD cycles. At the time of analysis, 34 patients had died from disease progression. The median survival time was 18 months and the 5-year overall survival rate was 20% (Figure 1). Considering the variation of disease status at the time of inclusion and of dose level administered to the 13 patients who received a second high-dose CT, it was impossible to draw any conclusions on differences in survival between patients who received only one HD cycle and those for whom a second cycle was proposed. Moreover, the heterogeneity of the population did not allow us to compare the survival of this population to the survival of patients treated with conventional chemotherapy or to draw any conclusions on survival differences.
Twenty-six patients having received topotecan at a dose level from 4 to 9.5 mg/m2/day × 5 days were included in the pharmacokinetic study. Eight blood samples were collected per patient up to 24 h after the beginning of topotecan administration on day 1 and 9 up to 48 h of their first HD cycle. A linear relationship between dose and AUC has thus been determined (Figure 2).
The end point of this phase I study was to define the MTD of HD topotecan used as a single agent supported by AHSCT in patients with advanced OC. This MTD has been defined as 9.0 mg/m2/day × 5 days, for a total dose of 45 mg/m2, given in a 30 min daily infusion, with grade IV diarrhoea as the dose-limiting factor, occurring in two out of five patients treated at this dose level.
Analysis of published data on treatment intensification in the management of advanced OC reveals several difficulties in interpretation: small cohorts of patients, median follow-up durations too short, various treatment intensification regimens, heterogeneous populations of patients, and highly variable tumour stages. An additional difficulty encountered in interpreting the results is that the response is rarely surgically confirmed.13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 Nevertheless, some points are worth emphasizing: the achievement of high response rates, including responses in refractory tumours (although the duration of response is rarely prolonged) and the substantial decrease in morbidity and mortality achieved by the use of AHSCT and G-CSF support.
Topotecan is a topoisomerase I inhibitor, with a specific mechanism of action. On the basis of phase I studies, the conventional scheme of administration was defined at the dose of 1.5 mg/m2/day × 5 days, as a 30 min infusion every 3 weeks. Its efficacy has been reported in two important phase III trials using topotecan at standard dose. Ten Bokkel Huinink et al.4 compared topotecan with paclitaxel (175 mg/m2 in 3 h), both every 3 weeks as second-line treatment in 226 patients. Time to progression and survival were similar. Gordon et al.5 compared topotecan to pegylated liposomal doxorubicin as second-line therapy in 474, patients both with platinum-refractory or platinum-sensitive OC. The median survival times were respectively 59.7 weeks and 62.7 weeks, P=0.05.
The impact of the schedule of administration of topotecan has been explored in different phase II conventional studies and in HD protocols. At conventional doses, haematopoietic toxicity was the dose-limiting factor. In the Creemers' study, grade IV neutropenia occurred in 40% of the cycles and 78.4% of the patients, and lasted for a median of 7 days.24 In the Kudelka et al.'s25 trial, a dose reduction was necessary in 21 patients. Grade III–IV neutropenia occurred in 66% of the patients, with a median duration of 10 days (range: 3–21 days). Grade III–IV thrombocytopenia was seen in 66% of the patients, with a median duration of 5 days (range: 2–17 days). Similar toxicities were observed in the two phase III studies described before trials conducted by ten Bokkel Huinink et al.4 and Gordon et al.5 Hoskins et al.26 have evaluated in a population of 66 patients the efficacy and the toxicity of standard dose topotecan (group A), compared to a 24 h infusion once a week for 4 weeks repeated every 6 weeks at a dose of 1.75 mg/m2 (group B). The response rate in arm A was 22.6% (95% confidence interval, 9.6–41.2%), which was significantly superior to that in arm B, 3.1% (95% confidence interval, 0.1–16%) (P=0.026). The regimens were not equitoxic, with 94% of patients on arm A experiencing grade 3 or 4 granulocytopenia as opposed to 52% on arm B.26
Beyond the standard dose, recourse to G-CSF became essential.27, 28 Rowinsky et al.28 reported their experience in a trial in which 36 patients received 121 cycles of topotecan, at the dose of 1.75 mg/m2/day × 5 days for highly pretreated patients and 4.2 mg/m2/day × 5 days for minimally pretreated patients. The recommended MTD for subsequent-phase studies of topotecan with G-CSF had to be set up at 3.5 mg/m2/day × 5 days.28 Other toxicities observed here were variable, moderate and generally rapidly reversible (macular or papular cutaneous rash, diarrhoea, peripheral neuropathy, myalgia and arthralgia).
At higher doses, many studies have been conducted and extra-haematopoietic toxicities depended both on the dose and the scheme of administration of topotecan, that is, a 30 min administration or a continuous infusion (CI) in 1 or 5 days (Table 4). Wall et al.29 and van Warmerdam et al.30 proposed an administration on day 1 respectively by a 30 min infusion or a 24 h CI. As a 30 min infusion and at a dose of 22.5 mg/m2, dose-limiting toxicity was the myelosuppression.29 Some grade I–II non-haematological toxicity (fever, vomiting, alopecia, diarrhoea, cutaneous rash) occurred. As a 24 h CI given every 28 days and at a dose of 10.5 mg/m2/day, the toxicity was primarily haematological, with grade III–IV neutropenia occurring in 30% of the patients and grade IV thrombocytopenia in 44% of the patients.30
Two other studies have explored an administration of HD topotecan for 5 days by a continuous 24 h infusion. In the Kantarjian et al.'s31 trial, the dose level tested ranged from 3.5 to 18 mg/m2. Mucosal toxicity was substantial beyond 11.8 mg/m2. The MTD was set up at 10 mg/m2. Oesophagitis and gastrointestinal haemorrhages were reported. In the Rowinskyet al.'s32 study, at 2.7 mg/m2/day a constant grade III–IV mucosal toxicity occurred. This severe toxicity affected the upper and lower gastrointestinal tracts with severe perianal ulcerations. It was maximal at days 10–15, and resolved at days 28–35. It became predominant as soon as the dose exceeded 2.1 mg/m2/day.This is the reason why previous pelvic radiotherapy was a non-inclusion criterion in our study.
In terms of pharmacokinetics, a linear relationship between dose and AUC has been determined in the dose range of 3–9 mg/m2/day × 5 days. According to Rowinsky et al.,28 pharmacokinetics were also linear within the dosing range of 2.0–3.5 mg/m2/day, but topotecan clearance was lower at the 4.2 mg/m2/day dose level. The pharmacokinetic parameters obtained here and those published by Wall et al.29 were in the same magnitude.
In conclusion, a 1-day single administration does not allow more than 22.5 mg/m2 in a 30 min administration29 or 10.5 mg/m2 in a 24 h CI.30 With a continuous 5-day infusion, the MTD was set up at 10.5 mg/m2.31, 32 Without and with AHSCT and G-CSF support, MTDs were respectively 10 and 17.5 mg/m2. Gastro-intestinal toxicities were mainly induced by a 1- or 5-day CI. The recourse to AHSCT and G-CSF support allows a substantial increase of the dose of topotecan administered. In our study, with a 30 min daily infusion on 5 days, the MTD was reached at 9.0 mg/m2/day × 5 days (45 mg/m2).
In view of these data, we recommend the following scheme for subsequent HD topotecan protocols in monotherapy: administration of treatment for 5 consecutive days, a 30 min infusion, use of AHSCT/G-CSF support and MTD of 9.0 mg/m2/day × 5 days. Based on a previously published report, we are now exploring the combination of HD topotecan, using a starting dose of 7.5 mg/m2/day × 5 days, and HD CPM. These regimens could merit further studies in various solid and haematologic tumours.33, 34, 35
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We thank all the research nurses of the Bone Marrow Transplant Units for their expert and compassionate care of our patients, the secretaries for their help in the realization of this study, Graham A Ross for his editorial assistance and GlaxoSmithKline and Amgen Laboratories.
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Lotz, JP., Pautier, P., Selle, F. et al. Phase I study of high-dose topotecan with haematopoietic stem cell support in the treatment of ovarian carcinomas: the ITOV 01 protocol. Bone Marrow Transplant 37, 669–675 (2006). https://doi.org/10.1038/sj.bmt.1705310
- ovarian carcinoma
- high-dose chemotherapy
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