Skip to main content
NCBI home page
Journal of Cancer Research and Clinical Oncology logoLink to Journal of Cancer Research and Clinical Oncology
. 2007 May 4;133(9):653–661. doi: 10.1007/s00432-007-0216-y

Topotecan, cyclophosphamide, and etoposide (TCE) in the treatment of high-risk neuroblastoma. Results of a phase-II trial

Thorsten Simon 1,✉, Alfred Längler 2, Urs Harnischmacher 3, Michael C Frühwald 4, Norbert Jorch 5, Alexander Claviez 6, Frank Berthold 1, Barbara Hero 1
PMCID: PMC12160921  PMID: 17479288

Abstract

Purpose

Relapsed high-risk neuroblastoma patients still have a poor prognosis. This phase-II trial assessed a new topotecan containing chemotherapy approach in patients with active disease.

Methods

Chemotherapy consisted of topotecan (1.0 mg/m2/day 168-h continuous infusion), cyclophosphamide (100 mg/m2/day 1-h-infusion days 1–7 starting 6 h prior to topotecan), and etoposide (100 mg/m2/day 1-h-infusion days 8–10). Patients with relapsed neuroblastoma were scheduled for six cycles, untreated patients for two cycles followed by standard high-risk treatment.

Results

Main toxicity observed during 153 cycles were grade 3–4 leukopenia (97% of cycles), thrombocytopenia (92%), neutropenic fever (52%), and mucositis (10%). No treatment related fatal toxicity occurred. Complete or partial response was achieved in 19 of 31 (61%) evaluable relapsed patients and 8 of 11 (72%) untreated patients.

Conclusions

The combination of topotecan, cyclophosphamide, and etoposide is tolerable and effective in relapsed and untreated neuroblastoma. Myelotoxicity is the main side effect but seems justified in view of the encouraging response rates. A randomized phase-III trial in primary disease has been commenced.

Keywords: Neuroblastoma, Relapse, Topotecan, Toxicity, Outcome, Child, Phase-II clinical trial

Introduction

Despite intensive chemotherapy, surgery, radiotherapy, and myeloablative chemotherapy, children with metastatic neuroblastoma still have a poor prognosis (Matthay et al. 1999; Tweddle et al. 2001; Berthold et al. 2005). Therefore, new treatment strategies are urgently needed for relapse and first line treatment.

Topotecan (9-[(dimethylamino)methyl]-10-hydroxy(20S)-camptotecin, Hycamtin® GlaxoSmithKline, Munich, Germany) acts as a topoisomerase I inhibitor (Pommier et al. 1995; Godard et al. 2002). It proved to be effective in murine neuroblastoma xenografts (Houghton et al. 1995; Vassal et al. 1997; Zamboni et al. 1998) and in phase I-II trials (Pratt et al. 1994; Tubergen et al. 1996; Blaney et al. 1998; Nitschke et al. 1998; Frangoul et al. 1999; Kramer et al. 2003; Kretschmar et al. 2004; Santana et al. 2005). The main side effects were myelosupression, nausea, vomiting, and mucositis. The combination of topotecan and etoposide can increase the cytotoxic effect by inhibition of topoisomerase I and II. Sequential application of topotecan followed by etoposide was found to be more effective because topoisomerase I and II are expressed reciprocally (Tan et al. 1989; Sugimoto et al. 1990; Kim et al. 1992; Bonner et al. 1996; Whitacre et al. 1997; Taron et al. 2000). Numerous clinical trials demonstrated feasibility and efficacy of this combination and found myelotoxicity and mucositis as main side effects (Herben et al. 1997; Hammond et al. 1998; Crump et al. 1999; Vey et al. 1999; Dowlati et al. 2001; Huisman et al. 2001; Kancherla et al. 2001; O’Neill et al. 2001; Mok et al. 2002). Pre-clinical data also suggest a positive interaction between topotecan and alkylating agents such as cyclophosphamide (Kaufmann et al. 1996; Coggins et al. 1998). Cyclophosphamide followed by topotecan was found to be tolerable in adults (Murren et al. 1997; Hanjani et al. 2002) and children with cancer (Saylors et al. 2001). Main side effects were bone marrow depression and infection. Combinations of cyclophosphamide and etoposide, the other two components of the drug combination, have been used in neuroblastoma (Tweddle et al. 2001) and osteosarcoma (Rodriguez-Galindo et al. 2002) for many years.

We previously reported on the effectiveness of topotecan monotherapy (1.0 mg/m2/day for 5 days) as palliative treatment (Langler et al. 2002). Based on our own experiences and published data, we initiated a trial of topotecan, etoposide, and cyclophosphamide (TCE) in the treatment of patients with high-risk neuroblastoma. Since protracted topotecan administration was found to be more effective (Houghton et al. 1995; Tubergen et al. 1996) and CNS penetration is time dependent (Baker et al. 1996), topotecan was given as continuous infusion over 7 days. The primary objective of this trial was toxicity secondary was response.

Patients and methods

Patient selection

A total of 44 neuroblastoma patients from 26 centers entered the trial between May 2003 and April 2005. Patients with relapsed neuroblastoma were screened for trial entry by the German neuroblastoma trial office, which coordinates 80 participating centers of the German neuroblastoma trials. However, the participation of any patient was an individual decision by the physician, the parents, and the patient considering the patient’s general condition, psychological factors, and the trial criteria. After interim analysis of the first ten relapsed patients had revealed acceptable response rates and toxicity, trial centers of the German neuroblastoma trials had the option to enroll newly diagnosed pilot patients on the new regimen.

Inclusion criteria were: Progressing active neuroblastoma, age between 1 and 21 years, neutrophil count 500/μl or higher, and platelet count 50,000/μl or higher unless bone marrow metastasis caused cytopenia. Patients were excluded if they received other anti-tumor therapy ≤4 weeks prior to or parallel to TCE treatment (i.e., other chemotherapy, retinoic acid therapy, tumor vaccination, external beam radiation therapy, or MIBG therapy), if grade ≥2 liver function toxicity was present, if renal function was substantially impaired, if hypersensitivity to one of the drugs was known, if life expectancy was estimated to be less than 6 weeks, or if informed consent could not be obtained.

The trial protocol was reviewed and approved by the ethics committee of the University of Cologne and the boards of the participating hospitals. In accordance with the Helsinki Declaration, informed parents’ consent for the treatment with TCE and for the collection of data were obtained prior to inclusion of a patient into the trial. Patients’ insurance coverage was provided.

Treatment

All patients were admitted to inpatient facility for TCE chemotherapy. The chemotherapy cycles consisted of topotecan (1.0 mg/m2/day continuous infusion during days 1–7, i.e., 168 h) and cyclophosphamide (100 mg/m2/day 1-h infusion on days 1–7) followed by etoposide 100 mg/m2/day 1-h infusions on days 8–10. Cyclophosphamide was started 6 h prior to topotecan. It was given parallel to the topotecan continuous infusion on days 2–7. Since topotecan and cyclophosphamide do not interact in vitro, simultaneous application was allowed even if the patient had single lumen central venous access. For prevention of hemorrhagic cystitis, all patients received hydration (2,000 ml/m2/day) and MESNA (three doses of 40 mg/m2 given prior, 4 h, and 8 h after cyclophosphamide). The TCE cycles had to be repeated every 28 days unless bone marrow reconstitution required further delay. If severe bone marrow or other toxicity caused delay of the next cycles beyond 30 days, topotecan does was reduced to 0.66 mg/m2/day in the next cycle. If the reduced topotecan cycle again resulted in protracted bone marrow reconstitution >30 days, additional reduction of cyclophosphamide to 66% was recommended. The use of granulocyte stimulating factor was not planned in the trial protocol but strongly recommended (G-CSF 5 μg/day as single daily subcutaneous dose) after ascertainment of the first patients who developed considerable bone marrow depression.

Relapsed patients were scheduled for a maximum of six TCE cycles unless progression or severe nonhematopoietic toxicity was observed. The response was assessed as the best tumor status achieved after a variable number of TCE cycles but no other tumor treatment. If the TCE treatment was stopped for any reason and/or therapy was continued using other elements after substantial response, the tumor status prior to the first additional treatment element was registered as the best response to TCE. Previously untreated patients received a window of two TCE cycles prior to the complete treatment according to the transplantation arm of the German NB97 neuroblastoma high-risk group trial (Berthold et al. 2005).

Assessment

Toxicity was monitored continuously by clinical examination and routine blood analysis at least every 2–4 days during and after each cycle. Toxicity symptoms were documented and reported according to the National Cancer Institute Common Toxicity Criteria Version 2.0 (http://www.ctep.cancer.gov).

At trial entry, all patients underwent complete staging including clinical status, tumor markers, imaging, MIBG scintigraphy, and centrally reviewed bone marrow cytology and immunocytology (four sites). Prior to each TCE cycle, clinical status, tumor markers, and ultrasound were assessed in order to identify refractory and progressing patients. All newly diagnosed patients underwent appropriate staging after two TCE cycles before they continued with NB97 standard high-risk treatment. Relapsed patients underwent appropriate staging according to the relapse pattern at least after every two TCE cycles. If progression was suspected or alternative chemotherapy was planned after six TCE cycles, complete staging was scheduled. If rapid progression was diagnosed unequivocally by clinical examination and/or imaging in relapsed patients, complete technical assessment was considered unethical and was not mandatory. According to the INSS criteria (Brodeur et al. 1993), response was defined as complete (CR), very good partial (VGPR), partial (PR), as stable disease (SD), or progressive disease (PD). Follow up data were collected by the German neuroblastoma trial office since all patients were registered in the German neuroblastoma trials NB90, NB97, and NB2004.

Statistics

The trial consisted of two strata. First, patients with ongoing relapse or progression of high-risk neuroblastoma (i.e., metastatic stage 4 or MYCN-amplification of any stage) were included. Two or more responses had to be seen among the first ten patients in order to continue the trial. At least six responses had to be seen in 29 relapsed patients in order to assume efficacy of TCE treatment (P 0 = 0.10, P 1 = 0.30, α = 0.05, and β = 0.20, where P 0 is the uninteresting response level and P 1 is the desirable response level) (Simon 1989). The second stratum consisted of previously untreated patients with metastatic neuroblastoma. Using identical boundaries, two objective responses were necessary among ten patients to assume effectiveness of TCE as primary treatment. Toxicity and response were analyzed separately for relapsed and newly diagnosed patients. The SPSS package (Release 11.0.1) was used for statistical analysis. Proportions were compared using the two-tailed χ 2-test or Fisher’s exact test as appropriate. Means were compared by Mann–Whitney U-test.

Results

Patients’ characteristics (Table 1)

Table 1.

Patients’ characteristics

Relapsed patients Untreated patients
Number of patients 33 11
Age at first diagnosis
Median (years) 3.9 2.4a
Range (years) 0–12.5 0.3–5.8a
Age at TCE start
Median (years) 6.4 2.6
Range (years) 1.3–21.2 1.1–5.8
Observation time
Median (years) 2.1 1.9
Range (years) 0.3–3.5 1.4–2.7
Sex
Male 19 6
Female 14 5
INSS stage at first diagnosis
1–3 9 1a
4 24 10
Extent of disease at TCE start
Localized 9 0
Metastatic 24 11
Disease pattern at TCE start
Primary site 20 11
Bone marrow 17 7
Bone 14 7
Liver 4 1
CNS 2 0
Distant lymph nodes 3 2
Pleura 1 1
MYCN status
Single copy 24 7
Amplified 9 4
Primary treatment
NB90 without ASCT 3
NB97 with ASCT 17
NB97 without ASCT 13
Open in a new tab

aOne patient had MIBG positive relapse with bone metastasis 10 months after diagnosis of stage 1 neuroblastoma

A total of 44 patients received 154 TCE cycles during relapse or first line treatment. Fifteen additional patients were excluded since they started relapse management with other chemotherapy regimens or underwent parallel radiation therapy (Fig. 1). The age at initial diagnosis was 3.3 years (range 0–12.5 years). The median age at first TCE cycle was 5.6 years (range 1.1–21.2 years).

Fig. 1.

Fig. 1

Open in a new tab

Trial profile

All 33 relapsed patients had received intensive front-line chemotherapy according to the German multi-center trials NB90 and NB97. This frontline therapy contained etoposide (cumulative dose 2,000 mg/m2 in NB90 and 1,200 mg in NB97) and ifosfamide (cumulative dose 30,000 mg/m2 in NB90 and 22,500 mg/m2 in NB97) (Berthold et al. 2003). No patient had previously received topotecan or cyclophosphamide. Seventeen relapsed patients had undergone myeloablative chemotherapy with autologous stem cell transplantation during initial treatment (Berthold et al. 2005). Nine children were treated for local relapse, 24 for metastatic relapse (with or without local tumor recurrence).

Toxicity

A total of 154 TCE cycles were applied during the trial. Twelve cycles were excluded from toxicity analysis because the cycles were stopped prematurely (n = 7), or documentation was not sufficient (n = 5). A total of 142 cycles (92%) were evaluable for toxicity: 120 cycles were given to relapsed patients and 22 cycles during first line treatment (Fig. 1). The toxicity symptoms are reported in Table 2. Grade 3–4 leukopenia was observed in 138 of 142 cycles (97%). The median time from the start of chemotherapy to leukocyte nadir was 14 days. It was longer in relapsed patients (15 days) than in newly diagnosed patients (13 days, P = 0.001). During neutropenia, 73 of 142 cycles (51%) were followed by febrile episodes and required additional hospital treatment. Cultures taken during these episodes were negative. Grade 3–4 thrombocytopenia occurred in 131 of 142 cycles (92%). The median interval between TCE start and platelet nadir was 15 days. It was very similar in relapsed patients (15 days) and newly diagnosed patients (15.5 days, P = 0.851). All patients who were evaluable for toxicity experienced at least one episode of grade 3–4 bone marrow toxicity during the complete TCE treatment. Either grade 3–4 oral mucositis or enterocolitis were observed after 14 cycles (10%). No treatment related death or fatal infection occurred among the patients in the trial.

Table 2.

Toxicity observed during 142 TCE cycles in 43 evaluable patients

Grade Relapsed patients Newly diagnosed patients
Cycles Patients Cycles Patients
n % n % n % n %
Total number 120 100 32 100 22 100 11 100
Leukopenia 3 35 29 7 22 6 27 2 18
4 81 67 25 78 16 73 9 82
Fever >38.5°C 62 52 31 97 11 50 8 72
Thrombocytopenia 3 9 7 0 0 2 9 0 0
4 100 83 32 100 20 91 11 100
Mucositis 3 2 2 2 6 0 0 0 0
4 2 2 2 6 0 0 0 0
Skin toxicity 3 2 2 2 6 1 5 1 9
4 0 0 0 0 0 0 0 0
Diarrhea/colitis 3 3 2 3 9 4 18 4 36
4 2 2 2 6 1 5 1 9
Nausea/emesis 3 5 4 2 6 0 0 0 0
4 3 2 2 6 0 0 0 0
Open in a new tab

Drug doses were reduced as recommended by the protocol in 52 of 142 TCE cycles. This detoxification reduced the rate of febrile infections from 63 to 33% (P = 0.001) but not the incidence of grade 3–4 leukopenia (P = 0.413) and grade 3–4 thrombocytopenias (P = 0.644). The median interval between subsequent TCE cycles was 34 days after full dose TCE cycles and 31 days after reduced dose TCE (P = 0.574).

Response and outcome

Patients with recurrent neuroblastoma received a median number of four TCE cycles (range 1–8) before they either experienced progression or received other treatment elements. Among the first ten patients, six objective responses were observed exceeding the planned two responses. Later, two patients entered the trial after complete resection of local relapse and were not evaluable for response. Among 31 relapsed patients evaluable for objective response, four patients achieved complete or very good partial remission and 15 patients achieved partial remission (61%) after treatment with median number of two TCE cycles (range 1–7). Details are listed in Table 3. The median duration of best response was 151 days (range 21–295 days). The response rate was not influenced by factors as ASCT during first line treatment (P = 0.707), presence of MYCN amplification (P = 1.000), localized versus metastatic disease at first diagnosis (P = 0.372), and local versus metastatic disease at relapse (P = 0.106). The mean time from TCE start to progression was 225 days (range 30–746 days). During the progression free interval, some patients received additional treatment elements after TCE response assessment. Eight patients with continuing response to TCE received treatment intensification by autologous stem cell transplantation. Unfortunately, seven of them later experienced further relapse and four of them subsequently have died of disease, so far. As of August 2006, 18 of 33 relapsed patients have died due to disease progression, three are alive with active disease, seven are in CR/VGPR, four are in PR, and one patient is under treatment for secondary AML. Among the patients who died, 11 had initially responded to TCE chemotherapy and seven had shown no response to TCE chemotherapy.

Table 3.

Disease pattern, response, and outcome of trial patients

Number Pre-treatment Disease pattern at TCE start Status after two cycles Best response Best response confirmed by Final outcome
1 NB97 HR BM, bone, LN PD PD Clinical DOD
2 NB97 HR PT, BM PR PR CT, BM DOD
3 NB97 HR PT, liver, LN n.a. PR Ultrasound DOD
4 NB97 HR PT PR PR MRI Relapse
5 NB97 SR PT SD PR MRI, MIBG Progression
6 NB97 HR PT, BM, bone PD PD MRI, BM DOD
7 NB97 HR PT, BM, bone PR PR MRI, MIBG DOD
8 NB97 HR PT, BM, bone PD PD MRI, MIBG DOD
9 NB90 HR Bone, pleura, liver n.a. SD MRI, MIBG SMD
10 NB97 HR BM PR PR MIBG, BM DOD
11 NB97 SR PT VGPR VGPR MRI, MIBG DOD
12 NB97 SR PT PR PR MRI CR2
13 NB90 HR BM, bone PD PD BM CR2
14 NB97 HR PT, BM, bone, liver PD PD MRI DOD
15 NB97 HR Bone PR CR MRI, MIBG, bone scan CR2
16 NB97 HR PT, BM PR PR MRI, BM DOD
17 NB97 HR PT PR PR MRI DOD
18 NB97 HR CNS PR PR CCT DOD
19 NB97 SR BM, bone PR PR MRI, BM Progression
20 NB97 SR PT, BM, bone PD PD MRI CR3
21 NB97 HR BM n.a. PR MIBG, BM PR
22 NB97 SR PT c.r. c.r. MRI CR3
23 NB97 HR PT, BM, bone PR PR MRI, MIBG, BM DOD
24 NB97 HR BM PD PD MRI, clinical DOD
25 NB97 HR Bone PR PR MIBG, MRI DOD
26 NB97 HR PT PR CR MRI DOD
27 NB90 HR + six cycles carboplatin/VP16 LN PR VGPR MRI CR3
28 NB97 HR PT PD PD MRI DOD
29 NB97 HR BM, bone n.a. PR MIBG, BM PR
30 NB97 HR BM, CNS PD PD MRI, clinical Progression
31 NB97 HR PT, BM, bone PD PD Clinical PR
32 NB97 SR PT (MIBG negative) c.r. c.r. MRI CR2
33 NB97 HR PT, liver PD PD MRI DOD
34 None PT, bone PR MRI CR2
35 None PT, BM, bone PR MRI, MIBG, BM Progression
36 None PT, BM, bone PR MRI, MIBG, BM DOD
37 None PT, LN, pleura PR MRI Progression
38 None PT, BM, bone SD Ultrasound, MIBG, BM DOD
39 None PT, BM PR Ultrasound, BM DOD
40 None PT, bone, LN PR MRI, MIBG CR1
41 None PT, bone, liver SD MRI, BM CR1
42 None PT, BM, bone PR MRI, MIBG, BM DOD
43 None PT, bone PR MRI CR1
44 None PT, BM, bone PD MRI, MIBG CR2
Open in a new tab

PT primary tumor, BM bone marrow, LN distant lymph node, n.a. not assessed, c.r. complete resection, DOD death of disease, SMD secondary malignant disease

In untreated patients, eight partial remissions and two stable diseases were achieved after two cycles (Table 3). One patient experienced progression during TCE treatment documented by occurrence of new lesions in MIBG scintigraphy and increase of urinary catecholamine excretion but later responded to standard high-risk chemotherapy. Of note, the NB97 trial found a very similar response rate of 88% after four cycles induction chemotherapy (P = 0.159). All 11 newly diagnosed TCE patients were able to finish the high-risk induction chemotherapy and to proceed with ASCT and retinoic acid consolidation therapy (Berthold et al. 2005). So far, 6 of the 11 patients developed relapse after completion of induction chemotherapy and ASCT at a median time of 1.6 years from diagnosis (range 0.6–2.9 years).

Discussion

This trial found the combination of TCE to be an effective therapy for relapsed and newly diagnosed neuroblastoma patients.

No unexpected toxicity was observed. Bone marrow depression was the main side effect. During leukopenia, more than half of the patients developed fever and required intravenous antibiotic treatment. The bone marrow toxicity is considered acceptable only in view of the high response rate. Dose escalation was not planned in the trial but the toxicity profile indicated that doses were at the limit. A very similar toxicity profile was observed after treatment with topotecan, doxorubicin, and vincristine (Garaventa et al. 2003). Transfusions of packed red cells and platelets were considered as requirement for any intensive chemotherapy and were not registered during this trial. Mucosal toxicity occurred less frequently. However, after the closure of the trial, a 6-year-old patient developed severe enterocolitis after the first TCE cycle and subsequently died due to neutropenic septicemia. It is important to emphasize that mucosal toxicity is a potential hazard of TCE chemotherapy. Unfortunately, this study did not collect pharmacokinetic data, which might have allowed better prediction of toxicity. It is well known that the topotecan lactone clearance is highly variable between individuals (Tubergen et al. 1996; Montazeri et al. 2000).

Response data on topotecan based triple drug chemotherapy in neuroblastoma are limited. The combination of cyclophosphamide (2 × 70 mg/kg), topotecan (4 × 2.0 mg/m2), and vincristine (1 × 0.067 mg/kg) achieved complete or partial response in 4 of 26 (15%) heavily pretreated relapsed or refractory neuroblastoma patients (Kushner et al. 2004). Myeloablative chemotherapy consisting of topotecan (5 × 2.0 mg/m2), thiotepa (3 × 300 mg/m2), and carboplatin (3 × 500 mg/m2) showed manageable toxicity in 11 poor risk neuroblastoma patients (Kushner et al. 2001). Response and outcome were not evaluated because the patients also received frontline induction therapy and anti-GD2-antibody based consolidation therapy. The similar chemotherapy regimen achieved response in four of five newly diagnosed patients with high-risk neuroblastoma (Park et al. 2000). Another study reported complete or partial response in 64% of relapsed patients after treatment with topotecan (1.5 mg/m2/day for 30 min days 1–5), doxorubicin (45 mg/m2 continuous infusion days 6–7), and vincristine (2.0 mg/m2 continuous infusion days 6–7) (Garaventa et al. 2003). This corresponds with the response data reported in our trial. We chose drugs other than doxorubicine and vincristine in order to avoid cumulative toxicity after primary chemotherapy containing this class of compounds or by addition of TCE to first line treatment protocols.

Response and outcome results in relapsed neuroblastoma patients cannot be as easily translated into response data as in newly diagnosed patients. Initial treatment intensity differs and tumor cells may acquire drug resistance during chemotherapy (Keshelava et al. 1998). This might be important even in topotecan naïve relapsed patients since cross-resistance between etoposide and topotecan has been reported (Keshelava et al. 2000; Calvet et al. 2004). Therefore, one can expect better response rates in untreated patients. Accordingly, between 39 and 64% of untreated neuroblastoma patients responded to topotecan monotherapy (Kretschmar et al. 2004; Santana et al. 2005). This is in line with our results showing partial response in 8 of 11 untreated high-risk neuroblastoma patients (72%).

Eight relapsed patients with continuing response to TCE underwent treatment intensification by autologous stem cell transplantation. Stem cell collection after TCE chemotherapy yielded sufficient numbers of stem cells. This phase-II trial did not collect detailed data on stem cell aphaeresis after TCE. Of note, six intensively pretreated relapsed neuroblastoma patients underwent stem cell aphaeresis after TCE chemotherapy in our hospital, so far. Despite the acute bone marrow toxicity of TCE chemotherapy it was possible to collect a median total number of 4.5 million CD34 positive cells per kg body weight.

The combination of TCE was found effective and tolerable in relapsed and newly diagnosed neuroblastoma patients. Considering the 3-year event free survival of 47% for high-risk neuroblastoma patients treated according to the ASCT arm of the NB97 trial (Berthold et al. 2005), additional TCE cycles might warrant further improvement of long-term survival in high-risk neuroblastoma. Therefore, the German neuroblastoma study group has opened a randomized multi-center window trial in newly diagnosed high-risk neuroblastoma patients. Patients are randomized to either receive two cycles of TCE followed by treatment with the NB97 ASCT arm or by this arm only.

Acknowledgments

We thank the following investigators for the participation in the study: R Mertens (Aachen), A Gnekow (Augsburg), G Henze (Berlin), U Bode (Bonn), W Eberl (Braunschweig), I Krause (Chemnitz), R Frank (Coburg), T Wiesel (Datteln), M Suttorp (Dresden), T Klingebiel (Frankfurt), A Reiter (Giessen), A Kulozik (Heidelberg), N Graf (Homburg/Saar), M Wright (Kassel), S Völpel (Krefeld), B Selle (Ludwigshafen), A Jobke (Nuremberg), O Peters (Regensburg), H-G Scheel-Walther (Tübingen), P-G Schlegel (Würzburg), and F Niggli (Zurich).

References

  1. Baker SD, Heideman RL, et al (1996) Cerebrospinal fluid pharmacokinetics and penetration of continuous infusion topotecan in children with central nervous system tumors. Cancer Chemother Pharmacol 37(3):195–202 [DOI] [PubMed] [Google Scholar]
  2. Berthold F, Boos J, et al (2005) Myeloablative megatherapy with autologous stem-cell rescue versus oral maintenance chemotherapy as consolidation treatment in patients with high-risk neuroblastoma: a randomised controlled trial. Lancet Oncol 6(9):649–658 [DOI] [PubMed] [Google Scholar]
  3. Berthold F, Hero B, et al (2003) Long-term results and risk profiles of patients in five consecutive trials (1979–1997) with stage 4 neuroblastoma over 1 year of age. Cancer Lett 197(1–2):11–17 [DOI] [PubMed] [Google Scholar]
  4. Blaney SM, Needle MN, et al (1998) Phase II trial of topotecan administered as 72-hour continuous infusion in children with refractory solid tumors: a collaborative Pediatric Branch, National Cancer Institute, and Children’s Cancer Group Study. Clin Cancer Res 4(2):357–360 [PubMed] [Google Scholar]
  5. Bonner JA, Kozelsky TF (1996) The significance of the sequence of administration of topotecan and etoposide. Cancer Chemother Pharmacol 39(1–2):109–112 [DOI] [PubMed] [Google Scholar]
  6. Brodeur GM, Pritchard J, et al (1993) Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment. J Clin Oncol 11(8):1466–1477 [DOI] [PubMed] [Google Scholar]
  7. Calvet L, Santos A, et al (2004) No topoisomerase I alteration in a neuroblastoma model with in vivo acquired resistance to irinotecan. Br J Cancer 91(6):1205–1212 [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Coggins CA, Elion GB, et al (1998) Enhancement of irinotecan (CPT-11) activity against central nervous system tumor xenografts by alkylating agents. Cancer Chemother Pharmacol 41(6):485–490 [DOI] [PubMed] [Google Scholar]
  9. Crump M, Lipton J, et al (1999) Phase I trial of sequential topotecan followed by etoposide in adults with myeloid leukemia: a National Cancer Institute of Canada Clinical Trials Group Study. Leukemia 13(3):343–347 [DOI] [PubMed] [Google Scholar]
  10. Dowlati A, Levitan N, et al (2001) Phase II and pharmacokinetic/pharmacodynamic trial of sequential topoisomerase I and II inhibition with topotecan and etoposide in advanced non-small-cell lung cancer. Cancer Chemother Pharmacol 47(2):141–148 [DOI] [PubMed] [Google Scholar]
  11. Frangoul H, Ames MM, et al (1999) Phase I study of topotecan administered as a 21-day continous infusion in children with recurrent solid tumors: a report from the Children’s Cancer Group. Clin Cancer Res 5(12):3956–3962 [PubMed] [Google Scholar]
  12. Garaventa A, Luksch R, et al (2003) A phase II study of topotecan with vincristine and doxorubicin in children with recurrent/refractory neuroblastoma. Cancer 98(11):2488–2494 [DOI] [PubMed] [Google Scholar]
  13. Godard T, Deslandes E, et al (2002) Detection of topoisomerase inhibitor-induced DNA strand breaks and apoptosis by the alkaline comet assay. Mutat Res 520(1–2):47–56 [DOI] [PubMed] [Google Scholar]
  14. Hammond LA, Eckardt JR, et al (1998) A phase I and translational study of sequential administration of the topoisomerase I and II inhibitors topotecan and etoposide. Clin Cancer Res 4(6):1459–1467 [PubMed] [Google Scholar]
  15. Hanjani P, Nolte S, et al (2002) Phase II evaluation of 3-day topotecan with cyclophosphamide in the treatment of recurrent ovarian cancer. Gynecol Oncol 85(2):278–284 [DOI] [PubMed] [Google Scholar]
  16. Herben VM, ten Bokkel Huinink WW, et al (1997) Phase I and pharmacological study of sequential intravenous topotecan and oral etoposide. Br J Cancer 76(11):1500–1508 [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Houghton PJ, Cheshire PJ, et al (1995) Efficacy of topoisomerase I inhibitors, topotecan and irinotecan, administered at low dose levels in protracted schedules to mice bearing xenografts of human tumors. Cancer Chemother Pharmacol 36(5):393–403 [DOI] [PubMed] [Google Scholar]
  18. Huisman C, Postmus PE, et al (2001) A phase I study of sequential intravenous topotecan and etoposide in lung cancer patients. Ann Oncol 12(11):1567–1573 [DOI] [PubMed] [Google Scholar]
  19. Kancherla RR, Nair JS, et al (2001) Evaluation of topotecan and etoposide for non-Hodgkin lymphoma: correlation of topoisomerase-DNA complex formation with clinical response. Cancer 91(3):463–471 [DOI] [PubMed] [Google Scholar]
  20. Kaufmann SH, Peereboom D, et al (1996) Cytotoxic effects of topotecan combined with various anticancer agents in human cancer cell lines. J Natl Cancer Inst 88(11):734–741 [DOI] [PubMed] [Google Scholar]
  21. Keshelava N, Groshen S, et al (2000) Cross-resistance of topoisomerase I and II inhibitors in neuroblastoma cell lines. Cancer Chemother Pharmacol 45(1):1–8 [DOI] [PubMed] [Google Scholar]
  22. Keshelava N, Seeger RC, et al (1998) Drug resistance patterns of human neuroblastoma cell lines derived from patients at different phases of therapy. Cancer Res 58(23):5396–5405 [PubMed] [Google Scholar]
  23. Kim R, Hirabayashi N, et al (1992) Experimental studies on biochemical modulation targeting topoisomerase I and II in human tumor xenografts in nude mice. Int J Cancer 50(5):760–766 [DOI] [PubMed] [Google Scholar]
  24. Kramer K, Kushner BH, et al (2003) Oral topotecan for refractory and relapsed neuroblastoma: a retrospective analysis. J Pediatr Hematol Oncol 25(8):601–605 [DOI] [PubMed] [Google Scholar]
  25. Kretschmar CS, Kletzel M, et al (2004) Response to paclitaxel, topotecan, and topotecan-cyclophosphamide in children with untreated disseminated neuroblastoma treated in an upfront phase II investigational window: a pediatric oncology group study. J Clin Oncol 22(20):4119–4126 [DOI] [PubMed] [Google Scholar]
  26. Kushner BH, Cheung NK, et al (2001) Topotecan combined with myeloablative doses of thiotepa and carboplatin for neuroblastoma, brain tumors, and other poor-risk solid tumors in children and young adults. Bone Marrow Transplant 28(6):551–556 [DOI] [PubMed] [Google Scholar]
  27. Kushner BH, Kramer K, et al (2004) Camptothecin analogs (irinotecan or topotecan) plus high-dose cyclophosphamide as preparative regimens for antibody-based immunotherapy in resistant neuroblastoma. Clin Cancer Res 10(1 Pt 1):84–87 [DOI] [PubMed] [Google Scholar]
  28. Langler A, Christaras A, et al (2002) Topotecan in the treatment of refractory neuroblastoma and other malignant tumors in childhood—a phase-II-study. Klin Padiatr 214(4):153–156 [DOI] [PubMed] [Google Scholar]
  29. Matthay KK, Villablanca JG, et al (1999) Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid. Children’s Cancer Group. N Engl J Med 341(16):1165–1173 [DOI] [PubMed] [Google Scholar]
  30. Mok TS, Wong H, et al (2002) A Phase I-II study of sequential administration of topotecan and oral etoposide (toposiomerase I and II inhibitors) in the treatment of patients with small cell lung carcinoma. Cancer 95(7):1511–1519 [DOI] [PubMed] [Google Scholar]
  31. Montazeri A, Boucaud M, et al (2000) Population pharmacokinetics of topotecan: intraindividual variability in total drug. Cancer Chemother Pharmacol 46(5):375–381 [DOI] [PubMed] [Google Scholar]
  32. Murren JR, Anderson S, et al (1997) Dose-escalation and pharmacodynamic study of topotecan in combination with cyclophosphamide in patients with refractory cancer. J Clin Oncol 15(1):148–157 [DOI] [PubMed] [Google Scholar]
  33. Nitschke R, Parkhurst J, et al (1998) Topotecan in pediatric patients with recurrent and progressive solid tumors: a Pediatric Oncology Group phase II study. J Pediatr Hematol Oncol 20(4):315–318 [DOI] [PubMed] [Google Scholar]
  34. O’Neill P, Clark PI, et al (2001) A phase I trial of a 5-day schedule of intravenous topotecan and etoposide in previously untreated patients with small-cell lung cancer. Oncology 61 Suppl 1:25–29 [DOI] [PubMed] [Google Scholar]
  35. Park JR, Slattery J, et al (2000) Phase I topotecan preparative regimen for high-risk neuroblastoma, high-grade glioma, and refractory/recurrent pediatric solid tumors. Med Pediatr Oncol 35(6):719–723 [DOI] [PubMed] [Google Scholar]
  36. Pommier Y, Jenkins J, et al (1995) DNA recombinase activity of eukaryotic DNA topoisomerase I; effects of camptothecin and other inhibitors. Mutat Res 337(2):135–145 [DOI] [PubMed] [Google Scholar]
  37. Pratt CB, Stewart C, et al (1994) Phase I study of topotecan for pediatric patients with malignant solid tumors. J Clin Oncol 12(3):539–543 [DOI] [PubMed] [Google Scholar]
  38. Rodriguez-Galindo C, Daw NC, et al (2002) Treatment of refractory osteosarcoma with fractionated cyclophosphamide and etoposide. J Pediatr Hematol Oncol 24(4):250–255 [DOI] [PubMed] [Google Scholar]
  39. Santana VM, Furman WL, et al (2005) Improved response in high-risk neuroblastoma with protracted topotecan administration using a pharmacokinetically guided dosing approach. J Clin Oncol 23(18):4039–4047 [DOI] [PubMed] [Google Scholar]
  40. Saylors RL III, Stine KC, et al (2001) Cyclophosphamide plus topotecan in children with recurrent or refractory solid tumors: a Pediatric Oncology Group phase II study. J Clin Oncol 19(15):3463–3469 [DOI] [PubMed] [Google Scholar]
  41. Simon R (1989) Optimal two-stage designs for phase II clinical trials. Control Clin Trials 10(1):1–10 [DOI] [PubMed] [Google Scholar]
  42. Sugimoto Y, Tsukahara S, et al (1990) Elevated expression of DNA topoisomerase II in camptothecin-resistant human tumor cell lines. Cancer Res 50(24):7962–7965 [PubMed] [Google Scholar]
  43. Tan KB, Mattern MR, et al (1989) Nonproductive rearrangement of DNA topoisomerase I and II genes: correlation with resistance to topoisomerase inhibitors. J Natl Cancer Inst 81(22):1732–1735 [DOI] [PubMed] [Google Scholar]
  44. Taron M, Plasencia C, et al (2000) Cytotoxic effects of topotecan combined with various active G2/M-phase anticancer drugs in human tumor-derived cell lines. Invest New Drugs 8(2):139–147 [DOI] [PubMed] [Google Scholar]
  45. Tubergen DG, Stewart CF, et al (1996) Phase I trial and pharmacokinetic (PK) and pharmacodynamics (PD) study of topotecan using a five-day course in children with refractory solid tumors: a pediatric oncology group study. J Pediatr Hematol Oncol 18(4):352–361 [DOI] [PubMed] [Google Scholar]
  46. Tweddle DA, Pinkerton CR, et al (2001) OPEC/OJEC for stage 4 neuroblastoma in children over 1 year of age. Med Pediatr Oncol 36(1):239–242 [DOI] [PubMed] [Google Scholar]
  47. Vassal G, Pondarre C, et al (1997) DNA-topoisomerase I, a new target for the treatment of neuroblastoma. Eur J Cancer 33(12):2011–2015 [DOI] [PubMed] [Google Scholar]
  48. Vey N, Kantarjian H, et al (1999) Combination of topotecan with cytarabine or etoposide in patients with refractory or relapsed acute myeloid leukemia: results of a randomized phase I/II study. Invest New Drugs 17(1):89–95 [DOI] [PubMed] [Google Scholar]
  49. Whitacre CM, Zborowska E, et al (1997) Topotecan increases topoisomerase IIalpha levels and sensitivity to treatment with etoposide in schedule-dependent process. Cancer Res 57(8):1425–1428 [PubMed] [Google Scholar]
  50. Zamboni WC, Stewart CF, et al (1998) Relationship between topotecan systemic exposure and tumor response in human neuroblastoma xenografts. J Natl Cancer Inst 90(7):505–511 [DOI] [PubMed] [Google Scholar]

Articles from Journal of Cancer Research and Clinical Oncology are provided here courtesy of Springer

RESOURCES