Phase I Trial and Pharmacokinetic (PK) and Pharmacodynamics (PD) Study of Topotecan Using a Five-Day Course in Children with Refractory Solid Tumors
David G. TubergenClinton F. StewartCharles B. PrattWilliam C. ZamboniNaomi J. WinickVictor M. SantanaZo Anne DryerJoanne KurtzbergBeverly BellHolcombe E. GrierTeresa J. Vietti
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Purpose A phase I trial was conducted in children with refractory solid tumors to determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics, and pharmacodynamics for topotecan administered by a 30-min infusion for 5 consecutive days. Patients and Methods Forty children with a variety of recurrent solid tumors, including nine patients with neuroblastoma and 10 with brain tumors, were given topotecan as a 30-min infusion for 5 consecutive days, beginning with a dose of 1.4 mg/m2/day. The dose was escalated in 20% increments after establishing that DLT was not present at the prior dose. Drug toxicity was graded using standard criteria. Dose-limiting toxicity was defined as grade 3 or 4 nonhematopoietic toxicity or grade 4 hematopoietic toxicity lasting >7 days. Pharmacokinetic studies were performed during the first infusion course. Results The DLT was hematopoietic and involved both platelets and neutrophils. Grade 4 hematopoietic toxicity of brief duration was seen at all dose levels. Over half of the patients received red blood cell transfusion support, and 19/40 received platelet transfusions. Hospital admissions for fever and neutropenia or for documented infections occurred in 32 of 169 courses of therapy. Gastrointestinal symptoms with nausea and vomiting or diarrhea were mild to moderate in 12 of the 40 patients. Antitumor responses were seen in three patients with neuroblastoma. An additional four patients (one with neuroblastoma. two with anaplastic astrocytomas, one with Ewing) had stable disease with continued therapy for >6 months. Using a limited sampling model, pharmacokinetic studies were performed in 36 of the 40 patients. Topotecan lactone and total clearance were similar to those reported in other pediatric populations receiving topotecan by continuous infusion. A pharmacodynamic relation between systemic exposure to topotecan lactone and myelosuppression was observed. Conclusions In heavily pretreated children, the MTD for topotecan given by intermittent 30-min infusion for 5 days is 1.4 mg/m2 without GCSF and 2.0 mg/m2/day with GCSK. The dose-limiting toxicity is hematopoietic. Data from this study provide the basis for further studies of topotecan in children with cancer.Keywords:
Topotecan
Pharmacodynamics
Refractory (planetary science)
Platelet Transfusion
Objective: Topotecan has recently been used as a second-line agent in treatment of advanced ovarian cancer. The aim of the study was to evaluate the response rate and toxicities of topotecan in patients with recurrent epithelial ovarian cancer who had been treated with platinum-containing chemotherapy. Methods: A retrospective review of all cases of recurrent ovarian cancer treated with topotecan was done. Response was evaluated using the clinical examination, CA-125 level and radiologic reports (CT, MRI) according to RECIST criteria. The toxicities were evaluated according to GOG criteria. Results: Between 1998 and 2004, 57 patients were treated with topotecan for recurrent epithelial ovarian cancer. The response rate in platinum-sensitive group was 30.8% (4/13) and the response rate in platinum-resistant group was 15.9% (7/44). The response rate in topotecan alone therapy group was 8.0% (2/25), and the response rate in topotecan plus platinum combination therapy group was 28.1% (9/32). However, topotecan plus platinum combination therapy did not demonstrate a statistically significant trend toward greater median survival than topotecan alone therapy (19.2 month versus 17.2 month, P=0.82). Neutropenia above grade 3 was noted in 70%, and anemia above grade 3 in 36.8%, and thrombocytopenia above grade 3 in 47.3%. Although most severe toxicities were due to bone marrow suppression, they were adequately managed by supportive care. Conclusion: The results suggest that topotecan has moderate activity in the recurrent epithelial ovarian cancer who have failed previous treatment with platinum-containing chemotherapy. The response of topotecan plus platinum combination therapy was better than topotecan alone and the potential of other combination regimen deserves further evaluations.
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Topotecan, a semi-synthetic derivative of the alkaloid camptothecin is an antitumor drug that like other camptothecin derivatives, targets DNA topoisomerase I, an enzyme that is present in cells in concentration relatively independent of the stage in the cell cycle. Topotecan stabilizes the complex formed between topoisomerase I and DNA, leading to DNA strand breakage and cell death. In accordance with preclinical studies, clinical efficacy of topotecan was documented in ovarian carcinoma, in small cell lung cancer and in childhood solid tumors. Myelosuppression is the dose-limiting toxicity and nonhematologic side effects are generally mild. The activity of topotecan against a number of hematological malignancies is now increasingly exploited as well as its role in high-dose chemotherapy programs with stem cell support. In both lymphoblastic and myeloid acute leukemias, topotecan has been widely utilised both as single agent or associated to other cytostatic drugs with proven efficacy in these diseases. Most of the published phase II studies demonstrated that heavily pre-treated, relapsing patients achieve a high percentage of overall responses with manageable toxicity. In myelodisplastic syndromes and acute myelomonocitic leukemias a recently published study shows positive results for the combination of topotecan and cytarabin. Topotecan seems to preferentially affect the abnormal cytogenetic clones and in patients achieving a complete response, a conversion from an aneuploid to a diploid karyotipe was documented. In non-Hodgkin lymphomas, several schedules have been tested in the phase I setting. When utilized alone and at very low dosage, the drug yielded 15% of objective responses and a lack of extrahematologic toxicity. Of particular interest seems to be the association of topotecan with taxanes that needs to be supported by growth factors. In multiple myeloma Topotecan has been utilized as single agent in heavily pre-treated patients. The obtained results show good activity and again myelosuppression as preminent toxicity. The use of topotecan in high-dose chemotherapy regimens for multiple myeloma has been proposed. The utilization of topotecan in high-dose chemotherapy is one of the newer and more interesting applications. Solid tumors (i.e. ovarian cancer and small cell lung cancer) are actually investigated by many authors, who have indicated that this drug can be used preferentially as a part of diversified programs containing overlimit dosages of different cytostatics. Furthermore, topotecan demonstrated to be an effective drug to mobilize CD34+ cells for autografting. A general conclusion is that topotecan is an interesting addition to the actual chemotherapy scenario, both because of its mechanism of action and its toxicity profile. The present review of the new possibility of utilization, give us the idea that topotecan has activity in several hematologic neoplasias; further investigations in these diseases (i.e., induction treatment, combination chemotherapy) are then warranted. The broad spectrum of antitumor activity and the characteristics of toxicity make it also interesting for use in both the circulating progenitor cell mobilization and in the consolidation phase of high-dose chemotherapy programs.
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Topotecan stabilizes the topoisomerase I (Topo I) cleavable complex. We measured Topo I levels in white blood cells of patients with ovarian cancer treated with topotecan. Topotecan was given i.v. daily x 5 q 3 weeks in combination with paclitaxel (1 day before topotecan) and cisplatin (just prior topotecan). Our aim was to correlate Topo I levels to pharmacokinetics and toxicity. Topo I levels were determined using Western blotting and were expressed relative to the Topo I level present in 10 microg cell lysate of the human IGROV1 ovarian cancer cell line. We found no correlation between Topo I levels and (non-)hematological toxicity. Topo I levels after the fifth topotecan infusion were significantly negatively correlated with the AUC of topotecan (R = -0.64, p = 0.026), in contrast with Topo I levels prior to (R = -0.25, p = 0.4) and after (R = -0.30, p = 0.3) the first topotecan infusion. Topo I levels after the fifth topotecan infusion (48 +/- 27%, mean +/- SD) were higher than Topo I levels prior to and after the first topotecan infusion (3.0 +/- 4.7 and 2.7 +/- 3.6%, respectively) (p = 0.001). In conclusion, we detected a significant inverse correlation between Topo I level and topotecan AUC at day 5, and we found increasing Topo I levels during a daily x 5 schedule of treatment with topotecan.
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In the meantime, as a logical consequence of its efficiency in the second-line treatment, topotecan has also been used as first-line therapy of small-cell lung cancer. Several studies in the USA and in Germany document the high activity of topotecan in combination with paclitaxel, etoposide or cisplatinum. These studies are currently underway and await final conclusions. Also interesting is the observation that brain metastases are diminished with this therapy. Possibly, topotecan may develop a protective effect against the clinical manifestation of brain metastasis. In conclusion, topotecan belongs to the most important and inevitable drugs in the treatment of small-cell lung cancer. Up to date, however, its position is only settled beyond any doubt in the second-line treatment. Treatment of the relapse in these patients is frequently difficult and problematic. In this situation, drugs with a good efficacy profile and low side effects are of special advantage. The presentations of the symposium ‘Revisiting Response in SCLC: Advantage with Topotecan?’ (Zurich, April 16.–18., 1999) confirm that topotecan belongs to the most potent substances for this tumor entity. The cytostatic drug has been intensively investigated during the last view years. Remission rates in previously untreated patients with extensive disease reach 40% and the median survival time is 10 month. Also in pretreated patients the drug proved its efficacy. In cases with remissions after primary therapy, the remission rate in secondline treatment was 38%, whereas it was only 6.4% in primarily refractory patients. In the randomized comparison within a phase III study, topotecan proved to be equipotent in the treatment of relapsed patients as a monotherapy compared with the combination of cyclophosphamide, doxorubicin and vincristine (CAV) with respect to remission rates and survival time, and it was even slightly superior with respect to symptom control.
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The lack of new highly efficacious drugs for cancer treatment promotes the search for innovative therapeutic modalities. The authors reported the results leading to the definition of parameters needed to demonstrate a possible radiopotentiation by topotecan (TPT) on two representative human rhabdomyosarcomas (RMSs) xenografted into nude mice. Experimental studies of radiopotentiation with different doses of topotecan showed that concomitant association of topotecan and RT for 5 consecutive days provided a synergistic therapeutic effect. Response rates were statistically higher with the radiochemotherapeutic combination (P < 0.001). Efficacy enhancement factors of this combination compared with the sum of the antitumoral activity of these treatments separately administrated were 1.54 and 1.60, respectively, on both rhabdomyosarcomas. Moreover, the efficiency of the combination of radiotherapy at the dose of 20 Gy with topotecan (12.5 mg/kg) was not statistically different from that of radiotherapy at the dose of 40 Gy. According to microscopy results, the analyses performed at different periods after topotecan treatment alone, radiotherapy alone, and their combination seemed to show that tumoral repopulation by malignant cells is as fast as the dose of radiotherapy and/or topotecan is low. Furthermore, lesions observed with the dose of 40 Gy were similar to those obtained with the association of topotecan at the dose of 12.5 mg/kg and radiotherapy at the dose of 20 Gy. In conclusion, all clinical and pathological results are consistent with a radiopotentiation effect of topotecan on the two xenografted human rhabdomyosarcomas and are currently leading to the design of clinical studies.
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