Synergy of topotecan in combination with vincristine for treatment of pediatric solid tumor xenografts.

Topotecan and vincristine were evaluated alone or in combination against 13 independent xenografts and 1 vincristine-resistant derivative, representing childhood neuroblastoma (n = 6), rhabdomyosarcoma (n = 5), or brain tumors (n = 3). Topotecan was given by i.v. bolus on a schedule found previously to be optimal. Drug was administered daily for 5 days on 2 consecutive weeks with cycles repeated every 21 days over a period of 8 weeks. Doses of topotecan ranged from 0.16 to 1.5 mg/kg to simulate clinically achievable topotecan lactone plasma systemic exposures. Vincristine was administered i.v. every 7 days at a fixed dose of 1 mg/kg. Given as a single agent, vincristine induced complete responses (CRs) in all mice bearing two rhabdomyosarcomas (Rh28 and Rh30) and some CRs in Rh12-bearing mice (57%) but relatively few CRs (<29%) in other tumors. As a single agent, topotecan induced CR in a low proportion of tumor lines. A dose-response model with a logit link function was used to investigate whether the combination of topotecan and vincristine resulted in greater than expected responses compared with the activity of the agents when administered alone. Only CR was used to evaluate tumor responses. The combination resulted in significantly greater than expected CRs than individual agents in nine tumor lines (four neuroblastoma, three brain tumors, and two rhabdomyosarcomas). Similar event-free (failure) distributions were shown in SJ-GBM2 glioblastoma xenografts, whether vincristine was administered on day 1 or day 5 of each topotecan course. To determine whether the increased antitumor activity with the combination was attributable to a change in drug disposition, extensive pharmacokinetic studies were performed. However, little or no interaction between these two agents was determined. Toxicity of the combination was marked by prolonged thrombocytopenia and decreased hemoglobin. However, approximately 75 and 80% of the maximum tolerated dose of each single agent, topotecan (1.5 mg/kg) or vincristine (1 mg/kg), could be given in combination, resulting in a combination toxicity index of approximately 1.5. These results show that the therapeutic effect of combining topotecan with vincristine was greater than additive in most tumor models of childhood solid tumors, and toxicity data suggest that this can be administered to mice with only moderate reduction in the dose levels for each agent.     

Relationship between tumor extracellular fluid exposure to topotecan and tumor response in human neuroblastoma xenograft and cell lines

Purpose: We have reported a 6-fold difference in the topotecan (TPT) lactone systemic exposure achieving a complete response in the human neuroblastoma xenografts NB-1691 and NB-1643. However, the relationship between tumor extracellular fluid (ECF) exposure to TPT and the antitumor activity in xenograft and in vitro models has not been established. Methods: TPT was given i.v. to mice bearing NB-1691 and NB-1643 tumors. Prior to dosing, microdialysis probes were placed in tumors of mice bearing NB-1691 and NB-1643 tumors. Plasma and tumor ECF concentrations of TPT lactone were assayed by high performance liquid chromatography. The inhibitory concentration (IC₅₀) was determined for NB-1691 and NB-1643 cell lines in vitro. Results: The TPT AUC_ECF values determined for NB-1691 (n=10) and NB-1643 (n=11) were 7.3 ± 0.84 and 25.6 ± 0.76 ng h ml⁻¹, respectively (P < 0.05). TPT tumor ECF penetration in NB-1691 and NB-1643 was 0.04 ± 0.04 and 0.15 ± 0.11 (P < 0.05), respectively. The IC₅₀ values recorded after 6 h of TPT exposure daily for 5 consecutive days for NB-1691 and NB-1643 were 2.7 ± 1.1  and 0.53 ± 0.19 ng/ml, respectively (P < 0.05). Conclusions: NB-1643 was more sensitive in vitro than NB-1691, and at similar plasma TPT exposures, NB-1643 had a greater degree of TPT tumor ECF exposure and penetration as compared with NB-1691. Potential factors affecting tumor TPT ECF disposition include tumor vascularity, capillary permeability, and interstitial pressure. The clinical importance of this study is underscored by the need to select anticancer agents with a high capacity for tumor penetration and to optimize drug administration to increase tumor penetration. Received: 20 April 1998 / Accepted: 25 August 1998     

Combination immunotherapy with clinical-scale enriched human gammadelta T cells, hu14.18 antibody, and the immunocytokine Fc-IL7 in disseminated neuroblastoma.

PURPOSE: To evaluate a combined cellular and humoral immunotherapy regimen in a mouse model of disseminated human neuroblastoma. We tested combinations of clinical-grade, isolated human gammadelta T cells with the humanized anti-GD2 antibody hu14.18 and a novel fusion cytokine, Fc-IL7. EXPERIMENTAL DESIGN: gammadelta T cells were large-scale enriched from leukapheresis product obtained from granulocyte colony-stimulating factor-mobilized donors. gammadelta T cell cytotoxicity was tested in a europium-TDA release assay. The effect of Fc-IL7 on gammadelta T-cell survival in vitro was assessed by flow cytometry. NOD.CB17-Prkdc(scid)/J mice received 1 x 10(6) NB-1691 neuroblastoma cells via the tail vein 5 to 6 days before therapy began. Treatment, for five consecutive weeks, consisted of injections of 1 x 10(6) gammadelta T cells weekly, 1 x 10(6) gammadelta T cells weekly, and 20 microg hu14.18 antibody four times per week, or 1 x 10(6) gammadelta T cells weekly with 20 microg hu14.18 antibody four times per week, and 20 mug Fc-IL7 once weekly. RESULTS: The natural cytotoxicity of gammadelta T cells to NB-1691 cells in vitro was dramatically enhanced by hu14.18 antibody. Fc-IL7 effectively kept cultured gammadelta T cells viable. Combination therapy with gammadelta T cells and hu14.18 antibody significantly enhanced survival (P = 0.001), as did treatment with gammadelta T cells, hu14.18 antibody, and Fc-IL7 (P = 0.005). Inclusion of Fc-IL7 offered an additional survival benefit (P=0.04). CONCLUSIONS: We have shown a new and promising immunotherapy regimen for neuroblastoma that requires clinical evaluation. Our approach might also serve as a therapeutic model for other malignancies.     

Up-front window trial of topotecan in previously untreated children and adolescents with metastatic rhabdomyosarcoma: an intergroup rhabdomyosarcoma study.

PURPOSE: To investigate the antitumor activity and toxicity of topotecan, used alone and in combination with conventional therapy, in patients with metastatic rhabdomyosarcoma (RMS). PATIENTS AND METHODS: Forty-eight patients younger than 21 years of age with newly diagnosed metastatic RMS received 2.0 to 2.4 mg/m(2) of topotecan intravenously daily for 5 days every 21 days before standard therapy. Two courses were given in the absence of progressive disease or excessive toxicity and response was assessed. Patients with at least a partial response (PR) to topotecan proceeded to therapy with alternating courses of vincristine 1.5 mg/m(2), dactinomycin 1.5 mg/m(2), and cyclophosphamide 2.2 g/m(2) (VAC) and vincristine 1.5 mg/m(2), topotecan 0.75 mg/m(2) daily x 5, and cyclophosphamide 250 mg/m(2) daily x 5. Patients who did not respond to topotecan received continuation therapy with VAC alone. RESULTS: The overall response rate to topotecan was 46% (complete response, 4%; partial response 42%). Unexpectedly, patients with alveolar RMS had a higher rate of response (65%) than those with embryonal RMS (28%; P: = .08). The most common grade 3 or 4 toxicities were neutropenia (67%), anemia (33%), thrombocytopenia (25%), and infection (21%). Two-year failure-free survival and survival estimates were 24% and 46%, respectively. Response to window therapy did not correlate with survival. CONCLUSION: The high response rate and acceptable toxicity profile of topotecan in children with advanced RMS support further evaluation of this agent in phase III trials. The superior responses in alveolar RMS are of interest.     

A randomized phase II trial of oral topotecan versus docetaxel in the second-line treatment of non-small-cell lung cancer

BACKGROUND: This randomized phase II trial evaluated the efficacy and toxicity of oral topotecan compared with intravenous docetaxel in the second-line treatment of patients with non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Eighty patients were randomized to receive topotecan (2 mg per day or 2.5 mg per day fixed dose for 5 of 7 days for 2 weeks) or docetaxel (75 mg/m2) every 21 days. Thirty-nine patients received 138 cycles of topotecan. RESULTS: The overall response rate (RR; ORR) was 8%, median time to progression (TTP) was 1.6 months, median survival was 8.4 months, and the 1- and 2-year survival rates were 36% and 13%, respectively, for patients receiving topotecan. Forty-one patients were randomized, but only 38 patients were actually treated with 136 cycles of docetaxel. The ORR was 8% (7% intent to treat RR), median TTP was 1.4 months, median survival was 7.6 months, and the 1- and 2-year survival rates were 29% and 13%, respectively, for patients receiving docetaxel. CONCLUSION: Oral topotecan appears to be active and well tolerated when administered as a fixed dose daily for 5 of every 7 days for 2 weeks every 21 days and might provide another treatment alternative for patients with advanced-stage NSCLC.     

Treatment of Small Cell Lung Cancer: Two-drug versus four-drug chemotherapy and loco-regional irradiation with or without prophylactic cranial irradiation

Fifty-five patients with untreated small cell lung cancer were allocated randomly to receive either a standard 2-drug or a 4-drug chemotherapy regimen. the patients were further randomized to receive or not to receive prophylactic cranial irradiation (PCI) 40 Gy/20 fractions/4 weeks. Each patient also received split-course irradiation against the primary turnour (55 Gy/25 fractions/8 weeks), the mediastinum, and the supraclavicular areas. the standard 2-drug regimen consisted of cyclophosphamide 10 mg/kg i.v. days 1-4 and vincristine 1 mg i.v. days 1+4; every 4 weeks. the 4-drug regimen comprised cyclophosphamide 10 mg/kg i.v. days 1-3, vincristine 2 mg i.v. day 1 and 1 mg i.v. day 5, methotrexate 30 mg i.v. days 3 and 5, CCNU 80 mg/m² i.v. day 2; every 7 weeks. the total treatment time for both protocols was 9 to 12 months. Objective response after 2 cycles of chemotherapy was seen in 46 % of patients with the 2-drug regimen and in 56 % with the 4-drug regimen. Local radiotherapy increased the response rates to 58% and 90% respectively. the median survival time was 12 months with the 2-drug regimen and 14 months with the 4-drug regimen. the 2-year and 3-year survival rates were 11 % and 0 % in the 2-drug group and 19 % and 15 % in the 4-drug group respectively. Toxicity was more severe in the 4-drug group with 4 deaths due to myelosuppression. Altogether, 25 patients received PCI. This did not in any subgroup increase median survival significantly but a reduction of relapses in the central nervous system was seen. Median survival was 13 months with versus 10 months without PCI; 2-year survival rates were 15% and 6% respectively. Morbidity due to PCI did not occur. Although no statistically significant survival advantage could be documented, there was obviously a higher rate of complete responses with multidrug therapy, and longer median duration of remission, median survival and maximal survival.     

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.

PURPOSE: Most children older than 1 year of age with metastatic neuroblastoma (NB) die despite intensive chemotherapy and bone marrow transplantation. The Pediatric Oncology Group conducted a study of paclitaxel, topotecan, and topotecan-cyclophosphamide (topo-cyclo) in newly diagnosed children with stage IV NB. PATIENTS AND METHODS: There were 102 patients enrolled between September 1993 and October 1995; two of them were later shown to be ineligible. Of the remaining 100 patients, the first cohort of 33 patients received paclitaxel 350 mg/m(2) intravenously (IV) over 24 hours every 14 to 21 days; the next 33 patients received topotecan 2 mg/m(2)/d for 5 days IV every 21 days; a third cohort of 34 patients were treated with IV cyclophosphamide 250 mg/m(2) followed by topotecan 0.75 mg/m(2) each day for 5 days every 21 days. Patients were re-evaluated after two courses and then treated with intensive induction therapy and bone marrow transplantation. RESULTS: Objective responses (complete response + partial response + mixed response) were documented in 67% of children who received topotecan, 76% after topo-cyclo, and 25% after paclitaxel. Four patients had grade 3 to 4 allergic reactions to paclitaxel; most patients developed grade 3 to 4 marrow suppression after topotecan or topo-cyclo. Neither disease-free survival nor overall survival differed significantly between children who received a phase II agent and those who did not. The 6-year disease-free survival and overall survival rates for all 100 children were 18% +/- 5% and 26% +/- 5%, respectively. CONCLUSION: Topotecan and topo-cyclo are active in children with NB, are well tolerated, and should be evaluated further in combination regimens.     

A phase II study of topotecan with vincristine and doxorubicin in children with recurrent/refractory neuroblastoma

BACKGROUND: A Phase II trial in children with advanced neuroblastoma was carried out in five Italian institutions to evaluate the antitumor activity and tolerability of topotecan followed by vincristine and doxorubicin. METHODS: Children older than age 1 year with Stage III or Stage IV neuroblastoma, all of whom had been treated previously with chemotherapy and were diagnosed with either refractory or recurrent disease, were treated with topotecan at an intravenous dose of 1.5 mg/m(2) (the dose was 0.75 mg/m(2) for patients who were treated within 1 year of previous megatherapy) per day for 5 days followed by 48-hour intravenous infusions of 2 mg/m(2) vincristine and 45 mg/m(2) doxorubicin. Cycles of therapy were repeated every 3 weeks. RESULTS: Twenty-five patients (2 with Stage III disease and 23 with Stage IV disease; 19 with refractory disease and 6 with recurrent disease) were treated with a total of 115 cycles. Four patients had complete responses, 12 patients had partial responses, 4 patients had minor responses or stable disease, and 5 patients had tumor progression. The overall response rate (including complete and partial responses) was 64% (95% confidence interval, 43-82%). Fifteen patients were alive at the time of the current report and were progression free at 4-16 months (median, 9 months) after the first course of this treatment. Toxicity generally was limited to the hematopoietic system. Dose-limiting toxicity was observed in only 1 patient (Grade 4 liver toxicity). There were no deaths due to infectious or toxic causes. CONCLUSIONS: The topotecan-vincristine-doxorubicin combination was active and well tolerated in previously treated patients with advanced neuroblastoma.     

Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer.

PURPOSE: Topotecan and cyclophosphamide, doxorubicin, and vincristine (CAV) were evaluated in a randomized, multicenter study of patients with small-cell lung cancer (SCLC) who had relapsed at least 60 days after completion of first-line therapy. PATIENTS AND METHODS: Patients received either topotecan (1.5 mg/m2) as a 30-minute infusion daily for 5 days every 21 days (n = 107) or CAV (cyclophosphamide 1,000 mg/m2, doxorubicin 45 mg/m2, and vincristine 2 mg) infused on day 1 every 21 days (n = 104). Eligibility included the following: bidimensionally measurable disease, Eastern Cooperative Oncology Group performance status of less than or equal to 2, and adequate marrow, liver, and renal function. Response was confirmed by blinded independent radiologic review. RESULTS: Response rate was 26 of 107 patients (24.3%) treated with topotecan and 19 of 104 patients (18.3%) treated with CAV (P = .285). Median times to progression were 13.3 weeks (topotecan) and 12.3 weeks (CAV) (P = .552). Median survival was 25.0 weeks for topotecan and 24.7 weeks for CAV (P = .795). The proportion of patients who experienced symptom improvement was greater in the topotecan group than in the CAV group for four of eight symptoms evaluated, including dyspnea, anorexia, hoarseness, and fatigue, as well as interference with daily activity (P< or =.043). Grade 4 neutropenia occurred in 37.8% of topotecan courses versus 51.4% of CAV courses (P<.001). Grade 4 thrombocytopenia and grade 3/4 anemia occurred more frequently with topotecan, occurring in 9.8% and 17.7% of topotecan courses versus 1.4% and 7.2% of CAV courses, respectively (P<.001 for both). Nonhematologic toxicities were generally grade 1 to 2 for both regimens. CONCLUSION: Topotecan was at least as effective as CAV in the treatment of patients with recurrent SCLC and resulted in improved control of several symptoms.     

Topotecan and cisplatin in combination with concurrent twice-daily chemoradiation in limited disease small cell lung cancer-a Danish Oncological Lung Cancer Group (DOLG) phase II trial

INTRODUCTION: The longest survival time reported in randomised trials of limited disease (LD) SCLC has been achieved with early twice-daily concurrent chemoradiation. Topotecan is active in recurrent SCLC and in extensive disease as first line treatment. AIM: To incorporate and assess the effect of topotecan with concurrent twice-daily radiochemotherapy in LD SCLC. PATIENT AND METHODS: Multicentre phase II study of three cycles of regimen A (topotecan i.v., 1.5mg/m(2), day 1-5; cisplatin 50mg/m(2), day 1) and three cycles of regimen B (etoposide i.v., 120mg/m(2), day 1-3; carboplatin, AUC=5, day 1; vincristine, 1.3mg/m(2), day 1) given in the following sequence: A-B-B-A-B-A every 21 days. Twice-daily radiotherapy (1.5Gyx30, 10fr/wk, 45Gy) was delivered concurrently with the first cycle B. Prophylactic cranial irradiation was offered to patients (pts) in complete remission. Eligible were pts with LD SCLC with no prior treatment for SCLC, adequate organ functions, and WHO performance status (PS) < or =2. Pts older than 64 years with PS=2 and LDH>two times the upper limit were excluded. RESULT: Fourty-five pts were included in four centres. Five patients did not meet the inclusion criteria. The median age of the eligible pts was 60 years, range 43-75. PS was < or =1 in 90% of pts. Non-haematological toxicity was mild except grade 3 esophagitis, which was observed in 26.5% of pts. One pt developed an esophageal stricture. Grade 3/4 leucopenia and thrombocytopenia were observed in 82.5% and 75.0 of pts, respectively. One patient died due to neutropenic sepsis. The overall response rate was 77.5% with 30.0% achieving a complete response. Median progression-free survival was 11.8 months (95% CI: 1.3-22.2). Median overall survival was 22.9 months (95% CI: 13.4-31.5) and 5-year survival was 21%. CONCLUSION: The combination of topotecan and cisplatin with concurrent twice-daily chemoradiation results in long-term survivors. As expected the incidence of severe esophagitis is high.     

Liposomal vincristine preparations which exhibit decreased drug toxicity and increased activity against murine L1210 and P388 tumors

The toxicity and antitumor activity of liposomal vincristine preparations have been examined. Vincristine was encapsulated inside egg phosphatidylcholine (EPC)/cholesterol (55/45, mol/mol) and distearoylphosphatidylcholine (DSPC)/cholesterol (55/45, mol/mol) vesicles utilizing transmembrane pH gradient (inside acidic) drug uptake processes. Trapping efficiencies approaching 100% were achieved for this procedure using drug:lipid ratios as high as 0.2:1 (w/w). Although both EPC/cholesterol and DSPC/cholesterol liposomal systems yielded high trapping efficiencies, DSPC/cholesterol vesicles exhibited superior drug retention properties. This ability to retain entrapped vincristine was related to maintenance of the transmembrane pH gradient as well as the membrane permeability properties. Thirty-day dose-response survival studies in mice indicated that vincristine encapsulated in DSPC/cholesterol liposomes was less toxic than free drug. The 50% lethal dose of 1.9 mg/kg in CD-1 mice observed for free vincristine increased to 4.8 mg/kg upon administration of the drug in liposomal form. Liposome encapsulation of vincristine also enhanced the antitumor activity against murine P388 and L1210 lymphocytic leukemia models. This resulted from increased efficacy for liposomal vincristine at doses equal to free drug (liposomal/free drug median survival times greater than 1.0) as well as the ability to administer increased doses of liposomal vincristine. The combined effects of decreased toxicity and increased antitumor efficacy of liposomal vincristine over free drug suggest significant clinical utility of appropriate liposomal vincristine systems.     

Paclitaxel/carboplatin/etoposide versus paclitaxel/topotecan for extensive-stage small cell lung cancer: a Minnie Pearl Cancer Research Network randomized, prospective phase II trial

PURPOSE: To compare the combination of paclitaxel (Taxol; Bristol-Myers Squibb, Princeton, NJ, http://www.bms.com) and topotecan (Hycamtin; Glaxo SmithKline, Philadelphia, http://www.gsk.com) with paclitaxel, carboplatin (Paraplatin; Bristol-Myers Squibb), and etoposide (Etopophos, VePesid; Bristol-Myers Squibb) in patients with previously untreated extensive-stage small cell lung cancer. PATIENTS AND METHODS: In this phase II trial, 120 patients were randomly allocated to receive either topotecan (1.5 mg/m(2) i.v. days 1, 2, and 3) and paclitaxel (175 mg/m(2) i.v. day 1) every 21 days orpaclitaxe l (200 mg/m(2) i.v. day 1), carboplatin (area under the concentration-time curve 6 i.v. day 1), and etoposide (50 mg/100 mg alternating daily by mouth days 1-10) every 21 days, each regimen for a maximum of eight cycles. The primary end points were objective response rate and time to progression. RESULTS: The paclitaxel-carboplatin-etoposide combination produced a significantly higher overall response rate (78% versus 48%), longer median time to progression (7.6 months versus 5.5 months), and greater number of patients free from progression at 1 year (14% versus 8%) compared with paclitaxel plus topotecan. There was no difference in overall survival. Toxicities were similar in the two treatment arms. CONCLUSIONS: The paclitaxel-carboplatin-etoposide combination produced a superior overall response rate and time to progression in patients with extensive-stage small cell lung cancer compared with paclitaxel plus topotecan. The platinum compounds continue to be a necessary component of the initial therapy for these patients.     

Reversal of drug resistance in a human colon cancer xenograft expressing MDR1 complementary DNA by in vivo administration of MRK-16 monoclonal antibody.

One strategy to overcome multidrug resistance in neoplasia is to inhibit the gp170 glycoprotein (relative molecular mass, 170,000) that functions as a plasma membrane, energy-dependent, drug-efflux pump. The human colon cancer cell line HT-29, which grows as an ascitic tumor in athymic NCr-nu/nu nude mice, was made multidrug resistant by infection with an MDR1 (also known as PGY1) retrovirus. Referred to as HT-29mdr1, it was used to study reversal of drug resistance in vivo by the anti-P-glycoprotein monoclonal antibody MRK-16. Flow cytometry and radioimmunoassay demonstrated a marked increase in MRK-16 reactivity on HT-29mdr1 cells as compared with its reactivity on the parental, uninfected cell line (HT-29par). The 50% inhibitory concentrations (IC50) of vincristine on HT-29par and HT-29mdr1 cells were 2.5 and 15 ng/mL, respectively. The MRK-16 monoclonal antibody did not affect the vincristine sensitivity of the HT-29par cells. Pretreatment of HT-29mdr1 cells with 10 micrograms/mL MRK-16 in tissue culture partially restored the vincristine sensitivity (IC50 = 7 ng/mL). This modulation of vincristine sensitivity by MRK-16 was then tested in vivo. The median survival times of mice given intraperitoneal transplants of 5 x 10(6) HT-29par or HT-29mdr1 were 37 and 39 days, respectively. Treatment of mice with 1 mg/kg vincristine weekly for 3 weeks, beginning 10 days after tumor injection, resulted in a significant increase in the median survival time of the HT-29par tumor-bearing mice (68 days, P less than .0001), but it had no effect on the HT-29mdr1 tumor-bearing mice. However, treatment of mice bearing the HT-29mdr1 tumor with MRK-16 before vincristine therapy reversed the resistance to the drug (median survival time = 64 days, P less than .0001). The MRK-16 monoclonal antibody alone had no effect on the median survival time of mice given an injection of either HT-29par or HT-29mdr1 cells. These results suggest that strategies employing monoclonal antibody against gp170 may be clinically useful to reverse multidrug resistance.     

Randomized phase III study of fludarabine phosphate versus cyclophosphamide, vincristine, and prednisone in patients with recurrent low-grade non-Hodgkin's lymphoma previously treated with an alkylating agent or alkylator-containing regimen.

PURPOSE: To compare in a phase III study the safety and efficacy of fludarabine to that of cyclophosphamide, vincristine, and prednisone (CVP) in recurrent, low-grade, non-Hodgkin's lymphoma after previous response to systemic treatment. PATIENTS AND METHODS: Patients were randomized to fludarabine (25 mg/m(2) intravenously on days 1 to 5, every 28 days) or CVP (cyclophosphamide 750 mg/m(2) and vincristine 1.2 mg/m(2) both intravenously on day 1 and prednisone 40 mg/m(2) orally on days 1 to 5, every 21 days). The primary outcome assessed was progression-free survival (PFS); secondary outcomes included treatment-free survival (TFS), overall survival (OS), treatment-related toxicity, and quality of life (QoL) according to the European Organization for Research and Treatment of Cancer's Quality of Life Questionnaire C-30 version 1.0 instrument. RESULTS: Ninety-one patients were randomized, 47 to fludarabine and 44 to CVP. There was no difference in response rates, with 64% (complete response [CR], 9%) for fludarabine versus 52% (CR, 7%) for CVP (P =.72). With a median follow-up of 42 months, median PFS (11 months v 9.1 months; P =.03) and TFS (15 months v 11 months; P =.02) were superior in patients receiving fludarabine. No difference in median overall survival was detected (57 months for fludarabine v 44 months for CVP; P =.95). Three patients receiving fludarabine died of treatment-related toxicity compared with none of the patients receiving CVP. Peripheral neuropathy and alopecia were more common with CVP. Patients receiving fludarabine had higher scores for social function (P =.008); no other differences in QoL were detected. CONCLUSION: In recurrent low-grade lymphoma, fludarabine improves PFS, TFS, and social function scores in comparison with CVP but does not improve OS.     

Evaluation of 9-dimethylaminomethyl-10-hydroxycamptothecin against xenografts derived from adult and childhood solid tumors

The topoisomerase I inhibitor 9-dimethylaminomethyl-10-hydroxycamptothecin (topotecan) was evaluated against a panel of xenografts comprising four lines of adult colon adenocarcinoma, three colon tumors derived from adolescents, six childhood rhabdomyosarcomas from previously untreated patients as well as sublines selected in vivo for resistance to vincristine and melphalan, and three lines of childhood osteogenic sarcoma. Efficacy was determined at maximal tolerated dose levels using intermittent i.p. administration [every 4 days for 4 doses (q4d×4)] or daily p.o. or i. p. administration 5 days per week for up to 20 courses. On a q4d×4 schedule, the maximum tolerated dose (MTD) was 12.5 mg/kg per administration, which caused marked weight loss and lethality in 5% of the tumor-bearing mice. This schedule caused significant growth inhibition (but no tumor regression) in advanced adult colon adenocarcinomas. The minimal treated/control (T/C) ratios were 0.49, 0.54, and 0.3 for three of the tumor lines and were achieved at 18–21 days after the initiation of treatment. In contrast, rhabdomyosarcomas were considerably more sensitive, with T/C ratios being <0.1 for three lines, whereas topotecan was less active against two other rhabdomyosarcoma xenografts (minimal T/C ratios, 0.17 and 0.14). As inhibitors of topoisomerase I have been demonstrated to have activity in the replication phase of the cell cycle (S-phase-specific), prolonged administration schedules were examined. Mice received topotecan 5 days per week for 3 weeks either by i.p. injection or by oral gavage (p.o.). In selected experiments, p.o. administration was continued for up to 20 weeks. Oral administration for 3 weeks (2 mg/kg per dose) resulted in complete regression of all six lines of rhabdomyosarcoma, with two lines demonstrating no regrowth during the period of observation (84 days). Similar results were obtained after i.p. administration, suggesting significant schedule dependency for these tumors. For colon tumors, the daily administration schedule (i.p. or p.o.) demonstrated some advantage over the intermittent schedule, resulting in partial regressions and significant inhibition of the growth of several colon adenocarcinoma lines. In rhabdomyosarcoma Rh 12 and VRC₅ colon adenocarcinoma, both of which demonstrated intermediate sensitivity to topotecan, and in osteosarcoma OS33, protracted p.o. administration for 13–20 weeks (1.0–1.5 mg/kg per dose given daily x 5 days) caused complete regression without regrowth in Rh12 and OS33 tumors and partial regression of all VRC₅ tumors. No toxicity was observed using this schedule of administration. Topotecan demonstrated significant activity against all three osteosarcoma xenografts examined, with optimal schedules causing complete regression in two lines. Topotecan demonstrated similar activity against KB 3-1 and KB 8-5 multidrug-resistant cells in culture, and the Rh 12/VCR an Rh 18/VCR xenografts selected for vincristine (VCR) resistance in vivo were as sensitive as their parental lines. However, Rh 28/L-PAM, selected for resistance to melphalan, was cross-resistant to topotecan. Plasma pharmacokinetics studies were carried out at the respective MTD for oral (2 mg/kg) or i.p. (1.75 mg/kg) administration. During oral administration the maximal plasma concentration (of the active lactone) was achieved at 0.25 h (C_max 41.7 ng/ml) and thet ₁/2 andt ₁/2 values were 0.55 and 2.8 h, respectively. Administration i.p. resulted in peak plasma levels of 523 ng/ml, witht ₁/2 andt ₁/2 elimination rates being 0.29 and 2.5 h, respectively. Although i.p. administration resulted in a 3-fold increase in AUC as compared with oral dosing, similar antitumor activity was observed against most xenograft lines. These results suggest that topotecan may have significant activity against several human cancers and that its efficacy may be schedule-dependent. Topotecan may have a particular role to play in the treatment of childhood solid tumors such as rhabdomyosarcoma and osteosarcoma.This work was supported in part by grants CA23099, CA21765 (CoRe) and by the American Lebanese Syrian Associated Charities (ALSAC)     

Using pharmacokinetic and pharmacodynamic modeling and simulation to evaluate importance of schedule in topotecan therapy for pediatric neuroblastoma.

PURPOSE: The study aims to use mathematical modeling and simulation to assess the relative contribution of topotecan systemic exposure and scheduling in the activity and myelosuppression of topotecan in pediatric patients with neuroblastoma. EXPERIMENTAL DESIGN: Pharmacokinetic and pharmacodynamic data were obtained from a phase II study for pediatric patients with high-risk neuroblastoma. The topotecan dosage was individualized to attain a topotecan lactone area under the plasma concentration-time curve between 80 and 120 ng/mL h and given over a protracted schedule (i.e., 10 days). Four mathematical models describing topotecan pharmacokinetics, tumor growth, and neutrophil and platelet dynamics were developed. The models were combined to simulate and compare different topotecan treatment strategies with respect to systemic exposure and schedule. RESULTS: The median change in tumor volume was significantly different between schedules (5% increase for D x 5 versus 60% decrease for D x 5 x 2; P < 0.0001) when administering the same total systemic exposure. Whereas protracted schedules showed increased neutropenia (median of 7 versus 12 days below an absolute neutrophil count of 500/microL; P < 0.0001) and thrombocytopenia (median of 3 versus 10 days below a platelet count of 20,000/microL; P < 0.00001), simulations showed that delays in topotecan therapy would not be required. Simulations showed that an increase in topotecan exposure on the D x 5 schedule by 2.4-fold resulted in a modest decrease in tumor volume (i.e., median percentage change tumor volume of 24% versus 3%). CONCLUSIONS: The present mathematical model gave an innovative approach to determining relevant topotecan schedules for possible evaluation in the clinic, which could lead to improved tumor response with minimized toxicities.     

A phase I study of topotecan as a radiosensitizer for brainstem glioma of childhood: first report of the Children's Cancer Group-0952

Our purpose was to establish the maximum tolerated dosage (MTD) of daily i.v. topotecan with conventionally fractionated radiotherapy (XRT) for patients with intrinsic pontine glioma of childhood. Topotecan was given as a 30-min i.v. infusion 30-60 min before each XRT treatment given daily for 33 days. Total XRT dose was 59.4 Gy. Dose escalation of topotecan was carried out using a standard phase I design. Dose limiting toxicity (DLT) was defined as an absolute neutrophil count (ANC) of < or =500/mm(3) for > or =7 days; platelets of < or =50,000/mm(3) for > or =7 days; >7 days platelet transfusions; fever and neutropenia (ANC < or =500/mm(3) for > or =7 days); and/or any > or=grade 3 non-hematologic toxicity. In this multi-institutional phase I study, 17 patients <21 years with intrinsic pontine glioma were enrolled. Sixteen patients completed treatment. An ANC < or =500/mm(3) for > or =7 days occurred in 2/5 patients at 0.50 mg/m(2) of topotecan, which was the DLT. The remaining 14 patients received topotecan without experiencing DLT. One patient at 0.40 mg/m(2) died of disease progression while on treatment. There were 6 other grade 4 hematologic events (5 ANCs <500/mm(3), 1 hemoglobin <6. 5 g/dl) not meeting DLT criteria. No significant non-hematologic toxicities were seen. The actuarial median survival time is 15 months (95% confidence interval, 9.6-19 months); 1-year survival is 53%. DLT of daily topotecan with cranial XRT is grade 4 neutropenia for > or =7 days at 0.50 mg/m(2) x 33 (total dosage = 16.5 mg/m(2)); the recommended safe MTD of daily topotecan for further phase II testing is 0.40 mg/m(2) x 33 (total dosage = 13.2 mg/m(2)).     

Topotecan and vincristine combination is effective against advanced bilateral intraocular retinoblastoma and has manageable toxicity

BACKGROUND:

New, effective chemotherapeutic agents are needed for intraocular retinoblastoma.

METHODS:

This institutional clinical trial sought to estimate the rate of response to 2 courses of vincristine and topotecan (VT) window therapy in patients with bilateral retinoblastoma and advanced disease (Reese‐Ellsworth group IV or V) in at least 1 eye. The topotecan dose started at 3 mg/m²/day for 5 days and was adjusted to target a systemic exposure of 140 ± 20 ng/mL · hour. The vincristine dose was 0.05 mg/kg for patients <12 months of age and 1.5 mg/m² for those >12 months of age at diagnosis.

RESULTS:

From February 2005 to June 2010, 27 patients received VT window therapy. Median age at enrollment was 8.1 months (range, 0.7‐22.1 months). Twenty‐four patients (88.9%) responded to window therapy (95% confidence interval = 71.3%‐96.9%). Hematologic toxicity comprised grade 4 neutropenia (n = 27), grade 3 anemia (n = 19), and grade 3/4 thrombocytopenia (n = 16). Thirteen patients had grade 3 nonhematologic toxicity. Granulocyte colony‐stimulating factor support was added after 10 patients had been treated, and it significantly reduced the duration of grade 4 neutropenia (median, 7 vs 24 days; P < .001). Pharmacokinetic studies showed rapid changes in topotecan clearance rates during the first year of life.

CONCLUSIONS:

The combination of topotecan and vincristine is effective for the treatment of advanced intraocular retinoblastoma. Granulocyte colony‐stimulating factor treatment alleviates the duration of grade 4 neutropenia. Appropriate topotecan starting doses for patients 0‐3, 3‐6, 6‐9, 9‐12, and >12 months of age are specified. Cancer 2012. © 2012 American Cancer Society.