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Intraarterial chemotherapy (Ophthalmic Artery Chemosurgery/OAC) for retinoblastoma has transformed management of retinoblastoma worldwide since Pierre Gobin MD and I introduced it in 2006. Case reports, institutional series, meta-analyses, and randomized trials have validated its effectiveness and safety. It allows more eyes to be saved (at Memorial Sloan Kettering Cancer Center (MSKCC) as a result, we have gone from removing 96% of retinoblastoma eyes that presented with leukocoria (comparable to modern day International Classification “D” and “E” eyes) to saving 95% of these eyes with primary OAC management allows the majority of advanced intraocular eyes to be salvaged (both “D” and “E” eyes) prior to the chemoreduction era to saving 95% of these eyes with primary OAC management. OAC attains cures faster than intravenous protocols, has fewer systemic side effects, and is overall cheaper than intravenous approaches (because of the absence of side effects which are the main driver of cost in pediatric oncology). Unlike systemic chemotherapy no ports are needed (and no removal of ports for life threatening infections), it does not alter the immune system (so children can be immunized), it does not affect patient growth (and children who had received systemic chemotherapy catch up in growth during OAC), it does not affect hearing (which systemic Carboplatin does-especially in children <6 months of age), it eliminates the second cancers caused by radiation and systemic chemotherapy and does not compromise survival with all series showing patient survival >98%. [ABSTRACT FROM AUTHOR]

Yolk sac tumors (YST) are commonly encountered gonadal germ cell tumors in children, especially in the prepubertal age group. In addition to gonadal primary, it can occur in multiple extragonadal sites, of which sacrococcygeal, retroperitoneum, gastric and mediastinum are the commonest. There are 4 previous reports of primary penile YST. We describe a primary penile yolk sac tumor in a child with achondroplasia. Yolk sac tumor can occur in the penis during the prepubertal period. Penile yolk sac tumor associated with achondroplasia has not been previously reported, but this could be incidental. [ABSTRACT FROM AUTHOR]

Atypical teratoid/rhabdoid tumor (AT/RT) is a rare aggressive central nervous system tumor that typically affects children under three years old and has poor survival with a high risk for neurologic deficits. The primary purpose of this study was to successfully treat the disease and delay or avoid whole-brain radiotherapy for children with AT/RT. A retrospective analysis was performed for six children diagnosed with AT/RT and treated with multimodal treatment at a single institute between 2014 and 2020. Furthermore, germline SMARCB1 aberrations and MGMT methylation status of the tumors were analyzed. One patient who did not receive a modified IRS-III regimen replaced with ifosphamide, carboplatin, and etoposide (ICE) in induction chemotherapy was excluded from this analysis. Five patients who received ICE therapy were under three years old. After a surgical approach, they received intensive chemotherapy and high-dose chemotherapy with autologous peripheral blood stem cell transplantation (HDCT/autoPBSCT) followed by intrathecal topotecan maintenance therapy. Three patients underwent single HDCT/autoPBSCT, and the other two received sequential treatment. Two patients with germline SMARCB1 aberrations and metastases died of progressive AT/RT or therapy-related malignancy, while 3 with localized tumors without germline SMARCB1 aberrations remained alive. One survivor received local radiotherapy only, while the other two did not undergo radiotherapy. All three surviving patients were able to avoid whole-brain radiotherapy. Our results suggest that AT/RT patients with localized tumors without germline SMARCB1 aberrations can be rescued with multimodal therapy, including induction therapy containing ICE followed by HDCT/autoPBSCT and intrathecal topotecan maintenance therapy without radiotherapy. Further large-scale studies are necessary to confirm this hypothesis. [ABSTRACT FROM AUTHOR]

Aims: Present cost-effectiveness analysis of nivolumab monotherapy vs. commonly prescribed thirdline (3 Lþ) treatment in small cell lung cancer (SCLC). Materials and methods: A three health states partitioned survival model (progression-free, progressed disease, and death; US payer perspective) was developed. The systematic literature review identified no randomized controlled or single-arm trials with separate outcomes for 3 LþSCLC patients. Topotecan was chosen as a comparator because it is frequently prescribed in real-world practice for 3 L SCLC. Clinical inputs for topotecan were derived from the Flatiron database with inclusion/exclusion criteria matched to patients treated with 3 Lþnivolumab in CheckMate 032. Intravenous (IV) and oral topotecan clinical efficacy were assumed equivalent. Base-case analysis used a 20-year lifetime horizon. An annual discount rate of 3.0% for costs and outcomes was applied. Uncertainty was assessed using sensitivity analyses adjusted for key parameters. Results: Incremental cost per quality-adjusted life-year (QALY) gained with nivolumab was US$153,312 vs. IV topotecan and US$123,003 vs. oral topotecan, respectively. When results were disaggregated, nivolumab-related costs were mainly driven by drug acquisition costs, and topotecan-related costs were primarily due to adverse event treatment. Mean overall survival (OS) was 21.69months with nivolumab and 5.80months with IV or oral topotecan. More favorable outcomes were found by the landmark response analyses. Deterministic sensitivity analyses showed that changes to the discount rate for costs and outcomes and body weight had the greatest impacts on results. Limitations: Included use of real-world data for OS outcomes associated with 3 L topotecan, use of second-line topotecan data for progression-free survival, and no indirect costs. Conclusions: Based on the literature on willingness-to-pay for a QALY in metastatic cancer, nivolumab monotherapy might represent a cost-effective option for 3 Lþtreatment of SCLC compared with IV and oral topotecan. Sensitivity analysis using response-based methods yielded further favorable costeffectiveness estimates. [ABSTRACT FROM AUTHOR]

In order to enhance the targeting efficiency and reduce anti-tumor drug's side effects, topotecan (TPT) and F7 were co-loaded in thermosensitive liposomes (F7-TPT-TSL), which show enhanced permeability and retention in tumors, as well as local controlled release by heating in vitro. TPT is a water-soluble inhibitor of topoisomerase I that is converted to an inactive carboxylate structure under physiological conditions (pH 7.4). F7 is a novel drug significantly resistant to cyclin-dependent kinase but its use was restricted by its high toxicity. F7-TPT-TSL had excellent particle distribution (about 103 nm), high entrapment efficiency (>95%), obvious thermosensitive property, and good stability. Confocal microscopy demonstrated specific higher accumulation of TSL in tumor cells. MTT proved F7-TPT-TSL/H had strongest cell lethality compared with other formulations. Then therapeutic efficacy revealed synergism of TPT and F7 co-loaded in TSL, together with hyperthermia. Therefore, the F7-TPT-TSL may serve as a promising system for temperature triggered cancer treatment. [ABSTRACT FROM AUTHOR]

. Intravitreal administration of topotecan shows activity against tumor vitreous seeding in the conservative treatment of retinoblastoma, a malignant tumor originated in the retina of small children. Adequate storage of the intravitreal topotecan solution would allow immediate availability for patients at health care institutions. The goal of the work was to address the stability of the intravitreal topotecan formulation upon reconstitution.. Intravitreal topotecan solutions were reconstituted (at a concentration of 0.2 mg topotecan in 1 mL saline solution vehicle, aliquoted in 1 mL plastic syringes) and stored either frozen or at room temperature for different times. Topotecan content was analyzed at time zero and at different conditions using a high performance liquid chromatography method to quantify topotecan lactone (active) and to detect its pH-dependent hydrolysis product, the open carboxylate.. We found that intravitreal topotecan syringes remained stable at room temperature at least for 24 h, at least for 167 days upon stored frozen at −20°C, and up to 8 h after thawing at day 6. The degradation carboxylate product did not appear in the analyzed thawed samples during the whole study.. This study confirms the stability of frozen intravitreal topotecan syringes and will help optimize the use of this chemotherapy modality at institutions with low resources. Storage of aliquots will also help reduce personnel exposure to chemotherapy at hospital pharmacies. [ABSTRACT FROM AUTHOR]

A new class of tyrosyl-DNA phosphodiesterase 1 (TDP1) inhibitors based on disaccharide nucleosides was identified. TDP1 plays an essential role in the resistance of cancer cells to currently used antitumour drugs based on Top1 inhibitors such as topotecan and irinotecan. The most effective inhibitors investigated in this study have IC50 values (half-maximal inhibitory concentration) in 0.4-18.5 µM range and demonstrate relatively low own cytotoxicity along with significant synergistic effect in combination with anti-cancer drug topotecan. Moreover, kinetic parameters of the enzymatic reaction and fluorescence anisotropy were measured using different types of DNA-biosensors to give a sufficient insight into the mechanism of inhibitor’s action. [ABSTRACT FROM AUTHOR]

Intravenous (IV) topotecan is approved for the treatment of various malignancies including lung cancer but its clinical use is greatly undermined by severe hematopoietic toxicity. We hypothesized that inhalation delivery of topotecan would increase local exposure and efficacy against lung cancer while reducing systemic exposure and toxicity. These hypotheses were tested in a preclinical setting using a novel inhalable formulation of topotecan against the standard IV dose. Respirable dry-powder of topotecan was manufactured through spray-drying technology and the pharmacokinetics of 0.14 and 0.79 mg/kg inhalation doses were compared with 0.7 mg/kg IV dose. The efficacy of four weekly treatments with 1 mg/kg inhaled vs. 2 mg/kg IV topotecan were compared to untreated control using an established orthotopic lung cancer model for a fast (H1975) and moderately growing (A549) human lung tumors in the nude rat. Inhalation delivery increased topotecan exposure of lung tissue by approximately 30-fold, lung and plasma half-life by 5- and 4-folds, respectively, and reduced the maximum plasma concentration by 2-fold than the comparable IV dose. Inhaled topotecan improved the survival of rats with the fast-growing lung tumors from 7 to 80% and reduced the tumor burden of the moderately-growing lung tumors over 5- and 10-folds, respectively, than the 2-times higher IV topotecan and untreated control (p < .00001). These results indicate that inhalation delivery increases topotecan exposure of lung tissue and improves its efficacy against lung cancer while also lowering the effective dose and maximum systemic concentration that is responsible for its dose-limiting toxicity. [ABSTRACT FROM AUTHOR]

The oral administration of water-soluble chemotherapeutical agents is limited by their serious gastrointestinal side effects, instability at intestinal pH, and poor absorption. Aiming to solve these problems, we chose topotecan (TPT) as a model drug and developed a novel lipid formulation containing core-shell lipid nanoparticle (CLN) that makes the water-soluble drug to ‘dissolve’ in oil. TPT molecules can be encapsulated into nanoparticles surrounded by oil barrier while avoiding the direct contact with intestinal environment, thus easing the intestinal hydrolytic degradation and gastrointestinal (GI) irritation. Microstructure and mean particle size of TPT-CLN were characterized by Transmission Electron Microscope (TEM) and Dynamic Light Scattering (DLS), respectively. The average size of nanoparticles was approximately 60 nm with a homogeneous distribution in shapes of spheres or ellipsoid. According toin vitrostability studies, more initial form of TPT was observed in presence of lipid nanoparticle compared with free topotecan solution in artificial intestinal juice (pH 6.5). After oral administration of TPT-CLN in rats, AUC and Cmaxof TPT were all increased compared with free TPT, indicating significant enhancement of oral absorption. Intestinal lymphatic transport was confirmed as the major way for CLN to enhance oral absorption of TPT by the treatment of blocking chylomicron flow. Lower GI irritation of TPT-CLN was observed in the gastrointestinal damage studies. Thein vivoantitumor activity of TPT-CLN showed an improved antitumor efficacy by oral treatment of TPT-CLN compared to free TPT. From the obtained data, the systems appear an attractive progress in oral administration of topotecan. [ABSTRACT FROM AUTHOR]

Topotecan (TPT) is indicated against a variety of solid tumors, but has restricted clinical use owing to associated pharmaceutical caveats. This study is focused at formulating a successful TPT PLGA nanosystem which ameliorates the rapid conversion of active lactone form of drug to its inactive carboxylate form and consequently improvises its efficacy. TPT PLGA nanoparticles were formulated by a double emulsion-solvent evaporation technique with sequential optimization to obtain desired particle size, PDI, zeta potential, and entrapment efficiency. Stability of TPT was ensured by maintaining an acidic pH in the drug-containing phase and the system was evaluated forin vitro–in vivoperformance including cytotoxic potency. The optimized nanosystem had a particle size of 187.33 ± 7.50 nm, a PDI of 0.179 ± 0.05, and an entrapment efficiency of 56 ± 1.2%. Low pH in the interior of nanoparticles stabilized the drug to remain in its active lactone form and revealed a biphasic release pattern till 15 d. Additionally, anin vitrocytotoxicity testing as well asin vivoantitumor efficacy demonstrated a significant potential of higher proliferation inhibition as compared with neat drug (TPT). Thus, the investigation summarized an innovative simple tool for developing stable TPT NPs for effective delivery for treating solid tumors. [ABSTRACT FROM PUBLISHER]

Purpose: To evaluate our experience with systemic Toptecan (TPT) chemotherapy as a second-line systemic chemotherapeutic regimen for treatment of refractory or recurrent intraocular retinoblastoma (RB). Methods and Materials: A retrospective case series of 14 eyes from patients with intraocular RB who received systemic TPT as second-line chemotherapy from April 2008 until June 2010. The following data were collected: patient demographics, laterality, international intraocular retinoblastoma stage (ICRB) at diagnosis, treatment received before and after TPT, side effects related to TPT, eye salvage, and survival. Results: The median age at diagnosis was 5 months (range, 1–16 months), and the median age at starting TPT was 10 months (range, 8–24 months). There were 6 (60%) females and 9 (90%) patients; all with bilateral retinoblastoma. The median number of TPT cycles was three per patient (range, 1–6), and the total number of administered cycles was 29. After TPT therapy; 4 (29%) eyes showed favorable response, 3 (21%) eyes showed minimal regression, 5 (36%) eyes had stable disease, and 2 (14%) eyes showed tumor progression. At a median follow-up of 48 months; 9 (64%) eyes were salvaged, 3 (21%) eyes received radiation therapy, and 3 (21%) eyes were enucleated (one was post radiation). Grade 3/4 neutropenia were noticed in a total of 59% of given cycles and admission for febrile neutropenia was required after seven cycles. Conclusions: Our report suggests that systemic TPT chemotherapy could be used as a salvage second-line regimen with low toxicity for patients with progressive intraocular retinoblastoma if systemic therapy is needed. [ABSTRACT FROM PUBLISHER]

Neuroendocrine tumors (NETs) comprise a heterogeneous group of tumors derived from peptide- and amine-secreting cells of the neuroendocrine system. NETs commonly arise in the gastrointestinal tract but can arise in most organs of the body. Although the incidence of NETs is not high, the prevalence is relatively high because many patients may live relatively long periods without major symptoms from the disease. Whilst many of these tumors take on an indolent clinical course, they constitute a therapeutic challenge when they progress, metastasize and become symptomatic. Treatment requires a multidisciplinary approach that may include cytotoxic chemotherapy. Almost all clinical trials investigating cytotoxic chemotherapy in NETs are small single-arm studies, hence guidelines are derived from expert opinion and from extrapolating results from small-cell lung cancer studies. This article provides a broad coverage of systemic therapies for NETs but focusses on the role of cytotoxic chemotherapy. [ABSTRACT FROM PUBLISHER]

Context: Synergistically active combinations have been used to enhance therapeutic efficacy for ovarian cancer chemotherapy. Objective: The synergistically active combination of paclitaxel-topotecan (Pac-Top; 20:1,w/w) were loaded into folate-anchored PEGylated liposomes (FPL-Pac-Top) for safe and effective treatment of ovarian cancer. Materials and methods: Coupling reactions were carried out using carbodiimide chemistry and confirmed by infrared spectral analysis. These liposomes were studied for shape and physical interaction (and integrity),in vitrodrug release kinetics, hemolytic toxicity,ex vivopharmacodynamics in OVCAR-3 cell lines, and pharmacokinetics in ovarian tumor-bearing mice. Results: The differential scanning calorimeter studies exhibited melting of liposomes (∼150 nm) at ∼41 °C. The drug(s) release from liposomes followed Fickian diffusion model. The hematological studies revealed insignificant toxicity to blood cells.In vivostudies showed long circulatory behavior (increased AUC0–tand AUMC0–tand MRT) and selective accumulation of FPL-Pac-Top in the ovaries. FPL-Pac-Top showed less necrosis and more apoptosis in flow cytometry. Kaplan–Meier survival analysis revealed the doubling of the survival time with FPL-Pac-Top in comparison to Pac-Top solution. Discussion and conclusion: Potentiated anti-cancer activity of FPL-Pac-Top was attributed to multiple features viz. thermosensitivity, long circulatory nature and targetability. Such approach could be a paradigm chemotherapeutic approach for safe and effective targeting of cancer. [ABSTRACT FROM PUBLISHER]

Topotecan hydrochloride (TPT) has potential for the treatment of ovarian cancer, but the activity of TPT tends to decrease due to the ring-opening at physiological pH. In this study, we proposed to incorporate TPT liposomes into injectable thermosensitivein situhydrogel, consisting of chitosan (CS) and β-glycerophosphate (β-GP), for sustained release and preservation of active lactone form of TPT. The rheology studies were carried out to investigate the sol–gel temperature, flow behavior and viscosity of these CS/β-GP systems. The optimized formulation exhibited sol–gel transition at 40.2 ± 0.4 °C, with pseudoplastic flow behavior. The drug release rate of TPT liposomes loaded CS/β-GP hydrogel in phosphate buffer saline (pH = 7.4) was found to be slowed down, and the lactone fraction of TPT in the hydrogel matrix was maintaining 40% after 50 h. In addition, the antitumor efficacy in Kunming mice bearing Hepatoma-22 tumor, after intratumoral injection of TPT liposomes loaded CS/β-GP hydrogel, was higher than that of TPT in saline and TPT in CS/β-GP hydrogel. Those results demonstrated that TPT liposomes loaded CS/β-GP hydrogel could become a potential formulation for improving the antitumor efficacy of TPT and suggested an important technology platform for intratumoral administration of derivative of camptothecin-family drugs. [ABSTRACT FROM AUTHOR]

Nanoassemblies were developed from the natural polyphenol chlorogenic acid (CGA) to create targeted drug delivery vehicles for the antitumor drug Topotecan. To specifically target tumor cells, we functionalized the formed assemblies with a tumor targeting peptide. Release profiles showed an initial burst release followed by sustained release up to 140 minutes for the fibrillar assemblies. Nanovesicles released the drug slower. Cell proliferation studies indicated that while chondrocytes continued to grow, tumor cells showed blebbing and their proliferation was significantly reduced in the presence of the drug loaded assemblies. Thus, we have developed new nanoassemblies for selective targeting of tumor cells. [ABSTRACT FROM PUBLISHER]

Introduction: The purpose of this paper is to perform a systematic review of the published literature on complications of intra-arterial chemothrapy (IAC) for the treatment of retinoblastoma. Materials and Methods: A literature search was performed using the Pubmed database using the terms. Complications were divided into extraocular and intraocular. Results: A total of 117 articles were found using this Pubmed search method; 35 articles were selected for review as they describe specifical complications of IAC for retinoblastoma. A variety of extraocular and intraocular complications were reported and discussed. Discussion: IAC for the treatment of retinoblastoma is a technique that has been gaining popularity in recent years, but is not without complications. Continued research is warranted to further improve current techniques and delivery of chemotherapeutic agents into the eye. [ABSTRACT FROM AUTHOR]

In an attempt to improve the antitumor activity of homocamptothecins (hCPTs), a series of novel 20-O-linked hCPT ester derivatives were first designed and synthesized based on a synthetic route, by which hCPTs are acylated with different substituted phenoxyacetic acid ester derivatives. Most of the derivatives were assayed for in vitro cytotoxicity against six human cancer cell lines KB, KB/VCR, A549, HCT-8, Bel7402, and A2780, and most of the assayed compounds exhibited good antiproliferative activity on these tumor cell lines especially on KB. [ABSTRACT FROM AUTHOR]

Patients with advanced pediatric sarcomas have a poor prognosis and novel combination therapies are needed to improve the response rates. Hematological and organ related toxicities have been observed when administering topotecan in combination with, e.g., high dose thiotepa. This study evaluates the toxicity of escalating doses of topotecan alone or in combination with thiotepa or treosulfan. We compared the toxicity including death of complication (DOC) of topotecan alone or in combination with thiotepa or treosulfan in advanced pediatric sarcomas ( n = 12). Ten of 12 patients (0.83) suffered from advanced tumors of the Ewing family (i.e., bone or marrow metastases or relapse <24 month after diagnosis, including one neuroepithelial tumor of the kidney) and two from alveolar rhabdomyosarcoma stage IV (0.17). Median age was 15 years (range 5-28). Ratio of female to male was 1:1. Two patients received topotecan alone (1.25 mg/m2 q 5d and 1.5 mg/m2 q 5d), three patients received four courses of topotecan (2 mg/m2 q d 1-5) in combination with thiotepa (100 mg/m2 q d 1-5), and seven patients received topotecan (2 mg/m2 q d 1-5) in combination with treosulfan (10g/m2 q d 3-5). Overall toxicity was not different between all three groups; mean scores were 1.6, 1.8, and 1.7 according to WHO grading (Scale 0-4). Organ related toxicity ranged between 0 and 4 and was not different as well. DOC was 0/2, 1/3, and 0/7 patients respectively. Escalating therapy with topotecan in combination with treosulfan has acceptable toxicity and warrants further investigation in advanced pediatric sarcomas. [ABSTRACT FROM AUTHOR]

Purpose: Topotecan has recently been used in the treatment of pediatric cancer. We evaluated our experience with the modified combination of vincristine, topotecan, and cyclophosphamide (VTC) given in 3 days, in children with recurrent Ewing sarcoma. Method: Children received vincristine (1.5 mg/m2/1st day), cyclophosphamide (600 mg/m2/day × 2 days) + mesna, and topotecan (1 mg/m2/day × 3 days) every 21 days. Result: A total of 118 courses of VTC were given to 13 patients. One patient received VTC both at first and at second relapse. Thus, 14 relapse episodes in 13 patients were evaluated. After three courses of VTC chemotherapy (CT), two achieved complete response (CR), five achieved partial response, thus an objective response was attained in 7/14 (50%) episodes. Two patients had stable disease and two patients progressed. In three episodes, CR was achieved by surgery before CT. One of them had a second relapse and attained CR with VTC. Median time from diagnosis to relapse was 23 months (5-45 months). Site of relapse was local in four patients, and metastatic in 10 episodes of nine patients. Seven patients are alive, three with no evidence of disease and four alive with disease; six have died of disease. Local treatment was used in 11 episodes. The toxicity of the VTC combination was limited mainly to the hematopoietic system. Conclusion: In conclusion, the modified VTC protocol in 3 days every 3 weeks seems to be effective and tolerable in children and adolescents with recurrent/progressive Ewing sarcoma. [ABSTRACT FROM AUTHOR]

After a first course of induction chemotherapy, 30-40% of patients with acute myeloid leukemia (AML) do not achieve a complete response (CR). A second course of an anthracycline and intermediate-dose cytarabine (IDAC) allows a significant number of patients with persistent AML at day 14 to finally achieve a CR. We hypothesized that use of a topotecan and cytarabine combination in this setting might improve tolerance and efficacy. Cytarabine (1000 mg/m2/12 h days 1-4) was combined with topotecan (TA, 1.25 mg/m2/day by continuous intravenous infusion [CIV] days 1-4) in 31 consecutive patients with ≥ 5% marrow blasts by day 14 of induction. The median follow-up was 36 months. The CR rate was 81%, and the 2-year probability of overall survival and cumulative incidence of relapse were 66% and 38%, respectively. No unexpected toxicity was observed. Comparison with historical controls treated with the combination of a similar schedule of cytarabine and an anthracycline showed a better CR rate ( p = 0.054), overall survival ( p = 0.03) and cumulative incidence of relapse ( p = 0.03). These results were confirmed in a multivariate analysis model. This work shows that the substitution of an anthracycline by topotecan is feasible and associated with significant efficacy for patients with AML with persistent leukemia at day 14 after standard-dose anthracycline induction. [ABSTRACT FROM AUTHOR]

The purpose of this study was to determine the activity of topotecan given by 21-day continuous infusion in patients previously treated with one prior therapy for a diffuse large-cell lymphoma or immunoblastic lymphoma. Patients with appropriate histology and measurable disease who had been treated with one prior chemotherapy regimen were eligible for study. Slides of tumor biopsies were submitted for central review of pathology. Patients were required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 and adequate bone marrow function. Patients were treated with continuous infusion topotecan, 0.4 mg/m2/day × 21 days. Therapy could be escalated to 0.5 and then 0.6 mg/m2/day in subsequent cycles if there was no dose-limiting toxicity at the initial dose level. Patients were treated with two cycles after achieving a complete response or until disease progression or unacceptable toxicity occurred. Thirty-seven patients were enrolled. However, only 26 cases were eligible due to a performance status of > 2 ( n = 2), more than one prior chemotherapy ( n = 1) and wrong histology on review ( n = 8). Due to the unexpectedly high ineligibility rate, two sets of analysis were done for all 37 patients enrolled and for the 26 eligible patients, respectively. Of the 37 patients (15 males and 22 females), the International Prognostic Index included 11% low risk, 30% low intermediate risk, 46% high intermediate risk and 8% high risk. The median follow-up was 77 months. A total of 136 cycles of therapy were given with a median of 3 cycles per patient. Grade 4 toxicities included: 14% grade 4 thrombocytopenia; 14% grade 4 granulocytopenia, 8% leukopenia, 3% each anemia, hemorrhage, infection, vomiting, thrombosis, liver toxicity and neuromotor toxicity. The response analysis including all 37 patients showed five complete responses (CRs) and four partial responses (PRs) for a total response rate of 24% (90% two-stage confidence interval 13-39%). Median progression-free survival (PFS) was 3.7 months, with 1- and 2-year PFS of 21% and 6%, respectively (90% confidence interval 11-34% and 2-15%). Median overall survival (OS) was 10.5 months, with 1- and 2-year OS of 41% and 27%, respectively (90% confidence interval 27-53% and 16-39%). Analysis including only eligible patients showed similar response rates and survival outcomes. Single agent topotecan has moderate activity for previously treated high-grade lymphoma equivalent to that of several newer agents, and should be considered for incorporation into multi-drug salvage chemotherapy programs. [ABSTRACT FROM AUTHOR]

A simple, rapid, accurate, robust, sensitive, and stability-indicating reversed-phase high-performance liquid chromatographic (RP-HPLC) analytical method has been developed for the separations of related impurities and degradants of topotecan in topotecan injection. Forced degradation studies performed on topotecan injection formulation revealed that the compound (topotecan) is extremely susceptible to all hydrolytic, oxidation, light exposure, and thermal stress. The method was tested in the presence of commonly used formulation excipients such as mannitol and tartaric acid. Separation of topotecan from its degradation products and three related impurities (Imp-A, Imp-B, Imp-C) as process impurities was achieved on ACE® C18, 150 × 4.6 mm i.d, 3 µm, stainless steel analytical column using a gradient elution. The elution of impurities employed multi-step gradient programmed mobile phase consisting of 0.02 M ammonium acetate (pH, 4.2) as mobile phase-A and a mixture of methanol and isopropyl alcohol in the ratio of 750:250 (v/v), respectively, as mobile phase-B. The mobile phase flow rate was maintained at 0.8 mL min-1. The column eluent was monitored at 267 nm. The column oven temperature was 25°C. The same method was also extended to LC-MS with the same gradient conditions used to identify the degradation products observed under forced degradation studies. The method was validated according to FDA, USP (general chapter 1225), and ICH guidelines, and statistical analysis of the data proved to be suitable for stability testing at quality control. The linearity of the proposed method for all the aforementioned related impurities and topotecan was investigated in the range of LOQ to 4.9 µg mL-1, respectively. The method was shown to separate topotecan well from the degradants and commonly used excipients. The specificity of the method was established through peak purity testing using a photodiode array detector. [ABSTRACT FROM AUTHOR]

A selective fluorimetric method was developed to quantify camptothecin (CPT) in irinotecan (CPT-11) and in topotecan (TPT) based anti-cancer drugs. Selectivity was achieved by experimental optimization and using synchronized scanning and second-order spectral derivatization. The limits of quantification for CPT were in the order of 1 × 10-7 mol L-1 with a linear response up to 1 × 10-5 mol L-1. The combined uncertainty associated with the CPT fluorescence measurement at a 5 × 10-7 mol L-1 level were 10.9% and 6% of the reference level, respectively, for TPT and CPT-11 based pharmaceutical formulations. The CPT recoveries of 95 ± 12% and 91 ± 5.6% (n = 3) were achieved, respectively, in samples containing CPT-11 and TPT. [ABSTRACT FROM AUTHOR]

As a class, camptothecin analogues via market entry of topotecan and irinotecan, have shown promise for the treatment of various solid tumours. Topotecan, in particular, was chosen as the substrate for allometric scaling and prediction of human parameter values for both total clearance (CL) and volume of distribution (Vss). The availability of published data in mouse, rat, dog, and monkey paved the way for interspecies scaling via allometry. Although it appeared that at a minimum mouse, rat, and dog would reasonably fit in a three-species allometry scale-up, the inclusion of monkey data enabled a better prediction of the human parameter values for total topotecan-e.g., CL: allometric equation: 1.5234W0.7865; predicted value = 43.04 l h-1: observed CL = 24-53 l h-1; Vss: allometric equation: 1.1939W1.0208; predicted value = 91.29 litres: observed Vss = 66-146 litres. The proximity of the allometric exponent values of CL (0.7885) and Vss (1.0208) to the suggested values of 0.75 and 1.00 was not only encouraging, but also confirmed the applicability of interspecies scaling approach for topotecan. The data suggest that allometric scaling approaches with suitable correction factors could potentially be used to predict the human pharmacokinetics of novel CPT analogues prospectively. [ABSTRACT FROM AUTHOR]

Background: To assess the efficacy of topotecan, a topoisomerase I specific inhibitor in S-phase, the reagent-induced apoptosis and cytotoxicity as well as related proteins expression, had been preliminarily investigated in human hepatoblastoma HepG2 cells. Methods: Microculture tetrazolium assay (MTT), HE staining, transmission electron microscopy (TEM), flow cytometry (FCM), quantitative immunocytochemistry (QI), gene tranfection and RNAi technology were employed to carry out the exploration. Results: Topotecan could potently kill HepG2 cells via inducing apoptosis and demonstrated strong cytotoxicity in a time, dose-dependent manner with IC50 of about 95 μ g/L. According to morphologic observation and FCM analyses, it was confirmed that the drug treatment, causing significant S-phase arrest, could trigger a typical interphase apoptosis, the main traits of which were identified as chromatin pycnosis and cytoplasm condensation. It was shown that the expression of Bcl-XL was simultaneously down-regulated with the up-regulation of Bcl-XS in cytoplasm, which was possibly a key downstream event following the topotecan-induced DNA damage in nucleus. The expression level of p27Kip1, a negative regulator in cell cycle at G1/S transient, was also elevated. Transfection of pcDNA 3.1-p27Kip1 into HepG2 cells could abrogate the cytotoxicity in a degree while silence of p27Kip1 with siRNA in drug treatments could significantly increased the chemosensitivity, strongly indicating that the up-regulation of p27Kip1 was not an apoptosis-promoting, but a self-rescue response against drug by moderate G0/G1 arrest. Conclusion: Topotecan had potent cytotoxicity against HepG2 cells by triggering an interphase apoptosis possibly mediated by increasing the ratio of Bcl-XS/Bcl-XL. Up-regulation of p27Kip1in TPT treatments could be a protective response for self-rescue and silence of the gene markedly augmented TPT cytotoxicity. Therefore, the experiment in vitro could provide a new idea for the clinical chemotherapy based on the combination of traditional drugs with the specific-siRNA targeted on the protective response gene. [ABSTRACT FROM AUTHOR]

Ovarian cancer remains one of the most difficult gynecologic cancers to treat, owing to its aggressive biology and high relapse rate, as well as the toxic side effects of available chemotherapeutic agents used to treat recurrent disease. Topoisomerase I inhibitors, including topotecan and irinotecan, are some of the most effective and tolerable treatment options for recurrent ovarian cancer. The ideal dosing, timing of administration, role in combination with other chemotherapies or biologics and potential role in up-front therapy remains an area of active research. This article reviews the mechanism of action of topoisomerase I inhibitors and the efficacy, dosing, schedule and toxicity for topotecan, irinotecan, 9-nitrocamptothecin, DX-8951 and 9-aminocamptothecin. Conclusions include a discussion of future avenues of research and ongoing projects. [ABSTRACT FROM AUTHOR]

Patients with primary malignant brain tumors have a poor prognosis. Standard treatment includes surgical resection, radiation therapy and chemotherapy. Topoisomerase I inhibitors such as topotecan and irinotecan (CPT-11) represent one class of chemotherapy drugs that have been used in this disease. Recent clinical trials have shown major antitumor activity in recurrent glioblastoma when adding the antiangiogenesis drug bevacizumab with CPT-11. The combination of targeted agents to topoisomerase I inhibitors represent a novel and promising approach. This review will summarize clinical trials with topoisomerase I inhibitors and discuss new treatment strategies for primary malignant brain tumors. [ABSTRACT FROM AUTHOR]

Ewing sarcoma (EWS) is a bone tumor occurring primarily in adolescence and young adulthood. Multi-institutional clinical trials have improved the outcome for patients with nonmetastatic EWS, but not with metastatic EWS. Furthermore, although 30% of EWS recur, multi-institutional studies have not been completed for this high-risk group. Planning such studies has been hampered by both the lack of novel therapies and the inability to incorporate the biology of EWS. While the importance and detail of the EWS-FLI-1 translocation between chromosomes 11 and 22 are described, these have not yet led to new drug development for this orphan tumor. However, recent evidence supporting novel cytotoxic therapy, antiangiogenic therapy, and receptor-targeted therapy provides reason for optimism for patients with high-risk disease. [ABSTRACT FROM AUTHOR]

This study reports the development of liposomal system for a potent antitumor drug, topotecan. To achieve this goal conventional and PEGylated liposomes were prepared according to a factorial design by hydration method followed by extrusion. Parameters such as type of lipid, percentage of cholesterol, percentage of phosphatidylglycerols, percentage of polyethylene glycol (PEG)-lipids, and drug to lipid molar ratio were considered as important factors for the optimizing the entrapment and retention of topotecan inside the liposomes. The size and zeta-potential of the PEGylated and conventional liposomes were measured by particle size analyzer and zeta-potentiometer, respectively. The stability and release characteristics of PEGylated liposome loaded topotecan were compared with conventional liposomes and free topotecan. The optimized PEGylated [distearoyl phosphatidylcholine (DSPC)/cholesterol/ distearoyl phosphatidylglycerol (DSPG)/ distearoyl phosphatidylethanolamine-PEG2000 (DSPE-PEG2000); 7:7:3:1.28] and related conventional [DSPC/cholesterol/DSPG; 7:7:3] liposomes showed a narrow size distribution with a polydipersity index of 0.15 and 0.10, an average diameter of 103.0 ± 13.1 and 95.2 ± 11.10 nm, and with drug loading of 11.44 and 6.21%, respectively. Zeta-potential was -10 ± 2.3 and -22 ± 2.8 mV for PEGylated and conventional liposomes, respectively. The results of stability evaluation showed that the lactone ring of topotecan was notably preserved upon liposome encapsulation. PEGylated liposomes containing topotecan showed a significant decrease (P < 0.001) in release rate in comparison with conventional leptosomes. These results indicate the suitability of PEGylated liposomes in controlling topotecan release. The prepared liposomes (especially PEGylated liposomes) as those described here may be clinically useful to stabilize and deliver topotecan for the treatment of cancer. [ABSTRACT FROM AUTHOR]

Lung cancer is the most prevalent and yet the most preventable malignancy worldwide. Owing to the propensity of small-cell lung cancer to early relapse and its relative resistance to subsequent treatment there is a need to improve currently available therapies. Topotecan has provided an efficacious and tolerable therapeutic option for patients with recurrent small-cell lung cancer, and the oral formulation has also been shown to be beneficial, even in elderly patients of poor performance status. Herein we review the role of topotecan in the treatment of small-cell lung cancer. [ABSTRACT FROM AUTHOR]

A series of exploratory investigations with multiple agents was carried out in normal rats and in rats with uranyl nitrate-induced acute renal failure to understand the disposition characteristics of intravenous topotecan (TPT) used as a model substrate. The disposition of TPT was unaltered in normal rats when treated with methotrexate, whereas treatment with probenecid increased the systemic exposure of TPT. In case of uranyl nitrate-induced acute renal failure (UN-ARF) rats, the systemic exposure of TPT was increased when compared with normal rats, whereas in UN-ARF rats treated with probenecid a further reduction in renal clearance of TPT was noted as compared with that of UN-ARF induced rats. Thus, TPT may be involved in the tubular secretory pathway when a passive glomerular filtration pathway for elimination was not possible. The disposition of TPT did not normalize in UN-ARF rats when treated with caffeine, a non-selective adenosine A1 receptor antagonist, whereas the selective adenosine A1 receptor antagonist (1,3-dipropyl-8-phenylxanthine, DPPX) normalized TPT pharmacokinetic disposition by improving renal function. Renal excretion studies demonstrated that CLR improved by almost fivefold following DPPX treatment in ARF rats. In addition, the qualitative stability/metabolism pattern of TPT in liver microsomes prepared from various groups of rats (normal rats, UN-ARF rats, rats treated with DPPX, and UN-ARF rats treated with DPPX) was found to be similar. In summary, using a pharmacokinetic tool as a surrogate, it has been shown that the pharmacokinetic disposition of TPT improved considerably upon treatment with DPPX, a selective adenosine A1 antagonist. [ABSTRACT FROM AUTHOR]

Epithelial ovarian cancer is the eighth most common cancer and fifth most common cause of cancer-related death in women in the USA. While most women with Stage III/IV disease respond to first-line therapy with a platinum/taxane combination, only 10-30% are long-term survivors. Topotecan, a topoisomerase I inhibitor, is approved by the US FDA for the treatment of relapsed disease at a dose and schedule of 1.5 mg/m2/day for 5 days every 21 days. This schedule causes significant, noncumulative myelosuppression, and various alternate regimens have been explored. A randomized Phase II Gynecological Oncology Group trial is currently investigating weekly topotecan versus a five-times daily schedule. Multiple randomized trials have evaluated incorporation of topotecan in front-line treatment of ovarian cancer, although none have demonstrated benefit for this approach. [ABSTRACT FROM AUTHOR]

Intrathecal administration of chemotherapy, with or without radiation therapy, is the primary treatment modality for the prevention and treatment of central nervous system (CNS) metastases in patients with leukemia or lymphoma. Although this treatment strategy has been very effective for patients with hematological malignancies, currently available intrathecal agents are relatively ineffective for patients with neoplastic meningitis resulting from an underlying solid or CNS tumor effective. This article provides an overview of some of the practical considerations and limitations associated with intrathecal chemotherapy, and is followed by a comprehensive review of some of the preclinical and early phase clinical trials of novel anticancer agents and treatment strategies using the intrathecal route. [ABSTRACT FROM AUTHOR]

This phase II trial investigated the safety and preliminary efficacy of a topotecan/thalidomide combination therapy in patients with myelodysplastic syndrome who had refractory anemia with excess blasts (RAEB), RAEB with transformation, or chronic myelomonocytic anemia. Patients received three 21-day cycles of topotecan 1.25 mg/m 2 on days 1–5, which was repeated for two additional cycles in patients whose bone marrow blast percentages did not decrease. Oral thalidomide was then started at 100 mg/day (with the dose escalated up to 300 mg/day if well tolerated) for up to 1 year. Patients were monitored throughout the trial for hematologic and clinical adverse events, and efficacy was assessed using International Working Group (IWG) criteria. Forty-five patients, mostly elderly (median age 68 years; range 52–79 years), were enrolled. Therapy was generally well tolerated compared to high-dose chemotherapy. Three patients died from disease progression/infections during topotecan therapy, and four patients discontinued topotecan because of high-grade neutropenia (two patients), syncope (one patient), or hip surgery (one patient). Of 24 patients who received thalidomide, three discontinued because of treatment-related toxicity. Thirty-eight patients were evaluable for response: nine (24%) had hematologic improvement and 13 (34%) had stable disease. Responses occurred in patients with all disease subtypes. Six patients achieved transfusion independence, and one patient had a trilineage response. Approximately one-third of the patients had decreases in bone marrow blasts of &geqslant;50%. Therefore, a topotecan and thalidomide combination therapy is promising, although further studies are needed to determine the optimum doses and schedule. [ABSTRACT FROM AUTHOR]

Pegfilgrastim is a pegylated form of a granulocyte colony-stimulating factor with a long half-life allowing for a single administration per chemotherapy cycle. The efficacy of a single dose of pegfilgrastim in supporting severely myelosuppressive regimens in previously treated cancer patients is unknown. Patients included in the present study had recurrent or refractory aggressive non-Hodgkin's lymphoma (NHL), had received two to three prior treatment regimens, and had good performance status and marrow reserve. Patients received intravenous paclitaxel 200 mg/m 2 on day 1 and topotecan 1 mg/m 2 daily for 5 days, repeated every 21 days for at least two cycles. On day 6, patients were given a single fixed dose of pegfilgrastim (6 mg) subcutaneously. Twenty patients were evaluable for analysis. After the first course of therapy, grade 4 neutropenia developed in all 20 patients. The median time to the neutrophil nadir was 9 days. The mean ± SD duration of grade 4 neutropenia was 3.8 ± 1.7 days. Nineteen (95%) patients received cycle 2 on time, on day 22. Five patients developed neutropenic fever (25%), which was associated with infection in one patient. In these previously treated patients with NHL, a single dose of pegfilgrastim was effective in promoting neutrophil count recovery after paclitaxel and topotecan, and allowed patients to receive the next planned dose on time. [ABSTRACT FROM AUTHOR]

Background : The objective of this study was to determine the feasibility and maximum tolerated dose (MTD) of combination topotecan and pegylated liposomal doxorubicin (PLD) administered in 4- or 3-week cycles in patients with advanced or refractory solid tumors. Patients and Methods : Patients were treated with intravenous topotecan (0.75–1.25 mg/m 2 ) for 3 days followed by PLD (25–40 mg/m 2 ) on Day 4. The following dose combinations (topotecan/PLD, mg/m 2 ) were explored: 0.75/40, 1.0/40, and 1.25/40 every 28 days; and 1.0/25 and 1.0/30 every 21 days. Results : Thirty-two patients were enrolled, and all had received prior chemotherapy. Most (84 percent) patients had ovarian cancer. A total of 157 cycles (median, 4 cycles; range, 1–19 cycles) of chemotherapy were administered. Dose-limiting toxicities were Grade 4 neutropenia and death at dose level 3 (1.25/40 mg/m 2 every 28 days), and neutropenic fever, Grade 3 stomatitis, and Grade 3 peripheral neuropathy (all in one patient) at dose level 5 (1/30 mg/m 2 every 21 days). Myelosuppression was the most common serious toxicity. Twenty-six patients were evaluable for response and 7 (27 percent) had partial responses. All responses were seen in patients with ovarian cancer. Conclusions : This combination is feasible and well tolerated; encouraging activity was observed in heavily pretreated patients with ovarian cancer. The recommended regimens for a Phase II study are topotecan 1.0 mg/m 2 on Days 1–3 followed by PLD 40 mg/m 2 on Day 4 of a 28-day cycle, and topotecan 1.0 mg/m 2 on Days 1–3 and PLD 30 mg/m 2 on Day 4 of a 21-day cycle. [ABSTRACT FROM AUTHOR]

Purpose. Topotecan is active in relapsed small cell lung cancer; thus, its addition to the standard carboplatin-etoposide regimen may improve outcomes in extensive-stage small cell lung cancer (ES-SCLC) patients. Significant interpatient variability in the topotecan systemic exposure results when it is dosed based on body surface area (mg/m 2 ). The purpose of this Phase I trial was to determine the maximally tolerated systemic exposure (MTSE) of topotecan in combination with carboplatin and etoposide. Methods. Thirty-four chemotherapy-naïve ES-SCLC patients received topotecan in combination with carboplatin AUC 5 mg/mL*min and oral etoposide 100 mg/m 2 /day. Topotecan was administered as a 30-minute infusion either on Days 1–5 or Days 1–3 and the dosage was individualized to attain a topotecan lactone AUC range (ng/mL*hr) in successive patient cohorts from 7 to 23; 24 to 36; 37 to 53; 54 to 66. Results. The majority (67 percent) of the measured topotecan AUCs were within target range. Overall, 8 of 34 patients experienced Cycle 1 dose-limiting toxicity (DLT), either neutropenia or thrombocytopenia. Carboplatin administration prior to topotecan resulted in 2 of 6 patients having Cycle 1 DLT. When the administration sequence was changed (topotecan, carboplatin, etoposide), Cycle 1 hematologic toxicity decreased; however, the maximum topotecan lactone AUC of 24–36 ng/mL*hr (median dose 0.82 mg/m 2 ) had significant cumulative hematologic toxicity. The number of topotecan doses were reduced from 5 to 3, which resulted in a maximum topotecan lactone AUC of 37 to 53 ng/mL*hr with only 1 of 6 patients having Cycle 1 DLT. Overall response rate was 71 percent with median survival of 10.8 months. Conclusion. It is feasible to target topotecan lactone AUC in adult ES-SCLC patients. However, this triplet regimen resulted in considerable hematologic toxicity and has a median survival comparable to carboplatin-etoposide. Alternative, less toxic regimens should be investigated for improving survival in ES-SCLC. [ABSTRACT FROM AUTHOR]

Background: To evaluate the possible influence of topotecan therapy on lipid peroxidation and antioxidant enzymes in rabbit liver tissue, the levels of thiobarbituric acid reactive substances (TBARS) and activities of the antioxidant enzymes superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) were investigated. Methods: A total of 24 adult, healthy New Zealand rabbits were divided into three groups (n = 8). Topotecan was administered intravenously via the ear vein for 3 days at 0.25 mg/kg/day for the low-dose group and 0.50 mg/kg/day for the high-dose group; physiological saline was used for the control group. All animals were sacrificed on day 15. Livers were removed and homogenised. The homogenate supernatant was used for measurement of TBARS levels, and SOD, GSH-Px, and CAT enzyme activities (expressed as IU/mg protein). Results: There were significant differences in the TBARS level and GSH-Px activity between control and the topotecan treatment groups. TBARS level of topotecan treatment groups was higher than control (89% and 126%, respectively, P = 0.001). It was also significantly higher in the high-dose group than the low-dose group (20%; P = 0.011). GSH-Px activity was lower in the low- and high-dose topotecan groups than the control (42% [P = 0.002] and 65% [P = 0.001], respectively). Enzyme activity was lowest in the high-dose group and the difference was also significant when compared with the topotecan groups (40%; P = 0.001). Although there was some decrease in SOD and CAT activities in the topotecan-treated groups, differences from the control group were not significant. Conclusions: These findings suggest that topotecan treatment results in an increase in lipid peroxidation and a decrease in antioxidant enzyme activities in healthy liver tissue from rabbits. We believe that the addition of antioxidants to topotecan therapy may reduce the harmful effects of topotecan on liver tissue. [ABSTRACT FROM AUTHOR]

The National Institute for Clinical Excellence (NICE), established in 1996 as a special Health Authority for England and Wales, provides the United Kingdom medical community with robust and reliable guidance on current "best practices" in medicine. Based on analyses of clinical efficacy, safety, and cost effectiveness, clinical guideline recommendations are developed in an attempt to standardize treatment of various diseases and medical conditions. To date, NICE has issued guidance for the use of three chemotherapeutic agents in the treatment of ovarian cancer: paclitaxel, topotecan, and pegylated liposomal doxorubicin. NICE guidance recommends surgery and adjuvant chemotherapy with paclitaxel/platinum combination therapy or platinum therapy alone as first-line treatment for ovarian cancer. NICE has also issued guidance recommending the use of topotecan or pegylated liposomal doxorubicin as second-line agents for the treatment of women with relapsed or refractory disease. Accounting for all available data, NICE guidance supports the appropriate roles of paclitaxel, topotecan, and pegylated liposomal doxorubicin in the treatment of advanced ovarian cancer. [ABSTRACT FROM AUTHOR]

The use of dichloromethane as a reagent, for the preparation of Topotecan {(4S)‐10‐(dimethylamino)methyl‐4‐ethyl‐4,9‐dihydroxy‐1‐H‐pyrano[3′,4′:6,7]indolizino‐[1,2‐b]quinoline‐3,14(4H,12H)dione} from 10‐hydroxy‐camptothecin under solid–liquid phase transfer catalysis, which behaves both as a solvent and a reagent serving as for C‐1 unit source for amino‐alkylation of 10‐hydroxy‐(4S)‐camptothecin. #US Patent no. 6,660,861 December 9, 2003. [ABSTRACT FROM AUTHOR]