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Introduction: In both developing and developed countries, cancer is among the leading causes of millions of deaths. The incidence of cancer is increasing due to environmental changes and modernization of life style. Lung and breast cancer deaths lead in number compared to other cancer deaths. Although the cause of cancer due to external factors like tobacco use, chemicals, radiation, infectious organisms and internal factors like immune conditions and genetic modification are known, the occurrence and deaths due to cancer cannot be controlled. Methods: It is expected that the incidence of cancer after two decades will increase by 70% and death rate will also increase by 50%, which is an alarming situation globally. Although synthetic compounds are being used in the control of cancer as chemopreventive agents, about 50% of these are related to natural products as the origin. There is an emerging evidence to show that in the past 50 years, natural products derived from plants and marine sources had beneficial effects in the treatment and prevention of cancer. Taxol, vincristine, vinblastine, cytarabine, eribulin mesylate and trabectidine are some of the anticancer compounds isolated from terrestrial and marine sources. Results: This review highlights mainly the role of natural compounds isolated from terrestrial and marine sources as anticancer agents through the docking of these compounds with the related macromolecular targets. Conclusion: Cell line studies for some of the compounds isolated from natural products are also reported.

We investigated the efficacy and safety of further bevacizumab therapy in patients with platinum‐resistant ovarian cancer whose disease had progressed after bevacizumab plus chemotherapy. In this multicenter, open‐label, phase II trial (JGOG3023), patients were randomized 1:1 to a single‐agent chemotherapy alone (either pegylated liposomal doxorubicin [40 or 50 mg/m2 administered intravenously], topotecan [1.25 mg/m2 intravenously], paclitaxel [80 mg/m2 intravenously], or gemcitabine [1000 mg/m2 intravenously]) or single‐agent chemotherapy + bevacizumab (15 mg/m2 intravenously). The primary endpoint was investigator‐assessed progression‐free survival (PFS) according to RECIST version 1.1. Secondary endpoints were overall survival (OS), objective response rate (ORR), and response rate according to Gynecological Cancer Intergroup cancer antigen 125 criteria. In total, 103 patients were allocated to chemotherapy (n = 51) or chemotherapy + bevacizumab (n = 52). Median investigator‐assessed PFS was 3.1 and 4.0 mo in each group, respectively (hazard ratio [HR] = 0.54, 95% confidence interval [CI]: 0.32‐0.90, P = .0082). Median OS was 11.3 and 15.3 mo in each group, respectively (HR = 0.67, 95% CI: 0.38‐1.17, P = .1556). Respective ORRs were 13.7% and 25.0% (P = .0599) and response rates were 16.7% and 21.4% (P = .8273). The incidence of grade ≥3 treatment‐related AEs was 42.0% in the chemotherapy group and 54.9% in the chemotherapy + bevacizumab group; AEs were well tolerated, with only 2 and 12 events leading to discontinuation of therapy, respectively. Bevacizumab was effective beyond progressive disease and AEs were manageable. The observed improvement in PFS requires further verification., We evaluated chemotherapy ± bevacizumab for platinum‐resistant recurrent ovarian cancer previously treated with bevacizumab. The results of this phase II study demonstrate the efficacy and manageable toxicity of continuing bevacizumab beyond progressive disease in patients with platinum‐resistant recurrent ovarian cancer previously treated with bevacizumab for front‐line or platinum‐sensitive recurrent ovarian cancer.

Objective The randomized phase 3 CORAIL trial evaluated whether lurbinectedin improved progression-free survival (PFS) compared to pegylated liposomal doxorubicin (PLD) or topotecan in patients with platinum-resistant ovarian cancer. Methods Patients were randomly assigned (1:1) to lurbinectedin 3.2 mg/m2 1-h i.v. infusion q3wk (experimental arm), versus PLD 50 mg/m2 1-h i.v. infusion q4wk or topotecan 1.50 mg/m2 30-min i.v. infusion Days 1–5 q3wk (control arm). Stratification factors were PS (0 vs. ≥1), prior PFI (1–3 months vs. >3 months), and prior chemotherapy lines (1–2 vs. 3). The primary endpoint was PFS by Independent Review Committee in all randomized patients. This study was registered with ClinicalTrials.gov , NCT02421588 . Results 442 patients were randomized: 221 in lurbinectedin arm and 221 in control arm (127 PLD and 94 topotecan). With a median follow-up of 25.6 months, median PFS was 3.5 months (95% CI, 2.1–3.7) in the lurbinectedin arm and 3.6 months (95% CI, 2.7–3.8) in the control arm (stratified log-rank p = 0.6294; HR = 1.057). Grade ≥ 3 treatment-related adverse events (AEs) were most frequent in the control arm: 64.8% vs. 47.9% (p = 0.0005), mainly due to hematological toxicities. The most common grade ≥ 3 AEs were: fatigue (7.3% of patients) and nausea (5.9%) with lurbinectedin; mucosal inflammation (8.5%) and fatigue (8.0%) in the control arm. Conclusions The primary endpoint of improvement in PFS was not met. Lurbinectedin showed similar antitumor efficacy and was better tolerated than current standard of care in patients with platinum-resistant ovarian cancer.

Retinoblastoma eyes with choroidal invasion may not have to be enucleated and may be successfully managed with OAC using Melphalan, Carboplatin and Topotecan without compromising patient survival.

OBJECTIVE To examine the therapeutic effects of camptothecin (CPT) and topotecan (TPT), inhibitors of transcription factor Fli-1 and topoisomerase, on lupus nephritis in (NZB × NZW)F1 (NZBWF1) mice, and to examine the effects of CPT and TPT on inflammatory mediators in human renal cells. METHODS Female NZBWF1 mice were treated with vehicle, cyclophosphamide (CYC), CPT (1 mg/kg or 2 mg/kg), or TPT (0.03 mg/kg, 0.1 mg/kg, or 0. 3 mg/kg) by intraperitoneal injection twice a week, beginning at the age of 25 weeks (n = 8-10 mice per group). Blood and urine were collected for monitoring autoantibodies and proteinuria. Mice were euthanized at 40 weeks, and renal pathology scores were assessed. Human renal endothelial and mesangial cells were treated with CPT or TPT, and cytokine expression was measured. RESULTS None of the NZBWF1 mice treated with 1 mg/kg or 2 mg/kg of CPT or 0.3 mg/kg of TPT had proteinuria >100 mg/dl at the age of 40 weeks. One of 8 mice treated with 0.1 mg/kg of TPT and 1 of 10 mice treated with CYC had proteinuria >300 mg/dl, whereas 90% of the mice treated with vehicle had proteinuria >300 mg/dl. Compared to vehicle control, mice treated with 1 mg/kg or 2 mg/kg of CPT, 0.1 mg/kg or 0.3 mg/kg of TPT, or CYC had significantly prolonged survival, attenuated renal injury, diminished splenomegaly, reduced anti-double-stranded DNA autoantibody levels, and reduced IgG and C3 deposits in the glomeruli (all P < 0.05). Human renal cells treated with CPT or TPT had reduced expression of Fli-1 and decreased monocyte chemotactic protein 1 production following stimulation with interferon-α (IFNα) or IFNγ. CONCLUSION Our findings indicate that low-dose CPT and TPT could be repurposed to treat lupus nephritis.

Venetoclax is a small molecule inhibitor of the prosurvival protein BCL-2 that has gained market approval in BCL-2–dependent hematologic cancers including chronic lymphocytic leukemia and acute myeloid leukemia. Neuroblastoma is a heterogenous pediatric cancer with a 5-year survival rate of less than 50% for high-risk patients, which includes nearly all cases with amplified MYCN. We previously demonstrated that venetoclax is active in MYCN-amplified neuroblastoma but has limited single-agent activity in most models, presumably the result of other pro-survival BCL-2 family protein expression or insufficient prodeath protein mobilization. As the relative tolerability of venetoclax makes it amenable to combining with other therapies, we evaluated the sensitivity of MYCN-amplified neuroblastoma models to rational combinations of venetoclax with agents that have both mechanistic complementarity and active clinical programs. First, the MDM2 inhibitor NVP-CGM097 increases the prodeath BH3-only protein NOXA to sensitize p53-wild-type, MYCN-amplified neuroblastomas to venetoclax. Second, the MCL-1 inhibitor S63845 sensitizes MYCN-amplified neuroblastoma through neutralization of MCL-1, inducing synergistic cell killing when combined with venetoclax. Finally, the standard-of-care drug cocktail cyclophosphamide and topotecan reduces the apoptotic threshold of neuroblastoma, thus setting the stage for robust combination efficacy with venetoclax. In all cases, these rational combinations translated to in vivo tumor regressions in MYCN-amplified patient-derived xenograft models. Venetoclax is currently being evaluated in pediatric patients in the clinic, including neuroblastoma (NCT03236857). Although establishment of safety is still ongoing, the data disclosed herein indicate rational and clinically actionable combination strategies that could potentiate the activity of venetoclax in patients with amplified MYCN with neuroblastoma.

Objective To establish the success rate of salvage intra-arterial chemotherapy (IAC), defined as the percentage of eyes that achieved tumoral remission and avoided enucleation. The second objective was the clinical characterization, catheterization results, and associated local and systemic complications. Methods Retrospective, interventional case series of 29 patients (35 eyes) with persistent or recurrent retinoblastoma. Results A total of 73 salvage IAC procedures with topotecan and melphalan were carried out. Success rate was 77% at a mean follow-up of 41.4 months. All patients with only one remaining eye avoided enucleation (10 cases). Catheterization was successful in 98.6% of cases. The types of catheterizations were as follows: 71.2% supraselective ophthalmic artery, 12.3% occlusion pump assisted supraselective ophthalmic artery, 16.4% selective external carotid with retrograde flow. 14% of patients suffered local adverse effects: 1 (2.8%) transitory ptosis, 1 (2.8%) transitory oculomotor nerve palsy, 2 (5.7%) aseptic cellulitis and 1 (2.8%) periorbitary pigmentation. 4.1% (3 cases) suffered neutropenia due to medullar chemosuppression. There were no cases of severe anemia or thrombocytopenia. There were no cerebral ischemic events or mortality associated to the procedure. Conclusion IAC with melphalan and topotecan is a safe and effective treatment option for persistent or recurrent retinoblastoma, able to reduce enucleation rates.

Background Pazopanib is active in refractory soft-tissue sarcoma (STS) and significantly prolongs PFS. Prior studies of combinations of metronomic topotecan with pazopanib have indicated preclinical evidence of response in patients with sarcoma. Methods This prospective, single arm, phase II study evaluated the efficacy of the combination of pazopanib with topotecan in patients with metastatic or unresectable non-adipocytic STS. Furthermore, it incorporated exploratory arms for osteosarcoma and liposarcoma. The primary endpoint was progression-free rate at 12 weeks in the non-adipocytic STS cohort. Results 57.5% of patients in the non-adipocytic STS cohort were progression free at 12 weeks, which did not meet the primary endpoint of the study (66%). The exploratory osteosarcoma cohort exceeded previously established phase II trial comparator data benchmark of 12% with a PFR at 12 weeks of 69.55%. Treatment with the combination of pazopanib and topotecan was accompanied by a grade 3 or 4 toxicities in most patients. Conclusions In this prospective trial in refractory metastatic or unresectable STS and osteosarcoma, the combination of pazopanib with topotecan did not meet its primary endpoint of progression-free rate at 12 weeks. The combination of pazopanib with topotecan was associated with a high degree of toxicity.

Background Medulloblastomas with chromothripsis developing in children with Li-Fraumeni Syndrome (germline TP53 mutations) are highly aggressive brain tumors with dismal prognosis. Conventional photon radiotherapy and DNA-damaging chemotherapy are not successful for these patients and raise the risk of secondary malignancies. We hypothesized that the pronounced homologous recombination deficiency in these tumors might offer vulnerabilities that can be therapeutically utilized in combination with high linear energy transfer carbon ion radiotherapy. Methods We tested high-precision particle therapy with carbon ions and protons as well as topotecan with or without PARP inhibitor in orthotopic primary and matched relapsed patient-derived xenograft models. Tumor and normal tissue underwent longitudinal morphological MRI, cellular (markers of neurogenesis and DNA damage-repair), and molecular characterization (whole-genome sequencing). Results In the primary medulloblastoma model, carbon ions led to complete response in 79% of animals irrespective of PARP inhibitor within a follow-up period of 300 days postirradiation, as detected by MRI and histology. No sign of neurologic symptoms, impairment of neurogenesis or in-field carcinogenesis was detected in repair-deficient host mice. PARP inhibitors further enhanced the effect of proton irradiation. In the postradiotherapy relapsed tumor model, median survival was significantly increased after carbon ions (96 days) versus control (43 days, P < .0001). No major change in the clonal composition was detected in the relapsed model. Conclusion The high efficacy and favorable toxicity profile of carbon ions warrants further investigation in primary medulloblastomas with chromothripsis. Postradiotherapy relapsed medulloblastomas exhibit relative resistance compared to treatment-naïve tumors, calling for exploration of multimodal strategies.

Although several ATR inhibitors are in development, there are unresolved questions regarding their differential potency, molecular signatures of patients with cancer for predicting activity, and most effective therapeutic combinations. Here, we elucidate how to improve ATR-based chemotherapy with the newly developed ATR inhibitor, M4344 using in vitro and in vivo models. The potency of M4344 was compared with the clinically developed ATR inhibitors BAY1895344, berzosertib, and ceralasertib. The anticancer activity of M4344 was investigated as monotherapy and combination with clinical DNA damaging agents in multiple cancer cell lines, patient-derived tumor organoids, and mouse xenograft models. We also elucidated the anticancer mechanisms and potential biomarkers for M4344. We demonstrate that M4344 is highly potent among the clinically developed ATR inhibitors. Replication stress (RepStress) and neuroendocrine (NE) gene expression signatures are significantly associated with a response to M4344 treatment. M4344 kills cancer cells by inducing cellular catastrophe and DNA damage. M4344 is highly synergistic with a broad range of DNA-targeting anticancer agents. It significantly synergizes with topotecan and irinotecan in patient-derived tumor organoids and xenograft models. Taken together, M4344 is a promising and highly potent ATR inhibitor. It enhances the activity of clinical DNA damaging agents commonly used in cancer treatment including topoisomerase inhibitors, gemcitabine, cisplatin, and talazoparib. RepStress and NE gene expression signatures can be exploited as predictive markers for M4344.

Cancer chemotherapeutic drugs acts in different manner to kill malignant cells. Most of the anticancer drugs available in clinical practice to treat cancer patients, are natural products including whole plant extract, crude plant extracts, isolated constituents, plant –based drug formulations etc. These natural compounds have been a basis for the development of several drugs against cancer. Agents such as topotecan, taxol, vinca alkaloids (vincristine, vinblastine, vinorelbine and vindesine), are important anticancer agents in widespread clinical use. Other agents, such as combretastatin, flavopiridol, betulinic acid were shown to have anti-tumor effects in both in vitro and in vivo experiments. In this review, we aim to make a brief description of classical plant-derived chemotherapeutics drugs and also to highlight the importance of these natural compounds in the development of new potential drugs in cancer treatment.

Patients with relapsed small-cell lung cancer (SCLC) have few treatment options and dismal survival. Phase I/II data show activity of nivolumab in previously treated SCLC.CheckMate 331 is a randomized, open-label, phase III trial of nivolumab versus standard chemotherapy in relapsed SCLC. Patients with relapse after first-line, platinum-based chemotherapy were randomized 1 : 1 to nivolumab 240 mg every 2 weeks or chemotherapy (topotecan or amrubicin) until progression or unacceptable toxicity. Primary endpoint was overall survival (OS).Overall, 284 patients were randomized to nivolumab and 285 to chemotherapy. Minimum follow-up was 15.8 months. No significant improvement in OS was seen with nivolumab versus chemotherapy [median OS, 7.5 versus 8.4 months; hazard ratio (HR), 0.86; 95% confidence interval (CI), 0.72-1.04; P = 0.11]. A survival benefit with nivolumab was suggested in patients with baseline lactate dehydrogenase ≤ upper limit of normal and in those without baseline liver metastases. OS (nivolumab versus chemotherapy) was similar in patients with programmed death-ligand 1 combined positive score ≥1% versus1%. Median progression-free survival was 1.4 versus 3.8 months (HR, 1.41; 95% CI, 1.18-1.69). Objective response rate was 13.7% versus 16.5% (odds ratio, 0.80; 95% CI, 0.50-1.27); median duration of response was 8.3 versus 4.5 months. Rates of grade 3 or 4 treatment-related adverse events were 13.8% versus 73.2%.Nivolumab did not improve survival versus chemotherapy in relapsed SCLC. No new safety signals were seen. In exploratory analyses, select baseline characteristics were associated with improved OS for nivolumab.

SummaryBackground Selinexor, a first-in-class, oral selective inhibitor of nuclear export (SINE) compound inhibits Exportin-1(XPO1), had demonstrated synergistic activity with many chemotherapies and conferred in vivo antitumor efficacy in hematologic as well as solid tumors. Methods This open-label, single-center, multi-arm phase 1b study used a standard 3 + 3 design and a “basket type” expansion. Selinexor with intravenous topotecan was given in one of the 13 parallel arms. Patients with advanced or metastatic relapsed/refractory solid tumors following prior systemic therapy, or in whom the addition of selinexor to standard chemotherapy deemed appropriate, were eligible. Results Fourteen patients with the median age of 61 years (range, 22–68years) were treated, and the most common cancer types were gynecological cancers; ovarian (n = 5), endometrial (n = 2), and 1 each with fallopian tube and vaginal cancers. Of the 14 patients treated, 12 (86 %) had at least one treatment-related adverse event (TRAE). The most common TRAEs were anemia (71 %), thrombocytopenia (57 %), hyponatremia (57 %), vomiting (57 %), fatigue (50 %), nausea (50 %), and neutropenia (36 %). Two patients had dose limiting toxicities. One patient dosed at selinexor 80 mg had grade 3 nausea and vomiting and one patient dosed at selinexor 60 mg experienced grade 4 neutropenia and thrombocytopenia. Of the 13 efficacy evaluable patients, one (8 %) with endometrial cancer achieved unconfirmed partial response (uPR) and the time-to-treatment failure (TTF) was 48 weeks, whereas 6 of the 13 (46 %) patients had stable disease (SD) contributing to the clinical benefit rate of 46 %. The median TTF for all patients was 9 weeks (range, 2–48weeks). Conclusions Once weekly selinexor in combination with topotecan was viable and showed some preliminary tumor efficacy. The recommend phase 2 dose of selinexor was 60 mg once weekly in combination with IV topotecan.Trial registration: NCT02419495. Registered 14 April 2015, https://clinicaltrials.gov/ct2/show/NCT02419495

Intra-arterial chemotherapy is a new retinoblastoma treatment associated with high rates of globe salvage that has been widely adopted for primary treatment of retinoblastoma but is less frequently used as secondary treatment for refractory retinoblastoma. This systematic review aims to summarize the reported outcomes of intra-arterial chemotherapy for refractory retinoblastoma. We conducted a systematic review of studies published on PubMed, Medline, and Embase from 2011 to 2021 reporting globe salvage rates following intra-arterial chemotherapy for secondary treatment of refractory retinoblastoma. Our search yielded 316 studies, and 24 met inclusion criteria. The 24 included studies were comprised of 1366 patients and 1757 eyes. Among these, 1184 (67%) eyes received secondary indication treatment, and globe salvage was achieved for 776 of these 1184 eyes (64%). Sixteen studies reported cannulation success rates from 71.8 to 100%. Pooled analysis of subjects revealed 21 patients (2.6%) with metastatic disease and 26 deaths (3%) during study follow-up periods (7–74 months). The most common ocular complications were vitreous hemorrhage (13.2%), loss of eyelashes (12.7%), and periocular edema (10.5%). The most common systemic complications were nausea/vomiting (20.5%), neutropenia (14.1%), fever (8.2%), and bronchospasm (6.2%). Intra-arterial chemotherapy is associated with high rates of globe salvage and low rates of serious complications in patients with refractory retinoblastoma. Unfortunately, current literature is predominantly comprised of retrospective case studies, and further high-quality evidence is necessary to inform clinical practice.

The majority of patients with high-risk neuroblastoma (HR-NB) in low- and middle-income countries (LMIC) do not have access to autologous stem cell transplant (ASCT) and dinutuximab. Consolidation with nonmyeloablative chemotherapy is not well-defined, and the outcomes are variable. We report a single-center outcome of patients with HR-NB, treated with nonmyeloablative consolidation. A tabulated compilation of similar reports is included. A retrospective chart review of patients with HR-NB was performed from January 2009 till June 2016. Patients were treated on the backbone of HR-NBL1/SIOPEN protocol. Treatment included induction with rapid-COJEC, surgery, followed by consolidation. Consolidation involved 4 cycles of topotecan, vincristine, and doxorubicin (TVD) instead of ASCT. Infusion of vincristine and doxorubicin were modified for ease and to enable administration in the clinic. Subsequent treatment included radiotherapy to the primary tumor and differentiation therapy with isotretinoin. Over 7½ years, 28 patients with HR-NB were treated. Two (7%) patients had therapy-related mortality. A relapse or disease progression occurred in 11 (39%) patients at a median duration of 17 months (IQR: 5, 18). Treatment abandonment was observed in 4 (14%) patients. The median follow-up of disease-free patients was 49 months (IQR: 45, 79). Patients with relapse were not treated further. A 4-year EFS of 29.3% was observed when 4-cycles of TVD were administered instead of ASCT in patients with HR-NB. The study and the review will aid decision-making for care of patients in LMIC while considering the options of treatment for HR-NB if access to ACST and dinutuximab is lacking.

Peripapillary and circumpapillary retinal intraocular metastases are rare and present a treatment challenge for ophthalmologists because of the high risk of iatrogenic injury to the optic nerve. There are no clear guidelines on the management of these lesions, and many clinicians will initially observe for improvement of the metastases with systemic chemotherapy before considering local therapy with external beam radiation. Radiation to the optic disc carries a significant risk of injuring the optic nerve, leading to worsening of vision. Alternative treatment approaches are needed. We present a patient with large-cell neuroendocrine carcinoma with metastasis to the peripapillary retina who was treated with intravitreal topotecan and with intravitreal aflibercept. Serial fundus photos, ultrasound, and optical coherence tomography demonstrated a reduction in size of the lesion and a decrease in subretinal fluid with intravitreal topotecan and aflibercept. In addition, visual acuity was stabilized during treatment. Intravitreal chemotherapy for intraocular metastases in vision-sensitive areas such as the peripapillary retina may be a viable alternative for patients who seek to preserve their vision and maintain their quality of life.

Objective: The utility of topotecan monotherapy for relapsed small-cell lung cancer (SCLC) after failure of amrubicin monotherapy has not been evaluated. We aimed to investigate the efficacy and safety of topotecan monotherapy in patients with relapsed SCLC after amrubicin monotherapy. Patients and Methods: We retrospectively analyzed data from 16 patients with relapsed SCLC who were treated with topotecan monotherapy after amrubicin monotherapy at our hospital. Results: The response rate, progression-free survival, and overall survival were 0%, 32.5 days (95% confidence interval [CI] = 18–51), and 112 days (95% CI = 55–267), respectively. The most common adverse events (grade ≥3) were leukopenia (31.3%) and thrombocytopenia (31.3%), followed by anemia, anorexia, edema, and lung infections. Conclusion: The efficacy of topotecan monotherapy for relapsed SCLC after amrubicin monotherapy is inconclusive. Therefore, further studies are warranted.

Drugs administered in chemotherapy influence the patient's hematopoietic system. The side effects of chemotherapy can force changes in both the dose of drugs and the schedule of their administration, which in turn may adversely affect the patient's health. During chemotherapy treatment, there is a necessity to continuously monitor basic blood parameters, including the number of neutrophils and blood platelets, responsible for the patient's immunity. The aim of this paper is to study the behavior of the hematopoietic system, during chemotherapy, by means of a modified mathematical model of neutrophil production. We conducted simulations for children from 1–15 years old, suffering from neuroblastoma, who are undergoing chemotherapy treatment with Topotecan (TPT). The proposed model provides an effective tool for signaling the moment when the number of mature neutrophils, circulating in the blood, drops below the critical level, that is, 500 cells/ μ L. Such a nadir persisting over time may result in severe neutropenia and consequently require a halt or change to the established treatment schedule. In addition, we analyzed the process of neutrophil production during chemotherapy, supported by the application of glycoprotein as a growth factor of stem cells.

Topotecan is potent anti-cancer drug approved for various malignancies but hematopoietic toxicities undermine its wider application and use of its most effective dose. This study aims to improve these limitations through inhalation-delivery. The pharmacokinetics, efficacy, and toxicity of 2–5 times lower inhalation doses of topotecan dry-powder were compared with the standard intravenous (IV) delivery once/twice-a-week. Human-derived EGFR-mutant (H1975), KRAS-mutant (A549), and EGFR/KRAS wild-type (H358) orthotopic and distant lung tumors were evaluated in murine models. Inhalation of 1 mg/kg topotecan significantly improved the half-life and drug exposure (area under the curve, AUC) compared to 5 mg/kg via IV-delivery. AUCs (h*ng/mL) for inhaled/IV topotecan in plasma, lung, liver, and brain were, 831/888, 60,000/1080, 8380/4000, and 297/15, respectively; while the half-life was also greatly increased in these tissues. The average lung tumor burden of H358-derived tumors was reduced from 15.0 g to 8.4 g (44%) in rats treated once-a-week with 2 mg/kg IV and 1.8 g (88%) with 1 mg/kg inhaled topotecan, corroborating previous findings using A549- and H1975-derived orthotopic lung tumors. Importantly, inhaled topotecan showed superior efficacy in suppressing lung tumors at distant sites. The growth of H1975- and H358-derived subcutaneous xenografts were completely arrested and A549-derived tumors were significantly reduced in mice treated twice-a-week with 1 mg/kg inhaled topotecan compared to a minor (H1975 and H358) or no reduction (A549) with twice-a-week 5 mg/kg IV topotecan.

Background: Among all cancers, lung cancer has high mortality among patients in most of the countries in the world. Targeted delivery of anticancer drugs can significantly reduce the side effects and dramatically improve the effects of the treatment. Folate, a suitable ligand, can be modified to the surface of tumor-selective drug delivery systems because it can selectively bind to the folate receptor, which is highly expressed on the surface of lung tumor cells. Objective: This study aimed to construct a kind of folate-targeted topotecan liposomes for investigating their efficacy and mechanism of action in the treatment of lung cancer in preclinical models. Methods: We conjugated topotecan liposomes with folate, and the liposomes were characterized by particle size, entrapment efficiency, cytotoxicity to A549 cells and in vitro release profile. Technical evaluations were performed on lung cancer A549 cells and xenografted A549 cancer cells in female nude mice, and the pharmacokinetics of the drug were evaluated in female SD rats. Results: The folate-targeted topotecan liposomes were proven to show effectiveness in targeting lung tumors. The anti-tumor effects of these liposomes were demonstrated by the decreased tumor volume and improved therapeutic efficacy. The folate-targeted topotecan liposomes also lengthened the topotecan blood circulation time. Conclusion: The folate-targeted topotecan liposomes are effective drug delivery systems and can be easily modified with folate, enabling the targeted liposomes to deliver topotecan to lung cancer cells and kill them, which could be used as potential carriers for lung chemotherapy.

Background This study compared the efficacy/safety of the camptothecin analogues belotecan and topotecan for sensitive-relapsed small-cell lung cancer (SCLC). Methods One-hundred-and-sixty-four patients were randomised (1:1) to receive five consecutive daily intravenous infusions of topotecan (1.5 mg/m2) or belotecan (0.5 mg/m2), every 3 weeks, for six cycles. Main outcomes were objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), tolerability and toxicity. The study statistical plan was non-inferiority design with ORR as the endpoint. Results In the belotecan vs. topotecan groups, ORR (primary endpoint) was 33% vs. 21% (p = 0.09) and DCR was 85% vs. 70% (p = 0.030). PFS was not different between groups. Median OS was significantly longer with belotecan than with topotecan (13.2 vs. 8.2 months, HR = 0.69, 95% CI: 0.48–0.99), particularly in patients aged p = 0.022). Conclusions The efficacy/safety of belotecan warrants further evaluation in Phase 3 trials. Belotecan potentially offers an alternative to topotecan for sensitive-relapsed SCLC, particularly in patients aged

ObjectiveEvidence on recurrence patterns after bevacizumab in epithelial ovarian cancer is still insufficient. The aim of this study was to evaluate recurrence patterns after treatment with bevacizumab as second-line treatment in patients with platinum-sensitive, recurrent epithelial ovarian cancer.MethodsWe retrospectively identified epithelial ovarian cancer patients who relapsed ≥6 months after primary treatment consisting of surgery and platinum-based chemotherapy between January 2008 and June 2019. Only those who received platinum-based doublet chemotherapy with bevacizumab or without bevacizumab as second-line treatment were included (n=192). To adjust confounders, we conducted 1:2 propensity score matching for platinum-free interval and secondary debulking surgery. Imaging studies were performed to locate newly developed or enlarged pre-existing tumors. Recurrence patterns were compared between bevacizumab users (study group) and non-users (control group).ResultsAfter matching, the study group (n=52) and control group (n=104) showed similar baseline clinicopathologic characteristics including platinum-free interval (median (range) 15.3 (6.2–87.3) vs 14.0 (6.2–143.5) months; p=0.29) and patient age at the time of first recurrence (median (range) 55.5 (33.7–72.4) vs 55.0 (35.7–84.2) years; p=0.56). Initially, FIGO stage III disease was the most common in both two groups (55.8% vs 66.3%; p=0.20). Bevacizumab users were less likely to develop disease recurrence in the retroperitoneal lymph nodes (13.5% vs 34.6%; p=0.005), pelvis (17.3% vs 35.6%; p=0.018), and abdomen (40.4% vs 61.5%; p=0.012). However, no difference in distant metastasis was observed between the groups (23.1% vs 24.0%; p>0.99). Multivariate analyses adjusting for stage, histologic type, grade, platinum-free interval, and secondary debulking surgery revealed that the use of bevacizumab significantly reduced risks of nodal (adjusted HR (aHR) 0.24; 95% CI 0.10 to 0.56; p=0.001), pelvic (aHR 0.32; 95% CI 0.15 to 0.68; p=0.003), and abdominal recurrences (aHR 0.43; 95% CI 0.26 to 0.71; p=0.001). Nevertheless, use of bevacizumab did not influence risk of distant metastasis (aHR 0.70; 95% CI 0.35 to 1.40; p=0.32).ConclusionsIn patients with platinum-sensitive, recurrent epithelial ovarian cancer, second-line chemotherapy with bevacizumab is associated with reduced risks of nodal, pelvic, and abdominal recurrences, but similar risks of distant metastases.

Introduction50–70% of epithelial ovarian cancers overexpress epidermal growth factor receptor, and its expression has been correlated with poor prognosis. We conducted a phase Ib/II trial to examine the efficacy, safety, and toxicity of gefitinib, a tyrosine kinase inhibitor, combined with topotecan in women with recurrent ovarian cancer with epidermal growth factor receptor positivity.MethodsPatients with measurable recurrent or persistent cancer after treatment with a platinum containing regimen with positive epidermal growth factor receptor expression, as determined by immunohistochemistry, were eligible for the study. Initial treatment was 250 mg/day gefitinib (oral) and 2.0 mg/m2 topotecan (intravenous) on days 1, 8, and 15, on a 28 day cycle. Dose escalations were planned for topotecan (dose levels 1–3: 2, 3, and 4 mg/m2) until the maximum tolerated dose was reached.Results19 patients received a total of 61 cycles. Median age was 59.8 years (range 42–76 years). Histologic types in treated patients included 74% serous (n=14), 11% mixed (n=2), 11% transitional (n=2), and 5% clear cell (n=1). For phase Ib, three patients were treated at dose level 1, three at dose level 2, and three at dose level 3 for topotecan. The maximum tolerated dose was 4.0 mg/m2 (days 1, 8, and 15) for topotecan and 250 mg (daily) for gefitinib. Therefore, dose level 3 was used for phase II. Among the 19 patients, 63.2% (n=12) had progressive disease, 15.8% (n=3) had stable disease, 10.5% (n=2) had a partial response, and 10.5% (n=2) were not evaluable. The most serious adverse events of any grade attributed to the therapy were anemia (89.4%), neutropenia (68.4%), abdominal pain (84%), constipation (78.9%), and diarrhea (78.9%).ConclusionAlthough the drug combination was relatively well tolerated, this prospective phase Ib/II clinical trial did not show sufficient clinical activity of topotecan combined with gefitinib in patients with epidermal growth factor receptor positive recurrent ovarian, fallopian tube, or peritoneal cancers.

Nearly all patients with extensive-stage small-cell lung cancer (ES-SCLC) relapse following first-line etoposide plus platinum (EP) with or without immune checkpoint inhibition. Topotecan and amrubicin are chemotherapies approved for these patients. The toxicities of these chemotherapies are significant and survival when treated with these regimens is minimal. The programmed death-1 (PD-1) inhibitors nivolumab and pembrolizumab are unlikely to be effective for patients who develop progressive disease on first-line chemoimmunotherapy. Newer systemic therapies (e.g., lurbinectedin and temozolomide plus poly-ADP ribose polymerase inhibition) have demonstrated greater response rates than topotecan, amrubicin or PD-1 inhibitors. The data on these newer systemic therapies and other agents that may soon enter clinic are reviewed in this manuscript. Additionally, some of the key questions arising following clinical trials of these newer agents are highlighted.

Background There are few treatment options for patients with leptomeningeal metastases (LM). Methods We report a case series of patients with breast cancer and LM treated with intra‐CSF topotecan (TOPO). Outcome was assessed by clinical exam and MRI at baseline, at end of induction (4‐5 weeks), then every 3 months; CSF cytology was determined at baseline and with each treatment. Results Thirty‐one women [median age, 58 (37‐81); median KPS 60 (40‐100)] received treatment. At baseline, 68% had positive CSF cytology, and 90%, leptomeningeal enhancement on MRI. 84% of patients also received focal RT (not during TOPO) and 77% received concomitant systemic hormonal or chemotherapy. Median number of TOPO treatments was 14.5 (range, 3‐71); median duration of treatment, 11 weeks (1‐176); and median OS, 6.9 months (range, 0.9‐48.8). Patients remaining progression‐free during 4‐6 weeks of induction (81%) had a median OS of 11.5 months (range, 1.8‐48.8). Overall neurologic PFS at 6, 12, and 24 months was 39%, 26%, and 6%, respectively. Clearing of CSF malignant cells for >3 consecutive samples occurred in 10/21 (48%) patients with positive CSF cytology at baseline, remaining clear for a median duration of 15.9 months (range, 1.4‐34.5). Grade 3 adverse events included headache or vomiting (3pts), T2 hyperintensity surrounding the ventricular catheter (2 pts), and meningitis (2 pts). Conclusions Intra‐CSF TOPO, with focal RT as needed for symptomatic areas of enhancement produced durable clearing of CSF malignant cells in 48% of patients positive at baseline, with promising median PFS and OS., In this case series, intra‐CSF topotecan treatment of women with leptomeningeal metastases and breast cancer was associated with durable CSF clearing of malignant cells in 48% of patients, median OS of 6.9 months, and 11.5 months in those completing 4‐6 weeks induction. Thirty‐two percentage of patients remained free of neurologic progression at 12 months. A method for treatment of patients with VP shunts and programmable valves is also described.

OBJECTIVEIntracerebral convection-enhanced delivery (CED) has been limited to short durations due to a reliance on externalized catheters. Preclinical studies investigating topotecan (TPT) CED for glioma have suggested that prolonged infusion improves survival. Internalized pump-catheter systems may facilitate chronic infusion. The authors describe the safety and utility of long-term TPT CED in a porcine model and correlation of drug distribution through coinfusion of gadolinium.METHODSFully internalized CED pump-catheter systems were implanted in 12 pigs. Infusion algorithms featuring variable infusion schedules, flow rates, and concentrations of a mixture of TPT and gadolinium were characterized over increasing intervals from 4 to 32 days. Therapy distribution was measured using gadolinium signal on MRI as a surrogate. A 9-point neurobehavioral scale (NBS) was used to identify side effects.RESULTSAll animals tolerated infusion without serious adverse events. The average NBS score was 8.99. The average maximum volume of distribution (Vdmax) in chronically infused animals was 11.30 mL and represented 32.73% of the ipsilateral cerebral hemispheric volume. Vdmax was achieved early during infusions and remained relatively stable despite a slight decline as the infusion reached steady state. Novel tissue TPT concentrations measured by liquid chromatography mass spectroscopy correlated with gadolinium signal intensity on MRI (p = 0.0078).CONCLUSIONSProlonged TPT-gadolinium CED via an internalized system is safe and well tolerated and can achieve a large Vdmax, as well as maintain a stable Vd for up to 32 days. Gadolinium provides an identifiable surrogate for measuring drug distribution. Extended CED is potentially a broadly applicable and safe therapeutic option in select patients.

Summary Background Topotecan is currently the only drug approved in Europe in a second-line setting for the treatment of small-cell lung cancer. This study investigated whether the doublet of carboplatin plus etoposide was superior to topotecan as a second-line treatment in patients with sensitive relapsed small-cell lung cancer. Methods In this open-label, randomised, phase 3 trial done in 38 hospitals in France, we enrolled patients with histologically or cytologically confirmed advanced stage IV or locally relapsed small-cell lung cancer, who responded to first-line platinum plus etoposide treatment, but who had disease relapse or progression at least 90 days after completion of first-line treatment. Eligible patients were aged 18 years or older and had an Eastern Cooperative Oncology Group performance status 0–2. Enrolled patients were randomly assigned (1:1) to receive combination carboplatin plus etoposide (six cycles of intravenous carboplatin [area under the curve 5 mg/mL per min] on day 1 plus intravenous etoposide [100 mg/m2 from day 1 to day 3]) or oral topotecan (2·3 mg/m2 from day 1 to day 5, for six cycles). Randomisation was done using the minimisation method with biased-coin balancing for ECOG performance status, response to the first-line chemotherapy, and treatment centre. The primary endpoint was progression-free survival, which was centrally reviewed and analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov , NCT02738346 . Findings Between July 18, 2013, and July 2, 2018, we enrolled and randomly assigned 164 patients (82 in each study group). One patient from each group withdrew consent, therefore 162 patients (81 in each group) were included in the intention-to-treat population. With a median follow-up of 22·7 months (IQR 20·0−37·3), median progression-free survival was significantly longer in the combination chemotherapy group than in the topotecan group (4·7 months, 90% CI 3·9–5·5 vs 2·7 months, 2·3–3·2; stratified hazard ratio 0·57, 90% CI 0·41–0·73; p=0·0041). The most frequent grade 3–4 adverse events were neutropenia (18 [22%] of 81 patients in the topotecan group vs 11 [14%] of 81 patients in the combination chemotherapy group), thrombocytopenia (29 [36%] vs 25 [31%]), anaemia (17 [21%] vs 20 [25%]), febrile neutropenia (nine [11%] vs five [6%]), and asthenia (eight [10%] vs seven [9%]). Two treatment-related deaths occurred in the topotecan group (both were febrile neutropenia with sepsis) and no treatment-related deaths occurred in the combination group. Interpretation Our results suggest that carboplatin plus etoposide rechallenge can be considered as a reasonable second-line chemotherapy option for patients with sensitive relapsed small-cell lung cancer. Funding Amgen and the French Lung Cancer Group (Groupe Francais de Pneumo-Cancerologie).

Ex vivo evaluation of personalized models can facilitate individualized treatment selection for patients, and advance the discovery of novel therapeutic options. However, for embryonal malignancies, representative primary cultures have been difficult to establish. We developed patient‐derived cell cultures (PDCs) from chemo‐naïve and post–treatment neuroblastoma tumors in a consistent and efficient manner, and characterized their in vitro growth dynamics, histomorphology, gene expression, and functional chemo‐response. From 34 neuroblastoma tumors, 22 engrafted in vitro to generate 31 individual PDC lines, with higher engraftment seen with metastatic tumors. PDCs displayed characteristic immunohistochemical staining patterns of PHOX2B, TH, and GD2 synthase. Concordance of MYCN amplification, 1p and 11q deletion between PDCs and patient tumors was 83.3%, 72.7%, and 80.0% respectively. PDCs displayed a predominantly mesenchymal‐type gene expression signature and showed upregulation of pro‐angiogenic factors that were similarly enriched in culture medium and paired patient serum samples. When tested with standard‐of‐care cytotoxics at human C max‐equivalent concentrations, MYCN‐amplified and non‐MYCN‐amplified PDCs showed a differential response to cyclophosphamide and topotecan, which mirrored the corresponding patients’ responses, and correlated with gene signatures of chemosensitivity. In this translational proof‐of‐concept study, early‐phase neuroblastoma PDCs enriched for the mesenchymal cell subpopulation recapitulated the individual molecular and phenotypic profile of patient tumors, and highlighted their potential as a platform for individualized ex vivo drug‐response testing., We developed a system to efficiently and consistently generate patient‐derived cultures (PDCs) of neuroblastoma that recapitulated individual patient’s cytogenetic and immunohistochemical features, and phenotypic responses to standard‐of‐care chemotherapy. PDCs predominantly express the gene signature of the recently described neuroblastoma mesenchymal super‐enhancer state. This proof‐of concept provides translational evidence supporting the proposed role of the mesenchymal cell subpopulation in determining clinical treatment response and offers a novel platform for developing personalized ex vivo therapeutic decision‐making strategies for neuroblastoma.

Natural products form a significant portion of medicinal agents that are currently used for the management of cancer. All these natural products have unique structures along with diverse action mechanisms with the capacity to interact with different therapeutic targets of several complex disorders. Although plants contribute as a major source of natural products with anti-cancer potential, the marine environment and microbes have also bestowed some substantial chemotherapeutic agents. A few examples of anti-cancer agents of natural origin include vincristine, vinblastine, paclitaxel, camptothecin and topotecan obtained from plants, bryostatins, sarcodictyin and cytarabine from marine organisms and bleomycin and doxorubicin from micro-organisms (dactinomycin, bleomycin and doxorubicin). The incredible diversity in the chemical structures and biological properties of compounds obtained from million species of plants, marine organisms and microorganisms present in nature has commenced a new era of potential therapeutic anti-cancer agents.

BACKGROUND AND PURPOSE: Intra-arterial chemotherapy for retinoblastoma has dramatically altered the natural history of the disease. The remarkable outcomes associated with a high safety profile have pushed the envelope to offer treatment for patients weighing ≤10 kg. The purpose was to determine the efficacy and safety of IAC infusions performed in infants weighing ≤10 kg with intraocular retinoblastoma. MATERIALS AND METHODS: A retrospective chart review was performed for patients diagnosed with retinoblastoma and managed with intra-arterial chemotherapy. RESULTS: The total study cohort included 207 retinoblastoma tumors of 207 eyes in 196 consecutive patients who underwent 658 intra-arterial chemotherapy infusions overall. Of these, patient weights were [Formula: see text] 10 kg in 69 (35.2%) and >10 kg in 127 (64.8%) patients. Comparison (≤10 kg versus >10 kg) revealed that the total number of intra-arterial chemotherapy infusions was 222 versus 436. Periprocedural complications were not significantly different (2 [0.9%] versus 2 [0.5%]; P = .49). Cumulative radiation exposure per eye was significantly lower in infants weighing ≤10 kg (5.0 Gym(2) versus 7.7 Gym(2); P = .01). Patients weighing [Formula: see text] 10 kg had a greater frequency of complete tumor regression (82.6% versus 60.9%; P = .02). Mean fluoroscopy time was not significantly different (7.5 versus 7.2; P = .71). There was a significant difference in the frequency of enucleation (16 [21.6%] versus 52 [39.1%]; P = .01). Patients weighing [Formula: see text] 10 kg had greater number of aborted procedures (12 [5.4%] versus 7 [1.6%]; P = .01). On multivariate analysis, weight ≤10 kg was not an independent predictor of complications or procedure failure. CONCLUSIONS: Intra-arterial chemotherapy in patients weighing ≤10 kg is a safe and effective treatment.

The emergence of resistance to chemotherapy drugs in patients with ovarian cancer is still the main cause of low survival rates. The present study aimed to identify key genes that may provide treatment guidance to reduce the incidence of drug resistance in patients with ovarian cancer. Original data of chemotherapy sensitivity and chemoresistance of ovarian cancer were obtained from the Gene Expression Omnibus dataset GSE73935. Differentially expressed genes (DEGs) between sensitive and resistant ovarian cancer cell lines were screened by Empirical Bayes methods. Overlapping DEGs between four chemoresistant groups were identified by Venn map analysis. Protein-protein interaction networks were also constructed, and hub genes were identified. The hub genes were verified by in vitro experiments as well as The Cancer Genome Atlas data. Results from the present study identified eight important genes that may guide treatment decisions regarding chemotherapy regimens for ovarian cancer, including epidermal growth factor-like repeats and discoidin I-like domains 3, NRAS proto-oncogene, hyaluronan and proteoglycan link protein 1, activated protein C receptor, CD53, cyclin-dependent kinase inhibitor 2A, insulin-like growth factor 1 receptor and roundabout guidance receptor 2 genes. Their expressions were found to have an impact on the prognosis of different treatment groups (cisplatin, paclitaxel, cisplatin + paclitaxel, cisplatin + doxorubicin and cisplatin + topotecan). The results indicated that these genes may minimise the occurrence of ovarian cancer drug resistance and may provide effective treatment options for patients with ovarian cancer.

Breast cancer resistance protein (BCRP) is expressed on the apical membrane of small intestinal epithelial cells and functions as an efflux pump with broad substrate recognition. Therefore, quantitative evaluation of the contribution of BCRP to the intestinal permeability of new chemical entities is very important in drug research and development. In this study, we assessed the BCRP-mediated efflux of several model drugs in Caco-2 cells using WK-X-34 as a dual inhibitor of P-glycoprotein (P-gp) and BCRP and LY335979 as a selective inhibitor of P-gp. The permeability of daidzein was high with an apparent permeability coefficient for apical-to-basal transport (PAB) of 20.3 × 10−6 cm/s. In addition, its efflux ratio (ER) was 1.55, indicating that the contribution of BCRP to its transport is minimal. Estrone-3-sulfate and ciprofloxacin showed relatively higher ER values (>2.0), whereas their BCRP-related absorptive quotient (AQBCRP) was 0.21 and 0.3, respectively. These results indicate that BCRP does not play a major role in regulating the permeability of estrone-3-sulfate and ciprofloxacin in Caco-2 cells. Nitrofurantoin showed a PAB of 1.8 × 10−6 cm/s, and its ER was 7.6. However, the AQBCRP was 0.37, suggesting minimal contribution of BCRP to nitrofurantoin transport in Caco-2 cells. In contrast, topotecan, SN-38, and sulfasalazine had low PAB values (0.81, 1.13, and 0.19 × 10−6 cm/s, respectively), and each AQBCRP was above 0.6, indicating that BCRP significantly contributes to the transport of these compounds in Caco-2 cells. In conclusion, Caco-2 cells are useful to accurately estimate the contribution of BCRP to intestinal drug absorption. SIGNIFICANCE STATEMENT We performed an in vitro assessment of the contribution of breast cancer resistance protein (BCRP) to the transport of BCRP and/or P-glycoprotein (P-gp) substrates across Caco-2 cell monolayers using absorptive quotient, which has been proposed to represent the contribution of drug efflux transporters to the net efflux. The present study demonstrates that the combined use of a BCRP/P-gp dual inhibitor and a P-gp selective inhibitor is useful to estimate the impact of BCRP and P-gp on the permeability of tested compounds in Caco-2 cells.

Purpose: Platinum resistance in ovarian cancer is associated with epigenetic modifications. Hypomethylating agents (HMA) have been studied as carboplatin resensitizing agents in ovarian cancer. This randomized phase II trial compared guadecitabine, a second-generation HMA, and carboplatin (G+C) against second-line chemotherapy in women with measurable or detectable platinum-resistant ovarian cancer. Patients and Methods: Patients received either G+C (guadecitabine 30 mg/m2 s.c. once-daily for 5 days and carboplatin) or treatment of choice (TC; topotecan, pegylated liposomal doxorubicin, paclitaxel, or gemcitabine) in 28-day cycles until progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS); secondary endpoints were RECIST v1.1 and CA-125 response rate, 6-month PFS, and overall survival (OS). Results: Of 100 patients treated, 51 received G+C and 49 received TC, of which 27 crossed over to G+C. The study did not meet its primary endpoint as the median PFS was not statistically different between arms (16.3 weeks vs. 9.1 weeks in the G+C and TC groups, respectively; P = 0.07). However, the 6-month PFS rate was significantly higher in the G+C group (37% vs. 11% in TC group; P = 0.003). The incidence of grade 3 or higher toxicity was similar in G+C and TC groups (51% and 49%, respectively), with neutropenia and leukopenia being more frequent in the G+C group. Conclusions: Although this trial did not show superiority for PFS of G+C versus TC, the 6-month PFS increased in G+C treated patients. Further refinement of this strategy should focus on identification of predictive markers for patient selection.

Lung cancer is a leading cause of cancer death in the United States and around the world. Approximately 13% of lung cancers are small cell lung cancer (SCLC). SCLC is generally classified as a limited-stage and extensive-stage disease depending on the extent of involvement. For patients with the extensive-stage disease, until recently, chemotherapy alone has been the recommended treatment, although radiotherapy could be used in select patients for palliation of symptoms. The standard of care for extensive-stage SCLC is platinum doublet chemotherapy with either cisplatin or carboplatin in combination with etoposide. Even though first-line therapy has an initial response rate of 60–80%, the prognosis is poor, with overall survival of 10–12 months. The only FDA-approved second line of therapy is topotecan, approved both as an intravenous formulation as well as an oral formulation, with response rates of 6–12% in chemorefractory disease and 15–37% in chemosensitive disease. Immunotherapy has recently been approved as a first-line agent in metastatic SCLC in combination with chemotherapy. It is also approved as a third-line agent in metastatic SCLC after the failure of two chemotherapy regimens. The FDA approved four drugs, two of them being PD-1 inhibitors (pembrolizumab, nivolumab), and two of them being PD-L1 inhibitors (atezolizumab and durvalumab) in SCLC. This review article summarizes the significance of immunotherapy in the treatment of extensive-stage SCLC, its side effects, and limitations.

Mitochondrion, the powerhouse of the cells, controls bioenergetics, biosynthesis, metabolism, and signaling. Consequently, it has become an unorthodox target for cancer therapeutics. However, specific targeting of mitochondria into subcellular milieu in cancer cells remains a major challenge. To address this, we have engineered polyethylenimine cloaked positively charged self-assembled graphene oxide nanoparticle (PEI-GTC-NP) comprising topotecan and cisplatin concurrently. These PEI-GTC-NPs effectively homed into mitochondria in HeLa cervical cancer cells at 6 h and impaired mitochondria leading to reactive oxygen species generation followed by remarkably improved cancer cell death. This platform can be used for specific subcellular organelle targeting for future cancer therapy.

The pentose phosphate pathway (PPP) of glucose metabolism in the brain serves as a primary source of NADPH which in turn plays a crucial role in multiple cellular processes, including maintenance of redox homeostasis and antioxidant defense. In our model of protective mild hypobaric hypoxia in rats (3MHH), an inverse correlation between hypoxia-inducible factor-1 (HIF1) activity and mRNA levels of glucose-6-phosphate dehydrogenase (G6PD), the key enzyme of PPP, was observed. In the present study, it was demonstrated that severe hypobaric hypoxia (SH) induced short-term upregulation of HIF1 alpha-subunit (HIF1α) in the hippocampal CA1 subfield and decreased the activity of G6PD. The levels of NADPH were also reduced, promoting oxidative stress, triggering apoptosis, and neuronal loss. Injection of a HIF1 inhibitor (HIF1i), topotecan hydrochloride (5 mg/kg, i.p.), before SH prevented the upregulation of HIF1α and normalized G6PD activity. In addition, HIF1i injection caused an increase in NADPH levels, normalization of total glutathione levels and of the cellular redox status as well as suppression of free-radical and apoptotic processes. These results demonstrate a new molecular mechanism of post-hypoxic cerebral pathology development which involves HIF1-dependent PPP depletion and support a recently suggested injurious role of HIF1 activation in the acute phase of cerebral hypoxia/ischemia. Application of PPP stimulators in early post-hypoxic/ischemic period might represent a promising neuroprotective strategy. Graphical abstract HIF1-dependent down-regulation of the pentose phosphate pathway contributes to the hypoxia-induced oxidative stress and neuronal apoptosis in the rat hippocampus.

Recurrent high-risk neuroblastoma is a childhood cancer that often fails to respond to therapy. Fenretinide (4-HPR) is a cytotoxic retinoid with clinical activity in recurrent neuroblastoma and venetoclax (ABT-199) is a selective inhibitor of the antiapoptotic protein B-cell lymphoma-2 (BCL-2). We evaluated activity of 4-HPR + ABT-199 in preclinical models of neuroblastoma. Patient-derived cell lines and xenografts from progressive neuroblastoma were tested. Cytotoxicity was evaluated by DIMSCAN, apoptosis by flow cytometry, and gene expression by RNA sequencing, quantitative RT-PCR, and immunoblotting. 4-HPR + ABT-199 was highly synergistic against high BCL-2–expressing neuroblastoma cell lines and significantly improved event-free survival of mice carrying high BCL-2–expressing patient-derived xenografts (PDX). In 10 matched-pair cell lines [established at diagnosis (DX) and progressive disease (PD) from the same patients], BCL-2 expression in the DX and PD lines was comparable, suggesting that BCL-2 expression at diagnosis may provide a biomarker for neuroblastomas likely to respond to 4-HPR + ABT-199. In a pair of DX (COG-N-603x) and PD (COG-N-623x) PDXs established from the same patient, COG-N-623x was less responsive to cyclophosphamide + topotecan than COG-N-603x, but both DX and PD PDXs were responsive to 4-HPR + ABT-199. Synergy of 4-HPR + ABT-199 was mediated by induction of NOXA via 4-HPR stimulation of reactive oxygen species that induced expression of ATF4 and ATF3, transcription factors for NOXA. Thus, fenretinide + venetoclax is a synergistic combination that warrants clinical testing in high BCL-2–expressing neuroblastoma.

Purpose To determine whether treatment order affects ophthalmic vascular event rates after intra-arterial chemotherapy (IAC) for retinoblastoma. Methods Patients who received IAC as primary or secondary treatment for retinoblastoma from January 2009 to January 2018 were included. All eyes were imaged with fundus photography and fluorescein angiography. Patient characteristics and vascular event rates were compared using t-test and Fisher's exact test. Results There were 196 patients treated with 682 infusions of IAC, divided into primary (no previous therapy, 98 eyes of 98 patients, 328 infusions) and secondary (after other therapy, 105 eyes of 98 patients, 354 infusions) treatment. Overall, ophthalmic vascular events were found after 5% of infusions (17% eyes). A comparison of ophthalmic vascular events (primary vs. secondary IAC), with mean three infusions per eye (median 3, range 1-7), revealed no difference in overall percentage of eyes affected (18% vs. 15%, P = 0.57). Adverse vascular events per eye included retinal vasculature attenuation (1% vs. 0%, P = 0.99), peripheral retinal pruning (1% vs. 0%, P = 0.99), branch retinal artery occlusion (0% vs. 1%, P = 0.99), central retinal artery occlusion (0% vs. 1%, P = 0.99), macular ischemia (0% vs. 2%, P = 0.51), vitreous hemorrhage (2% vs. 3%, P = 0.92), subretinal hemorrhage (1% vs. 0%, P = 0.99), retinal pigment epithelium atrophy (6% vs. 3% P = 0.43), choroidal atrophy (4% vs. 2%, P = 0.92), optic disk pallor (1% vs. 0%, P = 0.99), and ophthalmic artery occlusion (9% vs. 6%, P = 0.35). Conclusion Ophthalmic vascular events after IAC for retinoblastoma affect only 5% of eyes per infusion (17% of treated eyes). Vascular event risk per eye is similar when using IAC as primary or secondary treatment.

A key limitation to glioma treatment involves the blood brain barrier (BBB). Convection enhanced delivery (CED) is a technique that uses a catheter placed directly into the brain parenchyma to infuse treatments using a pressure gradient. In this manuscript, we describe the physical principles behind CED along with the common pitfalls and methods for optimizing convection. Finally, we highlight our institutional experience using topotecan CED for the treatment of malignant glioma.

PURPOSE The primary aim of this phase III randomized trial was to test whether the addition of vincristine, topotecan, and cyclophosphamide (VTC) to interval compressed chemotherapy improved survival outcomes for patients with previously untreated nonmetastatic Ewing sarcoma. METHODS Patients were randomly assigned to receive standard five-drug interval compressed chemotherapy (regimen A) for 17 cycles or experimental therapy with five cycles of VTC within the 17 cycles (regimen B). Patients were stratified by age at diagnosis (< 18 years and ≥18 years) and tumor site (pelvic bone, nonpelvic bone, and extraosseous). Tumor volume at diagnosis was categorized as < 200 mL or ≥ 200 mL. Local control occurred following six cycles. Histologic response was categorized as no viable or any viable tumor. Event-free survival (EFS) and overall survival (OS) were compared between randomized groups with stratified log-rank tests. RESULTS Of 642 enrolled patients, 309 eligible patients received standard and 320 received experimental therapy. The 5-year EFS and OS were 78% and 87%, respectively. There was no difference in survival outcomes between randomized groups (5-year EFS regimen A v regimen B, 78% v 79%; P = .192; 5-year OS 86% v 88%; P = .159). Age and primary site did not affect the risk of an EFS event. However, age ≥ 18 years was associated with an increased risk of death at 5 years (hazard ratio 1.84; 95% CI, 1.15 to 2.96; P = .009). The 5-year EFS rates for patients with pelvic, nonpelvic bone, and extraosseous primary tumors were 75%, 78%, and 85%, respectively. Tumor volume ≥ 200 mL was significantly associated with lower EFS. CONCLUSION While VTC added to five-drug interval compressed chemotherapy did not improve survival, these outcomes represent the best survival estimates to date for patients with previously untreated nonmetastatic Ewing sarcoma.

Targeting myeloid cells, especially microglia, for the treatment of neuroinflammatory diseases such as multiple sclerosis (MS), is underappreciated. Here, we screened a library of compounds and identified the topoisomerase 1 (TOP1) inhibitor camptothecin (CPT) as a promising drug candidate for microglial modulation. CPT and its FDA-approved analog topotecan (TPT) inhibited inflammatory responses in microglia and macrophages, and ameliorated neuroinflammation in mice. Transcriptomic analysis of sorted microglia revealed an altered transcriptional phenotype following TPT treatment, with Ikzf1 identified as a potential target. Importantly, TOP1 expression was found elevated in several neuroinflammatory conditions, including human MS brains. To achieve targeted delivery to myeloid cells we designed a nanosystem using DNA origami and loaded TPT into it (TopoGami). TopoGami also significantly suppressed the inflammatory response in microglia and mitigated disease progression in MS-like mice. Our findings suggest that TOP1 inhibition represents a therapeutic strategy for neuroinflammatory diseases, and the proposed nanosystem may foster future research and drug development with a demand to target myeloid cells.

Introduction/Background* bevacizumab is an anti-VEGF monoclonal antibody that has shown efficacy in platinum-resistant recurrent epithelial ovarian cancer (EOC) in clinical trials. Our aim was to evaluate real-world effectiveness of bevacizumab in northern Portugal in this setting. Methodology retrospective observational series of cases in a single comprehensive cancer center between 2015 and 2020. We reviewed consecutive medical records of platinum-resistant recurrent EOC patients, who underwent bevacizumab with chemotherapy (CT). Primary endpoint was overall survival (OS). Secondary endpoints were overall response rate (ORR), progression free survival (PFS) and safety according to CTCAE v4.0. Descriptive analysis of main demographic, clinical and treatment variables were performed. Kaplan-Meier method was used for OS and PFS. Result(s)* 21 EOC patients with median age of 61 years (47-72 years). Majority were FIGO stage III (10, 47.6%) or IV (8, 38.1%) and had high-serous morphology (11, 52.5%). Most patients had been previously submitted to up-front (42,9%) or interval (42,9%) debulking surgery. All underwent platinum-based CT as 1st line of treatment (LOT). At baseline, more than half of the patients (57.4%) had previously undergone 2 or more LOT. Median number of cycles of bevacizumab was 9 (2-62), concomitant with pegylated liposomal doxorubicin in 10 (47.6%), paclitaxel in 8 (38,1%) and topotecan in 3 (14.3%) patients. Median follow-up time was 19.3 months (4.9-40.8 months). ORR was 42.9%: 2 (9,5%) complete response and 7 (33.3%) partial response. Nine patients (42.9%) had stable disease. Median OS was 25.8 months [IC95% 11.3-40.3] and PFS 10.8 months [IC95% 7.0-14.7]. Grade ≥3 hypertension incidence was 14.3% and grade ≥3 proteinuria 4.8%. There was one death due to gastrointestinal fistula (4.8%). Conclusion* bevacizumab had the predictable safety profile, with better effectiveness than the published in clinical trials, reflecting the small number of patients included in our real-world unicentric series. Nevertheless, new molecular biomarkers and clinical trials urge to improve outcomes in platinum-resistant recurrent ovarian cancer patients in clinical practice.

Introduction/Background* Cervical cancer is the fourth most common cancers among women worldwide. Primary therapy of cervical cancer depends on the disease extent and is based on radical hysterectomy or chemoradiation. However, therapeutical approaches in metastatic and recurrent disease of cervical cancer are limited. Particular effort in drug development focuses on essential serine/threonine kinases like the death-associated protein kinase 1 (DAPK1) and Polo-like kinase 1 (PLK1) as potential therapeutic targets in cervical cancer. Methodology and Result(s)* Our study examined the role of DAPK1 during the cell cycle of cervical cancer cells. We found that DAPK1 is autophosphorylated in mitosis, exhibiting only low activity towards exogenous substrates. Furthermore, DAPK1 localizes together with PLK1 at centrosomes, which can phosphorylate DAPK1. Finally, we could show that Topotecan, which is used in different clinical trials to treat cervical cancer, induces cell death, which partially depends on DAPK1. Conclusion* Topotecan is an effective drug for the treatment of cervical cancer. We explored the role of DAPK1 in Topotecan-induced cervical cancer cell death and revealed that the RNAi-based silencing of DAPK1 downregulates the apoptotic activity suggesting that DAPK1 could be a biomarker for the response to Topotecan in clinical trials.

The α7-human papillomavirus (HPV)-related cervical squamous cell carcinoma (SCC) is associated with poor prognosis. We compared the genomic profiles of this disease in a cohort corresponding to the 2001–2014 period with various responses to radiotherapy or concurrent chemoradiation through microRNA (miR) profiling involving miR 4.0 array and human transcriptome array 2.0 analyses. A real-time quantitative polymerase chain reaction was then conducted to identify the predictive biomarkers. A significantly lower expression of miR143-3p in recurrent tumors (p = 0.0309) relative to that in nonrecurrent tumors was observed. The miR143-3p targeted the mRNA expression of the baculoviral inhibitor of the apoptosis protein (IAP) repeat-containing 2 (BIRC2, p = 0.0261). The BIRC2 protein levels (p = 0.0023) were significantly higher in recurrent tumors than in nonrecurrent tumors. Moreover, the miR-143-3p sensitized the response of α7-HPV-related cervical SCC to chemotherapy by targeting BIRC2. A combination of BIRC2-inhibitor LCL161 and topotecan exerted synergistic effects on cancer cells and animal tumor models. In a pooled cohort of α7-HPV-related cervical SCC (including mixed infections with non-α7-HPV) treated between 1993 and 2014, high BIRC2 expression was associated with significantly worse outcomes (cancer-specific survival, hazard ratio (HR) = 1.42, p = 0.008, progression-free survival, HR = 1.64, p = 0.005). Summarily, BIRC2 constitutes a novel prognostic factor and therapeutic target for α7-HPV-related cervical SCC.

Objective: The apoptotic and cytotoxic effects of arsenic trioxide (ATO) makes it a potentially suitable agent for the treatment of patients with neuroblastoma with poor prognosis; therefore, we try to evaluate the effectiveness and safety of ATO combined with reinduction/induction chemotherapy in children with recurrent/refractory or newly diagnosed stage 4 neuroblastoma. Methods: Retrospective analysis was performed on seven pediatric patients with recurrent /refractory or newly diagnosed stage 4 neuroblastoma treated with traditional reinduction/induction chemotherapy combined with ATO. Results: A total of 7 patients were treated synchronously with ATO and chemotherapy for up to nine courses; all patients received conventional chemotherapy plus a 0.16 mg/kg/day dose of intravenous ATO during reinduction/induction chemotherapy. Treatment was effective in five patients and ineffective in the other two patients. The overall response rate was 71.43% (5 of 7). The side effects of the ATO combination were minor, whereby only treatment in one patient was terminated at the sixth course due to a prolonged QT interval (0.51 s), which returned to normal after symptomatic treatment. Conclusions: ATO can be safely and effectively combined with chemotherapy drugs as a potential alternative means of treatment for high-risk stage 4 neuroblastoma, and we have observed that ATO can restore the sensitivity of chemotherapy in some patients who were resistant to previous chemotherapy. Further investigations and clinical data are required to confirm these observations.

PURPOSE Induction therapy is a critical component of the therapy of high-risk neuroblastoma. We aimed to assess if the Memorial Sloan Kettering Cancer Center (MSKCC) N5 induction regimen (MSKCC-N5) would improve metastatic complete response (mCR) rate and 3-year event-free survival (EFS) compared with rapid COJEC (rCOJEC; cisplatin [C], vincristine [O], carboplatin [J], etoposide [E], and cyclophosphamide [C]). PATIENTS AND METHODS Patients (age 1-20 years) with stage 4 neuroblastoma or stage 4/4s aged < 1 year with MYCN amplification were eligible for random assignment to rCOJEC or MSKCC-N5. Random assignment was stratified according to national group and metastatic sites. Following induction, therapy comprised primary tumor resection, high-dose busulfan and melphalan, radiotherapy to the primary tumor site, and isotretinoin with ch14.18/CHO (dinutuximab beta) antibody with or without interleukin-2 immunotherapy. The primary end points were mCR rate and 3-year EFS. RESULTS A total of six hundred thirty patients were randomly assigned to receive rCOJEC (n = 313) or MSKCC-N5 (n = 317). Median age at diagnosis was 3.2 years (range, 1 month to 20 years), and 16 were younger than 1 year of age with MYCN amplification. mCR rate following rCOJEC induction (32%, 86/272 evaluable patients) was not significantly different from 35% (99/281) with MSKCC-N5 ( P = .368), and 3-year EFS was 44% ± 3% for rCOJEC compared with 47% ± 3% for MSKCC-N5 ( P = .527). Three-year overall survival was 60% ± 3% for rCOJEC compared with 65% ± 3% for MSKCC-N5 ( P = .379). Toxic death rates with both regimens were 1%. However, nonhematologic CTC grade 3 and 4 toxicities were higher with MSKCC-N5: 68% (193/283) versus 48% (129/268) ( P < .001); infection 35% versus 25% ( P = .011); stomatitis 25% versus 3% ( P < .001); nausea and vomiting 17% versus 7% ( P < .001); and diarrhea 7% versus 3% ( P = .011). CONCLUSION No difference in outcome was observed between rCOJEC and MSKCC-N5; however, acute toxicity was less with rCOJEC, and therefore rCOJEC is the preferred induction regimen for International Society of Pediatric Oncology European Neuroblastoma Group.

Small cell lung cancer (SCLC) is exceptionally responsive to chemotherapy and radiotherapy. In relapsed patients, particularly in resistant/refractory cases, the progression of disease occurs rapidly with second-line agents. Topotecan (TOPO), a camptothecin analog, is the only agent able to increase overall survival (OS) compared with the best supportive care alone. However, the efficacy of platinum-based chemotherapy rechallenge or other agents has not been systematically explored. In the present review, published articles, which evaluated outcome and toxicity associated with TOPO or non-TOPO-based chemotherapy in patients with SCLC from inception to September 2020 were systematically searched and identified by searching the PubMed, EMBASE and Cochrane Library databases. The primary outcome of interest was the risk of death (OS), and the secondary endpoints were risk of progression progression-free survival (PFS), overall response rate (ORR) and G3-4 hematological toxicities. A total of nine studies were included in quantitative synthesis for a total of 1,689 patients. They included platinum-based rechallenge, anthracycline-based combinations or camptothecin analogs. TOPO did not improve OS with respect to other therapies [hazard ratio (HR), 0.92; 95% confidence interval (95% CI), 0.78-1.09; P=0.33]. Similarly, PFS was similar in the two arms (HR, 1.1; 95% CI, 0.72-1.67; P=0.66). The ORR was not statistically higher with non-TOPO agents (relative risk, 1.53; 95% CI, 0.95-2.48). In subgroup analysis, combination chemotherapy was associated with an improved PFS but not OS or ORR compared with TOPO alone (HR, 1.85; 95% CI, 1.52-2.24; P

Background and Purpose Intra-arterial chemotherapy (IAC) infusion for the treatment of intraocular retinoblastoma is an effective and relatively safe therapeutic option.1–3 However, one of the well described systemic complications following IAC is neutropenia.4 The purpose of this retrospective study is to examine the incidence of neutropenia over the course of treatment for each patient, and to further analyze if the incidence is affected by systemic chemotherapy or number of chemotherapeutic agents used for IAC. Methods We retrospectively identified 76 patients from a neurointerventional database spanning 10 years (March 2010 - August 2020) who underwent 214 cycles of IAC. Patient demographics, treatment course, angiographic technique as well as pre and post procedural complete blood counts were extracted from the medical record. Neutropenia, including all grades I-IV, is defined by an absolute neutrophil count (ANC) equal to or less than 1.5 x 10(9)/L. Eleven patients who did not obtain a post-procedural complete blood count during their treatment course were excluded. The presence of postprocedural neutropenia was further subdivided based on whether systemic intravenous chemotherapy was administered as well as according to the number of intra-arterial chemotherapeutic agents. Results The overall incidence of neutropenia was 62% in our total patient cohort. There was no statistically significant difference between the incidence of neutropenia in patients who did and did not receive systemic chemotherapy. The majority of patients received two chemotherapeutic agents (melphalan and topotecan), of which 58% and 54% of patients experienced neutropenia with and without systemic chemotherapy, respectively. The highest incidence of neutropenia was 100%, in five patients who received systemic chemotherapy and a three agent intra-arterial regimen (melphalan, topotecan, carboplatin). Conclusion Neutropenia is a systemic toxicity in more than half of patients who receive IAC infusion for intraocular retinoblastoma, and does not significantly differ in patients who do and do not receive systemic chemotherapy. References Ammanuel S, Alexander MD, Damato B, et al. Improved procedural safety following protocol changes for selective ophthalmic arterial infusion of chemotherapy for treatment of ocular retinoblastoma. Interv Neuroradiol. 2018;24(3):345–350. Yousef YA, Soliman SE, Astudillo PPP, et al. Intra-arterial Chemotherapy for Retinoblastoma: A Systematic Review. JAMA Ophthalmol. 2016;134(5):584–591. Monroy JE, Orbach DB, VanderVeen D. Complications of intra-arterial chemotherapy for retinoblastoma. Semin Ophthalmol. 2014;29(5–6):429–433. Dunkel IJ, Shi W, Salvaggio K, et al. Risk factors for severe neutropenia following intra-arterial chemotherapy for intra-ocular retinoblastoma. PLoS One. 2014;9(10):e108692. Disclosures A. Baker: None. S. Ammanuel: None. M. Caton: None. K. Narsinh: None. A. Ashfar: None. A. Banerjee: None. D. Cooke: None. C. Dowd: None. M. Amans: None. V. Halbach: None. R. Higashida: None. S. Hetts: None.

Background. Adult retinoblastoma (RB) is a rare intraocular tumor, leading to delayed diagnosis and, eventually, enucleation of the involved eyes. Therefore, this diagnosis should be considered if attributable signs and symptoms occurred. Here, the authors report a case of an adult group D RB, treated successfully with intra-arterial chemotherapy (IAC) as primary treatment followed by cryotherapy. The authors briefly review the literature on the prognosis and management of adult RB. Case Presentation. A 22-year-old man has noticed floaters in his right eye for 2 months. Right eye examination revealed diffuse white spherical calcified vitreous seeds in all quadrants and a large white endophytic mass in the superonasal quadrant with engorged feeding vessels. Based on clinical data, the group D RB tumor was classified and the IAC was started with 2 medications, melphalan (5 mg) and topotecan (1 mg), for 3 cycles. Trans-scleral triple freeze-thaw cryotherapy was used as an adjunctive treatment at the latest hospital visit. Thirteen months after the last treatment, the RB tumor showed type 4 regression (flat chorioretinal scar) and no evidence of recurrence was identified. Conclusion. It seems that IAC, as the first line of treatment, either alone or in conjunction with adjuvant therapies may allow us to salvage the globe of adult patients involved with RB.

Extensive stage small cell lung cancer carries extremely poor prognosis and adding immune checkpoint inhibitor to platinum etoposide combination in first line only improved outcomes modestly. Once disease recurs, treatment response is only transient in nature. Various strategies that are being explored include dual checkpoint blockade, BiTE and CAR-T cell approaches. Immune checkpoint inhibitors are being combined with PARP inhibitors. Other approaches currently being investigated include liposomal irinotecan and combining known active agents for SCLC in relapsed setting such as newly approved lurbinectedin with doxorubicin, paclitaxel, irinotecan or topotecan with ATR inhibitor (Berzosertib). Temozolomide has also been tested in combination with a Parp inhibitor. New antibody or small molecule drug conjugates are being actively investigated, so is a biomarker based approach. Better understanding of small cell lung cancer disease biology via high through-put genomic, proteomic and methylation profiling offer glimpse of hope in our efforts to contain this deadly disease. A table of representative molecular targets under investigation is provided in the end.