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Cancer Research Communications Jul 2023Prostate cancer is the second leading cause of noncutaneous cancer-related deaths in American men. Androgen deprivation therapy (ADT), radical prostatectomy, and...
UNLABELLED
Prostate cancer is the second leading cause of noncutaneous cancer-related deaths in American men. Androgen deprivation therapy (ADT), radical prostatectomy, and radiotherapy remain the primary treatment for patients with early-stage prostate cancer (castration-sensitive prostate cancer). Following ADT, many patients ultimately develop metastatic castration-resistant prostate cancer (mCRPC). Standard chemotherapy options for CRPC are docetaxel (DTX) and cabazitaxel, which increase median survival, although the development of resistance is common. Cancer stem-like cells possess mesenchymal phenotypes [epithelial-to-mesenchymal transition (EMT)] and play crucial roles in tumor initiation and progression of mCRPC. We have shown that low-dose continuous administration of topotecan (METRO-TOPO) inhibits prostate cancer growth by interfering with key cancer pathway genes. This study utilized bulk and single-cell or whole-transcriptome analysis [(RNA sequencing (RNA-seq) and single-cell RNA sequencing (scRNA-seq)], and we observed greater expression of several EMT markers, including , , , , , , and in European American and African American aggressive variant prostate cancer (AVPC) subtypes-mCRPC, neuroendocrine variant (NEPC), and taxane-resistant. The taxane-resistant gene was also expressed highly in single-cell subclonal populations in mCRPC. Furthermore, metronomic-topotecan single agent and combinations with DTX downregulated these EMT markers as well as CD44 and CD44/CD133 "stem-like" cell populations. A microfluidic chip-based cell invasion assay revealed that METRO-TOPO treatment as a single agent or in combination with DTX was potentially effective against invasive prostate cancer spread. Our RNA-seq and scRNA-seq analysis were supported by and studies, suggesting METRO-TOPO combined with DTX may inhibit oncogenic progression by reducing cancer stemness in AVPC through the inhibition of EMT markers and multiple oncogenic factors/pathways.
SIGNIFICANCE
The utilization of metronomic-like dosing regimens of topotecan alone and in combination with DTX resulted in the suppression of makers associated with EMT and stem-like cell populations in AVPC models. The identification of molecular signatures and their potential to serve as novel biomarkers for monitoring treatment efficacy and disease progression response to treatment efficacy and disease progression were achieved using bulk RNA-seq and single-cell-omics methodologies.
Topics: Male; Humans; Docetaxel; Topotecan; Prostatic Neoplasms, Castration-Resistant; Administration, Metronomic; Androgen Antagonists; Epithelial-Mesenchymal Transition; Taxoids; Disease Progression; Carrier Proteins; Microfilament Proteins
PubMed: 37476073
DOI: 10.1158/2767-9764.CRC-22-0427 -
The Oncologist 2004Topotecan dosing considerations and alternative dosing schedules to reduce and manage myelosuppression during the treatment of relapsed ovarian cancer were reviewed. The... (Review)
Review
Topotecan dosing considerations and alternative dosing schedules to reduce and manage myelosuppression during the treatment of relapsed ovarian cancer were reviewed. The myelosuppression patterns from phase I, II, and III clinical trials were analyzed to evaluate the degree of hematologic toxicity and to determine risk factors predictive of myelosuppression. Additionally, recent publications of alternative topotecan doses and schedules were examined. Extent of prior therapy, prior platinum therapy (particularly carboplatin), advanced age, impaired renal function, and prior radiation therapy were identified as potential risk factors for greater hematologic toxicity after topotecan therapy. Reducing the starting topotecan dose to 1.0 or 1.25 mg/m2/day is recommended to reduce the incidence of severe myelosuppression in high-risk individuals receiving topotecan for 5 consecutive days. Hematopoietic growth factors, transfusion therapy, and schedule adjustments may also help manage myelosuppression. Alternative schedules of 3-day or weekly dosing appear to have less myelotoxicity and are currently under evaluation. The clinical aspects of topotecan-related myelosuppression and results from clinical trials indicate that the dose, and possibly the dosing schedule, of topotecan can be modified to reduce hematologic toxicity and improve tolerance without compromising efficacy. Prospective individualization of topotecan dosing may prevent or minimize dose-limiting myelosuppression and allow patients to achieve the maximum topotecan benefit by improving their ability to complete therapy with fewer treatment delays. Ongoing clinical trials evaluating alternative dosing schedules with superior hematologic tolerability may facilitate the inclusion of topotecan in combination regimens for patients with ovarian cancer. Proposed topotecan dosing guidelines to reduce and manage myelosuppression are outlined.
Topics: Antineoplastic Agents; Drug Administration Schedule; Female; Hematologic Diseases; Humans; Incidence; Ovarian Neoplasms; Practice Guidelines as Topic; Receptors, Colony-Stimulating Factor; Recurrence; Risk Factors; Topotecan
PubMed: 14755013
DOI: 10.1634/theoncologist.9-1-33 -
International Journal of Biological... 2022Triple-negative breast cancer (TNBC) does not respond to anti-estrogen and anti-HER2 therapies and is commonly treated by chemotherapy. TNBC has a high recurrence rate,...
Triple-negative breast cancer (TNBC) does not respond to anti-estrogen and anti-HER2 therapies and is commonly treated by chemotherapy. TNBC has a high recurrence rate, particularly within the first 3 years. Thus, there is an urgent clinical need to develop more effective therapies for TNBC. Topoisomerase I (TOP1) inhibitors cause DNA damage, making these drugs desirable for TNBC treatment since DNA repair machinery is defective in this subtype of breast cancer. Among the main molecular subtypes of breast cancer, the TNBC cell lines exhibited the highest TOP1 inhibition sensitivity. However, clinically used TOP1 inhibitors, such as topotecan and irinotecan, have shown limited clinical applications and the reasons remain unclear. Understanding the mechanism of differential responses to TOP1 blockade and identifying the predictive markers for cancer cell sensitivity will help further TOP1-targeted therapy for TNBC treatment and improve the clinical use of TOP1 inhibitors. Viability assays were used to evaluate breast cancer cell sensitivity to topotecan and other TOP1 inhibitors as well as TOP2 inhibitors. An -derived topotecan-resistant TNBC cell model and TNBC xenograft models were employed to confirm cancer cell response to TOP1 blockade. RNA-seq was used to identify potential predictive markers for TNBC cell response to TOP1 blockade. Western blotting and qRT-PCR were performed to measure the protein levels and RNA expression. ATAC-seq and luciferase reporter assays were used to examine transcriptional regulations. The effects of MYC and JNK in cancer cell response to TOP1 inhibition were validated via loss-of-function and gain-of-function experiments. We observed two distinct and diverging cancer cell responses - sensitive versus resistant to TOP1 inhibition, which was confirmed by TNBC xenograft mouse models treated by topotecan. TNBC cells exhibited bifurcated temporal patterns of ATR pathway activation upon TOP1 inhibitor treatment. The sensitive TNBC cells showed an "up then down" dynamic pattern of ATR/Chk1 signaling, while the resistant TNBC cells exhibited a "persistently up" profile. On the contrary, opposite temporal patterns of induced expression of MYC, a key regulator and effector of DNA damage, were found in TNBC cells treated by TOP1 inhibitors. Mechanistically, we showed that TOP1-induced JNK signaling upregulated MYC expression. Furthermore, pharmacological inhibition of ATR reversed TNBC cell resistance to topotecan, whereas knockdown and JNK inhibition reduced cancer cell sensitivity. Dynamic temporal profiles of induced ATR/Chk1 and JNK activation as well as MYC expression, may predict cancer cell response to TOP1 inhibitors. JNK activation-mediated constitutive elevation of MYC expression may represent a novel mechanism governing cancer cell sensitivity to TOP1-targeting therapy. Our results may provide implications for identifying TNBC patients who might benefit from the treatment with TOP1 inhibitors.
Topics: Animals; Cell Line, Tumor; Cell Proliferation; DNA Topoisomerases, Type I; Humans; Mice; Proto-Oncogene Proteins c-myc; Signal Transduction; Topotecan; Triple Negative Breast Neoplasms
PubMed: 35844787
DOI: 10.7150/ijbs.70583 -
Journal of Comparative Effectiveness... May 2023Compare lurbinectedin versus other second-line (2L) small-cell lung cancer (SCLC) treatments. An unanchored matching-adjusted indirect comparison connected the... (Meta-Analysis)
Meta-Analysis
Compare lurbinectedin versus other second-line (2L) small-cell lung cancer (SCLC) treatments. An unanchored matching-adjusted indirect comparison connected the platinum-sensitive SCLC cohort of a single-arm lurbinectedin trial to a network of three randomized controlled trials (oral and intravenous [IV] topotecan, and platinum re-challenge) identified by systematic literature review. Network meta-analysis methods estimated relative treatment effects. In platinum-sensitive patients, lurbinectedin demonstrated a survival benefit and favorable safety profile versus oral and IV topotecan and platinum re-challenge (overall survival, hazard ratio [HR]: 0.43; 95% credible interval [CrI]: 0.27, 0.67; HR: 0.43; 95% CrI: 0.26, 0.70; HR: 0.42; 95% CrI: 0.30, 0.58 respectively). Lurbinectedin showed a robust survival benefit and favorable safety versus other SCLC treatments in 2L platinum-sensitive SCLC.
Topics: Humans; Topotecan; Small Cell Lung Carcinoma; Carbolines; Platinum; Lung Neoplasms; Antineoplastic Combined Chemotherapy Protocols; Randomized Controlled Trials as Topic
PubMed: 37079341
DOI: 10.57264/cer-2022-0098 -
Health Technology Assessment... May 2010This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of topotecan in combination with cisplatin... (Review)
Review
This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of topotecan in combination with cisplatin for the treatment of recurrent and stage IVB carcinoma of the cervix, in accordance with the licensed indication, based upon the evidence submission from the manufacturer to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. The outcomes measured were overall survival, progression-free survival, response rates, adverse effects of treatment, health-related quality of life (HRQoL) and quality-adjusted life-years (QALYs) gained. The manufacturer stated that topotecan plus cisplatin is the only combination regimen to date to have demonstrated a statistically significant survival advantage compared to cisplatin monotherapy in the licensed population. The clinical evidence came from three clinical trials comparing topotecan plus cisplatin with cisplatin monotherapy (GOG-0179), topotecan plus cisplatin with paclitaxel plus cisplatin (GOG-0169), and four cisplatin-based combination therapies: topotecan plus cisplatin, paclitaxel plus cisplatin, gemcitabine plus cisplatin, and vinorelbine plus cisplatin (GOG-0204). Results from GOG-0179 showed greater median overall survival with topotecan plus cisplatin than with cisplatin monotherapy: 9.4 months versus 6.5 months. Similar results were also reported for median progression-free survival. Response rates also showed an advantage with topotecan plus cisplatin compared with cisplatin monotherapy. The response rates in patients receiving cisplatin monotherapy were very low, but the potential reasons for this were not discussed in the manufacturer's submission. Patients receiving topotecan plus cisplatin experienced a greater number of adverse events and the ERG was concerned with some of the assumptions related to HRQoL. In the base-case direct comparison, the incremental cost-effectiveness ratio (ICER) of topotecan plus cisplatin versus cisplatin monotherapy was 17,974 pounds per QALY in the main licensed population, 10,928 pounds per QALY in the cisplatin-naive population (including stage IVB patients) and 32,463 pounds per QALY in sustained cisplatin-free interval patients. In response to the point for clarification raised by the ERG, the manufacturer submitted a revised indirect comparison incorporating HRQoL and a longer time horizon. Where the hazard ratio derived from GOG-0169 was employed, paclitaxel plus cisplatin was dominated by topotecan plus cisplatin, but, where the hazard ratio from GOG-0204 was adopted, paclitaxel plus cisplatin was found to have an ICER of 13,260 pounds per QALY versus topotecan plus cisplatin. At present there is a paucity of evidence available on the clinical effects of topotecan plus cisplatin and the effects of palliative treatment in general for women with advanced and recurrent carcinoma of the cervix. Further trials, or the implementation of registries, are required to establish the efficacy and safety of topotecan plus cisplatin. The guidance issued by NICE on 28 October 2009 as a result of the STA states that topotecan in combination with cisplatin is recommended as a treatment option for women with recurrent or stage IVB cervical cancer, only if they have not previously received cisplatin. Women who have previously received cisplatin and are currently being treated with topotecan in combination with cisplatin for the treatment of cervical cancer should have the option to continue therapy until they and their clinicians consider it appropriate to stop.
Topics: Antimetabolites, Antineoplastic; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Cisplatin; Cost-Benefit Analysis; Cross-Linking Reagents; Deoxycytidine; Disease Progression; Drug Therapy, Combination; Female; Humans; Neoplasm Recurrence, Local; Neoplasm Staging; Quality of Life; Quality-Adjusted Life Years; Radiation-Sensitizing Agents; Topotecan; Treatment Outcome; United Kingdom; Uterine Cervical Neoplasms; Vinblastine; Vinorelbine; Gemcitabine
PubMed: 20507804
DOI: 10.3310/hta14Suppl1/08 -
Journal For Immunotherapy of Cancer Nov 2023The survival of patients with cervical cancer who are treated with cisplatin in conjunction with the topoisomerase I inhibitor topotecan is enhanced when compared with...
BACKGROUND
The survival of patients with cervical cancer who are treated with cisplatin in conjunction with the topoisomerase I inhibitor topotecan is enhanced when compared with patients treated with only one of these chemotherapeutics. Moreover, cisplatin-based and T cell-based immunotherapy have been shown to synergize, resulting in stronger antitumor responses. Here, we interrogated whether topotecan could further enhance the synergy of cisplatin with T cell-based cancer immunotherapy.
METHODS
Mice bearing human papilloma virus 16 (HPV16) E6/E7-expressing TC-1 tumors were vaccinated with HPV16 E7 long peptides and additionally received chemotherapy consisting of cisplatin and topotecan. We performed an in-depth study of this combinatorial chemoimmunotherapy on the effector function and expansion/contraction kinetics of vaccine-induced CD8 T cells in the peripheral blood and tumor microenvironment (TME). In addition, we interrogated the particular role of chemotherapy-induced upregulation of costimulatory ligands by tumor-infiltrated myeloid cells on T cell proliferation and survival.
RESULTS
We show that E7 long peptide vaccination combined with cisplatin and topotecan, results in CD8 T cell-dependent durable rejection of established tumors and 94% long-term survival. Although topotecan initially repressed the expansion of vaccine-induced CD8 T cells, these cells eventually expanded vigorously, which was followed by delayed contraction. These effects associated with the induction of the proliferation marker Ki-67 and the antiapoptosis molecule Bcl-2 by intratumoral tumor-specific CD8 T cells, which was regulated by topotecan-mediated upregulation of the costimulatory ligand CD70 on myeloid cells in the TME.
CONCLUSIONS
Taken together, our data show that although treatment with cisplatin, topotecan and vaccination initially delays T cell expansion, this combinatorial therapy results eventually in a more robust T cell-mediated tumor eradication due to enhancement of costimulatory molecules in the TME.
Topics: Female; Humans; Animals; Mice; Cisplatin; CD8-Positive T-Lymphocytes; Cancer Vaccines; Topotecan; DNA Topoisomerases, Type I; Papillomavirus E7 Proteins; Vaccines, Subunit; Uterine Cervical Neoplasms; Cell Proliferation; Tumor Microenvironment; CD27 Ligand
PubMed: 38030302
DOI: 10.1136/jitc-2023-007158 -
International Journal of Gynecological... Jul 2017Despite advances in cervical cancer prevention and diagnosis, outcomes for patients given a diagnosis of advanced and recurrent disease are poor. In the GOG240 trial,... (Meta-Analysis)
Meta-Analysis Review
Systematic Review and Network Meta-Analysis of Bevacizumab Plus First-Line Topotecan-Paclitaxel or Cisplatin-Paclitaxel Versus Non-Bevacizumab-Containing Therapies in Persistent, Recurrent, or Metastatic Cervical Cancer.
OBJECTIVE
Despite advances in cervical cancer prevention and diagnosis, outcomes for patients given a diagnosis of advanced and recurrent disease are poor. In the GOG240 trial, the addition of bevacizumab to paclitaxel-topotecan or paclitaxel-cisplatin has been shown to prolong survival compared with paclitaxel-topotecan or paclitaxel-cisplatin in patients with persistent, recurrent, or metastatic disease. However, standards of care vary between regions and countries. The purpose of this systematic review and network meta-analysis was to enable a comparison between bevacizumab + chemotherapy with multiple monotherapy or combination chemotherapy regimens in the treatment for women with advanced, recurrent, or persistent cervical cancer.
METHODS/MATERIALS
A systematic literature review was conducted to identify randomized or nonrandomized controlled trials of patients with recurrent, persistent, or metastatic cervical cancer published in English from 1999 to 2015. A feasibility study was performed to assess the heterogeneity of the trials, and a network meta-analysis was conducted. Fixed- and random-effects models were fitted to calculate the hazard ratio for overall survival (OS) for all pairwise comparisons and ranking of all interventions.
RESULTS
Twenty-three studies (19 trials) met inclusion criteria and were included in the review. Sample sizes ranged from 69 to 452, and median patient age ranged from 45 to 53 years. There was a trend toward prolonged OS with cisplatin-paclitaxel-bevacizumab and topotecan-paclitaxel-bevacizumab compared with all non-bevacizumab-containing therapies. Cisplatin-paclitaxel-bevacizumab had the highest probability of being the most efficacious compared with all regimens (68.1%), and cisplatin monotherapy had the lowest (0%).
CONCLUSIONS
The results of this network meta-analysis show that bevacizumab in combination with paclitaxel-topotecan or paclitaxel-cisplatin is likely to prolong OS over other non-bevacizumab-containing chemotherapies (eg, paclitaxel-carboplatin), which were not included in the GOG240 trial. In patients with advanced, persistent, and recurrent cervical cancer, cisplatin-paclitaxel-bevacizumab and topotecan-paclitaxel-bevacizumab showed the highest efficacy in all regimens investigated in this analysis.
Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Cisplatin; Female; Humans; Neoplasm Metastasis; Neoplasm Recurrence, Local; Paclitaxel; Topotecan; Uterine Cervical Neoplasms
PubMed: 28448304
DOI: 10.1097/IGC.0000000000001000 -
Health Technology Assessment... Mar 2010To assess the clinical effectiveness and cost-effectiveness of topotecan as second-line treatment for small cell lung cancer (SCLC). (Review)
Review
OBJECTIVES
To assess the clinical effectiveness and cost-effectiveness of topotecan as second-line treatment for small cell lung cancer (SCLC).
DATA SOURCES
Bibliographic databases were searched from 1990 to February 2009, including the Cochrane library, MEDLINE (Ovid), EMBASE (Ovid), PREMEDLINE In-Process & Other Non-Indexed Citations. Bibliographies of related papers were assessed and experts were contacted to identify additional references and the manufacturer's submission to NICE was also searched.
REVIEW METHODS
Two reviewers independently screened titles and abstracts for eligibility. Inclusion criteria were applied to the full text of retrieved papers using a standard form. For the clinical effectiveness review, the studies were randomised controlled trials (RCTs), which included adult participants with relapsed SCLC who responded to first-line treatment and for whom re-treatment with first-line therapy was inappropriate. The treatment was topotecan (oral or intravenous, i.v.) compared with one another, best supportive care (BSC) or other chemotherapy regimens. Outcomes included measures of response or disease progression and measures of survival. For the cost-effectiveness review studies were eligible for inclusion if they reported cost-effectiveness, cost-utility, cost-benefit or cost-consequence analyses. Data extraction and quality assessment of included studies was undertaken by one reviewer and checked by a second. Studies were synthesised through a narrative review with full tabulation of results. An independent economic model estimated the cost-effectiveness of topotecan (oral or i.v.) compared with BSC. The model used survival analysis methods to derive estimates of mean survival for patients treated with topotecan or receiving BSC alone. These were combined with quality of life (QoL) weights to derive estimates of mean quality-adjusted life expectancy for patients receiving BSC alone or topotecan plus BSC. Categories of costs included in the model included drug use, chemotherapy administration and on-treatment monitoring, management of adverse events, monitoring for disease progression and palliative care.
RESULTS
A total of 434 references were identified of which five were included in the clinical effectiveness review. In these trials topotecan was compared with BSC, CAV [cyclophosphamide, Adriamycin (doxorubicin) and vincristine] or amrubicin, or oral topotecan was compared with i.v. topotecan. No economic evaluations were identified. There were no statistically significant differences between groups when i.v. topotecan was compared with either CAV or oral topotecan for overall response rate (ORR). Response rate was significantly better in participants receiving i.v. amrubicin than in those receiving a low dose of i.v. topotecan (38% versus 13%, respectively, p = 0.039). There was a statistically significant benefit in favour of oral topotecan compared with BSC (HR 0.61, 95% CI 0.43 to 0.87, p = 0.01). Drug acquisition costs for four cycles of treatment were estimated at 2550 pounds for oral topotecan and 5979 pounds for i.v. topotecan. Non-drug treatment costs accounted for an additional 1097 pounds for oral topotecan and 4289 pounds for i.v. topotecan. Total costs for the modelled time horizon of 5 years were 4854 pounds for BSC, 11,048 pounds for oral topotecan and between 16,914 pounds and 17,369 pounds for i.v. topotecan (depending on assumptions regarding time progression). Life expectancy was 0.4735, 0.7984 and 0.7784 years for BSC, oral topotecan and i.v. topotecan respectively. Total quality-adjusted life-years (QALYs) were 0.2247 and 0.4077, for BSC and oral topotecan respectively, resulting in an incremental cost-effectiveness ratio (ICER) of 33,851 pounds per QALY gained. Total QALYs for i.v. topotecan were between 0.3875 and 0.4157 (depending on assumptions regarding time progression) resulting in an ICER between 74,074 pounds and 65,507 pounds per QALY gained.
CONCLUSIONS
Topotecan appeared to be better than BSC alone in terms of improved survival, and was as effective as CAV and less favourable than i.v. amrubicin in terms of response. Oral topotecan and i.v. topotecan were similar in efficacy. Topotecan offers additional benefit over BSC, but at increased cost. ICERs for i.v. topotecan, compared with BSC, were high and suggest that it is unlikely to be a cost-effective option. The ICER for oral topotecan is at the upper extreme of the range conventionally regarded as cost-effective from an NHS decision-making perspective. Further research into the QoL of patients with relapsed SCLC could identify the impacts of disease progression and treatment response.
Topics: Adult; Antineoplastic Agents; Cost-Benefit Analysis; Humans; Lung Neoplasms; Small Cell Lung Carcinoma; Topotecan
PubMed: 20356561
DOI: 10.3310/hta14190 -
Health Technology Assessment... 2001Ovarian cancer is the most common gynaecological cancer with an annual incidence of 21.6 per 100,000 in England and Wales. Due to the often asymptomatic nature of the... (Comparative Study)
Comparative Study Review
BACKGROUND
Ovarian cancer is the most common gynaecological cancer with an annual incidence of 21.6 per 100,000 in England and Wales. Due to the often asymptomatic nature of the early stages of the disease, most cases are not detected until the advanced stages. Consequently, the prognosis after diagnosis is poor and the 5-year survival rate in the UK is only about 30%. Current recommendations suggest that first-line chemotherapy for ovarian cancer should involve paclitaxel and platinum (Pt)-based therapy (cisplatin/ carboplatin), however, most patients develop resistant or refractory disease and require second-line therapy. Patients may respond to re-challenge with Pt-agents if the treatment-free interval is > 6 months, but an alternative is often required. Topotecan is one of six drugs currently licensed in the UK for second-line therapy, and recent reviews suggest that it has modest efficacy in the treatment of advanced disease and performs favourably against paclitaxel. However, these reviews are based on a limited number of reports mainly consisting of non-randomised Phase I and II studies.
OBJECTIVES OF THE REVIEW
To examine the clinical effectiveness and cost-effectiveness of oral and intravenous topotecan (Hycamtin, SmithKline Beecham, UK) for the treatment of all stages of ovarian cancer.
SEARCH STRATEGY
Sixteen electronic databases from inception to September 2000 and Internet resources were searched, in addition to the bibliographies of retrieved articles and submissions from pharmaceutical companies.
INCLUSION AND EXCLUSION CRITERIA
Two reviewers independently screened all titles/abstracts and included/excluded studies based on full copies of manuscripts. Any disagreements were resolved through discussion. Only randomised controlled trials (RCTs) and full economic evaluations comparing topotecan to non-topotecan regimens were included. All stages of therapy and disease were considered, and the outcomes included were survival, response, symptom relief, quality of life, adverse effects and costs.
METHODS
DATA EXTRACTION STRATEGY: Data were extracted into an Access database by one reviewer and checked by a second. Any disagreements were resolved through discussion.
METHODS
QUALITY ASSESSMENT STRATEGY: Two reviewers, using specified criteria, independently assessed the quality of the clinical effectiveness studies and the economic evaluations. Any disagreements were resolved through discussion.
METHODS
ANALYSIS STRATEGY: Due to the limited number of studies included in the review and the fact that they compared topotecan with different comparators, the out-come data could not be pooled statistically. Clinical effectiveness data are discussed separately under the different outcome subheadings. For time-to-event data, hazard ratios with 95% confidence intervals are presented where available, and for the remaining outcomes, relative risks are reported or calculated where sufficient data were available. Relative risk data are also presented in the form of Forest plots without pooled estimates. Economic data are presented in the form of a summary and critique of the evidence, and a grading (A-I) assigned to each study indicating the direction and magnitude of the cost-effectiveness data.
INCLUDED STUDIES
A total of 568 titles/abstracts were identified and screened for relevance. Full copies of 72 papers were assessed and seven published manuscripts reporting details of two studies of clinical effectiveness and one economic evaluation were included. Further details of the two clinical effectiveness studies and two new economic evaluations were identified from confidential company submissions. Overall, two international multicentre RCTs of effectiveness comparing topotecan with paclitaxel (trial 039) and topotecan with caelyx (trial 30-49) were included in the review. The three economic evaluations included in the review comprised one cost-minimisation analysis (CMA) comparing topotecan with caelyx, one cost-consequences analysis (CCA) comparing topotecan with paclitaxel, etoposide and altretamine and one cost-effectiveness analysis (CEA) comparing topotecan with paclitaxel.
RESULTS
QUALITY OF CLINICAL EFFECTIVENESS DATA: Both clinical effectiveness studies (trial 30-49 and 039) were of reasonable quality, although it was unclear whether either performed valid intention-to-treat analyses. In addition, trial 30-49 failed to state whether the outcome assessors were blinded to treatment allocation. RESULTS --QUALITY OF ECONOMIC EVALUATIONS: The CCA (comparing topotecan with three comparators) was of poor quality and of little relevance to the UK NHS. The CMA and CEA were of reasonable quality overall and relevant to the UK NHS. However, both, in particular the CEA, suffered from methodological problems, and thus their findings should be interpreted with caution.
RESULTS
ASSESSMENT OF CLINICAL EFFECTIVENESS: The assessment of clinical effectiveness was based on limited data. Only two trials with a total of 709 participants were identified. In general, with a few minor exceptions, there were no statistically significant differences between topotecan and paclitaxel, or topotecan and caelyx in survival, response rate, median time to response, median duration of response and quality of life. Significant differences that were reported were mainly identified in subgroup analyses (Pt-sensitive disease and disease without ascites) of questionable validity and their relevance to a general advanced ovarian cancer patient population undergoing second-line chemotherapy is unclear. However, statistically significant differences were observed in the incidence of adverse effects. Topotecan was associated with increased incidences of haematological toxicities (including neutropenia, leukopenia, anaemia and thrombocytopenia), alopecia, nausea and vomiting. Caelyx-treated patients suffered from significantly increased incidences of Palmar-Plantar erythrodysesthesia, stomatitis, mucous membrane disorders and skin rashes. Paclitaxel was associated with significant increases in alopecia, arthralgia, myalgia, neuropathy, paraesthesiae, skeletal pain and flushing.
RESULTS
ASSESSMENT OF COST-EFFECTIVENESS: The assessment of cost-effectiveness was also based on limited data, with three evaluations identified, one of which was not relevant. The two remaining studies, comparing topotecan with paclitaxel (CEA) and topotecan with caelyx (CMA), both used effectiveness data from multicentre RCTs and based their costs on 1999/2000 UK sources. The evaluations were conducted from a UK NHS perspective and findings presented in GB pounds/Euros. Topotecan for the second-line treatment of advanced ovarian cancer was shown to be more cost-effective than paclitaxel (32,513 GB pounds versus 46,186 GB pounds per person in terms of any response (complete or partial), incremental cost-effectiveness = 3065 GB pounds) in all respects except cost per time without toxicity or symptoms, but less cost-effective than caelyx (14,023 GB pounds versus 9979 GB pounds per person regardless of whether the patient responded). However, direct comparisons of the cost findings between the two studies is difficult because they used different designs, different time horizons for the cost analyses and the findings were presented as costs per person for only patients who responded in one study (topotecan versus paclitaxel) and costs per person regardless of whether they responded in the other study (topotecan versus caelyx).
CONCLUSIONS
This review indicates that there is little evidence in the form of RCTs on which to base an assessment of the effectiveness of topotecan as second-line therapy for advanced ovarian cancer. The evidence suggests there were no statistically significant differences overall between topotecan and paclitaxel, or topotecan and caelyx in clinical outcomes. However, statistically significant differences were observed in the incidence of adverse effects. The clinical significance of the findings is not discussed. Overall, the effects of topotecan could at best be described as modest, but the alternative agents offer no real advantages except fewer side-effects and possibly improved cost-effectiveness. Both of the clinical effectiveness studies on which this evidence is based had methodological flaws, the most serious being the lack of a blinded assessor in the topotecan versus caelyx trial, which is important for unbiased assessment of response outcomes. The economic evaluations also suffered from a number of potential problems.
CONCLUSIONS
RECOMMENDATIONS FOR RESEARCH: Further good quality RCTs and CEAs are required comparing topotecan with other licensed and potentially useful (soon to be licensed) second-line treatments for ovarian cancer. At present, it is difficult to make any decisions about topotecan and other drugs for second-line therapy without good quality direct comparisons. In view of the ongoing studies identified, an update of the current review should be considered in approximately 18 months (Summer 2002) or possibly sooner if the recently commissioned National Institute for Clinical Excellence review of caelyx for ovarian cancer identifies additional data relevant to topotecan.
Topics: Antineoplastic Agents; Cost-Benefit Analysis; Female; Humans; Ovarian Neoplasms; Randomized Controlled Trials as Topic; Survival Analysis; Technology Assessment, Biomedical; Topotecan
PubMed: 11701100
DOI: 10.3310/hta5280 -
The British Journal of Ophthalmology Feb 2022Current melphalan-based intravitreal regimens for retinoblastoma (RB) vitreous seeds cause retinal toxicity. We assessed the efficacy and toxicity of topotecan...
BACKGROUND
Current melphalan-based intravitreal regimens for retinoblastoma (RB) vitreous seeds cause retinal toxicity. We assessed the efficacy and toxicity of topotecan monotherapy compared with melphalan in our rabbit model and patient cohort.
METHODS
Rabbit experiments: empiric pharmacokinetics were determined following topotecan injection. For topotecan (15 μg or 30 µg), melphalan (12.5 µg) or saline, toxicity was evaluated by serial electroretinography (ERG) and histopathology, and efficacy against vitreous seed xenografts was measured by tumour cell reduction and apoptosis induction.
PATIENTS
retrospective cohort study of 235 patients receiving 990 intravitreal injections of topotecan or melphalan.
RESULTS
Intravitreal topotecan 30 µg (equals 60 µg in humans) achieved the IC across the rabbit vitreous. Three weekly topotecan injections (either 15 µg or 30 µg) caused no retinal toxicity in rabbits, whereas melphalan 12.5 µg (equals 25 µg in humans) reduced ERG amplitudes 42%-79%. Intravitreal topotecan 15 µg was equally effective to melphalan to treat WERI-Rb1 cell xenografts in rabbits (96% reduction for topotecan vs saline (p=0.004), 88% reduction for melphalan vs saline (p=0.004), topotecan vs melphalan, p=0.15). In our clinical study, patients received 881 monotherapy injections (48 topotecan, 833 melphalan). Patients receiving 20 µg or 30 µg topotecan demonstrated no significant ERG reductions; melphalan caused ERG reductions of 7.6 μV for every injection of 25 µg (p=0.03) or 30 µg (p<0.001). Most patients treated with intravitreal topotecan also received intravitreal melphalan at some point during their treatment course. Among those eyes treated exclusively with topotecan monotherapy, all eyes were salvaged.
CONCLUSIONS
Taken together, these experiments suggest that intravitreal topotecan monotherapy for the treatment of RB vitreous seeds is non-toxic and effective.
Topics: Animals; Antineoplastic Agents, Alkylating; Humans; Intravitreal Injections; Melphalan; Neoplasm Seeding; Rabbits; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Topotecan; Vitreous Body
PubMed: 33972235
DOI: 10.1136/bjophthalmol-2020-318529