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Clinical Cancer Research : An Official... Nov 2019Irinotecan and topotecan have been widely used as anticancer drugs for the past 20 years. Because of their selectivity as topoisomerase I (TOP1) inhibitors that trap... (Review)
Review
Irinotecan and topotecan have been widely used as anticancer drugs for the past 20 years. Because of their selectivity as topoisomerase I (TOP1) inhibitors that trap TOP1 cleavage complexes, camptothecins are also widely used to elucidate the DNA repair pathways associated with DNA-protein cross-links and replication stress. This review summarizes the basic molecular mechanisms of action of TOP1 inhibitors, their current use, and limitations as anticancer agents. We introduce new therapeutic strategies based on novel TOP1 inhibitor chemical scaffolds including the indenoisoquinolines LMP400 (indotecan), LMP776 (indimitecan), and LMP744, and on tumor-targeted delivery TOP1 inhibitors using liposome, PEGylation, and antibody-drug conjugates. We also address how tumor-specific determinants such as homologous recombination defects (HRD and BRCAness) and Schlafen 11 (SLFN11) expression can be used to guide clinical application of TOP1 inhibitors in combination with DNA damage response inhibitors including PARP, ATR, CHEK1, and ATM inhibitors.
Topics: Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; DNA Topoisomerases, Type I; Humans; Irinotecan; Molecular Targeted Therapy; Neoplasms; Poly(ADP-ribose) Polymerase Inhibitors; Precision Medicine; Topoisomerase I Inhibitors; Topotecan
PubMed: 31227499
DOI: 10.1158/1078-0432.CCR-19-1089 -
Journal of Thoracic Oncology : Official... Sep 2021DLL3, an atypical Notch ligand, is expressed in SCLC tumors but is not detectable in normal adult tissues. Rovalpituzumab tesirine (Rova-T) is an antibody-drug conjugate... (Randomized Controlled Trial)
Randomized Controlled Trial
INTRODUCTION
DLL3, an atypical Notch ligand, is expressed in SCLC tumors but is not detectable in normal adult tissues. Rovalpituzumab tesirine (Rova-T) is an antibody-drug conjugate containing a DLL3-targeting antibody tethered to a cytotoxic agent pyrrolobenzodiazepine by means of a protease-cleavable linker. The efficacy and safety of Rova-T compared with topotecan as second-line therapy in patients with SCLC expressing high levels of DLL3 (DLL3-high) was evaluated.
METHODS
The TAHOE study was an open-label, two-to-one randomized, phase 3 study comparing Rova-T with topotecan as second-line therapy in DLL3-high advanced or metastatic SCLC. Rova-T (0.3 mg/kg) was administered intravenously on day 1 of a 42-day cycle for two cycles, with two additional cycles available to patients who met protocol-defined criteria for continued dosing. Topotecan (1.5 mg/m) was administered intravenously on days 1 to 5 of a 21-day cycle. The primary end point was overall survival (OS).
RESULTS
Patients randomized to Rova-T (n = 296) and topotecan (n = 148) were included in the efficacy analyses. The median age was 64 years, and 77% had the extensive disease at initial diagnosis. The median OS (95% confidence interval) was 6.3 months (5.6-7.3) in the Rova-T arm and 8.6 months (7.7-10.1) in the topotecan arm (hazard ratio, 1.46 [95% confidence interval: 1.17-1.82]). An independent data monitoring committee recommended that enrollment be discontinued because of the shorter OS observed with Rova-T compared with topotecan. Safety profiles for both drugs were consistent with previous reports.
CONCLUSIONS
Compared with topotecan, which is the current standard second-line chemotherapy, Rova-T exhibited an inferior OS and higher rates of serosal effusions, photosensitivity reaction, and peripheral edema in patients with SCLC. A considerable unmet therapeutic need remains in this population.
Topics: Adult; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Benzodiazepinones; Humans; Immunoconjugates; Intracellular Signaling Peptides and Proteins; Lung Neoplasms; Membrane Proteins; Middle Aged; Small Cell Lung Carcinoma; Topotecan
PubMed: 33607312
DOI: 10.1016/j.jtho.2021.02.009 -
Journal of Clinical Oncology : Official... Dec 2021The primary aim of this phase III randomized trial was to test whether the addition of vincristine, topotecan, and cyclophosphamide (VTC) to interval compressed... (Randomized Controlled Trial)
Randomized Controlled Trial
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 regimen B, 78% 79%; = .192; 5-year OS 86% 88%; = .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; = .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.
Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Cyclophosphamide; Female; Humans; Infant; Infant, Newborn; Male; Sarcoma, Ewing; Topotecan; Vincristine
PubMed: 34652968
DOI: 10.1200/JCO.21.00358 -
Lancet (London, England) Oct 2017On Aug 14, 2014, the US Food and Drug Administration approved the antiangiogenesis drug bevacizumab for women with advanced cervical cancer on the basis of improved... (Comparative Study)
Comparative Study Randomized Controlled Trial
Bevacizumab for advanced cervical cancer: final overall survival and adverse event analysis of a randomised, controlled, open-label, phase 3 trial (Gynecologic Oncology Group 240).
BACKGROUND
On Aug 14, 2014, the US Food and Drug Administration approved the antiangiogenesis drug bevacizumab for women with advanced cervical cancer on the basis of improved overall survival (OS) after the second interim analysis (in 2012) of 271 deaths in the Gynecologic Oncology Group (GOG) 240 trial. In this study, we report the prespecified final analysis of the primary objectives, OS and adverse events.
METHODS
In this randomised, controlled, open-label, phase 3 trial, we recruited patients with metastatic, persistent, or recurrent cervical carcinoma from 81 centres in the USA, Canada, and Spain. Inclusion criteria included a GOG performance status score of 0 or 1; adequate renal, hepatic, and bone marrow function; adequately anticoagulated thromboembolism; a urine protein to creatinine ratio of less than 1; and measurable disease. Patients who had received chemotherapy for recurrence and those with non-healing wounds or active bleeding conditions were ineligible. We randomly allocated patients 1:1:1:1 (blocking used; block size of four) to intravenous chemotherapy of either cisplatin (50 mg/m on day 1 or 2) plus paclitaxel (135 mg/m or 175 mg/m on day 1) or topotecan (0·75 mg/m on days 1-3) plus paclitaxel (175 mg/m on day 1) with or without intravenous bevacizumab (15 mg/kg on day 1) in 21 day cycles until disease progression, unacceptable toxic effects, voluntary withdrawal by the patient, or complete response. We stratified randomisation by GOG performance status (0 vs 1), previous radiosensitising platinum-based chemotherapy, and disease status (recurrent or persistent vs metastatic). We gave treatment open label. Primary outcomes were OS (analysed in the intention-to-treat population) and adverse events (analysed in all patients who received treatment and submitted adverse event information), assessed at the second interim and final analysis by the masked Data and Safety Monitoring Board. The cutoff for final analysis was 450 patients with 346 deaths. This trial is registered with ClinicalTrials.gov, number NCT00803062.
FINDINGS
Between April 6, 2009, and Jan 3, 2012, we enrolled 452 patients (225 [50%] in the two chemotherapy-alone groups and 227 [50%] in the two chemotherapy plus bevacizumab groups). By March 7, 2014, 348 deaths had occurred, meeting the prespecified cutoff for final analysis. The chemotherapy plus bevacizumab groups continued to show significant improvement in OS compared with the chemotherapy-alone groups: 16·8 months in the chemotherapy plus bevacizumab groups versus 13·3 months in the chemotherapy-alone groups (hazard ratio 0·77 [95% CI 0·62-0·95]; p=0·007). Final OS among patients not receiving previous pelvic radiotherapy was 24·5 months versus 16·8 months (0·64 [0·37-1·10]; p=0·11). Postprogression OS was not significantly different between the chemotherapy plus bevacizumab groups (8·4 months) and chemotherapy-alone groups (7·1 months; 0·83 [0·66-1·05]; p=0·06). Fistula (any grade) occurred in 32 (15%) of 220 patients in the chemotherapy plus bevacizumab groups (all previously irradiated) versus three (1%) of 220 in the chemotherapy-alone groups (all previously irradiated). Grade 3 fistula developed in 13 (6%) versus one (<1%). No fistulas resulted in surgical emergencies, sepsis, or death.
INTERPRETATION
The benefit conferred by incorporation of bevacizumab is sustained with extended follow-up as evidenced by the overall survival curves remaining separated. After progression while receiving bevacizumab, we did not observe a negative rebound effect (ie, shorter survival after bevacizumab is stopped than after chemotherapy alone is stopped). These findings represent proof-of-concept of the efficacy and tolerability of antiangiogenesis therapy in advanced cervical cancer.
FUNDING
National Cancer Institute.
Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Cisplatin; Disease Progression; Disease-Free Survival; Drug Administration Schedule; Female; Humans; Infusions, Intravenous; Middle Aged; Paclitaxel; Topotecan; Uterine Cervical Neoplasms
PubMed: 28756902
DOI: 10.1016/S0140-6736(17)31607-0 -
Journal of Clinical Oncology : Official... Nov 2009The purpose of this study was to compare the outcome of patients with intermediate-risk rhabdomyosarcoma (RMS) treated with standard VAC (vincristine, dactinomycin, and... (Randomized Controlled Trial)
Randomized Controlled Trial
Vincristine, actinomycin, and cyclophosphamide compared with vincristine, actinomycin, and cyclophosphamide alternating with vincristine, topotecan, and cyclophosphamide for intermediate-risk rhabdomyosarcoma: children's oncology group study D9803.
PURPOSE
The purpose of this study was to compare the outcome of patients with intermediate-risk rhabdomyosarcoma (RMS) treated with standard VAC (vincristine, dactinomycin, and cyclophosphamide) chemotherapy to that of patients treated with VAC alternating with vincristine, topotecan, and cyclophosphamide (VAC/VTC).
PATIENTS AND METHODS
Patients were randomly assigned to 39 weeks of VAC versus VAC/VTC; local therapy began after week 12. Patients with parameningeal RMS with intracranial extension (PME) were treated with VAC and immediate x-ray therapy. The primary study end point was failure-free survival (FFS). The study was designed with 80% power (5% two-sided alpha level) to detect an increase in 5-year FFS from 64% to 75% with VAC/VTC.
RESULTS
A total of 617 eligible patients were entered onto the study: 264 were randomly assigned to VAC and 252 to VAC/VTC; 101 PME patients were nonrandomly treated with VAC. Treatment strata were embryonal RMS, stage 2/3, group III (33%); embryonal RMS, group IV, less than age 10 years (7%); alveolar RMS or undifferentiated sarcoma (UDS), stage 1 or group I (17%); alveolar RMS/UDS (27%); and PME (16%). At a median follow-up of 4.3 years, 4-year FFS was 73% with VAC and 68% with VAC/VTC (P = .3). There was no difference in effect of VAC versus VAC/VTC across risk groups. The frequency of second malignancies was similar between the two treatment groups.
CONCLUSION
For intermediate-risk RMS, VAC/VTC does not significantly improve FFS compared with VAC.
Topics: Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Cyclophosphamide; Dactinomycin; Disease-Free Survival; Female; Humans; Infant; Kaplan-Meier Estimate; Male; Neoplasm Staging; Rhabdomyosarcoma; Topotecan; Vincristine
PubMed: 19770373
DOI: 10.1200/JCO.2009.22.3768 -
Journal of Clinical Oncology : Official... Oct 2009Assess toxicity and efficacy of cisplatin (Cis) doublet combinations in advanced and recurrent cervical carcinoma. (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Assess toxicity and efficacy of cisplatin (Cis) doublet combinations in advanced and recurrent cervical carcinoma.
PATIENTS AND METHODS
Patients were randomly assigned to paclitaxel 135 mg/m(2) over 24 hours plus Cis 50 mg/m(2) day 2 every 3 weeks (PC, reference arm); vinorelbine 30 mg/m(2) days 1 and 8 plus Cis 50 mg/m(2) day 1 every 3 weeks (VC); gemcitabine 1,000 mg/m(2) day 1 and 8 plus Cis 50 mg/m(2) day 1 every 3 weeks (GC); or topotecan 0.75 mg/m(2) days 1, 2, and 3 plus Cis 50 mg/m(2) day 1 every 3 weeks (TC). Survival was the primary end point with a 33% improvement relative to PC considered important (85% power, alpha = 5%). Quality-of-life data were prospectively collected.
RESULTS
A total of 513 patients were enrolled when a planned interim analysis recommended early closure for futility. The experimental-to-PC hazard ratios of death were 1.15 (95% CI, 0.79 to 1.67) for VC, 1.32 (95% CI, 0.91 to 1.92) for GC, and 1.26 (95% CI, 0.86 to 1.82) for TC. The hazard ratios for progression-free survival (PFS) were 1.36 (95% CI, 0.97 to 1.90) for VC, 1.39 (95% CI, 0.99 to 1.96) for GC, and 1.27 (95% CI, 0.90 to 1.78) for TC. Response rates (RRs) for PC, VC, GC, and TC were 29.1%, 25.9%, 22.3%, and 23.4%, respectively. The arms were comparable with respect to toxicity except for leucopenia, neutropenia, infection, and alopecia.
CONCLUSION
VC, GC, and TC are not superior to PC in terms of overall survival (OS). However, the trend in RR, PFS, and OS favors PC. Differences in chemotherapy scheduling, pre-existing morbidity, and toxicity are important in individualizing therapy.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Deoxycytidine; Fatigue; Female; Humans; Kaplan-Meier Estimate; Leukopenia; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Neutropenia; Paclitaxel; Prognosis; Quality of Life; Topotecan; Treatment Outcome; Uterine Cervical Neoplasms; Vinblastine; Vinorelbine; Young Adult; Gemcitabine
PubMed: 19720909
DOI: 10.1200/JCO.2009.21.8909 -
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 -
Cell Reports Aug 2023The neddylation inhibitor MLN4924/Pevonedistat is in clinical trials for multiple cancers. Efficacy is generally attributed to cullin RING ligase (CRL) inhibition, but...
The neddylation inhibitor MLN4924/Pevonedistat is in clinical trials for multiple cancers. Efficacy is generally attributed to cullin RING ligase (CRL) inhibition, but the contribution of non-CRL targets is unknown. Here, CRISPR screens map MLN4924-monotherapy sensitivity in retinoblastoma to a classic DNA damage-induced p53/E2F3/BAX-dependent death effector network, which synergizes with Nutlin3a or Navitoclax. In monotherapy-resistant cells, MLN4924 plus standard-of-care topotecan overcomes resistance, but reduces DNA damage, instead harnessing ribosomal protein nucleolar-expulsion to engage an RPL11/p21/MYCN/E2F3/p53/BAX synergy network that exhibits extensive cross-regulation. Strikingly, unneddylatable RPL11 substitutes for MLN4924 to perturb nucleolar function and enhance topotecan efficacy. Orthotopic tumors exhibit complete responses while preserving visual function. Moreover, MLN4924 plus melphalan deploy this DNA damage-independent strategy to synergistically kill multiple myeloma cells. Thus, MLN4924 synergizes with standard-of-care drugs to unlock a nucleolar death effector network across cancer types implying broad therapeutic relevance.
Topics: Topotecan; Tumor Suppressor Protein p53; bcl-2-Associated X Protein; Cell Line, Tumor; Cyclopentanes; Ribosomal Proteins; Apoptosis; NEDD8 Protein
PubMed: 37552601
DOI: 10.1016/j.celrep.2023.112925 -
Gynecologic Oncology Apr 2023To determine whether a non‑platinum chemotherapy doublet improves overall survival (OS) among patients with recurrent/metastatic cervical carcinoma. (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
To determine whether a non‑platinum chemotherapy doublet improves overall survival (OS) among patients with recurrent/metastatic cervical carcinoma.
METHODS
Gynecologic Oncology Group protocol 240 is a phase 3, randomized, open-label, clinical trial that studied the efficacy of paclitaxel 175 mg/m plus topotecan 0.75 mg/m days 1-3 (n = 223) vs cisplatin 50 mg/m plus paclitaxel 135 or 175 mg/m (n = 229), in 452 patients with recurrent/metastatic cervical cancer. Each chemotherapy doublet was also studied with and without bevacizumab (15 mg/kg). Cycles were repeated every 21 days until progression, unacceptable toxicity, or complete response. The primary endpoints were OS and the frequency and severity of adverse effects. We report the final analysis of OS.
RESULTS
At the protocol-specified final analysis, median OS was 16.3 (cisplatin-paclitaxel backbone) and 13.8 months (topotecan-paclitaxel backbone) (HR 1.12; 95% CI, 0.91-1.38; p = 0.28). Median OS for cisplatin-paclitaxel and topotecan-paclitaxel was 15 vs 12 months, respectively (HR 1.10; 95% CI,0.82-1.48; p = 0.52), and for cisplatin-paclitaxel-bevacizumab and topotecan-paclitaxel-bevacizumab was 17.5 vs 16.2 months, respectively (HR 1.16; 95% CI, 0.86-1.56; p = 0.34). Among the 75% of patients in the study population previously exposed to platinum, median OS was 14.6 (cisplatin-paclitaxel backbone) vs 12.9 months (topotecan-paclitaxel backbone), respectively (HR 1.09; 95% CI, 0.86-1.38;p = 0.48). Post-progression survival was 7.9 (cisplatin-paclitaxel backbone) vs 8.1 months (topotecan-paclitaxel backbone) (HR 0.95; 95% CI, 0.75-1.19). Grade 4 hematologic toxicity was similar between chemotherapy backbones.
CONCLUSIONS
Topotecan plus paclitaxel does not confer a survival benefit to women with recurrent/metastatic cervical cancer, even among platinum-exposed patients. Topotecan-paclitaxel should not be routinely recommended in this population. NCT00803062.
Topics: Survival Analysis; Topotecan; Paclitaxel; Uterine Cervical Neoplasms; Humans; Female; Cisplatin; Bevacizumab; Young Adult; Adult; Middle Aged; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols
PubMed: 36898292
DOI: 10.1016/j.ygyno.2023.01.010 -
The Cochrane Database of Systematic... Apr 2008Chemotherapeutic agents such as topotecan can be used to treat ovarian cancer. The effects of using topotecan as a therapeutic agent have not been previously been... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Chemotherapeutic agents such as topotecan can be used to treat ovarian cancer. The effects of using topotecan as a therapeutic agent have not been previously been systematically reviewed.
OBJECTIVES
To systematically evaluate the effectiveness and safety of topotecan for the treatment of ovarian cancer.
SEARCH STRATEGY
We searched the Cochrane Central Register of Controlled Trials (CENTRAL), (Issue 4, 2006); Cochrane Gynaecological Cancer Review Group (CGCRG) Specialised Register (Cochrane Library Issue 4, 2006); MEDLINE (January 1990 to 27 July 2006); EMBASE (January 1990 to 27 July 2006); The European Organization for the Research and Treatment of Cancer (EORTC) database (to 1 August 2006); CBM (Chinese Biomedical Database) (January 1990 to 27 July 2006).
SELECTION CRITERIA
Randomised controlled trials (RCTs) which randomized patients with ovarian cancer to single or combined use of topotecan versus interventions without topotecan, or different remedies of topotecan.
DATA COLLECTION AND ANALYSIS
Two review authors independently extracted and analysed data.
MAIN RESULTS
Six studies including 1323 participants were eligible for this review (Gordon 2004a; Gore 2001a; Gore 2002; Hoskins 1998; Huinink 2004; Placido 2004) All studies, as reported, were identified as being of poor methodological quality. Topotecan had comparable effectiveness to prolong progression-free survival (PFS) compared with pegylated liposomal doxorubicin (PLD), (16.1 weeks versus 17.0 weeks; p = 0.095). Overall survival (OS) time was similar in participants using PLD compared with topotecan (56.7 weeks versus 60 weeks; p = 0.341). Topotecan was more hematologically toxic compared with paclitaxel or PLD, relative risks (RRs) of hematological events: ranged from 1.03 to 14.46 and 1.73 to 27.12 respectively. A 21-day cycle of topotecan was more toxic than a 42-day cycle (RRs of hematological and non-hematological events ranged from 1.03 to 8). Intravenous and oral topotecan had comparable toxicity. Topotecan delayed progression more effectively compared with paclitaxel (23.1 weeks versus 14 weeks, p = 0.0021). Participants were more likely to respond to topotecan on a 21-day cycle as opposed to a 42-day cycle (RR 7.23, 95% CI 0.94 to 55.36). Small tumor diameter, sensitivity to platinum-based chemotherapy was associated with better prognosis. Small sample size, methodological flaws and poor reporting of the included trials made measurement bias of the trials difficult to assess.
AUTHORS' CONCLUSIONS
Topotecan appears to have a similar level of effectiveness as paclitaxel and PLD, though with different patterns of side effects. Larger, well-designed RCTs are required in order to define an optimal regime.
Topics: Antineoplastic Agents; Doxorubicin; Female; Humans; Ovarian Neoplasms; Paclitaxel; Polyethylene Glycols; Randomized Controlled Trials as Topic; Topotecan
PubMed: 18425923
DOI: 10.1002/14651858.CD005589.pub2