Topotecan Weekly Versus Conventional 5-Day Schedule in Patients With Platinum-Resistant Ovarian Cancer: A Randomized Multicenter Phase II Trial of the North-Eastern German Society of Gynecological Oncology Ovarian Cancer Study Group

Sehouli, Jalid; Stengel, Dirk; Harter, Philipp; Kurzeder, Christian; Belau, A.; Bogenrieder, Thomas; Markmann, S.; Mahner, Sven; Mueller, Lothar; Lorenz, Ralf; Nugent, A.; Wilke, Jochen; Kuznik, Andreas; Doering, Gabriele; Wischnik, A.; Sommer, H.; Meerpohl, Hans-Gerd; Schroeder, W.; Lichtenegger, W.; Oskay-Oezcelik, G.

doi:10.1200/jco.2009.27.8911

Cited by 93 publications

(64 citation statements)

References 30 publications

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“…Topotecan, typically given weekly, seemed less active than weekly paclitaxel, with intermediate results for PLD. This observation is aligned with data suggesting suboptimal efficacy of weekly topotecan, 3 whereas weekly paclitaxel induces high ORRs but disappointing PFS. [4][5][6] However, median OS with chemotherapy alone was similar between cohorts and consistent with historical data.…”

Section: Journal Of Clinical Oncology C O R R E S P O N D E N C Esupporting

confidence: 65%

Bevacizumab Combined With Weekly Paclitaxel, Pegylated Liposomal Doxorubicin, or Topotecan in Platinum-Resistant Recurrent Ovarian Cancer: Analysis by Chemotherapy Cohort of the Randomized Phase III AURELIA Trial

Poveda

Selle

Hilpert

et al. 2015

JCO

190

112

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Section: Journal Of Clinical Oncology C O R R E S P O N D E N C Esupporting

confidence: 65%

Bevacizumab Combined With Weekly Paclitaxel, Pegylated Liposomal Doxorubicin, or Topotecan in Platinum-Resistant Recurrent Ovarian Cancer: Analysis by Chemotherapy Cohort of the Randomized Phase III AURELIA Trial

Poveda

Selle

Hilpert

et al. 2015

JCO

190

112

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“…Topotecan has also been evaluated in randomised controlled trials (RCTs) at an i.v. dose of 4.0 mg/m 2 weekly, 23 and as an oral treatment (dose of 2.3 mg/m 2 /day). 24 A dose for oral administration of topotecan has not been recommended for ovarian cancer.…”

Section: Topotecanmentioning

confidence: 99%

“…For example, based on CA125 level alone, a patient could be categorised as PPS at baseline but as FPS 4 months later with radiological confirmation. Of the trials identified, seven RCTs 23,28,29,31,48,62,68 reported that patients with only CA125 level as an indicator of recurrent disease were enrolled. In trials in patients with platinum-sensitive disease, there was considerable variation across the trials in the proportion of patients with non-measurable disease at baseline, ranging from 8.5% to 38.2%.…”

Section: Comparability Of Baseline Characteristicsmentioning

confidence: 99%

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Topotecan, pegylated liposomal doxorubicin hydrochloride, paclitaxel, trabectedin and gemcitabine for advanced recurrent or refractory ovarian cancer: a systematic review and economic evaluation

Edwards¹,

Barton²,

Thurgar³

et al. 2015

Health Technology Assessment

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BackgroundOvarian cancer is the fifth most common cancer in the UK, and the fourth most common cause of cancer death. Of those people successfully treated with first-line chemotherapy, 55–75% will relapse within 2 years. At this time, it is uncertain which chemotherapy regimen is more clinically effective and cost-effective for the treatment of recurrent, advanced ovarian cancer.ObjectivesTo determine the comparative clinical effectiveness and cost-effectiveness of topotecan (Hycamtin®, GlaxoSmithKline), pegylated liposomal doxorubicin hydrochloride (PLDH; Caelyx®, Schering-Plough), paclitaxel (Taxol®, Bristol-Myers Squibb), trabectedin (Yondelis®, PharmaMar) and gemcitabine (Gemzar®, Eli Lilly and Company) for the treatment of advanced, recurrent ovarian cancer.Data sourcesElectronic databases (MEDLINE®, EMBASE, Cochrane Central Register of Controlled Trials, Health Technology Assessment database, NHS Economic Evaluations Database) and trial registries were searched, and company submissions were reviewed. Databases were searched from inception to May 2013.MethodsA systematic review of the clinical and economic literature was carried out following standard methodological principles. Double-blind, randomised, placebo-controlled trials, evaluating topotecan, PLDH, paclitaxel, trabectedin and gemcitabine, and economic evaluations were included. A network meta-analysis (NMA) was carried out. A de novo economic model was developed.ResultsFor most outcomes measuring clinical response, two networks were constructed: one evaluating platinum-based regimens and one evaluating non-platinum-based regimens. In people with platinum-sensitive disease, NMA found statistically significant benefits for PLDH plus platinum, and paclitaxel plus platinum for overall survival (OS) compared with platinum monotherapy. PLDH plus platinum significantly prolonged progression-free survival (PFS) compared with paclitaxel plus platinum. Of the non-platinum-based treatments, PLDH monotherapy and trabectedin plus PLDH were found to significantly increase OS, but not PFS, compared with topotecan monotherapy. In people with platinum-resistant/-refractory (PRR) disease, NMA found no statistically significant differences for any treatment compared with alternative regimens in OS and PFS. Economic modelling indicated that, for people with platinum-sensitive disease and receiving platinum-based therapy, the estimated probabilistic incremental cost-effectiveness ratio [ICER; incremental cost per additional quality-adjusted life-year (QALY)] for paclitaxel plus platinum compared with platinum was £24,539. Gemcitabine plus carboplatin was extendedly dominated, and PLDH plus platinum was strictly dominated. For people with platinum-sensitive disease and receiving non-platinum-based therapy, the probabilistic ICERs associated with PLDH compared with paclitaxel, and trabectedin plus PLDH compared with PLDH, were estimated to be £25,931 and £81,353, respectively. Topotecan was strictly dominated. For people with PRR disease, the probabilistic ICER associated with topotecan compared with PLDH was estimated to be £324,188. Paclitaxel was strictly dominated.LimitationsAs platinum- and non-platinum-based treatments were evaluated separately, the comparative clinical effectiveness and cost-effectiveness of these regimens is uncertain in patients with platinum-sensitive disease.ConclusionsFor platinum-sensitive disease, it was not possible to compare the clinical effectiveness and cost-effectiveness of platinum-based therapies with non-platinum-based therapies. For people with platinum-sensitive disease and treated with platinum-based therapies, paclitaxel plus platinum could be considered cost-effective compared with platinum at a threshold of £30,000 per additional QALY. For people with platinum-sensitive disease and treated with non-platinum-based therapies, it is unclear whether PLDH would be considered cost-effective compared with paclitaxel at a threshold of £30,000 per additional QALY; trabectedin plus PLDH is unlikely to be considered cost-effective compared with PLDH. For patients with PRR disease, it is unlikely that topotecan would be considered cost-effective compared with PLDH. Randomised controlled trials comparing platinum with non-platinum-based treatments might help to verify the comparative effectiveness of these regimens.Study registrationThis study is registered as PROSPERO CRD42013003555.FundingThe National Institute for Health Research Health Technology Assessment programme.

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“…However, reduced dosing is widely used in standard clinical practice (e.g., 1.25 mg/m 2 ), which confers decreased toxicity and similar outcome [51]. In addition, similar effectiveness with significantly lower hematologic toxicity has been observed in several studies when topotecan is administered on a weekly schedule [52]. Based on this evidence, a conventional (1.25 mg/m 2 on days 1-5 of a 3 week schedule) and an alternative (4.0 mg/m 2 on days 1, 8 and 15 of a 4 week cycle) schedule of topotecan administration were selected for FORWARD I.…”

Section: Background and Rationalementioning

confidence: 85%

FORWARD I: A Phase III Study of Mirvetuximab Soravtansine Versus Chemotherapy in Platinum-Resistant Ovarian Cancer

Moore

Vergote²,

Oaknin

et al. 2018

Future Oncol.

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Mirvetuximab soravtansine, an antibody-drug conjugate that binds with high affinity to folate receptor-α to provide tumor-directed delivery of the potent microtubule-disrupting agent DM4, has emerged as a promising investigational agent for the treatment of ovarian cancer, particularly in the setting of platinum-resistant disease. Here we describe the rationale and design of FORWARD I (NCT02631876), the first randomized, multicenter Phase III study to compare the safety and efficacy of mirvetuximab soravtansine versus investigator's choice of chemotherapy in women with folate receptor-α-positive, platinumresistant epithelial ovarian, primary peritoneal or fallopian tube cancer. Patients will be randomized in a 2:1 ratio. The primary end point is progression-free survival, and key secondary objectives include comparison of overall response rates, overall survival and duration of response. Ovarian cancer is a leading cause of gynecologic cancer mortality worldwide, responsible for over 150,000 deaths each year [1]. Family history and the presence of penetrant mutations in genes such as BRCA1 and BRCA2 are significant risk factors for the development of ovarian cancer; epidemiological research has also identified a variety of hormonal and reproductive factors that can either increase (e.g., older age at menopause, hormone replacement therapy) or decrease (e.g., parity, lactation, oral contraceptive use) the likelihood of disease (reviewed in [2]). Epithelial ovarian cancer (EOC) accounts for approximately 95% of ovarian cancer malignancies [3,4]. EOC is highly chemosensitive, with the current standard-of-care treatment for newly diagnosed cases involving debulking surgery and adjuvant platinum-and taxane-based combination chemotherapy. Most individuals achieve remission with front-line therapy; unfortunately up to 80% of patients will relapse during or after treatment with eventual drug-resistant disease [5]. Disease recurring within 6 months of platinum-based chemotherapy is classified as platinum-resistant, whereas disease recurring >6 months after therapy is considered platinum sensitive. Patients with platinum-sensitive disease have a high likelihood of responding to additional platinum-based therapy; however, almost all will eventually develop acquired (secondary) platinum resistance [5,6] ovarian cancer typically receive single-agent chemotherapy at relapse. Outcomes for these patients remain poor, with low response rates to further chemotherapy (15-20%), progression-free survival (PFS) of 3-4 months [7][8][9], and a median overall survival rate of less than a year [5]. In addition, this treatment approach is associated with additional, cumulative toxicities and limited tolerability for patients. It has been suggested that natural compounds, such as phytochemicals, may alleviate chemotherapy-induced side effects and therefore may be useful as adjuvants to standard treatment [10]; however, this field remains in its infancy. These measures underscore a critical need for innovative and effective therapeutic stra...

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Topotecan Weekly Versus Conventional 5-Day Schedule in Patients With Platinum-Resistant Ovarian Cancer: A Randomized Multicenter Phase II Trial of the North-Eastern German Society of Gynecological Oncology Ovarian Cancer Study Group

Abstract: With regard to effectiveness in terms of response and PFS, Tc remains the standard of care in patients with platinum-resistant recurrent ovarian cancer. However, comparable OS rates and a favorable toxicity profile make Tw another viable treatment option in this setting.

Cited by 93 publications

References 30 publications

Bevacizumab Combined With Weekly Paclitaxel, Pegylated Liposomal Doxorubicin, or Topotecan in Platinum-Resistant Recurrent Ovarian Cancer: Analysis by Chemotherapy Cohort of the Randomized Phase III AURELIA Trial

Bevacizumab Combined With Weekly Paclitaxel, Pegylated Liposomal Doxorubicin, or Topotecan in Platinum-Resistant Recurrent Ovarian Cancer: Analysis by Chemotherapy Cohort of the Randomized Phase III AURELIA Trial

Topotecan, pegylated liposomal doxorubicin hydrochloride, paclitaxel, trabectedin and gemcitabine for advanced recurrent or refractory ovarian cancer: a systematic review and economic evaluation

FORWARD I: A Phase III Study of Mirvetuximab Soravtansine Versus Chemotherapy in Platinum-Resistant Ovarian Cancer

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