A phase II study of topotecan plus gemcitabine in the treatment of patients with relapsed ovarian cancer after failure of first-line chemotherapy

Sehouli, Jalid; Stengel, Dirk; Oskay, G.; Camara, O.; Hindenburg, Hans-Joachim; Klare, Peter; Blohmer, Jens-Uwe; Heinrich, Georg; Elling, Dirk; Ledwon, P.; Lichtenegger, W.

doi:10.1093/annonc/mdf294

Cited by 32 publications

(17 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Although single-agent topotecan is widely used for the treatment of relapsed ovarian cancer, combinations identified in this study may offer additional insights. The high degree of synergy that we reported previously for topotecan/ gemcitabine in ovarian cancer specimens (Su et al, 2001) is supported by the results of a phase II study, in which seven of 11 (64%) patients with relapsed ovarian cancer achieved objective responses with this combination (Sehouli et al, 2001). Topotecan combinations might also be investigated in diseases that are historically resistant to chemotherapy.…”

Section: Discussionsupporting

confidence: 75%

Ex vivo analysis of topotecan: advancing the application of laboratory-based clinical therapeutics

et al. 2003

View full text Add to dashboard Cite

Topotecan is currently approved for relapsed small-cell lung cancer and ovarian cancer. Topotecan's efficacy in the second-line setting and novel mechanism of action suggest broad antitumour activity. We utilised a clinically validated, cell-death, ex vivo assay in human tumour explants to examine the activity profile of topotecan alone and in combination with other antitumour agents. Serial dilutions of topotecan alone and in combination with other cytotoxic agents were applied to biopsy specimens of non-small-cell lung cancer (NSCLC) and breast, colon, and prostate cancers. Dose -response curves were interpolated to provide 50% lethal concentrations (LC 50 ). The degree of synergy (by median effect) and normalised Z-scores (raw scores converted to relative activity distributed around the mean) were then computed. Single-agent activity was observed for topotecan in all four tumour types. In 57 chemotherapy-naive specimens, NSCLC revealed the highest activity, demonstrated by the lowest LC 50 value (0.2670.06 mg ml À1 ; P ¼ 0.002). Overall, previously treated and chemotherapy-naive specimens revealed no significant differences in mean LC 50 's. Synergy was observed for several combinations, including topotecan plus cisplatin in prostate and for topotecan plus 5-fluorouracil in breast cancers. The Z-score analyses conducted suggest activity for previously unexplored drug regimens, including topotecan plus 5-fluorouracil, vinorelbine, and mitomycin-C in NSCLC and breast cancer. Phase II studies are underway to determine the degree to which these ex vivo findings will translate into improved clinical results. Topotecan, a semisynthetic, water-soluble derivative of camptothecin, is an inhibitor of topoisomerase I (Kingsbury et al, 1991). This derivative is more stable, has increased solubility, a shorter half-life, and decreased toxicity compared with its parent compound (Verweij et al, 1993;Burke and Mi, 1994;Rothenberg, 1997). Topoisomerase I is a nuclear enzyme that relieves torsional strain on supercoiled DNA and creates single-strand breaks during DNA replication. Topotecan prevents topoisomerase I from repairing the cleaved DNA, which results in double-stranded DNA breaks and eventually apoptosis. The unique mechanism of action of topotecan and lack of clinical crossresistance with other antineoplastic compounds suggest that topotecan has the potential for broad antitumour activity.The activity of topotecan has been demonstrated in several open-label, randomised phase II and III trials. Currently, topotecan is approved for the treatment of relapsed small-cell lung cancer (SCLC) (Eckardt et

show abstract

Section: Discussionsupporting

confidence: 75%

Ex vivo analysis of topotecan: advancing the application of laboratory-based clinical therapeutics

et al. 2003

View full text Add to dashboard Cite

show abstract

“…The drug has synergistic activity with platinum by forming platinum-DNA adduct which inhibits ribonucleotide reductase. Several clinical studies have demonstrated high efficacy of the combined drugs: RRs of 16-70% with cisplatin (Nagourney et al, 2003;Rose et al, 2003;Brewer et al, 2006;Bozas et al, 2007), 40% with paclitaxel (Garcia et al, 2004;Poole et al, 2006), 13-64% with topotecan (Greggi et al, 2001;Sehouli et al, 2002), or 34% with PLD (Ferrandina et al, 2005). Our study could not demonstrate any RR by a combination regimen in platinum-resistant patients except one patient who could achieve SD.…”

Section: Discussioncontrasting

confidence: 52%

“…Third was the regimen of gemcitabine. Some studies found RRs of 6-29% from single agent (Shapiro et al, 1996;Friedlander et al, 1998;D'Agostino et al, 2003;Markman et al, 2003;Mutch et al, 2007;Ferrandina et al, 2008;Watanabe et al, 2008;Suprasert et al, 2012;Yoshino et al, 2012) while others could demonstrate RRs of 13-70% from gemcitabine in combination with platinum or other agents (Greggi et al, 2001;Sehouli et al, 2002;Nagourney et al, 2003;Rose et al, 2003;Garcia et al, 2004;Papadimitriou et al, 2004;Ferrandina et al, 2005;Brewer et al, 2006;Pfisterer et al, 2006;Poole et al, 2006;Bozas et al, 2007). Another reason which might be under-recognized was the setting when gemcitabine was used or numbers of prior chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

“…Gemcitabine was also tested with other drugs as a combination regimen e.g. cisplatin (Nagourney et al, 2003;Rose et al, 2003;Brewer et al, 2006;Bozas et al, 2007) or carboplatin (Papadimitriou et al, 2004;Pfisterer et al, 2006), PLD (Ferrandina et al, 2005), paclitaxel (Garcia et al, 2004;Poole et al, 2006), topotecan (Greggi et al, 2001;Sehouli et al, 2002), producing high RRs of 13-70% (Greggi et al, 2001;Sehouli et al, 2002;Nagourney et al, 2003;Rose et al, 2003;Garcia et al, 2004;Papadimitriou et al, 2004;Ferrandina et al, 2005;Brewer et al, 2006;Pfisterer et al, 2006;Poole et al, 2006;Bozas et al, 2007).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Treatment Outcomes of Gemcitabine in Refractory or Recurrent Epithelial Ovarian Cancer Patients

Chanpanitkitchot

Tangjitgamol²,

Khunnarong³

et al. 2014

Asian Pacific Journal of Cancer Prevention

View full text Add to dashboard Cite

Background: To study the response rate (RR), progression-free survival (PFS) and toxicity profiles of recurrent epithelial ovarian cancer (EOC) patients treated with gemcitabine. Materials and Methods: Recurrent EOC patients who were treated with gemcitabine between January 2000 and December 2013 at the Department of Obstetrics and Gynecology, Faculty of Medicine Vajira Hospital were identified and medical records were reviewed. Clinico-pathological features including data of gemcitabine treatment, response and toxicity were collected. Results: We identified 43 EOC patients who had gemcitabine treatment. All except one patient who did not receive any adjuvant treatment, had received platinum-based chemotherapy. Among these 42 patients, 31.0% had refractory cancer to first-line chemotherapy while 69.0% had recurrence with 48.8% being platinumsensitive. The total cycles of gemcitabine used were 203 (median 4, range 2-9 cycles). Overall RR was 11.6%: 19% in platinum-sensitive vs 4.5% in platinum-resistant groups (p=0.158) and 42.9% in the patients having gemcitabine together with platinum vs 5.6% using gemcitabine alone (P=0.024). Median PFS was 3.6 months (95% confidence interval [CI], 2.73-4.49 months): 8.1 months (95% CI, 2.73-4.49 months) in combination regimen vs 3.2 months (95% CI, 2.01-4.42 months) in single regimen (p=0.077) and 8.1 months (95% CI, 4.73-11.48 months) with the gemcitabine combination vs 2.7 months (95% CI, 1.98-3.38 months) by single gemcitabine in platinum sensitive patients (P=0.007). Common toxicities were hematologic which were well tolerated and manageable. Conclusions: Gemcitabine has modest activity in pre-treated EOC. A combination regimen had higher activity than single agent in platinum sensitive patients with a significant improvement in RR and PFS.

show abstract

“…Recent data have suggested that gemcitabine may have a possible role in overcoming platinum resistance by its inhibition of excision repair enzymes (84). The results of smaller phase II trials also suggest that either liposomal doxorubicin or topotecan administered in conjunction with gemcitabine improves tumor response rates compared with historical results observed with single agents (85,86). Gemcitabine is non-cross-resistant to other agents, is generally well tolerated, has an absence of cumulative toxicity, and is convenient.…”

Section: Gemcitabinementioning

confidence: 99%

Recurrent Ovarian Cancer

Herzog

2004

Clinical Cancer Research

137

View full text Add to dashboard Cite

Ovarian cancer is increasingly recognized as a chronic disease whose treatment is often characterized by administration of multiple, sequential active agents, each of which may or may not be accompanied by a tumor response. Despite the large proportion of patients who relapse and undergo longer-term treatment, the question of optimal treatment duration has not been fully addressed to date. For patients who progress on therapy, the answer is straightforward: they are switched to another active agent, presumably having a different mechanism of action from previous therapies with, ideally, limited overlapping toxicities. However, for patients who remain in partial response or who have stable disease, the answer is less apparent and less clear. The majority of oncologists believe that treatment beyond 6 cycles of a given therapy does not provide any additional benefit to patients. There are some data to support that treatment strategy. However, with the advent of new, less toxic agents, treatment to progression should be further explored. Agents that are potentially well suited for extended treatment intervals may include such properties as absence of cumulative toxicity, non-cross-resistance, positive benefit on quality of life, and convenient schedule. A number of active agents in ovarian cancer (platinum, paclitaxel, topotecan, liposomal doxorubicin, docetaxel, gemcitabine, and etoposide) will be reviewed in the context of what is known about cumulative toxicity, potential adverse effects on patients' quality of life, and evidence addressing the potential benefits of longer-term treatment.

show abstract

A phase II study of topotecan plus gemcitabine in the treatment of patients with relapsed ovarian cancer after failure of first-line chemotherapy

Abstract: Topotecan combined with gemcitabine has a favourable toxicity profile and encouraging efficacy in patients with recurrent ovarian cancer.

Cited by 32 publications

References 17 publications

Ex vivo analysis of topotecan: advancing the application of laboratory-based clinical therapeutics

Ex vivo analysis of topotecan: advancing the application of laboratory-based clinical therapeutics

Treatment Outcomes of Gemcitabine in Refractory or Recurrent Epithelial Ovarian Cancer Patients

Recurrent Ovarian Cancer

Contact Info

Product

Resources

About