Update to topotecan for the treatment of advanced cervical cancer

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Update to topotecan for the treatment of advanced cervical cancer

Original article by: Yuet Wan

Source: London Cancer New Drugs Group

Date published: 09/09/2009 00:00

Summary

by: Yuet Wan

Single agent cisplatin is the current standard treatment for recurrent cervical cancer, resulting in response rates (RR) of 20 to 30% and overall survival (OS) of about 7 months. Numerous combination regimens have been tested in an attempt to improve outcomes.
Topotecan has been assessed in the Gynecologic Oncology Group (GOG) 0179 phase III trial (n= 356), the first prospective trial to identify a chemotherapy regimen yielding a statistically significant survival advantage in patients with advanced or recurrent disease. Cisplatin 50mg/m2 every 3 weeks (CPT, n=146) was compared with cisplatin 50mg/m2 day 1 plus topotecan 0.75mg/m2 days 1 to 3 every 3 weeks (CT, n= 147), and methotrexate 30mg/ m2 days 1, 15 and 22, vinblastine 3mg/m2 days 2, 15 and 22, doxorubicin 30mg/m2 day 2 and cisplatin 70mg/m2 day 2 every 4 weeks (MVAC, n= 63). The treatments were administered for a maximum of 6 cycles or until disease progression or unacceptable toxicity. Survival was the primary endpoint of the study. The MVAC arm was closed after 4 treatment related deaths. According to the intention to treat (ITT) analysis, median survival was 6.5 months for CPT and 9.4 months for CT (unadjusted relative risk [RR] = 0.76; 95% CI, 0.593 – 0.979; p = 0.017). The RR was similar when adjusted for performance status, age and baseline disease status. Post hoc analyses suggest that patients who have received prior treatment with cisplatin may not respond as well and the added value of topotecan was also smaller for this group. Haematological toxicity occurred more frequently and was more severe in the CT arm: grade 3 and 4 neutropenia was reported in 70% receiving CT and 1.4% receiving CPT, febrile neutropenia in 17.7% on CT vs. 7.5% on CPT, grade 3 or 4 thrombocytopenia in 31.3% on CT vs. 3.4% on CPT. More infections were noted in the CT group because of the increased incidence of grade 3 or 4 adverse events. More cardiovascular adverse events were reported in patients on CT; grade 2 events in 12 on CT and 4 on CPT. There was no statistical evidence to indicate that quality of life and adverse effect scores in GOG 0179 changed differently over time across regimens, during the treatment period or up to 9 months after randomisation.
The GOG 0204 study (unpublished) comparing doublet therapy [cisplatin with either paclitaxel (PC, reference arm), vinorelbine or topotecan] in patients with stage IVB, recurrent or persistent disease, was closed before reaching accrual maturity on the basis that none of the treatment arms was predicted to provide significant advantage over PC by the end of the study.
Topotecan in combination with cisplatin is licensed for use in patients with carcinoma of the cervix recurrent after radiotherapy and for patients with Stage IVB disease. Patients with prior exposure to cisplatin require a sustained treatment free interval to justify treatment with the combination, therefore the license excludes patients with persistent disease, and this is a somewhat narrower population of patients than that which made up the ITT population of GOG 0179.
The cost of 6 cycles of CT (CPT 50mg/m2 day 1 and topotecan 0.75mg/m2 days 1- 3) is approximately £2000 vs. £290 for CPT in patient with average BSA 1.73m2.
The SMC and the AWMSG have accepted for restricted use topotecan in combination with cisplatin for cisplatin-naïve patients with either recurrent carcinoma of the cervix after radiotherapy or stage IVB disease.
According to preliminary recommendations from NICE in its Appraisal Consultation Document, topotecan in combination with cisplatin, within its licensed indication, is not recommended for the treatment of women with recurrent or stage IVB cervical cancer, as it did not represent a good use of NHS resources (only data from GOG-0179 was included in its clinical effectiveness review).