Purpose: Topotecan, a camptothecin analog previously approved for the treatment of ovarian cancer and small-cell lung cancer, was granted regular approval by the US Food and Drug Administration (FDA) on June 14, 2006, for use in combination with cisplatin to treat women with stage IVB, recurrent, or persistent carcinoma of the cervix not amenable to curative treatment with surgery and/or radiation therapy. The purpose of this summary is to review the database supporting this approval.
Experimental Design: In a randomized multicenter study enrolling 293 eligible patients, topotecan plus cisplatin (TC) was compared with cisplatin monotherapy. The TC regimen consisted of cisplatin 50 mg/m2 IV over 1 hour on day 1 and topotecan 0.75 mg/m2 IV over 30 minutes on days 1, 2, and 3 every 21 days.
Results: There was a clinically relevant and statistically significant improvement in overall survival in the TC treatment arm. Median overall survival was 9.4 months (95% confidence interval [CI]:7.9-11.9) in the TC arm, compared to 6.5 months (95% CI:5.8-8.8) with cisplatin alone. The unadjusted hazard ratio for overall survival between treatment arms was 0.76 (95% CI: 0.59-0.98, P = .033) favoring the combination arm. The most common toxicities with TC included myelosuppression, nausea and vomiting, mucositis, rash, and hepatotoxicity.
Conclusions: This report describes the FDA's review supporting this first approval of a chemotherapeutic drug for advanced cervical cancer based on demonstration of a survival benefit.
Topotecan (Hycamtin) is an antineoplastic agent that acts by inhibiting the activity of topoisomerase I, a cellular enzyme that relieves torsional strain in DNA by inducing reversible single-strand breaks. Topotecan binds to the enzyme-DNA complex and prevents religation of these single-strand breaks. Its cytotoxicity is thought to be due to the accumulation of double-strand DNA damage, which mammalian cells cannot efficiently repair.
Topotecan has been previously approved by the US Food and Drug Administration (FDA) for patients with metastatic carcinoma of the ovary after failure of initial or subsequent chemotherapy and for the treatment of sensitive small-cell lung cancer after failure of first-line chemotherapy.
Stage IVB, recurrent, or persistent carcinoma of the cervix not amenable to curative treatment with surgery and/or radiation therapy is associated with an estimated median survival of 7 to 10 months.[1-3] No single agent or combination regimen has previously shown a survival benefit in this setting, and no chemotherapeutic drug or drug combinations have been approved by the FDA for this patient population.
Cisplatin appears to be the most active single-agent chemotherapy regimen for this indication, based on response rates of 21% to 31%. Combination chemotherapy regimens generally produce higher response rates and longer progression-free survival (PFS) than cisplatin monotherapy in this population. However, toxicity is greater with no statistically significant improvement in overall survival.[5-16]
Topotecan has been evaluated using a daily × 5 schedule, either every 3 weeks or every 4 weeks, in single-arm studies for patients with cervical cancer that was refractory to or had relapsed following cisplatin-based chemotherapy. Objective overall response rates of 12% to 19% have been noted.[17-19]
GOG-0179 was a Gynecologic Oncology Group (GOG)-sponsored study conducted at 94 study centers in the United States. It was designed to compare topotecan plus cisplatin (TC) with a control arm of cisplatin monotherapy. The design and findings of this study are outlined below.
The main protocol-specified inclusion criteria included histologically or cytologically confirmed International Federation of Gynecology and Obstetrics stage IVB, recurrent, or persistent squamous cell, adenosquamous, or adenocarcinoma of the cervix not amenable to curative treatment with surgery and/or radiotherapy, measurable disease by physical examination or imaging, GOG performance status 0-2, and adequate bone marrow, renal, and hepatic function. Except for use as radiosensitization, prior chemotherapy was not allowed. Patients with bilateral hydronephrosis not amenable to decompression or with known brain or leptomeningeal involvement were excluded.
Objectives and Statistical Plan
The primary efficacy endpoint was overall survival, defined as time from randomization to the date of death from any cause. The final efficacy analysis was planned to be conducted after a total of 111 deaths were observed in the cisplatin monotherapy group. The study cutoff date for the primary analysis was October 31, 2003, the date on which the sponsor received notification of the 129th event. All patients known to be alive at the cutoff date were censored either on the date of last assessment or on the cutoff date if the last contact had taken place subsequently. In order to account for one early interim analysis for futility, the nominal two-sided significance level for the final analysis was set at 0.044. The unstratified log-rank test was prospectively selected as the primary means of determining whether TC increased overall survival compared with cisplatin monotherapy.
Patients were randomized in a 1:1 ratio to receive either TC or cisplatin monotherapy. Patients randomized to TC received topotecan 0.75 mg/m2 intravenously over 30 minutes on days 1, 2, and 3, after hydration and premedication with granisetron (Kytril) and dexamethasone, followed by cisplatin 50 mg/m2 in 500 mL 3% saline intravenously over 1 hour on day 1. Patients randomized to cisplatin received 50 mg/m2 in 500 mL 3% saline intravenously over 1 hour on day 1.
A third treatment arm consisting of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) was closed after 64 patients had been enrolled due to excess toxic deaths. Data from patients enrolled to that arm were not submitted with this application.
Patients in each arm were to continue treatment for six cycles or until disease progression or unacceptable toxicity. Patients in either group with objective responses and acceptable toxicity were permitted to continue their assigned treatment beyond six cycles after discussion with the study chair.
Patient Population/ Demographics
A total of 300 patients (150 per arm) were randomized to receive TC vs cisplatin monotherapy. The primary efficacy analysis was conducted on a modified intent-to-treat population (n = 293), consisting of all of the randomized patients with the exception of seven who were subsequently found not to meet major criteria for enrollment. The safety database consisted of 284 patients who received at least one dose of study drug (140 of whom received TC).
Median patient ages were 46 and 48 years in the TC and cisplatin arms, respectively. In each treatment arm, over 70% of patients were white and almost half were GOG performance status 0.
Baseline disease characteristics and prior therapy of the study population are listed in Table 1 and are evenly distributed across treatment groups.
>br />Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
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