I read with great interest the paper by Michael Brave and colleagues from the US Food and Drug Administration (FDA). The authors describe the FDA's review supporting this first approval of a chemotherapeutic drug for advanced cervical cancer. This decision was made after a Gynecologic Oncology Group trial (GOG-0179) conducted at 94 American study centers demonstrated a survival benefit in patients with stage IVB, recurrent, or persistent carcinoma of the cervix who received cisplatin(Drug information on cisplatin) plus topotecan(Drug information on topotecan) (Hycamtin) compared with those who received cisplatin alone.
The article describes the study design, efficacy, and safety of GOG-0179, and briefly addresses cisplatin-topotecan interactions and considerations for special populations such as elderly or nonwhite patients. However, it fails to mention other similar randomized phase III trials conducted by the GOG. Although GOG-0179 was the only trial to demonstrate a survival benefit, the inferior survival with cisplatin monotherapy should be confirmed, and further studies are required to determine which regimen should be the first-line treatment for advanced cervical cancer. In addition, the study did not answer the question of whether combination therapy was better than sequential single-agent therapy in this cohort of patients.
In 2006, an estimated 9,710 new cases of cervical cancer will be diagnosed and 3,700 patients will die of the disease in the United States. After careful clinical evaluation and staging, a majority of early-stage cervical cancer can be cured by surgical resection and/or radiation. When patients present with stage IVB, recurrent, or persistent cervical cancer, the prognosis is very poor, with a median survival of 7 to 10 months and a 1-year survival rate of less than 20% in cases not amenable to curative surgery and/or radiation. Chemotherapy has a limited role in prolonging survival or improving quality of life in this cohort of patients. Among available agents, cisplatin is regarded as the cornerstone of chemotherapy for cervical cancer. Promising chemotherapeutic combinations have been studied in multiple clinical trials that showed clinical benefit but no survival advantage until GOG-0179.
The GOG has completed five randomized phase III trials (GOG-0077, 0110, 0149, 0169, and 0179) in this patient population and is currently conducting a four-armed trial (GOG-0204). GOG-0077 compared carboplatin(Drug information on carboplatin) with iproplatin decades ago. Both arms showed inferior response, progression-free survival (PFS), and overall survival (OS) compared to historical controls treated with cisplatin. GOG-0110 was the first trial comparing combinations of either cisplatin plus mitolactol or cisplatin plus ifosfamide(Drug information on ifosfamide) with cisplatin monotherapy. Despite higher response rates and greater PFS with a regimen of cisplatin plus ifosfamide, there was no significant difference in OS among the three groups. Subsequently, GOG-0149 demonstrated no benefit to adding bleomycin(Drug information on bleomycin) to the cisplatin-plus-ifosfamide regimen.
Recently, the GOG published two randomized phase III trials. Both trials demonstrated higher response rates and greater PFS for the combination regimens compared with cisplatin alone, similar to GOG-0110. However, in contrast to cisplatin plus paclitaxel(Drug information on paclitaxel) in GOG-0169, cisplatin plus topotecan in GOG-0179 produced a survival benefit. This finding led to the first regular approval by the FDA on June 14, 2006, for the treatment of women with stage IVB, recurrent, or persistent carcinoma of the cervix.
The reason this FDA-approval trial (GOG-0179) showed an inferior OS in the control arm (6.5 months in GOG-0179 vs 8.0 months in GOG-0110 and 8.8 months in GOG-0169) was not clear, since these trials involved use of the same regimen (cisplatin, 50 mg/m2 once every 3 weeks) in the same cohort of patients by the same group of investigators. There is no doubt that the inferior OS in the control arm in GOG-0179 led to a statistically significant survival benefit by use of cisplatin plus topotecan. Therefore, a confirmatory trial should be conducted before we conclude that cisplatin plus topotecan is a superior regimen. Similar survivals were observed among all experimental arms of the GOG studies—9.4 months in GOG-0179 vs 8.3 months in GOG-0110 and 9.7 months in GOG-0169.
Criteria for Drug Approval
It seems that the FDA tried its best to use a survival benefit as the gold standard for granting regular approval of a cancer treatment regimen, and I absolutely agree with this approach. But this is not enough, since therapeutic trials rarely use a placebo for their control arm. If the FDA insists on a survival benefit as the only standard by which to grant drug approval, and GOG-0204 demonstrates similar OS among all four chemotherapeutic regimens, this will create quite a dilemma. When numerous therapeutic options display equivalent clinical benefit without a placebo control arm, the gold standard for drug approval becomes complicated.