Trial Information

Randomized Phase III Clinical Trial of Weekly Versus Tri-weekly Cisplatin Based Chemoradiation in Locally Advanced Cervical Cancer

Cervical carcinoma is one of the most common gynecologic cancers worldwide. The prognosis of
cervical cancer is favorable, with around 80-90% 5-year survival rate in early stage
disease. However, advanced disease carries a poor prognosis. Current standard treatment for
locally advanced cervical cancer, which is not eligible for surgical treatment, is
cisplatin-based concurrent chemoradiation (CRT). Based on the results of five randomized
clinical trials, which consistently showed improved survival in patients treated with
cisplatin-based CRT, the National Cancer Institute (NCI) of the United States announced that
'Strong consideration should be given to the incorporation of concurrent cisplatin-based
chemotherapy with RT in women who require radiation therapy for treatment of cervical
cancer' in 1999.

Although recently reported meta-analysis studies also demonstrated improved local control
rates and survival with cisplatin-based chemotherapy concurrent to radiation therapy (RT),
the optimal cisplatin dose and dosing schedule are still undetermined. Among the previous
five randomized clinical trials, two trials performed by the Gynecologic Oncology Group
(GOG) used weekly cisplatin 40 mg/m2 while the other three trials used tri-weekly cisplatin
at a dosage range of 50 mg/m2 to 75 mg/m2 combined with 5-fluorouracil (5-FU). Despite the
diversity in cisplatin dose and dosing schedules, weekly cisplatin at a dose of 40 mg/m2
concurrent to RT is widely accepted as the standard regimen of CRT because of its
convenience, equal effectiveness, and favorable toxicity in comparison to other 5-FU
combined regimens.

However, as a result of the GOG 165 study, which was closed prematurely because an interim
analysis found that patients in the 5-FU treatment group were not likely to achieve a better
outcome, the role of 5-FU (previously popularly included in clinical trials) as a
radiosensitizer became subject to debate. Furthermore, a clinical trial performed by the NCI
in Canada comparing pelvic RT alone with weekly cisplatin 40 mg/m2 concurrent to RT failed
to show improvement of progression free and 5-year survival. While the authors suggested
several possible reasons for why their study failed to demonstrate a survival benefit with
concurrent weekly cisplatin 40 mg/m2 chemotherapy, other investigators have tried to find
another optimal dose and dosing schedule for cisplatin administration.

In light of the results of the previous clinical trial that indicated 5-FU may not be an
active radiosensitizer, weekly cisplatin 40 mg/m2 and tri-weekly cisplatin 75 mg/m2 remain
the most popular cisplatin doses and dosing schedules. However, despite the possible
advantages of tri-weekly cisplatin 75 mg/m2, which offer an increased peak concentration of
cisplatin and cisplatin administration during brachytherapy, no clinical trials thus far
have directly compared weekly and tri-weekly cisplatin-based chemotherapy concurrent to RT.

Recently the investigators reported a randomized phase II trial to compare the compliance to
and toxicity of weekly cisplatin 40 mg/m2 and tri-weekly cisplatin 75 mg/m2 administration
concurrent to RT. The study showed that tri-weekly cisplatin 75 mg/m2 concurrent to RT is
feasible and increase 5-year survival rate significantly compared to weekly cisplatin 40
mg/m2 in patients with locally advanced cervical cancer (66.5% in the weekly arm, 88.7% in
the tri-weekly arm; HR=0.375, 95% CI: 0.154-0.914, p= .03).

Therefore, in this randomized phase III trial, The investigators intend to confirm the
survival difference between weekly cisplatin 40 mg/m2 and tri-weekly cisplatin 75 mg/m2
administration concurrent to RT in this patient population.