Randomized Comparison of Weekly Cisplatin or Protracted Venous Infusion of Fluorouracil in Combination with Pelvic Radiation in Advanced Cervix Cancer: A GOG study

Source:J Clin Oncol. 2005 Nov 20;23(33):8289-95
Authors: Lanciano R, Calkins A, Bundy BN, Parham G, Lucci JA 3rd, Moore DH, Monk BJ, O'Connor DM.

Background

• Concurrent chemoradiation is the standard of care in locally advanced cervical cancer.
• Locally advanced cervical cancer is defined by parametrial or pelvic wall invasion, the presence of hydronephrosis, or spread to regional nodes or adjacent organs.
• A previous randomized trial (Whitney et al., 1999) demonstrated superior local control (LC) and overall survival (OS) with the combination of 5-fluorouracil (FU) and cisplatin with radiation versus hydroxyurea with radiation.
• In addition, Rose et al. (1999) demonstrated improved OS and progression-free survival (PFS) with the combination of cisplatin and radiation versus hydroxyurea and radiation.
• However, patients treated with combined cisplatin/FU/hydroxyurea and radiation had much greater hematologic toxicity versus patients treated with cisplatin and radiation, without any significant improvement in OS or PFS.
• Although the previous studies demonstrated significant benefits with cisplatin, studies in rectal cancer have shown improved OS with protracted venous infusion FU (PVI FU), and a benefit was observed with FU in a subset analysis of early stage cervical cancer.
• This study was conducted to compare cisplatin concurrent with radiation versus PVI FU concurrent with radiation in patients with locally advanced cervical cancer.

Methods

• Patients with locally advanced cervical cancer were randomized to either: cisplatin, given weekly for 6 weeks at 40 mg/m 2 starting with day 1 of radiation, or PVI FU concurrent with radiation, given 5 days a week for 6 weeks at a dose of 225 mg/m 2 .
• Chemotherapy was held or reduced for toxicity.
• Radiation was delivered via combined external beam and intracavitary treatment (either high-dose rate or low-dose rate) to achieve a dose to point A of 85 Gy.
• The analysis was based on intent-to-treat.
• A one-sided test was used to determine whether radiation and PVI FU decreased the risk of disease progression when compared to radiation and cisplatin.
• A formal futility analysis was planned after 50 recurrences were observed to consider study closure should there be an excess rate of recurrence in the PVI FU group.

Results

• Initially, a third arm was planned with radiation alone, though this arm was closed in 1998 when results from Eifel et al. were available showing worse outcome with extended field radiation compared to combined cisplatin and radiation.
• An interim analysis was performed in July 2000, after 54 disease relapses and 4 deaths were reported.
• Due to a 35% increase in risk of progression in the PVI FU arm, the study was prematurely closed after accrual of only 316 patients (159 patients in the cisplatin arm and 157 patients in the PVI FU arm).
• Median follow-up of those patients still alive at time of analysis was 40.4 months.
• Cumulative toxicities were higher in the cisplatin arm, even after reversible hematologic toxicity was excluded.
• PFS at 4 years was not statistically different between the cisplatin and PVI FU groups (57% versus 50%, respectively).
• Survival at 4 years was not statistically significant between the two groups (64% in cisplatin group versus 55% in PVI FU group).
• Disease relapse was observed in the pelvis, lung, abdomen, and para-aortic lymph nodes. Patients in the PVI FU arm had more overall failures and more distant failures than patients in the cisplatin arm (29% versus 18%, respectively), although pelvic failures were similar between the two groups (16% in PVI FU arm versus 14% in cisplatin arm).

Discussion and Comments

• PVI FU concurrent with radiation is not superior to cisplatin with radiation for definitive treatment of locally advanced cervical cancer.

The authors investigated if PVI FU in combination with radiation therapy could be more efficacious than cisplatin in combination with radiation therapy in the treatment of locally advanced cervical cancer. However, previous studies had already demonstrated essentially equivalent outcomes with cisplatin and radiation versus a combination of cisplatin/FU/hydroxyurea and radiation. In analysis of the data, a one-sided test was used, the authors did not explicitly state why this was chosen. Regardless, within less than three years of its opening, the study was prematurely closed due to the finding of an increased risk of progression in the PVI FU arm. This study provided further evidence that weekly cisplatin concurrent with radiation therapy should continue to be the standard of care for locally advanced cervical cancer.