Impact of adjuvant chemotherapy and surgical staging in early-stage ovarian carcinoma: European Organisation for Research and Treatment of Cancer-Adjuvant ChemoTherapy in Ovarian Neoplasm trial.
BACKGROUND
All randomized trials of adjuvant chemotherapy for early-stage ovarian cancer have lacked the statistical power to show a difference in the effect on survival between adjuvant chemotherapy and no adjuvant chemotherapy. They have also not taken into account the adequacy of surgical staging. We performed a prospective unblinded, randomized phase III trial to test the efficacy of adjuvant chemotherapy in patients with early-stage ovarian cancer, with emphasis on the extent of surgical staging.


METHODS
Between November 1990 and January 2000, 448 patients from 40 centers in nine European countries were randomly assigned to either adjuvant platinum-based chemotherapy (n = 224) or observation (n = 224) following surgery. Endpoints were overall survival and recurrence-free survival, and the analysis was on an intention-to-treat basis. The Kaplan-Meier method was used to perform time-to-event analysis, and the log-rank test was used to compare differences between treatment arms. Statistical tests were two-sided.


RESULTS
After a median follow-up of 5.5 years, the difference in overall survival between the two trial arms was not statistically significant (hazard ratio [HR] = 0.69, 95% confidence interval [CI] = 0.44 to 1.08; P =.10). Recurrence-free survival, however, was statistically significantly improved in the adjuvant chemotherapy arm (HR = 0.63, 95% CI = 0.43 to 0.92; P =.02). Approximately one-third of patients (n = 151) had been optimally staged and two-thirds (n = 297) had not. Among patients in the observation arm, optimal staging was associated with a statistically significant improvement in overall and recurrence-free survival (HR = 2.31 [95% CI = 1.08 to 4.96]; P =.03 and HR = 1.82 [95% CI = 1.02 to 3.24] P =.04, respectively). No such association was observed in the chemotherapy arm. In the non-optimally staged patients, adjuvant chemotherapy was associated with statistically significant improvements in overall and recurrence-free survival (HR = 1.75 [95% CI = 1.04 to 2.95]; P =.03 and HR = 1.78 [95% CI = 1.15 to 2.77]; P =.009, respectively). In the optimally staged patients, no benefit of adjuvant chemotherapy was seen.


CONCLUSIONS
Adjuvant chemotherapy was associated with statistically significantly improved recurrence-free survival in patients with early-stage ovarian cancer. The benefit of adjuvant chemotherapy appeared to be limited to patients with non-optimal staging, i.e., patients with more risk of unappreciated residual disease.
Trimbos
J Baptist
JB
Leiden University Medical Center, Leiden, The Netherlands. J.B.M.Z.Trimbos@lumc.nl
Vergote
Ignace
I
Bolis
Giorgio
G
Vermorken
Jan B
JB
Mangioni
Constantino
C
Madronal
Caterina
C
Franchi
Massimo
M
Tateo
Saverio
S
Zanetta
Gerardo
G
Scarfone
Giovanna
G
Giurgea
Livia
L
Timmers
Petra
P
Coens
Corneel
C
Pecorelli
Sergio
S
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D016190:Carboplatin / Q000008:administration & dosage; D002277:Carcinoma / Q000188:drug therapy* / Q000473:pathology* / Q000601:surgery; D017024:Chemotherapy, Adjuvant; D002945:Cisplatin / Q000008:administration & dosage; D016001:Confidence Intervals; D018572:Disease-Free Survival; D005060:Europe; D005260:Female; D006801:Humans; D007391:International Cooperation; D008875:Middle Aged; D009367:Neoplasm Staging; D019370:Observation; D016017:Odds Ratio; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology* / Q000601:surgery; D011379:Prognosis; D012307:Risk Factors; D016019:Survival Analysis; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D016190:Carboplatin; D002945:Cisplatin