Riego de imprimación

of the surgical staging of early

ovarian cancer

94 Chapter 6

ABS TRACT

Background: The purpose of this study was to determine the effect of lymph node sampling and taking of blind biopsies as part of the surgical staging procedure for early ovarian cancer on disease-free survival (DFS) and overall survival (OS) in patients who received no adjuvant chemotherapy.

Methods: In the EORTC ACTION trial 448 patients with early ovarian carcinoma were randomized between November 1990 and March 2000, 224 patients to observation and 224 to adjuvant platin-based chemotherapy. Only patients allocated to observation were included for the current study. Analyses were performed in a subgroup of 75 optimally staged patients (group A), 46 patients in whom all staging steps were performed except para-aortic or pelvic lymph node sampling (group B) and 14 patients who fulfilled all staging criteria but in whom no blind peritoneal biopsies were taken (group C). The study group did not differ in stage distribution, cell type or tumor grade.

Results: Significantly improved 5-year DFS (P = 0.03) and 5-year OS (P = 0.01) were found in group A (optimally staged) versus group B (no lymph node sampling). A significant difference was also shown in 5-year DFS (P = 0.02) and 5-year OS (P = 0.003) between group A and group C (no blind biopsies). Recurrences occurred in 11/75 patients (14.6%) in group A , 16/46 patients (34.8%) in group B and 5/14 (35.7%) in group C. The 5-year DFS in group A was 79% versus 61% and 64% in group B and C respectively. The 5-year OS decreases from 89% in group A to 71% in group B and 65% in group C.

Conclusions: In this study statistically significant differences were found in patients in whom para-aortic and pelvic lymph node sampling and taking of blind peritoneal biopsies were undertaken compared with patients in whom these staging steps had been omitted. These findings support the relevance of lymph node sampling and the taking of blind peritoneal biopsies in the surgical staging of early ovarian cancer.

Lymph node sampling and blind biopsies 95

6

INTRODUCTION

Early ovarian cancer patients are often surgically understaged. Figures of 33% to 67% of patients with inadequate surgical staging have been reported [1,2], depending on the definition of optimal staging.

The two staging steps that are most frequently omitted include retroperitoneal lymph node dissection and the taking of blind biopsies [3,4]. These omissions take place despite the well documented route of metastasis via the peritoneal fluid and the retroperitoneal lymph nodes. The Gynecologic Oncology Group (GOG) and the European Organisation for Research and Treatment of Cancer (EORTC) has well described guidelines for the staging laparotomy of early ovarian cancer patients [5,6].

The incidence of lymph node involvement in apparently early ovarian cancer is approximately 14% for stage I and 38% for stage II [7-16]. Lymph node metastasis in stage I ovarian cancer is mostly found in stage Ic patients, grade 3 tumors and serous carcinoma [7-15]. Positive findings of blind biopsies of various peritoneal sites in apparently early-stage ovarian cancer has been demonstrated between 3 and 17% of the cases [17,18].

Despite the overwhelming evidence of the importance of these two routes of tumor spread, the particular staging steps to detect it carry inherent problems in clinical practice. The reasons that lymph node dissection and blind biopsies are so often neglected have been reported partly because of lack of technical skills and partly because of lack of knowledge of early ovarian cancer spread [3].

Contrary to the large number of papers analyzing the incidence of lymph node spread or intraperitoneal dissemination of early ovarian cancer, studies on the prognostic significance of lymph node removal or taking of blind peritoneal biopsies are scarce [9- 11]. This scarcity is the more problematic because a proven prognostic consequence of these staging steps may contribute to a general acceptance of the importance of these staging elements.

The current study was undertaken to analyze the prognostic significance of lymph node sampling and the taking of blind peritoneal biopsies during surgical staging of early ovarian cancer.

96 Chapter 6

PATIENTS AND METHODS

In the EORTC Adjuvant ChemoTherapy in Ovarian Neoplasm (ACTION) trial 448 patients were included between November 1990 and January 2000 by 40 centers from nine European countries. Patients with FIGO stages Ia-Ib, grade II-III, all stages Ic-IIa and all stages I-IIa clear cell carcinoma were eligible for the study. After surgical treatment and staging, including total abdominal hysterectomy and bilateral salpingo-oophorectomy using a midline incision, patients were randomized between an observation arm or adjuvant chemotherapy arm consisting of at least four courses of platinum-based chemotherapy. Surgical staging had to consist of at least careful inspection and palpation of all peritoneal surfaces, with biopsies of any suspect lesions, such as adhesions adjacent to the ovarian tumor. However, far more comprehensive staging was strongly advised, including omentectomy, peritoneal washings, blind biopsies from the peritoneum in the pelvis (pouch of Douglas, bladder, pelvic sidewalls), the paracolic gutters, the right hemidiaphragm and iliac and para-aortic lymph node sampling. Only if all staging steps had been performed, the procedure was categorized as optimal. For a detailed description of the inclusion criteria of this trial we refer to a previous publication [2].

Data from the EORTC ACTION trial were used for the present study. The dataset comprises detailed information on staging steps and prognosis. The median follow-up duration at the time of analysis was 5.5 years.

SPSS version 15.0 (SPSS inc., Chicago, IL) was used for statistical analysis. Categorical

variable comparisons were conducted by 2-tailed χ² and Fisher exact tests. Parametric

comparisons were compared by analysis of variance and Student t test. Survival

estimates were calculated using the Kaplan-Meier product limit method. Comparisons between survival curves were made using the log-rank-test. Two-tailed P values are

reported, with the a for all tests set at < 0.05 as significant.

RESULTS

From the 448 patients of the ACTION trial, 224 patients were randomized to the adjuvant cisplatin-based chemotherapy arm en 224 to the observation arm. For the present analysis only patients in the observation arm were included. From the 224 observation arm patients 75 patients were optimally staged (group A) and from 46 patients all staging steps were performed except para-aortic or pelvic lymph node sampling (group B). Group C consisted of patients in whom the taking of blind biopsies was omitted but all other steps were carried out (n=14). The other 89 patients out of

Lymph node sampling and blind biopsies 97

6