For the EORTCACTION Collaborators
Affiliation of authors: J. B. Trimbos, P. Timmers, Leiden University Medical Center, Leiden, The Netherlands; I. Vergote, University Hospital Gasthuisberg, Leuven, Belgium; G. Bolis, G. Scarfone, Istituto Mangiagalli and Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy; J. B. Vermorken, University Hospital Antwerp, Antwerp, Belgium; C. Mangioni, G. Zanetta, Ospedale San Gerardo, Monza, Italy; C. Madronal, Institut dOncologia Corachan, Barcelona, Spain; M. Franchi, Ospedale di Circolo e Fondazione Macchi, Varese, Italy; S. Tateo, Policlinico San Matteo, Pavia, Italy; L. Giurgea, C. Coens, European Organisation for Research and Treatment of Cancer (EORTC) Data Center, Brussels, Belgium; S. Pecorelli, Universita di Brescia, Brescia, Italy.
Correspondence to: J. Baptist Trimbos M.D., Ph.D., Department of Gynecology, Leiden University Medical Center, POB 9600, 2300RC, Leiden, The Netherlands (e-mail: J.B.M.Z.Trimbos{at}lumc.nl).
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ABSTRACT |
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INTRODUCTION |
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This high recurrence rate has led to attempts to use different forms of adjuvant treatment, but solid scientific proof of the clinical effectiveness of adjuvant treatment is lacking. Not only is the clinical significance of adjuvant treatment unclear, but the definition of which patients are at high risk of recurrencethat is, in potential need of adjuvant treatmenthas remained obscure.
Few randomized trials have tried to address the uncertainties that have been created by this act-before-proof approach. Young et al. (2) reported a Gynecologic Oncology Group (GOG) study in which patients with stage Ia or Ib and grade I or II ovarian cancer were randomly assigned to either observation or intermittent oral melphalan following surgery. There was no survival difference between the two groups of patients. Although the number of patients in this trial was too small to draw definitive conclusions, the authors advocated not administering any adjuvant treatment following surgery and comprehensive staging in patients with this stage and grade of disease (2).
Recently the results of two randomized European trials that included an observation arm have become available (3,4). In the Italian study (3), patients with early-stage ovarian cancer were randomly assigned to receive either cisplatin or observation following surgery. Patients in both arms received salvage therapy on recurrence. A statistically significant difference in recurrence-free survival was found in favor of chemotherapy, but no difference in overall survival was demonstrated (overall survival: hazard ratio [HR] = 1.15 [95% confidence interval [CI] = 0.44 to 2.98]; recurrence-free survival: HR = 0.35 [95% CI = 0.14 to 0.89]). The authors suggested that salvage treatment was more effective in the observation arm than in the adjuvant chemotherapy arm and that, although patient numbers were small, these findings support a policy of deferring chemotherapy until the actual time of recurrence (3). In the Scandinavian study (4), 162 patients with early-stage ovarian carcinoma were randomly assigned to receive carboplatin or observation following surgery. No difference in disease-specific survival or disease-free survival was seen (disease-specific survival: HR = 0.94 [95% CI = 0.37 to 2.36]; disease-free survival: HR = 0.98 [95% CI = 0.52 to 1.83]) (4). However, both the Italian and Scandinavian studies lacked the power to draw definitive conclusions and did not take into account the extent of the surgical staging of their study groups. The quality of surgical staging in ovarian cancer relates to the reliability of the diagnosis of early-stage disease because it has been well documented that approximately 24% of non-optimally staged patients with early-stage ovarian cancer actually harbor occult residual disease in the peritoneal cavity (stage III disease) (58).
In 1990 the European Organisation for Research and Treatment of CancerGynaecological Cancer Group (EORTCGCG) initiated a randomized clinical trial comparing platinum-based adjuvant chemotherapy with no further treatment (i.e., observation) following surgery in patients with early-stage ovarian cancer. The study, called Adjuvant ChemoTherapy in Ovarian Neoplasm (ACTION), which ran between November 1990 and January 2000, was designed to have more statistical power than previous trials to detect a survival difference and to emphasize the completeness of surgical staging in the analysis of the endpoints of the study. At the same time, the International Collaborative Ovarian Neoplasm Collaborators initiated a similar trial (ICON1), the results of which are reported in this issue (9). In this article we report on the findings of the ACTION trial.
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PATIENTS AND METHODS |
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Patients with International Federation of Gynecology and Obstetrics (FIGO) stages IaIb, grade IIIII; all stages Ic and IIa, and all stages IIIa with clear-cell epithelial cancer of the ovary were eligible for the study (10,11). Surgical treatment had to consist of total abdominal hysterectomy and bilateral salpingo-oophorectomy, followed by surgical staging. In cases of stage Ia cancer, unilateral salpingo-oophorectomy followed by surgical staging was permitted. This kind of conservative surgery has been shown to be adequate treatment for women with stage Ia disease who wish to preserve fertility (12,13). Patients with a prior or concomitant second malignancy were excluded, as were patients with a World Health Organization (WHO) performance status of more than 3, previous treatment with chemotherapy or radiation therapy, expected inadequacy of follow-up, and an interval of more than 6 weeks between surgical staging procedure and randomization. The Institutional Review Board of each participating center had to approve the study, and informed consent of each patient was a prerequisite.
Surgical Staging
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, and the right hemidiaphragm; and iliac and periaortic lymph node sampling. If all of these staging requirements were met, the staging performance was considered to be optimal. Three other, less comprehensive staging categories were defined: modified, minimal, and inadequate (Table 1). Strict guidelines were also given for the microscopic assessment of histologic cell type and for the assessment of tumor differentiation, according to WHO criteria (10).
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Patients were centrally randomly assigned to either the adjuvant chemotherapy arm or the observation arm by a computer program, using a minimization procedure, at the EORTC Data Center in Brussels. Randomization was stratified according to institution, FIGO stage, and grade of tumor differentiation.
Adjuvant Chemotherapy
Treatment in the adjuvant chemotherapy arm had to consist of at least four courses of a platinum-based regimen following surgery; however, six courses of treatment were recommended. Single-agent platinum chemotherapy was also allowed as well as combination regimens. In the case of cisplatin, the required dose was 75 mg/m2, and for carboplatin the required dose was 350 mg/m2. Dose modifications in the case of drug toxicity were given when appropriate. Each center had to define its adjuvant chemotherapy regimen in advance and had to remain with that regimen for the duration of the trial. After surgery, patients in the observation arm were not treated again until recurrence. Tumor recurrence had to be confirmed cytologically or histologically. Patients in the observation arm who had tumor recurrence were given the same chemotherapy regimen that their particular center was using in the adjuvant chemotherapy arm.
Statistical Analysis
Analysis of results was on an intention-to-treat basis. The primary endpoint was overall survival, and the secondary endpoint was recurrence-free survival. Time-to-event analyses were based on the KaplanMeier method (14) and events were compared using the log-rank test. Prognostic factor analysis used the Cox proportional hazards regression model, after necessary assumptions were met, to determine statistically significant covariates, such as FIGO stage, tumor grade, histologic cell type, completeness of surgical staging, age, tumor marker carcino antigen 125 (CA 125) level and performance status. Differences in relative size of treatment effect between subgroups of staging performance were tested using a chi-square (2) test for interaction.
Because of the relatively long life expectancy of patients with early-stage ovarian carcinoma and the small expected improvements in survival, the sample size was set, more or less arbitrarily, to 1000 or more patients. An independent interim data-monitoring committee assessed the data and the progress of the study at fixed intervals. A single independent data-monitoring committee monitored the combined accumulating data from ACTION and the parallel trial (ICON1). Interim analyses were interpreted by using conservative statistical significance tests. If the P value for the comparison of survival between treatment arms fell below .01, consideration was given to stopping the trial. Because patient accrual took longer than expected, the committee decided to close the study in 2000, before the target number of patients was accrued. Audits by an independent quality control panel were done during the course of the study to verify the quality of the data. A separate publication on the findings of this panel is in preparation, but preliminary analysis has confirmed the reliability of the surgical staging data.
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RESULTS |
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Between November 1990 and January 2000, a total of 448 patients were accrued to the trial by 40 centers from nine European countries. Analysis is complete through March 26, 2001 (Fig. 1). Table 2
shows the clinical and tumor characteristics of the patients in both trial arms. The majority of patients in the chemotherapy arm received cisplatin combined with cyclophosphamide (102 patients or 47%) or single-agent carboplatin (71 patients or 33%). The various clinical and pathologic risk factors were well balanced between the two arms. Thirteen patients in the observation arm received chemotherapy, and 14 patients in the adjuvant chemotherapy arm did not. The reasons for these protocol violations were morbidity, disease progression, administrative error, and patient refusal. Follow-up ranged from 3 months to 9 years, with a median follow-up of 5.5 years. Nine patients were lost to follow-up, six in the observation arm and three in the chemotherapy arm.
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KaplanMeier analysis of overall survival yielded 5-year survival figures in the observation and the adjuvant chemotherapy arms of 78% and 85%, respectively, a difference of 7% (95% CI = 1.08% to 15.72%). The difference in overall survival between the two arms was not statistically significant, as depicted in Fig. 2 (HR = 0.69 (95% CI = 0.44 to 1.08); P = .10). The KaplanMeier curves for recurrence-free survival in both arms are shown in Fig. 3
. Patients in the adjuvant chemotherapy arm had statistically significantly better recurrence-free survival than patients in the observation arm, with an HR of 0.63 (95% CI = 0.43 to 0.92; P = .02). These results translate into 5-year survival figures of 68% for patients in the observation arm and 76% for patients in the adjuvant chemotherapy arm, an improvement in recurrence-free survival of 8% (95% CI = 0.88% to 18.04%).
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To determine possible prognostic factors for overall and recurrence-free survival, we performed univariate and multivariable analyses of possible risk factors apart from treatment on the survival data. In Table 4, the univariate and multivariable analyses of possible risk factors apart from treatment are summarized. CA 125 analysis was performed in too few of the patients to be considered in the multivariable analysis. FIGO stage was not a statistically significant prognostic factor. Staging adequacy and tumor grade were statistically significant prognostic factors for overall survival and recurrence-free survival in the univariate and multivariable analysis. Histologic cell type was a statistically significant prognostic factor only for overall survival in the univariate and multivariable analysis.
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DISCUSSION |
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In addition to the well known risk factors for overall and recurrence-free survival, such as tumor grade and histologic cell type (16), the completeness of surgical staging was found to be an independent prognostic factor. The impact of surgical staging on prognosis is not surprising, because the extent of staging influences the likelihood of residual disease. Optimal surgical staging minimizes the likelihood of residual stage III disease, and incomplete surgical staging increases the possibility of hidden occult cancer in the peritoneal cavity. The finding that completeness of surgical staging is an independent prognostic factor is not completely new. For example, in 1992 the Department of Obstetrics and Gynecology at Yale University compared expert and comprehensive surgery (i.e., complete surgical staging) in early-stage ovarian cancer with incomplete surgical staging and tumor removal (17). Although the number of patients in that study was small, a statistically significant survival advantage was demonstrated in favor of the completely staged group. More recently, Italian investigators have also identified the extent of surgical staging with early-stage ovarian carcinoma as an independent prognostic factor in their multivariable analysis (18).
In the current study, patients in the observation arm who were optimally staged had statistically significantly better overall and recurrence-free survival than patients who were non-optimally staged (Fig. 5, A and C). However, the poor prognosis of the non-optimally staged patients could be corrected by administering adjuvant chemotherapy (Fig. 5
, B and D). This finding suggests that adjuvant chemotherapy in early-stage ovarian cancer may work predominantly by affecting small-volume or microscopic tumor implants or metastases that remain unnoticed at the time of surgical staging. This hypothesis is supported by the finding that chemotherapy improved both overall and recurrence-free survival in the non-optimally staged patients (i.e., those patients who may have had residual disease) and not in the optimally staged patients (i.e., those patients who had only a minimal chance of residual disease) (Fig. 6
, B and D). The finding that adjuvant chemotherapy is effective in non-optimally staged patients might also explain the results of the ICON1 trial (9) and the combined ICON1/ACTION analysis (19), in which the majority of patients were most probably not optimally staged.
Although FIGO stage is generally a well known risk factor for survival of patients with ovarian cancer, it was not found to be a prognostic factor in this study. For example, stage Ic disease was not associated with a higher risk of recurrence or death compared with moderately and poorly differentiated stages Ia and Ib disease (data not shown). In addition, in a recent meta-analysis of more than 1500 cases of early-stage ovarian cancer, Vergote et al. (16) found that stage Ic disease had a prognosis similar to that of stage Ib disease. Thus, these findings might be an important consideration when redefining high-risk early-stage ovarian cancer.
Salvage treatment of patients with recurrent disease showed a difference in salvage rate (i.e., the percentage of patients successfully treated for tumor recurrence) between the optimally staged and the non-optimally staged patients. In the non-optimally staged patients, the salvage rate in the observation and the adjuvant chemotherapy arms was similar (70% and 64%, respectively). In the optimally staged patients, salvage treatment with adjuvant chemotherapy was more successful in the observation arm than in the adjuvant chemotherapy arm (75% and 46%, respectively). The number of patients involved in this analysis was small, but it is of interest that the same difference in the effectiveness of chemotherapy salvage treatment was found in the Italian Gruppo Interregionale Collaborative Oncology Group (GICOG) study, in which patients also underwent complete surgical staging (3). If this difference in the effectiveness of salvage treatment were to be observed in larger studies, it would give additional support to a policy of postponing chemotherapy until the time of actual tumor recurrence, providing that optimal surgical staging had been performed.
Like other analyses of this kind, this study has several potential limitations. First, the ACTION trial was not specifically designed to compare different surgical staging procedures, and patients were not prospectively stratified according to the various surgical staging categories. Retrospective stratification, however, showed a well-balanced distribution of the four staging categories between the two treatment arms (data not shown) and no differences in the distribution of other risk factors, such as tumor grade and histologic cell type, between optimally and non-optimally staged patients. Second, the numbers of patients become increasingly smaller when performing subgroup analyses. Although this study is the largest randomized trial in early-stage ovarian cancer in terms of the number of assessable patients, it still suffers from a limited sample size. Therefore, the interpretation of results should be made with sufficient care, because, although interactions of this kind are generally hard to detect, a lack of statistically significant differences between two groups does not necessarily imply equivalence. Statistical tests to analyze the potential interaction between the chemotherapy effect and the staging adequacy showed only trends and no proof (P = 0.15). In Fig. 7, a graphic representation of this analysis can be seen. The hazard ratios of optimal and non-optimal staging regarding overall survival seem to be different, but statistical proof at a P = .05 level was prevented by the large 95% confidence interval in the optimally staged patients. The main determinant of the width of the 95% confidence interval is the number of events, and events were infrequent following complete surgical staging. It is, therefore, exactly the factor that has to be proven that is hampering the statistical ability to do so. This effect, the opposite of a self-fulfilling prophecy, sheds doubt on the possibility that stronger statistical proof will ever be feasible in terms of necessary numbers of patients.
Although we have stressed the clinical significance of complete surgical staging of early-stage ovarian cancer, some concern may be raised about its feasibility in clinical practice. In the ACTION trial, even though strict guidelines for optimal surgical staging were set, only one-third of the patients were optimally staged according to the guidelines in Table 1. The reasons for this low number of patients actually receiving staging according to trial protocols are well known. Early-stage ovarian cancer often presents with symptoms mimicking a benign ovarian cyst. This clinical condition is then dealt with by surgeons with either a lack of knowledge of ovarian cancer spread or a lack of surgical experience (e.g., in lymph node sampling) (20,21). The findings of this study underscore the clinical significance of surgical staging and will hopefully influence the current practice of referral and centralization to oncology centers of suspected early-stage ovarian cancer patients.
In conclusion, this trial studied patients who were completely and comprehensively (i.e., optimally) staged in only one-third of cases. Taking all patients into account, adjuvant chemotherapy statistically significantly improved recurrence-free survival, but no improvement was seen in overall survival. Tumor grade, histologic cell type, and completeness of surgical staging were independent prognostic factors. In the subgroup analysis of different staging adequacy, indications were found that adjuvant chemotherapy is not effective in optimally staged patients. Thus, we suggest that adjuvant chemotherapy in early-stage ovarian cancer is predominantly effective in patients with occult residual disease and that its effectiveness is dependent on the likelihood of remaining ovarian cancer spread. The adequacy of surgical staging is indicative of the likelihood of unappreciated residual cancer, and the observed benefit of adjuvant chemotherapyprimarily in non-optimally staged patientsmay be indicative of a benefit of adjuvant chemotherapy only in patients with appreciable residual disease. In the next EORTC trial we will attempt to confirm the findings that adjuvant chemotherapy in early-stage ovarian cancer is not effective after optimal surgical staging. We are considering a trial protocol to randomly assign non-optimally staged patients into either restaging (i.e., to make the patient optimally staged) followed by observation or direct adjuvant chemotherapy without restaging. Because the two trial arms may be equivalent in terms of survival, quality-of-life issues will be an important endpoint of this study.
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APPENDIX: EORTCACTION TRIAL COLLABORATORS AND AFFILIATIONS: |
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NOTES |
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See "Appendix" for a full list of names and affiliations of the EORTCAdjuvant ChemoTherapy in Ovarian Neoplasm (ACTION) collaborators.
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REFERENCES |
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Manuscript received April 17, 2002; revised November 7, 2002; accepted November 14, 2002.
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