the Department of Gynaecological-Oncology, Southampton University Hospitals Trust, Southampton
    Cancer Research United Kingdom, Department of Medical Oncology
    Department of Gynaecological-Oncology, North Glasgow University Hospitals Trust, Glasgow, Scotland
    Royal Marsden Hospital, London, United Kingdom
    Division of Oncology, Royal Brisbane and Womens' Hospital, Brisbane, Australia.

    ABSTRACT

    PURPOSE: Studies indicate that ovarian cancer patients who have been optimally debulked survive longer. Although chemotherapy has been variable, they have defined standards of care. Additionally, it is suggested that patients from the United Kingdom (UK) have inferior survival compared with some other countries. We explored this within the context of a large, international, prospective, randomized trial of first-line chemotherapy in advanced ovarian cancer (docetaxel-carboplatin v paclitaxel-carboplatin; SCOTROC-1). The Scottish Randomised Trial in Ovarian Cancer surgical study is a prospective observational study examining the impact on progression-free survival (PFS) of cytoreductive surgery and international variations in surgical practice.

    PATIENTS AND METHODS: One thousand seventy-seven patients were recruited (UK, n = 689; Europe, United States, and Australasia, n = 388). Surgical data were available for 889 patients. These data were analyzed within a Cox model.

    RESULTS: There were three main observations. First, more extensive surgery was performed in non-UK patients, who were more likely to be optimally debulked ( 2 cm residual disease) than UK patients (71.3% v 58.4%, respectively; P < .001). Second, optimal debulking was associated with increased PFS mainly for patients with less extensive disease at the outset (test for interaction, P = .003). Third, UK patients with no visible residual disease had a less favorable PFS compared with patients recruited from non-UK centers who were similarly debulked (hazard ratio = 1.85; 95% CI, 1.16 to 2.97; P = .010). This observation seems to be related to surgical practice, primarily lymphadenectomy.

    CONCLUSION: Increased PFS associated with optimal surgery is limited to patients with less advanced disease, arguing for case selection rather than aggressive debulking in all patients irrespective of disease extent. Lymphadenectomy may have beneficial effects on PFS in optimally debulked patients.

    INTRODUCTION

    Maximal surgical debulking plus platinum-based chemotherapy has been accepted management for ovarian cancer over the last 30 years.1 Although the evidence for adjuvant chemotherapy is based on prospective randomized trials,2-6 the evidence for debulking surgery has mainly relied on small retrospective clinical series.

    Surgery in ovarian cancer is unique because radical resections are undertaken even in patients in whom the likelihood of complete macroscopic (visible) removal of tumor is small. The concept of maximal surgical debulking was introduced in the 1970s.7,8 Since then, the aim has been to perform surgery with an ideal goal of no residual disease, but more commonly, the goal is to reduce the diameters of the remaining tumor to less than 1 or 2 cm (so-called optimal debulking). The exact cutoff varies according to the published series, but all of these measures are crude approximations in practice. There have been numerous reports that have provided the continuing evidence for surgical debulking in advanced ovarian cancer. Most of these studies are small, retrospective, hospital-based series that have been subjected to meta-analysis.9-11 In these studies, the extent of residual disease after surgery has been analyzed as predictive of survival, along with other prognostic factors. Almost all of these studies show an association between achieving an optimally debulked state and an improved survival. This has been the justification for standard surgical management consisting of total abdominal hysterectomy with bilateral salpingo-oophorectomy and omentectomy, along with additional procedures such as bowel resection, to optimally debulk the patient of disease.

    There are weaknesses with this argument. Most reports are small, retrospective, case series where the surgical data have been abstracted from case records. There has been little attempt to standardize the estimation of residual disease, and the chemotherapy has been variable. An attempt to address these latter points has been carried out in a meta-analysis of 81 published cohorts.12 In this analysis, there was an observed statistical gradient between the proportion of the cohort optimally debulked and the median survival time in patients with International Federation of Gynecology and Obstetrics stage III and IV disease. Although causation has not been adequately established, this literature has driven surgical practice for all patients with ovarian cancer irrespective of the distribution of disease at presentation.

    Some studies have questioned whether the resectability of a patient's tumor is a reflection of the tumor biology13-15; that is, whether the extent to which a surgeon can actually remove sufficient tumor so that the maximal diameter is less than a certain threshold is determined primarily by the nature of the tumor rather than the skill of the surgeon per se. More recently, reports have suggested that, for some patients with advanced disease, primary treatment with chemotherapy rather than surgery does not result in a survival disadvantage.16-18 The use of neoadjuvant chemotherapy followed by surgery at a later stage is being examined prospectively by the European Organisation for Research and Treatment of Cancer 55971 and Chemotherapy or Up-Front Surgery studies.19 Despite these concerns, the standard of care in most specialist units remains an initial attempt at maximum surgical cytoreduction.

    The Eurocare studies suggested that there are international variations in survival among patients with ovarian cancer. These studies drew attention to the possibility that patients treated within the United Kingdom (UK) had inferior survival compared with patients treated within other comparable countries in Europe.20-22 Such potential differences in survival from ovarian cancer have several possible explanations. These include differences in registration procedures across the world (quite likely), differences in tumor biology (possible, but unlikely), and differences in the delivery of treatment (possible). Because the major elements in treatment comprise chemotherapy and surgery, it should be possible to examine the possible impact of variations in surgical practice in the context of a randomized trial of chemotherapy, where the delivery of chemotherapy, as specified within the trial protocol, should not vary.

    The Scottish Randomised Trial in Ovarian Cancer (SCOTROC) was a large, international, prospective, randomized trial comparing docetaxel-carboplatin with paclitaxel-carboplatin as first-line chemotherapy for stage IC to IV epithelial ovarian cancer.23 SCOTROC provided a unique opportunity to examine differences in surgical practice and to relate these differences to differences in survival. The trial was large, with more than 1,000 patients recruited and carefully observed. Two thirds of the patients were treated in centers within the UK, and a third of the patients were recruited from Europe, the United States, and Australasia. Chemotherapy was carefully defined; comprehensive data on all relevant pretreatment characteristics were obtained; and patient recruitment to the trial was not conditional on the success of the surgery performed. These factors made SCOTROC an appropriate vehicle for examining surgical practice. It was well resourced both to maximize patient recruitment and to provide the necessary logistics for the collection of detailed surgical data at an international level. The aims of this study were to evaluate the role of cytoreductive surgery in the context of a randomized international chemotherapy trial and to evaluate the extent of variation of surgical practice internationally and the impact this may have on outcome.

    PATIENTS AND METHODS

    Design

    SCOTROC-1 was a phase III, international, prospective, randomized trial comparing carboplatin-docetaxel with carboplatin-paclitaxel. The trial is described in detail elsewhere23 but is summarized in the following sections.

    Patients

    Women with histologically confirmed epithelial ovarian carcinoma or ovarian-type peritoneal carcinomatosis, International Federation of Gynecology and Obstetrics stage IC to IV disease, and Eastern Cooperative Oncology Group performance status of 0 to 2 were included. Exclusion criteria included mixed mesodermal tumors, borderline tumors, tumors termed possibly malignant, concurrent malignancies, and malignancy within the previous 5 years.

    The study had full multicenter ethics committee approval, and all patients provided written informed consent. Random assignment was within 6 weeks of surgery.

    Chemotherapy Treatment

    Six cycles of chemotherapy were administered at 3-week intervals, and the first cycle was started within 2 weeks of random assignment. Docetaxel 75 mg/m2 was administered by 1-hour intravenous infusion, and paclitaxel 175 mg/m2 was administered by 3-hour intravenous infusion; both were followed by carboplatin area under the curve of 5.

    Clinical Assessments

    Before chemotherapy, assessment included computed tomography (CT) scan and CA-125. CA-125 was repeated before each cycle. Response was assessed by CT scan after cycles 3 and 6 and also if CA-125 increased or plateaued. Clinical responses were graded according to modified Southwest Oncology Group criteria, and CA-125 was graded according to Rustin et al.24

    Follow-up was performed every 2 months until there was increasing CA-125 and symptoms or radiologic evidence of disease progression. Follow-up intervals were extended after 2 years.

    Surgical Study

    Surgical study was planned as an integral part of the trial at the outset. All centers were given surgical data collection forms (Fig 1) based on a previously designed form.25 Detailed information was collected on the procedures performed, operating time, and residual disease. Forms were distributed to the surgeons who referred into the medical oncology centers to collect contemporaneous surgical data. In those instances where this form had not been completed, a personalized reminder was sent to the referring surgeon for completion at random assignment. This was coordinated by one of the authors (S.C.C.), and every effort was taken to maximize data collection to ensure a prospective and comprehensive data set. The surgical data were linked to the main clinical research file that contained biologic and radiologic data before statistical analysis using SPSS (SPSS Inc, Chicago, IL).

    Residual Disease Status

    Residual disease status was defined according to the maximum diameter of residual disease at the time of random assignment, after surgery, and after a CT scan.

    Progression-Free Survival

    Progression-free survival (PFS) was the time from random assignment to progression or death from any cause, whichever occurred first. Progression was defined as one of the following: a 25% or greater increase in size of at least one measurable lesion; a clear worsening from previous assessment of any assessable disease; the reappearance of any lesion that had disappeared; or the appearance of any new lesion.23

    Statistical Analysis

    The size of the study was determined by the chemotherapy trial and was designed with an 80% power to detect a 25% difference in median PFS with a two-sided 5% level of significance. This required 1,050 patients with a minimum follow-up of 1 year.

    The comparison between country groups of surgical rates and residual disease rates were made using Pearson's 2 test. The Mann-Whitney U test was used for the comparison of operating times. More detailed examination of operating times incorporating stage was made using analysis of variance techniques on the logged operation time data.

    To determine whether debulking extent and country had an effect beyond that explained by presurgery clinical and biologic factors, a prognostic Cox model was built in two phases based on these factors alone. In the first phase of this process, conventional potential presurgery prognostic factors (grade, stage, age, performance status, histology, and CA-125) were considered, and a preliminary model was built based on these factors. A conventional forward stepwise approach was adopted for this phase.

    Presurgery CA-125 values were not available for 28% of the patients for who surgical information was available. However, there is a strong association between pre- and postsurgery CA-125 values (R2 = 0.49), and the data from those patients who had both pre- and postsurgery CA-125 values were used to estimate a regression equation relating these variables. This equation was then used to impute the missing presurgery CA-125 values from the postsurgery values, which were more generally available.

    In the second phase, biologic characteristics of the tumor, which were available from the surgical data, were considered for addition to the first-phase Cox model (presence of ascites, adherence of the ovary, invasion of the pelvic side wall, invasion of the colon, invasion of the small bowel, invasion of the bladder, invasion of the uterus, and presence of omental cake). These characteristics were entered into the model one at a time because, depending on the end point, they were not present for between 11% and 28% of the patients with surgical data. The most statistically significant variable was retained (assuming it reached the minimum requirements of statistical significance at 5%), and the process was repeated. A check for the presence of two-way interactions was made at the end of both phases.

    A prognostic score was calculated on the basis of the beta coefficients from the final Cox model, and the patients were stratified into four equally sized prognostic groups based on the quartiles of this score. The effect of debulking surgery and country of operation was assessed in a Cox model after stratifying for this prognostic grouping.

    RESULTS

    Between October 1998 and May 2000, 1,077 patients from 83 international centers were randomly assigned. Patient characteristics are listed in Table 1.

    At the time of analysis, 686 patients had experienced disease progression or died. Detailed surgical data were obtained for 889 patients.

    Differences in Surgical Practice Between the UK and Other International Centers

    Table 2 lists differences in the surgical procedures performed. There was no observed difference in the rate of removal of the ovaries along with the uterus and omentum between UK and non-UK centers. However, there was significant difference in the overall success of cytoreduction; 71.3% of patients from non-UK centers were optimally cytoreduced ( 2 cm residual disease) compared with 58.4% of patients from UK centers. The frequency of large bowel resection and lymphadenectomy was significantly greater in non-UK centers, and the fact that there is no difference in the colostomy rate suggests that primary anastomosis was achieved more commonly too. Table 3 shows that the difference in lymphadenectomy and large bowel resection between the UK and non-UK cohorts is marked in patients in whom complete macroscopic clearance was possible. However, the difference diminishes as the residual disease increases; there is little difference between cohorts for patients in whom the residual disease was greater than 2 cm.

    The median operating time was longer in non-UK compared with UK centers (136 v 95 minutes, respectively; P < .001), and Figure 2 illustrates that the difference in operating times between the country groups depends on stage (test for interaction from analysis of variance, P = .015). In UK patients, the operating time was similar irrespective of the stage of disease presentation (P = .768), whereas in non-UK patients, operating times depended on stage (P = .002), with most time spent on patients with stage III disease.

    Presurgery Clinical and Biologic Prognostic Score for PFS

    Table 4 lists the details of the final clinical and biologic multivariate Cox model. A prognostic score for each patient was calculated from this model as the sum of each beta corresponding to the patient's biologic characteristics plus the product of the CA-125 beta and the presurgery CA-125 level for that patient. This prognostic score was used to stratify the patients into four equally sized presurgery prognostic groups based on the score quartiles. This is illustrated in Figure 3.

    Effect of the Bulk of Residual Disease After Surgery on PFS

    As a univariate variable ( 2 v > 2 cm), residual disease was highly statistically significant, with a hazard ratio of 2.58 (95% CI, 2.13 to 3.11; P < .001). After adjusting for the four presurgery prognostic groups, residual disease was still highly significant, but the effect size was much reduced (hazard ratio = 1.62, 95% CI, 1.32 to 1.99; P < .001). Note that an almost identical result is obtained for the adjusted effect of debulking if, rather than stratifying for the four prognostic groups, all of the presurgery variables are straightforwardly entered into a Cox model with the debulking variable.

    The benefit of optimal debulking seems to depend on presurgery prognostic group (ie, on the extent of disease before surgery; test for interaction, P = .003; Fig 4). This suggests that, in less extensive ovarian cancer, optimal debulking is associated with a large survival benefit, whereas in the most advanced group of ovarian cancers, the benefit of optimal debulking is much smaller.

    Effect of Country of Surgery (UK v non-UK) on PFS

    The effect of the country of surgery was examined. Patients from the UK were compared with patients recruited from other international centers (non-UK), which did not result in a statistically significant difference after adjusting for presurgery prognostic groups (hazard ratio for UK v non-UK = 1.05; 95% CI, 0.86 to 1.29; P = .611). The survival curves reveal a late separation, suggesting a group of long-term survivors in the non-UK group that is not present in the UK group. We further examined the UK effect with respect to categories of residual disease adjusted for prognostic score; we can show how this late separation arises (test for interaction between UK and residual disease, P = .009 adjusting for the four presurgery prognostic groups identified earlier). Surgery in the UK seems to have an adverse PFS only in patients who are optimally debulked (hazard ratio = 1.85; 95% CI, 1.16 to 2.97; P = .010). The geographic location of surgery (UK or non-UK) does not have a clear effect in the other residual disease groups (Fig 5). A more detailed comparison was made between the types of surgery that differed between the UK and non-UK centers; differences were most striking in the group with no macroscopic residual disease, particularly for lymphadenectomy.

    The relationship between PFS and these same procedures was examined in the group with no macroscopic residual disease. There was a trend to improved outcome with lymphadenectomy after adjusting for presurgery prognostic groups (para-aortic lymphadenectomy: hazard ratio = 1.73; 95% CI, 0.90 to 3.34; P = .102; pelvic lymphadenectomy: hazard ratio = 1.62; 95% CI, 0.88 to 2.99). No such trend was apparent for large bowel resection. Moreover, when the Kaplan-Meier curves for para-aortic lymphadenectomy versus no para-aortic lymphadenectomy are plotted by bulk of residual disease, we see a similar pattern to that observed for UK versus non-UK (data not shown; ie, it primarily makes a difference for the patients with no residual disease). This pattern was also observed for pelvic lymphadenectomy.

    Surgical times also differed markedly between UK and non-UK centers, and there was a trend (P = .196) for increased surgical time to be associated with improved PFS in patients with no macroscopic residual disease after adjusting for presurgery prognostic factors. However, the pattern of association across the categories of residual disease was not similar to the pattern for UK versus non-UK, with long surgery times actually seeming to be detrimental for patients with bulky disease (P = .018).

    DISCUSSION

    This SCOTROC surgical study is important because it uses a novel approach to investigate the impact of surgical variation on survival in ovarian cancer. Although it is acknowledged that the primary aim of SCOTROC-1 was an assessment of two chemotherapy schedules, it is unlikely that a study of surgical practice of this size could have been conducted in isolation. The results from SCOTROC (chemotherapy trial) show that there is no difference in PFS between the docetaxel and paclitaxel arms.23 This means that all patients effectively had similar chemotherapy. PFS was chosen as the primary end point, and this means that the potential influence of subsequent management on overall survival would not be relevant to the interpretation of these data.

    There were three main observations. First, more extensive surgery was performed in patients recruited from centers outside the UK, and those patients were more likely to be optimally debulked ( 2 cm). Second, optimal debulking ( 2 cm) is associated with an increase in PFS mainly for patients with less extensive disease at the outset. Third, patients from the UK with no visible residual disease after primary surgery were observed to have a less favorable PFS compared with patients recruited from centers outside of the UK who were similarly macroscopically debulked.

    It would be reasonable to suppose that the main benefit of surgery might be in patients with less advanced disease at presentation, and this study does confirm that the impact of cytoreductive surgery differs according to initial disease extent. This suggests that biology has an important role and supports the data from the Gynecologic Oncology Group 52 study.26 In this study, the volume of initial disease was found to be inversely associated with survival despite subsequent optimal debulking to less than 1 cm in all patients who entered this study.

    Traditionally, it has been recommended that all patients with ovarian cancer should undergo debulking surgery irrespective of the distribution and extent of disease at presentation. The results in this article suggest that this approach may not be appropriate for all patients. Case selection might identify patients in whom the disadvantages of surgery outweigh the likely benefits. What this study does not define is at what point this balance may change. It should be noted that the primary aim of the study was not to develop a prognostic model for clinical use but, instead, to enable the effect of surgery to be disentangled from background biologic factors. Nevertheless, this study supports the current Chemotherapy or Up-Front Surgery pilot study and the European Organisation for Research and Treatment of Cancer 55971 prospective randomized study. These studies aim to compare neoadjuvant chemotherapy followed by surgery versus primary surgery followed by chemotherapy.

    The data also indicate that there was a group of patients recruited from UK centers who had a survival disadvantage compared with patients recruited from centers outside the UK. It is important to note that this study recruited patients in the time period from 1998 to 2000 before much of the reorganization of cancer services in the UK.27 Previous studies, such as EUROCARE,28 had suggested that UK patients, across a range of tumor types, were at a survival disadvantage. These large epidemiologic studies raised the possibility of differences but did not suggest why the differences existed. One possibility is variation in surgical practice.

    The SCOTROC surgical study provides an opportunity to explore this relationship further because the results of chemotherapy across both treatment areas are similar and because the outcome data are carefully adjusted for presurgery biologic prognostic factors. The results suggest that the survival difference could be related to differences in surgical practice between UK and non-UK centers at the time of the trial but that the difference is only significant in the group of patients in whom complete macroscopic debulking was performed. Examining differences in surgical practice in more detail, it is noteworthy that lymphadenectomy is commonly performed in patients from outside the UK but rarely performed in patients from the UK. These procedures are associated with better survival mainly in patients who have been macroscopically cleared of disease. This study cannot confirm that lymphadenectomy is the cause of this survival difference. Because SCOTROC was a chemotherapy trial, the requirements of surgery were not specified per se. One possibility is that the process of lymphadenectomy made it less likely that otherwise undetected bulk disease remained undetected. Although this study did not quantify the completeness of lymphadenectomy, it does support the recently published randomized trial that demonstrated an improved PFS with systematic lymphadenectomy.29

    In the UK, current guidelines introduced over the last 2 to 3 years require that the management of ovarian cancer should be by gynecologic oncologists based in cancer centers. There may well be significant differences in surgical practice today compared with 4 to 6 years ago. If the main benefit of surgery is in patients with less advanced disease, then it may be that the greatest overall benefit will be achieved by gynecologic oncologists concentrating on these patients, but this will need to be assessed carefully in prospective studies.

    In conclusion, this study suggests that tumor biology is a major determinant in PFS and that optimal surgery cannot fully compensate for tumor biology. Nevertheless, in less extensive disease, surgical debulking is associated with better survival. This suggests that a more individualized approach to surgery should be considered and confirms the importance of specialist care for patients with ovarian cancer.

    Authors' Disclosures of Potential Conflicts of Interest

    Although all authors completed the disclosure declaration, the following author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

    Acknowledgment

    This study is published on behalf of the members of the Scottish Gynaecological Cancer Trials Group, and their help and continued support is acknowledged. The help of the Cancer Research United Kingdom trials unit in Glasgow is acknowledged for the extensive data management required during this study. The authors also thank all of the clinicians who entered their patients in the SCOTROC-1 clinical trial. The support of the West of Scotland Cancer Surveillance Unit is appreciated.

    NOTES

    Supported by Grants from Aventis Pharmaceuticals and research Grant No. K/MRS/50/C2763 (S.C.C.) from The Chief Scientist's Office (Edinburgh, United Kingdom). J.P. is funded by Cancer Research United Kingdom.

    Presented in part at the 41st Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 13-17, 2005.

    Authors' disclosures of potential conflicts of interest are found at the end of this article.

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《临床肿瘤学医学期刊》2005年12月第23卷第12期