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Natural History of Stage IV Epithelial Ovarian Cancer

From the Royal Marsden Hospital, London, United Kingdom.

Address reprint requests to M.E. Gore, PhD, FRCP, Gynaecology Unit, Royal Marsden Hospital, Fulham Rd, London SW3 6JJ, United Kingdom.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: In this report we present the natural history, prognostic factors, and therapeutic implications of stage IV epithelial ovarian cancer (EOC).

PATIENTS AND METHODS: We reviewed 192 patients with stage IV EOC as defined in 1985 by the International Federation of Gynecology and Obstetrics.

RESULTS: The site of stage IV–defining disease was cytologically positive pleural effusion in 63 patients, liver in 50 patients, lymph nodes in 26 patients, lung in six patients, other sites in 15 patients, and disease at multiple stage IV–defining metastatic sites in 32 patients. Surgery was performed before chemotherapy in 169 patients; 25 patients (14.8%) were left with only microscopic residual disease or less than 2 cm of macroscopic residual disease. The overall response rate to chemotherapy was 56%; the complete response rate was 18%. The median progression-free survival was 7.1 months, and the median overall survival was 13.4 months. The median overall survival of patients with positive pleural effusions only was 13.4 months as compared with 10.5 months for patients with visceral disease only, but this difference was not statistically significant. The 5-year survival rate was 7.6%, with only six patients surviving more than 5 years. Univariate and multivariate analysis showed that two parameters were associated with a shorter survival time: visceral involvement (lung or liver) and diagnosis before 1984.

CONCLUSION: Patients with stage IV EOC initially respond to chemotherapy as often as those with less advanced disease, but the long-term prognosis is very poor. The size of residual disease is not a prognostic factor in this group of patients, and, therefore, the role of debulking surgery in these patients needs to be reconsidered.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
EPITHELIAL OVARIAN CANCER (EOC) is the most common cause of death from gynecologic malignancy in the United Kingdom, as well as in Europe and the United States.^1-3 The most powerful prognostic factor that determines outcome is the stage of disease at presentation⁴; most patients with early-stage EOC survive, whereas only a minority of patients with advanced EOC are cured.^4,5 The majority of patients present with advanced disease because early EOC is often asymptomatic, and this may account for the overall poor prognosis of this cancer. Stage IV EOC is relatively rare, occurring in a minority of patients (16%),⁶ and it is noted for its very poor long-term survival.⁴

In most therapeutic studies, stage IV patients are entered together with those who have stage III and sometimes stage II disease. This is because stage IV EOC is relatively rare, and there are seldom enough patients within an individual study to allow a meaningful separate statistical analysis of stage IV patients. Thus, there is little specific data on stage IV EOC and no assessment of whether or not the biology of this stage is different from that of others. For instance, it is not certain whether the distribution of age, histologic subtype, response to chemotherapy, and prognostic factors are different compared with patients with stage III EOC. The issue of the biology of this stage of EOC is important, because this group of patients could be separately targeted for more aggressive and innovative treatments in view of their poor prognosis, and if successful, these treatments could then be further evaluated in other groups of patients with EOC. To examine some of these issues, we present here the largest single series of patients with stage IV EOC. This study has allowed us to perform a detailed analysis of the natural history of these patients and the prognostic factors that influence their outcome.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patients
All patients presenting to the Royal Marsden Hospital in London between 1972 and 1994 with a diagnosis of stage IV EOC were eligible for this study. Although we now keep prospective computerized records, because the study period spanned so many years, the clinical notes of all patients—containing details of surgery, chemotherapy, and follow-up—were also reviewed retrospectively. These data were collected onto proformas and entered into a computer program specifically designed for this study. Stage IV disease was defined according to the criteria outlined by the Oncology Committee of the International Federation of Gynecology and Obstetrics (FIGO) at the 1985 meeting and first published in 1987.⁷ The FIGO definition of stage IV disease is as follows: "growth involving one or both ovaries with distant metastasis. If pleural effusion is present, there must be positive cytology test results to allot a case to stage IV. Parenchymal liver metastasis equals stage IV." Histologic material was reviewed prospectively at the time of diagnosis and was classified as serous, mucinous, endometrioid, clear cell, unclassified, or mixed.⁴ Differentiation was recorded as "well" (grade 1), "moderate" (grade 2), "poor" (grade 3), or "not graded"; grading was based on the least differentiated component of the tumor.

A total of 285 patients were referred to the Royal Marsden Hospital with a presumptive diagnosis of stage IV EOC. We excluded 34 patients for the following reasons: pleural effusion without positive cytology (three patients), metastatic adenocarcinoma of unknown origin (three patients), Krukenberg's tumor (one patient), borderline tumor (two patients), pseudomyxoma peritonei (one patient), concomitant other malignant disease (four patients: breast carcinoma, three patients; colon carcinoma, one patient), nonepithelial histology on review (six patients: carcinosarcoma, four patients; teratoma, one patient; androblastoma, one patient), and clinical records unavailable for verification (14 patients). There were an additional 59 patients who were initially thought to have stage IV disease by virtue of liver metastasis but were found on examination of the surgical note or on imaging to have liver surface deposits only; these patients were therefore not included in the analysis. Thus we analyzed 192 patients with documented stage IV invasive EOC.

Treatment
Surgery was performed at the referring hospital in 162 patients and at the Royal Marsden Hospital in seven patients; radiotherapy and chemotherapy were administered at the Royal Marsden Hospital. One hundred ninety of 192 patients received first-line chemotherapy; 163 patients were treated with platinum-based regimens, 14 were treated with single-agent paclitaxel, and 13 were treated with other drugs. Two patients did not receive chemotherapy: one patient was not well enough to receive treatment and the other patient refused therapy. Seventy-two patients were treated out of study, and 118 (62%) were entered onto prospective phase II or III trials^8-13 (Table 1). The patients who were treated out of study received the following chemotherapy: cisplatin alone (13 patients), cisplatin in combination (10 patients), carboplatin alone (33 patients), carboplatin in combination (four patients), or other chemotherapeutic agents (12 patients: chlorambucil, seven patients; vincristine-fluorouracil-procarbazine-cyclophosphamide in combination, three patients; mitozantrone, two patients). The details of treatment for patients treated in a study are listed in Table 1.

Response Assessment
Responses were assessed according to standard criteria¹⁴ : complete response (CR) was defined as complete disappearance of all disease for at least 4 weeks; partial response (PR) was defined as a decrease of 50% in the sum of the products of the perpendicular diameter of all measured lesions without the appearance of any new lesions for at least 4 weeks; progressive disease (PD) was defined as development of new lesions or an increase in any measured lesion of 25% of the products of two perpendicular diameters; stable disease (SD) was defined as no change in measurable lesions or changes that do not fulfill the criteria for either PR or PD for at least 8 weeks.

Statistical Methods
We analyzed the duration of response, progression-free survival (PFS), and overall survival (OS) in the 190 patients who received chemotherapy. The duration of response was calculated from the first day of chemotherapy to the date of progression. PFS was similarly calculated from the first day of chemotherapy to the date on which progressive disease was first noted. Patients whose disease progressed on chemotherapy and who were therefore never progression-free were considered to have a time to progression of zero. Patients who died without disease progression were counted as having events for the PFS curves. OS was calculated from the first day of chemotherapy to death, patients who were still alive at last the follow-up appointment were censored. Life-tables were constructed to examine PFS and OS using the Kaplan-Meier method¹⁵ and were compared using the log-rank test.¹⁶ Multivariate analysis of prognostic factors was undertaken using Cox proportional hazards regression.¹⁷

	RESULTS

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Patient Characteristics
The characteristics of the 192 patients analyzed are listed in Table 2. The median age of patients was 56 years (range, 20 to 86 years) and the majority had a World Health Organization performance status of 0 to 1. Histologic subtyping was performed in 159 patients and was as follows: serous, 76%; mucinous, 9.5%; mixed, 6%; clear cell, 5%; endometrioid, 4%. It was not possible to classify 33 tumors. One hundred sixty-six tumors were graded as follows: grade 1, 3%; grade 2, 36%; grade 3, 61%.

We analyzed the distribution of stage IV–defining metastatic sites in all 192 patients (Table 3). We have used the term metastases in this report to describe only those sites that define a patient as having stage IV disease and have not taken into account other (non–stage IV-defining) disease; eg, intra-abdominal lymph nodes or peritoneal involvement. The most common sites of stage IV–defining metastases were cytologically positive pleural effusion only (33%), parenchymal liver metastasis (26%), and metastatic lymph node disease (13%). Six patients (3%) presented with lung metastases alone and 15 patients (8%) presented with disease at other sites: umbilical nodule, three patients; spleen, three patients; abdominal wall subcutaneous nodule, two patients; anterior abdominal wall infiltration, two patients; sternal mass (soft tissue), one patient; adrenal gland, one patient; gall bladder, one patient; vaginal nodules, one patient; and brain, one patient. Thirty-two patients (17%) presented with disease at multiple stage IV–defining (metastatic) sites. Methods used to diagnose disease at single stage IV–defining sites are listed in Table 3.

Thirty-eight patients (20%) underwent complete surgery, ie, total abdominal hysterectomy (TAH), bilateral salpingo-oophorectomy, omentectomy, or completion surgery after having previously had gynecologic surgery (eg, hysterectomy for fibroids). Ninety-two patients (48%) had incomplete surgery, including 26 patients who had a TAH and BSO but no omentectomy. Thirty-nine patients (20%) had a biopsy only. Residual disease status was known in 175 patients (91%); of these, seven patients (4%) were left without any residual disease, 18 patients (10%) had residual disease less than 2 cm, 143 patients (82%) had residual disease 2 cm, and seven patients (4%) had residual disease of unrecorded size. Thirty-eight patients underwent secondary interval surgery after completion of chemotherapy; three of these patients became long-term survivors (see Response to Chemotherapy). Thirteen patients were rendered disease-free after surgery, of whom two became long-term survivors; 13 patients had residual disease less than 2 cm, of whom one survived long term. Twelve patients had residual disease greater than 2 cm after interval surgery.

Response to Chemotherapy
One hundred sixty-seven patients with measurable disease were treated, five patients with assessable disease only were treated, and 18 patients who were not assessable were treated (pleural effusion only, five patients; failure to complete two cycles, eight patients; no residual disease after surgery, three patients; no postchemotherapy assessment, two patients). The method of response assessment in the 167 patients with measurable disease was as follows: clinical, 16 patients; computed tomography (CT), 41 patients; ultrasonography, 92 patients; second-look surgery, 11 patients. The method of assessment was not recorded for seven patients. The total number of cycles administered was 846; the median number per patient was four (range, one to 12 cycles).

Table 4 shows the first-line response data for patients with measurable disease: 30 patients (18%) achieved a CR (30 of 167 patients; 95% confidence interval [CI], 12 to 24) and 63 patients (38%) achieved a PR (63 of 167 patients; 95% CI, 30 to 45) . The OR for patients with measurable lesions was, therefore, 56% (93 of 167 patients; 95% CI, 48 to 63). The median duration of response was 10.5 months (range, 2.9 to 75+ months). The OR for patients with measurable disease treated with a platinum-based regimen in a study was 61% (57 of 94 patients; 95% CI, 50 to 71); 18 patients achieved a CR (18 of 94 patients or 19%; 95% CI, 12 to 29) and 39 patients achieved a PR (39 of 94 patients or 41%; 95% CI, 31 to 52). The OR for patients with measurable disease treated out of a study with a platinum-based regimen was 57% (30 of 53 patients; 95% CI, 40 to 70); 10 patients achieved a CR (10 of 53 patients or 19%; 95% CI, 9 to 32) and 20 patients achieved a PR, (20 of 53 patients or 38%; 95% CI, 25 to 52). Responses at sites of stage IV–defining disease were as follows: liver and lung, 45%; pleura, 59%; and lymph nodes or other sites, 68%.

One hundred eleven patients received second-line chemotherapy for relapsed or primary resistant disease. Among patients with measurable disease, the response rate was 23% (19 of 81 patients,) with six patients achieving a CR. The response duration in these patients was 10 months (range, 3.1 to 16.7 months). Thirty-three patients received third-line chemotherapy, but only three of 23 patients with measurable disease responded (13%). Twenty-three patients underwent radiotherapy as follows: to the primary lesion (pelvic radiotherapy), eight patients; for local relapse, one patient; for a metastatic lesion, 12 patients (umbilical nodule, two patients; brain, two patients; liver, one patient; bone metastasis, four patients; peripheral lymph nodes, three patients); and whole abdominal radiotherapy for peritoneal/intra-abdominal involvement, four patients.

Survival
The median follow-up period for surviving patients was 32 months (range, 8 to 154 months). The median PFS after first-line chemotherapy was 7.1 months (range, 0 to 75+ months), the median survival was 13.4 months (range, 0 to 122+ months), and the 5-year survival rate was 7.6% (95% CI, 4.1 to 12.6) (Fig 1).

View larger version (12K): [in this window] [in a new window]   Fig 1. Overall survival.

A univariate analysis for OS was performed on the following parameters: age, performance status, histologic type and differentiation, size of residual disease after primary surgery (< 2 cm v 2 cm), and whether or not patients were treated as part of a prospective study. None of these factors influenced OS (Table 5). We then investigated the prognostic significance of site of stage IV–defining (metastatic) disease: lung, liver, spleen, adrenal, vagina, brain, skin, lymph nodes, and pleura. Initially, only patients with disease at a single metastatic site were included. This univariate analysis suggested that OS was significantly different (P = .03) according to the site of stage IV–defining disease, patients with disease in liver or lung having the worst prognosis and patients with disease in lymph nodes or other having the best prognosis (Table 5). The effect of pleural involvement was intermediate between these two groups but was not clearly distinct from either using a pairwise comparison. A second univariate analysis included patients with multiple sites who were allocated to the group corresponding to their worst site of involvement according to the previous analysis (for example, a patient with pleural and liver involvement was allocated to the visceral group and a patient with pleural and lymph node involvement was allocated to the pleural group). The results were similar to those obtained in patients with single metastatic sites. The OS according to the site of disease was significantly different (P = .02), patients with disease in liver or lung having a worse prognosis than patients with disease in lymph nodes or other sites (Table 5 and Fig 2). The OS of patients with pleural involvement remained intermediate between these two groups but was not clearly distinct from either using a pairwise comparison. We also performed a univariate analysis according to the year of diagnosis and found that OS was different according to the year of treatment (P = .005; Table 5), with a trend-test in favor of patients treated recently (P < .01). As a result, we also examined the effect on PFS and OS of the use of platinum-based (n = 163) or nonplatinum-containing (n = 13) chemotherapy as first-line treatment. We did not include the patients treated with paclitaxel alone, because the study was only recently completed and, therefore, has a relatively short follow-up period. PFS was significantly different in favor of patients treated with a platinum-based regimen (P = .004), but no difference in OS was found. We must emphasize that among patients initially treated with a nonplatinum-based regimen, seven patients received platinum in second- or third-line treatment, and only six patients never received a platinum drug.

View larger version (16K): [in this window] [in a new window]   Fig 2. Overall survival according to site of stage IV–defining disease. Patients with more than one site were analyzed according to the site with the worst prognosis on multivariate analysis.

The finding that the date of diagnosis and the site of stage IV–defining disease in patients with a single metastatic site influenced OS allowed us to perform a multivariate analysis to examine whether or not these two parameters were independent factors (Table 6). Patients with lung or liver disease had a worse PFS and OS compared with patients with lymph node disease or other metastatic sites (P = .002 and P = .005, respectively). Patients with pleural disease had a significantly worse OS than did patients with lymph node disease or other metastatic sites (P = .05) but their prognosis did not differ significantly from those with lung or liver disease. With regard to PFS, pleural disease conferred an intermediate but not significantly different prognosis to the other disease sites. In addition, PFS and OS were significantly better after 1984 than they were before 1980 (Table 6).

Long-Term Survivors
Six patients (median age, 49 years; range, 41 to 54 years) survived more than 5 years; their characteristics are detailed in Table 7. The stage IV–defining metastatic sites in these six patients were as follows: pleural effusion only, two patients; multiple sites including liver involvement, two patients; and multiple sites without liver involvement, two patients. In all of these patients, the residual disease after primary surgery was > 2 cm; three patients had poorly differentiated tumors. The performance status was 0 to 1 in four patients, with two patients having a performance status of 2 and 3, respectively. All patients responded to first-line chemotherapy; five patients achieved a CR and one achieved a PR. Secondary interval surgery was undertaken in three of these patients after the fourth and fifth cycles of chemotherapy (TAH and bowel resection, one patient; omentectomy, one patient; and biopsy only, one patient). Four patients relapsed at 2.5, 3.8, 5.7, and 6.8 years from diagnosis. Four long-term survivors remain alive without any evidence of disease. Among these, two relapsed and went into CR after second-line chemotherapy; they are disease-free at 9.9 and 6.8 years from diagnosis. The other two survivors have never relapsed and are alive at 7.8 and 6.3 years.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
The FIGO definition of stage IV EOC is clear and unambiguous. Despite this, in our experience, more than 20% of patients (62 of 267 patients, or 23.2%) are incorrectly designated as having stage IV EOC by referring institutions. The most common error of staging involved uncertainty or confusion regarding the presence of parenchymal liver metastases as opposed to liver surface deposits. On examination of the surgical note or after imaging, 59 of 267 patients were found to have liver surface deposits only. Therefore, our experience suggests that unless there is a clear description in the surgical note of parenchymal liver metastasis, a postoperative abdominal CT or ultrasonography is mandatory to adequately stage patients. There was a failure to perform cytology on the pleural fluid in an additional three patients. In this series, disregarding patients with pleural effusions, there were an additional 12 patients who were defined as having stage IV disease by virtue of intrathoracic metastases (pulmonary metastases, six patients; mediastinal lymphadenopathy, one patient; internal mammary lymphadenopathy, two patients; and paracardiac nodes, three patients). In the nine patients with disease in the lung, mediastinal nodes, or internal mammary lymph nodes, the chest x-ray was abnormal. A CT scan of the thorax was performed in eight of these patients, but it failed to provide any useful additional information. The remaining three patients had paracardiac lymph node involvement, which was diagnosed after a careful evaluation of the abdominal CT. We would therefore recommend that CT scans of the thorax do not form part of the routine staging investigations for patients with advanced EOC, but that a chest x-ray and abdominal CT with careful examination of the paracardiac nodes is sufficient.

We compared the characteristics of our patients with those of patients entered onto the larger randomized therapeutic trials in advanced EOC in which 70% to 100% of patients have stage III disease.^18-25 In these studies, the median age of patients ranges from 56 to 60 years, the performance status ranges from 0 to 1 in 77% to 86% of patients and from 2 to 3 in 5% to 18% of patients, and the tumors are serous in 46.5% to 66% of patients and poorly differentiated in 54% to 95%.^18-25 These patient characteristics are very similar to those found in our stage IV patients. A number of independent prognostic factors predicting for survival in patients with advanced EOC, apart from stage, histology and chemotherapy regimen, have been suggested and include age,^26,27 performance status,^20,26-28 size of residual disease after primary surgery,^20,22,27,28 and race.²⁶However, none of these factors are constantly recognized as independent prognostic factors (Table 8). Moreover, these series have included either stage III patients only or were predominantly stage III patients; consequently, the prognostic factors are mainly stage III prognostic factors. From our data, it seems that age, performance status, and size of residual disease after primary surgery are not independent prognostic factors in stage IV disease. We did, however, identify two independent prognostic factors, namely, the site of stage IV–defining disease (visceral involvement, defined as lung or liver metastases) and the date of diagnosis (before 1984); both were associated with a shorter PFS and OS (Table 6). The prognostic significance of the year of diagnosis must be interpreted with caution. The better prognosis associated with diagnosis after 1984 could be due to improvements in chemotherapy or supportive measures, but it may equally be a consequence of changes in staging methods (eg, the wider use of abdominal CT).

Many studies, mainly involving patients with stage III disease, have demonstrated that residual disease after initial surgery has a very significant effect on survival.^20,22,27,28 The theoretical goal of primary debulking surgery is to achieve an optimal cytoreduction with residual disease less than 2 cm in diameter; this is in order to reduce the frequency of cells with genetic mutations encoding for proteins responsible for the mechanisms of chemoresistance.²⁹ However, in our univariate analysis, the size of residual disease after primary surgery (< 2 cm v 2 cm) is not a prognostic factor. This result suggests that there may still be some doubt about the value of aggressive debulking surgery at the time of presentation. This finding is inconsistent with the accepted view of the relationship between survival and size of residual disease and is best exemplified by the fact that all our long-term survivors had greater than 2 cm residual disease before chemotherapy despite attempts at debulking surgery. In our study, only 14% of patients had optimal residual disease before chemotherapy. This is lower than that of other reports on stage IV disease in which the range of patients with optimal residual disease is 33% to 45%.^30-33 In two series, the size of residual disease was a prognostic factor in a multivariate analysis^31,33; in one series, it was a prognostic factor in a univariate analysis³²; and in a fourth series, it was of no significance.³⁰ It has also been suggested that secondary debulking surgery (ie, after two to three courses of chemotherapy) confers a similar advantage.^34-36 In our series, 38 patients underwent secondary interval surgery, of whom 26 were optimally debulked (< 2 cm). The PFS and OS of these secondarily optimally debulked patients was the same as for those who had optimal cytoreduction at primary surgery. Data from randomized trials are required to clearly define the role of surgery in relation to stage, residual disease, and timing of chemotherapy, in particular to assess whether a reasonable strategy in stage IV patients might be not to strive to optimally debulk patients before chemotherapy, but to treat patients with chemotherapy first and then to proceed to surgery in those patients who do not have progressive disease. This question is to be addressed in a randomized study of the European Organization for Research and Treatment of Cancer (Trial 55871) comparing adjuvant versus neoadjuvant chemotherapy in stage III and IV disease. A neoadjuvant strategy would be consistent with the results of the recently published European Organization for Research and Treatment of Cancer trial in which patients with suboptimally debulked disease were randomized to chemotherapy alone or secondary debulking surgery after three courses of chemotherapy.³⁷ This study showed a 33% reduction in risk of death for patients who had a secondary debulking procedure (median survival, 26 v 20 months). There was no evidence that there was a difference between stage III and IV patients in this regard.

The OS of patients with stage IV disease in this and other series remains significantly worse than that of stage III patients. We have not been able to explain this on the basis of patient characteristics such as histologic characteristics, histologic subtype, or tumor grade. Similarly, response rates to chemotherapy seem to mirror those obtained in patients with stage III disease.^18-24 Furthermore, one of the most important prognostic factors in EOC, namely residual disease, does not seem to explain the dismal outcome of these patients. It is therefore possible that stage IV disease is biologically different from stage III, and perhaps treatment strategies for stage IV patients need not slavishly follow those set out for patients with stage III disease. More novel approaches to therapy (eg, high-intensity regimens) should be piloted in this group of patients, because despite the fact that the majority of patients with stage IV disease have a good performance status at presentation, more than 90% will be dead within 5 years of diagnosis.

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Submitted April 1, 1998; accepted November 4, 1998.

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