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Mucinous Epithelial Ovarian Cancer: A Separate Entity Requiring Specific Treatment

From the the Gynaecology Unit, Royal Marsden Hospital, London, United Kingdom.

Address reprint requests to Martin Gore, PhD, FRCP, Royal Marsden Hospital, Fulham Rd, London SW3 6JJ, United Kingdom; e-mail: martin.gore{at}rmh.nthames.nhs.uk

	ABSTRACT

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PURPOSE: Invasive mucinous carcinoma of the ovary (mucinous epithelial ovarian cancer [mEOC]) is a histologic subgroup of epithelial ovarian cancer (EOC). Chemotherapy for mEOC is chosen according to guidelines established for EOC. The purpose of this study is to determine whether this is appropriate.

PATIENTS AND METHODS: Women with advanced mEOC (International Federation of Gynecology and Obstetrics stage III or IV) who underwent first-line platinum-based chemotherapy were compared with women with other histologic subtypes of EOC in a case-controlled study.

RESULTS: Eighty-one patients (27 cases, 54 controls) treated with platinum-based regimens were analyzed. The response rates for cases and controls were 26.3% (95% CI, 9.2% to 51.2%) and 64.9% (95% CI, 47.5% to 79.8%), respectively (P = .01). The odds ratio for complete or partial response to chemotherapy for mEOC was 0.19 (95% CI, 0.06 to 0.66; P = .009) compared with other histologic subtypes of EOC. Median progression-free survival was 5.7 months (95% CI, 1.9 to 9.6 months) versus 14.1 months (95% CI, 12.0 to 16.2 months; P < .001) and overall survival was 12.0 months (95% CI, 8.0 to 15.6 months) versus 36.7 months (95% CI, 25.2 to 48.2 months; P < .001) for cases and controls, respectively. The hazard ratio for progression and death was 2.94 (95% CI, 1.71 to 5.07; P < .001) and 3.08 (95% CI, 1.69 to 5.6; P < .001), respectively, for mEOC patients as compared with controls.

CONCLUSION: Patients with advanced mEOC have a poorer response to platinum-based first-line chemotherapy compared with patients with other histologic subtypes of EOC, and their survival is worse. Specific alternative therapeutic approaches should be sought for this group of patients, perhaps involving fluorouracil-based chemotherapy.

	INTRODUCTION

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Mucinous carcinoma of the ovary (mucinous epithelial ovarian cancer [mEOC]) accounts for 7% to 14% of all primary epithelial ovarian cancer (EOC) [1]. In general, patients with this histologic subtype of EOC undergo the same first-line treatment as patients who fall into other, more common histopathologic groups. On the basis of randomized controlled trials (RCTs), the current standard treatment is surgery followed by platinum-based chemotherapy [2-6].

However, the number of patients with mucinous histology in these RCTs for advanced disease is relatively small. The two Gynecologic Oncology Group (GOG) trials (GOG 111 and 132) that evaluated the role of paclitaxel as first-line treatment for advanced disease included 14 and 16 patients with mEOC [2,4]. In the European-Canadian study (OV-10), which was similar to GOG 111, 30 of 680 patients had mucinous histology [3], and Neijt et al [5] reported on only 11 mEOC patients in their comparison of cisplatin plus paclitaxel and carboplatin plus paclitaxel. In the largest RCT in ovarian cancer (International Collaborative Ovarian Neoplasm Group 3 [6]), the number of patients with mucinous histology was 148, but one third of patients had stage I or II disease, so the actual number of mEOC patients with advanced disease is smaller than this. Furthermore, the impact of what is now regarded as standard chemotherapy is difficult to ascertain because patients with all stages were enrolled and only 45 mEOC patients in total received carboplatin plus paclitaxel because of the 2:1 randomization in this trial. The authors of both GOG 111 [2] and the International Collaborative Ovarian Neoplasm Group 3 trial [6] state that their conclusions did not alter when the histologic subgroups were analyzed separately. However, this relates to intertreatment comparisons, and none of the above RCTs report response and survival data for the mucinous subgroup as an entity separate from other histopathologic subtypes.

It has been suggested that mEOC behaves differently to the more common histologic subtypes of EOC, and to examine this possibility, we specifically investigated the efficacy of platinum-based first-line chemotherapy in patients with advanced mEOC.

	PATIENTS AND METHODS

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The study group consisted of all patients with advanced (International Federation of Gynecology and Obstetrics stage III or IV) mEOC treated with a first-line platinum-based therapy on the Gynecology Unit of the Royal Marsden Hospital (RMH) in London, United Kingdom, between September 1992 and January 2001. For each case, two controls with advanced non-mEOC undergoing first-line platinum-based therapy were randomly chosen from the unit's database. Controls were matched for date of diagnosis and stage of disease, in this order of priority.

In all patients (cases and controls), the diagnosis had to be histologically confirmed. Histopathologic slides had to be available and were reviewed by the RMH pathologists to the Gynecology Unit. No patients with tumor of borderline malignant potential were included. Patients with primary peritoneal tumors were excluded.

Data of cases and controls were obtained using electronic patient records, and the following parameters were collected: histology (defining cases v controls), age, date of diagnosis (matched), stage of disease (III or IV, matched), grade, measurability of disease, residual disease after primary surgery, tumor markers (CA-125 and carcinoembryonic antigen) before and after chemotherapy, chemotherapy regimen (type of platinum-based therapy), number of cycles, response to treatment, time to progression, and date of death or last follow-up. All treatment was given at the RMH, and electronic records of the RMH pharmacy were used to verify the chemotherapy regimen, dose, and number of cycles administered. Imaging (usually computed tomography scan) was performed at baseline and after every two to three cycles or at the first sign of progressive disease. Computed tomography scans were performed at the RMH, or outside films were reviewed by an RMH radiologist. Response to chemotherapy was assessed according to WHO criteria in all patients with measurable disease [7].

Time to progression was defined as the time between the first day of treatment and either radiologic evidence of progressive disease or the first day of second-line treatment, whichever came first. Follow-up for all patients after treatment was at least every 3 months for the first year and then at least every 6 months until death.

Statistical Analysis
The study design was a retrospective, case-controlled study, and the case-to-control ratio was 1:2. The two groups were compared using 2 x 2 tables for binary factors (optimal debulking v no optimal debulking; single-agent platinum v platinum-based combination therapy; age < 60 years v age 60 years; performance status; stage III v IV disease; case v control) using Fisher's exact test. The Mann-Whitney U test for trend was used to compare ordered categoric data (grades 1, 2, 3). Significance level for all analyses was .05, and CIs quoted for proportions are exact CIs. Odds ratios (ORs) were calculated using the logistic model. Overall survival (OS) and progression-free survival (PFS) were compared between different groups using the log-rank test; hazard ratios (HRs) for both univariate and multivariate analysis were calculated by the Cox proportional hazards model. Life-table curves were calculated using the Kaplan-Meier method [8]; 95% CIs for 2-year event rates are shown on the plots.

	RESULTS

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Patient Characteristics
Fifty patients with a histologically confirmed diagnosis of invasive mEOC presented at the Gynecology Unit of the RMH between September 1992 and January 2001. Fourteen patients had stage I or II disease and were therefore not included. Seven other patients were not included because they were treated at peripheral centers and follow-up data were incomplete. Another two patients were lost to follow-up and were excluded from the analysis. The final study group therefore consisted of 27 patients with advanced mEOC (International Federation of Gynecology and Obstetrics stage III or IV), and all of these patients underwent first-line platinum-based chemotherapy. Four of these 27 patients received their first-line chemotherapy at first relapse after a policy of observation only for stage IA disease (diagnosed 2 to 6 years earlier). The 54 control patients with advanced non-mEOC were matched for the date of diagnosis as well as for the stage of disease. Patient characteristics of both the study and control groups are shown in Table 1.

The histopathologic subtypes in the control patients were as follows: serous adenocarcinoma (68%), adenocarcinoma not otherwise specified (13%), endometrioid (4%), mixed serous/endometrioid (9%), and clear-cell carcinoma (6%). Despite the advanced stage of the patients, histology was well differentiated in 15% of patients in the mucinous group and 6% of patients in the control group, but this difference was not statistically significant.

Before chemotherapy, the serum CA-125 was elevated in 77% of patients with mEOC and in 85% of patients in the control group. The absolute values of CA-125 at diagnosis were lower for patients with mEOC (mean, 290 U/mL; 95% CI, 67 to 513 U/mL) as compared with controls (mean, 682 U/mL; 95% CI, 379 to 985 U/mL; P = .05). Carcinoembryonic antigen was more often assessed at baseline in the mEOC patients (16 patients; 59%). It was elevated in two patients (13%) with mEOC, but it was normal in all of the 19 control patients in whom it was assessed.

Chemotherapy
Patients were matched for the date of diagnosis to correct for changes in treatment over time, and the two groups were well balanced in this regard. In each group, one third of patients were treated with single-agent platinum (33% with mEOC; 35% in the control group). Platinum-based combination therapies were administered to 67% and 65% of patients with mEOC and non-mEOC, respectively. The mean number of administered courses of first-line chemotherapy was 4.44 in the study group and 5.48 in the control group (P = .01). In the mEOC group, 52% of patients underwent fewer than the planned six cycles; in contrast, 81% of the control patients completed six or more cycles of chemotherapy (P = .004). These statistically significant differences may reflect the relative chemoresistance of mEOC and the different progression rates between the two groups of patients (see below).

Response and Survival
In the mEOC group, 63% of patients experienced disease progression while on platinum-based chemotherapy. One patient achieved a complete response, and four of 19 patients with measurable disease achieved a partial remission. The overall response rate was therefore 26.3% (95% CI, 9.2% to 51.2%) in the study group. The overall response rate in the 37 patients with measurable disease in the control group was 64.9% (95% CI, 47.5% to 79.8%), including six patients (16%) who had a complete response (P = .01).

The OR for response (complete and partial) for the mEOC versus the control group was 0.19 (95% CI, 0.06 to 0.66; P = .009). On univariate analysis, age (< 60 years v > 60 years), performance status, stage (IV v III), histopathologic grade (1, 2, 3), and chemotherapy regimen (single-agent platinum v combination chemotherapy) were not found to be significant predictors of response. There was a suggestion that stage was important; the OR (stage IV v III) was 0.245 (95% CI, 0.058 to 01.037; P = .056).

Median PFS for mEOC patients was 5.7 months (95% CI, 1.9 to 9.6 months) as compared with 14.1 months (95% CI, 12.0 to 16.2 months) in the control group (P < .001; Fig 1). The HR for risk of progression for patients with mEOC as compared with controls was 2.94 (95% CI, 1.71 to 5.07; P < .001) on univariate analysis. Stage of disease (IV v III) was the only other significant factor for predicting PFS on univariate analysis (HR, 2.12; 95% CI, 1.09 to 4.12; P = .03), but this factor lost its significance in the multivariate model.

View larger version (24K): [in this window] [in a new window]   Fig 1. (A) Progression-free and (B) overall survival for patients with mucinous epithelial ovarian cancer and matched controls. PFS, progression-free survival; OS, overall survival.

	DISCUSSION

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This case-controlled study shows that mEOC is less responsive to platinum-based chemotherapy compared with other histologic subtypes of EOC. Furthermore, patients with advanced mEOC have a worse PFS and OS. The significant difference in platinum sensitivity of mEOC compared with other EOC, as demonstrated here, challenges the current practice of treating all patients with EOC with the same first-line chemotherapy regimen and raises the possibility that mEOC may represent a separate disease entity. It has previously been recognized that the natural history of mEOC differs from that of other histologic subtypes of EOC. It is more often diagnosed at an early stage and therefore confers a better overall prognosis for survival [1]. Conversely, once the disease is advanced, mucinous histology has been associated with a poorer survival than other histopathologic subgroups [9-11]. The mechanisms leading to this more aggressive course for patients with advanced disease have not been studied in detail. Failure to respond to platinum-based treatment, as shown here, would explain a poorer survival in mEOC patients, because platinum-sensitivity is one of the main prognostic factors for patients with advanced EOC [12].

Investigating mEOC as a separate entity to other histopathologic subtypes of EOC is complicated by several factors. First, the rarity of the disease accounts for the fact that subgroup analyses of mEOC in RCTs of EOC [2-5] can rarely be performed because of a lack of statistical power of any conclusion. Second, different histopathologic definitions of mucinous carcinoma make it difficult to compare studies that focus on this group. Third, many reports combine borderline and invasive mucinous carcinoma [13-15] or patients with early and advanced disease stages [16]. Finally, differentiating mEOC from gastrointestinal cancer [17,18], mainly carcinomas of the appendix and colorectal cancer, by morphology alone can be difficult. To allow unambiguous conclusions, the mEOC patients studied here represent a fairly homogenous group: all presented with invasive disease and had stage III or IV disease, and an ovarian primary was strongly suggested by history, disease distribution, histology, and tumor markers.

Recent molecular studies support the hypothesis that mEOC represents a biologically distinct entity. Several groups [19,20] have found that mutations in the tumor suppressor gene p53, which are often observed in serous EOC, do not seem to be present as often in mEOC. In contrast, the k-ras oncogene is often overexpressed in mEOC but is rarely overexpressed in serous EOC [20]. Interestingly, k-ras is also known to be overexpressed in mucinous carcinomas of gastrointestinal origin, such as colorectal or pancreatic cancer [21]. Similarly, cDNA microarray studies on ovarian clear-cell carcinoma [22], another rare histopathologic subtype of EOC, have shown similar genetic patterns to those found in clear-cell carcinoma of the endometrium and kidney rather than the microarray findings in the other histologic subgroups of EOC. These observations suggest that we should perhaps base our treatments on the molecular characteristics of tumors rather than their organ of origin.

Treatment options tailored to the mucinous nature of the histology of patients with mEOC should be considered in future studies. For instance, we hypothesize that there may be a role for fluorouracil, which is the mainstay of treatment for mucinous gastrointestinal carcinomas, although good evidence from randomized studies is obviously required before such an approach could be recommended. Shimizu et al in Japan [23], where mEOC seems to be more common [24], suggested that irinotecan might be effective in this histologic subtype. Based on in vitro chemosensitivity data [25], they conducted a phase II trial [23] of combined irinotecan and mitomycin in 25 patients with platinum-refractory clear-cell and mucinous ovarian carcinoma. The overall response rate was reported to be 52% and the median OS was 15.3 months.

Our data suggest that perhaps patients with advanced mEOC should be excluded from future trials of first-line chemotherapy for ovarian cancer or at least be analyzed separately. Initial trials for these patients might explore the role of the more commonly used regimens for gastrointestinal cancers, such as fluorouracil, irinotecan, or oxaliplatin.

	Authors' Disclosures of Potential Conflicts of Interest

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The authors indicated no potential conflicts of interest.

	NOTES

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

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
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Submitted August 11, 2003; accepted December 22, 2003.

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