MARGARETHA ÅKESON 1,2, BRITT-MARIE ZETTERQVIST 3, KALLE DAHLLÖF 4, MATS BRÄNNSTRÖM 5 &GYÖRGY HORVATH 1

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1 Acta Obstetricia et Gynecologica. 2008; 87: ORIGINAL ARTICLE Effect of adjuvant paclitaxel and carboplatin for advanced stage epithelial ovarian cancer: A population-based cohort study of all patients in western Sweden with long-term follow-up MARGARETHA ÅKESON 1,2, BRITT-MARIE ZETTERQVIST 3, KALLE DAHLLÖF 4, MATS BRÄNNSTRÖM 5 &GYÖRGY HORVATH 1 1 Department of Oncology, Sahlgrenska Academy, Gö teborg University, Gö teborg, Sweden, 2 Division of Obstetrics and Gynecology, SÄ S, Borås, Sweden, 3 Division of Obstetrics and Gynecology, NÄ L, Trollhä ttan, Sweden, 4 Regional Oncologic Centre, Western Sweden Health Care Region, Gö teborg, Sweden, 5 Department of Obstetrics and Gynecology, Gö teborg University, Gö teborg, Sweden Abstract Objective. To evaluate long-term survival and prognostic factors for all epithelial ovarian cancer (EOC) patients after adjuvant treatment with paclitaxel and carboplatin. Design. Prospectively collected data from a population-based cohort. Setting. Western Sweden Health Care Region. Population. All women diagnosed with EOC between 1998 and Methods. Data related to age, stage, surgery, histopathology, grade, ploidy status, CA-125, follow-up, recurrence and death of EOC patients (n976) were prospectively collected in a quality register. No patient was lost to follow-up and the median follow-up was 68 months (range: 27110). Main outcome measures. Relative survival at 5 and 8 years for all and for those treated with chemotherapy; median progression-free survival (PFS) for stage IIBIV patients treated with paclitaxel and carboplatin. Results. Relative 5- and 8-year survival rates in the subgroup of patients treated with chemotherapy after surgery (n853) were 50.4% (95% CI: ) and 40.5% (95% CI: ), respectively. The median relative survival time of the entire group of patients was 60 months (95% CI: 5273). The median PFS for the patients in stage IIBIV treated with paclitaxel and carboplatin was 18 months (95% CI: 1720). Well-established prognostic factors of age, stage, residual tumor and post-operative CA-125 were of prognostic significance. Conclusion. Post-surgical adjuvant chemotherapy of paclitaxel and carboplatin for advanced stages of EOC does not seem to increase the relative 5-year survival rate or the median PFS compared to results of earlier studies of a similar patient cohort from the same geographical area. Key words: Long-term survival, paclitaxel, surgical centralization, prognostic factors, ovarian cancer Introduction Ovarian cancer is the most common cause of death from gynaecologic malignancy in Sweden and the rest of the Western world (1). There has been a decline in the age-standardized incidence in Sweden, from 22.6 per 100,000 women in 1986 to 15.3 in 2005 (2). The decrease in incidence of epithelial ovarian cancer (EOC) in Sweden may partly be an effect of the more common use of ovulation-inhibiting oral contraceptives in age groups now reaching the peak for ovarian cancer, since this is one important protective factor (3). The relative 5-year survival rate of EOC patients reported by the Surveillance, Epidemiology and End Results (SEER) program in the US increased over about 20 years from 37% ( ) to 43% ( ) (4). Data from the Finnish Cancer Registry revealed a 5-year relative survival rate, ranging from 36.0% ( ) to 45.7% ( ) (5). A comparison between European and SEER registries found higher relative long-term survival rates in US patients for most cancers; however, ovarian cancer had a higher 5-year survival rate in Sweden and some other European countries (6). Correspondence: Margaretha Åkeson, Division of Obstetrics and Gynecology, SÄS, SE Borås, Sweden. makeson@tele2.se (Received 5 May 2008; accepted 20 September 2008) ISSN print/issn online # 2008 Informa UK Ltd. (Informa Healthcare, Taylor & Francis AS) DOI: /

2 1344 M. Åkeson et al. Most studies on long-term survival of EOC patients report results of advanced stages, selected populations or both (7,8). FIGO s Annual Report gave 5-year overall survival rates of 49.7% during the period (9), but the results may be biased by selection of populations. Thus, there is a need for population-based studies with complete follow-up. In the 1970s, platinum-based chemotherapy after surgery was recognized as a first-line therapy for EOC (10). Later, the introduction of paclitaxel in combination with cisplatin, in the landmark study GOG-111 (11), confirmed by the European Canadian Intergroup (OV 10) (12), led to a general change in treatment for advanced EOC, and soon the combination of paclitaxel and carboplatin became the gold standard. However, other studies could not confirm the superiority of paclitaxel over single-agent carboplatin or other platinum combinations not including paclitaxel (13,14). Recent results indicate superior results with intraperitoneal chemotherapy, although with a higher rate of toxic side effects (15). The aim of this study was to evaluate long-term survival and prognostic factors in an entire geographically based population of EOC patients, where advanced cases were treated with carboplatin and paclitaxel. This allowed us to compare their survival rate with a very recent earlier cohort (16) from the same area. Materials and methods From the Regional Oncologic Center of the Western Sweden Health Care Region (OC), we collected data from a prospective database of all new patients with invasive EOC from 1 June 1998 to 31 May In the period studied, 976 patients with EOC were reported to the OC quality register. All cases were re-examined by an experienced gyne-oncologic pathologist. To ascertain that all cases were included, we double-checked the material against the National Cancer Registry of Sweden (established 1958), which includes all cancer patients in Sweden reported by both clinicians and pathologists. In this register, we found 1,019 cases of EOC, but we excluded the extra 43 women because 33 of them were diagnosed incidentally at autopsy, six were considered after pathological review to have had a wrong diagnosis of EOC, and four had a very unclear diagnosis with no histological verification and with a clinical course not indicative of EOC. Of the 976 patients studied, 955 had a laparotomy, 15 had only a diagnostic surgical procedure and six had no surgery. No chemotherapy was given to 123 patients (12.6%) because of low risk (n 35, defined as diploid tumors stage IA, grade I), poor general condition (n 40), death before first treatment (n 36) or lack of patient consent (n 12). The remaining 853 patients were admitted from the five hospitals in the region to Sahlgrenska University Hospital s Oncology Department for final staging and the first chemotherapy treatment. New clinical guidelines with prospective data collection were implemented for western Sweden (population around 1.6 million) in 1993 and revised in The data registered and reported to the OC quality register were age, type of surgery (laparotomy with debulking surgery following strict clinical guidelines vs a diagnostic procedure when more extensive surgery seemed inappropriate), the size of residual disease after surgery (no macroscopic residual tumor, 51 or 1 cm of tumor left), FIGO stage, histopathology, grade, post-operative CA-125 levels, ploidy status, chemotherapy treatment, recurrence and death. In the new clinical guidelines from 1998, we introduced the chemotherapy regimen in advanced cases (FIGO stage IIBIV) with a combination of carboplatin 5 (GFR25) and paclitaxel (175 mg/m 2 ) every third week. Stage IIIA had chemotherapy treatment with single-agent carboplatin 7 (GFR25) every fourth week, which was identical to that of the previous guidelines from 1993 (16). The protocol included six courses of chemotherapy if complete remission (evaluated by palpation under general anesthesia, a normal CA- 125 value and, in some cases, CT scan). The chemotherapy courses given are described in Table I. Data on possible second or third lines of chemotherapy were not recorded. The distribution of FIGO stage is shown in Table II. The histopathology and grade of the tumors are shown in Table III. Tumor samples for DNA-ploidy analysis were taken perioperatively and could be evaluated in 667 cases. These were classified according to Hiddeman s system to define ploidy status (17). We used the staining solution developed by Lee et al. (18). Table I. Chemotherapy administered to patients with epithelial ovarian cancer from 1 June 1998 to 31 May Carboplatinpaclitaxel 540 Carboplatin 223 Carboplatinepirubicincyclophosphamide (8 primary because of allergic reaction to paclitaxel) Carboplatindocetaxel (study) 33 Carboplatinpaclitaxeltopotecan (study) 17 Carboplatinpaclitaxelgemcitabin 5 Various other combinations 16 Total 853

3 Lack of improved survival with paclitaxel 1345 Table II. Distribution of FIGO stage in 976 patients with epithelial ovarian cancer. Stage n (%) IA IB IC Total IIA IIB IIC Total IIIA IIIB IIIC Total IV Total Blood samples for analysis of CA-125 were obtained from patients after surgery and immediately before chemotherapy; in 745 cases (out of 853) we were able to evaluate the samples. The CA-125 values were divided in three different groups 535, 3665 and 65 U/ml. These cut-off levels were based on earlier studies (19,20). The data points not included in the statistical analysis of ploidy status and CA-125 are considered missing completely at random. No patient was lost to follow-up, and relative 5- and 8-year survival analyses for all patients were conducted at the end of August 2007, giving a median follow-up duration of 68 months (range: ). Reports on deaths were given in the quality register at OC and were checked with population registers. Information on cause of death was taken from the OC register and from the Cause of Death Register of Sweden. Table III. Histopathology and grade in 976 epithelial ovarian cancer tumors. Histopathology n (%) Serous cystadenocarcinoma Mucinous cystadenocarcinoma Endometrioid cancer Clear cell cancer Undifferentiated cancer Mixed tumor Total Grade High Moderate Low Undifferentiated or could not be assessed Total The Ethics Committee of Gothenburg University approved the study. Statistical methods SAS software was used for the statistical analysis. Relative survival was used for comparing survival between patient groups (21). Relative survival is the ratio between the observed survival rate in the patient group and the expected survival rate; thus it gives a measure of the excess mortality in the patient group. Annual mortality risk, in 1-year cohorts, for the entire female population of Sweden was used to calculate expected survival. Cox regression was used for univariate and multivariate analyses of prognostic factors. Median progression-free survival (PFS) was analyzed using the KaplanMeier method. Results The median age at diagnosis was 64 years (range: 2394) and the mean age was 63.2 years; the age distribution in 5-year age classes is shown in Figure 1. The relative 5- and 8-year survival rates in the entire sample were 48.8% (95% CI: ) and 39.7% (95% CI: ), respectively. The median relative survival times were 56 months (95% CI: 4865) for the entire sample and 30 months (95% CI: 2632) for the subgroup including only stages IIIIV. The relative 5-year survival rates per stage I, II, III and IV for all patients were 92.2, 82.5, 27.2 and 15.7%, respectively. When divided per age-class B70 years versus 70 years, the relative 5-year survival rates were 54.6% (95% CI: ) and 33.0% (95% CI: ), respectively (p B0.0001). The relative 5- and 8-year survival rates in the subgroup of patients with EOC treated with chemotherapy after surgery (n 853) were 50.4% (95% CI: ) and 40.5% (95% CI: ). The median relative survival time of this group of patients was 60 months (95% CI: 5273), and 36 months (95% CI: 3140) for the subgroup of stage IIIIV. The relative 5-year survival rates per stage I, II, III and IV for the subgroup receiving chemotherapy were 89.9, 83.0, 30.4 and 20.0%, respectively (Figure 2). For patients in stage IIBIV receiving carboplatin and paclitaxel chemotherapy, the relative 5-year survival rate was 33.3% (95% CI: ) and the median relative survival time was 40 months (95% CI: 3543). The median PFS for these patients was 18 months (95% CI: 1720). For the

4 1346 M. Åkeson et al. Figure 1. Age distribution in 5-year age-classes in percentage of all 976 epithelial ovarian cancer patients. patients in stage IIIA receiving single-agent carboplatin, the 5-year relative survival rate was 87.1% (95% CI: ). Table IV shows the overall and disease-specific survival rates, together with the relative survival rate for comparison, as well as stage-related relative survival. Patients with no residual tumor after surgery (n 434, 44.5%) who were treated with chemotherapy had a significantly better 5-year survival rate than those with 51 and1 cm tumor left (pb0.0001) (Figure 3). For patients with CA-125 values 535 U/ ml (n273) at the start of chemotherapy, the 5-year relative survival rate was 77.3%, while it was 60.1 and 29.1% for patients with CA-125 values of 3665 U/ml (n97) and 65 U/ml (n365), respectively (p B0.0001). For chemotherapy-treated patients with diploid tumors (n 169), the 5-year survival rate was 67.1% and for those with aneuploid tumors (n 424) it was 46.8% (p B0.0004). There were more aneuploid tumors in the higher FIGO stages, Figure 2. Relative 5-year survival according to stage in 853 epithelial ovarian cancer patients treated with chemotherapy. Values for p in relation to stage I: stage II pb0.26, stage III pb0.0001, stage IV pb

5 Lack of improved survival with paclitaxel 1347 Table IV. Relative survival (RS) compared to disease-specific survival (DS) and overall survival (OS) in all patients (n976) and those epithelial ovarian cancer patients treated with chemotherapy after surgery (n853), as well as stage-related 5-year RS. RS 95% CI 5-year RS/stage DS 95% CI OS 95% CI All 5-year 48.8% ( ) I 92.2% (n271) 47.0% ( ) 45.0% ( ) II 82.5% (n90) III 27.2% (n464) IV 15.7% (n151) 8-year 39.7% ( ) 40.7% ( ) 34.1% ( ) Treated 5-year 50.4% ( ) I 89.9% (n226) 48.7% ( ) 46.8% ( ) II 83.0% (n88) III 30.4% (n416) IV 20.0% (n123) 8-year 40.5% ( ) 42.0% ( ) 35.3% ( ) with aneuploidy in 51.2, 65.2, 76.9 and 84.5% of stages I, II, III and IV, respectively. In the subgroups of stage III there was aneuploidy of 58.3, 69.0 and 79.5% in stages IIIA, IIIB and IIIC (pb0.04). The 5-year survival rate also differed between patients with tumors of high, moderate or low grades of differentiation, at 83.7, 49.1 and 39.7%, respectively (pb0.0001). The results of univariate Cox regression analysis of the 853 EOC patients treated with chemotherapy after surgery are shown in Table V. Age, stage, residual tumor, serous histopathological subtype, grade, CA-125 level and ploidy status showed prognostic statistical significance. Complete data including CA-125 values for 745 patients was available for multivariate analysis. The factors showing prognostic significance were age, stage, residual tumor after surgery and post-operative CA-125 values 65 U/ml (Table VI). The different subtypes of histopathology did not show statistical significance and grade was only significant, with a hazard ratio of 1.7, when moderate and low grade was grouped together versus high grade (data not shown). Tumors from 253 patients out of 464 in the subgroup of stage III, where data on both ploidy status and CA-125 values were available, were also analyzed. In this subgroup stage IIIB, stage IIIC, and CA-125 ]35 were factors with increased hazard ratios, whereas ploidy status was not (Table VII). Discussion The present study is, to our knowledge, the only population-based study from the last decade to Figure 3. Relative 5-year survival according to residual tumor after surgery in 853 epithelial ovarian cancer patients treated with chemotherapy. Significantly different (pb0.0001) between no residual tumor and residual tumors 51 and 1 cm.

6 1348 M. Åkeson et al. Table V. Univariate Cox analysis of prognostic variables for 853 epithelial ovarian cancer patients treated with chemotherapy after surgery. Table VII. Multivariate Cox analysis of prognostic variables for the subgroup of 253 patients with stage III epithelial ovarian cancer tumors and existing values of CA-125 and ploidy status. Variable n Hazard ratio 95% CI Age (per 10 years) * Stage I II III * IV * Residual macroscopic tumor Tumor free (cm) * * Histopathological subtype Endometroid Mucinous Clear cell Serous * Grade High Moderate * Low * Undifferentiated or could not be * assessed CA-125 level B * * Ploidy status Diploid Aneuploid * *Prognostic variables. Table VI. Multivariate Cox analysis of prognostic variables including post-operative CA-125 values for 745 patients with epithelial ovarian cancer. Variable n Hazard ratio 95% CI Age (per 10 years) * Stage I II III * IV * Residual macroscopic tumor No residual (cm) * * CA-125 level B * *Prognostic variables. Variable n Hazard ratio 95% CI Stage IIIA IIIB * IIIC * DNA Aneuploid Diploid CA-125 level * *Prognostic variables. include all EOC patients from a defined geographical area with data on long-term survival and complete follow-up. The 5-year relative survival rate of the entire population was 48.8%, and for patients treated with chemotherapy after surgery it was 50.4%. The median PFS in patients of stage IIB IV, treated with carboplatin and paclitaxel, was 18 months. Multivariate analysis identified age, FIGO stage, residual tumor and post-operative CA-125 as prognostic factors. We consider relative survival analysis to be the most relevant method to describe survival of EOC patients, because it gives an indication of the excess mortality of EOC by taking into account the expected mortality rate of a well-controlled population (22). From the 1990s, there are reports from the US and Finland of relative 5-year survival rates of EOC patients of 4346% (4,5), the same general range as the present study. However, most studies of EOC only report either overall or disease-specific survival; in the present paper we give both these survival figures for comparison. Overall survival was used in a study looking at the effect of a centralized primary ovarian cancer surgery in Denmark, which reported a 4-year overall survival rate of 49.2% during the period (23). An advantage of that study is that it included nearly all (95.5%) patients in a defined geographical area. The present study represents 100% of the EOC patients in the region and we found a 5-year overall survival rate of 45%. However, the median overall survival times were similar in our study (47 months) and the Danish study (46 months). In keeping with the clinical guidelines, we have introduced a structure in the management of EOC patients, involving fewer gynecologic surgeons at the five hospitals in our region (16), but we have not centralized gynecologic surgery to one hospital. The outcome of ovarian cancer surgery is improved

7 Lack of improved survival with paclitaxel 1349 when performed by specialist teams and this could enhance median survival (2426). Many studies of survival data of EOC patients include only advanced stages of disease (10,27,28). The Gynecologic Oncology Group (GOG-111) during compared paclitaxel and cisplatin with cisplatin and cyclophosphamide in a randomized trial of 386 women of suboptimally debulked FIGO stage IIIIV EOC (11). They found the median PFS to be 18 months versus 13 months in favor of the paclitaxel-containing chemotherapy. This is in line with the median PFS of 18 months in the present study in women with stage IIBIV disease treated with paclitaxel and carboplatin. However, in the present study we included all cases receiving paclitaxel and carboplatin in stage IIBIV without selection and with a considerably longer follow-up time. The European-Canadian intergroup (OV10) study further supported the superiority of the paclitaxelcontaining chemotherapy (12). However, in the GOG-132 study of 614 EOC patients with stage IIIIV treated during the period , a threearm trial compared cisplatin, paclitaxel, and the two in combination (14). They found that cisplatin alone resulted in a significantly longer median PFS of 16.4 months versus 11.2 months for paclitaxel and 14.0 months for the combination. In that study, the overall survival did not differ significantly between the arms, and the authors admit a substantial amount of crossover in the three arms. The fourth large randomized study on this subject is the ICON 3 ( ), which included 2,074 EOC patients with FIGO stage IIV comparing paclitaxel and carboplatin with two different control arms. One control arm was with single-agent carboplatin and the other was with cyclophosphamide, doxorubicin and cisplatin (13). The study showed no difference in overall survival between the arms; the median PFS was 17.3 months in the paclitaxel and carboplatin combination and 16.1 months in the control arms. This is in the same range as the PFS of 18 months in the stage IIBIV patients treated with paclitaxel and carboplatin in the present study; however, in the ICON 3 study, they also included patients with stages I and IIA. These four large randomized studies with conflicting results are thoroughly discussed elsewhere (29), where it is suggested that the positive results in favor of the paciltaxel/cisplatin combination in two of these trials can be explained by the use of suboptimal control arms and that single-agent carboplatin is also a safe and effective chemotherapy treatment for advanced EOC. We have a unique opportunity to compare two historical cohorts from the same geographical area; one from the pre-paclitaxel era ( ) with one from the paclitaxel era ( ) of the present study. EOC patients in early stages were treated with the same chemotherapy (single-agent carboplatin) during the two time periods, whereas EOC patients of advanced stages (IIBIV) in western Sweden from 1993 to 1998 were treated with a regimen of carboplatin, cyclophosphamide and epirubicin (16). The relative 5-year survival rate of the advanced cases treated with carboplatin, cyclophosphamide and epirubicin in the first group was 34.3% (95% CI: ) (our unpublished results) and the relative 5-year survival rate of the patients treated with paclitaxel and carboplatin in the present study was 33.3% (95% CI: ). The cumulative relative survival during 5 years in each of the previous and the present study is shown in Figure 4. Furthermore, there was no difference in the median PFS for chemotherapy-treated patients with stage IIBIV of 19 months (95% CI: 1722) during the first period (Akeson et al; Int J Gynecol Cancer 2008 in press) and 18 months (95% CI: 17 20) during the present study. The relative 5-year survival rates of the single-agent carboplatin-treated patients (stage IIIA) during the two periods, and , were 81.9% (95% CI: ) and 87.1% (95% CI: ), respectively. We acknowledge that our comparisons are on populations of two different time periods and that the significance of this is less than when comparing two randomized treatment groups during the same period. However, the major strength of our studies is that they are of non-selected population. The samples in the two studies are very similar on several parameters, including mean age, percentage of patients with stage IIBIV (73.0 vs 70.4%), grade, histopathology and distribution of patients with no macroscopic residuals (41.9 vs 44.5% in the latter period). We want to stress that the relative 5-year survival rates and the median PFS of stage IIBIV EOC patients treated during the two periods were both very similar. It should also be pointed out that the introduction of paclitaxel in combination with carboplatin for treatment of gynecologic cancer has led to a greater risk of neurotoxicity (30,31). Furthermore, the cost of taxanes is considerably higher than that of traditional chemotherapy agents. The present study did not examine toxicity or cost because appropriate data were not available from the prospectively collected database. Similar results showing no advantage for paclitaxel and carboplatin over carboplatin and cyclophosphamide were shown in advanced EOC patients ]70 years (31). In the present study, age was of prognostic significance in both the univariate and the multivariate analyses, which confirms the results of earlier

8 1350 M. Åkeson et al. Figure 4. Relative 5-year survival in epithelial ovarian cancer patients stage IIBIV in period 1 ( ) (ref. 16) treated with carboplatin, cyclophosphamide and epirubicin (34.3%) and period 2 ( ) treated with carboplatin and paclitaxel (33.2%). publications (32,33). In patients aged 70 and older, we and others (31) found a lower 5-year survival rate than in younger patients. It is well established that survival in EOC patients is related to FIGO stage (34,35). We found in the multivariate analysis that stage was the most powerful prognostic factor with a hazard ratio of 4.1 in stage IV disease in relation to stage I. We defined low risk as stage IA, grade I, diploid tumor; women with low-risk cancer did not receive chemotherapy according to our clinical guidelines. The relative 5-year survival of all stage I patients was 92.2%, a rate only slightly better than for the subgroup of stage I patients having chemotherapy (89.9%). Thus, it seems reasonable to continue to exclude the defined low-risk group of women with stage IA EOC from chemotherapy. In a recent review of the literature from 1970 to 2006 regarding chemotherapy for early-stage EOC, the authors warn against overtreatment with chemotherapy considering the risks of the treatment versus the benefit to survival (36). The possible inclusion of ploidy status and other factors as determinants in dividing stage I EOC into high and low-risk groups was evaluated in a prospective study, where the patients were divided into two groups of equal size, one with carboplatin treatment and the other without (37). There was no difference in disease-specific survival between the groups, but when data was pooled for analysis of prognostic factors, it was found that DNA-ploidy, grade, extracapsular growth and tumor rupture were independent prognostic factors. In the present study, we found 51.2% of tumors at stage I to be aneuploid, and these patients were standardly treated with carboplatin. However, aneuploidy was not an independent prognostic factor in the multivariate analysis. The amount of residual tumor after surgery was the second strongest prognostic factor for survival in the multivariate analysis. In this study, we set the limits at not macroscopic, 51 and1 cm. In a study from the US of stage IIIC EOC using the same limits of residual tumor as the present study, significantly different survival rates were found between the groups (27). In the present study, the relative 5-year survival of patients treated with chemotherapy after surgery was 82.0% with no residual tumor, and 41.8 and 18.2% with 51 and 1 cm, respectively. In a meta-analysis including 6,885 patients with stage IIIIV ovarian cancer, it was concluded that each 10% increase in maximal cytoreduction would give a 5.5% increase in median survival time (38). The same analysis suggests that further centralization of primary surgery in EOC at expert centers would be the most effective way to enhance survival results. Evidence supporting that concept has been shown in studies in well-controlled populations in the Scandinavian countries (23,39,40). With further centralization, the rate of 44.5% of patients who had no residual tumor after surgery in the present study should be even higher. A practical way to implement additional centralization is to use the risk-of-malignancy index (RMI), a scoring system on menopausal status, ultrasound

9 Lack of improved survival with paclitaxel 1351 features and CA-125 introduced by Jacobs (41), which has been used with favorable results (42). A component of the RMI index is CA-125. Most studies of CA-125 take into account preoperative values or repeated values during follow-up (43). However, in our study, the post-operative CA-125 levels taken just before chemotherapy were used for analysis. This measure of CA-125, when grouped into the three groups of B35, 3565 and 65 U/ml, showed different relative 5-year survival rates; the level of 65 U/ml was an independent prognostic variable in the multivariate analysis. In the univariate analysis, we found serous histopathology as opposed to endometrioid histology, and moderate to low grade versus high-grade differentiation, to be significant factors for prognosis. In an earlier study from Sweden, mucinous tumors seemed to have a good prognosis in localized disease, but worse prognosis at higher stages (44). Mucinous and clear cell histology was associated with a worse PFS and OS in a recent review of six GOG studies on stage III EOC (45), but in the current study we could not identify any independent prognostic factors in the subgroups of histopathology in the multivariate analysis. Concerning grade, a study from the SEER database in the US, including over 26,000 EOC patients, found grade I tumors versus grade III tumors to be independent prognostic factors for improved survival (35). In the multivariate analysis of the present study, grade IIIII, when grouped together, were significant versus grade I. This is in concordance with previously published results (46). In summary, the present study of a whole cohort of EOC patients from western Sweden shows relative 5- and 8-year survival rates of around 50 and 40%, respectively in those patients treated with chemotherapy. Age, stage, residual disease after surgery and post-operative CA-125 were independent prognostic values. Moreover, patients with stage IIBIV from the same geographical region during the time period immediately preceding that of the present study, treated with carboplatin, cyclophosphamide and epirubicin, had the same relative 5-year survival rate and median PFS as patients treated with paclitaxel and carboplatin in the present study. A randomized study, also including toxicity and quality of life aspects, comparing paclitaxel and carboplatin with the combination of carboplatin, cyclophosphamide and epirubicin as adjuvant chemotherapy in advanced EOC in an unselected population would help us to clarify whether paclitaxel is of further benefit to patients with advanced EOC. Acknowledgements Research and development funding has been provided by the Västra Götaland Regional Authority and from the Göteborg Medical Society. The cooperation of the Regional Oncologic Centre, Western Sweden Health Care Region, Gothenburg, was a prerequisite for our success in compiling and processing our data. 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