Wade Marlinda Prognosis Artikel.pdf

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JOURNAL OF CLINICAL ONCOLOGY

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Prognostic Factors for Stage III Epithelial Ovarian Cancer: A Gynecologic Oncology Group Study William E. Winter III, G. Larry Maxwell, Chunqiao Tian, Jay W. Carlson, Robert F. Ozols, Peter G. Rose, Maurie Markman, Deborah K. Armstrong, Franco Muggia, and William P. McGuire From the Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Brooke Army Medical Center, Ft Sam; Medical Oncology, The University of Texas M.D. Anderson, Houston, TX; Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Walter Reed Army Medical Center, Washington, DC; Gynecologic Oncology Group Statistical and Data Center, Roswell Park Cancer Institute, Buffalo; Departments of Medicine and Medical Oncology, Kaplan Cancer, Center, New York University Medical Center, New York, NY; Gynecologic Oncology of West Michigan, Grand Rapids, MI; Medical Science, Fox Chase Cancer Center, Philadelphia, PA; Division of Gynecologic Oncology, Case Western Reserve University; Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Cleveland Clinic Foundation, Cleveland, OH; Oncology, Gynecology, and Obstetrics, Johns Hopkins Kimmel Cancer Center; and the Harry and Jeanette Weinberg Cancer Institute, Franklin Square Hospital Center, Baltimore, MD. Submitted December 22, 2006; accepted May 15, 2007. Supported by National Cancer Institute grants to the Gynecologic Oncology Group administrative office (CA 27469) and statistical office (CA 37517). Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article. Address reprint requests to G. Larry Maxwell, MD, Department of Obstetrics and Gynecology, Walter Reed Army Medical Center, Washington, DC 20307; e-mail: george.maxwell@ na.amedd.army.mil. © 2007 by American Society of Clinical Oncology 0732-183X/07/2524-3621/$20.00 DOI: 10.1200/JCO.2006.10.2517

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Purpose Conflicting results on prognostic factors for advanced epithelial ovarian cancer (EOC) have been reported because of small sample size and heterogeneity of study population. The purpose of this study was to identify factors predictive of poor prognosis in a similarly treated population of women with advanced EOC. Patients and Methods A retrospective review of demographic, pathologic, treatment, and outcome data from 1,895 patients with International Federation of Gynecology and Obstetrics stage III EOC who had undergone primary surgery followed by six cycles of intravenous platinum/paclitaxel was conducted. A proportional hazards model was used to assess the association of prognostic factors with progression-free survival (PFS) and overall survival (OS). Results Increasing age was associated with increased risks for disease progression (HR ⫽ 1.06; 95% CI, 1.02 to 1.11 for an increase every 10 years) and death (HR ⫽ 1.12; 95% CI, 1.06 to 1.18). Mucinous or clear-cell histology was associated with a worse PFS and OS compared with serous carcinomas. Patients with performance status (PS) 1 or 2 were at an increased risk for recurrence compared with PS 0 (HR ⫽ 1.12; 95% CI, 1.01 to 1.24). Compared with patients with microscopic residual disease, patients with 0.1 to 1.0 cm and ⬎ 1.0 cm residual disease had an increased risk of recurrence (HR ⫽ 1.96; 95% CI, 1.70 to 2.26; and HR ⫽ 2.36; 95% CI, 2.04 to 2.73, respectively) and death (HR ⫽ 2.11; 95% CI, 1.78 to 2.49; P ⬍ .001; and HR ⫽ 2.47; 95% CI, 2.09 to 2.92, respectively). Conclusion Age, PS, tumor histology, and residual tumor volume were independent predictors of prognosis in patients with stage III EOC. These data can be used to identify patients with poor prognosis and to design future tailored randomized clinical trials. J Clin Oncol 25:3621-3627. © 2007 by American Society of Clinical Oncology

INTRODUCTION

The American Cancer Society (Atlanta, GA) estimates there will be 22,220 new cases of epithelial ovarian cancer (EOC) in 2005 and 16,210 diseaserelated deaths.1 Unfortunately, the majority of patients diagnosed with ovarian cancer present with advanced stage disease. Although aggressive surgical cytoreduction and platinum/paclitaxel combination chemotherapy have resulted in improved outcomes for many ovarian cancer patients over the past decade, the long-term survival has not been uniformly improved. For this reason, identification of prognostic factors predictive of poor outcome in patients with ovarian cancer may facilitate more targeted therapeutic regimens in the future.

Several factors are recognized as prognostic of clinical outcomes in patients with EOC. International Federation of Gynecology and Obstetrics stage and residual volume of tumor after primary surgical cytoreduction are the most consistently reported prognostic factors.2-4 The Gynecologic Oncology Group (GOG) previously analyzed prognostic factors in 726 women with suboptimal stage III or IV EOC treated on two randomized phase III trials: protocols 22 and 47.5 In that report, age, performance status (PS), and tumor histology were independent predictors of overall survival (OS). However, only 28% of the patients received a platinum-based regimen, and no patient received paclitaxel as part of primary therapy. Furthermore, optimal stage III patients were not included in the cohort (unlike the current study). However, the role 3621

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Winter et al

played by other factors such as age, PS, race, tumor histology, and grade has been reported in recent literature.6-8 These conflicting results may be partially explained by small sample sizes or heterogeneity of the study population, which in combination with other confounding influences makes analysis difficult. Given the inconsistent results of recent studies, it is unclear whether these patient factors (suggesting a biologic impact that may not be overcome by therapy) have the same impact today, considering the improved progression-free survival (PFS) and OS seen with current standard paclitaxel/platinum-based chemotherapy. Also, in light of our recent analysis of prognostic factors for patients with stage IV EOC (unpublished data), separate analyses of residual disease in patients with stage III and IV EOC, as opposed to combining these groups, seemed prudent. Over the past 13 years, GOG has conducted six randomized phase III trials using chemotherapy consisting of a platinum agent and paclitaxel following primary surgical cytoreduction for advanced EOC. Using this large and similarly treated group of patients, we performed an analysis of the pooled data aimed at identifying independent prognostic factors in this population and to update PFS and OS estimates for patients with invasive EOC treated with a contemporary regimen. PATIENTS AND METHODS The current study was a retrospective review of data from patients treated with platinum and paclitaxel combination chemotherapy on one of six prospective randomized clinical trials conducted by GOG: protocols 111,9 114,10 132,11 152,12 158,13 and 172.14 With the exception of the experimental arm(s) from GOG 152 and 158, patients included in this study were treated with primary surgical cytoreduction followed by six cycles of a 24-hour infusion of intravenous paclitaxel (135 mg/m2) followed by intravenous cisplatin (75 mg/m2), the control arm of all six trials. We included the experimental arms of GOG 152 and 158 because these trials demonstrated statistically equivalent clinical outcomes between the control and experimental arms. Table 1 details the treatment regimens from each protocol included in this study. Details regarding eligibility criteria, treatment, and outcome for each particular study have been previously published.9-14 Patients provided written informed consent consistent with all federal, state, and local requirements before receiving protocol therapy. The primary end points for all six studies were disease recurrence, PFS, and OS. PFS was calculated from the date of

study enrollment to the date of disease recurrence, death, or most recent follow-up visit. OS was calculated from the date of study enrollment to the date of death or last contact. Laboratory and clinical data were collected at specified intervals per protocol. Patients were divided into three groups for analysis, based on residual disease status: microscopic, 0.1 to 1.0 cm, and ⬎ 1.0 cm. Clear-cell carcinomas were assigned grade 3. Baseline PS before initiating chemotherapy was defined according to GOG criteria as 0 for normal activity, 1 for symptomatic and fully ambulatory, and 2 for symptomatic and in bed less than 50% of the time. Cox proportional hazards model was used to assess the association between the clinical and pathologic factors, and disease progression and survival. The logarithm of the hazard versus logarithm of the time curve was used to validate the model assumption of proportional hazards. Multivariate analysis was then conducted to identify the independent prognostic factors as well as to estimate their effects on PFS and OS adjusted for covariates (age group, race, PS, histology, tumor grade, and residual disease). Kaplan-Meier survival curves by clinical characteristics were calculated and compared using the log-rank test. All statistical tests were two-tailed with a significance level set at 5%. All statistical analyses were performed using Statistical Analysis Software version 9.1 (SAS Institute, Cary, NC).

RESULTS

Data from 1,895 patients with stage III invasive EOC who underwent primarysurgicalcytoreductionfollowedbypaclitaxel/platinumchemotherapy, while participating in one of six GOG clinical trials (Table 1), was analyzed for the present study. Table 2 summarizes the demographic and clinical characteristics of the study population. The median age was 57 years (range, 16 to 86 years), 88% were white, and 59% had a baseline PS 1 or 2. Twenty-three percent had no visible disease, 42% had 0.1 to 1.0 cm tumor residual, and 35% had a tumor residual of ⬎ 1.0 cm after surgical cytoreduction. Seventy-four percent of patients had serous histology, and 53% had poorly differentiated tumors. One thousand five hundred five recurrences and 1,323 deaths were identified during a median follow-up period of 43 months. Overall, the median PFS was 17.1 months (95% CI, 16.4 to 17.8 months), and the median OS was 45.3 months (95% CI, 43.0 to 47.7 months).

Table 1. GOG Protocols and Study Populations Patient Eligibility

Treatment Regimenⴱ

1119

Suboptimal (⬎ 1-cm residual), stage III/IV EOC

11410

Optimal (⬍ 1-cm residual), stage III EOC

13211

Suboptimal (⬎ 1-cm residual), stage III/IV EOC

15212

Suboptimal (⬎ 1-cm residual), stage III EOC

15813

Optimal (ⱕ 1-cm residual), stage III EOC

17214

Optimal (ⱕ 1-cm residual), stage III EOC/PSPC

IV paclitaxel 135 mg/m2, cisplatin 75 mg/m2, ⫻ six cycles IV paclitaxel 135 mg/m2, cisplatin 75 mg/m2, ⫻ six cycles IV paclitaxel 135 mg/m2, cisplatin 75 mg/m2, ⫻ six cycles IV paclitaxel 135 mg/m2, cisplatin 75 mg/m2, ⫻ six cycles ⫾ interval debulking IV paclitaxel 135 mg/m2 (24 hours), cisplatin 75 mg/m2, ⫻ six cycles or IV paclitaxel 175 mg/m2 (3 hours), carboplatin AUC 7.5, ⫻ six cycles IV paclitaxel 135 mg/m2, cisplatin 75 mg/m2, ⫻ six cycles

GOG Protocol No.

No. of Patients Eligible 123 226 147 397 792

210

Abbreviations: GOG, Gynecologic Oncology Group; EOC, epithelial ovarian cancer; IV, intravenously; AUC, area under the curve; PSPC, papillary serous. ⴱ Patients with stage IV disease were not eligible for this study.

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Prognostic Factors in Ovarian Cancer

Table 2. Patient Characteristics (N ⫽ 1,895) Characteristic Age, years Median Range ⬍ 40 40-49 50-59 60-69 ⱖ 70 Race White African American Other GOG performance status 0 1 2 Tumor grade 1 2 3 Histology Serous Endometrioid Clear cell Mucinous Mixed epithelial Adenocarcinoma unspecified Undifferentiated Other Residual disease Microscopic 0.1-1.0 cm ⬎ 1.0 cm

No. of Patients

Table 3. Median Progression-Free Survival and Overall Survival by Patient Characteristics %

PFS Characteristic

57 16-86 116 414 559 539 267

6.1 21.9 29.5 28.4 14.1

1,669 111 115

88.1 5.9 6.1

784 950 161

41.4 50.1 8.5

179 719 997

9.5 37.9 52.6

1,392 166 62 34 142 49 26 24

73.5 8.8 3.3 1.8 7.5 2.6 1.4 1.3

437 791 667

23.1 41.7 35.2

Abbreviation: GOG, Gynecologic Oncology Group.

Age group, years ⬍ 40 40-50 50-59 60-69 ⱖ 70 Race White African American Other GOG performance 0 1 2 Histology Serous Endometrioid Clear cell Mucinous Mixed epithelial Adenocarcinoma unspecified Undifferentiated Other Tumor grade 1 2 3 Disease residual Microscopic 0.1-1.0 cm ⬎ 1.0 cm

OS

No. of Patients

Median (months)

116 414 559 539 267

21.8 17.8 17.5 16.8 15.8

.03

60.1 47.9 47.7 44.5 36.6

⬍ .001

1669 111 115

16.8 18.0 19.8

.23

45.3 42.6 52.6

.15

784 950 161

18.0 16.3 16.5

.003

51.4 43.2 34.3

⬍ .001

1392 166 62 34 142 49

16.9 24.8 11.4 10.5 16.4 23.7

.006

45.1 56.0 24.0 14.8 47.6 50.8

⬍ .001

26 24

15.2 14.1

179 719 997

17.7 17.0 17.1

437 791 667

33.0 ⬍ .001 16.8 14.1

P

Median (months)

P

51.5 47.0 .05

52.2 43.0 45.5

.02

71.9 42.4 35.0

⬍ .001

Abbreviations: PFS, progression-free survival; OS, overall survival; GOG, Gynecologic Oncology Group.

Univariate Analysis Table 3 shows median PFS and OS based on patient characteristics. Increasing age was associated with decreased PFS and OS. Median PFS and OS were shorter for patients with a PS of 1 or 2 when compared with those with a PS of 0. No difference in median PFS was evident between PS 1 and PS 2 patients, whereas the difference in median OS between the same groups was observed. Based on tumor histology, patients with endometrioid histology had improved clinical outcomes compared with those with serous tumors. Patients with mucinous or clear-cell tumors had decreased PFS and OS. Patients with mucinous cell type had a median OS of only 15 months compared with 24, 45, and 56 months for clear-cell, serous, and endometrioid cell types, respectively (Fig 1A and 1B). These results were further demonstrated by multivariate analysis below. Patients with microscopic residual disease had the longest PFS and OS—33 and 72 months, respectively— compared with patients with any gross residual disease. The differences in median PFS and OS between the 0.1 to 1.0 cm and ⬎ 1.0 cm residual disease groups were also evident, albeit small (3 months in median PFS and 7 months in median OS; Fig A1, online only). Patients with grade 2 or 3 tumors were associated with decreased PFS and OS. Race was not significantly associated with PFS or OS.

Multivariate Regression Analysis All variables considered as potential prognostic factors were included in a Cox proportional hazards regression model to identify independent prognostic factors, the results of which are illustrated in Table 4. Increasing age was linearly associated with increased risk of disease progression and death. When age was reanalyzed as a continuous variable, an interval increase of 10 years was estimated to lead to a 6% (HR ⫽ 1.06; 95% CI, 1.02 to 1.11; P ⫽ .008) increased risk for disease progression and a 12% (HR ⫽ 1.12; 95% CI, 1.06 to 1.18; P ⬍ .001) increased risk for death (Fig 2). Patients whose GOG PS was 1 or 2 had an increased risk of disease progression (HR ⫽ 1.12; 95% CI, 1.01 to 1.24; P ⫽ .03) compared with those with a PS of 0. Results were similar for OS. When compared with serous histology, mucinous (HR ⫽ 2.18; 95% CI, 1.48 to 3.22; P ⬍ .001) and clear-cell (HR ⫽ 1.37; 95% CI, 1.01 to 1.85; P ⫽ .04) histology were associated with a decreased PFS. Results were similar for OS. Using the same referent, patients with endometrioid histology demonstrated a significantly better PFS (HR ⫽ 0.76; 95% CI, 0.64 to 0.92; P ⫽ .004) and OS (HR ⫽ 0.79; 95% CI, 0.65 to 0.97; P ⫽ .02). Using microscopic residual disease as the referent, the hazard ratio for disease progression 3623

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PFS Probability

1.0

NP P Total Serous 199 1,193 1,392 Endometrioid 33 133 166 Clear cell 15 47 62 Mucinous 5 29 34

0.8

0.6

0.4

0.2

0

12

24

36

48

60

Time on Study (months)

B

Alive Dead Total Serous 412 980 1,392 Endometrioid 60 106 166 Clear cell 21 41 62 Mucinous 6 28 34

1.0

OS Probability

0.8

0.6

0.4

0.2

0

12

24

36

48

60

Time on Study (months) Fig 1. (A) Estimated progression-free survival (PFS) by histology. Adjusted relative risk of disease progression for endometrioid, clear-cell, and mucinous cell type as compared with serous cell type was 0.76 (95% CI, 0.64 to 0.92; P ⫽ .004), 1.37 (95% CI, 1.01 to 1.85; P ⫽ .04), and 2.18 (95% CI, 1.48 to 3.22; P ⬍ .001), respectively. There is a suggestion that mucinous cell type was also at increased risk for disease progression compared with clear-cell type (HR ⫽ 1.59; 95% CI, 0.98 to 2.59; P ⫽ .06). (B) Estimate of overall survival (OS) by histology. OS probability adjusted relative risk of death for endometrioid, clear-cell, and mucinous cell type as compared with serous cell type was 0.79 (95% CI, 0.65 to 0.97; P ⫽ .02), 1.74 (95% CI, 1.26 to 2.41; P ⬍ .001), and 4.14 (95% CI, 2.77 to 6.19; P ⬍ .001), respectively. Relative risk of mucinous v clear-cell type was 2.38 (95% CI, 1.43 to 3.95; P ⬍ .001). NP, no progression; P, progression.

in patients with 0.1 to 1.0 cm and ⬎ 1.0 cm was 1.96 (95% CI, 1.70 to 2.26; P ⬍ .001) and 2.36 (95% CI, 2.04 to 2.73; P ⬍ .001), respectively. OS also was decreased for patients with 0.1 to 1.0 cm (HR ⫽ 2.11; 95% CI, 1.78 to 2.49; P ⬍ .001) and ⬎ 1.0 cm (HR ⫽ 2.47; 95% CI, 2.09 to 2.92; P ⬍ .001) residual disease compared with those with only microscopic residual disease. Neither tumor grade nor race was independently associated with clinical outcomes. DISCUSSION

This study represents a retrospective analysis of a large group of patients with stage III EOC who received primary cytoreduction and intravenous platinum and paclitaxel chemotherapy during participation in a GOG trial. Although the prognostic factors identified in this study have been reported, the conclusions of these studies are inconsistent and have included heterogeneous patient populations that 3624

were treated with dissimilar nonpaclitaxel-based adjuvant chemotherapy.3,4,15,16 In the current study, age, PS, tumor histology, and residual disease volume were statistically significant prognostic factors in the multivariate analysis. The strength of our study compared with previous reports is the size and similarity of the population, which confers enhanced statistical power to detect independent variables predictive of poor outcome and, more important, to provide a precise estimation of the magnitude of the effect while controlling for confounding influences, which would otherwise make these results less generalizable. Recent investigations have evaluated the relationship between age at diagnosis of ovarian cancer and prognosis. In general, younger patients have a higher frequency of borderline and well-differentiated invasive EOC. Patients younger than 30 to 40 years present with early-stage disease more than half of the time8,17-22 and are more likely to be optimally cytoreduced when compared with those older than 40 years.8,17 An analysis of 18,191 patients (2,560 patients ⬍ 45 years old) in the Surveillance, Epidemiology, and End Results Program18 with either borderline or invasive EOC, who were treated with a wide variety of chemotherapy, radiotherapy, and surgical procedures, demonstrated that 5-year OS was improved for patients younger than 45 years (45%) compared with those older than 85 years. However, the analysis did not control for variables such as type of therapy, borderline tumors, stage of disease, residual disease after cytoreduction, or comorbidities. A descriptive study17 of 2,123 patients with invasive EOC from GOG protocols 22, 25, 47, 52, 60, and 97 reported that patients older than 69 years exhibited poorer survival even after adjusting for residual disease, tumor grade, PS, and stage. Although four of the six protocols included cisplatin in at least one treatment arm, there were a total of 13 different chemotherapy regimens, and none included paclitaxel. Nonetheless, the study suggested that survival among ovarian cancer patients might differ according to age. Our data suggest that older women are at increased risk of recurrence and death. Differences in tumor biology, immune response, and comorbidities may explain the poorer prognosis in elderly patients. In addition, many providers may be hesitant to treat older patients aggressively (particularly with salvage therapies), and this reluctance potentially could have contributed to the linear relationship between age and progression. However, an analysis of age and the proportion of patients completing their chemotherapy regimen revealed that only patients older than 70 years (14% of the total) in our study had an associated decrease in the number of individuals completing six cycles of treatment. Patients older than 70 years completed 77% of planned cycles. The association between poor PS and decreased PFS and OS has been previously described.6,23-25 In the studies included in our report, a PS of 0 to 2 was an eligibility criterion. Our analysis showed that PS was an independent predictor of recurrence and survival, even without PS 3 and 4 patients. Some investigators have suggested that PS should determine treatment in elderly patients with EOC. Data from the National Cancer Institute (Bethesda, MD) have demonstrated that elderly patients with good PS tolerate the same level of dose-intensive platinum therapy as younger patients.26 Previous studies have inconsistently described the relationship between tumor histology and prognosis. One study found that tumor histology in stage III and IV EOC was not an independent predictor of clinical outcome.7 In contrast, a study of stage IV EOC found that patients with mucinous and clear-cell histologies had a worse OS JOURNAL OF CLINICAL ONCOLOGY

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Prognostic Factors in Ovarian Cancer

Table 4. Multivariate Analysis of Prognostic Factors Characteristic

HR

Disease Progression 95% CI

P

HR

Death 95% CI

P

ⴱ

Age, years ⬍ 40 40-49 50-59 60-69 ⱖ 70 Race White African American Other GOG performance status† 0 1 2 Histology Serous Endometrioid Clear cell Mucinous Mixed epithelial Adenocarcinoma unspecified Undifferentiated Other Tumor grade 1 2 3 Residual disease Microscopic 0.1-1.0 cm ⬎ 1.0 cm

1.0 1.17 1.22 1.28 1.37

0.92 to 1.48 0.96 to 1.54 1.01 to 1.61 1.06 to 1.76

.21 .10 .04 .02

1.0 1.24 1.29 1.40 1.68

0.95 to 1.62 0.99 to 1.68 1.08 to 1.83 1.26 to 2.22

.12 .06 .01 ⬍ .001

1.0 1.12 0.87

0.91 to 1.38 0.70 to 1.08

.29 .20

1.0 1.11 0.80

0.88 to 1.39 0.62 to 1.04

.38 .09

1.0 1.13 1.10

1.01 to 1.25 0.92 to 1.33

.03 .30

1.0 1.18 1.45

1.05 to 1.33 1.19 to 1.76

.005 ⬍ .001

1.0 0.76 1.37 2.18 0.97 0.74

0.64 to 0.92 1.01 to 1.85 1.48 to 3.22 0.80 to 1.18 0.54 to 1.02

.004 .04 ⬍ .001 .79 .06

1.0 0.79 1.74 4.14 1.02 0.96

0.65 to 0.97 1.26 to 2.41 2.77 to 6.19 0.83 to 1.26 0.69 to 1.33

.02 ⬍ .001 ⬍ .001 .83 .81

0.80 1.04

0.50 to 1.28 0.67 to 1.63

.35 .86

0.81 1.02

0.48 to 1.36 0.63 to 1.63

.42 .95

1.0 1.10 1.07

0.91 to 1.33 0.89 to 1.30

.34 .47

1.0 1.21 1.12

0.97 to 1.50 0.90 to 1.40

.09 .30

1.0 1.96 2.36

1.70 to 2.26 2.04 to 2.73

⬍ .001 ⬍ .001

1.0 2.11 2.47

1.78 to 2.49 2.09 to 2.92

⬍ .001 ⬍ .001

Abbreviations: HR, hazard ratio; GOG, Gynecologic Oncology Group. ⴱ With every 10 years of increase, HR ⫽ 1.06 (95% CI, 1.02 to 1.11; P ⫽ .008) for disease progression and HR ⫽ 1.12 (95% CI, 1.06 to 1.18; P ⬍ .001) for death. †For performance status 1 and 2 v performance status 0, HR ⫽ 1.12 (95% CI, 1.01 to 1.24; P ⫽ .03) for disease progression.

relative to those with serous tumors.6 More recently, a small study of EOC, in which mucinous histology was compared with matched controls of other histologies, found a significantly decreased PFS and OS in patients with mucinous histology.27 The current study suggests that mucinous and clear-cell carcinomas are associated with a worse PFS and OS when compared with serous histology. Clear-cell histology has been generally accepted as an unfavorable histology. Further, recent microarray experiments have revealed that clear-cell carcinoma has a genomic expression pattern that differs from serous epithelial ovarian cancers, suggesting that the biologic phenotype of the clear-cell subtype is unique.28 In the current study, mucinous histology was associated with almost twice the risk of death relative to clear-cell histology. Because mucinous carcinoma of the ovary is rare, our understanding of its molecular alterations is limited. However, its associated poor prognosis suggests a more aggressive biologic activity. Although tumor specimens collected from participants in the six trials were reviewed centrally by the GOG Pathology Committee to confirm the diagnosis, it is possible that some of the mucinous tumors may have been primary colon cancers with metastasis to the ovary. No pretreatment assessment of the gastrointestinal tract was required by protocol. Some investigators have suggested that 7% of ovarian cancers may

actually be metastatic, with the majority representing extension from a gastrointestinal primary.29,30 An inaccurate diagnosis of a gastrointestinal carcinoma as a mucinous ovarian primary would result in inappropriate adjuvant chemotherapy. Recent genomic and proteomic high-throughput array experiments have identified markers that may assist in distinguishing ovarian and primary colon cancers in the future.31 Although tumor grade is a significant prognostic variable in early-stage EOC,32 it does not appear to be a predictor of poor outcome advanced disease.33,34 Investigators have suggested that the response to surgical cytoreduction is not significantly affected by tumor grade.35 Also, responsiveness to platinum-based chemotherapy in International Collaborative Ovarian Neoplasm Collaborators trial 3 was not associated with tumor grade.36 In the current study, grade was not an independent predictor of outcome. This conclusion did not change even when clear-cell cancers were designated as grade 3 and included in the model. The median survival for African Americans with advanced EOC is nearly 1 year less than that of white women (22 v 32 months; P ⬍ .0001).37 Data from the National Cancer Data Base has revealed that the racial disparity in outcome is particularly evident for patients 3625

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treated with the current standard therapy of primary cytoreductive surgery followed by intravenous platinum/paclitaxel chemotherapy. It would appear that the magnitude of improvement in PFS and OS provided by the addition of taxanes to adjuvant therapy is not large enough to abrogate the impact of these prognostic factors. Residual tumor size continues to be an important prognostic factor, especially when all macroscopic disease is removed. Although translational research is important in determining whether these results are due to tumor biology and unaffected by improved therapy, future study designs might incorporate stratifications based on these independent predictors of PFS and OS as has been recommended previously.5

0.6 Progression Death

0.5

Log(HR)

0.4 0.3 0.2 0.1 0.0 < 40

40-49

50-59

60-69

70 +

Age Group (years) Fig 2. Assessment of association of age with clinical outcomes adjusted for covariates. Increasing every 10 years in age was associated with a 6% increase in risk for disease progression (95% CI, 2% to 11%; P ⫽ .008) and a 12% increase in risk for death (95% CI, 6% to 18%; P ⬍ .001).

with stage III disease. Further, the 5-year survival rate for African Americans is 18% versus 29% for white women.38 Reports from both the NCDB38 and the population-based SEER Program39 have indicated that African American women are less likely to receive aggressive therapy and are more likely to be treated with chemotherapy alone than with a combination of surgery and chemotherapy. The current study involved women who were treated with a standardized regimen of primary surgical cytoreduction followed by adjuvant paclitaxel and platinum chemotherapy, irrespective of race. There were no differences in PFS and OS between white and African American patients in multivariate regression analyses. Our results suggest that when patients are treated on protocol requiring equivalent care according to a regimented algorithm, the disparity in outcome between races is not apparent. Patients in the current study with microscopic residual disease have a far better PFS and OS than previously reported for optimal cohorts, which included patients with ⱕ 1.0 cm of residual disease, including microscopic residual disease. As with previous studies, patients with gross residual disease ⱕ 1.0 cm had improved clinical outcomes compared with those with gross residual disease ⬎ 1.0 cm. Further detailed analysis of an association between varying degrees of residual disease volume and clinical outcome is warranted. In conclusion, increasing age, impaired PS, and mucinous or clear-cell histology, and gross residual disease are all independent predictors of decreased PFS and OS in patients with stage III EOC REFERENCES 1. Jemal A, Murray T, Ward E, et al: Cancer statistics 2005. CA Cancer J Clin 55:10-30, 2005 2. Ng LW, Rubin S, Hoskins WJ, et al: Aggressive chemosurgical debulking in patients with advanced ovarian cancer. Gynecol Oncol 38:358-363, 1990 3. Hoskins WJ, McGuire WP, Brady MF, et al: The effect of diameter of largest residual disease on survival after primary cytoreductive surgery in patients with suboptimal residual epithelial ovarian carcinoma. Am J Obstet Gynecol 170:974-979, 1994 4. Hoskins WJ, Bundy BN, Thigpen T, et al: The influence of cytoreduction surgery on 3626

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following authors or their 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. Employment: N/A Leadership: N/A Consultant: Robert F. Ozols, Bristol-Myers Squibb Co, Eli Lilly & Co, Novartis Inc, Genentech, GlaxoSmithKline, Telik Inc, Unither Pharmaceuticals; Franco Muggia, Bristol-Myers Squibb Co, Ortho Biotech Stock: Robert F. Ozols, Celgene, Pfizer, Biogenidex Honoraria: Robert F. Ozols, Eli Lilly & Co, Bristol-Myers Squibb Co; Franco Muggia, Ortho Biotech Research Funds: Franco Muggia, Roche, Bristol-Myers Squibb Co Testimony: N/A Other: N/A

AUTHOR CONTRIBUTIONS Conception and design: William E. Winter III, G. Larry Maxwell, Jay W. Carlson Provision of study materials or patients: Robert F. Ozols, Peter G. Rose, Maurie Markman, Deborah K. Armstrong, William P. McGuire Collection and assembly of data: William E. Winter III, Chunqiao Tian, Deborah K. Armstrong, Franco Muggia, William P. McGuire Data analysis and interpretation: William E. Winter III, G. Larry Maxwell, Chunqiao Tian, Maurie Markman, Deborah K. Armstrong, William P. McGuire Manuscript writing: William E. Winter III, G. Larry Maxwell, Chunqiao Tian, Jay W. Carlson Final approval of manuscript: William E. Winter III, G. Larry Maxwell, Chunqiao Tian, Robert F. Ozols, Peter G. Rose, Maurie Markman, Deborah K. Armstrong, Franco Muggia, William P. McGuire

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Prognostic Factors in Ovarian Cancer

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Acknowledgment The Acknowledgment is included in the full-text version of this article, available online at www.jco.org. It is not included in the PDF version (via Adobe® Reader®). Appendix The Appendix is included in the full-text version of this article, available online at www.jco.org. It is not included in the PDF version (via Adobe® Reader®).

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