VOLUME

25

NUMBER

FEBRUARY

2007

JOURNAL OF CLINICAL ONCOLOGY

O R I G I N A L

R E P O R T

Multi-Institutional Reciprocal Validation Study of Computed Tomography Predictors of Suboptimal Primary Cytoreduction in Patients With Advanced Ovarian Cancer
Allison E. Axtell, Margaret H. Lee, Robert E. Bristow, Sean C. Dowdy, William A. Cliby, Steven Raman, John P. Weaver, Mojan Gabbay, Michael Ngo, Scott Lentz, Ilana Cass, Andrew J. Li, Beth Y. Karlan, and Christine H. Holschneider
From the University of California Los Angeles (UCLA) Medical Center; Olive View-UCLA Medical Center; CedarsSinai Medical Center; Kaiser Permanente Sunset Medical Center, Los Angeles, CA; Johns Hopkins Medical Institutions, Baltimore, MD; and the Mayo Clinic, Rochester, MN. Submitted June 7, 2006; accepted November 17, 2006. Presented in part during plenary presentations at the 34th Annual Meeting of the Western Association of Gynecologic Oncologists, Santa Fe, NM, June 15-18, 2005; and at the 37th Annual Meeting of the Society of Gynecologic Oncologists, Palm Springs, CA, March 22-26, 2006. Authors disclosures of potential conicts of interest and author contributions are found at the end of this article. Address reprint requests to Christine H. Holschneider, MD, Olive View-UCLA Medical Center, Department of Obstetrics and Gynecology, 14445 Olive View Dr, Rm 2B-163, Sylmar, CA 91342; e-mail: CHolschneider@ladhs.org. 2007 by American Society of Clinical Oncology 0732-183X/07/2504-384/$20.00 DOI: 10.1200/JCO.2006.07.7800

Purpose Identify features on preoperative computed tomography (CT) scans to predict suboptimal primary cytoreduction in patients treated for advanced ovarian cancer in institution A. Reciprocally cross validate the predictors identied with those from two previously published cohorts from institutions B and C. Patients and Methods Preoperative CT scans from patients with stage III/IV epithelial ovarian cancer who underwent primary cytoreduction in institution A between 1999 and 2005 were retrospectively reviewed by radiologists blinded to surgical outcome. Fourteen criteria were assessed. Crossvalidation was performed by applying predictive model A to the patients from cohorts B and C, and reciprocally applying predictive models B and C to cohort A. Results Sixty-ve patients from institution A were included. The rate of optimal cytoreduction ( 1 cm residual disease) was 78%. Diaphragm disease and large bowel mesentery implants were the only CT predictors of suboptimal cytoreduction on univariate (P .02) and multivariate analysis (P .02). In combination (model A), these predictors had a sensitivity of 79%, a specicity of 75%, and an accuracy of 77% for suboptimal cytoreduction. When model A was applied to cohorts B and C, accuracy rates dropped to 34% and 64%, respectively. Reciprocally, models B and C had accuracy rates of 93% and 79% in their original cohorts, which fell to 74% and 48% in cohort A. Conclusion The high accuracy rates of CT predictors of suboptimal cytoreduction in the original cohorts could not be conrmed in the cross validation. Preoperative CT predictors should be used with caution when deciding between surgical cytoreduction and neoadjuvant chemotherapy. J Clin Oncol 25:384-389. 2007 by American Society of Clinical Oncology

INTRODUCTION

Ovarian cancer remains the leading cause of mortality from a gynecologic malignancy in the United States with 16,210 deaths annually.1 The majority of cases are advanced stage (stage III/ IV) at the time of diagnosis. Current front-line therapy consists of cytoreductive surgery and platinum-based chemotherapy. Optimal primary cytoreduction has been demonstrated for the past 30 years to be a highly signicant predictor of outcome in patients with advanced ovarian cancer. A recent meta-analysis of maximal cytoreduction and survival in 81 published patient cohorts demonstrated that cohorts in which there was a high proportion of maximal cytoreduction
384

( 75%) had a 50% increase in median survival compared with those with a less than 25% maximal cytoreduction rate (33.9 v 22.7 months).2 A higher response rate to chemotherapy and improved survival in patients with optimal cytoreduction, dened by residual disease 1 cm, continues to be observed with contemporary rst-line chemotherapy with a platinum compound and taxane. This can be illustrated by a comparison of two Gynecologic Oncology Group (GOG) studies, GOG 1113 and GOG 158.4 In GOG 111, patients with suboptimally cytoreduced ovarian cancer demonstrated a 26% complete pathologic response rate to cisplatin and paclitaxel as determined by second-look surgery. In GOG 158, where optimally cytoreduced patients were treated with paclitaxel and either carboplatin

Downloaded from jco.ascopubs.org on July 6, 2011. For personal use only. No other uses without permission. Copyright 2007 American Society of Clinical Oncology. All rights reserved.

CT Predictors of Ovarian Cancer Cytoreduction

or cisplatin, the complete pathologic response rate at second-look surgery was almost twice as high (49%), with an associated difference in median survival of 15 months (38 months [GOG 111] v 53 months [GOG 158]). Striving for maximal primary cytoreduction becomes even more important in light of recently published data from GOG 172, a randomized trial of patients with optimally cytoreduced ovarian cancer that compared intravenous paclitaxel plus cisplatin versus intravenous paclitaxel plus intraperitoneal cisplatin and paclitaxel. An additional gain in median survival to 66 months was observed for patients in the intraperitoneal treatment arm.5 For women with advanced ovarian cancer, rates of optimal primary cytoreduction vary widely from 25% to more than 90%.6 GOG data have demonstrated that women whose tumors cannot be cytoreduced to smaller than 2 cm residual disease do not derive any signicant survival benet from primary cytoreductive surgery.7 Thus, patients who undergo suboptimal primary cytoreduction may incur signicant surgical morbidity without associated gain in survival. This has prompted investigations into neoadjuvant chemotherapy. Several trials have demonstrated decreased operative morbidity8 and improved maximal tumor debulking rates at interval cytoreduction after neoadjuvant chemotherapy.9-15 To date, there are no published randomized trials that compare survival in patients who receive neoadjuvant chemotherapy with interval cytoreduction versus those who undergo primary cytoreduction followed by chemotherapy. A European Organisation for Research and Treatment of Cancer trial is currently underway, which addresses this question.16 An extensive review of retrospective and nonrandomized prospective studies of neoadjuvant chemotherapy versus primary cytoreduction suggests improved median survival with neoadjuvant chemotherapy over that observed in patients who underwent suboptimal primary cytoreduction (26 months v 20 months).6 However, in the literature available to date, survival of patients treated with neoadjuvant chemotherapy appears inferior to that observed after optimal primary cytoreduction (26 months v 51 months).6 Thus, the accurate pretreatment identication of patients whose disease is not optimally cytoreducible at primary surgery becomes one of the most critical issues surrounding neoadjuvant chemotherapy for ovarian cancer. Investigators have attempted to identify specic preoperative predictors of suboptimal cytoreduction. A number of studies have demonstrated an association between the preoperative CA-125 level and the inability to achieve optimal cytoreduction, yet the overall accuracy rates at predicting surgical outcome (ie, optimal v suboptimal cytoreduction) were only 50% to 78% with most studies using a CA-125 cut off value of 500 U/mL.17-23 The two series with high optimal cytoreduction rates ( 70%) found preoperative CA-125 levels completely lacking as predictors of surgical outcome.20-22 Five small studies have been published to date,22,24-27 which have attempted to identify specic radiological predictors of suboptimal cytoreduction on preoperative computed tomography (CT) scans. For example, Bristow et al26 created a model including 13 radiographic features and performance status to calculate predictive index scores with a 93% accuracy rate for optimal versus suboptimal primary debulking. Dowdy and colleagues22 found only diffuse peritoneal thickening to be an independent predictor of suboptimal surgical cytoreduction. Interpretation of these studies published to date is limited due to their retrospective nature, the highly variable rates of optimal cytoreduction (33% to 80%), the fact that most2,24,25,27 included patients with both early and advanced stage disease, and the
www.jco.org

quite different combination of CT predictors that correlated with suboptimal cytoreduction in each of the study cohorts; the latter calling into question the applicability of identied CT predictors to other patient populations. We therefore undertook the current study with the following two objectives: to identify radiologic features on preoperative CT scans that predict suboptimal primary cytoreduction in a specic cohort of patients with advanced stage (III/IV) ovarian cancer treated at University of California, Los Angeles (Los Angeles, CA) and associated teaching institutions, where the surgical practice is characterized by a strong commitment to optimal primary cytoreduction (cohort A); and to reciprocally cross validate the CT predictors identied in cohort A with those from two previously published cohorts of patient with stage III/IV ovarian cancer who underwent primary cytoreduction at Johns Hopkins Medical Institute26 (Baltimore, MD; cohort B) or the Mayo Clinic22 (Rochester, MN; cohort C).
PATIENTS AND METHODS
Objective 1 Institutional review board approval of the study protocol was obtained from all participating institutions. Patients who underwent primary surgery for stage III and stage IV epithelial ovarian cancer between 1999 and 2005 at one of four teaching institutions afliated with the University of California, Los Angeles Gynecologic Oncology training program (patient cohort A) were identied through pathology databases and institutional tumor registries. Only patients who had preoperative CT scans performed within 4 weeks before primary cytoreductive surgery and whose CT lms were available for review were included in the study. CT scanning protocols varied given the inclusion of four different institutions. In general, all images were obtained using 5 mm to 10 mm collimation through the abdomen and pelvis with PO and IV contrast unless the latter was medically contraindicated. Patients whose preoperative CT scans had been performed at outlying institutions were not eligible for this study given the large variation in the imaging techniques used and the fact that images had generally been returned to the originating institution. CT scans performed at the study institutions were systematically re-reviewed by study radiologists who were blinded to surgical outcomes. Fourteen radiologic criteria were chosen from pertinent positive predictors gathered from previous studies22,26 and supplemented with potential predictors from clinical experience. These criteria included large volume ascites, pleural effusion, diffuse peritoneal thickening, omental caking, omental extension to spleen or stomach, suprarenal lymph nodes larger than 1 cm, infrarenal or inguinal lymph nodes larger than 2 cm, and tumor implants larger than 2 cm on small and large bowel mesentery, peritoneum, diaphragm, liver, or porta hepatis. Large volume ascites was dened as the presence of ascites on two thirds of abdominopelvic CT scan cuts. Diffuse peritoneal thickening was dened as peritoneal thickening to 4 mm involving at least two of the ve following areas: lateral colic gutters, lateral conal fascia, anterior abdominal wall, diaphragm, and pelvic peritoneal reections, as described by Dowdy.22 Demographic data, surgical ndings, and pathologic data were retrospectively obtained from the medical record. All surgeries were performed by one of 12 gynecologic oncologists at one of the four study institutions. Optimal cytoreduction was dened as 1 cm residual disease. The American Society of Anesthesiologists (ASA) physical status classication was obtained from the anesthesia record. Laboratory values collected included preoperative CA-125 and serum albumin levels obtained within 4 weeks before surgery. Univariate comparisons of the percentage of patients who underwent suboptimal cytoreduction were carried out using Fishers exact tests for each of the 14 potential radiologic predictors. The Wilcoxon rank sum test was used to compare median age, albumin, ASA status, and CA-125 levels between patients with optimal versus suboptimal cytoreduction. The Kruskal-Wallis test was used to study the association between increasing ASA classication and the
385

Downloaded from jco.ascopubs.org on July 6, 2011. For personal use only. No other uses without permission. Copyright 2007 American Society of Clinical Oncology. All rights reserved.

Axtell et al

proportion of patients with suboptimally cytoreduced ovarian cancer. Simultaneous multivariate assessment of all 14 radiologic and four clinical variables was carried out using backward stepwise logistic regression with a liberal P .15 variable retention criterion and a model predictive of suboptimal cytoreduction was developed (predictive model A). Sensitivity, specicity, and accuracy of the model were calculated based on receiver operating curve analysis. Stratication of the data by surgeon and/or procedures performed would have been desirable since optimal cytoreduction depends in part on the surgeons practice, philosophy, and skill set. However, in this study, the number of patients per surgeon and/or per radical surgical technique was too small to allow for a stratied analysis. In order to safeguard against statistical overtting, we performed a leave one out (statistical) cross validation. In short, an observation was left out of the data set, the process of identifying (variable selection) and tting the model was performed on all the remaining data, and then the tted model was used to predict the probability of a suboptimal cytoreduction for the observation left out. These steps were repeated for each observation in the data set, a receiver operating curve curve was formed, and resultant sensitivity, specicity, and accuracy reported. Objective 2 Cross validation of the predictors of suboptimal cytoreduction identied in this study (predictive model A) with those identied from two previously published studies was performed by applying predictive model A to patient cohorts B and C and reciprocally applying predictive models B and C to patient cohort A. Patient cohorts B26 and C22 were chosen from the ve previously published studies on CT predictors of cytoreduction,22,24-27 as those were the only studies restricted, similar to cohort A, to patients with advanced-stage ovarian cancer. Patient cohort B was comprised of 41 previously published patients with stage III/IV disease who underwent preoperative CT scans followed by cytoreductive surgery at Johns Hopkins Medical Institutions or the Massachusetts General Hospital with a 48% optimal cytoreduction rate.26 Predictive model B entailed an additive predictive index score 4 calculated based on 13 radiologic criteria and performance status with each variable present being allotted a weighted point value between 1 and 2. Patient cohort C consists of 87 patients from a previously published study22 who underwent preoperative CT scanning followed by cytoreductive surgery for stage III/IV ovarian cancer at the Mayo Clinic with a 71% optimal cytoreduction rate. Predictive model C was comprised of two radiologic factors identied on preoperative CT scansdiffuse peritoneal thickening and large volume ascites. For all cross validations we report sensitivity, specicity, and unweighted accuracy. Sensitivity reports the percentage of those patients with suboptimal debulking that are predictedsuboptimalbythemodel.Specicityreportsthepercentageofthosewith optimal debulking that are predicted optimal. Unweighted accuracy is dened as the unweighted average of sensitivity and specicity.

Table 1. Clinical Data and Tumor Characteristics of Study Cohort A (N Patients Characteristic Age, years 50 50-59 60-69 70-79 80 FIGO stage III A/B III C IV Histologic subtype Serous Clear cell Mixed Endometrioid Optimal cytoreduction Suboptimal cytoreduction No.

65)

17 18 19 9 2 4 53 8 52 6 6 1 51 14

26 27 29 14 4 6 82 12 80 9 9 1 78 22

Abbreviation: FIGO, International Federation of Gynecology and Obstetrics staging system.

RESULTS

Sixty-ve consecutive patients from institution A met study inclusion criteria. Demographic and clinical data are described in Table 1. Eighty-eight percent of patients had International Federation of Gynecology and Obstetrics staging system (FIGO) stage III disease while 12% of patients had FIGO stage IV disease. Fifty-one patients (78%) were optimally cytoreduced to 1 cm residual disease at the time of primary surgery. There were no statistically signicant differences between the median age (optimal: 62 years; range, 33 to 82 years; suboptimal: 56 years; range, 34 to 87 years; P .92), ASA status (optimal: 2; range, 2 to 4; suboptimal: 3; range, 2 to 4; P .12), serum albumin (optimal: 3.5 g/dL; range, 2.2 to 4.7 g/dL; suboptimal, 3.4 g/dL; range, 2.7 to 4.0 g/dL; P .62) and CA-125 levels (optimal: 860 U/mL; range, 15 to 7,960 U/mL; suboptimal: 780 U/mL; range, 105 to 2,866 U/mL); P .42) of individuals who were optimally cytoreduced when com386

pared with those who were suboptimally debulked. An association was noted between the ASA classication and the proportion of patients who underwent suboptimal cytoreduction, but this did not reach statistical signicance: 13% of patients with an ASA classication of 2 underwent suboptimal cytoreduction, this increased to 25% with an ASA class of 3 and to 40% with an ASA classication of 4 (P .12). Table 2 presents the percentage of patients who underwent suboptimal debulking for each of the 14 preoperative CT variables. Diaphragmatic disease larger than 2 cm (P .02) and large bowel mesentery implants larger than 2 cm (P .02) were the only statistically signicant univariate predictors of suboptimal cytoreduction. Forty-seven percent of women who were positive for diaphragm disease and 50% of those with disease of the large bowel mesentery on preoperative CT scan were suboptimally debulked. All 14 radiologic and four clinical criteria were candidates for predicting suboptimal debulking in the backward multivariate logistic analysis. Of these 18 potential predictors, the logistic regression identied only diaphragm disease (risk ratio [RR], 5.69; P .01) and large bowel mesentery implants (RR, 6.07; P .011) as signicant predictors of suboptimal cytoreduction. While ASA status and omental extension to stomach and spleen demonstrated borderline signicance on univariate analysis, they lost any trend toward signicance on multivariate analysis. Using a model where only the presence of both diaphragm disease and large bowel mesentery implants is considered predictive of suboptimal cytoreduction (predictive model A), the nominal sensitivity was 79%, the specicity was 75%, and the accuracy was 77% in patient cohort A. These nominal sensitivity, specicity, and accuracy rates were conrmed by a leave one out statistical validation. In this analysis, both diaphragm disease and large bowel mesentery implants continued to be the only signicant predictors. Across the 65 runs the mean sensitivity for suboptimal cytoreduction was 78.6% (95% CI, 56.6% to 100%), the mean specicity was 74.5% (95% CI, 62.5 to 86.5%), and the mean accuracy was 76.5% (95% CI, 51.5% to 100%).
JOURNAL OF CLINICAL ONCOLOGY

Downloaded from jco.ascopubs.org on July 6, 2011. For personal use only. No other uses without permission. Copyright 2007 American Society of Clinical Oncology. All rights reserved.

CT Predictors of Ovarian Cancer Cytoreduction

Table 2. Univariate Analysis of Computed Tomography Predictors of Suboptimal Cytoreduction Patients With Variable Present Predictor Diaphragm disease 2 cm Large bowel mesentery implants 2 cm Omental extension to stomach or spleen Omental cake Small bowel mesentery implants 2 cm Suprarenal lymph nodes 1 cm Porta hepatis or gall bladder fossa disease Diffuse peritoneal thickening Pleural effusion Large volume ascites Peritoneal implants 2 cm Liver implants Inguinal canal disease Infrarenal lymph nodes 2 cm No. 15 12 23 46 11 5 6 12 28 40 24 8 2 2 Suboptimal (%) 46 50 35 16 36 0 33 17 25 20 21 25 0 0 No. 50 53 42 19 54 60 59 53 37 25 41 57 63 63 With Variable Absent Suboptimal (%) 14 14 14 11 19 33 20 33 19 24 22 21 22 22 P .02 .02 .07 .20 .23 .35 .60 .73 .76 .76 .99 .99 .99 .99

Those patients with no disease on the diaphragm or large bowel mesentery had the lowest rates of suboptimal cytoreduction (7%), patients with one, but not both risk factors had intermediate rates of suboptimal cytoreduction (42% to 44%), whereas those with both diaphragm and large bowel mesentery implants on preoperative CT had the highest rates of suboptimal cytoreduction (67%). Thus, patients with both CT predictors were 9.11 times more likely to be suboptimally debulked than those with neither predictor (Table 3). In order to study the applicability of our thus identied CT predictors of suboptimal cytoreduction to other patient cohorts, we applied predictive model A to patient cohorts B and C (Table 4). The resultant sensitivity of predictive model A fell to 15% and 72%, specicity to 32% and 56%, and accuracy to 34% and 64% when applied to patient cohorts B and C, respectively. For reciprocal cross validation, we applied the CT predictors previously identied in patient cohorts B (predictive model B) and C (predictive model C) to the present patient cohort A (Table 5). When CT predictor models B and C were applied to patient cohort A, the original accuracy rates of 93% and 79% fell to 74% and 48%, respectively. The CT predictors identied in three additional studies in the literature were not used as primary outcome measure for cross validation as the original study cohorts included early-stage ovarian cancer.23,24,26 However, when the predictors from these three studies were applied to cohort A for comparison purposes, a similar loss in accuracy was observed from 79% to 88% in the original cohorts to 51% to 62% in cohort A. In other words,

64% to 86% of patients in cohort A predicted to undergo suboptimal cytoreduction using any of the ve published models were actually optimally cytoreduced.
DISCUSSION

Table 3. Multivariate Risk Factors for Suboptimal Cytoreduction Large Bowel Mesentery No Yes No Yes Suboptimal No. 41 9 12 3 % 7 44 42 67 Risk Ratio 1.00 6.07 5.69 9.11

Our current study identies diaphragm disease and large bowel mesentery implants as being the only statistically signicant predictors of suboptimal cytoreduction. Despite this statistical significance, the clinical relevance of this nding remains questionable because approximately half of our own patients whose preoperative CT scans were positive for either of these predictors actually underwent optimal cytoreduction at the time of primary surgery. Even when applying our multivariate model, which required the presence of both, diaphragm disease and disease of the large bowel mesentery on the preoperative CT scan in order to be predictive of suboptimal cytoreduction, there was still a 33% false positive rate. Despite optimizing our model, one of every three patients predicted to undergo suboptimal tumor debulking could actually be left with minimal residual disease after operation with therapeutic intent. If we had followed our CT predictor model, each of these patients would have been deprived of the potential survival advantage associated with optimal primary cytoreductive surgery. As becomes evident from the review of all published CT predictor data to date, each of the retrospective studies,22,24-27 including our own, identied a different set of predictors of cytoreductive surgery outcome, raising the question as to their applicability to patient

Diaphragm No No Yes Yes

Table 4. Validation Set for the Prediction of Suboptimal Cytoreduction (predictive model A applied to patient cohorts A, B, and C) Patient Cohort A B C Sensitivity (%) 79 15 72 Specicity (%) 75 32 56 Accuracy (%) 77 34 64

Using absence of diaphragm and large bowel mesentery disease as the referent.

www.jco.org

387

Downloaded from jco.ascopubs.org on July 6, 2011. For personal use only. No other uses without permission. Copyright 2007 American Society of Clinical Oncology. All rights reserved.

Axtell et al

Table 5. Cross Validation Set for the Prediction of Suboptimal Cytoreduction (predictive models B and C applied to patient cohort A) and Comparative Application of the Three Other Published CT Predictor Models to Patient Cohort A for the Prediction of Suboptimal Cytoreduction Original Cohort (%) Study and Model Cross validation set Bristow26 (model B) Dowdy22 (model C) Comparative application of other published CT predictor models Nelson24 Meyer25 Qayyum27 Sensitivity Specicity Accuracy Sensitivity Cohort A (%) Specicity Accuracy

100 52

85 90

93 71

93 7

55 88

74 48

92 58 76

79 100 99 41; model C, N

86 79 88 87; Nelson: N

79 57 50 42; Meyer: N

45 45 65 28; Qayyum: N 137.

62 51 58

NOTE. Number of patients per cohort: model A, N 65; model B, N Abbreviation: CT, computed tomography. Includes performance status in predictive index score. All include patients with early-stage disease. Includes CT and magnetic resonance imaging.

cohorts other than the one they were developed in. The lack of generalizability of any of the CT predictive models identied to date is illustrated by our cross validation studies. Reciprocal accuracy rates in the validation cohorts were poor across all models and cohorts studied. Most importantly, there was an unacceptable overprediction of suboptimal cytoreduction in the reciprocal cross validation scenarios of 64% to 86%. Which is to say that 64% to 86% of those patients predicted in the cross validation cohorts to undergo suboptimal cytoreduction using any of the published prediction models actually underwent optimal primary tumor cytoreduction, leaving the patient with minimal residual disease. This high rate of overcall of suboptimal cytoreduction by CT predictors becomes particularly concerning in light of the well-documented survival advantage associated with intraperitoneal chemotherapy in patients with optimally cytoreduced cancer,5,28,29 especially when juxtaposed to data from a recent meta-analysis of neoadjuvant chemotherapy which suggests a 4.1-month reduction in survival for each cycle of chemotherapy given before surgical tumor debulking.30 One of the principle difculties in the development of any reliable predictive model of surgical outcome for patients with advanced ovarian cancer is the challenge of factoring in the signicant impact of each individual surgeons philosophy, effort, and ability to utilize advanced surgical techniques to achieve maximal cytoreduction.31 Subset analysis of the suboptimally debulked patients by individual surgeon was not possible in our study due to the low number of patients with suboptimal cytoreduction for each of the 12 surgeons in institution cluster A. However, an overall optimal cytoreduction rate of 78% in patient cohort A is an attestation to the surgical practice at University of California, Los Angeles and afliated teaching institutions that is characterized by a strong commitment to optimal primary cytoreduction and the inclusion of advanced surgical techniques in the surgeons armamentarium to achieve resection of the tumor. In summary, identication of risk factors for suboptimal cytoreduction in small retrospective populations such as ours and all previously published cohorts, are not reproducible in alternate populations. Until prospective, randomized trials have demonstrated that neoadjuvant chemotherapy followed by interval cytoreduction is equivalent in terms of survival outcomes to primary optimal cytoreduction followed by chemotherapy, extreme caution should be used
388

when applying preoperative imaging predictors to decide between primary surgical exploration and neoadjuvant chemotherapy in the medically t patient. Only the patient who is the most unlikely to undergo optimal cytoreduction should be offered neoadjuvant chemotherapy, unless her medical condition renders her unsuitable for primary surgery. Ultimately, only a multi-institutional prospective trial would answer the question of whether or not an accurate and reproducible preoperative model using CT or other imaging modalities could be developed for the prediction of surgical outcome. Such a model would have to take into consideration the impact of variable surgical practices and the surgeons philosophical commitment to aggressive tumor debulking and skills in advanced cytoreductive surgical techniques.
AUTHORS DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The authors indicated no potential conicts of interest.

AUTHOR CONTRIBUTIONS
Conception and design: Allison E. Axtell, Margaret H. Lee, Christine H. Holschneider Administrative support: Allison E. Axtell, Christine H. Holschneider Provision of study materials or patients: Robert E. Bristow, Sean C. Dowdy, William A. Cliby, Scott Lentz, Andrew J. Li, Beth Y. Karlan, Christine H. Holschneider Collection and assembly of data: Allison E. Axtell, Margaret H. Lee, Steven Raman, John P. Weaver, Mojan Gabbay, Michael Ngo, Ilana Cass, Christine H. Holschneider Data analysis and interpretation: Allison E. Axtell, Robert E. Bristow, Sean C. Dowdy, William A. Cliby, Steven Raman, John P. Weaver, Scott Lentz, Ilana Cass, Andrew J. Li, Beth Y. Karlan, Christine H. Holschneider Manuscript writing: Allison E. Axtell, Robert E. Bristow, Sean C. Dowdy, William A. Cliby, Christine H. Holschneider Final approval of manuscript: Allison E. Axtell, Margaret H. Lee, Robert E. Bristow, Sean C. Dowdy, William A. Cliby, Steven Raman, John P. Weaver, Mojan Gabbay, Michael Ngo, Scott Lentz, Ilana Cass, Andrew J. Li, Beth Y. Karlan, Christine H. Holschneider

JOURNAL OF CLINICAL ONCOLOGY

Downloaded from jco.ascopubs.org on July 6, 2011. For personal use only. No other uses without permission. Copyright 2007 American Society of Clinical Oncology. All rights reserved.

CT Predictors of Ovarian Cancer Cytoreduction

REFERENCES
1. American Cancer Society. Cancer Facts & Figures 2005. http://www.cancer.org/downloads/ STT/CAFF2005f4PWSecured.pdf 2. Bristow RE, Tomacruz RS, Armstrong DK, et al: Survival effect of maximal cytoreductive surgery for advanced ovarian carcinoma during the platinum era: A meta-analysis. J Clin Oncol 20:1248-1259, 2002 3. McGuire WP, Hoskins WJ, Brady MF, et al: Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med 334:1-6, 1996 4. Ozols RF, Bundy BN, Greer BE, et al: Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: A Gynecologic Oncology Group study. J Clin Oncol 27:3194-3200, 2003 5. Armstrong DK, Bundy B, Wenzel L, et al: Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med 354:34-43, 2006 6. Holschneider CH, Berek JS: Cytoreductive surgery: Principles and rationale, in Bristow RE, Karlan BY, Montz FJ (eds): Surgery for Ovarian Cancer: Principles and Practice. Lancaster, United Kingdom, The Parthenon Publishing Group, 2005, pp 141-143 7. 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 8. Schwartz PE, Rutherford TJ, Chambers JT, et al: Neoadjuvant chemotherapy for advanced ovarian cancer: Long term survival. Gynecol Oncol 72:93-99, 1999 9. Kayikciog F, Rose MF, Boran N, et al: Neoadjuvant chemotherapy or primary surgery in advanced epithelial ovarian cancer. Int J Gynecol Cancer 11: 466-470, 2001 10. Fanfani F, Ferrandina G, Corrado G, et al: Impact of interval debulking surgery on clinical outcome in primary unresectable FIGO stage IIIC ovarian cancer patients. Oncology 65:316-322, 2003 11. Morice P, Dubernard G, Rey A, et al: Results of interval debulking surgery compared with primary

debulking surgery in advanced stage ovarian cancer. J Am Coll Surg 197:955-963, 2003 12. Shibata K, Kikkawa F, Mika M, et al: Neoadjuvant chemotherapy for FIGO stage III or IV ovarian cancer: Survival benet and prognostic factors. Int J Gynecol Cancer 13:587-592, 2003 13. Ansquer Y, LeBlanc E, Clough K, et al: Neoadjuvant chemotherapy for nonresectable ovarian carcinoma: A French multicenter study. Cancer 91: 2329-2334, 2001 14. Kuhn W, Rutke S, Spathe K, et al: Neoadjuvant chemotherapy followed by tumor debulking prolongs survival for patients with poor prognosis in International Federation of Gynecology and Obstetrics stage IIIC ovarian carcinoma. Cancer 92:25852591, 2001 15. Vergote I, DeWever I, Tjalma W, et al: Neoadjuvant chemotherapy or primary debulking surgery in advanced ovarian carcinoma: A retrospective analysis of 285 patients. Gynecol Oncol 71:431-436, 1998 16. European Organization for Research and Treatment of Cancer: Randomized phase III study comparing upfront debulking surgery versus neo-adjuvant chemotherapy in patients with stage IIIc or IV epithelial ovarian cancer (EORTC protocol 55971). http://www .eortc.be/protoc/Details.asp?Protocol 55971 17. Chi DS, Venkatraman ES, Masson V, et al: The ability of preoperative serum CA-125 to predict optimal primary tumor cytoreduction in stage III epithelial ovarian carcinoma. Gynecol Oncol 77:227231, 2000 18. Gemer O, Segal S, Kopmar A, et al: Preoperative CA-125 level as a predictor of non-optimal cytoreduction of advanced epithelial ovarian cancer. Acta Obstet Gynecol Scand 80:583-585, 2001 19. Saygili U, Guclu S, Uslu T, et al: Can serum CA-125 levels predict the optimal primary cytoreduction in patients with advanced ovarian carcinoma? Gynecol Oncol 86:57-61, 2002 20. Cooper BC, Sood AK, Davis CS, et al: Preoperative CA-125 levels: An independent prognostic factor for epithelial ovarian cancer. Obstet Gynecol 100:59-64, 2002 21. Memarzadeh S, Lee SB, Berek JS, et al: CA-125 levels are a weak predictor of optimal cytoreductive surgery in patients with advanced epithelial ovarian cancer. Int J Gynecol Cancer 13:120-124, 2003

22. Dowdy SC, Mullany SA, Brandt KR, et al: The utility of computed tomography scans in predicting suboptimal cytoreductive surgery in women with advanced ovarian carcinoma. Cancer 101:346-352, 2004 23. Brockbank EL, Ind TE, Barton DP, et al: Preoperative predictors of suboptimal primary surgical cytoreduction in women with clinical evidence of advanced primary epithelial ovarian cancer. Int J Gynecol Cancer 14:42-50, 2004 24. Nelson BE, Roseneld AT, Schwartz PE: Preoperative abdominopelvic computed tomographic prediction of optimal cytoreduction in epithelial ovarian carcinoma. J Clin Oncol 11:166-172, 1993 25. Meyer JI, Kennedy AW, Friedman R, et al: Ovarian carcinoma: Value of CT in predicting success of debulking surgery. Am J Roentgenol 165: 875-878, 1995 26. Bristow RE, Duska LR, Lambrou NC, et al: A model for predicting surgical outcome in patients with advanced ovarian carcinoma using computed tomography. Cancer 89:1532-1540, 2000 27. Qayyum A, Coakley FV, Westphalan AC, et al: Role of CT and MRI imaging in predicting optimal cytoreduction of newly diagnosed primary epithelial ovarian cancer. Gynecol Oncol 96:301306, 2005 28. Alberts DS, Liu PY, Hannigan EV, et al: Intraperitoneal cisplatin plus intravenous cyclophosphamide versus intravenous cisplatin plus intravenous cyclophosphamide for stage III ovarian cancer. N Engl J Med 335:1950-1955, 1996 29. Markman M, Bundy BN, Alberts DS, et al: Phase III trial of standard-dose intravenous cisplatin plus paclitaxel versus moderately high-dose carboplatin followed by intravenous paclitaxel and intraperitoneal cisplatin in small-volume stage III ovarian carcinoma: An intergroup study of the Gynecologic Oncology Group, Southwestern Oncology Group, and Eastern Cooperative Oncology Group. J Clin Oncol 19:1001-1007, 2001 30. Bristow RE, Chi DS: Platinum-based neoadjuvant chemotherapy and interval cytoreduction for advanced ovarian cancer: A meta-analysis. Gynecol Oncol 103:1070-1076, 2006 31. Aletti GD, Gostout BS, Podratz KC, et al: Ovarian cancer surgical resectability: Relative impact of disease, patient status, and surgeon. Gynecol Oncol 100:33-37, 2006

Acknowledgment We thank Jeffrey Gornbein, PhD, Department of Biostatistics, David Geffen School of Medicine at University of California, Los Angeles, for assistance with the statistical analysis.

www.jco.org

389

Downloaded from jco.ascopubs.org on July 6, 2011. For personal use only. No other uses without permission. Copyright 2007 American Society of Clinical Oncology. All rights reserved.