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Prospective Study of the Correlation Between Postoperative Computed Tomography Scan and Primary Surgeon Assessment in Patients With Advanced Ovarian, Tubal, and Peritoneal Carcinoma Reported to Have Undergone Primary Surgical Cytoreduction to Residual Disease 1 cm or Less

Dennis S. Chi, Pedro T. Ramirez, Jerrold B. Teitcher, Svetlana Mironov, Debra M. Sarasohn, Revathy B. Iyer, Eric L. Eisenhauer, Nadeem R. Abu-Rustum, Yukio Sonoda, Douglas A. Levine, Carol L. Brown, Carol Aghajanian, David M. Gershenson, William J. Hoskins, Hedvig Hricak, Richard R. Barakat

From the Gynecology Service, Department of Surgery, Department of Radiology, and Solid Tumor Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY; and Departments of Gynecologic Oncology and Radiology, M.D. Anderson Cancer Center, Houston, TX

Address reprint requests to Dennis S. Chi, MD, Gynecology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021; e-mail: gynbreast{at}mskcc.org or chid{at}mskcc.org

	ABSTRACT

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Purpose To compare surgeons' operative assessments of residual disease (RD) to those identified on postoperative computed tomography (CT) scans in patients with advanced ovarian carcinoma reported to have undergone optimal primary cytoreduction.

Patients and Methods All patients at one of two institutions, who were scheduled to have primary surgery for presumed advanced ovarian cancer, were asked to consent to a postoperative CT scan if cytoreduction to 1 cm RD was reported. CT scan findings were graded using a qualitative analysis scale from 1 (normal) to 5 (definitely malignant).

Results From January 2001 to September 2006, 285 patients were enrolled. A total of 78 patients met eligibility criteria and had postoperative CT scans. In 41 cases (52%), postoperative scan findings correlated with the surgical report of no RD more than 1 cm, and in seven cases (9%), the CT findings were indeterminate. In 10 cases (13%), more than 1 cm RD was noted by the radiologist as probably malignant, and in 20 cases (26%), definitely malignant. In these 30 cases, the radiologically reported median largest residual mass was 1.9 cm (range, 1.1 to 5.1), with RD more than 1 cm reported most commonly in the right upper quadrant (15 patients [50%]) and central abdomen (nine patients [30%]).

Conclusion There was only a 52% correlation between surgeons' assessments and postoperative CT scan evaluations of RD in patients reported to have undergone optimal cytoreduction. Further study is required to determine whether this lack of correlation is due to rapid interval tumor regrowth, RD underestimated by the surgeons, and/or overestimated by the radiologists; and to determine the clinical implications of these discrepancies.

	INTRODUCTION

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Numerous studies have demonstrated that there is a survival advantage when patients with advanced ovarian cancer undergo "optimal" versus "suboptimal" primary surgical cytoreduction or "debulking."^1,2 Although various cutoff points for residual disease between 0 and 3.0 cm have been used for this division, the current Gynecologic Oncology Group (GOG) definition of optimal residual disease status uses 1 cm as a cut- off point.^3,4

Before the publication by Armstrong et al⁵ of GOG protocol 172 in 2006, the differentiation of optimal versus suboptimal cytoreduction was mainly of prognostic significance, as both groups of patients were routinely treated with systemic chemotherapy.³ However, GOG 172, a phase III trial that compared intravenous paclitaxel plus cisplatin with intravenous paclitaxel plus intraperitoneal (IP) cisplatin and paclitaxel in patients with optimally debulked stage III ovarian cancer, demonstrated a significant, 16-month median survival advantage for patients who were given IP and systemic chemotherapy compared with those given systemic chemotherapy alone. As a result, the National Cancer Institute issued a clinical announcement recommending that women with stage III ovarian cancer who undergo optimal surgical cytoreduction be considered for IP chemotherapy.⁴ Therefore, the differentiation of optimal versus suboptimal residual disease currently has taken on significant treatment implications since patients with suboptimal residual disease are currently not candidates for primary IP chemotherapy.⁵

Currently, this crucial factor of residual disease status is based on an individual surgeon's informal visual and manual measurement of the diameter of the largest remaining tumor nodule after debulking surgery. This measurement is subjective and not routinely confirmed by any objective means. The purpose of this study was to compare the primary surgeon's intraoperative assessment of residual disease to that identified on postoperative computed tomography (CT) scan of the abdomen and pelvis in patients with advanced ovarian, tubal, and peritoneal carcinoma who were reported to have undergone primary surgical cytoreduction to residual disease 1 cm.

	PATIENTS AND METHODS

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Eligibility
This is a two-part, prospective, institutional review board–approved, clinical trial. All patients 18 years of age at one of two institutions, who were undergoing surgery by an attending gynecologic oncologist for presumed advanced ovarian cancer, were eligible. The aim of the first part of the study was to evaluate the ability of preoperative serum CA-125 and CT scan to predict cytoreductive outcome. Accrual is ongoing for this part.

For the second part, all patients were asked preoperatively to consent to a postoperative CT scan of the abdomen and pelvis with oral and intravenous contrast. To be eligible for this second part, patients must have had histologically confirmed, stage III or IV ovarian, fallopian tube, or primary peritoneal cancer. The surgeon must have reported cytoreduction to 1 cm residual disease. The CT scan had to be done 7 to 35 days postoperatively, before the initiation of postoperative chemotherapy. If the patient did not get a postoperative CT scan, she was not excluded from the preoperative CT scan analysis, but she was nonassessable for the postoperative correlative study.

CT Scans
The CT scans were done with contiguous sections of 5- to 7.5-mm slice thicknesses after bolus injection of intravenous contrast and administration of oral contrast. CT scans performed at outside institutions were submitted to one of the protocol radiologists and were included in the study only if judged to be of acceptable quality. The protocol radiologists were all experienced in body CT scanning and blinded as to the exact surgeon-reported site and size of residual disease.

Image Analysis
Image analysis and interpretation were performed by one of the protocol radiologists in the following manner. Quantitative bidimensional measurements were determined for all visualized abnormalities, including visceral lesions, peritoneal surface lesions, and enlarged lymph nodes. Qualitative analysis (QA) was performed using a five-point scale categorizing the degree of radiologic certainty that a radiologically identified lesion represented a metastatic neoplasm. This QA score was documented as: 1 = definitely normal; 2 = probably normal; 3 = indeterminate; 4 = probable; and 5 = definitely a metastatic neoplasm. There were no specific criteria for each QA score; the protocol radiologists were instructed to use their experience and judgment, comparison to preoperative scans, and the characteristics of the masses (eg, ill-defined v well-defined, solid v cystic) to determine the score. No further histologic confirmation of the postoperative CT scan findings was required.

Data Collection and Statistical Analysis
This study represents the analysis of the postoperative CT scan findings in relation to the primary surgeon's intraoperative documentation of residual disease. For each patient, demographic, clinical, surgical, and pathologic data were collected. The highest QA scale score for reported residual lesions more than 1 cm was determined for each patient and used for the correlative analysis.

Categorical variables were evaluated by ² analysis or Fisher's exact test as appropriate for category size. Continuous variables were evaluated by the t test or Wilcoxon-Mann-Whitney test for normally and non–normally distributed data, respectively. Logistic regression was performed to determine factors independently associated with a postoperative CT scan identification of lesions more than 1 cm with a QA score of 4 or 5. Patients with reported residual lesions more than 1 cm and QA scores 4 or 5 were compared with those with no reported lesions more than 1 cm combined with those with lesions more than 1 cm but QA scores 1 or 2 using statistical tests as appropriate for the data distribution. All statistical tests were two-sided, and differences were considered statistically significant at P < .05. Data analysis was performed with Stata statistical software (version 8.2; StataCorp LP, College Station, TX).

	RESULTS

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From January 2001 to September 2006, 285 patients were enrolled onto the study. Of these 285 patients, 74 declined the postoperative CT scan or did not have it done within 35 days of surgery, 48 underwent suboptimal cytoreduction, 42 did not have ovarian, tubal, or peritoneal carcinoma, 27 withdrew from the study, and 16 did not have advanced disease. This left a total of 78 patients who met the eligibility criteria of optimally cytoreduced advanced-stage disease and had a postoperative CT scan performed. Sixty-four (82%) of the 78 cases were enrolled at the primary study institution. Table 1 summarizes the patient and tumor characteristics for the entire 78-patient cohort. The 15 patients with stage IV disease had parenchymal liver disease and/or malignant pleural effusions.

Logistic regression analysis of the entire 78-patient cohort was performed to determine which variables, if any, were associated with CT evidence of more than 1 cm residual lesions and a QA score of 4 or 5. For the variable regarding days between surgery and the postoperative scan, 14 days was used as a cutoff, as this was the median number for the entire group. Of the variables analyzed, only the surgeon-reported category of residual disease 0.6 to 1.0 cm when compared with microscopic residual demonstrated a statistically significant association (Table 4).

	DISCUSSION

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The need for an objective quantification of residual disease may not be desired or utilized in situations in which the same clinician does the surgery and also administers the postoperative chemotherapy. However, in cases when a physician has referred a patient who has had surgery elsewhere, postoperative CT scans are frequently used to document the amount of residual disease after cytoreduction and as a baseline before initiating chemotherapy. Furthermore, in situations in which an IP port had not been placed at primary surgery, accurate information regarding residual disease could potentially guide the physician as to whether or not to have an intraperitoneal port placed before the initiation of primary chemotherapy or to simply proceed with systemic therapy. Frequently, prospective clinical trials, including those of the GOG, require a postoperative CT scan before the initiation of chemotherapy. Patients can be deemed ineligible for these trials based on the findings of the CT scan despite the fact that the accuracy of radiologic findings in this postoperative setting has never been validated.

The aim of this study was to evaluate the correlation between surgeons' assessments of residual disease and postoperative CT scan findings. While the reliability of direct visualization and palpation are unquestionable, the intraoperative quantification of disease diameter is subjective and can be dependent on numerous factors, such as surgeon, patient and familial expectations, as well as adequate exposure and evaluation of potential tumor sites.^9-11

In an analysis of 131 patients with advanced ovarian carcinoma who had tumor involving the diaphragm and who underwent primary cytoreduction to residual disease of 1 cm, Aletti et al¹¹ found a significant 5-year survival advantage for those patients who underwent diaphragm surgery compared to those who did not. They proposed that the difference in survival may have been due to the underestimation of the amount of residual disease in patients who did not undergo diaphragm surgery (and presumably also did not undergo liver mobilization for complete visualization), therefore falsely assigning them to "optimal" residual disease status.

While the subjective nature of surgeon-reported residual disease status and the need for more objective quantification is apparent, the results of this and other studies do not provide definitive evidence that postoperative CT scans will provide the required objective answer. In this study, we did not require verification as to whether areas identified as residual disease on postoperative CT scan were in fact residual cancer. The most accurate way to have done this would have been to subject patients to a second surgical procedure, which was not warranted in this investigational setting. However, previous studies that have compared preoperative CT scan and subsequent intraoperative findings in patients with ovarian, colorectal, and appendiceal carcinomatosis have demonstrated significant interobserver differences, poor detection of individual peritoneal implants, wide variation of accurate tumor detection per anatomic site, and especially poor sensitivity with tumor implants 1 cm.^12,13

Given that an analysis of postoperative CT scan findings has not previously been performed, the aims for this study were predominantly hypothesis-generating. To our knowledge, the QA scale used in this study has not been used or described before. The QA scale was used in an attempt to objectively quantify a qualitative finding that can be admittedly very subjective. Before the initiation of this trial, we anticipated that there might be discordance between the surgeons' reports of residual disease and the postoperative CT scans, but of unknown degree. Factors that were anticipated to potentially contribute to a lack of concordance included postoperative tissue inflammatory reaction, sequestration and collections of fluid and blood debris, and the placement of hemostatic agents, such as Gelfoam (Pharmacia and Upjohn Company, Kalamazoo, MI). Although it is impossible from the operative reports to accurately determine how many patients had hemostatic agents placed, at least five (24%) of the 21 patients who were reported to have residual disease more than 1 cm that was characterized as definitely malignant were documented to have Gelfoam or other hemostatic materials used at the time of surgery. It is beyond the scope of this study to determine whether or not the disease more than 1 cm identified by the radiologists was in fact hemostatic compounds, but this remains a distinct possibility, and the confusing radiologic appearance of these products has been previously reported.¹⁴

In an attempt to assess potential confounding variables, we analyzed patients' body mass indexes to see if it had any potential effect on the residual disease measurements; estimated blood loss to see if higher loss lead to more inflammation or accumulation of debris; surgeon-reported residual disease to determine if larger reported residual disease was more frequently associated with CT scan findings of more than 1 cm lesions; and time between surgery and the postoperative CT scan to assess if longer intervals were associated with greater frequencies of discordance due to postoperative tumor growth. The only statistically significant finding in the above subset analysis was that patients with microscopic residual disease at primary surgery were significantly less likely to have CT scans showing more than 1 cm lesions than patients left with 0.6-1.0 cm residual disease.

In the 30 patients reported to have lesions more than 1 cm on postoperative CT scan that were probably or definitely malignant, the surgeon did note residual disease in the same area identified on the scan in 60% of cases. However, residual disease was not noted at all in the CT-identified area in 40% of cases. Furthermore, in the majority of discordant cases, the largest mass identified on the CT scan was 2 cm. Although this difference of 1 cm as reported by the surgeon and the most commonly identified finding of 1.1 to 2.0 cm lesions on the CT scan is in fact a strict lack of correlation, given the subjective assessment of the surgeon of perhaps dozens of nodules, combined with the potential difficulty and variability of radiologically measuring lesions to an accuracy of millimeters, this discordance is understandable and to some degree expected.^9-13,15

In this study, we were not able to determine the proportional contributions to the 38% (30 of 78) discordance rate of surgeon underestimation of residual disease versus CT scan overestimation of residual disease. More importantly, however, the clinical significance of this discordance is unclear as we do not have follow-up data to determine if patients who had CT scan findings that correlated with the operative report had better outcomes that those who did not. Only further study will allow us to evaluate this question.

In summary, in this study there was only a 52% correlation between the primary surgeon's assessment and the postoperative CT scan evaluation of residual disease in patients reported to have undergone optimal cytoreduction. In approximately 40% of cases, residual lesions more than 1 cm were identified as probably or definitely malignant. The most common site of discrepancy was the right upper quadrant of the abdomen. Residual lesions were significantly more frequently identified when the surgeon-reported residual disease was 0.6 to 1.0 cm as compared to microscopic. In the cases of discordance, it is unclear whether residual disease was underestimated by the primary surgeons, overestimated by the protocol radiologists, or both. Another possible contributing factor to the discordance could be rapid tumor regrowth that occurs after the surgery, before the postoperative CT scan. Although the number of days between the two was not shown to be a significant factor, given the irrefutable fact that with time tumor does grow, there is a distinct possibility that in a larger set of patients, this variable would prove to be significant. We are planning further studies to compare the clinical outcomes of those patients with concordant versus discordant CT findings. At this point, we feel these results are hypothesis-generating, and we do not advocate postoperative CT scanning as a routine modality to supplant the intraoperative assessment of the operating surgeon, but we do feel that surgeons should pay special attention to the sites of discrepancy identified in this study, especially the right upper quadrant. We hope that this study will lead to others that will further explore and evaluate these very important issues.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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The author(s) indicated no potential conflicts of interest.

	AUTHOR CONTRIBUTIONS

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Conception and design: Dennis S. Chi, Hedvig Hricak

Provision of study materials or patients: Dennis S. Chi, Pedro T. Ramirez, Eric L. Eisenhauer, Nadeem R. Abu-Rustum, Yukio Sonoda, Douglas A. Levine, Carol L. Brown, Carol Aghajanian, David M. Gershenson, William J. Hoskins, Richard R. Barakat

Collection and assembly of data: Dennis S. Chi, Pedro T. Ramirez, Eric L. Eisenhauer, Nadeem R. Abu-Rustum, David M. Gershenson, William J. Hoskins, Richard R. Barakat

Data analysis and interpretation: Dennis S. Chi, Pedro T. Ramirez, Jerrold B. Teitcher, Svetlana Mironov, Debra M. Sarasohn, Revathy B. Iyer, Eric L. Eisenhauer, Nadeem R. Abu-Rustum, Carol Aghajanian, David M. Gershenson, William J. Hoskins, Hedvig Hricak, Richard R. Barakat

Manuscript writing: Dennis S. Chi, Pedro T. Ramirez, Jerrold B. Teitcher, Svetlana Mironov, Debra M. Sarasohn, Revathy B. Iyer, Eric L. Eisenhauer, Nadeem R. Abu-Rustum, Yukio Sonoda, Douglas A. Levine, Carol L. Brown, Carol Aghajanian, David M. Gershenson, William J. Hoskins, Hedvig Hricak, Richard R. Barakat

Final approval of manuscript: Dennis S. Chi, Pedro T. Ramirez, Jerrold B. Teitcher, Svetlana Mironov, Debra M. Sarasohn, Revathy B. Iyer, Eric L. Eisenhauer, Nadeem R. Abu-Rustum, Yukio Sonoda, Douglas A. Levine, Carol L. Brown, Carol Aghajanian, David M. Gershenson, William J. Hoskins, Hedvig Hricak, Richard R. Barakat

	NOTES

 
Presented at the Society of Gynecologic Oncologists 38th Annual Meeting in San Diego, CA, March 3 to 7, 2007.

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

	REFERENCES

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1. 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[Abstract/Free Full Text]

2. Chi DS, Eisenhauer EL, Lang J, et al: What is the optimal goal of primary cytoreductive surgery for bulky stage IIIC epithelial ovarian carcinoma? Gynecol Oncol 103 : 559 -564, 2006[CrossRef][Medline]

3. 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 21 : 3194 -3200, 2003[Abstract/Free Full Text]

4. National Cancer Institute: Clinical Announcement: Intraperitoneal chemotherapy for ovarian cancer, 2006 . http://ctep.cancer.gov/highlights/clin_annc_010506.pdf

5. Armstrong DK, Bundy B, Wenzel L, et al: Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med 354 : 34 -43, 2006[Abstract/Free Full Text]

6. Nelson BE, Rosenfield AT, Schwartz PE: Preoperative abdominopelvic computed tomographic prediction of optimal cytoreduction in ovarian carcinoma. J Clin Oncol 11 : 166 -172, 1993[Abstract]

7. 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[CrossRef][Medline]

8. Axtell AE, Lee MH, Brisow RE, et al: Multi-institutional reciprocal validation study of computed tomography predictors of suboptimal primary cytoreduction in patients with advanced ovarian cancer. J Clin Oncol 25 : 384 -389, 2007[Abstract/Free Full Text]

9. Prefontaine M, Gelfand AG, Donavan JT, et al: Reproducibility of tumor measurements in ovarian cancer: A study of interobserver variability. Gynecol Oncol 66 : 87 -90, 1994

10. Eisenkop SM, Spirtos NM, Lin WM: "Optimal" cytoreduction for advanced epithelial ovarian cancer: A commentary. Gynecol Oncol 103 : 329 -335, 2006[CrossRef][Medline]

11. Aletti GD, Dowdy SC, Podratz KC, et al: Surgical treatment of diaphragm disease correlates with improved survival in optimally debulked advanced stage ovarian cancer. Gynecol Oncol 100 : 283 -287, 2006[CrossRef][Medline]

12. Coakley FV, Choi PH, Pothuri B, et al: Peritoneal metastases: Detection with spiral CT in patients with ovarian cancer. Radiology 223 : 495 -499, 2002[Abstract/Free Full Text]

13. de Bree ED, Koops W, Kroger R, et al: Peritoneal carcinomatosis from colorectal or appendiceal origin: Correlation of preoperative CT with intraoperative findings and evaluation of interobserver agreement. J Surg Oncol 86 : 64 -73, 2004[CrossRef][Medline]

14. O'Connor AR, Coakley FV: Retained surgical materials in the postoperative abdomen and pelvis. Semin Ultrasound CT MR 25 : 290 -302, 2004[CrossRef][Medline]

15. Thiesse P, Ollivier L, DiStefano-Louineau D, et al: Response rate and accuracy in oncology trials: Reasons for interobserver variability. J Clin Oncol 15 : 3507 -3514, 1997[Abstract/Free Full Text]

Submitted April 19, 2007; accepted August 13, 2007.

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