computed tomography—A prospective study

Available online at www.sciencedirect.com

Gynecologic Oncology 108 (2008) 265 – 270 www.elsevier.com/locate/ygyno

Prediction of suboptimal primary cytoreduction in primary ovarian cancer with combined positron emission tomography/computed tomography—A prospective study S. Risum a,⁎, C. Høgdall b , A. Loft c , A.K. Berthelsen c , E. Høgdall d , L. Nedergaard e , L. Lundvall b , S.A. Engelholm a a

Department of Oncology, The Finsen Center, Rigshospitalet, Copenhagen University Hospital, Denmark Gynecologic Clinic, The Juliane-Marie Center, Rigshospitalet, Copenhagen University Hospital, Denmark c PET and Cyclotron Unit, Department of Clinical Physiology & Nuclear Medicine, Centre of Diagnostic Investigations, Rigshospitalet, Copenhagen University Hospital, Denmark d Institute of Cancer Epidemiology, Department of Virus, Hormones and Cancer, Danish Cancer Society, Denmark Department of Pathology, Centre of Diagnostic Investigations, Rigshospitalet, Copenhagen University Hospital, Denmark b

e

Received 14 September 2007 Available online 4 December 2007

Abstract Objective. To prospectively identify combined PET/CT predictors of incomplete/suboptimal primary cytoreduction in advanced ovarian cancer. Methods. From September 2004 to March 2007, 179 patients with a Risk of Malignancy Index (RMI) N 150 based on serum CA-125, ultrasound examinations and menopausal state, underwent PET/CT within 2 weeks prior to standard surgery/debulking of a pelvic tumor. Ten PET/CT features were identified and evaluated as predictors of cytoreduction in 54 patients with advanced ovarian cancer. Results. Complete cytoreduction (no macroscopic residual disease) was achieved in 35% and optimal cytoreduction (b1 cm residual disease) was achieved in 56%. Using univariate analysis, predictors of incomplete cytoreduction were large bowel mesentery implants (LBMI) (P b 0.003), pleural effusion (P b 0.009), ascites (P b 0.009) and peritoneal carcinosis (P b 0.01). LBMI (P b 0.03) and ascites (P b 0.05) were also predictors of suboptimal cytoreduction. Using multivariate analysis, LBMI was the only independent predictor of incomplete cytoreduction (P = 0.004) and no predictor of suboptimal cytoreduction was found. Conclusion. PET/CT predictors of cytoreduction were found. But they should not be used to withhold patients form primary cytoreductive surgery. We suggest PET/CT as a supplementary image modality prior to surgery in primary OC patients whenever accurate and comprehensive preoperative evaluation of primary tumor and metastases is desired. © 2007 Elsevier Inc. All rights reserved. Keywords: Positron emission tomography; Prediction of optimal cytoreduction; Surgery; Primary ovarian cancer

Introduction Standard treatment of ovarian cancer (OC) includes primary cytoreduction surgery and subsequent staging according to Federation of Obstetricians and Gynecologists (FIGO), followed by platinum-based chemotherapy [1,2]. Multiple studies have reported the extent of primary debulking to independently ⁎ Corresponding author. Fax: +45 3545 3990. E-mail address: [email protected] (S. Risum). 0090-8258/$ - see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2007.11.002

influence survival [3–13]. However, it is debated if primary surgery should be withheld from subgroups of patients with extensive disease who cannot be optimally cytoreduced at primary surgery [14–19]. Currently, we are awaiting the results of a European Organisation for Research and Treatment of Cancer trial to clarify which patients should be allocated to neoadjuvant chemotherapy followed by interval debulking [20]. A critical issue surrounding neoadjuvant chemotherapy is pretreatment identification of patients with advanced OC whose

266

S. Risum et al. / Gynecologic Oncology 108 (2008) 265–270

Table 1 Histological diagnoses in 54 patients with primary ovarian cancer

PET/CT scanning procedure

Diagnosis

Number of patients

Serous adenocarcinoma Stage III OC Stage IV OC Mucinous adenocarcinoma Endometrioid adenocarcinoma Transitional cell carcinoma

50 47 3 2 (both stage III OC) 1 (stage III OC) 1 (stage IV OC)

PET was performed with an integrated PET/CT (GE Discovery PET/CT, General Electric Medical Systems, Milwaukee, WI). The patient fasted for a minimum of 6 h prior to PET acquisition. Sixty minutes after injection of 400 MBq FDG (2-[18F]flouoro-2-deoxy-d-glucose) in a cubital vein, the CT scan was performed. The patient was asked to void before scan start. Oral and intravenous contrast agents were given prior to the CT scan. The duration of the CT scan was 20 s and it was performed with 140 kV and 90–120 mA. Immediately thereafter, the static emissions in 2-D acquisition were obtained with 7–8 consecutive frames, each of 3 min emission, from the proximal femur to the scalp. The PET acquisition lasted approximately 25 min. The CT data were used for attenuation correction of the PET data. Images were reconstructed and stored in 5 mm transaxial, coronal and sagittal slices. The images were fused on the GE eNTEGRA workstation.

disease cannot be optimally cytoreduced at primary surgery [21]. Retrospective studies have been published identifying preoperative CT predictors of suboptimal cytoreduction [18,22,23]. Lately, Axtell et al. found diaphragm disease and large bowel mesentery implants (LBMI) to be such predictors, but the predictors in the original cohorts could not be validated when tested on another cohort of patients [21]. To our knowledge, the value of combined positron emission tomography/computed tomography (PET/CT) in predicting suboptimal cytoreduction has never been investigated. PET/ CT was recently reported to have a high sensitivity and specificity for diagnosing OC [24]. The aim of this prospective study was to investigate possible combined PET/CT predictors of incomplete/suboptimal primary cytoreduction. The study was conducted as part of the Danish Pelvic Mass study. Methods Approval to conduct this study was obtained from The Scientific Ethical Committee in the study area (KF01-227/03). From September 2004 to March 2007, 179 patients referred to surgery for a suspected pelvic tumor underwent PET/CT within 2 weeks prior to standard surgery/debulking. All patients had a Risk of Malignancy Index (RMI) N150 based on serum CA-125, ultrasound examinations and menopausal state [25]. Patients were excluded if they were suffering from claustrophobia, severe obesity, known allergy to contrast media, diabetes or other severe medical condition or had a history of previous cancer or borderline tumor. The result of the PET/CT scan was given to the referring surgeon. Patients with a suspicious pelvic mass had an exploratory laparotomy performed by one of the 6 gynecologic oncologists at our clinic. OC patients were staged according to FIGO. An experienced pathologist did evaluation of operation specimens according to the latest WHO classification (2002). Fifty-four patients with advanced OC were eligible for this PET/CT study.

Table 2 Location of PET/CT metastases indicating stage IV in 24 stage III patients Location

Number of metastases

Parenchymatous metastases Pleura or lung Spleen Lymph node metastases Neck Axilla Parasternal Mediastinum Inguinal canal

13 12 1 25 6 5 9 4

Imaging analysis The same nuclear medicine physician and radiologist blinded to surgical outcomes evaluated CT and PET images separately and as fused images in consensus. A pathological uptake was described as focal areas visual in all three planes with the same co-ordinates (x,y,z). Artifactual and physiological soft tissue FDG accumulation was taking into account in the visual interpretation of PET.

Data analysis Cytoreduction was performed with the intention of removing all visible tumor tissue. Complete cytoreduction was defined as no macroscopic tumor left in the pelvis or abdomen at the end of surgery. Optimal surgical resection was defined as b1 cm maximal diameter pelvic/abdominal residual disease. Based on reported studies of CT predictors of suboptimal cytoreduction and on location of tumor on PET/CT, 10 PET/CT features were identified as potential indicators of surgical outcome in 54 stage III–IV OC patients [21–23]. These features included peritoneal carcinosis (PC), LBMI, small bowel mesentery implants (SBMI), pelvic lymph nodes N1 cm, retroperitoneal lymph nodes N1 cm, lymph nodes outside abdomen N1 cm, inguinal lymph nodes N1 cm, rectal implants, pleural effusion and ascites. All features except ascites were defined as having pathological FDG-uptake on PET. On CT, PC was defined as thickening of the peritoneum. Using Fisher's exact test, the 10 potential PET/CT predictors were tested as univariate predictors of either incomplete or suboptimal pelvic/abdominal cytoreduction. To identify independent predictive variables for incomplete or suboptimal cytoreduction, statistically significant predictors of incomplete or suboptimal cytoreduction found by univariate analysis were further analyzed by stepwise logistic multivariate analysis.

Results Patient characteristics and histopathology Fifty-four patients with advanced OC composed the study population. Median age was 63 years (range 40–85 years). Fifty-two patients (96%) had a GOG performance status of 2 or Table 3 Percentage of patients cytoreduced in relation to PET/CT results in 50 stage III OC patients

No visible tumor left Optimal debulking b1 cm

PET/CT indicating stage III (%)

PET/CT indicating stage IV (%)

26 patients

24 patients

54 73

13 33

P

0.004 0.01

S. Risum et al. / Gynecologic Oncology 108 (2008) 265–270

267

Table 4 Univariate analysis of PET/CT predictors of incomplete pelvic/abdominal cytoreduction in 19 patients with no macroscopic residual disease and 35 patients with macroscopic residual disease PET/CT predictor

Large bowel mesentery implants Pleural effusion Ascites Peritoneal carcinosis (PC) Lymph nodes outside abdomen N1 cm Small bowel mesentery implants Inguinal lymph nodes N1 cm Rectal implants Retroperitoneal lymph nodes N1 cm Pelvic lymph nodes N1 cm

Patients With variable present

With variable absent

No. incomplete (%)

No. incomplete (%)

33 11 34 41 20 20 6 8 22 10

better and 49 patients (91%) had an ASA status of 2 or better. Three patients had stage IIIa, 5 stage IIIb, 42 stage IIIc and 4 stage IV. Histological diagnoses appear from Table 1. Operative results Cytoreduction with no macroscopic residual tumor (complete debulking) was accomplished in 19 patients (35%). Thirty patient (56%) were optimally cytoreduced with b 1 cm residual tumor and 37 patients (69%) were cytoreduced with b 2 cm residual tumor. In 24 of the 50 stage III patients (2 stage IIIb, 22 stage IIIc), PET/CT revealed extraabdominal metastases indicating stage IV. Fifteen patients had metastases at 1 location, 5 patients at 2 locations, 3 patients at 3 locations and 1 patient at 4 locations. Locations of metastases seen on PET/CT are listed in Table 2. The metastases were not bioptically verified. No false positive pathological PET/CT foci were found in patients with benign pelvic tumors on PET/CT (81 of the 179 included patients). Stage III patients were less likely to be completely or optimally cytoreduced if PET/CT results indicated stage IV. The different rates of complete and optimal debulking between stage

77 31 77 89 46 46 14 17 43 20

21 43 120 13 34 34 48 46 32 44

P

32 0 37 53 21 21 5 11 37 16

0.003 0.009 0.009 0.01 0.13 0.13 0.60 0.82 0.89 1.00

III patients with and without distant metastases on PET/CT were statistically significant (P = 0.004 and P = 0.01) (Table 3). Three of the 4 stage IV patients were not only optimally debulked b 1 cm but they also had complete removal of distant lymph node metastases seen on PET/CT. In two patients, the lymph node metastases were located in the inguinal canal and in one patient in the neck. PET/CT predictors of cytoreduction Tables 4–6 present the number of patients presenting with each of the 10 investigated PET/CT factors. Lymph nodes outside the abdomen were seen in 20 patients and consisted of 9 mediastinal lymph nodes, 7 lymph nodes in the neck (5 infraclaviculary lymph nodes and 2 supraclaviculary lymph nodes), 5 parasternal lymph nodes, 6 inguinal lymph nodes and 1 axillary lymph node. The 10 evaluated preoperative PET/CT features were subjected to univariate analysis to determine their ability to predict incomplete cytoreduction (macroscopic residual disease), suboptimal cytoreduction with N 1 cm residual disease and cytoreduction with N 2 cm residual disease (Tables 4–6).

Table 5 Univariate analysis of PET/CT predictors of suboptimal (N1 cm) pelvic/abdominal cytoreduction in 30 patients with b1 cm residual disease and 24 patients with N1 cm residual disease PET/CT predictor

Large bowel mesentery implants Ascites Pleural effusion Rectal implants Peritoneal carcinosis (PC) Small bowel mesentery implants Lymph nodes outside abdomen N1 cm Inguinal lymph nodes N1 cm Pelvic lymph nodes N1 cm Retroperitoneal lymph nodes N1 cm

Patients With variable present

With variable absent

No. incomplete (%)

No. incomplete (%)

33 34 11 8 41 20 20 6 10 22

79 79 33 25 88 50 46 17 21 42

21 201 43 46 13 34 34 48 44 32

P

47 50 110 7 67 27 30 7 17 40

0.03 0.05 0.08 0.13 0.14 0.14 0.36 0.47 0.96 1.00

268

S. Risum et al. / Gynecologic Oncology 108 (2008) 265–270

Table 6 Univariate analysis of PET/CT predictors of suboptimal (N2 cm) pelvic/abdominal cytoreduction in 37 patients with b2 cm residual disease and 17 patients with N2 cm residual disease PET/CT predictor

Small bowel mesentery implants Large bowel mesentery implants Ascites Rectal implants Pleural effusion Peritoneal carcinosis (PC) Retroperitoneal lymph nodes N1 cm Pelvic lymph nodes N1 cm Lymph nodes outside abdomen N1 cm Inguinal lymph nodes N1 cm

Patients With variable present

With variable absent

No. incomplete (%)

No. incomplete (%)

20 33 34 8 11 41 22 10 20 6

LBMI (P b 0.003), ascites (P b 0.009), pleural effusion (P b 0.009) and peritoneal carcinosis (P b 0.01) were all found to be statistically significant univariate predictors of incomplete cytoreduction. In 77% of women undergoing incomplete cytoreduction, PET/CT showed LBMI or ascites. In 31% of women undergoing incomplete cytoreduction, PET/CT showed pleural effusion and in 89% PET/CT showed PC. Using univariate analysis, LBMI (P b 0.03) and ascites (P b 0.05) were also statistically significant predictors of suboptimal cytoreduction N 1 cm. In 79% of women undergoing suboptimal N1 cm debulking, PET/CT showed LBMI or ascites. SBMI (P b 0.05) were the only statistically significant univariate predictor of suboptimal N 2 cm cytoreduction. In 59% of women undergoing suboptimal N 2 cm debulking, PET/CT showed SBMI. Using multivariate logistic analysis, LBMI was found to be the only statistically significant independent predictor of incomplete cytoreduction (risk ratio [RR], 1.7; P = 0.004). No statistically significant independent predictors of suboptimal cytoreduction were found. Discussion PET/CT results indicated lymph node metastases outside the abdomen in 20 of the 54 investigated patients (37%). Going through the literature, lymph node metastases beyond the abdominal cavity at initial presentation are reported to be rare in OC [26,27]. The reported incidence of lymph node metastases outside the abdomen is generally based on clinical examinations. Our PET/CT study indicated that when distant lymph nodes are assessed solely by clinical examination at the time of diagnosis, it is possible that distant lymph node metastases in a large number of patients are unrecognized. As a consequence, the patients are not only diagnosed with a lower stage than the actual stage but some patients may also be deprived a possible survival benefit from removal of distant tumors or undergo suboptimal postoperative chemotherapy with suboptimal evaluation of residual tumor between cycles. Cytoreductive surgery for advanced OC was first reported by Meigs in 1934 as a way to enhance the effects of postoperative

59 82 82 29 35 88 29 24 35 12

34 21 20 46 43 13 32 44 34 48

P

27 51 54 8 14 70 56 16 38 11

0.05 0.06 0.08 0.11 0.14 0.27 0.40 0.77 1.00 1.00

radiation therapy [28]. More than 40 years later, Griffiths reported an inverse relationship between residual tumor b1.6 cm and patient survival [3]. Multiple other investigators have now shown that patients gain a survival benefit if they undergo cytoreduction with residual tumor b 2 cm prior to chemotherapy [1,5,7]. During the last decade, researchers have found postoperative residual tumor to be one of the most important independent prognostic factors of survival in OC [6–13]. Today, aggressive surgical effort with intended removal of all macroscopic tumor is considered the optimal goal of cytoreductive surgery and is feasible in most patients. Chi et al. recently published a retrospective study of 465 stage IIIc OC patients where 67 patients (15%) with no macroscopic residual disease had a median overall survival of 106 months compared to a median overall survival of 66 months in patients cytoreduced to b0.5 cm [9]. Retrospective studies have also demonstrated a survival benefit associated with cytoreductive surgery in stage IV patients [29–31]. In these studies, the reported rate of optimally cytoreduced (b 2 cm residual disease) ranged from 30% to 43%. Optimally cytoreduced patients survived on average 10 to 22 months longer than patients suboptimally cytoreduced. In another retrospective study of 84 patients, Bristow et al. reported a survival gain of 28 months in the 30% patients cytoreduced with b 1 cm residual disease [32]. In the same study, 6 of 17 optimally cytoreduced patients with liver metastases also underwent optimal cytoreduction of liver metastases. These 6 patients survived on average 23 months longer than the 11 patients optimally cytoreduced but with suboptimal hepatic disease. Whether stage IV patients also gain a survival benefit from removal of extraabdominal metastases is still unanswered in clinical trials. To evaluate the potential effects of such cytoreduction on survival, a new definition of residual tumor is needed. Currently, most studies investigating the effect of surgery in OC define residual tumor as the amount of tumor left in the pelvic/abdominal region after surgery. However, this definition is only applicable in stage I–III patients where all tumor tissue is located in the pelvis/abdomen. Following the conventional definition of optimal cytoreduction, stage IV patients could be classified as optimally cytoreduced and still

S. Risum et al. / Gynecologic Oncology 108 (2008) 265–270

have tumors left outside the abdomen. The different rates of complete and optimal debulking between stage III patients with and without distant metastases on PET/CT support the PET/CT findings of stage IV disease in 24 stage III patients. However, interpreting the differences in surgical outcome, it must be considered that the surgeons were informed about the PET/CT results prior to debulking. Knowledge of the PET/CT results could have influenced the surgical effort. In interpreting the surgical results, it must also be taken into account that we did not investigate tumor biology prior to surgery. In the current study, 24 of the 54 stage III/IV patients (44%) underwent cytoreduction with N1 cm residual disease. In the attempt to localize those patients who will undergo suboptimal surgery, several investigators have retrospectively tried to specify preoperative CT predictors of suboptimal cytoreduction in stage III/IV patients [21–23]. The previously found predictors have been different for each cohort of investigated patients and they have shown a lack of generalizability when applied to other cohorts of patients [21]. In the current prospective study using univariate analysis, we found LBMI, pleural effusion, ascites and PC to be statistically significant predictors of incomplete cytoreduction. LBMI and ascites were also statistically significant predictors of suboptimal cytoreduction N1 cm and SBMI was statistically significant predictor of suboptimal cytoreduction N 2 cm (Tables 4–6). Using multivariate stepwise logistic analysis, LBMI was the only statistically significant independent predictor of incomplete cytoreduction. No independent predictors of suboptimal cytoreduction were found. Despite the statistical significance, the clinical relevance of these PET/CT predictors remains questionable since no predictor was found that consistently identified patients with surgically unresectable disease. In almost every group of patients with a predictor of incomplete/suboptimal cytoreduction present, there were some patients who were completely/optimally cytoreduced (Tables 4–6). Of 33 patients with LBMI, 18% underwent complete debulking, and of 41 patients with PC, 24% underwent complete debulking. Our results illustrate in consistency with previous research that no radiological features should be used to deprive patients the survival advantage associated with an optimal primary cytoreduction. In summary, combined PET/CT locates potentially resectable distant metastases not recognized by common staging procedures. We suggest PET/CT as a supplementary image modality prior to surgery in primary OC patients whenever accurate and comprehensive preoperative evaluation of primary tumor and metastases is desired and especially when clinical protocols are being evaluated. Statistically significant PET/CT predictors of cytoreduction were found in this study, but such predictors should not be used to withhold patients from primary cytoreductive surgery until prospective randomized trials have demonstrated that neoadjuvant chemotherapy followed by interval debulking is equivalent in terms of survival outcomes to primary optimal cytoreduction followed by chemotherapy. Future prospective clinical trials are still needed to clarify if stage IV patients gain a survival advantage from removal of distant metastases.

269

References [1] Bristow RE, Tomacruz RS, Armstrong DK, Trimble EL, Montz FJ. Survival effect of maximal cytoreductive surgery for advanced ovarian carcinoma during the platinum era: a meta-analysis. J Clin Oncol 2002;20: 1248–59. [2] Bristow RE. Surgical standards in the management of ovarian cancer. Curr Opin Oncol 2000;12:474–80. [3] Griffiths CT. Surgical resection of tumor bulk in the primary treatment of ovarian cancer. Natl Cancer Inst Monogr 1975;42:131–6. [4] Bertelsen K. Tumor reduction surgery and long-term survival in advanced ovarian cancer: a DACOVA study. Gynecol Oncol 1990;38:203–9. [5] Hoskins WJ, McGuire WP, Brady MF, Homesley HD, Creasman WT, Berman M, 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 1994;170: 974–9. [6] Eisenkop SM, Friedman RL, Wang HJ. Complete cytoreductive surgery is feasible and maximizes survival in patients with advanced epithelial ovarian cancer: a prospective study. Gynecol Oncol 1998;69:103–8. [7] Eisenkop SM, Spirtos NM, Lin WCM. Optimal“ cytoreduction for advanced epithelial ovarian cancer: a commentary. Gynecol Oncol 2006;103:329–35. [8] Eisenkop SM, Spirtos NM, Friedman RL, Lin WCM, Pisani AL, Perticucci S. Relative influences of tumor volume before surgery and the cytoreductive outcome on survival for patients with advanced ovarian cancer: a prospective study. Gynecol Oncol 2003;90:390–6. [9] Chi DS, Eisenhauer EL, Lang J, Huh J, Haddad L, Abu-Rustum NR, et al. What is the optimal goal of primary cytoreductive surgery for bulky stage IIIC epithelial ovarian carcinoma (EOC)? Gynecol Oncol 2006;103: 559–64. [10] Eisenhauer EL, Abu-Rustum NR, Sonoda Y, Levine DA, Poynor EA, Aghajanian C, et al. The addition of extensive upper abdominal surgery to achieve optimal cytoreduction improves survival in patients with stages IIIC–IV epithelial ovarian cancer. Gynecol Oncol 2006;103:1083–90. [11] Aletti GD, Dowdy SC, Gostout BS, Jones MB, Stanhope CR, Wilson TO. Aggressive surgical effort and improved survival in advanced-stage ovarian cancer. Obstet Gynecol 2006;107:77–85. [12] Aletti GD, Dowdy SC, Podratz KC, Cliby WA. Surgical treatment of diaphragm disease correlates with improved survival in optimally debulked advanced stage ovarian cancer. Gynecol Oncol 2006;100: 283–7. [13] Wimberger P, Lehmann N, Kimmig R, Burges A, Meier W, Du Bois A. Prognostic factors for complete debulking in advanced ovarian cancer and its impact on survival. An exploratory analysis of a prospectively randomized phase III study of the Arbeitsgemeinschaft Gynaekologische Onkologie Ovarian Cancer Study Group (AGO-OVAR). Gynecol Oncol 2007;106:69–74. [14] Vergote I, Dewever I, Tjalma W, Van Gramberen M, Decloedt J, van Dam P. Neoadjuvant chemotherapy or primary debulking surgery in advanced ovarian carcinoma: a retrospective analysis of 285 patients. Gynecol Oncol 1998;71:431–6. [15] Kuhn W, Rutke S, Späthe K, Schmalfeldt B, Florack G, von Hundelshausen B, 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 2001;92:585–91. [16] Ansquer Y, Leblanc E, Clough K, Morice P, Dauplat J, Mathevet P, et al. Neoadjuvant chemotherapy for unresectable ovarian carcinoma: a French multicenter study. Cancer 2001;91:2329–34. [17] Morice P, Dubernard G, Rey A, Atallah D, Pautier P, Pomel C, et al. Results of interval debulking surgery compared with primary debulking surgery in advanced stage ovarian cancer. J Am Coll Surg 2003;197:955–63. [18] Everett EN, French AE, Stone RL, Pastore LM, Jazaeri AA, Andersen WA, et al. Initial chemotherapy followed by surgical cytoreduction for the treatment of stage III/IV epithelial ovarian cancer. Am J Obstet Gynecol 2006;195:568–76. [19] Bristow RE, Chi DS. Platinum-based neoadjuvant chemotherapy and interval surgical cytoreduction for advanced ovarian cancer: a metaanalysis. Gynecol Oncol 2006;103:1070–6.

270

S. Risum et al. / Gynecologic Oncology 108 (2008) 265–270

[20] European Organization for Research and Treatment of Cancer: randomized phase III study comparing upfront debulking surgery versus neoadjuvant chemotherapy in patients with stage IIIc or IV epithelial ovarian cancer (EORTC protocol 55971). (http://www.eortc.be/protoc/Details. asp?Protocol=55971). [21] Axtell AE, Lee MH, Bristow RE, Dowdy SC, Cliby WA, Raman S, et al. Multi-institutional reciprocal validation study of computed tomography predictors of suboptimal primary cytoreduction in patients with advanced ovarian cancer. J Clin Oncol 2007;25:384–9. [22] Dowdy SC, Mullany SA, Brandt KR, Huppert BJ, Cliby WA. The utility of computed tomography scans in predicting suboptimal cytoreductive surgery in women with advanced ovarian carcinoma. Cancer 2004;101:346–52. [23] Bristow RE, Duska LR, Lambrou NC, Fishman EK, O´Neill MJ, Trimble EL, et al. A model for predicting surgical outcome in patients with advanced ovarian carcinoma using computed tomography. Cancer 2000;89:1532–40. [24] Risum S, Hogdall C, Loft A, Berthelsen AK, Hogdall E, Nedergaard L, et al. The diagnostic value of PET/CT for primary ovarian cancer—a prospective study. Gynecol Oncol 2007;105:145–9. [25] Tingulstad S, Hagen B, Skjeldestad FE, Halvorsen T, Nustad K, Onsrud M. The risk-of-malignancy index to evaluate potential ovarian cancers in local hospitals. Obstet Gynecol 1999;93:448–52.

[26] Hockstein S, Keh P, Lurain JR, Fishman DA. Ovarian carcinoma initially presenting as metastatic axillary lymphadenopathy. Gynecol Oncol 1997;65:543–7. [27] Fanti S, Nanni C, Castellucci P, Farsad M, Rampin L, Gross MD, et al. Supra-clavicular lymph node metastatic spread in patients with ovarian cancer disclosed at 18F-FDG-PET/CT: an unusual finding. Cancer Imaging 2006;23: 20–3. [28] Meigs JV. Tumors of the female pelvic organs. NY: Macmillan: New York; 1934. [29] Liu PC, Benjamin I, Morgan M, King SA, Mikuta JJ, Rubin SC. Effect of surgical debulking on survival in stage IV ovarian cancer. Gynecol Oncol 1997;64:4–8. [30] Curtin JP, Malik R, Venkatraman ES, Barakat RR, Hoskins W. Stage IV ovarian cancer: impact of surgical debulking. Gynecol Oncol 1997;64: 9–12. [31] Munkarah AR, Hallum III AV, Morris M, Burke TW, Levenback C, Atkinson EN, et al. Prognostic significance of residual disease in patients with stage IV epithelial ovarian cancer. Gynecol Oncol 1997;64:13–7. [32] Bristow RE, Montz FJ, Lagasse LD, Leuchter RS, Karlan BY. Survival impact of surgical cytoreduction in stage IV epithelial ovarian cancer. Gynecol Oncol 1999;72:278–87.