Standardized FDG uptake as a prognostic variable and as a predictor of incomplete cytoreduction in primary advanced ovarian cancer

Abstract

Introduction. In patients with advanced ovarian cancer undergoing preoperative PET/CT, we investigated the prognostic value of SUV in the primary tumor and we evaluated the value of SUV for predicting incomplete primary cytoreduction (macroscopic residual tumor). Material and methods. From September 2004 to August 2007, 201 consecutive patients with a pelvic tumor and a Risk of Malignancy Index (RMI) > 150 based on serum CA-125, ultrasound examinations and menopausal state, underwent PET/CT within two weeks prior to standard surgery/debulking of a pelvic tumor. At two-year follow-up (August 15, 2009) the association between SUV and overall survival/cytoreductive result were analyzed in 60 ovarian cancer patients (58 stage III and two stage IV). Results. At inclusion median age was 62 years (range 35–85 years); 97% (58/60) had a performance status ≤2; 42% (25/60) underwent complete debulking (no macroscopic residual tumor); median SUV_max was 13.5 (range 2.5–39.0). Median follow-up was 30.2 months. At follow-up 57% (34/60) were alive and 43% (26/60) had died from ovarian cancer. SUV_max in patients alive was not statistically different from SUV_max in dead patients (p=0.69), and SUV_max was not correlated with the amount of residual tumor after surgery (p=0.19). Using univariate Cox regression analysis, residual tumor was a significant prognostic variable (p=0.001); SUV_max was not a statistically significant prognostic variable (p=0.86). Discussion. FDG uptake (SUV_max) in the primary tumor of patients with advanced ovarian cancer was not a prognostic variable and the FDG uptake did not predict complete cytoreduction after primary surgery. Future prospective clinical trials will need to clarify if other PET tracers can serve as prognostic variables in ovarian cancer.

In FDG-PET, the FDG uptake in tumors is measured as the standardized uptake value (SUV) [1,2]. Multiple cancer studies indicate that a high SUV in a primary tumor correlates with tumor aggressiveness and poor patient outcome [2–7]. However, no reports exist describing the prognostic value of SUV in primary ovarian cancer.

In ovarian cancer, standard treatment includes primary cytoreductive surgery followed by adjuvant chemotherapy. In theory, ovarian tumors with high SUVs might be more aggressive and patients with such tumors might have a higher risk of undergoing incomplete cytoreduction with macroscopic residual tumor after primary surgery. The value of SUV for predicting residual abdominal tumor after primary surgery has never been described.

The aim of this study was to investigate the prognostic value of SUV in primary ovarian cancer and to evaluate the value of SUV for predicting incomplete primary cytoreduction.

The study was conducted as part of the Danish Pelvic Mass study.

Material and methods

Approval to conduct this study was obtained from the Scientific Ethics Committee in the study area (KF01-227/03 and KF01-143/04).

From September 2004 to August 2007, 201 consecutive patients referred to surgery for a suspected pelvic tumor underwent PET/CT within two weeks prior to standard surgery/debulking. All patients had a Risk of Malignancy Index (RMI) > 150 based on serum cancer antigen 125 (CA-125), ultrasound examinations and menopausal state [8]. 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 six gynecologic oncologists at our clinic. Of the 201 patients undergoing PET/CT, 94 had ovarian cancer; seven were sent to neoadjuvant chemotherapy and 87 underwent maximal tumor reduction and staging according to FIGO. Complete debulking was defined as no macroscopic tumor left in the pelvis or abdomen at the end of surgery. An experienced pathologist evaluated all operation specimens according to the latest WHO classification (2002). Sixty of the 87 patients undergoing primary debulking surgery had advanced ovarian cancer and a primary pelvic tumor and were eligible for this SUV study (Figure 1).

Figure 1. Flowchart illustrating the inclusion of patients.

PET/CT scanning procedure

PET was performed with an integrated PET/CT (GE Discovery PET/CT, General Electric Medical Systems, Milwaukee, WI). The patient fasted a minimum of six hours before PET acquisition. Sixty minutes after injection of 400 MBq FDG 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 before the CT scan. The CT scan lasted 20 seconds and it was performed with 140 kV and 90–120 mA. Immediately after, the static emissions in 2D acquisition were obtained with 7–8 consecutive frames, each of three minutes’ emission, from the proximal femur to the scalp. The PET acquisition lasted approximately 25 minutes. 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.

Imaging analysis

The same nuclear medicine physician and radiologist 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. For each PET study, the SUV_max of the primary pelvic tumor was measured. SUV is a semiquantitative analysis of radiotracer uptake and is defined as the ratio of radiotracer activity per milliliter of tissue to the activity in the injected dose corrected for decay and the patient's body weight [9].

Data analysis

Non-parametric analysis was applied to the data. Validated patient data, data about residual tumor after primary surgery, and the date and cause of death were obtained from the Danish Gynecological Cancer Database. Overall survival was calculated as the interval from primary surgery to death due to ovarian cancer or to August 15, 2009. Using the Mann-Whitney test, SUV_max in patients alive at follow-up was compared with SUV_max in patients dead at follow-up, and SUV_max in patients undergoing complete debulking was compared with SUV_max in patients undergoing incomplete debulking.

The correlation between SUV_max and the amount of residual tumor after surgery was estimated by the Spearman's rank correlation coefficient. The influence of SUV_max and residual tumor on overall survival was explored using univariate Cox regression analysis [10]. Survival curves comparing the survival of patients with SUV_max above the median SUV_max with the survival of patients with SUV_max below the median SUV_max were constructed using the method of Kaplan and Meier [11]. The level of significance was tested using the Log Rank test. P<0.05 was considered the level of significance. The SPSS statistical software system for Windows (SPSS version 18.0, Chicago, IL) was used for the statistical analysis.

Results

Patient characteristics

Sixty patients composed the study population; 58 patients were diagnosed with FIGO stage III; two were diagnosed with FIGO stage IV (one patient had metastases to lymph nodes on the neck, and one patient had liver metastases). Histological diagnoses and stages are listed in Table I. The median age of the 60 patients was 62 years (range 35–85), 58 (97%) had a Gynecologic Oncology Group (GOG) performance status of 2 or better, and the median serum CA125 was 512 U/ml (range 39–4 400 U/ml).

Table I. Histological diagnoses and stages in 60 stage III/IV ovarian cancer patients.

Diagnosis	Number of patients
Serous adenocarcinoma	52
Stage IIIa	5
Stage IIIb	2
Stage IIIc	44
Stage IV	1
Mucinous adenocarcinoma	3
Stage IIIb	2
Stage IIIc	1
Endometrioid adenocarcinoma	2 (stage IIIc)
Transitional cell carcinoma	1 (stage IV)
Carcinosarcoma	2 (stage IIIc)

All patients underwent maximal debulking surgery followed by six to eight series of standard chemotherapy with carboplatin and docetaxel. Complete debulking was accomplished in 25 (42%) patients (24 FIGO stage III, and one FIGO stage IV); 36 (60%) underwent cytoreduction with ≤1 cm residual tumor; 44 (73%) underwent cytoreduction with ≤2 cm residual tumor.

Survival analysis

After a median follow-up of 30.2 months, 34 of the 60 patients (57%) were alive and 26 patients (43%) had died from ovarian cancer. The median overall survival of all patients was 30.2 months (range 1.1–58.3 months; quartiles 23.6–42.8 months); the median overall survival of the 34 patients alive at follow-up was 35.9 months (range 23.8–58.3 months; quartiles 28.5–45.4); the median overall survival of patients dead at follow-up was 21.0 months (range 1.1–49.9 months; quartiles 10.9–38.2 months). Of the 25 patients undergoing complete debulking five (20%) had died from ovarian cancer; of the 35 patients undergoing incomplete debulking 21 (60%) had died from ovarian cancer. Table II lists the median SUV_max of all patients, patients alive at follow-up, patients dead at follow-up, patients undergoing complete debulking, and patients undergoing incomplete debulking. At follow-up SUV_max in patients alive was not statistically different from SUV_max in dead patients (p=0.69). SUV_max was not correlated with the amount of residual tumor (p=0.19); SUV_max in patients undergoing complete debulking was not statistically different from SUV_max in patients undergoing incomplete debulking (p=0.38).

Table II. Median SUV_max in 60 stage III/IV ovarian cancer patients, in patients alive/dead at follow-up, and in patients undergoing complete/incomplete debulking.

Patients	Median SUVmax	Range	Quartiles
All patients (60 patients)	13.5	2.5–39.0	8.7–17.8
Alive at follow-up (34 patients)	13.4	5.2–22.6	8.6–15.9
Dead at follow-up (26 patients)	13.6	2.5–39.0	8.7–19.7
Complete debulking (25 patients)	13.2	5.2–26.5	7.9–16.7
Incomplete debulking (35 patients)	13.6	2.5–39.0	10.0–18.0

Additionally, SUV_max and residual tumor after primary surgery were evaluated as prognostic variables using univariate Cox regression analysis. Residual tumor was a significant prognostic variable (p=0.001); however, SUV_max was not a statistically significant prognostic variable (p=0.86). The median SUV_max was 13.5. In Figure 2 the survival curve of patients with SUV_max ≥13.5 is compared with the survival curve of patients with SUV_max <13.5; the difference between the curves was not statistically significant (p=0.76).

Figure 2. Kaplan-Meier plot illustrating the survival of patients with SUV≥13.5 compared with the survival of patients with SUV<13.5. The difference between the curves was statistically insignificant (p = 0.76).

Discussion

In this study, the FDG uptake (SUV_max) in the primary tumor was not a prognostic variable. The FDG uptake in tumors is influenced by the expression of glucose transport proteins and cytoplasmatic hexokinase activity. Additionally, the FDG uptake is affected by the variability in cellular density, macroscopic and microscopic blood supply, the extent of hypoxic tissue, cellular proliferation, and multiple enzyme systems determining the metabolic activity [12]. These factors also contribute to characterize the tumors’ aggressiveness and malignant potential. This might explain the observed association between high FDG uptake in primary tumors of different cancers and poor patient outcome [2–7].

However, our results show that in stage III/IV ovarian cancer patients, overall survival does not correlate with high FDG uptake in the primary tumor.

In theory, FDG uptake might still have prognostic value in stage I/II ovarian cancer patients or in subgroups of patients with the same tumor histology. In this study, the number of included patients was too small to compare survival of histological subgroups.

Multiple studies have shown that residual tumor after primary surgery is an independent predictor of survival in ovarian cancer patients [13–15]. Researchers have attempted to find clinical and radiological predictors of incomplete cytoreduction; however, no predictor has been located that consistently identify those patients who will undergo incomplete cytoreduction [15–18], and predictors have shown a lack of generalizability when applied to different cohorts of patients [19]. In this study, we investigated the value of FDG for predicting residual tumor after primary surgery (incomplete cytoreduction); however, we found no relation between the FDG uptake (SUV_max) in the primary tumor and incomplete debulking. Consequently, a high FDG uptake in the primary tumor should not be used to withhold ovarian cancer patients from primary surgery and the potential survival benefit of optimal cytoreduction. In primary ovarian cancer, the diagnostic value of FDG-PET and combined FDG-PET/CT is high [9,20,21]. Preliminary data suggest that FDG-PET may be promising for early prediction of response to chemotherapy [22,23]. Additionally, FDG-PET and FDG-PET/CT have proven valuable for detecting recurrent ovarian cancer, especially when CA-125 levels are rising and CT findings are normal or inconclusive [24,25].

Imaging modalities visualizing metabolic pathways provide an opportunity to monitor the metabolism of tumors in vivo and follow the results of therapy. In this study, FDG was not a prognostic variable. Nevertheless, future translational research might find other biomarkers with prognostic value that can be visualized on PET. These biomarkers could potentially alter the treatment course of ovarian cancer patients. However, routine use of new biomarkers or new imaging modalities cannot be advised before the clinical benefit of using these new diagnostic tests have been documented in prospective clinical trials.

In this study, the FDG uptake (SUV_max) in the primary tumor of patients with advanced ovarian cancer was not a prognostic variable and the FDG uptake did not predict complete cytoreduction after primary surgery.

Future prospective clinical trials will need to clarify if other PET tracers can serve as prognostic variables in ovarian cancer.

Before new diagnostic tests are implemented in daily clinical practice, they should undergo careful evaluation in clinical trials using patient related endpoints such as overall survival.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.