CT scanning in patients with cervical cancer: A prospective study

Gynecologic Oncology 106 (2007) 29 – 34 www.elsevier.com/locate/ygyno

The diagnostic value of PET/CT scanning in patients with cervical cancer: A prospective study Annika Loft a,⁎, Anne Kiil Berthelsen a,b , Henrik Roed b , Christian Ottosen c , Lene Lundvall c , Jens Knudsen c , Lotte Nedergaard d , Liselotte Højgaard a , Svend Aage Engelholm b a

PET and Cyclotron Unit 3982, Department of Clinical Physiology and Nuclear Medicine, Centre of Diagnostic Investigations, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen, Denmark b Department of Radiation Oncology, The Finsen Centre, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark c Department of Gynaecology, The Juliane Marie Center, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark d Department of Pathology, Centre of Diagnostic Investigations, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark Received 1 December 2006 Available online 7 May 2007

Abstract Objective. To investigate the clinical value of PET/CT as a supplement to FIGO staging in patients with cervical cancer stage ≥1B. Methods. This prospective study included 120 consecutive patients. After staging, a whole-body PET/CT scan was performed and these examinations were divided into two groups: (1) patients suitable for radical hysterectomy including lymph node dissection and (2) patients referred to combined chemo/radiation therapy. The results were compared to histopathological findings and/ or follow-up. Results. Twenty-seven patients underwent radical surgery; four of these had PET/CT scans revealing pathological foci in the pelvis. Three (11%) were true positive; one was false positive. Twenty-two patients had true negative PET/CT scans concerning pelvic lymph nodes. One patient had a false negative node. For these patients, we found the positive predictive value (PPV) to be 75%, negative predictive value (NPV) 96%, sensitivity 75%, specificity 96%. Regarding para-aortal nodal disease in the total population of 119 patients, 15 patients had true positive scans. The number of true negatives was 103, resulting in PPV 94%, NPV 100%, sensitivity 100% and specificity 99%. PET/CT scans showed distant metastases in 19 patients, 10 were true positive and nine were false positive. The remaining 100 patients were considered true negative for distant metastases and for these patients, we found PPV 63%, NPV 100%, sensitivity 100% and specificity 94%. Conclusions. Whole-body FDG PET/CT scanning for newly diagnosed cervical cancer FIGO stage ≥ 1B has a high sensitivity and specificity, and can be a valuable supplement to the FIGO staging procedure. © 2007 Elsevier Inc. All rights reserved. Keywords: Cervical cancer; Staging; PET/CT

Introduction The status of the para-aortic lymph nodes has been found to be the most important prognostic factor in cervical cancer [1]. Despite this fact, the staging according to FIGO (International Federation of Gynecology and Obstetrics) is based on a nonsurgical clinical examination, only supplemented with a cystoscopy, a urography and a chest X-ray [2]. This staging procedure does not include information about lymph node status. ⁎ Corresponding author. Fax: +45 3545 3898. E-mail address: [email protected] (A. Loft). 0090-8258/$ - see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2007.03.027

PET (positron emission tomography) scanning with the tracer FDG (18F-fluoro-deoxy-glucose) utilizes the fact that malignant cells have an increased glucose metabolism and upregulated membrane bound glucose transporters [3,4] and therefore a higher uptake of FDG compared to normal tissue. PET is a functional imaging method without the precise anatomical resolution of CT or MRI. PET/CT scanners combine functional information from PET with anatomical information from CT, and the use of this imaging modality in cancer patients has increased very rapidly since it was introduced in 2001. Prospective studies on the use of PET/CT in patients with lung cancer have shown that integrated PET/CT improved the diagnostic accuracy of the staging of non-small-cell lung cancer

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compared to CT alone [5,6]. At present only a few studies with smaller patient numbers have investigated the usefulness of PET/CT in cervical cancer, and the results have been promising [7–9]. A larger study, which included 60 patients, reported low sensitivity of PET for patients with cervical cancer stage 1A2– 2A, but this was performed without combined CT [10]. When the CT scan of a combined PET/CT examination is performed as a diagnostic quality CT scan including intravenous and oral contrast agents, the quality of the joint PET/CT procedure is improved and a separate CT scan can be avoided [11]. It has been demonstrated that combined PET/CT has a higher accuracy than separate PET and CT scans read side-by-side [12]. The aim of this prospective study was to investigate the clinical value of PET/CT performed with diagnostic quality CT as a supplement to the FIGO staging procedure in patients with newly diagnosed cervical cancer stage ≥ 1B. Materials and methods Patient characteristics The study was designed as a prospective study including 120 consecutive patients with newly diagnosed cervical cancer stage ≥ 1B referred to the Department of Oncology or the Department of Gynaecology at Rigshospitalet, Copenhagen University Hospital, Denmark, from November 2002 until October 2005. Exclusion criteria were: current previous or malignant disease of another type, diabetes mellitus, pregnancy, claustrophobia, extreme obesity or other reasons due to which the PET/CT scan could not be performed. The patients were divided into two groups: (1) patients clinically found to be suitable for radical hysterectomy including lymph node dissection and (2) patients not suitable for surgery. These patients were further referred to combined chemo/ radiation therapy. The protocol was approved by the Ethical Committee of Copenhagen ((KF) 01-023/02), and was performed in accordance with the Helsinki II declaration (patients gave informed consent after oral and written information). The patients were staged according to FIGO and the whole-body PET/CT scan was performed within 2 weeks.

PET/CT scanning procedure The PET/CT scanning was performed with a GE Discovery LS PET/CT scanner (GE Medical Systems, Milwaukee, WI, USA). The patients fasted a minimum of 6 h prior to intravenous injection of 400 MBq FDG (2-[18F]fluoro2-deoxy-D-glucose). At 30 min before scan start, the patients were asked to drink oral contrast media (500 ml, Ioxitalamat 12.6 mg I/ml, Pharmacy of Rigshospitalet, Denmark), and immediately before scan start, they were asked to void. We did not use bladder catheters or diuretics for bladder emptying. The examination was performed with the patient positioned supine with the arms placed over the head. CT scans were performed immediately prior to the PET scan with the multi-detector four slice spiral CT scanner. CT scans were acquired as diagnostic CT scans. With a pre-scan start delay of 40 s, intravenous contrast media (100 ml Ultravist 300 mg I/ml, Schering, Germany) was injected with an automatic injection system (Medrad Envision CT injector, Medrad Inc., Pittsburgh, PA, USA) with a flow rate of 2.5 ml/min. The CT scan was performed with a rotation time of 0.5 s, speed 15.0 mm/rotation, helical thickness 5 mm, pitch 1.5:1, kV and mA relative to the body mass of the patient. The PET scan followed immediately with an acquisition time of 3 min per bed position. Whole-body PET scanning (2D, 1 slice overlap) consisted of imaging from the proximal thigh to the base of the skull using 5–7 axial fields of view with coverage of 14 cm.

The CT data were used for attenuation correction of the PET data. Both image sets were reconstructed in trans-axial, coronal and sagittal images with a slice thickness of 5 mm. A nuclear medicine physician and a radiologist in collaboration interpreted the PET and the fused PET/CT images on the GE eNTEGRA PET workstation (GE Medical Systems). CT images were reviewed at a picture archiving and communication system (PACS)-workstation (AGFA Impax 4.1, Germany). The result of the PET/CT scan was given to the referring clinician. Regarding dosimetry, the effective dose for the PET/CT scan was approximately 18 mSv with 8 mSv from the FDG-dose and 10 mSv from the CT scan [13].

Statistical analysis End points: In patients where FIGO stage and clinical status indicated surgery, the histology was obtained hereby for foci located in the pelvis. PET positive foci outside the pelvis were verified by biopsy, if possible. Otherwise, the foci were verified by other imaging modalities or by clinical follow-up. In Denmark, surgical staging on non-operable patients is not routinely used. PET positive foci found outside the pelvis in these patients were, if possible, confirmed by biopsy. PET positive foci in regions not suitable for biopsy were verified by other imaging modalities and a control PET/CT scan after 5– 6 months along with clinical follow-up. We assumed a sensitivity rate of 50% for detecting pelvic lymph node metastasis with FDG-PET. On the basis of a 95% CI of ±25%, approximately 15 patients with pelvic lymph node metastases would be necessary. Calculated from the literature, we assumed that α = 0.05 and β = 0.2, and for a pelvic lymph node metastasis rate of 15–20% in the eligible patients approximately 120 patients should be included. Sensitivity was given as the nosographic true positive rate, calculated as the number of true positives/the total number of patients with the disease. Specificity was given as the nosographic true negative rate, and is calculated as the number of true negatives/total number of patients without disease. Positive predictive values (PPV) were calculated as true positives/the total number of positive scans and negative predictive values (NPV) as true negatives/total number of negative scans.

Results 120 consecutive patients were included in this study. One patient who had had a hysterectomy performed prior to the scan was included by mistake, and her data were excluded from further analysis. A description of the remaining 119 patients including clinical stage and histological diagnosis appears from Table 1. The primary tumor was FDG avid and seen on the PET/CT scan in 111 patients. The remaining eight patients had all had a cone biopsy performed prior to inclusion in this study. In these Table 1 The distribution of patients according to FIGO and histological diagnosis FIGO

1B1 1B2 2A 2B 3A 3B 4A Total

Histological diagnosis Squamous cell carcinoma

Adenocarcinoma

Others

Total

21 3 5 24 1 39 4 97

6 1 1 3 0 1 1 13

1 0 1 4 0 3 0 9

28 (24%) 4 (3%) 7 (6%) 31 (26%) 1 (1%) 43 (36%) 5 (4%) 119

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patients there was either none or only slight FDG uptake in the cervix. Twenty-seven patients underwent radical surgery where all pelvic lymph nodes were resected despite of their size, and for all these patients, histological specimens were obtained from lymph nodes in the pelvis. The data are shown in Table 2. Focusing on the status of pelvic nodal disease as the only manifestation in these patients, four had PET/CT scans revealing pathological FDG-avid foci. Three of these (11%) were true positive; one patient (4%) was false positive, where histological examination showed granuloma. Twenty-two patients (81%) had true negative PET/CT scans concerning pelvic lymph nodes. Two of these had false positive foci located outside the pelvis (one patient had a lymph node in the axilla, which had disappeared on a control PET/CT 3 months later, another patient had a lymph node in the inguinal region with benign histological diagnosis). One patient (4%) had a false negative para-cervical lymph node, which was not suspicious of malignancy on the PET/CT scan (Fig. 1). The other 92 patients were referred for chemo/radiation therapy. Fourteen patients had FDG-avid lymph nodes only in the pelvis, which were not examined histologically. It was considered unethical to biopsy these patients, as the results would not influence the treatment plans. The follow-up examinations could not be used to confirm PET-positive lymph nodes in the pelvis, since vanished lymph nodes on a control PET/CT scan could be due to response to treatment to a metastatic node or could be due to an initial false positive focus. These 14 patients were therefore excluded from further statistical calculations concerning pelvic lymph node status. Because their scans did not reveal pathological foci outside the pelvis and follow-up did not reveal metastases they were considered true negative for para-aortal lymph node involvement and for distant metastases. The data from the remaining 78 patients are shown in Table 3. One patient had a true positive pelvic lymph node confirmed by histological examination. Nine patients had true positive para-aortal disease as the only manifestation outside the pelvis, eight (89%) of these also had PET positive pelvic lymph nodes. These patients were offered extended radiation fields. Ten patients had true positive distant metastases in lymph nodes in the neck or mediastinum, metastases in the liver, lung, omentum, bones (Fig. 2) or adrenal gland. One patient had an Table 2 Results of PET/CT concerning nodal status in the pelvis compared to histological diagnosis in operated patients, N = 27 PET/CT

Fig. 1. A false negative para-cervical lymph node on the left side of cervix (yellow dotted line).

FDG-avid tumor in the lung, which turned out to be a primary lung cancer. Of the seven false positive foci, three were small bone lesions with normal MRI or control PET/CT scans 3 months after completed therapy. Two patients had histiocytosis verified by histological examination in the mediastinum and the abdomen, respectively (Fig. 3). One had a focus in the superior mediastinum, which could not be confirmed by ultrasound, and one had a neck lymph node with benign histological diagnosis. In this group, 50 patients were found to have true negative PET/CT scans as judged by clinical followup and PET/CT scans performed 3 months after therapy. Regarding para-aortal nodal disease in the total population of 119 patients, 15 patients were found to have true positive scans, 12 of these were confirmed by histological examination, three by other modalities or follow-up (Fig. 4). Of these 15 patients, 13 (87%) also had PET positive lymph nodes in the pelvis. One patient had a false positive neck lymph node verified by biopsy and PET positive para-aortal lymph nodes, which were not biopsied. Due to the neck node result, we chose to define the para-aortic lymph nodes as false positive. The number of true negatives was 103 (Table 4). Table 3 Results of PET/CT compared to histological diagnosis or results of other modalities/follow-up in non-operated patients, N = 78 PET/CT

Histology

Other modalities/ follow-up

Histology POS

POS NEG Total

31

3 1b 4

NEG 1 22 23

a

Total 4 23 27

Positive predictive value 75%, negative predictive value 96%, sensitivity 75%, specificity 96%. a An iliac PET positive lymph node with histological verified granuloma. b A PET negative para-cervical lymph node with histological verified metastasis.

POS NEG Total

POS

NEG

POS

NEG

17 0 17

3 – 3

4 0 4

4 50 54

Total

28 50 78

Fourteen patients with PET positive foci only in the pelvis have been excluded from statistical calculations, since these results are unverified. The total number of true positives is 21, true negatives 50, false positives 7 and false negatives 0. Positive predictive value 50%, negative predictive value 95%, sensitivity 75%, specificity 87%.

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Fig. 4. Two para-aortal lymph node metastases.

Fig. 2. A bone metastasis in the cervical spine verified by histological examination.

In all 119 patients PET/CT scans showed distant metastatic disease in 19 of which ten were confirmed true positive either by histological examination (N = 8) or by other imaging modalities or follow-up (N = 2). Nine were found to be false positive either by histological examination (N = 3) or by other imaging modalities (MRI, ultrasound) or follow-up (N = 6). The remaining 100 patients, including the one with a new primary lung cancer, were considered true negative for distant metastases. Data are found in Table 5. Table 6 gives an overview of all false positive PET/CT scans in this study. Discussion A study by Heller et al. demonstrated that 24% of patients stage 2B–4A have para-aortic spreading after surgical staging

at the time of diagnosis [14]. Many treatment centers do not use surgical staging routinely due to the high morbidity following this procedure and in Denmark surgical staging is not part of the nationally approved treatment protocol in cervical cancer patients. Advanced imaging techniques with CT and MRI for depicting lymph node metastases has been introduced during the recent years. The criteria used for defining malignancy are solely based on size of the lymph nodes, which explains their relative low sensitivities. Yet the use of CT and MRI has been increasing [15]. In a meta-analysis by Scheidler et al. MRI and CT perform similarly in the detection of lymph node metastasis from cervical cancer [16]. Grigsby et al. found in a large retrospective study that FDG PET detects abnormal lymph node regions more often than CT does [17]. FDG is not a specific cancer tracer, and it is well known that false positive foci occur due to FDG uptake in some benign tumors (i.e. histiocytosis), infection and inflammation and false positives occur due to misinterpretation of physiological FDG uptake and excretion. The abdomen and the female pelvis can be especially difficult to interpret due to FDG activity in the ovaries, intestines and ureters. Even though the image fusion of function and anatomy in a PET/CT scan increases the diagnostic

Table 4 Results of PET/CT concerning para-aortal nodal disease compared to histological diagnosis or other modalities/follow-up in all patients, N = 119

Fig. 3. A false positive abdominal focus, histological examination showed histiocytosis.

PET/CT

Histology

Other modalities/ follow-up

POS

NEG

POS

NEG

POS NEG Total

12 0 12

0 – 0

3 0 3

1a 103 104

Total

16 103 119

The total number of true positives is 15, true negatives 103, false positives 1 and false negatives 0. Positive predictive value 94%, negative predictive value 100%, sensitivity 100%, specificity 99%. a One patient had a false positive neck lymph node verified by biopsy and PET positive para-aortal lymph nodes, that are unverified but judged to be false positive due to the neck node result.

A. Loft et al. / Gynecologic Oncology 106 (2007) 29–34 Table 5 Results of PET/CT concerning distant metastases compared to histological diagnosis or other modalities/follow-up in all patients, N = 119 PET/CT

POS NEG Total

Histology

Other modalities/ follow-up

POS

NEG

POS

NEG

8 – 8

3 – 3

2 0 2

6 100 106

Total

19 100 119

The one patient with a new primary (lung cancer) is here considered being true negative for distant metastases. The total number of true positives is 10, true negatives 100, false positives 9 and false negatives 0. Positive predictive value 63%, negative predictive value 100%, sensitivity 100%, specificity 94%.

accuracy, pitfalls still exist [18], and a certain learning curve should be taken into consideration. Histological verification should therefore be obtained from PET positive foci before change of treatment strategy. Previous prospective studies regarding the usefulness of PET for staging have shown sensitivities between 38% and 86% in relatively small patient populations (21–54 patients) but with the capability of depicting even small lymph node metastases and the possibility of detecting distant metastases [19–21]. Prospective studies on the use of PET/CT in patients with lung cancer have shown that integrated PET/CT improved the diagnostic accuracy of the staging of non-small-cell lung cancer compared to CT alone [5,6]. In a study including 22 stage 1B– 4A cervical cancer patients, Choi et al. found that PET/CT had a higher sensitivity (77%) than MRI (39%) concerning lymph node detection [9]. Sironi et al. studied 47 patients with stage 1 disease with PET/CT and found a sensitivity of 73% for detection of lymph node metastases [7]. A larger study, including 60 patients stage 1A2–2A, found a low value of PET, but this was performed without combined CT [10]. It has been demonstrated that combined PET/CT has a higher accuracy than separate PET and CT scans read side-by-side [12]. The vast majority of all new PET scanners installed worldwide during the past few years have been combined PET/ CT scanners; therefore the use of PET alone is decreasing relatively. When the CT scan of a combined PET/CT examination is performed as a diagnostic quality CT scan including intravenous and oral contrast agents, the quality of the joint PET/CT procedure is improved and a separate CT scan can be avoided, providing a more simple diagnostic procedure for the patient [11]. Also, the radiation dose to the patient is reduced. The latter is a matter of increasing concern, especially in Europe, where newly implemented EU guidelines emphasise this [13]. This prospective study investigated the utility PET/CT as a supplement to a clinical staging procedure. The patients were divided into two groups based on the FIGO and clinical criteria: one group suitable for operation (radical hysterectomy), and the other group with patients who were offered chemo/radiation therapy. In the operated patients PET/CT had a sensitivity of 75% and a specificity of 96% for nodal status in the pelvis. In the non-operated patient group it was 75% and 87%, respectively. PET/CT had a sensitivity of 100% and a specificity

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of 99% for para-aortic nodal disease in all patients, and a sensitivity and specificity of 100% and 94% for distant metastases in all patients. In the group of patients who underwent radical surgery, PET/CT results were compared with histological diagnoses for all PET/CT positive foci in the pelvis, and results from non-FDG avid lymph nodes were employed to verify true negative and false negative nodes. In these patients, all lymph nodes were resected despite the size of the lymph nodes. The risk of sampling error and hereby overlooking and not resecting a PET positive lymph node resulting in false positive PET is minimal. This increases the risk of false negative PET, since micrometastases would be found by the histological examination. For these patients, the negative predictive value of 96% was reliable. For the nonoperated patients, the negative foci were for obvious reasons not confirmed. The negative predictive value of 100% for distant metastases and para-aortal nodal disease does not take false negative foci into consideration, and micro metastases can still be overlooked. The sensitivity was high (100%) for detecting para-aortal and distant metastatic disease. The high sensitivity in our study for detecting lymph node metastases is comparable to the results from most other authors reporting on this subject looking either at PET or PET/CT [7,16,18]. Roh et al. found, in a study including 54 patients stage 1B–4A, that PET exhibited low sensitivity (38%) and PPV (65%) especially for microscopic metastases and hence cannot replace surgical staging, although it might still be useful for detecting metastases in patients with clinical conditions that make surgical staging inappropriate [21]. Since surgical staging has a high morbidity, PET/CT could be useful as a non-invasive method for staging although microscopic disease can be overlooked. A randomised study by Landoni et al. including 343 patients with stage 1B and 2A cervical cancer showed that a combination of surgery and radiotherapy has a higher morbidity than surgery or radiotherapy alone, which increases the necessity of correct staging in order to offer the optimal treatment for the patient [22]. In conclusion, the results of this prospective clinical study showed that use of whole-body FDG PET/CT scanning for newly diagnosed cervical cancer with FIGO stage ≥ 1B has a high sensitivity and specificity, and seems to be useful for

Table 6 The localisation and verification of false positive foci Patient

Localisation

Verification

1 2 3 4

Iliac lymph node Axillary lymph node Inguinal lymph node Lymph node in mediastinum sup. Abdomen Bone Bone Bone Mediastinum Neck

Granuloma

Histology

5 6 7 8 9 10

Other modalities NEG control PET/CT

Benign NEG US Histiocytosis NEG MRI NEG MRI NEG control PET/CT Histiocytosis Benign

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planning a better treatment strategy. Histological confirmation is necessary before change of treatment, and the PET/CT scan can be used for biopsy guidance. Initially clinically operable patients with PET positive lymph nodes confirmed histologically can be offered radio/chemotherapy instead of surgery, and patients with para-aortal spreading can be offered extended fields. At our institution, we have now changed the diagnostic work-up by including an early PET/CT scan followed by a laparoscopic staging procedure guided by the PET/CT results.

[10]

[11]

[12]

Acknowledgments The PET/CT scanner was donated by The John and Birthe Meyer Foundation.

[13]

[14]

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