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Low Value of [¹⁸F]-Fluoro-2-Deoxy-D-Glucose Positron Emission Tomography in Primary Staging of Early-Stage Cervical Cancer Before Radical Hysterectomy

From the Departments of Obstetrics and Gynecology, Nuclear Medicine, Radiology, Pathology, and Radiation Oncology, Chang Gung Memorial Hospital; and Graduate Institutes of Basic Medical Sciences and Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan.

Address reprint requests to Chyong-Huey Lai, MD, Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital Linkou Medical Center, 5 Fu-Shin St, Kueishan, Taoyuan 333, Taiwan; e-mail: sh46erry{at}ms6.hinet.net

	ABSTRACT

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PURPOSE: The role of positron emission tomography (PET) with [¹⁸F]-fluoro-2-deoxy-D-glucose (FDG) in early-stage cervical cancer is unclear. We aimed to investigate the clinical benefit of FDG-PET in primary staging before radical hysterectomy and pelvic lymphadenectomy (RH-PLND).

PATIENTS AND METHODS: Patients with untreated stage IA2 to IIA adenocarcinoma (AD) or adenosquamous carcinoma (ASC) or nonbulky ( 4 cm) squamous cell carcinoma cervical cancer with magnetic resonance imaging (MRI) –defined negative nodal metastasis were enrolled onto a prospective study with a two-stage design. All patients had a preoperative dual-phase FDG-PET, technetium-99m–sulfur colloid lymphoscintigraphy, and intraoperative sentinel lymph node (LN) detection at RH-PLND. The gold standard of LN metastasis is histologic. A sample size of 120 patients was calculated to fit study aims (diagnostic efficacy of PET and sentinel LN sampling). An interim analysis was performed when 60 patients were accrued, which led to the current report.

RESULTS: There were 36 SCCs, 20 ADs, and four ASCs. Of the 60 patients, 10 (16.7%) had pelvic LN metastases, and one (1.7%) had para-aortic LN (PALN) metastasis histologically. FDG-PET detected the single PALN metastasis (one of one patient) but detected only one (10%) of the 10 pelvic LN metastases. The PET false-negative pelvic LN micrometastases measured a median of 4.0 x 3.0 mm (range, 0.5 x 0.5 to 7 x 6 mm). The second stage of this trial will be continued without PET.

CONCLUSION: This study shows that dual-phase FDG-PET has little value in primary, nonbulky, stage IA2 to IIA and MRI-defined, LN-negative cervical cancer.

	INTRODUCTION

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Early-stage cervical cancer can be cured on an average rate of 80% with either radical surgery or definitive radiation. Pelvic lymph node (LN) metastasis is the most important prognostic factor in early-stage cervical cancer.^1-3 Therefore, the evaluation of pelvic LN status becomes a crucial part in management. Magnetic resonance imaging (MRI) is better than computed tomography (CT) in defining tumor volume and depth of stromal invasion. Both methods rely on size and morphologic criteria to recognize LN metastasis, but small metastatic LNs are more often than not undetected.^4-8

The [¹⁸F]-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) scan gives functional imaging of malignant cells. It has been shown to be superior to MRI and/or CT for evaluation of various malignancies.⁹ High sensitivity and specificity of FDG-PET in the detection of para-aortic LN (PALN) metastasis in patients with advanced/recurrent cervical cancer and in post-therapy surveillance has already been reported.^10-16 A few investigators considered FDG-PET useful in detecting metastatic pelvic LNs,^11,17,18 although controversial results have also been reported.^13,19 However, the predictive value of PET in the assessment of pelvic LNs in early-stage cervical cancer is not yet clear.

Sentinel LNs (SLNs) are the first LNs to receive lymphatic drainage from the primary tumor. When nodal metastases occur, SLNs will be initially involved. Therefore, the presence or absence of metastasis in the SLN should reflect the overall state of the entire drainage area. Aside from the success in melanoma and breast cancer, several reports advocate the use of SLN detection in cervical cancer.^20-24 However, there has been no consensus reached because of limited sample sizes and various techniques of lymphatic mapping and SLN detection.²⁵

We conducted a prospective study to investigate the potential benefits and limitations of combined FDG-PET and SLN identification in patients with early-stage cervical cancer undergoing radical surgery as the primary treatment. An interim analysis was performed when 60 patients were accrued, which led to the current report.

	PATIENTS AND METHODS

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Study Population
Eligible patients were cervical cancer patients scheduled to receive type II or III radical hysterectomy (RH) and pelvic lymphadenectomy (PLND)²⁶ as the primary treatment and had to meet the following eligibility criteria: (1) histologically confirmed invasive carcinoma of the uterine cervix; (2) International Federation of Gynecology and Obstetrics (FIGO) stage IA2, IB, or IIA disease²⁷; (3) squamous cell carcinoma (SCC; 4 cm by MRI) or adenocarcinoma (AD) or adenosquamous carcinoma (ASC) of any size; (4) MRI showed no suspicious LNs (score 2); (5) age 18 to 70 years; (6) no medical or surgical contraindications to RH-PLND; and (7) written informed consent. Patients with any of the following conditions were excluded: (1) small-cell carcinoma; (2) MRI showing suspected pelvic LNs (score 3) or SCC with MRI-defined cervical tumor diameter greater than 4 cm or stromal invasion greater than two thirds; (3) histologically proven metastasis to PALN; (4) ever received radiotherapy and/or chemotherapy for cervical cancer; (5) history of allergy to the radiotracer technetium-99m–sulfur colloid; (6) unable to cooperate with the PET or lymphoscintigraphic procedure, as judged by the physician in charge or nuclear medicine physician in charge; (7) a previous diagnosis of cancer other than nonmelanoma skin cancer; and (8) concomitant pregnancy.

MRI Imaging
All MRIs were obtained with a 1.5-T Magnetom Vision or a Magnetom Expert Scanner (Siemens Medical Systems, Erlangen, Germany) using a phased-array body coil with a 50-cm transverse field of view. For pelvis and abdomen transaxial, sagittal, and coronal sections, T2-spin echo (time repetition/time echo, 4,000/99) and T1-spin echo (time repetition/time echo, 500/15) sequences were used. Matrix size was 256 x 256 pixels. Slice thickness was 5 mm in the transaxial plane was 5 mm and 2.5 mm in the sagittal and coronal planes for the pelvis and abdomen.

PET Imaging
The FDG was produced by the Institute of Nuclear Energy Research-Taiwan, and the imager was an ECAT EXACT HR+ PET camera (CTI, Knoxville, TN), with full width at half-maximum of 4.5-mm and 15-cm transaxial field of view. For optimal tumor identification, all patients were catheterized and administered diuretics to reduce bladder activity. After fasting for more than 6 hours and intravenous administration of 370 MBq of FDG, dual-phase PET images were acquired at 40 minutes (40 to 96 minutes after FDG injection) from head to upper thigh using a two-dimensional mode followed by a second session of 3-hour scans (180 to 210 minutes after injection) using a three-dimensional mode from T-11 to upper thigh. For dual-phase PET, early and late images were combined to determine whether the lesion observed was fixed or not and to determine changes in standardized uptake values (SUVs). Data acquisition and reconstruction were performed according to our previous protocol.^14-16

Image Analysis
Three experienced nuclear physicians scored the FDG-PET images by consensus on a 5-point scale. Images were interpreted visually and semiquantitatively on early and available late scans without explicit interpretative criteria. There was no preselected SUV cutoff value.^14-16

For dual-phase PET, we combined early and late images to determine whether the lesion observed was fixed or not and to calculate changes in SUV from early to late results. Films of MRI/CT were analyzed separately by an experienced radiologist who was blinded to the FDG-PET results. The 5-point scoring criteria were also used for MRI/CT image interpretation and were as follows: score 0 = a normal finding; 1 = visible LNs less than 0.5 cm in size considered reactive and unrelated to metastasis; 2 = any LN of 1 cm or a little less in length, giving an overall equivocal impression; 3 = LNs more than 1 cm in length in the short axis and/or multiple LNs (n 3) with sizes of 0.5 to 1 cm for PALNs or bilaterally situated for pelvic LNs; and 4 = confluent LNs with central necrosis or irregular contours.^14-16

Study Procedures and Determination of Lesion Status
An FDG-PET scan was performed within 1 week of the MRI. RH-PLND was performed on all patients within the 2 weeks after accrual. Additional MRI/CT scans were performed as clinically needed; for example, a chest or head and neck CT scan was performed on patients with suspicions of lung or SLN metastases by PET. A CT- or ultrasound-guided biopsy was performed to confirm the diagnosis of suspicious lesions detected by FDG-PET scans. If a distant metastasis was confirmed histologically before surgical treatment, RH-PLND was to be abandoned, and concurrent chemoradiotherapy or palliative therapy was determined according to current clinical standard.

Preoperative Lymphoscintigraphy
Preoperative lymphoscintigraphy was undertaken by the injection of a total of 1.0 mL (1 mCi) of filtered technetium-99m–sulfur colloid (450 nm) into the normal cervical stroma, peripheral to the cervical tumor, at 8 AM of the operation day. The colloid was divided into four aliquots and injected into each quadrant at a 5-mm depth from the surface by using insulin syringes with constant gentle pressure. Lymphoscintigrams were obtained using a dual-head gamma camera 30 minutes after injection and were repeated 2 hours after the injection.

SLN Identification
The patient was directly sent to the operation room for preparation immediately after the scintigraphy. A supraumbilical midline incision was used. Both the medial and lateral LN basins, including the common iliac, external and internal iliac, and obturator regions, were explored. The LN basins were visually inspected and scanned with a hand-held gamma counter consecutively.

The radioactive LN, with a count equal to at least 10-fold greater than the background radiation level, was considered sentinel and removed after recording its location. The radioactivity of the SLN was measured ex vivo. After taking all SLNs, pelvic LN basins were scanned again to confirm no residual radioactivity 10-fold greater than the background. A complete PLND was then performed. The non-SLNs located below the bifurcation were considered as lower pelvic LNs. PALNs were not routinely dissected unless they were positive on preoperative FDG-PET or any LN metastasis was documented intraoperatively. RH was not required to be abandoned as a result of intraoperative proven LN metastasis.

Pathologic Evaluation
The SLNs were sent for frozen section after all SLNs had been collected. Nodes with a short axis smaller than 2 mm were bivalved and cut for four different levels for reading. Nodes thicker than 2 mm were cut perpendicular to the long axis into sections 2 mm and sectioned for four levels for reading.

Handling radioactive specimens was performed according to the recommendations of the College of Anatomic Pathologists.²⁸ The other non-SLNs and the remainder of SLNs were fixed in 10% formalin for hematoxylin and eosin staining, whereas cytokeratin immunohistochemistry study was performed only for the remainder of each SLN.

Statistical Analysis
The result of a lesion observed by either FDG-PET or MRI/CT was considered positive with a score of 3 or 4 or negative with a score of 0, 1, or 2. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were calculated. This study was a single-arm safety and efficacy trial with a two-stage design.^29,30 The primary end point was proportion of patients with pelvic LN metastasis detected by FDG-PET. Secondary end points were the SLN detection rate and negative predictive value of negative SLNs. We assumed a sensitivity rate of 50% for detecting pelvic LN metastasis with FDG-PET. On the basis of a 95% CI of ± 25%, approximately 15.4 patients with pelvic LN metastasis would be necessary. For a pelvic LN metastasis rate of 15% to 20% in the eligible patients (calculated from the literature), approximately 120 patients were to be accrued to provide 15 to 18 events (pelvic LN metastasis) to evaluate the efficacy of PET and SLN procedures. Here, we assumed that = .05 and ß = .2 and that the number of patients with events (pelvic LN metastases) for the first stage is n₁. An interim analysis was to be performed when 10 events (n₁ = 10) had occurred (or approximately 50 to 66 patients had been enrolled). According to the two-stage design, if the true probability of response is not greater than P₀ (10%); that is, should an extremely low sensitivity of PET ( 10%) be encountered, the second stage of this trial will be continued with SLN mapping without PET. However, if the sensitivity is statistically significantly greater than P₀, the second stage will proceed with both PET and SLN. Moreover, if the true response rate in the second stage exceeds some interesting value, such as P₁ (30%), then the procedure will be declared a success. P < .05 was considered significant. All statistical tests were two sided.

	RESULTS

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A total of 62 patients were registered initially. Two patients were not eligible because their initial diagnosis of cervical AD was changed to endometrial cancer after the protocol workups. These two patients were treated according to the endometrial cancer protocol, and their disease was proven by final pathology. The remaining 60 eligible patients completed preoperative and intraoperative surveys. Patient characteristics of the eligible patients are listed in Table 1.

View larger version (38K): [in this window] [in a new window]   Fig 1. Magnetic resonance imaging (MRI) revealed a 2.5-cm cervical tumor without lymph node (LN) enlargement. (A) Preoperative lymphoscintigraphy showed sentinel LN locations at left external iliac (arrow) and right common iliac (arrow) and right para-aortic LN (PALN; arrowhead). (B) The [18F]-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography showed increased FDG accumulation in uterine cervix and PALN but (C) negative pelvic nodes. (D) Re-examining MRI failed to localize the PALN.

View larger version (65K): [in this window] [in a new window]   Fig 2. (A) The lymph node (long axis diameter of 15 mm and short axis diameter of 8 mm) contains a cancerous part measuring 5 x 2 mm surrounded by histiocytes. (B) Radioactive nucleotide particles (arrow) are shown in the lymphatic channel.

	DISCUSSION

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To our surprise, dual-phase FDG-PET detected only one (10%) of the 10 pelvic LN metastases in our series. The PET false-negative pelvic LN micrometastases measured up to 7.0 mm in diameter, whereas the metastatic foci measured 6 x 5 mm in the single success (patient 3) of PET.

The clinical value of SLN detection depends on the detection rate and the negative predictive value of negative SLN. The SLNs were submitted for frozen section because we wanted to know whether frozen section would be good enough for abandoning removal of non-SLNs when SLNs were negative. The answers to these important questions will be revealed after the full study is completed. If the accuracy of frozen section should be unsatisfactory, the value of SLN procedures for guiding the extent of LN dissection in a one-stage surgery would be compromised. However, identifying SLNs could highlight which nodes should be examined with more intense pathologic evaluation.

Reinhardt et al¹⁸ reported a prospective surgical/pathologic study of 35 FIGO stage IB to II cervical cancer patients who underwent RH-PLND and had a preoperative abdominal and pelvic FDG-PET and MRI. On a patient basis, LN staging resulted in a sensitivity of 91% with PET and 73% with MRI (P > .05). On an LN site basis, PET achieved a positive predictive value of 90%, and MRI achieved a positive predictive value of 64% (P < .05). In the series by Reinhardt et al,¹⁸ the overall pelvic LN metastasis rates was 31.4% (11 of 35 patients). Among these 11 patients with pelvic LN metastases, PET detected 10 metastases, and MRI detected eight metastases. As a matter of fact, of the MRI-negative patients (n = 27), only three had histologically proven pelvic LN metastasis, and PET detected two of these metastases. Narayan et al¹⁷ compared PET with CT/MRI in 27 stage IB to IV cervical cancer patients; PET detected 83% of pelvic LN metastasis (10 of 12 metastases) and MRI detected 50% of pelvic LN metastases (six of 12 metastases) in the 24 patients with assessable pelvic LNs. In their series, the pelvic LN metastasis rate was 50% (12 of 24 patients). Sugawara et al¹¹ reported an 86% sensitivity rate with PET in seven cervical cancer patients (stage IB to IIB) with known LN metastases (one by surgical assessment and six by clinical follow-up).

In contrast, Williams et al¹⁹ retrospectively reviewed 18 patients with gynecologic malignancies and MRI, CT, and PET scans before LN dissection (504 nodes obtained), 16 of whom had cervical cancers (14 primary and two recurrent cancers). Eight patients (50%) had 34 (6.7%) surgically proven metastatic pelvic LNs. On an individual nodal basis, the sensitivity rates were 53.7% for MRI, 48.1% for CT, and 24.5% for PET. Belhocine et al¹³ reported 22 untreated cervical cancer patients (FIGO stage unknown), of whom 18 underwent PLND. Five patients (27.8%) had pelvic LN metastasis. PET detected only two metastases (sensitivity: 40% on a patient basis and 20% on a nodal basis), whereas MRI detected five metastases.

As a rule of thumb, the higher the ratios of histologic pelvic LN metastasis and/or simultaneous MRI/CT-positive pelvic LN, then the higher the sensitivity of PET will be expected. On the contrary, the added benefit of FDG-PET in a group of patients with negative MRI is relatively small. No patient was excluded for preoperative FDG-PET–detected occult metastasis in the current study. However, there were two patients with FIGO stage IB1 and IIA AD treated before the trial started whose solitary lung metastases were found by FDG-PET. Therefore, FDG-PET is not recommended before RH-PLND for early cervical SCC. Although it is still controversial whether AD/ASCs are more aggressive than their SCC counterparts stage for stage,^31,32 they are relatively less well studied because of the limited number of cases. Therefore, we decided to continue to enroll all AD/ASC cervical cancer patients for PET study onto a separate trial regardless of type of primary treatment.

In a recently published report, 29 cervical cancer patients and 15 endometrial cancer patients were enrolled onto a study to evaluate the diagnostic performance of nanoparticle-enhanced MRI. MRI was performed before (size criteria) and after the use of ultrasmall particles of iron oxide before lymphadenectomy. On a node by node basis, the sensitivity of detecting LN metastasis was significantly better using ultrasmall particles of iron oxide (93%) compared with size criteria alone (29%).³³ It is still unknown whether this new approach could work as well for early-stage nonbulky cervical cancer.

In conclusion, this study shows that dual-phase FDG-PET has little value in primary staging of nonbulky stage IA2 to IIA disease and MRI-defined LN-negative cervical cancer (especially SCC) before RH-PLND. Pragmatic use of this expensive imaging technology should be based on well-designed and well-conducted prospective studies targeting specific indications. It is also crucial that cost-effectiveness analyses of using PET scan according to clinical indications should be evaluated.^34,35

	Authors' Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
The authors indicated no potential conflicts of interest.

	Author Contributions

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 

Conception and design: Hung-Hsueh Chou, Ting-Chang Chang, Chyong-Huey Lai Administrative support: Ting-Chang Chang, Tzu-Chen Yen, Koon-Kwan Ng, Chyong-Huey Lai Provision of study materials or patients: Hung-Hsueh Chou, Ting-Chang Chang, Tzu-Chen Yen, Koon-Kwan Ng, Swei Hsueh, Huei-Jean Huang, Angel Chao, Tzu-I Wu, Shih-Ming Jung, Yen-Ching Wu, Cheng-Tao Lin, Kuan-Gen Huang, Chyong-Huey Lai Collection and assembly of data: Hung-Hsueh Chou, Tzu-Chen Yen, Koon-Kwan Ng, Shih-Ya Ma Data analysis and interpretation: Hung-Hsueh Chou, Ting-Chang Chang, Tzu-Chen Yen, Koon-Kwan Ng, Swei Hsueh, Chee-Jen Chang, Chyong-Huey Lai Manuscript writing: Hung-Hsueh Chou, Ting-Chang Chang, Swei Hsueh, Chee-Jen Chang, Chyong-Huey Lai Final approval of manuscript: Hung-Hsueh Chou, Ting-Chang Chang, Tzu-Chen Yen, Koon-Kwan Ng, Swei Hsueh, Shih-Ya Ma, Chee-Jen Chang, Huei-Jean Huang, Angel Chao, Tzu-I Wu, Shih-Ming Jung, Yen-Ching Wu, Cheng-Tao Lin, Kuan-Gen Huang, Chyong-Huey Lai

 

	NOTES

 
Supported by Grants No. NSC-93-NU-7-182-003 from the National Science Council and the Institute of Nuclear Energy Research, Taiwan, and CMRPG32022 and CMRPG32029 from Chang Gung Memorial Hospital.

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

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Submitted July 24, 2005; accepted October 5, 2005.

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