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© 2001 American Society for Clinical Oncology Lymph Node Staging by Positron Emission Tomography in Patients With Carcinoma of the CervixByFrom the Mallinckrodt Institute of Radiology and the Siteman Cancer Center, Washington University School of Medicine, St Louis, MO. Address reprint requests to Perry W. Grigsby, MD, Radiation Oncology Center, Box 8224, Washington University Medical Center, 4939 Children’s Place, Ste 5500, St Louis, MO 63110; email: grigsbyp{at}netscape.net
PURPOSE: The aim of this study was to compare the results of computed tomography (CT) and positron emission tomography (PET) with [18F]-fluoro-2-deoxy-D-glucose (FDG) for lymph node staging in patients with carcinoma of the cervix and to evaluate the relationship of the imaging findings to prognosis. PATIENTS AND METHODS: We retrospectively compared the results of CT lymph node staging and whole-body FDG-PET in 101 consecutive patients with carcinoma of the cervix. Patients were treated with standard irradiation and chemotherapy (as clinically indicated) and observed at 3-month intervals for a median of 15.4 months (range, 2.5 to 30 months). Progression-free survival was evaluated by the Kaplan-Meier method. RESULTS: CT demonstrated abnormally enlarged pelvic lymph nodes in 20 (20%) and para-aortic lymph nodes in seven (7%) of the 101 patients. PET demonstrated abnormal FDG uptake in pelvic lymph nodes in 67 (67%), in para-aortic lymph nodes in 21 (21%), and in supraclavicular lymph node in eight (8%). The 2-year progression-free survival, based solely on para-aortic lymph node status, was 64% in CT-negative and PET-negative patients, 18% in CT-negative and PET-positive patients, and 14% in CT-positive and PET-positive patients (P < .0001). A multivariate analysis demonstrated that the most significant prognostic factor for progression-free survival was the presence of positive para-aortic lymph nodes as detected by PET imaging (P = .025). CONCLUSION: This study demonstrates that FDG-PET detects abnormal lymph node regions more often than does CT and that the findings on PET are a better predictor of survival than those of CT in patients with carcinoma of the cervix.
THE INTERNATIONAL Federation of Gynecology and Obstetrics (FIGO) staging system for carcinoma of the cervix is based on physical examination. The status of the pelvic, para-aortic, and supraclavicular lymph nodes, as determined by radiologic imaging studies, is not considered a part of the clinical staging system. An analysis of prognostic variables in 626 patients enrolled in clinical trials by the Gynecologic Oncology Group in patients with stages I to IVa cervical cancer who were staged surgically and then treated with irradiation revealed that the most significant prognostic factor was the status of the para-aortic lymph nodes.1 In their multivariate analysis, the relative risk for time to recurrence was 11.0 if the para-aortic lymph nodes were positive for disease. The next most significant prognostic factor was a tumor size of 10 cm or more, with a relative risk of 3.9. Several different radiologic methods have been used to assess pelvic and retroperitoneal lymph nodes in patients with cervical carcinoma; these include lymphangiography (LAG), computed tomography (CT), ultrasonography, and magnetic resonance imaging (MRI).2 Recently, a national Patterns of Care Study conducted by the American College of Surgeons evaluated the diagnostic assessments performed in patients with invasive cancer of the cervix and found that CT scans of the abdomen and pelvis were used to evaluate the majority of patients in order to determine lymph node status.3 A meta-analysis of studies assessing the radiologic evaluation of lymph node metastases in patients with cervical cancer concluded that CT, LAG, and MRI perform similarly and have only moderate sensitivity and specificity for the detection of lymph node metastases from cervical cancer.4 More recently, positron emission tomography (PET) with the glucose analog [18F]-fluoro-2-deoxy-D-glucose (FDG) has been shown to be a more sensitive method than CT for detection of lymph node metastases in patients with cervical carcinoma.5-8 Only limited data are available regarding correlation of PET findings with histologic evaluation of pelvic and para-aortic lymph nodes.5,6 The current study was performed in the absence of surgical staging as a specificity validation of PET for assessing the lymph node status in patients with newly diagnosed cervical carcinoma. The results of PET have been compared with those of CT by use of progression-free survival as the definitive end point.
We retrospectively evaluated the medical records of 101 consecutive patients with invasive carcinoma of the cervix who were referred to the Mallinckrodt Institute of Radiology for definitive irradiation from February 1998 to June 2000. All of these patients were initially evaluated with a history and physical examination, routine laboratory studies, cervical biopsy, and routine imaging studies, including chest radiography, CT of the abdomen and pelvis, and whole-body FDG-PET. The PET, CT, and LAG findings in the first 11 of these patients have been reported previously.8 CT examinations were performed on fourth-generation CT units. Patients received both orally and intravenously administered contrast agents before they were scanned. Axial images from the base of the lungs and extending to the pubic symphysis were obtained by 8- to 10-mm contiguous slices. Lymph nodes greater than 10 mm in maximum diameter were considered abnormal. PET was performed with an ECAT EXACT scanner (Siemens-CTI, Knoxville, TN), which allows for simultaneous collection of 47 transverse slices for a span of 16.2 cm. Beginning approximately 40 minutes after intravenous administration of 10 to 15 mCi (370 to 555 MBq) of FDG, a series of four to six overlapping, 47-slice emission and transmission PET images were obtained to image the region from the upper neck to the upper thighs. The reconstructed spatial resolution under clinical imaging conditions is approximately 10 mm (full width at half maximum). Patients fasted for at least 4 hours before injection of FDG, and to identify patients with fasting hyperglycemia, the blood glucose concentration was determined before FDG administration. Renal, ureteral, and bladder activity were minimized by intravenously administered hydration, diuretic administration, and bladder catheterization during the study. Image processing and reconstruction were performed on a SUN computer workstation. The PET images were reconstructed either by the method of filtered back projection with the use of a Hanning filter (frequency cutoff, 0.6 x Nyquist) or by the method of ordered-subset estimation-maximization iterative algorithm and a Butterworth filter (frequency cutoff in the range of 0.2 to 0.4 cycles per pixel). Images were displayed in three orthogonal projections and as whole-body maximum-pixel-intensity reprojection images for visual interpretation. CT and PET images were interpreted in routine clinical fashion. Previously performed imaging studies were available for review when these studies were interpreted. The data analysis in this report is based on the clinical reports of the imaging findings for each imaging study. Therapy of the cervical cancer was based on standard treatment policies at the Mallinckrodt Institute of Radiology. Treatment consisted of external irradiation to the pelvis and intracavitary brachytherapy and concurrent weekly cisplatin chemotherapy in most patients. Para-aortic external irradiation was administered to all seven patients with positive para-aortic lymph nodes detected by CT and to four of 14 of those with such nodes detected only by PET. Follow-up evaluation of patients was performed at 6 weeks after completion of irradiation and at 3-month intervals thereafter. Follow-up times for patients alive at the time of last follow-up ranged from 2.5 to 30 months (median, 15.4 months). Progression-free survival was measured from the date of the initiation of irradiation to the date of death or recurrence. Persistence of tumor was counted as immediate recurrence as of day 1. Time to recurrence at any site was measured from the date of initiation of irradiation to the date of the first recurrence. The progression-free survival rates were estimated by the Kaplan-Meier method.9 Equivalence of survival curves was tested with the generalized Savage (Mantel-Cox) statistic.10 The Cox proportional hazards model was used to evaluate independent prognostic variables.11
Demographic Data The patients ranged in age from 26 to 88 years (mean, 53 years). The FIGO clinical stages of their tumors were as follows: stage Ia in two, Ib1 in eight, Ib2 in 18, IIb in 39, III in 29, IVa in one, and IVb in four. Cervical biopsy specimens were positive for invasive cancer in all patients. The tumor histology was squamous cell carcinoma in 92 patients, adenosquamous carcinoma in four, adenocarcinoma in three, clear-cell adenocarcinoma in one, and small-cell carcinoma in one.
Primary Tumors
Lymph Node Metastasis
Survival At the time of last follow-up, 68 patients were alive and had no evidence of cervical cancer, nine were alive with residual or recurrent cervical cancer, 23 had died due to cervical cancer, and one patient had died of intercurrent disease. Figure 1 shows the Kaplan-Meier progression-free survival estimates based solely on pelvic lymph node status. The 2-year progression-free survival rate was 73% for CT-negative (CT-) and PET-negative (PET-) patients, 49% for CT- and PET+ patients, and 39% for CT+ and PET+ patients (P = .001). The 2-year progression-free survival rate based only on para-aortic lymph node status was 64% for CT- and PET- patients, 18% for CT- and PET+ patients, and 14% for CT+ and PET+ patients (P < .0001) (Fig 2). Patients with negative para-aortic lymph nodes by CT evaluation had a 64% 2-year progression-free survival rate if the para-aortic lymph nodes were found to be negative for disease by PET, but if the PET was positive, the 2-year progression-free survival rate decreased to 18% (P < .0001) (Fig 3).
A multivariate analysis of prognostic variables for progression-free survival was performed. The variables included patient age, tumor stage, tumor histology, lymph node status by CT, and lymph node status by PET. The only significant prognostic variable was lymph node status by PET (P = .01) (Table 2). A multivariate analysis of prognostic variables was performed after excluding the eight patients with PET+ supraclavicular lymph nodes (all eight patients died of their disease). The analysis evaluated patient age, tumor stage, tumor histology, lymph node status by CT in the pelvis and para-aortic regions, and lymph node status by PET in the pelvis and para-aortic regions. The analysis demonstrated that the most significant independent prognostic factor for progression-free survival was the status of the para-aortic lymph nodes as determined by PET (P = .025) (Table 3).
Carcinoma of the cervix metastasizes in a predictable pattern. Tumor usually spreads from the primary cervical lesion sequentially to pelvic lymph nodes, para-aortic lymph nodes, and supraclavicular lymph nodes, and then ultimately to nonnodal distant metastatic sites such as lung, liver, and bone. Metastasis to para-aortic lymph nodes in the absence of pelvic lymph node metastasis is exceptionally uncommon.12,13 Our imaging data bear out the observations noted in these surgical staging studies.14,15 All patients with para-aortic lymph node metastases by CT had pelvic lymph node metastases by CT, and all patients with para-aortic lymph node metastases by PET had pelvic lymph node metastases by PET. In addition, all patients with supraclavicular lymph node metastases on PET had pelvic and para-aortic lymph node metastases by PET. Staging of carcinoma of the cervix is a clinically based system. The presence of lymph node metastasis to the pelvic and para-aortic lymph node regions does not alter clinical stage.16 However, clinically detected inguinal and supraclavicular lymph node metastasis does alter clinical stage (ie, stage IVb). Although not part of the FIGO staging system, the presence of pelvic and para-aortic lymph node metastasis is nonetheless an important finding that does alter the method of therapy (ie, surgery, radiotherapy, and chemotherapy), as well as the radiotherapy treatment plan (irradiated volume and irradiation dose). In the current study, seven of 101 patients were found to have para-aortic lymph node metastases on the basis of CT findings. An additional 14 patients had abnormal FDG uptake in para-aortic lymph nodes, and therefore, the irradiated volume could be modified on the basis of PET findings to include the para-aortic lymph node region in 14% of the patients we studied. Detection of lymph node metastases by conventional imaging methods is based on distortion of normal lymph node architecture (LAG) or lymph node enlargement (CT, ultrasonography, or MRI). All of these methods have limited sensitivity. Heller et al17 evaluated the detection of para-aortic lymph node metastases by ultrasonography, CT, and LAG in patients with cervical cancer. Imaging results were confirmed by surgical staging in all patients. The sensitivity and specificity of LAG were 79% and 73%, respectively, compared with 34% and 96% for CT and 19% and 99% for ultrasonography, respectively. A more recent meta-analysis compared the utility of LAG, CT, and MRI in the detection of pelvic and para-aortic lymph node metastasis in patients with cervical cancer.4 The authors concluded that the three imaging studies perform similarly in the detection of lymph node metastasis from cervical cancer. PET is an imaging method that depends on metabolic, rather than anatomic, alterations for detection of disease. The metabolic characteristic that is exploited for the oncologic applications of FDG-PET is the increased glycolysis demonstrated by most neoplastic cells. Because of the ability of FDG-PET to detect metastases in normal-sized lymph nodes, it has been shown to be more sensitive than conventional imaging methods for detection of nodal metastases and has been used successfully in the preoperative staging of several primary tumors, including cancers of the lung, esophagus, breast, and ovary. Our results and those of other investigators5,8 demonstrate that FDG-PET in patients with cervical cancer reveals abnormalities consistent with lymph node metastases more often than does CT. Rose et al5 evaluated 32 patients with cervical cancer by FDG-PET. They observed abnormal FDG uptake in 91% of the primary cervical tumors, and they found that FDG-PET had a sensitivity of 75% and a specificity of 92% for detecting tumor in para-aortic lymph nodes when compared with the results of surgical staging. Surgical staging was not performed in the patients in this study because all of them had been referred for radiotherapy as the principal mode of treatment. However, eight of our patients had abnormal FDG uptake in the left supraclavicular lymph nodes, and tumor was histologically confirmed in these lymph nodes by fine-needle aspiration in all eight. The primary end point of our study was progression-free survival. Our data indicate that abnormal FDG uptake in lymph nodes is a robust predictor of disease progression. We have also shown that the site of lymph node regions exhibiting abnormal FDG uptake is of prognostic significance. Stehman et al1 analyzed 626 patients who had previously been enrolled onto Gynecologic Oncology Group clinical studies. Patients in their analysis had all undergone surgical para-aortic lymph node sampling. Patients’ tumors were staged I to IVa. They performed a multivariate analysis of prognostic factors that included patient age, tumor stage, tumor size, and lymph node status. The authors found that the relative risk for progression of disease was 11.0 for para-aortic lymph nodes positive for disease and that positive para-aortic lymph nodes were "the most significant predictor of recurrence and death, overwhelming all other risk factors." In their study, 15% of all patients had positive para-aortic lymph nodes. The presence of positive para-aortic lymph nodes changed the original treatment plan for these patients, similar to our findings. The authors concluded that because of the significance of para-aortic lymph node status, it would be difficult to interpret the results of a prospective clinical trial that did not identify or stratify for this highly important risk factor. Accordingly, by utilizing progression-free survival as an end point, we have validated the specificity of FDG-PET as a method for detecting lymph node metastases in patients with cervical cancer. The sensitivity and specificity of PET for assessing lymph node status in carcinoma of the cervix, in comparison to those of CT and surgical staging, are inadequately defined. Our results suggest that routine diagnostic evaluation of patients with carcinoma of the cervix should include PET imaging. The primary limitation of our study is that it is a retrospective review of the routine clinical CT and PET reports. The predictive value of negative FDG-PET findings in lymph nodes is unknown. However, increased FDG uptake in lymph node regions is associated with a worse prognosis and can alter therapeutic management of patients. Our results also suggest that clinical trials in carcinoma of the cervix should require FDG-PET for staging because the therapeutic strategy (ie, surgery, radiotherapy, and chemotherapy) and outcome will be altered by positive PET lymph node findings.
1. Stehman F, Bundy B, DiSaia P, et al: Carcinoma of the cervix treated with irradiation therapy: I. A multivariate analysis of prognostic variables in the Gynecologic Oncology Group. Cancer 67: 2776-2785, 1991[Medline] 2. Yu KK, Forstner R, Hricak H: Cervical carcinoma: Role of imaging. Abdom Imaging 22: 208-215, 1997[Medline] 3. Russell AH, Shingleton HM, Jones WB, et al: Diagnostic assessments in patients with invasive cancer of the cervix: A national patterns of care study of the American College of Surgeons. Gynecol Oncol 63: 159-165, 1996[Medline]
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Scheidler J, Hricak H, Yu KK, et al: Radiological evaluation of lymph node metastases in patients with cervical cancer: A meta-analysis. JAMA 278: 1096-1101, 1997
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Rose PG, Adler LP, Rodriguez M, et al: Positron emission tomography for evaluating para-aortic nodal metastasis in locally advanced cervical cancer before surgical staging: A surgicopathologic study. J Clin Oncol 17: 41-45, 1999
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Reinhardt MJ, Ehritt-Braun C, Vogelgesang D, et al: Metastatic lymph nodes in patients with cervical cancer: Detection with MR imaging and FDG PET. Radiology 218: 776-782, 2001
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Sugawara Y, Eisbruch A, Kosuda S, et al: Evaluation of FDG PET in patients with cervical cancer. J Nucl Med 40: 1125-1131, 1999 8. Grigsby PW, Dehdashti F, Siegel BA: FDG-PET evaluation of carcinoma of the cervix. Clin Positron Imaging 2: 105-109, 1999[Medline] 9. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53: 457-481, 1958 10. Mantel N: Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 50: 163-170, 1966[Medline] 11. Cox DR: Regression models and life tables. J R Stat Soc 34: 187-220, 1972 12. Morice P, Sabourin JC, Pautier P, et al: Isolated para-aortic node involvement in stage IB/II cervical carcinoma. Eur J Gynaecol Oncol 21: 123-125, 2000[Medline] 13. Deppe G, Lubicz S, Galloway BT, et al: Aortic node metastases with negative pelvic nodes in cervical cancer. Cancer 53: 173-175, 1984[Medline] 14. Sakuragi N, Satoh C, Takeda N, et al: Incidence and distribution pattern of pelvic and paraaortic lymph node metastasis in patients with stages IB, IIA, and IIB cervical carcinoma treated with radical hysterectomy. Cancer 85: 1547-1554, 1999[Medline] 15. Michel G, Morice P, Castaigne D, et al: Lymphatic spread in stage IB and II cervical carcinoma: Anatomy and surgical implications. Obstet Gynecol 91: 360-363, 1998[Medline] 16. Fleming ID, Cooper JS, Henson DE, et al: AJCC Cancer Staging Manual ( ed 5 ). Philadelphia, PA, Lippincott-Raven, 1997 17. Heller PB, Malfetano JH, Bundy BN, et al: Clinical-pathologic study of stage IIB, III, and IVA carcinoma of the cervix: Extended diagnostic evaluation for paraaortic node metastasis—A Gynecologic Oncology Group study. Gynecol Oncol 38: 425-430, 1990[Medline] Submitted March 14, 2001; accepted May 10, 2001.
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
