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Journal of Clinical Oncology, Vol 24, No 36 (December 20), 2006: pp. 5687-5694 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.07.4799 Early Invasive Cervical Cancer: Tumor Delineation by Magnetic Resonance Imaging, Computed Tomography, and Clinical Examination, Verified by Pathologic Results, in the ACRIN 6651/GOG 183 Intergroup Study
From the Department of Radiology, Thomas Jefferson University, Philadelphia, PA; Center for Statistical Sciences, Brown University, Providence, RI; Department of Radiology, University of California, San Francisco; Synarc Inc, San Francisco, CA; Department of Radiology, University of Miami Medical School, Miami, FL; Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, NY; Department of Radiology, Armed Forces Institute of Pathology, Washington, DC; Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD; Department of Diagnostic Radiology, McGill University Health Center, Montreal, Quebec; and the Department of Radiation Oncology, Toronto Sunnybrook Cancer Centre, Toronto, Ontario, Canada Address reprint requests to Donald G. Mitchell, MD, Department of Radiology, Thomas Jefferson University Hospital, 132 S 10th St, 1094 Main Bldg, Philadelphia, PA 19107; e-mail: donald.mitchell{at}jefferson.edu
PURPOSE: To compare magnetic resonance imaging (MRI), computed tomography (CT), and clinical examination for delineating early cervical cancer and for measuring tumor size. PATIENTS AND METHODS: A 25-center study enrolled 208 patients with biopsy-proven invasive cervical cancer for MRI and CT before attempted curative radical hysterectomy. Each imaging study was interpreted prospectively by one onsite radiologist and retrospectively by four independent offsite radiologists, who were all blinded to surgical, histopathologic, and other imaging findings. Likelihood of cervical stromal and uterine body involvement was rated on a 5-point scale. Tumor size measurements were attempted in three axes. Surgical pathology was the standard of reference. RESULTS: Neither MRI nor CT was accurate for evaluating cervical stroma. For uterine body involvement, the area under the receiver operating characteristic curve was higher for MRI than for CT for both prospective (0.80 v 0.66, respectively; P = .01) and retrospective (0.68 v 0.57, respectively; P = .02) readings. Retrospective readers could measure diameter by CT in 35% to 73% of patients and by MRI in 79% to 94% of patients. Prospective readers had the highest Spearman correlation coefficient with pathologic measurement for MRI (rs = 0.54), followed by CT (rs = 0.45) and clinical examination (rs = 0.37; P < .0001 for all). Spearman correlation of multiobserver diameter measurements for MRI (rs = 0.58; P < .0001) was double that for CT (rs = 0.27; P = .03). CONCLUSION: In patients with cervical cancer, MRI is superior to CT and clinical examination for evaluating uterine body involvement and measuring tumor size, but no method was accurate for evaluating cervical stroma.
Cervical carcinoma, if confined to the lower pelvis, can be cured by surgery or chemoradiotherapy.1-9 Transvaginal radical trachelectomy can preserve fertility in women with tumors smaller than 2 cm without uterine involvement.10 In women with lymphatic metastases, surgery alone is not sufficient, and pelvic irradiation will be unsuccessful if there are lymphatic metastases above the irradiated field. Unfortunately, even fluorodeoxyglucose positron emission tomography/computed tomography (CT) is insensitive for cervical carcinoma lymphatic metastases with a short axis diameter of less than 5 mm,11 so secondary indicators, such as tumor size or spread to the cervical stroma, uterine corpus, or parametrium, are used for treatment decisions.12-26 Improved tumor delineation by imaging extent contributes to treatment decisions and increases the precision of targeted radiation therapy.27-31 Although CT is not a component of International Federation of Gynecology and Obstetrics (FIGO) staging, it is obtained in most patients with cervical carcinoma, particularly for detecting enlarged lymph nodes or bulky extent beyond the cervix.32-34 CT has not proven accurate for assessing parametrium or tumor size because of insufficient contrast between local tumor and parametrium.35-38 Initial reports indicate that magnetic resonance imaging (MRI) is more effective than CT for delineating cervical tumor boundaries and for measuring tumor size.25,37,39-53 An interdisciplinary multicenter clinical trial was recently conducted by the American College of Radiology Imaging Network (ACRIN) and the Gynecologic Oncology Group (GOG) to compare the diagnostic performance of clinical staging, MRI, and CT for evaluating cervical cancer. The results of tumor staging and parametrial extent have been published separately.54 The current study compares the accuracy of MRI, CT, and clinical examination for delineating clinically important morphologic aspects of primary tumor extent, using radical hysterectomy findings as the reference standard.
This prospective, multicenter, interdisciplinary clinical trial was conducted jointly by ACRIN and GOG (ACRIN 6651/GOG 183). Each participating institution was required to be a GOG participant with a proven record of 20 surgical patients with gynecologic cancer per year and to submit a protocol-specific application to ACRIN. Participating institutions were required to have 1.5-T MRI (any manufacturer) and helical CT equipment (any manufacturer) and two radiologists, a gynecologic oncologist, and a pathologist designated as adequately qualified and committed to the study's goals. All institutions had study-specific institutional review board approval, which was verified at ACRIN headquarters before registering patients. The study commenced in March 2000 and was closed in November 2002, with 208 patients accrued from 25 academic and community health centers.
Patients The decision for surgical treatment was based on pre-enrollment FIGO assessment, including an initial clinical estimate of tumor size. However, imaging findings suspicious for metastatic involvement of lymph nodes (lymph node size > 1 cm in the short axis) were permitted to influence the decision to perform surgical biopsy or lymphadenectomy and potentially to cancel plans for radical hysterectomy in accordance with the recommended treatment of choice. Patients were excluded if they were pregnant, could not give informed medical consent, were unwilling or unable to undergo contrast-enhanced CT and MRI, or were not surgical candidates.
Data Acquisition Radical hysterectomy was planned for all women, although it was abandoned in some women depending on surgical findings. Each surgeon completed a data form specifying the extent of disease found at surgery. Pathologists completed a similar data form specifying presence or absence of malignancy in the inner fibrous cervical stroma, uterus, parametrium, rectum, bladder, and regional lymph nodes and measured the diameter of the primary tumor, in three axes if possible. The maximal depth of stromal invasion was recorded in millimeters. Data were collected, managed, and analyzed by the Biostatistics and Data Management Center of ACRIN.
Image Interpretation All image readers recorded individual imaging findings relevant for staging on standardized data forms using a 5-point scale (1 = cancer definitely absent, 5 = cancer definitely present), including primary tumor extension to uterine corpus, parametrium, or adjacent tissues and presence of lymph node metastases. The onsite prospective readers similarly rated suspicion of cervical stromal invasion, whereas the offsite retrospective readers categorized cervical stromal invasion as partial or full (no intact stroma visible between tumor and parametrium). If tumor margins could be delineated, tumor size was measured in three axes, if possible.
Statistical Analysis Deep cervical fibrous stromal invasion was measured pathologically and used to provide the following two thresholds for stromal invasion: any stromal invasion (> 0 mm) or deep invasion (> 5 mm). For the primary imaging readers, accuracy was assessed via ROC analysis of the 5-point scale of suspicion, described earlier. Sensitivity and specificity were estimated using a threshold of greater than or equal to 4 (probably or definitely present) as positive and were compared between modalities by means of McNemar's test. For the retrospective multiobserver analyses, four separate sets of accuracy statistics were calculated using pathologic thresholds of 0 mm and 5 mm of invasion and imaging thresholds of partial-thickness (none v partial/full) and full-thickness (none/partial v full) invasion.
Primary tumor measurements by clinical assessment, CT, and MRI were compared based on average diameter using the pathologic average measured diameter as the reference standard. If a tumor could not be measured in all three axes, the average diameter was calculated based on the one or two available measurements. We did not distinguish between lack of visible tumor and tumor with a diameter of less than 1 cm because biopsy proof of cervical malignancy, which was an essential entry criterion for this study, constituted reader bias in favor of visible tumor. Two axes were recorded for clinical assessment, which was based primarily on physical examination, although oncologists may have had access to prior imaging data. To correct for difficulty in measuring small tumors, we categorized the average diameter for each modality as less than 1 cm or no tumor visible, 1 to 2 cm, 2 to 4 cm, or more than 4 cm. The linear correlation between categorized average diameters as determined by pathology versus the diameters determined by MRI, CT, and clinical examination was estimated using the Spearman correlation coefficient, and agreement was estimated using simple and Cicchetti-Allison weighted In both the retrospective MRI and CT analysis sets, average diameter data were not measured on the pathologic specimen in 13 and 14 participants, respectively. In addition, all dimensions from the pathologic specimen were recorded as 0 for 34 women, but a tumor size category could be imputed from other surgical or pathologic recorded data for 14 of these women.
Patient Cohort and Data Related to the Primary Aim (Prospective Staging) A more detailed description of the patient cohort for this clinical trial is described in Hricak et al.54 Of the 208 patients enrolled, nine (4%) were deemed ineligible because of enrollment disqualifications, and 27 (13%) were excluded because of missing or incomplete data. Thus, 172 participants (83%) were included in the final analysis of the prospective readings based on having submitted data from clinical assessment, CT, MRI, surgery, and pathology. Tumor histology was squamous cell in 124 women (72%), adenocarcinoma in 38 women (22%), and other in 10 women (6%). Surgicopathologic findings, which were classified based on components of FIGO staging, corresponded to stage IA in 13 women (8%), IB in 111 women (65%), IIA in six women (3%), IIB in 16 women (9%), greater than IIB in 20 women (12%), and not determined in six women (3%).
Patient Cohort and Data Related to the Retrospective Multiobserver Study
Tumor Size
For the multiobserver retrospective readings for which pathologic tumor sizes were available, a minority of tumors were measured retrospectively by CT readers, ranging from 38 to 81 tumors (Table 2). MRI readers measured more tumors (range, 94 to 111 tumors). Continuous size measurements were recorded by two or more retrospective readers for 65 tumors using CT and for 110 tumors using MRI.
For CT retrospective readers, the simple statistics ranged from 0.04 to 0.19, although only one CT retrospective reader had a value that was significantly different from zero. In contrast, for MRI retrospective readers, the simple statistics ranged from 0.19 to 0.37, all of which were significantly different from zero. Spearman correlation coefficients for MRI ranged from 0.48 to 0.53 (P < .0001 for all); Spearman correlation coefficients for CT readers ranged from 0.003 (P > .05) to 0.44 (P = .01) When measurements were averaged among multiple readers, Spearman correlation for MRI (rs = 0.58; P < .0001) was double that for CT (rs = 0.27; P = .03).
Uterine Involvement
Cervical Stromal Involvement Among the 172 specimens in the prospectively read analysis set, pathologic data for cervical stromal involvement was incomplete for 30 (17%). Of the remaining 142 specimens, 30 (17%) had no stromal invasion, 75 (44%) had shallow ( 5 mm) invasion, and 37 (22%) had deep (> 5 mm) invasion. Imaging grades were unassessable by MRI in 40 specimens (23%) and by CT in 23 specimens (13%). Among CT primary readers, 65 (38%) rated stromal invasion as indeterminate compared with nine MRI primary readers (5%). This contributed to lower sensitivity (P < .0001) and higher specificity (P = .003) for CT (Table 3). The AUC was low for both modalities at thresholds of any invasion (AUC, 0.51 for MRI v 0.56 for CT) and deep invasion (AUC, 0.58 for MRI v 0.49 for CT), with no significant difference.
CT retrospective readers ranked an average of only 48 specimens compared with 106 specimens ranked by MRI retrospective readers. However, the accuracy of both modalities was poor at both pathologic thresholds using imaging criteria of either partial-thickness or full-thickness invasion. An example of images and corresponding data from clinical examination and pathology is illustrated in Figures 2 and 3.
This collaborative ACRIN/GOG trial is the only intergroup, multicenter study in women with presumed early-stage cervical carcinoma to use surgical pathology as the basis of comparison between initial clinical assessment, MRI, and CT, including both prospective and retrospective multiobserver evaluation of MRI and CT. Our results regarding tumor size measurements, as well as determination of uterine involvement, showed higher agreement and correlation with pathology for MRI than for CT or clinical assessment, which is in agreement with earlier studies.25,37,39-53,57 Not only was CT less accurate, but CT readers could not even record measurements in most instances. If an expert reader cannot measure a tumor, delineating its margins for treatment planning is likely to be problematic. The low correlation for clinical assessment of tumor size with pathologic measurement suggests that the common clinical practice of estimating the size of cervical tumors by physical examination may not be valid, particularly when MRI is available. Although we did not directly evaluate the use of MRI for localizing tumor for targeted brachytherapy, the apparent superiority of MRI over CT and physical examination for delineating gross tumor margins is consistent with the recent proposed guidelines of the Image-Guided Brachytherapy Working Group, which recommended MRI as the preferred method for delineating cervical carcinoma.28 An earlier report from this ACRIN 6651/GOG 183 trial showed that, for detecting pathologic features corresponding to FIGO stage IIB or higher, sensitivity and specificity were 42% and 82% for CT and 53% and 75% for MRI, respectively.54 The most critical factor for this imaging task is determination of parametrial extent. This requires distinction between tumor that minimally invades versus tumor that merely abuts adjacent fibroadipose tissue. CT is limited by poor soft tissue contrast, whereas MRI currently has lower spatial resolution and is more frequently degraded by artifact. For these reasons, CT and MRI have not achieved high accuracy for diagnosing minimal parametrial extent of cervical tumor. Similarly, neither MRI nor CT could accurately distinguish between women with versus without microscopic or deep invasion of cervical stroma, in contrast to results from some previous studies.13,58 Although dynamic contrast techniques13 and higher resolution imaging might enable accurate determination of cervical stromal invasion, our results indicate that MRI and CT as performed currently in clinical practice may not provide this capability. The image attributes needed to detect microscopic tumor invasion are different from those needed to estimate tumor size or to delineate gross tumor boundaries for treatment planning. These latter tasks depend on soft tissue contrast but do not require submillimeter spatial resolution. Therefore, current MRI technology seems well suited for delineating tumor boundaries, as confirmed by our findings. Although uterine involvement is not part of FIGO staging, it has been associated with increased risk of nodal metastases26 and may affect planning of trachelectomy10 and brachytherapy.28 Tumor size is a component of FIGO staging and helps determine prognosis and choice of treatment. Newly developed multislice CT technology enables rapid acquisition of thin slices, allowing somewhat improved contrast by imaging immediately after rapid administration of iodinated contrast material, but results will depend on other variables, such as tumor vascularity, coexisting benign pelvic disease, and cardiac output. Furthermore, iodinated contrast agent administration is an additional risk to the patient. Finally, the need for dynamic imaging precludes repeated imaging during repositioning of intracavitary devices or other interventions. However, MRI can be used to delineate gross tumor margins without contrast enhancement in most patients, as shown in this series. This ACRIN/GOG cooperative trial was originally powered based on the primary end point of determining accuracy of imaging for staging,54 rather than the secondary end points of tumor delineation addressed here. Our conclusions are thus more exploratory in nature, limited somewhat by our available sample size. Additionally, the added costs of MRI must be considered along with its potential benefits for guiding treatment. In conclusion, analysis of prospective as well as retrospective multiobserver readings show that MRI is superior to CT and clinical examination for measuring cervical carcinoma size and uterine extension, two important prognostic indicators. Neither MRI nor CT was accurate for detecting cervical stromal invasion. The superiority of MRI over CT for determining cervical carcinoma size and uterine extension results from improved delineation of tumor margins, suggesting that it may additionally be preferred for guiding brachytherapy and other forms of targeted treatment.
The authors indicated no potential conflicts of interest.
Supported by National Cancer Institute Grants No. U01 CA079778 and U01 CA080098. Conducted jointly by the American College of Radiology Imaging Network (ACRIN) and the Gynecologic Oncology Group (GOG). Presented in part at the 92nd Scientific Assembly Annual Meeting of the Radiological Society of North America, November 26-December 1, 2005, Chicago, IL. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Gynecol Oncol 79:451-456, 2000[CrossRef][Medline] Submitted May 30, 2006; accepted September 29, 2006. This article has been cited by other articles:
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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