(Radiology. 1999;211:519-528.)
© RSNA, 1999
Treated Ovarian Cancer: Comparison of MR Imaging with Serum CA-125 Level and Physical Examination-A Longitudinal Study1
Russell N. Low, MD,
Fred Saleh, MD,
S. Y. Thomas Song, MD,
Thomas A. Shiftan, MD,
Robert M. Barone, MD,
Conley G. Lacey, MD and
Paul M. Goldfarb, MD
1 From the Departments of Diagnostic Radiology, Oncology, and Surgical and Gynecologic Oncology, Sharp and Children's MRI Center, Sharp Memorial Hospital, 7901 Frost St, San Diego, CA 92123. From the 1997 RSNA scientific assembly. Received March 30, 1998; revision requested June 25; revision received August 7; accepted November 6. Address reprint requests to R.N.L.
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Abstract
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PURPOSE: To evaluate whether gadolinium-enhanced magnetic resonance (MR) imaging can demonstrate clinically occult tumors in women with treated ovarian cancer and to compare the diagnostic accuracy of MR imaging, serum CA-125 (ovarian cancer antigen) level, and physical examination.
MATERIALS AND METHODS: From 1992 to 1997, a longitudinal study comparing MR imaging findings, CA-125 values, and physical examination results with eventual clinical outcome in 69 women with treated ovarian cancer was performed. Tumor presence was determined with surgery, by an elevated CA-125 value, or with follow-up of patients longitudinally to assess for tumor recurrence. Absence of tumor was accepted with a disease-free interval of at least 2 years.
RESULTS: Twenty-three of 39 patients in clinical remission with a normal CA-125 level and physical examination result had subclinical tumor proved at laparotomy or clinical follow-up. Gadolinium-enhanced MR imaging correctly demonstrated residual tumor in 20 of 23 patients. In all 69 patients, MR images had a 91% sensitivity, 87% specificity, 90% accuracy, and 72% negative predictive value and were superior to serum CA-125 level (53%, 94%, 63%, and 38%, respectively) (P < .001) and physical examination (26%, 94%, 43%, and 29%, respectively) (P < .001) in the depiction of residual tumor.
CONCLUSION: Gadolinium-enhanced MR imaging is a valuable clinical tool in patients with ovarian cancer. An abnormal MR examination with a normal CA-125 value is a strong indication of residual or recurrent tumor.
Index terms: Abdomen, MR, 791.121411, 791.121412, 791.121415, 791.12143 • Magnetic resonance (MR), contrast agents, 791.12143 • Ovary, neoplasms, 852.32 • Pelvis, MR, 44.121411, 44.121412, 44.121415, 44.12143 • Peritoneum, neoplasms, 791.33
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Introduction
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Ovarian cancer is the second most common gynecologic malignancy. It is the fourth leading cause of cancer deaths of women in the United States and has the highest mortality rate of all of the gynecologic malignancies (1). The clinical treatment of women with ovarian cancer has traditionally included initial surgical staging and aggressive cytoreduction, followed by platinum and paclitaxel-based adjuvant chemotherapy (2).
The response to therapy has been determined by following the CA-125 level, which is initially elevated in 80% of women who have epithelial ovarian cancer. Serial measurements of CA-125 have been shown to correlate with tumor response to chemotherapy, and an elevated serum CA-125 level is a strong indication of residual or recurrent tumor (3).
However, the detection of clinically occult tumors is problematic. It is well recognized that a normal CA-125 level does not exclude the presence of a tumor (4). In a study in which the preoperative CA-125 levels in women undergoing second-look laparotomy were compared, Rubin et al (5) found that the negative predictive value of a normal CA-125 level was 38%. Of 29 patients with a CA-125 level less than 35 U/mL, 18 (62%) had residual tumor confirmed at laparotomy. In a summary of six studies in which the CA-125 level was compared with the operative findings at secondary surgery for ovarian cancer, 82 (47%) of 173 patients with a normal CA-125 level had a tumor that was identified surgically (5).
In the past, surgical reassessment after initial chemotherapy had an important role in documenting complete tumor remission and performing secondary cytoreduction in patients with residual tumors (6). However, the predictive value of a negative second-look laparotomy is limited, because 50% of these patients will eventually develop recurrent tumor (7–9). The role of second-look laparotomy is now more limited. In 1995, the National Institutes of Health Consensus Conference on Ovarian Cancer recommended that second-look surgeries be limited to those performed in patients in clinical trials or in patients in whom the results of surgery would affect clinical management decisions (2).
In this clinical setting, the need for more sensitive and accurate tumor markers and imaging studies is clear. Prior reports (10–12) have shown that small peritoneal tumors enhance with the intravenous administration of gadolinium chelates and thereby increase in conspicuity on contrast material–enhanced MR images. The results of some studies (10) have suggested that gadolinium-enhanced MR imaging is more sensitive than is computed tomographic (CT) scanning in depicting small peritoneal tumors and carcinomatosis. We undertook this longitudinal study to determine whether gadolinium-enhanced MR imaging can depict clinically occult tumors in women with ovarian cancer. Because of the difficulties in establishing the true presence of tumor by using the CA-125 level and laparotomy, we chose to follow patients longitudinally, with clinical outcome as the reference-standard for determination of tumor presence.
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MATERIALS AND METHODS
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Study Overview
This was a 6-year longitudinal nonprospective study performed in cooperation by the departments of radiology, oncology, and surgical oncology at our institution from 1992 through 1997. During this period, all patients with treated ovarian cancer managed by three medical oncologists (F.S., S.Y.T.S., T.A.S.) were examined with MR imaging. Surgical oncology patients also underwent MR imaging before second-look laparotomy. Sixty-nine women (mean age, 56 years) with treated ovarian cancer were included in the study group.
All MR examinations were performed as part of clinical studies ordered by the patient's oncologist. A total of 162 MR examinations were performed; however, only the 69 index MR examinations were included in the study. Index MR examinations were chosen to correspond to the time of maximum clinical response following adjuvant chemotherapy, as determined by a decreasing CA-125 level following chemotherapy and clinical and imaging evidence of tumor regression. We justify the selection of this index MR examination because at this point, following surgical and chemotherapeutic cytoreduction, important clinical decisions with regard to additional consolidation chemotherapy require accurate assessment of any residual tumors.
All MR images were interpreted without knowledge of the most recent serum CA-125 level or physical examination result. After the MR images were interpreted and at periodic intervals during the study, the oncologists were interviewed, and the patient's current serum CA-125 level and physical examination results were recorded in an ongoing database. With regard to patients who underwent second-look laparotomy, the surgical and gynecologic oncologists (R.M.B., C.G.L., P.M.G.) were interviewed following surgery, or the principal author (R.N.L.) observed and recorded the operative findings. Twenty of the 69 MR examinations have been included in previous reports (10,13).
The presence of a tumor was established with surgery, an elevated CA-125 level at the time of the index MR examination, or subsequent clinical or surgical evidence of tumor recurrence established at follow up. Because this was an ongoing clinical study, we could not determine in advance the method used to prove tumor presence. Due to the low negative predictive value of a single normal CA-125 level or normal second-look surgery, complete clinical response was only accepted after a disease-free interval of more than 2 years.
Patients were followed up longitudinally: the clinical follow-up ranged from 1 to 62 months (mean, 22.6 months; median, 19 months). Seven patients with recurrent tumor were followed up for less than 6 months. The clinical data regarding tumor cell type and initial tumor staging were obtained by reviewing patient charts and our institution's computerized tumor registry database.
Histopathologic Features and Tumor Stage
The 69 women with treated ovarian cancer had the following histopathologic cell types: serous adenocarcinoma (12 patients), papillary adenocarcinoma (seven patients), papillary serous adenocarcinoma (11 patients), poorly differentiated adenocarcinoma (21 patients), endometrioid adenocarcinoma (three patients), mucinous adenocarcinoma (four patients), clear cell adenocarcinoma (four patients), small cell adenocarcinoma (one patient), and ovarian tumor of low malignant potential (six patients). The International Federation of Gynecology and Obstetrics tumor stage at initial diagnosis was stage I in 10, stage II in two, stage III in 53, and stage IV in four patients.
MR Imaging
All MR imaging was performed with a Signa 1.5-T imager (GE Medical Systems, Milwaukee, Wis) by using a body coil. MR imaging included axial T1-weighted, T2-weighted fast spin-echo, and gadolinium-enhanced breath-hold fast multiplanar spoiled gradient-recalled-echo imaging through the abdomen and pelvis.
Conventional axial T1-weighted spin-echo images were obtained with respiratory-ordered phase encoding and superior and inferior saturation pulses. The imaging parameters included 300/11 (repetition time msec/echo time msec), a 256 x 192 matrix, and two signal acquired. The images were acquired with a 7-mm section thickness and 3-mm intersection gap. The acquisition time was 8 minutes, 17 seconds for each set of 24 sections. In a group of patients who underwent imaging later, T1-weighted breath-hold fast multiplanar spoiled gradient-recalled-echo imaging was substituted for spin-echo T1-weighted imaging. The parameters used to obtain these images included 111/4.2, a 256 x 192 matrix, and one signal acquired. Contiguous 10-mm-thick sections were acquired. The acquisition time was 28 seconds for 12 sections.
T2-weighted fast spin-echo imaging was performed in the axial and sagittal planes. The imaging parameters were 4,600/91–96, a 256 x 256 matrix, two signals acquired, an echo train of eight, and a ±32-kHz receiver bandwidth, with saturation pulses superior and inferior to the section. The sections were acquired with a 7-mm section thickness and 3-mm intersection gap. Fat saturation and flow compensation were used for artifact reduction. The acquisition time for this sequence was 5 minutes, 14 seconds for each set of 24 sections.
Breath-hold axial fast multiplanar spoiled gradient-recalled-echo images were obtained through the entire abdomen and pelvis at 0 and 10 minutes after the intravenous bolus administration of 0.1 mmol of gadopentetate dimeglumine per kilogram of body weight during a 10-second injection. Coronal breath-hold fast multiplanar spoiled gradient-recalled-echo imaging also was performed. The imaging parameters included 141/2.6, a 256 x 192 matrix with a three-quarter field of view, which produced an effective matrix of 256 x 256, one signal acquired, 10-mm-thick sections with no intersection gap, ±16-kHz receiver bandwidth, and 70° flip angle. We chose to use a minimum echo time of 2.6 msec to decrease the breath-holding time and to maximize the fat suppression by combining opposed-phase imaging with chemically selective fat suppression. Noninterleaved sets of 8 sections were obtained during each 24-second breath hold. Fat saturation was used with the gadolinium-enhanced fast multiplanar spoiled gradient-recalled-echo imaging in 43 of the 69 MR examinations. The approximate MR examination time was 60 minutes. All MR images were interpretable; none was excluded from the study on the basis of image quality.
Oral contrast material was administered starting at 60–90 minutes before MR imaging. Early in the study, 11 patients received 600 mL of perflubron (Imagent GI; Alliance Pharmaceuticals, San Diego, Calif). Perflubron, which is no longer available, is a negative intestinal contrast material on T1-weighted and T2-weighted images. Subsequently, 39 patients received 1,350 mL of 2% barium sulfate (ReadiCat; E-Z-EM, Westbury, NY) for bowel opacification. Dilute barium is a negative contrast material at T1-weighted MR imaging and a positive contrast material at T2-weighted MR imaging. One milligram of glucagon was administered intravenously at the time of the gadolinium-based contrast material injection in patients who were given oral contrast material. A bowel preparation was not administered. The remaining 19 patients underwent imaging without oral contrast material.
MR Image Interpretation
Sixty-two of the 69 MR studies were interpreted by the principal author of this study (R.N.L.); the remaining seven MR studies were interpreted by one of five other radiologists. All interpreting radiologists were experienced in body MR imaging; they had 2–7 years experience interpreting body MR images.
Nonenhanced T1-weighted and fast spin-echo T2-weighted MR images were evaluated for evidence of tumor masses that represented either local pelvic recurrence or distant abdominal metastases. Gadolinium-enhanced fast multiplanar spoiled gradient-recalled-echo MR images were assessed for any evidence of peritoneal, omental, or serosal thickening and enhancement more intense than that of the abdominal musculature. Serosal tumor was noted if there was abnormal enhancement of the bowel wall with mural thickening and adjacent peritoneal enhancement. The enhancement of peritoneal tumors may be smooth and continuous or nodular and discontinuous. Obvious tumor masses also were noted on the gadolinium-enhanced MR images. Lymphadenopathy and ascites on nonenhanced and enhanced MR images were recorded.
Proof of Tumor Presence
Various reference standards were used as proof of residual or recurrent tumor. In the 69 patients, tumor was proved on the basis of a positive second-look laparotomy result in 26 patients, a concurrently elevated CA-125 level (
35 U/mL) in 13 patients, and the clinical follow-up results in 14 patients who were in clinical remission initially but later developed an elevated CA-125 level, which doubled from the baseline value. These 14 patients also had imaging evidence of obvious tumor progression at sequential MR examinations, although this was not a requirement to establish tumor recurrence. A patient who was in imaging and/or clinical remission but later developed recurrent tumor was considered to have clinically occult tumor at the time of the prior evaluation.
The complete clinical remission with absence of tumor in 16 patients was proved by following up these patients longitudinally for at least 2 years (range, 24–62 months; mean, 40 months) with clinical monitoring and follow-up imaging studies. A normal second-look laparotomy, clinical examination, or MR examination result was not accepted as proof of tumor absence until the patient had been in clinical remission for at least 2 years with normal serial CA-125 levels, physical examination results, and normal follow-up imaging studies. One patient had a transiently elevated CA-125 level at the time of the MR examination that returned to normal without treatment. This patient was in clinical and imaging remission for 3 years.
Use of a persistently elevated CA-125 level as proof of tumor is supported by prior studies that have shown that an elevated CA-125 value (35 U/mL) is nearly 100% predictive of residual or recurrent tumor in women with epithelial ovarian cancer that was initially seropositive (3,5).
Definitions of True-Positive, False-Positive, False-Negative, and True-Negative Examination Results
In each of the 69 patients, the MR examination finding, serum CA-125 level, and physical examination result were recorded as a true-positive, false-positive, false-negative, or true-negative result. The overall sensitivity, specificity, accuracy, and negative and positive predictive values for MR imaging, CA-125 level, and physical examination also were calculated.
True-positive MR findings were recorded when a tumor mass or enhancing peritoneal tumors were observed and the findings were proved on the basis of surgical and histopathologic results, a concurrently elevated CA-125 level, or a palpable tumor. Clinical follow-up also was used to determine true-positive MR images when a patient later developed clinical evidence of recurrent tumor as indicated by a rising CA-125 level, a palpable mass, or surgical proof of tumor at the anatomic site suspected on the prior MR study. A follow-up MR imaging result alone was never used as proof of tumor presence. A true-positive CA-125 level was recorded when the CA-125 level was elevated greater than or equal to 35 U/mL. True-positive physical examination findings were recorded in patients who had a palpable mass that was determined to represent tumor by the patient's oncologist or gynecologic oncologist.
False-negative MR findings, CA-125 levels, or physical examination findings were recorded when the MR images were interpreted as normal, the CA-125 level was less than 35 U/mL, and bimanual palpation was normal, but the patient had tumor proved at surgery or later developed recurrent tumor. Second-look surgery was recorded as false-negative when surgical reassessment demonstrated no residual tumor, but the patient later developed clinical evidence of tumor recurrence with an elevated CA-125 level or palpable tumor.
False-positive MR findings were recorded when the MR images were interpreted as showing tumor, but the tumor markers, surgical and histopathologic examination results, and clinical follow-up results were negative. A false-positive CA-125 level was noted in one patient in whom the elevated value returned to normal without treatment. One false-positive physical examination finding was noted when a questionable pelvic mass resolved without treatment in a patient who had been in clinical remission for more than 2 years. The results of MR examinations, CA-125 levels, physical examinations, and second-look surgeries were accepted as true-negative only after a 2-year, disease-free interval, as determined at clinical follow-up.
Statistical Analyses
The sensitivity, specificity, accuracy, and positive and negative predictive values for MR imaging and the CA-125 level were compared by using the McNemar test of correlated proportions with the Yate continuity correction. Two-tailed P values were reported with the null hypothesis rejected for P less than .05.
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RESULTS
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Clinical follow-up data on the 69 women in our study group showed that, at the time this article was written, 29 of these patients were living and undergoing chemotherapy for residual or recurrent tumor, 20 were in at least short-term remission, and 20 were deceased.
Patients with Proved Residual or Recurrent Tumor
Among the 69 patients, 53 (77%) had evidence of residual or recurrent tumor, and 16 (23%) were in complete clinical remission. MR imaging enabled the correct identification of tumor in 48 of the 53 patients with proved tumor (91% sensitivity) compared with the CA-125 level, which was elevated in 28 of the 53 patients (sensitivity 53%) and the physical examination, which enabled the detection of tumor in 14 of the 53 patients (sensitivity 26%) (Fig 1).
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Figure 1a. Gadolinium-enhanced breath-hold fast multiplanar spoiled gradient-recalled-echo MR images (140/2.6, 70° flip angle) with fat saturation obtained in a 74-year-old woman with stage III ovarian cancer 10 minutes after intravenous gadolinium-based contrast material injection. (a, b) Images obtained in July 1994. The patient presented with symptoms of primary ovarian carcinoma and a markedly elevated serum CA-125 level (28,000 U/mL). (a) Image through the upper part of the abdomen shows bulky tumor extending into the superior recess of the lesser sac (open arrows) and a thin rim of enhancing right subphrenic and perihepatic peritoneal tumor (solid arrows). (b) Image through the middle part of the abdomen shows diffuse enhancing carcinomatosis (arrows) involving the anterior peritoneum, omentum, and bowel serosa. (c, d) Images obtained in February 1995. After multiple cycles of adjuvant chemotherapy, the patient was in clinical remission with a normal serum CA-125 level (7 U/mL) and physical examination. (c) Image through the upper part of the abdomen shows minimal residual right subphrenic tumor (arrows). (d) Image through the middle part of the abdomen shows complete resolution of peritoneal enhancement, which is an indication of response to interval chemotherapy. Residual right subphrenic tumor nodules were confirmed at second-look laparotomy. (e, f) Images obtained in September 1996. The patient presented with clinical evidence of recurrence with an elevated serum CA-125 level (890 U/mL). (e) Image through the upper part of the abdomen shows interval increase in the thick rim of enhancing right subphrenic tumor (arrows). (f) Image through the middle part of the abdomen shows interval tumor recurrence (straight arrows), with anterior peritoneal and serosal small-bowel and right colonic tumor. Note the improved bowel distention owing to the use of 2% barium as the oral contrast material.
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Figure 1b. Gadolinium-enhanced breath-hold fast multiplanar spoiled gradient-recalled-echo MR images (140/2.6, 70° flip angle) with fat saturation obtained in a 74-year-old woman with stage III ovarian cancer 10 minutes after intravenous gadolinium-based contrast material injection. (a, b) Images obtained in July 1994. The patient presented with symptoms of primary ovarian carcinoma and a markedly elevated serum CA-125 level (28,000 U/mL). (a) Image through the upper part of the abdomen shows bulky tumor extending into the superior recess of the lesser sac (open arrows) and a thin rim of enhancing right subphrenic and perihepatic peritoneal tumor (solid arrows). (b) Image through the middle part of the abdomen shows diffuse enhancing carcinomatosis (arrows) involving the anterior peritoneum, omentum, and bowel serosa. (c, d) Images obtained in February 1995. After multiple cycles of adjuvant chemotherapy, the patient was in clinical remission with a normal serum CA-125 level (7 U/mL) and physical examination. (c) Image through the upper part of the abdomen shows minimal residual right subphrenic tumor (arrows). (d) Image through the middle part of the abdomen shows complete resolution of peritoneal enhancement, which is an indication of response to interval chemotherapy. Residual right subphrenic tumor nodules were confirmed at second-look laparotomy. (e, f) Images obtained in September 1996. The patient presented with clinical evidence of recurrence with an elevated serum CA-125 level (890 U/mL). (e) Image through the upper part of the abdomen shows interval increase in the thick rim of enhancing right subphrenic tumor (arrows). (f) Image through the middle part of the abdomen shows interval tumor recurrence (straight arrows), with anterior peritoneal and serosal small-bowel and right colonic tumor. Note the improved bowel distention owing to the use of 2% barium as the oral contrast material.
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Figure 1c. Gadolinium-enhanced breath-hold fast multiplanar spoiled gradient-recalled-echo MR images (140/2.6, 70° flip angle) with fat saturation obtained in a 74-year-old woman with stage III ovarian cancer 10 minutes after intravenous gadolinium-based contrast material injection. (a, b) Images obtained in July 1994. The patient presented with symptoms of primary ovarian carcinoma and a markedly elevated serum CA-125 level (28,000 U/mL). (a) Image through the upper part of the abdomen shows bulky tumor extending into the superior recess of the lesser sac (open arrows) and a thin rim of enhancing right subphrenic and perihepatic peritoneal tumor (solid arrows). (b) Image through the middle part of the abdomen shows diffuse enhancing carcinomatosis (arrows) involving the anterior peritoneum, omentum, and bowel serosa. (c, d) Images obtained in February 1995. After multiple cycles of adjuvant chemotherapy, the patient was in clinical remission with a normal serum CA-125 level (7 U/mL) and physical examination. (c) Image through the upper part of the abdomen shows minimal residual right subphrenic tumor (arrows). (d) Image through the middle part of the abdomen shows complete resolution of peritoneal enhancement, which is an indication of response to interval chemotherapy. Residual right subphrenic tumor nodules were confirmed at second-look laparotomy. (e, f) Images obtained in September 1996. The patient presented with clinical evidence of recurrence with an elevated serum CA-125 level (890 U/mL). (e) Image through the upper part of the abdomen shows interval increase in the thick rim of enhancing right subphrenic tumor (arrows). (f) Image through the middle part of the abdomen shows interval tumor recurrence (straight arrows), with anterior peritoneal and serosal small-bowel and right colonic tumor. Note the improved bowel distention owing to the use of 2% barium as the oral contrast material.
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Figure 1d. Gadolinium-enhanced breath-hold fast multiplanar spoiled gradient-recalled-echo MR images (140/2.6, 70° flip angle) with fat saturation obtained in a 74-year-old woman with stage III ovarian cancer 10 minutes after intravenous gadolinium-based contrast material injection. (a, b) Images obtained in July 1994. The patient presented with symptoms of primary ovarian carcinoma and a markedly elevated serum CA-125 level (28,000 U/mL). (a) Image through the upper part of the abdomen shows bulky tumor extending into the superior recess of the lesser sac (open arrows) and a thin rim of enhancing right subphrenic and perihepatic peritoneal tumor (solid arrows). (b) Image through the middle part of the abdomen shows diffuse enhancing carcinomatosis (arrows) involving the anterior peritoneum, omentum, and bowel serosa. (c, d) Images obtained in February 1995. After multiple cycles of adjuvant chemotherapy, the patient was in clinical remission with a normal serum CA-125 level (7 U/mL) and physical examination. (c) Image through the upper part of the abdomen shows minimal residual right subphrenic tumor (arrows). (d) Image through the middle part of the abdomen shows complete resolution of peritoneal enhancement, which is an indication of response to interval chemotherapy. Residual right subphrenic tumor nodules were confirmed at second-look laparotomy. (e, f) Images obtained in September 1996. The patient presented with clinical evidence of recurrence with an elevated serum CA-125 level (890 U/mL). (e) Image through the upper part of the abdomen shows interval increase in the thick rim of enhancing right subphrenic tumor (arrows). (f) Image through the middle part of the abdomen shows interval tumor recurrence (straight arrows), with anterior peritoneal and serosal small-bowel and right colonic tumor. Note the improved bowel distention owing to the use of 2% barium as the oral contrast material.
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Figure 1e. Gadolinium-enhanced breath-hold fast multiplanar spoiled gradient-recalled-echo MR images (140/2.6, 70° flip angle) with fat saturation obtained in a 74-year-old woman with stage III ovarian cancer 10 minutes after intravenous gadolinium-based contrast material injection. (a, b) Images obtained in July 1994. The patient presented with symptoms of primary ovarian carcinoma and a markedly elevated serum CA-125 level (28,000 U/mL). (a) Image through the upper part of the abdomen shows bulky tumor extending into the superior recess of the lesser sac (open arrows) and a thin rim of enhancing right subphrenic and perihepatic peritoneal tumor (solid arrows). (b) Image through the middle part of the abdomen shows diffuse enhancing carcinomatosis (arrows) involving the anterior peritoneum, omentum, and bowel serosa. (c, d) Images obtained in February 1995. After multiple cycles of adjuvant chemotherapy, the patient was in clinical remission with a normal serum CA-125 level (7 U/mL) and physical examination. (c) Image through the upper part of the abdomen shows minimal residual right subphrenic tumor (arrows). (d) Image through the middle part of the abdomen shows complete resolution of peritoneal enhancement, which is an indication of response to interval chemotherapy. Residual right subphrenic tumor nodules were confirmed at second-look laparotomy. (e, f) Images obtained in September 1996. The patient presented with clinical evidence of recurrence with an elevated serum CA-125 level (890 U/mL). (e) Image through the upper part of the abdomen shows interval increase in the thick rim of enhancing right subphrenic tumor (arrows). (f) Image through the middle part of the abdomen shows interval tumor recurrence (straight arrows), with anterior peritoneal and serosal small-bowel and right colonic tumor. Note the improved bowel distention owing to the use of 2% barium as the oral contrast material.
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Figure 1f. Gadolinium-enhanced breath-hold fast multiplanar spoiled gradient-recalled-echo MR images (140/2.6, 70° flip angle) with fat saturation obtained in a 74-year-old woman with stage III ovarian cancer 10 minutes after intravenous gadolinium-based contrast material injection. (a, b) Images obtained in July 1994. The patient presented with symptoms of primary ovarian carcinoma and a markedly elevated serum CA-125 level (28,000 U/mL). (a) Image through the upper part of the abdomen shows bulky tumor extending into the superior recess of the lesser sac (open arrows) and a thin rim of enhancing right subphrenic and perihepatic peritoneal tumor (solid arrows). (b) Image through the middle part of the abdomen shows diffuse enhancing carcinomatosis (arrows) involving the anterior peritoneum, omentum, and bowel serosa. (c, d) Images obtained in February 1995. After multiple cycles of adjuvant chemotherapy, the patient was in clinical remission with a normal serum CA-125 level (7 U/mL) and physical examination. (c) Image through the upper part of the abdomen shows minimal residual right subphrenic tumor (arrows). (d) Image through the middle part of the abdomen shows complete resolution of peritoneal enhancement, which is an indication of response to interval chemotherapy. Residual right subphrenic tumor nodules were confirmed at second-look laparotomy. (e, f) Images obtained in September 1996. The patient presented with clinical evidence of recurrence with an elevated serum CA-125 level (890 U/mL). (e) Image through the upper part of the abdomen shows interval increase in the thick rim of enhancing right subphrenic tumor (arrows). (f) Image through the middle part of the abdomen shows interval tumor recurrence (straight arrows), with anterior peritoneal and serosal small-bowel and right colonic tumor. Note the improved bowel distention owing to the use of 2% barium as the oral contrast material.
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The interpretation of a normal MR study was incorrect in five patients, in whom tumor was subsequently confirmed. In two of these patients, the CA-125 level was also falsely normal (<35 U/mL), whereas in three, it correctly indicated the presence of tumor. Among the five patients in whom the MR interpretation was false-negative, the tumor was microscopic in two patients, smaller than 1 cm in one patient, 1–2 cm in one patient, and larger than 2 cm in one patient, who had extraabdominal metastasis.
Patients without Residual or Recurrent Tumor
In the 16 patients who were in complete clinical remission without evidence of tumor for more than 2 years, MR imaging correctly demonstrated no evidence of tumor in 14 patients compared with the CA-125 level, which was normal in 15 patients (Table 1), and the physical examination, which was normal in all 16 patients.
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TABLE 1. Comparison of MR Imaging with CA-125 Level in the Detection of Residual or Recurrent Ovarian Cancer in 43 Patients in Whom the Concurrent or Follow-Up CA-125 Level Was Used as Proof of Disease
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Two false-positive MR image interpretations occurred in two patients who presented with acute small-bowel obstructions. One of these two patients had a concurrently elevated CA-125 level, which returned to normal without therapy and has remained normal for more than 1 year. One false-positive physical examination result was obtained in a patient who has remained in clinical and imaging remission for more than 2 years.
All Patients with Ovarian Cancer
Table 2 summarizes the data on all 69 women, with a comparison of the MR imaging findings with the corresponding CA-125 level and physical examination findings in enabling the prediction of the presence or absence of residual tumor. For detecting patients with residual tumor, MR images had a 91% sensitivity, 87% specificity, 90% accuracy, and 72% negative predictive value. The CA-125 level had a corresponding 53% sensitivity, 94% specificity, 63% accuracy, and 38% negative predictive value. The physical examination had a 26% sensitivity, 94% specificity, 43% accuracy, and 29% negative predictive value. The difference in sensitivity and accuracy between MR imaging and the CA-125 level or physical examination was significant (P <.001), as was the difference between the CA-125 level and physical examination (P <.001) (Fig 1).
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TABLE 2. Comparison of MR Imaging Findings with CA-125 Level and Physical Examination Findings in the Detection of Residual or Recurrent Tumor in 69 Patients with Treated Ovarian Cancer
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Figure 2 graphically depicts the combined performance of MR imaging, CA-125 level, and physical examination in enabling the prediction of the presence or absence of tumor. In 25 patients (36%), all three parameters enabled an accurate prediction of the presence or absence of tumor, whereas in 13 patients (19%), the MR examination result and CA-125 level were correct. In 20 patients (29%), only the MR examination result was correct (Fig 3). In these 20 patients, MR imaging correctly demonstrated tumor, whereas the serum CA-125 level and physical examination result were falsely normal. By comparison, in one patient (1%), the CA-125 level alone was correct in indicating the presence of tumor, whereas the MR imaging and physical examination findings were falsely normal.
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Figure 2. Graph shows the combined performance of MR imaging, the CA-125 level, and the physical examination (PE) in determining tumor presence in treated ovarian cancer.
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Figure 3a. Breath-hold fast multiplanar spoiled gradient-recalled-echo MR images (140/2.6, 70° flip angle) with fat saturation obtained in a 77-year-old woman with treated stage III ovarian cancer 10 minutes following intravenous gadolinium-based contrast material injection. (a, b) Images obtained in February 1994. The patient's CA-125 level was normal (8 U/mL) following adjuvant chemotherapy. Second-look laparotomy revealed no residual tumor. Peritoneal washings were not submitted. (a) Image through the upper part of the abdomen shows residual enhancing right subphrenic tumor (arrows). (b) Image through the middle part of the abdomen shows normal tissue. (c, d) Images obtained in May 1995. The patient's CA-125 level was still normal (20 U/mL). (c) Image through the upper part of the abdomen shows persistent enhancing right subphrenic tumor (arrows), which is more nodular in appearance. (d) Image through the middle part of the abdomen shows a new 2-cm mass (long arrow) anteriorly on the right and an irregular enhancing tumor (short arrow) on the left. (e, f) Images obtained in September 1996. The patient had an elevated CA-125 level (103 U/mL) and presented with clinical evidence of tumor progression. (e) Image through the upper part of the abdomen shows right subphrenic tumor (solid arrows) and new biliary obstruction due to periportal extension (open arrows) of peritoneal tumor. (f) Image through the middle part of the abdomen shows enlargement of the right-sided anterior mass (curved arrow).
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Figure 3b. Breath-hold fast multiplanar spoiled gradient-recalled-echo MR images (140/2.6, 70° flip angle) with fat saturation obtained in a 77-year-old woman with treated stage III ovarian cancer 10 minutes following intravenous gadolinium-based contrast material injection. (a, b) Images obtained in February 1994. The patient's CA-125 level was normal (8 U/mL) following adjuvant chemotherapy. Second-look laparotomy revealed no residual tumor. Peritoneal washings were not submitted. (a) Image through the upper part of the abdomen shows residual enhancing right subphrenic tumor (arrows). (b) Image through the middle part of the abdomen shows normal tissue. (c, d) Images obtained in May 1995. The patient's CA-125 level was still normal (20 U/mL). (c) Image through the upper part of the abdomen shows persistent enhancing right subphrenic tumor (arrows), which is more nodular in appearance. (d) Image through the middle part of the abdomen shows a new 2-cm mass (long arrow) anteriorly on the right and an irregular enhancing tumor (short arrow) on the left. (e, f) Images obtained in September 1996. The patient had an elevated CA-125 level (103 U/mL) and presented with clinical evidence of tumor progression. (e) Image through the upper part of the abdomen shows right subphrenic tumor (solid arrows) and new biliary obstruction due to periportal extension (open arrows) of peritoneal tumor. (f) Image through the middle part of the abdomen shows enlargement of the right-sided anterior mass (curved arrow).
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Figure 3c. Breath-hold fast multiplanar spoiled gradient-recalled-echo MR images (140/2.6, 70° flip angle) with fat saturation obtained in a 77-year-old woman with treated stage III ovarian cancer 10 minutes following intravenous gadolinium-based contrast material injection. (a, b) Images obtained in February 1994. The patient's CA-125 level was normal (8 U/mL) following adjuvant chemotherapy. Second-look laparotomy revealed no residual tumor. Peritoneal washings were not submitted. (a) Image through the upper part of the abdomen shows residual enhancing right subphrenic tumor (arrows). (b) Image through the middle part of the abdomen shows normal tissue. (c, d) Images obtained in May 1995. The patient's CA-125 level was still normal (20 U/mL). (c) Image through the upper part of the abdomen shows persistent enhancing right subphrenic tumor (arrows), which is more nodular in appearance. (d) Image through the middle part of the abdomen shows a new 2-cm mass (long arrow) anteriorly on the right and an irregular enhancing tumor (short arrow) on the left. (e, f) Images obtained in September 1996. The patient had an elevated CA-125 level (103 U/mL) and presented with clinical evidence of tumor progression. (e) Image through the upper part of the abdomen shows right subphrenic tumor (solid arrows) and new biliary obstruction due to periportal extension (open arrows) of peritoneal tumor. (f) Image through the middle part of the abdomen shows enlargement of the right-sided anterior mass (curved arrow).
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Figure 3d. Breath-hold fast multiplanar spoiled gradient-recalled-echo MR images (140/2.6, 70° flip angle) with fat saturation obtained in a 77-year-old woman with treated stage III ovarian cancer 10 minutes following intravenous gadolinium-based contrast material injection. (a, b) Images obtained in February 1994. The patient's CA-125 level was normal (8 U/mL) following adjuvant chemotherapy. Second-look laparotomy revealed no residual tumor. Peritoneal washings were not submitted. (a) Image through the upper part of the abdomen shows residual enhancing right subphrenic tumor (arrows). (b) Image through the middle part of the abdomen shows normal tissue. (c, d) Images obtained in May 1995. The patient's CA-125 level was still normal (20 U/mL). (c) Image through the upper part of the abdomen shows persistent enhancing right subphrenic tumor (arrows), which is more nodular in appearance. (d) Image through the middle part of the abdomen shows a new 2-cm mass (long arrow) anteriorly on the right and an irregular enhancing tumor (short arrow) on the left. (e, f) Images obtained in September 1996. The patient had an elevated CA-125 level (103 U/mL) and presented with clinical evidence of tumor progression. (e) Image through the upper part of the abdomen shows right subphrenic tumor (solid arrows) and new biliary obstruction due to periportal extension (open arrows) of peritoneal tumor. (f) Image through the middle part of the abdomen shows enlargement of the right-sided anterior mass (curved arrow).
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Figure 3e. Breath-hold fast multiplanar spoiled gradient-recalled-echo MR images (140/2.6, 70° flip angle) with fat saturation obtained in a 77-year-old woman with treated stage III ovarian cancer 10 minutes following intravenous gadolinium-based contrast material injection. (a, b) Images obtained in February 1994. The patient's CA-125 level was normal (8 U/mL) following adjuvant chemotherapy. Second-look laparotomy revealed no residual tumor. Peritoneal washings were not submitted. (a) Image through the upper part of the abdomen shows residual enhancing right subphrenic tumor (arrows). (b) Image through the middle part of the abdomen shows normal tissue. (c, d) Images obtained in May 1995. The patient's CA-125 level was still normal (20 U/mL). (c) Image through the upper part of the abdomen shows persistent enhancing right subphrenic tumor (arrows), which is more nodular in appearance. (d) Image through the middle part of the abdomen shows a new 2-cm mass (long arrow) anteriorly on the right and an irregular enhancing tumor (short arrow) on the left. (e, f) Images obtained in September 1996. The patient had an elevated CA-125 level (103 U/mL) and presented with clinical evidence of tumor progression. (e) Image through the upper part of the abdomen shows right subphrenic tumor (solid arrows) and new biliary obstruction due to periportal extension (open arrows) of peritoneal tumor. (f) Image through the middle part of the abdomen shows enlargement of the right-sided anterior mass (curved arrow).
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Figure 3f. Breath-hold fast multiplanar spoiled gradient-recalled-echo MR images (140/2.6, 70° flip angle) with fat saturation obtained in a 77-year-old woman with treated stage III ovarian cancer 10 minutes following intravenous gadolinium-based contrast material injection. (a, b) Images obtained in February 1994. The patient's CA-125 level was normal (8 U/mL) following adjuvant chemotherapy. Second-look laparotomy revealed no residual tumor. Peritoneal washings were not submitted. (a) Image through the upper part of the abdomen shows residual enhancing right subphrenic tumor (arrows). (b) Image through the middle part of the abdomen shows normal tissue. (c, d) Images obtained in May 1995. The patient's CA-125 level was still normal (20 U/mL). (c) Image through the upper part of the abdomen shows persistent enhancing right subphrenic tumor (arrows), which is more nodular in appearance. (d) Image through the middle part of the abdomen shows a new 2-cm mass (long arrow) anteriorly on the right and an irregular enhancing tumor (short arrow) on the left. (e, f) Images obtained in September 1996. The patient had an elevated CA-125 level (103 U/mL) and presented with clinical evidence of tumor progression. (e) Image through the upper part of the abdomen shows right subphrenic tumor (solid arrows) and new biliary obstruction due to periportal extension (open arrows) of peritoneal tumor. (f) Image through the middle part of the abdomen shows enlargement of the right-sided anterior mass (curved arrow).
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Patients in Clinical Remission with Clinically Occult Tumor
Thirty-nine patients were in clinical remission and had a normal CA-125 level and normal physical examination at the time of the MR examination. In 23 (59%) of these 39 patients, residual or recurrent tumor was proved by using laparotomy or follow-up examination. Two of these patients had seronegative epithelial ovarian cancer. Gadolinium-enhanced MR imaging correctly demonstrated residual or recurrent tumor in 20 of the 23 patients (Fig 4), with one false-positive interpretation, for an 87% sensitivity and 89% accuracy when there was no clinical evidence of tumor. In these 23 patients, the time interval between the MR examination and the eventual clinical evidence of tumor ranged between 1 and 15 months (mean, 6.4 months). The size of the tumor detected on the MR images was smaller than 1 cm in 12 patients, 1–2 cm in three patients, and larger than 2 cm in five patients. In the three patients with undetected tumor at MR imaging, the tumor size was microscopic or less than 1 cm in diameter.
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Figure 4a. Breath-hold fast multiplanar spoiled gradient-recalled-echo MR images (140/2.6, 70° flip angle) with fat saturation obtained 10 minutes following intravenous gadolinium injection in a 63-year-old woman 4 years after the initial diagnosis of stage IV ovarian cancer. (a, b) Images obtained in September 1994. The patient's CA- 125 level was normal (12 U/mL), and her physical examination was unremarkable. (a) Coronal image shows a 5-cm cystic posterior subhepatic mass (arrow). (b) Axial image shows an enhancing perisplenic tumor (arrows). (c, d) Images obtained in September 1995. The patient's CA- 125 level was elevated (47 U/mL). (c) Coronal image shows enlarging 8-cm subhepatic mass (arrow) with a mural nodule. (d) Axial image through the upper part of the abdomen shows increasing bulky perisplenic tumor (arrows) and enhancing right subhepatic tumor (arrowheads). (e) Image through the pelvis obtained in September 1995 shows a 2-cm mesenteric mass (arrowhead). The diffuse serosal small-bowel enhancement (straight arrows) represents peritoneal tumor spread. Abnormal enhancement and thickening of the sigmoid colon (curved arrow) is also noted.
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Figure 4b. Breath-hold fast multiplanar spoiled gradient-recalled-echo MR images (140/2.6, 70° flip angle) with fat saturation obtained 10 minutes following intravenous gadolinium injection in a 63-year-old woman 4 years after the initial diagnosis of stage IV ovarian cancer. (a, b) Images obtained in September 1994. The patient's CA- 125 level was normal (12 U/mL), and her physical examination was unremarkable. (a) Coronal image shows a 5-cm cystic posterior subhepatic mass (arrow). (b) Axial image shows an enhancing perisplenic tumor (arrows). (c, d) Images obtained in September 1995. The patient's CA- 125 level was elevated (47 U/mL). (c) Coronal image shows enlarging 8-cm subhepatic mass (arrow) with a mural nodule. (d) Axial image through the upper part of the abdomen shows increasing bulky perisplenic tumor (arrows) and enhancing right subhepatic tumor (arrowheads). (e) Image through the pelvis obtained in September 1995 shows a 2-cm mesenteric mass (arrowhead). The diffuse serosal small-bowel enhancement (straight arrows) represents peritoneal tumor spread. Abnormal enhancement and thickening of the sigmoid colon (curved arrow) is also noted.
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Figure 4c. Breath-hold fast multiplanar spoiled gradient-recalled-echo MR images (140/2.6, 70° flip angle) with fat saturation obtained 10 minutes following intravenous gadolinium injection in a 63-year-old woman 4 years after the initial diagnosis of stage IV ovarian cancer. (a, b) Images obtained in September 1994. The patient's CA- 125 level was normal (12 U/mL), and her physical examination was unremarkable. (a) Coronal image shows a 5-cm cystic posterior subhepatic mass (arrow). (b) Axial image shows an enhancing perisplenic tumor (arrows). (c, d) Images obtained in September 1995. The patient's CA- 125 level was elevated (47 U/mL). (c) Coronal image shows enlarging 8-cm subhepatic mass (arrow) with a mural nodule. (d) Axial image through the upper part of the abdomen shows increasing bulky perisplenic tumor (arrows) and enhancing right subhepatic tumor (arrowheads). (e) Image through the pelvis obtained in September 1995 shows a 2-cm mesenteric mass (arrowhead). The diffuse serosal small-bowel enhancement (straight arrows) represents peritoneal tumor spread. Abnormal enhancement and thickening of the sigmoid colon (curved arrow) is also noted.
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Figure 4d. Breath-hold fast multiplanar spoiled gradient-recalled-echo MR images (140/2.6, 70° flip angle) with fat saturation obtained 10 minutes following intravenous gadolinium injection in a 63-year-old woman 4 years after the initial diagnosis of stage IV ovarian cancer. (a, b) Images obtained in September 1994. The patient's CA- 125 level was normal (12 U/mL), and her physical examination was unremarkable. (a) Coronal image shows a 5-cm cystic posterior subhepatic mass (arrow). (b) Axial image shows an enhancing perisplenic tumor (arrows). (c, d) Images obtained in September 1995. The patient's CA- 125 level was elevated (47 U/mL). (c) Coronal image shows enlarging 8-cm subhepatic mass (arrow) with a mural nodule. (d) Axial image through the upper part of the abdomen shows increasing bulky perisplenic tumor (arrows) and enhancing right subhepatic tumor (arrowheads). (e) Image through the pelvis obtained in September 1995 shows a 2-cm mesenteric mass (arrowhead). The diffuse serosal small-bowel enhancement (straight arrows) represents peritoneal tumor spread. Abnormal enhancement and thickening of the sigmoid colon (curved arrow) is also noted.
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Figure 4e. Breath-hold fast multiplanar spoiled gradient-recalled-echo MR images (140/2.6, 70° flip angle) with fat saturation obtained 10 minutes following intravenous gadolinium injection in a 63-year-old woman 4 years after the initial diagnosis of stage IV ovarian cancer. (a, b) Images obtained in September 1994. The patient's CA- 125 level was normal (12 U/mL), and her physical examination was unremarkable. (a) Coronal image shows a 5-cm cystic posterior subhepatic mass (arrow). (b) Axial image shows an enhancing perisplenic tumor (arrows). (c, d) Images obtained in September 1995. The patient's CA- 125 level was elevated (47 U/mL). (c) Coronal image shows enlarging 8-cm subhepatic mass (arrow) with a mural nodule. (d) Axial image through the upper part of the abdomen shows increasing bulky perisplenic tumor (arrows) and enhancing right subhepatic tumor (arrowheads). (e) Image through the pelvis obtained in September 1995 shows a 2-cm mesenteric mass (arrowhead). The diffuse serosal small-bowel enhancement (straight arrows) represents peritoneal tumor spread. Abnormal enhancement and thickening of the sigmoid colon (curved arrow) is also noted.
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Patients Who Underwent Second-Look Laparotomy
Thirty-four patients also underwent second-look laparotomy to determine the presence or absence of residual tumor. By using clinical outcome as the reference-standard for tumor presence, there was no significant difference between second-look laparotomy and gadolinium-enhanced MR imaging (87% sensitivity, 75% specificity, and 85% accuracy) (P > .05). In this subset of patients, second-look laparotomy and MR imaging were superior to the serum CA-125 level (60%, 100%, and 65%, respectively) (P < .05) for the detection of abdominal and pelvic tumor (Table 3). In two patients, who were in clinical remission, the MR image depicted residual tumor that was not identified at second-look laparotomy. However, the results of follow-up examination within several months revealed recurrent tumor, as was predicted by using the MR examination. In two other patients, surgical reexploration revealed a small-volume, microscopic tumor that was not depicted on the MR image. In one patient, who presented with an acute small-bowel obstruction, MR imaging and surgical findings helped to identify an obstructing mass that was believed to represent recurrent tumor. This patient underwent a partial bowel resection. The operative impression of recurrent tumor and the MR imaging findings both were incorrect; histopathologic evaluation revealed a fibrotic mass without evidence of tumor.
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TABLE 3. Use of Surgical Reassessment as Proof of Residual Tumor in 34 Patients with Ovarian Cancer: Comparison of Surgical Findings, MR Imaging Findings, and CA-125 Level
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DISCUSSION
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At the time of diagnosis, 67% of patients with epithelial ovarian cancer have tumors that have already spread beyond the ovary (1,2). Tumor surface shedding with intraperitoneal dissemination, a landmark of this malignancy, challenges accurate diagnosis and imaging. The extensive area of the peritoneum, omentum, mesentery, and bowel serosa provides a large surface for microscopic tumor seeding. Even at laparotomy, the detection of all tumors is not feasible; up to 50% of patients who have a negative second-look surgery result eventually develop recurrent tumor (7–9). Decreased use of surgical reassessment of ovarian cancer has made it more difficult for oncologists to determine the tumor status after adjuvant chemotherapy.
The goals of reassessment during and after adjuvant chemotherapy include not only determining the presence or absence or tumor but also establishing the volume of residual tumor, its location, and the degree of tumor response to initial therapy (14). Recent developments in consolidation or salvage chemotherapy, including paclitaxel, topotecan, high-dose chemotherapy with hematologic support, and intraperitoneal chemotherapy, have increased the options in treating women with residual or recurrent tumor (2,15). Identifying patients with minimal residual disease is critical, because these women have the best chance for complete clinical response and long-term survival following second-line chemotherapy (14).
Serial measurements of the serum CA-125 level is a routine practice in the management of ovarian cancer. Doubling or halving of the CA-125 level correlates in 87% of patients with tumor progression or regression, respectively. A CA-125 level that remains elevated following chemotherapy is a strong indication of residual tumor, although the tumor marker cannot predict the size of residual disease (16). Conversely, a CA-125 level that falls into the normal range with treatment does not indicate complete response; up to 50% of patients with this response will have occult tumor detected if they undergo laparotomy (4,5). Therefore, determining an appropriate end point to chemotherapy cannot be based on a normal CA-125 level because of the low negative predictive value of this tumor marker (4,5). Using a lower threshold value for an abnormal CA-125 value would result in an increase in sensitivity with a predictable decrease in specificity. In our study group, decreasing the normal CA-125 level from less than 35 U/mL to greater than 25 U/mL would have increased the sensitivity of tumor detection from 53% to 62% and decreased the specificity from 94% to 87%.
Detecting clinically occult tumor is critical in determining appropriate patient treatment. In our study, 23 (59%) of 39 patients in clinical remission had proved residual tumor. In this subset of patients, gadolinium-enhanced MR imaging correctly showed residual or recurrent tumor in 20 of 23 patients. The improved sensitivity of gadolinium-enhanced MR imaging in demonstrating small-volume tumors compared with that of the CA-125 level alone provides our oncologists with information that is critical to patient treatment; the technique provides a more accurate means of monitoring response to adjuvant chemotherapy and detecting recurrence after the initial response. In our experience, gadolinium-enhanced MR imaging often demonstrates residual tumor in patients after adjuvant chemotherapy, which indicates a need for additional treatment (Fig 5). As the results of our study confirmed, a normal CA-125 level is not useful in excluding the presence of residual or recurrent tumor. Similarly, tumor recurrence can be detected by using contrast-enhanced MR imaging prior to an elevation in tumor markers or the development of a palpable tumor. Even with elevated tumor markers, determining the volume and location of residual tumor by using cross-sectional imaging is important in following the response to chemotherapy. Finally, in the 20% of patients with ovarian cancer that does not express CA-125, imaging studies play a critical role in determining the presence or absence of tumor.
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Figure 5a. (a, b) Breath-hold fast multiplanar spoiled gradient-recalled-echo MR images (140/2.6, 70° flip angle) with fat saturation obtained in a 60-year-old woman with stage III ovarian cancer 10 minutes following intravenous gadolinium injection. Following multiple cycles of chemotherapy, the CA-125 level decreased to the normal range (34 U/mL), and the physical examination results were normal. (a) Coronal image shows a large residual mesenteric mass (arrow). (b) Axial image shows ascites (curved arrows), an enhancing subphrenic tumor (long arrows), and a tumor in the left intersegmental fissure (open arrow).
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Figure 5b. (a, b) Breath-hold fast multiplanar spoiled gradient-recalled-echo MR images (140/2.6, 70° flip angle) with fat saturation obtained in a 60-year-old woman with stage III ovarian cancer 10 minutes following intravenous gadolinium injection. Following multiple cycles of chemotherapy, the CA-125 level decreased to the normal range (34 U/mL), and the physical examination results were normal. (a) Coronal image shows a large residual mesenteric mass (arrow). (b) Axial image shows ascites (curved arrows), an enhancing subphrenic tumor (long arrows), and a tumor in the left intersegmental fissure (open arrow).
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Gadolinium-enhanced, fat-suppressed MR images are highly effective in depicting small-volume peritoneal tumors and carcinomatosis (10–13). Marked enhancement of small peritoneal tumors with gadolinium chelates on delayed MR images facilitates the detection of metastases to free peritoneal surfaces and bowel serosa (10–13). Optimizing MR imaging for the demonstration of small peritoneal tumors requires careful attention to detail. Fat suppression with breath-hold imaging reduces the competing high signal of adjacent fat, and imaging during suspended respiration eliminates respiratory artifact. In our experience, fat-suppressed gadolinium chelate–enhanced fast multiplanar spoiled gradient-recalled-echo images are the most sensitive for depicting peritoneal tumors and are clearly superior to nonenhanced T1-weighted and T2-weighted MR images (10,13). The use of a thinner (<10-mm) section thickness combined with surface coil imaging would improve inplane image resolution. Imaging the abdomen and pelvis would require moving the surface coil three times for the pre- and postcontrast images and thereby make this approach logistically difficult and time-consuming.
More recent refinements in this technique include the addition of a negative oral contrast material and the intravenous administration of glucagon to reduce bowel peristalsis (13). The sensitivity of the gradient-echo pulse sequences to motion artifact requires the use of glucagon for adequate evaluation of the large and small bowels. Our current MR imaging protocol includes orally administered dilute 2% barium sulfate. We instruct patients to drink 1,350 mL (ie, three bottles) of this agent, starting 1.0–1.5 hours before the MR examination. By serving as a source of stabilized water, the dilute barium sulfate distends the small intestine and colon and provides negative intraluminal contrast on T1-weighted images. Dilute barium does produce high intraluminal signal on T2-weighted images, and this can produce motion artifact. Administering glucagon intramuscularly or using single-shot rapid acquisition with relaxation enhancement, T2-weighted imaging may help to reduce or eliminate this artifact. Perflubron was used as a negative oral contrast material early in the study, but it is no longer available. Similarly, rectal water can be used to distend the rectum and colon and thereby provide negative intraluminal contrast, which facilitates depiction of enhancing serosal, mural, or adjacent omental tumor implants.
The depiction of serosal tumor requires adequate bowel distention with a negative intraluminal contrast material (23). Collapsed bowel shows marked enhancement with gadolinium-based contrast material and can be difficult to distinguish from tumor. Well-distended normal bowel will show mild and uniform concentric mural enhancement and enhancement of the haustral folds. In our experience, serosal tumor typically produces abnormal mural enhancement, which may be nodular, thickened, eccentric, or concentric. Because serosal tumors manifest on the outside of bowel, typically there is also involvement of the adjacent peritoneum and mesentery. In these cases, confluent, thickened, and enhancing peritoneal and serosal tumors can be identified at fat-suppressed, gadolinium-enhanced MR imaging (Figs 1, 4). Isolated bowel wall thickening and enhancement is a nonspecific finding. Small (<1-cm) individual serosal tumor implants cannot be accurately depicted on MR images. The presence of tumor masses involving the bowel, mesentery, or omentum obviously simplifies image interpretation.
Our tailored MR examination evolved during the course of this study. As such, in patients who underwent imaging early in the study, we did not use fat saturation or oral contrast material, which probably decreased the depiction of small-volume peritoneal and serosal tumors. In our study group, there was no difference in the per-patient sensitivity and accuracy of tumor detection in the 50 patients who received oral contrast material compared with the 19 patients who did not. In both groups, the sensitivity was over 90%. However, the depiction of serosal tumor specifically was not evaluated to obtain these data. In our experience, bowel distention is an important finding in the detection of small serosal tumors (Fig 4).
It is important to acknowledge that enhancement with gadolinium chelates is a nonspecific finding. The sites of peritoneal or bowel inflammation will enhance and can have an appearance that is identical to that of peritoneal tumors on gadolinium-enhanced spoiled gradient-echo images. Enhancement adjacent to the surgical incisions is also a common finding anteriorly in the middle region of the abdomen and pelvis. Also, in the setting of acute bowel obstruction, it is difficult to differentiate intestinal and mesenteric enhancement caused by bowel obstruction from recurrent tumor. It is notable that both of the false-positive MR image interpretations in our study occurred in patients who presented with small-bowel obstruction. We exercise caution in this clinical setting and recommend repeat MR imaging after resolution of symptoms, when possible.
CT scanning has been limited because it provides reduced contrast between the peritoneal tumors and the adjacent soft tissues, with an overall sensitivity of 40%–60% (17–21). While helical CT performed during breath holding eliminates section misregistration, the greater contrast resolution of enhanced MR imaging allows better differentiation between small peritoneal tumors and the adjacent soft tissues and ascites (13). In prior studies (22–24) in which CT and MR images in patients with ovarian cancer were compared, mixed results have been reported. A comparison of gadolinium-enhanced MR imaging with CT scanning (10) indicated that enhanced MR images depicted 81% of individual sites of peritoneal metastases compared with CT scans, which depicted 51% of individual sites. Gadolinium-enhanced MR images depicted 71% of sites with small (<1-cm) tumors compared with CT scans, which depicted 32%. In other studies (22–24), no significant difference between MR images and CT scans in depicting tumor in patients with ovarian cancer was found. These discrepant results reflect differences in MR imaging technique, which varies widely between studies.
The allocation of limited imaging resources in an environment of increasing cost awareness makes it impractical to use multiple imaging examinations in each patient with ovarian cancer. Outcomes analysis will be required to determine the most cost-effective means of reassessing patients with ovarian cancer. While the results of our study indicate that gadolinium-enhanced MR imaging can help detect clinically occult tumors and provide information that is important to clinical management, the question of whether MR imaging affects patient outcome or the length of the disease-free interval was not addressed in this study.
The limitations of this study include the lack of histopathologic proof at the time of each MR examination and CA-125 level determination. In our study, various clinical and surgical reference standards were used to confirm tumor presence; each standard had a different level of proof. For example, although an elevated CA-125 level indicates tumor presence, it provides no localizing information. In all cases, we carefully reviewed the MR images to confirm that the MR examination demonstrated tumor at a site that was in agreement with the results of subsequent laparotomy, physical examination, and follow-up imaging that showed tumor progression. In no case was the MR imaging result alone used as proof of tumor presence. Tumor absence is more difficult to establish. We believe that in view of the high rate of false-negative surgical and laparoscopic findings, the clinical outcome of each patient is the most accurate indication of tumor presence or absence. We accepted a disease-free interval of 2 years or longer as evidence of complete clinical response. Longer clinical follow-up of patients in remission probably would have revealed a larger number of recurrences.
Another limitation of this study stems from the 6-year duration of the longitudinal study. Changes in MR imaging hardware and pulse sequences that could have improved the overall accuracy of MR imaging occurred during the study.
Some degree of selection bias may have occurred in our study. We had no control over when oncologists ordered an MR examination. Early in the study, we typically performed imaging in patients during treatment and when there was clinical evidence of recurrence. More recently, MR imaging has become an integral part of the examination of patients in remission from ovarian cancer. Patients in clinical remission pose the greatest challenge in accurately determining the presence or absence of small-volume tumors. Thirty-nine (56%) of the 69 MR examinations were performed in women who were in clinical remission at the time of the study. If our patient group had included more women who were in clinical remission with microscopic or minimal residual tumor, the sensitivity of MR imaging and the serum CA-125 level would have been lower. Finally, a direct comparison with other imaging studies, including helical CT and immunoscintigraphy can be useful. However, the logistics and expense of performing multiple imaging examinations made this impractical.
In conclusion, in patients who are in clinical remission with a normal CA-125 level and physical examination, an abnormal MR examination is a strong indication of residual or recurrent clinically occult tumor. At our institution, gadolinium-enhanced MR imaging has become the imaging examination of choice in patients with known or suspected peritoneal tumors. Gadolinium-enhanced MR imaging can provide additional clinically important information in patients with ovarian cancer and is more accurate in enabling the prediction of disease status than is the serum CA-125 level alone. The combined information from serum tumor markers and accurate imaging studies allows oncologists to optimize patient diagnosis and treatment.
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Footnotes
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Author contributions: Guarantor of integrity of entire study, R.N.L.; study concepts, R.N.L., F.S.; study design, R.N.L.; definition of intellectual content, R.N.L.; literature research, R.N.L.; clinical studies, R.N.L., F.S., S.Y.T.S., T.A.S., R.M.B., C.G.L., P.M.G.; data acquisition, R.N.L., F.S., S.Y.T.S., T.A.S., R.M.B., C.G.L., P.M.G.; data and statistical analyses, R.N.L.; manuscript preparation, R.N.L.; manuscript editing, R.N.L., F.S.; manuscript review, R.N.L., F.S., S.Y.T.S., T.A.S., R.M.B., C.G.L., P.M.G.
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References
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Abstract
Introduction
