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Annals of Surgical Oncology 8:779-786 (2001)
© 2001 Society of Surgical Oncology

ORIGINAL ARTICLES

A Prospective Study of 2-[18F] Fluoro-2-Deoxy-D-Glucose/Positron Emission Tomography Scan, 99mTc-Labeled Arcitumomab (CEA-Scan), and Blind Second-Look Laparotomy for Detecting Colon Cancer Recurrence in Patients With Increasing Carcinoembryonic Antigen Levels

Steven K. Libutti, MD, H. Richard Alexander, Jr, MD, Peter Choyke, MD, David L. Bartlett, MD, Stephen L. Bacharach, PhD, Millie Whatley, RNMT, Frederic Jousse, MD, William C. Eckelman, PhD, Karen Kranda, RN, Ronald D. Neumann, MD and Jorge A. Carrasquillo, MD

From the Surgery Branch (SKL, HRA, DLB, KK), Center for Cancer Research, National Cancer Institute, Bethesda, Maryland; and the Departments of Diagnostic Radiology (PC), Nuclear Medicine (SLB, MW, FJ, RDN, JAC), and Positron Emission Tomography (WCE), the Warren G. Magnuson Clinical Center, National Institutes of Health, Bethesda, Maryland.

Correspondence: Address correspondence and reprint requests to: Steven K. Libutti, MD, National Institutes of Health/NCI, Building 10, Room 3C428, Bethesda, MD 20892-1502; Fax: 301-402-1788; E-mail: slibutti{at}nih.gov


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: An increasing carcinoembryonic antigen (CEA) level in the absence of disease on imaging studies can present a diagnostic challenge. We evaluated 2-[18F] fluoro-2-deoxy-D-glucose and positron emission tomography (FDG-PET) scan and CEA scan before second-look laparotomy as a means of localizing recurrent colorectal cancer.

Methods: Patients underwent computed tomography scan, bone scan, colonoscopy, and magnetic resonance imaging, and those without evidence of disease or resectable disease in the abdomen had FDG-PET and CEA scans. At second-look laparotomy, a surgeon blinded to the results of the FDG-PET and CEA scans performed an exploration and mapped findings. A second surgeon, with knowledge of the FDG-PET and CEA scans, then explored the patient; all lesions were biopsied or resected for pathology.

Results: In 28 patients explored, disease was found at operation in 26 (94%). Ten had unresectable disease. FDG-PET scans predicted unresectable disease in 90% of patients. CEA scans failed to predict unresectable disease in any patient. In 16 patients found to have resectable disease or disease that could be treated with regional therapy, FDG-PET scan predicted this in 81% and CEA scan in 13%.

Conclusions: FDG-PET scan can predict those patients who would likely benefit from a laparotomy. If the FDG-PET scan indicates resectable disease, laparotomy can be considered. However, if the findings predict unresectable disease or the absence of disease, the patient should pursue systemic therapy or continued observation.

Key Words: Carcinoembryonic antigen • Positron emission tomography • FDG • Colon cancer recurrence • Radioimmunoscintigraphy


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Cancers of the colon and rectum are the second leading cause of cancer death in the United States, with an estimated mortality of 50% and an estimated incidence of 135,400 in 2001.1 Cancer of the colon and rectum are the third and fourth most common sites of malignancy in most Western countries. More than 80% of patients will be resectable with curative intent at the time of presentation, but nearly two thirds of these patients will experience a recurrence.2,3

Early detection and management of recurrent disease has been associated with improved survival, particularly when disease is confined to liver or lung metastases.4–8 Most physicians recommend careful surveillance after resection of the primary tumor, with surveillance consisting of computed tomography (CT) scan, colonoscopy, and serial serum carcinoembryonic antigen (CEA) determinations.9 The value of following serum CEA may be most evident in patients who have increased levels preoperatively that decrease to normal after resection of the primary tumor. The American Society of Clinical Oncology guidelines suggest that repeating CEA measurements every 2 to 3 months after resection may be useful.9 These same guidelines suggest a more targeted approach to CT scans, rather than routinely performing CT for surveillance. Overall, 70% of patients with recurrent disease will demonstrate an increase in the serum CEA.3

The management of patients with recurrent disease that is detected by CT scan or colonoscopy generally follows one of several paradigms based on clinical factors. Patients will either be resectable and proceed to surgery or will be unresectable and go on to further systemic or regional therapies. Those patients without imageable disease in the face of a persistently increasing CEA level present a more challenging problem. Studies have demonstrated that 60% to 90% of patients with an increased serum CEA and the absence of imageable disease by CT scan will have recurrent disease at laparotomy.3,10 Roughly 50% of patients will have resectable disease and may benefit from a 5-year survival rate of as high as 40%.11

A major challenge for clinicians has been to enhance the detection of occult disease in the presence of an increasing serum CEA to identify those patients who would benefit from an exploration and, further, to more accurately localize lesions before surgery. One strategy has been to use radiolabeled antibodies, a technique known as immunoscintigraphy or radioimmunodetection.12,13 Another has been to make use of the ability of 2-[18F] fluoro-2-deoxy-D-glucose (FDG) and positron emission tomography (PET) to localize metabolically active tumor tissues.14–16 FDG is transported through the GLUT glucose transporter and then phosphorylated by hexokinase and metabolically trapped.17 We prospectively evaluated and compared CEA antibody immunoscintigraphy (arcitumomab, CEA-ScanTM; Immunomedics, Inc., Morris Plains, NJ),18–20 FDG-PET scan, and second-look laparotomy for the detection of occult colorectal cancer recurrence in patients with increasing serum CEA levels.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients 18 years of age or older with a history of colorectal cancer and an increasing CEA level >=6 µg/L on two successive tests were screened in the Surgery Branch of the National Cancer Institute (NCI). Eligible patients had to be without evidence of recurrent disease on standard imaging studies (CT, magnetic resonance imaging, bone scan, and colonoscopy) or with evidence of a single site of otherwise resectable disease to participate in this NCI institutional review board (IRB)–approved clinical protocol. Pathology from the primary resection was reviewed for each patient to confirm the original diagnosis of adenocarcinoma of the colon or rectum.

All patients underwent a total colonoscopy, bone scan, CT scan of the chest/abdomen/pelvis, magnetic resonance imaging of the liver, and a chest x-ray. Patients found to have disease outside of the abdomen on any of these screening studies were excluded from the trial. Patients without any evidence of disease in the abdomen on any of the screening studies were placed onto the occult disease arm of the study (arm 1). Patients with evidence of a single site of recurrent or metastatic disease, which was deemed resectable by a consulting surgeon, but for whom additional sites of disease were not known and no imageable disease other than the solitary site of potentially resectable disease was identified, were placed onto the single site of disease arm of the trial (arm 2). Patients with evidence of unresectable disease on screening imaging studies in the abdomen were excluded from the trial. All patients enrolled onto the trial must have had no visible residual disease in the abdomen at the time of their last surgical exploration. All patients had Eastern Cooperative Oncology Group performance status of 0 or 1 and had no medical contraindications to an abdominal exploration.

PET Scanning
FDG was prepared by the method of Hamacher et al.21 Patients fasted for a minimum of 6 hours and were encouraged to drink water before intravenous injection of 20 mCi of FDG. After FDG injections, patients rested quietly for 40 minutes. All patients had a urinary catheter in place to minimize interference of tracer in the bladder with surrounding structures. The patients were imaged from the inguinal region to the nose starting 40 minutes after injection by use of a GE AdvanceTM PET scanner (General Electric Medical Systems, Milwaukee, WI). Ten-minute emission scans were acquired in two-dimensional mode and for attenuation correction. Eight-minute transmission scans were also obtained. Images were acquired in a 256 x 256 matrix, and reconstruction was performed with an iterative ordered-subset expectation maximization algorithm.22 Both attenuation-corrected and nonattenuation-corrected images were reconstructed and reviewed by use of an orthogonal display. In addition, maximal-intensity projection images were also generated, and all images were reviewed at the same session. One reviewer (R.D.N.) read the FDG scans independently of any clinical or radiographic correlation.

CEA Imaging
Patients underwent radioimmunoscintigraphy with 99mTc-labeled arcitumomab (CEA-Scan).18 The 99mTc-labeled CEA kit was labeled according to the manufacturer’s instructions in the package insert. Patients received 30 mCi of CEA-Scan intravenously and underwent imaging 4 hours after injection; a single-photon emission computed tomography (SPECT) study was repeated at approximately 18 hours. As with the FDG scan, all patients had a urinary catheter to minimize interference from the bladder radioactivity. Anterior and posterior whole-body scans, typically acquired for 25 minutes, were performed at 4 hours after tracer administration by use of a dual-headed gamma camera (VertexTM, ADAC laboratories, Inc., Milpitas, CA). After the whole-body scans, two SPECT scans were performed extending from the inguinal region into the cervical region by use of a triple-headed gamma camera (Trionix XLTTM, Trionix Laboratories, Twinsburg, OH). In all cases, a repeat SPECT study of the abdomen and pelvis was performed at 18 hours after tracer administration. SPECT images were acquired in a 128 x 128 matrix over 360° by use of a noncircular orbit with 40 steps at 30 seconds per step, with the low-energy high-resolution collimator. The CEA SPECT scan was reconstructed with a filtered back projection and a Butterworth filter with Nyquist frequency of 1.116. An experienced observer (J.A.C.) who had reviewed the patient’s CT scans read the CEA scans. CEA scans were performed in all patients within 1 day of the FDG-PET scan and within 14 days of the CT scan. The FDG-PET and CEA scan were performed a maximum of 14 days before the patient’s laparotomy.

Surgical Exploration
The results of the CEA scan and the FDG-PET scan were reviewed before surgical exploration by a team of nuclear medicine physicians, radiologists, and surgeons. Three separate physicians blinded to the results of the other studies performed the initial review of the CT, FDG-PET, and CEA scans. Lesions were scored on a scale of 1 to 5: 1, definitively negative; 2, probably negative; 3, equivocal; 4, probably positive; 5, definitively positive. The results of the CEA scan and FDG-PET scan were indicated on a standardized diagram (Fig. 1). If putative disease was detected on the FDG-PET scan or the CEA scan outside of the abdominal cavity, further studies and potentially biopsies were performed to either establish or eliminate the presence of extra-abdominal disease. Patients found to have biopsy-proven extra-abdominal disease did not go on to surgical exploration. All patients without evidence of extra-abdominal disease, regardless of the FDG-PET or CEA scan findings in the abdomen, underwent exploratory laparotomy as follows.



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  		FIG. 1. The anatomical diagram used to indicate location and score of each lesion found on imaging or at laparotomy.

 
One surgeon did not know the results of the CEA scan or FDG-PET scan and was therefore designated the blinded surgeon. The blinded and the unblinded surgeon had the opportunity to review all prior conventional imaging studies, examine the patient, and review the patient’s history and the results of all laboratory tests. The blinded surgeon began the exploration, carefully searching the abdomen and pelvis for any evidence of recurrence. This surgeon also had the ability to perform an intraoperative ultrasound examination to better image the liver. The blinded surgeon then recorded, on a standardized diagram (Fig. 1), the location of any suspicious lesions. A second surgeon then explored the patient. This second surgeon had access to all the same information as the blinded surgeon, with the addition of a careful independent evaluation of the results of the CEA scan and the FDG-PET scan with the nuclear medicine and radiology physicians. With use of these diagrams and the information gathered by the review of the CEA scan and FDG-PET scan, the second surgeon performed a careful abdominal exploration and intraoperative ultrasound of the liver. The second surgeon then indicated on a separate diagram the findings at operation.

At the completion of both surgical explorations, all lesions were resected if possible or biopsied to confirm the presence of recurrent or metastatic disease. All specimens were reviewed by surgical pathology for confirmation. Patients with unresectable disease confined to the liver or carcinomatosis found in the abdomen without visceral spread were considered for other IRB-approved regional therapeutic protocols being performed in the Surgery Branch of the NCI. As was the case with the scoring of the diagram for CEA scan and FDG-PET scan, each lesion found at laparotomy was scored on a scale of 1 to 5.

All patients received standard postoperative care as determined by the type of operation they received. The results of the CEA scan, FDG-PET scan, and blind second-look laparotomy were then compared against the results of the second surgeon’s laparotomy, and the final pathology was determined on the tissues removed. Sensitivity, specificity, positive predictive value, and negative predictive value were determined for each modality.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Thirty patients were found to meet eligibility criteria and underwent an FDG-PET scan and CEA scan. Fifteen patients were enrolled on the occult arm of the trial and 15 patients on the single site of disease arm. Patient demographics are listed in Table 1. Four patients had increased blood glucose at the time of FDG imaging. Two patients were found to have disease outside of the abdomen on their FDG-PET scan; this was subsequently proven by biopsy. These two patients did not undergo an abdominal exploration (Fig. 2). In 28 patients who were explored, disease was found at operation in 26 (94%). FDG-PET scans detected disease in 23 patients, whereas CEA scans detected disease in 4 patients. Figure 3 demonstrates an example of an FDG-PET scan, CEA scan, and CT scan in a patient with a single site of disease thought to be otherwise resectable. Figure 4 demonstrates the results of a CEA scan, FDG-PET scan, and CT scan in a patient on the occult arm of the trial who was found, with advanced imaging and second-look laparotomy, to have disease.


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  		TABLE 1. Patient demographics
 


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  		FIG. 2. 2-[18F] fluoro-2-deoxy-D-glucose and positron emission tomography and computed tomography images of two patients found to have disease outside of the abdomen. These lesions were biopsied and proven to be cancer, and these patients went on to receive systemic chemotherapy and were not explored.

 


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  		FIG. 3. A patient with a single liver lesion, seen clockwise on 2-[18F] fluoro-2-deoxy-D-glucose and positron emission tomography, carcinoembryonic antigen scan, magnetic resonance imaging, and computed tomography scan. This patient had no other site of disease and underwent a liver resection. MRI, magnetic resonance imaging.

 


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  		FIG. 4. A patient on the occult disease arm of the trial who was found to have a lesion in the right retroperitoneum only on 2-[18F] fluoro-2-deoxy-D-glucose and positron emission tomography (FDG-PET) scan. The blind second-look laparotomy results were negative in this patient, as were the results of computed tomography (CT) and carcinoembryonic antigen (CEA) scans. This lesion was resected.

 
On a patient-by-patient basis, FDG-PET scan demonstrated a sensitivity of 89%, a specificity of 50%, a positive predictive value of 96%, and a negative predictive value of 25% (Table 2). CEA scan had a sensitivity of 18%, a specificity of 33%, a positive predictive value of 50%, and a negative predictive value of 10%. Blind second-look laparotomy had a sensitivity of 92%, a specificity of 100%, a positive predictive value of 100%, and a negative predictive value of 50%. In Table 3, a similar calculation is presented on a lesion-by-lesion basis, rather than for each patient, for all 119 lesions detected at surgery in the 28 patients explored. Table 4 illustrates a comparison of the ability of CEA scan, FDG-PET scan, or blind second-look laparotomy to detect recurrent disease in patients with occult versus single-site disease.


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  		TABLE 2. Results by patient (n = 28)
 

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  		TABLE 3. Results by lesion (n = 119)
 

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  		TABLE 4. Occult versus single site
 
Of the 28 patients explored, 10 were found to have unresectable disease. These patients were referred for systemic therapies or experimental protocols. Sixteen patients were found to have resectable disease or disease that could be treated with regional peritoneal- or liver-directed therapy on other NCI-IRB approved protocols. For these 16 patients who received therapy in the form of a resection or regional treatment, CEA levels decreased postoperatively in all 16 patients. Two of the 28 patients explored had negative second-look laparotomies and had a negative CEA scan. One of these patients had a false-positive reading on the FDG-PET scan. These patients were observed with serial standard imaging studies and follow-up FDG-PET scans. One patient has been observed for 4 years and has a continued increase of serum CEA in the range of 7 to 11 µg/L. This patient has still failed to manifest any site of recurrent disease, and all subsequent CT scans and FDG-PET scans have remained negative. The second patient was followed with serial CEA determination and serial imaging studies. Approximately 2 years after the blind second-look laparotomy this patient was found to have a primary lung cancer, which was resected. The patient’s CEA value decreased to normal after this resection.

FDG-PET scan predicted unresectable disease in 90% (9 of 10) of patients who were found to be unresectable at second-look laparotomy. CEA scan failed to predict the presence of unresectable disease in any of the patients that were explored. Of the 16 patients found to have resectable disease (or who were eligible for regional therapy protocols) at second-look laparotomy, FDG-PET scan predicted this in 81% and CEA scan in 13%.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The follow-up of patients after resection of a primary colon or rectal carcinoma varies from clinician to clinician. However, most physicians use serum CEA determination as a simple and reliable means of observing patients to detect the earliest signs of recurrence, in accordance with American Society of Clinical Oncology guidelines.9 During the follow-up period, an increase in the serum CEA level that is persistent often results in a series of imaging studies performed on the patient in an attempt to identify the site and extent of disease. For patients with recurrent disease found in the liver or lung, surgical resection can be performed, with results indicating an improvement in 5-year survival for selected patients.4–8 Although it is unclear whether patients found to have disease in other locations will benefit from either surgery or systemic therapy, such patients may be eligible for clinical protocols that use agents or strategies that have the potential for benefit.23–27

Patients with an increasing serum CEA level without evidence of recurrent disease on imaging studies present a particular challenge to clinicians. The options available to these patients include continued surveillance, blind second-look laparotomy, or initiation of systemic chemotherapy. Each of these options has significant drawbacks.

Continued surveillance can become frustrating for both the clinician and the patient. It is often difficult to resist the temptation to treat the patient when the CEA continues to increase even in the absence of a definitive site of disease. Both the patient and physician often feel helpless in this setting. Although blind second-look laparotomy has been shown to yield findings in a majority of patients,3,28,29 often the disease that is found is not amenable to surgical management. Therefore, patients have undergone a nontherapeutic surgical procedure. Finally, it is often difficult to justify the side effects and limited benefits of systemic chemotherapy in the face of an isolated abnormal laboratory value (increased CEA) without definitive proof of recurrent cancer.

Advanced imaging modalities such as functional imaging with PET and antibody immunoscintigraphy have gained more widespread use in the field of oncology.15,16,30–34 These techniques have the theoretical advantage over standard imaging studies of being more sensitive and specific for neoplastic tissue. PET with FDG has been shown to improve detection of several different malignant histologies, including colon cancer, lung cancer, esophageal cancer, melanoma, and lymphoma.15,16,35 The use of radiolabeled antibodies with specificity against tumor markers has also been shown to increase the detection of a variety of malignant histologies, including colon cancer.33,36–38 This study compared these two approaches, as well as blind second-look laparotomy, for the detection of occult colorectal cancer recurrence.

We chose to study two groups of patients. Our group consisted of patients who were truly in the occult category, that is, without any evidence of disease on standard imaging studies. We also studied patients who were thought to be resectable on standard imaging studies and who had the potential for additional occult disease; this would render a surgical resection less likely to be effective. We used a blinded surgeon model as a means of reproducing what would be the common second-look laparotomy strategy in centers without the ability to obtain the advanced imaging studies. A second surgeon equipped with the knowledge of the advanced imaging studies as well as definitive pathologic examination of all suspicious tissues and close follow-up of the patients postoperatively served as a gold standard for comparison.

We found that FDG-PET was successful preoperatively at predicting those patients who would benefit from an abdominal exploration. FDG-PET accurately predicted unresectable disease in 90% of patients who were found to be unresectable at second-look laparotomy. Furthermore, FDG-PET accurately predicted resectable disease in 81% of the patients found to be resectable at second-look laparotomy. With a patient-by-patient analysis, FDG-PET had a sensitivity of 89% and a specificity of 50%. The specificity of 50% warrants further discussion. Only two patients of our 28 who were explored were found to be free of disease. FDG-PET accurately predicted this in one patient and had a false-positive reading in the other. With only two patients to compare, an accurate calculation of specificity is limited. We did not find CEA-Scan immunoscintigraphy to be helpful preoperatively in predicting either resectable or unresectable disease.

Blind second-look laparotomy detected disease in 26 of 28 patients who were explored. Although this technique proved to be the most successful, not all patients derived a benefit from laparotomy. Therefore, on the basis of these findings we would propose the following recommendations. Patients who are being observed with serum CEA values after resection of a primary colon or rectal cancer, and who are found to have an increasing serum CEA >=to 6 µg/L on two consecutive studies, should undergo CT scans of the chest/abdomen/pelvis and a colonoscopy. If these studies are negative, the patient should undergo an FDG-PET scan. If the FDG-PET scan does not find any evidence of recurrent disease, the patient should be observed with serial CEA determinations and selective repeat imaging at 3- to 6-month intervals. If the FDG-PET scan detects evidence of disease, a determination of resectability should be made and either surgical resection or appropriate systemic therapy recommended, depending on the site and extent of disease found. For patients who are found to have a single site of otherwise resectable disease on standard imaging studies, an FDG-PET scan should be obtained to rule out additional sites of disease. For those patients who are found not to have additional sites of disease on an FDG-PET scan, surgical resection should be recommended. For those patients found to have additional sites of disease on the FDG-PET scan, the enthusiasm for surgical resection should be tempered, and systemic therapies should be considered.

Received for publication March 17, 2001. Accepted for publication July 30, 2001.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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