- Email: [email protected]
Detection of hepatic metastases from cancer of the breast
Detection of Hepatic Metastases from Cancer of the Breast Paul H. Sugarbaker MD,* Boston, Judith 0. Beard, BA, Boston, David E. Drum, MD, Boston,
Massachusetts
Massachusetts Massachusetts
Appropriate combinations of surgery and chemotherapy have reduced the incidence of recurrent breast cancer [1,2]. In addition, significant remissions of metastatic disease in response to both chemotherapy and ablative endocrine surgery have been described [3,4]. To secure optimal benefit from these therapeutic advances, it is essential that the extent of local disease and metastasis be accurately assessed in each patient. The liver is properly a major focus of such assessment because 35 to 65 per cent of patients with breast primaries have hepatic metastases at &topsy [5]. Moreover, two studies have indicated that responses to endocrine ablation and/or chemotherapy for metastatic breast cancer are reduced when the liver is a major metastatic site [6,7]. Several helpful methods for detecting hepatic metastases are available, but their sensitivity and specificity are less than optimal. This paper presents joint application of the liver scan and carcinoembryonic antigen (CEA) assay as a means for more accurate evaluation of the hepatic status of patients with cancer of the breast.
of alkaline phosphatase (AP) (normal, 16 to 95 IU), aspart& aminotransferase @GOT) (normal, 8 to 33 IU), and lactate dehydrogenase (LDH) (normal, 88 to 196 IU). Assays for plasma CEA were done according to the Hansen method [8] with reagents provided by Roche Laboratories. A test result greater than 2.5 ng/ml was considered abnormal. Liver scintiphotography was performed and evaluated according to criteria previously reported appropriate for breast carcinoma [9]. Scans were considered abnormal when focal defects, heterogeneous distribution of radiocolloid, or hepatomegaly was observed. Characterization of diagnostic accuracy for these tests was based on computation of two parameters for each single test or composite [IO]. The true-positive percentage is the proportion of patients with hepatic metastases whose tests generated abnormal results. The false-positiue percentage is the proportion of patients whose liver was not involved by metastases but whose tests yielded abnormal results. The accuracy was calculated for each of these tests alone and then in various combinations. For a composite to be scored abnormal, both tests that formed the composite had to be abnormal.
Material and Methods Clinical records of fifty-five patients who had sixty-six liver scintiphotos (liver scans) for suspected metastatic breast cancer were reviewed in detail. (Table I.) These patients had a liver scan, liver function tests, and at least one plasma CEA assay obtained in the course of a single evaluation. Hepatic status was documented by one or both of two methods: (1) patients had direct examination of their liver within one month of the scan; or (2) livers once shown to contain metastases were assumed to contain them at any later time of scanning, and livers free of metastases at autopsy or surgery were assumed to be free of such deposits at any prior time. Liver function tests were performed by the Technicon SMAC@ system and comprised assays for serum activity From the Departmentsof Surgeryand Radiology,HarvardMedical School and Peter Bent BrighamHospital,Boston,Massachusetts.This work was supported by NIH grants GM-1561. GM-16674, AA-02668, and CA04486. Reprintrequestsshouldbe addressedto DavidE. Drum, MD, Peter Bent Brigham Hospital, 721 Huntington Avenue, Boston, Massschusetts 02115. Presentedat the Fifty-SeventhAnnualMeetingof the New EnglandSurgical Society, Whitefield,New Hampshire,September 23-26, 1978. * Presentaddress:SurgeryBranch,NationalCancer Instltute,Bethesda, Maryland.
volume 133, April 1977
TABLE
I
Features
of the Patients
Total Number of Patients Stage of disease Initial presentation Recurrence evaluation Extent of disease No other metastases Bone metastases Other metastases On chemotherapy Known alcoholism Deceased Mode of direct liver examination for each scan* Endocrine ablation/inspection Endocrine ablation/biopsy Autopsy Laparoscopy Closed needle biopsy
Studied Hepatic Metastases -__ Present Absent 29 26 3 26
5 21
9 17 16 26 1 22
5 14 15 26 2 12
10
20 0 6 2 0
10 16 0 2
*The number of scans performed for patients with liver metastases was 38; for those without metastases, 28.
531
Sugarbaker. Beard, and Drum
TABLE II
Accuracy of Ancillary Tests for Detection of Liver
Metastases:
Single Percentage
Abnormal
Test
Liver scan AP SGOT LDH CEA (>2.5 ng/ml) CEA (> 1.0 ng/ml)
loo
Results
Tests
Individual
of Abnormal
Tests
With Liver Metastases (truepositives)
No Liver Metastases (falsepositives)
89 71 74 74 .76 95
14 40 31 58 25 43
k 0
2 L
x p
b
0
to
1
0
c
0
00
0
0.1
NEGATIVE LIVER
-
POSITIVE SCAN
Figure 1. AppNcation of the liver scan and CEA assay to detectti of hepatk metastases (0 = patients with liver metastaseq 0 = patients without liver me&stases). CEA values greater than 100 q/ml and values reported as “greater than 20” are drawnas if equal to these numbers for graphkal convenience.
532
Any one of these tests, if abnormal, correctly signaled the presence of hepatic metastases in more than 70 per cent of patients with such deposits. (Table II.) The highest detection sensitivity for a single test was 89 per cent, achieved by the liver scan. Interpretation of liver scan with this degree of sensitivity resulted in a false-positive rate of 14 per cent. AP was quite sensitive to the presence of hepatic metastases with a true-positive incidence of 71 per cent but was nonspecific with a false-positive rate of 40 per cent. SCOT and LDH were similarly sensitive, 74 per cent, with false-positive rates of 31 and 58 per cent, respectively. The CEA assay was more sensitive to the presence of hepatic metastases (76 per cent true-positive) &an AP, and it was also more specific with a 25 per cent false-positive rate. If the arbitrary cutoff point was lowered to a CEA value of 1.0 ng/ml, the CEA sensitivit.y increased to 95 per cent and the false-positive rate increased to 43 per cent. composite
I
Tests
Tests
The composite analyses showed how false-positive results might be minimized by comparing the CEA assay and liver scan. (Figure 1.) For thirty-eight abnormal (positive) liver scans, liver metastases were present thirty-four times. Among the four patients with falsely positive liver scans, none had an elevated CEA. If the diagnosis of hepatic metastases was reserved for patients in whom both liver scan and CEA were abnormal, no false-positive diagnoses would have been made for this very select group of patients. The improved specificity of the liver scan-CEA composite test did not markedly reduce sensitivity. Twenty-eight of thirty-eight abnormal liver scans (74 per cent) occurred in patients with abnormal CEA tests. Joined with a CEA cutoff value of 1.0 ng/ml, the abnormal liver scans would have detected 89 per cent of patients with liver metastases with no false-positive reports.* Seven patients with elevated CEA assays but with normal liver scans did not have liver metastases although they had disseminated breast cancer at other sites. The sites of metastatic disease in these seven patients were bone (3 patients), supraclavicular and mediastinal lymph nodes (2), lung (l), and skin (1). .-. * It should be emphasized that this observed specificity of the CEA value 1.0 ng/ml may arise both from the smalI select sample of patients described here and from use of a plasma blank substraction in computing the assay result [B].
The American Jaurnal of SW-
Breast Cancer
Thus, in this group of patients, the CEA test was elevated in certain patients with breast cancer who did not have liver metastases. The composite evaluation did little to reduce the false negative liver scans. Only one of four patients with hepatic metastases and a normal liver scan had an abnormal CEA (a value of 2.6 ng/ml). Table III shows other composite test results. When the liver scan result was combined with AP, SGOT or LDH, the true-positive rates were 58,71, and 64 per cent, respectively with false-positive values of 8 to 12 per cent. For SGOT and CEA jointly, the results were identical to those of SGOT and liver scan. Other composites were increasingly restrictive, leading to unacceptably low sensitivity. Comments
Both the liver scan and plasma CEA may exhibit diagnostic abnormalities when breast cancer metastases involve the liver. Lunia et al [11] reported that 77 per cent of such patients exhibited focal defects in the liver scan, and more recently a sensitivity of 67 to 87 per cent, depending upon the criteria for image abnormality, has been reported [9]. Accuracy of the liver scan is compromised by the 10 to 30 per cent incidence of false-positive interpretations. The scan would be a far more reliable means of localizing metastatic cancer if the false-positive rates could be reduced. Plasma CEA levels seem potentially useful in this regard, for they are frequently elevated in patients with hepatic metastases from breast cancer. Chu and Nemoto [12] found that fourteen of fifteen patients with hepatic metastases had CEA concentrations above 2.5 ng/ml and that marked elevation of CEA (>25.0 ng/ml) was observed most frequently in patients with hepatic metastases. Alcoholic liver disease also may cause an elevated CEA level [13] as well as a heterogeneous distribution of radiocolloid on liver scan [14]. Therefore some patients with heterogeneous distribution of radiocolloid and abnormal CEA values may not have liver metastases, but CEA values greater than 10 ng/ml are unusual in non-cancer patients [15]. Together with an abnormal liver scan, a CEA value above 10 nglml appears to so greatly increase the likelihood of hepatic metastases as to preclude the need for needle biopsy. A normal or slightly elevated CEA would indicate the need for biopsy. If the changes in liver pathophysiology that cause falsepositive liver scans do not result in CEA elevation, the theoretical basis for the composite proposed here would be sound. Our findings and others [16] support this possibility.
Volume 133, April 1977
TABLE
III
and Hepatic
Metastases
Accuracy of Ancillary Tests for Detection of Liver Metastases: Composite Tests
Abnormal Tests
Percentage Abnormal Tests _____ With Liver No Liver Metastases Metastases (true(falsepositives) positives)
Scan and CEA p2.5
ng/ml) Scan and CEA (> 1.0 ng/ml) Scan and AP Scan and SGOT Scan and LDH AP and CEA (B2.5 ng/ml) SGOT and CEA (>2.5 ng/ml) LDH and CEA (b2.5 ng/ml) AP and SGOT -__
74 89 58 71 64 58 72 58 57
0 0 8 8 12 12 8 20 13
The data from these patients show that composite evaluation of CEA and liver scans can increase the specificity of diagnosis in metastatic liver disease. The liberal criteria employed to evaluate the liver scans in this study yielded a high true-positive rate. It was accompanied by a high false-positive rate because true-positive and false-positive diagnoses vary directly in response to changes in diagnostic criteria [9,10]. Using strict scintigraphic criteria (focal defects only) for diagnosing hepatic metastases in less selected patients with breast cancer yields a truepositive rate of only 67 per cent and a false-positive rate of 9 per cent [9]. The more liberal criteria for positive diagnosis (such as focal defects and heterogeneous distribution of radiocolloid or hepatomegaly) applied to the scans for the patients described here increased the true-positive rate to 89 per cent and the false-positive rate to 14 per cent. Addition of the requirement for an elevated CEA assay eliminated these false-positive rates and maintained a high true-positive rate not attainable with strict interpretive criteria. If the liver scan and CEA assay disagree, other methods should be used to improve diagnostic accuracy. For example, since metastases rarely occur as single or only two focal deposits in the liver [17], patients whose liver scan shows one or two discrete focal defects may profit from ultrasonography to exclude benign cysts [18]. In the past, some reports have expressed concern that the limited reliability of the radiocolloid liver scan severely restricts its benefit for patient management [19,20]. The data reported here indicate that joint application of the liver scan and CEA assay afforded a highly accurate gauge of liver status in this
533
Sugarbaker, Beard, and Drum
selected group of patients. Whether these observations may be extended to patients with other primary tumors awaits further study. In view of both the significant differences in surgical and medical management for patients with and without liver metastases and the ease with which samples for CEA analysis can be obtained at the time of scanning, this investigation lends strong support to the value of composite evaluation of CEA and the liver scan. Summary
The liver scan and CEA assay were employed as a composite to increase the accuracy with which hepatic metastases from breast cancer may be detected. The number of false-positive interpretations was markedly reduced in this selected groups of patients. Other combinations of tests were examined and found less effective. In view of the potential benefits found in this study, it appears worthwhile to extend the principles applied here to other groups of patients at different stages of this disease and with other primary tumors. Acknowledgment:
We wish to thank Doctors Menelaos Aliapoulios and Norman Zamcheck for their review of this manuscript, and the technical staff of the Mallory Gastrointestinal Laboratory who performed the CEA assays. References 1. Fisher 6. Carbone P, Economou SG, et al: L-phenylanine mustard (L-PAM) in the management of primary breast cancer: a report of early findings. N Engl J A&d 292: 117. 1975. 2. Bonadonna G, Brusamolino E, Valagussa P, et al: Combination chemotherapy as an adjuvant treatment in operable breast cancer. N Enol J Med 294: 405. 1976. 3. Carter SK: Sin& and combination nonhormonal chemotheraov .in breast cancer. Cancer 30: 1543, 1972. 4. Moore FD, Van Devanter SB, Boyden CM, Lokich J, Wilson RE: Adrenalectomy with chemotherapy in the treatment of advanced breast cancer: objective and subjective response rates, duration and quality of life. Surgery 76: 376, 1974. 5. Haagensen CD: Diseases of the Breast. WB Saunders, Philadelphia, 1971, p 426. 6. Wilson RE, Piro AJ, Aliapoulios M, Moore FD: Treatment of metastatic breast cancer with a combination of adrenalectomy and 5-fluorouracil: progress report. Cancer 26: 962, 1971. 7. Canellos GP, DeVita VT, Gold GL, Chabner BA, Schein PS, Young RC: Combination chemotherapy for advanced breast cancer: response and effect on survival. Ann intern AM 64: 369. 1976. 6. Kupchik HZ, Zamcheck N, Saravis CA: lmmunochemical studies of carcinoembryonic antigens: methodologic considerations and some clinical implications. J Nat/Cancer lnst 51: 1741,1973. 9. Drum DE, Beard JO: Scintigraphic criteria for hepatic metastases from cancer of the colon and breast. J Nucl Med 17: 677, 1976.
534
10. McNeil BJ, Ad&t&n SJ: Determining the value of diagnostic and screening tests. J Nucl Med 17: 439. 1976. 11. Lunia S, Patthasarathy KL, Bakshi S. et al: An evaluation of Tc-sulfur colloid liver scintiscans and their usefulness in metastatic workup: a review of 1,424 studies. J Nucl Med 16: 62, 1975. 12. Chu TM, Nemoto T: Evaluation of carcinoembryonic antigen inhumanmammarycarcinoma. JNaflCancerfnsf51: 1119, 1973. 13. Moore T, Dhar P, Zamcheck N, et al: Carcinoembryonic antigen(s) in liver disease. I. Clinical and morphological studies. Gastroenterology 63: 66, 1972. 14. Drum DE: Liver scintigraphic features associated with chronic alcoholism. Manuscript submitted for publication. 15. Ashman LK, Ludbrook J, Marshall VR: Probabilistic application of plasma carcinoembryonic antigen assay in cancer patients. Brit A&d J 26: 721, 1975. 16. McCartney WH, Hoffer PB: Carcinoembryonic antigen assay in hepatic metastases detection. JAMA 236: 1023, 1976. 17. Ozarda A, Pickren J: The topographic distribution of liver metastases: its relation to surgical and isotope diagnosis. J NUT/ M&3: 149, 1962. 16. Taylor KJW, Carpenter DA, Hill CR, McCready VI? Gray scale ultrasound imaging. Radiology 119: 415, 1976. 19. Rosenthal S, Kaufman S: The liver scan in rnetastatic disease. Arch Surg 106: 656, 1973. 20. Kilgore ES, Calabretta AM, Weidner WA, Graham WP: The accuracy of liver scanning in the detection of metastatic disease. J Surg Oncol7: 351. 1975.
Discussion Menelaos Aliapoulios (Boston, MA): Once again the program selection committee and the Peter Bent Brigham Hospital have come up with a significant contribution to the clinical evaluation of the most common malignancy in females, namely breast cancer. These data are corroborated by similar findings by McCartney and Hoffer at the University of Chicago. The dilemma in the evaluation of the breast cancer patient is to determine whether the disease is localized or systemic when recurrence occurs and to judge response to therapy. The employment of the “noninvasive” methods described in this paper is a valuable tool in detecting metastatic breast cancer, but it will not exclude other traditional diagnostic maneuvers. In the case of a woman who has had a mastectomv and in whom you are considering additional therapy, the next step is clearly a giant step, namely whether or not to commit the patient to additive therapy in the form of chemotherapy or ablutiue therapy in the form of adrenalectomy. Obviously, an immunologic assay based on an antigen isolated from the primary breast cancer would improve the specificity of making that determination. There are studies currently underway in that regard utilizing polyamines and nucleotides, but until such studies become clinically available it seems to me that at the present time clinic2 judgment plus this combination of liver scan and CEA are very valuable contributions to our evaluation of patients with this problem. Are the authors willing to embark on the next giant step of additive or ablative therapy in breast cancer on the basis of scan and CEA studies alone? Also, how frequently would you suggest that we apply these studies in following our patients with breast cancer?
The American Journal ol Surgery
Breast Cancer and Hepatic Metastases
Claude E. Welch (Boston, MA): I have enjoyed this paper very much though I do have some questions that probably are unanswerable at the present time. Undoubtedly very shortly the total body scanner will be the optimum diagnostic tool to determine whether or not metastatic disease is present in the liver. This raises the question of how many diagnostic tests should be carried out before a presumably operable cancer of the breast is removed. Should we obtain a xerogram, a thermogram, a metastatic series, a bone scan, and a total body scan? How many of these are really cost-effective? Furthermore, if defects are shown in the liver, can we be content that they represent metastatic disease, or could they possibly represent congential liver cysts? For example, if defects are discovered in the liver, it is quite conceivable that before intensive chemotherapy is started, an absolute cytologic diagnosis should be established of metastatic disease. If a diagnostic laparotomy has to be carried out in addition, we could occupy ourselves with an enormous number of diagnostic tests before we come to grips with the potentially curable procedure, namely the removal of the carcinoma. My only point is that we may forget about curative therapy in the midst of all of our diagnostic measures and possibly even fail to remove a tumor that can be cured because of supposed metastatic disease. I am not sure that it is necessary for Doctor Sugarbaker even to comment on this philosophical consideration. Benjamin A. Barnes (Boston, MA): I enjoyed this presentation very much and I think it stresses an important point about the probabilistic nature of the diagnostic process. This attempt to assign values of false-positives, false-negatives, and so on of tests is extremely important. It gives us an idea as to how many tests have to be done and how many have to be combined to achieve a certain probability of obtaining a diagnosis. This might answer the question Doctor Welch raised, because we have to reduce by tests the probability of disease to some reasonably low level. This is not one in a million chances, but it perhaps should be one in a hundred or one in a thousand; and pursuing diagnostic measures until you reduce the chances of a disease to a ridiculously low incidence is impractical. We have to decide in advance to what degree we wish to examine a patient so we can say there’s no disease here with one chance in a hundred or one in a thousand of being wrong. That’s the conceptual issue that I think will help straighten out our thinking. Your slide showed that there were no false-positives. But, of course, in fact there will be some false-positives
voluma 193, April 1977
when you pursue it a little further. I thought perhaps from the figures you gave in your paper that might be about 5 per cent. Paul H. Sugarbaker (closing): Doctor Aliapoulios’ first question concerned the adequacy of liver scan plus CEA without biopsy confirmation to establish a diagnosis of recurrent breast cancer. I think tissue proof is required before embarking on chemotherapy or endocrine ablative surgery, because of the significant associated morbidity and mortality. Even with multiple filling defects on liver scan, I would obtain biopsy proof of hepatic recurrence. Laparoscopy and directed needle biopsy of the liver would be the most reliable way to obtain this information. Perhaps exceptions to the necessity of biopsy proof are multiple metastases seen on chest roentgenogram or bone survey. Doctor Aliapoulios’ second question regarded the frequency with which one might employ the CEA test to detect recurrence after a patient undergoes a mastectomy for primary cancer. Chu and Nemoto (JNutl Cancerlnst 51: 1119, 1973) found little correlation of disease recurrence or response to palliative therapy with serial CEA levels. I think the usefulness of serial CEA assays to screen patients with a history of primary breast cancer for clinically nonapparent recurrent disease deserves more study. On the other hand, the patient population who have in the past had colorectal cancer usually show a progressive increase in serial CEA assays before disease recurrence is apparent clinically. This allows more knowledgeable patient management, but because there are at present no good remedies for disseminated colorectal cancer, this may not improve or prolong survival. Currently, several groups are exploring the possibility of using second look surgery or early aggressive chemotherapy in patients with resected colorectal cancer who have progressively rising CEA titers. Doctor Welch’s question concerned medical economic aspects of liver scanning and CEA assays. I agree there is nothing worse than an expensive test that gives inaccurate or even confusing information. We have tried to improve an expensive test, the liver scan, by coupling it with the CEA assay. We have not reduced the cost of the examination, but perhaps we have improved the quality of the information obtained. Doctor Barnes’ comments are very well taken. When one uses a composite test, inaccuracies are reduced but not eliminated. I am sure the false-positive percentage for our liver scan-CEA composite is not 0 per cent as found with these early data.
535
Massachusetts
Massachusetts Massachusetts
Appropriate combinations of surgery and chemotherapy have reduced the incidence of recurrent breast cancer [1,2]. In addition, significant remissions of metastatic disease in response to both chemotherapy and ablative endocrine surgery have been described [3,4]. To secure optimal benefit from these therapeutic advances, it is essential that the extent of local disease and metastasis be accurately assessed in each patient. The liver is properly a major focus of such assessment because 35 to 65 per cent of patients with breast primaries have hepatic metastases at &topsy [5]. Moreover, two studies have indicated that responses to endocrine ablation and/or chemotherapy for metastatic breast cancer are reduced when the liver is a major metastatic site [6,7]. Several helpful methods for detecting hepatic metastases are available, but their sensitivity and specificity are less than optimal. This paper presents joint application of the liver scan and carcinoembryonic antigen (CEA) assay as a means for more accurate evaluation of the hepatic status of patients with cancer of the breast.
of alkaline phosphatase (AP) (normal, 16 to 95 IU), aspart& aminotransferase @GOT) (normal, 8 to 33 IU), and lactate dehydrogenase (LDH) (normal, 88 to 196 IU). Assays for plasma CEA were done according to the Hansen method [8] with reagents provided by Roche Laboratories. A test result greater than 2.5 ng/ml was considered abnormal. Liver scintiphotography was performed and evaluated according to criteria previously reported appropriate for breast carcinoma [9]. Scans were considered abnormal when focal defects, heterogeneous distribution of radiocolloid, or hepatomegaly was observed. Characterization of diagnostic accuracy for these tests was based on computation of two parameters for each single test or composite [IO]. The true-positive percentage is the proportion of patients with hepatic metastases whose tests generated abnormal results. The false-positiue percentage is the proportion of patients whose liver was not involved by metastases but whose tests yielded abnormal results. The accuracy was calculated for each of these tests alone and then in various combinations. For a composite to be scored abnormal, both tests that formed the composite had to be abnormal.
Material and Methods Clinical records of fifty-five patients who had sixty-six liver scintiphotos (liver scans) for suspected metastatic breast cancer were reviewed in detail. (Table I.) These patients had a liver scan, liver function tests, and at least one plasma CEA assay obtained in the course of a single evaluation. Hepatic status was documented by one or both of two methods: (1) patients had direct examination of their liver within one month of the scan; or (2) livers once shown to contain metastases were assumed to contain them at any later time of scanning, and livers free of metastases at autopsy or surgery were assumed to be free of such deposits at any prior time. Liver function tests were performed by the Technicon SMAC@ system and comprised assays for serum activity From the Departmentsof Surgeryand Radiology,HarvardMedical School and Peter Bent BrighamHospital,Boston,Massachusetts.This work was supported by NIH grants GM-1561. GM-16674, AA-02668, and CA04486. Reprintrequestsshouldbe addressedto DavidE. Drum, MD, Peter Bent Brigham Hospital, 721 Huntington Avenue, Boston, Massschusetts 02115. Presentedat the Fifty-SeventhAnnualMeetingof the New EnglandSurgical Society, Whitefield,New Hampshire,September 23-26, 1978. * Presentaddress:SurgeryBranch,NationalCancer Instltute,Bethesda, Maryland.
volume 133, April 1977
TABLE
I
Features
of the Patients
Total Number of Patients Stage of disease Initial presentation Recurrence evaluation Extent of disease No other metastases Bone metastases Other metastases On chemotherapy Known alcoholism Deceased Mode of direct liver examination for each scan* Endocrine ablation/inspection Endocrine ablation/biopsy Autopsy Laparoscopy Closed needle biopsy
Studied Hepatic Metastases -__ Present Absent 29 26 3 26
5 21
9 17 16 26 1 22
5 14 15 26 2 12
10
20 0 6 2 0
10 16 0 2
*The number of scans performed for patients with liver metastases was 38; for those without metastases, 28.
531
Sugarbaker. Beard, and Drum
TABLE II
Accuracy of Ancillary Tests for Detection of Liver
Metastases:
Single Percentage
Abnormal
Test
Liver scan AP SGOT LDH CEA (>2.5 ng/ml) CEA (> 1.0 ng/ml)
loo
Results
Tests
Individual
of Abnormal
Tests
With Liver Metastases (truepositives)
No Liver Metastases (falsepositives)
89 71 74 74 .76 95
14 40 31 58 25 43
k 0
2 L
x p
b
0
to
1
0
c
0
00
0
0.1
NEGATIVE LIVER
-
POSITIVE SCAN
Figure 1. AppNcation of the liver scan and CEA assay to detectti of hepatk metastases (0 = patients with liver metastaseq 0 = patients without liver me&stases). CEA values greater than 100 q/ml and values reported as “greater than 20” are drawnas if equal to these numbers for graphkal convenience.
532
Any one of these tests, if abnormal, correctly signaled the presence of hepatic metastases in more than 70 per cent of patients with such deposits. (Table II.) The highest detection sensitivity for a single test was 89 per cent, achieved by the liver scan. Interpretation of liver scan with this degree of sensitivity resulted in a false-positive rate of 14 per cent. AP was quite sensitive to the presence of hepatic metastases with a true-positive incidence of 71 per cent but was nonspecific with a false-positive rate of 40 per cent. SCOT and LDH were similarly sensitive, 74 per cent, with false-positive rates of 31 and 58 per cent, respectively. The CEA assay was more sensitive to the presence of hepatic metastases (76 per cent true-positive) &an AP, and it was also more specific with a 25 per cent false-positive rate. If the arbitrary cutoff point was lowered to a CEA value of 1.0 ng/ml, the CEA sensitivit.y increased to 95 per cent and the false-positive rate increased to 43 per cent. composite
I
Tests
Tests
The composite analyses showed how false-positive results might be minimized by comparing the CEA assay and liver scan. (Figure 1.) For thirty-eight abnormal (positive) liver scans, liver metastases were present thirty-four times. Among the four patients with falsely positive liver scans, none had an elevated CEA. If the diagnosis of hepatic metastases was reserved for patients in whom both liver scan and CEA were abnormal, no false-positive diagnoses would have been made for this very select group of patients. The improved specificity of the liver scan-CEA composite test did not markedly reduce sensitivity. Twenty-eight of thirty-eight abnormal liver scans (74 per cent) occurred in patients with abnormal CEA tests. Joined with a CEA cutoff value of 1.0 ng/ml, the abnormal liver scans would have detected 89 per cent of patients with liver metastases with no false-positive reports.* Seven patients with elevated CEA assays but with normal liver scans did not have liver metastases although they had disseminated breast cancer at other sites. The sites of metastatic disease in these seven patients were bone (3 patients), supraclavicular and mediastinal lymph nodes (2), lung (l), and skin (1). .-. * It should be emphasized that this observed specificity of the CEA value 1.0 ng/ml may arise both from the smalI select sample of patients described here and from use of a plasma blank substraction in computing the assay result [B].
The American Jaurnal of SW-
Breast Cancer
Thus, in this group of patients, the CEA test was elevated in certain patients with breast cancer who did not have liver metastases. The composite evaluation did little to reduce the false negative liver scans. Only one of four patients with hepatic metastases and a normal liver scan had an abnormal CEA (a value of 2.6 ng/ml). Table III shows other composite test results. When the liver scan result was combined with AP, SGOT or LDH, the true-positive rates were 58,71, and 64 per cent, respectively with false-positive values of 8 to 12 per cent. For SGOT and CEA jointly, the results were identical to those of SGOT and liver scan. Other composites were increasingly restrictive, leading to unacceptably low sensitivity. Comments
Both the liver scan and plasma CEA may exhibit diagnostic abnormalities when breast cancer metastases involve the liver. Lunia et al [11] reported that 77 per cent of such patients exhibited focal defects in the liver scan, and more recently a sensitivity of 67 to 87 per cent, depending upon the criteria for image abnormality, has been reported [9]. Accuracy of the liver scan is compromised by the 10 to 30 per cent incidence of false-positive interpretations. The scan would be a far more reliable means of localizing metastatic cancer if the false-positive rates could be reduced. Plasma CEA levels seem potentially useful in this regard, for they are frequently elevated in patients with hepatic metastases from breast cancer. Chu and Nemoto [12] found that fourteen of fifteen patients with hepatic metastases had CEA concentrations above 2.5 ng/ml and that marked elevation of CEA (>25.0 ng/ml) was observed most frequently in patients with hepatic metastases. Alcoholic liver disease also may cause an elevated CEA level [13] as well as a heterogeneous distribution of radiocolloid on liver scan [14]. Therefore some patients with heterogeneous distribution of radiocolloid and abnormal CEA values may not have liver metastases, but CEA values greater than 10 ng/ml are unusual in non-cancer patients [15]. Together with an abnormal liver scan, a CEA value above 10 nglml appears to so greatly increase the likelihood of hepatic metastases as to preclude the need for needle biopsy. A normal or slightly elevated CEA would indicate the need for biopsy. If the changes in liver pathophysiology that cause falsepositive liver scans do not result in CEA elevation, the theoretical basis for the composite proposed here would be sound. Our findings and others [16] support this possibility.
Volume 133, April 1977
TABLE
III
and Hepatic
Metastases
Accuracy of Ancillary Tests for Detection of Liver Metastases: Composite Tests
Abnormal Tests
Percentage Abnormal Tests _____ With Liver No Liver Metastases Metastases (true(falsepositives) positives)
Scan and CEA p2.5
ng/ml) Scan and CEA (> 1.0 ng/ml) Scan and AP Scan and SGOT Scan and LDH AP and CEA (B2.5 ng/ml) SGOT and CEA (>2.5 ng/ml) LDH and CEA (b2.5 ng/ml) AP and SGOT -__
74 89 58 71 64 58 72 58 57
0 0 8 8 12 12 8 20 13
The data from these patients show that composite evaluation of CEA and liver scans can increase the specificity of diagnosis in metastatic liver disease. The liberal criteria employed to evaluate the liver scans in this study yielded a high true-positive rate. It was accompanied by a high false-positive rate because true-positive and false-positive diagnoses vary directly in response to changes in diagnostic criteria [9,10]. Using strict scintigraphic criteria (focal defects only) for diagnosing hepatic metastases in less selected patients with breast cancer yields a truepositive rate of only 67 per cent and a false-positive rate of 9 per cent [9]. The more liberal criteria for positive diagnosis (such as focal defects and heterogeneous distribution of radiocolloid or hepatomegaly) applied to the scans for the patients described here increased the true-positive rate to 89 per cent and the false-positive rate to 14 per cent. Addition of the requirement for an elevated CEA assay eliminated these false-positive rates and maintained a high true-positive rate not attainable with strict interpretive criteria. If the liver scan and CEA assay disagree, other methods should be used to improve diagnostic accuracy. For example, since metastases rarely occur as single or only two focal deposits in the liver [17], patients whose liver scan shows one or two discrete focal defects may profit from ultrasonography to exclude benign cysts [18]. In the past, some reports have expressed concern that the limited reliability of the radiocolloid liver scan severely restricts its benefit for patient management [19,20]. The data reported here indicate that joint application of the liver scan and CEA assay afforded a highly accurate gauge of liver status in this
533
Sugarbaker, Beard, and Drum
selected group of patients. Whether these observations may be extended to patients with other primary tumors awaits further study. In view of both the significant differences in surgical and medical management for patients with and without liver metastases and the ease with which samples for CEA analysis can be obtained at the time of scanning, this investigation lends strong support to the value of composite evaluation of CEA and the liver scan. Summary
The liver scan and CEA assay were employed as a composite to increase the accuracy with which hepatic metastases from breast cancer may be detected. The number of false-positive interpretations was markedly reduced in this selected groups of patients. Other combinations of tests were examined and found less effective. In view of the potential benefits found in this study, it appears worthwhile to extend the principles applied here to other groups of patients at different stages of this disease and with other primary tumors. Acknowledgment:
We wish to thank Doctors Menelaos Aliapoulios and Norman Zamcheck for their review of this manuscript, and the technical staff of the Mallory Gastrointestinal Laboratory who performed the CEA assays. References 1. Fisher 6. Carbone P, Economou SG, et al: L-phenylanine mustard (L-PAM) in the management of primary breast cancer: a report of early findings. N Engl J A&d 292: 117. 1975. 2. Bonadonna G, Brusamolino E, Valagussa P, et al: Combination chemotherapy as an adjuvant treatment in operable breast cancer. N Enol J Med 294: 405. 1976. 3. Carter SK: Sin& and combination nonhormonal chemotheraov .in breast cancer. Cancer 30: 1543, 1972. 4. Moore FD, Van Devanter SB, Boyden CM, Lokich J, Wilson RE: Adrenalectomy with chemotherapy in the treatment of advanced breast cancer: objective and subjective response rates, duration and quality of life. Surgery 76: 376, 1974. 5. Haagensen CD: Diseases of the Breast. WB Saunders, Philadelphia, 1971, p 426. 6. Wilson RE, Piro AJ, Aliapoulios M, Moore FD: Treatment of metastatic breast cancer with a combination of adrenalectomy and 5-fluorouracil: progress report. Cancer 26: 962, 1971. 7. Canellos GP, DeVita VT, Gold GL, Chabner BA, Schein PS, Young RC: Combination chemotherapy for advanced breast cancer: response and effect on survival. Ann intern AM 64: 369. 1976. 6. Kupchik HZ, Zamcheck N, Saravis CA: lmmunochemical studies of carcinoembryonic antigens: methodologic considerations and some clinical implications. J Nat/Cancer lnst 51: 1741,1973. 9. Drum DE, Beard JO: Scintigraphic criteria for hepatic metastases from cancer of the colon and breast. J Nucl Med 17: 677, 1976.
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10. McNeil BJ, Ad&t&n SJ: Determining the value of diagnostic and screening tests. J Nucl Med 17: 439. 1976. 11. Lunia S, Patthasarathy KL, Bakshi S. et al: An evaluation of Tc-sulfur colloid liver scintiscans and their usefulness in metastatic workup: a review of 1,424 studies. J Nucl Med 16: 62, 1975. 12. Chu TM, Nemoto T: Evaluation of carcinoembryonic antigen inhumanmammarycarcinoma. JNaflCancerfnsf51: 1119, 1973. 13. Moore T, Dhar P, Zamcheck N, et al: Carcinoembryonic antigen(s) in liver disease. I. Clinical and morphological studies. Gastroenterology 63: 66, 1972. 14. Drum DE: Liver scintigraphic features associated with chronic alcoholism. Manuscript submitted for publication. 15. Ashman LK, Ludbrook J, Marshall VR: Probabilistic application of plasma carcinoembryonic antigen assay in cancer patients. Brit A&d J 26: 721, 1975. 16. McCartney WH, Hoffer PB: Carcinoembryonic antigen assay in hepatic metastases detection. JAMA 236: 1023, 1976. 17. Ozarda A, Pickren J: The topographic distribution of liver metastases: its relation to surgical and isotope diagnosis. J NUT/ M&3: 149, 1962. 16. Taylor KJW, Carpenter DA, Hill CR, McCready VI? Gray scale ultrasound imaging. Radiology 119: 415, 1976. 19. Rosenthal S, Kaufman S: The liver scan in rnetastatic disease. Arch Surg 106: 656, 1973. 20. Kilgore ES, Calabretta AM, Weidner WA, Graham WP: The accuracy of liver scanning in the detection of metastatic disease. J Surg Oncol7: 351. 1975.
Discussion Menelaos Aliapoulios (Boston, MA): Once again the program selection committee and the Peter Bent Brigham Hospital have come up with a significant contribution to the clinical evaluation of the most common malignancy in females, namely breast cancer. These data are corroborated by similar findings by McCartney and Hoffer at the University of Chicago. The dilemma in the evaluation of the breast cancer patient is to determine whether the disease is localized or systemic when recurrence occurs and to judge response to therapy. The employment of the “noninvasive” methods described in this paper is a valuable tool in detecting metastatic breast cancer, but it will not exclude other traditional diagnostic maneuvers. In the case of a woman who has had a mastectomv and in whom you are considering additional therapy, the next step is clearly a giant step, namely whether or not to commit the patient to additive therapy in the form of chemotherapy or ablutiue therapy in the form of adrenalectomy. Obviously, an immunologic assay based on an antigen isolated from the primary breast cancer would improve the specificity of making that determination. There are studies currently underway in that regard utilizing polyamines and nucleotides, but until such studies become clinically available it seems to me that at the present time clinic2 judgment plus this combination of liver scan and CEA are very valuable contributions to our evaluation of patients with this problem. Are the authors willing to embark on the next giant step of additive or ablative therapy in breast cancer on the basis of scan and CEA studies alone? Also, how frequently would you suggest that we apply these studies in following our patients with breast cancer?
The American Journal ol Surgery
Breast Cancer and Hepatic Metastases
Claude E. Welch (Boston, MA): I have enjoyed this paper very much though I do have some questions that probably are unanswerable at the present time. Undoubtedly very shortly the total body scanner will be the optimum diagnostic tool to determine whether or not metastatic disease is present in the liver. This raises the question of how many diagnostic tests should be carried out before a presumably operable cancer of the breast is removed. Should we obtain a xerogram, a thermogram, a metastatic series, a bone scan, and a total body scan? How many of these are really cost-effective? Furthermore, if defects are shown in the liver, can we be content that they represent metastatic disease, or could they possibly represent congential liver cysts? For example, if defects are discovered in the liver, it is quite conceivable that before intensive chemotherapy is started, an absolute cytologic diagnosis should be established of metastatic disease. If a diagnostic laparotomy has to be carried out in addition, we could occupy ourselves with an enormous number of diagnostic tests before we come to grips with the potentially curable procedure, namely the removal of the carcinoma. My only point is that we may forget about curative therapy in the midst of all of our diagnostic measures and possibly even fail to remove a tumor that can be cured because of supposed metastatic disease. I am not sure that it is necessary for Doctor Sugarbaker even to comment on this philosophical consideration. Benjamin A. Barnes (Boston, MA): I enjoyed this presentation very much and I think it stresses an important point about the probabilistic nature of the diagnostic process. This attempt to assign values of false-positives, false-negatives, and so on of tests is extremely important. It gives us an idea as to how many tests have to be done and how many have to be combined to achieve a certain probability of obtaining a diagnosis. This might answer the question Doctor Welch raised, because we have to reduce by tests the probability of disease to some reasonably low level. This is not one in a million chances, but it perhaps should be one in a hundred or one in a thousand; and pursuing diagnostic measures until you reduce the chances of a disease to a ridiculously low incidence is impractical. We have to decide in advance to what degree we wish to examine a patient so we can say there’s no disease here with one chance in a hundred or one in a thousand of being wrong. That’s the conceptual issue that I think will help straighten out our thinking. Your slide showed that there were no false-positives. But, of course, in fact there will be some false-positives
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when you pursue it a little further. I thought perhaps from the figures you gave in your paper that might be about 5 per cent. Paul H. Sugarbaker (closing): Doctor Aliapoulios’ first question concerned the adequacy of liver scan plus CEA without biopsy confirmation to establish a diagnosis of recurrent breast cancer. I think tissue proof is required before embarking on chemotherapy or endocrine ablative surgery, because of the significant associated morbidity and mortality. Even with multiple filling defects on liver scan, I would obtain biopsy proof of hepatic recurrence. Laparoscopy and directed needle biopsy of the liver would be the most reliable way to obtain this information. Perhaps exceptions to the necessity of biopsy proof are multiple metastases seen on chest roentgenogram or bone survey. Doctor Aliapoulios’ second question regarded the frequency with which one might employ the CEA test to detect recurrence after a patient undergoes a mastectomy for primary cancer. Chu and Nemoto (JNutl Cancerlnst 51: 1119, 1973) found little correlation of disease recurrence or response to palliative therapy with serial CEA levels. I think the usefulness of serial CEA assays to screen patients with a history of primary breast cancer for clinically nonapparent recurrent disease deserves more study. On the other hand, the patient population who have in the past had colorectal cancer usually show a progressive increase in serial CEA assays before disease recurrence is apparent clinically. This allows more knowledgeable patient management, but because there are at present no good remedies for disseminated colorectal cancer, this may not improve or prolong survival. Currently, several groups are exploring the possibility of using second look surgery or early aggressive chemotherapy in patients with resected colorectal cancer who have progressively rising CEA titers. Doctor Welch’s question concerned medical economic aspects of liver scanning and CEA assays. I agree there is nothing worse than an expensive test that gives inaccurate or even confusing information. We have tried to improve an expensive test, the liver scan, by coupling it with the CEA assay. We have not reduced the cost of the examination, but perhaps we have improved the quality of the information obtained. Doctor Barnes’ comments are very well taken. When one uses a composite test, inaccuracies are reduced but not eliminated. I am sure the false-positive percentage for our liver scan-CEA composite is not 0 per cent as found with these early data.
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