Journal of Neuro-Oncology 8: 281-287, 1990. © 1990 Kluwer Academic Publishers. Printed in the Netherlands.
Clinical Study
Plasma carcinoembryonic antigen as an indicator of cerebral metastases Elizabeth A. Eden, Julia M. Muggia, Emile M. Hiesiger and Franco M. Muggia
Kaplan Cancer Center, 550 First Avenue, New York, N Y 10016, USA
Key words: carcinoembryonic antigen (CEA), tumor markers, cerebral metastases Abstract
Four patients in whom the plasma CEA reflected the clinical course of intracranial disease are presented. We conclude that a search to explain an elevated CEA should include the central nervous system. In addition, in selected patients with brain metastases the plasma CEA is a helpful indicator of tumor control and of its response to radiation and chemotherapy.
Introduction
Patient # 1 (Fig. 1)
Clinical studies have suggested that elevations of plasma carcinoembryonic antigen (CEA) may reflect the extent of disease in a number of epithelial malignancies. Although abnormalities in CEA have only relative specificity [1], in a patient with known cancer, CEA levels have proven useful in monitoring the clinical course of selected patients with colon, breast, lung, bladder, and occasionally other carcinomas [1-3]. The site of metastasis may influence CEA levels: highest values are usually associated with liver and bone involvement and the lowest levels with primary lesions or metastases most amenable to surgical removal or localized soft-tissue invasion [3]. Based on the evolution in 2 patients, Lokich et al. specifically indicated that correlation with tumor mass does not pertain to lesions in the central nervous system (CNS) [2]. We present here experience with 4 patients in whom plasma CEA levels appeared to reflect the course of intracranial metastastic disease. Serial determinations were obtained during therapeutic assessment. CEA levels were determined in plasma by the radioimmunoassay of Roche Laboratories. Normal values (including 2 standard deviations) are 2.5ng/ml in non smokers and 5.0ng/ml for smokers.
E.W., a 63 year old woman with a moderate cigarette smoking history, was diagnosed as having a poorly differentiated adenocarcinoma of the lung with metastasis to the mediastinum in November 1982. Radiation therapy to the mediastinum and adjacent left lung tumor was given with a complete response. Medical Oncology consultation was sought in February 1983 and baseline tumor markers, blood chemistries, and computerized tomography (CT) scans of chest and abdomen were also obtained. All were unremarkable except for changes in the radiated area and a CEA of 8.7 ng/ml. In June 1983 the patient began to have seizures and multiple brain metastases were discovered by computerized tomography (CT). On her admission for intracranial disease the plasma CEA was 32.1 ng/ ml. Serum chemistries and chest x-ray were unchanged. Plasma CEA levels continued to rise following radiation therapy to brain and a regimen of cisplatin and vinblastine was started in late July. The CEA values steadily declined over the next four months as head CT scans also improved. A head CT scan in February 1984, was near normal while other findings were negative at a time when the CEA was noted to rise again. It continued to rise in March concomitantly to clinical deteriora-
282 E.W.
CASE 1
Ii
100
Seizure In~orovement documented m neurological s t a t u s and scan
o~hea~CT
90-
Clinical
remlslJon
80WBRT
70 -
m
CDDP/VLB
N\\\'g//////////'////////A)///////////////A
E e-
,K
I.U
6050-
L~ 40 A
C 20 10 0 0
1
2
3
4
5
6
7
8
9
10
11
12
Months Fig. 1. Patient EW. Plasma C E A in relation to clinical course and treatment. Abbrev. W B R T : whole brain radiotherapy; C D D P : cisplatin; VLB: vinblastine.
tion. In May 1984 the patient died shortly after detection of carcinomatous meningitis.
Patient # 2 (Fig. 2) L.G., a 65 year old man, also heavy smoker presented with recent onset of an unsteady gait. Upon evaluation, head CT scans revealed multiple metastatic lesions in both hemispheres and in the mid brain. Extensive evaluations including abdominal and chest CT scans, percutaneous fine needle aspiration of bilateral upper lung field infiltrates, laryngoscopy, bronchoscopy anfd thyroid scan were negative. Subsequent attempts to localize a primary malignancy were unsuccessful. He under-
went whole brain radiation therapy (WBRT) from April to June 1982. At this time plasma CEA was 3.7ng/ml, and slightly above normal, consistent with a moderate cigarette smoking habit. A CT scan showed improvement but in August 1982, seizures and headaches were associated with reappearance of the left hemispheric lesion. Surgery was performed with removal of a left parietal mass; microscopically the diagnosis was that of a papillary adenocarcinoma. The patient recovered from craniotomy but a persistent right hemiparesis required extended rehabilitation. Because of neurologic deterioration coupled with new findings on head CT scan and continued normal findings by exams and CT scans elsewhere, cisplatin and vinblastine were begun December 1982 when a plasma
283 L.G.
CASE 2
L!
Crlniotomy
140
JJ
Incrtsle in size Of lesion [J on CT eclm from m o n t h 1211
IO0 ,-,
90 WBRT
8O
CDDP/VI R
FAM
!=
i "/j'////////'//2
•
5O 4O 3O 2O
A,B
10 0
I
0 I
I
I
I
I
I
-
!
I
I
I
I
l
I
I
I
I
I
I
I
I
I
[
I
l
2 3 4 5 6 7 8 9 1011 12 13 1415 1617 18 19 20 2122 23 ~ 25 Months
Fig. 2. PatientLG. PlasmaCEA in relationto clinicalcourseand treatment.Abbrev.WBRT:wholebrainradiotherapy;CDDP: cisplatin;VLB:vinblastine,FAM:Fluorouracil-Adriamycin-Mitomycin.
CEA was 6.2ng/ml. By April 1983 this had decreased to 3.6ng/ml. Head CT scan at that time showed improvement to nearly normal although two residual lesions could be faintly visualized, one of which was in the region of the previous surgery. In July after increasing headaches and a rise in CEA levels, the CT scan showed better visualization of both lesions. In September, both the CEA and the lesions on the CT scan increased further. As it appeared that the chemotherapy was no longer effective a course of 5-Fluorouracil, doxorubicin (Adriamycin) and Mitomycin C (FAM) was started. At the outset of this treatment the plasma CEA was quite elevated at 38.7 ng/ml while abdomen and chest CT and other findings were unchanged. Over the next three to four months the CEA steadily declined and the patient improved as he received chemotherapy. In February 1984 it reversed direction and continued rising on serial de-
terminations. This relentless increase paralleled neurologic deterioration leading to full custodial care by March 1984. By May CEA levels had reached 190ng/ml with the patient becoming totally aphasic. He died on July 8, 1984.
Patient # 3 (Fig. 3) A.B., a 59 year old woman with a heavy smoking habit was diagnosed in November 1982 as having a poorly differentiated adenocarcinoma of the lung with positive hilar lymph nodes. She underwent a right upper lobectomy followed by radiation therapy to the mediastinum. In April 1983, slow onset of a left hemiparesis led to CT scan detection of a mass lesion in the right parietal lobe. The patient was treated with a full course of cranial irradiation during that month, while her chest and other find-
284
A.B. CASE 3 CDDPI VLB
FAM
~/////////////A
170 160 150 140 130 E 120 OI
c
110 lO0
O
Ii
90-
IncreaSe in size of leaoo~ on CT scan II from months 1 and 2 IJ Funct ion=l in~r Ile'eme~ t IIH
8O 70
6O 1
4O F l
1
1
l
1
1
1
1
2
3
4
5
6
7
Months Fig. 3. Patient A B . P l a s m a C E A in relation to clinical course and t r e a t m e n t . A b b r e v . s a m e as Fig. 2.
ings by physical examinations, chest x-ray, CT scans of chest and abdomen and chemistries remained unchanged for the remainder of her course. An abnormally high CEA level of 40.9 ng/ml was recorded in June 1983 which rose precipitously to 156 ng/ml in August of that year. Such change was interpreted as evidence of progression in unknown sites, possibly the brain since persistence of the CT scan lesion was documented. Three courses of cisplatin and vinblastine every three weeks were administered initially with stability of CEA levels but by October 1983 the size of the head CT lesion and the CEA had increased, while the patient was showing signs of functional impairment. A course of FAM was begun, with CEA levels rising transiently and eventually declining at a time when she
improved neurologically to return to paying golf. When deteriotation ensued on February 29, 1984 a craniotomy was performed with total removal of the right parietal tumor. Unfortunately, no postoperative CEA values were measured, until the patient's death in May 1984 as a consequence of a massive pulmonary embolus.
Patient # 4 (Fig. 4) JD, a 62 year old woman with a 20-year history of hypertension was noted to have bilateral T1 breast carcinomas in December 1983. Modified radical mastectomies were carried out and findings included 3 of 20 positive left axillary and 3 of 15 positive
285
J.D. CASE 4 WBRT
7
WBRT
6 5 E ¢-
4'
v
< LLI
3
A
Discovery of right temperoparietal- mass
B
D e m e n t i a ; C N S or b o d y scans: n e g a t i v e for
(9
2
~ _ " ~
metastases
1 I
0
2
,//
I
i
I
I
I
19
21
23
25
27
,,
l
I
,J
29
31
33
Months Fig. 4. Patient JD. Plasma CEA in relation to clinical course and treatment. Abbrev. WBRT: whole brain radiotherapy.
right axillary lymph nodes. Only the left sided tumor was positive for estrogen receptors. She was begun on adjuvant chemotherapy consisting of 14 days oral cyclophosphamide and intravenous fiuorouracil and methotrexate given on the first and eighth day and repeated every 28 days. She completed adjuvant chemotherapy on September 1984 and then was placed on tamoxifen. Plasma CEAs (4.2, 3.6) were considered normal in relation to a prior cigarette smoking habit (1 pack per day). She remained well until January 1986 at which time slurred speech, unsteady gait, and mild left hemiparesis became apparent. The CEA was 4.6 ng/ml while the head CT scan revealed a large enhancing mass lesion with a central lucency in the right posterior temperoparietal region with ventricular compression. Bone scan and x-ray remained normal. Tamoxifen was discontinued and the patient received whole brain radiation to a dose of 30 Gy in 10 fractions over 2 weeks. The course was complicated by a phenytoin rash and steroid psychosis, and CEA levels were not checked. Follow up CT scans in March and June 1986 revealed only residual abnormalities associated with some right ventricular dilatation.
She continued to show neurologic abnormalities, at times associated with marked psychosis and dementia, with the plasma CEA levels becoming abnormal at a level of 6.2. In January 1987 the head CT scan showed further increase in cerebral atrophy; in addition one area was interpreted as showing edema as a result of recurrent tumor. A 1.5 cm nodule was present in the left lung on chest CT scan but no other areas of disease were noted on the abdominal CT, bone scans and serum chemistries. With no other apparent cause for deterioration a second course of radiation to the brain was given. However, no benefit ensued and she expired in April 1987. CEA levels had declined and remained low.
Discussion The clinical usefulness of carcinoembryonic antigen determinations remains controversial. The prognostic significance of this tumor-associated antigen has been studied most extensively in colorectal and breast cancers. In 30% of patients with a gastrointestinal malignancy, a rise in CEA may be
286 the first indication that there has been progression of disease. Sequential measurement of CEA has proved successful in the monitoring of metastatic gastrointestinal cancer and in the detection of recurrent tumor [3]. A 90% correlation has been found between increasing levels of plasma CEA and disease progression of colorectal cancer [4]. A rising CEA level in breast cancer also usually closely correlates with disease progression. Falkson et al. reported that 79% of patients had a simultaneous clinical and CEA change [5]. In 16% of patients disease progression was clinically documented 2-5 months before CEA levels increased and in 5% of patients CEA rose before there was clinical evidence of progression. The value of serial CEA measurements as a tool for monitoring progression of disease in breast cancer was further contested by Loprinzi et al. [6]. In a study evaluating CEA levels and chemotherapeutic regimens in metastatic breast cancer they conclude that CEA levels 'rarely provide a clinically meaningful lead time prior to the appearance of other clinical evidence of disease progression' [6]. By contrast Mughal et al. found plasma CEA in remission to be useful as an indicator of clinical freedom from progression [7]. In addition others have pointed to its usefulness in the follow up of patients with osseous metastases [8]. CEA does not readily cross the intact blood/ brain barrier. Elevated cerebrospinal fluid (CSF) CEA levels occur with leptomeningeal cancer or with brain metastases abutting the ventricular system [3, 9]. In contrast, intraparenchymal metastases do not significantly elevate CSF CEA, since the released CEA presumably is reabsorbed systemically through a locally disrupted blood/brain barrier. A high blood level (-> 100ng/ml), however, will result in a mild elevation of CSF CEA, reflecting a 'spilling over' effect [3]. A study has specifically evaluated the relationship between plasma and CSF CEAs in patients with leptomeningeal cancer. Snitzer et al. report the elevation of both plasma and CSF CEA in a patient with adenocarcinoma of the breast and meningeal carcinomatosis [10]. In that study, treatment directed primarily at the leptomeningeal can-
cer resulted in a decrease in CSF CEA levels with persistence of the plasma CEA elevation. Our current experience suggests that CEA determinations may on occasion reflect the presence of CNS metastases. Each of our four patients had intraparenchymal contrast-enhancing metastases (presumably indicating blood/brain barrier breakdown) without progressive manifestations of systemic disease. In the first two patients, the plasma CEA fall and the improvement in brain metastases were both noted after systemic chemotherapy. In the third patient, who had relapsed after cranial irradiation, persistent CNS manifestations and rising CEA levels occurred during one chemotherapeutic regimen; a modest decline in CEA was followed by neurologic improvement. Although in these three patients plasma CEA changes closely paralleled the status of CNS disease, one cannot exclude that they reflected a concomitant change in undisclosed systemic sites. While this is not a possibility in the fourth patient, who was treated solely with brain irradiation, the changes in plasma CEA were quite modest, and reflect perhaps other factors such as smoking habits. This experience is limited by its retrospective nature and lack of autopsy documentation. Further immunohistochemical studies for CEA or cerebrospinal fluid studies were not done. Nevertheless, based on our experience, we believe an elevated plasma CEA in a neurologically asymptomatic patient free of gross systemic disease warrants a CT scan examination of the brain. Moreover, serial CEA measurements may prove useful in evaluating therapeutic responses of brain metastases. These observations with CEA and other markers should be confirmed by prospective study.
Acknowledgement Peggy Nixdorf's and Dianne Moody's assistance in preparation of the manuscript and figures is gratefully acknowledged. Supported in part by Education Grant # CA 18002 and Cancer Center Core Grant # CA 16087.
287 References 1. Tormey DC, Davis TE, Waalkes TP: Tumor markers. In: Carter SK, Glatstein E, Livingston RB (eds) Principles of Cancer Treatment. McGraw-Hill Inc. 1982, pp 170-177 2. Lokich JJ, Zamcheck N, Lowenstein M: Sequential carcinoembryonic antigen levels in the therapy of metastatic breast cancer. Annals Internal Med 89: 902-906, 1978 3. Wasserstrom WR, Schwartz MK, Fleisher M, Posner JB: Cerebrospinal fluid biochemical markers in central nervous system tumors: A review. Annals of Clinical and Laboratory Science. Vol. 11, No. 3, 23%251, 1981 4. Falkson HC, Vander Watt JJ, Portugal MA, Schoeman HS, Falkson G: Role of plasma carcinoembryonic antigen in evaluating patients with breast cancer treated with adjuvant chemotherapy. Cancer Treat Rep 63(8): 1303-1309, 1979 5. Falkson HC, Van der Watt JJ, Portugal MA, Pitout MJ, Falkson G: Carcinoembryonic antigen in patients with breast cancer. Cancer 42: 1308-1313, 1978 6. Loprinzi CL, Tormey DC, Rasmussen P, Falkson G, Davis TE, Falkson HC, Chang AYC: Prospective evaluation of carcinoembryonic antigen levels and alternating chemo-
7.
8.
9.
10.
therapeutic regimens in metastatic breast cancer. J Clin Oncol 4: 45-56, 1986 Mughal AW, Hortobagyi GN, Fritsche HA, Buzdar AU, Yap HY, Blumenschein GR: Serial plasma carcinoembryonic antigen measurements during treatment of metastatic breast cancer. JAMA 249(14): 1881-1886, 1983 Haagensen DE, Barry WF, McCook TA, Giannola J, Ammirata S, Wells SA: The value of serial plasma levels of carcinoembryonic antigen and gross cyst disease fluid protein in patients with breast carcinoma and osseous metastases. Annals of Surgery 191(5): 59%603, 1980 Klee GG, Tallman RD, Goellner JR, Yanagihara T: Elevation of carcinoembryonic antigen in cerebrospinal fluid among patients with meningeal carcinomatosis. Proc Mayo Clinic 61(1): %13, 1986 Snitzer LS, McKinney EC, Tejada F, Sigel MM, Rosomoff HL, Zubrod CG: Cerebral metastases and carcinoembryonic antigen in CSF. N Engl J Med 293(21), 1975
Address for offprints: F.M. Muggia, USC Norris Cancer Center, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA
Clinical Study
Plasma carcinoembryonic antigen as an indicator of cerebral metastases Elizabeth A. Eden, Julia M. Muggia, Emile M. Hiesiger and Franco M. Muggia
Kaplan Cancer Center, 550 First Avenue, New York, N Y 10016, USA
Key words: carcinoembryonic antigen (CEA), tumor markers, cerebral metastases Abstract
Four patients in whom the plasma CEA reflected the clinical course of intracranial disease are presented. We conclude that a search to explain an elevated CEA should include the central nervous system. In addition, in selected patients with brain metastases the plasma CEA is a helpful indicator of tumor control and of its response to radiation and chemotherapy.
Introduction
Patient # 1 (Fig. 1)
Clinical studies have suggested that elevations of plasma carcinoembryonic antigen (CEA) may reflect the extent of disease in a number of epithelial malignancies. Although abnormalities in CEA have only relative specificity [1], in a patient with known cancer, CEA levels have proven useful in monitoring the clinical course of selected patients with colon, breast, lung, bladder, and occasionally other carcinomas [1-3]. The site of metastasis may influence CEA levels: highest values are usually associated with liver and bone involvement and the lowest levels with primary lesions or metastases most amenable to surgical removal or localized soft-tissue invasion [3]. Based on the evolution in 2 patients, Lokich et al. specifically indicated that correlation with tumor mass does not pertain to lesions in the central nervous system (CNS) [2]. We present here experience with 4 patients in whom plasma CEA levels appeared to reflect the course of intracranial metastastic disease. Serial determinations were obtained during therapeutic assessment. CEA levels were determined in plasma by the radioimmunoassay of Roche Laboratories. Normal values (including 2 standard deviations) are 2.5ng/ml in non smokers and 5.0ng/ml for smokers.
E.W., a 63 year old woman with a moderate cigarette smoking history, was diagnosed as having a poorly differentiated adenocarcinoma of the lung with metastasis to the mediastinum in November 1982. Radiation therapy to the mediastinum and adjacent left lung tumor was given with a complete response. Medical Oncology consultation was sought in February 1983 and baseline tumor markers, blood chemistries, and computerized tomography (CT) scans of chest and abdomen were also obtained. All were unremarkable except for changes in the radiated area and a CEA of 8.7 ng/ml. In June 1983 the patient began to have seizures and multiple brain metastases were discovered by computerized tomography (CT). On her admission for intracranial disease the plasma CEA was 32.1 ng/ ml. Serum chemistries and chest x-ray were unchanged. Plasma CEA levels continued to rise following radiation therapy to brain and a regimen of cisplatin and vinblastine was started in late July. The CEA values steadily declined over the next four months as head CT scans also improved. A head CT scan in February 1984, was near normal while other findings were negative at a time when the CEA was noted to rise again. It continued to rise in March concomitantly to clinical deteriora-
282 E.W.
CASE 1
Ii
100
Seizure In~orovement documented m neurological s t a t u s and scan
o~hea~CT
90-
Clinical
remlslJon
80WBRT
70 -
m
CDDP/VLB
N\\\'g//////////'////////A)///////////////A
E e-
,K
I.U
6050-
L~ 40 A
C 20 10 0 0
1
2
3
4
5
6
7
8
9
10
11
12
Months Fig. 1. Patient EW. Plasma C E A in relation to clinical course and treatment. Abbrev. W B R T : whole brain radiotherapy; C D D P : cisplatin; VLB: vinblastine.
tion. In May 1984 the patient died shortly after detection of carcinomatous meningitis.
Patient # 2 (Fig. 2) L.G., a 65 year old man, also heavy smoker presented with recent onset of an unsteady gait. Upon evaluation, head CT scans revealed multiple metastatic lesions in both hemispheres and in the mid brain. Extensive evaluations including abdominal and chest CT scans, percutaneous fine needle aspiration of bilateral upper lung field infiltrates, laryngoscopy, bronchoscopy anfd thyroid scan were negative. Subsequent attempts to localize a primary malignancy were unsuccessful. He under-
went whole brain radiation therapy (WBRT) from April to June 1982. At this time plasma CEA was 3.7ng/ml, and slightly above normal, consistent with a moderate cigarette smoking habit. A CT scan showed improvement but in August 1982, seizures and headaches were associated with reappearance of the left hemispheric lesion. Surgery was performed with removal of a left parietal mass; microscopically the diagnosis was that of a papillary adenocarcinoma. The patient recovered from craniotomy but a persistent right hemiparesis required extended rehabilitation. Because of neurologic deterioration coupled with new findings on head CT scan and continued normal findings by exams and CT scans elsewhere, cisplatin and vinblastine were begun December 1982 when a plasma
283 L.G.
CASE 2
L!
Crlniotomy
140
JJ
Incrtsle in size Of lesion [J on CT eclm from m o n t h 1211
IO0 ,-,
90 WBRT
8O
CDDP/VI R
FAM
!=
i "/j'////////'//2
•
5O 4O 3O 2O
A,B
10 0
I
0 I
I
I
I
I
I
-
!
I
I
I
I
l
I
I
I
I
I
I
I
I
I
[
I
l
2 3 4 5 6 7 8 9 1011 12 13 1415 1617 18 19 20 2122 23 ~ 25 Months
Fig. 2. PatientLG. PlasmaCEA in relationto clinicalcourseand treatment.Abbrev.WBRT:wholebrainradiotherapy;CDDP: cisplatin;VLB:vinblastine,FAM:Fluorouracil-Adriamycin-Mitomycin.
CEA was 6.2ng/ml. By April 1983 this had decreased to 3.6ng/ml. Head CT scan at that time showed improvement to nearly normal although two residual lesions could be faintly visualized, one of which was in the region of the previous surgery. In July after increasing headaches and a rise in CEA levels, the CT scan showed better visualization of both lesions. In September, both the CEA and the lesions on the CT scan increased further. As it appeared that the chemotherapy was no longer effective a course of 5-Fluorouracil, doxorubicin (Adriamycin) and Mitomycin C (FAM) was started. At the outset of this treatment the plasma CEA was quite elevated at 38.7 ng/ml while abdomen and chest CT and other findings were unchanged. Over the next three to four months the CEA steadily declined and the patient improved as he received chemotherapy. In February 1984 it reversed direction and continued rising on serial de-
terminations. This relentless increase paralleled neurologic deterioration leading to full custodial care by March 1984. By May CEA levels had reached 190ng/ml with the patient becoming totally aphasic. He died on July 8, 1984.
Patient # 3 (Fig. 3) A.B., a 59 year old woman with a heavy smoking habit was diagnosed in November 1982 as having a poorly differentiated adenocarcinoma of the lung with positive hilar lymph nodes. She underwent a right upper lobectomy followed by radiation therapy to the mediastinum. In April 1983, slow onset of a left hemiparesis led to CT scan detection of a mass lesion in the right parietal lobe. The patient was treated with a full course of cranial irradiation during that month, while her chest and other find-
284
A.B. CASE 3 CDDPI VLB
FAM
~/////////////A
170 160 150 140 130 E 120 OI
c
110 lO0
O
Ii
90-
IncreaSe in size of leaoo~ on CT scan II from months 1 and 2 IJ Funct ion=l in~r Ile'eme~ t IIH
8O 70
6O 1
4O F l
1
1
l
1
1
1
1
2
3
4
5
6
7
Months Fig. 3. Patient A B . P l a s m a C E A in relation to clinical course and t r e a t m e n t . A b b r e v . s a m e as Fig. 2.
ings by physical examinations, chest x-ray, CT scans of chest and abdomen and chemistries remained unchanged for the remainder of her course. An abnormally high CEA level of 40.9 ng/ml was recorded in June 1983 which rose precipitously to 156 ng/ml in August of that year. Such change was interpreted as evidence of progression in unknown sites, possibly the brain since persistence of the CT scan lesion was documented. Three courses of cisplatin and vinblastine every three weeks were administered initially with stability of CEA levels but by October 1983 the size of the head CT lesion and the CEA had increased, while the patient was showing signs of functional impairment. A course of FAM was begun, with CEA levels rising transiently and eventually declining at a time when she
improved neurologically to return to paying golf. When deteriotation ensued on February 29, 1984 a craniotomy was performed with total removal of the right parietal tumor. Unfortunately, no postoperative CEA values were measured, until the patient's death in May 1984 as a consequence of a massive pulmonary embolus.
Patient # 4 (Fig. 4) JD, a 62 year old woman with a 20-year history of hypertension was noted to have bilateral T1 breast carcinomas in December 1983. Modified radical mastectomies were carried out and findings included 3 of 20 positive left axillary and 3 of 15 positive
285
J.D. CASE 4 WBRT
7
WBRT
6 5 E ¢-
4'
v
< LLI
3
A
Discovery of right temperoparietal- mass
B
D e m e n t i a ; C N S or b o d y scans: n e g a t i v e for
(9
2
~ _ " ~
metastases
1 I
0
2
,//
I
i
I
I
I
19
21
23
25
27
,,
l
I
,J
29
31
33
Months Fig. 4. Patient JD. Plasma CEA in relation to clinical course and treatment. Abbrev. WBRT: whole brain radiotherapy.
right axillary lymph nodes. Only the left sided tumor was positive for estrogen receptors. She was begun on adjuvant chemotherapy consisting of 14 days oral cyclophosphamide and intravenous fiuorouracil and methotrexate given on the first and eighth day and repeated every 28 days. She completed adjuvant chemotherapy on September 1984 and then was placed on tamoxifen. Plasma CEAs (4.2, 3.6) were considered normal in relation to a prior cigarette smoking habit (1 pack per day). She remained well until January 1986 at which time slurred speech, unsteady gait, and mild left hemiparesis became apparent. The CEA was 4.6 ng/ml while the head CT scan revealed a large enhancing mass lesion with a central lucency in the right posterior temperoparietal region with ventricular compression. Bone scan and x-ray remained normal. Tamoxifen was discontinued and the patient received whole brain radiation to a dose of 30 Gy in 10 fractions over 2 weeks. The course was complicated by a phenytoin rash and steroid psychosis, and CEA levels were not checked. Follow up CT scans in March and June 1986 revealed only residual abnormalities associated with some right ventricular dilatation.
She continued to show neurologic abnormalities, at times associated with marked psychosis and dementia, with the plasma CEA levels becoming abnormal at a level of 6.2. In January 1987 the head CT scan showed further increase in cerebral atrophy; in addition one area was interpreted as showing edema as a result of recurrent tumor. A 1.5 cm nodule was present in the left lung on chest CT scan but no other areas of disease were noted on the abdominal CT, bone scans and serum chemistries. With no other apparent cause for deterioration a second course of radiation to the brain was given. However, no benefit ensued and she expired in April 1987. CEA levels had declined and remained low.
Discussion The clinical usefulness of carcinoembryonic antigen determinations remains controversial. The prognostic significance of this tumor-associated antigen has been studied most extensively in colorectal and breast cancers. In 30% of patients with a gastrointestinal malignancy, a rise in CEA may be
286 the first indication that there has been progression of disease. Sequential measurement of CEA has proved successful in the monitoring of metastatic gastrointestinal cancer and in the detection of recurrent tumor [3]. A 90% correlation has been found between increasing levels of plasma CEA and disease progression of colorectal cancer [4]. A rising CEA level in breast cancer also usually closely correlates with disease progression. Falkson et al. reported that 79% of patients had a simultaneous clinical and CEA change [5]. In 16% of patients disease progression was clinically documented 2-5 months before CEA levels increased and in 5% of patients CEA rose before there was clinical evidence of progression. The value of serial CEA measurements as a tool for monitoring progression of disease in breast cancer was further contested by Loprinzi et al. [6]. In a study evaluating CEA levels and chemotherapeutic regimens in metastatic breast cancer they conclude that CEA levels 'rarely provide a clinically meaningful lead time prior to the appearance of other clinical evidence of disease progression' [6]. By contrast Mughal et al. found plasma CEA in remission to be useful as an indicator of clinical freedom from progression [7]. In addition others have pointed to its usefulness in the follow up of patients with osseous metastases [8]. CEA does not readily cross the intact blood/ brain barrier. Elevated cerebrospinal fluid (CSF) CEA levels occur with leptomeningeal cancer or with brain metastases abutting the ventricular system [3, 9]. In contrast, intraparenchymal metastases do not significantly elevate CSF CEA, since the released CEA presumably is reabsorbed systemically through a locally disrupted blood/brain barrier. A high blood level (-> 100ng/ml), however, will result in a mild elevation of CSF CEA, reflecting a 'spilling over' effect [3]. A study has specifically evaluated the relationship between plasma and CSF CEAs in patients with leptomeningeal cancer. Snitzer et al. report the elevation of both plasma and CSF CEA in a patient with adenocarcinoma of the breast and meningeal carcinomatosis [10]. In that study, treatment directed primarily at the leptomeningeal can-
cer resulted in a decrease in CSF CEA levels with persistence of the plasma CEA elevation. Our current experience suggests that CEA determinations may on occasion reflect the presence of CNS metastases. Each of our four patients had intraparenchymal contrast-enhancing metastases (presumably indicating blood/brain barrier breakdown) without progressive manifestations of systemic disease. In the first two patients, the plasma CEA fall and the improvement in brain metastases were both noted after systemic chemotherapy. In the third patient, who had relapsed after cranial irradiation, persistent CNS manifestations and rising CEA levels occurred during one chemotherapeutic regimen; a modest decline in CEA was followed by neurologic improvement. Although in these three patients plasma CEA changes closely paralleled the status of CNS disease, one cannot exclude that they reflected a concomitant change in undisclosed systemic sites. While this is not a possibility in the fourth patient, who was treated solely with brain irradiation, the changes in plasma CEA were quite modest, and reflect perhaps other factors such as smoking habits. This experience is limited by its retrospective nature and lack of autopsy documentation. Further immunohistochemical studies for CEA or cerebrospinal fluid studies were not done. Nevertheless, based on our experience, we believe an elevated plasma CEA in a neurologically asymptomatic patient free of gross systemic disease warrants a CT scan examination of the brain. Moreover, serial CEA measurements may prove useful in evaluating therapeutic responses of brain metastases. These observations with CEA and other markers should be confirmed by prospective study.
Acknowledgement Peggy Nixdorf's and Dianne Moody's assistance in preparation of the manuscript and figures is gratefully acknowledged. Supported in part by Education Grant # CA 18002 and Cancer Center Core Grant # CA 16087.
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Address for offprints: F.M. Muggia, USC Norris Cancer Center, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA
