J o u r n a l o f Surgical O n c o l o g y 9:257-265 (1977)
Carcinoembryonic Antigen in Osteosarcoma ........................................................................................... ........................................................................................... ENGRACIO P. CORTES, M.D., T. MING CHU, Ph.D., JAW J. WANG, M.D., DOUGLAS HOLYOKE, M.D., H. JAMES WALLACE, M.D. and G. P. MURPHY, M.D. Plasma carcinoembryonic antigen (CEA) assay was done in 30 patients with osteosarcoma. CEA was found positive (> 2.5 ng/ml) in 17 of 21 patients who had active evidence of disease and negative (< 2.5 ng/ml) in all 9 patients who were in complete remission resulting from previous amputation or chemotherapy. Serial CEA determinations demonstrated a fall to normal in 7 of 9 patients following successful surgery or chemotherapy and a rise and fall (fluctuation) of levels in 8 patients who had tumor progression while on chemotherapy. Clinical recurrence of disease in two instances preceded or coincided with CEA elevation. The CEA assay in osteosarcoma although nonspecific could be used as an inportant adjunct to experienced clinical judgment, periodic x-ray examination, and laboratory study to prognosticate the course of osteosarcoma during therapy. The interpretation of a rising or falling CEA titer alone, however, must be made with caution.
........................................................................................... ........................................................................................... Key words: osteosarcoma, carcinoembryonic antigen, tumor marker
INTRODUCTION The 5-year survival rate of osteogenic sarcoma is approximately 20%, regardless of primary therapy (surgery, radiotherapy, or combination of the two) (1,2). The median time from primary diagnosis t o pulmonary metastases is 8.5 months (3). This suggests that subclinical metastases occur in at least 80% of the cases prior to or at the time of radical primary therapy, giving rise to the nearly universal poor survival rate. Cytotoxic agents such as adriamycin and high-dose methotrexate followed with citrovorum factor rescue have been shown t o be of value in metastatic osteosarcoma in
From Roswell Park Memorial Institute, New York State Department of Health and the State University of New York at Buffalo Presented in part at the 64th Annual Meeting of the American Association for Cancer Research, April 11-13, 1973, Atlantic City, New Jersey. Engracio P. Cortes is now physician-in-charge, Oncology Service, Department of Medicine, Long Island Jewish Medical Center, Queens Hospital Center Affiliation, 82-68 164th Street, Jamaica, NY 11432. Address reprint requests to him there.
@ 1977 A l a n R. Liss, Inc., 150 F i f t h Avenue, New York, NY 10011
Cortes et al.
approximately 40% of the cases (4, 5). Furthermore, preliminary results suggest that the administration of either of these anticancer agents as an adjunct of primary surgical amputation seems to delay the occurrence of pulmonary metastases and prolong survival of the patients (6-8). Roentgenologic examination in osteogenic sarcoma can easily miss a metastatic lesion t o the lungs or elsewhere if it is less than l c m in diameter. Any new tests capable of detecting osteosarcoma activity at a subclinical level and of following the course of the osterosarcoma would therefore be of significant value diagnostically, therapeutically, and prognostically. Carcinoembryonic antigen (CEA) was originally discovered in malignant and fetal digestive tissue by Gold and Freedman (9). It is a glycoprotein antigen in human cancer of the colon. Elevated carcinoembryonic antigen determinations have been found not only in colon carcinoma, but also in nongastrointestinal malignancy and nonmalignant disorders, such as alcholic liver cirrhosis, pancreatitis, ulcerative colitis, regional ileitis, and even in chronic obstructive lung disease and in some heavy cigarette smokers (10). Preliminary studies from this laboratory showed that CEA was also elevated in osteosarcoma (1 1). To update these data, we are reporting the results of carcinoembryonic antigen study of 30 osteosarcoma patients t o assess 1) the usefulness of plasma CEA in the diagnosis of osteosarcoma at its various stages; 2) the prognostic value of CEA before and during therapy, such as surgical amputation of the primary lesion, resection, and/or chemotherapy in metastatic lesions; and 3) the relationship of CEA to other serum enzymes, such as alkaline phosphatase, lactic acid dehydrogenase (LDH) and serum glutamic-oxaloacetic acid transaminase (SGOT).
MATERIALS AND METHODS hitial CEA determinations were done in 30 patients with histologically proven osteogenic sarcoma referred to Roswell Park Memorial Institute. The method of plasma CEA radioimmunoassay used was that of Hansen et a1 (12). The concurrent control population consisted of 357 normal subjects from the plasmapheresis program in our institute. These donors were periodically examined and all were in a state of good health. All determinations were carried out in duplicate. Individuals from the control population had levels between 0 and 2.5 ng/ml. The value of 2.5 chosen as the limit between negative and positive results is the same as that reported by others (13-1 5). The extent of osteogenic sarcoma was carefully defined by clinical measurement, roentgenologic study, and biochemical examination. In previously diagnosed cases, periodic blood samples for CEA were drawn on admission or during clinic visits; in newly diagnosed cases, the samples were obtained prior to and after surgery or chemotherapy. Of the 30 osteosarcoma patients, 9 had their disease in complete remission from prior surgery or chemotherapy (no evidence of disease). Twelve had solitary lesions, either primary or metastatic, and 9 had multiple lesions, either primary or metastatic. Of the 30 patients 15 had three or more CEA determinations at least 1 month apart following surgery or chemotherapy. Simultaneous determination of serum alkaline phosphatase, LDH, and SGOT using the Technicon SMA 12/60 were done in 4 2 , 4 0 , and 40 instances, respectively, out of 113 CEA assays.
CEA in Osteosarcoma
RESULTS Figure 1 illustrates the distribution of the initial CEA in 30 osteosarcoma patients in relation t o their stages of presentation. Carcinoembryonic antigen levels greater than 2.5 ng/ml were seen in none of 9 patients with no evidence of disease, 10 of 12 (84%)in the presence of a solitary lesion either primary or metastatic, and 8 of 9 (89%)in multiple osteosarcoma lesions. While the CEA levels were higher in the presence of clinically evident osteogenic sarcoma than in those patients who were in complete remission (no evidence of disease), no significant difference in the CEA levels between patients with solitary and patients with multiple lesions were noted. Of the three patients who had normal initial CEA despite evident osteosarcoma, all had CEA elevations on subsequent followup determinations. Table I shows the changes of elevated CEA in 15 osteosarcoma patients undergoing various forms of therapy ( 2 patients were evaluated twice because of two different treatments on two different occasions). Of the seven patients undergoing either amputation of m
L ................... MULTIPLE
0 NO EVIDENCE OF DISEASE
P SOLITARY IDOR METASTATIC LESION
Fig. 1. CEA levels in relation to various stages of osteosarcoma in 30 patients.
TABLE I. Changes of Elevated CEA Following Various Forms of Treatment in Osteosarcoma
Form of therapy
Primary amputation Resection of lung lesion Chemotherapy
5 2 10 -
Response (case no.) CR CR PR Prog
CEA after Rx Dec
(2) (2) (8)
1 2 0
0 0 0 6
1 1 0 2
Abbreviations: CR - complete remission; PR - partial remission; Prog - progression; Dec - decrease to normal; Inc - increase; Fluc - fluctuation (a rise and fall of CEA titer).
Cortes et al.
their primary lesions or resection of metastatic lesions, the elevated CEA levels became normal in five and fluctuated in two (rise and fall to normal in CEA readings) despite no apparent disease recurrence. The persistent elevations of CEA in two patients who had undergone surgical removal of their tumors were paralleled by the appearance of metastatic lesions. Two of 10 patients achieved objective tumor reduction (> 50%)following chemotherapy. The drop of CEA t o normal was noted even before complete disappearance of the osteosarcoma lesions. The resulting complete remission in one of these patients, however, was accompaned by a CEA rise (10.8 nglml) 2 weeks after discontinuation of chemotherapy. There was no residual tumor or metastatic lesion found on extensive work-up including chest tomogram, bone scan, and even biopsy at the site of the previously incomplete resection of the primary lesion. The patient remained free of disease 6 months after the occurrence of CEA rise. Of the eight patients whose metastatic lesions progressed while on chemotherapy, six had a further rise of their CEA, while in two, fluctuating CEA levels were noted before persistent elevation occurred prior to the patients' demise. Figure 2 illustrates the CEA responses in three patients treated by amputation of '01
Period In Weeks Fig. 2. Serial CEA determinations following surgical amputation (designated by the arrows) of primary osteosarcoma lesion.
CEA in Osteosarcoma
AXlLlARV AOENOPATHY RECURRENT L U N G METS
Period in Months Fig. 3. Serial CEA determinations in a 13-year-old boy who relapsed after surgical amputation of primary lesion and resection of metastatic lesion.
the primary lesions. Two of these three patients had a CEA rise a week after surgery. After amputation and adjunctive chemotherapy, one patient had a drop of his CEA (Fig. 3) to normal; The development of lung metastases was accompained by a rise of CEA. Resection of his metastatic lesion resulted in a second fall of CEA followed again by a rising level with the reappearance of new lesion. The patient in Fig. 4 had a fall of CEA paralleling a decrease in tumor volume during chemotherapy. The CEA level, however, remained normal with the subsequent increase of tumor size. Resection of the metastatic lung lesion resulted in a rise of CEA 1 week after surgery and was followed by fluctuation in the level of the assay. Extensive clinical work-up failed t o reveal any apparent osteosarcoma lesion. The patient, meanwhile, continued t o do well, free of disease 15 months after thoractomy. Her CEA levels had finally become normal on the last three determinations. Figure 5 presents the CEA determinations of a patient who had inoperable osteosarcoma and failed t o respond t o chemotherapy. His CEA and alkaline phosphatase levels kept on fluctuating during the course of therapy. The transient drop of his CEA seemed t o be influenced by the initiation of chemotherapy and radiotherapy. The distribution of serum enzymes levels in relation t o CEA assays is shown in Figure 6. The mean value of alkaline phosphatase activity was significantly higher (p < 0.05) in the group of patients with CEA over 2.5 than in the group with CEA less than 2.5 ng/ml; 414 k 85 SE vs 147 f 40 SE. No significant difference, however, was noted in the mean values of LDH and SGOT levels in relation to positive or negative CEA readings. Although alkaline phosphatase was elevated in 87%of CEA levels > 2.5 and in 35% of samples with CEA levels < 2.5 ng/ml, there was so much overlap of the alkaline phosphatase values that no direct correlation could be made between the elevation of the enzyme activity and the CEA positivity.
- 50 COMPLETE TUMOR
... ... . . '.#"
HIGH DOSE MTX + CF
....._0 . "
ALK P'TASE CEA
. .....* ...
PERIOD IN MONTHS Fig. 5. Serial CEA determinations in a 16-year-old boy whose osteosarcoma lesions did not respond to various forms of therapy.
CEA in Osteosarcoma
- 200 -3 EE 100
”:..... .............. .....$. € A
.............. .....n ......
H . . .
e 2 . 5 -2.5
CEA CIA -2.5
Fig. 6. Levels of various serum enzymes in relation to CEA positivity (< 2.5). Normal values: alkaline phosphatase, 30-85; LDH, 50-225, SGOT, 5-40. Solid horizontal line across various enzyme levels signifies the mean, broken horizontal line shows upper limits of normal enzyme values.
DISCUSSION The elevation of carcinoembryonic antigen in osteogenic sarcoma in this series is further confirmation of the nonspecificity of the assay. The data reported by various investigators showing the correlation of CEA levels with the clinical activity of colon or lung carcinoma (16-18) also hold true in osteosarcoma. In the present series it is shown that those patients with apparent disease have CEA levels over 2.5 ng/ml compared t o those patients in complete remission, where none have a positive assay. Furthermore, serial CEA determinations seem t o be an important prognostic tool in determining the effectiveness of therapy. An occasional unexplained CEA spike in some of our cases, however, was misleading and it did not always indicate that the disease had recurred or progressed. In most instances, however, the progression or relapse of osteosarcoma preceded and/or coincided with CEA elevation. The normalization of CEA in the presence of clinically evident residual osteosarcoma following successful chemotherapy suggests that small foci of tumor can occur without a rise of CEA assay. The significance of CEA rise immediately following surgical amputation in three primary lesions and resection of metastatic lesion in one patient is intriguing. Fortunately,
Cortes e t al.
the CEA rise did not reflect incomplete tumor removal or development of new lesions, for these patients continued to remain free of disease for more than 3 months after surgery and their succeeding serial CEA levels dropped down t o normal. Speculation can be made that surgical manipulation of the tumor and the surrounding area could release more tumor-related antigens into circulation. During the healing process of the surgical wound, regenerating cells may produce antigens that cross-react with anti-CEA serum, giving rise to a transient elevated CEA value. This concept, however, needs t o be proven. In conclusion, although CEA levels correlate well with osteosarcoma activity and response to therapy, the assay is not disease-specific. An occasional elevation of CEA in the absence of clinical disease and its normal level in the presence of minimal lesion is disturbing at this time. The failure of CEA t o rise just prior to the development of evident metastatic lesion does not improve the accuracy in detecting subclinical osteosarcoma activity. Carcinoembryonic assay alone cannot be relied upon in assessing the patient. A CEA rise should be interpreted with caution but it can be an important adjunct t o (but not a substitute for) experienced clinical judgment, periodic x-ray examination, and laboratory study in following the course of osteosarcoma patients during therapy.
ACKNOWLEDGMENTS This investigation was supported in part by Hoffman-La Roche, Inc., and the Na National Cancer Institute. We thank Miss N. Allein and Mr. R. Kajdasz for technical assistance and Dr. Edward Meilman for critical evaluation of the manuscript.
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