Medical and Pediatric Oncology 7: 351-359 (1979)
Hepatic Toxicity of Adjuvant Chemotherapy for Carcinoma of the Breast William P. Vaughan, MD, Patti M. Wilcox, RN, CANP, Phillip 0.Alderson, M D, David S. Ettinger, MD, and Martin D. Abeloff, M D The Johns Hopkins Oncology Onter (W.P. V., P.M.W., D.S.E., M.D.A.)and Department of Radiology, Division of Nuclear Medicine (P.O.A.), The Johns Hopkins University School of Medicine, Baltimore
Four patients developed abnormal liver function tests and focal defects on liver scan while receiving cyclosphosphamide, methotrexate and 5-fluorouracil as adjuvant chemotherapy following mastectomy for breast cancer. Liver biopsies showed severe focal inflammation. The biopsy findings and the subsequent clinical course of the patients strongly suggest that these abnormalities were due to hepatic toxicity of the chemotherapy and not metastic breast cancer. A review of serial liver function tests performed on 24 patients in that chemotherapy program revealed that four out of eight patients with elevated alkaline phosphatase prior to therapy developed early metastatic cancer. Elevated alkaline phosphatase occurring during chemotherapy on the other hand was quite common but more likely due to hepatic toxicity of the drugs. The development of abnormal liver function tests even in association with focal defects on liver scan is not sufficient to diagnose metastatic breast cancer in patients receiving adjuvant chemotherapy. Key words: methotrexate, CMF,hepatic toxicity, adjuvant chemotherapy, breast cancer
INTRODUCTION
Following mastectomy for breast cancer, administration of cytotoxic chemotherapy to women at high risk for the development of metastatic disease (adjuvant chemotherapy) has been shown to significantly prolong the disease-free interval [ 1,2] . The most commonly used regimen contains cyclophosphamide, methotrexate and 5-fluorouracil (CMF). Because of the intensity of the chemotherapy and the presumption that undetected micrometastases are present, these patients are followed closely. However, the majority of the patients are healthy young women and have been reported t o tolerate CMF well. Elevated serum alkaline phosphatase (AP)is a sensitive indicator of metastatic breast cancer in either bone or liver [3] . Bone or visceral (including liver) organs are involved at the time metastatic disease is first detected in 40-60% of breast cancer patients [4] , so AP is followed closely. In a series of 24 patients treated with adjuvant CMF for breast Address reprint requests to William P. Vaughan, MD, The Johns Hopkins Oncology Center, 600 N Wolfe Street, Baltimore, MD 21205.
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cancer at The Johns Hopkins Oncology Center, four patients developed rising AP associated with focal defects on liver scan which resolved when methotrexate alone or CMF was stopped. Liver biopsies demonstrated severe focal inflammation and no metastatic breast cancer. This experience prompted us t o review serial serum chemistry and liver scan data for the entire group of patients. PATIENTS AND METHODS
From November 1975 until Devember 1976 all patients with histologically confirmed adenocarcinoma of the breast involving four or more axillary lymph nodes were considered candidates for adjuvant chemotherapy if they were in good general health and had no evidence or residual or metastatic breast cancer following mastectomy. In that 13-month period 24 such patients (all female) consented to begin a two-year program of CMF chemotherapy (Fig. 1). Each patient had a baseline history and physical examination, serum alkaline phosphatase (AP) and glutamic oxalic transaminase (GOT) determinations. a chest roentgenograph and a 99mTC phosphate bone scan. The patients were examined monthly during therapy and GOT and AP determinations were performed at least every three months. Liver scans were obtained at the discretion of the individual patient's physician. All patients received phenothiazines as prophylaxis against nausea and vomiting, but n o other medicines were routinely given. Serum AP and GOT determinations were performed on the SMA 12/60 autoanalyzer using standard reagents. The upper limit of normal by this method in our laboratory for AP was 32 IU/L and for GOT was 19 IU/L. Liver scans (n = 48) were obtained following a 3 mCi intravenous injection of 99mTC-sulfur colloid. A 400.000 count anterior liver image was obtained and imaging time (sec) was recorded. Other views (right lateral, posterior, obliques) were acquired for this same imaging time. The scans were reviewed by one of us (PA) without knowledge of the prior interpretation or the patient's clinical status. Control scans (n = 10) were included in this review to lessen observer bias. These control scans included normals, and scans from patients with
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hepatic parenchymal disease and from patients not on adjuvant chemotherapy who had proven metastatic breast cancer. Scans were interpreted as normal, nonhomogeneous or showing focal defects. The size of the liver and spleen and the distribution of colloid were noted. By November 1, 1 9 7 8 , l l patients had completed 24 cycles of CMF and the remaining 13 had therapy discontinued (Table I). Eight of the original 24 patients (33%) have developed metastatic breast cancer. Metastatic disease was first detected in all eight patients in sites other than the liver, but bone or liver involvement was ultimately documented in all but one and none had a liver scan less than three months prior to the discovery of metastatic disease. One of the patients who developed metastases was one of the three patients who withdrew from the study early because of nausea. Three additional patients had therapy stopped or modified for evaluation of focal defects on liver scan in association with abnormal serum chemistries. A fourth patient developed a similar syndrome at the conclusion of her planned two-year course. Only one of these four patients (Case Report 3) has subsequently developed metastatic disease. The case reports of these four patients and the results of serum chemistry determinations and liver scans on all 24 patients are presented. CASE REPORTS Case 1
A 52-year-old secretary was referred from another hospital in April 1976 after a simple mastectomy and axillary node sampling for adenocarcinoma. The two sampled axillary nodes were involved. Postoperative evaluation included normal bone scan, and a chest x-ray which showed only an old healed fracture of right posterior third rib. The baseline AP was 28 IU/L. Because both of the sampled axillary nodes were involved and because of the referring surgeon’s impression of “inflammatory carcinoma,” she was begun on adjuvant chemotherapy with CMF. Three months later the GOT was noted to be 31 IU/L. The AP was 29 IU/L at that time but one month later was 33 IU/L and remained elevated (34-40) for the next six months. The GOT returned to normal and physical exam never revealed hepatomegaly or other evidence of recurrent breast cancer. Normal 5‘ nucleotidease was noted on several occasions and carcinoembryonic antigen (CEA)remained below 2.0 mg/ml. A bone scan, chest x-ray, and xerommamogram were performed at nine months and were normal, but the liver scan showed a small focal defect in the superior portion of the right lobe (Fig. 2A). An abdominal sonogram revealed two suspicious lesions. CMF was
TABLE 1. Current Status of Study Population Patients begun on CMF Age at mastectomy Follow-up Completed therapy Metastatic breast cancer Withdrew Thmapy stopped due to presumed liver toxicity aAfter 4 , 6 , and 10 months of CMF. patient later developed metastatic disease.
24 32-66 (median - 49) 24-36 months (median - 30) 1 1 (46%) 8 (33%) 3a, b 4b
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discontinued. A needle biopsy of the liver revealed acute and chronic inflammatory changes, but no evidence of carcinoma. Repeat scans and sonograms over the next two months showed improvement, but continued to be interpreted as probable metastatic disease. The AP and GOT became normal by three months off therapy. One year later, the patient remains free of demonstrable disease. The liver scan has become normal (Fig. 2B), but abdominal sonogram continues t o detect an abnormality near the dome of the diaphragm. Consequently, computerized axial tomography of the liver was performed and is normal. Case 2
A 34-year-old housewife had a right modified radical mastecomy for infiltrating duct carcinoma in October 1975. Six of 38 axillary nodes contained tumor. The baseline AP was 31 IU/L. Adjuvant chemotherapy with CMF was begun. Elevated AP and GOT were first noted one year later. These abnormalities progressed over several months. The AP reached a high of 59 IU/L and liver scan revealed a focal defect in the right lobe of the liver. The sonogram was normal. The patient underwent open liver biopsy which revealed focal nonspecific inflammation and fat accumulation. The CMF was discontinued for two months and the AP and SCOT stopped rising but did not drop. Upon restarting CMF the AP rose to 73 IU/L but the GOT returned to normal. Liver scan and sonogram also became normal. Because of the rising AP apparently due t o chemotherapy, the CMF was discontinued after a total of 13 months. The patient remains free of metastatic disease one year later. Case 3
A 49-year-old nurse’s aide had a left modified radical mastectomy in November 1975 for infiltrating ductal carcinoma. Five of 13 axillary lymph nodes were involved. Sinus histiocytosis was noted. Postoperatively the AP was 40 IU/L and the GOT was also elevated, but chest x-ray, liver scan, and bone scan were negative for metastatic disease and the CEA was normal. The patient was begun on CMF adjuvant chemotherapy. Her other medications included haloperidol and amytriptilene.
Fig. 2. Anterior view liver scan in patient 1 demonstrating a single focal defect in the rielit lobe after 9 months of CMF (A) and complete resolution 12 months after stopping CMF (B).
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The AP dropped to 29 IU/L over the first three months of CMF but then rose steadily to 58 IU/L by 15 months when a repeat liver scan revealed multiple focal defects, seen best in the lateral view (Fig. 3A). Bone scan at the time was unchanged from the previous scan and the GOT was normal. An abdominal sonogram was reported to show diffuse scattered metastases in the liver. CMF was discontinued to evaluate the liver changes. The patient had a repeat liver scan two months later which showed partial resolution of the filling defects (Fig. 3B), but the AP and GOT continued to be elevated. Percutaneous liver biopsy was performed revealing inflammatory changes. The adjuvant chemotherapy program was restarted omitting the methotrexate. A subsequent liver scan was normal but the AP remained in the 55-66 IU/L range. Six months later a supraclavicular mass was noted and despite aggressive management, local recurrence and cytology positive pleural effusion developed. The liver remained clinically uninvolved but the pulmonary involvement progressed rapidly. She died with disseminated pulmonary lymphangitic carcinoma in April 2978. No autopsy was performed Case 4
A 60-year-old housewife had a left modified radical mastectomy in December 1975 for infiltrating ductal carcinoma. Four of the 11 lymph nodes in the surgical specimen contained tumor. In the postoperative period she complained of abdominal pain and an elevated AP (62 IU/L) was noted. The liver scan was normal. She was found to have cholelithiasis and cholecystitis and a cholecystectomy was performed, but she was able to begin CMF approximately eight weeks after mastectomy. After cholecystectomy, her AP decreased to 36 IU/L but remained abnormal (35-47 IU/L) and 23 months after starting CMF focal defects were noted on liver scan. The GOT was normal during this entire period except for values of 21 IU/L and 24 IU/L at nine and 12 months. The chemotherapy was discontinued and the abnormalities on scan improved but did not resolve completely. A sonogram was normal. Liver biopsy three months after stopping CMF revealed focal congestion, nonspecific inflammation and fat deposition. She remains well eight movths after her last anti-cancer therapy with AP of 47 IU/L.
Fig. 3. Liver scan (right lateral view) in patient 3 demonstrating multiple focal defects after 15 months of CMF (A) and partial resolution 2 months after stopping CMF (B).
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RESULTS
Baseline and serial AP and GOT data and liver scans were reviewed for the entire group of 24 patients and correlated with their clinical course. None of the patients had a history of liver disease or condition predisposing to liver disease. Sixteen patients had normal baseline AP and eight patients had an elevated AP prior to therapy. Patients with elevated baseline AP were not more likely to withdraw from study or have therapy stopped and their duration of follow-up is the same as patients with normal baseline AP (Table 11). Among patients who did not withdraw from therapy early, four of seven with elevated baseline AP developed metastases while three of 14 with normal baseline AP developed metastases (p = 0.1 1, Fisher’s exact test). Two of three patients with baseline GOT elevations developed early metastatic disease (six and seven months), but these patients also had elevated baseline AP. A total of 48 liver scans were done on 18 of the patients, but baseline scans were done on only ten patients. Baseline liver scans were done on two patients with elevated AP.These scans were both normal and these two patients remain free of disease at 29 and 34 months. Eight patients with normal baseline AP had baseline liver scans and these scans were also normal. One of these patients developed metastatic disease in bone 20 months later but the rest are currently free of disease. Ten of the 16 patients whose baseline AP was normal developed elevated values during study (Table 111). The magnitude of these AP abnormalities was small. The median of the highest AP values from the ten patients whose AP became abnormal was only 43 IU/L and only one patient had an AP greater than 50 IU/L (upper limit of normal = 32 IU/L). These ten patients have continued to have mdd AP elevations during follow-up, 12-30 months from the initial abnormal value. Despite this duration of follow-up and no change in therapy, only two of these patients have developed metastatic cancer. During the same interval two patients whose AP remained normal also developed metastatic breast cancer. GOT elevations were more common than AP abnormalities, but tended to be transient in nature. Less than half of the patients with elevated AP values had simultaneous or prior elevations in GOT, but 17 of 21 patients with normal baseline GOT values have had a GOT elevation at some time in their course. The range of highest values was 22-49 IU/L (upper limit of normal = 19 IU/L) with a median of 2 5 . Only one patient had a GOT value above 30.
TABLE 11. Relationship of Baseline AP and Subsequent Clinical Course
Patients Range of AP values (median) Age range (median) Follow-up (median) Completed therapy Developed metastatic breast cancer Withdrew Therapy stopped due to presumed liver toxicity
Baseline AP normal
Baseline AP abnormal
16 16-32 IU/L (22) 32-59 years (40) 29-37 months (30) 9 4a ( 8 , 2 0 , 21, 24 months) 2
8 33-62 IU/L (40) 37-66 years (55) 24-35 months (30) 2 4 ( 5 , 6 , 13, 25 months) 1
2
2
%ne of these had withdrawn from the study after only four treatment cycles.
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Eight patients had their first liver scan because of the development of abnormal AP or GOT. Six of these patients had normal liver scans. The other two (case reports 1 and 2) had scans that showed focal defects which subsequently resolved off CMF. Eleven patients had serial scans. Nine of these patients had serial normal scans. Two patients (case reports 3 and 4) had normal baseline scans, focal defects during CMF therapy and resolution of the scan defects after withdrawal of CMF. DISCUSSl0 N
The purpose of adjuvant chemotherapy for patients with primary breast cancer and positive axillary lymph nodes is to eradicate systemic micrometastases present at the time of diagnosis which will become clinically apparent in the majority of patients if left untreated. Because these patients are at high risk for metastatic disease, the appearance of focal liver scan defects after the development of abnormal serum chemistries during adjuvant chemotherapy could easily lead to the conclusion that metastatic disease had developed. In the four patients reported here, the absence of evidence for metastatic disease at other sites and the patient’s lack of symptoms led t o further diagnostic studies including biopsy. These studies and the subsequent clinical course are most consistent with the conclusion that the chemical and scintigraphic findings were due to the chemotherapy and not metastatic disease. Of the three drugs in the CMF regimen, methotrexate seems the most likely cause of this hepatic toxicity. Methotrexate hepatotoxicity was first reported over 20 years ago [S] and it has been well established that long term low dose oral administration of methotrexate may result in significant liver function test abnormalities and hepatic cirrhosis and fibrosis [6]. Similar histologic changes to those we observed in the patients reported here have been induced in rats with methotrexate [7] . Combination chemotherapy with actinomycin D or methotrexate has been associated with focal defects on liver scan at sites where radiation therapy was previously given [8]. Radiation therapy alone may have produced these lesions but it was noted that some chemotherapeutic agents including methotrexate increase the biologic effects of ionizing irradiation.
TABLE 111. Relationship of Development of Abnormal AP While on CMF to Subsequent clinical Course
Patients Follow-up (median) Month AP first abnormal (median) Follow-up since first abnormal AP (median) Highest AP value/patient (median) Developed abnormal GOT Developed metastatic disease
AP remained normal
AP became abnormal
6 24-36 months (28) -
10 24-36 months (30) 3-20 (9)
-
6 2 (20, 24 months)a
“One patient withdrew from therapy after five months. bThree and six months after first abnormal AP.
12-30 (22) 38-73 (43) 9 2 ( 8 , 2 0 months)b
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The hepatic toxicity we have observed has not been symptomatic or associated with jaundice. Since the optimum duration of adjuvant chemotherapy is not known and little long-term follow-up data on toxicity is available, however, it seems prudent to stop methotrexate after focal defects appear on liver scan. We do not discontinue chemotherapy when patients develop abnormal AP in the absence of focal defects on liver scan and no serious consequences of this decision have yet been observed. The recognition that chemical and scintigraphic abnormalities ordinarily associated with early metastatic disease can be due to chemotherapy significantly compromises the usefulness of serum chemistries and scans for early detection of metastases in the adjuvant setting. While the baseline AP results confirm the sensitivity of this measurement as a test for metastatic cancer, an abnormal GOT or AP occurring during chemotherapy did not predict early development of metastatic disease. GOT elevations occurred in almost every patient at some time but the abnormalities were small and not persistent. Patients who developed an abnormal AF’ on chemotherapy all had persistent elevations but no apparent increased risk of early metastatic disease. The number of patients (10/16, 62.5%) who developed an elevated AP on CMF is considerably higher than the expected early recurrence rate [2]. In addition eight of these ten patients remained free of metastatic breast cancer for up to 36 months without any additional antineoplastic therapy. Even focal defects appearing on the liver scans of four of these patients proved not to be due to metastatic disease. These observations suggest that AP and GOT elevations occurring during CMF therapy are more likely due to hepatic toxicity than early metastatic involvement of the liver with breast cancer. The liver scan has been found to be more specific than liver chemistries for detecting metastatic cancer in the liver [9, 101. However, nonmalignant disease in the liver of cancer patients has been reported to cause a small but significant rate of false positive liver scans even in patients not receiving hepatotoxic drugs [ 111 ,and non-focal liver scan abnormalities have been reported in patients with severe chemical hepatitis [ 121. Two recent publications [ l 1 , 131 suggest that CEA determinations might further increase the specificity of liver scans. Our experience confirms the ability of the liver scan to detect hepatic disease. However, since breast cancer metastases are often seen as small focal defects or an “inhomogeneous” pattern on liver scans [14, 151 it is difficut to distinguish metastases from the hepatotoxicity of CMF. Other nonivasive imaging techniques may help resolve the problem, but sonography has failed to do so in our limited experience. Two patients with liver scan defects secondary to CMF had normal sonograms, but two other patients had both liver scan and sonogram abnormalities in regions of drug-induced hepatic inflammation. However, the one patient in our series (Case 1) on whom computed tomography of the liver was perfomed had this study after the liver scan had become normal and no abnomality was seen. Computed tomography of the liver might provide discrimination in patients on CMF with abnormal liver scans. This possibility should be investigated in a prospective study. Adjuvant chemotherapy has significantly prolonged the disease-free interval and survival of patients with breast cancer and has generally been well tolerated [16]. Because of this success it is important for clinicians to become aware of the multiple effects of these drugs on host organs and consider the implications of these effects in the management of these patients. Specifically the development of abnormal liver chemistries, even in association with evidence of focal hepatic parenchymal destruction, should not lead to the diagnosis of metastatic disease in the absence of a biopsy or simultaneous recurrence elsewhere.
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ACKNOWLEDGMENTS
The authors would like to thank Dr. Allyn W. Kimball, Jr, Professor of Biostatistics, Johns Hopkins University for assistance in analyzing the data. Supported in part by Public Health Service grants CA-06973-16 and GM-10548, the National Cancer Institute, National Institutes of Health, Department of Health, Education and Welfare. Dr. Vaughan is the recipient of an American Cancer Society Junior Faculty Clinical Fellowship. REFERENCES 1. Fisher B, Carbone P, Economou SG, et al: L-Phenylalanine mustard (L-PAM) in the management of primary breast cancer: A report of early findings. N Engl J Med 292:117-122, 1975. 2. Bonadonna C, Brussamolina E, Valagussa P, et al: Combination chemotherapy as an adjuvant treatment in operable breast cancer. N Engl J Med 294:405-410, 1976. 3. Coombes RC, Powles TJ, Gazet, et al: Biochemical markers in human breast cancer. Lancet i:132-134,1977. 4. Rossi A, Valagussa P, Bonnadonna G: Surgery and adjuvant chemotherapy in the treatment of operable breast cancer. In Montague ACW, Stonesifer GL, Lewison EF (eds): “Breast Cancer.” New York: Alan R Liss Inc, 1977, pp 391-404. 5. Colsky J, Greenspan EM, Warren TN: Hepatic fibrosis in children with acute leukemia treated with folic acid antagonists. Arch Pathol59: 198-206, 1955. 6. Podurgiel BJ, McGU DB, Ludrig J, et al: Liver injury associated with methotrexate therapy for psoriasis. Mayo Clin Proc 48:787-792, 1973. 7. Custer RP, Freeman-Narrod M, Narrod SA: Hepatotoxicity in Wistar rats following chronic methotrexate administration: A model of human reaction. J Natl Cancer Inst 58:lOll-1015, 1977. 8. Tefft M, Mitus A, Jaffe N: Irradiation of the liver in children: Acute effects enhanced by concomitant chemotherapeutic administration. Am J Roetgenol Radium ”her Nucl Med 111 : 165-173,1971. 9. Gollin FF, Sims LR, Cameron JR: Liver scanning and liver function tests. JAMA 187:lll-118, 1964. 10. Jhinran SG, Jordan L, Johns MF, et al: Liver scintigrams compared with alkaline phosphatase and BSP determinations in the detection of metastatic carcinoma. J Nucl Med 12:227-230, 1971. 11. Sugarbaker PH, Beard JH, Drum DE: Detection of hepatic metastases from cancer of the breast. Am J Surg 133531-535,1977. 12. Lokich JJ, Drum DE, Kaplan W: Hepatic toxicity of nitrosourea analogues. Clin Pharmacol Ther 16:363-367,1974. 13. McCartney WH, Haffer PB: Carcinoembryonic antigen assay in hepatic metastases detection - An adjunct to liver scanning. JAMA 236:1023-1027, 1976. 14. Drum DE, Cristacopoulas JS: Hepatic scintigraphy in clinical decision making. J Nucl Med 13~908-915, 1972. 15. Drum DE, Beard JM: Scintigraphic criteria for hepatic metastases from cancer of the colon and breast. J Nucl Med 17:667-680, 1976. 16. Bonnadonna G, Valagussa P, Rossi A, et al: Are surgical adjuvant trials altering the course of breast cancer. Seminars in Oncology 5:450-464, 1978.
Hepatic Toxicity of Adjuvant Chemotherapy for Carcinoma of the Breast William P. Vaughan, MD, Patti M. Wilcox, RN, CANP, Phillip 0.Alderson, M D, David S. Ettinger, MD, and Martin D. Abeloff, M D The Johns Hopkins Oncology Onter (W.P. V., P.M.W., D.S.E., M.D.A.)and Department of Radiology, Division of Nuclear Medicine (P.O.A.), The Johns Hopkins University School of Medicine, Baltimore
Four patients developed abnormal liver function tests and focal defects on liver scan while receiving cyclosphosphamide, methotrexate and 5-fluorouracil as adjuvant chemotherapy following mastectomy for breast cancer. Liver biopsies showed severe focal inflammation. The biopsy findings and the subsequent clinical course of the patients strongly suggest that these abnormalities were due to hepatic toxicity of the chemotherapy and not metastic breast cancer. A review of serial liver function tests performed on 24 patients in that chemotherapy program revealed that four out of eight patients with elevated alkaline phosphatase prior to therapy developed early metastatic cancer. Elevated alkaline phosphatase occurring during chemotherapy on the other hand was quite common but more likely due to hepatic toxicity of the drugs. The development of abnormal liver function tests even in association with focal defects on liver scan is not sufficient to diagnose metastatic breast cancer in patients receiving adjuvant chemotherapy. Key words: methotrexate, CMF,hepatic toxicity, adjuvant chemotherapy, breast cancer
INTRODUCTION
Following mastectomy for breast cancer, administration of cytotoxic chemotherapy to women at high risk for the development of metastatic disease (adjuvant chemotherapy) has been shown to significantly prolong the disease-free interval [ 1,2] . The most commonly used regimen contains cyclophosphamide, methotrexate and 5-fluorouracil (CMF). Because of the intensity of the chemotherapy and the presumption that undetected micrometastases are present, these patients are followed closely. However, the majority of the patients are healthy young women and have been reported t o tolerate CMF well. Elevated serum alkaline phosphatase (AP)is a sensitive indicator of metastatic breast cancer in either bone or liver [3] . Bone or visceral (including liver) organs are involved at the time metastatic disease is first detected in 40-60% of breast cancer patients [4] , so AP is followed closely. In a series of 24 patients treated with adjuvant CMF for breast Address reprint requests to William P. Vaughan, MD, The Johns Hopkins Oncology Center, 600 N Wolfe Street, Baltimore, MD 21205.
0098-1 532/79/0704-035 1$02.00 0 1979 Alan
R. Liss, Inc.
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cancer at The Johns Hopkins Oncology Center, four patients developed rising AP associated with focal defects on liver scan which resolved when methotrexate alone or CMF was stopped. Liver biopsies demonstrated severe focal inflammation and no metastatic breast cancer. This experience prompted us t o review serial serum chemistry and liver scan data for the entire group of patients. PATIENTS AND METHODS
From November 1975 until Devember 1976 all patients with histologically confirmed adenocarcinoma of the breast involving four or more axillary lymph nodes were considered candidates for adjuvant chemotherapy if they were in good general health and had no evidence or residual or metastatic breast cancer following mastectomy. In that 13-month period 24 such patients (all female) consented to begin a two-year program of CMF chemotherapy (Fig. 1). Each patient had a baseline history and physical examination, serum alkaline phosphatase (AP) and glutamic oxalic transaminase (GOT) determinations. a chest roentgenograph and a 99mTC phosphate bone scan. The patients were examined monthly during therapy and GOT and AP determinations were performed at least every three months. Liver scans were obtained at the discretion of the individual patient's physician. All patients received phenothiazines as prophylaxis against nausea and vomiting, but n o other medicines were routinely given. Serum AP and GOT determinations were performed on the SMA 12/60 autoanalyzer using standard reagents. The upper limit of normal by this method in our laboratory for AP was 32 IU/L and for GOT was 19 IU/L. Liver scans (n = 48) were obtained following a 3 mCi intravenous injection of 99mTC-sulfur colloid. A 400.000 count anterior liver image was obtained and imaging time (sec) was recorded. Other views (right lateral, posterior, obliques) were acquired for this same imaging time. The scans were reviewed by one of us (PA) without knowledge of the prior interpretation or the patient's clinical status. Control scans (n = 10) were included in this review to lessen observer bias. These control scans included normals, and scans from patients with
I
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CYCLOPHOSPHAMIDE 100mg/m2/d Po DAYS 1-14 METHOTREXATE 40mg/m2 IV DAYS I AND 8 5-FLUOROURACIL 6 0 0 m g / m 2 IV DAYS I AND 8 FiF. 1 . CMF combination chemotherapy. The treatment cycle is repeated at 28-day intervals.
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hepatic parenchymal disease and from patients not on adjuvant chemotherapy who had proven metastatic breast cancer. Scans were interpreted as normal, nonhomogeneous or showing focal defects. The size of the liver and spleen and the distribution of colloid were noted. By November 1, 1 9 7 8 , l l patients had completed 24 cycles of CMF and the remaining 13 had therapy discontinued (Table I). Eight of the original 24 patients (33%) have developed metastatic breast cancer. Metastatic disease was first detected in all eight patients in sites other than the liver, but bone or liver involvement was ultimately documented in all but one and none had a liver scan less than three months prior to the discovery of metastatic disease. One of the patients who developed metastases was one of the three patients who withdrew from the study early because of nausea. Three additional patients had therapy stopped or modified for evaluation of focal defects on liver scan in association with abnormal serum chemistries. A fourth patient developed a similar syndrome at the conclusion of her planned two-year course. Only one of these four patients (Case Report 3) has subsequently developed metastatic disease. The case reports of these four patients and the results of serum chemistry determinations and liver scans on all 24 patients are presented. CASE REPORTS Case 1
A 52-year-old secretary was referred from another hospital in April 1976 after a simple mastectomy and axillary node sampling for adenocarcinoma. The two sampled axillary nodes were involved. Postoperative evaluation included normal bone scan, and a chest x-ray which showed only an old healed fracture of right posterior third rib. The baseline AP was 28 IU/L. Because both of the sampled axillary nodes were involved and because of the referring surgeon’s impression of “inflammatory carcinoma,” she was begun on adjuvant chemotherapy with CMF. Three months later the GOT was noted to be 31 IU/L. The AP was 29 IU/L at that time but one month later was 33 IU/L and remained elevated (34-40) for the next six months. The GOT returned to normal and physical exam never revealed hepatomegaly or other evidence of recurrent breast cancer. Normal 5‘ nucleotidease was noted on several occasions and carcinoembryonic antigen (CEA)remained below 2.0 mg/ml. A bone scan, chest x-ray, and xerommamogram were performed at nine months and were normal, but the liver scan showed a small focal defect in the superior portion of the right lobe (Fig. 2A). An abdominal sonogram revealed two suspicious lesions. CMF was
TABLE 1. Current Status of Study Population Patients begun on CMF Age at mastectomy Follow-up Completed therapy Metastatic breast cancer Withdrew Thmapy stopped due to presumed liver toxicity aAfter 4 , 6 , and 10 months of CMF. patient later developed metastatic disease.
24 32-66 (median - 49) 24-36 months (median - 30) 1 1 (46%) 8 (33%) 3a, b 4b
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discontinued. A needle biopsy of the liver revealed acute and chronic inflammatory changes, but no evidence of carcinoma. Repeat scans and sonograms over the next two months showed improvement, but continued to be interpreted as probable metastatic disease. The AP and GOT became normal by three months off therapy. One year later, the patient remains free of demonstrable disease. The liver scan has become normal (Fig. 2B), but abdominal sonogram continues t o detect an abnormality near the dome of the diaphragm. Consequently, computerized axial tomography of the liver was performed and is normal. Case 2
A 34-year-old housewife had a right modified radical mastecomy for infiltrating duct carcinoma in October 1975. Six of 38 axillary nodes contained tumor. The baseline AP was 31 IU/L. Adjuvant chemotherapy with CMF was begun. Elevated AP and GOT were first noted one year later. These abnormalities progressed over several months. The AP reached a high of 59 IU/L and liver scan revealed a focal defect in the right lobe of the liver. The sonogram was normal. The patient underwent open liver biopsy which revealed focal nonspecific inflammation and fat accumulation. The CMF was discontinued for two months and the AP and SCOT stopped rising but did not drop. Upon restarting CMF the AP rose to 73 IU/L but the GOT returned to normal. Liver scan and sonogram also became normal. Because of the rising AP apparently due t o chemotherapy, the CMF was discontinued after a total of 13 months. The patient remains free of metastatic disease one year later. Case 3
A 49-year-old nurse’s aide had a left modified radical mastectomy in November 1975 for infiltrating ductal carcinoma. Five of 13 axillary lymph nodes were involved. Sinus histiocytosis was noted. Postoperatively the AP was 40 IU/L and the GOT was also elevated, but chest x-ray, liver scan, and bone scan were negative for metastatic disease and the CEA was normal. The patient was begun on CMF adjuvant chemotherapy. Her other medications included haloperidol and amytriptilene.
Fig. 2. Anterior view liver scan in patient 1 demonstrating a single focal defect in the rielit lobe after 9 months of CMF (A) and complete resolution 12 months after stopping CMF (B).
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The AP dropped to 29 IU/L over the first three months of CMF but then rose steadily to 58 IU/L by 15 months when a repeat liver scan revealed multiple focal defects, seen best in the lateral view (Fig. 3A). Bone scan at the time was unchanged from the previous scan and the GOT was normal. An abdominal sonogram was reported to show diffuse scattered metastases in the liver. CMF was discontinued to evaluate the liver changes. The patient had a repeat liver scan two months later which showed partial resolution of the filling defects (Fig. 3B), but the AP and GOT continued to be elevated. Percutaneous liver biopsy was performed revealing inflammatory changes. The adjuvant chemotherapy program was restarted omitting the methotrexate. A subsequent liver scan was normal but the AP remained in the 55-66 IU/L range. Six months later a supraclavicular mass was noted and despite aggressive management, local recurrence and cytology positive pleural effusion developed. The liver remained clinically uninvolved but the pulmonary involvement progressed rapidly. She died with disseminated pulmonary lymphangitic carcinoma in April 2978. No autopsy was performed Case 4
A 60-year-old housewife had a left modified radical mastectomy in December 1975 for infiltrating ductal carcinoma. Four of the 11 lymph nodes in the surgical specimen contained tumor. In the postoperative period she complained of abdominal pain and an elevated AP (62 IU/L) was noted. The liver scan was normal. She was found to have cholelithiasis and cholecystitis and a cholecystectomy was performed, but she was able to begin CMF approximately eight weeks after mastectomy. After cholecystectomy, her AP decreased to 36 IU/L but remained abnormal (35-47 IU/L) and 23 months after starting CMF focal defects were noted on liver scan. The GOT was normal during this entire period except for values of 21 IU/L and 24 IU/L at nine and 12 months. The chemotherapy was discontinued and the abnormalities on scan improved but did not resolve completely. A sonogram was normal. Liver biopsy three months after stopping CMF revealed focal congestion, nonspecific inflammation and fat deposition. She remains well eight movths after her last anti-cancer therapy with AP of 47 IU/L.
Fig. 3. Liver scan (right lateral view) in patient 3 demonstrating multiple focal defects after 15 months of CMF (A) and partial resolution 2 months after stopping CMF (B).
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RESULTS
Baseline and serial AP and GOT data and liver scans were reviewed for the entire group of 24 patients and correlated with their clinical course. None of the patients had a history of liver disease or condition predisposing to liver disease. Sixteen patients had normal baseline AP and eight patients had an elevated AP prior to therapy. Patients with elevated baseline AP were not more likely to withdraw from study or have therapy stopped and their duration of follow-up is the same as patients with normal baseline AP (Table 11). Among patients who did not withdraw from therapy early, four of seven with elevated baseline AP developed metastases while three of 14 with normal baseline AP developed metastases (p = 0.1 1, Fisher’s exact test). Two of three patients with baseline GOT elevations developed early metastatic disease (six and seven months), but these patients also had elevated baseline AP. A total of 48 liver scans were done on 18 of the patients, but baseline scans were done on only ten patients. Baseline liver scans were done on two patients with elevated AP.These scans were both normal and these two patients remain free of disease at 29 and 34 months. Eight patients with normal baseline AP had baseline liver scans and these scans were also normal. One of these patients developed metastatic disease in bone 20 months later but the rest are currently free of disease. Ten of the 16 patients whose baseline AP was normal developed elevated values during study (Table 111). The magnitude of these AP abnormalities was small. The median of the highest AP values from the ten patients whose AP became abnormal was only 43 IU/L and only one patient had an AP greater than 50 IU/L (upper limit of normal = 32 IU/L). These ten patients have continued to have mdd AP elevations during follow-up, 12-30 months from the initial abnormal value. Despite this duration of follow-up and no change in therapy, only two of these patients have developed metastatic cancer. During the same interval two patients whose AP remained normal also developed metastatic breast cancer. GOT elevations were more common than AP abnormalities, but tended to be transient in nature. Less than half of the patients with elevated AP values had simultaneous or prior elevations in GOT, but 17 of 21 patients with normal baseline GOT values have had a GOT elevation at some time in their course. The range of highest values was 22-49 IU/L (upper limit of normal = 19 IU/L) with a median of 2 5 . Only one patient had a GOT value above 30.
TABLE 11. Relationship of Baseline AP and Subsequent Clinical Course
Patients Range of AP values (median) Age range (median) Follow-up (median) Completed therapy Developed metastatic breast cancer Withdrew Therapy stopped due to presumed liver toxicity
Baseline AP normal
Baseline AP abnormal
16 16-32 IU/L (22) 32-59 years (40) 29-37 months (30) 9 4a ( 8 , 2 0 , 21, 24 months) 2
8 33-62 IU/L (40) 37-66 years (55) 24-35 months (30) 2 4 ( 5 , 6 , 13, 25 months) 1
2
2
%ne of these had withdrawn from the study after only four treatment cycles.
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Eight patients had their first liver scan because of the development of abnormal AP or GOT. Six of these patients had normal liver scans. The other two (case reports 1 and 2) had scans that showed focal defects which subsequently resolved off CMF. Eleven patients had serial scans. Nine of these patients had serial normal scans. Two patients (case reports 3 and 4) had normal baseline scans, focal defects during CMF therapy and resolution of the scan defects after withdrawal of CMF. DISCUSSl0 N
The purpose of adjuvant chemotherapy for patients with primary breast cancer and positive axillary lymph nodes is to eradicate systemic micrometastases present at the time of diagnosis which will become clinically apparent in the majority of patients if left untreated. Because these patients are at high risk for metastatic disease, the appearance of focal liver scan defects after the development of abnormal serum chemistries during adjuvant chemotherapy could easily lead to the conclusion that metastatic disease had developed. In the four patients reported here, the absence of evidence for metastatic disease at other sites and the patient’s lack of symptoms led t o further diagnostic studies including biopsy. These studies and the subsequent clinical course are most consistent with the conclusion that the chemical and scintigraphic findings were due to the chemotherapy and not metastatic disease. Of the three drugs in the CMF regimen, methotrexate seems the most likely cause of this hepatic toxicity. Methotrexate hepatotoxicity was first reported over 20 years ago [S] and it has been well established that long term low dose oral administration of methotrexate may result in significant liver function test abnormalities and hepatic cirrhosis and fibrosis [6]. Similar histologic changes to those we observed in the patients reported here have been induced in rats with methotrexate [7] . Combination chemotherapy with actinomycin D or methotrexate has been associated with focal defects on liver scan at sites where radiation therapy was previously given [8]. Radiation therapy alone may have produced these lesions but it was noted that some chemotherapeutic agents including methotrexate increase the biologic effects of ionizing irradiation.
TABLE 111. Relationship of Development of Abnormal AP While on CMF to Subsequent clinical Course
Patients Follow-up (median) Month AP first abnormal (median) Follow-up since first abnormal AP (median) Highest AP value/patient (median) Developed abnormal GOT Developed metastatic disease
AP remained normal
AP became abnormal
6 24-36 months (28) -
10 24-36 months (30) 3-20 (9)
-
6 2 (20, 24 months)a
“One patient withdrew from therapy after five months. bThree and six months after first abnormal AP.
12-30 (22) 38-73 (43) 9 2 ( 8 , 2 0 months)b
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The hepatic toxicity we have observed has not been symptomatic or associated with jaundice. Since the optimum duration of adjuvant chemotherapy is not known and little long-term follow-up data on toxicity is available, however, it seems prudent to stop methotrexate after focal defects appear on liver scan. We do not discontinue chemotherapy when patients develop abnormal AP in the absence of focal defects on liver scan and no serious consequences of this decision have yet been observed. The recognition that chemical and scintigraphic abnormalities ordinarily associated with early metastatic disease can be due to chemotherapy significantly compromises the usefulness of serum chemistries and scans for early detection of metastases in the adjuvant setting. While the baseline AP results confirm the sensitivity of this measurement as a test for metastatic cancer, an abnormal GOT or AP occurring during chemotherapy did not predict early development of metastatic disease. GOT elevations occurred in almost every patient at some time but the abnormalities were small and not persistent. Patients who developed an abnormal AF’ on chemotherapy all had persistent elevations but no apparent increased risk of early metastatic disease. The number of patients (10/16, 62.5%) who developed an elevated AP on CMF is considerably higher than the expected early recurrence rate [2]. In addition eight of these ten patients remained free of metastatic breast cancer for up to 36 months without any additional antineoplastic therapy. Even focal defects appearing on the liver scans of four of these patients proved not to be due to metastatic disease. These observations suggest that AP and GOT elevations occurring during CMF therapy are more likely due to hepatic toxicity than early metastatic involvement of the liver with breast cancer. The liver scan has been found to be more specific than liver chemistries for detecting metastatic cancer in the liver [9, 101. However, nonmalignant disease in the liver of cancer patients has been reported to cause a small but significant rate of false positive liver scans even in patients not receiving hepatotoxic drugs [ 111 ,and non-focal liver scan abnormalities have been reported in patients with severe chemical hepatitis [ 121. Two recent publications [ l 1 , 131 suggest that CEA determinations might further increase the specificity of liver scans. Our experience confirms the ability of the liver scan to detect hepatic disease. However, since breast cancer metastases are often seen as small focal defects or an “inhomogeneous” pattern on liver scans [14, 151 it is difficut to distinguish metastases from the hepatotoxicity of CMF. Other nonivasive imaging techniques may help resolve the problem, but sonography has failed to do so in our limited experience. Two patients with liver scan defects secondary to CMF had normal sonograms, but two other patients had both liver scan and sonogram abnormalities in regions of drug-induced hepatic inflammation. However, the one patient in our series (Case 1) on whom computed tomography of the liver was perfomed had this study after the liver scan had become normal and no abnomality was seen. Computed tomography of the liver might provide discrimination in patients on CMF with abnormal liver scans. This possibility should be investigated in a prospective study. Adjuvant chemotherapy has significantly prolonged the disease-free interval and survival of patients with breast cancer and has generally been well tolerated [16]. Because of this success it is important for clinicians to become aware of the multiple effects of these drugs on host organs and consider the implications of these effects in the management of these patients. Specifically the development of abnormal liver chemistries, even in association with evidence of focal hepatic parenchymal destruction, should not lead to the diagnosis of metastatic disease in the absence of a biopsy or simultaneous recurrence elsewhere.
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ACKNOWLEDGMENTS
The authors would like to thank Dr. Allyn W. Kimball, Jr, Professor of Biostatistics, Johns Hopkins University for assistance in analyzing the data. Supported in part by Public Health Service grants CA-06973-16 and GM-10548, the National Cancer Institute, National Institutes of Health, Department of Health, Education and Welfare. Dr. Vaughan is the recipient of an American Cancer Society Junior Faculty Clinical Fellowship. REFERENCES 1. Fisher B, Carbone P, Economou SG, et al: L-Phenylalanine mustard (L-PAM) in the management of primary breast cancer: A report of early findings. N Engl J Med 292:117-122, 1975. 2. Bonadonna C, Brussamolina E, Valagussa P, et al: Combination chemotherapy as an adjuvant treatment in operable breast cancer. N Engl J Med 294:405-410, 1976. 3. Coombes RC, Powles TJ, Gazet, et al: Biochemical markers in human breast cancer. Lancet i:132-134,1977. 4. Rossi A, Valagussa P, Bonnadonna G: Surgery and adjuvant chemotherapy in the treatment of operable breast cancer. In Montague ACW, Stonesifer GL, Lewison EF (eds): “Breast Cancer.” New York: Alan R Liss Inc, 1977, pp 391-404. 5. Colsky J, Greenspan EM, Warren TN: Hepatic fibrosis in children with acute leukemia treated with folic acid antagonists. Arch Pathol59: 198-206, 1955. 6. Podurgiel BJ, McGU DB, Ludrig J, et al: Liver injury associated with methotrexate therapy for psoriasis. Mayo Clin Proc 48:787-792, 1973. 7. Custer RP, Freeman-Narrod M, Narrod SA: Hepatotoxicity in Wistar rats following chronic methotrexate administration: A model of human reaction. J Natl Cancer Inst 58:lOll-1015, 1977. 8. Tefft M, Mitus A, Jaffe N: Irradiation of the liver in children: Acute effects enhanced by concomitant chemotherapeutic administration. Am J Roetgenol Radium ”her Nucl Med 111 : 165-173,1971. 9. Gollin FF, Sims LR, Cameron JR: Liver scanning and liver function tests. JAMA 187:lll-118, 1964. 10. Jhinran SG, Jordan L, Johns MF, et al: Liver scintigrams compared with alkaline phosphatase and BSP determinations in the detection of metastatic carcinoma. J Nucl Med 12:227-230, 1971. 11. Sugarbaker PH, Beard JH, Drum DE: Detection of hepatic metastases from cancer of the breast. Am J Surg 133531-535,1977. 12. Lokich JJ, Drum DE, Kaplan W: Hepatic toxicity of nitrosourea analogues. Clin Pharmacol Ther 16:363-367,1974. 13. McCartney WH, Haffer PB: Carcinoembryonic antigen assay in hepatic metastases detection - An adjunct to liver scanning. JAMA 236:1023-1027, 1976. 14. Drum DE, Cristacopoulas JS: Hepatic scintigraphy in clinical decision making. J Nucl Med 13~908-915, 1972. 15. Drum DE, Beard JM: Scintigraphic criteria for hepatic metastases from cancer of the colon and breast. J Nucl Med 17:667-680, 1976. 16. Bonnadonna G, Valagussa P, Rossi A, et al: Are surgical adjuvant trials altering the course of breast cancer. Seminars in Oncology 5:450-464, 1978.
