| Japanese Journal of Clinical Oncology | Pages |
Multiple Liver Metastases of Breast Cancer: Report of a Case Successfully Treated with Hormone-Cytokine-Chemotherapy
Introduction
Case
Present Illness
Physical Examination on Admission
Ultrasonic Examination of the Liver
Laboratory Findings
Angiographic Findings
CT Findings
Bone Scintigraphic Findings
Course After Admission
Present General Condition
Discussion
References
Multiple Liver Metastases of Breast Cancer: Report of a Case Successfully Treated with Hormone-Cytokine-Chemotherapy
INTRODUCTION
Breast cancer usually shows favorable sensitivity to anticancer agents (1). However, the development of hepatic metastases from primary breast cancer carries a poor prognosis, with a median survival of 6-11 months, as reported for brain metastases and diffuse bone metastases (2-6). In patients with metastatic breast cancer, even when a complete clearance of all measurable metastatic lesions is achieved with treatment, none are usually cured of their disease. Patients with metastatic breast cancer in whom complete remission (CR) is obtained have a better survival time than patients without CR (7). Although metastatic breast cancer is commonly recognized to be a non-curable disease, a recent report states that a small percentage of patients clearly are alive and progression free for prolonged periods after initiation of systemic treatments. However, in that report, there was no case with liver metastasis in patients with first CR (complete remission) continued progression-free 5 years after beginning systemic treatment (8). Ikeda et al. (9) reported that continuous intra-arterial chemotherapy for liver metastasis from breast cancer resulted in a good response (response rate 63%) without CR. However, the duration of response is short even when treatment is fairly effective, resulting in a fatal outcome in a short period along with the rapid growth of cancer (4). In this study, we performed cytokine- and hormone-chemotherapy in a breast cancer patient with liver dysfunction related to multiple liver metastases. Complete regression was achieved. To date, there has been no relapse during the 8-year follow-up period after the therapy was started, which includes 7 years after remission.
CASE
A 39-year-old female (on admission to our hospital).
Present Illness
In 1987, the patient underwent modified radical mastectomy for left breast cancer. Postoperative diagnosis suggested papillotubular carcinoma (It., A., 7.0 × 2.0 cm, pT3pN0pM0, Stage IIB according to pTNM pathological classification). Vascular or lymphatic invasion was detected. Neither estrogen nor progesterone receptor in the primary tumor was negative. After surgery, the patient underwent radiotherapy (40 Gy). Medroxyprogesterone acetate (Provera, 2 times/day) was administered. At the beginning of 1990, general fatigue and skin eruption developed. In February 1990, physical examination showed liver dysfunction. Computed tomography (CT) and ultrasonography (US) revealed liver metastasis from breast cancer. The patient consulted our hospital and was admitted.
Physical Examination on Admission
There was no yellow coloring in the skin, lymph node swelling on the body surface or palpable nodes in soft tissues. In the liver, palpation revealed swelling below the costal arch. There were no other abnormal findings.
Ultrasonic Examination of the Liver
Ultrasonography of the liver on admission revealed multiple diffuse foci in the whole liver (Fig. 1).
Figure 1. Ultrasonography showed remarkable enlargement of the liver and the multiple foci appeared to be metastatic nodules. Table 1 shows the initial labolatory studies. Liver function tests showed the elevation of aspartate aminotransferase, alkaline phosphatase, lactate dehydrogenase and [gamma]-glutamyl transpeptidase. The serum calcium level rose to 14.0 mg/dl. Tumor markers including CA15-3 and CEA were significantly elevated. Hepatic arteriography revealed diffuse large or small nodes throughout the liver. The periphery showed a dark shadow, while the center showed a low intensity. These findings were considered compatible with metastatic liver tumors (Fig. 2A and B). CT revealed diffuse large or small space-occupying lesions (SOL). Large lesions existed at the hepatic portal. The tumor comprised 50% or more of the hepatic volume. No metastasis in other soft tissues or lung was detected (Fig. 3A-C). Bone scintigraphy did not reveal any hot spots. There were no abnormal findings. Table 1. 
Laboratory Findings
Angiographic Findings
CT Findings
Bone Scintigraphic Findings
WBC
9200/mm3
LAP
273 IU/l
RBC
349 × 104/mm3
GTP
865 IU/l
Hb
11.3 g/dl
CHE
53 IU/l
Ht
33.3%
LDH
546 IU/l
Plt
21.9 × 104/mm3
Na
42 mmol/l
TP
6.81 g/dl
K
3.2 mmol/l
Alb
3.26 g/dl
Cl
107 mmol/l
T.Bil
0.78 mg/dl
Ca
14.0 mg/dl
D.Bil
0.33 mg/dl
UN
17.0 mg/dl
AST
89 IU/l
CRTN
0.86 mg/dl
ALT
37 IU/l
T.Chol
149 mg/dl
ALP
417 IU/l
CRP
1.4 mg/dl
Tumor markers:
CA15-3
3968.3 ng/ml (<30)
CEA
639 ng/ml (<5.0)
CA12-5
76.1 U/ml (<35)
Ferritin
109.5 ng/ml (200)
TPA
4659.0 U/ml (<110)
Course After Admission
A
 |
B
 |
Figure 2. Angiographic studies of the liver revealed multiple liver tumors. The peripheral area of the tumor was highly stained. Staining of the central area was much lower than that of peripheral area. Bull's eye-like signs appeared to be metastatic foci (A, tumors indicated by arrow in venous phase; B, portal phase).
A
 |
B
 |
C
 |
Figure 3. Computed tomography on admission indicated a large low-density area in the center of the liver with multiple nodules showing bull's eye-like appearance. Multiple small and large nodules were detected in the whole area of the liver (A, B, C).
On July 17, 1990, cannulation of the common hepatic artery was performed and a reservoir was inserted subcutaneously. After obtaining informed consent, an arterial catheter was inserted into the proper hepatic artery. The catheter was then connected to an access port in subcutaneous tissue. From days 1 to 28, the patient received intraarterial bolus infusion of 250 mg/day of 5FU followed by continuous intravenous infusion of 100 mg/day of cyclophosphamide (CPA), 11 400 JRU/day of tumor necrosis factor (TNF)-[alpha] and 4 × 106 IU/day of interferon (IFN)-[alpha] in 1 h, with the approval of Institutional Review Board of our hospital. This protocol, as a cycle, was followed by a 2 week pause in drug administration. The treatment was continued until opportunistic infection occured. A 20 mg amount of epirubicin hydrochloride was injected intraarterially (bolus) once a month. Total dosages administered until October 1997 at discontinuation intervals were 21 500 mg for 5FU, 17 200 mg for cyclophosphamide, 60 mg for epirubicin hydrochloride, 814 000 JRU for TNF-[alpha] and 28 500 × 104 IU for IFN-[alpha]. During the treatments with cytokines and chemotherapeutic agents, the patient did not suffer from critical toxicity such as general malaise, severe bone marrow suppression or heart failure. The leukocyte count was 2300/mm3 at the bottom, because of the supportive treatment with granulocyte colony stimulating factor. Fever caused by cytokine administration was avoided by the use of NSAIDs. The serum calcium level, which was high (14.0 mg/dl) on admission, decreased to within the normal range by 1 week after beginning treatment. That elevation of serum calcium level was thought to be due to tumor destruction.
On October 29, 1990, Aspergillus pneumonitis related to opportunistic infection caused adult respiratory distress syndrome (ARDS). In the intensive care unit (ICU), respiratory and systemic control were performed. Improvement was achieved. After the general condition improved, the patient was started with oral administration of medroxyprogesterone acetate (Hysron H, 600 mg/day ) and transferred to a local clinic on January 7, 1991. Thereafter, she underwent intermittent therapy of arterial injection of epirubicin hydrochloride(20 mg) and 5FU (250 mg) and intravenous injection of CPA (100 mg).
CT and US revealed that the tumor nodes were markedly reduced. Changes in tumor markers are shown in Fig. 4. Since March 1991, levels of all markers have been within normal ranges.
Figure 4. The change of tumor markers and drugs administered are shown. After initial treatment, the serum levels of CA15-3 and CEA decreased rapidly. Tumor markers were within the normal range after January 1991. Concerning tumor markers, both CA12-5 and CEA levels are within normal ranges. The patient is continuing to work at the same workplace. CT revealed calcification in the liver, but there were no other abnormal findings (Fig. 5A-C). The reservoir was removed 7.5 years after insertion.
Figure 5. Computed tomography in 1998 showed calcification and deformity of the liver without a metastatic nodule in each slice (A, B, C). Among patients with liver metastasis from breast cancer, hepatectomy has been performed in those with solitary lesion and in some patients with only rare metastatic nodes and relatively good prognoses have been reported. However, these cases are extremely rare. Many patients with liver metastasis demonstrate multiple or diffuse hepatic metastasis, for which resection is not indicated (10). O'Reilly et al. (4) reported that hepatomegaly, jaundice and ascites were detected in 60, 13 and 7% of patients with liver metastasis from breast cancer, respectively, at diagnosis and that aspartate transaminase (AST) levels were increased in most patients. To treat liver metastasis, systemic chemotherapy and arterial injection chemotherapy with a catheter inserted into the hepatic artery are generally performed. The response rate for systemic chemotherapy is relatively favorable. However, the duration of response is short and this therapy does not currently contribute to improving the prognosis (4). O'Reilly et al. analyzed 312 patients and reported that the median survival after the diagnosis of liver metastasis was 3.8 months (4). Concerning the results of arterial injection chemotherapy, Fraschini et al. (11) reported that the response rate was 36% and that the median survival was 11 months. Stehlin et al. (12) reported that the response rate was 45% and that the median survival was 16 months in responders. In addition, the longest survival was 5 years. Hence prognoses do not currently reflect improvement in response rates for systemic chemotherapy and arterial injection chemotherapy. Generally, it has been reported that survival does not exceed 2 years (10). In recent years, therapeutic strategies after relapse of breast cancer have gradually changed. Since 1982, endocrine chemotherapy has been systematically used. In chemotherapy for recurrent breast cancer, the efficacy of adriamycin (ADM), methotrexate (MTX), 5-fluorouracil (5FU), cyclophosphamide (CPM), vincristine (VCR) and mitomycin C (MMC) has been demonstrated. Antitumor cytokines such as TNF-[alpha] and IFN-[alpha] have also been used in clinical practice. We previously reported that TNF-[alpha] and IFN-[alpha] exhibited synergistic antitumor effects on human-derived malignant tumor in vitro and in vivo. By analyzing the cellular cycle, we clarified that the mechanism involved S-phase accumulation and S to G2/M block (12-14). Furthermore, we performed combination cytokine-chemotherapy with TNF-[alpha], IFN-[alpha] and anticancer agents including 5-FU by applying actions that are synchronous with the S phase (15). In our patient, the possibility that inhibitory effects on the tumor were enhanced by combining endocrine chemotherapy with cytokines cannot be denied. In our patient, hormone-chemoimmunotherapy achieved complete regression. Rehabilitation was achieved after recovery, although pneumonitis related to opportunistic infection developed and ICU management for ARDS was required. There has been no relapse during the 8-year follow-up period after relapse. It is extremely difficult to achieve such a long survival in patients with diffuse liver metastasis from breast cancer. Multidisciplinary treatment may be most important for the initial treatment at relapse. Administering intensive therapy with anticancer agents in accordance with leukemia treatment under careful control before breast cancer cells develop drug resistance may be effective. Taking the results into consideration, these combined treatments including cytokines can be a rational therapy for metastatic breast cancer after analyzing the precise mechanism of actions and side effects. Our patient was a medical professional. Informed consent was sufficiently conducted regarding the state of the disease and treatment after this treatment was started. The patient's aggressive attitude may have favorably affected the treatment course.
Present General Condition
A
B
C
DISCUSSION
References
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Last modification: 23 Aug 1999
Copyright© 1999 Foundation for Promotion of Cancer Research.
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