A MULTIPLE CHEMOTHERAPEUTIC APPROACH TO THE MANAGEMENT OF HEPATOBLASTOMA

A Preliminary Report CIIARLENE P. HOLTON, MD,* JOHN D. BURRINGTON, MD,+ AND EDWIN I. HATCH, M D ~

In 1970, a staging based on surgical resectability of hepatic tumors was devised. Adjuvant chemotherapy with vincristine, 5-fluorouracil, and cyclophosphamide has been given to seven recent cases. Objectives of this study were to set up unified clinical staging and followup; to evaluate the effect of combination chemotherapy on survival in advanced disease; and to evaluate early adjunctive combination chemotherapy in surgically resectable lesions to, hopefully, prevent metastasis. Results to date in seven patients are: no change I in the poor prognosis of the three female patients presenting with Stage 111-IV hepatocellular carcinoma; the three males with Stage 1-11 hepatoblastoma have done well and survive free of disease at 47 months, 44 months, and 28 months; one patient with hepatoblastoma had lung metastasis at diagnosis and died at 7 months with tumor. No toxicity was noted with the use of adjunctive combina- tion chemotherapy following major hepatic resection.

Cancer 35:1083-1087, 1975.

Y 1970, A R E V I E W OF PRIMARY CHILD- I hood hepatic malignancy at the Children’s Hospital, Denver, and the University of Colo- rado Medical Center was undertaken jointly b y pediatric oncology and surgery. The fact that no 3-year survivors were found in a group of 20 children, treated in various ways, led to the establishment of a protocol for workup, staging, and therapy.

The review of the 20 children, ages 3 months to 17 years, revealed that 4 patients were treated with surgery alone; 4 with surgery plus single agent chemotherapy with either cyclophospha- mide (CVCLO), methotrexate (MTX), dac- tinomycin (DACTINO), or vincristine sulfate

Presented at the 10th Annual hleeting of the American Society ol Clinical Oncology, Houston, TX, March 27-28, 1974.

k‘rom the Children’s Hospital Oncology Center and the L‘niversity of Colorado hledical Center, Denver, CO.

Supported by National Cancer Institute Grant No. 1 PO2 CA 1 2 2 4 7 4 2 , and the American Cancer Society.

* Director, the Children’s Hospital Oncology Center. ‘ Surgeon-in-Chief, the Children’s Hospital. American Cancer Society Pediatric Oncology Surgical

Fellow. .4ddress for reprints: Charlene P. Holton, MD, Director,

the Children’s Hospital Oncology Center, 1056 E. 19th Ave., Deriver, C O 802111.

The authors are grateful to Gail Levine, MD, Blaise E. Favarn, hlU, William Bailey, MD, Joseph Browning, MD, James Carland, h.111, and Emily S. Wayrynen, Medical Secretary, for their technical assistance.

Received for publication June 7, 1974.

(VCR). Of the 7 patients with unresectable tumor, 3 underwent liver transplantations, 2 died during surgery, and 3 had distant metas- tasis when seen. These grim facts led us to: 1) set up a unified clinical staging based on the extent of the disease at diagnosis, 2) evaluate the effect of combination chemo- therapy on survival in advanced disease, and 3 ) assess the use of early adjunctive com- bination chemotherapy with surgically resect- able lesions, to, hopefully, prevent metastasis.

MATERIALS A N D METHODS

The charts, clinical data, and pathologic materials were studied in the 20 cases of hepatic cancer occurring before 1970. The 7 patients diagnosed since 1970 were placed on the newly designed hepatoma protocol.

An organized workup consisting of complete history, physical examination, and photograph was done. Laboratory evaluation included com- plete blood counts, phase platelet counts, bone marrow aspiration, reticulocyte counts, urinaly- sis, blood urea nitrogen, uric acid, and creati- nine. Liver function studies included bilirubin, protein electrophoresis, alkaline phosphatase, lactic acid dehydrogenase, prothrombin time, cholesterol, Australia antigen titer, and alpha- fetoprotein.

Radiologic evaluaticn included a posterior,

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C A N C E R April 1975 Vol. 35 1084

TABLE 1. Staging

I Unicentric lobar lesion less than 6 cm, resectable I1 Unicentric lobar lesion more than 6 cm

A. Margin clear B. M-argin involved C. Multicentric, 1 lobe

111 Multicentric, both lobes involved 1V Metastatic disease

A. Direct extension to adjacent viscera. B. Distant spread.

anterior, lateral, and oblique chest roentgeno- gram, an intravenous pyelogram, skeletal sur- vey, and liver scan.

The laboratory, clinical, and surgical extent of the disease was analyzed, and the patients' tumors were staged based on size, resectability, and extent of tumor (Table 1).

The therapy of the patient was based on the above staging (Table 2).

RESULTS

There were seven children entered on study: four boys with hepatoblastoma and three girls with hepatic carcinoma. Ages ranged from 2 Y2

months to 10 years. There was a history of jaun- dice shortly after birth in one patient of Chinese descent whose father had had hepatitis at age 15 years. One mother had taken Depo-provera dur- ing the early months of pregnancy. Her child was thought to have hypothyroidism and was place on dessicated thyroid. It is of interest that three of seven children were breast fed. There was no history of radiation or drug exposure, or

TABLE 2. Hepatoma 'Treatment

Stage I VCR 1.5 mg/m2 i.v. weekly

Surgery CYCLO 200 mg/m2 for 6 weeks 5-FU 200 mg/m2 and disc.

Stage 11 A, 8, C Surgery-Chemotherap y

Same as Stage I for 6 weeks, then every 2 weeks for 1 year

Stage 111-IV A, B Surgery if possible-Chemotherapy

VCK 1.5 mg/m2 i.v. weekly for CYCLO 300 mg/m2-6 wk, then every 5-FU 3UO mg/m2 wk for 2 yr

Progression Adriamycin 80-100 mg/m*i.v. every 3 wk, not to exceed 550 mg/m2 total dose. Radiation therapy for palliation as needed.

L2

unusual infections; nor was there a strong family history of cancer.

The liver scan was positive in five of seven cases, and the execretory urogram showed downward displacement of the right kidney in two of seven cases. Chest roentgenogram re- vealed pulmonary metastasis in two of seven patients. One patient had generalized de- mineralization of the skeletal system.

Thrombocytosis was noted in five of seven patients, ranging from 500,000 to 1,500,000 platelets per mm3. One patient with extensive hepatocellular carcinoma presented with anemia and jaundice. Liver function tests did not correlate with response, and were abnormal in four patients. Alpha-fetoprotein was positive in four patients, cholesterol was elevated in two patients, and one patient was noted to have foamy histiocytes on bone marrow examination.

The clinical presenting complaint was an ab- dominal mass in six of seven cases. The seventh patient presented with extensive wasting, jaun- dice, and hepatic failure at age 10 years. No patient was noted to have hemihypertrophy or virilization.

At surgery, three patients had disease in both lobes of the liver and were unresectable at diagnosis. All three of those who had disease limited to the right lobe had total right hepatic lobectomies. One patient had left lobectomy in spite of pulmonary metastasis. It was noted that five patients had evidence of extramedullary hematopoiesis on pathologic study.

Therapy was well tolerated; no hematologic or gastrointestinal toxicity was noted, except for occasional nausea and vomiting in three patients .

I t is of interest that all four patients with hepatoblastoma were male, and the three patients with hepatic carcinoma were in- operable and female. Response to therapy is noted in Table 3. The child in Fig. 1 is 47 months post-therapy and shows no evidence of long-term toxicity following therapy of extensive tumor of the right lobe, as noted in Fig. 2.

DISCUSSION

Primary cancer of the liver in children is rare. An epidemiologic study by Fraumeni, et al. has suggested an embryonal origin, since the peak incidence is during infancy in children with hepatoblastoma, whereas the hepatocellular carcinoma occuring in older children mimics the adult c a r ~ i n o r n a . ~

The histologic classification of malignant

No. 4 CHILDHOOD HEPATIC MALIGNANCY Holton et 01. 1085 TABLE 3 Results of 'Therapy According to Pathologic Diagnosis, Site, Stage, Age, and Sex

Age at Dx Sex DX Stage Site Status

1 I j m o F HC 111 R-L lobe DD 6 mo 2 10yr F HC IVA R-L lobe, DD 4 days

3 15mo F HC IVB R-L lobe, DD 3 mo

4 2 ' r m o M HB I R lobe NED 47 mo 5 10mo M HB IIC R lobe NED 44 mo 6 4k:mo M HB I I B R lobe NED 28 mo 7 17mo M HB IVB L lobe. D D 7 mo

abdomen

lung

lung

HC-hepatocarcinoma, HB-hepatoblastoma, NED-no evidence of disease, DD-died of disease

tumors in the liver of infants and children has significance in estimating prognosis; the hepatoblastoma patients generally do better than those with hepatocellular c a r c i n ~ m a . ~ ~ ~ ~ ~

The surgical management of hepatoblastoma was established in 1951 as excision of tumor.' In 1954, the first description of a right hepatic lobectomy in a child was reported by Debre.' Rickham raised the point in 1969 that if surgical excision of hepatoblastoma is feasible, why are the results so much worse than those following excision of other embryomas, for instance nephroblastoma, despite the fact that the lat- ter growth seems to produce earlier distant metastasis than hepatoblastoma? The possible explanation he advocated is that in cases of hepatoblastoma it is impossible to ligate all veins draining the tumor until the end of the operation, in contrast with the nephroblastoma, where early ligation of the renal vein is often possible.

Extensive hepatectomy is a challenge to sur- geons and anesthetists; even today, as in the past, preoperative and postoperative mortality is as high as 30 to 40% in cases operated on for trauma and tumor.

The use of radiation therapy in primary tumors of the liver has not been curative; the liver of the young child appears to be more sen- sitive to radiation damage. 13v1' For these reasons radiation therapy was used for palliation only in this study.

Various chemotherapeutic agents have been used in advanced disease in several dose schedules and routes. Vincristine, 5-fluorouracil (5-FU), MTX, and CYCLO have been reported to show occasional effect by several au- thorS.4,7.11.15 tumors Seem to respond well to combinations of

The fact that FIL. 1. The child is 47 months postsurgery and combina- tion chemotherapy. No prolonged toxicity was noted on re-

chemotherapy led us to devise the current cent examination.

1086 CANCER April 1975 VOl. 35

FIG 2. Extensive tumor of right lobe of liver noted at initla1 surgery in patient shown in Fig. 1.

schedule using intravenous VCR, CYCLO, and 5-FU, with Adriamycin as a Phase I1 agent for resistant cases with progressive disease.

The practice of using adjunctive combination chemotherapy even when there has been total resection of tumor seems logical in view of the fact that micrometastasis may already be pres- ent or may occur at the time this vascular tumor in a highly vascular organ is operated on. The fact that we now have three long-term sur- vivors since using adjunctive combination chemotherapy following hepatic lobectomy, in contrast with earlier cases that were also deemed totally resected and succumbed to their

disease, is encouraging. We will continue to ex- plore this method of therapy in hepatoblastoma of childhood. The cases with hepatocellular car- cinoma all presented very late in the course of disease and did not benefit from this chemotherapeutic regimen. However, we did see disease remain static for 2 and 3 months when Adriamycin was used as a second line of defense after progression on the triple drug regimen.

The need for early detection and aggressive surgery for the resectable lesions is proven. Ad- junctive chemotherapy with VCR, CYCLO, and 5-FU may be additive in the management of this aggressive and rare pediatric neoplasm.

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