Pretransplant chemotherapy in pediatric hepatocellular carcinoma

Pretransplant ByThomas

Chemotherapy

in Pediatric

Carcinoma

A. Broughan, Carlos 0. Esquivel, David P. Vogt, Gregory C. Griffin, and Donald G. Norris Cleveland, Ohio; San Francisco, California; and Sacramento, California

l The prognosis for pediatric patients with hepatocellular carcinoma is poor, except for fewer than half the patients, who can be rendered disease-free with conventional liver resection, Multicentric, bilobar liver cancer remains unresectable, even after radiation and chemotherapy. Liver transplantation alone for primary hepatic cancer has had limited success. Chemotherapy has been reserved for use after transplantation, with little demonstrable benefit. A pilot program of pretransplant chemotherapy was undertaken. Four adolescent patients with unresectable, multicentric, bilobar hepatocellular carcinoma were staged noninvasively, underwent chemotherapy followed by a final staging laparotomy, and then had liver transplantation. Three of the four patients survived and have no evidence of recurrence 64.67, and 47 months after diagnosis and 76, 65, and 44 months after transplantation. Pretransplant chemotherapy has four potential advantages: (1) minimized risk of post-transplant opportunistic infections, (2) less tumor bulk at the time of transplantation, (3) fewer local recurrences, and (4) a lower rate of metastasis. Copyright o 1994 by W. 6. Saunders Company

INDEX WORDS: tion.

Hepatocellular

Hepatocellular

carcinoma, liver transplanta-

S therapy

URGICAL RESECTION is the cornerstone of for hepatocellular carcinoma. Too often, the cases are unresectable for cure, or they are resectable but the patients die of recurrent disease.1-4 Chemotherapy and radiation have been used in attempts to increase resectability and improve survival in pediatric patients with hepatocellular carcinoma.‘- Hepatoblastoma has proven more amenable to such treatment than has hepatocellular carcinoma. When an adolescent presented with a large nonfibrolamellar hepatocellular carcinoma and multiple bilobar lesions, the stimulus was provided to combine pretransplant chemotherapy and liver transplantation. Administering most of the chemotherapy before transplantation allowed a more intensive course of therapy to be given, minimizing the risk for posttransplant opportunistic infections. Based on the initial favorable experience with this patient, we report our experience with three other patients having nonfibrolamellar hepatocellular carcinoma who were treated in a similar fashion. MATERIALS AND METHODS The age range of the four patients was 10 to 17 years (Table 1). Patient 2 was the only female. Patients 1 and 2 were managed at the Cleveland Clinic Foundation, and patients 3 and 4 were treated at the California Pacific Medical Center. Patrents 1, 2, and 4 had serological evidence of previous hepatitis B infection; two surviving patients, 3 and 4. were carriers. Three patients were symptomatic,

Journalof Pediarnc Surgery, Vol29, No 10 Ioctober), 1994: pp 1319.1322

and patient 1 had a large asymptomatic abdominal mass discovered during evaluation for trauma. All patients had multiple bilobar, biopsy-proven hepatocellular carcinomas that were unresectable by conventional means. The pretransplant evaluation included computed tomography (CT) or magnetic resonance imaging (MRI) of the liver, chest x-rays, a bone marrow biopsy, measurement of the alpha-fetoprotein (AFP) level, and a liver biopsy. One patient underwent laparotomy before chemotherapy to attempt a hepatic lobectomy, but multiple bilobar lesions rendered the tumor unresectable, and only regional lymph node sampling was possible. Right atrial catheters were inserted in each patient to provide access for chemotherapy (Table 2) and total parenteral nutrition (TPN). The Cleveland group used a Pediatric Oncology Group protocol (POG no. 8103) with which they were familiar. The California group chose more simplified regimens and chose to give a short course of posttransplant chemotherapy. After chemotherapy and before transplantation, all patients underwent an exploratory laparotomy to be sure that no extrahepatic intraabdominal disease was present. Posttransplant follow-up has consisted of CT or MRI of the abdomen, chest x-rays, and measurement of the AFP level. The frequency of these tests was variable and has lessened over time. Orthotopic liver transplantation was conducted in a routine manner. An effort was made to excise the entire lesser omentum, and the vascular structures in the porta hepatis were skeletonized to remove all the lymphatic tissue. Cyclosporine and prednisone were used for immunosuppression. When the California group administered posttransplant chemotherapy, the doses of cyclosporine and prednisone were reduced by 50% to try to prevent infections.

RESULTS

Several different staging systems are available for describing the extent of disease in our patients. Using the TNM system, all our patients were stage IVA (T4, NO, M(Q6 According to Evans et al,’ our patients would be in group III; according to King et aJ4 they would have stage I disease. In summary, each patient had multiple lesions in both lobes of the liver, with no evidence of extrahepatic spread using noninvasive imaging, bone marrow biopsy, and pretransplant laparotomy. With chemotherapy, the patients had some degree of leukopenia, lost their hair, and became anorexic, requiring TPN. The two patients with chronic hepati-

From the Cleveland Clinic Foundation, Cleveland. OH: the California Pacific Medical Center, San Francisco, CA; and the University of California Davis Medical Center, Sacramento, CA. Date accepted: August 13, 1993. Address reprint requests to Thomas A. Broughan, MD, Universi@ of Texas Medical Branch, Department of Surgery, 301 Unrversity Blvd, Galveston, TX 77555-0538. Copyright o 1994 by WB. Saunders Company 0022-3468194/2910-0007$03.OOiO 7319

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BROUGHAN ET AL

Table 1. Clinical Features for Four Pediatric Patients With Hepatocellular

therapy, both livers could not be palpated. The other two patients had a less-dramatic partial response. Despite intense chemotherapy, all explanted livers had viable tumor cells. The tumor deposits were multiple and bilateral in all patients (Table 3). Patient 3 had portal vein invasion, but none had invasion of the hepatic veins or inferior vena cava. No disease was found in the abdomen outside of the liver. Patients 1,3, and 4 are alive and disease-free today, 76, 65, and 44 months after initial liver transplantation and 84, 67, and 47 months after diagnosis. The two hepatitis B carriers had reinfection of their grafts. Patient 4 required a second liver transplant 23 months after the first because of recurrent hepatitis B, and no hepatocellular carcinoma was found. Patient 2 died (38 months after diagnosis and 32 months after transplantation) of recurrent and metastatic hepatocellular carcinoma.

Carcinoma Patient No.

1

2

3

4

Date of orthotopic liver transplantation Age W Race

4tzwa7

II/I3/87

12/30/89

3/30/68

11

15

I7

IO

White

White

White

Oriental Yes

Symptoms and signs Pain

No

Yes

Yes

Weight loss

No

Yes

Yes

Yes

Hepatomegaly

Yes

Yes

Yes

Yes

Splenomegaly

No

No

Yes

Yes

Ascites

No

No

Yes

Yes

Laboratory values Total bilirubin (mg%)

0.6

3.0

2.6

0.4

64

365

237

63

Alanine transaminase (IU/L) Alkaline phosphatase (IU/Lj

341

340

591

116

AFP (ng/mL)

1,431

129,000

35,937

1,77I,OOO

Carcinoembryonic antigen (ng/mL) Ascites cytology

~2.3

52.3

No ascites No ascites

so.7

so.7

Benign

Benign

DISCUSSION

Primary hepatic carcinoma is rare in the pediatric age group, comprising 1.1% of all pediatric cancers and afflicting one in 1.4 million children.’ The incidence of hepatoblastoma predominates that of hepatocellular carcinoma, with a ratio ranging from 1.3:1 to 6.4:1.8 In a survey of the Surgical Section of the American Academy of Pediatrics (1974), it was noted that complete surgical excision could be obtained in 78 (60%) of 129 cases of hepatoblastoma, with 45 (35%) of 129 patients surviving disease-free.’ For hepatocellular carcinoma, the same survey showed complete surgical excision in 33 (36%) of 92 patients, with only 12 (13%) of 92 patients surviving diseasefree; the length of survival was not specified. None of

tis B were passively immunized with hepatitis B hyperimmune globulin during transplantation. The two California patients received posttransplant chemotherapy; in one, mucositis and fever developed, which required a short readmission to the hospital. While on chemotherapy, all the patients had a decrease in tumor size preoperatively, noted by CT scan. The two patients with the largest tumors had a greater-than-50% response to chemotherapy; both patients had been managed in Cleveland with POG protoco1 no. 8103. These liver masses were palpable at the iliac crest before treatment. After chemo-

Table 2. Adjuvant Chemotherapy PatientNo.

Before Orthotopic

LiverTransplantation Cycle 1

3

1

2

Vincristine I.5 mg/m*, days I

Vincristine I.5 mg/ms, days I

and 22; cyclophosphamide

and 22; cyclophosphamide

500 mg/m*, days 2 and 23;

500 mg/m2, days 2 and 23;

5-fluorouracil 500 mg/m2,

5-fluorouracil500

days 24 and 31; Adria-

days 24 and 31; Adria-

Adriamycin 60 mg/m*

Cisplatin 90 mg/m*; vincristine I.5 mg/mz: 5-fluorouracil600

mg/m*,

mycin 25 mg/m2, days I, 2,

mycin 25 mg/m2, days I, 2,

and 3; bleomycin 5 U/m*,

and 3; bleomycin 5 U/m2,

days 22,23 and 24: cis-

days 22,23 and 24; cis-

platin 3 mg/kg, day 25

Cisplatin 90 mg/m?

4

platin 3 mg/kg, day 25 Same as cycle I

None

Same as cycle 1

None

None

Same as cycle 1

None

None

None

Same as cycle I

Cycle 5

None

None

Same as cycle 1

Same as cycle I

Cycle 6

None

None

Same as cycle I

Same as cycle 1

Cycle 2

Same as cycle 1

Cycle 3

Cyclophosphamide

500 mg,

day 2; Adriamycin 25 mg/mz. days I, 2, and 3 Cycle 4 After transplantation

mg/m2

TRANSPLANTATION

FOR HEPATOCELLULAR

1321

CARCINOMA

Table 3. Pathological Findings of the Explanted Livers Vena Cava & nepatic Patient No

Abbreviations:

Vein Invasion

Tumor Necrosis

Cirrhosis

Bilateral

No

No

Yes

No

Yes

No

No

No

No

Yes

Yes

3 x 3 x 3 (LL)

Yes

No

No

Yes

Yes

Yes

6 x 8 x 8 (LLI

No

No

Yes

Yes

Yes

Yes

Size of Primary Tumor (cm)

Portal Vein Invasion

8 x 12 x 13 (RL) 7 x 9 x 15 (RL)

Multiple

Nodules

Yes

RL, right lobe; LL, left lobe.

these patients received chemotherapy preoperatively. The two barriers to better success noted in this survey were metastases and the inability to completely resect the neoplasm from the liver. Using intensive chemotherapy for incompletely resected hepatic cancer, King et al also reported a survival advantage for hepatoblastoma over hepatocellular carcinoma, 63% versus 17% at 2 years.4 For patients with initially unresectable or incompletely resected hepatoblastoma who had received chemotherapy followed by further surgery, the Children’s Cancer Group (CCG) reported a 66.6% predicted survival rate at 2 years, compared with a 7% survival rate (one of 14 patients) for those with hepatocellular carcinoma.3 Hepatocellular carcinoma remains a deadly neoplasm. Three of our four patients had evidence of hepatitis B infection, and two were carriers. Our results with liver transplantation and chemotherapy for these patients are promising compared with those of Ni et al, who reported on 49 children with hepatocellular carcinoma from Taiwan, where hepatitis B is endemic.8 A resectability rate of 9.8% and a median survival period of 4 months were noted. Only two of their patients lived for more than 2 years. Chemotherapy has pIayed two roles in the management of potentially curable primary hepatic cancer: conversion of an unresectable tumor into a resectable lesion, and prevention of recurrences in patients who have had apparent successful and complete resection. In choosing pretransplant chemotherapy, first we were trying to achieve tumor shrinkage. Although tumor size decreased considerably in two patients, partial resection was not possible. Second, we were trying to prevent recurrence. Resection of hepatocellular carcinoma must provide compIete resection of microscopic and gross disease, and it must preserve enough liver for function. Liver transplantation represents the ultimate in liver resection, but previous experience in treating hepatic cancer with transplantation alone has not produced totally favorable results.9J0 Iwatsuki et al described 25 liver transplant recipients who had nonfibrolamellar hepatocellular and no preoperative chemotherapy.9 Only five patients lived for more than 1 year, and only one of them was alive with no

evidence of disease at 15 months. Five of the 25 patients were children. All the children were dead by 14 months except one who had received postoperative chemotherapy and was alive at 6 months. In a later series from this group, four of nine patients who had transplantation for hepatocellular carcinoma survived for 2.3 & 1.2 years.‘O A Iaparotomy before chemotherapy was deleted from our protocol after the first patient. It had nothing to do with the strength of our reliance on the noninvasive imaging results. The point was that these children would be offered chemotherapy regardless of the initial laparotomy results. The laparotomy after chemotherapy and before transplantation was the critical step. Potentially, lymph node metastases could appear or disappear during chemotherapy, but only the nodal status and presence of intraabdominal metastases at the time of listing for transplantation counted. This thinking obviated an operation and a delay in starting chemotherapy while waiting for the patient to recover from a large operation. Our use of pretransplant chemotherapy and Iiver transplantation was a pilot program. Adult protocols for chemotherapy after liver transplantation for hepatocellular carcinoma are currently under investigation. In 1989, Haas et al reported the histopathology and prognosis of childhood hepatoblastoma and hepatocellular carcinoma for 196 patients, gathered from the Children’s Cancer Group, Southwest Oncology Group, and Pediatric Oncology Group studies.5 The patients with “resectable or gross residual but not metastatic disease” underwent surgery, radiotherapy and/or chemotherapy, and possible further surgery. Six hepatocellular carcinoma patients (21%) had complete resection, 13 (46%) had no metastasis outside of the liver, but complete resected could not be obtained, and nine had metastases. It is the 46% of patients with no metastases but with unresectable tumors that pretransplant chemotherapy and liver transplantation could benefit. Hepatocellular carcinoma is a very aggressive neoplasm that frequently is multiple and bilobar. The outcome after conventional resection or liver transplantation alone has been poor. Giving the bulk of therapy before transplantation minimizes the chances

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BROUGHAN ET AL

of posttransplant opportunistic infection. At this time, chemotherapy and liver transplantation provides the best opportunity to decrease tumor bulk and control recurrence and metastases. This pilot pro-

gram of pretransplant chemotherapy and liver transplantation provides hope for the sizable percentage of children who have no metastases but have unresectable tumors despite chemotherapy and/or radiation.

REFERENCES 1. Exelby PR, Filler RM, Grosfeld JL: Liver tumors in children in the particular reference to hepatoblastoma and hepatocellular carcinoma: American Academy of Pediatrics Surgical Section Surgery-1974. J Pediatr Surg 10:329-337,1975 2. Evans AE, Land VJ, Newton WA, et al: Combination chemotherapy (vincristine, Adriamycin, cyclophosphamide, and 5-fluorouracil) in the treatment of children with malignant hepatoma. Cancer 50:821-826,1982 3. Ortega JA, Krailo MD, Haas JE, et al: Effective treatment of unresectable or metastatic hepatoblastoma with cisplatin and continuous infusion doxorubicin chemotherapy: A report from the Children’s Cancer Study Group. J Clin Oncol9:2167-2176,199l 4. King DR, Ortega J, Campbell J, et al: The surgical management of children with incompletely resected hepatic cancer is facilitated by intensive chemotherapy. J Pediatr Surg 26:1074-1081, 1991 5. Haas JE, Muczynski KA, Krailo M, et al: Histopathology and

prognosis in childhood hepatoblastoma and hepatocarcinoma. Cancer 64:1082-1095,1989 6. American Joint Committee on Cancer. Liver (including intrahepatic bile ducts), in Beahrs OH, Henson DE, Hutter RVP, et al (eds): Manual for Staging of Cancer (ed 4). Philadelphia, PA, Lippincott, 1992, pp 87-89 7. Silverberg E, Lubrea J: Cancer statistics 1986. CA Cancer J Clin 36:9-25,1986 8. Ni YH, Chang MH, Hsu HY, et al: Hepatocellular carcinoma in childhood: Clinical manifestations and prognosis. Cancer 68:17371741,1991 9. lwatsuki S, Gordon RD, Shaw BW Jr, et al: Role of liver transplantation in cancer therapy. Ann Surg 202:401-407,198s 10. Tagge EP, Tagge DU, Reyes J, et al: Resection, including transplantation, for hepatoblastoma and hepatocellular carcinoma: Impact on survival. J Pediatr Surg 27:292-297, 1992