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Treatment of Unresectable and Metastatic Hepatoblastoma: A Pediatric Oncology Group Phase II Study

From Department of Pediatrics and Surgery, Northwestern University and Children’s Memorial Hospital, Chicago, IL; Department of Statistics, University of Florida and Children’s Oncology Group Statistical Department, Gainesville, FL; AstraZeneca Pharmaceuticals LP, Wilmington, DE; Swiss Pediatric Oncology Group, Bern, Switzerland; Baylor College of Medicine, Houston, TX; and AFLAC Cancer Center, Emory University, and Children’s Healthcare of Atlanta, Atlanta, GA.

Address reprint requests to Howard M. Katzenstein, MD, Children’s Oncology Group, PO Box 60012, Arcadia, CA 91066-6012; email: howard.katzenstein{at}choa.org

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To estimate the disease-response rate, proportion of patients whose tumors can be made resectable, event-free survival (EFS), and toxicity in children with unresectable or metastatic hepatoblastoma (HB) after sequential treatment with the following: (1) carboplatin (CARBO); (2) CARBO, vincristine, and fluorouracil (CARBO-VCR-5-FU); and (3) high-dose cisplatin and etoposide (HDDP-ETOP).

PATIENTS AND METHODS: Thirty-three assessable patients with stage III (n = 22) and stage IV (n = 11) HB were treated sequentially with one course of CARBO (700 mg/m²), followed by three courses of CARBO (700 mg/m²), day 0; 5-FU (1,000 mg/m²/d), by continuous infusion days 0 to 2; and VCR (1.5 mg/m²), days 0, 7, and 14. After that therapy, patients whose tumors were resectable underwent surgery and then received two additional courses of CARBO-VCR-5-FU. Children whose tumors remained unresectable after CARBO-VCR-5-FU or who demonstrated no response or progressive disease during this therapy received two courses of HDDP (40 mg/m²/d), days 1 to 5; and ETOP (100 mg/m²/d), days 2 to 4.

RESULTS: Five-year EFS estimates were 59% ± 11% for stage III disease (n = 22) and 27% ± 16% for stage IV disease (n = 11), respectively (P = .037). Twenty-seven (82%) of 33 patients had at least a partial response to chemotherapy; 18 (55%) of 33 responded to CARBO; 24 (80%) of 30 responded to CARBO and CARBO-VCR-5-FU; and nine (75%) of 12 responded to HDDP-ETOP. Surgical resection was achieved in 19 (58%) of 33 patients, including 15 (68%) of 22 stage III patients and four (36%) of 11 stage IV patients. Five-year EFS for patients whose tumors were completely resected was 79% ± 10%.

CONCLUSION: Patients treated sequentially with CARBO, CARBO-VCR-5-FU, and HDDP-ETOP had response rates and EFS comparable to other therapeutic regimens. This regimen is effective in treating localized, unresectable HB and potentially has less toxicity than other regimens. Novel approaches are needed for patients with metastatic disease.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
HEPATOBLASTOMA (HB) is the most common primary liver tumor in children and typically presents in the first years of life as a palpable abdominal mass.^1,2 Surgical resection remains the foundation of curative therapy for HB, but unfortunately, these tumors are resectable in only half of newly diagnosed patients.^2-4 Metastatic disease at diagnosis portends an extremely poor prognosis, and patients rarely achieve long-term survival with chemotherapy and aggressive surgical resection of all tumor sites.^5-8

Cisplatin (CDDP), doxorubicin (DOX), vincristine (VCR), and fluorouracil (5-FU) in different combinations have demonstrated clinical activity in the treatment of HB.^9-11 Adjuvant chemotherapy with CDDP and DOX has improved the survival of patients with HB who have undergone a complete initial resection.^5,12 In children with unresectable HB, chemotherapy has also effectively enhanced the resectability of primary lesions. Survival rates for children with delayed complete resection are comparable to patients who had a complete resection at diagnosis.^{3,5,6,9,11-14} Dose intensification of CDDP has been demonstrated to be effective in improving response and survival in other pediatric embryonal malignancies but is associated with significant toxicity.¹⁵

Pediatric Oncology Group (POG) study 9345 was designed to increase therapeutic efficacy and diminish toxicity in children with unresectable and metastatic HB by incorporating carboplatin (CARBO) in lieu of CDDP, eliminating DOX, and adding weekly VCR and continuous infusion 5-FU. Patients whose tumors remained unresectable would have their therapy intensified with high-dose cisplatin (HDDP) and etoposide (ETOP). Herein, we report the use of sequential treatment with (1) CARBO, (2) CARBO-VCR-5-FU, and (3) HDDP-ETOP for children with unresectable and metastatic HB to improve tumor resectability and long-term survival in these children.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patients
POG study 9345 was open from May 1993 to February 1995. Patients were eligible for study if they were younger than 21 years old at diagnosis and had biopsy-proven HB that was either unresectable or metastatic at presentation and that had previously been untreated. Protocols were approved by the National Cancer Institute and the individual institutional review boards of participating POG institutions. Informed consent was obtained from all patients before study entry.

Stage of disease was determined by surgical criteria after the assessment of initial resectability as determined by the institutional surgeon in consultation with the treating oncologist, and after either a surgical resection or biopsy was performed before the initiation of chemotherapy. Stage III was gross total resection with nodal involvement, or incomplete resection with gross residual intrahepatic disease; and stage IV was metastatic disease with either complete or incomplete resection of the primary tumor or biopsy. Histologic diagnosis was confirmed by central review by one of the authors (M.J.F.).

Treatment
Patients were treated according to the schema in Fig 1. Patients were initially treated with one course of intravenous (IV) CARBO (700 mg/m² for patients 10 kg and 25 mg/kg for patients < 10 kg), administered over 1 hour, and were assessed for response. Patients then received three courses of CARBO (dosage as before), VCR (1.5 mg/m² for patients 10 kg and 0.05 mg/kg for patients < 10 kg, IV push), and continuous infusion 5-FU (1,000 mg/m²/d for patients 10 kg and 33 mg/kg/d for patients < 10 kg) provided for 72 consecutive hours and initiated immediately after CARBO. Additional doses of VCR were administered weekly, for 2 more weeks, as part of each course.

View larger version (21K): [in this window] [in a new window]   Fig 1. Treatment regimen and patient responses for POG 9345. Doses and schedules are provided in Patients and Methods. DOD, dead as a result of disease; PD, progressive disease; CR, complete response.

Patients then were reevaluated for resectability, and patients whose tumors were completely resected received no additional therapy and were observed. In patients whose tumors remained unresectable, protocol therapy was considered unsuccessful, and other therapeutic options were considered. Cycles of CARBO-VCR-5-FU were provided 3 weeks apart, and courses of HDDP-ETOP were provided 4 weeks apart, depending on recovery of peripheral neutrophil and platelet counts to 500 and 100,000 cells/µL, respectively. Treatment could be delayed as a result of myelosuppression for up to 2 weeks without any change in therapy. Delays of more than 2 weeks were to be discussed and managed on an individual basis with the study coordinator. Granulocyte colony-stimulating factor (5 µg/kg/d) was subcutaneously administered to all patients beginning 24 hours after the last dose of each course of chemotherapy and was discontinued when the absolute neutrophil count recovered to 1,000 cells/µL for 2 consecutive days.

Evaluation of Response
Physical examination, blood counts, serum -fetoprotein (AFP) levels, and appropriate imaging studies, including computed tomographic (CT) scans of the chest and either CT or magnetic resonance imaging scans of the abdomen, were performed before therapy. Subsequent physical examinations were performed and AFP levels assessed before every additional cycle of chemotherapy. Imaging studies were repeated before cycles 2, 3, and 5, and at the end of therapy. Patients were observed off therapy with physical examinations and AFP levels monthly for 6 months and then at 8, 10, 12, 15, 18, 21, 24, 28, 32, 36, 42, 48, and 60 months after the completion of therapy. Chest radiographs were performed at visits during the first year after the completion of therapy. Complete response (CR; no evidence of disease) was defined as no evidence of tumor by physical examination and CT scans or magnetic resonance imaging scans of the liver, and a normal AFP level. Partial response (PR) was defined as a decrease of 50% in the sum of the products of the maximum perpendicular diameters of all measurable lesions, with no evidence of new lesions or progression in any lesion. NR was defined as less than 25% decrease in the sum of the products of the maximum perpendicular diameters of all measurable lesions, with no evidence of new lesions or progression in any lesion. For purposes of this article, residual disease was defined as either a PR or NR. PD was defined as the increase of at least 25% in the sum of the maximum perpendicular diameters of all measurable lesions, or the appearance of a new lesion.

Toxicity of Treatment
Toxicity was graded on a scale of 1 to 4, according to common toxicity criteria. The specific toxicity scales used in this study are available from the Children’s Oncology Group Operations Office on request. Patients who developed grade 4 stomatitis lasting longer than 4 days had their 5-FU infusion reduced to 48 hours. Patients who experienced grade 4 neurotoxicity had their VCR held until symptoms resolved and then their therapy was reinstituted at half the initial dose. Audiometry was to be performed before the initiation of therapy, before each course of HDDP-ETOP, and at the end of therapy.

Statistical Methods
Estimates of survival rates were made by the method of Kaplan-Meier,¹⁶ and differences in survival curves were tested by a two-sided log rank test. All tests were performed at a significance level of 0.05 with SAS version 8 software (SAS, Cary, NC).

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patients
A total of 34 patients were enrolled onto the study. One patient was later determined to be ineligible because of an incorrect diagnosis (neuroblastoma), and data from this patient were excluded from analysis. The median age at diagnosis was 22 months (range, 2 days to 10 years). There were 21 male subjects and 12 female subjects (male:female ratio, 1.75:1). Twenty-two patients (67%) had stage III disease, and 11 patients (33%) had stage IV disease.

Central histologic review was performed on all patients. In three patients, the distinction between HB and hepatocellular carcinoma was difficult because of limited material for review after the initial biopsy. In all three patients, the final pathologic diagnosis of the treating institution was HB, and all patients remained on the study and are included in this analysis.

Survival
The 5-year event-free survival (EFS) for the entire cohort was 48% ± 9% (Fig 2), with a 5-year overall survival of 57% ± 9% and a median follow-up period of 6.2 years for the surviving patients (range, 1.3 to 7.0 years). Superior survival was observed in patients without metastatic disease, with 5-year EFS of 59% ± 11% and 27% ± 16% in stage III and IV patients, respectively (P = .037) (Fig 3). Overall estimates of survival at 5 years were similar, with 73% ± 10% in stage III and 27% ± 16% in stage IV, respectively (P = .012).

View larger version (8K): [in this window] [in a new window]   Fig 2. EFS curve for 33 children with HB.

View larger version (10K): [in this window] [in a new window]   Fig 3. EFS curves for children with HB according to stage of disease: stage III (n = 22) v stage IV (n = 11) (P = .037).

Twenty-four (80%) of 30 assessable patients (17 stage III and seven stage IV) experienced response to CARBO-VCR-5-FU; two patients exhibited PD and did not survive. Ten (71%) of 14 patients who had a CR after this therapy and surgical resection remained free of disease, with 5-year EFS of 71% ± 14%.

Nine (75%) of 12 assessable patients (six stage III and three stage IV) had responses to HDDP-ETOP, with two patients experiencing PD. As described above, the disease of four patients progressed before they could receive HDDP-ETOP, and two others did not receive this therapy because of parental refusal. Each of the five patients who had a CR after HDDP-ETOP and resection has remained free of disease, with a minimum follow-up period of at least 5.5 years. Among the 12 patients who received HDDP-ETOP, 5-year EFS was 42% ± 14%.

Surgical Results
Disease of 19 (58%) of the initial 33 patients were able to be completely resected. Fifteen (68%) of 22 stage III patients had complete resections, 11 after CARBO-VCR-5-FU and four after HDDP-ETOP. Four (36%) of 11 stage IV patients had a complete resection of the primary tumor, three after CARBO-VCR-5-FU and one after HDDP-ETOP. There was no difference in survival at 5 years for the 14 patients who had an earlier complete resection after CARBO-VCR-5-FU (71% ± 14%) compared with those who had a later resection after HDDP-ETOP (100%) (P = .20). Of the 19 patients whose disease was completely resected, 5-year EFS was 79% ± 10%, with a median follow-up period of 6.3 years (range, 1.3 to 7.0 years) for the 16 surviving patients (Fig 4). Three of the 14 patients who did not undergo a complete resection went on to receive an orthotopic liver transplant, and two are long-term survivors. Liver transplantation was not performed in the other unresectable patients because of either early progression (n = 9) or metastatic disease (n = 1). One additional patient was taken off the study at parental request and responded to alternative therapy with DOX.

View larger version (10K): [in this window] [in a new window]   Fig 4. EFS curves for children with HB according to surgical resectability: complete resection (n = 19) v no complete resection (n = 11) (P < .0001).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
In this therapeutic trial, a novel treatment regimen with intensification of therapy determined by tumor response was administered in an effort to improve the overall surgical resectability and decrease the long-term sequelae of children with unresectable and metastatic HB. Sequential administration of chemotherapy that included CARBO, followed by CARBO-VCR-5-FU and HDDP-ETOP, yielded at least partial tumor responses in 82% of patients, similar to what has been described in other regimens used to treat patients with gross residual disease.^5,6,12,13,17 Fifty-eight percent of patients were eventually amenable to resection, which is also similar to what has previously been reported.^3,5,9,11-13 Among 28 patients considered for resection after CARBO-VCR-5-FU, 14 underwent complete tumor resections, 12 were considered unresectable radiographically and received HDDP-ETOP, and two patients refused HDDP-ETOP treatment. The 5-year EFS rate for the 14 who were spared HDDP-ETOP was 71% ± 14%, whereas the 5-year EFS rate for the 12 who received HDDP-ETOP was 42% ± 14% (P = .122). Those who were spared HDDP-ETOP had good survival rates but avoided the nephrotoxic and ototoxic effects of HDDP. Not surprisingly, there was a trend toward improved survival for the patients who had a better initial response and did not receive intensification with HDDP-ETOP. However, there was no difference in EFS for patients who had either an early or a late CR. Importantly, then, the patients who did go on to receive the intensification portion of treatment had durable responses, which suggested that drug resistance was not increased by the time of HDDP-ETOP administration.

The ability to tailor chemotherapy administration on the basis of tumor responsiveness has been successfully employed in other pediatric tumors such as acute lymphoblastic leukemia and Hodgkin’s disease.^18,19 This approach might result in a lower incidence of both acute and long-term sequelae. Importantly, no permanent renal dysfunction was experienced by any patient on this study. Ototoxicity was still observed in this study, but with a much lower frequency in the patients who did not receive HDDP-ETOP. The occurrence of hearing loss in patients who did not receive HDDP supports the use of amifostine as a cytoprotectant in the current intergroup trial. The German Cooperative Group has previously reported the efficacy of CARBO and ETOP in treating 14 children with advanced and recurrent HB.²⁰ Although the previous use of CARBO in HB has been limited, it provides a less toxic agent to use in tumors that are most responsive to platinum-based compounds.^11,21 A PR was observed in 55% of patients after only one course of CARBO. It is difficult to compare this response to other agents such as CDDP and DOX that have only bee rarely reported after multiple cycles of single agent therapy.^10,21,22

In children with unresectable HB, chemotherapy has effectively enhanced the resectability of the primary lesion. Survival rates of children with delayed complete resection of HB are comparable to those of patients who underwent a complete resection at diagnosis.^{3,5,6,9,11-14} Ortega et al¹² noted an improved response rate and increased overall survival in 47 patients with initially unresectable or metastatic HB treated with CDDP and continuous infusion DOX in a study from the Children’s Cancer Group (CCG). Toxicity in that study included one chemotherapy-related death as a result of tumor lysis syndrome, four episodes of sepsis, three patients with significant hearing loss, two reversible episodes of cardiac dysfunction, and two patients who had to discontinue CDDP because of renal toxicity manifested by hypomagnesemia. POG pilot study 8697 used CDDP, single-dose VCR, and bolus 5-FU to treat children with HB and similarly found a high response rate that included 24 of 33 stage III patients who were able to undergo a delayed complete resection.⁵ There were no documented toxic deaths; two episodes of sepsis occurred, and three patients required hearing aids. Stage IV patients on both of these studies fared poorly.

The results of Pediatric Intergroup Hepatoma Protocol INT-0098 (POG-8945/CCG-8881) were reported in which patients with HB were randomized to treatment regimens consisting of either CDDP, VCR, and 5-FU, or CDDP and continuous-infusion DOX.⁶ There was no difference in survival between the two regimens with 5-year EFS of 64% (SD 5%) for 83 stage III patients and 25% (SD 7%) for 40 stage IV patients. Increased toxicity was observed in the patients treated with the DOX-containing regimen including three infection-related deaths and two cardiac-related deaths. Five-year EFS for the combined group of advanced stage patients who underwent secondary complete resection was 83% (SD 6%).⁶

A report from the International Society of Pediatric Oncology (SIOP) described the use of the platinum doxorubicin regimen to treat 138 patients with HB preoperatively.¹⁴ In comparison with the intergroup study, DOX was administered with a shorter duration of infusion (48 v 96 hours) and to a lower cumulative dose (360 v 480 mg/m²), and a slightly lower dose of CDDP was provided during a longer infusion (24 v 6 hours).⁶ However, comparisons between the SIOP study and this series are difficult because of the use of different staging systems and because the majority of patients in the SIOP study were treated preoperatively, regardless of whether the initial lesion was considered resectable. Tumor responses defined as "any tumor shrinkage associated with a serial decrease in the AFP level concentration" were observed in 82% of the SIOP patients, similar to the response rate in this study.

Complete surgical resection without orthotopic liver transplantation was performed in 72% of patients treated with preoperative chemotherapy. Toxicity included three chemotherapy-related deaths, seven surgery-related deaths, four patients with permanent cardiac dysfunction, and some degree of hearing loss in 32 patients, with at least six children requiring hearing amplification. Although 5-year EFS was 66% ± 7% for the entire group, a separate report from the same study demonstrated 28% ± 16% 5-year EFS in 31 patients with metastatic disease,⁷ which is quite similar to this series. Therefore, the therapeutic results in this POG series are comparable to other regimens, but with potentially less toxicity (Table 1).

	ACKNOWLEDGMENTS

 
Supported in part by grant no. CA309969 from the National Cancer Institute, Bethesda, MD.

We thank the clinical research associates of our member institutions for their hard work and diligence in data collection and their responses to our inquiries, and we thank Shaun Mason for editorial assistance.

	REFERENCES

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Submitted July 5, 2001; accepted March 21, 2002.

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