Treatment options for hepatoblastoma that is not resectable or…

Approximately 70% to 80% of children with hepatoblastoma have tumors that are not resected at diagnosis. COG surgical guidelines (AHEP0731 [NCT00980460] appendix) recommend a diagnostic biopsy without an attempt to resect the tumor in children with PRETEXT II tumors with less than 1-cm radiographic margin on the vena cava and middle hepatic vein and in all children with PRETEXT III and IV tumors.

Source links and citations

AHEP0731 [NCT00980460]

Treatment options for hepatoblastoma that is not resectable or is not resected at diagnosis include the following:

Chemotherapy followed by reassessment of surgical resectability and complete surgical resection.

Chemotherapy followed by reassessment of surgical resectability and orthotopic liver transplant.[54,71,98-103]

Source links and citations

Transarterial chemoembolization (TACE) and transarterial radioembolization (TARE). TACE and TARE may be used to improve resectability before definitive surgical approaches.[104-106]

Source links and citations

Tumor rupture at presentation, resulting in major hemorrhage that can be controlled by transcatheter arterial embolization or partial resection to stabilize the patient, does not preclude a favorable outcome when followed by chemotherapy and definitive surgery.[107]

Source links and citations

107

In recent years, most children with hepatoblastoma have been treated with chemotherapy. In European cancer centers, children with resectable hepatoblastoma at diagnosis are treated with preoperative chemotherapy, which may reduce the incidence of surgical complications at the time of resection.[54,56,73] Treatment with preoperative chemotherapy has been shown to benefit children with hepatoblastoma. In contrast, an American intergroup study of treatment of children with hepatoblastoma encouraged resection at the time of diagnosis for all tumors amenable to resection without undue risk. The study (COG-P9645) did not treat children with stage I tumors of well-differentiated fetal histology with preoperative or postoperative chemotherapy unless they developed progressive disease.[52] In this study, most patients with PRETEXT III and all PRETEXT IV tumors were treated with chemotherapy before resection or transplant.

Source links and citations

Patients whose tumors remain unresectable after chemotherapy should consider a liver transplant.[54,71,98-102] In the presence of features predicting unresectability, early coordination with a pediatric liver transplant service is critical.[78] In the COG AHEP0731 (NCT00980460) study, early referral (i.e., based on imaging done after the second cycle of chemotherapy) to a liver specialty center with transplant capability was recommended for patients with POSTTEXT III tumors with positive V or P and POSTTEXT IV tumors with positive F.

Source links and citations

Evidence (chemotherapy followed by reassessment of surgical resectability and complete surgical resection or liver transplant):

In the SIOPEL-1 study, preoperative chemotherapy (doxorubicin and cisplatin) was given to all children with hepatoblastoma with or without metastases. After chemotherapy, and excluding those who underwent a liver transplant (<5% of patients), complete resection was performed.[54]

Source links and citations

54

In the SIOPEL-1 study, preoperative chemotherapy (doxorubicin and cisplatin) was given to all children with hepatoblastoma with or without metastases. After chemotherapy, and excluding those who underwent a liver transplant (<5% of patients), complete resection was performed.[54]

The chemotherapy was well tolerated.

In the SIOPEL-1 study, preoperative chemotherapy (doxorubicin and cisplatin) was given to all children with hepatoblastoma with or without metastases. After chemotherapy, and excluding those who underwent a liver transplant (<5% of patients), complete resection was performed.[54]

Complete resection was obtained in 87% of children.

In the SIOPEL-1 study, preoperative chemotherapy (doxorubicin and cisplatin) was given to all children with hepatoblastoma with or without metastases. After chemotherapy, and excluding those who underwent a liver transplant (<5% of patients), complete resection was performed.[54]

This strategy resulted in an OS rate of 75% at 5 years after diagnosis.

Identical results were seen in a follow-up international study (SIOPEL-2).[56]

Source links and citations

56

The SIOPEL-3 study compared cisplatin alone with cisplatin and doxorubicin in patients with preoperative standard-risk hepatoblastoma. Standard risk was defined as tumor confined to the liver and involving as many as three sectors.[97][Level of evidence A1]

Source links and citations

The SIOPEL-3 study compared cisplatin alone with cisplatin and doxorubicin in patients with preoperative standard-risk hepatoblastoma. Standard risk was defined as tumor confined to the liver and involving as many as three sectors.[97][Level of evidence A1]

The resection rates and OS rates were similar for the cisplatin (95%) and cisplatin/doxorubicin (93%) groups.

In a pilot study, SIOPEL-3HR, cisplatin alternating with carboplatin/doxorubicin was administered in a dose-intensive fashion to high-risk patients with hepatoblastoma.[57]

Source links and citations

57

In a pilot study, SIOPEL-3HR, cisplatin alternating with carboplatin/doxorubicin was administered in a dose-intensive fashion to high-risk patients with hepatoblastoma.[57]

In 74 patients with PRETEXT IV tumors, 22 of whom also had metastases, 31 patients had tumors that became resectable, and 26 patients underwent transplant. The 3-year OS rate was 69% (± 11%).

In a pilot study, SIOPEL-3HR, cisplatin alternating with carboplatin/doxorubicin was administered in a dose-intensive fashion to high-risk patients with hepatoblastoma.[57]

Of the 70 patients with metastases enrolled in the trial, the 3-year EFS rate was 56%, and the OS rate was 62%. Of patients with lung metastases, 50% were able to achieve complete remission of metastases with chemotherapy alone (without lung surgery).

SIOPEL-4 (NCT00077389) was a multinational feasibility trial of dose-dense cisplatin/doxorubicin chemotherapy and radical surgery for a group of children with high-risk hepatoblastoma. Surgical removal of all remaining tumor lesions after chemotherapy was performed if feasible (including liver transplant and metastasectomy, if needed). Patients who underwent liver resection or liver transplant after three cycles of chemotherapy subsequently received two postoperative cycles of carboplatin and doxorubicin. Patients whose tumors remained unresectable after three cycles of chemotherapy received two cycles of very intensive carboplatin and doxorubicin before surgery. The primary tumor masses were identified as PRETEXT groups II (27%), III (44%), and IV (26%).[74][Level of evidence B4]

Source links and citations

SIOPEL-4 (NCT00077389) was a multinational feasibility trial of dose-dense cisplatin/doxorubicin chemotherapy and radical surgery for a group of children with high-risk hepatoblastoma. Surgical removal of all remaining tumor lesions after chemotherapy was performed if feasible (including liver transplant and metastasectomy, if needed). Patients who underwent liver resection or liver transplant after three cycles of chemotherapy subsequently received two postoperative cycles of carboplatin and doxorubicin. Patients whose tumors remained unresectable after three cycles of chemotherapy received two cycles of very intensive carboplatin and doxorubicin before surgery. The primary tumor masses were identified as PRETEXT groups II (27%), III (44%), and IV (26%).[74][Level of evidence B4]

Ninety-seven percent of patients (60 of 61) had a partial response with chemotherapy.

SIOPEL-4 (NCT00077389) was a multinational feasibility trial of dose-dense cisplatin/doxorubicin chemotherapy and radical surgery for a group of children with high-risk hepatoblastoma. Surgical removal of all remaining tumor lesions after chemotherapy was performed if feasible (including liver transplant and metastasectomy, if needed). Patients who underwent liver resection or liver transplant after three cycles of chemotherapy subsequently received two postoperative cycles of carboplatin and doxorubicin. Patients whose tumors remained unresectable after three cycles of chemotherapy received two cycles of very intensive carboplatin and doxorubicin before surgery. The primary tumor masses were identified as PRETEXT groups II (27%), III (44%), and IV (26%).[74][Level of evidence B4]

Eighty-five percent of patients (53) underwent complete macroscopic resection; tumor was microscopically present in five patients, all of whom are disease-free survivors.

SIOPEL-4 (NCT00077389) was a multinational feasibility trial of dose-dense cisplatin/doxorubicin chemotherapy and radical surgery for a group of children with high-risk hepatoblastoma. Surgical removal of all remaining tumor lesions after chemotherapy was performed if feasible (including liver transplant and metastasectomy, if needed). Patients who underwent liver resection or liver transplant after three cycles of chemotherapy subsequently received two postoperative cycles of carboplatin and doxorubicin. Patients whose tumors remained unresectable after three cycles of chemotherapy received two cycles of very intensive carboplatin and doxorubicin before surgery. The primary tumor masses were identified as PRETEXT groups II (27%), III (44%), and IV (26%).[74][Level of evidence B4]

Two patients died postoperatively.

SIOPEL-4 (NCT00077389) was a multinational feasibility trial of dose-dense cisplatin/doxorubicin chemotherapy and radical surgery for a group of children with high-risk hepatoblastoma. Surgical removal of all remaining tumor lesions after chemotherapy was performed if feasible (including liver transplant and metastasectomy, if needed). Patients who underwent liver resection or liver transplant after three cycles of chemotherapy subsequently received two postoperative cycles of carboplatin and doxorubicin. Patients whose tumors remained unresectable after three cycles of chemotherapy received two cycles of very intensive carboplatin and doxorubicin before surgery. The primary tumor masses were identified as PRETEXT groups II (27%), III (44%), and IV (26%).[74][Level of evidence B4]

There were 37 partial hepatectomies and 16 liver transplants.

SIOPEL-4 (NCT00077389) was a multinational feasibility trial of dose-dense cisplatin/doxorubicin chemotherapy and radical surgery for a group of children with high-risk hepatoblastoma. Surgical removal of all remaining tumor lesions after chemotherapy was performed if feasible (including liver transplant and metastasectomy, if needed). Patients who underwent liver resection or liver transplant after three cycles of chemotherapy subsequently received two postoperative cycles of carboplatin and doxorubicin. Patients whose tumors remained unresectable after three cycles of chemotherapy received two cycles of very intensive carboplatin and doxorubicin before surgery. The primary tumor masses were identified as PRETEXT groups II (27%), III (44%), and IV (26%).[74][Level of evidence B4]

The study had a total of 62 high-risk patients; 74% of patients (62%–84%) underwent resection.

SIOPEL-4 (NCT00077389) was a multinational feasibility trial of dose-dense cisplatin/doxorubicin chemotherapy and radical surgery for a group of children with high-risk hepatoblastoma. Surgical removal of all remaining tumor lesions after chemotherapy was performed if feasible (including liver transplant and metastasectomy, if needed). Patients who underwent liver resection or liver transplant after three cycles of chemotherapy subsequently received two postoperative cycles of carboplatin and doxorubicin. Patients whose tumors remained unresectable after three cycles of chemotherapy received two cycles of very intensive carboplatin and doxorubicin before surgery. The primary tumor masses were identified as PRETEXT groups II (27%), III (44%), and IV (26%).[74][Level of evidence B4] › The study had a total of 62 high-risk patients; 74% of patients (62%–84%) underwent resection.

The 3-year disease-free survival (DFS) rate was 76% (95% CI, 65%–87%).

SIOPEL-4 (NCT00077389) was a multinational feasibility trial of dose-dense cisplatin/doxorubicin chemotherapy and radical surgery for a group of children with high-risk hepatoblastoma. Surgical removal of all remaining tumor lesions after chemotherapy was performed if feasible (including liver transplant and metastasectomy, if needed). Patients who underwent liver resection or liver transplant after three cycles of chemotherapy subsequently received two postoperative cycles of carboplatin and doxorubicin. Patients whose tumors remained unresectable after three cycles of chemotherapy received two cycles of very intensive carboplatin and doxorubicin before surgery. The primary tumor masses were identified as PRETEXT groups II (27%), III (44%), and IV (26%).[74][Level of evidence B4] › The study had a total of 62 high-risk patients; 74% of patients (62%–84%) underwent resection.

The 3-year OS rate was 83% (95% CI, 73%–93%).

SIOPEL-4 (NCT00077389) was a multinational feasibility trial of dose-dense cisplatin/doxorubicin chemotherapy and radical surgery for a group of children with high-risk hepatoblastoma. Surgical removal of all remaining tumor lesions after chemotherapy was performed if feasible (including liver transplant and metastasectomy, if needed). Patients who underwent liver resection or liver transplant after three cycles of chemotherapy subsequently received two postoperative cycles of carboplatin and doxorubicin. Patients whose tumors remained unresectable after three cycles of chemotherapy received two cycles of very intensive carboplatin and doxorubicin before surgery. The primary tumor masses were identified as PRETEXT groups II (27%), III (44%), and IV (26%).[74][Level of evidence B4]

Of the 16 patients with PRETEXT IV tumors, 11 were downstaged after chemotherapy—6 patients to PRETEXT group III, 4 patients to PRETEXT group II, and 1 patient to PRETEXT group I. Twelve tumors became resectable; subsequently, four patients underwent a partial hepatectomy and eight patients underwent a liver transplant. For patients who presented with PRETEXT IV disease:

SIOPEL-4 (NCT00077389) was a multinational feasibility trial of dose-dense cisplatin/doxorubicin chemotherapy and radical surgery for a group of children with high-risk hepatoblastoma. Surgical removal of all remaining tumor lesions after chemotherapy was performed if feasible (including liver transplant and metastasectomy, if needed). Patients who underwent liver resection or liver transplant after three cycles of chemotherapy subsequently received two postoperative cycles of carboplatin and doxorubicin. Patients whose tumors remained unresectable after three cycles of chemotherapy received two cycles of very intensive carboplatin and doxorubicin before surgery. The primary tumor masses were identified as PRETEXT groups II (27%), III (44%), and IV (26%).[74][Level of evidence B4] › Of the 16 patients with PRETEXT IV tumors, 11 were downstaged after chemotherapy—6 patients to PRETEXT group III, 4 patients to PRETEXT group II, and 1 patient to PRETEXT group I. Twelve tumors became resectable; subsequently, four patients underwent a partial hepatectomy and eight patients underwent a liver transplant. For patients who presented with PRETEXT IV disease:

The 3-year DFS rate was 73% (95% CI, 51%–96%).

SIOPEL-4 (NCT00077389) was a multinational feasibility trial of dose-dense cisplatin/doxorubicin chemotherapy and radical surgery for a group of children with high-risk hepatoblastoma. Surgical removal of all remaining tumor lesions after chemotherapy was performed if feasible (including liver transplant and metastasectomy, if needed). Patients who underwent liver resection or liver transplant after three cycles of chemotherapy subsequently received two postoperative cycles of carboplatin and doxorubicin. Patients whose tumors remained unresectable after three cycles of chemotherapy received two cycles of very intensive carboplatin and doxorubicin before surgery. The primary tumor masses were identified as PRETEXT groups II (27%), III (44%), and IV (26%).[74][Level of evidence B4] › Of the 16 patients with PRETEXT IV tumors, 11 were downstaged after chemotherapy—6 patients to PRETEXT group III, 4 patients to PRETEXT group II, and 1 patient to PRETEXT group I. Twelve tumors became resectable; subsequently, four patients underwent a partial hepatectomy and eight patients underwent a liver transplant. For patients who presented with PRETEXT IV disease:

The 3-year OS rate was 80% (95% CI, 60%–100%).

In approximately 75% of children and adolescents with initially unresectable hepatoblastoma, tumors can be rendered resectable with cisplatin-based preoperative chemotherapy, and 60% to 65% of patients will survive disease-free.[108]

Source links and citations

108

In the United States, patients with unresectable tumors have been treated with chemotherapy before resection or transplant.[51,52,66,67] On the basis of radiographic imaging, most stage III and IV hepatoblastomas are rendered resectable after two cycles of chemotherapy.[109] A combination of ifosfamide, cisplatin, and doxorubicin followed by postinduction resection has also been used in the treatment of advanced-stage disease.[110] Some centers have also used extended resection of selected POSTTEXT III and IV tumors rather than liver transplant.[78,111-114] Other options, such as TARE and TACE, have been used to shrink residual tumor mass. TARE may also facilitate surgical resection by tumor shrinkage when added to chemotherapy.[106]

Source links and citations

The COG conducted a single-arm phase III trial (AHEP0731 [NCT00980460]) for patients with intermediate-risk hepatoblastoma. The study included 93 patients with unresectable nonmetastatic disease and 9 patients with a complete resection at diagnosis. All of the tumors had small cell undifferentiated histology. The addition of doxorubicin to standard treatment (cisplatin, fluorouracil, and vincristine) was assessed for feasibility and efficacy. In the 93 patients with initially unresectable disease, the 5-year EFS rate was 85% (95% CI, 79%–93%), and the OS rate was 95% (95% CI, 87%–98%).[115]

Source links and citations

Chemotherapy followed by TACE, then high-intensity focused ultrasound, showed promising results in China for patients with PRETEXT III and IV tumors, some of which were resectable. Patients did not undergo surgical resection because of parent refusal.[116]

Source links and citations

116

Treatment options for hepatoblastoma that is not resectable or not resected at diagnosis

Studies cited in this source section

Publication references