Children With Hepatoblastoma: Could Less Chemo Be Used?

Alexander M. Castellino, PhD

November 05, 2014

A retrospective analysis of data on children with hepatoblastoma has suggested that many of these cases are resectable after only two cycles of chemotherapy.

However, a small proportion of tumors that were still unresectable after two rounds became resectable after a further two cycles of chemotherapy.

The results come from a study published online October 28 in the British Journal of Surgery, which reviewed data on 20 pediatric patients.

At initial diagnosis, 80% of these tumors were considered unresectable; this decreased to 35% after two courses of chemotherapy and then to 20% after four courses of chemotherapy.

Most Common Liver Cancer in Children

Hepatoblastoma is the most common malignant tumor of the liver in children under age 5 years, explained senior investigator Leo Mascarenhas, MD, liver tumor oncologist in the Division of Hematology, Oncology and Bone Marrow Transplant at the Children's Hospital in Los Angeles, California.  Surgical resection of the primary tumor — whether done immediately or after one or several rounds of chemotherapy — is essential for cure, he said.

Many patients with initially unresectable hepatoblastoma can have their livers resected after two courses of preoperative chemotherapy, and some after four courses. Further courses of chemotherapy are not helpful, and the children whose tumor remains unresectable after four courses of chemotherapy are candidates for liver transplants, Dr Mascarenhas told Medscape Medical News.

In the standard clinical management of hepatoblastoma, pediatric patients are provided a combined total of six courses of preoperative and postoperative chemotherapy, he noted. The data from this study suggest that chemotherapy could be reduced in up to 65% of children with hepatoblastomas compared with the current standard of care.

Important to Seek Expertise in Hepatoblastoma

Approached for comments, Howard M. Katzenstein, MD, medical director of the Division of Hematology and Oncology at the Vanderbilt University Medical School, Nashville, Tennessee, told Medscape Medical News that the conclusions of this study are very important in the management of these patients.

Hepatoblastoma is a surgical disease and needs to be treated "aggressively" to remove the tumor as early as possible. This study suggests that imaging be done after a few courses of chemotherapy to determine whether the tumor is resectable, he added.

Dr Katzenstein also provided insights into the differences in philosophical approaches to treating these children in the United States and elsewhere in the world. "We have a more aggressive approach to undertake upfront surgery. Our international colleagues tend to give CT [chemotherapy] upfront to make the tumor smaller before surgery," he said.

In addition, given the rarity of hepatoblastomas, not all cancer centers have expertise in their clinical management. Thus, in cases of uncertainty or discomfort about how to manage these children, physicians should not hesitate to contact centers where this expertise is readily available. It is in the best interests of patients, Dr Katzenstein said.

Effect of Chemotherapy on Surgical Resection of Pediatric Hepatoblastoma

In the study, researchers reviewed 57 radiographic images from 20 patients with grade III and IV surgically unresectable hepatoblastomas who were treated at the Children's Hospital Los Angeles between 1991 and 2008. Of the 20 patients analyzed in the study, 18 underwent surgical resection of their hepatoblastomas.

A pediatric surgeon and a pediatric transplant surgeon with extensive experience in hepatic surgery determined surgical resectability. The surgeons were blinded to when the children actually underwent surgery.

On the basis of blinded radiographic evaluation, six of 20 tumors (30%) were considered resectable (downstaged) after two courses of chemotherapy and three (15%) were considered resectable after four courses.

In addition, five of seven tumors considered unresectable after two courses and four that were unresectable after four courses of CT would qualify the patient for liver transplantation, the researchers noted.

Patients appropriate for liver transplantation can be identified early and should not have to go through the long-term adverse effects of chemotherapy, which can include compromised hearing, kidney, and cardiac function, the researchers concluded.

Dr Katzenstein agreed. "It is important to identify patients who are candidates for liver transplant as expeditiously as possible. If we wait longer, patients will get more CT, which they do not need," he said.

The Hypothesis Being Tested

Dr Mascarenhas said earlier work suggested that effectiveness of chemotherapy plateaued after two courses. However, current consensus is to resect tumors following four courses of chemotherapy and to attempt early resection if surgical management was possible after two courses.

The researchers tested the hypothesis that surgical resectability did not improve after two courses of chemotherapy.

Nearly half of the tumors considered inoperable after just two courses of chemotherapy were actually resectable after four. This is in contrast to the researchers' own hypothesis, based on prior observations of tumor response to chemotherapy, Dr Mascarenhas told Medscape Medical News.

Surgical resection of hepatoblastoma is curative for children, Dr Mascarenhas explained to Medscape Medical News. Because pediatric survivors have a long life ahead, it is important to reduce the long-term effects of chemotherapy, he added.

Limitations and Future Direction

The small sample size and the different chemotherapy regimens used upfront were some of the limitations of the study, Dr Mascarenhas explained.

The two chemotherapy regimens currently used in clinical management of hepatoblastomas include the regimens of cisplatin, 5-fluorouracil, and vincristine and of cisplatin and doxorubicin.

In their discussion, the researchers write, "Presently, patients who undergo tumor resection after 2 courses continue to receive 4 chemotherapy courses post-surgery. It is not clear if 4 additional chemotherapy courses are needed to treat possible microscopic disease. Since hepatoblastoma is a rare cancer, this question can be answered only in prospective cooperative group studies."

Currently, the ongoing AHEP0731 study is addressing several questions:

  • In the very-low-risk group, is postoperative chemotherapy needed at all?

  • In the low-risk group, are two courses of chemotherapy (cisplatin, 5-fluorouracil, and vincristine) after surgery enough?

  • In the intermediate-risk group that will receive six courses of chemotherapy, how will the combination of all four drugs (cisplatin, 5-fluorouracil, vincristine, and doxorubicin) improve surgical resectability? What is the efficacy of two vs four courses of preoperative chemotherapy?

In addition, an international study is being planned to evaluate which chemotherapy to use and whether two courses of preoperative chemotherapy followed by two courses of postoperative chemotherapy is sufficient for surgical resection.

In the current retrospective analysis, researchers did not include children who had enrolled in the AHEP0731 study. The study in a small group of pediatric patients suggests that earlier surgery and reduced chemotherapy exposure after surgery could lead to an overall reduction in complications from chemotherapy. Results from the AHEP0731 study are awaited for confirmation.

This study was funded in part by a grant from the Names Family Foundation to Dr. Mascarenhas. The authors and Dr Katzenstein have disclosed no relevant financial relationships.

Br J Surg. Published online October 28, 2014. Abstract

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