Chemo Plus Transplant Promising For Advanced Hepatocellular Cancer

MONTREAL, Canada--Combining neoadjuvant chemotherapy and livertransplantation appears to be a very encouraging approach forpatients with advanced stage primary hepatocellular carcinoma(HCC), Brian I. Carr, MD, FRCP, PhD, said at the 19th InternationalCongress of Chemotherapy.

Results from a preliminary study show that a combination of thetwo therapeutic modalities offers a significant improvement insurvival over liver transplantation alone for these patients,who generally have a very poor prognosis, said Dr. Carr, professor,Hepatobiliary Tumor Service, Transplant Institute, Universityof Pittsburgh.

Initial efforts to improve survival in patients with advancedprimary HCC involved the selective delivery of chemotherapy throughthe hepatic artery. Dr. Carr explained that unlike metastaticcancer involving the liver, primary HCC is peculiar in that itsblood supply is fed almost completely by the hepatic artery, whereasthe normal liver is fed by the portal vein.

Blocking the Hepatic Artery

It was felt possible that the blood supply to the tumor couldbe blocked by obstructing the hepatic artery, either by physicalligation or by some agent such as gelatin, polyvinyl iodine, orglass beads.

Unfortunately, this approach was only partially successful, Dr.Carr said, since most patients with HCC have both cancer and cirrhosis,and in cirrhosis patients, interfering with the hepatic arterycan be dangerous.

A phase I/II study was carried out in two steps to ascertain whetherchemotherapy and a new blocking agent, degradable starch microspheres,would provide an effective and safer approach than previous techniquesfor the treatment of primary HCC, Dr. Carr said.

The two most currently useful drugs, doxorubicin 30 mg/m²and cisplatin (Platinol) 100 mg/m², were administered every4 to 5 weeks. At the same time, the starch microspheres were infusedinto the hepatic artery until there was complete cessation ofblood flow by angiogram.

Twelve patients were entered in the first step of the trial, andwhen more than three positive responses were recorded, the secondpart of the study, encompassing up to 38 patients, was instituted,Dr. Carr said. In 26 evaluable patients (three too early to evaluateand nine uneval-uable), there were two complete responses and13 partial responses, for a total objective response rate of 58%.Eleven of these individuals are alive at greater than 1 year.

Response Rate Plateaus at 60%

The problem with this approach is that while many institutionscan now get objective responses of 50% to 60%, higher responserates cannot be achieved, Dr. Carr said.

He added that a single drug used to its maximum effect might possiblybe more efficacious, and that one such drug should be selectedand a maximum tolerated dose developed for use in the presenceof cirrhosis.

The Pittsburgh researchers also began to think about transplantationas a treatment for more advanced (stage III or IVa) HCC, Dr. Carrsaid. They reasoned that if a simple surgical resection couldnot be done because of the late stage of disease, because bothlobes of the liver were involved, or because of underlying cirrhosis,removal of the whole liver and transplantation might be the wayto go.

The difficulties with this approach in advanced HCC, as with othertypes of advanced cancer, were recurrence rates of 80% and deathwithin 1 year, an unacceptable condition for a $200,000 operationwith its own mortality rate of 10%.

Since surgery can remove the bulk of the disease but not the microscopicdisease, and chemotherapy has the potential for removing the microscopicdisease, it makes sense to attempt a multimodality approach totreatment, Dr. Carr said.

The University of Pittsburgh was one of the first institutionsto accumulate a series of such patients. In 1992, results fromthe first 18 patients showed that three cycles of intraarterialchemotherapy involving doxorubicin and cisplatin prior to transplantproduced a 90% survival rate at 1 year, instead of the usual 80%recurrence rate.

Now, at almost 5 years follow-up, in 26 evaluable patients, 16persons with advanced HCC are disease free from 16 to 55 months,with a median time of survival of 44 months, Dr. Carr pointedout. This is a considerable improvement over liver transplantationalone.

It is obvious, he said, that a randomized study of chemotherapyplus transplantation versus transplantation alone is needed. Sinceno single institution could do this because of the small numberof transplants done in cancer patients, this would be an idealsituation for a multi-institutional study to answer an importantquestion about a potentially valuable, but expensive, procedure.