The article, Management of Hepatocellular Carcinoma, by
Drs. Nakakura and Choti, is an excellent, comprehensive overview of
the treatment modalities used for one of the most challenging
cancers. The thoroughness of this review underscores the current
frustration of the clinician in the management of this disease and
the inadequacies of available therapies. The authors list more than
17 treatments for the various stages of this disease. However, if any
one of the therapies mentioned offered cure to a majority of
patients, there would be little need for more review articles or
randomized controlled trials. There are few cancers that command such
a vast array of differing therapies from so many different specialties.
No Successful Therapies
Most of the treatments mentioned in the article have been in use in
some form for over 20 years. The authors note that any therapy a
physician chooses should be properly assessed in prospective
randomized clinical trials. The problem is not a lack of clinical
trials but that none has resulted in therapies that are particularly
successful. The reason for this is threefold.
First, the pathophysiology and biology of hepatocellular cancer (HCC)
is unclear. No genetic predisposition or genetic defect associated
with a specific causative environmental factor has been identified.
There is a strong association with numerous hepatotoxins, but none
have been shown to cause a specific reproducible genetic defect that
results in HCC. Further investigation of the basic biology of this
disease is necessary if we are to make a major therapeutic advance.
The second factor that has hindered the development of effective
treatments is, as Nakakura and Choti indicate, the lack of randomized
controlled prospective trials. This is due, in part, to the fact that
there are few centers in the United States that have enough HCC
patients to participate in large-scale studies. The worldwide
incidence of this disease is alarmingly high, but in the United
States, it is less common than breast, prostate, lung, and other
gastrointestinal cancers. There would need to be a unique
collaborative effort among multiple US centers in order to conduct a
randomized controlled trial.
Impact of Hepatocellular Function
The third factor that impedes the development of novel therapies is
the behavior of the tumor. Hepatocellular cancer grows rapidly.
Because it involves a major organ that cannot be removed or replaced,
if left untreated, it results in death from liver failure within 3 to
6 months. In addition, just as any tumor treatment depends to some
degree on the stage at which it is discovered, staging of
hepatocellular function is equally important because it determines
the ability of the liver to tolerate therapy. The need to assess the
level of organ function is not critical in the treatment of most
All available therapies for HCC have a dramatic impact on hepatic
function, and most require intact hepatocellular function for the
patient to survive. Intact hepatocellular function is essential for
clearance and degradation of chemotherapeutic agents. Radiation
therapy also has a significant impact on hepatic function, and
surgical therapies result in the direct removal of parenchyma that
immediately diminish hepatic function.
Hepatocellular cancer is frequently associated with impaired hepatic
parenchymal function and cirrhosis, thus increasing the complexity of
choosing an appropriate therapy. Both tumor and hepatocellular
function should be simultaneously staged during the evaluation for
Considerations for Therapy
In the treatment of this disease, some therapies considered more
effective from a cancer control standpoint cannot be implemented
because of hepatic parenchymal disease, and other therapies
considered superior from a hepatic function standpoint are less
attractive as anticancer treatments. The management strategy outlined
in Nakakura and Chotis review is reasonable, but most centers
use the following five disease groupings to classify therapies: (1)
early-stage disease with good hepatocellular function; (2)
early-stage disease with poor hepatocellular function; (3) advanced
local/regional disease with good hepatocellular function; (4)
advanced local/regional disease with poor hepatocellular function; or
(5) extrahepatic/systemic disease.
Standards of Care
Drs. Nakakura and Choti list many treatments, but there are only four
widely accepted treatments that are considered standard of care. Many
of the other treatments mentioned evolved from phase I or phase II
trials, and should not be recommended as standard therapies.
The accepted therapies include hepatic resection, hepatic
transplantation, percutaneous ethanol injection, or intra-arterial
chemotherapies including chemoembolization. Patients should undergo
hepatic resection if they have early-stage disease and good hepatic
function. Patients with poor hepatic function and early disease
should be considered for hepatic transplantation. Percutaneous
ethanol injection can also be used in the case of poor hepatic
function (Childs C).
Patients with advanced local disease (nodular variant or unresectable
fibrolamellar) and good hepatic function should undergo
intra-arterial chemotherapy or chemoembolization. Those with advanced
local disease and poor hepatic function should undergo
chemoembolization, whereas patients with systemic disease should be
offered palliative care.
Many authors recommend that patients with stage IV advanced
local/regional disease and poor hepatic function or systemic disease
should be enrolled in phase I or phase II trials. Most surgical
oncologists believe that appropriate phase I or phase II trials
should be offered to patients at all stages of disease, if there is a
significant opportunity for improved outcomes.
A Nonhierarchical Approach
Prospective randomized trials in HCC require multi-institutional
cooperation and a multidisciplinary approach, as the current
treatment paradigms involve cross-disciplinary evaluation and
management. The latter emphasizes the need to abandon the traditional
vertical paradigm of patient evaluation by primary care physicians,
medical oncologists, radiation oncologists, and surgeons. A
multidisciplinary team that comprises radiation oncologists, medical
oncologists, surgical oncologists, and interventional radiologists
should undertake the initial management of the patient with
hepatocellular carcinoma, including the diagnostic evaluation of the
A nonhierarchical approach to treatment is the single most important
step toward significant advances in therapeutic outcomes. This
approach obviates many delays in therapy that now occur as a result
of evaluations that may take from 3 to 6 months and that
significantly alter the patients chances for effective therapy
James V. Sitzmann, MD
1. Sitzmann JV: Hope for a cure through earlier detection of
hepatocellular cancer. Ann Surg Oncol 6(2):619-629, 1999.
2. Sitzmann JV: Malignant liver tumors, in Cameron JL (ed): Current
Surgical Therapy, pp 343-346. Mosby, St. Louis, 1998.