Non-surgical Treatment
Multidisciplinary Approach to Hepatocellular Carcinoma
The treatment of Hepatocellular Carcinoma (HCC) is quite
challenging and requires a multidisciplinary approach. A recent review of patients seen at
M. D. Anderson Cancer Center (MDACC) indicated that the population attributable risk (PAR)
for HCC was 23.9% due to hepatitis C virus (HCV), approximately 10% due to hepatitis B
virus (HBV), and approximately 41% related to daily alcohol consumption, while in 25% no
clear cause could can be identified. At least 50%-60% of all HCC patients seen at M. D.
Anderson Cancer Center have associated liver cirrhosis which can be clinically diagnosed.
The presence of liver cirrhosis presents a major challenge to the treatment of
hepatocellular carcinoma. Associated thrombocytopenia and neutropenia excludes the use of
myelosuppressive chemotherapy. Ascites, and third spacing associated with intravascular
hypovolemia may prohibit the use of agents such as cisplatin which require intravascular
volume expansion. Hyperbilirubinemia may prevent the use of anthracyclines or require dose
adjustments. Commonly present portal vein occlusion by clot or tumor may rule out in most
cases effective hepatic artery chemoembolization. Patients who have severe encephalopathy
and liver failure are more likely to die from liver failure rather than from HCC. Thus,
treatment of hepatocellular carcinoma has to take into consideration the residual
functioning liver reserve.
Small HCC liver lesions may be managed by interventions such as
resection, radio frequency - or cryo-ablation, alcohol ablation, or even orthotopic liver
transplantation (OLT). Obviously, such interventions are limited by the size, the number,
the location of tumors and the underlying liver reserve. Most importantly, none of these
interventions will deal with micrometastatic disease or additional primary lesions present
in the liver or outside the liver. Moreover, the need for anti-rejection drugs following
OLT may promote tumor growth and accelerate tumor recurrence.
For all these reasons our approach has taken into consideration
underlying liver disease, and the potential presence of micro-metastatic HCC and has
focused on investigating systemic therapies reserving liver directed therapy to patients
with disease limited to the liver who may become candidates for tumor resection,
radiofrequency ablation (RFA), cyroblation or for OLT.
When opting for liver directed therapy, we have preferred hepatic
arterial infusion (HAI) of chemotherapy over hepatic artery chemoembolization for the
following reasons:
Hepatic artery infusion of chemotherapy is feasible even in the
presence of portal vein occlusion, hepatofugal blood flow, and it can be accomplished with
implantable infusion pumps.
Hepatic artery chemoembolization requires arteriography, it is
contra-indicated in the presence of severe portal hypertension, portal vein occlusion,
hepatofugal blood flow, and decompensated liver cirrhosis.
Repeated chemoembolizations are commonly associated with
occlusion of the hepatic artery, preventing further access to it and precluding further
arterial therapy.
Naturally, when opting for hepatic artery infusion over hepatic
artery chemoembolization, the advantage of increased local drug concentration, prolonged
drug dwell time and associated the anti-tumor effect of ischemia induced by hepatic artery
chemoembolization are forfeited.
With these considerations, we have opted for hepatic arterial
infusional chemotherapy delivered most commonly via an implantable hepatic artery infusion
pump. Placement of such a pump secures patency of the hepatic artery and allows long term
liver directed therapy.
Our current HAI treatment for HCC utilizes four agents: cisplatin
(P) recombinant interferon a -2b (rIFNa
-2b) (I), doxorubicin (A) and 5-fluorouracil (5-FU) (F) using the acronym PIAF. All the
agents including rIFNa -2b are delivered into the hepatic
artery.
When choosing systemic therapies, one has to assess the
patient’s underlying liver disease so as to increase benefit and minimize the risk
associated with treatment. The following algorithms demonstrate our current approach to
treatment based on the patient’s underlying liver reserve (Figures 1 & 2). Thus,
treatment of HCC in the absence of liver cirrhosis or when child A liver cirrhosis is
present commences with investigational agents that are given as part of phase II trials
followed by re-staging after two treatment cycles. Patients who respond to treatment will
obviously continue with the same therapy. Our current of front-line treatment is with a
Topoisomerase I inhibitor, DX-8951f manufactured by Daiichi Pharmaceuticals. The most
significant associated toxicity has been myelosuppression. One minor response has been
observed among the first 12 patients and therefore the study continues. Patients who fail
this therapy will be treated on a planned phase III trial comparing the combination of
systemic cisplatin (P), platinum, rIFNa -2b (I), doxorubicin
(A), and 5-FU (F) (PIAF) vs. the same three chemotherapy agents but excluding interferon
(cisplatin, doxorubicin, and 5-FU or [PAF]). The study is planned as a multi-institutional
trial. Responders to this treatment, whose cancer becomes resectable or are amenable to
ablative therapy such as RFA, or cryo or alcohol ablation or even OLT, will undergo the
procedure. Following the procedure adjuvant treatment will be given with the same regimen
that induced the response and will be continued for 3-6 more months. In case there is no
response to the treatment or a response that is inadequate to render the disease amenable
to surgical intervention, and the tumor is still confined to the liver HAI of PIAF, will
be initiated.
Figure 1:
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the large version of this picture (54kb)
Figure 2:
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the large version of this picture (50kb)
Patients with child class B liver cirrhosis are not candidates for
systemic or hepatic arterial PIAF chemo-biotherapy, or for other myelo-suppressive
treatment. These patients require tolerable therapies. We have completed a pilot study of
capecitabine (XelodaTM). Treatment was tolerated even by patients with
significant liver cirrhosis and was associated with a 15% PR rate and a median survival of
approximately 15 months.
Another investigational agent, thalidomide (ThalomidÔ ) is in phase II trials. Initial analysis suggests a PR rate of
close to 10% and disease stability (SD) in 30-40%. Major toxicities have been drowsiness
and skin reactions. Another therapy that can be tolerated by patients with child B liver
cirrhosis is a continuous I.V. infusion of 5-FU and S.C. rIFNa
-2b. Resection, RFA, or liver transplantation would be offered to patients with some
evidence of response or at least long-term disease stability. However, patients who have
progression of their disease, especially if this is rapid, while being on therapy, would
not be candidates for any of those surgical interventions and obviously OLT should not be
attempted.
The presence of Child’s Class C cirrhosis with refractory
encephalopathy would indicate that the patient is not a candidate for any anti-cancer
therapy and should be treated palliatively and referred to hospice care. Patients with
Child C liver cirrhosis with very small tumors (less than 3 cm – 5 cm) who are placed
on the waiting list for OLT may be candidates for a tolerable systemic therapy with an
agent such as Xeloda, 5-FU, or thalidomide while awaiting liver transplantation.
Obviously, prior to liver transplantation, reassessment has to be conducted and if
necessary even an exploratory laparotomy may be required prior to the anhepatic phase to
determine whether the patient should even be given the scarce liver. It is obvious that
patients whose HCC progresses while awaiting liver transplantation will not benefit in the
long-term from the procedure and will have used up a resource that could potentially
benefit other patients.
Thus, we have been focusing our efforts on identifying agents that
can be tolerated by patients with liver cirrhosis and have used tolerable conventional
agents (e.g. 5-FU) as salvage therapy. It is obvious that only a multidisciplinary
approach that includes oncologists, surgical oncologists, transplant surgeons,
pathologists, hepatologists, and gastroenterologists, may manage more successfully these
difficult patients. It has been recently reported that the incidence of HCC has been
increasing. This may be related to the prevalence of HCV infection in the US (1.8%).
Indeed, it is estimated that approximately 4 million Americans are carriers of the virus.
Between 5% and 10% of all infected HCV carriers will develop HCC. Therefore, it is
anticipated that between 200,000 – 400,000 individuals will develop this cancer in
the next few decades. The progression from cirrhosis to HCC seems to proceed through a
dysplastic nodule to eventually become cancer. Prevention of progression from cirrhosis to
HCC may be the only way to decrease the incidence of HCC. Therefore, efforts should be
directed at HCV infected individuals, mostly those with liver cirrhosis in an effort to
decrease the incidence of this malignancy.
