Hepatic Artery Chemoembolization for Advanced Stage HCC: Experience of 650 Patients
Brian I Carr MD, PhD, FRCP
Thomas E. Starzl Transplant Institute, University of Pittsburgh, Pittsburgh, USA Corresponding Author: Brian I. Carr, MD, PhD, FRCP, Professor and Director, Liver Cancer Center Thomas E. Starzl Transplant Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA Tel: +1412 624-6684, Fax: +1412 624-6666, E-Mail: carrbi@msx.upmc.edu
Summary: Hepatic artery chemotherapy using cisplatin in various protocols was examined in 650 patients. Overall objective tumor response rate (PR) was 65%. Average survival was 7.5 mo in patients with tumor progression, 18.0 mo for tumor stability and 32.0 mo for PR. 1- and 2-yr survival was 70% and 40% in responders, 20% and 0% in progressors. Prognostic factors were examined in 155 patients treated with cisplatin and gelfoam chemo-occlusion. In survival groups of > 24 mo, 4-24 mo and < 4 mo, similar numbers had cirrhosis, hepatitis B virus, hepatitis C virus and alcoholism. Decreased survival was associated with abnormal bilirubin, albumin and prothrombin time. Tumor vascularity and response to chemotherapy were associated with prolonged survival. Tumor vascularity seemed important for tumor response. Portal vein thrombosis occurred in all groups. Lesion number, bilobarity and maximum size had no correlation with response or survival. We analyzed the cause of death in 425 patients. No evidence of hepatocellular carcinoma progression, judged by absence of change in CT scan or tumor marker in the last 4 months of life, was found in 42%. A group of 57 patients were treated with cisplatin in dose range 125-200 mg/m2 alone or with gelfoam. In both groups, responders survived longer than non-responders: cisplatin alone responder mean survival, 29.0 mo, non-responder 11.1 mo, P < 0.0001. There was a strong effect of dose density on median survival for cisplatin alone, but not for cisplatin and gelfoam. CONCLUSIONS: A large experience of single-agent cisplatin chemo-occlusion is summarized. Good liver function and tumor vascularity are associated with response to chemotherapy, which in turn is associated with enhanced survival. Many deaths are due to cirrhosis and not hepatocellular carcinoma.
PRINCIPLES
The Underlying Disease
Cancers that spread to the liver from the breast, colon or lung, typically have an otherwise normal liver. By contrast, most patients with hepatocellular carcinoma (HCC) have a diseased underlying liver as well as cancer. Although this varies from country to country between 60 and 90% of patients with HCC typically have underlying cirrhosis. The sause of this may vary, but the most common factors are hepatitis B (HBV), hepatitis C (HCV), chronic alcoholism and probably chronic exposure to mycotoxins, such as aflatoxin B1. This has Major implications for therapy, since the cirrhosis limits the ability of the surgeon to resect liver and limits the ability of the chemotherapist to deliver cytotoxic drugs without risk of liver failure.
HCC is a Multifocal Disease
Since HCC typically arises an the basis of cirrhosic nodules and there are millions of cirrhosic nodules in an individual liver, HCC is often Multi-focal and bilobar. Although countries with acreening programs are able to diagnose early and limited HCC, its natural history includes the development of multiple "satellite" lesions in both lobes of the liver over time. The cause of this is two-fold. Studies with HBV integration sites suggest that multiple distinct primary tumors can arise in different parts of the liver either synchronously or metachronously, or a clonal HCC can spread throughout the liver via portal vein invasion. In addition, the evidence from liver transplant indicates that HCC is commonly a whole organ disease.
HCC is a Vascular Tumor
A characteristic of HCC which distinguishes it from most metastases to the liver is that it is a highly vascular tumor. This is typically found an the arterial phase of fast helical CAT scans or an hepatic angiography. This is in contrast to metastases from colon cancer, which are typically hypovascular. This vascularity provides an opportunity for selective delivery of drugs to the tumor, since the vascular supply to HCC typically arises from hepatic arteries, whereas the delivery of oxygenated blood to the underlying liver is mainly from the Portal vein. This provides a partial basis for intrahepatic chemoembolization or intrahepatic chemotherapy.
Portal Vein Invasion Characterizes HCC
The tendency of HCC to invade the hepatic vein and particularly the Portal vein is characteristic of HCC and distinguishes it from most metastases from other organ sites to the liver. It is manifested clinically as thrombosis of a major portal vein or portal vein branch seen on CAT scan or microscopically as presence of HCC in the walls or lumens of normal hepatic vessels. It is also probably the most important negative prognostic factor in the evaluation of the HCC patient for any form of surgery, but particularly for liver transplant. Since the portal vein is: thrombosed, it can be safely biopsied by a percutaneous needle (1) and this provides proof for the malignant nature of portal vein thrombosis in the presence of HCC. It is currently deemed to be a major contraindication for liver transplant. Portal vein thrombosis has previously been thought to be a contraindication for hepatic artery chemotherapy, because if the portal vein is blocked by tumor and the hepatic artery is embolized for therapeutic purposes, then that lobe of the liver is thought to undergo necrosis, with resultant liver failure. However, shown below, most of our patients with advanced HCC have portal vein thrombosis, at least of a major branch, most of them are unresectable and most of them have been treated with intrahepatic chemoembolization with little deleterious effect on the underlying liver, provided certain precautions are observed.
HCC is Relatively Resistant to the Toxic Effects of Most Chemotherapeutic Agents
It has been known for more than 70 years since the experiments of Haddow and others (2-4), that the liver that has been damaged by carcinogenic and other toxic chemicals, becomes remarkably resistant to a subsequent challenge by other toxic agents. Most other cancers such as breast cancer adapt to chemotherapy by developing "acquired resistance" to the toxic effects of the chemotherapy. It is thought that most HCC arises ab initio as a drug resistant tumor. This was most clearly demonstrated in the drug resistance/growth inhibition model of rodent carcinogenesis first described by Solt and Farber (5). The clinical consequence of this is that most clinical trials of phase 2 and phase 3 chemotherapy drugs have shown responses to single drugs in less than 20% of the patients and no effect on survival. However, the same drugs when given by the hepatic artery route have been found to result in tumor shrinkage and "partial responses" (PR) in 30-70% of the patients (6,7), usually in association with some form of hepatic artery occluding agent. Hepatic artery occlusion alone does not appear to impact the tumor, as the results of hepatic artery ligation showed long ago.
HCC: SPECIAL CONSIDERATIONS FOR THE ONCOLOGIST
HCC arises on the basis of a diseased liver, which is more sensitive to toxic damage by chemotherapeutic agents than normal liver. In addition, cirrhosis causes portal hypertension, which poses additional hazards for the chemotherapist. These are:
1. Hypersplenism
Portal hypertension is associated with splenomegaly and associated leukopenia and thrombocytopenia. Unlike the myelosuppression that results from systemic chemotherapy and can be attributed to chemotherapy-based damage to the cells of the bone marrow, the leukopenia and thrombocytopenia consequent to splenomegaly is thought to be the result of sequestration of these cells in the spleen, in the presence of a normal marrow. Although the starting values of white blood cell count (WBC) and platelets in the patient with cirrhosis are typically lower than are permitted in most cancer clinical chemotherapy trials, it is our experience that patients rarely come to any harm from chemotherapy with a starting WBC greater than 3, or platelet count greater than 60,000. In any case, the recent introduction of granulocyte colony stimulating factors (CSF) into clinical practice means that the WBC can be restored to safe levels by the oncologist at will.
2. GI bleeding
Portal hypertension is associated with esophageal and gastric variceal bleeding in addition to colonic bleeding. This is a hazard for the cancer chemotherapist to consider, since the consequence of the chemotherapy is often a decrease in platelet counts. Our experience is that preventive banding or injecting varices does not appear to make any difference compared to treating the varices only after there is a bleed.
3. The cirrhotic liver has decreased xenobiotic metabolizing capacity
The decreased metabolic capacity and particularly the ability to detoxify xenobiotics results in increased half-life of many of the common chemotherapeutic agents. This can result in life-threatening prolongation in the myelosuppression. Careful dose adjustment to the individual tolerance of the patient needs to be taken into account by the experienced oncologist. Whereas most patients tolerate cisplatin, Doxorubicin and FUDR, prolonged and frightening thrombocytopenia can result from use of mmitomyinC.
4. Decreased synthetic activity associated with portal hypertension
Low albumin resulting in ascites and increased prothrombin time from decreased synthetic capacity of the liver pose hazards for the vascular radiologist. We typically treat patients with fresh frozen plasma or platelet transfusions for a platelet count below 50,000 prior to femoral artery puncture, but any chemotherapy delivered with a baseline INR above 1.5, risks hepatocellular failure, in our experience.
HEPATIC ARTERY CHEMOTHERAPY AND CHEMOEMBOLIZATION
The hepatic artery delivery of drugs such as chemotherapeutic agents, is done with 2 aims. Firstly, since the HCC is supplied mainly by hepatic arterial blood in contrast to the portal delivery of blood to the underlying liver, this offers a semi-selective means for delivering drug to the tumor rather than to the underlying liver. In clinical practice, the resulting transient elevation of several of the liver function tests suggests that the underlying liver is not really spared. Secondly, delivery of many drugs into the liver via the hepat- is artery appears to result in much higher hepatic extraction of drug compared with systemic delivery (8,9). As a consequence, since most HCCs are vascular, quite high concentrations of drugs can be delivered to individual HCC tumor masses.
Commonly Used Drugs
Chemotherapeutic agents that have been used in many centers included cisplatin (Platinol), Doxorubicin (Adriamycin), Mitomycin C, in addition to the much lower experience with neocarzinostatin (SMANCS), Vincristine, Gemcitabine (Gemsar) and Streptozotocin.
Hepatic Arterial Occlusion
Various agents have been introduced into the hepatic artery together with chemotherapy to cause vascular slowing (occlusion) or embolization (TACE, transarterial catheter embolization). These include Gelfoam (gelatin sponge -our favorite), Ivalon (poly vinyl alcohol which is irreversible and more dangerous, in our experience), blood clots, degradable starch microspheres (Spherex, a relatively safe and attractive product) and steel coils. Our main experience has been with Gelfoam and Spherex, since both are degradable and appear to be least hepato-toxic with transient vascular occlusion, allowing further chemotherapy sessions after several weeks. Lipiodol (Ethiodol) has been widely used particularly in Europe and Japan. We have not noticed any particular added effect of Lipiodol to chemotherapy (10) in terms of tumor response, in addition to which, it often obscures the subsequent interpretation of CAT scans. We have therefore abandoned its use.
University of Pittsburgh Protocol for Chemoembolization of HCC
Our largest experience has been with cisplatin. This is based upon the fact that it has moderate tumor shrinking ability and has minimal myelosuppressive activity compared with most other agents. In addition, it is also relatively well tolerated by the cirrhotic liver. It is usually given at a starting dose of 125mg per meter squared of body surface area (BSA). This dose is essentially tolerated by everyone with a bilirubin of less than 1.5, a normal INR and without ascites. Patients who tolerate this well, without change in their blood count or increase in their liver functions, typically have the dose increased after 2 or 3 cycles to 150mg per meter squared. The cisplatin is given in 100mL of normal saline and infused into the hepatic artery over 30 minutes together with Dexamethazone 20mg and morphine sulfate 5mg and antibiotics (Ancef or Vancomycin). A pressure pump is used to deliver the drug over the 30 minutes. 250mL of 3% saline is given intravenously at the same time. In addition, the patients are aggressively given intravenous hydration with 2 liters of half normal saline over 2 hours immediately prior to the infusion and immediate intravenous infusion of 12.5g of Mannitol during the cisplatin infusion. Aggressive triple anti-emetics consisting of Reglan, Zofran (or Kytril) and Dexamethazone are all given for the next 24 hours. Prior to cisplatin, we give a single intravenous dose of Kytril 1mg (granisetron) or Zofran 32mg (Ondansetrone) and Decadron 4mg. After cisplatin, we give intravenous Reglan 2mg/kg (Metoclopramide), Benadryl 12.5mg and Decadron 4mg every 3 hours for the next 12 hours. In addition, we give an intravenous bolus of sodium thiosulfate 9g/m2 immediately before the chemotherapy and a 6-hour intravenous infusion of 1.5g/m2/hr afterwards. This has resulted in essential disappearance of ototoxicity and neurotoxicity of cisplatin. The patients are typically hospitalized overnight and discharged the following morning. However, whether they need to be kept as an inpatient overnight is not really clear. Most patients require some form of bolus intravenous morphine sulfate, typically 2-mg or 5-mg injections, every 3-4 hours for 2 or 3 administrations after the vascular occlusion.
Gelfoam sponge particles (not powder) are typically given at the beginning of the administration of chemotherapy, half way through and again at the end of the cisplatin administration. The idea is to cause vascular slowing but never complete occlusion. Thus we do not actually perform embolization. This has resulted in a much greater safety margin for our protocol. The arterial flow is monitored during the chemotherapy by regular bolus injections of angiographic dye, to check the vascular flow. Gelfoam powder is thought to be too toxic and is not used in our institution. Similarly, Ivalon is not given because of its hepatotoxicity and irreversibility, limiting the ability to give future doses of chemotherapy.
The chemotherapy is typically repeated every 8 to 12 weeks, depending upon the hepatic tolerance, the response and recovery of the WBC and Platelets and on the period of clinical patient recovery. The main toxicity appears to be tiredness and loss of appetite for 7 to 10 days post-treatment. We have found with this regimen that nausea and vomiting are minimal and hepatic pain is also limited. The patients thus do not typically fear their repeated treatments.
SAFETY CONSIDERATIONS OF HEPATIC ARTERY CHEMO-OCCLUSION
Unilobar Treatments are Given
It is possible to safely give chemotherapy to the whole liver through the proper hepatic artery to an entirely normal liver with metastatic cancer. It is also possible to do this with multifocal bilobar HCCs with completely normal liver function and no ascites in the complete absence of hepatitis and cirrhosis. However, our experience is that the chemo-occlusion is much safer when only one lobe of the liver is given treatment at any one-treatment session. This is now our standard operating procedure. The lobe of the liver with the maximum amount of tumor is normally selected for treatment and several treatments are given to this lobe until tumor control is achieved. Then the other liver lobe is treated on subsequent treatment sessions.
Vascular Slowing is Performed without Complete Occlusion
Chemotherapy is given with regular pulses of Gelfoam to achieve vascular slowing, but complete
occlusion of the arterial blood flow is avoided to minimize subsequent hepatotoxicity.
Drug Doses are Tailored to Each Individual
Almost all patients with a bilirubin of less than 1.5mg/dL tolerate cisplatin 125mg per meter squared. Doses on subsequent treatments can be escalated through 150, 175 to 200mg per meter squared, although few patients can tolerate this. A completely normal blood count and no change in liver function tests is used as basis for increasing the dose of cisplatin by one dose level on a subsequent treatment. By contrast, the prolongation of a prothrombin time or elevation of the bilirubin to above normal levels is normally used to decrease the cisplatin to 100mg per meter squared on a subsequent treatment, or down one dose level if a higher dose level has been used. A nadir WBC above 2.0 or nadir platelet count above 40,000 rarely requires a decrease in the dose of cisplatin on subsequent treatments. The timing of repeated treatments is somewhat arbitrary. A newly diagnosed patient is typically put on a schedule of repeat treatments every 6 or 8 weeks for the first 2 or 3 treatments until some form of tumor response can be seen. After this point, the time between treatments is rapidly increased up to a maximum of 12 weeks. We think that extending the intertreatment intervals beyond 12 weeks is associated with increasing likelihood of tumor growth.
RESULTS OF CHEMO-OCCLUSION WITH CISPLATIN
A response to chemotherapy can be found using a variety of parameters. The standard for oncologic practice is a decrease in tumor measurements by CAT scan. The definition of a partial response (PR) is a 50% or greater decrease in the product of 2 perpendicular diameters of tumor as measured by a CAT scan (x times y). Although this is the accepted oncologic standard for response to chemotherapy, it is not always useful for HCC. This is because a response to chemotherapy can result in loss of tumor vascularity without change in size, for reasons that are presently unclear to the author. Thus, many patients can go for prolonged periods without change in size of their tumor. As the following tables show, tumor stability appears to be a useful result. In addition, a major decrease in tumor markers, particularly alfa-fetoprotein (elevated before treatment in only 50% of our patients) and/or DCP (PIVKA II) are used as supporting evidence of a response to chemotherapy. If there is a major elevation in baseline alfa-fetoprotein, then a major and sustained decrease is clear evidence of response to treatment. However, this is not useful for the 50% of patients that do not have an elevated alfafetoprotein at the beginning of treatment (11-13). We have sometimes seen a decrease in DCP without decrease of alfa-fetaprotein and do not believe that this represents a tumor response.
| TABLE 1 Relationship between the Background Liver and Survival for Patients who Underwent Chemoembolization with Cisplatin | |||
| Survival (months) |
<4 | 4-24 | >24 |
| Patients | 26 | 80 | 49 |
| Background liver | Percentage of Patients | ||
| Etiology of cirrhosis | 88 | 84 | 73 |
| HBV related | 31 | 29 | 28 |
| HCV related | 35 | 36 | 30 |
| Alcoholic | 19 | 15 | 12 |
| Laboratory Data | |||
| Bilirubin > 1.6mg/dL | 42 | 71 | 96 |
| Albumin > 3.4mg/mL | 35 | 47 | 76 |
| INR <1.2 | 31 | 60 | 80 |
| Platelets >150000/L | 27 | 55 | 71 |
| Clinical features | |||
| No ascites | 38 | 90 | 92 |
| Portal thrombosis | 85 | 45 | 35 |
The outcomes of intrahepatic chemotherapy or intrahepatic chemoembolization for advanced stage unresectable HCC are highly varied and confusing in the literature. Each institution appears to have a different protocol with different drugs, different combinations of drugs and different doses of the same drugs. Also, the use of a chemo-occlusive or chemoembolizing agent appears to be highly varied with some institutions being more aggressive and different agents being used at different institutions. In order to try and gain experience with one relatively simple protocol with a reasonably effective drug, we have gained a huge experience with use of a single drug, cisplatin (Platinol or Dichloro-diamino-cisplatinum), together with a single vascular occluding agent, Gelfoam, in order to ascertain its effectiveness and to try and sort out some of the confounding and confusing variables that are associated with the assessment of tumor response and survival. The data are presented for 155 consecutive patients who were treated with cisplatin 125mg per meter squared and Gelfoam chemo-occlusion, using one lobe of the liver at any one treatment session. The patient characteristics are shown in Table 1, and survival is presented in three groups; prolonged survival of greater than 24 months, survival of 6-24 months and survival of less than 6 months. Most of the patients in this series had cirrhosis. Approximately 30% have HCV, 30% have HBV and only approximately 15% have alcohol-associated cirrhosis. The remaining 10-15% of the patients with cirrhosis had a variety of causes including hemochromatosis, autoimmune hepatitis, primary sclerosing cholangitis and primary biliary cirrhosis. Approximately 20% of our patients have no evidence of cirrhosis or hepatitis. The correlation of patient survival with their baseline lab values is particularly interesting. There was a clear association of baseline hepatocellular failure with very poor survival of less than 6 months. This was seen both in the CAT scan evidence of portal hypertension, especially the presence of ascites, low platelet counts, elevated bilirubin and prothrombin time. This appears to be an important correlation, since a major determinant of survival in these patients is the hepatic dysfunction and not only the extent of the tumor. A likely explanation of the difficulty of many groups in showing enhanced survival for the chemotherapy may be because many of the patients do not die of their tumor, but because of their hepatocellular failure. Unlike other cancers that spread to the liver, the evaluation of survival as a function of treatment for HCC is particularly difficult, because of the complex interplay between the cirrhosis and HCC. In future clinical trials, in order to most clearly demonstrate an effect of chemotherapy on survival, only patients without cirrhosis or with Child class A cirrhosis would seem to be appropriate for inclusion, to limit the confounding and confusing effects of cirrhosis on survival of these patients. All the patients in this group had multifocal stage III or bilobar stage IVa HCC.
The characteristics of the tumors in this group of patients are shown in Table 2. Most patients had multifocal disease, and most had bilobar tumors, rendering them untreatable with hepatic resection. A variable number had portal vein invasion of a major trunk, the highest percentage being in those patients with less than 6 months survival. Most patients in all three survival categories had large tumors and the size of the tumor did not appear to be associated with patient survival. There was no clear correlation between the level of alfa-fetoprotein and patient survival either. However, 90% of patients with prolonged survival had highly vascular tumors. Possibly the most important correlation between treatment and survival was the response to chemotherapy (PR). Over 80% of the patients who survived more than 24 months had a major response to chemotherapy (Table 2) as contrasted with less than 10% of those who survived less than 6 months. Interestingly, even tumor stability appears to be useful, since 16% of the patients who survived more than 24 months did not have a response but did have disease stability. No patient with disease progression was in a prolonged survival category.
Since response to chemotherapy (Table 2) appears to be so important in determining survival, an attempt was made to analyze the factors associated with response to chemotherapy. The same 155 patients were examined (Table 3) by response to chemotherapy as partial response (98 patients), stable tumor (29 patients) or progressive tumor (28 patients). More than 8096 of the patients with progressive tumors died within 6 months. Most of the patients with a partial response were in a prolonged survival category. A slightly smaller percentage of patients with prolonged survival had cirrhosis (65%) as compared to those who had limited survival (79%). The tumor vasculature appeared to be a major factor associated with response to chemotherapy (85% of responders) (14). Although a major proportion (86%) of patients in the progressive category had major branch portal vein thrombosis, so did 48% of patients who had a response to chemotherapy. Thus portal vein thrombosis does not preclude either response to chemotherapy or prolonged survival. Neither the number of tumors in the liver nor the maximum size of tumors appear to have any influence on either response to chemotherapy or survival.
| TABLE 2: Relationship between Tumor Features and Survival for Patients who Underwent Chemoembolization with Cisplatin |
|||
| Survival (months) | <4 | 4-24 | >24 |
| Patients | 26 | 80 | 49 |
| Tumor features | Percentage of Patients | ||
| Stage | |||
| Unilobar | 8 | 15 | 29 |
| Bilobar | 92 | 85 | 71 |
| >3cm | 85 | 83 | 78 |
| Portal vein invasion | 73 | 56 | 41 |
| Any tumor >5cm | 85 | 83 | 76 |
| Metastases | 15 | 17 | 6 |
| Other features | |||
| Vascular tumors | 42 | 80 | 90 |
| AFP > 100ng/mL | 46 | 30 | 12 |
| Response to chemotherapy | |||
| PR | 8 | 69 | 84 |
| Tumor stability | 4 | 25 | 16 |
| TABLE 3: Effectiveness of Cisplatin + Gelfoam Chemoembolization for HCC |
|||
| Survival (months) | PR | Stable | Progression |
| Patients | 98(63%) | 29(19%) | 28(18%) |
| Survival | |||
| <6 months | 2(2.0%) | 1(3%) | 23(82%) |
| 6-24 months | 55(56%) | 20(69%) | 5(18%) |
| >24 months | 41(42%) | 8(28%) | 0 |
| Cirrhosis | |||
| No | 34(35%) | 10(34%) | 6(21%) |
| Yes | 64(65%) | 19(66%) | 22(79%) |
| Tumor Features | |||
| Vasculature | |||
| - | 5(5%) | 1(3%) | 14(50%) |
| -/+ | 10(10%) | 5(17%) | 2(7%) |
| ++ | 83(85%) | 23(79%) | 12(43%) |
| Portal vein thrombosis | |||
| 51(52%) | 17(58%) | 4(14%) | |
| + | 47(48%) | 12(41%) | 24(86%) |
| Number | NO CORRELATION | ||
| Size | NO CORRELATION | ||
Contribution of Cisplatin Dose Intensity and Addition of Gelfoam to Chemotherapy Responses
In a separate series of 2 consecutive treatment cohorts, patients were treated with either cisplatin chemotherapy alone or cisplatin + gelfoam vascularocclusion (15,16). In both series, the cisplatin was increased if their liver function tests and blood counts permitted. In order to take into account the effects of variability in the number of weeks between treatments, a computation of "dose density" was used. The patients were analyzed based upon those who received less than or equal to cisplatin 125mg per meter squared per month and those who received more than 125mg per meter squared per month of cisplatin either with or without gelfoam. Table 4A shows responses to treatment of cisplatin alone (42% PR) compared with cisplatin + gelfoam vascular-occlusion (58% PR). The effect of this response on median survival was examined (Table 4B). The median survival was enhanced in a statistically significant manner for patients who responded to chemotherapy with either cisplatin alone or in the cisplatin + gelfoam vascularocclusion group, with responders for cisplatin having a median survival of 29 months and responders for cisplatin + gelfoam having 25 months. By contrast, the non-responders in each group had a median survival of 11 and 15 months, respectively. These results confirm our previous impression that responders survived longer than non-responders. However, when overall treatment type was examined (Table 4C) the advantage was clearly with the cisplatin + gelfoam vascularocclusion group (median survival 30 months) compared with cisplatin alone (median survival 19 months). The effects of dose density for cisplatin were then examined (Table 4D). There was a clear difference between the survival for patients with high dose cisplatin for both the cisplatin alone group and the cisplatin + gelfoam group. However, this enhanced survival was statistically significant only in the cisplatin group, possibly because of the low numbers of patients in the groups overall.
| TABLE 5 Hepatic Artery Chemoembolization in 650 Patients with Cisplatin for Unresectable HCC overall results | ||
| Overall Survivals |
Patients | Median Survival (months) |
| Untreated | 270 | 4.5 |
| Treated | 650 | |
| <3 cycles | 7.0 | |
| 3 or more cycles | 18.0 | |
| Tumor Progression | 7.5 | |
| Tumor Response | 32.0 | |
| Tumor Stability | 18.0 | |
| Survival by chemotherapy
response ° |
1 year | 2 years |
| Responders (PR)* | 70 | 40 |
| Progressors | 20 | 0 |
| ° Expressed in percentage of patients.
*Overall Objective Response Rate (PR) = 65%. |
||
Overall Survival in 650 Patients Treated with Cisplatin Chemotherapy
During the 13 years of the existence of the Liver Cancer Center at the University of Pittsburgh Transplant Institute, approximately 650 patients have been treated with some form of cisplatin intrahepatic chemotherapy or chemoembolization in various trials (10,15,17-20), up to the time of this writing. It is useful to examine the overall results of this approach (Table 5). In several clinical trials the overall objective response rate was 65%. This is probably an under-estimate of a true response rate, since many patients had a decrease in tumor vascularity without change in size. These are probably also chemotherapy responses, but cannot be included as objective responses by conventional oncologic criteria. Interestingly, there were very few complete responses (CR). The reason for this is unclear. Graphs were drawn of the survival of patients in the various treatment categories and the 50% survival (months) was calculated for each treatment group. As a baseline, an additional 270 patients who were evaluated for chemotherapy but could not receive it because of their poor liver function or metastatic disease were followed up and found to have a mean survival of 4.5 months. Patients who had any amount of treatment no matter how inadequate, had a 50% survival of 7.0 months. This probably reflects the deteriorating condition of the untreated patient, rather than the effects of any treatment in those patients who had less than 3 cycles of treatment. In the vast majority of patients who received 3 or more cycles of treatment (the minimum necessary to assess a response by CAT scan), 50% survival was 18.0 months, although there was a major difference between the responders (32 months) and the non-responders (7.5 months).
Interestingly, patients with stable disease had an intermediate survival of 18 months, essentially double that of those patients who had 3 or more treatment cycles, but who had progressive disease on their treatment. The effects of response on survival are more clearly seen in the bottom of Table 5. 70% of patients who had a response were alive at 1 year compared to only 20% of patients whose tumor progressed. Essentially no patients with progressive tumor survived 2 years, but only 40% of those who had a response survived for 2 years. It has been difficult for us to improve on these numbers with the current protocol.
CAUSES OF DEATH IN PATIENTS WITH UNRESECTABLE HCC
Why do patients with unresectable HCC die? The patient characteristics shown in Table 2 indicate that only a tiny percentage develop metastases, the general route for demise in other solid tumors. The high response rates in prolonged survival patients shown in Table 2 and the high incidence of responders in the patients surviving more than 24 months in Table 3, might suggest that prolonged survival would be an outcome of response to chemotherapy. However, this is only relative. As Table 5 shows, it is very difficult to get large numbers of patients to survive to three years and beyond, and 60% of the patients who do respond have died by 24 months. A likely explanation is suggested in Table 1, in which the patients in the worst surviving group all had poor liver function. In order to examine this concept further, 425 patient deaths were examined. The causes of death in 425 patients who were treated over the last 12 years with intrahepatic chemotherapy were examined (Table 6). Interestingly, 58% of the patients had progressive HCC and therefore presumably died from the physical destruction of the liver by progressive tumor growth. However, 42% of the patients did not have any evidence of tumor progression. This was defined as absence of change in the size or number of the tumors or elevation of the alfa-fetoprotein during the 6 months prior to death. Since the majority of these patients also had cirrhosis, the CAT scan evidence of lack of progressive disease in this category, together with the strong association with hepatocellular failure with poor survival in Table 1, suggests that hepatocellular failure from the underlying cirrhosis is the cause of death in this 42% of patients. If true, then no tumor therapy can improve on this statistic without some means of reversing the effects of cirrhosis. Only liver transplantation offers the possibility of prolonged survival in patients who have cirrhosis, hepatocellular failure and controlled, tumor at this time. Although opinion as to the role of liver transplantation in the presence of multifocal, bilobar or advanced HCC is in the process of flux, there has never been a clinical trial of the effects of controlling the tumor prior to liver transplantation in patients with advanced stages III and IV A HCC. A response to chemotherapy in the management of HCC might rationally be a selection criterion that might be expected to predict a prolonged survival after liver transplantation in that group of patients. With the availability of living-related donor liver transplants, a randomized trial comparing response to chemotherapy versus no response to chemotherapy for liver transplantation of non-metastatic HCC might seem reasonable. An attractive alternative approach would compare the results of survival after liver transplant for patients with advanced stage HCC who had a response to chemotherapy compared to those without cancer. Since only chemotherapy is a treatment for advanced and multifocal cancer, but liver transplant is the only current treatment for cirrhosis, the combination is expected to result in prolonged survival for patients with stages III and IVa HCC.
NEW HORIZONS AND FUTURE DIRECTIONS
New Therapies
The current generation of anti-cancer agents is based upon the idea of cell cytotoxicity. Since these agents are essentially non-selective in their action, they are effective at killing both normal cells and tumor cells. This results in what is called "side effects". A new paradigm is needed, for drugs that are developed with a quite different mode and intent of action, based not on killing cells but on the manipulation of cell growth and cell differentiation (21). Several new agents are beginning to appear on the horizon. These include antibodies against the EGF receptor, since many hepatoma cells have EGF receptors and are stimulated either by EGF or TGF-alpha. Phase one and two clinical studies with antibodies against the EGF receptor produced by several companies are currently in progress. A second approach is to restore the function of tumor suppressor genes that are known to be rendered dysfunctional or mutated in the carcinogenic process and include the tumor suppressor genes pRB and p53. Gene therapy trials are currently underway using gene therapy with constructs for the wild type p53. The anti-HCC activity is currently not yet known. A third approach involves the use of agents directed against the angiogenesis that is a hallmark of many cancers, but particularly HCC. In our patients whose tumors respond to chemotherapy, the angiograms clearly change and thus the tumor neovasculature is therefore plastic. Several systemic agents are currently in clinical trials with action against neovasculature and therefore against the tumors that depend upon the new vasculature. These agents include Thalidomide and antibodies against the growth factors that are sp
| TABLE 6 Relationship between Death and Tumor Progression
| ||
| Patients | Rate (%) | |
| HCC progression | 247 | 58 |
| No HCC proggression | 178 | 42 |
Although HCC is thought to be in general a radioresistant tumor, there is some evidence of anti-tumor activity with radio actively administered agents delivered into the hepatic artery, including 131I-Lipiodol. These agents have only mild activity so far. A new agent that appears promising employs Yttrium-90 glass spheres, either imbedded in a resin or in glass beads (20) (Therasphere) (22). The University of Pittsburgh is currently in the middle of a phase 2 clinical trial using hepatic arterial Therasphere and 25 patients have been treated so far. The main attraction of the pure betaemitting agent with a 1-cm maximum path length and 62-hour half-life, is that very high doses of radiation can be given to vascular tumors with minimal hepatotoxicities so far. In addition, only very small numbers of treatment applications are required, the tolerance is high and the side effects are low. Thus, patients appear to have promising quality of life during such treatment. A randomized comparison of Therasphere with intrahepatic chemotherapy will be needed to determine whether one treatment or the other is associated with prolonged survival and increased quality of life.
TABLE 7 Conclusions1. Patients with HCC have 2 diseases. Effective HCC therapy only treats one of them. Thus, either liver trans plant will be needed, or the focus needs to be on HCC prevention. Even with tumor responses, it is difficult to enhance survival. |
| 2. Vascular HCC often responds to TACE. The cirrhotic liver limits chemotherapy delivery. Thus, a new generation of anti-HCC drugs are needed. |
| 3. Even with tumor responses, it is difficult to enhance survival, due to liver disease. |
| 4. Prevention Strategies: |
| a) Vaccination against or treatment of hepatitis. |
| b) Refrigeration of stored grains. |
| c) Inhibitors of carcinogenesis. |
| d) Potential New Therapies: |
Earlier Diagnosis is Needed
Given that survival by surgery is significantly enhanced for lower stage HCC compared to advanced stage HCC, screening programs resulting in early diagnosis with lower stage disease would be predicted to result in more prolonged survival after treatment. Any screening program is predicated on knowledge of the etiological or predisposing factors to the HCC and a long time interval between the action of such factors and the development of the tumor. Both of these criteria are satisfied for HCCs that develop on the basis of chronic HCV, chronic HBV or cirrhosis from any cause. Annual screening of patients by ultrasound and tumor marker (alfa-fetoprotein and DCP) should be expected to result in the diagnosis of tumors at an earlier stage of disease than most of the tumors currently presenting at our center.
Liver Transplantation is Still Needed
Even if chemotherapy is completely successful in eradicating or inhibiting the growth of HCCs after diagnosis, more than 80% of the patients still have another chronic disease, mainly the cirrhosis. Since this probably plays a large part in the limited survival of patients with advanced stage HCC, some form of liver replacement therapy is still needed for the treatment of HCC that is based upon cirrhosis. Whether this is based upon cadaveric donor liver transplantation, living-related donor liver transplantation, partial liver transplantation, hepatocyte transplantation, stem cell transplantation or the ability to biologically reverse the fibrosis in a cirrhotic liver, these are all possibilities for the future total care of patients with HCC.
HCC Prevention
The ideal long-term advance in HCC management would be cancer prevention entirely. This is entirely feasible, given that we know the etiological cause in such a high percentage of these patients. Two obvious strategies are immediately available, and include vaccination and prevention of hepatitis or the treatment of chronic carriers of hepatitis, as well as refrigeration of stored foodstuffs in the third world (Table 7). In those third world countries where HCC is most common, most of the population is agrarian and most food staples such as rice are stored in unrefrigerated village silos. After the monsoons, the high humidity encourages the growth of carcinogenic fungi, of which Aspergillus producing Aflatoxins are only the best studied. The provision of refrigerated granaries for stored grains is expected to go a long way to reducing the conditions under which such carcinogenic organisms can flourish and thus decrease the exposure and the risk of the population to hepatocarcinogens.
1 Dodd GR, Carr BI: Percutaneous biopsy of portal vein thrombus; A new stating technique for hepatocellular carcinoma. Man J Radiol 1993; 161:229-233.
2 Haddow A: Cellular inhibition and origin of cancer. Acts. Unio Int Contra Cancrum 1938; 3:342-352.
3 MacNider WDB: A study of the acquired resistance of fixed tissue cells morphologically altered through process of repair. II. The resistance of liver epithelium altered morphologically as a result of an injury from uranium, followed by repair to the hepetotoxic action of chloroform. J Pharm Exp Ther 1936; 56:373-382.
4 Carr BI, Laishes BA: Carcinogen-induced drug resistance in rat hepatocytes. Cancer Res 1981; 41:1715-1719.
5 Solt D, Farber E: New principle for the analysis of chemical carcinogenesis. Nature 1976; 263:701-703.
6 Carr BI, Livraghi N, Makuuchi T, Buscarini ML, (Eds.): Diagnosis of treatment of hepatocellular carcinoma. London: Greenwich Medical Media, 1997; pp. 367-392.
7 Carr BI, Flickinger JC, Lotze MT, Davita N, Hellman WT, Rosenberg SA (Eds.): Cancer. In: Hepato-biliary cancers Principles and practice of oncology. 5th Edition. Philadelphia: Lippincott-Raven, 1997; pp. 1087-1114. 8 Civalleri D: Methods to enhance the efficacy of regional chemotherapeutic treatment of liver malignancies. In: Kemery N, et al (Eds.). An update on regional treatment of liver tumors. Wells Medical UK, 1995; pp. 26-45.
9 Collins J: Pharmacologic rationale for regional drug delivery. J Clin Oncol 1984; 2:498-504.
10 Carr BI, Iwatsuki S, Baron R, Selby R, Madariaga J, Barnes J: Intrahepatic arterial cisplatin and Doxorubicin with or without Lipiodol for advanced HCC: A perspective randomized study. Proc ASCO 1993; 12:668.
11 Virji MA, Piper M, Carr BE Alfa-fetes protein and desgamma-carboxy prothrombin in hepatocellular carcinoma and chronic liver diseases. Hepatology 1992; 16:538.
12 Nakao, Virji MA, Iwaki Y, Carr BI, Iwatsuld S, Starzl TE: Abnormal pro-thrombin (DCP) in hepatocellular carcinoma. Hepatogastroenterology 1991; 38:450-453.
13 Carr BI Evidence of tumor markers with hepatocellular carcinoma, alfa-fetoprotein and DCP, are independently controlled. Hepatology 2000; 32:619A.
14 Katyal S, Oliver JH, Peterson MS, Chang PJ, Baron LR, Carr BE Prognostic significance of arterial phase CT for prediction of response to transcatheter arterial chemoembolization in unresectable HCC. Am J Roentgenol 2000; 175:1665-1672.
15 Carr BI, Dvorchik I: Effects of cisplatin dose-intensity on response and survival for patients unresectable and untransplantable HCC. Jap J Cancer Chemother 2001; 27:432-435.
16 Carr BI Escalating cisplatin doses by intrahepatic infusion for advanced stage hepatocellular carcinoma. Proc ASCO 1996; 15:23.
17 Carr BI, Orons P, Zajko A, Sammon J, Brown K, Barron R: Prolonged survival with chemo-therapy alone for HCC with intra-arterial chemotherapy. Proc ASCO 1994; 13:606.
18 Carr BI, Zajko A, Brown K, Orons P, Sammon J, Baron R: Phase II study of Spherex injection into the hepatic artery in conjunction with Doxorubicin with Cisplatin with treatment of advance stage hepatocellular carcinoma. Semin Oncol 1997; 24:SF 6, 97-99.
19 Carr BI Long-term survival for unresectable HCC of patients treated with intrahepatic chemotherapy. Hepatology 1999; 30:471.
20 Lau WY, Ho S, Leung TV, et al: Selective internal radiation therapy for non-resectable HCC with intra-arterial infusion of 90-Yttrium microspheres. Intern J Radiat Onc Biol Phys 1998; 40:583-592.
21 Carr BI, Michaelopoulos GK: Biology of human hepatocellular carcinoma. In: Brechot C (Ed.). Primary liver cancer. London and Tokyo: CRC Press Boca Rotten, 1994; pp. 249-268.
22 Carr BI, Brown M, France M, Rosen J, Sheetz M, Zajko A: 90 Yttrium labeled glass microspheres in the treatment of HCC. Proc ASCO 2001; 20:2346.