CLINICAL REVIEW

Management of hepatocellular carcinoma

W.Y. LAU

Department of Surgery, The Chinese University of Hong Kong, New Territories, Hong Kong

Introduction Liver resection Multi-modality therapy Liver transplantation

Local treatment Hepatic artery - based treatment Systematic treatment Conclusion References

Keywords: hepatocellular carcinoma, surgical treatment, non-surgical treatment

This article reviews the recent advances in the management of hepatocellular carcinoma (HCC). Partial hepatectomy still remains the mainstay of therapy for early HCC. The limits of liver resection have been extended with the use of a multi-modality approach, and neoadjuvant/adjuvant treatment has improved the results of liver resection. Orthotopic liver transplantation works better than partial hepatectomy in a subgroup of patients with poor liver function and with early HCC. For locally advanced HCC, which is still confined to the liver, debulking surgery gives excellent palliation and prolongs patient survival. Non-operative local ablative therapy shows encouraging results. Hepatic artery chemoembolisation has been shown, by systemic review or meta-analysis, to have no significant impact on patient survival. Initial results with transarterial radioembolisation are promising. For patients with advanced HCC, systemic chemotherapy has little clinical benefit. The results of systemic immunotherapy or systemic tamoxifen on HCC are controversial and need further evaluation. Early results of chemoimmunotherapy are encouraging

J.R.Coll.Surg.Edinb., 47, February 2002, 389-399 

INTRODUCTION

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, with an annual occurrence of at least one million new cases. Even this number represents an underestimate because in many of the countries with a high incidence of HCC, cancer statistics are far from complete.¹

There are many treatment options available for HCC. The long list reflects the fact that there are no proven standard, effective treatments for HCC (perhaps with the exception of surgical resection with curative intent). The choice of treatment depends on the general condition of the patient, stage of the disease, the liver function of the patient, the choice of the patient, as well as the treatment protocol and availability of expertise of the individual medical centre.^2,3

LIVER RESECTION (CURATIVE INTENT)

Recent improvements in diagnosis and perioperative management have made partial hepatectomy for HCC safe.⁴ Resectability rates ranging from 10% to 67% have been reported for patients with HCC, with many centres recording improved resectability for more recent time periods.^5,6 At the same time, a higher proportion of small tumours is recorded as a result of refined diagnostic procedures and screening programmes. Wide differences in resection rates, therefore, are thought to be due mostly to patient selection rather than to improvement of surgical techniques.⁷ The perioperative mortality ranges from 0.5% to 21.5%, with a median of around 5% to 10%.^3,8,9 The overall 5-year survival for liver resection for HCC ranges from 11% to 76%, with a median survival of around 30%.^{3, 10, 11} Comparison of survival data is difficult, as no generally accepted staging system is in use, and because many authors choose to exclude perioperative mortality when reporting long-term survival.7 Involvement of adjacent organs by HCC is no longer considered a contraindication to resectional surgery with curative intent.¹² A case-controlled study has shown that en-bloc-resection of the tumour with the adjacent involved organ should be attempted.¹³ On the other hand, attempts have been made to improve on the safety of liver resection by embolising the portal vein supplying the part of the liver containing the tumour, thus, inducing compensatory hypertrophy of the uninvolved part of the liver.^14,15

MULTI-MODALITY THERAPY

A number of procedures have been shown to shrink tumours, thereby, allowing unresectable tumours to become resectable.³ Procedures with the potential to down-stage HCC for a secondary resection include transarterial chemoembolisation; combined chemotherapy and radiation; a combination of hepatic artery ligation with hepatic arterial infusion of a chemotherapeutic agent, radioimmunotherapy and fractionated regional radiotherapy; transarterial yttrium90 microspheres; and, systemic chemoimmunotherapy.^{12, 16-20} The main problem with tumour shrinkage is that only a small proportion of patients respond significantly to the treatment, thereby, enabling secondary liver resection to be carried out; it is difficult to predict responders.

An alternative way to improve on the results of ‘curative’ liver resection is to use neoadjuvant (preoperative) or adjuvant (postoperative) therapy. Non-randomised studies looking at neoadjuvant multimodality treatment for resectable tumours have been carried out but with conflicting results. These procedures include the following: portal vein embolisation of the tumour using starch microspheres; transcatheter arterial embolisation (TAE); a combination of TAE and portal vein embolisation; and, transcatheter arterial chemoembolisation (TACE).^{17, 21-25} Neoadjuvant therapy has the potential to reduce the tumour mass, thus, making subsequent surgery easier, and it can destroy microscopic tumour foci. The potential benefits, however, can be offset by the overall delay in surgery and may eventually prove to be detrimental to those patients who do not respond well to the therapy.

Non-randomised studies on the use of adjuvant therapy showed no benefit with oral 5-fluorouracil (5-FU).²⁶ The place of TACE is controversial.^22,27,28

Randomised studies and systematic reviews have been conducted to evaluate the place of neoadjuvant/adjuvant therapy for HCC. A randomised study has shown that adjuvant systemic and transarterial chemotherapy resulted in significantly worse results in the treated group, when compared with the control group.²⁹ A systematic review of randomised controlled trials using TACE concluded that there was a trend towards a worst prognosis in the treated patients, when compared with the controls.³⁰ A more recent systematic review of randomised trials of neoadjuvant/adjuvant therapy for operable HCC also concluded that there was no evidence for efficacy of any of the neoadjuvant/adjuvant protocols reviewed.³¹

A number of randomised studies, however, have been shown to provide some benefit to patients in the neoadjuvant/adjuvant setting. It is interesting to take a more detailed look at these studies.

The use of polyprenoeic acid has been shown to significantly decrease the chance of tumour recurrence after curative resection or percutaneous ethanol injection for HCC, when compared with placebo-treated patients.³² This study can be criticised because the control arm comprised an unknown proportion of curative surgical resections and percutaneous ethanol cases; the authors clearly favouring the latter in their discussion.³¹ This study was also primarily concerned with the prevention of onset of a second primary tumour and not absolute survival. The important outcome measurements in neoadjuvant/adjuvant studies should be death from tumours secondary to the original resected primary, and delay in tumour recurrence.

A study using a complex regimen of locoregional chemoand immunotherapy, before and after surgery, showed significant survival benefit favouring the treatment arm.³³ The problems with this study are the markedly poor survival rate in the control group and the way in which the data were analysed.³¹

Randomised studies, using adjuvant oral 1-hexylcarbamoyl 5-FU, adjuvant TACE with doxorubicin and mitomycin C and adjuvant adoptive immunotherapy, have shown to significantly improve the disease-free survival after curative liver resection for HCC.^34-36 Unfortunately, no difference was detected in the absolute survival, when the treatment group was compared with the control group, in these studies.

Significant improvement in survival and disease-free intervals in patients who received transarterial lipiodol iodine¹³¹ after liver resection for HCC, compared with a control group who received no treatment, has been reported.³⁷

As the adjuvant therapy has very limited side effects, it is likely that it will find an important place in the management of HCC.

LIVER TRANSPLANTATION

Liver transplantation is mainly considered for HCC confined to the liver when partial hepatectomy cannot be performed either because of intrahepatic tumour spread or compromised liver function in cirrhotic patients. Occasionally, incidental foci of HCC, not detected by preoperative workup, were found by the pathologist in the explanted liver in liver transplantations carried out for end-stage liver disease.

The mortality associated with liver transplantation for primary liver tumours has been reported to vary from 5% to 29%.^38,39 The 5-year survival rate of liver transplantation for HCC ranges from 20% to 36%.^40,41 The best results are obtained in patients with ‘incidentoma’ found unexpectedly in the explanted liver.⁷ Good results are also seen in patients with fibrolamellar carcinoma, with 5-year survival rates of 38% to 50% being reported following transplantation.^42,43 Liver transplantation for HCC produces survival results equivalent to partial hepatectomy.³ In a subgroup of patients with a single tumour < 5 cm, or patients with multiple (< 1) tumours and < 3 cm in diameter, liver transplantation may produce better results than partial hepatectomy.^38,44,45 Hepatitis B infection is no longer considered a contraindication to liver transplantation because of the advent of new antiviral drugs, such as lamivudine.⁴⁶ In many countries, especially in Asia, where HCC is prevalent, cadaveric livers are scarce and liver resection remains the preferred curative treatment of choice for HCC.

The recurrence of HCC after liver transplantation is high. Neoadjuvant and adjuvant therapies have been tried in an attempt to improve the results of liver transplantation, including the use of systemic chemotherapy, TACE and chemoradiotherapy.^{3, 25,38, 42, 47-49} In spite of the promising results of these studies, the question of when to commence the therapy and what treatment to give remains unanswered.

LOCAL TREATMENT

Cytoreductive Surgery

Debulking surgery aims at removal or destruction of all macroscopic tumours, but allowing microscopic foci to persist. Debulking surgery for good risk patients with HCC has been shown to prolong survival and provide excellent symptomatic relief to patients.^50,51 The palliative resection can be combined with cryosurgery, intralesional alcohol injection and microwave tissue coagulation to induce tumour necrosis.^52-54 (see table 1) The microscopic tumour foci can subsequently be dealt with by regional or systemic therapy, which will be described in more detail in the latter part of this review.⁵⁰

Table 1: Local Ablative Therapy for HCCs

Local Ablative Therapy

Local ablative therapy can be applied to patients with small HCC confined to the liver, although the technique is difficult in patients with multiple lessons. (Table 1) It is especially suitable for patients whose tumours cannot be resected because of poor liver function or because of recurrent tumour after partial hepatectomy. It is contraindicated in patients with gross ascites, uncorrectable coagulopathy and obstructive jaundice for fear of post-procedural bleeding and bile peritonitis. Increased risks of bleeding and tumour seeding have to be considered when the tumours are situated at, or protruding out of the liver surface, although the risks are minimal.⁵⁵

Percutaneous ethanol injection (PEI) is the most commonly used form of local ablative therapy. Percutaneous ethanol injection is carried out under ultrasound guidance and is usually repeated twice a week for up to four to six sessions. Follow-up serum alpha fetoprotein, ultrasound and computed tomography are usually used to monitor the therapeutic response. Additional ethanol injections are given to patients with incomplete tumour necrosis, and side effects are usually minimal. Although non-randomised studies have shown PEI to give reasonably good survival results, with a 3-year survival rate of 55 to 77%, post-treatment recurrence within the liver is high and is in the range of 50% at 2 years. Two randomised studies have shown PEI to have no impact on patient survival. A meta-analysis combining these two randomised studies showed the survival effect at 1 year with PEI was not significant with the Der Simonian and Laird method but was significant with the method devised by Peto and colleagues.⁶¹ As the two randomised studies were conducted on large HCCs, which are usually considered not suitable for PEI, and the number of patients used and the number of trials were insufficient, there is not enough evidence to enable a firm conclusion to be drawn for the value of PEI. Percutaneous acetic acid injection, although less extensively studied than PEI, has been shown by a randomised controlled study to be better than PEI.⁶² Percutaneous ethanol injection, however, still remains the gold standard of local ablative therapy.

Other forms of local ablative therapy have been reported. These include intratumoural injection of glass microspheres containing yttrium90, ultrasound-guided microwave coagulation treatment, percutaneous laser, percutaneous radio frequency, electrocautery, intralesional hyperthermic saline and water.^63-73

The initial encouraging results of these treatment procedures must be further evaluated to determine their true value in the treatment of HCC. Furthermore, concern has been expressed about the possible side-effects of these procedures, especially on the potential radiation hazard associated with percutaneous injection of glass microspheres containing yttrium90.⁶³ Also, percutaneous radio frequency ablation for small HCCs (5cm or below) has been shown by a phase II study to be associated with a high incidence (12.5%) of biopsy-proven needle-track tumour seeding.⁷⁴

HEPATIC ARTERY - BASED TREATMENT

A range of therapeutic options are available using the transcatheter hepatic artery route. These are discussed below and summarisied in Table 2.

Transarterial Embolisation (TAE)

The liver has a dual blood inflow from the hepatic artery and the portal vein. Occluding the hepatic artery, which is the major blood supply to the tumour, induces ischaemia and necrosis of the tumour. It does not affect, however, the nontumourous part of the liver as this part of the liver derives its blood supply mainly from the portal vein. Transarterial embolisation (TAE) is relatively contraindicated if the portal system is blocked by tumour thrombus or invasion.

Hepatic artery ligation at laparotomy has been reported to result in an unacceptably high mortality of 36% in patients with cirrhosis, although other authors have reported lower operative mortality.^75-77 It has now been replaced by the use of hepatic artery embolisation during angiography, using steel coils and Ivalon for permanent occlusion, and gelatin sponge particles and degradable starch for temporary occlusion. A temporary occlusion can allow subsequent intraarterial treatment after the vessel opens up again.

There is a lack of long-term clinical efficacy of TAE. This is probably due to the rapid development of collateral vessels, which can originate from any of the surrounding arteries. Neovascularisation can occur within one week of hepatic artery ligation.⁷⁸ Randomised studies have failed to demonstrate any survival advantage with surgical hepatic dearterialisation or TAE, when compared with a control group, and TAE, when compared with systemic chemotherapy.^79-81 The side effects of TAE are usually mild and consist of pain, fever, nausea and a transient increase in liver enzymes.⁸² Although TAE has failed to improve survival, it gives good symptomatic palliation for well selected patients. It remains the choice of palliative treatment for pain or tumour rupture.⁸³

Transarterial Chemotherapy (TAC)

Transarterial chemotherapy has the theoretical advantage of achieving a higher concentration of cytotoxic drugs within the tumour because HCC derives its main blood supply from the hepatic artery, thus, improving tumour cell kill and decreasing the side-effects of treatment.^{84, 85} This higher drug concentration depends, in addition to the blood supply to the tumour, the extraction of the drug by the liver. Drugs such as 5-FU, 5-FUDR, cisplatin, doxorubicin and 4’-epidoxorubicin are commonly used in TAC because they have high liver extraction rates and short plasma half-lives.⁸⁶ The fluoropyrimidines (5-FU and 5-FUDR) are perhaps the best agents for TAC because they have a high rate of systemic clearance and also have prolonged drug exposure to hepatic tumours. Pharmacokinetic studies, however, showed either a relatively small pharmacokinetic advantage of chemotherapeutic agents delivered by TAC, when compared with systemic chemotherapy, or no difference at all.^{87, 88}

There is a lack of good randomised studies using TAC. Transarterial chemotherapy, using single chemotherapeutic agents, suggests a better response rate than that of systemic chemotherapy in phase II clinical studies. However, interpretation of the results of these studies is hampered by a difference in response criteria. With combination therapy, TAC appears to give a higher tumour response rate than single agents.^{89, 90} However, disappointingly low response rate has been reported with combination therapy.⁹¹ When combination chemotherapy was used, significant toxicity such as cholangitis and bone marrow suppression was noted.^89-91 An implantable arterial port is also necessary for drug infusion. Instead, when single agent TAC is used, the drug can be given through a percutaneously placed angiographic catheter.

Transarterial Chemo-embolisation (TACE)

The term TACE has been used indiscriminately to describe a treatment procedure using the transhepatic arterial route to inject chemotherapeutic and embolising agents in the treatment of liver cancer (Table 2). There has not been any standardised protocol in the choice of the chemotherapeutic agents, the dosage, the rate of injection and the time interval between the treatments. Similarly, there is no agreement on the choice of the embolising agent, the degree of embolisation and whether the chemotherapeutic agent should be given together or before the embolising agent.

A commonly performed TACE is to mix hydrophilic chemotherapeutic agents in an emulsion with lipiodol. Lipiodol is an oily contrast agent derived from poppy seed oil. It is retained selectively by HCC for many weeks after intraarterial administration into the liver.^92-93 Although nonrandomisedstudies have shown promising results using this form of TACE with lipiodol, randomised studies have failed to show any survival benefit, when compared with symptomatic treatment or with TAC.^94-100

Another form of TACE is to embolise the hepatic artery after TAC. The aim is to slow down arterial blood flow so as to achieve longer contact time of the drug with the tumour cells. The embolisation can be temporary, using gelfoam pellets or degradeable starch particles, or permanent, using coils or Ivalon particles. Non-randomised studies have shown good results, with tumour response rates varying from 17 to 58%.^101-103 Randomised studies, however, have failed to show any improvement in survival when this form of TACE was used, when compared with no treatment, with systemic chemotherapy and with this treatment using different regimens.^{102, 104,105}

Transarterial chemo-embolisation can also involve combining the intraarterial administration of hydrophilic chemotherapeutic agents with lipiodol in an emulsion followed by temporary or permanent embolisation of the hepatic artery. Again, although non-randomised studies showed this form of TACE to produce promising results, randomised studies either showed no survival benefit, when compared with symptomatic treatment, or a worse outcome, when compared with TAE with gelfoam.^106-110

The benefit of the various forms of TACE cannot be substantiated using systematic review and meta-analysis of the published randomised studies.^30-61 Also, randomised studies comparing different regimens of TACE showed no convincing advantages of one regimen over another, nor was there any significant difference in the response rates between TACE and TAE.^111-113

The results of randomised studies cannot explain the good results of TACE with some of the non-randomised studies; unresectable tumours have responded and being down-staged to become resectable.^{114, 115} Studies have shown that TACE works poorly in large tumours (>9 cm in diameter) and in Child C cirrhosis.^{25, 106} Perhaps, the beneficial effects of TACE in certain subgroups of patients is off-set by the toxic sideeffects of the treatment on another subgroup so that the impact on the overall survival of the whole patient group becomes less obvious.

Contraindications to TACE include portal vein thrombosis, marked arterio-venous shunting to portal or hepatic vein and poor liver function. Side-effects are quite common and include fever, abdominal pain, nausea and vomiting. The chemotherapeutic and embolising agents may cause cholecystitis, pancreatitis, gastric erosions or ulcer, if they are inadvertently injected into these organs. Infection of the necrotic tumour with subsequent liver abscess formation can also occur.

Transarterial Radioembolisation

Conventional external radiotherapy has a limited role in the treatment of HCC because of the adverse effects of irradiation to the surrounding non-tumourous liver tissue leading to radiation hepatitis. New developments include conformal radiotherapy, with or without a radiosensitiser, and proton irradiation, both of which need more studies to define their true role in the management of HCC.

Selective internal radiation therapy is based on the principle that if radioactive isotopes are concentrated in the tumour, a therapeutic dose of irradiation can be delivered to the tumour while the rest of the liver and the patient’s body receive minimal irradiation, thus, minimising the side effects.

The intraarterial delivery of lipiodol iodine¹³¹ has shown (by a dosimetry study) that the radioactive lipiodol was preferentially taken up and retained by HCC, and the tumour received, on average, eight times the irradiation dose of the normal liver.¹¹⁶ Non-randomised studies with lipiodol iodine¹³¹ have shown promising results.^117-119 Complete histological response of HCC to this therapy has been reported.120Arandomised study has shown lipiodol iodine¹³¹ to be useful in prolonging patient survival, even in the presence of portal vein tumour thrombi.¹²¹

The limitation of lipiodol iodine¹³¹ is the radiation hazards to medical personnel in treating large tumours (> 5 cm), as radioactive iodine gives off gamma and beta irradiation.

Yttrium90 has the advantages over iodine¹³¹ in that it has a shorter half-life, greater mean energy and penetration and it is a pure beta emitter. These characteristics make yttrium90 a better isotope to use in larger tumours. The isotope can be incorporated either into resin-based or glass microspheres.^122-124 The microspheres used are 32 um, approximately the size of the precapillary diameter; they are not degradable. When injected into the arterial blood supply to the liver, the yttrium90 microspheres preferentially go to the HCC, as the tumour receives more arterial blood supply than the nontumourous part of the liver. The microspheres are permanently lodged within the tumour and release the planned radiation dose. Non-randomised studies have shown yttrium90 microspheres to give promising results in HCC, both the glass and resin-based microspheres.^{19, 125} Unresectable tumours have been converted to resectable tumours and complete histological responses have also been reported.¹⁹

There are minimal side-effects associated with yttrium90 microspheres treatment. The most common complaint is right upper quadrant discomfort due to the embolising effects of the microspheres. Alarge scale prospective randomised study is required to prove the safety and efficacy of this mode of treatment.

SYSTEMIC TREATMENT

Systemic Chemotherapy

HCC is relatively resistant to systemic chemotherapy. Doxorubicin is the most commonly used drug, either as a single agent or in combination with other drugs. The overall response rate from thirteen published doxorubicin trials is about 19% and median survival is only four months.¹²⁶ Although doxorubicin has been shown by a randomised study to improve survival, when compared with no treatment, systematic review and meta-analysis of the published randomised studies on HCC have shown that neither doxorubicin nor any other chemotherapeutic agent used singly or in combination, have any impact on survival.^{30, 61, 127} Systemic chemotherapy, therefore, should not be recommended as standard therapy and be used only in the context of a clinical trial. The criteria for recruitment of patients into trials are unresectable HCC, reasonable liver function, good (> 70%) Karnofsky performance score and age < 70 years.

Systemic Immunotherapy

Immunotherapy using high dose recombinant interferon-a2 has been shown to be better than systemic doxorubicin and symptomatic treatment, in randomised studies.^{128, 129} Another randomised study showed interferon-ß to have a slightly longer 1-year but a shorter 2-year survival, when compared with patients who received the systemic chemotherapeutic agent menogaril.¹³⁰ In all these studies, the dosage of interferon used was very high. Flu-like symptoms occurred in all the patients treated. Significant toxicities, requiring dose reduction, was documented.

Systematic review and meta-analysis of all published randomised studies on systemic immunotherapy concluded that the number of randomised studies was insufficient to provide a definitive guideline on the role of systemic immunotherapy for HCC. Novel approaches, using dendritic cell immunisation regimens are currently being assessed.

Systemic Chemoimmunotherapy

A combination of cisplatin, doxorubicin, 5-FU and interferon-a has resulted in a partial response rate of 26%, ones and induced complete pathological remission in some down-staged inoperable tumours to resectable of the resected specimens.^{20, 131} The treatment, although toxic, shows very promising results. Systemic chemoimmunotherapy needs a large scale randomised trial to define its role in the management of patients with advanced HCC.

  Table 2: Hepatic artery transcatheter therapy for HCC

Systemic Anti-Hormonal Therapy

The results with the use of tamoxifen on HCC has been controversial. While three randomised studies showed tamoxifen to be better than no treatment or placebo, tamoxifen was shown to be ineffective in both a nonrandomised and randomised study.^132-136 Tamoxifen has also been shown to give no additional benefit, when combined with systemic doxorubicin and compared with systemic doxorubicin alone.¹³⁷ Pooled data in systematic review and meta-analysis suggest tamoxifen may have minimal growth restraining activity against HCC. Further large scale randomised trials are required to define its true role in the management of HCC.

Anti-androgenic treatment including ketoconazole has not been demonstrated to be effective, although a small number of patients showed some objective response to cyproterone acetate therapy with a fall in free levels of 5a-dihydrotestosterone.^{138, 139}

Systemic Somatostatin Analogues

Somatostatin receptors have been identified in a variety of malignant tumours, including HCC. Octreotide, a somatostatin analogue, exerts a cell growth regulatory or suppressive effect in some tumours. A randomised study has shown octreotide to extend the survival of patients with HCC.¹⁴⁰ However, the number of patients studied was small and the data does not allow definitive conclusions to be drawn. Further studies to explore the role of octreotide are needed.¹⁴¹

Other Treatments

Gene therapy is on the horizon. Before this can become an accepted therapy, significant problems have to be solved to enhance the delivery of the gene of choice to target cells by a highly efficient, specific and nonimmunogenic vector.¹⁴²

Supportive treatment forms an important aspect of management of HCC as a significant proportion of patients have advanced malignancy at the time of diagnosis. This consists of nutritional support, pain relief, and management of ascites. For terminally ill patients, hospice services ( homeor hospital-based) should be provided. There are four goals of hospice care: relief of pain and other symptoms; psychological and spiritual care to help patients come to terms with death; a support system to maintain personal integrity and self-esteem; and a system to support the family members during the patients’ final days and in their bereavement.¹⁴³

Table 3: Systematic therapy for HCC

CONCLUSION

There has been much improvement in the treatment of HCC. Surgery still remains the mainstay of therapy for early HCC. For patients with advanced tumours, new and novel treatment modalities are being introduced and some of these show promising results.

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Copyright date: 5th October 2001

Correspondence: W.Y. Lau, Department of Surgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong E-mail: josephlau@cuhk.edu.hk