Powerful radiotherapy for hepatocellular carcinoma.

Abstract

See article on page 1025. Primary hepatocellular carcinoma (HCC) is a malignant tumour with an extremely poor prognosis and an estimated incidence of approximately 1 million patients per year worldwide. 1 This malignancy is observed at high rates of incidence in the Far East and sub-Saharan Africa. 2,3 Recently, a significant increase in the incidence of HCC among patients with antibodies to hepatitis C virus (anti-HCV; an increase of 70% over the past 20 years) has been observed, although the prevalence of HCC among hepatitis B virus (HBV) carriers has remained steady. 4 Progress in imaging techniques that use ultrasonography, angiography and computed tomography (CT) permits earlier diagnosis of small HCC. However, its prognosis is very poor in untreated patents. Intensive follow up of the high-risk group, which comprises patients with liver cirrhosis and chronic hepatitis associated with HBV and HCV infection, is also contributing to the early detection of HCC. 5,6 The prognosis of HCC is very poor. Among the 13 991 patients with HCC treated in Japan over the 2-year period from January 1992 to December 1993, surgical resection was conducted in 34.4%, transarterial embolization (TAE) in 44.7%, lipiodol-chemoembolism (L-TAI) in 58.76%, ethanol injection in 19.3% and radiation in only 1.0%. 4 Although surgery is the mainstay of treatment, postoperative recurrence of HCC in the residual liver is very frequent. Takayasu et al. found that 54.2% of 107 patients had a recurrence of HCC within a mean period of 14.9 months from their operation. 7 Furthermore, many patients have unresectable tumours at the time of presentation. It has also become increasingly obvious that the number of resectable cases is limited even for small HCC, because of the unique clinicopathological characteristics of this carcinoma that include multifocality, early vascular invasiveness and/or coexisting advanced liver cirrhosis. 8 Therefore, alternative non-surgical therapies have been introduced, such as TAE, 9–12 lipiodol-targeted chemotherapy, 12,13 percutaneous ethanol injection therapy (PEIT), 14,15 microwave coagulation therapy, radiotherapy, cryotherapy, and hyperthermia or liver transplantation, 16 and have been shown to be at least marginally successful. However, their anticancer effects are often insufficient to maintain good local tumour control. Complicating portal tumour thrombus, multifocality or diffuse infiltration of the tumour hamper both surgical resection and tumour embolization. Many studies on the therapeutic efficacy of treatments, including radiotherapy, are difficult to compare because the study design, patient selection and response criteria are not uniform. In fact, the survival period largely depends on the underlying cirrhosis and hepatic dysfunction and radiation therapy has been regarded to be of limited use compared with the recently developed therapeutic options. Early attempts at radiation therapy for HCC yielded insufficient results. 17–20 Whole liver irradiation was performed as early as 1940. Due to the potentially severe adverse effects on the liver and other organs, irradiation of a sufficient dose and duration was generally not possible, leading to poor local tumour control and ultimately to a poor outcome. The major reasons for the limited use of radiation therapy include the past failure of radiation to cure HCC, as well as the fact that the tolerance of normal liver to radiation is much lower than the tumoricidal dose. It has long been known that the tolerance dose of the whole normal liver is in the range 25–40 Gy. 21–23 Although the exact radiation tolerance of cirrhotic tissue is not known, it is speculated that the cirrhotic liver can tolerate less irradiation than normal liver. Therefore, the obstacle that has most hindered the application of radiation therapy to the treatment of HCC is the necessity to deliver an adequate dose of radiation to the tumour without inducing liver injury to the surrounding hepatic tissue. Accordingly, the recent improvements in imaging techniques in distinctly localizing tumours of the liver have led to new attempts at partial liver irradiation. Some reports have indicated that tumour regression with a durable response is possible using an adequate dose of radiation. There have, however, been some reports of conventional radiotherapy for HCC from Japan. Some studies demonstrated that good tumour response was possible using a high dose of radiation. Ohto et al. treated 39 patients with HCC using the linear accelerator and a total irradiated dose of 30–50 Gy. 24 In patients with tumours smaller than 5 cm, size reduction was observed in 90%. In those with tumours > 5 cm, approximately 60% showed a size reduction of more than 50%. Matsuura et al. treated residual or recurrent HCC with radiation of 58–64 Gy following transarterial embolization; good local tumour control was gained in 75% of treated patients at 6 months, in 45% at 2 years and 36% at 3 years. 25 In contrast to these reports, Aoki et al. showed that 50–70 Gy local irradiation reduced tumour size by 33%, but all patients showed marked shrinkage of the liver at autopsy. 26 Histological examination revealed viable cancer cells in all cases. They concluded that local radiotherapy of 50–70 Gy was inadequate to completely cure HCC. It has been assumed that a dose greater than 50 Gy should be targeted for killing HCC cells. 27 Le Pechoux et al. also reported successful treatment of a patient with HCC by using TAE followed by limited-field irradiation. 28 Radiation of 60 Gy in 30 fractions produced no sign of clinical hepatitis. However, the most important point is that conventional approaches in which the whole liver is irradiated could have caused radiation hepatitis and eventual hepatic failure, especially in patients complicated with cirrhosis. The role of external conventional radiotherapy in HCC has always been limited by the inability of the whole liver and its hepatocytes to tolerate a therapeutic dose. Recent reports have demonstrated that three-dimensional (3-D) radiation treatment planning, so-called conformal radiotherapy, can be fashioned to minimize beam scatter and deliver potentially therapeutic doses of radiation to tumours within the liver. Cheng et al. carried out an interesting pilot conformal radiotherapy trial for HCC, which is reported in the current issue of the journal. 29 They examined the potential role of CT-assisted radiotherapy in the treatment of unresectable HCC. Their trial radiation dose ranged from 40 to 60 Gy and partial response was observed in 58% of the patients, and minimal response in another 25%. They concluded that 3-D reconstruction of the tumour and surrounding organs helped to avoid excessive exposure of the liver and adjacent organs to radiotherapy and made it a safer treatment modality for unresectable HCC. Therefore, tumour location and size were apparently no longer limiting factors to treatment, although a control study is warranted in the future. Radiation hepatitis can occur when the whole liver has received 30 Gy in 3 weeks. 30 Histograms relating dose and liver volume may be useful in assessing liver radiation tolerance. Three-dimensional treatment planning permits the derivation of these histograms. Previous discussions on liver tolerance were in the setting of whole-liver radiation only. For that purpose, dose–volume histograms (DVH) which depict the distribution of dose over specifically defined volumes, were applied for partial liver irradiation. The goal of this approach is to deliver a maximum possible dose to the tumour within a prescribed normal tissue complication probability. Austin-Seymour et al. suggested that integral dose–volume histograms were useful in assessing organ tolerance when whole and partial organ irradiation has occurred. 22 They maintained that liver doses in excess of 30–35 Gy should be limited to 30% of the liver or less when 18 Gy of whole liver radiation is delivered at 2 Gy/fraction in addition to primary radiation of the pancreas or biliary system. Lawrence et al. reported that 3-D treatment planning based on beam’s eye view (BEV) displays and DVH analysis can be used on a routine basis to safely deliver high-dose radiation therapy as boost treatment to patients with intrahepatic malignancies for good local tumour control. They concluded that their preliminary treatment was more effective than conventional therapy. 31 They carried out a 3-D dose–volume analysis to predict radiation hepatitis. 32 According to their results, radiation hepatitis is infrequent at doses less than 30 Gy, but the risk increases significantly at more than 35 Gy. Therefore, they concluded that DVH analysis could be used to quantify the tolerance of the liver to radiation. The results of Lawrence et al.33 and Robertson et al.34 showed that conformal radiation with or without combined intrahepatic arterial chemotherapy attained varying degrees of response, although subacute or long-term toxicity was observed in some cases. The irradiated doses ranged from 48 to 72.6 Gy. Thus, the availability of 3-D treatment planning based on the DVH concept is increasing and data are becoming available to quantify the tolerance of the liver to radiation. Experiences of partial liver irradiation with or without other modalities will increase in the future. Particles that are heavier than electrons are called heavy particles and are either charged or uncharged. The fast neutron is a heavy uncharged particle, while the proton, heavy ion (carbon, neon or argon), helium and negative pi-meson are all heavy charged particles. The proton is positively charged and is 1836-fold heavier than an electron. A heavy ion is bigger and heavier than protons, neutrons and pi-mesons. Unlike the conventional radiation beam, proton and heavy ion beams have a unique dose distribution. They have a peak area (Bragg-peak) in which rapidly increasing doses are deposited at the end of the beam range defined by the particular beam energy. 35–38 Therefore, proton and heavy ion therapy have an advantage in that a large dose of radiation can be focused on the target, with very limited irradiation of surrounding non-tumorous tissues. The Bragg peak of heavy ions is as sharp as that of protons. Moreover, biological effects of heavy ions are stronger than those of protons. However, in contrast to protons, their dose is deposited in the region beyond the distal edge of the peak to some extent because of fragmentation of the incident particles. Therefore, it still remains to be determined whether this heavy ion irradiation is of practical benefit. In 1938, the Lawrence Berkeley Laboratory (LBL) initiated the first heavy particle treatment by using fast neutrons supplied from an accelerator designed for a physics laboratory. Initially their beam was composed of protons, followed by helium ions and still heavier particles. In 1990, Loma Linda University set up the first hospital-based, proton-beam treatment centre dedicated to medical service and research. 39 Currently, proton therapy is being carried out in 18 facilities worldwide, with more than 22 000 patients receiving treatment. Our previous studies have shown that proton irradiation is a safe and effective therapeutic option for treatment of nodular HCC in terms of tumour size reduction, and excellent local tumour control was obtained during the observation period. 40–43 Treatment using 250 MeV proton beams provided a total dose of 33–87 Gy (median 72 Gy). Cumulative local tumour control was 99.1% at 1 year and 91.4% at 3–5 years. We conclude that this therapy is safe and effective and that it has the special merit of allowing an excellent quality of life without associated complaints during the treatment period. 44 Moreover, one of the striking advantages of this therapy is that it can be used to treat patients with deep-seated tumours and patients with serious complications. The only major limitations of this method are that the HCC should be of a nodular but not diffuse type and the total cost is very high. This was first carried out at LBL in 25 patients with oesophageal cancer using helium-ion beams which are similar to protons in physical and biological properties. 45 They received a total dose of 62–70 Gy at a 2.0–2.25 Gy/fraction, 4 days/week. It was concluded that helium ion beams had no advantages over conventional radiotherapy because of the high local recurrence rate. The USA discontinued heavy ion particle radiotherapy because of these results and a poor cost–benefit ratio. At the moment, only two facilities in the world are undertaking clinical trials for malignancies using carbon ion. These facilities are the Heavy Ion Medical Accelerator in Chiba, Japan and Gesellschaft für Schwerioen-forschung at Darmstadt, Germany. In Japan, the co-operative group for HCC treatment using carbon ion started a phase I/II study of heavy ion (carbon) charged-particle radiotherapy for HCC in 1995. The safety and efficacy of the treatment were confirmed in 1998. Cumulative local control rates were 95.7% at 1 year and 90.3% at 2 years. These data are excellent and are similar to the results obtained for proton therapy for HCC. 46 Therefore, charged-particle radiotherapy as well as conformal radiotherapy are important, safe and available therapeutic options for HCC in the future. The presence of portal vein thrombosis in HCC results in a very poor prognosis for HCC. In this current issue, Cheng et al. reported on seven patients with portal thrombosis and their survival time was 2–15 months, median 5 months and suggested that 3-D conformal radiotherapy was an alternative treatment option for patients with main portal vein thrombosis. 29 Therefore, 3-D conformal radiotherapy seems a very promising treatment approach for non-advanced HCC and highly advanced HCC. As shown in the study by Ohto et al. in which they irradiated portal thrombosis, limited-field irradiation for portal vein invasion seemed effective to some extent. 24 As a result, three of four portal thrombi were reduced in size and the fourth stopped growing. Chen et al. investigated the effect of external radiation in the control of portal vein invasion. 47 After TAE, portal vein thrombi were irradiated with 30–50 Gy and the tumours completely disappeared and partial shrinkage of portal vein thrombus occurred. We performed proton radiotherapy for far-advanced multinodular HCC with liver cirrhosis and tumour thrombus both in the portal and inferior vena cava. 43 As a result, portal and inferior vena cava tumour thrombi were markedly reduced in size. Recently, Takayama et al. demonstrated that adoptive immunotherapy may delay or prevent the recurrence of highly advanced HCC. 48 In that study, the patient also had right portal vein thrombi and right adrenal metastasis and was treated with proton radiotherapy and adoptive immunotherapy. Therefore, in cases of highly advanced HCC, proton therapy may be effective as an initial treatment modalitiy. In highly advanced HCC, conformal and proton radiotherapy are effective, useful and safe therapeutic options for initial treatment. Considering the clinicopathological characteristics of HCC, additional combination therapy will be needed to prevent metastasis and the progression of HCC. Interest has recently focused on the use of radiation therapy, such as conformal and heavy charged particle radiotherapy, for treatment of HCC, as it has been shown that irradiation has the potency to be curative. Currently, proton radiotherapy is being performed in 18 facilities worldwide. There are currently two hospital-based facilities in Asia: at Tsukuba (Proton Medical Research Center) and Kashiwa (National Cancer Center) in Japan. Three more centres are proposed for Japan, one for Taiwan and one for the People’s Republic of China. 49 Much progress has been made over the past 10 years in efforts to deliver a large, tumoricidal radiation dose with an acceptable level of complications. In the future, radiotherapy for HCC should be considered a safe and effective therapeutic option which can be applied with curative intent. It is, thus, essential to choose an adequate treatment modality from the many options, although there are arguments about the relative efficacy of each treatment. The author thanks Professor Toshiaki Osuga, University of Tsukuba, for helpful suggestions about this editorial.