Radiation therapy for hepatocellular carcinoma - Wiley Online Library

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Radiation Therapy for Hepatocellular Carcinoma From Palliation to Cure

Maria A. Hawkins, M.D. Laura A. Dawson, M.D. Department of Radiation Oncology, Princess Margaret Hospital, University of Toronto, Toronto, Ontario, Canada.

Presented in part at the 2005 American Society of Clinical Oncology Gastrointestinal Cancer Symposium, Hollywood, Florida.

Technologic advances have provided the means to deliver tumoricidal doses of radiation therapy (RT) to patients with unresectable hepatocellular carcinoma (HCC) while avoiding critical normal tissues, providing the opportunity to use RT for curative intent treatment of HCC. For the current report, the expanded role of external beam RT in the setting of HCC from palliation to cure was reviewed. A systematic literature search was undertaken using the MEDLINE data base and secondary references to identify peer-reviewed, English-language articles that reported clinical outcomes after external beam RT alone or in combination with other treatments for HCC. Abstracts from the 2005 American Society of Clinical Oncology, American Society for Therapeutic Radiology and Oncology, American Gastrointestinal Association, and Society of Surgical Oncology Gastrointestinal Cancer Symposium also were included in the search. More than 60 articles reporting on clinical outcomes among patients who received RT for HCC have been published since 1990, including 20 articles that described unique sets of at least 15 patients. RT was used for palliation, to improve local control, and with curative intent in a wide spectrum of patients who most often were unsuitable for surgery and other treatments. Pain reduction following RT was noted in approximately 75% of patients with bone metastases from HCC who received RT. For patients with liver-confined disease treated with conformal RT, proton beam RT, and/or image guided RT with or without transarterial chemoembolization (TACE), local control response rates ranged from 40% to 90%, and the median survival ranges from 10 months to 25 months. For patients with HCC who had portal vein thrombus, the median survival after RT to treat the thrombus and/or the hepatic tumor with or without TACE ranged from 5.3 months to 9.7 months. Although outcomes after high-dose conformal RT for liver-confined HCC were excellent, the potential survival benefit of RT should be tested in randomized controlled trials that require international collaboration. Cancer 2006;106:1653– 63. © 2006 American Cancer Society.

The authors thank Dr. J. Knox and the reviewers for their thoughtful comments regarding this article.

KEYWORDS: hepatocellular carcinoma, conformal radiation therapy, proton radiation, transarterial chemoembolization.

Address for reprints: Laura A. Dawson, M.D., Department of Radiation Oncology, Princess Margaret Hospital, University of Toronto, 610 University Avenue, Toronto, Ontario M5G 2M9, Canada; Fax: (416) 946-6566; E-mail: laura.dawson@rmp. uhn.on.ca

H

Laura A. Dawson is a recipient of an American Society of Clinical Oncology Career Development Award. Received August 15, 2005; revision received November 6, 2005; accepted November 9,2005.

epatocellular carcinoma (HCC) is the sixth most common cancer in the world (626,000 diagnoses per year) and is the third most common cause of cancer-related death (598,000 deaths per year).1 Although HCC predominantly is a problem in developing countries, its incidence is expected to rise over the next decade in North America largely because of the increasing incidence of hepatitis C2 and the 1% to 4% risk per year of HCC developing in patients with cirrhosis.3 Unfortunately, the overall 5-year survival rate for all patients with HCC has remained steady at 3% to 5%.1 HCC is particularly challenging to treat because of to the common locally advanced or multifocal presentation of disease that de-

© 2006 American Cancer Society DOI 10.1002/cncr.21811 Published online 15 March 2006 in Wiley InterScience (www.interscience.wiley.com).

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CANCER April 15, 2006 / Volume 106 / Number 8

TABLE 1 The “Okuda” Staging System for Hepatocellular Carcinoma

Criterion*

Median Survival (mo)

Tumor size: ⬎ 50% (positive) vs. ⬍ 50% (negative)† Ascites: clinically detectable (positive) vs. absent (negative) Albumin: ⬍ 3 g/dL (positive) vs. ⬎ 3 g/dL (negative) Bilirubin: ⬎ 3 mg/dL (positive) vs. ⬍ 3 mg/dL (negative) Disease stage Stage I (0 positive criteria) Stage II (1 or 2 positive criteria) Stage III (3 or 4 positive criteria)

28 8 1

* Based on Okuda et al.5 The largest cross-sectional area of tumor to the largest cross-sectional area of liver.

†

velops in a background of cirrhosis. Because the survival of patients with HCC is related strongly to underlying liver function,4 factors related to liver function are important components of staging systems for HCC. In 1 of the most commonly used staging system, the Okuda system5 (Table 1), tumor size is the only tumor factor considered in addition to liver function factors. Other adverse prognostic factors include extrahepatic disease, portal vein thrombus, and a high serum ␣-fetoprotein level.6 –11 Resection and liver transplantation are the treatments for HCC with the most mature outcome data.12–15 Five-year survival after resection ranges from 31%16 to 56%,17 with serious morbidity and mortality rates of approximately 5%.18 Resection often is not possible because of poor liver function or macrovascular tumor invasion. Liver transplantation is an option for some patients who have a single HCC that measures ⬍ 5 cm in greatest dimension or 3 lesions that measure ⬍ 3 cm in greatest dimension and with no macrovascular invasion or extrahepatic disease.19 The 5-year survival rates after transplantation ranges from 50% to 71%.20 Unfortunately, prolonged wait times for donor organs are associated with tumor progression and with some patients becoming unsuitable for transplantation or dying while they are on the wait list.21 Because ⬍ 15% of patients with HCC are candidates for resection or transplantation, many other therapies have been investigated. Radiofrequency ablation22,23 is associated with excellent local control for small tumors (⬍ 4 cm) and with survival rates that approach the rates achieved after resection.24 Radiofrequency ablation in larger tumors is associated with an increased rate of local recurrence. Other ablative techniques, including percutaneous ethanol injection, microwave coagulation therapy,25 laser-induced ther-

motherapy, and high-intensity focused ultrasound,26 have been used or are being investigated in this setting. The most suitable tumors for these interventions measure ⬍ 5 cm in greatest dimension. In 2 randomized trials27,28 and 1 metaanalysis,29 transarterial chemoembolization (TACE) was found to improve survival compared with supportive care in patients with unresectable HCC. Llovet et al. reported 2-year survival rates of 63% for TACE and 27% for supportive care,30 whereas Lo et al. reported respective 2-year survival rates of 31% and 11% respectively,28 demonstrating that patient selection has a substantial impact on outcomes. The median survival after TACE ranges from 11.2 months to 29.8 months, and the 5-year survival after TACE is ⬍ 10%. The patients most likely to benefit from TACE are those without macrovascular tumor invasion (e.g., portal vein thrombus), where tumor control probably is reduced and complications are more likely. Systemic chemotherapy has had limited impact in HCC.31–33 Newer targeted biologic therapies, such as those that target epidermal growth factor receptor, vascular endothelial growth factor, Raf kinase, and other targeted approaches, are being investigated in clinical trials and may show evidence of efficacy in the future. In summary, there is a need for novel therapies for unresectable HCC, especially for tumors that measure ⬎ 5 cm in greatest dimension. Historically, radiation therapy (RT) has played a minor role in the management of patients with unresectable liver cancer, primarily because of the low tolerance of the whole liver to RT and challenges associated with delivering highly conformal, high-dose RT to liver tumors while sparing dose to the uninvolved liver. There is a ⬎ 5% risk of radiation-induced liver injury after uniform whole-liver RT of 28 gray (Gy) to 35 Gy delivered over 3 weeks,34,35 doses that are far less than those required to eradicate tumor. The most common liver toxicity observed in North America is radiation-induced liver disease (RILD), which is a clinical syndrome of anicteric hepatomegaly, ascites, and elevated liver enzymes (particularly serum alkaline phosphatase) that occurs from 2 weeks to 3 months after external beam RT.35 Treatment for RILD consists of supportive measures, and, in the minority of patients, it can result in liver failure. Reactivation of viral hepatitis and precipitation of underlying liver disease also can occur after RT for HCC.36 In addition to liver toxicities, normal tissues adjacent to the liver, including the stomach, duodenum, and kidneys, are at risk of injury from RT if dose cannot be spared from these organs. Advancements that allow the safe delivery of higher dose external beam RT to liver tumors include

Radiation Therapy for HCC/Hawkins and Dawson

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FIGURE 1.

This is an example of a highly conformal plan for treating hepatocellular carcinoma with radiotherapy. This patient was treated with 45 gray (Gy) in 6 fractions (equivalent to ⬎ 150 Gy in 2 Gy per fraction). The pink represents the target volume.

advanced imaging to improve tumor definition, 3-dimentional radiation planning techniques to deliver high doses that conform tightly to the tumor, imageguided radiotherapy to localize the tumor at the time of treatment, tumor immobilization and organ tracking to account for organ motion because of breathing, and improved knowledge of the partial volume tolerance of the liver to radiation. With such advances,10,37– 42 it has been possible to deliver far higher doses to unresectable HCC than was previously possible with a low risk of complications. An example of a typical conformal radiation plan for a patient with HCC is displayed in Figure 1. Other methods of delivering radiation to HCC include hepatic arterial delivery of 90-Yttrium-labeled microspheres43 or 131-iodine-labeled lipiodol44 and interstitial brachytherapy. These approaches are not the focus of the current report.

Palliative RT Given the challenges associated with the delivery of high-precision RT to HCC, lower doses of RT were investigated first with palliative intent. Even low RT doses to local, regional, and metastatic HCC have been associated with radiographic responses, reductions in serum ␣-fetoprotein levels, and palliative improvements. Lymph node metastases,45 bone metastases,46,47

brain metastases,48,49 and other soft tissue metastases50 from HCC have been treated with palliative RT with good symptom control. Pain relief from bone metastases was observed in 73% to 83% of patients in 2 of the largest series published to date,46,47 emphasizing the radiation responsiveness of HCC. Reduction of mass effects and pain from bulky disease, cessation of bleeding, and prevention of tumor rupture are other palliative indications for RT. The radiation doses used for palliation vary from 8 Gy in 1 fraction for patients with poor performance status or widespread disease to 50 Gy in 20 fractions for patients with isolated metastasis and good performance status.

Liver Tolerance to Radiation With responses observed after low-dose RT, it was hypothesized that higher dose RT should lead to sustained local control and possible cure of localized HCC. RT dose escalation for primary and metastatic liver cancer has been investigated at the University of Michigan since 1987.51 Some of the most useful data on the liver tolerance to RT come from this series of prospectively collected outcome data. Computed tomography (CT)-based conformal radiation planning allowed measurement of the effective volume of normal liver irradiated (defined as the normal liver volume, which, if irradiated to the prescribed dose, would be associated with the same normal tissue complica-

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reduced in patients who had hepatitis B compared with patients who had hepatitis C.36

Conformal RT

FIGURE 2. This is a schematic of an isotoxicity curve for radiation-induced liver disease (RILD) after conformal radiation therapy delivered in 1.5 gray (Gy) twice daily (bid) (effective volume of uninvolved liver irradiated vs. dose delivered). The curve represents the relation of volume irradiated and dose for a 5% risk of RILD. When the volume irradiated is ⬍ 20%, it is predicted that ⬎ 100 Gy (in 1.5 Gy per fraction) will be associated with a very low risk of toxicity (data from Dawson et al.84).

tion probability as the nonuniform dose actually delivered)52 and allowed quantification of the correlation between the liver volume irradiated, the dose delivered, and the risk of liver toxicity. Analyses of ⬎ 200 patients who received conformal liver radiation confirmed that, just as a portion of the liver may be removed safely, very high doses (up to 90 Gy) may be delivered safely if the volume of liver irradiated is low enough.53 The partial volume tolerance of the liver to RT can be summarized by plotting the effective liver volume irradiated versus the dose delivered for an equivalent risk of liver toxicity (Fig. 2). For an effective liver volume of ⬍ 20%, very potent doses can be delivered safely. For larger volumes of liver irradiated, tumor doses can be individualized for a specified isotoxicity level52 of radiation-induced liver toxicity. Patients with hepatobiliary cancer had a lower liver tolerance to RT than patients with liver metastases, likely related to their underlying liver disease.53 The risk of RILD can be estimated from the mean radiation dose to uninvolved liver. The mean liver dose associated with a 5% risk of RILD for patients with HCC is 28 Gy in 2 Gy per fraction.54 Because the majority of patients in the Michigan analysis had Child A liver function, these results cannot be used to describe the risk of toxicity in patients with Child B or C liver function. In an analysis of patients with HCC who were treated with RT in Taiwan, the tolerance of the liver to radiation was less predictable, and the most common toxicity consisted of elevation of transaminases rather than RILD.36 The tolerance of the liver to radiation was

Modern technology allows greater confidence in ascertaining the HCC target volume to be irradiated. Three-dimensional imaging data sets that are used in radiation planning include contrast-enhanced CT and magnetic resonance imaging studies that can be coregistered, allowing better visualization of tumor and its relation to normal tissues. Although liver motion because of breathing (up to 3 cm in some patients) can make high-precision radiation a challenge, liver immobilization with breath hold and/or respiratory gating of the RT beam to 1 phase of the respiratory cycle can minimize the adverse effects of breathing motion, allowing more certainty in tumor position during the delivery of treatment. Treatment plans are individualized and use multiple fields from different angles, including nonaxial beams, with different beam weighting to treat the tumor with a small margin, allowing for microscopic spread, set-up uncertainties, and residual motion of the liver. An example of a typical radiation plan is displayed in Figure 1. Intensity-modulated RT (IMRT) is another technologic advancement that facilitates the delivery of highly conformal RT. With IMRT, radiation is delivered with multiple small fields (“segments” as small as 1 ⫻ 1 cm) within each beam, producing a modulated fluence pattern for each beam angle. Computer-aided, automated optimization of segment weights (or “inverse planning”) is conducted to obtain to the best target coverage and sparing of dose to the normal tissues. Clinical experience with IMRT for the treatment of HCC is limited.42 Planning studies have suggested that IMRT may have a benefit for some patients with HCC.37,55 56 IMRT for tumors of the upper abdomen is more prone to uncertainties introduced from motion because of breathing, which must be accounted for if IMRT is to be implemented safely for HCC. Stereotactic body RT (SBRT) is another method for delivering high-dose, highly conformal radiation to target volumes. SBRT is defined as a treatment method for delivering a high dose of radiation to the target by using either a single dose or a small number of fractions with a high degree of precision within the body.57 It generally refers to the use of very potent doses of RT delivered in ⱕ 5 fractions. At the University of Michigan, conformal RT has been used with concurrent hepatic arterial fluorodeoxyuridine as a radiosensitizer for the treatment of primary and metastatic liver cancers. Using the isotoxicity model described previously to prescribe individualized tumor doses, up to 90 Gy in 1.5 Gy per


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FIGURE 3.

Pretreatment computed tomography (CT) scans of a rapidly progressive, unresectable hepatocellular carcinoma in a male patient age 67 years with hepatitis C (A) and 3 months after 32 gray of radiation therapy in 6 fractions (B). The tumor shrinkage continued at 6 months after treatment; however, new tumor foci outside of the high-dose radiation volume were observed.

fraction twice daily was delivered safely with little toxicity.51,58 The initial median survival of patients with hepatobiliary cancers who received treatment with this approach was 11 months, with 1-year and 3-year survival rates of 47% and 25%, respectively.51 More mature outcome data from 128 patients who were treated on that study were reported recently.59 The objective response rate in patients with HCC was 56%. The median survival of 35 patients with HCC was 15.2 months, and the 1-year and 5-year survival rates were 57% and 11%, respectively (unpublished results). Higher radiation doses were related significantly to survival (P ⫽ .0003).59 Improved local control and survival with higher doses of RT also have been observed by others, with no obvious correlation between dose and potential confounding factors, such as tumor size and performance status.11,51,59,60 To our knowledge, the largest experience with RT in patients with HCC is from Asia, where sustained, long-term local control and survival have been reported in patients who received treatment with a variety of radiation fractionation schemes with conformal RT techniques. One-year survival rates in those patients ranges from 50% to 95%, and the 5-year survival rate ranges from 9% to 25% after 40 Gy to 60 Gy delivered over 1 to 5 weeks6,55,61-63 (Table 3). Reasons for the large range of outcomes include substantial heterogeneity in patient selection, treatment intent, and treatment delivered. Patients with Child A and B

liver function were included in most those series. Some series reported on outcomes in patients with liver-confined disease; however, many of the series reported on patients who had portal vein thrombus or regional metastases and were treated with palliative intent RT. Based on these encouraging results, at the Princess Margaret Hospital in Toronto, a Phase I study of hypofractionated, high-precision RT for patients with unresectable primary or metastatic cancer was initiated. This protocol uses an individualized treatment approach similar to that from the University of Michigan, in which the prescribed tumor dose is dependent on the volume of liver irradiated. To date, 22 patients with HCC have received treatment with doses ranging from 24 Gy to 54 Gy delivered in 6 fractions over 2 weeks. No dose-limiting toxicity has been observed, and radiographic responses have been common (Fig. 3), demonstrating the feasibility of an isotoxicity study design using hypofractionated, highly conformal RT to treat a wide spectrum of tumor sizes and locations.64

Radiation and TACE The majority of recurrences after focal liver RT occur within the liver, outside the high-dose irradiated liver volume, providing rationale for combining RT with other therapies such as TACE. There is a large Asian experience in combining RT with TACE,6,9 –11,36,39,55,61– 63,65–74

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TABLE 2 Outcomes After Photon RT for Hepatocellular Carcinoma

Study

No. of Patients

Liver Function (Child A-C), No. of Patients

Treatment

Ben Josef et al., 200559

35

Child A, 35

RT and hepatic artery FudR

Cheng et al., 200436

89

Child A, 68; Child B, 21

Liu et al., 200439

44

Zeng et al., 200467

54

Seong et al, 200311

158

Li et al., 20036

45

Child A, 32; Child B, 12 Child A, 44; Child B, 10 Child A, 117; Child B, 41 Child C, 0

89 RT (TACE, 74 patients: 39 prior, 7 after, 28 preRT and post-RT) RT (39 failed TACE)

Wu et al., 200463

94

Park et al., 200070

158

Guo et al., 200361

76

Park et al., 200566

59

Child A, 43; Child B, 51 Child A, 117; Child B, 41 Child A, 63; Child B, 13 Child A, 38; Child B, 3

RT Dose in Gy (Dose/Fraction)

TACE and RT TACE and RT; RT for salvage post-TACE TACE ⫻ 2, and RT, and TACE ⫻ 2 TACE and RT TACE and RT TACE and RT RT (48 failed TACE); 51% with PVT

Response Rate

Median Survival (mo)*

OS Rate

40-90 (1.5/fraction bid) 36-66 (1.8-3.0/ fraction)

CR, 3%; PR, 37%; SD, 31%

15.2

1 y, 57%†; 3 y, 11%

NA

NA

NA

39.6-60.0 (1.8/ fraction) 36-60 (2/fraction) 25.2-50.0 (1.8/ fraction) 50.4 (1.8/fraction) 48-60 (4-8/fraction) 25.2-59.4 (1.8/ fraction) 30-50 (1.8-2.0/ fraction) 30-55 (2-3/fraction)

CR, 14%; PR, 48%; SD, 25% CR, 6%; PR, 70%; SD, 24% CR, 0.6%; PR, 67%; SD, 26% CR, 13%; PR, 77%; SD, 8% CR, 13%; PR, 78%; SD, 6% CR, 0%; PR, 67%; SD, 26% CR, 7%; PR, 41%; SD, 40% CR, 8%; PR, 58%; SD, 25%

15.2

1 y, 60%; 3 y, 32% 1 y, 72%; 3 y, 24% 1 y, 59%; 5 y, 9% 1 y, 68%; 3 y, 22% 1 y, 93%; 3 y, 26% 1 y, 59%; 2 y, 30% 1 y, 64%; 5 y, 19% 1 y, 47%; 2 y, 27%

20.0 16.0 23.5 25.0 16.0 19.0 10.0

RT: radiotherapy; Gy: gray; OS: overall survival; FudR: fluorodeoxyuridine; bid: twice daily; CR: complete response; PR: partial response; SD: stable disease; TACE: transarterial chemoembolization; NA: not available; PVT: portal vein thrombus. * Survival was measured in months from the time of RT. † Includes patients with cholangiocarcinoma and liver metastases.

including 3 prospective studies51,62,75 (Table 2). Three strategies of combining RT with TACE have been studied. The first involves using RT to treat portal vein and inferior vena cava tumor thrombus to complement TACE without irradiation of the primary tumor71,72,75 76 (Table 3). The rationale for this approach is that TACE is less effective in patients with portal vein tumor thrombus, and RT may make TACE more effective if portal vein disease can be eradicated.27 From 50 Gy to 60 Gy over 5 to 6 weeks have been delivered safely to the macrovascular disease, and limited liver volume was required to be irradiated.71,72,75 If all of the macroscopic tumor is not irradiated, then this is a palliative approach. A second strategy of combining RT and TACE is to deliver RT as a “consolidation” planned procedure to target residual hepatic tumor after TACE. The rationale for this approach is that RT targets cancer cells at the tumor periphery that may remain viable through blood supply from collateral circulation or recanalization of the embolized artery and that the chemotherapy agents used during TACE may act as radiosensitizers. This is a curative-intent approach. A final approach is to use TACE up front with RT as salvage therapy for recurrences or RT up front with TACE as salvage therapy for recurrences.

Many methods of combining TACE and consolidative RT have been described to date. The most common approaches include the use of 1 TACE procedure followed by RT, RT sandwiched between TACE procedures,6 or repetitive TACE until optimal response or ⬎ 50% of normal liver is replaced by HCC followed by RT.71 The interval between TACE and RT varies from 7 to 14 days,10,62 3 to 4 weeks,63,75 4 to 8 weeks,39,61 and longer if RT is used as salvage therapy for tumor progression after TACE10,70 (Table 4). A planned combined approach has some advantages over reserving RT as salvage therapy. Reduction of tumor volume after TACE may allow less uninvolved liver to be irradiated, permitting the use of higher doses of radiation with less toxicity. Despite the variation in techniques and timing, the majority of studies have suggested a benefit of RT and TACE in patients with advanced HCC, often with macrovascular invasion, compared with contemporaneous patients treated without RT. The partial response rates range from 25%71 to 78%63 at 1 month after RT, with complete response rates as high as 13%.6,39,63 The 2-year and 5-year survival rates range from 10.2% to 53.8% and from 9% to 19%, respectively.61– 63,66 The heterogeneity


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TABLE 3 Outcomes After Photon RT to Tumor Thrombus Only for Macrovascular Invasion Liver Function (Child A-C or Okuda I-III), No. of Patients

Treatment

Study

No. of Patients

RT Dose (Dose/Fraction), Gy

Zeng et al., 200572

44

Okuda I, 34; Okuda II, 8; Okuda III, 2

RT to PVT (25 patients failed TACE)

36-60 (2/fraction)

Tazawa et al., 200171

24

Child A, 12; Child B, 8; Child C, 4

TACE and RT to PVT

50 (2/fraction)

Yamada et al., 200362

19

Child A, 13; Child B, 5; Child C, 1

TACE and RT to PVT

46-60 (2/fraction)

Ishikura et al., 200275

20

Child A, 9; Child B, 10; Child C 1

TACE and RT to PVT

50 (2/fraction)

Response Rate CR, 34%; PR, 11%; SD, 52% CR, 8%; PR, 25%; SD, 25% CR, 0%; PR, 57%; SD, 42% CR, NA; PR, 50%; SD, NA

Median Survival (mo)*

OS Rate

8.0

1 y, 35%

9.7

1 y, 61%; 3 y, 10%

7.0

1 y, 40%; 2 y, 10%

5.3

1 y, 25%

RT: radiotherapy; Gy: gray; OS: overall survival; PVT: portal vein thrombus; TACE: transarterial chemoembolization; CR: complete response; PR: partial response; SD: stable disease; NA: not available. * Survival was measured in months from the time of RT.

of disease, patients, and treatment make comparisons of reported series limited. Because RT combined with TACE appears to be a promising therapeutic approach, this approach should be investigated in a randomized trial. Although survival would be the primary endpoint, quality of life is also important because of the poor prognosis for these patients. To our knowledge, there have been few studies evaluating quality of life in patients with HCC.77

Proton and Heavy-Ion RT Protons and carbon-ion particles are heavier than electrons. They have a positive charge and a unique dose distribution, which makes them well suited for the treatment of deep-seeded tumors surrounded by normal tissues. Protons have a peak area (Bragg-peak) in which rapidly increasing doses are deposited at the end of the beam range at a depth within the patient that is defined by the particular beam energy. This facilitates more dramatic sparing of dose to normal tissues surrounding the tumor than conformal photon RT techniques. The relative biologic effectiveness of protons and heavy ions is greater compared with that of photons (e.g., protons have 10% higher relative biologic effectiveness). Proton dose in patients is reported in Cobalt gray equivalents (GyE), which translate into equivalent photon dose measured in Gy. It has been possible to deliver high doses (up to 79.5 GyE in 15 fractions) to HCCs using proton and heavy-ion therapy. Kato et al.78 reported results from a Phase I/II escalation trial of carbon-ion therapy in 25 patients who were treated with escalation of the dose per frac-

tion in 10% increments. The total dose ranged from 49.5 GyE to 79.5 GyE delivered in 15 fractions over 5 weeks. The local control rates at 1 year and 5 years were 92% and 81%, respectively, and the 5-year survival rate was 25%. At a follow-up of 71 months, there were only 4 local recurrences (17%), but ⬎ 50% of patients had recurrences in untreated portions of the liver, and 25% of patients developed systemic metastases, providing rationale for combining RT with improved whole-liver and systemic therapies. The only Grade 3 toxicity observed after carbon-ion therapy was skin desquamation in the high-dose fields. Tokuuye et al. treated 79 patients who had HCC with proton beam RT.79 A median total dose of 72 GyE in 16 fractions was delivered. At 5 years, local control and survival rates were 89% and 27%, respectively. Kawashima et al. used the same fractionation scheme in 30 patients with HCC with an indocyanine green retention rate at 15 minutes (ICG R15)⬎15%.65 Complete disappearance of tumors occurred in 24 patients (80%). The 2-year local progression-free rate in that study was 96%, and the 1-year and 3-year survival rates were 77% and 62%, respectively. Eight patients developed hepatic insufficiency, which presented as anicteric ascites, elevated transaminase levels, and/or asterixis from 1 to 4 months after therapy. The pretreatment ICG R15 value, which was used as a measure of liver reserve, was correlated strongly with hepatic insufficiency and survival. No hepatic insufficiency was observed if the pretreatment ICG R15 value was ⬍ 20%, whereas 3 of 4 patients who had pretreatment ICG R15 values ⬎ 50% developed hepatic insufficiency. Other investigators also have reported

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TABLE 4 Grade > 3 Toxicity Reported (NCI Common Toxicity Criteria, Version 3) Toxicity, No. of Patients Study

No. of Patients

RILD

GI toxicity

Other toxicity

Cheng et al., 200436 Ben Josef et al., 200559 Zeng et al., 200467 Guo and Yu, 200085

89 128* 54 107

17 (7 deaths) 5 (1 death) None None

Ishikura et al., 200275

20

None

None reported Fever, 4; 1 LFTs, 4; thrombocytopenia, 1 1 Bilirubin, 2; leucopenia, 4 Fever, most patients; ascites, 12; 1 LFTs, 29; thrombocytopenia, 32 Fever, 19; thrombocytopenia, 1

Li et al., 20036 Liu et al., 200439 Park et al., 200566 Park et al., 200270

45 44 59 158

Seong et al., 200310

158

9 (1 death) None 3 (0 deaths) 11 (1 after dose ⬍40 Gy, 3 after doses 40-50 Gy, 7 after doses ⬎50 Gy) 11 (0 deaths)

None reported nausea and emesis, 3; GI bleed, 6 anorexia Nausea/emesis, common; fatal variceal bleeds, 2 Gastritis and GI bleed, 1; abdominal pain, 8 GI bleed, 3 (1 fatal); nausea/emesis, 2 None reported Gastroduodenal ulcer, 3; gastritis, 2 Gastroduodenal ulcer, 9; gastroenteritis, 8

Tazawa et al., 200171

24

Not reported

Wu et al., 200463 Yamada et al., 200362

94 19

12 (4 deaths) Not reported

Zeng et al., 200572

44

None

Gastroduodenal ulcer, 9; gastroenteritis, 8; colitis requiring resection, 1 Nausea/emesis, 2; diarrhea, 1 Gastroduodenal ulcer, 5 GI Grade 3, 2; liver Grade 3 (no details given) Nausea, 1; GI bleed, 1 (fatal)

Fever, 40; 1 LFTs (transient), 43 No Grade 3 toxicities 1 LFTs, 2; 1 bilirubin, 2; ascites, 12 1 Ascites, 24

Fever, 31; 1 LFTs, 60; thrombocytopenia, 18 Fever, 18; 1 LFTs (transient), 3; thrombocytopenia, 3 Fever, 51; thrombocytopenia, 13 Thrombocytopenia, 5; leucopenia, 1 1 ALT (transient), 7

NCI: National Cancer Institute; RILD: radiation-induced liver disease; GI: gastrointestinal; LFTs: liver function tests; 1: elevated; Gy: gray; ALT: alanine aminotransferase. * Includes patients with cholangiocarcinoma and liver metastases.

excellent response rates after proton and heavy-ion therapy.80 Further evidence of the effectiveness of RT was reported by Bush et al.81 Those authors evaluated 6 patients with HCC who underwent liver transplantation 6 to 18 months after proton therapy (63 GyE in 15 fractions). In 2 patients, there was no evidence of tumor pathologically, demonstrating that high doses of RT can eradicate HCC. Pathologic complete responses also were observed by Merle et al.82 In summary, proton and heavy-ion RT for HCC have been associated with some of the best outcomes after RT, perhaps because of the ability to deliver high doses very conformally around the tumor while substantially sparing dose to surrounding, uninvolved liver.78,83 Unfortunately, proton and carbon-ion therapies are limited to a few centers in the world and are very expensive. Nonetheless, the positive experience with proton and carbon-ion therapy demonstrates the proof of principle that, if high enough doses of RT can be delivered, then HCC can be controlled in the majority of patients.

Conclusions In addition to the role of RT in locally advanced and metastatic HCC, technologic advancements have

made RT a potentially curative treatment option for patients with liver-confined HCC. High-dose RT delivered in a variety of fractionations schemes, with and without hepatic arterial chemotherapy or TACE, has been used safely in these patients with encouraging results. Outcomes are improved in patients who receive higher doses of RT, and toxicity is related strongly to pretreatment liver function and to the dose delivered to the uninvolved liver. For small tumors (⬍ 5 cm), RT is associated with excellent local control, and it is likely that most RT strategies and fractionation schemes will control such tumors as long as a high enough dose is delivered. For these patients and for patients with more advanced disease, TACE and RT have been used with promising results. The optimal scheduling of RT and TACE is unknown. Because most of the experience in RT among patients with HCC is from Asia, there is a need for multiinstitutional prospective trials in North America. Ultimately, RT should be tested in a randomized controlled trial, such as TACE versus TACE plus RT. Multiinstitutional international collaborations will be required to conduct randomized trials in this setting. Technical requirements to deliver high precision RT are no longer strong barriers to such trials.


Finally, the greatest benefits to patients will be seen only once advances occur in all aspects of HCC care, including local, regional, and systemic cancer therapy, as well as treatment of underlying liver disease. RT has a potential role in a wide spectrum of HCC presentations, from early-stage, curable disease to advanced disease with regional lymph node metastases, and for palliation of distant metastases. The advances recently seen with targeted systemic agents in other solid tumors may translate into an additive benefit to patients with HCC either in an adjuvant setting or as potential radiosensitizers, especially in patients who have disease with macrovascular invasion. We look forward to working with specialists from hepatology, surgical oncology, interventional radiology, and medical oncology in designing future clinical trials to investigate the optimal integration of RT with other therapies.

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