Hepatocellular Carcinoma Radiation Therapy: Review of Evidence and Future Opportunities

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1 CME International Journal of Radiation Oncology biology physics Critical Review Hepatocellular Carcinoma Radiation Therapy: Review of Evidence and Future Opportunities Jonathan Klein, MD, and Laura A. Dawson, MD Department of Radiation Oncology, Princess Margaret Hospital/University of Toronto, Toronto, Ontario, Canada Received Aug 7, 2012, and in revised form Aug 29, Accepted for publication Aug 29, 2012 Hepatocellular carcinoma (HCC) is a leading cause of global cancer death. Curative therapy is not an option for most patients, often because of underlying liver disease. Experience in radiation therapy (RT) for HCC is rapidly increasing. Conformal RT can deliver tumoricidal doses to focal HCC with low rates of toxicity and sustained local control in HCC unsuitable for other locoregional treatments. Stereotactic body RT and particle therapy have been used with long-term control in early HCC or as a bridge to liver transplant. RT has also been effective in treating HCC with portal venous thrombosis. Patients with impaired liver function and extensive disease are at increased risk of toxicity and recurrence. More research on how to combine RT with other standard and novel therapies is warranted. Randomized trials are also needed before RT will be generally accepted as a treatment option for HCC. This review discusses the current state of the literature and opportunities for future research. Ó 2013 Elsevier Inc. Introduction Primary liver cancer is the world s third most common cause of cancer death (1). Eighty-five percent of cases occur in developing countries, and it is the fastest growing cause of cancer death in the United States (2). Hepatocellular carcinoma (HCC), the focus of this review, accounts for 85%-90% of primary liver cancers. Risk factors for HCC include hepatitis B, hepatitis C, alcohol ingestion, and cirrhosis from any cause. Patients with HCC are often asymptomatic at the time of diagnosis, with a liver lesion incidentally detected via imaging. Classic imaging characteristics of arterial-phase enhancement and venous-phase washout in high risk patients with lesions >2 cm are diagnostic for HCC even without a biopsy (3). Many HCC staging systems have been developed, and most are based on the extent of tumor and vascular invasion (4). Figure 1 illustrates the Barcelona Clinic Liver Cancer system, which incorporates tumor stage, liver function, and performance status to facilitate treatment decisions (5). In this review, the role of external beam radiation therapy (RT) for HCC will be summarized, and opportunities for future research highlighted. Percutaneous brachytherapy and radio-embolization have also been used to treat HCC, but are not the focus of the present review. General Treatment Overview HCC tends to remain within the liver, although multifocality and vascular invasion (eg, to the portal vein) are common (6). The common presence of underlying liver disease increases the risks of all HCC therapies compared with liver metastases occurring in a noncirrhotic liver. Cure with preserved liver function is an overall treatment goal, and liver function is an important component of treatment decisions. Surgical resection, an option for the minority of tumors, results in 5-year survival rates of 60%-70% (5, 7). Liver transplantation can cure both the cancer and underlying liver disease. Four-year survival Reprint requests to: Laura A. Dawson, MD, c/o Radiation Medicine Program, UHN - Princess Margaret Hospital, 610 University Ave, Toronto ON M5G 2M9. Tel: (416) ; Fax: (416) ; laura. dawson@rmp.uhn.on.ca NotedAn online CME test for this article can be taken at astro.org/moc. L.A.D. has obtained research funding from Bayer and has a licensing agreement with Raysearch Laboratories. Conflict of interest: none. Int J Radiation Oncol Biol Phys, Vol. 87, No. 1, pp. 22e32, /$ - see front matter Ó 2013 Elsevier Inc. All rights reserved.

2 Volume 87 Number Radiation therapy for hepatocellular carcinoma 23 Fig. 1. Barcelona Clinic Liver Cancer classification for HCC with description of therapeutic options, and suggestions for RT randomized trials. CLT Z cadaver liver transplantation; HCC Z hepatocellular cancer; LDLT Z living donor liver transplantation; M Z metastases stage; N Z nodal stage; PEI Z percutaneous ethanol injection; PST Z performance status based on Eastern Cooperative Oncology Group score; RF Z radiofrequency ablation; RT Z radiation therapy; TACE Z transarterial chemoembolization. Reprinted with permission (95). for HCC within the Milan criteria (single HCC <5cmor3 HCC <3 cm) is 70%-85% after transplantation (8). Expanded HCC eligibility criteria have been used, with an increased risk of falling off the transplant wait list (9). Bridging therapies are used reduce the potential for drop off resulting from HCC progression. As an alternative to surgery, percutaneous or laparoscopic radiofrequency ablation (RFA) or alcohol injection are used as curative therapies for early HCC, with optimal outcomes in HCCs <3 cm away from large vessels (5). For unresectable HCC unsuitable for ablative therapies, transarterial chemoembolization (TACE) has a survival benefit compared to best supportive care. (10, 11). TACE is less effective against large HCC (>10 cm) or HCC with major portal venous thrombosis (PVT). Sorafenib, a multikinase inhibitor, improved median survival from 4.2 to 6.5 months in an Asia-Pacific trial and from 7.9 to 10.2 months in the Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol (SHARP) trial (12, 13), with less benefit in patients with PVT or extrahepatic disease (14). Sorafenib is only approved for Child-Pugh class A HCC (5). A phase 3 trial comparing sorafenib with sunitinib was stopped early because of futility and safety concerns with the sunitinib arm (15). Systemic doxorubicin has shown activity in HCC (16) and it is being investigated in combination with sorafenib in a large randomized trial. Challenges and Opportunities in HCC RT Delivery of sufficient RT to control HCC while avoiding liver toxicity is a fine balance. Advanced RT technologies such as breathing motion management and image guided radiation therapy (IGRT) have facilitated dose escalation to focal HCCs. Experience with conformal RT, intensity modulated RT (IMRT), stereotactic body RT (SBRT), and particle therapy is rapidly increasing (Fig. 2 and Tables 2-4). A typical RT plan for an HCC with PVT is shown in Figure 3. RT has a potential role across all stages of HCC, particularly for liver-confined HCC unsuitable for, or refractory to, other locoregional therapies. However, RT is generally not considered an option in HCC consensus documents or national guidelines, primarily because of the lack of level 1 evidence. Figure 1 illustrates where RT may fit in HCC treatment allocation and highlights potential populations where randomized trials may be feasible (17). Major challenges to the effective delivery of RT to the liver and opportunities for overcoming them are summarized in Table 1. A better understanding of the RT dose (and dose per fraction) response relationship is needed for tumor control as well as normal tissue toxicities. New targeted therapies showing activity in HCC have the potential to be synergistic with radiation; preclinical and early phase studies will help elucidate mechanisms and determine optimal combinations and sequencing before testing in phase 3 trials. Functional imaging advances may help to target the most resistant portions of the tumor selectively with dose painting while possibly sparing the highest functioning portions of the liver (18, 19). Strategies to mitigate liver toxicity also represent an important area of study that may open the window for expanded role of RT in HCC.

3 24 Klein and Dawson International Journal of Radiation Oncology Biology Physics Fig. 2. Graph of number of liver cancer RT publications over time. Citation count based on a search of the MEDLINE database limited to each 5-year period. Blue line: search for radiation therapy and liver neoplasms. Red line: search for radiation therapy and hepatocellular carcinoma. Orange line: search for radiation therapy and hepatocellular carcinoma, with results limited to clinical trials only. HCC Z hepatocellular carcinoma; RT Z radiation therapy. Table 1 Challenges and opportunities in HCC RT Challenge Barrier Opportunity Late presentation Lack of screening of high-risk patients Patient/physician education Improved screening techniques Limited standard therapies Complex HCC pathophysiology and diseased liver Targeted therapies - Preclinical research - Phase 1 studies of RT and new agents Concurrent liver disease Competing risks of from hepatitis/ Cross-disciplinary collaboration cirrhosis vs HCC Patient selection for RT Lack of level 1 evidence Randomized trials Limited dissemination of RT literature Multidisciplinary education to non-rt experts Tumor identification Imaging requires technical expertise Standardize imaging protocols Radiation oncology education/radiology collaboration Radiology/pathology correlative research Functional imaging RT contour variability Few published guidelines Consensus guidelines Appropriate RT dose Uncertainty in dose-response Clinical studies to improve dose-outcome models Deformable image registration and dose accumulation Research of high dose per fraction biologic effects Conforming dose to tumor Not enough liver Advanced RT planning - Stereotactic body RT - Volume-modulated arc therapy - Charged particle therapy Identifying tumor at treatment Image-guided radiation therapy - Technology advances (eg, magnetic resonance linac) - Respiratory correlated imaging (eg, 4D CBCT) Liver toxicity Luminal gastrointestinal toxicity Understanding mechanism Few effective interventions Proximity of duodenum, bowel to liver - Contrast agents to identify tumor Regenerative research - Stem cell/hepatocyte transplant - Novel agents to mitigate injury Spacers to move luminal tissue away from hepatocellular carcinoma Normal tissue protectors Abbreviations: CBCT Z cone beam computed tomography; HCC Z hepatocellular carcinoma; linac Z linear accelerator; RT Z radiation therapy.

4 Volume 87 Number Radiation therapy for hepatocellular carcinoma 25 Table 2 Stereotactic body therapy for hepatocellular carcinoma Author, year Patients Design PVT (%) CP-B (%) Tumor size (cm) Dose (Gy)/ fractions Survival 1 y Toxicity grade 3 Andolino, Ret NA cm CP-A: 30-48/3 67% (2 y) 36.7%; 20% CP Progression 3.1 cm (med) CP-B: 24-48/ mo (med) 17 patients had grade 2 at baseline (out of 21 with grade 2 toxicity) Cardenes, Pro 18 NA 6 cm CP-A: 36-48/4 75% 18% grade 3 RILD CP-B: 26-42/3 or 40/5 Kwon, Ret ml 30-39/3 93% 2% Seo, Ret NA 10 <10 cm 33-57/3-4 69% 0% Louis, Ret cm (med) 45/3 79% 8% Choi, Pro ml 30-39/ mo (med) 3% 25.2 ml (med) Tse, Pro ml 48% 29% 173 ml (med) Mendez-Romero, Pro NA 37.5/4 if <4 cm 75% 12.5% grade 5 RILD 25/5 or 30/3 if 4 cm Abbreviations: CP Z Child-Pugh; Gy Z Gray; HCC Z hepatocellular carcinoma; LC Z local control; med Z median; mo Z months; NA Z not available; Pro Z prospective; pts Z patients; PVT Z portal vein thrombosis; Ret Z retrospective; RILD Z radiation-induced liver disease; y Z years. Palliative RT Experience with palliative-intent RT underscores the radiosensitivity of HCC. Pain control rates of 73%-83% have been reported after RT for HCC bone metastases (20, 21). HCC lung, brain, and lymph node metastases have also successfully been palliated with RT using doses from 8 Gy in 1 fraction to 60 Gy in 20 fractions (22, 23). There are few published data on the role of low-dose RT for palliation of symptoms from diffuse HCC unsuitable for standard therapies of focal RT. Low-dose RT for palliation of hepatic symptoms from diffuse HCC may be studied in randomized trials comparing RT with best supportive care. Conformal RT Studies investigating conformal RT for HCC are summarized in Table 2. The potential for tumoricidal doses to be delivered to focal HCC was first described at the University of Michigan by using an individualized dose allocation approach based on a normal tissue control probability (NTCP) calculation (24). The last phase 2 trial delivered RT twice daily in 1.5 Gy fractions concurrently with hepatic artery floxuridine and reported 1-year local control and survival rates of 81% and 57%, respectively, in 35 HCC patients. Higher doses were associated with increased response rates (25). A prospective French phase 2 trial in 27 patients with small HCC reported 1 year local control of 76% after 66 Gy in 33 fractions. An increased risk in toxicity was seen for Child-Pugh B patients (26). The largest of several retrospective analyses from Asia reported 1-year survival of 45% with no grade 3 or higher toxicity grade. Similar to other studies, higher RT doses were associated with improved 2-year survival (31% for 53.1 Gy vs 22% for lower doses) (27). Another study (28) reported 61% 1-year survival with no grade 3 toxicity. The importance of baseline liver function is emphasized in a Chinese study that demonstrated 65% 1-year survival rate in 128 patients, 16% with Child-Pugh B at baseline. Sixteen patients (13%) developed fatal liver toxicity. The 1- and 2-year survival was 70% and 50%, respectively, for Child-Pugh A patients compared with only 30% and 0%, respectively, for Child-Pugh B patients (29). Conformal RT may be used with sustained local control and minimal toxicity in focal HCC. Outcomes are best in early-stage patients, and conformal RT should be considered as an option for patients who are unsuitable for resection, transplant, or RFA. Conformal RT has also shown efficacy in patients with intermediate stage HCC and should be considered for focal HCC unsuitable or refractory to TACE. The risk of toxicity after conformal RT in Child-Pugh class B or C HCC is high, and RT should be limited to small tumors in this setting. Randomized trials should be considered to compare conformal RT to best supportive care in Child-Pugh B patients and in addition to or in place of TACE in Child-Pugh A patients. SBRT SBRT series are summarized in Table 2 (31, 33-39). Blomgren et al first used SBRT to treat liver malignancies in An objective

5 26 Klein and Dawson International Journal of Radiation Oncology Biology Physics Table 3 Charged-particle therapy for hepatocellular carcinoma Author, year Patients Design PVT (%) CP-B (%) CP-C (%) Patient subgroup Bush, Pro Cirrhosis Komatsu, Pro Advanced stage 101 Pro % BCLC-C, 2% BCLC-D Mizumoto, Ret NA 23 1 NA Nakayama, Pro Close to GI tract Sugahara, Pro >10 cm Imada, Pro % stage III, 14% stage IV Nakayama, Pro NA Fukumitsu, Pro Away from GI tract Sugahara, Ret NA Mizumoto, Ret Adjacent to porta hepatis Hata, Ret >80 y Hata, Ret NA Hata, Ret NA CP C Kawashima, Pro NA Hata, Pro HCC with PVT Chiba, Ret tumors Kato, Pro NA Abbreviations: BCLC Z Barcelona Clinic Liver Cancer system; CP Z Child-Pugh; GI Z gastrointestinal; GyE Z Gray equivalents; HCC Z hepatocellular carcinoma; LE Z liver enzymes; med Z median; mo Z months; NA Z not available; P or C Z proton or carbon-ion therapy; Pro Z prospective; pts Z patients; PVT Z portal vein thrombosis; Ret Z retrospective; y = years. * Estimated from survival curve. y Thrombocytopenia, leukemia, liver enzyme elevation. response rate of 70% was observed in 20 patients (8 with HCC), whereas stable disease was observed in another 20% (30). Tse et al conducted a phase 1 trial of liver SBRT using a 6-fraction model that selected the dose based on the effective volume of liver required to be treated. Using this strategy in patients with extensive HCC (>50% with vascular invasion), 1 year survival was 48%. Twentynine percent of patients developed grade 3 or higher toxicity at 3 months (31). Price et al conducted a prospective study of 17 HCC patients treated with Gy in 4 fractions for Child-Pugh A liver function and either 3 fractions (26-42 Gy) or 5 fractions (40 Gy) for Child-Pugh class B. No local failures were observed at 1 year, and 1- year survival was 77%. Three instances of grade 3 toxicity, more likely in Child-Pugh B patients, were observed (32). A retrospective trial analyzed 60 patients with early stage HCC. Child-Pugh A patients received Gy in 3 fractions and Child-Pugh B patients received Gy in 5 fractions. Median time to progression was 47.8 months and 2-year survival was 67%. No grade 3 toxicity was seen (33). Another trial (34) treated 42 patients with Gy in 3 fractions, with a resultant 1 year survival of 93%. Toxicity was low; 1 patient experienced a grade 4 hepatic toxicity and died 20 months posttherapy. In patients who have gone on to have a liver transplant, pathologic complete responses of HCCs treated with SBRT (and protons) have been observed (40). SBRT has comparable effectiveness in treating HCC compared with other local therapies, and it should be considered for early-stage HCC unsuitable for standard surgical or ablative therapies. Observed pathologic complete responses and sustained local control demonstrate that SBRT can eradicate HCC. Dedicated early-phase trials should further investigate SBRT for Child-Pugh B patients. The role of SBRT relative to other treatments warrants investigation in phase 3 trials. Charged Particle Therapy Charged particles, such as protons and carbon ions, allow dose escalation through increased sparing of surrounding hepatic tissue. In general, outcomes following particle therapy are better than those after conformal RT or SBRT, as shown in Table 3 (41-58). A prospective phase 2 trial from 2009 prescribed Gy equivalent (GyE) in fractions to 318 patients (24% Child- Pugh B, 2% Child-Pugh C). Survival was 90% at 1 year and 45% at 5 years; 1.5% of patients experienced grade 3 toxicity (42). Mizumoto et al reviewed 266 patients receiving proton therapy, with the fractionation schedule depending on tumor location: 77 GyE in 35 fractions for HCC <2 cm from the gastrointestinal tract (to reduce the risk of luminal gastrointestinal toxicity), 72.6 GyE in 22 fractions for HCC <2 cm from the porta hepatis (to reduce the risk of biliary toxicity), and 66 GyE in 10 fractions for others. No significant survival differences were seen among the 3 doses. Survival at 1, 3, and 5 years for the whole cohort was 87%, 61%, and 48%, respectively (45). Bush et al reported on 76 patients with cirrhosis (47% Child-Pugh B; 24% Child-Pugh C) who were treated with 63 Gy in 15 fractions. Median progression-free and overall survival was 36 and 18 months respectively, with the majority of deaths resulting from non-cancer liver dysfunction. No grade 3 toxicity was reported (43). A retrospective analysis of 343 patients treated with protons (nz242, GyE in 4-38 fractions) or carbon (nz101, GyE in 4-20 fractions) reported 5-year survival rates of 38% and 36% for proton and carbon therapy, respectively. The patient

6 Volume 87 Number Radiation therapy for hepatocellular carcinoma 27 Table 3 (continued) Author, year Particle Dose (GyE) No. fractions Survival (1 y) Survival (5 y) Toxicity grade 3 Bush, 2011 P mo (med) NA 0% Komatsu, 2011 P %* 38% 3% C %* 37% 4% Mizumoto, 2011 P % NA 3% Nakayama, 2011 P % NA 2% Sugahara, 2010 P % NA 0% Imada, 2010 C NA 56% (3 y) 39% (all grade 3) Nakayama, 2009 P % NA 2% Fukumitsu, 2009 P %* 39% 2% Sugahara, 2009 P % (2 y) NA 8% Mizumoto, 2008 P % (2 y) NA 0% Hata, 2007 P % NA 10% Hata, 2006 P % (2 y) NA 0% Hata, 2006 P % NA 0% Kawashima, 2005 P %* 62% (3 y) 40% (mostly biochemical y ) Hata, 2005 P % (2 yr) NA 0% Chiba, 2005 P % NA 3.1% (grade 2) Kato, 2004 C mo (med) NA 26% (1 skin, 10 hematologic) and tumor characteristics were similar in the 2 groups. Child-Pugh status was the only independent predictor of survival, with a drop in 5-year survival rate for Child-Pugh B or C patients from 47% to 8% for protons and from 41% to 33% for carbon ions (44). Charged particle therapy appears to be an effective HCC treatment, with local control and survival rates comparable to those Table 4 Radiation therapy for hepatocellular carcinoma with portal venous thrombosis Author, year Patients Design CP-B (%) CP-C (%) RT only Dose (Gy) Fractionation Median survival (mo) Toxicity grade 3 Rim, Ret % Gy/fx % Yoon, Ret % Gy/fx % Chuma, Ret fx 12 15% Katamura, Ret Gy/fx gr. 4, 7 gr. 3 leuk 6gr.3thromb,1gr.3anorexia Zhang, Ret Gy/fx 7 0 Huang, Ret NA 0 100% Gy/fx 4 0 Han, Pro fx gr. 5 liver dysfunction 9 gr. 4, 33 gr. 3 toxicities RT or chemo caused toxicity Toya, Ret % Gy/fx Lin, SBRT Pro % 45 3 Gy/fx, 6 0 gr. 3 3 fx/week 21 CRT Gy/fx /43 pts finished RT Kim, Ret % Gy/fx Zeng, Ret NA NA 23% Gy/fx 8 0 Yamada, Pro Gy/fx 7 5 gr. 3 thromb, 2 gr. 3 leuk 2 gr. 3 GI ulcers Ishikura, Pro fx 5.3 5% Tazawa, Ret fx CP-A: % CP-B: 2.6 Abbreviations: chemo Z chemotherapy; CP Z Child-Pugh; CRT Z conformal radiation therapy; fx Z fraction(s); gr. Z grade; GI Z gastrointestinal; Gy Z Gray; HCC Z hepatocellular carcinoma; leuk Z leukopenia; mo Z months; NA Z not available; Pro Z prospective; pts Z patients; Ret Z retrospective; RT Z radiation therapy; SBRT Z stereotactic body radiation therapy; thromb Z thrombocytopenia.

7 28 Klein and Dawson International Journal of Radiation Oncology Biology Physics Fig. 3. Typical radiation therapy plans with gross tumor volume and planning target volume delineated by red and blue lines, respectively. Plan A (first row): 33 Gy in 6 fractions for HCC with portal vein thrombosis. Plan B (second row): 45 Gy in 5 fractions for HCC recurrence after transarterial chemoembolization. HCC Z hepatocellular carcinoma. seen after surgery and better than most other RT series. The largest benefit of charged particle therapy is likely in HCC with Child- Pugh class B or C liver function. Randomized trials and/or comparative effectiveness research, considering the increased cost of particle therapy, are needed to elucidate which patients are more likely to benefit from charged particles over photon RT. RT as a Bridge to Liver Transplant Use of local therapies to halt progression of HCC in patients on waiting lists for liver transplantation may allow more patients to remain eligible for transplantation (59). RT has mostly been investigated in patients not suitable for other bridging therapies (60). Sandroussi et al reported on 10 patients with HCC outside Milan criteria who received bridging RT for progressive HCC (5 Child-Pugh B; 1 Child-Pugh C). Five patients successfully underwent transplantation, 3 were awaiting transplant at the time of publication, and 2 developed disease progression (61). Two phase 2 RT trials reported on subsets of patients who underwent transplant. The first reported on 18 patients who underwent transplantation, from a total of 76 treated with protons, with a mean time to transplant of 13 months, and 3-year survival after transplant of 70% (43). The second study reported on 23 patients, of 60 treated with SBRT, who underwent transplantation, with a 2-year survival of 96% (33). Other retrospective series have demonstrated feasibility of SBRT (35-54 Gy in 3, 50 Gy in 5) as a bridge to control HCC on the waitlist for transplant (62). No intraoperative or long-term complications have been noted in any series. RT has been delivered safely as a bridge to liver transplant, and should be considered if HCC bridging is required (eg, long wait list, rapidly growing HCC), especially if other bridging therapies are contraindicated. Prospective studies of bridging (including RT) Table 5 Liver dose limitation recommendations for hepatocellular carcinoma Conformal RT Child-Pugh class A A B Mean non-gtv liver dose 28 Gy, <2 Gy* <13 Gy in 3* <6 Gy in 4-6 Gy* 13 Gy if Pres. D Z 50 Gy in 5*,y 15 Gy if Pres. D Z 40 Gy in 5*,y 16 Gy if Pres. D Z 30 Gy in 5*,y Critical volume model <18 Gy to 800 ml liver, in 3* Abbreviations: Gy Z Gray; GTV Z gross tumor volume; Pres. D Z prescribed dose; RT Z radiation therapy; SBRT Z stereotactic body RT. * From unpublished analysis of data from Tse (31). y Fraction(s). SBRT

8 Volume 87 Number Radiation therapy for hepatocellular carcinoma 29 Table 6 Liver dose constraints employed in selected clinical trials RT technique Study Liver constraint Median dose (range), fractionation Conformal RT Ben-Josef, 2005 V eff based dose; 15% risk predicted by NTCP model 67.5 Gy (40-90 Gy), 1.5 Gy per fx Mornex, 2006 If 50% isodose line encompassed the following % of 66 Gy (54-66 Gy), 2 Gy per fx liver: <33%, 66 Gy prescribed 33%-66%, 50 Gy prescribed >66%, 36 Gy prescribed SBRT Andolino, 2011 CP-A: V 10 33% liver; 500 ml of liver <7 Gy CP-B: V 18 33% liver; 500 ml of liver <12 Gy CP-A: 44 Gy (30-48 Gy), 14 (6-16) fx CP-B: 40 Gy (24-48 Gy), 8 (8-16) fx Kwon, 2010 V 20 50% liver 33 Gy (30-39 Gy), 3 fx Proton Bush, % isodose line encompasses 1/3 of liver 63 Gy, 15 fx HCC with PVT Yoon, % isodose line encompasses <50% of liver 40 Gy (21-60 Gy), 2-5 Gy per fx Abbreviations: CP Z Child-Pugh; fx Z fraction(s); Gy Z Gray; HCC Z hepatocellular carcinoma; liver Z non-gtv liver volume; NTCP Z normal tissue complication probability; PVT Z portal venous thrombus; RT Z radiation therapy; SBRT Z stereotactic body radiation therapy; V eff Z effective liver volume irradiated. versus no bridging are warranted, as are studies investigating the potential for RT to downstage HCC and expand eligibility criteria for liver transplant. RT for HCC With Portal Venous Thrombosis (PVT) Most HCC with PVT or other vascular invasion are unresectable and unsuitable for other locoregional therapies (63). In 1989, Takagi et al reported a 29% response rate in 7 patients irradiated for HCC with PVT (64). Since then, many studies, mostly retrospective, have established efficacy of RT in treating HCC with PVT, with a range of median survival rates from 4 to 15 months and a generally favorable toxicity profile (Table 4) (65-78). Response of PVT to RT tends to be slow, but eventual recanalization has been observed (73). A series of 412 patients with PVT treated with Gy in 2- to 5-Gy fractions reported a median survival of 10.6 months and 2-year survival of 23%. Child-Pugh class B liver function, extensive venous involvement (ie, main or bilateral portal veins), elevated AFP levels, and large HCC were identified as poor prognostic factors (67). Another series from Asia of 312 patients with PVT reported a substantially lower median survival after RT than other trials (4 months). A total of 48% of patients were categorized as missing status, with presumed early mortality and a median survival of 2.5 months. In contrast, patients who had a complete or partial response of PVT to RT had a median survival of 13.3 and 11.7 months, respectively (65). In a comparative study, Zhang et al reported significantly improved survival in 16 patients treated with TACE and RT compared with 45 patients treated with TACE alone (33% vs 7% 1-year survival) (70). The addition of RT to a combination of 5-FU and interferon for HCC with PVT has been compared with the systemic combination alone in 2 trials. Chuma et al demonstrated improved median survival (12.0 vs 9.1 months) and time-to-progression (6.9 vs 4.0 months) in the RT group (68) Katamura et al reported a significantly improved objective response rate and reduced portal hypertension-related toxicity in the RT arm, with no difference in survival (79). In Toronto, 55% of 102 patients with locally advanced HCC treated on sequential phase 1/2 SBRT studies had PVT. PVT was the strongest adverse prognostic factor, with a median survival of 10.6 months versus 21.5 months for HCC without PVT (80). A randomized study of sorafenib versus SBRT and sorafenib is planned for HCC with PVT (Radiation Therapy Oncology Group 1112). Many retrospective and several phase 2 studies have demonstrated responses of HCC with PVT to RT. Outcomes are best in patients with preserved liver function, less extensive PVT, and lower levels of tumor markers. Guidelines for assessing response of PVT and other vascular invasion from HCC are needed. A phase 3 study of SBRT will help to clarify the role of RT in this setting. Combined Modality Treatment RT in a range of doses has been combined with locoregional therapies such as TACE (81-83). One phase 1 dose escalation study (84) demonstrated that 62 Gy and 52 Gy were safe doses for HCC <10 cm and >10 cm, respectively, in conjunction with TACE. Koo et al (85) prospectively studied 42 patients who received TACE followed by RT. Survival in this cohort was improved compared with a historical control group of 29 patients who received TACE alone (median survival 11.7 vs 4.7 months). Other studies (86, 87) of RT after TACE have reported 2-year survival rates ranging from 37% to 46%. RT has also been compared with regional and systemic therapies (25). Two studies reported outcomes in HCC patients treated with RT delivered with concurrent capecitabine. A 94% response rate was seen in 20 patients treated with 50 Gy in 20 fractions. Median survival was 22.5 months in Child-Pugh A patients versus 8.0 months in Child-Pugh B patients (88). Another study delivered Gy in 10 fractions, with a response rate of 45% and a median survival of 12.3 months (89). A retrospective Taiwanese study reported a median survival of 16 months in 23 HCC patients (8 Child-Pugh B, 5 with major PVT) treated with hypofractionated RT (52.5 Gy in 15).

9 30 Klein and Dawson International Journal of Radiation Oncology Biology Physics Maintenance sunitinib was the most significant factor for survival. There were 3 episodes of upper gastrointestinal bleeding and 1 episode of pancreatitis. Ten patients had grade 2 or more elevation of liver enzymes, and 15 developed grade 2 or more thrombocytopenia (90). Phase 1 trials of RT and sorafenib are ongoing. RT may be combined safely with TACE and randomized studies of TACE with or without RT are warranted. Fewer studies have been conducted of RT with targeted agents; HCC-specific phase 1 studies of RT and novel agents are recommended. RT Toxicity Avoidance Classic radiation-induced liver disease (RILD) presents as a clinical syndrome of anicteric hepatomegaly, elevated liver enzymes and ascites occurring between 2 weeks and 3 months after RT; it is largely preventable if published liver dose constraints are implemented. However, HCC patients with underlying liver disease (eg, hepatitis, cirrhosis) usually develop nonclassical RILD, which is more difficult to prevent, and includes any other liver toxicity including reactivation of hepatitis, elevation of liver enzymes, or any decline in liver function. Interested readers are directed to a more thorough review on the topic by Guha et al (91). Patients with worse baseline liver function are at higher risk for developing RILD (92). In one phase 1 SBRT study, Child- Pugh A patients received 48 Gy without dose-limiting toxicity, but 2 Child-Pugh B patients developed grade 3 toxicity after receiving 42 Gy. A reduction in the dose to 40 Gy in 5 fractions lead to no further grade 3 toxicities in 17 HCC patients (35). Recommended liver dose constraints to keep the risk of liver toxicity to a minimum for different fractionations are shown in Table 5 (25, 31, 78, 96). Examples of liver dose constraints employed in various HCC studies are shown in Table 6 (25, 26, 33, 34, 43, 67). RT has been shown to reactivate hepatitis B in HCC patients (93). Thus, antiretroviral therapy in hepatitis B patients is recommended before initiating RT for HCC. Nonhepatic normal structures (such as duodenum and bowel) also need to be considered because their tolerance appears lower in HCC patients compared with other patients and such organs may limit the dose of RT and impact the fractionation (94). More research is required regarding mitigation of all toxicities (91). Conclusion There is a growing clinical experience in HCC RT with promising clinical outcomes. RT should be considered as a treatment option in patients unsuitable for other established local therapies, and the combination of RT with other treatments should be investigated further. Randomized trials of RT in HCC and comparative effectiveness studies of different RT techniques are needed. 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