Proton Beam Therapy and Carbon Ion Radiotherapy for Hepatocellular Carcinoma

Proton Beam Therapy and Carbon Ion Radiotherapy for Hepatocellular Carcinoma Smith Apisarnthanarax,* Stephen R. Bowen,† and Stephanie E. Combsz,x Charged particle therapy with proton beam therapy (PBT) and carbon ion radiotherapy (CIRT) has emerged as a promising radiation modality to minimize radiation hepatotoxicity while maintaining high rates of tumor local control. Both PBT and CIRT deposit the majority of their dose at the Bragg peak with little to no exit dose, resulting in superior sparing of normal liver tissue. CIRT has an additional biological advantage of increased relative biological effectiveness, which may allow for increased hypofractionation regimens. Retrospective and prospective studies have demonstrated encouragingly high rates of local control and overall survival and low rates of hepatotoxicity with PBT and CIRT. Ongoing randomized trials will evaluate the value of PBT over photons and other standard liver-directed therapies and future randomized trials are needed to assess the value of CIRT over PBT. Semin Radiat Oncol 28:309320 Ó 2018 Elsevier Inc. All rights reserved.

Introduction and Rationale

A

s described in the accompanying articles in this issue, technological advances in imaging and delivery of radiation therapy and improved understanding of dose and/or volume relationships in the liver have resulted in encouragingly high rates of local control for hepatocellular carcinoma (HCC) patients treated with stereotactic body radiation therapy (SBRT) or high-dose hypofractionated 3D-conformal radiation therapy. Although “classic” radiation-induced liver disease is now rarely encountered after liver radiation, “non-classic” radiationinduced liver disease (ncRILD) toxicity is still being reported. Depending on the toxicity endpoint (eg, Child-Pugh [CP] class progression, CP score + 2) and the patient cohort (eg, CP-A vs CP-B class) being reported, ncRILD has ranged from 3% to 46%,1-9 and remains an important and clinically relevant issue to consider when treating HCC patients. Mitigating radiation hepatotoxicity while maintaining high local tumor control rates forms the basis for assessing other radiation modalities to improve the therapeutic index. Charged particle therapy (CPT)

*

Department of Radiation Oncology, University of Washington, Seattle, WA Departments of Radiation Oncology and Radiology, University of Washington, Seattle, WA z Department of Radiation Oncology, University Hospital Rechts der Isar, Technical University M€ unchen, Munich, Germany x Institute of Innovative Radiotherapy, Helmholtzzentrum M€ unchen, Munich, Germany Address reprint requests to Smith Apisarnthanarax, Department of Radiation Oncology, University of Washington, 1959 NE Pacific St, Box 356043, Seattle, WA 98195. Tel.: +1 206 598 4100; fax: +1 206 598-3498. Email: [email protected] y

https://doi.org/10.1016/j.semradonc.2018.06.008 1053-4296/© 2018 Elsevier Inc. All rights reserved.

represents another step in the evolutionary ladder of technological advancement in the treatment of HCC patients. Both proton beam therapy (PBT) and carbon ion radiotherapy (CIRT) have emerged as promising CPTs for these patients.

Rationale for Proton Beam Therapy The impetus to use PBT in HCC patients lies in the physical characteristics of proton particles that impart a dosimetric advantage. Compared to photons that deposit dose along the beam path, resulting in exit dose to adjacent normal tissue distal to the tumor, protons have a finite range in tissue. As they enter tissue, protons lose only small amounts of their energy until they reach the end of the beam range, at which point the remaining energy is deposited over a short distance. This sharp dose accumulation and fall-off is called the “Bragg peak” (Fig. 1).10 To create clinically useful proton beams, multiple Bragg peaks of different energies are stacked together to form a spread-out Bragg peak. This favorable dosimetric characteristic results in little to no exit dose beyond the tumor target, conferring an advantage over photon-based treatments. In HCC patients, this dosimetric advantage translates to significantly lower doses to the normal (nontumor) liver, primarily at low to moderate dose levels, compared to photon-based treatments (Fig. 2).11-15 Because recent data have suggested that doses as low as 2.5 to 10 Gy may mediate ncRILD in HCC patients,4,16 particularly for less compensated liver patients, PBT has the potential to reduce the risk of radiation-induced liver disease 309

S. Apisarnthanarax et al.

310

Rationale for Carbon Ion Radiotherapy

Figure 1 Depth dose characteristics of photons compared to protons and carbon ions (single beam displayed). Compared to photons, protons and carbon ions deliver less radiation dose proximal and distal to tumors due to the spread-out Bragg peak (SOBP). Compared to protons, carbon ions have a dosimetric advantage of less entrance dose.

(RILD) without compromising the ability to deliver definitive doses of radiation to HCC tumors. Although the relative biological effectiveness (RBE) of protons is thought to be dependent on various factors such as tissue-specific radiosensitivity, biological endpoint, dose level, and oxygen concentration,17-19 an RBE of approximately 1.1 is routinely used in the clinic for PBT. The benefits of PBT, therefore, lie heavily in the dosimetric and not in the biologic advantages for HCC tumors.

Compared to protons, carbon ions offer comparable physical characteristics with steep dose fall off after the Bragg peak, but with slightly less entrance dose (Fig. 1). However, the biological properties are substantially different. While the RBE for protons is approximately 1.1, the RBE for carbon ions is significantly higher. Depending on the tissue, the endpoint, the depth, and other characteristics, the RBE of carbon ions varies between 2 and 5.20,21 This higher RBE is due to the high-linear energy transfer radiobiological damage produced by heavier ions: mainly double strand breaks that are difficult to repair by intrinsic cellular repair mechanisms.22-24 These radiobiological characteristics argue for the use of carbon ions particularly for radiation resistant tumor types, such as chordoma and chondrosarcoma or adenoid cystic carcinoma, but also for HCC.25 Based on preclinical experiments, RBE values vary between 2 and 4 depending on the HCC subtype and may be potentiated when combined with chemotherapy or targeted agents.20,26 Although HCC tumors are considered relatively radiosensitive, they often present with a large mass within surrounding normal liver tissue that is also highly sensitive to radiation. For liver tissue, the consideration of delivered tumor dose and irradiated normal liver tissue volume and dose are equally important.27-29 In this setting, the improved dose distributions of CPT compared to photons, and the slightly superior dose distributions for carbon ions compared to protons may be valuable.30 Moreover, the possibility of extremely hypofractionated regimens (less than 5 fractions) may be beneficial in HCC when combined with CIRT. Preclinical experiments have shown that while RBE is decreased with hypofractionation, this decrease is much steeper in normal liver tissue than in

Figure 2 Proton beam therapy vs intensity modulated radiotherapy (IMRT) plan comparison. Both plans deliver 67.5 Gy over 15 fractions to the tumor. Proton plan (left panel) uses a two-beam approach (right lateral and left posterior oblique) with pencil-beam scanning. IMRT plan (right plan) uses a volumetric modulated arc therapy (VMAT) technique.

Particle Therapy for HCC tumors, which contributes to a beneficial risk-benefit profile.31,32 Therefore, the clear benefit of high-linear energy transfer particles, such as carbon ions, lie both in superior dosimetric treatment plans, as well as in the biological properties of the ion beams.33

Clinical Outcomes for Proton Beam Therapy The majority of the PBT HCC clinical experience has been reported from Asia, predominantly from Japan; however, clinical data from Western countries are emerging. As shown in Table 1, several trends can be seen when examining the worldwide collective PBT experience. Similar to SBRT studies, the majority of patients treated with PBT had well-compensated liver function (proportion of patients with CP-A ranging from 67% to 89%, excluding a study that solely reported on patients with CP-C liver function). The median tumor size treated with PBT ranged from 3.9 to 6.0 cm (excluding a study that only reported outcomes with tumor sizes larger than 10 cm), which was notably larger than the majority of SBRT studies (tumor size ranging from approximately 1.5 to 3.7 cm). The BED10 of PBT doses in these studies ranged was similar to those reported in SBRT studies (80125 GyE). Long-term clinical outcomes exist for PBT with the majority of data being reported at 2-5 years. Overall survival (OS) at these time points varied from 21% to 69%. The lower end of OS rates was seen in studies that included high-risk patient subgroups, such as patients with severe cirrhosis (CP-C), large tumors (>10 cm), or vascular invasion. The higher end of OS rates was reported in studies with more favorable patient subgroups, such as those with primarily Barcelona Clinic Liver Cancer (BCLC) stage A tumors. Long-term local control (LC) at 5-years ranged from 64% to 94%. With the exception of a phase I dose escalation study that reported a relatively low LC rate of 64% at 5-years, LC was greater than 90% in all other studies. The first clinical report on the use of PBT for HCC tumors was from the University of Tsukuba in the early 1990s.34 Since this first publication, investigators from the University of Tsukuba have published several studies on their PBT experience using a tumor location-adapted regimen that varies the total dose and dose per fraction based on proximity of the tumors to adjacent gastrointestinal organs-at-risk (GI OARs) and porta hepatis.34-49 Tumors that were located close to GI OARs were treated with a more conventional fractionation regimen, whereas those located distant to GI OARs were treated with a higher BED10 dose in a hypofractionated approach: tumors within 2 cm of GI OARs received 77 Gy relative biologic equivalent (GyE) in 35 fractions (BED10 94 GyE), tumors within 2 cm of the porta hepatis received 72.6 GyE in 22 fractions (BED10 97 GyE), and peripheral tumors >2 cm from GI OARs and porta hepatis received 66 GyE in 10 fractions (BED10 110 GyE). The largest study using this approach reported on the clinical outcomes of 259 patients.43 LC and OS at 3 years was 87% and 61%, respectively, and were similar across the 3 treatment protocols.

311 The most recent study from University of Tsukuba reported on clinical outcomes according to the BCLC staging system also had the longest follow-up to date.36 Of the 129 patients in this study, the majority of patients had BCLC stage C disease (50%) with approximately equivalent percentage of patients with BCLC stage A (23%) and B (26%). As expected, LC, progression-free survival (PFS) and OS at 5-years declined with increasing BCLC stage. Importantly, BCLC stage A patients had clinical outcomes (5-year LC 94%, PFS 28%, OS 69%) that were comparable to patients historically treated with other standard-of-care local therapies (hepatectomy and radiofrequency ablation). In addition, patients with gross tumor vascular invasion in major portal vessels and inferior vena cava had excellent LC at 90% and OS of 34%, highlighting PBT as a viable treatment option for patients with gross vascular invasion. Studies from other institutions in Japan have reported similar results. Investigators from Chiba treated 30 HCC patients on a phase II protocol to 76 GyE in 20 fractions (BED10 105 GyE).50 Two-year LC was 96% and 2-year OS was 66%. Komatsu et al. treated 242 HCC patients with PBT at the Hyogo Ion Beam Medical Center on various treatment protocols (52.8-84.0 GyE in 4-38 fractions).51 Five-year LC and OS rates were 91% and 38%, respectively. A phase I dose escalation study from Korea treated 27 patients at 3 dose levels to determine the optimal treatment dose based on dose-limiting toxicities: 60 GyE in 20 fractions (BED10 78 GyE), 65 GyE in 22 fractions (BED10 84 GyE), and 72 GyE in 24 fractions (BED10 94 GyE).52 No dose-limiting toxicities or RILD were observed. All tumors treated at the highest dose level demonstrated complete radiographic response by modified Response Evaluation Criteria in Solids Tumors, while the tumors treated at the other lower dose levels had lower complete radiographic response rates ranging from 57% to 63%. Although it is unclear whether a dose-response relationship truly exists for HCC tumors treated with radiation, this study suggests that LC may be dependent on delivered dose and that dose escalation can be safely achieved with PBT. The first study from North America on the use of PBT for HCC patients was from Loma Linda.53 Bush et al. published their preliminary data in 2004 and subsequently reported their long-term results using a 15 fraction regimen of 63 GyE (BED10 90 GyE).54 Crude LC, which included biochemical (alpha-feta protein) control, was 80%, and median progression-free survival was 36 months for all patients. Three-year OS was 70% in the 18 patients who went on to receive an orthotopic liver transplant. A more recent study from the United States was a multicenter phase II trial of PBT for HCC and intrahepatic cholangiocarcinoma that utilized a tumor-located-based treatment regimen,55 similar to the University of Tsukuba approach, with the expection that all these patients were treated over 15 fractions. For peripheral tumors located more than 2 cm from the porta hepatis, 67.5 GyE in 15 fractions (BED10 97.9 GyE) was used, and for central tumors within 2 cm of porta hepatis, 58.05 GyE in 15 fractions (BED10 80.5 GyE) was utilized. For the 44 HCC patients, the 2-year LC and OS rates were 95% and 63%, respectively.

312

Table 1. Clinical Outcomes of Select Institutional Proton Beam Therapy Studies of HCC Patients Institution (year)

Patients (n)

CP Status

Median Tumor Size (range)

PVTT

Dose/# Fx/BED10

OS

LC

Chiba, Japan (2005)50

30

CP-A 67%

4.5 cm (2.58.2 cm)

40%

76 GyE/20/87.4 GyE

2-year 66%

2-yearr 96%

University of Tsukuba (2006)38

19

CP-B 33% CP-C 100%

Median 4 cm

NR

Median 72 GyE/16/104.4 GyE

1-year 53%

Crude 95%

University of Tsukuba (2009)48

35

CP-A 80%

(2.5-8 cm) Median 6 cm

100%

(range 50-84 GyE/10-24) Median 72.6 GyE/10-35/87.4-125.3 GyE (range 55.0-77.0 GyE)

2-year 42% 2-year 48%

2-year 91%

University of Tsukuba (2010)49

22

CP-B 20% CP-A 50%

(2.5-13 cm) Median 11 cm

50%

Median 72.6 GyE/22/96.6 GyE

5-year 21% 1-year 64%

5-year 91% 2-year 87%

HIBMC (2011)51

242

(range 47.3-89.1 GyE/10-35) 52.8-84.0 GyE/4-38/91.2-122.5 GyE

2-year 36% 5-year 38%

5-year 90%

259

(10-14 cm) <5 cm 71% 5-10 cm 23% >10 cm 6% 3.4 cm (0.613.0 cm)

26%

University of Tsukuba (2011)43

CP-B 50% CP-A 76% CP-B 23% CP-C 1% CP-A 76%

NR

 Peripheral: 66 GyE/10/109.6 GyE

3-year 61%

3-year 87%

3-year 70% (OLT)

Crude 80%

Loma Linda (2011)54

76

5.5 cm

5%

Goyang, Korea (2015)52

27


5 cm 81%

NR

Dose escalation regimen:

3-year 56%

3-year 80%

CP-B 11%

>5 cm 19%

5-year 42%

5-year 64%

CP-A 73%

5.0 cm (1.912.0 cm)

30%

 60 GyE/20/78 GyE (n = 8)  66 GyE/22/85.8 GyE (n = 7)  72 GyE/24/93.6 GyE (n = 12)  Peripheral: 67.5 GyE/15/97.9 GyE

MGH/MDACC/ UPenn (2016)55

44

2-year 63%

2-year 95%

3.9 cm (113.5 cm)

13% Vp 2-4


2 cm porta hepatis: 58.05 GyE/15/ 80.5 GyE  Peripheral: 66 GyE/10/109.6 GyE

5-year

5-year

BCLC A 69%

BCLC A 94%

BCLC B 66%

BCLC B 87%

BCLC C 25%

BCLC C 75%

CP-B 21% University of Tsukuba (2017)36

129 untreated

CP-A 78% CP-B 22%


2 cm porta hepatis: 72.5 GyE/22/96.6 GyE 
2 cm GI structure: 77 GyE/35/93.9 GyE

CP, Child-Pugh; PVTT, portal vein tumor thrombus; Fx, fraction; BED10, biologic equivalent dose with a/b of 10; OS, overall survival; LC, local control; NR, not reported; HIBMC, Hyogo Ion Beam Medical Center; OLT, orthotopic liver transplant; MGH, Massachusetts General Hospital; MDACC, MD Anderson Cancer Center; UPenn, University of Pennsylvania; Vp: portal vein tumor thrombus grade; BCLC, Barcelona Clinic Liver Cancer. Sections in bold highlight specific patient subgroups being studied.

S. Apisarnthanarax et al.

CP-A 29% CP-B 47% CP-C 24% CP-A 89%


2 cm porta hepatis: 72.5 GyE/ 22/96.6 GyE 
2 cm GI structure: 77 GyE/35/ 93.9 GyE 63 GyE/15/89.5 GyE

CP-B 22%

Particle Therapy for HCC

Close-GI-tract: 60 GyE/12/90 GyE Others: 52.8-60 GyE/4/122.5-150 GyE 10% 4.5 cm (1.5-9.3 cm)

126

31 Age  80

NIRS (2017)59

GHMC (Shiba) (2017)61

CP-A 87% CP-B 13%

6 HIT (2013)21

CP-B 23%

101 HIBMC (2011)51

CP, Child-Pugh; PVTT, portal vein tumor thrombus; Fx, fraction; BED10, biologic equivalent dose with a/b of 10; OS, overall survival; LC, local control; NIRS, National Institute of Radiological Sciences in Japan; NR, not reported; HIBMC, Hyogo Ion Beam Medical Center; MST, median survival time; HIT, Heidelberg Ion Therapy Center; GHMC, Gunma University Heavy Ion Medical Center. Section in bold highlight specific patient subgroup being studied.

3-year 91% 5-year 90% 2-year 89% 3-year 50% 5-year 25% 2-year 82%

1-year 95% 1-year 90%

 Phase I: 54, 48, 48 GyE/12, 8, 4/78.3, 76.8 GyE/105.6 GyE  Phase II: 52.8 GyE/4/122.5 GyE 17%

NR

64 NIRS (2010)58

CP-B 33% CP-A 77% CP-B 23% CP-A 77% CP-B 20% CP-C 3% CP-A 80% CP-B 20% CP-A 77%

4.0 cm (1.0-12 cm)

Crude 100% MST 11 months 40 GyE/4/80 GyE

5-year 93% 5-year 36% 18%

<5 cm 75% 5-10 cm 20% >10 cm 5% 3.5 cm (0.9-4.5 cm)

52.8-76.0 GyE/4-20/87.6-122.5 GyE

70% 4.0 cm (1.2-12 cm)

52.8 GyE/4/122.5 GyE

1-year 92% 3-year 50% 5-year 25% 5-year 22% 49.5-79.5 GyE/15/65.8-121.6 GyE 13% 5.0 cm (2.1-8.5 cm) 24 NIRS (2004)56

CP-A 67%

OS Dose/# Fx/BED10 PVTT Median Tumor Size (range) CP Status Patients (n) Institution (year)

Table 2. Clinical Outcomes of Select Institutional Carbon Ion Radiation Therapy Studies of HCC Patients

Both retrospective and prospective studies from Japan and Germany have assessed the value of CIRT for HCC. As summarized in Table 2, the clinical experience with CIRT is not as extensive as PBT, although a couple of studies have reported on over 100 patients. Similar to SBRT and PBT studies, the majority of patients treated with CIRT have wellcompensated CP-A liver function (67%-87% of patients). Both the tumor size (median 4-5 cm) and BED10 delivered doses (65.8-150 GyE) were similar to those reported in PBT studies. A key difference, however, is that many of the CIRT studies investigated more extreme hypofractionated regimens (4-12 fractions) compared to PBT studies (10-35 fractions). Long-term clinical outcome data are also available for CIRT treated patients and are encouraging with 5-year OS of 22%-36% and 5-year LC of 81%-93%. Early data came from National Institute of Radiological Sciences (NIRS) and were reported by Kato et al.56 and Tsujii et al.57 Kato et al. included 24 patients into a feasibility doseescalation study which was performed stepwise from 49.5 to 79.5 GyE in 15 fractions.56 The median follow-up was 71 months and no severe adverse effects or treatment-related deaths were observed. The overall tumor response rate was 71%. The LC and OS rates were 92% and 92%, 81% and 50%, and 81% and 25% at 1, 3, and 5 years, respectively. Patients without any pretreatment had a significantly higher survival compared to heavily pretreated patients. In patients who received doses of 72 GyE or higher, no local recurrence was observed. Serious adverse events were only observed in one patient in the form of radiation dermatitis which resolved over time. Thus, at that time, treatment recommendations were 72 GyE in 15 fractions. Subsequently, several studies of more hypofractionated regimens were performed with the radiobiological rationale that with increased hypofractionation, the RBE values for tumor and normal tissue are lower with higher fraction doses, with significantly higher decrease in normal tissue than in tumors.31,32,57 Thus, an increased therapeutic ratio was anticipated. With a hypofractionated regimen of 52.8 GyE delivered over four fractions, LC at 3 years was 94% in study performed at NIRS.57 Imada et al. evaluated 64 patients with HCC treated with this regimen and focused on outcome with respect to location within the liver: 5-year OS and LC rates were 22.2% and 87.8% in the porta hepatis group and 34.8% and 95.7% in the nonporta hepatis group, respectively. Therefore, it is important to stress that CIRT is also safe and highly effective in patients with HCC located near the porta hepatis (within 2 cm of the portal vein).58 A recent study reported on 83 patients enrolled on phase I (68 patients) and II (15 patients) dose-escalation trials from NIRS that evaluated decreasing number of fractions with varying doses per fraction.59 Fractionation and dose were 12 fractions from 54 to 69.6 GyE, then 8 fractions from 48 to 58 GyE, and 4 fractions from 48 to 52.8 GyE. From these levels, 52.8 GyE in 4 fractions (BED10 122.5 GyE) was established as the recommended dose fractionation regimen for

LC

Clinical Outcomes for Carbon Ion Radiotherapy

1-year 92% 3-year 81% 5-year 81% 5-year 88%

313

S. Apisarnthanarax et al.

314 the phase II component of the trial. A follow-up phase II trial evaluated 46 patients with HCC treated with 52.8 GyE in 4 fractions. From the pooled analysis of both studies of 124 patients, LC was 94.7% at 1 year, 91.4% at 3 years, and 90% at 5 years. No predictive factors for LC were found, including tumor volume, number of nodules in the target volume, tumor thrombus, fraction number of other clinical parameters. However, in spite of high LC, OS was comparably low with a median OS of 35 months. The authors argue that this may be related to the inclusion of primarily recurrent or locally advanced HCC tumors which were not amenable to curative resection. At the Heidelberg Ion-Beam Therapy Center, a prospective clinical trial (PROMETHEUS trial) evaluated dose-escalated CIRT by increasing the dose per fraction with a fixed number of fractions using active raster scanning.60 The trial was designed as a dose-escalation study evaluating the optimal carbon ion dose with respect to toxicity and tumor control. Primary endpoint was toxicity and secondary endpoints were progression-free survival and response. Total dose was planned from 40 to 56 GyE in 4 fractions over five dose levels ranging from 10 to 14 GyE per fraction. Preliminary data confirmed safety and promising efficacy with active raster scanning21; however, the final study results are still pending. The use of noninvasive treatment options in elderly patients is becoming more and more important due to the growth of the elderly population and the need to offer an optimal risk-benefit profile in these patients. Shiba et al. studied CIRT in HCC patients 80 years of age or older.61 Of the 31 patients included, median age was 83 years, and primarily had CP-A cirrhosis (87%). Two-year LC and OS were 89.2% and 82.3%, respectively, and only one patient progressed locally within 3 months after treatment. Within this group, 14 patients (45%) had tumors in the porta hepatis region and had 2-year LC and OS rates of 82.5% and 50.9%, respectively. Thus, this study shows safety and efficacy independently of location within the liver in the elderly population.

Radiation Hepatotoxicity for Proton Beam Therapy The rate of radiation hepatotoxicity in HCC patients treated with PBT has been reported to be low (Table 3). In the University of Tsukuba experience, ncRILD as defined by CP score progression of 1 point was 16% and progression of 2 points (CP score + 2) was 11% at 1 year.16 In the multi-institutional US phase II study, CP class progression was observed in 3.6% in the setting of mean liver doses of 9.6 GyE (BED3 11.6 GyE).55 It must be noted that the majority of the patients in these studies had CP-A cirrhosis (73%-76%). The phase II study from Loma Linda, however, primarily included CP-B (47%) and CP-C (24%) patients and 24% of all patients eventually underwent liver transplantation after PBT.54 No RILD was observed in this study, which was defined as statistically significant changes in transaminases, alkaline phosphatase, bilirubin, albumin, or Model for End-Stage Liver Disease (MELD) scores for up to 6 months post-treatment.

Whether radiation hepatotoxicity is truly reduced with PBT in comparison to SBRT is unclear. Due to the heterogeneity of tumor characteristics, baseline liver function, and definitions of RILD reported across studies, it is difficult to directly compare hepatotoxicity rates between SBRT and PBT institutional series. Depending on the definition of ncRILD, hepatotoxicity rates in SBRT studies have ranged from 3% to up to 44%.1,3-5,7,62,63 When assessing CP class progression, 29% to 44% of SBRT patients exhibited this toxicity endpoint.1,4 CP class progression in the Hong et al. PBT study was only 3.6%, suggesting that PBT may be less toxic.55 Because the mean liver dose (EQD2Gya/b3) in the Hong et al. PBT study was lower than in the Bujold et al. SBRT study (15 GyE vs 18 Gy), it is possible to speculate that the superior normal liver sparing of PBT may be responsible for the reduced hepatotoxicity. However, this issue may not be as clear-cut when focusing on CP score + 2, a metric that has been shown by multiple groups to be most clinically relevant for OS.2,8 The rates of CP score + 2 were 9%-10% in SBRT studies that primarily treated CP-A patients.7,63 The rates of CP score + 2 at 1 year in the University of Tsukuba PBT experience was similar at 11%.16 Thus, depending on the ncRILD endpoint that is being assessed, PBT may or may not appear to reduce hepatotoxicity. Only a randomized study would be able to provide more clarity on the relative merits of reducing radiation hepatotoxicity with PBT compared with photons (see below).

Radiation Hepatotoxicity for Carbon Ion Radiotherapy Relative to many SBRT and PBT studies, radiation hepatotoxicity data after CIRT have been reasonably well described (Table 4), with nearly all studies comprehensively reporting rates of CP score and class progression after treatment. It is difficult to assess the relative risk of hepatotoxicity after CIRT, particularly in comparison to PBT. This is due to the heterogeneity of patients treated and definitions of hepatotoxicity, as well as the comparably small patients0 number compared to PBT studies. However, due to the physical and biological properties of the carbon ion beam, it could be anticipated that CIRT might be more beneficial in this regard, especially in patients with larger tumor volumes. In the 15 fraction Kato et al. study, only 22% and 25% of patients had an increase of CP score by
2 points in the early (
3 months) and late (>3 months) phases and no patient had a CP score increase more than 2 points.56 In the Kasuya et al. study,59 detailed information on CP score and class progression were provided. CP score + 1 was seen in 29% at 3 months, which decreased to 22% at 6 months, suggesting that these patients may exhibit some degree of liver function recovery over time. CP score + 2 was reported in 3% at 3 months with a slight increase to 5% at 6 months.

Patient Selection Although the clinical efficacy and radiation hepatotoxicity have been favorable in studies to date, determination of which

Particle Therapy for HCC

Table 3. Radiation Hepatotoxicity of Select Institutional Proton Beam Therapy Studies of HCC Patients Institution (year) Chiba, Japan (2005)

50

Patients (n)

CP Status

RILD Definition

RILD Time Frame

RILD Rate

RILD Deaths

30

CP-A 67%

“Proton-inducing hepatic insufficiency”

6 months

27%

NR

CP score progression CP class progression

1 month 3 months

0% 11%

NR 0%

“Liver failure”

NR

14%

0%

CTCAEv2: AST, ALT

NR

G2: 3% G3: 1%

0%

CP+1

24 months

3.5%

CP+2 CTCAEv2: AST, ALT, AP, T-bili, albumin, INR

6 months

6, 12, 24 months CP+1: 11%, 16%, 8% CP+2: 9%, 11%, 22% 0% statistically significant change

CP+1

3 months

4%

NR

CTCAEv3 CP class progression (CPCP)

NR

G3 T-bili: 1% CPCP: 3.6%

NR

University of Tsukuba (2006)38 University of Tsukuba (2009)48

19 35

University of Tsukuba (2010)49

22

HIBMC (2011)51

242

University of Tsukuba (2011)43

259

CP-B 33% CP-C 100% CP-A 80% CP-B 20% CP-A 50% CP-B 50% CP-A 76% CP-B 23% CP-C 1% CP-A 76%

Loma Linda54

76

CP-B 22% CP-A 29%

Goyang, Korea (2015)52

27

MGH/MDACC/UPenn55

44

CP-B 47% CP-C 24% CP-A 89% CP-B 11% CP-A 73% CP-B 21%

NR

CP, Child-Pugh; RILD, radiation-induced liver disease; CTCAE, Common Terminology Criteria for Adverse Events; NR, not reported; HIBMC, Hyogo Ion Beam Medical Center; MGH, Massachusetts General Hospital; MDACC, MD Anderson Cancer Center; UPenn, University of Pennsylvania.

315

S. Apisarnthanarax et al.

316

Table 4. Radiation Hepatotoxicity of Select Institutional Carbon Ion Radiation Therapy Studies of HCC Patients Institution (year)

Patients (n)

CP Status

NIRS (2004)56

24

NIRS (2010)58

64

HIBMC (2011)51

242

CP-A 67% CP-B 33% CP-A 77% CP-B 23% CP-A 76%

HIT (2013)21

6

CP-B 23% CP-C 1% CP-A 80%

NIRS (2017)59

126

CP-B 20% CP-A 77%

RILD Definition

RILD Time Frame

CP+1 CP+2 CP+1 CP+2 CTCAEv2: AST, ALT

3 months NR (“late phase”) NR

31

CP-A 87%

Age  80

CP-B 13%

CP+1: 30% CP+2: 22% CP+1: 84% CP+2: 16% G2: 3%

RILD Deaths 0% NR 0%

G3: 1% CTCAEv4.03: AST, ALT

NR

G2: 40%

0%

CP score and class progression

3 and 6 months

3 months

3%

3 and 6 months

CP+1: 29% CP+2: 3% CP+3: 1% 6 months CP+1: 22% CP+2: 5% CP-A!B 13% 3 months

NR

CP-B 23%

GHMC (2017)61

RILD Rate

CP score and class progression

CP+1: 13% CP+2: 3% 6 months CP+1: 16% CP+2: 3% CP-A!B 3%

CP, Child-Pugh; RILD, radiation-induced liver disease; CTCAE, Common Terminology Criteria for Adverse Events; NIRS, National Institute of Radiological Sciences in Japan; NR, not reported; HIBMC, Hyogo Ion Beam Medical Center; HIT, Heidelberg Ion Therapy Center; GHMC, Gunma University Heavy Ion Medical Center. Section in bold highlight specific patient subgroup being studied.

HCC patients are most appropriate for CPT continues to evolve and be investigated. In light of the limited number of PBT and CIRT facilities worldwide, the high upfront and maintenance costs, as well as the high cost of CPT itself, the judicious selection of appropriate patients for CPT is an important and timely issue.64 It is unlikely that all HCC patients would benefit from PBT or CIRT. For example, a dosimetric analysis on the differential advantages of PBTbased SBRT versus photon-based SBRT found that PBT had minimal liver-sparing advantages for tumors <3 cm in size, regardless of tumor location.11 Certain patient subgroups, however, may benefit from PBT over photon-based radiotherapy (RT): patients with moderate to severe cirrhosis (CP-B/C class), large tumors, and a history of prior liver radiation. It is fairly well established that patients with CP-B/C cirrhosis are at higher risk for RILD compared to patients with more compensated liver function. In the initial University of Indiana SBRT experience, 4 of the first 8 patients with CP-B8 and above cirrhosis developed progressive liver failure after SBRT, 25% of which proved fatal.65 In a study dedicated to reporting clinical outcomes and toxicity specifically in CP-B/C patients, 34% of patients developed CP score + 2 ncRILD at 3 months after SBRT.3 It was also noted by the investigators that “The liver dose was limited in 89% of cases.” These toxicity data in combination with the dosimetric finding that liver doses as low as 2.5 Gy are

predictive for hepatotoxicity in CP-B patients provide strong clinical rationale to employ CPT in patients with less compensated baseline liver function. The clinical safety of using PBT in CP-B/C patients, however, is unclear, as the majority of patients treated with PBT have had CP-A liver function. The University of Tsukuba published their experience on the use of PBT in CP-C patients (CP-C10 to 14) to a median dose of 72 GyE in 16 fractions.38 Median OS was 17 months and 2-year OS and PFS were both at 42%. These survival outcomes are encouraging when considering the median OS for CP-C patients is historically 3-9 months. No patients experienced CP score progression, and CP score improvement was observed in 74%. The authors speculate that the improvement in liver function may be due to the reduction in the tumor burden that was initially contributing to the poor pretreatment liver function. Tumor size is a known prognostic factor for HCC, particularly for tumors larger than 10 cm.66,67 Clinical data on the safety and clinical efficacy of SBRT for large tumors are limited. The majority of published SBRT studies treated patients with median tumor sizes ranging from 2 to 5 cm. Tumors greater than 5-10 cm in size that cannot be adequately or safely treated with SBRT may represent another subgroup of patients that may benefit from PBT. Dosimetric studies support the superiority of PBT over photon-based treatments for

Particle Therapy for HCC larger sized tumors.11,14 PBT may allow for tumor dose escalation while maintaining normal liver dose constraints. Gandhi et al. demonstrated that PBT could theoretically allow dose escalation up to 80 Gy in 5 fractions (BED10 208 GyE) while still meeting liver dose constraints for tumors >5 cm.11 The potential for high rates of LC with PBT for tumors >10 cm was shown by the University of Tsukuba investigators, who reported on their outcomes on 22 patients treated with a median dose of 72.6 GyE in 22 fractions.49 Two-year LC was 87% and 2-year OS was 36%, which were superior to historic controls. Patients who have received prior liver irradiation, either with external beam RT or internal with radioembolization, pose many challenges when treating with definitive intent liver RT. The function of the remaining normal liver after liver RT is difficult to assess and the safety of liver reirradiation can be uncertain making the treatment potentially dangerous. This safety concern is perhaps best illustrated in a Stanford University study that assessed the safety of 90Y radioembolization when combined with external beam RT.68 Of the 13 patients who received prior external beam RT in combination with radioembolization, ncRILD as defined by Common Terminology Criteria for Adverse Events grade 2 liver toxicity was observed in 54%, which proved fatal in 29% of patients. A recent study from University of Tsukuba reported on their use of multiple courses of liver PBT for HCC patients.47 Eighty-three, 15, and 3 patients received 2, 3, and 4 courses of PBT, respectively. The average maximum liver dose was 124.9 GyE (range 66.7-248.1 GyE) and the average mean liver dose was 24.2 GyE (range 5.4-66.5 GyE) for all patients. Despite these high cumulative doses to the liver, no RILD was observed. Liver reirradiation with PBT for HCC patients, therefore, may be feasible and safe and provide a reasonable treatment option for patients with limited treatment options.

Limitations and Challenges Although an in-depth discussion on the details of liver CPT treatment planning is beyond the scope of this article, a brief discussion on the unique challenges for treatment planning and delivery specific to CPT is important in understanding the limitations and challenges of treating liver tumors with CPT. Because the proton beam range is highly dependent on the electron density (related to the Hounsfield Units) of the tissues it transverses, uncertainties such as range uncertainty, setup uncertainties, and target motion, must be considered. Two potential sources affect the range uncertainty of a proton beam (the spatial uncertainty on where exactly the Bragg peak occurs in tissue): inaccuracies arising from dose calculation algorithms and inaccuracies in Hounsfield Unit values from the planning CT scan. To account for this range uncertainty, an additional uncertainty margin is generally applied during treatment planning. This addition of an uncertainty margin results in additional volume that is treated at the prescription dose and a decrease in the high dose conformality in comparison to intensity modulated radiotherapy. In addition, in order to ensure the robustness of a CPT plan when taking

317 into account uncertainties in density calculations and patient setup, the plan is reevaluated by increasing or decreasing the density of tissues by 3% and moving the isocenter with respect to the patient's anatomy by 3-5 mm in all directions.69 These treatment planning considerations unique to CPT can pose challenges when treating tumor targets that are in close proximity or abutting dose-limiting OARs. Careful consideration must be taken when treating tumors abutting visceral GI OARs, such as stomach or duodenum, with CPT and especially with CIRT given the higher RBE of carbon ions. Intensity modulated radiotherapy may be better suited for these clinical scenarios where the dose gradient between the tumor and OARs may be steeper and provide superior high-dose sparing to closely adjacent OARs. Assessment and management of motion is critical and potentially more important for CPT compared to photonbased treatments. As previously mentioned, the proton beam range is highly susceptible to changes in tissue electron density along its beam, particularly when treating the liver due to the air, bone, and soft tissue interface near the dome of the diaphragm. This effect is pronounced in the liver due to the motion of the liver during respiration and can result in underdosing of tumor targets and/or overdosing of normal tissue. Motion management when treating liver tumors with CPT is paramount and strategies such as respiratory gating, breath hold, and abdominal compression should be considered. Patients with tumors that still exhibit considerable motion despite appropriate motion management techniques may be suboptimal candidates for CPT.

Summary CPT possess dosimetric advantages over photons of superior normal liver sparing, particularly in the low to moderate dose range, that make the use of PBT and CIRT attractive for patients with HCC or any liver cancer patient with cirrhosis. CIRT has an additional radiobiological advantage over PBT of higher RBE, which may allow for more extreme hypofractionation regimens or dose escalation in HCC tumors thought to be unusually radioresistant. Worldwide clinical experience on the use of both PBT and CIRT is relatively large in comparison to other gastrointestinal malignances with nearly 1000 HCC treated patients reported in the literature. Long-term data retrospective and prospective exist that support excellent local control of greater than 90% and favorable toxicity profile, including hepatotoxicity.

Future Directions Currently, the use of PBT for HCC tumors is supported by the NCCN Guidelines v4.2017, which state that “Proton beam therapy may be appropriate in specific situations.”70 HCC tumors are also included in the updated 2017 ASTRO Proton Beam Therapy Model Policy in the Group 1 recommendation in which published clinical data and medical necessity requirement support the use of PBT. Despite these

318 national recommendations, there is a lack of level I clinical evidence supporting the routine use of PBT for HCC tumors. However, randomized controlled trials (RCTs) are ongoing and compare the use of PBT in HCC patients against standard-of-care therapies. A phase III trial from Loma Linda is evaluating the effectiveness and complications of PBT with those of transarterial chemoembolization, a standard treatment approach for HCC patients. Preliminary results from an interim analysis demonstrate a trend toward improved 2-year LC (88% vs 45%, P = 0.06) and PFS (48% vs 31%, P = 0.06) in favor of PBT with equivalent OS (59% for all patients).71 PBT also had a superior toxicity profile as defined by days in the hospital post-treatment (24 days vs 166 days, P < 0.001). NRG-GI003 is a recently opened phase III RCT that compares PBT head-to-head against photon-based treatment with OS as the primary study endpoint in patients with unresectable HCC with relatively well-compensated liver function (CP-A to B7 cirrhosis). Patients in both arms will be treated with either 5 or 15 fractions based on physician discretion and with an individualized dosing approach based on planned liver minus tumor dose (delivered tumor dose will be dictated by achievable dose delivered to normal liver). Patients will be stratified according to fractionation scheme and presence of tumor vascular thrombus. The study will be powered to demonstrate an improvement in median OS from 14 months with photons to 24 months with PBT. Since tumor control and liver failure often compete for OS in these patients, evaluating secondary endpoints including PFS, LC, toxicity, and quality of life metrics will also be critical. As this study will be an important study to help demonstrate the value of PBT over photons, brief comments on RCT design for PBT vs photons, specifically in relation to HCC patients, are worthy of discussion. Two key elements should be heavily considered: (1) Primary endpoints and associated trial design: should the study be powered to detect differences in OS and/or LC or toxicity? Should the study be designed under isotoxic or isoeffective tumor control conditions to detect differences in OS and/or LC or toxicity, respectively? In other words, is the reduction of normal tissue exposure with PBT being leveraged to increase tumor dose or to reduce toxicity? The primary endpoint in NRG-GI003 is OS, which is arguably the most objective endpoint that could be studied and the most likely endpoint to appease insurers. This endpoint, however, may be problematic in HCC patients as OS is dictated by multiple competing factors: the disease itself and the accompanying comorbidity of cirrhosis. This study is designed to test the OS superiority of PBT in isotoxic conditions with its individualized dosing approach based on liver dose. Due to the ability to spare more normal liver with PBT, patients in the PBT cohort would be expected to receive higher tumor doses. The hypothesis, therefore, in this study design is that differences in delivered tumor dose will translate into improved

S. Apisarnthanarax et al. LC, which will then translate into improved OS. The potential truth in this hypothesis is based on two basic assumptions: radiation dose escalation is essential to achieve LC in HCC tumors and LC is critical to OS in HCC patients. These assumptions unfortunately are controversial among liver cancer experts and may represent fallacies rather than truths as the data supporting these assumptions are conflicting.1,72-74 As an example, HCC is known to be a disease with common out-of-field progressions, so LC of a targeted lesion may not necessarily equate to prolonged OS. An alternative approach would be to design the trial under isoeffective conditions where the tumor dose remains constant across cohorts with variable doses delivered to the normal liver. In this setting, patients in the PBT cohort would be expected to receive less doses to the normal liver, translating into less RILD-related deaths and improved OS. Another alternative trial design is to use different primary endpoints, such as hepatotoxicity or local progressionfree survival (under isotoxic conditions). These endpoints, however, also have challenges as there has been little consensus until recently on what hepatotoxicity metrics should be routinely reported. Consensus on which imaging response criteria [eg, Response Evaluation Criteria in Solids Tumors, modified Response Evaluation Criteria in Solids Tumors, and European Association for the Study of the Liver (EASL)] is most appropriate for assessing HCC tumor response to radiation is also lacking. (2) Patient selection: should selection be broad and more generalizable or more selective to patient subgroups that would be estimated to benefit the most from PBT?75 A study that is too generalized in patient inclusion runs the risk of having negative results because the benefit in patients in whom PBT is the most useful may be diluted by patients who benefit very little from PBT (eg, patients with a 2 cm HCC tumor in the setting of CP-A5 cirrhosis). A study that is too restrictive in its eligibility may not be generalizable. The eligibility criteria in NRG-GI003 appear to be both broad and restrictive. The study allows a wide range of tumor types, including larger tumors (up to 15 cm), limited multifocal tumors (up to 3), and tumors with portal vein tumor thrombosis. However, the study does not allow patients with severe cirrhosis (CP-B8 and higher), who may benefit substantially from PBT liver sparing. In addition, although there needs to be a limit to stratification variables, the study does not stratify for tumor size or liver function. By random chance, it is possible that the majority of patients randomized to the photon arm have CP-A5 liver function with 3 cm tumors and the majority of PBT patients have CP-B7 cirrhosis with 8 cm tumors. In this scenario, clinical outcomes could be inferior with PBT due to patient characteristics rather than treatment modality. Rather than having broad

Particle Therapy for HCC eligibility criteria, an alternative approach would be to limit enrollment of patients with characteristics deemed at highest risk for affecting OS, such as patients with larger tumors (greater than 5-6 cm) and/ or patients with CP-B/C cirrhosis. This approach may be supported by recent nomogram and multivariable models and multi-institutional data suggesting that liver function and tumor size are more important than radiation dose levels.76,77 Designing RCTs to assess the value of a PBT over photons, therefore, is challenging, particularly for HCC patients when considering the degree and amount of complex, interplaying variables in these patients. Different RCT designs each have their own strengths and weaknesses. Ideally, multiple RCTs should be performed in parallel to gather the highest quality level of evidence. Finally, in terms of determining the value of CIRT over PBT, a prospective comparative study of PBT and CIRT is ultimately warranted. Previously, Komatsu et al. at the Hyogo facility evaluated 343 consecutive HCC patients treated with either PBT (242 patients) or CIRT (101 patients) with various dosing and fractionation schemes.51 LC was 90% for PBT and 93% for CIRT at 5 years. Tumor size was an independent risk factor: LC was comparable for smaller lesions (<5.0 cm diameter), but in larger lesions, CIRT appeared to be superior. However, these data must be confirmed in a randomized prospective trial with strict treatment regimens and comparable inclusion criteria for both treatment groups.

References 1. Bujold A, Massey CA, Kim JJ, et al: Sequential phase I and II trials of stereotactic body radiotherapy for locally advanced hepatocellular carcinoma. J Clin Oncol 31:1631–1639, 2013 2. Chapman TR, Bowen SR, Schaub SK, et al: Toward consensus reporting of radiation-induced liver toxicity in the treatment of primary liver malignancies: defining clinically relevant endpoints. Pract Radiat Oncol http://dx.doi.org/10.1016/j.prro.2017.10.013, 2017 3. Culleton S, Jiang H, Haddad CR, et al: Outcomes following definitive stereotactic body radiotherapy for patients with Child-Pugh B or C hepatocellular carcinoma. Radiother Oncol 111:412–417, 2014 4. Lasley FD, Mannina EM, Johnson CS, et al: Treatment variables related to liver toxicity in patients with hepatocellular carcinoma, Child-Pugh class A and B enrolled in a phase 1-2 trial of stereotactic body radiation therapy. Pract Radiat Oncol 5:e443–e449, 2015 5. Que J, Kuo HT, Lin LC, et al: Clinical outcomes and prognostic factors of cyberknife stereotactic body radiation therapy for unresectable hepatocellular carcinoma. BMC Cancer 16:451, 2016 6. Sanuki N, Takeda A, Oku Y, et al: Influence of liver toxicities on prognosis after stereotactic body radiation therapy for hepatocellular carcinoma. Hepatol Res 45:540–547, 2015 7. Sanuki N, Takeda A, Oku Y, et al: Stereotactic body radiotherapy for small hepatocellular carcinoma: a retrospective outcome analysis in 185 patients. Acta Oncol 53:399–404, 2014 8. Song JH, Jeong BK, Choi HS, et al: Defining radiation-induced hepatic toxicity in hepatocellular carcinoma patients treated with stereotactic body radiotherapy. J Cancer 8:4155–4161, 2017 9. Velec M, Haddad CR, Craig T, et al: Predictors of liver toxicity following stereotactic body radiation therapy for hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 97:939–946, 2017 10. Ling TC, Kang JI, Bush DA, et al: Proton therapy for hepatocellular carcinoma. Chin J Cancer Res 24:361–367, 2012

319 11. Gandhi SJ, Liang X, Ding X, et al: Clinical decision tool for optimal delivery of liver stereotactic body radiation therapy: Photons versus protons. Pract Radiat Oncol 5:209–218, 2015 12. Kim JY, Lim YK, Kim TH, et al: Normal liver sparing by proton beam therapy for hepatocellular carcinoma: Comparison with helical intensity modulated radiotherapy and volumetric modulated arc therapy. Acta Oncol 54:1827–1832, 2015 13. Taddei PJ, Howell RM, Krishnan S, et al: Risk of second malignant neoplasm following proton versus intensity-modulated photon radiotherapies for hepatocellular carcinoma. Phys Med Biol 55:7055–7065, 2010 14. Toramatsu C, Katoh N, Shimizu S, et al: What is the appropriate size criterion for proton radiotherapy for hepatocellular carcinoma? A dosimetric comparison of spot-scanning proton therapy versus intensitymodulated radiation therapy. Radiat Oncol 8:48, 2013 15. Wang X, Krishnan S, Zhang X, et al: Proton radiotherapy for liver tumors: dosimetric advantages over photon plans. Med Dosim 33:259–267, 2008 16. Mizumoto M, Okumura T, Hashimoto T, et al: Evaluation of liver function after proton beam therapy for hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 82:e529–e535, 2012 17. Giovannini G, Bohlen T, Cabal G, et al: Variable RBE in proton therapy: comparison of different model predictions and their influence on clinical-like scenarios. Radiat Oncol 11:68, 2016 18. Paganetti H. Relative biological effectiveness (RBE) values for proton beam therapy. Variations as a function of biological endpoint, dose, and linear energy transfer. Phys Med Biol 59:R419–R472, 2014 19. Paganetti H, Niemierko A, Ancukiewicz M, et al: Relative biological effectiveness (RBE) values for proton beam therapy. Int J Radiat Oncol Biol Phys 53:407–421, 2002 20. Habermehl D, Ilicic K, Dehne S, et al: The relative biological effectiveness for carbon and oxygen ion beams using the raster-scanning technique in hepatocellular carcinoma cell lines. PLoS One 9:e113591, 2014 21. Habermehl D, Debus J, Ganten T, et al: Hypofractionated carbon ion therapy delivered with scanned ion beams for patients with hepatocellular carcinoma - feasibility and clinical response. Radiat Oncol 8:59, 2013 22. El Shafie RA, Habermehl D, Rieken S, et al: In vitro evaluation of photon and raster-scanned carbon ion radiotherapy in combination with gemcitabine in pancreatic cancer cell lines. J Radiat Res 54(Suppl 1):i113–i119, 2013 23. Dreher C, Habermehl D, Ecker S, et al: Optimization of carbon ion and proton treatment plans using the raster-scanning technique for patients with unresectable pancreatic cancer. Radiat Oncol 10:237, 2015 24. Combs SE, Zipp L, Rieken S, et al: In vitro evaluation of photon and carbon ion radiotherapy in combination with chemotherapy in glioblastoma cells. Radiat Oncol 7:9, 2012 25. Kamada T, Tsujii H, Blakely EA, et al: Carbon ion radiotherapy in Japan: an assessment of 20 years of clinical experience. Lancet Oncol 16:e93– e100, 2015 26. Dehne S, Fritz C, Rieken S, et al: Combination of photon and carbon ion irradiation with targeted therapy substances temsirolimus and gemcitabine in hepatocellular carcinoma cell lines. Front Oncol 7:35, 2017 27. Dawson LA, Eccles C, Craig T. Individualized image guided iso-NTCP based liver cancer SBRT. Acta Oncol 45:856–864, 2006 28. Dawson LA, Ten Haken RK. Partial volume tolerance of the liver to radiation. Semin Radiat Oncol 15:279–283, 2005 29. Dawson LA, Normolle D, Balter JM, et al: Analysis of radiation-induced liver disease using the Lyman NTCP model. Int J Radiat Oncol Biol Phys 53:810–821, 2002 30. Kosaki K, Ecker S, Habermehl D, et al: Comparison of intensity modulated radiotherapy (IMRT) with intensity modulated particle therapy (IMPT) using fixed beams or an ion gantry for the treatment of patients with skull base meningiomas. Radiat Oncol 7:44, 2012 31. Koike S, Ando K, Uzawa A, et al: Significance of fractionated irradiation for the biological therapeutic gain of carbon ions. Radiat Prot Dosimetry 99:405–408, 2002 32. Ando K, Koike S, Uzawa A, et al: Biological gain of carbon-ion radiotherapy for the early response of tumor growth delay and against early response of skin reaction in mice. J Radiat Res 46:51–57, 2005 33. Dreher C, Habermehl D, Jakel O, et al: Effective radiotherapeutic treatment intensification in patients with pancreatic cancer: higher doses alone, higher RBE or both? Radiat Oncol 12:203, 2017

320 34. Tanaka N, Matsuzaki Y, Chuganji Y, et al: Proton irradiation for hepatocellular carcinoma. Lancet 340:1358, 1992 35. Chiba T, Tokuuye K, Matsuzaki Y, et al: Proton beam therapy for hepatocellular carcinoma: a retrospective review of 162 patients. Clin Cancer Res 11:3799–3805, 2005 36. Fukuda K, Okumura T, Abei M, et al: Long-term outcomes of proton beam therapy in patients with previously untreated hepatocellular carcinoma. Cancer Sci 108:497–503, 2017 37. Fukumitsu N, Sugahara S, Nakayama H, et al: A prospective study of hypofractionated proton beam therapy for patients with hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 74:831–836, 2009 38. Hashimoto T, Tokuuye K, Fukumitsu N, et al: Repeated proton beam therapy for hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 65:196–202, 2006 39. Hata M, Tokuuye K, Sugahara S, et al: Proton beam therapy for hepatocellular carcinoma patients with severe cirrhosis. Strahlenther Onkol 182:713–720, 2006 40. Hata M, Tokuuye K, Sugahara S, et al: Proton beam therapy for hepatocellular carcinoma with portal vein tumor thrombus. Cancer 104:794–801, 2005 41. Hata M, Tokuuye K, Sugahara S, et al: Proton beam therapy for aged patients with hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 69:805–812, 2007 42. Matsuzaki Y, Osuga T, Chiba T, et al: New, effective treatment using proton irradiation for unresectable hepatocellular carcinoma. Intern Med 34:302–304, 1995 43. Mizumoto M, Okumura T, Hashimoto T, et al: Proton beam therapy for hepatocellular carcinoma: a comparison of three treatment protocols. Int J Radiat Oncol Biol Phys 81:1039–1045, 2011 44. Mizumoto M, Tokuuye K, Sugahara S, et al: Proton beam therapy for hepatocellular carcinoma adjacent to the porta hepatis. Int J Radiat Oncol Biol Phys 71:462–467, 2008 45. Nakayama H, Sugahara S, Fukuda K, et al: Proton beam therapy for hepatocellular carcinoma located adjacent to the alimentary tract. Int J Radiat Oncol Biol Phys 80:992–995, 2011 46. Nakayama H, Sugahara S, Tokita M, et al: Proton beam therapy for hepatocellular carcinoma: the University of Tsukuba experience. Cancer 115:5499–5506, 2009 47. Oshiro Y, Mizumoto M, Okumura T, et al: Analysis of repeated proton beam therapy for patients with hepatocellular carcinoma. Radiother Oncol 123:240–245, 2017 48. Sugahara S, Nakayama H, Fukuda K, et al: Proton-beam therapy for hepatocellular carcinoma associated with portal vein tumor thrombosis. Strahlenther Onkol 185:782–788, 2009 49. Sugahara S, Oshiro Y, Nakayama H, et al: Proton beam therapy for large hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 76:460–466, 2010 50. Kawashima M, Furuse J, Nishio T, et al: Phase II study of radiotherapy employing proton beam for hepatocellular carcinoma. J Clin Oncol 23:1839–1846, 2005 51. Komatsu S, Fukumoto T, Demizu Y, et al: Clinical results and risk factors of proton and carbon ion therapy for hepatocellular carcinoma. Cancer 117:4890–4904, 2011 52. Kim TH, Park JW, Kim YJ, et al: Phase I dose-escalation study of proton beam therapy for inoperable hepatocellular carcinoma. Cancer Res Treat 47:34–45, 2015 53. Bush DA, Hillebrand DJ, Slater JM, et al: High-dose proton beam radiotherapy of hepatocellular carcinoma: preliminary results of a phase II trial. Gastroenterology 127:S189–S193, 2004 54. Bush DA, Kayali Z, Grove R, et al: The safety and efficacy of high-dose proton beam radiotherapy for hepatocellular carcinoma: a phase 2 prospective trial. Cancer 117:3053–3059, 2011 55. Hong TS, Wo JY, Yeap BY, et al: Multi-institutional phase ii study of high-dose hypofractionated proton beam therapy in patients with localized, unresectable hepatocellular carcinoma and intrahepatic cholangiocarcinoma. J Clin Oncol 34:460–468, 2016 56. Kato H, Tsujii H, Miyamoto T, et al: Results of the first prospective study of carbon ion radiotherapy for hepatocellular carcinoma with liver cirrhosis. Int J Radiat Oncol Biol Phys 59:1468–1476, 2004

S. Apisarnthanarax et al. 57. Tsujii H, Mizoe J, Kamada T, et al: Clinical results of carbon ion radiotherapy at NIRS. J Radiat Res 48(Suppl A):A1–A13, 2007 58. Imada H, Kato H, Yasuda S, et al: Comparison of efficacy and toxicity of short-course carbon ion radiotherapy for hepatocellular carcinoma depending on their proximity to the porta hepatis. Radiother Oncol 96:231–235, 2010 59. Kasuya G, Kato H, Yasuda S, et al: Progressive hypofractionated carbonion radiotherapy for hepatocellular carcinoma: Combined analyses of 2 prospective trials. Cancer 123:3955–3965, 2017 60. Combs SE, Habermehl D, Ganten T, et al: Phase I study evaluating the treatment of patients with hepatocellular carcinoma (HCC) with carbon ion radiotherapy: the PROMETHEUS-01 trial. BMC Cancer 11:67, 2011 61. Shiba S, Abe T, Shibuya K, et al: Carbon ion radiotherapy for 80 years or older patients with hepatocellular carcinoma. BMC Cancer 17:721, 2017 62. Huertas A, Baumann AS, Saunier-Kubs F, et al: Stereotactic body radiation therapy as an ablative treatment for inoperable hepatocellular carcinoma. Radiother Oncol 115:211–216, 2015 63. Takeda A, Sanuki N, Tsurugai Y, et al: Phase 2 study of stereotactic body radiotherapy and optional transarterial chemoembolization for solitary hepatocellular carcinoma not amenable to resection and radiofrequency ablation. Cancer 122:2041–2049, 2016 64. Leung HWC, Chan ALF. Cost-utility of stereotactic radiation therapy versus proton beam therapy for inoperable advanced hepatocellular carcinoma. Oncotarget 8:75568–75576, 2017 65. Andolino DL, Johnson CS, Maluccio M, et al: Stereotactic body radiotherapy for primary hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 81:e447–e453, 2011 66. Poon RT, Fan ST, Lo CM, et al: Long-term prognosis after resection of hepatocellular carcinoma associated with hepatitis B-related cirrhosis. J Clin Oncol 18:1094–1101, 2000 67. Mok KT, Wang BW, Lo GH, et al: Multimodality management of hepatocellular carcinoma larger than 10 cm. J Am Coll Surg 197:730–738, 2003 68. Lam MG, Abdelmaksoud MH, Chang DT, et al: Safety of 90Y radioembolization in patients who have undergone previous external beam radiation therapy. Int J Radiat Oncol Biol Phys 87:323–329, 2013 69. McGowan SE, Burnet NG, Lomax AJ. Treatment planning optimisation in proton therapy. Br J Radiol 86:20120288, 2013 70. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Hepatobiliary Cancers (version 4.2017). National Comprehensive Cancer Network, 2017 71. Bush DA, Smith JC, Slater JD, et al: Randomized clinical trial comparing proton beam radiation therapy with transarterial chemoembolization for hepatocellular carcinoma: results of an interim analysis. Int J Radiat Oncol Biol Phys 95:477–482, 2016 72. Jang WI, Kim MS, Bae SH, et al: High-dose stereotactic body radiotherapy correlates increased local control and overall survival in patients with inoperable hepatocellular carcinoma. Radiat Oncol 8:250, 2013 73. Lausch A, Sinclair K, Lock M, et al: Determination and comparison of radiotherapy dose responses for hepatocellular carcinoma and metastatic colorectal liver tumours. Br J Radiol 86:20130147, 2013 74. Ohri N, Tome WA, Mendez Romero A, et al: Local control after stereotactic body radiation therapy for liver tumors. Int J Radiat Oncol Biol Phys https://doi.org/10.1016/j.ijrobp.2017.12.288, 2018 75. Apisarnthanarax S, Swisher-McClure S, Chiu WK, et al: Applicability of randomized trials in radiation oncology to standard clinical practice. Cancer 119:3092–3099, 2013 76. Vickress J, Lock M, Lo S, et al: A multivariable model to predict survival for patients with hepatic carcinoma or liver metastasis receiving radiotherapy. Future Oncol 13:19–30, 2017 77. Yamashita H, Onishi H, Murakami N, et al: Survival outcomes after stereotactic body radiotherapy for 79 Japanese patients with hepatocellular carcinoma. J Radiat Res 56:561–567, 2015