Radiotherapy and Oncology xxx (2014) xxx–xxx

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Review

Is there a role for proton therapy in the treatment of hepatocellular carcinoma? A systematic review Francesco Dionisi a,b,⇑, Lamberto Widesott a,b,c, Stefano Lorentini a,b, Maurizio Amichetti a,b a Agenzia Provinciale per la Protonterapia (ATreP); b Proton therapy Unit, Azienda Provinciale per i Servizi Sanitari (APSS), Trento, Italy; c Department of Physics, Swiss Institute of Technology (ETH), Zurich, Switzerland

a r t i c l e

i n f o

Article history: Received 1 April 2013 Received in revised form 28 January 2014 Accepted 2 February 2014 Available online xxxx Keywords: Hepatocellular carcinoma Proton therapy Systematic review

a b s t r a c t This paper aimed to review the literature concerning the use of proton therapy systematically in the treatment of hepatocellular carcinoma, focusing on clinical results and technical issues. The literature search was conducted according to a specific protocol in the Medline and Scopus databases by two independent researchers covering the period of 1990–2012. Both clinical and technical studies referring to a population of patients actually treated with protons were included. The PRISMA guidelines for reporting systematic reviews were followed. A final set of 16 studies from seven proton therapy institutions worldwide were selected from an initial dataset of 324 reports. Seven clinical studies, five reports on technical issues, three studies on treatment related toxicity and one paper reporting both clinical results and toxicity analysis were retrieved. Four studies were not published as full papers. Passive scattering was the most adopted delivery technique. More than 900 patients with heterogeneous stages of disease were treated with various fractionation schedules. Only one prospective full paper was found. Local control was approximately 80% at 3–5 years, average overall survival at 5 years was 32%, with data comparable to surgery in the most favorable groups. Toxicity was low (mainly gastrointestinal). Normal liver V0Gy < 30%volume and V30Gy < 18–25%volume were suggested as cut-off values for hepatic toxicity. The good clinical results of the selected papers are counterbalanced by a low level of evidence. However, the rationale to enroll patients in prospective studies appears to be strong. Ó 2014 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology xxx (2014) xxx–xxx

Primary liver cancer is the third most prevalent cause of death from cancer worldwide [1], with a growing incidence in Europe and in the United States in the last decades [2]. Hepatocellular carcinoma (HCC) represents 90% of all liver cancers. In most cases, HCC is associated with an underlying chronic liver disease developed in the presence of well-known risk factors such as viral hepatitis, alcohol abuse and exposure to aflatoxin. Cancer progression, mainly loco-regional progression is the cause of the majority of deaths in HCC population [3]; indeed, the rate of extrahepatic metastases is limited even in patients with advanced, unresectable HCC [4]. Therefore, a strong rationale exists for the improvement of locoregional therapies in HCC patients. Early stages can be treated with a curative approach; local control (LC) and prolongation of survival are the goals in the treatment of advanced HCCs. Surgery (resection or liver transplantation) achieves the best outcomes in the treatment of HCC, with a reported rate of survival ⇑ Corresponding author at: Proton therapy Unit (APSS), via al Desert, 14 38123 Trento, Italy. E-mail addresses: [email protected], [email protected] (F. Dionisi).

greater than 70% at 5 years in selected series [5]. However, the percentage of HCC patients suitable for surgery is limited by both tumor and patient related contraindications. Other therapeutic approaches for localized HCC consist of ablation with percutaneous ethanol injection (PEI) or, more recently, radiofrequency ablation (RFA) [6]. However, the occurrence rate in the ablation site is not negligible, especially for tumors larger than 3 cm [7]. Transarterial chemoembolization (TACE), a non-curative treatment with a positive impact on survival [8], is considered the strategy of choice for multinodular HCCs, which corresponds to intermediate Stage B disease according to the commonly adopted Barcelona-Clinic Liver Cancer staging system [9]. Localized cancers at other sites greatly benefit from radiotherapy, which is currently a robust competitor of surgery in several oncological diseases. In the context of HCC, radiotherapy has a narrow therapeutic window due to 1) the low-radio-tolerance of the liver and 2) the need for high doses of radiation for disease control. Irreversible hepatic failure can occur as a consequence of radiation- induced liver disease (RILD) [10]. Recent advances in radiotherapy delivery techniques could help to enlarge the therapeutic window for HCC, allowing for a better

http://dx.doi.org/10.1016/j.radonc.2014.02.001 0167-8140/Ó 2014 Elsevier Ireland Ltd. All rights reserved.

Please cite this article in press as: Dionisi F et al. Is there a role for proton therapy in the treatment of hepatocellular carcinoma? A systematic review. Radiother Oncol (2014), http://dx.doi.org/10.1016/j.radonc.2014.02.001

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Proton therapy in liver cancer

tailoring of the dose distribution on the target volume while improving the sparing of nearby tissues. Several studies have demonstrated that partial hepatic RT with X-rays is feasible, resulting in promising responses in unresectable HCC patients [11,12]. Nevertheless, the possible role of external radiotherapy in HCC treatment is still under debate: the recently published guidelines of the European Association for the Study of the Liver and of the European Organisation for Research and Treatment of Cancer (EASL-EORTC) on the management of HCC briefly stated that ‘‘no evidence to support’’ the use of external radiotherapy for the treatment of HCC exists, and encouraged ‘‘further research testing modern approaches’’ [13]. Conversely, among the National Comprehensive Cancer Network (NCCN), guidelines indicate that radiotherapy (hypofractionated, stereotactic radiotherapy or conformal radiotherapy with conventional fractionation) could represent an alternative to ablation/embolization for unresectable HCC [14]. In the context of radiation therapy, proton therapy (PT), due to its unique dosimetric characteristics (i.e., a finite range in tissue along with a near zero dose beyond the end of its path), could be an excellent option for the treatment of this disease. In general, comprehensive reviews concerning the use of PT in cancer revealed a potential benefit for HCC patients. Some limitations of these reviews with respect to the selection of the HCC studies should be noted: only one paper was identified in the review of Olsen et al. [15], while the three studies retrieved by De Ruysscher et al. [16] came from a single Institution (Tsukuba, Japan) and presented an overlap in the population of the included patients, which might be a confounding element for the data analysis. In light of these limitations, the present study aimed to systematically review the role of PT in the treatment of HCC while focusing on the following objectives:  to define its effectiveness and safety;  to register the currently adopted delivery techniques;  to address the specific technical issues regarding the use of protons in the treatment of HCC. Materials and methods All aspects relative to the research questions were identified and formulated in a specific protocol approved by all the authors (supplementary appendix). The literature search was limited to English language papers and carried out in the Medline and Scopus databases on December 2012 for the period 1990–2012. The electronic database search was performed independently by two researchers (FD and LW) plus one additional researcher to settle any possible disputes (MA). The following search terms and their combination were employed: ‘‘proton therapy OR hadron therapy OR particle therapy OR charged particle therapy’’ AND ‘‘hepatocellular carcinoma OR hepatoma OR primary liver cancer OR HCC.’’ The reference list of selected studies was also screened for other eligible studies. In addition, a manual search was performed that focused on the abstracts of meetings of the American and the European Societies of Therapeutic Radiation Oncology (ASTRO, ESTRO), the Particle Therapy Co-operative Group (PTCOG) and the American Society of Clinical Oncology (ASCO) annual congresses for possible inclusion of supplementary studies. The study eligibility criteria included papers reporting outcome and/or toxicity for HCC patients treated with PT. Studies reporting patients treated with carbon ions or other heavy particles were excluded. Studies reporting technical issues were included if they referred to a population of patients actually treated. Experimental studies as well as plan comparisons studies were excluded. Data are reported according to the PRISMA guidelines [17].

According to the report eligibility criteria, any type of study could be accepted with the exception of single case reports. To avoid overlap of the patient populations, which could bias the results of the review, only the most updated population was included in the review if multiple series referred to the same population of patients. Results Literature search results A total of 324 citations were retrieved to be screened for eligibility. The entire process of review (Fig. 1) led to a final set of 16 studies to be included in the review: seven studies reported clinical outcomes [18–24], five works dealt with technical issues [25–29], while three analyzed potential predictors of treatment-related toxicity [30–32] and the last study reported both clinical outcomes and an analysis of liver function after PT [33]. The most relevant data that originated from the clinical studies that were not presented as a full paper [22–24] were reported in the supplementary appendix (Table 1A). Several studies from Tsukuba, Hyogo and Kashiwa were retrieved during the review process; both overall clinical results, concerning the use of PT for HCC, and the outcomes of specific subgroups of patients were reported (supplementary appendix Table 2A). Two studies were published from Kashiwa, Japan, the former in 2005 [34] and the latter in 2011 [33]. Only the more comprehensive papers were considered to comply with the inclusion criteria. Clinical studies The clinical experience (five full papers) originated from the following PT centers: the Proton Medical Research Center (PMRC, Tsukuba, Japan), the Hyogo Ion Beam Medical Center (HIBMC, Tatsuno, Japan), the National Cancer Center Hospital East (NCCHE, Kashiwa, Japan), and the Loma Linda University Medical Center (LLUMC, Loma Linda, USA). Four retrospective studies and one prospective study were retrieved. Table 1 shows the main relevant clinical inclusion criteria of the selected studies along with the relevance of both the studies design and their clinical findings according to the classification system developed by the National Cancer Institute. Proton delivery techniques and treatment planning procedures The main technical characteristics of the selected studies are detailed in Table 2. Patient population More than 800 HCC patients received PT in the studies reported as a full paper. The main characteristics of patients included in the selected studies are illustrated in Table 3 (full volume table is reported in the supplementary appendix). Treatment regimens and clinical results A description of the various treatment schedules adopted by the selected studies along with the main results in terms of clinical outcome are provided in Table 4 (full volume table is reported in the supplementary appendix). Briefly, the LC and OS at 5 years were 86.9% and 23.5%, respectively, in the first report from Tsukuba [19]. In the second report from Tsukuba a 5-year survival of 55.9% was registered for ChildPugh (CP) A disease, which was significantly higher than the 44.5% survival at 5 years reported for Child-Pugh B patients.

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Literature search Databases = Pubmed and Scopus Meeting abstracts/proceedings = (ASTRO, ESTRO, ASCO, PTCOG) Limits = English Language studies only; years: 1990-2012 When = December, 2012

Search results combined = 324

No. of records eligible for manuscript review = 96

No. of records Excluded = 80 General particle therapy reviews = 8 General proton reviews = 11 Not HCC, particle therapy studies = 6 Other particles, not proton HCC studies = 8 subsequently updated abstracts = 15 case reports = 5 experimental studies = 6 multiple publications = 21

No. of records included = 16

Full text articles = 12 Reporting clinical outcome and toxicity = 8 Reporting technical issues = 4

No. of records Excluded = 228 Not oncological studies = 39 Not radiotherapy studies = 127 X-ray therapy studies = 18 General HCC reviews = 5 Duplicates = 39

Abstracts/proceedings = 4 Reporting clinical outcome and toxicity = 3 Reporting technical issues = 1

Fig. 1. Flow diagram of study selection.

Table 1 Main relevant inclusion criteria of the selected studies. Center Country, period [references]

Type of study Level of evidence*

Liver Max tumor function size

Max no. of tumors

Ascites

Transplant candidate

Extrahepatic disease

Adjacent to GI tract

PMRC [19]

Japan, 1985–1998

Retrospective 3 AD

CP A-C

3

Not reported

Ineligible

Ineligible

Eligible

PMRC [20]

Japan, 2001–2007

Retrospective 3 AD

CP A-C

3

Uncontrolled ascites ineligible

Not reported Ineligible

Ineligible

HIMBC [21] Japan, 2001–2009

Retrospective 3 AD

CP A-C

The maximum size covered by a single field The maximum size covered by a single field 15 cm

Uncontrolled ascites ineligible

Not reported Ineligible

Eligible

NCCHE [33] Japan, 1999–2007

Retrospective 3 AD

CP A-B

10 cm

Ineligible

Not reported Ineligible

Ineligible

LLUMC [18] USA, 1998–2006

Prospective

CP A-C

Tumors of any size eligible

The maximum number of lesions covered by a single field Multinodular HCCs eligible if (1) a single CTV could be created or (2) lesions far from target controlled by other therapies 3

2 AD

Pts with tense Eligible ascites ineligible

Ineligible

Eligible

See text for proton center abbreviations. Other abbreviations: Max: maximum, GI: gastrointestinal, CP: Child-Pugh score, CTV: Clinical target volume, Pts: patients. According to the classification system developed by the National Cancer Institute. A numeric scale is used for the strength of the study design: 1 = randomized controlled trials, 2 = non-randomized controlled trials, 3 = case series, 4 = best case series. A progressive alphabetical scale classifies the reported findings of the study: A = overall survival, B = disease-specific survival, C = quality of life, D = indirect surrogates including disease-free survival, progression-free survival, tumor response rate. *

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Table 2 Main technical characteristics of the selected PT centers. Center [references]

Beam production

Delivery technique

Beam modification devices

Immobilization devices

Treatment planning data

Beam number, arrangement

PMRC (old facility) [19]

Synchrotron 250 MeV Emax

scattering in fixed lines (V or H)

Ridge filter, collimatorcompensator

fiducial markers in iridium and gating

CTV = GTV + 5–10 mm margins

PMRC (new facility) [20]

Synchrotron 155–250 MeV

Scattering in fixed line or gantry

Ridge filter, multileaf collimator, bolus

Fiducial markers and gating

HIMBC [21]

Synchrotron 230 MeV Emax

Wobbling in gantry and fixed line

Ridge filter, collimatorcompensator

Gating

NCCHE [33]

Cyclotron

Wobbling in gantry

Ridge filter, multileaf collimator, bolus

Gating

LLUMC [18]

Synchrotron 70–250 MeV

Scattering in fixed line or gantry

Collimatorcompensator

Full immobilization voluntary breath hold (expiration phase)

Planning CT = 5 mm slice in expiratory phase CTV = GTV + 5–10 mm margins PTV = CTV + 5–10 mm + additional 5 mm caudally Planning CT scan (expiratory phase) fused with MRI CTV = GTV + 5 mm PTV = CTV + 5 mm + additional 5–10 mm caudally Planning CT scan in expiratory phase CTV = GTV + 5 mm PTV = CTV + 3 mm isotropic 2 pts = personalized CTV encompassing (1) the right lobe and 2) the right anterior portal segment CT scan in expiratory phase PTV = GTV + 1–2 cm

2, Vertical and horizontal rightangled, trying to avoid gastrointestinal tract Not specified

Energy range

235 MeV Emax

2, Lateral oblique and posterior

2, Angled in order to minimize healthy tissue irradiation

2, Customized according to patient anatomy

See text for proton center abbreviations. Other abbreviations: MeV: megaelectronvolt, Emax: maximum energy, V: vertical, H: horizontal, GTV: gross tumor volume, CTV: clinical target volume, PTV: planning target volume.

Table 3 Patient characteristics of the selected studies. Center [references]

No. of patients

Age

PS

Stage

Liver function

Vascular invasion (%)

Size

PMRC [19]

162

median age 62.5 y (range 41– 84)

WHO 0 = 61 1 = 79 2 = 21 3=1

TNM stage* I = 66 II = 70 IIIA = 25 IIIB = 1

PVTT = 10 (6)

Median = 3,8 cm Range = 1.5– 14.5

PMRC [20]

318

Median age 69 y

Not reported

242

5 cm = 18

LLUMC [18]

76

Median age 62.7 y (range 40– 83)

Not reported

CP score A = 47 B = 13 C=0 CP score A = 22 B = 36 C = 18

PVTT = 4 (5)

Median = 5,5 cm 0–2 cm = 5 2–5 cm = 34 5–10 cm = 33 >10 cm = 4

MELD score stage 6–10 = 29 11–14 = 34 15–20 = 9 >20 = 3

See text for proton center abbreviations. Other abbreviations: y: years, PS: performance status, WHO: World Health Organization. International Union Against Cancer, tumor-node- metastases classification, 6th edition, CP: Child-Pugh, EORTC: European Organization for Research and Treatment of Cancer, PVTT: portal vein tumor thrombosis, IVCTT: Inferior vena cava tumor thrombosis, ECOG: Eastern Cooperative Oncology Group, BCLC: Barcelona Clinic Liver Cancer, MELD: model of end-stage liver disease.

*

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F. Dionisi et al. / Radiotherapy and Oncology xxx (2014) xxx–xxx Table 4 Main results of the selected studies adopting PT for HCC patients. Center [references]

Treatment regimen*

Equivalent dose 2 Gy/fr a/b = 10

Median F-UP (range)

Local control

Overall survival

Liver-toxicity endpoint (LTE) toxicity

PMRC [19]

TD = 72 Gy dpf = 4.5 Gy TD = 78 Gy dpf = 3.9 Gy TD = 84 Gy dpf = 3.5 Gy TD = 50 Gy dpf = 5 Gy miscellaneous regimens = 97 T

87 Gy 90.4 Gy 94.5 Gy 62.5 Gy –

31.7 m (3.1–133.2)

86.9% at 5 y

23.5% at 5 y

PMRC [20]

T 6 2 cm from GI tract TD = 77 Gy dpf = 2.2 Gy (65 pts) T 6 2 cm from ph TD = 72.6 Gy dpf = 3.3 Gy (85 pts) Peripheral T TD = 66 Gy dpf = 6.6 Gy (104 pts) miscellaneous regimens = 64 pts

78.3 Gy

19.3 m

83.3% at 5 y

44.6% at 5 y

LTE: bilirubin " > 51.3 lmol/l Acute toxicity: 9.7% " transaminase level Late toxicity: 1.1% Infection biloma 0.5% Biliary duct stenosis 1.1% GI bleeding LTE: NA

80.4 Gy

(1.2–63.6)

(peripheral, single T)

TD = 76 Gy dpf = 2 Gy (11 pts) TD = 56 Gy dpf = 7 Gy (4 pts) TD = 60 Gy dpf = 6 Gy (89 pts) TD = 76 Gy dpf = 3.8 Gy (70 pts) TD = 66 Gy dpf = 6.6 Gy (53 pts) TD = 80 Gy dpf = 4 Gy (3 pts) TD = 84 Gy dpf = 4.2 Gy (3 pts) TD = 52.8 Gy dpf = 13.2 Gy (9 pts) TD = 76 Gy dpf = 3.8 Gy TD = 60 Gy dpf = 6 Gy (3 pts) TD = 65 Gy dpf = 2.5 Gy (11 pts)

76 Gy 79.3 Gy 80 Gy 87.4 Gy 91.3 Gy 93.3 Gy 99.4 Gy 102 Gy 87.4 Gy 80 Gy 67.7 Gy

31 m

90.2% at 5 y

38% at 5 y

43 m (25–92)

56% at 3 y 25% at 5 y

TD = 63 Gy dpf = 4.2 Gy (76 pts)

74.5 Gy

NA

LPFS at 3 y = 90% LPFS at 5 y = 86% 80% at 5 y

HIMBC [21]

NCCHE [33]

LLUMC [18]

Late toxicity:

91 Gy

PFS for patients within Milan criteria = 60% at 3 y PFS for patients outside Milan criteria = 20% at 3 y

3 G2 GI 1 G3 GI (? surgery) 3 G2 rib fractures 28 G2 skin toxicities LTE RILD NOS PG3 late toxicities in 8 pts 1 RILD 8 G2 rib fractures

LTE: PHI PHI in 11 pts, 7deaths (5 without recurrence) 3 P G2 GI toxicities LTE: RILD** Late toxicity: 5 G2 GI toxicities No RILD

*

Dose intended as Gy RBE. See text for proton center abbreviations. Other abbreviations: TD: total dose, dpf: dose per fraction, T: tumor, m: months, y: years, CP: Child-Pugh score, NA: not available, GI: gastrointestinal, ph: porta hepatis, LC: local control, OS: overall survival, pts: patients, BCLC: Barcelona Clinic Liver Cancer, RILD: radiation induced liver disease, NOS: not otherwise specified, LPFS: local progression free survival, PFS: progression free survival, PS: performance status, PHI: proton hepatic insufficiency (anicteric ascites and/or asterixis without disease progression) occurring within 6 months after P. ** According to the clinical and laboratory parameters suggested by Lawrence et al. Int J Radiat Oncol Biol Phys 23 (1992) 781–788.

Another single-institution experience was reported by Komatsu et al. [21] from the HIBMC; the 5-year LC and OS were 90.2% and 38%, respectively. The retrospective study from the NCCHE [33] analyzed both clinical results and possible predictors of liver toxicity. The local progression-free rates at 3 and 5 years were 90% and 86%, respectively. The OS rates at 3 and 5 years were 56% and 25%, respectively, with the majority (64%) of deaths occurring for intrahepatic recurrences. Liver toxicity is reported in the next section. A prospective phase II trial was conducted in the USA by the group of LLUMC [18] with the aim of evaluate the 3-year progression-free survival (PFS) of HCC patients within the Milan criteria [35] treated with 63 Gy RBE in 15 daily fractions. However, the patient population enrolled in the period 1998–2006 represented a cohort with advanced stage HCC, with only 35 out of the 76 patients being within the Milan criteria. A 60% PFS at 3 years was registered for patients within the Milan criteria. Liver transplantation after PT was performed in 18 patients; a complete-near complete response was obtained in 72% of patients. Toxicity (clinical studies) The treatment-related toxicities registered in the clinical studies along with the specific liver morbidity endpoints evaluated are reported in Table 4. Acute toxicities were modest; skin-dermatological and gastrointestinal toxicity were the most frequent late complications. Late biliary toxicities were observed in the first report from Tsukuba. Liver toxicity was low in all studies with the exception of the study form NCCHE (see below).

Treatment related toxicity studies The review process retrieved a total of four studies that analyzed the potential predictors of clinical toxicity with the use PT for HCC. The earliest analysis [32] was conducted by the PMRC and the National Institute of Radiological Sciences (NIRS, Chiba, Japan). The authors analyzed 159 pre-treatment and follow-up CT scans from 26 patients undergoing PT for HCC between 1990 and 1994 (total dose range 50–84 Gy in 11–24 fractions). They evaluated if the ‘‘planned treated volume’’ (i.e., the volume of liver receiving the threshold dose of 30 Gy) could replace the planned resected liver volume in the prediction score (PS) formula [36]. The authors concluded that the PS most likely underestimates the limit of radiation tolerance due to different reasons, such as the timing of the reduction of liver functional capacity, which in surgery occurs more acutely than in radiotherapy. A more recent study from the PMRC aimed to identify potential prognostic factors of an increase of P1 in the Child-Pugh score after PT [30]. Upon univariate analysis, the factors associated with post treatment liver function were the percentage of normal liver receiving at least 0, 10, 20, and 30 Gy RBE (V0–30, dose per fraction range 2.2/6.6 Gy RBE), mean dose to normal liver, tumor size, pre-treatment CP score and hepatitis. The suggested cut-off values for V0, V10, V20, and V30 were 30%, 20%, 26% and 18%, respectively. The authors considered a value of V0 as the most useful index for the evaluation of liver function after PT. The third study was conducted by the group of the NCCHE [33]. The authors identified three groups of patients according to the pre-treatment 15-min indocyanine green retention rate (ICG R15)

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Proton therapy in liver cancer

values: patients with values of ICG R15 6 20% (group A, n = 20, all CP A) > 20 25% experienced PHI (P = 0.037). DVH analysis did not help to predict the non-occurrence of PHI registered in group A patients. The incidence of PHI was 6% in CP A patients and 64% in CP B patients. The latest study aimed to determine possible predictors of rib fracture by retrospectively analyzing the patients’ characteristics and DVHs from 67 cases treated with a hypofractionated schedule of 66 Gy RBE in 10 fractions [31]. The clinical factors did not differ significantly between patients with and without rib fractures. The fractured ribs showed significantly higher dose–volume parameters compared to non-affected ribs. The most useful parameter was found to be the volume of rib receiving a biological effective dose of 60 Gy RBE (a/b = 3), with a cut-off value of 4.48 cc. Technical issues studies Four studies that focused on some technical issues related to the use of PT in HCC patients were retrieved. In the context of motion issue, Oshiro et al. [26] evaluated the target position and stability at a fixed respiratory phase in 30 patients. A wave-like respiratory signal was obtained using a laser range finder that monitored the movement of the patient’s body surface. Once a gating signal was developed at a certain point on the respiratory waveform, the accelerator was triggered within 0.1 s to deliver proton beams. The results of the study indicated that tumor location at a fixed phase in end-expiration was highly reproducible. Fukumitsu et al. [25] evaluated whether an adequate irradiation dose was actually delivered to the tumor based on the change in Hounsfield Unit (HU) that occurs in the liver after PT. They investigated the cause of geometric errors in 21 patients with liver tumors treated with PT: CT images obtained after PT were subtracted from the images obtained prior to PT. They analyzed whether the area of the large HU change around the tumor (peak) was consistent with the high-dose (i.e., 90%) distribution area. The ratio of the peaks was highest in the lateral directions and lowest in the supero-inferior direction. The authors concluded that patients with extremely irregular respiratory rhythms might require education regarding respiration or should be treated using a larger margin (median calculated increase in PTV margin = 4 mm, 3.4 mm and 6 mm in lateral, cranio-caudal and superoinferior direction, respectively) or an alternative technique. A major concern in PT is related the anatomical changes during treatment course. The challenges of liver cancer are unique in this respect, such as the presence of uncontrollable ascites. Hata et al. [28] proposed a method for adjusted single fraction proton irradiation for HCC with uncontrollable ascites and possible intraabdominal organ instability. CT was repeated in the treatment position for three patients immediately before irradiation, on the treatment day. The center position of radiation fields was subsequently determined, and the beam range was adjusted based on data obtained from CT, and referring to previously obtained treatment-planning CT data. To adjust the beam range, acryl plates available per millimeter in water-equivalent thickness were inserted in the beam line as compensators. In this way, proton beams were successfully adjusted immediately prior to irradiation and a single high dose (24 Gy RBE) PT could be safely delivered. Shin et al. [27] evaluated the influence of a lipiodol chemoembolization agent on the proton beam range. They compared the

calculated proton beam ranges and the measured values. Iodinecontaining agents, such as contrast agent and lipiodol, increased the HU value in tissues and the uncertainties for the range calculation. In contrast to iodine agents, however, lipiodol shows intensive uptake in HCC lesions and did not ‘‘wash out’’ on CT images because it may selectively remain in tumors for long periods. The authors showed that the HU value of lipiodol on the CT images could result in an overestimation of the actual stopping power and that the actual distal range in a partially lipiodolized lesion is more similar to that of normal liver than the range calculated according to its HU value. Therefore, the authors suggested that the HU values of the partially lipiodolized lesions inside the PTV should be replaced by the average HU value of the surrounding normal liver. Discussion The rationale of using PT in primary liver cancer lies in the physics peculiarities of protons, which allow for a better sparing of organs at low and medium doses when compared to photon radiotherapy [37]. These properties fit well with liver irradiation: its tolerance to radiation, in fact, is strongly correlated with the mean dose and the organ volume receiving a certain amount of radiation [10]. These theoretical advantages of PT need to be confirmed by clinical data. In light of this need, the current systematic review aimed to collect and evaluate the currently available scientific evidence about the clinical use of PT in HCC. Clinical results As expected, the majority of the reports originated from eastern countries, where the incidence of HCC is highest [1] and where the availability of proton centers is high [38]. The first published results are from the center of Tsukuba, where clinical application of PT started in 1983. The only reports from western countries originated from the USA. Published results from European centers were not found. During the thirty-year experience of using PT for HCC, several treatment schedules were developed and delivered to a heterogeneous group of patients (i.e., various staging, and various degrees of liver function). Furthermore, different staging systems were reported (Table 3). This study demonstrated the wide clinical feasibility of PT, while the possibility to retrieve consistent data about its effectiveness is jeopardized. We decided to refer to conventional photon radiotherapy, delivered both with standard [39] and hypofractionated ‘‘stereotactic’’ regimens [40], for benchmarking purposes regarding the results registered in the present review. Local control and survival A high and long lasting LC, greater than 80% at 5 years, was registered with the use of PT for HCC. The other treatment modalities that the patients had received before or after PT did not influence the LC, as shown in the series from PMRC [19] and HIBMC [21]. As expected, the occurrence rate of a new tumor outside the treated volume was high in all studies, ranging from 36% to 85%. In most cases, the burden of recurrent disease was exclusively intrahepatic. In this context, a new local treatment could be of benefit. Theoretically, the risk of adding toxicity in a previously irradiated liver with new local treatments (RF, TACE) could be a minor issue in the development of a treatment strategy for an intrahepatic recurrence after PT when taking into account the better sparing of noncancerous liver which can be obtained with PT compared with conventional radiotherapy. Moreover, repeated PT could be an

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option for new HCCs developed after the first course of treatment. Data from Hashimoto et al. [41] showed that repeated PT could be a safe and effective treatment option, especially for peripherally located tumors and CP A patients. Data on survival are impressive at a first glance, with rates comparable to surgery in the most favorable groups; good outcomes can also be observed in patients with poor prognosis, such as the 30% survival at 5 years for stage C disease in the series from Hyogo. The possible gain in OS with the addition of PT to the actual standard of care for advanced disease [42] is currently under investigation in a randomized controlled trial (NCT01141478). The rate of survival (70% at 3 years) for patients undergoing liver transplantation after PT in the study from LLUMC enhances the hypothesis of PT as an option for patients listed for liver transplantation. The low quality of the retrieved studies, the retrospective nature of most of the reports and the lack of data regarding treatments received after PT highly reduce both the scientific and clinical impact of these encouraging data and raise questions about the reproducibility of such good outcomes in well-designed, prospective clinical trials. A direct comparison of PT with the studies using conventional radiotherapy was limited by the differences in the treatment schedule and the association with TACE in some photon studies. Some remarks based on the X-ray therapy series can be addressed: (1) The amount of the dose delivered is significantly correlated with the tumor response with a possible impact on survival of HCC patients. A relationship between dose and LC rate in PT series was not well established, likely due to the heterogeneity of the patient population. In the study from HIMBC [21], the 5 year OS for patients treated with a biological effective dose (BED10) P 100 was higher than the 5 year OS achieved with a BED10 6 100 (43.9% vs. 31.7%, respectively). (2) The escalation of the radiation dose is accompanied by increased liver and gastrointestinal toxicity. The liver toxicity from the PT series was quite low, while several strategies were developed to reduce the rate of GI toxicities (see below). (3) The association between RT and TACE represents a promising option in the treatment of HCC, with improved outcomes compared to TACE alone, as confirmed by the meta-analysis from Meng et al. [43]. No data are available reporting this combination with PT. The use of stereotactic, hypofractionated radiotherapy for the treatment of HCC is a relatively new approach that shows encouraging rates of LC in the published series, even though the limited number of treated patients biased the results. The underlying deteriorated liver function of HCC CP B patients represents a relevant issue for hypofractionated regimens, given that the risk of liver toxicity seriously increased [44]. Moreover, a recent report by Bujold et al. registered a 7% risk of death related to SBRT, even in CP A patients [45]. The use of protons, the physical properties of which allow for a reduction of liver irradiation, should be considered to enhance the therapeutic ratio for these patients. Toxicity and liver radiation tolerance studies The retrospective design of most of the retrieved studies must be taken into account when evaluating data on treatment toxicity. However, PT was considered a well-tolerated treatment in all the reported series; skin-dermatological and gastrointestinal toxicity represented the most frequent reported adverse events. Skin subcutaneous toxicity Skin-subcutaneous toxicity is a known event occurring during PT; it is due to the less skin-sparing effect achievable with protons compared to photon treatments. Because skin toxicity depends on

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field arrangement, it can be significantly reduced by adding a second beam for single-field therapy, as performed in HYMBC [21]. Gastrointestinal toxicity Mild radiation toxicity to the gastrointestinal tract was often registered after PT when tumors were located in close proximity to gastrointestinal organs, with few cases of severe toxicities requiring surgical intervention. A dose per fraction higher than 2.2 Gy up to a total dose of 55 Gy and the serial functioning of gastrointestinal mucosa were at the basis for the risk of radiation toxicity in the series from Tsukuba. Possible strategies to overcome serious adverse events in this setting were reported by the PMRC [46] and the LLUMC [18]. Their decision to reduce field margins if tumors were close to the gastrointestinal tract successfully eliminated the risk of bowel injuries; a decrease in tumor control probability was not reported. Conversely, the proximity to the gastrointestinal tract was found to be an independent risk factor for local failure by the group of HYMBC [47]. The authors suggested the insertion of a spacer between the tumor and the digestive tract to improve the treatment outcome of centrally located lesions. Biliary toxicity Late biliary toxicities were observed, especially in the first experience from Tsukuba [19]: the reduction of the total dose with the adoption of a less hypofractionated treatment schedule was also confirmed as an effective strategy to minimize the risk of bile duct toxicity for tumors adjacent to the porta hepatis in this setting [48]. Biliary toxicity is rarely reported in photon series, and reliable DVH parameters to prevent treatment related complications are lacking; a non-mandatory organ dose constraint for the common bile duct (Dmax = 50 Gy in five fractions) was suggested by the recent RTOG 1112 trial (NCT01730937). In a recent analysis of patients treated with SBRT for centrally located tumors, a total dose of 40 Gy in five fractions was considered safe with regards to biliary complications [49]. Hepatic toxicity All the retrieved studies with the exception of the experience from NCCHE [33] showed an extremely low risk of hepatic toxicity, with transient liver enzyme elevation being the most common observed acute toxicity. The retrospective nature of most of the studies could have hampered the detection of transient liver function deterioration. Moreover, the liver-morbidity endpoints differed in the selected studies (Table 4), which reduced the possibility to retrieve consistent treatment parameters with respect to liver tolerance to PT. The study from Tsukuba [30] that evaluated liver function after PT indicated the percentage of noncancerous liver receiving 0 Gy (V0) as the most significant index for an increase in the CP score P1, with a preferred value of V0 6 30%. No correction was made to account for dose per fraction differences. Regarding X-ray studies, the work of Son et al. [50], which evaluated dose–volumetric parameters predicting toxicity in liver SBRT, showed that the volume of liver receiving the lowest dose (identified as 5 Gy) was the most significant factor associated with a CP score that worsened upon univariate analysis. The finding that the volume of normal organ which is completely or near completely spared by irradiation influences liver function fits with the well-known parallel functioning of liver tissue [10]. Cirrhotic livers could benefit most from having a substantial percentage of their volume totally preserved by the radiation dose. Moreover, other local therapies such as TACE and RFA could take advantage of this finding, both in combination with radiotherapy and alone as salvage therapy after disease progression.

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The rate of proton induced hepatic insufficiency was high (18%) in the results from NCCHE. Both clinical parameters (CP score and ICG R15 values) and DVH parameters proved to be useful indicators of the risk of developing PHI. A value of V30 (dose per fraction range 2.5–6 Gy RBE) 20% < 50%. Child Pugh A patients with ICG R15 < 40% presented a low risk ( 40%. Interestingly, (1) all CP B patients presented with baseline ICG R15 > 20% and (2) no patient with a baseline ICG R15 value 620% suffered from PHI. The work of Yoon et al. [51] reported a similar cut-off value in a retrospective analysis of 146 patients treated with photon-RT at a median dose of 45 Gy. The incidence of RILD was 40.7% in patients presenting with a baseline ICGR15 value P22%, while only 3.4% of patients with lower levels of ICGR15 suffered from radiation hepatitis (P < 0.0001). Notably, similar findings were obtained for two highly different total treatment doses (photon-RT = 45 Gy median total dose with median fractionation 1.8 Gy vs PT = 87 Gy equivalent dose at 2 Gy per fraction). Although a direct comparison is impossible, a high dose curative approach with PT could be speculated as safe in patients with preserved liver function. Furthermore, this approach could be attempted at a certain risk in patients whose liver function is deteriorated at baseline (not for ICGR15 value superior to 40–50%). Conversely, the costbenefit ratio of photon-RT when the baseline liver function is deteriorated seems extremely low. Whether an increase in the X-ray dose (i.e. with hypofractionated stereotactic radiotherapy) in patients with baseline low ICGR15 levels would result in safe and effective outcomes remains unclear. Other heavy particles such as carbon ions have been explored in the treatment of HCC (Table 5A in the supplementary appendix): the results of almost 200 patients were reported [21,52–54]. Tumor control was high (>80% at 5 years) and comparable with PT data. Hypofractionated regimens were frequently delivered with carbon ions, the most frequent treatment being 52.8 Gy in 4 fractions. Similar fractionation schemes were rarely adopted for PT: they are currently under investigation in the RTOG 1112 trial. Another aspect of clinical research in C-ion therapy that could be integrated in PT was the use of modern delivery techniques (i.e., active scanning), as reported in the small, innovative experience from the Heidelberg Ion Beam Therapy center [54].c Technical issues Many variables can influence the precision and reliability of a radiotherapy plan, particularly a PT plan: anatomical changes (inter and intra fraction), set-up error, delivery/imaging misalignment, etc. Motion is definitely a major technical problem in PT. In the context of gated proton delivery, the results reported by Oshiro et al. [26] indicated that tumor location at a fixed phase in end-expiration was highly reproducible. In the same report, the use of markers (implantable) was highlighted as in other RT studies [55]. Not only interfraction setup variations and intrafraction breathing movements, but also the changes in Hounsfield units (HU) during breathing, mechanical response delays, and tumor volume changes during the treatment course may change the dose distributions. The hypoattenuation of the irradiated areas on CT images occurs after hepatic irradiation [56]. In PT, a rapid increase in the dose at the end of the beam range is allowed [57] which results in a clearly distinguishable hypoattenuation area in and surrounding the tumor after irradiation [58]. In this context, Fukumitsu et al. [25] found that some uncertainty in the dose delivery may exist in the directions influenced by large intrafraction breathing movements and interfraction setup variations. As above reported, the risk of low radiation tolerance in close proximity/contact with the gastrointestinal tract is high and the

application of RT or PT for huge HCC could be restricted. Recently, Fukumoto et al. [59] developed a new option for the curative treatment of a large unresectable HCC: a novel 2-step treatment with surgical spacer placement and subsequent proton radiotherapy. Another important issue in PT is the expected lower incidence of secondary cancer (SC) compared to other irradiation techniques. Taddei et al. [60] reported a model to predict the risk of developing SC for a patient with HCC between PT and IMRT. They found that PT reduced the risk by approximately 40% relative to IMRT (from 19.2% to 11.4% lifetime risk). Finally, we must underline that almost all the clinical data from PT in liver cancer are associated with the use of the passive scattering technique. The most recent proton centers are equipped with active scanning technology [61,62] that allows intensity modulated proton therapy (IMPT), a lower secondary neutron dose [63] (i.e., less expected radiation induced secondary cancers), better proximal edge conformity and dose optimization [64]. On the contrary, an active scanned proton beam has usually worse lateral penumbra [65], a slower delivery time [66] and could be more sensible to motion [67]. Special features should be implemented with the introduction of IMPT plans, such as beam-specific PTV [68], robustness optimization and evaluation tools [69], respiration management (repainting, image guidance etc.) [70]. All these tools are still under development and validation. Limitations The results of the review process pointed out some limitations of the study to be emphasized. Only five out of the eight retrieved clinical studies were produced as a full paper. Among the full published selected studies, only one prospective study was found. Therefore, the quality of all the designs of the studies was low. Conversely, the strength of the end-points of all studies was high, with all works measuring OS as a specific outcome (Table 1). Conclusions The low quality of the retrieved studies reduces without eliminating the interest toward the impressive clinical results that have been registered in several stages of HCC. The cost-benefit of proton versus other treatment options is worth of study given the high cost of protons [71]. A number of PT centers are currently recruiting patients in various prospective trials and are testing PT alone (NCT00976898), comparing PT vs TACE (NCT00857805), or evaluating the role of PT in advanced disease (NCT01141478). A positive outcome of such trials would suggest the role of PT as an effective option in the local treatment of unresectable HCC. Active-scanning based PT treatment for HCC is under development, and it should be considered one of the ‘‘modern approaches’’ to be tested in the next future. Conflict of interest No conflict of interest to declare. Acknowledgments We thank Elsevier language editing web service and Mrs. Valentina Piffer for their language editing of the manuscript. We thank the reviewers’ work, which contribute to improve the quality of the manuscript. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.radonc.2014.02. 001.

Please cite this article in press as: Dionisi F et al. Is there a role for proton therapy in the treatment of hepatocellular carcinoma? A systematic review. Radiother Oncol (2014), http://dx.doi.org/10.1016/j.radonc.2014.02.001

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