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17 Intraoperative Imaging Techniques inLiver Surgery
lesions using the “water-bath” technique [11] and vessel
and bile duct integrity of the remnant liver.
17.2.1 Anatomy
IOUS examination is started by placing the ultrasound probe
on the diaphragmatic face of the liver in the central portion
(at the level of segment 4) to obtain an ultrasound section of
the main portal bifurcation. From here, the examination continues following the left portal vein and its branches for
segments 2, 3 and 4 (upper and lower) and then the left and
middle hepatic veins, thus achieving the precise delimitation
of the segments of the left hemiliver. After repositioning the
ultrasound probe at the portal bifurcation, the examination
follows the right portal vein with its branches for the right
anterior section (with the portal branches for segments 8 and
5), and then, after returning to the right portal bifurcation, for
the right posterior section (with the corresponding branches
for segments 6 and 7). Then, the right and middle hepatic
veins are followed to the conuence with the inferior vena
cava, achieving the delimitation of the segments of the right
hemiliver. The examination is completed with segment 1
exploration.
Intraoperative ultrasound can be performed before any
dissection and repeated at will to guide the surgeon especially when hilar mapping is difcult due to brosis, inammation or tumor inltration. IOUS may be repeated as many
times as needed during surgery, prior, during and after the
resection, assisting in mapping the biliary, arterial, portal and
hepatic veins system, in detecting all their aberrant anatomy
[12], guiding the resection plane in order to prevent biliary
and vascular injuries, controlling the results after resection,
and, as discussed in this paper, identifying the corresponding
drainage territories of the bile duct stumps on the liver cut
surface for a proper biliary reconstruction.
147
Fig. 17.2 IOUS detection of a 4mm colorectal liver metastasis
diagnosing impairments such as cirrhosis, cholestasis, and
steatosis. The use of contrast agent further increases the sensitivity and specicity of IOUS [18]. New generation liverspecic contrast agents, such as peruorobutane (Sonazoid,
Daiichi Sankyo, Tokyo) further improves the detection and
differential diagnosis of focal liver lesions [19, 20].
Additionally, IOUS precisely denes the 3D relationships
between the FLLs and the surrounding main vessels, helping
in establishing the proper strategy and resection planning,
while maximizing the volume of the future liver remnant
(FLR). IOUS can change the resection planning in up to 72%
of cases [21].
17.2.3 Resection Guidance
This step involves IOUS techniques that guide the liver
resection planned based on information gathered by IOUS,
IOUS-guided techniques that are integrated in the surgical
technique as follows:
17.2.2 Diagnosis
IOUS is superior to preoperative imaging methods, detecting
10–50% more focal liver lesions (FLL) [13, 14]. While per-
cutaneous ultrasound, computed tomography (CT) and magnetic resonance imaging (MRI) are limited in identifying
FLL <2cm, IOUS easily detects FLL of 3–5mm [15, 16]
(Fig. 17.2). The sensitivity of CT in the FLL detection is
72%, while for IOUS is 98%. CT sensitivity decreases with
tumor size, reaching 35% for tumor of 1 cm, while IOUS
sensitivity is maintained in this scenario [17]. Moreover,
thrombosis of any vascular and/or biliary structure is easily
identied at IOUS, and helps in establishing its tumoral feature. IOUS also effectively assesses the background liver,
1. Demarcation of the resection area.
2. Resection guidance.
3. Identication of intrahepatic vessels.
4. Evaluation of post-resection results.
17.2.3.1 Demarcation oftheResection Area
IOUS-guided demarcation of the resection area is achieved
by using:
• IOUS-guided placement of the tip of the electrocautery:
the tip is placed between the ultrasound probe and the
liver surface, generating a specic artefact at ultrasound
exploration that helps the precise positioning of the tip at
148
Fig. 17.3 Electrocautery tip placement between the ultrasound probe
and the liver surface, generating a specic artefact at ultrasound exploration that helps the precise positioning of the tips at the level of the
planned resection plane, in a patient with HCC on HBV-related
cirrhosis
the level of the planned resection plane (Fig.17.3). In this
way, multiple key points are marked onto the liver surface, that are afterwards united by a closed-shaped line
(demarcating the resection area) in a such manner that
this area includes the lesion/lesions to be resected with
safety margins, while excluding key structures of the
future liver remnant (FLR), thus insuring its viability and
function. The resection volume is virtually delimited,
based on the demarcated resection area and intrahepatic
landmarks identied at IOUS; these landmarks are few
key points located in vicinity of the deepest part of the
lesion to be resected, and/or of a key vascular element that
is to be preserved for the FLR and exposed on the resection plane. This technique is used commonly used for
non-anatomical LR;
• tattooing technique [22]—consists in puncturing the
portal branch(es) that vascularize(s) the (sub)segments
that encompasses the tumor, and injecting a dye (carmine blue) that colors the anatomical territory to be
resected both on the liver surface and in depth (intraparenchymal delimitation is not as clear), thus guiding the
resection plane. When this technique is not feasible, the
counterstaining may be used, consisting in puncturing
and injecting the portal branches that serve the segments/subsegments adjacent to the resection territory.
This technique was designed for anatomical liver resection, particularly recommended in hepatocellular carcinoma [23, 24];
F. Botea et al.
Fig. 17.4 Demarcation for S7 subsegmentectomy based on the isch-
emia induced by ultrasound-guided portal pedicle compression, in a
patient with HCC on HBV chronic hepatitis
• IOUS-guided digital compression of intrahepatic
vessels:
– of intrahepatic portal pedicles—alternative to the tat-
tooing technique: IOUS locates the portal branch(es)
for the (sub)segment to be resected, and clamped
between the ultrasound probe and the surgeon’s nger
placed opposite to the probe onto the liver surface; the
induced transient ischemia of the corresponding parenchyma allows the demarcation of the resection area
(Fig. 17.4). When not feasible, the counter-compression may be used as an alternative (the concept is analogous to the counterstaining) [25];
– of the hepatic veins (HV)—while the HV planned to
be resected is nger clamped under IOUS-guidance,
the identication at eco-Doppler of hepato-hepatic
shunts (between the branches of the clamped HV and
those of the neighboring HV) and certication of a
normal ow in the portal branch(es) related to the
drained parenchyma of the nger-occluded HV allows
to preserve the drained territory of the HV to be
resected [26].
17.2.3.2 Resection Guidance
Using IOUS-guidance, the resection plane is established
between the border of the resection area marked by electrocautery (and easily visualized in IOUS, similarly to the tip of
the electrocautery), the deepest point of the future specimen,
and the key intrahepatic vessels in relation to the resection
plane which are to be preserved for the FRL, that are usually
exposed on the cut surface. The transection plane is visualized
17 Intraoperative Imaging Techniques inLiver Surgery
149
at IOUS as a hyperechoic irregular line, due to the presence of
air and coagulated blood between the two hepatic tranches
[27]. Thus, under ultrasound control, the transection plane is
guided and changed in real-time if necessary, adapting it in
real time in such way to correspond to the planned resection.
17.2.3.3 Identication ofIntrahepatic Vessels
During transection, any signicant vessel exposed on the
transection plane can be identied by the hooking technique
[10]: a reference surgical thread placed around the key vessel
is visualized at IOUS as a hyperechoic point with a posterior
shadow cone; by gently pulling the thread during IOUS, the
traction point on the vessel is identied [10].
17.2.3.4 Evaluation ofPost-Resection Results
The IOUS evaluation of immediate postresection results
consists of:
– control of tumor clearance: IOUS exploration of the rem-
nant liver identies potentially missed lesions. In case of
very small lesion, IOUS certies its presence in the specimen immersed in saline solution (the “water-bath” technique) (Fig.17.5), and guides the sectioning the specimen,
allowing the marking of the lesion, so the pathologist
wouldn’t miss it.
– control of the vascularization and biliary drainage of the
remnant liver: control of vascularization is performed by
intraoperative Doppler echo, any signicant alteration of
vascularization found at Doppler IOUS is sanctioned by
repositioning the remaining liver (in case of torsion,
angulation or traction of vessels), thrombectomy (in the
case of portal thrombosis), or resection of the ischemic/
congested territory. Detection of any signicant biliary
dilatation usually involves the resection of the corresponding territory.
IOUS ensures optimal tumor clearance. In case of nonassisted IOUS LR, positive oncological safety margins were
registered in 16–18% of cases, while no such case was
recorded after IOUS-guided LR [28]. Postoperative morbidity also appears to be lower with IOUS-guided LR [29]. The
main advantage of such LR is the maximization of functional
residual liver volume, preventing the risk of liver failure [29],
while allowing extensive multiple resections to be performed
in a single operation [30, 31]. Another important benet is
the possibility of repeated liver resections in the case recurrences, with a signicant impact on the oncological outcome
[32, 33]. The disadvantages of such procedure are represented by the cost of the equipment, and the slow learning
curve. We emphasize that, unlike the diagnostic IOUS that
can be performed by the radiologist, the IOUS guidance of
LR can be done only by the liver surgeon.
Literature analysis proved ultrasound as a safe, quick,
non-irradiating, cost-effective technique, which is well
known but largely under-utilized, probably due to the perception of a difcult learning curve.
IOUS is a precise real-time method of diagnosis and guid-
ance of LR, that must be part of the arsenal of liver surgery,
being optimally exploited when performed by the liver
surgeon.
Fig. 17.5 “Water-bath” technique for detecting a 5-mm colorectal liver metastasis in the specimen
150
F. Botea et al.
17.3 Intraoperative Fluorescence Imaging
The use of intraoperative uorescence imaging (IFI) in liver
surgery has signicantly increased and improved, offering
new perspectives. In selected patients, especially during
minimally invasive surgery, IFI adds useful data to visual
inspection, palpation, and intraoperative ultrasound, limited
to a depth of 5–10mm [34]. IFI is based on the visualization
at a special infrared camera of certain areas where indocyanine green (ICG) injected intravenously accumulates or not.
The main use of IFI is the visualization of the biliary anatomy, due to ICG biliary excretion starting approximately
30min after intravenous injection (Fig.17.6). This is useful
especially resections of centrally located liver tumors and
hilar cholangiocarcinoma [35, 36]. IFI cholangiography can
detect bile duct leakages during hepatectomies, that are
missed by other routine tests [37].
IFI may also be used as an alternative to the tattooing
technique, by injecting ICG into the portal branch (instead of
the colored dye) [38]. However, one of the disadvantages of
this procedure is difcult tracking of the stained plane during
transection. The ICG within the targeted segment gradually
disappears and repeated ICG injection or temporally clamping the hepatic artery (for reducing washout of the dye) is
necessary to continuously track the transection plane.
Additionally, a small amount of ICG recirculates the liver
after the initial passage through the portal vein branch, that
lead eventually to the staining of the entire liver. To avoid
this, intermittent Pringle maneuver is recommended [39] in
order to obtains continuous uorescence tracking during
transection, allowing a persistent visualization of the segmental boundaries [40].
Moreover, IFI enables identication of subcapsular liver
tumors through accumulation of ICG administered preoperatively in malignant tissues, as in case of hepatocellular carcinoma (HCC), or in the surrounding parenchyma in case of
intrahepatic cholangiocarcinoma and liver metastases
(Fig.17.7). However, only tumors located 5mm or closer to
the liver surface are usually detected at IFI, while tumors
located ≥8 mm from the liver surface cannot be identied
[41]. Nevertheless, in this thin supercial zone of the liver,
IFI may detect up to 29% more liver metastasis with diameter≤3mm [42].
Fluorescens patterns are related to the type of cancer and
its grade of differentiation [43]. Impaired bile excretion in
HCC cells retains the ICG within the tumor, therefore welldifferentiated HCCs appears at IFI as strong, homogenous
uorescence emissions. In contrast, in poorly-differentiated
Fig. 17.6 Intraoperative uorescence imaging depicting the gallbladder, cystic and the main bile ducts
17 Intraoperative Imaging Techniques inLiver Surgery
151
Fig. 17.7 Liver metastasis from breast cancer: intraoperative uorescence imaging depicts the hallow surrounding the lesion
HCCs and liver metastases, ICG is retained in the cytoplasm
of the surrounding parenchyma, inducing a rim type uorescence pattern.
Recent experimental study showed that IFI may be used
as a drug delivery system in combination with photodynamic therapy may not only detect cancer tissue but also
treat it [44].
17.4 Navigation Assisted Liver Resection
Some attempts were made on computer-aided navigationassisted LR, using preoperative imaging superimposed intraoperatively onto the anatomical structures of the liver
[45–47]. However, the implementation of this procedure in
liver surgery is impeded by intraoperative organ shift and
deformation, and differences of total liver volume and vascular anatomy (when compared to the preoperative imaging),
the respiratory movements during surgery, along with the
lack of intraoperative external liver landmarks. Efforts are
made to overcome these obstacles, but still remains only a
future perspective [48, 49].
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Use ofRadiotherapy Alone
andinCombination withOther
Therapies forHepatocellular
Carcinoma: Rationale andFuture
Directions
DanG.Duda andFranziskaD.Hauth
18
Abstract
The continuous rise in incidence of hepatocellular carcinoma (HCC) worldwide has led to renewed efforts to
improve therapeutic strategies. The gold standard of curative therapy for patients with HCC is surgery. However, in
HCC patients with tumors with specic anatomical locations, such as near gastrointestinal structures or vessels, or
with vascular occlusions, surgery may be particularly challenging. Poor baseline liver function is often an additional
limiting factor for many established treatment modalities,
especially for liver resection. Therefore, available treatment options have been very limited in efcacy, which led
to dismal survival rates. In recent years, radiotherapy has
emerged as a new and promising local treatment option for
certain patients with HCC. Advances in technology and
delivery techniques have aided in establishing radiotherapy
as a safe and effective treatment modality. As a painless,
non-invasive, outpatient treatment procedure, radiotherapy
may have many advantages over other treatment modalities. This chapter will discuss recent developments and
advances in establishing radiotherapy as a new pillar of
treatment for patients with HCC, review available data
from retrospective and prospective trials, and give an overview of potential future combinational treatment approaches
with systemic therapies to further expand the benets.
D. G. Duda (*)
Department of Radiation Oncology, Massachusetts General
Hospital Research Institute, Boston, MA, USA
Edwin L. Steele Laboratories for Tumor Biology,
Massachusetts General Hospital, Boston, MA, USA
e-mail: duda@steele.mgh.harvard.edu
F. D. Hauth
Department of Radiation Oncology, Massachusetts General
Hospital Research Institute, Boston, MA, USA
Edwin L. Steele Laboratories for Tumor Biology,
Massachusetts General Hospital, Boston, MA, USA
Department of Radiation Oncology, University Clinic Tuebingen,
Tuebingen, Germany
18.1 Introduction
Hepatocellular carcinoma (HCC) is a primary cancer of the
liver and is often associated with chronic liver injury. The
etiology of chronic liver injury is different in various regions
of the world. While in Eastern areas the development of
HCC is often based on viral infections of the liver (Hepatitis
B and C), the rising incidence of liver tumors (~42,800 cases/
year) in the US is linked to increased rates of non-alcoholic
fatty liver disease (NAFLD) [1]. Although, therapeutic
options have evolved in the last decade, mortality from liver
cancer is still high (6% of all cancer related deaths in men in
the USA) [1], and ve-year survival ranges between 20%
(after ablation) and 67% (after liver transplantation) [2].
The gold standard for curative therapy remain total resection of the tumor or liver transplantation for patients within
Milan criteria (single tumor <5 cm or up to three lesions
<3 cm, no angioinvasion, no extrahepatic disease) [3, 4].
However, less than one-third of patients are eligible for these
treatments, mainly due to limited overall health status or
underlying liver disfunction [2, 5]. Moreover, HCC tumors
are often multifocal, including pre-cancerous and cancerous
areas, further limiting surgical options [2]. Other local treatment options include radiofrequency ablation (RFA), percutaneous ethanol injection (PEI), microwave ablation and
trans-arterial chemoembolization (TACE) [6]. Especially for
RFA and TACE, treatment efcacy is limited in patients with
portal vein thrombosis or vascular invasion due to delivery
technique via the vascular system. Another limitation of
these treatment approaches is tumor size, as they are less
effective against larger tumors [7, 8].
In recent years, technological advances in radiation oncology have led to the establishment of radiotherapy as a locoregional treatment option for patients with HCC.In particular,
hypofractionated image-guided radiotherapy (HIGRT), better known as stereotactic body radiotherapy (SBRT), has
been shown to be a safe and effective way to deliver ablative
doses of radiation to liver tumors. In general, hypofraction-
© The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2022
M. Makuuchi et al. (eds.), The IASGO Textbook of Multi-Disciplinary Management of Hepato-Pancreato-Biliary Diseases,
https://doi.org/10.1007/978-981-19-0063-1_18
153
154
D. G. Duda and F. D. Hauth
ated (stereotactic) radiotherapy refers to delivery of high
radiation doses in few, usually in less than 10 fractions.
These fractions may be delivered daily or spaced apart by
several days, generally between two to seven days. Precision
and accuracy are at the heart of this new therapy.
Improvements in treatment planning and delivery techniques
as well as the establishment of new imaging solutions during
radiotherapy have accelerated its implementation for liver
cancer treatment. This holds especially true for tumors in
challenging locations including tumors near blood vessels or
GI organs. As a non-invasive, painless, outpatient treatment
procedure with short treatment periods the benets for
patients are indisputable. While efcacy of RFA greatly
diminishes with tumor diameters above 3cm, radiotherapy
has been shown to achieve high local control rates also
inlocally advanced patients [9–11].
In this chapter, we provide an overview of the advances in
liver cancer radiotherapies, including photon and charged
particle therapy, review the available data from retrospective
and prospective studies, and point to potential future combination with novel systemic therapies.
18.2 Photon Therapy
Photon radiotherapy is the most readily available form or
radiotherapy. Historically, patients have been treated with
conventionally fractionated radiotherapy, resulting in generally low local control (LC) rates. This was mainly due to the
inability to deliver tumor ablative radiation doses within the
constraints of normal tissue tolerance. Technological
advancements in recent years have made it possible to precisely deliver higher radiation doses and to improve normal
tissue preservation, therefore reducing risk of liver- associated
side effects.
Efcacy of SBRT has been shown both for patients with
single site HCC as well as for patients with large or locally
advanced tumors. Currently available data is summarized in
Table 18.1. Overall survival (OS) rates after irradiation in
these studies shows very promising results with local control rates between 65% and 100%. In a Phase II trial, Takeda
and his group reported high LC as well as OS rates in
patients with solitary HCC with a maximal dimension of
4cm. Good treatment outcomes were independent of pretreatment or residual tumor burden or treatment in recurrent
settings [33]. Similarly, Kang etal. and Bujold etal. reported
high local control rates for patients with large or multiple
HCC lesions [34, 35]. As with many other treatment modalities, local control rates largely depend on tumor size. In a
retrospective analysis Yoon and colleagues reported 76.3%,
93.3% and 100% local recurrence- free survival rates for
patients with HCC>3cm, between 2.1–3cm, and≤2cm,
respectively [17].
Possible side effects after liver irradiation include elevation of liver enzymes, increase of Child-Pugh (CP) score and
worsening of liver function and hematologic toxicities as
well as fatigue and erythema. In general, side effects could
be separated into early (within 90days after treatment) and
late toxicities (>90days after treatment). Whereas early side
effects have the potential to resolve without treatment, late
onset toxicities are more likely to persist. A summary of side
effects Grade 3 or more is provided in Table18.1.
The optimal radiation dose as well as the timing of radiation in relation to other treatments remains unclear to date
[39]. However, studies have indicated a distinct dose-dependence of tumor response for HCC.In this context, Park and
colleagues observed increasing response rates correlating to
radiation dose (<40 Gy: 29%; 40–50 Gy: 69%; >50 Gy:
77%) [40]. In line with this observation, Kang and his group
reported a dose-dependence of two-year LC rates for patients
treated with SBRT: Patients receiving >54Gy showed a LC
of 100% whereas patients treated with doses <54Gy had a
LC rate of 81.7% [34]. However, in this study patients were
treated in a primary tumor setting and results are unlikely
relevant for adjuvant treatment settings. Similar results from
other studies led to the assumption that a radiation dose
>50Gy is required to achieve effective LC for HCC patients
[24, 41, 42]. A retrospective analysis by Su and colleagues
indicated that a biologically effective dose (BED10) ≥100Gy
and an equivalent dose in 2Gy fractions (EQD2)≥74Gy are
correlated with longer OS [20]. Similarly, Kim etal. reported
signicant higher two-year PFS and OS for patients treated
with BED10>105Gy [15]. In this study, a gross tumor volume < 214 cm3 was also correlated with OS. Of note, a
review of the national cancer database for patients treated
with SBRT revealed no association between a BED > 100
and overall survival. Further studies are needed to clarify the
relationship between dose, fractionation and patient survival
and to answer the outstanding questions.
In addition, the majority of previous studies have focused
on the treatment of patients with low grade liver cirrhosis
(mainly CP class A patients) due to the increased risk of
development of side effects after radiotherapy. A small study
by Culleton etal. in 29 patients with CP class B and C tested
SBRT with a median dose of 30Gy in six fractions. They
reported favorable survival data with a median OS of
7.9month in this patient cohort with very limited treatment
options. However, 63% of treated patients showed a worsening of CP sore of at least two points after treatment. Whether
these changes were correlated with treatment toxicity or due
to natural decline of liver function in these patients with
underlying liver diseases remained uncertain. The authors
argued for the application of the lowest effective radiation
dose in this very vulnerable patient population, and postulated that use of combinational treatment approaches may
allow further dose reduction [22]. In line with this conclu-
18 Use of Radiotherapy Alone and in Combination with Other Therapies for Hepatocellular Carcinoma: Rationale and Future…
Table 18.1 Overview over current data on photon therapy
Baseline liver
function (CPA/
CPB/CPC) [%] LC [%] OS [%] Toxicities
(median)
y)
45.2(2 y)
53.8 (3 y)
35Gy: 48/52/0
40Gy: 99/1/0
NA 89.2 33months
62.5/37.5/0 73 (1 y)
91 (3 y) 70 (3 y)
(2 y)
32.9% (3 y)
32.9% (5 y)
(median)
60 (1 y)
62 (2 y)
56 (5 y)
(6m)
40 (2 y)
21 (5 y)
75.8 (1 y) 45.5 (2 y)• 24.2% fatigue grade 1–2
• No ≥ grade 3
score
• 4 deaths (liver failure)
• No ≥ grade 3
• 29.1% worsening of CPC
score≥2pt
• 1 patient grade 4 GI
toxicity
class
• 13% increase hepatic
dysfunction
• 6.5%≥grade 3
• 13%≥grade 3
• 10.3% worsening of CP
score by 2
• Grade 5 liver failure 2
patients
• Acute: 2.6%≥grade 3
• Long-term: 2.6%≥grade
3
• 1/50 death (RILD)
• 5/50 grade≥3
• 1/37≥grade 3
score≥2
• Grade 3 thrombocytopenia
14/17% (1/3months)
• Grade 3/4 elevated
transaminases 10.3%
• Grade 3 and 4
hyperbilirubinemia
17/28% and 14/3.5%
(1/3months)
toxicity
• 3.8% worsening of CP
score≥2
• 20% worsening of CP
score≥2
• 2.5% duodenal ulcer
• 33.3% grade 1–2 GI
toxicity
hepatic enzymes
n
Retrospective analysis
Lou etal.
2019 [12]
Hara etal.
2019 [11]
Park etal.
2018 [13]
Bae etal.
2012 [14]
Kim etal.
2017 [15]
Andolino
etal. 2011
[16]
Yoon etal.
2013 [17]
Sanuki etal.
2014 [18]
Huertas
etal. 2015
[19]
Su etal.
2016 [20]
Jacob etal.
2015 [21]
Culleton
etal. 2014
[22]
Park etal.
2013 [23]
Huang etal.
2013 [24]
Yao etal.
2018 [25]
Katz etal.
2012 [26]
75 30–48 (3–4Gy/
374 34/40 (5 fx) 1.7 (1.0–3.0) 96/4/0 NA 63.6 (3 y) • 8.2% worsening of CP
77 35–50 (10 fx) 2.4 (0.8–5.6) 56/21/0 72.6 (5 y)52.3 (3 y) 40.9 (5 y)• 1.3% grade 3
20 50 (10 fx) 80% <3cm 90/10/0 85 100 (1 y) 87.9 (2
72 33–60 (3–10 fx) 7 (5.0–10.0) 87.5/12.5/0 NA 70.1 (1 y)
66 CPA: 44 (3 fx)
93 30–60Gy (3–4
185 CPA: 40 CPB:
77 45 (3 fx) 2.4 85.7/14.3/0 99 (1/2 y)81.8 (1 y) 56.6%
50 30–50 (3–5 fx) 8.5 (5.1–21.0) 82/18/0 NA 62.4% (1 y)
37 36/45/60 (3 fx) 7.8±3.3
29 30 (6 fx) 8.6 (4.1–26.6) 0/28/1 NA 32.3 (1 y) • 63% worsening of CP
26 40–50 (10 fx) 2.8 (1.1–5.7) 73.1/26.9/0 87.6 (2 y)88.5 (1 y) 67.2 (2 y)• 3.8% grade 3 hepatic
40 40–66 (14–23
33 39–45 (3–5 fx) NA 100/0/0 84.8
18 50 (10 fx) 4 (1.2–6.5) 16.7/44.4/22.2 NA NA • 5.5% grade 3 increase of
Dose
(fractionation)
[Gy]
fx)
CPB: 40 (5 fx)
fx)
35 (5 fx)
fx)
Tumor size
median (range)
[cm]
NA 88/12/0 NA 10months
3.2 54.5/36.4/0 90 (2 y) 67 (2 y) • 20% progression CTP
2 (1.0–6.0) 74.2/25.8/0 92.1 (3 y)86(1 y)
35 Gy: 2.7
(1.0–5.0)
40Gy: 2.4
(0.8–5.0)
(mean+SD)
<5: 62.5%
5–10: 35%
>10: 2.5%
155
(continued)
156
Table 18.1 (continued)
n
Prospective studies
MendezRomero
etal. 2006
[27]
Tse etal.
2008 [28]
Scorsetti
etal. 2015
[29]
Lee etal.
2020 [30]
Seo etal.
2008 [31]
Cardenes
etal. 2010
[32]
Takeda etal.
2016 [33]
Kang etal.
2012 [34]
Bujold etal.
2013 [35]
Lasely etal.
2015 [36]
Weiner etal.
2016 [37]
Takeda etal.
2008 [38]
25 (8 HCC,
17
metastasis)
41 36 (24–54) (6
48 48–75 (3 fx),
23 40 (5 fx) 3.1
65 61 (34 fx) 10.8 (6.1–15.5) 66.2/33.8/0 NA 34.7(1 y) • 15.4% did not complete
17 40/48 (3–5 fx) 4
101 35–40 (5 fx) 2.3
50 42–60 (3 fx) 2.9 (1.3–7.8) 87.2/12.8/0 94.6 (2 y)68.7 (2 y) • 6.4% grade 3 GI toxicity
102 24–54 (6 fx) 9.9 (1.8–43.3) 100/0/0 87% (1 y)17months
59 40 (5 fx), 48Gy
26 55 (5 fx) 5 (1.6–12.3) 88/12/0 91 (1 y) 45 (1 y)
16 35–50 (5–7 fx) (1.9–7) 87.5/12.5/0 NA NA • 37.5% transient elevation
Dose
(fractionation)
[Gy]
12.5/10 (3 fx), 5
(5 fx)
fx)
36–60 (6 fx)
(3 fx)
Tumor size
median (range)
[cm]
3.2
(0.5–7.2)
173ml
(9–1913ml)
4.8
(1–12.5)
(1–10)
(2–6)
(1–4)
NA 64.4/35.6/0 CPA:
Baseline liver
function (CPA/
CPB/CPC) [%] LC [%] OS [%] Toxicities
5(8)/2(8)/0 94% (1
y) 82%
(2 y)
41/0/0 65% (1 y)51% (1 y) • 7% increase CP class
53/47/0 85.8 (1
y)
64.4 (2
y)
0/78.3/21.7 92.3 (1 y)56.5 (1 y) • 43% CP score progression
35.3/64.7/0 100 (2 y)75 (1 y)
91/9/0 96.3 (3 y)66.7 (3 y) • 8.9% worsening of CP
92
(6m)
CPB:
93
(6m)
82%(1 y)
54% (2 y)
77.9 (1 y)
45.3 (2 y)
60 (2 y)
(median)
CPA: 94/72/61.3
(1/2/3 y)
CPB:
57.1/32.7/26.1
(1/2/3 y)
D. G. Duda and F. D. Hauth
• 1 grade 5 (death)
• 16%≥grade 3
• 12% grade 3 increase liver
enzymes.
• 16%≥grade 3
• 4.2% worsening of CP
score
• 17% worsening of CP
score≥2
• 7 liver related deaths
RT (HCC/liver function
detoriation)
• 6.2%≥grade 3
Hepatic events
• 9.2%≥grade 3
Hematologic events
• 17.6% RILD
• 47% grade 3
• 11.8% grade 4
score≥2
• 6.6% grade 3
• 4.3% grade 4 gastric ulcer
perforation.
• 30%>grade 3
• 6.9% grade 5
• 7 patient’s death possibly
related to SBRT
• 50%/33.3% worsening of
CP score (CPA/CPB)
• 10.5/38%≥grade 3
hepatic toxicity (CPA/
CPB)
• 5.1% RILD
• 23/19.2%≥grade 3 GI
toxicity (acute/late)
• 65.4/69.2%≥grade 3
(acute/late)
• 34.6% worsening of CP
score≥2
of CP score
sion, a recent study by Lee and colleagues reported slightly
longer OS rate at oneyear of 56.5% and worsening of CP
sore by at least two points in only 17% of patients with CP
score B and C after treatment with SBRT.Of note, patients in
this cohort had less advanced disease compared to the cohort
reported by Culleton etal. (tumor diameter: 3.1 vs. 8.6cm;
portal vein thrombosis: 4.3% vs. 76%) [30].
18.3 Charged Particles Therapy
In recent years, charged particle therapy in form of Proton
Beam Therapy (PBT) and Carbon Ion Radiotherapy (CIRT)
has been developed into an exciting new treatment modality to overcome the limitations of photon-based radiotherapy in HCC.