Japanese Journal of Clinical Oncology, 2022, 52(7)779–784

[Link]
Advance Access Publication Date: 9 April 2022
Original Article

Original Article

Palliative radiotherapy for multiple liver

metastases: a retrospective analysis of 73 cases
Kei Ito *, Yumi Ogoshi and Takuya Shimizuguchi

Downloaded from [Link] by guest on 20 June 2025

Division of Radiation Oncology, Department of Radiology, Tokyo Metropolitan Cancer and Infectious Diseases
Center Komagome Hospital, Tokyo, Japan
*For reprints and all correspondence: Kei Ito, Division of Radiation Oncology, Department of Radiology, Tokyo Metropolitan
Cancer and Infectious Diseases Center Komagome Hospital, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo 113-8677, Japan.
E-mail: keiito@[Link]
Received 23 November 2021; Editorial Decision 14 March 2022; Accepted 19 March 2022

Abstract
Background: Whole-liver radiotherapy for diffuse liver metastases can improve symptoms and
abnormal liver-related blood data. However, whole-liver radiotherapy is uncommonly used in
clinical practice in Japan. Therefore, we aimed to clarify palliative radiotherapy outcomes in
Japanese patients with liver metastases.
Methods: We retrospectively reviewed databases in our institution to identify patients treated with
radiotherapy (8 Gy in a single fraction) for multiple liver metastases between December 2014 and
April 2021. The endpoints included pain response, liver-related blood data and adverse effects.
We investigated aspartate transaminase, alanine transaminase, lactate dehydrogenase, alkaline
phosphatase, γ -glutamyl transpeptidase and albumin. The mean values at whole-liver radiotherapy
and after 2–4 weeks were compared using the Wilcoxon rank-sum test.
Results: A total of 73 cases in 71 patients were included. The median clinical target volume was
2118 ml (range, 133–7867 ml). Fifty-seven patients (78%) had finished aggressive treatment at
the time of radiotherapy. The median follow-up period was 6 weeks. The pain response rate
was 64% (18/28). The mean values of five parameters significantly improved 2–4 weeks after
radiotherapy compared to those at baseline: aspartate transaminase (118 vs. 83 U/l P < 0.01);
alanine transaminase (84 vs. 61 U/l P < 0.01); lactate dehydrogenase (1351 vs. 1007 U/l P = 0.027);
alkaline phosphatase (1624 vs. 1216 U/l P < 0.01) and γ -glutamyl transpeptidase (663 vs. 450 U/l
P = 0.037). No patients experienced radiation-induced liver disease.
Conclusions: Palliative radiotherapy is efficient and safe in Japanese patients with liver metastases.
These findings will help encourage whole-liver radiotherapy use in Japan.

Key words: whole-liver radiotherapy, liver metastases, pain response, hepatic blood data, radiation-induced liver disease

Introduction Moreover, LM can cause hepatic dysfunction (6) and result in

The liver is one of the most common sites of metastasis (1), and liver liver failure, which is fatal (7). A few small case series suggest
metastases (LM) often cause symptoms such as pain, discomfort and improvements in hepatic blood data after WLRT (7,8). Therefore,
nausea (2,3). Several prospective clinical trials have demonstrated patients with diffuse LM can benefit from WLRT, which may prolong
that low-dose palliative radiotherapy for LM can relieve symptoms their survival. In addition, WLRT allows patients with liver dysfunc-
with relatively low levels of toxicity (2,4). Accordingly, a review tion who are unsuitable for chemotherapy to resume chemotherapy.
article has recommended low-dose whole-liver radiotherapy (WLRT) Although WLRT for diffuse LM has several advantages, as men-
for patients with symptomatic LM refractory to standard therapies tioned previously, this treatment is not generally performed in Japan,
(5). and the local guidelines on radiotherapy do not include palliative

© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: [Link]@[Link]. 779
780 Palliative RT for liver metastases

Evaluation and statistical analyses

The study endpoints were overall survival (OS), pain response,
hepatic blood data and adverse effects (AEs), including radiation-
induced liver disease (RILD). OS was defined as the interval between
the radiotherapy and the most recent follow-up or death from any
cause. Pain status at the LM sites was self-reported by the patients
and was measured using a numerical rating scale (NRS) of 0–10,
where 0 represented no pain and 10 represented extreme pain. The
worst score for the previous 3 days was recorded. Pain response was
determined according to the International Consensus on Palliative
Radiotherapy Endpoints guidelines, which evaluated pain according
to the pain scale and the amount of analgesic consumption (10).
Furthermore, this study investigated abnormal results from hepatic
blood tests at WLRT, particularly abnormal data that were iden-
tified in >30 cases. Six parameters met this criterion: aspartate

Downloaded from [Link] by guest on 20 June 2025

transaminase (AST), alanine transaminase (ALT), lactate dehydroge-
nase (LDH), alkaline phosphatase (ALP), γ -glutamyl transpeptidase
(GGT) and albumin.
The primary analysis compared the mean values at the initiation
of WLRT (baseline) and 2–4 weeks after WLRT to evaluate the
short-term effects of WLRT. A supplementary comparison between
Figure 1. Representative case of a 78-year-old man with diffuse liver metas- blood tests 2–4 weeks before WLRT and baseline was conducted
tasis from prostate cancer. (a) Computed tomography (CT) images with con- to evaluate disease worsening trends. RILD was defined as elevated
touring, including the clinical target volume (red, 2916 ml) and the planning transaminases of at least 5-fold the upper limit of normal or pre-
target volume (green), for whole-liver radiotherapy. (b) CT images with dose
treatment levels without any documented progressive disease (11).
distribution of whole-liver radiotherapy. The dose distribution heterogeneity
was allowed.
Other AEs were evaluated according to the National Cancer Institute
Common Terminology Criteria for Adverse Events (NCI-CTCAE)
version 5 (12).
OS was estimated using the Kaplan–Meier method. The Wilcoxon
WLRT (9). We have conducted the WLRT of 8 Gy in a single fraction
rank-sum test was used to compare the mean values, and results were
based on a Phase II trial (4). Thus, this study aimed to clarify the
considered significant at P values <0.05. All statistical analyses were
efficacy and safety of palliative radiotherapy in Japanese patients
performed using EZR software, version 1.54 (13).
with multiple LM.

Materials and methods Results

Patients and data acquisition Patient and tumor characteristics
We retrospectively reviewed databases of Tokyo Metropolitan Can- A total of 73 LM cases in 71 Japanese patients were included in this
cer and Infectious Diseases Center Komagome Hospital (Tokyo, study (Table 1). The median CTV was 2118 ml (range, 133–7867 ml)
Japan) to identify patients with LM treated with palliative radiother- and 100% (range, 16.3–100%) of the total liver volume. The CTV
apy between December 2014 and April 2021. Palliative radiotherapy of 44 lesions was the whole liver. The Child–Pugh classification
was performed for patients with any symptoms of LM or abnormal was class A in 26 cases, B in 41 and C in 6. Index symptoms that
values of hepatic blood test. No contraindications for WLRT based triggered irradiation were abdominal pain in 49 (67%) cases, and
on performance status, expected survival time, hepatic function or other symptoms in 19 (26%) cases (the detail of other symptoms are
blood tests were documented. shown in Table 2). Fifty-seven (78%) cases were not scheduled to
This study was approved by our institutional ethical review board receive any further courses of systemic therapy at the time of WLRT.
(approval number, 2083). Written informed consent was obtained The mean NRS at WLRT was 6.82 (range, 3–10), and the daily oral
from all patients. morphine equivalent (OME) consumption was 48.75 mg (range, 0–
420 mg).

Whole-liver radiotherapy
Radiotherapy was planned based on free-breathing computed Clinical outcomes
tomography (CT) scans. Gross tumor volume was not determined. The median follow-up after radiotherapy was 6 weeks (range, 0–
The clinical target volume (CTV) was defined as the liver segments, 39 weeks). The 1-month OS rate was 61.8%, and the median survival
including the tumor contributing to symptoms, and generally time was 7 weeks for the entire cohort. Among 49 cases with painful
encompassed the majority or entirety of the liver. The planning metastases at baseline, 28 cases were evaluable after 1 month (death
target volume (PTV) margins were 5–10 mm to accommodate organ in 12 patients, lost to follow-up in 2 cases and undocumented
motion and setup errors (Fig. 1a). The prescribed dose was 8 Gy in NRS values in 7 cases rendered those cases unevaluable). The mean
a single fraction, delivered using the conventional technique of two change in NRS and daily OME consumption from baseline was −5
to four ports, and the planning goal was 95% of the PTV to receive [standard deviation (SD), 2.2] and + 9.6 mg (SD, 31.78 mg), respec-
a minimum of 7 Gy (Fig. 1b). tively. The complete response, partial response, pain progression and
 Jpn J Clin Oncol, 2022, Vol. 52, No. 7 781

Table 1. Patient and treatment characteristics

Characteristics 73 Cases in 71 patients

Sex
Male/Female 39/32
Mean/Median age (years) (range) 62.6/63 (28–83)
ECOG PS
0–1/2/3/4/unknown 24/17/22/9/1
Primary malignancy
Lung 18 (25%)
Colorectal 9 (12%)
Breast 7 (10%)
Esophagus 7 (10%)
Thymus 6 (8%)
Prostate 5 (7%)

Downloaded from [Link] by guest on 20 June 2025

Other 21 (29%)
Clinical target volume
Mean/Median (range) 2262 ml/2118 ml (133–7867 ml)
Child-Pugh class
A/B/C 26 (36%)/41 (56%)/6 (8%)
Index symptom that triggered irradiation
Pain 49
Other symptoms 19
None (abnormal blood data) 5
Systemic therapy at WLRT
Before the start 1
Ongoing 14
After the end (supportive care) 57
Unknown 1
Abnormal value of each inspection item
AST/ALT/LDH 57/39/68
ALP/GGT/Bilirubin 63/42/19
Albumin/PT/Cholesterol 61/11/4

Abbreviations: ALP, alkaline phosphatase; ALT, alanine transaminase; AST, aspartate transaminase; ECOG, Eastern Cooperative Oncology Group; GGT, γ -
glutamyl transpeptidase; LDH, lactate dehydrogenase; PS, performance status; PT, prothrombin time; WLRT, whole-liver radiotherapy.

Table 2. Liver metastases-related symptoms and the response to radiotherapy

Symptoms Cases Improved Not improved Unevaluable

Abdominal pain 49 18 10 21
Abdominal discomfort 17 4 3 10
Leg edema 9 6 1 2
Anorexia 6 1 1 4
Nausea 3 0 1 2
Jaundice 3 1 2 0
Dyspnea 3 1 0 2
Malaise 2 1 1 0
Ascites 1 0 0 1

indeterminate response at 4 weeks were observed in 7, 11, 0 and upon comparisons of the mean values at 2–4 weeks before WLRT
10 lesions, respectively, resulting in pain response of 64%. Among with the values at the baseline (P < 0.01 for all parameters). The
18 cases with pain response, pain re-progression was confirmed in mean values for all parameters except albumin showed significant
two cases (the two cases then received a second course of WLRT). improvement between baseline and 2–4 weeks after WLRT: AST
Pain response rates at 8 and 12 weeks were 90% (9 of 10 cases) and (118 U/l vs. 83 U/l, P < 0.01); ALT (84 U/l vs. 61 U/l, P < 0.01);
86% (6 of 7 cases), respectively. The details of other symptoms than LDH (1351 U/l vs. 1007 U/l, P = 0.027); ALP (1624 U/l vs. 1216 U/l,
abdominal pain are summarized in Table 2. P < 0.01) and GGT (663 vs. 450, P < 0.01; Fig. 2). The mean
The number of cases with abnormal values at the time of WLRT albumin concentration continued to deteriorate from 2.7 g/dl at
for AST, ALT, LDH, ALP, GGT and albumin was 57, 39, 68, 63, baseline to 2.4 g/dl at 2–4 weeks after WLRT. In a comparison of
42 and 61, respectively. All six parameters showed worsening trends values at 2–4 weeks after radiotherapy with the baseline values, there
782 Palliative RT for liver metastases

Table 3. Adverse effects

Grade 2 Grade 3 Grades 4–5

Nausea 4 0 0
Malaise 2 0 0
Tumor lysis syndrome NA 3 0

Abbreviations: NA, not applicable.

Table 4. WLRT literature review

N Lesions Child–Pugh Prescribed Symptom or Hepatic blood Severe

classification dose pain palliation data toxicity

Bydder et al. (2) 28 LM NA 10 Gy/2 fx 65% NA 7%

Yeo et al. (8) 10 LM from B = 8, C = 2 21 Gy/7 fx 100% Improvement in 0

Downloaded from [Link] by guest on 20 June 2025

CRC AST, ALP, and TB
Soliman et al. (4) 41 HCC and LM A = 34, B = 7 8 Gy/1 fx 48% NA 2%
Edyta et al. (14) 27 LM NA 18 Gy/10 fx 100% NA 3%
Yeung et al. (15) 52 HCC A = 32, 8 Gy/1 fx 52% NA 4%
B = 20
Present study 73 LM A = 26, 8 Gy/1 fx 64% Improvement in 4%
B = 41, C = 6 AST, ALT, LDH,
ALP, and GGT

Abbreviations: ALP, alkaline phosphatase; ALT, alanine transaminase; AST, aspartate transaminase; CRC, colorectal cancer; GGT, γ -glutamyl transpeptidase;
HCC, hepatocellular carcinoma; LDH, lactate dehydrogenase; LM, liver metastases; NA, not applicable; RILD, radiation-induced liver disease; TB, total
bilirubin.

were 13, 18, 6, 12 and 8 cases that showed a major improvement (≤ The use of WLRT in the treatment of LM is not popular in Japan’s
−50%) in AST levels, an improvement (> −50, ≤ −10%) in AST clinical practice (9). In this study, we have outlined several advantages
levels, no change (> −10%, < +10%) in AST levels, worsening (≥ of WLRT. First, WLRT was effective and less toxic. Previous studies,
+10%) levels of AST and unevaluable levels of AST, respectively including the current study, have reported reproducible results, with
(overall improvement: 54%); 14, 10, 3, 4 and 8 cases, respectively, a pain response rate of >60% and low toxicity (Table 4). In addition,
for ALT (overall improvement: 62%); 9, 28, 6, 15 and 10 cases, the results of this study suggest that WLRT may be effective even for
respectively, for LDH (overall improvement: 54%); 5, 30, 9, 11 and end-of-life care (78% of patients in this study had completed active
8 cases for ALP (overall improvement: 56%) and 5, 11, 5, 5 and 16 cancer treatment). Second, single fractionation does not significantly
cases, respectively, for GGT (overall improvement: 38%). In addition, increase the patients’ medical burden, as they only have to visit a hos-
8 cases showed an improvement (≥ +10%) in albumin levels, 20 pital once for treatment. Third, WLRT is a versatile approach, and it
cases showed no change (< +10%, > −10%,) in albumin levels, 22 can be performed using the conventional radiotherapy technique.
cases showed worsening (≤ − 10%) albumin levels and 11 cases were Various studies have reported that radiation decreases metabolic
unevaluable for albumin levels (overall improvement: 13%). liver function (16,17); however, the results of the present study have
None of the patients experienced RILD. Pain flare was observed proven otherwise. The risk of RILD is especially high in patients with
in five cases; however, pain flare was not included in the NCI- low hepatic function (16). In the present study, >60% of the included
CTCAE. Acute Grade 2 nausea and malaise were confirmed in patients had Child–Pugh B or C. One of the reasons for the absence
four and two cases, respectively (Table 3). NCI-CTCAE defined the of RILD and other severe AEs may be the low prescribed dose at
occurrence of tumor lysis syndrome as Grade 3 or more. Although 8 Gy. Especially for patients classified as Child–Pugh C, the number
Grade 3 tumor lysis syndrome was observed in three cases, all cases of reports on WLRT was extremely small (Table 4). In our study,
improved with conservative treatment. No other Grade 2 or greater WLRT of 8 Gy did not cause severe AEs in Child–Pugh C patients.
toxicity was observed. The six patients classified as Child–Pugh C did Although we consider that WLRT for Child–Pugh C patients with
not experience severe AEs (Grade 2 nausea and tumor lysis syndrome LM is not contraindicated, the safety of this approach should be
in each patient), with a median follow-up of 3 weeks (range, 0– investigated in future research.
7 weeks). Two patients irradiated to the whole liver twice did not Several prospective clinical trials have demonstrated the palliative
experience severe AEs (Grade 1 nausea in one patient). efficacy of WLRT for LM (2,4). However, whether this treatment
provides any survival advantage remains unknown. Furthermore,
the effects of WLRT on hepatic blood tests and liver function have
Discussion not yet been identified. Our findings demonstrated a significant
This retrospective case series demonstrated that palliative radio- improvement in several liver enzymes and related factors by WLRT.
therapy at a dose of 8 Gy could provide pain palliation with few Theoretically, the improvement in blood test results could have
toxicities in Japanese patients with multiple LM. In addition, liver contributed to an improved liver function and subsequent prolon-
radiotherapy achieved significant improvement in several hepatic gation of survival. Moreover, WLRT may provide additional sur-
blood tests showing exacerbation trends before radiotherapy. vival benefits from resuming chemotherapy. Although the standard
 Jpn J Clin Oncol, 2022, Vol. 52, No. 7 783

Downloaded from [Link] by guest on 20 June 2025

Figure 2. Box plots showing concentrations of (a) AST, (b) ALT, (c) LDH, (d) ALP and (e) GGT. The horizontal line within the box indicates the median, and ‘+’ in
the box indicates the mean. These figures show an inverted V-shaped recovery. (Abbreviations: AST, aspartate transaminase; ALT, alanine transaminase; LDH,
lactate dehydrogenase; ALP, alkaline phosphatase; GGT, γ -glutamyl transpeptidase).

treatment for LM cases is systemic therapy, it is occasionally difficult increase in the analgesic dose brought by other painful lesions.
to administer chemotherapy, such as platinum, antipyrimidine, tax- Second, we only showed hepatic blood tests improvements. These
anes and topoisomerase inhibitors, due to hepatic dysfunction caused results alone do not confirm any positive effect of WLRT on the
by LM. A retrospective report on WLRT for diffuse LM and severe hepatic function or survival time. Third, the follow-up duration was
hepatic dysfunction suggested that patients who were able to resume short (median, 6 weeks; range, 0–39 weeks). The occurrence rate of
chemotherapy after WLRT had a longer OS than those who could not AEs observed in our study may have been underestimated. However,
(8). Thus, WLRT may be a crucial approach not only for improving in clinical practice, patients with diffuse LM have extremely short
symptoms but also for prolonging OS. life expectancies; thus, these data would be useful in the real world.
This study had a few limitations. First, several pain cases could Fourth, quality of life was not measured as an endpoint because of
not be evaluated due to death, non-compliance to follow-up, undoc- the retrospective nature of the study. Ideally, the endpoint should be
umented NRS values and indeterminate response because of the quality of life, since this treatment is classified as palliative therapy.
784 Palliative RT for liver metastases

To clarify the impact on the quality of life, the results of a prospective of capecitabine and its metabolites. Clin Cancer Res 1999;5:
randomized controlled trial conducted by the Canadian Cancer Trials 1696–702.
Group are awaited (NCT02511522). 7. Ito K, Osawa Y, Shimizuguchi T, Ogawa H, Nihei K, Karasawa K. Whole-
In conclusion, this is the first study to investigate the efficacy and liver radiotherapy for diffuse liver metastases improves liver enzymes and
related factors. Acta Oncol 2019;58:512–4.
safety of palliative radiotherapy in Japanese patients with multiple
8. Yeo SG, Kim DY, Kim TH, Kim SY, Hong YS, Jung KH. Whole-liver
LM. This study demonstrated that liver radiotherapy at 8 Gy can
radiotherapy for end-stage colorectal cancer patients with massive liver
relieve pain and improve hepatic blood data with less toxic side metastases and advanced hepatic dysfunction. Radiat Oncol 2010;5:
effects. We believe that these findings will help encourage the use 97.
of WLRT in Japan in the future. 9. Japanese Society for Radiation Oncology. JASTRO Guidelines 2020 for
Radiotherapy Treatment Planning. Japan: Kanehara, 2020.
10. Chow E, Hoskin P, Mitera G, et al. Update of the international consensus
Funding on palliative radiotherapy endpoints for future clinical trials in bone
None declared. metastases. Pract Radiat Oncol 2012;82:1730–7.
11. Cheng JC, Wu JK, Huang CM, et al. Radiation-induced liver disease
after radiotherapy for hepatocellular carcinoma: clinical manifestation
Conflicts of interest and dosimetric description. Radiother Oncol 2002;63:41–5.

Downloaded from [Link] by guest on 20 June 2025

The authors declare no conflict of interest. 12. Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0.
Available via DIALOG. [Link]
lectronic_applications/docs/CTCAE_v5_Quick_Reference_5x7.pdf. (21
References November 2021, date last accessed).
1. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA 13. Kanda Y. Investigation of the freely available easy-to-use software “EZR”
Cancer J Clin 2005;55:74–108. for medical statistics. Bone Marrow Transplant 2013;48:452–8.
2. Bydder S, Spry NA, Christie DR, et al. A prospective trial of short- 14. Edyta WR, Jakub L, Jerzy W. Whole liver palliative radiotherapy
fractionation radiotherapy for the palliation of LM. Australas Radiol for patients with massive liver metastases. Asian Pac J Cancer Prev
2003;47:284–8. 2015;16:6381–4.
3. Borgelt BB, Gelber R, Brady LW, Griffin T, Hendrickson FR. The palliation 15. Yeung CSY, Chiang CL, Wong NSM, et al. Palliative Liver Radiother-
of hepatic metastases: results of the Radiation Therapy Oncology Group apy (RT) for symptomatic hepatocellular carcinoma (HCC). Sci Rep
pilot study. Int J Radiat Oncol Biol Phys 1981;7:587–91. 2020;10:1254.
4. Soliman H, Ringash J, Jiang H, et al. Phase II trial of palliative radio- 16. Xu ZY, Liang SX, Zhu J, et al. Prediction of radiation-induced liver
therapy for hepatocellular carcinoma and liver metastases. J Clin Oncol disease by Lyman normal-tissue complication probability model in three-
2013;31:3980–6. dimensional conformal radiation therapy for primary liver carcinoma. Int
5. Høyer M, Swaminath A, Bydder S, et al. Radiotherapy for liver metastases: J Radiat Oncol Biol Phys 2006;65:189–95.
a review of evidence. Int J Radiat Oncol Biol Phys 2012;82:1047–57. 17. Dawson LA, Normolle D, Balter JM, McGinn CJ, Lawrence TS, Haken
6. Twelves C, Glynne-Jones R, Cassidy J, et al. Effect of hepatic RKT. Analysis of radiation-induced liver disease using the Lyman NTCP
dysfunction due to liver metastases on the pharmacokinetics model. Int J Radiat Oncol Biol Phys 2002;53:810–21.