Evaluation of Liver Function After Proton Beam Therapy for Hepatocellular Carcinoma

doi:10.1016/j.ijrobp.2011.05.056

International Journal of Radiation OncologyBiologyPhysics

Volume 82, Issue 3, 1 March 2012, Pages e529-e535

, , , , , , , , , , , , , , , ,

https://doi.org/10.1016/j.ijrobp.2011.05.056 Get rights and content

Purpose

Our previous results for treatment of hepatocellular carcinoma with proton beam therapy (PBT) revealed excellent local control. In this study, we focused on the impact of PBT on normal liver function.

Methods and Materials

The subjects were 259 patients treated with PBT at the University of Tsukuba between January 2001 and December 2007. We evaluated the Child–Pugh score pretreatment, on the final day of PBT, and 6, 12, and 24 months after treatment with PBT. Patients who had disease progression or who died with tumor progression at each evaluation point were excluded from the analysis to rule out an effect of tumor progression. An increase in the Child–Pugh score of 1 or more was defined as an adverse event.

Results

Of the 259 patients, 241 had no disease progression on the final day of PBT, and 91 had no progression within 12 months after PBT. In univariate analysis, the percentage volumes of normal liver receiving at least 0, 10, 20, and 30 GyE in PBT (V0, 10, 20, and 30) were significantly associated with an increase of Child–Pugh score at 12 months after PBT. Of the 91 patients evaluated at 12 months, 66 had no increase of Child–Pugh score, 15 had a 1-point increase, and 10 had an increase of ≥2 points. For the Youden index, the optimal cut-offs for V0, V10, V20, and V30 were 30%, 20%, 26%, and 18%, respectively.

Conclusion

Our findings indicate that liver function after PBT is significantly related to the percentage volume of normal liver that is not irradiated. This suggests that further study of the relationship between liver function and PBT is required.

Introduction

Hepatocellular carcinoma (HCC) is a common malignancy 1, 2 that is treated curatively with surgery, radiofrequency ablation and liver transplantation. Transarterial chemoembolization and systemic therapy may be used in cases in which these curative treatments are not suitable 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16. Curative treatment is normally selected as the initial treatment, but is limited by the size, number of tumors, and residual liver function. Radiotherapy is used for the treatment of HCC, but the radiation dose is often insufficient to achieve good local control compared with other curative treatment 17, 18, 19, 20. We previously showed that proton beam therapy (PBT) for HCC can achieve good local control without severe late toxicity 21, 22, 23, 24. PBT may also extend treatment to cases of HCC with large tumors, tumor thrombi, and poor liver function 25, 26, 27, 28, 29, 30, 31. The 5-year local control rate after PBT is 80% to 90% 32, 38, but the adverse effects of PBT on normal liver function remain unknown. Therefore, in the current study, we focused on the impact of PBT on normal liver function.

Section snippets

Patients

From September 2001 to November 2007, a total of 266 patients with HCC who met the following criteria underwent PBT at our center (the Proton Medical Research Center): no active tumors outside the target volume; a performance status (PS) ≤2; hepatic function levels characterized by a Child–Pugh score ≤10; no extrahepatic metastasis; white blood cell count ≥1,000/mm³, hemoglobin level ≥6.5 g/dl, and platelet count ≥25,000/mm³; and no uncontrolled ascites. Written informed consent was obtained

Changes in Child–Pugh score

A total of 241 of the 259 patients had no disease progression on the final day of PBT, and 150, 91, and 49 patients had no progression at 6, 12, and 24 months after PBT, respectively. On the final day of PBT, the Child–Pugh score increased by 0, 1, and 2 in 196, 44, and 1 of the 241 patients included in the analysis. At 6 months (150 patients), increases in the Child–Pugh score of 0, 1, and ≥2 occurred in 120, 17, and 13 patients, respectively. At 12 months (91 patients), increases of 0, 1 and

Discussion

The BED of proton beam therapy is considered to be approximately 1.1. Therefore, the treatment effect of PBT and photon radiotherapy is almost equal if the irradiated dose is similar. However, PBT has excellent dose concentration, and this facilitates irradiation at a higher dose compared with conventional radiotherapy, with tolerable late toxicity 38, 39, 40. We have previously shown that PBT of 77 GyE in 35 fractions, 72.6 GyE in 22 fractions, and 66 GyE in 10 fractions for HCC achieves good

Conclusion

In conclusion, our findings indicate that liver function after PBT is significantly associated with the percentage volume of normal liver that is not irradiated in PBT. The relationship between posttreatment liver function and PBT requires further investigation.

Acknowledgment

Supported in part by a Grant-in-Aid for Young Scientists (B) from the Ministry of Education, Culture, Sports, Science and Technology of the Japanese Government.

References (44)

S. Arii et al.
Results of surgical and nonsurgical treatment for small-sized hepatocellular carcinomas: A retrospective and nationwide survey in Japan. The Liver Cancer Study Group of Japan
Hepatology
(2000)
I. Ikai et al.
Report of the 15th follow-up survey of primary liver cancer
Hepatol Res
(2004)
K. Takayasu et al.
Prospective cohort study of transarterial chemoembolization for unresectable hepatocellular carcinoma in 8510 patients
Gastroenterology
(2006)
J.E. Koo et al.
Combination of transarterial chemoembolization and three-dimensional conformal radiotherapy for hepatocellular carcinoma with inferior vena cava tumor thrombus
Int J Radiat Oncol Biol Phys
(2010)
S. Shirai et al.
Feasibility and efficacy of single photon emission computed tomography-based three-dimensional conformal radiotherapy for hepatocellular carcinoma 8 cm or more with portal vein tumor thrombus in combination with transcatheter arterial chemoembolization
Int J Radiat Oncol Biol Phys
(2010)
N. Fukumitsu et al.
A prospective study of hypofractionated proton beam therapy for patients with hepatocellular carcinoma
Int J Radiat Oncol Biol Phys
(2009)
M. Mizumoto et al.
Proton beam therapy for hepatocellular carcinoma: A comparison of three treatment protocols
Int J Radiat Oncol Biol Phys
(2011)
M. Hata et al.
Proton beam therapy for aged patients with hepatocellular carcinoma
Int J Radiat Oncol Biol Phys
(2007)
M. Mizumoto et al.
Proton beam therapy for hepatocellular carcinoma adjacent to the porta hepatis
Int J Radiat Oncol Biol Phys
(2008)
S. Sugahara et al.
Proton beam therapy for large hepatocellular carcinoma
Int J Radiat Oncol Biol Phys
(2010)

H. Tsujii et al.

Clinical results of fractionated proton therapy

Int J Radiat Oncol Biol Phys

(1993)

K. Ohara et al.

Irradiation synchronized with respiration gate

Int J Radiat Oncol Biol Phys

(1989)

Y. Tsunashima et al.

Correlation between the respiratory waveform measured using a respiratory sensor and 3D tumor motion in gated radiotherapy

Int J Radiat Oncol Biol Phys

(2004)

H. Paganetti et al.

Relative biological effectiveness (RBE) values for proton beam therapy

Int J Radiat Oncol Biol Phys

(2002)

M. Mizumoto et al.

Phase I/II trial of hyperfractionated concomitant boost proton radiotherapy for supratentorial glioblastoma multiforme

Int J Radiat Oncol Biol Phys

(2010)

S. Sugahara et al.

Clinical results of proton beam therapy for cancer of the esophagus

Int J Radiat Oncol Biol Phys

(2005)

G. Fattovich et al.

Morbidity and mortality in compensated cirrhosis type C: A retrospective follow-up study of 384 patients

Gastroenterology

(1997)

K. Tanaka et al.

Hepatitis C and hepatitis B in the etiology of hepatocellular carcinoma in the Japanese population

Cancer Res

(1991)

Cancer incidence and incidence rates in Japan in 1995: Estimates based on data from nine population-based cancer registries

Jpn J Clin Oncol

(2000)

M.S. Chen et al.

A prospective randomized trial comparing percutaneous local ablative therapy and partial hepatectomy for small hepatocellular carcinoma

Ann Surg

(2006)

G.T. Huang et al.

Percutaneous ethanol injection versus surgical resection for the treatment of small hepatocellular carcinoma: A prospective study

Ann Surg

(2005)

R.A. Lencioni et al.

Small hepatocellular carcinoma in cirrhosis: Randomized comparison of radio-frequency thermal ablation versus percutaneous ethanol injection

Radiology

(2003)

Cited by (53)

Clinical and Dosimetric Results of Proton or Photon Radiation Therapy for Large (>5 cm) Hepatocellular Carcinoma: A Retrospective Analysis
2024, International Journal of Radiation Oncology Biology Physics
Our purpose was to report the clinical and dosimetric attributes of patients with large unresectable hepatocellular carcinoma (HCC) undergoing proton or photon radiation therapy.
We retrospectively analyzed the outcomes and dosimetric indices of 159 patients with >5 cm nonmetastatic HCC who underwent definitive radiation therapy using either protons (N = 105) or photons (N = 54) between 2014 and 2018. Additional photon plans were performed in the 105 proton-treated patients using the same dose prescription criteria for intragroup dosimetric comparison.
After a median follow-up of 47 months, patients with biologically effective dose (BED10) ≥ 75 Gy exhibited significantly better local control (LC; 2-year: 85.6% vs 20.5%; P < .001), progression-free survival (PFS; median, 7.4 vs 3.2 months; P < .001), and overall survival (OS; median, 18.1 vs 7.3 months; P < .001) compared with those with BED10 < 75 Gy. Notably, proton-treated patients had a significantly higher BED10 (96 vs 67 Gy; P < .001) and improved LC (2-year: 88.5% vs 33.8%; P < .001), PFS (median, 7.4 vs 3.3 months; P = .001), and OS (median, 18.9 vs 8.3 months; P < .001) than those undergoing photon radiation therapy. Furthermore, patients treated with protons had significantly lower V1 of the liver (P < .001), mean upper gastrointestinal tract dose (P < .001), and mean splenic dose (P < .001), with significantly decreased incidences of radiation-induced liver disease (P = .007), grade ≥3 upper gastrointestinal bleeding (P = .001), and grade ≥3 lymphopenia (P = .003). On multivariate analysis, proton radiation therapy consistently correlated with superior LC (P < .001), PFS (P < .001), and OS (P < .001). In intragroup dosimetric comparison, photon plans demonstrated significantly higher mean liver dose (P < .001) compared with actually delivered proton treatments, and 72 (69%) of them had mean liver dose exceeding 28 Gy, which necessitated target dose de-escalation.
In the context of large HCC radiation therapy, a higher target BED10 was associated with improved outcomes. Notably, proton therapy has demonstrated the capability to deliver ablative doses while also being accompanied by fewer instances of severe toxicity.
Proton Beam Therapy for Hepatocellular Carcinoma: Multicenter Prospective Registry Study in Japan
2024, International Journal of Radiation Oncology Biology Physics
A prospective multicenter registry study was started May 2016 in Japan to evaluate the efficacy and safety of proton beam therapy (PBT) for hepatocellular carcinoma (HCC).
Patients who received PBT for HCC from May 2016 to June 2018 were registered in the database of the Particle Beam Therapy Committee and Subcommittee of the Japanese Society for Radiation Oncology. Overall survival (OS), progression-free survival (PFS), and local recurrence were evaluated.
Of the 755 registered patients, 576 with initial PBT and no duplicate cancer were evaluated. At final follow-up, 322 patients were alive and 254 had died. The median follow-up period for survivors was 39 months (0-58 months). The median OS time of the 576 patients was 48.8 months (95% CI, 42.0-55.6 months) and the 1-, 2-, 3-, and 4-year OS rates were 83.8% (95% CI, 80.5%-86.6%), 68.5% (64.5%-72.2%), 58.2% (53.9%-62.2%), and 50.1% (44.9%-55.0%), respectively. Recurrence was observed in 332 patients, including local recurrence in 45 patients. The median PFS time was 14.7 months (95% CI, 12.4-17.0 months) and the 1-, 2-, 3-, and 4-year PFS rates were 55.2% (95% CI, 51.0%-59.2%), 37.5% (33.5%-41.5%), 30.2% (26.3%-34.2%), and 22.8% (18.5%-27.4%), respectively. The 1-, 2-, 3-, and 4-year OS rates were significantly higher for tumor size <5 versus 5 to 10 cm (P < .001) and <5 versus ≥10 cm (P < .001); Child-Pugh score A/B versus C (P < .001); and distance of the tumor from the gastrointestinal tract <1 versus 1 to 2 cm (P < .008) and <1 versus >2 cm (P < .001). At final follow-up, 27 patients (4.7%) had late adverse events of grade 3 or higher, with liver failure (n = 7), and dermatitis (n = 7) being most common.
This multicenter prospective data registry indicated that PBT for HCC gives good therapeutic effects (3-year local control rate of 90%) with a low risk of severe late adverse events.
The American Brachytherapy Society consensus statement for permanent implant brachytherapy using Yttrium-90 microsphere radioembolization for liver tumors
2022, Brachytherapy
To develop a multidisciplinary consensus for high quality multidisciplinary implementation of brachytherapy using Yttrium-90 (⁹⁰Y) microspheres transarterial radioembolization (⁹⁰Y TARE) for primary and metastatic cancers in the liver.
Members of the American Brachytherapy Society (ABS) and colleagues with multidisciplinary expertise in liver tumor therapy formulated guidelines for ⁹⁰Y TARE for unresectable primary liver malignancies and unresectable metastatic cancer to the liver. The consensus is provided on the most recent literature and clinical experience.
The ABS strongly recommends the use of ⁹⁰Y microsphere brachytherapy for the definitive/palliative treatment of unresectable liver cancer when recommended by the multidisciplinary team. A quality management program must be implemented at the start of ⁹⁰Y TARE program development and follow-up data should be tracked for efficacy and toxicity. Patient-specific dosimetry optimized for treatment intent is recommended when conducting ⁹⁰Y TARE. Implementation in patients on systemic therapy should account for factors that may enhance treatment related toxicity without delaying treatment inappropriately. Further management and salvage therapy options including retreatment with ⁹⁰Y TARE should be carefully considered.
ABS consensus for implementing a safe ⁹⁰Y TARE program for liver cancer in the multidisciplinary setting is presented. It builds on previous guidelines to include recommendations for appropriate implementation based on current literature and practices in experienced centers. Practitioners and cooperative groups are encouraged to use this document as a guide to formulate their clinical practices and to adopt the most recent dose reporting policies that are critical for a unified outcome analysis of future effectiveness studies.
Proton beam therapy for a giant hepatic hemangioma: A case report and literature review
2021, Clinical and Translational Radiation Oncology
Hepatic hemangiomas are benign tumors with a favorable prognosis, but giant hepatic hemangiomas can cause abdominal symptoms and are indicated for treatment. Most cases are treated with surgery, but radiotherapy has also been used. However, to date, there have been no reports of proton beam therapy for a hepatic hemangioma.
A 46-year-old woman had a tumor of 80 × 80 mm in the left medial lobe of the liver, which was diagnosed as a giant hemangioma based on the contrast pattern. Therapy was required for a giant hepatic hemangioma with symptoms, but the patient refused blood transfusion due to religious reasons, which made surgical resection difficult. Therefore, she was referred to our hospital for proton beam therapy. At her first visit, liver function was Child-Pugh A (5 points) and there was no elevation of tumor markers. Proton beam therapy of 28.6 Gy (RBE) given in 13 fractions was performed without interruption. The only observed acute radiation toxicity was Grade 1 dermatitis. One year after proton beam therapy, the hemangioma had significantly decreased, and a complete response has been maintained for 15 years based on ultrasound and MRI.
This case is the first reported use of proton beam therapy for a hepatic hemangioma. The outcome suggests that this treatment may be effective for a giant liver hemangioma.
Four-dimensional carbon-ion pencil beam treatment planning comparison between robust optimization and range-adapted internal target volume for respiratory-gated liver and lung treatment
2020, Physica Medica
We investigated the dose differences between robust optimization-based treatment planning (4DRO) and range-adapted internal target volume (rITV). We used 4DCT dataset of 20 lung cancer and 20 liver cancer patients, respectively, who had been treated with respiratory-gated carbon-ion pencil beam scanning therapy. 4DRO and rITV plans were created with the same clinical target volume (CTV) and organs at risk (OAR) contours. Four-dimensional dose distribution was calculated using deformable image registration. Dose metrics (e.g. D95, V20) were analyzed. Statistical significance was assessed by the Wilcoxon signed-rank test. For the lung cases, the mean CTV-D95 value for the rITV plan (=98.5%) was same as that for the 4DRO plan (=98.5%, P = 0.106), while the mean D95 value for the CTV + setup margin contour for the rITV plan (=98.2%) was higher than that for the 4DRO plan (95.2%, P < 0.001). For the liver cases, the mean CTV-D95 value for the rITV plan (=98.1%) was slightly lower than that for the 4DRO plan (=98.5%, P < 0.01), while the mean D95 value for the CTV + setup margin contour for the rITV plan (=98.0%) was higher than that for the 4DRO plan (94.1%, P < 0.001). For the doses to the organs at risk (OARs), the ipsilateral lung-V20/liver-V20 values for the rITV plan (=10.1%/19.7%) was significantly higher than that for the 4DRO plan (=8.6%/17.6, P < 0.001). Although the target coverage for 4DRO plan may be worse than that for rITV plan in the presence of the setup error, the 4DRO plan can improve OAR dose while preserving acceptable target dose coverage.
Dosimetric Analysis and Normal-Tissue Complication Probability Modeling of Child-Pugh Score and Albumin-Bilirubin Grade Increase After Hepatic Irradiation
2020, International Journal of Radiation Oncology Biology Physics
This study aimed to develop robust normal-tissue complication probability (NTCP) models for patients with hepatocellular carcinoma treated with radiation therapy (RT) using Child-Pugh (CP) score and albumin-bilirubin (ALBI) grade increase as endpoints for hepatic toxicity.
Data from 108 patients with hepatocellular carcinoma treated with RT between 2008 and 2017 were evaluated, of which 47 patients (44%) were treated with proton RT. Of these patients, 29 received stereotactic body RT and 79 moderately hypofractionated RT to median physical tumor doses of 43 Gy in 5 fractions and 59 Gy in 15 fractions, respectively. A generalized Lyman-Kutcher-Berman (LKB) model was used to model the NTCP using 2 clinical endpoints, both evaluated at 3 months after RT: CP score increase of ≥2 and ALBI grade increase of ≥1 from the pre-RT baseline. Confidence intervals on LKB fit parameters were determined using bootstrap resampling.
Compared with previous NTCP models, this study found a stronger correlation between normal liver volume receiving low doses of radiation (5-10 Gy) and a CP score or ALBI grade increase. A CP score increase exhibited a stronger correlation to normal liver volumes irradiated than an ALBI grade increase. LKB models for CP increase found values for the volume-effect parameter of a = 0.06 for all patients, and a = 0.02/0.09 when fit to photon/proton patients separately. Subset analyses for patients with superior initial liver functions showed consistent dose–volume effects (a = 0.1) and consistent dose-response relationships.
This study presents an update of liver NTCP models in the era of modern RT techniques using relevant endpoints of hepatic toxicity, CP score and ALBI grade increase. The results show a stronger influence of low-dose bath on hepatic toxicity than those found in previous studies, indicating that RT techniques that minimize the low-dose bath may be beneficial for patients.

View all citing articles on Scopus

: Conflict of interest: none.

View full text

Clinical InvestigationEvaluation of Liver Function After Proton Beam Therapy for Hepatocellular Carcinoma

Purpose

Methods and Materials

Results

Conclusion

Introduction

Section snippets

Patients

Changes in Child–Pugh score

Discussion

Conclusion

Acknowledgment

Hepatology

Hepatol Res

Gastroenterology

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Gastroenterology

Hepatitis C and hepatitis B in the etiology of hepatocellular carcinoma in the Japanese population

Cancer Res

Cancer incidence and incidence rates in Japan in 1995: Estimates based on data from nine population-based cancer registries

Jpn J Clin Oncol

A prospective randomized trial comparing percutaneous local ablative therapy and partial hepatectomy for small hepatocellular carcinoma

Ann Surg

Percutaneous ethanol injection versus surgical resection for the treatment of small hepatocellular carcinoma: A prospective study

Ann Surg

Small hepatocellular carcinoma in cirrhosis: Randomized comparison of radio-frequency thermal ablation versus percutaneous ethanol injection

Radiology

Clinical Investigation
Evaluation of Liver Function After Proton Beam Therapy for Hepatocellular Carcinoma