Analysis of radiation-induced liver disease using the Lyman NTCP model

doi:10.1016/S0360-3016(02)02846-8

International Journal of Radiation OncologyBiologyPhysics

Volume 53, Issue 4, 15 July 2002, Pages 810-821

Presented in part at the American Society for Therapeutic Radiology and Oncology (ASTRO) Annual Meeting, San Francisco, California, November 2001.

https://doi.org/10.1016/S0360-3016(02)02846-8 Get rights and content

Abstract

$Purpose$ : To describe the dose—volume tolerance for radiation-induced liver disease (RILD) using the Lyman—Kutcher—Burman (LKB) normal tissue complication probability (NTCP) model.

$Methods and Materials$ : A total of 203 patients treated with conformal liver radiotherapy and concurrent hepatic arterial chemotherapy were prospectively followed for RILD. Normal liver dose—volume histograms and RILD status for these patients were used as input data for determination of LKB model parameters. A complication was defined as Radiation Therapy Oncology Group Grade 3 or higher RILD ≤4 months after completion of radiotherapy. A maximal likelihood analysis yielded best estimates for the LKB NTCP model parameters for the liver for the entire patient population. A multivariate analysis of the potential factors associated with RILD was also completed, and refined LKB model parameters were obtained for patient subgroups with different risks of RILD.

$Results$ : Of 203 patients treated with focal liver irradiation, 19 developed RILD. The LKB NTCP model fit the complication data for the entire group. The “n” parameter was larger than previously described, suggesting a strong volume effect for RILD and a correlation of NTCP with the mean liver dose. No cases of RILD were observed when the mean liver dose was <31 Gy. Multivariate analysis demonstrated that in addition to NTCP and the mean liver dose, a primary hepatobiliary cancer diagnosis (vs. liver metastases), bromodeoxyuridine hepatic artery chemotherapy (vs. fluorodeoxyuridine chemotherapy), and male gender were associated with RILD. For 169 patients treated with fluorodeoxyuridine, the refined LKB model parameters were n = 0.97, m = 0.12, tolerance dose for 50% complication risk for whole organ irradiated uniformly [TD₅₀(1)] = 45.8 Gy for patients with liver metastases, and TD₅₀(1) = 39.8 Gy for patients with primary hepatobiliary cancer.

$Conclusion$ : These data demonstrate that the liver exhibits a large volume effect for RILD, suggesting that the mean liver dose may be useful in ranking radiation plans. The inclusion of clinical factors, especially the diagnosis of primary hepatobiliary cancer vs. liver metastases, improves the estimation of NTCP over that obtained solely by the use of dose—volume data. These findings should facilitate the application of focal liver irradiation in future clinical trials.

Introduction

Radiation-induced liver disease (RILD) is a dose-limiting complication of liver irradiation. RILD is a clinical syndrome of anicteric hepatomegaly, ascites, and elevated liver enzymes (particularly serum alkaline phosphatase) occurring typically 2 weeks to 4 months after completion of hepatic irradiation. RILD resembles the suprahepatic vein obstruction and hepatic toxicity seen after high-dose chemotherapy (with or without total body irradiation) for bone marrow transplantation. The pathologic lesion in RILD is venoocclusive disease, characterized by areas of marked venous congestion in the central portion of each lobule, with sparing of the larger veins. Unfortunately, the treatment options for RILD are limited, and, in severe cases, liver failure and death can occur (1).

The tolerance of the whole liver to radiation is low, and RILD is seen in 5–10% of patients treated with 30–35 Gy to the whole liver. For this reason, radiation has traditionally had a limited role in the treatment of intrahepatic cancers. However, treatment of parts of the liver with higher radiation doses is possible without adverse consequences as long as an adequate volume of normal liver is not irradiated to high doses 2, 3, 4, 5. Patients with focal unresectable intrahepatic malignancies treated with higher radiation doses have better response rates, symptom improvement, and survival rates than do patients treated with lower doses 6, 7, 8. Additional knowledge of the partial liver tolerance to radiation may permit safer dose escalation and lead to improvements in clinical outcomes for patients with intrahepatic malignancies. In addition, knowledge of partial organ tolerances to radiation is required for successful implementation of novel radiotherapy (RT) strategies such as automated optimization for intensity-modulated RT.

A number of models estimating the volume dependence of normal tissue toxicity have been used to compare the relative merits of competing three-dimensional RT plans 9, 10, 11, 12. The Lyman model assumes a sigmoid relationship between a dose of uniform radiation given to a volume of an organ and the chance of a complication occurring (9) (see “Methods and Materials” below). We have used the Lyman model (13) clinically, because it is relatively simple (containing 3 parameters) and, when implemented using the Kutcher—Burman (KB) effective volume (V_eff) dose—volume histogram (DVH) reduction scheme (14), it permits comparisons between plans based on DVHs before assigning the dose (15). Our previous effort (16) to reestimate the parameters for the Lyman model was limited by a relatively small number of patients, few cases of RILD, and a simplified statistical analysis. The purpose of this study was to describe more quantitatively the dose—volume relationship of the liver to RILD, based on dose—volume data from more than twice as many patients as previously analyzed, using the LKB normal tissue complication probability (NTCP) model. When a multivariate analysis demonstrated that RILD was associated with nondosimetric factors such as diagnosis, the LKB model was used to describe the dose—volume effects for patient subgroups with different risks of RILD.

Section snippets

Patients

All patients included in this analysis had unresectable intrahepatic cancer (hepatocellular carcinoma, cholangiocarcinoma, or colorectal carcinoma metastatic to the liver) and were treated in prospective clinical trials (Table 1). Ninety-three patients included in this analysis have been previously described 16, 17.

To be eligible for treatment with liver RT, patients had to have an estimated life expectancy of ≥12 weeks, be ≥18 years old, and have had normal liver function (prothrombin and

Results

A total of 203 patients were assessable for RILD analysis. Two patients, who were lost to follow-up after 2 months, were considered to be without RILD; all other patients were followed for a minimum of 4 months after RT completion. Of the 203 patients, 19 developed Grade 3 or higher RILD (Table 2). Of the 19 patients, 6 were treated with whole liver RT, 6 were treated with whole liver RT plus higher dose partial liver RT, and 7 were treated with partial liver RT alone.

Using the maximal

Discussion

Inherent biologic uncertainties are present in all NTCP models, and some authors have challenged their utility (25). Thus, clinical correlation with the NTCP predictions is needed. This report describes the largest series of patients with intrahepatic cancer treated with prospective dose—volume analyses and evaluation for RILD. We used the LKB NTCP model to study the dose—volume tolerance for RILD. Using this model with revised parameters, we were better able to describe the risk of RILD,

Acknowledgements

The authors thank Steve Kronenberg for assistance with figure preparation.

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^☆: Supported in part by NIH Grants P01 CA59827, R01 CA85684, and M01-RR00042.

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Clinical investigation: normal tissueAnalysis of radiation-induced liver disease using the Lyman NTCP model☆

Abstract

Introduction

Section snippets

Patients

Results

Discussion

Acknowledgements

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

Radiother Oncol

Int J Radiat Oncol Biol Phys

Radiother Oncol

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

Clinical investigation: normal tissue
Analysis of radiation-induced liver disease using the Lyman NTCP model☆