Radiation-Induced Liver Injury in Three-Dimensional Conformal Radiation Therapy (3D-CRT) for Postoperative or Locoregional Recurrent Gastric Cancer: Risk Factors and Dose Limitations

RESEARCH ARTICLE Radiation-Induced Liver Injury in ThreeDimensional Conformal Radiation Therapy (3D-CRT) for Postoperative or Locoregional Recurrent Gastric Cancer: Risk Factors and Dose Limitations Guichao Li, Jiazhou Wang, Weigang Hu, Zhen Zhang* Department of Radiation Oncology, Fudan University Shanghai Cancer Center and Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China a11111 * Abstract Purpose OPEN ACCESS Citation: Li G, Wang J, Hu W, Zhang Z (2015) Radiation-Induced Liver Injury in Three-Dimensional Conformal Radiation Therapy (3D-CRT) for Postoperative or Locoregional Recurrent Gastric Cancer: Risk Factors and Dose Limitations. PLoS ONE 10(8): e0136288. doi:10.1371/journal. pone.0136288 This study examined the status of radiation-induced liver injury in adjuvant or palliative gastric cancer radiation therapy (RT), identified risk factors of radiation-induced liver injury in gastric cancer RT, analysed the dose-volume effects of liver injury, and developed a liver dose limitation reference for gastric cancer RT. Methods and Materials Data Availability Statement: All relevant data are within the paper and its Supporting Information file. Data for 56 post-operative gastric cancer patients and 6 locoregional recurrent gastric cancer patients treated with three-dimensional conformal radiation therapy (3D-CRT) or intensity-modulated radiation therapy (IMRT) from Sep 2007 to Sep 2009 were analysed. Forty patients (65%) were administered concurrent chemotherapy. Pre- and post-radiation chemotherapy were given to 61 patients and 43 patients, respectively. The radiation dose was 45–50.4 Gy in 25–28 fractions. Clinical parameters, including gender, age, hepatic B virus status, concurrent chemotherapy, and the total number of chemotherapy cycles, were included in the analysis. Univariate analyses with a non-parametric rank test (Mann–Whitney test) and logistic regression test and a multivariate analysis using a logistic regression test were completed. We also analysed the correlation between RT and the changes in serum chemistry parameters [including total bilirubin, (TB), direct bilirubin (D-TB), alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST) and serum albumin (ALB)] after RT. Funding: The authors have no support or funding to report. Results Competing Interests: The authors have declared that no competing interests exist. The Child-Pugh grade progressed from grade A to grade B after radiotherapy in 10 patients. A total of 16 cases of classic radiation-induced liver disease (RILD) were observed, and 2 Editor: Eric Y. Chuang, National Taiwan University, TAIWAN Received: February 24, 2015 Accepted: August 2, 2015 Published: August 20, 2015 Copyright: © 2015 Li et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. PLOS ONE | DOI:10.1371/journal.pone.0136288 August 20, 2015 1 / 10 Radiation Induced Liver Injury in Radiotherapy for Gastric Cancer patients had both Child-Pugh grade progression and classic RILD. No cases of non-classic radiation liver injury occurred in the study population. Among the tested clinical parameters, the total number of chemotherapy cycles correlated with liver function injury. V35 and ALP levels were significant predictive factors for radiation liver injury. Conclusions In 3D-CRT for gastric cancer patients, radiation-induced liver injury may occur and affect the overall treatment plan. The total number of chemotherapy cycles correlated with liver function injury, and V35 and ALP are significant predictive factors for radiation-induced liver injury. Our dose limitation reference for liver protection is feasible. Introduction Gastric cancer is one of the most common cancers in China, and patients with lymph nodepositive disease have a 5-year survival rate as low as 15–20%. Even node-negative patients have a 5-year survival rate of only 45–55% if the T stage is advanced (T3-T4N0) [1]. Three-dimensional radiation therapy (3D-RT) is a common treatment method for gastric adenocarcinoma [2]. However, the radiation volume for gastric cancer is very large, including the clinical target volume (CTV) that is adjacent to the liver and contains the tumour bed, anastomosis, gastric remnant (pT3-T4), and regional draining lymph nodes. Furthermore, a larger margin should be added to the CTV for the respiratory motion and inter-fractional variability, thus increasing the planning tumour volume (PTV). Additionally, the liver occupies a large proportion of the upper abdominal cavity, and hepatic hilar lymph nodes need to be contained in the CTV for the majority of patients. The liver inevitably receives a high dose in post-operative or locoregional recurrence gastric cancer patients. Thus, it is difficult to deliver an effective prescription dose to the target while keeping the exposure of normal tissue (e.g., liver and kidney) to a low dose. Moreover, patients with advanced stages of cancer require radiation therapy (RT) and chemotherapy. The advantage of oral chemotherapy drugs, such as capecitabine and S-1, has been shown in a randomized clinical trial [3–5]; however, the safety profile of both oral drugs includes liver toxicity. Thus, the combination of these chemotherapy drugs and radiotherapy can induce severe liver injury [6]. Radiation-induced liver injury may affect the treatment plan. Thus, it is important to protect the liver from radiation injury during RT. The normal tissue tolerance of the liver reported in the NCCN guideline is V30<60% for gastric cancer radiotherapy; however, this large value may result in liver injury. A more detailed dose-limitation reference for the RT for gastric cancer patients is urgently needed. A number of models have been used to predict the risk of radiation-related liver injury. The probability of radiation-induced liver disease (RILD) using the Lyman-Kutcher-Burman model of normal tissue complication probability (NTCP) for primary liver cancer (PLC) treated with three-dimensional conformal radiation therapy (3D-CRT) was established by Dawson et al. and Xu et al. [7,8]. The relationship between the mean liver dose and RILD was also provided. Other models, such as dose-volume effect [9,10], artificial neural networks [11] and parallel-type organ damage [12,13], have also been used to estimate RILD. These previous studies assessed liver cancer, and the findings may not apply to patients with gastric cancer. Unfortunately, there are fewer reports on the relationship between dose distribution and radiation-related liver complications in patients with gastric cancer. PLOS ONE | DOI:10.1371/journal.pone.0136288 August 20, 2015 2 / 10 Radiation Induced Liver Injury in Radiotherapy for Gastric Cancer The aims of current study were to investi (...truncated)