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ORIGINAL ARTICLE
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Role of rapid arc-image-guided radiotherapy in hepatocellular carcinoma with portal vein tumor thrombosis: A study from tertiary care center in Punjab, India


1 Department of Radiation Oncology, DMCH Cancer Center, Ludhiana, Punjab, India
2 Department of Radiology, SPS Hospital, Ludhiana, Punjab, India
3 Department of Medical Physics, DMCH Cancer Center, Ludhiana, Punjab, India

Date of Submission03-Mar-2021
Date of Acceptance12-Jul-2021
Date of Web Publication25-Apr-2022

Correspondence Address:
Manjinder Singh Sidhu,
Department of Radiation Oncology, DMCH Cancer Center, Ludhiana, Punjab
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.jcrt_365_21

 > Abstract 


Background and Objectives: Treatment of hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT) is very challenging with poor outcome. In this situation, radiotherapy has become an alternative treatment modality, more precisely due to advances in radiation techniques. The goal of our study is to do analysis of these patients treated with rapid arc image-guided technology (RA-IGRT) at our institution.
Materials and Methods: Thirteen patients were included in the study. As per intuition policy, patient set up, contouring, and treatment plans were generated. Radiological response assessment was done 1-month post-radiotherapy. Survival analysis curve along with Chi-square test for prognostic factors assessment was done using SPSS.
Results: With median dose of 45 Gy in 20 fractions, we were able to achieve 27.3% objective response rate with median survival of 5 months in eligible patients.
Conclusions: One-year overall survival up to 30% can be achieved in HCC with PVTT, especially in patients with objective response to radiotherapy with Japan Integrated Staging score 2, provided it is precisely hit by RA-IGRT.

Keywords: Hepatocellular carcinoma, portal vein tumor thrombus, prognostic factors, rapid arc image-guided technology, survival analysis



How to cite this URL:
Sidhu MS, Ramandeep, Sood S, Aggarwal R, Singh K, Sood D. Role of rapid arc-image-guided radiotherapy in hepatocellular carcinoma with portal vein tumor thrombosis: A study from tertiary care center in Punjab, India. J Can Res Ther [Epub ahead of print] [cited 2022 Nov 29]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=343918




 > Introduction Top


Hepatocellular carcinoma (HCC) remains the most common primary malignancy of the liver with rising incidence worldwide.[1] Moreover, in developing countries, due to the absence of standard surveillance protocol for HCC, patients present at advanced stages.[2] Furthermore, portal vein tumor thrombosis (PVTT) occurs in almost 40% of patients with advanced HCC and is often associated with extremely poor prognosis.[3],[4] In addition, among patients with unresectable tumors, the probability of developing portal PVTT at 1 and 3 years is 21% and 46%, respectively.[5]

Currently, PVTT is thought of as a bottleneck in the treatment of HCC.[6] There is no standard treatment strategy for patients with HCC and PVTT. Evidence shows that trans arterial chemoembolization (TACE) can be performed for patients with PVTT as long as there is sufficient collateral hepatoportal flow and good hepatic reserve.[7] Researches[8],[9],[10] have observed promising outcome in patient with PVTT treated with radiotherapy.

We conducted this study to describe clinic-demographic profile coupled with outcome of HCC with PVTT-treated patients, precisely with image-guided radiotherapy.


 > Materials and Methods Top


Study type

This was single institution prospective observational study.

Study place

The study was done at tertiary care center in Punjab, India.

Study period

The study was conducted between May 2018 and May 2020. The last follow-up of the patient was in December 2020.

Selection criteria of patients

Thirteen unresectable HCC complicated with PVTT referred to our department which met inclusion criteria were included in study. Neither TACE nor surgery was recommended for these patients due to concern about poor hepatic reserve, poor efficacy, and high complication rates. All patients were of tablet sorafenib 400 mg twice daily when referred to the radiotherapy department. Furthermore, tablet sorafenib (dose as per tolerance) was continued during radiotherapy.

Patients with the following characteristics were excluded from receiving radiotherapy: Previously treated for primary HCC, Eastern Cooperative Oncology Group performance status of 3 or more, liver function of Child–Pugh class C, and extrahepatic metastasis.

The diagnosis of HCC was based on the American Association for the Study of Liver Diseases guidelines.[11] PVTT was confirmed as a filling defect adjacent the primary tumor on the contrast-enhanced computed tomography (CT) scans with complete occlusion of the vessel lumen in the portal vein. All patients had a pretreatment evaluation including complete history, physical examination, hematology and biochemistry profiles, hepatitis screening, chest radiographs, abdominal sonography, and CT scan of the abdomen. Clinical staging was done by Japan Integrated Staging Score (JIS score).[12]

Procedure

Set up and treatment planning

All patients were immobilized using a vacloc in the supine treatment position with both arms aside. During simulation alignment of the patient was done by moving LAP lasers. Free-breathing CT scans with contrast enhancement were acquired in helical mode using a 2.5-mm slice thickness. Targets and normal tissues were contoured on axial planning CT images. The spinal cord, bilateral kidney, normal liver, stomach, and small intestine were delineated as organs at risk. The recommendations for specifying gross tumor volume (GTV), clinical target volume (CTV), and planning target volume (PTV) for treatment planning followed the International Commission on Radiation Units Report No. 50.[13]

GTV was defined as the hypodense intraluminal filling defect area within the portal vein. CTV was GTV plus 1-cm uniform three-dimensional (3D) margins. If the primary tumors were contiguous with the portal vein tumor (PVT) area, the partial primary tumor volume might be included within the CTV. The PTV included the CTV plus a nonuniform 3D expansion, 0.5-cm radial margins, and 1.5-cm craniocaudal margins to compensate for setup uncertainty and respiratory movement of the liver. Prescribed dose to PTV was 45 Gy in 20 fractions (equivalent dose in 2 Gy fractions [EQD2] =56). Treatment plans were generated using the Eclipse planning system, version 16.1 (Varian Medical System, Palo Alto, CA, USA). Rapid arc plans were generated to confirm the high-dose volume to the PTV and to meet the dose constraints. The fraction volume of the normal liver receiving 30 Gy or more (V30 Gy) was kept <30%. Normal liver was quantified as the total liver minus the liver tumor and PVT area. The mean dose delivered to each kidney was kept <20 Gy. The maximal dose to the spinal cord was kept <45 Gy. The volume of stomach and small intestine receiving >50 Gy was kept <1 cc. Planning goal was to deliver more than 95% of the prescription dose to encompass at least 95% of the PTV. Daily cone-beam computed tomography (CBCT) was done during treatment and imaging dose received by patient during CBCT was ignored in planning dose.

Follow-up as well as treatment response and liver toxicity evaluation

Follow-up was done monthly by means of physical examination and biochemistry after completion of radiotherapy. In addition, treatment response was evaluated with CT scan performed 4 weeks after the completion of radiotherapy. Furthermore, response assessment was done as per the World Health Organization criteria:[14] Complete response (CR) (complete disappearance of PVT), partial response (PR) (>50% of PVT regression), stable disease (SD) (<50% of PVT regression or <25% of PVT progression), and progressive disease (PD) (>25% of PVT progression). Likewise, objective response rates were defined as the sum of the CR and PR rate. And patient showing CR or PR was defined a “responder,” whereas a patient showing SD or PD was defined a “nonresponder.” In addition, overall survival (OS) was defined as time from date of date Radiation therapy (RT) began to the date of death or the date of the last follow up.

Radiation-induced acute liver toxicities (RILD) were defined as per the common toxicity criteria.[15] More precisely RILD was defined as anicteric nonmalignant ascites and elevation of alkaline phosphatase levels to more than twice the pretreatment values.

Ethical approval

Ethical approval was not taken as role of radiotherapy in PVTT is already an established protocol.[16]

Statistical analysis

All data were analyzed using SPSS Statistics for Windows, Version 20.0 (IBM Corp., Armonk, NY, USA).


 > Results Top


Before we analyzed the data, two participants were removed as they were lost to follow-up. A total of 11 patients completed the prescribed dose of radiotherapy.

The patient characteristics are listed in [Table 1].
Table 1: Patient characteristic

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The mean age of patients was 57 years and was mostly males. Bilobed multifocal with main portal vein invasion was most common and majority of our patients were of Child Pug A and of JIS score 3. All patients underwent Rapid arc with image-guided technology (IGRT) with mean dose of 45 Gy in 20 fractions.

CR was noted in 1 patient (9.1%), PR seen in 2 patients (18.2%), SD in 4 patients (36.4%), and PD in 2 patients (18.2%). The objective response rate was 27.3%.

At the time of analysis, 2 patients were alive 1-year OS rate was 30% with a median survival of 5 months for the entire cohort of patients.

Kaplan–Meier survival curve is shown in [Figure 1].
Figure 1: Kaplan-Meier curve :Overall survival analysis

Click here to view


Furthermore, univariate analysis revealed: Objective response to treatment X2 (1) =5.14, P = 0.02 and JIS score X2 (1) =5.143, P = 0.02 as significant prognostic factors for OS.

Acute radiation-related toxicities of Grade 1 or 2 were noted in 80% of patients. Specifically, no acute radiation-related toxicity ≥ Grade 3 and RILD was noted.


 > Discussion Top


In the present article, we were able to achieve 27.3% objective response coupled with no Grade 3 acute toxicity with the use of mean 45 Gy in 20 fractions (EQD2 = 56) radiotherapy by Rapid arc technology. Furthermore, no patient had RILD. It is important to note that in our study 1-year OS was 30% with median survival of 5 months. In addition, JIS clinical classification along with responder to RT was prognostic factor for survival.

The mean age of the patients in our study was 57 years coupled with multifocal bilobular presentation which is similar to other earlier series from India.[1],[17] Furthermore, in our HCC with PVT patients, Child Pug A and of JIS score 3 was seen in 90.9% and 72.7% respectively, likewise study done by Yeh et al.[16] which had 78.3% and 64.2% patients of Child Pug A and JIS score 3.

Median survival of HCC with PVT left untreated or treated with only symptomatic management is reported to be <3 months.[18] However, with the use of advanced radiation therapy techniques objective tumor response rates ranging from 25.2% to 56.6% have been reported[19] like in our study where we achieved objective response of 27.3% by the use of IGRT technique. Our finding of 1-year OS of 30% with median survival of 5 months' converge with finding of other studies[8],[19],[20] in literature which have reported 1-year OS rate ranging from 16.7% to 45.1% with median survival ranging from 3.8 to 9.7 months. RILD typically occurs 4–8 weeks after the completion of radiotherapy and limits the size of radiation doses.[10] In our study, we did not note any Grade 3 acute toxicity and RILD as supported by studies[21],[22] which have shown that RILD can be prevented if the mean dose to the normal liver is kept below 30 Gy. More precisely in our study mean dose of liver was <14 Gy. An optimal staging system plays an important role in predicting the prognosis and directing the treatment strategy. To best assess the prognosis of HCC, it has been recommended that an ideal staging system should take tumor stage, liver function, and physical status into account. Currently, there is no agreement on which staging systems would be optimal for patients with HCC and PVT. The Child–Pugh classification is widely used to evaluate the liver damage in cirrhotic patients and has been demonstrated to have predictive significance in HCC patients.[23] The JIS score is the sum of the simplified Tumor Node Metastasis score and the Child–Pugh score[12] and it exhibit a better prognostic ability.[12] We found that not only JIS score but also total equivalent RT dose >45 Gy and PVTT responder to RT are an important prognostic factor for survival as supported by study by Im et al.[24] and Bae et al.[25]

Taken together, our finding and finding of previous studies point toward significant survival benefit in HCC with PVTT treated by radiotherapy who are with IJS 2 score, most importantly patients with objective response on first follow-up.

The most important limitation of our study is that the sample size was less. Although the sample size was less, we observed PR in 18.2% coupled with 3post-radiotherapypostradiotherapy. Future research may extend this work especially by integrating post-RT local therapies, like chemoembolization in selected PR/SD patients with well-preserved liver functions it is important to note that unfortunately this was not was not part of our treatment protocol in view of financial constraints.


 > Conclusion Top


To summarize highly conformal modern radiotherapy, technology is a viable option for HCC with PVT especially in JIS 2 score patients. However, the major parameters (e.g., the prescribed radiation and fraction) have not been fully established, the exact role that radiation therapy plays in PVTT has not been clarified.[26] Well-designed randomized controlled trials are needed to provide high-level evidence to support the use of EBRT in these patients.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

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Paul SB, Chalamalasetty SB, Vishnubhatla S, Madan K, Gamanagatti SR, Batra Y, et al. Clinical profile, etiology and therapeutic outcome in 324 hepatocellular carcinoma patients at a tertiary care center in India. Oncology 2009;77:162-71.  Back to cited text no. 2
    
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Ishikura S, Ogino T, Furuse J, Satake M, Baba S, Kawashima M, et al. Radiotherapy after transcatheter arterial chemoembolization for patients with hepatocellular carcinoma and portal vein tumor thrombus. Am J Clin Oncol 2002;25:189-93.  Back to cited text no. 9
    
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Yamada K, Izaki K, Sugimoto K, Mayahara H, Morita Y, Yoden E, et al. Prospective trial of combined transcatheter arterial chemoembolization and three dimensional conformal radiotherapy for portal vein tumor hrombosis in patient with unresectable hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 2003;57:113-9.  Back to cited text no. 10
    
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Kudo M, Chung H, Osaki Y. Prognostic staging system for hepatocellular carcinoma (CLIP score): Its value and limitations, and a proposal for a new staging system, the Japan Integrated Staging Score (JIS score). J Gastroenterol 2003;38:207-15.  Back to cited text no. 12
    
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Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer 1981;47:207-14.  Back to cited text no. 14
    
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Yeh SA, Chen YS, Perng DS. The role of radiotherapy in the treatment of hepatocellular carcinoma with portal vein tumor thrombus. J Radiat Res 2015;56:325-31.  Back to cited text no. 16
    
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Sarin SK, Thakur V, Guptan RC, Saigal S, Malhotra V, Thyagarajan SP, et al. Profile of hepatocellular carcinoma in India: An insight into the possible etiologic associations. J Gastroenterol Hepatol 2001;16:666-73.  Back to cited text no. 17
    
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Zeng ZC, Fan J, Tang ZY, Zhou J, Qin LX, Wang JH, et al. A comparison of treatment combinations with and without radiotherapy for hepatocellular carcinoma with portal vein and/or inferior vena cava tumor thrombus. Int J Radiat Oncol Biol Phys 2005;61:432-43.  Back to cited text no. 18
    
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Kim JY, Chung SM, Choi BO, Kay CS. Hepatocellular carcinoma with portal vein tumor thrombosis: Improved treatment outcomes with external beam radiation therapy. Hepatol Res 2011;41:813-24.  Back to cited text no. 19
    
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Huang YJ, Hsu HC, Wang CY, Wang CJ, Chen HC, Huang EY, et al. The treatment responses in cases of radiation therapy to portal vein thrombosis in advanced hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 2009;73:1155-63.  Back to cited text no. 20
    
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Kim TH, Kim DY, Park JW, Kim SH, Choi JI, Kim HB, et al. Dose-volumetric parameters predicting radiation-induced hepatic toxicity in unresectable hepatocellular carcinoma patients treated with three-dimensional conformal radiotherapy. Int J Radiat Oncol Biol Phys 2007;67:225-31.  Back to cited text no. 22
    
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Im JH, Yoon SM, Park HC, Kim JH, Yu JI, Kim TH, et al. Radiotherapeutic strategies for hepatocellular carcinoma with portal vein tumour thrombosis in a hepatitis B endemic area. Liver Int 2017;37:90-100.  Back to cited text no. 24
    
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