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Early complete tumor response as a survival predictor in hepatocellular carcinoma patients receiving stereotactic body radiation therapy

  • Author Footnotes
    1 Qi-Qiao Wu and Yi-Xing Chen contributed equally to the article thus should be assigned as co first-author.
    Qi-Qiao Wu
    Footnotes
    1 Qi-Qiao Wu and Yi-Xing Chen contributed equally to the article thus should be assigned as co first-author.
    Affiliations
    Department of Radiation Oncology, Fudan University Zhongshan Hospital, Xiamen Branch, Jinhu Road 668, Xiamen 361006, China
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  • Author Footnotes
    1 Qi-Qiao Wu and Yi-Xing Chen contributed equally to the article thus should be assigned as co first-author.
    Yi-Xing Chen
    Footnotes
    1 Qi-Qiao Wu and Yi-Xing Chen contributed equally to the article thus should be assigned as co first-author.
    Affiliations
    Department of Radiation Oncology, Fudan University Zhongshan Hospital, Fenglin Road 188, Shanghai 200030, China
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  • Shi-Suo Du
    Affiliations
    Department of Radiation Oncology, Fudan University Zhongshan Hospital, Fenglin Road 188, Shanghai 200030, China
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  • Yong Hu
    Affiliations
    Department of Radiation Oncology, Fudan University Zhongshan Hospital, Fenglin Road 188, Shanghai 200030, China
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  • Ping Yang
    Affiliations
    Department of Radiation Oncology, Fudan University Zhongshan Hospital, Fenglin Road 188, Shanghai 200030, China
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  • Zhao-Chong Zeng
    Correspondence
    Corresponding author at: Department of Radiation Oncology, Fudan University Zhongshan Hospital, Shanghai, China.
    Affiliations
    Department of Radiation Oncology, Fudan University Zhongshan Hospital, Fenglin Road 188, Shanghai 200030, China
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  • Author Footnotes
    1 Qi-Qiao Wu and Yi-Xing Chen contributed equally to the article thus should be assigned as co first-author.
Open AccessPublished:August 08, 2022DOI:https://doi.org/10.1016/j.ctro.2022.03.010

      Highlights

      • The time gap for HCC patients received SBRT achieved complete tumor response varies.
      • Patients were categorized as early responders or non-early responders.
      • Early complete tumor response predicts for better survival outcomes.

      Abstract

      Background and Purpose

      To evaluate the different response patterns after Stereotactic Body Radiation Therapy (SBRT) and their predictive value in local control and progression of hepatocellular carcinoma (HCC).

      Materials and methods

      Seventy-two HCC patients who were treated with SBRT during 2015–2020 were included in this retrospective study. The assessment was made using MRI, CT, and PET-CT. Local and systemic responses were determined according to modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria during follow up. Patients were categorized as early responders (complete response during 6 months after radiotherapy) or non-early responders (the rest of the patients). Prognostic factors were determined using multivariate logistic models.

      Results

      The median follow-up was 24.0 months (range, 7.7–74.5 months). We found that 84.7%(61/72) of patients achieved a complete response. Early responses occurred in 45 patients (45/72, 62.5%), and they had 1-, 2-, and 5- year intrahepatic outfield-free survival (OutFFS) rates of 86.2%, 80.3%, and 76.3% vs. 55.3%, 44.7%, and 33.5% in non-early responses patients, whereas the 1-, 2-, and 5- year distant metastasis-free survival (DMFS) were 95.5%, 84.5% and 79.5% and 74.1%, 56.2% and 56.2%, respectively. The 1-, 2-, and 5-year overall survival (OS) were 97.7%, 92.1%, 79.1%, and 85.2%, 53.8%, and 40.3%, respectively. Multivariate analysis revealed that early tumor response was an independent predictor of OutFFS, DMFS, and OS.

      Conclusions

      Early complete tumor response within 6 months after radiotherapy predicted better intrahepatic outfield-free survival, distant metastasis-free survival, and overall survival outcomes. Confirmation is warranted for early response on SBRT to guide decision making.

      Keywords

      Introduction

      Hepatocellular carcinoma (HCC) is the fifth most common cancer and the second most frequent cause of cancer-related death globally [
      • Llovet J.M.
      • Zucman-Rossi J.
      • Pikarsky E.
      • Sangro B.
      • Schwartz M.
      • Sherman M.
      • et al.
      Hepatocellular carcinoma.
      ]. Despite recent advances in therapy, 5-year survival rates still remain low (<10-∼50%) [
      • Mendiratta-Lala M.
      • Masch W.
      • Owen D.
      • Aslam A.
      • Maurino C.
      • Devasia T.
      • et al.
      Natural history of hepatocellular carcinoma after stereotactic body radiation therapy.
      ]. Curative treatments for HCC are surgery, liver transplantation, and ablation according to the guidelines [
      • Marrero J.A.
      • Kulik L.M.
      • Sirlin C.B.
      • Zhu A.X.
      • Finn R.S.
      • Abecassis M.M.
      • et al.
      Diagnosis, Staging, and Management of Hepatocellular Carcinoma: 2018 Practice Guidance by the American Association for the Study of Liver Diseases.
      ,
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      • Piscaglia F.
      • Raoul J.-L.
      • et al.
      EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma.
      ]. However, some HCC patients are contraindicated for these treatments because of poor general condition or technical difficulties due to the location of tumors [
      • Bruix J.
      • Sherman M.
      Management of hepatocellular carcinoma.
      ]. Stereotactic body radiotherapy (SBRT) allows the precise delivery of high-dose radiation to the tumor in a small number of fractions and can achieve good local control for HCC regardless of the tumor’s location [
      • Rim C.H.
      • Kim H.J.
      • Seong J.
      Clinical feasibility and efficacy of stereotactic body radiotherapy for hepatocellular carcinoma: A systematic review and meta-analysis of observational studies.
      ,
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      • Ten Haken R.K.
      • Dawson L.A.
      • et al.
      Local Control After Stereotactic Body Radiation Therapy for Liver Tumors.
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      • Dawson L.A.
      • Krishnan S.
      • Seong J.
      • Cheng J.C.
      • Sarin S.K.
      • et al.
      Radiotherapy for Hepatocellular Carcinoma: New Indications and Directions for Future Study.
      ,
      • Durand-Labrunie J.
      • Baumann A.-S.
      • Ayav A.
      • Laurent V.
      • Boleslawski E.
      • Cattan S.
      • et al.
      Curative Irradiation Treatment of Hepatocellular Carcinoma: A Multicenter Phase 2 Trial.
      ,
      • Huang W.-Y.
      • Jen Y.-M.
      • Lee M.-S.
      • Chang L.-P.
      • Chen C.-M.
      • Ko K.-H.
      • et al.
      Stereotactic body radiation therapy in recurrent hepatocellular carcinoma.
      ]. Given that it is a one-time shot, tumor response after SBRT became the top concern for clinicians.
      Most of the studies utilized Modified Response Evaluation Criteria in Solid Tumors (mRECIST) [
      • Lencioni R.
      New data supporting modified RECIST (mRECIST) for hepatocellular carcinoma.
      ] as an imaging-based algorithm to evaluate tumor response after locoregional treatments. By which enhancement as a key imaging biomarker indicating viable disease. However, HCCs treated with stereotactic body radiation therapy (SBRT) often exhibit residual arterial phase hyperenhancement (APHE) and/or a “washout” in venous phase for 3 months or more [
      • Mendiratta-Lala M.
      • Masch W.
      • Owen D.
      • Aslam A.
      • Maurino C.
      • Devasia T.
      • et al.
      Natural history of hepatocellular carcinoma after stereotactic body radiation therapy.
      ,
      • Mendiratta-Lala M.
      • Masch W.
      • Shankar P.R.
      • Hartman H.E.
      • Davenport M.S.
      • Schipper M.J.
      • et al.
      Magnetic Resonance Imaging Evaluation of Hepatocellular Carcinoma Treated With Stereotactic Body Radiation Therapy: Long Term Imaging Follow-Up.
      ,
      • Oldrini G.
      • Huertas A.
      • Renard-Oldrini S.
      • Taste-George H.
      • Vogin G.
      • Laurent V.
      • et al.
      Tumor response assessment by MRI following stereotactic body radiation therapy for hepatocellular carcinoma.
      ]. The time gap between APHE to no-enhancement in all phases varies among individuals. Mishal [
      • Mendiratta-Lala M.
      • Masch W.
      • Shankar P.R.
      • Hartman H.E.
      • Davenport M.S.
      • Schipper M.J.
      • et al.
      Magnetic Resonance Imaging Evaluation of Hepatocellular Carcinoma Treated With Stereotactic Body Radiation Therapy: Long Term Imaging Follow-Up.
      ] et al. reported the natural history of HCC after SBRT using mRECIST criteria and found that the patients’ best tumor response (CR) rate at 3, 12, and 24 months were 23%, 64%, and 81%, respectively. Que [
      • Que J.
      • Kuo H.T.
      • Lin L.C.
      • Lin K.L.
      • Lin C.H.
      • Lin Y.W.
      • et al.
      Clinical outcomes and prognostic factors of cyberknife stereotactic body radiation therapy for unresectable hepatocellular carcinoma.
      ] et al. indicated that tumor response after SBRT (CR vs.PR/stable) was an independent predictor of Overall Survival. However, the RECIST criteria was used; no further relations between progression related survival data (intrahepatic or distant) were investigated.
      Our study was conceived from the previous studies mentioned above and further divided tumor response into early and non-early patterns using mRECIST criteria. We assumed that early response pattern (CR within 6 months after SBRT) had a better progression-free survival outcome.

      Materials and methods

      Patients

      We enrolled the patients from January 2015 to May 2020. Informed consent was obtained, and this study was approved by the institutional review board of the Ethics Committee of Zhongshan Hospital, Fudan University. SBRT was considered for patients with primary HCC who were not suitable for surgery for the following reasons: it was technically or medically inoperable or the patients refused to undergo surgery; tumors were not suitable for TACE or RFA due to tumor hypovascularity or its location in the liver dome or near the major vessels; and the presence of recurrent lesions after multiple treatments, including TACE and RFA. The inclusion criteria were as follows: 1) hepatocellular carcinoma based on biopsy-proven HCC or clinical guideline defined HCC [
      • Galle P.R.
      • Forner A.
      • Llovet J.M.
      • Mazzaferro V.
      • Piscaglia F.
      • Raoul J.-L.
      • et al.
      EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma.
      ,

      Benson AB, D’Angelica MI, Abbott DE, Anaya DA, Anders R, Are C, et al. Hepatobiliary cancers, Version 2.2021. JNCCN J Natl Compr Cancer Netw 2021;19:541–65. https://doi.org/10.6004/jnccn.2021.0022.

      ,
      • Ayuso C.
      • Rimola J.
      • Vilana R.
      • Burrel M.
      • Darnell A.
      • García-Criado Á.
      • et al.
      Diagnosis and staging of hepatocellular carcinoma (HCC): current guidelines.
      ]; 2) HCC treated with SBRT; 3) patient with complete follow-up radiological data (multiphasic CT or MRI performed within 3 months prior to initiation of SBRT, has multiphasic CT or MRI performed before patient has progression diseases or reached survival endpoint following completion of SBRT; 4) ECOG score: 0 to 2, age ≥ 18 years old, volume of normal liver: >700 cm2 and Child-Pugh class A or B. We excluded the following: 1) patients who received other locoregional treatments after radiotherapy before progression happens; and 2) patients with lymph node metastasis, distant metastasis, or double primary malignancy. Seventy-two of 122 patients (59.0%) were assessed for response and eligible for tumor response analysis. Seven patients were not considered, because they had pathology confirmation of cholangiocellular carcinoma. Six patients were excluded, because they received other locoregional treatments before progression. Thirty-seven patients were excluded due to their incomplete imaging data (Fig. 1).
      Figure thumbnail gr1
      Fig. 1Flow diagram for the patient selection process. Abbreviations; SBRT: Stereotactic Body Radiation Therapy; HCC: Hepatocellular carcinoma; CR: complete response.

      Stereotactic body radiation therapy procedure

      All patients received Helical Tomotherapy (Hi-ART System, Accuray). Abdominal compression technique [
      • Hu Y.
      • Zhou Y.-K.
      • Chen Y.-X.
      • Zeng Z.-C.
      Magnitude and influencing factors of respiration-induced liver motion during abdominal compression in patients with intrahepatic tumors.
      ,
      • Hu Y.
      • Zhou Y.K.
      • Chen Y.X.
      • Shi S.M.
      • Zeng Z.C.
      4D-CT scans reveal reduced magnitude of respiratory liver motion achieved by different abdominal compression plate positions in patients with intrahepatic tumors undergoing helical tomotherapy.
      ] was used to reduce respiratory liver motion; patient underwent 4D-CT with slice thickness of 3 mm (Siemens Somatom Sensation; Siemens Healthineers Corporation). The gross tumor volume (GTV) included all tumors detected via dynamic CT and MRI; an internal target volume (ITV) was generated after including the extension of GTV on the 4D-CT scanning. The planning target volume (PTV) was created as ITV plus a radial margin of 3 mm. Patients were treated with 48–60 Gy dose in 5–10 fractions, patients underwent on-board MVCT daily for image guidance. The variance in dosage was due to the tumor location being near the intestine.

      Response evaluation

      Patients were assessed before SBRT and after completion of treatment at 1 month, every 3 months for the first 12 months, and every 6 months thereafter. Imaging interpretation was performed in consensus by the radiologist and two radiation oncologists with 8 and 3 years of experience in liver imaging using a PACS (Universal Viewer ZFP, GE Healthcare IT). Both radiation oncologists were aware of the diagnosis of HCC and the imaging reports. If there was a discrepancy between reports and review, then a final response evaluation was performed on the basis of a consensus decision between the radiologist and radiation oncologists.
      The following details were recorded for each HCC on the pre-treatment and post-treatment imaging examinations: HCC location and maximum diameter. The Modified Response Criteria in Solid Tumors (mRECIST) was used to evaluate treatment response, complete response was defined as disappearance of any intratumoral arterial enhancement of all targets [
      • Lencioni R.
      New data supporting modified RECIST (mRECIST) for hepatocellular carcinoma.
      ], patients who has complete response (CR) within 6 months after treatment were categorized as Early response pattern (Fig. 3) while the rest were categorized as non-early response pattern (Fig. 4). Local failure was defined as an infield recurrence within the planning target volume (PTV). Outfield failure was defined as outfield intrahepatic metastasis, and distant failure as extrahepatic metastasis.
      Figure thumbnail gr2
      Fig. 2The Complete Response Rate(percentage) at 3 months(25.0%), 6 months(62.5%), 9 months(80.6%), 12 months or later(84.7%).
      Figure thumbnail gr3
      Fig. 3Example of Early response group: A 69-year-old male with HCC. (A), HCC with APHE (arrow) pre-treatment. (B), HCC APHE disappears (arrow) at 1 month post-SBRT. (C), A patchy“ treatment specific expected enhancement pattern”(arrow) at 6 monthes post-SBRT.(D),HCC with“washout”in venous phase pre-treatment (arrow). (E), HCC venous phase at 1 month post-SBRT (arrow). (F) Patchy“ treatment specific expected enhancement pattern”is not washed out in the portal venous phase (arrow).
      Figure thumbnail gr4
      Fig. 4Example of Non-early response group: A 86-year-old male with HCC. (A), HCC with APHE (arrow) pre-treatment. (B), APHE exists (arrow) at 3 monthes post-SBRT. (C), APHE exists (arrow) at 9 monthes post-SBRT. (D),HCC with“washout”in venous phase pre-treatment (arrow). (E), HCC with“washout”in venous phase at 3 monthes post-SBRT (arrow). (F) HCC with “washout” in venous phase at 9 monthes post-SBRT (arrow).

      Data analysis

      Demographic data (sex, hepatitis B infection, α-fetoprotein (AFP) level > 400 ng/ml, and previous treatments) were summarized with counts and percentages. Age and tumor size (mm) before the treatment were summarized with median and range. Tumor responses (mRECIST) were summarized at the lesion level pre- and post-treatment. All time-to-event outcomes were calculated from the start of treatment with censoring at the date of last clinical follow-up. Local failure-free survival (LFFS), outfield intrahepatic failure-free survival (OutFFS), and distant metastasis-free survival (DMFS) were estimated using the Kaplan-Meier method. The logistics method was used for multivariate analysis, variables that were considered to have relevance or have a p value of < 0.1 in univariate analysis were further subjected to multivariate analysis. The analysis was conducted in SPSS version 26 (IBM Corp).

      Results

      Patient characteristics

      The study population included 58 males (80.6%) and 14 females (19.4%) aged 36–98 years old (Table.1). The majority of the patients (91.7%) had hepatitis B infection. Only 15 patients (20.8%) had AFP level>400 ng/ml before radiotherapy. The largest tumor diameters ranged from 7 mm to 68 mm with a median of 27 mm. Fifteen patients (20.8%) received SBRT as initial treatment.
      Table 1Clinical features and different tumor Response Patterns of study participants (N = 72).
      All(n = 72)Responsep-Value
      Early(n = 45)Non-early(n = 27)
      Age(y)0.604
      Median(range)62(36–98)62(37–83)62(36–98)
      Sex0.442
      Male58(80.6%)35(77.8%)23(85.2%)
      Female14(19.4%)10(22.2%)4(14.8%)
      Hepatitis B infection0.665
      Yes66(91.7%)42(93.3%)24(88.9%)
      No6(8.3%)3(6.7%)3(11.1%)
      AFP level0.410
      >400 ng/ml15(20.8%)8(17.4%)7(25.9%)
      <400 ng/ml57(79.2%)37(82.2%)20(74.1%)
      Largest tumor Diameter0.396
      Median(range)in mm27(7–68)25(7–60)27(8–68)
      Previous Treatments0.330
      Yes57(79.2%)34(75.6%)23(85.2%)
      No15(20.8%)11(24.4%)4(14.8%)

      Response and patterns of failure

      An objective response was documented in all patients, and it was an early response for 45 patients (62.5%). Eighteen patients (25.0%) showed complete response (CR) within 3 months, 45 patients (62.5%) showed CR at 6 months, 58 patients (80.6%) showed CR at 9 months, and 61 patients (84.7%) showed CR at 12 months or later (Fig. 2). Among 61 patients with complete response, five patients had both intrahepatic outfield failure and distant failure, 11 patients had intrahepatic outfield failure while 9 patients had distant metastasis. Among 11 patients who did not achieve complete response during follow-up, two patients were evaluated as stable disease (SD), whereas five patients were evaluated as Partial response (PR), 4 patients experienced local failures. Eight patients experienced disease progression, and the initial failure sites were as follows: 6 outfield failures; and 2 concurrent outfield and distant failures. In the early response group, there were 2 concurrent intrahepatic outfield and distant failure; 7 patients had intrahepatic outfield failure; and 5 patients developed distant metastasis. No patient had local failure. Two patients experienced concurrent local, intrahepatic, and distant failures; 2 with local failures, and 4 with both outfield and distal failures; 8 with outfield failure; and 4 with distant failure in the non-early response group (Table 3).

      Relevance of early response for LFFS, OutFFS, DMFS, and OS

      The overall tumor local control rate was 93.6% during follow-up. The 1-, 2-, and 5-year overall local tumor control rates were 95.8%, 93.6%, and 93.6%, respectively. The 1-, 2-, and 5-year LFFS for Non-early response group were 88.9%, 80.8%, and 80.8 %, whereas these were 100%, 100%, and 100% for early response group (Fig. 5), respectively.
      Figure thumbnail gr5
      Fig. 5Response patterns influencing local recurrence free survival.
      The median intrahepatic outfield progression-free survival time was 13.1 months (range, 1.8–71.9 months) for non-early response group and 28.1 months (range, 7.9–74.5 months) for the early response group. The 1-, 2-, and 5- year outfield progression-free survival rates were 86.2%, 80.3%, and 76.3% in the early response group with huge differences compared with 55.3%, 44.7%, and 33.5% in the non-early response group (Fig. 6), respectively.
      Figure thumbnail gr6
      Fig. 6Response patterns influencing intrahepatic outfield progression free survival.
      The median distant metastasis-free survival rates for early and non-early group were 26.6 months (range, 8.8–74.5 months) and 16.2 months (range, 1.8–71.9 months), respectively. The 1-, 2-, and 5-year of DMFS rates in early responders were 95.5%, 84.5%, and 79.5%, whereas those of the non-early response group were 74.1%, 56.2%, and 56.2%, respectively (Fig. 7).
      Figure thumbnail gr7
      Fig. 7Response patterns influencing distant metastasis free survival.
      In the early response group, the median overall survival was 34.6 months (range, 8.8–74.5 months), whereas this was 17.8 months (range, 7.7–71.9 months) in the non-early response group. The 1-, 2-, and 5- year OS rates for early and non-early groups were 97.7%, 92.1%, and 79.1% and 85.2%, 53.8%, and 40.3%, respectively (Fig. 8).
      Figure thumbnail gr8
      Fig. 8Response patterns influencing Overall Survival.
      Early response patterns (vs. non-early, p < 0.001), older age (vs. <65 years old, p = 0.003), and received surgery as previous treatment (vs. did not receive surgery before SBRT, p = 0.029) were related to the intrahepatic outfield control rate in univariate analysis. In the multivariate analysis, early response (HR = 0.209, CI:0.089–0.487, p < 0.001) and older age (HR = 0.135, CI:0.031–0.582, p = 0.007) both correlated significantly with better intrahepatic outfield control rate (Table 2 and Fig. 6). Early response pattern (p = 0.014) and whether or not the patient received previous surgery treatments (p = 0.018) were two factors that correlated with the distant metastasis control rate, whereas only early response pattern (p = 0.031) maintained its relevance significantly in multivariate analysis (Table 2 and Fig. 7). Early response pattern was also correlated with overall survival significantly in multivariate analysis (HR = 0.232, CI:0.084–0.638, p = 0.005).
      Table 2Factors influencing intrahepatic out field free survival and distant metastasis free survival.
      Intrahepatic Out Field Free SurvivalDistant Metastasis Free SurvivalOverall Survival
      UVAMVAUVAMVAUVAMVA
      95%CIPHR95%CIP95%CIPHR95%CIP95%CIPHR95%CIP
      Response pattern<0.0010.0140.002
      EarlyN/A0.2090.089–0.487<0.001N/A0.3370.125–0.9080.031N/A0.2320.084–0.6380.005
      Non-Early4.283–35.366N/A0.000–129.839
      Age0.0030.3470.4230.6030.186–1.9600.4
      >65N/A0.1350.031–0.5820.007N/AN/A
      ≤65N/AN/AN/A
      Culmulative diameter0.2910.2290.349
      >2cmN/AN/AN/A
      ≤2cmN/AN/AN/A
      AFP level0.2520.7570.699
      >400 ng/mlN/AN/AN/A
      ≤400 ng/mlN/AN/AN/A
      Previous treatments(Yes vs. No)
      TACE0.169N/A0.226N/A0.209
      RFA0.58N/A0.278N/A0.555
      Surgery0.0290.5660.241–1.3290.191N/A0.0180.6730.250–1.8120.433N/A0.290.9030.327–2.4900.844
      Abbreviations: UVA: univariate analysis; MVA: multivariate analysis; HR: hazard ratio; CI: confidence interval.
      Table 3Failure patterns and different tumor Response Patterns.
      All(n = 72)Responsep-Value
      Early(n = 45)Non-early(n = 27)
      Failure Pattern
      Local4(5.6%)0(0%)4(14.8%)0.017
      Outfield24(33.3%)9(20.0%)15(55.6%)0.002
      Distant17(23.6%)7(15.6%)10(37.0%)0.038

      Discussion

      Our study retrospectively analyzed 72 HCC patients who received SBRT, and we first demonstrated the impact of earliness in tumor response on patients’ intrahepatic outfield progression-free survival, distant metastasis-free survival, and overall survival.
      Several imaging-based assessment algorithms (i.e., European Association for the Study of Liver Disease (EASL) [
      • Galle P.R.
      • Forner A.
      • Llovet J.M.
      • Mazzaferro V.
      • Piscaglia F.
      • Raoul J.-L.
      • et al.
      EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma.
      ], Modified Response Evaluation Criteria in Solid Tumors (mRECIST) [
      • Lencioni R.
      New data supporting modified RECIST (mRECIST) for hepatocellular carcinoma.
      ], and Liver Reporting and Data System (LI-RADS) treatment response algorithm (TRA) v.2018 [
      • Kielar A.
      • Fowler K.J.
      • Lewis S.
      • Yaghmai V.
      • Miller F.H.
      • Yarmohammadi H.
      • et al.
      Locoregional therapies for hepatocellular carcinoma and the new LI-RADS treatment response algorithm.
      ] can be used to evaluate the post-treatment tumor response. LI-RADS treatment response algorithm was designed to assess treated tumor while considering the treatment-specific enhancement pattern. However, the level of inter-observer agreement among different radiologists has not been assessed [
      • Kielar A.
      • Fowler K.J.
      • Lewis S.
      • Yaghmai V.
      • Miller F.H.
      • Yarmohammadi H.
      • et al.
      Locoregional therapies for hepatocellular carcinoma and the new LI-RADS treatment response algorithm.
      ]. Some believe that iRECIST [

      Seymour L, Cancer C, Group T, Bogaerts J, Perrone A, Medicine T, et al. iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics. Lancet Oncol 2017;18:e143–52. https://doi.org/10.1016/S1470-2045(17)30074-8.iRECIST.

      ,
      • Vernuccio F.
      • Godfrey D.
      • Meyer M.
      • Williamson H.V.
      • Salama J.K.
      • Niedzwiecki D.
      • et al.
      Local tumor control and patient outcome using stereotactic body radiation therapy for hepatocellular carcinoma: IRECIST as a potential substitute for traditional criteria.
      ] (immune-based therapeutics) provided more robust interpretation of HCC response after SBRT than mRECIST and RECIST, but it was based on RECIST 1.1 and focused more on the true progression, because it needs two consecutive follow-up images to make the final decision. In our study, we still used mRECIST criteria to evaluate the tumors after radiotherapy, because it emphasizes tumor enhancement and size and is currently the most widely used evaluation method for post-treatment HCC [
      • Oldrini G.
      • Huertas A.
      • Renard-Oldrini S.
      • Taste-George H.
      • Vogin G.
      • Laurent V.
      • et al.
      Tumor response assessment by MRI following stereotactic body radiation therapy for hepatocellular carcinoma.
      ,

      Paper O, Boer D. r vi ew On r Fo Re vi ew On ly 2013:0–34. https://doi.org/10.3837/tiis.0000.00.000.

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      ].
      The CR rate in our study was 25.0% at 3 months, which was similar to those obtained by Mishal’s (23%) [
      • Mendiratta-Lala M.
      • Masch W.
      • Owen D.
      • Aslam A.
      • Maurino C.
      • Devasia T.
      • et al.
      Natural history of hepatocellular carcinoma after stereotactic body radiation therapy.
      ] and Naoko’s (24%) [
      • Sanuki N.
      • Takeda A.
      • Mizuno T.
      • Oku Y.
      • Eriguchi T.
      • Iwabuchi S.
      • et al.
      Tumor Response on CT following hypofractionated stereotactic ablative body radiotherapy for small hypervascular hepatocellular carcinoma with cirrhosis.
      ]. At 6 months, our study showed higher CR rate (62.5%) than the rate obtained by Mendiratta (41.7%) [
      • Mendiratta-Lala M.
      • Masch W.
      • Shankar P.R.
      • Hartman H.E.
      • Davenport M.S.
      • Schipper M.J.
      • et al.
      Magnetic Resonance Imaging Evaluation of Hepatocellular Carcinoma Treated With Stereotactic Body Radiation Therapy: Long Term Imaging Follow-Up.
      ] and lower than that obtained by Naoko’s (67%) [
      • Sanuki N.
      • Takeda A.
      • Mizuno T.
      • Oku Y.
      • Eriguchi T.
      • Iwabuchi S.
      • et al.
      Tumor Response on CT following hypofractionated stereotactic ablative body radiotherapy for small hypervascular hepatocellular carcinoma with cirrhosis.
      ]. At 1 year after treatment, studies have shown CR rates ranging from 64% to 87.5% [
      • Mendiratta-Lala M.
      • Masch W.
      • Owen D.
      • Aslam A.
      • Maurino C.
      • Devasia T.
      • et al.
      Natural history of hepatocellular carcinoma after stereotactic body radiation therapy.
      ,
      • Mendiratta-Lala M.
      • Masch W.
      • Shankar P.R.
      • Hartman H.E.
      • Davenport M.S.
      • Schipper M.J.
      • et al.
      Magnetic Resonance Imaging Evaluation of Hepatocellular Carcinoma Treated With Stereotactic Body Radiation Therapy: Long Term Imaging Follow-Up.
      ,
      • Que J.
      • Kuo H.T.
      • Lin L.C.
      • Lin K.L.
      • Lin C.H.
      • Lin Y.W.
      • et al.
      Clinical outcomes and prognostic factors of cyberknife stereotactic body radiation therapy for unresectable hepatocellular carcinoma.
      ,
      • Sanuki N.
      • Takeda A.
      • Mizuno T.
      • Oku Y.
      • Eriguchi T.
      • Iwabuchi S.
      • et al.
      Tumor Response on CT following hypofractionated stereotactic ablative body radiotherapy for small hypervascular hepatocellular carcinoma with cirrhosis.
      ], whereas we obtained 84.7%. The best response rate in each phase of our study was similar to the previously reported ones [
      • Mendiratta-Lala M.
      • Masch W.
      • Owen D.
      • Aslam A.
      • Maurino C.
      • Devasia T.
      • et al.
      Natural history of hepatocellular carcinoma after stereotactic body radiation therapy.
      ,
      • Mendiratta-Lala M.
      • Masch W.
      • Shankar P.R.
      • Hartman H.E.
      • Davenport M.S.
      • Schipper M.J.
      • et al.
      Magnetic Resonance Imaging Evaluation of Hepatocellular Carcinoma Treated With Stereotactic Body Radiation Therapy: Long Term Imaging Follow-Up.
      ,
      • Que J.
      • Kuo H.T.
      • Lin L.C.
      • Lin K.L.
      • Lin C.H.
      • Lin Y.W.
      • et al.
      Clinical outcomes and prognostic factors of cyberknife stereotactic body radiation therapy for unresectable hepatocellular carcinoma.
      ,
      • Sanuki N.
      • Takeda A.
      • Mizuno T.
      • Oku Y.
      • Eriguchi T.
      • Iwabuchi S.
      • et al.
      Tumor Response on CT following hypofractionated stereotactic ablative body radiotherapy for small hypervascular hepatocellular carcinoma with cirrhosis.
      ], which demonstrated the typical HCC response pattern after receiving SBRT. Unlike transcatheter or other loco-ablative therapy [
      • Wahl D.R.
      • Stenmark M.H.
      • Tao Y.
      • Pollom E.L.
      • Caoili E.M.
      • Lawrence T.S.
      • et al.
      Outcomes after stereotactic body radiotherapy or radiofrequency ablation for hepatocellular carcinoma.
      ], a rapid tumor size reduction or immediate de-vascularization might not be seen in HCC patients that received SBRT. In the very early post-radiation period (∼1 month), tumor size and enhancement may transiently increase; this phenomenon mimics tumor progression. In the early post-radiation period (∼3 months), there is a great likelihood that typical HCC enhancement pattern (APHE and/or “washout”) can still be seen in the venous phase [
      • Mendiratta-Lala M.
      • Masch W.
      • Owen D.
      • Aslam A.
      • Maurino C.
      • Devasia T.
      • et al.
      Natural history of hepatocellular carcinoma after stereotactic body radiation therapy.
      ]. The successfully treated mass may experience necrosis and fibrosis over time, as it shows iso-enhancement or hypo-enhancement, or it remains a patchy “treatment specific expected enhancement pattern”; the enhanced lesion corresponds to the high-dose area with a certain threshold and is not washed out in the portal venous phase [
      • Takeda A.
      • Oku Y.
      • Sanuki N.
      • Kunieda E.
      • Koike N.
      • Aoki Y.
      • et al.
      Dose volume histogram analysis of focal liver reaction in follow-up multiphasic CT following stereotactic body radiotherapy for small hepatocellular carcinoma.
      ,
      • Sanuki N.
      • Takeda A.
      • Oku Y.
      • Eriguchi T.
      • Nishimura S.
      • Aoki Y.
      • et al.
      Threshold doses for focal liver reaction after stereotactic ablative body radiation therapy for small hepatocellular carcinoma depend on liver function: Evaluation on magnetic resonance imaging with Gd-EOB-DTPA.
      ,
      • Mendiratta-Lala M.
      • MD*, Everett Gu, MD*, Dawn Owen, MD, PhD†, Kyle C. Cuneo, MD†, Latifa Bazzi, BSc†, Theodore S. Lawrence, MD, PhD†, Hero K. Hussain, MD* and MS, Davenport M.
      Imaging Findings Within the First 12 Months of Hepatocellular Carcinoma Treated With Stereotactic Body Radiation Therapy Mishal.
      ,

      C. Yip G.J.R. Cook K. Owczarczyk V. Goh Challenges in imaging assessment following liver stereotactic body radiotherapy: Pitfalls to avoid in clinical practice Chinese Clin Oncol 6 2017 1 9 https://doi.org/10.21037/cco.2017.06.06.

      ].
      An early study [
      • Que J.
      • Kuo H.T.
      • Lin L.C.
      • Lin K.L.
      • Lin C.H.
      • Lin Y.W.
      • et al.
      Clinical outcomes and prognostic factors of cyberknife stereotactic body radiation therapy for unresectable hepatocellular carcinoma.
      ] suggested that several factors, including tumor sizes>4 cm, Child Pugh (A vs. B), and Portal vein tumor thrombosis (positive vs. negative), were independent predictors of OS. Higher dosage (42–60 Gy vs. 36–44 Gy) and pre-radiotherapy multi-segment recurrence were independent prognostic factors for Local Failure Free Survival (LFFS) and OutFFS, respectively [
      • Kim J.W.
      • Kim D.Y.
      • Han K.
      • Seong J.
      for hepatocellular carcinoma.
      ]. However, none of the studies investigated the relation between the tumor response pattern and its association with progression-related survival and overall survival. Despite the excellent local control for SBRT [

      Y.-X. Chen Y. Zhuang P. Yang J. Fan J. Zhou Y. Hu et al. Helical IMRT-Based Stereotactic Body Radiation Therapy Using an Abdominal Compression Technique and Modified Fractionation Regimen for Small Hepatocellular Carcinoma Technol Cancer Res Treat 19 2020 10.1177/1533033820937002 153303382093700.

      ], intrahepatic outfield recurrence accounts for the major problem. Early response was associated with a statistically significant OutFFS prolongation by 15.0 months as compared with non-early responders. Our study also suggested that patients with early response pattern had a 10.4 months prolongation of DMFS and a 16.8 months prolongation of OS than non-early response pattern. Such finding further suggested that the achievement of an early response could translate into an outfield recurrence-free survival and overall survival benefit, which might be explained by the following reasons. In non-early response pattern, it takes longer for the tumor feeding vessels to go through necrosis and fibrosis, as they are still able to uptake the contrast, thereby providing more opportunities for the tumor to seed elsewhere. Studies have tried to investigate the biological explanation of “persistent arterial phase enhancement” of HCC after SBRT. Mustafa’s study points out that veno-occlusive diseases, such as changes in liver parenchyma injury, could lead to the congestion of contrast, which would further lead to the persistent enhancement [
      • Haddad M.M.
      • Merrell K.W.
      • Hallemeier C.L.
      • Johnson G.B.
      • Mounajjed T.
      • Olivier K.R.
      • et al.
      Stereotactic body radiation therapy of liver tumors: post-treatment appearances and evaluation of treatment response: a pictorial review.
      ]. In Katerina’s study, which connected with both the histological changes and radiological tumor response after SBRT in HCC patients: after 134 days post radiation treatment, there are still some residual hepatocellular carcinoma cells accounting for the hyperenhancement [
      • Mastrocostas K.
      • Fischer S.
      • Munoz-Schuffenegger P.
      • Jang H.-J.
      • Dawson L.A.
      • Liu Z.A.
      • et al.
      Radiological tumor response and histopathological correlation of hepatocellular carcinoma treated with stereotactic body radiation therapy as a bridge to liver transplantation.
      ].
      Naoko’s study have shown that the median time for HCC to reach CR was 5.9 months (range, 1.2–34.2 months) [
      • Sanuki N.
      • Takeda A.
      • Mizuno T.
      • Oku Y.
      • Eriguchi T.
      • Iwabuchi S.
      • et al.
      Tumor Response on CT following hypofractionated stereotactic ablative body radiotherapy for small hypervascular hepatocellular carcinoma with cirrhosis.
      ]. In our study, the median time for HCC to reach CR was 4.9 months (range, 1.3–23.0 months). Given the result in our study, when HCC patients have not reached their best tumor response within 6 months, the clinician should be concerned and actively take action (e.g., follow-the patients more frequently or use a combination of other therapies).
      Our study has several limitations. First, the mRECIST criteria emphasizes enhancement and tumor size only, whereas some successfully treated HCC (by SBRT) might exhibit treatment-related perfusion changes, which might hamper the assessment of a viable tumor. More accurate post-treatment HCC-specific radiologic criteria are needed in future studies. Second, because it is a retrospective study, some of the patients’ information were missing. External beam radiation therapy and systemic therapies may be used in combination, and some of the patients’ concurrent treatments might affect their progression-free survival. In our study, certain patients (37/122 = 30.3%) were excluded due to their incomplete imaging data, which could lead to selection bias. Third, as much as possible, as we want the imaging interpretation to be reliable, but it still cannot be the “golden standard” for the diagnosis of viable post-treatment HCCs. A previous study demonstrated that the tumor size shown on the image was reasonably well correlated with the histological tumor size [
      • Mastrocostas K.
      • Fischer S.
      • Munoz-Schuffenegger P.
      • Jang H.-J.
      • Dawson L.A.
      • Liu Z.A.
      • et al.
      Radiological tumor response and histopathological correlation of hepatocellular carcinoma treated with stereotactic body radiation therapy as a bridge to liver transplantation.
      ], while our study lacks pathological confirmation for the quantification of the viable tumor, and laboratory verifications are needed to support our results.
      In summary, we demonstrated the early response pattern prediction for a better progression-free survival and overall survival outcome compared with non-early response pattern. This finding might help in future clinical decision making.

      Declaration of Competing Interest

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

      Appendix A. Supplementary data

      The following are the Supplementary data to this article:

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