Continuation of First-line Therapy With Radiotherapy Versus Early Switch to Second-line Therapy in Oligoprogressive HCC
NCT ID: NCT06841172
Last Updated: 2025-08-01
Study Results
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Basic Information
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RECRUITING
PHASE3
132 participants
INTERVENTIONAL
2025-07-21
2028-07-01
Brief Summary
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Detailed Description
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For patients undergoing first-line systemic therapy (FLST) who develop oligoprogression - defined as the progression of a limited number of lesions during systemic treatment - the standard approach is typically to move to second-line systemic therapy (SLST). However, available SLST options remain limited, with median progression-free survival (PFS) of only 2.6-3.1 months, underscoring the urgent need for optimized treatment strategies.
The investigators hypothesize that administering local radiotherapy to oligoprogressive lesions while continuing current FLST - provided it remains effective for non-progressing disease - could delay the need for SLST and potentially improve both PFS and OS. This treatment approach has been validated in prospective studies in other malignancies. In addition, our recent multicenter retrospective study published in the Red Journal demonstrated that maintaining FLST in combination with radiotherapy for oligoprogressive lesions significantly prolonged PFS in patients with HCC.
Based on these findings, this study aims to conduct a prospective, randomized, controlled Phase III clinical trial in patients with oligoprogressive HCC following FLST. The trial will evaluate whether adding radiotherapy to oligoprogressive lesions while continuing current FLST provides clinical benefit compared to early transition to SLST.
The primary endpoint of this trial is PFS. The secondary endpoints include OS, objective response rate (ORR), disease control rate (DCR), duration of response (DOR), and safety (assessed according to CTCAE 5.0).
This trial will enroll patients with HCC who experience oligoprogression while receiving FLST, provided they have received at least three months of FLST prior to oligoprogression. Patients will be randomized 1:1 to one of two cohorts:
Cohort 1: Radiotherapy targeting oligoprogressive lesions while continuing current FLST.
Cohort 2: Early transition to SLST. In addition, exploratory objectives include the collection and analysis of circulating tumor DNA (ctDNA) to assess dynamic changes at baseline (time of oligoprogression), at first follow-up after radiotherapy, and at subsequent disease progression. A subset of participants will also undergo biopsies of both primary tumors and progressive lesions at baseline (oligoprogression) and at subsequent progression to further investigate molecular and genomic changes.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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Radiotherapy group
Patients will continue their current first-line systemic treatment, which may include, but is not limited to, combinations such as atezolizumab plus bevacizumab, tremelimumab plus durvalumab, or monotherapies such as lenvatinib, sorafenib, tislelizumab, durvalumab, or pembrolizumab, at the discretion of the treating physician. All oligoprogressive lesions will receive radiotherapy. Radiotherapy Techniques: 3D-CRT, IMRT, IGRT. Radiation dose and fractionation: radiation dose will be biologically effective dose (BED) ≥60 Gy, adjusted based on tumor location and size. For intrahepatic oligoprogressive lesions, eligibility for radiotherapy is determined by multidisciplinary team (MDT) consultation, and patients must meet the following criteria
1. Residual normal liver volume ≥700 mL
2. D ≥ 700 cc ≤ 23 Gy (for Child-Pugh B patients) If oligoprogression recurs after ≥3 months, additional radiotherapy will be administered in addition to continuation of current first-line systemic therapy.
radiotherapy
Radiotherapy (Biologically Equivalent Dose \[BED\]≥60Gy)
Systemic therapy (Continuation of current first-line systemic therapy)
Continuation of current first-line systemic therapy, which may include, but is not limited to, combinations such as atezolizumab plus bevacizumab, tremelimumab plus durvalumab, or monotherapies such as lenvatinib, sorafenib, tislelizumab, durvalumab, or pembrolizumab, at the discretion of the treating physician.
Control
For patients who received sorafenib as FLST, regorafenib will be the preferred second-line option. For patients who received other FLST regimens, the SLST selection will be determined through an MDT discussion led by the treating physician based on the patient's overall condition, prior therapies, drug indications, and potential adverse effects, ensuring an individualized treatment approach. The specific dosing regimen, administration frequency, and dose adjustments will strictly follow the same prescribing information for each drug.
Systemic therapy (Early switch to second-line systemic therapy)
For patients who received sorafenib as FLST, regorafenib will be the preferred second-line option. For patients who received other FLST regimens, the SLST selection will be determined through an MDT discussion led by the treating physician based on the patient's overall condition, prior therapies, drug indications, and potential adverse effects, ensuring an individualized treatment approach. The specific dosing regimen, administration frequency, and dose adjustments will strictly follow the same prescribing information for each drug.
Interventions
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radiotherapy
Radiotherapy (Biologically Equivalent Dose \[BED\]≥60Gy)
Systemic therapy (Continuation of current first-line systemic therapy)
Continuation of current first-line systemic therapy, which may include, but is not limited to, combinations such as atezolizumab plus bevacizumab, tremelimumab plus durvalumab, or monotherapies such as lenvatinib, sorafenib, tislelizumab, durvalumab, or pembrolizumab, at the discretion of the treating physician.
Systemic therapy (Early switch to second-line systemic therapy)
For patients who received sorafenib as FLST, regorafenib will be the preferred second-line option. For patients who received other FLST regimens, the SLST selection will be determined through an MDT discussion led by the treating physician based on the patient's overall condition, prior therapies, drug indications, and potential adverse effects, ensuring an individualized treatment approach. The specific dosing regimen, administration frequency, and dose adjustments will strictly follow the same prescribing information for each drug.
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* 2\. BCLC stage C at the time of first-line systemic treatment.
* 3\. Oligoprogression must be confirmed by imaging or histopathology during first-line systemic therapy (FLST). The number of oligoprogressive lesions is limited to 1-5, involving no more than 1-3 organs or systems. These lesions may represent either new metastatic sites or progression of pre-existing lesions. In addition, they must fit one of the two classifications defined in the ESTRO-EORTC consensus on oligometastases: repeat oligoprogression or induced oligoprogression. Oligoprogression may occur within intrahepatic lesions. In the case of lymph node progression, each lymphatic drainage region is considered a separate lesion. For example, the para-aortic lymph nodes (number 16a and number 16b) are each counted as separate lymph node regions.
* 4\. Patients must have experienced oligoprogression while receiving their current FLST and must not have previously received any other FLST that resulted in disease progression. Additionally, the current FLST must have maintained disease stability (SD) for at least three months prior to the occurrence of oligoprogression. Furthermore, the expected survival time must be ≥6 months.
* 5\. Oligoprogressive lesions must be eligible for radiotherapy and should have at least one measurable lesion that meets RECIST v1.1 criteria; Bone metastases without soft tissue formation are eligible but are considered non-measurable lesions; Bone metastases with soft tissue formation that meet RECIST v1.1 measurable criteria are considered measurable lesions.
* 6\. Liver function must be assessed as Child-Pugh score ≤7 points.
* 7\. Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0-1.
* 8\. Participants must be able to understand and voluntarily sign a written informed consent prior to the initiation of any study-specific procedures and must agree to comply with the treatment and follow-up requirements of the study.
* 9\. Male or female patients between 18 and 75 years of age.
* 10\. Availability of tumor and blood samples for biomarker assessment.
Exclusion Criteria
* 2\. Tumor progression occurring within 3 months after initiation of FLST.
* 3\. Patients with combined hepatocellular-cholangiocarcinoma (cHCC-CC)
* 4\. History of grade ≥3 serious adverse events due to FLST.
* 5\. Presence of brain, peritoneal or omental metastases with bleeding after FLST.
* 6\. Previous radiation therapy to the site of the oligoprogressive lesion.
* 7\. Active untreated hepatitis B, defined as HBsAg positive with HBV DNA levels above the upper limit of normal in the participating center's laboratory.
* 8\. Oligoprogressive lesions not amenable to radiotherapy.
* 9\. Alpha-fetoprotein (AFP) level ≥10,000 ng/mL at the time of oligoprogression.
* 10\. Diagnosis of malignancy other than liver cancer within 3 years prior to enrollment (excluding curatively treated basal cell carcinoma, squamous cell carcinoma of the skin, and/or carcinoma in situ).
* 11\. Currently participating in any interventional clinical research treatment or having received any other investigational drug or investigational device therapy within the last 4 weeks prior to enrollment.
* 12\. Presence of autoimmune disease or other conditions requiring long-term steroid use.
* 13\. Severe impairment of the heart, lungs, kidneys, or other vital organs, active infections (other than viral hepatitis), or other serious comorbidities that render the patient unable to tolerate treatment.
* 14\. known or suspected allergy to any study drug or to any drug related to this study.
* 15\. History of organ transplantation
* 16\. Pregnant or breastfeeding women
* 17\. Any other factor that the investigator believes may affect the enrollment of patients or the evaluation of study results.
18 Years
75 Years
ALL
No
Sponsors
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Shandong Cancer Hospital and Institute
OTHER
Responsible Party
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Jinbo Yue
Director of Radiation Oncology Department
Principal Investigators
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Jinbo Yue, Doctor
Role: PRINCIPAL_INVESTIGATOR
Shandong Cancer Hospital and Institute
Locations
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Jinan, Shandong 0531
Jinan, Shandong, China
Countries
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Central Contacts
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Facility Contacts
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References
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Leng B, Wang H, Ge Y, Sun X, Dong P, Dong X, Duan X, Wang Q, Xia Y, Ding L, Dai H, Liu T, Shi F, Zhang X, Yue J. Maintaining First-Line Therapy Plus Radiation Therapy May Prolong Progression-Free Survival and Delay Second-Line Therapy for Oligoprogressive Hepatocellular Carcinoma. Int J Radiat Oncol Biol Phys. 2025 Jun 1;122(2):325-338. doi: 10.1016/j.ijrobp.2024.12.039. Epub 2025 Jan 15.
Choi SH, Lee BM, Kim J, Kim DY, Seong J. Efficacy of stereotactic ablative radiotherapy in patients with oligometastatic hepatocellular carcinoma: A phase II study. J Hepatol. 2024 Jul;81(1):84-92. doi: 10.1016/j.jhep.2024.03.003. Epub 2024 Mar 11.
Doyle E, Killean AJ, Harrow S, Phillips ID. Systematic review of the efficacy of stereotactic ablative radiotherapy for oligoprogressive disease in metastatic cancer. Radiother Oncol. 2024 Jul;196:110288. doi: 10.1016/j.radonc.2024.110288. Epub 2024 Apr 20.
Tan VS, Padayachee J, Rodrigues GB, Navarro I, Shah PS, Palma DA, Barry A, Fazelzad R, Raphael J, Helou J. Stereotactic ablative radiotherapy for oligoprogressive solid tumours: A systematic review and meta-analysis. Radiother Oncol. 2024 Nov;200:110505. doi: 10.1016/j.radonc.2024.110505. Epub 2024 Aug 26.
Wang Q, Yu J, Sun X, Li J, Cao S, Han Y, Wang H, Yang Z, Li J, Hu C, Zhang Y, Jin L. Sequencing of systemic therapy in unresectable hepatocellular carcinoma: A systematic review and Bayesian network meta-analysis of randomized clinical trials. Crit Rev Oncol Hematol. 2024 Dec;204:104522. doi: 10.1016/j.critrevonc.2024.104522. Epub 2024 Sep 26.
Cappuyns S, Corbett V, Yarchoan M, Finn RS, Llovet JM. Critical Appraisal of Guideline Recommendations on Systemic Therapies for Advanced Hepatocellular Carcinoma: A Review. JAMA Oncol. 2024 Mar 1;10(3):395-404. doi: 10.1001/jamaoncol.2023.2677.
Llovet JM, Castet F, Heikenwalder M, Maini MK, Mazzaferro V, Pinato DJ, Pikarsky E, Zhu AX, Finn RS. Immunotherapies for hepatocellular carcinoma. Nat Rev Clin Oncol. 2022 Mar;19(3):151-172. doi: 10.1038/s41571-021-00573-2. Epub 2021 Nov 11.
Quail DF, Joyce JA. Microenvironmental regulation of tumor progression and metastasis. Nat Med. 2013 Nov;19(11):1423-37. doi: 10.1038/nm.3394.
Other Identifiers
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SDZLEC2025-025-02
Identifier Type: -
Identifier Source: org_study_id
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