Neoadjuvant Hypofractionated Stereotactic Body Radiation Therapy Prior to Surgery for Hepatocellular Carcinoma: a Feasibility Study.

Study Overview
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Brief Summary
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Hepatocellular carcinoma (HCC) is the fifth more common cancer in the world, with high mortality rates, due to the low number of patients who are eligible for therapy with curative intent, like surgical resection. Moreover, surgical resection is associated with a high risk of tumor recurrence, because of the tumor seeding through microscopic intrahepatic vessels that surround the tumor, the so-called microvascular invasion. To adequately deal with this phenomenon, the surgeon has to perform either an 'anatomical' liver resection, which remove not only the tumor but also the whole corresponding vascular network, or a 'tumorectomy' with resection margins of at least 2 cm. Unfortunately, these principles cannot always be achieved due to underlying liver cirrhosis that is present in more than 80% of patients. Stereotactic body radiation therapy (SBRT) has been proven to efficiently necrotize or stabilize HCC nodules when surgery is not possible. Our hypothesis is that pre-treatment with SBRT prior to surgical resection of HCC might improve the results through the destruction of possible seeding in the peritumoral environment. Given the novelty of this therapeutic strategy, it is necessary to verify its feasibility and safety, prior to test its efficacy in patients with HCC. The KARCHeR-1 study aims at making sure that preoperative SBRT would not result in important delays or serious adverse events such as to cancel the planned surgical resection, in patients who otherwise could have benefited from it. This issue is commonly called 'drop-out'. Thirty patients are expected to be included in the KARCHeR-1 study, which would be in favor of continuing to evaluate this therapeutic strategy if less than 3 drop-outs occur, and would be immediately discontinued if 3 drop-outs occur. Other outcomes will also been studied, like intraoperative issues, postoperative morbi-mortality, pathological features on the surgical specimen and its correlation with preoperative imaging, and finally, tumor recurrence and survival.

Official Title
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A Pilot Study on the Feasibility and Tolerance of Neoadjuvant Hypofractionated, Stereotactic Body Radiation Therapy Prior to Surgical Resection of Uninodular Hepatocellular Carcinoma.

Conditions
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Hepatocellular Carcinoma

Intervention / Treatment
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* Combination Product: Surgery with Neoadjuvant stereotactic body radiation therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Biopsy-proven hepatocellular carcinoma or EASL/AASLD criteria Single nodule, 3 to 8 cm of largest diameter Hepatocellular carcinoma eligible for conventional liver resection with curative intent (R0), without preoperative portal vein embolization Exclusion Criteria: Performance status > 2 Severe comorbidity with contraindication for either surgery or radiation therapy Decompensated liver cirrhosis (Child-Pugh B or C) Neoplastic portal vein thrombosis or extra-hepatic metastases Previous anticancer therapy within the last 5 years

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental group<br> | Combination Product: Surgery with Neoadjuvant stereotactic body radiation therapy<br>* Stereotactic hypofractionated robotic radiation therapy (24-45 Gy / 3 fractions) followed after 4-6 weeks by conventional hepatectomy (either anatomical liver resection, or non-anatomical liver resection with intention to achieve a minimal 2 cm margin).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Drop-out rate | Drop-out rate: proportion of patients in whom surgical resection cannot be achieved, due to (at least one of the following reasons): serious adverse events related to radiation therapy (especially liver decompensation); disease progression while receiving radiation therapy or awaiting surgery; patient's death. | Five months after the inclusion of the last participating patient | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Intraoperative number of packed red blood cells transfused (if any). |  | Postoperative 90 days | 
| Toxicity of radiation therapy using the National Cancer Institute CTCAE v.5.0 criteria |  | Postoperative 90 days | 
| Duration of surgery. |  | Postoperative 90 days | 
| Volume of intraoperative blood loss |  | Postoperative 90 days | 
| Quality of life by EORTC QLQ-C30 |  | between before and after stereotactic radiotherapy | 
| Intraoperative adverse events |  | Postoperative 90 days | 
| Postoperative severe and overall morbidity rate | defined using the Comprehensive Complication Index and graded with the Dindo-Clavien score | Postoperative 90 days | 
| Postoperative mortality rate. |  | Postoperative 90 days | 
| Correlation between radiological observations on preoperative imaging and pathological features on surgical specimen (like percentage of tumor necrosis). |  | Postoperative day 30. | 
| Actuarial overall survival and disease-free survival. |  | Postoperative 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hepatocellular carcinoma, Stereotactic body radiation therapy, Hepatectomy, Neoadjuvant therapy, Drop-out