Abstract
Introduction
Small liver tumours are difficult to identify during hepatectomy, which prevents curative tumour excision. Preoperative marking is a standard practice for small, deep-seated tumours in other solid organs; however, its effectiveness for liver tumours has not been validated. The objective of this study is to evaluate the effectiveness of preoperative markings for curative resection of small liver tumours.
Methods and analysis
This is an open-label, single-arm, single-centre, phase II study. Patients with liver tumours of ≤15 mm requiring hepatectomy will be enrolled and will undergo preoperative marking by placing a microcoil near the tumour using either the percutaneous or transvascular approach. The tumours, including the indwelling markers, will be excised. The primary endpoint will be the successful resection rate of liver tumours, defined as achieving a surgical margin of ≥5 mm and ≤15 mm. Secondary endpoints will include the results of preoperative marking and hepatectomy.
Ethics and dissemination
Ethical approval for this trial was obtained from the Ethical Committee for Clinical Research of Hiroshima University, Japan. The results will be published at an academic conference or by submitting a paper to a peer-reviewed journal.
Trial registration number
jRCTs062220088.
Keywords: Hepatobiliary tumours, Hepatobiliary surgery, Interventional radiology
STRENGTHS AND LIMITATIONS OF THIS STUDY.
Small liver tumours of ≤15 mm will be marked preoperatively by indwelling microcoils in their vicinity.
Preoperative marking will be performed using the percutaneous or transvascular approach.
The markers will be confirmed by intraoperative ultrasound, and liver tumours will be resected along with the markers.
The resected specimens will be pathologically evaluated for surgical margins.
This study adopted a new method of using marking coils that does not allow for blinding of the use of marking coils.
Introduction
Surgery remains the primary treatment for hepatocellular carcinoma (HCC) and metastatic liver cancer, despite the development of multimodal therapies.1–3 Identification of liver tumours using intraoperative ultrasonography (IOUS) is necessary for safe hepatectomy.4–6 However, some tumours are difficult to identify intraoperatively,6 7 which can lead to tumour exposure or insufficient securing of surgical margins. Positive surgical margins are associated with a poor prognosis.8 Although liver resection is often expanded to avoid tumour exposure, improper and extensive resection can lead to posthepatectomy liver failure.9 10 Therefore, a reliable method to avoid missing liver tumours intraoperatively should be established.
Especially in small liver tumours, identification can be difficult during hepatectomy. In cases of HCC with liver cirrhosis, the differential diagnosis between regenerative nodules and small liver tumours is difficult with IOUS.6 In cases of metastatic liver cancer undergoing preoperative chemotherapy, successful chemotherapy can lead to an imaging complete response (CR).7 11 Almost 70% of the imaging CR cases have microscopic residual disease in the resected specimen.12 Therefore, even if imaging CR is achieved, the area where the tumour is present should be resected.12 13 Advances in imaging modalities have improved the diagnostic yield for small liver cancers.14 Multidisciplinary therapy, including preoperative chemotherapy, is progressing to improve the prognosis of metastatic liver cancer.11 In the future, hepatectomies for small liver tumours that are difficult to identify intraoperatively are likely to increase in number.
Although preoperative marking is a standard technique for small, deep-seated tumours in other solid organs,15 the validation of its effectiveness for liver tumours remains insufficient. Only one pilot study has examined preoperative percutaneous marking for metastatic liver cancer,7 and no study has validated preoperative percutaneous marking for HCC. In addition, early stage small HCC cannot always be identified by ultrasound or CT,16 in which percutaneous marking is difficult. Angiography has been widely evaluated for its diagnostic ability and therapeutic usefulness in liver tumours.17 18 Based on this evidence, we aimed to demonstrate the usefulness of transvascular and percutaneous markings for both primary and metastatic liver tumours.
Ensuring sufficient surgical margins is essential for curative resection because it affects the curability of liver cancer.19 Hence, this phase II clinical study aims to determine the effectiveness of preoperative percutaneous or transvascular marking for the curative resection of small liver tumours. The primary endpoint will be the success rate of tumour resection, defined as a surgical margin of 5–15 mm.
Methods and analysis
Study design
This clinical study is a phase II trial of preoperative percutaneous or transvascular marking to achieve curative resection for small liver tumours that are expected to be missed during hepatectomy. This study will examine the usefulness of a new method of using marking coils, which cannot be blinded to the use of marking coils for preoperative marking. This will be a single-arm, open-label, historical control study. The study protocol was issued on 27 January 2023, and the amendment number is 1.1. The study is scheduled to be conducted between January 2023 and December 2024. The study design is illustrated in figure 1.
Figure 1.
Study design.
Potential participants
Patients with liver tumours ≤15 mm who meet all the following inclusion criteria and none of the exclusion criteria will be included. It is assumed that IOUS makes it difficult to distinguish between regenerative nodules and tumours in liver cirrhosis. It is often difficult to differentiate large regenerative nodules from small liver tumours, with a common size of 5–15 mm.20
Inclusion criteria
The inclusion criteria will be patients:
Who have scheduled a diagnostic percutaneous biopsy or contrast catheterisation of liver tumour or liver tissue.
Who have liver tumours requiring hepatic resection.
With Eastern Cooperative Oncology Group performance status of 0–1.
≥18 years of age.
Who have liver tumours that can be detected by various imaging modalities, including CT or MRI.
Who have no intervening organs in the puncture path at the time of marking and can be safely punctured under CT or ultrasound guidance.
With preserved major organ function, white cell count ≥3.0×109/l, haemoglobin ≥80.0 g/L, platelet count ≥50.0×109/l and total bilirubin ≤3.0 mg/dL.
Who has signed written informed consent.
Who can discontinue anticoagulants on the day of marking.
The percutaneous method will be used for patients who meet items 1–9. The transvascular method will be used for patients with an estimated glomerular filtration rate ≥60 mL/min/1.73 m3 in whom the catheter can be safely guided to the target vessel, in addition to the above items 1–9. In both methods, the number of liver tumours will not be fixed.
Exclusion criteria
The exclusion criteria will be patients:
With New York Heart Association class III or higher ischaemic heart disease.
With cirrhosis of liver damage grade C.
With dyspnoea requiring oxygen administration due to interstitial pneumonia or pulmonary fibrosis.
With chronic renal failure requiring dialysis.
Who have malignant diseases under treatment other than liver tumours.
Who are complicated by psychosis or psychiatric symptoms and judged to be difficult to participate in the study.
Who are deemed inappropriate for this study by the principal investigator or co-investigator.
With hypersensitivity to platinum alloys.
Sample size calculation
The success rate (surgical margin: 5–15 mm) of partial resection for liver tumours ≤15 mm not in contact with major vessels performed at our hospital between 2015 and 2018 was calculated to be 61%. Based on this value as the threshold, if the surgical success rate based on preoperative markings was estimated to be 85%, the sample size required to maintain a power of 80% with a one-sided test (significance level of 5%) is 21 cases. Considering a dropout rate of approximately 10%, the target number of patients in this study was set at 25.
Treatment protocol
Preoperative marking will be performed by the percutaneous or transvascular method and will be conducted simultaneously with the diagnostic examination for liver tumours to avoid additional invasive procedures and radiation exposure. A microcoil will be placed in the vicinity of the liver tumour as a marking. A C-stopper (Piolax Medical Devices, Yokohama, Japan) will be used as the marking coil. The position of the marking coil will be confirmed by CT before and after the marking procedure.
In cases where a percutaneous liver or tumour biopsy is scheduled to be performed under CT or ultrasound guidance, the percutaneous method will be performed. In cases where angiography is scheduled to be conducted, the transvascular method will be performed. If the tumour can be confirmed by plain CT or ultrasound and can be punctured from the body surface, the percutaneous method will be selected; if the tumour cannot be confirmed by this method or will be difficult to puncture, the transvascular method will be selected. Both procedures will be completed by an interventional radiology specialist certified by the Japanese Society for Interventional Radiology.
In cases of preoperative chemotherapy, marking will be performed before chemotherapy. The chemotherapy regimen will not be fixed. The period from marking to surgery will be the best time for each patient.
Our facility’s surgical treatment policy for liver cancer is as follows. Regarding metastatic liver cancer, the number of liver metastases and the presence or absence of lymph nodes are considered when deciding whether to perform preoperative chemotherapy. Upfront hepatectomy will not be performed in patients with suspected metastasis of the lymph nodes around the liver, and hepatectomy will only be performed in situations where the disease is under control after preoperative chemotherapy. In contrast, with regard to HCC, cases in which lymph node metastasis is evident in preoperative testing will not be candidates for upfront hepatectomy and chemotherapy will be performed.
Percutaneous marking
The liver tumour will be marked percutaneously with CT or ultrasound guidance under local anaesthesia. Following liver biopsy, the same site will be punctured again for marking. A puncture needle will be used to insert the tip near the tumour (within the range that could be removed along with the tumour at the time of hepatectomy), and one or two microcoils will be placed via the needle. The needle will not puncture the tumour directly to avoid dissemination.
Transvascular marking
The tumour will be marked transvascularly after diagnostic angiography. No new vascular puncture will be performed for only marking. A microcatheter will be introduced through the femoral artery using the Seldinger technique, and abdominal angiography will be conducted to identify the feeding artery of the liver tumour. The catheter will be advanced to the vicinity of the tumour (within the range that could be removed along with the tumour at the time of hepatectomy) under angiography, and the microcoil will be placed after confirming the target position by CT.
Hepatectomy
The indwelling marking coil will be confirmed using IOUS and excised along with the liver tumour. In principle, the puncture route for marking using the percutaneous method will be included in the resection area. The resected specimens will be pathologically examined for surgical margins and whether there is liver tissue degeneration associated with the marking coil.
Outcomes
To assess the effectiveness of this protocol, the primary endpoint will be the success rate of liver tumour resection when preoperative marking is performed.
The secondary endpoints will be preoperative marking outcomes, including (1) marking success rate, (2) marking visibility preoperatively (evaluated by percutaneous ultrasound and CT), (3) marking visibility intraoperatively (evaluated by IOUS), (4) marker-to-tumour distance, (5) marking complications and surgical outcomes, including (6) operative time, (7) amount of blood loss, (8) liver resection volume and (9) postoperative complications.
Definition of successful liver tumour resection
Successful liver tumour resection will be defined as achieving a surgical margin of ≥5 mm and ≤15 mm. The local recurrence rate has been reported to be high when the resection margin is ≤5 mm.19 In addition, especially in cases of damaged liver, such as cirrhosis, excessive liver resection is difficult to regard as accurate from the perspective of promoting liver damage. Therefore, the surgical margin should not be extremely small or large for partial liver resection. The surgical margin distance will be measured on the resected specimen by a pathologist.
Data monitoring and safety assessments
The principal investigator or subinvestigator will prepare a case report form promptly after collecting the evaluation data and adverse events (AEs). AEs will be collected up to 30 days after the hepatectomy. The implementation status will be regularly reported to the Ethical Committee for Clinical Research of Hiroshima University every year from the day the implementation plan is published in the Japan Registry of Clinical Trials (jRCT). The principal investigator or subinvestigator will discontinue or suspend clinical research on the participant in the following cases: (1) when the research participant withdraws consent to participate in the research, (2) when it turns out that the eligibility (inclusion criteria/exclusion criteria) is not met after registration, (3) if the continuation of the study is judged unfavourable due to deterioration of the primary disease, (4) when it is difficult to continue the study due to exacerbation of complications, (5) when it is difficult to continue the study due to AEs or (6) when the principal investigator determines that it is appropriate to discontinue the research. This clinical trial will be terminated when the following occur: (1) when critical information regarding the quality, safety or efficacy of research equipment is obtained; (2) when it is judged difficult to achieve the planned number of cases within the study period; (3) when information that undermines the ethical validity or scientific rationality of the research is obtained and (4) based on the aforementioned events, if the review committee recommends or instructs to discontinue.
Statistical analysis plan
The primary objective is to verify the successful resection rate of small liver tumours using preoperative marking in all study participants. The success rate of liver tumour resection and its one-sided 95% CI will be calculated. Whether it falls below the threshold of 61% (the liver tumour resection success rate when marking is not performed) will be verified. CIs will be calculated using an exact method (Clopper-Pearson) based on a binomial distribution. If the liver tumour resection success rate and 95% CI in this study protocol do not fall below the threshold of 61%, preoperative marking will be determined to be effective. The primary and secondary endpoints will also be analysed separately for percutaneous and transcatheter marking cases. Regarding safety evaluation, the number and rate of AEs will be calculated for each follow-up period (timing of preoperative marking and hepatectomy).
Patient and public involvement
The patients and/or the public were not involved in the design, conduct, reporting or dissemination of this research.
Ethics and dissemination
This clinical trial will be performed in accordance with the principles of the Declaration of Helsinki. Written informed consent will be obtained from all patients before their inclusion in the study. The protocol was approved by the Ethical Committee for Clinical Research of Hiroshima University, Japan, and has been prospectively registered in the jRCT.
A primary endpoint report will be provided to the competent authorities and the Ethical Committee for Clinical Research of Hiroshima University within 1 year after the completion of the study. Anonymised information obtained during the study will be retained for 5 years from the date of completion of the study. Trial results will be presented at an academic conference or published in a peer-reviewed journal. The datasets used in this study will be available from the corresponding author on reasonable request.
Discussion
This trial will investigate whether preoperative marking contributes to curative liver resection of small liver tumours. Preoperative marking will be performed either by using a transcatheter or percutaneously by using a microcoil. This research, which will use marking coils for a new application, will be conducted as an open-label and single-arm study because it is difficult to blind the use or non-use of preoperative marking for liver tumours. The primary endpoint will be the success rate of liver tumour resection with adequate surgical margins. Secondary endpoints will include marker visibility during hepatectomy, measurement of the marker-to-tumour distance, complications during preoperative marking and surgical outcomes. Since this study primarily focuses on the short-term safety and efficacy of this protocol, further studies will be needed to determine whether resection of small liver tumours using this protocol contributes to an improved long-term prognosis.
The usefulness of indocyanine green (ICG) fluorescence and intraoperative contrast-enhanced ultrasonography as navigation systems during hepatectomies has been reported.21 22 However, both methods have limitations. ICG fluorescence is only effective against tumours on the liver surface. It is often difficult to detect small tumours in patients with liver cirrhosis using intraoperative contrast-enhanced ultrasound. A navigation system that uses this preoperative marking protocol can address these limitations.
A concern with this preoperative marking protocol is the presence of cases where the microcoil remains in the body. Cases in which liver resection will not be indicated include those due to failure of chemotherapy after marking and in which the coil will not be included in the resected specimen due to the long distance between the marker and tumour. However, the microcoil used in this protocol is for embolising blood vessels that were originally designed to remain permanently in the body. Therefore, the debris may not adversely affect organ function.
Therefore, we will analyse the safety and effectiveness based on this treatment protocol. We expect that these findings will lead to future phase III clinical trials.
Supplementary Material
Footnotes
Contributors: SK, TKobayashi and HO conceived the study. RN, HS, HT and MO designed the study and developed treatment protocols. SF, YN, KO, KM, DT, NH, TKawaoka and MT assisted in preparing the study protocol. KC and KA critically appraised the marking technique. SF drafted the original manuscript and critically reviewed the protocol. SK supervised the study. HO designed the trial, prepared the study protocol and conducted the correspondence. All authors critically revised and approved the manuscript.
Funding: This study was supported by the Tsuchiya Memorial Medical Foundation. Marking coils will be provided by Piolax Medical Devices (Yokohama, Japan).
Competing interests: This study will be conducted with the provision of research targeting medical equipment from Piolax Medical Devices, Yokohama, Japan. Piolax Medical Devices provides information on research equipment but does not intervene in research data management, statistical analysis and auditing.
Patient and public involvement: Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review: Not commissioned; externally peer reviewed.
Ethics statements
Patient consent for publication
Not applicable.
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