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Combinación de quimioembolización transarterial (TACE) y ablación térmica versus TACE sola para el carcinoma hepatocelular

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Antecedentes

El carcinoma hepatocelular es el sexto cáncer más frecuente en todo el mundo. La resección hepática se considera el tratamiento curativo del carcinoma hepatocelular. Sin embargo, sólo el 20% de las personas con carcinoma hepatocelular son candidatas a la resección, lo que pone de manifiesto la importancia de tratamientos no quirúrgicos eficaces. Hasta ahora, la quimioembolización transarterial (transcatheter arterial chemoembolisation [TACE]) es el tratamiento paliativo más común para el carcinoma hepatocelular, pero sus beneficios clínicos todavía no son satisfactorios. Durante los últimos años, algunos estudios han informado que la combinación de TACE más ablación térmica puede conceder un pronóstico más favorable que la TACE sola. Sin embargo, falta evidencia clara y contundente que demuestre los efectos beneficiosos o perjudiciales de la combinación de TACE y terapia de ablación térmica.

Objetivos

Evaluar los efectos beneficiosos y perjudiciales de la combinación de ablación térmica con TACE versus TACE sola en personas con carcinoma hepatocelular.

Métodos de búsqueda

Se realizaron búsquedas en el Registro de ensayos controlados del Grupo Cochrane Hepatobiliar (Cochrane Hepato‐Biliary Group), el Registro Cochrane central de ensayos controlados (Cochrane Central Register of Controlled Trials) en la Biblioteca Cochrane, MEDLINE, Embase, LILACS, Science Citation Index Expanded y Conference Proceedings Citation Index‐Science. Se procuró identificar ensayos clínicos aleatorizados relevantes también en las bases de datos China National Knowledge Infrastructure (CNKI) y Wanfang. Se buscaron estudios en curso en los sitios web de registro de ensayos. También se buscó de forma manual en fuentes de literatura gris. La fecha de la última búsqueda fue el 22 de diciembre de 2020.

Criterios de selección

Se planificó incluir todos los ensayos clínicos aleatorizados que compararan la combinación de TACE más ablación térmica versus TACE sola para el carcinoma hepatocelular, sin importar el idioma, el año de publicación, el estado de publicación ni los desenlaces informados.

Obtención y análisis de los datos

Se previó utilizar los procedimientos metodológicos estándar recomendados por Cochrane. Se planificó calcular las razones de riesgos (RR) con los correspondientes intervalos de confianza (IC) del 95%. Para las variables de tiempo hasta el evento, se planificó utilizar los métodos de análisis de supervivencia y expresar el efecto de la intervención como un cociente de riesgos instantáneos (CRI) con lC del 95%. Si el logaritmo del CRI y la varianza no se proporcionaban directamente en los informes, se previó calcularlos indirectamente, siguiendo los métodos para incorporar los datos resumidos de tiempo hasta el evento en el metanálisis. Se tenía previsto evaluar el riesgo de sesgo de los estudios incluidos mediante la herramienta RoB 2. Se planificó evaluar la certeza de la evidencia con el método GRADE y presentar la evidencia en una tabla de resumen de los hallazgos.

Resultados principales

De los 2224 registros recuperados con las búsquedas, 135 registros elegibles se consideraron para la revisión del texto completo. Se excluyeron 21 de estos registros porque las intervenciones utilizadas estaban fuera del alcance de esta revisión o los estudios no eran ensayos clínicos aleatorizados. Los 114 registros restantes, que informaron sobre 114 estudios, se incluyeron en la categoría de estudios en espera de clasificación porque no fue posible estar seguros de que fueran ensayos clínicos aleatorizados a partir de la información del documento del estudio. No fue posible obtener información sobre el registro del protocolo de estudio de ninguno de los 114 estudios. Tampoco fue posible obtener información sobre la aprobación de los estudios por parte de los comités regionales de ética de la investigación, ni de los autores de los estudios ni a través de las búsquedas realizadas en los registros de ensayos. Los autores correspondientes no respondieron a las preguntas sobre el diseño ni la realización de los estudios, excepto uno del que no se recibió una respuesta satisfactoria. También se les hizo llegar estas preocupaciones a los editores de las revistas que publicaron los 114 estudios, y no se recibió respuesta con información útil. Además, pareció haber una inclusión inadecuada de los participantes de los ensayos, sobre la base del estadio del cáncer y la gravedad de la enfermedad hepática, que deberían haber recibido otras intervenciones según las guías de las sociedades científicas.

En consecuencia, no se encontraron ensayos clínicos aleatorizados confirmados que evaluaran la combinación de TACE más ablación térmica versus TACE sola en personas con carcinoma hepatocelular para su inclusión en esta revisión.

Se identificaron cinco ensayos en curso, mediante una búsqueda manual en los sitios web de ensayos clínicos.

Conclusiones de los autores

No fue posible encontrar para inclusión ensayos clínicos aleatorizados confirmados que evaluaran los efectos beneficiosos o perjudiciales de la combinación de TACE más ablación térmica versus TACE sola en personas con carcinoma hepatocelular. Por lo tanto, los resultados de esta revisión no mostraron ni rechazaron la eficiencia de la combinación de TACE más ablación térmica versus TACE sola en personas con carcinoma hepatocelular.

Se necesitan ensayos que comparen los efectos beneficiosos y perjudiciales de la combinación de TACE más ablación térmica versus TACE sola en personas con carcinoma hepatocelular, no elegibles para tratamientos con intención curativa (trasplante hepático, resección quirúrgica por ablación) y que tengan suficiente reserva hepática, según la evaluación de la puntuación de Child Pugh, y que no presenten metástasis extrahepáticas. Por lo tanto, los participantes de los ensayos futuros deben estar clasificados en el estadio B del Barcelona Clinic Liver Cancer (estadio intermedio) (BCLC‐B) o un equivalente, con otros sistemas de estadiaje.

Combinación de quimioembolización transarterial y ablación térmica frente a TACE sola para el carcinoma hepatocelular

Antecedentes

El carcinoma hepatocelular (un tipo frecuente de cáncer de hígado) es el sexto cáncer más común en el mundo. La quimioembolización transarterial (TACE) (inyección de agentes en los vasos de alimentación del tumor para reducir la irrigación de sangre al tumor y destruirlo) es el tratamiento más común para el carcinoma hepatocelular, pero el desenlace clínico es deficiente. En los últimos años, la combinación de TACE más ablación térmica (eliminación de las células tumorales mediante la producción de calor o frío) ha demostrado ser más eficaz que la TACE sola. Sin embargo, todavía no hay evidencia que demuestre el efecto beneficioso o perjudicial de la combinación de TACE con ablación en las personas con carcinoma hepatocelular.

Objetivo

El objetivo era evaluar los efectos beneficiosos y perjudiciales de la combinación de TACE con ablación térmica frente a TACE sola para el carcinoma hepatocelular.

Resultados clave

Se consideraron 135 registros elegibles para la revisión del texto completo. Se excluyeron 21 de estos registros porque las intervenciones utilizadas estaban fuera del alcance de esta revisión o los estudios no eran ensayos clínicos aleatorizados. Los 114 registros restantes, que informaron sobre 114 estudios, se incluyeron en la categoría de estudios en espera de clasificación porque no fue posible estar seguros de que fueran ensayos clínicos aleatorizados a partir de la información del documento del estudio. No fue posible obtener información sobre el registro del protocolo de estudio de ninguno de los 114 estudios. Tampoco fue posible obtener información sobre la aprobación de los estudios por parte de los comités regionales de ética de la investigación, ni de los autores de los estudios ni a través de las búsquedas realizadas en los registros de ensayos. Los autores correspondientes no respondieron a las preguntas sobre el diseño ni la realización de los estudios, excepto uno del que no se recibió una respuesta satisfactoria. También se les hizo llegar estas preocupaciones a los editores de las revistas que publicaron los 114 estudios, y no se recibió respuesta con información útil. Además, pareció haber una inclusión inadecuada de los participantes de los ensayos, sobre la base del estadio del cáncer y la gravedad de la enfermedad hepática, que deberían haber recibido otras intervenciones según las guías de las sociedades científicas.

Se identificaron cinco ensayos en curso, mediante una búsqueda manual en los sitios web de ensayos clínicos.

Conclusiones

No se encontraron ensayos clínicos aleatorizados confirmados que evaluaran la combinación de TACE más ablación térmica frente a TACE sola en personas con carcinoma hepatocelular para su inclusión en esta revisión. Por lo tanto, no es posible establecer conclusiones sobre el tratamiento del carcinoma hepatocelular con TACE más ablación térmica frente a TACE sola.

Se necesitan ensayos que comparen los efectos beneficiosos y perjudiciales de la combinación de TACE más ablación térmica versus TACE sola en personas con carcinoma hepatocelular, no elegibles para tratamientos con intención curativa (trasplante hepático, resección quirúrgica por ablación) y que tengan suficiente reserva hepática, según la evaluación de la puntuación de Child Pugh, y que no presenten metástasis extrahepáticas. Por lo tanto, los participantes de los ensayos futuros deben estar clasificados en el estadio B del Barcelona Clinic Liver Cancer (estadio intermedio) (BCLC‐B) o un equivalente, con otros sistemas de estadiaje.

Authors' conclusions

Implications for practice

No eligible randomised clinical trials assessing the beneficial and harmful effects of the combination of TACE plus thermal ablation versus TACE alone were included into this review. Therefore, our results did not show or reject the efficiency of any treatment strategy for hepatocellular carcinoma.

Implications for research

Large prospectively registered trials with rigorous methods comparing the beneficial and harmful effects of the combination of TACE plus thermal ablation versus TACE alone in hepatocellular carcinoma are needed. Such randomised clinical trials should be designed according to the SPIRIT statement (Chan 2013); registered in a WHO data register; with obtained full ethical approval; and reported according to the CONSORT statement (Schulz 2010). Such trials should be conducted in people who are not eligible for treatments with curative intent (liver transplantation, ablation surgical resection), who have sufficient liver reserve as assessed by the Child Pugh score, and do not have extrahepatic metastases. Therefore, future trial participants must be classified at Barcelona Clinic Liver Cancer Stage B (intermediate stage) (BCLC‐B) or an equivalent, with other staging systems.

In view of the large number of studies we have identified as potentially problematic, there is an urgent need for validated tools to assist systematic review teams in identifying problematic studies. Our approach to assessing the 114 studies identified through electronic searching reinforces the importance of systematic review teams carefully appraising the studies they identify in order to reduce the impact of potentially problematic studies on evidence used to inform healthcare decision‐making.

Background

Description of the condition

Hepatocellular carcinoma is the most predominant form of primary liver cancer, accounting for approximately 90% of occurrences, and it represents an increasing serious health problem worldwide (Mohd 2013; Laursen 2014; National Center for Health Statistics (US) 2015). The pathogenesis of hepatocellular carcinoma is a highly complex process which usually occurs in the context of liver cirrhosis, mainly involving chronic inflammation injury and the accumulation of genetic alterations (Schulze 2016). Hepatocellular carcinoma is the sixth most common cancer and the second most common cancer‐related cause of death worldwide. Around 782,000 people are diagnosed and 746,000 die from hepatocellular carcinoma every year worldwide, with China accounting for about 50% of the total number of cancers and deaths (Torre 2015; Forner 2018). The incidence of hepatocellular carcinoma varies among different global regions. Approximately 80% of hepatocellular carcinomas occur in sub‐Saharan Africa and eastern Asia, due to the high prevalence of hepatitis B virus infection and the intake of aflatoxin B1, with an incidence of over 20 per 100,000 individuals (El‐Serag 2012). An intermediate hepatocellular carcinoma burden occurs in Mediterranean countries, with an incidence of 10 to 20 per 100,000 individuals. In America, the incidence is lower than 5 per 100,000 individuals (Mittal 2013). The main causes of hepatocellular carcinoma in Europe and America is hepatitis C virus infection and alcohol abuse (Trad 2017). Hepatocellular carcinoma incidence among men is four to eight times higher than among women (Yang 2014). Most hepatocellular carcinoma patients are older than 45 years (Llovet 2016).

The most prevalent staging system for hepatocellular carcinoma is the Barcelona Clinic Liver Cancer (BCLC) system which divides hepatocellular carcinoma into five stages based on the size and number of tumours, vascular invasion, and liver function (EASL‐EORTC 2012). The main risk factors are liver cirrhosis, infection with hepatitis B virus and C virus, intake of toxic substance (alcohol and aflatoxin B1), and metabolic syndromes (diabetes, obesity, non‐alcoholic fatty liver disease, and hereditary haemochromatosis). Approximately 80% of hepatocellular carcinoma develops in people with liver cirrhosis (Kew 2014). The hepatocellular carcinoma mortality among men with a high baseline body mass index is five times higher than among men with a normal body mass index (Forner 2018). Other risk factors include age, tobacco use, and coinfection of human immunodeficiency virus (HIV). Diagnosis of hepatocellular carcinoma is confirmed by either histopathological biopsy or imaging techniques (ultrasound, contrast‐enhanced computed tomography, or contrast‐enhanced magnetic resonance imaging (MRI)) according to the current practice guideline of the American Association for the Study of Liver Diseases (AASLD) (Bruix 2011).

The treatment for hepatocellular carcinoma can be divided into curative therapies and palliative therapies. Resection, liver transplantation, and locoregional ablation are radical therapies with the curative intention of prolonging survival. However, only 20% of hepatocellular carcinoma patients, mostly diagnosed by regular screening, may gain survival benefit from resection and liver transplantation (Abdel‐Rahman 2013). Curative ablation is recommended for patients with only two or three nodules which are less than 3 cm or a single nodule. The palliative therapies mainly involve transcatheter arterial chemoembolisation (TACE), sorafenib, and systemic treatment, with no, or moderate survival benefits (Oliveri 2011; Chacko 2016).

Description of the intervention

In this review, we planned to focus on the combination of TACE with sequential thermal ablation therapy. During this combined therapy, TACE is performed firstly for all baseline tumours, followed by thermal ablation on all baseline tumours or only tumours that remain active after TACE. Baseline tumours refer to all active tumours before TACE. Active tumours are defined as 'living' tumours, which show characteristic vascular features of hepatocellular carcinoma — arterial hyper‐vascularisation with washout in the portal venous system or the late phase at contrast‐enhanced computed tomography, or contrast‐enhanced MRI.

TACE is the most common treatment for hepatocellular carcinoma, which is recommended as the first‐line treatment for intermediate stage hepatocellular carcinoma, according to the BCLC staging system (EASL‐EORTC 2012). The mechanism of TACE consists of the injection of chemotherapeutic drugs, lipiodol and vascular occlusive agents into the hepatic artery; these can inhibit tumour growth, promote cell death, and maybe prolong survival (Oliveri 2011). The rationale for TACE is based on the concept that most of the blood supply of intra‐hepatic tumours is provided by the hepatic artery, while 75% of the blood flow of the normal liver parenchyma is supplied by the portal vein (Vogl 2003). Therefore, TACE can lead to selective necrosis of the liver tumour while it hardly affects normal liver parenchyma (Jaeger 1996). Alternatively, TACE can also be used to downsize a tumour or as a bridge to liver transplantation (Martin 2015).

Thermal ablation refers to the ablation therapies that induce irreversible cellular injury of tumour cells through heat mechanisms or cold mechanisms. Most kinds of ablation therapies are performed using a percutaneous approach, under real‐time contrast‐enhanced computed tomography, dynamic MRI, or ultrasound guidance. A puncture needle is used to lead the electrode into the target. After setting appropriate output power and duration, the electrode begins to produce heat or cold to surrounding tissue to induce complete necrosis (Ahmed 2011).

There are five main thermal ablation techniques (Goldberg 2003): radiofrequency ablation (Ahmed 2011), microwave ablation (Brace 2007; Lubner 2013; Poggi 2015), laser ablation (Ahmed 2011), ultrasound ablation (Wijlemans 2012), and cryoablation (Rubinsky 1990; Ahmed 2011)

Radiofrequency ablation is the most widely used and the most well‐studied thermal ablation, and it is regarded as the standard therapy for BCLC‐A tumours which are not suitable for surgery (EASL‐EORTC 2012). It has been proved to have a therapeutic efficacy similar to that of surgical resection or liver transplantation for hepatocellular carcinoma with a diameter within 3 cm (Zhu 2016). Radiofrequency ablation can induce complete necrosis of surrounding tissue by generating heat. The radiofrequency ablation technique also serves as a model for exploring the use of thermal ablation in clinical practice.

Microwave ablation can induce tumour cell death by microwave heating, which is generated by dielectric hysteresis (Ahmed 2011). Microwave ablation can reduce tumour tissue in a more efficient way by producing faster heating and higher temperatures compared to radiofrequency ablation (Brace 2007; Yang 2007). Furthermore, microwave ablation, compared to radiofrequency ablation, has better performance on overcoming heat sink effect (Ahmed 2011). However, microwave ablation is still a novel ablation technique; more details should be explored in further clinical practice.

Laser ablation is an ablative therapy that can induce electromagnetic heating to increase tissue temperatures to lethal levels by laser beam and results in complete necrosis of surrounding tissue (Ahmed 2011).

Ultrasound ablation therapy can concentrate intersecting beams of ultrasound on a target tumour through an acoustic lens and thus induce irreversible damage (Zhu 2013a).

Cryoablation destroys cells by the application of alternating freezing and thawing to induce irreversible cellular injury (Awad 2009; Song 2016a).

How the intervention might work

TACE is a palliative therapy, with a tumour response rate of 24% to 53% (Yang 2009). Generally, several sessions of TACE are needed to achieve a high necrosis rate and local tumour control (Satake 2008). Due to high toxicity and adverse effects of chemotherapeutic agents, repeated TACE may result in liver failure (Li 2010). Besides, the incomplete necrosis of the tumour after TACE may cause intra hepatic recurrence of malignancy (Wu 2005).

Thermal ablation is a minimally invasive and curative therapy, with a complete necrosis rate of 76% to 100% for small hepatocellular carcinoma (Morimoto 2010); and 30% to 70% for larger hepatocellular carcinoma (Livraghi 2000). In patients with early‐stage hepatocellular carcinoma (BCLC 0 or A) who are not suitable for resection, ablation therapy achieved five‐year survival rates of 50% to 70% (EASL‐EORTC 2012). The main advantages of thermal ablation include effective tumour ablation, preservation of maximal normal liver parenchyma, and low rates of complications (Yang 2009). The introduction of the mechanism of five types of thermal ablation therapies is shown below.

During radiofrequency ablation, an electrical circuit is created between a radiofrequency probe, the patient, and the grounding pads (Ahmed 2011). The alternating current leads to frictional agitation at the ionic level and heat generation around the probe (Corwin 2001). Dehydration and subsequent carbonisation of surrounding tissues would occur when the temperature is above 100°C (Poggi 2015).

Microwave ablation generates heat through a process known as dielectric hysteresis, in which polar molecules in tissue (primarily water) are forced to continuously realign with the oscillating electric field (Lubner 2013). Thus, the kinetic energy of reformed molecules and the temperature of tissue increase. Microwave power can produce extremely high temperatures (> 150 °C) and induce necrosis of tissue (Brace 2007).

Laser ablation treats the tumour by irradiating it with a laser beam, which is an efficient and precise energy source for tissue heating (Ahmed 2011).

Ultrasound ablation is a non‐invasive therapy. The main mechanism of ultrasound ablation is the thermal energy deposition by a focussed ultrasound beam. The targeted tissue absorbs a significant amount of energy from a highly directional ultrasound beam, resulting in elevation of temperature (Wijlemans 2012).

Cryoablation is an ablative technique which can induce protein denaturation, cellular dehydration and subsequent tissue necrosis by the application of extreme low temperatures to tumour tissue (Rubinsky 1990; Wu 2015).

The rationale of the combination of TACE and sequential ablation is that sequential ablation therapy can remedy the limitation of TACE alone. Firstly, ablation therapy can directly destroy tumour tissue, increase complete necrosis rate and produce a favourable prognosis (Li 2010); secondly, sequential ablation therapy reduces the time needed for interventional treatment, which reduces liver damage and improves quality of life (Li 2016). In addition, the combination of TACE and sequential ablation has synergistic effects on treating liver tumours. The occlusion of hepatic arteries achieved by TACE can reduce blood flow and decrease the heat sink effect, which is helpful for enlarging the ablation zone and achieving complete necrosis (Peng 2013).

Why it is important to do this review

Hepatic surgical resection is regarded as a curative therapy for hepatocellular carcinoma. However, only about 20% of hepatocellular carcinoma patients are candidates for surgical resection, which highlights the importance of effective non‐surgical therapies (Yin 2014). Until now, TACE is the most commonly used palliative therapy for hepatocellular carcinoma, but the effect remains unsatisfactory (Oliveri 2011). In recent years, the combination of TACE plus thermal ablation has shown better survival than TACE alone for people with hepatocellular carcinoma. Some studies have reported that the combination modality can confer a more favourable prognosis than TACE alone for different stages of hepatocellular carcinoma (Yang 2009; Azuma 2016; Hyun 2016; Song 2016a). However, there is still a lack of clear and compelling evidence on the beneficial or harmful effect of the combination of TACE and thermal ablation therapy. Therefore, we embarked on this Cochrane Review hoping to provide the best available level of evidence of the role of the combination of TACE plus thermal ablation versus TACE alone for hepatocellular carcinoma.

Objectives

To assess the beneficial and harmful effects of the combination of TACE plus thermal ablation compared with TACE alone in people with hepatocellular carcinoma.

Methods

Criteria for considering studies for this review

Types of studies

We planned to include all randomised clinical trials comparing the combination of TACE and thermal ablation with TACE alone for hepatocellular carcinoma, irrespective of publication status or blinding.

Types of participants

All trial participants older than 18 years, with hepatocellular carcinoma, diagnosed by either histopathological biopsy or the radiological criteria in clinical practice guidelines.

Types of interventions

Experimental intervention

  • A combination of TACE plus thermal ablation. Thermal ablation can be performed with any of the following techniques: radiofrequency ablation, microwave ablation, laser ablation, ultrasound ablation, and cryoablation.

Control intervention

  • TACE alone

For both experimental group and control groups, we planned to include all TACE treatments irrespective of dosage and types of chemotherapeutic drugs, and vascular occlusive agents (Imai 2014).

Types of outcome measures

We planned to measure the outcomes listed below. We planned to base our primary conclusions on the outcome results at the longest follow‐up. We planned to include trials regardless of whether they reported on our outcomes of interest.

Primary outcomes

  • All‐cause mortality.

  • Progression‐free survival. This is defined as the period from the date of first treatment to the date of the first documented disease progression by either radiological assessment or liver biopsy or death caused by any reason, whichever happened first.

  • Proportion of participants with serious adverse events. We planned to use the definition of serious adverse events in the International Conference on Harmonisation (ICH) Guidelines for Good Clinical Practice (ICH‐GCP 1997): that is, any untoward medical occurrence that results in death, is life‐threatening, requires hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability or incapacity, or any medical event that might have jeopardised the patient, or required intervention to prevent it. All other adverse events were considered as non‐serious adverse events. We planned to accept all reported serious adverse events assessed at variable time points throughout the conduct of the review. If possible, we noted the period of reported serious adverse events and classified them as short‐term (primary observed period) and long‐term serious adverse events.

Secondary outcomes

  • Tumour response. We planned to evaluate the tumour response according to the Modified Response Evaluation Criteria in Solid Tumours (mRECIST) guideline (Lencioni 2010), as follows.

    • Complete response (CR): disappearance of any intratumoural arterial enhancement in all target lesions.

    • Partial response (PR): at least a 30% decrease in the sum of diameters of viable (enhancement in the arterial phase) target lesions, taking as reference the baseline sum of the diameters of target lesions.

    • Progressive disease (PD): an increase of at least 20% in the sum of the diameters of viable (enhancing) target lesions, taking as reference the smallest sum of the diameters of viable (enhancing) target lesions recorded since treatment started.

    • Stable disease (SD): any cases that do not qualify for either partial response or progressive disease.

Whenever appropriate, we also planned to consider other criteria, such as World Health Organization (WHO) criteria (Kim 2015) and the Response Evaluation Criteria in Solid Tumours (RECIST) guideline (Therasse 2000). However, the mRECIST guideline was considered as the main tool.

  • Proportion of participants with adverse events not considered serious. We planned to accept all reported non‐serious adverse events assessed at variable time points throughout the conduct of the review. If possible, we planned to note the period of reported non‐serious adverse events and classify them as short‐term (primary observed period) and long‐term adverse events.

  • Health‐related quality of life as defined by the trial authors (short term: up to one year; medium term: one to five years; long term (primary time point): beyond five years).

  • Duration of hospital stay.

Search methods for identification of studies

Electronic searches

We performed electronic searches in the Cochrane Hepato‐Biliary Group Controlled Trials Register (searched through the Cochrane Library; December 2020), The Cochrane Central Register of Controlled Trials (CENTRAL; 2020, issue 12) in the Cochrane Library, MEDLINE (PubMed; December 2020), Embase (www.embase.com; December 2020), LILACS (Bireme; 1982 to December 2020), Science Citation Index Expanded (Web of Science; 1900 to December 20209), and Conference Proceedings Citation Index‐Science (Web of Science; 1990 to December 2020). We also endeavoured to identify relevant RCTs in the China National Knowledge Infrastructure (CNKI) and Wanfang databases. Appendix 1 shows the search strategies with the time spans of the searches.

Searching other resources

We checked the reference lists of potentially relevant articles identified in the electronic searches. We also searched trial registration resources such as ClinicalTrials.gov, Chinese Clinical Trial Register (ChiCTR), and the World Health Organisation (WHO) International Clinical Trial Registry Platform (www.who.int/ictrp) to identify study protocols of the identified studies from the electronic searches and also to identify ongoing studies. We also handsearched grey literature sources, such as meeting abstracts and internal reports. We adapted the same or similar search terms to those used in the searching of English electronic databases.

During the selection of trials, whenever we identified observational studies of interest to the topic of this review (i.e. quasi‐randomised studies, cohort studies, case‐control studies, case reports, and case series) and also reporting on harms, we planned to discuss the data on harm in the review discussion part. We also planned to create a table with the extracted data on harm. In this way, we pay attention to late‐occurring or rare events which are often underreported or overlooked by trialists (Storebø 2018).

Data collection and analysis

Selection of studies

We merged all search results and removed duplicates by using reference management software. Two review authors (BZL and WL) independently examined titles and abstracts of the electronic search output to remove obviously irrelevant publications. After the initial assessment, we retrieved the full text of all potentially eligible articles, and we linked together multiple reports of the same trial.

Two review authors (BZL and WL) independently screened the full text to evaluate whether these trials met the inclusion criteria. We resolved disagreements on the eligibility of a trial by discussion. We consulted HC (the last author) or we wrote to the original trial investigators when necessary, to clarify trial eligibility. Then, we made a final decision on which trials fulfilled the inclusion criteria of our review. We did not blind our selection process regarding article information. We recorded the details of the whole screening process in a PRISMA flow chart. We also added information on the excluded studies in the 'Characteristics of excluded studies' table.

Data extraction and management

Two authors (BZL and YCZ) planned to independently extract the data from all included publications on the trials and complete the 'Characteristics of included studies' table. We planned to contact the authors of original trials whenever needed. We planned to resolve disagreement by discussion. We planned to consult HC (another review author), or we planned to write to the original trial investigators whenever needed. Two authors (HC and WL) planned to enter data into Review Manager 5. We planned to double‐check that the data had been entered correctly by comparing the data presented in the systematic review with those in the data extraction form, which we had pre‐piloted for the purpose of the review.

We planned to extract the following trial characteristics.

  • Source (e.g. author, year of publication, contact details, journal citation, trial registration, ethics committee approval)

  • Methods (e.g. trial design, total trial duration, sequence generation, allocation sequence concealment, blinding and other concerns about bias)

  • Participants (e.g. age, sex, country, number randomised, number lost to follow‐up/withdrawn, number analysed, inclusion criteria, exclusion criteria, diagnostic criteria)

  • Interventions (e.g. intervention, comparison)

  • Outcomes (for each outcome listed in the protocol, e.g. outcome definition and unit of measurement (if relevant), time points reported, scales, intensity)

  • Miscellaneous (e.g. funding for trial, a notable conflict of interests of trial authors).

Assessment of risk of bias in included studies

Two review authors (BZL and WL) planned to independently assess the risk of bias in the included studies. We planned to assess risk of bias by using the RoB 2 tool, according to Chapter 8 in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2019a). We planned to use the following domains.

Domain 1: bias arising from the randomisation process;

Domain 2: bias due to deviations from intended interventions;

Domain 3: bias due to missing outcome data;

Domain 4: bias in measurement of the outcome;

Domain 5: bias in selection of the reported report.

For each domain, there are a series of signalling questions: 'Yes’, ‘Probably yes’, ‘Probably no’, ‘No’, and ‘No information’.

Based on the replies, we planned to reach a risk‐of‐bias judgement, and we assigned one of three levels to each domain: ‘low risk of bias’, ‘some concerns’, or ‘high risk of bias’, following the RoB 2 tool (Sterne 2019).

Overall risk of bias

The following definitions of risk of bias were considered.

Low risk of bias: the trial is judged to be at low risk of bias for all domains for this result.

Some concerns: the trial is judged to raise some concerns in at least one domain for this result, but not to be at high risk of bias for any domain.

High risk of bias: the trial is judged to be at high risk of bias in at least one domain for this result; or the trial is judged to have some concerns for multiple domains in a way that substantially lowers confidence in the result.

We planned to present information in support of each response in the free‐text box alongside the signalling questions and judgements. Additionally, for domain 2, we planned to assess the effect of the assignment to the intervention.

In this review, we planned to assess the risk of bias in the following outcome results: all‐cause mortality; time to progression; serious adverse events; tumour response rate; and health‐related quality of life, all at the longest follow‐up.

Measures of treatment effect

For dichotomous variables, we planned to calculate the risk ratio (RR) and 95% confidence interval (CI) and Trial Sequential Analysis adjusted‐CI.

For continuous variables, we planned to use the mean difference (MD) (if all studies were made on the same scale) or the standardised mean difference (SMD) (if different scales were used) with 95% CI and Trial Sequential Analysis adjusted‐CI.

For time‐to‐event variables, we planned to use the methods of survival analysis and express the intervention effect as a hazard ratio (HR) with 95% Cl. If the logHR and their variance were not directly reported in reports, we planned to calculate them indirectly, following the methods introduced by Tierney 2007.

Unit of analysis issues

We planned to set the unit of analysis according to the methods mentioned in Chapter 6 and Chapter 23 in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2019b; Higgins 2019c).

We planned to analyse data at the single randomised individual level (Higgins 2019b). In trials with a two‐parallel‐group design, we planned to compare the experimental intervention group versus the control group. In the trials with a parallel‐group design with more than two intervention groups, if relevant, we planned to compare separately each of the experimental groups with half of the control group if used within the same comparison (Higgins 2019c).

When only a subset of relevant participants was included in a trial, we planned to consider the trial only when the results were presented separately for the subgroup of interest for this review.

For cluster‐randomised trials, we planned to analyse data by using the average cluster size and an estimate of the intraclass correlation coefficient (ICC) and the design effect to calculate effective sample size (Higgins 2019b; Higgins 2019c).

For crossover trials, we planned to only include data from the first intervention period to avoid carry‐over effects (Higgins 2019a).

Dealing with missing data

We planned to contact the original investigators to request missing data; and we planned to extract all data for an intention‐to‐treat (ITT) analysis if data were available. Otherwise, we planned to perform available case analyses, which assume that data are missing at random. We planned to assess if this assumption was reasonable by collecting data on the number of participants excluded or lost to follow‐up, and the reasons for loss to follow‐up by treatment group, from each included study (as reported). We planned to address the potential impact of missing data on the findings of the review in the Discussion section.

Assessment of heterogeneity

We planned to assess clinical and methodological heterogeneity by carefully examining the characteristics and design of the included trials. We planned to assess the presence of clinical heterogeneity by comparing effect estimates in people with different BCLC stage of hepatocellular carcinoma, different Child‐Pugh Class of liver function, different criteria on assessment of tumour response and different follow‐up time. Different study designs and risk of bias may contribute to methodological heterogeneity.

We planned to explore statistical heterogeneity by the Chi² test with significance set at a P value of less than 0.10. In addition, we planned to access the degree of heterogeneity by using the I² statistic, which describes the percentage of the variability in effect estimates that is due to heterogeneity rather than sampling error.

Interpretation of I² is listed as follows.

  • 0% to 40%: might not be important

  • 30% to 60%: may represent moderate heterogeneity*

  • 50% to 90%: may represent substantial heterogeneity*

  • 75% to 100%: considerable heterogeneity*

*The importance of the observed value of I² depends on (i) magnitude and direction of effects and (ii) strength of evidence for heterogeneity, e.g. P value from the Chi² test, or a confidence interval for I².

Assessment of reporting biases

We planned to assess reporting bias by drawing funnel plots if ten or more trials were included.

Data synthesis

Meta‐analysis

We aimed to conduct this review following the instructions stated in Chapter 10 in Cochrane Handbook for Systematic Reviews of Interventions (Deeks 2019). We planned to meta‐analyse data whenever possible. Otherwise, we planned to provide a summary of the trial results in a narrative way. We planned to perform the primary analyses by pooling the results of all eligible trials, regardless of their risk of bias. We planned to analyse data using the Review Manager 5 software (Review Manager 2014) and RevMan Web provided by Cochrane (RevMan Web 2019). We aimed to perform all meta‐analyses using the random‐effect model because we expected that the included trials would be heterogeneous. We planned to present dichotomous outcomes as RR with 95% CI. We planned to present continuous outcomes as MD or SMD, with 95% CI.

Subgroup analysis and investigation of heterogeneity

We aimed to assess differences between subgroups using the formal test for subgroup differences in Review Manager Web (RevMan Web 2019). We aimed to conduct the following subgroup analyses.

  • Trials at low risk of bias, at some concern, and at high risk of bias

  • Different ablation methods

Sensitivity analysis

We planned to perform sensitivity analyses by excluding studies at high risk of bias. Additionally, if cluster‐randomised studies were found, we planned to perform sensitivity analysis to investigate possible effects of the randomisation unit. We planned to assess the intervention effect on mortality at one, three, and five years. We planned to repeat our analyses with the fixed‐effect model.

We also planned to use Trial Sequential Analysis to assess imprecision for the following outcomes: all‐cause mortality; time to progression; serious adverse events; tumour response; and quality of life (Thorlund 2011; Castellini 2018; Gartlehner 2019).

Trial Sequential Analysis

To control random errors from sparse data and repeated significance testing, we planned to apply Trial Sequential Analysis in our meta‐analysis (Thorlund 2011; TSA 2011; Wetterslev 2017). Trial Sequential Analysis is a methodology that includes a combination of techniques, providing the threshold for a statistically significant treatment effect and the threshold for futility. Conclusions conducted by Trial Sequential Analysis indicate the potential to be more reliable than those using traditional meta‐analysis techniques (Thorlund 2011; Wetterslev 2017).

For dichotomous outcomes, we aimed to calculate the required meta‐analysis information size based on the event proportion in the control group; assumption of a plausible RR reduction of 20% or the RR reduction observed in the included trials at low risk of bias; a risk of type I error of 2.5% because of our three primary outcomes and 2.0% because of four secondary outcomes (Jakobsen 2014); a risk of type II error of 10%; and the assumed diversity of the meta‐analysis (Wetterslev 2009). For continuous outcomes, we aimed to calculate the required information size based on the SD observed in the control group of trials with low risk of bias and a minimal relevant difference of 50% of this SD, an alpha of 2.5%, a beta of 10%, and the diversity suggested by the trials in the meta‐analysis.

The underlying assumption of Trial Sequential Analysis is that testing for significance may be performed each time a new trial is added to the meta‐analysis. We aimed to add the trials according to the year of publication. If more than one trial was published during the same year, we planned to add trials alphabetically according to the last name of the first author. We aimed to construct trial sequential monitoring boundaries on the basis of the required information size (Wetterslev 2008; Thorlund 2011; Wetterslev 2017). These boundaries determine the statistical inference one may draw regarding the cumulative meta‐analysis that does not reach the required information size; if the trial sequential monitoring boundary is crossed before the required information size is reached, firm evidence may, perhaps, have been established and further trials may be superfluous. On the other hand, if the boundaries are not surpassed, it probably is necessary to continue conducting trials in order to detect or reject a certain intervention effect. That is determined by assessing if the cumulative Z‐curve crosses the trial sequential boundaries for futility.

Summary of findings and assessment of the certainty of the evidence

We aimed to create the Summary of findings tables using GRADEpro GDT software (GRADEpro GDT). We aimed to assess all‐cause mortality, progression‐free survival, serious adverse events, tumour response rate, and health‐related quality of life. We planned to provide a range of follow‐up, and median follow‐up, for all outcomes.

We aimed to use the GRADE approach to assess the certainty of evidence based on risk of bias, indirectness of evidence (population, intervention, control, outcomes), unexplained heterogeneity, inconsistency of results (including problems with subgroup analyses), imprecision of results, and a high probability of publication bias (Atkins 2004). The details are shown as follows:

(1) Risk of bias or limitations in the detailed design and implementation: the results of assessment of risk of bias by using RoB 2 tool in included RCTs were to be fed directly into the domain of 'Risk of bias' in GRADE. In particular, ‘low’ risk of bias would indicate ‘no limitation’; ‘some concerns’ would indicate either ‘no limitation’ or ‘serious limitation’; and ‘high’ risk of bias would indicate either ‘serious limitation’ or ‘very serious limitation’. We also planned to use our judgements to decide between alternative categories, depending on the likely magnitude of the potential biases.
(2) Unexplained heterogeneity or inconsistency of results: when studies yield widely differing estimates of effect (heterogeneity or variability in results), investigators should look for robust explanations for that heterogeneity.
(3) Indirectness of evidence: two types of indirectness are relevant. First, a review comparing the effectiveness of alternative interventions (say A and B) may find that randomised trials are available, but they have compared A with placebo and B with placebo. Second, a review may find randomised trials that meet eligibility criteria but address a restricted version of the main review question in terms of population, intervention, comparator or outcomes.
(4) Imprecision of results: when studies include few participants or few events, and thus have wide confidence intervals, review authors can lower their rating of the certainty of the evidence.
(5) High probability of publication bias: the certainty of evidence level may be downgraded if investigators fail to report studies on the basis of results (typically those that show no effect: publication bias) or outcomes (typically those that may be harmful or for which no effect was observed: selective outcome non‐reporting bias).

We planned to define the levels of evidence as 'high', 'moderate', 'low', or 'very low' certainty. These grades are defined as follows.

  • High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.

  • Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.

  • Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.

  • Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Results

Description of studies

Results of the search

Appendix 1 shows the search strategies. We identified 2803 records through the electronic database search of the Cochrane Hepato‐Biliary Group Controlled Trials Register (n = 8), CENTRAL (n = 224), PubMed (n = 173), Embase (n = 825), LILACS (n = 2), Web of Science (n = 735), CNKI (n = 457), and Wanfang databases (n = 379).

After removing duplicates, we screened the titles and abstracts of 2224 records. In total, we considered 135 records eligible for full‐text screening. We excluded 21 of these records (see below). We listed the remaining 114 records, reporting on 114 studies, under studies awaiting classification because we could not be sure that these were randomised clinical trials from the information in the study paper. We could not obtain information on the registration of the study protocol for any of the 114 studies. We could not obtain information on study approval by regional research ethics committees, neither from the study authors nor through our own searches of trial registries. Corresponding authors did not respond to our enquiries about the design and conduct of the studies, except for one from whom we did not receive a satisfactory response. We also raised awareness of our concerns to editors of the journals that published the 114 studies, and we did not hear back with useful information. Moreover, there seemed to be inappropriate inclusion of trial participants based on cancer stage and severity of liver disease, who should have obtained other interventions according to guidelines from learned societies (Omata 2010; EASL‐EORTC 2012; Heimbach 2018).

We identified five ongoing trials, by hand‐searching in clinical trial websites (see Characteristics of ongoing studies).

The details of our selection are shown in the flow diagram (Figure 1).


Study flow diagram
Date of last search 22 December 2020

Study flow diagram
Date of last search 22 December 2020

Included studies

We were unable to identify any randomised clinical trials evaluating the combination of TACE plus thermal ablation versus TACE alone for people with hepatocellular carcinoma. Please see above.

Excluded studies

The reasons for exclusion of the 21 studies are shown in Characteristics of excluded studies. The main reasons for exclusion of the studies were that studies used interventions outside the scope of our review, or studies were not randomised clinical trials.

Risk of bias in included studies

There were no trials to assess.

Effects of interventions

We could not assess the beneficial or harmful effects of the combination of TACE with ablation versus TACE alone for people with hepatocellular carcinoma, as we could find no trials for inclusion.

Discussion

Summary of main results

Although we identified 114 potentially eligible studies, claiming to assess the beneficial or harmful effects or both combination of TACE plus thermal ablation versus TACE alone for hepatocellular carcinoma, these are all listed as awaiting classification and were not analysed.

There are a number of points that deserve attention and discussion.Firstly, there was absence of evidence of randomisation in the published reports, i.e. that the participants were indeed randomised. This means that the randomisation process was not described, or that the study authors did not provide details on the randomised trial design; there was no description of the methods used for generation of the allocation sequence and allocation concealment. Secondly, study authors, except for one, did not reply to our requests for missing information. We identified no multiple publications of the studies in order to check for required information. Furthermore, we could not obtain information from the study authors on the registration of the study protocol and on study approval by regional research ethics committees. We also raised awareness of our concerns to editors of the journals that published the 114 studies, and we did not hear back with useful information. Thirdly, there was no mention of ethical approval of the studies with appropriate approval number and documentation of the ethical review board. Fourthly, none of the 113 studies conducted after 2005 or the one study from 2003 (Jin 2003) were registered at the protocol stage as per current requirement for randomised clinical trials. There was no study registration number or similar identification and no published protocol, and we were not able to find these studies in any trial registry. Fifthly, there seemed to be inappropriate inclusion of participants based on cancer stage and severity of liver disease, that contravenes guidelines from learned societies (Omata 2010; EASL‐EORTC 2012; Heimbach 2018). This could have resulted in significant harm for participants and raised important ethical issues. TACE should not be offered in patients with Child Pugh B8/B9 or Child Pugh C due to significant risk of deterioration of liver function and death (EASL‐EORTC 2012;Granito 2017). TACE should also not be first‐line treatment in patients with tumours greater than 3 cm, where therapies with curative intent such as resection, ablation, or liver transplantation are recommended. All these recommendations are clearly stated in the Asian Pacific Association for the Study of the Liver (APASL), European Association for the Study of the Liver (EASL), and AASLD guidelines (Omata 2010; EASL‐EORTC 2012; Heimbach 2018). In the studies awaiting classification, 6% to 23% of included patients had Child Pugh C cirrhosis, and there was no information on Child Pugh B8/B9 (apart from the fact that up to 50% of patients had Child Pugh B). Moreover, 25% of patients had TNM stage I (and should, therefore, have received a curative treatment, not TACE which is a palliative treatment (Sirivatanauksorn 2011)). Therefore, there are significant concerns on the selection of patients.

If our decision to list all 114 studies in studies awaiting classification is not considered appropriate in any way, we hereby invite trialists or journal editors to send us information that can prove or disprove that these studies were indeed randomised clinical trials. We wrote to the journals that published the 114 studies, and we did not hear back with useful information.

Overall completeness and applicability of evidence

We designed comprehensive and scientific search strategies. We searched in English, Spanish, and Chinese databases.

Quality of the evidence

We found no eligible randomised clinical trials evaluating the beneficial or harmful effects, or both, of the combination of TACE plus thermal ablation versus TACE alone, thus we cannot analyse the certainty (quality) of evidence.

Potential biases in the review process

The systematic review has been conducted following the corresponding protocol (Liu 2019a). The process of preparing this review was rigorous. We did a comprehensive search for eligible trials.

Agreements and disagreements with other studies or reviews

We found 15 meta‐analyses (Fan 2009; Fan 2011; Sun 2011; Lei 2013; Zhao 2013; Cao 2014; Gu 2014; Hu 2015; Wang 2016b; Katsanos 2017; Yang 2017; Zhao 2017; Liu 2018a; Xiong 2018a; Xiong 2018b) comparing the efficacy and safety of TACE plus radiofrequency ablation versus TACE alone. These 15 meta‐analyses were based on the same studies that we have identified during our trial selection. We have not included these studies in our review for the reasons listed above.

Study flow diagram
Date of last search 22 December 2020

Figuras y tablas -
Figure 1

Study flow diagram
Date of last search 22 December 2020