Authors:
Eugene P. Ceppa1, Amelia T. Collings2, Moustafa Abdalla3, Edwin Onkendi4, Daniel W. Nelson5, Ahmad Ozair6, Emily Miraflor7, Faique Rahman8, Jake Whiteside1, Mihir M. Shah9, Subhashini Ayloo10, Rebecca Dirks1, Sunjay S. Kumar 11, Mohammed T. Ansari12, Iswanto Sucandy13, Kchaou Ali14, Sam Douglas15, Patricio M. Polanco16, Timothy J. Vreeland17, Joseph Buell18, Ahmed M. Abou-Setta19, Ziad Awad20, Choon Hyuck Kwon21, John B. Martinie22, Fabio Sbrana23, Aurora Pryor24, Bethany J. Slater25, William Richardson26, Rohan Jeyarajah27, Adnan Alseidi28
ABSTRACT
Background: Primary hepatocellular carcinoma (HCC) and colorectal liver metastases (CRLM) represent the liver’s two most common malignant neoplasms. Liver-directed therapies such as ablation have become part of multidisciplinary therapies despite a paucity of data. Therefore, an expert panel was convened to develop evidence-based recommendations regarding the use of microwave ablation (MWA) and radiofrequency ablation (RFA) for HCC or CRLM less than 5 cm in diameter in patients ineligible for other therapies.
Methods: A systematic review was conducted for six key questions (KQ) regarding MWA or RFA for solitary liver tumors in patients deemed poor candidates for first-line therapy. Subject experts used the GRADE methodology to formulate evidence-based recommendations and future research recommendations.
Results: The panel addressed six KQs pertaining to MWA vs. RFA outcomes and laparoscopic vs. percutaneous MWA. The available evidence was poor quality and individual studies included both HCC and CRLM. Therefore, the six KQs were condensed into two, recognizing that these were two disparate tumor groups and this grouping was somewhat arbitrary. With this significant limitation, the panel suggested that in appropriately selected patients, either MWA or RFA can be safe and feasible. However, this recommendation must be implemented cautiously when simultaneously considering patients with two disparate tumor biologies. The limited data suggested that laparoscopic MWA of anatomically more difficult tumors has a compensatory higher morbidity profile compared to percutaneous MWA, while achieving similar overall 1-year survival. Thus, either approach can be appropriate depending on patient-specific factors (very low certainty of evidence).
Conclusions: Given the weak evidence, these guidelines provide modest guidance regarding liver ablative therapies for HCC and CRLM. Liver ablation is just one component of a multimodal approach and its use is currently limited to a highly selected population. The quality of the existing data is very low and therefore limits the strength of the guidelines.
Key Words:
Hepatocellular carcinoma, Colorectal liver metastases, Microwave ablation, Guideline, Radiofrequency ablation, Liver tumor
EXECUTIVE SUMMARY
Background: The multidisciplinary management of both primary hepatocellular carcinoma (HCC) and colorectal liver metastases (CRLM) may include liver-directed therapies as part of treatment algorithms; these algorithms focus heavily on control of liver-specific disease as in many cases this serves as a proxy for long-term survival. Hepatectomy is the primary treatment option in patients who can tolerate resection for both HCC and CRLM. Liver-directed therapies include arterial embolization, stereotactic body radiation therapy, and liver ablation. Over the last several decades, microwave ablation (MWA) and radiofrequency ablation (RFA) of liver tumors have been used in high-risk patients unfit for surgical intervention or tumors not amenable to local control with other therapies. As ablation is an evolving technology, outcomes data are primarily reported in liver tumors less than 3 cm in diameter, while data for liver tumors greater than 3 cm are limited for both HCC and CRLM.
The authors sought to perform a systematic review of the existing data to assess for meaningful conclusions. Therefore, a multidisciplinary expert panel was convened to develop evidence-based recommendations to support clinicians, patients, and others regarding the role of liver ablation in the treatment of HCC and CRLM up to 5 cm in diameter. Methods A systematic review was conducted for six key questions (KQ) regarding the use of either MWA or RFA for solitary HCC or CRLM. Due to the paucity of evidence available, HCC and CRLM less than 5 cm in diameter were combined into two final KQs which were used to develop recommendations. Evidence-based recommendations were formulated using the GRADE methodology by subject matter experts. Additionally, the panel developed recommendations for future research. Interpretation of strong and conditional recommendations All guideline recommendations were assigned “conditional” recommendations. These were based on the GRADE approach. The words “the guideline panel suggests” were used for conditional recommendations.
Key questions addressed by these guidelines
- Should MWA (laparoscopic or open) vs. RFA (laparoscopic or open) be used for HCC or CRLM less than 5 cm ineligible for other therapies?
- Should laparoscopic MWA vs. percutaneous MWA be used for HCC and/or CRLM less than 5c m ineligible for other therapies?
Recommendations
- Should MWA (laparoscopic or open) vs. RFA (laparoscopic or open) be used for HCC or CRLM less than 5 cm ineligible for other therapies?
The panel suggests MWA and RFA are both safe and feasible. There was insufficient evidence to recommend one modality over another in terms of oncologic outcomes (conditional recommendation, very low certainty of evidence).
- Should laparoscopic MWA vs. percutaneous MWA be used for HCC and/or CRLM less than 5 cm ineligible for other therapies?
The panel suggests that either ablative approach achieves similar overall outcomes, albeit through distinct patterns. The laparoscopic approach obtained better local control and the percutaneous approach had fewer morbidities while obtaining similar overall 1-year survival (conditional recommendation, very low certainty of evidence).
How to use these guidelines
The aim of these guidelines is to assist surgeons and physicians in making management decisions for patients with HCC or CRLM. Given that the evidence for this guideline was based on very low certainty evidence, these guidelines should be applied with caution. They are also intended to provide education, inform advocacy, and describe future areas for research. The guidelines are not meant to mandate a particular approach or strategy given the lack of evidence and intricacies of the healthcare environment, individual patient needs, co-morbidities, and surgeon experience. Specific situations require adjustment of treatment plans to suit the needs and priorities of the individual patient. Finally, since the guidelines take a patient-centered approach, patients can use these guidelines as a source of information and for discussion with their physicians.
INTRODUCTION
Aim of these guidelines and specific objectives
The purpose of these guidelines is to provide evidence-based recommendations from a surgeon and patient perspective regarding the ablation of HCC and CRLM as part of the treatment algorithm of malignant liver tumors in patients who are poor candidates for surgical resection. The panel was clear that these two tumor types have different and unique characteristics that make their combined data collection an intrinsic problematic feature of this guideline document. However, due to the paucity of data, the panel decided to combine these two tumor types and focus on technique rather than tumor biology. These guidelines address management equipoise related to microwave ablation (MWA) vs. radiofrequency ablation (RFA) as well as equipoise related to laparoscopic vs. percutaneous MWA for malignant liver tumors. The target audience for the guidelines includes patients, surgeons, oncologists, interventional radiologists, and other health care providers in a clinical setting. In addition, policymakers and insurance providers may take these guidelines into consideration in their discussions and planning.
Given that a patient-surgeon perspective was taken, and not a population perspective, considerations such as resources required, the certainty of the evidence of required resources, cost-effectiveness and equity were not evaluated.
Description of the health problems
The two most common malignant liver tumors include HCC and CRLM. HCC is the sixth most common malignancy in the world with an associated second highest cancer-specific mortality [1]. Approximately 550,000 to 700,000 new cases of HCC are diagnosed annually worldwide [2]. The incidence of HCC continues to grow annually [3]. About 1.5 million new colorectal cancers are diagnosed annually worldwide [2]. In the United States, 150,000 patients are newly diagnosed with colorectal cancer each year, and roughly half of these patients will develop liver metastases during their life [4, 5].
Over the past two decades significant improvements have been made in the treatment of HCC and CRLM due to earlier diagnosis, evolution of interventional techniques, and improved systemic therapies. Simultaneously, the morbidity and mortality profile associated with hepatectomy have improved considerably with advances in operative technique and perioperative care. Overall, this has led to increased consideration of hepatectomy for both HCC and CRLM. Certain patients with resectable tumors are not offered hepatectomy due to concerns for insufficient future liver remnant, tumor size, multifocal tumors, locally advanced features (contralateral hepatic artery/portal venous involvement; IVC/contralateral hepatic vein involvement), or underlying comorbid conditions (cirrhosis, heart failure, or other cardiopulmonary disease). Despite increasing safety of hepatic resection and techniques to induce hypertrophy the future liver remnant, many patients with potentially resectable liver tumors are unable to undergo definitive resection [6-9].
Liver ablation of tumors via the direct application of energy or chemicals was developed for patients with small lesions who were not candidates for resection or other curative treatment modalities. Ablative technology serves as a form of local therapy with reduced damage to surrounding normal liver tissue. When used correctly, it can reduce many of the concerns associated with surgical resection regarding future liver remnant. For the most part, ablation may be used to treat a limited number of small lesions in the liver either as primary therapy or as an adjunct to resection in patients that cannot achieve complete clearance of the liver through resection due to comorbidities, inadequate liver volume, or in cases where resection of all lesions cannot be achieved due to technical considerations. In most cases ablation may be performed as an outpatient procedure which minimizes short-term morbidity in patients with significant comorbid conditions. MWA and RFA are the two most commonly used and studied methods of thermal ablation in the literature for HCC and CRLM. Similar to advances in ablation technology, surgical resection now can be done in a minimally invasive and some in an outpatient setting. In many medical institutions, these patients are discussed in a multidisciplinary liver tumor conference amongst liver specialists (hepatologists, hepatobiliary surgeons, diagnostic radiologists, interventional radiologists, medical oncologist, and radiation oncologists) in which a consensus is achieved about which treatment modality is best suited for the patient.
The contemporary decision as to which ablative technique to utilize has become a real-time dilemma as numerous options have been developed. The application of ablative techniques has been performed by percutaneous and surgical (open or laparoscopic) approaches. While both are typically performed under general anesthesia, and both can be done with minimal inpatient stay (when resection is done in a minimally invasive fashion), it is important to note that some anatomic locations favor one modality over the other. Therefore, with the clear understanding that safety is paramount, these guidelines provide recommendations for the choice of technique comparing MWA vs. RFA and percutaneous vs. laparoscopic MWA from both safety and oncologic perspectives.
These guideline recommendations are based on a systematic review of the relevant literature. The strengths and weaknesses of the available evidence are highlighted, and expert opinion was sought when evidence was lacking.
METHODS
A systematic review of the evidence informed the guideline recommendations [10]. The guideline panel developed and graded the recommendations using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach and the GRADE guideline development tool [11-13]. Reporting of the guideline adheres to the Essential Reporting Items for Practice Guidelines in Healthcare (RIGHT) checklist [14]. A detailed description of the process and methodology used by the SAGES Guidelines Committee and this manuscript’s development has been published separately [15].
Guideline Panel Organization
International experts in liver surgery were invited to participate in the Guideline Panel. All panel members were experienced in both open and laparoscopic ablation of liver tumors as well as hepatectomy. The panel was primarily composed of surgeons from the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) and the Americas Hepato-Pancreato-Biliary Association (AHPBA). In addition, a methodologist with guideline development expertise (M.T.A.) and the SAGES Guidelines Committee Fellow (A.C.) facilitated guideline panel meetings as non-voting members of the panel.
The Chair of the panel (E.P.C.) declared no personal conflicts of interest (COI). He assessed the conflicts of the panelists and found no relevant conflicts that would be likely to influence the direction or strength of the recommendations. A full list of all contributors to the guideline development is provided in Appendix A.
Guideline Funding & Declaration and Management of Competing Interests
SAGES provided funding for the librarian who conducted the systematic review literature search, the methodologists (M.T.A. & A.A.S.), and half the Guidelines Committee Fellow (A.C. & S.K.) salary. A portion of funding came from a
SAGES Education & Research Foundation grant and no support came from industry, nor any input into the conception or development of this guideline. The guideline lead (E.P.C.) collected a SAGES standard COI form from all guideline contributors. A full list of declarations is listed at the end of the manuscript.
Selection of Questions and Outcomes of Interest
The choice of ablative technique used to treat HCC or CRLM is the focus of this guideline. After an introductory online conference, the panel convened for a series of virtual meetings to specify guideline key questions. Originally the panel chose six KQs evaluating the use of MWA or RFA for either HCC or CRLM tumors less than 3 cm and 3-5 cm diameter. However, due to the limited body of evidence, the six questions had to be condensed into two with a combined population of HCC and CRLM tumors less than 5 cm diameter. The authors note that the treatment of tumors of 3-5 cm by ablation is considered controversial and clearly led to the paucity of data in this domain. Relevant patient, intervention, comparator, and outcomes (PICOs) were pre-specified. Outcome selection reflected their decision-making importance from a patient-surgeon dyad perspective.
Evidence Review and Synthesis
A systematic review and meta-analysis informing the guideline recommendations has been published separately [10].
Determining the Certainty of Evidence
Methods outlined in the GRADE handbook were used to judge the certainty of evidence for each outcome of interest [16]. As per the GRADE approach, certainty of evidence may be categorized as high, moderate, low, or very low (Table 1).
GRADE evidence profile and summary of findings Tables were created. Briefly, certainty of the body of evidence for each important outcome was rated across the domains of risk of bias, inconsistency across studies, indirectness or generalizability, imprecision or statistical power, and detection of publication bias.
Values and Preferences
Guideline panelists used their collective experience to assign disutility (or aversiveness) most patients and surgeons would place on various outcomes. Outcome disutility or values and preferences determine the magnitude of desirable or undesirable outcome and the balance between them.
Development of Recommendations
The panel used the GRADE evidence-to-decisions (EtD) framework to determine the direction and strength of recommendations [11,12]. In extensive deliberations, the panel addressed EtD criteria such as the magnitude of desirable and undesirable effects, the overall certainty of evidence, variability in values that may be assigned to outcomes, and the balance of these effects. The panel also made judgments regarding the acceptability and feasibility of the intervention. Additional considerations voiced by panel members were also noted. The online GRADEPro application was used to populate question-specific EtD frameworks.
Guided by the EtD framework criteria the panel voted on the final recommendation for the key question. While serial voting was used to come to a consensus on individual components of the EtD, 80% panel agreement was mandatory for all final recommendations. Voting was done anonymously. Full EtD tables are presented in Appendix B & C and summarized in the following recommendations.
Recommendations with the GRADE approach are categorized as strong or conditional. Strong recommendations reflect the panel’s high confidence that the desirable effects of the recommended management option clearly outweigh any undesirable consequences. Conditional (or discretionary) recommendations are issued when the balance of desirable and undesirable effects is close such that variability in values assigned to the various decision-making outcomes may change the balance for a minority of patients, when there is some uncertainty associated with the overall evidence, or when considerations of acceptability and feasibility are likely to remain despite guideline implementation efforts.
Guideline Document Review
The provisional guideline draft was reviewed and edited by all panel members. The revised draft was then distributed to the SAGES Guidelines Committee for comments and approval in accordance with SAGES Guidelines Committee policies. After incorporating these edits, the guideline was then submitted to the SAGES Executive Committee, AHPBA Executive Committee, and Board of Directors for approval. The guideline was published online on its website (https://www.sages.org) for a period of public comment for additional quality assurance.
RECOMMENDATIONS
KEY QUESTION 1: Should MWA (laparoscopic or open) vs. RFA (laparoscopic or open) be used for HCC or CRLM less than 5 cm ineligible for other therapies?
Recommendation: The panel suggests MWA or RFA as a primary ablative approach for HCC and/or CRLM as both technologies were deemed safe and feasible (conditional recommendation; very low certainty of evidence).
Summary of the evidence
There were no randomized trials addressing this question. A total of eight observational studies met the inclusion criteria [17-25]. These studies were used to inform the panel’s decision on the key question. The main limitations were that several larger studies possessed high risk of bias due to baseline differences in the compared cohorts, the overall low event rate leading to most endpoints crossing thresholds from meaningful harm to benefit, and the substantial risk of bias stemming from the retrospective and non-randomized nature of these studies.
Benefits
The panel judged that there are moderate benefits to MWA compared to RFA across critical outcomes.
- Perioperative complications defined as Clavien-Dindo Grade >3 (8 observational studies with a total of 882 participants) absolute difference of 3 fewer patients per 1,000 (95% CI 46 fewer to 54 more) [17-24]
- Incomplete Ablation (6 observational studies with a total of 715 participants) absolute difference of 3 fewer per 1,000 (95% CI 21 fewer to 39 more) [17, 18, 20-22, 24]
- Local/Regional Recurrence (6 observational studies with a total of 668 participants) absolute difference of 11 fewer patients per 1,000 (95% CI 97 fewer to 108 more) [17-21, 23]
- 5-year Disease Free Survival (DFS) (4 observational studies with a total of 177 participants) absolute difference of 32 more patients achieving 5-year disease free per 1,000 (95% CI 75 fewer to 183 more) [17, 20, 21, 24]
- 5-year Overall Survival (OS) (6 observational studies with a total of 782 participants) absolute difference of 7 more patients per 1,000 (95% CI 59 fewer to 73 more) [17, 19-21, 24, 25]
Harms and burdens
There was no evidence reported of harms or burdens from MWA or RFA of HCC and CRLM for any important or critical outcomes in any studies meeting the inclusion criteria. Thus, the panel judged the potential harms to be unknown.
Certainty of evidence
The certainty of the above evidence was evaluated as very low based on the reported outcomes for decision making. These outcomes were primarily limited by high risk of bias due to baseline differences in comparative cohorts without statistical matching and by the range of estimated effects crossing meaningful thresholds from benefit to harms (Appendix B).
Decision criteria
For this judgement, the panel considered the value for decision-making that informed patients would place on the main outcomes based on their experience and the available evidence. Perioperative complications, 5-year DFS, and 5-year OS were determined to be outcomes of critical importance for decision-making.
Regarding perioperative complications, the panel’s consensus was that patients and health care providers place significant weight on the expected oncologic benefit as well as the risk of morbidity when choosing a treatment option.
With regards to DFS, the consensus of the panel was that DFS was most reflective of differences in efficacy of the ablative technique. Therefore, the panel elected to concentrate on this outcome as measured at five years from ablation.
With regards to OS, the consensus was that patients with HCC or CRLM have other factors including age (i.e., survival altered by other benign diseases) and the natural history of HCC (development of other de novo liver tumors, progression of underlying liver disease) and CRLM (progression of extrahepatic micro-metastatic disease, response to chemotherapy) altering overall survival. Although these issues make OS a problematic outcome due to being a composite end point. After much deliberation, the panel decided on including OS at 5 years as it was one of the few commonly reported endpoints in many of the published studies. This was despite the clear understanding that survival in HCC is also determined by underlying liver function, confounding any comparison to CRLM.
The panel also considered the outcomes of incomplete ablation and local/regional recurrence but ultimately gave them a much lower priority. The panel felt that patients would be more interested in 5-year DFS and OS. Incomplete ablation and local/regional recurrence are only important as surrogates for DFS and OS, and each of them would be subject to re-intervention when feasible. Given that meaningful data existed for the critical outcomes of 5-year DFS and OS, the panel considered but did not weigh heavily the surrogate outcomes of incomplete ablation and local/regional recurrence as part of the final recommendation for KQ1.
Conclusions
Overall, there was insufficient data to suggest that MWA was superior to RFA. The opinion of the panel was that there was no evidence to support or refute one technology over the other.
KEY QUESTION 2: Should laparoscopic MWA vs. percutaneous MWA be used for HCC and/or CRLM less than 5 cm ineligible for other therapies?
Recommendation: The panel suggests that either MWA approach achieves overall similar outcomes, albeit through distinct patterns. The laparoscopic approach achieved better local control and the percutaneous approach had fewer morbidities but both approaches obtained similar overall 1-year survival (conditional recommendation; very low certainty of evidence).
The panel judged that there are moderate desirable effects to laparoscopic MWA across critical and important outcomes, and moderate undesirable effects due to perioperative morbidity. For this key question, there was substantial uncertainty throughout the data, with very low certainty of evidence, leading to a conditional recommendation for either MWA approach.
Summary of the Evidence
There were no randomized trials addressing this question, and two observation studies met the inclusion criteria [26, 27]. The main limitations to the available studies were incongruent baseline characteristics in the comparator groups (tumor location, energy applied during MWA), ambiguity of long-term follow up, low event rates for most outcomes and substantial risk of bias stemming from the retrospective and non-randomized nature of these studies.
Benefits
The panel judged that there were moderate desirable effects to laparoscopic MWA across critical outcomes.
- Incomplete Ablation (2 observational studies with a total of 151 participants) absolute difference of 67 fewer per 1,000 (95% CI 88 fewer to 51 more) [26, 27]
- Local/Regional Recurrence (1 observational study with a total of 75 participants) absolute difference of 127 fewer patients per 1,000 (95% CI 200 fewer to 167 more) [27]
- 1-year Disease Free Survival (DFS) (1 observational study with a total of 75 participants) absolute difference of 111 more (95% CI 48 fewer to 303 more) [27]
- 1-year Overall Survival (OS) (1 observational study with a total of 75 participants) absolute difference of 0 more patients per 1,000 (95% CI 70 fewer to 70 more) [27]
Several of the outcomes of interest were judged to be noninformative by the panel. Due to the wide confidence intervals, the anticipated absolute effects were equally likely to result in a benefit or a harm to the patient. These outcomes included incomplete ablation, local/regional recurrence and 1-year OS; 1-year DFS was more likely a benefit of laparoscopic MWA.
Harms and Burdens
The panel determined the potential harms (morbidity) are moderate for laparoscopic MWA performed as compared to percutaneous MWA. The estimated effects ranged from large benefit to large harms (anticipated absolute effect 118 more patients per 1,000; 95% CI 7 more to 539 more) [26, 27].
Certainty of evidence or effects
The certainty of the above evidence was evaluated as very low based on the reported outcomes for decision making. The certainty was limited by the observational nature of the available studies, imprecision, and some inconsistency between studies (Appendix C).
Decision criteria
For this judgement, the panel considered the value that informed patients would place on the main outcomes based on their experience and the available evidence.
As with KQ1, the panel determined perioperative complications, DFS, and OS to be outcomes of critical importance for decision-making by providers and patients alike. However, KQ2 was dissimilar to KQ1 in that the studies in these guidelines included only 1-year DFS or OS and not 5-year DFS or OS. The panel recognized that 1-year outcomes are not a particularly meaningful to assess these cancer-specific outcomes. Furthermore, as in KQ1, differences in therapies available for HCC and CRLM and the timing of ablative therapies in these multidisciplinary pathways varies significantly for these tumor types (earlier for HCC and much later for CRLM). Overall the outcomes assessed were equivocal. In particular, the juxtaposition of the DFS and OS evidence was unconvincing with DFS possibly having a benefit while OS was equivocal in terms of absolute difference. There was no clear evidence of harm or benefit in oncologic outcomes given substantial imprecision of the data.
The discussion amongst the panel around KQ2 centered around the uncertainty of the available evidence due to a paucity of data available and differences in background variables leading to incomplete comparisons of patient populations. There was broad agreement that when patients are selected through multidisciplinary approaches, that percutaneous MWA is applied in easier to reach lesions and resulted in fewer periprocedural complications. Whereas laparoscopic MWA is typically reserved for tumors that cannot be reached percutaneously due to superior or posterior lesions and/or location near major vascular structures. Laparoscopic MWA allows for a higher total energy delivered to a tumor due to proximity to the tumor and improved patient comfort during the procedure due to the use of general anesthesia. These latter two points result in higher perioperative morbidity and possibly fewer incomplete ablations and improved local control.
Conclusions
The panel judged that no clear benefit was derived from the laparoscopic MWA approach as compared to the percutaneous MWA approach. There was an indication of increased complications for laparoscopic ablation. The panel agreed that due to differences in timing of ablation and tumor anatomical differences, the outcomes assessed reflect these differences and are not a true comparison. Overall, there was very low certainty of evidence for this key question, and mixed outcomes on DFS and OS. As a result, the panel decided on a conditional recommendation for either percutaneous or laparoscopic MWA approach in the situation that hepatectomy is not recommended after multidisciplinary review of the patient’s case.
Recommendations for Future Research – KQ1 and KQ2
The panel made multiple suggestions for future research priorities. With regards to endpoints reported, the panel recommended improved granularity of collected data to decrease heterogeneity in the published literature on the topic. The bare minimum of critical endpoints to report include tumor size, tumor location (segment or section of liver), proximity to major vasculature, exact tumor biology (differentiation), focality (unifocal vs. multifocal), definition of recurrence, modality to diagnose recurrence (MRI vs. CT; panel preferred MRI with Eovist), as well as 1-year and 5-year DFS and OS. When reporting on ablation of liver tumors, efforts should be made to identify patients who had no concomitant or subsequent therapy to evaluate the outcomes of liver ablation as singular therapy as opposed to salvage therapy. In addition, the panel recommended research assessing MWA for HCC separate from CRLM, as well as studies comparing TACE (transarterial chemoembolization) + MWA vs. MWA alone.
DISCUSSION
Purpose of this guideline
Despite a significant number of published manuscripts on liver ablation of tumors as well as accelerated development of technologies to improve ablation efficiency and tumor targeting, no clear assessment of the quality of the data available nor formal guidelines have been previously developed. This guideline aims to make evidence-based recommendations based on outcomes critical to clinical decision-making and individualized recommendations based on a balance of clinical effects. This guideline emphasizes the values key stakeholders place on different outcomes and how this can affect individual recommendations. A secondary aim was to develop research recommendations based on where the panel felt there was a paucity of evidence during systematic review of the literature. This should help guide future research endeavors to where they are most needed.
Limitations of these guidelines
One of the main limitations of these guidelines is related to the very low certainty of the evidence for all liver tumor ablation. This was found to be true not only in the excluded manuscripts reviewed but equally so in those that were valid from the inclusion criteria. The key questions were condensed artificially to include HCC and CRLM in one assessment even though they were separate at the outset of the systematic review [10]. Combining HCC and CRLM into the same analysis results in challenges in interpreting this data as the biologic behavior, multi-modal treatment options and clinical outcomes for these two diseases are extremely different. Furthermore, many treatment guidelines recommend ablation as an option for small lesions (<3 cm) acknowledging the increased risk of local recurrence and incomplete ablation with larger lesions. Extending the size threshold to 5 cm in this analysis was necessary given the paucity of data and thus results should be interpreted and applied with caution. In addition, there was minimal long-term data addressing oncologic specific outcomes such as DFS and OS. Additionally, the panel comprised academic surgeons with specialized training in hepatobiliary surgery and ablation of liver tumors. The panel did not include providers in non-surgical specialties such as interventional radiology, medical oncology, or hepatology. Considering all of these limitations and current data regarding management of liver tumors, the panel was explicit in that only after multidisciplinary discussion determined that the gold standard of hepatectomy was deemed not suitable on a case-by-case scenario that MWA of HCC or CRLM less than 5 cm in diameter would be an option. Although every effort was made to limit the bias of the participating individuals, their opinions and experience may be represented in their voting. Lastly, the importance of outcomes was not rated by patient advocates, but instead determined by the surgeon panel members based on their collective experience. However, a strength of this guideline is the careful consideration for patient values and preferences in view of individual critical outcomes.
Implementation and revision of these guidelines
Implementation
The panel believes that these recommendations should be used with great caution, as they were based on limited, very low quality evidence. Moreover, the combination of two tumor types, which was undertaken due to limited available data, makes these recommendations limited in their utility. As stated above, these recommendations are based on literature that includes the treatment of either HCC or CRLM less than 5 cm in diameter with MWA by surgeons with extensive training and experience with hepatectomy and ablation or interventional radiologists with specialty training and experience with liver-directed therapies. Implementation of these recommendations will require continued specialized training. Much of the data reviewed was not complete and made comparisons challenging. Thus, future investigations should focus on assessing outcomes using one approach vs. another focusing on anatomical factors as well as single tumor type as the tumor biology and treatment algorithms for HCC and CRLM are vastly disparate.
Updating these guidelines
After publication of these guidelines, SAGES Living Guidelines Task Force will plan to perform repeat literature searches on a frequent interval to search for any new evidence. When substantive literature is identified, the guideline will undergo formal update. Future guidelines will focus on tumor specific outcomes (i.e. HCC or CRLM only analyses) and possibly distinguishing formally when to use percutaneous vs. surgical MWA.
ACKNOWLEDGEMENTS
We would like to thank Sarah Colón, the SAGES senior program coordinator, Holly Ann Burt, the SAGES librarian, and the SAGES Guidelines Committee members for their help with the creation of this guideline.
DISCLAIMER
Clinical practice guidelines are intended to indicate the best available approach to medical conditions as established by a systematic review of available data and expert opinion. The approach suggested may not necessarily be the only acceptable approach given the complexity of the healthcare environment. These guidelines are intended to accommodate the numerous variables inherent to the treatment of an individual patient. Treatment strategy must be tailored to the patient on case-by-case basis. These guidelines are applicable to all physicians who are appropriately credentialed regardless of specialty at institutions with appropriate expertise in both laparoscopic and percutaneous approaches.
These guidelines are developed under the auspices of SAGES and AHPBA, the guidelines committee, and approved by the Board of Governors of both societies. The recommendations of each guideline undergo multidisciplinary review and are considered valid at the time of production based on the data available. New developments in medical research and practice pertinent to each guideline are reviewed, and guidelines are periodically updated.
Funding: This work was funded by Society of American Gastrointestinal and Endoscopic Surgeons.
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APPENDICES
Appendix A: Authorship roles, panel voting members, and conflicts of interest
Appendix B: Key Question 1 Evidence to Decision Table
Appendix C: Key Question 2 Evidence to Decision Table
Author affiliations:
Eugene P. Ceppa1, Amelia T. Collings2, Moustafa Abdalla3, Edwin Onkendi4, Daniel W. Nelson5, Ahmad Ozair6, Emily Miraflor7, Faique Rahman8, Jake Whiteside1, Mihir M. Shah9, Subhashini Ayloo10, Rebecca Dirks1, Sunjay S. Kumar 11, Mohammed T. Ansari12, Iswanto Sucandy13, Kchaou Ali14, Sam Douglas15, Patricio M. Polanco16, Timothy J. Vreeland17, Joseph Buell18, Ahmed M. Abou-Setta19, Ziad Awad20, Choon Hyuck Kwon21, John B. Martinie22, Fabio Sbrana23, Aurora Pryor24, Bethany J. Slater25, William Richardson26, Rohan Jeyarajah27, Adnan Alseidi28
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
- Hiram C. Polk, Jr. Department of Surgery, University of Louisville School of Medicine, Louisville, KY, USA
- Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Department of Surgery, Texas Tech University Health Sciences Center, Lubbock, TX, USA
- Department of Surgery, William Beaumont Army Medical Center, El Paso, TX
- King George’s Medical University, Lucknow, India
- UCSF East Bay Department of Surgery, UCSF, Oakland, CA, USA
- Jawaharlal Nehru Medical College, Aligarh Muslim University, Aligarh, India
- Division of Surgical Oncology, Department of Surgery, Emory University Winship Cancer Institute, Atlanta, GA, USA
- Department of Surgery, Brown University, Providence, RI, USA
- Department of Surgery, Thomas Jefferson University Hospital, Philadelphia, PA, USA
- School of Epidemiology and Public Health, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
- Digestive Health Institute, AdventHealth, Tampa, FL, USA
- Department of Surgery A, Sfax Medical School, Sfax, Tunisia
- Department of Surgery, Naval Medical Center Portsmouth, Portsmouth, VA, USA
- Division of Surgical Oncology, Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX, USA
- Department of Surgery, Brooke Army Medical Center, San Antonio, TX, USA
- Department of Surgery, Mission Health Care System, Asheville, NC, USA
- University of Manibota, Winnepeg, Cnada
- Department of Surgery, University of Florida, Jacksonville, FL, USA
- Department of General Surgery, Cleveland Clinic, Cleveland, OH, USA
- Department of Surgery, Atrium Health, Charlotte, NC, USA
- Department of Surgery, Chicago Medical School, Rosalind Franklin University, Chicago, IL, USA
- Department of Surgery, Stony Brook University, Stony Brook, NY, USA
- Department of Surgery, University of Chicago, Chicago, IL, USA
- Department of Surgery, Ochsner Clinic, Jefferson, LA, USA
- TCU/UNTHSC School of Medicine, Fort Worth, TX, USA
- Department of Surgery, University of California, San Francisco, CA, USA
# Address all correspondence to:
Eugene P. Ceppa, MD
Indiana University School of Medicine, Indianapolis, IN 46202
For more information please contact:
11300 West Olympic Blvd., Suite 600
Los Angeles, CA 90064
- Tel:
- (310) 437-0544
- Fax:
- (310) 437-0585
- Email:
- publications@sages.org
Guidelines for clinical practice are intended to indicate preferable approaches to medical problems as established by experts in the field. These recommendations will be based on existing data or a consensus of expert opinion when little or no data are available. Guidelines are applicable to all physicians who address the clinical problem(s) without regard to specialty training or interests, and are intended to indicate the preferable, but not necessarily the only acceptable approaches due to the complexity of the healthcare environment. Guidelines are intended to be flexible. Given the wide range of specifics in any health care problem, the surgeon must always choose the course best suited to the individual patient and the variables in existence at the moment of decision.
Guidelines are developed under the auspices of the Society of American Gastrointestinal and Endoscopic Surgeons and its various committees, and approved by the Board of Governors. Each clinical practice guideline has been systematically researched, reviewed and revised by the guidelines committee, and reviewed by an appropriate multidisciplinary team. The recommendations are therefore considered valid at the time of its production based on the data available. Each guideline is scheduled for periodic review to allow incorporation of pertinent new developments in medical research knowledge, and practice.