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Department of General, Visceral, and Transplantation Surgery, Ruprecht Karl University, Heidelberg, GermanyStudy Center of the German Surgical Society (SDGC), Heidelberg University Hospital, Heidelberg, Germany
Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) has expanded and spearheaded development in hepatobiliary surgery. Monosegment-ALPPS tests liver regeneration limits and may present as the last feasible curative treatment option.
Methods
Electronic databases (MEDLINE, Web of Science, Google Scholar, Cochrane Library and WHO International Clinical Trials Registry Platform) were searched for publications on mono-ALPPS using a predefined strategy without date or language restrictions. Individual patient data was extracted and analyzed.
Results
237 publications were identified. 19 patients were identified to have undergone mono-ALPPS. Primarily, mono-ALPPS has been utilized as curative treatment for CRLM (17 of 19 cases). Successful mono-ALPPS was possible in FLR above 8% SLV. All patients received either chemotherapy alone or in combination with radiotherapy prior to surgery. 8 of 19 patients experienced PHLF grade A or B. There was no in-hospital mortality described. Recurrent disease has occurred in 7 of 19 patients and 3 have died during follow-up.
Conclusion
Mono-ALPPS is an experimental procedure that provides a reasonably safe opportunity to curatively treat extensive liver malignancies in patients with FLR as low as 8% SLV. PHLF is the most prevalent complication in mono-ALPPS. Mono-ALPPS should be evaluated in a multicentral study setting.
Background
After first reports of associating liver partition and portal vein ligation for staged hepatectomy (ALLPS) approximately a decade ago,
Right portal vein ligation combined with in situ splitting induces rapid left lateral liver lobe hypertrophy enabling 2-staged extended right hepatic resection in small-for-size settings.
it has gained tremendous popularity. The reporting peak was reached in 2017, with 101 publications indexed through MEDLINE (via PubMed) that year. Various alterations to the original technique have been reported
Technical modifications and outcomes after associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) for primary liver malignancies: a systematic review.
varying from minor amendments, such as utilization of a plastic bag to prevent adhesions, to major modifications including tourniquet technique instead of a liver partition,
Long-Term outcome after conventional two-stage hepatectomy versus tourniquet-ALPPS in colorectal liver metastases: a propensity score matching analysis.
and monosegmental-ALPPS (mono-ALPPS). Mono-ALPPS is a risky procedure that aims to curatively treat extensive liver malignancy by removing all but one segment.
20% of colorectal cancer patients are diagnosed with liver metastases at the time of the primary diagnosis and additional 60% develop metachronous liver lesions in the course of disease.
Liver resection is the only curative option for the majority of these patients but its extent is limited by post-hepatectomy liver failure (PHLF) that occurs in up to 30% of patients.
Typically more than 30% of the total liver volume (TLV) should be preserved. ALPPS; however, alters this threshold, as the technique utilizes the liver's natural compulsion to regenerate upon mechanical injury. Notwithstanding a FLRs deemed insufficient for traditional hepatectomies, ALPPS induces a powerful regeneration response.
Intermediate-term survival and quality of life outcomes in patients with advanced colorectal liver metastases undergoing associating liver partition and portal vein ligation for staged hepatectomy.
Mono-ALPPS attempts to push the limit for FLR even further. With minimal FLR for ALPPS still undecided, mono-ALPPS is a risky procedure in desperate need of evaluation and evidence-based decision on its feasibility. Although currently an experimental treatment with little evidence, mono-ALPPS may provide the last potentially curative treatment for patients with extensive liver malignancies.
The aim of this systematic review was to assess the safety of to-date reported mono-ALPPS procedures and thus to critical appraise if the indications of this technique as a last resort curative treatment are to be broadened.
Methods
The systematic review is reported according with the current PRISMA guidelines.
The aim of the search was to identify all reports on ALPPS with FLR consisting of one segment (with or without segment 1), thus the search strategy included following expressions: “segment”, “monosegment” and “ALPPS” (Appendix). The searches were performed with MEDLINE via PubMed, Web of Knowledge, Google Scholar, Cochrane Library and WHO International Clinical Trials Registry Platform. An additional hand search was performed through the references provided by included studies. The last search was performed on February 12, 2021. No language or data restriction was applied.
Study selection
No restriction to the study methodology was defined as a scarcity of studies on mono-ALPPS was anticipated. All studies describing the technique and outcomes were included. Comments, editorials, meeting abstracts, correspondence and reviews were excluded. The screening of titles, abstracts, as well as of full texts was carried out by two independent reviewers. All disagreements were resolved through discussion and consensus.
Data extraction
Data extraction of included studies was completed independently by two reviewers using a standardized form composed by the authors prior to data extraction. Data for each publication included the title of the publication, year, authors, country, journal, source of funding, study design, number in the cohort, patient characteristics, intervention, and clinical outcomes, including follow-up and recurrence rates.
Statistical analysis
Pooled data analysis of characteristics involved descriptive statistics and most results were presented in percentages. Continuous variables were presented as means with standard deviations and median with ranges.
Critical appraisal of included studies
The methodological quality assessment of all included studies was performed using a tool proposed by Murad et al.,
as only case reports and a case series were identified. Detailed information about assessed qualities is provided as supplementary material (Supplementary Table 1).
Results
237 publications were identified through databases and hand-searches. After exclusion of duplicates, 78 titles and abstracts of articles were reviewed by two independent reviewers. Seven publication reporting on 19 patients were included in the final analysis.
Expanding the limits of resectability: associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) using monosegment 6, facilitated by an inferior right hepatic vein.
As all identified reports were case reports or series, high selection bias is present. Additionally, only successful mono-ALPPS have been reported, raising a concern of publication bias. Overall, the quality of case reports/series presented are rated as moderate to high based on domains “selection”, “ascertainment”, “causality”, and “reporting”.
Patient demographics
A total of 19 patients were reported to have undergone the ALPPS procedure resulting in the liver remnant consisting of one liver segment (with or without auxiliary segment 1). The median age of the pooled cohort was 58 years (mean 53.2 ± 17.3 years). 17 patients underwent mono-ALPPS for extensive hepatic metastases of colorectal carcinoma (CRLM), involving all but one segment. Patients with primary hepatic tumors had a large tumor encasing the supplying vessels or a large tumor involving all but one segment. Detailed information of baseline patient characteristics is provided in Table 1 (Table 1).
Most commonly, segments 4 and 1 were left after the procedures. All patients received the second stage of the procedure. The distribution of segments comprising the liver remnant after mono-ALPPS is provided in Fig. 1 (Fig. 1).
Figure 1Distribution of liver segments after mono-ALPPS
The median interval between the first and second stage of the procedure was 12 days (mean 13 ± 5 days). Blood loss during first stage was reported for 16 patients and was below 1000 ml in 11 cases. 10 patients received intraoperative transfusion.
All patients received chemotherapy before surgery. Preoperative estimation of the future liver remnant amounted to 15.9% ± 4.2% and ranged from 8% to 22% of the standardized liver volume (SLV) and was reported for 16 patients of 19. After first stage of mono-ALPPS, estimated FLR was 38.4% ± 8.3% and ranged from 26% to 53% of the SLV. 12 patients had an increase of FLR by more than 100%. All patients were treated curatively and were tumor-free after the second stage of the procedure. 8 of 19 patients developed a post-hepatectomy liver failure, as defined by the ISGLS
– 2 patients developed PHLF grade B, while 6 were diagnosed with PHLF grade A. 3 of 19 patients developed postoperative intraabdominal fluid collections requiring drainage. Two patients developed postoperative pneumonia and one a wound infection. One patient was also reported to have developed a hepatic artery thrombosis and one an acute liver failure. No in-hospital mortality was reported for identified patients.
Median follow-up was 20 months (mean 18.7 ± 12.9 months, range 3–55 months). Seven patients developed a recurrence during the follow-up period. Three patients died during follow-up after progressive disease: two patients died 5 months after surgery, while one two years after the procedure.
Discussion
The surfeit of evidence shows a benefit of liver surgery in patients with colorectal liver metastasis and other liver malignancies over other modalities.
With many patients still not presented in oncological tumor boards for surgical evaluation, due to supposed extensive hepatic metastatic disease, development of ALPPS and its modifications aiming to increase resectability, stands in clear contrast. It is imperative for surgeons to propagate knowledge of surgical innovation and insist on surgical evaluation to offer more patients a potentially curative treatment.
This article aimed to assess current outcomes of ALPPS technique variation that pushes liver regeneration to a new limit, leaving only one full segment (occasionally with the auxiliary segment 1) after the second stage of surgery, the monosegmental ALPPS (mono-ALPPS). Introduction of ALPPS in 2012 brought innovation into hepatobiliary surgery.
Right portal vein ligation combined with in situ splitting induces rapid left lateral liver lobe hypertrophy enabling 2-staged extended right hepatic resection in small-for-size settings.
In addition to improved resectability, ALPPS shortens the interval between surgeries for two-stage hepatectomies due to the rapid induction of FLR volumetric increase.
Safety, feasibility, and efficacy of associating liver partition and portal vein ligation for staged hepatectomy in treating hepatocellular carcinoma: a systematic review.
ALPPS provides hope for patients and considerably lowers the future liver remnant volume limit to below 30%.
Mono-ALPPS requires only one segment to be unaffected by malignancy. With patients in the cohort having as little liver as 8% SLV, and 12 patients experiencing a more than 100% increase of FLR volume between the two stages, mono-ALPPS provides the highest regeneration response of the liver compared to ALPPS or PVE.
Rapid liver volume increase induced by associating liver partition with portal vein ligation for staged hepatectomy (ALPPS): is it edema, steatosis, or true proliferation?.
With this technique, we must rethink the limits and dynamics of liver regeneration. Although no volumetric limit has yet been defined for ALPPS, this should be the next step in multi-institutional analyses.
None of the reported patients experienced death due to small liver remnant or PHLF grade C; however, the high percentage of patients with PHLF grades A and B raises concern. Yet, in contrast to PHLF grade C, grades A and B require either no treatment or supportive care.
Due to the novelty of mono-ALPPS, technical considerations and learning curve must also be considered. No in-house mortality was reported for the cohort. Lack of reports of in-house mortality and PHLF C could be an indication of publication or reporting bias. The recurrence rate of est. 37% (7of 19 cases) is doubtlessly relatively high, yet as mono-ALPPS is the last feasible curative treatment for the affected patients, it underlines that certain patients can be adequately treated with this procedure. As 3- and 5-year overall survivals in patients with stage IV colorectal cancer is 20.7% and 10.5% under chemotherapy treatment,
a procedure that expands curative therapy options needs serious clinical consideration. Median survival of 20 months in this cohort is higher than described for most systemic chemotherapies for colorectal cancer (7.8–19.5 months for FOLFOX and 15.0–17.6 for irinotecan with 5-fluorouracil and leucovorin).
Seeing the forest through the trees: a systematic review of the safety and efficacy of combination chemotherapies used in the treatment of metastatic colorectal cancer.
Unfortunately, comorbidities were not reported in the original studies identified by this systematic review. It is plausible that patients who were offered mono-ALPPS presented with very few comorbidities, as otherwise the risk of experimental major liver surgery would be unjustifiable. It is also important to consider publication bias, as patients with severe adverse outcomes may not have been reported. Future research must focus on identification of risk factors for patients undergoing ALPPS, and especially radical variations of the technique, such as mono-ALPPS. Similarly to assessments proposed for patients requiring conventional hepatectomies,
algorithms for patients presenting for ALPPS consideration should be designed. Mono-ALPPS might provide a unique insight in this, since this technique leaves the smallest liver remnant currently conceivable.
In summary, mono-ALPPS is a unique technique that provides curative treatment to patients with extensive liver malignancies. Although feasible in patients with FLR as low as 8% SLV, comorbidities, general patient fitness and centers experience must be thoroughly considered. With publication on mono-ALPPS from the international ALPPS registry dating 2015 and increase in popularity of ALPPS procedures and variations, the hepatobiliary community is surely eagerly awaiting new publication on mono-ALPPS, with special emphasis on volumetry, PHLF rates, completion of second stage and comorbidities.
Certainty of evidence
The certainty of evidence derived by a systematic is invariably dependent on the methods and evidence of included studies. The certainty of evidence is affected by each publication though its risk of bias and reporting disparities. Publication bias too presents a hurdle, especially when assessing rare techniques or novel approaches. Inevitably, certainty of evidence derived from case reports will be very low. Yet, novelty does not come in great numbers and extrapolations must be made from the few to serve the many. Systematic reviews of new, currently rarely used techniques can guide decision-making and research into the treatments crucial for the patients.
The methodological quality assessment was completed with a tool for evaluating the methodological quality of case reports and case series. It assessed the selection, ascertainment, causality and reporting of the included case reports/series.
Although the quality of case reports was rated as moderate to high, due to the study methodology, consisting of case reports and one series, the overall quality of evidence is very low. This is currently the highest quality of evidence to date.
A limitation of the review is additionally rooted in information constraint of included case reports. In cases where segment 4 remained, the extent of S4a or S4b resection was imprecisely described. Thus, it is difficult to distinguish between monosegmental and partially larger liver remnant, despite authors' statements of monosegmental procedures. As FLR was consistently under 22% of SLV, despite uncertainty, the cases have not been excluded, although the certainty of evidence was downgraded.
Conclusion
Mono-ALPPS is a novel, reasonably safe, curative treatment for extensive liver malignancies. FLR required for mono-ALPPS may be as low as 8% SLV and only one complete tumor-free segment is needed. PHLF A and B are the most prevalent complications in mono-ALPPS with 42% of patients affected. Yet, through systematic assessment of profiting patients, mono-ALPPS can be a prudent approach in the arsenal of liver surgery.
Previous communication to a society or meeting
None.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Availability of data and materials
All data generated or analyzed during this study are included in this published article and its supplementary information files.
Funding
The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Authors' contributions
Dr. A. Murtha-Lemekhova conceived the original idea. Drs. A. Murtha-Lemekhova and J. Fuchs performed the systematic review of publications and data extraction. Dr. Murtha-Lemekhova, Prof. Dr. K. Hoffmann, Prof. Dr. P. Probst and Dr. J. Fuchs developed the methodology. Dr. A. Murtha-Lemekhova drafted the manuscript. Prof. Dr. K. Hoffmann, Dr. A. Sterkenburg and Dr J. Fuchs revised and edited the manuscript. All authors read and approved the final manuscript.
Acknowledgements
Not applicable.
Conflict of interest
None declared.
Appendix A. Supplementary data
The following are the Supplementary data to this article:
Right portal vein ligation combined with in situ splitting induces rapid left lateral liver lobe hypertrophy enabling 2-staged extended right hepatic resection in small-for-size settings.
Technical modifications and outcomes after associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) for primary liver malignancies: a systematic review.
Long-Term outcome after conventional two-stage hepatectomy versus tourniquet-ALPPS in colorectal liver metastases: a propensity score matching analysis.
Intermediate-term survival and quality of life outcomes in patients with advanced colorectal liver metastases undergoing associating liver partition and portal vein ligation for staged hepatectomy.
(Pushing the limit of liver regeneration – safety and survival after monosegment-ALPPS: systematic review and pooled data analysis. PROSPERO 2021 CRD42021231710 Available from:)
Expanding the limits of resectability: associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) using monosegment 6, facilitated by an inferior right hepatic vein.
Safety, feasibility, and efficacy of associating liver partition and portal vein ligation for staged hepatectomy in treating hepatocellular carcinoma: a systematic review.
Rapid liver volume increase induced by associating liver partition with portal vein ligation for staged hepatectomy (ALPPS): is it edema, steatosis, or true proliferation?.
Seeing the forest through the trees: a systematic review of the safety and efficacy of combination chemotherapies used in the treatment of metastatic colorectal cancer.
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