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Corresponding author. Karolinska Institutet, Dept. of Clinical Science, Intervention and Technology Division of surgery, C1 77, Karolinska University Hospital, Huddinge SE-141 86, Stockholm, Sweden.
Division of Surgery, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
Division of Surgery, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
Division of Surgery, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
Both satellite lesions and other multiple lesions found to be prognostic factors
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Tumor distribution and number should be reported in intrahepatic cholangiocarcinoma
•
Evaluation of both tumor distribution and number could improve risk stratification
Abstract
Background
Presence of multiple hepatic lesions in intrahepatic cholangiocarcinoma (iCCA) is included in staging as a negative prognostic factor, but both prognostic value and therapeutic implications remain debated. The aim of this study was to systematically review the prognostic influence of multiple lesions on survival after resection for iCCA, with stratification for distribution and number of lesions.
Methods
Medline and Embase were systematically searched to identify records (2010–2021) reporting survival for patients undergoing primary resection for iCCA. Included were original articles reporting overall survival, with data on multiple lesions including tumour distribution (satellites/other multiple lesions) and/or number. For meta-analysis, the random effects model and inverse variance method were used. PRISMA 2020 guidelines were followed.
Results
Thirty-one studies were included for review. For meta-analysis, nine studies reporting data on the prognostic influence of satellite lesions (2737 patients) and six studies reporting data on multiple lesions other than satellites (1589 patients) were included. Satellite lesions (hazard ratio 1.89, 95% confidence interval 1.67–2.13) and multiple lesions other than satellites (hazard ratio 2.41, 95% confidence interval 1.72–3.37) were significant negative prognostic factors. Data stratified for tumour number, while limited, indicated increased risk per additional lesion.
Conclusion
Satellite lesions, as well as multiple lesions other than satellites, was a negative prognostic factor in resectable iCCA. Considering the prognostic impact, both tumour distribution and number of lesions should be evaluated together with other risk factors to allow risk stratification for iCCA patients with multiple lesions, rather than precluding resection for the entire patient group.
European Network for the Study of Cholangiocarcinoma
EUR
Europe
FR
France
FU
follow-up;
GER
Germany
G3
grade 3 (low differentiation)
HBV
hepatitis B virus
HCV
hepatitis C virus
hep,
hepatectomy
HR
hazard ratio
iCCA
intrahepatic cholangiocarcinoma
IV
inverse variance
IT
Italy
KOR
Korea
LND
lymph node dissection
md
median
MeSH
medical subject headings
MF
mass-forming
mm
millimeter
MRI
magnetic resonance imaging
mult
multiple
N1
lymph node metastasis
N.AM
North America
NAT
neoadjuvant therapy
No
number
NS
reported not significant
PAT
histopathology
Pts
patients
RAD
radiology
R1
microscopically tumour positive resection margin
R2
macroscopically tumour positive resection margin
Ref
reference
SE
standard error
SEER
Surveillance, Epidemiology, and End Results Program
TNM
TNM Classification of Malignant Tumours
TWN
Taiwan
US
United States
vs
versus
1. Introduction
The presence of multiple tumours in intrahepatic cholangiocarcinoma (iCCA) is included in the AJCC/TNM staging system as a negative prognostic factor [
Assessment of hepatic arterial infusion of floxuridine in combination with systemic gemcitabine and oxaliplatin in patients with unresectable intrahepatic cholangiocarcinoma: a phase 2 clinical trial.
]. With regard to oncological therapy in iCCA, advances have been made in immunotherapy as well as systemic and regional oncological therapy, but with a majority of studies in patients with advanced disease and with evidence from randomized controlled-trials for neoadjuvant therapy still lacking [
], this analysis however did not take into account number or distribution of lesions, nor did it stratify for other factors including nodal and resection status [
According to the College of American Pathologists and the 8th edition of the AJCC/TNM staging system, the term multiple lesions comprises tumours with satellite nodules as well as multiple separate lesions (intrahepatic metastases and/or multifocal primary cholangiocarcinomas) [
The aim of this study was therefore to systematically review survival outcomes after resection of multiple iCCA, stratified according to distribution and number of multiple lesions.
2. Materials and methods
The PRISMA 2020 guidelines were followed in reporting this review [
]. The PRISMA 2020 Checklist for the study is presented in Supplemental Table 1. The study was preregistered in the International prospective register of systematic reviews (PROSPERO, study ID: CRD42021244952) [
A broad systematic search of MEDLINE (Ovid) (28 April 2021) and Embase (4 May 2021) was undertaken in consultancy with specialized librarians at the Karolinska Institutet university library. The database searches were repeated on 15 December 2021 before finalisation of study screening. Medical subject headings (MeSH) and synonyms for ‘surgical resection’, ‘intrahepatic cholangiocarcinoma’ and ‘prognosis’ were combined. The search was limited to reports in English, published 2010 and later. The search was not limited to records mentioning tumour multiplicity/multifocality or synonyms thereof in title or abstract. Duplicate records were removed before screening. The search strategy documentation is presented in Supplemental Tables 2 and 3
Two authors (HJ and CV) independently screened and assessed the identified records. Discrepancies were solved by discussion and input from a third reviewer (ES). The PRISMA 2020 flow diagram is presented in Fig. 1. Non-automated screening on title and abstract was performed in a reference manager for systematic reviews (Rayyan, Rayyan Systems Inc. Cambridge, MA, USA) [
]. Original research articles reporting prognosis after primary resection of iCCA were assessed for inclusion. Review articles reporting prognosis after primary resection of iCCA were also assessed for any additional records. Studies not reporting overall survival after primary resection of iCCA, or lacking comparative univariable survival data for patients with and without multiple tumours, were excluded, as were case reports/series of <10 patients. The outcome of interest was postoperative long-term survival and outcome data collected was limited to overall survival. Studies further stratifying survival outcomes depending on multiple tumour distribution (satellites i.e. nodules surrounding a primary lesion; or multiple lesions other than satellites) or for subgroups according to number of lesions were included for review, and assessed for inclusion in meta-analysis. For studies found to report overlapping cohorts, the largest or if similar cohort size the most recent, was chosen for comparison. When studies with overlapping cohorts reported additional data, they were included for comparison. For meta-analyses, no overlapping cohorts were included.
For included studies, the following demographic/clinicopathological characteristics were recorded: country/region, number of patients, time period and setting, staging modalities employed, any study specific limits to inclusion (e.g. only certain iCCA patient subgroups/iCCA subtypes), median follow-up time, median overall survival, median age, median tumour size, neoadjuvant/adjuvant therapy and proportion of patients with: lymph node metastasis (N1), microscopic tumour positive resection margin (R1), high tumour grade (poor tumour differentiation), mass-forming iCCA, underlying cirrhosis and viral hepatitis. The overall proportion of patients with multiple lesions as well as proportions with satellite lesions, multiple lesions other than satellites and in subgroups according to number of lesions were recorded. Overall survival for patients with a single tumour and for patients with multiple tumours (multiple all distributions, satellites, multiple other than satellites, subgroup according to number of lesions) was recorded. Non-automated data collection was performed by one reviewer (HJ), and recorded data assessed by a second reviewer (ES). Study quality and risk of bias was assessed independently with the Newcastle-Ottawa scale [
Quality assessment of observational studies in a drug-safety systematic review, comparison of two tools: the Newcastle-Ottawa Scale and the RTI item bank.
The methodological quality assessment tools for preclinical and clinical studies, systematic review and meta-analysis, and clinical practice guideline: a systematic review.
Wells G, Shea B, O'Connell D, Peterson J, Welch V, Losos M, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp. Accessed 10 January 2022.
] by two reviewers (HJ and ES). For meta-analysis the hazard ratios with confidence intervals or the comparison group sizes, number of events and log rank p-values were recorded. For studies reporting event data only as Kaplan-Meier curves with numbers at risk, survival proportion data was extracted using Engauge Digitizer v12.1 [
], using the inverse variance method and the random effects model. To compute pooled hazard ratios, the standard error of the log hazard ratio was calculated from summary statistics according to Parmar et al. [
]. Heterogeneity was assessed by the I2 statistic and Chi-square test, and publication bias assessed graphically with funnel plots. Categorical variables were reported with numbers and percentages, continuous variables with medians. Relative risks were presented as hazard ratios with 95% confidence intervals, when reported, or as estimated when sufficient data was available from published survival and follow-up. Sensitivity analyses were performed excluding studies with the highest risk of bias according to study quality assessment.
3. Results
3.1 Identification of studies
A total of 4184 unique records were identified after database searches of Medline (Ovid) and Embase, with deduplication. After first screening on title and abstract, 855 reports were assessed for eligibility. Reasons for exclusion are given in the PRISMA diagram in Fig. 1. Out of 248 reports with univariable overall survival data for patients with multiple lesions, 204 reports lacked data stratified for distribution or number of lesions. Thirteen reports of overlapping cohorts were excluded [
Development and validation of nomograms for predicting cancer-specific survival in elderly patients with intrahepatic cholangiocarcinoma after liver resection: a competing risk analysis.
Ke Q, Wang L, Lin Z, Lou J, Zheng S, Bi X, Wang J, Guo W, Li F, Wang J, Zheng Y, Li J, Cheng S, Zhou W, Zeng Y. Prognostic Value of Lymph Node Dissection for Intrahepatic Cholangiocarcinoma Patients With Clinically Negative Lymph Node Metastasis: A Multi-Center Study From China. Front Oncol. 2021 Mar 11;11:585808.
], and are presented in Supplemental Table 4. A total of 31 studies, all retrospective cohort studies, were included in this review and are presented in Table 1. The included studies comprised 21 single center studies [
Clinical features of sarcomatoid change in patients with intrahepatic cholangiocarcinoma and prognosis after surgical liver resection: a Propensity Score Matching analysis.
Preoperative risk score for prediction of long-term outcomes after hepatectomy for intrahepatic cholangiocarcinoma: report of a collaborative, international-based, external validation study.
A machine-based approach to preoperatively identify patients with the most and least benefit associated with resection for intrahepatic cholangiocarcinoma: an international multi-institutional analysis of 1146 patients.
]. Seventeen studies showed overlap between cohorts as evaluated according to reported center and study period (Table 1). Qualitative assessment according to the Newcastle-Ottawa scale is presented in Supplemental Table 5. The median score on the scale was seven stars. Three studies had a total score of four [
Preoperative risk score for prediction of long-term outcomes after hepatectomy for intrahepatic cholangiocarcinoma: report of a collaborative, international-based, external validation study.
A machine-based approach to preoperatively identify patients with the most and least benefit associated with resection for intrahepatic cholangiocarcinoma: an international multi-institutional analysis of 1146 patients.
Clinical features of sarcomatoid change in patients with intrahepatic cholangiocarcinoma and prognosis after surgical liver resection: a Propensity Score Matching analysis.
Characteristics of the included studies and cohorts are presented in Table 1. The proportion of resected iCCA patients with satellite lesions ranged from 8 to 44%, while the proportion of patients resected with multiple lesions ranged from 15 to 47%. The proportion of patients with multiple lesions not including satellites was reported in 10 studies, ranging from three to 17%. Among patients with multiple lesions, the proportion with two or two-three lesions was reported in five studies, ranging from 40 to 71%. Twenty studies reported data for iCCA patients in general, while 11 studies reported data only for patients with a disease subtype (i.e. mass-forming iCCA), or within a certain prognostic group (e.g. patients with radical/non-radical resection margin or underlying cirrhosis).
3.3 Overall survival and surgical data
Overall survival outcomes, median follow-up times and surgical data for the included studies are presented in Table 2. Median follow-up ranged from 18 to 55 months. Median overall survival for all resected patients ranged from 17 to 53 months. The proportion of patients undergoing major resections ranged from 40 to 86% and the proportion of patients operated with hepatic resection and associated lymphadenectomy ranged from 33 to 93%. In the five studies in which a majority of patients underwent lymphadenectomy, the proportion of patients with lymph node metastases ranged from 21 to 38%. While five studies limited inclusion to only patients with radical or non-radical resection, the proportion of patients with positive resection margin among the remaining studies ranged from six to 42%. Sixteen studies reported the overall proportions of patients treated with neoadjuvant or adjuvant oncological therapy. The proportion of patients with neoadjuvant therapy ranged from zero to nine percent, while the proportion of patients treated with adjuvant therapy ranged from 20 to 53%.
Table 2Overall survival and surgical data for included studies.
Study (year)
Overall md FU/md OS (months)
Md OS (months) Single/Multiple/Satellites
HR (95% CI) Multiple Yes vs No/Satellites Yes vs No/Other
HR (95% CI) Subgroup number of lesions [Subgroup vs Ref. group]
Preoperative risk score for prediction of long-term outcomes after hepatectomy for intrahepatic cholangiocarcinoma: report of a collaborative, international-based, external validation study.
A machine-based approach to preoperatively identify patients with the most and least benefit associated with resection for intrahepatic cholangiocarcinoma: an international multi-institutional analysis of 1146 patients.
Clinical features of sarcomatoid change in patients with intrahepatic cholangiocarcinoma and prognosis after surgical liver resection: a Propensity Score Matching analysis.
A machine-based approach to preoperatively identify patients with the most and least benefit associated with resection for intrahepatic cholangiocarcinoma: an international multi-institutional analysis of 1146 patients.
A machine-based approach to preoperatively identify patients with the most and least benefit associated with resection for intrahepatic cholangiocarcinoma: an international multi-institutional analysis of 1146 patients.
]. Both the number of lesions chosen to subgroup patients, and the reference categories used when comparing survival, differed between studies (Table 1, Table 2), precluding any meta-analysis.
Four studies presented relative risk data for patients with two or three lesions compared to patients with a single lesion (Table 2 and Supplemental Figure 1) [
], Bednarsch et al., Liu et al. and Wang et al. reported non-significant survival differences (HR 1.68, 95% CI 0.93–3.05, HR 0.77, 95% CI 0.47–1.26 and HR 1.39, 95% CI 0.89–2.17 respectively) [
], compared to patients with a solitary tumour. Chen et al. reported the relative risk increase per additional lesion in a cohort of resected iCCA patients with underlying cirrhosis, with hazard ratio 1.44 (95% CI 1.29–1.60) [
]. Nuzzo et al. reported similar survival for patients with one or two lesions as for patients with a single lesion (both groups median OS = 29 months) [
]. Bednarsch et al. reported a significant survival difference only for patients with more than five lesions compared to patients with a single lesion (median OS = 10 months compared to OS = 32 months) [
3.5 Systematic review: prognostic influence of other categories of tumour distribution
Six studies reported tumour distribution with specific categories other than satellites or multiple lesions not including satellites, out of which five presented overall survival data for these categories (Table 1, Table 2). Limited data and heterogeneity between studies precluded any meta-analysis. While three studies reported data for patients with ‘intrahepatic metastases’ (Table 2), Kim et al. included patients with satellite lesions to this group and reported a significantly decreased survival [
]. Aherne et al. included all multiple lesions not specified as satellites and found no significant survival difference, without reporting survival or summary data [
]. Fu et al. did not specify criteria for the categorisation of lesions as intrahepatic metastases and reported a significant decrease in overall survival [
Two studies analysed survival in multiple iCCA with lesions also in the contralateral liver lobe (Table 2). While Addeo et al. found patients with multiple lesions in the contralateral hemiliver to have similar survival as patients with single lesions [
], Bartsch et al. reported patients with multiple lesions and a ‘translobar’ dissemination to the contralateral hemiliver to have significantly decreased survival [
]. Bartsch et al. included patients with diffuse tumour infiltration in the ‘translobar’ subgroup but found similar outcomes (no data reported) for patients with and without diffuse infiltration [
3.6 Meta-analysis: prognostic influence of satellite lesions
Seventeen studies presented data on overall survival for patients with and without satellites, 14 reporting hazard ratios or data allowing hazard ratio calculation (Table 2). The study by Addeo et al. was excluded from meta-analysis as it included all patients presenting with multiple lesions confined to one liver lobe in the satellite lesion subgroup [
Preoperative risk score for prediction of long-term outcomes after hepatectomy for intrahepatic cholangiocarcinoma: report of a collaborative, international-based, external validation study.
Clinical features of sarcomatoid change in patients with intrahepatic cholangiocarcinoma and prognosis after surgical liver resection: a Propensity Score Matching analysis.
], including the study by King et al. where four patients with other multiple lesions than satellites were included in the satellite lesion group in survival analysis [
The meta-analysis of nine non-overlapping studies comparing survival for 2737 patients with and without satellite lesions is presented in Fig. 2 A and B. The pooled result indicated a significantly decreased overall survival for patients with satellite lesions (HR 1.89, 95% CI 1.67–2.13), with limited statistical heterogeneity among studies and no apparent bias as evaluated by funnel plot symmetry (Fig. 2B). Pooled data also including the study by Addeo et al. [
] are presented in Supplemental Fig. 2 A and B, with concurrent results (HR 1.91, 95% CI 1.69–2.14). Pooled data excluding three studies with a score of five or less on the Newcastle-Ottawa scale are presented in Supplemental Fig. 3 A and B, with similar results (HR 2.05, 95% CI 1.75–2.39).
Fig. 2Meta-analysis of satellite lesions as prognostic factor for overall survival after resection for iCCA, A) Forest plot B) Funnel plot.
3.7 Meta-analysis: prognostic influence of multiple lesions not including satellites
Six non-overlapping studies reported overall survival data for 1589 patients depending on presence or absence of multiple lesions not including satellites (Table 2), with a meta-analysis presented in Fig. 3 A and B. The overlapping study by Zhou et al. was excluded [
]. For this comparison, a higher degree of statistical heterogeneity was present between studies (I2 = 35% P = 0.18). The pooled result indicated a significant decrease in overall survival for patients with multiple lesions other than satellites (HR 2.41, 95% CI 1.72–3.37). Pooled data excluding one study with a score less than five on the Newcastle-Ottawa scale is presented in Supplemental Fig. 4 A and B, with similar results (HR 2.53, 95% CI 1.64–3.91).
Fig. 3Meta-analysis of multiple lesions (not including satellites) as prognostic factor for overall survival after resection for iCCA, A) Forest plot B) Funnel plot.
Considering GRADE domains for rating of evidence for the pooled hazard ratio for satellite lesions, concerns for risk of bias remained also after sensitivity analyses. Included studies lacked data on diagnostic modalities [
Preoperative risk score for prediction of long-term outcomes after hepatectomy for intrahepatic cholangiocarcinoma: report of a collaborative, international-based, external validation study.
Preoperative risk score for prediction of long-term outcomes after hepatectomy for intrahepatic cholangiocarcinoma: report of a collaborative, international-based, external validation study.
]. Inconsistency among results was evaluated with limited heterogeneity. Directness, or generalisability for the pooled estimate, was assessed with only one study limiting inclusion to a subgroup of resected patients [
]. The imprecision of the pooled estimate for the full meta-analysis implied a risk increase spanning from 69 to 114% for patients with satellites. There was no evidence of publication bias.
Considering GRADE domains for pooled estimates for multiple lesions other than satellites, concerns for risk of bias were similar to studies reporting outcomes for patients with satellite lesions. Included studies lacked data on diagnostic modalities [
]. Concerns for inconsistency were present, with low to moderate heterogeneity. Funnel plot analysis revealed asymmetry suggesting possible bias. Directness was assessed with only one study limiting inclusion to a subgroup of patients [
]. Imprecision was more pronounced with a pooled estimated risk increase spanning from 72 to 237%. Grade evidence profiles are summarised in Supplemental Table 6.
3.9 Multivariable comparisons
Among the nine studies included for meta-analysis of the prognostic influence of satellite lesions, five studies reported multivariable analyses incorporating satellite lesions with other risk factors including lymph node status [
Preoperative risk score for prediction of long-term outcomes after hepatectomy for intrahepatic cholangiocarcinoma: report of a collaborative, international-based, external validation study.
]. Of these studies, two found satellite lesions to be a significant independent factor (Conci et al.: HR 3.10, 95% CI 1.55–6.2053;Moro et al.: HR 1.65, 95% CI 1.34–2.0455), while the study by Bartsch et al. reported significance for a compound prognostic score including number and distribution of lesions, tumour size, extension and volume [
]. Brustia et al. and Tabrizian et al. both reported non-significance for satellites on multivariable analysis including lymph node metastasis (Brustia et al.: HR 1.42, 95% CI 0.88–2.3051, Tabrizian et al.: no multivariable HR or P-value reported [
As noted in current discussions about prognostic factors in resectable iCCA, the term multiple lesions can incorporate a considerable heterogeneity among patients regarding tumour distribution (satellites and other multiple lesions) and number of lesions. This heterogeneity could extend to prognostic differences within the group of iCCA patients diagnosed with multiple intrahepatic lesions, and impact therapeutic choices when considering resection or locoregional oncological therapies.
While one previous study found patients with satellite lesions to have outcomes not significantly inferior to those with a single tumour [
In this systematic review, with a meta-analysis including nine studies reporting univariable survival data for 2737 patients with/without satellites, from a variety of settings and including both radiologically and histopathologically diagnosed lesions, satellite lesions were found to be a significant negative prognostic factor after resection for iCCA. The statistical heterogeneity among studies was low, and with no apparent publication bias.
When analyzing outcomes for patients with/without multiple lesions other than satellites, in a meta-analysis including six studies and 1589 patients, multiple separate lesions were likewise found to be a significant negative prognostic factor, but with a higher degree of heterogeneity among studies.
In the broader review, different categories of multiple lesions other than satellites were reported, with conflicting data from the two studies reporting outcomes in multiple iCCA with contralateral lesions [
]. A possible explanation to such opposing outcomes could be underlying differences in other prognostic factors, e.g. tumour size and tumour number between studies and subgroups.
To what degree multiple lesions other than satellites represent intrahepatic metastases of iCCA or multifocal synchronous lesions, and whether such a differentiation would have a prognostic significance, is not clear from the reviewed literature. In a recent study, performing genomic profiling on multiple tumours from a small group of patients, all multiple lesions (including satellites) were found to represent metastases [
]. It could be hypothesised that multifocal synchronous lesions on a background of chronic liver disease could imply a better oncological prognosis compared to metastasized iCCA, but criteria to differentiate metastases from multifocality remain to be defined, and any possible associated survival difference to be further studied.
The degree of overlap and of collinearity between prognostic factors also needs to be considered. While negative prognostic factors overlap in some patients, a proportion of patients with satellites but without other multiple lesions, or vice versa, were presented in several studies [
]. If, and to what extent, underlying differences in other prognostic factors (such as presence of lymph node metastasis) between patients with and without multiple lesions explain the observed survival differences is not clear. Moro et al., with the largest international multicentric cohort in this review, reported satellite lesions to be an independent negative prognostic factor in a multivariable model adjusted for important variables such as lymph node metastasis, tumour differentiation, resection margin and tumour size [
The broader question of clinical benefit of resection, compared to other therapy options for patients with multiple iCCA, which has been addressed in several studies in recent years, was beyond the scope of this review. While single-center regional therapy cohorts (hepatic arterial infusion [
Surgical resection does not improve survival in multifocal intrahepatic cholangiocarcinoma: a comparison of surgical resection with intra-arterial therapies.
]) have reported similar survival as with surgical resection, analysis of data from a United States national registry (SEER) found improved survival in resected patients with multiple lesions, also when adjusting for chemoradiotherapy in a multivariable model [
]. In a large European multi-center cohort (ENSCCA), when surgery was analysed as a univariable prognostic factor, resection in patients with multiple iCCA was associated with improved survival [
]. Which iCCA patients with multiple lesions would benefit most from resection surgery, and how surgery compares to locoregional therapies in different risk groups within the multiple lesion group, remains to be further studied. The overall proportion of patients receiving neoadjuvant therapy reported from cohorts in this review remained low, and the role for neoadjuvant systemic chemotherapy in iCCA with multiple lesions or other negative prognostic factors is an important focus for clinical trials [
NEO-GAP: a phase II single-arm prospective feasibility study of neoadjuvant gemcitabine/cisplatin/nab-paclitaxel for resectable high-risk intrahepatic cholangiocarcinoma.
]. The overall proportion of patients receiving adjuvant therapy, when reported, remained below 50% in nine out of eleven studies. How real-world outcomes of surgery will develop with current implementation of adjuvant chemotherapy after recent randomized controlled trials also remains to be studied [
This systematic review was based on a broad search of the current literature, focusing specifically on resected iCCA patients, evaluating overall survival outcomes for patients with multiple lesions according to both tumour distribution and number. Furthermore, it permitted the meta-analysis of relative risks according to distribution of multiple lesions, the first such analysis to date to our knowledge. A previous systematic review of prognostic factors for overall survival in patients undergoing resection for iCCA, published in 2014, included five studies with data on multiple tumours in meta-analysis, without further stratification [
]. With a comprehensive search, the current study was able to include nine and six studies respectively in meta-analyses, with granular data on tumor distribution and relative risks, allowing sensitivity analyses and presenting a synthesis of best available current evidence to shape further scientific discussion and research specifically for the sizable group of patients with multiple iCCA.
However, the study also had several limitations. A considerable heterogeneity was found among studies regarding definitions, diagnostic modalities and patient cohorts. Several criteria to define satellite lesions have been proposed, such as lesions within 10 mm of the main tumour [
Correlation of CT patterns of primary intrahepatic cholangiocarcinoma at the time of presentation with the metastatic spread and clinical outcomes: retrospective study of 92 patients.
], and different definitions of proximity to the primary lesion were employed in the reviewed studies. Most studies did not specify which diagnostic modalities were used to determine tumour multiplicity. Among studies reporting survival for patients with satellite lesions compared to patients without satellites, it is possible that the reference category in some reports could include multiple lesions without satellites, and not only patients with single lesions. Regarding terminology for tumour distribution, the terms bilobar or bilateral iCCA were not investigated in this review, as they also describe patients with large or central single lesions engaging both hemilivers [
]. A majority of studies reported single center data. For studies reporting survival curves with numbers at risk, relative risks were estimated from summary data. Upon review, data was limited for number of lesions and other categories of tumour distribution, only permitting qualitative synthesis. For meta-analyses, assessment of evidence indicated risk of bias both for studies reporting data on satellite lesions and other multiple lesions, with further limitations for the meta-analysis on multiple lesions not including satellites, with a higher degree of imprecision in the pooled estimate and further possible bias.
In conclusion, this systematic review and meta-analysis of the prognostic influence of multiple lesions in resectable iCCA found patients with satellite lesions, as well as patients with multiple lesions not including satellites, to have significantly decreased overall survival. Data stratified for number of lesions was limited, but suggested increased risk per additional lesion. Number of tumours, presence of satellite lesions and presence of multiple lesions other than satellites should be separately reported, to allow further analysis as possible additive prognostic factors. To evaluate these variables separately, together with other prognostic factors, could permit an improved risk stratification for the considerable proportion of iCCA patients presenting with multiple lesions, rather than contraindicating surgery for an entire patient group.
Sources of funding and role of the funding source
Hannes Jansson was supported by grants from Region Stockholm and the Swedish Society of Medicine. Ernesto Sparrelid was supported by grants from the Bengt Ihre Foundation, the Center for Innovative Medicine at Karolinska Institutet, the Swedish Society for Medical Research (SSMF) and Region Stockholm. The funding sources were not involved in the design or conduct of the review, the writing of the report or the decision to submit the article for publication.
Data availability statement
The data collected and analysed during the current review are available from the corresponding author on reasonable request.
CRediT authorship contribution statement
Hannes Jansson: Conceptualization, Investigation, Writing – original draft, Writing – review & editing. Christina Villard: Conceptualization, Investigation, Writing – review & editing. Lynn E. Nooijen: Investigation, Writing – review & editing. Poya Ghorbani: Writing – review & editing. Joris I. Erdmann: Conceptualization, Writing – review & editing. Ernesto Sparrelid: Conceptualization, Investigation, Writing – original draft, Writing – review & editing, Supervision, All authors contributed to interpretation of data, critical revisions, and approved the final version of the manuscript.
Conflict of interest disclosure
Hannes Jansson, Christina Villard, Lynn E. Nooijen, Poya Ghorbani, Joris I. Erdmann and Ernesto Sparrelid have no conflicts of interest do disclose.
Acknowledgements
The authors would like to acknowledge Narcisa Hannerz and Emma-Lotta Säätelä (the search consultation service of the Karolinska Institutet University Library); and the EURO-CHOLANGIO-NET European Cholangiocarcinoma Network.
Appendix A. Supplementary data
The following is the Supplementary data to this article.
Assessment of hepatic arterial infusion of floxuridine in combination with systemic gemcitabine and oxaliplatin in patients with unresectable intrahepatic cholangiocarcinoma: a phase 2 clinical trial.
(PROSPERO 2021 CRD42021244952)Prognostic influence of multifocal tumor distribution in intrahepatic cholangiocarcinoma: a systematic review. 2021 (. Published)
Quality assessment of observational studies in a drug-safety systematic review, comparison of two tools: the Newcastle-Ottawa Scale and the RTI item bank.
The methodological quality assessment tools for preclinical and clinical studies, systematic review and meta-analysis, and clinical practice guideline: a systematic review.
Wells G, Shea B, O'Connell D, Peterson J, Welch V, Losos M, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp. Accessed 10 January 2022.
Clinical features of sarcomatoid change in patients with intrahepatic cholangiocarcinoma and prognosis after surgical liver resection: a Propensity Score Matching analysis.
Preoperative risk score for prediction of long-term outcomes after hepatectomy for intrahepatic cholangiocarcinoma: report of a collaborative, international-based, external validation study.
A machine-based approach to preoperatively identify patients with the most and least benefit associated with resection for intrahepatic cholangiocarcinoma: an international multi-institutional analysis of 1146 patients.
Surgical resection does not improve survival in multifocal intrahepatic cholangiocarcinoma: a comparison of surgical resection with intra-arterial therapies.
NEO-GAP: a phase II single-arm prospective feasibility study of neoadjuvant gemcitabine/cisplatin/nab-paclitaxel for resectable high-risk intrahepatic cholangiocarcinoma.
Correlation of CT patterns of primary intrahepatic cholangiocarcinoma at the time of presentation with the metastatic spread and clinical outcomes: retrospective study of 92 patients.
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