Defining oligometastatic pancreatic cancer: a systematic review and critical synthesis of consensus

Background Small retrospective series suggest that local consolidative treatment (LCT) may improve survival in oligometastatic pancreatic ductal adenocarcinoma (PDAC). However, no uniform definition of oligometastatic disease (OMD) in PDAC exists; this impedes meaningful conclusions. Patients and methods A systematic literature search using PubMed, Web of Science, and Cochrane CENTRAL registries for studies and protocols reporting on definitions and/or LCT of OMD in PDAC was performed. The primary endpoint was the definition of OMD. Levels of agreement were categorized as consensus (≥75% agreement between studies), fair agreement (50%-74%), and absent/poor agreement (<50%). Results After screening of 5374 abstracts, the full text of 218 studies was assessed, of which 76 were included in the qualitative synthesis. The majority of studies were retrospective (n = 66, 87%), two were prospective studies and eight were study protocols. Studies investigated mostly liver (n = 38, 51%) and lung metastases (n = 15, 20%). Across studies, less than one-half (n = 32, 42%) reported a definition of OMD, while 44 (58%) did not. Involvement was limited to a single organ (consensus). Additional criteria for defining OMD were the number of lesions (consensus), metastatic site (poor agreement), metastatic size (poor agreement), treatment possibilities (poor agreement), and biomarker response (poor agreement). Liver OMD could involve three or fewer lesions (consensus) and synchronous disease (fair agreement), while lung metastases could involve two or fewer lesions and metachronous disease (consensus). The large majority of studies were at a high risk of bias or did not include any control groups. Conclusion Definitions of OMD were not used or varied widely between studies hampering across-study comparability and highlighting an unmet need for a consensus. The present study is part of a multistep process that aims to develop an interdisciplinary consensus on OMD in pancreatic cancer.


BACKGROUND
Pancreatic ductal adenocarcinoma (PDAC) is a deadly malignancy with rising incidence. 1Surgery offers the only potential chance of cure; however, only 10%-20% of patients are initial candidates for surgical resection while the majority of patients presents with locally advanced disease or distant metastasis.
In recent years, multimodal chemotherapy regimens, as well as advanced surgical techniques, significantly increased the chance of potentially curative surgery, resulting in resection of previously unresectable locally advanced tumors in up to 60% of cases. 2 In parallel, perioperative mortality rates decreased. 3However, the large majority of cancer-related deaths in PDAC continues to be driven by metastatic spread. 46][7] Macroscopically visible systemic tumor spread seems to render a localized treatment approach futile, making systemic chemotherapy the treatment of choice. 5However, LCT is increasingly investigated in patients with PDAC presenting with a limited number of metastases based on the concept of oligometastatic disease (OMD). 80][11] Some clinical evidence supports the concept of an oligometastatic state in PDAC: on the one hand, survival seems to differ in metastatic pancreatic cancer dependent on the site of initial metastasis, 12,13 on the other hand, resection of isolated metachronous pulmonary metastases has been associated with improved survival compared with other sites of metastases in retrospective series. 14,15Yet, no widely accepted definition of oligometastatic PDAC exists and variable definitions lead to controversy and confusion. 16,17mportantly, standardized definitions are a prerequisite for future treatment progress.The primary aim of this systematic review was to identify definitions of OMD in PDAC and synthesize a consensus based on these.The secondary aim encompassed the provision of a comprehensive descriptive synopsis of survival.

METHODS
This study was registered in the PROSPERO registry of systematic reviews (CRD42023439102) and conducted according to the Synthesis Without Meta-analysis (SWiM) reporting guidelines. 18

Eligibility criteria
All studies reporting on OMD in PDAC were eligible for inclusion, including randomized trials, nonrandomized trials, study protocols, and case series with six patients or more.No age or period restrictions were applied.Studies that did not report a definition of OMD and/or did not report on LCT of OMD were excluded.Non-English language studies, narrative reviews, meta-analyses, conference abstracts, and case series with less than six patients were also excluded.Furthermore, studies solely focusing on extra-regional lymph node metastases were excluded.Registry studies were included in the qualitative synthesis if they provided a definition of OMD.However, they were excluded from any investigations concerning the effect on survival after LCT.

Search strategy
A systematic search using PubMed, Web of Science, and Cochrane CENTRAL registries was carried out and our last update was on 17 October 2022.No limitations on the time frame were set.The search strategy for MEDLINE is depicted in the Supplementary Materials, available at https://doi.org/10.1016/j.esmoop.2023.102067; the other search strategies are available upon request.
The search strategy was validated by cross-comparison of the results with a recent systematic review on LCT in oligometastatic PDAC and manual checking if selected references were included in the retrieved results. 19

Screening and data extraction
Covidence systematic review software (Veritas Health Innovation, Melbourne, Australia) was used to manage references.Titles and abstracts of all references were screened independently by two reviewers (CSL and TH).In case of disagreement, a discussion was initiated among the investigators until a consensus was reached (defined as !75% agreement).Additional studies were identified by manually checking the reference lists of selected studies.
For data extraction, a specific extraction form was designed and pilot-tested using selected studies.Extracted basic data included first author, publication year, country, sample size, study type, study period, age, and sex.
In addition, definitions of OMD, data on the treatment of the primary tumor and metastases, existence of a control group, median overall survival (OS), median disease-free interval (DFI), size of metastases, number of metastatic sites, number of affected organ(s), time pattern of metastases, performance status, biochemical response, imaging modality, and imaging response were retrieved.

Critical appraisal
The Risk Of Bias In Non-randomised Studies -of Interventions (ROBINS-I) tool was used to judge the quality of the eligible studies. 20This tool was selected as it is specifically designed for observational studies and most eligible studies were anticipated to be of nonrandomized design.The domains included bias due to confounding, bias due to selection of participants, bias in classification of interventions, bias due to deviations from intended interventions, bias due to missing data, bias in measurement of outcomes, and bias in selection of the reported result.Each potential source of bias was graded as low, moderate, serious, and critical.
The risk of bias in the respective domains and overall bias was assessed by two reviewers (CSL and TH) working independently.Disagreements were resolved through consultations among the investigators as described previously.

Data synthesis
Based on the data extraction of the first half of the eligible articles, it was determined that a meta-analysis based on pooled hazard ratios of survival outcomes was not appropriate because of substantial methodological and statistical heterogeneity.All data synthesis without meta-analysis was performed according to the Cochrane Handbook and the SWiM guidelines, respectively. 18,213][24][25] In brief, !75% agreement between studies was considered 'consensus', agreement of 50%-74% was considered 'fair agreement', and agreement <50% was considered 'absent/ poor agreement'. 22or the definition of consensus, studies were grouped based on the metastatic site.As only a small number of appropriate studies was expected per group, a minimum of two studies was required for a definition of consensus.Subsequently, the following four categories were identified for metastatic sites: (i) liver metastases, (ii) lung metastases, (iii) liver and/or lung metastases, and (iv) other metastatic sites.
To identify the criteria most commonly used for defining OMD, frequency counts were used, resulting in five different categories: (i) Treatment possibilities (ii) Size of metastatic lesion (iii) Affected organ (iv) Number of metastases (v) CA 19-9 biomarker response in cases of systemic therapy before LCT Subsequently, a consensus was synthesized as described above.

Statistics
As most studies did not include a control group or did not provide measures of effect between intervention and control groups, no formal meta-analysis could be conducted.
For survival analysis, the median OS after resection was used.OS times between diagnosis and the resection of primary tumor were equated for the calculation of the weighted median of medians.The weighted median of medians was calculated according to the method described by McGrath and colleagues. 26ll statistical analysis was conducted using R (R Foundation, Vienna, Austria).A two-sided P-value <0.05 was considered significant.

Patient and public involvement
Patients as well as representatives of patient organizations were involved during the process of this systematic review.Their ideas and opinions regarding potentially relevant differences in metastatic PDAC were taken into account in personal discussions during meetings.Furthermore, suggestions concerning the avoidance of technical terms were considered whenever possible without compromising the scientific content.

RESULTS
After screening of 5374 abstracts, 218 full-text articles were assessed for eligibility (Figure 1).Finally, 76 studies were identified, which provided a definition of OMD in PDAC and/or reported LCT of OMD (Table 1).3][84][85][86][87][88][89] After the exclusion of study protocols and registry studies, the studies comprised a total of 2365 patients and most reported single-center data.

Consensus for other locations of oligometastasis
The trial by Sherry and colleagues 81 was excluded from this analysis as it only contained one patient with pancreatic cancer.Subsequently, three studies were identified, which included multiple sites of metastasis or did not specify a specific anatomical location 32,82,84 (Table 2).In these, three or fewer metastatic lesions (consensus, 100%) were considered OMD while two of these studies specified the time pattern of metastases.Here, synchronous and/or metachronous (consensus, 100%) were considered OMD. 32,81In addition, four studies were identified, which involved liver and lung metastases without specifically differentiating between the two 16,39,49,68 (Table 2).In these, four or fewer metastatic lesions (consensus, 75%) and

Critical appraisal and survival analysis
All studies were at a high risk of bias based on the ROBINS-I tool (Supplementary Figure S1, available at https://doi.org/10.1016/j.esmoop.2023.102067).The weighted median OS of all the 17 studies that reported a definition of OMD and resection of the primary tumor was 16 months (95% CI 12.3-23.091,96 Nine of these studies reported survival data for a control group, resulting in a weighted median OS of 7.5 months (95% CI 7.5-10.4months). 2,39,48,56,69,72,73,75,96Notably, the other studies did not include a control group or reported its survival.A harvest plot including studies defining OMD and reporting median OS is presented in Figure 2C.

DISCUSSION
An increasing number of studies investigate oligometastatic PDAC.However, no uniform definition exists.Based on the present systematic review oligometastatic PDAC encompasses either three or fewer synchronous liver metastases or two or fewer metachronous lung metastases.Importantly, of the 76 studies identified, only 32 provided a definition of OMD.Noteworthy, none of the identified eight study protocols registered at ClinicalTrials.govused the same definition of oligometastatic PDAC.
1][102] In colorectal liver metastases, positive lymph node status, extrahepatic disease, short DFI, high preoperative tumor markers, size of the primary tumor, and others have been identified as negative predictors of poor survival. 103Moreover, stereotactic body radiotherapy resulted in a survival benefit in different types of oligometastatic cancers in a multicenter randomized controlled trial. 1046][107][108][109][110][111][112][113][114] In particular, complete response to chemotherapy based on imaging criteria has encouraged clinicians to seek resection of metastases in addition to the primary tumor as part of individualized treatment strategies. 44,115,116owever, a lack of an accepted definition of OMD is a relevant hindrance to any meaningful conclusions.Other tumor entities lead the way.An international panel of experts recently proposed a definition of oligometastatic esophagogastric cancer (Table 3). 24OMD was defined as one or two metastases in either the liver, lung, retroperitoneal lymph nodes, adrenal glands, or soft tissue/bone.Interestingly, OMD additionally applied to no evidence of progressive disease at restaging after 18 weeks of systemic therapy. 24Similarly, definitions of OMD have been Drewes, 2019 36 Elamir, 2022 39 Frigerio, 2022 91 Hackert, 2016 2 Hong, 2018 46 Ji, 2021 48 Kandel, 2018 49 Lee, 2021 54 Lovecek, 2017 55 Lu, 2022 56 Safi, 2021 64,65 Schwarz, 2020 96 Scorsetti, 2020 68 Shao, 2021 69 Tachezy, 2016 72 Takeda, 2023  developed for NSCLC as well as breast cancer. 9,117,118otably, the National Comprehensive Cancer Network (NCCN) guidelines and the eight edition of the tumore nodeemetastasis (TNM) system already incorporate an oligometastatic stage into the classification of NSCLC. 119wo previous papers proposed a definition of OMD in PDAC.Damanakis et al. 16 defined an oligometastatic state as CA 19-9 <1000 U/ml, four or fewer metastases in the liver/lung, and response or stable disease after first-line chemotherapy based on survival outcome without LCT.Applying these criteria, a subgroup of patients with significantly extended OS was identified.A recent study from Japan identified 54 patients who underwent staging laparoscopy or gastrointestinal bypass surgery as suffering from oligometastatic pancreatic cancer based on CA 19-9 <2000 U/ml and either one to four liver metastases or peritoneal metastasis localized to the adjacent peritoneum or limited to the distant peritoneum. 17Oligometastatic patients had a significantly longer survival compared with a polymetastatic control cohort.
For surgical treatment of metastases, two minimal prerequisites must be fulfilled: (1) both primary tumor and metastatic lesions must be technically resectable and (2) patients must be in good general health to be able to tolerate a large resection.Importantly, to justify LCT, the median OS should at least be >11 months which can be achieved with FOLFIRINOX-based systemic treatment in metastatic PDAC. 120n the absence of randomized trials, no high-quality evidence exists for any LCT strategy.The Chinese Study Group of Pancreatic Surgery (CSPAC) launched the multicenter phase III CSPAC-1 trial (NCT03398291) which aims to enroll 300 patients with pancreatic cancer with three or fewer synchronous liver metastases undergoing simultaneous resection after induction chemotherapy. 89The German HOLIPANC study is a phase II trial launched in 2021 and includes patients with five or fewer synchronous liver metastases treated with preoperative chemotherapy and then undergoing resection if the restaging shows stable disease or response according to RECIST 1.1 (NCT04617457). 99ETAPANC is a phase III study investigating the effect of intensified chemotherapy followed by surgery for oligometastatic liver disease defined as three or fewer resectable liver metastases. 121Furthermore, laboratory values as well as Eastern Cooperative Oncology Group (ECOG) status were considered in the published protocol.However, no registration on ClinicalTrials.govhas been published so far, hence the study was not considered in the data synthesis of the present systematic review.
The present systematic review has several limitations, which need to be recognized.First, the total number of identified studies was small, far smaller than that of other tumor entities. 24,25This most likely reflects the current clinical practice as well as the unique tumor biology of PDAC.In addition, due to a high degree of methodological heterogeneity, no formal meta-analysis was conducted.Accordingly, we adhered to the SWiM guidelines for systematic reviews without metaanalysis, which have been developed to improve the reporting of findings and validity when using alternative synthesis methods. 18Furthermore, some of the identified studies did not provide sufficient data granularity for further analysis or did not clearly delineate between synchronous or metachronous metastases in the reported results. 16,39,49,68o correctly identify OMD, imaging plays a key role.The EORTC recently published recommendations on preferred imaging modalities of OMD in several cancers. 122By contrast, in the identified studies, only rarely the specific imaging modality to define OMD was reported.
Future work is necessary to identify the underlying molecular differences that determine the capacity of the tumor cell to metastasize.The concept of OMD implicitly assumes a hierarchical metastatic progression.Recent work indicates that the loss of the tumor suppressor gene SMAD4 is associated with metastatic capacity and preclinical models support differences in metastatic capacity based on transcriptomic subtypes. 123,124As most patients who present with initially limited metastases quickly suffer from widespread systemic dissemination, it will be important to develop molecular biomarkers that will allow clinicians to tailor treatment to underlying tumor biology. 76Evidence from a xenograft mouse model indicates that the microRNA-200 family might be involved in the regulation between an oligometastatic and a polymetastatic state. 125

Conclusion
In summary, the majority of studies reporting on OMD do not provide a definition, leading to controversy and hampering comparability.We systematically reviewed the literature and synthesized a consensus definition of oligometastatic PDAC.It will be necessary to establish reliable criteria upon which patients will most likely benefit from LCT of metastases.A standardized definition of oligometastatic pancreatic cancer is an important step in that direction.

FUNDING
None declared.

Figure 2 .
Figure 2. (A) Criteria used to define oligometastatic pancreatic cancer.(B) Graphical summary of consensus definitions of oligometastatic pancreatic cancer by metastatic site.(C) Harvest plot depicting median postresection survival after resection of the primary tumor.Blue shading indicates the sample size, icons indicate whether or not the respective study contains a control group.Labels 'serious', 'critical' next to icons indicate the overall risk of bias based on the Risk Of Bias In Nonrandomised Studies -of Interventions (ROBINS-I) tool.

Table 1 .
Study characteristics NA, not applicable; OMD, oligometastatic disease.a Excluding study protocols and registry studies.

Table 2 .
Study characteristics of pancreatic cancer with liver metastases, lung metastases, and multiple/other sites of OMD

Table 3 .
Definitions of oligometastatic disease in other cancer entities