“Oligometastatic pancreatic cancer” definition: The first step

Mximos Frountzs ,Dimitrios Shizs ,Stylinos Kyklos ,Konstntinos G Toutouzs

a First Propaedeutic Department of Surgery,Hippocration General Hospital,National and Kapodistrian University of Athens,School of Medicine,Athens,Greece

b First Department of Surgery,Laikon General Hospital,National and Kapodistrian University of Athens,School of Medicine,Athens,Greece

c Second Department of Propaedeutic Surgery,Laikon General Hospital,National and Kapodistrian University of Athens,School of Medicine,Athens,Greece

Pancreatic ductal adenocarcinoma (PDAC) is nowadays the fourth leading cause of cancer-related death worldwide,but according to recent estimations it will become the second leading cause of cancer-related deaths in the USA up to 2030,following lung cancer.The implementation of neoadjuvant chemotherapy during recent years led to an increase of overall survival at 35 months in PDAC after R0 resection [1].However,pancreatic cancer has a particularity that makes it a real challenge for clinicians: only 20% of patients are diagnosed early enough to have a resectable pancreatic cancer,whereas 40% of patients present with locally advanced or non-resectable disease,while the rest present with distant metastases [2].Systemic chemotherapy plays the main role in metastatic PDAC treatment: polychemotherapy regimens such as FOLFIRINOX (folinic acid,5-fluorouracil,irinotecan and oxaliplatin)or combination of gemcitabine/nab-paclitaxel seemed to improve median overall survival from 6.8 to 11.1 months and 6.7 to 8.5 months,respectively [3].

During recent years,the meticulous analysis of outcomes regarding metastatic PDAC patients demonstrated that there might be an intermediate stage of disease between localized and systematically spread disease,the so called “oligometastatic” PDAC.A recent meta-analysis by De Simoni et al.[4]demonstrated a significant difference in overall survival between highly selected patients with metastatic PDAC treated with a multimodal therapeutic approach and patients treated with definite chemotherapy (23-56 vs.11-16.4 months,P=0.007).This approach consists of the initial implementation of neoadjuvant chemotherapy followed by surgical management of the primary tumor along with the metastatic lesions using locoregional approaches such as metastasectomy,radiofrequency ablation,irreversible electroporation or stereotactic body radiation therapy.

The term “oligometastatic” was first introduced by Hellman and Weichselbaum in 1995,describing an intermediate state between widespread metastatic and localized disease,whereby metastases are limited in number and confined to a single or limited number of organs;in such cases curative treatment could still be possible [5].Apart from the primary tumor located at the pancreas,metastases are restricted to a single or limited number of organs,usually liver or lung,and rarely to regional lymph nodes or adrenal glands.Although oligometastatic PDAC has been considered as an anatomically “limited disease”,a unique and widely accepted definition is actually lacking.Consequently,“oligometastatic state” in PDAC has to be precisely defined considering specific features of the disease,such as accurate number,size and sites of metastases,surgical resectability,response to neoadjuvant treatment and biologic behavior.

In some studies [2,6],oligometastatic PDAC was defined by ≤4 metastases in liver or lung,whereas in other studies [7,8]the definition referred to patients with totally ≤2 metastatic tumors in liver or lung,each <4 cm.The rationale behind restrictions in number and size of metastatic lesions is based on the feasibility of their resectability or the efficacy of previously mentioned locoregional therapies.Pancreatectomy combined with a formal hepatectomy would lead to increased morbidity and mortality and has not been suggested in most cases.Therefore,atypical resections or ablative procedures are preferred in order to reduce morbidity and mortality [9].Radiofrequency ablation criteria include liver metastases up to 3 cm diameter in size,≤5 lesions and no other distant metastases [6].

Another crucial feature of oligometastatic PDAC patients is the low metastatic potential of their lesions,as they seem to have a “better biology” compared to patients with diffuse metastases.Clinical characteristics of these patients,such as tumor response after neoadjuvant chemotherapy and carbohydrate antigen 19-9(CA19-9) levels,have been utilized to predict a “better tumor biology”.Neoadjuvant chemotherapy serves as “a test of time” for pancreatic tumors to express their metastatic potential.Therefore,patients with tumor progress over treatment seem to suffer from PDAC with high metastatic potential;thus,surgical resection of metastases would not be beneficial [10].On the other hand,patients with responsive or stable disease after neoadjuvant chemotherapy according to the Response Evaluation Criteria in Solid Tumours (RECIST) criteria could be considered as oligometastatic [11].Furthermore,patients with CA19-9 levels below 10 0 0 U/mL or with a significant reduction of CA19-9 levels,should be considered as suffering from PDAC of “good biology” and therefore could be included in the oligometastatic group [12].Finally,Kandel et al.[7]described that Eastern Cooperative Oncology Group (ECOG) status in metastatic PDAC patients who underwent metastasectomy was associated with overall survival.

Apart from synchronous metastases,patients with pancreatic cancer may present a relapse that occurs either locally or systemically,usually as liver (70% during the course of disease) or lung metastases.The concept of a specific group of patients that would benefit from multidisciplinary treatment of metachronous metastatic PDAC,including surgical excision of the metastatic lesions,is nowadays under consideration.The definition criteria for this specific group of patients are similar to the “oligometastatic PDAC” patients and refer to “limited disease” and tumors with“good biology”.Schwarz et al.[13]demonstrated that the longterm survival in such patients is 36.8 months after metastasectomy compared to 9.2 months after definite chemotherapy.Based on all aforementioned data,the new term of “oligorecurrence”could be introduced for patients with metachronous metastatic PDAC that fulfill the criteria for surgical excision of metastatic lesions.The new term of “PDAC oligorecurrence” helps in distinguishing synchronous from metachronous metastases in PDAC patients that would benefit from metastasectomy and has,also,been implemented in the past for patients with other metastatic tumors(esophageal adenocarcinoma) [14].

Oligometastatic PDAC presents a special entity compared to other gastrointestinal cancers,such as esophageal or colorectal cancer: only patients with “limited” metastatic lesions of “good biology” would benefit from a multimodal therapeutic approach.Therefore,definition of “oligometastatic PDAC” should distinguish these patients from others in whom only the top of the iceberg is visible.

The proposed selection criteria for oligometastatic PDAC,according to all available studies (Table 1),are based on these two previously mentioned axes: “limited disease” and “good tumor biology”.It is also noteworthy,that the qualitative parameters which define these axes are actually similar among the included studies: “limited disease” is characterized by a specific number of organs with metastatic lesions,which have a precise number and size,while “good tumor biology” is characterized by the response after neoadjuvant chemotherapy and CA19-9 level.Nevertheless,a high heterogeneity is observed among the specific thresholds of these characteristics: for example,the number of metastatic lesions and the CA19-9 levels that show an adequate tumor response.

Table 1Studies evaluating multimodal approach in oligometastatic PDAC.

Given the complexity of metastatic PDAC behavior,we believe that the introduction of a precise definition for oligometastatic PDAC based on all four previously mentioned qualitative parameters that define “limited disease” and “good tumor biology” (Fig.1)is of paramount importance.From a surgeon’s point of view,it seems essential that these patients should be candidates for extended surgical procedures,that guarantee R0 resection,only after receiving neoadjuvant chemotherapy.Therefore,it might be advisable to further expand these criteria of oligometastatic PDAC,by adapting ECOG performance status as well.Consequently,a possible definition for “oligometastatic PDAC” could include pancreatic tumors with up to 2 or 3 metastatic lesions in 1 or 2 organs,that present response or at least remain stable after neoadjuvant therapy according to RECIST criteria,and could be potentially excised providing a R0 resection avoiding major organ or vascular resections in patients with ECOG score 0 or 1,that have low (<10 0 0 U/mL) or significantly reduced CA19-9 levels after neoadjuvant therapy.

Fig.1.Oligometastatic pancreatic ductal adenocarcinoma definition.CA19-9: carbohydrate antigen 19-9;ECOG: Eastern Cooperative Oncology Group.

As depicted in oligometastatic PDAC,patients with “PDAC oligorecurrence” present similar characteristics.Therefore,it seems rational to propose that the definition of “PDAC oligorecurrence”should also be based on the aforementioned qualitative parameters that define “limited disease” and “good tumor biology” (Fig.1).In addition,time interval between index operation and recurrence represents another important clinical factor in that patient group.This parameter should be also taken into consideration,since it seems to be suggestive of the biological behavior of the tumor:longer intervals characterize tumors with “better biology”.Finally,“PDAC oligorecurrence” could be stated only if the primary tumor has been completely resected.Thus,primary resection site should be free of recurrence (Fig.1).

The efficacy of metastasectomy plus systemic chemotherapy compared to systemic chemotherapy alone in terms of increasing overall survival in oligometastatic PDAC patients,has been proven only in small-scale retrospective case-control studies so far [2,7,8].However,there is actually limited related evidence,in order to accurately estimate the quantitative parameters that should define oligometastatic PDAC.Case-matched retrospective studies based on large databases of metastatic PDAC patients are required in order to precisely define the terms of “oligometastatic PDAC” and “PDAC oligorecurrence”.In more detail,the number of metastatic sites,the size and number of metastatic lesions and CA19-9 cut off value have to be accurate defined.

This could serve as a basis for the design of large-scale randomized controlled trials in order to investigate the role and feasibility of metastasectomy in metastatic PDAC.Very recently,the Chinese Study Group for Pancreatic Cancer (CSPAC) launched a prospective,multicenter,randomized,controlled phase III trial (NCT03398291)entitled CSPAC-1 in order to select patients who might benefit from simultaneous resection of primary pancreatic cancer and liver metastases;the results of this trial are expected in 2025 [15].Finally,using the precise definitions of these entities,clinical trials focusing on molecular features of PDAC metastases could be designed.In that way,novel biomarkers could probably define patients with tumors of mild biological behavior who are suitable for metastasectomy with favorable outcome.

Acknowledgments

None.

CRediTauthorshipcontributionstatement

MaximosFrountzas:Methodology,Writing -original draft.DimitriosSchizas:Conceptualization,Writing -review &editing.StylianosKykalos:Data curation,Methodology.KonstantinosG Toutouzas:Formal analysis,Supervision.

Funding

None.

Ethicalapproval

Not needed.

Competinginterest

No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.