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Stereotactic radiotherapy or metastasectomy for oligometastatic esophagogastric cancer: A nationwide population-based cohort study

Open AccessPublished:August 23, 2022DOI:https://doi.org/10.1016/j.ctro.2022.08.012

      Highlights

      • This nationwide study included patients with esophagogastric cancer and OMD.
      • Local treatment of OMD was associated with improved OS.
      • Local treatment of OMD plus systemic therapy was associated with better OS.
      • Randomized trials are warranted to conform results.

      Abstract

      Background and purpose

      This nationwide population-based study analyzed the outcomes of local treatment (i.e. stereotactic body radiotherapy [SBRT] or metastasectomy) or systemic therapy for oligometastatic disease (OMD) in patients with esophagogastric cancer in The Netherlands.

      Materials and methods

      Between 2015 and 2016, all patients in The Netherlands with esophagogastric cancer and synchronous or metachronous OMD were eligible for inclusion. Patients who underwent local treatment of OMD (SBRT or metastasectomy) and/or systemic therapy were included. OMD was defined as distant metastases in 1 organ or 1 extra-regional lymph node region. The primary outcomes were overall survival (OS) and independent prognostic factors for OS. OS was calculated from diagnosis of OMD. Prognostic factors for OS were analyzed using a multivariable Cox proportional hazard model.

      Results

      A total of 594 patients were included, of whom 83 underwent local treatment for OMD alone, 22 local treatment plus systemic therapy, and 489 systemic therapy alone. Median OS after local treatment for OMD alone was 16.0 months, local treatment plus systemic therapy 22.7 months, and after systemic therapy alone 8.5 months. Improved OS was independently associated with local treatment for OMD alone or combined with systemic therapy as compared with systemic therapy alone (hazard ratio [HR] 0.52, 95% CI: 0.31–0.90 and HR 0.42, 95% CI: 0.22-0.82, respectively) and a controlled primary tumor(HR 0.48, 95% CI: 0.27–0.86). Worse OS was independently associated with worse performance scores (HR 1.41, 95%: 1.32-1.75), poorly or undiffertumor as compared with good or moderadifferentiated tumor (HR 1.37, 95% CI: 1.06-1.76), and peritoneal as compared with lymph mode metastases (HR 1.39, 95% CI: 1.00-1.93).

      Conclusion

      Local treatment of OMD alone or combined with systemic therapy was independently associated with improved OS as compared with systemic therapy alone in this population-based cohort study in The Netherlands. Randomized controlled trials are warranted to confirm these results.

      Graphical abstract

      Keywords

      Abbreviations:

      OS (Overall survival), OMD (Oligometastatic disease), SBRT (Stereotactic body radiotherapy), NCR (Netherlands Cancer Registry), RCT (Randomized controlled trial), HR (Hazard ratio), SD (Standard deviation), IQR (Interquartile range)

      Introduction

      Gastric and esophageal cancer are the 5th and 7th most common cancers worldwide and the incidence of esophageal cancer is rapidly rising [
      • Sung H.
      • Ferlay J.
      • Siegel R.L.
      • Laversanne M.
      • Soerjomataram I.
      • Jemal A.
      • et al.
      Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.
      ]. Approximately 30–50 % of patients with esophagogastric cancer (i.e. esophageal or gastric cancer) have metastatic disease at the time of initial diagnosis (i.e. synchronous) [
      • Koemans W.J.
      • Luijten J.C.H.B.M.
      • van der Kaaij R.T.
      • Grootscholten C.
      • Snaebjornsson P.
      • Verhoeven R.H.A.
      • et al.
      The metastatic pattern of intestinal and diffuse type gastric carcinoma – A Dutch national cohort study.
      ]. In addition, >30 % of patients develop metastatic disease during follow-up after initial primary tumor treatment with curative intent (i.e. metachronous) [
      • Wu S.-G.-G.
      • Zhang W.-W.-W.
      • Sun J.-Y.-Y.
      • Li F.-Y.-Y.
      • Lin Q.
      • He Z.-Y.-Y.
      Patterns of distant metastasis between histological types in esophageal cancer.
      ,
      • Bernards N.
      • Creemers G.J.
      • Nieuwenhuijzen G.A.P.
      • Bosscha K.
      • Pruijt J.F.M.
      • Lemmens V.E.P.P.
      No improvement in median survival for patients with metastatic gastric cancer despite increased use of chemotherapy.
      ]. Patients with metastatic esophagogastric cancer have a poor prognosis, with a median overall survival (OS) between 3 and 9 months [
      • Bernards N.
      • Creemers G.J.
      • Nieuwenhuijzen G.A.P.
      • Bosscha K.
      • Pruijt J.F.M.
      • Lemmens V.E.P.P.
      No improvement in median survival for patients with metastatic gastric cancer despite increased use of chemotherapy.
      ,
      • Parry K.
      • Visser E.
      • van Rossum P.S.N.
      • Mohammad N.H.
      • Ruurda J.P.
      • van Hillegersberg R.
      Prognosis and treatment after diagnosis of recurrent esophageal carcinoma following esophagectomy with curative intent.
      ,
      • Bernards N.
      • Haj Mohammad N.
      • Creemers G.J.
      • Rozema T.
      • Roukema J.A.
      • Nieuwenhuijzen G.A.P.
      • et al.
      Improvement in survival for patients with synchronous metastatic esophageal cancer in the south of the Netherlands from 1994 to 2013.
      ], and are usually treated with systemic therapy or best supportive care [

      Lordick F, Mariette C, Haustermans K, et al. Oesophageal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2016;27:v50-v57. doi:10.1093/annonc/mdw329.

      ,
      • Smyth E.C.
      • Verheij M.
      • Allum W.
      • Cunningham D.
      • Cervantes A.
      • Arnold D.
      Gastric cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up.
      ,
      • Ajani J.A.
      • D’Amico T.A.
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      • Chao J.
      • Corvera C.
      • Das P.
      • et al.
      Esophageal and esophagogastric junction cancers, version 2.2019, NCCN Clinical Practice Guidelines in Oncology.
      ,
      • NCCN
      NCCN Guidelines: Gastric cancer.
      ].
      In a small portion of metastatic patients, distant metastases are limited in number and distribution, so-called oligometastatic disease (OMD) [
      • Hellman S.
      • Weichselbaum R.R.
      Oligometastases.
      ]. OMD reflects a disease state between locoregional and widespread metastatic disease [
      • Hellman S.
      • Weichselbaum R.R.
      Oligometastases.
      ]. Randomized controlled trials (RCTs) have shown that local treatment (e.g. metastasectomy or stereotactic body radiotherapy [SBRT]) improves OS as compared with systemic therapy alone in patients with breast, prostate, colorectal, or lung cancer [
      • Gomez D.R.
      • Blumenschein G.R.
      • Lee J.J.
      • Hernandez M.
      • Ye R.
      • Camidge D.R.
      • et al.
      Local consolidative therapy versus maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer without progression after first-line systemic therapy: a multicentre, randomised, controlled, phase 2 study.
      ,
      • Palma D.A.
      • Olson R.
      • Harrow S.
      • Gaede S.
      • Louie A.V.
      • Haasbeek C.
      • et al.
      Stereotactic ablative radiotherapy versus standard of care palliative treatment in patients with oligometastatic cancers (SABR-COMET): a randomised, phase 2, open-label trial.
      ]. For esophagogastric cancer, phase II trials have suggested improved OS after local treatment of OMD [
      • Al-Batran S.-E.
      • Homann N.
      • Pauligk C.
      • Illerhaus G.
      • Martens U.M.
      • Stoehlmacher J.
      • et al.
      Effect of neoadjuvant chemotherapy followed by surgical resection on survival in patients with limited metastatic gastric or gastroesophageal junction cancer: The AIO-FLOT3 trial.
      ,
      • Liu Q.i.
      • Zhu Z.
      • Chen Y.
      • Deng J.
      • Ai D.
      • Liu Q.
      • et al.
      Phase 2 study of stereotactic body radiation therapy for patients with oligometastatic esophageal squamous cell carcinoma.
      ], which is currently being investigated in RCTs [
      • Al-Batran S.-E.-E.
      • Goetze T.O.
      • Mueller D.W.
      • et al.
      The RENAISSANCE (AIO-FLOT5) trial: Effect of chemotherapy alone vs. chemotherapy followed by surgical resection on survival and quality of life in patients with limited-metastatic adenocarcinoma of the stomach or esophagogastric junction - a phase III tri.
      ,

      ECOG-ACRIN Cancer Research. Testing the addition of radiotherapy to the usual treatment (chemotherapy) for patients with esophageal and gastric cancer that has spread to a limited number of other places in the body. clinicaltrials.gov/NCT04248452. 2020. doi:10.31525/ct1-nct04248452.

      ,

      Mariette C. Palliative gastric resection plus chemotherapy versus chemotherapy alone in stage IV gastric cancer. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03042169. Accessed July 11, 2019.

      ].
      However, the applicability and generalizability of the currently available data from the literature is unclear since clinical trial results cannot always be reproduced in the real-world setting due to strict selection criteria [
      • Averitt A.J.
      • Weng C.
      • Ryan P.
      • Perotte A.
      Translating evidence into practice: eligibility criteria fail to eliminate clinically significant differences between real-world and study populations.
      ]. Therefore, real-world population-based data are a valuable addition to trial results because they deepen the understanding of the outcome of therapies in patients encountered on a day-to-day basis, making results better interpretable in clinical practice [
      • Booth C.M.
      • Tannock I.F.
      Randomised controlled trials and population-based observational research: Partners in the evolution of medical evidence.
      ]. Furthermore, population-based studies enable us to analyze a relatively large population considering the proportion of patients receiving local treatment for OMD is relatively small [
      • Kroese T.E.
      • Christ S.M.
      • van Rossum P.S.N.
      • Burger M.D.L.
      • Buijs G.S.
      • Mühlematter U.
      • et al.
      Incidence and survival of patients with oligometastatic esophagogastric cancer: a multicenter cohort study.
      ]. Finally, the adoption of local treatment of OMD varies and knowledge on outcomes on a population-based level is currently lacking. Therefore, this study aimed to determine OS and independent prognostic factors for OS after local treatment or systemic therapy for OMD in patients with esophagogastric cancer on a nationwide population-based level.

      Methods and materials

      Study design

      This study included patients registered in the Netherlands Cancer Registry (NCR). The NCR is the only national oncological registry in The Netherlands and provides cancer statistics among all 17.4 million residents. According to the Central Committee on Research involving Human Subjects, this study did not need approval by an institutional review board in The Netherlands. The study was approved by the Privacy Review Board of the Netherlands Cancer Registry and the scientific committee of the Dutch Upper GI Cancer Group (DUCG). The study was reported according to the guidelines of The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement (Supplementary File A) [
      • Moons K.G.M.
      • Altman D.G.
      • Reitsma J.B.
      • Ioannidis J.P.A.
      • Macaskill P.
      • Steyerberg E.W.
      • et al.
      Transparent reporting of a multivariable prediction model for individual prognosis or diagnosis (TRIPOD): Explanation and elaboration.
      ].

      Patient inclusion

      Consecutive patients with synchronous or metachronous metastatic esophagogastric cancer were identified from the NCR between 2015 and 2016 (i.e. according to UICC/AJCC 7th edition [

      Mariette C. Palliative gastric resection plus chemotherapy versus chemotherapy alone in stage IV gastric cancer. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03042169. Accessed July 11, 2019.

      ] as Tx-4b, Nx-N3, M1 and according to ICD-10 [
      • Allen P.W.
      ICDO — International Classification of Diseases for Oncology.
      ] as 15.3–15.5, 15.8, 15.9, and 16.0–16.9). The years 2015 and 2016 were selected because the NCR registered additional data on metachronous metastases for these years only. OMD was defined as distant metastases in 1 organ or 1 extra-regional lymph node region comparable with a recent systemic review on definitions of oligometastatic esophagogastric cancer in current literature [
      • Kroese T.E.
      • Van L.H.
      • Nilsson M.
      • et al.
      Definition of oligometastatic esophagogastric cancer and impact of local oligometastasis-directed treatment: A systematic review and meta-analysis.
      ]. OMD was not defined by a maximum number of lesions per organ/extra-regional lymph node station because this was not recorded by the NCR. Patients undergoing local treatment of OMD (i.e. SBRT or metastasectomy) or systemic therapy were included. SBRT was defined as radiotherapy according to one of the following radiotherapy schemes: ≥10 Gy per fraction with ≥1 fraction, ≥5 Gy per fraction with ≤12 fractions, or ≥7 Gy per fraction with ≤5 fractions. All other radiotherapy schemes were considered palliative radiotherapy. Patients undergoing palliative radiotherapy were not included. Metastasectomy was defined as surgery, which could include radiofrequency ablation.

      Variables

      From the NCR patient characteristics were extracted, including sex, age, and WHO performance score. WHO performance score was determined at the time of treatment of OMD. Collected disease characteristics included clinical and pathological disease stage (according to UICC 7th edition [
      • Rice T.W.
      • Blackstone E.H.
      • Rusch V.W.
      7th edition of the AJCC Cancer Staging Manual: esophagus and esophagogastric junction.
      ], histology, tumor differentiation grade, and morphology (i.e. signet ring cell carcinoma). The OMD state was categorized into synchronous or metachronous (defined as before or after completion of primary tumor treatment, respectively [
      • Guckenberger M.
      • Lievens Y.
      • Bouma A.B.
      • Collette L.
      • Dekker A.
      • deSouza N.M.
      • et al.
      Characterisation and classification of oligometastatic disease: a European Society for Radiotherapy and Oncology and European Organisation for Research and Treatment of Cancer consensus recommendation.
      ]. The location of OMD lesions was categorized into a distant organ (e.g. lung, liver, or brain), an extra-regional lymph node region (i.e. head and neck, intra-thoracic, intra-abdominal, axilla, pelvic, multiple locations, or not specified [
      • Allen P.W.
      ICDO — International Classification of Diseases for Oncology.
      ], or peritoneal (i.e. peritoneum, ovary, or omentum). Finally, treatment characteristics were extracted, including treatment of the primary tumor and OMD and the type of hospital where this treatment was performed. Hospitals were categorized into ‘academic’, or ‘non-academic’.

      Treatment of primary tumor and oligometastasis

      The primary tumor was considered controlled in patients who underwent primary tumor resection or definitive chemoradiotherapy (radiotherapy to dose ≥50 Gy with concurrent chemotherapy) without evidence of locoregional recurrence at the time of OMD detection. Treatment of OMD was categorized into 1) local treatment alone (i.e. SBRT and/or metastasectomy); 2) local treatment plus systemic therapy (i.e. chemotherapy or targeted therapy); 3) systemic therapy alone. The administration of systemic therapy was divided into before or after local treatment of OMD. The first-line systemic therapy regimen administrated after the diagnosis of current OMD was analyzed (i.e. second-line systemic therapy for recurrent or progressive disease was not analyzed).

      Outcome

      The primary outcomes of this study were OS and prognostic factors for OS. OS was defined as the time interval between the diagnosis of OMD and death or end of follow-up. Vital status was obtained through annual linkage with the municipal population registers and was last updated on January 31, 2021. Prognostic factors for OS were expressed using hazard ratios (HRs) with 95% confidence intervals (CIs). Kaplan-Meier curves were constructed for OS and independent prognostic factors for OS and were compared using log-rank test.

      Statistical analysis

      Parametric data were presented as mean with standard deviation (SD) and were compared using Student’s T test. Non-parametric data were presented as median with interquartile range (IQR) and compared using Mann Whitney U test. Categorical data were presented as frequencies with proportions and compared using Fisher’s exact test. Factors previously identified in literature [
      • ter Veer E.
      • van Kleef J.J.
      • Schokker S.
      • van der Woude S.O.
      • Laarman M.
      • Haj Mohammad N.
      • et al.
      Prognostic and predictive factors for overall survival in metastatic oesophagogastric cancer: A systematic review and meta-analysis.
      ] as prognostic factors for OS in metastatic esophagogastric cancer were entered into univariable and multivariable Cox proportional hazard model, which included WHO performance score (WHO 0 versus >0 versus missing) [
      • Shapiro J.
      • van Lanschot J.J.B.
      • Hulshof M.C.C.M.
      • van Hagen P.
      • van Berge Henegouwen M.I.
      • Wijnhoven B.P.L.
      • et al.
      Neoadjuvant chemoradiotherapy plus surgery versus surgery alone for oesophageal or junctional cancer (CROSS): Long-term results of a randomised controlled trial.
      ], tumor differentiation grade (well/moderate versus poorly/undifferentiated versus missing) [
      • Rice T.W.
      • Ishwaran H.
      • Blackstone E.H.
      • Hofstetter W.L.
      • Kelsen D.P.
      • Apperson-Hansen C.
      Recommendations for clinical staging (cTNM) of cancer of the esophagus and esophagogastric junction for the 8th edition AJCC/UICC staging manuals: Esophageal cancer staging recommendations: clinical.
      ], histology (adenocarcinoma versus squamous cell carcinoma) [
      • Shapiro J.
      • van Lanschot J.J.B.
      • Hulshof M.C.C.M.
      • van Hagen P.
      • van Berge Henegouwen M.I.
      • Wijnhoven B.P.L.
      • et al.
      Neoadjuvant chemoradiotherapy plus surgery versus surgery alone for oesophageal or junctional cancer (CROSS): Long-term results of a randomised controlled trial.
      ], OMD state (synchronous versus metachronous) [
      • Kim J.H.
      • Rha S.Y.
      • Kim C.
      • Kim G.M.
      • Yoon S.H.
      • Kim K.H.
      • et al.
      Clinicopathologic features of metachronous or synchronous gastric cancer patients with three or more primary sites.
      ], primary tumor treatment status (controlled versus not controlled) [
      • Goense L.
      • van Rossum P.S.N.
      • Xi M.
      • Maru D.M.
      • Carter B.W.
      • Meijer G.J.
      • et al.
      Preoperative nomogram to risk stratify patients for the benefit of trimodality therapy in esophageal adenocarcinoma.
      ], treatment of OMD (local treatment versus local treatment plus systemic therapy) [
      • Depypere L.
      • Lerut T.
      • Moons J.
      • Coosemans W.
      • Decker G.
      • Van Veer H.
      • et al.
      Isolated local recurrence or solitary solid organ metastasis after esophagectomy for cancer is not the end of the road.
      ], and location of OMD (extra-regional lymph node versus peritoneum versus organ) [
      • Al-Batran S.-E.
      • Homann N.
      • Pauligk C.
      • Illerhaus G.
      • Martens U.M.
      • Stoehlmacher J.
      • et al.
      Effect of neoadjuvant chemotherapy followed by surgical resection on survival in patients with limited metastatic gastric or gastroesophageal junction cancer: The AIO-FLOT3 trial.
      ]. The disease-free interval for metachronous OMD was defined as the time interval between the diagnosis of the primary tumor and OMD. Complete-case analyses were performed. The median follow-up time was estimated using the reverse Kaplan-Meier estimator (i.e. reverse event indicator). Data were analyzed using R for Windows, version 3.6.3. A two-sided p-value < 0.05 was considered statistically significant.

      Results

      Between 2015 and 2016, 4265 patients with synchronous or metachronous metastatic esophagogastric cancer were identified from the NCR, of whom 594 patients who underwent local treatment or systemic therapy for OMD were included. First, the 105 patients undergoing local treatment for OMD with or without systemic therapy will be described. Subsequently, the 489 patients undergoing systemic therapy alone for OMD (Fig. 1).
      The 105 included patients were generally male (71%) with a mean age of 64 years (SD: ±8) and mostly had a WHO performance score of 0–1 at the time of treatment (62%). The primary tumors were predominantly adenocarcinomas (80%) located in the distal third of the esophagus (57%). The predominant clinical tumor stage was cT3 (66%) and nodal stage cN1 (45%). For patients who underwent primary tumor resection (n = 74), the predominant pathological tumor stage was pT3 (45%) and nodal stage pN0 (45%).
      Most patients had metachronous OMD (62%, i.e. OMD detected after primary tumor treatment). OMD was located in 1 distant organ (79%), 1 extra-regional lymph node region (12%), or the peritoneum (9%). The median disease-free interval for metachronous OMD was 17 months (IQR: 14–24) after diagnosis of the primary tumor. OMD was confirmed with pathological assessment (71%) or repeated follow-up imaging (29 %, Table 1).
      Table 1Patient and tumor characteristics of included patients.
      FactorLocal +/− systemic therapy (n = 105)Systemic therapy only (n = 489)P-value
      Mean age in years (±SD)64 (±8)64 (±10)0.894
      Sex0.460
       Male75 (71 %)369 (75 %)
       Female30 (29 %)120 (25 %)
      WHO performance score<0.001
       035 (33 %)119 (24 %)
       127 (29 %)165 (34 %)
       >16 (5 %)53 (11 %)
      Missing37 (33 %)152 (31 %)
      Location of the primary tumor<0.001
       Upper or middle third esophagus14 (13 %)51 (10 %)
       Lower third esophagus60 (57 %)187 (38 %)
       Esophagus not specified2 (2 %)14 (3 %)
       Gastroesophageal junction/cardia13 (12 %)80 (16 %)
       Stomach16 (15 %)157 (32 %)
      Clinical tumor stage<0.001
       cT1b or cT225 (24 %)169 (35 %)
       cT3 or cT474 (70 %)168 (35 %)
       Missing5 (5 %)102 (21 %)
      Clinical nodal stage0.124
       cN030 (29 %)121 (25 %)
       cN148 (46 %)165 (34 %)
       cN2 or cN326 (25 %)168 (34 %)
       Missing1 (1 %)28 (6 %)
      Pathological tumor stage
      For patients with a resected primary tumor.
      Total (n = 74)Total (n = 89)0.349
       pT012 (16 %)8 (9 %)
       pT1 or pT225 (33 %)37 (42 %)
       pT3 or pT436 (48 %)42 (47 %)
       Missing1 (1 %)2 (2 %)
      Pathological nodal stage
      For patients who received resection or definitive chemoradiotherapy of the primary tumor.
      Total (n = 74)Total (n = 89)0.747
       pN033 (44 %)34 (38 %)
       pN119 (26 %)22 (25 %)
       pN2 or pN321 (28 %)22 (25 %)
       Missing1 (1 %)11 (12 %)
      Histology of the primary tumor0.459
       Adenocarcinoma84 (80 %)407 (84 %)
       Squamous cell carcinoma21 (20 %)80 (16 %)
      Signet ring cell carcinoma7 (7 %)42 (9 %)0.695
      Differentiation grade<0.001
       Good-moderate40 (38 %)114 (23 %)
       Poor/undifferentiated46 (44 %)187 (38 %)
       Missing19 (18 %)188 (38 %)
      Timing of detection<0.001
       Synchronous43 (41 %)372 (77 %)
       Metachronous62 (59 %)114 (23 %)
      Median disease-free interval [IQR]
      For patients who received resection or definitive chemoradiotherapy of the primary tumor.
      17 [14,24]18 [15,27]0.546
      Location of OMD<0.001
      Distant organ83 (79 %)298 (61 %)
       Brain32 (30 %)1 (0 %)
       Lung15 (14 %)39 (8 %)
       Bone12 (11 %)17 (3 %)
       Liver10 (10 %)182 (37 %)
       Soft tissue8 (8 %)4 (1 %)
       Other distant organ6 (6 %)55 (11 %)
      Extra-regional lymph nodes13 (12 %)111 (23 %)
      Peritoneum9 (9 %)80 (16 %)
      Confirmation of OMD<0.001
       Histology75 (71 %)226 (46 %)
       Repeated follow-up imaging30 (29 %)263 (54 %)
      * For patients with a resected primary tumor.
      ** For patients who received resection or definitive chemoradiotherapy of the primary tumor.
      Primary tumor treatment consisted of surgery in 74 patients (71%), definitive chemoradiotherapy in 12 patients (12 %), or no primary tumor treatment in 19 patients (17%). Treatment of OMD consisted of local treatment alone in 83 patients (79%), including SBRT alone in 34 patients (33%), metastasectomy alone in 35 patients (32%), or both metastasectomy and SBRT in 14 patients (14%). Local treatment of OMD was combined with systemic therapy in 22 patients (21%), including metastasectomy plus systemic therapy in 14 patients (14%), SBRT plus systemic therapy in 7 patients (7%), or both metastasectomy and SBRT plus systemic therapy in 1 patient (1%). Systemic therapy was predominantly administrated before local treatment of OMD (73%) and generally consisted of 2 chemotherapy agents (68 %). The most common chemotherapy regimen consisted of capecitabine and oxaliplatin (36%, Table 2).
      Table 2Treatment characteristics of included patients.
      FactorLocal +/− systemic

      therapy (n = 105)
      Systemic therapy only (n = 489)P-value
      Treatment of primary tumor<0.001
      Surgery7571 %7916 %
        Esophagectomy5955 %5110 %
        Gastrectomy1615 %286 %
       Definitive chemoradiotherapy1112 %10321 %
       No treatment1918 %30763 %
      Treatment of OMD
      Local treatment alone8379 %00 %
       SBRT3433 %00 %
       Metastasectomy3532 %00 %
       Metastasectomy + SBRT1414 %00 %
      Systemic therapy plus:2221 %00 %
       SBRT77 %00 %
       Metastasectomy1414 %00 %
       Metastasectomy + SBRT11 %00 %
      Systemic therapy alone00 %489100 %
      Metastasectomy hospital type (n = 64)
       Academic hospital3860 %00 %
       Non-academic hospital2640 %00 %
      Radiotherapy hospital type (n = 56)
       Academic hospital3664 %00 %
       Non-academic hospital2036 %00 %
      Sequencing of systemic therapy (n = 22)
       Before local treatment for OMD1673 %00 %
       After local treatment for OMD627 %00 %
      Systemic therapy hospital type (n = 489)
       Academic hospital7815 %
       Non-academic hospital41185 %
      First-line systemic therapyTotal (n = 22)Total (n = 489)
      Monotherapy00 %4910 %
       Capecitabine00 %4910 %
      Doublet1568 %25753 %
       Capecitabine/oxaliplatin (CapOx)836 %11824 %
       Carboplatine/paclitaxel (not for primary tumor)314 %10020 %
       5-FU/oxaliplatin (FOLFOX)29 %398 %
       Other210 %276 %
      Triplet627 %8317 %
       Epirubicine/oxaliplatine/capecitabine (EOX/EOC)627 %5912 %
       Epirubicine/cisplatine/capecitabine (ECC/ECX)00 %82 %
       Docetaxel/oxaliplatine/capecitabine (DOC)00 %82 %
       Epirubicine/cisplatine/5-fluorouracil (ECF)00 %82 %
      Targeted therapy (trastuzumab)11 %7315 %
      OMD = oligometastatic disease; SBRT = stereotactic radiotherapy.
      A total of 64 patients underwent metastasectomy. Metastasectomy was more commonly applied than SBRT for OMD in the liver (80%), the extra-regional lymph nodes (67%), or the peritoneum (100%). A total of 56 patients underwent SBRT. Applied SBRT schedules are provided in Supplementary File B. SBRT was more often performed than metastasectomy for OMD in the lung (73%) or bone (75%). Local treatment of OMD plus systemic therapy was common in patients with OMD in the liver (50%) or peritoneum (78%, Supplementary File C).
      Patients with synchronous as compared with metachronous OMD less often underwent primary tumor resection (47% versus 87%), more often underwent local treatment of OMD plus systemic therapy (37% versus 10%), and had extra-regional lymph node oligometastases (19% versus 2%). Patients with metachronous as compared with synchronous OMD more often underwent local treatment of OMD alone (90% versus 63%) and had brain oligometastases (45% versus 9%, Supplementary File D).
      A total of 489 patients who underwent systemic therapy alone for OMD. Patients who underwent systemic therapy alone for OMD more often had gastric cancer (32% versus 15%, p < 0.001), synchronous OMD (77% versus 41%, p < 0.001), liver metastases (37% versus 10%, p < 0.001), and an uncontrolled primary tumor (63% versus 18%, p < 0.001) as compared with patients who underwent local treatment for OMD with or without systemic therapy (Table 1 and Table 2).
      The median follow-up time for patients undergoing local treatment for OMD with or without systemic therapy was 49.8 months (IQR: 37.2-55.0) and for patients undergoing systemic therapy alone was 59.0 months (IQR: 50.0-62.0). The median OS after local treatment of OMD plus systemic therapy was 22.7 months (95% CI: 14.7-42.6), versus 16.0 months (95% CI: 12.7-21.8) after local treatment of OMD alone, and 8.5 months (95% CI: 7.9-9.6) after systemic therapy alone (Fig. 2).
      Figure thumbnail gr2
      Fig. 2Overall survival curve stratified for treatment of oligometastatic disease.
      In multivariable analysis (Table 3), worse OS was independently associated with worse WHO performance scores (HR 1.41, 95% CI: 1.32-1.75; Supplementary File E), poorly or undifferentiated tumor as compared with a good or moderately differentiated tumor (HR 1.37, 95% CI: 1.06-1.76; Supplementary File F), and peritoneal as compared with extra-regional lymph node metastases (HR 1.39, 95% CI: 1.00-1.93; Supplementary File G).
      Table 3Results of univariable and multivariable Cox proportional hazard models for overall survival.
      UnivariableMultivariable
      N =HR (95 % CI)p-valueHR (95 % CI)p-value
      Age (continuous)1.00 (0.99–1.02)0.0791.28 (1.00–1.02)0.018
      Performance score
       WHO 0154ReferenceReference
       WHO > 01951.38 (1.11–1.72)0.0041.41 (1.32–1.75)0.033
       Missing1871.37 (1.10–1.72)0.0051.37 (1.09–1.73)0.008
      Tumor location
       Esophagus328ReferenceReference
       Stomach2661.29 (1.10–1.53)0.0020.82 (0.57–1.01)0.051
      Clinical tumor stage
       cT1b or cT2193ReferenceReference
       cT32381.32 (0.62–0.92)0.0050.90 (0.73–1.12)0.348
       cT4470.94 (0.77–1.47)0.7181.07 (0.77–1.51)0.677
       Missing1160.78 (1.00–1.61)0.0471.03 (0.80–1.33)0.806
      Clinical nodal stage
       cN0151ReferenceReference
       cN12130.78 (0.63–0.97)0.0290.80 (0.59–1.00)0.050
       cN2 or cN31940.99 (0.80–1.24)0.9620.88 (0.69–1.12)0.295
       Missing361.74 (1.20–2.50)0.0031.18 (0.81–1.72)0.400
      Histology
       Squamous cell carcinoma491ReferenceReference
       Adenocarcinoma1011.32 (1.06–1.66)0.0151.18 (0.81–1.72)0.227
      Signet ring cell carcinoma
       No545ReferenceReference
       Yes490.68 (0.51–0.92)0.0111.03 (0.94–1.79)0.170
      Differentiation grade
       Good-moderate114ReferenceReference
       Poor/undifferentiated1871.32 (1.04–1.67)0.0221.37 (1.06–1.76)0.015
       Missing2930.70 (0.56–0.87)0.0021.09 (0.85–1.40)0.479
      Timing of detection
       Synchronous415ReferenceReference
       Metachronous1760.95 (0.62–1.46)0.7691.06 (0.85–1.32)0.690
      Location of OMD
       Extra-regional lymph node124ReferenceReference
       Distant organ3201.03 (0.83–1.28)0.7911.08 (0.85–1.38)0.529
       Peritoneum1291.62 (1.26–2.09)<0.0011.39 (1.01–1.93)0.047
      Primary tumor controlled
       No505ReferencerefReferenceref
       Yes860.78 (0.44–1.36)0.3760.48 (0.27–0.86)0.013
      Treatment for OMD
       Systemic486ReferenceReference
       Local830.32 (0.24–0.41)<0.0010.52 (0.31–0.90)0.018
       Local + Systemic220.32 (0.19–0.52)<0.0010.42 (0.22–0.82)0.011
      Improved OS was independently associated with local treatment of OMD alone or combined with systemic therapy as compared with systemic therapy alone (HR 0.52, 95% CI: 0.31-0.90 and HR 0.42, 95% CI: 0.22-0.82, respectively), and a controlled primary tumor versus uncontrolled primary tumor (HR 0.48, 95% CI: 0.27-0.86; Supplementary File H).

      Discussion

      This nationwide population-based cohort suggests that local treatment of OMD alone or combined with systemic therapy can be a preferred treatment approach for patients with oligometastatic esophagogastric cancer since this treatment approach was independently associated with improved OS as compared with systemic therapy of OMD alone (median OS of 16.0 months or 22.7 months versus 8.5 months). However, these results must be interpreted with care because selection may have resulted in a potential overestimation of OS after local treatment of OMD because patients with favorable patient- and tumor characteristics were more often selected for treatment (i.e. confounding by indication) [
      • Kyriacou D.N.
      • Lewis R.J.
      Confounding by indication in clinical research.
      ]. In addition, the NCR did not record the number or size of OMD lesions which may have impacted on OS [
      • ter Veer E.
      • van Kleef J.J.
      • Schokker S.
      • van der Woude S.O.
      • Laarman M.
      • Haj Mohammad N.
      • et al.
      Prognostic and predictive factors for overall survival in metastatic oesophagogastric cancer: A systematic review and meta-analysis.
      ]. Therefore, randomized controlled trials are warranted to confirm our results.
      The benefit of local treatment of OMD plus systemic therapy over systemic therapy alone has been previously suggested by a phase II non-randomized trial by Al-Batran et al. [
      • Al-Batran S.-E.
      • Homann N.
      • Pauligk C.
      • Illerhaus G.
      • Martens U.M.
      • Stoehlmacher J.
      • et al.
      Effect of neoadjuvant chemotherapy followed by surgical resection on survival in patients with limited metastatic gastric or gastroesophageal junction cancer: The AIO-FLOT3 trial.
      ]. This study included patients with gastric or gastroesophageal junction adenocarcinoma with synchronous OMD. Patients who responded to fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) chemotherapy underwent resection of the primary tumor and metastases [
      • Al-Batran S.-E.
      • Homann N.
      • Pauligk C.
      • Illerhaus G.
      • Martens U.M.
      • Stoehlmacher J.
      • et al.
      Effect of neoadjuvant chemotherapy followed by surgical resection on survival in patients with limited metastatic gastric or gastroesophageal junction cancer: The AIO-FLOT3 trial.
      ]. This study showed improved OS after resection of the primary tumor and metastases in patients who responded to FLOT chemotherapy as compared with patients who did not respond to systemic therapy (median OS of 31.3 months versus 15.9 months, respectively) [
      • Al-Batran S.-E.
      • Homann N.
      • Pauligk C.
      • Illerhaus G.
      • Martens U.M.
      • Stoehlmacher J.
      • et al.
      Effect of neoadjuvant chemotherapy followed by surgical resection on survival in patients with limited metastatic gastric or gastroesophageal junction cancer: The AIO-FLOT3 trial.
      ]. These results have resulted in an ongoing phase III RENAISSANCE trial in which patients with gastric or gastroesophageal junction adenocarcinoma with synchronous OMD who respond to FLOT chemotherapy will be randomized to either continuation of FLOT chemotherapy or resection of the primary tumor and metastases [
      • Al-Batran S.-E.-E.
      • Goetze T.O.
      • Mueller D.W.
      • et al.
      The RENAISSANCE (AIO-FLOT5) trial: Effect of chemotherapy alone vs. chemotherapy followed by surgical resection on survival and quality of life in patients with limited-metastatic adenocarcinoma of the stomach or esophagogastric junction - a phase III tri.
      ]. In addition, the results of our study are comparable with the phase II trial by Liu et al. This study included patients with esophageal squamous cell carcinoma with metachronous OMD who underwent SBRT and 50 % received adjuvant systemic therapy [
      • Liu Q.i.
      • Zhu Z.
      • Chen Y.
      • Deng J.
      • Ai D.
      • Liu Q.
      • et al.
      Phase 2 study of stereotactic body radiation therapy for patients with oligometastatic esophageal squamous cell carcinoma.
      ]. This study showed an OS of 24.6 months [
      • Liu Q.i.
      • Zhu Z.
      • Chen Y.
      • Deng J.
      • Ai D.
      • Liu Q.
      • et al.
      Phase 2 study of stereotactic body radiation therapy for patients with oligometastatic esophageal squamous cell carcinoma.
      ]
      Although several non-randomized studies have suggested excellent OS in patients undergoing local treatment of OMD plus systemic therapy [
      • Al-Batran S.-E.
      • Homann N.
      • Pauligk C.
      • Illerhaus G.
      • Martens U.M.
      • Stoehlmacher J.
      • et al.
      Effect of neoadjuvant chemotherapy followed by surgical resection on survival in patients with limited metastatic gastric or gastroesophageal junction cancer: The AIO-FLOT3 trial.
      ,
      • Liu Q.i.
      • Zhu Z.
      • Chen Y.
      • Deng J.
      • Ai D.
      • Liu Q.
      • et al.
      Phase 2 study of stereotactic body radiation therapy for patients with oligometastatic esophageal squamous cell carcinoma.
      ], this study shows that only 21% of patients undergoing local treatment receivedcombined systemic therapy as compared with 100% [
      • Al-Batran S.-E.
      • Homann N.
      • Pauligk C.
      • Illerhaus G.
      • Martens U.M.
      • Stoehlmacher J.
      • et al.
      Effect of neoadjuvant chemotherapy followed by surgical resection on survival in patients with limited metastatic gastric or gastroesophageal junction cancer: The AIO-FLOT3 trial.
      ] and 50% [
      • Liu Q.i.
      • Zhu Z.
      • Chen Y.
      • Deng J.
      • Ai D.
      • Liu Q.
      • et al.
      Phase 2 study of stereotactic body radiation therapy for patients with oligometastatic esophageal squamous cell carcinoma.
      ] in these phase II trials. The limited use of combined local treatment plus systemic therapy in our population-based study was mainly seen in patients with brain oligometastasis, which formed a relatively large proportion of our study population (30%). Chemotherapy has limited activity in the brain, which has been mainly attributed to the blood–brain barrier [
      • Brastianos H.C.
      • Cahill D.P.
      • Brastianos P.K.
      Systemic therapy of brain metastases.
      ]. Patients with brain oligometastasis were excluded from these phase II trials [
      • Al-Batran S.-E.
      • Homann N.
      • Pauligk C.
      • Illerhaus G.
      • Martens U.M.
      • Stoehlmacher J.
      • et al.
      Effect of neoadjuvant chemotherapy followed by surgical resection on survival in patients with limited metastatic gastric or gastroesophageal junction cancer: The AIO-FLOT3 trial.
      ,
      • Liu Q.i.
      • Zhu Z.
      • Chen Y.
      • Deng J.
      • Ai D.
      • Liu Q.
      • et al.
      Phase 2 study of stereotactic body radiation therapy for patients with oligometastatic esophageal squamous cell carcinoma.
      ]. Besides the high portion of patients with brain oligometastasis, the limited use of systemic therapy combined with local treatment of OMD might also be explained by the lack of evidence-based guidelines to guide treatment decision-making and the lack of completed RCTs in the setting of esophagogastric OMD.
      In addition to the German RENAISSANCE trial, , several phase 3 trials are currently investigating the benefit of local treatment for OMD plus systemic therapy over systemic therapy alone [
      • Al-Batran S.-E.-E.
      • Goetze T.O.
      • Mueller D.W.
      • et al.
      The RENAISSANCE (AIO-FLOT5) trial: Effect of chemotherapy alone vs. chemotherapy followed by surgical resection on survival and quality of life in patients with limited-metastatic adenocarcinoma of the stomach or esophagogastric junction - a phase III tri.
      ,

      ECOG-ACRIN Cancer Research. Testing the addition of radiotherapy to the usual treatment (chemotherapy) for patients with esophageal and gastric cancer that has spread to a limited number of other places in the body. clinicaltrials.gov/NCT04248452. 2020. doi:10.31525/ct1-nct04248452.

      ,

      Mariette C. Palliative gastric resection plus chemotherapy versus chemotherapy alone in stage IV gastric cancer. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03042169. Accessed July 11, 2019.

      ]. In the American ECOG study (NCT04248452), patients with synchronous or metachronous OMD limited to 3 metastases will be included [

      ECOG-ACRIN Cancer Research. Testing the addition of radiotherapy to the usual treatment (chemotherapy) for patients with esophageal and gastric cancer that has spread to a limited number of other places in the body. clinicaltrials.gov/NCT04248452. 2020. doi:10.31525/ct1-nct04248452.

      ]. Patients with response to chemotherapy will be randomized to either SBRT plus continuation of chemotherapy or continuation of chemotherapy alone [

      ECOG-ACRIN Cancer Research. Testing the addition of radiotherapy to the usual treatment (chemotherapy) for patients with esophageal and gastric cancer that has spread to a limited number of other places in the body. clinicaltrials.gov/NCT04248452. 2020. doi:10.31525/ct1-nct04248452.

      ]. Finally, in the French SURGIGAST trial (NCT03042169), patients with synchronous gastric cancer with synchronous OMD limited to the retroperitoneal lymph nodes and/or 1 organ with metastases will be included [

      Mariette C. Palliative gastric resection plus chemotherapy versus chemotherapy alone in stage IV gastric cancer. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03042169. Accessed July 11, 2019.

      ]. Patients with response to “standard chemotherapy” will be randomized to either resection of the primary tumor and oligometastases or continuation of chemotherapy [

      Mariette C. Palliative gastric resection plus chemotherapy versus chemotherapy alone in stage IV gastric cancer. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03042169. Accessed July 11, 2019.

      ].
      However, none of these studies have incorporated immunotherapy in the treatment algorithm for OMD, although several studies have shown improved survival outcomes for patients with esophagogastric cancer treated with immunotherapy in the first-line palliative setting [
      • Janjigian Y.Y.
      • Shitara K.
      • Moehler M.
      • Garrido M.
      • Salman P.
      • Shen L.
      • et al.
      First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial.
      ] or in the adjuvant setting after a pathological incomplete response after neoadjuvant chemoradiotherapy and surgery [
      • Kelly R.J.
      • Ajani J.A.
      • Kuzdzal J.
      • Zander T.
      • Van Cutsem E.
      • Piessen G.
      • et al.
      Adjuvant nivolumab in resected esophageal or gastroesophageal junction cancer.
      ]. Currently, it is unknown if immunotherapy also improves survival outcomes in the OMD setting before and/or after local treatment for OMD in patients with esophagogastric cancer. Therefore, a potential future study could assess the benefit of immunotherapy plus local treatment for OMD in patients with esophagogastric cancer.
      Certain limitations apply to this study that warrants caution for the interpretation of results. First, no additional prognostic factors could be analyzed in the multivariable Cox proportional hazard model because of the risk of overfitting given the relatively limited sample size [
      • Harrell F.E.
      • Lee K.L.
      • Califf R.M.
      • Pryor D.B.
      • Rosati R.A.
      Regression modelling strategies for improved prognostic prediction.
      ]. Second, missing data on performance status and differentiation grade may have reduced the power of the current study. Third, no propensity score-matching could be performed due to the limited number of patients in treatment subgroups. However, this is the first population-based cohort study, to the best of our knowledge, on the management and outcomes of local treatment and systemic therapy of esophagogastric OMD. Therefore, this is the first study that provides real-world generalizability and applicability. Other strengths include the register-based follow-up resulting in complete follow-up information for all patients.
      The OligoMetastatic Esophagogastric Cancer (OMEC) project aims to achieve consensus on the definition and treatment of oligometastatic esophagogastric cancer (https://www.OMECproject.eu). OMEC is a consortium of 50 esophagogastric cancer expert centers across 16 countries in Europe. Studies of the OMEC-project include a systematic review of definitions of esophagogastric OMD (OMEC-1 [
      • Kroese T.E.
      • Van L.H.
      • Nilsson M.
      • et al.
      Definition of oligometastatic esophagogastric cancer and impact of local oligometastasis-directed treatment: A systematic review and meta-analysis.
      ]), distribution of clinical cases to experts asking for multidisciplinary team responses on diagnosis and treatment (OMEC-2) [
      • Kroese T.E.
      • van Hillegersberg R.
      • Schoppmann S.
      • Deseyne P.R.A.J.
      • Nafteux P.
      • Obermannova R.
      • et al.
      Definitions and treatment of oligometastatic oesophagogastric cancer according to multidisciplinary tumour boards in Europe.
      ], Delphi consensus through 2 Delphi rounds and a consensus meeting (OMEC-3). The OMEC project will result in a multidisciplinary European consensus statement for oligometastatic esophagogastric cancer (OMEC-4), laying the basis for a prospective clinical study incorporating immunotherapy and local treatment for OMD for these patients (OMEC-5).

      Conclusion

      In conclusion, our results suggest that the preferred approach to oligometastatic esophagogastric cancer includes radical local treatment of OMD alone (e.g. metastasectomy or SBRT) or a combined approach consisting of radial local treatment of OMD plus systemic therapy (e.g. chemotherapy) . However, our results are most likely biased. Therefore, randomized controlled trials are warranted to confirm these results.

      Declaration of Competing Interest

      The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. van Laarhoven reports consultant or advisory role: BMS, Dragonfly, Lilly, Merck, Nordic Pharma, Servier; research funding and/or medication supply: Bayer, BMS, Celgene, Janssen, Incyte, Lilly, Merck, Nordic Pharma, Philips, Roche, Servier; Dr. Verhoeven reports grants from Bristol-Myer Squibb and Roche, outside the submitted work; Dr. Haj Mohammad reports personal fees from BMS, Lilly, MSD, Servier, and Astra Zeneca, outside the submitted work; the other authors have nothing to disclose..

      Appendix A. Supplementary data

      The following are the Supplementary data to this article:

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