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Primary Tumor Resection is Associated with Improved Disease-Specific Mortality in Patients with Stage IV Small Intestinal Neuroendocrine Tumors (NETs): A Comparison of Upfront Surgical Resection Versus a Watch and Wait Strategy in Two Specialist NET Centers

  • Endocrine Tumors
  • Published:
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Abstract

Introduction

Small intestinal neuroendocrine tumors (SI-NETs) often present with metastatic disease. An ongoing debate exists on whether to perform primary tumor resection (PTR) in patients with stage IV SI-NETs, without symptoms of the primary tumor and inoperable metastatic disease.

Objective

The aim of this study was to compare a treatment strategy of upfront surgical resection versus a surveillance strategy of watch and wait.

Methods

This was a retrospective cohort study of patients with stage IV SI-NETs at diagnosis, between 2000 and 2018, from two tertiary referral centers (Netherlands Cancer Institute [NKI] and Aintree University Hospital [AUH]) who had adopted contrasting treatment approaches: upfront surgical resection and watch and wait, respectively. Patients without symptoms related to the primary tumor were included. Multivariable intention-to-treat (ITT), per-protocol (PP), and instrumental variable (IV) analyses using ‘institute’ as an IV were performed to assess the influence of PTR on disease-specific mortality (DSM).

Results

A total of 557 patients were identified, with 145 patients remaining after exclusion of stage I–III disease or symptoms of the primary tumor (93 from the NKI and 52 from AUH). The cohorts differed in performance status (PS; p = 0.006) and tumor grade (p < 0.001). PTR was independently associated with reduced DSM irrespective of statistical methods employed: ITT hazard ratio [HR] 0.60, p = 0.005; PP HR 0.58, p < 0.001; and IV HR 0.07, p = 0.019. Other factors associated with DSM were age, PS, high chromogranin A, and somatostatin analog treatment.

Conclusion

Taking advantage of contrasting institutional treatment strategies, this study identified PTR as an independent predictor of DSM. Future prospective studies should aim to validate these results.

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Acknowledgment

The authors thank all the patients, investigators of the study and supporting teams at both participating centers. They also thank Rob Kessels and Mutamba Kayembe for statistical coding support.

Funding

No funding was received for this study.

Author information

Author notes

  1. Koert F. D. Kuhlmann and Margot E. T. Tesselaar contributed equally to this work.

Authors and Affiliations

  1. Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands

    Sonja Levy MD & Margot E. T. Tesselaar MD, PhD

  2. Department of Surgery, Liverpool University Hospital NHS Foundation Trust, Liverpool, UK

    James D. Arthur MD, Melissa Banks Nurse practitioner, Stephen W. Fenwick MD & Rafael Diaz-Nieto MD

  3. Department of Surgical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands

    Niels F. M. Kok MD, PhD & Koert F. D. Kuhlmann MD, PhD

  4. Department of Gastroenterologic Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands

    Monique E. van Leerdam MD, PhD

  5. Institute of Cardiovascular and Metabolic Medicine, University of Liverpool, Liverpool, UK

    Daniel J. Cuthbertson MD, PhD

  6. Department of Endocrinology, Liverpool University Hospital NHS Foundation Trust, Liverpool, UK

    Daniel J. Cuthbertson MD, PhD

  7. Department of Endocrine Oncology, University Medical Centre Utrecht, Utrecht, The Netherlands

    Gerlof D. Valk MD, PhD

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  1. Sonja Levy MD
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Corresponding author

Correspondence to Sonja Levy MD.

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Disclosures

Daniel J. Cuthbertson declares to have received consultancy fees and/or investigator-initiated research support from IPSEN and Novartis. Stephen W. Fenwick declares to have received funding to support a nurse educational event. Sonja Levy, James D. Arthur, Melissa Banks, Niels F.M. Kok, Rafael Diaz-Nieto, Monique E. van Leerdam, Gerlof D. Valk, Koert F.D. Kuhlmann, and Margot E.T. Tesselaar have no conflicts of interest to declare.

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Levy, S., Arthur, J.D., Banks, M. et al. Primary Tumor Resection is Associated with Improved Disease-Specific Mortality in Patients with Stage IV Small Intestinal Neuroendocrine Tumors (NETs): A Comparison of Upfront Surgical Resection Versus a Watch and Wait Strategy in Two Specialist NET Centers. Ann Surg Oncol 29, 7822–7832 (2022). https://doi.org/10.1245/s10434-022-12030-0

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