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  • Review Article
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Preoperative chemotherapy, radiotherapy and surgical decision-making in patients with borderline resectable and locally advanced pancreatic cancer

Nature Reviews Gastroenterology & Hepatology volume 21, pages 101–124 (2024)Cite this article

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Abstract

Surgical resection combined with systemic chemotherapy is the cornerstone of treatment for patients with localized pancreatic cancer. Upfront surgery is considered suboptimal in cases with extensive vascular involvement, which can be classified as either borderline resectable pancreatic cancer or locally advanced pancreatic cancer. In these patients, FOLFIRINOX or gemcitabine plus nab-paclitaxel chemotherapy is currently used as preoperative chemotherapy and is eventually combined with radiotherapy. Thus, more patients might reach 5-year overall survival. Patient selection for chemotherapy, radiotherapy and subsequent surgery is based on anatomical, biological and conditional parameters. Current guidelines and clinical practices vary considerably regarding preoperative chemotherapy and radiotherapy, response evaluation, and indications for surgery. In this Review, we provide an overview of the clinical evidence regarding disease staging, preoperative therapy, response evaluation and surgery in patients with borderline resectable pancreatic cancer or locally advanced pancreatic cancer. In addition, a clinical work-up is proposed based on the available evidence and guidelines. We identify knowledge gaps and outline a proposed research agenda.

Key points

  • Preoperative multi-agent chemotherapy (for example, FOLFIRINOX or gemcitabine plus nab-paclitaxel) is now routinely used in patients with borderline resectable pancreatic cancer (BRPC) or locally advanced pancreatic cancer (LAPC), both to obtain local and systemic control and to select suitable candidates for surgery.

  • Considerable variation exists among national and international guidelines and clinical practices regarding preoperative therapy in patients with BRPC or LAPC, including the type and duration of chemotherapy and the role, type, and timing of radiotherapy; a uniform, evidence-based international guideline with support from all relevant societies is needed.

  • Three randomized controlled trials reported improved outcomes with neoadjuvant chemotherapy or chemoradiotherapy compared with upfront surgery in patients with BRPC; more randomized trials assessing the effect of modern multi-agent chemotherapy and radiotherapy are needed and several are ongoing.

  • Response evaluation after preoperative chemotherapy and chemoradiotherapy is a major challenge as conventional cross-sectional imaging mostly underestimates the tumour response. Biological response evaluation is therefore advised (particularly a relative decrease of serum CA19-9). However, there is an urgent need for more accurate tumour markers.

  • Surgery after preoperative therapy in patients with BRPC and LAPC requires high-volume expertise for patient selection, intraoperative decision-making, extended resections and postoperative care; preoperative counselling and shared decision-making are crucial.

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Fig. 1: Borderline resectable and locally advanced pancreatic tumours.
Fig. 2: Proposed clinical work-up for patients with BRPC and LAPC.

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Acknowledgements

The authors thank Faridi S. van Etten-Jamaludin (Clinical Librarian, Amsterdam UMC, location University of Amsterdam) for her contribution to the construction of the literature search strategy.

Author information

Author notes

  1. These authors contributed equally: Thomas F. Stoop, Rutger T. Theijse, Leonard W. F. Seelen.

Authors and Affiliations

  1. Amsterdam UMC, location University of Amsterdam, Department of Surgery, Amsterdam, Netherlands

    Thomas F. Stoop, Rutger T. Theijse & Marc G. Besselink

  2. Cancer Center Amsterdam, Amsterdam, Netherlands

    Thomas F. Stoop, Rutger T. Theijse, Geertjan van Tienhoven, Johanna W. Wilmink & Marc G. Besselink

  3. Division of Surgical Oncology, Department of Surgery, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA

    Thomas F. Stoop & Marco Del Chiaro

  4. Department of Surgery, Regional Academic Cancer Center Utrecht, University Medical Center Utrecht and St. Antonius Hospital Nieuwegein, Utrecht, Netherlands

    Leonard W. F. Seelen, Hjalmar C. van Santvoort & I. Quintus Molenaar

  5. Department of Surgery, Erasmus MC Cancer Institute, Erasmus Medical Center, Rotterdam, Netherlands

    Bas Groot Koerkamp & Casper H. J. van Eijck

  6. Division of Surgical Oncology, Department of Surgery, New York University Medical Center, New York City, NY, USA

    Christopher L. Wolfgang

  7. Amsterdam UMC, location University of Amsterdam, Department of Radiation Oncology, Amsterdam, Netherlands

    Geertjan van Tienhoven

  8. Amsterdam UMC, location University of Amsterdam, Department of Medical Oncology, Amsterdam, Netherlands

    Johanna W. Wilmink

  9. Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Matthew H. G. Katz

  10. Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany

    Thilo Hackert

  11. Department of General, Visceral and Thoracic Surgery, University Hospital Hamburg-Eppendorf, Hamburg, Germany

    Thilo Hackert

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  1. Thomas F. Stoop
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  14. Marc G. Besselink
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Consortia

International Collaborative Group on Locally Advanced Pancreatic Cancer

  • Bas Groot Koerkamp
  • , Casper H. J. van Eijck
  • , Christopher L. Wolfgang
  • , Geertjan van Tienhoven
  • , Hjalmar C. van Santvoort
  • , I. Quintus Molenaar
  • , Johanna W. Wilmink
  • , Marco Del Chiaro
  • , Matthew H. G. Katz
  • , Thilo Hackert
  •  & Marc G. Besselink

Contributions

M.G.B. and T.F.S. researched data for the article, made a substantial contribution to the discussion of content, wrote the article, and reviewed/edited the manuscript before submission. R.T.T. and L.W.F.S. researched data for the article, made a substantial contribution to the discussion of content, and reviewed/edited the manuscript before submission. The other authors reviewed/edited the manuscript before submission.

Corresponding author

Correspondence to Marc G. Besselink.

Ethics declarations

Competing interests

M.D.C. received an industry grant (Haemonetics, Inc.) to conduct a multicentre study to evaluate the prognostic implications of TEG in pancreatic cancer. M.D.C. is co-principal investigator of a Boston Scientific-sponsored international multicentre study on the use of intraoperative pancreatoscopy of patients with intraductal papillary mucinous neoplasms. T.F.S. and M.G.B. received two grants from the Dutch Cancer Society (KWF) and Deltaplan Alvleesklierkanker for the Dutch PREOPANC-4 trial on the multidisciplinary management of locally advanced pancreatic cancer (NCT05524090).

Peer review

Peer review information

Nature Reviews Gastroenterology & Hepatology thanks Helmut Friess and Giuseppe Malleo for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Review criteria

A systematic literature search on PubMed was performed (30 November 2022); see Supplementary Table 1 for the search strategy. Literature (n = 2,978 records) was screened by title and abstract (by T.F.S., L.W.F.S. and R.T.T.) and the preliminary articles included (n = 801) were subsequently screened by full-text (by L.W.F.S. and R.T.T.). Additional literature was identified via the references of included literature to further nuance certain topics. In addition, the WHO International Clinical Trials Registry Platform was searched (6 December 2022) for ongoing and completed randomized controlled trials. Trials about advanced pancreatic cancer were not included. On 6 February 2023, the status of included ongoing or completed trials was checked. Inclusion criteria concerned any type of original studies about preoperative chemotherapy or chemoradiotherapy for borderline resectable pancreatic cancer and/or locally advanced pancreatic cancer (LAPC; any definition), published in the period 2010(1) to 2022(11). Studies were included when they reported about (1) indications for preoperative chemotherapy or chemoradiotherapy or subsequent patient selection; and/or (2) (radical) resection rate and/or overall survival. Randomized controlled trials were included whereas primarily only observational studies with a sample size of ≥50 patients with borderline resectable pancreatic cancer and/or LAPC were selected. Single-centre studies with at least 200 patients with LAPC and multicentre studies with at least 100 patients were specifically included. Finally, smaller series were used to illustrate certain topics when larger series were not available.

Supplementary information

Glossary

5-Fluorouracil

(5-FU). A single-agent chemotherapy.

ABC

(Anatomical – Biological – Conditional). Multi-domain parameters that are used to (re)stage patients with pancreatic cancer before and after preoperative therapy. This includes, among others, vascular tumour involvement (anatomical), tumour markers (biological) and patient fitness (condition).

Adjuvant therapy

Adjuvant therapy for patients with pancreatic cancer often concerns systemic chemotherapy (with or without radiotherapy) that is given with a curative intention after surgery.

Adverse events

Adverse events can be classified following the Common Terminology Criteria for Adverse Events, ranging from grade 1 (mild) and grade 2 (moderate) to grade 3 (severe or medically significant), grade 4 (life-threatening) or grade 5 (death).

American Joint Committee on Cancer

(AJCC). The AJCC developed a staging system for pancreatic cancer, comprising the three-tier system T stage (tumour), N stage (lymph nodes) and M stage (distant metastases).

Arterial divestment

A surgical technique whereby the (tumour) tissue is peeled off from an artery, without the need for an arterial resection.

Borderline resectable pancreatic cancer

(BRPC). Resectability of a pancreatic tumour is often based on the presence and extent of vascular tumour involvement. Biological and conditional factors can also be part of resectability criteria. A borderline resectable pancreatic tumour means that the benefit of removing the tumour by surgery is uncertain or debatable.

BRPC-A

Borderline resectable pancreatic cancer (BRPC) due to the presence of arterial involvement (that is, superior mesenteric artery, coeliac axis and/or hepatic artery).

BRPC-PV

Borderline resectable pancreatic cancer (BRPC) due to the presence and extent of tumour involvement with the portomesenteric axis (that is, portal vein, confluence and superior mesenteric vein).

Capecitabine

A single-agent chemotherapy.

Carbohydrate antigen 19-9

(CA19-9). A serological tumour marker that is measurable in 80–85% of patients with pancreatic cancer. It is the most commonly used tumour marker in patients with pancreatic cancer.

Carbohydrate antigen 125

(CA125). A serological tumour marker that might be of clinical value in patients with pancreatic cancer.

Carcinoembryonic antigen

(CEA). A serological tumour marker that is elevated in 30–60% of patients with pancreatic cancer and could be of clinical value.

Coeliac axis

The arterial branch that originates from the aorta and trifurcates into the common hepatic artery, left gastric artery and splenic artery in case of normal arterial anatomy.

Complete pathological response

The absence of vital tumour cells in the resection specimen in response to therapy.

Computed tomography

(CT). A type of cross-sectional imaging.

Cross-sectional imaging

Advanced imaging modalities such as computed tomography and magnetic resonance imaging.

Diffusion-weighted MRI

A specific modality of magnetic resonance imaging (MRI).

Duke pancreatic monoclonal antigen type 2

(DUPAN2). A serological tumour marker that might be of clinical value in patients with pancreatic cancer.

Eastern Cooperative Oncology Group (ECOG) performance status

A classification to indicate the condition of a patient, ranging from grade 0 (fully active) to grade 5 (deceased).

External beam radiotherapy

(EBRT). A conventional radiation modality.

Extrapancreatic disease

(Suspected) pancreatic cancer located outside the pancreas (that is, lymphadenopathy and/or distant metastases).

FDG-PET

Fluorodeoxyglucose-positron emission tomography (PET) is combined with either computed tomography or magnetic resonance imaging.

FOLFIRINOX

Multi-agent chemotherapy, comprising a combination of 5-fluorouracil, leucovorin, irinotecan and oxaliplatin.

Gemcitabine

A single-agent chemotherapy.

Gemcitabine-capecitabine

A multi-agent chemotherapy, comprising gemcitabine and capecitabine.

Gemcitabine-oxaliplatin

A multi-agent chemotherapy, comprising gemcitabine and oxaliplatin.

Gemcitabine plus nab-paclitaxel

A multi-agent chemotherapy, comprising gemcitabine and albumin-bound paclitaxel.

Gemcitabine-S1

A multi-agent chemotherapy, comprising gemcitabine and S1.

Histopathological tumour response

The presence (and extent) of tumour response on preoperative therapy in the resected specimen can be assessed and graded.

Hypofractionated image-guided radiotherapy

A type of radiation therapy that enables higher and more precise dosage whereby surrounding health tissue is spared.

Induction therapy

Preoperative therapy for patients with locally advanced pancreatic cancer, using chemotherapy with or without radiation.

Intensity-modulated radiotherapy

(IMRT). A type of radiation therapy that enables higher and more precise dosage whereby surrounding health tissue is spared.

Irinotecan

A single-agent chemotherapeutic drug but often used as part of the multi-agent chemotherapy FOLFIRINOX.

Localized pancreatic cancer

Pancreatic cancer without signs of metastatic disease.

Locally advanced pancreatic cancer

(LAPC). Resectability of a pancreatic tumour is often based on the presence and extent of vascular tumour involvement. A locally advanced pancreatic tumour means that the tumour has sufficient contact with major peri-pancreatic vasculature that an upfront surgical resection is associated with significant risks.

Magnetic resonance imaging

(MRI). A type of cross-sectional imaging.

Maximum standard uptake value

(SUVmax). A measure of the highest metabolic activity on a fluorodeoxyglucose-positron emission tomography scan.

Neoadjuvant therapy

Preoperative therapy for patients with (borderline) resectable pancreatic cancer, using chemotherapy with or without radiation.

Pancreatic fistula

Leakage of anastomosis from the pancreas with stomach or jejunum, whereby pancreatic enzymes leak into the abdominal cavity.

Pancreatoduodenectomy

Resection of the pancreatic head, duodenum, gallbladder and proximal jejunum, eventually combined with resection of the distal stomach.

‘Pick-the-winner’ design

A method that can be used for randomized controlled trials in which the best treatment of choice is chosen, also weighing alongside the efficacy factors such as toxicity, quality of life and health-care costs.

Portomesenteric venous axis

The venous system that drains blood from the small bowel and colon to the liver. The main branches that are most relevant for the resectability from pancreatic cancer are the portal vein, confluence and superior mesenteric vein.

Primary resectable pancreatic cancer

(PRPC). Resectability of a pancreatic tumour is often based on the presence and extent of vascular tumour involvement. A primary resectable pancreatic tumour means that it seems beneficial to remove the tumour by surgery.

R0

R status indicates whether the resection margins are free from vital tumour cells: R0, margins are microscopically tumour-free.

R1

R status indicates whether the resection margins are free from vital tumour cells: R1, margins are microscopically (closely) involved by vital tumour.

R2

R status indicates whether the resection margins are free from vital tumour cells: R2, macroscopically tumour tissue is left after resection, examined intraoperatively.

Response Evaluation Criteria for Solid Tumors

(RECIST). A classification system used to classify disease response and/or progression over time or in disease response to treatment.

S1

A single-agent chemotherapy.

Stereotactic body radiotherapy

(SBRT). A type of radiation therapy that enables higher and more precise dosage whereby surrounding health tissue is spared.

Total pancreatectomy

Resection of the complete pancreas (that is, pancreatic head, body and tail), at least combined with resection of gallbladder, duodenum, proximal jejunum and, eventually, the distal stomach.

Upfront surgery

Immediate surgery without preoperative therapy with chemotherapy or chemoradiotherapy.

Volumetric modulated arc therapy

A type of radiation therapy that enables higher and more precise dosage whereby surrounding health tissue is spared.

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Stoop, T.F., Theijse, R.T., Seelen, L.W.F. et al. Preoperative chemotherapy, radiotherapy and surgical decision-making in patients with borderline resectable and locally advanced pancreatic cancer. Nat Rev Gastroenterol Hepatol 21, 101–124 (2024). https://doi.org/10.1038/s41575-023-00856-2

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