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  • Review Article
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Therapeutic developments in pancreatic cancer: current and future perspectives

Nature Reviews Gastroenterology & Hepatology volume 15, pages 333–348 (2018)Cite this article

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Abstract

The overall 5-year survival for pancreatic cancer has changed little over the past few decades, and pancreatic cancer is predicted to be the second leading cause of cancer-related mortality in the next decade in Western countries. The past few years, however, have seen improvements in first-line and second-line palliative therapies and considerable progress in increasing survival with adjuvant treatment. The use of biomarkers to help define treatment and the potential of neoadjuvant therapies also offer opportunities to improve outcomes. This Review brings together information on achievements to date, what is working currently and where successes are likely to be achieved in the future. Furthermore, we address the questions of how we should approach the development of pancreatic cancer treatments, including those for patients with metastatic, locally advanced and borderline resectable pancreatic cancer, as well as for patients with resected tumours. In addition to embracing newer strategies comprising genomics, stromal therapies and immunotherapies, conventional approaches using chemotherapy and radiotherapy still offer considerable prospects for greater traction and synergy with evolving concepts.

Key points

  • Pancreatic cancer is currently the fourth leading cause of cancer-associated mortality and is projected to be the second leading cause within the next decade in Western countries.

  • For resectable tumours, surgery followed by adjuvant chemotherapy (gemcitabine plus capecitabine) is the standard of care; median survival in these patients is 26 months, with a 5-year survival of 30%.

  • For borderline resectable and locally advanced, unresectable tumours, neoadjuvant protocols are utilized, with a shift towards chemotherapy rather than radiochemotherapy, although good evidence from randomized controlled trials is lacking.

  • In the metastatic setting, FOLFIRINOX and nab-paclitaxel–gemcitabine are standard treatment options in patients with good performance status; both combinations have shown a survival advantage over previously standard gemcitabine monotherapy.

  • Second-line therapies, notably nanoliposomal irinotecan plus 5-fluorouracil–folinic acid, might prolong survival after first-line gemcitabine failure.

  • Pathway-specific targeted therapies have failed to provide clinically relevant benefits; therapies targeting the stroma as well as immunotherapies hold promise for the future but are currently not standard of care.

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Fig. 1: Suggested treatment algorithm for patients with pancreatic cancer.
Fig. 2: The microenvironment of pancreatic tumours.
Fig. 3: Tumour antigens and the role of regulatory and effector T cells in pancreatic cancer.
Fig. 4: Macrophages in the pancreatic tumour microenvironment.
Fig. 5: Drugs to modulate immune function in pancreatic cancer.

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Acknowledgements

The work of J.K. and J.P.N. is supported by the European Cooperation in Science and Technology action BM1204, “EUPancreas: An integrated European platform for pancreas cancer research: from basic science to clinical and public health interventions for a rare disease”.

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Authors and Affiliations

  1. Department of General Surgery, University of Heidelberg, Heidelberg, Germany

    John P. Neoptolemos

  2. Department of Visceral, Vascular and Endocrine Surgery, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany

    Jörg Kleeff

  3. Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, UK

    Jörg Kleeff, Eithne Costello, William Greenhalf & Daniel H. Palmer

  4. Department of Internal Medicine I, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany

    Patrick Michl

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  1. John P. Neoptolemos
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  3. Patrick Michl
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  4. Eithne Costello
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  5. William Greenhalf
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The authors contributed equally to the Review.

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Correspondence to John P. Neoptolemos or Jörg Kleeff.

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Competing interests

J.P.N. reports grants from AstraZeneca, Cancer Research UK, Clovis Oncology and Ventana, Immunovia, KAEL & GemVax (Korea), Pharma Nord and Taiho Pharma (Japan); payment for lectures from Amgen and Mylan; paid consultancy from Astellas, Boehringer Ingelheim Pharma GmbH & Co KG, Erytech, KAEL & GemVax, Novartis Pharma AG, Redhill Biopharma and Tragovax; and educational travel grants from NuCana, all of which were not related to the submitted work. J.P.N. was a UK National Institute for Health Research (NIHR) senior investigator. D.H.P. reports grants from Cancer Research UK, the NIHR and NuCana and paid consultancy from NuCana. E.C. and W.G. report grants from Cancer Research UK, Immunova, the NIHR and the European Union. J.K. and P.M. declare no competing interests.

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Glossary

Hand–foot syndrome

A condition that can occur after chemotherapy in which there is redness, swelling, numbness and/or skin peeling on the palms of the hands and the soles of the feet.

FOLFIRINOX

A therapy combination including folinic acid, 5-fluoruracil, irinotecan and oxaliplatin.

Irreversible electroporation

(IRE). A nonthermal ablation technique that uses short (microsecond) pulses of high voltage electrical current to create permanent, lethal nanopores in the cell membrane.

Radiofrequency ablation

(RFA). An ablation technique that uses heat generated from medium frequency alternating current.

Stereotactic body radiation

(SBRT). A specialized type of external beam radiation therapy that uses focused radiation beams to precisely target a tumour that is well defined by detailed imaging scans.

High-intensity focused ultrasound

(HIFU). A procedure that uses an acoustic lens to concentrate multiple intersecting beams of ultrasound on a target.

Nanoliposomal irinotecan

An artificial, nanosized liposomal delivery system for irinotecan that is designed to keep irinotecan in circulation for longer than free irinotecan.

Cancer-associated fibroblasts

(CAFs). Fibroblasts within the tumour microenvironment that promote tumorigenic features by initiating the remodelling of extracellular matrix or by secreting cytokines.

T cell checkpoints

Molecules in the immune system that can either turn up (via co-stimulatory pathways) or turn down (via inhibitory pathways) immune responses

Regulatory T cells

(Treg cells). A subpopulation of T cells that modulate immune system function, maintain self-tolerance and prevent autoimmune disease.

Myeloid-derived suppressor cells

A heterogeneous group of immune cells of myeloid lineage (derived from bone marrow stem cells), they are strongly immunosuppressive rather than immunostimulatory.

Effector T cells

A subpopulation of T cells that have an important role in executing immune functions, including releasing T cell cytokines.

Antigen-presenting cells

(APCs). Cells that display antigens complexed with major histocompatibility complexes on their cell surfaces.

Suicide cassettes

Components of vector DNA consisting of a suicide gene and regulatory sequence to be expressed by a transfected cell, which cause the transfected cell to undergo apoptosis.

Kynurenine

A metabolite of tryptophan produced by indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO).

Neo-antigen

A new antigen expressed exclusively by tumour cells that is generated by the progressive mutational process that drives cancer evolution.

Abscopal effects

A phenomenon whereby local radiotherapy causes regression of not only the targeted tumour but also distant tumours.

Intensity-modulated radiation therapy

A high-precision conformal radiotherapy approach to deliver precise radiation doses to a malignant tumour or specific areas within the tumour.

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Neoptolemos, J.P., Kleeff, J., Michl, P. et al. Therapeutic developments in pancreatic cancer: current and future perspectives. Nat Rev Gastroenterol Hepatol 15, 333–348 (2018). https://doi.org/10.1038/s41575-018-0005-x

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