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The Evolving Treatment Landscape of Merkel Cell Carcinoma

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Opinion statement

Merkel cell carcinoma (MCC) has a high risk of recurrence and requires unique treatment relative to other skin cancers. The patient population is generally older, with comorbidities. Multidisciplinary and personalized care is therefore paramount, based on patient preferences regarding risks and benefits. Positron emission tomography and computed tomography (PET-CT) is the most sensitive staging modality and reveals clinically occult disease in ~ 16% of patients. Discovery of occult disease spread markedly alters management. Newly diagnosed, localized disease is often managed with sentinel lymph node biopsy (SLNB), local excision, primary wound closure, and post-operative radiation therapy (PORT). In contrast, metastatic disease is usually treated systemically with an immune checkpoint inhibitor (ICI). However, one or more of these approaches may not be indicated. Criteria for such exceptions and alternative approaches will be discussed. Because MCC recurs in 40% of patients and early detection/treatment of advanced disease is advantageous, close surveillance is recommended. Given that over 90% of initial recurrences arise within 3 years, surveillance frequency can be rapidly decreased after this high-risk period. Patient-specific assessment of risk is important because recurrence risk varies widely (15 to > 80%: Merkelcell.org/recur) depending on baseline patient characteristics and time since treatment. Blood-based surveillance tests are now available (Merkel cell polyomavirus (MCPyV) antibodies and circulating tumor DNA (ctDNA)) with excellent sensitivity that can spare patients from contrast dye, radioactivity, and travel to a cancer imaging facility. If recurrent disease is locoregional, management with surgery and/or RT is typically indicated. ICIs are now the first line for systemic/advanced MCC, with objective response rates (ORRs) exceeding 50%. Cytotoxic chemotherapy is sometimes used for debulking disease or in patients who cannot tolerate ICI. ICI-refractory disease is the major problem faced by this field. Fortunately, numerous promising therapies are on the horizon to address this clinical need.

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Abbreviations

ADAM:

ADjuvant Avelumab in Merkel

AE:

Adverse effect

ATTAC:

Autologous Transgenic T cells, Avelumab and Class I MHC upregulation for Advanced Checkpoint-inhibitor resistant Merkel cell carcinoma

CLL:

Chronic lymphocytic leukemia

ctDNA:

Circulating tumor DNA

CTLA-4:

Cytotoxic T lymphocyte-associated protein 4

CI:

Confidence interval

CR:

Complete response

CT:

Computed tomography

FGF:

Fibroblast growth factor

GM-CSF:

Granulocyte-macrophage colony-stimulating factor

HR:

Hazard ratio

HIV:

Human immunodeficiency virus

ICI:

Immune checkpoint inhibition

irAEs:

Immune-related adverse events

IHC:

Immunohistochemical

IFN-y:

Interferon gamma

IL-12:

Interleukin 12

IT:

Intratumoral

AMERK:

MCPyV antibody test

MCC:

Merkel cell carcinoma

MCPyV:

Merkel cell polyomavirus

MHC:

Major histocompatibility complex

mMCC:

Metastatic Merkel cell carcinoma

NCCN:

National Comprehensive Cancer Network

NED:

No evidence of disease

NET:

Neuroendocrine tumors

OS:

Overall survival

ORR:

Overall response rate

PR:

Partial response

PET-CT:

Positron emission tomography and computed tomography

PFS:

Progression-free survival

PD:

Progressive disease

PDGF:

Platelet-derived growth factor

PRRT:

Peptide receptor radionucleotide therapy

PORT:

Post-operative radiation therapy

PD-(L)1:

Programmed cell death (ligand) 1

RT:

Radiation therapy

RFS:

Recurrence-free survival

SFRT:

Single fraction radiation therapy

SLNB:

Sentinel lymph node biopsy

SSAs:

Somatostatin analogs

SSTR:

Somatostatin receptors

SRS:

Somatostatin receptor scintigraphy

SD:

Stable disease

T-VEC:

Talimogene Laherparepvec

TKIs:

Tyrosine kinase inhibitors

TLR4:

Toll-like receptor-4

TLR9:

Toll-like receptor-9

UV:

Ultraviolet

FDA:

US Food and Drug Administration

VEGF:

Vascular endothelial growth factor

VP:

Virus positive

WES:

Whole exome sequencing

WLE:

Wide local excision

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Funding

Supported in part by the National Institutes of Health/National Cancer Institute, MD, USA, P01 CA225517 and P30 CA015704, the MCC Patient Gift Fund at UW, and Kelsey Dickson Team. Science Courage Research Team Award from the Prostate Cancer Foundation, Santa Monica, CA, USA (Award PCF#19CHAS02). The funding agencies did not participate in the preparation, review, or approval of the manuscript or the decision to submit the manuscript for publication.

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  1. Neha Singh and Erin McClure contributed equivalently.

Authors and Affiliations

  1. Department of Medicine, Division of Dermatology, University of Washington, 850 Republican Street, Box 358050, Seattle, WA, USA

    Neha Singh BS, Erin M. McClure BS, Tomoko Akaike MD, Song Y. Park MD, Emily T. Huynh BS, Peter H. Goff MD, PhD & Paul Nghiem MD, PhD

  2. Virginia Tech Carilion School of Medicine, Roanoke, VA, USA

    Neha Singh BS

  3. University of South Florida, Morsani College of Medicine, Tampa, FL, USA

    Erin M. McClure BS

  4. Department of Radiation Oncology, University of Washington, Seattle, WA, USA

    Peter H. Goff MD, PhD

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Correspondence to Paul Nghiem MD, PhD.

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Conflict of Interest

Paul Nghiem has served as a consultant for: EMD Serono, Merck, and Pfizer/Regeneron; his institution has received research funding from Bristol-Myers Squibb and EMD Serono. Neha Singh, Erin McClure, Peter Goff, Emily Huynh, Song Park, and Tomoko Akaike declare no conflicts of interest with this work.

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Singh, N., McClure, E.M., Akaike, T. et al. The Evolving Treatment Landscape of Merkel Cell Carcinoma. Curr. Treat. Options in Oncol. 24, 1231–1258 (2023). https://doi.org/10.1007/s11864-023-01118-8

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