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NCCN Flash Updates: NCCN Guidelines Updated for Merkel Cell Carcinoma

NCCN has published updates to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®), the NCCN Drugs & Biologics Compendium (NCCN Compendium^®),  the NCCN Radiation Therapy Compendium™, and the NCCN Imaging Appropriate Use Criteria (NCCN Imaging AUC™) for Merkel Cell Carcinoma. These NCCN Guidelines^® are currently available as Version 1.2024.

Link directly to the Updates section of the NCCN Guidelines: Merkel Cell Carcinoma

Global changes:

• Extracapsular extension (ECE) changed to extranodal extension (ENE).
• Principles of Excision changed to Principles of Surgery.

MCC-1

• Additional Workup, fourth bullet revised: If patient is immunosuppressed For patients who are immunocompromised, consider modification or reduction of immunosuppression as appropriate.
• New header added to far left of page: Treatment.
  • Following Clinical N0, option revised: Primary and Additional Treatment (MCC-2) and (MCC-3).
  • Following Clinical N+, option revised: Primary and Additional Treatment: Management of Primary Tumor (MCC-4) Management of the Draining Nodal Basin (MCC-4).
  • Following Clinical M1, option revised: Treatment (MCC-5).
• Footnotes revised:
  • Footnote b: Imaging is encouraged for staging of most cases of MCC, because occult metastatic disease resulting in upstaging has been detected in 12%–20% of patients presenting without suspicious H&P findings (Singh N, et al. J Am Acad Dermatol 2021;84:330-339). Several studies indicate whole-body FDG-PET with fused axial imaging is more sensitive for detecting occult metastatic disease at baseline; however, CT with contrast of chest/abdomen/pelvis and neck if primary tumor on head/neck (and neck/MRI of the brain with and without contrast if clinical suspicion of brain metastases) is an acceptable alternative. . .
  • Footnote c: Quantitation of serum Merkel cell polyomavirus (MCPyV) oncoprotein antibodies may be considered as part of initial workup; patients who test seronegative patients may have a higher risk of recurrence; in patients who test seropositive patients, a rising titer may be an early indicator of recurrence; baseline testing should be performed within 3 months of treatment, because titers are expected to decrease significantly after clinically evident disease is eliminated. (Also page MCC-6)
  • Footnote d: As immunosuppression in MCC is a risk factor for poor outcomes, immunosuppressive treatments should be minimized as clinically feasible in consultation with the relevant managing physician. As immunosuppressed patients who are immunocompromised are at high risk for recurrence, more frequent follow-up may be indicated. (Also pages MCC-5 and MCC-6)

MCC-2

• Header revised: Clinical N0 Disease, Local MCC Only, Surgically Resectable.
• Far left column revised: Clinical N0 (local MCC only, surgically resectable).
• Primary Treatment, options revised: Excision with 1- to 2-cm margins, or Mohs in certain circumstances, with sentinel lymph node biopsy (SLNB) and For non-surgical candidates consider multidisciplinary consultation and discussion of definitive RT vs. systemic therapy SLNB with appropriate immunopanel.
  • Following Excision with 1- to 2-cm margins, or Mohs in certain circumstances:
    • Second pathway revised: Microscopically P positive margins.
    • Third pathway revised: Narrow clinical margin (<1 cm) excision and/or A adverse risk factors.
• Additional Treatment:
  • Option following Microscopically positive margins revised: Adjuvant radiation therapy (RT) (preferred) and/or re-excision.
  • Option following SLN negative, second bullet revised: May consider RT to the nodal basin in patients at high risk for increased risk of a false-negative SLNB.

MCC-2A

• Footnotes revised:
  • Footnote h: SLNB is an important staging tool. This procedure and subsequent treatment impacts regional control for patients with positive SLNs. It is recommended, regardless of surgical approach, that every effort is made to coordinate surgical management such that SLNB is performed prior to or at the time of definitive excision. (Also pages MCC-3 and MCC-4)
  • Footnote l: Consider empiric RT to the nodal basin when: 1) the accuracy of SLNB may have been subject to anatomic compromise (lymphoma involved nodes, or history of remote LN excision); 2) when the risk of false-negative SLNB is high due to aberrant LN drainage and presence of multiple SLN basins (such as in head & neck or midline trunk MCC); or 3) in cases of profound immunosuppression. See Principles of Radiation Therapy (MCC-B).
• New footnote j added: Imaging via FDG-PET/CT or CT with contrast of chest, abdomen, pelvis, and neck if primary on head/neck (and MRI of the brain with and without contrast if clinical suspicion of brain metastases or direct extension). (Also pages MCC-4 and MCC-6)
• Footnotes removed:
  • Imaging is encouraged for staging of most cases of MCC as occult metastatic disease resulting in upstaging has been detected in 12%–20% of patients presenting without suspicious H&P findings (Singh N, et al. J Am Acad Dermatol 2021;84:330-339). Several studies indicate whole-body PET with fused axial imaging is more sensitive for detecting occult metastatic disease at baseline; however, CT with contrast of chest/abdomen/pelvis (and neck/brain if clinical suspicion) is an acceptable alternative. Imaging may also be useful to evaluate for the possibility of a skin metastasis from a noncutaneous primary neuroendocrine carcinoma (eg, small cell lung cancer), especially in cases where CK20 is negative. The most reliable staging tool to identify subclinical nodal disease is SLNB (George A, et al. Nucl Med Commun 2014;35:282-290; Hawryluk EB, et al. J Am Acad Dermatol 2013;68:592-599; Siva S, et al. J Nucl Med 2013;54:1223-1229). (Also pages MCC-4 and MCC-6)
  • Principles of Systemic Therapy (MCC-D).

MCC-3

• New page added for Clinical N0 (locally advanced MCC when curative surgery and adjuvant RT are not feasible), which includes:
• Primary Treatment:
  • Neoadjuvant nivolumab may be considered in patients who are surgical candidates.
  • For non-surgical candidates, due to comorbidities, tumor characteristics, or progression on neoadjuvant nivolumab, discuss RT for durable local control vs. systemic therapy.

MCC-4

• Far left column revised: Clinical N+ (regional MCC)/in-transit disease).
• Following Imaging studies recommended, option added: MANAGEMENT OF THE PRIMARY TUMOR: MCC-2 and MCC-3.
• Header revised: Primary Treatment.
  • Options revised: MANAGEMENT OF THE PRIMARY TUMOR: MCC- 2 and MCC-3 AND MANAGEMENT OF THE DRAINING NODAL BASIN: Immunopanel, Fine-needle aspiration (FNA) or core biopsy with appropriate immunopanel AND/OR MANAGEMENT OF IN-TRANSIT DISEASE: Biopsy confirmation.
• Additional Treatment:
  • Following M0, fourth bullet revised: Clinical trial for adjuvant therapy preferred if available.
  • Following M1, option revised: Treatment of M1 Disease (MCC-5).
  • Following Radiographic surveillance or excisional biopsy, option revised: Follow appropriate Clinical N0 pathway (MCC-2) and (MCC-3).
  • Following MANAGEMENT OF IN-TRANSIT DISEASE, new options added:
    • Multidisciplinary consultation.
    • Clinical trial.
    • Surgery or RT.
    • Systemic therapy if curative surgery and/or RT are not feasible.
• Footnote removed: Adjuvant chemotherapy may be considered in select clinical circumstances; however, available retrospective studies do not suggest survival benefit for adjuvant chemotherapy. No data are available to support the adjuvant use of immunotherapy outside of a clinical trial.

MCC-6

• Following Recurrence:
  • First pathway revised: Local, Locally advanced and/or Regional.
  • New pathway added: In-transit disease.
• Treatment, following In-transit disease, new option added: MCC-4.
• Footnote s revised: Patients at high risk of Risk factors for recurrence include those who are immunosuppressed and patients who have positive non-SLN metastases immunosuppression, advancing age, advancing stage of disease (stage II–IV), individuals assigned male at birth, non-sentinel lymph node metastases, Merkel Cell polyomavirus negative status, as well as additional factors as determined by the treating physicians.

MCC-A

• Fourth bullet, first sub-bullet revised: Depth Thickness (Breslow, in mm).

MCC-B (1 of 2)

• General Treatment Information-Primary MCC Tumor Site, second bullet, second sub-bullet revised: In the palliative setting, a wide range of fractionation schedules may be used, including less protracted fractionation schedules such as 30 Gy in 10 fractions, 20 Gy in 4 or 5 fractions, or 8 Gy in 1 fraction. These schedules are under a clinical trial for curative intent.
• New references added:
  • Reference 1: Rush Z, Fields RC, Lee N, Brownell I. Radiation therapy in the management of Merkel cell carcinoma: current perspectives. Expert Rev Dermatol 2011;6:395-404.
  • Reference 2: Rao NG. Review of the role of radiation therapy in the management of Merkel cell carcinoma. Curr Probl Cancer 2010;34:108-117.

MCC-B (2 of 2)

• Footnote removed: Microscopic nodal disease (SLN positive) is defined as nodal involvement that is neither clinically palpable nor abnormal by imaging criteria, and microscopically consists of small metastatic foci without ECE.

MCC-C

• Surgical Approaches:
  • First bullet revised: It is recommended, regardless of the surgical approach, that every effort be made to coordinate surgical management such that SLNB is performed prior to or at the time of definitive excision. . .
    • Third sub-bullet revised: Techniques for more exhaustive histologic margin assessment may be considered (Mohs or other forms of peripheral and deep en face margin assessment [PDEMA]), provided they do not interfere with SLNB when indicated. If SLNB is not performed concurrently, it is recommended that SLNB is performed prior to definitive excision with exhaustive histologic margin assessment (ie, Mohs).

MCC-D (1 of 4)

• Revised page for Local Disease N0.
  • Bullet revised: For primary disease, adjuvant chemotherapy systemic therapy is not recommended outside of a clinical trial.
  • New preference stratification table added:
    • Primary resectable disease.
    • Primary locally advanced (if curative surgery and curative RT not feasible):
      • Preferred Regimens
        • New regimen added: Avelumab.
        • Pembrolizumab.
      • Other Recommended Regimens, new regimen added: Retifanlimab-dlwr.
      • Useful in Certain Circumstances, new regimen added: Neoadjuvant nivolumab.
    • Recurrent locally advanced (if curative surgery and curative RT not feasible):
      • Preferred Regimens, regimens moved from Other recommended Regimens:
        • Pembrolizumab.
        • Retifanlimab-dlwr.
      • Other Recommended Regimens, new regimen added: Avelumab.

MCC-D (1 of 4) (continued)

• Footnote b revised: Data from non-randomized trials in patients with MCC demonstrate that rates of durable response are improved with PD-1/PD-L1 blockade compared with cytotoxic therapy. The safety profiles for checkpoint immunotherapies are significantly different from cytotoxic therapies. Consult prescribing information for recommendations on detection and management of immune-related adverse events associated with checkpoint immunotherapies. Clinician and patient education is critical for safe administration of checkpoint immunotherapies. See NCCN Guidelines for Management of Immunotherapy-Related Toxicities. (Also pages MCC-D 2 of 4 and MCC-D 3 of 4)
• Footnote removed: NCCN Guidelines for Management of Immunotherapy-Related Toxicities. (Also pages MCC-D 2 of 4 and MCC-D 3 of 4)

MCC-D (2 of 4)

• Revised page for Regional Disease N+.
• Bullet removed: For regional disease, adjuvant chemotherapy is not routinely recommended as survival benefit has not been demonstrated in available retrospective studies but could be used on a case-by-case basis if clinical judgment dictates. No data are available to support the adjuvant use of immunotherapy outside of a clinical trial.
• New preference stratification table added:
  • Primary regional disease:
    • Useful in Certain Circumstances:
      • Carboplatin ± etoposide.
      • Cisplatin ± etoposide.
      • Neoadjuvant nivolumab.
  • Recurrent regional disease (if curative surgery and curative RT not feasible):
    • Preferred Regimens:
      • Clinical trial
      • Regimens moved from Other Recommended Regimens:
        • Pembrolizumab.
        • Retifanlimab-dlwr.
    • Other Recommended Regimens, new regimen added: Avelumab.
• New footnote c added: For regional disease, adjuvant chemotherapy is not routinely recommended as survival benefit has not been demonstrated in available retrospective studies but could be used on a case-by-case basis if clinical judgement dictates. No data are available to support the adjuvant use of immunotherapy outside of a clinical trial.

MCC-D (3 of 4)

• Revised page for Disseminated Disease M1.
• New preference stratification table added:
  • Preferred Regimens:
    • Clinical trial
    • Avelumab
    • Nivolumab
    • Pembrolizumab
    • Regimen moved from Other Recommended Regimens: Retifanlimab-dlwr.
  • Useful in Certain Circumstances, descriptor revised: If anti-PD-L1 or anti-PD-1 therapy is contraindicated or disease has progressed on this therapy anti-PD-L1 or anti-PD-1 monotherapy, may consider.
    • Carboplatin ± etoposide
    • Cisplatin ± etoposide
    • Cyclophosphamide, doxorubicin (or epirubicin), and vincristine (CAV)
    • Ipilimumab ± nivolumab
    • Topotecan
    • Octreotide long acting release (LAR) (Somatostatin analog therapy if somatostatin receptor testing is positive) (category 2B)
    • Pazopanib (category 2B)
    • Talimogene laherparepvec (T-VEC) (category 2B)

MCC-D (4 of 4)

• References updated.

 

 

 

NCCN has published updates to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®), the NCCN Imaging Appropriate Use Criteria (NCCN Imaging AUC™). These NCCN Guidelines^®  for Squamous Cell Skin Cancer are currently available as Version 1.2024. 

 

 

For the complete updated versions of the NCCN Guidelines, NCCN Guidelines with NCCN Evidence Blocks™, the NCCN Drugs & Biologics Compendium (NCCN Compendium^®), the NCCN Biomarkers Compendium^®, the NCCN Chemotherapy Order Templates (NCCN Templates^®), the NCCN Radiation Therapy Compendium™, and the NCCN Imaging Appropriate Use Criteria (NCCN Imaging AUC™), please visit NCCN.org.

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