Treatment algorithm

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ACUTE

localized disease: stage I or II (T-any cN0 M0)

1st line – surgical wide local excision ± radiation therapy to tumor bed

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ACUTE
|
localized disease: stage I or II (T-any cN0 M0)
|
surgically resectable
1st line – 

surgical wide local excision ± radiation therapy to tumor bed

A multidisciplinary approach involving specialists with expertise in management of rare skin cancers is recommended for management of MCC, regardless of stage.[3][7][19]​​​​​​​

In patients who present with localized disease (AJCC8 clinical stage I or II: i.e., T-any cN0 M0) that is surgically resectable, the recommendation is for concomitant management of the primary tumor and staging of the lymph node basin with sentinel lymph node biopsy.[3][19]​​[40][44]​​​​​​​

  • Adjuvant systemic therapy is not recommended outside of a clinical trial for this patient group.[3]

Surgical wide local excision of the primary tumor ± radiation therapy

First-line treatment for the primary MCC tumor is surgical wide local excision to remove the lesion with histologically clear margins. Multidisciplinary consultation and local guidelines should steer the approach regarding surgical margins.

The National Comprehensive Cancer Network (NCCN) recommends a 1-2 cm margin while noting that surgical margins should be balanced with the morbidity associated with surgery.[3]

  • For clear margins in a patient with no adverse risk factors, observation can be considered.

  • For microscopically positive margins, adjuvant radiation therapy is preferred over re-excision +/- adjuvant radiation.

  • For narrow clinical margin (<1 cm) and/or the presence of additional risk factors, excision should be followed by adjuvant radiation therapy. Relevant risk factors include: tumor size (primary tumor >1 cm); immunosuppressed state (chronic T-cell immunosuppression, HIV, chronic lymphocytic leukemia (CLL), solid organ transplant); tumor location (head/neck primary site); presence of lymphovascular invasion (LVI).

  • If adjuvant radiation therapy is indicated, this should be initiated as soon as wound healing permits.[3] A delay > 8 weeks in starting radiation therapy has been associated with worse outcomes.[78]​​

European guidelines recommend a 1-2 cm margin. If this is difficult or not feasible (e.g., in cosmetically sensitive locations such as the face or in proximity to joints), a narrower margin of 0.5 to 1.0 cm with adjuvant radiation therapy may be acceptable.[7][19]

  • Adjuvant radiation therapy to the tumor bed is recommended for tumors ≥1 cm and/or with negative prognostic features.

In selected patients (e.g., for sensitive areas such as the head and neck), a tissue-sparing approach such as Mohs or another form of peripheral and deep en face margin assessment (PDEMA) may be appropriate in place of wide local excision.[3][7][19]

Ongoing monitoring

After initial treatment, the patient should be monitored for disease recurrence with clinical surveillance and imaging studies as indicated.[3][7][29]​​​​​ If there are clear margins and no risk factors present, observation may be appropriate with regular follow-up to monitor for recurrence.[3]

Plus – sentinel lymph node biopsy (SLNB)

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ACUTE
|
localized disease: stage I or II (T-any cN0 M0)
|
surgically resectable
Plus – 

sentinel lymph node biopsy (SLNB)

Treatment recommended for ALL patients in selected patient group

It is imperative to identify occult lymph node metastases in patients with early-stage localized disease. SLNB is an important staging tool, and every effort must be made to coordinate surgical management so that it can be performed before, or at the same time as, excision of the primary tumor.[3][19]

  • SLNB has been demonstrated to detect occult spread to the lymph node basin in up to one third of patients who have no clinical evidence of node disease and would therefore have otherwise been staged as node-negative.[52]

  • Patients found to have occult lymph node disease on SLNB are upstaged to stage IIIA.

Consider – reduction of any immunosuppressive treatment for another condition

Back
ACUTE
|
localized disease: stage I or II (T-any cN0 M0)
|
surgically resectable
Consider – 

reduction of any immunosuppressive treatment for another condition

Treatment recommended for SOME patients in selected patient group

For patients who are immunocompromised, it is important to reduce any immunosuppressive treatments as clinically feasible, in consultation with the relevant managing physician.[3][7]​​ More frequent follow-up may be indicated for patients who are immunosuppressed.[3]

  • Immunosuppression in MCC is associated with an increased risk of recurrence and poorer outcomes.[18][27][76][77]​​​​​​​​​

1st line – multidisciplinary team consideration of neoadjuvant immunotherapy plus surgery and sentinel lymph node biopsy (SLNB)

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ACUTE
|
localized disease: stage I or II (T-any cN0 M0)
|
curative surgery/curative radiation therapy not initially feasible and surgical candidate
1st line – 

multidisciplinary team consideration of neoadjuvant immunotherapy plus surgery and sentinel lymph node biopsy (SLNB)

A multidisciplinary approach involving specialists with expertise in management of rare skin cancers is recommended for management of MCC, regardless of stage.[3][7][19]​​​​

For patients with locally advanced MCC in whom curative surgery and curative radiation therapy are not feasible due to tumor characteristics or comorbidities, multidisciplinary consultation should inform management.[3][7][29]

  • In patients who are candidates for surgery, neoadjuvant nivolumab may be considered prior to excision and SLNB.[3][19]

  • If progression on nivolumab means surgery is not feasible, radiation therapy may be considered.[3]

See local specialist protocol for dosing guidelines.

Primary options

nivolumab

Consider – reduction of any immunosuppressive treatment for another condition

Back
ACUTE
|
localized disease: stage I or II (T-any cN0 M0)
|
curative surgery/curative radiation therapy not initially feasible and surgical candidate
Consider – 

reduction of any immunosuppressive treatment for another condition

Treatment recommended for SOME patients in selected patient group

For patients who are immunocompromised, it is important to reduce any immunosuppressive treatments as clinically feasible, in consultation with the relevant managing physician.[3][7]​​ More frequent follow-up may be indicated for patients who are immunosuppressed.[3]

  • Immunosuppression in MCC is associated with an increased risk of recurrence and poorer outcomes.[18][27][76][77]​​​​​​​​​

1st line – radiation therapy

Back
ACUTE
|
localized disease: stage I or II (T-any cN0 M0)
|
curative surgery/curative radiation therapy not feasible and nonsurgical candidate
1st line – 

radiation therapy

A multidisciplinary approach involving specialists with expertise in management of rare skin cancers is recommended for management of MCC, regardless of stage.[3][7][19]​​​

For patients with locally advanced MCC in whom curative surgery and curative radiation therapy are not feasible and who are nonsurgical candidates (due to tumor characteristics and/or comorbidities), multidisciplinary consultation should inform management.[3][7][29]

  • The tumor may be treated with radiation therapy.[3][19][29]

Consider – reduction of any immunosuppressive treatment for another condition

Back
ACUTE
|
localized disease: stage I or II (T-any cN0 M0)
|
curative surgery/curative radiation therapy not feasible and nonsurgical candidate
Consider – 

reduction of any immunosuppressive treatment for another condition

Treatment recommended for SOME patients in selected patient group

For patients who are immunocompromised, it is important to reduce any immunosuppressive treatments as clinically feasible, in consultation with the relevant managing physician.[3][7]​​ More frequent follow-up may be indicated for patients who are immunosuppressed.[3]

  • Immunosuppression in MCC is associated with an increased risk of recurrence and poorer outcomes.[18][27][76][77]​​​​​​​​​

regional disease: stage IIIA

1st line – radiation therapy to nodal basin and/or lymph node dissection

Back
ACUTE
|
regional disease: stage IIIA
1st line – 

radiation therapy to nodal basin and/or lymph node dissection

A multidisciplinary approach involving specialists with expertise in management of rare skin cancers is recommended for management of MCC, regardless of stage.[3][7]​​​

For patients with sentinel lymph node biopsy (SLNB)-positive stage IIIA disease (i.e., with identified occult lymph node metastasis), treatment of the nodal basin is recommended along with baseline imaging studies to screen for distant metastases if not already performed. Multidisciplinary consultation should be sought.[3][7]

  • Note that because regional disease will only have been detected by SLNB, the primary tumor will already have been resected, together with consideration of adjuvant radiation therapy to the primary site. See the Localized disease patient group for details.

For treatment of the nodal basin, the National Comprehensive Cancer Network (NCCN) recommends:[3]

  • Radiation therapy to the nodal basin or

  • Lymph node dissection, which can be combined with adjuvant radiation therapy when indicated (e.g., for multiple involved nodes and/or in the presence of extranodal extension [ENE]).

European guidelines recommend:[19]

  • Multidisciplinary team discussion to consider adjuvant radiation therapy alone or complete lymph node dissection with adjuvant radiation therapy.[7]

  • Consideration of entry into a clinical trial for neoadjuvant or adjuvant systemic therapy is also recommended, if available.

Consider – reduction of any immunosuppressive treatment for another condition

Back
ACUTE
|
regional disease: stage IIIA
Consider – 

reduction of any immunosuppressive treatment for another condition

Treatment recommended for SOME patients in selected patient group

For patients who are immunocompromised, it is important to reduce any immunosuppressive treatments as clinically feasible, in consultation with the relevant managing physician.[3][7]​ More frequent follow-up may be indicated for patients who are immunosuppressed.[3]

  • Immunosuppression in MCC is associated with an increased risk of recurrence and poorer outcomes.[18][27][76][77]​​​​​​​​​

regional disease: unknown primary tumor with clinically apparent nodal disease

1st line – lymph node dissection ± radiation therapy

Back
ACUTE
|
regional disease: unknown primary tumor with clinically apparent nodal disease
1st line – 

lymph node dissection ± radiation therapy

A multidisciplinary approach involving specialists with expertise in management of rare skin cancers is recommended for management of MCC, regardless of stage.[3][7]​​​

Patients with MCC with unknown primary site present with a clinically identified, pathologically confirmed MCC metastasis to a lymph node without a primary MCC tumor.

  • In the 8th edition of the American Joint Committee on Cancer (AJCC8) staging system, these patients were downstaged to IIIA (T0pN1bM0) as their prognosis aligns with the prognosis for patients with occult lymph node metastasis.[10]​​[35]​​​[45][46]​​​​​​​​​​​​[47][70]

Multidisciplinary consultation will guide the preferred treatment approach in these patients, with nodal lesions managed similarly to those in patients with stage IIIB MCC.[19]​ See the Regional disease: stage IIIB, with lymph node metastasis but no in-transit disease patient group.

Consider – reduction of any immunosuppressive treatment for another condition

Back
ACUTE
|
regional disease: unknown primary tumor with clinically apparent nodal disease
Consider – 

reduction of any immunosuppressive treatment for another condition

Treatment recommended for SOME patients in selected patient group

For patients who are immunocompromised, it is important to reduce any immunosuppressive treatments as clinically feasible, in consultation with the relevant managing physician.[3][7] More frequent follow-up may be indicated for patients who are immunosuppressed.[3]

  • Immunosuppression in MCC is associated with an increased risk of recurrence and poorer outcomes.[18][27][76][77]​​​​​​​​​

regional disease: stage IIIB

1st line – lymph node dissection and radiation therapy to nodal basin ± neoadjuvant immunotherapy

Back
ACUTE
|
regional disease: stage IIIB
|
with lymph node metastasis but no in-transit disease (pN1b)
1st line – 

lymph node dissection and radiation therapy to nodal basin ± neoadjuvant immunotherapy

Multidisciplinary consultation is recommended for any individual with stage IIIB disease.[3][7]

Stage pN1b patients have metastases to the draining lymph node basin (clinically/radiologically detected and pathologically confirmed), without in-transit disease.

For management of the metastatic draining nodal basin in patients with stage IIIB MCC, the National Comprehensive Cancer Network (NCCN) recommends:[3]

  • Lymph node dissection with postoperative radiation therapy (preferred, although either dissection or radiation therapy alone may also be used)

  • Clinical trial enrollment, if available

  • Consideration of neoadjuvant systemic immunotherapy prior to surgery, based upon multidisciplinary recommendations (e.g., nivolumab).

The European guidelines recommend a multidisciplinary team discussion to determine the best therapy options. Entry into a clinical trial is preferred. Surgical options include complete regional lymph node dissection with postoperative radiation therapy (or definitive radiation therapy in patients who are not surgical candidates).[7][19]

  • The European Society for Medical Oncology (ESMO) guideline also recommends consideration of entry into a clinical trial of adjuvant or neoadjuvant immunotherapy, if available, on the basis that neither adjuvant radiation therapy nor adjuvant chemotherapy has been found to have any statistically significant impact on overall survival.[19]

See local specialist protocol for dosing guidelines.

Primary options

nivolumab

Plus – surgical wide local excision of primary tumor ± radiation therapy to primary tumor

Back
ACUTE
|
regional disease: stage IIIB
|
with lymph node metastasis but no in-transit disease (pN1b)
Plus – 

surgical wide local excision of primary tumor ± radiation therapy to primary tumor

Treatment recommended for ALL patients in selected patient group

In patients with stage IIIB MCC, the primary tumor is managed in the same way as for localized disease, with surgical wide local excision to remove the lesion with histologically clear margins and consideration of adjuvant radiation therapy. For details, see the Localized disease patient group.

Consider – reduction of any immunosuppressive treatment for another condition

Back
ACUTE
|
regional disease: stage IIIB
|
with lymph node metastasis but no in-transit disease (pN1b)
Consider – 

reduction of any immunosuppressive treatment for another condition

Treatment recommended for SOME patients in selected patient group

For patients who are immunocompromised, it is important to reduce any immunosuppressive treatments as clinically feasible, in consultation with the relevant managing physician.[3][7] More frequent follow-up may be indicated for patients who are immunosuppressed.[3]

  • Immunosuppression in MCC is associated with an increased risk of recurrence and poorer outcomes.[18][27][76][77]​​​​​​​​​

1st line – enrollment in clinical trial, surgery and/or radiation therapy, or systemic therapy

Back
ACUTE
|
regional disease: stage IIIB
|
with in-transit disease with or without lymph node metastasis (pN2/pN3)
1st line – 

enrollment in clinical trial, surgery and/or radiation therapy, or systemic therapy

Multidisciplinary consultation is recommended for any individual with stage IIIB disease.[3][7]

  • Stage pN2 patients have in-transit metastasis without lymph node disease.

  • Stage pN3 patients have both lymph node metastasis (clinically/radiologically detected and pathologically confirmed) and in-transit disease.

Various factors will determine the most appropriate approach to management of in-transit disease, including a decision on whether the disease is resectable. There is a lack of evidence to direct care in this scenario.

The National Comprehensive Cancer Network (NCCN) recommends multidisciplinary consultation for consideration of:[3]

  • Clinical trial enrollment, if available. Depending on the trial protocol, some standard management steps for MCC might also be required.

  • Surgery and/or radiation therapy.

  • Case-by-case consideration of systemic therapy, according to clinical judgment, if neither curative surgery nor radiation therapy is feasible. In practice, this scenario would generally be managed in the same way as stage IV disease.

The European Society for Medical Oncology (ESMO) guideline recommends surgery and/or radiation therapy or entry into a clinical trial for patients with in-transit disease but recommends against adjuvant chemotherapy.[19]

If surgery and/or radiation therapy rather than systemic therapy is used, the primary tumor and any lymph node disease must also be managed.

  • The primary tumor is managed in the same way as for stage I/II MCC. For details, see the Localized disease patient group.

  • Nodal disease is managed as for pN1b disease. For details, see the With lymph node metastases but no in-transit disease (pN1b) patient group.

Consider – reduction of any immunosuppressive treatment for another condition

Back
ACUTE
|
regional disease: stage IIIB
|
with in-transit disease with or without lymph node metastasis (pN2/pN3)
Consider – 

reduction of any immunosuppressive treatment for another condition

Treatment recommended for SOME patients in selected patient group

For patients who are immunocompromised, it is important to reduce any immunosuppressive treatments as clinically feasible, in consultation with the relevant managing physician.[3][7] More frequent follow-up may be indicated for patients who are immunosuppressed.[3]

  • Immunosuppression in MCC is associated with an increased risk of recurrence and poorer outcomes.[18][27][76][77]​​​​​​​​​

distant metastatic disease: stage IV

1st line – enrollment in clinical trial; immunotherapy or chemotherapy and/or radiation therapy and/or surgery

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ACUTE
|
distant metastatic disease: stage IV
1st line – 

enrollment in clinical trial; immunotherapy or chemotherapy and/or radiation therapy and/or surgery

Local protocols for metastatic MCC vary between countries and institutions, and the management plan for each individual is agreed on a case-by-case basis following discussion among the multidisciplinary team.

For disseminated metastatic MCC (AJCC8 stage IV), multidisciplinary consultation is recommended together with comprehensive imaging.[3][7][29]

The recommended approach to these patients (according to both US and European guidelines) is one of the following:[3][7]​​[19][29]

  • Enrollment in a clinical trial, if available (preferred) or

  • Any one of, or a combination of, the following therapies:

    1. Systemic immunotherapy with a programmed cell death protein-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitor (preferred agents include avelumab, pembrolizumab, nivolumab, and retifanlimab).[3][29]

    2. For patients who have contraindications to immune checkpoint inhibitors, systemic chemotherapy with cisplatin or carboplatin with or without etoposide, topotecan monotherapy, or cyclophosphamide plus doxorubicin (or epirubicin) plus vincristine (CAV) can be considered.[3]

    3. Radiation therapy.

    4. Surgery.

  • Note that systemic therapy and radiation therapy are the primary options in most patients, with surgery reserved for selective circumstances (e.g., for resection of oligometastases or symptomatic lesions).[3]

Depending on the extent of the disease and other individual patient circumstances, palliative care alone may be the most appropriate option for some patients disseminated metastatic MCC. This may include radiation therapy or systemic therapy.

See local specialist protocol for dosing guidelines.

Primary options

avelumab

OR

pembrolizumab

OR

nivolumab

OR

retifanlimab

Secondary options

cisplatin

OR

carboplatin

OR

cisplatin

or

carboplatin

-- AND --

etoposide

OR

topotecan

OR

cyclophosphamide

-- AND --

doxorubicin

or

epirubicin

-- AND --

vincristine

Consider – reduction of any immunosuppressive treatment for another condition

Back
ACUTE
|
distant metastatic disease: stage IV
Consider – 

reduction of any immunosuppressive treatment for another condition

Treatment recommended for SOME patients in selected patient group

For patients who are immunocompromised, it is important to reduce any immunosuppressive treatments as clinically feasible, in consultation with the relevant managing physician.[3][7] More frequent follow-up may be indicated for patients who are immunosuppressed.[3]

  • Immunosuppression in MCC is associated with an increased risk of recurrence and poorer outcomes.[18][27][76][77]​​​​​​​​​

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Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups. See disclaimer

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