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

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

1st line – surgical wide local excision ± radiotherapy to tumour bed

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

surgical wide local excision ± radiotherapy to tumour 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 localised 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 tumour 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 tumour ± radiotherapy

First-line treatment for the primary MCC tumour 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.

In the US, 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 radiotherapy 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 radiotherapy. Relevant risk factors include: tumour size (primary tumour >1 cm); immunosuppressed state (chronic T-cell immunosuppression, HIV, chronic lymphocytic leukaemia (CLL), solid organ transplant); tumour location (head/neck primary site); presence of lymphovascular invasion (LVI).

  • If adjuvant radiotherapy is indicated, this should be initiated as soon as wound healing permits.[3] A delay > 8 weeks in starting radiotherapy has been associated with worse outcomes.[74]​​

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 radiotherapy may be acceptable.[7][19]

  • Adjuvant radiotherapy to the tumour bed is recommended for tumours ≥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]

Note that in many Australian centres, radiotherapy is used as the primary modality after histopathological diagnosis.[38][73]​​​​​​​

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
|
localised 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 localised 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 tumour.[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.

Note that false-negative SLNBs may be seen in patients with profound immunosuppression, or in those who have anatomical compromise of the lymphatic system, such as those with aberrant lymph node drainage or multiple possible draining SLN basins (e.g., in MCC of the head, neck, or midline trunk).[19]

  • Because of this, the European Society for Medical Oncology (ESMO) guideline recommends consideration of adjuvant radiotherapy to the nodal basin for patients who are SLN-negative but who have one or more of these risk factors for a false-negative result. This decision should be made by specialists at a high-volume referral centre.

Consider – reduction of any immunosuppressive treatment for another condition

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

reduction of any immunosuppressive treatment for another condition

Additional 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][71][72]​​​​​​​​​

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

Back
ACUTE
|
localised disease: stage I or II (T-any cN0 M0)
|
curative surgery/curative radiotherapy 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 radiotherapy are not feasible due to tumour characteristics or comorbidities, multidisciplinary consultation should inform management.[3][7][29]

  • In patients who are candidates for surgery, neoadjuvant therapy with a programmed cell death protein-1 (PD-1) inhibitor such as nivolumab may be considered prior to excision and SLNB.[3][19]

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

  • Note that practice varies between countries, so check your local protocol. In the UK, the National Institute for Health and Care Excellence (NICE) has not recommended any checkpoint inhibitors for use in non-metastatic MCC.

See local specialist protocol for dosing guidelines.

Primary options

nivolumab

Consider – reduction of any immunosuppressive treatment for another condition

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

reduction of any immunosuppressive treatment for another condition

Additional 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][71][72]​​​​​​​​​

1st line – radiotherapy

Back
ACUTE
|
localised disease: stage I or II (T-any cN0 M0)
|
curative surgery/curative radiotherapy not feasible and non-surgical candidate
1st line – 

radiotherapy

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 radiotherapy are not feasible and who are non-surgical candidates (due to tumour characteristics and/or comorbidities), multidisciplinary consultation should inform management.[3][7][29]

  • The tumour may be treated with radiotherapy.[3][19][29]

Consider – reduction of any immunosuppressive treatment for another condition

Back
ACUTE
|
localised disease: stage I or II (T-any cN0 M0)
|
curative surgery/curative radiotherapy not feasible and non-surgical candidate
Consider – 

reduction of any immunosuppressive treatment for another condition

Additional 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][71][72]​​​​​​​​​

regional disease: stage IIIA

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

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

radiotherapy 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 tumour will already have been resected, together with consideration of adjuvant radiotherapy to the primary site. See the Localised disease patient group for details.

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

  • Radiotherapy to the nodal basin or

  • Lymph node dissection, which can be combined with adjuvant radiotherapy 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 radiotherapy 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

Additional 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][71][72]​​​​​​​​​

regional disease: unknown primary tumour with clinically apparent nodal disease

1st line – lymph node dissection ± radiotherapy

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

lymph node dissection ± radiotherapy

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 tumour.

  • 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 tumour with clinically apparent nodal disease
Consider – 

reduction of any immunosuppressive treatment for another condition

Additional 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][71][72]​​​​​​​​​

regional disease: stage IIIB

1st line – lymph node dissection and radiotherapy 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 radiotherapy 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) in the US recommends:[3]

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

  • Clinical trial enrolment, 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 radiotherapy (or definitive radiotherapy 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 radiotherapy 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 tumour ± radiotherapy to primary tumour

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

surgical wide local excision of primary tumour ± radiotherapy to primary tumour

Treatment recommended for ALL patients in selected patient group

In patients with stage IIIB MCC, the primary tumour is managed in the same way as for localised disease, with surgical wide local excision to remove the lesion with histologically clear margins and consideration of adjuvant radiotherapy. For details, see the Localised 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

Additional 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][71][72]​​​​​​​​​

1st line – enrolment in clinical trial, surgery and/or radiotherapy, or systemic therapy

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

enrolment in clinical trial, surgery and/or radiotherapy, 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 US National Comprehensive Cancer Network (NCCN) recommends multidisciplinary consultation for consideration of:[3]

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

  • Surgery and/or radiotherapy.

  • Case-by-case consideration of systemic therapy, according to clinical judgement, if neither curative surgery nor radiotherapy 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 radiotherapy or entry into a clinical trial for patients with in-transit disease but recommends against adjuvant chemotherapy.[19]

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

  • The primary tumour is managed in the same way as for stage I/II MCC. For details, see the Localised 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

Additional 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][71][72]​​​​​​​​​

distant metastatic disease: stage IV

1st line – enrolment in clinical trial; immunotherapy or chemotherapy and/or radiotherapy and/or surgery

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

enrolment in clinical trial; immunotherapy or chemotherapy and/or radiotherapy 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]​ Patients should receive treatment in centres that specialise in rare skin cancers and have access to clinical trials.[19]

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

  • Enrolment 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]​​​ The European Society for Medical Oncology (ESMO) guideline lists immunotherapy as a first-line option alongside enrolment in a clinical trial.[19] Note that in the UK, only avelumab is recommended for use in metastatic MCC by the National Institute for Health and Care Excellence (NICE).[75]

    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. Radiotherapy.

    4. Surgery.

  • Note that systemic therapy and radiotherapy 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

Additional 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][71][72]​​​​​​​​​

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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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