Summary of recommendations

This page provides a summary of the recommendations of the completed clinical questions published so far in the Melanoma guidelines. Other sections of the guidelines are currently in progress and will be published iteratively.

For explanation of the different types of recommendations, see NHMRC approved recommendation types and definitions below.

Refer to the Guideline development process for details on the levels of evidence and recommendation grades.

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Identification and management of high-risk individuals

What are the genetic determinants of high risk for new primary melanoma?

Practice point
Clinical genetic testing for CDKN2A mutations and genetic counselling should be considered in individuals with a strong family history of melanoma (3 or more cases related in the first- or second-degree) where predictive features are present, such as multiple primary melanoma, early age of onset, or pancreatic cancer.

Practice point
Detection (genotyping) of melanoma susceptibility SNPs may have a future role in assessing and managing individual risk of melanoma.

What validated models integrate genetic and clinical risk factors into an overall measurement of high risk from new primary melanoma?

Evidence-based recommendation	Grade
Assess all patients for future risk of melanoma, using validated risk factors and a model that integrates personal risk factors into an overall index of risk.	B

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What interventions have been shown to provide clinical benefit in those assessed to be at high risk of new primary melanoma?

Evidence-based recommendation	Grade
Individuals at very high risk of melanoma and their partner or carer should be educated to recognise and document lesions suspicious of melanoma. These individuals should be checked regularly by a clinician with six-monthly full skin examination supported by total body photography and dermoscopy.	C

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Diagnosis

What are the clinical features of melanoma and how do atypical melanomas present?

Practice point

Melanomas are generally distinguished from benign lesions by their history of change and thick melanomas often do not conform to the ‘ABCD’ rule, but are Elevated, Firm and Growing. Therefore, careful history taking is important and any lesion that continues to grow or change in size, shape, colour or elevation over a period of more than one month should be biopsied and assessed histologically or referred for expert opinion.

Practice point
Suspicious raised lesions should be excised and not monitored.

What is the role of dermoscopy in melanoma diagnosis?

Practice point
Dermoscopy can also identify diagnostic features in non-pigmented (amelanotic) lesions.

Evidence-based recommendation	Grade
Clinicians who are performing skin examinations for the purpose of detecting skin cancer should be trained in and use dermoscopy.	A

What is the role of sequential digital dermoscopy imaging in melanoma diagnosis?

Practice point
Only flat or slightly raised lesions should undergo dermoscopy monitoring. Suspicious nodular lesions should not be monitored but should be excised.

Practice point
The interval for short-term monitoring is 3 months where any change leads to excision. Where lentigo maligna is in the differential diagnosis it is recommended an additional 3 months of monitoring performed, i.e. total of 6 months.

Practice point
The usual interval for long-term monitoring is 6-12 months. Unlike short-term monitoring, certain specific changes are required for excision to be indicated.

Evidence-based recommendation	Grade
To assess individual melanocytic lesions of concern, recommend the use of short-term sequential digital dermoscopy imaging (dermoscopy monitoring) to detect melanomas that lack dermoscopic features of melanoma.	B

Evidence-based recommendation	Grade
To assess individual or multiple melanocytic lesions in routine surveillance of high risk patients, recommend the use of long-term sequential digital dermoscopy imaging (dermoscopy monitoring) to detect melanomas that lack dermoscopic features of melanoma.	B

What is the role of automated instruments in melanoma diagnosis?

Evidence-based recommendation	Grade
There is insufficient evidence to recommend the routine use of automated instruments for the clinical diagnosis of primary melanoma. However, particularly when a benign measurement is found using the cited protocols of Nevisense™ and MelaFind™, this information may aid the clinician.	D

What is the role of skin surface imaging (total body photography) in the early diagnosis of patients at high risk of developing melanoma?

Evidence-based recommendation	Grade
Consider the use of total body photography in managing patients at increased risk for melanoma, particularly those with high naevus counts and dysplastic naevi.	C

Practice point
TBP allows monitoring of most of the skin surface, including most existing skin lesions. TBP should be the primary imaging intervention for early melanoma detection in patients at elevated risk who have high naevus counts or multiple dysplastic naevi.

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Biopsy

What type of biopsy should be performed for a pigmented lesion suspicious for melanoma?

Evidence-based recommendation	Grade
The optimal biopsy approach for a suspicious pigmented lesion is complete excision with a 2 mm clinical margin and upper subcutis.	C

Evidence-based recommendation	Grade
Partial biopsies may not be fully representative of the lesion and need to be interpreted with caution and in light of the clinical findings to minimise incorrect false negative diagnoses and understaging.	C

Evidence-based recommendation	Grade
In carefully selected clinical circumstances (such as large in situ lesions, large facial or acral lesions or where the suspicion of melanoma is low) and in the hands of experienced clinicians, partial incisional, punch or shave biopsies may be appropriate.	C

Practice point
It is advisable to discuss unexpected pathology results with the reporting pathologist.

Practice point
Punch biopsy should not be utilised for the routine diagnosis of suspected melanoma because this technique is associated with high rates of histopathological incorrect false negative diagnosis. Where a punch biopsy has been used for the diagnosis of a suspected BCC or SCC, and the diagnosis has been found to be melanocytic, then consideration should be given to excision of the entire lesion.

Practice point
The use of deep shave excision (saucerisation) should be limited to in situ or superficially invasive melanomas to preserve prognostic features and optimise accurate planning of therapy.

What clinical information should the clinician give the pathologist to aid diagnosis of melanoma?

Practice point
It is advisable that as much relevant clinical information (Table 1) as possible be provided to pathologists to aid in the diagnosis of melanoma.

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Management of primary melanoma and lentigo maligna

What are the recommended safety margins for radical excision of a primary melanoma (in situ)?

Evidence-based recommendation

Grade

After initial excision biopsy, the radial excision margins, measured clinically from the edge of the melanoma, should be 5-10 mm (measured with good lighting and magnification) with the aim of achieving complete histological clearance.

Melanoma in situ of non-lentigo maligna type is likely to be completely excised with 5mm margins whereas lentigo maligna may require wider excision. Minimum clearances from all margins should be stated/assessed. Consideration should be given to further excision if necessary; positive histological margins are unacceptable.

D

Practice point
Excisions should have vertical edges to ensure consistent margins.

Practice point
For all melanomas, minimum clearances from all margins should be stated/assessed. When necessary, further excision should be performed in order to achieve the appropriate margin of clearance.

Practice point
Excision biopsy of the complete lesion with a narrow (2mm) margin is appropriate for definitive diagnosis of primary melanoma. Once the diagnosis of melanoma has been made, re-excision of the lesion (biopsy site) should then be performed in order to achieve the definitive, wider margins that are recommended in these guidelines.

Practice point

Depth of excision in usual clinical practice is excision down to but not including the deep fascia unless it is involved or has been reached during the diagnostic excision. For body sites where there is particularly deep subcutis, it is usual practice to excise to a depth equal to the recommended lateral (radial) excision margins for that specific melanoma; in these cases it is not deemed necessary to excise right down to fascia.

Practice point
Where tissue flexibility is limited, a flap repair or skin graft may be necessary subsequent to an adequate margin of removal.

Practice point
Most primary melanomas can be treated as an outpatient under local anaesthesia or as a day-case.

Practice point
Patients should be informed that surgical excision may be followed by wound infection, bleeding, haematoma, failure of the skin graft or flap, risk of numbness, a non-cosmetic scar, dehiscence and the possibility of further surgery.

Practice point

Some tumours may be incompletely excised despite using the above-recommended margins. These include melanomas occurring in severely sun-damaged skin (e.g. LM) and those with difficult-to-define margins (eg amelanotic and desmoplastic melanomas). In these categories, the presence of atypical melanocytes at the margins of excision should be detected by comprehensive histological examination (including immunohistochemical staining) and followed by wider excision as appropriate. Alternatively, staged serial excision (also known as ‘slow Mohs’ surgery) may be utilised to achieve complete histological clearance of melanoma in situ/lentigo maligna. Pre-operative mapping of the extent of some lesions with confocal microscopy may be useful and is available in some centres. Referral to a specialist melanoma centre or discussion in a multidisciplinary meeting should be considered for difficult or complicated cases.

Practice point
Amelanotic melanoma can present significant difficulties for defining a margin with up to one third of subungual and nodular melanomas being non-pigmented. This may dictate choice of a wider margin, or further re-excision, where practicable.

What are the recommended safety margins for radical excision of invasive melanomas?

Evidence-based recommendation	Grade
(pT1) melanoma < 1.0 mm After initial excision biopsy, the radial excision margins, measured clinically from the edge of the melanoma, should be 1 cm. Minimum clearances from all margins should be stated/assessed. Consideration should be given to further excision if necessary; positive histological margins are unacceptable.	B

Evidence-based recommendation	Grade
(pT2) melanoma 1.01 mm–2.00 mm After initial excision biopsy, the radial excision margins, measured clinically from the edge of the melanoma, should be 1–2 cm. Minimum clearances from all margins should be stated/assessed. Consideration should be given to further excision if necessary; positive histological margins are unacceptable.	B

Evidence-based recommendation

Grade

(pT3) melanoma 2.01 mm–4.00 mm
After initial excision biopsy, the radial excision margins, measured clinically from the edge of the melanoma, should be 1–2 cm. Minimum clearances from all margins should be stated/assessed. Consideration should be given to further excision if necessary; positive histological margins are unacceptable.

Caution should be exercised for melanomas 2.01–4.00 mm thick, especially with adverse prognostic factors, because evidence concerning optimal excision margins is unclear. Where possible, it may be desirable to take a wider margin (2 cm) for these tumours depending on the tumour site and characteristics, and prevailing surgeon/patient preferences.

B

Evidence-based recommendation	Grade
(pT4) melanoma > 4.0 mm After initial excision biopsy, the radial excision margins, measured clinically from the edge of the melanoma, should be 2 cm. Minimum clearances from all margins should be stated/assessed. Consideration should be given to further excision if necessary; positive histological margins are unacceptable.	B

Evidence-based recommendation	Grade
Acral lentiginous and subungual melanoma are usually treated with a minimum margin as set out above, where practicable, including partial digital amputation usually incorporating the joint immediately proximal to the melanoma.	D

Evidence-based recommendation	Grade
Excision margins might be modified to accommodate individual anatomic sites or functional considerations, but this practice would be based solely on case-series information, and individual factors, rather than RCT evidence which is currently lacking.	D

Practice point
Excisions should have vertical edges to ensure consistent margins.

Practice point
For all melanomas, minimum clearances from all margins should be stated/assessed. Consideration should be given to further excision if necessary because positive histological margins are unacceptable.

Practice point
Excision biopsy of the complete lesion with a narrow (2mm) margin is appropriate for the definitive diagnosis of primary melanoma. Once the diagnosis of melanoma has been made, re-excision of the lesion (biopsy site) should then be performed in order to achieve the definitive, wider margins that are recommended in these guidelines.

Practice point

Depth of excision in usual clinical practice is excision down to but not including the deep fascia unless it is involved or has been reached during the diagnostic excision. For body sites where there is particularly deep subcutis, it is usual practice to excise to a depth equal to the recommended lateral (radial) excision margins for that specific melanoma; in these cases it is not deemed necessary to excise right down to fascia.

Practice point
Where tissue flexibility is limited, a flap repair or skin graft is often necessary subsequent to an adequate margin of removal.

Practice point
Most primary melanomas can be treated as an outpatient under local anaesthesia or as a day-case.

Practice point
Patients should be informed that surgical excision may be followed by wound infection, bleeding, haematoma, failure of the skin graft or flap, risk of numbness, a non-cosmetic scar, dehiscence and the possibility of further surgery.

Practice point

Some tumours may be incompletely excised despite using the above-recommended margins. These include melanomas occurring in severely sun-damaged skin (e.g. lentigo maligna) and those with difficult-to-define margins (e.g. amelanotic and desmoplastic melanomas). In these categories, the presence of atypical melanocytes at the margins of excision should be detected by comprehensive histological examination (including immunohistochemical staining) and followed by wider excision.

Practice point
Amelanotic melanoma can present significant difficulties for defining a margin with up to one third of subungual and nodular melanomas being non-pigmented. This may dictate choice of a wider margin, or further re-excision, where practicable.

Practice point
For patients with deeper invasive melanomas (> 1 mm thick), referral to a specialised melanoma centre or discussion in a multidisciplinary meeting should be considered to ensure that best practice is implemented and for the collection of national outcome data. This may present logistic difficulties in regional and remote areas, but input from a specialist melanoma centre.

When is sentinel lymph node biopsy (SLNB) indicated?

Evidence-based recommendation	Grade
Sentinel lymph node biopsy should be considered for all patients with melanoma greater than 1 mm in thickness and for patients with melanoma greater than 0.75 mm with other high risk pathological features to provide optimal staging and prognostic information and to maximise management options for patients who are node positive.	B

Practice point
Sentinel lymph node biopsy (SLNB) should be performed at the time of the primary wide excision.

Practice point
Sentinel lymph node biopsy (SLNB) should be performed in a centre with expertise in the procedure, including nuclear medicine, surgery and pathology to optimise the accuracy of the test.

Practice point
Patients being considered for sentinel lymph node biopsy (SLNB) should be given an opportunity to fully discuss the risks and benefits with a clinician who performs this procedure.

Practice point
A consideration of sentinel lymph node biopsy (SLNB) forms an important part of the multidisciplinary management of patients with clinically node negative cutaneous melanoma.

Practice point

Sentinel lymph node biopsy provides accurate staging of the lymph node basin by presenting a high-yield, low volume tissue sample for histopathological assessment. Not surprisingly, there is an increased rate of detection of micrometastatic disease when increasing numbers of sections are evaluated pathologically including when supplemented by immunohistochemistry for melanoma associated antigens. However there is no consensus as to the optimal number of sections that should be examined, the levels at which they should be cut from the paraffin block and which immunostains should be utilised.

Practice point

Sentinel lymph nodes (SLNs) should be removed intact, preferably with a thin rim of surrounding adipose tissue and be devoid of crush or diathermy artefacts that may complicate pathological assessment. The pathology request form should indicate the number of removed SLNs and their anatomical locations and the specimens clearly labelled. Any “second tier” lymph nodes or non-SLNs that have also been removed should be indicated as such on the request form and the specimens clearly labelled. The pathologist should slice the SLN using either the bivalving procedure along its longitudinal axis through the median plane or cut the SLN into multiple transverse slices using the “bread loaf” technique to make available the largest cut surface area of lymph node tissue for pathological examination. To identify low volume metastases, pathologists should examine multiple haematoxylin-eosin and immunohistochemically-stained sections from each SLN. Sections from each slice of all SLNs should be stained with both H&E and immunohistochemistry for melanoma associated antigens. HMB-45, S100, SOX10, Melan A and tyrosinase have all been utilised as immunohistochemical stains. As per AJCC guidelines, in patients with positive SNs, the single largest maximum dimension (measured in millimeters to the nearest 0.1 mm using an ocular micrometer) of the largest discrete metastatic melanoma deposit should be recorded in the pathology report. Routine frozen section examination of SNs from melanoma patients is not recommended.

Should all patients with a positive sentinel lymph node biopsy have a complete node dissection?

Evidence-based recommendation	Grade
CLND is no longer the preferred treatment for patients with a positive SLNB. CLND or active surveillance are equivalent in terms of 3 year melanoma specific survival but CLND is more morbid.	B

Evidence-based recommendation	Grade
CLND offers high levels of immediate regional control for patients with positive SLNB however good regional control can be achieved with delayed CLND.	C

Practice point

To date there is no subgroup of patients for whom immediate CLND is likely to provide a clear benefit, however patients with a high risk of further non-SLN involvement and particularly those who are less likely to suffer significant morbidity from CLND may choose to have the procedure to reduce the risk of lymph node field relapse. A risk calculator for defining the likelihood of non-SLN involvement such as the N-SNORE (Murali et al. 2010) can be of assistance to more accurately estimate the probability of residual non-SN positive nodes.

Practice point
Close clinical and ultrasound surveillance using a protocol equivalent to that followed in MSLT-II and DeCOG-SLT of 3-4 monthly clinical examination and ultrasound of the regional lymph node field for 2 years and then the same at least 6 monthly for a total of 5 years, then annual clinical review is required if a patient with a positive SLNB chooses active surveillance.

What is the optimal management for primary desmoplastic melanomas?

Evidence-based recommendation	Grade
Desmoplastic melanomas and neurotropic melanomas should be excised with the same margins as would be performed on a non-desmoplastic/neurotropic melanoma of the same Breslow thickness.	B

Evidence-based recommendation	Grade
Adjuvant radiotherapy to the primary excision site should be considered for patients with desmoplastic or neurotropic melanoma for whom adequate (≥8mm) pathological resection margins cannot be achieved.	C

Practice point
It is important for all clinicians performing skin checks to be aware of DM and its often subtle clinical presentation.

Practice point
MRI and nerve biopsy should be considered for patients with facial DM located close to named nerves.

What is the role of sentinel node biopsy for desmoplastic melanomas?

Evidence-based recommendation	Grade
SLNB should be considered for patients with DM, as it would be for non-DM. See When is a sentinel node biopsy indicated?	C

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Management of melanoma in children

How should melanoma in children be managed?

Practice point
The pathology slides of all Spitz-like lesions in children suspected of being malignant should be referred to histopathologists who are highly experienced in the differential diagnosis of such lesions.

Practice point
All facets of melanoma treatment and follow-up in adults may be integrated into the treatment and follow-up of children. Parents may be assured that survival in children is at least equivalent and probably better than it is in adults with the same stage of disease.

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Management of melanocytic tumour of unknown malignant potential

The role of sentinel node biopsy in the management of MelTUMPs (melanocytomas)

Evidence-based recommendation	Grade
The routine use of sentinel lymph node biopsy for MelTUMPs is not recommended. In the event of a positive node, its significance should be reviewed by a multidisciplinary melanoma team with expertise in such diagnostic dilemmas.	C

Evidence-based recommendation	Grade
Age should not be used to determine the prognosis of a patient with a MelTUMP.	C

Practice point
It is advisable to have pathologists with expertise in the examination of melanocytic lesions review the tumour slides to confirm or reject a suspected diagnosis of MelTUMP.

Excision margins for patients with MelTUMPs

Practice point
It is advisable to excise MelTUMPs with a 5mm clinical margin and ensure there is at least a 2mm histological margin.

Practice point
It is advisable to follow up patients for at least five years following a diagnosis of MelTUMP, given the uncertainty surrounding the diagnosis. Six-monthly follow-up is advisable for the first 2 years.

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Management of melanoma in pregnancy

Pregnancy following diagnosis of melanoma

Practice point
Regular skin examination should be performed in pregnant women so that suspicious lesions can be dealt with in a timely fashion.

Practice point
Women of childbearing age who are within five years of primary treatment of a high-risk melanoma should be fully informed of their prognosis when considering pregnancy.

Optimal management of pregnant women with melanoma

Evidence-based recommendation	Grade
Where possible, surgical procedures requiring general anaesthesia should be deferred to the second trimester.	B

Evidence-based recommendation	Grade
Where possible, radiotherapy should be postponed until the post partum period unless the tumour is not located near the uterus and appropriate shielding is used.	B

Evidence-based recommendation	Grade
Use of targeted therapies and immunotherapies should be avoided during pregnancy until there is more evidence regarding their safety in this situation.	B

Evidence-based recommendation	Grade
In pregnant women, sentinel node biopsy should be performed without the use of Patent Blue dye.	B

Practice point
The treatment of melanoma during pregnancy should be approached the same way as in other melanoma patients, but needs to take into account the stage of the pregnancy and the stage of the melanoma. These patients should be managed by an expert MDT with input from the obstetrician.

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Investigations and follow-up for melanoma patients

What investigations should be performed following a diagnosis of primary cutaneous melanoma for asymptomatic stage I and stage II patients?

Evidence-based recommendation	Grade
Chest x-ray imaging for initial staging should not be performed	C

Evidence-based recommendation	Grade
CT head, chest, abdomen and pelvis imaging are not recommended for initial staging in asymptomatic patients with stage IIB or IIC melanoma. In addition, there is no evidence to support CT imaging in Stage I and IIA melanoma.	C

Evidence-based recommendation	Grade
CT imaging for initial staging is not recommended for patients with stage I-II melanoma	C

Evidence-based recommendation	Grade
PET/CT imaging for initial staging is not recommended for patients with a thin, or intermediate Breslow thickness primary melanoma (Stage I-IIB).	C

Evidence-based recommendation	Grade
MRI imaging of the head, spine or extremities is not recommended for initial staging in patients with stage I or stage II melanoma.	D

Evidence-based recommendation	Grade
S100B, MIA and LDH or standard blood tests are not recommended at initial staging for diagnosis of metastatic melanoma.	C

Practice point
Low sensitivity, specificity, and accuracy for general laboratory profiles (S100B, MIA, LDH blood tests) make them ineffective in the detection of subclinical recurrence and their roles are yet to be defined.

What investigations should be performed when in-transit and/or regional node disease (stage III melanoma) is diagnosed?

Evidence-based recommendation	Grade
FNB, with or without ultrasound guidance can be used to confirm the diagnosis of lymph node or intransit metastatic melanoma	B

Evidence-based recommendation	Grade
Core biopsy can be used to confirm the diagnosis of lymph node or intransit metastatic melanoma	C

Evidence-based recommendation	Grade
Consider NOT performing PET/CT or CT in newly diagnosed sentinel node positive patients	C

Evidence-based recommendation	Grade
Perform a PET/CT scan for the initial staging of stage III melanoma patients with palpable nodal disease.	B

Evidence-based recommendation	Grade
A brain scan (high resolution CT or MRI) should be added to a PET/CT scan to assess for the presence of brain metastases.	B

Evidence-based recommendation	Grade
Consider using an MRI scan rather than a CT scan to assess for the presence of brain metastases.	B

Practice point
Ultrasound may be used for identification of the extent of intransit and nodal disease, and also used to diagnose liver metastases.

Practice point
Other countries consider performing S100B in stage III patients with palpable nodal disease, but this is not PBS available in Australia.

What investigations should be performed when stage IV melanoma is diagnosed?

Practice point
Serum LDH level should be measured at the time of diagnosis of stage IV melanoma.

Evidence-based recommendation	Grade
Whole body PET scanning or PET/CT is required in patients diagnosed with stage IV melanoma if the result will change management.	A

Evidence-based recommendation	Grade
Brain imaging with contrast enhanced CT or MRI is appropriate in asymptomatic patients diagnosed with stage IV melanoma.	C

Practice point
Documentation of the presence/absence of activating V600 BRAF mutations in tumour tissue is required before commencing systemic therapy for stage IV melanoma.

Follow up after initial definitive treatment for each stage of melanoma

Evidence-based recommendation	Grade
Self-examination is recommended following definitive local treatment for melanoma patients of any stage.	C

Evidence-based recommendation	Grade
History and physical examination by a patient’s preferred medical practitioner should be undertaken for the detection of early, treatable recurrence following definitive treatment of stage I to stage III melanoma.	C

Evidence-based recommendation	Grade
Routine blood or radiological investigations are not recommended for the follow-up of asymptomatic stage I to stage IIB melanoma patients after definitive local treatment.	C

Evidence-based recommendation	Grade
Routine radiological investigations every 3-12 months may be considered for the first three years of follow up after definitive local treatment of stage IIC and III melanoma where detection of recurrence would allow early commencement of systemic therapy. However, there are currently no high-quality data that early detection and treatment of recurrence improves survival.	C

Practice point
Skin self-examination by patients is essential and they should be taught the process. Routine follow-up by the patient’s preferred health professional may be appropriate to emphasise sun smart behaviour and perform skin checks, especially in ‘hard to see’ areas.

Practice point
Routine radiological imaging PET/CT or CT may be considered for patients with stage IIC or III melanoma for the early detection of recurrence, particularly in the context of a clinical trial. However, patients should be counselled regarding the potential risks of false positives, anxiety, and the risks of radiation including thyroid cancer and cataracts.

Ideal settings, duration and frequency of follow-up for patients with melanoma

Evidence-based recommendation	Grade
Routine follow-up by the patient’s preferred doctor may be appropriate to emphasise sun smart behaviour and perform skin checks.	C

Practice point
It may be beneficial for medical professionals conducting follow up examinations for melanoma patients to be familiar with skin examination and dermatoscopy.

Evidence-based recommendation	Grade
Risk adjusted follow up looking for recurrence based on stage at presentation should be considered over a time period of 5-10 years for stages I-II melanoma. For surgically resected stage III melanoma, the most intensive follow up should be for the first 3 years.	C

Evidence-based recommendation	Grade
Melanoma survivors should be made aware of their risk of developing further primary melanomas, and of the consequent need for careful lifelong skin surveillance.	C

Evidence-based recommendation	Grade
Follow-up intervals: Stage I: follow-up annually for 10 years Stage IIA: every 6 months for 2 years, then annually for 8 years Stage IIB and IIC: every 3 to 4 months for 2 years, every 6 months during year 3, then annually for 5 years. Stage IIIA-C: every 3 months for 2 years, every 6 months during year 3, then annually for 5 years.	C

Evidence-based recommendation	Grade
While it is important that clinicians weigh up the advantages and disadvantages of undertaking routine follow-up, individual patient’s needs should be considered before appropriate follow-up is offered.	C

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Satellite and in-transit metastases

What are the most effective treatments of satellite and in-transit metastases?

Evidence-based recommendation	Grade
Sentinel node biopsy provides important prognostic information and should be performed if surgical excision of in-transit recurrence is planned.	C

Evidence-based recommendation	Grade
Limited disease may be treated with topical diphencyprone otherwise isolated limb infusion may be appropriate.	C

Evidence-based recommendation	Grade
Isolated limb infusion is preferred to isolated limb perfusion despite slightly reduced effectiveness because of less frequent and less severe toxicity and reduced resource utilisation.	C

Practice point
The role of surgery has not been evaluated prospectively but supported by limited poor quality retrospective evidence and current practice surgical excision of limited disease is appropriate. Repeat excision is appropriate for patients with limited disease.

Practice point
Radiotherapy is particularly valuable for palliation of larger symptomatic lesions.

Practice point
For patients with extensive, recurrent or progressive disease, systemic therapy (targeted and immune-therapies) is appropriate. Patients should be considered for trials. See Systemic therapy for stage 3C unresectable and stage 4 melanoma

Practice point
Sentinel node biopsy provides important prognostic information and should be considered for patients presenting with in-transit metastases who are to undergo complete surgical excision.

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Macroscopic nodal metastases

What is the appropriate treatment of macroscopic (i.e. detectable clinically or by ultrasound) nodal metastases?

Practice point
Patients with macroscopic nodal disease should have the diagnosis confirmed preoperatively by image guided fine needle aspiration cytology and undergo staging with whole body PET-CT and MRI brain or CT Brain, Chest Abdomen and Pelvis.

Practice point
Patients with a parotid lymph node recurrence should undergo a superficial parotidectomy and upper neck dissection (levels 1B, 2, 3, and upper 5 and possibly 1a).

Evidence-based recommendation	Grade
Complete lymphadenectomy is recommended for patients with palpable or imaging detected lymph node field recurrence.	C

Practice point
Complete lymphadenectomy results in improved regional control over lesser procedures.

Practice point
All patients with Stage III B/C disease should be presented at a multidisciplinary management meeting.

Practice point
These high risk patients should be offered the opportunity to enrol in systemic adjuvant or neoadjuvant therapy trials.

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Surgical therapy for patients with distant metastases

Recommended surgical approach to brain metastases in patients with advanced melanoma

Practice point
Brain metastases that are symptomatic or generate mass effect at presentation are best treated with surgery, which results in rapid relief of symptoms and maintenance of functional independence.

Practice point
Surgical resection of brain metastases provides safe, durable local disease control. The use of the operating microscope, neuro navigation and an en bloc resection technique are recommended. The integration of surgery with systemic therapy and radiotherapy should be discussed by a multidisciplinary team.

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Treatment approaches to brain metastases for patients with melanoma

Systemic drug therapy in the management of patients with advanced melanoma brain metastases

Practice point
Systemic drug therapy is effective in untreated melanoma brain metastases and can be considered as first-line treatment (as an alternative to local brain therapy) in asymptomatic patients, with multidisciplinary support from a radiation oncologist and a neurosurgeon.

Recommended surgical approach to brain metastases in patients with advanced melanoma

Practice point
Brain metastases that are symptomatic or generate mass effect at presentation are best treated with surgery, which results in rapid relief of symptoms and maintenance of functional independence.

Practice point
Surgical resection of brain metastases provides safe, durable local disease control. The use of the operating microscope, neuro navigation and an en bloc resection technique are recommended. The integration of surgery with systemic therapy and radiotherapy should be discussed by a multidisciplinary team.

For patients with distant metastases (other than brain metastases), when is radiotherapy indicated?

Evidence-based recommendation	Grade
Stereotactic radiosurgery (SRS) should be considered for patients with single or a small number of brain metastases to maximise local control.	C

Evidence-based recommendation	Grade
For patients with multiple brain metastases, whole brain radiation therapy may provide some palliative benefits.	C

Practice point
All melanoma patients with distant metastases should be reviewed at a multidisciplinary team meeting to ensure optimal drug, surgery and RT treatment combination.

Practice point
Patients with single or a small number of brain metastases should be given the opportunity to discuss adjuvant radiotherapy to the surgical cavity and/or the whole brain.

Practice point
Patients with painful bone metastasis should be considered for short course of RT for pain relief.

Practice point
RT should be considered in patients with problematic skin, soft tissue or nodal metastasis that have not responded to systemic therapy.

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Systemic therapy

What is the role of adjuvant systemic therapy in patients with resected stage II and stage III melanoma?

Evidence-based recommendation	Grade
All patients with resected stage III melanoma should discuss the benefits, potential toxicities and out-of-pocket costs of adjuvant systemic therapy with an experienced melanoma medical oncologist who is part of a multidisciplinary melanoma team, including the role of clinical trials.	C

Evidence-based recommendation	Grade
Patients with BRAF V600E/K resected stage III melanoma may be considered for 12 months adjuvant treatment with combination dabrafenib/trametinib. Note: Adjuvant dabrafenib/trametinib is not TGA approved or PBS listed	B

Evidence-based recommendation	Grade
Patients with resected stage IIIB/C or IV melanoma may be considered for 12 months adjuvant treatment with nivolumab. Note: Adjuvant nivolumab is not PBS funded.	B

Evidence-based recommendation	Grade
Patients with resected stage III melanoma may be considered for 12 months adjuvant treatment with pembrolizumab. Note: Adjuvant pembrolizumab is not TGA approved or PBS funded.	B

Evidence-based recommendation	Grade
Patients for whom adjuvant nivolumab, pembrolizumab or dabrafenib/trametinib is not appropriate or is not available, routine follow-up may be appropriate. Patients may consider treatment with IFN-α after discussion with a medical oncologist regarding the associated toxicity and potential benefit.	B

Evidence-based recommendation	Grade
Ipilimumab is not recommended because it has inferior efficacy and greater toxicity than nivolumab.	B

Evidence-based recommendation	Grade
Outside of a clinical trial adjuvant systemic therapy is not recommended for patients with resected stage II melanoma.	C

Practice point
Patients should be treated in a medical oncology facility with a melanoma multidisciplinary team and experience in using immunotherapy and BRAF/MEK inhibitors.

Practice point
At present neither dabrafenib/trametinib or pembrolizumab are TGA approved for adjuvant therapy and neither dabrafenib/trametinib, nivolumab or pembrolizumab are PBS funded. As such, enrolment in a clinical trial should be discussed.

Practice point
There are no data comparing combination dabrafenib/trametinib and nivolumab/pembrolizumab in patients whose tumours are BRAF V600 mutant, as such individual patient discussions are required for patients whose tumours are BRAF mutant.

Practice point
For those with stage III melanoma not able to receive dabrafenib/trametinib, nivolumab or pembrolizumab (or a clinical trial), interferon may be considered, but given the minimal overall survival benefit and significant toxicity, routine follow-up is usually preferred. See How should patients at each stage of melanoma be followed after initial definitive treatment?

Summary of recommendations and practice points: Immunotherapy for melanoma

Evidence-based recommendation	Grade
Anti-PD-1 based immunotherapy should be considered for the first-line/upfront drug treatment for patients with unresectable stage III/IV melanoma.	B

Evidence-based recommendation	Grade
A BRAF inhibitor combined with a MEK inhibitor should be considered as first-line/upfront drug treatment for patients with V600 BRAF mutation positive melanoma.	B

Consensus-based recommendation
Consensus Statement: Anti-PD-1 based therapies versus combination BRAF inhibitor plus MEK inhibitor have not been compared head to head, see Practice Points 6, 7 and 10.

Practice point
Practice point 1 All patients with unresectable stage III/IV metastatic melanoma (especially patients with brain metastases) should be discussed at a multidisciplinary team meeting, and managed by medical oncologists who have expertise using targeted and immune therapies.

Practice point
Practice point 2 Clinical trials should be considered for all patients with unresectable stage III/IV metastatic melanoma.

Practice point
Practice point 3 All patients with unresectable stage III/IV metastatic melanoma should have molecular testing of their melanoma for the V600 BRAF mutation, including V600E, V600K, V600R, V600D and V600M. Methodology should be used to detect appropriate mutations and be performed in an accredited laboratory using appropriate controls.

Practice point
Practice point 4 Baseline PD-L1 expression on melanoma cells should not be used to select patients for anti-PD-1 therapy due to its low predictive value.

Practice point
Practice point 5 Drug therapy is active in untreated melanoma brain metastases, and can be considered as first-line treatment (as an alternative to local brain therapy) in asymptomatic patients with multidisciplinary support with a radiation oncologist and neurosurgeon. See the Brain metastases section.

Practice point

Practice point 6 Cross phase III trial comparisons of landmark survival analyses (progression-free and overall survival) suggest that more durable responses and possibly higher long-term landmark survival values may be achieved with anti-PD-1-based therapy compared with combined BRAF inhibitor and MEK inhibitor in the first-line setting.^

^Check PBS guidelines before prescribing any drug.

Practice point
Practice point 7 Anti-PD-1-based therapy should be administered as first-line therapy as opposed to following BRAF inhibitor-based therapy.

Practice point
Practice point 8 While not formally compared, there is no suggestion that there is a difference in efficacy or toxicity between pembrolizumab and nivolumab.

Practice point
Practice point 9 While not formally compared, there is no suggestion that there is a difference in efficacy between dabrafenib/trametinib, vemurafenib/cobimetinib or encorafenib/binimetinib combinations, but toxicity profiles are distinct.

Practice point

Practice point 10 The combination of ipilimumab and nivolumab causes immune-related side effects, inducing grade 3/4 drug-related toxicities in 59% of patients, including asymptomatic laboratory abnormalities. Disease factors that may be considered in the selection of patients for this combination regimen include: rapidly progressive melanoma, baseline serum lactate dehydrogenase (LDH) > upper limit of normal, mucosal melanoma, active brain metastases, BRAF mutation-positive melanoma and low PDL-1 expression on melanoma cells (assay as per CheckMate 067).

Practice point
Practice point 11 Ipilimumab (anti-CTLA-4 immunotherapy), alone or in combination with anti-PD-1 may be administered following progression on anti-PD-1 monotherapy.

Practice point

Practice point 12 Any patient on immunotherapy can develop an auto-immune toxicity directed of any organ (and this risk must be discussed with the patient), The common toxicities are fatigue, rash, itch, diarrhoea, thyroiditis and hepatitis. Although a rare toxicity, it is important to note hypophysitis (inflammation of the pituitary gland) with subsequent hypopituitarism may occur, especially in regimens containing anti-CTLA-4 (e.g. ipilimumab).

Practice point
Practice point 13 Anti-PD-1 monotherapy may be administered in selected patients with auto-immune diseases with careful monitoring and after discussion with the patient and relevant clinicians regarding the risk of a flare of the auto-immune disease, planned treatment of the flare, and risk of death from auto-immune disease or melanoma.

Practice point
Practice point 14 Toxicity to one class of checkpoint inhibitor (e.g. anti-CTLA-4, ipilimumab) does not preclude use of a separate class of checkpoint inhibitor (e.g. anti-PD-1).

Practice point
Practice point 15 BRAF inhibitor monotherapy is not a recommended alternative to BRAF inhibitor combined with MEK inhibitor. Absolute contraindications to MEK inhibitors are rare, and single agent BRAF inhibitors are inferior to the combination in both efficacy and toxicity.

Practice point
Practice point 16 Patients with serum lactate dehydrogenase >2 x upper limit of normal at baseline have shorter progression-free and overall survival for both immune and targeted therapies, thus patients should be appropriately followed up and counselled.

Practice point
Practice point 17 Chemotherapy and binimetinib (for NRAS mutant melanoma) can be considered only after progression on immune checkpoint and BRAF inhibitor-based therapy, if appropriate.

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Radiotherapy

For patients with distant metastases (other than brain metastases), when is radiotherapy indicated?

Evidence-based recommendation	Grade
Stereotactic radiosurgery (SRS) should be considered for patients with single or a small number of brain metastases to maximise local control.	C

Evidence-based recommendation	Grade
For patients with multiple brain metastases, whole brain radiation therapy may provide some palliative benefits.	C

Practice point
All melanoma patients with distant metastases should be reviewed at a multidisciplinary team meeting to ensure optimal drug, surgery and RT treatment combination.

Practice point
Patients with single or a small number of brain metastases should be given the opportunity to discuss adjuvant radiotherapy to the surgical cavity and/or the whole brain.

Practice point
Patients with painful bone metastasis should be considered for short course of RT for pain relief.

Practice point
RT should be considered in patients with problematic skin, soft tissue or nodal metastasis that have not responded to systemic therapy.

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Management of mucosal melanoma

Mucosal melanoma

Practice point
The primary lesion for melanoma of the anorectal region should be managed by sphincter preserving complete local excision in most cases. Abdominoperineal resection is indicated only for patients with loco-regional disease whose primary tumour cannot be resected by a limited procedure.

Practice point
The routine use of sentinel node biopsy is not recommended.

Practice point
Adjuvant or post-operative radiotherapy after wide local excision may be considered particularly for patients with close/involved margins.

Practice point
The care of patients with anorectal melanoma should be undertaken by a multidisciplinary team experienced in the management of these patients.

Practice point
Patients with mucosal melanoma of the head and neck are best managed by complete surgical excision. Adjuvant radiotherapy should be considered particularly for patients with close and or involved margins after surgical resection.

Practice point
Patients to be referred to a specialist unit with experience in head and neck melanoma.

Practice point
Radical resection can be considered in patients with limited disease.

Practice point
Wide excision is recommended rather than penectomy for melanoma of the glans penis, skin of penis and scrotum.

Practice point
The role of SNB is not established for melanoma of the glans penis, skin of penis and scrotum.

Practice point
Histologically confirmed melanoma of the vulva can be managed by wide excision with limited margins (1–2cm). Extensive lesions particularly those centrally located may require extensive/exenterative procedures. In the absence of proven regional lymph node spread lymphadenectomy is not indicated.

Practice point
Patients with vulval melanoma be referred to a specialist unit with expertise.

Practice point
Any suspicious lesions of the genital tract should be biopsied.

Practice point
As there is a high incidence of systemic disease in these cases, a CT or PET scan is indicated prior to radical surgery.

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Management of ocular melanoma

Ocular melanoma

Evidence-based recommendation	Grade
Ocular melanoma is a complex and uncommon form of melanoma that should be managed in specialised units where multidisciplinary ocular cancer services are available.	C

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Multidisciplinary care of melanoma patients

Multidisciplinary care in the management of melanoma

Recommendation	Grade
Multidisciplinary care should be considered in the management of all patients with stage III and stage IV melanoma.	C

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This guideline includes evidence-based recommendations (EBR), consensus-based recommendations (CBR) and practice points (PP) as defined in the table below. Recommendations and practice points were developed by working party members and sub-committee members.

Each EBR was assigned a grade by the expert working group, taking into account the volume, consistency, generalisability, applicability and clinical impact of the body of evidence according to NHMRC Level and Grades for Recommendations for Guidelines Developers.^[1]

NHMRC approved recommendation types and definitions

Type of recommendation	Definition
Evidence-based recommendation	A recommendation formulated after a systematic review of the evidence, indicating supporting references
Consensus-based recommendation	A recommendation formulated in the absence of quality evidence, after a systematic review of the evidence was conducted and failed to identify admissible evidence on the clinical question
Practice point	A recommendation on a subject that is outside the scope of the search strategy for the systematic review, based on expert opinion and formulated by a consensus process

Source: National Health and Medical Research Council. Procedures and requirements for meeting the NHMRC standard for clinical practice guidelines. Melbourne: National Health and Medical Research Council, 2011

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References

↑ National Health and Medical Research Council. NHMRC levels of evidence and grades for recommendations for guideline developers. Canberra: National Health and Medical Research Council; 2009 Available from: https://www.nhmrc.gov.au/_files_nhmrc/file/guidelines/developers/nhmrc_levels_grades_evidence_120423.pdf.

[Citation:National_Health_and_Medical_Research_Council._2009-1] National Health and Medical Research Council. NHMRC levels of evidence and grades for recommendations for guideline developers. Canberra: National Health and Medical Research Council; 2009 Available from: https://www.nhmrc.gov.au/_files_nhmrc/file/guidelines/developers/nhmrc_levels_grades_evidence_120423.pdf.

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