Cutaneous melanoma

Introduction

1. Cutaneous melanoma is a malignancy of the melanocytes, or pigment-producing cells of the skin. It can range from a relatively innocuous lesion to high burden metastatic disease representing an acute risk to health and life. The Alliance is a leading provider of expertise and experience in the management of melanoma.

2. Alliance guidelines are based on extensive network experience, scientific literature review and conference attendance, local patterns of practice and the 2022 update to NICE guideline [NG14]. Where there is significant variance to NICE recommendations, this is highlighted with an asterisk. 

3. A melanoma care pathway diagram has previously been prepared.

Initial management

Suspected melanoma and first phase management

1. Excision in primary care should be avoided. Two week rule referral forms are available for each Trust. Please consider discussing cases with dermatology prior to two-week rule referral. Criteria for referral, including the weighted checkpoint list, are given in a NICE Clinical Knowledge Summary.

2. Suspicious lesions may be assessed for the first time in secondary care or identified during follow-up. 

3. Lesions should be assessed by dermoscopy carried out by healthcare professional trained in this technique.

4. For a clinically atypical lesion that does not need excision at first presentation, use baseline photography (preferably dermoscopic) and review the clinical appearance after three months.

5. Discuss all suspected atypical spitzoid lesions at the SSMDT meeting. Manage a spitzoid lesion of uncertain malignant potential as a melanoma.

6. Where melanoma is clinically suspected, an excision biopsy should be taken ensuring a 2 - 5 mm clinical margin of normal skin with a cuff of subdermal fat. Narrow margin excision allows for the assessment of the entire lesion, without compromising subsequent surgery and sentinel node mapping. Full thickness incisional biopsy is occasionally acceptable for large lesions and should target the clinically or dermscopically most suspicious area with further mapping biopsies. Shave and punch biopsies are not recommended in suspected melanoma.

7. Excision should take place on the day of presentation where possible.

8. A full skin check and examination of the draining nodal basins should take place.

9. If clinically apparent pathologic lymphadenopathy is present, this should be evaluated by ultrasound and, if indicated, fine needle aspiration cytology.

First phase histopathology and MDT review

1. Pathology departments will adhere to guidelines on specimen handling and reporting as described in the Royal College of Pathology Minimum Data Set (MDS) for melanoma.

2. RSH clinicians are encouraged to use a dedicated form for submission of samples to histopathology.

3. pT1a lesions should be registered at the LSMDT but formal discussion is not required.

4. pT1b disease and above should be submitted for discussion at the SSMDT meeting. Histopathology will be reviewed by the specialist skin pathologist (Professor Martin Cook and Dr Thiagarajah Balamurugan). A further investigation and management plan will be agreed.

5. Patients should be informed within 28 days of diagnosis and CNS support should be made available.

Definitive management: principles and overview

Wide local excision (WLE)

1. Almost all cases of invasive disease will require wider excision after initial excision biopsy. The clinical margin should be around the biopsy scar and take into account the primary melanoma margin.

2. In general terms, the target clinical margin is:

• 1 cm when excising stage I (T1a - T2a) melanoma, or when a 2 cm margin would cause unacceptable disfigurement or morbidity

• 2 cm when excising stage II (T2b+) melanoma

Sentinel lymph node biopsy (SLNB)

1. SLNB is performed under ARSAC licences at RSH and FPH. Experienced clinicians are Farrokh Pakzad, Elizabeth Clayton, Carrie Newlands, Ben Gurney, James Sloane, Raouf Daoud and Kuen Chin.

2. Clinicians are encouraged to use the Melanoma Institute of Australia sentinel node metastasis risk calculator to guide the discussion with the patient.

3. SLNB should be performed within 12 hours of lymphoscintigraphy.

4. Advantages and disadvantages of SLNB are given in NICE NG14. Decisions regarding SLNB will also rest on the patient's overall potential for benefit from adjuvant oncological therapy. In patients with limited life expectancy, significant comorbidity or predisposition to adverse effects from oncological therapy, the value of SLNB is diminished; this should be addressed in the SSMDT meeting prior to the procedure. 

5. Where it is possible that sentinel nodes will map to both neck and infraclavicular sites, the procedure should be coordinated so that both head and neck and systemic skin surgeons are in attendance for lymph node sampling.

6. Sentinel node lymphoscintigraphy protocols are maintained by the departments of Nuclear Medicine. A specimen is given below.

20 – 40 MBq technetium -99 nanoncolloid injected intradermally around excision site. Dynamic series (over 30 minutes) to identify primary lymphatic tracks (head & neck / lower limbs), static delayed imaging at 1 hours post injection (standard protocol), high count static images of sentinel nodes, survey of limb/trunk to look for aberrant sentinel nodes, Co-57 flood source views, depth estimation of sentinel nodes, sites of sentinel nodes marked on overlying skin in shortest skin-node projection. Use of SPECT/CT recommended for anatomically difficult sites (e.g. head and neck / pelvic side wall). System for marking scar and the sentinel nodes agreed with surgical team and reporting pathologists. 

7. Sentinel lymph node evaluation is performed according to the EORTC protocol, which was led by Professor Martin Cook.

Molecular pathology

1. The 2022 update to the NICE guidelines suggests that BRAF testing should be considered in patients with stage IIA or IIB melanoma, and definitely performed in patients with stage IIC or above. The Alliance strongly supports early BRAF and NRAS testing in all eligible patients to guide prognostication and, with respect to BRAF, lodge information of high therapeutic value in case of future acute disease relapse.

2. NICE guidance advises immunohistochemistry as the first test for BRAF V600E. The NICE committee rationale for IHC has been reviewed. Alliance practice remains to use up-front targeted sequencing.* 

3. Centres are encouraged to use the molecular pathology service at the Royal Surrey Hospital NHS Foundation Trust for speed and consistency.

4. For metastatic disease, if secondary melanoma tissue is available, both* the secondary tissue and potential primary tissue should be submitted for triple panel testing. If there is clinical urgency and/or tissue is not readily available for testing, BRAF mutation may be sought in circulating tumour DNA (ctDNA).*

5. Secondary tissue should be molecularly tested in cases of more than one potential primary melanoma. In some cases, molecular and morphologic concordance will help establish the likely site of origin.

6. In patients who have previously been diagnosed with BRAF non-mutant, NRAS non-mutant disease, but in whom other systemic therapies have been exhausted, clinicians should consider repeat BRAF testing on ctDNA or new biopsy tissue*.

Radiological assessments

1. NICE guidance is for staging scans of brain and body ordinarily to be with contrast-enhanced CT. Alliance practice has been for staging and surveillance scans to consist of contrast-enhanced MRI of the brain and PETCT of the whole body.* MRI of the brain has sufficient resolution for detection of small metastases, clinically relevant because disease is much more likely to be radically treatable at this stage. Whole body PETCT allows detection of metabolically active disease that would otherwise be missed by CT, and always includes limbs, with relevance for potential in transit disease. However it is recognised that this approach incurs significantly greater resource usage and burden of travel for patients, and surveillance imaging practice is currently left as a matter of discussion between clinician and patient, taking all individual factors into account.

2. NICE guidance suggests that whole body and brain MRI should be considered in preference in children and young adults (up to 24 years), and pregnant women. This is not currently available in the NHS locally* but is planned to be developed after the installation of new MRI machines at RSH in late 2022.

Classic and alternative presentations

1. Patients may present alternatively with established stage III or stage IV disease, or progress after initial definitive management.

2. Management by stage and type of disease is summarised by below.

Surgical domain

Stage 0-IA (Tis-T1a) melanoma and premalignant lesions

1. Surgery is the treatment of choice. A policy for marginal excision was agreed at the Tumour Group meeting of September 2021 and is given below. At the network meeting of 5 Oct 2023 it was agreed that there should be a general bias towards avoiding further surgery for premalignant lesions. 

2. Topical imiquimod can be considered especially for lentigo maligna, in adults, if surgery to remove the entire lesion with a 5 mm clinical margin would lead to unacceptable disfigurement or morbidity. Consider a repeat biopsy after topical imiquimod to check whether it has been effective. This remains an off-licence use of imiquimod. Dr Kate Fife presented the Cambridge experience and protocol at the BSDS meeting of September 2023. An 85.7% clearance rate was described. It was found to be necessary to induce 6-8 weeks of inflammation for the treatment to be effective. Four-weekly reviews are required for appropriate assessment of response and treatment adjustment. Whilst historically regional practice has been to limit treatment to 6-12 weeks, it was recommended to prolong courses to achieve appropriate inflammation. Treatment can be repeated multiple times. A suggested regimen was as follows:

   1. Commence imiquimod five days per week for the first four weeks.

   2. Review at four weeks. If inflammation achieved, continue. If no inflammation, increase to daily application for four weeks.

   3. Review at further four weeks. If ongoing inflammation, continue. If no inflammation, add occlusive dressing tosite.

   4. Review at further four weeks. If ongoing inflammation, continue. If no inflammation, add 0.1% retinoid eg Adapalene.

   5. Discontine once 6-8 weeks of inflammation achieved.

3. Radiotherapy* may also be considered for lentigo maligna, with an anticipated control rate of 70-100%.

Stage IB (T1b-T2a N0) melanoma

1. Wide local excision should take place with a target histologic margin of 1 cm.

2. Sentinel lymph node biopsy should be considered in melanoma with a Breslow thickness of 0.8 mm to 1.0 mm and at least one of the following features:

• ulceration

• lymphovascular invasion

• mitoses 2/mm^2 or more.

3. Sentinel lymph node biopsy should be considered in pT2a melanoma.

Stage IIA-IIC (T2b-T4b N0) melanoma

1. Wide local excision should take place with a target histologic margin of 2 cm.

2. Sentinel lymph node biopsy should be offered.

3. Radiological staging should be offered to patients with stage IIB (T3b) melanoma or above.

Second phase histopathology and MDT review

1. Wide local excision and sentinel lymph node biopsy specimens are evaluated by the SSMDT pathologist.

2. Cases of T1b - T3a melanoma with negative wide local excisions and sentinel lymph node biopsies may be listed at the SSMDT for tabling only.

3. Cases of T3b - T4b N0 melanoma are eligible for adjuvant therapy and should be listed for full SSDT discussion.

Stage IIB-IIC melanoma post negative sentinel lymph node biopsy

1. Patients with stage IIB-IIC melanoma are eligible for adjuvant immunotherapy with pembrolizumab.* The full NICE technology appraisal is expected to be published on 26 Oct 2022.

2. Pembrolizumab 200mg IV three-weekly is associated with an improvement in both any recurrence, and an distant metastasis-free survival, of about 35%. At nearly two years, 24% of patients in the placebo group had had a recurrence or died, versus 15% in the pembrolizumab group.

3. As this is a relatively new indication, all such patients should be offered a referral to Oncology for a discussion about the risks and benefits. In future it is anticipated that some discussions will remain with the surgical team and not all patients will require an Oncology referral.

Stage III melanoma (N1-3 by sentinel lymph node biopsy)

1. If not already performed, patients should have a whole body 18FDG-PETCT and MRI brain and molecular pathology.

2. Comletion lymphadectomy is not routinely offered. NICE recommends that completion lymphadenectomy if there are factors that might make recurrent nodal disease difficult to manage, or people for whom stage III adjuvant therapies are contraindicated. In addition the Alliance recognises that it may be considered where there is a large number of positive sentinel nodes and/ or extranodal extension. We note that SLNB itself may have therapeutic value.

3. Patients should be discussed at the SSMDT and, if supported by holistic case discussion, offered a referral to Oncology to discuss adjuvant medical therapy.

Stage III disease (clinical or radiological nodal N1-3)

1. Clinically or radiologically detected nodal involvement should be confirmed, normally by ultrasound-guided fine needle aspiration cytology. Core biopsy as an alternative is currently under review.

2. If not already performed, patients should have a whole body 18FDG-PETCT and MRI brain and molecular pathology.

3. The SSMDT will appraise the operability of the disease, which will take into account various patient- and tumour-related factors. If operable, patients should be offered complete lymph node dissection of the affected region(s).

4. The extent of neck dissection should be considered case by case with clear documentation of the recommendation at the SSMDM. Levels 1-2 can potentially be omitted for trunk primaries metastasising to the neck. Level 1 can be omitted for head and neck primaries posterior to the ear. Level 5 can potentially be omitted in central face primary lesions. 

5. There is controversy about the extent of lymph node dissection for inguinal disease. This is addressed by the EAGLE FM study but results will not be available for some years. At present, individualised decision-making should occur based on factors such as disease volume, morbidity risks and potential for benefit from adjuvant therapy.

6. Patients should then be offered a referral to Oncology to discuss adjuvant medical therapy.

Stage III disease (microsatellite, in transit or locally recurrent (MSI) disease already demonstrated)

1. These patients gain no additional benefit from SLNB.

2. Where possible, the MSI should be resected.

3. If not already performed, patients should have a whole body 18FDG-PETCT and MRI brain and molecular pathology.

4. Patients should then be discussed at the SSMDM with the following active treatment options under consideration.

• Systemic anticancer therapy.

• Isolated limb infusion or perfusion: requiring referral to St George's Hospital.

• Radiotherapy.

• Electrochemotherapy: requiring referral to St George's Hospital.

• Topical imiquimod. This is an off-licence use that has been formally appraised and adopted as such by St Luke's pharmacy.

• combinations of the above, notably imiquimod + radiotherapy +/- systemic immunotherapy, which has been anecdotally highly effective in Alliance experience.

5. Talimogene laherparepvec, whilst recommended by NICE as an option, is not available as an NHS treatment within the Alliance.* Significant experience has been gained in the private sector, in which complete remissions have been seen, but without the durability of immune checkpoint blockade. This is consistent with the negative results of the Masterkey-265 trial. However, certain patients with contraindications to systemic immunotherapy and limited disease may derive useful disease control and its use should continue to be considered; at present this is dependent on NHS capacity at Guys and St Thomas' Hospital to whom referrals should be made.

Operable stage IV disease

1. Distant metastatic disease may be operable at any site inluding distant skin, nonregional lymph nodes, lung, liver and brain.

2. If completely resected, patients should be offered a referral to Oncology to discuss adjuvant medical therapy.

Final staging and prognostication 

1. Every case will be staged by AJCC 8ed, giving TNM and aggregate stage grouping. This will be documented at the SSMDT discussion.

2. Estimates of melanoma-specific survival by stage, in the absence of adjuvant therapy, are given in the table below.

3. MIA provides a thin melanoma recurrence risk calculator.

Oncological domain

Adjuvant treatment

1. Patients with resected stage III disease should be considered for adjuvant medical therapy. Three options are currently available, all for one year of treatment:

• Pembrolizumab, three- or six-weekly.

• Nivolumab, two- or four-weekly.

• If BRAF V600 mutant, dabrafenib-trametinib, continuous on 4-8 weekly prescription cycles.

2. Three-weekly pembrolizumab is the default choice for the majority of patients in the Alliance. Patients at lower risk who are tolerating treatment well may be switched to six-weekly pembrolizumab. Dabrafenib-trametinib is preferred if there are contraindications to immunotherapy or oral therapy is desired.

3. Patients with stage IIIA disease have a good prognosis and the SSMDT will normally recommend that they do not undergo adjuvant therapy, but instead follow a surveillance schedule, with the likelihood of highly effective rescue therapies for any future recurrence. This discussion will typically take place between the patient and the specialist skin surgeon. However certain patients with higher risk disease (upper categories of stage IIIA, bulky or rapidly growing disease, high mitotic rate, BRAF/NRAS mutation) or who are younger with greater capacity for long term benefit, may be offered a further discussion about adjuvant treatment with Oncology.

4. Patients with resected stage III disease defined solely by MSI should normally be offered adjuvant immunotherapy, rather than BRAF-targeted treatment, based on available evidence, but it is recognised that both treatment types are offered in this setting in other centres and the Alliance adopts a similar pragmatic approach.

5. Adjuvant radiotherapy in stage III melanoma has been principally informed by the ANZMTG 01.02/TROG 02.01 trial that showed a significant improvement in lymph node field control, without an impact on survival. As opposed to the radiotherapy schedule used in this trial (48 Gy in 20 fractions), it is possible that melanoma submits better to more hypofractionated treatment. A retrospective study showed similar five year in-field control rates, RFS and OS with hypofractionation (33 Gy in 6 fractions over 3 weeks v 48 Gy in 20 fractions), ie with no emergent evidence of a survival advantage from adjuvant radiotherapy. NICE guidance from 2015 has not been revised and suggests that adjuvant radiotherapy should not be offered to people with resected stage III melanoma except in stages IIIB-D where the risk of local recurrence is estimated to outweigh the risk of significant adverse effects. In practice it is rarely used within the Alliance.

6. Patients with resected stage IV disease should be offered adjuvant therapy with nivolumab.

7. Repeat staging sans should be considered before starting adjuvant treatment, unless appropriate imaging has been done within the past 8 weeks.

Advanced disease

Principles

1. A full discussion will take place at the SSMDT about optimal oncological and palliative approaches on a case-by-case basis. It is expected that the patient's primary physician will have full knowledge of the patient's condition and circumstances and act as their advocate for most appropriate care.

2. The choice of systemic anticancer therapy for advanced stage III or IV melanoma is complex and dependent on multiple factors, including patient comorbidities and performance status; risk of treatment toxicity; whether potential toxicity will be tolerated; the presence of symptomatic brain metastases; disease burden and kinetics and acuity of illness.

3. Based on extensive practice experience, and supported by the SECOMBIT and DREAMseq trial results, immunotherapy is the firstline treatment of choice when sustained disease control is the goal, in the absence of contraindications to immunotherapy, and where is a rapid response is not required.

Immune checkpoint blockade

1. Options are as follows.

   1. Ipilimumab-nivolumab followed by nivolumab immunotherapy.

   2. Single agent PD-1 blockade, typically pembrolizumab.

2. The decision between dual agent or single agent immunotherapy is guided by multiple factors, the experience of the treating oncologist, and patients' informed choice.

3. The Melanoma Insitute of Australia has an immunotherapy outcomes prediction tool taking into account parameters such as neutrophil/lymphocyte ratio, LDH and types of metastasis. Patients are not often best served by actuarial response and survival statistics, but poor projected outcomes may support clinical consultations and guidance of patients and families towards a more symptom-directed, least-harm approach.

BRAF-MEK inhibition

1. Two schedules are licensed and NICE-approved, dabrafenib-trametinib and encorafenib-binimetinib. A third-regimen, vemurafenib-cobimetinib, is not recommended by NICE.

2. Within the targeted therapy paradigm, dabrafenib-trametinib is the firstline regimen of choice within the Alliance. Encorafenib-binimetinib can be substituted in if there is dose-limiting toxicity with dabrafenib-trametinib and in the absence of disease progression.

3. The use of dabrafenib-trametinib and encorafenib-binimetinib are subject to Cancer Drugs Fund access criteria.

4. MEK inhibition has been shown to severely impair wound healing in a preclinical model. In distinction, BRAF inhibition alone may accelerate wound healing. Alliance practice is to suspend MEK inhibition from seven days prior to any planned surgery. It is restarted at seven days after surgery if there are no wound complications.

Metastases to the central nervous system

In development

Optimising immunotherapy

Physical activity

In development

Microbiome

In development

Vitamin D

In development

Psychological support

In development

Concomitant medications

1. Antihistamines. In a chart review of concomitant medications in patients receiving immunotherapy at the MD Anderson, among 40 common drugs, second generation or HRH1-specific antihistamines were significantly correlated with better survival. Supportive mechanistic studies were performed. HRH1-specific antihistamines include fexofenadine, loratidine and cetirizine. In a Swedish registry study, use of desloratidine and loratidine was associated with better survival in immunogenic tumours. Pragmatically, it is suggested that patients suffering with dermatitis and other allergic-type symptoms during immunotherapy should be strongly considered for an oral antihistamine alongside other standard symptomatic measures.

Adverse effect management

In development

Special situations

Desmoplastic melanoma

1. Sentinel lymph node biopsy is not normally performed in pure desmoplastic melanoma.

2. The role of adjuvant radiotherapy after resection of desmoplastic melanoma is contentious. A retrospective review of 277 patients found that in patients with positive resection margins, the rate of recurrence was 14% in those who received radiotherapy versus 54% in those who did not. In patients with negative margins and high risk features including head and neck location, Breslow thickness >4mm, radiotherapy was found to significantly improve local control. In a single arm phase II study, patients with margin-negative desmoplastic melanoma recieved radiotherapy, 30Gy in five fractions, to the operative bed with 2-3 cm margins. 2/10 showed local relapse within 2 years of treatment. A case review found no difference in median survival between patients who received radiotherapy versus those who did not. Another retrospective study found no difference in survival up to five years, except in those with margin-positive tumours. Of note, desmoplastic melanoma shows a high response rate to PD-1 blockade and therefore salvage immunotherapy on inoperable relapse, or adjuvant immunotherapy after local recurrence, may represent a more tailored approach.

3. Alliance experience is mixed, including recurrences of desmoplastic melanoma outside radiation fields with generous margins.

4. Pending additional evidence, including the result of the RTN2 trial, Alliance policy is that patients will be offered a discussion with Oncology in the following circumstances: pure desmoplastic melanoma, especially positive margins, head and neck location, clear neurotropism. Radiation will generally be avoided in younger patients due to the high likelihood of long-term survival in this condition and therefore the additional cosmetic, carcinogenic risks and potential cognitive risks.

MelTUMP

1. Alliance policy has been that melanocytic lesions of unknown malignant potential (MelTUMPs), or melanocytomas, are managed as potential melanomas. They should be discussed at the SSMDT and treatment and follow up will typically be personalised.

2. A recent metaanalysis of 1649 patients found that 94.7% were alive without disease at last review. 1.8% had died of metastatic melanoma. However the rate of sentinel node positivity in 837 patients was high at 32%. The authors suggest that SLNB should not be offered routinely for MelTUMPs due its lack of prognostic utility. They did not however address the potential therapeutic value of SLNB in this group as a contributor to good outcomes. Positive non-sentinel nodes were reported in 27% of 170 SLNB+ patients who had a completion lymph node dissection. There was insufficient evidence on excision margins, but 10 mm was the most common practice and suggested for what is typically a young patient group.

3. These data strongly suggest that adjuvant immunotherapy is likely to be of little or no value in patients with MelTUMPS, and SLNB decisions will need to be carefully considered case by case.

Pregnancy and fertility

In development.

1. Patients with melanoma where SACT is being considered should have a consultation with appropriate professional regarding the implications for future fertility where appropriate. This will be arranged by the oncology team. This introduces a potential increase in the time to SACT to the pathway and referral of these cases to oncology should be prompt. 

2. In pregnant women, the option of delaying SLNB until after pregnancy is completed should be discussed.

HIV

1. In a retrospective study of 390 people with HIV treated with anti-PD-1 or anti-PD-L1 therapies for advanced cancers, melanoma patients showed a 47% overall response rate, which is similar to expectations for people without HIV. Any grade immune related adverse effects (irAEs) occurred in 20% of people with HIV and a matched cohort, and grade 3+ irAEs occurred in approximately 10% of both cohorts. The rate of irAEs in patients with CD4+ T cell counts less or more than 200 cells/microlitre were comparable. However patients with CD4:CD8 > 0.4 had a higher incidence of irAEs, an observation that has been seen in non-HIV melanoma patients.

2. The effects of immune checkpoint blockade on HIV levels appear to vary across publications. One study of 40 patients found that ipilimumab-nivolumab may be associated with reversal of HIV latency; another found this effect with pembrolizumab. This may contribute towards HIV control and close liaison should occur with patients' HIV physicians during therapy at least to obtain serial viral load monitoring to contribute to the knowledge base.

3. Alliance experience is limited to two patients. The first achieved a partial response to treatment which was curtailed by significant irAEs. There was significant residual bulk nodal disease which however remained stable for approximately seven months after cessation of treatment. The second patient has only recently started treatment (mid-2023).

Genetic screening

In development

Horizon scanning and non-funded approaches

Neoadjuvant therapy

1. In the S1801 phase 2 trial, patients with clinically detectable, surgically resectable, stage IIIB to IVC melanoma, were ransomised to three doses of neoadjuvant pembrolizumab followed by 15 doses of adjuvant pembrolizumab, or surgery followed by 18 doses of adjuvnat pembrolizumab. At a median follow up of 14.7 months, the neoadjuvant-adjuvant (NA) group had significantly longer event-free survival (EFS) than the adjuvant-only (AO) group. EFS at two years was 72% in the NA group and 49% in the AO group. Events were defined as disease progression or toxic effects that precluded surgery; the inability to resect all gross disease; disease progression; surgical complications; toxic effects of treatment that precluded the timley initiation of adjuvant therapy; death from any cause.

2. In the PRADO extension cohort of the OpACIN-neo trial, response-guided treatment was assessed. Patients with stage IIIB-D melanoma were studied. The largest lymph node metastasis at baseline was identified as the index lymph node (ILN). Two cycles of ipilimumab 1mg/kg and nivolumab 3m/kg were administered and the ILN was resected. The pathologic response rate was 72%, including 61% major pathologic response (MPR; <=10% viable tumour). In patients achieving MPR, therapeutic lymph node dissection (TLND) and adjuvant therapy were omitted. In patients with pathologic partial response (pPR; >10 to <=50% viable tumour), TLND only was performed. Patients with non-response (pNR) underwent TLND with adjuvant systemic therapy (immunotherapy or BRAF-targeted therapy) +/- synchronous radiotherapy. The 24 month RFS and DMFS rates were 93% and 98% in patients with MPR, 64% and 64% in patients with pPR, and 71% and 76% in patients with pNR, respectively. 

3. This paradigm was developed into the phase III NADINA trial

4. Alliance experience is mixed. During the COVID pandemic, several patients with operable stage III disease were treated with primary medical therapy and have achieved complete clinical and radiological remissions, sustained for 1-3 years. During early 2023, two patients with high volume nodal disease were treated with primary pembrolizumab immunotherapy, then showing major progression, one with metastatic disease that was subsequently controlled with targeted therapy and one with progressive nodal disease that has been operated, but with more difficulty than would have been the case at baseline. Notably these cases had a high disease burden at baseline which may prompt consideration of early 'debulking' surgery or primary ipilimumab-nivolumab immunotherapy instead.

Adjuvant mRNA vaccine

1. The Moderna mRNA-4157 vaccine has recevied considerable professional and public attention. This is an individualised neoantigen therapy that has been combined iwth pembrolizumab as adjuvant treatment for stage IIIB-IV melanoma in the KEYNOTE-942 trial. In the phase IIb study of 157 patients, two year recurrence free survival was 75% in the combination arm versus 56% with pembrolizumab alone. It reduced the risk of distant metastasis by 62%. However the 2.5y overall survival benefit was slight, 96% v 90%. At the time of writing, the phase III INTerpath-001 study is recruiting with the Marsden representing the nearest centre in the UK; UCLH is the lead hospital. This individualised treatment is likely to be high cost, and emergent results with neoadjuvant treatment may largely negate the advantage of adding the adjuvant mRNA vaccine at present.

Ipilimumab-nivolumab after failure of PD-1 blockade

1. Current NHS funding rules (2023) only allow access to single agent ipilimumab after progression on pembrolizumab or nivolumab as single agents. Ipilimumab is limited to four doses, following which funding for any further immunotherapy ceases. This is not a commonly used option.

2. Private practice experience has shown repeatedly that ipilimumab-nivolumab can rescue a significant proportion of patients who progression through PD-1 blockade alone, and this can provide an iterative, risk-adapted approach for some patients in whom the risk/ benefit ratio of up-front ipilimumab-nivolumab is less favourble.

3. A phase 2 trial assessed ipilimumab-nivolumab v ipilimumab alone after progression on PD-1 or PD-L1 blockade. Objective response rates were 28% and 9% respectively. G3+ adverse events occurred in 57% and 35% respectively. Progression free survival was improved with a hazard ratio of 0.63.

4. In rare circumstances (due to the extremely high costs) it may be possible for patients to consider self-paying for ipilimumab-nivolumab after PD-1 failure. Under insured cover, this remains a salient option. Regional clinicians will continue to argue the case for funding for secondline ipilimumab-nivolumab directly to NHSE and via professional associations. 

Follow up and adjunctive care

Principles

Vitamin D levels and concurrent drug treatment

1. Vitamin D levels should be measured at diagnosis.

2. Vitamin D should be instituted in all patients due to receive immunotherapy at their first consultation*. This is variant to NICE guidance. This is (a) for practical reasons, as reviewing vitamin D results and instituting vitamin D supplementation may take significant further time or be overlooked; (b) vitamin D intake, agnostic of baseline vitamin D levels, is associated with a reduced risk of immune checkpoint inhibitor colitis. If excess vitamin D levels are found at baseline or follow up then supplementation should be suspended.

3. The preferred formulation for vitamin D, based on endocrinology advice, is a transmucosal intraoral spray with dose strength 3000U/spray, once a day, escalated to twice a day as required.

4. NICE provides further guidance on vitamin D supplementation.

5. NICE recommends that concurrent non-immunosuppressive drug treatments in general should not be changed on diagnosis of melanoma. The Alliance notes that thiazide diuretics are associated with an increased risk of skin cancers. Regarding immunosuppressants, the patient's specialist clinician should be consulted, balancing quality of life and health detriments with melanoma risk. Alliance experience is that some patients are maintained long term on immunosuppressants for historic indications and can be successfully weaned; withdrawal may contribute to subsequent anti-cancer immune reconstitution.

General principles of follow up

1. Patients should be counselled to examine their skin regularly and systemically, as well as at-risk lymph node regions. The Primary Care Dermatology Society has patient information on skin self-examination and BAD has guidance for patients on lymph node examination.

2. Patients should have access to a clinical nurse specialist for support and advice, and have a clear mechanism for re-escalation back to the treating clinician and MDT.

3. In time it is expected that a significant proportion of patients will move to a formal patient-initiated follow up programme, which is to be developed.

4. A named clinician should be assigned responsibility for follow-up for each patient. This may be a dermatologist, surgeon, CNS or oncologist. As a first principle, follow up should be as close to the patient's home as possible. The clinician should hav skills and expertise in skin cancer and lymph node exmination, and should have access to dermoscopy and medical photography.

5. Time zero for follow-up is the date of completion of primary treatment, which should be clearly recorded in clinical correspondence and the SSMDM proforma.

6. Patients with multiple melanomas or multiple mole syndrome will have bespoke clinical review which will take precedence over the scheme below.

7. Frequency and modality of follow up were discussed at the Alliance meeting of 13 October 2022.

   1. It was in particular noted that NICE 2022 recommends that patients do not have routine PETCT during follow-up and that this is markedly variant to existing Alliance practice. It was agreed to move towards contrast-enhanced CT of the body for routine surveillance imaging.

   2. It was also noted that follow-up by stage is complex, and can be made even more complex by personalisation to individual patient risks and circumstances, but there was a strong majority desire for simplicity and a limited panel of follow up schedules. This is variant to NICE 2022* but results in only minor intensification, rather than any de-intensification, of routine follow-up, and reduces risk and improves real-world execution of follow-up by multiple providers.

   3. Imaging during and after oncological treatment is subject to a much wider range of parameters and is more personalised to each patient. A clear plan should be given in the clinical summary at the head of every patient letter. In general, follow up after adjuvant therapy should follow the standard schedules, taking the date of surgery, not the completion of adjuvant treatment, as time zero. PETCT may be better supported to help justify continuation of high-resource treatments, and because patients will frequently be traveling to Guildford during this period.

   4. For brain imaging, it was agreed to adopt routine CT head in line with NICE guidance, accepting a potential loss of ability to detect small volume asymptomatic metastases. In practice, the probability of developing isolated brain metastases in the absence of systemic progression is low, and it would be expected that detection of systemic recurrence will lead to full evaluation including MRI brain.

   5. Also regarding brain imaging, it was felt that the number of CT head scans mandated for younger patients, not just those aged under 24, potentially eight over five years, presents an excessive radiation risk and this has been adapted in Alliance policy.* Lastly, patients with treated brain metastases will require routine MRI brain rather than CT head, but these patients are expected to rest under Oncology follow-up, whether or not they have had systemic therapy, and therefore be on bespoke follow-up schedules.

   6. A move to routine CT, rather than PETCT follow-up, will require that scan reports are sent alongside images when cases are to be reviewed at the SSMDM. CT scans cannot be fully and reliably reported live during the meeting.

8. Follow-up includes the following elements:

CLINICAL REVIEW (C)

Records review Clinical correspondence; all imaging results, blood tests and histopathology. The Alliance recognises the value of a 'sweeper system' to ensure important clinical results are not missed, regardless of who ordered the investigations.

History Skin lesions (especially changing), growths on and under skin, systemic malaise, pain, medical and drug history.

Examination Primary site, locoregional skin and lymph nodes, full skin check.

Clinical advice Self-examination and by partner; exercise, diet, sunlight exposure, vitamin D management and advice on stopping smoking as suggested by NICE.

Documentation

Bookings (a) scheduled imaging (b) triggered special imaging/ biopsy/ blood tests/ MDM review (c) next appointment

ULTRASOUND (U)

• Ultrasound as an option in the following groups:

  • patients who have been considered for, but did not proceed with, sentinel lymph node biopsy. It should be viewed as an alternative option to SLNB for this patient group, rather than for patients who were unfit for benefit from sentinel lymph node biopsy, in whom a primarily symptom-drive approach with lower-burden follow up may be more appropriate;

  • patients who have had a positive SLNB;

  • patients who have had resection of in transit, satellite or locally recurrent disease, and who thereby will not normally have had a SLNB.

• In accordance with NICE guidelines, ultrasound is alternated with cross-sectional imaging where practicable. However where intervening clinical review is not scheduled, ultrasound is performed at the same time as CT as Alliance experience is that it can provide additional resolution for pathological lymphadenopathy.

• The region at risk and for ultrasound monitoring should be defined by the surgeon and recorded at the SSMDM. In practice, some primaries may drain to lymph nodes in two, three or more regions. No more than two lymph node regions are to be monitored by ultrasound.

CROSS-SECTIONAL IMAGING (X)

40 years and younger MRI brain and CT neck-chest-abdo-pelvis +/- involved limb. Whole body MRI is in development.

Over 40 years CT head-neck-chest-abdo-pelvis +/- involved limb

Women who are pregnant Whole body MRI when introduced into practice; otherwise use ultrasound and clinical review only until delivery.

9. The derived Alliance follow up schedules for resected, invasive melanoma are given below.

Follow-up schedules