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Although more common in the West, melanoma, a highly aggressive form of skin cancer, still affects Asians. In the ‘Hi Doc, My Dark Mole is Growing’ Continuing Medical Education (CME) webinar last September, Dr Dennis Lim discussed the role of surgery for early stage melanoma in the age of immunotherapy, followed by a presentation by Dr Richard Quek on systemic treatment options for melanoma.

It was only since the early 2010s, with the approval of immune checkpoint inhibitors, that survival rates for Stage 3 and 4 melanoma improved greatly, says Dr Lim. Despite the rarity of the disease in Southeast Asia, he shared that it is still important to be aware of common subtypes amongst Asians such as acral lentiginous and mucosal melanoma.

In the clinical diagnosis for melanoma, a dermatologist can provide the best evaluation of suspicious skin lesions.

Generally, the depth of invasion has a direct correlation to survival rates, shared Dr Lim. He noted that Breslow’s depth is a key parameter used for staging melanoma and it is easier to measure compared with Clark’s level, which requires a more detailed evaluation.

He then highlighted key additions to the American Joint Committee of Cancer (AJCC) staging which include:

• Simplified T staging Breslow’s depth is now expressed to the nearest 0.1mm, and the presence or absence of ulceration is now binary.

• N staging is now based on the nature of the nodal disease:
  • Category A – clinically occult (detected pathologically after excision)
  • Category B – clinically detected
  • Category C – presence of in-transit, satellite and microsatellite lesions

SLN biopsy in surgical dec

Up to the 1980s, treatment for lymph node involvement in melanoma was binary; radical nodal dissection was done for clinically positive lymph nodes, while a ‘watch and wait’ approach was observed for negative cases.

These days, lymph node dissection is no longer done to check if the nodes are affected as this procedure is morbid and does not improve survival of patients. It has now been replaced with SLN biopsy.

Typically, staging is first carried out using a PET scan. If the PET scan shows nodal spread, patients are advised to go for complete nodal clearance surgery. Conversely, if the PET scan shows no nodal spread, SLN biopsy is offered.

If the SLN biopsy shows cancer, and the nodes involved are at Stage 3, the patient is recommended to go for adjuvant treatment. Otherwise, if the SLN biopsy shows no cancer and disease is at Stage 1 or 2, surgery alone is enough.

The role of the surgeon - how it has changed

Using case studies, Dr Lim illustrated how the role of the surgeon has changed with SLN.

In two cases of typical melanoma presentations in Asians, SLN was detected using SPECT/CT and in both cases, the patients were treated with excision of the lymph node basin and are now disease-free.

Dr Lim warned participants of lesions presenting in young patients using a case of a young Caucasian presenting with a head lesion. The patient’s dermatologist did not suspect melanoma, but a biopsy showed a 2.2mm ulcerated melanoma with lymphovascular invasion and metastases. The patient was treated with wide local excision and posterolateral neck dissection.

Dr Lim concluded his presentation by stating that today, the pathologist plays an important role in multidisciplinary management of the disease. Determining the histological type, characteristics of the melanoma and molecular subtyping is key to determining prognosis and treatment.

Systemic treatment for melanoma

Dr Quek continued the webinar with his presentation on systemic treatment options for melanoma.

He reminded participants that malignant skin lumps should be suspected through the ‘ABCDE’ rule of melanoma – Asymmetry, Border, Colour, Diameter and Evolution – warning participants to be wary of abnormalities and changing characteristics of a skin mole.

He then highlighted key mutations in melanoma including BRAF, NRAS and cKIT, and addressed that ultraviolet light damage is not the only cause of melanoma. He shared that melanomas can be divided into 4 categories based on molecular etiology:

1. Chronic sun-induced damage
2. Non-chronic sun-induced damage (NCSID)
3. Palms, soles, and acral regions
4. Mucosal regions

Overview of melanoma treatments

For localised disease, Dr Quek recommended surgery, SLN biopsy in the appropriate patient, and adjuvant therapy for those with resected Stage 3 or Stage 4 disease. For metastatic disease, systemic treatment is the mainstay of treatment.

Modern day systemic treatment modalities in melanoma are broadly divided into 2 approaches: targeted therapy and immunotherapy.

Single agent vs combination drugs for targeted therapy

Dr Quek shared a study that found that single agent BRAF targeted therapy was more effective than traditional chemotherapy, with an overall response rate of 48% compared to 5% in chemotherapy.

However, he noted that when single agent BRAF inhibitor is used, the RAF blockade can upregulate up- and down-stream signaling pathways, causing the tumour to circumvent the blockade. As a result, clinical worsening is typically observed after 6 months.

Fortunately, a combination of BRAF and MEK inhibitors that completely blocks the BRAF pathway can improve progression-free survival by 50% and give an overall response rate as high as 70%.

Immunotherapy in metastatic melanoma

Anti-CTLA-4 and anti-PD1 are approved classes for immunotherapy in metastatic melanoma, continued Dr Quek.

In a study he shared on the first generation immunotherapy—ipilimumab, a CTLA-4 inhibitor—in patients with advanced melanoma, 20% of ipilimumab-treated patients remain free of disease at 5 years. He pointed out that nowadays, doctors tend to use anti-PD1 drugs such as pembrolizumab and nivolumab as they are less toxic.

Taken together, with the development of all these therapies, 30–40% of patients with advanced melanoma who previously suffered from a very poor prognosis, now remain disease-free after treatment.

However, he also warned that combining drugs such as ipilimumab and nivolumab—though more effective in improving median survival—can also be more toxic, and is best reserved for younger and fitter patients.

He illustrated this by sharing a case study of a middle-aged patient with mucosal melanoma who was given single agent anti-PD1, but experienced disease progression after 7-8 months. Fortunately, she responded to the addition of an anti-CTLA-4. With dual immunotherapy, she achieved a sustained and complete remission.

Adjuvant treatment in localised melanoma

Dr Quek stressed that adjuvant (prevention) therapy is an important development in the melanoma world and is now the standard of care.

He highlighted studies on adjuvant treatment which included drugs such as ipilimumab, nivolumab and pembrolizumab as well as dabrafenib and trametinib. These studies were conducted in patients with stage 3 and resected stage 4 disease. Adjuvant systemic treatment significantly delayed cancer relapse.

He also cautioned that patients with stage 2B and 2C melanoma are also at an increased risk of relapse, but at present, adjuvant therapies are not recommended pending completion of clinical trials.

In conclusion

To conclude his presentation, Dr Quek reminded participants of the paradigm change in the approach and treatment of melanoma.

He emphasised that different subtypes of melanoma can be effectively treated with targeted therapy and/or immunotherapy. It is important to identify patients who would benefit from adjuvant treatment. Despite its aggressive nature, melanoma is highly treatable and in some cases curable even at Stage 4.