Overview

Melanoma (skin cancer) is a cancer which starts in skin cells called melanocytes. Melanocytes are responsible for the pigment in the skin with dark skin having more pigment than light skin. Melanoma is characterised by new skin lesions or changes in an existing mole, such as shape, size, or general appearance.

Early diagnosis is best to achieve complete recovery as melanoma can spread to other parts of the body making treatment more difficult. Many people are diagnosed at later stages where the chances of the cancer recurring are higher, even with initial successful treatment.¹ Here we will discuss the use of interferon therapy (IFN) for advanced melanoma to help patients who are at risk of recurrence with limited options.

Types of melanoma

There are 4 main types of melanoma:

• Superficial spreading
• Nodular
• Lentigo maligna
• Acral lentiginous

Less common types of melanoma include:²

• Amelanotic melanoma
• Desmoplastic melanoma
• Spitzoid melanoma
• Malignant blue naevus

Risk factors associated with melanoma

Several factors increase the chances of melanoma. Awareness of these can help you to protect yourself and identify the changes in your body, so any abnormal skin cells can be found at the earliest opportunity to give you the best chance of recovering. These risk factors are:²

• Exposure to UV light
• High number of moles
• Family history of melanoma
• Skin type that burns easily
• Previous sunburns
• Compromised immune system

Stages of melanoma

There are 5 stages of melanoma; each stage reflecting the progression of the disease.³

Stage 0: melanoma cells are only on the top layer with a low risk of spreading.

Stage 1: melanoma is less than 2mm thick with no spreading.

Stage 2: melanoma is up to 4mm thick but has not spread.

Stage 3: spreads to the lymphatic vessels or lymph nodes close to melanoma. It is usually thick.

Stage 4: melanoma cells have spread to other organs in the body. This is called metastatic melanoma.

Current treatment options for melanoma

The most common and primary treatment for melanoma is surgery. Removing the skin lesion before it can spread has the highest survival rate. Upon spreading, treatments include:

• Chemotherapy
• Radiotherapy
• Targeted therapy
• Immunotherapy

Many cases of melanoma are diagnosed at later stages when the cancer has already started to spread. The advanced disease becomes very difficult to treat as it develops resistance against any treatment. Many patients will suffer from relapse and succumb to the disease. High rates of occurrence, relapse, and deaths show us that further research needs to be carried out to improve the overall management of melanoma. Research should focus on prevention, diagnosis, and reducing resistance against targeted therapies.⁴ 

IFN therapy

Explanation of IFN

Naturally present in the body, IFNs are cytokines released by infected cells to make the immune system aware that they are damaged. The release of cytokines helps surrounding cells to build up their defences and activates immune cells to react to the infection promptly. IFNs are also known to have antitumour properties, so they can be used in cancer treatment as immunotherapy.⁵ Immunotherapy drugs enable the immune system to detect and destroy tumours. 

IFN therapy was first approved by The United States Food and Drug Administration (FDA) in 1995 as an adjuvant therapy. Its initial use was to prevent melanoma from recurring or spreading further in patients who had surgery to remove the tumours.⁶

Types of IFN therapy

Type I

Type I IFN can be divided into five groups called:

• IFN-α (13 subtypes)
• IFN-β
• IFN-ε
• IFN-κ
• IFN-ω

IFN-α and IFN-β are the best understood and the most active in relation to cancer treatments.

Type I IFN can activate genes promoting cell death, have anti-tumour activity and arrest the cell cycle. Cancerous cells have damaged DNA. To let the immune system know, they emit signals by releasing different chemicals including type I IFN. The immune cells of the body called dendritic cells are activated by the IFN, stimulating other cells to destroy the cancer cells.

As type I IFNs are produced after DNA damage, their release usually leads to the senescence of cancer cells.⁷

Type II

The sole type II IFN is known as IFNγ. IFNγ is mainly produced by immune cells called natural killer cells and T cells when they detect cancerous cells but can be released by others, such as the dendritic cells. 

Type II IFNs cause the cancer cells to express major histocompatibility complex (MHC) class I molecules on the surface, improve the chances of an immune response from the body, and slow the growth of the cancer. MHC class I molecules are used by cancer cells to display a small strand of damaged DNA inside them for the immune cells so they can find and destroy them. Type II can also increase the amount of DNA strands to display, increasing the chances of detection.⁵

Type III

IFN-λ is the only type III IFN but has four subtypes IFN-λ1, IFN-λ2, IFN-λ3, and IFN-λ4. 

Type III works similarly to type I, by countering angiogenesis, arresting the cell cycle, slowing the spread of the cancer, and destroying cancer cells by apoptosis (programmed cell death).

The microenvironment of the tumour is the surrounding material the cancer sits in. It includes many cells, structural proteins, and chemicals. Type III IFN boosts the presence of T cells and natural killer cells in this microenvironment so they can respond to the cancer cells and eliminate them. Like type II, type III also increases the number of MHC class I molecules on the surface making detection of the cancer cells more likely.⁷ 

Side effects and adverse reactions

Common side effects of IFN therapy

Factors causing side effects during IFN therapy include:

• High dose of IFN
• Treatment duration
• Age
• Underlying conditions
• Performance status

The following side effects are observed at varying degrees:⁹

• Fever
• Muscle pain
• Feeling sick
• Vomiting
• Fatigue
• Less blood production
• Depression
• Liver injury
• Anorexia
• Heart damage
• Autoimmunity
• Erectile dysfunction
• Eye toxicity

Management of side effects

Side effects can be managed in a variety of ways which include:⁹

• Dose adjustments
• Improve nutritional status
• Frequent meals
• High-protein supplements
• Multivitamins
• Use of antidepressants 
• Increase hydration
• Schedule periods of rest and activity
• Discontinue IFN

Patient selection and treatment regimens

Criteria for selecting patients for IFN therapy

Patients most likely to benefit from IFN therapy are those whose cancer has spread to lymph nodes, have thick primary tumours, and those with bleeding or very sore tumours on the skin and are therefore at higher risk of relapse after surgery.⁹

Different treatment regimens for melanoma patients

High dose

Induction phase: IFN is injected into the blood at a dose of 20 million units a day, 5 days a week for 4 weeks.

Maintenance phase: IFN is injected into the skin at a dose of 10 million units 3 times a week for 48 weeks.

Intermediate dose

Induction phase: IFN is injected into the blood at a dose of 10 million units a day 5 days a week for 4 weeks.

Maintenance phase: IFN is injected into the skin at a dose of 5–10 million units 3 days a week for varying durations.

Low dose

IFN is injected into the skin at a dose of 3 million units 3 days a week for varying lengths of time.⁹

FAQs

Is interferon still used for melanoma?

Two medicines have been approved as an adjuvant therapy following surgery: interferon alfa-2b and peginterferon alfa-2b. These are for patients with recurrent melanoma or those at high risk of recurrence.

What are the long-term side effects of interferon for melanoma?

Side effects can include:

• Fatigue
• Nausea
• Loss of appetite
• Depression
• Weight loss

Many side effects can be managed during treatment and will usually lose their intensity as your body gets used to the treatment itself. If any side effects persist, talk to your doctor as soon as possible to avoid long-term damage to the body.

How long does interferon treatment last?

Treatment can last for a year typically. However, it depends on how you respond to the treatment. Additional time could be added if needed.

Summary

Melanoma treatment is improving with new strategies being developed in relation to prevention, detection, and immunotherapies which have led to an increased number of patients surviving. However, many patients will eventually suffer from recurrence therefore there is a great need to develop novel treatments that will offer hope.

Unfortunately, therapies that are making a real difference to patients can also be damaging and can cause severe side effects. More research on managing the side effects of IFN therapies and novel combination treatments will be the answer moving forward. Personalised treatment directed to individuals most likely to respond may help more patients recover and live longer healthier lives.