Background

Melanoma is a malignant melanocyte type of tumor. The melanocytes produces melanin pigment. It can develop on skin, mucosal surfaces, and uveal tract.

Uveal melanomas differ in incidence, prognostic variables, molecular features, and treatment. The patients with stage 0 melanoma has a 97% survival rate in five-year.

Epidemiology

Melanoma incidence is increasing at a faster rate than any other cancer. It seen more in white people than black people and in Asians.

It is fifth most prevalent cancer in males and on seventh place in women. The average diagnosis age is 57 with 75% of them are under 70 years old.

Anatomy

Pathophysiology

Melanomas can develop in healthy skin of people, so the most common cause is solar exposure.

Melanomas also develop in non-sun exposed areas such as palms, soles, and perineum. It grow in radial and vertical stages.

In radial growth phase the malignant cells develop in the epidermis. In vertical development phase the malignant cells infiltrate dermis and spread.

Etiology

In 5 to 10% of patients have family history and the chance of this disorder increase risk by 2.2 times.

In immunocompromised individuals, transplant patients, and hematological malignancies are more affected. Use of sunscreen blocks UVB radiation as it increases UVA exposure.

Use of tanning beds, sunburns, and low latitude increase melanomas incidence.

Genetics

If any of your direct relatives (parents, brothers, sisters, or children) has had melanoma, your risk of developing it is increased. Around 10% of all melanoma patients have a family history of the disease.

A common family lifestyle of regular sun exposure, a family tendency to have pale skin, gene mutations that run in families, or a combination of these factors presents a higher risk of developing this condition.

Most specialists don’t recommend genetic testing to check for mutations that may increase risk in individuals with a family history of melanoma, because genetic testing is still not a reliable diagnostic tool for this condition.

Instead, experts recommend individuals with family history of melanoma to examine their skin regularly. Such individuals are also suggested to avoid facilities such as tanning beds (man-made UV exposure) and be cautious of sun exposure.

Prognostic Factors

Thickness of tumor is gives worse outcomes with thicker lesions. In stage 3 tumor it shows regional lymph nodes.

In stage 4 it shows greater quantity of positive lymph nodes. The poor prognosis after metastasis development also average survival rate is found below 20%.

Clinical History

Age Group:

Melanoma increases with age. It is rarely seen in children.

In most cases it is diagnosed in individuals over 50-years-old.

Physical Examination

Body Examination

Use of Dermoscopy

Age group

Associated comorbidity

Prolonged exposure to UV radiation from the sun or tanning beds is a significant risk factor for melanoma. If someone has had melanoma before, they are at a higher risk of developing it again. Individuals with atypical moles have an increased risk of developing melanoma.

People with a weakened immune system, either due to medical conditions or medications, may be at a higher risk of developing melanoma. Individuals with a family history of melanoma have an increased risk of developing the disease.

Associated activity

Acuity of presentation

Monitor the appearance of new moles or pigmented lesions. Look for asymmetry, irregular borders, varied colors, larger than 6 mm diameter.

Observe evolution or changes over time. Smaller lesions or skin changes around mole may indicate melanoma.

Differential Diagnoses

Benign Moles

Seborrheic Keratosis

Hemangiomas

Merkel Cell Carcinoma

Laboratory Studies

Imaging Studies

Procedures

Histologic Findings

Staging

Treatment Paradigm

The high recurrence risk may require adjuvant therapy with interferon.

Immunotherapy drugs boost immune response against cancer cells.

by Stage

by Modality

Chemotherapy

Radiation Therapy

Surgical Interventions

Hormone Therapy

Immunotherapy

Hyperthermia

Photodynamic Therapy

Stem Cell Transplant

Targeted Therapy

Palliative Care

use-of-non-pharmacological-approach-for-melanoma

Regular use of sunscreen with a high SPF level help to protect the skin from harmful ultraviolet radiation. Avoid tanning beds emit UV radiation which can increase the risk of melanoma.

Patient should adopt lifestyle changes can contribute to a reduced risk of melanoma. Healthy lifestyle should be maintained with a balanced diet, and regular exercise.

Role of Targeted Therapy

Role of Targeted Therapy:

Trametinib is a MEK inhibitor often used in combination with BRAF inhibitors to target the MAPK pathway.

Use of Immunotherapy

Ipilimumab is an immune checkpoint inhibitor. It enhances the immune response to melanoma cells.

use-of-intervention-with-a-procedure-in-treating-melanoma

Sentinel lymph node biopsy is used for thicker or high-risk melanomas which determines cancer spread.

Mohs surgery removes thin layers of tissue and examines each under a microscope until no cancer cells are detected.

use-of-phases-in-managing-melanoma

The diagnosis phase involves clinical evaluation of suspicious skin lesions. In treatment phase, the adjuvant therapy recommended to reduce post-surgery recurrence risk.

It also has targeted therapy with BRAF and MEK inhibitors for advanced-stage melanoma with specific genetic mutations.

Medication

cobimetinib

60

mg

Tablet

Oral

once a day

21

days

Take the dose until disease progression or unacceptable toxicity 

trametinib

Metastatic melanoma:

2

mg

oral

once a day

as a single agent or in combination with dabrafenib

binimetinib

45

mg

Tablet

Orally 

every 12 hrs

The dose is given in combination with encorafenib; continue the therapy until disease progression or severe health side effects

Dose Adjustments

Renal Dose Adjustments: No adjustment is recommended.   Liver Dose Adjustments:  For hepatic impairment, a dose of 30 mg orally twice a day is recommended  

ipilimumab

3 mg per kg given IV over 90 minutes every three weeks for a maximum of 4 doses
Adjuvant treatment of melanoma:
10 mg per kg given IV over 90mins every three weeks for four doses, followed by 10 mg per kg given IV over 90mins every 12 weeks for up to 3yrs

pembrolizumab

Monotherapy:

200

mg

Intravenous (IV)

every 3 weeks or 400 mg IV every 6 weeks and administer it over 30 minutes; continue the treatment until disease progression or unacceptable toxicity
Adjuvant treatment: 200 mg IV every 3 weeks OR 400 mg IV every 6 weeks and administer it over 30 minutes; continue the treatment until disease progression or unacceptable toxicity or up to 12 months

dacarbazine

2 - 4.5

mg/kg

Intravenous (IV)

once a day

10

days

; repeat every 4 weeks
OR 250 mg/m2 Intravenous (IV) once a day 5 days; repeat every 3 weeks

temozolomide

peginterferon alfa - 2b

6

mcg/kg

Subcutaneous (SC)

once a week

for 8 doses, followed by 3 mcg/kg once a week up to 5 years

interferon alfa - 2b

Induction phase:

20 million IU/m2/day IV through 20-minute infusion 5 days per week for 4 weeks Maintenance phase: 10 million IU/m2 SC 3 times a week for 48 weeks

tebentafusp

20 mcg intravenously on day 1
30 mcg intravenously on day 8
68 mcg intravenously from the next week until toxicity is reduced

nivolumab

Adjuvant Treatment of Melanoma:

Recommended for melanoma in patients who have undergone complete resection and have lymph node involvement or metastatic disease in the adjuvant context
240 mg intravenously every 2 weeks or 480 mg intravenously every 4 weeks

Continue the therapy until the unacceptable toxicity or disease progression for up to a year

Unresectable or Metastatic Melanoma
It is indicated for single-agent use or in combination with ipilimumab.

Single-agent
240 mg intravenously every 2 weeks or 480 mg intravenously every 4 weeks
Continue until the disease is progressed or unacceptable toxicity is achieved
In combination with ipilimumab
1 mg/kg nivolumab intravenously every 3 weeks, with
3 mg/kg ipilimumab intravenously on the same day (maximum of 4 doses)
After completion of combination therapy: administer 240 mg nivolumab intravenously every 2 weeks or 480 mg intravenously every 4 weeks
Continue the therapy until the disease is progressed or unacceptable toxicity is reduced

encorafenib

encorafenib treats metastatic melanoma. It is given in combination with binimetinib as 450 mg orally, four times daily.

Dose Modifications:
If binimetinib is held back, reduce encorafenib maximum to a dose of 300 mg/day
1st dose reduction: 300 mg orally each day
2nd dose reduction: 225 mg orally each day
Subsequently, discontinue the dose permanently if unable to tolerate more than 225 mg/day

sorafenib

(Orphan)
Treatment of stage II B is through stage IV melanoma

talimogene Laherparepvec

starting dose: about 4 mL concentration of 106 (one million) PFU/mL
Second dose: about 4 mL concentration in 108 (100 million) PFU/mL administered three weeks after the initial therapy
All subsequent therapies (reinitiation included): about 4 mL concentration in 108 (100 million) PFU/mL administered two weeks after the previous therapy
Continue therapy for 6 months or till there are no more injectable lesions.
If unresectable subcutaneous, cutaneous, or nodal lesions develop after a full response, restart therapy.
Determine the dose volume for every lesion
The size of a lesion depends on its longest dimension.
When the lesions are grouped together, they should be injected as a singular lesion based on the following:
Above 5 cm: 4 mL/lesion
Above 2.5 to 5 cm: 2 mL/lesion
Above 1.5 to 2.5 cm: 1 mL/lesion
Above 0.5 to 1.5 cm: 0.5 mL/lesion
Below 0.5 cm: 0.1 mL/lesion

Dose Adjustments

Dosage Modifications
Renal or Hepatic impairment: there are No clinical trials have been conducted on the pharmacokinetics of talimogene laherparepvec with renal or hepatic impairment.

nivolumab

480 mg of nivolumab/160 mg of relatlimab Intravenous every four Weeks
Continue till unacceptable toxicity or disease progression occurs

Dose Adjustments

Dosage Modifications
Immune mediated adverse reactions (IMARs) general dose modifications
IMARs of severe (Grade 3): Delay
Life-threatening Recurrent severe (Grade 3) or Grade 4 Inability to lower corticosteroid dosage to 10 mg or less on prednisone or an equivalent within 12 weeks of starting steroids or IMARs requiring systemic immunosuppressive therapy: discontinue permanently
Pneumonitis
Grade 2
Delay therapy; Resume once complete or partial improvement (Grade below 1) has been achieved following corticosteroid tapering
If there isn't any complete or partial improvement within 12 weeks of starting steroids or if prednisone cannot be reduced to below 10 mg/day (or an equivalent amount) within 12 weeks of starting steroids, permanently discontinue.
Grade 3 and 4: Discontinue permanently
Colitis
Grade 2 and 3
Delay therapy; Resume once complete or partial improvement (Grade below 1) has been achieved following corticosteroid tapering
If there isn't any complete or partial improvement within 12 weeks of starting steroids or if prednisone cannot be reduced to below 10 mg/day (or an equivalent amount) within 12 weeks of starting steroids, permanently discontinue.
Grade 4: Discontinue permanently
Hepatitis
Total bilirubin increasing to more than 1.5 and 3 times ULN or AST or ALT increasing to more than 3 and 8 times ULN: Delay therapy; Resume once complete or partial improvement (Grade below 1) has been achieved following corticosteroid tapering
If there isn't any complete or partial improvement within 12 weeks of starting steroids or if prednisone cannot be reduced to below 10 mg/day (or an equivalent amount) within 12 weeks of starting steroids, permanently discontinue.
AST or ALT increasing to more than 8 times ULN or TB increasing to more than 3 times ULN: discontinue Permanently
Endocrinopathies
Grade 3 and 4: Delay till clinically gets stable or discontinue permanently based on the severity
Nephritis with the renal impairment
Grade 2 and 3 increased blood creatinine
Delay therapy; Resume once complete or partial improvement (Grade below 1) has been achieved following corticosteroid tapering
If there isn't any complete or partial improvement within 12 weeks of starting steroids or if prednisone cannot be reduced to below 10 mg/day (or an equivalent amount) within 12 weeks of starting steroids, permanently discontinue.
Grade 4 increase in the blood creatinine levels: discontinue Permanently
Dermatologic Exfoliative conditions
toxic epidermal necrolysis (TEN), Suspected Stevens-Johnson Syndrome (SJS), or Drug Rash with Eosinophilia Systemic Symptoms (DRESS): Delay therapy
Confirmed SJS, DRESS or TEN: discontinue Permanently
Myocarditis
Grade 2, 3, and 4: discontinue Permanently
Neurologic toxicities
Grade 2
Delay therapy; Resume once complete or partial improvement (Grade below 1) has been achieved following corticosteroid tapering
If there isn't any complete or partial improvement within 12 weeks of starting steroids or if prednisone cannot be reduced to below 10 mg/day (or an equivalent amount) within 12 weeks of starting steroids, permanently discontinue.
Grade 3 and 4: discontinue Permanently
Infusion-related reactions
Grade 1 or 2: slow the infusion rate or interrupt
Grade 3 or 4: discontinue Permanently
Hepatic impairment
Mild and moderate (TB below 3 times ULN and at any AST): dosage adjustment is not necessary
Severe: pharmacokinetics effects of relatlimab and nivolumab are not known
Renal impairment
Mild and moderate (eGFR 30 to 89 mL/min/1.73 m2): dosage adjustment is not necessary
Severe: pharmacokinetics effects of relatlimab and nivolumab are not known

nivolumab and relatlimab

480 mg of nivolumab/160 mg of relatlimab Intravenous every four Weeks
Continue till unacceptable toxicity or disease progression occurs

Dose Adjustments

Dosage Modifications
Immune mediated adverse reactions (IMARs) general dose modifications
IMARs of severe (Grade 3): Delay
Life-threatening Recurrent severe (Grade 3) or Grade 4 Inability to lower corticosteroid dosage to 10 mg or less on prednisone or an equivalent within 12 weeks of starting steroids or IMARs requiring systemic immunosuppressive therapy: discontinue permanently
Pneumonitis
Grade 2
Delay therapy; Resume once complete or partial improvement (Grade below 1) has been achieved following corticosteroid tapering
If there isn't any complete or partial improvement within 12 weeks of starting steroids or if prednisone cannot be reduced to below 10 mg/day (or an equivalent amount) within 12 weeks of starting steroids, permanently discontinue.
Grade 3 and 4: Discontinue permanently
Colitis
Grade 2 and 3
Delay therapy; Resume once complete or partial improvement (Grade below 1) has been achieved following corticosteroid tapering
If there isn't any complete or partial improvement within 12 weeks of starting steroids or if prednisone cannot be reduced to below 10 mg/day (or an equivalent amount) within 12 weeks of starting steroids, permanently discontinue.
Grade 4: Discontinue permanently
Hepatitis
Total bilirubin increasing to more than 1.5 and 3 times ULN or AST or ALT increasing to more than 3 and 8 times ULN: Delay therapy; Resume once complete or partial improvement (Grade below 1) has been achieved following corticosteroid tapering
If there isn't any complete or partial improvement within 12 weeks of starting steroids or if prednisone cannot be reduced to below 10 mg/day (or an equivalent amount) within 12 weeks of starting steroids, permanently discontinue.
AST or ALT increasing to more than 8 times ULN or TB increasing to more than 3 times ULN: discontinue Permanently
Endocrinopathies
Grade 3 and 4: Delay till clinically gets stable or discontinue permanently based on the severity
Nephritis with the renal impairment
Grade 2 and 3 increased blood creatinine
Delay therapy; Resume once complete or partial improvement (Grade below 1) has been achieved following corticosteroid tapering
If there isn't any complete or partial improvement within 12 weeks of starting steroids or if prednisone cannot be reduced to below 10 mg/day (or an equivalent amount) within 12 weeks of starting steroids, permanently discontinue.
Grade 4 increase in the blood creatinine levels: discontinue Permanently
Dermatologic Exfoliative conditions
toxic epidermal necrolysis (TEN), Suspected Stevens-Johnson Syndrome (SJS), or Drug Rash with Eosinophilia Systemic Symptoms (DRESS): Delay therapy
Confirmed SJS, DRESS or TEN: discontinue Permanently
Myocarditis
Grade 2, 3, and 4: discontinue Permanently
Neurologic toxicities
Grade 2
Delay therapy; Resume once complete or partial improvement (Grade below 1) has been achieved following corticosteroid tapering
If there isn't any complete or partial improvement within 12 weeks of starting steroids or if prednisone cannot be reduced to below 10 mg/day (or an equivalent amount) within 12 weeks of starting steroids, permanently discontinue.
Grade 3 and 4: discontinue Permanently
Infusion-related reactions
Grade 1 or 2: slow the infusion rate or interrupt
Grade 3 or 4: discontinue Permanently
Hepatic impairment
Mild and moderate (TB below 3 times ULN and at any AST): dosage adjustment is not necessary
Severe: pharmacokinetics effects of relatlimab and nivolumab are not known
Renal impairment
Mild and moderate (eGFR 30 to 89 mL/min/1.73 m2): dosage adjustment is not necessary
Severe: pharmacokinetics effects of relatlimab and nivolumab are not known

peginterferon alfa-2b

6mcg/kg subcutaneous weekly once for eight weeks, followed by 3mcg/kg subcutaneous weekly once for up to 5 years
Indication: indicated for the adjuvant management of melanoma following definitive surgical resection, including total lymphadenectomy, within 84 days of microscopic or gross nodal involvement

volociximab

Individuals diagnosed with advanced solid malignancies underwent treatment with increasing doses of this medication via intravenous (i.v.) infusion lasting 60 minutes
The drug has been demonstrated to be safely administered at a weekly intravenous dose of 15 mg/kg

Dose Adjustments

Limited data is available

lifileucel

It is Utilised as naturally sourced tumour infiltrating lymphocyte cells extracted from the tumour tissue of the patient, it provides an individually tailored therapy
A single intravenous infusion is administered as the dosage for this medication
Patients will undergo a lymphodepleting chemotherapy regimen cyclophosphamide plus mesna a day for two days, followed by fludarabine for five days prior to receiving this medication
Pre-medication will consist of diphenhydramine & acetaminophen or similar H1-antihistamine given half to one hour prior to this medication

cobimetinib

Safety and efficacy not established

binimetinib

Safety and efficacy not established

ipilimumab

Age: >12yrs
3 mg per kg given IV over 90 minutes every three weeks for a maximum of 4 doses
Adjuvant treatment of melanoma:
10 mg per kg given IV over 90mins every three weeks for four doses, followed by 10 mg per kg given IV over 90mins every 12 weeks for up to 3yrs

nivolumab

Indicated for Unresectable or Metastatic Melanoma as a single-agent use or in combination with ipilimumab.
Single-agent
• For <12 years: 3 mg/kg intravenously every 2 weeks or 6 mg/kg intravenously every 4 weeks
• For >12 years: 240 mg intravenously every 2 weeks or 480 mg intravenously every 4 weeks
• Continue until the disease is progressed or unacceptable toxicity is achieved
In combination with ipilimumab
• 1 mg/kg nivolumab intravenously every 3 weeks, with 3 mg/kg ipilimumab intravenously on the same day (maximum of 4 doses)
• After completion of combination therapy administer nivolumab
• For >12 years: 240 mg intravenously every 2 weeks or 480 mg intravenously every 4 weeks
• Continue the therapy until the disease is progressed or unacceptable toxicity is reduced

nivolumab and relatlimab

Below 12 yrs: Safety & efficacy were not established
Above 12 yrs and above 40 kg
480 mg of nivolumab/160 mg of relatlimab Intravenous every four Weeks
Continue till unacceptable toxicity or disease progression occurs

Dose Adjustments

Dosage Modifications
Immune mediated adverse reactions (IMARs) general dose modifications
IMARs of severe (Grade 3): Delay
Life-threatening Recurrent severe (Grade 3) or Grade 4 Inability to lower corticosteroid dosage to 10 mg or less on prednisone or an equivalent within 12 weeks of starting steroids or IMARs requiring systemic immunosuppressive therapy: discontinue permanently
Pneumonitis
Grade 2
Delay therapy; Resume once complete or partial improvement (Grade below 1) has been achieved following corticosteroid tapering
If there isn't any complete or partial improvement within 12 weeks of starting steroids or if prednisone cannot be reduced to below 10 mg/day (or an equivalent amount) within 12 weeks of starting steroids, permanently discontinue.
Grade 3 and 4: Discontinue permanently
Colitis
Grade 2 and 3
Delay therapy; Resume once complete or partial improvement (Grade below 1) has been achieved following corticosteroid tapering
If there isn't any complete or partial improvement within 12 weeks of starting steroids or if prednisone cannot be reduced to below 10 mg/day (or an equivalent amount) within 12 weeks of starting steroids, permanently discontinue.
Grade 4: Discontinue permanently
Hepatitis
Total bilirubin increasing to more than 1.5 and 3 times ULN or AST or ALT increasing to more than 3 and 8 times ULN: Delay therapy; Resume once complete or partial improvement (Grade below 1) has been achieved following corticosteroid tapering
If there isn't any complete or partial improvement within 12 weeks of starting steroids or if prednisone cannot be reduced to below 10 mg/day (or an equivalent amount) within 12 weeks of starting steroids, permanently discontinue.
AST or ALT increasing to more than 8 times ULN or TB increasing to more than 3 times ULN: discontinue Permanently
Endocrinopathies
Grade 3 and 4: Delay till clinically gets stable or discontinue permanently based on the severity
Nephritis with the renal impairment
Grade 2 and 3 increased blood creatinine
Delay therapy; Resume once complete or partial improvement (Grade below 1) has been achieved following corticosteroid tapering
If there isn't any complete or partial improvement within 12 weeks of starting steroids or if prednisone cannot be reduced to below 10 mg/day (or an equivalent amount) within 12 weeks of starting steroids, permanently discontinue.
Grade 4 increase in the blood creatinine levels: discontinue Permanently
Dermatologic Exfoliative conditions
toxic epidermal necrolysis (TEN), Suspected Stevens-Johnson Syndrome (SJS), or Drug Rash with Eosinophilia Systemic Symptoms (DRESS): Delay therapy
Confirmed SJS, DRESS or TEN: discontinue Permanently
Myocarditis
Grade 2, 3, and 4: discontinue Permanently
Neurologic toxicities
Grade 2
Delay therapy; Resume once complete or partial improvement (Grade below 1) has been achieved following corticosteroid tapering
If there isn't any complete or partial improvement within 12 weeks of starting steroids or if prednisone cannot be reduced to below 10 mg/day (or an equivalent amount) within 12 weeks of starting steroids, permanently discontinue.
Grade 3 and 4: discontinue Permanently
Infusion-related reactions
Grade 1 or 2: slow the infusion rate or interrupt
Grade 3 or 4: discontinue Permanently
Hepatic impairment
Mild and moderate (TB below 3 times ULN and at any AST): dosage adjustment is not necessary
Severe: pharmacokinetics effects of relatlimab and nivolumab are not known
Renal impairment
Mild and moderate (eGFR 30 to 89 mL/min/1.73 m2): dosage adjustment is not necessary
Severe: pharmacokinetics effects of relatlimab and nivolumab are not known