J Clin Med Res

Journal of Clinical Medicine Research, ISSN 1918-3003 print, 1918-3011 online, Open Access

Article copyright, the authors; Journal compilation copyright, J Clin Med Res and Elmer Press Inc

Journal website http://www.jocmr.org

Review

Volume 8, Number 2, February 2016, pages 63-75

Novel Drugs and Combination Therapies for the Treatment of Metastatic Melanoma

Figure 1. Overview of the signal transduction pathway like mitogen-activated protein kinase/extracellular signal-regulated kinases signaling pathway.

**Table 1.** Adverse Effects of Immunotherapy and Management
Treatment related adverse effects	Grade 1	Grade 2	Grade 3	Grade 4
AST: aspartate aminotransferase; ALT: alanine aminotransferase; ULT: upper limit of normal.
Skin toxicity. Most common adverse effect.	Mild to moderate localized rash or pruritus; papules/pustules covering < 10-30% of body surface. Rx: topical corticosteroids.	Non-localized rash (diffuse, ≤ 50% of skin surface) Rx: topical corticosteroids and monitoring.	Intense or widespread rash > 30%; skin sloughing < 10-30% of body surface; epidermal or mucus membrane detachment. Rx: systemic corticosteroids, hospitalization and hold immunotherapy.	Stevens-Johnson syndrome, toxic epidermal necrolysis (1% of cases), or rash complicated by full-thickness dermal ulceration, bullous and blisters. Rx: immediate hospitalization, systemic steroids and discontinue drug permanently.
GI toxicity/diarrhea. Second most common	< 4 stools per day over baseline Rx: symptomatic treatment.	4 - 6 stools per day over baseline. Rx: IV fluids for < 24 h, and symptomatic treatment. Rule out infectious causes. If not improving, hold drug and consider oral/IV steroids.	≥ 7 stools per day over baseline. Rx: IV fluids for > 24 h, hospitalization and IV steroids.	Life-threatening consequences (e.g., hemodynamic collapse). Rx: hospitalization, IV fluids, IV steroids. If symptoms not improving with IV steroids, consider infliximab.
Hepatotoxicity. Occurs in about 10% of patients.	Asymptomatic or mild symptoms. Rx: clinical or diagnostic observations only; intervention not indicated	AST or ALT > 2.5 to ≤ 5.0× ULN and/or total bilirubin > 1.5 to ≤ 3.0× ULN. Rx: frequent monitoring of LFTs. Consider holding immunotherapy.	AST or ALT > 5× ULN and/or total bilirubin > 3.0× ULN. Rx: hold immunotherapy and frequent monitoring of LFTs. Rule out viral, autoimmune or drug induced hepatitis.	High ammonia levels and hepatic encephalopathy. Rx: discontinue drug permanently and start high dose steroids (2 mg/kg/day). If not improving in 48 h, consider oral mycophenolate (500 mg twice daily).
Endocrine toxicity. Occurs in 4-8% of patients.	Asymptomatic. Rx: clinical or diagnostic observations only; intervention not indicated	Moderate symptoms. Rx: if suspicious for hypophysitis is high, complete endocrine workup should be done. Hormone replacements may be considered.	Severe symptoms. Rx: hospitalization indicated. Stop immunotherapy. Short course of steroids may improve pituitary function.	Adrenal crisis: severe dehydration, hypotension, or shock. Life-threatening consequences Rx: high dose IV steroids.

Table 1. Adverse Effects of Immunotherapy and Management

Treatment related adverse effects

Grade 1

Grade 2

Grade 3

Grade 4

AST: aspartate aminotransferase; ALT: alanine aminotransferase; ULT: upper limit of normal.

Skin toxicity.
Most common adverse effect.

Mild to moderate localized rash or pruritus; papules/pustules covering < 10-30% of body surface.
Rx: topical corticosteroids.

Non-localized rash (diffuse, ≤ 50% of skin surface)
Rx: topical corticosteroids and monitoring.

Intense or widespread rash > 30%; skin sloughing < 10-30% of body surface; epidermal or mucus membrane detachment.
Rx: systemic corticosteroids, hospitalization and hold immunotherapy.

Stevens-Johnson syndrome, toxic epidermal necrolysis (1% of cases), or rash complicated by full-thickness dermal ulceration, bullous and blisters.
Rx: immediate hospitalization, systemic steroids and discontinue drug permanently.

GI toxicity/diarrhea.
Second most common

< 4 stools per day over baseline
Rx: symptomatic treatment.

4 - 6 stools per day over baseline.
Rx: IV fluids for < 24 h, and symptomatic treatment.
Rule out infectious causes.
If not improving, hold drug and consider oral/IV steroids.

≥ 7 stools per day over baseline.
Rx: IV fluids for > 24 h, hospitalization and IV steroids.

Life-threatening consequences (e.g., hemodynamic collapse).
Rx: hospitalization, IV fluids, IV steroids.
If symptoms not improving with IV steroids, consider infliximab.

Hepatotoxicity.
Occurs in about 10% of patients.

Asymptomatic or mild symptoms.
Rx: clinical or diagnostic observations only; intervention not indicated

AST or ALT > 2.5 to ≤ 5.0× ULN and/or total bilirubin > 1.5 to ≤ 3.0× ULN.
Rx: frequent monitoring of LFTs.
Consider holding immunotherapy.

AST or ALT > 5× ULN and/or total bilirubin > 3.0× ULN.
Rx: hold immunotherapy and frequent monitoring of LFTs.
Rule out viral, autoimmune or drug induced hepatitis.

High ammonia levels and hepatic encephalopathy.
Rx: discontinue drug permanently and start high dose steroids (2 mg/kg/day).
If not improving in 48 h, consider oral mycophenolate (500 mg twice daily).

Endocrine toxicity.
Occurs in 4-8% of patients.

Asymptomatic.
Rx: clinical or diagnostic observations only; intervention not indicated

Moderate symptoms.
Rx: if suspicious for hypophysitis is high, complete endocrine workup should be done.
Hormone replacements may be considered.

Severe symptoms.
Rx: hospitalization indicated.
Stop immunotherapy.
Short course of steroids may improve pituitary function.

Adrenal crisis: severe dehydration, hypotension, or shock. Life-threatening consequences
Rx: high dose IV steroids.