Melanoma

More than half of melanoma cases are over diagnosed, meaning that the cancers never would’ve caused harm had they been left undetected and untreated.

Only thyroid cancers or more over diagnosed then melanomas.

Melanoma incidence in the white population in the US ranks third worldwide behind Australia and New Zealand.

World Health Organization  estimates worldwide and there are 66,000 deaths from skin cancer annually, with approximately 80% due to melanoma (WHO).

In 2024 there was an estimated 8290 deaths and 100,640 werediagnosed with melanoma in the United States.

Increasing at a greater rate than any other cancer in the U.S.

The number of cases is rising at a rate of 3% per year, especially among fair skinned people.

Its incidence is six times as high as it was 40 years ago.

The rise in melanomas diagnoses is restricted to the cutaneous form, as the incidence of noncutaneous melanomas has remained stable.

Increasing in men more rapidly than any other malignancy and more rapidly in women than any other malignancy except lung cancer.

Lifetime risk is 1.5 times higher in males than in females.

Male predominance is reversed in young adults, and in some younger age ranges, the female-male ratio as high as 1.8.

Estimated 101: 000 new cases in 2021.

Expected about 7100 individuals will die of metastatic melanoma in 2021.

Accounts for 1.5% of cancer related deaths.

Accounts for approximately 4% of skin cancers but around 79% of deaths related to skin cancer.

The fifth most common cancer in men and seventh in women in the U.S.

Among young adults, melanoma is the second most common invasive cancer, behind breast cancer.

Among patients younger than 15 years, the incidence is higher in females, and younger wome are particularly vulnerable.

Among individuals older than 50 years, melanoma incidence in men is nearly twice that of women.

Noncutaneous forms of melanoma including mucosal and ocular subtypes classically have worse prognosis.

From 1981 to 2002 incidence has increased nearly 2.8 times and is associated with increased tendencies to perform biopsies on pigmented lesions.

In 2005 age-adjusted incidence 24.6 per 100,000 for men and 15.6 per 100,000 for women.

Between 1975 and 2006 the incidence in men increased from 8.5 to 26.1 100,000 population, and in women from 7.4-17.6 per 100,000 population.

Incidence increased at an average of 4.6% annually from 1975 to 1985 and 2.7% annually from 1986 to 2007.

In 2010 46,770 cases of the in situ melanoma cases were expected.

Number of new cases increased 8 fold among young women and 4 fold among young men between 1970-2009.

Average increase in melanoma 2% annually in individuals between 0-19 years.

Incidence rates vary between gender, age, ethnicity and geographical location.

Increases in incidence has been observed in all histologic subtypes and tumor thicknesses, suggesting increases in incidence not due to screening alone or more thinner lesions would be found compared to deeper lesions.

Absent metastases there is no definitive diagnostic criteria for the pathological diagnosis of melanoma.

As a result, the diagnosis is subjective, and pathologists disagree about the presence of melanomas particularly with lesions in the diagnostic gray zone.

There are increasingly small, ambiguous lesions with nearly 90% of melanomas now in the less than 1 mm thickness category.

The increased frequency of ambiguous lesions, subjective criteria, and asymmetric incentives for underdiagnosing but not for over diagnosing melanoma, may explain the lower pathological threshold to diagnose melanoma.

Higher incidence rate among women younger than 45 years and in men older than 45 years.

Familial mutations explain only a small portion of melanoma cases with only 2% of melanoma patients having a CDKN2A mutation.

Mutations are likely to confer susceptibility to melanoma if the patient has three or more primary melanoma lesions or has more than one primary and a family history.

Approximately 85% of cases are diagnosed with early stages when surgery is curative.

Lifetime probability of developing invasive disease is 3% in men 2% in women.

The genetic basis of susceptibility to melanoma is unknown in 30 to 40% of families featuring four or more cases.

Can be subclassified into chronic sun damage skin melanoma and non-chronic sun damaged melanomas.

Chronic sun damaged melanomas typically arise in older patients on sun exposed areas and are associated with driver mutations BRAF non V600E, NRAS, F1 or KIT.

NRAS is the predominant mutated isoform of RAS oncogene, with mutation rates of approximately 13 to 25% in melanoma.

NRAS mutations appear most common in elderly and chronically UV exposed patients and are related to more aggressive prognosis including higher rates of visceral and CNS metastases.

Non chronic skin damage to melanomas typically arise inyounger individuals with intermittent sexposed areas and associated with BRAF B600 EE/K driving occasions.

A gene mutation that appears to increase the risk of inherited and sporadic cases of melanoma is the germ line mutation encoding M1TF, a transcription factor controlling the expression of several important proteins some related to pigmentation in melanocytes, the melanoma precursor cells.

Before age 40 years incidence higher in each age category of young women.

After age 40 years the incidence increases rapidly in men and the rate dramatically slow for women.

A combination of female, lower extremity sites, and superficial spreading melanoma mostly seen in early age onset disease, and the combination of male, head and neck or upper extremity site ad lentigo maligna melanoma mostly seen in late onset in age.

Ranks in the top 10 types of cancer in the U.S.

In 2008 62,480 individuals expected to develop melanoma in 2008 with 1 in 39 men and 1 in 58 women developing this potentially lethal cancer during lifetimes (Jemal).

One fourth of cases discovered by physicians.

Incidence has risen by 3-8% per year in Caucasian population since the 1960s.

Mortality rates increased by 28% over the past 25 years.

Five year survival for invasive melanoma has risen from 82.6% for cases diagnosed from 1975-1979, to 93.1% for cases diagnosed in 2002 (Altekruse SF et al).

Median survival of patients with stage IV melanoma is less than one year-historical data.

The improved survival is accounted for by earlier detection since there has been no substantial changes in the primary surgical excisional treatment.

Survival rates for stage IV disease is 33% at one year (Balch C)- historical data.

Cutaneous melanomas also categorized as: localized disease with no evidence of regional resistant distant metastases (stage 0-II), regional nodal/in-transit disease (stage III), and distant metastatic disease (stage IVj.

Lymphatic metastasis within or adjacent to the melanoma biopsy site or subsequent wide excision scar are termed satellite metastases, whereas those located between the primary tumor and the original lymph node basin or termed in-transit metastases.

Both of these conference stage III diagnosis, as do microsatellites.

In-transit metastases, microsatellite, and microscopic satellites all confer worse survival.

With stage I/ II melanoma the presence of microsatellites is linked to higher rates of SLN (sentinel lymph node)  positivity.

Cutaneous melanoma typically presents with a localized primary lesion, and most regional nodal melanoma present microscopically and is detected by sentinel lymph node biopsy.

Patient with a positive SLNB are at higher risk of recurrence and now may be followed with ultrasound surveillance without without completion lymph node dissection, given the lack of improvement assessing the merits of complete lymph node dissection versus clinical observation with nodal ultrasound.

Considered an immunogenic cancer because it can undergo spontaneous regression, are often associated with lymphocytic infiltration that correlates with histologic regression, and a higher incidence is reported in organ transplant patients receiving immuno suppressive therapy.

Regardless of molecular subtype the presence of lymphocytic infiltration is related to improved survival.

Cutaneous melanoma in situ (CMIS) the malignant melanocytes remain confined within the skin epithelium without invading the basal membrane.

The rapid rise in the incidence of cutaneous melanoma is driven largely by increased diagnostic scrutiny,  with the incidence of melanoma in situ now 50 times as high as it was in 1975.

The rising detection and treatment of melanoma in situ has not reduce the incidence of invasive melanoma, which has increased from 7.9 to 25.4 per 100,000 population of the same.

Risk factors: male sex, age greater than 50 years, tendency to burn, numerous or atypical nevi, genetic mutation, personal or family history of melanoma, excessive exposure to UV radiation in people with lighter skin tones.

People with red hair and fair skin are at significantly higher risk of developing melanoma than are people with the skin.

Elevated risk among fair skinned people is not restricted to sun exposed skin, raising the suspicion that UV radiation may not be the only risk factor for melanoma.

The pigment responsible for red hair causes oxidative damage in skin, and that damage promotes melanoma formation independent of UV radiation (Fischer DE).

Obesity associated with an increased risk of melanoma in men, and increased Breslow staging scale thickness.

Patients with higher BMI associated with a worse survival in patients with surgically resected melananoma.

CMIS believed to be a precursor of invasive disease.

Recommended excision margins of 5 mm as standard treatment for melanoma in situ.

Sentinel lymph node excision is probably the most important diagnostic and potentially therapeutic procedure.

Sentinel node biopsy staging of intermediate thickness or thick primary melanomas compared to wide resection and nodal observation vs immediate lymphadenectomy for positive nodes associated with prolonged disease free survival, and distant disease free survival for intermediate thickness melanomas (Morton DL et al).

In general of patient’s risk of a positive sentinel lymph node is less than 5% as in a T1 a melanoma,  it is not recommended to perform SLNB.

With a T1B melanoma the risk of a positive SLN is 5-10% and SLNB should be considered.

Wide local excision and sentinel lymph node biopsy recommended for lesions 0.76-1.00 mm thick or greater with ulceration or with a mitotic rate of 1/mm2 or greater, or lesions more than 1 mm thick.

Wide excision with sufficient margins result in very high rates of local control of 96% or greater.

Biopsy to establish a definitive diagnosis is best done with complete/excisional biopsy to maximize histopathologic of examination and micro staging of the primary tumor.

Complete biopsy with 1 to 3 mm margins around concerning lesion and may be full thickness, or punch techniques, or involve shave removal into the deep reticular dermis.

The presence of primary tumor regression is associated with mixed results in clinical studies, as far as prognosis is concerned.

Studies suggest that neural invasion may increase the chance for local recurrence.

The mitotic rate is an independent prognostic factor for melanoma specific survival of across all thickness categories.

A mitotic rate of 11 millimeters squared reduces five year melanoma specific survival of patients with node negative T1-T for melanoma to 84%.

A mitotic index of greater than 2 mm/m² is significantly associated with a higher risk of sentinel lymph node positivity in thin melanoma.

Melanoma Staging

Stage 0: Melanoma in Situ (Clark Level I), 99.9% survival

Stage I/II: Invasive Melanoma, 85–99% Survival

T1a: Less than 1.00 mm primary tumor thickness, w/o Ulceration and mitosis < 1/mm2

T1b: Less than 1.00 mm primary tumor thickness, w/Ulceration or mitoses ≥ 1/mm2

T2a: 1.00–2.00 mm primary tumor thickness, w/o Ulceration

Stage II: High Risk Melanoma, 40–85% Survival

T2b: 1.00–2.00 mm primary tumor thickness, w/ Ulceration

T3a: 2.00–4.00 mm primary tumor thickness, w/o Ulceration

T3b: 2.00–4.00 mm primary tumor thickness, w/ Ulceration

T4a: 4.00 mm or greater primary tumor thickness w/o Ulceration

T4b: 4.00 mm or greater primary tumor thickness w/ Ulceration

Stage III: Regional Metastasis, 25–60% Survival

N1: Single Positive Lymph Node

N2: 2–3 Positive Lymph Nodes OR Regional Skin/In-Transit Metastasis

N3: 4 Positive Lymph Nodes OR Lymph Node and Regional Skin/In Transit Metastases

Stage IV: Distant Metastasis, 9–15% Survival

M1a: Distant Skin Metastasis, Normal LDH

M1b: Lung Metastasis, Normal LDH

M1c: Other Distant Metastasis OR Any Distant Metastasis with Elevated LDH

Immunosuppressed patients at an increased risk of dying from melanoma, indicating that cells might be susceptible to surveillance by the immune system.

A meta-analysis of 42 phase II trials, the median survival for metastatic disease was 6.2 months, with a mean one year survival rate of 25.5% regardless treatment regimen (Korn EL).

Ranks second to adult leukemia in loss of years of potential life, per death

Case survival rate for newly diagnosed melanoma has increased substantially.

Nearly 630,000 Americans presently living with a diagnosis of invasive melanoma.

Prevalence and incidence increases with age, and particularly after the age of 50.

Projected lifetime risk 1 in 63 for Americans.

For someone born in 2005 the lifetime risk may be as high as 1 in 55 (SEER).

Incidence increasing rapidly in children.

In children accounts for less than 3% of all cancer cases in children under the age of 20 years.

In the first 10 years of life accounts for 0.9% of all cancers and in the adolescent years accounts for 7% of all cancers.

Median age for men is 60 years and for women is 53 years of age.

Can arise in any tissue that contains epidermal melanocytes includes mucocutaneous sites such as oral mucosa, nasopharynx, sinuses, tracheobronchial tree, vulva, vagina, anus, urinary tract, central nervous system and eye.

Most lesions develop from malignant transformation of melanocytes that reside in the basal epidermal layer in skin.

More than 50% of the cases arise in apparently normal areas of the skin.

Derived from melanocytes that originate in the neural crest and migrate toward the epithelium.

Typically initially grows horizontally within the epidermis (in-situ), and with time penetrates into the dermis and becomes invasive.

The vertical depth of the lesion is the factor that this correlates with prognosis.

Primary tumor features with prognostic significance include radial and vertical growth, regression, angiolymphatic invasion, perneural involvement, tumor infiltrating lymphocytes, and angiotropism.

Immune mechanism implied by rare spontaneous remissions, autoimmune phenomena of associated vitiligo and retinopathy.

Can arise de novo, independent of a preexisting melanocytic lesion, and can arise where UV irradiation is unlikely to contribute to carcinogenesis, although the vast majority of lesions arise in a cutaneous lesion on sun exposed skin and is identified as the primary site.

Risk factors include family history, dysplastic nevi, inability to tan, fair skin that burns easily with sun exposure, inherited genetic mutations, diseases that suppress the immune system, past history of squamous or basal cell cancers of the skin, prolonged exposures to coal tar, pitch, creosote, arsenic compounds and radium.

Can be seen in any ethnic group and even in individuals without exposure to the sun.

Epidemiological studies reveal that outdoor workers do not have an increased risk of melanoma over otherwise similar individuals who do not work in the sun.

The relationship between solar exposure and the risk of melanoma has not been demonstrated.

The malignancy is one of intermittent sun exposure rather then of chronic sun exposure.

Paradoxically, sun exposure may be protective under certain circumstances.

The number of melanocytic nevi present in individuals is the best predictor for cutaneous melanoma. Nevi ≥ 2 mm in diameter on the whole body surface, number of nevi > 6 mm, eye and skin color, modality of sun reaction, history of sunburn in childhood, and solar lentigines associated with increased risk of melanoma.

Light-skinned people are the predominant group affected by melanoma with lesions most common on the trunk, arms and legs where sun exposure is intermittent, while the chronically exposed face has less frequent involvement.

Most melanomas are related to the ultraviolet exposure and can be classified by high, medium, or low-mutation burden corresponding with the degree of sun exposure.

Chronically sun exposed skin has a different genetic profile than skin areas without such exposure and is different from extracutaneous mucosal and choroidal melanomas, underscoring the etiologic relationship between UV radiation and melanoma.

It is suggested that chronic exposure to ultraviolet light may be protective of melanoma.

The most common melanoma subtype in the US arises from non-chronically sun-damaged skin often contains active mutations in BRAF.

Mucosal, acral and chronically sun-damaged skin melanoma sites only infrequently have BRAF mutations, but frequently have amplification or activating mutations of KIT.

In mucosal melanoma mutations of BRAF and KIT genes are rare, with frequencies less than 10%.

In mucosal melanoma , as well as in acral melanoma , in which disease is not the result of events spurred by ultraviolet light, tumor, proliferation is attributed to a combination of early chromosomal instability, characterized by copy number gains in TERTIARY, CCNDI, and KIT genes, and non ultra violet relating activating mutations in KIT and PDGFRA genes

KIT normally expressed on melanocytes and plays a critical role in melanocyte migration, survival, proliferation and differentiation.

KIT mutations is expressed in some melanomas, and loss of its expression is seen with progression of disease from superficial to invasive disease, suggesting that KIT possesses tumor suppressor function.

KIT mutations and mutations have been identified in melanomas arising from the mucosal, acral or chronically sun damage surfaces.

KIT mutations are only 5 to 10% of all melanoma subtypes, but these mutations rarely occur in conjunction with BRAF or NRAS mutations and are typically not observed in cutaneous melanomas arising in the absence of chronic sun exposure.

KIT targeted agents such as  imatinib provide benefit to patients whose tumor harbors KIT mutations.

A high mitotic rate is a more powerful prognostic indicator than ulceration(Azzola MF et al).

Data extracted from patients with Stage I and II with mitotic rate available: 10 year survival ranged from 93% for patients with 0 mitosis/mm2 to 48% with 20/mm2, mean number of mitosis/mm2 increased as the primary melaoma became thicker-1 for melanomas 1mm, up to 9.6 >8mm (Thompson JF et al).

Ulceration of primary lesion assciated with higher mitotic rate.

In patients with advanced melanoma KIT gene mutations, treatment with imatinib results in clinical responses in a subset of patients (Carvajal RD et al).

BRAF (about 50%) and N-RAS (about 10%) genes are commonly mutated in melanoma.

BRAF mutations may be a negative prognostic marker for survival in metastatic melanoma.

40-60% of melanomas and 7-8% of all cancers have a activating mutation in the gene encoding the serine-threonine protein kinase B-R-A-F (BRAF).

90% of BRAF mutations result in a glutamic acid for valine substitution at amino acid 600 ( V600E mutation).

BRAF mutation activates BRAF and downstream signal transduction in the MAP kinase pathway (mitogen- activated protein kinase pathway).

BRAF mutations present in up to 70% of all lesions.

BRAF mutations common in melanomas arising in areas that are intermittently exposed to sun and rarely are related to melanomas on skin chronically exposed to sun or to areas on acral skin and mucous membranes that are rarely or never exposed.

BRAF is most common mutation in melanoma.

BRAF mutation rate declines with age-more than 80% of those aged 20-40 years to 50% of those aged 41-70 years, and to less than 25% of those older than 70 years.

BRAF V600E mutations occur in 86% of younger patients aged 20-30 years, and V600K mutation emerge in older patients.

Approximately 70% of BRAF mutations are reported to be V600E and 20% are V600K.

BRAF positive melanoma occurs in approximately 50% of cases that arise in the skin, 10 to 20% of cases that arise on mucosal surfaces, such as the mouth, sinuses, genitals, and rectum, 20 to 25% of cases of ocular melanoma affecting the conjunctiva, and no cases of ocular   melanomas affecting the choroid.

PLX4032 targets BRAF kinase and has a 83% tumor regression response in preliminary studies.

The Ras/Raf/mitogen activated protein kinase (MAPK) signaling pathway plays a part in tumor cell proliferation and angiogenesis and is activated by a mutant BRAF gene.

Melanomas associated with BRAF mutations include younger age, a few of markers of chronic sun damage in this skin, higher total body nevus counts, histopathologic findings of large epithelioid cells, heavy melanization, and prominent scatter of melanocytes.

The presence of BRAF mutation in a primary melanoma has no impact on disease free interval or overall survival.

Encorafenib and binimetinib are now approved in combination for the treatment of unresectable or metastatic melanomas with a BRAF V600E or V600K mutation.

Encorafenib and binimetinib approval is based on the randomized, active-controlled, open-label, multicenter COLOMBUS trial in which 577 patients with BRAF V600E or V600K mutations-positive unresectable or metastatic melanoma were randomized (1:1:1) to receive binimetinib (45 mg) twice daily plus encorafenib (450 mg) once daily, encorafenib (300 mg) once daily, or vemurafenib (960 mg) twice daily.

The combination of a BRAF/MEK kinases have been approved for his treatment of patients with metastatic melanoma that is unresectable.

Encorafenib/binimetinib combination for a BRAF mutational melanoma ( Braftovi/Mektovi).

The median progression-free survival was 14.9 months for patients receiving binimentinib plus encorafenib compared with 7.3 months for patients in the vemurafenib monotherapy arm.

Overall response rated were 63% and 40%, respectively.

In the above study median duration of response was 16.6 months and 12.3 months, respectively.

In the above study overall survival is 33.6 months in patients treated with the combination, compared to 16.9 months in patients treated with vemuafenib.monotherapy.

The most common adverse effects in patients receiving the encorafenib and binimetinib combination were fatigue, nausea, diarrhea, vomiting, abdominal pain, and arthralgia.

The combination of BRAF/MEK inhibition and PD-L1 inhibitors are considered upfront therapies for patients with late stage, aggressive disease.

WNT5A gene expression and signaling through WNT5A receptor associated with highly invasive melanoma.

Palm, sole and mucous membrane lesions have distinctive chromosomal aberrations compared to other sites of melanoma.

Acral and mucosal melanomas have an increased frequency of changes in copy number and gene amplification than cutaneous melanomas and distinct regions of the genome are affected in each type.

Genomic classification has subclassified tumors in four molecular subtypes: tumors associated with mutant BRAF, mutant RAS, mutant NF1, and triple wild-type melanoma.

The genomic subtypes correlate with clinical and prognostic features and with therapeutic options.

Indoor workers have a higher risk of melanoma than outdoor workers.

Palms, soles and mucosal surfaces may develop melanoma with relative to complete solar protection.

Head and neck melanoma patients have higher levels of TP53 protein and a higher frequency of non melanoma skin cancers and lower number of melanocytic nevi than patients with trunk melanomas.

Tumor thickness is the most important histological feature in predicting prognosis.

Older men continue to present with thicker lesions and have poor prognoses.

People with a white racial background have at least a 10-fold increase in the incidence of melanoma compared with blacks and seven-fold incidence compared with American Hispanic: survival among these groups is also worse.

For patients who have one melanoma, the risk of developing a second is 10-25 times greater than for patients without a history of melanoma.

A history of nonmelanoma skin cancer may increase a person’s risk of developing melanoma by threefold to fivefold.

About 95% of melanomas have chromosomal aberrations.

Approximately 35% of women with melanoma are of childbearing age.

Amelanotic melanoma constitutes 2-15% of all cases of melanoma.

Ten percent of melanoma patients have at least one affected first-degree relative, while 1% of melanomas occur in families with multiple affected members.

Melanoma is an immunogenic tumor.

Melanoma has a worse prognosis in clinical settings of immunosuppression.

Melanoma induces immunosuppression via number of mechanisms recruiting down regulation of surface, mutations within malignant cells, slacked off Costonia Letory function, secretion of immunosuppressive cytokines, induction of tolerance (McCarter MD et al).

CD4+, CD25+ T cells express FOXP3 and are associated with failed clinical response of melanoma to immunologic based therapies.

Patients with advanced stage disease have statistically greater number of regulatory T cells than healthy adults and subjects with stage 1 melanoma and CD4+CD25+T cells have a twofold increased frequency in lymph nodes that have melanoma metastases compared with tumor free lymph nodes.

ABCD acronym for diagnosis refers to Asymmetry, Border irregularity, Color variegation, Diameter greater than 6 mm.

Diagnostic sensitivity for ABCD for melanoma ranges from 57-90% and specificity from 59-90%.

Not all melanomas have all four ABCD features.

Glascow 7-point checklist for diagnosis includes three major criteria of change in size, shape, color and four minor criteria of sensory change, diameter of 7 mm or greater, and the presence of inflammation, crusting, or bleeding (Mackie RM).

ABCDE is the enhanced acronym with E referring to Evolving recognizing lesion changes that enhance the ability to recognize melanomas at the earliest stages.

Diagnosis: a suspicious melanocytic neoplasm requires complete excisional skin biopsy when feasible.

This type of biopsy optimizes pathologic micro staging to assess Breslow thickness,  presence of ulceration, microsatellites, and dermal mitotic rate

Has a primary resistance to chemotherapy, a rapid tumor doubling time and a tendency to metastasize to the brain.

Cutaneous melanocytes exist in a hypoxic environment and rely on growth factor signaling from adjacent keratinocytes and inflammatory cells for survival.

Familial melanomas occur at an earlier age with a median age of 35 years versus 54 years in sporadic cases.

Estimated 82-85% of patients present with localized disease, while 10-13% have regional disease ad 2-5% present with metastatic disease.

With localized disease and a primary tumor thickness of 1.0 mm or less have a 5 year survival in more than 90% of patients.

With localized melanoma and a more than 1.0 mm in thickness lesion survival rates range from 50-90%.

In a review of 18,499 patients with melanoma from 1998-2001, 10% of patients with stage IA disease were overtreated with sentinel node biopsy (7.1%) or lymph node dissection (1.3%) (Cormier JN et al).

The 5-year survival rate decreases 20%-50% with the development of lymph node metastases.

When regional lymph nodes are involved survival rates are roughly halved.

Survival rate at 5 years for patients with metastatic disease is less than 15-20% and a median survival of 6-7 months (Barth A).

In the presence of stage III disease 5 year survival rates range from 20-70% depending on nodal tumor burden.

20-25% of patients with melanoma will die from metastases.

Metastatic melanoma associated with a 10-year survival of 2.5-17%.

Survival decreases as the number of positive lymph nodes increases.

Of skin overall 5-year survival 88%.

Of uveal tract 5-year survival about 75%.

Of the uveal tract is the most common primary intraocular malignancy and the only potentially fatal eye malignancy in adults.

Of head and neck 5-year survival greater than 31%.

Lentigo type 5-year survival 93%.

Superficial spreading type 5-year survival >91%.

Complete excision results in a greater than 95% 8-year survival rate for thin (<1mm), invasive melanoma and essentially cures melanoma in-situ.

For patients with primary tumors 1.0 mm in thickness the 5 year survival is greatly 90%.

The survival rates for patients with melanomas grade than 1 mm thickness range from 50-90%.

Within stage III survival range from 20-70%, Depending on the nodal tumor burden.

Imiquimod may be effective therapy in the management of lentigo maligna.

Lesions thicker than 1.5 mm treated with low dose αIF improves disease free survival but not overall survival.

Nodular type overall 5-year greater than 64%.

Acral type 5-year survival greater than 66%.

Stage IV 5-year survival rate less than 5%.

Stage IV-median survival of 4 to 6 months.

Stage 0-5-year survival 96%.

Stage I 5-year survival 92.5%.

Stage II 5-year survival 74.8%.

Risk of recurrence for T4N0M0 (AJCC IIB) disease is approximately 60%.

Risk of recurrence approximately 75% in patients with T1-4N1M0 (AJCC III) disease.

Suspicious lesions should be excised, preferably with 1-3 mm margins.

Orientation of excisional biopsy should be planned for definitive treatment in mind.

Biopsy should be planned so that it will not interfere with lymphatic mapping and sentinel nodes biopsy.

With biopsy plan of wider margins should be avoided.

Sentinel lymph node biopsy standard of care for staging melanoma.

Sentinel lymph node burden is the most important prognostic factor for patients with early stage melanoma (Morton DL et al).

Sentinel lymph node biopsy considered for patients with melanoma thickness between .75 mm and 4 mm without evidence of regional or distant metastases Stages T2-3,N0,M0).

Sentinel lymph node biopsy positive 3-year disease-free survival rate of 37% and a 3-year survival rate of 70%.

5-year survival consistently less than 50% with node positive disease.

Sentinel lymph node biopsy negative 3-year disease-free survival rate of 73% and a 3-years survival rate of 82%.

Sentinel lymph node positibity rates depend on median and mean Breslow thickness of the primary, ulceration rates and vary from 14-30%.

About 20% of patients who are sentinel node positive will have further node involvement by completion lymph node dissection, the nonsentinel node positivity rate.

Sentinel node morphometric parameters that should be measured in positive sentinel nodes: Dewar criteria-the microanatomic location, and Rotterdam criteria-the maximum diameter of the largest tumor lesion.

Patients woth positive sentinel lymph node biopsy wth metastases <1mm, especially when present in the subcapsular area only, have a melanoma specific survival of 95%, a statistic indistinguishab;e from sentinel ln negative patients (van der Ploeg APT et al).

SLNB is indicated for melanomas ≥ 0.75 mm.

Only 10%-20% of patients present with occult lymph nodes metastases.

Approximately 15-25% of patients with a clinically negative lymph nodes have microscopic nodal metastases.

Sentinel lymph node biopsy positivity associated with increasing Breslow thickness, Clark level of more than III, the presence of ulceration and patient age of 60 years or less as the most important independent variables.

Estimated risk of nodal recurrence after a negative SLN biopsy is less than 5% in a study of more than 25,000 meta=analysis patients.(Valsecchi ME et al).

Ulceration of the primary tumor is ranked increasingly important as presaging aggressive biology equal to lymph node involvement.

As a prognostic factor Clark’s level is falling out of favor.

Sentinel lymph node biopsy spares 75-80% of patients the need for complete lymphadenectomy.

If sentinel lymph node is found to contain metastases a complete nodal resection is recommended.

The MSLT-I trial indicated that a positive sentinel node followed by a completion lymphadenectomy was associated with an improved melanoma specific survival compared to nodal observation.

MSLT-II phase three trial showed immediate completion of node dissection conferred no survival benefit compared with nodal observation to patients with melanoma who had sentinel node metastases.

The above study has now changed the previous standard of care for completion of lymphadenectomy.

Lesions less than 1 mm thick are associated with a less than 5% rate of regional metastases.

Lesions thicker than 4 mm are associated with a 30-50% rate of nodal involvement.

Patients with sentinel lymph node metastases associated with a 6.5 fold likelihood of dying compared to patients with a negative sentinel lymph node biopsy.

!5-20% of patients with melanoma will develop lymph node metastases.

Multicenter Selective Lymphadenectomy Trial-I compared wide excision alone the wide excision and sentinel node biopsy with cutaneous melanoma with lesions 1.2-3.5 mm (intermediate thickness) results in an increase in the likelihood of being disease free at 5 years, 78% for the sentinel node sampling to 73% to observation, based on lower risk of nodal failure.

Therapeutic lymph node dissection is potentially curable with clinical lymph node metastases: however regional recurrences develop in 30-50% of these patients with a 10-year overall survival rate of 25-40% (Calabro A).

In a phase 3 study complete lymph node dissection does not improve survival after positive sentinel lymph node biopsy (Garbe C) suggesting current practice may be unnecessary.

Regional lymph mde recurrence after lymph node dissection associated with multiple positive nodes, large nodes and extracapsular extension (Lee RJ).

Adjuvant regional radiation after resection of involved lymphnodes, associated with an 89% 5-year regional lymph node basin control rate (Ballo MT).

Adjuvant regional radiation may achieve regional control after lymphadenectomy for node positive disease, the 5 year disease free and disease specific survival rates are 44% and 49%, respectively (Ballo MT).

In an integroup randomized trial the use of adjuvant nodal basin radiotherapy improved regional lymphatic control for high-risk patients compared with no further treatment after lymphadenectomy (Burmeister B et al).

In the above study radiation dose of 48 Gy 20 fractions was used, and while it improved the risk of local relapse, overall survival did not differ significantly.

Size of axillary lymph nodes is a significant predictor of outcome following axillary lymphadenectomy with a 5 year survival rate of 73% for patients with palpable noeds < 2cm versus 46% with palpable lymph nodes measuring between 2-4 cm (Karakousis CP).

Frozen sections of sentinel lymph nodes is not recommended as the studies are not sensitive enough.

Clark levels should not be utilized to select patients with thin melanomas for sentinel node biopsy.

Recommended surveillance Stage I-annual, Stage II-every 6 months for 2 years than annual, Stage III-every 3 months for 1 year, every 4 months for second year, every 6 months for years 3-5. Exams should include physical examination, CBC, liver function tests, and annual chest x-ray.

No strong evidence exists that women have a better prognosis than men when compared stage for stage but they have a more favorable natural history between initial diagnosis and development of distant metastases.

For patients with lesions thinner than 1.5 mm, the 5-year disease-free survival prospects are over 90%: for those with lesions thicker than 3 mm, the 5-year disease-free survival rate falls to below 50%.

In the past elective lymph node dissection advocated for patients with intermediate-thickness lesions at risk for clinically occult regional nodal metastases.

Only one of four prospective randomized trials shown a survival benefit for elective lymphadenectomy, and this was within a subset of patients younger than 60 or with melanomas 1-2 mm thick.

Elective lymph node dissection with clinically negative but histologically positive nodes have a 50-60% chance for survival compared to a 15-35% survival for those who develop apparent metastases in the regional lymph nodes during follow-up.

Lesions up to 2 mm in thickness can safely be excised with a 1-cm margin with no detrimental effect on patient survival.

In the treatment of intermediate thickness melanomas (1-4mm) there are no differences among patients treated with 2-cm vs 4-cm margins with regard to overall and disease-free survival or local recurrence.

1-cm margins are appropriate for melanomas on the trunk and proximal extremities with lesions smaller than 2-cm in diameter.

1.5-cm margins are appropriate for tumors greater than 2 cm in diameter.

For melanomas on the head, neck, hands and feet, a minimum surgical margin of 1.5 cm is recommended.

For melanomas with diameters greater than 3 cm a margin of 2.5 cm is recommended.

Margins of resection for localized cutaneous melanoma thicker then 2 millimeters, (T3-T4,N0M0, IIA-IIC) is still controversial, but in a study of 936 patient’s with cutaneous melanoma thicker than 2 mm randomized either 2 centimeter or 4 cm. surgical resection margins: The five year survival was 65% in the 2 centimeter group and 65% in the four centimeter group (Gillgren P et al).

Complicating pregnancy ranges from 0.1 to 2.8 per 1000 pregnancies.

The most likely cancer to metastasize to the placenta and fetus.

The placentas of women with melanoma should be examined for metastases.

With placental involvement neonates have a 22% risk of developing metastatic melanoma.

Stage T1a-<1mm if nonulcerated or Level II or III lesions, stage T1b-< 1mm if ulcerated or Level IV or V lesions.

10-year survival 83% for ulcerated <1 mm lesions and 92% for patients with nonulcerated <1 mm lesions.

In selected patients surgical resection of pulmonary, gastrointestinal and adrenal metastases can result in a median survival between 24 and 49 months.

10-20% of stage IV patients have clinical evidence of liver metastases, but most have metastases at autopsy.

Presentation of stage IV melanoma with isolated liver metastases has a median survival of 4 to 6 months

Up to 95% of patients with ocular melanoma and stage IV disease develop liver metastases.

In ocular melanoma the liver is the sole site of metastases in 60-80% of cases with multiple lesions.

One of the most common malignancies associated with metastases to the gastrointestinal tract.

Gastrointestinal involvement can be primary or metastatic.

Primary gastrointestinal melanoma can arise in mucosal sites such as the oral cavity, esophagus, small intestine, colon, rectum, and anus since all of these areas have HMB-45 and S-100 positive immunochemistry stains for melanocytes.

Benign melanocytes can be present in lymph nodes as nodal nevi, with reported incidences varying from less than 5% to as high as 22% of lymphadenectomy specimens in melanoma patients.

Median survival of patients with hepatic metastases as their initial site of metastatic disease associated with a median survival of only 4.4 months.

High dose adjuvant alfa interferon in high-risk patients improves 5-year relapse free survival by 10% but does not increase overall survival.

High dose alfa interferon 20 million units per metered squared intravenously for 4 weeks, followed by 10 million units per metered squared three times per week given subcutaneously for 48 weeks.

ECOG 1684 study highly statistical significant survival and relapse interval benefits for high doses of adjuvant interferon given for 1 year.

ECOG 1690 trial of high doses of interferon for 1 year compared to lower doses for 2 years and compared to a third arm of observation: indicted a increased relapse free survival for high dose interferon, but not an increases in overall survival.

ECOG 1694 tested high dose interferon compared to GMK vaccine with 16 month data showing a higher relapse rate and 1.5 times greater mortality in the vaccine group.

gp100, is a melonosomal protein. the presence of which may increase the efficacy of high dose interleukin- 2 in patients with metastatic melanoma.

Low dose adjuvant alfa interferon in high-risk patients does not increase relapse free or overall survival.

Benefits of high dose interferon treatment compared with observation decreases substantially with increasing age at the time of diagnosis.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) in high risk melanoma patients with IL-2 resulted in 60% of 45 high risk patients being free of disease at 21 months, with an overall survival rate of 64%: lesions were satellitosis and in-transit metastases.

GM-CSF activates dendritic cells increasing the efficiency of cytotoxic T lymphocytes.

Dendritic cells are rich in costimulatory factors B7-1, B7-2.

Dendritic cells increase IL-2 receptors on T cells and enhance efficacy of IL-2 induced cytotoxic T cells.

IL-2 stimulates natural killer cells, CD8 positive cells and tumor infiltrating lymphocte proliferation and function.

In patients with advanced melanoma progression free survival was significantly longer among those who received TIL (tumor infiltrating lymphocyte) therapy than among those who received ipilimumab.

Benefits of high dose interferon treatment compared with observation decreases substantially with increasing age at the time of diagnosis.

Greatest benefit seen in patients younger than 60 years and with stage IIIC, this is in part due to the fact that IIIC disease has the highest rate of recurrence (approximately 70% at 5 years) so that there is a greater proportion of benefits for high dose interferon.

Patients with American Joint Committee on Cancer stage IIB, IIC, or III have risks of relapse and death of greater than 40% and are candidates for adjuvant high dose interferon for melanoma.

Cerebral metastases ultimately diagnosed in up to 10% of patients.

Cerebral metastases identified at autopsy in 49-73% of patients who die of melanoma.

Brain metastases more likely in male patients, those with primary site lesions on the trunk, head and neck and with thickened and ulcerated primary lesions.

Median survival 2-3 months with brain metastases.

Since the approval of checkpoint blockade immunotherapy (CBI) and BRAFV600-targeted therapy in 2011, survival times for patients with melanoma brain metastases (MBMs) have significantly improved, with a 91% increase in 4-year overall survival (OS) from 7.4% to 14.1%.

Among people with melanoma whose tumors have spread to the brain, the combination of nivolumab and ipilimumab produces a complete response in 26% of asymptomatic patients, according to an open-label, phase 2 U.S. study of 94 volunteers with stage 4 disease (CheckMate 204).

Among patients with advanced disease sustained long-term overall survival at five years was greater in patients who received nivolumab plus ipilimumab or nivolumab alone than those who received ipilimumab alone.

Long-Term Survival of Patients With Melanoma With Active Brain Metastases Treated With Pembrolizumab on a Phase II Trial

Melanoma is the solid tumor with the highest risk for dissemination to the CNS

Long-term follow-up of pembrolizumab-treated patients with new or progressing brain metastases treated on a phase II clinical trial.

We enrolled 23 patients with melanoma with one or more asymptomatic, untreated 5- to 20-mm brain metastasis not requiring corticosteroids; 70% of patients had prior systemic therapy.

Pembrolizumab was administered for up to 24 months.

Six patients (26%) had a brain metastasis response.

The median progression-free and overall survival times were 2 and 17 months, respectively.

48% were alive at 24 months, suggesting pembrolizumab is active in melanoma brain metastases with acceptable toxicity and durable responses.

Melanoma brain metastases incidence at autopsy is up to 70%.

Whole-brain radiation is typically ineffective for melanoma.

All patients with extracerebral response also responded in the CNS.

The median PFS time was 2 months, and the median OS time was 17 months.

At 24 months of follow-up, 11 patients (48%) remained alive

23 patients were enrolled and although the brain metastasis RR was only 26%, three patients who were unevaluable for CNS response remained alive and progression free at 24 months.

All patients who responded systemically also responded in the CNS, and all responses were ongoing for the 24-month duration of the study.

The median OS time was 17 months, and 48% of patients were alive at 2 years.

Brain metastasis response rates are greater than 50% in BRAF-mutant melanoma, treated with BRAF/MEK inhibitors, although the duration of response tends to be short.

Ipilimumab, administered with untreated brain metastases, was less active than PD-1 inhibitors, similar to extracerebral disease.

In a trial of nivolumab or nivolumab plus ipilimumab in patients with brain metastasis; the RRs to monotherapy and combination therapy were 20% and 42%, respectively, in asymptomatic patients.

Patients previously treated with BRAF/MEK inhibitors had a worse outcome.

Tawbi presented early results of a trial of ipilimumab and nivolumab in patients with untreated with brain metastasis, demonstrating a brain metastasis RR of 55%.

Combination therapy should be considered for patients with brain metastases.

All patients who achieved an objective response remained in response at 24 months, which is longer than the CNS response in patients treated with BRAF/MEK inhibitors.

Brain metastases, particularly when small and not located in critical sites can safely be treated with systemic therapy or systemic therapy combined with local therapy.

Prophylactic antiepileptics are recommend for patients with untreated brain metastases treated with immune therapy.

The incidence of radionecrosis (30.4%) was higher than expected based on historical observations, which may be as a result of immune therapy, improved longevity, or both.

There is no clear threshold for PD-L1 positivity below which responses are not seen.

About 30% of patients with stage IV disease manifest with brain metastases at some point in their disease course.

Approximately 20% of patients with metastatic melanoma have brain metastases at diagnosis.

Cerebral hemispheres are the site of 80% of melanoma brain metastases, followed by cerebellum (15%) and brainstem (5%).

12 month survival of patients with brain metastases treated with BRAF inhibitors was 37% (Kotacha R).

Brain metastases from melanoma are generally considered more radio-resistant than other types of brain metastases.

Patients who are symptomatic with brain metastases but who are unfit for surgery or stereostatic radiosurgery because of large numbers of metastases, poor performance status or uncontrolled extracranial metastases are generally treated with whole brain radiation therapy.

STAT3 signalling is involved in extravasation, angiogenesis, and prevention of anoikis, which is death due to inadequate attachment to extracellular matrix.

CNS a frequent site of relapse in patients with an initial complete response to biochemotherapy.

Combination of chemotherapy and biologic response modifiers associated with higher response rates (30-50%), than single agent (10-20%)chemotherapy or single agent biologic response modifiers (15%).

Higher biochemotherapy response rates do not translate into improved survival in randomized trials.

A phase II study of maintenance biotherapy after induction concurrent biochemotherapy for patients with metastatic melanoma indicated a prologation of progression free survival and improve survival compared with trials of biochemotherapy or chemotherapy (O’Day SJ).

Lower incidence of brain metastases with the use of Temozolomide vs. the use of DTIC (dacarbazine).

Temozolomide with Sorafenib has a 39% partial response in chemotherapy naïve melanoma patients.

Temozolomide with Sorafenib did not restore temozolomide sensitivity in patients who failed prior treatment for melanoma.

Temozolomide-with Sorafenib, patients experienced lymphopenia, hand-foot syndrome, rash and nausea.

Older patients present with thicker melanomas and have a higher incidence of ulceration but decreased frequency of sentinel lymph node metastases.

Nodal basin recurrence rate 1.6-11% following negative sentinel lymph node dissections.

Survival for older patients decreased compared to younger patients secondary to impaired immunity, comorbid problems and the fact that they are less likely to receive adjuvant immunotherapy.

15% overall response to high-dose IL-2 in advanced melanoma with a 7% complete response rate.

A phase III study adding gp100:209-217(210M) peptide vaccine to IL-2 more than doubled response rate of IL-2 alone , 22.1% vs. 22.1%, respectively: and progression free survival and overall survival were also longer (Schwartzentbruber DJ).

Long term follow up of patients treated with high dose IL-2 reveals an overall response rate of 16%, with a durable response rate of 4%, and a median overall survival of 12 months (Atkins et al.), while 6% had a complete remission with median duration of complete remission at the time of the report of greater than 59 months.

Patients with advanced disease that respond with complete remission to IL-2 have durable responses and a median duration of response of greater than 7 years.

Hepatic artery treatment for liver metastases with fotemustine associated with a 40% response rate and overall survival of 14 months (Leyvraz S et al).

Response rate of Temozolomide about 12% in metastatic disease.

DTIC response rate in metastatic disease about 12%-20%.

DTIC (Dacarbazine) median response 4-6 months in metastatic disease.

Randomized trials among patients with metastatic melanoma associated with a median survival of less than eight months for dacarbazine.

DTIC does not increases survival time in randomized trials of patients with metastatic disease.

Combining temozolomide with dacarbazine does not increase response rates.

Response rate for Temozolomide and thalidomide 15-32% in metastatic disease.

GM-CSF may offer benefits in high risk patients by increasing and differentiating dendritic cells, which correlate with delayed recurrence of disease in high risk patients.

Response rate to paclitaxel in metastatic disease 13-15%.

Response rate with the combination of carboplatinin and paclitaxel as high as 20%.

A total of 676 HLA-A0201 positive patients when unresectable stage III or IV melanoma whose disease has progressed were randomized to receive ipilimumab plus gp100, ipilimumab alone, or gp100 alone: Median survival 10 months among patients receiving b plus gp100, as compared with 6.4 months among patients receiving gp100 alone (Hodi FS).

Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) blockade with ipilimumab prolongs survival in patients with metastatic melanoma and the addition of GM-CSF results on longer overall survival and lower toxicity, but no difference in progression free survival.

The addition of GM-CSF to ipilimubab resulted in 69% survival of patients at 1 year, with metastatic melanoma compared to 53% of those that got ipilimubab alone, for a 35% reduction in risk of death (Hodi FS et al).

Adjuvant ipilimumab for patients with lymph node positive stage III melanoma randomized to ipilimumab vs placebo decreased recurrence by 25% after median follow up at 2.7 years (Eggermont et al).

Ipilimumab approved for adjuvant treatment of patients with stage III melanoma with nodal involvement following complete resection and lymphadenectomy.

In adjuvant therapy the drug reduces recurrence rate by 25% vs placebo.

The extended use of Ipilimumab approval was based in the results from the international, double-blind phase 3 EORTC 18071 trial involving 951 patients with stage III cutaneous melanoma who had adequate resection of lymph nodes.

In the above study patients were randomized in a 1:1 ratio to receive ipilimumab ( 10 mg/kg IV) or placebo every 3 weeks for 4 doses, then every 3 months for up to 3 years.

The median relapse free survival (RFS) was 26.1 versus 17.1 months with ipilimumab versus placebo, respectively, and the 3-year RFS rate was 46.5% in the ipilimumab arm compared with 34.8% in the placebo group.

Combining Nivolumab and Ipilimumab for the treatment of advanced melanoma: ipilimumab was held at a fixed dose of 3 mg/kg while nivolumab was escalated from 0.3 mg/kg to 3 mg/kg. The drugs were given together every 3 weeks for a total of 4 doses demonstrated an objective response rate of 40% and an 80% survival rate at 1 year.

In the above study there was a 1-year survival of 85%, 2-year survival rate of 79%, and median survival of 40 months in the first 53 patients.

Check-Mate-069 demonstrated an objective response rate of 61%, including a 22% complete response rate with a combination nivolumab and ipilimumab.

In CheckMate trial 238 adjuvant nivolumab extended recurrence free-survival compared to adjuvant ipilimubab.

Five-year survival for metastatic melanoma is approximately 35% with PD-1 inhibitors.

Nivolumab approved for the adjuvant treatment of patients with melanoma with involvement of lymph nodes or metastatic disease who have undergone complete resection.

COMBI-AD study of patients with Stage III completely resected melanoma with BRAF mutation were assigned to dabrafenib and trametinib or placebo: estimated 3 year relapse free survival was 58% with dabrafenib and trametinib vs. 39% for placebo, decreasing the risk for death or recurrence by 53%.

In a phase 2 trial of vemurafenib in patients previously treated with BRAF V600 mutant metastatic melanoma involving 132 patients with a median follow-up of 12.9 months was associated with an overall response rate of 53%, 6% complete response, median duration of response, 6.7 months and median progression free survival 6.8 months, and median survival of 15.9 months (Sosman JA et al).

Dabrafenib (Tafinlar) is drug for the treatment of cancers associated with a mutated version of the gene BRAF.

Dabrafenib (Tafinlar) acts as an inhibitor of the associated enzyme B-Raf, which plays a role in the regulation of cell growth.

Dabrafenib has clinical activity with a manageable safety profile in clinical trials of phase 1 and 2 in patients with BRAF(V600)-mutated metastatic melanoma.

Trametinib (Mekinist®) in combination with dabrafenib (Tafinlar®) for treatment of unresectable melanoma or metastatic melanoma with BRAF V600E or V600K mutations phase 2 component of the phase 1/2 open-label study demonstrated an overall response rate of 76% in the combination treatment arm versus 54% in the dabrafenib-alone arm.

Pembrolizumab approved as a treatment for patients with advanced or unresectable melanoma following progression on prior therapies.

Now approved as first line agent in melanoma.

At the recommended dose for pembrolizumab of 2 mg/kg, the overall response rate (ORR) was 24%, with a response duration lasting from 1.4 to 8.5 months.

Pembrolizumab (Keytruda) yielded significantly better outcomes compared with ipilimumab (Yervoy) in a randomized phase III trial of patients with advanced melanoma.

Pembrolizumab treatment among patients with advanced melanoma is associated with an overall objective response of 33%, twelve-month progression free survival of 35%, the median overall survival of 23 months, and grade 3 or 4 treatment related adverse events occurred in 14% (Ribas A).

Adjuvant therapy for high-risk stage III melanoma, 200 mg of pembrolizumab administered every 3 weeks for up to 1 year resulted in significantly longer recurrence-free survival than placebo, with no new toxic effects identified.

Niviolumab has been approved for use in metastatic melanoma in patients with advanced disease who previously received ipilimumab on the basis of study Check-mate-037 clinical trial.

In the above study a 32% overall response rate was reported.

In melanoma recommended dosage is 3 mg per kilogram administered as an intravenous infusion for 60 minutes every two weeks.

In the CheckMate-067 study a randomized phase 3 trial testing Nivolumab alone or in combination with Ipilimumab: Nivolumab alone double the median progression free survival time for Ipilimumab alone and the benefit was greatest with the combination resulting in a median progression free survival of 11.5 months (Wolchok JD et al).

In the above study efficacy was demonstrated regardless of PD-L1 expression or BRAF mutation status.

In the above study tumor responses were significantly higher in the combination treatment 57.6% versus 43.7% in Nivolumab alone and 19% in Ipilimumab alone.

In the CheckMate-067 study the overall survival rates at 3 years were 58% in the nivolumab plus ipilimumab arem, 52% in the nivolumab arm.

In the above study approximately half of the patients did not survive 3 years under nivolumab monotherapy.

Combination therapy was associated with a high risk of toxicity:59% experienced grade 3 or 4 adverse events.

In a phase 2 trial of Vemurafenib in patients previously treated with BRAF V600 mutant metastatic melanoma involving 132 patients with a median follow-up of 12.9 months was associated with an overall response rate of 53%, 6% complete response, median duration of response, 6.7 months and median progression free survival 6.8 months, and median survival of 15.9 months (Sosman JA et al).

It has been estimated that over 1/3 of melanomas in the United States and Australia could be prevented with regular sunscreen use.