Melanoma
From Standard of Care
Accounts for 2% of all cancers in the U.S.
Worldwide increase in incidence of 5% per year.
World Health Organization estimates worldwide and there are 66,000 deaths from skin cancer annually, with approximately 80% due to melanoma (WHO).
In 2009 there was an estimated 8600 deaths from melanoma in the United States.
Increasing at a greater rate than any other cancer in the U.S.
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 76,250 new cases in 2012 and approximately 9180 deaths in the U.S.
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.
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 are expected.
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.
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.
The genetic basis of susceptibility to melanoma is unknown in 30 to 40% of families featuring four or more cases.
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.
Incidence of melanoma 1998-2002 17.2 per 100,000 population compared to 5.7 per 100,000 population in 1973.
Globally 160,000 cases per year are diagnosed.
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.
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).
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.
Cutaneous melanoma in situ (CMIS) the malignant melanocytes remain confined within the skin epithelium without invading the basal membrane.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Has a primary resistance to chemotherapy, a rapid tumor doubling time and a tendency to metastasize to the brain.p
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 10% 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.
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).
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.
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).
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 lymp nodes 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).
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.
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.
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).
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).
Systemic Therapy for Advanced or Metastatic Melanoma
Day 1: Ipilimumab 3mg/kg IV once. Repeat cycle every 3 weeks for 4 cycles.
Dacarbazine (DTIC) Day 1: Dacarbazine 2–4.5mg/kg/day IV for 10 days. Repeat cycle every 4 weeks
Or
Days 1–5: Dacarbazine 250mg/m2/day IV. Repeat cycle every 3 weeks.
Temozolomide (Temodar; TMZ) Days 1–5: Temozolomide 200mg/m2/day orally for 5 days. Repeat cycle every 4 weeks.
High-dose interleukin-2 (aldesleukin; Proleukin; IL-2;) Monotherapy Days 1–5: IL-2 22mcg/kg (360,000 IU/kg), 33mcg/kg (540,000 IU/kg), 36mcg/kg (600,000 IU/kg), or 44mcg/kg (720,000mcg/kg) IV every 8 hours for up to 14 consecutive doses as clinically tolerated.
Vemurafenib (Zelboraf) V600 mutated BRAF gene only: Vemurafenib 960mg orally twice daily
Dacarbazine + cisplatin (Platinol; CDDP) + vinblastine (Velban; VLB)
Days 1 and 22: Dacarbazine 800mg/m2 IV, plus Days 1–4 and 22–25: Cisplatin 20mg/m2 IV + vinblastine 2mg/m2 IV. Repeat cycle every 3 weeks for 2 cycles.
OR
Day 1: Dacarbazine 800mg/m2 IV, plus Days 1–4: Cisplatin 20mg/m2 IV + vinblastine 1.2mg/m2 IV. Repeat cycle every 3 weeks for max 4 cycles.
Dacarbazine + paclitaxel (Taxol) + cisplatin
Day 1: Dacarbazine 800mg/m2 IV, plus Days 1–4: Cisplatin 20mg/m2 IV, plus Days 1 and 8: Paclitaxel 100mg/m2 IV.
Low-dose IL-2 + granulocyte macrophage-stimulating factor (sargramostim; GM-CSF; Leukine)
Days 1–5: IL-2 1 million IU/m2/day SC, plus Days 1–14: GM-CSF 125mcg/m2/day SC. Repeat cycle every 4 weeks for 12 cycles.
Paclitaxel + carboplatin (Paraplatin) Days 1, 8, and 15: Paclitaxel 100mg/m2 IV + carboplatin AUC=2mg/mL/min IV. Repeat cycle every 4 weeks until disease progression.
Paclitaxel + carboplatin ± sorafenib (Nexavar)
Day 1: Carboplatin AUC=6mg/mL/min IV + paclitaxel 225mg/m2 IV, followed by Days 2–19: Sorafenib 400mg orally twice daily. Repeat cycle every 3 weeks.
Imatinib (Gleevec) NOTE: For C-KIT mutated tumors. 400mg orally twice daily until disease progression or unacceptable toxicity.
