MELANOMAVAISHNAVI SURESH NAIR

MELANOMA:

These tumours originate in the pigment-producing melanocytes

in the basal layer of the epidermis.

These cancerous growths develop when unrepaired DNA

damage occurs on melanocytes which triggers mutations that

lead the skin cells to multiply rapidly and form malignant tumours.

Melanomas often resemble moles; some develop from moles. The majority of melanomas are black or

brown, but they can also be skin coloured, pink, red, purple, blue or white.

Melanoma is caused mainly by intense, occasional UV exposure(frequently leading to sunburn),

especially in those who are genetically predisposed to the disease.

If melanoma is recognized and treated early, it is almost always curable, but if it is not, the cancer can

advance and spread to other parts of the body, where it becomes hard to treat and can be fatal.

While it is not the most common of the cancers, it causes the most deaths.Male (5%),Female(4%)

Everyone is at some risk for melanoma, but increased risk depends on several factors:

sun exposure, number of moles on the skin, skin type and family history, genetic mutations etc.

CAUSES & RISK FACTORS

SUN EXPOSURE

Both UVA and UVB rays are dangerous to the skin, and can induce skin cancer, including melanoma.

Blistering sunburns in early childhood especially increase risk, but sunburns later in life and cumulative

exposure also may be factors.

People who live in locations that have more sunlight — like Florida, Hawaii, and Australia — develop more

skin cancers, but some more northern locations with light-skinned populations also have a high number

of skin cancers.

Avoid using a tanning booth or tanning bed, since it increases the exposure to UV rays, raising your risk of

developing melanoma and other skin cancers.

MOLES

There are two kinds of moles: normal moles — the small brown blemishes, growths, or "beauty marks" that

appear in the first few decades of life in almost everyone — and atypical moles, also known as dysplastic nevi.

Atypical moles can be precursors to melanoma, and having them puts you at increased risk of melanoma.

But regardless of type, the more moles you have, the greater your risk for melanoma.

SKIN TYPE

As with all skin cancers, people with fairer skin, lighter hair and eye colour are at increased risk.

PERSONAL HISTORY

Once you have had melanoma, you run an increased chance of recurrence.

People who have or have had basal cell carcinoma or squamous cell carcinoma are also at increased risk for

developing melanoma.

WEAKENED IMMUNE SYSTEM

Compromised immune systems as the result of chemotherapy, an organ transplant, excessive sun exposure, and

diseases such as HIV/AIDS or lymphoma can increase your risk of melanoma.

FAMILY HISTORY

Heredity plays a major role in melanoma. About one in every 10 patients diagnosed with the disease has a family

member with a history of melanoma.

If your mother, father, siblings or children have had a melanoma, you are in a melanoma-prone family.

Each person with a first-degree relative diagnosed with melanoma has a 50 percent greater chance of

developing the disease than people who do not have a family history of the disease.

EXAMINE CLOSE RELATIVES

When melanoma is diagnosed, it is standard practice for physicians to recommend that close relatives be

examined immediately for melanoma and for the presence of unusual or atypical moles.These moles are

also called "dysplastic nevi."

FAMILY SYNDROME

When atypical moles are found in an individual belonging to a melanoma family, the condition is

known as FAMMM (Familial Atypical Multiple Mole Melanoma Syndrome).

People with this syndrome are at the greatest risk of developing melanoma.

A research study found that those family members who did not have atypical moles were much less likely

to develop melanoma.

GENETIC RISK FACTORS

BRAF gene mutations:

A mutation BRAF gene, can play a part in causing many melanomas. This mutated gene is found in about half

of all melanomas.

The discovery of BRAF was an exciting research breakthrough, and with the development of vemurafenib

( Zelboraf TM).

Increasing understanding of the BRAF gene could lead to the development of new diagnostic tools and has

already led to the development of several new and improved drug therapies.

p53 gene mutations:

The mutations most commonly seen in familial melanoma occur in gene, p53. When this gene is in its normal

state, it functions as a tumour suppressor, giving damaged cells the chance to repair themselves without

progressing to cancer. But when the gene is altered, it becomes unable to perform this function, and cancer can

result.

New research shows that the same ultraviolet (UV) damage that produces skin damage can damage p53,

causing the alterations that eliminate its ability to suppress tumours.

A number of gene mutations in addition to p53 and BRAF have been associated with familial melanoma, notably

the CDKN2A (cyclin-dependent kinase inhibitor 2A) gene.

MOLES IN ACTIVE STAGE

Moles in people belonging to melanoma-prone families are subject to change at certain times of life. They may

get larger or show alterations in colour or elevation, so for those periods, they are described as being active.

While the reasons for these changes are not fully known, there could be a hormonal component: Moles are

more active at puberty and during pregnancy.

Most physicians advise high-risk individuals not to take hormonal medications, such as oral contraceptives or

hormone replacement therapy.

EXAMINATION SCHEDULING

Individuals with atypical mole syndrome can improve their chances of early detection by increasing the frequency

of skin self-examination and by visiting a physician more often for a full-body skin exam.

The clinician may take photographs to document whether there are new moles or changes in older ones.

IN CHILDREN:

Children in melanoma-prone families need special care, because familial melanoma is likely to make its

appearance early in life.

Even though these cancers usually do not appear until after adolescence, they may arise in much

younger children who have a family history of melanoma.

Most physicians, therefore, advise parents to make a point of studying a child's skin frequently from infancy

on.

Physician examination in these families should start at the age of 10 and continue on a twice-a-year

basis thereafter.

Particular care should be taken at puberty and during adolescence when hormonal changes activate

the moles.

As melanoma families are on the lookout for the disease and seek professional consultation early, the

survival rate for familial melanoma is even higher than that for non-familial melanomas.

SYMPTOMS OF MELANOMA:

In the early stages, melanoma may not cause any symptoms (what you

feel). But sometimes melanoma will:

Itch.

Bleed.

Feel painful.

Many melanomas have these signs and symptoms, but not all. There are

different types of melanoma. One type can first appear as a brown or black

streak underneath a fingernail or toenail. Melanoma also can look like a

bruise that just won’t heal.

Hidden melanomasMelanomas can also develop in areas of your body that have little or no exposure to the sun, such as the spaces

between your toes and on your palms, soles, scalp or genitals. These are sometimes referred to as hidden

melanomas because they occur in places most people wouldn't think to check. When melanoma occurs in people

with darker skin, it's more likely to occur in a hidden area.

Hidden melanomas include:

•Melanoma under a nail:

Acral lentiginous melanoma is a rare form of melanoma that can occur under a fingernail or toenail. It can

also be found on the palms of the hands or the soles of the feet. It's more common in blacks and in other people

with darker skin pigment.

•Melanoma in the mouth, digestive tract, urinary tract or vagina:

Mucosal melanoma develops in the mucous membrane that lines the nose, mouth, oesophagus, anus,

urinary tract and vagina. Mucosal melanomas are especially difficult to detect because they can easily be mistaken

for other far more common conditions.

•Melanoma in the eye:

Eye melanoma, also called ocular melanoma, most often occurs in the uvea — the layer beneath the white

of the eye (sclera). An eye melanoma may cause vision changes and may be diagnosed during an eye exam.

TYPES OF MELANOMA

There are four basic types of melanomas.

3 of them begin in situ (meaning they occupy only the top layers of the skin) and sometimes become

invasive.

The fourth is invasive from the start.

Invasive melanomas are more serious, as they have penetrated deeper into the skin and may have

spread to other areas of the body.

Superficial spreading melanoma

It is the most common type, (about 70 percent of all cases.)

Most often seen in young people.

It grows along the top layer of the skin for a fairly long time before penetrating more deeply.

The first sign is the appearance of a flat or slightly raised discoloured patch that has

irregular borders and is somewhat asymmetrical in form.

Lentigo maligna

It is in situ type & similar to superficial spreading type.

It remains close to the skin surface for quite a while, and usually

appears as a flat or mildly elevated mottled tan, brown or dark brown

discolouration.

It is found most often in the elderly, arising on chronically sun-exposed,

damaged skin on the face, ears, arms and upper trunk.

Lentigo maligna is the most common form of melanoma in Hawaii.

When this cancer becomes invasive, it is referred to as lentigo maligna

melanoma.

The colour varies, and you may see areas of tan, brown, black,

red, blue or white.

This type of melanoma can occur in a previously benign mole.

The melanoma can be found almost anywhere on the body, but is

most likely to occur on the trunk in men, the legs in women, and

the upper back in both.

Acral lentiginous melanoma

It also spreads superficially before penetrating more deeply.

It usually appears as a black or brown discolouration under the nails or on

the soles of the feet or palms of the hands.

This type of melanoma is sometimes found on dark-skinned people,

and can often advance more quickly than superficial spreading melanoma and

lentigo maligna.

It is the most common melanoma in African-Americans and Asians,

and the least common among Caucasians.

Nodular melanoma

It is usually invasive at the time it is first diagnosed.

The malignancy is recognized when it becomes a bump.

It is usually black, but occasionally is blue, gray, white, brown, tan, red or skin

tone.

The most frequent locations are the trunk, legs, and arms, mainly of elderly

people , as well as the scalp in men.

This is the most aggressive of the melanomas, and is found in 10 to 15 percent

of cases.

New Melanoma Staging System

The classification system recommended by the American Joint Commission on Cancer (AJCC) has

been updated as of 2010 & new findings about melanoma are incorporated to provide the most accurate

diagnosis and prognosis (a forecast of how the disease is likely to progress).

Breslow’s thickness

The most important factors in the new staging system are the thickness of the tumour, known as

Breslow’s thickness (also called Breslow’s depth), the appearance of microscopic ulceration (, and mitotic rate,

the speed of cell division (how fast-growing the cancer cells are).

Breslow's depth

Stage Depth

Stage I less or equal to 0.75mm

Stage II 0.75 mm - 1.5mm

Stage III 1.51 mm - 2.25mm

Stage IV 2.25 mm - 3.0mm

Stage V greater than 3.0 mm

Prognostic importance

tumour Depth

Approximate 5 year survival

<1 mm 95-100%

1 - 2 mm 80-96%

2.1 - 4 mm 60-75%

>4 mm 50%

Level 1 : Melanoma confined to the epidermis (melanoma in situ)

Level 2 : Invasion into the papillary dermis

Level 3 : Invasion to the junction of the papillary and reticular dermis

Level 4 : Invasion into the reticular dermis

Level 5 : Invasion into the subcutaneous fat

Clark’s level of invasion:

Formerly, very thin tumours were classified according to Clark’s level of invasion, the number of layers

of skin penetrated by the tumour. In the newest staging system, Clark’s level has far less importance.

Clark’s level will enter into serious consideration only in the rare instances when mitotic rate cannot

be determined.

To be exact, Breslow’s thickness measures in millimeters (1 mm equals 0.04 inch) the distance

between the upper layer of the epidermis and the deepest point of tumour penetration.

The thinner the melanoma, the better the chance of a cure.

Therefore, Breslow’s thickness is considered one of the most significant factors in predicting the

progression of the disease.

The presence of microscopic ulceration upgrades a tumour’s seriousness and can move it into a later stage.

Therefore, the physician may consider using a more aggressive treatment than would otherwise be selected.

Mitotic rate has been introduced into the staging system based on recent evidence that it is also an independent

factor predicting prognosis.

The presence of at least one mitosis (cancer cell division) per millimeter squared (mm2) can upgrade a thin

melanoma to a later stage at higher risk for metastasis.

In situ (non-invasive) melanoma remains confined to the

epidermis.

Thin tumours are less than 1.0 millimeter (mm) in Breslow’s

depth.

Intermediate tumours are 1.0-4.0 mm.

Thick melanomas are greater than 4.0 mm.Two examples of thin melanomas

STAGES OF MELANOMA

The stage refers to the thickness, depth of penetration, and the degree to which the melanoma has spread. The

staging is used to determine treatment.

Stage 0 tumours are in situ, meaning that they are non invasive and have not penetrated below

the surface of the skin

Stage I tumours have invaded the skin but are small, non ulcerated, and are growing at a slow

mitotic rate.

Stage II tumours though localized, are larger (generally over 1 mm. thick) and/or may be ulcerated

or have a mitotic rate of greater than 1/mm2; they are considered intermediate melanomas.

Stages III and IV They have spread (metastasized) to other parts of the body. There are also

subdivisions within stages.

EARLY MELANOMAS (CLINICAL STAGE I & II) - These melanomas (Stages 0 and I) are localized.

LATER STAGES (CLINICAL STAGE III & IV) - They are more advanced melanomas

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

Stage I / II: Invasive melanoma, 89–95% survival

T1a: Less than 1.0 mm primary tumour thickness, without ulceration, and mitosis < 1/mm2

T1b: Less than 1.0 mm primary tumour thickness, with ulceration or mitoses ≥ 1/mm2

T2a: 1.01–2.0 mm primary tumour thickness, without ulceration

Stage II:

High risk melanoma, 45–79% survival

T2b: 1.01–2.0 mm primary tumour thickness, with ulceration

T3a: 2.01–4.0 mm primary tumour thickness, without ulceration

T3b: 2.01–4.0 mm primary tumour thickness, with ulceration

T4a: Greater than 4.0 mm primary tumour thickness, without ulceration

T4b: Greater than 4.0 mm primary tumour thickness, with ulceration

Stage III:

Regional metastasis, 24–70% survival

N1: Single positive lymph node

N2: Two to three positive lymph nodes or regional skin/in-transit metastasis

N3: Four positive lymph nodes or one lymph node and regional skin/in-transit metastases

Stage IV:

Distant metastasis, 7–19% survival

M1a: Distant skin metastasis, normal LDH

M1b: Lung metastasis, normal LDH

M1c: Other distant metastasis or any distant metastasis with elevated LDH

PHYSICAL EXAMINATION

Total body examination

A total-body skin examination is crucial when evaluating a patient with an atypical nevus or a melanoma. The

skin examination should be performed on initial evaluation of the patient and during all subsequent visits

Crucial to a good skin examination is a well-lit examining room and a completely disrobed patient.

Serial photography and new techniques, such as epiluminescence microscopy and computerized image

analysis, are useful adjuncts.

Epiluminescence microscopy uses a magnifying lens to examine a lesion that has had oil applied.

Computerized image analysis stores images of the lesions and makes them available for comparison over time.

Skin examination

During a skin examination, assess the total number of nevi present on the patient's skin. Attempt to

differentiate between typical and atypical lesions.

Lymph node examination

If a patient is diagnosed with a melanoma, examine all lymph node groups. Melanoma may disseminate through

the lymphatics, leading to the involvement of regional lymph nodes, and hematogenously, leading to the

involvement of any node basin in the body.

WARNING SIGNS:THE ABCDEs OF MELANOMA

Moles, brown spots and growths on the skin are usually harmless — but not always.

Anyone who has more than 100 moles is at greater risk for melanoma.

The first signs can appear in one or more atypical moles.

Look for the ABCDE signs of melanoma, and if you see one or more, consult a physician immediately.

A – ASSYMETRY

If you draw a line through this mole, the two halves will not

match.

B - BORDER

The borders of an early melanoma tend to

be uneven. The edges may be scalloped or

notched.

C- COLOR

Having a variety of colours is another

warning signal. A number of different shades

of brown, tan or black could appear. A

melanoma may also become red, blue or

some other colour

D - DIAMETER

Melanomas usually are larger in diameter than the size of

the eraser on your pencil (1/4 inch or 6 mm), but they may

sometimes be smaller when first detected.

E - EVOLVING

Any change — in size, shape, colour, elevation, or

another trait, or any new symptom such as bleeding,

itching or crusting — points to danger.

Dx OF MELANOMA

Sometimes cancer can be detected simply by looking at your skin, but the only way to accurately diagnose

melanoma is with a biopsy. In this procedure, all or part of the suspicious mole or growth is removed, and a

pathologist analyses the sample. Biopsy procedures used to diagnose melanoma include:

Punch biopsy. During a punch biopsy, your doctor uses a tool with a circular blade. The blade is pressed into

the skin around a suspicious mole, and a round piece of skin is removed.

Excisional biopsy. In this procedure, the entire mole or growth is removed along with a small border of

normal-appearing skin.

Incisional biopsy. With an incisional biopsy, only the most irregular part of a mole or growth is taken for

laboratory analysis.

The type of skin biopsy procedure you undergo will depend on your situation. Doctors prefer to use punch biopsy

or excisional biopsy to remove the entire growth whenever possible. Incisional biopsy may be used when other

techniques can't easily be completed.

Diagnostic Considerations

Differentials to consider in the diagnosis of malignant melanoma include the following conditions:

Benign melanocytic lesions

Dysplastic nevus

Squamous cell carcinoma

Metastatic tumours to the skin

Blue nevus

Epithelioid (Spitz) tumour

Pigmented spindle cell tumour

Halo nevus

Atypical fibroxanthoma

Pigmented actinic keratosis

Sebaceous carcinoma

Histiocytoid hemangioma

Differential Diagnoses

Basal Cell Carcinoma

Lentigo Maligna Melanoma

Mycosis Fungoides

PREVENTION

Since its inception in 1979, The Skin Cancer Foundation has always recommended using a sunscreen with an SPF 15

or higher as one important part of a complete sun protection regimen. But sunscreen alone is not enough.

Seek the shade, especially between 10 AM and 4 PM.

Do not burn.

Avoid tanning and never use UV tanning beds.

Cover up with clothing, including a broad-brimmed hat and UV-blocking sunglasses.

Use a broad spectrum (UVA/UVB) sunscreen with an SPF of 15 or higher every day. For extended outdoor

activity, use a water-resistant, broad spectrum (UVA/UVB)sunscreen with an SPF of 30 or higher.

Apply 1 ounce (2 tablespoons) of sunscreen to your entire body 30 minutes before going outside. Reapply every

two hours or immediately after swimming or excessive sweating.

Keep new-borns out of the sun. Sunscreens should be used on babies over the age of six months.

Examine your skin head-to-toe every month.

See your physician every year for a professional skin exam.

SURGICAL TECHNIQUES

The first step in treatment is the removal of the melanoma, and the standard method of doing this is by surgical

excision (cutting it out).

Patients do just as well after the laser surgery, which is easier to tolerate and produces a smaller scar.

Surgical excision is also called resection, and the borders of the entire area excised are known as the margins.

TREATMENT

OP/OFFICE SURGERY

In most cases, the surgery for thin melanomas can be done in the doctor’s office or as an outpatient procedure

under local anaesthesia. Stitches (sutures) remain in place for one to two weeks, and most patients are advised to

avoid heavy exercise during this time. Scars are usually small and improve over time.

Dis colourations and areas that are depressed or raised following the surgery can be concealed with cosmetics

specially formulated to provide camouflage. If the melanoma is larger and requires more extensive surgery, a better

cosmetic appearance can be obtained with flaps made from skin near the tumour, or with grafts of skin taken from

another part of the body. For grafting, the skin is removed from areas that are normally or easily covered with

clothing.

There is now a trend towards performing sentinel node biopsy and tumour removal surgery at the same time,

provided the tumour is 1 mm or more thick. When the procedures are combined in this way, the patient is spared an

extra visit.

SURGICAL EXCISION

It is also called resection, and the borders of the entire area excised are known as the margins. Surgical excision

is used to treat all types of skin cancer.

The physician begins by outlining the tumour with a marking pen. A "safety margin" of healthy-looking tissue will

be included, because it is not possible to determine with the naked eye how far microscopic strands of tumour

may have extended. The extended line of excision is drawn, so the skin may be sewn back together.

The physician will administer a local anaesthetic, and then cut along the lines that were drawn. The entire

procedure takes about thirty minutes for smaller lesions.

Wounds heal rapidly, usually in a week or two. Scarring depends on many factors, including the placement of

the tumour and the patient's care of the wound after the procedure.

The tissue sample will be sent to a lab, to see if any of the "safety margin" has been invaded by skin cancer. If

this is the case, it is assumed that the cancer is still present, and additional surgery is required.

Sometimes, Mohs micrographic surgery is a good option at this point.

SETTING THE MARGINS

In the new approach to surgery, much less of the normal skin around the tumour is removed and the margins,

therefore, are much narrower than they ever were before. This spares significant amounts of tissue and reduces

the need for postoperative cosmetic reconstructive surgery.

Most US surgeons today follow the guidelines recommended by the National Institutes of Health and the American

Academy of Dermatology Task Force on Cutaneous Melanoma.

When there is an in situ melanoma, the surgeon excises 0.5-1 centimetre of the normal skin surrounding the

tumour and takes off the skin layers down to the fat.

In removing an invasive melanoma that is 1 mm or less in Breslow’s thickness, the margins of surrounding skin

are extended to 1 cm and the excision goes through all skin layers and down to the fascia (the layer of tissue

covering the muscles).

If the melanoma is 1.01 to 2 mm thick, a margin of 1-2 cm is taken.

If the melanoma is 2.01 mm thick or greater, a margin of 2 cm is taken.

These margins all fall within the range of what is called “narrow” excision. When you consider that until recently,

margins of 3 to 5 cm (wide excision) were standard, even for comparatively thin tumours, you can see how

dramatically surgery has changed for the better. When melanomas have reached a thickness of 4 mm or more,

increasing the margins beyond 2 cm does not increase survival.

MOHS MICROGRAPHIC SURGERY

Mohs Micrographic Surgery is the most effective technique for removing basal cell and squamous cell

carcinomas (the two most common skin cancers), is being increasingly used as an alternative to standard

excision for certain melanomas.

In this technique, one thin layer of tissue is removed at a time, and as each layer is removed, its margins are

studied under the microscope for the presence of cancer cells. If the margins are cancer-free, the surgery is

ended.

If not, more tissue is removed, and this procedure is repeated until the margins of the final tissue examined are

clear of cancer. Mohs surgery can eliminate the guesswork in the removal of skin cancers and pinpoint the

cancer’s location when it is invisible to the naked eye.

Mohs surgery differs from other techniques since the microscopic examination of all excised tissues during the

surgery eliminates the need to “estimate” how far out or deep the roots of the skin cancer go. This allows the

Mohs surgeon to remove all of the cancer cells while sparing as much normal tissue as possible.

In recent years, however, efforts to improve and refine the Mohs surgeon’s ability to identify melanoma cells

have resulted in the development of special stains that highlight these cells. These special stains are known as

immunocytochemistry or immunohistochemistry (IHC) stains and use substances that preferentially stick to

pigment cells (melanocytes), where melanoma occurs, making them much easier to see with the microscope.

ADJUVANT THERAPY

For patients with Stages III and IV disease, surgery is usually followed with an additional adjuvant therapy.

CHEMOTHERAPY

Used as Mono/poly chemotherapy.

Dacarbazine (DTIC), given by injection.

DTIC may be combined with carmustin (BCNU) and tamoxifen, or with cisplatin and vinblastine.

Temozolomide, an oral drug closely resembling DTIC, is FDA-approved for brain cancers but also used off-label for

melanomas that have spread to the brain or nervous system.

Another class of drugs, based on a different principle, has come into use more recently. They are anti- angiogenic,

which means that they prevent new blood vessels from forming. It cut off the blood supply that would nourish the

cancer cells and enable them to grow. Studies are under way with the anti- angiogenic drug thalidomide, combined

with the chemotherapeutic agent, temozolomide.

Angiostatin and endostatin are two other drugs in this class that have shown some degree of activity against

melanoma in preliminary studies.

Isolated Limb Perfusion Method This palliative treatment, which relieves symptoms, is sometimes used when melanoma metastases have reached

an arm or leg.

“Isolated” means that the chemotherapy is “perfused” (shunted directly) to the blood flowing through the affected

limb, but to no other part of the body, to limit toxic effects. The drug melphalan is the chemotherapy most frequently

used, often combined with other agents.

IMMUNOTHERAPY

Clinical trials of various types of vaccine are under way with patients whose disease is in Stages III and IV. The

vaccines are intended to stimulate the immune system so that it reacts more strongly against a patient's melanoma

cells, destroying the cancer or slowing the progression. These vaccines are not a part of routine treatment at this

time.

Another type of immunotherapy (also known as biologic therapy) makes use of chemicals that occur naturally in

the body. Also there is injectable interferon (IFN) alpha-2b, the only drug with FDA approval to treat “high-risk”

Stage II and Stage III melanomas.

High-risk melanomas are tumours that have a high chance of recurring (such as those that are ulcerated or over 4

mm thick) or have spread to the nearby lymph nodes. At first, IFN alpha-2b appeared to increase overall 5-year

survival. After further study, it proved to give patients a longer period without relapse, extending their disease-free

interval to an average of 9 months, but did not lengthen overall survival. It has significant flu-like side effects.

In 2011, the FDA approved a new drug, peginterferon alfa-2b (also known as Sylatron), to treat Stage III melanoma

patients – those found to have microscopic or palpable metastatic disease that has reached the lymph nodes. The

drug, injected subcutaneously, was the first adjuvant, or additional, therapy for Stage III patients approved since

high-dose IFN alfa-2b in 1995.

This approval followed on the heels of a trial in which melanoma patients taking Sylatron remained relapse-free an

average of nine months longer than patients not taking the drug (34.8 months vs. 25.5 months). There was no

difference in overall survival.

tumour necrosis factor (tumor-killing) factor is another of these naturally occurring substances. Both of these —

especially interferon alpha-2b — are produced by white cells (lymphocytes) when they come in contact with

tumour cells, viruses or other harmful substances, and have been shown to kill a number of tumours, including

melanomas. They have some anti-angiogenic properties as well. Interferon alpha-2b is FDA-approved, tumour

necrosis factor is not.

Lymphokines, immune chemicals naturally produced by the white blood cells in small quantities, are being used

for Stage IV patients. They may also be produced by white blood cells that have been specially stimulated by

antigens, a basic part of the immune system, to make them better “killers” of malignant cells.

The best known of these therapies uses the injectable lymphokine interleukin-2 (IL-2), with or without the addition

of interferon alpha or other biotherapies and chemotherapies. It enters melanoma cells and attacks them. High-

dose IL-2 (“Proleukin”) was the first FDA-approved immunotherapy used to treat Stage IV metastatic melanoma.

It is associated with very significant side effects when given in high doses, but has been found to increase

disease-free and overall survival in some patients. About 10-16 percent of carefully selected patients on IL-2

regimens respond to the drug, with 6 percent having complete responses (remissions), and about 60 percent of

the complete responders have significantly extended lives.

Tumor-infiltrating lymphocytes (TILs) also play a part in some new therapies for advanced melanoma. Of

special note is a technique from the National Cancer Institute called adoptive cell transfer (ACT), which involves

harvesting TILs from the patient’s blood, then isolating from them the cells expressing T cell receptors that can

recognize melanoma-specific antigens; in other words, the most aggressive melanoma-killing lymphocytes are

identified and isolated. These are then grown in large numbers in the lab and reinjected into the patient in the

hope that they will massively attack the patient’s melanoma cells.

High doses of IL-2 may be added to make these tumor-fighting cells mature and multiply, and certain drugs are

used to eliminate immune factors that might inhibit the tumor-fighting cells; this is called lymphodepletion. In

clinical trials with metastatic melanoma patients who had not responded to previous treatment, the patients’

response rates have been far higher than those seen with chemotherapy.

In the latest trials, total-body irradiation was added to enhance lymphodepletion, and response rates up to 72

percent were observed in 93 patients, with 11 achieving complete remissions lasting 18 to 75 months or more.

CHECKPOINT BLOCKADE THERAPY

Anti-CTLA-4 therapy is another important new direction for melanoma immunotherapy. CTLA-4 is a kind of natural

“brake” in the immune system that can inhibit activation of healing T-cells to keep them from overproducing. Anti-

CTLA-4 therapies are designed to block CTLA-4 so that more T-cells can be produced when needed to fight a

cancer. The therapy is also referred to as “checkpoint blockade” immunotherapy.

The first successful checkpoint blockade therapy was ipilimumab (YervoyTM), approved by the FDA in 2011 for

patients with advanced melanoma. A monoclonal antibody (a purified class of antibodies cloned and mass-

produced in the lab from one specific type of cell or cell line) that blocks CTLA-4, ipilimumab has yielded dramatic,

sustained responses akin to “cures” in certain patients, with some surviving more than 5 years.

Two additional immune-checkpoint-blockading drugs, nivolumab and MK-3475 (pembrolizumab), are in late-stage

clinical trials and are likely to be FDA-approved in 2014 or 2015. Both inhibit another molecule (programmed

death-1, or PD-1) that suppresses T-cells.

PD-1 can directly interact with tumour cells by binding to a molecule called programmed death ligand-1 (PD-L1),

and cancer cells may use PD-L1 to hide from attack by T-cells, but these drugs can release the T-cells to fight the

cancer.

A third drug, MPDL3280A, is designed to inhibit PD-L1, and appears to hold promise in early clinical studies.

Initial results indicate that PD-1/PD-L1 blockade results in higher response rates and a more favorable side effect

profile than that seen with ipilmumab. Several randomized trials comparing ipilimumab with anti-PD-1 therapy are

ongoing.

TARGETED THERAPY

Targeted therapies are types of treatment that use drugs or other substances to identify and attack specific types of

cancer cells, or to block the action of certain enzymes, proteins or other molecules that promote the growth and

spread of cancer cells.

vemurafenib (Zelboraf TM), FDA-approved in 2011, which inhibits the gene called BRAF.

BRAF produces a protein that normally regulates skin cells, causing them to multiply only when growth is needed.

However, a specific mutated version of BRAF called v600E (found in about half of all melanoma patients) produces

an abnormal version of the protein that stays switched on. This leads to out-of-control growth, i.e., cancer.

Vemurafenib can bind to the defective protein and deactivate it. Phase I and II studies showed striking and rapid

antitumor activity in patients with BRAF v600E-mutated melanoma.

Then, a randomized Phase III trial comparing vemurafenib to standard chemotherapy showed both a progression-

free and overall survival (OS) advantage in vemurafenib patients (median OS of 13.6 months for vemurafenib

patients vs. 9.7 months for chemotherapy patients). As with imatinib, the hope is that altering the dosing regimen

and combining vemurafenib v with other therapies will significantly lengthen survival.

Another targeted therapy, imatinib (Gleevec), has produced encouraging but mixed early results in metastatic

melanoma, and greater numbers of patients must be tested. Imatinib inhibits c-KIT, the receptor for an enzyme

called tyrosine kinase, which has been associated with some cancers, including melanoma.

Genetic aberrations or mutations in KIT have been frequently found in certain gastrointestinal tumours and

leukemias, which have responded well to treatment with imatinib.

Some types of melanoma also frequently have KIT mutations, so it has been hypothesized that these melanomas

will similarly respond to imatinib treatment. Indeed, lab experiments have been promising, and some patients,

especially those with acral lentiginous melanoma and mucosal melanoma, have initially responded well, but thus

far, significant clinical improvements from the drug as a single therapy have been minimal. Imatinib is continuing to

be tested in different dosage regimens and combined with other therapies.

In 2013, two other treatments directed toward BRAF and a related molecule called MEK were also approved:

the BRAF inhibitor dabrafenib (Taflinar®) and the MEK inhibitor trametinib (Mekinist®).

Recently, the FDA also approved the use of these two drugs in combination for patients with inoperable or

metastatic melanoma with a BRAF V600E or V600K mutation. The hope is that these different drugs and drug

combinations will increase tumour shrinkage and extend the length of time before the melanoma starts growing

again.

GENE THERAPY

This treatment is in the very early stages of research, and its effectiveness is yet to be proven conclusively.

One form of gene therapy is based on creating alterations in the white blood cells or in the tumor-infiltrating

lymphocytes (TILS) so that they will attack the melanoma. This is achieved by removing these cells from the

patient, growing them outside the body and treating them so as to increase their number.

The next step is the addition of genetic material that produces one of the many growth factors which make the

lymphocytes more aggressive as cancer-fighters. These more aggressive lymphocytes are returned to the

patient's body in an effort to stimulate the immune system to kill the melanoma and its metastases.

The focus of current research is the identification of genes for specific melanoma antigens. These are molecules

found on the cell wall that stimulate the production of antibodies, which are a part of the body's immune defence

system. An antibody attaches itself to only one type of antigen.

By injecting the gene for the melanoma antigens, the hope is to increase their number and produce a broad

attack by the patient's immune system.

IMPROVING LONG TERM SURVIVAL

The advances in understanding melanoma and the immune system have set the stage for continual

improvements in the treatment of advanced disease. Some patients have already derived significant long-term

benefits.

One recent report suggested that 20 percent of patients who received ipilimumab are alive after 10 years. (In

contrast, only about 4-6 percent of patients were ever found to achieve long-term survival with Interleukin-2, and

no overall survival advantage was ever demonstrated with chemotherapy.)

Similarly, early clinical trials have described an improved likelihood of significant tumour shrinkage using

combinations of these new drugs, specifically dabrafenib combined with trametinib or ipilimumab with

nivolumab.

The next goal will be to determine which combinations and methods are most suitable to shrink melanoma most

effectively, maintain the best possible quality of life for patients and extend patients’ lives as long as possible.

Many other novel approaches are also on the horizon, currently either in active laboratory study or clinical trials;

the hope is to turn metastatic melanoma from a deadly disease into a manageable chronic condition.

CLINICAL TRIALS

Many patients, especially those with advanced disease, are participating in clinical

trials to obtain new treatments that are still experimental and not generally available.

Patients who have Stage III and IV melanoma might consider enrolling in a clinical

trial of a new or experimental treatment.

There are risks involved in enrolling in a clinical trial, but there can be benefits as

well. More treatment possibilities exist than ever before, giving new hope to people with

melanoma.