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Interleukin-2 (IL-2) therapy is approved by the FDA for the treatment of meta-static melanoma, and it is a reasonable option for patients with this stage of the disease.

Combination chemotherapy or biochemotherapy increases toxicity significantly without offering overall survival benefit; thus, they are not standards of care for stage IV melanoma.

© One of the most common sites of metastasis for melanoma is the brain and treatment options for brain metastasis include surgery, radiation, and chemotherapy. The choice of therapy depends on the number of metastatic lesions, accessibility of the lesions for surgery, the presence of neurologic symptoms, and the status of extracranial disease.

Skin cancer is the most prevalent of all malignancies occurring in humans, and in the United States, it accounts for more than 50% of all cancers. The most common cutaneous malignancies are basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and malignant melanoma (MM). BCC and SCC are categorized as nonmelanoma skin cancer. Worldwide, the incidence of nonmelanoma skin cancer (NMSC) and

MM is increasing at a rate of 3% to 8% per year in fair-skinned Caucasian populations. The mortality rate for MM is on the rise in North America, Australia, and New

Zealand at a pace of 2% to 4% annually. Ultraviolet (UV) radiation exposure is the leading environmental factor causing skin cancer. This is a modifiable risk factor, and prevention of skin cancer development is possible through a sun protection regimen that includes wearing protective clothing, avoidance of prolonged, intense sun exposure and sunburns, and regular application of sunscreen. If skin cancer is detected in its early stage, survival is improved, and the disease is curable. Therefore, campaigns for primary and secondary prevention of skin cancer are important in combating this tumor. NMSC and MM differ with regard to prognosis, metastatic potential, mortality, curability, and treatment options. This chapter will review the pathogenesis and risk factors for the development of skin cancer and provide current data on the recommendations for the prevention and treatment of both NMSC and MM.

melanoma epidemiology and etiology

MM is ranked as the fifth most common cancer among men and the sixth most common cancer in women.1 In 2008, it is estimated that 62,480 new cases of invasive melanoma will be diagnosed. MM is a major public health problem of significant worldwide concern because of its dramatic rise in incidence and mortality. In the United States in 1935, the lifetime risk of melanoma was estimated at 1 in 1,500; in 2002, the lifetime risk was 1 in 68 persons. In Australia, the country with the highest incidence of melanoma in the world, the hazard is even higher at an estimated lifetime risk of 1 in 25 persons.4 The incidence of melanoma is not evenly dispersed among all populations. Race, gender, and age confer different incidence rates.4 Caucasians have higher risks than Asians, Hispanics, and African Americans.4 The rate of MM is 10 times higher in whites than in African Americans.1 MM generally occurs in the young, and is diagnosed primarily in the third or fourth decades of life. Sixty-two percent of cases are diagnosed before patients reach 65 years of age, and the median age of death is 67 years.6 Overall, in the United States, males have higher incidence rates than females.5 The incidence rises with age, and older men have the highest melanoma risk in the United States.5

risk factors

The maintenance of cellular homeostasis involves a balance of cell division, differentiation, senescence, and apoptosis. Cancer occurs when the growth and function of cells are "out of control" in relation to normal tissue. The combination of genetic alterations and environmental toxins is the most frequent contributor to the process of carcinogenesis. In the development of skin cancer, the risk factors are categorized as environmental (solar UV radiation), genetic (family history), immunosuppression, and previous history of skin cancer.

Patient Encounter 1, Part 1

KM is a 71-year-old man being evaluated in the dermatology clinic for a recent change in a mole on his shoulder. The mole has been on his shoulder for as long as he can remember. A year ago it began to itch, and his wife noted that it seemed to be getting darker in color. On physical examination, it is noted that the primary lesion is a 9-mm nodule, the border is ragged and irregular, and it is brown, black, and white in color. There is no oozing, bleeding, or crusting around the lesion. A couple of years ago, he had a complete excision of an in situ melanoma on his back.

KM has light-brown hair, blue eyes, and fair skin. He has a history of numerous severe blistering sunburns in his childhood. As a teenager and young adult, he spent many hours outdoors as a construction worker and a lifeguard. He lives with his wife in Denver, Colorado, and they enjoy outdoor activities such as hiking, skiing, and canoeing. He does not have a family history of melanoma.

What are KM's risk factors for malignant melanoma (MM)? What information is suggestive of MM?

What should be done to confirm the diagnosis of MM? How is the stage of the melanoma determined?

What primary prevention measures are recommended to prevent skin cancer?

O Exposure to ultraviolet radiation from the sun is recognized as one of the primary triggers for skin carcinogenesis. UV radiation (specifically UVB) is absorbed by DNA in the cells in the epidermal layer and may induce DNA lesions by forming dimers between neighboring pyrimidine bases, resulting in the development of cyclobutane pyrimidine dimers (CPDs) and pyrimidine-pyrimidone(6-4)

photo-products. Gene mutations may then transpire, leading to carcinogenesis. Other mechanisms of UV radiation-induced DNA damage include the generation of reactive oxygen species (ROS), e.g., 8-hydroxydeoxyguanosine, (8-OHdG), which can cause oxidative stress to DNA base pairs, and protein-DNA cross-links and singlestrand breaks. It is estimated that 60% to 70% of MMs are linked to UV exposure, particularly in the form of severe sunburns and intermittent (recreational or vacation) exposure. The association between sun exposure and melanoma is not clearly defined, though, because cutaneous melanoma can arise frequently in areas of the body not exposed to the sun.8 Exposure to sources of artificial UV radiation such as tanning beds have also been linked to increased risk of skin cancer.9

Genetics play a significant role in the development of MM. Patients with two or more family members with melanoma are significantly more likely to develop melanoma at a younger age and to develop multiple melanomas.5 The inherited mutation of two highly penetrant melanoma genes has been identified in families with melanoma susceptibility: the CDKN2A gene (also known as INK4/ARF, MTS1, and CDK1) and the CDK4 gene. Polymorphism of the MC1R gene, which is associated with red hair, also increases susceptibility to melanoma.10 Mutations affecting the serine-threonine kinase B-RAF gene have been reported with high rates in individuals with MM.

Another risk factor for the development of melanoma is the dysplastic nevus syndrome (also known as B-K syndrome, familial atypical mole, or Clark's nevus). This is an autosomal dominant disorder with incomplete penetrance, in which microscopic examination of the nevi shows disordered proliferation of melanocytes with varying degree of atypia without evidence of invasion. An individual typically may have 25 to 75 abnormal nevi present on his or her body. The cumulative lifetime risk for melanoma development in individuals with dysplastic syndrome is almost 100%.

In individuals without a family history of melanoma (sporadic melanoma), the presence of benign melanocytic nevi (benign moles) is consistently identified as the strongest risk factor for the future development of melanoma.6 The greater the number of benign nevi (greater than 20), the greater the susceptibility to melanoma growth.11

Aging is a risk factor for skin carcinogenesis because the passage of time allows more instances for the initiation and promotion of tumor formation through exposure to UV radiation. Furthermore, the capacity to repair DNA decreases with age, and the capability to remove DNA photoproducts such as CPDs and pyrimidine-pyrimod-one(6-4) from UV-irradiated skin also diminishes with age, leading to an increased rate of genetic mutations. These characteristics may account for the exponential increase in the incidence of NMSC and MM in the elderly population.

primary prevention of skin cancer

Ultraviolet (UV) radiation exposure from the sun is the major cause of NMSC and MM. Primary prevention strategies for skin cancer aim at educating people against excessive exposure to the sun and are spearheaded by the American Academy of Dermatology, the American Cancer Society, the Environmental Protection Agency, and the Centers for Disease Control and Prevention. The aims of these programs are to increase public awareness about the harmful effects of sun exposure and the risk of skin cancer, change attitudes about the social norms related to sun protection and tanned skin, and decrease the incidence of skin cancer and deaths related to this malignancy. Recommendations for prevention of skin cancer are universal and include a variety of simple strategies to minimize exposure to UV rays:12

• Avoid direct exposure to the sun between the hours of 10 am to 4 pm, when UV rays are most intense.

• Wear hats with a broad enough brim to shade the face, ears, and neck.

• Wear protective clothing (especially tightly woven apparel) that covers as much as possible the arms, legs, and torso.

• Cover skin with a sunscreen lotion with a skin protection factor (SPF) of at least 15, protecting against UV radiation (both UVA and UVB).

• Reapply sunscreens every 2 hours (especially if sweating or swimming).

• Avoid sun lamps and tanning beds, which provide an additional source of UV radiation.

• Seek shade when outdoors.

The use of chemical sunscreen is only one of many strategies, and it should not be the sole agent used for cancer prevention. The lay public should be warned not to use sunscreen with a higher SPF with the intent to extend the duration of exposure because it is observed that DNA damage can occur long before sunburn appears, and the

long-term effects of increased sun exposure are not known. Sunscreen protective agents have been proven only to reduce the risk of actinic keratosis and SCC. There is no convincing evidence that sunscreen application has protective effect against BCC or MM.13

secondary prevention of skin cancer

Secondary prevention of skin cancer involves early detection of premalignant cancers for early intervention with the hope that it will reduce mortality and increase cure. Skin cancer screening consistently identifies MMs that are, on average, thinner than those found during usual care. Unfortunately, at this time, there is no evidence that skin cancer screening reduces morbidity or mortality.14 Given this lack of evidence for a beneficial effect of skin cancer screening, recommendations vary with different agencies. The American Cancer Society recommends skin examination as part of cancer-related check-ups every 3 years for people between 20 and 40 years of age and on a yearly basis for those over 40 years of age. The American College of Preventive Medicine recommends total-body skin examination only in high-risk individuals. High-risk individuals are defined as those with a family or personal history of skin cancer, predisposing phenotypic characteristics, increased occupational or recreational exposure to sunlight, or clinical evidence of precursor lesions. The National Institutes of Health Consensus Panel recommends screening for MM as part of routine primary care.14 Routine self-examination of the skin is a method in which individuals can take responsibility for identifying MM early when it is curable. Pamphlets and online information describing the method of skin self-examination are available from agencies such as the American Cancer Society (www. cancer. org), the American Academy of Dermatology (www.aaJ.org), and the Skin Cancer Foundation (www.skincancer.org).

pathophysiology Skin Anatomy

The skin contains three layers: the epidermis (top layer), the dermis (middle layer), and the subcutis (innermost layer).10 The epidermis serves as a barrier to the environment to protect internal organs, and within its layers are squamous cells that produce keratin to provide its protective effect.10 Melanocytes, cells that synthesize melanin, also reside in the epidermis.10 Melanin is a brown-black pigment that is distributed to surrounding keratinocytes within the dermis and epidermis via dendriticprojections. The dermis gives the skin its strength, resiliency, and resistance to tearing. 0 It is made up of a dense network of collagen and elastic fibers that anchors hair follicles, sweat glands, blood vessels, and nerves. Basal cells separate the epidermis from the dermis, and these cells divide continually to replace the older cells that slough off the skin. The subcutis is composed of collagen and loose adipose connective tissue. It serves to conserve heat and act as a shock absorber to protect the inner organs10 (Fig. 97-1).

MM involves the abnormal growth and proliferation of melanocytes and begins with the proliferation of a single melanocyte from within the epidermis. After a series of intraepithelial events, the melanocyte migrates to the dermis, possibly deeper into the cutis, and proliferates therein.15 From within the dermis and subcutis, melanoma may metastasize and spread to distant sites via lymphatic and vascular channels.15 The overwhelming majority of MMs originate from the skin, although they also may arise less commonly from the retina, meninges, or GI tract.

Table 97-1 Characteristics of Different Types of Skin Cancer

Malignant Melanoma

' Nonmelanoma Skin CinHr

Table 97-1 Characteristics of Different Types of Skin Cancer

Malignant Melanoma

' Nonmelanoma Skin CinHr

Superficial

Maligna

Acral

Baial Cell

3-quameus Cell

Sproading

Modular

Mfftnom«

Lcntiginoui

Carcinoma

Cirilngmi

Frequency

Wft

4-Hrtfi

Less lh:in lfiflt

to aafc

Jins

Location

Tiunt in men

lrunk.lK.md, rrcck

iunejpoied

J'jfims ol ¡he

HMdAWC* trunks

Backs of the fund,

Legs in Aonvri

H^lKI

kifylv (oleiof

lowier limbs

htVLtU.1tyl.IIHt

Upper bdek

loot, nailbeds

ears

Age^Jefidir «

Mitftfleiofiiti

Any j^c (pith le

Jft

SOI

lix kU'rKtL inc il'JW^

hi ¡dCmiO Incr^Mn

presentation

Women moie th.m

siMfi decades)

Hair> before So

■ifirt age 4D

men

Men monelhan

WGdMn

Eihn.ruy

Caucasian

Caucasian

Caucasian

African

Mcjst common In

Most common

Americans

Caucasuns, raae

in Alncan

Aiim;,

hdarkiUined

Hispanlcs

people

IftCW g finvlh

fatal

ftireveilrtJl

fadiai

RkM

fiMPJl

ftadiar

Clinical features

Long horizontal

Yay ¿jgrc-bLk-c*

Lentigo

iOstfail

Fotii subtypes

Ifcually presents

■growth phase.

without

maligru— In

melanomas

1. ItoduLti BCC

as o poifJcsi,

m<ynhJWyWS

UBMUi

¡ilu fcum

IP

(50-K«j,

nyihematguy.

before invatHrq

horizontal liicwNi

of lentigo

Asians, And

moal common

poorly defined

wertktily

phJ«r (fcfi ply

mjliyr-tj

Hiiivjriics; ICft

sublypt

Iftk» will

Mf^npnwin

imjuJi* ii The

melanoma

of melanomas

I. Superficial 0CC

flwahed bailers

situ—confined to

Iktw of dnqrBstt,

in Caucasians

least

tlK? eTttfcriTii!

attOiiatttJ with

[rjntfoim no

jc^iesiiwe

POCS pnsgrKKis

m.ilHi^nr

i. WjoipheafcMfn

melanomj

(2-Siij, moll

J^ittlivie

4 fVjmerned (?r

mtutyQlal BCC

clinical presentation, diagnosis, and staging

There are four major subtypes of MM: superficial spreading, nodular, lentigo maligna melanoma, and acral lentiginous (Table 97-1). They each vary in clinical and growth characteristics.

Data from the Surveillance, Epidemiology, and End Results (SEER) study show that 82% of patients diagnosed with MM present with localized disease, 9% with re gional disease, and 4% with distant disease.4 Once skin cancer is diagnosed, it is important to determine the stage of the cancer to find out if the cancer is confined to the original tumor site or has spread to other sites, such as the lymph nodes, liver, brain, lungs, or bone. The purpose of staging cancer is to determine prognosis, categorize patients with regard to metastatic potential and survival probability, and aid in clinical decision making. As with most solid tumors, the tumor node metastasis (TNM) classification is used to stage MM, and the latest guidelines for staging MM proposed by the American Joint Committee on Cancer were implemented in 2002 (see Table 97-2).

Breslow Classification
FIGURE 97-1. Skin anatomy: Breslow microstaging and Clark's levels. (From Langley RGB, Barnhill RL, Mihm Jr MC, et al. Neoplasms: Cutaneous melanoma. In: Freedberg IM, Eisen AZ, Wolff K, et al., eds. Fitzpatrick's Dermatology in General Medicine, 6th ed. New York: McGraw-Hill; 2003:938.)

Table 97-2 2002 AJCC Revised Melanoma Staging System

_OwnlftffiHi

Slagg_IttW^h Feature_iYearsW 10- Y-gan

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ofany tumuf Ihk kneü with "o ukef Jtkm wilh two to Uuee lympli rxxfei invtfved a>xJ mlCi^meiayia?^

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M. To ail ijihif vUteral llies llMer} Of dKTjrn meTa^wii ir any iiie with eleviieil ienjm LOH

iClùflft ICvil rtfiflS Ei (IV k'vi(H ïji [Mf ■■ ri -irh into Elu? (Iff lur. Ficj *)7 1) Rii < Ly^ fclPOTl mfjyi il^ I un** Il ill ki^^S. ill from the epldei mn to 1he deepest depth of penelfation Into (he damfe fcee Fkj J7-IJ.

Determination of lymph node status is important in melanoma staging because it is an independent prognostic factor, and it provides the oncologist with guidance for therapy decisions. For patients with melanomas who are at risk of spreading to the lymph nodes, a sentinel lymph node (SLN) biopsy is performed. The SLN, the first lymph node to receive lymph draining from the tumor, is identified by injecting a radioactive material, technetium-99m-labeled radiocolloids, and vital blue dye into the skin next to the tumor and tracing the flow of lymph from the tumor site to the nearest lymph node chain. Once the SLN is located, it is removed and analyzed for the presence of MM cells. If it is positive for the presence of MM, then the whole lymph node basin in that area is dissected; this is also known as lymphadenectomy. An SLN biopsy is the initial procedure to assess the status of lymph node involvement to prevent the morbidity associated with a total lymphadenectomy.

In addition to the stage of the disease and the status of disease involvement in the lymph nodes, other prognostic factors for outcome in MM include patient age and gender, tumor location, and histology of the MM. Specific patient-related and histopathological criteria that have been identified to characterize high-risk patients, in particular among those diagnosed with thin cutaneous melanomas, include male gender, mitogenicity, and evidence of regression.16 Table 97-3 provides complete

information on factors that confer good prognosis for a patient diagnosed with MM. Skin Examination

The ABCDE acronym is a helpful mnemonic for recognizing the signs and symptoms of early MM (Fig. 97-2). It was devised in 1985 by clinicians working in the Melanoma Clinical Cooperative Group at New York University School of Medicine and is used to educate health care professionals who are not dermatologists in differentiat-

ing common moles from cancer. It is also a useful tool to educate the lay public to assess pigmented lesions and screen for suspicious moles to help identify the MM in its early stage when it is curable. Not all MMs, including nodular melanoma, have all four ABCDE characteristics, and it is not meant to provide a comprehensive list of all MM features. The characteristics for each of the letters are described in the "Clinical Presentation" box. It should be noted that evolution of a lesion is one of the most important warning signs of danger in the assessment of moles for MM.

Table 97-3 Prognostic Factors in Melanoma

Factor (Better Prognosis)

Age (less than 65 years) Less than 30 years 60 years 70 years 80 years Gender (female) Female

Male

68

Tumor location (extremities)

10-year survival (%)

Extremities

90

Trunk, head, or neck

70

Histologic Factors (Better Prognosis)

Tumor thickness {less than

Clark's level (level 1)

1 mm)

Ulceration (none)

Tumor vascularity (absent)

Nodal status (none)

Regression (absent)

Vascular invasion (none)

Mitotic rate (low)

Microsatellites (none)

Tumor infiltrating lymphocytes

(presen:)

FIGURE 97-2. ABCDE features of early melanoma. (Images courtesy of the Skin Cancer Foundation, New York, www. skincancer. org.)

Clinical Presentation of MM

Patients with skin cancer generally present with a lesion that may be located anywhere on the body. The most common sites are the head, neck, trunk, and extremities. Changes in any characteristics of a lesion are important danger warning signals. Abnormal presentations of a mole/lesion indicate the need for further assessment.

• Asymmetry: Half the lesion does not mirror the other half.

• Border: Sharp, ragged, uneven, and irregular borders.

• Color : Multiple colors of various hues of light brown, dark brown, black, red, blue, or gray.

• Diameter: Larger than 6 mm or the size of a pencil head eraser.

• Evolving: Significant change in shape, size, symptoms, surface, or shades of color. Other signs and symptoms to monitor for in a lesion, in addition to ABCDE, include:

• Sudden or continuous enlargement of a lesion or elevation of a lesion

• Changes in the skin surrounding the nevus

• Redness, swelling, itching, tenderness, or pain

• Ulceration: friability of the lesion with bleeding or oozing. This is a danger signal. Less Common Sites and Manifestations of MM

It is important to examine these sites for "hidden" MM:

• Mucosal tissue

In the nailbed, a black streak or wide variegated brown streak, elevation of nailbed, skin next to nail becomes darker, nail looks deformed or is being destroyed; size of nail streak increases over time.

Diagnostic Tests

• Dermoscopy

Staging Tests (Depending on Patient's Presentation)

• Baseline chest x-ray

• Lactate dehydrogenase level

• Sentinel lymph node (SLN) biopsy: The status of the SLN is one of the most powerful independent prognostic factors predicting survival. It also provides the oncologist with guidance for therapy decisions and accurate staging.

• Positron emission tomography (PET scan)

• Magnetic resonance imaging (MRI) From Refs. 20, 22.

treatment

Diagnostic accuracy and clinical skills are two essential factors in the appropriate management of skin cancer. Early diagnosis of skin cancer is the key to improved prognosis. On presentation to a clinician's office, patients may offer a history of a new growth or an area of irritation. Conversely, the skin cancer may have been present for years undetected by the patient. The definitive diagnosis of any suspected cutaneous malignancy should be confirmed by a biopsy prior to treatment.

The modality of treatment for skin cancer depends on the size, location, and stage of the tumor; the age of the patient; and the type of skin cancer. Treatment options for skin cancer include surgery, radiation, chemotherapy, and immunotherapy. Surgery is the primary treatment modality for nonmelanoma and melanoma skin cancer.

Desired Outcome

The primary goals of therapy for skin cancer are to completely eradicate the tumor and minimize the risk of tumor recurrence and metastasis. Secondary goals of therapy include preserving normal tissue, maintaining function, and providing optimal cosmetic outcomes.18 Patients with local disease MM (stages I and IIA) are curable with surgical resection of the tumor. Thus the aim is to diagnose patients at the earliest stage in order to increase the probability of cure. Patients with regional disease (stages IIB, IIC, and III) have a high recurrence risk, and the goal of therapy is to prevent relapse of the disease. Disseminated, metastatic MM is not curable, and the goal of therapy is local control of the disease and palliation of symptoms.

Patient Encounter 1, Part 2: Medical History, Physical Examination, and Diagnostic Tests

PMH: Hypertension, currently controlled; gastroesophageal reflux disease

FH: No known family history of cancer; specifically, no NMSC, MM, or hereditary dysplastic nevus syndrome

SH: Patient is retired. His sun-exposure history is as described in Patient Encounter 1, Part 1

Meds: Hydrochlorothiazide 25 mg orally once daily; famotidine 20 mg orally twice daily

ROS: No changes in vision, headaches, SOB, cough, fever, nausea, vomiting, diarrhea PE:

• VS: BP 126/84, P 80, RR 16, T 37°C (98.6°F), ht 68 in. (173 cm), wt 72 kg (158 lb)

• Skin: Fair complexion, multiple scattered nevi, 9 mm nodule on shoulder as described

• HEENT: PERRLA, EOMI, sclera nonicteric, nose and throat clear without exudates or lesions

• Neck and lymph nodes: Supple, no lymphadenopathy

• Lungs: CTA bilaterally

• CV: RRR without murmurs

• Abd: Soft, nontender, nondistended, no hepatosplenomegaly

• Exts: No cyanosis, clubbing, edema

• Neuro: Alert and oriented x 3. Cranial nerves II-XII are intact, nonfocal.

• Labs: Within normal limits

• CT scan of chest, abdomen, and pelvis: Negative

Treatment: KM underwent surgical resection of the primary tumor, and an SLN biopsy was positive for lymph node involvement. A lymphadenectomy was performed. After extensive discussion with his oncologist, the decision was made to start KM on inter-feron-a2b.

Given this additional information, what is KM's stage of MM?

What is the goal of therapy for KM?

What are the treatment options for KM after surgery? What data support the use of high-dose IFN in KM?

Treatment Options for MM (Fig. 97-3)

Stages I and IIA MM

The primary treatment modality for carcinoma in situ (stage I and IIA cutaneous

MM) is surgical excision of the tumor.19 The 5-year survival rates for patients with

stages I and II tumors are 78% to 95%. Achieving adequate surgical margins for the primary tumor is important in preventing local recurrence and improving overall survival. The thickness of the tumor dictates the extent of the surgical margin. For tumors that are greater than 1 mm, or if the tumor is less than 1 mm but has ulceration, it is recommended that an SLN biopsy be performed to rule out occult nodal metastas-20

is. There is no recommendation for systemic therapy in patients with stage I or IIA MM.

Stages IIB, IIC, and III MM (High-Risk MM)

® Excision of the tumor with clear margins is the primary treatment modality for stages IIB and IIC. In addition to surgical excision of the primary tumor site, removal of the involved lymph node chain, a lymphadenectomy, is the standard treatment for stage III MM.19 Patients at these stages are considered to be high risk because of their potential for recurrence and distant metastases. The role of adjunct immunotherapy after surgery to decrease the incidence of recurrence for high-risk melanoma is controversial.

Interferon-« 2b for High-Risk MM Interferon-a2b (IFN) has diverse mechanisms of action, including antiviral activity, impact on cellular metabolism and differentiation, and antitumor activity. The antitumor activity is due to a combination of direct an-

tiproliferative effect on tumor cells and indirect immune-mediated effects. IFN is currently approved by the FDA as adjuvant therapy for patients who are free of disease after curative surgical resection but are at high risk of MM recurrence. This includes patients with bulky disease or regional lymph node involvement such as stages

III disease ZJ It is controversial if IFN should be offeredfor high risk melanoma, as different doses of IFN have not proved definitively that IFN improves overall patient survival.

The doses of IFN used in clinical trials can be classified into three groups: highdose (HDI), intermediate-dose (IDI), and low-dose (LDI) interferon (Table 97-4). Data from many clinical trials assessing LDI in patients with high or intermediate risk of recurrence did not demonstrate an impact on overall survival, and it is unclear if

OA O/i disease-free survival is improved. - Therefore, at this time, LDI cannot be considered efficacious as adjuvant therapy for high-risk, stage III MM.

HDI has shown activity against MM in the adjuvant setting. In the evaluation of HDI for high-risk MM, data from a pooled analysis of four major clinical trials showed improved relapse-free survival, with an approximate 10% reduction in the

risk of recurrence, but no effect on overall survival in patients receiving HDI. A pooled analysis of several high-dose IFN trials and a trial comparing HDI with vaccine (E1694) also confirmed a reduction in the risk of recurrence with HDI without

28 29

significant improvement in overall survival. '

HDI has substantial side effects (Table 97-5) and is an expensive therapy. The constellation of side effects associated with the administration of IFN can be divided into acute and chronic manifestations and categorized into four major side-effect groups: constitutional, neuropsychiatric, hematologic, and hepatic.3 It is very important to educate patients on the side effects to expect and the interventions that are available to minimize the toxicities in order to reassure the patient.

HpÇlitnai K1T1 (Jf wrlhgyl tçmçj^pmidu Or dnicnJ 1nal

Observe and isptai í-íjri

Corader rasMbMi

S^temic frarapy [ditosrbnfruí or IL-ÍJ (ir nhr ul InnJ

HpÇlitnai K1T1 (Jf wrlhgyl tçmçj^pmidu Or dnicnJ 1nal

FIGURE 97-3. Algorithm for management of cutaneous melanoma. (From Ref. 39.)

The clinical dilemma in the use of HDI as adjuvant therapy for high-risk MM patients becomes: Is the benefit of preventing recurrence in only a small portion of patients without much improvement in overall survival worth the risk of considerable disabling toxicity? Which MM patient at risk for recurrence should receive HDI as adjuvant therapy? Decision guidelines proposed by Kilbridge and colleagues suggest that the patient should be willing to undergo the side effects of HDI treatment, understanding that it may decrease the chance of MM recurrence in 5 years by 10% or

less. Other factors that should be considered in the decision include the patient's

comorbidities and/or contraindications to receiving HDI. If the patient is eligible, encouragement to participate in clinical trials designed to address the issues of sur-

vival, quality of life, and treatment costs is also reasonable.

Stage IV MM

The prognosis for patients diagnosed with stage IV MM varies with the location of the metastases and the number of metastatic sites. Treatment options for stage IV meta-static MM include surgical excision of the lesion and radiation therapy for palliation of symptoms.

Surgical excision of the tumor is not curative for metastatic MM, and the primary goal of therapy is local control of the disease and relief of identifiable symptoms. In highly selected patients, such as those with good performance status, less aggressive tumor biology, prolonged period of disease-free interval from the time of primary tumor treatment, and limited disease that is contained within a single location, complete surgical resection results in a median survival of 2 years and a 5-year

survival rate of 10% to 25%. For most other patients with stage IV MM, unfortunately, the survival rate is measured in months rather than years, with overall median

survival of 5 to 8 months and a 5-year survival rate of less than 5%. Table 97-4 Immunotherapy Dosinga

Interferon Regimes Used in Clinical Trials_

High dose (HDI) 20 million units/nrv IV daily x S days/week for

A weeks, followed by 10 million units/m SC 3 times/week for 48 weeks

Intermediate 10 million units x 5 days/week for 4 weeks, dose (IDI) followed by 10 million units SC 3 times/week for varying durations

Low dose (LDI) 3 million units SC 3 times/week for varying durations

1 million units SC every other day for 1 year

Interleukln 2 Dosing Regimens"_

IL-2 600.000 or 720,000 lUAg by 15-minute infusion every 8 hours for 14 consecutive doses over 5 days as tolerated

IL-2 720,000 IUIV over 15 minutes beginning at 6 pm on day I and subsequently at 8 and 6 m up to a maximum of 8 total doses on days 1 to 5 (first treatment course) and repeated on days 15 to 19 {second treatment course)

Chemotherapy0_

Dacarbazlne 250 mg/m /day IV, days 1 to 5. every 21 days

No guidelines exist for dose adjustment in patients with renal or hepatic impairment

Temozolomide 150 to 200 mg/m /day by mouth x 5 days, every 28 days

Caution should be used in patients with severe renal or hepatic impairment, no specific guidelines exist

Measure absolute neutrophil count (ANC) and platelets on day 22 and 29

if ANC is less than 1.000/L or platelet ¡s less than 50,000/L postpone therapy until ANC is greater than 1,500/L and platelet

Table 97-5 IFN Toxicities

Common Acute Toxicity

Management

Flu-Like Symptoms rever, rigors, chills, ' headaches, myalgia, nausea, emesis

Neutropenia Hepatic enzyme elevation

Cutaneous— alopecia, transient mild rashlike reaction

Last 1-12 hours after dose and tolerance develops with continued therapy Bedtime administration helps with tolerating si cíe effects Pre medic ate with acetaminophen or NSAID and administer meperidine for severe chills and rigors b-HT. antagonist prochlorperazine, metoclopramide, fluids helps wit hi nausea and vomiting Weekly CRC; reduce dose by 30-50% Livef function tests {LFTs) at baseEine, weekly during induction, monthly during first 3 months of maintenance,, then every 3 months. Withhold treatment until LFTs normalize; restart al 30-50% dose reduction; reversible on dose reduction or cessation interferon Es contraindicated in patients with psoriasis because exacerbation of psoriasis has been noted during 3FN therapy

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