Trinh Pham and Jennifer Nam Choi
LEARNING OBJECTIVES
Upon completion of the chapter, the reader will be able to:
1. Identify the risk factors associated with skin cancer.
2. Describe the common signs and symptoms of skin cancer and identify the features of a mole that are suspicious for melanoma.
3. Identify the key features in the different stages of melanoma and their correlation with prognosis.
4. Explain the goals of therapy for the treatment of nonmelanoma and melanoma skin cancer.
5. Devise a plan of lifestyle modifications for the prevention of skin cancer.
6. Discuss the pros and cons of interferon-α therapy for melanoma, and formulate a monitoring plan for patients receiving interferon-α.
7. Discuss the pros and cons of interleukin-2 (IL-2) therapy for melanoma, and formulate a monitoring plan for patients receiving IL-2.
8. Discuss the different treatment options for melanoma with brain metastasis.
9. Discuss the role of temozolomide in the treatment of stage IV melanoma with or without CNS metastasis.
10. Discuss the different treatment options for nonmelanoma skin cancer.
KEY CONCEPTS
Exposure to ultraviolet radiation from the sun is recognized as one of the primary triggers for skin cancer development.
Staging of malignant melanoma is important to determine prognosis, categorize patients with regard to metastatic potential and survival probability, and aid in clinical decision making.
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.
Surgery is the primary treatment modality for nonmelanoma and melanoma skin cancer.
Stages IIB, IIC, and III melanoma are considered to be high risk because of their potential for recurrence and distant metastasis. The primary treatment modality is surgical excision of the tumor and a lymphadenectomy for patients with positive lymph nodes.
Interferon-α2b is approved by the FDA as adjuvant therapy for high-risk melanoma. It is controversial if it should be offered to every patient at high risk for recurrence.
Stage IV melanoma is not curable, and the primary goal of therapy is local control of the disease and relief of identifiable symptoms.
Interleukin-2 (IL-2) therapy is approved by the FDA for the treatment of metastatic 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.1 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.2 The mortality rate for MM is on the rise in North America, Australia, and New Zealand at a pace of 2% to 4% annually.2 Ultraviolet (UV) radiation exposure is the leading environmental factor causing skin cancer.3 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.2In 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.4The 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.5 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?
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.7 Gene mutations may then transpire, leading to carcinogenesis.7 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 single-strand breaks.7 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.6The 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-pyrimodone(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.13 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.aad.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 dendritic projections. The dermis gives the skin its strength, resiliency, and resistance to tearing.10 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
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 regional 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).
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
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.17
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 differentiating common moles from cancer.12 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
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:
• Nailbed
• Mucosal tissue
• Scalp
• Eye
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
• Biopsy
Staging Tests (Depending on Patient’s Presentation)
• Baseline chest x-ray
• Lactate dehydrogenase level
• CT of chest, abdomen, pelvis
• 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 × 3. Cranial nerves II–XII are intact, nonfocal.
• Labs: Within normal limits
• CT scan of chest, abdomen, and pelvis: Negative
• CXR: 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 interferon-α2b.
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%.20Achieving 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.21For 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 metastasis.20 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-α 2b for High-Risk MM Interferon-α2b (IFN) has diverse mechanisms of action, including antiviral activity, impact on cellular metabolism and differentiation, and antitumor activity.22 The antitumor activity is due to a combination of direct antiproliferative effect on tumor cells and indirect immune-mediated effects.22 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 IIB, IIC, or III disease.23 It is controversial if IFN should be offered for 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: high-dose (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 disease-free survival is improved.24–26 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.27 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 significant improvement in overall survival.28,29
HDI has substantial side effects (Table 97–5) and is an expensive therapy.30 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.30 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.
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.31 Other factors that should be considered in the decision include the patient’s comorbidities and/or contraindications to receiving HDI.31 If the patient is eligible, encouragement to participate in clinical trials designed to address the issues of survival, quality of life, and treatment costs is also reasonable.31
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 metastatic 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%.32 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%.32
Table 97–4 Immunotherapy Dosinga
Table 97–5 IFN Toxicities
Interleukin 2 for Stage IV MM Interleukin 2 (IL-2) therapy is approved by the FDA for the treatment of metastatic MM, and it is a reasonable option for patients with this stage of the disease. IL-2 indirectly causes tumor cell lysis by proliferating and activating cytotoxic T lymphocytes (CTL).33 The overall objective response rate for patients with metastatic MM receiving high-dose IL-2 is 16%, with a complete response in 6% of patients and a partial response in 10% of patients.34 The median duration of response is 8.9 months for all responding patients and 5.9 months for patients with a partial response.35 The median duration of complete response has not been reached but is at least 59 months. Disease progression is not observed in any patient responding for longer than 30 months.35 Good performance status and no prior systemic therapy are the only prognostic factors that are associated with response, with objective response rate being twice that of patients with poor performance status and who received prior chemotherapy.34 The site of metastasis did not influence response, and patients had responses in all organ sites, including lung, liver, adrenal, bone, liver, kidney, and spleen.34 The data are encouraging because for the small number of patients who responded to therapy, the effect is of a long duration, and some patients may be considered to be cured of the disease (Refer to Table 97–4 for an example dosing regimen.)
High-dose IL-2 therapy is associated with severe toxicities.34,36,37 Table 97–6 lists the most common side effects experienced by patients receiving IL-2 therapy and recommendations for management. Patients receiving IL-2 may be managed on the oncology unit as long as cardiac telemetry is available; however, it is important that all medical staff involved with the care of these patients be well educated on the side effects to monitor for and in the management of critical-care issues such as hypotension.34
Chemotherapy for Stage IV MM Dacarbazine, an alkylating agent, is the most active single-agent chemotherapy against MM, achieving response rates of 15% to 25%.38 It is the only chemotherapy agent approved by the FDA for the treatment of metastatic MM. A recent phase III clinical trial in patients with advanced metastatic MM demonstrated a response rate of 12% and stable disease in 16% of patients treated with dacarbazine alone.38 The response duration was not long-standing, with a median survival time of 6.4 months.38 Nausea and vomiting are the most common side effects of dacarbazine. Combining dacarbazine with other chemotherapy agents with activity against MM in single-institution phase 2 trials resulted in response rates of between 30% and 50%.39 Two phase III clinical trials assessing the CVD (cisplatin, vinblastine, and dacarbazine) regimen and the Dartmouth regimen (carmustine, cisplatin, dacarbazine, and tamoxifen) versus single-agent dacarbazine showed that there was a trend toward improved response rate, but the results were not statistically significant.40 Furthermore, there was no significant survival advantage over single-agent dacarbazine alone, but toxicity was greater with the combination chemotherapy.33 Therefore, combination chemotherapy is not a standard of care for stage IV MM.
Table 97–6 IL-2 Toxicities
Biochemotherapy for Stage IV MM Clinical trials combining chemotherapy and immunotherapy are based on the observations of independent clinical activity of each of these treatment modalities in treating metastatic MM. This combination is known as biochemotherapy. Only one phase III clinical trial showed significant improvement in response rate, time to progression, and median survival favoring the biochemotherapy arm versus the combination-chemotherapy arm.41 A systematic review of the literature to evaluate the use of biochemotherapy for the treatment of metastatic MM was conducted by Hamm and colleagues.42 The results revealed inconsistent response, time to progression, and survival with consistently high toxicity rates. Therefore, currently, the use of biochemotherapy is not justified outside a clinical trial in patients with stage IV MM.33,39,43
In summary, systemic therapy for stage IV MM is controversial. Combination chemotherapy and biochemo-therapy increase toxicity significantly without offering overall survival benefit; thus they are not the standard of care for stage IV MM. Both high-dose IL-2 and dacarbazine are approved for the treatment of stage IV MM. High-dose IL-2 may be preferred in patients with a good performance status. Enrollment in a clinical trial and best supportive care are also reasonable alternatives.44
MM With Brain Metastases
Radiation for Brain Metastases One of the most common sites of metastasis for MM is the brain, and MM is reported to be the third most common cause of brain metastasis.45 The incidence of brain metastasis is reported to range from 10% to 40% in clinical studies.45 Treatment options for brain metastases include surgery, radiation (which includes whole-brain radiotherapy and stereotactic surgery [SRS]), or chemotherapy. The choice of therapy depends on the number of metastatic lesions, accessibility of the lesion for surgery, the presence of neurologic symptoms, and the status of extracranial disease.
Surgery followed by whole-brain radiotherapy (WBRT) is best indicated for patients with an accessible single brain lesion and controlled or limited systemic MM.45,46 For those patients with multiple metastatic brain lesions and systemic disease, surgery generally is not considered to be appropriate.44 In some cases, however, it may be necessary to resect the one “dominant” lesion that is causing symptoms such as intracranial hypertension, seizures, hemorrhage, or other severe neurologic side effects.45,46 WBRT is indicated for patients with multiple (more than three) CNS metastases, surgically inaccessible lesions, and extensive systemic disease.47 WBRT for metastatic CNS MM does not improve survival or provide a cure; however, it is effective in relieving neurologic symptoms.47
Stereotactic radiosurgery (SRS) may be considered over surgery for patients with fewer than three metastatic CNS lesions that are deep, nonsymptomatic, and less than 3 cm in size.47 SRS delivers high doses of focused ionizing external-beam radiation to a well-defined target area in one session of radiation therapy.47 This technique maximizes the dose of radiation to the tumor with a rapid dose falloff outside the target area, resulting in sparing of the surrounding nontarget normal tissue.
The median survival for patients with CNS metastasis is 3.5 months with best supportive care and corticosteroids.48 Patients treated with WBRT and SRS or SRS alone have a median survival of 28 to 40 weeks, and the cause of death for most of these patients is progressive extracranial disease.45
Systemic Therapy for Brain Metastases Temozolomide (TMZ) is an oral chemotherapy agent that is structurally and functionally similar to dacarbazine, and it belongs to a new class of alkylating agents known as imidazotetrazines. Temozolomide possesses activity against MM cells and the ability to cross the blood–brain barrier because of its lipophilicity, thus making it an ideal chemotherapy agent to be investigated for the treatment of MM with CNS metastases. It is stable in the acidic pH of the stomach and is absorbed readily in the digestive tract with 100% bioavailability. Once it is in the CNS, temozolomide is hydrolyzed to the active metabolite MTIC (5-[3-dimethyl-1-triazenyl] imidazole-4-carboxamide). MTIC breaks down rapidly to form the reactive methyldiazonium ion, which methylates guanine residues in the DNA molecule causing cytotoxicity. TMZ does not cause cross-linking of DNA strands, making it less toxic to hematopoetic progenitor cells in the bone marrow than the nitrosoureas, platinum compounds, procarbazine, and dacarbazine. A recent phase III clinical trial comparing single-agent TMZ with dacarbazine demonstrated that TMZ is at least as effective as dacarbazine against advanced metastatic MM without CNS involvement.38 The role of TMZ, either alone or as combination therapy, in the prevention and treatment of MM CNS metastasis is an area of active research.49–51 In a phase 2 trial involving patients who have not received prior systemic chemotherapy for the treatment of MM brain metastases, single-agent TMZ showed a response rate of 7%, stable disease in 29% of patients, and a median overall survival of 3.5 months.52 When TMZ was administered in combination with WBRT in patients with CNS metastasis, the response rate was only 10%, with the duration of response ranging from 2 to 7 months.49 The combination of TMZ and a biochemotherapy regimen that included cisplatin, IL-2, IFN was evaluated in a phase 2 outpatient clinical trial for metastatic MM.50The results suggest that the rate of CNS metastasis may be decreased in patients who have either a complete or partial response owing to the addition of a CNS-active agent (TMZ).50 Thalidomide in combination with TMZ has also been studied, showing a response rate of 12%.51 In light of these promising data with TMZ, further trials are being conducted to confirm the benefit of TMZ in preventing progression or treating CNS metastases.
OUTCOME EVALUATION
The outcome of patients diagnosed with MM depends on the stage of the disease at diagnosis. The overall 5-year survival rate for patients with localized disease (stages I and IB) is the best at 89% to 95%.20For patients with stage IIA to IIIA disease, the 5-year survival rate is greater than 50%, ranging from 63% to 77%.20 In patients with more advanced regional metastatic disease (stage IIIB to IIIC), the 5-year survival rate ranges from 27% to 53%.20Patients with stage IV distant metastatic disease have the worst 5-year survival rate at only 10% to 19%.20
Patient Encounter 1, Part 3: Create a Care Plan
Create a care plan while KM is receiving INF therapy. Your plan should include: (a) the goal of therapy with INF, and (b) a plan related to dealing with the side effects to expect from this therapy.
What supportive measures should be used to minimize side effects?
What laboratory parameters need to be monitored?
What are the indications to discontinue or hold therapy?
When may the therapy be restarted after the doses were held?
What are the pharmacologic and nonpharmacologic recommendations for managing side effects?
How frequently should KM be monitored while on therapy?
Be able to discuss with the patient the following for INF:
• The differences between acute and chronic side effects
• The side effects that the patient will develop tolerance to
• The best time of the day to administer the drug
• The importance of keeping regular follow-up appointments to monitor for long-term side effects of the therapy and draw blood for routine lab tests
• Reassure the patient that therapy may be stopped at any time if side effects are intolerable
• What is the follow-up plan for KM after he has completed therapy with interferon-α2b?
After diagnosis and treatment of skin cancer, the next crucial step in management is monitoring for recurrence. Most recurrences materialize in the first 5 years, and the majority appears within the first 2 to 3 years following treatment.19 The site of recurrence can be at the original site of the disease or in a different, distant anatomic location. Early detection of tumor recurrence is crucial because response rate is decreased significantly with tumor relapse.18 Recurrences are found equally by physicians and patients, and one study demonstrated that 94% of recurrences were detected by the patient.53 Thus it is imperative to educate patients on how to perform a total skin self-examination appropriately. Additionally, patients need to understand the importance of scheduling regular follow-up visits with the oncologist or dermatologist after the diagnosis and treatment of skin cancer.
There is no universal guideline for follow-up care for MM. The National Comprehensive Cancer Network recommends annual skin examination for all patients.44 Educate patients with stage IA disease to have a history and physical examination every 3 to 12 months as clinically indicated and an annual skin examination for life. For stages IB to III disease, schedule a history and physical examination every 3 to 6 months for 3 years, every 4 to 12 months for 2 years, and then annually as indicated. It is optional to obtain a chest x-ray, LDH, CBC, and liver function tests (LFTs) every 3 to 12 months. CT scan can be obtained as indicated clinically.44
Patients who received immunotherapy after stage III or IV MM may experience fatigue and other chronic side effects. Develop a plan to order laboratory tests such as LFTs, thyroid-stimulating hormone, and white blood cell count at baseline and on a weekly or monthly basis as indicated. Monitor and evaluate patients for side effects of IL-2 or IFN, and educate patients on what to expect and how the side effects will be managed. Assess the patients’ psychological, physical, and social functioning. Counsel patients to contact the hospital’s social service department or the American Cancer Society for assistance in dealing with the disease emotionally, and recommend that patients consider attending support group meetings or talking to a counselor if or before they become overwhelmed with the diagnosis.
NONMELANOMA SKIN CANCER
EPIDEMIOLOGY AND ETIOLOGY
NMSC accounts for nearly half of all newly diagnosed cancers in the United States each year, and it is estimated that more than 1 million cases will be diagnosed in 2008. The true prevalence of NMSC may be underestimated because it is treated in outpatient settings, and no formal reporting to cancer registries is required.54 BCC is the most common form of NMSC in Caucasians and comprises 75% of newly diagnosed NMSC. SCC accounts for 20% of NMSC.54 NMSCs occur at a lower incidence in darker-skinned people or in descendants of African, Asian, and Mediterranean countries. In African Americans, the most common form of NMSC is SCC.18 The majority of NMSCs are curable and the mortality rate is low; cure rates approach 98%, and the overall 5-year survival rate is greater than 95%.18 Metastasis occurs in less than 0.1% of BCCs compared with an average of 3.6% of SCCs. Seventy-five percent of all NMSC deaths are attributed to SCC.18 NMSC is associated with considerable morbidity owing to functional and cosmetic deformity. In addition, it is an economic burden to the health care system because costs associated with NMSC treatment are estimated at approximately $426 million per year.55
RISK FACTORS
It is estimated that 90% of NMSCs are linked to UV exposure and data from epidemiologic studies indicate that greater cumulative lifetime exposure is associated with a higher risk of developing SCC, whereas severe sunburns correlates more with BCC.6
Most cases of BCC are sporadic; however, it occurs frequently in the rare individuals with hereditary disorders such as basal cell nevus syndrome (also known as Gorlin’s syndrome) and xeroderma pigmentosum (XP). The patched gene (PTCH), a tumor-suppressor gene, has been shown to be mutated in XP and 50% to 60% of sporadic BCCs.7 The oncogene bcl-2, which suppresses programmed cell death (apoptosis), also has been found to be expressed in high levels in patients with BCC.56
There is clear evidence linking defects of the immune system to the development of NMSC. For example, it is observed that patients receiving chronic immunosuppressant therapy for organ transplantation have a 50% risk of developing SCC within 20 years of transplantation, and 30% of these cancers are highly aggressive.57 Additionally, patients with HIV infection are predisposed to melanoma. Data also support the idea that UV radiation exposure induces immunosuppression and that this is associated with carcinogenesis.58 Langerhans’ cells are responsible for antigen processing and initiation of the immune cascade in the skin, and it has been demonstrated that UVB alters their function.58 UV radiation also induces suppressor T cells and activates biologic response modifiers by initiating cytokine cascades, ultimately leading to a state of immune tolerance and unsuppressed tumor growth.
PATHOPHYSIOLOGY
NMSCs arise from epidermal keratinocytes and involve primarily squamous cells and basal cells of the epidermis and dermis skin layers. BCCs arise from basal cells or keratinocytes in hair follicles or sebaceous glands.
CLINICAL PRESENTATION, DIAGNOSIS, STAGING
Like MM, BCC is also divided into four main histologic sub-types: nodular, superficial, morpheaform, and pigmented (or metatypical) (Table 97–1). BCC has indolent growth characteristics, with a very low metastatic rate, ranging from 0.0028% to 0.55%.18 Paradoxically, BCCs can cause extensive local destruction and significant disfigurement.
SCCs are more aggressive than BCCs (Table 97–1). The rate of metastasis for SCC is 2% to 6% and may be as high as 10% to 14% in high-risk sites such as the ear and lip and 30% in the genital area.18 SCCs are preceded by leukoplakia, actinic keratosis, radiation damage, or sun damage to the skin.17 Actinic keratosis, a small papule that appears on areas of sun damage on the skin, has a 1 in 400 risk of transforming to SCC.18
Clinical Presentation of NMSC
Five Warning Signs of BCC
The appearance of some BCCs is similar to plaque, psoriasis, or eczema, and these benign disorders are included in the differential diagnosis.
• An open sore that bleeds, oozes, or crusts and remains open for 3 or more weeks
• A reddish patch or irritated area that may crust, itch, hurt, or persist with no noticeable discomfort
• A shiny bump or nodule that is pearly or translucent and may be pink, red, or white. In dark-haired people, it may be tan, black, or brown and can be confused with a mole
• A pink growth with slightly elevated, rolled border and a crusted indentation in the center
• A scarlike area that is white, yellow, or waxy with poorly defined borders
Warning Signs and Symptoms of SCC5,26
• A wartlike growth, a persistent scaly red patch with irregular borders, or an open sore that crusts or bleeds
• An elevated growth with a central depression that bleeds occasionally. This growth type increases in size rapidly
• In situ SCC: red scaling macule or plaque
• Invasive SCC: firm or friable red papule or nodule covered with scale or crust
• Precursor of invasive SCC (actinic keratosis): scaly erythematous macule or papule on areas of chronic sun exposure
From Ref. 22.
Lymph Node Consideration in NMSC
In patients with SCC, metastatic spread to the lymph nodes occurs in less than 5%.59 Patients are still potentially curable with this stage of the disease, but they are at high risk of experiencing regional relapse and distant metastasis to the bones and lungs. A tumor thickness of greater than 4 mm has been suggested as the threshold at which nodal metastasis should be suspected and an SLN biopsy should be considered.59
TREATMENT
In patients diagnosed with BCC and SCC, the primary goal of therapy is to cure the patient and to prevent recurrence. Although NMSC has a low mortality rate, morbidity owing to tissue destruction, functional impairment, and disfigurement is a significant issue. Therefore, secondary goals of therapy for NMSC are preservation of function and restoration of cosmesis.18
Nonpharmacologic Therapy
Surgery
Surgery is the primary treatment modality for all patients diagnosed with either BCC or SCC. Full-thickness ablative procedure in the form of surgical excision of the tumor along with a margin of normal tissue surrounding the tumor is the preferred method for high-risk tumors. Obtaining negative surgical margins is critical for cure and decreasing the risk of tumor recurrence. For lesions that are less than 2 cm in diameter, a minimum margin of 4 mm is usually adequate.21 Depending on the tumor size, degree of differentiation, and invasion of surrounding structures, larger margins of resection may be necessary.
Low-risk tumors can be treated with superficial ablative techniques, including electrodessication and curettage (ED&C) and cryotherapy.19 ED&C is a simple, cost-effective technique that utilizes repeated cycles of using a curette to cut through malignant tissue, followed by electrodesiccation, which involves the application of high voltage, low current to the skin, causing drying or desiccation of the tissue. ED&C is most appropriate for well-defined superficial lesions that are not located in areas with increased risk for metastasis.
Cryotherapy is a procedure used primarily for smaller, low-risk NMSCs with clearly defined margins. It involves delivering liquid nitrogen at subzero temperatures as a spray or with a supercooled metal probe to destroy the malignant tissue.18 While cryotherapy is cost-effective and easy to deliver, the recurrence rate is high.18
NMSC is considered to be high risk if it has any of the following features: it is recurrent, the location is at a high risk site (e.g., mask areas of the face, lips, ears, hands, and feet), it is larger than 2 cm in diameter or greater than or equal to 4 mm in depth, it is moderately or poorly differentiated, it is fast growing, it has ill-defined borders, there is positive perineural or vascular invasion, the patient is immunosuppressed, or it is the morpheaform or metatypical subtype of BCC.19 If the tumor is located on the trunk or extremities, less than 2 cm in diameter and less than 4 mm in depth, well differentiated, slow growing, has well-defined borders, and is the nodular or superficial subtype of BCC, then it is considered to be low risk.19 For high risk NMSC, Mohs’ micrographic surgery (MMS) provides the highest cure rate.18 The goal of this therapy is complete removal of the cancer with preservation of as much surrounding normal tissue as possible. MMS involves careful dissection, staining of frozen sections, and anatomic mapping of the tumor specimen. Sections are assessed immediately under the microscope in the operating theater and the process is repeated until a tumor-free margin is attained.18
The 5-year survival rate for surgical excision, electro-desiccation and curettage, and MMS is 90% or better for NMSC.19
Radiation
Radiation is not standard therapy for the treatment of skin cancer; however, there are circumstances in which radiation may be preferred. Older patients or patients who are poor candidates for surgery may be offered radiation as an option.48 Radiation offers good cosmetic results, but it requires multiple visits over the course of several months, making it inconvenient for patients.19 In the treatment of NMSC, radiation results in poorer cosmetic outcomes than surgery or electrodesiccation and curettage.7 Disadvantages of radiation include radiation-induced dermatitis, high cost, and the increased risk of secondary malignancy, including SCC and BCC.7
Photodynamic Therapy
Photodynamic therapy is a noninvasive treatment option for actinic keratoses and is being investigated in the treatment of superficial BCC and SCC. A photosensitizing agent is administered IV or topically to the target area, followed by exposure to a light source. The energy absorbed by the sensitizer is transferred to molecular oxygen to create an activated form of oxygen called singlet oxygen, which reacts with cellular component to cause cell damage and death.60 One of the most commonly used photosensitizing agents is topical 5-aminolevulinic acid, a solution that is applied for 14 to 18 hours to the lesion and irradiated for 5 to 20 minutes.61 Response rates for superficial SCC have ranged from 75% to 100%, while those for superficial BCC range from 90% to 100%.7 Side effects of topical agents are usually limited to local skin reactions, while those of IV agents often include generalized photosensitivity.
Pharmacologic Therapy
Nonsurgical treatment is used frequently for superficial NMSCs. Topical 5-fluorouracil has been used for the treatment of actinic keratoses, superficial BCCs, and SCCs in situ.62 Fluorouracil interferes with the synthesis of DNA and to a lesser extent RNA by blocking the methylation reaction of deoxyuridylic acid to thymidylic acid, ultimately causing cell death, particularly of more rapidly dividing cells. Topical applications of 5% 5-fluorouracil usually consist of a twice daily dosing for at least 3 to 6 weeks, for up to 12 weeks. Intralesional 5-fluorouracil has also been used successfully in treating SCC using 8 weekly injections.63 Imiquimod cream is another treatment option for actinic keratoses and low-risk NMSC. It is a Toll-like receptor 7 (TLR7) agonist that promotes Th1-type immunity and induces cytokines, including interferon-α. It is FDA-approved for treatment of actinic keratoses and superficial BCC. Response rates of superficial BCC with application of 5% imiquimod cream five times a week for 6 weeks range from 70% to 88%,64 with lower cures for nodular BCC.65 Imiquimod has also been shown to be an effective treatment for SCC in situ; in a placebo-controlled trial, 11 of 15 lesions resolved versus 0 in the placebo-treated group.66 The most common side effects of both 5-fluorouracil and imiquimod are erythema, itching, pain, and crusting that are mild to moderate. Finally, intralesional injection of interferon-α2b three times weekly for 3 weeks has been used to treat BCC, with cure rates up to 97%.67
OUTCOME EVALUATION
BCC and SCC have excellent outcomes, with cure rates approaching 98%.18 Recurrence of NMSC during a 5-year follow-up is around 30% to 50% and 70% to 80% of recurrence develops within the first 2 years after initial therapy. Therefore, it is crucial to advise patients to schedule routine follow-up visits with their dermatologist and educate them about the value of sun protection and total body skin self-examination. For patients at high risk for recurrence, they should be monitored every 1 to 3 months for the first year, every 2 to 4 months in the second year, every 4 to 6 months for years 3 to 5, then every 6 to 12 months annually for life. The follow-up recommendation for low-risk patients is every 3 to 6 months for 2 years, every 6 to 12 months for year 3, then annually for life.
Patients receiving topical agents such as fluorouracil or imiquimod should be educated to wash the treatment area with mild soap and water before applying the cream, use gloves to apply enough to cover the area with a 1-cm margin and wash their hands thoroughly after each application. They should avoid sun exposure and be counseled to monitor for side effects such as pain, itching, and inflammation. They should consult their dermatologist if the side effects are intolerable.
Patient Care and Monitoring
1. Obtain a thorough patient medication history, both prescription and nonprescription, to prevent drug interactions with the current therapy the patient is receiving.
2. Obtain the appropriate baseline laboratory tests, and determine a time interval for reevaluation of specific laboratory tests to determine toxicity.
3. Provide education on the side effects of therapy:
• What to administer/take to prevent side effects
• When to administer/take the medication to decrease side effects
• Nonpharmacologic recommendations to minimize side effects
• Drugs that may interact with therapy
• Lab tests that need to be monitored on a regular basis
• The parameters for discontinuing or holding therapy
• If therapy is to be reinitiated, the new dose of therapy
4. Assess the patient for adverse drug reactions and drug–drug interactions.
5. Educate the patient on the signs and symptoms of infection.
6. Assess for changes in the patient’s quality of life owing to side effects of drug therapy.
7. Educate the patient on measures that should be undertaken to limit sun exposure and prevent skin cancer.
8. Educate the patient on how to do skin self-examination for suspicious moles.
9. Educate the patient on follow-up recommendations after treatment for skin cancer is completed.
Abbreviations Introduced in This Chapter
Self-assessment questions and answers are available at http://www.mhpharmacotherapy.com/pp.html.
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