Advances in Oral Retinoid Therapy

Advances in Oral Retinoid Therapy
Recognition and Management of Nonmelanoma Skin Cancer in Solid Organ Transplant Recipients: Advances in Oral Retinoid Therapy

Learning Objectives On completing this program, participants will be able to: Give an overview of the epidemiology and pathogenesis of nonmelanoma skin cancer (NMSC) in organ transplant recipients Describe the presenting features and natural history of common skin cancers Identify risk factors for NMSC in organ transplant recipients Describe appropriate therapies for managing NMSC in organ transplant recipients, including oral retinoids Recognize possible adverse effects and drug interactions resulting from NMSC preventive therapies Understand the common adverse effects (AEs) of systemic retinoid chemoprevention and their prevention and management

Overview of Skin Cancers

Number of Transplants and Transplant Survival,
The OTR Population Number of Transplants and Transplant Survival, by Organ Number of Transplants Patient Survival, % To Date In 2004 5 Years 10 Years All organs 338,640 27,029 Kidney 201,846 15,999 81.0* 58.3* Liver 69,057 6167 72.6* 55.3* Pancreas 4282 603 80.3 62.7 Kidney/pancreas 12,392 880 85.3 62.1 Heart 36,764 2016 72.5 49.4 Lung 12,453 1173 46.0 23.7 Heart/lung 869 39 38.7 23.1 Intestine 977 152 56.8 15.8 Approximately 155,000 living allograft recipients in the United States Incidence of skin cancer increases significantly with prolonged survival OTRs are the largest population of individuals at high risk for NMSC. Because of the success of organ transplantation techniques and the immunosuppressive medications needed to prevent rejection, organ transplantation is common, and OTRs frequently enjoy long survival after receiving their transplant. In 2004, nearly 30,000 individuals received transplants.1 Among patients receiving the most commonly transplanted organs (kidney, liver, and heart), 72% to 81% survive more than 5 years, and 49% to 58% survive more than 10 years.1 These long survival times mean that there is time for NMSC to develop in OTRs. References Organ Procurement and Transplantation Network. Accessed May 3, OPTN/SRTR 2004 Annual Report HHS/HRSA/HSB/DOT; UNOS; URREA. 113_dh.pdf *Deceased donors only. OTR, organ transplant recipient. Organ Procurement and Transplantation Network. Accessed May 3, 2005. OPTN/SRTR 2004 Annual Report HHS/HRSA/HSB/DOT; UNOS; URREA.

Common Types of Skin Cancer
Types of skin cancer in the general population1-3 ~80%: basal cell carcinoma (BCC) ~16%: squamous cell carcinoma (SCC) ~4%: melanoma <1%: others Actinic keratoses (AKs)3,4 Precursors to NMSC Estimated 10 million Americans affected Dramatic increase in NMSC in the OTR population5,6 65 x risk of SCC 10 x risk of BCC In the general population1-3 About 80% of skin cancer cases are BCC. About 16% are SCC. About 4% to 5% are melanoma. Other rare forms of NMSC also occur but make up less than 1% of the total number of NMSC cases. These include1,2: Merkel cell carcinoma1 Atypical fibroxanthoma Extramammary Paget’s disease1 Sebaceous carcinoma3 Angiosarcoma4 Kaposi’s sarcoma4 Dermatofibromasarcoma protuberans1 Cutaneous T-cell lymphoma1 AKs, believed to be possible precursors to NMSC, result from ultraviolet (UV) damage to skin and affect an estimated 10 million Americans.5 The rate of NMSC is dramatically increased in the OTR population, with SCCs much more prevalent than BCCs.6,7 References American Academy of Dermatology. Available at: Accessed May 24, 2005. American Academy of Dermatology. Available at: Accessed May 24, 2005. Brash DE, Safai B. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: Principles and Practice of Oncology. 5th ed. Philadelphia, Pa: Lippincott-Raven Publishers; 1997: Brennan MF, Casper ES, Harrison LB. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: Principles and Practice of Oncology. 5th ed. Philadelphia, Pa: Lippincott-Raven Publishers; 1997: American Academy of Dermatology. Available at: and+Sun+Safety/WarningSignsSkinCancer.htm. Accessed May 3, 2005. Jensen P et al. J Am Acad Dermatol. 1999;40(2 pt 1): Berg D, Otley CC. J Am Acad Dermatol. 2002;47:1-17. 1. American Academy of Dermatology. Available at: Accessed May 24, American Academy of Dermatology. Available at: Accessed May 24, 2005. 3. Brash DE, Safai B. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: Principles and Practice of Oncology. 5th ed. Philadelphia, Pa: Lippincott-Raven Publishers; 1997: American Academy of Dermatology. Available at: ignsSkinCancer.htm. Accessed May 3, Jensen P et al. J Am Acad Dermatol. 1999;40(2 pt 1): Berg D, Otley CC. J Am Acad Dermatol. 2002;47:1-17.

Distribution of Lesion Types: General Population and OTRs
This graphic further illustrates the differences in NMSC types in the general vs. the OTR populations. Among the general population, a large majority of skin cancers are BCC: approximately 84% of NMSC episodes are BCC, representing an incidence 5 times greater than the incidence of SCC.1-3 The risks of SCC and BCC both increase dramatically among organ transplant recipients. The risk increase is much greater for SCC: one study estimated that the risks of SCC and BCC are 65 times and 10 times higher respectively among OTRs than among the general population.4 This results in a reversal of the ratio of SCC to BCC among OTRs, with most studies reporting that the incidence of SCC is approximately 3 times to 4 times greater than that of BCC.5,6 Skin cancer is more aggressive and has higher morbidity and mortality in OTRs than in the general population.6-8 In addition, SCC is more aggressive and prone to malignancy than BCC,3 so this reversal represents a significant risk increase for OTRs. References American Academy of Dermatology. Available at: Accessed May 24, 2005. American Academy of Dermatology. Available at: Accessed May 24, 2005. Brash DE, Safai B. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: Principles and Practice of Oncology. 5th ed. Philadelphia, Pa: Lippincott-Raven Publishers; 1997: Jensen P et al. J Am Acad Dermatol. 1999;40(2 pt 1): Berg D, Otley CC. J Am Acad Dermatol. 2002;47:1-17. Ong CS et al. J Am Acad Dermatol. 1999;40:27-34. Penn I. Hematol Oncol Clin North Am. 1993;7: American Academy of Dermatology. Available at: Accessed May 24, 2005. Ong CS et al. J Am Acad Dermatol. 1999;40:27-34.

2005 Estimated Skin Cancer Annual Incidence and Mortality1
Epidemiology NMSC is the most prevalent form of cancer in the United States1 US residents have a 20% lifetime chance of developing NMSC2 Mortality is relatively low 2005 Estimated Skin Cancer Annual Incidence and Mortality1 Incidence Mortality NMSC >1,000,000 2820 Melanoma 59,580 7770 NMSC is by far the most common form of cancer in the United States, with an incidence estimated at more than 1 million cases per year.1 More than half of all cancer cases in the United States are NMSC.2 About 1 in 5 US residents will have an episode of NMSC within their lifetime.2 Estimates of NMSC incidence are probably low because many cases are treated during office visits and are not reported.3 Fortunately, in the general population, NMSC is almost always treatable, and mortality is relatively low.1 For comparison, melanoma is about 1/16th as prevalent as NMSC, but causes almost 3 times as many deaths.1 References American Cancer Society. Available at: Accessed March 2, 2005. American Academy of Dermatology. Available at: Accessed May 24, 2005. Brash DE, Safai B. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: Principles and Practice of Oncology. 5th ed. Philadelphia, Pa: Lippincott-Raven Publishers; 1997: OTRs have a higher risk of metastases and mortality3,4 American Cancer Society. Available at: Accessed March 2, 2005. American Academy of Dermatology. Available at: Accessed May 24, 2005. Gray DT et al. Arch Dermatol. 1997;133: Bavinck JN et al. Transplantation. 1996;61:

Incidence and Mortality From Common Cancers (General Population)
> The upper graph compares the incidence of NMSC with the incidence of the 10 most common other cancers. The incidence of NMSC is more than 4 times higher than that of prostate cancer, the next most common. In contrast, as shown in the lower graph, mortality due to NMSC is much less than mortality from the 10 cancers causing the highest numbers of US deaths. Reference American Cancer Society. Available at: Accessed March 2, 2005. American Cancer Society. Available at: Accessed March 2, 2005.

Actinic Keratoses (AKs)
Presenting features1,2 Occur on sun-exposed skin Balding scalp, forehead, face, dorsal hands, and forearms Papules or macules Typically 1-4 mm diameter Usually skin colored, possibly erythematous Possibly pigmented (red, pink, or brown) Surface is rough, scaly, or hyperkeratotic Possibly easier to detect by palpation than examination Natural history1,2 Caused by genetic damage from repeated sun exposure May develop into SCC Estimated risk of progression 0.1%-0.24% Single lesion, 1 year 10%-20% Multiple lesions, long term AKs should be usually be treated to prevent progression1,2 Treat organ transplant recipients aggressively and early3,4 Actinic keratoses (AKs) are common early manifestations of sun-damaged skin. They usually occur on sun-exposed areas, especially the scalp, forehead, face, dorsal hands, and forearms They present as papule or macules ranging from 1mm to 4mm in diameter The lesions are usually skin-colored, but may be erythematous or pigmented red, pink, or brown The surface of the lesions are usually rough, scaly, or hyperkeratotic Because the visual appearance of AKs is often similar to that of normal skin, it may be easier to detect them by palpation than by visual examination. AKs are caused by genetic damage resulting from UV exposure They are a precursor to SCC1,2 Some authors go further and describe AKs as an early, non-invasive stage of SCC2 Estimates of the rate AK progression to SCC are variable. For a single lesion, reported estimates of the probability of progression within one year range from 0.1% to 0.24%1,2 For multiple lesions, estimates of the long term probability of progression range from 10% to 20%. 1,2 Because of the possibility that AKs will develop into SCC, AKs should usually be treated.1 Treatment should be aggressive and early among organ transplant recipients.3,4 References Leffell DJ, Carucci JA. In: Cancer: Principles and Practice of Oncology [book on CD-ROM]. Based on: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: Principles and Practice of Oncology, 6th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2001: Lober BA, Lober CW. South Med J. 2000: Berg D, Otley CC. J Am Acad Dermatol. 2002;47:1-17. Stasko T et al. Dermatol Surg. 2004;30(4 pt 2): 1. Leffell DJ, Carucci JA. In: Cancer: Principles and Practice of Oncology [book on CD-ROM]. Based on: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: Principles and Practice of Oncology. 6th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2001: 2. Lober BA, Lober CW. South Med J. 2000;93:

Actinic Keratoses (AKs)
Multiple AK lesions on the hand AK lesions on the scalp This slide shows examples of AKs on the hand and scalp, two common locations. Reprinted with permission from Lotze MT et al. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: Principles and Practice of Oncology, 6th ed. Philadelphia, Pa: Lippincott Williams & Wilkins. 2001: Book on CD. (Fig ) Photo courtesy of T. Stasko, MD.

Immunosuppressed patient with multiple common warts
Presenting features1 Flesh-colored to brown papules Usually occur on the hands Hyperkeratotic Exophytic Appearance often similar to SCC2 Immunosuppressed patients Increased incidence3 Multiple warts common2 Natural history Results from human papillomavirus (HPV) infection1 May promote NMSC2 Immunosuppressed patient with multiple common warts Warts result from human papillomavirus (HPV) infection.1 Common warts present as hyperkeratotic, exophytic papules that are usually flesh-colored or brown in color. They can appear anywhere on the body, but are most common on the hands 1 The appearance of common warts is often similar to that of common SCC lesions2 Immunosuppressed patients are more vulnerable to HPV:3 The incidence of common warts increases significantly among immunosuppressed individuals3 Multiple warts are more common, to the point that the presence of multiple warts raises suspicion of immunosuppression2 HPV infections may promote NMSC, possibly by inhibiting the p53 tumor suppressor gene.3 The incidence of HPV is high in SCC lesions in both immunocompetent and immunosuppressed patients, reaching as high as 90% among OTRs3 References Reichman RC. In: Kasper DL, Brunwald E, Fauci AS, Hauser S, Longo D, Jameson JL, eds. Harrison’s Principles of Internal Medicine. 16th ed. New York, NY: McGraw-Hill Professional;2005: Cottam AJ et al. Infect Med. 1999;16: Berg D, Otley CC. J Am Acad Dermatol. 2002;47:1-17. Reichman RC. In: Kasper DL, Brunwald E, Fauci AS, Hauser S, Longo D, Jameson JL, eds. Harrison's Principles of Internal Medicine. 16th ed. New York, NY: McGraw-Hill Professional; 2005: Cottam AJ et al. Infect Med. 1999;16: Berg D, Otley CC. J.Am Acad Dermatol. 2002;47:1-17.

Squamous Cell Carcinoma
Presenting features1 Usually on sun-exposed areas Hyperkeratotic papule or nodule Usually erythematous, scaly and raised Natural history More aggressive than BCC Local invasion, tissue destruction, and possible metastasis if untreated Metastasis rates Estimates range from 0.3% to 5% on sun-damaged skin1,2 10% to 30% on mucosal surfaces and sites of injury1 Much higher risk of metastases in transplant recipients with SCC SCC on the nose of a 75-year-old woman SCC is more aggressive than BCC. It usually occurs on sun-exposed areas, but can appear anywhere on the body. Other sites include1: Mucosal surfaces (lips, genitalia) Sites of tissue damage (scars, chronic ulcers) SCC typically presents as a hyperkeratotic papule or macule, which is usually red and rises slightly above the surrounding normal skin.1 SCC in situ has no metastatic potential. However, if left untreated, the tumor may grow invasively. When this occurs, the tumor may cause tissue destruction and develops significant metastatic potential. SCC lesions on sun-damaged skin have a 3% to 5% incidence of metastasis.1 Other locations have higher rates of metastasis, ranging form 10% to 30%.1 The risk of metastasis increases among OTRs.2 References Leffell DJ, Carucci JA. In: Cancer: Principles and Practice of Oncology [book on CD-ROM]. Based on: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: Principles and Practice of Oncology. 6th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2001: Berg D, Otley CC. J Am Acad Dermatol. 2002;47:1-17. Reprinted with permission from DeVita VT Jr, Hellman S, Rosenberg SA. Cancer: Principles and Practice of Oncology. 6th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; Book on CD. (Fig SCC-31) Leffell DJ, Carucci JA. In: Cancer: Principles and Practice of Oncology [book on CD-ROM]. Based on: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: Principles and Practice of Oncology. 6th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2001: Leshin B, White WL. In: Arndt KA, LeBoit PE, Robinson JK, Wintroub BU, eds. Cutaneous Medicine and Surgery: an Integrated Program in Dermatology. Philadelphia, Pa: WB Saunders Company; 1996:

Squamous Cell Carcinoma
Multiple SCC and AK lesions on the hand of a renal transplant recipient SCC lesion recurring in the scar of a previously excised tumor This slide shows examples of SCC on the hand and scalp. The left hand photo shows SCC and AKs on the hand of a renal transplant recipient. SCC frequently occurs with AKs. The hands are frequent sites of SCC development because of their history of sun exposure. The right hand photo shows a recurrent SCC tumor. The recurrence was rapid, suggesting an aggressive carcinoma. Reprinted with permission from Snow SN, Mikhail GR, eds. Mohs Micrographic Surgery. 2nd ed. Madison, Wis: University of Wisconsin Press; 2005. Reprinted with permission from DeVita VT Jr, Hellman S, Rosenberg SA. Cancer: Principles and Practice of Oncology. 6th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; Book on CD. (Fig SCC-40)

Basal Cell Carcinoma Three primary types: nodular, superficial, and morpheaform1 Less common than SCC among OTRs2 (SCC is more common than BCC by > 3:1) Usually slow growing, with extremely low metastatic potential2 Local invasion and tissue destruction if left untreated2 Other BCCs exist, consisting of mixed tumors and rare types BCC is much more common than SCC in the general population, with an incidence about 4 times higher. However, as discussed later, these proportions reverse among OTRs.1 (SCCs are more common by > 3:1) BCCs are usually slow growing and unlikely to metastasize. However, untreated BCC can invade locally and cause significant tissue destruction.2 There are three primary BCC types: nodular, superficial, and morpheaform (also known as “aggressive-growth” or “infiltrative”). Other less common types include pigmented and cystic BCC and the fibroepithelioma of Pinkus.2 Nodular BCC is the most common type. It usually occurs on facial areas with a history of sun exposure, but can occur elsewhere. Clinically, it presents as a papule or nodule, often raised or translucent, and often with telangiectasia.2 Superficial BCC occurs most commonly on the trunk, presenting as an erythematous scaly area. Differentiating clinically between superficial BCC, AKs, and dermatitis may be difficult.2 Morpheaform BCC, the most aggressive type of BCC lesion, presents as a flat, firm area that may be difficult to differentiate from a scar.2 References Berg D, Otley CC. J Am Acad Dermatol. 2002;47:1-17. Leffell DJ, Carucci JA. In: Cancer: Principles and Practice of Oncology [book on CD-ROM]. Based on: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: Principles and Practice of Oncology. 6th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2001: 1. Leffell DJ, Carucci JA. In: Cancer: Principles and Practice of Oncology [book on CD-ROM]. Based on: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: Principles and Practice of Oncology. 6th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2001: 2. Berg D, Otley CC. J Am Acad Dermatol. 2002;47:1-17.

Basal Cell Carcinoma Type Example Presenting Features1
Nodular (50%-79% of cases)1,2 Usually on sun-exposed facial areas Papule or nodule Often raised or translucent Telangiectasia often present Superficial (15% of cases)1,2 Erythematous macule Usually scaly or eroded Often located on the trunk Morpheaform (5%-6% of cases)1,2 The most aggressive type Appearance similar to a scar Flat, slightly firm, borders not well demarcated Also “aggressive-growth” or “infiltrative” BCC is much more common than SCC in the general population, with an incidence about 4 times higher. However, as discussed later, these proportions reverse among OTRs.1 BCCs are usually slow growing and unlikely to metastasize. However, untreated BCC can invade locally and cause significant tissue destruction.2 There are three primary BCC types: nodular, superficial, and morpheaform (also known as “aggressive-growth” or “infiltrative”). Other less common types include pigmented and cystic BCC and the fibroepithelioma of Pinkus.2 Nodular BCC is the most common type. It usually occurs on facial areas with a history of sun exposure, but can occur elsewhere. Clinically, it presents as a papule or nodule, often raised or translucent, and often with telangiectasia.2 Superficial BCC occurs most commonly on the trunk, presenting as an erythematous scaly area. Differentiating clinically between superficial BCC, AKs, and dermatitis may be difficult.2 Morpheaform BCC, the most aggressive type of BCC lesion, presents as a flat, firm area that may be difficult to differentiate from a scar.2 Roll your cursor over the photos to enlarge References Berg D, Otley CC. J Am Acad Dermatol. 2002;47:1-17. Leffell DJ, Carucci JA. In: Cancer: Principles and Practice of Oncology [book on CD-ROM]. Based on: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: Principles and Practice of Oncology. 6th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2001: Photos courtesy of T. Stasko, MD. Leffell DJ, Carucci JA. In: Cancer: Principles and Practice of Oncology [book on CD-ROM]. Based on: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: Principles and Practice of Oncology. 6th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2001: Scrivener Y et al. Br J Dermatol. 2002;147:41-47.

Comparison of NMSC Types
Multiple AK lesions (possible SCC, biopsy is indicated) SCC in situ in an immunocompromised patient Nodular BCC This slide presents examples of lesions resulting from UV damage. The patient in the left-hand photo had a history of AKs treated by cryotherapy, but the AKs have recurred. The lesions may represent SCC and should be biopsied. The center photo shows SCC in situ in the left ear of an immunocompromised patient. Invasive SCC was discovered and removed during treatment by Mohs surgery (discussed later) The right-hand photo shows nodular BCC of the upper lip. Reprinted with permission from DeVita VT Jr, Hellman S, Rosenberg SA. Cancer: Principles and Practice of Oncology. 6th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; Book on CD. (Fig SCC-11A, SCC-20, BCC-47)

Superficial Spreading Melanoma
Malignant Melanoma Presenting features: ABCDE1 Asymmetry Irregular or diffuse Borders Color variation Diameter >5 mm Enlargement or Evolution Natural history2 Radial growth (melanoma in situ) Invasive vertical growth Metastasis 91% 5-year survival in the general population3 Superficial Spreading Melanoma Melanoma typically presents as a discolored patch of skin. The ABCDE mnemonic describes features that should create suspicion of melanoma.1 Asymmetry irregular or diffuse Borders Color variation Diameter > 5 mm Enlargement or Evolution Melanoma typically begins from a normal nevus that develops into a tumor.2 The tumor initially spreads radially on the skin surface. Eventually, the tumor begins to grow vertically, invading the deep layers of the skin. Tumors in the vertical growth phase are potentially metastatic. Between , about 9% of patients with melanoma died within 5 years of diagnosis.3 References Lotze MT, Dallal RM, Kirkwood JM, Flickinger JC. In: Cancer: Principles and Practice of Oncology [book on CD-ROM]. Based on: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: Principles and Practice of Oncology. 6th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2001: Herlyn M, Satyamoorthy K. In: Cancer: Principles and Practice of Oncology [book on CD-ROM]. Based on: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: Principles and Practice of Oncology. 6th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2001: Jemal A et al. CA Cancer J Clin. 2005;55:10-30. Lotze MT et al. In: Cancer: Principles and Practice of Oncology [book on CD-ROM]. Based on: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: Principles and Practice of Oncology. 6th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2001: Herlyn M, Satyamoorthy K. In: Cancer: Principles and Practice of Oncology [book on CD-ROM]. Based on: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: Principles and Practice of Oncology. 6th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2001: Jemal A et al. CA Cancer J Clin. 2005;55:10-30.

Pathogenesis of NMSC Healthy individuals with UV exposure
UV light causes mutations and reduces immunity Immune System Removes cells with mutations Suppression In a healthy individual with minimal UV exposure, few skin mutations occur, and DNA repair mechanisms and the immune system almost always destroy the mutations before they can cause cancers to develop. References Euvrard S et al. N Eng J Med. 2003;348: Skin illustration modified from UV Radiation Mutations p53 and others NMSC Most mutations destroyed Very few cancers develop DNA Repair Mechanisms Correct mutations UV, ultraviolet. Euvrard S et al. N Eng J Med. 2003;348:

Pathogenesis of NMSC: UV
UV light causes mutations and reduces immunity Immune System Removes cells with mutations Controls HPV UV Exposure Reduces Local Immunity Inhibits antigen-presenting cells Decreases Langerhans’ cells density Mutations p53 and others UV Radiation UV radiation induces still more mutations and suppresses the skin’s cellular immune system. Although most mutations are still destroyed, UV exposure increases carcinogenesis, and is a risk factor for NMSC. References Euvrard S et al. N Engl J Med. 2003;348: Berg D, Otley CC. J Am Acad Dermatol. 2002;47:1-17. Brash DE, Safai B. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: Principles and Practice of Oncology. 5th ed. Philadelphia, Pa: Lippincott-Raven Publishers; 1997: Skin illustration modified from: Accessed 5/1/2005. HPV NMSC Most mutations destroyed A few cancers develop Perpetuates and induces mutations DNA Repair Mechanisms Correct mutations HPV, human papillomavirus. Euvrard S et al. N Engl J Med. 2003;348: Berg D, Otley CC. J Am Acad Dermatol. 2002;47: Brash DE, Safai B. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: Principles and Practice of Oncology. 5th ed. Philadelphia, Pa: Lippincott-Raven Publishers; 1997:

Pathogenesis of NMSC: HPV
Human papillomavirus Immune System Removes cells with mutations Controls HPV Suppression HPV, when present, increases the mutation rate by inducing some mutations and perpetuating others. However, the immune system suppresses HPV, and most mutations are still destroyed before cancers develop. References Euvrard S et al. N Eng J Med. 2003;348: Skin illustration modified from Mutations p53 and others UV Radiation HPV NMSC Most mutations destroyed A few cancers develop Perpetuates and induces mutations DNA Repair Mechanisms Correct mutations Euvrard S et al. N Eng J Med. 2003;348:

Pathogenesis of NMSC: Immunosuppression
Immunosuppression reduces immunity dramatically Some agents may also be mutagenic Immune System Removes cells with mutations Controls HPV UV reduces immunity Inhibits antigen-presenting cells Decreases Langerhans’ cells density Immunosuppression Suppression X X Immunosuppression dramatically reduces the body’s ability to destroy mutations and control HPV. Thus, many mutations survive and develop into cancers. References Euvrard S et al. N Eng J Med. 2003;348: Skin illustration modified from Mutations p53 and others UV Radiation HPV NMSC Many cancers develop Perpetuates and induces mutations DNA Repair Mechanisms Correct mutations Euvrard S et al. N Eng J Med. 2003;348:

OTRs and NMSC

Implications of NMSC for the OTR Population
Increased risk of NMSC and SCC Estimated mean 10-year incidence of NMSC ranges from 10% to 45%2 Depends on sun exposure NMSC onset 10 years sooner than non-OTR population3 Increased aggressiveness, morbidity, mortality2-4 27% of deaths in cardiac transplant recipients in Sydney due to skin cancer from 4th posttransplant year onward3 Skin cancer mortality can affect survival rates for transplant center statistics Increased tumor burden OTRs are at high risk for metastasis and death from SCC5,6 7% incidence of metastasis for SCC 54% 3-year survival from metastatic SCC in OTRs A history of pretransplant NMSC is associated with a high tumor burden7 SCC BCC Risk increase vs general population1,2 65x 10x OTRs are at dramatically increased risk of NMSC than the general population, and face a more aggressive disease with increased morbidity and mortality.1-3 The risk of SCC increases by a factor of 65. The risk of BCC increases by a factor of 10. In contrast to the general population, SCC is more common than BCC among OTRs. Estimates of the 10-year incidence of SCC among OTRs range from 10% to 45% depending on sun exposure. NMSC strikes 10 years sooner among OTRs than in the general population.4-6 OTRs have a high tumor burden, with an average of almost 2 NMSC lesions per year. 12% have more than 5 SCC lesions per year. Some OTRs have a tremendous tumor burden, with more than 100 SCC lesions per year.5,6 These patients are at high risk of metastasis and death. High tumor burdens are associated with a history of pretransplant NMSC.7 References Jensen P et al. J Am Acad Dermatol. 1999;40(2 pt 1): Berg D, Otley CC. J Am Acad Dermatol. 2002;47:1-17. Ong CS et al. J Am Acad Dermatol. 1999;40:27-34. Penn I. Hematol Oncol Clin North Am. 1993;7: Gray DT et al. Arch Dermatol. 1997;133: Bavinck JN et al. Transplantation. 1996;61: Carroll RP et al. Am J Kidney Dis. 2003;41: 1. Jensen P et al. J Am Acad Dermatol. 1999;40(2 pt 1): Gray DT et al. Arch Dermatol. 1997;133: 2. Berg D, Otley CC. J Am Acad Dermatol. 2002;47: Bavinck JN et al. Transplantation. 1996;61: 3. Ong CS et al. J Am Acad Dermatol. 1999;40: Carroll RP et al. Am J Kidney Dis. 2003;41: 4. Penn I. Hematol Oncol Clin North Am. 1993;7:

Risk Factors for NMSC in the OTR Population
General risk factors1 Age Skin type Sun exposure History of prior NMSC These risk factors are accentuated in the OTR population OTR-related risk factors Immunosuppression Level of immunosuppression is directly related to NMSC incidence1,2 Effects of different immunosuppressive agents are not well understood1 Transplanted organ: kidney (highest) > liver > heart (lowest)1 HPV infection HPV is more prevalent among immunosuppressed patients1 Several risk factors for NMSC have been identified in the OTR population. Most OTR risk factors are also risk factors for the general population. However, their effects are much stronger among OTRs.1 Risk factors common to OTRs and the general population are1: Age Skin type Individuals with fair skin, blond or red hair, or blue, green, or gray eyes are at higher risk Sun exposure History of prior NMSC Risk factors specific to the OTR population are: Level and duration of immunosuppression1,2 Presence of HPV infection1 The transplant organ (Kidney transplant recipients are at the highest risk of NMSC, heart transplant recipients at the lowest)1 References Berg D, Otley CC. J Am Acad Dermatol. 2002;47:1-17. Otley CC, Maragh SLH. Dermatol Surg. 2005;31: Other references on risk factors Karagas MR et al. Br J Cancer. 2001;85: Jensen P et al. J Am Acad Dermatol. 1999;40(2 pt 1): Caforio AL et al. Circulation. 2000;102(19 suppl 3):III–222-III–227. Shamanin V et al. J Natl Cancer Inst. 1996;88: Boxman IL et al. J Invest Dermatol. 1997;108: Nachbar F et al. Acta Derm Venereol. 1993;73: Aste N et al. J Eur Acad Dermatol Venereol. 2001;15:89-90. Bavinck JN et al. Transplantation. 1996;61: Bunney MH et al. Nephrol Dial Transplant. 1990;5: Glover MT et al. Lancet. 1997;349: Hiesse C et al. Transplant Proc. 1997;29: Roeger LS et al. Clin Transplant. 1992;6: Blohme I, Larko O. Transplant Proc. 1992;24:313. Gruber SA et al. Clin Transplant. 1994;8: Green C, Hawk JL. Clin Exp Dermatol. 1993;18:30-31. 1. Berg D, Otley CC. J Am Acad Dermatol. 2002;47:1-17. 2. Otley CC, Maragh SLH. Dermatol Surg. 2005;31:

Diagnosis of NMSC Identification of a suspicious lesion1
Skin examinations Patient or clinician Signs and symptoms Papule or nodule Erythema Others High index of suspicion for organ transplant recipients2 Biopsy and pathologic confirmation1 Shave, punch, or excisional biopsy Pathological examination A diagnosis of non-melanoma skin cancer begins when a lesion is identified as suspicious, usually during a skin examination by the patient or a clinician.1 NMSC often presents as an erythematous nodule or papule. The signs and symptoms of NMSC were discussed earlier. 1 Because of the high incidence of NMSC among OTRs, clinicians should have a high index of suspicion for NMSC.2 Once a suspicious lesion is identified, pathological examination of a biopsy sample is needed to confirm the diagnosis. The standard biopsy techniques used are shave, punch, and excisional biopsies.1 References Leffell DJ, Carucci JA. In: Cancer: Principles and Practice of Oncology [book on CD-ROM]. Based on: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: Principles and Practice of Oncology. 6th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2001: Berg D, Otley CC. J Am Acad Dermatol. 2002;47:1-17. Leffell DJ, Carucci JA. In: Cancer: Principles and Practice of Oncology [book on CD-ROM]. Based on: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: Principles and Practice of Oncology. 6th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2001: Berg D, Otley CC. J Am Acad Dermatol. 2002;47:1-17.

SCC Treatment Modalities
Therapy Description1 Advantages and disadvantages1 Recommendations for OTRs2,3 Mohs Surgery Surgical removal of the tumor and a small margin with immediate100% microscopic examination of the margins Repeated until no tumor is found Recommended for recurrent cancers and when maximal tissue conservation is needed Optimal for high-risk tumors Excision Surgical removal of the tumor and a margin of uninvolved tissue Effective for small, nonrecurrent, noninfiltrative cancers Low-risk tumors High-risk (with intraoperative frozen section control) Electro-desiccation and curettage Tumor and a 2mm-4mm margin is removed by curettage; 1mm margins are then removed by electrodessication Superficial NMSC Cannot evaluate margins Multiple repetitions may be needed to avoid recurrence Cryotherapy Tumor is destroyed by exposure to cryogenic temperatures using liquid nitrogen or a cryoprobe Radiation Tumor is treated by fractionated doses of radiation When surgery is not feasible Recurrence is possible Inoperable tumors Adjuvant therapy A spectrum of treatment strategies are available for management of NMSC in OTRs. The standard strategies include: Mohs surgery Excision Electrodesiccation and curettage Cryotherapy Radiation Expanded definitions will appear when your cursor rolls over “high-risk” and “low-risk." References Berg D, Otley CC. J Am Acad Dermatol. 2002;47:1-17. Stasko T et al. Dermatol Surg. 2004;30(4 pt 2): Leffell DJ, Carucci JA. In: Cancer: Principles and Practice of Oncology [book on CD-ROM]. Based on: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: Principles and Practice of Oncology. 6th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2001: Berg D, Otley CC. J Am Acad Dermatol. 2002;47: Stasko T et al. Dermatol Surg. 2004;30(4 pt 2):

Prevention of NMSC Among OTRs

Preventive Strategies
Patient Group Preventive Strategies1,2 All patients Education Dermatology surveillance Photoprotection Premalignant lesions Topical therapy High NMSC burden Systemic retinoids Reduction of immunosuppression Several strategies are appropriate for preventing NMSC among OTRs. Each of these strategies is discussed in more detail in the following slides. The level of intervention depends on the patient’s NMSC risk and the rate of NMSC lesion formation All patients should receive education on photoprotection, sun avoidance, recognition of NMSC lesions and self-examination.1 Regular surveillance by a dermatologist aids in providing early detection of developing lesions, and gives an opportunity for additional education and reinforcement. Premalignant lesions such as warts and AKs can develop into NMSC and should be treated aggressively. Topical therapies can be effective.1,2 Atypical premalignant lesions should be biopsied. Systemic preventive or suppressive therapy should be considered for patients with a high NMSC burden. Possible therapies include1,2: Systemic chemosuppression with oral retinoids Reduction of immunosuppression (where appropriate) References Berg D, Otley CC. J Am Acad Dermatol. 2002;47:1-17. Stasko T et al. Dermatol Surg. 2004;30(4 pt 2): Berg D, Otley CC. J Am Acad Dermatol. 2002;47:1-17. Stasko T et al. Dermatol Surg. 2004;30(4 pt 2):

Education Transplant handbook, pamphlets on NMSC
Sun avoidance, photoprotection, role and sources of UV light Dermatologist referral NMSC risk factor history Full skin exam on a regular basis Nodal exam if history of high risk skin cancer Reinforce/repeat UV education Self-examination and recognition of common skin cancers Education should be extensive and repetitive Education on NMSC prevention is critical for all OTRs. However, not all OTRs receive appropriate education. Typical written sources of information on NMSC prevention include: The institution’s transplant handbook A variety of pamphlets on NMSC Key elements of patient eduction include: UV Light Information on the role of UV light in NMSC pathogenesis A description of common sources of UV light Discussion of the need for sun avoidance and photoprotection and effective means of photoprotection The need for dermatologist follow-up for early detection. The follow-up will include: An NMSC risk factor history Full skin exam Nodal exam for high-risk patients Reinforcement and repetition of the education on UV light and photoprotection Training on self-examination and recognition of common skin cancers Patient education should be extensive and should be repeated regularly to help insure that patients retain and utilize the information. References Berg D, Otley CC. J Am Acad Dermatol. 2002;47:1-17. Stasko T et al. Dermatol Surg. 2004;30(4 pt 2): National Comprehensive Cancer Network. Available at: Accessed March 1, 2005. Berg D, Otley CC. J Am Acad Dermatol. 2002;47:1-17. Stasko T et al. Dermatol Surg. 2004;30(4 pt 2): National Comprehensive Cancer Network. Available at: Accessed March 1, 2005.

Surveillance and Follow-up
Early recognition and treatment is critical1 Monthly self-exams1,2 Regular dermatology exams1-3 Frequency depends on risk of NMSC Low threshold for skin biopsy Treat AKs early Recommended Examination Frequency3 Risk Level Frequency (mo) No other risk factors for NMSC 12 NMSC risk factors present, but no history of AK or NMSC 6-12 AK or 1 NMSC lesion present 3-6* Multiple NMSC lesions present 3* One high-risk NMSC present Metastatic NMSC present 1-3* Adapted with permission from Stasko T et al. Dermatol Surg. 2004;30 (4 pt 2): Early recognition and treatment of NMSC is especially critical in OTRs.1 To aid in early detection, OTRs should be educated in self-examination techniques and should give themselves self-examinations at least once per month.1,2 In addition, OTRs should be receive regular dermatology exams.1-3 The recommended examination frequency, shown in the table, depends on the patient’s risk for NMSC. The examining dermatologist should have a low threshold for skin biopsy and should treat cancers and AKs early and aggressively. References Otley CC, Pittelkow MR. Liver Transpl. 2000;6: Berg D, Otley CC. J Am Acad Dermatol. 2002;47:1-17. Stasko T et al. Dermatol Surg. 2004;30(4 pt 2): *Frequency of follow-up after lesion is treated. Otley CC, Pittelkow MR. Liver Transpl. 2000;6: Berg D, Otley CC. J Am Acad Dermatol. 2002;47:1-17. Stasko T et al. Dermatol Surg. 2004;30(4 pt 2):

Photoprotection Stringent sun avoidance and protection
Use sunscreen/sunblock Wear protective clothing, sunglasses, and hats Avoid peak sun periods Avoid tanning booths Sunscreen (SPF >30) Prevents UVA and UVB mutagenic pathways and photoimmunosuppression Safe, inexpensive, easy to use Complements other preventive therapies Patient education on photoprotection should emphasize stringent sun avoidance and protection, including Use of sunscreen/sunblock (when and how to apply, types of sunscreen) Use of protective clothing, sunglasses, and hats Avoidance of peak sun periods Avoidance of tanning booths Sunscreen is a key element in photoprotection. In many ways, sunscreen is an ideal chemopreventive agent: It blocks mutagenic pathways involving both UVA and UVB It prevents or limits photoimmunosuppression It is safe, inexpensive, and easy to use It complements other preventive therapies References Berg D, Otley CC. J Am Acad Dermatol. 2002;47:1-17. Stasko T et al. Dermatol Surg. 2004;30(4 pt 2): National Comprehensive Cancer Network. Available at: Accessed March 1, 2005. UVA, ultraviolet A; UVB, ultraviolet B. Stasko T et al. Dermatol Surg. 2004;30(4 pt 2): National Comprehensive Cancer Network. Available at: Accessed March 1, 2005.

Chemoprevention vs Chemosuppression
Chemoprevention (eg, sunscreen) Blocks an early step in carcinogenesis Delayed and prolonged effect Episodic or continuous treatment Chemosuppression (eg, oral retinoids) Blocks a late step in carcinogenesis Late and transient effect Continuous treatment Rebound NMSC if treatment is stopped Both strategies have pros and cons and both should be considered in OTRs for prevention of skin cancer Medications that prevent NMSC can be classified as chemopreventive or chemosuppressive. Chemopreventive agents Block an early step in carcinogenesis Typically have a delayed effect, but one that extends well past the cessation of treatment Are effective whether given episodically or continually Sunscreen is the primary example of a chemopreventive NMSC therapy. Chemosuppressive agents Block a late step in carcinogenesis Typically have a transient effect Are only effective if given continually Allow cancer rebound when treatment is stopped Oral retinoids are the primary examples of chemosuppressive NMSC therapies.

Topical Agents (Chemoprevention)
Used to treat AKs and possibly prevent NMSC Agent* Indications Notes 5-FU1-3 Multiple actinic or solar keratoses of the face and anterior scalp Potential for delayed hypersensitivity reaction Possibility of increased absorption through ulcerated or inflamed skin Imiquimod1,2,4,5 External genital and perianal warts/condyloma Theoretic concern about immune stimulation Local skin reactions are common Diclofenac6,7 AKs 3% NSAID gel Less irritating than other topical therapies Oral administration of other NSAIDs such as aspirin at anti-inflammatory/analgesic doses should be limited Tretinoin8,9 Acne vulgaris Exposure to sunlight, including sunlamps, should be minimized Aminolevulinic acid HCl plus blue light illumination (PDT)10,11 Effective but can result in severe reactions Avoid exposure of treatment sites to sunlight or bright indoor light *EGCG, perillyl alcohol, DFMO, silymarin, and colchicine are also being investigated6,12-14 A variety of topical therapies are used to treat AKs. These therapies may also prevent NMSC. They include1-8: 5-FU1-3 Imiquimod1,2,4,5 Diclofenac6,7 Tretinoin8,9 PDT10,11 5-FU and imiquimod are the primary agents of choice The table summarizes the indications for each agent and gives notes on its application for AK treatment and NMSC prevention. Investigational agents under study for topical NMSC chemoprevention include: EGCG12 Perillyl alcohol12 DFMO12,13 Silymarin14 Colchicine1 References Stasko T et al. Dermatol Surg. 2004;30(4 pt 2): Tutrone WD et al. Cutis. 2003;71: Carac® cream [package insert]. Berwyn, Pa: Dermik Laboratories, Inc.; 2003. Aldara™ [package insert]. St. Paul, Minn: 3M Pharmaceuticals; 2004. Benson E. Australas J Dermatol. 2004;45: Tutrone WD et al. Cutis. 2003;71: Solaraze™ gel [package insert]. Fairfield, NJ: Doak Dermatologics; 2004. Retin-A® [package insert]. Raritan, NJ: Ortho Dermatological; 1996. De Graaf YGL et al. Dermatol Surg. 2004;30(4 pt 2): Levulan® Kerastick® [package insert]. Wilmington, Mass: DUSA Pharmaceuticals, Inc.; 2003. Dragieva G et al. Transplantation. 2004;77: Einspahr JG et al. Recent Results Cancer Res. 2003;163: Alberts DS et al. Cancer Epidemiol Biomarkers Prev. 2000;9: Katiyar SK. Int J Oncol. 2005;26: NSAID, nonsteroidal anti-inflammatory drug; EGCG, epigallocatechin gallate, green tea extract; DFMO, difluoromethylornithine. 1. Stasko T et al. Dermatol Surg. 2004;30(4 pt 2): Tutrone WD et al. Cutis. 2003;71: Carac® cream [package insert]. Berwyn, Pa: Dermik Laboratories, Inc.; Aldara™ [package insert]. St. Paul, Minn: 3M Pharmaceuticals; Benson E. Australas J Dermatol. 2004;45: Tutrone WD et al. Cutis. 2003;71: Solaraze™ gel [package insert]. Fairfield, NJ: Doak Dermatologics; Retin-A® [package insert]. Raritan, NJ: Ortho Dermatological; De Graaf YG et al. Dermatol Surg. 2004;30(4 pt 2): Levulan® Kerastick® [package insert]. Wilmington, Mass: DUSA Pharmaceuticals, Inc.; Dragieva G et al. Transplantation. 2004;77: Einspahr JG et al. Recent Results Cancer Res. 2003;163: Alberts DS et al. Cancer Epidemiol Biomarkers Prev. 2000;9: Katiyar SK. Int J Oncol. 2005;26:

Thresholds for Initiating Systemic Therapy (Chemosuppression)
Who Patients with any of the following: Field AK + multiple SCCs Multiple skin cancers per year (>5-10/year) Acutely increased frequency of SCC formation Single skin cancer with high metastatic risk (>20%) Metastatic skin cancer In conjunction with decreased immunosuppression Patients at high risk of NMSC are appropriate candidates for systemic therapy. Who is at high risk? The standard criteria are: Field AK plus multiple low-risk or single high-risk SCC Multiple skin cancers per year (>5-10/year) Acutely increased frequency of SCC formation Single skin cancer with high metastatic risk (>20%) Metastatic skin cancer In conjunction with decreased immunosuppression After clearance of significant tumors

Thresholds for Initiating Systemic Therapy
When The thresholds are reached If no contraindications How Consider oral retinoids Consider reduction of immunosuppression Maximize tolerability Discussed later in the presentation When should OTRs receive therapy? Most patients should receive systemic chemopreventive therapy as soon as they are determined to be at high risk. Exceptions include female patients of childbearing age and patients with other contraindications. How should they be treated? Oral retinoids are the standard systemic therapy. Reduction of immunosuppression should be considered. Treatment should be introduced gradually to minimize adverse events and maximize tolerability and adherence. Treatment is discussed in more detail later in the presentation.

Systemic Agents: Retinoids
Indications Data on NMSC Prevention Notes Acitretin1 Severe psoriasis2 3 RCTs, many uncontrolled studies and case reports Most commonly used systemic preventive agent for NMSC Isotretinoin Severe recalcitrant nodular acne3 Proven for XP, Gorlin’s syndrome AE profile different from that of acitretin Preferred for women of childbearing potential1 Fenretinide4-7 -- Ongoing phase 2 trial Phase 1 trial of head-and-neck SCC starting Effective for oral leukoplakia Retinol8-10 SCC ↓ 26% in 2297 patients with AKs treated with 25,000 IU retinol Long-term lipid changes Higher doses were also safe Retinoids are the most commonly used systemic agents for NMSC chemoprevention. This table lists the oral retinoids that have been used or investigated for NMSC prevention, along with their indications, the available clinical data related to NMSC prevention, and notes on their use for NMSC prevention.1-10 Acitretin is the most commonly used oral retinoid and has the most relevant data. Isotretinoin is preferred for women of childbearing potential because of its shorter half-life.1 References De Graaf YGL et al. Dermatol Surg. 2004;30(4 pt 2): Soriatane® (acitretin capsules) prescribing information. Palo Alto, Calif: Connetics Corporation; July 2004. Accutane® (isotretinoin capsules) prescribing information. Nutley, NJ: Roche Laboratories Inc; June 2002. Chiesa F et al. Oral Oncol Eur J Cancer. 1992;28B: Chiesa F et al. Int J Cancer. 2005;115: National Cancer Institute. Available at: Accessed May 24, 2005. National Cancer Institute. Available at: Accessed May 24, 2005. Moon TE et al. Cancer Epidemiol Biomarkers Prev. 1997;6: Cartmel B et al. Am J Clin Nutr. 1999;69: Alberts D et al. Clin Cancer Res. 2004;10: RCT, randomized controlled trial; AE, adverse event. 1. De Graaf YGL et al. Dermatol Surg. 2004;30(4 pt 2): 2. Soriatane® (acitretin capsules) prescribing information. Palo Alto, Calif: Connetics Corporation; July 2004. 3. Accutane® (isotretinoin capsules) prescribing information. Nutley, NJ: Roche Laboratories Inc; June 2002. 4. Chiesa F et al. Oral Oncol Eur J Cancer. 1992;28B: 5. Chiesa F et al. Int J Cancer. 2005;115: 6. National Cancer Institute. Available at: Accessed May 24, 2005. 7. National Cancer Institute. Available at: Accessed May 24, 2005. 8. Moon TE et al. Cancer Epidemiol Biomarkers Prev. 1997;6: 9. Cartmel B et al. Am J Clin Nutr. 1999;69: 10. Alberts D et al. Clin Cancer Res. 2004;10:

Thresholds for Systemic Therapy: Field AK + Multiple SCCs
Case example 54-year-old male renal transplant recipient Developed field AK and 9 SCC lesions on the dorsum of his left hand 3 years posttransplantation Treated with a split-thickness skin graft Also developed 8 lesions on his right hand Oral retinoids might also be suitable after removal of invasive SCC The lesions on this patient’s left hand were dense enough to make field treatment appropriate. The dorsum of his left hand was replaced with a split-thickness skin graft, which does well for long periods. His untreated right hand developed 8 lesions. Oral retinoid therapy might be appropriate in this patient to decrease the frequency of SCC lesion development. Reprinted with permission from Snow SN, Mikhail GR, eds. Mohs Micrographic Surgery. 2nd ed. Madison, Wis: University of Wisconsin Press; 2005.

Thresholds for Systemic Therapy: Acutely Increased Frequency of SCC Formation
Case example 58-year-old cardiac transplant recipient* Abrupt increase in NMSC Acitretin mg/d NMSC cut in half Acitretin Initiated Transplant took place in Increased SCC formation is common multiple years after transplant *Transplant took place in 1998.

Thresholds for Systemic Therapy: Acutely Increased Frequency of SCC Formation
Case example 64-year-old male renal transplant recipient with Hx of sustained sun exposure Began developing >20 SCCs/year Required dose reduction and eventually termination because of renal impairment Acitretin Initiated Terminated This patient received acitretin to manage an acute increase in SCC formation rates. The retinoids significantly reduced the incidence of SCC. However, therapy was terminated due to adverse events. His renal impairment required dose reduction and, eventually, termination of medication. Acitretin is not typically associated with renal impairment. Plasma concentration of acitretin was significantly (59.3%) lower in end-stage renal failure subjects (n=6) when compared to age-matched controls, following single 50 mg oral doses. Acitretin was not removed by hemodialysis in these subjects.1 This case illustrates the efficacy of oral retinoid therapy and the importance of managing adverse effects. Reference Soriatane® (acitretin capsules) prescribing information. Palo Alto, Calif: Connetics Corporation; July 2004.

Decreased Immunosuppression
Thresholds for Systemic Therapy: In Conjunction With Decreased Immunosuppression Case example 73-year old male cardiac transplant recipient with Hx of sustained sun exposure Very heavy tumor burden, >100 lesions/year Initiated etretinate but discontinued because of mucocutaneous AEs Tumor burden lessened with decreased immunosuppression Decreased Immunosuppression Etretinate Initiated Terminated This patient received etretinate, which was the drug of choice at the time, but is no longer available. Acitretin is a metabolite of etretinate. It is currently preferred because of its much shorter half-life (49 hours vs 120 days). The retinoids significantly reduced the incidence of SCC. However, therapy was terminated due to AEs. This patient had significant mucocutaneous effects, including fragile nails, waxy skin, and hair loss. He perceived them to be worse than his tumor burden of more than 100 lesions per year. This case demonstrates that retinoids and reduction of immunosuppression can be complementary. In this man, retinoids did not work out due to AEs, but reduction of immunosuppression came in and worked for him.

Other Systemic Agents: Investigational
Indications Data on NMSC Prevention Notes Capecitabine1 Colorectal cancer2 Pilot Oral prodrug of 5-FU Primary therapy for colon cancer Celecoxib3,4 Arthritis5 Acute pain5 Dysmenorrhea5 Human trials planned, status uncertain Mouse trials: improvement in tumor latency and multiplicity DFMO6 -- Ongoing phase 3 trial Other systemic agents being investigated for NMSC prevention are listed in this table. They include capecitabine, celecoxib, and DFMO.1-6 The status of celecoxib studies is uncertain because of the recently identified association between cyclooxygenase-2 inhibitors and the risk of cardiovascular disease. References Wong SJ. Unpublished data, 2005. Xeloda® (capecitabine tablets) prescribing information. Nutley, NJ: Roche Laboratories Inc; June 2005. Orengo IF et al. Arch Dermatol. 2002;138: National Cancer Institute. Available at: Accessed May 3, 2005. Celebrex® (celecoxib capsules) prescribing information. New York, NY: Pfizer Inc; February 2005. National Cancer Institute. Available at: Accessed May 3, 2005. 1. Wong SJ. Unpublished data, 2005. 2. Xeloda® (capecitabine tablets) prescribing information. Nutley, NJ: Roche Laboratories Inc; June 2005. 3. Orengo IF et al. Arch Dermatol. 2002;138: 4. National Cancer Institute. Available at: Accessed May 3, 2005. 5. Celebrex® (celecoxib capsules) prescribing information. New York, NY: Pfizer Inc; February 2005. 6. National Cancer Institute. Available at: Accessed May 3, 2005.

Reduction of Immunosuppression
When considering oral retinoids, also consider reduction of immunosuppression (RI) Adjuvant strategy, synergistic with chemopreventive medications Especially for life-threatening NMSC Reduction of a patient’s immunosuppression can decrease the incidence of new NMSC and slow or stop its progression. RI should be considered as an adjuvant strategy for patients whenever oral retinoids are considered. Patients at moderate to high risk of NMSC Life-threatening NMSC RI is synergistic with chemopreventive and chemosuppressive medications such as oral retinoids. Reference Otley CC, Maragh SLH. Dermatol Surg. 2005;31: Otley CC, Maragh SLH. Dermatol Surg. 2005;31:

Reduction of Immunosuppression: Clinical Trial Results
Dantal J et al. Lancet. 1998 Study design Open-label study comparing low-dose with normal-dose immunosuppression Patient population 231 renal transplant recipients receiving one of the following: Cyclosporine with azathioprine (77%) Cyclosporine with prednisolone (18%) Cyclosporine alone (5%) Treatment regimen Low dose: ng/mL trough cyclosporine concentrations Normal dose: ng/mL trough cyclosporine concentrations 66-month follow-up A few clinical trials have investigated reduction of immunosuppression for NMSC prevention. The largest was by Dantal et al in 1998. The trial compared low-dose with normal-dose regimens of cyclosporine in combination with patients’ other existing immunosuppressive medications in 231 renal transplant recipients over an average follow-up of 66 months. Reference Dantal J et al. Lancet. 1998;351: Dantal J et al. Lancet. 1998;351:

Reduction of Immunosuppression: Clinical Trial Results
No significant difference in patient or organ survival Low-dose group Fewer cancers (P<.034) Fewer NMSCs (P<.05) AEs Acute rejection More common in the low-dose group, but manageable No significant difference in graft survival Number of Patients With NMSC Type of Skin Cancer Normal Dose (n=115) Low Dose (n=116) SCC 15 8 BCC 9 4 Other 2 5 Total 26 17 The trial found no significant difference in patient or organ survival between the low-dose and normal-dose groups. The low-dose group had fewer cancers (P<.034) and fewer NMSCs (P<.05). The table shows the number of skin cancers occurring in each group. The mean numbers of skin cancer lesions in the low-dose and normal-dose groups were 1.9 and 2.1, respectively. The primary AE was acute rejection, which was significantly more frequent in the low-dose group than the normal-dose group (9 episodes vs 1 episode, respectively; P<.02), but did not affect graft survival (89% vs 82% at 6 years). Reference Dantal J et al. Lancet. 1998;351: Dantal J et al. Lancet. 1998;351:

Reduction or Cessation of Immunosuppression for Head-and-Neck SCC
Moloney FJ et al. Dermatol Surg. 2004 Study design: retrospective Patient population: 9 renal transplant recipients with aggressive head-and-neck SCC Treatment regimen 5 patients: no change in immunosuppression 4 patients: significant reduction or cessation of immunosuppression Results Improved survival for patients with RI or CI (P=.023) No change: all 5 patients died from cancer within 18 months. RI/CI: 3 patients were alive at the time of writing (13- to 27-month survival); 1 patient died from cancer after 16 months 2 of the 3 survivors maintained graft function Moloney et al reported on a retrospective study of reduction or cessation of immunosuppression as a treatment for individuals with aggressive head-and-neck SCC. The study reported on 9 renal transplant recipients with aggressive SCC. 5 had no change in immunosuppression. All died of metastatic disease within 18 months. 4 had immunosuppression reduced or stopped. 1 died of metastatic disease after 16 months. 3 survived for 13 to 27 months. 1 survivor required dialysis starting at 24 months; the other 2 maintained graft function despite RI Reference Moloney FJ et al. Dermatol Surg. 2004;30: CI, cessation of immunosuppression. Moloney FJ et al. Dermatol Surg. 2004;30:

Cessation of Immunosuppression
Otley CC et al. Arch Dermatol. 2001 Study design: uncontrolled Patient population: 6 transplant recipients with allograft failure and/or uncontrolled skin cancer Treatment regimen: no immunosuppressive therapy Results 4 of 6 patients had decreased cutaneous carcinoma formation and improved skin quality In 2001, Otley et al reported an uncontrolled study of cessation of immunosuppression in 6 transplant recipients (5 kidney, 1 pancreas). Immunosuppressive therapy was withdrawn because of: Allograft failure (5 patients) A large number of aggressive cutaneous carcinomas (1 patient) In 4 of the 6 patients, the rate of cutaneous carcinoma formation dropped dramatically after immunosuppressive therapy was withdrawn. Reference Otley CC et al. Arch Dermatol. 2001;137: Otley CC et al. Arch Dermatol. 2001;137:

Optimizing Oral Retinoid Therapy

Retinoid Mechanism of Action
Retinoids Arrest growth of tumor cells Induce apoptosis of tumor cells Modulate immune response Modulate keratinocyte differentiation Inhibit HPV growth These mechanisms may operate in combination Investigations into the mechanism of action of systemic retinoids suggest several mechanisms, including: Induction of growth arrest or apoptosis of tumor cells Modulation of immune response Modulation of keratinocyte differentiation Inhibition of HPV growth These mechanisms may operate in combination. Reference De Graaf YG et al. Dermatol Surg. 2004;30(4 pt 2): De Graaf YGL et al. Dermatol Surg. 2004;30(4 pt 2):

Efficacy of Retinoids in Preventing NMSC
Retinoids reduce: AK, arsenical keratoses, warts1 May permit easier inspection of skin SCC (may be less effective for BCC )1-3 30% to 89% reduction in SCC occurrence Keratoacanthoma4 Development of malignancies in XP5,6 Epidermodysplasia verruciformis5 Severe UV exposure Benefits typically appear within 1 to 3 months Only occur while the medication is being taken1 NMSC recurs and may rebound after discontinuation1 Retinoids have been shown to reduce several aspects of NMSC. These include: Reduction of AK, arsenical keratoses, and warts1 Significant decreases in the number of SCC lesions, with reported reductions ranging from 30% to 89%1-3 Reduced keratoacanthoma4 Retinoids are probably less effective in preventing BCC. The benefits are not limited to OTRs. They extend to high-risk populations, including patients with genetic conditions that confer a high risk of NMSC and patients with a history of severe UV exposure.5,6 The benefits of retinoids typically appear within 1 to 3 months after the initiation of treatment and last until therapy is terminated. NMSC recurs and may rebound after retinoid therapy is stopped.1 References Bavinck JN et al. J Clin Oncol. 1995;13: George R et al. Australas J Dermatol. 2002;43: Nijsten TE, Stern RS. J Am Acad Dermatol. 2003;49: Lippman SM, et al. J Dermatol Surg Oncol. 1988;14: Kraemer KH et al. N Engl J Med. 1988;318: DiGiovanna JJ. J Am Acad Dermatol. 1998;39(2 pt 3):S82-S85. 1. Bavinck JN et al. J Clin Oncol. 1995;13: Lippman SM, et al. J Dermatol Surg Oncol. 1988;14: 2. George R et al. Australas J Dermatol. 2002;43: Kraemer KH et al. N Engl J Med. 1988;318: 3. Nijsten TE, Stern RS. J Am Acad Dermatol. 2003;49: DiGiovanna JJ. J Am Acad Dermatol. 1998;39(2 pt 3):S82-S85.

Retinoid Randomized Controlled Clinical Trials
Study Design Results Adverse Effects Bavinck 19951 6-month double-blind RCT 44 patients with >10 AKs Acitretin 30 mg/d vs placebo 89% fewer new lesions with acitretin Acitretin: 2 lesions Placebo: 18 lesions Mucocutaneous effects No deterioration in renal function George 20022 2-year randomized crossover 23 renal transplant recipients with Hx of NMSC Acitretin 25 mg/d, adjusted for tolerability Crossover to no therapy at 1 year Significant reduction in number of SCC lesions Significant flattening of AKs Withdrawals due to AEs Acitretin: 9 No therapy: 3 de Sévaux 20033 1-year open-label dose comparison 26 renal transplant recipients .4 mg/kg/d (32 mg/d*) vs 0.2 mg/kg/d (16 mg/d*), adjusted for tolerability No significant effect on SCC incidence Reduced AKs Most patients required dose reduction * For a 180-lb patient This table summarizes the 3 trials of acitretin for prevention of NMSC in OTRs. 2 trials (Bouwes Bavinck 1995 and George 2002) reported significant reductions in the numbers of NMSC lesions.1,2 One dose-comparison trial (de Sévaux 2003) found no significant effect on SCC incidence, but a reduction in AK formation.3 Mucocutaneous side effects were common in all 3 trials, but no deterioration in renal function was observed.1-3 References Bavinck JN et al. J Clin Oncol. 1995;13: George R et al. Australas J Dermatol. 2002;43: de Sévaux RGL et al. J Am Acad Dermatol. 2003;49: Bavinck JN et al. J Clin Oncol. 1995;13: George R et al. Australas J Dermatol. 2002;43: de Sévaux RGL et al. J Am Acad Dermatol. 2003;49:

Acitretin for Prevention of NMSC Among Patients at High Risk: Other Reports
Study Design Results Adverse Effects Vandeghinste 1992 Case report Acitretin 0.5 mg/kg/d No new lesions Well-tolerated xerosis of skin and mucosae Yuan 1995 Uncontrolled trial Acitretin 10 to 50 mg/d Improved skin appearance Fewer AKs and cancers 9 patients had cutaneous AEs McKenna 1999 Acitretin 0.3 mg/kg/d Significant reduction in number of new tumors 2 discontinuations 2 patients had hyperlipidemia McNamara 2002 Acitretin 10 or 25 mg/d Large to moderate reduction in the number of new tumors and AKs 1 temporary discontinuation Lebwohl 2003 Acitretin 25 mg/d Decreased incidence of SCC None mentioned The use of acitretin for NMSC prevention among high-risk patients has been described in several other reports, summarized in the table on this slide and the next.1-9 These uncontrolled trials and case reports generally report a significant reduction in the number of AKs and new tumors. Most of the studies reported mucocutaneous AEs.1-4,7,9 Hyperlipidemia was reported in one study.3 References Vandeghinste N et al. Dermatology. 1992;185: Yuan ZF et al. N Z Med J. 1995;108: McKenna DB, Murphy GM. Br J Dermatol. 1999;140: McNamara IR et al. J Heart Lung Transplant. 2002;21: Lebwohl M et al. J Dermatolog Treat. 2003;14(suppl 2):3-6. Tan SR, Tope WD. Dermatol Surg. 2004;30: Smit JV et al. J Am Acad Dermatol. 2004;50: Carneiro RV et al. Clin Transplant. 2005;19: Harwood CA et al. Arch Dermatol. 2005;141: Vandeghinste N et al. Dermatology. 1992;185: Yuan Z et al. N Z Med J. 1995;108: McKenna DB, Murphy GM. Br J Dermatol. 1999;140: McNamara IR et al. J Heart Lung Transplant. 2002;21: Lebwohl M et al. J Dermatolog Treat. 2003;14(suppl 2):3-6.

Acitretin for Prevention of NMSC Among Patients at High Risk: Other Reports
Study Design Results Adverse Effects Tan 2004 Open-label controlled trial to assess effect on wound healing No statistically significant differences in wound healing None mentioned Smit Uncontrolled trial assessed histology and immunohistochemistry Acitretin up to 0.4 mg/kg/d Reduced epidermal thickness (44%, P<.01) Significant increase in some differentiation parameters Most patients required a dose reduction because of mucocutaneous effects Carneiro 2005 Uncontrolled trial Acitretin 20 mg/d Improved AK Only 1 carcinoma Increased epidermal Langerhans cells Well tolerated No significant laboratory abnormalities Harwood Retrospective trial Systemic retinoids 0.2 to 0.4 mg/kg/d Significant reduction in SCCs for at least 3 years Generally well tolerated Tan SR, Tope WD. Dermatol Surg. 2004;30: Smit JV et al. J Am Acad Dermatol. 2004;50: Carneiro RV et al. Clin Transplant. 2005;19: Harwood CA et al. Arch Dermatol. 2005;141:

Isotretinoin for Prevention of NMSC Among Patients at High Risk
No high-dose controlled studies among OTRs Low doses are ineffective Study Design Results Adverse Effects Kraemer 1988 3-year controlled study, 5 patients with XP Isotretinoin 2 mg/kg/d for 2 years then 1 year w/o treatment 63% decrease in number of tumors Cheilitis and xerosis, usually relieved with topical lubricants Increased blepharitis and conjunctivitis One patient discontinued due to LFT abnormalities Somos 1999 Case report, 1 patient with XP Isotretinoin 2 mg/kg/d for 1 year then 1 mg/kg/d for 2 years 75% decrease in NMSC tumors Mild skin dryness Mild lower extremity pain Bellman 1996 Case report, 1 renal transplant recipient Isotretinoin 0.5 mg/kg/d 50% decrease in SCC lesions within 2 months No renal effects Levine 1997 Double-blind RCT 525 patients with Hx of ≥4 SCCs and/or BCCs Isotretinoin 5-10 mg/d vs retinol 25,000 units/d vs placebo for 3 years No significant differences in SCC incidence 9.7% of patients reported Level 2 or higher AEs at the first visit AE rates declined after the first visit Tangrea 1992 981 patients with Hx of ≥2 BCCs Isotretinoin 10 mg/d vs placebo for 36 months No significant differences in BCC incidence Elevated triglycerides Hyperostosis Mucocutaneous effects Only one published report describes the use of high-dose isotretinoin for NMSC prevention in OTRs. However, there are some data on isotretinoin use in other high-risk populations. This table summarizes the data.1-5 Kraemer et al and Somos et al reported a significant decrease in tumor formation with isotretinoin therapy among patients with XP.1,2 Bellman et al reported a significant decrease in new tumors in a renal transplant recipient with isotretinoin therapy.3 Levine et al and Tangrea et al found no preventive effects and significant adverse effects from low doses of isotretinoin in large trials among high-risk segments of the general population.4,5 References Kraemer KH et al. N Engl J Med. 1988;318: Somos S et al. Anticancer Res. 1999;19: Bellman BA et al. Transplantation. 1996;61:173. Levine N et al. Cancer Epidemiol Biomarkers Prev. 1997;6: Tangrea JA et al. J Natl Cancer Inst. 1992;84: LFT, liver function test. Kraemer KH et al. N Engl J Med. 1988;318: Somos S et al. Anticancer Res. 1999;19: Bellman BA et al. Transplantation. 1996;61: Levine N et al. Cancer Epidemiol Biomarkers Prev. 1997;6: Tangrea JA et al. J Natl Cancer Inst. 1992;84:

Acitretin Safety Warnings for use in females of childbearing potential
Only for nonpregnant women who are severely affected by NMSC and are unresponsive to other therapies or when there is no other therapy that may be used 2 negative pregnancy tests before beginning treatment 2 forms of contraception for at least one month prior to starting acitretin, during therapy, and for at least 3 years after discontinuing therapy Not microdosed progestin Alcohol consumption prolongs half-life Patients must not donate blood during and for at least 3 years following discontinuation of acitretin Consider isotretinoin rather than acitretin for use in women of childbearing potential (shorter half-life) Acitretin is a known teratogen and should not be used in women of childbearing potential if any other acceptable therapy can be used. The product labeling for acitretin states several requirements for women of childbearing age who are receiving acitretin: 2 negative pregnancy tests before beginning therapy 2 effective forms of contraception before, during, and after therapy Microdosed progestin should not be used as a contraceptive because acitretin interferes with its contraceptive effects The elimination half-lives of isotretinion and acitretin are 21 hours and 49 hours, respectively If coadministered with ethanol, acitretin is converted to etretinate, which has a half life of 120 days. Patients receiving acitretin must not donate blood because of the possibility that a woman of childbearing age could receive acitretin or etretinate in the donated blood Consider isotretinoin for women of childbearing potential because of its much shorter half-life. Reference Soriatane® (acitretin capsules) prescribing information. Palo Alto, Calif: Connetics Corporation; July 2004. Soriatane® (acitretin capsules) prescribing information. Palo Alto, Calif: Connetics Corporation; July 2004.

Acitretin Contraindications and Warnings
Pregnancy Category X Severely impaired liver or kidney function Chronically elevated blood lipids In combination with methotrexate or tetracycline Patients with hypersensitivity to any component Contraindications: Acitretin should not be used in Female patients of childbearing potential (Pregnancy Category X) Patients with severely impaired liver or kidney function Patients with chronically elevated blood lipids In combination with methotrexate or tetracycline Patients with hypersensitivity to any component or to other retinoids Warnings: Acitretin has been associated with: Hepatoxicity Hyperostosis Elevated triglycerides and total cholesterol with decreased high-density lipoprotein cholesterol Ophthalmologic effects Pancreatitis Pseudotumor cerebri (benign intracranial hypertension) Depression and other psychiatric reactions Reference Soriatane® (acitretin capsules) prescribing information. Palo Alto, Calif: Connetics Corporation; July 2004. Soriatane® (acitretin capsules) prescribing information. Palo Alto, Calif: Connetics Corporation; July 2004.

Acitretin: Common AEs Mucocutaneous effects Lipid profile changes
Increased LFT values AEs are dose dependent Most AEs are mild to moderate and manageable with appropriate therapy The most common AEs associated with acitretin therapy are: Mucocutaneous effects Lipid profile changes Increased values on LFTs These effects are dose dependent. In most cases, the AEs are mild to moderate and can be managed with appropriate therapy. Reference Soriatane® (acitretin capsules) prescribing information. Palo Alto, Calif: Connetics Corporation; July 2004. Soriatane® (acitretin capsules) prescribing information. Palo Alto, Calif: Connetics Corporation; July 2004.

Managing Mucocutaneous Adverse Events
Common retinoid-related mucocutaneous AEs:1 Xerosis Cheilitis Pruritis Management: Aggressive emollients Petrolatum to lips and nares qhs Good skin care Moisturizers bid Moisturizing soap Tepid showers/baths Artificial tears Adjust dose and manage AEs rather than discontinuing therapy Consider decreasing dose by 25% for severe involvement Mucocutaneous AEs are commonly associated with systemic retinoid therapy. They include:1 Xerosis (dry skin) Cheilitis (chapped lips) Pruritis (itching) Management of these AEs revolves around use of emollients and good skin care. Specific recommendations include: Aggressive emollients Petrolatum to lips and nares qhs Good skin care Moisturizers bid Moisturizing soap Tepid showers/baths Artificial tears Prevention of mucocutaneous AEs is much more effective than managing them after they occur. Thus, these therapies should be used proactively to prevent the development of AEs. Because of the SCC prevention benefits of acitretin therapy, intolerable AEs should prompt a dose reduction rather than a discontinuation of therapy. Reference Naldi L, Griffiths CE. Br J Dermatol. 2005;152: 1. Naldi L, Griffiths CE. Br J Dermatol. 2005;

Mucocutaneous AEs Rates of Common Mucocutaneous AEs Alopecia Event
% of Patients Cheilitis (>75%) Alopecia (50-75%) Skin peeling Nail disorders (25-50%) Rhinitis Pruritis This slide shows clinical examples of mucocutaneous AEs resulting from systemic acitretin therapy. Cheilitis Nail Abnormalities Xerosis and Skin Peeling Soriatane® (acitretin capsules) prescribing information. Palo Alto, Calif: Connetics Corporation; July 2004.

Acitretin: Laboratory AEs*
% of Patients Laboratory Test 66 Increased triglycerides 40 Decreased HDL cholesterol 33 Increased cholesterol Increased LDH Increased AST, ALT <33 Increased reticulocytes WBC in urine 25-50 Increased CPK Increased fasting blood sugar This table gives the most common abnormal laboratory values in patients in clinical studies treated for psoriasis, listed in the product labeling information for acitretin. Reference Soriatane® (acitretin capsules) prescribing information. Palo Alto, Calif: Connetics Corporation; July 2004. *In patients treated for psoriasis. HDL, high-density lipoprotein; LDH, lactate dehydrogenase; AST, aspartate aminotransferase; ALT, alanine aminotransferase; CPK, creatinine phosphokinase; WBC, white blood cell count. Soriatane® (acitretin capsules) prescribing information. Palo Alto, Calif: Connetics Corporation; July 2004.

Systemic Retinoid Pharmacokinetics
Acitretin1 Isotretinoin2 Dosing frequency qd bid Effect of food Take with food Take with food; Absorption is increased with a high-fat meal Tmax (h) 2.7 (range, 2-5) 5.3 T1/2 (h) 49 (range, 33-96) 21.0 ± 8.2 Metabolism Forms etretinate (T1/2=120 days) when taken with alcohol Major metabolite is 4-oxo-isotretinoin (T1/2= 24.0 ± 5.3 hours) Distribution 99.9% protein bound This slide summarizes the pharmacokinetic data presented in the prescribing information for acitretin and isotretinoin.1,2 References Soriatane® (acitretin capsules) prescribing information. Palo Alto, Calif: Connetics Corporation; July 2004. Accutane® (isotretinoin capsules) prescribing information. Nutley, NJ: Roche Laboratories Inc; June 2002. 1. Soriatane® (acitretin capsules) prescribing information. Palo Alto, Calif: Connetics Corporation; July 2004. 2. Accutane® (isotretinoin capsules) prescribing information. Nutley, NJ: Roche Laboratories Inc; June 2002.

Systemic Retinoids: Drug Interactions
PI Mention Medication Interaction Recommendation Acitretin and Isotretinoin1,2 Vitamin A Possible additive toxic effects Avoid Microdosed progestin Inadequate method for contraception Other contraceptives No established significant interactions Use 2 forms of Tetracyclines Pseudotumor cerebri/ increased intracranial pressure Contraindicated This slide summarizes the drug interactions mentioned in the prescribing information for acitretin and isotretinoin The prescribing information for both acitretin and isotretinoin discusses drug interactions with vitamin A, microdosed progestin, other contraceptives, and tetracyclines In addition, the prescribing information for acitretin discusses interactions with methotrexate, phototherapy, ethanol, glibenclamide, and phenytoin. The prescribing information for isotretinoin discusses interactions with phenytoin and systemic corticosteroids. References Soriatane® (acitretin capsules) prescribing information. Palo Alto, Calif: Connetics Corporation; July 2004. Accutane® (isotretinoin capsules) prescribing information. Nutley, NJ: Roche Laboratories Inc; June 2002. PI, prescribing information. 1. Soriatane® (acitretin capsules) prescribing information. Palo Alto, Calif: Connetics Corporation; July 2004. 2. Accutane® (isotretinoin capsules) prescribing information. Nutley, NJ: Roche Laboratories Inc; June 2002.

Systemic Retinoids: Drug Interactions
PI Mention Medication Interaction Recommendation Acitretin1 Methotrexate Increased risk of hepatitis Contraindicated Increase LFT monitoring Phototherapy erythema Decrease dosage Ethanol Forms etretinate (T1/2=120 days) Glibenclamide Potentiates glucose lowering effects Careful supervision for patients with diabetes Phenytoin Reduced protein binding Isotretinoin2 Possible effect on bone loss Use with caution Systemic corticosteroids Possible interactive effects on osteoporosis This slide summarizes the drug interactions mentioned in the prescribing information for acitretin and isotretinoin The prescribing information for both acitretin and isotretinoin discusses drug interactions with vitamin A, microdosed progestin, other contraceptives, and tetracyclines In addition, the prescribing information for acitretin discusses interactions with methotrexate, phototherapy, ethanol, glibenclamide, and phenytoin. The prescribing information for isotretinoin discusses interactions with phenytoin and systemic corticosteroids. References Soriatane® (acitretin capsules) prescribing information. Palo Alto, Calif: Connetics Corporation; July 2004. Accutane® (isotretinoin capsules) prescribing information. Nutley, NJ: Roche Laboratories Inc; June 2002. 1. Soriatane® (acitretin capsules) prescribing information. Palo Alto, Calif: Connetics Corporation; July 2004. 2. Accutane® (isotretinoin capsules) prescribing information. Nutley, NJ: Roche Laboratories Inc; June 2002.

Managing Oral Retinoid Therapy
Gradual dose escalation Routine laboratory monitoring Pregnancy testing in women of reproductive potential Lipids LFTs Preventive AE management Early toxicity may be reversible; advanced toxicity may require discontinuation Mucocutaneous AEs: emollients, good skin care Dyslipidemia: lipid management Adjust dose and manage AEs rather than discontinuing therapy Acitretin therapy is associated with AEs that may prompt poor adherence or discontinuation of therapy in some patients. Several strategies, discussed in the following slides, can aid in minimizing and managing these AEs. They include: Gradual dose escalation Routine laboratory monitoring Preventive management of AEs For OTRs and other individuals at high risk of NMSC, the benefits of retinoid therapy can be significant. Thus, in these populations, the occurrence of AEs should prompt AE management and dose reduction rather than cessation of therapy.

Acitretin: Laboratory Monitoring in OTRs
Baseline Lipids, LFTs, glucose, creatinine, CBC, mental status, ± spinal x-ray or bone densitometry for patients at risk for osteoporosis or calcification Every 2 weeks for 2 months, then every 3 to 6 months Lipids, LFTs, mental status Periodically as indicated CBC Spinal x-ray Allograft function tests for OTRs Laboratory monitoring is required to identify some possible AEs. Baseline tests should include: Lipid levels LFTs Glucose levels Creatinine levels CBC Mental status review For patients at risk for osteoporosis or calcification, a spinal x-ray or bone densitometry should be obtained. Lipid levels, LFTs, and a mental status review should be repeated biweekly for 2 months after the initiation of therapy, and then every 3 to 6 months. Complete blood count, a spinal x-ray or bone densitometry, and allograft function testing for OTRs should be repeated periodically as indicated. Reference Soriatane® (acitretin capsules) prescribing information. Palo Alto, Calif: Connetics Corporation; July 2004. Soriatane® (acitretin capsules) prescribing information. Palo Alto, Calif: Connetics Corporation; July 2004.

Acitretin: Management of Lab Abnormalities—Hyperlipidemia
Important to recognize and treat due to accelerated atherosclerosis in transplant patients Hypercholesterolemia Prescribe statins Very effective Hypertriglyceridemia Prescribe gemfibrozil Lower dose of acitretin for pancreatitis (rare)

Acitretin: Management of Lab Abnormalities—LFT Elevations
Discontinue other hepatotoxic agents (acetaminophen, ethanol) Check for hepatitis Minor LFT elevation Repeat labs Discontinue alcohol Lower dose Elevation greater than 3x normal Discontinue Consult hepatologist

Summary: NMSC in OTRs Carcinogenesis in skin is frequent and aggressive in organ transplant recipients Prevention Sunscreen, sun avoidance, and photoprotection Regular dermatology follow-up Treatment Mild actinic damage Topical chemopreventive strategies Multiple AKs or few superficial NMSC Mohs micrographic surgery, excision, electrodesiccation and curettage, cryotherapy, radiation Extensive or high risk NMSC Aggressive conventional tumor management Systemic retinoid chemoprevention Consider reducing immunosuppression The strategies appropriate for managing and preventing NMSC in high-risk populations depend on the risk of NMSC Photoprotection, sun avoidance, and sunscreen use are a critical part of NMSC prevention for all patients Topical chemopreventive agents are appropriate for patients with mild actinic damage Standard therapies are appropriate for patients with multiple AKs or a few NMSC lesion AKs and NMSC lesions should be treated early and aggressively. Mohs micrographic surgery Surgical excision Electrodesiccation and curettage Cryotherapy Radiation therapy For patients with extensive or high-risk NMSC, aggressive conventional tumor management, systemic retinoid chemoprevention or reduction of immunosuppression should be considered

Summary: Oral Retinoids for NMSC Prevention
Who Individuals with a high tumor burden or at high risk of metastasis NOT women of childbearing potential Why Oral retinoids are effective in reducing the rate and numbers of NMSC formation 20% to 89% reduction May delay recurrence of high-risk or metastatic skin cancer How Start at a low dose, and gradually titrate up to optimize tolerability Monitor lipids and LFTs routinely Adjust dose and proactively manage AEs rather than discontinuing therapy Consider isotretinoin instead of acitretin in women of reproductive potential with strict adherence to pregnancy prevention programs Who needs oral retinoids? Individuals with a high tumor burden or at high risk for metastasis NOT women of childbearing potential Why are oral retinoids useful? They significantly reduce the rate of NMSC formation and may delay the recurrence of NMSC. How should oral retinoids be administered? Start with a low dose and increase it gradually. Monitor lipid levels and perform LFTs routinely. Use proactive AE management to prevent AEs and discontinuation. When AEs occur, reduce the dose and manage the AE rather than stopping therapy. Consider isotretinoin instead of acitretin in women of reproductive potential with strict adherence to pregnancy prevention programs.

Advances in Oral Retinoid Therapy

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