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  • 1. CUTANEOUS TOXICITIES OF CANCER THERAPY
    • Saiama Waqar
  • 2. Outline
    • Alopecia
    • Hyperpigmentation
    • Hand-foot syndrome
    • Radiation sensitivity and recall
    • Hypersensitivity
    • Nail dystrophies
    • Extravasation injuries
    • Skin toxicity from targeted therapies
    • Conclusion
  • 3. Alopecia
    • Drugs that target rapidly dividing cells often affect the proliferating cells in the hair follicle
    • Terminal hair follicles with rapid matrix formation more affected (scalp more than body hair, eyebrows, eyelashes)
      • completely lost in a short time: transplant
      • gradually lost over several weeks: cyclic chemotherapy
  • 4. Alopecia
    • Methotrexate: affects the follicle melanocytes, resulting in depigmented band of hair, “flag sign”
    • Visible regrowth within 3-6 months
    • Often regrows with a change in color or texture (switching from straight to curly), mechanism of change unclear
    • Psychologically, one of the most stressful side effects
  • 5. Grading of alopecia Grade Minimal loss, grade 1 < 25%; obvious to the patient but not necessarily to others Moderate loss, grade 2 25 to 50 %; obvious thinning of scalp hair but not enough to lead to the use of a wig or alternate head covering Severe loss, grade 3 > 50% of hair lost; generally indicates the need for a wig or alternate head covering in those for whom alopecia is a major concern
  • 6. Chemotherapy drugs causing alopecia
    • Often
      • Bleomycin
      • Etoposide
      • Methotrexate
      • Mitoxantrone
      • Paclitaxel
    • Common
      • Cyclophosphamide
      • Daunorubicin
      • Doxorubicin
      • Docetaxel
      • Idarubicin
      • Ifosphamide
      • Paclitaxel
    • Infrequent
      • 5-FU
      • Hydroxyurea
      • Thiotepa
      • Vinblastine
      • Vincristine
      • Vinorelbine
    • Rare
      • procarbazine
  • 7. Prevention of alopecia
    • scalp tourniquets:
      • pneumatic device placed around the hairline during chemo infusion
      • inflated to a pressure >SBP
      • Several studies: effective for preventing hair loss
        • utilized different techniques, variation in chemotherapy regimens, tourniquet pressure, sample size, and criteria to assess alopecia (data difficult to interpret)
      • Side effects: headache, varying degrees of nerve compression
  • 8. Prevention of alopecia
    • Hypothermia with scalp icing devices:
      • Vasoconstriction of scalp blood vessels, less absorption of chemo as hair follicles less metabolically active at 24C
      • ice turban, gel packs, cool caps, thermocirculator, room air conditioner
      • 50-80% response, though variable chemotherapy regimens and definitions of alopecia, small sample size
    • Not effective in liver disease
      • Delayed drug metabolism, persistent levels beyond protective period
    • Scalp metastases:
      • mycosis fungoides, limited to scalp. CR after chemo without scalp cooling
      • 61 pts with met breast cancer and liver dysfunction, 1 pt scalp met
  • 9. Preventive devices
    • 1990- FDA stopped sale of these devices citing absence of safety or efficacy data
    • Cranial prostheses (wigs) and scarves use encouraged
  • 10. Pharmacologic interventions for alopecia
    • Topical minoxidil (shorten time to maximum regrowth, did not prevent alopecia)
    • AS101(NSCLC pts: garlic-like halitosis and post-infusion fevers)
    • Alpha tocopherol (cardioprotection for doxorubicin, noted less alopecia)
    • Topical calcitriol (cell lines- protects cancer cells)
    • IL-1(rats, cytarabine, cell cycle specific, protected)
    • Inhibitors of p53 (mice deficient p53, no alopecia)
  • 11. HYPERPIGMENTATION
    • usually resolves with drug discontinuation
      • gingival margin pigmentation seen with cyclophosphamide is usually permanent
    • Patterns of pigmentation:
      • Diffuse
      • Local at site of infusion
    • Sites of pressure /trauma
      • Hydrea and cisplatin
  • 12. Hyperpigmentation
    • Busulfan
      • “ busulfan tan” can mimic Addison's disease.
      • Although busulfan can also cause adrenal insufficiency, the skin change is 2/2 toxic effect on melanocytes
      • Distinguish busulfan toxicity from true Addison's disease by normal levels of MSH & ACTH
    • Liposomal doxorubicin
      • macular hyperpigmentation over the trunk and extremities, including the palms and soles
      • not been described with unencapsulated doxorubicin
  • 13. Drugs causing hyperpigmentation Alley E. Green R, Schuchter. Cutaneous toxicities of cancer therapy. Curr Opin Oncol. 2002 Mar;14(2):212-6
  • 14. HAND-FOOT SYNDROME
    • also known as palmar–plantar erythrodysesthesia (PPE)
    • originally described in patients receiving high-dose cytarabine
    • skin lesions begin as erythema and edema of the palms or soles and is associated with sensitivity to touch or paresthesia
    • can progress to desquamation of the affected areas and significant pain
  • 15. Hand foot syndrome Acral erythema from docetaxel
  • 16. Pathogenesis
    • Unclear: small capillaries in the palms and soles rupture with increased pressure from walking or use, creating an inflammatory reaction
    • formulation of drugs and duration of exposure can impact the incidence
      • liposome-encapsulated doxorubicin more than standard formulation
      • 5-FU bolus lower than CIVI and capecitabine (converted into 5-FU in vivo)
  • 17. Hand foot syndrome Grading Cancer Therapy Evaluation Program Common Toxicity Criteria for Adverse Events, version 3.0, June 2003 Scheithaur, W, Blum, J. Coming to grips with and-foot syndrome: Insights from clinical trials evaluating capecitabine. Oncology 2004; 18:1161 Grade Signs and symptoms 1 Minimal skin changes or dermatitis (eg, erythema) without pain 2 Skin changes (eg, peeling, blisters, bleeding, edema) or pain, not interfering with function 3 Skin changes with pain, interfering with function
  • 18. Treatment
    • No proven preventive therapy
      • Pyridoxine (vitamin B6) may help reduce the incidence and severity
      • Celecoxib reported to reduce incidence
    • Management largely symptomatic with reduction of drug doses where appropriate
    • emollients and protective gloves can be helpful
  • 19. Radiation sensitization and recall
    • Some chemotherapeutic agents can sensitize the skin to radiation
    • recall phenomenon in previously irradiated tissue (wks to yrs after RT)
      • when chemotherapy is administered
    • Exact mechanism not clearly understood,
      • radiation effects on the microvasculature
      • altered cutaneous immunologic responses
    • maculopapular eruptions with erythema, vesicles, desquamation
      • mild rash to severe skin necrosis
  • 20. Radiation sensitization and recall
    • No specific therapy recommended
      • topical corticosteroids
      • Ultraviolet radiation
    • caution about sun exposure
      • wear protective clothing
      • sunscreen products
        • 5-FU increases photosensitivity to sunlight
        • MTX may reactivate a sunburn
  • 21. Radiation sensitization and recall Alley E. Green R, Schuchter. Cutaneous toxicities of cancer therapy. Curr Opin Oncol. 2002 Mar;14(2):212-6
  • 22. Hypersensitivity reactions
    • Can occur either from drug itself or from solubility vehicle (eg. Cremophor for paclitaxel)
    • Prevention: premedicate
      • Steroids (dexamethasone), H1 blockers (benadryl), H2 blockers (pepcid)
    • Management of hypersensitivity reactions:
      • epinephrine, hydrocortisone, and histamine blockers, along with monitoring of BP
  • 23. Drugs causing hypersensitivity Alley E. Green R, Schuchter. Cutaneous toxicities of cancer therapy. Curr Opin Oncol. 2002 Mar;14(2):212-6
  • 24. NAIL DYSTROPHY
    • Color changes
      • Mee’s lines - transverse white
      • hyperpigmentation
    • Beau’s lines - transverse grooves/lines
      • related to the effect of chemotherapy causing decreased nail growth
    • Paronychia -inflammation of the nail fold
      • Seen with cetuximab
    Beau’s lines Mortimer, NJ, Mills, J. Images in clinical medicine: Beau's lines. N Engl J Med 2004; 351:1778.
  • 25.
    • Onycholysis (separation of the nail plate from the nail bed)
      • can be painful
      • anthracyclines, taxanes (especially weekly paclitaxel), and topical 5-fluorouracil
    • frozen-glove study to prevent docetaxel-induced onycholysis & cutaneous toxicity
      • 45 patients, frozen glove for 90 minutes on the right hand, using the left hand as control
      • Frozen glove reduced the nail and skin toxicity
  • 26. Grading of nail changes Common terminology Criteria for Adverse events v 3.0 Nail changes with docetaxel Grade Nail changes/toxicity 1 Discoloration, ridging (koilonychias), pitting 2 Partial or complete loss of nail(s), pain in nailbed(s) 3 Interfering with ADL
  • 27. Drugs causing nail changes
    • Pigmentary changes
      • Bleomycin
      • Busulfan
      • Cisplatin
      • Cyclophosphamide
      • Docetaxel
      • Doxorubicin
      • Etoposide
      • Fluorouracil
      • Hydroxyurea
      • Idarubicin
      • Ifosfamide
      • Melphalan
      • Methotrexate
      • Mitomycin
      • Mitoxantrone
    • Onycholysis
      • Paclitaxel
      • Docetaxel
      • Gemcitabine
      • Capecitabine
      • Cyclophosphamide
      • Doxorubicin
      • Etoposide
      • Fluorouracil
      • Hydroxyruea
    • Inflammatory changes
      • Gefitinib
      • Cetuximab
      • Capecitabine
      • Docetaxel
      • Paclitaxel
  • 28. Extravasation injury
    • The accidental extravasation of intravenous drugs occurs in approximately 0.1% to 6% of patients receiving chemotherapy
    • Depending on the agent and amount, the sequelae of extravasation can range from erythema and pain to necrosis and sloughing of the skin
    • The most toxic drugs are the vesicants, such as the anthracyclines, vinca alkaloids, nitrogen mustards, as well as paclitaxel and cisplatin
  • 29. Vesicants and irritants Alley E. Green R, Schuchter. Cutaneous toxicities of cancer therapy. Curr Opin Oncol. 2002 Mar;14(2):212-6
  • 30. Treatment of extravasation
    • immediate discontinuation of the infusion
    • cooling with ice packs
      • warm soaks for vinca alkaloids
    • for persistent/progressive local symptoms - surgical consult
    • early local debridement of can reduce extent of later injury
    Extravasation of vinblastine in a 57-year-old male receiving chemotherapy for bladder cancer Viale PH. Chemotherapy and cutaneous toxicities: implications for oncology nurses. Semin Oncol Nurs 2006 Aug;22(3):144-51. Review.
  • 31. Antidotes for extravasation
      • topical DMSO (dimethyl sulfoxide) to enhance absorption of the extravasated drug, routine use still controversial
      • Thiosulfate -nitrogen mustard extravasation (injection of a 1/6 molar solution into the area of extravasation)
      • Dexrazoxane - anthracycline extravasation
    • Regardless of antidote, local therapy, and prompt surgical intervention is paramount
  • 32. Skin Toxicity from targeted therapy
    • Because the EGFR is also expressed by basal keratinocytes, sebocytes, the outer root sheath, and some endothelial cells, agents that inhibit EGFR are associated with dermatologic side effects
    Erlotinib eruption on the arms
  • 33. Cutaneous reactions associated with molecularly targeted agents Monoclonal antibodies to EGFR Infusion reactions; acneiform eruption; paronychial inflammation; photosensitivity
    • Cetuximab, panitumumab
    EGFR pathway inhibitors Acneiform eruption; paronychial inflammation; photosensitivity
    • Erlotinib
    • Gefitinib
    • Lapatinib
    Multitargeted tyrosine kinase inhibitors Skin exanthem; SJS; acute generalized exanthematous pustulosis; Sweets syndrome; hand-foot syndrome; photosensitivity; pigmentary changes, hair depigmentation; alopecia
    • Imatinib
    • Dasatinib
    • Sorafenib
    • Sunitinib
  • 34. EGFR-inhibitor induced skin changes
    • (a-c) stratum corneum thickness, (d) apoptosis (apoptotic cells by 10,000).
    • On-therapy (gefitinib) biopsy specimen showing (e) keratin plugs and micro-organisms in dilated infundibula and (f) acute folliculitis.
    Segaert S, Taberno J, Chosidow O et al. The management of skin reactions in cancer patients receiving epidermal growth factor receptor targeted therapies. J Dtsch Dermatol Ges. 2005 Aug;3(8):599-606
  • 35. Cetuximab skin toxicity Moderate rosacea-like eruption from cetuximab 80 year old patient receiving cetuximab and radiation for nasopharyngeal cancer
  • 36. Segaert S, Taberno J, Chosidow O et al. The management of skin reactions in cancer patients receiving epidermal growth factor receptor targeted therapies. J Dtsch Dermatol Ges. 2005 Aug;3(8):599-606
  • 37. Erlotinib rash treatment Viale PH. Chemotherapy and cutaneous toxicities: implications for oncology nurses. Semin Oncol Nurs 2006 Aug;22(3):144-51. Review. Severity of Rash Treatment Protocol Mild Topical clindamycin 2%, with hydrocortisone 1% in lotion base applied twice-daily. Moderate Topical clindamycin 2%, with hydrocortisone 1% in lotion base applied twice-daily AND oral minocycline 100mg twice-daily for a minimum of 4 weeks and continuing thereafter as required, until resolution of the rash by one severity grade. Scalp lesions will be treated with a topical lotion clindamycin 2%, triamcinolone acetonide 0.1% in equal parts of propylene glycol and water. Severe Stop erlotinib therapy for 1 week and restart at 100mg once-daily. Treatment of rash with topical clindamycin 2%, with hydrocortisone 1% in lotion base applied twice-daily AND oral minocycline 100mg twice-daily for a minimum of 4 weeks and continuing thereafter as required. Scalp lesions will be treated with a topical lotion clindamycin 2%, triamcinolone acetonide 0.1% in equal parts of propylene glycol and water until resolution.
  • 38. Dose modification guidelines for cetuximab (Erbitux) based upon dermatologic toxicity Payne AS, Harris JE, Saverese DMF. Cutaneous complications of chemotherapy. www.uptodate.com. Last updated Oct 7, 2008 Severe acneiform rash Initial management Outcome Dose modification First occurrence Delay infusion 1 to 2 weeks Improvement Continue at 250 mg/m2 No improvement Discontinue cetuximab Second occurrence Delay infusion 1 to 2 weeks Improvement Reduce dose to 200 mg/m2 No improvement Discontinue cetuximab Third occurrence Delay infusion 1 to 2 weeks Improvement Reduce dose to 150 mg/m2 No improvement Discontinue cetuximab Fourth occurrence Discontinue cetuximab  
  • 39. Conclusions
    • Variety of cutaneous toxicities from chemotherapy
    • Range from cosmetic (alopecia and hyperpigmentation) to serious (hypersensitivity and extravasation)
    • Awareness of the psychological and physical effects of these cutaneous compliactions is important
  • 40. Dermatology referral
    • Dr. Milan Anadkat
      • Chemotherapy-induced skin reactions
      • 362-2643
  • 41. Clinicaltrials.gov
    • STEPP: A Phase 2, Open-Label, Randomized Clinical Trial of Skin Toxicity Treatment in mCRC Subjects Receiving Panitumumab Concomitantly With Second-Line Irinotecan Based Chemotherapy
    • Phase II Study of Skin Toxicity Dosing of IRESSA (Gefitinib) in Squamous Cell Carcinoma of the Head and Neck
    • A Study of Tarceva (Erlotinib) in Combination With Gemcitabine in Unresectable and/or Metastatic Cancer of the Pancreas: Relationship Between Skin Toxicity and Survival
  • 42.  
  • 43. References
    • Segaert S, Taberno J, Chosidow O et al. The management of skin reactions in cancer patients receiving epidermal growth factor receptor targeted therapies. J Dtsch Dermatol Ges. 2005 Aug;3(8):599-606
    • Lacouture ME, Melosky BL.Cutaneous reactions to anticancer agents targeting the epidermal growth factor receptor: a dermatology-oncology perspective.Skin Therapy Lett. 2007 Jul-Aug;12(6):1-5. Review.
    • Alley E. Green R, Schuchter. Cutaneous toxicities of cancer therapy. Curr Opin Oncol. 2002 Mar;14(2):212-6
    • Viale PH. Chemotherapy and cutaneous toxicities: implications for oncology nurses. Semin Oncol Nurs 2006 Aug;22(3):144-51. Review.
    • Heidary N, Naik H, Burgin S. Chemotherapeutic agents and the skin: An update. J Am Acad Dermatol 2008 Apr;58(4):545-70
    • Payne AS, Harris JE, Saverese DMF. Cutaneous complications of chemotherapy. www.uptodate.com. Last updated Oct 7, 2008
    • Scheithaur, W, Blum, J. Coming to grips with and-foot syndrome: Insights from clinical trials evaluating capecitabine. Oncology 2004; 18:1161
    • NCI Common Toxicity Criteria V3.0 ctep.cancer.gov/reporting/ctc.html
    • Mortimer, NJ, Mills, J. Images in clinical medicine: Beau's lines. N Engl J Med 2004; 351:1778.