Cutaneous Toxicities Of Cancer Therapy

CUTANEOUS TOXICITIES OF CANCER THERAPY
Saiama Waqar

Outline
Alopecia
Hyperpigmentation
Hand-foot syndrome
Radiation sensitivity and recall
Hypersensitivity
Nail dystrophies
Extravasation injuries
Skin toxicity from targeted therapies
Conclusion

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

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

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

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

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

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

Preventive devices
1990- FDA stopped sale of these devices citing absence of safety or efficacy data
Cranial prostheses (wigs) and scarves use encouraged

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)

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

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

Drugs causing hyperpigmentation Alley E. Green R, Schuchter. Cutaneous toxicities of cancer therapy. Curr Opin Oncol. 2002 Mar;14(2):212-6

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

Hand foot syndrome Acral erythema from docetaxel

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)

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

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

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

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

Radiation sensitization and recall Alley E. Green R, Schuchter. Cutaneous toxicities of cancer therapy. Curr Opin Oncol. 2002 Mar;14(2):212-6

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

Drugs causing hypersensitivity Alley E. Green R, Schuchter. Cutaneous toxicities of cancer therapy. Curr Opin Oncol. 2002 Mar;14(2):212-6

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.

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

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

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

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

Vesicants and irritants Alley E. Green R, Schuchter. Cutaneous toxicities of cancer therapy. Curr Opin Oncol. 2002 Mar;14(2):212-6

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.

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

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

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

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

Cetuximab skin toxicity Moderate rosacea-like eruption from cetuximab 80 year old patient receiving cetuximab and radiation for nasopharyngeal cancer

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.

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

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

Dermatology referral
Dr. Milan Anadkat
Chemotherapy-induced skin reactions
362-2643

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

References
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.

Cutaneous Toxicities Of Cancer Therapy

by fondas vak on Feb 04, 2010

Accessibility

Categories

Tags

Upload Details

Usage Rights

2 Embeds 8

Statistics

Cutaneous Toxicities Of Cancer Therapy — Presentation Transcript

http://www.slideshare.net	5
http://radiotherapyhome-fondas.blogspot.com	3