cutaneous toxicities of cancer therapy
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CUTANEOUS CUTANEOUS TOXICITIES OF TOXICITIES OF CANCER THERAPYCANCER THERAPY
Saiama Waqar
OutlineOutlineAlopeciaHyperpigmentationHand-foot syndromeRadiation sensitivity and recallHypersensitivityNail dystrophiesExtravasation injuriesSkin toxicity from targeted therapiesConclusion
AlopeciaAlopeciaDrugs 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 Alopecia Methotrexate: affects the follicle
melanocytes, resulting in depigmented band of hair, “flag sign”
Visible regrowth within 3-6 monthsOften 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 alopeciaGrading of alopeciaGrade
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 Chemotherapy drugs causing alopeciaalopecia
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 alopeciaPrevention of alopeciascalp 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 alopeciaPrevention of alopeciaHypothermia 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 periodScalp 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 devicesPreventive devices1990- FDA
stopped sale of these devices citing absence of safety or efficacy data
Cranial prostheses (wigs) and scarves use encouraged
Pharmacologic interventions Pharmacologic interventions for alopeciafor alopeciaTopical 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)
HYPERPIGMENTATIONHYPERPIGMENTATIONusually resolves with
drug discontinuationgingival margin
pigmentation seen with cyclophosphamide is usually permanent
Patterns of pigmentation:◦ Diffuse ◦ Local at site of infusion
◦ Sites of pressure /trauma◦ Hydrea and cisplatin
HyperpigmentationHyperpigmentation• 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 Drugs causing hyperpigmentationhyperpigmentation
Alley E. Green R, Schuchter. Cutaneous toxicities of cancer therapy. Curr Opin Oncol. 2002 Mar;14(2):212-6
HAND-FOOT SYNDROMEHAND-FOOT SYNDROMEalso known as palmar–plantar
erythrodysesthesia (PPE)originally described in patients
receiving high-dose cytarabineskin 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 syndromeHand foot syndrome
Acral erythema from docetaxel
PathogenesisPathogenesisUnclear: 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 Hand foot syndrome GradingGrading
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
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
TreatmentTreatmentNo 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 Radiation sensitization and recalland recallSome chemotherapeutic agents can
sensitize the skin to radiationrecall 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 Radiation sensitization and recalland recallNo 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 Radiation sensitization and recalland recall
Alley E. Green R, Schuchter. Cutaneous toxicities of cancer therapy. Curr Opin Oncol. 2002 Mar;14(2):212-6
Hypersensitivity reactionsHypersensitivity reactionsCan 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 Drugs causing hypersensitivityhypersensitivity
Alley E. Green R, Schuchter. Cutaneous toxicities of cancer therapy. Curr Opin Oncol. 2002 Mar;14(2):212-6
NAIL DYSTROPHYNAIL DYSTROPHYColor 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 linesMortimer, 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-fluorouracilfrozen-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 changesGrading of nail changesGrade Nail changes/toxicity
1 Discoloration, ridging (koilonychias), pitting
2 Partial or complete loss of nail(s), pain in nailbed(s)
3 Interfering with ADLCommon terminology Criteria for Adverse events v 3.0
Nail changes with docetaxel
Drugs causing nail Drugs causing nail changeschanges• 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 injuryExtravasation injuryThe 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 irritantsVesicants and irritants
Alley E. Green R, Schuchter. Cutaneous toxicities of cancer therapy. Curr Opin Oncol. 2002 Mar;14(2):212-6
Treatment of Treatment of extravasationextravasation
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 Antidotes for extravasationextravasation
◦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 Skin Toxicity from targeted therapytherapy
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 Cutaneous reactions associated with molecularly associated with molecularly targeted agentstargeted agentsMonoclonal 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 EGFR-inhibitor induced skin changeschanges
(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 toxicityCetuximab skin toxicity
Moderate rosacea-like eruption from cetuximab
80 year old patient receiving cetuximab and radiation for nasopharyngeal cancer
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
Erlotinib rash treatmentErlotinib rash treatmentSeverity 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.
Viale PH. Chemotherapy and cutaneous toxicities: implications for oncology nurses. Semin Oncol Nurs 2006 Aug;22(3):144-51. Review.
Dose modification guidelines for Dose modification guidelines for cetuximab (Erbitux) based upon cetuximab (Erbitux) based upon dermatologic toxicity dermatologic toxicity Severe acneiform rash
Initial management
Outcome Dose modification
First occurrence
Delay infusion 1 to 2 weeks
ImprovementContinue at 250 mg/m2
No improvement
Discontinue cetuximab
Second occurrence
Delay infusion 1 to 2 weeks
ImprovementReduce dose to 200 mg/m2
No improvement
Discontinue cetuximab
Third occurrence
Delay infusion 1 to 2 weeks
ImprovementReduce dose to 150 mg/m2
No improvement
Discontinue cetuximab
Fourth occurrence
Discontinue cetuximab
Payne AS, Harris JE, Saverese DMF. Cutaneous complications of chemotherapy. www.uptodate.com. Last updated Oct 7, 2008
ConclusionsConclusionsVariety of cutaneous toxicities
from chemotherapyRange from cosmetic (alopecia
and hyperpigmentation) to serious (hypersensitivity and extravasation)
Awareness of the psychological and physical effects of these cutaneous compliactions is important
Dermatology referralDermatology referralDr. Milan Anadkat
◦Chemotherapy-induced skin reactions
◦362-2643
Clinicaltrials.govClinicaltrials.govSTEPP: 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
ReferencesReferences1. 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
2. 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.
3. Alley E. Green R, Schuchter. Cutaneous toxicities of cancer therapy. Curr Opin Oncol. 2002 Mar;14(2):212-6
4. Viale PH. Chemotherapy and cutaneous toxicities: implications for oncology nurses. Semin Oncol Nurs 2006 Aug;22(3):144-51. Review.
5. Heidary N, Naik H, Burgin S. Chemotherapeutic agents and the skin: An update. J Am Acad Dermatol 2008 Apr;58(4):545-70
6. Payne AS, Harris JE, Saverese DMF. Cutaneous complications of chemotherapy. www.uptodate.com. Last updated Oct 7, 2008
7. Scheithaur, W, Blum, J. Coming to grips with and-foot syndrome: Insights from clinical trials evaluating capecitabine. Oncology 2004; 18:1161
8. NCI Common Toxicity Criteria V3.0 ctep.cancer.gov/reporting/ctc.html
9. Mortimer, NJ, Mills, J. Images in clinical medicine: Beau's lines. N Engl J Med 2004; 351:1778.