Cutaneous Toxicities Of Cancer Therapy

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


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


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


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


ImprovementReduce dose to 200 mg/m2

No improvement


Third occurrence


ImprovementReduce dose to 150 mg/m2

No improvement


Fourth occurrence


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.

Health & Medicine

Cutaneous Toxicities Of Cancer Therapy