Cutaneous Toxicities of Cancer Therapy

Cutaneous Toxicities of Cancer Therapy
By:Dr.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)
o completely lost in a short time: transplant
o gradually lost over several weeks: cyclic chemotherapy
* 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
o Bleomycin
o Etoposide
o Methotrexate
o Mitoxantrone
o Paclitaxel
* Common
o Cyclophosphamide
o Daunorubicin
o Doxorubicin
o Docetaxel
o Idarubicin
o Ifosphamide
o Paclitaxel
* Infrequent
o 5-FU
o Hydroxyurea
o Thiotepa
o Vinblastine
o Vincristine
o Vinorelbine
* Rare
o procarbazine

Prevention of alopecia
* scalp tourniquets:
o pneumatic device placed around the hairline during chemo infusion
o inflated to a pressure >SBP
o 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)
o Side effects: headache, varying degrees of nerve compression

Prevention of alopecia
* Hypothermia with scalp icing devices:
o Vasoconstriction of scalp blood vessels, less absorption of chemo as hair follicles less metabolically active at 24C
o ice turban, gel packs, cool caps, thermocirculator, room air conditioner
o 50-80% response, though variable chemotherapy regimens and definitions of alopecia, small sample size
* Not effective in liver disease
o Delayed drug metabolism, persistent levels beyond protective period
* Scalp metastases:
o mycosis fungoides, limited to scalp. CR after chemo without scalp cooling
o 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
o gingival margin pigmentation seen with cyclophosphamide is usually permanent
* Patterns of pigmentation:
o Diffuse
o Local at site of infusion
* Sites of pressure /trauma
o Hydrea and cisplatin
* Busulfan
o “busulfan tan” can mimic Addison's disease.
o Although busulfan can also cause adrenal insufficiency, the skin change is 2/2 toxic effect on melanocytes
o Distinguish busulfan toxicity from true Addison's disease by normal levels of MSH & ACTH
* Liposomal doxorubicin
o macular hyperpigmentation over the trunk and extremities, including the palms and soles
o not been described with unencapsulated doxorubicin

Drugs causing hyperpigmentation

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
o liposome-encapsulated doxorubicin more than standard formulation
o 5-FU bolus lower than CIVI and capecitabine (converted into 5-FU in vivo)

Hand foot syndrome Grading
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
o Pyridoxine (vitamin B6) may help reduce the incidence and severity
o 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)
o when chemotherapy is administered
* Exact mechanism not clearly understood,
o radiation effects on the microvasculature
o altered cutaneous immunologic responses
* maculopapular eruptions with erythema, vesicles, desquamation
o mild rash to severe skin necrosis

Radiation sensitization and recall
* No specific therapy recommended
o topical corticosteroids
o Ultraviolet radiation
* caution about sun exposure
o wear protective clothing
o sunscreen products
+ 5-FU increases photosensitivity to sunlight
+ MTX may reactivate a sunburnes 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
o Steroids (dexamethasone), H1 blockers (benadryl), H2 blockers (pepcid)
* Management of hypersensitivity reactions:
o epinephrine, hydrocortisone, and histamine blockers, along with monitoring of BP

Drugs causing hypersensitivity
NAIL DYSTROPHY
* Color changes
o Mee’s lines - transverse white
o hyperpigmentation
* Beau’s lines - transverse grooves/lines
o related to the effect of chemotherapy causing decreased nail growth
* Paronychia -inflammation of the nail fold
o Seen with cetuximab

Beau’s lines
* Onycholysis (separation of the nail plate from the nail bed)
o can be painful
o anthracyclines, taxanes (especially weekly paclitaxel), and topical 5-fluorouracil
* frozen-glove study to prevent docetaxel-induced onycholysis & cutaneous toxicity
o 45 patients, frozen glove for 90 minutes on the right hand, using the left hand as control
o Frozen glove reduced the nail and skin toxicity

Grading of nail changes
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
Nail changes with docetaxel

Drugs causing nail changes
* Pigmentary changes
o Bleomycin
o Busulfan
o Cisplatin
o Cyclophosphamide
o Docetaxel
o Doxorubicin
o Etoposide
o Fluorouracil
o Hydroxyurea
o Idarubicin
o Ifosfamide
o Melphalan
o Methotrexate
o Mitomycin
o Mitoxantrone

* Onycholysis
o Paclitaxel
o Docetaxel
o Gemcitabine
o Capecitabine
o Cyclophosphamide
o Doxorubicin
o Etoposide
o Fluorouracil
o Hydroxyruea
* Inflammatory changes
o Gefitinib
o Cetuximab
o Capecitabine
o Docetaxel
o 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
Treatment of extravasation
* immediate discontinuation of the infusion
* cooling with ice packs
o 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

Antidotes for extravasation
o topical DMSO (dimethyl sulfoxide) to enhance absorption of the extravasated drug, routine use still controversial
o Thiosulfate -nitrogen mustard extravasation (injection of a 1/6 molar solution into the area of extravasation)
o 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.

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

Erlotinib rash treatment
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

Cutaneous Toxicities of Cancer Therapy.ppt