Cutaneous toxicities of cancer therapy

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
6
Chemotherapy drugs causing alopecia

• Ifosphamide
• Paclitaxel
• Infrequent
• 5-FU
• Hydroxyurea
• Thiotepa
• Vinblastine
• Vincristine
• Vinorelbine
• Rare
• procarbazine

• Often
• Bleomycin
• Etoposide
• Methotrexate
• Mitoxantrone
• Paclitaxel
• Common
• Cyclophosphamide
• Daunorubicin
• Doxorubicin
• Docetaxel
• Idarubicin

7
Prevention of alopecia

• scalp tourniquets
• pneumatic device placed around the hairline
  during chemo infusion
• inflated to a pressure gtSBP
• 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)

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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
Mar14(2)212-6
14
HAND-FOOT SYNDROME

• also known as palmarplantar 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
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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 181161
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
Mar14(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
Mar14(2)212-6
24
NAIL DYSTROPHY

• Color changes
• Mees lines - transverse white
• hyperpigmentation
• Beaus lines - transverse grooves/lines
• related to the effect of chemotherapy causing
  decreased nail growth
• Paronychia -inflammation of the nail fold
• Seen with cetuximab

Beaus lines Mortimer, NJ, Mills, J. Images in
clinical medicine Beau's lines. N Engl J Med
2004 3511778.
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
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

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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
Mar14(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 Aug22(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
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
Aug3(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
Aug3(8)599-606
37
Erlotinib rash treatment
Viale PH. Chemotherapy and cutaneous toxicities
implications for oncology nurses. Semin Oncol
Nurs 2006 Aug22(3)144-51. Review.
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
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

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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
  Aug3(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-Aug12(6)1-5. Review.
• Alley E. Green R, Schuchter. Cutaneous toxicities
  of cancer therapy. Curr Opin Oncol. 2002
  Mar14(2)212-6
• Viale PH. Chemotherapy and cutaneous toxicities
  implications for oncology nurses. Semin Oncol
  Nurs 2006 Aug22(3)144-51. Review.
• Heidary N, Naik H, Burgin S. Chemotherapeutic
  agents and the skin An update. J Am Acad
  Dermatol 2008 Apr58(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 181161
• 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
  3511778.