Dermatologic complications of chemotherapy by niusheng11

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									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                      ◦ Ifosphamide
     ◦   Bleomycin              ◦ Paclitaxel
     ◦   Etoposide             Infrequent
     ◦   Methotrexate           ◦   5-FU
     ◦   Mitoxantrone           ◦   Hydroxyurea
     ◦   Paclitaxel             ◦   Thiotepa
    Common                     ◦   Vinblastine
     ◦   Cyclophosphamide       ◦   Vincristine
     ◦   Daunorubicin           ◦   Vinorelbine
     ◦   Doxorubicin           Rare
     ◦   Docetaxel              ◦ procarbazine
     ◦   Idarubicin
      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: smallcapillaries 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
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        Scheithaur, W, Blum, J. Coming to grips with
Toxicity Criteria for Adverse Events, version   and-foot syndrome: Insights from clinical
3.0, June 2003                                  trials evaluating capecitabine. Oncology 2004;
                                                18:1161
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
                                       Beau’s lines
    ◦ Seen with cetuximab              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
                      prevent docetaxel-
 frozen-glove study to
 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
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
            Common terminology Criteria for Adverse events v 3.0




                          Nail changes with docetaxel
Drugs causing nail changes
•   Pigmentary changes   •   Onycholysis
    – Bleomycin              – Paclitaxel
    – Busulfan               – Docetaxel
    – Cisplatin              – Gemcitabine
    – Cyclophosphamide       – Capecitabine
    – Docetaxel              – Cyclophosphamide
    – Doxorubicin            – Doxorubicin
    – Etoposide              – Etoposide
    – Fluorouracil           – Fluorouracil
    – Hydroxyurea            – Hydroxyruea
    – Idarubicin
                         •   Inflammatory changes
    – Ifosfamide
                             – Gefitinib
    – Melphalan
                             – Cetuximab
    – Methotrexate
                             – Capecitabine
    – Mitomycin
                             – Docetaxel
    – Mitoxantrone
                             – 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           Extravasation of vinblastine in a 57-
                                       year-old male receiving chemotherapy
  can reduce extent of later           for bladder cancer

  injury
                                       Viale PH. Chemotherapy and cutaneous toxicities:
                                       implications f or 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
              antidote, local therapy, and
 Regardless of
 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;
Cetuximab, panitumumab         photosensitivity
EGFR pathway inhibitors
Erlotinib                      Acneiform eruption; paronychial
Gefitinib                      inflammation; photosensitivity
Lapatinib
Multitargeted tyrosine kinase
inhibitors                      Skin exanthem; SJS; acute generalized
Imatinib                       exanthematous pustulosis; Sweets
                                syndrome; hand-foot syndrome;
Dasatinib
                                photosensitivity; pigmentary changes,
Sorafenib                      hair depigmentation; alopecia
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 f actor receptor targeted therapies. J Dtsch
                   Dermatol Ges. 2005 Aug;3(8):599-606
Cetuximab skin toxicity




Moderate rosacea-like eruption   80 year old patient receiving
from cetuximab                   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 f actor receptor targeted therapies.
J Dtsch Dermatol Ges. 2005 Aug;3(8):599-606
Erlotinib rash treatment
Severity of   Treatment Protocol
Rash
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 f or oncology
                           nurses. Semin Oncol Nurs 2006 Aug;22(3):144-51. Review.
Dose modification guidelines for cetuximab
(Erbitux) based upon dermatologic toxicity
Severe             Initial                                                Dose
                                           Outcome
acneiform rash     management                                             modification
                                                                          Continue at 250
                                           Improvement
                   Delay infusion 1                                       mg/m2
First occurrence
                   to 2 weeks                                             Discontinue
                                           No improvement
                                                                          cetuximab
                                                                          Reduce dose to
                                           Improvement
Second             Delay infusion 1                                       200 mg/m2
occurrence         to 2 weeks                                             Discontinue
                                           No improvement
                                                                          cetuximab
                                                                          Reduce dose to
                                           Improvement
                   Delay infusion 1                                       150 mg/m2
Third occurrence
                   to 2 weeks                                             Discontinue
                                           No improvement
                                                                          cetuximab
Fourth             Discontinue
occurrence         cetuximab
                               Payne AS, Harris JE, Saverese DMF. Cutaneous complications of
                               chemotherapy. www.uptodate.com. Last updated Oct 7, 2008
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
1.   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.

								
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