Cutaneous toxicity EGFR inhibitors (EGFRIs) cutaneous side effects

1
Cutaneous toxicityEGFR inhibitors (EGFRIs)
cutaneous side effects

• Paolo Amerio, MD, PhD p.amerio_at_unich.it
• Matteo Auriemma, MD matteo.auriemma_at_gmail.com
• Dermatologic Clinic, G. D'Annunzio University
  Chieti

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EGFRIs drugs

• Unlike standard chemotherapy, which affects most
  replicating cells, EGFR inhibitors (EGFRIs)
  target pathways that are crucial for cancer cell
  growth and survival.
• Treatment with EGFRIs is associated with a
  decreased incidence of systemic side effects
  compared with standard chemotherapeutic drugs.
• The increasing clinical use of EGFRIs have led to
  the identification of a commonly occurring range
  of EGFRI-specific side effects, resulting in
  decreased quality of life as well as a decrease,
  interruption or discontinuation of EGFRI
  treatment.
• These reactions are most evident in tissues that
  are crucially dependent on EGFR signaling for
  normal function, such as the skin.

Lacouture ME. Nat Rev Cancer. 2006
Oct6(10)803-12.
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EGF, EGFR and skin

• EGFR is crucial for the normal development and
  physiology of the epidermis
• There exist a number of compound in the EGF
  family (TGF-?, anfiregulin, heparin binding-EGF,
  epiregulin) involved in cellular proliferation
  and differentiation.
• Those molecules act through atocrine and
  paracrine mechanisms
• Numerous molecules can activate EGFR (cyitokines,
  UV-ray, integrins), being this receptor involved
  in numerous functions proliferation, toumor cell
  mobility, skin inflammation.

Pastore S, Mascia F, Mariani V, Girolomoni G. The
Epidermal Growth Factor Receptor System in Skin
Repair and Inflammation. J Invest Dermatol. 2007
Nov 29
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EGF, EGFR and skin

• The skin is composed of three layers the
  epidermis, the dermis and the hypodermis
  (adipose tissue).
• Epidermis is primarily composed of keratinocytes
  (approximately 90 of cells), expressing EGFR at
  the highest concentration in the basal and
  suprabasal layers.
• The basal layer and the bulge of the hair
  follicle contain proliferating stem cells, which
  give rise to terminally differentiating
  keratinocytes.
• The outer root sheath of the hair follicle is
  contiguous with the basal layer, sharing
  biochemical properties and high EGFR expression.

Lacouture ME. Nat Rev Cancer. 2006
Oct6(10)803-12.
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EGF, EGFR and skin

• EGFR is primarily expressed in undifferentiated,
  proliferating keratinocytes in the basal and
  suprabasal layers of the epidermis and the outer
  layers of the hair follicle
• Expression of EGFR is lost as keratinocytes exit
  the basal layer
• Activation of EGFR by its ligands EGF,
  amphiregulin and HBEGF (heparin-binding EGF)
  regulates normal keratinocyte proliferation,
  differentiation, migration and survival
• EGFR-driven proliferation is mediated by the
  PI3KAkt and MAPK pathways, which regulate genes
  that contribute to growth and the
  undifferentiated state
• Treatment of cultured normal human keratinocytes
  with EGFRIs inhibits DNA synthesis and
  progression from G1 to S phase of the cell cycle

Jost, M., Kari, C. Rodeck, U. Eur. J. Dermatol.
10, 505510 (2000). Nanney, L. B. et al. J.
Invest. Dermatol. 94, 742748 (1990). Miettinen,
P. J. et al. Nature 376, 337341 (1995).
Murillas, R. et al. EMBO J. 14, 52165223
(1995). Pasonen-Seppanen. S. et al. J. Invest.
Dermatol. 120, 10381044 (2003). Peus, D., et al.
J. Invest. Dermatol. 109, 751756
(1997) Kobayashi, T., et al. J. Invest. Dermatol.
111, 616620 (1998).
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EGF, EGFR and skin

• Inhibition of EGFR signalling induces apoptosis
  in normal keratinocytes
• No effect on melanocytes or fibroblasts ?
  keratinocytes are the primary target in
  EGFRI-mediated cutaneous toxicities
• EGF addition to cultured keratinocytes
  downregulates the expression of
  terminal-differentiation markers and inhibits the
  formation of the cornified envelope
• EGFR inhibition induces the expression of
  terminal differentiation markers, such as KRT1
  (keratin 1) and KRT10, in normal cultured
  keratinocytes and contribute to keratinocyte
  apoptosis
• Premature hair keratinization and maturation of
  the inner root sheath is seen in EGFR-null mice

Mimeault, M. et al. Skin Pharmacol. Physiol. 17,
153166 (2004) Sayama, K. et al. J. Biol. Chem.
276, 9991004 (2001) Threadgill, D. W. et al.
Science 269, 230234 (1995).
Pasonen-Seppanen. S. et al. J. Invest. Dermatol.
120, 10381044 (2003). Peus, D.et al. J. Invest.
Dermatol. 109, 751756 (1997).
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ACNEIFORM ERUPTION PATHOGENESYS

• EGFR, through its ligand TGF-a, modulates
  cytokines production thus regulating skin
  inflammation in vivo
• EGFR blockade enhance inflammatory cells
  migration
• EGFR blockade enhance chemokines production
  MCP-1, RANTES, TARC, eotaxin-3, CCL27.
• EGFR blockade reduces the expression of IP-10,
  MIP-3a and IL-8.
• EGFR blockade reduces the expression of
  ß-defensin 1 (hBD1) and 2 leading to
  Stappylococcus Aureus hyper-proliferation.

Mascia F. ... Amerio P et al. J Invest
Dermatol. 2010 Mar130(3)682-93
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EGFRIs
Blockade of EGFR results in growth arrest and
apoptosis in cells that are dependent on EGFR for
survival, through the inhibition of the MAPK
pathway, the PI3K (phosphatidylinositol
3-kinase)Akt pathway, the stress-activated
proteinkinase pathway that involves protein
kinase C, and the Janus kinase (Jak)STAT (signal
transducer and activator of transcription) pathway
Mendelsohn, J. Baselga, J. J. Clin. Oncol. 21,
27872799 (2003).
Inhibition of the EGFR-mediated signaling
pathways affects keratinocytes by inducing growth
arrest and apoptosis, decreasing cell migration,
increasing cell attachment and differentiation,
and stimulating inflammation, all of which result
in distinctive cutaneous manifestations.
Kari, C. et al. Cancer Res. 63, 15 (2003).
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EGFRIs
In clinical practice two types of EGFRIs exists
Monoclonal antibodies (Cetuximab and
Panitumumab) competitive inhibition of the
binding of ligands to the extracellular region
Low-molecular-weight tyrosine kinase inhibitors
(TKIs) (Gefitinib and Erlotinib) blocking
cytoplasmic-domain phosphorylation2
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Side effects

• Cutaneous toxicities that result from treatment
  with EGFRIs are common, affecting 45100 of
  patients.
• Rarely life-threatening, cause significant
  physical and psycho-social discomfort? QoL and
  the modification or discontinuation of anticancer
  therapy.
• No established guidelines to prevent or manage
  these reactions.

Perez-Soler R, Saltz L. J Clin Oncol
2005235235-5246. Segaert S, Van Cutsem E. Ann
Oncol 2005161425-1433.
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Skin toxicities to egfris

• Papulopustular rash (face and upper trunk)
  45-100
• Dry , desquamating and itchy skin 4-35
• Paronichia (onicolysis, piogenic granuloma)
  6-16
• Hypersensitivity reactions (anaphylaxis,
  orticaria) 2-3
• Alopecia of the scalp, tricomeglaia of the
  eyelashes facial hair 21

Perez-Soler R, Saltz L. J Clin Oncol
2005235235-5246. Segaert S, Van Cutsem E. Ann
Oncol 2005161425-1433. Lacouture ME. Nat Rev
Cancer. 2006 Oct6(10)803-12.
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Skin toxicities to egfris
Acneiform rash
Dry skin
Fissures
Relative intensity
1 2 3 4 5 6 7 8
9 10 11 12 13 14
Weeks
Paronychia
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Acneiform eruption and patients QoL

• The importance of skin toxicity is underscored by
  the patients psyco-phisic distress moreover
  rash severity could predict clinical outcome of
  EGFRIs treatment
• Perez-Soler R. Oncology 20041723-28
• Perez-Soler R et al. J Clin Oncol
  2005223238-3247.

Bonner J et al. Int J Radiat Oncol Biol Phys
200872(Suppl)Abstract LB3
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Acneiform eruption and patients QoL

• EGFRIs skin toxicity could profoundly impact QoL
  and be determinant for treatment withdrawal
• Molinari E et al. Dermatology 2005211330-3.
• Psycological distress lead to praecox treatment
  withdrawal
• Journagan S et al. J Am Acad Dermatol
  200654358-60.
• The correct treatment setting is influenced by an
  accurate starting evaluation

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Adverse events prevention

• Are EGFRIs side effects a multidisciplinary task,
  in which dermatologists can play a role?
• YES usually EGFRIs are withdrawal due to their
  side effects a dermatological consult could
  reduce cutaneous side effects, improving
  treatment adherence
• A strict collaboration between dermatologists and
  oncologists is needed to ensure treatment
  adherence

Lacouture ME et al. J. Support. Oncol. 4, 236238
(2006)
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Side effects Prevention Management

• A correct management of EGFRIs correlated side
  effects depends on an adequate grading.
• The National Cancer Institute Common Toxicity
  Criteria (NCI-CTC) is the more used grading
  scale for EGFRIs side effects.
• NCI-CTC is a useful tool to evaluate patients
  side effects, to plan a correct therapeutical
  strategy and to evaluate any possible therapies.
• Skin toxicities evaluation is based on clinical
  distintion of erythema, papulae, pustolae and
  nodules and on subjective evaluation of hitch and
  burning sensation ? specialists experience?

National Cancer Institute (NCI). Common
Terminology Criteria for Adverse Events v3.0
(CTCAE). Available at http//ctep.cancer.gov/forms
/CTCAEv3.pdf. Accessed February 14, 2007.
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Assessment of skin involvement
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STUDY DESIGN

• TO DEFINE A STANDARDIZED SYSTEM to quantify skin
  toxicities due to EGFRIs therapies, especially of
  the acneiform reaction. An highly specific scale
  is needed for medicians (oncologist or
  dermatologist) for systematic evaluation of skin
  reactions
• EVALUATION OF A NEW SCALE the Eruption Scoring
  System and its validation compared to the
  NCI-CTCAE scale.

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MM

• Patients of the Oncology Department of the SS.
  Annunziata hospital in Chieti, suffering of
  acneiform eruption
• All patients underwent treatment for lung,
  breast, rectus or cervix cancer
• Cetuximab (MoAb) or Erlotinib (TKIs)
• Inclusion criteria
• M or F gt 18 aa
• Patients in treatment
• Informed consent
• Ethic committee approval

• 17 patients
• 11 dermatologists and 2 oncologists performed
  each evaluation
• Digital pictures evaluation
• Each picture has been evaluated randomly by each
  specialist to avoid any confounding bias
• Kendalls coefficent of concordance to evaluate
  results

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Cetuximab Eruption Scoring System
(CESS)assessment of a new scale

• Localizzation factor x grade (0-4) local score
•  
• I forehead 2
• II right cheek 2
• III left cheek 2
• IV nose 1
• V chin 1
• VI upper chest 2
• VII lower chest 1
• VIII upper back 2
• XI lower back 1
•  
• Grade 0 no lesions
• Grade 1 gt 1 erithematous maculae
• Grade 2 gt 1 papula
• Grade 3 gt 1pustola
• Grade 4 gt 1 plaque (fusion of more pustolae) or
  one nodule

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Cetuximab Eruption Scoring System (CESS)?

• Global score local score I IIIIIIVVVI
  
• Global score legend
• 0 none
• 1-18 mild
• 19-30 moderate
• 31-38 intense
• gt 39 severe
•  

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Cetuximab Eruption Scoring System (CESS)?

• Secondary elements worsening the score
• Hitch
• Burning sensation
•  
• Other manifestations
• Blefaritis ? mild ? moderate ?severe
• Paronichia ? mild ? moderate ? severe

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National Cancer Institute Common Terminology
Criteria for Adverse Event (NCI-CTCAE)?

• This scale deals only with dry skin, nails
  alterations, hitch, rash/desquamations and
  rash/acneiform eruption not considering
  localization and patient's perceptions.

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National Cancer Institute Common Terminology
Criteria for Adverse Event (NCI-CTCAE)?

• NCI-CTCAE --- in ACNEIFORM ERUPTION 5 degrees
• I II grade erythema, papulae in lt 50 of skin
  surface no intervention
• III grade moderate eruption gt 50 of skin
  surface pain, ulceration and/or desquamation
• IV grade exfoliative dermatitis, ulcers,
  blisters, severe involvement (MOF)
• V grade death.

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NationalCancer Institute Common Terminology
Criteria for adverse events
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Results (1)?
NCI evaluation scale only a slight concordance
among the evaluations
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Results (2)?
Eruption Scoring System better result
concordance
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RESULTS (3)
similar results with the OMS scale and CESS scale
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CONCLUSIONS

• The OMS score generates high differences among
  the different operators.
• That result could be due to the low expertise of
  the different evaluator.

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Conclusions II

• Results due to the scale itself the evaluation
  of rash/desquamation and nails alteration needs a
  good expertice meanwile the Acneiform scale is
  highly unspecific

National Cancer Institute (NCI). Common
Terminology Criteria for Adverse Events v3.0
(CTCAE). Available at http//ctep.cancer.gov/forms
/CTCAEv3.pdf
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Conclusions III

• CESS scale is highly reproducible being less
  operator dependant
• CESS scale gives more uniform results among
  operators compared to the OMS scale.
• CESS scale evaluates the Acneiform Rash, lesions
  type and localization, being more detailed
  compared to the OMS scale.

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Conclusions IV

• The Eruption Scorig System (ESS) collects more
  detailed information in a short time compared to
  the OMS scale giving the opportunity of a more
  specific and operator-indipendent evaluation.
• Those characteristics could enhance patients and
  care management

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Management
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Side effects management
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side effects management

• Rash (papulae/pustolae)
• ANTIBIOTICI SISTEMICI
• Tetracicline 500 mg/die
• Minociclina 100 mg/die
• Doxiciclina 100 mg/die
• TRATTAMENTI TOPICI
• Eritromicina
• Clindamicina
• Acido fusidico
• Sulfamethoxazolo-trimethoprim
• Metronidazolo

• RETINOIDI TOPICI
• Tretionina crema 0.025, 0.05, 0.1
• Tazarotene crema/gel 0.05, 0.1
• BENZOIL PEROSSIDO
• ZOLFO 6
• AGENTI ANTINFIAMMATORI
• Steroidi topici
• Inibitori della calcineurinaa

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side effects management

• Treatment of side effects has to be continued
  although EGFRIs interruption, or reduction skin
  toxicities can last for a long time.
• As soon as skin toxicities become asymptomatic,
  EGFRIs treatment has to be restarted or enhanced.

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Other considerations

• Topical therapies has to be continued for at
  least one week to reduce skin toxicities.
• Continuous application of steroids could worsen
  the clinical course of the reaction and enhance
  superinfectious risk
• Topical steroids are suggested as follows 2
  weeks of treatment ... 1 week without treatment
• Doxiciclin has to be preferred in renal failure
  patients although it has more photo-sensitizing
  properties than minocicline

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Adverse events managment

• Whenever skin rush involver more than 50 of skin
  surfaces, EGFRIs has to be tapered or suspended.
• Periods of treatment can be alternated with
  periods of withdrawal (on/off therapies 2 weeks -
  1 weeks).

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Adverse events management more than rash

• Paronichia and other nails alterations usually
  stars 2-4 months after Cetuximab treatment is
  started (12).
• Topical or systemic antibiotics can be used
  together with FANS to control pain. Those
  therapies will improve symptoms although wont
  prevent paronichia itself.

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Adverse events management more than rash

• Paronichia Aluminium acetate,
• Potassium permanganate KMnO4.
• Fissurations Ointments.
• Desquamazione Moisturizing creams.
• Prurito Anti-Histamin.

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considerations

• The EGFRIs are key players in solid tumours
  treatment although its use is afflicted by
  several skin side effect of variable intensity.
• Usually EGFRIs side effects can be treated
  without reducing or withdrawing anti cancer
  therapies. Unfortunately not every side effect
  can be treated leading to a EGFRIs tapering.
• Therapeutical algorithms are useful tools.
• Cooperation between oncologists and
  dermatologists should be mandatory.