CUTANEOUS TOXICITY

EGFR INHIBITORS (EGFRIS) CUTANEOUS SIDE EFFECTS

Paolo Amerio, MD, PhD p.amerio@unich.it

Matteo Auriemma, MD matteo.auriemma@gmail.com

Dermatologic Clinic, G. D'Annunzio University – Chieti

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 Oct;6(10):803-12.

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

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 Oct;6(10):803-12.

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 PI3K–Akt 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

Murillas, R. et al. EMBO J. 14, 5216–5223 (1995).Pasonen-Seppanen. S. et al. J. Invest. Dermatol. 120, 1038–1044 (2003).

Peus, D., et al. J. Invest. Dermatol. 109, 751–756 (1997)Kobayashi, T., et al. J. Invest. Dermatol. 111, 616–620 (1998).

Jost, M., Kari, C. & Rodeck, U. Eur. J. Dermatol. 10, 505–510 (2000).Nanney, L. B. et al. J. Invest. Dermatol. 94, 742–748 (1990).Miettinen, P. J. et al. Nature 376, 337–341 (1995).

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

Pasonen-Seppanen. S. et al. J. Invest. Dermatol. 120, 1038–1044 (2003).Peus, D.et al. J. Invest. Dermatol. 109, 751–756 (1997).

Mimeault, M. et al. Skin Pharmacol. Physiol. 17, 153–166 (2004)

Sayama, K. et al. J. Biol. Chem. 276, 999–1004 (2001)

Threadgill, D. W. et al. Science 269, 230–234 (1995).

ACNEIFORM ERUPTION PATHOGENESYS

• EGFR, through it’s ligand TGF-α, 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-3α and IL-8.

• EGFR blockade reduces the expression of β-defensin 1 (hBD1) and 2 leading to Stappylococcus Aureus hyper-proliferation.

Mascia F. ... Amerio P et al. J Invest Dermatol. 2010 Mar;130(3):682-93

EGFRIsBlockade 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, 2787–2799 (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, 1–5 (2003).

EGFRIS

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

In clinical practice two types of EGFRIs exists:

SIDE EFFECTS

• Cutaneous toxicities that result from treatment with EGFRIs are common, affecting 45–100% 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 2005;23:5235-5246.Segaert S, Van Cutsem E. Ann Oncol 2005;16:1425-1433.

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 2005;23:5235-5246.Segaert S, Van Cutsem E. Ann Oncol 2005;16:1425-1433.

Lacouture ME. Nat Rev Cancer. 2006 Oct;6(10):803-12.

Acneiform rash

Dry skin

Fissures

Paronychia

1 2 3 4 5 6 7 8 9 10 11 12 13 14

Weeks

Rela

tive in

ten

sit

y

SKIN TOXICITIES TO EGFRIs

ACNEIFORM ERUPTION AND PATIENT’S QoL

• The importance of skin toxicity is underscored by the patient’s psyco-phisic distress; moreover rash severity could predict clinical outcome of EGFRIs treatment

Perez-Soler R. Oncology 2004;17:23-28

Perez-Soler R et al. J Clin Oncol 2005;22:3238-3247.

Bonner J et al. Int J Radiat Oncol Biol Phys 2008;72(Suppl):Abstract LB3

ACNEIFORM ERUPTION AND PATIENT’S QoL

• EGFRIs skin toxicity could profoundly impact QoL and be determinant for treatment withdrawal

Molinari E et al. Dermatology 2005;211:330-3.

• Psycological distress lead to praecox treatment withdrawal

Journagan S et al. J Am Acad Dermatol 2006;54:358-60.

• The correct treatment setting is influenced by an accurate starting evaluation

ADVERSE EVENTS PREVENTIONAre 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, 236–238 (2006)

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 specialist’s 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.

ASSESSMENT OF SKIN INVOLVEMENT

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 it’s validation compared to the NCI-CTCAE scale.

M&M• 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 > 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

• Kendall’s coefficent of concordance to evaluate results

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: > 1 erithematous maculae

Grade 2: > 1 papula

Grade 3: > 1pustola

Grade 4: > 1 plaque (fusion of more pustolae) or one nodule

CETUXIMAB ERUPTION SCORING SYSTEM (CESS)

Global score: [local score I +II+III+IV+V+VI] = Global score legend:

0 none

1-18 mild

19-30 moderate

31-38 intense

> 39 severe 

CETUXIMAB ERUPTION SCORING SYSTEM (CESS)

Secondary elements worsening the score:

Hitch:

Burning sensation:

 

Other manifestations:

Blefaritis mild moderate severe

Paronichia mild moderate severe

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.

NATIONAL CANCER INSTITUTE COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENT (NCI-CTCAE)

NCI-CTCAE --- in ACNEIFORM ERUPTION 5 degrees:

– I II grade: erythema, papulae in < 50% of skin surface: no intervention

– III grade: moderate eruption > 50% of skin surface + pain, ulceration and/or desquamation

– IV grade: exfoliative dermatitis, ulcers, blisters, severe involvement (MOF)

– V grade: death.

NationalCancer Institute Common Terminology Criteria for adverse events

RESULTS (1)

NCI evaluation scale : only a slight concordance among the evaluations

RESULTS (2)

”Eruption Scoring System” :better result concordance

similar results with the OMS scale and CESS scale

RESULTS (3)

CONCLUSIONS

The OMS score generates high differences among the different operators.

That result could be due to the low expertise of the different evaluator.

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

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.

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

MANAGEMENT

SIDE EFFECTS MANAGEMENT

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

TOPICITretionina crema 0.025%,

0.05%, 0.1%

Tazarotene crema/gel

0.05%, 0.1%

BENZOIL

PEROSSIDO

ZOLFO 6%

AGENTI

ANTINFIAMMAT

ORISteroidi topici

Inibitori della calcineurinaa

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.

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

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).

• Paronichia and other nail’s 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.

ADVERSE EVENTS MANAGEMENT – MORE THAN RASH

• Paronichia: Aluminium acetate,Potassium permanganate

KMnO4.

• Fissurations: Ointments.

• Desquamazione: Moisturizing creams.

• Prurito: Anti-Histamin.

ADVERSE EVENTS MANAGEMENT – MORE THAN RASH

CONSIDERATIONS

• The EGFRIs are key players in solid tumours treatment although it’s 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.