Mario E. Lacouture, MD Associate Attending Department of Medicine Memorial Sloan-Kettering Cancer Center New York, New York EGFR Inhibitor–Related Dermatologic

Mario E. Lacouture, MDAssociate AttendingDepartment of MedicineMemorial Sloan-Kettering Cancer CenterNew York, New York

EGFR Inhibitor–Related Dermatologic Toxicities: Applying MASCC Guidelines in Prevention and Treatment

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Faculty

Mario E. Lacouture, MD Associate AttendingDepartment of MedicineMemorial Sloan-Kettering Cancer CenterNew York, New York


Faculty Disclosures

Mario E. Lacouture, MD, has disclosed that he has received consulting fees from Advanced Cell Technology, Amgen, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Genentech, Genzyme, GlaxoSmithKline, ImClone, Lilly, Onyx, OSI, Pfizer, Roche, and Wyeth.


Thymidylate Synthase

Grb2

Ras

Sos

Raf

Mek

Erk

Targeting Tumors

Survival, proliferation,

invasion/motility

EGFR

TGFα

Roberts PJ, et al. Oncogene. 2007;26:3291-3310. Montagut C, et al. Cancer Letters. 2009;283:125-134.

EGFR overexpressed

– CRC: 27% to 77%; pancreatic: 30% to 50%; lung: 40% to 80%; NSCLC: 14% to 91%

EGFR mutated

– NSCLC: 10%; glioblastoma: 20%

Ras mutated

– Pancreatic: 90%; papillary thyroid: 60%; colon: 50%; NSCLC: 30%

Raf mutated

– Melanoma: 70%; papillary thyroid: 50%; colon: 10%


And Targeting the Skin

1.6 million people diagnosed each yr

– Prior to therapy, 45.1% with skin findings (N = 700)

– Tinea pedis/onychomycosis, xerosis, pruritus, pyoderma

Consequences of dermatologic conditions

– Psychosocial impact

– Financial burden

– Physical health

– Anticancer treatment disruptionKiliç A, et al. Int J Dermatol. 2007;46:1055-1060. Lacouture ME. Nat Rev Cancer. 2006;6:803-812.

Eye/eyelashabnormalities

Periungual/nail

alterations

Hair loss

Papulopustularrash

Xerosis/pruritus


EGFR in Skin

EGFR is constitutively expressed in the epidermis, follicle, sebaceous, eccrine glands, dendritic APCs

EGFR inhibition leads to negative effects in skin – Apoptosis, inflammation, atrophy, telangiectasias, ↓ photoprotection

EGFR

Lacouture ME. Nat Rev Cancer. 2006;6:803-812. Busam KJ, et al. Br J Dermatol. 2001;144:1169-1176.


Timing of EGFR Inhibitor–Associated Dermatologic Toxicities

Van Cutsem E. Oncologist. 2006;11:1010-1017. Lacouture ME, et al. J Clin Oncol. 2010;28:1351-1357.Scope A, et al. J Clin Oncol. 2007;25:5390-5396.

Wk of EGFR-Targeted Therapy

Acne-like rash Postinflammatory effects

Dry skin

FissureParonychia

1 2 3 4 5 6 7 8 9

Pruritus


Prevention and Treatment of EGFR Inhibitor–Assoc. Dermatologic ToxicitiesLevels of Evidence

Level I evidence is reserved for meta-analyses of randomized controlled trials or randomized trials with high power

Level II evidence includes randomized trials with lower power

Level III evidence includes nonrandomized trials, such as cohort or case-controlled series

Level IV evidence includes descriptive and case studies

Level V evidence includes case reports and clinical examples

Recommendation Grades

Grade A is reserved for level I evidence or consistent findings from multiples studies of level II, III, or IV evidence

Grade B is for level II, III, or IV evidence with generally consistent findings

Grade C is similar to grade B but with inconsistencies

Grade D implies little or no evidence

Lacouture ME, et al. Support Care Cancer. 2011;19:1079-1095.


EGFR Inhibitor–Induced Rash Red papulopustules[1]

– Pruritus, tenderness in 62% Erlotinib 150 mg QD[2]

– All grade: 75%

– Grade 3: 9% Cetuximab[3]

– All grade: 85%

– Grade 3: 10% Panitumumab[4]

– All grade: 90%

– Grade 3: 16% Lapatinib[5]

– All grade: 27%

– Grade 3: 1%

1. Lacouture ME, et al. Br J Dermatol. 2006;155:852-854.2. Shepherd FA, et al. N Engl J Med. 2005; 353:123-132.3. Rosell R, et al. Ann Oncol. 2008;19:362-369.4. Van Cutsem E, et al. J Clin Oncol. 2007;25:1658-1664.5. Geyer CE, et al. N Engl J Med. 2006;355:2733-2743.


1. Lacouture ME, et al. Br J Dermatol. 2006;155:852-854.2. Shepherd FA, et al. N Engl J Med. 2005; 353:123-132.3. Rosell R, et al. Ann Oncol. 2008;19:362-369.4. Van Cutsem E, et al. J Clin Oncol. 2007;25:1658-1664.5. Geyer CE, et al. N Engl J Med. 2006;355:2733-2743.

EGFR Inhibitor–Induced Rash Red papulopustules[1]

– Pruritus, tenderness in 62% Erlotinib 150 mg QD[2]

– All grade: 75%

– Grade 3: 9% Cetuximab[3]

– All grade: 85%

– Grade 3: 10% Panitumumab[4]

– All grade: 90%

– Grade 3: 16% Lapatinib[5]

– All grade: 27%

– Grade 3: 1%


QoL[1] Cost[2]

Impact of EGFR Inhibitor Dermatologic Toxicities on QoL and Cost

Survey of 58 patients with Skindex-16

Top domain: emotions (P < .05)

Inverse corr age-emotions (r = -0.26; P = .03)

Mean cost/pt: $2788

Med

ian

Ove

rall

Ski

nd

ex-1

6 S

core

NCI-CTCAE v3.0 Papulopustular Rash Grade

100

40

80

60

20

01 2 3

Drugs

Clinic Visits

Lab Tests

Procedures

1. Joshi SS, et al. Cancer. 2010;116:3916-3923. 2. Borovicka JH, et al. ASCO 2010. Abstract 3569.

Avg

. Co

st/P

t fo

r M

anag

emen

t o

f E

GF

R

Inh

ibit

or

Der

mat

olo

gic

To

xici

ties

($) 1497

862

338

91

0

200

400

600

800

1000

1200

1400

1600


Impact of EGFR Inhibitor Skin Toxicity on Oncologists Survey of 110 oncology practices, 51 questions on EGFR

inhibitor rash

Per

cen

tag

e o

f R

esp

on

der

s w

ho

Ob

serv

e In

dic

ated

Ras

h

Gra

de

in >

50%

of

Pat

ien

ts

Wit

h R

ash

Dose reduction: 60%Dose interruption: 76%

Drug discontinuation: 32%

Boone SL, et al. Oncology. 2007;72:152-159.

Rash CTCAE Grade

Grade 1 Grade 2 Grade 3 Grade 4

40

30

20

10

0

39

34

4 3


Vincenzi 2006[1]

P = .06

Saltz 2004[2]

P = .02

Hecht 2007[3]

HR: 0.72; 95% CI: 0.54-0.97 Grade 0-1Grade 2-4

Grades 0-2Grade 3

Grade 0Grade 3

Median OS (Mos)0 5 10

Cetuximab

Cetuximab

Panitumumab

Ras

h G

rad

e

Correlation: Rash and Survival/Response in CRC

1. Vincenzi B, et al. Br J Cancer. 2006;94:792-797. 2. Saltz LB, et al. J Clin Oncol. 2004;22:1201-1208. 3. Hecht JR, et al. Cancer. 2007;110:980-988.


Tazarotene and Minocycline for Rash Prevention

Cetuximab therapy for CRC

2 mos

Total lesion count each side of face

Randomize

Daily Placebo

(N = 24)

0.05% tazarotene cream daily to left

half of face(n = 12)

0.05% tazarotene cream daily to right


Minocycline 100 mg/day

(N = 24)

0.05% tazarotene cream daily to left


0.05% tazarotene cream daily to right


18 Analyzed 17 Analyzed

Scope A, et al. J Clin Oncol. 2007;25:5390-5396.


Minocycline for Rash Prevention: Total Lesion Counts

Prophylaxis with minocycline results in decreased severity of rash in first mo of cetuximab therapy

There was no difference with tazarotene treatment

Scope A, et al. J Clin Oncol. 2007;25:5390-5396.

7

6

5

4

3

2

1

0

Lo

g-T

ota

l Les

ion

Co

un

t

Study Wk1 2 4 8

MinocyclinePlacebo


Lacouture ME, et al. J Clin Oncol. 2010;28:1351-1357.

STEPP Study: Preemptive vs Reactive Skin Toxicity Treatment in Metastatic CRC Open‑label phase II study

Prophylactic skin treatment regimen administered Wks 1-6 (beginning Day 1)

– Skin moisturizer

– Sunscreen (PABA free, SPF ≥ 15, UVA/UVB protection)

– Topical steroid (1% hydrocortisone cream)

– Doxycycline 100 mg BID

Per investigator discretion, reactive skin treatment administered anytime during Wks 1-6


STEPP: Dermatologic Toxicities

0

5

10

15

20

25

Dermatitis Acneiform Pruritus Pustular Rash Paronychia

Prophylactic skin treatment

Reactive skin treatment

Gra

de

3 T

oxi

cit

y (

%)

Prophylactic (n = 48)

Reactive (n = 47)

Patients with grade 2 or higher skin toxicity, n (%) 14 (29) 29 (62)

OR (95% CI) 0.3 (0.1-0.6)

Lacouture ME, et al. J Clin Oncol. 2010;28:1351-1357.


Case 1

The patient is a 48-yr-old man with colorectal cancer that is EGFR positive and KRAS wild type. You opt to initiate treatment with cetuximab plus irinotecan


Based on the MASCC guidelines, which of the following strategies do you recommend for this pt to prevent acneiform rash during the first 1-6 wks of cetuximab therapy?

A. Topical hydrocortisone 1% cream with sunscreen and moisturizer twice daily

B. Topical tazarotene 0.05% cream daily

C. Systemic tetracycline

D. Systemic minocycline or doxycycline


Based on the MASCC guidelines, which of the following strategies do you recommend for this pt to prevent acneiform rash during the first 1-6 wks of cetuximab therapy?

A. Topical hydrocortisone 1% cream with sunscreen and moisturizer twice daily (level II, grade C)

B. Topical tazarotene 0.05% cream daily

C. Systemic tetracycline

D. Systemic minocycline or doxycycline (level II, grade A)

Doxycycline is preferred in patients with renal impairment

Minocycline is less photosensitizing and thus preferred in areas that have a high UV index


Acneiform Rash Management RecommendationsPreventive Recommended Not

RecommendedLevel of

EvidenceRecommend-ation Grades

Comments

TopicalHydrocortisone 1% cream with moisturizer, sunscreen twice

daily

Pimecrolimus 1% cream

Tazarotene 0.05% cream

Sunscreen as single agent

II* C

Systemic Minocycline 100 mg/day Doxycycline 100 mg BID

Tetracycline 500 mg BID

II* A Doxycycline is preferred in patients

with renal impairment; minocycline is less photosensitizing

Treatment Recommend Not Recommended

Level of Evidence

Recommend-ation Grades

Comments

TopicalAlclometasone 0.05% cream

Fluocinonide 0.05% cream BIDClindamycin 1%

Vitamin K1 cream

IV* C

Systemic Doxycycline 100 mg BID Minocycline 100 mg/day Isotretinoin at low doses

(20-30 mg/day)

Acitretin IV* C Photosensitizing agents

Lacouture ME, et al. Support Care Cancer. 2011;19:1079-1095.*EGFR inhibitor study.


Additional Dermatological Toxicities to EGFR Inhibitors: Xerosis Patients receiving EGFR inhibitors

> 6 mos (n = 16)

– Range on therapy (6-27 mos)

– Cutaneous toxicities in 100%

– Dose mod in 37.5%

Symptom, n (%) Any Grade

Xerosis 16 (100)

Paronychia 9 (56)

Alopecia 6/12 (50)

Hair Modifications 14 (87.5)

Xerotic Dermatitis

Fissures

Lacouture ME, et al. Br J Dermatol. 2006;155:852-854. Mitchell EP, et al. Oncology (Williston Park). 2007;21(11 suppl 5):4-9. Osio A, et al. Br J Dermatol. 2009;161:515-521.


Case 2

A 68-yr-old woman has been receiving maintenance erlotinib monotherapy for the treatment of metastatic non-small-cell lung cancer that responded to 4 cycles of first-line chemotherapy. Eight wks after initiating erlotinib, she presents with moderate xerosis on her back and shoulders


Case 2: Moderate Xerosis


Based on the MASCC guidelines, which of the following strategies do you recommend to treat this pt’s xerosis?

A. Benzoyl peroxide

B. Fragrance-free, occlusive, emollient creams packaged in a jar/tub

C. Alcohol-based lotions that can be pumped

D. Topical retinoids


Based on the MASCC guidelines, which of the following strategies do you recommend to treat this pt’s xerosis?

A. Benzoyl peroxide

B. Fragrance-free, occlusive, emollient creams packaged in a jar/tub (level III, grade B)

C. Alcohol-based lotions that can be pumped

D. Topical retinoids


Xerosis Management Recommendations

Preventive Recommended Not Recommended

Level of Evidence


Comments

Topical Bathing techniques using bath oils or mild moisturizing soaps

and bathing in tepid waterRegular moisturizing creams

III B

Other Avoid extreme temperatures and direct sunlight

III* B

Treatment Recommended Not Recommended

Level of Evidence


Comments

Topical (mild/moderate)

Emollient creams that are packaged in a jar/tub that lack fragrances or potential irritantsOcclusive emollients containing urea creams, colloidal oatmeal, and petroleum-based creams For scaly areas, ammonium lactate or lactic acid cream

Alcohol-containing

lotionsRetinoids or

benzoyl peroxide

III B More greasy creams for use on the limbs,

but caution use of greasy

creams on the face and chest

Topical (severe)

Medium- to high-potency steroid creams

III B


*EGFR inhibitor study.


Fissure Recommendations


Level of Evidence


Comments

Topical Wear protective footwear and avoid friction with fingertips, toes, and heels

III B


Level of Evidence


Comments

Topical Thick moisturizers or zinc oxide (13% to 40%) creams

Liquid glues or cyanoacrylate to seal cracks

Steroids or steroid tape, hydrocolloid dressings, topical antibiotics

Bleach soaks to prevent infection

Zinc oxide

III*† B Cream application

often impractical

*EGFR inhibitor study.†Non–EGFR inhibitor cancer treatment study.



Pruritus

Pruritus

– In 30% to 50%

– Decreased QoL

– Sleep deprivation

– Scratching and secondary infections

Haley AC, et al. Support Care Cancer. 2011;19:545-554.



Level of Evidence


Comments

Topical Gentle skin care instructions IV*† D Consensus of experts

Systemic Steroids IV*† D Consensus of experts


Level of Evidence


Comments

Topical Menthol 0.5% pramoxine, 1% doxepin Medium- to high-potency steroids

(triamcinolone acetonide 0.025%;, desonide 0.05%, fluticasone propionate 0.05%, alclometasone 0.05%)

III† B Treat underlying condition first (rash, xerosis)

Topical Antihistamines,lidocaine

II† C These agents can become allergens and can be

absorbed systemically

Systemic Antihistamines† I‡ A Nonsedating first; some may need adjustment for

renal impairment

Systemic Aprepitant* V* D

Systemic Gabapentin/pregabalin* V*† D Recommended as second-line treatment only

if antihistamines fail

Systemic Doxepin V* D

Pruritus Recommendations

*EGFR inhibitor study.†Non–EGFR inhibitor noncancer treatment study.‡Non-EGFR inhibitor cancer treatment study.



Symptom, n (%) Any Grade

Xerosis 16 (100)

Paronychia 9 (56)

Alopecia 6/12 (50)

Hair modifications 14 (87.5)

Additional Dermatologic Toxicities to EGFR Inhibitors: Paronychia Patients receiving EGFR inhibitors

> 6 mos (n = 16)

– Range on therapy (6-27 mos)

– Cutaneous toxicities in 100%

– Dose mod in 37.5%

Lacouture ME, et al. Br J Dermatol. 2006;155:852-854. Mitchell EP, et al. Oncology (Williston Park). 2007;21(11 suppl 5):4-9. Osio A, et al. Br J Dermatol. 2009;161:515-521.


Case 3

A 40-yr-old woman has been receiving panitumumab for the treatment of colorectal cancer. After 4 mos, she developed paronychia and periungual granulation tissue in her fingernails, which limits self-care activities of daily living


Case 3: Paronychia and Periungual Granulation Tissue


Based on the MASCC guidelines, which of the following strategies do you recommend to treat this pt’s paronychia?

A. Clobetasol ointment daily

B. Obtain bacterial cultures

C. Cephalexin therapy for 10 days

D. Nail avulsion


Based on the MASCC guidelines, which of the following strategies do you recommend to treat this pt’s paronychia?

A. Clobetasol ointment daily (level II, grade A)

B. Obtain bacterial cultures (level IV, grade D)

C. Cephalexin therapy for 10 days

D. Nail avulsion (level IV, grade D)


Paronychia Management RecommendationsPreventive Recommended Not Recommended Level of

EvidenceRecommend-ation Grades

Comments

TopicalDilute bleach baths

Avoid irritantsII* A Recommend final

concentration of ~ 0.005%‡

Treatment Recommended Not Recommended Level of Evidence


Comments

TopicalCorticosteroids

Calcineurin inhibitors

AntifungalsAntibiotics

II* A Recommend usage of ultrapotent topical steroids as first-line therapy given

cost and availability of these agents

Systemic TetracyclinesAntimicrobials:

reserved for culture proven infectionBiotin for brittle

nails

Empiric antibiotics, employed without

culturing lesional skinAntifungals

IV†/II*

III*

D/A

B

Other Silver nitrate chemical

cauterization wklyElectrodessication

Nail avulsion

IV* D Reserved for pyogenic granulomata;

consensus of experts

Lacouture ME, et al. Support Care Cancer. 2011;19:1079-1095.*Non-EGFR inhibitor noncancer treatment study. †EGFR inhibitor study. ‡Dilution: ~ 1/4-1/8 cup 6% bleach for 3-5 gal water.


Trichomegaly

Alopecia

Hirsutism

Corneal Erosion

Additional Dermatologic Toxicities With EGFR Inhibitors: Hair Changes Pts receiving therapy > 3 mos

– Scalp alopecia and hair curling

– Hirsutism on face

– Eyelash trichomegaly

Lacouture ME, et al. Br J Dermatol. 2006;155:852-854. Roe E, et al. J Am Acad Dermatol. 2006;55:429-437. Vano-Galvan S, et al. J Am Acad Dermatol. 2010;62:531-533. Kerob D, et al. Arch Dermatol. 2006;142:1656-1657. Foerster CG, et al. Cornea. 2008;27:612-614.


Hair Changes Recommendations

Recommended Not Recommended

Level of Evidence


Comments

Preventive hair loss

Topical For scarring alopecia, follow rash recommendations

Preventive interventions for nonscarring alopecia

V D

Systemic For scarring alopecia, follow rash recommendations

Preventive interventions for nonscarring alopecia

V D

Treatment for hair loss

Topical Nonscarring • Minoxidil 2%, 5% BID

Scarring • Class 1 steroid lotion,

shampoo, or foam• Antibiotic lotion

I*/II/III/IV† B/D Consensus of experts

Preventive increased hair

Patient education and support IV B Consensus of experts

Treatment for increased hair

Facial hypertrichosis

Eflornithine Lasers

Waxing, chemical depilatories

IV,† II* B Consensus of experts

Eyelash trichomegaly

Eyelash trimmings regularly IV B

*Non–EGFR inhibitor noncancer treatment study.†EGFR inhibitor study.



Eilers RE, et al. J Natl Cancer Inst. 2010;102:47-53. Hill A, et al. Am J Clin Oncol. 2004;27:361-363.

Enterococcal Cellulitis

Radiation Dermatitis ImpetigoDermatologic Infections With EGFR Inhibitors S aureus infection in grade 3/4 radiation

dermatitis EGFR inhibitor treated pts: 38% with

infections– Severe radiation dermatitis: 10/14

S aureus+

In oncology, SSTI may result in bacteremia– Skin and mucosa entry in 64%; 16%

mortality

Analysis conducted of 221 pts treated with EGFR inhibitors– 38% with bacterial, viral, fungal

– Higher risk in leukopenic patients (P < .05)


Conclusions

Skin toxicities during EGFR inhibitor therapy are amenable to study and treatment

Early/proactive approach toward toxicities is advisable

Characterization of dermatologic toxicities will increase in importance

– Adjuvant setting

– Dose escalation and combination studies

– Longer survival


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Mario E. Lacouture, MD Associate Attending Department of Medicine Memorial Sloan-Kettering Cancer Center New York, New York EGFR Inhibitor–Related Dermatologic