Update on Nursing Management of Cancer Therapy-Related Dermatologic Toxicities Victoria Sherry, DNP, CRNP, AOCNP ® Oncology Nurse Practitioner Abramson Cancer Center Hospital of the University of Pennsylvania
Update on Nursing Management of Cancer Therapy-Related Dermatologic Toxicities
Victoria Sherry, DNP, CRNP, AOCNP®
Oncology Nurse PractitionerAbramson Cancer Center
Hospital of the University of Pennsylvania
Disclosures
Dr. Sherry has no relevant financial relationships to disclose.
Learning Objectives
Distinguish current clinical applications for novel targeted therapies and immunotherapies in cancer
Describe appropriate grading of dermatologic toxicities associated with novel targeted therapies and immunotherapies
Apply evidence-based treatment strategies for dermatologic toxicities associated with novel targeted therapies and immunotherapies
Targeted Therapies and Immunotherapies
Cancer treatment is moving away from traditional chemotherapy
Treatment is increasingly tailored to individual patients Age, performance status, comorbidities Tumor biology and genetics
Patients are now living longer with incurable malignancies
What is targeted therapy?
A drug with a focused mechanism that specifically acts on a well-defined target or biologic pathway, which when inactivated causes regression or destruction of the malignant process
Administered as a single agent or in combination with chemotherapy, radiation, or immunotherapy
Approved for multiple tumor types
How does targeted therapy work?
YY
LigandReceptor
Cell Signaling
Cancer Cell Cancer Cell
Cell SignalingPrevented
Antibody
X
Signal Transduction Molecular Pathways
Maione et al, 2006.
RasRaf1
MEKERK
PI3K
Akt
mTOR
• Cell cycle• CDK and
gene transcription
• Cell Cycle• Cell growth
mRNA translati
on
P
P
P
P
Tyrosine Kinase
Activation
ErbB familyEGFR, HER2/neu
PDGFR, c-KIT
IGFR, cytokines, etc
Phospholipids
Extracellular Signals
Cell Membrane
Intracellular Signals
Turnover/degradation by ubiquitin-proteasome pathway (molecular chaperone: HSP-90)
What is immunotherapy?
The immune system plays a critical role in identifying and destroying cancer cells in the body but has trouble recognizing them due to tumor-induced immune suppression
Tumors use numerous strategies to avoid recognition of the immune system enabling them to grow and spread unrestrained: Conditioning the immune system through induced
immunosuppression Adaptation to immune recognition by altering expression of surface
markers
Swann & Smyth, 2007; Stewart & Smyth, 2011.
What is immunotherapy? (cont.)
Immunotherapy is the clinical application of pharmacological agents that directly induce or substitute for host antitumor immunity
Therapies designed to enhance the immune system identify and destroy tumor cells include: cytokines, monoclonal antibodies, cancer vaccines and coinhibitory receptor blockade (immune checkpoint inhibitors)
Swann & Smyth, 2007; Stewart & Smyth, 2011.
How does the immune system work?
Dunn et al, 2007.
How does immunotherapy work?
TCR = T-cell receptor; MHC = major histocompatibility complex; APC = antigen-presenting cell; Ag = antigen.Pardoll, 2014.
Types of Targeted Therapy
VEGF = vascular endothelial growth factor; BCR-ABL = breakpoint cluster Abelson; HNSCC = head and neck squamous cell carcinoma; HCC = hepatocellular carcinoma; RCC: renal cell carcinoma; GIST = gastrointestinal stromal tumor; CML = chronic myelogenous leukemia; ALL = acute lymphoblastic leukemia; MDS = myelodysplastic syndromes.
Therapy Agent Indication
EGFR inhibitors
Erlotinib GefitinibAfatinibCetuximabLapatinibPanitumumab NecitumumabOsimertinib
Lung, pancreaticLungLungHNSCCBreastColonLungLung
VEGF inhibitors
SorafenibSunitinibVandetinibPazopanibAxitinib
HCC, RCC, thyroidGIST, pancreatic, RCCThyroidRCCRCC
c-MET inhibitors Cabozantinib RCC
Types of Targeted Therapy (cont.)Therapy Agent Indication
BCR-ABL inhibitors
ImatinibDasatinibNilotinib
CML, ALL, MDS, GISTCML, ALLCML
BRAF inhibitors VemurafenibDabrafenib
MelanomaMelanoma
mTOR inhibitorsTemsirolimusEverolimus
RCCBreast, RCC, brain, neuroendocrine, carcinoid
MEK inhibitors TrametinibCobimetinib
MelanomaMelanoma
Types of Immunotherapy
Therapy Agent Indication
PD-1 inhibitorsPembrolizuma
bNivolumab
Melanoma, lung, SCCHN, Merkel cell carcinoma
PD-L1 inhibitors Atezolizumab Melanoma, lung, Hodgkin lymphoma, RCC, SCCHN
CTLA-4 inhibitors Ipilimumab Lung, urothelial cancer,melanoma
Dermatologic Toxicities
Targeted therapies: Approximately 50% to 90% of patients will experience
dermatologic toxicities that affect the skin, hair, and nails Immunotherapies:
CTLA-4 inhibitors: 50% of patients will develop dermatologic toxicity any grade; 2.4% grade 3/4
PD-1 inhibitors: 25.4 % of patients will develop dermatologic toxicity; 40.3% of those who receive an anti-CTLA-4 and anti-PD-L1 combination
Petrou, 2015; Larkin et al, 2015; Minkis et al, 2013; Yervoy® prescribing information, 2015.
How Do Dermatologic Toxicities Affect Patient Outcomes?
Dose reductions Treatment delays
Decreased overall survival Hospitalizations Death
QOL = quality of life; ADL = activities of daily living.Lacouture et al, 2008.
Decreased QOL Impaired ADL and social
functioning
Grading Adverse Events: NCI-CTCAE
Instrumental ADL: preparing meals, shopping for groceries or clothes, using the telephone, managing money
Self-care ADL: bathing, dressing and undressing, feeding, using the toilet, taking medications
NCI, 2010.
Grade 1 Grade 2 Grade 3 Grade 4 Grade 5
Mild ModerateSevere or Medically Significant but not
Immediately Life-Threatening
Life-Threatening
ConsequencesDeath
• Asymptomatic or mild symptoms• Clinical or
diagnostic observations only• Intervention not
indicated
• Minimal, local, or noninvasive intervention indicated
• Limiting age-appropriate instrumental ADL
• Hospitalization or prolongation of hospitalization indicated
• Disabling• Limiting self-care ADL
• Urgent intervention indicated
• Death related to adverse event
NCI-CTCAE Grading Scales for IndividualSkin and Subcutaneous Tissue Disorders
Alopecia Body odor Bullous dermatitis Dry skin Erythema multiforme Fat atrophy Hirsutism Hyperhidrosis Hypertrichosis Hypohidrosis Lipohypertrophy
Nail discoloration Nail loss Nail ridging Pain of skin Palmar-plantar
erythrodysesthesia syndrome Periorbital edema
NCI, 2010.
NCI-CTCAE Grading Scales for IndividualSkin and Subcutaneous Tissue Disorders (cont.)
Photosensitivity Pruritus Purpura Rash acneiform Rash maculopapular Scalp pain Skin atrophy Skin hyperpigmentation Skin hypopigmentation Skin induration Skin ulceration
Stevens-Johnson syndrome Telangiectasia Toxic epidermal necrolysis Urticaria Skin and subcutaneous tissue
disorders - other
NCI, 2010.
Grade 1 Grade 2 Grade 3 Grade 4 Grade 5
Rash acneiformaPapules and/or pustules covering <10% BSA, which may or may not be associated with symptoms of pruritus or tenderness
Papules and/or pustules covering 10-30% BSA, which may or may not be associated with symptoms of pruritus or tenderness; associated with psychosocial impact; limiting to instrumental ADL
Papules and/or pustules covering >30% BSA, which may or may not be associated with symptoms of pruritus or tenderness; limiting self-care ADL; associated with local superinfection, with oral antibiotics indicated
Papules and/or pustules covering any % BSA, which may or may not be associated with symptoms of pruritus or tenderness and are associated with extensive superinfection with IV antibiotics indicated; life-threatening consequences
Death
NCI-CTCAE: Rash
aA disorder characterized by an eruption of papules and pustules, typically appearing on face, scalp, upper chest, and back.BSA = body surface area; IV = intravenous.NCI, 2010.
Dermatologic Toxicities: VEGF Inhibitors
Nexavar® prescribing information, 2013; Sutent® prescribing information, 2015; Votrient® prescribing information, 2015; Inlyta® prescribing information, 2014; Caprelsa® prescribing information, 2016; Schmidinger, 2013; Massey et al, 2015; Balagula & Lacouture, 2011.
Sorafenib Sunitinib Pazopanib Axitinib Vandetanib
Rash 19-40%(Gr 3/4: <1-5%)
14-29%(Gr 3/4: 0-2%)
8-18%(Gr 3/4: <1%)
13% (Gr 3/4: <1%)
53% (Gr 3/4: 5%)
Pruritus 14-20%(Gr 3/4: 0.5-1%)
12%(Gr 3/4: <1%)
7% (Gr 3/4: 0%)
11% (Gr 3/4: 1%)
HFSR 51% (Gr 3/4: 16%)
50% (Gr 3/4: 4-8%)
6-11%(Gr 3/4: 1-2%)
27% (Gr 3/4: 5%)
Xerosis 10-13%(Gr 3/4: 0-0.5%)
15-23%(Gr 3/4: <1%)
10% (Gr 3/4: 0%)
15% (Gr 3/4: 0%)
Hair color changes 20-29%(Gr 3/4: 0-1%)b
38-39%(Gr 3/4: <1%)
Alopecia 14-67% (Gr 3/4: <1%)
8-12%(Gr 3/4: 0%)
4% (Gr 3/4: 0%)
8% (Gr 3/4: 0%)
Skin hypopigmentation
11%(Gr 3/4: 0%)
Dermatologic Toxicities: EGFR Inhibitors
Tafinlar® prescribing information, 2016; Zelboraf® prescribing information, 2016; Larkin et al, 2014; Mekinist® prescribing information, 2015; Balagula et al, 2010; Lynch et al, 2007; Miller et al, 2012.
Gefitinib Erlotinib Cetuximab Panitumumab Lapatinib
Necitumumab (+
Gem/Cisp)Osimertinib Afatinib
Papulopustular rash
47%(Gr 3/4: 2%)
76%(Gr 3/4: 9%)
90%(Gr 3/4: 10%)
57%(Gr 3/4: 7%)
47%(Gr 3/4: 3%)
15%(Gr 3/4: 1%)
41%(Gr 3/4: 0.5%)
78% (Gr 3/4: 14%)
Trichomegaly 11%(Gr 3/4: 6%)
12%(Gr 3/4: 5%)
6%(Gr 3/4: N/A) <1%
Paronychia 10-15% 14%(Gr 3/4: N/A)
14% (Gr 3/4: 0.3%)
25% (Gr 3/4: 2%)
<1%(Gr 3/4: <1%)
7%(Gr 3/4: 0.4%)
25%(Gr 3/4: 0%)
58%(Gr 3/4: 11%)
Mucosal involvement
19%(Gr 3/4: <1%)
11%(Gr 3/4: <1%)
6%(Gr 3/4: <1%)
44%(Gr 3/4: <0%)
11%(Gr 3/4: 1%)
12%(Gr 3/4: 0%)
Pruritus8%(Gr 3/4: <1%)
13%(Gr 3/4: <1%)
11%(Gr 3/4: 1%)
57%(Gr 3/4: 2%)
3%(Gr 3/4: N/A)
7%(Gr 3/4: 0.2%)
41%(Gr 3/4: 0%)
Dermatologic Toxicities: BRAF + MEK Inhibitors
SCC = squamous cell carcinoma.Tafinlar® prescribing information, 2016; Zelboraf® prescribing information, 2016; Larkin et al, 2014; Mekinist® prescribing information, 2015; Peuvrel & Dreno, 2014.
Dabrafenib Vemurafenib Dabrafenib + Trametinib
Vemurafenib + Cobimetinib Trametinib
Rash 27% (Gr 3/4: 1.4%)
37% (Gr 3/4: 8%)
32% (Gr 3/4: 1.1%)
33% (Gr 3/4: 6%)
57%(Gr 3/4: 8%)
Alopecia 45% (Gr 3/4: <1%)
Hyperkeratosis 37% (Gr 3/4: 1%)
24% (Gr 3/4: 1%)
10%(Gr 3/4: 0%)
Pruritus 23% (Gr 3/4: 1%)
10%(Gr 3/4: 2%)
Xerosis 16% (Gr 3/4: 0%)
19% (Gr 3/4: 0%)
10%(Gr 3/4: 0%)
11%(Gr 3/4: 0%)
Photosensitivity
33% (Gr 3/4: 3%)
46% (Gr 3/4: 4%)
Cutaneous SCC 7%(Gr 3/4: 4%)
24% (Gr 3/4: 22%)
6% (Gr 3/4: 6%)
Dermatologic Toxicities: c-MET Inhibitors
Cabometyx® prescribing information, 2016.
Cabozantinib
Palmar-plantar erythrodysesthesia syndrome 42% (Gr 3/4: 8%)
Rash 23% (Gr 3/4: <1%)
Xerosis 11% (Gr 3/4: 0%)
Dermatologic Toxicities: mTOR Inhibitors
Afinitor® prescribing information, 2016; Torisel® prescribing information, 2016; Peuvrel & Dreno, 2014.
Everolimus Temsirolimus
Rash29-59% (Gr 3/4: 0.5-1%)
47% (Gr 3/4: 5%)
Pruritus 13-21% (Gr 3/4: 0-1%)
19% (Gr 3/4: 1%)
Xerosis 13% (Gr 3/4: <1%)
11% (Gr 3/4: 1%)
Nail disorder 14% (Gr 3/4: 0%)
Dermatologic Toxicities: BCR-ABL Inhibitors
Gleevec® prescribing information, 2016. Sprycel® prescribing information, 2016; Pretel-Irazabal et al, 2014; Tasigna® prescribing information, 2016.
Imatinib Dasatinib Nilotinib
Rash 19% (Gr 3/4: 2%)
18% (Gr 3/4: 2%)
38% (Gr 3/4: <1%)
Hypopigmentation 41%
Pruritus 7% (Gr 3/4: 0%)
12% (Gr 3/4: 2%)
21% (Gr 3/4: <1%)
Xerosis 6% (Gr 3/4: 0%)
12% (Gr 3/4: 0%)
Alopecia 7% (Gr 3/4: 0%)
13% (Gr 3/4: 0%)
Dermatologic Toxicities: Immunotherapies
Opdivo® prescribing information, 2016; Keytruda® prescribing information, 2016; Yervoy® prescribing information, 2015; Tecentriq® prescribing information, 2016; Larkin et al, 2015; Bristol Myers-Squibb, 2016.
Nivolumab Pembrolizumab Ipilimumab Atezolizuma
b
Pruritus
23% (Gr 3/4: 0.5%)
28% (Gr 3/4: 0%)
31-45% (Gr 3/4: 0-2.3%)
13% (Gr 3/4: 0.3%)
Rash 28% (Gr 3/4: 1.5%)
24% (Gr 3/4: 0.2%)
29-50% (Gr 3/4: 2%)
13% (Gr 3/4: 0.3%)
Vitiligo 11% (Gr 3/4: 0%)
13% (Gr 3/4: 0%)Combination Therapy Nivolumab + Ipilimumab
Rash 53% (Gr 3/4: 4.8%)
Is there a correlation between dermatologic toxicities and clinical benefit of
targeted therapies and immunotherapies?
Dermatologic Toxicities and Response to Therapy
EGFR: Liu and colleagues (2013) reviewed 33 studies on EGFR TKIs and demonstrated a correlation between rash and clinical benefit Rash was a significant predictor of clinical benefit for NSCLC
patients receiving EGFR inhibitor therapy Rash predicted overall response rate, longer PFS, and longer OS
BRAF: No literature MEK: No literature mTOR: No literature BCR-ABL: No literature
TKIs = tyrosine kinase inhibitors; PFS = progression-free survival; OS = overall survival. Liu et al, 2013; Strumberg et al, 2006; Zheng et al, 2015; Rini et al, 2013; Sanlorenzo et al, 2015.
Dermatologic Toxicities and Response to Therapy (cont.)
VEGF: Patients who experienced skin toxicity while receiving sorafenib
gained significantly more benefit than those without toxicity. Rash and diarrhea are independent protective factors of both PFS and OS
PD-1/CTLA-4: The development of cutaneous adverse events, especially of
vitiligo, in patients affected by melanoma has been shown to be indicative of better treatment response– Skin reactions during pembrolizumab therapy associated with longer PFS– Patients with skin reactions received more treatment cycles
Liu et al, 2013; Strumberg et al, 2006; Zheng et al, 2015; Rini et al, 2013; Hua et al, 2016;Sanlorenzo et al, 2015.
Management of Dermatologic Toxicities
Papulopustular Rash
Photos courtesy of Victoria Sherry, DNP, CRNP, AOCNP®.Lacouture et al, 2011.
Papulopustular Rash Management
National Comprehensive Cancer Network Guidelines Created by task force of experts including oncologists,
dermatologists, an ophthalmologist, and nurse practitioners Few recommendations are evidence-based; most are anecdotal
Multinational Association of Supportive Care in Cancer Guidelines International, interdisciplinary group of experts in dermatology,
medical and supportive oncology, health-related QOL, and pharmacovigilance
Based on nononcology dermatologic trial data as well as oncology trials
Rash: NCCN Recommendations for Prophylactic/Mitigating Treatments
Prophylactic/mitigating treatments (ie, to decrease the severity of rash) Tetracycline antibiotics: minocycline, doxycycline, tetracycline
Not recommended (based on anecdotal or nonrandomized studies) Retinoids: isotretinoin (problem with paronychia), acitretin
Reactive treatment for infection Bacterial culture essential, especially around nose, abscesses, and
pustules on body Antistaphylococcal antibiotics: cephalexin, dicloxacillin Antimethicillin-resistant Staphylococcus aureus antibiotics:
sulfamethoxazole/trimethoprim, linezolid
Burtness et al, 2009.
Rash: MASCC Recommendations for Prevention
Lacouture et al, 2011.
Schedule for Weeks 1–6, 8 of EGFR Inhibitor Initiation
Recommended Not Recommended Comments
TopicalHydrocortisone 1% cream with moisturizer and sunscreen twice daily
Pimecrolimus 1% creamTazarotene 0.05% creamSunscreen as a single agent
38% (Gr 3/4: <1%)
Systemic
Minocycline 100 mg dailyDoxycycline 100 mg twice daily
Tetracycline 500 mg twice daily
Doxycycline is preferred in patients with renal impairment; minocycline is less photosensitizing
Rash: MASCC Recommendations for Treatment
Lacouture et al, 2011.
Recommended Not Recommended Comments
TopicalAlclometasone 0.05% creamFluocinonide 0.05% twice dailyClindamycin 1%
Vitamin K1 cream
Systemic
Doxycycline 100 mg twice dailyMinocycline 100 mg dailyIsotretinoin at low doses 20-30 mg/d
Acitretin Photosensitizing agents
Maculopapular Rash
Photo courtesy of Victoria Sherry, DNP, CRNP, AOCNP®.Lacouture, 2012.
Treatment: Topical corticosteroids Antihistamines
– Grade 1: topical– Grade 2/3: oral
Maculopapular Rash
Photos courtesy of Victoria Sherry, DNP, CRNP, AOCNP®.
Nail Changes Paronychia, slow growth, onycholysis, and fragile
and brittle nails
Photo courtesy of Victoria Sherry, DNP, CRNP, AOCNP®.
Paronychia Management
Lacouture et al, 2011.
Treatment Recommended Not
Recommended Comments
Topical
Other
Diluted bleach soaks
Not cutting the nails flushAvoiding skin trauma associated with manual work or wearing tight shoesWearing gloves when handling skin irritants
Recommend final concentration of approximately 0.005% (approximately 1/4-1/8 cup of 6% bleach for 3-5 gal water)
Topical Corticosteroids
Calcineurin inhibitors
Antifungals
Antibiotics
Recommend usage of ultrapotent topical steroids as first-line therapy given cost and availability of these agents
Paronychia Management (cont.)Treatment Recommended Not Recommended Comments
Systemic• Tetracyclines• Antimicrobials:
reserved for culture proven infection
• Biotin for brittle nails
• Empiric antibiotics-employed without culturing lesional skin
• Antifungals
Other
• Silver nitrate chemical cauterization weekly
• Electrodessication• Nail avulsion
Reserved for pyogenic granulomata
Topical • Corticosteroids• Calcineurin inhibitors
• Antifungals• Antibiotics
Recommend usage of ultra potent topical steroids as first-line therapy given cost and availability of these agents
Lacouture et al, 2011.
Recommended Not Recommended
Hair loss
Nonscarring:• Minoxidil 2%, 5%
bidScarring:• Class 1 steroid
lotion, shampoo, or foam
• Antibiotic lotionFacial hypertrichosis (hirsutism)
• Eflornithine• Lasers
Waxing, chemical depilatories
Eyelash trichomegaly
• Eyelash trimmings regularly
Photos courtesy of Victoria Sherry, DNP, CRNP, AOCNP®.
Management of Hair Changes
Pruritus Management
Lacouture et al, 2011; Santini et al, 2012.
Recommended Not Recommended Comments
Preventative
Topical Gentle skin care instructions
Systemic • SteroidsTreatment
Topical• Menthol 0.5%• Pramoxine 1%• Doxepin
• Antihistamines• Lidocaine
Nonsedating antihistamine first; some may need adjustment for renal impairment
Systemic• Antihistamines• Gabapentin/pregabalin• Doxepin• Aprepitant
Recommended as second-line treatment only if antihistamines fail
Xerosis Management
No evidence-based guidelines; recommendations from experts
Photo credit: Rash Resource.Lacouture et al, 2011; Bensadoun et al, 2013.
Xerosis Management (cont.)Recommended Not Recommended Comments
Preventive
Topical Bathing techniques using bath oils or mild moisturizing soaps and bathing in tepid water
Regular moisturizing creams
None
Other Avoid extreme temperatures and direct sunlight
TreatmentTopical (mild/moderate)
Emollient creams that are packaged in a jar/tub that lack fragrances or potential irritants
None
Topical (severe)Lacouture et al, 2011.
Xerosis Management (cont.)Treatme
nt Recommended Not Recommended Comments
Topical (mild/moderate)
• Emollient creams that are packaged in a jar/tub that lack fragrances or potential irritants
• Occlusive emollients containing urea, colloidal oatmeal, and petroleum-based creams
• For scaly areas, use exfoliants: ammonium lactate 12% or lactic acid cream 12%
• Urea creams (10-40%)• Salicylic acid 6%• Zinc oxide (13-40%)
• Alcohol-containing lotions
• Retinoids or benzoyl peroxide
More greasy creams for use on the limbs, but caution use of greasy creams on the face and chest
Exfoliants may sting or burn when applied to eroded or erythematous skin—apply only on intact skin
Topical (severe)
Medium-to-high-potency steroid creams (triamcinolone acetonide 0.025%; desonide 0.05%; fluticasone proprionate 0.05%; alclometasone 0.05%)
Lacouture et al, 2011.
Hand-Foot Skin Reaction
ESMO, 2014; Weitzman & Cabanillas, 2015.
HFSR Prophylaxis
Pedicure before treatment to remove hyperkeratosis Reduce the exposure of their hands and feet to hot water Emollients (topical exfoliating products: urea-based and
salicylic acid-based) Protection of pressure-sensitive areas (eg, shoes with soft
insoles)
HFSR = hand-foot skin reaction.Lacouture et al, 2008; Schmidinger, 2013.
HFSR Prophylaxis (cont.)
Avoid excessive friction on the skin when applying lotion, during massages, or in the process of everyday tasks, such as typing
Vigorous exercise or activities that place undue stress on the hands and feet should also be avoided, especially during the first month
Thick cotton gloves or socks can be worn to prevent injury and keep palms and soles dry
Lacouture et al, 2008; Schmidinger, 2013.
No HFSR Maintain frequent contact with physician/advanced practice provider to ensure early diagnosis of HFSR
Therapy initiationFull-body skin exam, pedicure, evaluation by orthotist; wear thick cotton gloves and/or socks; avoid hot water,
constrictive footwear, and excessive friction
If symptoms develop at 2-week clinical evaluation or within first month, proceed to next step
HFSR Severity Intervention
MKI = multikinase inhibitor.Lacouture et al, 2008.
Management of MKI-Associated HFSR
Grade 1 Maintain current dose of MKI; monitor for change in severity
• Numbness• Tingling• Dysesthesia• Paresthesia• Painless swelling• Erythema• Discomfort of hand or feet• No interference in ADL
Avoid hot water; use moisturizing creams for relief; wear thick cotton gloves and/or socks; 30%-40% urea
If symptoms worsen after clinical evaluation at 2 weeks, proceed to next step
HFSR Severity Intervention
Management of MKI-Associated HFSR (cont.)
Lacouture et al, 2008.
Grade 2 Dose reduction to 50% of dose for 7-28 days
• Painful erythemas• Swelling of hands
and/or feet• Interferes with
patient’s ADL
Treat as with grade 1 toxicity, with the following additions: clobetasol 0.05% ointment, 2% lidocaine, codeine,
pregabalin for pain
If symptoms worsen after clinical evaluation at 2 weeks, proceed to next step
HFSR Severity Intervention
Management of MKI-Associated HFSR (cont.)
Lacouture et al, 2008.
Grade 3 Interrupt treatment for 7 days and until improvement to grade 0-1
• Moist desquamation• Ulceration• Blistering• Severe pain of hands
and/or feet• Patient unable to
perform ADL
Treat as with grades 1 or 2
HFSR Severity Intervention
Management of MKI-Associated HFSR (cont.)
Lacouture et al, 2008.
Photosensitivity Management
No evidence-based guidelines; recommendations from experts
Prophylaxis: Strict photoprotection, including behind windows Clothing and sunscreen with both anti-UVB and UVA filters Sunscreen SPF >30 (UVB) plus 5 (UVA) rating
Treatment: Emollients
Peuvrel & Dreno, 2014; Welsh & Corrie, 2015.
Hyperkeratosis Management
Includes papillomas, cysts, keratoacanthomas (KA), and cutaneous SCC
Treatment: KA and cutaneous SCC should
be removed for histological analysis
When the lesions are too numerous, KA may be destroyed by liquid nitrogen application
Photo credit: Medical Treasure.Peuvrel & Dreno, 2014; Welsh & Corrie, 2015.
Case Study 1: Targeted Therapy
52-year-old Asian man presented with RUQ pain and unexplained weight loss. On physical examination found to be jaundiced
Diagnosed with HCC Deemed inoperable due to extrahepatic disease Treatment plan: sorafenib 400 mg twice daily without
food
RUQ = right upper quadrant.
Case Study 1: Targeted Therapy (cont.)
Prior to beginning therapy, which prophylactic measures would you discuss with this patient? Pedicure before treatment to remove hyperkeratosis Using tepid versus hot water when washing Using emollients Wearing shoes with soft insoles Avoiding excessive friction on the hands and feet Wearing thick cotton gloves or socks to prevent injury and keep
palms and soles dry
Case Study 1: Targeted Therapy (cont.)
Patient begins therapy; when he arrives for his 2-week toxicity evaluation, he presents with grade 2 HFSR
Photo courtesy of Victoria Sherry, DNP, CRNP, AOCNP®.
NCI-CTCAE: HFSR
NCI, 2010.
Adverse Event Grade 1 Grade 2 Grade 3 Grade 4
Grade 5
HFSR
Minimal skin changes or dermatitis (eg, erythema, edema, or hyperkeratosis) without pain
Skin changes (eg, peeling, blisters, bleeding, edema, or hyperkeratosis) with pain; limiting instrumental ADL
Severe skin changes (eg, peeling, blisters, bleeding, edema, or hyperkeratosis) with pain; limiting self care ADL
– –
HFSR definition: A disorder characterized by redness, marked discomfort, swelling, and tingling in the palms of the hands or the soles of the feet
Case Study 1: Targeted Therapy (cont.)
Patient is started on clobetasol 0.05% ointment, 2% lidocaine, and pregabalin for pain. Treatment remains at 400 mg twice daily
Patient is re-evaluated in clinic 1 week later and his HFSR is worse (grade 3) despite interventions
Cuesta et al, 2011; Lacouture et al, 2008.
Case Study 1: Targeted Therapy (cont.)
What is the next step? Treatment is held until HFSR resolves to a grade 0/1 2 weeks later, patient is able to restart sorafenib at 400
mg daily. Remains on this dose with a good response for several months with no recurrence of HFSR
Lacouture et al, 2008.
Case Study 2: Immunotherapy
68-year-old woman with newly diagnosed metastatic melanoma is started on nivolumab + ipilimumab
No prophylactic treatment is recommended for dermatologic side effects; however, timely recognition is vital for successful management
Case Study 2: Immunotherapy (cont.)
After 6 weeks of therapy, patient calls the clinic with complaints of a pruritic rash
Physical examination reveals a reticular, maculopapular, faintly erythematous rash on the trunk and extremities
NCI-CTCAE: grade 2
Photo courtesy of Victoria Sherry, DNP, CRNP, AOCNP®.
Case Study 2: Immunotherapy (cont.)
The patient was prescribed topical corticosteroid cream (betamethasone 0.1% cream) and an oral antipruritic (eg, hydroxyzine, diphenhydramine)
1 week later, there is no improvement. The rash/pruritus now covers 30% of her body and is affecting her ADL (she is unable to sleep at night, embarrassed to go to social events)
Prednisone (0.5-1 mg/kg/day) is added and nivolumab + ipilimumab is held until her symptoms are mild to resolved
Villadolid & Amin, 2015.
Case Study 3: Sequential Targeted Therapy
51-year-old never-smoking woman presents with persistent cough and pain in her lower back
Chest x-ray and computed tomography scan of chest reveal a large right-upper-lobe lung mass with hilar adenopathy
Magnetic resonance imaging scan of the lumbar spine reveals L2–L3 metastases
Biopsy from bronchoscopy reveals adenocarcinoma of the lung, and molecular testing is positive for exon 21 (L858R) EGFR mutation
Case Study 3: Sequential Targeted Therapy (cont.)
Treatment plan is to start her on erlotinib 150 mg/d on an empty stomach
Dermatologic adverse events: 89% any grade rash, 16% grade 3/4 rash
Initiate prophylactic treatment with hydrocortisone 1% cream + moisturizer and sunscreen twice daily
Janjigian et al, 2011.
Case Study 3: Sequential Targeted Therapy (cont.)
2 weeks into treatment, patient presents with a grade 3 papulopustular rash on her face, chest, and back
Recommendation is to withhold erlotinib and treat rash with topical clindamycin 1% gel and oral minocycline 100 mg twice daily
Patient education: Avoid hot water; wear sunscreen and protective clothing when in the sun; keep skin moisturized with emollient
Photos courtesy of Victoria Sherry, DNP, CRNP, AOCNP®.
Case Study 3: Sequential Targeted Therapy (cont.)
4 months into therapy the patient develops hair thinning and trichomegaly
Treatment recommendations: Minoxidil twice daily and
oral biotin 5 mg daily Trim eyelashes carefully!
Photo courtesy of Barbara Burtness, MD.
Future Directions in the Management of Cancer Therapy-Related Dermatologic
Toxicities Conducting well-controlled clinical trials to evaluate agents used to treat dermatological toxicities is essential to create evidence-based guidelines
Establishing whether a rash can improve the efficacy of these agents (ie, BRAF, MEK, mTOR) as this could be a potent tool to ensure that patients have maximum benefit
Taking a multidisciplinary approach when treating dermatologic toxicities by integrating dermatologists into the care of cancer patients
Key Takeaways
Novel targeted therapies and immunotherapies have changed the landscape of cancer treatment; however, they are associated with distinctive dermatologic toxicities that can impair QOL and patient outcomes
Early identification and prompt treatment is essential to maximize benefit and maintain a favorable QOL
Dermatologic toxicity can be a predictor of clinical benefit with some targeted agents and immunotherapies
References
Afinitor® (everolimus) prescribing information (2016). Novartis Pharmaceuticals. Available at: https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/afinitor.pdf
Balagula Y, Lacouture ME, & Cotliar JA (2010). Dermatologic toxicities of targeted anticancer therapies. J Support Oncol, 8(4):149-161.Balagula Y & Lacouture ME (2011). Dermatologic Toxicities. The MASCC Textbook of Cancer Supportive Care and Survivorship. 1st Edition.
Springer International Publishing: 361-380.Bensadoun RJ, Humbert P, Krutman J, et al (2013). Daily baseline skin care in the prevention, treatment, and supportive care of skin toxicity
in oncology patients: Recommendations from a multinational expert panel. Cancer Manag Res, 5:401-408. DOI: 10.2147/CMAR.S52256Bristol-Myers Squibb (2016). Opdivo® (nivolumab) and Yervoy® (ipilimumab) combination regimen shows clinically meaningful responses in
first-line advanced non-small cell lung cancer, in updated phase 1b study CheckMate-12. Available at: http://investor.bms.com/investors/news-and-events/press-releases/press-release-details/2016/Opdivo-nivolumab-and-Yervoy-ipilimumab-Combination-Regimen-Shows-Clinically-Meaningful-Responses-in-First-Line-Advanced-Non-Small-Cell-Lung-Cancer-In-Updated-Phase-1b-Study-CheckMate--012/default.aspx
Burtness B, Anadkat M, Basti S, et al (2009). NCCN Task Force Report: management of dermatologic and other toxicities associated with EGFR inhibition in patients with cancer. J Natl Compr Canc Netw, 7(Suppl 1):S5-S21.
Cabometyx® (cabozantinib) prescribing information (2016). Exelixis. Available at: https://www.cabometyx.com/downloads/CABOMETYXUSPI.pdf
Caprelsa® (vandetanib) prescribing information (2016). AstraZeneca. Available at: http://www.caprelsa.com/files/caprelsa-pi.pdfCuesta L, Betlloch I, Toledo F, et al (2011). Letter: severe sorafenib-induced hand-foot skin reaction. Dermatol Online J, 17(5):14. Dunn GP, Old LJ, & Schreiber RD (2004). The immunobiology of cancer immunosurveillance and immunoediting. Immunity, 21(2):137-148.European Society for Medical Oncology (2014). Skin changes – hand-foot skin reaction. Available at: http://oncologypro.esmo.org/Guidelines-
Practice/Multikinase-Inhibitor-Related-Skin-Toxicity/Healthcare-Professionals/Symptoms-and-Grading/Skin-Changes/Hand-Foot-Skin-Reaction
Gleevec® (imatinib mesylate) prescribing information (2016). Novartis Pharmaceuticals. Available at: https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/gleevec_tabs.pdf
Hua C, Boussemart L, Mateus C, et al (2016). Association of vitiligo with tumor response in patients with metastatic melanoma treated with pembrolizumab. JAMA Dermatol, 152(1):45-51. DOI:10.1001/jamadermatol.2015.2707
References
Inlyta® (axitinib) prescribing information (2014). Pfizer. Available at: http://labeling.pfizer.com/ShowLabeling.aspx?id=759Janjigian YY, Groen HJ, Horn EF, et al (2011). Activity and tolerability of afatinib (BIBW 2992) and cetuximab in NSCLC patients with acquired
resistance to erlotinib or gefitinib. J Clin Oncol Asco Annual Meeting Abstracts, 29. Abstract 7525.Keytruda® (pembrolizumab) prescribing information (2016). Merck. Available at:
https://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdfLacouture ME, Anadkat MJ, Bensadoun RJ, et al (2011). Clinical practice guidelines for the prevention and treatment of EGFR inhibitor-
associated dermatologic toxicities. Support Care Cancer, 19(8):1079-1095. DOI:10.1007/s00520-011-1197-6Lacouture ME, Wu S, Robert C, et al (2008). Evolving strategies for the management of hand-foot skin reaction associated with the
multitargeted kinase inhibitors sorafenib and sunitinib. Oncologist, 13(9):1001-1011. DOI:10.1634/theoncologist.2008-0131Lacouture ME (2012). Skin care for cancer patients. Clin Adv Hematol Oncol, 10(11):748-750. Larkin J, Ascierto PA, Dréno B, et al (2014). Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med,
371(20):1867-1876. DOI:10.1056/NEJMoa1408868Larkin J, Chiarion-Sileni V, Gonzalez R, et al (2015). Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J
Med, 373(1):23-34. DOI:10.1056/NEJMoa1504030Liu HB, Wu Y, Lv TF, et al (2013). Skin rash could predict the response to EGFR tyrosine kinase inhibitor and the prognosis for patients with
non-small cell lung cancer: a systemic review and meta-analysis. PLoS One, 8(1):e55128. DOI:10.1371/journal.pone.0055128Lynch TJ Jr, Kim ES, Eaby B, et al (2007). Epidermal growth factor receptor inhibitor-associated cutaneous toxicities: an evolving paradigm in
clinical management. Oncologist, 12(5):610-621.Medscape (2009). Management of dermatologic and other toxicities associated with EGFR inhibition in cancer patients. Available at:
http://www.medscape.org/viewarticle/701860_transcript_2Maione P, Gridelli C, Troiani T, & Ciardello F (2006). Combining targeted therapies and drugs with multiple targets in the treatment of
NSCLC. Oncologist, 11(3):274-284.
References
Massey PR, Okman JS, Wilkerson J, & Cowen EW (2015). Tyrosine kinase inhibitors directed against the vascular endothelial growth factor receptor (VEGFR) have distinct cutaneous toxicity profiles: a meta-analysis and review of the literature. Support Care Cancer, 23(6):1827-1835. DOI:10.1007/s00520-014-2520-9
Mekinist® (trametinib) prescribing information (2015). Novartis. Available at: https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/mekinist.pdf
Miller VA, Hirsh V, Cadranel J, et al (2012). Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial. Lancet Oncol, 13(5):528-538. DOI:10.1016/S1470-2045(12)70087-6
Minkis K, Garden BC, Wu S, et al (2013). The risk of rash associated with ipilimumab in patients with cancer: a systematic review of the literature and meta-analysis. J Am Acad Dermatol, 69(3):e121-e128. DOI:10.1016/j.jaad.2012.12.963
National Cancer Institute (2010). Common Terminology Criteria for Adverse Events (CTCAE). Version 4.0. Available at: http://www.cancer.govNexavar® (sorafenib) prescribing information (2013). Bayer. Available at:
http://labeling.bayerhealthcare.com/html/products/pi/Nexavar_PI.pdfOpdivo® (nivolumab) prescribing information (2016). Bristol-Myers Squibb. Available at: https://packageinserts.bms.com/pi/pi_opdivo.pdfPardoll D (2014). Cancer immunotherapy through checkpoint blockade: the future of cancer treatment. Medicographia, 36(3):274-284. Petrou, I (2015). Quality of life impact of anticancer drugs. Dermatology Times. Available at:
http://dermatologytimes.modernmedicine.com/dermatology-times/news/quality-life-impact-anticancer-drugsPretel-Irazabal M, Tuneu-Valls A, & Ormaechea-Perez N (2014). Adverse skin effects of imatinib, a tyrosine kinase inhibitor. Actas
Dermosifiliogr, 105(7):655-662. DOI:10.1016/J.AD.2013.01.009Peuvrel L & Dréno B (2014). Dermatological toxicity associated with targeted therapies in cancer: optimal management. Am J Clin Dermatol,
15(5):425-444. DOI:10.1007/s40257-014-0088-2Rini B, Melichar B, Ueda T, et al (2013). Axitinib with or without dose titration for first-line metastatic renal-cell carcinoma: a randomised,
double-blind phase 2 trial. Lancet Oncol, 14(12):1233-1242. DOI:10.1016/S1470-2045(13)70464-9
References
Sanlorenzo M, Vujic I, Daud A, et al (2015). Pembrolizumab cutaneous adverse events and their association with disease progression. JAMA Dermatol, 151(11):1206-1212. DOI:10.1001/jamadermatol.2015.1916
Santini D, Vincenzi B, Guida FM et al (2012). Aprepitant for management of severe pruritis related to biological cancer treatments: a pilot study. Lancet Oncol, 13(10):1020-1024. DOI:10.1016/S1470-2045(12)70373-X
Schmidinger M (2013). Understanding and managing toxicities of vascular endothelial growth factor (VEGF) inhibitors. EJC Suppl, 11(2):172-191. DOI:10.1016/j.ejcsup.2013.07.016
Sprycel® (dasatinib) prescribing information (2016). Bristol-Myers Squibb. Available at: http://packageinserts.bms.com/pi/pi_sprycel.pdfStewart TJ & Smyth MJ (2011). Improving cancer immunotherapy by targeting tumor-induced immune suppression. Cancer Metastasis Rev,
30(1):125-140. DOI:10.1007/s10555-011-9280-5Strumberg D, Awada A, Hirte H, et al (2006). Pooled safety analysis of BAY 43-9006 (sorafenib) monotherapy in patients with advanced solid
tumours: Is rash associated with treatment outcome? Eur J Cancer, 42:548-556. Sutent® (sunitinib malate) prescribing information (2015). Pfizer. Available at: http://labeling.pfizer.com/ShowLabeling.aspx?id=607Swann JB & Smyth MJ (2007). Immune surveillance of tumors. J Clin Invest, 117(5):1137-1146. DOI:10.1172/JCI31405Tafinlar® (dabrafenib) prescribing information (2016). Novartis Pharmaceuticals. Available at:
https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/tafinlar.pdfTasigna® (nilotinib) prescribing information (2016). Novartis. Available at:
https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/tasigna.pdfTecentriq® (atezolizumab) prescribing information (2016). Genentech. Available at:
https://www.gene.com/download/pdf/tecentriq_prescribing.pdfTorisel® (temsirolimus) prescribing information, (2016). Wyeth Pharmaceuticals. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/022088lbl.pdfVilladolid J & Amin A (2015). Immune checkpoint inhibitors in clinical practice: update on management of immune-related toxicities. Transl
Lung Cancer Res, 4(5):560-575. DOI:10.3798/j.issn.2218-6751.2015.06.06Votrient® (pazopanib) prescribing information (2015). Novartis. Available at:
https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/votrient.pdf
References
Weitzman SP & Cabanillas ME (2015). The treatment landscape in thyroid cancer: a focus on cabozantinib. Cancer Manag Res, 2015(7):265-278. DOI:10.2147/CMAR.S68373
Welsh S & Corrie P (2015). Management of BRAF and MEK inhibitor toxicities in patients with metastatic melanoma. Ther Adv Med Oncol, 7(2):122-136. DOI:10.1177/1758834014566428
Yervoy® (ipilimumab) prescribing information (2015). Bristol-Myers Squibb. Available at: http://packageinserts.bms.com/pi/pi_yervoy.pdfZelboraf® (vemurafenib) prescribing information. Genentech. Available at: https://www.gene.com/download/pdf/zelboraf_prescribing.pdfZheng Y, Wang F, Wu, G, et al (2015). The relationship between the adverse events and efficacy of sorafenib in patients with metastatic
renal cell carcinoma: a multicenter retrospective study from Northwest China. Medicine, 94(49):e2222. DOI:10.1097/MD.0000000000002222