Chemoprevention Chemoprevention PearlsPearls

Korbkarn Pongpairoj, MD, MSc26 June, 2015

AAD Highlight 2015

Disclosures:Disclosures: Affiliations with Affiliations with

ActavisActavis AllerganAllergan AquaAqua BayerBayer DusaDusa ExeltisExeltis FerndaleFerndale

GaldermaGalderma LeoLeo MerzMerz NeriumNerium NovartisNovartis PharmaDermPharmaDerm Promius Promius ValeantValeantNeal Bhatia, MDNeal Bhatia, MD

Director of Clinical Dermatology Director of Clinical Dermatology Therapeutics Clinical Research 2015 Therapeutics Clinical Research 2015

AAD Annual MeetingAAD Annual Meeting

Three main types of skin cancerThree main types of skin cancer

Squamous cell carcinoma

Basal cell carcinoma

Malignant melanoma

Non melanoma skin cancer (NMSC)

Risk Factors for NMSCRisk Factors for NMSC

General risk factorsGeneral risk factors AgeAge Skin phototype I-IIISkin phototype I-III Sun exposeSun expose History of prior NMSCHistory of prior NMSC Male > FemaleMale > Female SmokingSmoking

Risks of NMSC in Risks of NMSC in Immunosuppressed PatientsImmunosuppressed Patients

TransplantationTransplantation Most common CA in organ transplant patients Uncommon clinical morphologies Uncommon clinical morphologies More frequently aggressive histological subtypes More frequently aggressive histological subtypes

Recent Results Cancer Res 2002;160:251-8.J Am Acad Dermatol 2002;47:1-17.

Dermatol Surg 2005;31:163-8.

Risks of NMSC in Risks of NMSC in Immunosuppressed PatientsImmunosuppressed Patients

TransplantationTransplantation The frequency of NMSC increases progressively The frequency of NMSC increases progressively

with time after transplantationwith time after transplantation Level of immunosupression is directly related to Level of immunosupression is directly related to

NMSC incidence.NMSC incidence. Transplanted organ Transplanted organ : pancreas or kidney (highest) >> heart >> liver (lowest): pancreas or kidney (highest) >> heart >> liver (lowest)

Recent Results Cancer Res 2002;160:251-8.J Am Acad Dermatol 2002;47:1-17.

Dermatol Surg 2005;31:163-8.

HPVHPV HPV type 21, 23, 38 linked to AKs and SCCHPV type 21, 23, 38 linked to AKs and SCC

Induced anti-apoptotic effects in UV-damaged cellsInduced anti-apoptotic effects in UV-damaged cells

Recent Results Cancer Res 2002;160:251-8.Actas Dermosifiliogr 2009;100:Supl. 2:55-8.

Plos ONE 2011;6(11):e27655.

Risks for Risks for Immunosuppressed PatientsImmunosuppressed Patients

Immunosuppressants and SCCImmunosuppressants and SCC

Increased riskIncreased risk CyclosporineCyclosporine AzathioprineAzathioprine TacrolimusTacrolimus VariconazoleVariconazole

Reduced riskReduced risk SirolimusSirolimus Mycophenolate mofetilMycophenolate mofetil

The Dermatologist 2014;22(2)

Prevention of Skin Cancer in High Risk Patients After Conversion to a Sirolimus-

based Immunosuppressive Protocol (PROSKIN)

Phase 4, Randomized, open label studyPhase 4, Randomized, open label study Objective : Objective : To assess whether a switch to a sirolimus To assess whether a switch to a sirolimus

immunosuppressive therapy decreases the incidence /reoccurrence of immunosuppressive therapy decreases the incidence /reoccurrence of skin neoplasm.skin neoplasm.

Condition : Renal transplant pts at high-risk for skin cancerCondition : Renal transplant pts at high-risk for skin cancer No study results were posted.No study results were posted.

ClinicalTrials.gov

This study has been TERMINATED. (no adequate recruitment)

Higher Risks of SCC Higher Risks of SCC with Variconazolewith Variconazole

Synergistic effect with immunosuppressive Synergistic effect with immunosuppressive medications medications develop aggressive SCC develop aggressive SCC Phototoxicity, lentigines, and actinic keratosesPhototoxicity, lentigines, and actinic keratoses Early warning signs of toxicityEarly warning signs of toxicity

J Heart Lung Transplant 2010;29(11):1240-4.Dermatol Surg 2010;36(11):1752-5.

History of Squamous Cell Skin Cancer is a Marker History of Squamous Cell Skin Cancer is a Marker of Poor Prognosis in Patients with Cancer.of Poor Prognosis in Patients with Cancer.

Type of cancer

RR of death at 1 year

NHL 1.33

Colon 1.24

Breast 1.19

Prostate 1.17

Lung 1.29

Ann Intern Med 1999;131(9):655-9.

NMSC Other cancerOther cancer

• Population-based cohort study• Sweden, 1958 to 1996.

** Hx of SCC may help to identify a subgroup of patients with cancer who need careful medical attention.

NMSC are associated with NMSC are associated with an increased incidence of subsequent cancer. an increased incidence of subsequent cancer.

Ann Intern Med 1999;131(9):655-9.

NMSC Other cancerOther cancer

esp. NHL

** Closer medical surveillance in patients with NMSC would lead to early detection of new

cancer and improved survival.

Chemoprevention for NMSCChemoprevention for NMSC Primary systemic strategiesPrimary systemic strategies

Reduction of immunosuppressionReduction of immunosuppression Intervention to reduce tumorigenesisIntervention to reduce tumorigenesis

Retinoids, celecoxib, phytoparticle, antimetabolites, Retinoids, celecoxib, phytoparticle, antimetabolites, immunomodulatorsimmunomodulators

Photodynamic therapyPhotodynamic therapy

The benefits of systemic chemoprevention The benefits of systemic chemoprevention must outweigh adverse effects.must outweigh adverse effects.

Dermatol Surg 2004;30(4 pt 2):642-50.National Comprehensive Cancer Network. Available at:

http://www.nccn.org/profressionals/physician_gls/PDF/nmsc.pdf. Accessed March 1, 2005.

Squamous Cell Carcinoma Squamous Cell Carcinoma ChemopreventionChemoprevention

Intervention of CarcinogenesisIntervention of Carcinogenesis

sunscreens imiquimodTopical 5FU/

lactic acid retinoids

UV

Normal cell P53 mutation

RAS mutation

p16 mutation

AK subclinical

AK clinical SCC

UV UV

Retinoids Retinoids vs Chemoprevention vs Chemoprevention

Acitretin in Chemoprevention for AK in Acitretin in Chemoprevention for AK in Organ Transplant RecipientsOrgan Transplant RecipientsStudy Study type,

durationNo. of

pts Dosage Results

Bavinck et al, 1995 RCT#, 6 months 38 30 mg/day

Statistically significantly fewer pts with new skin cancers compared to placebo; reduction of number of AK.

Yuan et al, 1995

NCG*, <6 to >12 months

15 50 mg/day Variable effects on skin cancer.

McKenna et al, 1999 NCG* 5 years 16 0.3 mg/kg/day

Statistically significant reduction of new skin cancers after 4 years compared to pretreatment period.

McNamara et al, 2002 NCG*, 10 to 24 months 5 10-25 mg/day 5 pts significant decrease in new

tumors compared to pretreat period;.

George et al, 2002 RCT#, 2 year 23 25 mg/day

Number of SCCs significantly lower on acitretin compared to drug-free period.

De Sevaux et al, 2003 RCT#, 1 year 26

0.4 mg/kg/day vs

0.2 mg/kg/day

Decrease of AK by 50% in both groups; no effects on development of skin cancers in both groups compared to pretreatment peroid.

Am Soc Dermatol Surg 2004;30(4 Pt 2):656-61.# RCT = Randomized, controlled trial* NCG = No control group

Pearls on Using RetinoidsPearls on Using Retinoids Start slow 10 mg acitretin daily and increase as Start slow 10 mg acitretin daily and increase as

tolerated, 25 mg qod then qdtolerated, 25 mg qod then qd Consider isotretinoin for women of childbearing age Consider isotretinoin for women of childbearing age

due to its shorter half-lifedue to its shorter half-life Titrate up and down to manage side effectsTitrate up and down to manage side effects

Risks will rebound with discontinuation so treat with a Risks will rebound with discontinuation so treat with a routine to balance dryness, labs, and risks of alopecia routine to balance dryness, labs, and risks of alopecia and neuro effects with dose modificationand neuro effects with dose modification

Watch expenses (no endpoints)Watch expenses (no endpoints)

The Dermatologist 2014;22(12).J Dermatol Treat 2013;24(3):235-7.

Study Study type, duration N Dosage Results

Euvrard et al. RCT#, 3 months 22 0.05%tretinoin once daily

Statistically significantly reduction of keratotic lesions after 3 months compared to placebo (45% vs 23%)

Euvrard et al. RCT#, 6 months 40 0.3% vs 0.1%adapaleneSignificant decrease in AK in 0.3% group compared to placebo (32% vs 21%)

Smit et al. CT*, 6 weeks 130.02%tretinoin vs

calcipotriol vs both vs emollient twice daily

Alone or in combination with calcipotriol showed no effect on clinical, IHC and histology.

Am Soc Dermatol Surg 2004;30(4 Pt 2):656-61.

# RCT = Randomized, controlled trial* CT = controlled trial

Topical Retinoids in Organ Transplant Recipients.Topical Retinoids in Organ Transplant Recipients.

NSAIDs vs SCC Chemoprevention

Rationale for COX2 Inhibitor as an Cancer Chemoprevention

NSAIDs Can reduce colorectal Can reduce colorectal

polypspolyps Own anti-cancer effectsOwn anti-cancer effects

FDA approved topical diclofenac sodium 3% gel for the treatment of AK

COX2 Increase expression in Increase expression in

invasive SCC of head invasive SCC of head and neck compared and neck compared with normal epitheliumwith normal epithelium

Involve in early and Involve in early and intermediate stages of intermediate stages of carcinogenesiscarcinogenesis

Progressively Progressively increases throughout increases throughout all stages of all stages of carcinogenesiscarcinogenesisCancer Prev Res 2014;7(3):283-91.

J Drugs Dermatol 2008;7(7):669-73.

NSAIDs and COX2 inhibitors have shown NSAIDs and COX2 inhibitors have shown impressive efficacy in preventing murine SCC. impressive efficacy in preventing murine SCC.

CelecoxibCelecoxib and difluoromethylornithine in combination have strong therapeutic activity against UV-induced skin tumors in mice.and difluoromethylornithine in combination have strong therapeutic activity against UV-induced skin tumors in mice. Carcinogenesis 2003;24:945-52.Carcinogenesis 2003;24:945-52.

Chemopreventive activity of celecoxib, a specific COX2 inhibitor, and indomethacin against UV-induced skin carcinogenesis. Chemopreventive activity of celecoxib, a specific COX2 inhibitor, and indomethacin against UV-induced skin carcinogenesis. Mol Mol Carcinog 1999;25:321-40.Carcinog 1999;25:321-40.

Reduction of UV-induced skin tumors in hairless mice by selective COX2 inhibition.Reduction of UV-induced skin tumors in hairless mice by selective COX2 inhibition. Carcinogenesis 1999;20:1939-44.Carcinogenesis 1999;20:1939-44.

Celecoxib, a COX2 inhibitor as a potential chemopreventive to UV-induced skin cancerr : a study in the hairless mouse model.Celecoxib, a COX2 inhibitor as a potential chemopreventive to UV-induced skin cancerr : a study in the hairless mouse model. Arch Dermatol 2002;138:751-5.Arch Dermatol 2002;138:751-5.

Chemotherapeutic efficacy of topical celecoxib in a murine model of UVB-induced skin cancer.Chemotherapeutic efficacy of topical celecoxib in a murine model of UVB-induced skin cancer. Mol Carcinog 2003;38:33-9.Mol Carcinog 2003;38:33-9.

NSAID use in the prevention and treatment of squamous NSAID use in the prevention and treatment of squamous cell carcinoma.cell carcinoma. Dermatol Surg 2004;30:1335-42.Dermatol Surg 2004;30:1335-42.

NSAIDs and the risk of AK and SCC of the skin.NSAIDs and the risk of AK and SCC of the skin. J Am Acad Dermatol 2005;53:966-72.J Am Acad Dermatol 2005;53:966-72.

Effect of NSAIDs on the recurrence of NMSC.Effect of NSAIDs on the recurrence of NMSC. Int J Cancer 2006;119:682-6.Int J Cancer 2006;119:682-6.

and some efficacy against human precancerous and some efficacy against human precancerous skin lesions and human SCCs.skin lesions and human SCCs.

CapecitabineCapecitabinevs Chemoprevention vs Chemoprevention

CapecitabineCapecitabine

Dermtol Surg 2009;35:1567-72.

FDA approved FDA approved indicationsindications Breast cancerBreast cancer Metastatic breast Metastatic breast

cancercancer Primary colon cancerPrimary colon cancer Metastatic colorectal Metastatic colorectal

cancercancer

5-FU

Oral 5-fluorouracil Oral 5-fluorouracil precursorprecursor

• Impair DNA synthesis• Inhibit cell division

liver

CapecitabineCapecitabine 12 transplant pts.12 transplant pts. > 6 invasive SCC/yr> 6 invasive SCC/yr Low dose capecitabine : 1 mg bid x 2 weeks, Low dose capecitabine : 1 mg bid x 2 weeks,

repeated in 3 week cyclesrepeated in 3 week cycles Reduce new SCC, but not BCCReduce new SCC, but not BCC

The Dermatologist 2014;22(12).Dermatol Surg 2013;39(4):634-45.

Chemoprevention through Phytochemicals

Name of phytochemicals Rich source

Humulone Humulus lupulus

Apigenin Parsley and Onions

Guggulsterone Commiphora mukul

5-Hydroxy-3,6,7,8,3’,4’-hexamethoxyflavone Fruits of citrus genus specially peels of sweet orange

3,3’-Diindolylmethane Cruciferous vegetables like broccoli, cabbage, and so forth

Xanthorrhizol Curcuma xanthorrhiza

Oleandrin Nerium oleander

Delphinidin Genus Delphinium

Myricetin Walnuts (Juglans regia)

Caffeic acid Coffee (Coffea canephora)

Alpha-santalol Sandalwood oil

Nicotinamide Peas, Asparagus, Mushroom, Squash

Norathyriol Mango, Hypericum elegans, Tripterospermum lanceolatum, and so forth

Retinoids Vitamin A rich food source like Carrot, Spinach, pumpkin, and so forth

Shikonin Lithospermum erythrorhizon

Ferulic acid Rich source in Phaseolus vulgaris, Rice and Maize Bran

Honokiol Magnolia plantBioMed Research International 2014.

BioMed Research International 2014.

• Antioxidant • Antimutagenic• Anticarcinogenesis • Detoxification carcinogen

Phytochemicals vs Chemoprevention of Skin Cancer

BioMed Research International 2014.

ทบทม

ถวเหลอง

ขมน

มะเดอ

ขง

องน

กระเทยม

ชาดำา/เขยว

Polypodium leucotomos

Anti-inflammation• Inhibit Th1

• IL-2, IL-6, TNF-α, IFN- γ• Impair mast cell infiltration induced by UV

Anti-oxidant• Phenolic compounds scavenge ROS• Caffeic acid • Ferulic acid• Restore activity of dendritic cells and lymphocytes

Methods Find Exp Clin Pharmacol 2006;28(3):157-60.J Drugs Dermatol 2014;13(2):613-6.

Cellular effectsCellular effects

AngiogenesisAngiogenesis PhotocarcinogenesisPhotocarcinogenesis Solar elastosisSolar elastosis

Cell membrane integrityCell membrane integrity Elastin expressionElastin expression Reduced lipid peroxidationReduced lipid peroxidation Increase MMP-1Increase MMP-1 Activation of P53 geneActivation of P53 gene Inhibition of COX-2Inhibition of COX-2

Methods Find Exp Clin Pharmacol 2006;28(3):157-60.J Drugs Dermatol 2014;13(2):613-6.

Oral Polypodium Leucotomos Extractvs Photoprotective Effects

Immunohistochemistry Results P valueCyclobutane pyrimidine dimers (CPDs) lower < 0.001*

Ki-67 (Epidermal proliferation) lower < 0.001*

Langerhans cells quantity and morphology

preservation NS

J Am Acad Dermatol 2004;51:910-8.J Drugs Dermatol 2014;13(2):613-6.

PLE in UV-irradiated hairless mice PLE in UV-irradiated hairless mice delays tumorigenesis delays tumorigenesis Increases epidermal p53 expression Increases epidermal p53 expression

and anti-oxidant status and anti-oxidant status

Exp Dermatol 2014;23(7):526-8.

Oral Polypodium Leucotomos Extract

vs Chemoprevention??

Photodynamic TherapyPhotodynamic Therapy for for Chemoprevention of NMSCChemoprevention of NMSC

Photodynamic TherapyPhotodynamic Therapy

Visible light

Photosensitizing agentROS

Local tissue

destruction

BJD 2010;162:171-5.

Preventive PDT in face and scalp cancerization

Randomized placebo-controlled studyRandomized placebo-controlled study 45 pts NMSC of face or scalp45 pts NMSC of face or scalp

AKs symmetrically distributed over the same regions.AKs symmetrically distributed over the same regions. Randomized for field treatment with 20%ALA-Randomized for field treatment with 20%ALA-

PDT on one side and placebo-PDT on the other.PDT on one side and placebo-PDT on the other. Evaluated for new NMSCs for 12-month period.Evaluated for new NMSCs for 12-month period.

BJD 2010; 162:171-5.

Follow-up (months)

Total no. of new lesions on ALA-PDT field

Total no. of new lesions on placebo-

PDT fieldP value

3 1 8 0.020*

6 2 15 0.001*

9 7 23 <0.001*

12 14 30 <0.001*

Preventive PDT in face and scalp cancerization

BJD 2010; 162:171-5.

Reduction in the incidence of SCC in solid organ Reduction in the incidence of SCC in solid organ transplant recipients treated with cyclic PDT.transplant recipients treated with cyclic PDT.

J Dermatol Surg 2009;35:1-7.

Assessment SCC lesion count, median (95% CI)

Reduction from baseline, % (95% CI)

12 months before treatment 20 (15-24)

12 months after treatment 4 (3-5) 79.05 (73.3-81.8)

24 months after

treatment1 (0-2) 95(87.5-100)

(MAL)-PDT vs Imiquimod 5%(MAL)-PDT vs Imiquimod 5% Split face, n =44Split face, n =44 Primary endpoint : number of new lesions during Primary endpoint : number of new lesions during

12-month follow-up period.12-month follow-up period. No statistically significant difference in No statistically significant difference in

development of new NMSCsdevelopment of new NMSCs MAL-PDT and IMIQ not differ.MAL-PDT and IMIQ not differ. Both regimens were well tolerated.Both regimens were well tolerated. Patients’ preference : MAL-PDTPatients’ preference : MAL-PDT

J Eur Acad Dermatol Venereol 2015;29(2):325-9.

Basal Cell Carcinoma Basal Cell Carcinoma ChemopreventionChemoprevention

Ineffective Ineffective SunscreensSunscreens Oral retinoidsOral retinoids Oral capecitabineOral capecitabine Beta-caroteneBeta-carotene Tea extractsTea extracts

May be effectiveMay be effective

COX2 inhibitorCOX2 inhibitor

Cancer Prev Res 2010;3:25-34.

NSAIDs vs BCC Chemoprevention

BCCs express high levels of COX enzymesBCCs express high levels of COX enzymes COX2 expression in stromal tissue and COX2 expression in stromal tissue and microenvironmentmicroenvironment Polymorphisms in COX2 may modify BCC risk Polymorphisms in COX2 may modify BCC risk (1 case-control study)(1 case-control study)

Cancer Prev Res 2010;3:25-34.

Celecoxib in Preventing BCC Celecoxib in Preventing BCC in Gorlin’s Syndromein Gorlin’s Syndrome

Phase II Randomized, Double-Blind TrialPhase II Randomized, Double-Blind Trial 60 pts with at least 5 prior BCCs and 4 within 60 pts with at least 5 prior BCCs and 4 within

the past yearthe past year Oral celecoxib 200 mg twice daily or placebo Oral celecoxib 200 mg twice daily or placebo

x 2 yrsx 2 yrs

Cancer Prev Res 2010;3:25-34.

Celecoxib in Preventing BCC Celecoxib in Preventing BCC in Gorlin’s Syndromein Gorlin’s Syndrome

Cancer Prev Res 2010;3:25-34.

N Placebo Celecoxib

Pdifference

All subjects (BCC number) 60 37% 26% 0.18

>/= 15 BCC at baseline 24 28% 32% 0.74< 15 BCC at baseline 36 48% 22% 0.043*

All subjects (BCC burden) 60 37% 25% 0.069>/= 15 BCC at baseline 24 33% 33% 0.97< 15 BCC at baseline 36 50% 20% 0.024*

** Celecoxib might have differential effects ** Celecoxib might have differential effects depending on disease severity.depending on disease severity.

How Often Should Patients How Often Should Patients Come Back?Come Back?

Early recognition and treatment is critical.Early recognition and treatment is critical. Monthly self-examsMonthly self-exams Regular dermatology examsRegular dermatology exams

Low threshold for skin biopsyLow threshold for skin biopsy Frequency depends on risk of NMSCFrequency depends on risk of NMSC

Liver Transpl 2000;6:253-62.J Am Acad Dermatol 2002;47:1-17.

Dermatol Surg 2004;30(4 pt 2):642-50.

Recommended Examination Frequency

Dermatol Surg 2004;30(4 pt 2):642-50.

Risk Level Frequency (month)

No other risk factors for NMSC 12

NMSC risk factors present, but no history of AK or NMSC 6-12

AK or 1 NMSC lesion present 3-6

Multiple NMSC lesions present 3

One high-risk NMSC present 3

Metastatic NMSC present 1-3

TTHHAANNK K YYOOUUkorbkarnp@hotmail.com