Reviewed by Dr. Jose Monzon (Medical Oncologist, Tom Baker Cancer Centre, University of Calgary)

Transcription

1 SQUAMOUS CELL, BASAL CELL AND OTHER RARE NON MELANOMA SKIN CANCER Updated December 2015 by Dr. Ines Menjak (PGY 5 Medical Onclgy Resident, University f Trnt) Reviewed by Dr. Jse Mnzn (Medical Onclgist, Tm Baker Cancer Centre, University f Calgary) DISCLAIMER: The fllwing are study ntes cmpiled by the abve PGY 5 medical nclgy residents and reviewed by a staff medical nclgist. They reflect what we feel is relevant knwledge fr graduating medical nclgy residents preparing fr their final examinatin. The infrmatin has nt been surveyed r ratified by the Ryal Cllege. A) PUBLIC HEALTH EPIDEMIOLOGY Incidence: Nn melanma skin cancer (NMSC) is the mst cmmn cancer diagnsed in Canadians. Estimated incidence in 2015: 78,300. Mrtality: Very lw mrtality. Estimated number f deaths in Canada fr 2015 is 500. RISK FACTORS Envirnmental/Chemical/Infectins: slar UV radiatin (#1), fair skinned patients particularly at risk. Radiatin expsure. Actinic keratsis are pre cancerus SCC lesins. Immunsuppressin (i.e. rgan transplant, lng term use f psrelen and UV A light [PUVA]), particularly predispse t SCC. Drugs: vandetanib, vemurafenib, vricnazle. BCC: chrnic arsenic expsure. Genetic: genetic syndrmes that predispse t NMSC : albinism, xerderma pigmentsum, basal cell nevus syndrme (Grlin s), Rmb, Bazex Dupre Christl, Dwling Meara simplex (a frm f epidermlysis bullsa), Dyskeratsis cngenita. PREVENTION & SCREENING Preventin: sun prtectin and avidance. Avid tanning beds. In a phase 3 trial, ral nictinamide 500 mg BID taken fr 12 mnths reduced incidence f SCC, BCC and actinic keratsis in high risk patients (had at least 2 nn melanma skin cancers in past 5 years). Screening: if knwn high risk patient, regular skin examinatin with dermatlgist (n clear guideline) B) PRESENTATION & DIAGNOSIS SYMPTOMS & SIGNS Cmmn Symptms: BCC: nn healing lesin, ften red/pink. Can be pruritic, smetimes bleed r ulcerate. SCC: nn healing lesin, may be wart like r ulcerated. May ntice lymph nde swelling. If nerve invlvement, may experience pain, numbness, tingling. Cmmn Signs: BCC may include any: crusted, ulcer, smth, pearly, waxy, telangiectasias clur can vary (pink, red, translucent, white, yellw), may bleed. SCC: firm lesin, ften a rugh scaly surface, flat reddish patch, versus a raised lesin with central depressin, r nn healing ulcer. Cmmn Presentatins: BCC: nn healing sre, cmmnly face, scalp, ears, hands, shulders, back. SCC: face, ears, neck, lips, hands, shulders, arms, legs. Can develp in existing scars r ulcers.

2 INVESTIGATIONS Labratry: nne. Diagnstic Imaging: Dermscpy by an experienced clinician ften shws arbrizing bld vesels, blue gray vid nests. Diagnstic Prcedures: Skin bipsy, excisinal preferred. Shave r punch bipsies can be dne but risk nt btaining accurate infrmatin regarding histlgic subtype. PATHOLOGY & MOLECULAR BIOLOGY Cmmn Histlgy: Basal cell carcinma (80%), squamus cell carcinma (20%) Cmmn Metastatic Sites: lymph ndes are mst cmmn. In rare cases, may spread t bne, lung, liver (BCC); bne, liver, brain (SCC). SCC 2 5% risk f metastasis. BCC <1%. Relevant Mlecular Bilgy: BCC: Snic hedgehg pathway: PTCH1 (patched 1) mutatin n chrmsme 9q (cdes fr snic hedgehg receptr). PTCH frms a receptr cmplex with smthened (SMO), and activates the snic hedgehg signaling pathway. Vismdegib is an SMO inhibitr used fr metastatic BCC. UV induced mutatins in p53 fr BCC, and many SCC. UV light induced inflammatin in skin caused partly thrugh inductin f COX 2. Muse studies shwed selective COX 2 inhibitrs decreased incidence f BCC and SCC STAGING TNM: AJCC des nt have specific staging fr BCC, it fcuses n SCC. High risk features differ frm AJCC and NCCN. Cutaneus SCC and ther cutaneus skin cancers AJCC 7 th editin T stage Characteristics T0 N primary tumur Tis Carcinma in situ T1 2 cm with <2 high risk features T2 >2 cm, OR any size tumur with 2 high risk features T3 Invasin f maxilla, mandible, rbit, r tempral bne T4 Invasin f skeletn (axilla r appendicular) r perineural invasin f skull base N stage N0 N reginal nde mets N1 Single ipsilateral nde 3 cm N2a Single ipsilateral nde >3cm but 6 cm N2b Multiple ipsilateral ndes all 6 cm N2c Bilateral/cntralateral ndes all 6cm N3 Any lymph nde met >6cm M stage M0 N distant mets M1 Distant mets Stage T N M Stage 0 Tis N0 M0 Stage I T1 N0 M0 Stage II T2 N0 M0 Stage III T3 N0 M0 T1 3 N1 M0 Stage IV T1 3 N2 M0 Any T N3 M0 T4 Any N M0 Any T Any N M1

3 AJCC high risk features fr T staging SCC Depth/invasin Anatmic lcatin Differentiatin >2mm thick Clark level IV Perinueral invasin Primary site ear Primary site hair bearing lip Prly differentiated r undifferentiated NCCN Risk f recurrence fr SCC: Lw risk High risk Lcatin/size Area L < 20mm Area M < 10 mm Area H < 6 mm Area L 20 mm Area M 10 mm Area H 6 mm Brders Well defined Prly defined Primary vs recurrence Primary Recurrent Immunsuppressin N Yes Site f prir radiatin r chrnic N Yes inflammatry prcess Rapidly grwing tumur N Yes Neurlgic symptms N Yes Pathlgy degree f differentiatin Well/mderate Pr Depth: thickness r Clark level < 2mm, r I III 2mm, r IV V Perineural, lymphatic, vascular invlvement N Yes NCCN Risk f recurrence fr BCC: Lw risk High risk Lcatin/size Area L < 20mm Area M < 10 mm Area H < 6 mm Area L 20 mm Area M 10 mm Area H 6 mm Brders Well defined Prly defined Primary vs recurrence Primary Recurrent Immunsuppressin N Yes Site f prir radiatin N Yes Pathlgy subtype Ndular, superficial Aggressive grwth pattern Perineural invlvement N Yes L: trunk, extremities (excludes pretibial, hands, feet, nail units, ankles) M: cheeks, frehead, scalp, neck, pretibial H: mask areas f face = central face, eyelids, eyebrws, perirbital, nse, lips, chin, mandible, pre /pst auricular skin and sulci, temple, ear. Genitalia, hands, feet. C) TREATMENT LOCALIZED / ADJUVANT Bttm Line General Apprach: BCC: surgical resectin. SCC: surgical resectin. BCC lw risk: Resectin is mst efficacius. Optins: A. Cnventinal surgical excisin: 4 mm margin. Healing by secnd intentin, linear repair r skin graft. B. Mhs surgery: micrgraphic surgery, allws histlgic evaluatin f peripheral margin at time f surgery. Usually dne fr cases where tissue sparing is valuable fr csmetic r functinal reasns, r fr high risk recurrence. It is a cstly and time cnsuming prcedure. C. Electrdessicatin and curettage (ED&C): shuld nt be dne n terminal hair bearing areas (scalp, pubic, axilla, beard)

4 Optins fr nn surgical candidates: A. Radiatin therapy B. Tpical therapy: Tpical 5 FU: antimetablite, inhibits thymidylate synthetase. 5% cream r slutin used fr BCC. Can be cnsidered fr superficial lesins in nn critical lcatins. Used fr several weeks. Imiquimd: 5% cream. Immune respnse mdifier, prmtes apptsis, stimulates cell mediated immunity. BCC high risk: Resectin is mst efficacius. Optins: A. Mhs surgery preferred t ascertain margins at time f surgery. B. Cnventinal surgical excisin acceptable with wider margins (n specified diameter given). Radiatin therapy fr nn surgical candidates. SCC lw risk : Resectin is mst efficacius. Optins: A. Cnventinal surgical excisin: 4 6 mm margin. Healing by secnd intentin, linear repair r skin graft. B. Electrdessicatin and curettage (ED&C): shuld nt be dne n terminal hair bearing areas (scalp, pubic, axilla, beard). Optins fr nn surgical candidates: A. Radiatin B. Tpical: treatment 5FU, imiquimd, crytherapy SCC high risk: Resectin is mst efficacius. Optins: A. Mhs surgery B. Surgical excisin with cmplete circumferential peripheral and deep margin assessment (CCPDMA) C. Cnventinal surgical excisin Optins fr nn surgical candidates: A. Radiatin therapy B. Systemic therapy: may supplement RT in rare cases (see head and neck sectin fr details f regimens). In general, efficacy limited in this setting. Can be cnsidered fr nn surgical candidates r lesins that can t be adequately managed with RT. Optins: cisplatin, 5 FU, capecitabine, methtrexate, blemycin, dxrubicin. Prgnsis: 5 year risk f recurrence 1 10% fr BCC and SCC depending n treatment

5 Imprtant Phase III Clinical Trials: Adjuvant 13 cis Retinid acid and IFN alpha fr aggressive SCC (Brewster, JCO, 2007, ) Regimen Arm 1: 13cRA 1mg/kg p daily + IFNalpha 3 x10 6 SC 3x/wk Arm 2: n adjuvant therapy Mechanism f Actin IFNalpha: cytkine that stimulates immune activatin f Experimental Drug 13 cis retinic acid: induces apptsis Primary Endpint Time t tumr recurrence r develpment f secnd primary tumur (SPT) Inclusin/Exclusin Inclusin: skin SCC with ne f the fllwing: 2 cm; perineural invasin; pathlgic/radilgy deep invasin r clinical fixatin t deep structures; r path/cytlgic prven reginal mets. N evidence f disease after surgery. Size (N) 66 patients Results Time t recurrence r SPT: N difference. HR 1.13, 95% CI ). 1 yr recurrence and SPT free survival rate: 70% vs 70%. Quality f Life: nt assessed Txicity Grade 3/4 in >4% pts: dry skin/skin rash, dry eye/cnjunctivitis, chills, myalgia, cheilitis, fatigue. Cnclusin Results d nt supprt the use f these agents in the adjuvant setting. Other Cmments Other Imprtant Published Data: (e.g. meta analysis, restrspective analyses, phase II) LOCALLY ADVANCED Bttm Line General Apprach: Lymph nde psitive SCC: nde dissectin +/ RT +/ systemic therapy. SCC: If psitive ndes: reginal lymph nde dissectin. If nt candidate fr surgery: cnsider RT +/ systemic therapy (i.e. as in head and neck). If psitive ndes n dissectin: cnsider adjuvant RT. If extra capsular extensin r incmplete excisin, cnsider adding cncurrent chem t RT. Neadjuvant systemic therapy rarely used Prgnsis: SCC: reginal lymph nde mets 25 35% OS at 5 years, <20% at 10 years. Imprtant Phase III Clinical Trials: Nne.

6 Other Imprtant Published Data: (e.g. meta analysis, restrspective analyses, phase II) Neadjuvant gefitinib fr aggressive cutaneus SCC f head and neck (phase II) (Lewis, Clin Can Res, 2012, ) Regimen Gefitinib 250 mg p daily x2 30 day cycles. If SD at day 15, increase t 500 mg daily. Ptential fr maintenance gefitinib fr all. Mechanism f Actin EGFR tyrsine kinase inhibitr f Experimental Drug Primary Endpint Disease cntrl rate Inclusin/Exclusin Inclusin: aggressive SCC head and neck: 2 cm; perineural invasin; deep invasin; and/r lymph nde mets. May have previus treatments with residual/recurrent disease. ECOG 0 2. Size (N) 22 evaluable pts Results Overall respnse rate: t inductin gefitinib: 45.5% (95% CI ). 2 year OS: 72.1% (95% CI ) 2 year Disease specific survival : 72.1% ( ) Txicity Grade 3/4 in >4% pts n gefitinib maintenance r dse escalatin: nne. Cnclusin Gefitinib in neadjuvant setting was active, well tlerated. Other Cmments METASTATIC Bttm Line General Apprach: First line is ften surgery r radiatin. N standard treatments. BCC: vismdegib (may als be cnsidered fr bassquamus). SCC: N standard. Chemtherapy: Cisplatin ± 5 FU, blemycin have been studied in small bservatinal studies. EGFR inhibitrs: Cetuximab, Gefitinib In transplant patients, cnsider reducing dses f immunsuppressants, r minimizing calcineurin inhibitrs and/r antimetablites in favur f mtor inhibitrs. Prgnsis: SCC: 5 year survival 3 6%. BCC 5 year survival 5%. Imprtant Phase III Clinical Trials: Nne.

7 Other Imprtant Published Data: (e.g. meta analysis, retrspective analyses, phase II ) Efficacy and Safety f VIsmdegib in Advanced BCC (ERIVANCE) (phase II) (Sekulic, NEJM, 2012, ) Regimen Vismdegib 150 mg p daily Mechanism f Actin Small mlecule inhibitr f smthened (SMO), part f the snic f Experimental Drug hedgehg signaling pathway Primary Endpint Objective respnse rate by independent review Inclusin/Exclusin Inclusin: lcally advanced r metastatic BCC. ECOG 0 2. Size (N) 96 patients Results Respnse Rate: 43% (95% CI 30 56, p<0.001) lcally advanced chrt, 30% (95% CI 16 48, p=0.001) metastatic chrt Duratin f respnse: Median 7.6 m (range ) bth chrts PFS: median PFS 9.5 m (95% CI ) Txicity Grade 3/4 in >4% pts: decrease in weight. Cnclusin Vismdegib assciated with tumur respnses in lcally advanced r metastatic BCC. Other Cmments Nn randmized, multicenter, tw chrts. Vismdegib in advanced BCC: interim analysis STEVIE (phase II) (Basset Seguin, Lancet Oncl, 2015, ) Regimen Vismdegib 150 mg p daily Mechanism f Actin Small mlecule inhibitr f smthened (SMO), part f the snic f Experimental Drug hedgehg signaling pathway Primary Endpint Safety by investigatr review Inclusin/Exclusin Inclusin: lcally advanced r metastatic BCC. ECOG 0 2. Size (N) 499 evaluable at clinical cutff date (1227 patients ttal) Results Overall Respnse Rate: 66.7% (95% ) lcally advanced, 37.9% (95% CI ) metastatic Duratin f respnse: 22.7 m (95% CI 16.8 NE) lcally advanced, 10.0 ms (95% CI 5.7 NE) metastatic PFS: median PFS: 20.2 m (95% CI 19.3 NE) Txicity Grade 3/4 in >4% pts: muscle spasms Cnclusin Studied in this setting f rutine clinical practice, Vismdegib is a nvel therapeutic ptin fr advanced BCC Other Cmments Nn randmized, multicenter, pen label

8 Cetuximab first line single agent in unresectable cutaneus SCC (phase II) (Maubec, JCO, 2011, ) Regimen Cetuximab 400mg/m 2 initial dse, then 250mg/m 2 weekly x 6 wks Mechanism f Actin Mnclnal antibdy cmpetitive inhibitr f EGFR f Experimental Drug Primary Endpint Disease cntrl rate at 6 weeks Inclusin/Exclusin Inclusin: lcally advanced r metastatic SCC with IHC strng/mderate EGFR expressin. Chemtherapy naïve. ECOG 0 2. Exclusin: radiatin within last 4 wks, prir EGFR agents, unstable systemic disease, uncntrlled infectin. Size (N) 36 pts Results Disease cntrl rate at wk 6: 69% (95% CI 52 84) ITT ppulatin Best verall respnse rate: 28% (95% CI 14 45) ITT ppulatin Overall survival: mean OS 8.1 ms (95% CI ) PFS: median PFS 4.1 ms (95% CI 1.7 5) Txicity Grade 3/4 in >4% pts: infectin, tumr bleeding. Cnclusin Cetuximab achieved a high disease cntrl rate in the first line setting. Phase III trial is warranted. Other Cmments IFNalpha, retinic acid, and cisplatin in advanced SCC (phase II) (Shin, JCO, 2002, ) Regimen IFNalpha 5x10 6 IU/m 2 SC 3x/wk + 13cRA 1 mg/kg p daily + Cisplatin 20 mg/m 2 IV weekly Mechanism f Actin IFNalpha: cytkine that stimulates immune activatin f Experimental Drug 13 cis retinic acid: induces apptsis Cisplatin: platinum chemtherapy, crsslinks DNA Primary Endpint Respnse rate and txicity Inclusin/Exclusin Inclusin: advanced skin SCC Size (N) 39 pts Results Overall respnse rate: 34%. Rate in lcally advanced: 67%, metastatic 17% (p=0.007). Overall survival: median OS 14.6 ms. Txicity Grade 3/4 in >4% pts: mild/md fatigue, muccutaneus dryness, md/ severe neutrpenia, neutrpenic fever Cnclusin Cmbined treatment was clinically active in lcally advanced disease. Other Cmments Prvided sme evidence fr cisplatin based treatment, ther studies were retrspective.

9 RARE NON MELANOMA SKIN CANCERS Merkel cell: Risk Factrs : fair skin, immunsuppressin, B cell malignancy Pathgenesis : Merkel cell plymavirus (`80% f cases), UV light, immunsuppressin Typical presentatin : firm ndule typically in head and neck, can be flesh clured r bluish red. Tends t have lcal recurrence and reginal LN mets. Staging: Stage I T 2 cm, nde negative Stage II T >2 cm (T2 r T3) r a primary tumr with invasin int bne, muscle, fascia, r cartilage (T4), nde negative Stage III Any T with reginal lymph nde metastases Stage IV Metastasis beynd the reginal lymph ndes Treatment: Lcalized: surgery (WLE and SLN bx), radiatin can be used as adjuvant fr high risk patients, r as definitive therapy if surgery nt pssible. N randmized trials fr adjuvant chemtherapy. Metastatic: n randmized trials. Chemtherapy with platinum and etpside ften used first line. PD 1 immuntherapy is an alternative thrugh clinical trials. Kapsi sarcma: Risk factrs : AIDS, immunsuppressin, HHV 8 endemic areas (i.e. mst cmmn in Mediterranean basin, Central and Eastern Eurpe), male Pathgenesis : HHV 8 (aka. Kapsi sarcma assciated Herpes virus) required fr develpment f Classic Kapsi sarcma. Typical presentatin : purplish, red blue, r dark brwn/black lesins. Rarely can invlve mucus membranes (muth, GI tract) and reginal ndes. Staging : n universal staging system. Treatment : n cnsensus n ptimal treatment. Lcalized: bservatin if asymptmatic with limited number f lesins. Radiatin, surgery, tpical treatments (cis retinic acid, imiquimd), crytherapy r laser therapy have been used fr lcal lesin cntrl. Widespread, bulky r rapidly prgressive disease, visceral invlvement: chemtherapy. Optins include pegylated lipsmal dxrubicin, taxane, ral etpside, vinblastine, gemcitabine. Cutaneus Adnexal Tumrs: Large spectrum f benign and malignant tumrs that shw differentiatin tward any f the fllwing primary adnexal structures: hair fllicles, sebaceus glands, apcrine glands, r eccrine glands. Risk Factrs : spradic, r assciated with genetic syndrmes such as Birt Hgg Dube, Brke Spiegler, Cwden, Muir Trre. Pathgenesis : large spectrum, the assciated genetic syndrme mutatins may be implicated fr individual patients. Typical presentatin : papule r ndule that is pink, flesh clured r bluish, may be ulcerated. Fllicular and sebaceus tend t be n the head and neck. Eccrine mst frequently n palms and sles. Apcrine are ften in the axilla, angenital regin and eyelids. Staging : cnslidated with SCC staging system (see abve). Treatment : Lcalized: WLE r Mhs surgery. Limited data fr radiatin, can be used if surgery is nt pssible r if psitive margins. SLN bipsy rle nt well established. Metastatic: chice determined n case by case basis, limited evidence.

10 D) REFERENCES 1. Pentland AP, Schggins JW, Sctt GA, et al. Reductin f UV induced skin tumrs in hairless mice by selective COX 2 inhibitin. Carcingenesis 1999; 20: Chen AC, Martin AJ, Chy B, et al. A phase 3 randmized trial f nictinamide fr skin cancer chempreventin. NEJM 2015; 373: Oreng IF, Gerguis J, Phillips R, et al. Celecxib, a cyclxygenase 2 inhibitr as a ptential chempreventive t UV induced skin cancer: a study in the hairless muse mdel. Arch Dermatl 2002; 138: Fischer SM, L HH, Grdn GB, et al. Chempreventive activity f celecxib, a specific cyclxygenase 2 inhibitr, and indmethacin against ultravilet light induced skin carcingenesis. Ml Carcing 1999; 25: Uptdate. (2015) at < and management f hi gh risk aggressive cutaneus squamus cell carcinma?surce=search_ result&search=squamus+cell+carcinma&selectedtitle=4%7e150 > 6. NCCN guidelines Basal cell skin cancer v Natinal Cancer Netwrk, Inc NCCN guidelines Squamus cell skin cancer v Natinal Cancer Netwrk, Inc Canadian Cancer Sciety (2015) at < infrmatin/cancer type/skin nn melanma/statistics/?regin=n > 9. ASCO Cancer.net (2015) at < types/skin cancer nn melanma/treatment ptins > 10. NIH Natinal Cancer Institute (2016) at < tissue sarcma/hp/kapsi treatment pdq#sectin/_21 > 11. Uptdate (2016) at < uptdate cm.myaccess.library.utrnt.ca/cntents/classic kapsi sarcma clinical f eatures staging diagnsis and treatment?surce=search_result&search=kapsi+sarcma&selected Title=1%7E150> 12. Uptdate (2016) < uptdate cm.myaccess.library.utrnt.ca/cntents/staging and treatment f merkel c ell carcinma?surce=see_link > 13. Uptdate (2016) < uptdate cm.myaccess.library.utrnt.ca/cntents/pathgenesis clinical features and diagnsis f merkel cell neurendcrine carcinma?surce=search_result&search=merkel+cell&s electedtitle=1%7e150 > 14. Uptdate (2016) < adnexal tumrs?surc e=search_result&search=cutaneus+adnexal+tumrs&selectedtitle=1%7e150#h >