1. Basal Cell Cancer: Update on Treatment and Management

2. Epidemiology  Most common cancer in humans  Most common skin cancer  Roughly 2,000,000 cases in the US annually  3:2 male to female ratio  Nonmelanoma skin cancers in the Medicare population went up an average of 4.2 percent every year between 1992 and 2006

3. Risk Factors UV Exposure Radiation (x-ray and Grenz) Arsenic Exposure Immunosuppression Syndromes- Basal cell nevus, XP, Bazex, Rombo

4. Treatment  Mohs Surgery  Excisional Surgery  Currettage and Electrodessication  Cryosurgery  Laser Surgery  Radiation  Photodynamic Therapy  Topical chemotherapy

5. Why pursue non-surgical treatment modalities  Patient not surgical candidate  Patient refuses surgical treatment  Lower costs??  Cosmetically more acceptable  Reasonable cure rate

7. Topical Chemotherapy

8.  Imiquimod  Immunomodulator  ↑ IFN-α, IL-6, TNF-α, natural killer cells,  ↑ nitric oxide secretion from macrophages  ↑ IFN- Gamma and antigen presentation  ↑ IL-12 and IL-18 via Toll-like Receptor 7  Imiquimod stimulates both the innate and cell-mediated arms of the immune system.

9. Imiquimod Indications  FDA approved Imiquimod 5% in 2004 for the treatment of superficial BCC (sBCC) in immunocompetent adults  Tumors > 0.5 cm 2 in area  < 2 cm in diameter located on trunk and extremities  5 x’s/week for 6 weeks  What about nodular and morpheaform subtypes??

10. Imiquimod  41 patients with 47 tumors  15 sBCC (including temple and forehead)  26 nodular BCC (including nose, temple and canthus)  6 sclerodermiform BCC (including nose and ear)  Protocol  Imiquimod 5% - 5 x’s/week for 6 weeks without occlusion  Additional punch biopsies from 22 tumors at treatment week 2 and week 6  Follow up at three intervals up to 17 months for 39 patients Schiessl, C et al. J Drugs Dermatol.. 2007;6(5):507–513

11. Imiquimod  Results  95.7% complete response rate, 6.6% recurrence rate and 89.3% long-term clearance rate  Non-responding lesions belonged to nodular group on forehead  Histologic anaylsis of 22 tumor biopsies  58% reduction of inflammatory infiltrate by from week 2 to week 6  72.7% clearance of tumor by week 2 (16 of 22 tumors) Schiessl, C et al. J Drugs Dermatol.. 2007;6(5):507–513

12. Imiquimod  Side effects  Most common reactions were itching, burning and erosions equally divided  Mild  Moderate  Severe (all sclerodermiform- causing protocol changes)  Side effects healed with topical antibiotics  14.9% scarring noted (not correlated with degree of side effect) Schiessl, C et al. J Drugs Dermatol.. 2007;6(5):507–513

13. Imiquimod Schiessl, C et al. J Drugs Dermatol.. 2007;6(5):507–513

14. Imiquimod  How do these findings compare??  Prospective, multicenter phase 3, open-label study of 169 patients- sBCC  Protocol – Daily for 6 weeks  Initial clearance rate is 94.1% and  Sustained clearance rate by 60 months is 85.4%  Other studies report clearance rates from 75.0-80.8% 5x’s/week and 73.0-87.1% for daily usage. Quirk C et al. Cutis. 2010;85:318-324. Geisse J et al. J Am Acad Dermatol. 2004 May 50(5):722-733. Gollnick H et al. Eur J Dermatol. 2005 September;15(5):374-381.

16. Pitfalls of Imiquimod  Can fail particularly if strict follow-up is not adhered to  How to determine if successful as clinical appearance may be misleading  Hypopigmentation and scarring can mask tumor  Ulceration from Imiquimod can mask tumor  2/3 patients appearing clinically tumor free have residual BCC at biopsy site  Follow-up biopsies has been officially recommended by consensus groups  Efficacy based on compliance Murphy et al. Dermatol. Surg. 2008: 34: 1258-63

17. Imiquimod vs Surgery  5 year Clearance rates  Mohs Surgery  0.7-6.5 % primary  4-10% recurrent  Excisional Surgery  1.2-10.1 %  Currettage and Electrodessication  3.3-7.7 % Rowe DE J Dermatol Surg Oncol. 1989 March;15(3):315-328. Silverman MK et al.. J Dermatol Surg Oncol. 1991 September;17(9): 720-726. Silverman MK et al J Dermatol Surg Oncol. 1992 June;18(6):471-476 Werlinger KD et al Dermatol Surg. 2002 December;28(12):1138-1142.

18. Imiquimod as Adjunctive Treatment  After Curettage and Electrodessication (C and E)  20 patient study  Receive either imiquimod 5% or placebo after C and E for one month  Endpoint to reduced residual tumor one month after treatment (8 weeks)  10% vs. 40% patients had residual tumor

19. Imiquimod as Adjunctive Treatment  Before Mohs Surgery…  31 patients with nasal nodular BCC  16 patients received Mohs surgery alone  15 patients received Mohs surgery after 4 weeks rest period following nightly application of Imiquimod 5% for 6 weeks Butler D, et al. Derm Surg 2009; 35 (1):24-9

20. Imiquimod as Adjunctive Treatment

22. Is Imiquimod Cost-Effective?  Few studies comparing cost of Imiquimod to surgical excision  European Literature  Spanish Public health care system  Surgical excision of sBCC <2 cm with Imiquimod (5x’s/week for 6 weeks) for one year  € 676 vs € 621  Treatment failures or cost to treat recurrences not addressed

23. Is Imiquimod Cost-Effective? Netherlands study Norwegian Study  Imiquimod more cost- effective in short term  €585 vs surgery €663  More expensive in the long run  €1471 vs surgery €1322  Limitation is that there were no calculated estimated efficacies of Imiquimod  Imiquimod less cost-effective than standards of care (excision surgery, cryosurgery)  € 16 higher in imiquimod  More cost effective than PDT group  Better outcomes than cryosurgery at higher cost De cock E et al. Value in Health. 2005 November;8(6):A144. Sverre JM et al. Value in Health. 2005;8(6, article A143)

25. Photodynamic Therapy

26. Photodynamic Therapy (PDT)  Utilizes oxygen radicals generated from a photoactive molecule to achieve a therapeutic tissue response  Photoactivating light + Photosensitizer + Tissue Oxygen + Target Cell = Photochemical Reaction

27. Photodynamic Therapy  Photosensitizers  Chemical Purity  Ability to target neoplastic tissue  Short interval between administration and peak accumulation in tumor  Short half-life  Rapid elimination from normal tissue  Ability to produce large amounts of cytotoxic products

28. PDT-Topical Photosensitizers 5-delta-aminolevulinic acid HCL (ALA) Methyl-esterified ALA (mAL)  Metabolic precursor for endogenous photosensitizer protoporphyrin IX (Pp IX)  FDA approved for the treatment of AK’s in 1999  More lipophilic and demonstrates deeper tissue penetration  FDA approved for the treatment of AK’s in 2004 NOT FDA approved for treatment of Basal Cell Carcinoma

29. PDT-Topical Photosensitizers  Tumor thickness should not exceed 2-3 mm if using ALA  MAL is more suitable due to greater lipophilicity, greater selectivity, and better capacity for penetration  Currettage prior to PDT is indicated Szeimies RM Dermatol Clin. 2007;25:89-94.

30. PDT- Light Sources  Broad spectrum lamps, diode lamps, and lasers  Light – emitting diodes (LED)  Pulsed Dye Lasers  Intense Pulsed Light  Maximum light absorption by porphyrins is close to 405 nm  Majority of studies use 625 to 633 nm permitting greater skin penetration (3 mm vs 0.75-1 mm) Kalka et al J Am Acad Dermatol. 2000;42:389-413; quiz 414-6.

32. PDT - Protocol  MAL-PDT (determined with Actilite Tm LED)  Lightly currette simply to debulk area (salicylic acid 3-5 % overnight if very crusted)  Apply MAL and allow to incubate under occlusion for 3 hours  Optional local anesthesia  635 nm red light  Total dose of 37 J/cm2 (range 50-150 J/cm2)  Post-op care  2 treatments, one week apart

33. PDT - Efficacy  MAL-PDT and ALA-PDT  76-97% clearance rates for sBCC  Haller et al treated 26 lesions twice one week apart with ALA-PDT  100% CR with one relapse 16 months post-PDT  Greater effectiveness if some type of debulking carried out prior  64-92% for nodular BCC  Thissen et al treated 24 lesions with 92% CR  Soler et al treated 350 BCCs and curretted nodular lesions prior with 79% cure rate Haller JC et al. Br J Dermatol 2000;143:1270–5. Thissen MR et al Br J Dermatol 2000;142:338– Soler AM et al. Br J Dermatol 2001;145:467–71.

34. PDT-Efficacy  Improves when photosensitizer injected intralesionally  For thicker skin cancers there are higher fluorescence levels and protoporphyrin IX levels after intralesional administration of 5- ALA as opposed to topical application  Therefore, enhanced efficacy and improved clearance rate Thissen MR et al. J Invest Dermatol 2002;118:239–45. De Blois AW et al. Lasers Med Sci 2002;17:208–15. Cappugi P et al. J Chemother. 2004 Oct;16(5):491-3.

35. Pitfalls of PDT  Not FDA approved  Limitations in studies especially in US literature  Penetration into skin not always adequate for bulkier tumors  Prolonged photosensitivity may be intolerable  Rare occurrences of skin cancer developing after PDT  Invasive SCC 4 months after three PDT treatment  Malignant Melanoma on scalp after multiple treatments  BCC on nose after one PDT treatment for biopsy proven actinic keratosis Varma S Br J Dermatol 2000;142:812–51 Wolf P Dermatology 1997;1:53–4 Karen J Dermatol Surg. 2010 Aug;36(8):1328-31.

36. PDT vs. Excision  MAL-PDT with red light- sBCC  Initial response rates similar  51/52 (98%) lesions with surgery vs. 48/53 (91%) PDT  Long term – 12 months tumor free rates  96% for surgery vs. 83% for MAL-PDT  MAL-PDT with red light- Nodular BCC  Similar findings for short term  91% for MAL-PDT versus 98% for surgery  5 –year clearance rate  14% for MAL-PDT vs. 4% for surgery Rhodes LE et al. Arch Dermatol 2004;140:17–23. Tope WD et al. J Eur Acad Dermatol Venerol 2004;18 (Suppl 2):413–4.

37. PDT vs. Imiquimod  MAL-PDT for sBCC  13 patients with PDT vs. patients with Imiquimod  7x’s day/week for three weeks over three months  One week between treatments  Clinical and histopathologic clearance rate at 3 months  12/13 PDT group  6/8 Imiquimod group Nikkels-Tassoudji N, et al. Acta Clin Belg 2005;60:227–34.

38. PDT as Adjuvant Therapy  Case Report  52 year old male with multifocal BCC on left shoulder  Treated with multiple surgical modalities 10 years prior  Biopsy showed recurrent BCC  Mohs surgery performed to 6 stages (12.5X9 cm)  More than 50% peripheral margin + for sBCC  MAL-PDT performed in lieu of continuing Mohs Reddy KK et al. J Drugs Dermatol. 2010 Feb;9(2):143-8

39. PDT as Adjuvant Therapy  MAL-PDT after 3 hours of occlusion  37 J/cm 2 for 10 minutes  Protocol repeated one week later  Clearance was clinically determined  Wound completely re-epithelialized at 4 wks  Patient please with cosmetic outcome (decreased scar formation compared to previous surgeries)

41. Is PDT Cost-Effective?  Study of sBCC and Bowen’s Disease  67 patients with 86 tumors (32 sBCC)  34 treated with surgery, 24 with Imiquimod and 28 with MAL-PDT  Clearance Rates  89.5% MAL-PDT, 87.5% Imiquimod, and 97.5% surgery  Cost  Euros 307 savings Imiquimod vs. Surgery  Euros 302 saving MAL-PDT vs. surgery

42. Summary  While surgery is clearly the gold standard, Imiquimod and photodynamic therapy clearly have a role in the treatment of basal cell carcinoma, especially superficial BCC  Utility as either primary or adjunctive treatment  Larger, prospective, randomized controlled- clinical trials are necessary to further determine the efficacy and cost-effectiveness of these treatments