Basal Cell Cancer: Update on Treatment and Management

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

Risk Factors

Syndromes- Basal cell nevus,

XP, Bazex, Rombo

Treatment

Mohs Surgery Excisional Surgery Currettage and Electrodessication Cryosurgery Laser Surgery Radiation Photodynamic Therapy Topical chemotherapy

Why pursue non-surgical treatment modalities Patient not surgical candidate

Patient refuses surgical treatment

Lower costs??

Cosmetically more acceptable

Reasonable cure rate

Topical Chemotherapy

Topical Chemotherapy

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.

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??

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

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

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

Imiquimod

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

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.

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

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):471-476Werlinger KD et al Dermatol Surg. 2002 December;28(12):1138-1142.

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

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

Imiquimod as Adjunctive Treatment

Imiquimod as Adjunctive Treatment

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

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)

 

Photodynamic Therapy

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

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

PDT-Topical Photosensitizers5-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

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.

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.  

PDT - Protocol

MAL-PDT (determined with ActiliteTm 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

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 rateHaller 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.

 

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.

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 keratosisVarma S Br J Dermatol 2000;142:812–51Wolf P Dermatology 1997;1:53–4Karen J Dermatol Surg. 2010 Aug;36(8):1328-31.

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 surgeryRhodes LE et al. Arch Dermatol 2004;140:17–23.

Tope WD et al. J Eur Acad Dermatol Venerol 2004;18 (Suppl 2):413–4.

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.

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

PDT as Adjuvant Therapy

MAL-PDT after 3 hours of occlusion 37 J/cm2 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)

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

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