"B.C.C. Management and Treatment Options. Dr J T Lear"

1. BCC – Management and
Treatment Options
Dr JT Lear,
Dermatology Centre
Manchester Royal Infirmary &
Dermatology Centre
Hope Hospital, Manchester

2. BASAL CELL CARCINOMA
Management and Treatment Options
November 2012
Dr John Lear
Consultant Dermatologist,
Central Manchester Hospitals
2

3. 3

4. 4

5. 5

6. 6

7. 7

8. Results in nBCC:
Lesion response & cosmesis (PP) 3- month follow-up
MAL-PDT Surgery MAL-PDT Surgery
100 98 100
91
90 90
82
80 80
70 70
60 60
50 50
40 40
33
30 30
20 20
10 10
0 0
Complete response Cosmetic outcomes
Rhodes et al; Arch Dermatol 2004; 140:17–23

9. nBCC: 5 year recurrence rates
MAL-PDT vs. surgery
100 98
91
90
80
70
60
50 MAL-PDT
40 Excision
30
20
14 14 14
10 10
4 0 0 2 4 4
0
3mth 12mth 24mth 36mth 48mth 60mth
CRR RR RR RR RR RR

10. nBCC:
5 year recurrence rates MAL-PDT
• MAL-PDT has now shown long term recurrence
rates:
- higher (14%) than surgery (4%)
– at least equivalent to recurrence rates of standard
alternative treatments to surgery
• PDT offers the benefit of non invasiveness,
rapid healing and better cosmetic outcome than
surgery

11. Long term outcomes MAL-PDT:
superficial basal cell carcinoma
(sBCC)

12. sBCC: 5 year recurrence rates
MAL-PDT vs cryotherapy
97 95
100
90
80
70
60
50 MAL-PDT
40
22 19 22 Cryotherapy
30 17 19 19 22 20
20 9 13
10
0
3mth 12mth 24mth 36mth 48mth 60mth
CRR RR RR RR RR RR

13. sBCC:
5 year recurrence rates MAL-PDT
• No new recurrences after 36 months
• Long term recurrence rates similar to recurrence
rates of standard cryotherapy (22% vs 20%)
• PDT offers non invasive, rapid healing and
better cosmetic outcome than cryotherapy
• Should be considered as a standard therapy for
sBCC

14. Long term outcomes MAL-PDT: Difficult-
to-treat basal cell carcinoma BCC

15. Why PDT for ‘difficult-to-treat’
BCC?
• Surgery, may be inappropriate in a number
of situations
– Large or many lesions, poor ability to heal, poor
vasculature, co-morbidities such as
immunosuppression, diabetes, anticoagulant
medication
– risk of keloid scarring

16. Study design
• Open studies in difficult-to-treat sBCC and
nBCC
• 94 patients, 123 lesions in European study
• 102 patients, 187 lesions in Australian study
• 2 MAL-PDT treatment sessions (160 mg/g, 3
hr); cycle repeated in the absence of CR
• Assessed clinical and histological response,
recurrence, cosmetic outcome, safety

17. Definition of ‘difficult-to-treat’
• Definition of ‘difficult-to-treat’
– large BCC:
• largest diameter >15 mm on extremities; >20 mm on trunk;
>15 mm on face
– BCC lesion located in H-zone
• as described by Swanson (mid-face, temple or ear)
– patient at high risk of surgical complications
• bleeding abnormalities, anticoagulant medication and/or
cardiac
– recurrent lesions
– Lesions in severely sun-damaged skin

18. Long term recurrence rates
100
92
90 87
80
70
60
% 50 Europe
40
29 Australia
30 28
24
20 1815 18 20
10 8 8
0
3m 12m 24m 36m 48m 60m
CRR RR RR RR RR RR
Horn et al; Br J Dermatol 2003; 149(6):1242–1249;
Vincuillo et al; Poster, World Congress of Cancers of the Skin, 2003

19. Imiquimod - Phase III Studies
• 724 patients enrolled
• Imiquimod 5% cream administered either
5x/week or 7x/week for 6 weeks vs vehicle
• Biopsy confirmed sBCC meeting study size
requirements (between 0.5 and 2.0 cm²)
• Tumour site clinically evaluated 12 weeks’
post-treatment, excised and evaluated
histologically
Geisse et al. 2004

20. Comparison of Clin / Histo,
and Histological Clearance
100 Clinical
90
& histological
82 clearance (ITT)
79
80 75 73 Histological
Response rate (%)
70 clearance (ITT)
60
p<0.001 vs vehicle groups
50
40
30
20
10 2 3 2 3
0
IMIQ 5x/week Veh 5x/week IMIQ 7x/week Veh 7x/week
Treatment group
Geisse et al. 2004

21. Correlation between Histological Clearance and
LSR
Imiquimod 5x/week
100 Severe
90 Moderate
Mild
% Complete responders
80
None
70
60
50
40
30
20
10
0
Erythema Erosion Scabbing/crusting
Test for trend: p<0.001 p=0.026 p<0.001
Geisse et al. 2004

22. Imiquimod 5x/week in the Treatment of sBCC:
Location: Upper mid back
Screening visit Treatment initiation Treatment week 3
Treatment week 6 Week 4 post-treatment Week 12 post-treatment

23. Evaluation of Long-term
Efficacy
• Multicentre, phase III, open label, long-term
follow-up study
• Imiquimod 5x per week for 6 weeks
• 182 patients (120m, 62f)
• Mean age 65 yrs
• Fitzpatrick skin phototypes II and III (90%)
• Majority of target tumours (62%) located on
trunk
• Target tumours ranged in size from 0.5 cm² to
2.0 (maximum diameter)
Gollnick et al. Poster presented at AAD 62nd Annual Meeting,
Washington DC, 7-9 Feb 2004

24. Long-term sBCC Study: Results to 2-year
Estimate of sustained clearance of BCC during
long-term follow-up (ITT) with 5x week dosing
97.5%
for 6 weeks
100 94.9% 93.7%
88.7%
90
80
Clearance rate (%)
70
60
50
40
30
20
10
0
Month 3 Month 6 Month 12 Month 24
Gollnick, presented at AAD 2004 & data on file

25. Conclusions
Imiquimod 5% cream:
• High clearance rates, comparable to
conventional treatment, with a sustained
effect up to one year
• Non-invasive, non-scarring treatment
option
– Excellent cosmetic results

26. Cryotherapy
• 395 patients
• Overall cure rate of 97%.
• Recurrences were seen in 6 out of 225 (2.7%), at median 18
months.
• The patients were treated as out-patients using local anaesthesia
and all tolerated the treatment well. 2 x 30 seconds
• Cryosurgery safe, low cost and effective method of treating selected
non-melanoma skin cancer
• Follow up carefully for 2 years post-operatively.
• Br J Dermatol. 1988 Aug;119(2):231-40. Holt P

27. 5 Flourouracil
• Fluorouracil clearance rates:
• 90% for superficial BCC and
• 27% to 85% for SCC in situ.
• Up to 100% applying fluorouracil, experienced at
least 1 adverse event. Adverse event intensity
ranged from mild to severe; erythema, pruritus,
and pain were common.
• Love WE. Arch Dermatol. 2009 Dec;145(12):1431-8.

28. Oral Agents
• See next presentation/
Slides 47 to 58

29. Advanced Basal Cell Carcinoma (aBCC)
•BCC is the most commonly diagnosed human
cancer worldwide1
•Most BCCs are curable by surgery; however,
some can progress to locally advanced (la) or
metastatic (m) disease2,3
•For patients with advanced forms of BCC, no
standard therapies exist2-4
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30. Oral Agents
• LDE in development
• 33 patients with metastatic or locally advanced BCC
• Median treatment 9.8 months.
• NEJM 2009 Sep 17;361(12):1164-72. Von Hoff DD et al.
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31. STEVIE: a Single-Arm Open-Label Study to
Assess the Safety of the Hedgehog Pathway
Inhibitor, Vismodegib, in Patients with
Advanced Basal Cell Carcinoma: Second
Interim Analysis
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32. Hedgehog signalling is critical for embryonic development1
Activation of SMO or functional loss of PTCH in >90 % of BCC2-5
1. Scales SJ, de Sauvage FJ. Trends Pharmacol Sci 2009;30:303–12. 2. Teh MT, et al. Cancer Res 2005;65:8597–603. 3. Kallassy M, et al. Cancer Res 1997;57:4731–5.
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4. Unden AB, et al. Cancer Res 1997;57:2336–40. 5. Reifenberger J, et al. Cancer Res 1998;58:1798–803.

33. Vismodegib is a first-in-class, oral, selective
Hedgehog pathway inhibitor (HPI)
• Vismodegib is a small-molecule,
Hedgehog pathway inhibitor, that
binds to SMO1
• Molecular weight 421.3 g/mol
• Vismodegib is a highly potent,
selective inhibitor of SMO
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1. Dirix L, Rutten A. Future Oncol 2012;8:915–28

34. ERIVANCE BCC, the pivotal study for
vismodegib
• ERIVANCE BCC led to approval of vismodegib by the FDA in
January 2012
 For the treatment of adults with metastatic BCC, or with locally
advanced BCC that has recurred following surgery or who are not
candidates for surgery and who are not candidates for radiation therapy
Sekulic A et al. New Engl J Med 2012;366:2171–9 34

35. STEVIE: study design and objectives
Progressive disease
Vismodegib
Patients with locally
(150 mg orally once daily) Other anti-BCC therapy
advanced, inoperable
Treatment until progressive (to be decided by
or metastatic BCC
disease, unexpected toxicity treating physician)
(n = up to 800)
or patient request to discontinue
• STEVIE is a single-arm open-label study to assess the safety of vismodegib in
patients with advanced BCC
Primary objective:
• Safety
Secondary objectives:
• Overall response (based on Response Evaluation Criteria in Solid Tumors
[RECIST]); objective response rate, duration of response, progression-free
survival (PFS) and overall survival
• Quality of Life
http://clinicaltrials.gov/ct2/show/NCT01367665 Accessed September 2012 35

36. Conclusions
• Each topical therapy has positives / negatives,
great to have a choice, but non-specific action
• Topical therapy increasingly important
• Specific pathway inhibition, promise orally, side
effect profile limits use
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