Anais Brasileiros de Dermatologia 2021;96(6):712---716

Anais Brasileiros de
Dermatologia
www.anaisdedermatologia.org.br

ORIGINAL ARTICLE

Vismodegib for treatment of periocular basal cell

carcinoma --- 6-year experience from a tertiary cancer
center夽,夽夽
a,∗
Catarina Xavier , Edgar Lopes a , Catarina Bexiga b
, Cecília Moura c
,
b
Emanuel Gouveia , Ana Filipa Duarte a,d

a
Department of Ophthalmology, Centro Hospitalar Universitário de Lisboa Central, Lisboa, Portugal
b
Department of Oncology, Instituto Português de Oncologia Francisco Gentil, Lisboa, Portugal
c
Department of Dermatology, Instituto Português de Oncologia Francisco Gentil, Lisboa, Portugal
d
Department of Ophthalmology, Instituto Português de Oncologia Francisco Gentil, Lisboa, Portugal

Received 25 March 2021; accepted 19 April 2021

Available online 11 September 2021

Abstract
KEYWORDS
Background: The treatment of advanced periocular basal cell carcinomas becomes a challenge
Hedgehog proteins; as surgery may involve highly mutilating procedures. Vismodegib is the first selective hedgehog
Skin neoplasms; inhibitor approved for the treatment of locally advanced tumors or metastatic disease.
Carcinoma, basal cell Objective: Analyze the results of treatment with vismodegib for advanced periocular basal cell
carcinomas in a real-life setting of a reference center between 2014 and 2020.
Methods: Retrospective longitudinal study. The patient’s demographic profile, comorbidities,
tumor characteristics, and treatment outcomes were analyzed.
Results: A total of 13 patients were included. Median follow-up and treatment duration were
15.9 and 10.5 months, respectively. Objective clinical response rate was 76.9%: 30.8% had
a complete response and 46.2% a partial response. The median duration of response was 13
months. Progressive disease was observed in 38.5% of cases, with a median of 19 months after
the beginning of treatment. Eighty-four percent of the patients had at least one adverse event,
and 61.54% needed to interrupt treatment temporarily or permanently to increase tolerability.
Study limitations: Being a retrospective study in a real-life setting, the evaluation of objective
clinical response was subjective to physician appreciation.

夽 How to cite this article: Xavier C, Lopes E, Bexiga C, Moura C, Gouveia E, Duarte AF. Vismodegib for treatment of periocular basal cell

carcinoma --- 6-year experience from a tertiary cancer center. An Bras Dermatol. 2021;96:712---6.
夽夽 Study conducted at the Instituto Português de Oncologia Francisco Gentil, Lisboa, Portugal
∗ Corresponding author.

E-mail: [email protected] (C. Xavier).

https://doi.org/10.1016/j.abd.2021.04.012
0365-0596/© 2021 Sociedade Brasileira de Dermatologia. Published by Elsevier España, S.L.U. This is an open access article under the CC
BY license (http://creativecommons.org/licenses/by/4.0/).
 Anais Brasileiros de Dermatologia 2021;96(6):712---716

Conclusion: Vismodegib is a safe and effective treatment for locally advanced basal cell carci-
noma. To prevent recurrences, the drug should be used continually when tolerated. The role of
neoadjuvant vismodegib before surgery is being investigated and might add an important step
in searching for a definitive treatment for these cases.
© 2021 Sociedade Brasileira de Dermatologia. Published by Elsevier España, S.L.U. This is an
open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Introduction date when still responding. Time and cause of death were
also registered.
Basal Cell Carcinoma (BCC) is the most common type of can- Lastly, the authors also studied the drug’s tolerability by
cer in the periocular area. It is a slowly growing tumor but analyzing each patient’s adverse events and if they led to
can cause extensive local destruction of skin, muscle, or treatment interruption or discontinuation.
even bone.1 These Locally Advanced Basal Cell Carcinomas
(laBCC) arise either from early lesions that have not been Results
treated or from a recurrence of aggressive subtypes of BCC.
When localized to the periocular area they can cause sub- Of a total of 26 patients who received vismodegib treat-
stantial morbidity. Metastatic Basal Cell Carcinomas (mBCC) ment, 13 had periocular laBCC and were included in the
are extremely rare.2,3 present study: 6 were males and 7 females, with a mean
In most cases, BCC can be treated with surgery, cryother- age of 73 (54---96) years old at the beginning of the treatment
apy, or laser ablation. Other non-surgical therapies such (Table 1).
as radiotherapy, photodynamic therapy, and topical treat- The treatment was administered during a median of 10.5
ment with imiquimod or 5-fluorouracil may be used in locally (2.7---41.2) months. ORR was 76.9%: 4 (30.8%) patients with
circumscribed BCC.2 The treatment of periocular laBCC CR and 6 (46.2%) with PR. SD was observed in 3 cases (23.1%).
becomes a challenge since extensive surgery and radiother- The median DOR was 13 (2.6---52.5) months.
apy may comprise considerable morbidity. With a median follow-up time of 15.9 (2.7---53.5) months,
The majority of sporadic BCC show mutations that ini- the total PD rate was 38.5% (5 patients) in a median time
tiate the sonic hedgehog pathway and cause uncontrolled of 19 (5.5---32.5) months after starting vismodegib. Two of
cell proliferation.4 Being the main driver in BCC pathogen- these cases were patients with SD, with a mean DOR of 32
esis and progression, the Hedgehog pathway represents a months; one of them was under intermittent treatment due
critical therapeutic target.4 Vismodegib is the first selec- to poor tolerability and died of an unknown cause 2 years
tive Hedgehog inhibitor approved for the treatment of laBCC after PD. Another case of PD was a PR who had a DOR of 5.5
or mBCC in adults who cannot be treated with surgery or months. This patient died due to complications of the BCC
radiotherapy.5 2 months after PD appearance. The other 2 cases with PD
This work aims to describe the experience from a tertiary had an initial clinical CR, with a mean DOR of 16 months;
cancer center using vismodegib for advanced periocular PD occurred after discontinuation of the treatment due to
BCCs. toxicity --- vismodegib was later reintroduced with PR. One
of these patients underwent a biopsy while on CR that didn’t
show neoplastic cells.
Methods Concerning the 4 cases with clinical CR, 2 had PD, as
described above, one is still under treatment (after 24
months) without PD, and the remaining one stopped the drug
We conducted a retrospective longitudinal consecutive
after undergoing surgery that didn’t show neoplastic cells on
study of the patients who started vismodegib (150 mg/day)
the histology. The latter died of other medical comorbidities
for periocular BCC in a tertiary cancer center (Instituto Por-
10 months after stopping vismodegib, without signs of PD.
tuguês de Oncologia Francisco Gentil, Lisbon) between July
Considering the safety profile and treatment tolerance,
2014 and January 2020. The patient’s demographic profile,
most patients (84.6%) had at least one adverse event, the
treatment outcomes, and adverse events were analyzed.
most common being muscle spasms (69%), fatigue (61.5%),
The primary outcome was defined as an Objective clinical
alopecia (46.2%), and dysgeusia (46.2%). Despite being
Response Rate (ORR), which was the sum of the com-
mostly mild toxicity, 1 patient (7,68%) discontinued the
plete and partial response rates. We considered Complete
treatment permanently, and 7 patients (53.85%) needed to
Response (CR) the absence of clinical tumor and Partial
interrupt vismodegib to increase tolerability. No patients
Response (PR) the decrease in the tumor’s size without its
had signs of rhabdomyolysis nor developed squamous cell
disappearance. Stable disease (SD) was considered when vis-
carcinoma. During follow-up, four patients died, only 1 of
modegib could cease the tumor’s progression, but there was
them related to PD.
no decrease in its size. When the tumor showed charac-
teristics of regrowth, it was considered Progressive Disease
(PD). Discussion
Other variables evaluated were the duration of treat-
ment, the Duration of Response (DOR) --- the time from the The treatment of advanced forms of BCC is a challenge, and
beginning of the therapy to PD, death, or the last control until recent years limited to surgery and/or radiation ther-

713
 Table 1 Demographic and treatment-related data of the patients included in this case series.

Demographic and treatment-related data

n Age Gender Duration of Objective DOR PD Currently Adverse events Last Timing and
treatment response (months) under follow-up cause of death
(months) (months)
1 83 F 30.8 SD 30.8 Yes No Fatigue 32.7 54.30 unknown
2 62 M 2.7 SD 2.6 No No --- 2.7 2.70 Septic
shock
3 78 F 24.1 CR 24 No Yes Muscle spasms, alopecia, 24.1 ---
dysgeusia, weight loss,

C. Xavier, E. Lopes, C. Bexiga et al.

fatigue, nausea, anorexia,
arthralgias
4 67 M 6 CR 19 Yes Yes Muscle spasms, dysgeusia, 15.9 ---
weight loss, fatigue
5 61 M 10.5 CR 13 Yes Yes Muscle spasms, alopecia, 21.9 ---
dysgeusia, fatigue, nausea,
diarrhea
714

6 82 F 6.5 PR 5.5 Yes No Fatigue, anorexia 6.5 7.6 Progressive

disease
7 70 M 3.8 CR 11.8 No No Muscle spasms, alopecia, 11.8 11.8 unknown
dysgeusia, weight loss,
fatigue
8 76 F 41.2 PR 41.2 No Yes Muscle spasms, alopecia, 41.2 ---
fatigue, nausea, anorexia
9 54 F 32.8 SD 32.5 Yes No Muscle spasms, alopecia, 48.8 ---
dysgeusia, fatigue, nausea,
anorexia
10 65 F 12.9 PR 52.5 No No Muscle spasms, alopecia, 53.5 ---
dysgeusia, weight loss
11 96 F 5.1 PR 5.1 No Yes --- 5.1 ---
12 71 M 9.3 PR 9.2 No Yes Muscle spasms 9.3 ---
13 84 M 10.5 PR 10.5 No Yes Muscle spasms 10.5 ---

M, Male; F, Female; SD, stable disease; CR, Complete Response; PR, Partial Response; PD, progressive disease; DOR, duration of response.
 Anais Brasileiros de Dermatologia 2021;96(6):712---716

apy. Vismodegib has unquestionably shifted the approach Conclusion

to these cases. Two international, multicenter clinical trials
showed ORRs of 68.5% and 60.3% for laBCC 4,6 with the use The present study’s results support the evidence that vis-
of this drug. These results are inferior to the ORR of 76.9% modegib is a safe and effective treatment for laBCC;
reported in this study, which is probably overestimated due nevertheless, further studies are needed to establish the
to less strict and more subjective clinical criteria used in efficacy of vismodegib, and most importantly, its place in
real-life practice. the neoadjuvant setting. Its role in unresectable laBCC as a
The most common adverse events described in the liter- bridge to surgery seems to be an important step toward the
ature are muscle spasm, dysgeusia, and alopecia,4 which definitive treatment of these challenging cases.
is in accordance with the present study’s results. These
were generally mild, however very frequent, and in a not
negligible number of cases lead to the discontinuation of
Financial support
treatment.
Temporary interruption of vismodegib (on and off regi- None declared.
men) is a commonly used strategy that allows patients to
remain on treatment without reducing efficacy.4 The pri- Authors’ contributions
mary analysis of the MIKIE study,7 which compared two
intermittent regimens with 8 weeks pauses, showed that Catarina Xavier: Approval of the final version of the
the interruption of treatment did not compromise the manuscript; critical literature review; data collection, anal-
activity of vismodegib. Both regimens controlled the dis- ysis, and interpretation; effective participation in research
ease during the entire treatment period in most patients.7 orientation; preparation and writing of the manuscript; sta-
An exploratory analysis of the STEVIE study4 also demon- tistical analysis; study conception and planning.
strated that an increased treatment interruption was Edgar Lopes: Approval of the final version of the
associated with increased median treatment duration and manuscript; critical literature review; data collection, anal-
overall response rate.4 Therefore, the interruption of ysis, and interpretation; effective participation in research
vismodegib has been included in a consensus recommen- orientation; preparation and writing of the manuscript.
dation of treatment strategies in patients with advanced Catarina Bexiga: Approval of the final version of the
BCC.7 manuscript; critical literature review; data collection, anal-
The authors noticed that 60% of the PD cases in the ysis, and interpretation; effective participation in research
present study occurred during periods of treatment inter- orientation; intellectual participation in propaedeutic
ruption superior to 8 weeks. The authors agree that as and/or therapeutic management of studied cases; study
long as the adverse events are tolerated, vismodegib can conception and planning.
be taken on a continuous regimen and that intermittent Cecília Moura: Approval of the final version of
regimens should limit the intervals without treatment to the manuscript; intellectual participation in propaedeu-
a maximum of 2 months, if possible. Importantly, in poor tic and/or therapeutic management of studied cases;
tolerability cases, an intermittent regimen should always manuscript critical review; study conception and planning.
be discussed before deciding to stop the treatment. The Cecília Moura: Approval of the final version of
authors believe that the study’s outcomes using vismodegib the manuscript; intellectual participation in propaedeu-
could be improved with a stricter protocol for cases that tic and/or therapeutic management of studied cases;
require an intermittent regimen. manuscript critical review; study conception and planning.
A histologic cure is not guaranteed with the Hedge- Ana Filipa Duarte: Approval of the final version of
hog inhibitor therapy alone, even when complete clinical the manuscript; intellectual participation in propaedeu-
remission is obtained. Some authors suggest that the dis- tic and/or therapeutic management of studied cases;
continuation of the drug without additional surgery may manuscript critical review; study conception and planning.
leave the residual or noncontiguous tumor, potentially resis-
tant to treatment.1 The risk of subsequent tumor regrowth,
Conflicts of interest
which may be more aggressive or difficult to treat, sup-
ports the use of these drugs in association with other
modalities of treatment.1,8 MS Ally et al.8 showed that the None declared.
use of vismodegib as neoadjuvant therapy for at least 3
months before surgery presented an overall benefit in redu- References
cing the tumor area and surgical defect size. However, if
skip areas of apparent tumor-free tissue alternating with 1. Tang N, Ratner D. Implementation of Systemic Hedgehog
clinical BCC develop, this modality could potentially lead Inhibitors in Daily Practice as Neoadjuvant Therapy. J Natl Compr
to delayed tumor recurrence in the supposedly treated Canc Netw. 2017;15:537---43.
areas.1,8 This could explain the disease’s recurrence in the 2. Martens U. Small Molecules in Oncology. Recent Results in Cancer
Research, 211. 3rd ed. USA: Springer; 2018. p. 125---39.
study’s patient with CR whose biopsy didn’t show malig-
3. Trakatelli M, Morton C, Nagore E, Ulrich C, Del Marmol V, Peris K,
nant cells. Such tumors would require wide-margin surgery
et al. Update of the European guidelines for basal cell carcinoma
to optimize local control and minimize the recurrence management. Eur J Dermatol. 2014;24:312---29.
risk.1,8

715
 C. Xavier, E. Lopes, C. Bexiga et al.

4. Sekulic A, Migden MR, Basset-Seguin N, Garbe C, Gesierich A, Lao 7. Dréno B, Kunstfeld R, Hauschild A, Fosko S, Zloty D, Labeille B,
CD, et al. Long-term safety and efficacy of vismodegib in patients et al. Two intermittent vismodegib dosing regimens in patients
with advanced basal cell carcinoma: final update of the pivotal with multiple basal-cell carcinomas (MIKIE): a randomised,
ERIVANCE BCC study. BMC Cancer. 2017;17:332. regimen-controlled, double-blind, phase 2 trial. Lancet Oncol.
5. Velleman J, Kaarela O, Vranckx JJ. Treatment of basal cell 2017;18:404---12.
carcinoma with vismodegib: future or present? Acta Chir Belg. 8. Ally MS, Aasi S, Wysong A, Teng C, Anderson E, Bailey-Healy I,
2019:1---6. et al. An investigator-initiated open-label clinical trial of vis-
6. Basset-Séguin N, Hauschild A, Kunstfeld R, Grob J, Dréno B, modegib as a neoadjuvant to surgery for high-risk basal cell
Mortier L, et al. Vismodegib in patients with advanced basal cell carcinoma. J Am Acad Dermatol. 2014;71:904---11.
carcinoma: Primary analysis of STEVIE, an international, open-
label trial. Eur J Cancer. 2017;86:334---48.

716