New findings in systemic treatment of basal cell carcinoma

Abstract

The majority of primary basal cell carcinomas (BCCs) are treated surgically or, in surface lesions, using non surgical methods. The risk of recurrence increases with tumour size, poorly defined lesion margins, an aggressive histologic sub-type and previous recurrence. In some cases, the tumour can destroy the surrounding tissues (muscles, bones, cartilage etc.) due to long-term absence of treatment or aggressiveness of the tumour (locally advanced form of BCC - IaBCC).
In extremely rare cases, BCC spreads also to distant tissues (metastatic BCC - mBCC). In multiple local recurrences or invasion of surrounding/distant structures (laBCC/mBCC), where surgery and/or radiation therapy are not appropriate, it is important to use a multidisciplinary approach in patient management.
Abnormal activation of the Hedgehog signalling pathway is responsible for the occurrence of the disease in 90 % of BCCs. By selectively binding to the transmembrane protein SMO (Smoothened Transmembrane Protein), the active substance vismodegib selectively inhibits the abnormally activated signalling pathway. Phase II clinical trial ERIVANCE BCC reported on the efficacy and safety of vismodegib in patients with laBCC and mBCC. The primary objective of this study was objective response rate (complete and partial) as assessed by an independent review board. The study results showed that an objective response was achieved in 33.3% of patients with mBCC and 47.6% of patients with laBCC. Disease control (objective response + stable disease) was confirmed in 94% of patients with mBCC and 83%
of patients with laBCC. After 24 weeks of treatment, a total of 54% of patients with laBCC had no histopathological signs of basal cell carcinoma. According to the most recent data, the median duration
of objective response was 14.8 months in mBCC and 26.2 months in laBCC. The encouraging results of treatment with vismodegib in a phase II trial show a significant decrease in the size of multiple lesions and number of newly occurred lesions in patients with Gorlin syndrome.
The most common adverse effects included muscle cramps, loss of taste, hair loss and fatigue.

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Povzetek

Večino primarnih bazalnoceličnih karcinomov (BCK) zdravimo kirurško ali pri površinskih lezijah z nekirurškimi metodami. Tveganje za ponovitev povečujejo velikost tumorja, slabo definiranimi robovi lezije, agresiven histološki podtip in prejšnja ponovitev. V nekaterih primerih lahko tumor uniči okoljna tkiva (mišice, kosti, hrustanec itd.), zaradi dolgotrajne odsotnosti zdravljenja ali agresivnosti tumorja (lokalno napredovala oblika BCK – lnBCK). V izjemno redkih primerih BCK napreduje v oddaljena tkiva (metastatski BCK – mBCK). Pri večkratnih lokalnih ponovitvah ali pri invaziji okoljnih/oddaljenih struktur (lnBCK/mBCK), kjer kirurgija in/ali obsevanje nista primerni, je pomemben multidisciplinarni pristop pri obravnavi bolnika.Nenormalna aktivacija signalne poti Hedgehog je odgovorna za nastanek bolezni pri 90 % BCK. S selektivno vezavo na transmembranski protein SMO (Smoothened TransmembraneProtein) učinkovina vismodegib selektivno zavira nenormalno aktivirano signalno pot. V klinični raziskavi faze II, ERIVANCEBCC, so poročali o učinkovitosti ter varnosti vismodegiba pri bolnikih z lnBCK in mBCK. Primarni cilj raziskave je bil objektivni delež odziva (popolni in delni), kot ga je ocenila neodvisna ustanova za pregled. Rezultati raziskave so pokazali,da je bil objektivni odgovor dosežen pri 33,3 % bolnikov zmBCK in 47,6 % bolnikov z lnBCK. Kontrola bolezni (objektivni odgovor + stabilna bolezen) je bila potrjena pri 94 % bolnikov z mBCK in 83 % bolnikov z lnBCK. Po 24 tednih zdravljenja 54 % bolnikov z lnBCK ni imelo histopatoloških znakov bazalnoceličnega karcinoma. Po zadnjih podatkih je bila mediana trajanja objektivnega odgovora 14,8 meseca pri mBCK in 26,2 meseca pri lnBCK. Vzpodbudni rezultati zdravljenja z vismodegibom v raziskavi faze II kažejo na bistveno zmanjšanje velikosti multiplih lezij in števila novonastalih lezij pri bolnikih z Gorlinovim sindromom. Najbolj pogosti neželeni učinki so bili mišični krči, spremembe okusa, izguba las in utrujenost.