CASE REPORT

Izabela Małgorzata Łasińska1, Jacek Kocur2, Tomasz Bajon3, Jacek Mackiewicz1, 4, 5

1Department of Clinical and Experimental Oncology, Heliodor Swiecicki Clinical Hospital, Medical University in Poznan

2Department of Radiology, Greater Poland Cancer Centre

3II Department of Radiotherapy, Greater Poland Cancer Centre

4Department of Biology and Environmental Protection, Medical University in Poznan

5Department of Diagnostics and Tumour Immunology, Greater Poland Cancer Centre

Vismodegib — a chance for improvement of quality of life in patients with locally advanced basal cell carcinoma — a case report

ABSTRACT

Basal cell carcinoma (BCC) is the most common non-melanocytic skin cancer. Therapeutic strategies available so far include: surgical resection, radiotherapy, or — in the case of low risk of recurrence — superficial application of drugs like 5-fluorouracil or imiquimod. The frequent localisation of BCC is eye bulb area, often with deep penetration into the tissues. Standard therapies in this area may lead to blindness. The Hedgehog (HH) pathway is a key point in BCC development. For patients with advanced BCC, not suitable for surgical resection or radiotherapy, oral small-molecule drug inhibitors of this pathway are the new therapeutic option. Here we present a case of a patient with locally advanced skin BCC localised on the face, sinuses, and eye-socket region. Wide excision with the right eye bulb resection was performed. Eight months after the treatment the patient developed regional recurrence. Due to the advanced stage of the disease the patient was disqualified from further surgical resection. Use of radiotherapy was associated with high risk of blindness of the left eye. The patient was treated with vismodegib and developed a complete response. Moreover, we avoided blindness after radiotherapy. Also, the patient’s symptoms due to locally spreading cancer resolved. The patient has been receiving HH inhibitor without any progression in imaging tests for 20 months.

Key words: basal cell carcinoma, Hedgehog pathway, vismodegib

Oncol Clin Pract 2016; 12, 1: 25–28

Introduction

Basal cell carcinoma is a tumour with low potential for metastasis. It shows, however, a tendency to invade and destroy the surrounding tissues. The most common localisation of BCC (approximately 80% of cases) is the skin of the head and neck. It is usually possible to conduct radical surgery in the case of tumours occurring on the skin of limbs or trunk. However, the face area is often a technical challenge due to difficulties in meeting the aesthetic expectations of patients. Radiation therapy is applied after non-radical resection or in unresectable cases [1]. Vismodegib and sonidegib are two inhibitors of the Hedgehog (HH) pathway currently registered for the treatment of patients with locally advanced BCC, who are not candidates for surgery or radiation therapy. Vismodegib can also be used for BCC patients with metastatic disease, which occurs very rarely [2, 3].

The HH pathway plays a key role during embryogenesis. It is responsible for both proliferation and differentiation of the tissues and the correct location of the body’s cells [4]. Disorders in HH signalling pathway during embryogenesis lead to significant deformation. Germinal mutations in the genes synthesising the components of HH pathway are responsible for multiple developmental defects [5]. In mature tissues HH pathway is muted; however, it might be activated during tissue repair. Incorrect reactivation of HH pathway can lead to cancer. Activation of HH pathway may depend or be independent on HH ligand. In the case of ligand-dependent activation HH protein binds to a specific inhibitory receptor PTCH1 (Patched 1) and consequently causes the activation of SMO protein (Smoothened). This leads to the activation of transcription factors GLI (glioma-associated oncogene) and its localisation in the nucleus with induction of target genes of HH pathway [6–9]. Ligand-independent activation of HH pathway results from mutations in the PTCH1 gene synthesising abnormal receptor for proteins SMO or GLI-1 [6–10]. In BCC the most frequent mutation occurs in the gene encoding PTCH1 and SMO [11, 12]. Mutations in the gene encoding PTCH1 can also be observed in Gorlin syndrome, which is an autosomal dominant disease. Typical for Gorlin syndrome is the occurrence of a large number of BCC, which can appear as early as in childhood. In addition, in patients with Gorlin syndrome, abnormalities within the shape of bones and cartilage, jaw cysts, and increased risk of developing cancer, i.e. medulloblastoma and rhabdomyosarcoma, can be observed [12–15].

Vismodegib and sonidegib are oral, low-weight molecular agents that bind to the SMO protein inhibiting its function and thus leading to blockage of signal transduction in HH pathway. Vismodegib was the first HH inhibitor registered in Europe. The activity of the drug (daily dose — 150 mg) was first demonstrated in a randomised, double-blind trial, which was conducted in a group of 41 patients with a diagnosis of Gorlin syndrome. The trial showed a significant reduction of the incidence of new BCC lesions after the application of vismodegib when compared to placebo. During treatment with vismodegib none of the patients experienced progression of BCC. Adverse events occurred most often in grades 1 and 2, and included the loss of taste, muscular pain, alopecia, and weight loss [16].

Sixty-three patients with locally advanced BCC and 33 patients with metastatic disease were included to a further study (ERIVANCE BCC) evaluating the effectiveness of vismodegib. There was no randomisation in the study, and patients with sporadic BCC and diagnosis of Gorlin syndrome were enrolled. In patients with locally advanced BCC objective response rate (ORR) as a result of the treatment occurred in 43% of patients, and stable disease (SD) was observed in 38% of patients. In the group of patients with metastatic BCC ORR was 30%, and SDs were observed in 64% of the treated group. Median progression-free survival (PFS) was 9.5 months in both groups. Median overall survival (OS) in patients with metastatic BCC reached 33.4 months, while in the group of patients with locally advanced BCC the median OS was not reached. Adverse events grade 3. and 4. occurred in 18% of patients — most often these were weight loss (5%), muscle cramps (4%), fatigue (4%), and decreased appetite (3%) [17]. The results of this study led to the registration of vismodegib in patients with locally advanced and metastatic BCC. The updated results of the ERIVANCE study demonstrated a median duration of response in patients with locally advanced BCC and metastatic BCC of 26.2 and 14.8 months, respectively [18].

Sonidegib is another registered HH pathway inhibitor; the drug is used in a daily dose of 200 mg. A phase II randomised trial (BOLT) compared the efficacy and toxicity of sonidegib at doses of 800 mg and 200 mg. The lower dose was less toxic and its application was associated with a higher percentage of ORR (43% vs. 38%) than the bigger dose. In the study 230 patients with locally advanced and metastatic BCC were enrolled. Gorlin syndrome was diagnosed in 16 of these patients. Of the 79 patients receiving sonidegib in a dose of 200 mg, the majority (66) were diagnosed with localised disease (13 patients in this group had metastatic disease). In patients with locally advanced BCC objective responses were observed in 47% of patients — complete response (CR) in 3%, and a partial response (PR) in 44% — while the SD occurred in another 44%. In patients with metastatic BCC PR and SD were recorded in 15% and 72%, respectively (no CR observed). In patients with locally advanced BCC the median PFS at the time of analysis was not reached, whereas in the group of patients with metastases median PFS was 13.1 months. In both groups a median duration of response was not reached. Grade 3. and 4. treatment-related adverse events were reported in 31% of the patients receiving sonidegib in a dose of 200 mg. The most common toxicities were increased level of serum creatinine (7%) and lipase (5%), muscle cramps (3%), fatigue (3%), and hypertension (3%) [19].

Case report

The patient was seen in December 2012 in the oncology outpatient clinic because of extensive tumour deriving from the skin of the face, which had been growing for approximately twelve years. The patient presented the result of a pathological examination of the biopsy taken from the tumour, which confirmed the diagnosis of BCC. Infiltration covered the nose with loss of tissue on the right side, the tumour invaded the forehead and zygomatic area and was spreading within the eye socket on the same side. The craniofacial computed tomography examination found a polycyclic mass causing destruction of the right nasal bone. The tumour infiltrated frontal sinus destroying its bottom and front walls. Through the destroyed roof of the orbit and the wall of the labyrinth the tumour invaded the front of the right ethmoid and right orbital area, filling its medial-upper and lower parts and moving the eyeball to the side. On the left side tumour grew from the back of the nose to the left eyebrow and through the destroyed section of the medial orbital floor into the front of the upper-medial angle of the orbit. The patient was referred to a laryngologist for qualification for surgical treatment. A non-radical (R1 — the presence of a tumour within the surgical margin) removal of the tumour was conducted. External nose and the skin around the zygomatic and forehead area was removed. Surgeons excised the frontal and ethmoid sinus and removed the content of the eye socket on the right side. Plastic surgery was conducted along with the filling of the tissue loss. Pathological examination results found invasive nodular BCC. Due to the wide post-resection lodge, post-operative radiotherapy was not decided and close follow-up was recommended. Eight months after the treatment no signs of recurrence were found on craniofacial computed tomography on the right side, while on the left side a relapse was observed. A tumour measuring 26 × 38 mm infiltrated the ethmoid bone and reached to dura mater of the middle cranial fossa. Upwards it directly infiltrated the eyelid and orbital wall, causing a protrusion on the left eyeball (Fig. 1A). Recurrence of the disease caused severe pain, and also vision disorder and lacrimation appeared. General condition of the patient assessed by the classification of ECOG (Eastern Cooperative Oncology Group) was 1.

Figure 1. Computed tomography picture before (A) and after three months of treatment with vismodegib (B)

The patient was disqualified from surgery and was initially offered radiotherapy. He was informed about possible side effects of the treatment, mainly resulting in the damage of the only left eyeball and the risk of blindness. The patient at the time agreed to the proposed treatment. During the consultation, a clinical oncologist suggested qualifying the patient for treatment with vismodegib. In October 2013, the patient began treatment, and after a month the computed tomography showed PR of the disease. After two months of treatment the patient was in CR (Fig. 1B). The patient’s general condition improved (ECOG 0) and he reported pain reduction, improved visual acuity, and disappearance of lacrimation. The patient has received Hedgehog pathway inhibitor for 20 months, still without any signs of recurrence in radiological examination. No previously reported symptoms associated with cancer therapy, or side effects of treatment, occurred.

Conclusions

Vismodegib and sonidegib show very high activity in patients with advanced BCC. The efficacy and toxicity profile of both drugs are similar. Vismodegib is additionally registered in patients with metastatic BCC. Basal cell carcinoma is the most common cancer occurring in the area of the eye, and counts for about 90% of cancers of the eyelids [20, 21]. In the literature there are single reports on the use of HH inhibitors for the treatment of tumours localised in the area of the eye [22]. A case was also described with use of an HH pathway inhibitor in the neoadjuvant setting. Significant reduction in the tumour size around the left eyeball allowed an adequate margin of resection with the assumption of aesthetic satisfaction and preserving the eyeball [23]. Treatment with vismodegib was associated with a significant benefit in our patient. On one siede, it allowed us to avoid the loss of the only eyeball, which could have been a consequence of radiation therapy. In addition, the patient’s symptoms improved. Treatment produced CR and more than 20-month’ progression-free survival (the response still persists). In the ERIVANCE study the median duration of response observed in patients with locally advanced BCC treated with vismodegib was about 26 months. Due to the effectiveness of the treatment and the absence of side effects, we plan to continue the current proceedings.

Further studies are required to determine the place of vismodegib in the treatment of patients with BCC. New treatment options, for instance with the use of vismodegib or sonidegib, allow a significant improvement in the quality of life of patients with BCC. Regardless of registration in Europe, the use of these drugs in Poland is not possible due to restrictions on reimbursement by the National Health Fund.

Address for correspondence:

Lek. Izabela Małgorzata Łasińska

Oddział Onkologii Klinicznej i Doświadczalnej, Szpital Kliniczny

im. Heliodora Święcickiego, Uniwersytet Medyczny w Poznaniu

ul. Grunwaldzka 16/18, Poznań

Phone: +48 (61) 85 47 986

e-mail: lasinska.izabela@spsk2.pl

Oncology in Clinical Practice

2016, Vol. 12, No. 1, 25–28

Translation: dr n. med. Hanna Koseła-Paterczyk

Copyright © 2016 Via Medica

ISSN 2450–1654

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