LAUSR

Dear Editor, Gorlin Goltz syndrome (GGS), also known as Nevoid basal cell carcinoma syndrome, is a rare, autosomal dominant multisystemic disorder with an estimated prevalence of, on average, 1 in 100,000 people. This condition is characterized by tens, hundreds, or even thousands of basal cell carcinomas (BCCs), starting in adolescence or even occasionally in childhood. BCCs can arise on the whole body but the majority is located on the head and neck region. In addition, the quality of life of these patients is often severely impaired as a consequence of the morbidity, local symptoms, and cosmetic impact of this disease. GGS can be considered a multidisciplinary challenge with a high risk of recurrence of BCCs making treatment and surveillance highly critical. Vismodegib, an inhibitor of the Hedgehog pathway, is the first drug approved both by the food and drug administration and european medicines agency for the treatment of metastatic or locally advanced basal BCC and in patients with GGS. In this report, two GGS cases successfully treated with a new Vismodegib maintenance protocol are discussed. Patient 1 is a 42-year-old female, at baseline had about 100 lesions covering her body (predominantly on the face and extremities). The prevalent type was superficial ( 95% of lesions). Clinically, pink macules and erythematous papules were the most represented structures (Figure 1A). Vismodegib 150 mg daily was administered from April 2016 to March 2017 and after 6 months of therapy the lesions were clinically reduced by approximately 50% (Figure 1B). During the first year of therapy, a complete clinical response was achieved. Unfortunately, during this first year of treatment, the patient also developed muscle cramps (Grade 2) and alopecia that continued until total alopecia of the scalp and of the eyebrows at month 12 occurred (Figure 1C). In order to reduce these side effects, starting from the second year of treatment, a dosing regimen, which included a 1-week drug holiday every month was initiated. To date, the patient is still treated with a holiday regimen with a complete clinical response and after 6 months of starting the patient also observed hair regrowth (Figure 1D). No new BCCs have appeared during the last 3 years. Patient 2 is a 40-year-old woman, who at baseline had about 150 lesions (above all superficial types) covering her body but predominantly on her back (Figure 1E, F) and chest (Figure 1H). After 8 months from starting of the standard therapy, we observed a complete clearance of skin tumors (Figure 1G, I) and the results were maintained after a further 12 months utilizing the drug holiday regimen (Figure 1J). With regard to side effects, she developed fatigue and diarrhea, which became more tolerable with the introduction of the new dosing regimen, consisting of 150 mg daily with a 1-week drug holiday every 4 weeks. Patients were monitored clinically every 6 months: no recurrences were observed at the 4-year follow-up. Both of the patients, who were very traumatized by the disease, refused to have skin biopsies for histopathological examination during the follow-up visits. Treatment of patients with GGS is challenging and requires a tailored and highly specialized approach. Chronic use of Vismodegib in patients with GGS typically results in alopecia (58%–86%), muscle spasms (63%–77%), weight loss (5%–68%), and dysgeusia (59%– 74%). These adverse side effects can be so severe that they can result in the suspension of medication. Furthermore, recent case reports have shown that Vismodegib could also be associated with amenorrhea or irregular menstruation. Previous studies have already shown that for these patients, where the treatment program needs to be continued indefinitely, alternative dosage regimens need to be explored.In particular, it was observed that patients in the Monday– Friday Group had comparable clinical responses but with milder adverse effect profiles when compared to patients treated daily. In addition, Wong et al. report that the initial average time to onset of adverse effects was 7.7 weeks in the Monday–Friday dosing group, compared to 6.4 weeks in the daily dosing group. Nevertheless today there is still a lack of standardization of regimens in treating patients with GGS, probably due to the fact that there are have been very few studies conducted which included only a small number of patients. In our cases, the approach of introducing a drug holiday based on a monthly week's break was effective in maintaining lesion clearance obtained during the first year of standard treatment and also controlling side effects. Although further data are required to better understand the optimal treatment scheme, the present protocol is proposed as an effective alternative for both reducing the intensity of common adverse events and increasing patient's compliance.