2. Systemic treatment of advanced cutaneous squamous and basal cell carcinomas

3. Despite their high prevalence,about 2 million BCC and one million SCC these NMSCs are rarely fatal. It is estimated that in 2012, approximately 1000 patients died of the disease. Squamous cell carcinomas are biologically more aggressive, and neglected lesions can be life-threatening due to local extension or metastasis. By contrast, basal cell carcinoma is only very rarely life- threatening.

6. systemic therapy distant metastases locally advanced disease

7. targeted therapy: Hedgehog pathway Itraconazole Chemotherapy systemic therapy BASAL CELL CARCINOMA

8. targeted therapy: Hedgehog pathway molecular and genetic studiease have shown that almost all basal cell carcinoma contain genetic alterations in the hedgehog signallinig pathway activation and uncontrolled proliferation.

9. hedgehog signaling pathway The hedgehog signaling pathway can cause basal cell proliferation and tumor growth. Signaling in this pathway is initiated by the cell surface receptor smoothened homolog (SMO). In adults, this pathway normally is inhibited by another cell surface receptor, the patched homolog 1 (PTCH1). Binding of the hedgehog ligand to PTCH1 prevents this inhibition.

12. Two mechanisms have been identified by which the hedgehog pathway may be involved in the pathogenesis of basal cell carcinoma hedgehog signaling pathway Mutations of PTCH1 may prevent inhibition of SMO activation of the hedgehog pathway mutations of SMO may result in constitutive activation of the pathway

13. SMO inhibitors vismodegib 150 mg as a single oral daily dose) is an oral small-molecule inhibitor of SMO Sonidegib 200 mg capsule once a day at least 1 hour before and 2 hours after a meal.

15. vismodegib The most extensive data on the safety and efficacy of vismodegib in basal cell carcinoma come from a pre-planned interim analysis of an international, open-label trial [9]. This analysis included results from 499 patients 468 with locally advanced disease that was not surgically treatable, 31 with metastatic basal cell carcinoma). Patients all had ≥12 months potential follow-up

16. locally advanced disease ●The objective response rate in those was 67 percen t 34 percent complete and 33 percent partial).

18. metastatic disease the objective response rate was : 38 percent 7 percent complete, 31 percent partial The median progression-free survival for the entire study population was 20 months (24.5 months in those with locally advanced disease and 13.1 months in those with metastatic disease).

19. most common adverse events muscle spasms 64% diffuse alopecia62% dysgeusia,54% weight loss,33% asthenia,28% decreased appetite25% development of cutaneous squamous cell carcinoma? in a case-control series that included 556 patients treated with vismodegib no increase in the risk of scc

21. Sonidegib

23. at either 200 or 800 mg orally once a day, with treatment continued until progressive disease or toxicity Overall, 230 patients 193 patients with locally advanced 37 with metastatic disease Results based upon the analysis 12 months after the final patient enrollment included the following: In a randomized phase II trial,

24. locally advanced disease The objective response rates for the 200 and 800 mg/day were 53 and 42 percent, respectively. The disease control rates, including those with stable disease, were 91 and 81 percent, respectively.

25. the objective response rates were 8 and 17 percent, respectively, in the low- and high- dose groups. The disease control rates, including those with stable disease, were 92 and 91 percent, respectively

27. Vismodegib or sondigib ?

29. nevoid basal cell carcinoma syndrome an inherited condition in which patients develop multiple basal cell carcinomas that are histologically identical to sporadic lesions. Nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant, multisystem disorder, due to mutations in the PTCH1 tumor suppressor gene. develop multiple basal cell carcinomas in their 20s and 30s NBCCS is associated with a variety of other cysts and tumors, including odontogenic keratocysts and medulloblastomas. Therapeutic radiation therapy needs to be avoided in such patients, since this can precipitate the development of numerous, aggressive BCCs.

30. nevoid basal cell carcinoma syndrome

31. Sonidegib topi cal The topical administration of an inhibitor of the hedgehog pathway may be a future option for the management of patients with NBCCS. In a randomized trial in which 27 BCCs in eight patients with NBCCS were treated with topical In a randomized trial in which 27 BCCs in eight patients with NBCCS were treated with topical vehicle twice daily for four weeks, complete or partial responses were observed in 12 out of 13 lesions treated with the Smoothened inhibitor compared with 1 out of 14 lesions treated with the placebo agent [114]. The effect of this treatment on BCCs in patients without NBCCS is unknown.

32. an antifungal agent, has been identified as a potent inhibitor of the hedgehog signaling pathway [. In a proof of concept study, 19 patients with bcc. 15 patients were treated with 200 mg twice daily for four weeks prior to surgery; 4 patients received 100 mg twice daily for one to four months result: Eight patients had tumor reduction and re-epithelialization. Of note, none of the three patients previously treated with vismodegib responded. Additional clinical studies will be required to determine whether itraconazole has a role in the management of patients with

33. Because of the rarity of metastatic basal cell carcinoma, the approach to systemic treatment is based primarily upon isolated case reports, with only a few small case series. A case report of one patient with basal cell carcinoma metastatic to the lungs observed a complete response with a combination of carboplatin and paclitaxel [23]. The authors also reviewed the literature and found 12 other patients with metastatic basal cell carcinoma who were treated with platinum-containing regimens. Among these 12, five had a complete response and four had a partial response.

35. Targeting agent Chemotherapy Checkpoint Inhibitor immunotherapy PDL1 antibodies directed against the programmed cell death-1 protein (PD-1) or its ligand (PD-L1).

36. Approved for recurrent or metastatic head and neck cancer Approved for head and neck cancer

37. targeted therapy: EGFR inhibitor Erbitux (Cetoximab) Vectibix (panitomomab) Gefitinib Erlotinib systemic therapy SQUAMOUS CELL CARCINOMA

39. Cetoximab monotherapy phase II study that included 36 patients. Median age of population was 79year 92 percent local-regional disease 8 percent had systemic metastases. weekly schedule (400 mg/m 2 on week 1 and then 250 mg/m 2 weekly) for at least 6 weeks with 48 weeks follow up Eight partial and two complete responses were observed (objective response rate 28 percent ), and 15 had stable disease an overall disease control rate of 69 percent. At 6 weeks accorgDing RESICT criteria Three patients were able to undergo complete resection of their tumor following treatment with cetuximab.

42. METHODS: From 2008 to 2013, all patients with a diagnosis of unresectable locally advanced skin squamous cell carcinoma were treated with neoadjuvant cetuximab alone (CM) or combined with a platinum salt and 5-fluorouracil (CC). Resectability, and clinical and pathological response, as well as relapse-free and overall survival were evaluated RESULTS: Thirty-four patients, with a median age of 74·5 years, were evaluated. Twenty-five patients received CC. After three cycles of CC, 23 of 25 patients whose tumours were initially unresectable became amenable to surgery (92%). A complete histological response was observed in 15 (65%) patients. The mean progression-free and mean overall survival in operated patients were 8·5 and 26·0 months, respectively CONCLUSIONS: There was a good response in terms of resectability and tumour control in the majority of patients, with few relapses, despite the initially poor prognosis of these tumours in this elderly group of patients. However, this therapeutic strategy needs to be validated in a prospective, randomized study.

43. In a small phase II study, 16 patients with SCC not suitable for local therapy panitumumab (6 mg/kg every two weeks) Objective responses were observed in five patients, including three partial and two complete responses. Grade 3 and 4 toxicity was observed in five cases (four with rash, one with fatigue).

44. Systemic chemotherapy There are only limited data on the role of systemic chemotherapy in the treatment of advanced cutaneous squamous cell carcinoma. Cisplatin-based combinations appear to be the most active regimens and have been adapted from those used for squamous cell cancers arising in other site Beliomycin 5FU

45. Antibody against (PD-1) or its ligand (PD-L1). Checkpoint inhibitor immunotherapy — Research into immunotherapy has led to important advances in the treatment of melanoma, non-small cell lung cancer, squamous cell carcinoma of the head and neck, and other malignancies using checkpoint inhibition, particularly with antibodies directed against the programmed cell death-1 protein (PD-1) or its ligand (PD-L1). The most extensive data come from a preliminary report of a prospective phase I expansion cohort using the experimental anti-PD-1 antibody REGN2810. This study included 26 patients, 10 with metastatic disease and 16 with unresectable, locally advance. The updated overall objective response rate was 46 percent, with two complete responses and 10 partial responses; 10 of 11 confirmed responses were ongoing, between 2 and 10 months, at the time of the reporting.