Vismodegib for Preservation of Visual Function in Patients with Advanced Periocular Basal Cell Carcinoma: The VISORB Trial

Abstract

Background: Basal cell carcinoma (BCC) is a common skin cancer often curable by excision; however, for patients with BCC around the eye, excision places visual organs and function at risk. In this article, we test the hypothesis that use of the hedgehog inhibitor vismodegib will improve vision-related outcomes in patients with orbital and extensive periocular BCC (opBCC).

Materials and methods: In this open-label, nonrandomized phase IV trial, we enrolled patients with globe- and lacrimal drainage system-threatening opBCC. To assess visual function in the context of invasive periorbital and lacrimal disease, we used a novel Visual Assessment Weighted Score (VAWS) in addition to standard ophthalmic exams. Primary endpoint was VAWS with a score of 21/50 (or greater) considered successful, signifying globe preservation. Tumor response was evaluated using RECIST v1.1. Surgical specimens were examined histologically by dermatopathologists.

Results: In 34 patients with opBCC, mean VAWS was 44/50 at baseline, 46/50 at 3 months, and 47/50 at 12 months or postsurgery. In total, 100% of patients maintained successful VAWS outcome at study endpoint. Compared with baseline, 3% (95% confidence interval [CI], 0.1-15.3) experienced major score decline (5+ points), 14.7% (95% CI, 5 to 31.1) experienced a minor decline (2-4 points), and 79.4% experienced a stable or improved score (95% CI, 62.1-91.3). A total of 56% (19) of patients demonstrated complete tumor regression by physical examination, and 47% (16) had complete regression by MRI/CT. A total of 79.4% (27) of patients underwent surgery, of which 67% (18) had no histologic evidence of disease, 22% (6) had residual disease with clear margins, and 11% (3) had residual disease extending to margins.

Conclusion: Vismodegib treatment, primary or neoadjuvant, preserves globe and visual function in patients with opBCC. Clinical trail identification number.NCT02436408.

Implications for practice: Use of the antihedgehog inhibitor vismodegib resulted in preservation of end-organ function, specifically with regard to preservation of the eye and lacrimal apparatus when treating extensive periocular basal cell carcinoma. Vismodegib as a neoadjuvant also maximized clinical benefit while minimizing toxic side effects. This is the first prospective clinical trial to demonstrate efficacy of neoadjuvant antihedgehog therapy for locally advanced periocular basal cell carcinoma, and the first such trial to demonstrate end-organ preservation.

Keywords: Basal cell; Cancer; Epiphora; Hedgehog; Lacrimal; Orbit; Orbital; PTCH; Patched; SMO; Smoothened; Tumor; Visual function.

Figure 1

Patient disposition and treatment duration. (A): Schematic highlighting patient disposition. ^# Patient's tumor histological subtype (infiltrative) prevented physical exam (PE) and MRI measurements. ^##No MRI/CT imaging available. (B): Treatment duration (green), missed doses (red), and excision (blue) for all patients. *Failed screening. **Lost to follow‐up. ***Missing drug diaries. ****Died prior to completing study. *****Patient's tumor histological subtype (infiltrative) prevented PE and MRI measurements. ******Left study prior to excision. Abbreviations: CT, computed tomography; MRI, magnetic resonance imaging; VAWS, Visual Assessment Weighted Score.

Figure 2

Visual function preservation during vismodegib treatment. (A): VAWS component status at screening, 3, 6, 9, and 12 months/postoperative (yes/good, green; fair, yellow; no/poor, red). (B): Average total VAWS score for all patients at screening, 3, 6, 9, 12 months/postoperative. (C): ∆VAWS 12 months or postoperative versus screening. (D): ∆VAWS 12 months/postoperative vs. screening by patient. (>5 point reduction, red; 2–4 point reduction, orange; <1 point reduction or improved score, blue; error bars indicate 95% confidence interval) Abbreviations: LAC, lacrimal; NE, not evaluable; VA, visual acuity; VAWS, Visual Assessment Weighted Score.

Figure 3

Tumor response to vismodegib treatment. (A‐1): Patient 30 (female, age 92) with left lower eyelid basal cell carcinoma (BCC) that obliterated her eyelid margin and canaliculus. (A‐2): Patient 25 (female, age 69) with recurrent left periocular BCC with perineural spread that invaded the orbit. (A‐3): Patient 18 (female, age 58) with long‐standing right lower eyelid BCC involving the lateral canthus, anchored to bone, with orbital extension, causing lower eyelid retraction and upper eyelid cicatricial ptosis. (A‐4): Patient 14 (female, age 65) with nodular BCC of her right medial canthus. They also had independent BCC tumors at the left medial canthus and central forehead. All three tumors responded to vismodegib therapy. (A‐5): Patient 1 (male, age 62) with BCC of the left medial canthus, with anchoring to bone. (A‐6): Patient 3 (male, age 69) with BCC of the right lower eyelid invading the anterior orbit. (B, C): PE (B) and MRI/CT (C) tumor measurement (percentage baseline) at 3, 6, 9, and 12 months after vismodegib treatment. (D): Tumor burden reduction (PE percentage baseline) at 12 months post treatment or presurgery. Abbreviations: MRI/CT, magnetic resonance imaging/computed tomography; PE, physical exam.

Figure 4

Adverse events related to vismodegib treatment. (A): Adverse events ranked by frequency of occurrence (error bars indicate 95% confidence intervals). (B): Tumor measurement versus alopecia onset. (C): Tumor measurement versus dysgeusia onset. (D): Tumor measurement versus myalgia onset. Abbreviation: PE, physical exam.