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We read with great interest the excellent paper by Sagiv and collegues Ocular preservation with neoadjuvant Vismodegib in patients with locally advanced periocular basal cell carcinoma.(1)
The article is a great contribution for a topic with a growing, but still limited worldwide experience. Our interest is to discuss the surgical approach after neoadjuvant Vismodegib.
The authors present a patient with a 5x4cm locally advanced periocular basal cell carcinoma (LAP-BCC) with small nerve perineural invasion (>0.1mm) involving lower eyelid, inner canthus and cheek. The patient showed a significant response after 10 months of Vismodegib. Anyhow, it was clearly a partial response with 3 suspicious areas of BCC after treatment. The authors decided to treat separately each area with surgery, and histology (en face sections) confirmed the presence of tumor in two. The reconstructive outcome was excellent, and at the time of publication the patient was free of disease, 11 months after surgery.
We agree with the authors, when they consider as a limitation the fact that “surgery did not always include the entire area of the original tumor”.
Most studies involving smoothened inhibitors thus far have measured clinical tumor shrinkage but not true histologic margin control. Even after a complete clinical response (CCR), there is no way to assure that it will result in a complete histological clearance (CHR).
Several authors discuss...
Several authors discussed this issue. Tang and Alcalay reported a small number of LA-BCC treated with neoadjuvant Vismodegib plus Mohs surgery (MS).2-3 Although they observed a significant tumor shrinkage, they found islands of BCC within all their debulking specimens.(2-3) Ching in a series with 6 LA-BCCs,(4) with bone involvement, reported that multiple superficial biopsies done after neoadjuvant Vismodegib, showed no evidence of BCC . However, all the surgically resected specimens revealed residual tumor. After this data, Ching states that the effect of Hh inhibitor is suppressive rather than curative and should be followed by definitive surgery.
Koekelkoren, after treating 4 cases with “giant” LA-BCC, indicates that resistance to Vismodegib seems to occur more often in deep tumor planes near bone or cartilage and suggests this may be related with suboptimal blood perfusion, resulting in lower Vismodegib tissue levels.(5)
So far, we have treated 13 patients with LAP-BCC with neoadjuvant Vismodegib + MS. The first eight cases were included in a paper published last year.(6) We observed 9 CCR, 3 partial responses and 1 patient progressed. Out of the 9 CCR one patient refused surgery and is without evidence of disease after 34 months. We confirmed 6/8 CHR and found persistent tumor with MS in 2 patients. With a mean follow up of 24.6 months, one patient with a CHR recurred 17 months after MS. Therefore, 3/9 cases with a CCR either had persistent tumor at the time of MS or recurred lately, probably due to skip tumor areas.
We believe this evidence supports our position. Neoadjuvant Vismodegib may lead to missing discontiguous tumor on surgery. This may eventually progress to more aggressive histology, including thin strands of BCC, immersed in dense inflammatory/scar tissue. The evaluation of surgical margins in this scenario may be challenging.
We also differ with the authors about the need of a free flap for reconstruction in this case. Due to the difference in color and texture with facial skin, we try to avoid free flaps for cheek reconstruction and prefer a Mustardé flap (or a cervicofacial flap) combined with an oculoplastic repair for the eyelids.
1. Sagiv O, Nagarajan P, Ferrarotto R, Kandl TJ, Thakar SD, Glisson BS, Altan M, Esmaeli B. Br J Ophthalmol. 2019 Jun;103(6):775-780. Ocular preservation with neoadjuvant vismodegib in patients with locally advanced periocular basal cell carcinoma Br J Ophthalmol. 2019 Jun;103(6):775-780
2. Tang N, Ratner D. Implementation of systemic hedgehog inhibitors in daily practice as neoadjuvant therapy. J Natl Compr Canc Netw 2017; 15:537–43
3. Alcalay J, Tauber G, Fenig E, Hodak E. Vismodegib as a neoadjuvant treatment to mohs surgery for aggressive basal cell carcinoma. J Drugs Dermatol 2015;14:219–23.
4. Ching JA, Curtis HL, Braue JA, Kudchadkar RR, Mendoza TI, Messina JL, Cruse CW, MD, Smith DJ, Harrington MA. The Impact of Neoadjuvant Hedgehog Inhibitor Therapy on the Surgical Treatment of Extensive Basal Cell Carcinoma. Ann Plast Surg 2015;74: S193–S197
5. Koekelkoren FHJ, Roodbergen SL, Baerveldt EM, Maat APWM, Monserez DA, Grunhagen DJ, Mureau MAM, de Haas ERM, PhD, Nijsten EC, Wakkee M. Vismodegib for giant, locally advanced, basal cell carcinoma and its complex position in clinical practice. JAAD Case Reports 2019; 5:267-70.
6. González AR, Etchichury D, Gil ME, Del Aguila R. Neoadjuvant Vismodegib and Mohs Micrographic Surgery for Locally Advanced Periocular Basal Cell Carcinoma. Ophthalmic Plast Reconstr Surg. 2019; 35(1):56-61.