- Email: [email protected]
Guidelines for vismodegib in the management of periocular basal cell carcinoma
ARTICLE IN PRESS
Guidelines for vismodegib in the management of periocular basal cell carcinoma Ahsen Hussain, MD, FRCOphth,* Nancy Tucker, MD, FRCSC,y Dan D. DeAngelis, MD, FRCSC,z Vivian T. Yin, MD, MPH, FRCSC,x Edsel Ing, MD, FRCSC, MPH, CPH,║ Bryan Arthurs, MD, FRCSC,{ Harmeet S. Gill, MD, FACS, FRCSC,** Isabelle Hardy, MD, FRCSC, DABO,yy Jeff Hurwitz, MD, FRCS (C),zz Vladimir Kratky, MD, FRCSC,xx Babak Maleki, MD, FRCSC,║║ Navdeep Nijhawan, MD, FRCSC,{{ James Oestreicher, MD, FRCSC,xx Aftab Zafar, MD, FRCSC*** ABSTRACT Objective: The management of advanced basal cell carcinoma (BCC) in the periocular region remains a clinical challenge. Vismodegib (ErivedgeTM) has been approved in 2013 by Health Canada for adult patients with “histologically confirmed metastatic BCC or locally advanced BCC inappropriate for surgery or radiation.” An expert consensus was sought to create a standardised approach in the use of this novel treatment. Methods: Fourteen practicing oculoplastic surgeons across Canada were involved in formulating and reviewing guidelines until consensus was reached. A consultancy meeting was followed by further ratification of guidelines over email. Two voting surveys were performed of the group to objectively assess agreement over each statement within the guidelines. Ratification continued until at least two-thirds of the group agreed on every guideline statement. Results: The guidelines summarize 21 statements in a major and minor criteria format. A multidisciplinary team review is suggested for each patient with the involvement of recommended specialists. The internal survey revealed 100% agreement over 9 statements, 91.7% agreement over 8 statements, 83.3% agreement over 4 statements, and 2 statements had 66.7% and 58.7% agreement each. All statements with less than 91.7% agreement were surveyed again, and they were kept, modified, or removed on the basis of a consensus of over 66.7%. Conclusions: These guidelines serve to act as a framework for physicians considering vismodegib for the medical management of patients with advanced or metastatic periocular BCC. Future applications, including neoadjuvant uses of the drug, may become apparent through further research.
Basal cell carcinoma (BCC) is the commonest eyelid malignancy, and if left untreated, it can present with orbital invasion.1 Management decisions and prognosis are influenced by patient factors such as advancing age and medical comorbidities, and disease factors such as tumour location, size, histological subtype, and multiple or recurrent lesions.2 The current standard of treatment for surgically manageable orbital and periocular BCCs is margin-controlled excision, which can be supplemented by adjuvant radiotherapy.35,6 In advanced cases, surgery may lead to extensive loss of adnexal tissue required for appropriate globe protection and function, in some cases requiring eye removal or formal exenteration. Furthermore, patients with inherited syndromes leading to multiple periocular malignancy (such as basal cell nevus syndrome) may not be suitable candidates for repetitive surgery. The treatment of advanced or metastatic periocular BCC therefore remains challenging. The Hedgehog pathway inhibitor vismodegib (Erivedge, Genentech, CA) is the first molecular-targeted oral therapy approved for the treatment of BCC. A dysregulated Hedgehog
signalling pathway was first found in families with basal cell nevoid syndrome, followed by the same finding in sporadic cases, resulting in uncontrolled proliferation of basal cells. Vismodegib, an inhibitor of the transmembrane protein smoothened (SMO) in the hedgehog pathway, was approved in 2013 by Health Canada for the “treatment of adult patients with histologically confirmed metastatic basal cell carcinoma or locally advanced basal cell carcinoma (BCC) inappropriate for surgery or radiotherapy.” Although studies have demonstrated efficacy of this treatment in select cases,712 the interpretation on when vismodegib should be used clinically remains open to considerable debate. On account of factors such as expense, requirement for pre-approval, and a not insignificant sideeffect profile, we sought to create a Canadian consensus document to provide a framework for clinicians considering this treatment for their patients.
TAGEDH1METHODSTAGEDEN In October 2017, a Canadian consultancy group met in Toronto, Ontario, to discuss the clinical applications of
© 2019 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jcjo.2019.11.004 ISSN 0008-4182 CAN J OPHTHALMOL—VOL. &, NO. &, & 2019
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ARTICLE IN PRESS Vismodegib for management of periocular basal cell carcinoma—Hussain et al. vismodegib in the management of advanced and metastatic periocular and orbital BCC. This group was composed of oculoplastic surgeons, an ocular oncologist, an ophthalmic pathologist, and medical oncologists. After this meeting, it was apparent that there would be varied interpretation in how this new medication could be potentially applied. This would be further influenced by differing provincial guidelines within Canada. The 3 primary authors (A.H., N.T., and D. D.) believed that approaching the group to form consensus guidelines would be beneficial in providing a framework for future modification. A modified Delphi process was employed to reach consensus using repeated iterative voting.13 After initial discussion at the meeting, members of a smaller group of 12 oculoplastic surgeons participated in email discussions, followed by 2 rounds of online surveys to finalize the guidelines (Fig. 1). Two further consensus members were added before the second group survey. Ratification of each individual statement within the guidelines continued until final agreement. A “major and minor” (M&M) criteria format was determined to best provide coverage of the most critical aspects of this guideline. A “consensus” was considered to have been reached when a minimum of two-thirds of all participants voted in favour of each statement within the guidelines, similar to other consensus building projects.13
TAGEDH1RESULTSTAGEDEN The consensus guidelines summarize 21 individual statements, and 91.7% of the consensus body agreed that an M&M criteria format was appropriate for these guidelines. Seven of the statements relate to preamble that is suggested before application of the M&M criteria. There are 4 major criteria statements and 11 minor criteria statements. At least 1 major criterion or 2 minor criteria should be fulfilled to consider first-line treatment with vismodegib. Table 18-12,14-18 presents the proposed guidelines from our consensus group. At the first survey, the format of using M&M criteria and the following statements each received 91.7% (11 members) or 100% agreement from the consensus group:
• Forum to discuss applicaon of vismodegib • Evidence reviewed • Highlighted need for preliminary guidelines
Consensus group • 12 members • Circulaon of dras via email • Comments and changes • Preliminary dra
Consultancy meeng
At least 1 major criterion or 2 minor criteria should be fulfilled to consider first-line treatment with vismodegib. This document neither serves to support nor discourages the use of the medication. Clinicians should apply these guidelines individually at their discretion. Multidisciplinary team review including preferably tumour board review. This should include as a minimum an oculoplastic surgeon (or a surgeon with expertise in periocular skin cancer), a radiologist, a medical oncologist, a radiation oncologist, and a pathologist. Consult head and neck surgery, neurosurgery, and plastic surgery as required. A clear definition of treatment (such as control or cure) should be established with the patient and multidisciplinary team (MDT)/tumour board. Ensure that the patient does not have any contraindications to the medication (see link to document below). Major criterion: Patient medically unfit to have surgery or radiotherapy. Major criterion: The patient has metastatic BCC (mBCC) disease considered untreatable by surgery or radiation. Major criterion: Surgery would lead to immediate loss of the eye. Minor criterion: BCC is located on side of only functioning eye. Minor criterion: BCC involving entire upper eyelid. Minor criterion: BCC involves entire lower eyelid AND medial canthus >5-mm-diameter area. Minor criterion: BCC involving medial canthus >5mm-diameter area and two-thirds or more of upper eyelid and/or lower eyelid. Minor criterion: Sclerosing or morpheaform (infiltrative) lesion with anticipated surgical defect involving anatomy described above. Minor criterion: BCC involving periosteum, orbital soft tissue, or frank bone invasion clinically and/or on finecut neuro-imaging. Minor criterion: BCC with (macroscopic) perineural invasion on neuroimaging.
• Individual points scrunized • Modificaon of dra based upon acceptance of all statements with 91.7% (11 member) or over agreement
Second group survey • Two further members = 14 • All statements receiving less than 91.7% re-surveyed • Opons of raficaon, inclusion of original or deleon offered on 2nd survey
First group survey
Fig. 1—Flowchart for Delphi process in achieving consensus on guidelines.
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• Guidelines in Major and Minor criteria format • 21 statements forming final consensus guideline
Finalisaon
ARTICLE IN PRESS Vismodegib for management of periocular basal cell carcinoma—Hussain et al. Table 1—Guidelines for consideration of vismodegib for the management of advanced periocular or metastatic basal cell carcinoma (BCC)8–12,14–18 Consensus group: Hussain A, Arthurs B, DeAngelis D, Gill H, Hardy I, Hurwitz J, Ing E, Kratky V, Maleki B, Nijhawan N, Oestreicher J, Tucker N, Yin V, Zafar A The use of vismodegib (Erivedge) has been approved for use by Health Canada for the “treatment of adult patients with histologically confirmed metastatic basal cell carcinoma or locally advanced basal cell carcinoma (BCC) inappropriate for surgery or radiotherapy.” Preamble: At least 1 major criterion or 2 minor criteria should be fulfilled to consider firstline treatment with vismodegib. Provincial/Health Canada approval guidelines should be taken into consideration. This document neither serves to support nor discourages the use of the medication. Clinicians should apply these guidelines individually at their discretion. For all patients, ensure: Multidisciplinary team review including preferably tumour board review. This should include as a minimum an oculoplastic surgeon (or a surgeon with expertise in periocular skin cancer), a radiologist, a medical oncologist, a radiation oncologist, and a pathologist. Consult head and neck surgery, neurosurgery, and plastic surgery as required. A clear definition of treatment (such as control or cure) should be established with the patient and MDT/tumour board. Ensure that the patient does not have any contraindications to the medication (see link to document below*). Major Criteria Patient medically unfit to have surgery or radiotherapy The patient has metastatic BCC disease considered untreatable by surgery or radiation Surgery would lead to immediate loss of the eye Basal cell nevus syndrome with multiple facial BCCs that cannot be reasonably excised surgically Minor Criteria BCC is located on side of only functioning eye Surgeon concern regarding functional deficit from surgery or radiation, such as: BCC involving entire upper eyelid BCC involves entire lower eyelid AND medial canthus >5-mm-diameter area BCC involves entire lower eyelid AND lateral canthus >10-mm-diameter area BCC involving medial canthus >5-mm-diameter area and two-thirds or more of upper eyelid and/or lower eyelid Sclerosing or morpheaform (infiltrative) lesion with anticipated surgical defect involving anatomy described above Patient with recurrent BCC with 2 or more previous margin-controlled excisions BCC involving periosteum, orbital soft tissue, or frank bone invasion clinically and/or on fine-cut neuro-imaging BCC with (macroscopic) perineural invasion on neuroimaging Patient and surgeon both concerned that cosmetic outcome of surgery may be unacceptable *www.bccancer.bc.ca/drug-database-site/Drug%20Index/Vismodegib_monograph_1 Sep2015.pdf
The following statements received less than 91.7% agreement (in parentheses is percentage agreement): Provincial guidelines should be taken into consideration (66.7%). Major criterion: Basal cell nevus syndrome with multiple facial BCCs involving at least 2 different eyelids (83.3%). Minor criterion: BCC involves entire lower eyelid AND lateral canthus >10-mm-diameter area (83.3%). Minor criterion: Surgery or radiation would lead to immediate or eventual loss of lacrimal drainage system (58.3%). Minor criterion: Patient with recurrent BCC with 2 or more previous margin-controlled excisions (83.3%). Minor criterion: Patient and surgeon both concerned that cosmetic outcome of surgery may be unacceptable (83.3%).
All preceding 6 statements were discussed via email within the group and then submitted for a second survey. This survey provided the option for further ratification of the statement, inclusion as per the original, or removal from the guidelines. Following are the final percentage agreements on these statements and the outcome. 1. Provincial guidelines should be taken into consideration (92.9%). Statement altered to: Provincial/Health Canada approval guidelines should be taken into consideration. 2. Major criterion: Basal cell nevus syndrome with multiple facial BCCs involving at least 2 different eyelids (85.7%). Statement altered to: Basal cell nevus syndrome with multiple facial BCCs that cannot be reasonably excised surgically. 3. Minor criterion: BCC involves entire lower eyelid AND lateral canthus >10-mm-diameter area (78.6%): Statement retained as original. 4. Minor criterion: Surgery or radiation would lead to immediate or eventual loss of lacrimal drainage system (64.2%): Statement removed. 5. Minor criterion: Patient with recurrent BCC with 2 or more previous margin-controlled excisions (71.4%): Statement retained as original. 6. Minor criterion: Patient and surgeon both concerned that cosmetic outcome of surgery may be unacceptable (85.7%): Statement retained as original. Where statements had over 66.7% (two-thirds) agreement and were provided with ratification comments without significant change of the original statement or meaning, these comments were incorporated into the original statement (statements 1 and 2). Statements with less than 66.7% or a minimum of 9member agreement were removed from the guidelines (statement 4). All other statements with over 66.7% without provision of ratification comments were retained as the original statement. A final consensus document was submitted for review and acceptance by the consensus group.
TAGEDH1DISCUSSIONTAGEDEN BCC is a malignant tumour originating from the follicular germinative basal cells within the epidermis. It is the most common non-melanoma skin cancer in Europe and the United States with an estimated incidence of 100 per 100 000 individuals.19,20 Cumulative UVB exposure (280320 nm) is considered the main risk factor for development of BCC. Other significant risk factors include genetic conditions such as xeroderma pigmentosum and basal cell nevus syndrome, previous radiotherapy, and CAN J OPHTHALMOL—VOL. &, NO. &, & 2019
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ARTICLE IN PRESS Vismodegib for management of periocular basal cell carcinoma—Hussain et al. immunosuppression. The latter may result in an increased prevalence of malignant tumours seen in patients treated with new immunomodulator therapies such as checkpoint inhibitors.21 Up to 80% of BCCs occur in the head and neck region, with around 20% of these occurring in the periocular area. BCC is the commonest malignancy to affect the eyelids, with the highest frequency occurring in the lower eyelid and at the medial canthus.15 Management of periocular BCC needs to take into consideration patient comorbidities, tumour characteristics, locally available resources, and treatment options. Traditionally, surgical excision was the main treatment modality offered to patients for resectable tumours. Other treatment methods usually employed for noneyelid and smaller tumours include cryotherapy, curettage and electrodessication, laser therapy, radiation, photodynamic therapy with delta-aminolevulinic acid, and topical immunomodulators such as imiquimod and fluorouracil. Margin-controlled excision via either Mohs micrographic surgery or frozen-section control are now considered the gold-standard in treatment.22,23 These approaches can be curative for over 90% of cases.35,2425 Where margin-controlled surgery was not used as the primary surgical modality, incomplete excision was found to be around 25% in 1 study5 and can range from between 16% and 40%.45,2627 This is particularly relevant in patients with morpheaform, infiltrative, and micronodular subtypes of BCC, which have a higher rate of subclinical spread and recurrence.2 Furthermore, locations such as the medial canthus can be associated with a higher risk of aggressive behaviour such as orbital invasion.28 In certain cases, orbital exenteration is required to achieve tumour clearance and prevent further morbidity29. As BCCs do not typically exhibit nodal or distant metastasis, such sight-compromising surgery is an unfortunate requirement in cases of neglect or delayed diagnosis.28 One challenge when planning surgery is that the extent of orbital invasion may have been underestimated. Biological behaviour of tumour subtypes and the presence of perineural spread must be taken into account. Required surgical margins of excision in the periocular area can also severely compromise remaining functional tissue to provide adequate protection to the globe. Vismodegib is a new first-in-class small-molecule inhibitor of SMO. In 2013, Health Canada approved the use of vismodegib based on evidence provided by the ERIVANCE trial.30 The statements in our guidelines serve to reflect the evidence provided in this trial and further studies that have clarified when a patient would be considered “inappropriate for surgery or radiotherapy” within the context of periocular disease. Accessibility of this treatment across Canada is also reliant upon varied provincial requirements (Table 2). To our knowledge, there are no current guidelines that exist for the application of this treatment to the management of BCC in the periocular region. The ERIVANCE trial,30 was a Phase 2 trial in which 33 patients with mBCC and 63 patients with locally advanced BCC (laBCC) received 150 mg of vismodegib orally. These
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patients were considered inappropriate for surgery on the basis of multiple recurrences and a low likelihood of surgical cure, or substantial anticipated disfigurement. All minor criteria statements within our proposed guidelines elaborate on defining clinical criteria for “locally advanced or inappropriateness of surgery or radiotherapy” (statements 1221), potential disfigurement as related to adnexal tissue loss of function and cosmetic disfigurement (statements 1316 and 21), loss of the patient’s only functioning eye (12) and multiple recurrences (18), or low likelihood of surgical cure (1720). The 21 patients in this study had confirmed or suspected basal cell nevus syndrome, all of whom had laBCC. The primary hypothesized outcome was an objective tumour reduction by at least 20% of the original size for laBCC and 10% for mBCC. This was determined by an independent review committee. This Phase 2 trial demonstrated an objective response rate of 43% in laBCC patients and 30% in mBCC patients. Each case exceeded the predefined criteria for the hypothesized minimal acceptable response. No patients with mBCC had a complete response, whereas 21% of patients with laBCC had a complete response. Furthermore, a post-hoc analysis of ERIVANCE31 showed higher objective response rate of 67% in basal cell nevoid syndrome compared with 30% in patients with laBCC. We therefore incorporated basal cell nevoid syndrome as a major criteria statement (11) within the guidelines. The SafeTy Events in VIsmodEgib (STEVIE) trial32 demonstrated that vismodegib is well tolerable; however, 98% of patients had one or more treatment emergent adverse event (TEAE), with serious TEAEs occurring in 23.8% of patients. Exposure beyond 12 months did not increase the incidence or severity of new TEAEs. After discontinuation of the drug, most TEAEs resolved by 12 months of initiating therapy. Statement 7 in the guidelines requires that contraindications are reviewed before considering vismodegib. According to recent guidelines of care for the management of BCC published by the American Academy of Dermatology,33 the eyelids, eyebrows, and periorbital skin are considered high-risk areas for recurrence of BCC, independent of size. Within the same category of high risk are lesions on the cheek, forehead, scalp, or neck more than 10 mm in size. Other high-risk parameters are irregular borders, recurrent tumours, prior radiation or active immunosuppression, and an aggressive growth pattern or perineural involvement. In formulating our guidelines, we propose statements 1316, which would significantly impact the protective function of the periorbital tissues. Reconstruction is feasible in these situations; however, on account of the large size of tumour and high-risk locations (such as medial canthus), the risk of disfiguring surgery and tumour recurrence are high. Outcomes of surgical approaches with such large tumours are dependent on surgeon and patient preference. Hence these statements have been placed in the minor criteria section in contrast to the strong indications described in the major criteria. Due to the complexity of managing these advanced cases, we recommend that multidisciplinary consultation should be sought (statement 5). Such
ARTICLE IN PRESS Vismodegib for management of periocular basal cell carcinoma—Hussain et al. Table 2—Canadian provincial criteria for application of funding of vismodegib treatment of advanced or metastatic periocular basal cell carcinoma (BCC) Province
Status
Date of Decision
Funding Criteria
All provinces (except Prince Edward Island and Nunavut)
See below
See below
Alberta
Funded
20 June 2014
British Columbia
Funded
1 Oct 2014
Manitoba
Funded
1 July 2014
For patients with locally advanced basal cell carcinoma (laBCC) who are inappropriate for surgery AND radiation therapy Patients must have an ECOG* score 02 Specifies metastatic BCC (mBCC) inoperable or inappropriate for surgery or radiotherapy Specifies basal cell nevus/Gorlin syndrome (BCN syndrome) Requires measurable metastatic disease or locally advanced disease Specifies dose at 150 mg daily until disease progression or unacceptable toxicity A separate nonordering physician must provide rationale and consult note for treatment Patient chart must confirm multidisciplinary team discussion Specifies inappropriate criteria for surgery as at least one of the following: technically not possible due to size/location/invasiveness recurrence after 2 or more procedures and curative resection unlikely substantial morbidity/deformity anticipated from surgery Specifies inappropriate criteria for radiation as at least one of the following: contraindication to radiation, e.g., BCN syndrome prior irradiated lesion suboptimal outcome expected due to size/location/invasiveness of BCC Patient preference for oral therapy will not be considered Prescribing limited to named physicians registered with Erivedge Pregnancy Prevention Program (EPPP) Specifies mBCC inappropriate for surgery or radiation Requires a “Compassionate Access Program” application with appropriate clinical information Specifies mBCC inappropriate for surgery or radiation Specifies BCN syndrome for coverage Requires measurable metastatic disease or locally advanced disease With measurable disease, at least one lesion >10 mm deemed inappropriate for surgery or radiation as documented by at least 2 specialist physicians Patients must be 18 years of age or older
Nunavut New Brunswick
Not funded Funded
25 June 2014
Newfoundland
Funded
1 Oct 2014
Nova Scotia
Funded
29 Dec 2014
Ontario
Funded
16 April 2014
Prince Edward Island Quebec
Under consideration Funded May 2018
Specifies mBCC inappropriate for surgery or radiation Requires measurable metastatic or locally advanced disease Patients must be 18 years of age or older Patient preference for oral therapy will not be considered Separate nonordering physicians must provide rationale for treatment including: Surgical consultation report Radiation therapy consultation report Confirmation required that patient has been discussed at MDT or equivalent (e.g., Regional Tumour Board) Renewal requires confirmation that patient has not experienced progression while on vismodegib Specifies inappropriateness for surgery or radiation as per Alberta criteria Specifies dose at 150 mg daily until disease progression or unacceptable toxicity Initial approval duration: 1 year Renewal approval duration: 1 year Specifies mBCC inappropriate for surgery or radiation Specifies basal cell nevus/Gorlin syndrome (BCN syndrome) Requires measurable metastatic or locally advanced disease Patients must be 18 years of age or older Specifies basal cell nevus/Gorlin syndrome (BCN syndrome) Requires MDT involvement Specifies mBCC inappropriate for surgery or radiation Specifies basal cell nevus/Gorlin syndrome (BCN syndrome) Requires measurable metastatic or locally advanced disease Patients must be 18 years of age or older Specifies dose at 150 mg daily until disease progression or unacceptable toxicity Approval duration: 1 year Separate nonordering physicians must provide rationale for treatment including: Surgical consultation report Radiation therapy consultation report Confirmation required that patient has been discussed at MDT or equivalent (e.g., Regional Tumour Board) Specifies inappropriateness for surgery or radiation as per Alberta criteria Patient preference for oral therapy will not be considered Maximum duration of each authorization is 4 months When requesting continuation of treatment, the physician must provide evidence of a beneficial clinical effect by the absence of disease progression (continued)
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ARTICLE IN PRESS Vismodegib for management of periocular basal cell carcinoma—Hussain et al. Table 2 (Continued) Province
Status
Date of Decision
Funding Criteria
Saskatchewan
Funded
18 July 2014
Specifies mBCC inappropriate for surgery or radiation Specifies basal cell nevus/Gorlin syndrome (BCN syndrome) Requires MDT involvement and specifies involvement of surgeons, dermatologists, radiation oncologists, and medical oncologists
*Eastern Cooperative Oncology Group (ECOG) Performance Status. Determines ability of patient to tolerate therapies in serious illness, specifically for chemotherapy:
consultation is also important in determining where vismodegib would not be suitable, and where cases of laBCC or mBCC may best be managed with chemotherapy, radiation, or supportive/palliative care. Clear objectives have to be defined through treatment before consideration of vismodegib with the patient, family, and MDT/tumour board. There have been multiple studies that have confirmed the clinical application and effectiveness of vismodegib for periocular and orbital BCC, as a reflection of the results of the ERIVANCE and STEVIE trials. Gill et al.8 presented results on 7 patients with biopsy-proven infiltrative BCC of the periocular region. All lesions represented recurrent laBCC not amenable to surgical resection or radiation. The mean duration of treatment with vismodegib was 11 weeks. Two patients showed a complete treatment response, 4 had a partial response (ranging from 15% to 90%), and 1 showed progression. Pretreatment lesion sizes ranged from 10 to 60 mm. Only 1 patient had no adverse reaction to the treatment. Demirci et al.16 studied 6 consecutive patients with biopsyproven orbital BCC and 2 patients with extensive periocular BCC. They considered vismodegib treatment if surgical morbidity was considered to be substantial (deformity, vision loss, diplopia, loss of the eye, or vital orbital structures). They defined a complete clinical response as regression of all visible areas of tumour, and a partial response was defined as at least 40% reduction of the original tumour size. The median duration of treatment was 8 months. Four patients showed a partial response and 4 showed a complete response to vismodegib. They found that, for patients with orbital involvement (6 cases), the best response was obtained in 2 patients where the drug was used as an off-label neoadjuvant therapy before surgery or as an off-label adjuvant therapy for residual microscopic disease after surgery. Studies continue to
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investigate neoadjuvant use of vismodegib; however, there is no current clear consensus on this potentially new application of the medication.3436 Therefore we have not included this aspect in our current proposed guidelines. Vismodegib is not licensed for neoadjuvant use in Canada. Emerging literature is also establishing the success of vismodegib in modifying prognosis for patients with laBCC.912 Sagiv et al.36 have recently demonstrated that, at last follow-up, 83% of their patients, treated after approval of vismodegib by the Food and Drug Administration, retained their eye, compared with 54% of patients treated before vismodegib approval. Furthermore, fewer patients with laBCC were treated with radiation after vismodegib approval (14% vs 38% before approval), thus sparing patients potentially significant periocular and ocular side effects of radiation. Variances exist across countries regarding authorization of vismodegib for the medical treatment of advanced or metastatic BCC. As comparative examples to Canada, the Pharmaceutical Benefits Scheme authority in Australia has authorized use of vismodegib along similar criteria.37 In contrast, the National Institute for Health and Care Excellence in the U.K. does not recommend vismodegib in the treatment of adult metastatic or laBCC that is inappropriate for surgery or radiotherapy.38 A fundamental reason for the formulation of our guidelines is to outline a standardized approach to the use of vismodegib and thereby contribute to future recommendations.
TAGEDH1CONCLUSIONSTAGEDEN We propose that clinicians consider vismodegib for the treatment of periocular laBCC or mBCC under the umbrella of Health Canada approval and our proposed guidelines. This document is likely to evolve as further evidence becomes
ARTICLE IN PRESS Vismodegib for management of periocular basal cell carcinoma—Hussain et al. available and with wider availability of vismodegib. Neoadjuvant use of this medication is a particular area of continuing research, and combining treatment arms for improved patient outcomes is an encouraging future frontier.
TAGEDH1REFERENCESTAGEDEN 1. Cook BE. Jr, Bartley GB. Epidemiologic characteristics and clinical course of patients with malignant eyelid tumors in an incidence cohort in Olmsted County, Minnesota. Ophthalmology. 1999;106:746–50. 2. Malhotra R, Huilgol SC, Huynh NT, Selva D. The Australian Mohs database, part II: periocular basal cell carcinoma outcome at 5-year follow-up. Ophthalmology. 2004;111:631–6. 3. Kakudo N, Ogawa Y, Suzuki K, Kushida S, Kusumoto K. Clinical outcome of surgical treatment for periorbital basal cell carcinoma. Ann Plast Surg. 2009;63:531–5. 4. Wong VA, Marshall JA, Whitehead KJ, Williamson RM, Sullivan TJ. Management of periocular basal cell carcinoma with modified en face frozen section controlled excision. Ophthal Plast Reconstr Surg. 2002;18: 430–5. 5. Nemet AY, Deckel Y, Martin PA, et al. Management of periocular basal and squamous cell carcinoma: a series of 485 cases. Am J Ophthalmol. 2006;142:293–7. 6. Gill HS, Moscato EE, Seiff SR. Eyelid margin basal cell carcinoma managed with full-thickness en-face frozen section histopathology. Ophthalmic Plast Reconstr Surg. 2014;30:15–9. 7. Sekulic A, Migden MR, Oro AE. Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med. 2012;366:2171–9. 8. Gill HS, Moscato EE, Chang AL, Soon S, Silkiss RZ. Vismodegib for periocular and orbital basal cell carcinoma. JAMA Ophthalmol. 2013;131:1591–4. 9. Yin VT, Pfeiffer ML, Esmaeli B. Targeted therapy for orbital and periocular basal cell carcinoma and squamous cell carcinoma. Ophthal Plast Reconstr Surg. 2013;29:87–92. 10. Yin VT, Merritt H, Esmaeli B. Targeting EGFR and sonic hedgehog pathways for locally advanced eyelid and periocular carcinomas. World J Clin Cases. 2014;2:432–8. 11. Kahana A, Worden FP, Elner VM. Vismodegib for eye-threatening orbital basal cell carcinoma. JAMA Ophthalmol. 2013;131:1364–6. 12. Kahana A, Worden FP, Elner VM. Vismodegib as eye-sparing adjuvant treatment for orbital basal cell carcinoma. JAMA Ophthalmol. 2013;131: 1364. 13. Vakil N, van Zanten SV, Kahrilas P, Dent J, Jones R, Globale Konsensusgruppe. [The Montreal definition and classification of gastroesophageal reflux disease: a global, evidence-based consensus paper] [article in German]. Z Gastroenterol. 2007;45:1125–40. 14. Pan-Canadian Oncology Drug Review Final Economic Guidance Report—Vismodegib (Erivedge) for Basal Cell Carcinoma, 2013. https://cadth.ca/pcodr 15. Shi Y, Jia R, Fan X. Ocular basal cell carcinoma: a brief literature review of clinical diagnosis and treatment. Oncol Targets Ther. 2017;10: 2483–9. 16. Demirci H, Worden F, Nelson CC, Elner VM, Kahana A. Efficacy of vismodegib (Erivedge) for basal cell carcinoma involving the orbit and periocular area. Ophthal Plast Reconstr Surg. 2015;31:463–6. 17. Furdova A, Lukacko P. Periocular basal cell carcinoma predictors for recurrence and infiltration of the orbit. J Craniofac Surg. 2017;28:e84–7. 18. BC Cancer Agency Cancer Drug Manual, 2015. http://www.bccancer. bc.ca/health-professionals/clinical-resources/cancer-drug-manual 19. Dessinioti C, Tzannis K, Sypsa V, et al. Epidemiologic risk factors of basal cell carcinoma development and age at onset in a Southern European population from Greece. Exp Dermatol. 2011;20:622–6. 20. Lomas A, Leonardi-Bee J, Bath-Hextall F. A systematic review of worldwide incidence of non-melanoma skin cancer. Br J Dermatol. 2012;166: 1069–80. 21. Mittal A, Colegio OR. Skin cancers in organ transplant recipients. Am J Transplant. 2017;17:2509–30. 22. Ceilley RI, Del Rosso JQ. Current modalities and new advances in the treatment of basal cell carcinoma. Int J Dermatol. 2006;45:489–98.
23. Cook B.E. Jr, Bartley GB. Treatment options and future prospects for the management of eyelid malignancies. Ophthalmology. 2001;108:2088–98. quiz 2099100, 2121. 24. Mohs FE. Micrographic surgery for the microscopically controlled excision of eyelid cancers. Arch Ophthalmol. 1986;104:901–9. 25. Glatt HJ, Olson JJ, Putterman AM. Conventional frozen sections in periocular basal-cell carcinoma. Ophthalmic Surg. 1992;23:6–8. discussion 9. 26. Hamada S, Kersey T, Thaller VT. Eyelid basal cell carcinoma: nonMohs excision, repair, and outcome. Br J Ophthalmol. 2005;89:992–4. 27. Randle HW. Basal cell carcinoma: identification and treatment of the high risk patient. Dermatol Surg. 1996;22:255–61. 28. Sun MT, Wu A, Figueira E, Huilgol S, Selva D. Management of periorbital basal cell carcinoma with orbital invasion. Future Oncol. 2015;11:3003–10. 29. Goldberg RA, Kim JW, Shorr N. Orbital exenteration: results of an individualized approach. Ophthal Plast Reconstr Surg. 2003;19: 229–36. 30. Sekulic A, Migden MR, Oro AE, et al. Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med. 2012;366:2171–9. 31. Tang JY, Mackay-Wiggan JM, Aszterbaum M, et al. Inhibiting the hedgehog pathway in patients with the basal-cell nevus syndrome. N Engl J Med. 2012;366:2180–8. 32. Basset-Seguin N, Hauschild A, Kunstfeld R, et al. Vismodegib in patients with advanced basal cell carcinoma: primary analysis of STEVIE, an international, open-label trial. Eur J Cancer. 2017;86:334–8. 33. Work Group; Invited Reviewers, Kim JYS, Kozlow JH, Mittal B, Moyer J, Olencki T, Rodgers P. Guidelines of care for the management of basal cell carcinoma. J Am Acad Dermatol. 2018;78:540–59. 34. Sagiv O, Nagarajan P, Ferrarotto R, et al. Ocular preservation with neoadjuvant vismodegib in patients with locally advanced periocular basal cell carcinoma. Br J Ophthalmol. 2019;103:775–80. 35. Gonzalez 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;35:56–61. 36. Sagiv O, Ding S, Ferrarotto R, et al. Impact of Food and Drug Administration approval of vismodegib on prevalence of orbital exenteration as a necessary surgical treatment for locally advanced periocular basal cell carcinoma. Ophthalmic Plast Reconstr Surg. 2019;35:350–3. 37. Pharmaceutical Benefits Scheme (PBS). Vismodegib: Capsule 150 mg; Erivedge. www.pbs.gov.au/info/industry/listing/elements/pbac-meetings/psd/2016-11/vismodegib-psd-november-2016. 38. National Institute for Health and Care Excellence. Vismodegib for treating basal cell carcinoma. www.nice.org.uk/guidance/ta489/resources.
Footnotes and Disclosure: The authors and consensus group attended a Hoffmann-La Roche consultancy meeting on the use of vismodegib for advanced or metastatic periocular basal cell carcinoma (BCC). These guidelines and publication were not influenced or sponsored by industry and were formulated without industry involvement. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. From the *Ophthalmic Plastic and Reconstructive Surgery, Department of Ophthalmology and Visual Sciences, QEII Health Sciences Centre, Dalhousie University, Halifax, N.S.; yMount Sinai Hospital, University of Toronto, Toronto, Ont.; zOphthalmic Plastic and Reconstructive Surgery, Mount Sinai Hospital, The Hospital for Sick Children, and Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, Ont.; xUniversity of British Columbia, Vancouver, B.C.; ║Michael Garron Hospital and University of Toronto, Toronto, Ont.; {Department of Ophthalmology and Visual Sciences, McGill University, Montreal, Que.; **Department of Ophthalmology and Eye Face Institute, University of CAN J OPHTHALMOL—VOL. &, NO. &, & 2019
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ARTICLE IN PRESS Vismodegib for management of periocular basal cell carcinoma—Hussain et al. Toronto, North York, Ont.; yyDepartment of Ophthalmology, University of Montreal, Montreal, Que.; zzMount Sinai Hospital, University of Toronto, Toronto Ont.; xxUniversity of Toronto, Toronto, Ont.; ║║Department of Ophthalmology, Queen’s University, Kingston, Ont.; {{Department of Ophthalmology and Vision Sciences, University of Toronto, Oshawa, Ont.; ***Kitchener, Ont.
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Originally received Sep. 7, 2019. Final revision Nov. 8, 2019. Accepted Nov. 13, 2019. Correspondence to Ahsen Hussain, MD, FRCOphth, 1276 South Park Street, Room 2035-2 West Victoria, Halifax, N.S. B3H 2Y9. [email protected]
Guidelines for vismodegib in the management of periocular basal cell carcinoma Ahsen Hussain, MD, FRCOphth,* Nancy Tucker, MD, FRCSC,y Dan D. DeAngelis, MD, FRCSC,z Vivian T. Yin, MD, MPH, FRCSC,x Edsel Ing, MD, FRCSC, MPH, CPH,║ Bryan Arthurs, MD, FRCSC,{ Harmeet S. Gill, MD, FACS, FRCSC,** Isabelle Hardy, MD, FRCSC, DABO,yy Jeff Hurwitz, MD, FRCS (C),zz Vladimir Kratky, MD, FRCSC,xx Babak Maleki, MD, FRCSC,║║ Navdeep Nijhawan, MD, FRCSC,{{ James Oestreicher, MD, FRCSC,xx Aftab Zafar, MD, FRCSC*** ABSTRACT Objective: The management of advanced basal cell carcinoma (BCC) in the periocular region remains a clinical challenge. Vismodegib (ErivedgeTM) has been approved in 2013 by Health Canada for adult patients with “histologically confirmed metastatic BCC or locally advanced BCC inappropriate for surgery or radiation.” An expert consensus was sought to create a standardised approach in the use of this novel treatment. Methods: Fourteen practicing oculoplastic surgeons across Canada were involved in formulating and reviewing guidelines until consensus was reached. A consultancy meeting was followed by further ratification of guidelines over email. Two voting surveys were performed of the group to objectively assess agreement over each statement within the guidelines. Ratification continued until at least two-thirds of the group agreed on every guideline statement. Results: The guidelines summarize 21 statements in a major and minor criteria format. A multidisciplinary team review is suggested for each patient with the involvement of recommended specialists. The internal survey revealed 100% agreement over 9 statements, 91.7% agreement over 8 statements, 83.3% agreement over 4 statements, and 2 statements had 66.7% and 58.7% agreement each. All statements with less than 91.7% agreement were surveyed again, and they were kept, modified, or removed on the basis of a consensus of over 66.7%. Conclusions: These guidelines serve to act as a framework for physicians considering vismodegib for the medical management of patients with advanced or metastatic periocular BCC. Future applications, including neoadjuvant uses of the drug, may become apparent through further research.
Basal cell carcinoma (BCC) is the commonest eyelid malignancy, and if left untreated, it can present with orbital invasion.1 Management decisions and prognosis are influenced by patient factors such as advancing age and medical comorbidities, and disease factors such as tumour location, size, histological subtype, and multiple or recurrent lesions.2 The current standard of treatment for surgically manageable orbital and periocular BCCs is margin-controlled excision, which can be supplemented by adjuvant radiotherapy.35,6 In advanced cases, surgery may lead to extensive loss of adnexal tissue required for appropriate globe protection and function, in some cases requiring eye removal or formal exenteration. Furthermore, patients with inherited syndromes leading to multiple periocular malignancy (such as basal cell nevus syndrome) may not be suitable candidates for repetitive surgery. The treatment of advanced or metastatic periocular BCC therefore remains challenging. The Hedgehog pathway inhibitor vismodegib (Erivedge, Genentech, CA) is the first molecular-targeted oral therapy approved for the treatment of BCC. A dysregulated Hedgehog
signalling pathway was first found in families with basal cell nevoid syndrome, followed by the same finding in sporadic cases, resulting in uncontrolled proliferation of basal cells. Vismodegib, an inhibitor of the transmembrane protein smoothened (SMO) in the hedgehog pathway, was approved in 2013 by Health Canada for the “treatment of adult patients with histologically confirmed metastatic basal cell carcinoma or locally advanced basal cell carcinoma (BCC) inappropriate for surgery or radiotherapy.” Although studies have demonstrated efficacy of this treatment in select cases,712 the interpretation on when vismodegib should be used clinically remains open to considerable debate. On account of factors such as expense, requirement for pre-approval, and a not insignificant sideeffect profile, we sought to create a Canadian consensus document to provide a framework for clinicians considering this treatment for their patients.
TAGEDH1METHODSTAGEDEN In October 2017, a Canadian consultancy group met in Toronto, Ontario, to discuss the clinical applications of
© 2019 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jcjo.2019.11.004 ISSN 0008-4182 CAN J OPHTHALMOL—VOL. &, NO. &, & 2019
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ARTICLE IN PRESS Vismodegib for management of periocular basal cell carcinoma—Hussain et al. vismodegib in the management of advanced and metastatic periocular and orbital BCC. This group was composed of oculoplastic surgeons, an ocular oncologist, an ophthalmic pathologist, and medical oncologists. After this meeting, it was apparent that there would be varied interpretation in how this new medication could be potentially applied. This would be further influenced by differing provincial guidelines within Canada. The 3 primary authors (A.H., N.T., and D. D.) believed that approaching the group to form consensus guidelines would be beneficial in providing a framework for future modification. A modified Delphi process was employed to reach consensus using repeated iterative voting.13 After initial discussion at the meeting, members of a smaller group of 12 oculoplastic surgeons participated in email discussions, followed by 2 rounds of online surveys to finalize the guidelines (Fig. 1). Two further consensus members were added before the second group survey. Ratification of each individual statement within the guidelines continued until final agreement. A “major and minor” (M&M) criteria format was determined to best provide coverage of the most critical aspects of this guideline. A “consensus” was considered to have been reached when a minimum of two-thirds of all participants voted in favour of each statement within the guidelines, similar to other consensus building projects.13
TAGEDH1RESULTSTAGEDEN The consensus guidelines summarize 21 individual statements, and 91.7% of the consensus body agreed that an M&M criteria format was appropriate for these guidelines. Seven of the statements relate to preamble that is suggested before application of the M&M criteria. There are 4 major criteria statements and 11 minor criteria statements. At least 1 major criterion or 2 minor criteria should be fulfilled to consider first-line treatment with vismodegib. Table 18-12,14-18 presents the proposed guidelines from our consensus group. At the first survey, the format of using M&M criteria and the following statements each received 91.7% (11 members) or 100% agreement from the consensus group:
• Forum to discuss applicaon of vismodegib • Evidence reviewed • Highlighted need for preliminary guidelines
Consensus group • 12 members • Circulaon of dras via email • Comments and changes • Preliminary dra
Consultancy meeng
At least 1 major criterion or 2 minor criteria should be fulfilled to consider first-line treatment with vismodegib. This document neither serves to support nor discourages the use of the medication. Clinicians should apply these guidelines individually at their discretion. Multidisciplinary team review including preferably tumour board review. This should include as a minimum an oculoplastic surgeon (or a surgeon with expertise in periocular skin cancer), a radiologist, a medical oncologist, a radiation oncologist, and a pathologist. Consult head and neck surgery, neurosurgery, and plastic surgery as required. A clear definition of treatment (such as control or cure) should be established with the patient and multidisciplinary team (MDT)/tumour board. Ensure that the patient does not have any contraindications to the medication (see link to document below). Major criterion: Patient medically unfit to have surgery or radiotherapy. Major criterion: The patient has metastatic BCC (mBCC) disease considered untreatable by surgery or radiation. Major criterion: Surgery would lead to immediate loss of the eye. Minor criterion: BCC is located on side of only functioning eye. Minor criterion: BCC involving entire upper eyelid. Minor criterion: BCC involves entire lower eyelid AND medial canthus >5-mm-diameter area. Minor criterion: BCC involving medial canthus >5mm-diameter area and two-thirds or more of upper eyelid and/or lower eyelid. Minor criterion: Sclerosing or morpheaform (infiltrative) lesion with anticipated surgical defect involving anatomy described above. Minor criterion: BCC involving periosteum, orbital soft tissue, or frank bone invasion clinically and/or on finecut neuro-imaging. Minor criterion: BCC with (macroscopic) perineural invasion on neuroimaging.
• Individual points scrunized • Modificaon of dra based upon acceptance of all statements with 91.7% (11 member) or over agreement
Second group survey • Two further members = 14 • All statements receiving less than 91.7% re-surveyed • Opons of raficaon, inclusion of original or deleon offered on 2nd survey
First group survey
Fig. 1—Flowchart for Delphi process in achieving consensus on guidelines.
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• Guidelines in Major and Minor criteria format • 21 statements forming final consensus guideline
Finalisaon
ARTICLE IN PRESS Vismodegib for management of periocular basal cell carcinoma—Hussain et al. Table 1—Guidelines for consideration of vismodegib for the management of advanced periocular or metastatic basal cell carcinoma (BCC)8–12,14–18 Consensus group: Hussain A, Arthurs B, DeAngelis D, Gill H, Hardy I, Hurwitz J, Ing E, Kratky V, Maleki B, Nijhawan N, Oestreicher J, Tucker N, Yin V, Zafar A The use of vismodegib (Erivedge) has been approved for use by Health Canada for the “treatment of adult patients with histologically confirmed metastatic basal cell carcinoma or locally advanced basal cell carcinoma (BCC) inappropriate for surgery or radiotherapy.” Preamble: At least 1 major criterion or 2 minor criteria should be fulfilled to consider firstline treatment with vismodegib. Provincial/Health Canada approval guidelines should be taken into consideration. This document neither serves to support nor discourages the use of the medication. Clinicians should apply these guidelines individually at their discretion. For all patients, ensure: Multidisciplinary team review including preferably tumour board review. This should include as a minimum an oculoplastic surgeon (or a surgeon with expertise in periocular skin cancer), a radiologist, a medical oncologist, a radiation oncologist, and a pathologist. Consult head and neck surgery, neurosurgery, and plastic surgery as required. A clear definition of treatment (such as control or cure) should be established with the patient and MDT/tumour board. Ensure that the patient does not have any contraindications to the medication (see link to document below*). Major Criteria Patient medically unfit to have surgery or radiotherapy The patient has metastatic BCC disease considered untreatable by surgery or radiation Surgery would lead to immediate loss of the eye Basal cell nevus syndrome with multiple facial BCCs that cannot be reasonably excised surgically Minor Criteria BCC is located on side of only functioning eye Surgeon concern regarding functional deficit from surgery or radiation, such as: BCC involving entire upper eyelid BCC involves entire lower eyelid AND medial canthus >5-mm-diameter area BCC involves entire lower eyelid AND lateral canthus >10-mm-diameter area BCC involving medial canthus >5-mm-diameter area and two-thirds or more of upper eyelid and/or lower eyelid Sclerosing or morpheaform (infiltrative) lesion with anticipated surgical defect involving anatomy described above Patient with recurrent BCC with 2 or more previous margin-controlled excisions BCC involving periosteum, orbital soft tissue, or frank bone invasion clinically and/or on fine-cut neuro-imaging BCC with (macroscopic) perineural invasion on neuroimaging Patient and surgeon both concerned that cosmetic outcome of surgery may be unacceptable *www.bccancer.bc.ca/drug-database-site/Drug%20Index/Vismodegib_monograph_1 Sep2015.pdf
The following statements received less than 91.7% agreement (in parentheses is percentage agreement): Provincial guidelines should be taken into consideration (66.7%). Major criterion: Basal cell nevus syndrome with multiple facial BCCs involving at least 2 different eyelids (83.3%). Minor criterion: BCC involves entire lower eyelid AND lateral canthus >10-mm-diameter area (83.3%). Minor criterion: Surgery or radiation would lead to immediate or eventual loss of lacrimal drainage system (58.3%). Minor criterion: Patient with recurrent BCC with 2 or more previous margin-controlled excisions (83.3%). Minor criterion: Patient and surgeon both concerned that cosmetic outcome of surgery may be unacceptable (83.3%).
All preceding 6 statements were discussed via email within the group and then submitted for a second survey. This survey provided the option for further ratification of the statement, inclusion as per the original, or removal from the guidelines. Following are the final percentage agreements on these statements and the outcome. 1. Provincial guidelines should be taken into consideration (92.9%). Statement altered to: Provincial/Health Canada approval guidelines should be taken into consideration. 2. Major criterion: Basal cell nevus syndrome with multiple facial BCCs involving at least 2 different eyelids (85.7%). Statement altered to: Basal cell nevus syndrome with multiple facial BCCs that cannot be reasonably excised surgically. 3. Minor criterion: BCC involves entire lower eyelid AND lateral canthus >10-mm-diameter area (78.6%): Statement retained as original. 4. Minor criterion: Surgery or radiation would lead to immediate or eventual loss of lacrimal drainage system (64.2%): Statement removed. 5. Minor criterion: Patient with recurrent BCC with 2 or more previous margin-controlled excisions (71.4%): Statement retained as original. 6. Minor criterion: Patient and surgeon both concerned that cosmetic outcome of surgery may be unacceptable (85.7%): Statement retained as original. Where statements had over 66.7% (two-thirds) agreement and were provided with ratification comments without significant change of the original statement or meaning, these comments were incorporated into the original statement (statements 1 and 2). Statements with less than 66.7% or a minimum of 9member agreement were removed from the guidelines (statement 4). All other statements with over 66.7% without provision of ratification comments were retained as the original statement. A final consensus document was submitted for review and acceptance by the consensus group.
TAGEDH1DISCUSSIONTAGEDEN BCC is a malignant tumour originating from the follicular germinative basal cells within the epidermis. It is the most common non-melanoma skin cancer in Europe and the United States with an estimated incidence of 100 per 100 000 individuals.19,20 Cumulative UVB exposure (280320 nm) is considered the main risk factor for development of BCC. Other significant risk factors include genetic conditions such as xeroderma pigmentosum and basal cell nevus syndrome, previous radiotherapy, and CAN J OPHTHALMOL—VOL. &, NO. &, & 2019
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ARTICLE IN PRESS Vismodegib for management of periocular basal cell carcinoma—Hussain et al. immunosuppression. The latter may result in an increased prevalence of malignant tumours seen in patients treated with new immunomodulator therapies such as checkpoint inhibitors.21 Up to 80% of BCCs occur in the head and neck region, with around 20% of these occurring in the periocular area. BCC is the commonest malignancy to affect the eyelids, with the highest frequency occurring in the lower eyelid and at the medial canthus.15 Management of periocular BCC needs to take into consideration patient comorbidities, tumour characteristics, locally available resources, and treatment options. Traditionally, surgical excision was the main treatment modality offered to patients for resectable tumours. Other treatment methods usually employed for noneyelid and smaller tumours include cryotherapy, curettage and electrodessication, laser therapy, radiation, photodynamic therapy with delta-aminolevulinic acid, and topical immunomodulators such as imiquimod and fluorouracil. Margin-controlled excision via either Mohs micrographic surgery or frozen-section control are now considered the gold-standard in treatment.22,23 These approaches can be curative for over 90% of cases.35,2425 Where margin-controlled surgery was not used as the primary surgical modality, incomplete excision was found to be around 25% in 1 study5 and can range from between 16% and 40%.45,2627 This is particularly relevant in patients with morpheaform, infiltrative, and micronodular subtypes of BCC, which have a higher rate of subclinical spread and recurrence.2 Furthermore, locations such as the medial canthus can be associated with a higher risk of aggressive behaviour such as orbital invasion.28 In certain cases, orbital exenteration is required to achieve tumour clearance and prevent further morbidity29. As BCCs do not typically exhibit nodal or distant metastasis, such sight-compromising surgery is an unfortunate requirement in cases of neglect or delayed diagnosis.28 One challenge when planning surgery is that the extent of orbital invasion may have been underestimated. Biological behaviour of tumour subtypes and the presence of perineural spread must be taken into account. Required surgical margins of excision in the periocular area can also severely compromise remaining functional tissue to provide adequate protection to the globe. Vismodegib is a new first-in-class small-molecule inhibitor of SMO. In 2013, Health Canada approved the use of vismodegib based on evidence provided by the ERIVANCE trial.30 The statements in our guidelines serve to reflect the evidence provided in this trial and further studies that have clarified when a patient would be considered “inappropriate for surgery or radiotherapy” within the context of periocular disease. Accessibility of this treatment across Canada is also reliant upon varied provincial requirements (Table 2). To our knowledge, there are no current guidelines that exist for the application of this treatment to the management of BCC in the periocular region. The ERIVANCE trial,30 was a Phase 2 trial in which 33 patients with mBCC and 63 patients with locally advanced BCC (laBCC) received 150 mg of vismodegib orally. These
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patients were considered inappropriate for surgery on the basis of multiple recurrences and a low likelihood of surgical cure, or substantial anticipated disfigurement. All minor criteria statements within our proposed guidelines elaborate on defining clinical criteria for “locally advanced or inappropriateness of surgery or radiotherapy” (statements 1221), potential disfigurement as related to adnexal tissue loss of function and cosmetic disfigurement (statements 1316 and 21), loss of the patient’s only functioning eye (12) and multiple recurrences (18), or low likelihood of surgical cure (1720). The 21 patients in this study had confirmed or suspected basal cell nevus syndrome, all of whom had laBCC. The primary hypothesized outcome was an objective tumour reduction by at least 20% of the original size for laBCC and 10% for mBCC. This was determined by an independent review committee. This Phase 2 trial demonstrated an objective response rate of 43% in laBCC patients and 30% in mBCC patients. Each case exceeded the predefined criteria for the hypothesized minimal acceptable response. No patients with mBCC had a complete response, whereas 21% of patients with laBCC had a complete response. Furthermore, a post-hoc analysis of ERIVANCE31 showed higher objective response rate of 67% in basal cell nevoid syndrome compared with 30% in patients with laBCC. We therefore incorporated basal cell nevoid syndrome as a major criteria statement (11) within the guidelines. The SafeTy Events in VIsmodEgib (STEVIE) trial32 demonstrated that vismodegib is well tolerable; however, 98% of patients had one or more treatment emergent adverse event (TEAE), with serious TEAEs occurring in 23.8% of patients. Exposure beyond 12 months did not increase the incidence or severity of new TEAEs. After discontinuation of the drug, most TEAEs resolved by 12 months of initiating therapy. Statement 7 in the guidelines requires that contraindications are reviewed before considering vismodegib. According to recent guidelines of care for the management of BCC published by the American Academy of Dermatology,33 the eyelids, eyebrows, and periorbital skin are considered high-risk areas for recurrence of BCC, independent of size. Within the same category of high risk are lesions on the cheek, forehead, scalp, or neck more than 10 mm in size. Other high-risk parameters are irregular borders, recurrent tumours, prior radiation or active immunosuppression, and an aggressive growth pattern or perineural involvement. In formulating our guidelines, we propose statements 1316, which would significantly impact the protective function of the periorbital tissues. Reconstruction is feasible in these situations; however, on account of the large size of tumour and high-risk locations (such as medial canthus), the risk of disfiguring surgery and tumour recurrence are high. Outcomes of surgical approaches with such large tumours are dependent on surgeon and patient preference. Hence these statements have been placed in the minor criteria section in contrast to the strong indications described in the major criteria. Due to the complexity of managing these advanced cases, we recommend that multidisciplinary consultation should be sought (statement 5). Such
ARTICLE IN PRESS Vismodegib for management of periocular basal cell carcinoma—Hussain et al. Table 2—Canadian provincial criteria for application of funding of vismodegib treatment of advanced or metastatic periocular basal cell carcinoma (BCC) Province
Status
Date of Decision
Funding Criteria
All provinces (except Prince Edward Island and Nunavut)
See below
See below
Alberta
Funded
20 June 2014
British Columbia
Funded
1 Oct 2014
Manitoba
Funded
1 July 2014
For patients with locally advanced basal cell carcinoma (laBCC) who are inappropriate for surgery AND radiation therapy Patients must have an ECOG* score 02 Specifies metastatic BCC (mBCC) inoperable or inappropriate for surgery or radiotherapy Specifies basal cell nevus/Gorlin syndrome (BCN syndrome) Requires measurable metastatic disease or locally advanced disease Specifies dose at 150 mg daily until disease progression or unacceptable toxicity A separate nonordering physician must provide rationale and consult note for treatment Patient chart must confirm multidisciplinary team discussion Specifies inappropriate criteria for surgery as at least one of the following: technically not possible due to size/location/invasiveness recurrence after 2 or more procedures and curative resection unlikely substantial morbidity/deformity anticipated from surgery Specifies inappropriate criteria for radiation as at least one of the following: contraindication to radiation, e.g., BCN syndrome prior irradiated lesion suboptimal outcome expected due to size/location/invasiveness of BCC Patient preference for oral therapy will not be considered Prescribing limited to named physicians registered with Erivedge Pregnancy Prevention Program (EPPP) Specifies mBCC inappropriate for surgery or radiation Requires a “Compassionate Access Program” application with appropriate clinical information Specifies mBCC inappropriate for surgery or radiation Specifies BCN syndrome for coverage Requires measurable metastatic disease or locally advanced disease With measurable disease, at least one lesion >10 mm deemed inappropriate for surgery or radiation as documented by at least 2 specialist physicians Patients must be 18 years of age or older
Nunavut New Brunswick
Not funded Funded
25 June 2014
Newfoundland
Funded
1 Oct 2014
Nova Scotia
Funded
29 Dec 2014
Ontario
Funded
16 April 2014
Prince Edward Island Quebec
Under consideration Funded May 2018
Specifies mBCC inappropriate for surgery or radiation Requires measurable metastatic or locally advanced disease Patients must be 18 years of age or older Patient preference for oral therapy will not be considered Separate nonordering physicians must provide rationale for treatment including: Surgical consultation report Radiation therapy consultation report Confirmation required that patient has been discussed at MDT or equivalent (e.g., Regional Tumour Board) Renewal requires confirmation that patient has not experienced progression while on vismodegib Specifies inappropriateness for surgery or radiation as per Alberta criteria Specifies dose at 150 mg daily until disease progression or unacceptable toxicity Initial approval duration: 1 year Renewal approval duration: 1 year Specifies mBCC inappropriate for surgery or radiation Specifies basal cell nevus/Gorlin syndrome (BCN syndrome) Requires measurable metastatic or locally advanced disease Patients must be 18 years of age or older Specifies basal cell nevus/Gorlin syndrome (BCN syndrome) Requires MDT involvement Specifies mBCC inappropriate for surgery or radiation Specifies basal cell nevus/Gorlin syndrome (BCN syndrome) Requires measurable metastatic or locally advanced disease Patients must be 18 years of age or older Specifies dose at 150 mg daily until disease progression or unacceptable toxicity Approval duration: 1 year Separate nonordering physicians must provide rationale for treatment including: Surgical consultation report Radiation therapy consultation report Confirmation required that patient has been discussed at MDT or equivalent (e.g., Regional Tumour Board) Specifies inappropriateness for surgery or radiation as per Alberta criteria Patient preference for oral therapy will not be considered Maximum duration of each authorization is 4 months When requesting continuation of treatment, the physician must provide evidence of a beneficial clinical effect by the absence of disease progression (continued)
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ARTICLE IN PRESS Vismodegib for management of periocular basal cell carcinoma—Hussain et al. Table 2 (Continued) Province
Status
Date of Decision
Funding Criteria
Saskatchewan
Funded
18 July 2014
Specifies mBCC inappropriate for surgery or radiation Specifies basal cell nevus/Gorlin syndrome (BCN syndrome) Requires MDT involvement and specifies involvement of surgeons, dermatologists, radiation oncologists, and medical oncologists
*Eastern Cooperative Oncology Group (ECOG) Performance Status. Determines ability of patient to tolerate therapies in serious illness, specifically for chemotherapy:
consultation is also important in determining where vismodegib would not be suitable, and where cases of laBCC or mBCC may best be managed with chemotherapy, radiation, or supportive/palliative care. Clear objectives have to be defined through treatment before consideration of vismodegib with the patient, family, and MDT/tumour board. There have been multiple studies that have confirmed the clinical application and effectiveness of vismodegib for periocular and orbital BCC, as a reflection of the results of the ERIVANCE and STEVIE trials. Gill et al.8 presented results on 7 patients with biopsy-proven infiltrative BCC of the periocular region. All lesions represented recurrent laBCC not amenable to surgical resection or radiation. The mean duration of treatment with vismodegib was 11 weeks. Two patients showed a complete treatment response, 4 had a partial response (ranging from 15% to 90%), and 1 showed progression. Pretreatment lesion sizes ranged from 10 to 60 mm. Only 1 patient had no adverse reaction to the treatment. Demirci et al.16 studied 6 consecutive patients with biopsyproven orbital BCC and 2 patients with extensive periocular BCC. They considered vismodegib treatment if surgical morbidity was considered to be substantial (deformity, vision loss, diplopia, loss of the eye, or vital orbital structures). They defined a complete clinical response as regression of all visible areas of tumour, and a partial response was defined as at least 40% reduction of the original tumour size. The median duration of treatment was 8 months. Four patients showed a partial response and 4 showed a complete response to vismodegib. They found that, for patients with orbital involvement (6 cases), the best response was obtained in 2 patients where the drug was used as an off-label neoadjuvant therapy before surgery or as an off-label adjuvant therapy for residual microscopic disease after surgery. Studies continue to
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investigate neoadjuvant use of vismodegib; however, there is no current clear consensus on this potentially new application of the medication.3436 Therefore we have not included this aspect in our current proposed guidelines. Vismodegib is not licensed for neoadjuvant use in Canada. Emerging literature is also establishing the success of vismodegib in modifying prognosis for patients with laBCC.912 Sagiv et al.36 have recently demonstrated that, at last follow-up, 83% of their patients, treated after approval of vismodegib by the Food and Drug Administration, retained their eye, compared with 54% of patients treated before vismodegib approval. Furthermore, fewer patients with laBCC were treated with radiation after vismodegib approval (14% vs 38% before approval), thus sparing patients potentially significant periocular and ocular side effects of radiation. Variances exist across countries regarding authorization of vismodegib for the medical treatment of advanced or metastatic BCC. As comparative examples to Canada, the Pharmaceutical Benefits Scheme authority in Australia has authorized use of vismodegib along similar criteria.37 In contrast, the National Institute for Health and Care Excellence in the U.K. does not recommend vismodegib in the treatment of adult metastatic or laBCC that is inappropriate for surgery or radiotherapy.38 A fundamental reason for the formulation of our guidelines is to outline a standardized approach to the use of vismodegib and thereby contribute to future recommendations.
TAGEDH1CONCLUSIONSTAGEDEN We propose that clinicians consider vismodegib for the treatment of periocular laBCC or mBCC under the umbrella of Health Canada approval and our proposed guidelines. This document is likely to evolve as further evidence becomes
ARTICLE IN PRESS Vismodegib for management of periocular basal cell carcinoma—Hussain et al. available and with wider availability of vismodegib. Neoadjuvant use of this medication is a particular area of continuing research, and combining treatment arms for improved patient outcomes is an encouraging future frontier.
TAGEDH1REFERENCESTAGEDEN 1. Cook BE. Jr, Bartley GB. Epidemiologic characteristics and clinical course of patients with malignant eyelid tumors in an incidence cohort in Olmsted County, Minnesota. Ophthalmology. 1999;106:746–50. 2. Malhotra R, Huilgol SC, Huynh NT, Selva D. The Australian Mohs database, part II: periocular basal cell carcinoma outcome at 5-year follow-up. Ophthalmology. 2004;111:631–6. 3. Kakudo N, Ogawa Y, Suzuki K, Kushida S, Kusumoto K. Clinical outcome of surgical treatment for periorbital basal cell carcinoma. Ann Plast Surg. 2009;63:531–5. 4. Wong VA, Marshall JA, Whitehead KJ, Williamson RM, Sullivan TJ. Management of periocular basal cell carcinoma with modified en face frozen section controlled excision. Ophthal Plast Reconstr Surg. 2002;18: 430–5. 5. Nemet AY, Deckel Y, Martin PA, et al. Management of periocular basal and squamous cell carcinoma: a series of 485 cases. Am J Ophthalmol. 2006;142:293–7. 6. Gill HS, Moscato EE, Seiff SR. Eyelid margin basal cell carcinoma managed with full-thickness en-face frozen section histopathology. Ophthalmic Plast Reconstr Surg. 2014;30:15–9. 7. Sekulic A, Migden MR, Oro AE. Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med. 2012;366:2171–9. 8. Gill HS, Moscato EE, Chang AL, Soon S, Silkiss RZ. Vismodegib for periocular and orbital basal cell carcinoma. JAMA Ophthalmol. 2013;131:1591–4. 9. Yin VT, Pfeiffer ML, Esmaeli B. Targeted therapy for orbital and periocular basal cell carcinoma and squamous cell carcinoma. Ophthal Plast Reconstr Surg. 2013;29:87–92. 10. Yin VT, Merritt H, Esmaeli B. Targeting EGFR and sonic hedgehog pathways for locally advanced eyelid and periocular carcinomas. World J Clin Cases. 2014;2:432–8. 11. Kahana A, Worden FP, Elner VM. Vismodegib for eye-threatening orbital basal cell carcinoma. JAMA Ophthalmol. 2013;131:1364–6. 12. Kahana A, Worden FP, Elner VM. Vismodegib as eye-sparing adjuvant treatment for orbital basal cell carcinoma. JAMA Ophthalmol. 2013;131: 1364. 13. Vakil N, van Zanten SV, Kahrilas P, Dent J, Jones R, Globale Konsensusgruppe. [The Montreal definition and classification of gastroesophageal reflux disease: a global, evidence-based consensus paper] [article in German]. Z Gastroenterol. 2007;45:1125–40. 14. Pan-Canadian Oncology Drug Review Final Economic Guidance Report—Vismodegib (Erivedge) for Basal Cell Carcinoma, 2013. https://cadth.ca/pcodr 15. Shi Y, Jia R, Fan X. Ocular basal cell carcinoma: a brief literature review of clinical diagnosis and treatment. Oncol Targets Ther. 2017;10: 2483–9. 16. Demirci H, Worden F, Nelson CC, Elner VM, Kahana A. Efficacy of vismodegib (Erivedge) for basal cell carcinoma involving the orbit and periocular area. Ophthal Plast Reconstr Surg. 2015;31:463–6. 17. Furdova A, Lukacko P. Periocular basal cell carcinoma predictors for recurrence and infiltration of the orbit. J Craniofac Surg. 2017;28:e84–7. 18. BC Cancer Agency Cancer Drug Manual, 2015. http://www.bccancer. bc.ca/health-professionals/clinical-resources/cancer-drug-manual 19. Dessinioti C, Tzannis K, Sypsa V, et al. Epidemiologic risk factors of basal cell carcinoma development and age at onset in a Southern European population from Greece. Exp Dermatol. 2011;20:622–6. 20. Lomas A, Leonardi-Bee J, Bath-Hextall F. A systematic review of worldwide incidence of non-melanoma skin cancer. Br J Dermatol. 2012;166: 1069–80. 21. Mittal A, Colegio OR. Skin cancers in organ transplant recipients. Am J Transplant. 2017;17:2509–30. 22. Ceilley RI, Del Rosso JQ. Current modalities and new advances in the treatment of basal cell carcinoma. Int J Dermatol. 2006;45:489–98.
23. Cook B.E. Jr, Bartley GB. Treatment options and future prospects for the management of eyelid malignancies. Ophthalmology. 2001;108:2088–98. quiz 2099100, 2121. 24. Mohs FE. Micrographic surgery for the microscopically controlled excision of eyelid cancers. Arch Ophthalmol. 1986;104:901–9. 25. Glatt HJ, Olson JJ, Putterman AM. Conventional frozen sections in periocular basal-cell carcinoma. Ophthalmic Surg. 1992;23:6–8. discussion 9. 26. Hamada S, Kersey T, Thaller VT. Eyelid basal cell carcinoma: nonMohs excision, repair, and outcome. Br J Ophthalmol. 2005;89:992–4. 27. Randle HW. Basal cell carcinoma: identification and treatment of the high risk patient. Dermatol Surg. 1996;22:255–61. 28. Sun MT, Wu A, Figueira E, Huilgol S, Selva D. Management of periorbital basal cell carcinoma with orbital invasion. Future Oncol. 2015;11:3003–10. 29. Goldberg RA, Kim JW, Shorr N. Orbital exenteration: results of an individualized approach. Ophthal Plast Reconstr Surg. 2003;19: 229–36. 30. Sekulic A, Migden MR, Oro AE, et al. Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med. 2012;366:2171–9. 31. Tang JY, Mackay-Wiggan JM, Aszterbaum M, et al. Inhibiting the hedgehog pathway in patients with the basal-cell nevus syndrome. N Engl J Med. 2012;366:2180–8. 32. Basset-Seguin N, Hauschild A, Kunstfeld R, et al. Vismodegib in patients with advanced basal cell carcinoma: primary analysis of STEVIE, an international, open-label trial. Eur J Cancer. 2017;86:334–8. 33. Work Group; Invited Reviewers, Kim JYS, Kozlow JH, Mittal B, Moyer J, Olencki T, Rodgers P. Guidelines of care for the management of basal cell carcinoma. J Am Acad Dermatol. 2018;78:540–59. 34. Sagiv O, Nagarajan P, Ferrarotto R, et al. Ocular preservation with neoadjuvant vismodegib in patients with locally advanced periocular basal cell carcinoma. Br J Ophthalmol. 2019;103:775–80. 35. Gonzalez 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;35:56–61. 36. Sagiv O, Ding S, Ferrarotto R, et al. Impact of Food and Drug Administration approval of vismodegib on prevalence of orbital exenteration as a necessary surgical treatment for locally advanced periocular basal cell carcinoma. Ophthalmic Plast Reconstr Surg. 2019;35:350–3. 37. Pharmaceutical Benefits Scheme (PBS). Vismodegib: Capsule 150 mg; Erivedge. www.pbs.gov.au/info/industry/listing/elements/pbac-meetings/psd/2016-11/vismodegib-psd-november-2016. 38. National Institute for Health and Care Excellence. Vismodegib for treating basal cell carcinoma. www.nice.org.uk/guidance/ta489/resources.
Footnotes and Disclosure: The authors and consensus group attended a Hoffmann-La Roche consultancy meeting on the use of vismodegib for advanced or metastatic periocular basal cell carcinoma (BCC). These guidelines and publication were not influenced or sponsored by industry and were formulated without industry involvement. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. From the *Ophthalmic Plastic and Reconstructive Surgery, Department of Ophthalmology and Visual Sciences, QEII Health Sciences Centre, Dalhousie University, Halifax, N.S.; yMount Sinai Hospital, University of Toronto, Toronto, Ont.; zOphthalmic Plastic and Reconstructive Surgery, Mount Sinai Hospital, The Hospital for Sick Children, and Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, Ont.; xUniversity of British Columbia, Vancouver, B.C.; ║Michael Garron Hospital and University of Toronto, Toronto, Ont.; {Department of Ophthalmology and Visual Sciences, McGill University, Montreal, Que.; **Department of Ophthalmology and Eye Face Institute, University of CAN J OPHTHALMOL—VOL. &, NO. &, & 2019
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ARTICLE IN PRESS Vismodegib for management of periocular basal cell carcinoma—Hussain et al. Toronto, North York, Ont.; yyDepartment of Ophthalmology, University of Montreal, Montreal, Que.; zzMount Sinai Hospital, University of Toronto, Toronto Ont.; xxUniversity of Toronto, Toronto, Ont.; ║║Department of Ophthalmology, Queen’s University, Kingston, Ont.; {{Department of Ophthalmology and Vision Sciences, University of Toronto, Oshawa, Ont.; ***Kitchener, Ont.
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Originally received Sep. 7, 2019. Final revision Nov. 8, 2019. Accepted Nov. 13, 2019. Correspondence to Ahsen Hussain, MD, FRCOphth, 1276 South Park Street, Room 2035-2 West Victoria, Halifax, N.S. B3H 2Y9. [email protected]