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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.
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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. Here we test the hypothesis that use of the hedgehog inhibitor vismodegib will improve vision-related outcomes in patients with orbital and extensive periocular...
Contexts in source publication
Context 1
... of tumor location, many patients displayed either complete or near-complete clinical response to vismodegib (Fig. 3A). Based on physical examination measurements, cross sectional tumor sizes were on average 44% of baseline size after 3 months of vismodegib and 22% www.TheOncologist.com of baseline after 6 months ( Fig. 3B-D). For the 10 patients who had not undergone surgery by 9 months, tumors were on average 22% of baseline. For the three patients ...
Context 2
... of tumor location, many patients displayed either complete or near-complete clinical response to vismodegib (Fig. 3A). Based on physical examination measurements, cross sectional tumor sizes were on average 44% of baseline size after 3 months of vismodegib and 22% www.TheOncologist.com of baseline after 6 months ( Fig. 3B-D). For the 10 patients who had not undergone surgery by 9 months, tumors were on average 22% of baseline. For the three patients who remained on vismodegib through the end of study (12 months), mean cross-sectional tumor size was 20% of baseline (Fig. 3B, C). A total of 19 (56%) patients achieved complete response (CR), 10 (29%) achieved ...
Context 3
... size after 3 months of vismodegib and 22% www.TheOncologist.com of baseline after 6 months ( Fig. 3B-D). For the 10 patients who had not undergone surgery by 9 months, tumors were on average 22% of baseline. For the three patients who remained on vismodegib through the end of study (12 months), mean cross-sectional tumor size was 20% of baseline (Fig. 3B, C). A total of 19 (56%) patients achieved complete response (CR), 10 (29%) achieved partial response (PR), 2 (6%) achieved stable disease (SD), and none achieved progressive disease (PD) based on best physical exam (PE) measurement ( Fig. 3D; Table 3). For MRI/CT measurements, tumors showed maximum response at 6 months (18.5% of baseline) ...
Context 4
... on vismodegib through the end of study (12 months), mean cross-sectional tumor size was 20% of baseline (Fig. 3B, C). A total of 19 (56%) patients achieved complete response (CR), 10 (29%) achieved partial response (PR), 2 (6%) achieved stable disease (SD), and none achieved progressive disease (PD) based on best physical exam (PE) measurement ( Fig. 3D; Table 3). For MRI/CT measurements, tumors showed maximum response at 6 months (18.5% of baseline) (Fig. 3C). Sixteen (47%) patients showed CR, nine (26.5%) showed PR, two (6%) showed SD, and zero showed PD (Table 3) fibrous replacement as previously described [20]. In total, 67% (18) of patients who underwent excision showed complete ...
Context 5
... 3B, C). A total of 19 (56%) patients achieved complete response (CR), 10 (29%) achieved partial response (PR), 2 (6%) achieved stable disease (SD), and none achieved progressive disease (PD) based on best physical exam (PE) measurement ( Fig. 3D; Table 3). For MRI/CT measurements, tumors showed maximum response at 6 months (18.5% of baseline) (Fig. 3C). Sixteen (47%) patients showed CR, nine (26.5%) showed PR, two (6%) showed SD, and zero showed PD (Table 3) fibrous replacement as previously described [20]. In total, 67% (18) of patients who underwent excision showed complete histologic clearance, six (22%) had evidence of residual disease but with clear margins, and three (11%) ...
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Background
Basal cell carcinoma is the most common type of skin cancer with major impact in health-related quality of life. The use of the formulation based on the combination of IFN-alpha 2b and IFN-gamma (HeberFERON) is an effective alternative in the treatment of basal cell carcinoma, immunogenic tumor, potentially responsible to immunotherapies...
Citations
... The literature regarding neoadjuvant use of sonidegib in BCC is currently limited to observational studies and case reports with promising results [9,[47][48][49], and a clinical trial evaluating neoadjuvant sonidegib followed by surgery or imiquimod for BCC is recruiting as of March 2024 [46]. Multiple clinical trials, observational studies, and case reports have also demonstrated the efficacy of vismodegib as a neoadjuvant therapeutic in BCC [47,[49][50][51][52][53][54][55][56][57][58][59][60]. For example, in the Phase II, open-label VIS-MONEO study enrolling 55 patients with laBCC, vismodegib treatment led to surgical downstaging in 44 (80.0%) patients, with a histologically confirmed complete response to vismodegib observed in 27 (49%) patients. ...
Hedgehog pathway inhibitors (HHIs) have broadened the treatment options available for patients with advanced basal cell carcinoma (BCC) for whom traditional therapeutic approaches are not feasible or effective. Sonidegib and vismodegib are oral HHIs that were approved for treatment of patients with advanced BCC after demonstrating promising efficacy in the pivotal Phase II BOLT (NCT01327053) and ERIVANCE (NCT00833417) trials, respectively. However, the incidence and types of treatment-emergent adverse events (AEs) observed with these agents may limit continuous use of HHIs and ultimately impact clinical outcomes. In this review, we summarize the safety and tolerability profiles of sonidegib and vismodegib and discuss potential management strategies for HHI class-effect AEs, including muscle spasms, creatine phosphokinase increase, alopecia, and dysgeusia. These AEs primarily occur early in treatment and can lead to treatment discontinuation. Differences in the pharmacokinetic profiles of sonidegib and vismodegib may contribute to the variability noted in times to onset and resolution of these and other AEs. Evidence suggests that protocol modifications, such as treatment interruptions and dose reductions, are effective ways to manage AEs while maintaining disease control. Nonpharmacologic and pharmacologic interventions may also be considered as part of an AE management strategy. Overall, healthcare providers and patients with advanced BCC should be aware of the HHI class-effect AEs and plan effective management strategies to avoid treatment discontinuation and optimize therapeutic response.
... 18 Advances in technology (eg, virtual surgical planning, proton therapy), delivery, and sequencing (eg, neoadjuvant immunotherapy) in various specialties have narrowed disparities in disease control and survival endpoints between treatment modalities over time, translating into more treatment options. [21][22][23][24][25][26][27][28] In this context, documenting patient-reported outcomes in addition to assessing treatment related adverse effects have become even more important for patient engagement and empowerment in both informed consent and the treatment decision-making process. ...
Background
Facial cancer surgery involving the midface (comprising the lower eyelids, nose, cheeks, and upper lip) can have debilitating life-changing functional, social, and psychological impacts on the patient. Midface symptoms are inadequately captured by existing patient-reported outcome measures (PROMs). PROMs are increasingly used for individual patient care, quality improvement, and standardized reporting of treatment outcomes. This study aimed to present our findings from the first phase of the development of a midface, specifically periocular and nasal, PROM.
Methods
After international guidance for PROM development, the first phase comprised identification of salient issues and item generation. Fifteen patients who had midface surgery and 10 clinicians from various specialties with more than 5 years’ experience treating these patients were recruited. Semi-structured interviews explored aesthetic, functional, social, and psychological outcomes, with specific attention to deficiencies in current PROMs. Thematic analysis was used to develop an item pool, and group interviews with clinicians were carried out to create and refine PROM scales.
Results
Qualitative data from patient interviews were grouped into aesthetic, functional, and psychosocial domains for the eyelids and nose. Ninety-nine draft items were generated across these domains. Following focus group discussions, the final version of the midface-specific PROM contained 31 items (13 eye-specific, 10-nose-specific, eight general midface items).
Conclusions
This midface-specific PROM is valuable in assessing and comparing patient-reported outcomes in those who have undergone complex resection and reconstruction of the midface. This PROM is currently undergoing field testing.
... When comparing VAWS scores at 12 months or postoperatively to screening scores, 27/33 (82%) had stable or improved VAWS scores, 5/33 (15%) had minor decline, and only 1/33 (3%) had a major decline of 5+ points in their VAWS score. 27 patients in this trial ultimately underwent excision following treatment with vismodegib and 18/27 (67%) had complete histologic response with no residual disease, 6/27 (22%) had residual disease with clear margins, and 3/27 had positive margins (49). A subsequent analysis of residual disease showed proliferation of hedgehog active "micro tumors" -enriched for a W535L mutation in SMO (50). ...
Management of cutaneous malignancies can be particularly challenging when they are located in the periocular region. The standard of care for localized disease is complete surgical excision, but this may not be possible without significant disruption to visual structures and facial appearance. Definitive radiation may be an option for some patients who cannot or do not wish to undergo surgery. Advances in systemic treatment options for locally advanced and metastatic skin cancers in the past 10 years have prompted investigation into neoadjuvant treatment of periocular cancers. The use of chemotherapy, immune checkpoint inhibitors, and targeted therapies have all been reported with varying degrees of success. For many patients, targeted therapies or immune checkpoint inhibitors should be considered depending on the cancer type, symptoms, and goals with the input of a multidisciplinary cancer care team. In this article, we systematically review the latest updates in surgical, radiotherapeutic, and medical management of periocular malignancies.
... Vismodegib selectively binds to SMO, inhibiting Hh pathway activation and tumor cascade proliferation [40]. It was approved in 2012 by the FDA, by the European Medicine Agency (EMA) in 2013, and in 2016 authorized by the Ministry of Health of our country for fnancing through our National Health System for use in locally advanced BCC tumors and in metastatic tumors, where surgical treatment is no longer possible or RT treatment is not sufcient [1,[62][63][64], being well tolerated and demonstrating efcacy in around 50% of cases [65][66][67]. Tere are more and more studies showing a favorable clinical response in the treatment of BCC with vismodegib, in the periocular region or in any part of the body and of any histological type, even in basosquamous carcinoma [15,65,68,69]. Tis also leads to an improvement in the emotional stress caused by the tumor in these patients [2]. ...
... Tis also leads to an improvement in the emotional stress caused by the tumor in these patients [2]. In recent years, its use has been tested in advanced tumors with orbital invasion, in isolated cases or in case series, with a complete response to treatment between 25% and 87.5% [6,40,56,[66][67][68][69][70][71]. Vismodegib has not only been used as a sole treatment but also combined with surgery, as of-label use, either as a prior neoadjuvant or adjuvant after surgery [6, 15, 17, 56, 59, 65-67, 69, 71, 72]. ...
... In no other case have we interrupted treatment due to side efects, even after 58 months of treatment. Te most frequently observed side efects are muscle spasms (71.4%), dysgeusia (57.1%), hair loss (50%), gastric discomfort, and weight loss (50%), which coincides with what other works have reported [15,65,67,68,70,79]. Interruptions in treatment are possible if we need to increase its tolerability and we want to avoid its abandonment. ...
Purpose. Basal cell carcinoma (BCC) is the most frequent malignant periocular tumor. It is associated with exposure to ultraviolet radiation, and its incidence is gradually increasing. It may occasionally display more aggressive behavior and result in orbital or intracranial invasion. Mortality from periocular BBC with orbital invasion is very low, but the associated morbidity can be significant, from disfigurement to blindness. Traditionally, these cases have been treated with orbital exenteration or with radiotherapy (RT), but in recent years, hedgehog pathway inhibitors (HPIs) have emerged, are effective in more serious cases, and are used primarily or combined with surgery, changing our perspective on the management of these patients. Methods. We studied 24 cases of periocular BCC with orbital invasion, some primary and others recurrent, which were treated between 2011 and 2021 in the same hospital. All patients had clinical or radiological evidence of orbital invasion. Orbital exenteration was performed on 9/24 of the patients (1 received vismodegib after surgery), and 12/24 were treated, surgically preserving the eyeball, with 3 of them receiving adjuvant vismodegib. Three of the twenty-four patients were treated exclusively with vismodegib (Erivedge®, Genentech). Results. One patient died due to poor tumor evolution, but the rest evolved favorably and they have had no recurrences. Vismodegib was generally well tolerated, except for in one patient who discontinued treatment due to the side effects. Conclusions. In advanced BBC with orbital invasion, mutilating surgical treatments such as exenteration or potentially vision-threatening treatments such as RT remain as options. In recent years, however, very promising new medical therapies have emerged, such as HPI, which can be used effectively instead of surgery or in combination with it, preserving the eye and vision, which implies a new approach to treatment.
... Notably, a rate of 23 % was observed in the study with the longest follow-up (median 24, range 12-78 months), an international multicenter retrospective case series involving patients from the UK, Australia, and New Zealand [84]. Additionally, in a phase IV clinical trial by Kahana et al., which constituted the largest study reporting on this outcome, only 2 out of 34 patients experienced tumor recurrence two years after the completion of the study [75]. ...
... Its impact on eye salvation was underlined by Sagiv et al. [120], who reported lower orbital exenteration prevalence in patients diagnosed after vismodegib approval. Moreover, Kahana et al. [75] showed that primary or neoadjuvant treatment with vismodegib preserves visual function in patients with extensive periocular or orbital BCC. ...
... A total of 200 articles were screened independently by all authors. After exclusions and the addition of 10 new studies, a total of 22 studies (N = 2384 patients) were included in the review (Table 1): 19 studies assessing both efficacy and safety [13,16,18,[21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37], 2 studies assessing safety only [38,39], and 1 study assessing efficacy only [17]. Across all the studies, the median drug exposure ranged from 1.3 to 17.2 months (median = 6), and the median follow-up time was 1.3 to 42 months (median = 11). ...
... SSHis are a breakthrough targeted therapy for advanced BCCs. Compared with a previous meta-analysis [19], there was a doubling in sample size (N = 2384 compared with 1102), including updates from five pivotal clinical studies [13,16,30,36,37] and additional new recent studies [31][32][33][34][35]. This updated meta-analysis also revealed a higher combined pooled ORR, CRR, and CBR with a narrower CI. ...
Background:
Basal cell carcinoma (BCC) of the skin is the most common form of skin cancer in the United States. In life-threatening, advanced BCC, sonic hedgehog inhibitors (SSHis) remain a pre-eminent treatment option for locally advanced BCC and metastatic BCC.
Objective:
In this updated systematic review and meta-analysis, we aimed to better characterize the efficacy and safety of SSHis by including final updates from pivotal clinical trials and additional new recent studies.
Methods:
An electronic database search was performed for articles including clinical trials, prospective case series, and retrospective medical record reviews on human subjects. Overall response rates (ORRs) and complete response rates (CRRs) were the primary outcomes. For safety assessment, the prevalence of the following adverse effects was analyzed: muscle spasms, dysgeusia, alopecia, weight loss, fatigue, nausea, myalgias, vomiting, skin squamous cell carcinoma, increased creatine kinase, diarrhea, decreased appetite, and amenorrhea. Analyses were performed using R statistical software. Data were pooled using linear models with fixed effects meta-analysis for primary analyses, along with 95% confidence intervals (CIs) and p-values. Intermolecular differences were calculated using Fisher's exact test.
Results:
A total of 22 studies (N = 2384 patients) were included in the meta-analysis: 19 studies assessing both efficacy and safety, 2 studies assessing safety only, and 1 study assessing efficacy only. Overall, the pooled ORR for all patients was 64.9% (95% CI 48.2-81.6%), implicating there is at least a partial response (z = 7.60, p < 0.0001) in most patients receiving SSHis. The ORR for vismodegib was 68.5% and 50.1% for sonidegib. The most common adverse effects for vismodegib and sonidegib were muscle spasms (70.5% and 61.0%, respectively), dysgeusia (58.4% and 48.6%, respectively), and alopecia (59.9% and 51.1%, respectively). Patients were likely to experience weight loss (35.1%, p < 0.0001) from vismodegib. Alternatively, patients taking sonidegib experienced more nausea, diarrhea, increased creatine kinase levels, and decreased appetite compared with those receiving vismodegib.
Conclusion:
SSHis are an effective treatment for advanced BCC disease. Given the high discontinuation rates, management of patient expectations is warranted for compliance and achieving long-term efficacy. It is essential to stay updated with the latest discoveries on the efficacy and safety of SSHis.
... Recent case series and studies have evaluated the efficacy of neoadjuvant therapy with inhibitor of the Hedgehog signaling pathway before surgical treatment in patients with laBCC in order to reduce tumor size, facilitate the surgical procedure, and limit esthetic damage [110][111][112][113][114][115][116][117][118][119][120]. ...
Introduction:
Basal cell carcinoma (BCC) is the most common malignant tumor in adult white populations. If BCCs are not treated for years, if they cause massive destruction of the surrounding tissues, if they are considered unresectable or not eligible for radiotherapy they become progressively "locally advanced" (laBCC) or metastatic (mBCC). These tumors are defined as 'difficult-to-treat BCC'.
Areas covered:
A comprehensive search on PubMed was conducted to identify relevant literature about the several approved and recommended treatment options for the management of difficult-to-treat BCC published from January 2012 to July 2022. Surgical options, radiotherapy, hedgehog inhibitors, immunotherapy and combined treatments are discussed. The keywords used were basal cell carcinoma; difficult-to-treat BCC; management of difficult-to-treat BCC; surgical therapy; radiotherapy; hedgehog inhibitors; immunotherapy.
Expert opinion:
Identifying the best approach to DTT BCCs is one of the main challenges for the dermato-oncologist. The introduction of HHI for the treatment of advanced BCCs has revolutionized the clinical management of DTT BCCs. The immune checkpoint inhibitor cemiplimab has been approved for the treatment of locally advanced or metastatic BCC refractory to HHI therapy or in patients intolerant to HHI therapy. Multidisciplinary teams (MDTs) play a key role in managing these complex patients.
... Case studies have highlighted the potential efficacy of vismodegib for preserving vision in patients with opBCC [19][20][21][22][23][24]. In 2015, we initiated the VISORB study: VISmodegib for ORbital and periocular Basal cell carcinoma [25]. Study subjects were prescribed 150 mg vismodegib daily (orally) for up to 12 months or until disease progression or unacceptable toxicity, upon which surgical excision was recommended. ...
... The primary goal of the study was to preserve end-organ function while treating advanced opBCC. 100% of patients achieved a successful visual function outcome, as measured by a Visual Assessment Weighted Score (VAWS) [25]. 56% of patients achieved a complete clinical response to vismodegib, and of patients who elected to undergo excision post-treatment, 67% had no evidence of residual disease in excision samples (Table 2) [25]. ...
... 100% of patients achieved a successful visual function outcome, as measured by a Visual Assessment Weighted Score (VAWS) [25]. 56% of patients achieved a complete clinical response to vismodegib, and of patients who elected to undergo excision post-treatment, 67% had no evidence of residual disease in excision samples (Table 2) [25]. Here, we further characterized pre-and post-vismodegib tissue samples from these patients to correlate clinical outcomes with gene expression and mutational analysis. ...
Basal cell carcinoma (BCC) is a common skin cancer caused by deregulated hedgehog signaling. BCC is often curable surgically; however, for orbital and periocular BCCs (opBCC), surgical excision may put visual function at risk. Our recent clinical trial highlighted the utility of vismodegib for preserving visual organs in opBCC patients: 67% of patients displayed a complete response histologically. However, further analysis of excision samples uncovered keratin positive, hedgehog active (Gli1 positive), proliferative micro-tumors. Sequencing of pre-treatment tumors revealed resistance conferring mutations present at low frequency. In addition, one patient with a low-frequency SMO W535L mutation recurred two years post study despite no clinical evidence of residual disease. Sequencing of this recurrent tumor revealed an enrichment for the SMO W535L mutation, revealing that vismodegib treatment enriched for resistant cells undetectable by traditional histology. In the age of targeted therapies, linking molecular genetic analysis to prospective clinical trials may be necessary to provide mechanistic understanding of clinical outcomes.
Trial Registration: ClinicalTrials.gov Identifier: NCT02436408 .
... Since its introduction, vismodegib has demonstrated effectiveness in treating BCC of diverse origins, including cosmetically sensitive and surgically challenging regions, such as the nose and periorbita [17,18]. ...
Basal cell carcinoma (BCC) is a common skin malignancy that can present reconstructive challenges in patients with locally advanced diseases of the extremities. This article highlights three cases of locally advanced BCC of the extremities managed with vismodegib (Erivedge, Genentech). Vismodegib is a sonic hedgehog pathway (Shh) inhibitor approved by the FDA for use in metastatic or recurrent BCC. All three patients in our case series demonstrated significant clinical responses with reductions in tumor size which obviated the need for complex reconstructive surgery or amputation.
... All patients maintained successful visual function. 38 While the Vismoneo and VISORB trials have shown effective tumor shrinkage that could aid in reducing morbidity of surgery, more data is needed on the effect of neoadjuvant vismodegib on long-term survival. ...
Neha Gupta, Emily S Ruiz Department of Dermatology, Brigham and Women’s Hospital, Harvard Medical School, Jamaica Plain, MA, USACorrespondence: Emily S RuizDepartment of Dermatology, Brigham and Women’s Hospital, Harvard Medical School, 1153 Centre Street, Suite 4J, Jamaica Plain, MA, 02130, USATel +1 617-983-4626Fax +1 617-983-4504Email esruiz@bwh.harvard.eduAbstract: Basal cell carcinoma (BCC) is the most common cancer in Caucasians, and its incidence continues to rise. Generally, BCCs have good outcomes when diagnosed and treated early. However, 1– 10% of patients will develop advanced disease due to either delays in accessing treatment or aggressive tumors that may be refractory to treatment. Locally advanced basal cell carcinomas (laBCCs) are large, aggressive, or recurrent tumors that have the potential to invade surrounding tissues including bone, cartilage, nerve, and muscle. Treatment requires a multi-disciplinary approach where different modalities including surgery, radiation therapy, Hedgehog Pathway Inhibitors, and immunotherapy can be considered.Keywords: hedgehog pathway inhibitors, surgery, radiotherapy, immunotherapy, skin cancer
