- Email: [email protected]
Hedgehog Pathway Inhibition for Locally Advanced Periocular Basal Cell Carcinoma and Basal Cell Nevus Syndrome
Accepted Manuscript Hedgehog pathway inhibition for locally advanced periocular basal cell carcinoma and basal cell nevus syndrome Omar K. Ozgur, Vivian Yin, Eva Chou, Sharon Ball, Merrill Kies, William N. William, Michael Migden, Bradley A. Thuro, Bita Esmaeli PII:
S0002-9394(15)00243-3
DOI:
10.1016/j.ajo.2015.04.040
Reference:
AJOPHT 9320
To appear in:
American Journal of Ophthalmology
Received Date: 2 December 2014 Revised Date:
23 April 2015
Accepted Date: 27 April 2015
Please cite this article as: Ozgur OK, Yin V, Chou E, Ball S, Kies M, William WN, Migden M, Thuro BA, Esmaeli B, Hedgehog pathway inhibition for locally advanced periocular basal cell carcinoma and basal cell nevus syndrome, American Journal of Ophthalmology (2015), doi: 10.1016/j.ajo.2015.04.040. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Abstract Purpose: To review our experience treating patients with the hedgehog pathway inhibitor, vismodegib, in patients with orbital or periocular locally advanced or metastatic basal cell carcinoma (BCC) or basal cell nevus syndrome. Design: Retrospective interventional case series. Methods: We reviewed all patients with locally advanced or metastatic orbital or periocular BCC or basal cell nevus syndrome treated with the hedgehog pathway inhibitor, vismodegib, at a comprehensive cancer center from 2009 through 2015. Reviewed data included age; gender; American Joint Commission on Cancer tumor, node, metastasis staging system designation; type and grade of drug-related side effects; response to treatment; duration of follow-up, and status at last follow-up. Results: The study included 10 white men and 2 white women; the median age was 64.5 years. Ten patients had locally advanced BCC; 2 had basal cell nevus syndrome. Among the patients with locally advanced BCC, 5 had T3bN0M0 disease at presentation; 1 each had T3aN0M0, T3bN1M0, T2N1M1, T4N1M1, and T4N2cM1 disease. Overall, 3 patients had a complete response, 6 had a partial response, and 3 had stable disease at last follow-up. Two patients developed progressive disease after a complete response for 38 months and stable disease for 16 months respectively. All patients developed grade I drug-related adverse effects, most commonly muscle spasms (12 patients), weight loss (10), dysgeusia (9), alopecia (9), decreased appetite (5), and fatigue (4). Five patients developed grade II adverse effects. At last follow-up, none of the 5 patients presenting with T3bN0M0, or the patient with T3bN1M0 disease had required orbital exenteration. Conclusion: Hedgehog pathway inhibition produces a significant clinical response in most patients with locally advanced or metastatic orbital or periocular BCC or basal cell nevus syndrome and can obviate orbital exenteration in some patients. Drug-related adverse effects are manageable in most patients.
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Hedgehog pathway inhibition for locally advanced periocular basal cell carcinoma and basal cell nevus syndrome Short title: Vismodegib for periocular basal cell carcinoma
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Omar K. Ozgur,1 Vivian Yin,1 Eva Chou,1 Sharon Ball,1 Merrill Kies,2 William N. William,2 Michael Migden,3 Bradley A. Thuro,1 and Bita Esmaeli1 1
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Orbital Oncology and Ophthalmic Plastic Surgery Program, Department of Plastic Surgery 2 Department of Head and Neck Medical Oncology 3 Department of Dermatology The University of Texas MD Anderson Cancer Center Houston, TX 77030, United States
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Corresponding author: Bita Esmaeli, MD, FACS, Orbital Oncology & Ophthalmic Plastic Surgery Program, Department of Plastic Surgery, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 1488, Houston, Texas 77030. Tel: 713-7924457. Fax: 713-794-4662. E-mail: [email protected]
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Introduction Basal cell carcinoma (BCC) is the most common human malignancy and accounts for 90% of eyelid tumors.1-3 Fortunately, periocular and facial BCC are typically amenable to local surgical excision with 5-year recurrence rates of 1% to 5.3%.1,3,4 For advanced periocular BCC, i.e., characterized by large tumor size, multiple lesions, or recurrent disease with extension into the orbit or paranasal sinuses, surgical treatment may not be possible without risk of significant ocular morbidity or loss of the eye. A related group of patients who may not be good candidates for surgery are patients with basal cell nevus syndrome (Gorlin syndrome) with numerous BCCs in the periocular region. Additionally, patients with periocular BCC with advanced age or multiple medical comorbidities may not be good candidates for surgery. The discovery of underlying genetic mutations of the Hedgehog pathway in BCC has allowed for the emergence of targeted medical therapy for advanced, inoperable cases of BCC or in cases that would result in high morbidity with surgery.5-9 The Hedgehog pathway includes the Patched-1 transmembrane receptor (Ptch-1), a tumor suppressor that normally inhibits the downstream receptor Smoothened (Smo).7,10,11 A mutation in the Hedgehog pathway may lead to Hedgehog protein binding to Ptch-1, and reversal of the normal inhibition of Smo leading to cellular proliferation and tumorigenesis as well as expression of the downstream product GLI1, which is thought to lead to the formation of BCC.7,12,13 Ptch-1 also plays a role in basal cell nevus syndrome, which is secondary to an autosomal-dominant mutation in the PTCH1 gene.9,11,14 Vismodegib (Erivedge, Genentech, South San Francisco, CA, GDC-0449) is a selective Hedgehog pathway inhibitor that blocks Hedgehog signaling by binding to Smo, inhibiting downstream activation of Hedgehog target genes.15,16 Vismodegib was first studied in humans in 2008 and was approved by the US Food and Drug Administration in January 2012 for treatment of metastatic or locally advanced unresectable BCC. Few studies have shown the response to treatment with Hedgehog pathway inhibition with long-term follow-up. Targeting the Hedgehog pathway in patients with locally advanced periocular and orbital BCC is of particular interest since successful nonsurgical treatment could mean avoidance of radical and disfiguring surgery in the periorbital region and in some instances orbital exenteration. To date, however, reports of Hedgehog pathway inhibition in patients with orbital or periocular lesions have been limited to single case reports or small case series.7-9,17-20 There is room for reporting of additional experience in this particular patient population. We herein report our clinical experience with Hedgehog pathway inhibition in patients with locally advanced or metastatic orbital or periocular BCC and in patients with basal cell nevus syndrome and significant periocular lesions. Patients and Methods The Institutional Review Board of The University of Texas MD Anderson Cancer Center retrospectively approved this study. The study was performed in accordance with HIPAA regulations. For this retrospective interventional case series, we performed a retrospective chart review of all consecutive eligible patients treated for locally advanced or metastatic periocular basal cell carcinoma and basal cell nevus syndrome 2
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with Hedgehog pathway inhibition from November 2009 through September 2014. All patients were at least 18 years of age. Data recorded for this analysis included age, race/ethnicity, sex, site(s) of primary tumor involvement, size of tumor, presence of orbital extension, sites of regional or distant metastasis, tumor, node, metastasis staging system (TNM) designation at presentation according to American Joint Committee on Cancer (AJCC) criteria, type and grade of drug-related adverse effects according to Common Terminology Criteria for Adverse Events (CTCAE), version 4.0 (Table 1), response to treatment according to Response Evaluation Criteria in Solid Tumors (RECIST) (Table 2), duration of follow-up, and status at last follow-up. 21-23
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Results We identified 13 patients who met the inclusion criteria. However, 1 patient with locally advanced BCC was ultimately not included in the data analysis because of a hypersensitivity reaction to vismodegib that led to its discontinuation only 5 days after initiation of treatment. This patient had an orbital exenteration. The remaining 10 men and 2 women were included in this study. All patients were white with a median age of 64.5 years (range, 33-86 years). Tumors were staged according to the AJCC, 7th edition TNM criteria using clinical, pathological, and radiographic data as part of each patient’s standard clinical management.21 In each case, the decision to start treatment with Hedgehog pathway inhibition was made with input from the senior treating oculoplastic surgeon (B.E.) and input from the Radiation Oncology service to ensure that radiation was not an option. Patients with BCC were treated with Hedgehog pathway inhibition only if it was believed that complete surgical excision of the locally advanced lesion was not possible without substantial ocular morbidity or orbitofacial deformity, for example, from an orbital exenteration. Patients with basal cell nevus syndrome were treated with Hedgehog pathway inhibition to avoid multiple surgeries in the periocular and facial regions. Patients were treated with vismodegib at a dose of 150 mg/day by mouth daily. Ten patients had locally advanced BCC, 4 of these 10 patients also had metastatic disease to lymph nodes or other sites. TNM designations at presentation for the 10 patients with locally advanced BCC were as follows: T3aN0M0 (1 patient), T3bN0M0 (5 patients), T3bN1M0 (1 patient), T2N1M1 (1 patient), T4N1M1 (1 patient), and T4N2cM1 (1 patient). The remaining 2 patients had basal cell nevus syndrome. All patients were treated with vismodegib. One of those patients was later switched to another Hedgehog pathway inhibitor after developing progression of disease. The median follow-up time from start of Hedgehog pathway inhibition to last follow-up, last contact, or death, whichever occurred first, was 12.5 months (range, 7-53 months). The median duration of treatment was 11.5 months (range, 7-49 months). The overall response rate (complete or partial response) was 86% (6 of 7 patients) for patients presenting with nonmetastatic locally advanced BCC, 100% (2 of 2 patients) for patients with basal cell nevus syndrome, and 33% (1 of 3 patients) for patients presenting with locally advanced but also metastatic BCC. Although none of the patients in our cohort had initial progression of disease during initial treatment with 3
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vismodegib, 2 of 12 patients (17%) developed disease progression during active treatment after initial significant clinical response or stabilization of disease lasting at least 16 months. Tumor size, details of treatment and outcomes for all patients with BCC are summarized in Table 3. Three of the 12 patients (25%) had a complete response (example shown in Figures 1) with follow-up times of 12, 18, and 38 months, respectively. Six patients (50%) had a partial response (examples shown in Figures 2,3) with a median follow-up time of 9.5 months (range, 7-19 months). Three patients (25%) had stable disease with follow-up times of 11, 13, and 16 months. The following paragraphs will present detailed data for patients with locally advanced BCC vs. patients with basal cell nevus syndrome. One patient with locally advanced BCC and one patient with basal cell nevus syndrome have been briefly mentioned in prior solicited reviews on targeted therapy.7,9
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Treatment and Outcomes in Patients with Locally Advanced Basal Cell Carcinoma Of the 10 patients with locally advanced BCC, 9 are alive at this writing. Of those, 7 continue to receive treatment, and 2 have stopped treatment. Of the 2 patients who stopped treatment, 1 stopped for economic reasons and was lost to follow-up. The other patient with locally advanced non-metastatic BCC stopped treatment with vismodegib after 11 months because of grade II dysgeusia, grade II weight loss, and a fall resulting in a broken hip. This patient developed a recurrence of BCC after 3 months off vismodegib. As of this writing, he is planning to restart vismodegib treatment. Of 6 patients with locally advanced, non-metastatic BCC at presentation, 2 patients had a complete response with a follow-up of 12 and 18 months, respectively. Of the 4 patients with locally advanced, metastatic BCC, 2 patients (50%) had a partial response for 7 and 9 months, and 2 patients (50%) had stable disease for 13 and 16 months. Five patients with locally advanced T3bN0M0 disease would have required orbital exenteration as surgical treatment for their tumor. None of these 5 patients had had an orbital exenteration or enucleation at last follow-up. There were 4 patients with locally advanced periocular BCC who also had metastatic disease. One had a metastatic parotid node, one had metastatic disease to the ipsilateral parotid and neck lymph nodes, hilar lymph nodes, and liver, and lungs, one had metastatic ipsilateral parotid and submandibular nodes, bilateral cervical lymph nodes, and multiple skin sites. One patient who presented with extensive distant metastatic disease of the skull base to the chest and sacrum died of metastatic disease progression after 16 months of having had stable disease while on vismodegib. Treatment and Outcomes in Patients with Basal Cell Nevus Syndrome Of the 2 patients with basal cell nevus syndrome, 1 patient had a complete response to vismodegib for 38 months. He was then found to have a new non-target lesion. After 49 months of treatment with vismodegib, this patient was switched to another Hedgehog inhibitor. The other patient with basal cell nevus syndrome had stable disease with vismodegib but stopped treatment 19 months after the drug was started because of economic reasons. 4
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Drug-Related Adverse Effects Drug-related adverse effects and their grades are listed in Table 4. The most common drug-related adverse effects were muscle spasms, which occurred in all 12 patients; weight loss, which occurred in 10 patients; dysgeusia, which occurred in 9 patients; and alopecia, which occurred in 9 patients. All patients began experiencing side effects within 2-4 months of onset of treatment. Five patients (42%) developed grade II adverse effects. Of the 12 patients in the study, 8 patients continue treatment with vismodegib, 2 stopped because of economic reasons, 1 stopped because of side effects and other medical co-morbidities as mentioned, and 1 stopped because of disease progression on vismodegib and death.
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Discussion Our findings show that a substantial proportion (70%) of patients with locally advanced orbital or perioorbital BCC achieved a complete or partial response to Hedgehog pathway inhibition with vismodegib, and the remainder achieved stable disease in response to vismodegib for reasonably long periods. Hedgehog pathway inhibition also produced objective responses in the 2 patients with basal cell nevus syndrome. In a prospective trial of the use of vismodegib Sekulic et al.24 reported a response rate of 43% for locally advanced BCC and 30% for metastatic BCC. The higher response rate observed by us maybe due to the smaller cohort in the current report or perhaps due to tumors restricted to the periocular region. . The response rates in our cohort were similar to the rates reported by Von Hoff et al.25 who found that patients with locally advanced BCC had about a 60% response rate. A recent report by Demirci et al.19 of 8 patients with periorcular lesions treated with vismodegib showed complete response in 4 patients and partial response in 4 patients. In our current study, no progression of disease was noted in any patient until after at least 16 months of significant clinical response or stable disease. All 5 patients with T3bN0M0 disease, who would have required orbital exenteration as surgical treatment for their tumor, avoided orbital exenteration because of treatment with vismodegib. This suggests that vismodegib may be considered as an alternative to orbital exenteration in selected patients with locally advanced BCC in the periorbital region. Long-term follow-up is needed to further evaluate the durability of response in such patients. Combining vismodegib with surgery, either as neoadjuvant or adjuvant treatment, may also be considered. Similar to findings of previous studies of Hedgehog pathway inhibitors, drugrelated side effects were common among our study cohort, but most were grade I and did not require further treatment.15,25 The types of side effects experienced by our patients were similar to those in previous reports, with the most frequent being muscle spasms, weight loss, dysgeusia, alopecia, decreased appetite, and fatigue. Forty-two percent of patients developed grade II side effects. None of the patients in our study experienced grade III adverse effects, while Von Hoff et al,25 found that 24% of patients in their report had grade III adverse effects. 5
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How often patients experience a local recurrence after discontinuation of Hedgehog pathway inhibition is not well established in the literature. The data from our patient cohort also cannot definitively answer this question. We found that 1 patient with locally advanced BCC and a partial response developed recurrence 3 months after stopping Hedgehog pathway inhibition. The role of vismodegib or other Hedgehog pathway inhibitors in the neoadjuvant setting remains unclear. Ally et al.26 reported on 15 patients with locally advanced BCC who received vismodegib between 2 and 6 months as neoadjuvant treatment prior to surgical resection of BCC. A benefit was not seen in patients treated for less than 3 months. For the 13 target lesions selected for surgery, vismodegib reduced the surgical defect area by 27% from baseline. Seven of 13 tumors (54%) appeared to have experienced complete clinical response; however, only 4 of these 7 tumors showed complete histologic response on serial sectioning. This discordance along with isolated reports of recurrence of BCC upon discontinuation of vismodegib27 may suggest that vismodegib does not lead to complete and total microscopic ablation of BCC. In the study by Ally et al.26, of the 11 patients who completed the trial, 1 patient had a BCC recurrence 17 months after surgery. It is possible that the most appropriate indication for Hedgehog pathway inhibition in the management of locally advanced BCC is changing a locally advanced tumor to a much smaller lesion that requires some type of chronic and long-term maintenance treatment. This is particularly an attractive option in the periorbital region where globe preservation and visual function is at stake. It is unclear if viable BCC cells remain in the “chemoreduced” margins, and it is unclear exactly what proportion of such lesions might lead to future recurrences and over how long. As our study eligibility criteria followed the current US Food and Drug Administration approved indications for vismodegib for treatment of BCC, the results should not be extrapolated to all patients with BCC. BCC remains the most common cancer in humans, and in greater than 90% of cases it is amenable to surgery with excellent outcomes.28-31 Vismodegib and other agents targeting the Hedgehog pathway should only be considered for a small proportion of patients with periocular BCC who have large enough and advanced enough lesions that surgery or radiation therapy would otherwise lead to loss of the eye, loss of vision, or significant periorbital and facial deformity; patients with basal cell nevus syndrome in whom the number and size of periocular lesions prohibits multiple and frequent surgeries as a good option; and patients in whom multiple other comorbidities or very advanced age may make surgery or radiation therapy not a good option.7,8 The cost of treatment for Hedgehog pathway inhibitors is another consideration in patient selection and compliance, particularly since long-term treatment may be necessary. It is estimated that the cost of vismodegib in the United States is approximately $7500 per month.26 Two of the patients in our cohort discontinued vismodegib treatment because of cost-related issues despite an excellent response.
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ACKNOWLEDGMENTS / DISCLOSURE:
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Funding/Support: This research was supported in part by the National Institutes of Health through MD Anderson's Cancer Center Support Grant, CA016672. (USA) Financial Disclosures: Dr Bita Esmaeli serves as a member of the Data Safety Monitoring Board (DSMB) for a vismodegib trial in Europe. (Roche, Basel, Switzerland) None of the other authors have any financial disclosures to report. Contributions of Authors: Design of the study (BE) Conduct of the study (OO, VY, EC, SB, BE) Collection, management, analysis, and interpretation of the data (OO, VY, EC, SB, MK, WW, MM, BT, BE) Preparation, review, or approval of the manuscript (OO, BE, VY, EC, SB, MK, WW, MM, BT)
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Other Acknowledgments: None
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Figure Legends Figure 1. Clinical photograph of a patient with locally advanced basal cell carcinoma. The photograph in top left shows the patient before treatment with vismodegib, middle photograph shows the patient 1 month after initiation of vismodegib treatment, and the top right photograph was taken at 18 months after initiation of vismodegib treatment. Figure 2. Clinical photograph of a patient with advanced basal cell carcinoma of the right periorbital region with involvement of the upper and lower eyelids and right brow and biopsy-proven metastasis to the right preauricular area (arrow). Top photograph is before treatment with vismodegib; bottom photograph seen 4 weeks after initiation of vismodegib treatment, shows a substantial partial response. The patient continued to respond to nearly complete resolution of the lesion at last follow-up (not shown). Figure 3. Clinical photograph of a patient with recurrent basal cell carcinoma involving the right lower eyelid and premaxillary area causing mechanical and cicatricial ectropion of the right lower eyelid. Top left photograph is before treatment with vismodegib. Top right panel is a magnetic resonance image of the patient before treatment with vismodegib and shows extension of the right lower eyelid mass in the right maxillary sinus (arrows). Bottom left panel shows a magnetic resonance image of the same patient seen 9 months after initiation of vismodegib treatment. The right lower eyelid mass had resolved substantially.
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Table 1. Grade Definitions per the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0,22 Used to Grade the Severity of Adverse Events in a Series of Patients with Locally Advanced or Metastatic Orbital or Periocular Basal Cell Carcinoma and Basal Cell Nevus Syndrome Grade Severity Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living. Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living. Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to adverse effects.
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Table 2. Response Definitions per the Response Evaluation Criteria in Solid Tumors, Version 1.1,23 Used to Classify Responses to Vismodegib in a Series of Patients with Locally Advanced or Metastatic Orbital or Periocular Basal Cell Carcinoma and Basal Cell Nevus Syndrome Response Definition Complete response Disappearance of all target lesions. Any lymph nodes containing disease must have reduction in short axis to <10 mm. Partial response At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. Progressive disease At least a 20% increase in the sum of diameters of target lesions with an absolute increase of at least 5 mm, or the appearance of 1 or more new lesions. Stable disease Neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease, taking the smallest sum of diameters as reference.
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Table 3. Demographic and Tumor Characteristics, Treatment, and Outcomes in a Series of Patients with Basal Cell Carcinoma and Basal Cell Nevus Syndrome Treated with Vismodegib
T3aN0M0
70 M
T3bN0M0
86 M
T3bN0M0
84 M
T3bN0M0
56 M
10
T3bN0M0
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69 F
Grade 2 and 3 Adverse Effects
Status at Last Follow-up
3.0 x 1.7 cm; Left upper lid, lower lid, medial canthus 9.3 x 7.9 cm; Left lower lid and skin 3.3 x 3 cm; Right lower lid and inferior orbit
PR
9; 9
Still on
None
Alive with disease
PR
10; 10
Economic reasons
None
Alive with disease, then lost to follow-up
SD
11; 11
None
Alive with disease
1.5 x 1.8 cm; Left upper lid, lower lid, lateral canthus
PR for 14 months, recurrence 3 mo after stopping HHI
11; 24
Other medical issues
G2: dysgeusia, decreased appetite
Recurrence after stopping vismodegib, planning on restarting
CR
12; 12
Still on
None
Alive with no evidence of disease
18; 18
Still on
G2: muscle spasms
Alive with no evidence of disease
7; 7
Still on
None
Alive with disease
9; 9
Still on
None
Alive with disease
13; 13
Still on
G2: muscle spasms, hypertension
Alive with disease
18; 20
Disease progression on treatment
None
Died of disease progression
Microscopic disease; Left upper lid, lower lid, medial canthus 9 x 8 cm; Left upper lid, lower lid, temple 2 x 3 cm; Right upper lid, orbit, temporal fossa 8.1 x 6.3 cm; Left ear, preauricular skin; Metastatic 2.3 x 1.5 cm; Left ear, preauricular and periorbital skin; Metastatic
SC
T3bN0M0
Response to HHI
Current Treatment, or Reason for Stopping
Still on
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Size and Location of Primary Lesion (s)
Duration of HHI and Total a Follow-up , mo
CR
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Age, yr; Sex
TNM Status at Presentat ion
58 M
T3bN1M0
51 F
T4N2cM1
76 M
T2N1M1
65 M
T4N1M1
11.5 x 8 cm; Left ear and skull base; Metastatic
N/A (Basal cell nevus syndrome)
Right medial canthus 2.7 x 1.2 cm, left medial canthus 1 x 0.5 cm, multiple other lesions
PR
19; 19
Economic reasons
G2: weight loss
Alive with disease, then lost to follow-up
N/A (Basal cell nevus syndrome)
1.8 x 2.6 cm, multiple other lesions
CR for 38 months then PD
49; 53
Switched to another HHI
G2: muscle spasms, fatigue
Alive with disease
51 M
PR
EP
SD
SD for 16 months then PD
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12
PR
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Yr, year; TNM, American Joint Committee on Cancer (AJCC) tumor, node, metastasis staging system; HHI, Hedgehog inhibition; Mo, months; P, Patient; M, male; F, female; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; G2, grade 2; G3, grade 3. a From initiation of vismodegib treatment.
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Grade III 0 0 0 0
Any Grade 12 10 9 9
Muscle spasm Weight loss Dysgeusia Alopecia Decreased appetite Fatigue Nausea Headache Diarrhea Back pain Hypomagnesemia Hypertension Others a Any adverse effect
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1
0
5
4 2 2 2 2 2 0 7
0 1 0 0 0 0 1 0
0 0 0 0 0 0 0 0
4 3 2 2 2 2 1 7
12
5
0
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9 9 8 9
Grade II 3 1 1 0
Grade I
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Table 4. Drug-related Adverse Effects by Grade in a Series of Patients with Locally Advanced or Metastatic Orbital or Periocular Basal Cell Carcinoma and Basal Cell Nevus Syndrome Treated with Vismodegib
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The following grade I side effects were experienced by only 1 patient each: neuropathy, anemia, hyperglycemia, bilateral extremity edema, thick saliva, dyschezia, constipation, chest cramping, depression, and stomach flu.
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Omar Ozgur, MD obtained his BS in Information and Computer Science at the University of California, Irvine, and completed medical school at the University of Vermont, College of Medicine. He completed transitional internship at the University of Hawaii, followed by ophthalmology residency at the New York Eye and Ear Infirmary of Mount Sinai. Omar is currently a fellow in ophthalmic plastic and reconstructive surgery and orbital oncology at the University of Texas, MD Anderson.
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Dr Bita Esmaeli is a Professor of Ophthalmology in the Department of Plastic Surgery at The University of Texas M. D. Anderson Cancer Center, where she has an orbital oncology and oncologic ophthalmic plastic surgery practice. Dr Esmaeli 's research interests include molecular signature of ocular and orbital tumors, tissue banking for rare ocular and orbital tumors , eye and vision-sparing treatment strategies for orbital and ocular cancers, and ocular side effects of cancer therapy.
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S0002-9394(15)00243-3
DOI:
10.1016/j.ajo.2015.04.040
Reference:
AJOPHT 9320
To appear in:
American Journal of Ophthalmology
Received Date: 2 December 2014 Revised Date:
23 April 2015
Accepted Date: 27 April 2015
Please cite this article as: Ozgur OK, Yin V, Chou E, Ball S, Kies M, William WN, Migden M, Thuro BA, Esmaeli B, Hedgehog pathway inhibition for locally advanced periocular basal cell carcinoma and basal cell nevus syndrome, American Journal of Ophthalmology (2015), doi: 10.1016/j.ajo.2015.04.040. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Abstract Purpose: To review our experience treating patients with the hedgehog pathway inhibitor, vismodegib, in patients with orbital or periocular locally advanced or metastatic basal cell carcinoma (BCC) or basal cell nevus syndrome. Design: Retrospective interventional case series. Methods: We reviewed all patients with locally advanced or metastatic orbital or periocular BCC or basal cell nevus syndrome treated with the hedgehog pathway inhibitor, vismodegib, at a comprehensive cancer center from 2009 through 2015. Reviewed data included age; gender; American Joint Commission on Cancer tumor, node, metastasis staging system designation; type and grade of drug-related side effects; response to treatment; duration of follow-up, and status at last follow-up. Results: The study included 10 white men and 2 white women; the median age was 64.5 years. Ten patients had locally advanced BCC; 2 had basal cell nevus syndrome. Among the patients with locally advanced BCC, 5 had T3bN0M0 disease at presentation; 1 each had T3aN0M0, T3bN1M0, T2N1M1, T4N1M1, and T4N2cM1 disease. Overall, 3 patients had a complete response, 6 had a partial response, and 3 had stable disease at last follow-up. Two patients developed progressive disease after a complete response for 38 months and stable disease for 16 months respectively. All patients developed grade I drug-related adverse effects, most commonly muscle spasms (12 patients), weight loss (10), dysgeusia (9), alopecia (9), decreased appetite (5), and fatigue (4). Five patients developed grade II adverse effects. At last follow-up, none of the 5 patients presenting with T3bN0M0, or the patient with T3bN1M0 disease had required orbital exenteration. Conclusion: Hedgehog pathway inhibition produces a significant clinical response in most patients with locally advanced or metastatic orbital or periocular BCC or basal cell nevus syndrome and can obviate orbital exenteration in some patients. Drug-related adverse effects are manageable in most patients.
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Hedgehog pathway inhibition for locally advanced periocular basal cell carcinoma and basal cell nevus syndrome Short title: Vismodegib for periocular basal cell carcinoma
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Omar K. Ozgur,1 Vivian Yin,1 Eva Chou,1 Sharon Ball,1 Merrill Kies,2 William N. William,2 Michael Migden,3 Bradley A. Thuro,1 and Bita Esmaeli1 1
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Orbital Oncology and Ophthalmic Plastic Surgery Program, Department of Plastic Surgery 2 Department of Head and Neck Medical Oncology 3 Department of Dermatology The University of Texas MD Anderson Cancer Center Houston, TX 77030, United States
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Corresponding author: Bita Esmaeli, MD, FACS, Orbital Oncology & Ophthalmic Plastic Surgery Program, Department of Plastic Surgery, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 1488, Houston, Texas 77030. Tel: 713-7924457. Fax: 713-794-4662. E-mail: [email protected]
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Introduction Basal cell carcinoma (BCC) is the most common human malignancy and accounts for 90% of eyelid tumors.1-3 Fortunately, periocular and facial BCC are typically amenable to local surgical excision with 5-year recurrence rates of 1% to 5.3%.1,3,4 For advanced periocular BCC, i.e., characterized by large tumor size, multiple lesions, or recurrent disease with extension into the orbit or paranasal sinuses, surgical treatment may not be possible without risk of significant ocular morbidity or loss of the eye. A related group of patients who may not be good candidates for surgery are patients with basal cell nevus syndrome (Gorlin syndrome) with numerous BCCs in the periocular region. Additionally, patients with periocular BCC with advanced age or multiple medical comorbidities may not be good candidates for surgery. The discovery of underlying genetic mutations of the Hedgehog pathway in BCC has allowed for the emergence of targeted medical therapy for advanced, inoperable cases of BCC or in cases that would result in high morbidity with surgery.5-9 The Hedgehog pathway includes the Patched-1 transmembrane receptor (Ptch-1), a tumor suppressor that normally inhibits the downstream receptor Smoothened (Smo).7,10,11 A mutation in the Hedgehog pathway may lead to Hedgehog protein binding to Ptch-1, and reversal of the normal inhibition of Smo leading to cellular proliferation and tumorigenesis as well as expression of the downstream product GLI1, which is thought to lead to the formation of BCC.7,12,13 Ptch-1 also plays a role in basal cell nevus syndrome, which is secondary to an autosomal-dominant mutation in the PTCH1 gene.9,11,14 Vismodegib (Erivedge, Genentech, South San Francisco, CA, GDC-0449) is a selective Hedgehog pathway inhibitor that blocks Hedgehog signaling by binding to Smo, inhibiting downstream activation of Hedgehog target genes.15,16 Vismodegib was first studied in humans in 2008 and was approved by the US Food and Drug Administration in January 2012 for treatment of metastatic or locally advanced unresectable BCC. Few studies have shown the response to treatment with Hedgehog pathway inhibition with long-term follow-up. Targeting the Hedgehog pathway in patients with locally advanced periocular and orbital BCC is of particular interest since successful nonsurgical treatment could mean avoidance of radical and disfiguring surgery in the periorbital region and in some instances orbital exenteration. To date, however, reports of Hedgehog pathway inhibition in patients with orbital or periocular lesions have been limited to single case reports or small case series.7-9,17-20 There is room for reporting of additional experience in this particular patient population. We herein report our clinical experience with Hedgehog pathway inhibition in patients with locally advanced or metastatic orbital or periocular BCC and in patients with basal cell nevus syndrome and significant periocular lesions. Patients and Methods The Institutional Review Board of The University of Texas MD Anderson Cancer Center retrospectively approved this study. The study was performed in accordance with HIPAA regulations. For this retrospective interventional case series, we performed a retrospective chart review of all consecutive eligible patients treated for locally advanced or metastatic periocular basal cell carcinoma and basal cell nevus syndrome 2
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with Hedgehog pathway inhibition from November 2009 through September 2014. All patients were at least 18 years of age. Data recorded for this analysis included age, race/ethnicity, sex, site(s) of primary tumor involvement, size of tumor, presence of orbital extension, sites of regional or distant metastasis, tumor, node, metastasis staging system (TNM) designation at presentation according to American Joint Committee on Cancer (AJCC) criteria, type and grade of drug-related adverse effects according to Common Terminology Criteria for Adverse Events (CTCAE), version 4.0 (Table 1), response to treatment according to Response Evaluation Criteria in Solid Tumors (RECIST) (Table 2), duration of follow-up, and status at last follow-up. 21-23
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Results We identified 13 patients who met the inclusion criteria. However, 1 patient with locally advanced BCC was ultimately not included in the data analysis because of a hypersensitivity reaction to vismodegib that led to its discontinuation only 5 days after initiation of treatment. This patient had an orbital exenteration. The remaining 10 men and 2 women were included in this study. All patients were white with a median age of 64.5 years (range, 33-86 years). Tumors were staged according to the AJCC, 7th edition TNM criteria using clinical, pathological, and radiographic data as part of each patient’s standard clinical management.21 In each case, the decision to start treatment with Hedgehog pathway inhibition was made with input from the senior treating oculoplastic surgeon (B.E.) and input from the Radiation Oncology service to ensure that radiation was not an option. Patients with BCC were treated with Hedgehog pathway inhibition only if it was believed that complete surgical excision of the locally advanced lesion was not possible without substantial ocular morbidity or orbitofacial deformity, for example, from an orbital exenteration. Patients with basal cell nevus syndrome were treated with Hedgehog pathway inhibition to avoid multiple surgeries in the periocular and facial regions. Patients were treated with vismodegib at a dose of 150 mg/day by mouth daily. Ten patients had locally advanced BCC, 4 of these 10 patients also had metastatic disease to lymph nodes or other sites. TNM designations at presentation for the 10 patients with locally advanced BCC were as follows: T3aN0M0 (1 patient), T3bN0M0 (5 patients), T3bN1M0 (1 patient), T2N1M1 (1 patient), T4N1M1 (1 patient), and T4N2cM1 (1 patient). The remaining 2 patients had basal cell nevus syndrome. All patients were treated with vismodegib. One of those patients was later switched to another Hedgehog pathway inhibitor after developing progression of disease. The median follow-up time from start of Hedgehog pathway inhibition to last follow-up, last contact, or death, whichever occurred first, was 12.5 months (range, 7-53 months). The median duration of treatment was 11.5 months (range, 7-49 months). The overall response rate (complete or partial response) was 86% (6 of 7 patients) for patients presenting with nonmetastatic locally advanced BCC, 100% (2 of 2 patients) for patients with basal cell nevus syndrome, and 33% (1 of 3 patients) for patients presenting with locally advanced but also metastatic BCC. Although none of the patients in our cohort had initial progression of disease during initial treatment with 3
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vismodegib, 2 of 12 patients (17%) developed disease progression during active treatment after initial significant clinical response or stabilization of disease lasting at least 16 months. Tumor size, details of treatment and outcomes for all patients with BCC are summarized in Table 3. Three of the 12 patients (25%) had a complete response (example shown in Figures 1) with follow-up times of 12, 18, and 38 months, respectively. Six patients (50%) had a partial response (examples shown in Figures 2,3) with a median follow-up time of 9.5 months (range, 7-19 months). Three patients (25%) had stable disease with follow-up times of 11, 13, and 16 months. The following paragraphs will present detailed data for patients with locally advanced BCC vs. patients with basal cell nevus syndrome. One patient with locally advanced BCC and one patient with basal cell nevus syndrome have been briefly mentioned in prior solicited reviews on targeted therapy.7,9
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Treatment and Outcomes in Patients with Locally Advanced Basal Cell Carcinoma Of the 10 patients with locally advanced BCC, 9 are alive at this writing. Of those, 7 continue to receive treatment, and 2 have stopped treatment. Of the 2 patients who stopped treatment, 1 stopped for economic reasons and was lost to follow-up. The other patient with locally advanced non-metastatic BCC stopped treatment with vismodegib after 11 months because of grade II dysgeusia, grade II weight loss, and a fall resulting in a broken hip. This patient developed a recurrence of BCC after 3 months off vismodegib. As of this writing, he is planning to restart vismodegib treatment. Of 6 patients with locally advanced, non-metastatic BCC at presentation, 2 patients had a complete response with a follow-up of 12 and 18 months, respectively. Of the 4 patients with locally advanced, metastatic BCC, 2 patients (50%) had a partial response for 7 and 9 months, and 2 patients (50%) had stable disease for 13 and 16 months. Five patients with locally advanced T3bN0M0 disease would have required orbital exenteration as surgical treatment for their tumor. None of these 5 patients had had an orbital exenteration or enucleation at last follow-up. There were 4 patients with locally advanced periocular BCC who also had metastatic disease. One had a metastatic parotid node, one had metastatic disease to the ipsilateral parotid and neck lymph nodes, hilar lymph nodes, and liver, and lungs, one had metastatic ipsilateral parotid and submandibular nodes, bilateral cervical lymph nodes, and multiple skin sites. One patient who presented with extensive distant metastatic disease of the skull base to the chest and sacrum died of metastatic disease progression after 16 months of having had stable disease while on vismodegib. Treatment and Outcomes in Patients with Basal Cell Nevus Syndrome Of the 2 patients with basal cell nevus syndrome, 1 patient had a complete response to vismodegib for 38 months. He was then found to have a new non-target lesion. After 49 months of treatment with vismodegib, this patient was switched to another Hedgehog inhibitor. The other patient with basal cell nevus syndrome had stable disease with vismodegib but stopped treatment 19 months after the drug was started because of economic reasons. 4
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Drug-Related Adverse Effects Drug-related adverse effects and their grades are listed in Table 4. The most common drug-related adverse effects were muscle spasms, which occurred in all 12 patients; weight loss, which occurred in 10 patients; dysgeusia, which occurred in 9 patients; and alopecia, which occurred in 9 patients. All patients began experiencing side effects within 2-4 months of onset of treatment. Five patients (42%) developed grade II adverse effects. Of the 12 patients in the study, 8 patients continue treatment with vismodegib, 2 stopped because of economic reasons, 1 stopped because of side effects and other medical co-morbidities as mentioned, and 1 stopped because of disease progression on vismodegib and death.
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Discussion Our findings show that a substantial proportion (70%) of patients with locally advanced orbital or perioorbital BCC achieved a complete or partial response to Hedgehog pathway inhibition with vismodegib, and the remainder achieved stable disease in response to vismodegib for reasonably long periods. Hedgehog pathway inhibition also produced objective responses in the 2 patients with basal cell nevus syndrome. In a prospective trial of the use of vismodegib Sekulic et al.24 reported a response rate of 43% for locally advanced BCC and 30% for metastatic BCC. The higher response rate observed by us maybe due to the smaller cohort in the current report or perhaps due to tumors restricted to the periocular region. . The response rates in our cohort were similar to the rates reported by Von Hoff et al.25 who found that patients with locally advanced BCC had about a 60% response rate. A recent report by Demirci et al.19 of 8 patients with periorcular lesions treated with vismodegib showed complete response in 4 patients and partial response in 4 patients. In our current study, no progression of disease was noted in any patient until after at least 16 months of significant clinical response or stable disease. All 5 patients with T3bN0M0 disease, who would have required orbital exenteration as surgical treatment for their tumor, avoided orbital exenteration because of treatment with vismodegib. This suggests that vismodegib may be considered as an alternative to orbital exenteration in selected patients with locally advanced BCC in the periorbital region. Long-term follow-up is needed to further evaluate the durability of response in such patients. Combining vismodegib with surgery, either as neoadjuvant or adjuvant treatment, may also be considered. Similar to findings of previous studies of Hedgehog pathway inhibitors, drugrelated side effects were common among our study cohort, but most were grade I and did not require further treatment.15,25 The types of side effects experienced by our patients were similar to those in previous reports, with the most frequent being muscle spasms, weight loss, dysgeusia, alopecia, decreased appetite, and fatigue. Forty-two percent of patients developed grade II side effects. None of the patients in our study experienced grade III adverse effects, while Von Hoff et al,25 found that 24% of patients in their report had grade III adverse effects. 5
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How often patients experience a local recurrence after discontinuation of Hedgehog pathway inhibition is not well established in the literature. The data from our patient cohort also cannot definitively answer this question. We found that 1 patient with locally advanced BCC and a partial response developed recurrence 3 months after stopping Hedgehog pathway inhibition. The role of vismodegib or other Hedgehog pathway inhibitors in the neoadjuvant setting remains unclear. Ally et al.26 reported on 15 patients with locally advanced BCC who received vismodegib between 2 and 6 months as neoadjuvant treatment prior to surgical resection of BCC. A benefit was not seen in patients treated for less than 3 months. For the 13 target lesions selected for surgery, vismodegib reduced the surgical defect area by 27% from baseline. Seven of 13 tumors (54%) appeared to have experienced complete clinical response; however, only 4 of these 7 tumors showed complete histologic response on serial sectioning. This discordance along with isolated reports of recurrence of BCC upon discontinuation of vismodegib27 may suggest that vismodegib does not lead to complete and total microscopic ablation of BCC. In the study by Ally et al.26, of the 11 patients who completed the trial, 1 patient had a BCC recurrence 17 months after surgery. It is possible that the most appropriate indication for Hedgehog pathway inhibition in the management of locally advanced BCC is changing a locally advanced tumor to a much smaller lesion that requires some type of chronic and long-term maintenance treatment. This is particularly an attractive option in the periorbital region where globe preservation and visual function is at stake. It is unclear if viable BCC cells remain in the “chemoreduced” margins, and it is unclear exactly what proportion of such lesions might lead to future recurrences and over how long. As our study eligibility criteria followed the current US Food and Drug Administration approved indications for vismodegib for treatment of BCC, the results should not be extrapolated to all patients with BCC. BCC remains the most common cancer in humans, and in greater than 90% of cases it is amenable to surgery with excellent outcomes.28-31 Vismodegib and other agents targeting the Hedgehog pathway should only be considered for a small proportion of patients with periocular BCC who have large enough and advanced enough lesions that surgery or radiation therapy would otherwise lead to loss of the eye, loss of vision, or significant periorbital and facial deformity; patients with basal cell nevus syndrome in whom the number and size of periocular lesions prohibits multiple and frequent surgeries as a good option; and patients in whom multiple other comorbidities or very advanced age may make surgery or radiation therapy not a good option.7,8 The cost of treatment for Hedgehog pathway inhibitors is another consideration in patient selection and compliance, particularly since long-term treatment may be necessary. It is estimated that the cost of vismodegib in the United States is approximately $7500 per month.26 Two of the patients in our cohort discontinued vismodegib treatment because of cost-related issues despite an excellent response.
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ACKNOWLEDGMENTS / DISCLOSURE:
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Funding/Support: This research was supported in part by the National Institutes of Health through MD Anderson's Cancer Center Support Grant, CA016672. (USA) Financial Disclosures: Dr Bita Esmaeli serves as a member of the Data Safety Monitoring Board (DSMB) for a vismodegib trial in Europe. (Roche, Basel, Switzerland) None of the other authors have any financial disclosures to report. Contributions of Authors: Design of the study (BE) Conduct of the study (OO, VY, EC, SB, BE) Collection, management, analysis, and interpretation of the data (OO, VY, EC, SB, MK, WW, MM, BT, BE) Preparation, review, or approval of the manuscript (OO, BE, VY, EC, SB, MK, WW, MM, BT)
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Figure Legends Figure 1. Clinical photograph of a patient with locally advanced basal cell carcinoma. The photograph in top left shows the patient before treatment with vismodegib, middle photograph shows the patient 1 month after initiation of vismodegib treatment, and the top right photograph was taken at 18 months after initiation of vismodegib treatment. Figure 2. Clinical photograph of a patient with advanced basal cell carcinoma of the right periorbital region with involvement of the upper and lower eyelids and right brow and biopsy-proven metastasis to the right preauricular area (arrow). Top photograph is before treatment with vismodegib; bottom photograph seen 4 weeks after initiation of vismodegib treatment, shows a substantial partial response. The patient continued to respond to nearly complete resolution of the lesion at last follow-up (not shown). Figure 3. Clinical photograph of a patient with recurrent basal cell carcinoma involving the right lower eyelid and premaxillary area causing mechanical and cicatricial ectropion of the right lower eyelid. Top left photograph is before treatment with vismodegib. Top right panel is a magnetic resonance image of the patient before treatment with vismodegib and shows extension of the right lower eyelid mass in the right maxillary sinus (arrows). Bottom left panel shows a magnetic resonance image of the same patient seen 9 months after initiation of vismodegib treatment. The right lower eyelid mass had resolved substantially.
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Ainbinder DJ, Esmaeli B, Groo SC, Finger PT, Brooks JP. Introduction of the 7th edition eyelid carcinoma classification system from the American Joint Committee on Cancer-International Union Against Cancer staging manual. Arch Pathol Lab Med. 2009;133(8):1256-1261. National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. NIH Publication No. 09-5410. http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-0614_QuickReference_5x7.pdf. Published May 28, 2009. Accessed February 1, 2015. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247. Sekulic A, Migden MR, Oro AE, et al. Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med. 2012;366(23):2171-2179. Von Hoff DD, LoRusso PM, Rudin CM, et al. Inhibition of the hedgehog pathway in advanced basal-cell carcinoma. N Engl J Med. 2009;361(12):1164-1172. Ally MS, Aasi S, Wysong A, et al. An investigator-initiated open-label clinical trial of vismodegib as a neoadjuvant to surgery for high-risk basal cell carcinoma. J Am Acad Dermatol. 2014;71(5):904-911. Chang AL, Oro AE. Initial assessment of tumor regrowth after vismodegib in advanced basal cell carcinoma. Arch Dermatol. 2012;148(11):1324-1325. Gulleth Y, Goldberg N, Silverman RP, Gastman BR. What is the best surgical margin for a basal cell carcinoma: a meta-analysis of the literature. Plast Reconstr Surg. 2010;126(4):1222-1231. Ho SF, Brown L, Bamford M, Sampath R, Burns J. 5 years review of periocular basal cell carcinoma and proposed follow-up protocol. Eye (Lond). 2013;27(1):78-83. Gill HS, Moscato EE, Seiff SR. Eyelid margin basal cell carcinoma managed with full-thickness enface frozen section histopathology. Ophthal Plast Reconstr Surg. 2014;30(1):15-19. Smeets NW, Kuijpers DI, Nelemans P, et al. Mohs' micrographic surgery for treatment of basal cell carcinoma of the face--results of a retrospective study and review of the literature. Br J Dermatol. 2004;151(1):141-147.
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Table 1. Grade Definitions per the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0,22 Used to Grade the Severity of Adverse Events in a Series of Patients with Locally Advanced or Metastatic Orbital or Periocular Basal Cell Carcinoma and Basal Cell Nevus Syndrome Grade Severity Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living. Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living. Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to adverse effects.
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Table 2. Response Definitions per the Response Evaluation Criteria in Solid Tumors, Version 1.1,23 Used to Classify Responses to Vismodegib in a Series of Patients with Locally Advanced or Metastatic Orbital or Periocular Basal Cell Carcinoma and Basal Cell Nevus Syndrome Response Definition Complete response Disappearance of all target lesions. Any lymph nodes containing disease must have reduction in short axis to <10 mm. Partial response At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. Progressive disease At least a 20% increase in the sum of diameters of target lesions with an absolute increase of at least 5 mm, or the appearance of 1 or more new lesions. Stable disease Neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease, taking the smallest sum of diameters as reference.
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Table 3. Demographic and Tumor Characteristics, Treatment, and Outcomes in a Series of Patients with Basal Cell Carcinoma and Basal Cell Nevus Syndrome Treated with Vismodegib
T3aN0M0
70 M
T3bN0M0
86 M
T3bN0M0
84 M
T3bN0M0
56 M
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69 F
Grade 2 and 3 Adverse Effects
Status at Last Follow-up
3.0 x 1.7 cm; Left upper lid, lower lid, medial canthus 9.3 x 7.9 cm; Left lower lid and skin 3.3 x 3 cm; Right lower lid and inferior orbit
PR
9; 9
Still on
None
Alive with disease
PR
10; 10
Economic reasons
None
Alive with disease, then lost to follow-up
SD
11; 11
None
Alive with disease
1.5 x 1.8 cm; Left upper lid, lower lid, lateral canthus
PR for 14 months, recurrence 3 mo after stopping HHI
11; 24
Other medical issues
G2: dysgeusia, decreased appetite
Recurrence after stopping vismodegib, planning on restarting
CR
12; 12
Still on
None
Alive with no evidence of disease
18; 18
Still on
G2: muscle spasms
Alive with no evidence of disease
7; 7
Still on
None
Alive with disease
9; 9
Still on
None
Alive with disease
13; 13
Still on
G2: muscle spasms, hypertension
Alive with disease
18; 20
Disease progression on treatment
None
Died of disease progression
Microscopic disease; Left upper lid, lower lid, medial canthus 9 x 8 cm; Left upper lid, lower lid, temple 2 x 3 cm; Right upper lid, orbit, temporal fossa 8.1 x 6.3 cm; Left ear, preauricular skin; Metastatic 2.3 x 1.5 cm; Left ear, preauricular and periorbital skin; Metastatic
SC
T3bN0M0
Response to HHI
Current Treatment, or Reason for Stopping
Still on
M AN U
64 M
Size and Location of Primary Lesion (s)
Duration of HHI and Total a Follow-up , mo
CR
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Age, yr; Sex
TNM Status at Presentat ion
58 M
T3bN1M0
51 F
T4N2cM1
76 M
T2N1M1
65 M
T4N1M1
11.5 x 8 cm; Left ear and skull base; Metastatic
N/A (Basal cell nevus syndrome)
Right medial canthus 2.7 x 1.2 cm, left medial canthus 1 x 0.5 cm, multiple other lesions
PR
19; 19
Economic reasons
G2: weight loss
Alive with disease, then lost to follow-up
N/A (Basal cell nevus syndrome)
1.8 x 2.6 cm, multiple other lesions
CR for 38 months then PD
49; 53
Switched to another HHI
G2: muscle spasms, fatigue
Alive with disease
51 M
PR
EP
SD
SD for 16 months then PD
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12
PR
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Yr, year; TNM, American Joint Committee on Cancer (AJCC) tumor, node, metastasis staging system; HHI, Hedgehog inhibition; Mo, months; P, Patient; M, male; F, female; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; G2, grade 2; G3, grade 3. a From initiation of vismodegib treatment.
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Grade III 0 0 0 0
Any Grade 12 10 9 9
Muscle spasm Weight loss Dysgeusia Alopecia Decreased appetite Fatigue Nausea Headache Diarrhea Back pain Hypomagnesemia Hypertension Others a Any adverse effect
4
1
0
5
4 2 2 2 2 2 0 7
0 1 0 0 0 0 1 0
0 0 0 0 0 0 0 0
4 3 2 2 2 2 1 7
12
5
0
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Grade II 3 1 1 0
Grade I
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Table 4. Drug-related Adverse Effects by Grade in a Series of Patients with Locally Advanced or Metastatic Orbital or Periocular Basal Cell Carcinoma and Basal Cell Nevus Syndrome Treated with Vismodegib
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The following grade I side effects were experienced by only 1 patient each: neuropathy, anemia, hyperglycemia, bilateral extremity edema, thick saliva, dyschezia, constipation, chest cramping, depression, and stomach flu.
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Omar Ozgur, MD obtained his BS in Information and Computer Science at the University of California, Irvine, and completed medical school at the University of Vermont, College of Medicine. He completed transitional internship at the University of Hawaii, followed by ophthalmology residency at the New York Eye and Ear Infirmary of Mount Sinai. Omar is currently a fellow in ophthalmic plastic and reconstructive surgery and orbital oncology at the University of Texas, MD Anderson.
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Dr Bita Esmaeli is a Professor of Ophthalmology in the Department of Plastic Surgery at The University of Texas M. D. Anderson Cancer Center, where she has an orbital oncology and oncologic ophthalmic plastic surgery practice. Dr Esmaeli 's research interests include molecular signature of ocular and orbital tumors, tissue banking for rare ocular and orbital tumors , eye and vision-sparing treatment strategies for orbital and ocular cancers, and ocular side effects of cancer therapy.
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