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; sex; 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, nor 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.
Basal cell carcinoma (BCC) is the most common human malignancy and accounts for 90% of eyelid tumors. Fortunately, periocular and facial BCC are typically amenable to local surgical excision, with 5-year recurrence rates of 1%–5.3%. For advanced periocular BCC—that is, 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. The Hedgehog pathway includes the Patched-1 transmembrane receptor (Ptch-1), a tumor suppressor that normally inhibits the downstream receptor Smoothened (Smo). 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. Ptch-1 also plays a role in basal cell nevus syndrome, which is secondary to an autosomal-dominant mutation in the PTCH1 g ene. Vismodegib (Erivedge; Genentech, South San Francisco, California, USA; GDC-0449) is a selective Hedgehog pathway inhibitor that blocks Hedgehog signaling by binding to Smo, inhibiting downstream activation of Hedgehog target genes. 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. 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 with Hedgehog pathway inhibition from November 1, 2009 through September 30, 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.
| 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 |
| 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 |
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 patients, 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, pathologic, and radiographic data as part of each patient’s standard clinical management. 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 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 Figure 1 ) with follow-up times of 12, 18, and 38 months, respectively. Six patients (50%) had a partial response (examples shown in Figures 2 and 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 1 patient with basal cell nevus syndrome have been briefly mentioned in prior solicited reviews on targeted therapy.
| Patient Age (y); Sex | TNM Status at Presentation | Size and Location of Primary Lesion(s) | Response to HHI | Duration of HHI; and Total Follow-up a (mo) | Current Treatment, or Reason for Stopping | Grade 2 and 3 Adverse Effects | Status at Last Follow-up |
|---|---|---|---|---|---|---|---|
| 64; M | T3bN0M0 | 3.0 x 1.7 cm; left upper lid, lower lid, medial canthus | PR | 9; 9 | Still on | None | Alive with disease |
| 69; F | T3aN0M0 | 9.3 x 7.9 cm; left lower lid and skin | PR | 10; 10 | Economic reasons | None | Alive with disease, then lost to follow-up |
| 70; M | T3bN0M0 | 3.3 x 3 cm; right lower lid and inferior orbit | SD | 11; 11 | Still on | None | Alive with disease |
| 86; M | T3bN0M0 | 1.5 x 1.8 cm; left upper lid, lower lid, lateral canthus | PR for 14 months, recurrence 3 months after stopping HHI | 11; 24 | Other medical issues | G2: dysgeusia, decreased appetite | Recurrence after stopping vismodegib, planning on restarting |
| 84; M | T3bN0M0 | Microscopic disease; left upper lid, lower lid, medial canthus | CR | 12; 12 | Still on | None | Alive with no evidence of disease |
| 56; M | T3bN0M0 | 9 x 8 cm; left upper lid, lower lid, temple | CR | 18; 18 | Still on | G2: muscle spasms | Alive with no evidence of disease |
| 58; M | T3bN1M0 | 2 x 3 cm; right upper lid, orbit, temporal fossa | PR | 7; 7 | Still on | None | Alive with disease |
| 51; F | T4N2cM1 | 8.1 x 6.3 cm; left ear, preauricular skin; metastatic | PR | 9; 9 | Still on | None | Alive with disease |
| 76; M | T2N1M1 | 2.3 x 1.5 cm; left ear, preauricular and periorbital skin; metastatic | SD | 13; 13 | Still on | G2: muscle spasms, hypertension | Alive with disease |
| 65; M | T4N1M1 | 11.5 x 8 cm; left ear and skull base; metastatic | SD for 16 months then PD | 18; 20 | Disease progression on treatment | None | Died of disease progression |
| 33; M | 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 |
| 51; M | 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 |
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 nonmetastatic 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, nonmetastatic 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; 1 had metastatic disease to the ipsilateral parotid and neck lymph nodes, hilar lymph nodes, liver, and lungs; and 1 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 nontarget 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.
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.
