Oral hedgehog pathway inhibitors offer treatment options to patients with basal cell carcinoma (BCC). Vismodegib (Erivedge) is the first hedgehog signaling pathway inhibitor approved by the FDA for the treatment of locally advanced basal cell carcinoma (laBCC) or metastatic basal cell carcinoma. Central to the BCC pathophysiology is the upregulation of the hedgehog signaling pathway.1 The drug received FDA approval after a phase 2 BCC study (ERIVANCE) demonstrated significant response rates in both the laBCC and metastatic BCC cohorts, who otherwise had limited treatment options.2 The median time patients received treatment was 5.5 to 6.7 months and the median safety follow-up was 6.5 months. Median duration of clearance was 7.3 months.3
In the ERIVANCE trial, patients were given 150 mg of vismodegib daily and continued until disease progression or intolerable toxicity occurred. Treatment breaks for limited time periods were allowed. The most frequent side effects of vismodegib include muscle spasm, weight decrease, dysguesia, fatigue, alopecia, nausea, and diarrhea.3,4 The median time of onset of the trial expected adverse events reported by Chang and colleagues vary from 30 to 175 days with alopecia and weight decrease having a later onset.3 The safety and efficacy of vismodegib continues to be evaluated in RegiSONIC postmarketing study along with other studies evaluating different treatment regimens and in case reports.3 Hepatotoxicity may be potentially related to vismodegib use; however, no causality has been demonstrated.5 Acquired resistance to vismodegib related to smoothened mutations has been observed.6
Cases
Limited data is available to providers on clinical variations of duration of treatment, rapidity of response, and long-term durability of response. This article will provide clinicians guidance with vismodegib treatment for laBCC based on our clinical experience with short courses of therapy in 2 patients. The delayed response to vismodegib occurring subsequent to discontinuing the drug in laBCC and the consideration of probable slow wound healing rather than a partial response to vismodegib are discussed. A case in another patient demonstrates a very rapid response showing both complete clinical resolution within 7 weeks of drug initiation and a complete histologic resolution that was documented 4 weeks after discontinuation of treatment. Both cases demonstrate that short courses of vismodegib may be a viable option for patients.
These cases provide clinicians with relevant information regarding the treatment of laBCC with vismodegib 150 mg daily when considering the duration of treatment and the tolerability of side effects, particularly in the elderly patient. Patients who have disease progression during treatment with vismodegib may have a subsequent delayed response after treatment discontinuation, probably, due to wound healing. A relatively short course of treatment may decrease the side effects and yield a complete clinical and histological response. A complete clinical response, as defined in the ongoing RegiSONIC observation trial is a lesion site with one or more of the following: negative histopathology, no clinical evidence of BCC, and complete tumor shrinkage.
Case 1
An 89-year-old woman, Eastern Cooperative Oncology Group (ECOG) status 1, presented with a 21 × 16 mm laBCC nodular plaque on the anterior lower right leg (Figure 1). The patient was not a primary candidate for surgery or radiation given her symptomatic peripheral vascular disease, stasis dermatitis, and significant chronic leg edema where wound healing from surgery and side effects of radiation were a concern. The patient was started on vismodegib 150 mg daily and completed 83 days of treatment. On day 53 of treatment, the lesion had increased in size measuring 22 × 23 mm and the patient reported grade 3 fatigue, grade 3 dysguesia, and grade 1 alopecia. Treatment was discontinued on day 83 secondary to intolerance of side effects, primarily the fatigue. The patient was considered a treatment failure. The patient declined a radiation oncology consult. 
Approximately 11 weeks after discontinuation of vismodegib, the patient was reevaluated and the BCC had clinically resolved (Figure 2). We continued to follow the patient and observed a sustained complete clinical response of this specific laBCC lesion for 18 months of follow-up status post discontinuation of vismodegib (Figure 3). No biopsy was performed on the treated site because of the potential for problematic healing and persistent ulceration on the edematous pretibia. The patient developed a second, small lesion 10 months after discontinuation of vismodegib. The second lesion was distal from the edge of the scar of the original BCC (Figure 4). The second lesion biopsy demonstrated a nodular BCC and in our opinion represented a new entity because there was no recurrence within the site of the previous BCC. While vismodegib may not be curative, it can provide a treatment alternative and a solid management option for difficult cases. The patient subsequently elected to treat the second lesion with vismodegib but stopped after 6 weeks due to unrelated medical issues.
Case 2
A 99-year old woman, ECOG status 1, presented with a 75 × 35 mm laBCC on the left upper forehead (Figure 5) in addition to other BCC lesions on her face. She declined radiation and surgery. The patient was started on vismodegib 150 mg daily. On days 14 and 30 of treatment, the lesion was noted to have significantly decreased in size and no side effects were present (Figure 6). At day 67 of treatment, a complete response of the BCC clinically was observed and the vismodegib was discontinued at the patient’s request—her only complaint was grade 1 hair loss, but she stated she did not want to live her remaining days without hair.
The patient presented to clinic one month later with a 20 × 20 mm, slightly erythematous dermatitis in the same area as the BCC which occurred within a day after seeing her hairdresser. A biopsy was performed and was negative for malignancy. The patient was given a topical steroid and the dermatitis rapidly resolved. Sixty-three days status post discontinuation of vismodegib, the patient continued to have a complete clinical response on the left upper forehead site and a partial clinical response in other biopsy proven BCCs on the face (Figure 7). The patient expired 43 days after her last visit at age 100 years and 4 days secondary to natural causes.
Discussion
These 2 cases suggest that a short course of vismodegib 150 mg daily ± 60 to 90 days can potentially yield a complete response of BCC in patients who may not be able to tolerate the side effects of a longer course of treatment. In one patient considered a treatment failure, we highlight a delayed response after discontinuation of vismodegib who subsequently had a clinically complete resolution with a durable response of 18 months in the target treatment area.LaBCC lesions can have an ulcerative component both clinically and/or histologically.
Pranteda and colleagues found in a retrospective study of patients diagnosed with BCC that clinical-pathological subtypes occur on different anatomical areas with ulcerative lesions occurring more frequently on the lower extremities.6 We know that patients with vascular insufficiency in the lower extremities will have slower wound healing.7 We propose that the delayed response may actually be slow wound healing after earlier clearance of the laBCC.
Gill and colleagues demonstrated 2 cases in which patients had complete responses with perioribital laBCCs with less than 8 weeks of treatment with vismodegib 150mg daily.8 One patient received a 4-week treatment course with a durable response of 10 months while the other patient had a 7-week treatment course with durable response of 6 months. Further data on these patients past the observation periods was not available. Viscusi and Hanke also discussed a case study in which the patient had a 5 cm ulcerated laBCC on the forehead that received a 5-week treatment course with a complete clinical response 4 months after treatment cessation. The treatment was discontinued secondary to social issues and nonfinancial barriers.9
Patients in the ERIVANCE trial discontinued vismodegib if there was disease progression, and the standard of care in clinical practice is often the same with laBCC. Our patient demonstrates that a possible consideration can include a period of watchful waiting in a treatment failure prior to initiating further invasive therapy.
In an investigator-initiated clinical trial evaluating the reduction of BCC surgical defect size prior to Mohs surgery, Ally and colleagues found that vismodegib was not effective in patients who received less than a 3-month treatment course, although this only included 2 patients.10 Our patients; however, had clinical clearing with less than 3 months of treatments and the duration in one patient was sustained. We believe that the duration of treatment is still an open question requiring additional studies and overall drug experience within the dermatology community.
Continued, larger studies on the long-term safety and efficacy with vismodegib for laBCC need to be performed. There have been reports of increased liver enzymes and other abnormal lab findings in patients who are taking vismodegib, although causality has not been thoroughly established. A new onset of congestive heart failure in one patient receiving vismodegib was discussed by Huizenga and colleagues.11
In published clinical studies, the duration of treatment courses vary, with the minimum treatment course being 3 months and the median treatment course being 5.5 to 6.7 months. Longer treatment courses are often dependent on the patient’s ability to tolerate side effects, primarily fatigue, dysguesia, and hair loss. Patients who have a positive initial response to vismodegib, but cannot tolerate side effects, may benefit from a treatment break for a few weeks and then resume the drug.12 The 2 cases presented demonstrate a complete response in both patients with a less than 90-day treatment course with an 18-month durable response in one patient.
Ms Grossi is a dermatology nurse practitioner in private practice at Advanced Dermatology and Cosmetic Care in Valencia, CA.
Dr Raskin is medical director of Advanced Dermatology and Cosmetic Care in Valencia, CA. He is on the speakers panel for Erivedge with Genentech.
Disclosure: The author reports no relevant financial relationships.
References
1. Epstein EH. Basal cell carcinomas: attack of the hedgehog. Nat Rev Cancer. 2008;8(10):743-754.
2. Maly TJ, Sligh JE. Defining locally advanced basal cell carcinoma. J Drugs Dermatol. 2014;13(5):528-529.
3. Chang AL, Solomon, JA, Hainsworth, JD, et al. Expanded access study of patients with advanced basal cell carcinoma treated with the Hedgehog pathway inhibitor, vismodegib. J Am Acad Dermatol. 2014;70(1):60-69.
4. Ventarola DJ, Silverstein DI. Vismodegib-associated hepatotoxicity: a potential side effect detected in postmarketing surveillance. J Am Acad Dermatol. 2014;71(2):397-398.
5. Brinkhuizen T, Reinders MG, van Geel M, et al. Acquired resistance to the Hedgehog pathway inhibitor vismodegib due to smoothened mutations in treatment of locally advanced basal cell carcinoma. J Am Acad Dermatol. 2014;71(5):1005-1008.
6. Pranteda G, Grimaldi M, Lombardi M, et al. Basal cell carcinoma: differences according to anatomic location and clinical-pathological subtypes. G Ital Dermatol Venereol. 2014;149(4):423-426.
7. Sieggreen MY, Kline RA. Arterial insufficiency and ulceration: diagnosis and treatment options. Adv Skin Wound Care. 2004;17(5 Pt 1):242-251.
8. Gill HS, Moscato EE, Chang AL, Soon S, Silkiss RZ. Vismodegib for periocular and orbital basal cell carcinoma. JAMA Ophthalmol. 2013;131(12):1591-1594.
9. Viscusi KS, Hanke CW. Vismodegib for locally advanced basal cell carcinoma: descriptive analysis of a case series and comparison to the literature. J Drugs Dermatol. 2015;14(9):956-962.
10. 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.e901.
11. Huizenga T, Newsom E, Fakhouri T, Kado J. New-onset congestive heart failure in a patient on vismodegib. Dermatol Surg. 20015;41(11):1329-1332.
12. Ibrahim, SA. Treating advanced basal cell carcinoma. The Dermatologist. 2015;23(5):23-26.
Oral hedgehog pathway inhibitors offer treatment options to patients with basal cell carcinoma (BCC). Vismodegib (Erivedge) is the first hedgehog signaling pathway inhibitor approved by the FDA for the treatment of locally advanced basal cell carcinoma (laBCC) or metastatic basal cell carcinoma. Central to the BCC pathophysiology is the upregulation of the hedgehog signaling pathway.1 The drug received FDA approval after a phase 2 BCC study (ERIVANCE) demonstrated significant response rates in both the laBCC and metastatic BCC cohorts, who otherwise had limited treatment options.2 The median time patients received treatment was 5.5 to 6.7 months and the median safety follow-up was 6.5 months. Median duration of clearance was 7.3 months.3
In the ERIVANCE trial, patients were given 150 mg of vismodegib daily and continued until disease progression or intolerable toxicity occurred. Treatment breaks for limited time periods were allowed. The most frequent side effects of vismodegib include muscle spasm, weight decrease, dysguesia, fatigue, alopecia, nausea, and diarrhea.3,4 The median time of onset of the trial expected adverse events reported by Chang and colleagues vary from 30 to 175 days with alopecia and weight decrease having a later onset.3 The safety and efficacy of vismodegib continues to be evaluated in RegiSONIC postmarketing study along with other studies evaluating different treatment regimens and in case reports.3 Hepatotoxicity may be potentially related to vismodegib use; however, no causality has been demonstrated.5 Acquired resistance to vismodegib related to smoothened mutations has been observed.6
Cases
Limited data is available to providers on clinical variations of duration of treatment, rapidity of response, and long-term durability of response. This article will provide clinicians guidance with vismodegib treatment for laBCC based on our clinical experience with short courses of therapy in 2 patients. The delayed response to vismodegib occurring subsequent to discontinuing the drug in laBCC and the consideration of probable slow wound healing rather than a partial response to vismodegib are discussed. A case in another patient demonstrates a very rapid response showing both complete clinical resolution within 7 weeks of drug initiation and a complete histologic resolution that was documented 4 weeks after discontinuation of treatment. Both cases demonstrate that short courses of vismodegib may be a viable option for patients.
These cases provide clinicians with relevant information regarding the treatment of laBCC with vismodegib 150 mg daily when considering the duration of treatment and the tolerability of side effects, particularly in the elderly patient. Patients who have disease progression during treatment with vismodegib may have a subsequent delayed response after treatment discontinuation, probably, due to wound healing. A relatively short course of treatment may decrease the side effects and yield a complete clinical and histological response. A complete clinical response, as defined in the ongoing RegiSONIC observation trial is a lesion site with one or more of the following: negative histopathology, no clinical evidence of BCC, and complete tumor shrinkage.
Case 1
An 89-year-old woman, Eastern Cooperative Oncology Group (ECOG) status 1, presented with a 21 × 16 mm laBCC nodular plaque on the anterior lower right leg (Figure 1). The patient was not a primary candidate for surgery or radiation given her symptomatic peripheral vascular disease, stasis dermatitis, and significant chronic leg edema where wound healing from surgery and side effects of radiation were a concern. The patient was started on vismodegib 150 mg daily and completed 83 days of treatment. On day 53 of treatment, the lesion had increased in size measuring 22 × 23 mm and the patient reported grade 3 fatigue, grade 3 dysguesia, and grade 1 alopecia. Treatment was discontinued on day 83 secondary to intolerance of side effects, primarily the fatigue. The patient was considered a treatment failure. The patient declined a radiation oncology consult. 
Approximately 11 weeks after discontinuation of vismodegib, the patient was reevaluated and the BCC had clinically resolved (Figure 2). We continued to follow the patient and observed a sustained complete clinical response of this specific laBCC lesion for 18 months of follow-up status post discontinuation of vismodegib (Figure 3). No biopsy was performed on the treated site because of the potential for problematic healing and persistent ulceration on the edematous pretibia. The patient developed a second, small lesion 10 months after discontinuation of vismodegib. The second lesion was distal from the edge of the scar of the original BCC (Figure 4). The second lesion biopsy demonstrated a nodular BCC and in our opinion represented a new entity because there was no recurrence within the site of the previous BCC. While vismodegib may not be curative, it can provide a treatment alternative and a solid management option for difficult cases. The patient subsequently elected to treat the second lesion with vismodegib but stopped after 6 weeks due to unrelated medical issues.
Case 2
A 99-year old woman, ECOG status 1, presented with a 75 × 35 mm laBCC on the left upper forehead (Figure 5) in addition to other BCC lesions on her face. She declined radiation and surgery. The patient was started on vismodegib 150 mg daily. On days 14 and 30 of treatment, the lesion was noted to have significantly decreased in size and no side effects were present (Figure 6). At day 67 of treatment, a complete response of the BCC clinically was observed and the vismodegib was discontinued at the patient’s request—her only complaint was grade 1 hair loss, but she stated she did not want to live her remaining days without hair.
The patient presented to clinic one month later with a 20 × 20 mm, slightly erythematous dermatitis in the same area as the BCC which occurred within a day after seeing her hairdresser. A biopsy was performed and was negative for malignancy. The patient was given a topical steroid and the dermatitis rapidly resolved. Sixty-three days status post discontinuation of vismodegib, the patient continued to have a complete clinical response on the left upper forehead site and a partial clinical response in other biopsy proven BCCs on the face (Figure 7). The patient expired 43 days after her last visit at age 100 years and 4 days secondary to natural causes.
Discussion
These 2 cases suggest that a short course of vismodegib 150 mg daily ± 60 to 90 days can potentially yield a complete response of BCC in patients who may not be able to tolerate the side effects of a longer course of treatment. In one patient considered a treatment failure, we highlight a delayed response after discontinuation of vismodegib who subsequently had a clinically complete resolution with a durable response of 18 months in the target treatment area.LaBCC lesions can have an ulcerative component both clinically and/or histologically.
Pranteda and colleagues found in a retrospective study of patients diagnosed with BCC that clinical-pathological subtypes occur on different anatomical areas with ulcerative lesions occurring more frequently on the lower extremities.6 We know that patients with vascular insufficiency in the lower extremities will have slower wound healing.7 We propose that the delayed response may actually be slow wound healing after earlier clearance of the laBCC.
Gill and colleagues demonstrated 2 cases in which patients had complete responses with perioribital laBCCs with less than 8 weeks of treatment with vismodegib 150mg daily.8 One patient received a 4-week treatment course with a durable response of 10 months while the other patient had a 7-week treatment course with durable response of 6 months. Further data on these patients past the observation periods was not available. Viscusi and Hanke also discussed a case study in which the patient had a 5 cm ulcerated laBCC on the forehead that received a 5-week treatment course with a complete clinical response 4 months after treatment cessation. The treatment was discontinued secondary to social issues and nonfinancial barriers.9
Patients in the ERIVANCE trial discontinued vismodegib if there was disease progression, and the standard of care in clinical practice is often the same with laBCC. Our patient demonstrates that a possible consideration can include a period of watchful waiting in a treatment failure prior to initiating further invasive therapy.
In an investigator-initiated clinical trial evaluating the reduction of BCC surgical defect size prior to Mohs surgery, Ally and colleagues found that vismodegib was not effective in patients who received less than a 3-month treatment course, although this only included 2 patients.10 Our patients; however, had clinical clearing with less than 3 months of treatments and the duration in one patient was sustained. We believe that the duration of treatment is still an open question requiring additional studies and overall drug experience within the dermatology community.
Continued, larger studies on the long-term safety and efficacy with vismodegib for laBCC need to be performed. There have been reports of increased liver enzymes and other abnormal lab findings in patients who are taking vismodegib, although causality has not been thoroughly established. A new onset of congestive heart failure in one patient receiving vismodegib was discussed by Huizenga and colleagues.11
In published clinical studies, the duration of treatment courses vary, with the minimum treatment course being 3 months and the median treatment course being 5.5 to 6.7 months. Longer treatment courses are often dependent on the patient’s ability to tolerate side effects, primarily fatigue, dysguesia, and hair loss. Patients who have a positive initial response to vismodegib, but cannot tolerate side effects, may benefit from a treatment break for a few weeks and then resume the drug.12 The 2 cases presented demonstrate a complete response in both patients with a less than 90-day treatment course with an 18-month durable response in one patient.
Ms Grossi is a dermatology nurse practitioner in private practice at Advanced Dermatology and Cosmetic Care in Valencia, CA.
Dr Raskin is medical director of Advanced Dermatology and Cosmetic Care in Valencia, CA. He is on the speakers panel for Erivedge with Genentech.
Disclosure: The author reports no relevant financial relationships.
References
1. Epstein EH. Basal cell carcinomas: attack of the hedgehog. Nat Rev Cancer. 2008;8(10):743-754.
2. Maly TJ, Sligh JE. Defining locally advanced basal cell carcinoma. J Drugs Dermatol. 2014;13(5):528-529.
3. Chang AL, Solomon, JA, Hainsworth, JD, et al. Expanded access study of patients with advanced basal cell carcinoma treated with the Hedgehog pathway inhibitor, vismodegib. J Am Acad Dermatol. 2014;70(1):60-69.
4. Ventarola DJ, Silverstein DI. Vismodegib-associated hepatotoxicity: a potential side effect detected in postmarketing surveillance. J Am Acad Dermatol. 2014;71(2):397-398.
5. Brinkhuizen T, Reinders MG, van Geel M, et al. Acquired resistance to the Hedgehog pathway inhibitor vismodegib due to smoothened mutations in treatment of locally advanced basal cell carcinoma. J Am Acad Dermatol. 2014;71(5):1005-1008.
6. Pranteda G, Grimaldi M, Lombardi M, et al. Basal cell carcinoma: differences according to anatomic location and clinical-pathological subtypes. G Ital Dermatol Venereol. 2014;149(4):423-426.
7. Sieggreen MY, Kline RA. Arterial insufficiency and ulceration: diagnosis and treatment options. Adv Skin Wound Care. 2004;17(5 Pt 1):242-251.
8. Gill HS, Moscato EE, Chang AL, Soon S, Silkiss RZ. Vismodegib for periocular and orbital basal cell carcinoma. JAMA Ophthalmol. 2013;131(12):1591-1594.
9. Viscusi KS, Hanke CW. Vismodegib for locally advanced basal cell carcinoma: descriptive analysis of a case series and comparison to the literature. J Drugs Dermatol. 2015;14(9):956-962.
10. 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.e901.
11. Huizenga T, Newsom E, Fakhouri T, Kado J. New-onset congestive heart failure in a patient on vismodegib. Dermatol Surg. 20015;41(11):1329-1332.
12. Ibrahim, SA. Treating advanced basal cell carcinoma. The Dermatologist. 2015;23(5):23-26.
Oral hedgehog pathway inhibitors offer treatment options to patients with basal cell carcinoma (BCC). Vismodegib (Erivedge) is the first hedgehog signaling pathway inhibitor approved by the FDA for the treatment of locally advanced basal cell carcinoma (laBCC) or metastatic basal cell carcinoma. Central to the BCC pathophysiology is the upregulation of the hedgehog signaling pathway.1 The drug received FDA approval after a phase 2 BCC study (ERIVANCE) demonstrated significant response rates in both the laBCC and metastatic BCC cohorts, who otherwise had limited treatment options.2 The median time patients received treatment was 5.5 to 6.7 months and the median safety follow-up was 6.5 months. Median duration of clearance was 7.3 months.3
In the ERIVANCE trial, patients were given 150 mg of vismodegib daily and continued until disease progression or intolerable toxicity occurred. Treatment breaks for limited time periods were allowed. The most frequent side effects of vismodegib include muscle spasm, weight decrease, dysguesia, fatigue, alopecia, nausea, and diarrhea.3,4 The median time of onset of the trial expected adverse events reported by Chang and colleagues vary from 30 to 175 days with alopecia and weight decrease having a later onset.3 The safety and efficacy of vismodegib continues to be evaluated in RegiSONIC postmarketing study along with other studies evaluating different treatment regimens and in case reports.3 Hepatotoxicity may be potentially related to vismodegib use; however, no causality has been demonstrated.5 Acquired resistance to vismodegib related to smoothened mutations has been observed.6
Cases
Limited data is available to providers on clinical variations of duration of treatment, rapidity of response, and long-term durability of response. This article will provide clinicians guidance with vismodegib treatment for laBCC based on our clinical experience with short courses of therapy in 2 patients. The delayed response to vismodegib occurring subsequent to discontinuing the drug in laBCC and the consideration of probable slow wound healing rather than a partial response to vismodegib are discussed. A case in another patient demonstrates a very rapid response showing both complete clinical resolution within 7 weeks of drug initiation and a complete histologic resolution that was documented 4 weeks after discontinuation of treatment. Both cases demonstrate that short courses of vismodegib may be a viable option for patients.
These cases provide clinicians with relevant information regarding the treatment of laBCC with vismodegib 150 mg daily when considering the duration of treatment and the tolerability of side effects, particularly in the elderly patient. Patients who have disease progression during treatment with vismodegib may have a subsequent delayed response after treatment discontinuation, probably, due to wound healing. A relatively short course of treatment may decrease the side effects and yield a complete clinical and histological response. A complete clinical response, as defined in the ongoing RegiSONIC observation trial is a lesion site with one or more of the following: negative histopathology, no clinical evidence of BCC, and complete tumor shrinkage.
Case 1
An 89-year-old woman, Eastern Cooperative Oncology Group (ECOG) status 1, presented with a 21 × 16 mm laBCC nodular plaque on the anterior lower right leg (Figure 1). The patient was not a primary candidate for surgery or radiation given her symptomatic peripheral vascular disease, stasis dermatitis, and significant chronic leg edema where wound healing from surgery and side effects of radiation were a concern. The patient was started on vismodegib 150 mg daily and completed 83 days of treatment. On day 53 of treatment, the lesion had increased in size measuring 22 × 23 mm and the patient reported grade 3 fatigue, grade 3 dysguesia, and grade 1 alopecia. Treatment was discontinued on day 83 secondary to intolerance of side effects, primarily the fatigue. The patient was considered a treatment failure. The patient declined a radiation oncology consult.
Approximately 11 weeks after discontinuation of vismodegib, the patient was reevaluated and the BCC had clinically resolved (Figure 2). We continued to follow the patient and observed a sustained complete clinical response of this specific laBCC lesion for 18 months of follow-up status post discontinuation of vismodegib (Figure 3). No biopsy was performed on the treated site because of the potential for problematic healing and persistent ulceration on the edematous pretibia. The patient developed a second, small lesion 10 months after discontinuation of vismodegib. The second lesion was distal from the edge of the scar of the original BCC (Figure 4). The second lesion biopsy demonstrated a nodular BCC and in our opinion represented a new entity because there was no recurrence within the site of the previous BCC. While vismodegib may not be curative, it can provide a treatment alternative and a solid management option for difficult cases. The patient subsequently elected to treat the second lesion with vismodegib but stopped after 6 weeks due to unrelated medical issues.
Case 2
A 99-year old woman, ECOG status 1, presented with a 75 × 35 mm laBCC on the left upper forehead (Figure 5) in addition to other BCC lesions on her face. She declined radiation and surgery. The patient was started on vismodegib 150 mg daily. On days 14 and 30 of treatment, the lesion was noted to have significantly decreased in size and no side effects were present (Figure 6). At day 67 of treatment, a complete response of the BCC clinically was observed and the vismodegib was discontinued at the patient’s request—her only complaint was grade 1 hair loss, but she stated she did not want to live her remaining days without hair.
The patient presented to clinic one month later with a 20 × 20 mm, slightly erythematous dermatitis in the same area as the BCC which occurred within a day after seeing her hairdresser. A biopsy was performed and was negative for malignancy. The patient was given a topical steroid and the dermatitis rapidly resolved. Sixty-three days status post discontinuation of vismodegib, the patient continued to have a complete clinical response on the left upper forehead site and a partial clinical response in other biopsy proven BCCs on the face (Figure 7). The patient expired 43 days after her last visit at age 100 years and 4 days secondary to natural causes.
Discussion
These 2 cases suggest that a short course of vismodegib 150 mg daily ± 60 to 90 days can potentially yield a complete response of BCC in patients who may not be able to tolerate the side effects of a longer course of treatment. In one patient considered a treatment failure, we highlight a delayed response after discontinuation of vismodegib who subsequently had a clinically complete resolution with a durable response of 18 months in the target treatment area.LaBCC lesions can have an ulcerative component both clinically and/or histologically.
Pranteda and colleagues found in a retrospective study of patients diagnosed with BCC that clinical-pathological subtypes occur on different anatomical areas with ulcerative lesions occurring more frequently on the lower extremities.6 We know that patients with vascular insufficiency in the lower extremities will have slower wound healing.7 We propose that the delayed response may actually be slow wound healing after earlier clearance of the laBCC.
Gill and colleagues demonstrated 2 cases in which patients had complete responses with perioribital laBCCs with less than 8 weeks of treatment with vismodegib 150mg daily.8 One patient received a 4-week treatment course with a durable response of 10 months while the other patient had a 7-week treatment course with durable response of 6 months. Further data on these patients past the observation periods was not available. Viscusi and Hanke also discussed a case study in which the patient had a 5 cm ulcerated laBCC on the forehead that received a 5-week treatment course with a complete clinical response 4 months after treatment cessation. The treatment was discontinued secondary to social issues and nonfinancial barriers.9
Patients in the ERIVANCE trial discontinued vismodegib if there was disease progression, and the standard of care in clinical practice is often the same with laBCC. Our patient demonstrates that a possible consideration can include a period of watchful waiting in a treatment failure prior to initiating further invasive therapy.
In an investigator-initiated clinical trial evaluating the reduction of BCC surgical defect size prior to Mohs surgery, Ally and colleagues found that vismodegib was not effective in patients who received less than a 3-month treatment course, although this only included 2 patients.10 Our patients; however, had clinical clearing with less than 3 months of treatments and the duration in one patient was sustained. We believe that the duration of treatment is still an open question requiring additional studies and overall drug experience within the dermatology community.
Continued, larger studies on the long-term safety and efficacy with vismodegib for laBCC need to be performed. There have been reports of increased liver enzymes and other abnormal lab findings in patients who are taking vismodegib, although causality has not been thoroughly established. A new onset of congestive heart failure in one patient receiving vismodegib was discussed by Huizenga and colleagues.11
In published clinical studies, the duration of treatment courses vary, with the minimum treatment course being 3 months and the median treatment course being 5.5 to 6.7 months. Longer treatment courses are often dependent on the patient’s ability to tolerate side effects, primarily fatigue, dysguesia, and hair loss. Patients who have a positive initial response to vismodegib, but cannot tolerate side effects, may benefit from a treatment break for a few weeks and then resume the drug.12 The 2 cases presented demonstrate a complete response in both patients with a less than 90-day treatment course with an 18-month durable response in one patient.
Ms Grossi is a dermatology nurse practitioner in private practice at Advanced Dermatology and Cosmetic Care in Valencia, CA.
Dr Raskin is medical director of Advanced Dermatology and Cosmetic Care in Valencia, CA. He is on the speakers panel for Erivedge with Genentech.
Disclosure: The author reports no relevant financial relationships.
References
1. Epstein EH. Basal cell carcinomas: attack of the hedgehog. Nat Rev Cancer. 2008;8(10):743-754.
2. Maly TJ, Sligh JE. Defining locally advanced basal cell carcinoma. J Drugs Dermatol. 2014;13(5):528-529.
3. Chang AL, Solomon, JA, Hainsworth, JD, et al. Expanded access study of patients with advanced basal cell carcinoma treated with the Hedgehog pathway inhibitor, vismodegib. J Am Acad Dermatol. 2014;70(1):60-69.
4. Ventarola DJ, Silverstein DI. Vismodegib-associated hepatotoxicity: a potential side effect detected in postmarketing surveillance. J Am Acad Dermatol. 2014;71(2):397-398.
5. Brinkhuizen T, Reinders MG, van Geel M, et al. Acquired resistance to the Hedgehog pathway inhibitor vismodegib due to smoothened mutations in treatment of locally advanced basal cell carcinoma. J Am Acad Dermatol. 2014;71(5):1005-1008.
6. Pranteda G, Grimaldi M, Lombardi M, et al. Basal cell carcinoma: differences according to anatomic location and clinical-pathological subtypes. G Ital Dermatol Venereol. 2014;149(4):423-426.
7. Sieggreen MY, Kline RA. Arterial insufficiency and ulceration: diagnosis and treatment options. Adv Skin Wound Care. 2004;17(5 Pt 1):242-251.
8. Gill HS, Moscato EE, Chang AL, Soon S, Silkiss RZ. Vismodegib for periocular and orbital basal cell carcinoma. JAMA Ophthalmol. 2013;131(12):1591-1594.
9. Viscusi KS, Hanke CW. Vismodegib for locally advanced basal cell carcinoma: descriptive analysis of a case series and comparison to the literature. J Drugs Dermatol. 2015;14(9):956-962.
10. 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.e901.
11. Huizenga T, Newsom E, Fakhouri T, Kado J. New-onset congestive heart failure in a patient on vismodegib. Dermatol Surg. 20015;41(11):1329-1332.
12. Ibrahim, SA. Treating advanced basal cell carcinoma. The Dermatologist. 2015;23(5):23-26.
