BJD
British Journal of Dermatology
CASE REPORT
Induction Hedgehog pathway inhibition followed by combined-modality radiotherapy for basal cell carcinoma D.R. Raleigh,1 A. Algazi,2 S.T. Arron,3 I.M. Neuhaus3 and S.S. Yom1 1
Department of Radiation Oncology, 2Department of Medicine and 3Department of Dermatology, University of California San Francisco, San Francisco, CA, U.S.A.
Summary Correspondence Sue S. Yom. E-mail: [email protected]
Accepted for publication 9 February 2015
Funding sources
Basal cell carcinoma (BCC), the most common cancer in the U.S.A., is treated primarily with local excision. In some cases, lesion size, location or extent prevent complete resection. Locally advanced BCC responds to systemic therapy with the Hedgehog pathway inhibitor vismodegib, but withdrawal of treatment may result in disease relapse. Here we present a case of locally advanced auricular BCC treated with induction vismodegib and radiation, resulting in durable local control and an acceptable level of acute toxicity.
None.
Conflicts of interest None declared. DOI 10.1111/bjd.13748
What’s already known about this topic?
• • •
Basal cell carcinoma (BCC) is dependent on misactivation of the Hedgehog signalling network. The Hedgehog pathway inhibitor vismodegib is an effective treatment for relapsed and disseminated BCC. Clinical responses to vismodegib are often partial, especially in cases of advanced local disease, and are not always durable. Many patients discontinue systemic treatment due to toxicity.
What does this study add?
• •
Although radiation can be used in combination with Hedgehog pathway inhibition to achieve durable local control of BCCs, the optimal sequence and timing of therapy is not yet known. This case demonstrates that induction therapy with vismodegib facilitates re-epithelialization as tumours regress, potentially sparing selected patients from nonhealing resulting from radiotherapy to open wounds.
Case report A 55-year-old Hispanic man presented with a 5-year history of a right-ear lesion for which he did not initially pursue medical care due to obligations to his ailing family. When he ultimately sought attention, he reported progressive growth, tenderness, bleeding and pain. Biopsy was consistent with infiltrative basal cell carcinoma (BCC). On 544
British Journal of Dermatology (2015) 173, pp544–546
examination, a 65 9 7-cm exophytic, fungating mass encompassed the entire right ear, where it obliterated the architecture and emitted a nonbloody discharge (Fig. 1a). There were no additional skin lesions on physical examination. Magnetic resonance imaging demonstrated limited extension into the external acoustic canal and superficial parotid gland, but no evidence of bone or perineural invasion (Fig. 1b). © 2015 British Association of Dermatologists
Vismodegib and radiotherapy for basal cell carcinoma, D.R. Raleigh et al. 545
(a)
(b)
Discussion
Fig 1. Pretreatment images. (a) Examination of the patient’s right ear revealed a 65 9 7-cm fungating mass with copious skin breakdown, destruction of the normal architecture and a milky white exudate. (b) Axial, noncontrast T1-weighted magnetic resonance imaging demonstrated a large, isointense, homogeneous exophytic mass involving the right pinna with extension to the posterior margin of the external auditory canal and superficial lobe of the parotid gland.
The patient was started on oral vismodegib at 150 mg daily and experienced only grade ≤ 2 side-effects including mild nausea, myalgias, alopecia and fatigue. After 12 weeks of systemic monotherapy, examination revealed a global reduction in the size of his right-ear BCC, with particular improvement in exophytic areas of skin breakdown (Fig. 2a). Vismodegib was continued in combination with intensity-modulated radiation therapy given to a total prescription dose of 7000 cGy in 35 daily sequential fractions to the right ear. Treatment-related side-effects included soft-tissue inflammation indicative of radiosensitization, and conductive hearing loss attributed to middle-ear inflammation. Vismodegib was discontinued at the end of radiation therapy, at which time the tumour mass had decreased, discharge had ceased and pain had resolved (Fig. 2b). At follow-up 13 months after the end of treatment, there was mild fibrosis consistent with the treatment effect, continued mild erythema and inflammation of the periauricular soft tissues, and persistent mild-to-moderate conductive hearing loss. Although this follow-up remains short in evaluating for recurrence of BCC, the patient does continue to be without evidence of residual or recurrent disease by both clinical and radiographical examination (Fig. 2c).
(a)
(b)
Vismodegib is a first-in-class small-molecule inhibitor of the Hedgehog signalling pathway that is associated with an excellent response rate in patients with advanced BCC.1 In contrast to Hedgehog pathway-associated medulloblastoma, data to suggest that BCC acquires resistance to vismodegib are lacking.2,3 Patients receiving vismodegib for BCC routinely report grade ≤ 2 adverse events such as loss of taste, nausea, muscle cramps, weight loss and alopecia.4 As a result, many patients discontinue systemic therapy, which may lead to eventual recurrence of BCC. These data indicate that drug-tolerant, dormant BCC cells persist despite vismodegib, and further suggest that definitive local therapy is required to consolidate gains from induction Hedgehog pathway inhibition. In response to vismodegib, BCCs often regress below the threshold of detection by either visual or histopathological examination, and consolidative radiation therapy may eliminate the remaining microscopic disease. However, while the combination of induction vismodegib followed by radiation is likely to be an effective treatment strategy for BCC, it is unknown whether the pattern or timing of late recurrence or late normal tissue toxicities might be altered following combination therapy. All patients treated with vismodegib, with radiotherapy or without, should be closely followed until more clinical experience is available. Given the role of Hedgehog signalling in wound healing, it is possible that Hedgehog pathway inhibition may contribute to impaired healing and/or persistent inflammation following radiotherapy.5 However, in cases of BCC involving skin breakdown, an induction vismodegib strategy may facilitate re-epithelialization as tumours regress, thus sparing patients from radiotherapy to open wounds that ultimately may require surgical reconstruction through skin graft or tissue flap placement over exposed bone or cartilage. To answer these and other questions, we are currently conducting a phase II trial to test the tolerability and efficacy of vismodegib as an induction then concurrent therapy in combination with radiotherapy for BCC. We caution that this approach, while potentially beneficial, should be regarded as investigational until mature clinical trial results are available.
(c)
Fig 2. Post-treatment images. (a) Global reduction in the size of the right-ear basal cell carcinoma following 12 weeks of vismodegib monotherapy, with crusting and healing of areas of skin breakdown. (b) Further reduction in size after seven additional weeks of intensitymodulated radiotherapy plus continued vismodegib. (c) No evidence of disease 7 months after completion of therapy. © 2015 British Association of Dermatologists
British Journal of Dermatology (2015) 173, pp544–546
546 Vismodegib and radiotherapy for basal cell carcinoma, D.R. Raleigh et al.
References 1 Sekulic A, Migden MR, Oro AE et al. Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med 2012; 366:2171–9. 2 Rudin CM, Hann CL, Laterra J et al. Treatment of medulloblastoma with hedgehog pathway inhibitor GDC-0449. N Engl J Med 2009; 361:1173–8. 3 Yauch RL, Dijkgraaf GJP, Alicke B et al. Smoothened mutation confers resistance to a Hedgehog pathway inhibitor in medulloblastoma. Science 2009; 326:572–4.
British Journal of Dermatology (2015) 173, pp544–546
4 Tang JY, Mackay-Wiggan JM, Aszterbaum M et al. Inhibiting the hedgehog pathway in patients with the basal-cell nevus syndrome. N Engl J Med 2012; 366:2180–8. 5 Briscoe J, Therond PP. The mechanisms of Hedgehog signalling and its roles in development and disease. Nat Rev Mol Cell Biol 2013; 14:416–29.
© 2015 British Association of Dermatologists
British Journal of Dermatology
CASE REPORT
Induction Hedgehog pathway inhibition followed by combined-modality radiotherapy for basal cell carcinoma D.R. Raleigh,1 A. Algazi,2 S.T. Arron,3 I.M. Neuhaus3 and S.S. Yom1 1
Department of Radiation Oncology, 2Department of Medicine and 3Department of Dermatology, University of California San Francisco, San Francisco, CA, U.S.A.
Summary Correspondence Sue S. Yom. E-mail: [email protected]
Accepted for publication 9 February 2015
Funding sources
Basal cell carcinoma (BCC), the most common cancer in the U.S.A., is treated primarily with local excision. In some cases, lesion size, location or extent prevent complete resection. Locally advanced BCC responds to systemic therapy with the Hedgehog pathway inhibitor vismodegib, but withdrawal of treatment may result in disease relapse. Here we present a case of locally advanced auricular BCC treated with induction vismodegib and radiation, resulting in durable local control and an acceptable level of acute toxicity.
None.
Conflicts of interest None declared. DOI 10.1111/bjd.13748
What’s already known about this topic?
• • •
Basal cell carcinoma (BCC) is dependent on misactivation of the Hedgehog signalling network. The Hedgehog pathway inhibitor vismodegib is an effective treatment for relapsed and disseminated BCC. Clinical responses to vismodegib are often partial, especially in cases of advanced local disease, and are not always durable. Many patients discontinue systemic treatment due to toxicity.
What does this study add?
• •
Although radiation can be used in combination with Hedgehog pathway inhibition to achieve durable local control of BCCs, the optimal sequence and timing of therapy is not yet known. This case demonstrates that induction therapy with vismodegib facilitates re-epithelialization as tumours regress, potentially sparing selected patients from nonhealing resulting from radiotherapy to open wounds.
Case report A 55-year-old Hispanic man presented with a 5-year history of a right-ear lesion for which he did not initially pursue medical care due to obligations to his ailing family. When he ultimately sought attention, he reported progressive growth, tenderness, bleeding and pain. Biopsy was consistent with infiltrative basal cell carcinoma (BCC). On 544
British Journal of Dermatology (2015) 173, pp544–546
examination, a 65 9 7-cm exophytic, fungating mass encompassed the entire right ear, where it obliterated the architecture and emitted a nonbloody discharge (Fig. 1a). There were no additional skin lesions on physical examination. Magnetic resonance imaging demonstrated limited extension into the external acoustic canal and superficial parotid gland, but no evidence of bone or perineural invasion (Fig. 1b). © 2015 British Association of Dermatologists
Vismodegib and radiotherapy for basal cell carcinoma, D.R. Raleigh et al. 545
(a)
(b)
Discussion
Fig 1. Pretreatment images. (a) Examination of the patient’s right ear revealed a 65 9 7-cm fungating mass with copious skin breakdown, destruction of the normal architecture and a milky white exudate. (b) Axial, noncontrast T1-weighted magnetic resonance imaging demonstrated a large, isointense, homogeneous exophytic mass involving the right pinna with extension to the posterior margin of the external auditory canal and superficial lobe of the parotid gland.
The patient was started on oral vismodegib at 150 mg daily and experienced only grade ≤ 2 side-effects including mild nausea, myalgias, alopecia and fatigue. After 12 weeks of systemic monotherapy, examination revealed a global reduction in the size of his right-ear BCC, with particular improvement in exophytic areas of skin breakdown (Fig. 2a). Vismodegib was continued in combination with intensity-modulated radiation therapy given to a total prescription dose of 7000 cGy in 35 daily sequential fractions to the right ear. Treatment-related side-effects included soft-tissue inflammation indicative of radiosensitization, and conductive hearing loss attributed to middle-ear inflammation. Vismodegib was discontinued at the end of radiation therapy, at which time the tumour mass had decreased, discharge had ceased and pain had resolved (Fig. 2b). At follow-up 13 months after the end of treatment, there was mild fibrosis consistent with the treatment effect, continued mild erythema and inflammation of the periauricular soft tissues, and persistent mild-to-moderate conductive hearing loss. Although this follow-up remains short in evaluating for recurrence of BCC, the patient does continue to be without evidence of residual or recurrent disease by both clinical and radiographical examination (Fig. 2c).
(a)
(b)
Vismodegib is a first-in-class small-molecule inhibitor of the Hedgehog signalling pathway that is associated with an excellent response rate in patients with advanced BCC.1 In contrast to Hedgehog pathway-associated medulloblastoma, data to suggest that BCC acquires resistance to vismodegib are lacking.2,3 Patients receiving vismodegib for BCC routinely report grade ≤ 2 adverse events such as loss of taste, nausea, muscle cramps, weight loss and alopecia.4 As a result, many patients discontinue systemic therapy, which may lead to eventual recurrence of BCC. These data indicate that drug-tolerant, dormant BCC cells persist despite vismodegib, and further suggest that definitive local therapy is required to consolidate gains from induction Hedgehog pathway inhibition. In response to vismodegib, BCCs often regress below the threshold of detection by either visual or histopathological examination, and consolidative radiation therapy may eliminate the remaining microscopic disease. However, while the combination of induction vismodegib followed by radiation is likely to be an effective treatment strategy for BCC, it is unknown whether the pattern or timing of late recurrence or late normal tissue toxicities might be altered following combination therapy. All patients treated with vismodegib, with radiotherapy or without, should be closely followed until more clinical experience is available. Given the role of Hedgehog signalling in wound healing, it is possible that Hedgehog pathway inhibition may contribute to impaired healing and/or persistent inflammation following radiotherapy.5 However, in cases of BCC involving skin breakdown, an induction vismodegib strategy may facilitate re-epithelialization as tumours regress, thus sparing patients from radiotherapy to open wounds that ultimately may require surgical reconstruction through skin graft or tissue flap placement over exposed bone or cartilage. To answer these and other questions, we are currently conducting a phase II trial to test the tolerability and efficacy of vismodegib as an induction then concurrent therapy in combination with radiotherapy for BCC. We caution that this approach, while potentially beneficial, should be regarded as investigational until mature clinical trial results are available.
(c)
Fig 2. Post-treatment images. (a) Global reduction in the size of the right-ear basal cell carcinoma following 12 weeks of vismodegib monotherapy, with crusting and healing of areas of skin breakdown. (b) Further reduction in size after seven additional weeks of intensitymodulated radiotherapy plus continued vismodegib. (c) No evidence of disease 7 months after completion of therapy. © 2015 British Association of Dermatologists
British Journal of Dermatology (2015) 173, pp544–546
546 Vismodegib and radiotherapy for basal cell carcinoma, D.R. Raleigh et al.
References 1 Sekulic A, Migden MR, Oro AE et al. Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med 2012; 366:2171–9. 2 Rudin CM, Hann CL, Laterra J et al. Treatment of medulloblastoma with hedgehog pathway inhibitor GDC-0449. N Engl J Med 2009; 361:1173–8. 3 Yauch RL, Dijkgraaf GJP, Alicke B et al. Smoothened mutation confers resistance to a Hedgehog pathway inhibitor in medulloblastoma. Science 2009; 326:572–4.
British Journal of Dermatology (2015) 173, pp544–546
4 Tang JY, Mackay-Wiggan JM, Aszterbaum M et al. Inhibiting the hedgehog pathway in patients with the basal-cell nevus syndrome. N Engl J Med 2012; 366:2180–8. 5 Briscoe J, Therond PP. The mechanisms of Hedgehog signalling and its roles in development and disease. Nat Rev Mol Cell Biol 2013; 14:416–29.
© 2015 British Association of Dermatologists
