Metastatic basal cell carcinoma (BCC) is a rare event, with estimated incidences ranging from 0.0028 to 0.1%. Lung and bone are the most common sites. If distant metastasis of BCC is suspected, confirmation should be obtained by biopsy.
The management of metastatic BCC is largely based on clinical evidence and experience in the management of locally advanced BCCs. Definitions of locally advanced BCC vary between clinical trial investigators and between disciplines, but it is generally acknowledged to include BCCs that have recurred after prior treatment, lesions in locations that preclude surgical excision, and large lesions.
In clinical practice, locally advanced BCC describes a range of clinical presentations in which a primary or locally recurrent BCC is not easily treated by local surgery or radiotherapy. Locally advanced BCC can arise due to tumour-related factors, patient-related factors or treatment-related factors.
To overcome the lack of an agreed definition of locally advanced BCC (and, in particular, to avoid over-reliance on lesion size as an independent criterion) the term ‘difficult-to-treat’ has been proposed to identify BCCs that require a treatment approach similar to that of advanced disease. A European study reported that 6.6% of all BCC were difficult to treat and 0.6% were very difficult to treat, while a tertiary referral centre in the UK reported that up to 20% of BCCs are difficult to treat although not necessarily advanced.
See: Prognosis of basal cell carcinoma and Table 1.
Tumour characteristics can include a large neglected primary lesion, infiltrative growth pattern, or proximity to a critical structure in the face. Patient factors can include comorbidities or the decision to decline certain treatment modalities. Treatment factors may include tumour recurrence after prior surgery and radiotherapy, or unsuitability of surgical excision where this would leave a large functional or cosmetic defect (e.g. orbital exenteration).
Tumour size alone does not necessarily determine whether the patient has locally advanced disease, as complexity may be more relevant. For example, a large, neglected BCC overlying the back in an otherwise reasonably healthy patient may be amenable to relatively straightforward curative-intent surgery with skin grafting, whereas it may be much more difficult to manage a small lesion located near the eye that has recurred after prior surgery, with an infiltrative growth pattern and poorly defined margins.
Patients with complex, locally advanced disease are best treated by a multidisciplinary team including surgeons, dermatologists, radiation oncologists and medical oncologists. Curative-intent surgery or radiotherapy (or both) is the optimal approach but, if these are not possible, systemic therapy with hedgehog pathway inhibitors (HPIs) can be considered.
Basal cell carcinoma may sometimes show metastatic spread to regional lymph nodes and, occasionally, in-transit metastases. In such cases direct treatment such as surgery or radiotherapy, if possible, would be appropriate after first evaluating if more widespread metastatic disease is present.
Radiotherapy may be useful in palliation of distant metastases.
Selecting patients appropriate for systemic therapy for advanced BCC requires consideration of the individual’s functional status, comorbidities, social support and likely compliance with treatment and follow-up. The clinician must discuss potential side effects of proposed treatment with the patient and ensure appropriate clinical support.
Overview of evidence (non-systematic literature review)
Hedgehog pathway inhibitors
Potential candidates for HPI therapy include patients with inoperable BCC, those in whom surgery is not appropriate, and those with metastatic BCC who have an adequate performance status. Hedgehog pathway inhibitors are administered orally once daily in an outpatient setting.
Targeted therapy using HPIs has been demonstrated to be effective in patients with proven metastatic BCC. Data are available from well-conducted trials in patients with confirmed histological diagnoses of metastatic BCC and response assessment according to modern radiological criteria.Research is currently underway assessing the use of systemic HPIs to achieve tumour reduction prior to definitive surgery in patients with locally advanced BCC.
Vismodegib, the first HPI, was reported to show a significant degree of activity in sporadic inoperable BCC. At long-term follow-up (39 months after accrual), objective response rates were 60.3% among patients with locally advanced BCC and 48.5% among those with metastatic BCC, with comparable findings across patient subgroups including those with aggressive histologic subtypes (e.g. infiltrative BCC). Median duration of response was 26.2 months among patients with locally advanced BCC and 14.8 months among those with metastatic BCC. Median overall survival was 33.4 months in the metastatic BCC cohort and could not be estimated in the locally advanced BCC cohort. Vismodegib has also been shown to reduce new lesion formation in patients with naevoid BCC syndrome (Gorlin’s syndrome)(naevoid BCC syndrome) an autosomal dominant syndrome characterised by multiple BCCs.
A phase 2 randomised controlled trial (RCT) comparing sonidegib 200mg or 800mg daily in patients with metastatic BCC or locally advanced BCC not amenable to curative surgery or radiation reported that efficacy was similar for both doses, while the lower dose showed a better toxicity profile. At 30 months’ follow-up, objective response rates for patients treated with sonidegib 200mg were 56.1% as assessed by central review and 71.2% as assessed by investigator review among patients with locally advanced BCC, and 7.7% (central)/23.1% (investigator) among those with metastatic BCC. Median duration of response was 26.1 months (central)/15.7 months (investigator) in among patients with locally advanced BCC and 24.0 months (central)/18.1 months (investigator) among those with metastatic BCC. Overall survival rates at 2 years were 93.2% for patients with locally advanced BCC and 69.3% for those with metastatic BCC. Median overall survival could not be calculated. Among patients with locally advanced BCC, efficacy did not differ between subgroups according to aggressive or non-aggressive histology.
The sonidegib registration trial used a more stringent response assessment method than was used in the vismodegib registration trial, resulting in lower rates of complete and partial responses. However, overall disease control rates were similar.
Allowing for differences in trial assessment, sonidegib and vismodegib appear to have similar efficacy.
Allowing for differences in trial assessment, sonidegib and vismodegib appear to have a similar spectrum of side effects. Elevated blood creatine kinase was noted in the registration sonidegib study, but creatine kinase levels were not routinely tested in the vismodegib studies. Symptomatic muscle cramps have been reported with both agents.
For a patient experiencing intolerable class side effects from HPI (such as hair loss, taste loss, cramps), switching between HPI agents may result in similar side effects. For other side effects that are likely to be agent-specific, switching to the alternative HPI is a reasonable strategy. Disease progression is unlikely to be sensitive to a change in HPI unless drug-specific side effects have prevented full dosing.Intermittent dosing has been proposed as a strategy for reducing side effects of HPI therapy while maintaining efficacy. A RCT evaluating two intermittent regimens in patients with multiple BCCs reported effective anti-cancer activity and acceptable adverse effects
Managing side effects
Patient and carer education and expectations about side effects are important and should be adequately discussed prior to commencing treatment and supported with written information (such as the EviQ patient information document). Attention to nutrition, monitoring of weight, and dietitian review if necessary help with taste loss with the goal of preventing weight loss and nutritional deficiencies.
Nausea, diarrhoea, constipation and abdominal cramps may be alleviated with specific supportive medications (such as anti-emetics, laxatives and spasmolytic agents such as hyoscine). For symptomatic cramps, magnesium supplements and calcium channel antagonists have been proposed as well as analgesia, which can include as-required opioids such as oxycodone for severe cramps. Minoxidil 5% twice daily has been suggested to treat alopecia.
Routine monitoring includes blood tests for full blood count, liver function tests, creatinine and creatine kinase.
For patients with metastatic/locally advanced BCC who develop resistance or intolerance to a first-line HPI, other systemic therapies can be considered.
Proposed resistance mechanisms by BCC to HPI include acquired mutations in smoothened (SMO) gene or glioma associated oncogene homolog (GLI) genes. Other pathways of resistance include over-expression of epidermal growth factor receptor (EGFR), Mitogen Activated Protein Kinase (MAPK) and Akt. Treatment with EGFR inhibitors has been proposed as a strategy for patients with treatment-resistant BCC with demonstrated expression of EGFR.
Ongoing research into escape mutations in hedgehog pathway signalling aims to develop newer drugs to help overcome resistance to sonidegib and vismodegib.
Combination with other therapies
Combination treatment with vismodegib, itraconazole, and imiquimod has been proposed in order to target different parts of the hedgehog signalling pathway. This strategy may help reduce the development of resistance and increase efficacy.
Systemic chemotherapy is rarely used in metastatic BCC or for locally advanced disease.
Single-case reports document responses to the combination of cisplatin or carboplatin with paclitaxel in patients with metastatic BCC. A 1996 review evaluating platinum containing chemotherapy in 46 patients with progressive BCC reported an overall response rate of 83%,with a median time to progression of 24 months. A 2004 Australian case study reported rapid symptomatic response to cisplatin in combination with paclitaxel in a patient with metastatic BCC, but noted late neurotoxicity.
The role of systemic chemotherapy in the era of HPI targeted therapy and immunotherapy remains to be defined.
PP 12.1.1. Patients with locoregional metastases of basal cell carcinoma should be offered surgical excision or radiotherapy if possible. It is appropriate to check for the presence of distant metastatic disease.
PP 12.1.2. Patients with distant metastatic basal cell carcinoma should be referred to a medical oncologist or multidisciplinary team for consideration of hedgehog signalling pathway inhibitor treatment.
- Paver K, Poyzer K, Burry N, Deakin M. Letter: The incidence of basal cell carcinoma and their metastases in Australia and New Zealand. Australas J Dermatol 1973 Apr;14(1):53 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/4753676.
- Dreier J, Cheng PF, Bogdan Alleman I, Gugger A, Hafner J, Tschopp A, et al. Basal cell carcinomas in a tertiary referral centre: a systematic analysis. Br J Dermatol 2014 Nov;171(5):1066-72 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/24974741.
- Lear JT, Corner C, Dziewulski P, Fife K, Ross GL, Varma S, et al. Challenges and new horizons in the management of advanced basal cell carcinoma: a UK perspective. Br J Cancer 2014 Oct 14;111(8):1476-81 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25211660.
- Ally MS, Aasi S, Wysong A, Teng C, Anderson E, Bailey-Healy I, 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 Nov;71(5):904-911.e1 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/24929884.
- Ching JA, Curtis HL, Braue JA, Kudchadkar RR, Mendoza TI, Messina JL, et al. The impact of neoadjuvant hedgehog inhibitor therapy on the surgical treatment of extensive basal cell carcinoma. Ann Plast Surg 2015 Jun;74 Suppl 4:S193-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25695449.
- Sekulic A, Migden MR, Oro AE, Dirix L, Lewis KD, Hainsworth JD, et al. Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med 2012 Jun 7;366(23):2171-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/22670903.
- Sekulic A, Migden MR, Basset-Seguin N, Garbe C, Gesierich A, Lao CD, et al. Long-term safety and efficacy of vismodegib in patients with advanced basal cell carcinoma: final update of the pivotal ERIVANCE BCC study. BMC Cancer 2017 May 16;17(1):332 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/28511673.
- Tang JY, Mackay-Wiggan JM, Aszterbaum M, Yauch RL, Lindgren J, Chang K, et al. Inhibiting the hedgehog pathway in patients with the basal-cell nevus syndrome. N Engl J Med 2012 Jun 7;366(23):2180-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/22670904.
- Migden MR, Rischin D, Schmults CD, Guminski A, Hauschild A, Lewis KD, et al. PD-1 Blockade with Cemiplimab in Advanced Cutaneous Squamous-Cell Carcinoma. N Engl J Med 2018 Jul 26;379(4):341-351 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/29863979.
- Lear JT, Migden MR, Lewis KD, Chang ALS, Guminski A, Gutzmer R, et al. Long-term efficacy and safety of sonidegib in patients with locally advanced and metastatic basal cell carcinoma: 30-month analysis of the randomized phase 2 BOLT study. J Eur Acad Dermatol Venereol 2018 Mar;32(3):372-381 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/28846163.
- Migden MR, Guminski A, Gutzmer R, Dirix L, Lewis KD, Combemale P, et al. Treatment with two different doses of sonidegib in patients with locally advanced or metastatic basal cell carcinoma (BOLT): a multicentre, randomised, double-blind phase 2 trial. Lancet Oncol 2015 Jun;16(6):716-28 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25981810.
- Sun Pharma ANZ Pty Ltd. Australian product information. Odomzo (sonidegib 200 mg capsule). [homepage on the internet] Therapeutic Goods Administration; 2016 Aug 6 [cited 2019 Aug 27]. Available from: https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2017-PI-02511-1&d=201908211016933.
- Roche Products Pty Ltd. Australian product information. Erivedge (vismodegib). [homepage on the internet] Therapeutic Goods Administration; 2018 Sep 19 [cited 2019 Aug 27]. Available from: https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2013-PI-01667-1.
- Dréno B, Kunstfeld R, Hauschild A, Fosko S, Zloty D, Labeille B, et al. Two intermittent vismodegib dosing regimens in patients with multiple basal-cell carcinomas (MIKIE): a randomised, regimen-controlled, double-blind, phase 2 trial. Lancet Oncol 2017 Mar;18(3):404-412 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/28188086.
- EviQ. Patient information - Basal cell carcinoma – sonidegib. [homepage on the internet] EviQ; Available from: https://www.eviq.org.au/medical-oncology/melanoma/non-melanoma/3410-basal-cell-carcinoma-locally-advanced-or-meta/patient-information#side-effects.
- EviQ. Patient information - Basal cell carcinoma – vismodegib. [homepage on the internet] EviQ; Available from: https://www.eviq.org.au/medical-oncology/melanoma/non-melanoma/1918-basal-cell-carcinoma-locally-advanced-or-meta/patient-information#side-effects.
- Lacouture ME, Dréno B, Ascierto PA, Dummer R, Basset-Seguin N, Fife K, et al. Characterization and Management of Hedgehog Pathway Inhibitor-Related Adverse Events in Patients With Advanced Basal Cell Carcinoma. Oncologist 2016 Oct;21(10):1218-1229 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/27511905.
- Dheeraj A, Rigby CM, O'Bryant CL, Agarwal C, Singh RP, Deep G, et al. Silibinin Treatment Inhibits the Growth of Hedgehog Inhibitor-Resistant Basal Cell Carcinoma Cells via Targeting EGFR-MAPK-Akt and Hedgehog Signaling. Photochem Photobiol 2017 Jul;93(4):999-1007 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/28120452.
- Yang X, Dinehart MS. Triple Hedgehog Pathway Inhibition for Basal Cell Carcinoma. J Clin Aesthet Dermatol 2017 Apr;10(4):47-49 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/28458774.
- Carneiro BA, Watkin WG, Mehta UK, Brockstein BE. Metastatic basal cell carcinoma: complete response to chemotherapy and associated pure red cell aplasia. Cancer Invest 2006 Jun;24(4):396-400 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16777692.
- Jefford M, Kiffer JD, Somers G, Daniel FJ, Davis ID. Metastatic basal cell carcinoma: rapid symptomatic response to cisplatin and paclitaxel. ANZ J Surg 2004 Aug;74(8):704-5 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15315581.
- Moeholt K, Aagaard H, Pfeiffer P, Hansen O. Platinum-based cytotoxic therapy in basal cell carcinoma--a review of the literature. Acta Oncol 1996;35(6):677-82 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/8938213.