Despite increased insight on skin cancer risk factors, the incidence continues to rise worldwide. This review article summarizes new treatment options available, which help to redefine and expand the diagnosis of advanced BCC and allow dermatologists to offer more effective therapy to a broader population.
Basal cell carcinoma (BCC) is the most commonly diagnosed cancer and the most common skin cancer in the world1-5. Despite increased insight on skin cancer risk factors, including excessive sun exposure and indoor tanning, the incidence of skin cancer continues to rise worldwide, particularly in younger populations6. In a recent study, it was estimated that more than four million cases are diagnosed annually in the United States alone6. Given the widespread prevalence of this disease, there is a substantial impact on overall patient morbidity and quality of life7-9. Similarly, medical treatment for skin cancer accounts for a considerable amount of healthcare expenditures and is often a large financial burden to patients and their families. As such, improved screening and treatment options are imperative to reduce the cost and to refine the outcome of this rising problem.
The prognosis for most patients with BCC is good as these tumors are generally slow growing and amenable to treatment if found early. There is much literature on the treatment of superficial BCCs with non-surgical therapies10-11. These treatments are generally well tolerated, with adverse effects limited to the treatment site. The majority of other BCC subtypes are treated with surgery10-11. Radiation therapy provides an alternative treatment option for some patients who do not desire surgery. However, radiation is associated with many adverse effects, including tissue necrosis, skin atrophy, and new primary tumor development12. In addition, the cosmetic results of radiation can worsen over time, making this a less attractive option10-12. With these drawbacks, radiation therapy is not recommended for patients under 50 years of age.
Despite the fact that the majority of BCCs are rarely fatal, a small subset can become destructive with significant tissue involvement11. Traditionally, advanced BCC refers to lesions that are invasive or metastatic, and not amenable to surgical or radiation therapy11. Recurrent BCCs are also considered complex, especially in patients with inherited conditions resulting in multiple tumors. Clinical management of these advanced BCCs is complicated as nonsurgical approaches are usually inadequate, and surgical management can result in considerable deformity. Fortunately, by definition these complex cases are extremely uncommon, with locally advanced disease accounting for 0.8% of all BCC and metastatic disease for 0.04%13. Many of these patients are in the geriatric age range with multiple medical comorbidities, thus at times a palliative, or a ‘watch and wait’ approach, is taken. However, for patients who do seek treatment, options are limited. Until recently, no systemic therapy was approved for advanced BCC, and patients were treated mainly with cisplatin alone or in combination with other chemotherapies14. These were associated with many unfavorable side effects and limited efficacy. There now exists an alternative targeted therapy, specifically inhibitors of the hedgehog-signaling pathway, which serves as an option for these patients.
Molecular studies have shown that more than 90% of patients with BCC have a mutation in the hedgehog-signaling pathway15. Usually, this mutation causes loss of function of patched homologue 1 (PTCH1), which normally acts to inhibit the signaling activity of smoothened homologue (SMO)16. Vismodegib (Erivdege, Genentech) is a first-in-class, small molecule inhibitor of SMO, approved for the treatment of locally advanced and metastatic BCC’s that are not amenable for surgery or radiotherapy15,16. A second inhibitor, sonidegib, was also recently approved for the same patient group with locally advanced BCC.
The most common adverse effects associated with Vismodegib include muscle spasm, arthralgia, alopecia, dysgeusia, weight loss, fatigue, nausea, vomiting, and diarrhea10,11,15,16. Although side effects are commonly reported, they are generally manageable with dose adjustments. In addition, these side effects usually have a delayed onset compared to cytotoxic chemotherapy. For example, alopecia occurs in 46-66% of vismodegib-treated patients, but it has been found to develop after at least two months of treatment17. Another study showed that the median time to first onset of common adverse events were 2.83 months for muscle spasms, 5.55 months for alopecia, and 6.51 months for dysgeusia18. Accordingly, by limiting the duration of therapy, we are able to decrease the incidence of these adverse events. For patients who need long-term treatment, such as patients with Gorlin’s syndrome, there are currently clinical studies being done to assess whether alternative-dosing regimens could increase tolerability and minimize patient dropout due to adverse events18.
Optical Coherence Tomography (OCT), a non-invasive imaging technique, permits the real-time detection and assessment of a variety of skin lesions. This device allows for high-resolution visualization of the tissue microarchitecture in the same plane as traditional histological cuts and up to a depth of two millimeters19-24. Many studies have established that these images are sufficiently detailed for identification of morphological criteria for BCC and other non-melanoma skin cancers (NMSC)19-24.
One aspect of which OCT is specifically useful is to evaluate the treatment success of orally administered hedgehog-inhibitors, such as vismodegib. The detection of residual BCC during or after treatment can be a challenge, as there is usually remaining scar tissue, which may cause residual tumor to be missed on clinical examination. Performing biopsies to confirm clearance is often not feasible since the area is either too large, or the patient has multiple tumors. One study used high definition OCT (HD OCT) to noninvasively monitor BCC after treatment with a hedgehog-inhibitor, and found that not only did all the typical features of BCC disappear upon tumor regression, but there was also the occurrence of pseudocysts, which corresponded to histologic findings of necrotic and fibrotic material where tumor nodules had previously existed25. Non-invasive imaging helps us to monitor lesion clearance and to tailor treatment appropriately. In addition, it allows us to research the link between treatment modality and resolution of BCC.
With the increasing incidence of BCC skin cancers, especially in younger populations, as well as the recent availability of novel treatments, it is beneficial to redefine the diagnosis of advanced BCC. A UK-based group of multidisciplinary experts came up with a new definition of advanced BCC to include ‘Basal cell carcinoma of the American Joint Committee on Cancer (AJCC) stage II or above, in which current treatment modalities are considered potentially contraindicated by clinical or patient-driven factors’11,26.
While this is a good initiative, a consensus definition for diagnosis is still needed.
To assess the complexity of BCC, they propose to look at factors such as size of the tumor, location on the body, and the histological subtype. For example, a facial BCC may be clinically small in size and therefore not considered advanced according to standard terminology. However, BCCs amenable to surgery that are located in the high-risk area (H-Zone), which includes the eyelids, nose, ear, chin, lips, mandible, periorbital, pre- and post- auricular skin, will still result in a less than ideal cosmetic outcome27.
It is also vital to be mindful of patient factors such as age and the presence of other comorbidities11,26. An elderly and/or frail patient with other medical conditions would not be a candidate for surgery, especially for large excisions requiring anesthesia. At the other end of the spectrum, radiation therapy is not a suitable option in patients under 50 years of age or in the immunocompromised population due to the increased risk of BCC recurrence11.
Lastly, a critical component to consider is the patient’s opinion on treatment and how it will impact their physical and emotional well-being.
With new treatment options available, redefining and expanding the diagnosis of advanced BCC allows us to offer more efficacious therapy to a broader population. Vismodegib offers patients a noninvasive alternative treatment of their advanced BCC. By combining this new remedy with imaging modalities, we can monitor the size of the lesion prior to surgical intervention, and thereby decrease the cosmetic impact of treatment while increasing patient satisfaction. In addition, by incorporating other therapies with vismodegib, patients may be eligible to undergo a shortened treatment length, further limiting adverse events. These variables are especially valuable in younger and more cosmetically concerned populations.
There are several case reports and pilot studies that demonstrate the usefulness of hedgehog-inhibitor therapy in this redefined group. Markowitz et. al report a case of a 54-year-old Caucasian man with a history of kidney and pancreatic transplants, on prednisone and mycophenolate mofetil suppressive therapy. He presented with a 1-cm pearly nodule on his nasal tip, that was biopsy proven infiltrative, nodular BCC. His local dermatologist recommended surgical Mohs excision with a paramedian forehead reconstructive nose skin flap as treatment. Hesitant about the cosmetic outcome, he sought a second opinion for a non-surgical approach. By combining continuous non-invasive lesion monitoring with vismodegib 150 mg once daily therapy and adjuvant imiquimod 5% topical cream, the patient showed complete disease clearance on clinical, OCT, and histological evaluation for currently over two years. This demonstrates the use of non-invasive imaging to tailor treatment in an advanced BCC patient who otherwise would have required an extensive surgery.
Another small study comprised of patients with biopsy proven BCC who were eligible for surgical removal, showed that neoadjuvant treatment with vismodegib for an average of four months before surgery reduced tumor area and surgical defect size28. Efficacy was duration dependent, and a minimum of three months of vismodegib was required28. Reducing the size of tumors, especially in high-risk locations, allows for wider surgical margins to be maintained, while also improving cosmetic results.
Complex cases of advanced or recurrent BCC continue to pose a significant management challenge for clinicians today. The promising results that have been shown in studies using hedgehog-inhibitors thus far, especially in a disease in which other systemic treatment options are limited, forces us to redefine and broaden the definition of advanced BCC. It is imperative for physicians to invest a continued interest in utilizing non-invasive oral therapy either alone or in combination with local therapy, surgery and/or radiation therapy for treatment of advanced BCCs, to reduce morbidity associated with treatment.
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Dr. Markowitz is a principal investigator for Michelson Diagnostics. Dr. Levine has no relevant conflicts of interest to declare. Both are affiliated with SUNY Downstate Medical Center, Brooklyn, New York; New York Harbor Healthcare System, Brooklyn, New York; Mount Sinai Medical Center, New York, New York.