(from the AHNS Cutaneous Cancer Section)
Skin Cancer is the most common malignancy that affects humans. Malignancies develop in tissues native to the skin, basal cell carcinoma (BCCA) and squamous cell carcinoma (SCCA), and those embryologically derived elsewhere that come to reside in cutaneous structures: malignant melanoma (melanocytes from neural crest) and Merkel Cell carcinoma (neuroectoderm), among others. A variety of less-common cutaneous malignancies form from adnexal and sustentacular cells.
The most common skin malignancy is BCCA, named for the cells that reside in the basal layer (stratum germinativum) of the epidermis. These cells continually divide and populate more superficial layers closer to the skin’s surface. A majority of BCCA lesions remain locally in their primary site rarely metastasizing to regional lymph nodes or distant sites. Surgical excision with negative margins is the mainstay of treatment and curative for most patients. Other local maneuvers such as curettage, cryotherapy, topical agents and, occasionally, radiation therapy, are also employed for patients with local disease. However, some experience multiple recurrences or tumors that have the potential to significantly affect function and appearance. Surgical resection can be offered in these situations, coupled with complex reconstruction that leverages free-tissue transfer techniques if needed. Resection/reconstruction can be accompanied by significant morbidity that affects quality of life, especially in those with limited life expectancies. Alternately, radiation therapy can be offered in the adjuvant setting, especially for those with large tumors or positive resection margins. Tumor response is dose-dependent. Though effective in selective cases, radiation is not particularly efficient and precludes the opportunity for additional pathologic review if the patient has a complete response. Additional tumor analysis may prove to be important for risk stratification and to define potential targets of future therapeutics.
The last decade has seen a rapid rise in the use of systemic therapies for locally advanced, recurrent, and metastatic malignancies involving the head and neck. Both cemiplimab and pembrolizumab have FDA approval for treatment of cutaneous SCCA. Cytotoxic platinum-based chemotherapy and others have been used for many years preceding these recent approvals. Cytotoxic therapies have demonstrated mixed local efficacy in the treatment of BCCA, especially when combined with taxanes and ifosfamide, though survival benefits have not been shown. As such, efforts to elucidate other targets for systemic therapies were undertaken. In 1980, the Hedgehog (Hh) signaling pathway was described in the Drosophila melanogaster model and was shown to play a critical role in normal stem cell differentiation. This pathway is normally not active after embryogenesis. Ligand-independent aberrant signaling was subsequently described in patients with Basal Cell Nevus Syndrome. BCCA was the first malignancy shown to exhibit abnormal Hh signaling, and is observed in 95% of patients with sporadic BCCA. Dysregulation in this pathway results in uncontrolled proliferation of basal cells. Several agents have been developed to block this aberrant pathway via the Smoothened (SMO) G-protein-coupled receptor. Cyclopamine was the first, but demonstrated limited in vivo activity. Several synthetic small molecule inhibitors of SMO have been evaluated. Vismodegib (Erivedge) received FDA approval in January 2012. Indications for its use include treatment of locally advanced BCCA in those who are not surgical candidates or who have failed radiation or have technically unresectable disease. Vismodegib is an oral agent taken once daily. Its side effects include fatigue, anorexia and weight loss, and muscle spasms. Patients may be able to tolerate treatment for many months and then need to take breaks from therapy as these side effects can be cumulative and significantly reduce quality of life in these patients seeking long-term palliation. Partial response rates range between 40% and 70%. Aggressive tumor regrowth following discontinuation of the drug has been reported. The optimal length of therapy is not known. Recent work has defined a possible role for Hh inhibition in the neoadjuvant setting, allowing for smaller resections, smaller radiation fields, or de-escalation of radiation dose
Sonidegib (Odomzo), also an oral therapeutic, is another small molecule inhibitor of the Hh pathway with observed rates approaching 60%. It was approved for use in July 2015. It has a similar side-effect profile to vismodegib. The monthly cost for these Hh inhibitor therapies can approach $13,000.00.
Most recently, cemiplimab (Libtayo) was approved for patients with advanced BCCA previously treated with Hh inhibitors or if Hh inhibitor therapy is contraindicated. It is delivered intravenously. The efficacy study leading to its approval reported a 29% response rate durable to approximately 6 months. Its cost approaches $10,000.00 monthly.
We met one of our favorite older patients having been treated for multiply recurrent BCCA of the left auricular/post-auricular skin. He had multiple comorbidities. He had undergone treatment by multiple clinicians including general dermatology, Mohs surgeons, general otolaryngologists, neurotologists, and radiation oncology. His treatment included multiple surgeries, topical agents (imiquamod) and radiation (60Gy). He had significant pain, especially near the temporomandibular joint, recurrent infection requiring frequent systemic antibiotics, and spontaneous bleeding that was robust. At our evaluation, dense, friable tumor measuring 8.2cm was present involving the auricular remnant and surrounding skin, including the upper neck, and middle ear. There was no purulence or bleeding. No lymph nodes were palpable. His cranial nerve exam was normal other than subjective hearing loss. A contrast enhanced CT scan confirmed a peri-auricular tumor mass involving the lateral temporal bone structures and lateral aspect of the TMJ. His previous pathology specimens were re-examined to confirm a diagnosis of BCCA and rule out attendant squamous cell carcinoma. Our radiation and medical oncology colleagues were consulted and he was discussed during our interdisciplinary head and neck tumor conference. Resection and free-tissue transfer for reconstruction were offered. A series of long discussions with him shed light on his goals of therapy: controlling pain and reducing the frequency of bleeding episodes and infection (improving cleanliness). He did not want to undergo surgery. Vismodegib therapy was instituted. Within three weeks of initiation, his pain improved, especially around his TMJ, and bleeding from his tumor stopped. He cancelled a planned CT scan at 8 weeks; satisfied that he was improving symptomatically. After 4 months of therapy, with excellent compliance, he decided to discontinue therapy because of increasing and profound fatigue and anorexia. He also was quite concerned about the monthly copays that he was required to pay for his treatment. His pain, bleeding, and purulent discharge returned again about 3 weeks later. He restarted therapy again approximately five weeks later. His pain and bleeding again quickly abated.
Our patient repeated this on-treatment/off-treatment cycle 3 more times over the next two years. When he was off treatment, he required home nursing to help him with his difficult wound. He eventually elected not to restart therapy and died a month later supported by home hospice staff of unsupported anemia and infection. Our experience with him illustrates the significant positive and negative impact targeted agents potentially have and, as such, the role they can play in the long-term palliation of patients with locally advanced BCC involving critical head and neck structures.
The preceding discussion may prompt some salient discussion points:
- There are multiple systemic treatment strategies available to treat these challenging patients. Each has its own unique risk/benefit (and significant cost) profile.
- There is heightened need to understand the molecular underpinnings of the carcinogenesis of cutaneous basal cells. Future discovery will positively affect millions of people worldwide. More importantly, are there “upstream” targets for prevention of this widespread disease?
- Many types of clinicians with diverse training backgrounds could potentially treat patients with advanced BCCA with therapies that have complicated risk profiles. Robust, peer-reviewed interdisciplinary team discussion, so valued in the delivery of care of other head and neck cancer patients, is now requisite for patients with cutaneous malignancy, including those with BCCA. Decision-making and treatment not informed by such a process will prove to be dated and dangerous.
- Pellegrini, C.; Maturo, M.G.; Di Nardo, L.; Ciciarelli, V.; Gutiérrez García-Rodrigo, C.; Fargnoli, M.C. Understanding the Molecular Genetics of Basal Cell Carcinoma. J. Mol. Sci.2017, 18, 2485.
- Koelblinger P, Lang R. New developments in the treatment of basal cell carcinoma: update on current and emerging treatment options with a focus on vismodegib. Onco Targets Ther. 2018;11:8327-8340.
- Sekulic A, Migden MR, Basset-Seguin N et al. . Correction to: Long-term safety and efficacy of vismodegib in patients with advanced basal cell carcinoma: final update of the pivotal ERIVANCE BCC study. BMC Cancer2019; 19: 366.
- Chen L, Aria AB, Silapunt S, et al. Treatment of advanced basal cell carcinoma with sonidegib: perspective from the 30-month update of the BOLT trial. Future Oncology 2017;16(6):515-525.
- Enrico Zelin, Iris Zalaudek, Marina Agozzino, Caterina Dianzani, Arianna Dri, Nicola Di Meo, Roberta Giuffrida, Giovanni Francesco Marangi, Nicoleta Neagu, Paolo Persichetti, Ludovica Toffoli, Claudio Conforti Curr Treat Options Oncol. 2021; 22(4): 35. Published online 2021 Mar 16. doi: 10.1007/s11864-021-00826-3.
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