BCC untreated. At the time of publication, 6 months after this course of treatment, there is no evidence of disease. As with other high-risk patients, he will be monitored closely.
There are significant issues in the treatment of partially resected BCCs, the most salient of which has been the lack of treatment options for patients with BCCs located near vital structures. Patients with large BCCs are a second category of patient for whom treatment options have been suboptimal to date. One consideration when considering treatment options for patients with positive margins is the fact that approximately one-third of these patients are subsequently found to have no residual tumor when repeat surgery is performed.8 Fortunately, other treatment options exist, such as topical 5-fluorouracil, topical imiquimod, photodynamic therapy, or cryotherapy.4-7 However, these options are not sufficient for locally advanced or metastatic BCCs. In January 2012, the United States Food and Drug Administration (FDA) approved vismodegib for the treatment of metastatic BCC or locally advanced BCC that has recurred after surgery, as well as for patients who are not candidates for surgery or radiation.
Patched homologue 1 (PTCH1) normally functions to inhibit smoothened (SMO) signaling. Without this inhibition, SMO induces transcription factors in basal cells that promote cell proliferation and growth. Hedgehog is key in the development of BCC by inhibiting PTCH1, and thus eliminating the inhibition of SMO, ultimately resulting in cell proliferation.9,10 Basal cell carcinomas most often result from loss of function mutations in PTCH1, but may also arise from activating mutations in SMO. The significance of vismodegib to BCC is in its ability to bind to and inhibit SMO, thereby bringing about crucial inhibition of basal cell proliferation regardless of whether the mutation is in PTCH1 or SMO.
In a phase 1 study to assess the safety and tolerability of vismodegib, 15 patients with locally advanced basal tumors, as with our patient, were enrolled. Two of these patients demonstrated complete clinical response, 7 showed partial response, 4 had stable disease, and 2 had progressive disease. In those who responded, median duration of response was 8.8 months.9 A phase 2 study to further assess efficacy and safety showed complete response in 13 patients (21%) with locally advanced BCC with a median duration of response of 7.6 months and median progression-free survival of 9.5 to 1.3 months.3
Adverse events identified during these studies included fatigue, muscle spasms, alopecia, dysgeusia, weight loss, anorexia, dyspnea, nausea, diarrhea, arthralgias, vomiting, and constipation. Three of 10 premenopausal women developed amenorrhea. Hyponatremia, azotemia, and hypokalemia were the most serious laboratory anomalies that arose. Rare events included atrial fibrillation, dyspepsia, aspiration, back pain, corneal abrasion, dehydration, keratitis, lymphopenia, pneumonia, urinary tract infection, prolonged QT interval, cholestasis, pulmonary embolism, dehydration and/or syncope, hypocalcemia, elevated alkaline phosphatase, and hyperkalemia; most of these developed in no more than one patient.3,9,11-13 All patients in the phase 2 trial experienced at least one AE.3
While the most common side effects are generally considered to be minor-to-moderate in severity, they can be unbearable for some patients. Their high frequency has resulted in many patients opting to discontinue the medication, a very unfortunate dilemma for patients in need of vismodegib as a therapeutic option. Another concern and potential limitation of vismodegib is the potential for resistance as well as a recurrence of BCC once the medication is discontinued. In one retrospective review, 21% of patients with advanced BCC experienced tumor regrowth while still on vismodegib treatment.14
Future options for these difficult to treat advanced BCCs are under study. Several inhibitors of GLI, a transcription factor downstream of SMO, have been identified.10,15,16 The antifungal itraconazole is also a Hh inhibitor and is under investigation for its applicability to BCC treatment, potentially in combination with arsenic trioxide.10 While the common AEs associated with vismodegib are thought to be a class effect of Hh inhibitors, it remains to be seen whether or not the side effects with these newer therapeutic options will be as significant or as unpleasant for patients, and how their efficacy compares to that of vismodegib.
The patient presented represents an unusual and instructive case because he presented with easily monitored disease, but no traditional treatment alternatives seemed to offer promise for disease control. The proximity of his tumor to his spinal cord mandated that some type of treatment be instituted to protect his central nervous system.
Patients with partially treated BCCs often present with similar circumstances to the patient presented in this report: they may have had Mohs surgery or other margin-controlled surgery that was not successful because of anatomic boundaries that could