EXPERIMENTAL AND CLINICAL TRANSPLANTATION

The hedgehog inhibitor vismodegib has been tested and suggested as an effective treatment option for cases of locally advanced or metastatic basal cell carcinoma. A 58-year-old female renal transplant patient with recurrent, inoperable basal-cell carcinoma that originated from nasal skin was evaluated by the transplantation counsel. After a multidisciplinary evaluation of the patient, vismodegib at a dose of 150 mg/day was started in February 2018. Her immunosuppressive regimen consisted of mycophenolate mofetil, tacrolimus, and prednisolone. At her last follow-up in July 2019, she remained disease free with no adverse effects that lowered the quality of life. Although experiences on the use of vismodegib’s efficacy and safety have been so far limited and consist of case reports in transplant patients, we experienced an excellent cosmetic result with minimal side effects in a renal transplant patient.

Key words : Basal cell skin cancer, Immunosuppression, Kidney transplantation

Although basal cell carcinoma (BCC) is the most common cancer worldwide and is rarely fatal, the incidence of BCC has been rapidly increasing.^1,2 Approximately 80% of nonmelanoma skin cancers are basal cell type. Fortunately, the vast majority of patients can be successfully treated and cured by a variety of local procedures, including topical medical treatments or simple surgical excisions. If locoregional disease is present, Mohs micrographic type therapy or more extensive surgical resections and radiation therapy are generally sufficient for cure. The use of systemic therapy has been limited to patients who are inoperable or metastatic but who cannot be adequately treated with local therapies. For this, the hedgehog inhibitor vismodegib has been tested and suggested as an effective treatment option for cases of locally advanced or metastatic BCC.³

Solid-organ transplant patients are at an increased risk of skin and some other malignancies versus the risk shown in healthy populations because of the requirement for long-term immunosuppression for maintaining tolerance of the transplanted organ.⁴ However, experiences on the use of vismodegib and its efficacy and safety have been so far limited and consist of case reports. Here, we report our experience with long-term vismodegib in a patient with recurrent and inoperable nasal BCC.

A 58-year-old female patient was referred to our medical oncology department for treatment of recurrent, inoperable nasal BCC. She received a renal transplant in 2012, and her immunosuppressive regimen consisted of mycophenolate mofetil 720 mg twice daily, tacrolimus 1 mg daily, and prednisolone 5 mg daily. The first diagnosis of BCC of the nose was in March 2015, and she subsequently underwent numerous cryotherapies and had used topical imiquimod 5% cream. In February 2018, because of the progression of the lesion, a second operation was planned (Figure 1). However, the patient refused the operation because of the comorbidities and potential cosmetic results. Because of lack of data with hedgehog inhibitors in immunosuppressive patients, the possible adverse effects, and the drug-drug interactions that may occur, we discussed other treatment options such as resurgery and radiotherapy with the patient, but she vigorously refused the operation and declared that she accepted medical management with vismodegib as the sole treatment.

After a multidisciplinary evaluation of the patient with the transplantation counsel, vismodegib at a dose of 150 mg/day was started in February 2018. During follow-up visits with medical oncology, dermatology, and nephrology, the patient complained of partial alopecia, dysgeusia, muscle cramps of legs that did not interfere with daily activities, and grade 1 fatigue. In December 2018, the patient had complete clinical response. At her last follow-up in July 2019, she remained disease free with no other reported adverse effects (Figure 2).

Compared with the general population, organ transplant patients are 6 to 16 times more prone to develop BCC.5 Reduced immunosurveillance, direct or indirect carcinogenic effects of some immunosuppressive agents (such as azathioprine or cyclosporine), and proliferation of oncogenic viruses in immunosuppressive state are probable mechanisms through which immunosuppression could lead to the development of skin malignancies.6,7 Although hedgehog pathway inhibitors have been used in locally advanced or metastatic patients since 2012, treatment of inoperable or metastatic BCC cases in transplant recipients is still a challenge, and data regarding their use in transplant recipients are limited. Here, we reported a renal transplant patient with advanced BCC who had a complete response and tolerated vismodegib quite well together with immunosuppressive agents and was still on this treatment at 19-month follow-up.

Molecular and genetic studies have shown that nearly all BCCs contain genetic alterations in the hedgehog signaling pathway. This pathway is normally inhibited by the patched homolog 1 (PTCH1), a cell surface receptor that has an inhibitory effect on signaling activity of a 7-transmembrane protein smoothened homologue (SMO).8,9 If inhibition of the hedgehog pathway is no longer present, basal cell proliferation and tumor growth can occur. Mutations of PTCH1 that prevent the inhibitory effects on SMO activation or mutations of SMO that cause constitutive activation are 2 mechanisms that may be involved in the pathogenesis of BCC via this pathway.^10,11

Vismodegib is a first-in-class small molecule inhibitor of SMO; until its approval by the US Food and Drug Administration in 2012 for patients with inoperable or metastatic BCC, there was no approved therapy for this patient group.¹² The approval was based on a phase 2 multicenter, international, parallel cohort, single-arm study that evaluated the efficacy and safety of 150 mg/day oral vismodegib in 33 patients with metastatic and 63 patients with locally advanced inoperable BCC. The study met its primary endpoint, as assessed by an independent review committee, of response rates of 30% and 43% in metastatic and locally advanced groups, respectively.³ Long-term (39 mo after completion of accrual) follow-up results demonstrated its efficacy (overall response rates of 48.5% and 60.3% in metastatic and locally advanced groups, respectively), together with median response durations of 14.8 and 26.2 months in the metastatic and locally advanced groups, respectively. Median progression-free survival was 9.3 months in the metastatic group and 12.9 months in the locally advanced group.¹³ However, transplant patients were not included in the study populations.

To our knowledge, this is the fourth case in the literature reporting vismodegib use in a transplant recipient who was receiving immunosuppressive agents. The first reported recurrent facial BCC case was a heart transplant patient who was receiving low-dose cyclosporine; the report stated that the patient had partial clinical response on vismodegib treatment and experienced fatigue, alopecia, leg cramps, and lower gastrointestinal bleeding, which were thought to be probably not related to vismodegib.⁴ The second case was a kidney and pancreas transplant patient who was receiving mycophenolate, as in our case, and who had BCC on his nasal tip. Because of cosmetic outcomes, he had insisted on nonsurgical approaches and elected to begin vismodegib. After a 6-month course, imaging results revealed a small residual lesion and vismodegib was discontinued and topical imiquimod was started.¹⁴The other report was a renal transplant patient on everolimus with recurrent BCC. After an R1 resection of the tumor, vismodegib was started as adjuvant treatment because imaging revealed no sign of residual lesions. After 6 months, vismodegib treatment was regulated on a 12-week-on and 8-week-off schedule to decrease side effects (alopecia and dysgeusia) and to improve quality of life.¹⁵

Our case is probably the longest reported experience of vismodegib use by a renal transplant patient concomitant with immunosuppressive agents. It was tolerated well by the patient, with the patient declaring that her quality of life was not negatively affected with use of this drug. Multidisciplinary evaluation and follow-up of patients who are using this agent are warranted for appropriate efficacy as both immunosuppressant and oncologic treatment. In addition, these cases have suggested that, in patients who are medically inoperable (because of either comorbidities or cosmetic reasons), oncologic treatment with vismodegib seems to be quite effective and may be a good alternative treatment option to surgery in selected cases.

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