Itraconazole and Vismodegib Combination for Basal Cell Carcinoma by Jeffrey Dach MD
The three most common skin cancers are squamous cell, basal cell and melanoma. Squamous cell and basal cell cancers are very curable when excized by the local dermatologist. If the patient either declines surgical excision, or is not a good surgical candidate, then medical treatment is the next option.
In this article we will discuss the extraordinary cure of two patients, both with large recurrent basal cell skin cancers, using in integrative oncology approach with two hedgehog inhibitor drugs. The first drug is vismodegib, FDA approved in 2012 specifically for basal cell carcinoma, and the second drug is itraconazole (FDA approved 2001), an old anti-fungal drug called Sporanox, repurposed as an anticancer drug. Both drugs are excellent hedgehog inhibitors, synergistic because they use different mechanisms. Inhibition of the hedgehog pathway is the key to curing basal cell carcinoma. (13-16)
Header Image: Boulevard Montmartre, Spring, 1897 oil on canvas, by Camille Pissarro (1830–1903) Courtauld Institute of Art. Image is in the public domain. Wikimedia Commons.
The problem with using vismodegib alone at the high dosage recommended is the high rate of adverse side effects, muscle spasm, fatigue, alopecia (hair loss), dysgeusia (a taste disorder), and weight loss which limit its use. In 2021, Dr. Jaeyoung Yoon from Wentzville, Missouri devised a clever way to allow reduction of vismodegib dosage by combining with itraconazole, an old anti-fungal drug repurposed as an anti-cancer drug. Now with this lower dosage of vismodegib, the medical treatment becomes feasible with very tolerable, minimal side effects. These are two case reports by Dr. Jaeyoung Yoon, a conventionl dermatologist who uses an integrative oncology approach for these two patients. (1)
Case Number One
An 84-year-old man was seen in the clinic for Basal Cell Carcinoma of the chin (See below figure 1). This is a recurrence of a large fixed ulcerated tumor two years after surgical resection (Mohs micrographic surgery) for the original basal cell cancer. Because the patient declined any further surgery, he was treated with vismodegib 150 mg once per week and itraconazole 200 mg/day. The very large and deep lesion was completely healed after 12 weeks of treatment. This patient experienced body hair loss and muscle spasms of the legs, which were described as mild and tolerable. There were no laboratory abnormalities throughout the treatment. See Images Below for: Complete clearing of deep ulcerating basal cell carcinoma of chin after 12 weeks of treatment with vismodegib 150 mg once per week and itraconazole 200 mg/day.
Case Number One: Fig 1. Deep recurrent Basal Cell Carcinoma left chin treated with vismodegib 150 mg once per week and itraconazole 200 mg/day. Panel A, Before treatment. Panel B, 4 weeks after starting treatment. C, 12 weeks after starting treatment. D, 16 months Courtesy of Yoon, (2021). (1)
Case Number Two
Case Number Two is an 85-year-old male with a large basal cell carcinoma of the right ear. He was offered Mohs micrographic surgery, but was concerned about cosmetic appearance and asked for medical treatment. The patient was treated with vismodegib 150 mg twice a week (Mondays and Fridays) and itraconazole 100 mg/day. See images below showing almost complete clearing of large basal cell carcinoma of ear after 8 weeks of treatment with vismodegib and itraconazole. There were no adverse side effects at all reported by this patient.
Left Image: Case Number Two (fig. 2 Yoon, (2021) showing large basal cell carcinoma right ear before treatment (Panel A, Red ellipse). Panel A, Pre-treatment. Panel B, 8 weeks of treatment. Panel C, 16 weeks of treatment. Panel D, 16 months after the initiation of therapy.
Conclusion: These two cases highlight the efforts of a local dermatologist to embrace integrative oncology concepts by combining two synergistic hedgehog inhibitor drugs to obtain greater efficacy with fewer side effects, with excellent results in these two cases. (1-42)
Read more about using repurposed drugs to treat cancer in my book (left image) available on Amazon, Cracking Cancer Toolkit.
Jeffrey Dach MD
7450 Griffin Road, Suite 190
Davie, Fl 33314
954-792-4663
my blog: www.jeffreydachmd.com
References for Basal Cell Carcinoma
1) Yoon, Jaeyoung. “Vismodegib dose reduction effective when combined with itraconazole for the treatment of advanced basal cell carcinoma.” JAAD Case Reports 7 (2021): 107-109.
Limitations of vismodegib are the side effects experienced by most patients. Over half of the patients have mild-to-moderate adverse events, and 21.2% of the patients discontinued therapy due to this in the international, multicenter, single arm, phase II ERIVANCE BCC clinical trial by Genentech.4 The most common side effects are muscle spasm, fatigue, alopecia, dysgeusia, and weight loss.
An 84-year-old man was seen in the clinic for a BCC of the left chin (Fig 1, A), which recurred 2 years after Mohs micrographic surgery. He presented with a large, fixed, ulcerated, firm tumor. Magnetic resonance imaging showed the tumor approximating the bone. He refused surgery given his age and the possibility of an extensive surgical intervention. He was administered vismodegib 150 mg once per week and itraconazole 200 mg/day.
see photos
Notable clinical improvement was observed after 4 weeks of treatment (Fig 1, B). After 12 weeks, the area was completely healed, and the tissue was more supple (Fig 1, C). He continued the medications for a total of 28 weeks. His last follow-up was 16 months after the initiation of treatment, and there was no clinical evidence of tumor progression (Fig 1, D).
This patient experienced body hair loss and muscle spasms of the legs, which were described as mild and tolerable. There were no laboratory abnormalities throughout the treatment.
USE THIS Protocol for Pt w/basal cell metastatic
Case 2 – He was placed on
vismodegib 150 mg twice a week (Mondays and Fridays) and
itraconazole 100 mg/day.
The patient in case 2 denied any adverse effects at all.
An 85-year-old man presented for Mohs micrographic surgery for a large BCC on his right ear (Fig 2, A). He was concerned about the risk of deformity and asked for an alternative treatment. He was placed on vismodegib 150 mg twice a week (Mondays and Fridays) and itraconazole 100 mg/day.
Case 2 – He was placed on
vismodegib 150 mg twice a week (Mondays and Fridays) and itraconazole 100 mg/day. The patient in case 2 denied any adverse effects at all.
He was administered vismodegib 150 mg once per week and itraconazole 200 mg/day.
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2) Patil, Nitin Krishna, and Aditya Kumar Bubna. “Substantial reduction of basal cell carcinoma tumor size with itraconazole following treatment failure with intralesional 5-fluorouracil.” Journal of the Egyptian Women’s Dermatologic Society 20.1 (2023): 60-62.
The patient was then started on itraconazole (100 mg twice daily) for 8 months. At the end of 4 months, surface changes of the growth could be appreciated (Fig. 1d),
Kim et al. [4] in their report outlined clinical outcomes following institution of itraconazole monotherapy (dosing: 100 mg OD to 200 mg BD) for BCC for a period of 1–12 months. Of these, 57 primary BCCs in eight patients demonstrated a mean area reduction of 24%.
Another report from Poland elaborated slight clinical improvement following oral itraconazole monotherapy for locally advanced facial BCC in a 70-year-old man. Skin lesions in this patient stopped seeping, and
temporal ulceration had healed partially following 8 months of treatment with itraconazole [5].
Ip and McKerrow [6] though did not demonstrate profitability of itraconazole (200 mg/day) for cutaneous BCC. However, they did elucidate 30% reduction of pulmonary metastasis secondary to BCC, following itraconazole administration.
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YOON COmplete Regression
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Yoon [7] reported complete regression of advanced facial BCC in two patients following low-dose vismodegib (150 mg once/twice per week) and itraconazole (100–200 mg/day).
After studying these reports, itraconazole definitely seems to hold promise as a new player for BCC therapy. However, one striking observation was that itraconazole monotherapy was ineffective in bringing about complete regression of the tumor, similar to our
finding. Only the report where vismodegib (low dose) and itraconazole were combined, was complete tumor remission obtained. So, whether itraconazole could be utilized as a valuable adjunct along with other treatments (medical and/or surgical) is something worth contemplating upon.
Currently, the exact duration of treatment with itraconazole for BCC has not been determined. Moreover, chronic administration of itraconazole, as well as likely adverse effects following its long-term intake, needs careful study. A report of Aspergillus spondylodiscitis in a patient with acute myeloid leukemia receiving 600–900 mg of itraconazole per day, however, elucidated a manageable toxicity profile [8].
At present, our patient is being maintained on itraconazole (100 mg Q12H), and even after a year of follow-up, there has neither been any increase or reduction in tumor size as when observed after 8 months of initiation of therapy. Besides, our patient is tolerating the drug well, without any untoward effects. Based on our findings, we suggest that itraconazole can be considered a second-line agent in certain cases of BCC, especially in those scenarios where access to surgery/radiotherapy (for BCC) is not available or when patients decline surgery or are unsuitable candidates for the same.
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3) Ip, Ken Hiu‐Kan, and Kevin McKerrow. “Itraconazole in the treatment of basal cell carcinoma: A case‐based review of the literature.” Australasian Journal of Dermatology 62.3 (2021): 394-397.
4) Li, Chun-Lan, et al. “Repurposed itraconazole for use in the treatment of malignancies as a promising therapeutic strategy.” Biomedicine & Pharmacotherapy 154 (2022): 113616.
5) Freitas, Raiza Dias, et al. “Inhibition of CAL27 oral squamous carcinoma cell by targeting hedgehog pathway with vismodegib or itraconazole.” Frontiers in Oncology 10 (2020): 563838.
6) El-Sheridy, Nabila A., et al. “Itraconazole for topical treatment of skin carcinogenesis: efficacy enhancement by lipid Nanocapsule formulations.” Journal of Biomedical Nanotechnology 18.1 (2022): 97-111.
7) Ramelyte, E., et al. “How to break resistance to hedgehog inhibitors in advanced basal cell carcinoma?.” British Journal of Dermatology 184.2 (2021): 359-361.
8) Svoboda, Steven A., Nathan M. Johnson, and Mariana A. Phillips. “Systemic Targeted Treatments for Basal Cell Carcinoma.” Cutis 109.6 (2022).
An open-label, exploratory phase 2 trial of 19 patients with BCC found that oral itraconazole 200 to 400 mg daily.
decreased tumor proliferative index by 45% (P=.04), as measured by Ki-67; SHH activity by 65% (P=.03), as measured by GLI1 messenger RNA; and mean tumor area by 24%.73 In a case series of 5 patients with mBCC refractory to conventional SHH inhibitor therapy, combined treatment with itraconazole and arsenic trioxide resulted in stable disease and a 75% reduction in SHH activity (P<.001).74 One case report documented tumor regression leading to stable disease for 15 months in a patient with laBCC treated with itraconazole monotherapy due to being unable to afford vismodegib or sonidegib. However, within 2 months of treatment discontinuation, the lesion progressed considerably.75 The efficacy of a topical formulation of itraconazole also has been tested in an open-label, placebo-controlled phase 2 trial, but no benefit was observed.76
Posaconazole is a second-generation antifungal agent that may serve as a potential alternative to itraconazole.77 Although clinical data are lacking, a basic science study
found that posaconazole could inhibit the growth of SHH-dependent BCC in vivo (in mice).78 Furthermore, posaconazole has demonstrated a better safety profile
with fewer and more mild side effects than itraconazole and does not require dose adjustment for those with hepatic or renal failure.79,80 Thus, posaconazole may be a
safer alternative to itraconazole for the treatment of BCC. Further clinical studies are needed to elucidate the potential synergistic effects of these antifungal agents with the
2 currently approved SHH inhibitors for the treatment of advanced BCC.
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9) Marzagalli, Monica, et al. “Estrogen receptor β in melanoma: from molecular insights to potential clinical utility.” Frontiers in endocrinology 7 (2016): 140.
In vitro and in vivo antitumor effects on melanoma were also reported for 2-methoxyestradiol, an endogenous metabolite of estradiol; however, it must be pointed out that the antitumor activity of this compound was not found to be mediated by ERs (both α and β) activation (123, 124).
10) Dobos J, Timar J, Bocsi J, Burian Z, Nagy K, Barna G, et al. In vitro and in vivo
antitumor effect of 2-methoxyestradiol on human melanoma. Int J Cancer (2004) 112:771–6. doi:10.1002/ijc.20473
11) Ireson CR, Chander SK, Purohit A, Perera S, Newman SP, Parish D, et al.
Pharmacokinetics and efficacy of 2-methoxyoestradiol and 2-methoxyoestradiol-bis-sulphamate in vivo in rodents. Br J Cancer (2004) 90:932–7. doi:10.1038/sj.bjc.6601591
12) Chen, Baozhi, et al. “Posaconazole, a second-generation triazole antifungal drug, inhibits the hedgehog signaling pathway and progression of basal cell carcinoma.” Molecular cancer therapeutics 15.5 (2016): 866-876.
13) Bakshi, Anshika, et al. “Basal cell carcinoma pathogenesis and therapy involving hedgehog signaling and beyond.” Molecular carcinogenesis 56.12 (2017): 2543-2557.
14) Gambini, Donatella, et al. “Basal cell carcinoma and hedgehog pathway inhibitors: focus on immune response.” Frontiers in Medicine 9 (2022): 893063.
15) Cocuz, Iuliu Gabriel, et al. “Pathophysiology, Histopathology, and Differential Diagnostics of Basal Cell Carcinoma and Cutaneous Squamous Cell Carcinoma—An Update from the Pathologist’s Point of View.” International Journal of Molecular Sciences 25.4 (2024): 2220.
16) Bengoa-González, Alvaro, et al. “Advanced Periocular Basal Cell Carcinoma with Orbital Invasion: Update on Management and Treatment Advances.” Journal of Ophthalmology 2024.1 (2024): 4347707.
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Fenofibrate
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O’Neill, W. Quinn, et al. “Repositioning fenofibrate to reactivate p53 and reprogram the tumor-immune microenvironment in HPV+ head and neck squamous cell carcinoma.” Cancers 14.2 (2022): 282.
Su, Tzu-Rong, et al. “Fenofibrate diminishes the self-renewal and metastasis potentials of oral carcinoma stem cells through NF-κB signaling.” Journal of the Formosan Medical Association 121.10 (2022): 1900-1907.
Fenofibrate OXPHOS inhibitor, 400 mg per day with evening meal.Plus Vitamin A, 25,000 to 50,000 iu/day
autophagy inhibitors enhance FF-induced glioblastoma cytotoxicity.
The combination of OXPHOS inhibitor fenofibrate with a GLYCOLYSIS inhibitor (such as DCA, diclofenac or quercetin), an autophagy inhibitor (such as hydroxychloroquine, loratidine, thymoquinone, etc.) and a microtubule inhibitor (such as mebendazole) might prove synergistic…
Be Careful with fenofibrate/Ivermectin combination both oxphas inhibitor with mitochonrial toxicity.
39) Jan, Chia-Ing, et al. “Fenofibrate suppresses oral tumorigenesis via reprogramming metabolic processes: potential drug repurposing for oral cancer.” International journal of biological sciences 12.7 (2016): 786.
40) Chang, Nai Wen, et al. “Fenofibrate exhibits a high potential to suppress the formation of squamous cell carcinoma in an oral-specific 4-nitroquinoline 1-oxide/arecoline mouse model.” Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease 1812.4 (2011): 558-564.
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ER-Beta (Estriol-ER-Beta) (Premarin Bring Steroids ER-Beta) (Prometrium downregulates ER Alpha) (Androgens – 3BetaDiol)
41) Mancuso, M., et al. “Modulation of basal and squamous cell carcinoma by endogenous estrogen in mouse models of skin cancer.” Carcinogenesis 30.2 (2009): 340-347.
These and previous data from studies in rodents (30) suggest that estrogens may be key modulators of skin tumorigenesis. The effects of estrogens are mediated by estrogen receptor (ER)-a and ERb, members of the nuclear steroid receptor superfamily. Both ERs have been detected in the skin of rodents and humans, though with distinct expression patterns (36); specifically, ERb has been indicated as the predominant ER in human scalp skin (37), whereas in murine skin both ERs are expressed during hair follicle cycling in hair cycle-dependent manner (38).
In ovariectomized Ptch1þ/ and Car-S females, basal and squamous tumor induction were drastically increased over intact controls (CNs), and restored to levels observed in males, showing that endogenous estrogens play a critical role in protection against BCC and SCC carcinogenesis by diverse agents in mouse skin.
The skin locally synthesizes significant amounts of sexual hormones with intracrine or paracrine actions. However, the local level of each sexual steroid depends on the expression of androgen-and estrogen-synthesizing enzymes in different cell types (50). The role of estrogen in the regulation of hair follicle cycling in mice was rediscovered in the past decade, following a seminal paper by Oh et al. (33), showing that an ER pathway within the dermal papilla regulates the telogen–anagen follicle transition and that 17-b-estradiol blocks hair growth and arrests hair follicles in telogen.
Experimental data from the present study support the concept that
female sex hormones can be protective in non-melanoma skin carcinogenesis; in fact, we found that skin tumor development was significantly enhanced after ovarian hormone withdrawal in two independent experimental models. The results shown here demonstrate increased skin tumor incidence and multiplicity and decreased tumor latency in ovariectomized versus CN females, regardless of the nature of the keratinocyte-initiating agent (i.e. chemical for SCC and physical for BCC). Remarkably, malignant progression of benign papillomas to SCC occurred almost exclusively in OVX Car-S and was rare in CN females following two-stage carcinogenesis by DMBA/TPA.
To shed light on potential mechanisms involved in estrogen modulation of skin tumor progression, we examined ER protein levels in benign skin papillomas from the different Car-S groups. Immunoblots of papilloma extracts showed significantly increased expression of ERa and downregulation of ERb in tumors from OVX relative to
CN tumors, suggesting a role of the ratio ERa:ERb in susceptibility of skin to estrogen-modulated carcinogenesis, and a correlation of decreased ERb expression with increased malignant progression of initially benign papillomas in ovariectomized Car-S mice.
Previous studies have established a complex relationship between ERs and cyclin D1, with important implications for proliferation of estrogen-responsive tissues and deregulation of proliferation in cancer (42,43). To further explore this issue, we analyzed tumors for expression of cyclin D1, which among D-type cyclins controlling cell cycle regulation has been most directly implicated in oncogenesis. In the presence of estrogen, cyclin D1 is one important target gene through which estrogen-complexed ERa mediates its proliferative action, whereas estrogen-complexed ERb represses cyclin D1 gene transcription and blocks ERa-mediated induction when both receptors are present (56).
In the absence of estrogen, however, cyclin D1 is able to bind to and activate transcription mediated by ER-alpha (42,43,57). Significantly, we detected cyclin D1 upregulation in tumors from OVX relative to CN mice. Thus, our results suggest that in tumors from intact mice, where the ratio ERa:ERb is low, the protective role of ER-beta may be privileged over the proliferation stimulus mediated by the a-isoform, whereas in tumors from ovariectomized animals, the inverted ERa:ERb ratio may favor proliferation and malignant progression, possibly due to the oncogenic role of cyclin D1. This hypothesis is supported by the higher proliferation rate observed in papillomas from OVX compared with intact CN mice, a finding also observed in ER-positive breast cancer, where high cyclin D1 expression correlates with high Ki67 expression (58). We cannot exclude, however, that ovariectomy may modulate other factors involved in the regulation of skin development and functions, such as progesterone levels (59) and that this modulation may in turn influence tumor development.
In summary, our study shows for the first time a protective role of endogenous estrogen against basal and squamous skin tumorigenesis caused by physical or chemical agents in independent mouse models Finally, our study suggests that reciprocal expression of ERa and ERb may be associated with estrogen-mediated modulation of squamous epithelial carcinogenesis, with a key role played by cyclin D1.
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Cracking Cancer
Itraconazole, also known as Sporonox, is a common antifungal drug developed in the
1980s, usually prescribed as 100 mg or 200 mg oral capsules with daily dosage in the 100–600 mg range. Itraconazole is well tolerated when used long term to prevent or treat chronic fungal infection in immunosuppressed patients.
Four hundred milligrams per day for a year is not uncommon for chronic pulmonary aspergillosis or blastomycosis, both fungal infections.
Human dosage required to achieve anti-cancer levels used in animal studies is in the 600–900 mg per day range. (1–2)
Itraconazole has been in clinical use for 30 years with an established safety record.
Multiple phase 2 clinical trials investigating itraconazole for non-small-cell lung cancer,
prostate cancer, and basal cell carcinoma have been completed, showing an increase in progression- free and overall survival. (3–7)
Phase 2 Trial for Basal Skin Cancer Itraconazole
In 2014, a phase two trial of oral itraconazole for basal cell carcinoma was reported by
Dr. Daniel Kim et al., yielding impressive results in 19 patients placed into two groups receiving either 200 mg a day or 400 mg a day of the itraconazole drug for 1–3 months. Cancer cell proliferation was reduced by 65%, Hedgehog (Hh) activity reduced by 65%, and tumor area reduced by 24%. (56)
Both basal cell and squamous cell types of skin cancer show upregulation of the hedgehog/
GLI pathway. High expression of the Hh pathway is a prognostic factor that confers a
poor overall survival. The Hh/Gli pathway is inhibited by itraconazole, thus serving as an
effective anti-cancer agent for basal cell and squamous cell skin cancer. (56–59)
Jeffrey Dach MD
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954-792-4663
my blog: www.jeffreydachmd.com
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