Hh inhibitors a less invasive tx for BCC

August 17, 2015

Advances in research have led to the emergence of medical therapies for BCCs; more research is needed to develop systemic therapies to treat SCCs.

With medical treatment now available, clinicians have less invasive therapies to manage metastatic basal cell carcinoma (BCC) or locally advanced BCC.

READ: Epidemiology of BCC

"We now have medical therapy which is quite effective," says David Hogg, M.D., F.R.C.P.(C)., an attending physician at the Princess Margaret Cancer Center in Toronto. "About 90% of basal cancers will respond to the hedgehog inhibitor vismodegib (Erivedge, Genentech/Roche). The drug is used for locally advanced carcinoma and metastatic melanoma."

Metastatic BCC has a median survival of eight to 14 months and a five-year survival rate of just 10%, and BCC is regarded as incurable when it has metastasized.

"BCC was strictly managed by surgeons or dermatologists," Dr. Hogg says. "Most of the time it is still managed through surgery or dermatological excision. Other modalities used are cryotherapy, freezing, or electrocautery."

The five-year cure rate for modalities like surgical excision, curettage and cautery, cryosurgery, and Mohs micrographic surgery are very high at 95% and greater.

Previously, when surgery could not be performed or when it would result in a significant deformity, other options such as radiotherapy, photodynamic therapy, chemotherapy, and topical therapy would be considered, according to Dr. Hogg. He is professor of medicine at the University of Toronto in Toronto, Canada.

In some instances, he says, radiotherapy would be a less attractive option, in cases where the maximum safe dose of radiation to the region had been reached, or when there was the risk of organ damage (such as blindness).

NEXT:  Hh signalling pathway

 

Hh signalling pathway

Research has shown that abnormal activation of the Hedgehog signalling pathway is involved in the pathogenesis and progression of all BCCs; in 90% of cases this activation arises from mutations of the Patched (PTCH) gene. Inhibitors of the Hedgehog pathway typically result in dramatic tumor responses, with shrinkage of the malignant tissue and healing of ulcerative lesions.

Tumors that are very large and cannot be removed surgically or are located near critical areas, such as around the eye, are suitable for medical therapy like vismodegib, Dr. Hogg explains.

"If they are near critical areas like the face, the tumor may involve the eye or cranial nerves, and can't be dealt with easily surgically," he says.

READ: Adjuvant radiation to prevent relapse

Patients who are being considered for medical therapy like vismodegib will have their cases discussed by a tumor board to discuss the suitability of the therapy for the patient, explains Dr. Hogg. When vismodegib therapy is initiated, patients should be monitored regularly, being seen about every 28 days.

"The patients have to be managed by a team including surgeons, radiation oncologists, medical oncologists, and pathologists," says Dr. Hogg.

Patients who have Gorlin syndrome, a rare hereditary condition that predisposes individuals to develop multiple BCCs, are good candidates for medical therapy like vismodegib. Investigators have observed that hand and foot pits, which are pathognomonic signs of the basal-cell nevus syndrome, were eliminated within a month of vismodegib therapy.

NEXT: Vismodegib benefits, side effects

 

Benefits, side effects

A major benefit of vismodegib is that most patients will respond to the therapy, but a disadvantage is that drug resistance to the therapy does develop.

"It takes about 16 to 18 months (for drug resistance to develop) in locally advanced cases and about nine months (for drug resistance to develop) in metastatic cases," Dr. Hogg notes.

Some of the toxicities associated with vismodegib include hair loss, unpleasant taste in the mouth, and leg cramps, Dr. Hogg says; but no dose-limiting or grade 5 events have been observed with vismodegib. Complete responses, however, are not often seen even in advanced disease, and do not occur in metastatic cases.

Alternatives to avoid drug resistance

To address the issue of drug resistance with vismodegib, investigators have looked at alternative approaches such as the use of the anti-fungal agent itraconazole, which has shown anti-BCC activity in animal models. A phase 2 study where 19 patients received itraconazole, and 10 patients vehicle, the active therapy demonstrated activity in humans: administration of itraconazole decreased cell-proliferation by 45 per cent, hedgehog pathway activity by 65 per cent, and tumor area by 24 per cent1.

"It is still early days," Dr. Hogg says. "The other drug that has been flagged is arsenic trioxide."

Indeed, itraconazole and arsenic trioxide (Trisenox, Cephalon) may be useful in combination to overcome resistance to systemic treatment with hedgehog inhibitors like vismodegib.

READ: Interventions for vismodebib drug resistance

Other emerging hedgehog inhibitors to treat locally advanced BCC or metastatic BCC include sonidegib, which Dr. Hogg predicts will likely perform similarly to vismodegib when it becomes available. Similar drugs are being explored in phase 1 studies to treat locally advanced and metastatic BCC.

NEXT: In need of better SCC therapies

 

In need of better SCC therapies

Squamous cell carcinoma, a relatively common tumor, is usually managed by simple surgical excision, but complex presentations of squamous cell carcinoma do occur, which are unresectable locally or metastatic disease, Dr. Hogg notes.

"We need better systemic treatment for this disease," says Dr. Hogg. "Many patients (who have complex cases of SCC) are old with co-morbid conditions and many have immunosuppression. They don't tolerate chemotherapy very well."

Research into genetic targets is required to find better systemic treatments for complex presentations of SCC. "The only target that has come up thus far is the EGFR (epidermal growth factor receptor) pathway," says Dr. Hogg.

Dr. Hogg sits on advisory boards for BMS, Merck, Roche, and GSK.

1Kim DJ, Kim J, Spaunhurst K, et al. Open-label, exploratory phase II trial of oral itraconazole for the treatment of basal cell carcinoma. J Clin Oncol. 2014;32(8):745-51.