Antiviral Sensitizes HPV Cervical Cancer to Chemoradiation

Pam Harrison

November 25, 2014

The antiviral agent cidofovir (Vistide, Gilead Sciences, Inc), which already has an established use in the treatment of retinal infections in patients with AIDS, may offer clinical benefit in patients with human papillomavirus (HPV)–related cervical cancer, early research suggests. Very preliminary results from a phase 1 study suggest that it could be used along with chemoradiation to improve responses, say the researchers, but an expert is sceptical and says there is no evidence of any benefit.

Lead researcher Eric Deutsch, MD, head of radiation oncology, Institut Gustave Roussy, Villejuif, France, told Medscape Medical News that previous studies have shown that "laryngeal papillomatosis which is also HPV-related can be treated with local injections of cidofovir." In addition, preclinical data have shown that the antiviral can markedly enhance sensitization to chemoradiation in HPV-expressing tumor cell lines.

"So that led us to hypothesize that this type of drug can have a sensitizing effect on HPV-related cervical cancer cells treated with chemoradiation," he said.

"In tumor biopsies taken before and after treatment, we observed exactly what we had observed in the lab, which is a restoration of p53 protein levels [in HPV-infected cells] after treatment with cidofovir," Dr Deutsch commented.

"This confirmed that our preclinical observations were translatable to at least some patients with cervical cancer, which is encouraging," he said.

Antiviral Intercepts HPV-Related Oncoproteins

Most high-risk human HPVs express the E6 and E7 oncoproteins that bind with several tumor suppressor proteins, including p53, and neutralize their function.

HPV-infected cells then become resistant to apoptosis.

Preclinical work by Dr Deutsch and colleagues indicated that cidofovir intercepts the activity of HPV-related oncoproteins and restores tumor-suppressing proteins, including p53, to normal levels within HPV-infected cells.

This action effectively "sensitizes" cancer cells to chemoradiation, and so when cancer cells are exposed to such therapy, they are more likely to die.

In their phase 1 safety trial, 15 patients with cervical cancer ranging from stage IB to IVA were treated with IV cidofovir at escalating doses from 1 to 6.5 mg/kg.

Cidofovir was given weekly for 2 weeks and then every 2 weeks until the start of chemoradiation.

Chemoradiation consisted of 45 Gy delivered to the pelvis and IV weekly carboplatin until the start of brachytherapy delivered to the uterus and vagina.

Women received a total of 6 injections of cidofovir; the median duration of therapy was 10 weeks.

Biological expression of the HPV oncoproteins E6 and E7 were analyzed during treatment, and tumor response was assessed according to RECIST criteria.

The primary objective of the study was to evaluate the safety of giving cidofovir prior to chemoradiation. Dr Deutsch reported that treatment was safe and that cidofovir did not increase either the toxicity of chemoradiation or worsen patients' tolerability of it.

Two of 6 patients receiving cidofovir at the maximum dose of 6.5 mg/kg did experience dose-limiting toxicities. For this reason, the recommended dose of cidofovir going forward into a phase 2 trial will be 5 mg/kg.

Response Rates

Although careful not to overinterpret response rates in a small phase 1 trial, Dr Deutsch and colleagues also found that the novel sensitizing strategy resulted in tumor shrinkage in all evaluable patients and that 80% of them achieved a complete response.

"The fact that the combination of cidofovir and chemoradiation did not lead to an increase in toxic side effects is a crucial finding because the women in our trial had locally advanced cervical cancer that had not spread to the rest of the body," Dr Deutsch said in a statement.

"So for the women in our trial, any increase in toxic side effects or a worsening of the tolerability of treatment would have been unacceptable."

No Industry Interest

Dr Deutsch commented that translating preclinical observations to a clinical study had been extremely difficult because they could not find any pharmaceutical company that was interested in sponsoring the trial. (In fact, it took the team more than 10 years to go from their first preclinical data to a phase 1 trial).

"The patent for cidofovir has expired," he told Medscape Medical News, "and we were not able to find any company that was willing to support us and provide the drug for the trial."

The drug is not even available through generic drug companies in Europe, though that may not be case elsewhere, Dr Deutsch added.

"We think cidofovir could end up as a targeted therapy for HPV-related cancers, especially cervical cancers, which are extremely frequent among developing countries, and it could be a targeted therapy that is affordable because the drug is cheap," Dr Deutsch said.

"The problem is, we need to find an industry partner or a generic drug manufacturer who would like to partner with us, and our hope is that at least someone in industry will be willing to do this, because there is a huge need for a drug like this in many countries."

No Evidence of Benefit

There is "absolutely no evidence" that patients benefited from this approach, said Maurie Markman, MD, who contributes regular videoblogs to Medscape Oncology. Dr Markman is clinical professor of medicine, Drexel University College of Medicine, and senior vice president for clinical affairs, Cancer Treatment Centers of America, Philadelphia, Pennsylvania.

"Patients received standard therapy, and so there just isn't any evidence that this particular substance that was given prior to standard treatment had any impact on the reported outcomes," Dr Markman told Medscape Medical News.

The suggestion that pretreatment with cidofovir might have clinical relevance is also "highly speculative," he added, and is not supported by the experimental evidence.

"There was also no support from any company for this research," Dr Markman said, "so it's quite uncertain whether it will go beyond this point."

The study was funded entirely by academia. Dr Deutsch has disclosed no relevant financial relationships. Dr Markman receives income in an amount equal to or greater than $250 from Celgene Corporation, Caris Life Sciences, Novartis Pharmaceuticals Corporation, sanofi-aventis, Amgen Inc, and Genentech Inc.

26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, Barcelona, Spain. Abstract 215. Presented November 20, 2014.

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