LONDON – An antiviral agent normally used to treat an AIDS-associated complication could increase the sensitivity of cancers associated with human papillomaviruses to chemoradiotherapy, according to preliminary study findings.
As reported at the European Society for Therapeutic Radiation Oncology Anniversary Conference, cidofovir appears to increase the sensitivity of locally advanced cervical carcinomas to the effects of radiotherapy and chemotherapy. It has resulted in no local failures or toxicities in 10 patients treated to date in an ongoing phase I dose escalation study.
Although still in very early days, the novel approach holds promise for using the antiviral agent as a possible radiosensitizer in HPV-related cancers, researchers at the Institut Gustave-Roussy in Villejuif, France, believe.
HPV infection has been associated with the development of several tumor types, including cervical, head and neck, and anal carcinoma, Dr. Eric Deutsch, a professor of radiation oncology at the institute, explained at a press briefing on May 11 .
"We know a lot about the underlying molecular mechanisms of HPV infection," Dr. Deutsch observed. "We know that HPV oncogenes [E6 and E7] are in fact dis-repairing tumor suppressor genes, and this is clearly associated with tumor progression and resistance to therapies."
Preclinical research has shown that cidofovir can prevent the transformation of HPV-infected cervical cells (Oncogene 2002;21:2334-46), and that it has antiangiogenic and antimetastatic activity (PLoS One 2009;4:e5018), Dr. Deutsch noted. Thus, it could be used as a potential adjunct to current therapy to improve the outcome of more than 10,800 women who are diagnosed with cervical cancer in the United States each year. In all, 24,900 HPV-related cancers occur each year in the U.S., according to Dr. Deutsch.
Cidofovir (Vistide) is an injectable antiviral drug approved for a very specific indication – the treatment of retinal inflammation due to cytomegalovirus in patients with AIDS. The fact that the drug is approved means that it is a known entity, and this could help fast-track its use if supported by suitable evidence.
On the basis of the preclinical evidence, Dr. Deutsch and his colleagues have initiated a phase I clinical trial in patients with locally advanced cervical cancer. Although cidofovir is not a new agent, a phase I trial is needed as the drug is being used in combination with the standard therapy for cervical cancer – and it’s important to show that there are no dose-limiting toxicities. According to the cidofovir package insert, patients need to be monitored closely for acute renal failure and neutropenia.
In the trial, the antiviral agent is being given once weekly and patients receive external-beam pelvic radiotherapy (45 Gy in 1.8-Gy fractions) plus carboplatin, followed by brachytherapy and chemotherapy. The dose levels explored so far range up to 5 mg/kg during the full course of radiotherapy, and no dose-limiting toxicities have been observed after up to 2 years for some doses. No local failures have been reported.
Target accrual is 12 patients, and a 10-patient extension is planned to evaluate efficacy. Phase I should be complete this year, and phase II in 2011-2012.
Although these data are preliminary, they indicate that cidofovir could be a potential radiosensitizer, Dr. Deutsch said. The fact that no toxicities have been seen to date also suggests that the risk-benefit ratio could favor combining the antiviral with radiation and chemotherapy. Phase II/III studies will be needed to confirm these results.
Dr. Deutsch noted that these findings could also potentially produce a quicker solution to tackling the problem of HPV-associated cancers, as current vaccination programs will need between 1 and 2 decades’ lead time before they could have any real effect.
The study is sponsored by the Institut Gustave Roussy. Dr. Deutsch did not state any conflicts of interest.