New approach pioneered for treating HPV-related cervical cancer
A drug that is already well established as a treatment for infection of the retina in people with AIDS has been shown, for the first time, to sensitize cervical cancer to chemotherapy and radiotherapy without an increase in toxic side-effects.
These results were presented at the 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in Barcelona, Spain, by Professor Eric Deutsch, MD, PhD, professor of radiation oncology and head of the radiation oncology department and research unit at the Institut Gustave Roussy in Villejuif, France.
Cidofovir is an antiviral drug that is effective against several viruses, including human papillomavirus (HPV), which is implicated in the onset of cervical cancer. It targets the cancer-causing proteins (oncoproteins) produced by HPV. These oncoproteins interfere with the action of other proteins that control genome stability and cell death, and so, when cells are infected with HPV they become resistant to dying.
However, preclinical work by researchers in France has shown that cidofovir stops the activity of the HPV-related oncoproteins, leading to a restoration of pro death proteins such as p53. This means that when the cervical cancer cells are targeted with chemotherapy and radiotherapy (chemoradiation), they are more likely to die.
Deutsch explained that although cidofovir was approved as a stand-alone therapy for infectious disease, until now it was unknown whether it was safe to use it in combination with chemoradiation.
"As a result of the findings from our preclinical studies, we have conducted what is, to my knowledge, the first phase I clinical trial in cervical cancer patients, using cidofovir to target the HPV oncoproteins in combination with chemoradiation," he said.
"The major finding from the trial is that cidofovir did not increase the toxicity or worsen the tolerability of chemoradiation. We also found that the combination resulted in tumor shrinkage in all the patients who could be evaluated in the trial, with a complete response, in which the tumors disappeared for a time, in 80% of these patients.”
Fifteen women joined the trial and received injections of cidofovir at doses ranging from 1 to 6.5 mg/kg weekly for 2 weeks, and then every 2 weeks from the start of chemoradiation (45 Gy radiotherapy delivered to the pelvis and intravenous weekly carboplatin) until the start of brachytherapy in the uterus and vagina. The women received a total of six injections of cidofovir. The median duration of therapy was 10 weeks. Results from all 15 women were available for evaluation at the time of the Barcelona meeting.
One of the major dose-limiting side-effects of cidofovir is permanent kidney damage. However, none was seen in this trial.
Two of the six patients receiving the maximum dose (6.5 mg/kg) experienced dose-limiting toxicities. One patient presented with febrile neutropenia and renal infection associated with bacteriemia. Another patient developed transient proteinuria; of interest, recovery of normal renal function was seen in this patient.
Most of the other side effects observed in other patients were relatively limited in intensity and are observed with the standard chemoradiotherapy regimen without cidofovir.