Feasibility Of Ultrasound Therapy For Human Papillomaviruses Infection Of The Uterine Cervix

BackgroundCervical cancer remains the second most common cancer in women worldwide and the most frequent in developing countries. Pre-neoplastic cervical lesions represent an additional burden in countries where screening is widespread. The human papillomavirus (HPV) prevalence and type distribution in normal smears and in cancer specimens are being described and show relatively small international variation. State-of-the-art detection techniques have unequivocally shown that HPV-DNA can be detected in 95% to 100% of adequate specimens of cervical cancer, supporting the claim that HPV is the necessary cause. For most people, HPV causes no complications and goes away on its own. However, in some cases, if left untreated, certain high-risk types of HPV lead to cervical cancer. The HPV vaccine was approved last year by the US Food and Drug Administration for using in young girls and women aged 9-26 years. The HPV vaccine is meant to be a preventative or prophylactic vaccine and that is why it should be given to adolescents in USA. China is a developing country and has no the vaccine. So we need to explore other therapeutic modality to treat this disease.Focused Ultrasound (FU) is a new local therapeutic modality "from inside to outside". The principle of FU: Using the Targeting, Penetration, focusing of focused ultrasound, acoustic energy is deposited in the target area, FU therapy eliminates stimulation to cervix and prevent the chronic inflammation from spreading, via thermal effect, cavitation effect and mechanical effect produced by High intensity acoustic power from the focus of ultrasound. Inflammatory cells and diseased tissues are far more sensitive to ultrasound energy than normal mesenchyme tissues (supporting structures). Therefore, the diseased tissues can be destroyed, while the normal mesenchyme tissues are kept intact. Focused ultrasound therapy has been used to treat the nonneoplastic intraepithelial disorders of vulva, symptomatic ectopy of the cervix and the genital condyloma acuminate successfully with excellent clinical results while with minimal risk.PurposeTo explore the feasibility, safe and efficacy of focused ultrasound therapy for cervical high-risk HPV infection and to find an auxiliary stop standard of the cervical infection of high-risk HPV with focused ultrasound therapy.MethodsThe study involves 3 parts. The following experiments were carried out.1. Basic feasible researches of ultrasound transducer for treating infection of cervical canal. On the basis of excised ox liver as scanning model, two ultrasound transducers were used to scan respectively by the same dosage. The temperature on the surface of ox liver was measured after the focused ultrasound continual irradiation with the same speed. And energy outputs of two ultrasound transducers were compared by measuring the surface temperature. The ultrasound transducer was used to mimic treat cervical canal in rabbit vagina. The therapeutic effects of focused ultrasound therapy were assessed after treatment, the relations between the temperature change and the scanning dosage were found.2. To study of quantified stop standard of focused ultrasound therapy. 120 patients with symptomatic, chronic cervicitis who had complete records'were enrolled in this research. After a single time focused ultrasound continual irradiation, the surface temperature was measured and recorded after the treatment immediately so as to seek the average temperature of two different scanning points. After 3 months, the therapeutic efficacy and adverse reaction were evaluated. And the suitable temperature range which was considered as the quantified stop standard was selected by finding relation between temperature and therapeutic efficacy or adverse reaction. 3. To study of focused ultrasound therapy on cervical HPV infection.40 patients with HPV infection who visited out-patient clinic from May to October 2007 were enrolled in this study. Patients aged 23 years and older were randomly assigned to ultrasound therapy group and control group. In ultrasound group, the patients were treated by the ultrasound therapeutic device Seapostar?, which was developed and produced by Chongqing Haifu (HIFU) Technology, Co. Ltd, China. We used combination two ultrasound transducers to treat the patient who was highly suspected and diagnosed infection with HPV in cervical canal. In control group, patients were injected recombinant human interferonα-2b injection into cervix tissue 6 times in one month. It was a tight follow-up for 3 months and the titer of HPV DNA was detected again after 3 month. After treatment, the therapeutic effect and adverse reaction was compared between focused ultrasound group and interferon group.Results1. The temperatures of two ultrasound transducer by 1,2,3,4,5,6 times respectively in 5 mm/s speed had no significant difference(F=0.2 p=0.9559). Temperatures were different after the ultrasound transducer for treatment cervical canal scanning the rabbit vaginal inside with different doses. Following the scan times increased, temperature had also increased immediately after irradiation. And after successive scanning 5 times or less , average temperature of target region was raised 7.65℃.Only engorgement of vaginal mucosa had been observed by naked eye. The chondrosome swelling had been observed by electron microscope. After successive scanning 6 times or more,average temperature of target region was raised 8.5℃, the necrocytosis appearance such as nuclear fragmentation, cavitation in endochylema, chromatin margination, organelle destroyed seriously had been observed by electron microscope.2. The effective rate of FU in unitarily treatment of chronic cervicitis was 96.67%. The cure rate of mild cervical erosion was 100%, the cure rate of moderate cervical erosion was 95.24%, and the cure rate of severe cervical erosion was 93.33%. 54 cases (45%) patients in treatment felt a mild pain, but the treatment could be finished continuously without any acesodyne. After treatment, the majority of patients about 114 cases(95%) occurred the vaginal discharge in one week after treatment, and continued about one week to two weeks. A few patients about 12 cases (10%) occurred a small amount of colporrhagia, duration one day to five days, which can be stopped automatically without any special treatment. In a long follow-up, it had not yet been found cervical ulcers, scarring and cervical canal stenosis, and so on. The basic temperature (37.5±0.52)℃is in the small range. When the temperature of targeted tissue immediately after FU exposure was between 40℃and 43℃, the therapeutic effects tended to be satisfactory (98.33%) with little adverse effects. 3. 40 women were randomly assigned into ultrasound therapy group (n=20) and Interferonα-2b treatment group (n=20). There were no significant differences between the two groups with respect to age, interval of follow-up,cytology and pathology. The titer of HPV DNA had been decreased to 1pg/ml or less in 15 patients of ultrasound therapy group (75%), while just only 8 patients in Interferonα-2b treatment group(40%) had the same change. There was a highly significant statistical difference between the ultrasound therapy group and the interferonα-2b treatment group[χ2=5.0128,p=0.025]. During the recovering of cervix, the rate of side-effect (including reactive vaginal discharge and colporrhagia) was found in ultrasound group. The reactive vaginal diacharge continued 3 weeks or less had been observed in 19 patients, and colporrhagia lasted 5 days or less had been observed in 4 patients and the volume of colporrhagia was no more than the half of normal menstrual volume. In the Interferonα-2b group, the weakness was the major adverse reaction which lasted 3 days or less. It had been observed in 12 patients. 4 cases of these patients had complained their normal work had been affected by the weakness. 5 patients were observed the body temperature increased, but those temperatures were not more than 38.5℃. Vaginal discharge, a mild pain, weakness and low-grade fever were not need special treatment. The mild colporrhagia was treated by gynecologic conventional therapy.Conclusions 1. In clinical use of common scanning speed, the energy deposition of ultrasound transducers are no different between for treatment cervical canal and for treatment cervix uteri. In the experiment of targeting rabbit vaginal, following the scanning dose increase, the temperature of target region had been increased. It is relatively safe that successive scanning 5 times or less.2. When the cervical canal treated with FU, the change of cervical canal couldn't be observed directly, so the change of temperature in target region should be used as one of the stop standard. It is provided experimental basis for treatment the cervical high risk HPV infection in clinic, and the two standards can be combined.3. For high-risk cervical HPV infection, focused ultrasound therapy is more effective than interferon treatment. Clinical trials are proved to be feasible, but a large amount of clinical cases and long-term follow-up experiments are still required.