Aim 5: Treatment


Although the intention of the Gynecologic Disease Program is to investigate multiple gynecologic diseases, the initial focus has been on tumors that affect the uterus. Tumors affecting the uterine corpus and uterine cervix accounted for over $4.5 billion dollars spent on inpatient management in 2004. The incidence of disease affecting the uterus exceeds that of the pathologic conditions involving the ovary.

Benign Uterine tumors

Uterine leiomyomata, or fibroids are among the most common tumors of the female reproductive tract and are a primary cause for heavy menstrual bleeding, pelvic pain, and other pelvic symptoms. While the exact prevalence is difficult to determine, based on pathologic data, up to 77% of hysterectomy specimens have fibroids. The prevalence among asymptomatic women detected clinically is less, perhaps reflecting the limitations of examination or imaging techniques. The prevalence increases with age as a woman progresses through her reproductive years and the symptoms associated with fibroids generally progress as a woman proceeds through her late thirties and forties, with African Americans more likely to be diagnosed at a younger age.


While fibroids generally regress after menopause, they may cause significant morbidity before that time. Hysterectomy, myomectomy, and other surgical interventions are commonly required at a huge cost to the health system; medical management and office visits add to that burden.


Hysterectomy has been the definitive treatment of fibroids and has been demonstrated to be effective in controlling symptoms. In most cases, health-related quality of life dramatically improves. However, there have been few studies comparing the outcome of hysterectomy to other surgical therapies or comparing the outcome to the normal population.


Similarly, myomectomy has not been evaluated in the context of other fibroid therapies. A new therapy, uterine fibroid embolization (UFE), has received considerable attention in recent years as a non-surgical alternative to myomectomy and hysterectomy. While there have been numerous case series suggesting that UFE is effective, the relative effectiveness of UFE, or for that matter hysterectomy and myomectomy, has not been studied in depth.


Part of the limitation of comparative studies in the past has been the lack of measures of outcome. Because the symptoms caused by fibroids are subjective and do not have clear objective correlates, measuring outcome has been difficult. What has been needed is a fibroid-specific questionnaire that assesses symptom severity and health-related quality of life. Such an instrument has now been created by members of the Gynecologic Disease Program and is intended to be used as both a cross sectional and longitudinal instrument for measuring fibroid-related symptoms and health impact. This quality of life study will involve enrollment of patients from Walter Reed Army Medical Center, Georgetown University Medical Center, the Magee Women's Hospital in Pittsburgh and the Cleveland Clinic.


Cancers affecting the Uterus

Uterine Corpus

Previous cDNA microarray experiments by our group have revealed that folate binding protein or folate receptor (FOLR) is overexpressed in papillary serous endometrial cancers. Real-time quantitative PCR assays confirmed that overexpression of FOLR in papillary serous cancers was even more striking than suggested by the microarray, showing a 60-fold increased level of expression compared to normal endometrium. Immunohistochemical analysis of papillary serous endometrial cancer using Mov18 antibody has also revealed overexpression of FOLR. Members of the gynecologic Disease Program have an immunogenic peptide for Folate Binding Protein that is currently being reviewed for IND by the FDA. The Phase I trial is expected to be activated in the Spring of 2005.

Uterine Cervix

Although implementation of screening programs has decreased the incidence of cervix cancer, approximately 25% of patients will be diagnosed with locally advanced disease (Federation of Gynecology and Obstetrics Stage IIB through IVA). Several randomized controlled trials have revealed that treatment regimens combining radiotherapy with chemotherapy containing cisplatin improve rates of survival and progression-free interval among women with stage IIB through IVA cervix cancer. Chemoradiation has subsequently become the accepted standard of care in the treatment of advanced cervix cancer. Advances in our understanding of the molecular biology of cervix cancer offers the opportunity to develop targeted genetic therapies aimed at enhancing the effectiveness of contemporary therapies.


The GeneSeed project is focused on the delivery of genetic therapy to cervix tumors. The GeneSeed consists of a small tube manufactured from high-purity titanium, as specified in the American Society for Testing of Materials F67-69 ³Standard Specifications for Unalloyed Ti for Surgical Implant Applications². The four year project will develop image-guided treatment planning and robotic needle delivery systems for interstitial radiosensitizing gene therapy. This gene therapy is packaged into novel devices known as GeneSeeds, which allow for concentrated, controlled delivery of a gene vector into a small area of tissue. A radiation sensitive promoter activates gene expression of the gene therapy in the presence of radiation.


The combination of technologies in this approach will enable highly conformal radiotherapy for cancer, increasing the likelihood of local disease control and minimizing toxicity. Although these systems will be designed for the treatment for cervical cancer, the technologies developed during this project should be readily adaptable to many other disease sites.