The use of Papanicolaou smears for cervical cancer screening has led to an increased detection of preinvasive conditions of the cervix, cervical intraepithelial neoplasia (CIN). Epidemiological studies have shown an association between low levels of dietary β-carotene and CIN. In this Phase II study, we have explored the effect of p.o. β-carotene administration on CIN I and II. Patients with documented CIN I or II were treated with 30 mg daily of β-carotene for 6 months. Response rates were determined at 0, 3, 6, and 12 months with cytology, colposcopy, and/or biopsies. Levels of β- carotene and vitamin E were determined at the same time intervals in vaginal mucosa cells and serum. Response rates were 18 of 30 (60%), 21 of 30 (70%), and 10 of 30 (33%) at 3, 6, and 12 months, respectively. Significant changes occurred in the serum β-carotene levels over time. Median levels over 2200 mg/ml were found at 3 and 6 months versus a baseline median level of 111 (P < 0.0001). Significant increases were also noted in the β-carotene levels of the vaginal mucosa compared to baseline (P = 0.01) and a significant correlation was noted between serum and vaginal β-carotene levels as well (P < 0.0001). This study indicates that a large percentage of patients with CIN I and II will respond clinically to p.o. β-carotene supplementation. There is a positive relationship between serum and tissue levels of β-carotene which suggests that serum levels can be used for monitoring purposes. Because of these encouraging results, prospective randomized studies are ongoing comparing the efficacy of β-carotene against an untreated control arm.

It has been speculated that tumor necrosis factor alpha (TNF-alpha) may decrease the cytotoxicity of radiotherapy by increasing the scavenging of toxic superoxide radicals. Because of the possible clinical implications, the cytotoxicity of TNF-alpha in combination with radiotherapy (RT) was compared with that of RT alone in a human ovarian cancer cell line. NIH:OVCAR-3 cells were incubated with TNF-alpha at 10.0, 1.0, 0.1, and 0.01 microgram/ml. Plates were divided into two groups; one received 150 cGy of radiotherapy and the other received no further therapy. Seventy-two hours later, supernatants were aspirated and viable cells were stained with a 1% solution of crystal violet. Survival of cells treated with RT plus TNF-alpha was expressed as a percentage of surviving irradiated controls. Analysis of results revealed minimal additive cell killing effect between TNF-alpha and radiotherapy at all concentrations of tumor necrosis factor, with the greatest difference noted in the group treated with 10 micrograms/ml TNF-alpha. A continued radiotherapy dose-response study with TNF-alpha showed a similar additive, not radioprotective, effect. This may have implication as a potentiator of RT in some human tumors.

Objective

The aim of this study was to describe recruitment strategies for a single-visit cervical cancer prevention study.

Methods

From January through December 1999, low-income, predominantly Latino women were recruited to participate in a single-visit cervical cancer prevention study. For the first 6 months, all women who had ever visited one of two community-based study clinics were invited to participate (clinic registry recruitment). For the remainder of the year, recruitment was modified to be primarily inclusive of advertisements in English- and Spanish-language community newspapers and fliers left in local businesses and organizations (media campaign recruitment). Eligible volunteers were randomized to one of two study arms, usual-care program or single-visit program. All study subjects completed demographic and medical questionnaires delivered by bilingual staff. Women who declined to participate in this study were asked to provide reasons for this preference. Statistical analyses included the use of chi-square, logistic regression, and Student's t test.

Results

The proportion of women who agreed to participate was higher in the media recruitment group than in the clinic registry group [51% (535/1041) compared to 26% (405/1542), P < 0.001]. The no-show rate among participants solicited from the media strategy was significantly less than that from the clinic registry. There were no significant differences in the median age, number of months since the last Papanicolaou smear, incidence of abnormal Papanicolaou smear, education, or income of the subjects based on the recruitment strategy.

Conclusion

A media-based recruitment strategy was effective for this single-visit cervical prevention study. This approach may be effective for recruitment of other low-income groups to clinical trials.

Objective

We initiated studies to develop cytokine-secreting human ovarian carcinoma cells for the purpose of using these cells as vaccines for the treatment of advanced epithelial ovarian cancer.

Study design

A human ovarian carcinoma cell line (UCI-107) was genetically engineered to secrete the cytokine interleukin-2 by retroviral-mediated gene transduction.

Results

One clone, termed UCI-107A IL-2 AS, constitutively secreted high levels of interleukin-2 (i.e., 2000 to 2300 pg/ml/10(5) cells per 48 hours) for > 55 passages and 8 months of study. Unlike parental- and vector-transduced cells, UCI-107A IL-2 AS cells were aneuploid and failed to express major histocompatibility complex class I and HER2/neu surface antigens. UCI-107A IL-2 AS cells were highly resistant to killing by gamma irradiation and continued to produce high levels of interleukin-2 even after irradiation with 10,000 cGy. Balb/C nude mice injected intraperitoneally with UCI 107-A IL-2 AS cells survived significantly longer than control animals, with 25% of the animals totally rejecting their tumors. UCI-107A IL-2 AS was totally resistant to killing by fresh allogeneic peripheral blood lymphocytes in four hour chromium 51 release assays but induced high levels of killing in 72-hour long-term cytotoxic assays.

Conclusion

The potential use of these interleukin-2-secreting ovarian carcinoma cells as vaccines for women with advance ovarian cancer will be discussed.

Objective

To perform a phase I study of topically applied dihematoporphyrin ether (DHE) in the photodynamic treatment (PDT) of cervical intraepithelial neoplasia (CIN) using fixed DHE doses and application schedules, and a variable dose of 630 nm red light delivered by an argon-pumped dye laser.

Methods

Between February 1993 and April 1994, 24 nonpregnant women with a histologic diagnosis of CIN were enrolled. All patients had lesions involving at least 25% of the cervix that were colposcopically visible. Using a cervical cap, 2 ml of a 1% solution of DHE (Photofrin) in a 4% Azone and isopropyl alcohol vehicle were applied to the cervix 24 hr prior to PDT. An argon-pumped dye laser providing light at 630 nm was then used to perform PDT. Light was coupled into a 400-microm silica fiber optic terminating in a microlens which focused the laser radiation onto a circular field of uniform light intensity perpendicular to the tissue. The entire ectocervix was treated in a single field including a margin of 3-5 mm of normal cervix. Using a constant power density (150 mW/cm2) to avoid thermal injury, the PDT energy was increased every 4 patients in a phase I fashion (40, 60, 80, 100, 120, and 140 J/cm2).

Results

Thirteen patients with CIN I, 7 patients with CIN II, and 4 patients with CIN III were treated. The maximal energy density was well tolerated. Toxicity was minimal with no patients experiencing local necrosis, sloughing, or scarring; however, a mild vaginal discharge was noted in several patients. Systemic effects were absent. After 12 months of follow-up at 3-month intervals, 22 patients are evaluable of whom 15 (68%) are disease free. One patient was lost to follow-up and in another the cervical cap was dislodged. Four of the 7 failures or recurrences occurred at energy densities of 80 J/cm2 or less, while 8 of 11 (73%) patients were treated successfully with PDT at an energy density of 100 to 140 J/cm2.

Conclusions

PDT with DHE and an argon-pumped dye laser at 630-nm wavelength delivering an energy density of 140 J/cm2 is safe and effective in treating CIN. Phase II studies using PDT at the prescribed application schedule and dose are indicated.

Objective

Our purpose was to evaluate the influence of the route of drug administration and target tissue vascularity on the distribution of a photosensitizer, Photofrin porfimer sodium, in the uterus.

Study design

The study was divided in two phases. In phase I 80 mature female rats were hormonally suppressed and then stimulated with estrogen. They were randomized to receive intravenous, intraperitoneal, or intrauterine Photofrin and killed 3, 6, 24, or 48 hours later. Drug distribution and levels were then determined. In phase II 40 female rats were randomized to receive hormonal stimulation, suppression, both, or neither. All received intrauterine Photofrin and were killed 24 hours later. Statistical analysis was performed with the unpaired t test and the two-way analysis of variance.

Results

Intrauterine administration was determined to be the simplest and most effective method of delivery because it provided for optimal uptake and distribution (p = 0.05) within the uterus, at lower doses.

Conclusions

Selective localization of photosensitizer within the target tissue suggests that highly selective photodynamic destruction of endometrial tissue can be achieved. Furthermore, the combination of intrauterine administration of photosensitizer with estrogen adjuvant may minimize the most debilitating side effect of Photofrin, cutaneous phototoxicity.

Interleukin-6 (IL-6) is a cytokine that has been implicated as a growth factor in human ovarian carcinoma, yet the in vivo source of IL-6 in patients remains undefined. We measured IL-6 by ELISA in cell-free ascites (CFA) of 19 patients with ovarian carcinoma. IL-6 was detectable in all samples (mean level 3.3 ng/ml). To identify the cellular source of IL-6, we measured this cytokine by ELISA in 24-48 h supernatants of cultured lymphocyte-, macrophage-, and tumor cell-enriched populations purified from three solid ovarian carcinomas by centrifugal elutriation. All cell populations spontaneously released IL-6; however, tumor cells and tumor-associated macrophage released levels of IL-6 that greatly exceeded those released by tumor-associated lymphocytes. Kinetic studies revealed that IL-6 was detectable at 6 h and that levels increased in all cultures examined over a 48 h time course. These data suggest that both tumor and infiltrating host cells may be the source of the high levels of IL-6 found in carcinomatous ascites. Furthermore, although all three cell types examined may contribute to IL-6 production in patients with ovarian carcinoma, tumor cells are perhaps the most clinically significant source.

Objective

Our purpose was to evaluate the role of interstitial brachytherapy in vulvar cancer management.

Study design

From 1985-1992 we performed a retrospective study of patients treated at the University of California, Irvine Medical Center, and Long Beach Memorial Medical Center.

Results

Eleven patients received interstitial brachytherapy, with (n = 5) or without (n = 6) external beam radiotherapy, for locally advanced (n = 5) or recurrent (n = 6) vulvar cancer. Local control was achieved in all patients. Ten patients have died of disease at a mean interval of 33 months from the time of treatment, with 9 patients having maintenance of local control at death. One patient is alive without disease after 77 months of follow-up. There were 2 cases of local necrosis (18%) and 1 case of rectovaginal fistula (9%).

Conclusion

Local control of advanced vulvar cancer can be achieved with interstitial brachytherapy, with or without external beam radiotherapy. With improved systemic therapy this treatment modality may be used to salvage women with bulky, symptomatic tumors.