Laila I. Muderspach

Cisplatin, radiation, and adjuvant hysterectomy compared with radiation and adjuvant hysterectomy for bulky stage IB cervical carcinoma

BACKGROUND Bulky stage IB cervical cancers have a poorer prognosis than smaller stage I cervical cancers. For the Gynecologic Oncology Group, we conducted a trial to determine whether weekly infusions of cisplatin during radiotherapy improve progression-free and overall survival among patients with bulky stage IB cervical cancer. METHODS Women with bulky stage IB cervical cancers (tumor, > or =4 cm in diameter) were randomly assigned to receive radiotherapy alone or in combination with cisplatin (40 mg per square meter of body-surface area once a week for up to six doses; maximal weekly dose, 70 mg), followed in all patients by adjuvant hysterectomy. Women with evidence of lymphadenopathy on computed tomographic scanning or lymphangiography were ineligible unless histologic analysis showed that there was no lymph-node involvement. The cumulative dose of external pelvic and intracavitary radiation was 75 Gy to point A (cervical parametrium) and 55 Gy to point B (pelvic wall). Cisplatin was given during external radiotherapy, and adjuvant hysterectomy was performed three to six weeks later. RESULTS The relative risks of progression of disease and death among the 183 women assigned to receive radiotherapy and chemotherapy with cisplatin, as compared with the 186 women assigned to receive radiotherapy alone, were 0.51 (95 percent confidence interval, 0.34 to 0.75) and 0.54 (95 percent confidence interval, 0.34 to 0.86), respectively. The rates of both progression-free survival (P<0.001) and overall survival (P=0.008) were significantly higher in the combined-therapy group at four years. In the combined-therapy group there were higher frequencies of transient grade 3 (moderate) and grade 4 (severe) adverse hematologic effects (21 percent, vs. 2 percent in the radiotherapy group) and adverse gastrointestinal effects (14 percent vs. 5 percent). CONCLUSIONS Adding weekly infusions of cisplatin to pelvic radiotherapy followed by hysterectomy significantly reduced the risk of disease recurrence and death in women with bulky stage IB cervical cancers.

Phase II study of liposomal doxorubicin in refractory ovarian cancer: antitumor activity and toxicity modification by liposomal encapsulation.

PURPOSE A phase II study of liposomal doxorubicin was conducted in patients with ovarian cancer who failed to respond to platinum- and paclitaxel-based regimens. Liposomal doxorubicin was selected as a result of its superior activity against ovarian cancer xenografts relative to free doxorubicin and activity in refractory ovarian cancer patients that was noted during the phase I study. PATIENTS AND METHODS Thirty-five consecutive patients were accrued in two institutions (22 in one and 13 in the other). All had progressive disease after either cisplatin or carboplatin and paclitaxel, or at least one platinum-based and one paclitaxel-based regimen. Patients received intravenous (I.V.) liposomal doxorubicin 50 mg/m2 every 3 weeks with a dose reduction to 40 mg/m2 in the event of grade 3 or 4 toxicities, or a lengthening of the interval to 4 weeks (and occasionally to 5 weeks) with persistence of grade 1 or 2 toxicities beyond 3 weeks. RESULTS Nine clinical responses (one complete response [CR], eight partial responses [PRs]) were observed in 35 patients (25.7%), with seven of these having been confirmed by two consecutive computed tomographic (CT) measurements. The median progression-free survival was 5.7 months with an overall survival of 1.5 to 24+ months (median, 11 months). Although 13 patients experienced grade 3 or 4 nonhematologic skin and mucosal toxicities (either hand-foot syndrome or stomatitis), with dose modifications, the treatment was very well tolerated. Nausea that was clearly attributable to the drug, hair loss, extravasation necrosis, or decreases in ejection fraction did not occur. CONCLUSION Liposomal doxorubicin has substantial activity against ovarian cancer refractory to platinum and paclitaxel. The responses achieved with liposomal doxorubicin were durable and maintained with minimal toxicity. This liposomal formulation should be evaluated further in combination with other drugs in less refractory patients.

Depression, Correlates of Depression, and Receipt of Depression Care Among Low-Income Women With Breast or Gynecologic Cancer

PURPOSE To assess the prevalence of depression among low-income, ethnic minority women with breast or gynecologic cancer, receipt of antidepressant medications or counseling services, and correlates of depression. PATIENTS AND METHODS Study patients were 472 women receiving cancer care in an urban public medical center. Women had a primary diagnosis of breast (stage 0 to III) or gynecologic cancer (International Federation of Gynecology and Obstetrics stage 0 to IIIB). A diagnostic depression screen and baseline questionnaire were administered before or during active treatment or during active follow-up. Self-report data were collected on receipt of depression treatment, use of supportive counseling, pain and receipt of pain medication, functional status and well-being, and perceived barriers to cancer care. RESULTS Twenty-four percent of women reported moderate to severe levels of depressive disorder (30% of breast cancer patients and 17% of gynecologic cancer patients). Only 12% of women meeting criteria for major depression reported currently receiving medications for depression, and only 5% of women reported seeing a counselor or participating in a cancer support group. Neither cancer stage nor treatment status was correlated with depression. Primary diagnosis of breast cancer, younger age, greater functional impairment, poorer social and family well-being, anxiety, comorbid arthritis, and fears about treatment side effects were correlated with depression. CONCLUSION Findings indicate that depressive disorder among ethnic minority, low-income women with breast or gynecologic cancer is prevalent and is correlated with pain, anxiety, and health-related quality of life. Because these women are unlikely to receive depression treatment or supportive counseling, there is a need for routine screening, evaluation, and treatment in this population.

The effect of highly active antiretroviral therapy on cervical cytologic changes associated with oncogenic HPV among HIV-infected women

ObjectiveCervical intraepithelial neoplasia (CIN), a common condition among HIV-infected women, has been linked to HIV load and immune status. Highly active antiretroviral therapy (HAART) improves immunologic and virologic status. This study was undertaken to determine the relationship between HAART use and CIN. DesignCohort study. The Womens Interagency HIV Study (WIHS) in five cities in the USA (Bronx/Manhattan, New York; Brooklyn, New York; Chicago, Illinois; Los Angeles, California; San Francisco Bay area, California; Washington, District of Columbia). MethodsHIV-infected women were followed every 6 months with Papanicolaou smears and cervicovaginal lavage for human papillomavirus (HPV) DNA testing. To characterize exposures that changed over time and to capture the dynamic nature of cytologic changes, Papanicolaou smear findings from each participants consecutive visits were defined as a pair. We determined the proportion of all pairs that exhibited either regression or progression, according to HAART exposure, HPV results and Papanicolaou smear status. As participants could contribute multiple pairs, inferences were based on robust methods to adjust for correlated observations. ResultsWomen with persistent HPV infection were more likely to have progression of their lesions. After adjustment for CD4 cell count and Papanicolaou smear status, women on HAART were 40% (95% confidence interval, 4–81%) more likely to demonstrate regression and less likely (odds ratio, 0.68; 95% confidence interval, 0.52–0.88) to demonstrate progression ConclusionsHAART altered the course of HPV disease in HIV-infected women, reducing progression and increasing regression. As HPV disease is a common sex-specific manifestation of HIV disease this effect of HAART would be a major additional benefit from this modality of therapy.

Prevalence and predictors of squamous cell abnormalities in papanicolaou smears from women infected with HIV-1

Background Cervical neoplasia occurs with increased frequency among women infected with HIV-1. Objective To characterize prevalence of and risk factors for abnormal cervical cytology among women with HIV and to compare them to uninfected women. Methods Baseline cervical cytology was obtained from 1713 women seropositive for HIV and 482 at-risk control women who were enrolled in the Womens Interagency HIV Study, a multicenter prospective cohort study conducted in six U.S. cities. Associations with sociodemographic, medical, and sexual variables were assessed by Fishers exact test, Mantel extension test, and logistic regression analysis. Results Cervical cytology was abnormal in 38.3% of HIV-infected women (atypical squamous cells of uncertain significance [ASCUS] 20.9%, low-grade squamous cells of uncertain significance [LSIL] 14.9%, high-grade squamous cells of uncertain significance [HSIL] 2.3%, cancer 0.2%) and 16.2% of HIV-uninfected women (ASCUS 12.7%, LSIL 2.3%, HSIL 1.2%, cancer 0.0%). Risk factors for any abnormal cytology in multivariate analysis included HIV infection, CD4 cell count, HIV RNA level, detection of human papillomavirus (HPV), a prior history of abnormal cytology, employment, and number of male sex partners within 6 months of enrollment. Prior abortion was associated with a decreased risk of cytologic abnormality. Conclusions Cervical cytologic abnormalities were frequent among women infected with HIV, although high-grade changes were found in only 2.5%. Factors linked to sexual and reproductive history, HPV infection, and HIV disease all influenced risk.

ZYC101a for treatment of high-grade cervical intraepithelial neoplasia: a randomized controlled trial.

OBJECTIVE: The objective of this study was to assess the safety and efficacy of a novel therapeutic, ZYC101a, for the treatment of women with histologically confirmed cervical intraepithelial neoplasia (CIN) 2/3. ZYC101a contains plasmid-DNA–encoding fragments derived from the E6 and E7 proteins of human papillomavirus (HPV) 16 and 18, and is formulated within small biodegradable microparticles. METHODS: A multicenter, double-blind, randomized, placebo-controlled trial was conducted in a group of women with biopsy-confirmed CIN 2/3. Subjects were randomized to 3 intramuscular doses of either placebo or ZYC101a (100 or 200 μg). Six months after the first injection, subjects underwent cervical conization. The primary endpoint for this study was histologically confirmed resolution of CIN 2/3. A total of 161 subjects were randomized, dosed, and evaluated for safety. After central pathology review, 127 subjects were evaluable for efficacy. RESULTS: The most common adverse events were related to the injection site, were mild to moderate, and did not worsen at later treatments. The proportion of subjects who resolved was higher in the ZYC101a groups compared to placebo (43% versus 27%), but the difference was not statistically significant (P = .12). In a prospectively defined population of women younger than 25 years (n = 43), resolution was significantly higher in the combined ZYC101a groups compared to placebo (70% versus 23%; P = .007). ZYC101a activity was not restricted to HPV-16– or HPV-18–positive lesions. CONCLUSIONS: ZYC101a was shown to be well tolerated in all patients and to promote the resolution of CIN 2/3 in women younger than 25 years. LEVEL OF EVIDENCE: I

Cervical cancer in pregnancy : reporting on planned delay in therapy

Objective:To report our experience with invasive carcinoma of the cervix during pregnancy, assessing maternal morbidity due to treatment delay and reporting maternal and fetal outcome.Methods:Twenty-seven patients with invasive cervical cancer, who were pregnant at the time of diagnosis or treatment

Evolution of cervical abnormalities among women with HIV-1: Evidence from surveillance cytology in the Women's Interagency HIV Study

Objective: To determine incidence, progression, and regression rates for abnormal cervical cytology and their correlates among women with HIV. Methods: In a multicenter prospective cohort study conducted October 1, 1994, through September 30, 1999 at university, public, and private medical centers and clinics, 1639 HIV‐seropositive and 452 seronegative women were evaluated every 6 months for up to 5 years using history, cervical cytology, T‐cell subsets, and quantitative plasma HIV RNA. Human papillomavirus (HPV) typing at baseline was determined by polymerase chain reaction. Cytology was read using the Bethesda system, with any smear showing at least atypia considered abnormal. Poisson regression identified factors associated with incident cytologic abnormalities whereas logistic regression identified those associated with progression and regression after an abnormality. Results: At least one abnormal smear was found during all of follow‐up among 73.0% of HIV‐seropositive patients and 42.3% of seronegatives (p < .001). Only 5.9% of seropositives ever developed high‐grade lesions, and the proportion with high‐grade findings did not rise over time. Incidence of atypical squamous cells of uncertain significance (ASCUS) or more severe lesions among HIV‐seropositive patients and seronegative patients was 26.4 and 11.0/100 woman‐years (rate ratio [RR], 2.4; 95% confidence interval [CI], 1.9‐3.0), whereas that of at least low‐grade squamous intraepithelial lesions (SIL) was 8.9 and 2.2/100 (RR, 4.0; CI, 2.6‐6.1). HIV status, detection of the presence of human papillomavirus (HPV), CD4 lymphocyte count, and HIV RNA level predicted incidence of abnormal cytology (p < .05); HPV detection and HIV RNA level predicted progression (p < .01); and HPV detection, CD4 lymphocyte count, and HIV RNA level predicted regression (p < .001). Rates of incidence, progression, and regression of abnormal cytology did not differ between HIV seronegative women and seropositive women with CD4 lymphocyte counts >200/mm3 and HIV RNA levels <4000/ml of similar HPV status. Conclusions: Although HIV infected women were at high risk for abnormal cytology, high‐grade changes were uncommon. HIV status, HPV detection, CD4 lymphocyte count, and HIV RNA level predicted the incidence of cervical cytologic abnormalities. Progression was significantly increased only among the most immunosuppressed women, while regression was significantly reduced in all HIV seropositive women except those with the best controlled HIV disease.

Cold-knife conization versus conization by the loop electrosurgical excision procedure: A randomized, prospective study

Abstract Objective: Our purpose was to compare the diagnostic ability and treatment efficacy of conization by the loop electrosurgical excision procedure with cold-knife conization. Study Design: One hundred eighty women who required conization for diagnosis and treatment of cervical dysplasia or microinvasive cervical carcinoma were prospectively enrolled in a randomized clinical trial to receive either cold-knife conization or conization by the loop electrosurgical excision procedure. Conization complications, rate of lesion clearance, and therapeutic outcome were assessed for the 2 study groups. Results: There were no statistically significant differences in the complication rate ( P = 1.00), the rate of lesion clearance ( P = .18), or the rate of disease recurrence ( P = .13) between the 2 study groups. The mean follow-up was 11.2 months in the cold-knife conization group and 10.4 months in the loop-excision conization group. Conclusion: Cold-knife conization and loop-excision conization yield similar diagnostic and therapeutic results. (Am J Obstet Gynecol 1999;180:276-82.)

Effect of HIV infection on menstrual cycle length.

Summary: HIV serostatus and menstrual function were examined using prospectively collected menstrual data from 802 HIV‐seropositive and 273 HIV‐seronegative women, ages 20 to 44, enrolled in two cohort studies of HIV infection in North American women. The associations between HIV serostatus and the probabilities of having a cycle lasting >40 days (n = 541 cycles), >90 days (n = 67 cycles), <18 days (n = 316 cycles) and mean length and variability of 18 to 40 day cycles (n = 3634) were assessed. After adjustment for demographic characteristics, body mass index, and substance use, seropositivity increased the odds of having a very short cycle (<18 days, odds ratio [OR], 1.45; 95% confidence interval [CI], 1.00‐2.11) and a very long cycle (>90 days, OR, 1.32; 95% CI, 0.68‐2.58) slightly, although the latter CIs include one. Seropositivity did not increase the odds of having a moderately long cycle (>40 days, OR, 1.14) or affect mean cycle length or variability (&bgr;, 0.30 ± 0.20; between‐woman standard deviation [SD], 2.2 days [HIV‐seronegative] and 1.9 days [HIV‐seropositive]; within‐woman SD, 3.5 days for both). Although seropositivity may slightly increase the probability of very short cycles, HIV serostatus has little overall effect on amenorrhea, menstrual cycle length, or variability. Among HIV‐seropositive women, higher viral loads and lower CD4+ counts were associated with increased cycle variability and polymenorrhea.