Rolland J. Barrett

Reproductive, menstrual, and medical risk factors for endometrial cancer : results from a case-control study

OBJECTIVE Our objective was to evaluate the risk for endometrial cancer in relation to reproductive, menstrual, and medical factors. STUDY DESIGN A case-control study of 405 endometrial cancer cases and 297 population controls in five areas of the United States enabled risk to be evaluated. RESULTS A major risk factor was the absence of a prior pregnancy (relative risk 2.8, 95% confidence interval 1.7 to 4.6). The protective effect of pregnancy appeared to reflect the influence of term births, because spontaneous and induced abortions were unrelated to risk. Among nulliparous women infertility was a significant risk factor, with women having sought medical advice having nearly eight times the risk of those without difficulty conceiving. After adjustment for other reproductive characteristics, age at first birth and duration of breast-feeding were not related to risk. CONCLUSIONS Elevated risks were found for subjects reporting early ages at menarche (relative risk 2.4 for ages < 12 vs > or = 15) and longer days of flow (relative risk 1.9 for > or = 7 vs < 4 days), but there was no relationship with late ages at natural menopause. Height was not associated with risk, but there was a significant relation to weight, with the risk for 200 versus < 125 pounds being 7.2 (95% confidence interval 3.9 to 13.3). After adjustment for weight and other factors, histories of hypertension and gallbladder disease were not significantly related to risk, but an effect of diabetes persisted (relative risk 2.0, 95% confidence interval 1.1 to 3.6). Hirsutism developing at older ages was also significantly related (relative risk 2.0, 95% confidence interval 1.2 to 3.4).

Phase II trial of ifosfamide and mesna in leiomyosarcoma ofthe uterus: A Gynecologic Oncology Group study

Summary OBJECTIVE : The purpose of this study was to evaluate the activity of ifosfamide (isophosphamide) inpatients with advanced or recurrent leiomyosarcoma not previously exposed to chemotherapy STUDY DESIGN : This is a phase II groupwide study of the Gynecologic Oncology Group. Thirty-fivepatients were treated with ifosfamide 1.5 gm/m2 daily intravenously for 5 days with mesna (mercaptoethane sodium sulfonate). Fifty-six patients had received prior abdominal hysterectomy and 15 prior radiotherapy. The dose was reduced to 1.2 gm/m2 daily in patients who had received prior radiotherapy. RESULTS : Gynecologic Oncology Group grade III or IV granulocytopenia occurred in 4 (11%) patients,and none had grade IV thrombocytopenia. One (2.8%) patient had grade IV neurotoxicity. Partial responses were observed in 6 of 35 (17.2%) patients. The 95% confidence interval for response was 6.6% to 33.7%. CONCLUSION : These results indicate that ifosfamide has modest activity in patients with advanced orrecurrent leiomyosarcomas of the uterus. (AM J OBSTET GYNECOL 1992;166:556-9.)

Selective pelvic and periaortic lymphadenectomy does not increase morbidity in surgical staging of endometrial carcinoma.

OBJECTIVE The objective of this study was to retrospectively assess whether there was increased morbidity associated with the addition of selective pelvic and periaortic lymphadenectomy to hysterectomy in patients with endometrial carcinoma. STUDY DESIGN From 1977 through 1988, 196 patients undergoing selective pelvic and periaortic lymphadenectomy plus hysterectomy were compared with 104 patients who underwent hysterectomy alone for endometrial adenocarcinoma. RESULTS Only after adjusting for covariates was selective pelvic and periaortic lymphadenectomy associated with a higher estimated blood loss, which increased linearly with weight and was higher for black than for white women. The transfusion rate was similar for the two groups (selective pelvic and periaortic lymphadenectomy 6%, hysterectomy 10%). The mean blood loss was significantly different among the four gynecologic oncology surgeons (range 343 to 652 ml). The operating time primarily depended on patient weight and race, surgeon, and estimated blood loss. Postoperative hospital stay increased significantly with age, surgeon, wound infections, thrombotic events, and serious complications. Selective pelvic and periaortic lymphadenectomy had no effect on wound infections, which were directly related to operating time. Seventy-five (38%) of the selective pelvic and periaortic lymphadenectomy group and 19 (18%) of the hysterectomy group (p < 0.01) received whole-pelvic radiation with no difference in bowel complications (selective pelvic and periaortic lymphadenectomy 2/75, hysterectomy 1/19). The risk of serious complications was associated only with increasing age. CONCLUSION Selective pelvic and periaortic lymphadenectomy in patients with endometrial carcinoma does not significantly add to morbidity from hysterectomy, which is related primarily to other factors such as patient weight, age, and race; operating time; and surgeon.

Dietary associations in a case-control study of endometrial cancer

Despite the established role of obesity in the etiology of endometrial cancer, limited data are available from analytical epidemiologic studies on the association of risk with dietary factors. A case-control study of 399 cases and 296 controls conducted in five areas of the United States from 1 June 1987 to 15 May 1990, enabled evaluation of risk related to dietary intakes adjusted for potential confounders. Caloric intake was associated modestly with increased risk (odds ratio [OR]=1.5,95 percent confidence interval [CI]=0.9–2.5 for highest cf lowest quartiles of intake), with the principal contributors being fat and protein calories. After adjustment for other risk factors, including body mass, increased risk was associated with higher intakes of fat. Several components of fat investigated were associated with increased risk, although associations were slightly stronger for saturated fat (OR=2.1, CI=1.2–3.7) and oleic acid (OR=2.2, CI=1.2–4.0) than for linoleic acid (OR=1.6, CI=0.9–2.8). Food-group analyses showed intake of complex carbohydrates—and specifically of breads and cereals—associated with reduced risks (OR=0.6, CI=0.4–1.1), whereas animal fat and fried foods were associated with elevated risks (OR=1.5 and 1.7, respectively). The relations of endometrial cancer with animal fat and complex carbohydrates were independent. No consistent associations were noted for intakes of cholesterol, fiber, vitamins A and C, individual carotenoids, or folate-rich foods. These data imply an etiologic role for a diet rich in total fat and/or animal fat and low in complex carbohydrates with endometrial cancer. These associations are consistent with a hormonal mechanism and were independent of the associations of obesity and other risk factors.

Past and present physical activity and endometrial cancer risk

We examined the relation between physical activity and endometrial cancer using data from a multicentre case-control study involving 405 endometrial cancer cases and 297 population controls. Estimates of recreational (i.e. active sport, walks and hikes) and nonrecreational activity (i.e. house cleaning, climbing stairs and walking or standing on the job) were obtained using interview information. After adjustment for age, study area, education, parity, years of use of oral contraceptives, years of use of menopausal oestrogens and cigarette smoking, recent recreational inactivity was associated with increased risk (RR = 1.9 for lowest vs highest tertile). Similarly, recent nonrecreational inactivity was associated with increased risk (RR = 2.2 for lowest vs highest tertile). Further adjustment for body mass and nonrecreational activity attenuated the association between risk and recent recreational inactivity (RR = 1.2; 95% CL = 0.7-2.0) but adjustment for body mass and recreational activity did not alter the association between risk and recent nonrecreational inactivity (RR = 2.0; 95% CL = 1.2-3.1). To evaluate the relation between risk and sustained inactivity, we simultaneously examined activity levels at three periods (RR i.e. age 20-29, age 30-39 and recently) in women age 50 and older. After adjustment for potential confounders and body mass, risk was elevated among women who were always recreationally inactive (RR = 1.5 for always active vs always inactive) and among women who were always nonrecreationally inactive (RR = 1.6 for always active vs always inactive). This study suggests that physically inactive women may be at increased risk of endometrial cancer because they are more likely to be overweight or obese. Our data also suggest that inactivity per se may be associated with an increased risk of endometrial cancer. However, we cannot rule out the possibility that our results, particularly those for nonrecreational activity, reflect unmeasured confounding factors. Future studies should attempt to obtain more detailed assessments of physical activity, including the intensity with which an individual engaged in an activity and the actual time involved in exertion.

A phase II trial of tricyclic nucleoside phosphate in patients with advanced squamous cell carcinoma of the cervix. A Gynecologic Oncology Group Study.

A Phase II trial of TCN-P was conducted in metastatic or recurrent squamous cell carcinoma of the cervix using a 5-day continuous infusion schedule. The starting dose was 35 mg/m2 × 5 days and courses were repeated every 6 weeks. Among 21 evaluable patients, 2 responses were observed. One patient had a complete response for 19+ months. Another patient had a partial response for 5+ months, but developed symptomatic hypocalcemia, requiring discontinuation of the drug. Using this dose and schedule TCN-P appears to have limited activity in metastatic or recurrent squamous cell cancer of the cervix.

Neuroendocrine features in poorly differentiated and undifferentiated carcinomas of the cervix

Neuroendocrine or argyrophil cell carinoma of the cervix has recently been accepted as a distinct clinical‐pathological entity. The histologic pattern of these carcinomas is usually poorly differentiated or undifferentiated. Twenty patients with a histologic diagnosis of small cell carcinoma, undifferentiated carcinoma, poorly differentiated adenocarcinoma, or poorly differentiated, adenosquamous carcinoma of the cervix were evaluated for neuroendocrine features. The results of studies to detect neurosecretory granules were positive in seven of the 20 cases. Not only small cell carcinomas, but also tumors classified as undifferentiated carcinoma and poorly differentiated, adenosquamous carcinoma contained cytoplasmic granules consistent with neuroendocrine carcinoma of the cervix. The prognosis for survival appears poorer for patients having tumors with neurosecretory granules after controlling for stage and histologic grade of the neoplasm.

Endometrial cancer: Stage at diagnosis and associated factors in black and white patients

OBJECTIVE This study examined the relationship of clinicopathologic, health status, medical system, and socioeconomic factors to differences in stage at diagnosis of endometrial cancer in black and white patients. STUDY DESIGN A population-based study of 130 black and 329 white patients with invasive endometrial cancer was conducted as part of the National Cancer Institutes Black/White Cancer Survival Study. Logistic regression was used to determine the relative importance of factors thought to be related to stage at diagnosis after age and geographic location were adjusted for. RESULTS High-grade (poorly differentiated) lesions increased the risk for stage III or IV disease (odds ratio 8.3, 95% confidence interval 3.4 to 20.3), as did serous histologic subtype (odds ratio 3.5, 95% confidence interval 1.4 to 8.8) and no usual source of care (odds ratio 5.5, 95% confidence interval 1.4 to 20.9). In the final statistical model these three factors also accounted for the majority of the excess risk of advanced stage for blacks. CONCLUSIONS Black-white racial disparities in stage at diagnosis appear to be related to higher-grade lesions and more aggressive histologic subtypes occurring more frequently in black patients with endometrial cancer.

Moderate Alcohol Consumption and the Risk of Endometrial Cancer

In a multicenter case-control study that included 400 cases and 297 controls, we examined the relation of moderate alcohol consumption to risk of endometrial cancer. We estimated average weekly intake of alcohol during adulthood from the reported frequency of intake of beer, wine, and liquor. The relative risk of endometrial cancer was 0.82 (95% confidence interval = 0.6-1.2) among women who drank, compared with lifelong abstainers. The weak protective effect of alcohol was due to a stronger inverse association among young women (< 55 years). In young women, the age-adjusted relative risks for three levels of drinking ( < 1, 1-4, > 4 drinks per week), from lowest to highest, were 0.78, 0.64, and 0.41 compared with nondrinkers. The risk estimates were not materially altered after adjustment for a variety of factors related to alcohol intake and to low risk of the disease (for example, smoking, oral contraceptive use, low body mass index, increased physical activity). The protective effect of alcohol could not be attributed to one particular type of alcohol-containing beverage, but beer appeared to have the most pronounced effect. These results suggest an inverse association between moderate alcohol consumption and endometrial cancer risk among young women, but support for a causal association is qualified and requires confirmation.

Circadian-timed combination doxorubicin-cisplatin chemotherapy for advanced endometrial carcinoma : a phase II study of the Gynecologic Oncology Group

Patients with advanced or recurrent endometrial cancer of any cell type having measurable disease have been entered into this study to determine the effectiveness and toxicity of circadian-timed doxorubicin-cisplatin chemotherapy. This Phase II study involved no randomization with treatment initiated with doxorubicin 60 mg/m2 over 30 minutes at 6:00 a.m., followed by cisplatin 60 mg/m2 over 30 minutes at 6:00 p.m. every 28 days. Treatment was continued for eight cycles or to a maximum tolerable doxorubicin dose of 480 mg/m2 for patients without progression. Thereafter, responders continued on cisplatin alone. A review of 30 evaluable patients showed 6 (20%) complete responses, 12 (40%) partial responses, and 7 (23%) with stable disease. The number of treatment courses ranged from 2 to 14 with a median of 6.5. the median white blood cell nadir for the 27 patients experiencing leukopenia was 1,600/mm3 (range: 300–3,600/mm3). For the 16 patients experiencing thrombocytopenia the median nadir was 48,500/mm3 (range: 8,000–138,000/mm3). There were no treatment-related deaths. Circadian-timed delivery of doxorubicin-cisplatin chemotherapy was reasonably well tolerated and demonstrated notable response rates in patients with advanced or recurrent endometrial carcinoma.