Thirty-year follow-up of chemo/hormonal therapy in node-positive breast cancer.

Results of a thirty-year follow-up of a clinical trial of chemo-hormonal therapy are reported. Eligible patients had recently diagnosed operable breast cancer, positive lymph nodes, no previous history of cancer, age less than 76 years, and no evidence of metastatic disease. A total of 311 patients were stratified by estrogen receptor (ER) status and number of axillary nodes involved with tumor. After stratification, patients were randomly assigned to one of three treatment regimens: cyclophosphamide, methotrexate and 5-fluorouracil (CMF) for 1 year; CMF chemotherapy combined with anti-estrogen therapy (tamoxifen) for 1 year; or CMF plus tamoxifen with BCG during the second year. The endpoint of the trial was a first recurrence. Factors measured at diagnosis and used in the analyses were age, body mass index, ER status, menopausal status, number of positive nodes, tumor diameter, Charlson comorbidity index, socioeconomic status, and race. Causes of death and incidence of other cancer primaries were obtained from death certificates and medical records. Patients treated with tamoxifen had a marginally longer disease-free survival (hazard ratio (HR)=0.83, 95% CI identical with [0.66, 1.04]) and statistically significant longer overall survival (HR=0.77, 95% CI identical with [0.63, 0.96]) that decreased with time. Incidence of other primary cancers and causes of death were similar for the two treatment groups. The addition of 1 year of tamoxifen to CMF therapy provides an early disease-free and overall survival advantage; however long-term effects are negligible. Similarly, the survival advantage of patients diagnosed with ER+ tumors persists for the first two decades after diagnosis.

Determinants of anemia in pre-school children in the occupied Palestinian territory.

This paper presents the main findings of an analysis linking the dependent variable - anemia in pre-school children - to its determinants, to identify priority groups for action. The study was a cross sectional survey of randomly selected pre-school children 6-59 months (n = 3331) in the occupied Palestinian territory during the current uprising. Anemia (Hb <11 g/dl) in children was determined by a blood sample. Other indicators were examined; 24 variables related to the family, housing, maternal and child characteristics, in addition to changes in income and food intake that occurred during the uprising. Multivariate analysis revealed that anemia was independently related to reduction in income, iron intake, infrequent gastrointestinal infections, stunting and current breast feeding status. In addition, region was an independent risk factor for anemia - in the West Bank there were fewer anemic children in the age group 6-35 months compared to children from the same age group living in the Gaza Strip.

Hospital readmission among long-term ventilator patients.

STUDY OBJECTIVES: Patients experiencing prolonged periods of in-hospital mechanical ventilation have been described as long-term ventilator (LTV) patients. The purpose of this study was to document the incidence of hospital readmission and to identify risk factors for readmission for LTV patients up to 6 months after hospital discharge. DESIGN: This study was part of a larger prospective longitudinal descriptive study of posthospital outcomes for LTV patients. SETTING AND PARTICIPANTS: One hundred ninety-nine ICU patients admitted to a university medical center, Veterans Administration hospital, or small community hospital who required > 96 h of continuous in-hospital mechanical ventilation were enrolled. MEASUREMENTS AND RESULTS: Descriptive statistics, logistic regression, and survival analytic techniques were used. The 6-month hospital readmission rate was 38%. Readmission occurred most often within days 1 to 60 days (mean, 39.2 days) posthospital discharge. Predictive variables for readmission were the following: length of the index hospital stay; length of the index mechanical ventilation; and the need for oxygen at hospital discharge. Using survival analysis, the age category of 66 to 71 years was statistically significant for the relative risk of readmission within the first 30 days of the index hospital discharge. CONCLUSIONS: LTV patients should be considered at risk for hospital readmission. Further study examining the impact of closer follow-up in the first 60 days posthospital discharge is necessary in order to determine whether there is a more effective way of reducing the risk of readmission for LTV patients.

Phase II and pharmacokinetic/pharmacodynamic trial of sequential topoisomerase I and II inhibition with topotecan and etoposide in advanced non-small-cell lung cancer.

PURPOSE: In vitro and in vivo preclinical models have demonstrated synergistic activity when topoisomerase I and II inhibitors are administered sequentially. Topoisomerase I inhibitors increase topoisomerase II levels and increase cell kill induced by topoisomerase II poisons. We evaluated this hypothesis in a cohort of patients with advanced non-small-cell lung cancer (NSCLC). METHODS: A group of 19 patients with advanced NSCLC (70% adenocarcinoma) received topotecan at a dose of 0.85 mg/m2 per day as a continuous 72-h infusion from days 1 to 3. Etoposide was administered orally at a dose of 100 mg twice daily for 3 days on days 7-9 (schedule and dose derived from prior phase I trials). Total and lactone topotecan concentrations were measured at the end of the 72-h infusion. Blood samples were obtained immediately after each 72-h topotecan infusion in order to measure the mutational frequency at the hypoxanthine phosphoribosyl transferase (HPRT) locus in peripheral lymphocytes. RESULTS: A total of 55 cycles were administered. Toxicity was mainly hematologic with grade 4 neutropenia occurring in 7% of courses. Only one partial response and two stable diseases were observed. The 1-year survival rate was 33%. There was a statistically significant difference between steady-state lactone concentrations between cycle 1 and cycle 2 with decreasing concentrations with cycle 2 (P = 0.02). This was explained by a statistically significant increase in the clearance of topotecan lactone during cycle 2 (P = 0.03). Total but not lactone concentrations correlated with nadir WBC, ANC and platelet levels. Steady-state plasma lactone levels correlated with the mutational frequency at the HPRT locus (P = 0.06). In the one patient with a partial response a sixfold increase in HPRT mutational frequency was observed, which was not seen in patients with progressive disease. CONCLUSION: The combination of topotecan and etoposide in this schedule of administration has minimal activity in adenocarcinoma of the lung. This lack of activity may be due to the delay in administration of etoposide after the topotecan as studies have shown that the compensatory increase in topoisomerase II levels after treatment with topoisomerase I inhibitors is shortlived (<24 h). The HPRT mutational frequency results suggest that the lack of clinical response may be associated with failure to achieve sufficient cytotoxic dose as indicated by a lack of increase in mutational frequency in those patients with progressive disease. HPRT mutational frequency may correlate with plasma steady-state topotecan lactone levels. Future studies should be directed toward earlier administration of topoisomerase II inhibitors after topoisomerase I inhibition.

The metabolic syndrome in the West Bank population: an urban-rural comparison.

OBJECTIVE: To compare the prevalence of components of the metabolic syndrome, including hypertension, abnormal glucose metabolism, dyslipidemia, central obesity, and overall obesity, between a rural and an urban Palestinian West Bank community. RESEARCH DESIGN AND METHODS: A total of 500 rural and 492 urban men and women aged 30-65 years participated in a community-based cross-sectional survey Diabetes and impaired glucose tolerance were diagnosed using the oral glucose tolerance test. BMI, waist-to-hip ratio, and blood pressure were measured, and blood samples were taken from each subject. Sociodemographic characteristics were investigated using a questionnaire. RESULTS: Hypertriglyceridemia, low HDL cholesterol, overall obesity, and smoking were significantly more prevalent in the urban population, whereas central obesity was more prevalent in the rural population. Prevalence of hypertension was not significantly different between the rural and urban populations (25.4 and 21.5%, respectively; P = 0.15). The age-adjusted prevalences of diabetes were high: 11.3% (8.5-14.1 95% CI) and 13.9% (10.8-17.0) in the rural and urban populations, respectively, but not significantly different. In each community, the age-adjusted prevalence of the metabolic syndrome as defined by the World Health Organization was 17%. CONCLUSIONS: Although no significant differences were found in the prevalences of hypertension and diabetes between the two populations, other components of the metabolic syndrome, namely elevated triglycerides, low HDL cholesterol, and overall obesity, were more prevalent in the urban population. Given the rapid urbanization of the Palestinian population, the implications for a rise in noncommunicable diseases should be a major public health concern.

A phase II and pharmacokinetic study of weekly 72-h topotecan infusion in patients with platinum-resistant and paclitaxel-resistant ovarian carcinoma.

BACKGROUND: As suggested by preclinical trials, prolonged administration of topotecan, a reversible inhibitor of topoisomerase-I, may have a therapeutic advantage. Following a phase I trial of weekly 72-h topotecan infusion, we performed a phase II trial utilizing this schedule in ovarian carcinoma. METHODS: Eligibility included platinum-/paclitaxel-resistant ovarian carcinoma, measurable disease, and adequate hematologic, renal, and hepatic function. A dose of 2.0 mg/m(2) of topotecan was administered as a 72-h infusion weekly via an ambulatory pump. Plasma topotecan concentrations were determined prior to and at the completion of each weekly course. RESULTS: Twenty-four patients were entered and 23 patients were evaluable for toxicity and response. Two hundred eighteen weekly courses of therapy were administered (median 7 weeks, range 4-46 weeks). Toxicity was mild with grade 3 leukopenia, neutropenia, and anemia occurring in 13, 13, and 17% of patients, respectively. Two of 23 patients (9.1%) (CI 1-28%) had partial responses of 2 and 3 months' duration and 6 had stable disease. Steady state plasma topotecan lactone concentrations were a median of 1.2 ng/ml (range 0.4-8.00 ng/ml) following the first week of infusion. Steady state topotecan lactone concentrations after the first week of infusion were highest in 2 patients with partial responses. Mean steady state plasma topotecan lactone concentrations after the first week of infusion were 4.6, 2.0, and 1.3 ng/ml for partial response, stable disease, and progressive disease, respectively. An analysis of variance of steady state plasma topotecan concentrations after the first week of infusion over all administered cycles demonstrated a significant difference in steady state plasma topotecan lactone concentrations between patients with partial response and stable disease and between partial response and no response (significant at the 0.05 level after adjustment for multiple comparisons). Controlling for cycle number, steady state topotecan lactone concentrations are significantly greater for patients with responding or stable disease than those with progressive disease (P = 0.0003) and have a lower bound of > or = 1.9 ng/ml (95% confidence level). CONCLUSION: Steady state topotecan lactone concentrations are associated with responding or stable disease in platinum- and paclitaxel-resistant ovarian cancer. Steady state topotecan concentrations could potentially be utilized to modify tumor exposure and response.

Managed care for the Medicaid disabled: effect on utilization and costs.

The objective of this study was to describe the effect on health care utilization and costs of a program of managed care for the Medicaid disabled. The study was designed as a pre/post enrollment cohort comparison and was carried out in three Ohio counties. The subjects were disabled Medicaid-insured patients who voluntarily enrolled in a managed care program for at least 6 months between July 1, 1995 and December 31, 1997, and who had (1) at least one Medicaid claim in the 24-months pre-enrollment period and (2) overall satisfactory postenrollment encounter-level data. Ohio Medicaid provided claims and reimbursements (costs) for the pre-enrollment period and encounter-level data for the postenrollment period. Postenrollment costs were estimated by applying category-specific average pre-enrollment costs to postenrollment utilization data. We measured the following per patient-month: (1) trends in category-specific utilization and costs for up to 24 months before and after enrollment, (2) differences in overall and category-specific costs 1 year before and after enrollment, and (3) changes in the distribution of services 1 year before and after enrollment. Utilization categories included inpatient care, outpatient hospital (including emergency department) care, physician services, prescription medications, durable medical equipment and supplies, and home health care. We found that satisfactory encounter data were available in two of three counties. Of 1,179 enrollees, 592 met all inclusion criteria. Before enrollment, utilization and costs were increasing significantly in four of six categories and were unchanging in two. Postenrollment, decreasing utilization was observed for three categories, one remained unchanged, and two were increasing, but from a lower "baseline." Except for physician services and home health care, there were lower utilization and estimated costs in all categories in the year after enrollment. Estimated inpatient and total costs declined by $155/patient-month (44.9%) and $210/patient-month (37.1%), respectively. Findings were similar across sites. Inpatient care, outpatient hospital care, and prescription medications accounted for 97% of the reductions in estimated costs in the postenrollment period. Among patients voluntarily enrolled for at least 6 months, managed care for the Medicaid disabled was associated with striking decreases in health care utilization and estimated costs. The effect of managed care on these patients' satisfaction, access to specialized services, quality of care, and health outcomes are understood incompletely.

O6-methylguanine-DNA methyltransferase (MGMT) transfectants of a 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU)-sensitive colon cancer cell line selectively repopulate heterogenous MGMT+/MGMT- xenografts after BCNU and O6-benzylguanine plus BCNU.

To evaluate the role of O6-alkylguanine-DNA alkyltransferase (AGT) in colon tumor chloroethylnitrosourea (CENU) resistance, AGT-deficient VACO 8 cells were transfected with a vector containing or lacking the human O6-methylguanine-DNA methyltransferase (MGMT) cDNA. VACO 8MGMT (V8MGMT) sublines possessed high levels of AGT activity in cell culture and were > 10-fold resistant to the CENU 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). V8MGMT cells, VACO 8neo cells, and mixtures of both were grown as xenografts in nude mice. MGMT expression in VACO 8 xenografts reflected the percentage of V8MGMT cells present in the tumor inoculum. Xenografts originally containing 0-10% V8MGMT cells were sensitive to BCNU, although partial resistance was observed as the percentage of V8MGMT cells increased. Tumors containing 30-100% V8MGMT cells were completely resistant to BCNU with no regressions and no growth delays. Pretreatment with O6-benzylguanine (BG) depleted tumor AGT activity for at least 6 h and sensitized xenografts containing 1 and 100% V8MGMT cells to BCNU. After BCNU or BG + BCNU, xenografts growing from inoculums containing as low as 0.1% V8MGMT cells had high AGT activities similar to that found in V8MGMT xenografts, with the majority of the cells expressing MGMT. These results provide evidence that MGMT expression influences both intrinsic and acquired colon tumor CENU resistance, that selective expansion of AGT+ colon tumor cells commonly occurs after CENU exposure, and that BG is effective in sensitizing colon tumors to CENUs, even when only a small fraction of the cells in a heterogeneous tumor express MGMT.

Relationship between the size and margin status of ductal carcinoma in situ of the breast and residual disease.

BACKGROUND: For women with ductal carcinoma in situ (DCIS) of the breast who have been treated with breastconserving surgery, the usefulness of size and surgical margin status (i.e., presence or absence of disease at the point of excision) as prognostic factors for predicting residual disease has not been well established. This study was conducted to determine more clearly the relationship between size and margin status of mammary DCIS to residual disease. METHODS: The pathology records of 232 consecutive patients with mammary DCIS who had been initially treated with lumpectomy at the University Hospitals of Cleveland were retrospectively reviewed. The size of the DCIS and the surgical margins of lumpectomy were analyzed. Residual disease was defined as the persistence of DCIS in the re-excision and/or mastectomy specimens. RESULTS: Residual disease was found in 15 of 101 patients with DCIS of less than 1.0 cm in longest dimension, in 27 of 96 patients with DCIS of 1.0-2.4 cm in size, and in 24 of 35 patients with DCIS of greater than or equal to 2.5 cm in size (P<.001). Residual disease was found in 30 of 77 patients with DCIS and positive margins, in 11 of 59 patients with DCIS and close margins (< or =1mm), and in 10 of 73 patients with DCIS and negative margins (>1 mm) (P =.001). In multivariate analysis, the occurrence of residual disease was associated with large tumor size (i.e., > or =2.5 cm) (odds ratio [OR] = 7.7; 95% confidence interval [CI] = 3.13-20.00; two-sided P = .0001) and with positive margin status (OR = 2.2; 95% CI = 1.02-4.55; two-sided P = .04). CONCLUSIONS: The size and margin status of DCIS each were found to be independent predictors of residual disease.

The results of intraoperative consultations in 181 ductal carcinomas in situ of the breast.

BACKGROUND: The utility of frozen section (FS) examination in the intraoperative management of breast lesions is well established. The accuracy of FS in the diagnosis of borderline noninvasive or preinvasive breast lesions is uncertain. METHODS: The authors retrospectively reviewed the results of intraoperative consultations/frozen section examinations of 181 ductal carcinomas in situ (DCIS) of the breast. Various clinical and pathologic factors were analyzed and correlated with FS diagnosis. RESULTS: FS examination was performed on 153 cases (85%) and only macroscopic examination on 28 cases (15%). FS diagnoses were as follows: DCIS in 76 cases (50%), atypical ductal hyperplasia/suspicious for DCIS in 8 cases (5%), benign in 55 cases (36%), deferred in 13 cases (8%), and invasive carcinoma in 1 case. FS accuracy, false-negative rate, and false-positive rate were 55%, 36%, and 0.6%, respectively. Sampling error was the main reason for the low detection rate, and technical inadequacy was a major factor contributing to interpretive problems. In multivariate regression analysis, FS accuracy was significantly associated with the clinical presentation of a palpable mass (odds ratio [OR] = 4.16, 95% confidence interval [CI]: 2.04-8.45), the macroscopic finding of a mass (OR = 3.03, 95% CI: 1.45-6.67), and necrosis (OR = 3.13, 95% CI: 1.4-6.67). CONCLUSIONS: The authors concluded that the accuracy of FS diagnosis of DCIS was low, mainly due to sampling error. In general, FS examination should not be performed when no lesion/mass is identified by macroscopic examination.

Topotecan increases topoisomerase IIalpha levels and sensitivity to treatment with etoposide in schedule-dependent process.

To elucidate the effect of topoisomerase (Topo) I inhibitors in the modulation of Topo II levels and sensitivity to Topo II-directed drugs, athymic mice bearing SW480 human colon cancer xenografts were treated with simultaneous, subsequent, or distant doses of topotecan and etoposide. This in vivo study demonstrates that simultaneous administration of topotecan and etoposide results in an antagonistic response. In contrast, inhibition of Topo I by topotecan results in a compensatory increase in Topo II alpha levels associated with increasing sensitivity of tumors to subsequent treatment with the Topo II inhibitor etoposide. Furthermore, we show that Topo II alpha levels decline 5 days after the last dose of topotecan, resulting in restoration of the original response of the xenografts to etoposide. Thus, this study emphasizes the critical role of schedule dependency to optimize the effectiveness of combination chemotherapy with Topo I and Topo II inhibitors.

Adjuvant chemotherapy plus tamoxifen compared with tamoxifen alone for postmenopausal breast cancer: meta-analysis of quality-adjusted survival.

BACKGROUND: Adjuvant tamoxifen for early breast cancer provides an improvement in relapse-free (RFS) and overall survival (OS), especially for older women. We carried out a meta-analysis to find out whether the benefit of adding chemotherapy to tamoxifen outweighs its costs in terms of toxic effects for postmenopausal patients. METHODS: The meta-analysis of quality-adjusted survival was based on data from 3920 patients aged 50 years or older with node-positive breast cancer randomly assigned in nine trials that compared combination chemotherapy plus tamoxifen with tamoxifen alone. The nine trials were included in the worldwide overview conducted by the early breast cancer trialists' collaborative group (EBCTCG). The quality-adjusted time without symptoms or toxicity (Q-TWiST) method was used to provide treatment comparisons incorporating differences in quality of life associated with subjective toxic effects of treatment and symptoms of disease relapse. FINDINGS: Within 7 years of follow-up the modest benefit of increased RFS and OS for patients who received chemotherapy just balanced the costs in terms of acute toxic side-effects. Chemotherapy-treated patients gained an average of 5.4 months of RFS and 2 months of OS (neither statistically significant), but had to receive cytotoxic treatment for between 2 and 24 months to achieve these gains. No values of preference weights for time spent undergoing chemotherapy and time after relapse gave significantly more Q-TWiST with chemotherapy plus tamoxifen than with tamoxifen alone. INTERPRETATION: Within 7 years of follow-up, adjuvant chemoendocrine therapy did not provide more quality-adjusted survival time than tamoxifen alone for women aged 50 years or older with node-positive breast cancer. Better selection and administration of chemotherapy regimen, different scheduling of chemotherapy and tamoxifen, and appropriate use of patient and tumour characteristics may increase the therapeutic advantage of the combination.

Association of education and income with estrogen receptor status in primary breast cancer.

The relation of education and income to the estrogen receptor status of primary breast tumors was studied using two patient groups. The first consisted of 887 women from northeastern Ohio who were diagnosed between late 1974 and 1985 and entered into either of two prospective breast cancer clinical trials. All estrogen receptor values were determined by one laboratory. Through loglinear regression, patterns of association were studied among patient characteristics such as age, race/ethnicity, menopausal status, census tract indices of poverty and education, tumor diameter, stage of disease, obesity, and height and weight at the time of diagnosis. In this group of patients, estrogen receptor status was directly related to age, poverty, educational level, and tumor size. Younger women (odds ratio (OR) = 1.57, 95% confidence interval (CI) 1.14-2.17), women from census tracts with greater poverty (OR = 1.77, 95% CI 1.28-2.44) or less education (OR = 1.98, 95% CI 1.43-2.73), and women with larger tumors (OR = 0.67, 95% CI 0.48-0.92) were more likely to have estrogen receptor-negative tumors at the time of diagnosis of primary breast cancer. The second group consisted of 604 patients from northeastern Ohio whose tumors were diagnosed between 1986 and mid-1992 at University Hospitals of Cleveland. All estrogen receptor values were determined by one laboratory. Results from this second group of patients confirmed those from the first. This association of estrogen receptor-negative tumors with low economic and educational levels provides a potential explanation for the poor prognosis of these women.

Modulation of O6-alkylguanine alkyltransferase-directed DNA repair in metastatic colon cancers.

PURPOSE: Carmustine (BCNU) resistance has been correlated with tumor expression of the DNA repair enzyme O6-alkylguanine-DNA alkyltransferase (AT). It has been shown that streptozotocin will deplete AT activity of human colon cancer cells in vitro and potentiate BCNU cytotoxicity. This clinical trial was conducted to determine whether streptozotocin can be used as a modulator of AT in metastatic colorectal cancers and thereby overcome clinical resistance to BCNU. PATIENTS AND METHODS: Fifteen patients with fluorouracil-resistant metastatic colon or rectal cancers were treated sequentially with 2 g/m2 of streptozotocin followed 5 1/2 hours later by BCNU. Sequential biopsies of metastases before and after streptozotocin were conducted to determine whether streptozotocin depletes tumor AT. Peripheral-blood mononuclear cells (PBMCs) were evaluated as a surrogate tissue for prediction of baseline AT levels and streptozotocin posttreatment modulation of the AT in metastases. RESULTS: Streptozotocin treatment led to a 78% (range, 69% to 89%) decrease in the AT levels in colon cancer metastases; however, myelosuppression and hepatic toxicity limited the BCNU dose to 130 mg/m2. A similar decrease in AT levels of PBMCs was found; however, the absolute levels of AT in PBMCs at baseline and following streptozotocin were not predictive of the levels expressed in metastases from the same patient. Despite the decrease in tumor levels of AT, no clinical responses were observed. CONCLUSION: Streptozotocin decreases but does not fully deplete AT activity in metastatic colorectal cancers and the residual AT level in metastases is sufficient to maintain clinical resistance to BCNU. We have also demonstrated that sequential computed tomography (CT)-directed biopsies of colorectal cancer metastases can be used to evaluate strategies to investigate modulators of AT-directed repair. AT levels of PBMCs do not predict for the AT level or degree of modulation achieved in the metastatic tumor.

Age does not predict breast cancer outcome.

OBJECTIVE: To determine whether age is a prognostic factor of breast cancer and should be used to make treatment recommendations, because younger patients are considered to have a poorer prognosis compared with that of older patients and, thus, often receive more aggressive therapy. DESIGN: A large group of patients with operable breast cancer, all of whom were followed up prospectively as part of two multicenter trials. SETTING: Case Western Reserve University, Cleveland, Ohio, was the primary hospital and study center, with 12 participating regional institutions. PATIENTS: All 1353 patients underwent uniform local-regional therapy that consisted of a modified radical mastectomy. Patients who were node negative were followed up, and patients who were node positive received systemic chemoendocrine therapy. MAIN OUTCOME MEASURES: Patients were followed up at regular intervals for either recurrence or death. RESULTS: Patients ranged in age from 22 to 75 years with a median age of 56 years. Younger patients had more estrogen receptor-negative tumors (P < .0001) and a greater number of positive lymph nodes (P < .0001). Of the 241 black patients in the study, a greater percentage were younger compared with white patients (P < .0001). Age was considered in a Cox's multivariate model, together with nodes, tumor diameter, estrogen receptor content, and race. Age was not a significant predictor of either disease-free (P = .33) or overall (P = .30) survival. Using mixture models with covariates, the estimated average hazards (where lambda indicates the force of mortality) of breast cancer deaths per year were similar (P, not significant) for patients 45 years old or younger (lambda = 0.061), older than 45 years but 65 years old or younger (lambda = 0.052), and older than 65 years (lambda = 0.061). CONCLUSIONS: In conclusion, younger patients as a group have more aggressive and advanced breast cancer at presentation compared with older patients. Considered in a multivariate model, together with other variables, age does not provide independent prognostic information and should not be used alone for management decisions.

Synergistic efficacy of O6-benzylguanine and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) in a human colon cancer xenograft completely resistant to BCNU alone.

The DNA repair protein O6-alkylguanine-DNA alkyltransferase (alkyltransferase) repairs cytotoxic DNA damage formed by 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). High levels of this repair protein cause tumor drug resistance to nitrosoureas. To investigate the ability of a direct alkyltransferase inhibitor, O6-benzylguanine, to reverse the nitrosourea resistance of human colon cancer cells, we studied the VACO 6 cell line which has high alkyltransferase and is completely resistant to BCNU at maximal tolerated doses in the xenograft model. O6-Benzylguanine at 0.5 microgram/mL for 1 hr inactivated VACO 6 alkyltransferase by > 98% and reduced the IC50 of BCNU by 3- to 4-fold. Further analysis indicated that these two agents act in a highly synergistic fashion. In xenograft bearing athymic mice, dose-dependent depletion of hepatic and tumor alkyltransferase was noted. To maintain alkyltransferase depletion in the xenograft for at least 24 hr, two doses of 60 mg/kg O6-benzylguanine were given 1 hr prior and 7 hr after BCNU. Under these conditions, VACO 6 xenografts became responsive to BCNU with significant reductions (P < 0.001) in the tumor growth rate. The combination increased toxicity to the host, reducing the maximum tolerated dose of BCNU by approximately 50%. This study provides definitive evidence that high alkyltransferase activity is responsible for BCNU resistance in human colon cancer xenografts and that with careful drug scheduling, O6-benzylguanine can sensitize a tumor which is completely unresponsive to BCNU alone. Further studies which optimize the therapeutic index of BCNU and O6-benzylguanine in vivo will define the schedule to be used in broader preclinical studies.

Using toxicity grades in the design and analysis of cancer phase I clinical trials.

Ethical considerations in a cancer phase I trial require a design allowing determination of the maximum tolerated dose with a minimum number of patients treated at low ineffectual or high overly toxic doses. It would also be advantageous to complete the phase I trial in as short a period of time and with as few patients as possible to allow further resources for later studies in which patients are treated at the optimal dose. Several dose escalation schemes are compared. These are the Fibonacci, two two-stage schemes, and a proposed scheme which uses knowledge of all toxicity grades. Estimates of the maximum tolerated dose are obtained and compared using the dose escalation schemes alone, a logit model, and a proposed mean response model. Confidence intervals using the delta method are obtained from the logit and mean response models. The proposed scheme and the two-stage schemes have the advantage of requiring fewer patients, particularly at low doses. Confidence intervals obtained from the mean response model have better coverage than those from the logit model. Data from a cancer phase I trial of dipyridamole and acivicin is presented to illustrate the methods.

Primary tumor size. Relevance to breast cancer survival.

In view of current emphasis on identifying prognostic factors for patients with early breast cancer, we studied the importance of tumor size to survival among 1392 patients with primary operable breast cancer who were followed up prospectively. All patients had modified radical mastectomies. Nine hundred seventeen patients had negative nodes and did not receive postoperative adjuvant therapy. Four hundred seventy-five patients had node involvement and received combination chemoendocrine therapy. In a Cox's proportional hazards model, tumor size was a significant predictor of disease-free and overall survival when the number of positive nodes, estrogen receptor status, menopausal status, and race were considered. Among the node-negative group, tumor size explained considerable variation in disease-free and overall survival, varying from a 10-year disease-free and overall survival of 80% and 99% for patients with estrogen receptor-positive tumors measuring 1 cm or less to a 10-year disease-free and overall survival of 51% and 59% for patients with tumors larger than 5 cm.

Socioeconomic factors and race in breast cancer recurrence and survival.

The relation of breast cancer recurrence and overall survival to age, level of estrogen receptors, number of positive lymph nodes, obesity, race, socioeconomic status, and tumor size at the time of diagnosis was considered for 1,392 breast cancer patients (253 black, 1,132 white, and 7 of other races) entered into two multi-institutional prospective clinical trials. Baseline for the first trial was 1974-1979, and that for the second was 1980-1985; follow-up for this report ended in August 1990. Univariately, all factors except age and obesity were significantly related to disease-free survival, and all except age were significantly related to overall survival. A multivariate analysis using Cox's proportional hazards model indicated that a greater number of positive lymph nodes, a larger tumor diameter, lower socioeconomic status, and negative estrogen receptors were significantly related to shorter disease-free survival. After adjustment for socioeconomic status, race ceased to be a significant indicator of either disease-free survival or overall survival. Patients of either race who are of a lower socioeconomic status are more likely to have a recurrence and to die of breast cancer.