Showing papers by "James N. Ingle published in 1997"

An individual patient-based meta-analysis of tamoxifen versus ovarian ablation as first line endocrine therapy for premenopausal women with metastatic breast cancer

Abstract: We performed a meta-analysis of randomized trials comparing tamoxifen to ovarian ablation carried out either by surgery or irradiation as first-line hormonal therapy for pre-menopausal women with metastatic breast cancer. Patients in all trials included were required to have measurable disease and to be currently menstruating or within 1 year of cessation of menses, and to have estrogen receptor (ER) positive or unknown disease (ER negative women were admitted to one of the studies). Individual patient data were obtained from the four studies identified and the results updated to June 1992. A total of 220 eligible patients were enrolled in the four trials. There was no difference in overall response rate between tamoxifen and oophorectomy across the four trials (p = 0.94, Mantel-Haenszel test). The odds reduction for progression was 14% ± 12% and for mortality 6% ± 13% in favour of tamoxifen, results which were not statistically significant (p = 0.32 and 0.72, respectively). Although the design of all four studies included a cross-over to the other therapy, only 54/111 patients receiving ovarian ablation and 34/109 patients receiving tamoxifen as primary therapy actually crossed over to the other arm at the time of disease progression. Response to initial treatment with tamoxifen was predictive of subsequent response to ovarian ablation (p < 0.05), and response to initial therapy with ovarian ablation was predictive of subsequent response to tamoxifen (p < 0.05). Support curves based on log-likelihood ratios revealed that this meta-analysis provides moderate evidence rejecting a 14% advantage for ovarian ablation compared to tamoxifen in terms of odds of disease progression. A 25% advantage for ovarian ablation with respect to odds of death is also rejected with moderate evidence. We conclude that the efficacy of tamoxifen appears to be similar to that of ovarian ablation by surgery or irradiation as first-line therapy for premenopausal, ER positive metastatic breast cancer, and is unlikely to be substantially inferior.

Evaluation of Continuous Infusion Suramin in Metastatic Breast Cancer: Impact on Plasma Levels of Insulin-like Growth Factors (IGFs) and IGF-binding Proteins'

Abstract: Suramin represents a new class of antitumor drugs that targets growth factor networks. In this Phase II trial, suramin was administered by continuous infusion to 10 patients with advanced breast cancer. The target level of 280 microgram/ml suramin was achieved in a median of 10 days; toxicities in this patient group were low. We monitored the insulin-like growth factor (IGF) network in these patients because of the previously defined growth-promoting role of the IGFs in breast cancer. Plasma levels of total IGF-I and total IGF-II showed variable responses to suramin with median decreases of 24 and 23%, respectively, for the 10 patients; for total IGF-I levels, this did not reach statistical significance. On the other hand, free IGF-I plasma levels were consistently and dramatically increased (over 250%) after suramin infusion. IGF-binding proteins (IGFBPs), modulators of IGF bioavailability, were also measured. Levels of IGFBP-3, the major carrier of IGFs in the circulation, were decreased 21% after suramin treatment when measured by immunoradiometric assay. However, the majority of the plasma IGFBP-3 remaining after suramin was not the intact high-affinity IGF-binding form but rather a 30-kDa fragment with markedly reduced affinity for IGF-I. IGFBP-3 protease activity was evident in the plasma of 3 of 10 patients after suramin. Measurements of plasma IGFBP-1, IGFBP-2, and IGFBP-4 revealed no significant changes in response to suramin. The dramatic increase in active free IGF-I seen after suramin raises concern and underscores the importance of measuring relevant biomarkers in clinical trials.

Accelerated hyperfractionation radiation therapy after lumpectomy and axillary lymph node dissection in patients with stage I or II breast cancer: pilot study.

Abstract: PURPOSE: To prospectively assess tolerance to accelerated hyperfractionation radiation therapy in patients undergoing breast-conservation therapy and to exclude, with 90% confidence, a 20% or greater risk of an acute toxic reaction of at least grade 3 (severe). MATERIALS AND METHODS: Thirty-seven patients (aged 33-80 years) with evaluatable cases received 48 Gy in twice-daily 1.6-Gy fractions to the breast and regional lymph nodes (if three or more lymph nodes were involved) and a boost of 9.6 Gy in twice-daily 1.6-Gy fractions. Acute and late effects were scored by using the Radiation Therapy Oncology Group and European Organization for the Research and Treatment of Cancer radiation morbidity criteria. RESULTS: One patient developed a grade 3 acute skin toxic reaction and another grade 3 (continuous) acute edema. There have been no grade 4 (life-threatening) acute toxic reactions, local recurrences, or cancer- or treatment-related deaths. CONCLUSION: This breast-conservation accelerated hyperfractionatio...

Breast cancer survival and the timing of tumor removal during the menstrual cycle.

Abstract: In a retrospective cohort study of 262 premenopausal breast cancer patients treated at the Mayo Clinic between 1965 and 1985, we investigated whether survival was associated with the timing of tumor removal during the menstrual cycle. Participants were women < or = 50 years old who had not used exogenous hormones, been pregnant, been lactating, or given birth within 6 months of diagnosis. The menstrual cycle day at surgery was used to assign women to group 1 (cycle days 0-7), group 2 (cycle days 8-15), or group 3 (after cycle day 15). Cox proportional hazards analysis adjusting for age at diagnosis, stage, tumor size, grade, and node involvement showed a nonsignificantly worse survival for group 2 than for group 3 [hazard ratio (HR), 1.41; 95% confidence interval (CI), 0.89-2.23]. Stratification revealed that the association between survival and timing of tumor removal during the menstrual cycle was slightly stronger among patients with stage II disease (adjusted HR, 1.56; 95% CI, 0.92-2.63). The association was the same among patients with stage II disease and node involvement (adjusted HR, 1.57; 95% CI, 0.82-3.03). Prospective studies using hormone measurements to define menstrual cycle status more accurately than the reported day of the menstrual cycle could provide further insight about the postulated association.

Evaluation of intravenous 6-thioguanine as first-line chemotherapy in women with metastatic breast cancer.

Abstract: 6-Thioguanine (6-TG) is a purine analog that has marked variability in plasma concentration after oral administration. Following the development of a multiple-day i.v. regimen, we performed a phase II trial of this agent as first-line chemotherapy in women with metastatic breast cancer. Forty-one patients with measurable (31 patients) or evaluable (10 patients) disease were entered into this trial. 6-TG was administered i.v. over a 10 min period daily for 5 consecutive days, with a planned cycle length of 35 days. The daily dosage level was 55 mg/m2 in the first 15 patients, but this was increased to 65 mg/m2 in the remaining patients due to inadequate myelosuppression at the lower dose. Six patients, all with measurable disease, achieved a complete response (CR) (two patients) or a partial response (PR) (four patients). Three responses occurred at the 55 mg/m2 level and three at the 65 mg/m2 level. The 95% confidence interval (CI) for the true response rate among patients with measurable disease was 6-39%. The median time to progression was 140 days and median survival time was 460 days. The regimen was well tolerated. We conclude that 6-TG, as given in this study, has limited activity as first-line chemotherapy for women with metastatic breast cancer.

Mitoxantrone dose augmentation utilizing filgrastim support in combination with fixed-dose 5-fluorouracil and leucovorin in women with metastatic breast cancer.

Abstract: Based on reports of substantial antitumor efficacy of the combination of mitoxantrone (DHAD), 5-fluorouracil (FU) and leucovorin (LV), a clinical trial was performed to attempt augmentation of the dose of DHAD with filgrastim support The doses and schedules, all intravenous, were DHAD (total dose divided over days 1 and 2), level I, 16 mg/m2; II, 20 mg/m2; III, 24 mg/m2; IV, 32 mg/m2; and LV, 300 mg, followed by FU, 350 mg/m2, on days 1-3 Filgrastim was given at 5 micrograms/kg/day subcutaneously on days 4-13 The planned cycle length was 21 days Three or 4 patients were to be entered at each dose level and the maximum tolerated dose (MTD) was defined as the dose immediately below that which resulted in 2 patients with dose-limiting toxicity (DLT) in cycle 1 Once an apparent MTD was identified, an additional 6 patients were to be entered Twenty patients (pts) were entered: level I: 3 pts; II: 3 pts; III: 10 pts: IV: 4 pts The major toxicity was found to be cumulative thrombocytopenia with platelet counts < or = 20,000/microL occurring after cycle 1 at all levels beyond level I and five pts (25%) were removed from treatment solely because of platelet toxicity Additional serious toxicities included grade 4 stomatitis in one patient (level IV) and cardiac toxicity in 2 patients with prior doxorubicin exposure Ten pts had measurable and 8 had evaluable disease, and in 17 pts assessed, 5 (29%) achieved an objective response The response rates in this study are lower than reported in the literature for the combination of DHAD, 5FU, LV and this may be related to the fact that only 40% of the patients were removed from protocol treatment because of disease progression On the basis of limited DHAD-dose augmentation, toxicities observed, and modest response rate, the filgrastim-supported DHAD, 5FU, LV regimen as utilized in this study cannot be recommended for further development for treatment of women with metastatic breast cancer