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Biomedical subjects

D C Tormey

Publications and source records attributed to D C Tormey.

At least 73 records · Page 4Linked to original sources
PubMed1989

Six-year results of the Eastern Cooperative Oncology Group trial of observation versus CMFP versus CMFPT in postmenopausal patients with node-positive breast cancer.

The Eastern Cooperative Oncology Group (ECOG) trial of adjuvant cyclophosphamide, methotrexate, fluorouracil, and prednisone (CMFP) or CMFP plus tamoxifen (CMFPT) for 1 year compared with observation alone in 265 postmenopausal patients with node-positive breast cancer is reported with 74 months median follow-up. Overall relapse-free survival tended to favor CMFPT (P = .08), but no survival differences existed between any treatment group. The addition of tamoxifen to CMFP led to slightly (but not significantly) better relapse-free status in all subgroups analyzed. Subgroup analysis based on stratification variables showed significant benefit from CMFP (+/- T) only in estrogen receptor (ER)-negative patients with respect to disease-free status (P = .0003), but not survival (P = .54). Relapse-free status was actually worse for CMFP-treated patients with ER-positive tumors, but not significantly so (P = .15). By multivariate analysis other significant risk factors for relapse-free status were primary tumor size, number of nodes pathologically involved, and the number of nodes examined. ER status was prognostic only for the observation group with the benefit from chemotherapy on ER-negative patients obliterating this difference in treated patients. Survival was affected by the number of involved nodes, tumor size, presence of tumor necrosis, and patient obesity. Analysis of toxicity showed elevation of liver enzymes during the first year to be more common in the observation group compared with those patients receiving adjuvant treatment and to be associated with early recurrence. Toxicity from adjuvant treatment persisted beyond termination of therapy in 53% of patients, but was usually mild and self-limited. We conclude CMFPT offers relapse-free survival benefit in ER-negative patients, but the value of chemotherapy in ER-positive postmenopausal, node-positive patients must be questioned.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1989

Myelodysplastic syndrome and acute nonlymphocytic leukemia secondary to mitolactol treatment in patients with breast cancer.

One thousand four hundred sixty patients with 2,590 patient-years of follow-up were treated on 15 protocols for metastatic breast cancer with dibromodulcitol (mitolactol; DBD)-containing regimens since 1976. Twenty-three patients developed myelodysplastic syndrome (MDS) and/or acute nonlymphocytic leukemia (ANLL). The overall risk of developing MDS or ANLL per person is 1.6%. In patients who had received more than 16,000 mg of DBD the risk per person is 6%, and in the high-dose subsets of patients who received no prior radiation or alkylator therapy, it is 7.9%. The risk per person increases to a maximum by 30 to 36 months (5.3%). The high risk was seen despite a study population of metastatic breast cancer patients with a median survival of 16 months. This analysis strongly suggests that DBD is one of the most potent of the reported leukemogenic-inducing agents. Further use of this drug in both the adjuvant and metastatic situation should be reconsidered.

Adult↗
PubMed1988

Phase I clinical trial of a combination of dipyridamole and acivicin based upon inhibition of nucleoside salvage.

A Phase I clinical trial of simultaneous 72-h infusions of dipyridamole and acivicin was carried out in patients with advanced malignancies. The objective of this trial was to determine the maximum tolerated dose of dipyridamole when administered as a 72-h infusion in combination with acivicin. The development of this combination is of interest because of in vitro observations which demonstrate that dipyridamole potentiates the cytotoxic action of acivicin by blocking nucleoside salvage. Patients were treated with concomitant i.v. infusions of dipyridamole and acivicin for 72 h. The acivicin dose infused remained constant during the trial at 60 mg/m2/72 h. The maximum tolerated dose (MTD) of dipyridamole was 23.1 mg/kg/72 h. Limiting toxicities at the MTD of dipyridamole with acivicin were severe gastrointestinal and constitutional symptoms which appeared to be caused by the high doses of dipyridamole administered. Escalation of dipyridamole did not potentiate the mild myelosuppression or the neurotoxicity which occurs with acivicin alone. At a dose of dipyridamole which was well below the MTD, one patient experienced symptomatic orthostatic hypotension, and another patient with coronary artery disease developed dizziness and transient electrocardiogram abnormalities. However, no other hypotensive or cardiovascular events occurred as dipyridamole was escalated to the MTD. Phlebitis occurred at the site of infusion when the dose of dipyridamole exceeded 13.5 mg/kg/72 h. Because of this local toxicity, it was necessary to administer dipyridamole through a central venous catheter to achieve maximum plasma levels. At the MTD of dipyridamole, steady-state total and free plasma levels of 11.9 microM and 27.8 nM, respectively, were attained by 24 h. These are free dipyridamole levels which in vitro were sufficient to block cytidine salvage and to potentiate the biochemical and cytotoxic effects of acivicin against human colon cancer cells (P.H. Fischer et al., Cancer Res., 44:3355-3359, 1984).

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1988

Endocrine status of premenopausal node-positive breast cancer patients following adjuvant chemotherapy and long-term tamoxifen.

The endocrine status of 49 premenopausal women taking tamoxifen after completion of adjuvant chemotherapy for breast cancer was determined by radioimmunoassay from serial blood samples. Of these 49 women, 7 had regular menses, 14 had irregular menses, 23 were amenorrheic, and 5 had undergone hysterectomies. A group of 12 premenopausal women who had no history of breast cancer and were not taking tamoxifen served as a control group. Evidence of ovarian function (estradiol levels of greater than 100 pg/ml) was seen in 7 of 7, 9 of 14, 2 of 23, and 1 of 5 women with a clinical history of regular menses, irregular menses, amenorrhea, and hysterectomy, respectively. Supraphysiological levels of estradiol (greater than 350 pg/ml) were noted in 13 of 19 women with endocrine evidence of ovarian function. Supraphysiological progesterone levels (greater than 20 ng/ml) were also seen in 5 of 7 of the regularly menstruating women taking tamoxifen. Supraphysiological levels of estradiol were associated with elevated follicle-stimulating hormone levels, but there was no mean change in the luteinizing hormone levels. Minimum and maximum serum follicle-stimulating hormone levels were 1.9 and 9.0 mIU/ml in the 12 normal women and 5.2 and 24.3 mIU in the 13 women with supraphysiological estradiol levels. Our findings demonstrate that the majority of women who continue to menstruate while taking continuous tamoxifen following cytotoxic chemotherapy have supraphysiologic estradiol levels. This is a potential mechanism for failure of tamoxifen therapy in these premenopausal women.

Adenocarcinoma↗
PubMed1988

Bone mineral density in women with breast cancer treated with adjuvant tamoxifen for at least two years.

While in limited animal studies tamoxifen is reported to protect against loss of bone mineral, data in humans are lacking. We measured bone mineral density (BMD) using single photon absorptiometry at the radius and dual photon absorptiometry at the lumbar spine in breast cancer patients treated with chemotherapy at our institution. In this group, 37 women were not treated with tamoxifen (NT) and 48 women were treated with tamoxifen (T) for at least two years. Younger age, greater weight and height, premenopausal status, and shorter time since menopause were found to be significant predictors of greater BMD. Tamoxifen-treated women had been postmenopausal for more years (p = 0.012). Regression analyses used to adjust for differences in risk of bone loss did not reveal significant differences in BMD between the two groups of women. For the postmenopausal women (27 NT and 34 T subjects), the adjusted mean BMD (g/cm2) at the spine was 1.11 (NT), 1.11 (T) (p = 0.93); and at the radius 0.63 (NT), 0.62 (T) (p = 0.30). This limited retrospective study suggests that tamoxifen does not have 'anti-estrogenic' effects on BMD.

Adult↗
PubMed1988

A phase II evaluation of combination chemotherapy plus aminoglutethimide in women with metastatic or recurrent breast carcinoma. An Eastern Cooperative Oncology Group Pilot Study.

The Eastern Cooperative Oncology Group (ECOG) conducted a pilot study of combination chemotherapy with cyclophosphamide, doxorubicin, and 5-fluorouracil plus aminoglutethimide (250 mg three times daily with hydrocortisone supplementation of 40 mg daily) as primary therapy for estrogen receptor-positive or unknown advanced breast carcinoma to assess whether these agents can be safely combined and to provide a preliminary estimate of response rate. A total of 47 patients, 45 with metastatic breast cancer and two with stage IV disease who were rendered clinically disease free following surgical resection of chest wall recurrence, were treated. Leukopenia and mucositis were the most frequent toxicities requiring dose reduction, but only five patients (10.6%; 95% confidence interval, 1.8-18.4%) experienced life-threatening leukopenia (less than 1000/mm3) at some point during their therapy. Neurologic side effects attributed to aminoglutethimide, predominantly lethargy, were reported in less than one-third of patients, and rarely required dose reduction. One elderly patient developed clinical hypothyroidism during the first 3 months on therapy and experienced a cardiac arrest at home while receiving supplemental thyroid hormones. The overall complete plus partial response rate in 45 patients was 55.5% (95% confidence interval, 41-70%). Among 16 patients with measurable disease, the complete plus partial response rate was 75% (95% confidence interval, 54-96%). The complete plus partial response rate in 29 patients with nonmeasurable but evaluable disease was 45% (95% confidence interval, 27-63%) and an additional 14% had improvement in bone pain. Eight patients electively discontinued chemotherapy after 7-24 months of therapy, but continued aminoglutethimide. The median time to disease progression is 462 days (15.4 months); 25% of patients died by 552 days (18.4 months), and the median duration of survival is predicted to be 889 days (29.6 months). We conclude that aminoglutethimide can be combined with this doxorubicin-based regimen with acceptable toxicity and an overall response rate which is similar to that observed on prior ECOG trials with cyclophosphamide, doxorubicin, and 5-fluorouracil.

Adult↗
PubMed1988

Identification of a subgroup of patients with breast cancer and histologically positive axillary nodes receiving adjuvant chemotherapy who may benefit from postoperative radiotherapy.

Risk factors for isolated local-regional (LR) recurrence following mastectomy for breast cancer were analyzed in a review of 627 women entered into Eastern Cooperative Oncology Group (ECOG) adjuvant chemotherapy trials between 1978 and 1982. Premenopausal patients were randomized to cyclophosphamide, methotrexate, and fluorouracil (5-FU) (CMF), cyclophosphamide, methotrexate, 5-FU, and prednisone (CMFP), or cyclophosphamide, methotrexate, 5-FU, prednisone, and tamoxifen (CMFPT). Postmenopausal patients were randomized to observation, CMFP, or CMFPT. Median follow-up time was 4.5 years. At 3 years, 225 patients relapsed and in 70 (31% of failures, 11% of all patients) the initial site was LR without distant metastases. In a multivariate analysis, the risk of an isolated LR recurrence significantly correlated with the number of positive axillary nodes, the primary tumor size, the presence of tumor necrosis, and the number of axillary nodes examined. Factors that significantly discriminated between an isolated LR recurrence and distant metastasis were the number of positive nodes and primary tumor size. Patients with four to seven positive nodes or tumor size greater than or equal to 5 cm had a chance of developing an isolated LR recurrence almost equal to the risk of distant metastases. These findings suggest a potential for improved survival in this subset of patients with the addition of postmastectomy radiation to chemotherapy, and continue to emphasize the presence of a group of patients at high risk for isolated LR recurrence despite adjuvant chemotherapy.

Adult↗
PubMed1988

Antiestrogen therapy for breast cancer: current strategies and future prospects.

The antiestrogen tamoxifen has had an enormous impact upon the therapy of breast cancer. It is the most widely used antihormonal therapy. The success of tamoxifen has stimulated broader applications of the drug (long-term adjuvant therapy and chemosuppression) and has spurred the development of toremifene, droloxifene, and zindoxifene. However, the clinical evaluation of tamoxifen as a chemosuppressive agent is not sufficiently advanced to be able to provide any conclusion about the success of this strategy. It may be a decade before a randomized clinical study can be analyzed and the value of chemosuppression assessed. In the near future, the clinical evaluation of new antiestrogens will provide additional information about the potential value of these drugs and will perhaps challenge our ideas about the mode of action of antiestrogens as antitumor agents.

Breast Neoplasms↗
PubMed1987

Combination hormone therapy for metastatic breast cancer. An ECOG study of megestrol and aminoglutethimide.

This study was performed to determine the toxicity and effectiveness of megestrol acetate used with aminoglutethimide-hydrocortisone in the treatment of patients with metastatic breast cancer. Forty-five patients were treated, 29 of whom were fully eligible. Twelve of the 45 who had diabetes and/or hypertension were also analyzed. All had measurable sites of disease. The median age was 63 years, and the median time from first recurrence to on-study was 19 months. Approximately half the patients already had chemotherapy, and about 90% had hormone therapy for advanced disease. The most common side effects were skin rash, weight gain, hyperglycemia, and renal and neurologic problems. No life-threatening or lethal toxicities were reported. The overall response rate (complete or partial) among the fully eligible patients was 34% (90% confidence intervals from 20% to 51%), with a 5-month median duration of response. Patients with soft tissue, visceral, and osseous disease responded. Seventy-two percent of fully eligible patients have progressed or relapsed. The median time to failure of treatment was 6 months, and the median survival time was 15 months.

Adult↗
PubMed1987

Long-term adjuvant therapy with tamoxifen: effects on sex hormone binding globulin and antithrombin III.

Plasma levels of luteinizing hormone, sex hormone binding globulin, and antithrombin III were measured in pre- and postmenopausal breast cancer patients receiving adjuvant combination chemotherapy or combination chemotherapy and long-term tamoxifen therapy. The aim was to determine the estrogen-like effects of tamoxifen. The premenopausal patients had received tamoxifen for between 434 and 2592 days and postmenopausal patients between 91 and 1560 days. Tamoxifen caused a consistent rise in sex hormone binding globulin in premenopausal (P less than 0.03) and postmenopausal (P less than 0.01) patients compared to chemotherapy controls. Luteinizing hormone levels were only significantly lowered (P less than 0.008) in premenopausal patients compared to chemotherapy controls. Antithrombin III levels were significantly depressed (P less than 0.001) in postmenopausal patients compared with chemotherapy controls. However, none of the patients had a value that was depressed by more than 30% of the laboratory control (the level of clinical significance). The mean for the group was 90% +/- 4 (mean +/- SD, N = 11). The estrogen-like rise in sex hormone binding globulin produced by adjuvant tamoxifen therapy could be advantageous for maintaining the antiestrogenic action of the drug. A decrease in antithrombin III occurred but was not within a range of clinical concern. We recommend, however, that patients with a history of thromboembolic disorders should be monitored carefully if placed on tamoxifen therapy.

Adult↗
PubMed1987

Phase I clinical trial and pharmacokinetic evaluation of acodazole (NSC 305884), an imidazoquinoline derivative with electrophysiological effects on the heart.

Acodazole (NSC 305884) is a synthetic imidazoquinoline which has antimicrobial as well as antineoplastic properties. A Phase I trial of acodazole administered as a 1-h i.v. infusion once weekly X 4 was conducted. Mild to moderate nausea and vomiting and moderate burning and erythema at the infusion site were the only toxicities seen among 33 patients treated over 51 courses at doses between 20 mg/m2/week and 888 mg/m2. The first patient treated at 1184 mg/m2 developed an irregular pulse and was found to have a prolonged cardiac output interval (Q-Ti) on electrocardiogram and polymorphic ventricular tachycardia ("torsades des pointes"). Careful study of five additional patients treated according to a modified schedule (340 mg/m2 week one, 500 mg/m2 week 2, 666 mg/m2 week 3, and 888 mg/m2 week 4) revealed 20% or greater Q-Ti prolongation after 20 of 27 treatments; Q-Ti prolongation had resolved 24-36 h after each infusion. Q-Ti prolongation occurred at all dose levels; no ventricular arrhythmias occurred. Acodazole was cleared with a long t1/2 (20.7 h) primarily by nonrenal mechanisms. No alterations in peak plasma levels or excretion were seen in the patients in whom Q-Ti prolongation was detected. No antitumor activity was seen. Further development of acodazole will require delineation of pharmacological means of surppressing this Q-Ti prolongation.

Adult↗
PubMed1987

Endocrine effects of adjuvant chemotherapy and long-term tamoxifen administration on node-positive patients with breast cancer.

Ovarian and pituitary hormones were determined in pre- and postmenopausal breast cancer patients before and at intervals during adjuvant chemotherapy or chemotherapy plus tamoxifen (TAM). Chemotherapy did not affect gonadotrophin levels in postmenopausal patients; however, inclusion of TAM in the regimen produced a partial (approximately 50%) reduction in circulating levels of luteinizing hormone (LH) and follicle-stimulating hormone. Gonadotrophin levels remained reduced as long as TAM therapy continued, at which time they rose to postmenopausal values. Chemotherapy (6-12 months) caused ovarian failure in premenopausal patients with decreases in estrogen (estrone plus estradiol) and rises in gonadotrophin levels to postmenopausal levels. Inclusion of TAM in the regimen caused an initial 3-fold rise in peak circulating estrogen levels before ovarian failure (6-9 months of therapy). Some younger patients (approximately 40 years of age) who had a short course (4 months) of chemotherapy plus TAM followed by continuous TAM therapy alone resumed ovulatory menstrual cycles. Estrogen, progesterone, and follicle-stimulating hormone levels were increased compared with control subjects. Those patients who experienced ovarian failure with adjuvant chemotherapy plus TAM only had a partial rise in gonadotrophins compared with patients receiving chemotherapy alone. TAM maintained the levels of gonadotrophins for as long as therapy was administered, at which time they rose to postmenopausal levels. Although TAM exhibited estrogen-like effects on gonadotrophins there was no estrogen-like increase in circulating prolactin levels in either pre- or postmenopausal patients. One patient experienced an estrogen receptor-positive recurrence during long-term tamoxifen therapy. Serum levels of tamoxifen and metabolites declined in the year prior to the recurrence and this was associated with a rise in gonadotrophins. This indicated noncompliance by the patient. Compliance can be monitored either directly with serum levels of TAM or by serial gonadotrophin determinations. We suggest that the optimal antitumor activity of TAM will be achieved in a low estrogen environment with continuous high levels of the drug in the serum. We recommend that patients undergoing long-term TAM therapy be monitored for complete ovarian failure and drug compliance.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1987

Drug dosage intensity--a panel discussion.

There is now widespread interest in the subject of drug dose intensity in cancer treatment. Recent retrospective analyses have shown a clear-cut benefit for those patients receiving either the intended drug dosage in a particular regimen or the highest dosage achievable through an escalation scheme. In this discussion, the participating physicians will review dose intensity in light of these retrospective studies, highlighting the particular tumor types in which benefits have been demonstrated. Other important issues will be discussed, such as scheduling of drug combinations and the importance of using toxicity as a biologic response monitor of drug efficacy. The panelists will also provide opinions as to the best design for a prospective clinical trial to test dose intensity.

Antineoplastic Agents↗
PubMed1987

Treatment of metastatic breast cancer in premenopausal women using CAF with or without oophorectomy: an Eastern Cooperative Oncology Group Study.

One hundred thirty-one premenopausal women with metastatic breast cancer who had received no prior systemic treatment for metastases were entered on study. Patients without prior chemotherapy with estrogen receptor (ER)-positive and ER-unknown disease were randomized to receive cyclophosphamide, Adriamycin (Adria Laboratories, Columbus, OH), and 5-fluorouracil (CAF) or surgical oophorectomy followed directly by CAF (O + CAF). ER-negative patients without prior chemotherapy were directly assigned to treatment with CAF. Among randomized patients 83% have responded, and 37% have achieved a complete remission. Among ER-negative patients the complete response rate was 38%, and the complete plus partial response rate was 70%. Characteristics significantly associated with a longer time to treatment failure were age 45 or over, one or two organ sites, and performance status O. The median survival time of ER-positive patients treated with CAF is 29 months, and with O + CAF it has not yet been reached, whereas for ER-unknown patients the equivalent survival times are 41 months and 43 months respectively. For ER-negative patients treated with CAF the median survival time is 17 months. Characteristics associated with significantly longer survival among randomized patients were age 35 or over (P = .009) and only one or two organ sites involved (P = .02). Neither treatment (P = .33) nor ER status (P = .70) was significant.

Adenocarcinoma↗
PubMed1987

Platinum analogue combination chemotherapy: cisplatin and carboplatin--a phase I trial with pharmacokinetic assessment of the effect of cisplatin administration on carboplatin excretion.

Cisplatin (NSC 119875) and carboplatin (NSC 241240) are platinum (II) analogues with very different spectra of toxicity. Cisplatin dose is limited by nausea and vomiting, renal dysfunction, and dose-related peripheral neuropathy, whereas carboplatin is myelosuppressive. There are also clinical and laboratory data that suggest that these drugs may not be completely cross-resistant. Therefore, the following phase I trial of combination therapy with cisplatin and carboplatin was undertaken. Since carboplatin toxicity is enhanced in the presence of renal impairment, carboplatin excretion was also evaluated in selected patients at the maximum tolerated dose. Thirty-three patients received 50 mg/m2 cisplatin and doses of carboplatin between 160 mg/m2 and 400 mg/m2. Sequential 20-minute infusions of carboplatin and then cisplatin were able to be administered at the standard doses of carboplatin (320 and 400 mg/m2) with thrombocytopenia to the degree expected if carboplatin alone had been given. However, 280 mg/m2 carboplatin followed by 25 mg/m2 cisplatin/d X 3 caused unexpectedly severe thrombocytopenia in seven of eight patients (median platelet nadir 45,000/microL; range, 12 to 321,000/microL; nadir was less than 90,000 in seven of eight patients). In three patients treated with 280 mg/m2 carboplatin plus 25 mg/m2/d X 3 cisplatin, pharmacokinetics of carboplatin were compared during consecutive monthly cycles without and with cisplatin. Modestly increased areas under the curve (AUC) for carboplatin (15% and 35%) with cisplatin were seen in the two patients who experienced more pronounced platelet suppression with combination therapy. No other limiting or unusual toxicity was seen with this combination. Responses, primarily in "platinum responsive" tumors, were seen. The combination of cisplatin plus carboplatin is feasible and merits further study.

Anemia↗