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Biomedical subjects

H Y Yap

Publications and source records attributed to H Y Yap.

At least 37 records · Page 2Linked to original sources
PubMed1984

Central nervous system pharmacology of Baker's antifolate (NSC139105) in man.

Radiolabelled Baker's Antifolate (BAF) was administered to 6 patients undergoing surgical resection of intracerebral tumors. Levels of radioactivity in resected tumor and edematous brain adjacent to tumor were generally higher than levels in concurrent plasma samples and were generally comparable to levels in temporalis muscle. Levels in tumor cyst fluid were far lower than concurrent plasma levels and levels in surrounding tumor. Chromatography was performed on tumor from 2 patients and revealed that only a small proportion of the radioactivity represented unchanged BAF. The major metabolite present in tissues was 1 000 times less potent as an inhibitor of dihydrofolate reductase than was BAF. Five patients had cerebrospinal fluid (CSF) sampled following administration of tracer doses of radiolabelled BAF. Radioactivity levels were far lower in CSF than in plasma. Levels of radioactivity in the CSF were also far lower than levels in tumor and brain samples from other patients and were slightly lower than tumor cyst fluid levels. Two patients had CSF collected after they received therapeutic doses of BAF. In these patients, both CSF and plasma were assayed using a dihydrofolate reductase inhibition assay. As with tracer dose studies, CSF concentrations of BAF were substantially lower than were concurrent plasma concentrations. Thus it appears that only very low concentrations of BAF are attainable in human CSF and intracerebral tumor, although a metabolite which is a very weak inhibitor of dihydrofolate reductase attains high concentrations in tumor.

Antineoplastic Agents↗
PubMed1984

Combined modality approach in breast cancer with isolated or multiple metastases.

One hundred thirty-six patients with isolated recurrence of breast cancer received regional therapy (surgery and/or irradiation) followed by combination chemotherapy with fluorouracil, doxorubicin, and cyclophosphamide (FAC). The disease-free survival of the group receiving FAC was compared to that of a historical control group treated with only regional therapy. The median disease-free interval between the first and second recurrence for the control group was 9 months and for the patients receiving FAC, 38 months (p less than 0.01). The median survivals from first recurrence for the control and the FAC groups were 40 months and 60 months, respectively (p less than 0.02). In addition, 20 selected patients with multiple sites of metastasis or bulky isolated recurrence were initially treated with FAC chemotherapy; following complete or partial response with chemotherapy, these patients had regional therapy at the known sites of metastases. At a median follow-up time of 54 months, 9/20 patients (45%) have remained in complete remission. Combined modality approach significantly prolongs the disease-free survival of patients with isolated recurrences of breast cancer, and in selected patients with multiple metastases, this approach results in extended complete remissions.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1984

Mitoxantrone, cyclophosphamide, and 5-fluorouracil in the treatment of hormonally unresponsive metastatic breast cancer.

Fifty-five patients with newly diagnosed, estrogen receptor negative, metastatic breast cancer were entered in a trial of mitoxantrone, 10 mg/m2 intravenous (IV), cyclophosphamide, 500 mg/m2 IV, and 5-fluorouracil, 1000 mg/m2 IV, which were given on day 1 of a 21-day treatment interval. This trial was designed to test the efficacy of substituting mitoxantrone for doxorubicin as part of a combination that has proved to be effective in inducing remission. The trial was also intended to evaluate the response of resistant disease and of stable metastatic disease to a combination of doxorubicin and vinblastine sulfate. The cardiotoxic potential of mitoxantrone was evaluated in all the patients by serial measurements of ejection fraction and by endocardial biopsy of the right ventricle. Patients who achieved a complete response or a partial response (with bone as the only site of disease) on the three-drug combination were continued on this treatment for 2 years, or for 1 year following a complete response, whichever was shorter or as cardiac monitoring permitted. Therapy with doxorubicin, 25 mg/m2/d for two days, followed by continuous infusion vinblastine sulfate, 1.4 mg/m2/d for four days, was given to all patients who progressed after two courses or were stable after six courses of three-drug therapy. The preliminary results from 50 patients show that 4 attained a complete response and 30 a partial response, giving a total response rate of 68%. The median duration of response was more than 7 months (range greater than 5 to greater than 15 months). One patient in complete remission relapsed after 8 months and failed reinduction therapy with doxorubicin-vinblastine sulfate. Myelosuppression, principally granulocytopenia, was the major side effect of cyclophosphamide-mitoxantrone-5-fluorouracil. Mild to moderate vomiting occurred in 76% of patients and alopecia in 88%. This therapy was discontinued in four patients because of a decreased cardiac ejection fraction and/or symptoms of heart failure. No cardiac biopsy score, however, has been greater than 1.0. These results suggest that a combination of cyclophosphamide-mitoxantrone-5-fluorouracil is effective in untreated, estrogen receptor negative, metastatic breast cancer and is comparable to the doxorubicin combination. Myocardial injury occurs with mitoxantrone, and a safe cumulative dose has yet to be established.

Adult↗
PubMed1983

Benign versus malignant hepatic lesions. A diagnostic dilemma with breast cancer patients.

The diagnosis of hepatic metastases heralds a grave prognosis in breast cancer patients. The authors describe seven patients with breast cancer who were found to have hepatic defects that were suspected to present metastatic disease on initial screening and investigations. However, these patients were subsequently shown to have benign hepatic lesions after careful history-taking and supplementary diagnostic techniques, in most cases with the aid of hepatic angiographic examinations. The authors believe that thorough investigation is indicated to elucidate the nature of hepatic defects, especially in cancer patients with no other site of metastatic involvement.

Adult↗
PubMed1983

Serial plasma carcinoembryonic antigen measurements during treatment of metastatic breast cancer.

Serial plasma carcinoembryonic antigen (CEA) levels were measured in 167 patients with metastatic breast cancer treated with fluorouracil, doxorubicin hydrochloride, and cyclophosphamide (FAC). In 84 patients, the pretreatment CEA value was abnormal. Response rates and remission duration were similar in patients with normal and abnormal pretreatment levels. Carcinoembryonic antigen concentrations decreased in 94% of patients who responded to FAC therapy. The duration of response was 22 months for patients in whom the CEA levels normalized v nine months in those in whom it decreased but never returned to normal. Increasing CEA levels correlated with progressive disease in 87% of patients and preceded clinical evidence of progression in 77%. Serial CEA measurements can monitor response to chemotherapy, provide useful prognostic information of response duration, and detect progressive disease early.

Adult↗
PubMed1983

Multimodal treatment of locoregionally advanced breast cancer.

Fifty-two patients with locally advanced primary breast cancer (T3, T4/N2, N3) without distant metastases were treated with three cycles of combination chemotherapy consisting of 5-FU, Adriamycin and cyclophosphamide (FAC) and immunotherapy with Bacillus Calmette-Guerin (BCG) followed by local therapy (simple mastectomy and/or radiotherapy to breast/chest wall and regional lymphatics) and adjuvant chemotherapy to complete two years of treatment. Forty-nine of 52 (94%) patients were rendered free of clinically detectable disease. The median disease-free interval was 24 months. At a median follow-up time of 60 months, 40% of patients remained free of disease, off all therapy. Those patients who completed two years of therapy and started adjuvant chemotherapy promptly after local treatment had a 48% disease-free survival at five years. Local recurrences were observed in 21% of patients. Distant metastases developed in 40% of patients. Despite good tolerance, treatment compliance was poor. The complete remission rate with this multimodal approach is high and long-term disease-free survival is achieved in a considerable number of patients.

Adult↗
PubMed1983

Phase II evaluation of vinblastine, methotrexate, and calcium leukovorin rescue in patients with refractory metastatic breast cancer.

Seventy-five evaluable patients with metastatic breast cancer refractory to frontline chemotherapy were treated with vinblastine 1.5 mg/m2 by continuous intravenous infusion for five days, intravenous infusion of methotrexate 200 mg/m2, and appropriate calcium leukovorin rescue. Thirty-eight patients were treated with vinblastine followed by methotrexate and calcium leukovorin, while 37 patients were treated with these same drugs in reverse sequence. In 17 patients (23%) an objective remission was achieved, while 39 remained stable for a period in excess of eight weeks. The median duration of remission was two months, and the median duration of survival was six months. The two regimens were well balanced for commonly used pretreatment prognostic factors. There was no difference in response rate and duration of response between the two treatment regimens. In patients with no prior exposure to methotrexate, the remission rate was 37% (11 of 30) compared with 13% (6 of 45). The treatment was well tolerated, and the dose-limiting toxicity was myelosuppression. This combination of drugs is effective in patients who have not been exposed to either drug, while it is only marginally effective in patients previously treated with methotrexate or vinblastine.

Adult↗
PubMed1983

Concentration of vinblastine in human intracerebral tumor and other tissues.

Uptake of vinblastine into human cerebrospinal fluid, intracerebral tumor and autopsy tissues was quantitated radiochemically after separating vinblastine from its metabolites by high pressure liquid chromatography. Only low concentrations of vinblastine were found in cerebrospinal fluid from a single patient. A second patient who received a tracer dose of radiolabelled vinblastine prior to surgical resection of an intracerebral tumor had slightly less radioactivity in tumor than in temporalis muscle, but more in tumor than in edematous brain surrounding the tumor. The radioactivity in tumor increased gradually and exceeded concurrent plasma radioactivity by 2 hr after drug administration. A third patient died 4 hr into a planned 24-hr infusion of radiolabeled vinblastine. Highest vinblastine concentrations were found in organs with high blood flow such as kidney and heart. Intermediate concentrations were found in liver and lung, and low concentrations were found in prostate, gastrointestinal tract, spleen, muscle, bladder, and hepatic and lymph node metastases. A fourth patient died one month after receiving radiolabeled vinblastine. Highest concentrations were in liver and next highest concentrations were in intracerebral tumor. Moderately high concentrations were found in pancreas, thyroid, lung, spleen, ovary, kidney, and kidney metastases. Lowest concentrations were found in omental metastases, heart, breast, and brain. Vinblastine concentration decreased with increasing distance into brain from the brain metastases. Thus, vinblastine was not selectively localized in tumors. The concentrations in tumor did not reflect the concentration in the organ in which the tumor was located. There was no indication that uptake into intracerebral tumor was impaired. Cerebrospinal fluid and brain concentrations of vinblastine did not give any indication of the concentration attainable in intracerebral tumor.

Adult↗
PubMed1983

Treatment of locoregionally advanced breast cancer with surgery, radiotherapy, and combination chemoimmunotherapy.

Fifty-two patients with locally advanced primary breast cancer (T3, T4, N2, N3) but no evidence of distant metastases were treated with three cycles of combination chemotherapy. The regimen consisted of 5-fluorouracil, Adriamycin, cyclophosphamide, and Bacillus Calmette-Guerin (FAC-BCG), followed by local therapy (simple mastectomy and/or radiotherapy to the breast/chest wall and the regional lymphatic system) and adjuvant chemotherapy for two full years. The results were compared with those in an historical control group of 52 patients matched for initial stage of disease who were treated by a simple mastectomy and postoperative radiotherapy only. Forty-nine (94%) of 52 FAC-treated patients and 48 (92%) of the control patients became free of clinically detectable disease. At the median follow-up time of 56 months, 37.5% of the FAC-treated patients and 19.5% of the control patients had remained free of disease. FAC-treated patients who completed 2 years of therapy and in whom adjuvant chemotherapy was started promptly after local treatment had a 48% disease-free survival rate of 4 years. In those in whom the initial manifestation was supraclavicular involvement, the estimated 5-year disease-free survival rate was 42% for patients treated with FAC and 9% for control patients. There were local recurrences in 25% of FAC-treated patients and 23% of control patients (not significant). Distant metastases developed in 50% of FAC-treated patients and 77% of control patients (p less than 0.01). The median disease-free interval was 25 months in the FAC-treated group and 11 months in the control group (p = 0.025). The greatest improvement in prognosis was in patients with supraclavicular involvement; the median disease-free survival was 26 months in FAC-treated patients and 6 months in the control group (p = 0.007). This multimodal approach effectively renders the majority of patients with locoregionally advanced breast cancer free of disease and prolongs the disease-free survival period.

Adult↗
PubMed1983

Multivariate analysis of prognostic factors in metastatic breast cancer.

Univariate and multivariate analyses were conducted on data collected from the records of 619 patients with metastatic breast cancer in whom an Adriamycin-containing chemotherapeutic regimen was used. Using a forward, stepwise logistic regression procedure, several models or equations in which a small number of pretreatment factors were incorporated were generated and the probability of response to therapy was accurately predicted. The predictive ability of these models was tested retrospectively in 546 of the 619 patients from whom the data were derived and prospectively in a new population of 200 patients with metastatic breast cancer also treated with a therapeutically equivalent Adriamycin combination. Using similar univariate techniques, pretreatment factors were correlated with the length of survival after therapy. The proportional hazard model of Cox was used to develop a regression model relating survival to pretreatment characteristics in much the same manner as that of the response model. The total population of the initial group of patients was divided according to four levels of hazard ratio, and survival distributions were compared. This model also was tested progressively and its predictive capability was confirmed. The prediction of individual outcome is a valuable capability in the comparison of clinical trials and the continuing evaluation of biologic changes in patients with metastatic carcinoma; such a method is described in this paper.

Analysis of Variance↗
PubMed1983

A phase I-II study of continuous 5-day infusion mitomycin-C.

A phase I-II study was undertaken to establish the maximum-tolerated dose of a continuous 5-day infusion of mitomycin-C and its efficacy in patients with advanced metastatic drug-resistant breast and gastrointestinal malignancies. The dose-limiting toxicity was myelosuppression, predominantly thrombocytopenia, and was severe and cumulative. Nonhematologic toxicity was infrequent, and no renal or cardiac toxicity was seen. For patients with breast cancer who had received extensive prior therapy, 3 mg/m2/day for 5 days repeated every 6-8 weeks were well-tolerated doses; and for patients with gastrointestinal cancer, the maximum-tolerated dose was 4 mg/m2/day. One patient with breast cancer had a partial response lasting 4 months, and no responses were observed in patients with gastrointestinal cancer. The administration of mitomycin-C by continuous infusion did not appear to have improved its therapeutic index.

Aged↗
PubMed1983

Hormonal therapy for metastatic male breast cancer.

Forty-one men with metastatic breast cancer were treated with 70 trials of hormone therapy. These included 25 orchiectomies and 45 additive hormonal treatments. The overall response rate was 31%. The response rate was 32% to orchiectomy, 17% to estrogens, 43% to steroids, 25% to tamoxifen citrate, and 60% to androgens. The response to additive hormonal therapy was 31% and was not affected by prior orchiectomy (33% v 30%). Median overall response duration was 12 months, 17.5 months following orchiectomy, 8.5 months following additive hormonal therapy, five months following estrogens, 11 months following steroids, and eight months following androgens. Median survival from first metastasis was significantly prolonged in patients responding to orchiectomy and additive hormonal therapy. Patients with a disease-free interval (DFI) longer than 12 months had a 59% response rate to hormonal therapy compared with 9% of those with a DFI no more than 12 months. Response to one form of hormonal therapy did not predict later hormonal response. Ablative and additive hormonal therapy offer effective palliation to one third of male breast cancer patients, produce little toxic effects and morbidity, and improve survival duration after metastasis in responders.

Adrenal Cortex Hormones↗
PubMed1983

Bisantrene, an active new drug in the treatment of metastatic breast cancer.

Forty-four patients with metastatic breast cancer who had previously received extensive conventional systemic therapy, including combination chemotherapy with doxorubicin, were treated with Bisantrene, a new anthracene derivative. The dose schedule was 250 to 300 mg/sq m body surface administered as a 1- to 2-hr i.v. infusion. Of 40 evaluable patients, there were nine partial responses, and 18 patients had stable disease. Responses were seen in all major sites of organ involvement with a median time to progression of 28 weeks. Moreover, responses were seen among patients who had either failed to respond or had demonstrated refractoriness to prior therapy with doxorubicin, suggesting an apparent lack of cross-resistance between doxorubicin and Bisantrene. Except for myelosuppression and one incidence of acute anaphylactoid reaction, Bisantrene was generally well tolerated by most patients. We believe that Bisantrene may ultimately have a major role in the effective treatment of metastatic breast cancer, and further clinical trials are warranted.

Adult↗
PubMed1983

Clinical pharmacokinetics of vinblastine by continuous intravenous infusion.

Vinblastine (VLB) is moderately active clinically against advanced breast cancer. Since VLB is extensively taken up by platelets and thus only partially available to tumor cells, to enhance the therapeutic index of VLB we have therefore administered this agent by continuous i.v. infusion to patients with advanced breast cancer. In conjunction with the clinical trial, we conducted pharmacokinetic studies of generally tritiated VLB, using radiochemical and chromatographic techniques. The elimination of VLB from the plasma of patients who received it by 5-day i.v. infusion at 1 to 2 mg/sq m daily was biphasic. In four patients who achieved partial remission, the average plasma half-life of VLB during the terminal phase was 29.4 +/- 14.6 days, with a total clearance of 36 +/- 8 ml/kg/hr, and a steady-state apparent volume of distribution of 28.1 +/- 8.5 liters/kg. However, in three patients whose disease merely stabilized, the plasma half-life was 6.4 +/- 1.6 days, the total clearance was 137 +/- 2.9 ml/kg/hr, and the volume of distribution was 33.0 +/- 11.6 liters/kg. In contrast, in five patients with refractory disease, these parameters were 2.3 +/- 0.3 days, 541 +/- 124 ml/kg/hr, and 37.6 +/- 8.6 liters/kg. Since the apparent volumes of distributions at steady state did not differ significantly among these three groups, whereas the values of the total clearance were markedly dissimilar, the plasma half-lives of VLB were significantly shorter in patients not responsive to continuous infusion therapy with this drug. Although the number of patients studied was small, it nevertheless appears that favorable clinical response of patients with advanced breast cancer is associated with slow total clearance of the drug.

Breast Neoplasms↗
PubMed1983

Phase II clinical evaluation of AZQ in metastatic breast cancer.

Thirty-three patients with metastatic breast cancer who have failed prior combination chemotherapy including adriamycin, cyclophosphamide, 5-fluorouracil and methotrexate, were treated with AZQ given on a 5-day I.V. schedule repeated every 4 weeks. The starting doses were 6 or 8 mg/m2/day for poor- and good-risk patients, respectively. There were two partial responses among 29 evaluable patients. Both had soft tissue and/or lymph node involvement. Six patients had stable disease. Myelosuppression, predominantly thrombocytopenia, was dose-limiting. Other toxicities were mild, including nausea, vomiting, anorexia, diarrhea, stomatitis, and malaise. Our results indicate that AZQ given on the 5-day schedule is unlikely to be effective in the treatment of refractory breast cancer.

Adult↗