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Biomedical subjects

W Hryniuk

Publications and source records attributed to W Hryniuk.

At least 19 recordsLinked to original sources
PubMed2001

Dosage parameters in chemotherapy of breast cancer.

The concept of dose intensity provides a starting point for studying dose-response relationships. The summation dose intensity method (SDI) is an improvement over previous methods of calculating dose intensity because it accounts for differences in drug activity and allows the dose intensity of combinations containing the different drugs to be compared on one scale. It may also ultimately prove useful in defining the contribution of cumulative dose and dose size. Results from initial randomized trials testing dose intensification in breast cancer suggested but did not confirm its importance because dose size and cumulative dose were usually increased concurrently. Results from several recent trials in which dose intensity was increased while cumulative dose was held constant suggest that dose intensity may not be pre-eminent, but that both dosage parameters affect outcome. In addition, there may be a threshold dose intensity that must be exceeded before treatment causes tumor regression. From both retrospective analyses and prospective trials of adjuvant chemotherapy, it is clear that the subsets of patients who benefit most from dosage increases are those with poor prognostic factors. Larger dose sizes contribute more toxicity but, within the conventional range, probably contribute little independent therapeutic benefit. In contrast, reduced size doses of non-antimetabolites given at very short intervals may reduce acute toxicity, maintain dose intensity above threshold, and allow delivery of larger cumulative amounts of chemotherapy. This dose dense strategy may produce results superior to the use of fewer but larger doses.

Journal Article↗
PubMed1998

A single scale for comparing dose-intensity of all chemotherapy regimens in breast cancer: summation dose-intensity.

PURPOSE: To construct a single scale for comparing the dose-intensity of all chemotherapy regimens in breast cancer. MATERIALS AND METHODS: First-line single-agent trials in metastatic disease were reviewed. The unit dose-intensity (UDI) that was required to produce a 30% complete response plus partial response (CR + PR) rate was determined for each drug. Randomized trials were then analyzed that prospectively tested dose-intensity. The dose-intensities of the drugs in each arm were expressed as fractions of their UDIs and added together. This yielded each arm's summation dose-intensity (SDI), which was then correlated with treatment outcomes. RESULTS: In the single-agent trials, dose-response relationships were linear when the studies covered a range of dose-intensities. In the randomized trials that tested dose-intensity in metastatic disease, response rates and median survival correlated linearly with the SDIs of the treatment arms. An increment of one SDI unit increased CR + PR rate by approximately 30%, CR rate by 10%, and median survival by 3.75 months. Metastatic disease trials were negative if the difference between the arms was less than 0.54 SDI units. Adjuvant trials that tested a dose-intensity difference of less than 0.65 SDI units were also negative. CONCLUSION: A single-agent dose-response database can be derived from historic literature that enables comparison of the dose-intensity of all combination regimens on one scale. The dose-intensity increase required to improve outcome can then be identified in earlier trials that tested that variable. SDI methodology should be tested prospectively in contemporary patients, and may be useful in guiding dosage increases beyond the conventional range.

Antineoplastic Agents↗
PubMed1998

The relationship between high-dose treatment and combination chemotherapy: the concept of summation dose intensity.

The most important variables for the clinical use of antitumor agents (AAs) are dose and combination chemotherapy. The objectives of this study were to analyze the relationship between these two variables and to propose a unified conceptual framework for the construct and interpretation of clinical trials. Definitions and variables with respect to dose include potency, therapeutic index, standard dose, efficacy, relative efficacy, dose-limiting toxicity (DLT), dose rate, dose density, dose intensity, and fractional dose intensity. Our overarching concept, that is, summation dose intensity (SDI), was calculated in several ways, depending upon the nature of the data, and included the relative efficacy method, the unit regimen method, and the high dose method. The SDI concept was then applied to disease categories and strategies to determine its usefulness and effectiveness in integrating dose and combinations. The tumors and settings were: mustargen-vincristine-procarbazine-prednisone in Hodgkin's disease, combination chemotherapy for acute lymphocytic leukemia in children, metastatic breast cancer including dose and combinations, selected other solid tumors, alternating chemotherapy, and high dose studies in the leukemias and lymphomas. SDI was effective in integrating and quantifying dose and combination chemotherapy. For classical AAs, the implication of SDI for the construct and analysis of clinical trials was emphasized. In addition to new drug development, emphasis should be given to reducing or eliminating DLTs, such as those of the marrow, now and, in the future, those of the gastrointestinal tract toxicity and other DLTs. The above was derived from and applies to the classical AAs. Whether they will apply to, with appropriate adjustment, agents with significantly different dose-response curves, such as biotherapeutics and hormonal agents, remains to be determined.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1997

Feasibility of a randomized trial of a high-vegetable diet to prevent breast cancer recurrence.

Epidemiologic evidence supports the concept that diet influences risk for breast cancer and suggests that prognosis after the diagnosis of breast cancer may also be related to modifiable nutritional factors. The purpose of this study was to investigate the feasibility of a randomized trial of a high-vegetable, reduced-fat, and increased-fiber diet intervention to reduce risk for recurrence among breast cancer survivors. This major change in dietary pattern was promoted through intensive telephone counseling. Participants were 93 women who had been diagnosed with breast cancer (stages I, II, and IIIA) within the previous four years and who had completed their initial treatment. We assessed adherence to the study diet using repeated 24-hour dietary recalls at 6 and 12 months and measurement of circulating carotenoid concentrations. Six months after randomization, the intervention group had significantly increased their mean intake of vegetables (+4.6 servings/day), fruit (+0.7 servings/day), and fiber (+6.4 g/1,000 kcal) and significantly reduced their intake of dietary fat (-9.9% of energy) compared with the control group. Circulating concentrations of carotenoids also increased in the intervention group. These changes persisted at the 12-month visit. Results of this study demonstrate that telephone counseling can be a useful approach in diet intervention and that breast cancer survivors can adopt and maintain a high-vegetable, reduced-fat dietary pattern.

Biomarkers↗
PubMed1993

Importance of multiagent chemotherapy regimens in ovarian carcinoma: dose intensity analysis.

BACKGROUND: In the previous meta-analysis of dose intensity (dosage) of chemotherapy in advanced ovarian cancer, we analyzed data on cyclophosphamide, altretamine (hexamethylmelamine), doxorubicin, and cisplatin. Only cisplatin showed statistically significant association of complete and partial clinical response with dose intensity. PURPOSE: This analysis updates the previous results and further characterizes response to cisplatin alone or in multiagent regimens. METHODS: We analyzed data from 18 regimens containing platinum (cisplatin or carboplatin) that were used in nine new randomized trials, in addition to data from the 60 groups of patients in our previous study in which responses were reported. Relative dose intensity was calculated as a fraction of the dosage of a drug in the standard regimen of cyclophosphamide, altretamine, doxorubicin, and platinum (CHAP). We performed single and multiple regression analyses to determine the relationship between disease outcome and relative dose intensity for cyclophosphamide, platinum, and doxorubicin alone or in combination. RESULTS: The association between outcome and dose intensity for platinum alone or in multiagent regimens was statistically significant. This association was of borderline significance for cyclophosphamide alone but was not significant for this drug in multiagent regimens. There were insufficient data to test the relationship for doxorubicin as a single agent, but in multiagent regimens, the relationship was borderline (P = .05). Multiagent regimens containing platinum produced greater response rates than platinum alone for any fixed, planned relative dose intensity for platinum. CONCLUSIONS: Our results support other published findings that use of cyclophosphamide and doxorubicin increases the efficacy of single-agent platinum. Relative dose intensity values for cyclophosphamide used alone were larger than those used in multiagent regimens, which might explain why the relationship between relative dose intensity and outcome for cyclophosphamide was not significant for use in multiagent regimens. Similarly, none of the multiagent regimens incorporated doxorubicin at a relative dose intensity for which the drug is found to be effective as a single agent. IMPLICATIONS: Prospective clinical trials are required to test the effect of higher relative dose intensity for doxorubicin and cyclophosphamide added to platinum in advanced ovarian cancer. An important element in the design of prospective trials will be to test for the relative importance of dose intensity versus total dose. This testing is best achieved in a three-arm study design such as that reported in adjuvant treatment of stage II breast cancer conducted by the Cancer and Leukemia Group B.

Altretamine↗
PubMed1989

Recruitment for an efficacy study in chemoprevention--the Concerned Smoker Study.

Efficacy studies are important for the development of long-term cancer prevention strategies. Recruitment aims for a highly motivated group of participants. The Concerned Smoker Study is aimed at smokers with at least a 15 pack-year history and bronchial atypia on sputum sampling Recruitment has been primarily through use of the media. During the first year of randomization 905 potential participants expressed interest. Of these, 80 were eventually randomized. With over 60 participants having completed the study only one has defaulted and compliance with the study protocol has been high. Participants became aware of the study through the following sources: daily newspaper 36.6%, weekly newspaper 16.2%, television 14.9%, radio 13.8%, community television 1.3%, other sources 13.3%. Over 90% of potential participants who initially express interest in such a chemoprevention project may not ultimately be suitable. The population chosen for such studies may not be very representative of the more general population; however, a high degree of compliance can be obtained which will provide valuable information on treatment efficacy.

Advertising↗
PubMed1988

The thrombogenic effect of anticancer drug therapy in women with stage II breast cancer.

Thromboembolic disease has long been recognized as a complication of cancer. Recent reports have suggested that drugs used in the treatment of cancer, including chemotherapeutic agents and hormones, may contribute to this risk, but it has not been possible to separate the effect of these drugs from that of the cancer. We performed a randomized trial comparing 12 weeks of chemohormonal therapy (using cyclophosphamide, methotrexate, fluorouracil, vincristine, prednisone, doxorubicin, and tamoxifen) with 36 weeks of chemotherapy (using cyclophosphamide, methotrexate, fluorouracil, vincristine, and prednisone) in patients with Stage II breast cancer. Among 205 patients randomly assigned to treatment, there were 14 episodes of thrombosis (6.8 percent). These 14 episodes occurred during 979 patient-months of chemotherapy; by comparison, there were no events during 2413 patient-months without therapy. During the first 12 weeks of the study, five patients in the 12-week group and four patients in the 36-week group had thrombosis. During the subsequent 24 weeks, when only patients in the 36-week group were still receiving chemotherapy, there was no thrombosis in the 12-week group, but there were five additional events in the 36-week group (P = 0.03). These findings suggest that chemotherapy contributes to thrombosis in patients with breast cancer.

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

The application of dose intensity to problems in chemotherapy of ovarian and endometrial cancer.

An attempt was made using dose intensity to resolve some of the conflicting issues regarding chemotherapy in ovarian cancer and endometrial cancer. Analyses were done to determine if dose intensity correlates with outcome of first-line and salvage chemotherapy of advanced ovarian cancer and chemotherapy of advanced endometrial cancer. The concept of dose intensity was used to analyze the relative contributions of individual drugs, such as cyclophosphamide, hexamethylmelamine, Adriamycin (Adria Laboratories, Columbus, OH) and cisplatin to outcome, and to suggest how such drugs should be used in combination.

Altretamine↗
PubMed1986

Analysis of dose intensity for adjuvant chemotherapy trials in stage II breast cancer.

We have analyzed the relationship between dose intensity of cyclophosphamide, methotrexate, and fluorouracil (CMF)-containing adjuvant chemotherapy of stage II breast cancer and 3-year relapse-free survival. Studies using only one or two drugs of CMF or melphalan instead of cyclophosphamide were included in the analysis by using simple techniques developed for this purpose. There was a clear-cut relationship between relapse-free survival and dose intensity in trials containing all four prognostic groups: less than 50 years, one to three and more than three positive nodes; and greater than or equal to 50 years, one to three and more than three positive nodes (P less than 10(-5)). Relapse-free survival also correlated with dose intensity for each of the four prognostic groups analyzed separately (P less than .005). Dose intensity was an independently significant correlate of relapse-free survival in multivariate analysis (P less than 10(-5)). This is a retrospective study, and the hypothesis that dose intensity contributes to outcome independently of other variables should be tested prospectively. Methods of increasing dose intensity also require testing in randomized trials before they can be applied to routine clinical practice.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1981

Prevention of infection and bleeding in leukemic patients receiving intensive remission maintenance therapy.

Leukemic patients were treated with intensive chemotherapy to reduce the number of leukemic cells remaining after complete remission was induced. This therapy resulted in periods of severe granulocytopenia and thrombocytopenia. Considering 13 patients who did not receive antibacterial prophylaxis, documented infection was quite common including four episodes of bacteremia and three urinary tract infections. By contrast, patients who received co-trimoxazole as antibacterial prophylaxis experienced one half as many febrile episodes and no serious infections. Prophylactic co-trimoxazole is beneficial for patients with marrow remission in this study. Similar benefit in patients with leukemic marrows remains to be established. All patients received prophylactic platelet transfusion three times a week when their platelet counts were less than 20,000/microliter. There were no episodes of bleeding other than petechiae.

Adult↗