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D M Cowen

Publications and source records attributed to D M Cowen.

18 recordsLinked to original sources
PubMed2001

Late rectal bleeding after conformal radiotherapy of prostate cancer. II. Volume effects and dose-volume histograms.

PURPOSE AND OBJECTIVE: Late rectal bleeding is a potentially dose limiting complication of three-dimensional conformal radiotherapy (3D-CRT) for prostate cancer. The frequency of late rectal bleeding has been shown to increase as the prescription dose rises above 70 Gy. The purpose of this study is to identify features of the cumulative dose-volume histogram (DVH) for the rectal wall that correlate with late rectal bleeding after 3D-CRT for prostate cancer. METHODS AND MATERIALS: Follow-up information on rectal bleeding is available for 261 and 315 patients treated using 3D-CRT at Memorial Sloan-Kettering Cancer Center for Stage T1c-T3 prostate cancer with minimum target doses of 70.2 and 75.6 Gy, respectively. All patients in this study were treated with a coplanar 6-field technique (2 lateral and 4 oblique fields). Patients were classified as having rectal bleeding if they bled (> or = Grade 2) before 30 months, and nonbleeding (< or = Grade 1) if they were without bleeding at 30 months, using the RTOG morbidity scale. Rectal bleeding was observed in 13 and 38 of the patients treated at 70.2 and 75.6 Gy, respectively. Treatment plans were analyzed for 39 nonbleeding and 13 bleeding patients receiving 70.2 Gy, and 83 nonbleeding and 36 bleeding patients receiving 75.6 Gy. Dose-volume histograms (DVHs) for the anatomic rectal wall were calculated. Average DVHs of the bleeding and nonbleeding patients were generated, and a permutation test was used to assess the significance of differences between them, for each dose group. The confounding effect of total rectal wall volume (V(RW)) was removed by calculating the average differences in DVHs between all combinations of bleeding and nonbleeding patients with similar V(RW)s. Finally, multivariate analysis using logistic regression was performed to test the significance of the DVH variables in the presence of anatomic, geometric, and medical variables previously found to correlate with rectal bleeding in a companion analysis of the same patients. RESULTS: The area under the average percent volume DVH for the rectal wall of patients with bleeding was significantly higher than those of patients without bleeding in both dose groups (p = 0.02, 70.2 Gy; p < 0.0001, 75.6 Gy). However, small V(RW)s were associated with rectal bleeding (p = 0.06, 70.2 Gy; p < 0.01, 75.6 Gy), resulting in an increase in average percent volumes exposed to all doses for patients with rectal bleeding. For patients with similar V(RW)s, rectal bleeding was significantly correlated with the volumes exposed to 46 Gy in both dose groups (p = 0.02, 70.2 Gy; p = 0.005, 75.6 Gy, tolerance in V(RW): 5 ccs). For the 75.6 Gy dose group, the percent volume receiving 77 Gy was significantly correlated with rectal bleeding (p < 0.005). Bivariate analysis using logistic regression, including V(RW) together with a single DVH variable, showed good agreement with the above analysis. Multivariate analysis revealed a borderline significant correlation of the percent volume receiving 71 Gy in the 70.2 Gy dose group. It also showed that the DVH variables were highly correlated with geometric and dosimetric variables previously found to correlate with rectal bleeding in multivariate analysis. CONCLUSION: Significant volume effects were found in the probability of late rectal bleeding for patients undergoing 3D-CRT for prostate cancer with prescription doses of 70.2 and 75.6 Gy. The percent volumes exposed to 71 and 77 Gy in the 70.2 and 75.6 Gy dose groups respectively were significantly correlated with rectal bleeding. The independent correlation of small V(RW) with rectal bleeding may indicate the existence of a functional reserve for the rectum. The independent association with larger percent volumes exposed to intermediate doses ( approximately 46 Gy) seen in both dose groups may indicate that a large surrounding region of intermediate dose may interfere with the ability to repair the effects of a central high dose region.

Algorithms↗
PubMed2000

Late rectal toxicity after conformal radiotherapy of prostate cancer (I): multivariate analysis and dose-response.

PURPOSE: The purpose of this paper is to use the outcome of a dose escalation protocol for three-dimensional conformal radiation therapy (3D-CRT) of prostate cancer to study the dose-response for late rectal toxicity and to identify anatomic, dosimetric, and clinical factors that correlate with late rectal bleeding in multivariate analysis. METHODS AND MATERIALS: Seven hundred forty-three patients with T1c-T3 prostate cancer were treated with 3D-CRT with prescribed doses of 64.8 to 81.0 Gy. The 5-year actuarial rate of late rectal toxicity was assessed using Kaplan-Meier statistics. A retrospective dosimetric analysis was performed for patients treated to 70.2 Gy (52 patients) or 75.6 Gy (119 patients) who either exhibited late rectal bleeding (RTOG Grade 2/3) within 30 months after treatment (i.e., 70.2 Gy-13 patients, 75. 6 Gy-36 patients) or were nonbleeding for at least 30 months (i.e., 70.2 Gy-39 patients, 75.6 Gy-83 patients). Univariate and multivariate logistic regression was performed to correlate late rectal bleeding with several anatomic, dosimetric, and clinical variables. RESULTS: A dose response for >/= Grade 2 late rectal toxicity was observed. By multivariate analysis, the following factors were significantly correlated with >/= Grade 2 late rectal bleeding for patients prescribed 70.2 Gy: 1) enclosure of the outer rectal contour by the 50% isodose on the isocenter slice (i.e., Iso50) (p < 0.02), and 2) smaller anatomically defined rectal wall volume (p < 0.05). After 75.6 Gy, the following factors were significant: 1) smaller anatomically defined rectal wall volume (p < 0.01), 2) higher rectal D(max) (p < 0.01), 3) enclosure of rectal contour by Iso50 (p < 0.01), 4) patient age (p = 0.02), and 5) history of diabetes mellitus (p = 0.04). In addition to these five factors, acute rectal toxicity was also significantly correlated (p = 0.05) with late rectal bleeding when patients from both dose groups were combined in multivariate analysis. CONCLUSION: A multivariate logistic regression model is presented which describes the probability of developing late rectal bleeding after conformal irradiation of prostate cancer. Late rectal bleeding correlated with factors which may indicate that a greater fractional volume of rectal wall was exposed to high dose, such as smaller rectal wall volume, inclusion of the rectum within the 50% isodose on the isocenter slice, and higher rectal D(max).

Analysis of Variance↗
PubMed1982

The assessment of response of murine transplantable colon tumors to combination chemotherapy.

The mouse adenocarcinoma of the colon (MAC) system, which has been shown to be a good model for human colorectal carcinoma in terms of its chemosensitivity, was tested with two modified human protocols (MeCCNU + 5 FU, BCNU + 5 FU) in an attempt to evaluate its suitability as a model for developing new regimens of combination chemotherapy for treating patients with colorectal carcinoma. This attempted evaluation raised problems regarding, firstly, the length of time available before tumours became too large in control and non-responding hosts to maintain adequate mobility and, secondly the assessment of response to the drugs. The commencement of drug administration 3 days after transplantation and the assessment of response by measuring delay in time for tumor growth to reach a given volume, with the results analysed by Gehan's (generalised Wilcoxon) test, gave a workable method of evaluation. This method is presented as being suitable for use in the study of transplantable solid tumor lines as models for combination chemotherapy.

Adenocarcinoma↗
PubMed1980

Some biological characteristics of transplantable lines of mouse adenocarcinomas of the colon.

During a 5-year period colon tumors induced by 1,2-dimethylhydrazine dihydrochloride treatment in NMRI mice were transplanted sc into isologous mice to obtain transplantable tumor lines that might serve as experimental models for human colon cancer. The resultant 17 serially transplantable tumor lines were adenocarcinomas varying in degree of differentiation and mucin production. Two of the lines passaged for 5 years and used in chemotherapy studies have shown histologic progression toward dedifferentiation with concomitant acceleration of growth rate.

Adenocarcinoma↗
PubMed1979

The multiple forms and kinetic properties of the N-acetyl-beta-D-hexosaminidases from colonic tumours and mucosa of rats treated with 1,2-dimethylhydrazine.

The separation and purification of the N-acetyl-beta-D-hexosaminidase activities from tumours induced by 1,2-dimethylhydrazine in the rat colon and from colonic mucosa of tumour-bearing animals are reported. Mucosa contained N-acetylhexosaminidases A and B, as well as a third form whose properties with regard to electrophoretic mobility and thermostability lay between those of A and B. Tumours contained only N-acetylhexosaminidase A and B activities. Each form possessed both N-acetylglucosaminidase (EC 3.2.1.30) and N-acetylgalactosaminidase (EC 3.2.1.53) activities, which could not be separated by a variety of techniques. The alteration of the ratio of the two specific activities in each form during purification, together with differences in the kinetic inhibition constants and behaviour during inactivation by various reagents or a temperature of 50 degrees C, supported the belief that each form contains the two enzyme activities, glucosaminidase and galactosaminidase, at separate active sites. This model is in contrast with that reported for these activities from a number of other sources. A variety of treatments reported to cause the conversion of form A into a form resembling B failed to produce such an effect on the rat colonic hexosaminidases.

Animals↗
PubMed1975

Chronic hepatotoxicity and intestinal bleeding in 1,2-dimethylhydrazine carcinogenesis in rats and mice.

The long term administration of dimethylhydrazine to mice induces severe hepatotoxic damage. Parenchymal cell pleomorphism and necrosis were later associated with reticulin collapse and bile duct proliferation. Withdrawing the drug after 17 weeks was followed by some improvement in the parenchymal cells but there was a chronic proliferative response tending towards early cirrhotic changes. The rats appeared relatively resistant to the hepatotoxic effects but unlike the mice the colon tumors arising in these animals bled frequently and could result in profound anemia.

Animals↗
PubMed1975

Studies on the kinetics of glycosidases from chemically-induced rat colonic tumours and normal rat colon.

K-m values of beta-N-acetylglucosaminidase (2-acetamido-2-deoxy-beta-D-glucoside acetamidodeoxyglucohydrolase EC 3.2.1.30), beta-N-acetylgalactosaminidase (EC 3.2.1.53), beta-galactosidase (beta-D-galactoside galactohydrolase EC 3.2.1.23) and alpha-L-fucosidase (alpha-L-fucoside fucohydrolase EC 3.2.1.51) of distal colonic tumours, induced in rats by 1,2-dimethylhydrazine, were found to be significantly different compared with the values for the enzymes of the colonic mucosa of the control and tumour-bearing animals and of the proximal colonic tumours. The inhibition kinetics data also showed a significant difference between the enzymes of the distal colon tumours and of other experimental tissues. The data on the effect of pH on enzyme kinetics (pK values) showed no significant difference in the catalytic groups of the active centres of enzymes from tumours and from the control colonic mucosa. Tumour beta-N-acetylglucosaminidase and beta-N-acetylgalactosaminidase compared with the enzymes from other experimental tissues were found to be different in their thermal inactivation kinetics. K-m values of 14 days old foetal intestinal beta-N-acetylglucosaminidase and beta-N-acetylgalactosaminidase were significantly different from the values obtained for the adult mucosal enzymes but were similar to those of the distal colonic tumour enzymes.

Acetylgalactosamine↗
PubMed1974

Glycosidases heterogeneity among dimethylhydrazine induced rat colonic tumours.

Activities of N-acetyl-β-D-glucosaminidase, N-acetyl-β-D-galactosaminidase, β-D-galactosidase and α-L-fucosidase were measured in rat colonic tumours induced by 1,2-dimethylhydrazine. Tumours varied considerably in their enzyme content, not only from different animals but also from the same animals. Enzymatic heterogeneity among tumours appeared to be related to their site of origin in the colon. The descending colon, which after the DMH treatment showed a significant increase in the levels of glycosidases, also gave rise to a larger number of adenocarcinomata than other parts of the colon. The relative changes in the activities of four glycosidases seemed to show a good correlation.

Animals↗
PubMed1974

Glycosidases in normal and dimethylhydrazine-treated rats and mice with special reference to the colonic tumours.

Activities of 12 glycosidases and of β-D-glucuronidase were measured in liver, kidney and in the gastrointestinal tract of rats and mice. The activities of different enzymes varied not only within one tissue but also among different tissues. In rats injected with 1,2-dimethylhydrazine, a many fold increase in N-acetyl-β-D-glucosaminidase, N-acetyl-β-D-galactosaminidase, β-D-galactosidase and α-L-fucosidase was found in colonic tumours and colonic mucosa. These enzymes were elevated significantly in the kidney of tumour bearing animals as well. Liver and other parts of the gastrointestinal tract showed an increase only in N-acetyl-hexosaminidase with the appearance of colonic tumours. In treated mice, 2 N-acetylhexosaminidases were elevated in colon, duodenum, liver and kidney. However, in liver and kidney, β-D-galactosidase was also significantly increased.

Animals↗
PubMed1973

Evaluation of dimethylhydrazine induced tumours in mice as a model system for colorectal cancer.

The evolution and structure of adenomatous polyps and adenocarcinomata of the colon in NMRI mice induced by dimethylhydrazine are described. Severe toxic reactions in the liver and other organs are produced by dimethylhydrazine (DMH), but tumours are induced only in the colon and around the anus. The 100% incidence and growth characteristics of the tumours make it potentially a good model system, but investigators should take into account the widespread nonspecific cellular injury induced by this carcinogen.

Adenocarcinoma↗
PubMed1973

A quantitative morphological analysis of the response of a transplantable rat fibrosarcoma to cyclophosphamide.

The response of a transplantable rat fibrosarcoma, RIB(5), to a single injection of 100 mg/kg body weight of cyclophosphamide, 0·5, 1, 2 and 3 days after treatment, has been studied by means of a morphometric analysis of tumour sections and has been compared to the changes occurring in untreated tumours. The results showed a transitory increase in thymidine labelling index 12 hours after drug injection accompanied by a low mitotic index which persisted for a further 12 hours. These observations are compared with, and confirm, a previous study involving analysis of smear preparations from tumour cell suspensions. The changes in the proportion of the tumour occupied by erythrocytes and necrotic elements are described. The results of the morphometric analysis have shown the changes occurring in the outer, intermediate and inner zones of the tumour. In all control tumours, and tumours up to 2 days after cyclophosphamide treatment, necrosis was predominant in the inner zone and tumour cell proliferation was most marked in the outer zone. In contrast, 3 days after cyclophosphamide treatment proliferation was predominant in the inner zone and the amount of necrosis was approximately the same in each zone.

Animals↗
PubMed1972

The effect of cyclophosphamide on the growth and cellular kinetics of a transplantable rat fibrosarcoma.

The gross response of a transplantable fibrosarcoma (RIB(5)) in rats treated with a single dose of 10, 50, 100 or 200 mg/kg body weight of cyclophosphamide (CP) is reported. The variation in mitotic and tritiated thymidine ((3)H-TdR) labelling indices after a single dose of 100 mg/kg CP was studied. Examination of chromosome spreads has shown the time course of the visible damage to DNA caused by CP and a transient arrest of cells in G(2) was demonstrated by microdensitometry. The effects of 100 mg/kg body weight CP given in 2 equal doses separated by various time intervals were examined in an attempt to relate tumour response to its altered cellular state at the time of the second dose.

Animals↗