Biomedical subjects

D M Stablein

Publications and source records attributed to D M Stablein.

51 records · Page 3Linked to original sources

PubMed1986

Importance of tumor pathology and morphology in patients with surgically resected colon cancer. Findings from the Gastrointestinal Tumor Study Group.

Previous analyses of findings from the Gastrointestinal Tumor Study Group (GITSG) study GI 6175, a four-arm randomized trial of patients with adjuvant colon cancer, have revealed no efficacy for chemotherapy or immunotherapy, but Dukes' Stage was found to have prognostic significance in both survival and disease-free survival. In this study, the exophytic tumor as primary type, maximal tumor dimension, and degree of differentiation were examined for prognostic importance. In a model simultaneously including treatment effects, significance levels for prognosis in total survival were: Dukes' stage (P less than 0.0001), exophytic tumors (P = 0.05), maximal dimension (P = 0.005), and well versus poor differentiated tumors (P = 0.06). This observation about tumor length, adjusted for stage and morphology, provides evidence that size is prognostic in colonic tumors. In addition, an interaction between tumor morphology and immunotherapy, adjusted for Dukes' stage, was noted. In 100 patients with exophytic tumors, significant survival and disease-free survival benefit (P less than 0.02) from immunotherapy occurred. Tumor morphology is found to be an important prognostic variable and should be carefully considered in the construction of future trials in this disease site.

Aged↗

PubMed1986

Prognostic indicators of colon tumors. The Gastrointestinal Tumor Study Group experience.

This study sought to replicate and expand findings reported by the National Surgical Adjuvant Breast and Bowel Project (NSABP) on prognostic factors in resectable colon cancer. Mantel-Haenszel tests and the Cox model were used to analyze prognostic significance and effect of primary disease symptoms and tumor location in 572 patients from the Gastrointestinal Tumor Study Group (GITSG), with resected Dukes' B2 and C colon cancer. Tumor location (left, right, and rectosigmoid/sigmoid) was of low prognostic importance (P greater than 0.10), and did not effect survival or disease-free survival (P greater than 0.10). Obstruction was an important indicator of prognosis, independent of Dukes' stage (P = 0.03). Bowel perforation is associated with poor prognosis in disease-free survival (P = 0.001). Rectal bleeding had a positive impact on survival (P = 0.08). Thus, obstruction, perforation, and rectal bleeding (but not location) are found to be prognostic factors in patients with Dukes' B2 or C colon cancer.

Colonic Neoplasms↗

PubMed1986

Toxicity associated with adjuvant postoperative therapy for adenocarcinoma of the rectum.

The Gastrointestinal Tumor Study Group's (GITSG) adjuvant rectal carcinoma study compared four postoperative treatment regimens: (1) control (no adjuvant therapy); (2) chemotherapy alone consisting of pulses of 5-fluorouracil and methyl CCNU for 18 months; (3) pelvic and perineal radiotherapy using parallel opposed fields with 4000 rad in 4.5 to 5 weeks or 4800 rad in 5 to 5.5 weeks; and (4) a combination of both modalities. The results of this study are published elsewhere and show a significantly reduced recurrence rate and prolonged disease-free survival time for the combined modality arm compared with the no therapy arm. Severe toxicity in the combined therapy arm was significantly worse (P less than 0.001) than in either single modality arm. Most of the differences in toxicity experienced between the three regimens involved diarrhea, thrombocytopenia, and leukopenia. Analysis of all parameters of radiotherapy quality assurance data was not significantly associated with toxicity. Radiation enteritis was noted in 5 patients of 96 (5.2%) in the two arms containing irradiation. All five required laparotomy. The two enteritis fatalities occurred late at 605 and 1000 days after start of combined modality treatment, respectively. One other patient on the chemotherapy arm died of acute nonlymphocytic leukemia. The authors conclude that combined radiotherapy and chemotherapy, although significantly more effective in reducing recurrence than no therapy, is significantly more toxic than single-modality therapy in many parameters, although most of the toxicity is transient and therefore not limiting. Late complications, which are less reversible and therefore much more important than early reactions, and radiation enteritis in this study were relatively uncommon. This schedule of combined modality therapy is not only effective but appears to have tolerable toxicity, because of the relative lack of late effects.

Adenocarcinoma↗

PubMed1986

Perineal effects of postoperative treatment for adenocarcinoma of the rectum.

Nine (4%) first recurrences that involved the perineum were identified in a randomized study of 202 patients treated by no further therapy, chemotherapy only, radiotherapy only, combined radiotherapy and chemotherapy, following complete surgical excision of adenocarcinoma of the rectum. Six of these were in unirradiated patients and in two of the three irradiated patients the perineum was included in the treatment volume. Eight of the nine patients were male and all nine had received abdominoperineal resection (APR). Our quality assurance procedures identified 22 of 96 irradiated patients in whom the perineum was grossly outside the fields. Sixteen of these had undergone APR. As only one of these 16 relapsed in the perineum no definite effect of the surgical procedure on the likelihood of perineal recurrence could be demonstrated. Examination of the pathology reports revealed that 28 patients undergoing APR had tumors within 2 cm of the anorectal junction (pectinate line). Five (17.8%) developed perineal recurrence compared with 4 (3.6%) of 110 patients whose tumors were more than 2 cm from the anus (p less than 0.02-Fisher exact test). No survival differences could be demonstrated between those receiving perineal irradiation and those not but perineal irradiation was associated with toxicity with at least nine (12.2%) out of 74 developing severe complications directly related to the perineum. The routine inclusion of the perineum in postoperative pelvic irradiation fields for all cases of adenocarcinoma of the rectum is questioned. Our current policy following APR includes optional coverage of the perineum for those tumors more than 5 cm from the anorectal junction.

Adult↗

PubMed1985

Therapeutic synergism.

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Antineoplastic Combined Chemotherapy Protocols↗

PubMed1985

A two-sample test sensitive to crossing hazards in uncensored and singly censored data.

Savage score statistics are employed to develop a test for comparing survival distributions with right-hand singly censored data. The procedure is motivated by the interest in developing a powerful method for determining differences when true survival distributions cross. Examination of small-sample characteristics under the null hypothesis indicate that asymptotic critical values yield a slightly conservative test. Power of the test compares favorably with other criteria, including the modified Smirnov procedure, particularly if there is a single crossing of the survival curves.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1983

Confidence regions for constrained optima in response-surface experiments.

The precision of the estimated optimum from a response-surface experiment is often indicated via a confidence region about the optimum. Sometimes, because of associated secondary responses, unconstrained optima produce unrealistic operating conditions, even when the true response surface is known. We consider confidence intervals for constrained optima for which the constraint function is known or separately estimated. An example from a cancer combination chemotherapy experiment illustrates the construction of such a region.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1982

Drug activity and therapeutic synergism in cancer treatment.

In work involving modeling of response surfaces to describe the effects of cancer chemotherapy treatments, it is important to define activity and therapeutic synergism in a statistically defensible manner. This requires the construction of confidence intervals around the estimated optimal treatment which has been achieved by use of an indirect method first proposed by Box and Hunter. Activity for a drug or a combination can be claimed at 100(1 - alpha)% level of confidence when the 100(1 - alpha)% confidence interval about the optimal treatment excludes a zero dose. Results of treatment of B16 melanoma and Lewis lung carcinoma with 3,4-dihydroxybenzohydroxamic acid are used to demonstrate this definition. Extensions of this concept lead to a statistically valid definition of therapeutic synergism. If the confidence region about the optimum combination of k drugs does not contact any of the k - 1 dimensional subspaces, then a k drug therapeutic synergism can be claimed. In the event that a k drug therapeutic synergism cannot be claimed, there may be subsets of the drugs which do combine with therapeutic synergy. These concepts are demonstrated by two- and three-drug combination experiments in L1210-bearing C57BL/6 x DBA/2 F1 (B6D2F1) mice. Razoxane and dacarbazine show therapeutic synergism at a 95% confidence level. A three-drug combination of 5-fluorouracil, Teniposide, and mitomycin C is considered. In this case, although the estimated optimum treatment includes 48.1 mg of 5-fluorouracil per kg, 15.9 mg of Teniposide per kg, and 3.9 mg of mitomycin C per kg, the confidence region generated failed to confirm at an 80% level of confidence that 5-fluorouracil was a necessary component of the best treatment.

Animals↗

PubMed1982

Studies of Baker's antifol, methotrexate, and razoxane in advanced gastric cancer: A Gastrointestinal Tumor Study Group Report.

In this multi-institutional study of advanced gastric cancer, 73 patients were evaluable for response or survival. Patients were treated with either triazinate (Baker's antifol), standard-dose methotrexate, or ICRF-159 (razoxane). Objective responses were seen in four patients receiving Baker's antifol, in three receiving methotrexate, and in none receiving razoxane. Baker's antifol produced a median survival of 18 weeks and methotrexate and razoxane produced a median survival of 8 and 9 weeks, respectively. Seventy of the 73 patients entered in this study had been previously treated, most frequently with combination chemotherapy regimens containing 5-FU or doxorubicin. This study appears to demonstrate that Baker's antifol is an active drug for patients with advanced gastric cancer, according to both response and survival criteria. Examination of the pretreatment prognostic characteristics of the patients further suggests that a possible survival advantage is due to treatment with Baker's antifol rather than the prognostic characteristics of the patients.

Adenocarcinoma↗

PubMed1981

Analysis of survival data with nonproportional hazard functions.

The log-rank test or the proportional hazard model is a valuable, widely accepted method for analyzing time-to-response data from comparative clinical trials. When the hazard ratio is constant in time, this procedure is optimal. Indiscriminate or unthinking use of this approach results in problems in the determination of treatment differences. For example, when the true survival curves intersect, the hazard ratio cannot be constant, i.e., the hazard functions are not proportional. It is shown that by considering time-by-treatment interactions we gain flexibility in describing the relationships among hazard functions. In this paper we demonstrate with the results of a clinical trial how available methodology can be used to permit tests for the appropriateness of the model and to enable informative analysis of such data.

Clinical Trials as Topic↗

PubMed1981

Noninvasive localization of brain-stem lesions in the cat with multimodality evoked potentials: correlation with human head-injury data.

Multimodality evoked potential (MEP) data from over 300 comatose head-injured patients suggest that central nervous system dysfunction of the brain stem and/or hemispheres can be localized with this noninvasive neuroelectric technique. Based on this work, decerebrate motor posturing and prolonged coma are not associated with brain-stem dysfunction but rather with dysfunction of the hemispheres, while absent pupillary and oculocephalic responses are correlated with brain-stem dysfunction alone. However, the accuracy with which MEP data localized human brain-stem or hemispheric dysfunction could not be confirmed by pathological correlation because of low mortality and the small number of autopsies obtained in the patients who died. Therefore, this study was undertaken in an animal model of brain-stem lesion. Complete brain-stem transections were made at the cervicomedullary junction, the medulla just caudal to the eighth nerve, and at the intercollicular region. All cortical visual evoked potential (VEP) peaks were reduced in amplitude and delayed by each of the brain stem transections, but none of the peaks was abolished. In spite of brain-stem transection, VEP's can be used to gain information about hemispheric function. Somatosensory (SEP) and auditory cortically generated evoked potentials (AEP) were abolished by these brain-stem transections, but early-latency brain-stem SEP and AEP data could accurately localize specific areas of brain-stem dysfunction caused by the lesions. Observations made on human MEP data seen to be confirmed by these animal experiments. Correlations between human and cat MEP data are discussed.

Animals↗

PubMed1980

Statistical methods for determining prognosis in severe head injury.

Determining the prognostic significance of clinical factors for patients with severe head injury can lead to an improved understanding of the pathophysiology of head injury and to improvement in therapy. A technique known as the sequential Bayes method has been used previously for the purpose of prognosis. The application of this method assumes that prognostic factors are statistically independent. It is now known that they are not. Violation of the assumption of independence may produce errors in determining prognosis. As an alternative technique for predicting the outcome of patients with severe head injury, a logistic regression model is proposed. A preliminary evaluation of the method using data from 115 patients with head injury shows the feasibility of using early data to predict outcome accurately and of being able to rank input variables in order of their prognostc significance.

Blood Pressure↗

PubMed1980

Survival analysis of drug combinations using a hazards model with time-dependent covariates.

Hazard functions in cancer chemotherapeutic situations may not be proportional, so a nonproportional hazard model has been developed. The dose-response surface is explored by regression analysis of experimental data, and after the estimation of the underlying hazard function the quality of the fit of the model is assessed. Further, treatment levels may be optimized, and estimated survival distributions can be plotted for any treatment combination. In an example of two-drug treatment of murine L1210 leukemia, statistically significant nonproportionality is determined. Analysis permits extraction of potentially important information on drug interrelationships, which has been previously unavailable.

Altretamine↗

PubMed1979

An improved method for analyzing survival data from combination chemotherapy experiments.

In this paper, we present a new method for analyzing survival data from combination chemotherapy experiments. The analysis consists of relating survival to the dosage level of each drug in the combination and using response surface techniques to determine the importance of drug interactions and to estimate optimal doses. A combination experiment using cyclophosphamide, mechlorethamine, and mitomycin C in early L1210 leukemia, advanced L1210 leukemia, and advanced P388 leukemia is used to illustrate the analyses. A therapeutic synergism has been shown. As a result of the various drug interactions, the predicted optimal dose of mitomycin C is found to be zero. This result was duplicated in each tumor system studied.

Animals↗

PubMedDate not supplied

The 1987 USA National CAPD Registry report.

The National CAPD Registry has noted encouraging trends in CAPD therapy in the U.S. Recently, trained patients have reported lower peritonitis rates, fewer days hospitalized for dialysis-related events, and lower probability of developing a first episode of a complication. If accumulating experience, better patient selection, and new technologic developments further these trends, then the relatively high transfer rates should begin to decrease since many transfers are related to peritonitis and other complications. The Registry's observations suggest that CAPD is an evolving therapy and that as complication rates and transfer rates decrease, CAPD may play an even greater role in the treatment of patients with end-stage renal disease.

Female↗