PubMed Health⌕ Search

Biomedical subjects

C N Coleman

Publications and source records attributed to C N Coleman.

At least 19 recordsLinked to original sources
PubMed1992

Enhancement of alkylating agent activity by SR-4233 in the FSaIIC murine fibrosarcoma.

BACKGROUND: The most commonly used antineoplastic drugs are more cytotoxic toward normally oxygenated tumor cells than toward hypoxic tumor cells. PURPOSE AND METHODS: To examine the ability of SR-4233, a new cytotoxic agent, to overcome the resistance of hypoxic tumor cells to antitumor alkylating agents, we tested the cytotoxic effect of SR-4233 alone and in combination with varying doses of cisplatin (CDDP), cyclophosphamide (CPM), carmustine (BCNU), or melphalan (L-PAM) on tumor cells and bone marrow cells isolated from C3H/FeJ mice bearing the FSaIIC fibrosarcoma. RESULTS: When SR-4233 alone was given, tumor cell killing was limited. When SR-4233 was administered just before single-dose treatment with CDDP, CPM, BCNU, or L-PAM, however, marked dose enhancement leading to increased cytotoxic effects on tumor cells and on bone marrow cells was observed. Similar experiments with tumor cell subpopulations, selected by Hoechst 33342 dye diffusion, confirmed that while cytotoxicity to both bright (oxygenated) and dim (hypoxic) cells was increased by combining each alkylating agent with SR-4233, the enhancement of the effect was relatively greater in the subpopulation of dim cells. The delay in the growth of tumors in animals treated with the combination of SR-4233 and CDDP, CPM, or L-PAM was 1.6-fold to 5.3-fold greater than that in animals treated with each alkylating agent alone. CONCLUSION: Our results suggest that SR-4233 may have the potential to improve the clinical efficacy of commonly used antitumor alkylating agents.

Alkylating Agents↗
PubMed1992

Elevation of mouse kidney thiol content following administration of glutathione.

We have found that kidney glutathione and cysteine content in C3H mice can be increased by intraperitoneal administration of either glutathione (GSH) or glutathione disulfide (GSSG). Kidney thiol content is maximal 20-60 min after administration of 1000 mg/kg glutathione and returns to normal values by 2 h. The same time-course of thiol perturbation was observed when acivicin, an inhibitor of gamma-glutamyl transpeptidase, was administered 15 min prior to GSSG administration. The increase in kidney thiols after GSSG administration appears to saturate, with little additional increase as the administered dose is increased above 750 mg/kg. There was no significant change in liver GSH or cysteine after GSSG administration. We suggest that glutathione administration may provide a strategy for selective radioprotection or chemoprotection of specialized cells which can effectively utilize systemic GSH precursors.

Animals↗
PubMed1992

Sensitization of Chinese hamster ovary cells to melphalan by etanidazole under intermittent hypoxia.

Incubation of Chinese hamster ovary cells with etanidazole under hypoxic conditions increases cell killing by subsequent treatment with melphalan under aerobic conditions. We report here that this sensitization can be achieved even if periods of hypoxia are interrupted by reoxygenation. Preincubation under hypoxia in the absence of etanidazole also results in sensitization to melphalan. Intermittent hypoxia is less effective than continuous hypoxia as a single sensitizing factor. Glutathione depletion does not appear to have more than an additive effect on chemosensitization by etanidazole. These results suggest that prolonged treatment with low doses of etanidazole may be a more effective strategy for clinical chemosensitization than a short exposure to a higher dose, in order to target intermittently as well as chronically hypoxic cells.

Animals↗
PubMed1992

The efficacy of pharmacokinetic monitoring and dose modification of etanidazole on the incidence of neurotoxicity: results from a phase II trial of etanidazole and radiation therapy in locally advanced prostate cancer.

Fifty-four patients have been entered on a Phase II trial to study the efficacy of etanidazole (ETA) for locally advanced prostate cancer. The primary goal was to study the incidence of and time to a complete response for patients receiving ETA and radiation therapy. The secondary goal was to prospectively evaluate the utility of pharmacokinetic monitoring and dose-modification of the incidence and severity of the dose-limiting peripheral neurotoxicity. Within a constant radiation therapy regimen, the dose of ETA was either (a) unmodified (2 g/m2, 3 times weekly for 17 doses); (b) altered by a schedule modification of either number of doses or dose adjustment; or (c) individualization of single dose size so that the total number of doses (19 doses) were maintained but the single dose size was adjusted to keep the total AUC of plasma concentration versus time to less than 40 mM-hr. Sufficient efficacy data are not yet available. The use of drug dose modification has reduced the incidence of neurotoxicity from (a) unmodified: 17/26 = 65% (1 grade II); (b) schedule adjustment: 5/9 = 55% (no grade II); and (c) individualized dose modification: 1/19 (no grade II) = 6%. The minimum number of time points needed to accurately assess the AUC will be determined. Pharmacokinetic monitoring will be important in the use of ETA so that drug underdosing can be avoided while minimizing the risk of serious neurotoxicity.

Adenocarcinoma↗
PubMed1992

Logistics in designing clinical trials for etanidazole (SR 2508): an RTOG experience.

In a Phase II study of etanidazole (SR 2508), the dose of 17 x 2 g/m2 (total drug dose: 34 g/m2) was tested in 33 patients and the toxicity was deemed acceptable. A Phase III trial is now in progress comparing conventional radiotherapy with conventional radiotherapy plus etandizole (2 g/m2 i.v. 30 to 60 min before radiotherapy each Monday, Wednesday, and Friday to 34 g/m2 in 17 doses) in patients with unresectable head and neck carcinomas. A recent analysis showed only 14.7% grade 1 and 3.9% Grade 2 peripheral neuropathy. In the initial study design, 133 evaluable patients per treatment arm could achieve an 80% level of power of detecting a 15% difference in local-regional control rates between the radiotherapy arm (25% local-regional control at 2 years) and the radiotherapy plus etanidazole arm (assuming a 40% rate). Allowing for 20 ineligible cases in each arm, a total number of 306 was required. An interim analysis showed that 27% of the patients assigned to radiotherapy plus etanidazole are receiving less than 14 doses of the drug. It is assumed that less than 14 drug doses will not produce any therapeutic gain, therefore, a true 40% local-regional control rate in the radiotherapy plus etanidazole arm will be observed as a 36% rate when analyzed by assigned treatment. Using this information, the study was modified to have an 80% level of power in detecting a difference between a 25% local-regional control rate in the radiotherapy group and a 36% rate in the radiotherapy plus etanidazole group. Allowing for a 10% patient ineligibility rate, 518 patients are required. With 12 patients entered per month, it is estimated that patient accrual to this study will continue through October 1991.

Carcinoma, Squamous Cell↗
PubMed1992

Distribution of etanidazole into human brain tumors: implications for treating high grade gliomas.

Etanidazole was developed as an oxygen-mimetic radiosensitizer less lipophilic than misonidazole. Sensitization depends on an adequate concentration of drug in the tumor at the time of irradiation. Therefore, due to the presence of the blood-brain barrier, brain tumors may theoretically be difficult to radiosensitize due to the hydrophilic characteristics of etanidazole. Based on previous reports of loss of BBB integrity in brain tumors, we investigated the ability of etanidazole to penetrate into malignant gliomas of patients receiving etanidazole as part of a Phase I continuous infusion protocol. The patients had completed previous external beam irradiation. Twenty-two patients were studied and their etanidazole plasma and biopsy data were compared to the 2-compartment model derived from a second group of 19 patients with bolus etanidazole. Etanidazole concentration in brain tumor biopsies varied widely and appeared to be clustered into a higher and a lower pharmacokinetic group having mean tumor to well-perfused second compartment ratios of 1 and 0.25, respectively. Both high and low etanidazole concentrations were evident in different biopsies obtained from the same patient. Correlations between histology and tissue concentrations suggested that the higher level correspond to malignant tissue. These data indicate that the blood brain barrier is disrupted to varying degrees by the brain tumor and/or prior irradiation and that etanidazole penetrates into brain tumors.

Brain Neoplasms↗
PubMed1992

Final report of the phase I trial of continuous infusion etanidazole (SR 2508): a Radiation Therapy Oncology Group study.

Seventy-eight patients have been treated on a Phase I trial using continuous infusion etanidazole while undergoing brachytherapy for locally advanced tumors. There were two sequential schemata, the first treated 63 patients with doses ranging from 8-23 g/m2 over 48 hr and the second treated 15 patients with doses ranging from 20-23 g/m2 over 96 hr. The tumor sites were: brain (n = 42), cervix (n = 22), and breast (n = 14). Patients received a loading dose of etanidazole of 2 g/m2 followed by a continuous infusion for a total of 48 or 96 hr while radioactive implants were in place. Of the 63 patients in the 48-hr study, 52 were entered at doses of less than or equal to 21 g/m2 and there were no definite neuropathies but two patients with the cramping/arthralgia syndrome. Of the 11 patients entered at 22-23 g/m2, 1 patient had symptoms of peripheral neuropathy (Grade II) and 6 had the cramping/arthralgia syndrome. This is a new syndrome, distinct from the peripheral neuropathy, characterized by transient alterations in sensations consisting of cramping, arthralgias, or tingling that resolved completely at intervals varying from a few hours to about 1 week post-treatment. The cramping/arthralgia syndrome limited dose escalation; therefore, the maximum tolerated dose over 48 hr was determined to be 20-21 g/m2. The 96-hr infusion was limited to patients with recurrent gliomas undergoing stereotactic implantation. To date, 15 patients have been treated with doses of 20-23 g/m2. No toxicity was encountered at doses less than or equal to 22 g/m2. At 23 g/m2, one patient developed Grade III neuropathy and three patients had mild cramping/arthralgia syndrome, for whom the drug was discontinued. Therefore, it appears the maximum tolerated dose at 96 hr will be approximately 23 g/m2, which is 10-15% higher than for the 48-hr infusion.

Brachytherapy↗
PubMed1992

Role of additional radiotherapy in advanced stages of Hodgkin's disease.

Although radiotherapy is widely used as additional treatment following chemotherapy, its precise role has never been clearly proven. Relapses tend to occur in previously involved bulky sites. Non-randomized studies may suggest a positive effect of the addition of radiotherapy. This effect however, might also be caused by selection. Randomized studies have not resulted in a survival advantage for the patients treated with additional radiotherapy compared to no further treatment or additional chemotherapy. The SWOG study 7808 suggest a 20% benefit in remission duration for the nodular sclerosis histology subgroup. Definitive conclusions have to wait for more mature results of randomized studies including the ongoing EORTC study and the possibility to perform an overview of all studies.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1991

The use of probenecid as a chemoprotector against cisplatin nephrotoxicity.

Probenecid inhibits cisplatin (CP) secretion in humans and protects against CP-induced nephrotoxicity in rats. The authors conducted a Phase I trial of escalating doses of CP using probenecid as a chemoprotector. Fifty-four courses of CP at doses ranging from 100 to 160 mg/m2 were given by 24-hour infusion to 36 patients. There was no renal impairment at any dose. Ototoxicity, however, became the dose-limiting toxicity; 14 patients experienced a 20 or greater decibel (dB) loss. Seven percent of courses were associated with a leukocyte count of less than 1.5 x 10/microliters, and 19% with a platelet count of less than 50 x 10(3)/microliters. Only three patients developed neurotoxicity. Correlating pharmacokinetic data and toxicity, the authors found that high cumulative dose, area under the curve (AUC) for unbound platinum, and cumulative AUC were associated with ototoxicity and peripheral neuropathy. It was concluded that probenecid may protect against CP nephrotoxicity and warrants further investigation. Its unique mechanism of action and lack of toxicity make it ideal to combine with other chemoprotectors.

Adult↗
PubMed1991

Modulation of alkylating agents by etanidazole and Fluosol-DA/carbogen in the FSaIIC fibrosarcoma and EMT6 mammary carcinoma.

Tumor cell survival assay in the FSaIIC murine fibrosarcoma demonstrated that when the modulator Fluosol-DA (0.3 ml; 12 ml/kg i.v.) was administered just prior to an alkylating agent plus carbogen breathing for 6 h or the modulator etanidazole (1 g/kg i.p.) was administered just prior to an alkylating agent, the combination treatment produced significantly more tumor cell killing across the dosage range of each alkylating agent tested compared with the alkylating agent alone. Each alkylating agent produced a dose-dependent log-linear tumor cell survival curve. There was an increase in tumor cell killing of 5-10-fold when either Fluosol-DA/carbogen or etanidazole was added to treatment with the alkylating agent. For cis-diamminedichloroplatinum(II) (CDDP) and N,N',N''-triethylenethiophosphoramide, the modulators used in combination increased tumor cell killing by only 2-3-fold over that obtained with a single modulator, but for the other alkylating agents, tumor cell killing was increased by 10-50-fold when the combination of modulators was used. Bone marrow granulocyte-macrophage colony-forming unit survival assays showed that the combination of modulators with the alkylating agents resulted in only small increases in bone marrow toxicity of the alkylating agents except for N,N',N''-triethylenethiophosphoramide and L-phenylalanine mustard (L-PAM), for which the toxicity to the bone marrow granulocyte-macrophage colony-forming unit was increased by 5-10-fold compared with the alkylating agents alone. The Hoechst 33342 dye diffusion defined tumor cell subpopulation assay, also in the FSaIIC tumor, demonstrated that the combination of modulators increased the toxicity of CDDP, cyclophosphamide, L-PAM, and 1,3-bis(2-chloroethyl)-1-nitrosourea by 9-55-fold compared with the alkylating agent alone in both the bright (euxoic-enriched) and dim (hypoxic-enriched) cells. For each alkylating agent except 1,3-bis(2-chloroethyl)-1-nitrosourea, the increase in tumor cell killing was greater in the dim cells than in the bright cells. Finally, tumor growth delay studies in both the FSaIIC tumor and the EMT-6 murine mammary adenocarcinoma confirmed that the combination of modulators significantly increased the tumor growth delay caused by CDDP, carboplatin, cyclophosphamide, N,N'N"-triethylenethiophosphoramide, L-PAM, and 1,3-bis(2-chloroethyl)-1-nitrosourea. The greatest increases (4-5-fold) were observed for carboplatin and L-PAM in the FSaIIC tumor and CDDP and cyclophosphamide in the EMT-6 tumor. These results suggest that Fluosol-DA/carbogen together with etanidazole may be an effective modulator combination of alkylating agents in the clinic.

Alkylating Agents↗
PubMed1991

In vivo somatic mutation in the lymphocytes of Hodgkin's disease patients.

While current medical therapies for Hodgkin's disease are usually quite effective, it has become increasingly clear that some of the therapies utilized carry an inherent risk for the induction of secondary malignancies. In order to examine the cellular and genetic responses to therapy for Hodgkin's disease among individuals, we have determined the mutant frequency of T-lymphocytes in 3 cohorts of patients (N = 86) and in controls (N = 71) using a T-cell cloning assay selecting for 6-thioguanine resistance. The Hodgkin's disease cohorts studied include 1) new and untreated, 2) radiotherapy, and 3) combined modality therapy patients. Additionally, two patients receiving chemotherapy alone were studied. In untreated patients, 3 of 18 (17%) mutant frequencies were above the upper 95% confidence limit for mutant frequency in controls (12.6 x 10(-6]. After therapy, 14 out of 45 (31%) of those treated with X-rays only and 10 of 23 (44%) patients treated with both X-rays and chemotherapy had mutant frequencies greater than 12.6 x 10(-6). Overall, the results indicated that the individual response to Hodgkin's disease therapy was a heterogeneous one with a sub-population of persons having elevated mutant frequencies even many years after their last treatment. The larger frequency of elevated MFs in those patients who received intensive therapy (chemotherapy and radiotherapy) is consistent with their increased risk for second cancer induction.

Adult↗
PubMed1991

Combination of etanidazole with cyclophosphamide and platinum complexes.

In an effort to improve the therapeutic efficacy and selectivity of cyclophosphamide (CTX), cis-diamminedichloroplatinum(II) (CDDP), and carboplatin (Carbo), these antitumor alkylating agents were combined with the 2-nitroimidazole drug etanidazole (ETA). As revealed by tumor-cell survival assay in the FSaIIC murine fibrosarcoma, the addition of ETA (1 g/kg, i.p.) just prior to the i.p. injection of various doses of the alkylating agents resulted in increases in the tumor-cell kill produced by each drug (CTX, 10-fold; CDDP, 20-fold; and Carbo, 5- to 15-fold), whereas toxicity to bone marrow granulocyte-macrophage colony-forming units (CFU-GM) increased only about 0- to 3-fold. When CTX was combined with either CDDP or Carbo, striking increases in tumor-cell killing were observed (20- to 100-fold across the CDDP dose range and 5- to 20-fold across the dose range of Carbo), which were supra-additive for CDDP and additive for Carbo as revealed by isobologram analysis. The addition of ETA to these alkylating-agent combinations produced a further approx. 20-fold increase in tumor-cell kill for both CTX/CDDP and CTX/Carbo. This effect was greatest at the lowest dose of the platinum drug tested and was supra-additive in the case of CDDP and additive for Carbo. Following treatment with ETA/CTX/CDDP, bone marrow CFU-GM toxicity increased only about 5-fold over that of CTX/CDDP alone, but the injection of ETA/CTX/Carbo resulted in a 10- to 20-fold increase in bone marrow toxicity as compared with that obtained using CTX/Carbo alone. Tumor growth-delay studies revealed significant increases in the antitumor effect of the alkylating agents when these were given in combination with ETA. Both the ETA/CTX/CDDP and the ETA/CTX/Carbo combinations produced tumor growth delays of 23 days, which represented approx. 1.6-fold increases over those obtained using the alkylating-agent combinations alone. These results suggest that ETA could significantly improve the therapeutic efficacy of these alkylating agents, whether they are given individually or in combination.

Animals↗
PubMed1990

Results of stereotactic brachytherapy used in the initial management of patients with glioblastoma.

Recent studies have shown a survival benefit for patients with recurrent glioblastomas treated with stereotactic brachytherapy. On the basis of these encouraging results, we began a prospective study in 1987 to evaluate the use of brachytherapy in patients with newly diagnosed glioblastoma. Patients were considered eligible for this study if they met the following criteria: Karnofsky performance status 70% or greater; tumor size not greater than 5 cm in any dimension; a radiographically well delineated, supratentorial lesion not involving the ependymal surfaces; and pathologically confirmed glioblastoma. We treated 35 such patients between 1987 and 1990 with stereotactic brachytherapy as part of their initial therapy. The treatment protocol involved surgery, partial brain external-beam radiotherapy (59.4 Gy in 33 fractions), and stereotactic brachytherapy with temporary high-activity iodine 125 sources giving an additional 50 Gy to the tumor bed. Chemotherapy was not used in the initial management of these 35 patients. To compare our results with those obtained in a matched control group, we identified 40 patients with glioblastoma treated with surgery and external radiotherapy, with or without chemotherapy, between 1977 and 1986 at our institution. These patients had clinical and radiographic characteristics that would have made them eligible for the brachytherapy protocol. Survival rates at 1 and 2 years after diagnosis were 87% and 57%, respectively, for patients receiving brachytherapy versus 40% and 12.5%, respectively, for the controls (P less than .001). We conclude that stereotactic brachytherapy improves the survival of patients with glioblastoma when it can be incorporated into the initial treatment approach. Unfortunately, only about one in four patients with glioblastoma are suitable candidates for brachytherapy at the time of initial presentation.

Adolescent↗
PubMed1990

Interaction of SR-4233 with hyperthermia and radiation in the FSaIIC murine fibrosarcoma tumor system in vitro and in vivo.

The effects of SR-4233 (3-amino-1,2,4-benzotriazine-1,4-dioxide), a hypoxic cell cytotoxic agent, were assayed against the FSaIIC murine fibrosarcoma in vitro and in vivo alone and in conjunction with hyperthermia and radiation. In vitro, a concentration of 500 microM of SR-4233 upon exposure of the cells for 1 h decreased the survival of hypoxic cells by about 1 log more than euoxic cells at 37 degrees C and pH 7.40. At the same concentration at pH 6.45, this difference in cytotoxicity increased to about 3 logs. In conjunction with 42 or 43 degrees C hyperthermia at pH 7.40, the killing of both euoxic and hypoxic cells was markedly increased (hypoxic greater than oxic), and the effect of hyperthermia on SR-4233 cytotoxicity was further increased at pH 6.45. SR-4233 proved to be an effective radiosensitizer of hypoxic cells in vitro, producing an enhancement ratio of 2.6 +/- 0.2 at pH 7.40 and 2.7 +/- 0.2 at pH 6.45. In vivo, however, SR-4233 (50 mg/kg) used with single dose radiation (10, 20, or 30 Gy) did not alter the slope of the radiation dose-dependent tumor growth delay curve but did produce a significant additive increase in tumor growth delay. Local hyperthermia (43 degrees C, 30 min) plus SR-4233 (30 mg/kg) produced a tumor growth delay of 9.1 +/- 2.2 days, whereas SR-4233 alone caused a tumor growth delay of only 1.7 +/- 0.9 days and the hyperthermia, only 1.4 +/- 0.7 days. The tumor growth delay increased to 28.2 +/- 4.4 days with the addition of daily radiation (3 Gy for 5 days) to SR-4233 and hyperthermia given on treatment day 1 only. Hoechst 33342 dye-selected tumor subpopulation analysis at 24 h following treatment demonstrated that SR-4233 (30 mg/kg) was more toxic to dim (presumably hypoxic) cells by about 1.8-fold. The addition of hyperthermia to treatment with SR-4233 increased the killing of dim cells by about 5-fold but of bright cells by only 2-fold. Trimodality treatment with SR-4233, hyperthermia, and radiation increased the killing of bright cells by about 6.5-fold and of dim cells by about 16.5-fold as compared with radiation alone. These results indicate that SR-4233 might be used quite effectively with radiation and/or hyperthermia to treat tumors with significant hypoxic subpopulations.

Animals↗
PubMed1990

Final report of the phase I trial of the hypoxic cell radiosensitizer SR 2508 (etanidazole) Radiation Therapy Oncology Group 83-03.

In a Phase I trial SR 2508 was administered by rapid intravenous infusion to 102 patients receiving radiation therapy. The dose-limiting toxicity was peripheral sensory neuropathy (PN) which was related to the cumulative dose administered. The highest single daily dose, 3.7 g/m2, was tolerated without toxicity. The lowest cumulative toxic dose was 21.6 g/m2, and the highest non-toxic dose was 40.8 g/m2. Grade 1 neuropathies were mild and self-limited; grade 2 neuropathies were long-lasting and debilitating. In a retrospective analysis, the risk of developing neurotoxicity was related to the cumulative drug exposure calculated by the area-under-the-curve (AUC) of plasma concentration versus time. There was an increased incidence of neuropathy in patients with a cumulative AUC of greater than or equal to 36 mM-hr. At a total dose of 34 g/m2 over 6 weeks, the incidence of Grade 1 neuropathy was approximately 30%; no grade 2 neuropathy occurred at this dose and schedule. Additional toxicities observed included nausea and vomiting (6%), skin rash (4%), and transient arthralgias (3%). One patient had transient abnormalities in liver function tests of unknown etiology. (In a more recent Phase II trial neutropenia has been observed which may be related to SR2508). Approximately three times more SR 2508 is tolerable compared to misonidazole, and it appears that severe neuropathy can be avoided by monitoring individual patient pharmacokinetic parameters. Evaluation of the efficacy of this hypoxic cell sensitizer is in progress.

Adult↗
PubMed1990

Radiation and chemotherapy sensitizers and protectors.

Radiosensitizers and radioprotectors are part of the chemical modifier approach to cancer therapy whereby the state of the tumor cells and/or normal tissues are modified such that a therapeutic gain is achieved using conventional radiation or chemotherapy. Radiosensitization can be achieved by the use of oxygen-mimetic compounds, agents that alter DNA sensitivity to irradiation, maneuvers that alter DNA repair processes, and manipulation of tissue oxygenation. Standard chemotherapeutic agents such as cisplatin can be utilized in a manner that optimizes the radiosensitization properties. Protection and sensitization can occur by altering the thiol status of the cell. The chemical modifiers field is both developing novel approaches to cancer treatment and increasing the understanding of basic cancer biology.

Animals↗
PubMed1990

Improved methodology for analyzing local and distant recurrence.

Studies of radiation therapy and/or surgery in the treatment of cancer frequently use actuarial methods to estimate curves of time to local failure and compare two such curves with statistical methods originally developed for survival data. In such analyses, patients who fail first in distant sites or die before local failure are considered censored for time to local failure. While the arithmetic of these calculations is usually correct, the interpretation of the results is almost universally incorrect. For example, an actuarial Kaplan-Meier curve of time to breast recurrence after breast conserving treatment consistently overestimates the percentage of patients who would benefit from a subsequent mastectomy. Actuarial methods require the assumption that time to local failure and time to distant failure are statistically independent. For most human malignancies this is not a reasonable assumption, since there are always some patient subgroups at high risk of both local and distant failure and some patient subgroups at low risk for either type of failure. Without the assumption of independence, the time to local failure distribution is not well defined. The basic problem is that estimating time to local failure falls into the category of analyzing "competing risks," since the various causes of failure are competing for the same patient. For this reason, the effects of a particular treatment on local failure cannot be assessed separately from its effects on distant failure. This report explains the concepts of statistical independence, nonidentifiability, and competing risks and illustrates the pitfalls of using actuarial methods to assess local tumor control.(ABSTRACT TRUNCATED AT 250 WORDS)

Actuarial Analysis↗