Multicenter Phase II trial of etoposide in refractory small cell lung cancer.
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Carcinoma, Small Cell↗
Biomedical subjects
G L Wampler
Publications and source records attributed to G L Wampler.
Confidence interval about the response at the stationary point of a response surface, with an application to preclinical cancer therapy.
A method of calculating a confidence interval about the response at the stationary point of a response surface is presented. We show that the technique can also be used to calculate a confidence region about the location of the stationary point. The procedure is applied, via Cox's proportional-hazards model, to the analysis of survival data from a preclinical cancer chemotherapy experiment involving the combination of two drugs. It is seen that the results can be useful in determining the existence of a therapeutic synergism.
Animals↗
Hexamethylmelamine in adenocarcinoma of the pancreas and liver.
Ten patients with advanced adenocarcinoma of the pancreas were treated with hexamethylmelamine 8 mg/kg/day in oral, divided doses. One of the five patients with measurable disease had a partial response which lasted 5 months. One of the five patients with no measurable disease treated for 52 months with hexamethylmelamine survived a total of 59 months. This experience suggests that hexamethylmelamine may be an active drug in the treatment of pancreatic cancer.
Adenocarcinoma↗
Antitumor activity of homo-aza-steroidal esters of [p-[bis(2-chloroethyl)amino]phenyl]acetic acid and [p-[bis(2-chloroethyl)amino]phenyl]butyric acid.
Three new modified steroidal alkylating agents, 3 beta-hydroxy-13 alpha-amino-13,17-seco-5 alpha-androstan-17-oic-13,17-lactam-p-bis(2-chloroethyl)aminophenylacetate, 3 beta-hydroxy-13 alpha-amino-13,17-seco-5 alpha-androstan-17-oic-13,17-lactam-p-bis-(2-chloroethyl)aminophenylbutyrate, and 17 beta-hydroxy-3-aza-A-homo-4 alpha-androsten-4-one-p-N,N-bis(2-chloroethyl)aminophenylacetate are active in treatment of L1210 and P388 leukemias. A stereoisomer of the first compound, 3 alpha-hydroxy-13 alpha-amino-13,17-seco-5 alpha-androstan-17-oic-13, 17-lactam-p-bis(2-chloroethyl)aminophenylacetate, was tested in L1210 leukemia. This stereoisomer, in which the alkylating agent is linked to the modified steroid in the axial position, is active only as much higher doses in L1210 leukemia. The results of testing these compounds and previous results from similar compounds allow certain conclusions to be drawn regarding structure-activity relationships. The presence of the lactam moiety is the major structural feature that confers activity in the murine leukemias. The steric arrangement of the alkylating moiety at position 3 and the hydrogen atom at position 5 influence toxicity and antileukemic activity.
Animals↗
The radioenhancement effects of 5-thio-D-glucose and insulin in vivo on a hypoxic P388 murine leukemia.
A radioresistant in vivo tumor consisting of a partially hypoxic P388 murine leukemia growing intraperitoneally (IP) in B6D2F1 female mice was used to test the radioenhancement potential of 5-Thio-D-Glucose (5TDG) and insulin. Pretreated animals were exposed to increasing doses of whole body radiation (5, 10, 20 Gy) and harvested tumor cells were re-injected into new hosts. In this experiment little benefit was demonstrated with 5TDG or the combination of 5TDG and insulin + radiation. The median survival of animals receiving cells pre-treated with insulin and radiation was improved, but, in general, did not reach statistical significance by the log rank method.
Animals↗
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↗
A pilot study with ethyl bis (2,2-dimethyl-1-aziridinyl) phosphinate (AB-163) and radiation therapy.
Ethyl bis (2,2 dimethyl-1-aziridinyl) phosphinate (AB-163), a TEPA analogue, was used with radiation therapy in treating 18 patients with advanced malignancies. There were 12 patients with esophageal carcinoma; 3 with adenocarcinomas of the gastrointestinal tract; one, squamous carcinoma of the cervix; and one, adenocarcinoma of the ovary. One hundred mg/M2 AB-163 was given by rapid i.v. drip one half-hour before conventional radiation therapy. The majority of patients received 10 combined treatments. Three of those with squamous cell carcinomas (two in the esophagus and one in the cervix) remained disease-free for more than 2 years. One with liver metastasis and unresectable carcinoma of the stomach survived for 9 months. The drug causes side effects mainly involving the central nervous system and gastrointestinal tract. Drug-related myelosuppression has not been observed. The mode of action is speculated to be a result of active intermediate hydrolysis products which appear capable of phosphorylating X ray induced DNA strand damage. However, much additional investigation is required, both in vitro and clinically, before its efficacy and safety can be demonstrated.
Adenocarcinoma↗
Effect of a delta 5-homo-aza-steroidal ester in P388 and L1210 murine leukemias.
3 beta-Hydroxy-13 alpha-amino-13,17-seco-5-androsten-17-oic-13,17-lactam P-N,N-bis-(2-chloroethyl)-amino phenylacetate gives results in P388 and L1210 leukemias in mice, by the intraperitoneal route of administration.
Animals↗
Activity of 3 beta-hydroxy-13 alpha-amino-13,17-seco-5 alpha-androstane-17-oic-13,17-lactam(p-(bis(2-chloroethyl)amino)-phenyl) acetate(NSC 290205) in murine solid tumors.
The modified steroidal alkylating agent, 3 beta-hydroxy-13 alpha-amino-13,17-seco-5 alpha-androstane-17-oic-13,17-lactam[p-[bis(2-chloroethyl)amino]-phenyl]acetate showed excellent activity in treatment of there murine solid tumors. Colon 26-bearing CD2F1 mice lived twice as long as controls with tumor free survivors at the end of the 70-day observation period. CD8F1 mammary tumor growth was suppressed greater than 90% compared to controls. B16 melanoma-bearing B6D2F1 mice lived 50% longer than controls. This agent had previously been shown to be active in treatment of the Theagenion-Bahner angiosarcoma, the T8 Guerin tumor, L1210 leukemia and P388 leukemia.
Animals↗
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↗
Response of metastatic cloacogenic carcinoma to treatment with semustine.
A case of cloacogenic carcinoma of the anorectal junction with pulmonary metastases is presented. Treatment with Semustine (Methyl-CCNU) resulted in a partial response lasting 15 months. Cloacogenic carcinoma is an uncommon neoplasm against which only a few chemotherapeutic agents have been tried. Semustine should be considered in the treatment of metastatic cloacogenic carcinoma.
Anus Neoplasms↗
Intracerebral metastases in solid-tumor patients: natural history and results of treatment.
In order to determine the natural history and results of treatment of intracerebral metastases in solid-tumor patients, the records of 191 patients with an antemortem diagnosis of intracerebral metastasis made during the period from August 1974 to November 1978 were reviewed. Malignancies included lung (122 patients), breast (26), unknown primary (16), melanoma (8), colorectal (6), hypernephroma (4), and others (12). Favorable prognostic factors included solitary brain metastasis (P less than 0.001), ambulatory performance status (P less than 0.001), symptoms of headache (P less than 0.001), or visual disturbances (P less than 0.02), and estrogen receptor positivity in breast cancer patients (P = 0.055). Poor prognostic factors included advanced age (P less than 0.04) and evidence of impaired consciousness, i.e., disorientation, lethargy, stupor, or coma (P less than 0.007). Median survival time after diagnosis of intracerebral metastasis was 3.7 months for the entire series. In those patients with a single intracerebral metastasis and minimal tumor burden, the type of treatment used had a significant impact on survival. Those cases treated with surgery and radiation had a median survival time of 9.7 months versus 3.7 months for those treated with radiation alone (P less than 0.02). When using a proportional hazard regression analysis to adjust for the three most important prognostic factors, treatment (surgery and radiation versus radiation alone) still appeared to be important. Intracerebral metastases were the immediate or contributing cause of death in 50% of the patients in this series. Patients at greater risk of dying of intracerebral metastases included those in whom the brain was the first site of distant metastasis, those with an intracerebral metastasis from an unknown primary site, and those whose presentation of malignancy was with symptoms of a brain metastasis. Although the therapeutic goal in intracerebral metastases is generally palliative, it appears that there are categories of cases that may benefit from more aggressive treatment.
Adult↗
Phase I study of ethylbis(2,2-dimethyl-1-aziridinyl) phosphinate (AB-163).
Ethylbis(2,2-dimethyl-1-aziridinyl)phosphinate (AB-163) was used to treat 27 patients in a phase I trial. The limiting toxicity on a weekly schedule of IV administration involved nausea and vomiting associated with a variety of cholinergic side effects, including possible seizures. A starting dose of 300--400 mg/M2/week is suggested for a Phase II trial. One partial response in a patient with squamous-cell carcinoma of the cervix metastatic to the lungs was seen.
Adult↗
Regulation of ribonucleotide reductase in mammalian cells by chemotherapeutic agents.
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Animals↗
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↗
Phase II study of VM-26 in adult malignancies.
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Breast Neoplasms↗
A new steroidal alkylating agent with improved activity in advanced murine leukemias.
The homo-aza-steroidal ester of [p-[bis(2-chloroethyl)amino]phenoxy] acetic acid, 3 beta-hydroxy 13 alpha - amino - 13,17 - seco - 5 alpha-androstan-17-oic-13,17-lactam-p-bis(2-chloroethyl)aminophenoxyacetate, gave a 100% increase in lifespan over controls in the treatment of L1210 leukemia by IP administration on a days 1 and 4 treatment schedule. This ester gave a maximum activity of 383% increased lifespan over controls in the treatment of P388 leukemia by IP administration on a daily treatment schedule. Activity in advanced L1210 (41% increased lifespan) and P388 leukemias (173% increased lifespan) was maintained, indicating that this compound is the most promising of a number of congeners tested to date.
Alkylating Agents↗
Clinical study of hydrazine sulfate in advanced cancer patients.
Twenty-five patients with a variety of solid tumors were treated with hydrazine sulfate. Hydrazine was given orally in the form of 60 mg capsules from one to four times daily. No patient had a 50% reduction of tumor size. Subjective benefit was seen in three patients but it was of brief duration.
Adolescent↗