After hydrazine sulfate showed promising results in a small pilot study, three large-scale, randomized studies of the compound were undertaken in patients with advanced cancers. Clinical trials are carried out to determine, in an objective, unbiased way, whether new treatments are safe and effective in people. These three clinical trials, published in June 1994, showed no benefit from hydrazine sulfate in patient survival, weight loss, or quality of life.

Supporters of hydrazine sulfate claimed that the studies were compromised because patients were permitted to take tranquilizers, alcohol, and barbiturates, compounds they said interfered with hydrazine sulfate, based on animal and laboratory studies. NCI scientists had reviewed the same data and disagreed on the need to prohibit those drugs, which were permitted in two of the three large studies. At the request of Congress, an investigation of the allegations was undertaken by the Government Accounting Office (GAO) beginning in July 1994 and lasting until April 1995.

After intense scrutiny, the GAO found that while tranquilizers, alcohol, and barbiturates were permitted in the studies, "subsequent analyses of the use of concurrent medications found no evidence to invalidate NCI’s conclusion that hydrazine sulfate is ineffective."

NCI stands behind the findings of the 1995 GAO report, "Cancer Drug Research: Contrary to Allegation, the National Institutes of Health Hydrazine Sulfate Studies Were Not Flawed." Because studies of hydrazine sulfate in more the 600 cancer patients showed no benefit in terms of patient survival, weight loss, or quality of life, no new NCI studies are planned.

Although the Food and Drug Administration (FDA) has not approved hydrazine sulfate for marketing in the United States, a number of drugs that help fight cancer cachexia have been approved by the FDA and are available to cancer patients. NCI supports hundreds of clinical studies of cancer treatments every year. Studies of compounds that may reverse cachexia and treatments to fight advanced cancers are under way.

Background

In the 1970s, Joseph Gold, M.D., a scientist in Syracuse, N.Y., proposed that hydrazine sulfate, a compound found in rocket fuel, could interrupt the altered glucose metabolism seen in cancer cachexia. In animal studies, Gold found that the compound also inhibited tumor growth and sometimes enhanced the anti-cancer effect of drugs. In preliminary studies in humans, Gold reported some tumor regression and other subjective improvements in patients. Similarly, Russian physicians using hydrazine sulfate claimed some patients benefited in similar ways. In the 1980s, a study of hydrazine sulfate took place at Harbor-UCLA Medical Center in Torrance, Calif. The trial included 65 patients with advanced lung cancer (nonsmall cell lung cancer) who had not yet received chemotherapy. Patients were randomized (divided by chance) to receive either hydrazine sulfate or a placebo in addition to a chemotherapy regimen (cisplatin, vinblastine, and bleomycin). The study was funded, in part, by the NCI.

All patients received nutrition counseling to increase their intake of calorie and nutrients, with no request to limit alcohol intake and no prohibition of barbiturates. The particular chemotherapy drugs being used were highly likely to cause nausea and vomiting, so patients were prescribed anti-emetic drugs to control these side effects. The anti-emetics were also tranquilizers (benzodiazepines and phenothiazines).

Data from the study suggested that some patients who took hydrazine sulfate -- those who were in good condition before the study began -- had better survival rates (about a 17-week increase in these terminal patients). All patients on hydrazine sulfate had greater caloric intake, although that did not translate into a significant weight gain. Preliminary findings from the study were presented in early 1987, and the study was published in January 1990.

Based on the findings of this study, with particular interest in the improvement in survival, NCI sponsored three large-scale clinical trials of the effects in patients with two types of advanced cancer -- nonsmall cell lung cancer and colon cancer.

In January 1988, the Cancer and Leukemia Group B (CALGB), an NCI-sponsored research network (called a cooperative group), was solicited to conduct a trial. From July 1989 to February 1991, 291 patients with late-stage nonsmall cell lung cancer who were in good condition (well enough to not be bedridden), were treated with a chemotherapy regimen of cisplatin and vinblastine and either hydrazine sulfate or a placebo. Other drugs thought to stimulate appetite were not permitted. Because the chemotherapy regimen could cause severe nausea and vomiting in almost all patients, CALGB investigators permitted the anti-emetic drugs that are also tranquilizers. Barbiturates were not specifically prohibited, and records show at least one patient received them. The study ultimately showed no benefit from hydrazine sulfate and results were published in June 1994.

From May 1990 to October 1992, 243 patients with nonsmall cell lung cancer were enrolled in the second NCI-funded study of hydrazine sulfate. Headed by the North Central Cancer Treatment Group (NCCTG), another NCI-cooperative group, the patients received cisplatin and etoposide as chemotherapy and were randomized to hydrazine sulfate or a placebo. Again, the chemotherapy regimen used induces severe nausea and vomiting, so patients were given anti-emetic medication. These medications included benzodiazepines, pheothiazines, and then newly available serotonin antagonists. Use of barbiturates and consumption of alcohol was prohibited.

No differences in survival, tumor regression, toxicities, or patient quality of life was seen between the patients receiving hydrazine sulfate and those on placebo. The study was published in June 1994. An unpublished analysis comparing patients who received only the newer kind of anti-emetics (serotonin antagonists) to those taking other anti-emetics, conducted for the GAO investigation, did not show any survival difference.

From October 1990 through November 1992, NCCTG enrolled 127 patients with metastatic colorectal cancer into a study of hydrazine sulfate or a placebo. Patients in this study had been treated with chemotherapy regimens, but their tumors had not responded. Appetite stimulants, alcohol, barbiturates, and planned use of tranquilizers were prohibited. Anti-emetic agents were permitted, because while no chemotherapy was being given, advanced colorectal cancer patients may experience nausea and vomiting as a symptom of their disease. Use of such anti-emetics was not widespread in these patients. In this study, published in June 1994, patients receiving hydrazine sulfate had a decreased survival compared to patients on placebo.

In 1994, Gold and other proponents of hydrazine sulfate alleged that NCI compromised these studies of hydrazine sulfate by permitting patients to have tranquilizers, barbiturates, and alcohol. He interpreted data from animal studies to suggest that hydrazine sulfate was incompatible with these drugs. NCI, NCCTG, and CALGB researchers reviewed the same data and did not interpret it to show such incompatibility. The study done at UCLA, which had not prohibited such agents, was the trial that had shown the greatest survival benefit from hydrazine sulfate. At the request of Congress, the General Accounting Office undertook an investigation about these allegations, which were found to be without merit.

Copies of the GAO report are available from the U.S. General Accounting Office, Post Office Box 6015, Gaithersburg, Md. 20884-6015, or call (202) 512-6000. The first copy of the report is free; additional copies are $2.00 each.

References

Chlebowski RT, Bulcavage L, Grosevenor M, et al. Hydrazine sulfate influence on nutritional status and survival in nonsmall cell lung cancer. Journal of Clinical Oncology 1990; 8(11): 9-15.

Kosty MP, Fleishman SB, Herndon JE, et al. Cisplatin, vinblastine, and hydrazine sulfate in advanced, non-small-cell lung cancer: A randomized placebo-controlled, double-blind phase III study of the Cancer and Leukemia Group B. Journal of Clinical Oncology 1994; 12(6): 1113-1120.

Loprinzi CL, Goldberg RM, Su JQ, et al. Placebo-controlled trial of hydrazine sulfate in patients with newly diagnosed non-small-cell lung cancer. Journal of Clinical Oncology 1994; 12(6): 1126-1129.

Loprinzi CL, Kuross SA, O’Fallon JR, et al. Randomized placebo-controlled evaluation of hydrazine sulfate in patients with advanced colorectal cancer. Journal of Clinical Oncology 1994; 12(6): 1121-1125.

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