Influence of Hydrazine Sulfate on Abnormal Carbohydrate Metabolism in Cancer Patients with Weight Loss ^*

[CANCER RESEARCH 44, 857-861, February 1984]

Rowan T. Chlebowski,^** David Heber, Betsy Richardson, and Jerome B. Block

Divisions of Medical Oncology [R.T.C., B.R., J.B.B.] and Endocrinology and Metabolism [D.H.], Department of Medicine, University of California Los Angeles School of Medicine, Harbor-UCLA Medical Center, Torrance, California 90509

ABSTRACT

Thirty-eight patients with advanced cancer and weight loss were tested in a prospectively randomized, double-blind, placebo-controlled trial to evaluate the influence of hydrazine sulfate on carbohydrate metabolism in cancer cachexia. All patients had an initial 3-day inpatient metabolic evaluation including: standard 5-hr p.o. glucose tolerance test, hormone studies, and total glucose production by infusion of [6-³H]glucose. After 30 days of treatment with capsules containing either placebo or hydrazine sulfate in a 60-mg, 3 times/day dosage, inpatient evaluation was repeated. A total of 62 metabolic inpatient evaluations were performed. The pretreatment characteristics of age, sex, prior therapy experience, nutritional parameters and tumor types were comparable in placebo and hydrazine treatment groups. On initial evaluation, abnormal glucose tolerance and increased glucose production were frequently seen. Serial assessment of glucose tolerance showed no improvement after 30 days of placebo treatment. However, the glucose tolerance was significantly improved in patients receiving 30 days of hydrazine sulfate [2-hr glucose; initial 169 +/- 24 (S.E.) mg/d] versus final 128 +/- 12 mg/ dl; p<0.05]. In addition, the rate of total glucose production was significantly decreased after 30 days of hydrazine sulfate compared to placebo treatment (2.46 mg/kg/min versus 3.07 mg/kg/min, respectively; p < 0.05). Toxic effects of hydrazine sulfate were minimal. Our results suggest that hydrazine sulfate can influence the abnormal carbohydrate metabolism associated with weight loss in patients with cancer.

INTRODUCTION

Weight loss is a significant complication of cancer which adversely influences patient outcome (7, 8). One of the earliest of the variety of hormonal (3, 26, 27) and metabolic abnormalities described in cancer patients with weight loss was glucose intolerance, first identified over 60 years ago (4, 18, 22, 25, 32). In addition, increased total glucose production (4, 15-17, 21) as well as increased recycling of glucose through lactate (Cori cycle) or alanine are seen in cancer patients with weight loss (16, 29 - 31). It has been suggested that inappropriate activation of these gluconeogenic pathways could lead to futile cycling and net host energy loss (13). If this hypothesis is correct, amelioration of the abnormal carbohydrate metabolism in the cancer-bearing host could provide a therapeutic approach to cancer cachexia.

Hydrazine sulfate inhibits the enzyme phosphoenolpyruvate carboxykinase which results in interruption of gluconeogenesis in animals (11, 24). However, the ability of hydrazine sulfate to influence glucose metabolism in humans has not been established previously. For this reason, we conducted a randomized, placebo-controlled, double-blind trial to assess the ability of hydrazine sulfate to correct the abnormal glucose metabolism associated with weight loss in patients with cancer.

MATERIALS AND METHODS

Patients with metastatic cancer were eligible for study if they had lost 10% or more of their usual body weight and had normal liver function and mental status. Patients with a known history of diabetes mellitus were ineligible. Patients were entered either prior to receiving systemic therapy or when a new systemic therapy program was initiated for disease progression. After informed consent was obtained, patients were admitted to the Clinical Research Center for a 3-day inpatient metabolic evaluation. No metabolic studies were performed within 4 weeks of prior chemotherapy. Patients were subsequently randomized in a double-blind fashion to receive either placebo or hydrazine sulfate. Patient randomization was stratified on the basis of concurrent chemotherapy and conducted using published random number tables. A hospital pharmacist held the code for the trial, thus ensuring that the patient, treating physician, and evaluating physician remained blinded to the treatment allocation. Capsules containing either hydrazine sulfate or placebo were prepared by Anabolic, Inc. (Irvine, CA). Following 30 days of treatment with hydrazine or placebo, the inpatient metabolic evaluation was repeated. In addition to the 38 cancer patients randomized to receive hydrazine sulfate or placebo, an additional 10 age-matched, cancer-free, control subjects had a similar 3day metabolic evaluation. These 10 cancer-free control patients were not treated with hydrazine.

During the 3 day inpatient evaluation, all patients received the following: (a) anthropometrics including body weight, triceps skinfold thickness, midarm circumference, and dietary history on Day 1; (b) p.o. glucose tolerance test on Day 2; and (c) determination of total glucose production on Day 3. All patients received a high-carbohydrate diet for 2 days prior to p.o. glucose tolerance testing. Total body glucose production was determined by infusion of [6-³H]glucose in the fasting state, using a primed constant infusion for 5 hr (31). Serial plasma supernatants were sequentially passed through anion and cation exchange columns and evaporated to dryness to remove labeled by-products of glucose metabolism and to eliminate any Vitiated water formed by glucose metabolism. Production rate (PA) was calculated from the following:

The data are expressed as glucose production rate in mg/kg/min. Standard 5-hr p.o. glucose tolerance was performed after 40 g/sq m glucose load with both glucose and insulin response determined. Plasma glucose was measured using a Beckman glucose analyzer. Insulin, growth hormone, glucagon, and cortisol were measured by established radioimmunoassay.

The treatment program consisted of an escalating schedule of capsules containing either 60 mg of hydrazine sulfate or placebo until the full dosage of 60 mg. 3 times/day, given before meals, was reached beginning on the eighth day. Patients were contacted weekly to assess compliance and kept daily compliance diaries.

Statistically significant differences between hydrazine and placebo groups relative to any pretreatment clinical factors were sought using chi squared contingency table analysis and Student’s t test. The statistical differences between data generated at 2 time periods were determined using the Student’s t test of the initial minus final values. The statistical differences between hydrazine and placebo treatment were determined using the 2 group t test; results are expressed as the mean +/- SEM.]

RESULTS

A total of 38 patients were randomized to receive either placebo or hydrazine sulfate treatment. No statistically significant differences in the pretreatment patient characteristics of the 2 treatment groups were seen (Table 1). Patients on the 2 arms were comparable with respect to sex, performance score, and tumor types. Stratification resulted in an equivalent number of patients receiving concurrent chemotherapy on both arms. Non-small cell lung cancer accounted for 38% of placebo and hydrazine patients. Other tumor types evaluated included adenocarcinomas of the gastrointestinal tract, oropharyngeal carcinoma, and breast carcinoma. Sites of metastatic disease were also closely comparable on the 2 arms with lung and liver prominent sites of involvement. Measurable disease was not an entry criterion. In accordance with eligibility criteria, all patients had experienced weight loss before entry on study. Weight loss prior to entry was substantial; patients on the hydrazine arm lost 19% of their preillness weight, while patients on the placebo arm lost 16% of their preillness weight. Consideration of other pretreatment variables including prior chemotherapy and radiotherapy experience, anthropometrics, and serum albumin revealed no significant differences between the hydrazine- and placebo-treated groups (Table 1).

The initial evaluation of p.o. glucose tolerance and glucose production in all 38 cancer patients entered on study is compared to values observed in the 10 cancer-free, age-matched controls in Table 2. Both significantly decreased glucose tolerance and significantly increased glucose production were seen when the cancer patients were compared to the cancer-free control population.

Twenty-four of the 38 cancer patients randomized on study completed 30 days of hydrazine or placebo treatment and had repeat inpatient metabolic evaluations: 13 of 19 on hydrazine (68%) and 11 of 19 on placebo (57%). Almost all remaining patients who were not restudied experienced disease progression during the 30-day treatment period, precluding metabolic reevaluation. Only one patient refused repeat metabolic study.

Chart 1.  Influence of 30 days of treatment with placebo () or hydrazine sulfate () on p.o. glucose tolerance after 40 g/sq m glucose load in cancer patients with weight loss.  Initial () evaluation before treatment and final (----) evaluation after 30 days of treatment for both glucose and insulin.  The improvement in glucose tolerance after hydrazine sulfate was statistically significant (p < 0.05).  Bars, S.E.

The influence of 30 days of placebo treatment on the abnormal p.o. glucose tolerance seen in cancer patients is illustrated in Chart 1. No change in either glucose or insulin levels was seen when the initial assessment was compared to the final assessment performed after 30 days of placebo therapy. In cancer patients randomized to receive hydrazine sulfate for 30 days, however, a statistically significant improvement in glucose tolerance was seen (Chart 1). Glucose levels decreased from 178 to 140 mg/dl at 1 hr and from 169 to 128 mg/dl at 2 hr (p < 0.05). No change in insulin levels accompanied the improved glucose tolerance associated with hydrazine treatment. Growth hormone and cortisol remained normal in all cases. Thirty days of hydrazine therapy also resulted in reduced total glucose production. The influence of 30 days of placebo or hydrazine therapy on total glucose production rates in all 24 cancer patients having repeat metabolic evaluation is illustrated as a scattergraph in Chart 2. Consideration of the initial minus final glucose production rate demonstrates a statistically significant (p < 0.05) reduction in glucose production for patients receiving hydrazine sulfate (initial 2.78 +/- 0.17 versus final 2.46 +/- 0.19 on hydrazine) compared to those receiving placebo treatment (initial 2.96 +/-0.24 versus final 3.07 +/- 0.34 on placebo).

Chart 2.  Influence of 30 days of treatment with placebo or hydrazine sulfate on total glucose production rates in cancer patients with weight loss.   Initial evaluation before treatment and final evaluation after 30 days of treatment for each patient completing repeat metabolic evaluation.  The reduction in glucose production after hydrazine sulfate was statistically significant (p < 0.05)

.
Twenty-five of the 38 patients entered were receiving concurrent chemotherapeutic regimens in addition to hydrazine or placebo treatment for the 30-day study period. In all cases, chemotherapy was given immediately following the initial metabolic evaluation, and repeat metabolic evaluations were conducted at least 4 weeks after such chemotherapy administration. The influence of chemotherapy on glucose metabolism is examined in Table 3. where initial and final glucose production rates are given for the 18 patients receiving concurrent chemotherapy and compared to those seen in the 8 patients not receiving concurrent chemotherapy. Although final values for 2-hr glucose and glucose production rates were slightly lower in patients receiving concurrent chemotherapy, these differences were not statistically significant. Chemotherapy treatment alone could not account for the improvement in metabolic parameters seen when hydrazine-treated patients are compared to those receiving one month of placebo treatment for 3 reasons. (a) A comparable number of patients on both arms received concurrent chemotherapy (12 on the placebo and 13 on the hydrazine arm). (b) As outlined in Table 3, glucose tolerance and glucose production rates were not significantly influenced by concurrent chemotherapy administration. (c) A comparable number of patients on both arms had an objective response to chemotherapy. Objective response (a >50% decrease in tumor dimensions) in this cancer patient population with advanced disease and extensive previous therapy was seen in only one patient on the placebo arm (with breast cancer) and in 2 patients on the hydrazine arm (one with lymphocytic lymphoma and one with gastric carcinoma). Since measurable disease parameters and quantitative definition of all disease sites were not entry criteria, no correlation between relative tumor burden and metabolic abnormalities can be made. However, since only 3 of these 38 advanced-disease patients demonstrated objective antitumor response, response to chemotherapy treatment was not a major determinant of the metabolic changes seen.

Patient tolerance to the p.o. 60-mg, 3 times/day dosage of hydrazine sulfate was excellent. Hypoglycemia was not seen. Transient dizziness was experienced by 2 patients. Therapy was discontinued by one patient on the hydrazine and one patient on the placebo arm, both for the reason of intolerable nausea.

The study protocol, including the 30day period of treatment and the patient entry criteria, was specifically designed to determine whether hydrazine sulfate could influence the abnormal glucose metabolism associated with cancer cachexia. The study protocol was not designed to assess whether any changes in metabolic parameters would be associated with clinical benefit. However, in the advanced-disease cancer patients receiving hydrazine treatment in this study, 7 of 9 patients with improved p.o. glucose tolerance (manifested by decreased 2-hr glucose levels after 30 days of therapy) either improved or stabilized their weight, while all 4 patients without improvement in p.o. glucose tolerance lost weight. As expected from a population of patients with solid tumors of these primary sites, almost all patients (with the exception of the 3 showing objective responses) demonstrated no measurable change in tumor dimensions during the 1-month period of observation (Table 4).

DISCUSSION

In the present study, both a decrease in glucose tolerance and an increase in the rate of total glucose production were seen in cancer patients with weight loss compared to age-matched, healthy controls. Such abnormalities of glucose metabolism have been reported previously in patients with cancer cachexia (4, 16, 17, 22, 25). The abnormal carbohydrate metabolism in our patients was not associated with major changes in the levels of hormones such as insulin, glucagon, and cortisol usually involved in regulating glucose tolerance and production. The increase in glucose production seen in cancer patients with weight loss differs from the situation in normal subjects experiencing weight loss due to starvation, where a decrease in total glucose production has been reported (17).

Hydrazine sulfate has a demonstrated capacity to inhibit gluconeogenesis in animal systems (11, 24). The use of hydrazine sulfate to influence the abnormal glucose metabolism in cancer cachexia has been proposed as a therapeutic approach to weight loss in the cancer patient (12). Previous experience with the use of hydrazine sulfate in patients with cancer has come from 2 types of clinical studies. In uncontrolled trials of hydrazine sulfate where subjective parameters were assessed, benefit was reported by investigators both in North America (13) and Russia (12). In uncontrolled trials of hydrazine sulfate, where reduction in tumor size was used as the major therapeutic endpoint in patients with far advanced disease, no benefit was seen (19, 23, 28). A major difficulty complicating interpretation of the previous clinical hydrazine experience has been study designs which were not controlled and did not evaluate changes in metabolic parameters. As a result, both the positive (12, 14) and negative (19, 23. 28) clinical trials have not given incontrovertible results. No prior clinical study has evaluated the influence of hydrazine sulfate on the abnormal carbohydrate metabolism seen in patients with cancer cachexia. Therefore, we addressed this specific question using a randomized, placebo-controlled, double-blind design.

In the present trial, hydrazine sulfate treatment resulted in significant improvement in the abnormal glucose metabolism seen in patients with weight loss and cancer. One month of placebo treatment had no influence on the decreased glucose tolerance seen in cancer patients in this trial. Total glucose production rates also remained elevated after 1 month of placebo treatment. Patients receiving 1 month of hydrazine treatment had a significant improvement in glucose tolerance and a significant decrease in total glucose production rates compared to those receiving 1 month of placebo. The improvement in glucose tolerance following hydrazine therapy occurred without major change in insulin levels, suggesting that hydrazine results in an increase in insulin sensitivity in cancer patients. Improved glucose tolerance may occur either as a result of an increase in the rate of exogenous glucose disposition or as a result of an impairment of new glucose formation. Further study, assessing incorporation of gluconeogenic substrates such as alanine or lactate into glucose, will be required to directly assess the mechanism mediating the hydrazine effect. However, the observation of a significant decrease in total glucose production following hydrazine therapy in the current trial indicates at least some influence on new glucose production.

The important question of whether the improvement in metabolic indices associated with hydrazine use in the present trial will result in improved clinical outcome for cancer patients with weight loss remains to be determined. Although the contribution of abnormal glucose metabolism to the net energy loss reported to occur in cancer cachexia (10) has not been quantified, the capacity of hydrazine sulfate to influence abnormal glucose metabolism in patients with weight loss and cancer suggests further study of this agent is indicated, especially in prospective clinical trials correlating metabolic, nutritional, and clinical out-come parameters.

For many types of cancer, an extremely poor prognosis is associated with weight toss (7, 8). Anorexia, leading to a decrease in caloric intake, frequently occurs in cancer patients with weight loss (6,9). As a result, nutritional supportive therapy has been studied as a means of improving the prognosis of such patients. However, in several randomized trials, provision of nutritional support using tong-term parenteral nutrition has had only limited impact on clinical outcome in this population (1, 20). The present study illustrates the use of a nonchemotherapeutic agent to ameliorate abnormal host metabolism in patients with weight loss and cancer. Correction of the abnormal metabolism associated with cancer cachexia using hydrazine sulfate or other agents (2, 27) may provide an alternative approach to the treatment of the cancer patient with weight loss.

In summary, we conclude: (a) abnormal glucose metabolism is commonly present in patients with weight loss and cancer; (b) hydrazine sulfate can influence the abnormal glucose metabolism associated with cancer cachexia; and (c) further studies of hydrazine sulfate correlating metabolic, nutritional, and clinical parameters are indicated in the cancer patient population.

^* Supported by Grant RD-163 from the American Cancer Society, and by the General Clinical Research Center Grant RR-00425, NIH.  This study was published and presented in part in abstract form (5).

^** To whom requests for reprints should be addressed, at Division of Medical Oncology, Harbor-UCLA Medical Center, 1000 W. Carson St., Torrance, CA 90509.  Received November 5, 1982; accepted November 8, 1983.

References

1. Brennan, M. F. Total parenteral nutrition in the cancer patient, N. Engl. J. Med., 305: 375-382, 1980.
2. Burt, M. E., Lowry, S. F.. Gorschboth. C.. and Brennan, M. F. Metabolic alterations in a noncachectic animal tumor system. Cancer Res., 42: 774-781.
3. Chleboswki, R.T., and Heber, D. Hypogonadism in male patients with metastatic cancer prior to chemotherapy. Cancer Res., 42:2495 – 2498, 1982.
4. Chlebowski, R.T., Heber D., and Block, J.B. Serial assessment of glucose metabolism in patients with cancer cachexia. Clin. Res., 30:69, 1982.
5. Chlebowski, R.T., Heber, D., Richardson, B., and Block, J.B. Influence of hydrazine sulfate on abnormal carbohydrate metabolism in cancer cachexia: a randomized, placebo-controlled trial. Proc. Am. Soc. Clin. Oncol., 1:59, 1982.
6. Costa, G., Bewley, P., Aragon, M., and Siebold, J. Anorexia and weight loss in cancer patients. Cancer Treat. Rep., 65: 3-7, 1981.
7. Costa, G., Lane, W.W., Vincent, R.G. Siebold, J.A., Aragon, M., and Bewley, P.T. Weight loss and cachexia in lung cancer. Nutr. Cancer, 2:98-103, 1980.
8. DeWys, W.D., Begg, C., and Lavin, P.T. Prognostic effect of weight loss prior to chemotherapy in cancer patients. Am. J. Med., 69:491 – 497, 1980.
9. DeWys, W.D., Costa, G., and Henkin, R. Clinical parameters related to anorexia. Cancer Treat. Rep., 65:49-52, 1981.
10.   Evans, W.K., Russell, D.M., Shepard, F.A., Shike, M., Feld, R., and Jeejeeboy, K.N. Alterations in metabolic and nutritional profiles in small cell cell lung cancer. Proc. Am. Soc. Clin. Oncol., 2:89, 1983
11. Fortney, S.R., Clark, D.A., and Stein, E.J. Inhibition of gluconeogenesis by hydrazine administration in rates. J. Pharmacol. Exp. Ther., 6:277 – 284, 1972
12.   Gershanovich, M.L., Danova, L.A., Ivin, B.A., and Filow, V.A. Results of clinical study of antitumor action of hydrazine sulfate. Nutr. Cancer, 3:4 12, 1981
13.   Gold, J. Proposed treatment of cancer by inhibition of gluconeogenesis. Oncology (Basel), 22:185 – 207, 1968.
14.    Gold, J. Use of hydrazine sulfate in terminal and preterminal cancer patients: results of investigational new drug (IND) study in 84 evaluable patients. Oncology (Basel), 32:1 – 10, 1975.
15. Heber, D., Chlebowski, R.T., Ishibashi, D.E., Herrold, J.N., and Block, J.B. Abnormalities in glucose and protein metabolism in noncachectic lung cancer patients. Cancer Res., 42:4815 – 4819, 1982.
16.   Holroyde, C.P., Gabuzda, T.G., Putnam, R.C., Paul, P., and Reichard, G.A. Altered glucose metabolism in metastatic carcinoma. Cancer Res., 35:3710 – 3714, 1975.
17.   Holroyde, C.P., and Reichard, G.A. Carbohydrate metabolism in cancer cachexia. Cancer Treat. Rep., 65:55 – 59, 1982.
18.   Jasani, B., Donaldson, L.S., and Ratcliffe, J.G. Mechanism of impaired glucose tolerance in patients with neoplasia. Br. J. Cancer, 38:287 – 292, 1978.
19.   Lerner, H.J., and Regelson, W. Clinical trial of hydrazine sulfate in solid tumors. Cancer Treat. Rep., 60: 959 – 960, 1976.
20.   Levine, A.S., Brennan, M.F., Raum, A., Fisher, R.I., Pizzo, P.A., and Glaubiger, D.L. Controlled clinical trials of nutritional intervention as an adjunct to chemotherapy with a comment on nutrition and drug resistance. Cancer Res., 42: 744 – 781, 1982.
21.   Lundholm, K., Edstrom, S., Karlberg, I., Ekman, L., and Schersten, T. Glucose turnover, gluconeogenesis from glycerol and estimation of net glucose cycling in cancer patients. Cancer (Phila), 50: 1142 – 1150, 1982
22. Marks, P.A., and Bishop, J.S. The glucose metabolism of patients with malignant disease and of normal subjects as studied by means of an intravenous glucose tolerance test. J. Clin. Invest., 36: 254 – 264, 1957.
23.   Ochoa, M., Jr., Wittes, R.E., and Drakoff, I.H. Trial of hydrazine sulfate (NSC-1S0014) in patients with cancer. Cancer Chemother. Rep., 39: 1151 – 1154, 1975.
24.   Ray, P.D., Hanson, R.L., and Lardy, H.A. Inhibition of hydrazine of gluconeogenesis in the rat. J. Biol. Chem., 245: 690 – 695, 1970.
25.   Rohdenburg, G.L., Bernhard, A., and Drehbiel, O. Sugar tolerance in cancer. J.A.M.A., 72: 1528 – 1529, 1919.
26.   Rose, D.P., and Davis, T.E. Plasma thyronine levels in carcinoma of the breast and colon. Arch. Intern. Med., 141: 1161 – 1164, 1981.
27.   Schein, P.S., Kisner, D., Haller, D., Blecher, M., and Hamosh, M. Cachexia of malignancy: potential role of insulin in nutritional management. Cancer (Phila.), 43: 2070 – 2076, 1979.
28. Spremulli, E., Wampler, G.L., and Regelson, W. Clinical study of hydrazine sulfate in advanced cancer patients. Cancer Chemother. Pharmacol., 3: 121 – 124, 1979.
29. Waterhouse, C. How tumors affect host metabolism. Ann. N. Y. Acad. Sci., 230: 86 – 93, 1974.
30. Waterhouse, C. Lactate metabolism in patients with cancer. Cancer (Phila.), 33: 66 – 71, 1974.
31. Waterhouse, C., Jeanpretre, N., and Keilson, J. Gluconeogensis from alanine in patients with progressive malignant disease. Cancer Res., 39: 1968 – 1972, 1979.
32. Wolf, R.R., Alsop, J.R., and Blarke, J.F. Glucose metabolism in man: responses to intravenous glucose infusion. Metabolism (Baltimore), 28: 210 – 220, 1979.

This page is designed and hosted by Next Generation Computer Systems, and is the property of the Syracuse Cancer Research Institute. © 1996, Syracuse Cancer Research Institute. All rights reserved.
Last modified on 22 September 1998 by webteam@ngen.com.