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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:

Infused [3H] glucose [cpm/dl X infusion rate (dl/min)]
PA (mg/min) = [3H] Glucose concentration at plateau (cpm/dl)
Plasma glucose concentration (mg/dl)

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).

Table 1

Pretreatment Characteristics of patients receiving placebo or hydrazine treatment
No differences between treatment arms were statistically significant.


Placebo Hydrazine

No. 19 19
Age
   Median 60 58
   Range 36-81 33-72
Sex (male:female) 13:6 13:6
Performance Score (median) 72 70
Prior Therapy
   None 3 2
   Chemotherapy 13 12
   Radiation 9 13
   Concurrent Chemotherapy 12 13
Tumor types evaluated
   Lung (non-small cell) 7 7
   Gastrointestinal adenocarcinoma 4 5
   Oropharyngeal 1 3
   Breast carcinoma 3 1
   Other 4 3
Nutritional Parameters
   Body wt (kg) 61 +/- 2 60 +/- 2
   Prior wt loss (%) 16 +/- 2 19 +/- 4
   Triceps skin fold 16 +/- 3 13 +/- 2
   Midarm circumference 25 +/-2 24 +/- 2
   Albumin (g/dl) 3.6 +/- 0.2 3.5 +/- 0.2



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.

Table 2

Glucose Tolerance p.o. and glucose production on initial assessment of cancer patients compared to cancer-free controls
Patient Group No. p.o. glucose tolerance (mg/dl) Glucose production
(mg/kg/min)

fasting 2-hr

Control 10 95 +/- 8a 142 +/- 13 2.04 +/- 0.10
Cancer 38 98 +/- 6 171 +/- 14b 2.86 +/- 0.10b

a Mean +/- S.E.

b Statistically significant difference comparing cancer to control patients; p<0.05.

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 (3877 bytes)
Chart 1.  Influence of 30 days of treatment with placebo (b.gif (122 bytes)) or hydrazine sulfate (a.gif (153 bytes)) on p.o. glucose tolerance after 40 g/sq m glucose load in cancer patients with weight loss.  Initial (c.gif (300 bytes)) 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).

chart2a.gif (3037 bytes)
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.

Table 3

Influence of concurrent chemotherapy on glucose tolerance production in cancer patients with weight loss.

  In no case was chemotherapy administered less than 4 weeks before the final metabolic evaluation.  No differences between the 2 groups were statistically significant.


Glucose tolerance (mg/dl) (2-hr glucose level)
Glucose production (mg/kg/min)
Patient Group No. Initial Final Initial Final

No concurrent chemotherapy 6 173 +/- 18a 159 +/- 14 2.93 +/- 0.25 2.89 +/- 0.27
Concurrent chemotherapy 18 175 +/- 11 153 +/- 9 2.84 +/- 0.19 2.71 +/- 0.21

a Mean +/- S.E.



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).

 

 

Table 4

Change in disease parameter over 30-day period of hydrazine treatment grouped by change in glucose tolerance and weight


Group Major disease parameter Change in parameter over 30 days

Glucose tolerance not improved, lost weight
  Patient A Lung infiltrate No change
  Patient B Hepatomegaly No change in size, alkaline phosphate
  Patient C Pleural effusion No change
  Patient D Lung infiltrate Slight increase in size, (not measurable)
Glucose tolerance improved, lost weight
  Patient E No measurable parameter
  Patient F Hepatomegaly Liver size slightly greater on physical examination
Glucose tolerance improved, weight stable
  Patient G Ascites No change
  Patient H Hepatomegaly No change
  Patient I Lung infiltrate Approximate 25% increase in size
  Patient J Hepatomegaly 25% decrease in size on physical examination a
  Patient K Lung infiltrate No change
  Patient L Hepatomegaly, lymphadenopathy No change in liver, slight decrease in adenopathy a
  Patient M Hepatomegaly No change

a Went on to achieve partial objective response



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.

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