Hydrazine Sulfate in Cancer Patients With Weight Loss

A Placebo-Controlled Clinical Experience

[Cancer 59:406-410, 1987]

ROWAN T. CHLEBOWSKI, MD, PHD, LINDA BULCAVAGE, MN, RN, MARY GROSVENOR, RD, MS, RAYNELLE TSUNOKAI, BS, JEROME B. BLOCK, MD, DAVID HEBER, MD, PHD, MICHELLE SCROOC, RD, JOAD S. CHLEBOWSKI, MD, JOCELYN CHI, MD, ENGIN OKTAY, MD, STEVE AKMAN, MD, AND ISHRAT ALI, MD

Reprinted from CANCER, Vol 59, No. 3, February 1, 1987.
Copyright © 1987, by the American Cancer Society, Inc. J.B. Lippincott Company.
Printed in U.S.A.

Hydrazine sulfate was evaluated using 24-hour dietary recalls and body weight determinations before and after 30 days of either placebo or hydrazine (60 mg, 3 times/d) oral administration in 101 heavily pretreated cancer patients with weight loss. After 1 month, 83% of hydrazine and only 53% of placebo patients completing repeat evaluation maintained or increased their weight (P < 0.05). In addition, appetite improvement was more frequent in the hydrazine group (63% versus 25%, P < 0.05). Although caloric intake was only slightly greater in hydrazine-treated patients, and increased caloric intake was more commonly associated with weight gain in patients receiving hydrazine compared with those receiving placebo (81% verse 53%, respectively). Hydrazine toxicity was mild, with 71 % reporting not toxic effects. Hydrazine sulfate circulatory levels were obtained from a subset of 14 patients who completed 30 days of treatment, with a single sample obtained in the morning at least 9 hours after the last dose. Mean maintenance hydrazine sulfate levels, determined using a spectrofluorometric assay, ranged from 0 to 89 ng/ml (man 45±16 ng/ml). These data, which demonstrate an association between 1 month of hydrazine sulfate administration and body weight maintenance in patients with cancer, suggests future clinical trials of hydrazine sulfate are indicated to definitively assess its long-term impact on important clinical outcome parameters in defined cancer populations.

Weight loss commonly accompanies cancer development and is associated with an adverse prognosis. Although intensive caloric support now can be provided such patients, clinical trials evaluating caloric provision alone have not reported improved outcome for chemotherapy-treated populations with advanced cancer. As a result, consideration of potential mechanisms underlying the development of weight loss in the cancer population has led to development of alternative strategies for clinical intervention in these patients. Altered glucose metabolism is a common metabolic abnormality in cancer patients with weight loss and it has been suggested that the inappropriate activation of pathways of glucose metabolism leads to futile cycling and cachexia development in this population. If this hypothesis is correct, amelioration of the abnormal carbohydrate metabolism could provide a therapeutic approach to the adverse outcome associated with cachexia development in the cancer-bearing host.

We previously demonstrated that hydrazine sulfate is metabolically active, improving the abnormal glucose tolerance and reducing the increased glucose production rates seen in cancer patients with weight loss. We now report clinical observations on short-term hydrazine sulfate use in a cancer population with weight loss using a prospective placebo-controlled study design.

Materials and Methods

The criteria for inclusion in this trial were: a diagnosis of advanced cancer; weight loss greater than 10% from usual body weight; absence of severe hepatic or renal dysfunction (bilirubin greater than 3 mg/dl and/or creatinine greater than 2 mg/dl); and normal mental status. Patients with a known history of diabetes mellitus or those receiving corticosteroid therapy were ineligible. Patients with ascites or clinically significant edema were not entered to avoid confounding weight determinations. Patients were entered either prior to receiving systemic chemotherapy or when a new systemic therapy program was initiated for disease progression. Measurable disease parameters were not required, and concurrent chemotherapy was permitted. Both initial and repeat assessment of all study parameters, however, were conducted at least 2 days before and 4 weeks after chemotherapy administration.

After informed consent was obtained, patients underwent an initial assessment of nutritional parameters, including caloric intake as described below. Patients subsequently were treated with capsules containing hydrazine sulfate (60 mg) or placebo which were prepared by Anabolic, Inc. (Irvine, California). Hydrazine sulfate was given under IND 17, 671 from the Food and Drug Administration (FDA) (obtained by Dr. Chlebowski). All institutional requirements for human subjects review were met. The treatment program consisted of an escalating schedule of capsules containing either hydrazine sulfate or placebo until the full dosage of 60 mg, 3 times/d given before meals, was reached beginning on the 8th day. This program was based on the extensive Russian experience. 15 Patients were contacted weekly to assess compliance and kept daily compliance diaries. The validity of daily compliance diaries was checked against intake based on returned prescription bottles. Following 30 days of either agent, the assessment of body weight, caloric intake, and other parameters was repeated.

During the initial and repeat evaluation, all patients received determination of body weight measured on the same printing scale; anthropometrics, including tricep skinfold thickness, mid-arm muscle circumference, and serum albumin; caloric intake using a 24-hour dietary recall history obtained by nutritionists and computer analyzed to give protein, carbohydrate, fat, and energy contents of the diet. Expected caloric intake was normalized for each patient by weight based on a calculated recommended daily allowance (RDA). Toxic effects of treatment and influence on appetite were determined by questionnaire.

In a subset of 14 patients, blood samples for hydrazine sulfate circulatory levels were obtained as a morning sample taken at least 9 hours from the last oral dose following 30 days of treatment. Hydrazine sulfate levels were measured using a defined spectrofluorometric assay in which reaction of hydrazine sulfate with dimethylaminobenzaldehyde produces a colored derivative. Fluorescence was subsequently determined in an Aminco Bowman (Silver Spring, MD) spectrophotofluorometer with an excitation wavelength of 466 nm and emission wavelength of 546 nm.

All patients were given defined, uniform dietary counseling based on nutritional status at entry to insure comparability of dietary information available to patients on hydrazine or placebo treatment. The nutritional guidelines all patients were provided with were designed to duplicate a routine clinical dietary assessment that would be expected to be a component of a cancer patient's standard clinical management. Enteral tube feedings or parenteral nutritional support was not given any patient while on study.

A total of 101 patients with advanced cancer underwent initial evaluation. Sixty-one consecutive patients (including all 30 patients given placebo and 31 given hydrazine) were randomly assigned treatment in a double-blind fashion with treatment assignment based on published random-number tables. An additional 40 patients received hydrazine sulfate and represented a consecutive series of patients seen in the Clinical Research Center meeting entry criteria for the trial. Statistically significant differences between hydrazine and placebo groups relative to pretreatment clinical factors were sought using chi square contingency table analyses and Student's t test. The statistical differences between hydrazine and placebo treatment were determined using the two-group t test.

Results

A total of 101 patients with a variety of advanced cancers underwent initial evaluation. Patients receiving hydrazine sulfate or placebo were comparable with respect to tumor type, age, sex, performance score, nutritional parameters and chemotherapy experience (Tables 1 and 2). The compromised nutritional status of the study population is demonstrated by the 16% average weight loss experienced by the overall population. Of this advanced disease population with weight loss, 58 patients were able to complete repeat evaluations after 30 days of treatment (41 were given hydrazine; 17, placebo). Early disease progression and/or death accounted for almost all cases not having repeat study. Only two patients refused repeat evaluation.

The influence of 30 days of hydrazine sulfate or placebo therapy on study parameters for all entered patients who underwent repeat evaluation is outlined in Table 3. Weight was maintained or increased in a higher proportion of patients receiving hydrazine sulfate compared to placebo therapy (83% versus 53%, respectively; P < 0.05). The use of weight loss as a study parameter was not compromised by the development of ascites or significant edema, as this did not occur in any patient over the 30 day period of observation. Anthropometrics were unchanged over the 30-day study period. Caloric intake was only slightly higher in the hydrazine treated population. When all patients experiencing an increase in caloric intake were considered, however, weight gain was seen in a significantly higher proportion of patients receiving hydrazine sulfate while increasing caloric intake compared with those who increased caloric intake while receiving placebo. The results using hydrazine sulfate were closely comparable in the 31 patients entered as part of the randomized trial when compared with the 40 patients added as a consecutive series. The results for the patients receiving hydrazine or placebo who were entered as part of the randomized trial were: weight maintained or increased, 71 % versus 53%; improvement in appetite, 63% versus 25%; caloric intake increased, 69% versus 37%; and increased caloric intake associated with weight gain, 77% versus 53% for the hydrazine versus placebo patients respectively. In addition, results in groups receiving or not receiving concurrent chemotherapy reflected those obtained in the entire group.

Thirty-five patients with cancer other than small cell lung cancer (the predominant tumor type studied) completed serial evaluation, with 26 receiving hydrazine sulfate and nine receiving a placebo. In the lung cancer patients, weight maintenance or increase was achieved in 83% of those receiving hydrazine sulfate compared with 33% of those receiving the placebo,

The short term hydrazine sulfate regimen used in this trial was well tolerated by study participants. Compliance forms were returned by 90% of patients who completed repeat evaluations, and indicated that 95% of the scheduled dose was taken by the study population completing 30 days of therapy. The mean maintenance plasma hydrazine sulfate levels obtained from a subset of 14 patients ranged from 0 to 89 ng/ml with a mean value of 45 ± 16 ng/ml. Clinical toxicity of patients receiving hydrazine sulfate was limited largely to mild to moderate nausea and lightheadedness with 71% of patients reporting no toxic effects from hydrazine use (Table 4). Treatment was discontinued for toxic effects in 10% of patients receiving hydrazine; while 6% of patients receiving placebo had treatment stopped for "toxic effects." Significantly, parasthesias or hypoglycemic symptoms were not reported by any patient receiving hydrazine in this trial.

Discussion

Short-term administration of hydrazine sulfate was better than a placebo in maintaining body weight and improving appetite in patients with advanced cancer in the current clinical experience. The weight effect apparently resulted from an increase in the effectiveness of the ingested calories, since a higher proportion of patients who increased their caloric intake on hydrazine were able to maintain or improve their body weight. The association that we have reported between weight maintenance and improved glucose metabolism in hydrazine-treated cancer patients suggests that interruption of abnormal metabolic pathway function may underlie the improved nutritional status seen with hydrazine sulfate in the current trial. If this hypothesis can be confirmed, hydrazine sulfate could represent one of a new class of metabolic/hormonal agents directed at influencing the abnormal metabolism seen frequently in patients with cancer.

No prior clinical experience with hydrazine sulfate in cancer patients has prospectively evaluated caloric intake or included a placebo control population. Single-arm studies involving 348 Russian and 84 American patients with cancer have emphasized subjective parameters. In the American experience, Gold reported that 70% of the treatment group demonstrated subjective improvement, including increased appetite with either weight gain or cessation of weight loss, increased strength and improved performance status, or decreased pain, as measured by need for analgesics. In the Russian experience, Gershanovich reported that 50% of patients receiving hydrazine sulfate as their sole therapeutic intervention achieved moderate or marked improvement in cachexia with associated favorable symptomatic effects on appetite and pain. Not all clinical studies of hydrazine sulfate have shown benefit. In three small trials of hydrazine sulfate (all entering less than 30 patients) where reduction in tumor size was used as a major therapeutic endpoint, little benefit was reported. The clinical effects of hydrazine sulfate on body weight observed in the current study in conjunction with the metabolic effects of hydrazine that we reported in 1984 now provides a strong rationale for further studies designed to assess the impact of hydrazine sulfate on clinical outcome in defined cancer populations.

Surprisingly, thirty-seven percent of weight-losing cancer patients given placebo in this trial increased their caloric intake by more than 10%, and 53% of the placebo group maintained or increased their body weight over the 1-month observation period. This result in the placebo population may have been related to the nutritional counseling that was given in identical fashion to patients on both treatment arms in this study. Placebo controls clearly are important in trials designed to alter and assess nutritional parameters in cancer populations.

The study protocol employed in our trial was not designed to assess the influence of hydrazine sulfate on tumor growth characteristics. The short 30-day period of treatment and entry criteria preclude assessment of hydrazine sulfate influence on this parameter. Almost all of our patients with advanced solid tumors refractory to initial therapy, however, demonstrated no change in tumor dimensions during the 1 -month period of observation.

The relative lack of toxicity of short-term hydrazine sulfate administration in a 60 mg 3 times/d schedule to a large cancer population receiving other concurrent chemotherapy treatment was noteworthy. In the previous limited clinical experience, only one report has emphasized significant toxicity; Ochoa and coworkers reported a 50% incidence of polyneuritis associated with hydrazine sulfate use in a 29-patient experience. In three trials and the present report, polyneuritis was seen in less than 1% of the more than 500-patient cumulative experience. The lack of toxicity in the current experience can be documented further by the good compliance reported by the patients in their diaries. The latter result is interesting considering the somewhat wide range of hydrazine sulfate maintenance circulatory levels observed in the pharmacokinetic component of this trial. However, these results are consistent with developing pharmacokinetic information regarding the half-time of oral hydrazine sulfate administration. These data suggest that future clinical trials involving hydrazine sulfate should include determination of chronic circulatory levels to assess hydrazine sulfate bioavailability and permit correlation with metabolic, nutritional and clinical endpoints.

Conclusion

This experience with hydrazine sulfate in an advanced cancer population points to a potential role for this agent in maintaining weight in patients with cancer cachexia. Whether maintenance of body weight under these conditions will be associated with improvement in important clinical outcome variables and overall survival will require future prospective, long-term, placebo-controlled evaluation in cancer populations with less advanced disease given defined systemic therapy. Such studies in the non-small-cell lung cancer population are currently in progress.

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