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Anabolic Profiles in Late-Stage Cancer Patients Responsive to Hydrazine Sulfate

[Nutrition and Cancer 3:13-19, 1981]

By Dr. Joseph Gold. J. Gold is Director of the Syracuse Cancer Research Institute, 600 East Genesee Street, Syracuse, N 13202.

Abstract

The anabolic profiles of 59 late-stage cancer patients responsive to hydrazine sulfate were examined; the drug had been given either as a sole agent or added to preexisting therapy to which the patients had become refractory. Most of the patients (79.7%) responded with Indicated Appetite Improvement (IAI), expressed by protocol-code, clinical evaluation and/or direct quantitation. In those patients receiving hydrazine sulfate alone the IAI was 86.1 %; in those in whom hydrazine sulfate was added to pre-existing therapy the IAI was 69.6%. Of those cases expressed in direct quantitation the average weight gain for patients receiving hydrazine sulfate alone was 8.2 lbs, whereas the average weight gain for those with pre-existing therapy was 0.6 lbs (p = 0.01). The results suggest the use of hydrazine sulfate as a specific chemotherapy for cancer cachexia, and implicate ineffective concurrent or prior therapy as an apparent negative factor in the generation of anabolic response.

Introduction

Hydrazine sulfate, a gluconeogenic blocking agent which interrupts the cycle of tumor energy gain-host energy loss at the enzymic level of phosphoenolpyruvate carboxykinase, has been indicated as a specific chemotherapeutic agent for cancer cachexia [1-4]. Increased food intake, improved performance status, decreased pain, diminution of anorexia, normalization of abnormal laboratory indices, disease stabilization and tumor regression have all been described as a result of clinical studies of this drug's action in late-stage cancer patients [5-10]. Despite agreement by practically all these studies of a primary, marked stimulation of appetite, few data on appetite and/or weight response per se are available. In order to bring to light a source of such data, and provide a preliminary assessment of this agent's anabolic potential, appetite and weight response statistics were extracted from a previously completed Investigational New Drug study [9], in which 59 of 84 evaluable late-stage patients were designated as "improved." The present study constitutes an analysis of these 59 patients in terms of appetite and weight response.

Methods

Protocols and procedures of this study are given elsewhere [9]. The total number of evaluable patients represented a random sample, selected by multiple-clinician input solely on the basis of advanced clinical disease.

Appetite and weight response statistics were extracted from the 59 individual case reports of those patients designated as "improved," and collated in terms of 2 categories: Indicated Appetite Improvement (IAI) and Weight Response. The former category, IAI, included protocol-coded appetite response (graded numerically from 4 to 1, representing severe limitation of appetite to no limitation of appetite, respectively), clinical evaluation and quantitative weight response, or a combination of 2 or more of these; the latter category included only those patients in whom IAI was expressed quantitatively, in terms of weight gain (or loss) per initial 3-week period of drug trial. Results were further categorized according to whether patients received hydrazine sulfate as a sole agent, or whether this substance was added to ongoing or prior (within 6 weeks) therapy to which the patients had already become refractory (chemotherapy, hormonotherapy, radiotherapy, immunotherapy and/or surgery). Weight response differentials, as specified in the individual case reports, were reflective of changes in true body mass and were not a function of fluid retention and/or mobilization.

Results

A high degree of appetite improvement characterized the findings of this study, as is apparent in the individual responses of each of the study patients illustrated in Tables 1-3. Specifically,

Table 1. Individual Responses to Hydrazinc Sulfate in Patients Receiving No Concurrent or Prior Therapy
    Indicated Appetite Improvement (IAI)  
Patient Number Diagnosis (site) Protocol-code Clinical Evaluation Weight Response (in lbs / initial 3 weeks of therapy)
1 Breast - - + 5.0
2 Breast - "Return of apetite" **
3 CNS (astrocytoma, Grades III and IV)   - + 11.0
4 CNS (glioblastoma multiforme) 3 - 1 - + 12.0
5 Gall bladder 4 -1 "Gaining weight" **
6 GI ("abdomen") - "Excellent" **
7 GI (colon) - "Weight gain" **
8 GI (rectosigmoid colon) - "Improved" + 3.0
9 GI (rectum) 2 - 1 - **
10 GI (stomach) - "Improved" + 7.0
11 Lung - "Poor - excellent" + 5.0
12 Lung - "Improved" + 5.0
13 Lung - "Increased" **
14 Lung - "Immediate return of appetite" **
15 Lung 4 - 2 - **
16 Lung (bronchogenic) 3 - 2 "Weight gain" + 5.0
17 Lung (bronchogenic) 3 - 1 "Marked weight loss ceased" **
18 Neck (neurosarcoma) - "Marked improvement" + 15.0
19 Neck (squamous cell) 2 - 1 - **
20 Ovaries 3 - 1 - + 15.0
21 Ovaries 3 - 1 - **
22 Ovaries - "Improved gradually" **
23 Pancreas 4 - 1 - + 8.0
24 Pancreas 2 - 1 - +11.0
25 Pancreas - "Weight stabilized" **
26 Primary unknown 3 - 2 - **
27 Skin (melanoma) - "Improved" **
28 Tonsil (palatine) 4 - 1 "Gaining weight" **
29 Urinary bladder (transitional cell, Gradc III) 4 - 2 - + 5.0
30 Uterus (cervix, stage IIB) - "Increased" **
31 Uterus (endometrium) 3 - 1 "Maintaining Weight" **
Protocol-code: 4 = severe limitation of appetite; 3 = moderate limitation; 2 = mild limitation; 1 = no limitation.
** = unspecified

of the 59 improved patients in this study an overall 47 (80%) responded with Indicated Appetite Improvement (IAI). Of these 47 patients 22 were entered into this category on the basis of improvement in any I of the following: protocoi-coded appetite response, direct clinical evaluation of appetite, quantitative weight measurements; 25 were entered on the basis of improvement in 2 or more of these criteria. In 20 of the patients IAI was expressed quantitatively, while in 12 of the overall study group (Table 3) appetite response was unspecified, either through nonevaluation or inadvertence.

The various individual primary sites and number of patients per site are summarized in Table 4. Of the 59 primary sites 45 were accounted for by gastrointestinal, lung, breast and genitourinary cancers, in effect mirroring the distribution of these malignancies in the general population.

IAI responses were recorded in 31 of 36 patients receiving no concurrent or prior therapy vs. 16 of 23 patients receiving concurrent or prior ineffective therapy, indicating the latter to be slightly poorer responders (86. 1 % vs. 69.6%, respectively); these figures, while not statistically significant, nevertheless exhibit confidence limits of 88% (Table 5).

The effect of such dichotomization is made more apparent in terms of quantitative weight response. In the 20 patients so reported the overall average weight gain was 5.6 lbs per patient. Yet, as demonstrated in Table 6, in those patients receiving no concurrent or prior therapy the average weight gain during the initial 3-week period of drug administration was 8.2 lbs per

Table 2. Individual Responses to Hydrazine Sulfate in Patients Receiving Concurrent or Prior Therapy
    Indicated Appetite Improvement (IAI)  
Patient Number Diagnosis (site) Protocol-code Clinical Evaluation Weight Response (in lbs / initial 3 weeks of therapy)
32 Breast 4 - 1 "Continucd to lose weight" **
33 Breast 4 - 2 - **
34 Breast - "Improved" + 10.0
35 GI (descending colon) - "Weight stabilized"
(Had been losing weight)
**
36 GI (colon) - "Weight gain" **
37 GI (colon) 3 - 2 - + 3.0
38 GI (colon) - "Considerably improved" **
39 GI (colon) - "Increased" + 5.0
40 GI (colon) - "Unchanged" + 1.0
41 GI (rectum) 3 - 2 - **
42 GI (stomach) 3 - 2 - **
43 Lung - "Improved markedly" **
44 Lung (oat cell) 3 - 1 "Weight gain" **
45 Ovaries - "Temporary improvement" + 1.0
46 Pancreas - "Unchanged" - 8.0 (weight loss)
47 Uterus (cervix) 3 - 2 - - 7.5 (weight loss)
Protocol-code: 4 = severe limitation of appetite; 3 = moderate limitation; 2 = mild limitation; 1 = no limitation.
** = unspecified

patient, whereas in patients receiving such therapy the average weight gain was only 0.6 lbs per patient-, this difference was statistically significant at the p = 0.01 level. Moreover, Table 7 indicates this difference not to be a function of the disproportionate number of weight response cases reported in each category; for whether in terms of total study patients (59) or in terms of total IAI patients (47), the percentage of patients reporting quantitatively from each category was the same (35.1 vs. 30.4 and 41.9 vs. 43.8, respectively).

Weight loss in the face of improved (or unchanged) appetite was an unexpected finding in 3 patients receiving (ineffective) concurrent or prior therapy; 2 of these patients incurred weight losses of 7.5 and 8.0 lbs, respectively. No corresponding weight loss was seen in patients receiving no concurrent or prior therapy.

Discussion

Even in terms of the 84 patients of the original study (59 "improved," 25 "no response") [9], the indicated overall appetite improvement is 56%, far in excess of what could be expected historically in these late-stage patients [11]. (Likewise, these results can be distinguished from placebo response, in that the latter-while giving rise to an occasional patient with long term

 

Table 3. Individual Patients in whom Appetite and/or Weight Response Were Unspecified
Patient Number Diagnosis (site) Concurrent or prior theray
48 Breast Yes
49 Breast Yes
50 Breast Yes
51 GI (stomach) Yes
52 Lung (alveolar cell) No
53 Lung (epidermal cell) Yes
54 Lung (large cell) No
55 Lung (pancoast) No
56 Pancreas No
57 Primary unknown No
58 Prostate Yes
59 Testis (teratocarcinoma) Yes

 

Table 4. Sites of Primary Cancers (Number of Patients)a
Gastrointestinal (14) Head and neck (2)
Lung (13) Primary unknown (2)
Breast (8) Gall bladder (1)
Pancreas (5) Melanoma (1)
Ovaries (4) Palatine tonsil (1)
Uterus (3) Prostate (1)
CNS (2) Testis (1)
  Urinary bladder (1)
a Total patients: 59.

 

Table 5. Indicated Appetite Improvement (IAI)
Mode Responses/Number of cases Percent IAI
No concurrent prior therapy 31 / 36 86.1a
Concurrent or prior therapy 16 / 23 68.6a
a Not statistically significant (p = 0.12).

 

Table 6. Weight Response (in Lbs per Initial 3 Weeks of Therapy)
Mode Number of cases Average weight gain
No concurrent prior therapy 13 8.2 lbsa
Concurrent or prior therapy 7 0.6 lbsa
a p = 0.01.

 

Table 7. Variant Analysis of Weight Response
  Percent reporting quantitative results
Mode No concurrent prior therapy Concurrent or prior therapy
Total patients (59) 35.1 (13 / 16)a 30.4 (7 / 23)a
Total IAI patients (47) 41.9 (13 / 31)b 43.8 (7 / 16)b
a Not statistically significant.
b Not statistically significant.

survival -- is unlikely to be correlated with a significant number of antineoplastic and other measurabic effects [9,11], as was the case in this study.) In terms of the 59 patients in the present study, however, the effect of increased appetite response (IAI) is markedly amplified -- occurring in virtually the entire group with the possible exception of the 12 patients delineated in Table 3, in whom omission of appetite and weight response statistics in the individual case reports appears inadvertent. (The noted findings in these 12 patients consisted of improved performance status, decreased pain, improvement in laboratory indices and paraneoplastic deficiencies, disease stabilization and tumor regression -- findings frequently accompanied by increased anabolic response.)

The anabolic effect of hydrazine sulfate was equally apparent in the weight response. Significant weight gain was demonstrated in a large proportion of the study patients, namely an average weight improvement of 5.6 lbs per patient during the first 3 weeks of therapy.

Dichotomization of the data into the 2 treatment groups additionally discloses an apparent, negative bias associated with concurrent or prior therapy. This effect is suggested in the IAI response (Table 5) and becomes statistically discernible in the weight response (Table 6). Indeed average weight gain in those patients receiving no concurrent or prior therapy was almost 14 times greater than in those receiving such therapy. It is emphasized that these differential findings-in seeming contradistinction to animal studies which demonstrate a favorable interaction between new and/or effective chemotherapy and hydrazine sulfate [12-15] reflect the use of ineffective concurrent or prior therapy and may well result from the burden imposed on the host by such therapy.

In the above regard weight loss in the face of increased or unchanged appetite occurred only in the group receiving (ineffective) concurrent or prior therapy. Whether these results are spurious or, too, a function of the toxic effect of such therapy on the host, must await clariflcation in further studies.

Conclusion

Preliminary results have indicated hydrazine sulfate, a gluconeogenic blocking agent, to induce measurable anabolic response in late-stage cancer patients. Increased appetite and/or weight gain were recorded in a majority of the study patients. Ineffective concurrent or prior therapy was indicated as an apparently negative influence in the outcome of these results. Placebo response and historical controls were ruled out as probable contributory factors.

References and Notes

1 .Gold, J: "Proposed Treatment of Cancer by Inhibition of Gluconeogenesis." Oncology 22, 185-207, 1968.
2. Gold, J: "Cancer Cachexia and Gluconeogenesis." Ann NYAcad Sci 230, 103-110, 1974.
3. Gold, J: "Hydrazine Sulfate and Cancer Cachexia." Nuir Cancer 1 (4), 4-9, 1979.
4. Gold, J: "Preservation of the Nutritional Integrity of the Cancer Patient: Reversal of Cancer Cachexia by Hydrazine Sulfate." Cancer Detection and Prevention 3 (1), 75, 1980.
5. Danova. LA, Gershanovich, ML, Filov, VA, Kondratyev, VB, and Evin, VA: "Study of Side Effects of tiydrazinc Sulfate." In Goldberg, ED (ed): Problems in Radiobiology and Biological Action of Cytostatic Compounds.
Tomsk: Tomsk Institute of Medicine, USSR, 1977, pp. 192-193.
6. Danova, LA, Kondratyev, V B. Gershanovich, M L. and Filov, VA: "Results of Administration of Hydrazine Sulfate to Patients With Hodgkins Disease.' Therap Arch: Probl Hematol 29 (8), 45-47, 1977.
7. Gershanovich, ML, Danova, LA, Kondratyev, VB, Malyugina. LL, Studkov, AN, Scits, JF, and Filov, VA: "Clinical Data on the Antitumor Activity of Hydrazine Sulfate." Cancer Treat Rep 60, 933-935, 1976.
8. Gershanovich, ML, and Filov, VA: "Hydrazine Sulfate in Late-Stage Cancer,. Completion of Initial Clinical Trials in 225 Evaluable Patients." Proc Ani Assoc Cancer Res 20, 240, 1979.
9. Gold, J: "Use of Hydrazine Sulfate in Terniinal and Preterminal Cancer Patients: Results of Investigational New Drug (IND) Study in 84 Evaluable Patients." Oncology 32. 1-10, 1975.
10. Seits, JF, Gershanovich, ML, Filov, VA, Danova, LA, Kondratyev, VB, Malyugina, LL, Muller, NR. Polina, RI. Rudakov, VG, and Stukov, AN: "Experimental and Clinical Data on the Antitumor Action of Hydrazinc Sulfate." Vopr Onkol 21(1), 45-52, 1975.
11. Creagan, ET. Moertel, CG, O'Fallon, JR, Schutt, AJ, O'Connell, MJ, Rubin, J, and Frytak. S: "Failure of High Dose Vitamin C (Ascorbic Acid) Therapy to Benefit Patients With Advanced Cancer." N Engl J Med 301, 687-690. 1979.
12. Bulovskaya, LN: "Acetylation Reaction in Normal and Tumour Bearing Micc." Vopr Onkol 22, 94-95, 1976.
13. Gold, J: "Enhancement by Hydrazine Sulfate of Antitumor Effectiveness of Cytoxan, Mitomycin-C. Methoirexate and Bleomycin, in Walker 256 Carcinosarcoma in Rats." Oncology 31, 44-53, 1975.
14. Gold, J: "Potentiation by Clofibrate of in vivo Tumor Inhibition by Hydrazine Sulfate and Cytotoxic Agents, in Walker 256 Carcinosarcoma." Cancer Biochem Biophys 3, 41-45, 1979.
15. Tretyakov, AV, and Filov, VA: "The Mechanism of Potentiation by Hydrazine Sulfate of the Action of Antitumoral Compounds." Vopr Onkot 23(5), 94-98, 197 7.
16. Request reprints from Dr. Joseph Gold, Director, Syracuse Cancer Research Institute. 600 E. Genesee St., Syracuse, NY 13202.

Gold, J: "Anabolic Profiles in Late Stage Cancer Patients Responsive to Hydrazine Sulfate." Nuir Cancer 3, 13-19, 1981.


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