Results Of Clinical Evaluation Of Hydrazine Sulfate

[Vopr Onkol 36(6): 721-726, 1990]

By  V. A. Filov, L. A. Danova, M. L. Gershanovich, B. A. Ivin, N. P. Dementyeva, P. V. Beyvis, V. P. Ragaishene, I. V. Kasyanenko, A. I. Lisitsa, S. S. Mindlin and N. I. Kurganova

Abstract

This paper discusses results of a cooperative study of the effectiveness of hydrazine sulfate therapy in 740 patients with primary advanced, recurrent and metastatic solid tumors and malignant lymphomas who had failed all other treatment modalities. Both objective response and symptomatic effect were assessed. Objective response was observed in neuroblastoma, recurrent desmoid, Hodgkin's disease, lung cancer, fibrosarcoma and other tumors. Since hydrazine sulfate provided relief of a wide spectrum of cancer symptoms, it may be recommended for patients with end-stage cancer.

Our previous publication [1] described the results of the experimental and clinical studies of hydrazine sulfate (HS). The clinical studies of American investigators in general were based on small numbers of patients, and the results have been controversial--some of them question the efficacy of HS, while others indicate very high efficacy. The high efficacy of HS as an anti-cachexia drug was demonstrated [2].

We have implemented a cooperative study of the efficacy of HS. 740 patients were treated up to 1988, from age 16 to 72, having common, widespread solid tumors, including recurrent and metastatic tumors, malignant lymphomas and recurrent desmoids. The largest groups consisted of patients with disseminated lung cancers (200), gastric cancer (138), breast cancer (66), recurrent Hodgkin's disease (63) and melanoma (31). Further details and characteristics of the cancers studied are given in the Table. The majority of patients were treated in the past by different modalities (surgery, radiation, cytotoxic chemotherapy, hormonotherapy) and the possibilities of these therapies were all exhausted prior to treatment with HS.

HS was administered in enteric-coated tablets of 60 mg, three times daily, and the duration of each treatment course was from 30 to 45 days. The sum of the dosage per treatment course was from 5.4 to 8.1 grams. In the instances of disease stabilization, repeated courses were prescribed using the same regimen, with interruptions of from 2 to 6 weeks between courses. The number of repeated courses as a rule was 2-3, but in some cases (neuroblastoma) there were 10, 20 or 40 repeated courses. In the instances of cancer of the esophagus or larynx, HS was administered as a 0.4% solution, the dose equivalent to tablet form by volume (15 ml = one 60 mg tablet). Barbiturates and alcohol were prohibited throughout the course of HS administration.

Evaluation of the anticancer efficacy of HS was accomplished after the end of the course, i.e., after 30-45 days from its beginning, and expressed in terms of the following categorization: 50% or greater tumor regression for at least 1.5 months; 25%-50% tumor regression for at least 1.0 month; 0%-25% tumor regression for up to 1.0 month; tumor stabilization unaccompanied by tumor regression (cessation of progression); tumor progression. The symptomatic (anti-cachexia) effect of the drug was evaluated as "pronounced," "moderate," and "no effect."

Regression of the tumors (primary, recurrent and metastatic) of greater than 50% for more than 1.5 months was observed only in 6 patients (1 lung cancer, 1 neuroblastoma, 1 fibrosarcoma of the peritoneal cavity, 2 recurrent desmoids of the abdominal wall, and 1 Hodgkin's disease, see Table).

Case 1. Patient K. was a 52 year old female with recurrent neuroblastoma of the Douglas cavity, with compression of the rectum and sigmoid colon. In January 1974 she underwent surgery with subsequent radiation therapy (41.8 Gr [4180 rad]/focus). [Repeated laparotomy with revision of the abdominal cavity organs and retroperitoneal space was performed on December 24, 1974],* but surgical resection of the neuroblastoma was impossible. From February 26, 1975 to March 27,1975 and from April 10, 1975 to May 11, 1975 two courses of HS were administered; as a result the tumor decreased in size and became softer in consistency. The patient gained 5 kg in body weight. In July 1975 the patient underwent radiation therapy with a dose of 30.06 Gr [3006 rad] but tumor progression was observed, accompanied by difficulty in defecation. From November 1975 to December 1988 the patient was treated only with HS. [By October 1976 the tumor had decreased not less than 20% in size. It became soft in consistency. Defecation normalized fully. In 1979 the tumor appeared only as a cord on the pelvis wall.]* At this time no tumor can be observed. During the entire period of treatment 40 courses of HS were administered (with an interruption of six months between courses for the last 7 years). During the last 9 years the patient has been working. Observation still continues.

Case 2. Patient G. was a 32 year old male with recurrent desmosarcoma of the anterior abdominal wall. Surgery was performed in 1963, 1965, 1966, 1969 and 1973. In our institute surgery was performed on October 24, 1974 and the recurrent desmoid was resected. After surgery a hard infiltrate was found in the left abdominal wall, adjacent to the anterior costal processes. The tumor was found to be non-resectable. Histology demonstrated desmosarcoma (fibrous type) with cellular inclusions. From November 1974 HS therapy was started. In January 1975 the tumor in the abdominal wall was no longer observed, but x-ray examination revealed the presence of the typical density adjacent to the left costal site. After the next courses of HS in January 1975, March 1975 and November 1975, x-ray examination indicated a decrease in tumor size. The patient was given a new course of HS in March 1977 and the recurrent desmoid was no longer observed. In April 1979 clinical and x-ray studies again revealed no recurrence. Complete regression of the tumor was documented in a new examination in April 1988. Observation of the patient still continues.

As can be seen from these cases, the effect of HS can be evaluated more certainly after repetitive courses; this was confirmed in 25 instances, in which decrease of tumor volume was between 25%--50% (see Table).

In the case of 47 patients (6.4%) tumor regression was no more than 25%, and this allows us to describe this effect as stabilization with minimal regression. This group contains 9 patients with generalized Hodgkin's disease, 4 patients with metastatic breast cancer, 11 patients with disseminated lung cancer, 4 patients with intestinal cancer, 3 patients with laryngeal cancer, and some with other tumors. Objective therapeutic effect of HS was also observed with so-called incurable patients with Hodgkin's disease, breast cancer, lung cancer, colon cancer, fibrosarcoma and others. A stabilizing effect on tumor growth is the most typical effect of the drug. Cessation of progressive tumor growth under the effect of HS for 1.5-2.0 months was observed in 216 patients (29.2%), and together with the 47 patients previously described, totals 26.3 cases (35.6%). This stabilizing effect was seen more frequently in cases of Hodgkin's disease, breast cancer, lung cancer, colon cancer, sigmoid or rectal cancer, and was especially notable in that it also occurred in cases of medullary kidney cancer (5 out of 9 patients), cervical cancer (8 out of 22 patients), endometrial cancer (7 out of 9 patients) and generalized melanoma (12 out of 31 patients). It must be stressed that in all these cases the patients were practically in the terminal phase of disease.

Thus during treatment by HS a pronounced objective effect, characterized by varying degrees of-tumor regression, was recorded in 10.8% of the cases; this effect, together with the cases of stabilization for 1.5 to 2.0 months, occurred in 40% of the patients. An example of stabilization is presented below.

Case 3. Patient A. was a 44 year old female, examined in our institute in 1977, with a diagnosis of recurrent para-ossal osteogenic sarcoma of the right femur, with extension to the acetabulum. Amputation of the right hip section took place on October 13, 1977. In November 1984 lung metastases were observed, treated in November-December 1984 by Adriablastin. In March 1985 tumor progression was noted. She was given supportive care of her symptoms. In October 1986 new lung metastases were observed. In December 1986 the first course of HS was administered, followed in March 1987 by a second course of HS therapy. In April 1987 x-ray examination demonstrated stabilization of the process; her general condition was much improved. In January 1989 the patient completed her seventh course of HS. The treatment still continues.

HS also has symptomatic effects that were demonstrated to differing degrees in 46.6% of the patients. This effect consists of a decrease in fever (some-times complete normalization of temperature), decrease or disappearance of hemoptysis, decrease in respiratory deficiencies , often a disappearance of edema and normalization of laboratory parameters. The symptomatic effect of HS also includes a pronounced improvement in the general condition, appearance of appetite, decrease in weakness, decrease and complete elimination of pain which in some cases permits cessation of narcotics therapy. Normally the generalized improvement takes place after 2 to 3 weeks of therapy, which also includes the decrease in pain, even in the cases of metastatic bone cancer (spinal column, ribs, hip). In some patients with bone metastases the symptomatic improvement was so great as to permit these patients once again to self-care and ambulate. This effect endured up to 2 months , even in the face of disease progression. A similar response was observed in patients with metastatic breast cancer to the bones, but less frequently and to a lesser degree.

One of the characteristic features of the symptomatic effect of HS is the psychotropic effect of the drug. After 2 to 3 weeks of HS administration a significant percentage of patients experience an increase in well-being and a decrease in critical evaluation of their own condition, and even overestimate their ability for motor activity, sometimes to the point of euphoria. This effect of HS persevered even in the cases of disease progression. In some cases (in particular, intestinal cancer with metastases to the liver and pancreas, with progressive cachexia) the patients were verbally active and their estimation of their condition fell far short of reality.

The frequency of the above described positive symptomatic effects in the cases of terminal patients was 54%** with Hodgkin's disease, 53% with breast cancer, 44% with intestinal cancer, 57% with laryngeal cancer, 71% with neuroblastoma and 90% with desmosarcoma.

The side effects of HS therapy were not pronounced. No single case of myelosuppression, hypertension , change in blood sugar or any biological parameters was observed; no cardiotoxic effects were recorded despite pronounced pathology of the cardiovascular system in some cases. The most frequent (5%-6%) side effect was dyspepsia in the form of nausea or vomiting. However, it must be mentioned that this group includes patients who had nausea induced by intoxication that accompanies very late stage cancer processes. Nausea and vomiting in some cases regressed without special treatment, after decreasing the total daily dose of HS from 180 mg to 120 mg. Giddiness and general excitement were observed in some cases but were not serious (on the contrary, some euphoria and increase in general well-being were considered positive by the patients). The most serious reactions to H S occurred in the peripheral nervous system, in the form of polyneuritis, which took place only in the cases of very prolonged and continuous (without interruption) HS treatment that was allowed only in the initial period of studies of the drug. Transition of treatment to interrupted courses eliminated this complication. Even in the cases of treatment of 5 to 10 years’ duration, no polyneuritis was observed. Thus the side effects were not significant and did not interfere with treatment.

*[An initial report of this case was published in Nutr Cancer 3(1): 7-12, 1981.]

**[The figure of 37% given in the Russian text is an apparent printer's error, see Table.]

REFERENCES

1. Filov VA, Danova LA, Gershanovich ML, et al. Hydrazine sulfate: experimental and clinical data, mechanisms of action. In Drug Therapy of Cancer, VA Filov, BA Ivin and ML Gershanovich (eds.), Leningrad: USSR Ministry of Health, 1983, pp 91-139.

2. Chlebowski, RT, Bulcavage L, Grosvenor M, et al. Hydrazine sulfate in cancer patients with weight loss, Cancer 59:406 – 410, 1987.

The N. N. Petrov Research Institute of Oncology of the USSR Ministry of Health, Leningrad.

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