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Experience of the treatment with Sehydrin (Hydrazine Sulfate, HS)* in the advanced cancer patients

[Investigative New Drugs 13:89-97, 1995]

Vladimir A. Filov, Michail L. Gershanovich, Lidia A. Danova and Boris A. Ivin
Prof. N.N. Petrov Research Institute of Oncology, Pesochny-2, St. Petersburg, 189646, Russia

Key words: Sehydrin, Hydrazine Sulfate, advanced cancer, chemotherapy

*Phase II of Hydrazine Sulfate was carried out according to the Pharmacological Committee of the Ministry of Health of Russia request. HS is permitted for use in the medical practice for the oncological patients under the name of Sehydrin by the decision of the Pharmacological Committee of Russia taken on December, 26, 1991.

Summary

The results of Sehydrin (Hydrazine Sulfate, HS) treatment of 740 patients with the advanced, recurrent or metastatic solid tumours of various localizations or malignant lymphomas, for whom all the methods of specific treatment (surgery, radiation, chemotherapy) had been exhausted arc presented in this work. The objective response, symptomatic therapeutic effects and toxicity were estimated. Clinically significant objective responses were registered in patients with the soft tissue sarcomas, including neuroblastomas, and paradoxically - in such semimalignant tumours as desmoids. Although the objective response in patients with the lung cancer (90% - non-small cell) was only 4% stabilization of long duration was registered in 22% of cases connected with the impressive relief of heavy common symptoms in 38.5% of the treated patients. Such a subjective response was established in 46.6% of all the 740 cases. The drug given per OS was well tolerated by patients in primary and subsequent courses and did not induce myelosuppression or other significant side effects. On the basis of observations available, Sehydrin may bc assessed as an alternative drug for the treatment and symptomatic therapy of patients with some advanced solid tumours and malignant lymphomas at a disease stage when the other methods of treatment can not be used. A possible mechanism of antitumour and symptomatic action is being discussed.

Introduction HS - a simple well-known compound - was proposed by J. Gold in lY74 as an antitumour drug, and induced a lot of controversials - rather because of inadequate clinical trials than because of basic experimental data [1]. According to a previous report, HS treatment of patients with the disseminated cancer of various localizations resulted in 14 patients complete or partial tumour regression (over 1 year) stabilization of the disease registration [1, 2]. At the same time, 59 patients showed a pronounced symptomatic effect. i.e. improved appetite, reversal of weight loss, and even weight gain. Their performance status was improved and pain was diminished or eliminated.

Some of the other studies of HS antitumour effect carried out on a small number of patients (less than 30) suggested the absence of the objective or even symptomatic effects [3-6]. Gold [7] insisted that evaluation was possible in 13 patients out of 29 estimated by Ochoa et al. [4] only. The other authors assessed the effect of HS by a decrease of tumour in not less than by 50% and for the period of not less than 2 months. These criteria are too strict according to Gold, who characterizes HS as a drug for the treatment of cancer cachexia [8 9]. In fact, the efficacy of HS as an anticachectic drug in patients with the malignant tumours has been demonstrated [10]. It was established in the randomized study with placebo that HS is a supplementary treatment to the combined chemotherapy of the non-small cell lung cancer that not only improved the nutritional status of patients, but also significantly prolonged the survival rates in them [11]. We have also studied the HS treatment in patients with the disseminated solid tumours [12-15] and also in the Hodgkin’s disease [16].

These positive results were not confirmed in the two last randomized multicenter placebo-control-led trials with the use of HS as a supplement to the combination chemotherapy (cisplatin and etoposide, or, in the double-blind study - cisplatin and vinblastine) in the advanced non-small cell lung cancer [17, 18].

Negative results were also obtained in the placebo-controlled randomized cooperative clinical trial that failed to demonstrate any statistically significant overall survival, quality of life or nutritional status advantages for HS in patients with the advanced colorectal cancer resistant to 5-fluorouracil [19].

The data on the animals tests that had confirmed the original antitumour effects of HS, the results of the phase I clinical trial and the contradictions in the evaluation of its therapeutical effects that had already appeared in the early publication became the reason for the organization and carrying out of the extended phase II clinical trial on the large group of patients with the advanced malignant tumours and lymphomas who had no perspectives to achieve any beneficial results with the help of any of the other methods of treatment. The goal of such a study was to determine the possible spectrum of antitumour effect and the HS effect on the disease-related symptoms.

This paper presents the final results of HS treatment in 740 patients with the advanced malignant tumours treated in several oncological clinics of’ the previous USSR according to a single treatment plan*.

*See Appendix

Patients and methods

The study embraced 740 patients (362 males and 378 females aged from 16 to 73 years) with the progressive disseminated tumours for whom the possibilities of surgery, radiation or cytotoxic therapy had been exhausted. The patients with the histologically or cytologically confirmed diagnosis, measurable or only assessable disease (including pleural effusion or ascites after the tumour cells were detected), ECOG performance score 2-4 and estimated life expectancy of >= 3 months, independent from the results of the laboratory tests on hematologic, renal and hepatic functions, were included into the clinical trial. The patients being pregnant or nursing, having insulin-requiring diabetes CNS metastases and psychiatric disorders (including the anamnestic data), clinically manifested syndromes compression (mediastinal, gastrointestinal obstruction, excluding mechanical jaundice), receiving according to the different indications prednisolone or other corticosteroids, androgens and progestins were excluded from the study. Taking into consideration the experimental data [20] and the well-known information about the increase of the toxicity of barbiturates, phenothiazine-type tranquilizers, antiemetic drugs and alcohol by the monoaminooxydaze inhibitors to which the HS also belongs, the use of these substances was forbidden.

The treatment with HS was started not earlier than 1.5 months after the completion of the previous therapy (surgery, radiotherapy. chemohormonotherapy) in all cases when the progression of the tumour was registered. In accordance with the aims of the phase II trial no randomization was foreseen.

Following these criteria, the total number of 763 patients was included into the trial. Because of the loss of some of them before the follow-up, only 740 patients (362 females and 378 males being from 16 to 73 years of age. the mean age 58.7 +/- 0.45 years) could be evaluated in the frames of the study. The distribution of these 740 assessed patients is presented in Table 1.

 

Table 1. Response to Sehydrin treatment


No. Type No. of pts. Objective Effect
Symptomatic Effect
CR PR NC PROGR Significant Moderate No effect
1. Hodgkin's disease 63 1 3 18 41 16 18 29
2. Non-Hodgkin’s lymphoma (relapse) 16 - 1 4 11 3 3 10
3. Breast cancer 66 - 2 28 36 15 20 31
4. Lung cancer 200 1a 7a 44 148 26 51 123
5. Oesophageal cancer 7 - - 2 5 - 2 5
6. Stomach cancer 138 - 1 56 81 7 55 76
7. Cancer of the pancreas 8 - - 5 3 1 4 3
8. Colorectal cancer 55 - 3 20 32 3 17 35
9. Vater's papilla cancer 3 - - 1 2 - 1 2
10. Hepatic cancer (primary) 2 - - - 2 - 1 1
11. Head and neck cancer 48 - 1 23 24 5 21 22
12. Bladder cancer 2 - 1 - 1 - 1 1
13. Renal cancer 9 - - 5 4 - 4 5
14. Ovarian cancer 6 - - 3 3 - 3 3
15. Cervical carcinoma 22 - 1 9 12 2 7 13
16. Endometrial carcinoma 9 - - 7 2 1 5 3
17. Cancer of the vulva 2 - - 1 1 1 - 1
18. Seminoma 1 - - 1 - - 1 -
19. Malignant melanoma 31 - 1 13 17 1 14 16
20. Mesothelioma 1 - - - 1 - 1 -
21. Neuroblastoma 7 1 - 4 2 3 2 2
22. Soft tissue sarcoma 32 1b 1b 15 15 9 10 13
23. Osteogenic sarcoma 1 - - 1 - 1 - -
24. Desmoid (recurrence) 11 2 3 4 2 5 5 1

Total 740 6 25 263 446 99 245 396
% 100 0.8 3.4 35.5 60.3 13.4 33.1 53.5

a squamous cell carcinoma; b CR and PR only, a group of 7 pts with fibrosarcoma; desmoid included as "semimalignant" tumour
  Two hundred and ninety-three of those 740 patients (39.6%) were previously treated with surgery. 142 (19.2%) and 105 (14.2%) received only chemohormon- and radiation therapy correspondingly. 12 1 (16.3%) got different combined modalities treatment. Seventy- nine out of these 740 patients (10.8%) received no types of the mentioned treatments in the past because of the grade of the tumour dissemination. The type of the tumour (resistant to cytostatics and the contra-indications coming from the con-comitant diseases and the patients’ performance status. HS was at once administered to these patients as the compelled kind of treatment. Oral in-formed consent was obtained from all of the patients included into the study.


Sehydrin (HS) was given per os 3 times a day, usually on the out-patient base, in the specially produced tablets containing 60 mg of‘ substance purified by the repeated crystallization with the constituents (1.0 g of NaCl ) each and being covered with the enterosoluble coat. These tablets were officially permitted for usage by the State Pharmacological Committee of the Ministry of Health of Russia. In some cases of dyspepsia disturbances the patients were administered 1 tablet a day during the period of 3-4 days, then 2 tablets a day up to the 9th day of treatment and after that 3 tablets a day if the patients weight exceeded 60 kg. The total course dose varied from 5.4 to 8.1g, the duration of the course 30-40 days. Repeated courses in case of disease stabilization were administered in the same manner after the intervals of 2 to 6 weeks. The number of the repeated courses was usually more than 2, it reached the number of 10-20 in the occasional patients, and even 40(!) in one patient with neuroblastoma. The patients having mechanical difficulties in taking the tablets (esophagus, larynx. pharynx cancer) were given a 0.4% solution of Sehydrin in the corresponding, doses (15 ml are equivalent to 1 tablet).


Adverse effects and response criteria were evaluated according .to the standard WHO (1979) criteria for the registration of complete and partial responses, stabilization and progression of the process. Complete response (CR) was defined as the disappearance of all the measurable or all the assessable tumour masses from the period of at least 4 weeks, and the absence of new lesions. Partial response (PR) was registered when more than 50% reduction in the total sum of products of the cross-sectional diameters of all the measurable lesions had been observed for the period of 4 weeks or more. Unmeasurable disease was evaluated as PR in case of more than 50% decrease in the tumour size for the period of more then 2 months. “Stabilization” or “No change" (Stable, NC) was defined in cases of less than 50% reduction in the same indices or less than 25% increase in the sum of products of the cross-sectional diameters of all the measured lesions and the absence of clear-cut regression or progression of the tumour for the period of 2 months or more, “Progression” (Progr.) - when the indicated sum increased greater than 25%, in patients with the clear-cut progression of the disease being the only one index that could be evaluated and the appearance of new lesions.


In accordance with the special aims of the trial, the influence of HS on the separate symptoms of the disease - fever, oedema, effusions, tachipnoe, nausea, vomitus, including the subjective ones that can be practically used as the quality-of-life parameters - pain, anorexia, weakness, apathy, depression -in the different combinations according to the type and localization of the tumour masses -was also registered. These registered HS effects were divided into three groups according to their grade: “significant” (disappearance or significant diminishing of the symptoms for the period of 2 months), “moderate” (the same effect but of the shorter duration), and “no effect". The influence of HS on the weight loss (cachexia). nutritional status (serum albumin level) and overall survival were not evaluated in this study.

Results


Table 1 shows that the complete regression of the tumours (primary, recurrent and metastatic) with the duration of the effect from 6 months till 9 years was observed in 6 cases (1 patient with the non-small cell lung cancer, 1 - with the neuroblastoma, 1 - the retroperitoneal fibrosarcoma, 2 - with the recurrences of desmoid of the anterior abdominal wall, and 1 -with the Hodgkin’s disease). A therapeutic effect of Sehydrin can be detected only after the repeated (2-3) courses. Partial responses were observed in 25 out of 740 patients resistant to combined chemotherapy, the patients with the lymphosarcoma, breast, lung, stomach, rectal, colon, pharyngeal, urinary bladder, cervical cancer, disseminated melanoma, fibrosarcoma, and desmoid tumour.


In 47 out of 740 patients (6.4%) tumour regression not exceeding 25 % evaluated as NC, was observed. This group included the patients with the Hodgkin’s disease, metastatic breast, lung, stomach cancer, laryngeal carcinoma, and several individual tumours.


The above-mentioned “stabilizing” influence on the tumour growth was the most typical therapeutic effect of Sehydrin. Interruption of the tumour progression during the administration of Sehydrin for the period of more then 3 months was observed in 216 out of 740 patients (29.2%). Stabilization (totally in 35.5% of patients) was most frequently observed in the patients with the Hodgkin’s disease, breast, lung, rectal, and colon cancer, in hypernephroma (in 5 out of 9 patients), generalized melanoma (in 13 out of 31 patients), soft tissues sarcoma (in 19 out of 39 patients), head and neck cancer (23 of 48 patients) and in the disseminated b cancer (28 out of 66 patients). It must be re-emphasized that the objective responses and stabilization of the tumour growth occurred in patients having the terminal phase of the disease.


The distinct above-mentioned symptomatic effects of Sehydrin were registered in 46.5% of patients. Symptom amelioration consisted of the decrease of fever, reduction or disappearance of hemoptysis, improvement of respiratory insufficiency, and frequent resolution of edema. Considerable improvement of the general state, appetite, weakness, and pain could be attributed to Sehydrin. As a rule, the improvement of the patient's general state occurred during the 2-3 weeks of treatment together with the decrease of pain, even in cases with bone metastases (spine, ribs, pelvis). Some patients with the bone metastases of lung cancer experienced such a pain relief that from a state of complete immobility connected with the severe pain syndrome they improved to a state of activity with the self-care and ambulation. This effect was of about 2 months duration, even against a background of evident tumour progression with the roentgenologically confirmed increase of the bone metastases. Although rare and with the less pronouncement, a similar effect was observed in patients with the bone metastases of breast cancer and metastatic tumours of the other localizations. A certain psychotropic influence of the drug in patients with the advanced malignant tumours can also be considered to be a symptomatic effect of Sehydrin. Already on the 2nd or 3rd week of Sehydrin treatment the majority of the patients revealed the improved spirit and even the overestimation of their motor activity, sometimes reaching a state of euphoria. Such effect of Sehydrin was observed even during the process of tumour progression and in the absence of the objective effect. The frequency of the described positive symptomatic effects was 25% in patients with the Hodgkin’s disease, 53% in the breast cancer patients, 44% in the stomach cancer patients, 57% in patients with the laryngeal carcinoma, 71% - with neuroblastoma, and 90% in patients with the desmoids.


Side effects of Sehydrin, albeit insignificant were still observed. There were no cases of myelo-suppression, hypotension, influence on blood sugar level or other biochemical indices. No cardiotoxic effects were registered. Dyspeptic symptoms such as nausea and vomiting were re-corded in 5.6% of patients, a local irritant effect of Sehydrin and nausea resulting from the advanced tumour process itself could not be differentiated. Nausea and vomiting sometimes regressed without any special treatment, but Sehydrin daily dose de-crease from 180 t o 120 mg was effective.


Dizziness and excitement observed in some cases did not appear to be a significant complication. The toxical effects of Sehydrin on the peripheral nervous system, such as polyneuritis (1.8% of patients) which occurred after the prolonged and continuous treatment at the early stages of Sehydrin study were more considerable. Interrupted and sometimes numerous courses helped to avoid this complication. Even in those cases when the treatment was conducted during 5 or 10 years. No polyneuritis were observed. It should be reemphasized that the registered side effects were insignificant and did not prevent the treatment.

The short excerptions from some case records can demonstrate the effects of Sehydrin (HS).

Case record 1 (according to the Hospital register No. 513).

Patient K., a female. 52 years old. The diagnosis: histologically confirmed relapse of neuroblastoma of the Douglas space with the secondary deformation of the rectum and colon. In 1974 she underwent a surgery laparotomy for neuroblastoma with the subsequent telegammatherapy (41.8 Gy on a focus). In October 1974 a recurrence of neuroblastoma of the Douglas space was diagnosed. A repeated laparotomy with the revision of the peritoneal organs was made: a removal of the tumour turned out to be impossible. During the periods of February 26 – March, 27, 1975 and April, 10 – May, 11, 1975 two courses of HS were carried out that resulted in the decrease of the tumour sizes and the softerness of the tumour. The patient put up her weight by 5 kg. In June 1875 the patient was subjected to telegammatherapy at a focal dose of 30.06 Gy. After that, the slow progression of the process was observed. A pronounced difficulty in defecation was noted. From November 1975 to December 1988 the patient was treated with HS only. Nowadays no signs of the tumour are found. On the whole, the patient underwent 40 courses of HS (with 6 months intervals during t h e period of the last 7 years). The patient keeps working during the period of last 10 years. The last examination was carried out in September 1994 - no signs of recurrence were found.

Case 2 (according to the Hospital register No.1839).

Patient G., a male, 32 years old. The diagnosis a relapse of the desmoid of the anterior peritoneal wall. Prior to his apply to the N.N. Petrov Research Institute of Oncology, the patient was operated in 1963, 1965, 1966, 1969 and on June 5, 1973. The histological conclusion: desmoid consisting of spindle cells with the layers of the fibrose tissue. On October, 24, 1974 the sixth surgery - dissection of the desmoid of the anterior peritoneal wall - was made to him at the N.N. Petrov Research lnstitute of Oncology. A dense infiltrate in the cohesion with the costal arch and the diaphragm was found in the left hypochondrium. The tumour was considered to be irremovable. The histological conclusion: desmoid (fibrose type) with the fragments of cell structure. HS treatment was started in November 1974. In January 1975 no tumours of the anterior peritoneal wall were detected. However, X-ray examination showed the typical infiltrations in the lateral sections of the left-side ribs. Subsequent courses of HS in January 1975. March 1975 and November 1975 resulted in the roentgenologically confirmed tumour decrease. Another course of HS was carried out in March 1977, and no desmoid recurrence was detected afterwards. No tumour recurrence was registered in April 1979 either clinically or roentgenologically. The effect of the complete tumour regression was registered again during the control follow-up examination in April 1988. The patient was lost for follow-up in 1988.


Case record 3 (according to the Hospital registers No. 1314, 1924).


Patient K.. a male. 44 years old. The diagnosis: Hodgkin’s disease (Stage III B), histologically confirmed in January 1989 at the N.N. Petrov Research Institute of Oncology. The lymph nodes of the neck, supraclavicular, inguino-iliac, para-aortal lymph nodes and mediastinal lymph nodes with the transition to the right lung were involved in the process; the patient also had a high fever and the other symptoms of the disease. After the 4 courses of the “hybrid” program of the MOPP/ABV combination chemotherapy (January - April 1989) the complete remission of the disease was diagnosed. For the purpose of the remission consolidation (in accordance with the Protocol) in April 1989 the radiation therapy (linear accelerator LUE-13 mV, braking regimen. gammatherapy) on the registrations of the involved lymphatic collectors and bulky tumour masses: right-side neck and supraclavicular lymph nodes (38.7 Gy), para-aortal (4U.8 Gy), left-side inguino-iliac (39.5 Gy), mediastinal (39.0 Gy), lymph nodes and spleen ( 12.6 Gy) was started. This treatment was finished in September 1989 because of the development of leukocyto- and thrombocytopenia of grade III.


In January 1990 the recurrence of the disease with the increase of the lymph nodes of the mediastinum, atelectasis of the upper lobe of the right lung, infiltration of the lower lobe of the right lung, right-side pleural effusion, fever with the temperature being up to 39C. excessive sweats and tachypnea were diagnosed. Because of the myelodepression being kept no chemotherapy could be administered to the patient, and that is why he got 3 courses of HS treatment in the dose of 180 mg daily (the total course dose - up to 4.0 g) with the 2-3 weeks interval. The treatment was started in February and finished in May 1990. As a result of this treatment the gradual improvement in the general condition, normalization of the body temperature and the decrease of the dyspnea were noted. The control examinations in June and October 1990 showed the regression of the exudate in the right-side pleural cavity (pleural layers,. increase in the pneumatization of the upper lobe and the complete regression of the infiltration of the right lung. In December 1991 the normalization of the sizes of the mediastinum was registered on the X-ray examination. The partial remission of the disease accompanied by the normal general status and activity of the patient and the normal levels of SES, WBC and trombocytes keeps being registered since 1991 (the last examination of the patient - in October 1994) No complications as a result of HS treatment were noted. The patient keeps being followed up at the N.N. Petrov Institute of Oncology.


Discussion


This clinical trial of Hydrazine Sulfate (Sehydrin) on a large group of patients with the disseminated forms of the so-called “signal” solid tumours and malignant lymphomas revealed the objective therapeutic effect of this drug in neuroblastoma, desmoids, Hodgkin’s disease, lung cancer, and fibrosarcoma. A certain stabilizing effect on the growth of the breast, .stomach, pancreas, larynx, endometrial and cervical cancer is also associated with Hydrazine Sulfate. In those cases when no distinct progression of the tumour is observed, the repeated courses of treatment have to be carried out in order to improve the potential for the therapeutic benefit from Sehydrin use. Sehydrin possesses a wide-scale symptomatic effect (decrease or elimination of the fever and pain syndrome as well as a positive psychotropic effect) observed in 46.5% of patients independently of the objective response. These effects have a clinical value especially in the so-called incurable cancer patients having the disease in its terminal stage. The anticachexian effect of the drug noted by some of the authors [8-10] that was manifested by the stabilization of the patients’ weight was of special importance. Side effects of Sehydrin, mainly the rare dyspeptic symptoms and polyneuritis, can be easily reversed, do not require any special correction and do not prevent the additional treatment.


The most important question is the one: whether the data from the single-arm trial being presented arc contradictory to the ones from the randomized placebo-controlled, double-blind, multicenter clinical studies mentioned above that failed to demonstrate any benefit for HS in the advanced colorectal cancer [19] or non-small cell lung cancer when this drug is administered along with the combination chemotherapy - cisplatin and etoposide 18 or cisplatin and vinblastine [ 17]. The comparison of the data from Table 1 and from the first of the mentioned publications makes it understandable that there are no significant contradictions in them. No tumour regression was seen in the multicenter trial in both the placebo and HS groups, while in this phase II trial PR were registered only in 5% of the patients that was within the limits of the measurement error. The frequency of stabilization is not indicated in the article, and the evaluation of the other therapeutic effects of HS was made with the use of different parameters: in the randomized study - quality of life according to the performance status, appetite, weight ratios, survival rates, and in this study - according to the effect of the drug on the separate disease symptoms. That is why the data are not comparable and can not be used as an argument against the results of this single-arm trial.


In the other two above-mentioned trials [17, 18] HS was given simultaneously with the chemotherapy drugs. Meanwhile, HS is not "a neutral substance” as regarding to the effects of cytostatics. Experimental data have indicated that the combination of HS with some of the cytostatics may result in the additive therapeutic or antagonistic effect [20].


The question of what type of these effects manifests itself in case of the combination of HS with cisplatinum, etoposide and vinblastine remains to be unclear. Anyway, until the special experiments on this subject are not carried out, it is possible to suppose that HS has a relatively probable unfavourable “intervention” into some of the variants of chemotherapy, and hence, that it is impossible to evaluate these data from the phase III trial as an argument against the results of the single-arm trials.


Clinical trials do not provide any information on the mechanisms of the drugs’ effect, although the psychotropic effects can be explained by the suppression of monoaminooxydase [12, 21] that is similar to the effect of some of the antidepressants [22]. Inhibition of monoaminooxydase may be also related to the antitumour effect of Sehydrin that is similar to the effect of the other inhibitors of this enzyme in the malignant growth [23, 24]. Gold [25] believes that HS's antitumour effect is provided by its inhibitory effect on phosphoenol-pyruvatecarboxykinase, a key enzyme of gluconeogenesis. Having tested the hypothesis, we found that the activity of the mentioned enzyme in Sehydrin treatment of animals with the experimental tumours remained unchanged [26] as well as gluconeogenesis did [27]. At the same time, in the conditions of the experimental therapy Sehydrin produces its effects on some of the other biological targets such as cytoplasmic and cell organelle membranes, mitochondria adenosinetriphosphatase microsomal uridine diphosphatase, etc. [12]. Antitumour effect of Sehydrin can be interpreted as an integrated effect on a number of biochemical units with the antimonoaminooxydase effect as the main one.


The clinical and experimental data do not allow us to consider Sehydrin (HS) to be the typical cytostatic and to evaluate the drug according to the results of the rather small rate of remissions in the whole group of patients. However, the matter of interest is the activity of the drug in the soft tissues sarcomas and particularly in patients with the desmoids resistant to the other cytostatics in a phase when all the possibilities of the surgical or any other treatment are exhausted.


Naturally, there exist the methods of the enough effective cytostatic therapy for the treatment of many other tumours, but, however, it ought to be taken into account that Sehydrin (HS) has a beneficial and adequate effect in the nearly terminal cases when these methods are exhausted. Together with the absence or nearly absence of adverse effects of Sehydrin including the treatment with the repeated courses lasting for the period of several years, peculiarities of objective and symptomatic therapeutical effects put forward the use of the drug in the treatment of disseminated forms of malignant tumours. It is rational to keep using Sehydrin in the future in, first of all, the inoperable malignant tumours of soft tissues and, possibly, taking into account its unusual effect, in desmoids, in some benign neoplasms with the extensive growth rate and difficult surgical access.

 

Appendix

Additional participating institutions include the following: P.A. Herzen Institute of Oncology. Moscow (Nelli P. Dementjeva. MD). Oncological Institute of Lithuania. Vilnius (Paul V. Breivis. MD: V.P. Ragashene. MD). Institute of Problems in Oncology of Ukrainian Academy of Sciences. Kiev (Inga V. Kasjanenko. MD: A. Lisitsa. MD). Rostov Institute of Oncology and Radiology. Rostov-na-Donu. Russia (Sofja S. Mindlin MD: N.I . Kurganova. MD).

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  27. Filov VA. Burova TM: Gluconeogenesis in hydrazine sulfate treatment of animals with experimental tumours. Bull of Exper Biol Med (Rus) 1:73 - 74, 1984

Address/or offprints: Prof. V.A. Filov, Prof. N.N. Petrov Re-search Institute of Oncology. 68 Leningradskaya str., Pesochny-2. St. Petersburg. 189646. Russia


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