Use of Hydrazine Sulfate in Terminal and Preterminal Cancer Patients: Results of Investigational New Drug (IND) Study in 84 Evaluable Patients
[Oncology 32: 1-10, 1975]
Key Words. Hydrazine sulfate therapy in advance cancer patients - Treatment of advanced human cancer with anti-gluconeogenic drugs - Interruption of cancer cachexia as a means of cancer chemotherapy - Interruption of gluconeogenesis as a means of cancer chemotherapy
Abstract. In a series of 84 various evaluable disseminated cancer patients treated with hydrazine sulfate as a result of a pharmaceutical-sponsored investigational new drug (IND) study, it was found that 59/84 or 70% of the cases improved subjectively and 14/84 or 17% improved objectively. Subjective responses included increased appetite with either weight gain or cessation of weight loss, increase in strength and improved performance status and decrease in pain. Objective responses included measurable tumor regression, disappearance of or decrease in neoplastic-associated disorders and long-term (over 1 year) stabilized condition. Of the overall 59 subjective improvements 25 (42%) had no concurrent or prior (within 3 months) anticancer therapy of any type. Of the 14 objective improvements 7 (50%) had no concurrent or prior anticancer therapy. Of the remaining cases in which there was either concurrent or prior anticancer therapy, improvements occurred only after the addition of hydrazine sulfate to the treatment regimen. Duration of improvement was variable, from temporary to long-term and continuing. Side effects were mild, comprising for the most part low incidences of extremity paresthesias, nausea, pruritis and drowsiness; there was no indication of bone marrow depression.
Hydrazine sulfate has been used as an investigational new drug (IND) for over 1 year in the treatment of advanced cancer. Its proposed mechanism of action is as a gluconeogenic blocking agent at the phosphoenolpyruvate carboxy-kinase (PEP CK) reaction, attenuating host energy loss as a result of increased gluconeogenesis in cancer and therefore interrupting the systemic cycle of tumor-energy gain-host-energy loss (tumor growth-host cachexia) (1, 2). Early reports indicated that hydrazine sulfate, administered orally to advanced cancer patients, resulted in marked subjective and objective improvements (3), subjective improvements including increase in appetite, cessation of weight loss and/or weight gain, improved performance status, and decrease in pain; objective improvements included measurable reduction in tumor size and reduction in or disappearance of neoplastic-associated disorders (effusions, jaundice, etc.). Duration of improvements was reported as variable and side effects, minimal. In further reports (4), in which hydrazine sulfate was used in conjunction with conventional chemotherapy in patients with disseminated neoplasia, it was unclear as to which type of therapy resulted in the reported subjective and objec-tive improvements. The present report, undertaken as a pharmaceutical-sponsored IND study and representing a series of 84 evaluable cases of various terminal and preterminal cancer patients, indicates a high degree of anticancer activity in patients treated with hydrazine sulfate alone.
Procedures and Protocols
Physician selection. This study was the result of separate inputs of many clinicians -- oncologists as well as others -- whose participation was under pharmaceutical IND sponsorship. As such, this study is designated as 'uncontrolled'.
Patient selection. Patients with any type of disseminated neoplasia, who no longer responded to chemotherapy and/or radiation, were considered eligible for hydrazine sulfate therapy. A minimum prognosis of 2 months was recommended.
Drug and protocol. The drug consisted of I 00% purity hydrazine sulfate mixed with an inert starch in capsular form (pharmaceutical IND preparation) for oral administration. Protocol of drug administration was as follows: 60 mg q.d. X 4; 60 mg b.i.d. X 4; then 60 mg t.i.d. as maintenance. In patients weighing less than 50 kg, dosages were halved (i.e., 30 mg q.d. x 4; 30 mg b.i.d. X 4; then 30 mg t.i.d.). In the event that a b.i.d. schedule produced satisfactory results, this dosage schedule was maintained at the clinician's discretion. In no event was a single dosage ever to exceed 60 mg.
Concurrent anticancer medication. The continuing use of concurrent anticancer medication was acceptable if it was no longer producing a demonstrable anticancer effect by itself.
Data presentation. A 4-sheet data page ('Patient Report Form') was required to be completed by the clinician during the course of treatment of each patient. These data sheets included the following information: detailed history, site of tumor and metastases, prior treatments (defined in this study as any type of anticancer therapy given within 3 months of the initiation of hydrazine sulfate therapy; prior treatment data included dates of therapy, types and quantitation), concurrent medications, performance status evaluation, objective tumor size and site evaluations, subjective observation ratings and check list, laboratory data, clinician's statement of patient evaluation prior to hydrazine sulfate therapy, clinician's statement of evaluation of results of hydrazine sulfate therapy, clinician's evaluation of side effects of hydrazine sulfate therapy, and clinician's signature.
Criteria for designation as 'improvement.' Designation of subjective improvements was made on the basis of improvements indicated in the subjective observations rating check list and/or affirmation of improvement in the clinician's statement under 'clinician evaluation' section. In general a subjective improvement was based on a quantitatively measurable or estimable parameter such as strength (number of hours ambulatory, quality of ambulation, etc.), appetite (food intake), weight (scale measurement) and pain (quantitative need for analgesics). Objective improvements were designated on the basis of measurable reduction in tumor size, long-term (1 year or more) stabilized condition in a previously rapidly growing neoplasm, and disappearance of or reduction in neoplastic-associated disorders. Each case in this category was to be supported by related laboratory measurements, where possible.
Criteria for designation as 'nonevaluable.' Cases were deleted from evaluation for any of the following reasons: (a) inadequate prognosis: patient survival of less than 3 weeks; (b) inadequate drug trial: drug trial of less than 3 weeks; (c) insufficient data submitted on Patient Report Form: no evaluation possible, and (d) concurrent treatment with newly initiated cytotoxic chemotherapy: patient response nonevaluable.
Of a total number of 158 cases submitted in the study, 84 were evaluable and 74 nonevaluable. Of the evaluable cases 14 (17 ) were categorized as 'objective (and subjective) improvement', 45 (54%) as 'subjective improvement only', and 25 (30%) as 'no improvement'. The indicated overall improvement rate was 59/84 cases, or 70%. Of the nonevaluable cases, 31 (42%) were included under inadequate prognosis, 25 (34%) under 'inadequate drug trial', 15 (20%) under 'insufficient data, and 3 (4%) under 'newly initiated cytotoxic chemotherapy'. Categorization of evaluable and nonevaluable cases is given in tables I and 11, respectively.
Improvements were noted in tumors from almost all of the 19 reported sites of origin. No particular site of origin or tumor type was 'most susceptible' to hydrazine sulfate therapy, although the largest number of cases came from colo-rectal and lung carcinoma, which reflects the general incidence of these diseases in the population. The duration of improvement was variable, being reported from very temporary (1 week) to in excess of 1 year and continuing. It was possible to obtain follow-up reports in only less than half of the improved cases.
Objective responses. Of the 14 reported objective responses, 7 (50%) showed measurable tumor regression; 2 of these were accompanied by a disappearance of or reduction in neoplastic-associated disorders (effusions, jaundice, etc.). An additional 2 (14%) of the 14 cases were classified as long-term 'stabilized condition', both of which represented preterminal lung cancers whose disease had been rapidly progressive prior to hydrazine sulfate therapy. They are currently both alive and well 17 and 18 months after initiation of hydrazine sulfate therapy, respectively; neither are on any kind of concurrent anticancer therapy. The remainder of the 5 (36%) cases were classified as objective responses on the basis of amelioration of neoplastic-associated disorders, accompanied by marked subjective improvements. (In this regard all 14 cases showed subjective improvements.) All objective responses were also accompanied by tumor-related laboratory improvements, where measured.
Subjective responses. A total of 45 cases displayed subjective improvements only; this number, added to the foregoing 14 cases, gave a combined total of 59 subjectively improved cases. 48 (81%) of these showed an increase in appetite with either weight gain or a cessation of weight loss. 48 (81%) showed an improvement in performance status as measured by an increase in strength, ambulation or both. And 21 (36%) showed a decrease in pain as measured by a dominated need for analgesics.
Ongoing concurrent (or prior) anticancer therapy. Various of the improved cases were treated with either steroids and/or cytotoxic chemotherapy and/or radiation, prior to initiation of hydrazine sulfate therapy, as indicated in table III. In all these cases the noted improvements occurred after the addition of hydrazine sulfate to the therapy. In regard to the objective responses 7 (50%) of the 14 cases were treated with hydrazine sulfate alone, without concurrent-or prior anticancer therapy of any type, while 7 (50%) of the cases did receive concurrent or prior anticancer therapy. In the subjective-only responses, 18/45 or 40% of the cases were treated only with hydrazine sulfate, without concurrent or prior anticancer therapy, while 27 of the cases (60%) did receive concurrent or prior anticancer therapy.
Of the 25 'no improvement' cases 2 (8%) expired within 3-4 weeks after initiation of hydrazine sulfate therapy; 2 (8%) had very little information. in their Patient Report Form so that actual categorization became difficult; 9 (36%) had a drug trial of only 3-4 weeks, and 14 (56%) had concurrent anticancer therapy which consisted of cytotoxic drugs, radiation, steroids or combinations thereof. In only 5 cases were these foregoing considerations not a factor, i.e., the patient had an adequate prognosis and drug trial, had no concurrent or prior anticancer therapy, and had sufficient information submitted on his Patient Report Form to support a categorization of 'no improvement'.
The general breakdown of categories of the 74 nonevaluable cases is given above and in table II. Of a total of 31 of these cases excluded from evaluation because of inadequate prognosis (survival time), 11 died within 1 week of initiation of hydrazine sulfate therapy, 22 died within 2 weeks, and the full 31 died within 3 weeks. Of a total of 25 additional cases excluded from evaluation for reasons of inadequate drug trial, 8 were on drug for only 1 week or less, 14 were on drug for 2 weeks or less, and the full 25 were on drug for 3 weeks or less. Thus, of the 56 cases excluded from consideration for the foregoing two reasons, 19 had a survival time or drug trial of 1 week or less, 36 had a survival time or drug trial of 2 weeks or less, and the full number -- 56 -- had a survival time or drug trial of 3 weeks or less.
Side effects were determined on the basis of evaluable cases only and were in general mild. They comprised: extremity paresthesias (5%); this condition was diminished or eliminated by a reduction of dosage and/or administration of pyridoxine hydrochloride (vitamin B6) in excess of 25 mg daily; nausea (4%), in most cases transient; nontransient nausea was eliminated by a reduction of dosage or withdrawal of medication for a period of several days, then reinstitution of treatment at lower dosage levels; dry skin or transient pruritis (3%); 'dizziness' (1%); 'drowsiness' (I%); possible thrombophlebitis (1%) (it was not known whether this condition was drug-related). The total evaluable cases showing side effects numbered 13/84 or an overall 15%. There were no deaths attributable to hydrazine sulfate therapy, either in the evaluable or in the non-evaluable cases.
It is important that a detailed analysis of a study of this nature include not only the obviously improved cases as a result of hydrazine sulfate administration, but also the nonimproved and nonevaluable cases. Such factors as poor patient and clinician selection as well as inadequate protocol planning, must be assessed as to their quantitative contribution to the latter two categories.
Nonimproved and Nonevaluable Cases
Lack of proper patient selection, via inadequate patient prognosis and inadequate drug trial, contributed heavily to the large number of nonevaluable and nonimproved cases. Minimum protocol-recommended prognosis was 2 months, yet as many as 31/74 or 42% of the nonevaluable cases were so designated because of a survival time of 3 weeks or less, while in the nonimproved category 2/25 or 8% of the cases had a survival time of only 3-4 weeks. In addition, as many as 25/74 or 34% of the nonevaluable cases were so designated because of an inadequate drug trial (3 weeks or less), while 9/25 or 36% of the nonim-proved cases had a drug trial of only 3-4 weeks. Thus, in the nonevaluable category the number of combined inadequate prognosis and inadequate drug trial cases totaled 56/74 or 76%, while in the nonimproved category the number of combined cases of 'borderline-acceptable' survival time and drug trial (3-4 weeks) totaled 11/25 or 44%. Such large percentages, representing inadequate prognosis and inadequate drug trial, must be attributed chiefly to improper patient selection and not to the occasional misevaluations which arise in any study.
Lack of proper clinician selection was also an apparent factor in this study, manifest chiefly in those cases in which too little information was submitted. In the nonevaluable category as many as 15/74 or 20 % of the cases were so designated because of lack of sufficient information upon which to make an evaluation. Even in the nonimproved category 2/25 or 8% of the cases had only a minimum of information submitted. Such numbers surely reflect a lack of interest or capability on the part of the clinician. (Indeed, inadequate patient selection itself may be a function of this type of clinician inadequacy.)
Poor protocol planning, manifest by the acceptability of concurrent anti-cancer therapy, also had a major input in these two categories. In the nonevaluable group 3/74 or 4 % of the cases were so designated because of newly initiated concurrent cytotoxic chemotherapy, rendering impossible any attributive evaluation of patient response. In the nonimproved group as many as 14125 or 56% of the cases had ongoing concurrent anticancer therapy which was no longer producing demonstrable clinical benefit, but which could, by virtue of its immunosuppressive and hematosuppressive effects, adversely affect or mask the results of any new drug concurrently administered. Clearly, the protocol was weakened by inclusion of any type of concurrent anticancer therapy whatsoever.
Thus, in retrospect many of the cases which fell into the nonevaluable and nonimproved categories should properly never have entered this study. This circumstance could have been obviated by better patient and clinician selection as well as by a 'tighter' protocol. It is hoped that a careful categorization in this study has dealt adequately with these factors.
Despite the above-described considerations, a large number of clearly improved cases emerged in this study. This improvement, moreover, was the result of administration of hydrazine sulfate alone in a large percentage of the cases and was not influenced by any, other mode of concurrent or prior anticancer therapy. Table III indicates that 50% of the objectively improved cases (7/14) were on hydrazine sulfate alone, with no prior or concurrent anticancer therapy; and 40% (18/45) of the subjective-only responses were also the result of hydrazine sulfate therapy alone. This constitutes strong prima faciae evidence indicating hydrazine sulfate to be a clinically active anticancer agent in itself. It is important to remember that even in those cases which received concurrent or prior anticancer therapy, the noted improvements occurred only after the addition of hydrazine sulfate to the treatment regimen. Thus, whether as a sole agent or in combination with other agents, administration of hydrazine sulfate to advanced cancer patients is linked to marked anticancer responses.
Moreover, hydrazine sulfate is apparently not a 'tumor-specific' agent, as can be seen from table I. Virtually all types of cancer -- especially those which ultimately promote a degree of host cachexia -- are apparently susceptible to its actions. Reports, in addition to those of this study, which have reached this laboratory, indicate that the spectrum of disease beneficially affected by hydrazine sulfate extends to cancers arising from all organ systems and/or tissues in the body. The most dramatic responses reported to date have been those with primary lung neoplasms, although this observation may prove to be premature as more and earlier cases are reported.
The duration of improvement has been unpredictable, but has generally been longer in those cases responding objectively (as well as subjectively). Some of the responses have been of very short duration. But others have been quite lengthy. To date three cases in this study -- two primary lung and one ovarian -- are alive 17, 18 and 21 months after institution of hydrazine sulfate therapy alone, respectively; all three were previously considered terminal or preterminal. Preliminary indications suggest that the improvements brought about hydrazine sulfate therapy -- whether objective or subjective -- have been accompanied by extension in survival time and that the quality of this survival time was high: patients who had obtained objective response and/or increased appetite, strength and decreased pain as a result of hydrazine sulfate therapy, were reported to have been restored to a more positive orientation toward living.
The duration of improvement may also be related to the degree of advancement of the disease. The patients in this study were in general in the very latest stages of disease, yet there were many improvements, some of which were marked. However, it is generally regarded that any modality of anticancer therapy has its best chances of success when used early in the course of disease. And this is probably true of hydrazine sulfate. There would seemingly be no disadvantage in instituting hydrazine sulfate therapy early in the course of disease, especially in those cases where the ultimate clinical course is virtually unaffected by any known therapeutic modality. Moreover, since the toxicity of hydrazine sulfate is apparently of a low order of magnitude, unlike many of the cytotoxic drugs whose 'side effects' can produce extreme patient discomfort and death, it would seem prudent to investigate the effect of this drug on early patients, rather than use it at the very last stages as a 'resurrective' type of therapy. If positive responses can be obtained in terminal patients -- as indicated in this study -- it seems only reasonable that a greater degree of positive response could be expected in early patients, as is the case with many other anticancer modalities.
The side effects of hydrazine sulfate are indeed of a very minor nature as reported in this study, with the possible exception of 'torpidity' or 'drowsiness' which had less than a 1% incidence and occurred only in very advanced bedridden case(s). The most frequent side effect, occurring usually after the 6th week of therapy, appears to be the development of mild extremity paresthesias, particularly of the fingers and toes. This condition reportedly can be diminished or eliminated by dosage reduction and/or addition of vitamin B6 (in excess of 25 mg daily) to the regimen. Other side effects such as nausea, pruritis, etc., appear to be transient in nature and not a clinical problem, with few exceptions. In general, since hydrazine sulfate is not a cytotoxic agent, there have been none of the severe side effects of these drugs reported with its use, and this is especially true of hematopoietic-suppressive effects. Hydrazine sulfate does not depress the bone marrow. On the contrary, several of the cases of this study with advanced prostatic or breast cancer showed net elevations in hemoglobin, hematocrit and platelets within 2 weeks of initiation of treatment. This observation has been confirmed in many case reports not a part of this study and thus is in contrast to the cytotoxic drugs, one of the prime limitations of which are their hematosuppressive effects. Finally, hydrazine sulfate has not been demonstrated clinically to possess immunosuppressive properties, although this must await verification by further basic studies.
Hydrazine sulfate therapy is a new type of chemotherapy. Its clinical use at present represents a beginning. Whether a study with any new drug is positive or negative, it must always be evaluated in terms of the 'state of the art'. Hydrazine sulfate represents the first of a class of new agents designed to interrupt host participation in cancer. Other agents in this class now in development may prove to be far superior to hydrazine sulfate. In addition, adjunctive agents to hydrazine sulfate therapy may also prove to be very important. In this respect it has already been learned by this laboratory that administration of a substance interfering with triglyceride synthesis, can greatly potentiate the anticancer action of hydrazine sulfate (paper in preparation). For these types of reasons it must be emphasized that the clinical potential of hydrazine sulfate-like drugs in cancer has only just begun to be explored, and much further work lies ahead before a more comprehensive understanding of their ultimate anticancer potential becomes clear.
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