Chapter Twenty-Two

PART FIVE

Physical, Traditional, and Pharmacological Therapies

Chapter Twenty-two

Joseph Gold–Does Hydrazine Sulfate Prevent Weight Loss and Extend Life with Cancer?

The story of Joseph Gold, M.D., makes a fascinating comparison with that of Stanislaw Burzynski. Like Burzynski, Gold made his discovery–of the anticancer effects of hydrazine sulfate–while working inside the medical establishment. But, unlike Burzynski, he stayed inside and faithfully played by the rules. Nonetheless, hydrazine sulfate spent 3 years on the American Cancer Society’s (ACS) “unproven methods” list before becoming recognized as a promising experimental therapy.

Even today, after numerous preclinical and clinical studies have established its modest toxicity, its capacity for enhancing the nutritional status of cancer patients and helping them avoid weight loss (cachexia), and its consequent potential to extend life–at least with some cancers–hydrazine sulfate remains a drug that is difficult for cancer patients to get, even through the efforts of sympathetic oncologists.

Gold is the Director of the Syracuse Cancer Research Institute in Syracuse, New York. In 1968, he published a paper suggesting that a new approach to cancer might be to block the primary damage cancer does to the body.

Gold had studied the work of Otto H. Warburg, winner of the Nobel Prize for Medicine in 1931. Gold’s innovation was based upon Warburg’s controversial theory of the nature of cancer cell metabolism. In normal cell metabolism, energy is obtained through respiration–taking in oxygen and giving off carbon dioxide and water. But under some circumstances–such as when the muscles or brain require a quick burst of energy–that energy can be produced through fermentation, a primitive and wasteful process common in simple forms of life. Warburg postulated that cancer cells fulfilled their energy needs in this way.1 Warburg’s theory has remained controversial, although it is currently regarded as probably partially correct.

Extrapolating from Warburg’s theory, Gold reasoned that if cancer cachexia–the weight loss often accompanying cancer–could be interrupted, the disease might be controlled.2 Gold found that cachexia resulted from the cancer’s recycling of its own wastes at the energy expense of the body. Cancer only partially metabolizes glucose, its fuel, producing lactic acid as a waste product. The body must then expend a great deal of energy to reconvert the lactic acid back into glucose. An ever-increasing amount of glucose then becomes available as fuel for the tumor, but only at great expense to the other tissues of the body.3

Working from this theoretical perspective, Gold began investigating ways of interrupting this “sick relationship.” He experimented with various drugs and diets before finding a scientific paper in the early 1970s that provided the key: a substance called hydrazine sulfate could block an enzyme in the liver critical to the process of converting lactic acid to glucose.4 Gold’s report that a cheap and readily available chemical might be of help to cancer was not of great interest to the pharmaceutical industry, but it did have considerable appeal to many cancer patients. Soon it was picked up by advocates of unconventional cancer therapies and thousands of patients were trying it.

An early pilot study by Manuel Ochoa at Memorial Sloan-Kettering Cancer Center in New York evaluated hydrazine sulfate with 29 “adequately treated” patients with a wide range of tumor types. He reported no significant subjective or objective gains but, to the contrary, found “major neurological toxicity was observed in half of the patients.”5 Gold strongly criticized the methodology of the study–convincingly in my view.6 Two other negative studies followed. Gold then published an article reporting positive effects of hydrazine sulfate in patients who were receiving the drug under the Food and Drug Administration (FDA) Investigational New Drug (IND) permits that had been given to a number of physicians.7 He found subjective improvement in 70% of adequately treated patients and objective improvement, including tumor regression and cancer stabilization, in 17% of patients. But in March 1976, probably owing largely to the fact that it had become a favored alternative cancer therapy without undergoing conclusive testing within the scientific community, hydrazine sulfate was placed on the ACS’s unproven methods list. Once the drug had been put on the ACS list, Gold’s funding dried up.8

Soviet Studies of Hydrazine Sulfate

Fortunately for science and for cancer patients, scientists in the former Soviet Union were not deterred by the negative opinion of the ACS and continued to evaluate the drug. In large nonrandomized single-arm trials at the Petrov Research Institute of Oncology in Leningrad begun in 1975 and 1976, 356 patients were given hydrazine sulfate alone. The difficulties with such uncontrolled single-arm studies are well known, but the merit of the studies was that no concurrent or incompatible chemotherapy or medication clouded the picture. Gold reports: “Results of the nine-year study revealed the following: 50% subjective (anticachexia) response; 46% antitumor response; restoration of (previously lost) sensitivity to cytotoxics [e.g., agents toxic to cancer cells]; instances of long-term survival; and the absence of important clinical side- effects.”9

Patients increased their weights and appetites and enjoyed improved strength and performance status. The cancer stabilized in 31% and regressed in an additional 15% of the sample. Says Gold: “Therapeutic effects were indicated as frequently not appearing until the second or third course of therapy [emphasis added], and their accrual in patients who were considered `practically in the terminal phase’ of their disease was cited as a `factor’ of potential clinical significance.”9

It is important to remember that the Soviet studies used cancer patients with a wide range of different kinds of tumors and reported positive results across the whole range. Note that the Soviets reported actual antitumor as well as anticachexia affects. In Gold’s view, hydrazine sulfate’s antitumor and anticachexia effects may be related:

With the advent of a specific anticachexia agent, more effective cancer control becomes possible. For the devastating aspects of this disease are due to two principle causes: invasion of tumor into vital organs with consequent destruction of their function; and decay of the body by virtue of cachexia and its resultant effect on the integrity of all body systems. Each of these processes has its own metabolic machinery, each is amenable to its own therapy, and each is to some degree functionally interdependent on the other.10

The National Cancer Institute (NCI) noted the results of the Soviet studies without enthusiasm, contrasting them with two earlier negative studies from the United States. But interest among physicians and patients in the United States continued to grow, and, finally, through its complex and contradictory bureaucratic political process, the NCI formally expressed interest in metabolic and anticachexia research along lines that suggested a recognition of hydrazine sulfate’s potential, but that placed obstacles in the way of additional funding for research. The struggle was more than one over hydrazine sulfate: it was a debate within the cancer establishment over how much emphasis should be placed on energy metabolism, cachexia, and nutritional factors in cancer. The antinutrition and anti-hydrazine sulfate forces were in the ascendancy, but the opposition had achieved mainstream respectability.11 It is highly ironic that later–in 1990–cancer scientists would pronounce cachexia as the “sole cause” of two thirds of all cancer deaths.12

American Cancer Society Takes Hydrazine Sulfate Therapy Off the Unproven Methods List

In 1982, the ACS withdrew hydrazine sulfate from its unproven methods list. In fact, ACS officials began to wonder whether placing the drug on the unproven methods list in the first place had been their proudest hour. In the Washington Post on May 17, 1988, reporter Sandy Rovner wrote:

What the circumstances were that actually got hydrazine sulfate onto the American Cancer Society’s list of “unproven methods” are somewhat cloudy, even the ACS concedes. …. Says ACS medical sociologist Helen Sheehan, who serves as director of Professional Education Programs for the ACS, “I suspect that because of the atmosphere created during the laetrile period there may have been some zealotry on the part of the committee. I think laetrile created a lot of that atmosphere and they [the patients using laetrile] were using hydrazine. In fact,” she notes, “they still are, and there are still all sorts of underground ways to get hydrazine outside of clinical trials.” ….

“From what I can understand of the past,” [Sheehan continues] “many things were referred to this department that had real research potential, but because they were mixed in with things like herbs and teas and so forth, everything sort of got tainted,” she said.13

Chlebowski Reports Life Extension in Lung Cancer

Hydrazine sulfate might well have remained in limbo in the United States for many years were it not for a young researcher named Rowan T. Chlebowski at the University of California, Los Angeles. Ralph Moss tells of the wonderfully ironic way in which Chlebowski came to conduct research on hydrazine sulfate:

Chlebowski is a bright, serious, and, by his own admission, loyal member of the cancer establishment. In 1980 he wanted to perform blood chemistry tests on cancer patients. Not surprisingly, few patients wished to volunteer for tests that did not hold out some hope for therapeutic benefit. At the same time, people were calling the hospital where he worked, pleading for hydrazine sulfate [emphasis added]. Chlebowski and his colleagues therefore decided to undertake a double-blind clinical trial of the drug while at the same time getting a chance to study blood chemistry.”14

This study and subsequent studies by Chlebowski showed very substantial effects of hydrazine sulfate on controlling weight loss from cancer. In a 1987 study in Cancer, the Chlebowski team reported that they had previously demonstrated that hydrazine sulfate was metabolically active and reduced the increased glucose production rates seen in cancer patients with weight loss. They then reported that their clinical observations on “short-term hydrazine sulfate use” in cancer patients who suffered weight loss resulted in 71% of patients on hydrazine maintaining or gaining weight while only 53% of those on placebo did so. Sixty-three percent of those on hydrazine sulfate showed improved appetite, while only 25% on the placebo did so; 77% on hydrazine sulfate showed increased caloric intake, while only 53% on the placebo did so. Moreover, 71% of the patients receiving hydrazine sulfate experienced no toxic side effects whatsoever and most of the rest experienced only mild to moderate nausea and lightheadedness. Treatment was discontinued in 10% of patients receiving hydrazine because of “toxic effects.” However, 6% of patients receiving placebo had treatment stopped for “toxic effects.”15

But the truly important news was still to come. In a potentially historic study in the January 1990 issue of the Journal of Clinical Oncology, Chlebowski and his colleagues at Harbor-UCLA Medical Center reported hydrazine sulfate had significantly increased survival in a randomized controlled clinical trial of 65 patients with advanced inoperable non-small-cell lung cancer.16 The hydrazine sulfate had been added to the best available conventional chemotherapeutic treatment for this very difficult cancer. Its life extension effect had been seen in patients who were “fully ambulatory”: for such patients, hydrazine sulfate extended life to a median of 328 days, compared to a median of 209 days for patients who had received chemotherapy only. The authors admitted that the moderate sample size meant that their study was not definitive, but said that it provided support for the multi-institutional study of hydrazine sulfate presently underway.

An accompanying editorial in the Journal warned against making too much of the results, given the small sample size and the methodology17–a position which drew a biting critique from Gold in a succeeding issue. He pointed out that the editorial writer had not mentioned that over half of the other articles in the same issue of the same journal had used fewer patients than the Chlebowski study and had not been singled out for criticism.18 “In focusing specifically upon the hydrazine sulfate study, this editorial in effect singles out this drug for continuing `skepticism’, despite the plethora of data indicating the opposite,” wrote Gold.

Conclusion

In evaluating the Chlebowski study with non-small-cell lung cancer, it is important to recall that the Soviet studies found benefits with hydrazine sulfate across a wide range of tumor types, not only in one of the most difficult of all cancers, non-small-cell lung cancer. So the question legitimately may be asked: If, in a controlled clinical trial, hydrazine sulfate is shown to extend life by a substantial proportion in one of the most difficult cancers, is it not reasonable for cancer patients to assume that its benefit for other cancers (as suggested by the Soviet studies) may also be confirmed? Further, might that benefit also be proportional, so that patients with cancers with longer or more variable natural histories might experience much more extended benefits?

Gold believes that, based on the studies to date, the best course is to prescribe hydrazine sulfate from the very outset of treatment–even before weight loss occurs–because the metabolic pathways for weight loss are similar to those for tumor growth.19

The next step in the hydrazine sulfate debate will be triggered by the publication of the outcomes of three phase III studies presently being sponsored by the NCI. The first, a study of non-small-cell lung cancer patients, is a large multi-institution controlled clinical trial that was initiated in July 1989. The second, initiated in April 1990, also studying non-small-cell lung cancer patients, is being carried out by the Mayo Clinic and the North Central Cancer Treatment Group (NCCTG). The third, also undertaken by the NCCTG and the Mayo Clinic, and begun in August 1990, is examining data from the Mayo Clinics around the country. Significantly, this last study is being conducted with patients who have a colorectal cancer, which is resistant to 5-fluorouracil (5-FU) chemotherapy, and is the only study that will assess the effectiveness of hydrazine sulfate where there has been no adjuvant chemotherapy.

Hydrazine sulfate is inexpensive and is not a substance that is likely to make scientific reputations or large fortunes for pharmaceutical companies. Because it was available and gave hope without too much toxicity, some Americans with cancer began to use it because they, personally, could not wait another 20 years for the scientific community to render a decisive opinion on it. As a result, 20 years after it was proposed–despite considerable preclinical and clinical evidence of its benefit–it remains difficult for patients to obtain hydrazine sulfate by legal means, though it is relatively easy to get on the alternative therapy black market. Now, it is finally undergoing the large-scale NCI-sponsored studies necessary for full scientific evaluation.

I began this chapter by comparing the outside track that Stanislaw Burzynski took with the inside track taken by Joseph Gold. Gold, who stayed inside the cancer establishment and played by the rules, has received little if any scientific credit for the decades of work that has brought hydrazine sulfate this far. But although Gold has not received the credit that is his due, by staying within the cancer establishment and playing by the rules, he has brought hydrazine sulfate significantly further than Burzynski has brought antineoplastons. And antineoplastons had the great additional benefit that they had all the early markings of a highly successful pharmaceutical product.

As this book was going to press, reports of negative findings in the multi- institutional trials of hydrazine sulfate began to appear. Gold and other advocates of the treatment responded to the negative findings with charges that there had been serious deficiencies in the methodology of the studies, an accusation that the researchers involved have denied. Analyzing the facts in this dispute will occupy the next phase in the controversy over hydrazine sulfate.20

References

1 Ralph W. Moss, The Cancer Industry (New York: Paragon House, 1989), 188.

2 Ibid., 188-9.

3 Ibid., 189.

4 Ibid., 189-90.

5 Manuel Ochoa et al., “Trial of Hydrazine Sulfate in Patients with Cancer,” Cancer Chemotherapy Reports Part 1 59(6):1151-4.

6 Moss, The Cancer Industry, 192.

7 Joseph Gold, “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).

8 Moss, The Cancer Industry, 194-5.

9 Joseph Gold, “Hydrazine Sulfate: A Current Perspective,” Nutrition and Cancer 9(2&3):59-66 (1987).

10 Ibid.

11 Moss, The Cancer Industry, 200-1.

12 Brett C. Sheppard et al., “Prolonged Survival of Tumor-Bearing Rats with Repetitive Low-Dose Recombinant Tumor Necrosis Factor,” Cancer Research 50:3931 (1990). See also, G. Darling, et al., “Cachectic Effects of Recombinant Human Tumor Necrosis Factor in Rats,” Cancer Research 50:4011 (1990).

13 Sandy Rovner, “For Cancer Drug, A Long Road to Recognition,” Washington Post, 17 May 1988.

14 Moss, The Cancer Industry, 206.

15 Rowan T. Chlebowski et al., “Hydrazine Sulfate in Cancer Patients with Weight Loss,” Cancer 59:406-10 (1987).

16 Rowan, Chlebowski et al., “Hydrazine Sulfate Influence on Nutritional Status and Survival in Non-Small-Cell Lung Cancer,” Journal of Clinical Oncology 8:9-15 (1990).

17 S. Piantadosi, “Hazards of Small Clinical Trials,” Journal of Clinical Oncology 8:1-3 (1990).

18 Gold, “Hydrazine Sulfate in Non-Small-Cell Lung Cancer,” Letter to the editor, Journal of Clinical Oncology 8:1117-8 (1990).

19 Joseph Gold, personal communication with the author, 12 November 1990.

20 Jeff Kamen, “Hope, Heartbreak and Horror,” Omni (September 1993).