1117
CORRESPONDENCE
Hydrazine Sulfate in Nonsmall-Cell Lung Cancer To the Editor: In regard to the editorial, "Hazards of Small Clinical Trials," by Steven Piantadosi that appeared in the Journalof Clinical Oncology,' Piantadosi takes issue with the report by Chlebowski et al, 2 on the basis of the number of patients65-in this randomized, prospective placebo-controlled trial and therefore the inherent statistical vagueries and uncertainties in such "small" studies. He restricts his criticisms entirely to the Chlebowski study and his remarks wholly to "hydrazine sulfate." However, in that very issue of the Journal, 12 out of a total of 22 papers-or 54.5%o--were of studies using less patients than in the Chlebowski' study; such studies report 15, 23, 24, 29, 30, 31, 31, 40, 40, 43, 49, and 51 patients, in order of ascending number. Yet, there was nary a word of criticism of these studies or any conclusions they reached. Specifically, Piantadosi expresses reservations with the Chlebowski report's design and possible inherent statistical weaknesses. Yet this study's design is very similar to that of many studies, including the National Cancer Institute's ongoing phase III multicentric study of hydrazine sulfate in nonsmall-cell lung cancer patients, using almost congruent 3 statistical methodology. Indeed, further on in the editorial, Piantadosi affirms that "the basic design of the Chlebowski et al trial is sound." Piantadosi states, "When true-positive results are sufficiently uncommon, most positive results are false ones." Thus he implies that true-positive results with hydrazine sulfate are uncommon. Nothing can be further from fact. In 1975, Gold 4 published a study of 84 assessable patients that demonstrated anticachexia and antitumor effects. In 1981, 5 Gershanovich et al published a study of 225 assessable patients that demonstrated anticachexia, tumor-stabilization, and tumor-regression response; in 1983, this study was extended to 356 assessable patients, in which increased 6 patient survival was additionally demonstrated. In 1984 and 8 7 in 1987, respectively, Chlebowski et a1 and Tayek et al, in randomized, prospective, placebo-controlled trials demonstrated normalization of abnormal carbohydrate and protein parameters by hydrazine sulfate in advanced cancer patients. 9 In 1987, Chlebowski et al, in a randomized, prospective, maintenance of body trial, demonstrated placebo-controlled weight in advanced cancer patients with progressive weight loss by hydrazine sulfate. Nor has there been a shortage of recent preclinical papers demonstrating "true-positive" results of hydrazine sulfate; these include effects on glucoseand lipid-regulating enzymes, modulation of endotoxin lethal4 ity in mice, and synergism with tumor necrosis factor.'"' In contrast, there have been only three small negative studies of 25, 25, and 29 heavily pretreated patients, respectively, reported in 1975 to 1979.5-17 Thus Piantadosi's phrase, "true-positive results are sufficiently uncommon" in regard to hydrazine sulfate, cannot be supported by the scientific literature. The editorial by Piantadosi implicating small studies to be inherently faultful simply by virtue of their size inveighs against the validity of the majority of studies, since many if not most studies are of the small size. 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. Joseph Gold Syracuse Cancer Research Institute, Inc Syracuse, NY REFERENCES 1. Piantadosi S: Hazards of small clinical trials. J Clin Oncol 8:1-3, 1990 (editorial) 2. Chlebowski RT, Bulcagage L, Grosvenor M: Hydrazine sulfate influence on nutritional status and survival in nonsmallcell lung cancer. J Clin Oncol 8:9-15, 1990 3. Kosty MP (chair): Cisplatin, vinblastine and hydrazine sulfate (NSC #150014) in advanced non-small cell lung cancer (NSCLC): A randomized, placebo controlled, double blind phase III study. National Cancer Institute, CALGB, activated July 25, 1989 4. Gold J: Use of hydrazine sulfate in terminal and preterminal cancer patients: Results of investigational new drug (IND) study in 84 evaluable patients. Oncology 32:110, 1975 5. Gershanovich ML, Danova LA, Ivin BA, et al: Results of clinical study of antitumor action of hydrazine sulfate. Nutr Cancer 3:7-12, 1981 6. Filov VA, Danova LA, Gershanovich ML, et al: Hydrazine sulfate: Experimental and clinical results, mechanism of action, in Filov VA, Ivin BA, Gershanovich ML (eds): Medical Therapy of Tumors. Leningrad, Union of Soviet Socialist Republics, USSR Ministry of Health, 1983, pp 92-139 7. Chlebowski RT, Heber D, Richardson B, et al: Influence of hydrazine sulfate on abnormal carbohydrate metabolism in cancer patients with weight loss. Cancer Res 44:857861, 1984 8. Tayek JA, Heber D, Chlebowski RT: Effect of hydrazine sulphate on whole-body protein breakdown measured by "4C-lysine metabolism in lung cancer patients. Lancet 2:241244, 1987 9. Chlebowski RT, Bulcavage L, Grosvenor M, et al: Hydrazine sulfate in cancer patients with weight loss. Cancer 59:406-410, 1987 10. Markosyan KA, Paityan NA, Nalbandyan RM: Influence of hydrazine on properties of cytochrome oxidase. Biochemistry USSR 53:985-991, 1988 11. Preece NE, Timbrell JA: Investigation of lipid peroxidation by hydrazine compounds in vivo in the rat. Pharmacol Toxicol 64:282-285, 1989 12. Silverstein R, Bhatia P, Svoboda DJ: Effect of hydrazine sulfate on glucose-regulating enzymes in the normal and cancerous rat. Immunopharmacol 17:37-43, 1989 13. Silverstein R, Christoffersen CA, Morrison DC: Modulation of endotoxin lethality in mice by hydrazine sulfate. Infect Immun 57:2072-2078, 1989 14. Hughes TK, Cadet P, Larned CS: Modulation of tumor necrosis factor activities by a potential anticachexia compound, hydrazine sulfate. Int J Immunopharmac 11:501507, 1989 15. Ochoa M, Wittes R, Krakoff I: Trial of hydrazine sulfate (NSC 150014) in patients with cancer. Cancer Chemother Rep 59:1151-1153, 1975 16. Lerner HJ, Regelson W: Clinical trial of hydrazine sulfate in solid tumors. Cancer Treat Rep 60:959-960, 1976
Downloaded from ascopubs.org by UNIVERSITY LIVERPOOL on April 21, 2019 from 154.059.124.102 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
1118
CORRESPONDENCE
17. Spremulli E, Wampler GL, Regelson W: Clinical study of hydrazine sulfate in advanced cancer patients. Cancer Chemother Pharmacol 3:121-124, 1979 Reply To the Editor:. Much of my editorial' was concerned with some serious general methodologic problems of clinical trials, many of which were present in the Chlebowski et al2 report. Many of these problems were avoidable, and all make it difficult to evaluate the underlying therapeutic efficacy of hydrazine sulfate. Dr Gold complains that my criticisms of Chlebowski et al are unfair because (1) many studies, including half of those in the same issue of the Journal of Clinical Oncology, are small, (2) studies using a similar design are being used elsewhere, (3) true-positive results attributable to hydrazine sulfate are already known, and (4) these criticisms could refer to the majority of studies. I will reply to each of these in turn. The smallness of some clinical studies does limit their usefulness. For example, contrast the implications that can be drawn from a single case report with the information available from a large randomized trial or other cohort study. On the other hand, a small comparative clinical trial, properly done with a highly statistically significant result, points to the likely presence of a large treatment effect. This evidence can be quite useful. Although there were a number of small studies in the January 1990 issue of the Journal,the question is not so much their size but the strength of their design, the robustness of their analysis, and the scope of their conclusions. There were four reports invoking the merits of a "randomized prospective clinical trial" in that issue. It is noteworthy that the reported sample sizes were 65, 231, 400, and 92. The combination of small size and casual analysis is particularly error prone. In any case, investigators are justified in demanding rigor from this methodology and in critically analyzing whatever is in print. There is no question that other investigations should and do use methods similar to Chlebowski et al. However, the use of randomization, concurrent controls, blinding, and statistical tests neither guarantees the legitimacy of the applications nor the validity of the conclusions. While the basic design concept for the Chlebowski et al study was sound, this merely indicates that a reasonable analysis can be performed, not that it actually was. Although the National Cancer Institute's (NCI's) phase III trial uses similar design features, it has a target sample size of 270 patients, four times larger than Chlebowski et al. This is hardly "congruent statistical methodology," especially not if the NCI study uses a rigorous analysis. Gold asserts in a variety of ways that true-positive results are known to exist for hydrazine sulfate. I am puzzled as to how this assertion can be made. Evidently, others are as well because of the ongoing randomized clinical trial addressing the issue. If the efficacy of hydrazine sulfate is already firmly established, then Gold should argue against additional comparative trials, even small ones. I am confident that Gold's assertions are those of bias and not of fact. Gold states that my criticism "inveighs against the validity of the majority of clinical studies." This may or may not be the case. However, the fact that some investigations are poorly done does not justify the flaws in other studies. Finally, hydrazine sulfate could be effective therapy. I
hope that the NCI trial helps to answer this question. Unfortunately, the Chlebowski et al report and Dr Gold's letter do not. Steven Piantadosi The JohnsHopkins Oncology Center Baltimore, MD REFERENCES 1. Piantadosi S: Hazards of small clinical trials. J Clin Oncol 8:1-3, 1990 (editorial) 2. Chlebowski RT, Bulcagage L, Grosvenor M: Hydrazine sulfate influence on nutritional status and survival in nonsmallcell lung cancer. J Clin Oncol 8:9-15, 1990
Inadvertant Omission of Leucovorin Rescue in a Report on Treatment of GastricLymphoma To the Editor: In the report by Maor et al on the treatment of gastric non-Hodgkin's lymphomas, they report that three of their patients received a regimen containing high-dose methotrexate (1,000 mg/m2). However, it is not clear from the text what day the methotrexate was given, nor is leucovorin mentioned as part of the regimen. Since methotrexate 1,000 mg/m 2 is lethal without leucovorin rescue, I assume that this was an inadvertant omission-I hope that no one will use the regimen as printed. Incidentally, I find the omission particularly ironic in an issue in which the lead editorial concerns leucovorin rescue. 2 James Lin MemorialSloan-KetteringCancer Center New York, NY REFERENCES 1. Maor MH, Velasquez WS, Fuller LM, et al: Stomach conservation in stage IE and IIE gastric non-Hodgkin's lymphoma. J Clin Oncol 8:266-271, 1990 2. Bertino JR: Leucovorin rescue revisited. J Clin Oncol 8:193-195, 1990
PrognosticSignificance of Staging in Gastric Lymphoma To the Editor: In reference to the report advocating stomach conservation in patients with stage IE and IIE gastric lymphoma published in the Journal of Clinical Oncology, Maor et al have presented a provocative analysis of the use of combination chemotherapy in a tumor where the definitive treatment remains poorly defined. Nevertheless, their contention that "surgery is not a necessary procedure in gastric lymphoma" may be premature from the data presented in the study. First, the use of the Ann Arbor staging classification may be suboptimal in these patients because of failure to address the issue of the extent of lymph node involvement. The Musshoff staging scheme, which defines stage IIE' as including gastric lymphomas with positive regional (perigastric, mesenteric) lymph nodes and stage IIE2 as including those cases with extraregional (paraaortic, iliac, etc) nodal involvement, may be more appropriate. 2 Other investigators have shown that the extent of nodal involvement is a significant prognostic
Downloaded from ascopubs.org by UNIVERSITY LIVERPOOL on April 21, 2019 from 154.059.124.102 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
CORRESPONDENCE
Hydrazine Sulfate in Nonsmall-Cell Lung Cancer To the Editor: In regard to the editorial, "Hazards of Small Clinical Trials," by Steven Piantadosi that appeared in the Journalof Clinical Oncology,' Piantadosi takes issue with the report by Chlebowski et al, 2 on the basis of the number of patients65-in this randomized, prospective placebo-controlled trial and therefore the inherent statistical vagueries and uncertainties in such "small" studies. He restricts his criticisms entirely to the Chlebowski study and his remarks wholly to "hydrazine sulfate." However, in that very issue of the Journal, 12 out of a total of 22 papers-or 54.5%o--were of studies using less patients than in the Chlebowski' study; such studies report 15, 23, 24, 29, 30, 31, 31, 40, 40, 43, 49, and 51 patients, in order of ascending number. Yet, there was nary a word of criticism of these studies or any conclusions they reached. Specifically, Piantadosi expresses reservations with the Chlebowski report's design and possible inherent statistical weaknesses. Yet this study's design is very similar to that of many studies, including the National Cancer Institute's ongoing phase III multicentric study of hydrazine sulfate in nonsmall-cell lung cancer patients, using almost congruent 3 statistical methodology. Indeed, further on in the editorial, Piantadosi affirms that "the basic design of the Chlebowski et al trial is sound." Piantadosi states, "When true-positive results are sufficiently uncommon, most positive results are false ones." Thus he implies that true-positive results with hydrazine sulfate are uncommon. Nothing can be further from fact. In 1975, Gold 4 published a study of 84 assessable patients that demonstrated anticachexia and antitumor effects. In 1981, 5 Gershanovich et al published a study of 225 assessable patients that demonstrated anticachexia, tumor-stabilization, and tumor-regression response; in 1983, this study was extended to 356 assessable patients, in which increased 6 patient survival was additionally demonstrated. In 1984 and 8 7 in 1987, respectively, Chlebowski et a1 and Tayek et al, in randomized, prospective, placebo-controlled trials demonstrated normalization of abnormal carbohydrate and protein parameters by hydrazine sulfate in advanced cancer patients. 9 In 1987, Chlebowski et al, in a randomized, prospective, maintenance of body trial, demonstrated placebo-controlled weight in advanced cancer patients with progressive weight loss by hydrazine sulfate. Nor has there been a shortage of recent preclinical papers demonstrating "true-positive" results of hydrazine sulfate; these include effects on glucoseand lipid-regulating enzymes, modulation of endotoxin lethal4 ity in mice, and synergism with tumor necrosis factor.'"' In contrast, there have been only three small negative studies of 25, 25, and 29 heavily pretreated patients, respectively, reported in 1975 to 1979.5-17 Thus Piantadosi's phrase, "true-positive results are sufficiently uncommon" in regard to hydrazine sulfate, cannot be supported by the scientific literature. The editorial by Piantadosi implicating small studies to be inherently faultful simply by virtue of their size inveighs against the validity of the majority of studies, since many if not most studies are of the small size. 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. Joseph Gold Syracuse Cancer Research Institute, Inc Syracuse, NY REFERENCES 1. Piantadosi S: Hazards of small clinical trials. J Clin Oncol 8:1-3, 1990 (editorial) 2. Chlebowski RT, Bulcagage L, Grosvenor M: Hydrazine sulfate influence on nutritional status and survival in nonsmallcell lung cancer. J Clin Oncol 8:9-15, 1990 3. Kosty MP (chair): Cisplatin, vinblastine and hydrazine sulfate (NSC #150014) in advanced non-small cell lung cancer (NSCLC): A randomized, placebo controlled, double blind phase III study. National Cancer Institute, CALGB, activated July 25, 1989 4. Gold J: Use of hydrazine sulfate in terminal and preterminal cancer patients: Results of investigational new drug (IND) study in 84 evaluable patients. Oncology 32:110, 1975 5. Gershanovich ML, Danova LA, Ivin BA, et al: Results of clinical study of antitumor action of hydrazine sulfate. Nutr Cancer 3:7-12, 1981 6. Filov VA, Danova LA, Gershanovich ML, et al: Hydrazine sulfate: Experimental and clinical results, mechanism of action, in Filov VA, Ivin BA, Gershanovich ML (eds): Medical Therapy of Tumors. Leningrad, Union of Soviet Socialist Republics, USSR Ministry of Health, 1983, pp 92-139 7. Chlebowski RT, Heber D, Richardson B, et al: Influence of hydrazine sulfate on abnormal carbohydrate metabolism in cancer patients with weight loss. Cancer Res 44:857861, 1984 8. Tayek JA, Heber D, Chlebowski RT: Effect of hydrazine sulphate on whole-body protein breakdown measured by "4C-lysine metabolism in lung cancer patients. Lancet 2:241244, 1987 9. Chlebowski RT, Bulcavage L, Grosvenor M, et al: Hydrazine sulfate in cancer patients with weight loss. Cancer 59:406-410, 1987 10. Markosyan KA, Paityan NA, Nalbandyan RM: Influence of hydrazine on properties of cytochrome oxidase. Biochemistry USSR 53:985-991, 1988 11. Preece NE, Timbrell JA: Investigation of lipid peroxidation by hydrazine compounds in vivo in the rat. Pharmacol Toxicol 64:282-285, 1989 12. Silverstein R, Bhatia P, Svoboda DJ: Effect of hydrazine sulfate on glucose-regulating enzymes in the normal and cancerous rat. Immunopharmacol 17:37-43, 1989 13. Silverstein R, Christoffersen CA, Morrison DC: Modulation of endotoxin lethality in mice by hydrazine sulfate. Infect Immun 57:2072-2078, 1989 14. Hughes TK, Cadet P, Larned CS: Modulation of tumor necrosis factor activities by a potential anticachexia compound, hydrazine sulfate. Int J Immunopharmac 11:501507, 1989 15. Ochoa M, Wittes R, Krakoff I: Trial of hydrazine sulfate (NSC 150014) in patients with cancer. Cancer Chemother Rep 59:1151-1153, 1975 16. Lerner HJ, Regelson W: Clinical trial of hydrazine sulfate in solid tumors. Cancer Treat Rep 60:959-960, 1976
Downloaded from ascopubs.org by UNIVERSITY LIVERPOOL on April 21, 2019 from 154.059.124.102 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
1118
CORRESPONDENCE
17. Spremulli E, Wampler GL, Regelson W: Clinical study of hydrazine sulfate in advanced cancer patients. Cancer Chemother Pharmacol 3:121-124, 1979 Reply To the Editor:. Much of my editorial' was concerned with some serious general methodologic problems of clinical trials, many of which were present in the Chlebowski et al2 report. Many of these problems were avoidable, and all make it difficult to evaluate the underlying therapeutic efficacy of hydrazine sulfate. Dr Gold complains that my criticisms of Chlebowski et al are unfair because (1) many studies, including half of those in the same issue of the Journal of Clinical Oncology, are small, (2) studies using a similar design are being used elsewhere, (3) true-positive results attributable to hydrazine sulfate are already known, and (4) these criticisms could refer to the majority of studies. I will reply to each of these in turn. The smallness of some clinical studies does limit their usefulness. For example, contrast the implications that can be drawn from a single case report with the information available from a large randomized trial or other cohort study. On the other hand, a small comparative clinical trial, properly done with a highly statistically significant result, points to the likely presence of a large treatment effect. This evidence can be quite useful. Although there were a number of small studies in the January 1990 issue of the Journal,the question is not so much their size but the strength of their design, the robustness of their analysis, and the scope of their conclusions. There were four reports invoking the merits of a "randomized prospective clinical trial" in that issue. It is noteworthy that the reported sample sizes were 65, 231, 400, and 92. The combination of small size and casual analysis is particularly error prone. In any case, investigators are justified in demanding rigor from this methodology and in critically analyzing whatever is in print. There is no question that other investigations should and do use methods similar to Chlebowski et al. However, the use of randomization, concurrent controls, blinding, and statistical tests neither guarantees the legitimacy of the applications nor the validity of the conclusions. While the basic design concept for the Chlebowski et al study was sound, this merely indicates that a reasonable analysis can be performed, not that it actually was. Although the National Cancer Institute's (NCI's) phase III trial uses similar design features, it has a target sample size of 270 patients, four times larger than Chlebowski et al. This is hardly "congruent statistical methodology," especially not if the NCI study uses a rigorous analysis. Gold asserts in a variety of ways that true-positive results are known to exist for hydrazine sulfate. I am puzzled as to how this assertion can be made. Evidently, others are as well because of the ongoing randomized clinical trial addressing the issue. If the efficacy of hydrazine sulfate is already firmly established, then Gold should argue against additional comparative trials, even small ones. I am confident that Gold's assertions are those of bias and not of fact. Gold states that my criticism "inveighs against the validity of the majority of clinical studies." This may or may not be the case. However, the fact that some investigations are poorly done does not justify the flaws in other studies. Finally, hydrazine sulfate could be effective therapy. I
hope that the NCI trial helps to answer this question. Unfortunately, the Chlebowski et al report and Dr Gold's letter do not. Steven Piantadosi The JohnsHopkins Oncology Center Baltimore, MD REFERENCES 1. Piantadosi S: Hazards of small clinical trials. J Clin Oncol 8:1-3, 1990 (editorial) 2. Chlebowski RT, Bulcagage L, Grosvenor M: Hydrazine sulfate influence on nutritional status and survival in nonsmallcell lung cancer. J Clin Oncol 8:9-15, 1990
Inadvertant Omission of Leucovorin Rescue in a Report on Treatment of GastricLymphoma To the Editor: In the report by Maor et al on the treatment of gastric non-Hodgkin's lymphomas, they report that three of their patients received a regimen containing high-dose methotrexate (1,000 mg/m2). However, it is not clear from the text what day the methotrexate was given, nor is leucovorin mentioned as part of the regimen. Since methotrexate 1,000 mg/m 2 is lethal without leucovorin rescue, I assume that this was an inadvertant omission-I hope that no one will use the regimen as printed. Incidentally, I find the omission particularly ironic in an issue in which the lead editorial concerns leucovorin rescue. 2 James Lin MemorialSloan-KetteringCancer Center New York, NY REFERENCES 1. Maor MH, Velasquez WS, Fuller LM, et al: Stomach conservation in stage IE and IIE gastric non-Hodgkin's lymphoma. J Clin Oncol 8:266-271, 1990 2. Bertino JR: Leucovorin rescue revisited. J Clin Oncol 8:193-195, 1990
PrognosticSignificance of Staging in Gastric Lymphoma To the Editor: In reference to the report advocating stomach conservation in patients with stage IE and IIE gastric lymphoma published in the Journal of Clinical Oncology, Maor et al have presented a provocative analysis of the use of combination chemotherapy in a tumor where the definitive treatment remains poorly defined. Nevertheless, their contention that "surgery is not a necessary procedure in gastric lymphoma" may be premature from the data presented in the study. First, the use of the Ann Arbor staging classification may be suboptimal in these patients because of failure to address the issue of the extent of lymph node involvement. The Musshoff staging scheme, which defines stage IIE' as including gastric lymphomas with positive regional (perigastric, mesenteric) lymph nodes and stage IIE2 as including those cases with extraregional (paraaortic, iliac, etc) nodal involvement, may be more appropriate. 2 Other investigators have shown that the extent of nodal involvement is a significant prognostic
Downloaded from ascopubs.org by UNIVERSITY LIVERPOOL on April 21, 2019 from 154.059.124.102 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
