2078
CORRESPONDENCE REFERENCES
1. Wils JA, Klein HO, Wagener DJTh, et al: Sequential high-dose methotrexate and fluorouracil combined with doxorubicin-A step ahead in the treatment of advanced gastric cancer: A trial of the European Organization for Research and Treatment of Cancer Gastrointestinal Tract Cooperative Group. J Clin Oncol 9:827-831, 1991 2. Biran H, Sulkes A, Biran S: 5-fluorouracil, doxorubicin (Adriamycin) and mitomycin-C (FAM) in advanced gastric cancer: Observations on response, patient characteristics, myelosuppression and delivered dosage. Oncology 46:83-87, 1989 3. Preusser P, Wilke H, Achterrath W, et al: Phase II study with the combination of etoposide, doxorubicin, and cisplatin in advanced measurable gastric cancer. J Clin Oncol 7:1310-1317, 1989 4. Preusser P, Achterrath W, Wilke H, et al: Chemotherapy of gastric cancer. Cancer Treat Rev 15:257-277, 1988
Reply To the Editor: We thank Drs Adenis and Bonneterre for their interesting remarks with regard to our study. They suggest that it cannot be excluded that the observed differences between FAM and FAMTX could in part be due to differences in prognostic factors. Multivariate analyses performed on our data indicate that the minor chance imbalances observed between the two treatment groups probably play no role in the apparent benefit of FAMTX. Of particular concern was the imbalance with regard to extent of disease, as more patients had primary and metastatic disease in place in the FAM group (50) than in the FAMTX group (38). The treatment comparison was, however, unchanged after adjusting for this imbalance through a stratified log-rank test (P = .002). In fact, the difference between FAMTX and FAM remained significant (P = .002) after adjustment for all known prognostic factors (extent of disease, performance status, weight loss, prior surgery, sex, and age) in a Cox regression model. These analyses were performed on the basis of complete survival information on almost all patients (176 deaths of 213 patients); thus, we can be confident that they will not be affected by further follow-up. With regard to the chemotherapy, it should be noted that one course of FAM covered 8 weeks, and one course of FAMTX covered 4 weeks. Therefore, the duration of chemotherapy in FAM was a median of 8 weeks (range, 4 to 48 weeks) and in FAMTX, a median of 16 weeks (range, 4 to 64 weeks). There was no major difference in the incidence of dose reduction or postponement of treatment. Patients treated with FAM simply progressed more rapidly. We did not find any major difference in metastatic sites between both groups of patients, nor could we confirm the data reported by Preusser et al' that patients with peritoneal metastases fare worse. However, this observation might be flawed because in our trial, patients with pleural or peritoneal effusions were only eligible in case these effusions could be adequately drawn to avoid methotrexate toxicity.
Finally, there was no difference in histologic subtypes in both arms of our trial, and we could not detect any difference in outcome between separate histologic types. J. Wils LaurentiusHospital Roermond, The Netherlands M. Buyse EORTC Data Center Brussels, Belgium H. Bleiberg InstituteJules Bordet Brussels, Belgium REFERENCE 1. Preusser P, Wilke H, Achterrath W, et al: Phase 11 study with the combination etoposide, doxorubicin, and cisplatin in advanced measurable gastric cancer. J Clin Oncol 7:1310-1317, 1989 Hepatic Resection in ColorectalCarcinoma and Survival To the Editor In the abstract of the report by Steele et al,' it is unsettling to read the untrue statement that, "Our results imply that curative resection leads to an increase in median survival." This study was not designed to test the value of surgical resection. Indeed, the authors acknowledge in their introduction that "This final question cannot be answered with anything less than a formal prospective trial in which surgically staged patients are randomized between those who undergo resection for cure of their liver metastases and those who have no resection." A true assessment of the results of this trial is that colorectal carcinoma patients with liver metastases that can be curatively resected live longer than those with metastases that cannot be removed completely. Whether the improved survival occurred as a result of the surgery or because resectability is a favorable prognostic factor independent of resection cannot be determined from this study. This valuable study was done well, provides much useful information, and was carefully and correctly Interpreted in the body of the report. It is unfortunate that the authors, the reviewers, and the editors have allowed a misstatement to stand in the abstract; it will now be quoted, incorrectly, as a justification for advocating resection of colorectal carcinoma liver metastases as a useful therapeutic procedure for improving the survival of these patients. Daniel E. Bergsagel Ontario CancerInstitute Pnncess MargaretHospital Toronto, Canada REFERENCE 1. Steele G Jr, Bleday R, Mayer RJ, et al: A prospective evaluation of hepatic resection for colorectal carcinoma metastases to the liver: Gastrointestinal Tumor Study Group protocol 6584. J Clin Oncol 9:1105-1112, 1991
Downloaded from ascopubs.org by UNIVERSITY of OTAGO on April 21, 2019 from 139.080.135.089 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
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Reply To the Editor: In his appropriate response to our somewhat hyperbolic abstract, Dr Bergsagel seems to imply a much more negative view (perhaps realistic would be a better word) of human nature than we have assumed. Quite simply, anyone who reads our full report is aware that a major stumbling block in the analysis of the benefit of hepatic resection for colorectal carcinoma metastases is our unfortunate inability to perform an adequately designed trial. We had hoped and perhaps even assumed that if the results of our study were to lead to therapy recommendations, such recommendations would be based on analysis after a complete reading of the report, including the data. Perhaps not. My solution to the generic problem suggested by Bergsagel, that is, people designing therapy recommendations based on abstracts, is that journals consider publishing reports with Materials and Methods and Results sections only. However, I have been assured by editors as well as publishers that this just wouldn't sell. Because of the design of our one-armed treatment plan, one can never go beyond implication concerning possible benefits of resecting hepatic metastases. However, if as we follow our group of patients who have been curatively resected we note a plateau in survival, then we will be able to imply that resection cures some small subset of patients with regionally recurrent colorectal cancer. Since no other therapy options have shown such a survival plateau, the crucial point is to select which patients should undergo curative resection and which should not. Presently, this is easier said than done. We appreciate the letter by Bergsagel and will be much more severe in our assessment of human nature in writing future abstracts. Glenn Steele, Jr New EnglandDeaconess Hospital Boston, MA
Clinical Use of Dronabinol To the Editor: Doblin and Kleiman' have noted that a significant number of physicians believe that smoked marijuana and/or oral synthetic dronabinol ([THC] Marinol; Unimed, Somerville, NJ) are effective antiemetic agents for patients on chemotherapy. Many also believe that smoked marijuana is more effective than Marinol. The results of the survey by Doblin and Kleiman have been used to fuel further the highly emotional controversy surrounding the legalization of marijuana. It is obvious from the survey that many oncologists perceive marijuana to be more effective than Marinol. However, it is not clear that even the 28% of the respondents who believed they knew enough to compare marijuana and Marinol had actually had enough experience with each to make an informed judgment. In reality, the data available on Marinol indicate that it is a highly effective agent, one with several benefits over mari-
juana, including the following: 1. Marinol has been proven to be an effective agent in oncology. The dozens of published papers and the Food and Drug Administration (FDA) approval are certainly evidence of this. Several clinical studies have shown Marinol to be at least as effective as marijuana in cancer patients, if not more so. This was the conclusion of a California study involving over 300 patients.2 Of patients receiving THC, 30% said it was very effective, as compared with only 17% of patients smoking marijuana. In a double-blind, crossover study of Marinol versus smoked marijuana in 20 patients, seven perferred Marinol, four marijuana, and nine had no preference.3 2. To date, there have been no comparative studies performed in acquired immune deficiency syndrome (AIDS) patients. However, work done on Marinol to date has shown it to be highly effective in increasing appetite and causing weight gain."' No data have been published or presented on the use of marijuana in AIDS. 3. Patients smoking marijuana receive a respiratory burden of four times as much particulate material and carbon monoxide as people smoking cigarettes.6 Although the development of lung cancer or atherosclerosis in the future may not be a concern in cancer or AIDS patients, further damage to already impaired respiratory and immune function in the lungs is a very real danger. This danger does not exist with Marinol. 4. Only Marinol is produced and sold under the requirements placed upon it by the FDA for meeting specific purity specifications, for manufacture under the rules of "Good Manufacturing Practice," and for strict quality control testing under the rules of "Good Laboratory Practice." Marijuana does not provide these protections. For example, its potency varies widely from batch to batch, and it contains various impurities. The purpose of these comments is not to enter the controversy regarding the legalization of marijuana. Rather, it is to point out that, contrary to some perceptions, there is a great deal of information suggesting that in most situations, Marinol will provide a safe, effective way of administering THC to patients. Terry F. Plasse Unimed, Inc Somerville, NJ REFERENCES 1. Doblin RE, Kleiman MAR: Marijuana as antiemetic medicine: A survey of oncologists' experiences and attitudes. J Clin Oncol 9:1314-1319 2. Research Advisory Panel: Seventeenth Annual Report of the Research Advisory Council. San Francisco, CA, Research Advisory Council, 1986 3. Levitt M, Fairman C, Hawks R, et al: Randomized double blind comparison of delta-9-tetrahydrocannabinol (THC) and marijuana as chemotherapy antiemetics. Proc Am Soc Clin Oncol 3:91, 1984 (abstr C-354) 4. Plasse TF, Gorter RW, Krasnow SH, et al: Clinical experience with dronabinol. Pharmacol Biochem Behav (in press)
Downloaded from ascopubs.org by UNIVERSITY of OTAGO on April 21, 2019 from 139.080.135.089 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
CORRESPONDENCE REFERENCES
1. Wils JA, Klein HO, Wagener DJTh, et al: Sequential high-dose methotrexate and fluorouracil combined with doxorubicin-A step ahead in the treatment of advanced gastric cancer: A trial of the European Organization for Research and Treatment of Cancer Gastrointestinal Tract Cooperative Group. J Clin Oncol 9:827-831, 1991 2. Biran H, Sulkes A, Biran S: 5-fluorouracil, doxorubicin (Adriamycin) and mitomycin-C (FAM) in advanced gastric cancer: Observations on response, patient characteristics, myelosuppression and delivered dosage. Oncology 46:83-87, 1989 3. Preusser P, Wilke H, Achterrath W, et al: Phase II study with the combination of etoposide, doxorubicin, and cisplatin in advanced measurable gastric cancer. J Clin Oncol 7:1310-1317, 1989 4. Preusser P, Achterrath W, Wilke H, et al: Chemotherapy of gastric cancer. Cancer Treat Rev 15:257-277, 1988
Reply To the Editor: We thank Drs Adenis and Bonneterre for their interesting remarks with regard to our study. They suggest that it cannot be excluded that the observed differences between FAM and FAMTX could in part be due to differences in prognostic factors. Multivariate analyses performed on our data indicate that the minor chance imbalances observed between the two treatment groups probably play no role in the apparent benefit of FAMTX. Of particular concern was the imbalance with regard to extent of disease, as more patients had primary and metastatic disease in place in the FAM group (50) than in the FAMTX group (38). The treatment comparison was, however, unchanged after adjusting for this imbalance through a stratified log-rank test (P = .002). In fact, the difference between FAMTX and FAM remained significant (P = .002) after adjustment for all known prognostic factors (extent of disease, performance status, weight loss, prior surgery, sex, and age) in a Cox regression model. These analyses were performed on the basis of complete survival information on almost all patients (176 deaths of 213 patients); thus, we can be confident that they will not be affected by further follow-up. With regard to the chemotherapy, it should be noted that one course of FAM covered 8 weeks, and one course of FAMTX covered 4 weeks. Therefore, the duration of chemotherapy in FAM was a median of 8 weeks (range, 4 to 48 weeks) and in FAMTX, a median of 16 weeks (range, 4 to 64 weeks). There was no major difference in the incidence of dose reduction or postponement of treatment. Patients treated with FAM simply progressed more rapidly. We did not find any major difference in metastatic sites between both groups of patients, nor could we confirm the data reported by Preusser et al' that patients with peritoneal metastases fare worse. However, this observation might be flawed because in our trial, patients with pleural or peritoneal effusions were only eligible in case these effusions could be adequately drawn to avoid methotrexate toxicity.
Finally, there was no difference in histologic subtypes in both arms of our trial, and we could not detect any difference in outcome between separate histologic types. J. Wils LaurentiusHospital Roermond, The Netherlands M. Buyse EORTC Data Center Brussels, Belgium H. Bleiberg InstituteJules Bordet Brussels, Belgium REFERENCE 1. Preusser P, Wilke H, Achterrath W, et al: Phase 11 study with the combination etoposide, doxorubicin, and cisplatin in advanced measurable gastric cancer. J Clin Oncol 7:1310-1317, 1989 Hepatic Resection in ColorectalCarcinoma and Survival To the Editor In the abstract of the report by Steele et al,' it is unsettling to read the untrue statement that, "Our results imply that curative resection leads to an increase in median survival." This study was not designed to test the value of surgical resection. Indeed, the authors acknowledge in their introduction that "This final question cannot be answered with anything less than a formal prospective trial in which surgically staged patients are randomized between those who undergo resection for cure of their liver metastases and those who have no resection." A true assessment of the results of this trial is that colorectal carcinoma patients with liver metastases that can be curatively resected live longer than those with metastases that cannot be removed completely. Whether the improved survival occurred as a result of the surgery or because resectability is a favorable prognostic factor independent of resection cannot be determined from this study. This valuable study was done well, provides much useful information, and was carefully and correctly Interpreted in the body of the report. It is unfortunate that the authors, the reviewers, and the editors have allowed a misstatement to stand in the abstract; it will now be quoted, incorrectly, as a justification for advocating resection of colorectal carcinoma liver metastases as a useful therapeutic procedure for improving the survival of these patients. Daniel E. Bergsagel Ontario CancerInstitute Pnncess MargaretHospital Toronto, Canada REFERENCE 1. Steele G Jr, Bleday R, Mayer RJ, et al: A prospective evaluation of hepatic resection for colorectal carcinoma metastases to the liver: Gastrointestinal Tumor Study Group protocol 6584. J Clin Oncol 9:1105-1112, 1991
Downloaded from ascopubs.org by UNIVERSITY of OTAGO on April 21, 2019 from 139.080.135.089 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
2079
CORRESPONDENCE
Reply To the Editor: In his appropriate response to our somewhat hyperbolic abstract, Dr Bergsagel seems to imply a much more negative view (perhaps realistic would be a better word) of human nature than we have assumed. Quite simply, anyone who reads our full report is aware that a major stumbling block in the analysis of the benefit of hepatic resection for colorectal carcinoma metastases is our unfortunate inability to perform an adequately designed trial. We had hoped and perhaps even assumed that if the results of our study were to lead to therapy recommendations, such recommendations would be based on analysis after a complete reading of the report, including the data. Perhaps not. My solution to the generic problem suggested by Bergsagel, that is, people designing therapy recommendations based on abstracts, is that journals consider publishing reports with Materials and Methods and Results sections only. However, I have been assured by editors as well as publishers that this just wouldn't sell. Because of the design of our one-armed treatment plan, one can never go beyond implication concerning possible benefits of resecting hepatic metastases. However, if as we follow our group of patients who have been curatively resected we note a plateau in survival, then we will be able to imply that resection cures some small subset of patients with regionally recurrent colorectal cancer. Since no other therapy options have shown such a survival plateau, the crucial point is to select which patients should undergo curative resection and which should not. Presently, this is easier said than done. We appreciate the letter by Bergsagel and will be much more severe in our assessment of human nature in writing future abstracts. Glenn Steele, Jr New EnglandDeaconess Hospital Boston, MA
Clinical Use of Dronabinol To the Editor: Doblin and Kleiman' have noted that a significant number of physicians believe that smoked marijuana and/or oral synthetic dronabinol ([THC] Marinol; Unimed, Somerville, NJ) are effective antiemetic agents for patients on chemotherapy. Many also believe that smoked marijuana is more effective than Marinol. The results of the survey by Doblin and Kleiman have been used to fuel further the highly emotional controversy surrounding the legalization of marijuana. It is obvious from the survey that many oncologists perceive marijuana to be more effective than Marinol. However, it is not clear that even the 28% of the respondents who believed they knew enough to compare marijuana and Marinol had actually had enough experience with each to make an informed judgment. In reality, the data available on Marinol indicate that it is a highly effective agent, one with several benefits over mari-
juana, including the following: 1. Marinol has been proven to be an effective agent in oncology. The dozens of published papers and the Food and Drug Administration (FDA) approval are certainly evidence of this. Several clinical studies have shown Marinol to be at least as effective as marijuana in cancer patients, if not more so. This was the conclusion of a California study involving over 300 patients.2 Of patients receiving THC, 30% said it was very effective, as compared with only 17% of patients smoking marijuana. In a double-blind, crossover study of Marinol versus smoked marijuana in 20 patients, seven perferred Marinol, four marijuana, and nine had no preference.3 2. To date, there have been no comparative studies performed in acquired immune deficiency syndrome (AIDS) patients. However, work done on Marinol to date has shown it to be highly effective in increasing appetite and causing weight gain."' No data have been published or presented on the use of marijuana in AIDS. 3. Patients smoking marijuana receive a respiratory burden of four times as much particulate material and carbon monoxide as people smoking cigarettes.6 Although the development of lung cancer or atherosclerosis in the future may not be a concern in cancer or AIDS patients, further damage to already impaired respiratory and immune function in the lungs is a very real danger. This danger does not exist with Marinol. 4. Only Marinol is produced and sold under the requirements placed upon it by the FDA for meeting specific purity specifications, for manufacture under the rules of "Good Manufacturing Practice," and for strict quality control testing under the rules of "Good Laboratory Practice." Marijuana does not provide these protections. For example, its potency varies widely from batch to batch, and it contains various impurities. The purpose of these comments is not to enter the controversy regarding the legalization of marijuana. Rather, it is to point out that, contrary to some perceptions, there is a great deal of information suggesting that in most situations, Marinol will provide a safe, effective way of administering THC to patients. Terry F. Plasse Unimed, Inc Somerville, NJ REFERENCES 1. Doblin RE, Kleiman MAR: Marijuana as antiemetic medicine: A survey of oncologists' experiences and attitudes. J Clin Oncol 9:1314-1319 2. Research Advisory Panel: Seventeenth Annual Report of the Research Advisory Council. San Francisco, CA, Research Advisory Council, 1986 3. Levitt M, Fairman C, Hawks R, et al: Randomized double blind comparison of delta-9-tetrahydrocannabinol (THC) and marijuana as chemotherapy antiemetics. Proc Am Soc Clin Oncol 3:91, 1984 (abstr C-354) 4. Plasse TF, Gorter RW, Krasnow SH, et al: Clinical experience with dronabinol. Pharmacol Biochem Behav (in press)
Downloaded from ascopubs.org by UNIVERSITY of OTAGO on April 21, 2019 from 139.080.135.089 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
