672
CORRESPONDENCE
neuroblastoma and malignant melanoma. J Clin Oncol 5:14301440, 1987
Interferon Beta for Malignant Glioma To the Editor:We read with interest the recent paper by Yung et al reporting the results of a phase I and II study of intravenous recombinant interferon-p (INF-P) for patients with recurrent malignant gliomas.' This concise, well-written report indicates that recombinant INF-0 administered in the dose and schedule described has antiglioma activity. Two questions came to mind as we read the article. First, did the two anaplastic oligodendrogliomas respond to interferon, and if so, to what degree and for how long? We, and others, have observed that recurrent anaplastic oligodendrogliomas often respond dramatically to nitrosourea-based chemotherapy with complete, or near complete, regression of large enhancing tumors. 23 More detailed information about these patients would be appreciated. Second, were the response criteria used in this report sufficiently rigorous? Is a 25% reduction in tumor volume a meaningful decrease in tumor size? Given observer error and other "noise in the system" many would be skeptical. A spherical tumor with a diameter of 4 cm has a volume of 33.5 cm 3. A 25% reduction in volume to 25.1 cm 3 reduces the diameter by only 0.4 cm (ie, to 3.6 cm). This translates into a 19% reduction in maximum cross-sectional area as traditionally measured (ie, maximum cross-sectional diameter x maximum diameter perpendicular to it). Patients entering onto this study had enlarging tumors; however, if they required steroids for symptom control, was a new baseline scan (on steroids) obtained before starting recombinant INF-P? If not, minor reductions in tumor size could simply be a steroid effect. 4 Yung et al also imply that stable disease is evidence of treatment effect, but is it? For better or worse, we have made recent recommends that investigators treating glioma with investigational drugs adopt uniform and more rigorous response criteria for phase II studies.' No criteria are perfect or apply to all situations, but less rigorous criteria may lead to a false sense of progress. It is our belief that this has been a particular problem in the brain tumor field. J. Gregory Cairncross David R. Macdonald London Regional CancerCentre London, Canada REFERENCES 1. Yung WKA, Prados M, Levin VA, et al: Intravenous recombinant interferon beta in patients with recurrent malignant gliomas: A phase I/II study. J Clin Oncol 9:1945-1949, 1991 2. Cairncross JG, Macdonald DR: Successful chemotherapy for malignant oligodendroglioma. Ann Neurol 23:360-364, 1988 3. Macdonald DR, Gaspar LE, Cairncross JG: Successful chemotherapy for newly diagnosed aggressive oligodendroglioma. Ann Neurol 27:573-574, 1990 4. Cairncross JG, Macdonald DR, Pexman JHW, et al: Steroidinduced CT scan changes in patients with recurrent malignant glioma. Neurology 38:724-726, 1988 5. Macdonald DR, Cascino TL, Schold SC, et al: Response criteria for phase II studies of malignant glioma. J Clin Oncol 8:1277-1280, 1990 In Reply: We appreciate Drs Cairncross and Macdonald's thoughtful letter. Unfortunately, the two anaplastic oligodendrogliomas
did not respond to INF-P13. However, this may not be too surprising because patients entered onto the INF-1 protocol all have had prior radiation therapy and chemotherapy. Secondly, the response criteria is based on cross-sectional diameter and not on tumor volume. All x-rays were reviewed by three independent observers. Initially, responses were tabulated according to the National Cancer Institute criteria of partial response (PR), minor response (MR), and stable disease (S). The PRs and MRs were reported as responses [R], as generally used in other brain tumor reports. At the time of response consideration, all responders must be on a stable or decreased dose of corticosteroids to avoid minor responses from steroid therapy as mentioned by Cairncross and Macdonald. As to the questions of patients in the S category, it is our experience that patients with S do have a longer survival than patients with progressive disease. Thus it is reasonable for them to be considered in the R category as long as they are clearly identified as patients with S rather than objective response. Finally, we fully agree with Cairncross and Macdonald that investigators treating brain tumors with investigational drugs should adopt uniform response criteria so that reports from different institutions can be compared easily. W.K. Alfred Yung The University of Texas M.D. Anderson CancerCenter Houston, TX
Oncologists and Clinical Trials: The Profit Motive To the Editor: We read with great interest the study by Benson et al' and the accompanying editorial2 on the accrual of patients to clinical trials. We believe that an important part of physician reluctance to enter patients onto clinical trial has been overlooked in this study-the profit motive. Physicians are not immune to the profit motive. They make career choices at least partly based on income and lifestyle. Doctors who have a direct financial incentive use more radiographs and laboratory tests than those who do not.) Both hospitals and physicians now recognize a profit motive as a substantial determinant in the amount of care offered to and received by patients.4-6 Oncologists are not immune to the profit motive either. We are not suggesting that the oncologist maximizes his or her income from each patient. The adjuvant treatment of breast and colorectal cancer patients constitutes a substantial portion of a practice volume. Because the patients are young, enthusiastic, and the service is well reimbursed, oncologists would be foolish to transfer the care to the nearest cancer center. Until we recognize this fact, we will be missing an important reason why patients are not referred for clinical trials. Given the community-physician viewpoint that clinical trials provide no better care than standard,' it will be hard to overcome this formidable barrier. There is no easy solution to this dilemma. Not all offices can use a data manager, yet this is the only way that adequate data can be collected. Not all oncologists are willing (or able) to forego income for the sake of clinical trials. The use of finder's fees or incentive payments to replace the lost revenue to practicing oncologists could be tried, but this would be a short-term solution at best. It would dramatically change referral patterns away from community practitioners and to cancer centers, at a time when diffusion to the community is a major goal of the National Cancer Institute. We should not assume that the reimbursement industry will be a willing partner in the switch, given that the cost of a clinical trial may be substantially higher than standard care.7 We have three concrete suggestions. First, let's examine the
Downloaded from ascopubs.org by RB DRAUGHTON LIBRARY on April 28, 2019 from 131.204.073.184 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
CORRESPONDENCE
neuroblastoma and malignant melanoma. J Clin Oncol 5:14301440, 1987
Interferon Beta for Malignant Glioma To the Editor:We read with interest the recent paper by Yung et al reporting the results of a phase I and II study of intravenous recombinant interferon-p (INF-P) for patients with recurrent malignant gliomas.' This concise, well-written report indicates that recombinant INF-0 administered in the dose and schedule described has antiglioma activity. Two questions came to mind as we read the article. First, did the two anaplastic oligodendrogliomas respond to interferon, and if so, to what degree and for how long? We, and others, have observed that recurrent anaplastic oligodendrogliomas often respond dramatically to nitrosourea-based chemotherapy with complete, or near complete, regression of large enhancing tumors. 23 More detailed information about these patients would be appreciated. Second, were the response criteria used in this report sufficiently rigorous? Is a 25% reduction in tumor volume a meaningful decrease in tumor size? Given observer error and other "noise in the system" many would be skeptical. A spherical tumor with a diameter of 4 cm has a volume of 33.5 cm 3. A 25% reduction in volume to 25.1 cm 3 reduces the diameter by only 0.4 cm (ie, to 3.6 cm). This translates into a 19% reduction in maximum cross-sectional area as traditionally measured (ie, maximum cross-sectional diameter x maximum diameter perpendicular to it). Patients entering onto this study had enlarging tumors; however, if they required steroids for symptom control, was a new baseline scan (on steroids) obtained before starting recombinant INF-P? If not, minor reductions in tumor size could simply be a steroid effect. 4 Yung et al also imply that stable disease is evidence of treatment effect, but is it? For better or worse, we have made recent recommends that investigators treating glioma with investigational drugs adopt uniform and more rigorous response criteria for phase II studies.' No criteria are perfect or apply to all situations, but less rigorous criteria may lead to a false sense of progress. It is our belief that this has been a particular problem in the brain tumor field. J. Gregory Cairncross David R. Macdonald London Regional CancerCentre London, Canada REFERENCES 1. Yung WKA, Prados M, Levin VA, et al: Intravenous recombinant interferon beta in patients with recurrent malignant gliomas: A phase I/II study. J Clin Oncol 9:1945-1949, 1991 2. Cairncross JG, Macdonald DR: Successful chemotherapy for malignant oligodendroglioma. Ann Neurol 23:360-364, 1988 3. Macdonald DR, Gaspar LE, Cairncross JG: Successful chemotherapy for newly diagnosed aggressive oligodendroglioma. Ann Neurol 27:573-574, 1990 4. Cairncross JG, Macdonald DR, Pexman JHW, et al: Steroidinduced CT scan changes in patients with recurrent malignant glioma. Neurology 38:724-726, 1988 5. Macdonald DR, Cascino TL, Schold SC, et al: Response criteria for phase II studies of malignant glioma. J Clin Oncol 8:1277-1280, 1990 In Reply: We appreciate Drs Cairncross and Macdonald's thoughtful letter. Unfortunately, the two anaplastic oligodendrogliomas
did not respond to INF-P13. However, this may not be too surprising because patients entered onto the INF-1 protocol all have had prior radiation therapy and chemotherapy. Secondly, the response criteria is based on cross-sectional diameter and not on tumor volume. All x-rays were reviewed by three independent observers. Initially, responses were tabulated according to the National Cancer Institute criteria of partial response (PR), minor response (MR), and stable disease (S). The PRs and MRs were reported as responses [R], as generally used in other brain tumor reports. At the time of response consideration, all responders must be on a stable or decreased dose of corticosteroids to avoid minor responses from steroid therapy as mentioned by Cairncross and Macdonald. As to the questions of patients in the S category, it is our experience that patients with S do have a longer survival than patients with progressive disease. Thus it is reasonable for them to be considered in the R category as long as they are clearly identified as patients with S rather than objective response. Finally, we fully agree with Cairncross and Macdonald that investigators treating brain tumors with investigational drugs should adopt uniform response criteria so that reports from different institutions can be compared easily. W.K. Alfred Yung The University of Texas M.D. Anderson CancerCenter Houston, TX
Oncologists and Clinical Trials: The Profit Motive To the Editor: We read with great interest the study by Benson et al' and the accompanying editorial2 on the accrual of patients to clinical trials. We believe that an important part of physician reluctance to enter patients onto clinical trial has been overlooked in this study-the profit motive. Physicians are not immune to the profit motive. They make career choices at least partly based on income and lifestyle. Doctors who have a direct financial incentive use more radiographs and laboratory tests than those who do not.) Both hospitals and physicians now recognize a profit motive as a substantial determinant in the amount of care offered to and received by patients.4-6 Oncologists are not immune to the profit motive either. We are not suggesting that the oncologist maximizes his or her income from each patient. The adjuvant treatment of breast and colorectal cancer patients constitutes a substantial portion of a practice volume. Because the patients are young, enthusiastic, and the service is well reimbursed, oncologists would be foolish to transfer the care to the nearest cancer center. Until we recognize this fact, we will be missing an important reason why patients are not referred for clinical trials. Given the community-physician viewpoint that clinical trials provide no better care than standard,' it will be hard to overcome this formidable barrier. There is no easy solution to this dilemma. Not all offices can use a data manager, yet this is the only way that adequate data can be collected. Not all oncologists are willing (or able) to forego income for the sake of clinical trials. The use of finder's fees or incentive payments to replace the lost revenue to practicing oncologists could be tried, but this would be a short-term solution at best. It would dramatically change referral patterns away from community practitioners and to cancer centers, at a time when diffusion to the community is a major goal of the National Cancer Institute. We should not assume that the reimbursement industry will be a willing partner in the switch, given that the cost of a clinical trial may be substantially higher than standard care.7 We have three concrete suggestions. First, let's examine the
Downloaded from ascopubs.org by RB DRAUGHTON LIBRARY on April 28, 2019 from 131.204.073.184 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
