Neurosurgical forum Letters
to
the
editor
BCNU and Malignant Glioma To THE EDITOR: The major study reported by Dr. Walker and his colleagues on treatment of anaplastic gliomas with 1, 3-bis(2-chloroethyl)-l-nitrosourea (BCNU) and/or radiotherapy (Walker MD, Alexander E Jr, Hunt WE, et al: Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas. A cooperative clinical trial. J Neurosurg 49:333-343, September, 1978) is being widely cited by both neurologists and neurosurgeons ::~ evidence against the efficacy of BCNU. This interpretation, evidently based upon reading the abstract, was surely not intended by the authors. They reported that BCNU alone was inferior to radiation alone, and was inferior to combined radiation and chemotherapy, in the Valid Study Group (VSG). However, BCNU alone was significantly better (p < 0.002) than supportive care in the "adequately treated group" (ATG), that survived long enough to receive two courses of therapy. There was a significantly greater survival for combination therapy than for radiation alone at 18 months, suggesting that the addition of BCNU did have some effect. The paper illustrates the tremendous difficulty of doing "clean" clinical trials: two centers were "unable" to enter patients into the Supportive Care arm, and in the end (partly because in the last 6 months patients were entered into only the radiotherapy or combination arms) twice as many patients received combination therapy as received supportive care. This imbalance in the numbers of patients assigned to the four groups raises the question of whether the sample sizes for the BCNU and supportive care groups were large enough to exclude a "false negative" result for BCNU alone. A further point in defense of BCNU is that two differences which were shown to be poor prognostic factors were "stacked against" BCNU alone: first, there was a higher incidence of biopsy only (10% versus 3% for radiotherapy alone); second, there was a higher incidence of parietal location (31% versus 10% for radiotherapy alone). The interval from first symptoms to operation was shorter for the group receiving BCNU alone, raising the question of whether these patients had more aggressive tumors. Although the Karnofsky rating, based on clinical performance status, was said to be an important prognostic factor, there was no discussion in the paper of differences between institutions or differences between treatment groups in respect of this factor. Since J. Neurosurg. / Volume 50 / June, 1979
there was a serious institutional imbalance in the randomization of patients, this is a serious issue that will require some comment from the authors. It seems clear from their data that Walker, et al., have ample justification for the conclusion that radiotherapy and combination therapy are more efficacious than supportive care. It would be unfortunate, however, if their paper were to be regarded as final evidence against the efficacy of BCNU in particular, or brain tumor chemotherapy in general. J. DAVIDSPENCE, M.D., F.R.C.P. (C) London, Ontario, Canada
RESPONSE: We appreciate Dr. Spence's thoughtful and intuitive comments and deplore, as he does, any misinterpretation of the data presented in our paper. BCNU does indeed have modest efficacy in the treatment of malignant glioma and probably represents the single best chemotherapeutic agent available today. A number of factors require clarification. When in the course of a study it becomes apparent that one therapy may be to the detriment of the patients involved, it is incumbent upon us to stop the use of that approach, although the entire study need not be stopped or invalidated. The imbalance in numbers of patients assigned to the four groups and sample size is taken into account in the analytic procedures used? The statistical analysis employed does not require equal numbers of patients in all arms, but takes into consideration both the difference in the survival experience among all the arms as well as the number of observations in each. If the actual difference is relatively small but the number of observations is very large; or conversely, if the difference is large and the number of observations is small, the "p value" determined will still indicate what the chances are of the observations being correct. From a practical point of view, we are more interested in reasonably large differences in survival than in demonstrating with great precision that a small change is highly significant. The median survival is only one point in the continuum, and a much better appreciation is obtained by examining the entire survival curve. In addition, those patients who were adequately treated clearly showed the value of BCNU as a single agent (p = 0.002). We agree with Dr. Spence that the prognostic factors were "stacked against" BCNU; however, none of these were of immense importance nor would they have altered in a major way the outcome of the study. 839
Neurosurgical forum The crux of good study design is in the use of randomization. One cannot solely depend upon randomization, however, as it is never totally equal and, therefore, good study design requires further analysis to demonstrate those factors that might be of significance. The initial performance status of all patients was 74 + 17 (mean + SD), and there was no significant difference in performance status between treatment groups. Other than expected differences in the ability of different institutions to accrue patients, there was no significant difference between the patients treated in the various participating institutions. Part of the misinterpretation might result from unduly high expectations for this therapy on the part of some readers. If a cure is being sought, then clearly survival curves, which go all the way down to the bottom, indicate that no cure is yet available. The significant factor, however, is not that the curves go all the way to the bottom but rather that there is a significant shift in the survival curve to the right. As Dr. Spence points out, a tantalizing piece of evidence is demonstrated in those patients receiving BCNU and radiotherapy who survive beyond 18 months. It is fortunate that the confirmatory study in 467 patients has been completed, and that BCNU and radiotherapy continue to be the best treatment arm we have? We concur with Dr. Spence that "clean" clinical trials are fraught with tremendous difficulty but believe that we have the most accurate clinical data available on brain tumor therapy to date. Qui sciat melius dicat/[Let anyone who has better information come forth.] MICHAELU. WALKER,M.D. Bethesda, Maryland
(gm-cm) impact injuries. We found that, in control animals, the SCBF in the mid-thoracic gray matter was 49.4 + 9.3 ml/100 gm/min in 17 rats, which is very similar to the control SCBF values reported by Rivlin and Tator. Following an injury of 50 gm-cm that left the animals with an impaired sensory level and paraplegia for an average of 5 days, we observed a decline of SCBF in the gray matter to approximately 70% of the levels in five control rats, but it returned to normal levels in less than 4 hours. With that injury, there was an immediate loss of the SER, although SER returned by the end of this 4-hour period with increased wave-component latencies. With injury forces greater than 125 gm-cm, the SCBF in gray matter was less than 10 ml/100 gm/min. The SER did not return, and these animals remained paraplegic with a high thoracic sensory level. Our observations also support the data Rivlin and Tator have presented in their previous articles on this model? ,4 I compliment the authors on their very interesting and careful work. The rat spinal cord injury model is, indeed, an economical and suitable means of investigating this most challenging and frustrating neurosurgical problem. I look forward to future data obtained in less severe injuries, and to an elucidation of the effect of various therapeutic regimens on SCBF in a more viable spinal cord. JAMESE. BOGGAN,M.D. San Francisco, California References
Pathophysiology of Spinal Cord Injury
1. Boggan JE, de la Torre J, Mullan S: A rat model for the investigation of spinal cord injury, in Cowan WM (ed): Approaches to the Cell Biology of Neurons. Bethesda, Md: Society for Neuroscience, Vol 2, 1977, p 961 (Abstract) 2. Boggan JE, de la Torre J, Mullan S: Spinal cord injury in the rat: A new model. Presented at the American Medical Students Association, University of Texas Medical Branch, National Student Research Forum, Galveston, Texas, April, 1976. Unpublished data 3. Rivlin AS, Tator CH: Effect of duration of acute spinal cord compression in a new acute cord injury model in the rat. Surg Neurol 10:39-43, 1978 4. Rivlin AS, Tator CH: Objective clinical assessment of motor function after experimental spinal cord injury in the rat. J Neurosurg 47:577-581, 1977
To THE EDITOR: The recent article by Drs. Rivlin and Tator (Rivlin AS, Tator CH: Regional spinal cord blood flow in rats after severe cord trauma. J Neurosurg 49:844-853, December, 1978) is a significant contribution to the investigation of the pathophysiology of spinal c o r d injury. In 1976, together with Drs. de la Torre and Mullan, I investigated and reported the measurement of regional spinal cord blood flow (SCBF) and the computer-averaged somatosensory evoked response (SER) in the rat following impact injury to the spinal cord. la Using a hydrogen-clearance technique, we measured the SCBF before and after 50-150 gram/centimeter force
RESPONSE: We are grateful to Dr. Boggan for his complimentary remarks about our work with the rat model and wish to thank him for providing information about his related studies on spinal cord blood flow (SCBF) in the rat. We are continuing our studies in the manner indicated by Dr. Boggan. For example, we are measuring rat SCBF after less severe injuries and are attempting to improve flow by various measures such as induced hypertension. ALEX S. RIVLIN,M.D. CHARLES H. TATOR, M.D. Toronto, Ontario, Canada
References
1. Gehan EA: A generalized Wilcoxon test for comparing arbitrarily singly-censored samples. Biometrika 52: 203-223, 1965 2. Walker MD, Alexander E Jr, Hunt WE, et al: An evaluation of BCNU and radiotherapy versus methyl-CCNU and/or radiotherapy in the treatment of malignant glioma. (In preparation)
840
J. Neurosurg. / Volume 50 / June, 1979
to
the
editor
BCNU and Malignant Glioma To THE EDITOR: The major study reported by Dr. Walker and his colleagues on treatment of anaplastic gliomas with 1, 3-bis(2-chloroethyl)-l-nitrosourea (BCNU) and/or radiotherapy (Walker MD, Alexander E Jr, Hunt WE, et al: Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas. A cooperative clinical trial. J Neurosurg 49:333-343, September, 1978) is being widely cited by both neurologists and neurosurgeons ::~ evidence against the efficacy of BCNU. This interpretation, evidently based upon reading the abstract, was surely not intended by the authors. They reported that BCNU alone was inferior to radiation alone, and was inferior to combined radiation and chemotherapy, in the Valid Study Group (VSG). However, BCNU alone was significantly better (p < 0.002) than supportive care in the "adequately treated group" (ATG), that survived long enough to receive two courses of therapy. There was a significantly greater survival for combination therapy than for radiation alone at 18 months, suggesting that the addition of BCNU did have some effect. The paper illustrates the tremendous difficulty of doing "clean" clinical trials: two centers were "unable" to enter patients into the Supportive Care arm, and in the end (partly because in the last 6 months patients were entered into only the radiotherapy or combination arms) twice as many patients received combination therapy as received supportive care. This imbalance in the numbers of patients assigned to the four groups raises the question of whether the sample sizes for the BCNU and supportive care groups were large enough to exclude a "false negative" result for BCNU alone. A further point in defense of BCNU is that two differences which were shown to be poor prognostic factors were "stacked against" BCNU alone: first, there was a higher incidence of biopsy only (10% versus 3% for radiotherapy alone); second, there was a higher incidence of parietal location (31% versus 10% for radiotherapy alone). The interval from first symptoms to operation was shorter for the group receiving BCNU alone, raising the question of whether these patients had more aggressive tumors. Although the Karnofsky rating, based on clinical performance status, was said to be an important prognostic factor, there was no discussion in the paper of differences between institutions or differences between treatment groups in respect of this factor. Since J. Neurosurg. / Volume 50 / June, 1979
there was a serious institutional imbalance in the randomization of patients, this is a serious issue that will require some comment from the authors. It seems clear from their data that Walker, et al., have ample justification for the conclusion that radiotherapy and combination therapy are more efficacious than supportive care. It would be unfortunate, however, if their paper were to be regarded as final evidence against the efficacy of BCNU in particular, or brain tumor chemotherapy in general. J. DAVIDSPENCE, M.D., F.R.C.P. (C) London, Ontario, Canada
RESPONSE: We appreciate Dr. Spence's thoughtful and intuitive comments and deplore, as he does, any misinterpretation of the data presented in our paper. BCNU does indeed have modest efficacy in the treatment of malignant glioma and probably represents the single best chemotherapeutic agent available today. A number of factors require clarification. When in the course of a study it becomes apparent that one therapy may be to the detriment of the patients involved, it is incumbent upon us to stop the use of that approach, although the entire study need not be stopped or invalidated. The imbalance in numbers of patients assigned to the four groups and sample size is taken into account in the analytic procedures used? The statistical analysis employed does not require equal numbers of patients in all arms, but takes into consideration both the difference in the survival experience among all the arms as well as the number of observations in each. If the actual difference is relatively small but the number of observations is very large; or conversely, if the difference is large and the number of observations is small, the "p value" determined will still indicate what the chances are of the observations being correct. From a practical point of view, we are more interested in reasonably large differences in survival than in demonstrating with great precision that a small change is highly significant. The median survival is only one point in the continuum, and a much better appreciation is obtained by examining the entire survival curve. In addition, those patients who were adequately treated clearly showed the value of BCNU as a single agent (p = 0.002). We agree with Dr. Spence that the prognostic factors were "stacked against" BCNU; however, none of these were of immense importance nor would they have altered in a major way the outcome of the study. 839
Neurosurgical forum The crux of good study design is in the use of randomization. One cannot solely depend upon randomization, however, as it is never totally equal and, therefore, good study design requires further analysis to demonstrate those factors that might be of significance. The initial performance status of all patients was 74 + 17 (mean + SD), and there was no significant difference in performance status between treatment groups. Other than expected differences in the ability of different institutions to accrue patients, there was no significant difference between the patients treated in the various participating institutions. Part of the misinterpretation might result from unduly high expectations for this therapy on the part of some readers. If a cure is being sought, then clearly survival curves, which go all the way down to the bottom, indicate that no cure is yet available. The significant factor, however, is not that the curves go all the way to the bottom but rather that there is a significant shift in the survival curve to the right. As Dr. Spence points out, a tantalizing piece of evidence is demonstrated in those patients receiving BCNU and radiotherapy who survive beyond 18 months. It is fortunate that the confirmatory study in 467 patients has been completed, and that BCNU and radiotherapy continue to be the best treatment arm we have? We concur with Dr. Spence that "clean" clinical trials are fraught with tremendous difficulty but believe that we have the most accurate clinical data available on brain tumor therapy to date. Qui sciat melius dicat/[Let anyone who has better information come forth.] MICHAELU. WALKER,M.D. Bethesda, Maryland
(gm-cm) impact injuries. We found that, in control animals, the SCBF in the mid-thoracic gray matter was 49.4 + 9.3 ml/100 gm/min in 17 rats, which is very similar to the control SCBF values reported by Rivlin and Tator. Following an injury of 50 gm-cm that left the animals with an impaired sensory level and paraplegia for an average of 5 days, we observed a decline of SCBF in the gray matter to approximately 70% of the levels in five control rats, but it returned to normal levels in less than 4 hours. With that injury, there was an immediate loss of the SER, although SER returned by the end of this 4-hour period with increased wave-component latencies. With injury forces greater than 125 gm-cm, the SCBF in gray matter was less than 10 ml/100 gm/min. The SER did not return, and these animals remained paraplegic with a high thoracic sensory level. Our observations also support the data Rivlin and Tator have presented in their previous articles on this model? ,4 I compliment the authors on their very interesting and careful work. The rat spinal cord injury model is, indeed, an economical and suitable means of investigating this most challenging and frustrating neurosurgical problem. I look forward to future data obtained in less severe injuries, and to an elucidation of the effect of various therapeutic regimens on SCBF in a more viable spinal cord. JAMESE. BOGGAN,M.D. San Francisco, California References
Pathophysiology of Spinal Cord Injury
1. Boggan JE, de la Torre J, Mullan S: A rat model for the investigation of spinal cord injury, in Cowan WM (ed): Approaches to the Cell Biology of Neurons. Bethesda, Md: Society for Neuroscience, Vol 2, 1977, p 961 (Abstract) 2. Boggan JE, de la Torre J, Mullan S: Spinal cord injury in the rat: A new model. Presented at the American Medical Students Association, University of Texas Medical Branch, National Student Research Forum, Galveston, Texas, April, 1976. Unpublished data 3. Rivlin AS, Tator CH: Effect of duration of acute spinal cord compression in a new acute cord injury model in the rat. Surg Neurol 10:39-43, 1978 4. Rivlin AS, Tator CH: Objective clinical assessment of motor function after experimental spinal cord injury in the rat. J Neurosurg 47:577-581, 1977
To THE EDITOR: The recent article by Drs. Rivlin and Tator (Rivlin AS, Tator CH: Regional spinal cord blood flow in rats after severe cord trauma. J Neurosurg 49:844-853, December, 1978) is a significant contribution to the investigation of the pathophysiology of spinal c o r d injury. In 1976, together with Drs. de la Torre and Mullan, I investigated and reported the measurement of regional spinal cord blood flow (SCBF) and the computer-averaged somatosensory evoked response (SER) in the rat following impact injury to the spinal cord. la Using a hydrogen-clearance technique, we measured the SCBF before and after 50-150 gram/centimeter force
RESPONSE: We are grateful to Dr. Boggan for his complimentary remarks about our work with the rat model and wish to thank him for providing information about his related studies on spinal cord blood flow (SCBF) in the rat. We are continuing our studies in the manner indicated by Dr. Boggan. For example, we are measuring rat SCBF after less severe injuries and are attempting to improve flow by various measures such as induced hypertension. ALEX S. RIVLIN,M.D. CHARLES H. TATOR, M.D. Toronto, Ontario, Canada
References
1. Gehan EA: A generalized Wilcoxon test for comparing arbitrarily singly-censored samples. Biometrika 52: 203-223, 1965 2. Walker MD, Alexander E Jr, Hunt WE, et al: An evaluation of BCNU and radiotherapy versus methyl-CCNU and/or radiotherapy in the treatment of malignant glioma. (In preparation)
840
J. Neurosurg. / Volume 50 / June, 1979
