CORRESPONDENCE The New InternationalNeuroblastomaStaging System: Some CriticalNotes To the Editor: Recently a new International Staging System for Neuroblastomas was published.: The new staging systems includes the following: (1) minimum criteria for establishing the diagnosis, (2) minimum staging requirements, (3) the criteria for staging according to the system, and (4) a response staging system. As stated,' ' it represents a major milestone in international cooperation, in that an international consensus in neuroblastoma has been reached regarding criteria for diagnosis, minimum staging requirements, and criteria for staging. Undoubtedly, the implementation of these criteria will facilitate comparison of clinical studies by different groups. 4 Regarding the criteria, I have only minor concerns. However, the International Neuroblastoma Response Criteria' presents a number of methodologic problems. First, the end point of clinical trials is a measurable, objective response within a specified time period.) Thus, for comparison of responses of different clinical trials, the time period between start of treatment and response evaluation should be 6 defined precisely" ; the recommendation of "usually 3 to 4 months after initiation of treatment"' ' may allow the time at which response is evaluated to vary considerably. Second, the duration of responses must be satisfied in two assessments at least 4 weeks apart in order to reduce errors of misclassification," "' and there is no definition of the minimal response duration or frequency of assessment, as stated in the three reports''; at least a three-dimensional determination of both the primary tumor and metastatic sites should be done every 4 weeks during treatment. Third, even if the response evaluation is based on the percentual reduction of assessable lesions, and thus in accordance with the concept of fractional cell kill, potentially deceptive interpretation of response may result, since tumor cross-sectional area and volume are not linearly related.5 Minor responses such as mixed response or no response (which equals stable disease) may probably be justified in phase II trials conducted in patients who have failed on standard treatment to exhibit any antitumor activity 5 that is potentially significant. "' However, the designation of these minor responses, unless of long duration, is 9 meaningless. '" Minimal responses or responses of short duration or based on only one assessment should otherwise be abandoned, since these are of little clinical value or entirely 9 due to an error of measurement. -" Fourth, the fractional cell-kill hypothesis establishes that irradiation and chemotherapeutic agents obey first-order kinetics with respect to cell kill, ie, a constant decrease in fraction.' The number of viable tumor cells at a given time within the same response category (with the exception of complete response [CR]) may thus vary considerably depending on the number of tumor cells present at the initiation of treatment.' Patients should probably not be randomized to different "maintenance" regimens on the basis of response categories, but on the basis of the actual tumor burden that is demonstrable at the time of randomization, ie, based on a postsurgical remission stage
grouping (for example, as proposed by Exelby' 2). Fifth, since it is well recognized that about 50% of patients with advancedstage neuroblastomas who achieve a clinical CR following chemo-irradiation have residual tumor found at surgical exploration, 3" since there is considerable discordance between diagnostic imaging and operative findings,""'6 and since the presurgical response categories may be changed according to postsurgical histopathologic findings,'' this presurgical response staging system with its apparent complexity may probably be of limited clinical value. Even if management of the primary tumor in disseminated disease remains controversial, some studies do suggest that aggressive surgical attempts to remove the primary tumor in 4 responding patients have beneficial effects on survival. '" In conclusion, I suggest that these criteria for response be excluded from the International Neuroblastoma Staging System and instead be the subject of a separate paper concerning methodologic guidelines for reports of neuroblastoma clinical trials. Niels L.T. Carlsen State University Hospital. Rigshospitalet, Copenhagen, Denmark REFERENCES I. Brodeur GM, Seeger RC, Barrett A, et al: International criteria for diagnosis, staging and response to treatment in patients with neuroblastoma, in Evans AE, D'Angio GJ, Knudson AG, et al (eds): Advances in Neuroblastoma Research 2. New York, NY, Liss, 1988, pp 509-524, 565-671 2. Brodeur GM, Seeger RC, Barrett A, et al: International criteria for diagnosis, staging, and response to treatment in patients with neuroblastoma. J Clin Oncol 6:1874-1881, 1988 3. Smith EI, Haase GM, Seeger RC, et al: A surgical perspective on the current staging in neuroblastoma-The International Neuroblastoma Staging System proposal. J Pediatr Surg 24:386-390, 1989 4. Carlsen NLT: Clinical staging of neuroblastomas: Assessment of the various staging systems, in Pochedly CE, (ed): Neuroblastoma: Tumor Biology and Therapy. Boca Raton, FL, CRC Press 1990 (in press) 5. Abelson HT: Cancer chemotherapy, in Nathan DG, Oski FA, (eds): Hematology of Infancy and Childhood (ed 9 3). Philadelphia, PA, Saunders, 1987, pp 81-1018 6. Anderson JR, Cain KC, Gelber RD, et al: Analysis and interpretation of the comparison of survival by treatment outcome variables in cancer clinical trials. Cancer Treat Rep 69:1139-1146, 1985 7. Osterlind K, Hansen HH, Dombernowsky P, et al: Determinants of complete remission induction and maintenance in chemotherapy with or without irradiation of small cell lung cancer. Cancer Res 47:2733-2736, 1987 8. Carlsen NLT, Schroeder H, Bro PV, et al: Response to multimodal treatment in advanced neuroblastomas. Factors associated with complete remission induction, and factors associated with prolonged survival. Anticancer Res 9:837844, 1989 9. Warr D, McKinney S, Tannock I: Influence of measure-
Journal of ClinicalOncology, Vol 8, No 5 (May), 1990: pp 935-943
Downloaded from ascopubs.org by University of Newcastle Upon Tyne on April 10, 2019 from 128.240.208.034 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
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ment error on response rates. Cancer Treat Rep 69:11271138, 1985 10. Baar J, Tannock I: Analyzing the same data in two ways: A demonstration model to illustrate the reporting and misreporting of clinical trials. J Clin Oncol 7:969-978, 1989 11. Goldie JH, Coldman AJ: A mathematic model for relating the drug sensitivity of tumors to their spontaneous mutation rate. Cancer Treat Rep 63:1727-1733, 1979 12. Exelby PR: The objectives and importance of operative staging of children with cancer. Cancer 58:421-425, 1986 13. Sitarz A, Finklestein J, Grosfeld J, et al: An evaluation of the role of surgery in disseminated neuroblastoma: A report from the Children's Cancer Study Group. J Pediatr Surg 18:147-151, 1983 14. Matsumura M, Atkinson JB, Hays DM, et al: An evaluation of the role of surgery in metastatic neuroblastoma. J Pediatr Surg 23:448-453, 1988 15. Haase GM, Wong KY, deLorimier AA, et al: Improvement in survival after excision of primary tumor in stage III neuroblastoma. J Pediatr Surg 24:194-200, 1989 16. Foglia RP, Fonkalsrud EW, Feig SA, et al: Accuracy of diagnostic imaging as determined by delayed operative intervention for advanced neuroblastoma. J Pediatr Surg 24:708-711, 1989
Reply To the Editor We appreciate the interest and comments of Dr Carlsen concerning the International Neuroblastoma Staging System and related issues. The publication concerning the "International Criteria for Diagnosis, Staging and Response to Treatment for Patients With Neuroblastoma" represents a consensus of agreement among the representatives of most of the major oncology groups from the United States, Europe, and Japan. This information was published in preliminary form at an International Symposium on Advances in Neuroblastoma Research,' and then definitively in the Journal of Clinical Oncology.2 It was also published in a more abbreviated form with a "surgical perspective."' There was broad (but not universal) representation in terms of oncology groups, countries, and disciplines in the drafting of this document. It was hoped that if an agreement could be reached by such a diverse group of individuals, this agreement could be extended, and any exclusion of particular individuals or groups by the initial organizers of this effort was unintentional Carlsen makes several important points, and a detailed response to all of them is not possible here. We think that the International Neuroblastoma Staging System and Response Criteria represents an important document of cooperation between pediatric oncologists representing many groups and nations. However, the strength of such a document is also its weakness. Any agreement among many individuals with different backgrounds and patterns of patient management must necessarily contain compromises in order to reach a consensus that will be acceptable to all. Thus, it was necessary to include some vagueness or flexibility on the point on time ("usually 3 to 4 months after the initiation of treatment") at which response to treatment is measured (point one) In fact, it would be inappropriate as part of these recommendations to mandate arbitrarily a specific time at which all
patients throughout the civilized world must be reevaluated. The recommendation of Carlsen that all patients have threedimensional imaging (computed tomography, magnetic resonance imaging) of their primary and metastatic lesions every 4 weeks throughout the course of treatment (point two) is economically unfeasible. It might be considered ideal or even possible in certain places where the cost of medical care is not an issue, but it is not a practical suggestion for most parts of the world. We agree that the assessments of "mixed response, no response, or stable disease" (point three) are of little if any value except in the evaluation of experimental agents after conventional therapy has failed, but these categories were included and defined for completeness, as pointed out in the text. We also agree that the postsurgical response probably would represent the most definitive response after initial treatment (point five), but presurgical response would be the only way to evaluate the effects of chemotherapy alone on primary and metastatic lesions, hence the recommendation to make both assessments. Point four does not really pertain to staging or response criteria but to protocol design, which is beyond the purview of the document in question. As to Carlsen's final comment, the response criteria outlined in our publication are not an integral part of the staging system but are an additional set of response criteria to provide a common meaning for these terms, which in turn can serve as a basis for comparison between therapeutic protocols reported by different institutions and countries. We intended this to be a basis on which future clarifications or improvements might be based. They are neither perfect nor particularly novel. However, a great deal of effort went into the formulation and specific wording of these definitions of response. We stand by these criteria for now and respectfully disagree with Carlsen's recommendation that they be excluded. However, we invite him to contribute any helpful comments or constructive criticisms, such as those stated above in his letter. A separate and more detailed report dealing with methodologic guidelines for reports of neuroblastoma clinical trials may be warranted in the future. Carlsen's input and contributions to such a document, with the definitions in reference 2 serving as a starting point, would be welcome. Garett M. Brodeur Washington UniversitySchool of Medicine St. Louis, MO on behalfof the International Conferees of the Neuroblastoma Stagingand Response Criteria REFERENCES 1. Brodeur GM, Seeger RC, Barrett A, et al: International criteria for diagnosis, staging and response to treatment in patients with neuroblastoma, in Evans AE, D'Angio GJ, Knudson AG, et al (eds): Advances in Neuroblastoma Research 2. New York, NY, Liss, 1988, pp 509-524, 565-571 2. Brodeur GM, Seeger RC, Barrett A, et al: International criteria for diagnosis, staging, and response to treatment in patients with neuroblastoma. J Clin Oncol 6:1874-1881, 1988 3. Smith El, Haase GM, Seeger RC, et al: A surgical perspective on the current staging in neuroblastoma-The International Neuroblastoma Staging proposal. J Pediatr Surg 24:386-390, 1989
Downloaded from ascopubs.org by University of Newcastle Upon Tyne on April 10, 2019 from 128.240.208.034 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
grouping (for example, as proposed by Exelby' 2). Fifth, since it is well recognized that about 50% of patients with advancedstage neuroblastomas who achieve a clinical CR following chemo-irradiation have residual tumor found at surgical exploration, 3" since there is considerable discordance between diagnostic imaging and operative findings,""'6 and since the presurgical response categories may be changed according to postsurgical histopathologic findings,'' this presurgical response staging system with its apparent complexity may probably be of limited clinical value. Even if management of the primary tumor in disseminated disease remains controversial, some studies do suggest that aggressive surgical attempts to remove the primary tumor in 4 responding patients have beneficial effects on survival. '" In conclusion, I suggest that these criteria for response be excluded from the International Neuroblastoma Staging System and instead be the subject of a separate paper concerning methodologic guidelines for reports of neuroblastoma clinical trials. Niels L.T. Carlsen State University Hospital. Rigshospitalet, Copenhagen, Denmark REFERENCES I. Brodeur GM, Seeger RC, Barrett A, et al: International criteria for diagnosis, staging and response to treatment in patients with neuroblastoma, in Evans AE, D'Angio GJ, Knudson AG, et al (eds): Advances in Neuroblastoma Research 2. New York, NY, Liss, 1988, pp 509-524, 565-671 2. Brodeur GM, Seeger RC, Barrett A, et al: International criteria for diagnosis, staging, and response to treatment in patients with neuroblastoma. J Clin Oncol 6:1874-1881, 1988 3. Smith EI, Haase GM, Seeger RC, et al: A surgical perspective on the current staging in neuroblastoma-The International Neuroblastoma Staging System proposal. J Pediatr Surg 24:386-390, 1989 4. Carlsen NLT: Clinical staging of neuroblastomas: Assessment of the various staging systems, in Pochedly CE, (ed): Neuroblastoma: Tumor Biology and Therapy. Boca Raton, FL, CRC Press 1990 (in press) 5. Abelson HT: Cancer chemotherapy, in Nathan DG, Oski FA, (eds): Hematology of Infancy and Childhood (ed 9 3). Philadelphia, PA, Saunders, 1987, pp 81-1018 6. Anderson JR, Cain KC, Gelber RD, et al: Analysis and interpretation of the comparison of survival by treatment outcome variables in cancer clinical trials. Cancer Treat Rep 69:1139-1146, 1985 7. Osterlind K, Hansen HH, Dombernowsky P, et al: Determinants of complete remission induction and maintenance in chemotherapy with or without irradiation of small cell lung cancer. Cancer Res 47:2733-2736, 1987 8. Carlsen NLT, Schroeder H, Bro PV, et al: Response to multimodal treatment in advanced neuroblastomas. Factors associated with complete remission induction, and factors associated with prolonged survival. Anticancer Res 9:837844, 1989 9. Warr D, McKinney S, Tannock I: Influence of measure-
Journal of ClinicalOncology, Vol 8, No 5 (May), 1990: pp 935-943
Downloaded from ascopubs.org by University of Newcastle Upon Tyne on April 10, 2019 from 128.240.208.034 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
935
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ment error on response rates. Cancer Treat Rep 69:11271138, 1985 10. Baar J, Tannock I: Analyzing the same data in two ways: A demonstration model to illustrate the reporting and misreporting of clinical trials. J Clin Oncol 7:969-978, 1989 11. Goldie JH, Coldman AJ: A mathematic model for relating the drug sensitivity of tumors to their spontaneous mutation rate. Cancer Treat Rep 63:1727-1733, 1979 12. Exelby PR: The objectives and importance of operative staging of children with cancer. Cancer 58:421-425, 1986 13. Sitarz A, Finklestein J, Grosfeld J, et al: An evaluation of the role of surgery in disseminated neuroblastoma: A report from the Children's Cancer Study Group. J Pediatr Surg 18:147-151, 1983 14. Matsumura M, Atkinson JB, Hays DM, et al: An evaluation of the role of surgery in metastatic neuroblastoma. J Pediatr Surg 23:448-453, 1988 15. Haase GM, Wong KY, deLorimier AA, et al: Improvement in survival after excision of primary tumor in stage III neuroblastoma. J Pediatr Surg 24:194-200, 1989 16. Foglia RP, Fonkalsrud EW, Feig SA, et al: Accuracy of diagnostic imaging as determined by delayed operative intervention for advanced neuroblastoma. J Pediatr Surg 24:708-711, 1989
Reply To the Editor We appreciate the interest and comments of Dr Carlsen concerning the International Neuroblastoma Staging System and related issues. The publication concerning the "International Criteria for Diagnosis, Staging and Response to Treatment for Patients With Neuroblastoma" represents a consensus of agreement among the representatives of most of the major oncology groups from the United States, Europe, and Japan. This information was published in preliminary form at an International Symposium on Advances in Neuroblastoma Research,' and then definitively in the Journal of Clinical Oncology.2 It was also published in a more abbreviated form with a "surgical perspective."' There was broad (but not universal) representation in terms of oncology groups, countries, and disciplines in the drafting of this document. It was hoped that if an agreement could be reached by such a diverse group of individuals, this agreement could be extended, and any exclusion of particular individuals or groups by the initial organizers of this effort was unintentional Carlsen makes several important points, and a detailed response to all of them is not possible here. We think that the International Neuroblastoma Staging System and Response Criteria represents an important document of cooperation between pediatric oncologists representing many groups and nations. However, the strength of such a document is also its weakness. Any agreement among many individuals with different backgrounds and patterns of patient management must necessarily contain compromises in order to reach a consensus that will be acceptable to all. Thus, it was necessary to include some vagueness or flexibility on the point on time ("usually 3 to 4 months after the initiation of treatment") at which response to treatment is measured (point one) In fact, it would be inappropriate as part of these recommendations to mandate arbitrarily a specific time at which all
patients throughout the civilized world must be reevaluated. The recommendation of Carlsen that all patients have threedimensional imaging (computed tomography, magnetic resonance imaging) of their primary and metastatic lesions every 4 weeks throughout the course of treatment (point two) is economically unfeasible. It might be considered ideal or even possible in certain places where the cost of medical care is not an issue, but it is not a practical suggestion for most parts of the world. We agree that the assessments of "mixed response, no response, or stable disease" (point three) are of little if any value except in the evaluation of experimental agents after conventional therapy has failed, but these categories were included and defined for completeness, as pointed out in the text. We also agree that the postsurgical response probably would represent the most definitive response after initial treatment (point five), but presurgical response would be the only way to evaluate the effects of chemotherapy alone on primary and metastatic lesions, hence the recommendation to make both assessments. Point four does not really pertain to staging or response criteria but to protocol design, which is beyond the purview of the document in question. As to Carlsen's final comment, the response criteria outlined in our publication are not an integral part of the staging system but are an additional set of response criteria to provide a common meaning for these terms, which in turn can serve as a basis for comparison between therapeutic protocols reported by different institutions and countries. We intended this to be a basis on which future clarifications or improvements might be based. They are neither perfect nor particularly novel. However, a great deal of effort went into the formulation and specific wording of these definitions of response. We stand by these criteria for now and respectfully disagree with Carlsen's recommendation that they be excluded. However, we invite him to contribute any helpful comments or constructive criticisms, such as those stated above in his letter. A separate and more detailed report dealing with methodologic guidelines for reports of neuroblastoma clinical trials may be warranted in the future. Carlsen's input and contributions to such a document, with the definitions in reference 2 serving as a starting point, would be welcome. Garett M. Brodeur Washington UniversitySchool of Medicine St. Louis, MO on behalfof the International Conferees of the Neuroblastoma Stagingand Response Criteria REFERENCES 1. Brodeur GM, Seeger RC, Barrett A, et al: International criteria for diagnosis, staging and response to treatment in patients with neuroblastoma, in Evans AE, D'Angio GJ, Knudson AG, et al (eds): Advances in Neuroblastoma Research 2. New York, NY, Liss, 1988, pp 509-524, 565-571 2. Brodeur GM, Seeger RC, Barrett A, et al: International criteria for diagnosis, staging, and response to treatment in patients with neuroblastoma. J Clin Oncol 6:1874-1881, 1988 3. Smith El, Haase GM, Seeger RC, et al: A surgical perspective on the current staging in neuroblastoma-The International Neuroblastoma Staging proposal. J Pediatr Surg 24:386-390, 1989
Downloaded from ascopubs.org by University of Newcastle Upon Tyne on April 10, 2019 from 128.240.208.034 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
