Thymectomy for myasthenia gravis: evaluation requires controlled prospective studies
2003; Elsevier BV; Volume: 76; Issue: 1 Linguagem: Inglês
10.1016/s0003-4975(03)00488-0
ISSN1552-6259
AutoresAlfred Jaretzki, Johan A. Aarli, Henry J. Kaminski, Lawrence H. Phillips, Donald B. Sanders,
Tópico(s)Parkinson's Disease and Spinal Disorders
ResumoIt is generally believed that a total thymectomy is indicated when thymectomy is used to treat autoimmune nonthymomatous myasthenia gravis (MG) and the best available data, albeit retrospective, suggest that the more complete the resection the better the results (Fig 1) [1Jaretzki III, A. Thymectomy for myasthenia gravis an analysis of the controversies regarding technique and results.Neurology. 1997; 48: S52-S63Crossref Google Scholar, 2Jaretzki III, A. Thymectomy for myasthenia gravis analysis of controversies—patient management.The Neurologist. 2003; 9: 77-92Crossref PubMed Scopus (66) Google Scholar]. However, there are no controlled prospective studies that determined unequivocally which thymectomy technique gives the best results, nor even that the entire thymus needs to be removed. In recent issues of this journal, there are two additional reports describing the results of two thymectomy techniques that are used in the treatment of MG.Shrager and associates [3Shrager J.B. Deeb M.E. Mick R. et al.Transcervical thymectomy for myasthenia gravis achieves results comparable to thymectomy by sternotomy.Ann Thorac Surg. 2002; 74: 320-327Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar] reported in a retrospective study their experience treating 78 patients with MG by using Cooper’s extended transcervical thymectomy. The authors noted that they did not remove all the cervical and mediastinal perithymic fat. Approximately 30% of the patients received steroids preoperatively. Kaplan-Meier life-table analysis revealed a complete remission rate of 31% and 43% at 2 and 5 years respectively. Among other observations, they conclude that their results “are comparable to transsternal thymectomy in the management of MG.”Pego-Fernandes and colleagues reported in two retrospective studies [4Pego-Fernandes P.M. deCampos J.R.M. Jatene F.B. et al.Thymectomy by partial sternotomy for the treatment of myasthenia gravis.Ann Thorac Surg. 2002; 74: 204-208Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar, 5deCampos J.R.M. Filomeno L.T.B. Marchiori P.E. Jatene F.B. Partial sternotomy approach to the thymus.in: Yim A.P. Hazelrigg S.R. Izzat B. Landreneau R.J. Mack M.J. Naunheim K.S. Minimal access cardiothoracic surgery. WB Saunders Co, Philadelphia, PA2000: 205-208Google Scholar] their combined experience with thymectomy using a partial sternotomy and removal of the entire thymus and surrounding fat in 478 patients with MG. The crude remission rate corrected for mean length of follow-up was 12.7% at 7.3 years. Corticosteroids were used in an unspecified number of patients. There were no deaths or nerve injuries. The authors stated that “the results are very similar to the literature data.”In the first study, the Kaplan-Meier remission rates, a desirable form of analysis, are impressive although not equal to those of the combined transcervical-transsternal thymectomy at 7.5 years (Fig 1). However, as is the problem with all the retrospective thymectomy studies, the patient cohorts are not the same and so might favor one or the other technique. In the second study, the reported corrected crude remission rate, although an unreliable measure, does not compare favorably with the 35% to 60% rate for the more aggressive resections [2Jaretzki III, A. Thymectomy for myasthenia gravis analysis of controversies—patient management.The Neurologist. 2003; 9: 77-92Crossref PubMed Scopus (66) Google Scholar]. In fact, it is lower than the basic transcervical thymectomy rate of Papatestas [6Papatestas A.E. Genkins G. Kornfeld P. Comparison of the results of the transcervical and transternal thymectomy in myasthenia gravis.Ann NY Acad Sci. 1981; 377: 766-778Crossref PubMed Scopus (37) Google Scholar] and approximately the same as the reported rate of spontaneous remissions [7Oosterhuis H.J. Observations of the natural history of myasthenia gravis and the effect of thymectomy.Ann NY Acad Sci. 1981; 377: 678-689Crossref PubMed Scopus (131) Google Scholar]. This marked variance suggests the existence of some major unrecognized unfavorable baseline characteristics in their patient cohort.Those reports are illustrative of the MG thymectomy literature [1Jaretzki III, A. Thymectomy for myasthenia gravis an analysis of the controversies regarding technique and results.Neurology. 1997; 48: S52-S63Crossref Google Scholar, 2Jaretzki III, A. Thymectomy for myasthenia gravis analysis of controversies—patient management.The Neurologist. 2003; 9: 77-92Crossref PubMed Scopus (66) Google Scholar] and demonstrate that attempts to conclude that one resectional technique is equal to or better than another by comparing retrospective studies, may be misleading. Among other factors, the patient populations, accompanying therapy, and details of evaluation are not the same. Furthermore, retrospective analyses do not address the extreme variability and unpredictability of MG, the differing response to treatment among patients with different subtypes of MG, or the variability in the selection of patients for thymectomy. The problems of analysis are compounded by a lack of common definitions of disease severity and response to therapy and a lack of objective preoperative and postoperative assessment criteria. In addition, when patients continue to take immunosuppressive medications after thymectomy, it is not possible to infer retrospectively what contribution to the ultimate result was made by the thymectomy per se [8Sanders D.B. Kaminski H.J. Jaretzki III, A. Phillips II, L.H. Thymectomy for myasthenia gravis in older patients.J Am Coll Surg. 2001; 193: 340-341Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar].Properly designed prospective studies are required to resolve the debate regarding the relative effectiveness of the various thymectomy resectional techniques. A prospective randomized clinical trial has been recommended to help resolve the role of thymectomy in any form in the treatment of MG [9Kissel J.T. Franklin G.M. American Academy of Neurology Quality Standards Subcommittee. Treatment of myasthenia gravis a call to arms.Neurology. 2000; 55: 3-4Crossref PubMed Scopus (21) Google Scholar, Class I evidence in the American Academy of Neurology (AAN) nomenclature [10Goodin D.S. Frohman E.M. Garmony G.P. et al.Disease modifying therapies in multiple sclerosis report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the MS Council for Clinical Practice Guidelines.Neurology. 2002; 58: 169-177Crossref PubMed Scopus (759) Google Scholar]. At this time such a study comparing immunosuppression alone with immunosuppression plus the extended transsternal thymectomy is being developed [11Wolfe GI, Kaminski HJ, Jaretzki A III, et al. Thymectomy trial in non-thymomatous myasthenia gravis patients receiving immunosuppressive therapy. Ann NY Acad Sci. In PressGoogle Scholar. However, it would be extremely difficult to develop a randomized study specifically comparing the various thymectomy resectional techniques, primarily because of surgeon resistance resulting in major recruitment problems; therefore, it is unlikely that such a study will be performed in the near future.Accordingly, because properly performed nonrandomized studies have been shown to be valid [12Concato J. Shah N. Horwitz R.I. Randomized, controlled trials, observational studies, and the hierarchy of research designs.N Engl J Med. 2000; 342: 1887-1892Crossref PubMed Scopus (2642) Google Scholar, 13Benson K. Hart A.J. A comparison of observational studies and randomized, controlled trials.N Engl J Med. 2000; 342: 1878-1886Crossref PubMed Scopus (1871) Google Scholar], we urge investigators to undertake nonrandomized prospective studies of two or more thymectomy techniques [14Kirklin J.W. Blackstone E.H. Clinical studies with non-randomly assigned treatment.in: Kirklin J.W. Barrett-Boyes B.G. Cardiac surgery. 2nd ed. Churchill-Livingstone, New York1993: 269-270Google Scholar] (class II or class III evidence in the American Academy of Neurology nomenclature, depending on whether there is a control arm) [10Goodin D.S. Frohman E.M. Garmony G.P. et al.Disease modifying therapies in multiple sclerosis report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the MS Council for Clinical Practice Guidelines.Neurology. 2002; 58: 169-177Crossref PubMed Scopus (759) Google Scholar]. The data bank concept should be employed in which two or more institutions would compare their techniques prospectively by using computer-based patient records. The assessment should be independent of the treating teams (Franklin G. Personal communication 2002; Co-Chair, Quality Standards Subcommittee, American Academy of Neurology). The use of clinical research standards, which include definitions of clinical classification, quantitative assessment of disease severity, grading systems of postintervention status, standardization of numeric grading for all significant variables, and approved methods of analysis is required [15Task Force of the Medical Scientific Advisory Board of the Myasthenia Gravis Foundation of America. Jaretzki A III, Barohn RB, et al. Myasthenia gravis: recommendations for clinical research standards. Ann Thorac Surg 2000;70:327–34Google Scholar, 16Task Force of the Medical Scientific Advisory Board of the Myasthenia Gravis Foundation of America, Jaretzki A III, Barohn RB, et al. Myasthenia gravis: recommendations for clinical research standards. Neurology 2000;55:16–23Google Scholar, 17Task Force of the Medical Scientific Advisory Board of the Myasthenia Gravis Foundation of America. Jaretzki A III, Barohn RB, et al. Myasthenia gravis: recommendations for clinical research standards. www.myasthenia.org/research/Clinical_Research_Standards.pdf. Accessed 2003 April 12Google Scholar]. A rigid auditing process must be in place to review all the clinical records and monitor the quality of the database, including validation for completeness and accuracy. Collaboration with experts in the field of biostatistics and outcomes analysis is mandatory in the design of the studies, collection of data, and evaluation of the results.A 3- to 5-year follow-up evaluation will probably be required. The primary focus of comparative analysis should be complete, stable remission. Survival instruments, which are used in the analysis of remission, are the most reliable determinant [7Oosterhuis H.J. Observations of the natural history of myasthenia gravis and the effect of thymectomy.Ann NY Acad Sci. 1981; 377: 678-689Crossref PubMed Scopus (131) Google Scholar]. Kaplan-Meier life-table analysis is the technique of choice [18Kaplan E.L. Meier P. Nonparametric estimation from incomplete observations.J Am Stat Assoc. 1958; 53: 457-481Crossref Scopus (47677) Google Scholar, 19Weinberg A, Gelijns A, Moskowitz A, Jaretzki A. Myasthenia gravis: outcomes analysis. http://www.myasthenia.org/research/Clinical_Research_Standards.pdf. Accessed 2003 April 12. Reprints available via Myasthenia Gravis Foundation of America, Inc. 5841 Cedar Lake Road, Suite 204, Minneapolis, MN 55416Google Scholar]. Levels of clinical improvement, although less definitive, can also be evaluated if performed quantitatively [16Task Force of the Medical Scientific Advisory Board of the Myasthenia Gravis Foundation of America, Jaretzki A III, Barohn RB, et al. Myasthenia gravis: recommendations for clinical research standards. Neurology 2000;55:16–23Google Scholar, 20Heagerty P.J. Zeger S.L. Marginal regression models for clustered ordinal measurements.J Am Stat Assoc. 1996; 91: 1024-1036Crossref Scopus (130) Google Scholar]. The use of crude data, crude data corrected for length of follow up, and clinical classifications to compare results must not be employed. Exacerbations after remission, as well as hospital and long-term morbidity and mortality data, should be compared. Quality of life evaluation should also be considered because therapy for MG may not be innocuous and may not produce a completely stable remission. Although disease-specific quality of life instruments for MG are highly desirable in this evaluation [19Weinberg A, Gelijns A, Moskowitz A, Jaretzki A. Myasthenia gravis: outcomes analysis. http://www.myasthenia.org/research/Clinical_Research_Standards.pdf. Accessed 2003 April 12. Reprints available via Myasthenia Gravis Foundation of America, Inc. 5841 Cedar Lake Road, Suite 204, Minneapolis, MN 55416Google Scholar], they are not available at this time. Quality of life evaluation, however, should not replace survival-remission analysis.Although such studies require considerable attention to detail in their development and execution, they must be performed and must replace retrospective analyses. Funding should be made available. The importance of research in MG exceeds the disorder’s relative rarity because the financial burden to society and the compromise of individual quality of life is high. In addition, in this era of outcome analyses, these steps are not only desirable but are mandatory. It is generally believed that a total thymectomy is indicated when thymectomy is used to treat autoimmune nonthymomatous myasthenia gravis (MG) and the best available data, albeit retrospective, suggest that the more complete the resection the better the results (Fig 1) [1Jaretzki III, A. Thymectomy for myasthenia gravis an analysis of the controversies regarding technique and results.Neurology. 1997; 48: S52-S63Crossref Google Scholar, 2Jaretzki III, A. Thymectomy for myasthenia gravis analysis of controversies—patient management.The Neurologist. 2003; 9: 77-92Crossref PubMed Scopus (66) Google Scholar]. However, there are no controlled prospective studies that determined unequivocally which thymectomy technique gives the best results, nor even that the entire thymus needs to be removed. In recent issues of this journal, there are two additional reports describing the results of two thymectomy techniques that are used in the treatment of MG. Shrager and associates [3Shrager J.B. Deeb M.E. Mick R. et al.Transcervical thymectomy for myasthenia gravis achieves results comparable to thymectomy by sternotomy.Ann Thorac Surg. 2002; 74: 320-327Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar] reported in a retrospective study their experience treating 78 patients with MG by using Cooper’s extended transcervical thymectomy. The authors noted that they did not remove all the cervical and mediastinal perithymic fat. Approximately 30% of the patients received steroids preoperatively. Kaplan-Meier life-table analysis revealed a complete remission rate of 31% and 43% at 2 and 5 years respectively. Among other observations, they conclude that their results “are comparable to transsternal thymectomy in the management of MG.” Pego-Fernandes and colleagues reported in two retrospective studies [4Pego-Fernandes P.M. deCampos J.R.M. Jatene F.B. et al.Thymectomy by partial sternotomy for the treatment of myasthenia gravis.Ann Thorac Surg. 2002; 74: 204-208Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar, 5deCampos J.R.M. Filomeno L.T.B. Marchiori P.E. Jatene F.B. Partial sternotomy approach to the thymus.in: Yim A.P. Hazelrigg S.R. Izzat B. Landreneau R.J. Mack M.J. Naunheim K.S. Minimal access cardiothoracic surgery. WB Saunders Co, Philadelphia, PA2000: 205-208Google Scholar] their combined experience with thymectomy using a partial sternotomy and removal of the entire thymus and surrounding fat in 478 patients with MG. The crude remission rate corrected for mean length of follow-up was 12.7% at 7.3 years. Corticosteroids were used in an unspecified number of patients. There were no deaths or nerve injuries. The authors stated that “the results are very similar to the literature data.” In the first study, the Kaplan-Meier remission rates, a desirable form of analysis, are impressive although not equal to those of the combined transcervical-transsternal thymectomy at 7.5 years (Fig 1). However, as is the problem with all the retrospective thymectomy studies, the patient cohorts are not the same and so might favor one or the other technique. In the second study, the reported corrected crude remission rate, although an unreliable measure, does not compare favorably with the 35% to 60% rate for the more aggressive resections [2Jaretzki III, A. Thymectomy for myasthenia gravis analysis of controversies—patient management.The Neurologist. 2003; 9: 77-92Crossref PubMed Scopus (66) Google Scholar]. In fact, it is lower than the basic transcervical thymectomy rate of Papatestas [6Papatestas A.E. Genkins G. Kornfeld P. Comparison of the results of the transcervical and transternal thymectomy in myasthenia gravis.Ann NY Acad Sci. 1981; 377: 766-778Crossref PubMed Scopus (37) Google Scholar] and approximately the same as the reported rate of spontaneous remissions [7Oosterhuis H.J. Observations of the natural history of myasthenia gravis and the effect of thymectomy.Ann NY Acad Sci. 1981; 377: 678-689Crossref PubMed Scopus (131) Google Scholar]. This marked variance suggests the existence of some major unrecognized unfavorable baseline characteristics in their patient cohort. Those reports are illustrative of the MG thymectomy literature [1Jaretzki III, A. Thymectomy for myasthenia gravis an analysis of the controversies regarding technique and results.Neurology. 1997; 48: S52-S63Crossref Google Scholar, 2Jaretzki III, A. Thymectomy for myasthenia gravis analysis of controversies—patient management.The Neurologist. 2003; 9: 77-92Crossref PubMed Scopus (66) Google Scholar] and demonstrate that attempts to conclude that one resectional technique is equal to or better than another by comparing retrospective studies, may be misleading. Among other factors, the patient populations, accompanying therapy, and details of evaluation are not the same. Furthermore, retrospective analyses do not address the extreme variability and unpredictability of MG, the differing response to treatment among patients with different subtypes of MG, or the variability in the selection of patients for thymectomy. The problems of analysis are compounded by a lack of common definitions of disease severity and response to therapy and a lack of objective preoperative and postoperative assessment criteria. In addition, when patients continue to take immunosuppressive medications after thymectomy, it is not possible to infer retrospectively what contribution to the ultimate result was made by the thymectomy per se [8Sanders D.B. Kaminski H.J. Jaretzki III, A. Phillips II, L.H. Thymectomy for myasthenia gravis in older patients.J Am Coll Surg. 2001; 193: 340-341Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar]. Properly designed prospective studies are required to resolve the debate regarding the relative effectiveness of the various thymectomy resectional techniques. A prospective randomized clinical trial has been recommended to help resolve the role of thymectomy in any form in the treatment of MG [9Kissel J.T. Franklin G.M. American Academy of Neurology Quality Standards Subcommittee. Treatment of myasthenia gravis a call to arms.Neurology. 2000; 55: 3-4Crossref PubMed Scopus (21) Google Scholar, Class I evidence in the American Academy of Neurology (AAN) nomenclature [10Goodin D.S. Frohman E.M. Garmony G.P. et al.Disease modifying therapies in multiple sclerosis report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the MS Council for Clinical Practice Guidelines.Neurology. 2002; 58: 169-177Crossref PubMed Scopus (759) Google Scholar]. At this time such a study comparing immunosuppression alone with immunosuppression plus the extended transsternal thymectomy is being developed [11Wolfe GI, Kaminski HJ, Jaretzki A III, et al. Thymectomy trial in non-thymomatous myasthenia gravis patients receiving immunosuppressive therapy. Ann NY Acad Sci. In PressGoogle Scholar. However, it would be extremely difficult to develop a randomized study specifically comparing the various thymectomy resectional techniques, primarily because of surgeon resistance resulting in major recruitment problems; therefore, it is unlikely that such a study will be performed in the near future. Accordingly, because properly performed nonrandomized studies have been shown to be valid [12Concato J. Shah N. Horwitz R.I. Randomized, controlled trials, observational studies, and the hierarchy of research designs.N Engl J Med. 2000; 342: 1887-1892Crossref PubMed Scopus (2642) Google Scholar, 13Benson K. Hart A.J. A comparison of observational studies and randomized, controlled trials.N Engl J Med. 2000; 342: 1878-1886Crossref PubMed Scopus (1871) Google Scholar], we urge investigators to undertake nonrandomized prospective studies of two or more thymectomy techniques [14Kirklin J.W. Blackstone E.H. Clinical studies with non-randomly assigned treatment.in: Kirklin J.W. Barrett-Boyes B.G. Cardiac surgery. 2nd ed. Churchill-Livingstone, New York1993: 269-270Google Scholar] (class II or class III evidence in the American Academy of Neurology nomenclature, depending on whether there is a control arm) [10Goodin D.S. Frohman E.M. Garmony G.P. et al.Disease modifying therapies in multiple sclerosis report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the MS Council for Clinical Practice Guidelines.Neurology. 2002; 58: 169-177Crossref PubMed Scopus (759) Google Scholar]. The data bank concept should be employed in which two or more institutions would compare their techniques prospectively by using computer-based patient records. The assessment should be independent of the treating teams (Franklin G. Personal communication 2002; Co-Chair, Quality Standards Subcommittee, American Academy of Neurology). The use of clinical research standards, which include definitions of clinical classification, quantitative assessment of disease severity, grading systems of postintervention status, standardization of numeric grading for all significant variables, and approved methods of analysis is required [15Task Force of the Medical Scientific Advisory Board of the Myasthenia Gravis Foundation of America. Jaretzki A III, Barohn RB, et al. Myasthenia gravis: recommendations for clinical research standards. Ann Thorac Surg 2000;70:327–34Google Scholar, 16Task Force of the Medical Scientific Advisory Board of the Myasthenia Gravis Foundation of America, Jaretzki A III, Barohn RB, et al. Myasthenia gravis: recommendations for clinical research standards. Neurology 2000;55:16–23Google Scholar, 17Task Force of the Medical Scientific Advisory Board of the Myasthenia Gravis Foundation of America. Jaretzki A III, Barohn RB, et al. Myasthenia gravis: recommendations for clinical research standards. www.myasthenia.org/research/Clinical_Research_Standards.pdf. Accessed 2003 April 12Google Scholar]. A rigid auditing process must be in place to review all the clinical records and monitor the quality of the database, including validation for completeness and accuracy. Collaboration with experts in the field of biostatistics and outcomes analysis is mandatory in the design of the studies, collection of data, and evaluation of the results. A 3- to 5-year follow-up evaluation will probably be required. The primary focus of comparative analysis should be complete, stable remission. Survival instruments, which are used in the analysis of remission, are the most reliable determinant [7Oosterhuis H.J. Observations of the natural history of myasthenia gravis and the effect of thymectomy.Ann NY Acad Sci. 1981; 377: 678-689Crossref PubMed Scopus (131) Google Scholar]. Kaplan-Meier life-table analysis is the technique of choice [18Kaplan E.L. Meier P. Nonparametric estimation from incomplete observations.J Am Stat Assoc. 1958; 53: 457-481Crossref Scopus (47677) Google Scholar, 19Weinberg A, Gelijns A, Moskowitz A, Jaretzki A. Myasthenia gravis: outcomes analysis. http://www.myasthenia.org/research/Clinical_Research_Standards.pdf. Accessed 2003 April 12. Reprints available via Myasthenia Gravis Foundation of America, Inc. 5841 Cedar Lake Road, Suite 204, Minneapolis, MN 55416Google Scholar]. Levels of clinical improvement, although less definitive, can also be evaluated if performed quantitatively [16Task Force of the Medical Scientific Advisory Board of the Myasthenia Gravis Foundation of America, Jaretzki A III, Barohn RB, et al. Myasthenia gravis: recommendations for clinical research standards. Neurology 2000;55:16–23Google Scholar, 20Heagerty P.J. Zeger S.L. Marginal regression models for clustered ordinal measurements.J Am Stat Assoc. 1996; 91: 1024-1036Crossref Scopus (130) Google Scholar]. The use of crude data, crude data corrected for length of follow up, and clinical classifications to compare results must not be employed. Exacerbations after remission, as well as hospital and long-term morbidity and mortality data, should be compared. Quality of life evaluation should also be considered because therapy for MG may not be innocuous and may not produce a completely stable remission. Although disease-specific quality of life instruments for MG are highly desirable in this evaluation [19Weinberg A, Gelijns A, Moskowitz A, Jaretzki A. Myasthenia gravis: outcomes analysis. http://www.myasthenia.org/research/Clinical_Research_Standards.pdf. Accessed 2003 April 12. Reprints available via Myasthenia Gravis Foundation of America, Inc. 5841 Cedar Lake Road, Suite 204, Minneapolis, MN 55416Google Scholar], they are not available at this time. Quality of life evaluation, however, should not replace survival-remission analysis. Although such studies require considerable attention to detail in their development and execution, they must be performed and must replace retrospective analyses. Funding should be made available. The importance of research in MG exceeds the disorder’s relative rarity because the financial burden to society and the compromise of individual quality of life is high. In addition, in this era of outcome analyses, these steps are not only desirable but are mandatory.
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