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Journal of Clinical Oncology, Vol 26, No 3 (January 20), 2008: pp. 406-413 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.12.2382 Initial Patient Characteristics Can Predict Pattern and Risk of Relapse in Localized Rhabdomyosarcoma
From the Olgahospital, Pediatrics 5 (Oncology, Hematology, Immunology), Department of Pediatric Oncology, and Department of Pediatric Surgery; Katharinenhospital, Department of Radiotherapy, Klinikum Stuttgart, Stuttgart; Institute of Pediatric Pathology, University of Kiel, Kiel; Department of Radiotherapy, University of Muenster; Department of Pediatric Hematology and Oncology, University Children's Hospital, Muenster; Department of Pediatric Oncology, University of Frankfurt (Main), Frankfurt; Department of Pediatric Oncology, University of Tuebingen, Tuebingen, Germany; Department of Pediatric Oncology, University of Zurich, Zurich, Switzerland; Department of Pediatric Oncology, University of Wroclaw, Wroclaw, Poland; Department of Pediatric Oncology, St. Anna Kinderspital, Vienna, Austria; and the Department of Pediatric Oncology, University of Lund, Lund, Sweden Corresponding author: Tobias M. Dantonello, MD, Olgahospital, Pediatrics 5 (Oncology, Hematology, Immunology), Klinikum Stuttgart, Bismarckstrasse 8, D-70176 Stuttgart, Germany; e-mail: tobias.dantonello{at}olgahospital-stuttgart.de or t.dantonello{at}olgahospital.de
Purpose Evaluation of primary tumor-, treatment-, and patient-related factors predicting relapse pattern, risk, and survival after relapse with the aim to design a risk-adapted, tumor-directed surveillance program for patients with localized rhabdomyosarcoma (RMS). Patients and Methods One thousand one hundred sixty-four patients with nonmetastatic RMS achieved complete remission at the end of multimodal therapy in the consecutive trials of the Cooperative Weichteilsarkom Studiengruppe (CWS)-81, CWS-86, CWS-91, and CWS-96 between 1980 and 2002 (median follow-up, 5 years). Three hundred thirty-seven of these individuals developed either locoregional, metastatic, or combined relapses. Predictive factors for relapse, its pattern, and postrelapse survival were analyzed. Results Age, histology, tumor size, tumor site, postsurgical stage, and omission of radiotherapy were identified as factors associated with an increased relapse risk in multivariate analyses. Relapse rates did not differ among the CWS trials. Median time to relapse was 1.43 years from first diagnosis (range, 0.13 to 13.5 years). There were 217 locoregional, 72 metastatic, and 48 combined recurrences. Only two patients developed metastases more than 4 years after diagnosis, and both had combined recurrences. Five-year postrelapse survival was 24%. Patient subsets with consistent relapse pattern, risk, and postrelapse survival rates were identified on the basis of histologic subtype and tumor size. Conclusion Initial patient and tumor characteristics predict pattern and risk of relapse and also correlate with postrelapse survival probabilities. In localized RMS, tumor-directed follow-up should focus on the primary site. Screening for metastatic relapse may not be necessary more than 4 years after diagnosis. The identification of subgroups with distinctive pattern and risk of relapse may be used to develop risk-adapted, tumor-directed guidance for detection of recurrent disease in localized RMS.
Rhabdomyosarcoma (RMS) is the fourth most common pediatric solid tumor with increasing incidence, predominantly affecting young children.1-3 Multimodal treatment has improved survival significantly during the last decades to approximately 70%.2,4 The prescribed treatment is risk adapted; that is, the therapy intensity depends on the estimated relapse risk. However, although the majority of patients achieve a complete remission (CR) with primary therapy, a substantial number still experience recurrences with poor prognosis.4-10 Most treatment protocols therefore include recommendations for tumor-related follow-up specifying frequency of hospital visits and laboratory and imaging investigations. These guidelines are based on the assumption that earlier recurrence detection results in improved postrelapse outcome. Routine tumor-directed surveillance programs, however, not only are expensive and time consuming, but also involve exposure to radiation, anesthesia and intravenous cannulation. In addition, they are disruptive to both child and family. Their value has been doubted because their assumed benefit has not yet been proven.11-15 Most recommendations for recurrence surveillance also include only general guidelines independent from the individual pattern and risk of relapse and respective postrelapse prognosis in contrast to risk-adapted primary therapy. This may be a result of the fact that most studies analyzing relapse pattern and risk were conducted in relatively small patient populations restricted to single studies or selected subgroups.6,7,9,10,16,17 To achieve a more rational approach to follow-up after successful primary therapy, tumor-, treatment-, and patient-related factors predicting pattern and risk of relapse were analyzed in a large cohort of unselected patients with localized RMS from consecutive trials of the Cooperative Weichteilsarkom Studiengruppe (CWS).
Patients This report is based on follow-up data as of June 2005. It includes all eligible individuals from a population of 1,578 unselected previously untreated patients 21years of age or younger with RMS and without substantial missing data treated within the consecutive trials CWS-81,8 CWS-86,7 CWS-91,18 and CWS-9619,20 between October 1980 and January 2003 in 107 participating institutions from Germany, Austria, Hungary, Poland, Sweden, and Switzerland. The vast majority of patients were recruited from Germany; as of 2002, 99% of all German RMS patients younger than 15 years in the German Childhood Cancer Registry were CWS trial patients.1 Two hundred seventy-two patients with primary metastatic disease and 142 individuals who were not in CR at the end of treatment were excluded. The remaining 1,164 patients with localized RMS in CR at the end of primary therapy were analyzed (CWS-96: n = 476, CWS-91: n = 291, CWS-86: n = 246, CWS-81: n = 151). All studies were approved by the appropriate ethics/review committees. Written informed consent according to the Declaration of Helsinki was obtained from patients, guardians or parents, or both.
Data Collection
Definition of Terms
Initial Therapy
Diagnosis and Treatment of Relapse
Statistical Methods
Patient and Tumor Characteristics of All Patients in CR The median age of the 1,164 patients at diagnosis was 5 years (range, birth to 21 years). Median duration of primary therapy was 0.6 years (Table 1).
Pattern of Recurrence Relapse occurred in 337 patients (29%; Table 1). Nineteen percent of patients had LR (n = 217) and 10% SR (n = 120; Table 2). Forty percent (n = 48) of SRs were combined, and multiple site categories were involved in the vast majority (n = 40) at the time of relapse. The most frequent site categories of SR were thorax (n = 57; 48%) and abdomen (n = 32; 27%). Six of the 11 patients who had recurrent disease at other sites had tumor in the breast at relapse. In 16 of 18 bone/bone-marrow SRs, synchronous metastases at other sites were present: either combined (n = 5) and/or affecting thorax and/or abdomen (n = 7, respectively). CNS SRs were never combined, nor did they involve other sites. Twelve of the 18 metastatic CNS relapses had a primary in HN-PM (10 of 12 in RME). The number of metastases could be determined in 72 of 120 affected patients: 52 had at least three and 20 had fewer than three metastases.
Point of Time of Recurrence The median time to relapse was 1.5 years (range, 0.2 to 13.5 years; Table 2) and did not differ significantly between LR and SR, nor was it correlated with histologic subtype. Only 12 of all 337 relapses occurred later than 4 years after diagnosis: Two were combined recurrences in RMA after 4.8 and 8.2 years; the remaining 10 were LRs, which all occurred in RME after a maximal interval of 13.5 years. Eight of the 10 late LRs appeared in RME no larger than 5 cm (Table A1, online only).
Comparison of Initial Characteristics of Relapsed and Nonrelapsed Patients
Follow-Up and Survival
Predictive Factors for Relapse Risk Analyzed parameters in multivariate analysis were age, sex, histologic subtype, tumor site, tumor size, TN classification, IRSG, use of radiation, and trial. The final model included six independent risk factors, which emerged as significant: histologic subtype (RME v RMA; risk ratio = 2.2), patient age (  10 v > 10 years; risk ratio = 1.6), tumor size ( 5 v > 5 cm; risk ratio: 1.3), IRSG (IRSG-I v IRSG-III; risk ratio = 2.1), site (unfavorable v favorable; risk ratio = 1.3), and application of RTX (radiation v no radiation; risk ratio = 1.6; Table 3). In univariate analysis, N classification (N1 [EFS 53% ± 8%] v N0 [EFS 69% ± 3%]; P < .0001) and T classification (T2 [EFS 61% ± 4%] v T1 [EFS 74% ± 4%]; P = .0002) also correlated with relapse risk.
Prediction of Pattern and Risk of Relapse and Postrelapse Survival The identified risk factors were used to define three subgroups with consistent pattern and risk of relapse by means of histologic subtype and tumor size: RME 5 cm or smaller, RME more than 5 cm, and RMA (Table 2). In the largest subgroup (ie, RME 5 cm) encompassing more than 40% of all patients, the relapse risk was much lower compared with all other patients; if a relapse occurred, it was systemic in less than 20% and never involved bone/bone marrow. In the remaining subgroups (ie, RME > 5 cm and RMA) the relapse risk was much higher, with a larger proportion of SR. The three subgroups are also characterized by distinctive postrelapse survival probabilities (Fig 2). In the subgroup RME 5 cm or smaller, nearly every second patient could be cured with salvage, especially if an RTX option remained. In RME more than 5 cm and RMA, less than 20% of patients were alive 5 years after relapse. Omission of radiation in RME during primary therapy was the only significant therapy-dependent parameter related to postrelapse survival (Table 4).
This report is one of the largest published series analyzing relapses in primarily localized RMS to date. The large patient number and broad entry criteria of an unselected population treated in four consecutive international multicenter studies conducted by the same investigators with more than 10 years of follow-up allowed for a robust sustainable analysis. Another publication5 reported 378 relapses, but selection criteria differed: Disease progressions were also included, but not, for example, patients who suffered toxic deaths or tumors without response. Our analysis confirms that disease recurrence must be expected in every third patient with primary nonmetastatic RMS despite achievement of a complete remission, mainly as LR. Only every 10th individual will experience systemic relapses, corresponding with data from other clinical trial groups.5,9,10,16 Relapse risk, pattern, and postrelapse survival probabilities, however, differ significantly between patients. These distinctions can already be predicted at the time of CR achievement by means of histologic subtype and tumor size. Both factors are not only therapy independent, but were also the most discriminative and informative ones when used in combination. Our study thus provides evidence that risk-adapted follow-up is possible and may be useful for avoiding unnecessary exposure to radiation and disruptive, expensive, and painful follow-up investigations if these procedures are unlikely to detect relapses. Nearly every second patient belonged to the largest subgroup, RME 5 cm or smaller. The recurrence risk of this group was distinctively lower, and the relapse pattern much more favorable compared with larger embryonal tumors or RMA. But not only the risk of relapse and its pattern were more favorable in small RME. If a relapse occurred, postrelapse prognosis was at least two times better compared with the remaining subgroups. Although subsets with favorable postrelapse prognosis have also been identified in other reports, only a small proportion of patients belonged to them, and they could merely be identified after relapse.5,16 On the other side, the high relapse risk and poor prognosis of RMA resulting from its propensity for lymph-node involvement and metastatic recurrences is well known and has been the reason for classifying the alveolar histotype as unfavorable. Many clinicians therefore prescribe close meshed surveillance with numerous follow-up investigations for these patients.5,9,10,16-18,23,26 In our report, we show for the first time to our knowledge, that relapse risk, pattern, and postrelapse survival of RME larger than 5 cm are similar to RMA, especially in older individuals. Our series did not consider methods used for relapse detection, but it sheds light on the sites at risk.26 Because most recurrences were locoregional and a large proportion of SRs were combined, tumor-directed surveillance should focus on the primary tumor location, especially more than 4 years after diagnosis. Although we saw isolated recurrences occurring after an interval of as long as 14 years, more than 95% of all relapses appeared within the first 4 years, again in accord with other reports.5,9,10 All recurrences arising more than 4 years after initial diagnosis included the primary site (ie, were either LRs or combined relapses), and if such late recurrences occurred, every second individual survived.27,28 It can thus be concluded that long-term tumor-related follow-up is necessary, but can be confined to surveillance of the initial tumor site after more than 4 years as long as both types of recurrence detection and the value of surveillance for earlier relapse discovery remain unclear.11,12,14,15 Screening for metastatic relapses should center on imaging of the thorax as the most frequently involved site.26 It is questionable whether imaging of other sites is beneficial. Bone scans, for example, are recommended in some follow-up programs because of the feared impact of osseous metastases on prognosis.21,22 However, systemic recurrences affecting bone were rare, and other sites were concomitantly involved in most cases, raising questions as to the usefulness of such scans. Imaging of sites apart from the thorax is even more doubtful in RME 5 cm or smaller, because less than 1% of systemic recurrences involved other sites if CNS relapses are not considered. Compared with small RME, the remaining patients are exposed to a higher relapse risk, poor postrelapse prognosis, and a patchy relapse pattern. However, every sixth relapsed patient nevertheless survived, and this remaining option for cure may warrant more intense surveillance. Although none of the trials of the four major clinical study groups investigating pediatric RMS was superior in the prevention of metastatic relapses, the incidence of LRs differed clearly: It was 19% in our series, more than 30% in the MMT,9,10 22% in the Associazione Italiana Ematologia Oncologia Pediatrica,16 and a mere 13% in the Intergroup Rhabdomyosarcoma study (IRS) trials.5,26 These discrepancies reflect the different treatment philosophies with the IRS and MMT groups as antipodes. Whereas the primary end point was EFS in the IRS trials, it was OS in the MMT trials.6,9,10 Although survival is better in IRS patients, local therapy is more aggressive, including irradiation of most patients,5,6 whereas the MMT group avoided "radical" surgery/radiotherapy, accepting a higher relapse rate.4,6,9,10,29-31 The burden of therapy may therefore differ depending on the respective treatment philosophies. The CWS trials aimed to find a middle way between these antipodal concepts, trying to avoid both too-radical local treatment and inadequate local control; our findings may thus not be universally applicable for patients who were not treated according to CWS protocols. Raney reported in 198326 that 95% of children with recurrent RMS die. Postrelapse prognosis has since improved, but the reported probabilities differ5,9,10,16: 13% in IRS trials and 44% for locoregional and 18% for systemic recurrences in the MMT trials. Because the postrelapse survival rates of our report are similar to the MMT data, salvage therapy must thus not necessarily be less effective despite the more aggressive primary local treatment measures in the CWS trials to achieve comparable postrelapse survival. In contrast to other reports, we did not find postrelapse survival of botryoid RME to be better compared with other RMS, but the small quantity limits explanatory power.5 Conflicting data concerning the impact of primary surgery on salvage odds have been published.5,16 In our series, completely resected tumors at the time of primary diagnosis had a trend toward lower relapse risk and better postrelapse prognosis. A detailed analysis of the therapeutic interventions influencing postrelapse survival is not in the content of this report, but our series may still add some information.5,10,16,23 The omission of radiation during primary therapy depended on protocol philosophy and is associated with an increased relapse risk for subsets. These subsets with a remaining radiation option, however, had an improved postrelapse survival in accord with data from smaller trials.10,23 The IRS trials could not analyze the role of radiation for salvage either because most patients were irradiated initially5,6 or because the number of survivors was too small.26 The high rate of locoregional and combined relapses emphasizes the difficulties in defining CR at the end of primary therapy.10,32 Better pathologic, molecular, imaging, and surgical techniques may allow for improved diagnosis and relapse prediction (eg, minimal residual disease) in the future. Apart from defining subgroups with characteristic relapse pattern, risk, and postrelapse survival rendering risk-adapted, tumor-directed surveillance possible, our analysis may also be useful for early selection of patients with poor postrelapse prognosis, for which experimental approaches for further treatment are justified.21 Last, but not least, this report may be helpful to provide patients, parents, and guardians with information about their individual relapse risk.
The author(s) indicated no potential conflicts of interest.
Conception and design: Tobias M. Dantonello, Andreas Schuck, Bernhard F. Schmidt, Thomas Klingebiel, Ewa Koscielniak Administrative support: Sylvia Kirsch, Stefan S. Bielack, Joern Treuner, Ewa Koscielniak Provision of study materials or patients: Peter Winkler, Ivo Leuschner, Bernhard F. Schmidt, Helmut Lochbuehler, Stefan S. Bielack, Felix Niggli, Bernarda Kazanowska, Ruth Ladenstein, Thomas Wiebe, Joern Treuner, Ewa Koscielniak Collection and assembly of data: Tobias M. Dantonello, Christoph Int-Veen, Peter Winkler, Ivo Leuschner, Helmut Lochbuehler, Erika Hallmen, Iris Veit-Friedrich, Felix Niggli, Bernarda Kazanowska, Ruth Ladenstein, Thomas Wiebe, Joern Treuner, Ewa Koscielniak Data analysis and interpretation: Tobias M. Dantonello, Christoph Int-Veen, Ivo Leuschner, Bernhard F. Schmidt, Stefan S. Bielack, Thomas Klingebiel, Ewa Koscielniak Manuscript writing: Tobias M. Dantonello, Stefan S. Bielack, Ewa Koscielniak Final approval of manuscript: Tobias M. Dantonello, Christoph Int-Veen, Peter Winkler, Helmut Lochbuehler, Stefan S. Bielack, Felix Niggli, Ruth Ladenstein, Ewa Koscielniak
Participating institutions (for non-German institutions, the respective country is provided in brackets): Universitätsklinikum, Aachen; Kantonsspital Aarau (Switzerland); Kinderklinik, Augsburg; Klinikum Bamberg; Kinderspital, Basel (Switzerland); Kinderklinik, Bayreuth; Universitätsklinikum der Freien Universität, Charité, Berlin; Helios-Klinikum, Berlin; Robert-Rössle-Klinik, Charité, Berlin; Bundeswehrkrankenhaus, Berlin; Gilead Krankenanstalten, Bielefeld; Universitätsklinikum, Bochum; Universitätsklinik, Bonn; Städtische Kinderklinik, Braunschweig; Prof.-Hess-Kinderklinik, Bremen; Madarász children's hospital, Budapest (Hungary); Kinderklinik, Chemnitz; Kinderklinik, Coburg; Carl-Thiem-Klinikum, Cottbus; Vestische Kinderklinik, Datteln; Gyermekklinika, Debrecen (Hungary); Klinikum Dortmund; Universitätskinderklinik, Dresden; Städt. Krankenhaus, Dresden-Neustadt; Kinderklinik, Duisburg; Universitätsklinik, Düsseldorf; Kinderklinik, Erfurt; Universitätsklinikum, Erlangen; Universitätsklinik, Essen; Universitätsklinikum, Frankfurt; Universitätsklinik, Freiburg; Universitätsklinikum, Giessen; Klinikum am Eichert, Göppingen; Drottning Silvias barnsjukhus, Göteborg (Sweden); Universitätsklinik, Göttingen; Universitätsklinikum, Graz (Austria); Universitätsklinik, Greifswald; Universitätsklinik, Halle; Universitätsklinikum, Hamburg; Altonaer Kinderkrankenhaus, Hamburg; Krankenhaus, Hamm; Universitätsklinik, Hannover; Kinderkrankenhaus auf der Bult, Hannover; Universitätsklinik, Heidelberg; Gemeinschaftskrankenhaus, Herdecke; Städt. Krankenhaus, Hildesheim; Universitätsklinik, Homburg/Saar; Universitätsklinik, Jena; Kinderkliniken, Karlsruhe; Städt. Kliniken, Kassel; Universitätskinderklinik, Kiel; Landeskrankenhaus, Klagenfurt (Austria); Klinikum Kemperhof, Koblenz; Städt. Kinderkrankenhaus, Köln; Universitätsklinik, Köln; Kinderklinik, Krefeld; Rehabilitationskrankenhaus, Karlsbad-Langensteinbach; Universitätsklinikum, Leipzig; Landeskrankenhaus, Leoben (Austria); Klinikum, Leverkusen; Universitetssjukhuset, Linköping (Sweden); Klinikum Lippe-Detmold, Detmold; Kinderklinik, Linz (Austria); St. Annastift, Ludwigshafen; Universitätskinderklinik, Lübeck; Universitetssjukhuset, Lund (Sweden); Kantonsspital, Luzern (Switzerland); Universitätsklinik, Magdeburg; Universitätsklinikum, Mainz; Universitätsklinik, Mannheim; Universitätsklinikum, Marburg; Kinderklinik, Minden; Dr. von Haunersches Kinderspital, München; Kinderklinik, München-Harlaching; Universitätsklinikum, München-Schwabing; Universitätskinderpoliklinik, München; Universitätskinderklinik, Münster; Dietrich-Bonhoeffer-Klinikum, Neubrandenburg; Cnopf'sche Kinderklinik, Nürnberg; Klinikum, Oldenburg; Klinikum, Osnabrück; Klinikum, Pforzheim; Klinikum Oberschwaben, Ravensburg; Kinderklinik St. Hedwig, Regensburg; Universitätsklinik, Rostock; Klinikum, Saarbrücken; Krankenanstalten, Salzburg (Austria); Leopoldinakrankenhaus, Schweinfurt; Kinderklinik, Schwerin; DRK-Kinderklinik, Siegen; Kinderklinik, St. Augustin; Ostschweizer Kinderspital, St. Gallen (Switzerland); Astrid Lindgrens barnsjukhus, Karolinska Institutet, Stockholm (Sweden); Olgahospital, Stuttgart; Mutterhaus der Borromäerinnen, Trier; Universitätsklinikum, Tübingen; Universitätskinderklinik und Bundeswehrkrankenhaus, Ulm; Universitetssjukhuset, Umeå (Sweden); Universitetssjukhuset, Uppsala (Sweden); St. Anna Kinderspital, Vienna (Austria); Dr.-Horst-Schmidt-Kliniken, Wiesbaden; Kantonsspital, Winterthur (Switzerland); University Hospital, Wroclaw (Poland); Kinderklinik, Wolfsburg; Universitätskinderklinik, Würzburg; Kinderklinik, Wuppertal; Universitätsklinikum, Zürich (Switzerland). 
We thank the staff of all participating institutions and all patients, parents, and guardians for their willingness to participate in the CWS trials. We also thank Lynn Hazlewood for excellent manuscript review.
Supported by Grant No. 50-2721 from the Deutsche Krebshilfe, Bonn, Germany, and by the Foerderkreis Krebskranke Kinder e.V., Stuttgart, Germany. Presented in part at the 1st International Sarcoma Meeting Stuttgart, June 15-17, 2005, Stuttgart, Germany. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Klingebiel T, Pertl U, Hess CF, et al: Treatment of children with relapsed soft tissue sarcoma: Report of the German CESS/CWS REZ 91 trial. Med Pediatr Oncol 30:269-275, 1998[CrossRef][Medline] 24. Kaplan EL, Meyer P: Non-parametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958[CrossRef] 25. Greenwood M: Reports on public health and medical subjects: The errors of sampling of the survivorship tables. London, United Kingdom, H.M. Stationery Office, 1926 26. Raney RB Jr, Crist WM, Maurer HM, et al: Prognosis of children with soft tissue sarcoma who relapse after achieving a complete response: A report from the Intergroup Rhabdomyosarcoma Study I. Cancer 52:44-50, 1983[CrossRef][Medline] 27. Punyko JA, Mertens AC, Baker KS, et al: Long-term survival probabilities for childhood rhabdomyosarcoma: A population-based evaluation. Cancer 103:1475-1483, 2005[CrossRef][Medline] 28. Sung L, Anderson JR, Donaldson SS, et al: Late events occurring five years or more after successful therapy for childhood rhabdomyosarcoma: A report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group. Eur J Cancer 40:1878-1885, 2004[CrossRef][Medline] 29. Donaldson SS, Anderson JR: Rhabdomyosarcoma: Many similarities, a few philosophical differences. J Clin Oncol 23:2586-2587, 2005 30. Oeffinger KC, Mertens AC, Sklar CA, et al: Chronic health conditions in adult survivors of childhood cancer. N Engl J Med 355:1572-1582, 2006 31. Stevens MC: Treatment for childhood rhabdomyosarcoma: The cost of cure. Lancet Oncol 6:77-84, 2005[CrossRef][Medline] 32. Robertson J, Int-Veen C, Dantonello T, et al: Outcome of residual structures present at the end of therapy in parameningeal rhabdomyosarcoma. Sarcoma 9:1/2, 2005 (abstr P132)[CrossRef] Submitted April 19, 2007; accepted October 15, 2007.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
3 [including effusions]). The metastatic sites were coded in five site categories: "bone" (bone and/or bone marrow), "CNS" (brain), "thorax" (mediastinum, lung, and chest wall), "abdomen" (abdominal), and "other." If metastases occurred in more than one site category, patients were assigned to them in the sequence bone > CNS > thorax > abdomen > other because of the poor prognosis of patients with primary osseous and CNS metastases.
2 test. Multivariate analyses were carried out using the Cox proportional hazards model. A stepwise forward procedure was performed to identify independent prognostic variables on EFS. Each variable has been tested for inclusion in the final model. After each entry, variables already in the model have been tested for removal using the likelihood ratio. 
