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© 2003 American Society for Clinical Oncology Disseminated Neuroblastoma in Children Older Than One Year at Diagnosis: Comparable Results With Three Consecutive High-Dose Protocols Adopted by the Italian Co-Operative Group for Neuroblastoma
From the Departments of Hematology-Oncology and Surgery, and Service of Pathology, Giannina Gaslini Children’s Hospital; Laboratory for Population Genetics, and Clinical Epidemiology Unit, National Cancer Research Institute, Genova; the Division of Oncology, Bambino Gesù Children’s Hospital, Roma; the Civic Hospital, Bergamo; and the Department of Pediatrics, Universities of Bologna, Brescia, Catania, Napoli, Padova, Palermo, Pavia, Torino, and Trieste, Italy. Address reprint requests to Bruno De Bernardi, MD, Giannina Gaslini Children’s Hospital, Largo Gerolamo Gaslini 5, 16147 Genova, Italy; email: brunodebernardi{at}ospedale-gaslini.ge.it.
Purpose: To compare the outcomes associated with modifications in three consecutive protocols employed by the Italian Co-Operative Group for Neuroblastoma (ICGNB) in disseminated neuroblastoma. Patients and Methods: Between January 1985 and November 1997, a total of 359 children aged 1 to 15 years with newly diagnosed stage 4 neuroblastoma were enrolled in three consecutive protocols. Compared with ICGNB-85, the ICGNB-89 protocol contained two more chemotherapy cycles, and some drugs were given at greater doses, whereas in the ICGNB-92 protocol, the induction phase included a chelating agent, and individual cycles contained four drugs instead of two. Results: A total of 330 of 359 evaluable children were included in this analysis; 106 children were treated with ICGNB-85, 65 children were treated with ICGNB-89, and 159 children were treated with ICGNB-92 protocols. Radical resection of primary tumor was carried out in 59.4%, 50.8%, and 57.9% of the patients, respectively. Major tumor response after induction therapy was achieved in 66.7%, 69.2%, and 68.6% of the patients, respectively. A total of 218 of 232 patients received consolidation therapy consisting of conventional chemotherapy in 65 patients and of high-dose chemotherapy in 153 patients. Disease recurrence or progression occurred in 82.1%, 69.2%, and 74.8% of the patients, respectively. Therapy-related deaths occurred in 1.9%, 12.3%, and 6.9% of the patients, respectively. Five-year overall survival (OS) for the three studies was 26%, 23%, and 28%, and event-free survival (EFS) was 19%, 17%, and 17%, respectively. Conclusion: The therapeutic modifications adopted in the ICGNB-89 and ICGNB-92 protocols were not associated with a significant improvement in response rate or in the 5-year OS and EFS as compared with the ICGNB-85 protocol. Attempts at intensifying chemotherapy were associated with greater toxicity.
APPROXIMATELY ONE half of the children with newly diagnosed neuroblastoma present with widespread disease, mostly involving the skeleton and bone marrow.1 In the past, except for infants (age 0 to 11 months),2 prognosis of children treated with standard-dose chemotherapy was almost uniformly poor.3 In the early 1980s, better supportive measures allowed physicians to significantly intensify chemotherapy and perform successful surgery on an increasing number of patients. This led to higher percentages of response and lengthening of both overall survival (OS) and event-free survival (EFS).4–15 The Italian Co-Operative Group for Neuroblastoma (ICGNB) was among the several groups reporting this progress. Compared with the previous study, the ICGNB-85 protocol induction therapy used almost twice the dose of cisplatin and peptichemio (a multipeptidic complex of m-L-phenylalanine mustard, endowed with alkylating and antimetabolic properties).16–18 An increase in the 5-year OS from 11% to 27%, and EFS from 9% to 18%, was observed.9 On the basis of these encouraging results, it was hypothesized that proper modifications of the ICGNB-85 protocol could further improve these results. In 1989 and 1992, two subsequent protocols were activated with this aim. In the ICGNB-89 protocol, the changes consisted of the addition of two cycles of chemotherapy in the early phases of treatment and an increase in peptichemio dosage. In the ICGNB-92 protocol, the changes were more profound: the number of drugs in each cycle of the induction phase was increased from two to four, and each cycle was preceded by the infusion of deferoxamine, a iron-chelating agent that inhibits ribonucleotide reductase, which is a critical enzyme for DNA synthesis and is capable of potent antiproliferative activity on human neuroblastoma cells in vitro.19–21 This article evaluates whether the above modifications were associated with a significant improvement in patients’ outcome.
Patients All children between 1 and 15 years of age with stage 4, previously untreated neuroblastoma diagnosed in 21 Italian pediatric institutions (see Appendix) were prospectively registered into three consecutive uncontrolled studies covering 13 years of activity of the ICGNB, provided that they had no major organ dysfunction. Diagnosis of neuroblastoma was made on histologic grounds or, in some cases, on the basis of unequivocal bone marrow infiltration associated with appropriate clinical presentation and imaging studies, usually supported by abnormal urinary catecholamine excretion.9 The biologic features of the tumors were determined in a single reference laboratory.22 Enrollment in the ICGNB-85 protocol began in January 1985 and was closed in April 1989. Enrollment in the ICGNB-89 protocol started in May 1989 and ended in June 1992. Enrollment in the ICGNB-92 protocol started in July 1992 and was closed in November 1997. The three studies were approved by the ethical committees of all participating centers. The patients’ parents or guardians were required to give their consent before therapy was started.
Treatment Protocols
ICGNB-85 Protocol Induction therapy consisted of a single cycle of peptichemio 450 mg/m2 followed by two cycles of cyclophosphamide 600 mg/m2, vincristine 1.5 mg/m2, and cisplatin 200 mg/m2. Early consolidation was made up of two cycles of doxorubicin 45 mg/m2 and teniposide 375 mg/m2. HDCT consisted of vincristine 4 mg/m2, total-body irradiation, and melphalan 140 mg/m2. For those who could not receive HDCT, the 3cCT consisted of one cycle of peptichemio; one cycle of vincristine, teniposide, and cisplatin; and one cycle of cyclophosphamide and doxorubicin.
ICGNB-89 Protocol
ICGNB-92 Protocol
Definition and Evaluation of Tumor Response In all three studies, tumor response is reported after induction therapy and before late consolidation phase. Furthermore, the best response to treatment protocol in each patient is reported. For ICGNB-85 protocol, the evaluation of tumor response included an imaging study of the primary lesion, a bone marrow study by at least one aspirate and a core biopsy, a bone study by x-ray and/or bone scintigraphy in case of bone involvement at diagnosis, and standard laboratory parameters including tumor markers. For ICGNB-89 and ICGNB-92 protocols, the bone marrow evaluation was more extensive and included two aspirates and two biopsies, and an iodine-123 (123I) or 131I-metaiodobenzylguanidine scintigraphy was performed in most patients to better detect skeletal involvement. For this study, objective response was reassessed by the same team of oncologists.
Surgical Resection of Primary Tumor
Statistical Analyses
Comparisons between proportions were performed by the Multivariate assessments of OS and EFS times were performed by Cox’s proportional hazards model. All potential prognostic factors were initially included in the multivariate model. Variables that were not significantly associated with OS or EFS were removed from the model by means of a step-down procedure on the basis of the likelihood ratio test. The same test was used to assess the significance of interaction terms between covariates. Hazard ratios, which estimated the ratio between rates of death or progression in two groups, were computed by exponentiation of the coefficients estimated in the multivariate model. All tests were two-tailed.
During the study period, a total of 1,109 patients with a diagnosis of neuroblastoma were registered at the data center of the ICGNB, of whom 977 were eligible to enter one of the ongoing protocols. The reasons for ineligibility included age above 15 years in 11 patients, previous antitumor treatment in 12 patients, diagnosis of malignancy other than neuroblastoma in 27 patients, diagnosis of ganglioneuroma in 33 patients, and other reasons in 29 patients. Of the 997 eligible patients, 476 had localized disease (stage 1 to 3), 421 had disseminated disease (stage 4), and 100 had stage 4s disease. Of the 421 patients with disseminated disease, 14 were not enrolled in the stage 4 neuroblastoma protocol active at that time for medical reasons or parental refusal. Of the 407 who were enrolled, 48 were younger than 1 year at the time of diagnosis, leaving 359 children aged between 1 and 15 years. Twenty-nine of these 359 patients were registered by one institution that discontinued registration during the study period to adopt a non-ICGNB protocol and were thus excluded from the analysis. Of the remaining 330 patients, 106 were enrolled in ICGNB-85, 65 were enrolled in ICGNB-89, and 159 were enrolled in the ICGNB-92 protocol. The enrollment rate of these patients during the study period, expressed as the number patients per month in the three studies, was 2.0, 1.7, and 2.4, respectively. This analysis reports the outcome of these studies as of October 2001, 48 months after the inclusion of the last patient.
The main characteristics at diagnosis of the three patient groups are shown in Table 1
Resection of Primary Tumor A total of 39 patients (11.8%) underwent radical resection of the primary tumor at the time of diagnosis, and 149 others (45.1%) had radical resection of the primary tumor at the end of induction therapy. In summary, radical resection was carried out in 57.0% of the patients (59.4%, 50.8%, and 57.9% for the three studies, respectively). Two patients died within the month following the operation; one patient was in the ICGNB-89 protocol and one was in the ICGNB-92 protocol.
Response to Induction Chemotherapy
Response After Early Consolidation Therapy Evaluation of disease status at completion of early consolidation therapy (which included surgery in most cases) showed a complete response rate of 40.6%, 23.1%, and 16.4%, respectively, and a partial response rate in 34.9%, 38.5%, and 54.1%, with an overall major response rate of 75.5%, 61.6%, and 70.5% for the three studies, respectively (Table 2  ). There were no deaths in this phase of treatment in the ICGNB-85 protocol, versus one death (therapy related) in the ICGNB-89 protocol, versus two deaths (one was therapy related) in ICGNB-92 protocol.
Late Consolidation Therapy Overall, 56.6%, 40.0%, and 42.1% of the patients for the three studies, respectively, achieved a complete response while treated with the respective protocols.
Disease Recurrence or Progression
Therapy-Related Deaths In the three studies, therapy-related deaths occurred in two (1.9%), eight (12.3%), and 11 (6.9%) patients, respectively (Table 3 ). In the ICGNB-85 protocol, both of the toxic deaths occurred after HDCT and were caused by renal failure in one patient and by myeloid leukemia (FAB M4 type, 50 to 54 XY karyotype with multiple trisomies and 11q23 translocation) in the other patient. In the ICGNB-89 protocol, three patients died during induction therapy (two of infection, one after surgery), one patient died after early consolidation therapy (renal failure), and four patients died after HDCT (one of sepsis and three of veno-occlusive disease). In the ICGNB-92 protocol, five patients died during induction therapy (two of infection, one of heart failure, one of renal failure, and one of brain hemorrhage), one patient died after surgery, and five patients died after HDCT (three of veno-occlusive disease, one of pneumonia, and one of brain hemorrhage).
Analysis of OS and EFS
Multivariate analyses included all of the patients (219 patients) for whom data were available regarding all of the prognostic factors that were considered (excluding MYCN gene). The analyses confirmed the lack of any significant improvement between ICGNB-85 and the following two studies for both OS and EFS (P = .57 and .38, respectively). The only factors that were significantly associated with OS were age (P = .01), LDH (P = .01), and with marginal significance, skeletal involvement (P = .06). The same results were seen for EFS (age, P = .01; LDH, P = .01; skeletal involvement, P = .04). When the analyses were restricted to the subset of 143 patients evaluated for MYCN gene, this characteristic was a significant multivariate predictor of both OS and EFS (P = .04 and 0.03, respectively). The possibility that the varying effectiveness of the study protocols only involve specific subgroups of patients was assessed by introducing the appropriate interaction terms into the multivariate models. A significant interaction was found for OS among the protocols and the two factors age at diagnosis (P = .04) and bone marrow involvement (P = .05). This interaction indicates greater efficacy of the two more recent protocols in children older than 2 years of age at diagnosis and in children without bone marrow involvement at diagnosis. For EFS, the presence of a significant interaction was only confirmed for bone marrow involvement (P = .01). However, these associations were observed in post hoc analyses, and no correction for multiplicity was made. The role of HDCT was investigated in 218 patients who achieved major response after induction chemotherapy and surgery and who received either HDTC or 3cCT as late consolidation. In a multivariate Cox model that included the treatment protocol and response status (complete response v partial response) as covariates, an improvement of marginal statistical significance was seen among patients who received HDCT for both OS (hazard ratio, 0.76; 95% CI, 0.53 to 1.09) and EFS (hazard ratio, 0.71; 95% CI, 0.51 to 1.01).
Until the early 1980s, only few children with widespread neuroblastoma detected after the age of 1 year were alive beyond 5 years from diagnosis.1,3 With the advent of intensified therapeutic regimens, however, several investigators,4–15 including ourselves,5,9,23 reported a significant increase in response rate and in the number of long-term survivors. This remarkable success encouraged researchers to seek further improvements through proper modifications of the regimens adopted in the early, intensified protocols. With this in mind, the ICGNB designed and activated the ICGNB-89 protocol, which had more chemotherapy cycles and increased dosage of some drugs compared with ICGNB-85. These changes were associated with greater toxicity with no improvement in tumor response, thus leading to the early closure of the study and the design of the ICGNB-92 protocol. ICGNB-92 was characterized by the administration of a chelating agent before cycles of induction phase and the increase from two to four drugs per cycle. Disappointingly, comparison of the results of ICGNB-89 and ICGNB-92 protocols to those of the ICGNB-85 fails to provide evidence of any noteworthy improvement. OS and EFS at 5 years from diagnosis were in fact similar in the three groups of patients, whereas the major response rate actually decreased from ICGNB-85 to the following two studies because of the stricter response evaluation criteria used in the last two protocols. The methodological limitations of this analysis require comment. First, the three groups of patients were not obtained by random assignment to treatment, and their comparability is, therefore, questionable. However, all patients of the three studies were consecutively registered by the same centers, and the enrollment rate was relatively stable in the three periods. Furthermore, these patients represent approximately three fourths of the patients with stage 4 neuroblastoma diagnosed in Italy during the study period, and there is little reason to believe that significant changes occurred over time in the selection process. These facts, together with the lack of recent major changes in the epidemiology of neuroblastoma or in the distribution of its biologic characteristics, indicate that any baseline differences among the three groups could have but marginal prognostic implications. Second, patients were diagnosed, evaluated for disease extent at diagnosis, and assessed for tumor response at different times when different technologies were being used, thus potentially biasing the comparison of outcome. It must be stressed, however, that the same staging criteria were used in the three studies and that the same team of oncologists reviewed all clinical data. Comparison with historical controls usually shows spurious survival improvement because of the lead-time bias caused by earlier diagnosis and stage migration. Despite these potential biases, OS, which was uniformly assessed during the entire period, was similar in the three groups, mirroring the lack of improvement that was observed in response rate and EFS. Last, one might rightly argue that the size of the three groups of patients being compared was inadequate to detect moderate yet clinically worthwhile treatment effects. Conversely, the greater toxicity of the ICGNB-89 and ICGNB-92 protocols (caused by the increase in the number of drugs, overall amount of drugs administered, and dose-intensity) could be justified only if associated with a substantially better outcome. On the basis of the observed results, clinically meaningful increases in long-term survival can be reasonably ruled out even with the limited size of our study groups. Thus, the modifications introduced in the two more recent protocols have proved to be ineffective and conversely associated with significantly greater toxicity. For instance, although no toxic mortality was recorded in the ICGNB-85 induction therapy, therapy-related deaths were approximately 3% in both the ICGNB-89 and ICGNB-92 protocols. In addition, possibly because of the more toxic up-front therapy, more ICGNB-89 and ICGNB-92 patients developed fatal complications after HDCT compared with ICGNB-85 patients. These facts indicate that attempts at further intensifying therapy to improve results may be associated with significant risks and may nullify the possible benefit of achieving greater dose-intensity. Analysis of survival shows that both OS and EFS curves of the three patient groups almost perfectly superimpose at 5 years from diagnosis. During the study period, the use of HDTC progressively became more common in the Italian participating institutions. Its efficacy in improving EFS was recently confirmed in a large, randomized study.13 Our own data also indicate that HDCT was apparently associated with improved OS and EFS in multivariate analysis, after adjustment for response status after early consolidation therapy. Yet although a greater percentage of ICGNB-89 and ICGNB-92 patients were treated with HDCT compared with ICGNB-85 (providing proof of the increasing number of institutions that became familiar with HDCT throughout the study period), this imbalance apparently did not translate into better outcome. Two possible explanations may account for this apparent discrepancy. First, the similar outcome observed in our three studies might depend on a dilution effect, because the possible benefit of HDCT would involve less than one half of the overall patient population. Second, the lack of clearly defined and stable criteria for response and selection of patients to be treated by HDCT undermines the reliability of the comparison of OS and EFS between these patients and those receiving conventional maintenance chemotherapy. As a consequence, the lack of improvement in the overall patient population could simply reflect the poor effectiveness of the procedure when deployed in the field, the different outcome between patients who had undergone HDCT and conventional chemotherapy being attributable to the selection criteria. Additional studies are needed to clarify this point. Overall, approximately one fourth of our patients survived at 5 years from diagnosis, and only one fifth did so without suffering any unfavorable events during this time. These figures are obviously disappointing. The comparison of our data with other reports is difficult because few publications have reported results of large multicentric trials.6,7,10,11,13 In particular, it is not appropriate to compare our results with those of studies of limited size15,27,29 or shorter follow-up8 or with results derived from studies for which patients were selected to be treated by HDCT on the basis of response to first-line therapy.10,12,27,30 Perhaps one comparable series is that of Matthay et al,13 which reports the results of a large study that included some stage 3 and relapsed stage 2 patients. Although the treatment for these patients was overall more aggressive than our three protocols and radiation therapy was regularly administered to primary tumor and nonresponding metastatic sites, the 3-year EFS of that series was only 30%—not far from our 24%. The stability of our results over time indicates that substantial therapeutic changes are needed. First, a more widespread and consistent use of treatments that have shown to favorably influence OS and EFS in high-risk neuroblastoma, such as HDCT and retinoic acid derivatives,13 is warranted. Second, new treatment modalities should be assessed in properly designed clinical trials. For example, chemotherapy could perhaps be rendered more effective by reducing the time interval between cycles, as tested in a recently completed randomized study of the European Neuroblastoma Study Group.31 Both irradiation of the primary tumor site32 and radiometabolic therapy33 could lower the high local relapse rate. Finally, the administration of biologic immunological therapies34 aimed at eradicating minimal residual disease should be considered in large cooperative studies.
The following main investigators and institutions participated in this study: Bruno De Bernardi, Alberto Garaventa, Massimo Conte, Giannina Gaslini Children’s Hospital, Genova; Alberto Donfrancesco, Alessandro Jenkner, Bambino Gesù Children’s Hospital, Roma; Paolo Indolfi, Fiorina Casale, Department of Pediatrics, University of Napoli, Napoli; Maurizio Bianchi, Department of Pediatrics, University of Torino, Torino; Modesto Carli, Department of Pediatrics, University of Padova, Padova; Giovanni Surico, Nicola Santoro, Department of Pediatrics, University of Bari, Bari; Andrea Pession, Third Department of Pediatrics, University of Bologna, Bologna; Margherita Lo Curto, Department of Pediatrics, University of Palermo, Palermo; Luca Tonegatti, Katia Tettoni, Departments of Pediatrics and Surgery, University of Brescia, Brescia; Andrea Zanazzo, Burlo Garofalo Children’s Hospital, Trieste; Monica Cellini, Department of Pediatrics, University of Modena, Modena; Giancarlo Izzi, Department of Pediatrics, University of Parma, Parma; Andrea Di Cataldo, Department of Pediatrics, University of Catania, Catania; Gabriella Bernini, Department of Pediatrics, University of Firenze, Firenze; Claudio Favre, Department of Pediatrics, University of Pisa, Pisa; Pier Emilio Cornelli, Division of Pediatrics, Civic Hospital, Bergamo; Maria Angelica Fabbro, Division of Pediatric Surgery, Civic Hospital, Vicenza; Federico Bonetti, Department of Pediatrics, University of Pavia, Pavia; Augusto Amici, Department of Pediatrics, University of Perugia, Perugia; Antonio Acquaviva, Department of Pediatrics, University of Siena, Siena; Roberto Targhetta, Department of Pediatrics, University of Cagliari, Cagliari; and Domenico Gallisai, Department of Pediatrics, University of Sassari, Sassari, Italy.
We thank Barbara Galleni and Filippo Papio for data management and assistance in statistical analyses and Sara Calmanti for excellent secretarial assistance. The authors are greatly indebted to the many physicians and nurses who heartily participated in the clinical care of the children enrolled in the three protocols.
Supported in part by research grants from the Giannina Gaslini Children’s Hospital and the Italian Neuroblastoma Association, Genova, Italy.
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13. Matthay KK, Villablanca JG, Seeger RC, et al: Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid. N Engl J Med 341:1165–1173, 1999 14. Frappaz D, Micron J, Coze C, et al: LMCE3 treatment strategy: Results in 99 consecutively diagnosed stage 4 neuroblastomas in children older than 1 year at diagnosis. J Clin Oncol 18:468–476, 2001 15. Cheung NK, Kushner BH, LaQuaglia MP, et al: N7: A novel multi-modal therapy of high-risk neuroblastoma in children diagnosed over 1 year of age. Med Pediatr Oncol 36:227–230, 2001[CrossRef][Medline] 16. Schmidt FA, Banks SE, Stock CC: Comparative antitumor effects of peptichemio and other alkylating agents. Cancer Treat Rep 61:473–475, 1977[Medline] 17. Barlogie B, Drewinko B, Gohde W, et al: Lethal and kinetic effects of peptichemio on cultured lymphoma cells. Cancer Res 37:2353–2358, 1977 18. De Bernardi B, Pastore G, Carli M, et al: Effect of peptichemio in nonlocalized neuroblastoma. Cancer 50:10–17, 1978
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27. Kletzel M, Katzenstein HM, Haut PR, et al: Treatment of high-risk neuroblastoma with triple-tandem high-dose therapy and stem-cell rescue: Results of the Chicago pilot II study. J Clin Oncol 20:2284–2292, 2002 28. McCowage GB, Vowels MR, Shaw PJ, et al: Autologous bone marrow transplantation for advanced neuroblastoma using teniposide, doxorubicin, melphalan, cisplatin, and total-body irradiation. J Clin Oncol 13:2789:2795, 1995 29. Klingebiel T, Bader P, Bares R, et al: Treatment of neuroblastoma stage 4 with 131-I-meta-iodo-benzylguanidine, high-dose chemotherapy and immunotherapy. A pilot study Eur J Cancer 34:1398–1402, 1998[CrossRef][Medline] 30. Hartmann O, Valteau-Couanet D, Vassal G, et al: Prognostic factors in metastatic neuroblastoma in patients over 1 year of age treated with high-dose chemotherapy and stem cell transplantation: A multivariate analysis in 218 patients treated in a single institution. Bone Marrow Transplant 23:789–795, 1999[CrossRef][Medline] 31. Pearson ADJ, Pinkerton CR, Lewis IJ: European Neuroblastoma Group fifth study (ENSG 5): A randomised study of dose intensity in stage 4 neuroblastoma over the age of one, in Evans AE, Biedler JL, Brodeur GM, D’Angio GJ, Nakagawara A (eds): Progress in Clinical and Biological Research-Advances in Neuroblastoma Research, New York, Wiley-Liss, 1994, pp 385–394
32. Kushner BH, Wolden S, LaQuaglia MP, et al: Hyperfractionated low-dose radiotherapy for high-risk neuroblastoma after intensive chemotherapy and surgery. J Clin Oncol 19:2821–2828, 2001 33. Garaventa A, Bellagamba O, Lo Piccolo MS, et al: 131-I-metaiodobenzylguanidine (131-I-MIBG) therapy for residual neuroblastoma: A mono-institutional experience with 43 patients. Br J Cancer 81:1378–1384, 1999[CrossRef][Medline] 34. Cheunk NK: Monoclonal antibody-based therapy for neuroblastoma. Curr Oncol Rep 2:547–553, 2000[Medline] Submitted May 29, 2002; accepted January 17, 2003.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test for heterogeneity or, when appropriate, by Fisher’s exact test. The probabilities of OS and EFS were calculated from the time of diagnosis, according to the Kaplan-Meier product-limit method. With regard to OS analyses, death by any cause was considered an event. In EFS analyses, disease progression, recurrence, and death by any cause, whichever first, were considered events. Survival curves were compared by means of the log-rank test. 
