Pediatr Blood Cancer 2014;61:2149–2150
HIGHLIGHT
by Patrick J. Leavey, MD*
Important Principles in Ewing Sarcoma Treatment
I
n this issue of Pediatric Blood Cancer, Raciborska et al. described their success in implementing complex protocolbased treatment of children under 18 years of age with newly diagnosed Ewing Sarcoma, in Poland, a country with limited health care resources [1]. The authors reviewed the development of a pilot consortium of seven treatment sites; developed regional guidelines based on published EURO-Ewing 99 experience [2] and implemented the centralization of surgical care during the period between 2000 and 2009. They concluded that through national collaborative groups, the coordination and optimization of limited resources are keys to the successful dissemination of complex cancer protocols worldwide. According to the World Bank, Poland ranks as a high-income country with a population of 38.5 million people and a gross domestic product of $517.5 billion [3]. In a report describing the outcomes for childhood cancer between 2000 and 2007, Poland reported worse outcomes compared to other European countries [4]. However, Poland had only partial representation of its population because of a limited cancer registry and reported the best overall survival within the eastern European category [4]. Furthermore two important attributes were identified: the development of a Polish National Cancer Plan, and the national Polish Society of Pediatric Hematology/Oncology efforts to implement European standards of care for children with cancer. Importantly since the time period overlaps with the current report by Raciborska et al., Ewing sarcoma was recognized as one of several tumors where no improved outcome was noted within the EUROCARE-5 data [4]. In the most recent Children’s Oncology Group (COG) nonmetastatic Ewing sarcoma study (2001–2005), patients who received the experimental arm of interval compressed chemotherapy experienced a 73% five-year event free survival [5]. This was statistically significantly better than the 65% 5-year EFS for patients who received standard therapy [5]. The results for the nonmetastatic Ewing sarcoma patient treated on the EURO-Ewing 99 study have not yet been reported in peer-reviewed literature, so published comparisons are not available, although the 68% estimated five-year overall survival for localized patients, reported by Raciborska et al., is similar to prior international experience [6]. Raciborska et al. emphasized the importance of surgical expertise. Fifty-three percent of patients had local control by surgery alone, and a further 11 patients underwent thoracotomy and metastectomy. While there are abundant data emphasizing the importance of adequate resection in Ewing sarcoma [7], the importance of surgical control of pulmonary metastases is less well defined [8,9] and is not universally implemented. However, centralizing surgery is consistent with recommendations from the ESMO clinical practice guidelines in their emphasis on referral to a
C
2014 Wiley Periodicals, Inc. DOI 10.1002/pbc.25214 Published online in Wiley Online Library (wileyonlinelibrary.com).
specialized bone sarcoma treatment center for such patients [10]. Twenty-six percent of patients achieved local control by a combination of surgery post-operative radiotherapy. The strategy of post-operative radiation for poor tumor necrosis, as recommended by Dunst et al. in their retrospective review [11], has not been incorporated into current COG studies. However, the authors correctly highlight the critical importance of central radiotherapy review, a factor that was highlighted by Cooperative Ewing Sarcoma Study (CESS) experience [12]. Given resource limitations experienced by Raciborska et al. and highlighted by others describing implementation of cancer programs in low/middle income countries (LMIC) [13,14], what can be further learned from this report? The conclusions drawn by Raciborska et al. are consistent with elements outlined by Rodriguez-Galindo et al. who described the global challenge of childhood cancer [14]. Cancer is the leading cause of nonaccidental death in children in high-income countries (HIC) and becoming so in less developed countries. Rodriguez-Galindo et al. identified the importance of cancer registries and development of national/regional treatment centers. They emphasized the importance of provider and patient education regarding the presentation and diagnosis of childhood cancer aimed at reducing the likelihood of therapy abandonment and reduction of the lag time between presentation and initiation of treatment. In a more disease focused report, Hunger et al. recommended intensity-adjusted algorithms in planning childhood acute lymphoblastic leukemia treatment and also highlighted the importance of adaptation of therapies [15]. Raciborska et al. have successfully implemented complex treatment strategies for patients with a highly aggressive solid tumor and have identified steps to continue to advance outcomes for children with Ewing sarcoma in their country [1]. In HIC, where the vast majority of worldwide cancer research expenditure is spent and where 94% of global economic cancer related estimated costs exists [14], there are increasing limitations on centralized resources. Experience, such as that documented by Polish colleagues in the current report, reinforces the need to sustain cooperative study
Division of Pediatric Hematology/Oncology, Department of Pediatrics the University of Texas Southwestern Medical Center, Dallas, Texas Conflict of interest: Nothing to declare. Correspondence to: Patrick J. Leavey, Associate Professor of Pediatrics, University of Texas Southwestern Medical Center Dallas, 5323 Harry Hines Blvd, Dallas, TX 75290-9063. E-mail: [email protected]
Received 15 July 2014; Accepted 17 July 2014
2150
Leavey
group funding, to adapt complex cytotoxic regimens for high-risk cancer, such as Ewing Sarcoma by incorporating novel agents and to advocate for more expedient availability of novel agents for evaluation in children.
REFERENCES 1. Raciborska AB K, Drabko K, Chaber R, et al. Validation of a multimodal treatment protocol for Ewing Sarcoma - A report from the Polish Pediatric Oncology Group. Pediatr Blood Cancer 2014. 2. Juergens C, Weston C, Lewis I, et al. Safety assessment of intensive induction with vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) in the treatment of Ewing tumors in the EURO-E.W.I.N. G. 99 clinical trial. Pediatr Blood Cancer 2006;47:22–29. 3. The World Bank Group - International Comparison Program. Poland fact sheet. http://data.worldbank. org/country/poland Published 2011. Accessed July 15, 2014. 4. Gatta G, Botta L, Rossi S, et al. Childhood cancer survival in Europe 1999–2007 : Results of EUROCARE-5–a population-based study. Lancet Oncol 2014;15:35–47. 5. Womer RB, West DC, Krailo MD, et al. Randomized controlled trial of interval-compressed chemotherapy for the treatment of localized Ewing sarcoma: A report from the Children’s Oncology Group. J Clin Oncol 2012;30:4148–4154.
Pediatr Blood Cancer DOI 10.1002/pbc
6. Grier HE, Krailo MD, Tarbell NJ, et al. Addition of ifosfamide and etoposide to standard chemotherapy for Ewing’s sarcoma and primitive neuroectodermal tumor of bone. New Engl J Med 2003;348:694–701. 7. Krasin MJ, Davidoff AM, Rodriguez-Galindo C, et al. Definitive surgery and multiagent systemic therapy for patients with localized Ewing sarcoma family of tumors: Local outcome and prognostic factors. Cancer 2005;104:367–373. 8. Letourneau PA, Shackett B, Xiao L, et al. Resection of pulmonary metastases in pediatric patients with Ewing sarcoma improves survival. J Pediatr Surg 2011;46:332–335. 9. Tronc F, Conter C, Marec-Berard P, et al. Prognostic factors and long-term results of pulmonary metastasectomy for pediatric histologies. Eur J Cardio-Thorac 2008;34:1240–1246. 10. Hogendoorn PC, Group EEW, Athanasou N, et al. Bone sarcomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2010;21:v204–213. 11. Dunst J, Schuck A. Role of radiotherapy in Ewing tumors. Pediatr Blood Cancer 2004;42:465–470. 12. Dunst J, Sauer R, Burgers JM, et al. Radiation therapy as local treatment in Ewing’s sarcoma. Results of the Cooperative Ewing’s Sarcoma Studies CESS 81 and CESS 86. Cancer 1991;67: 2818–2825. 13. Gupta S, Rivera-Luna R, Ribeiro RC, et al. Pediatric oncology as the next global child health priority: The need for national childhood cancer strategies in low- and middle-income countries. PLoS medicine 2014;11:e1001656. 14. Rodriguez-Galindo C, Friedrich P, Morrissey L, et al. Global challenges in pediatric oncology. Curr Opin Pediatr 2013;25:3–15. 15. Hunger SP, Sung L, Howard SC. Treatment strategies and regimens of graduated intensity for childhood acute lymphoblastic leukemia in low-income countries: A proposal. Pediatr Blood Cancer 2009;52: 559–565.
HIGHLIGHT
by Patrick J. Leavey, MD*
Important Principles in Ewing Sarcoma Treatment
I
n this issue of Pediatric Blood Cancer, Raciborska et al. described their success in implementing complex protocolbased treatment of children under 18 years of age with newly diagnosed Ewing Sarcoma, in Poland, a country with limited health care resources [1]. The authors reviewed the development of a pilot consortium of seven treatment sites; developed regional guidelines based on published EURO-Ewing 99 experience [2] and implemented the centralization of surgical care during the period between 2000 and 2009. They concluded that through national collaborative groups, the coordination and optimization of limited resources are keys to the successful dissemination of complex cancer protocols worldwide. According to the World Bank, Poland ranks as a high-income country with a population of 38.5 million people and a gross domestic product of $517.5 billion [3]. In a report describing the outcomes for childhood cancer between 2000 and 2007, Poland reported worse outcomes compared to other European countries [4]. However, Poland had only partial representation of its population because of a limited cancer registry and reported the best overall survival within the eastern European category [4]. Furthermore two important attributes were identified: the development of a Polish National Cancer Plan, and the national Polish Society of Pediatric Hematology/Oncology efforts to implement European standards of care for children with cancer. Importantly since the time period overlaps with the current report by Raciborska et al., Ewing sarcoma was recognized as one of several tumors where no improved outcome was noted within the EUROCARE-5 data [4]. In the most recent Children’s Oncology Group (COG) nonmetastatic Ewing sarcoma study (2001–2005), patients who received the experimental arm of interval compressed chemotherapy experienced a 73% five-year event free survival [5]. This was statistically significantly better than the 65% 5-year EFS for patients who received standard therapy [5]. The results for the nonmetastatic Ewing sarcoma patient treated on the EURO-Ewing 99 study have not yet been reported in peer-reviewed literature, so published comparisons are not available, although the 68% estimated five-year overall survival for localized patients, reported by Raciborska et al., is similar to prior international experience [6]. Raciborska et al. emphasized the importance of surgical expertise. Fifty-three percent of patients had local control by surgery alone, and a further 11 patients underwent thoracotomy and metastectomy. While there are abundant data emphasizing the importance of adequate resection in Ewing sarcoma [7], the importance of surgical control of pulmonary metastases is less well defined [8,9] and is not universally implemented. However, centralizing surgery is consistent with recommendations from the ESMO clinical practice guidelines in their emphasis on referral to a
C
2014 Wiley Periodicals, Inc. DOI 10.1002/pbc.25214 Published online in Wiley Online Library (wileyonlinelibrary.com).
specialized bone sarcoma treatment center for such patients [10]. Twenty-six percent of patients achieved local control by a combination of surgery post-operative radiotherapy. The strategy of post-operative radiation for poor tumor necrosis, as recommended by Dunst et al. in their retrospective review [11], has not been incorporated into current COG studies. However, the authors correctly highlight the critical importance of central radiotherapy review, a factor that was highlighted by Cooperative Ewing Sarcoma Study (CESS) experience [12]. Given resource limitations experienced by Raciborska et al. and highlighted by others describing implementation of cancer programs in low/middle income countries (LMIC) [13,14], what can be further learned from this report? The conclusions drawn by Raciborska et al. are consistent with elements outlined by Rodriguez-Galindo et al. who described the global challenge of childhood cancer [14]. Cancer is the leading cause of nonaccidental death in children in high-income countries (HIC) and becoming so in less developed countries. Rodriguez-Galindo et al. identified the importance of cancer registries and development of national/regional treatment centers. They emphasized the importance of provider and patient education regarding the presentation and diagnosis of childhood cancer aimed at reducing the likelihood of therapy abandonment and reduction of the lag time between presentation and initiation of treatment. In a more disease focused report, Hunger et al. recommended intensity-adjusted algorithms in planning childhood acute lymphoblastic leukemia treatment and also highlighted the importance of adaptation of therapies [15]. Raciborska et al. have successfully implemented complex treatment strategies for patients with a highly aggressive solid tumor and have identified steps to continue to advance outcomes for children with Ewing sarcoma in their country [1]. In HIC, where the vast majority of worldwide cancer research expenditure is spent and where 94% of global economic cancer related estimated costs exists [14], there are increasing limitations on centralized resources. Experience, such as that documented by Polish colleagues in the current report, reinforces the need to sustain cooperative study
Division of Pediatric Hematology/Oncology, Department of Pediatrics the University of Texas Southwestern Medical Center, Dallas, Texas Conflict of interest: Nothing to declare. Correspondence to: Patrick J. Leavey, Associate Professor of Pediatrics, University of Texas Southwestern Medical Center Dallas, 5323 Harry Hines Blvd, Dallas, TX 75290-9063. E-mail: [email protected]
Received 15 July 2014; Accepted 17 July 2014
2150
Leavey
group funding, to adapt complex cytotoxic regimens for high-risk cancer, such as Ewing Sarcoma by incorporating novel agents and to advocate for more expedient availability of novel agents for evaluation in children.
REFERENCES 1. Raciborska AB K, Drabko K, Chaber R, et al. Validation of a multimodal treatment protocol for Ewing Sarcoma - A report from the Polish Pediatric Oncology Group. Pediatr Blood Cancer 2014. 2. Juergens C, Weston C, Lewis I, et al. Safety assessment of intensive induction with vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) in the treatment of Ewing tumors in the EURO-E.W.I.N. G. 99 clinical trial. Pediatr Blood Cancer 2006;47:22–29. 3. The World Bank Group - International Comparison Program. Poland fact sheet. http://data.worldbank. org/country/poland Published 2011. Accessed July 15, 2014. 4. Gatta G, Botta L, Rossi S, et al. Childhood cancer survival in Europe 1999–2007 : Results of EUROCARE-5–a population-based study. Lancet Oncol 2014;15:35–47. 5. Womer RB, West DC, Krailo MD, et al. Randomized controlled trial of interval-compressed chemotherapy for the treatment of localized Ewing sarcoma: A report from the Children’s Oncology Group. J Clin Oncol 2012;30:4148–4154.
Pediatr Blood Cancer DOI 10.1002/pbc
6. Grier HE, Krailo MD, Tarbell NJ, et al. Addition of ifosfamide and etoposide to standard chemotherapy for Ewing’s sarcoma and primitive neuroectodermal tumor of bone. New Engl J Med 2003;348:694–701. 7. Krasin MJ, Davidoff AM, Rodriguez-Galindo C, et al. Definitive surgery and multiagent systemic therapy for patients with localized Ewing sarcoma family of tumors: Local outcome and prognostic factors. Cancer 2005;104:367–373. 8. Letourneau PA, Shackett B, Xiao L, et al. Resection of pulmonary metastases in pediatric patients with Ewing sarcoma improves survival. J Pediatr Surg 2011;46:332–335. 9. Tronc F, Conter C, Marec-Berard P, et al. Prognostic factors and long-term results of pulmonary metastasectomy for pediatric histologies. Eur J Cardio-Thorac 2008;34:1240–1246. 10. Hogendoorn PC, Group EEW, Athanasou N, et al. Bone sarcomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2010;21:v204–213. 11. Dunst J, Schuck A. Role of radiotherapy in Ewing tumors. Pediatr Blood Cancer 2004;42:465–470. 12. Dunst J, Sauer R, Burgers JM, et al. Radiation therapy as local treatment in Ewing’s sarcoma. Results of the Cooperative Ewing’s Sarcoma Studies CESS 81 and CESS 86. Cancer 1991;67: 2818–2825. 13. Gupta S, Rivera-Luna R, Ribeiro RC, et al. Pediatric oncology as the next global child health priority: The need for national childhood cancer strategies in low- and middle-income countries. PLoS medicine 2014;11:e1001656. 14. Rodriguez-Galindo C, Friedrich P, Morrissey L, et al. Global challenges in pediatric oncology. Curr Opin Pediatr 2013;25:3–15. 15. Hunger SP, Sung L, Howard SC. Treatment strategies and regimens of graduated intensity for childhood acute lymphoblastic leukemia in low-income countries: A proposal. Pediatr Blood Cancer 2009;52: 559–565.
