- Email: [email protected]
Primary radiotherapy for childhood ependymoma?
Reflection and Reaction
of repair of endothelial injury caused by the cancer, rather than the direct cause of such injury. This notion is supported by the fact that a definite time interval exists between the onset of TTP and the use of these treatments. Thus, although an awareness of the possibility that different chemotherapeutic drugs might cause TTP is important, the pathogenetic role of the underlying cancer also needs to be kept in mind.
The author declared no conflicts of interest. 1
2
3
4
Jecko Thachil Royal Liverpool University Hospital, Liverpool, UK [email protected]
5
Zupancic M, Shah PC, Shah-Khan F, Nagendra S. Gemcitabineassociated thrombotic thrombocytopenic purpura. Lancet Oncol 2007; 8: 634–41. Snyder HW, Mittelman A, Oral A, et al. Treatment of cancer chemotherapyassociated thrombotic thrombocytopenic purpura/hemolytic uremic syndrome by protein A immunoadsorption of plasma. Cancer 1993; 71: 1882–92. Sack GH Jr, Levin J, Bell WR. Trousseau’s syndrome and other manifestations of chronic disseminated coagulopathy in patients with neoplasms: clinical, pathophysiologic, and therapeutic features. Medicine (Baltimore) 1977; 56: 1–37. Orr FW, Wang HH, Lafrenie RM, Scherbarth S, Nance DM. Interactions between cancer cells and the endothelium in metastasis. J Pathol 2000; 190: 310–29. Nangaku M, Nishi H, Fujita T. Pathogenesis and prognosis of thrombotic microangiopathy. Clin Exp Nephrol 2007; 11: 107–14.
Primary radiotherapy for childhood ependymoma? The article by Grundy and colleagues1 in a recent issue of The Lancet Oncology tested the hypothesis that chemotherapy would delay or eliminate the need for radiotherapy in children with CNS tumours and, therefore, decrease late toxic effects associated with radiotherapy without compromising treatment efficacy. The authors are to be commended on undertaking one of the largest phase II trials for this vexing disease. Given this hypothesis, however, one must ask whether the results support the authors’ conclusions, and some of their conclusions seem to need tempering, especially with regard to the role of primary radiotherapy in the treatment of childhood ependymoma. First, the authors compare their results to the phase II trial of conformal radiotherapy done at St Jude Children’s
Should radiotherapy be avoided in children with CNS tumours?
758
Research Hospital (Memphis, TN, USA), which involved 88 children with ependymoma (48 [55%] of whom were <3 years of age).2 Grundy and colleagues state that the 3-year overall survival of 79·3% in their study was higher than the 3-year progression-free survival of 69·5% in the St Jude study. Although the overall survival was not reported in the St Jude study, equating overall survival with event-free survival (EFS) seems unreasonable. The appropriate comparison would be 3-year EFS in the study by Grundy and colleagues of 47·6% (95%CI 36·2–58·1) compared with the predicted 3-year EFS in the St Jude study of 74·7±5·7%. In the UK study, even when confined to the favourable subgroup of patients without metastases at diagnosis, only 35% (28 of 80) of patients were progression free without radiotherapy. Second, Grundy and colleagues compare the EFS in their study with that of the subgroup of patients less than 3 years of age in the St Jude study. However, in both these studies, age was not predictive of EFS; therefore, would it not be more appropriate to compare the EFS in their study with that of the whole patient group within the St Jude study? Younger age might correlate with receiving inadequate radiotherapy and not necessarily with worse tumour control in those irradiated. This theory is consistent with the findings of the US Pediatric Oncology Group 8633 study,3 in which younger patients with ependymoma did have worse EFS and OS; however, this finding was related to a longer duration of chemotherapy and the associated delay to radiotherapy (2 years) in patients less than http://oncology.thelancet.com Vol 8 September 2007
Reflection and Reaction
24 months of age. By contrast, those aged between 24 and 36 months received radiotherapy after only 1 year of chemotherapy with improved tumour control.3,4 Third, one could argue that systemic chemotherapy might have decreased metastatic relapse; however, the patterns of failure would not support this assertion either. Local failure as any part of failure (ie, local relapse plus or minus metastases) was 59·6% (53 of 89) in the study by Grundy and colleagues and 13·6% (12 of 88) in the St Jude trial. By contrast, the addition of chemotherapy resulted in no substantial difference in metastatic failure between the two studies (11·2% (10 of 89) in the UK study and 13·6% (12 of 88) in the St Jude study), despite only 18·2% (16 of 88) of patients receiving chemotherapy in the St Jude trial. Thus, the up-front use of high-dose chemotherapy with delayed or no radiotherapy did not seem to provide a benefit in terms of metastasis-free survival and was substantially worse than up-front radiotherapy in terms of both local control and EFS. Finally, one of the benefits of up-front chemotherapy would be to delay or eliminate radiotherapy and, thus, decrease the neurocognitive injury associated with conventional radiation treatments.5 Unfortunately, in the UK study, prospective neurocognitive testing was not done; therefore, the authors reported on only nine children without progression who had normal IQ assessments as part of a parallel study.6 Relapse of brain tumours followed by salvage treatments (including repeat resection, further chemotherapy, and radiotherapy) are key contributors to neurocognitive decline;5 thus, until the neurocognitive outcome of more than 60% of patients who relapsed and underwent salvage treatment is known, the conclusion cannot be made that the treatment in the UK study prevents neurocognitive injury. By comparison, in the St Jude study, all patients were treated with modern radiotherapy techniques, which substantially decreased both the dose and volume of uninvolved brain irradiated to high doses.2 Serial neurocognitive testing before and after radiotherapy was comprehensively used and there was no significant decline in neurocognitive function independent of patient age; although patients less than 3 years old at diagnosis did have lower initial scores on neurocognitive testing before radiotherapy.2 http://oncology.thelancet.com Vol 8 September 2007
In conclusion, the study by Grundy and colleagues1 attempted to defer or eliminate large-field radiotherapy with its long-term neurocognitive effects while still maintaining appropriate tumour control. However, studies have suggested that the use of advanced planning and delivery of radiotherapy might no longer be worth avoiding at all costs, because the detrimental neurocognitive effects of radiotherapy might be substantially reduced by the use of such techniques compared with older radiotherapy techniques.2,7–9 Thus, the current US Children’s Oncology Group ependymoma study (ACNS0121), which includes serial neurocognitive testing, might reap benefits through the use of short-duration chemotherapy and the option of second surgical resection in combination with the early use of appropriately delivered radiotherapy. Only time will tell if this treatment paradigm can avoid the high rate of relapse and salvage treatment reported in the UK study, and still preserve neurocognitive function. Daniel A Hamstra Department of Radiation Oncology, University of Michigan Medical Center, Ann Arbor, MI 48109-0100, USA [email protected] The author declared no conflicts of interest. 1
2
3
4
5
6
7
8
9
Grundy RG, Wilne SA, Weston CL, et al. Primary postoperative chemotherapy without radiotherapy for intracranial ependymoma in children: the UKCCSG/SIOP prospective study. Lancet Oncol 2007; 8: 696–705. Merchant TE, Mulhern RK, Krasin MJ, et al. Preliminary results from a phase II trial of conformal radiation therapy and evaluation of radiation-related CNS effects for pediatric patients with localized ependymoma. J Clin Oncol 2004; 22: 3156–62. Duffner PK, Horowitz ME, Krischer JP, et al. Postoperative chemotherapy and delayed radiation in children less than three years of age with malignant brain tumors. N Engl J Med 1993; 328: 1725–31. Duffner PK, Krischer JP, Sanford RA, et al. Prognostic factors in infants and very young children with intracranial ependymomas. Pediatr Neurosurg 1998; 28: 215–22. Mulhern RK, Merchant TE, Gajjar A, Reddick WE, Kun LE. Late neurocognitive sequelae in survivors of brain tumours in childhood. Lancet Oncol 2004; 5: 399–408. Gumley D, Phipps K, Reynolds J, Michalski A. Infants with ependymoma: outcome following surgery and baby brain chemotherapy. Neuro Oncol 2004; 6: 457. Carrie C, Muracciole X, Gomez F, et al. Conformal radiotherapy, reduced boost volume, hyperfractionated radiotherapy, and online quality control in standard-risk medulloblastoma without chemotherapy: results of the French M-SFOP 98 protocol. Int J Radiat Oncol Biol Phys 2005; 63: 711–16. Mulhern RK, Palmer SL, Merchant TE, et al. Neurocognitive consequences of risk-adapted therapy for childhood medulloblastoma. J Clin Oncol 2005; 23: 5511–19. Merchant TE, Kiehna EN, Kun LE, et al. Phase II trial of conformal radiation therapy for pediatric patients with craniopharyngioma and correlation of surgical factors and radiation dosimetry with change in cognitive function. J Neurosurg 2006; 104(2 Suppl): 94–102.
759
of repair of endothelial injury caused by the cancer, rather than the direct cause of such injury. This notion is supported by the fact that a definite time interval exists between the onset of TTP and the use of these treatments. Thus, although an awareness of the possibility that different chemotherapeutic drugs might cause TTP is important, the pathogenetic role of the underlying cancer also needs to be kept in mind.
The author declared no conflicts of interest. 1
2
3
4
Jecko Thachil Royal Liverpool University Hospital, Liverpool, UK [email protected]
5
Zupancic M, Shah PC, Shah-Khan F, Nagendra S. Gemcitabineassociated thrombotic thrombocytopenic purpura. Lancet Oncol 2007; 8: 634–41. Snyder HW, Mittelman A, Oral A, et al. Treatment of cancer chemotherapyassociated thrombotic thrombocytopenic purpura/hemolytic uremic syndrome by protein A immunoadsorption of plasma. Cancer 1993; 71: 1882–92. Sack GH Jr, Levin J, Bell WR. Trousseau’s syndrome and other manifestations of chronic disseminated coagulopathy in patients with neoplasms: clinical, pathophysiologic, and therapeutic features. Medicine (Baltimore) 1977; 56: 1–37. Orr FW, Wang HH, Lafrenie RM, Scherbarth S, Nance DM. Interactions between cancer cells and the endothelium in metastasis. J Pathol 2000; 190: 310–29. Nangaku M, Nishi H, Fujita T. Pathogenesis and prognosis of thrombotic microangiopathy. Clin Exp Nephrol 2007; 11: 107–14.
Primary radiotherapy for childhood ependymoma? The article by Grundy and colleagues1 in a recent issue of The Lancet Oncology tested the hypothesis that chemotherapy would delay or eliminate the need for radiotherapy in children with CNS tumours and, therefore, decrease late toxic effects associated with radiotherapy without compromising treatment efficacy. The authors are to be commended on undertaking one of the largest phase II trials for this vexing disease. Given this hypothesis, however, one must ask whether the results support the authors’ conclusions, and some of their conclusions seem to need tempering, especially with regard to the role of primary radiotherapy in the treatment of childhood ependymoma. First, the authors compare their results to the phase II trial of conformal radiotherapy done at St Jude Children’s
Should radiotherapy be avoided in children with CNS tumours?
758
Research Hospital (Memphis, TN, USA), which involved 88 children with ependymoma (48 [55%] of whom were <3 years of age).2 Grundy and colleagues state that the 3-year overall survival of 79·3% in their study was higher than the 3-year progression-free survival of 69·5% in the St Jude study. Although the overall survival was not reported in the St Jude study, equating overall survival with event-free survival (EFS) seems unreasonable. The appropriate comparison would be 3-year EFS in the study by Grundy and colleagues of 47·6% (95%CI 36·2–58·1) compared with the predicted 3-year EFS in the St Jude study of 74·7±5·7%. In the UK study, even when confined to the favourable subgroup of patients without metastases at diagnosis, only 35% (28 of 80) of patients were progression free without radiotherapy. Second, Grundy and colleagues compare the EFS in their study with that of the subgroup of patients less than 3 years of age in the St Jude study. However, in both these studies, age was not predictive of EFS; therefore, would it not be more appropriate to compare the EFS in their study with that of the whole patient group within the St Jude study? Younger age might correlate with receiving inadequate radiotherapy and not necessarily with worse tumour control in those irradiated. This theory is consistent with the findings of the US Pediatric Oncology Group 8633 study,3 in which younger patients with ependymoma did have worse EFS and OS; however, this finding was related to a longer duration of chemotherapy and the associated delay to radiotherapy (2 years) in patients less than http://oncology.thelancet.com Vol 8 September 2007
Reflection and Reaction
24 months of age. By contrast, those aged between 24 and 36 months received radiotherapy after only 1 year of chemotherapy with improved tumour control.3,4 Third, one could argue that systemic chemotherapy might have decreased metastatic relapse; however, the patterns of failure would not support this assertion either. Local failure as any part of failure (ie, local relapse plus or minus metastases) was 59·6% (53 of 89) in the study by Grundy and colleagues and 13·6% (12 of 88) in the St Jude trial. By contrast, the addition of chemotherapy resulted in no substantial difference in metastatic failure between the two studies (11·2% (10 of 89) in the UK study and 13·6% (12 of 88) in the St Jude study), despite only 18·2% (16 of 88) of patients receiving chemotherapy in the St Jude trial. Thus, the up-front use of high-dose chemotherapy with delayed or no radiotherapy did not seem to provide a benefit in terms of metastasis-free survival and was substantially worse than up-front radiotherapy in terms of both local control and EFS. Finally, one of the benefits of up-front chemotherapy would be to delay or eliminate radiotherapy and, thus, decrease the neurocognitive injury associated with conventional radiation treatments.5 Unfortunately, in the UK study, prospective neurocognitive testing was not done; therefore, the authors reported on only nine children without progression who had normal IQ assessments as part of a parallel study.6 Relapse of brain tumours followed by salvage treatments (including repeat resection, further chemotherapy, and radiotherapy) are key contributors to neurocognitive decline;5 thus, until the neurocognitive outcome of more than 60% of patients who relapsed and underwent salvage treatment is known, the conclusion cannot be made that the treatment in the UK study prevents neurocognitive injury. By comparison, in the St Jude study, all patients were treated with modern radiotherapy techniques, which substantially decreased both the dose and volume of uninvolved brain irradiated to high doses.2 Serial neurocognitive testing before and after radiotherapy was comprehensively used and there was no significant decline in neurocognitive function independent of patient age; although patients less than 3 years old at diagnosis did have lower initial scores on neurocognitive testing before radiotherapy.2 http://oncology.thelancet.com Vol 8 September 2007
In conclusion, the study by Grundy and colleagues1 attempted to defer or eliminate large-field radiotherapy with its long-term neurocognitive effects while still maintaining appropriate tumour control. However, studies have suggested that the use of advanced planning and delivery of radiotherapy might no longer be worth avoiding at all costs, because the detrimental neurocognitive effects of radiotherapy might be substantially reduced by the use of such techniques compared with older radiotherapy techniques.2,7–9 Thus, the current US Children’s Oncology Group ependymoma study (ACNS0121), which includes serial neurocognitive testing, might reap benefits through the use of short-duration chemotherapy and the option of second surgical resection in combination with the early use of appropriately delivered radiotherapy. Only time will tell if this treatment paradigm can avoid the high rate of relapse and salvage treatment reported in the UK study, and still preserve neurocognitive function. Daniel A Hamstra Department of Radiation Oncology, University of Michigan Medical Center, Ann Arbor, MI 48109-0100, USA [email protected] The author declared no conflicts of interest. 1
2
3
4
5
6
7
8
9
Grundy RG, Wilne SA, Weston CL, et al. Primary postoperative chemotherapy without radiotherapy for intracranial ependymoma in children: the UKCCSG/SIOP prospective study. Lancet Oncol 2007; 8: 696–705. Merchant TE, Mulhern RK, Krasin MJ, et al. Preliminary results from a phase II trial of conformal radiation therapy and evaluation of radiation-related CNS effects for pediatric patients with localized ependymoma. J Clin Oncol 2004; 22: 3156–62. Duffner PK, Horowitz ME, Krischer JP, et al. Postoperative chemotherapy and delayed radiation in children less than three years of age with malignant brain tumors. N Engl J Med 1993; 328: 1725–31. Duffner PK, Krischer JP, Sanford RA, et al. Prognostic factors in infants and very young children with intracranial ependymomas. Pediatr Neurosurg 1998; 28: 215–22. Mulhern RK, Merchant TE, Gajjar A, Reddick WE, Kun LE. Late neurocognitive sequelae in survivors of brain tumours in childhood. Lancet Oncol 2004; 5: 399–408. Gumley D, Phipps K, Reynolds J, Michalski A. Infants with ependymoma: outcome following surgery and baby brain chemotherapy. Neuro Oncol 2004; 6: 457. Carrie C, Muracciole X, Gomez F, et al. Conformal radiotherapy, reduced boost volume, hyperfractionated radiotherapy, and online quality control in standard-risk medulloblastoma without chemotherapy: results of the French M-SFOP 98 protocol. Int J Radiat Oncol Biol Phys 2005; 63: 711–16. Mulhern RK, Palmer SL, Merchant TE, et al. Neurocognitive consequences of risk-adapted therapy for childhood medulloblastoma. J Clin Oncol 2005; 23: 5511–19. Merchant TE, Kiehna EN, Kun LE, et al. Phase II trial of conformal radiation therapy for pediatric patients with craniopharyngioma and correlation of surgical factors and radiation dosimetry with change in cognitive function. J Neurosurg 2006; 104(2 Suppl): 94–102.
759