International Journal of
Radiation Oncology biology
physics
www.redjournal.org
EDITORIAL
Hyperfractionation: Fractious or Not? Anne Laprie, MD, PhD,* Amanda K. LaMarre, PhD,y and Daphne A. Haas-Kogan, MDy *Department of Radiation Oncology, Institut Claudius Regaud, Centre de Lutte Contre le Cancer de Toulouse, Toulouse, France; and yDepartments of Radiation Oncology and Neurological Surgery, University of California, San Francisco, San Francisco, California Received Oct 30, 2013. Accepted for publication Oct 31, 2013. Medulloblastoma is the most frequent brain tumor in children, and multimodality therapy generally includes surgery, chemotherapy, and craniospinal irradiation (CSI). Progressive improvements in treatment strategies have led to overall survival rates exceeding 80% for children with average-risk medulloblastoma, highlighting concerning long-term side effects that can include neurocognitive, growth, endocrine, hearing, and general quality of life impairments. In this issue of the International Journal of Radiation Oncology, Biology, Physics, Kennedy et al (1) report results of quality of survival and growth for patients treated on the primitive neuroectodermal tumor 4 (PNET4) European controlled trial of hyperfractionated (HFRT) versus conventional radiation therapy for standard-risk medulloblastoma. They found that HFRT had less impact on executive function than standard CSI but resulted in greater height impairment. The Behavior Rating Inventory of Executive Function (BRIEF) questionnaire aims to assess impairment of executive function for individuals aged 5-18 years. The BRIEF questionnaire involves 8 parameters and gives the clinician insight into the behavior and everyday function of the child or adolescent being testeddinformation that serves to complement performance measures. Of the 4 main outcome measures, only executive function (BRIEF) was inferior in the HFRTarm, whereas the other 3 outcome measuresdhealth status, behavioral difficulties, and health-related quality of lifeddid not differ between arms. In addition, only a limited proportion of children in either radiation group (10%-23%) had BRIEF scores in the range of executive dysfunction. Because executive function has significant implications for everyday social and academic function, these results shed light on the cognitive, behavioral, and socialeemotional developmental consequences of treatment for our patients (2).
In addition to neurocognitive deficits, growth and endocrine dysfunction are frequent in medulloblastoma survivors, as a consequence of pituitary gland, hypothalamic axis, and whole-spine radiation. In this study, rates of hormone deficiencies were equivalent in both radiation arms, suggesting that the greater height decrements observed in the HFRT arm were due to direct effects on bone matrix and epiphyseal plates. The authors hypothesize that the greater deficits in spine growth in the HFRTarm were due to the “early reacting” characteristics of epiphyseal tissues (resulting in less normal tissue sparing by hyperfractionation) and/or the higher estimated biologically equivalent dose of the HFRT regimen compared with the conventional fractionation arm. The greater biologically equivalent dose of the HFRT regimen is likely a major contributor to the spine growth disparity: it is 27.0 Gy for hyperfractionated CSI (1.0 Gy twice daily to a total dose of 36.0 Gy) and 22.2 Gy for the standard regimen (1.8 Gy once daily to a total dose of 23.4 Gy). Additionally, if indeed epiphyseal plates constitute acute-reacting tissues and a greater a/b ratio is appropriate, let us say a/b Z 10, the equivalent dose for the HFRT arm is 33.0 Gy, whereas it is 24.2 Gy for the conventional arm. It is possible that these differences in biologically equivalent doses between the HFRT and standard arm also played a role in the greater use of hearing aids in the HFRT arm, because boost volumes, boost equivalent doses, and chemotherapy regimens, which can all contribute to hearing loss, are similar between arms. The authors and investigators of the PNET4 European controlled trial of HFRT versus conventional radiation therapy for standard-risk medulloblastoma should be commended for addressing critical issues of neurocognitive function and quality of life in survivors of pediatric brain tumors. Although previous studies have reported deficits in academic performance, overall
Reprint requests to: Daphne Haas-Kogan, MD, University of California, San Francisco, Helen Diller Cancer Center, Departments of Radiation Oncology and Neurosurgery, 1600 Divisadero St., Suite H1031, San Francisco, CA 94143-1708. Tel: (415) 353-7175; E-mail: dhaaskogan@ radonc.ucsf.edu This research was supported in part by The Grand Philanthropic Fund (D.A.H.-K.), Mount Zion Health Fund (D.A.H.-K.), University of
California, San Francisco Clinical and Translational Science Institute Catalyst and Resource Allocation Programs (D.A.H.-K.), and the University of California Cancer Research Coordinating Committee (D.A.H.-K.). Conflict of interest: none.
Int J Radiation Oncol Biol Phys, Vol. 88, No. 2, pp. 269e271, 2014 0360-3016/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ijrobp.2013.10.044
270
Laprie et al.
intellect, and key cognitive skills in children treated for medulloblastoma, many studies suffer from limitations due to their retrospective nature and inclusion of mixed diagnoses. The report by Kennedy et al (1) underscores the unique strengths of assessing cognitive function and quality of life in prospective randomized trials. The report herein complements a recent publication by Palmer et al (3) that prospectively and longitudinally measures key cognitive skills of children treated for medulloblastoma and demonstrates greatest vulnerability in processing speed and greatest decrements in younger children and those with high-risk disease. The article by Kennedy et al (1) is an important first step in assessing quality of life in children and young adults with medulloblastoma who are treated with HFRT versus conventionally fractionated standard treatment. The strength of the study lies in its ability to compare children treated with 2 different radiation regimens, finding that patients treated with HFRT had significantly better outcomes with respect to executive functioning, a domain of cognition important for mental flexibility, planning for future events, and inhibition of non-goal-oriented behaviors. Although the 2 groups did not differ in outcome measures of health status, behavioral issues, and health-related quality of life, the mean scores between groups trended in consistent directions. Importantly, patients were randomized to treatment groups, thereby reducing the likelihood of a systematic confound as the cause for group differences. Future studies could improve upon their design by increasing overall sample size and prospectively collecting standardized neuropsychological data for each of the patients, rather than relying on information provided by parents, which is less reliable and could obscure treatment impact. The publication by Palmer et al (3) complements the weaknesses of the study by Kennedy et al. Their recent article in the Journal of Clinical Oncology prospectively investigates the effects of radiation therapy on cognitive outcomes in patients with medulloblastoma and elegantly addresses a number of methodologic issues that have obscured our understanding of this topic. For example, although many studies focus on episodic memory performance as the primary outcome for cognitive ability (4-6), Palmer et al (3) thoughtfully chose well-known, standardized neuropsychological tests that measure cognitive domains highly dependent on white matter integrity (processing speed, broad attention, and working memory) and thus are more likely to be affected by radiation treatment. In addition, they use a sophisticated statistical modeling technique (linear mixed-effects models) capable of handling complicated longitudinal data such as theirs, in which the total number of follow-ups or time between followups is unequal between patients. Use of this technique allows them to make meaningful statements regarding longitudinal cognitive changes that may have been obscured if analyzed with less-powerful techniques. The investigators of the PNET4 European study have led the way in including critical neuropsychological and behavioral assessments within the structure of a prospective, randomized trial. Other cooperative groups have recognized the importance of these endpoints, evident by their commitment to prospective neuropsychological and behavioral assessments as crucial components of monitoring late effects. For example, the Children’s Oncology Group has streamlined and standardized such assessments as part of the ALTE07C1 neuropsychological and behavioral battery that focuses on critically relevant functional domains. Similarly,
International Journal of Radiation Oncology Biology Physics European cooperative groups will include the same evaluations as described in the present article with standardized patient/parentrated measurements of health status, executive function, behavioral outcome, and quality of life. In this large, randomized European study that enrolled patients with standard-risk medulloblastoma from more than 100 centers, equivalent event-free survival and overall survival rates were achieved by HFRT and conventional fractionation, a finding previously published by Lannering et al (7). Hyperfractionated radiation therapy resulted in a potential benefit in executive function, no differences in any other measures, including health status, behavior, or quality of life, and potentially worse growth and hearing deficits. Taken together, the equivalent clinical outcomes, the mixed toxicity results, and the above-described limitations lead us to support the conventional CSI regimen of 1.8 Gy once daily to a total dose of 23.4 Gy as the current standard of care. That said, the ongoing Children’s Oncology Group phase 3 study for children with standard-risk medulloblastoma (ACNS0331) randomizes children 3-7 years of age to either 18.0 Gy or 23.4 Gy of CSI. Results of this trial are eagerly awaited. Furthermore, both European and North American cooperative groups aim to incorporate molecular profiles into the overall approach to medulloblastoma therapy. For example, across both continents, the approach to the clinically favorable WNT tumors, characterized by nuclear immunoreactivity for b-catenin, will likely include reduced-dose radiation and/or limited chemotherapy. Other trends are also shared between the continents, for example targeting the primary tumor rather than the entire posterior fossa in the boost volume. Two noteworthy points arise from the study by Kennedy et al First, the mean scores for both groups fall within the “average” range and suggest that overall, radiation treatment, regardless of modality, caused only modest impairments in quality of life for the majority of study patients. Second, behavioral, social, and emotional difficulties, as well as deficits in attention, memory, and executive abilities, take a significant toll on survivors of medulloblastoma. Results such as those reported by Kennedy et al should propel us to develop and implement empirically tested cognitive remediation and intervention programs, to improve quality of survivorship for all of our patients requiring brain irradiation.
References 1. Kennedy C, Bull K, Chevignard M, et al. Quality of survival and growth in children and young adults in the PNET4 European controlled trial of hyper-fractionated versus conventional radiotherapy for standard risk medulloblastoma. Int J Radiat Oncol Biol Phys 2014;88:292-300. 2. Gioia GA, Isquith PK. Ecological assessment of executive function in traumatic brain injury. Dev Neuropsychol 2004;25:135-158. 3. Palmer SL, Armstrong C, Onar-Thomas A, et al. Processing speed, attention, and working memory after treatment for medulloblastoma: An international, prospective, and longitudinal study. J Clin Oncol 2013;31:3494-3500. 4. Mulhern RK, Kepner JL, Thomas PR, et al. Neuropsychologic functioning of survivors of childhood medulloblastoma randomized to receive conventional or reduced-dose craniospinal irradiation: A Pediatric Oncology Group study. J Clin Oncol 1998;16:1723-1728. 5. Carrie C, Grill J, Figarella-Branger D, et al. Online quality control, hyperfractionated radiotherapy alone and reduced boost volume for standard risk medulloblastoma: Long-term results of MSFOP 98. J Clin Oncol 2009;27:1879-1883.
Volume 88 Number 2 2014 6. Grill J, Renaux VK, Bulteau C, et al. Long-term intellectual outcome in children with posterior fossa tumors according to radiation doses and volumes. Int J Radiat Oncol Biol Phys 1999;45: 137-145.
Hyperfractionation
271
7. Lannering B, Rutkowski S, Doz F, et al. Hyperfractionated versus conventional radiotherapy followed by chemotherapy in standard-risk medulloblastoma: Results from the randomized multicenter HIT-SIOP PNET 4 trial. J Clin Oncol 2012;30:3187-3193.
Radiation Oncology biology
physics
www.redjournal.org
EDITORIAL
Hyperfractionation: Fractious or Not? Anne Laprie, MD, PhD,* Amanda K. LaMarre, PhD,y and Daphne A. Haas-Kogan, MDy *Department of Radiation Oncology, Institut Claudius Regaud, Centre de Lutte Contre le Cancer de Toulouse, Toulouse, France; and yDepartments of Radiation Oncology and Neurological Surgery, University of California, San Francisco, San Francisco, California Received Oct 30, 2013. Accepted for publication Oct 31, 2013. Medulloblastoma is the most frequent brain tumor in children, and multimodality therapy generally includes surgery, chemotherapy, and craniospinal irradiation (CSI). Progressive improvements in treatment strategies have led to overall survival rates exceeding 80% for children with average-risk medulloblastoma, highlighting concerning long-term side effects that can include neurocognitive, growth, endocrine, hearing, and general quality of life impairments. In this issue of the International Journal of Radiation Oncology, Biology, Physics, Kennedy et al (1) report results of quality of survival and growth for patients treated on the primitive neuroectodermal tumor 4 (PNET4) European controlled trial of hyperfractionated (HFRT) versus conventional radiation therapy for standard-risk medulloblastoma. They found that HFRT had less impact on executive function than standard CSI but resulted in greater height impairment. The Behavior Rating Inventory of Executive Function (BRIEF) questionnaire aims to assess impairment of executive function for individuals aged 5-18 years. The BRIEF questionnaire involves 8 parameters and gives the clinician insight into the behavior and everyday function of the child or adolescent being testeddinformation that serves to complement performance measures. Of the 4 main outcome measures, only executive function (BRIEF) was inferior in the HFRTarm, whereas the other 3 outcome measuresdhealth status, behavioral difficulties, and health-related quality of lifeddid not differ between arms. In addition, only a limited proportion of children in either radiation group (10%-23%) had BRIEF scores in the range of executive dysfunction. Because executive function has significant implications for everyday social and academic function, these results shed light on the cognitive, behavioral, and socialeemotional developmental consequences of treatment for our patients (2).
In addition to neurocognitive deficits, growth and endocrine dysfunction are frequent in medulloblastoma survivors, as a consequence of pituitary gland, hypothalamic axis, and whole-spine radiation. In this study, rates of hormone deficiencies were equivalent in both radiation arms, suggesting that the greater height decrements observed in the HFRT arm were due to direct effects on bone matrix and epiphyseal plates. The authors hypothesize that the greater deficits in spine growth in the HFRTarm were due to the “early reacting” characteristics of epiphyseal tissues (resulting in less normal tissue sparing by hyperfractionation) and/or the higher estimated biologically equivalent dose of the HFRT regimen compared with the conventional fractionation arm. The greater biologically equivalent dose of the HFRT regimen is likely a major contributor to the spine growth disparity: it is 27.0 Gy for hyperfractionated CSI (1.0 Gy twice daily to a total dose of 36.0 Gy) and 22.2 Gy for the standard regimen (1.8 Gy once daily to a total dose of 23.4 Gy). Additionally, if indeed epiphyseal plates constitute acute-reacting tissues and a greater a/b ratio is appropriate, let us say a/b Z 10, the equivalent dose for the HFRT arm is 33.0 Gy, whereas it is 24.2 Gy for the conventional arm. It is possible that these differences in biologically equivalent doses between the HFRT and standard arm also played a role in the greater use of hearing aids in the HFRT arm, because boost volumes, boost equivalent doses, and chemotherapy regimens, which can all contribute to hearing loss, are similar between arms. The authors and investigators of the PNET4 European controlled trial of HFRT versus conventional radiation therapy for standard-risk medulloblastoma should be commended for addressing critical issues of neurocognitive function and quality of life in survivors of pediatric brain tumors. Although previous studies have reported deficits in academic performance, overall
Reprint requests to: Daphne Haas-Kogan, MD, University of California, San Francisco, Helen Diller Cancer Center, Departments of Radiation Oncology and Neurosurgery, 1600 Divisadero St., Suite H1031, San Francisco, CA 94143-1708. Tel: (415) 353-7175; E-mail: dhaaskogan@ radonc.ucsf.edu This research was supported in part by The Grand Philanthropic Fund (D.A.H.-K.), Mount Zion Health Fund (D.A.H.-K.), University of
California, San Francisco Clinical and Translational Science Institute Catalyst and Resource Allocation Programs (D.A.H.-K.), and the University of California Cancer Research Coordinating Committee (D.A.H.-K.). Conflict of interest: none.
Int J Radiation Oncol Biol Phys, Vol. 88, No. 2, pp. 269e271, 2014 0360-3016/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ijrobp.2013.10.044
270
Laprie et al.
intellect, and key cognitive skills in children treated for medulloblastoma, many studies suffer from limitations due to their retrospective nature and inclusion of mixed diagnoses. The report by Kennedy et al (1) underscores the unique strengths of assessing cognitive function and quality of life in prospective randomized trials. The report herein complements a recent publication by Palmer et al (3) that prospectively and longitudinally measures key cognitive skills of children treated for medulloblastoma and demonstrates greatest vulnerability in processing speed and greatest decrements in younger children and those with high-risk disease. The article by Kennedy et al (1) is an important first step in assessing quality of life in children and young adults with medulloblastoma who are treated with HFRT versus conventionally fractionated standard treatment. The strength of the study lies in its ability to compare children treated with 2 different radiation regimens, finding that patients treated with HFRT had significantly better outcomes with respect to executive functioning, a domain of cognition important for mental flexibility, planning for future events, and inhibition of non-goal-oriented behaviors. Although the 2 groups did not differ in outcome measures of health status, behavioral issues, and health-related quality of life, the mean scores between groups trended in consistent directions. Importantly, patients were randomized to treatment groups, thereby reducing the likelihood of a systematic confound as the cause for group differences. Future studies could improve upon their design by increasing overall sample size and prospectively collecting standardized neuropsychological data for each of the patients, rather than relying on information provided by parents, which is less reliable and could obscure treatment impact. The publication by Palmer et al (3) complements the weaknesses of the study by Kennedy et al. Their recent article in the Journal of Clinical Oncology prospectively investigates the effects of radiation therapy on cognitive outcomes in patients with medulloblastoma and elegantly addresses a number of methodologic issues that have obscured our understanding of this topic. For example, although many studies focus on episodic memory performance as the primary outcome for cognitive ability (4-6), Palmer et al (3) thoughtfully chose well-known, standardized neuropsychological tests that measure cognitive domains highly dependent on white matter integrity (processing speed, broad attention, and working memory) and thus are more likely to be affected by radiation treatment. In addition, they use a sophisticated statistical modeling technique (linear mixed-effects models) capable of handling complicated longitudinal data such as theirs, in which the total number of follow-ups or time between followups is unequal between patients. Use of this technique allows them to make meaningful statements regarding longitudinal cognitive changes that may have been obscured if analyzed with less-powerful techniques. The investigators of the PNET4 European study have led the way in including critical neuropsychological and behavioral assessments within the structure of a prospective, randomized trial. Other cooperative groups have recognized the importance of these endpoints, evident by their commitment to prospective neuropsychological and behavioral assessments as crucial components of monitoring late effects. For example, the Children’s Oncology Group has streamlined and standardized such assessments as part of the ALTE07C1 neuropsychological and behavioral battery that focuses on critically relevant functional domains. Similarly,
International Journal of Radiation Oncology Biology Physics European cooperative groups will include the same evaluations as described in the present article with standardized patient/parentrated measurements of health status, executive function, behavioral outcome, and quality of life. In this large, randomized European study that enrolled patients with standard-risk medulloblastoma from more than 100 centers, equivalent event-free survival and overall survival rates were achieved by HFRT and conventional fractionation, a finding previously published by Lannering et al (7). Hyperfractionated radiation therapy resulted in a potential benefit in executive function, no differences in any other measures, including health status, behavior, or quality of life, and potentially worse growth and hearing deficits. Taken together, the equivalent clinical outcomes, the mixed toxicity results, and the above-described limitations lead us to support the conventional CSI regimen of 1.8 Gy once daily to a total dose of 23.4 Gy as the current standard of care. That said, the ongoing Children’s Oncology Group phase 3 study for children with standard-risk medulloblastoma (ACNS0331) randomizes children 3-7 years of age to either 18.0 Gy or 23.4 Gy of CSI. Results of this trial are eagerly awaited. Furthermore, both European and North American cooperative groups aim to incorporate molecular profiles into the overall approach to medulloblastoma therapy. For example, across both continents, the approach to the clinically favorable WNT tumors, characterized by nuclear immunoreactivity for b-catenin, will likely include reduced-dose radiation and/or limited chemotherapy. Other trends are also shared between the continents, for example targeting the primary tumor rather than the entire posterior fossa in the boost volume. Two noteworthy points arise from the study by Kennedy et al First, the mean scores for both groups fall within the “average” range and suggest that overall, radiation treatment, regardless of modality, caused only modest impairments in quality of life for the majority of study patients. Second, behavioral, social, and emotional difficulties, as well as deficits in attention, memory, and executive abilities, take a significant toll on survivors of medulloblastoma. Results such as those reported by Kennedy et al should propel us to develop and implement empirically tested cognitive remediation and intervention programs, to improve quality of survivorship for all of our patients requiring brain irradiation.
References 1. Kennedy C, Bull K, Chevignard M, et al. Quality of survival and growth in children and young adults in the PNET4 European controlled trial of hyper-fractionated versus conventional radiotherapy for standard risk medulloblastoma. Int J Radiat Oncol Biol Phys 2014;88:292-300. 2. Gioia GA, Isquith PK. Ecological assessment of executive function in traumatic brain injury. Dev Neuropsychol 2004;25:135-158. 3. Palmer SL, Armstrong C, Onar-Thomas A, et al. Processing speed, attention, and working memory after treatment for medulloblastoma: An international, prospective, and longitudinal study. J Clin Oncol 2013;31:3494-3500. 4. Mulhern RK, Kepner JL, Thomas PR, et al. Neuropsychologic functioning of survivors of childhood medulloblastoma randomized to receive conventional or reduced-dose craniospinal irradiation: A Pediatric Oncology Group study. J Clin Oncol 1998;16:1723-1728. 5. Carrie C, Grill J, Figarella-Branger D, et al. Online quality control, hyperfractionated radiotherapy alone and reduced boost volume for standard risk medulloblastoma: Long-term results of MSFOP 98. J Clin Oncol 2009;27:1879-1883.
Volume 88 Number 2 2014 6. Grill J, Renaux VK, Bulteau C, et al. Long-term intellectual outcome in children with posterior fossa tumors according to radiation doses and volumes. Int J Radiat Oncol Biol Phys 1999;45: 137-145.
Hyperfractionation
271
7. Lannering B, Rutkowski S, Doz F, et al. Hyperfractionated versus conventional radiotherapy followed by chemotherapy in standard-risk medulloblastoma: Results from the randomized multicenter HIT-SIOP PNET 4 trial. J Clin Oncol 2012;30:3187-3193.
