Treatment developments and the unfolding of the

Childs Nerv Syst DOI 10.1007/s00381-014-2388-5

REVIEW PAPER

Treatment developments and the unfolding of the quality of life discussion in childhood medulloblastoma: a review Thora Gudrunardottir & Birgitta Lannering & Marc Remke & Michael D. Taylor & Elizabeth M. Wells & Robert F. Keating & Roger J. Packer

Received: 26 January 2014 / Accepted: 11 February 2014 # Springer-Verlag Berlin Heidelberg 2014

Abstract Purpose To describe how the quality of life (QOL) discussion in childhood medulloblastoma (MB) relates to treatment developments, survival and sequelae from 1920 to 2014. Methods Articles containing “childhood medulloblastoma” and “quality of life” were identified in PubMed. Those containing phrases pertaining to psychological, emotional, behavioral or social adjustment in the title, abstract or keywords were selected. Inclusion of relevant older publications was assured by cross-checking references. Results 1920–1930s: suction, electro-surgery, kilovolt (KV) irradiation. Survival = months. Focus on operative mortality, symptoms and survival. 1940s: radiotherapy improved. 1950s: chemotherapy and intubation. Survival = years. Opinions oscillated between optimism/awareness of physical sequelae of radiotherapy. 1960s: magnified vision, ventriculoperitoneal (VP) shunts, megavolt (MV) irradiation. Long-term survival shifted the attention towards neurological problems, disability and carcinogenesis of radiotherapy. 1970s: CT,

microscope, bipolar coagulation, shunt filters, neuroanesthesia, chemotherapy trials and staging studies. Operative mortality decreased and many patients (re)entered school; emphasis on neuropsychological sequelae, IQ and academic performance. 1980s: magnetic resonance imaging (MRI), Cavitron ultrasonic aspiration (CUSA), laser surgery, hyper-fractionated radiotherapy (HFRT). Cerebellar mutism, psychological and social issues. 1990s: pediatric neurosurgery, proton beams, stem cell rescue. Reflections on QOL as such. 21st century: molecular genetics. Premature aging, patterns of decline, riskand resilience factors. Discussion QOL is a critical outcome measure. Focus depends on survival and sequelae, determined after years of follow-up. Detailed measurements are limited by time, money and human resources, and self-reporting questionnaires represent a crude measure limited by subjectivity. Therapeutic improvements raise the question of QOL versus cure. QOL is a potential primary research endpoint; multicenter international studies are needed, as are web-based tools that work across cultures.

T. Gudrunardottir (*) : R. J. Packer Center for Neuroscience and Behavioral Medicine, Children’s National Medical Center, Washington, DC, USA e-mail: [email protected]

Keywords Medulloblastoma . Surgery . Radiotherapy . Chemotherapy . Molecular biology . Anesthesiology . Quality of life . Review

B. Lannering Department of Pediatrics, Children’s Cancer Center, University of Gothenburg, Gothenburg, Sweden M. Remke : M. D. Taylor Department of Laboratory Medicine and Pathobiology, Hospital for Sick Children, Toronto, Canada E. M. Wells Department of Neurology and the Brain Tumor Institute, Children’s National Medical Center, Washington, DC, USA R. F. Keating Department of Neurosurgery, Children’s National Medical Center, Washington, DC, USA

Abbreviations CNS CT CUSA EEG HFRT IQ KV MB MRI MV

Central nervous system Computerized tomography Cavitron ultrasonic aspiration Electro-encephalography Hyper-fractionated radiotherapy Intelligence quotient Kilovolt Medulloblastoma Magnetic resonance imaging Megavolt

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QOL SHH TNM VP WNT

Quality of life Sonic hedgehog Tumor, nodes, metastasis Ventriculo-peritoneal Winged

Introduction In a famous quote from 1969, Donald D. Matson describes the treatment of childhood medulloblastoma (MB) as being “certainly one of the darkest chapters in neurosurgery” [76]. Treatment developments during the past decades have brought about a considerable increase in survival in some subsets of children with MB, but at a commensurate high price in the form of severe intellectual, physical and emotional sequelae, leading to a reduction of what is referred to in the literature as “the quality of their lives.” A major limitation is that investigators refer to a wide range of aspects when mentioning this topic in their writings, and to this day there exists little consensus about the definition of the concept [126]. A closer look reveals a clear logic in the way the discussion has evolved; there was no focus on quality of life (QOL) during the early decades of the 20th century because most patients died within months, but each time physicians discovered new and more effective therapies against the disease, including new technology, survival rates rose. This meant that investigators gradually became aware of the many things that were important with regard to the quality of their patients’ lives, as more and more children had the opportunity to mature and develop both physically, intellectually, emotionally and as social beings (Fig. 1). Assessment of QOL is today considered invaluable in terms of complete clinical assessment, and decisions about how to optimize treatment focus simultaneously in QOL and the impact of survival. The purpose of this article is to trace historical advances in MB treatment and to explore the relationship between treatment developments, survival, awareness of sequelae and the QOL discussion as it relates to this highly malignant disease through a journey back in time.

as death within a month from surgery, and survival rates1 were used as a measure of treatment developments. The survival rates were not always easy to come by, and tend to vary between studies covering the same decades of the 20th century. The best outcome statistics published were chosen to represent each of the periods, which can be criticized for presenting a skewed picture of the situation. Importantly, they were used as an illustrative representation of the increase in survival that has occurred during the past 100 years. Even if the lowest reported survival rates per decade had been used, the survival curve in Fig. 1 would have had the same shape as it does now, with a gradual increase during the first decades of the century followed by a rapid — and notably parallel — rise in 5- and 10-year survival rates as of the 1960s. A similar observation can be made for operative mortality — it was high during the first 60 years of the century, but virtually disappears in the seventies. It can be hard to use retrospective studies to explore the QOL discussion during a certain period in the past, because the norms of the authors belong to a later point in time. Additionally, the period that researchers were documenting often spans several decades. This has been tackled by freely using raw data such as survival rates and treatment details from retrospective studies, while keeping the analysis of the QOL discussion based on articles written within or shortly after the period in question whenever possible.

Results 1920–1939 Surgery Radiotherapy Imaging

Survival Materials, methods and limitations of the review Articles containing the words “childhood medulloblastoma” and “quality of life” were identified in Medline, and those containing phrases pertaining to psychological, emotional, behavioral or social adjustment in the title, abstract or keywords were selected. Citations from review articles and previously located articles were cross-examined for inclusion. The inclusion of relevant older articles and books/book chapters was assured by working in a retrograde fashion through reference lists and citations. Operative mortality was defined

QOL discussion

Suction. Electro-surgery [8, 27]. Total extirpation versus no operation [8, 28]. KV technique. Localized versus whole craniospinal axis [8, 27]. Microscopic examination of fresh tissue during operations. Roentgenograms. Ventriculography. Angiography [8, 27, 52]. Months [27]. Operative mortality 24 % [77]. Operative mortality, symptoms and survival [8, 27]

During the first decades of the 20th century the diagnosis of MB was considered tantamount to a death sentence. Operative mortality was high, life expectancy was measured in months and the purpose of surgery was primarily palliative [13, 27].

1 Overall survival rates were used for the 20th century while 5-year average risk survival rates were used for the 21st century, since overall survival rates were not available for that period.

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Fig. 1 The relationship between treatment developments (x-axis), survival rates (y-axis), sequelae and QOL parameters (horizontal text attached to 5-year survival curve) in childhood MB. Every treatment development and diagnostic advancement has caused an increase in

survival and the appearance of new sequelae. Duration of survival and spectrum of sequelae have in turn determined the focus of the QOL discussion

Three things contributed to improved survival during the 1920s — namely the discovery that MB is radiosensitive in 1919, the implementation of a suction apparatus in 1925 and electro-surgical methods in 1927 [27]. Localized irradiation slowed the progress of the disease, suction allowed for more radical tumor removal, and electro-surgical methods contributed to better hemostasis and coagulation during operations with a corresponding drop in operative mortality. In his description of experiences with cerebellar MB between 1903 and 1929, Harvey Cushing makes no effort to hide his frustrations with tumors of the fourth ventricle, describing them as offering a most perplexing therapeutic problem, craving great respect and needing primary attention. For these reasons he performed increasingly radical extirpations throughout the years — an approach that led to an operative mortality rate of 32 % — but provided the survivors with a longer symptom-free period of survival in return [27]. During this period, neurosurgeons also directed radiation therapy. In 1927, Cushing and his assistant Bailey noticed the MB’s propensity to form metastasis in the subarachnoid space, and thereafter extended the field of irradiation to routinely include the spinal axis [77, 115]. During the thirties the focus of treatment shifted away from radical surgery towards systematic irradiation of the entire CNS, with

some investigators going as far as recommending no surgery at all [8, 28]. Operative mortality rates continued to drop but survival did not rise accordingly, and the discussion of patient outcomes remained centered around operative mortality, survival and symptoms of the disease [8, 27]. There was little room for a sophisticated discussion about the children’s QOL since survival was so poor. 1940–1959 Anesthesiology Radiotherapy Chemotherapy Survival QOL discussion

Intubation [21]. Intensive care units [71]. Sedation, dose, timing and shielding of vital organs [55, 69, 102, 115]. Radiogold [61]. 3 years 54 % [13]. Operative mortality 24 % [77]. Optimism versus awareness of physical sequelae of radiotherapy [15, 102, 115].

Doctors experimented further with the application of radiotherapy during the forties, and 3-year survival rates became a reality [13, 69]. This advance initially gave rise to optimism. There was even talk of a cure since some of the children were

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living longer than 5 years, and radiotherapy seemed to hold the answer: “We believe that we are fully justified to conclude that children with malignant intracranial neoplasms can be irradiated adequately and without fear of undue sequelae…” [15]. The survivors were noted as being in excellent health with no apparent neurological difficulty, and abnormalities were blamed on the tumor, the operation or considered exceptions to the rule [15, 55]. The discussion about how the children were doing was minimal, but positive. However, this was not true for all. Richard A. Smith speculated that irradiation might be the cause of mental retardation and seizures, and consequently changed his radiation methods in 1950. His efforts showed no change in morbidity, but can nevertheless be considered to be the first conscious attempt to improve the QOL of MB survivors [115]. Three years later Paterson reported growth retardation, skin changes, hair loss, leukopenia and sterility in some of his patients, likewise attributing these to radiotherapy [102]. The fifties generally represent a shifting phase in the treatment of MB, heralding a wave of rapid improvements in the sixties. Initial attempts at chemotherapy were carried out [61] and adjustments were made to radiation procedures with emphasis on sedation, dose, timing and shielding of vital organs [55, 69, 102, 115]. There was much growth within the field of anesthesiology, with intensive care units being established [71] and intubation becoming common practice during operations [21]. Overall focus, however, was still on improving survival [68, 69, 102]. It was not until the subsequent decades, when the late effects of radiotherapy started surfacing and the cases from the 1940s and 1950s were reviewed in hindsight, that important new concepts emerged in relation to QOL of these “new” survivors — namely, endocrinologic dysfunction and trouble with schooling [6], behavioral and psychological impairment [13, 46] together with reflections on social status [45] and “useful survival” [77].

The 1960s introduced MV radiation to the standard treatment of MB [13, 55], which improved dose distribution to the cranium, minimized “junctional hot spots” in the spine and reduced radiation sequelae of skin, eyes and bone [23]. Animal studies simultaneously demonstrated the extreme sensitivity of the immature nervous system to ionizing radiation, and in 1964 Hirsch et al. [53] started administering reduced doses to children under the age of 3. Many experiments were made with chemotherapy, but researchers continued to be doubtful of its beneficial effects [76]. Surgeons incorporated VP shunts into treatment regimens to relieve intracranial hypertension and there was a return to Cushing’s idea of total extirpation, greatly facilitated by the use of magnified vision [11, 76, 101]. Several new diagnostic methods aided surgical improvements: EEG assisted with differential diagnosis between posterior fossa tumors and lesions of the cerebral hemispheres, ultrasound enabled the detection of dilated ventricles, radioisotope scans facilitated the diagnosis of the actual tumor mass in the cerebellum, and myelography was used to screen for spinal metastasis [76]. Operative mortality decreased [76] and survival improved considerably [11, 77] with a corresponding change in awareness regarding the children’s well-being: the actual term “QOL” was used for the first time, and a formal system for assessing how MB children fared post-treatment was established (Bloom’s scale) [13]. The focus was on physical deformities, brain damage, neurological sequelae and possible carcinogenesis of the treatment, which makes sense as increasing amounts of patients finally lived long enough for these late effects to become apparent [13, 77]. Bloom neither defined what he meant by QOL nor paid specific attention as to how the survivors were adjusting emotionally, and it is important to note that the disease was still, after all, considered incurable. 1970–1979 Surgery

1960–1969 Surgery Radiotherapy

Chemotherapy Imaging Survival

QOL discussion

Magnified vision. VP shunting [76]. MV technique [13, 55]. Initial experimenting with reduced doses to children under the age of 3 [53]. Methotrexate. Vincristine [77]. EEG. Ultrasound. Radioisotopes. Myelography [76]. 5 years: 47 %; 10 years: 30 % [11, 77]. Operative mortality ~18 % [6, 13, 76]. Neurological sequelae. Physical disability. Carcinogenesis of radiotherapy [13, 77].

Anesthesiology Radiotherapy

Chemotherapy

Operating microscope. Bipolar coagulation. Shunt filters [53, 90, 101]. Neuroanesthesiology [2]. Operative TNM staging system for MB guides radiotherapy [23]. Average versus poor risk patients [94]. Radiotherapy omitted to children under the age of 3 [9]. Chemotherapy or not? SIOP-I and CCG-942 [39, 118]. Lomustine (CCNU). Methylchlorethamine. Procarbazine. Prednisone [9, 90, 101]

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Imaging Survival

QOL discussion

CT [90]. 5 years: 56 % [98]; 10 years: 43 % [11]. Operative mortality drops [101]. Neuropsychological sequelae, IQ and schooling [16, 53].

1980–1989 Surgery Radiotherapy

Chemotherapy Three important elements arrived on the scene in the treatment of MB during the 1970s — the CT scanner, operating microscope and increased use of chemotherapy. CT improved diagnosis, allowed for better planning of operations and reduced the number of pre-operative drains needed [56, 90, 101]. This was considered a step forward, as shunting appeared to facilitate metastasis of the tumor. The aim became to avoid such interventions whenever possible, and Millipore filters were incorporated into the shunts to hinder possible spread of the cancer [11]. The operating microscope improved depth perception with improved illumination which enabled more complete tumor removal, and it finally seemed certain that total resection rendered the highest survival rates [90, 101, 105]. Bipolar coagulation also contributed to a drop in operative mortality in conjunction with better visualization secondary to the microscope [53], and neuroanesthesiology was officially recognized as a subspecialty [2]. Oncology, however, was the word of the day: chemotherapy became an integrative part of many treatment schemes [9, 90, 101] and in 1969 an operative TNM staging system was set up for MB to guide intensive, strategic radiotherapy attacks on major areas of tumor involvement according to the extent of the disease (staging studies) [23, 39]. Two large prospective, randomized trials comparing the effect of radiotherapy alone versus radiotherapy and adjuvant chemotherapy were carried out [39, 118] while some did the opposite — omitted radiotherapy in favor of chemotherapy alone for children under the age of 3, in an attempt to spare the immature brain [9]. The aforementioned changes caused operative mortality to dramatically decrease [101]. Survival continued to improve [11, 94], and many patients were living long enough to start/return to school after treatment. Thus, the children’s neuropsychological status received ever-increasing attention. Researchers included interviews, questionnaires and cognitive and neuropsychological tests in their studies, with a strong preference for Wechsler’s IQ scales and information on school performance. Most agreed that MB patients’ IQ dropped after treatment and/or that they did worse academically than their peers [53, 62, 66, 70, 74, 98, 101, 112, 113]. The term QOL frequently shows up in the literature, and two reports specifically addressed the subject for the first time [70, 98]. None of the researchers defined the concept as such, but they did tie it to a long range of physical, cognitive, emotional/behavioral parameters [1, 11, 16, 24, 53, 62, 66, 67, 70, 98, 101, 116, 130] and treatment variables [98, 130]. The radius of the QOL concept kept enlarging.

Imaging Survival QOL discussion

CUSA. Laser surgery [14, 38, 122]. Reduce irradiation? SIOP-II, POG-8361/CCG-923 [7, 30]. HFRT [75]. Who, when, what and how? Many large studies [31, 44, 65, 81]. Cisplatin. Carboplatin. Cyclophosphamide. Etoposide [51]. MRI [1]. 5 years: 60 %; 10 years: 53 % [56]. Psychological and social aspects [72, 86]. Cerebellar mutism [106].

The formula for treatment of MB that had been established in the 1970s (surgery, radiotherapy and chemotherapy) was further developed during the eighties. There was an ongoing exploration of who should receive what kind of chemotherapy, when and how [7, 9, 31, 44, 65, 81, 85, 133], the effects of reduced irradiation were studied systematically [7, 30] and hyper-fractionated radiotherapy (HFRT) was tried out in the hope of therapeutic improvement and reduction of long-term sequelae [42, 75]. Magnetic resonance imaging (MRI) and rapid advances within the field of neuroanesthesiology improved perioperative management and aided survival [1, 2]. Cavitron ultrasonic aspiration (CUSA) made surgery faster and theoretically safer [14], enabling more gross total resections [14, 122]. This put increasing pressure on neurosurgeons to obtain “total” resection for improved survival, but more aggressive tumor removal came at a price: in 1985, cerebellar mutism — a puzzling phenomenon of transient mutism — was described for the first time following posterior fossa surgery [106]. It appears to be related to removal of large, midline tumors of the cerebellum/fourth ventricle, and is thought to be caused by surgical damage to the dentate nuclei and their outflow tracts [48]. On a national level in the United States, 25 % or more of children were diagnosed with cerebellar mutism, and one-half of those affected had permanent sequelae definitively affecting QOL [109]. A change in surgical technique (avoiding vermian dissection in favor of a telovelar approach, as well as minimal use of both retraction and the CUSA) at the Children’s National Medical Center in Washington was noted to decrease the incidence of mutism from 39 % to 13 % over an 8-year period [114]. Radiographic studies have demonstrated longstanding cerebellar atrophy as well as evidence of damage to the dentato–thalamo–cortical pathway [127], and there has been increasing evidence of permanent cortical dysfunction as a result of damage to these outflow tracts [128]. Researchers noticed that their patient’s IQ not only dropped shortly after treatment, but kept on decreasing over the years [56]. They came to realize that intelligence is not the only

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measure of the functional status of the patient [98], and increasing attention was paid to the psychological and social problems they were facing. Areas of interest included activities of daily living, participation in social activities, relationship status and employment history [41, 56, 58, 72, 86, 112], and the Child Behavior Checklist was commonly used to identify deficient social competence and behavioral problems as reported by primary caregivers [20, 41, 58, 71, 84, 129]. Various sequelae seemed to worsen with time, and routine psychological and neuropsychological testing of the patients was recommended [41, 56, 58, 86, 129]. Many had problems with work and marriage [56, 62, 70], and specific family adjustment assessment was suggested with the aim of psychosocial interventions during and after treatment, due to the long-term difficulties the patients and their relatives faced [20, 58, 112]. Growth within the field of pediatric neurology contributed to increased awareness around the child’s development, and it became apparent how difficult it can be to define factors that determine the functional status of children surviving brain tumors; that objective criteria are needed for doing so, and that there is a danger of discrepancies between the physician’s positive ratings and the patient’s wide-ranging problems [72, 86]. 1990–1999 Surgery Radiotherapy Chemotherapy Survival QOL discussion

Pediatric neurosurgery [3]. Proton beams [4, 79, 80]. High-dose chemotherapy and stem cell rescue [33]. Rarely mentioned; continues to improve. What is QOL and how do we measure it? [60, 74]. Posterior fossa syndrome [104].

The 1990s may be described as the “Quality of Life Era” for survivors of childhood MB and patients in general. Pediatric neurosurgery became established as a mature subspeciality [3] and doctors continued fine-tuning irradiation and chemotherapy protocols [47, 64, 78, 96, 121]. Proton therapy promised improved local control and less morbidity by increasing irradiation of cancer-containing parts of the CNS, while simultaneously reducing volume and dose to the surrounding normal tissue [4, 79, 80]. High-dose chemotherapy followed by stem cell rescue seemed to provide long-term survival in some patients with recurrent MB [32, 40], primarily those who had local recurrence and had not received prior chemotherapy, or infants with local recurrence who had not received radiotherapy. And yet an interesting thing is deemphasized in MB articles for the first time — namely the survival rates. The main issue to be dealt with was no longer if or for how long the children would live, but how they would

live. It had become clear that MB survivors were struggling in just about every area of their lives and something had to be done about it [5, 10, 29, 56, 57, 60, 74, 82, 83, 112]. Furthermore, most of those affected by cerebellar mutism seemed to suffer from a range of other neurobehavioral, neurological, speech and language-related symptoms termed the posterior fossa syndrome [104], with a profound effect on their personality, overall level of functioning and long term outcomes [48]. Investigators knew they needed to assess the children’s QOL in a broad sense, and wondered about the best ways in which that could be done [5, 10, 18, 19, 60, 74, 83]. Thus, in 1990 the National Cancer Institute in the USA sponsored a workshop in QOL assessment in cancer clinical trials specifically to promote the inclusion of QOL endpoints in research on cancer, and in 1992 the journal Quality of Life Research: An International Journal of Quality of Life Aspects of Treatment, Care and Rehabilitation was published for the first time [88]. The whole discussion was quite critical — both of itself and of previous efforts made within this area of patient care. In 1994, Seaver et al. [112] pointed out a lack of a standard definition of QOL and an acceptable scale for measuring it in children, and in 1999 Kennedy and Leyland [60] responded with the first official definition: “Health related quality of life includes emotional and social dimensions of health and depends also on the subjective perception of the person about his/her state of health, which again was defined by the World Health Organization as ”a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity.“ Kennedy and Leyland [60] also pointed out that health-related QOL is likely to be affected by sensory, motor and cognitive function, that it may be particularly affected by emotional/behavioral problems, and disproportionately reduced by the interaction between multiple impairments and between impairments and socio-economic status. There it finally was — a definition of QOL that aimed to embrace most of the things that previously had been associated with the concept in pediatric MB survivors, and attempted to account for their interrelationship.

The 21st century Mol. biology/genetics

Chemotherapy

Survival

Molecular markers [34, 89]. Four core subgroups of MB [92, 93, 120]. Cellular pathway inhibitors. Growth factor inhibitors [26, 95, 110]. Anti-angiogenic drugs. Pro-apoptotic agents [87]. 5 years: 85 % (average risk patients) [99]; 10 years: 73 % (overall) [125].

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QOL discussion

Premature aging and long-term patterns of decline. Risk- and resilience factors. Parents and the rest of the family [35, 97, 124, 131, 132].

The 21st century has given birth to may new ideas and options in the treatment of childhood MB, most notably within the field of molecular biology and genetics. The current consensus recognizes four core subgroups (WNT, SHH, Group 3, Group 4) with distinct mutational signatures [91], biological, genomic, clinical, demographic and prognostic features [92, 93, 120]. WNT tumors are associated with an excellent outcome (>95 % 5-year overall survival) [63], while patients with Group 3 tumors have a poor prognosis despite the application of the same multimodal treatment strategies [92, 120]. The understanding of molecular biology of MB subgroups becomes increasingly relevant with the development of targeted therapies for specific disease variants like SHH-driven tumors [108, 110] as well as in the context of outcome prediction strategies focusing on subgroup-specific models, in addition to surgical strategies related to degree of resection [107]. Upcoming multicenter trials will stratify MB according to molecular biology and clinicopathological risk factors. Age-adapted strategies have been devised sparing infants radiation as first-line treatment modality to avoid neurocognitive sequelae [111], growth receptor inhibitors, anti-angiogenic factors and pro-apoptotic agents are all being tested as drugs [87], and 5-year survival rates as high as 85 % are already a reality for average-risk patients [99]. At the same time there are continuing developments within the field of QOL research. Current areas of interest include comparison of brain tumor children to their siblings together with the effect that chronic pediatric disease has on the rest of the family [97, 124, 131, 132], and the results of previous efforts at measuring QOL in children are being evaluated [12, 19, 36, 43, 119, 123, 124]. A few reports on intervention studies aimed at remediating cognitive deficits have also been published [17, 54, 103]. Importantly, researchers have become aware of the time factor — that the quality of the children’s lives tends to change as the years go by — with corresponding emphasis on long-term studies and assessments at regular intervals [22, 35, 73]. Survivors tend to suffer from premature aging, specific patterns of decline in skills and intelligence have been elucidated, and many are unable to achieve independence. This obviously raises concerns as to how they will manage when their caregivers pass away, and underscores the importance of identifying factors that contribute to risk and resilience in this patient population [35]. Measurements of QOL continue to be refined with multivariate analysis of treatment-, socioeconomic- and patient-related factors amongst others, and specific pediatric inventories (e.g., Pediatric Quality of Life Inventory (PedsQL) and the Health Utilities Index Mark

3 [HUI3]) are now being incorporated as secondary outcome measurements in most pediatric brain tumor protocols [25].

Discussion The QOL concept There is general consensus among investigators of childhood MB, be they oncologists, neurosurgeons, radiation therapists or neurologists, that QOL is a critical outcome measure in assessment of the efficacy of any treatment. Subjective phenomena like QOL may be difficult to measure adequately, and precise definitions are imperative for meaningful comparisons between multiple cohorts. The close relationship between increased survival and gradual broadening of the QOL concept is neatly illustrated by reviewing treatment developments in pediatric MB, and there is a clear logic in the way the discussion has unfolded itself (Fig. 1). Treatments, time and sequelae Almost every “advancement” in the management of children with MB, while contributing to increased survival, has also been associated with potential risks to the long-term functioning of survivors. Surgery has improved dramatically in a stepwise fashion, but attempts at complete tumor removal have resulted in increased post-operative sequelae like mutism, emotional lability/blunting and abnormalities in tone and motor function, which can be hard to quantify. Techniques associated with radiotherapy have vastly improved, but the long-term benefits of some of the newer ones have yet to be shown; as an example, although proton beam irradiation does seem to spare other organs, the effects on the development and function of the brain can only be determined after many years of follow-up. Chemotherapy has improved survival rates and allowed a reduction in the total dose of craniospinal irradiation, but it too has its own long-term sequelae. Cisplatin can cause hearing loss with detrimental effects on schooling and social capabilities [50], and vincristine can cause neurologic problems, especially in adolescents [117]. Lastly, the use of chemotherapy may result in a higher incidence of secondary malignancies which at a minimum can be life-altering, and often result in death of the patient [100]. The MB story illustrates how important it is to think ahead and outside the frame when it comes to the possible late effect of a new treatment, since the task of filling out the entire spectrum of sequelae requires a substantial amount of time. Range of problems versus QOL questionnaires Apart from those mentioned above, a host of other neurologic sequelae such as tinnitus, delayed onset of motoric and balance

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deficits, epilepsy and ocular complications have been increasingly noted in long-term follow-up studies of MB survivors [49]. The identification of these have relied on self-reporting questionnaires, which are likely a crude measure of long-term difficulties, and are limited by significant patient and family subjectivity. Other long-term problems such as chronic fatigue, sleep disturbances and overall poor psychosocial functioning are also noted in the questionnaires [37, 49, 97, 131], but are probably just the tip of the iceberg of the difficulties that survivors face. The endocrinologic issues have been touched upon earlier in this manuscript, but the effects of obesity and short stature cannot be underestimated. Money, time and human resources Complicating the assessment of type, incidence and causation of long-term sequelae are the mounting pressures put on investigators to make their studies more cost-effective. Sequential assessments of detailed neurocognitive outcomes including executive functioning are expensive, and have by and large been poorly performed in cooperative group settings. This has led to many “cognitive studies” being curtailed, limited or dropped, especially in long-term follow up. They have been replaced by “QOL assessments,” which are easier to administer and less expensive. However, many of these, although validated in other children with chronic disease, have not been fully validated in children and young adults with brain tumors. Early interventions Assessing the deficits the children have and developing new and better tools to determine long-term sequelae are only the first steps in the process of improving QOL for children with MB. Interventions early in the treatment such as intensive cognitive remediation, pharmacologic therapies or early physical therapy are important potential adjuncts. Determination of utility of these interventions will require detailed study, and likely rely on some of the aforementioned QOL questionnaires to assess efficacy. Cure versus QOL As the pendulum swings to increased emphasis on QOL of survivors of MB, improvements have to be placed in the context of the need to cure patients. As more complex chemotherapeutic regimens become common in attempts to reduce the dose and volume of radiation therapy, there is an increasing possibility that disease control may not be as great, or that sequelae of alternative therapies may be more detrimental in the long term than the ones they are trying to replace. Similarly, there are discussions concerning limiting the amount of surgery to decrease sequelae — especially the

posterior fossa syndrome — and although this may improve QOL for some patients, it may also result in poorer survival. Furthermore, the introduction of biologic therapy is a near reality as the molecular underpinnings of MB are better understood. However, the long-term consequences of such therapy, which risks altering normal molecular functions in the brain and other organs, must be carefully assessed over time. Endpoints, approaches and future aims The endpoints of previous treatment protocols have traditionally featured survival as a primary endpoint, and QOL as a secondary one [64, 96]. This is likely to change, however, as there are already discussions about creating protocols that have survival and QOL as joint primary endpoints [99]. Sois the QOL scene set for the next decades? There is agreement that in this rare disease, multicenter studies are necessary to obtain sufficient number of patients to answer clinical research questions. Consequently in Europe this requires a common (international) set of basic QOL tools that will work across cultures and age groups to be able to compare QOL data. Additionally researchers will use new methods to investigate QOL. Another task is to make sure the QOL evaluations actually happen. In the recently published European multicenter study on standard/average risk MB (PNET-4) the response rate was 62 % in long-term survivors, which was considered relatively high [59]. However, in order to further improve this number a web based system will be applied in the upcoming PNET-5. This will give patients/parents the option to answer questionnaires from home at a time preferable to them. The concept and definition of HRQL is likely to keep evolving in the setting of continual advances being made within the field of medicine, underscoring the importance of continued discussion and research within this area of patient care.

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