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Cognitive Sparing during the Administration of Whole Brain Radiotherapy and Prophylactic Cranial Irradiation: Current Concepts and Approaches

Cognitive Sparing during the Administration of Whole Brain Radiotherapy and Prophylactic Cranial... Hindawi Publishing Corporation Journal of Oncology Volume 2010, Article ID 198208, 16 pages doi:10.1155/2010/198208 Review Article Cognitive Sparing during the Administration of Whole Brain Radiotherapy and Prophylactic Cranial Irradiation: Current Concepts and Approaches JamesC.Marsh,BenjaminT.Gielda,ArnoldM.Herskovic,and Ross A. Abrams Department of Radiation Oncology, Rush University Medical Center, Chicago, IL 60612, USA Correspondence should be addressed to James C. Marsh, james c marsh@rush.edu Received 17 September 2009; Accepted 7 April 2010 Academic Editor: Rolf Bjerkvig Copyright © 2010 James C. Marsh et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Whole brain radiotherapy (WBRT) for the palliation of metastases, or as prophylaxis to prevent intracranial metastases, can be associated with subacute and late decline in memory and other cognitive functions. Moreover, these changes are often increased in both frequency and severity when cranial irradiation is combined with the use of systemic or intrathecal chemotherapy. Approaches to preventing or reducing this toxicity include the use of stereotactic radiosurgery (SRS) instead of WBRT; dose reduction for PCI; exclusion of the limbic circuit, hippocampal formation, and/or neural stem cell regions of the brain during radiotherapy; avoidance of intrathecal and/or systemic chemotherapy during radiotherapy; the use of high-dose, systemic chemotherapy in lieu of WBRT. This review discusses these concepts in detail as well as providing both neuroanatomic and radiobiologic background relevant to these issues. 1. Introduction radiosurgery (SRS) alone (particularly for Class I patients), or SRS in combination with WBRT [5–9]. Unfortunately, Whole brain radiation therapy (WBRT) is a mainstay of WBRT is associated with late brain toxicities, which range therapy for the treatment of primary and metastatic tumors in severity from mild deficits in cognitive dysfunction to involving the brain [1–3]. WBRT entails treatment of the overt dementia in up to 11% of patients depending on whole intracranial compartment (brain and brainstem) the population studied, the length of follow up, and the down to the foramen magnum or to the bottom of either type of chemotherapy employed [10–13]. The sequelae of the first or second cervical vertebrae, with a uniform dose of treatment are even more severe in pediatric patients treated radiation, typically administered with opposed lateral fields with WBRT, in whom hearing loss, severe global cognitive and blocks to protect the lenses. Multiple dose fractionation deficiencies, and neuro-endocrine deficits may develop [14– regimens have been employed for WBRT, with no one 16]. In patients 60 years of age and older with primary schedule having been conclusively proven better than others, CNS lymphoma, the combination of WBRT and high- although single fraction therapy (ex. 10 Gy in a single dose methotrexate regimens has resulted in severe to fatal fraction) has been shown to result in greater toxicity [4]. leukoencephalopathy resulting in the frequent omission of Common utilized treatment schedules include 2.5 Gy × cranial radiotherapy in this context [17]. 14 or 15 fractions, or 3 Gy × 10 fractions. In the setting Prophylactic cranial irradiation (PCI) has become a stan- of intracranial metastases, patients with RTOG RPA class dard of care for selected patients with limited and extensive III (Table 1) disease are often managed with WBRT alone, stage small cell lung cancer (SCLC) who have shown benefit while patients with RPA class I or II disease are frequently managed by a combination of modalities, including WBRT with systemic treatment. PCI has also been explored in the alone, surgical resection followed by WBRT, stereotactic context of nonsmall cell lung cancer (NSCLC), but in this 2 Journal of Oncology Table 1: RTOG RPA Classification for brain metastases. to cause significant late sequelae and this knowledge has prompted reductions in the indications for, and doses of, PCI Median Survival Class Characteristics in this context [30–34]. (months) In this article we review these issues in further detail and KPS 70 or greater, age 65 years discuss the different methods currently being employed and or less, primary disease 7.1 explored in an effort to reduce neurocognitive toxicity. controlled, no extracranial metastases II All others 4.2 2. Toxicity of Cranial Irradiation III KPS < 70 2.3 The effects of cranial irradiation may be roughly divided into acute, subacute, and chronic [35]. Acute side effects, context has not been shown to improve overall survival [18– which occur during or within a few weeks of radiation 22]. A recent RTOG study (RTOG 0214) exploring the use of therapy, include fatigue, alopecia, nausea, and effects related PCI in NSCLC was presented at the 2009 ASTRO (American to exacerbation of baseline cerebral edema such as headache, Society for Therapeutic Radiology and Oncology) meeting in nausea, focal deficits, and when severe changes in mental Chicago, IL. [23, 24] 340 patients with Stage III nonsmall cell status. Subacute symptoms (those occurring after the com- lung cancer, who showed no evidence of tumor progression pletion of radiotherapy but within three months of the end after treatment of their primary tumor, were randomized to of treatment) are relatively rare and limited primarily to be treated with PCI or undergo observation from 2002 to the somnolence syndrome and, less frequently, early onset 2007. PCI resulted in a reduction in the incidence of brain leukoencephalopathy. The pathophysiology of the somno- metastases from 18% to 8%, but did not impact overall lence syndrome is probably related to transient demyeli- survival [24]. Importantly, while PCI did not significantly nation of cerebral white matter (analogous to Lhermitte’s impact overall reported quality of life, it did result in lower syndrome after spinal irradiation). Leukoencephalopathy, rates of both immediate and delayed recall, suggested that the on the other hand, is believed to represent a more severe use of PCI impairs memory function in treated patients [24]. manifestation of demyelination and may be fatal. These The concept underlying PCI is to eliminate microscopic white matter changes may be more prominent in older deposits of metastatic tumor within the brain and/or patients with vascular risk factors, and evidence of this brainstem before they become clinically manifest. Without damage can be identified before other gross changes are PCI, more than 60% of small cell lung cancer patients will evident on MRI by early changes in fractional anisotropy eventually develop clinically detectable and/or symptomatic (FA) as identified on diffusion tensor imaging (DTI) after brain metastases at some point during the course of their the delivery of PCI [36]. Similar changes in FA on DTI can disease, and PCI reduces this rate to approximately 20% [25]. be seen in pediatric patients who have been treated with The treatment field for PCI is similar to WBRT in that the radiotherapy for medulloblastoma, with one recent study whole brain and brainstem down to the foramen magnum showing a mean reduction in FA of 16.5% in treated patients or the bottom of the first or second cervical vertebrae is versus controls [37]. These reductions in FA were found treated to a uniform dose, with most patients being treated to correlate with a younger age at the time of treatment using opposed laterals with lens blocks. Multiple treatment anddeclinesinschoolperformance [37]. Late side effects, schedules are employed, with no one schedule clearly which occur six months or later after radiation therapy, showing superiority to others [26]. Arecentprospective include overt radionecrosis of the brain (with areas of study found that there was no significant reduction in the focal coagulative necrosis) and progressive microvascular number of brain metastases for 36 Gy in 18 fractions versus or vascular occlusion with a subsequent increased risk of 25 Gy in 10 fractions, while overall survival was worse for stroke. Rarely this may mimic Moyamoya syndrome as seen unclear reasons in the higher dose arm [26]. The authors in other contexts not involving radiotherapy or malignancy concluded that 25 Gy in 10 fractions should remain the [38–41]. standard of care in this setting [26]. In the setting of both Various systems have been developed to describe these limited and extensive stage small cell lung cancer, the use effects, including (among others) the NCI Common Toxicity of PCI has resulted in statistically significant improvements Criteria Version 2.0 (available at http://ctep.cancer.gov) in overallsurvival(OS)[27, 28]. As these patients are at and the RTOG/EORTC LENT-SOMA systems [42]. These risk for cognitive deficits from multiple causes such as age- scoring systems’ definitions of neurotoxicity are shown in related cerebral atrophy, preexisting cerebrovascular disease, Tables 2 and 3. However, more subtle deficits in cognitive anxiety, depression, and chemotherapy effects, there has been function are not accounted for in these systems, nor are all controversy regarding the extent to which PCI contributes of the neuroendocrinologic sequelae of therapy. to observed neurocognitive deficits [29]. However, with Late toxicities in the brain are highly feared sequelae of recent increases in mean overall survival and an increased cranial irradiation in both adults and children because they number of longer-term survivors, the contribution of PCI are highly debilitating and irreversible. The axonal tracts to the development of neurocognitive deficits is becoming that connect the cerebral cortex to the subcortical gangliae, more clearly defined [30]. Finally, PCI for pediatric patients spinal cord, and brain stem nuclei do so in series, such that with high risk acute lymphocytic leukemia (ALL) is known damage to any part of the sequence adversely affects [43]. Journal of Oncology 3 Table 2: RTOG/EORTC Late Morbidity Scoring System for Brain. WBRT (but not PCI) patients after 1–3 fractions and at the completion of treatment, while subacute declines in Grade 0 None verbal memory were seen in both WBRT and PCI patients Mild headache, slight 6–8 weeks after the completion of treatment [13]. On Grade 1 lethargy multivariate analysis, they found that these deficits persisted Moderate headache, great even after accounting for the use of chemotherapy, KPS score, Grade 2 lethargy and the presence of depression and/or anxiety. They found Severe headache, severe no significant declines in visual memory or attention span Grade 3 CNS dysfunction (partial [13]. loss of power or dyskinesia) In some cases, late neurological deficits can be severe Grade 4 Seizure, paralysis, coma enough to cause overt dementia, wherein the patient’s global Grade 5 Death level of functioning is severely impaired and the patient is not aware of these changes. This is in contrast to more subtle cognitive deficits that are commonly seen and of which the patient is typically well aware. The incidence of dementia The generally accepted TD5/5 and TD50/5 (radiation doses after cranial irradiation has been reported to be as high as 11% in patients with long-term followup [11], and these which, when delivered to a given type of tissue in a typical patient population, will result in a 5% or 50% rate of Grade long-term sequelae have been shown to correlate with and 3 or higher toxicity at a time point 5 years removed from precede decline in patient-reported quality of life (QOL), [12, 13]. the radiation exposure, resp.) after treating the whole brain with standard fractionation are 45 Gy and 60 Gy, respectively, PCI has variably been described as having no effect on and for partial brain radiation exposure are 60 Gy and 75 Gy cognitive function, adversely affecting cognitive function, [44]. Due to the slow rate of cell turnover for neuronal and and even initially improving cognitive function in adult glial elements, the brain represents a late responding tissue, patients [13, 47–51]. As reported by Welzel et al., PCI patients appear to start out with lower baseline cognitive with an accepted α/β ratio of about 2 Gy [45]. This suggests that treatment of the brain with smaller daily or fractional functioning scores than the WBRT patients, have a transient radiation doses might reduce risk of late sequelae. However, improvement in simple reaction time (the ability to respond to an acutestimulus) during andatthe endofradiation the use of smaller radiation fractions also necessitates the delivery of a higher total dose of radiation to achieve the same therapy, and subsequently have a decline in verbal memory degree of tumor control [43]. 6–8 weeks after completing therapy [13]. A report recently Various treatment schedules have been developed for the released by the EORTC of patient-reported quality of life administration of WBRT in the setting of brain metastases scores after PCI showed a significant decline in QOL up [46]. Onecommonlyutilizedscheduleis30Gyin10 to 3 months after the completion of treatment, although fractions, which (assuming an alpha/beta ratio of 2 Gy the most frequently reported complaints were for alopecia for late neurologic sequelae) correlates with a biologically and fatigue and the global QOL scores were less adversely affected [30]. For individual patients demonstrating brain equivalent dose (BED) of 75 Gy , theoretically below the TD5/5 of whole brain (45 Gy by standard fractionation at metastases following PCI, it can be difficult to determine 2 Gy per fraction, which corresponds to a BED of 100 Gy ). the relative contribution of the recurrence and the PCI when neurocognitive decline is identified [52]. Tumor progression Other commonly used schedules include 2.5 Gy × 14 or 15 fractions, which result in BED values of 78.75 Gy and may particularly contribute to declines in cognitive function 84.4 Gy , respectively, again below the accepted TD5/5 for in patients with significant peritumoral edema [53]. Finally, whole brain radiation exposure. Thus, all of these treatment small cell lung cancer may, even in the absence of overt schedules should result in rates of late neurologic sequelae intracranial metastatic involvement, adversely affect cogni- that are significantly less than 5%. However, the NCI and tive function by mechanisms that are not clearly understood, EORTC/RTOG toxicity scoring systems (Tables 2-3)donot possibly paraneoplastic [54]. include the readily clinically identified changes in cognition Exposure of cerebral vasculature, particularly small arter- ies and arterioles, is known to cause the late development and behavior that are well documented after these therapies [10–16]. of hyaline-type arteriosclerosis with a subsequent increased Themostfrequentlydescribed adverseeffects in adults risk of ischemic stroke [38]. In very young children with treated with WBRT include problems with the consolidation significant exposures to the anterior Circle of Willis region, of new memory, poor attention span/concentration, visual- changes can be seen which include bilateral carotid occlusion spatial difficulties, difficulty with executive planning, and with the subsequent development of transdural anastamoses poor fine motor control [10]. A recently published study and a “net” or “cloud” of small collateral vessels; these by Welzel et al. prospectively assessed cognitive function changes collectively are known as moyamoya syndrome [38– 41]. The moyamoya changes seen after cranial irradiation in patients being treated with either WBRT (40 Gy in 20 fractions or PCI (36 Gy in 18 fractions) at baseline, after 1– are essentially identical to those seen in primary moyamoya 3 fractions, after the last fraction, and at 6–8 weeks after (Nishimoto’s disease) and result in similar clinical manifes- tations such as cerebral ischemic strokes, recurrent transient the completion of radiation therapy [13]. These authors found that acute declines in verbal memory were seen with ischemic attacks (TIAs), motor deficits, sensory deficits, 4 Journal of Oncology Table 3: NCI Common Toxicity Criteria Version 2.0 Summary. Grade 0 Normal Confusion/disorientation which resolves without sequelae, somnolence/dizziness/extrapyramidal symptoms/insomnia/memory loss/mood alterations/neuropathy/personality changes/pyramidal Grade 1 symptoms/tremor/vertigo not interfering with daily function, mild atrophy or limited T2 hyperintensities on MRI (<1/3 of cerebrum), nystagmus Persistent confusion/disorientation/poor attention span not interfering with daily function, somnolence/dizziness/extrapyramidal symptoms/insomnia/memory loss/mood Grade 2 alterations/neuropathy/personality changes/pyramidal symptoms/tremor/vertigo/cranial neuropathies not interfering with activities of daily living (ADL), moderate atrophy or more extensive T2 hyperintensities on MRI (1/3-2/3 of cerebrum) extending into centrum ovale, nystagmus Delusions, hallucinations, syncope, severe atrophy or near total T2 hyperintensities on MRI +/− focal white matter necrosis, persistent confusion/disorientation/poor attention span/somnolence/dizziness/extrapyramidal Grade 3 symptoms/insomnia/memory loss/mood alterations/neuropathy/personality changes/pyramidal symptoms/tremor/vertigo/cranial neuropathies interfering with activities of daily living (ADL) Bedridden/disabled due to brain toxicity, requiring hospitalization doe to risk to self/others, psychotic, unable Grade 4 to communicate, amnesia, diffuse calcification or necrosis, paralysis Grade 5 Death global cognitive dysfunction, convulsions, and/or migraine- For pediatric patients with acute lymphoblastic leukemia like headaches [38]. (ALL) and acute myelogenous leukemia (AML), WBRT is The significant late sequelae associated with cranial RT utilized as an effective therapy for patients who present with have stimulated interest in finding ways to avoid this toxicity overt CNS involvement and those who relapse in the CNS without sacrificing clinical outcomes for this effective and [66–69]. However, given the known late effects of cranial widely available therapy. irradiation in the pediatric population, a number of groups and institutions have developed protocols which exclude WBRT even in patients with overt CNS involvement or who relapse in the brain after initial treatment [70–72]. 3. WBRT and PCI in the Pediatric Population PCI is currently employed as part of standard therapy for 2–20% of patients with ALL who have no overt CNS WBRT is a standard part of the treatment approach for involvement but have a number of other high risk features primary CNS pediatric tumors that have a propensity for dis- (age >9years oldor <1 year old, T cell phenotype, WBC semination along the neuraxis, including anaplastic ependy- greater than 50,000 or 100,000, extramedullary disease, moma, medulloblastoma, ependymoblastoma, pineoblas- presence of Philadelphia chromosome, and poor response to toma, atypical rhabdoid/teratoid tumor, nonseminomatous induction therapy) [66, 67]. ThedoseofPCI hassystemically germ cell tumor, and choroid plexus tumors. WBRT in this been reduced from 24Gy to 18Gy, and some protocols now setting may or may not be combined with spinal irradiation, employ doses as low as 12 Gy [73–75]. However, even at and the doses used vary depending upon the tumor type, the a dose of 18 Gy, there is evidence of late cognitive and age of the patient, and the clinical context [55–59]. A number neuron-endocrinologic sequelae in these patients, even when of approaches have been used to minimize the late toxicity of treatment is delivered on a hyperfractionated schedule of cranial irradiation for these patients. 0.9 Gy twice daily [16, 70–74]. For standard risk medulloblastoma, the dose of cranial St. Jude Children’s Hospital has extensively studied the spinal irradiation (CSI) (including the WBRT dose) has been cognitive and other late neurologic side effects of cranial reduced from 36Gy to 23.4Gy in an effort to reduce some irradiation in children [15, 34, 76–78]. In one study, they of the late effects of cranial irradiation [60]. For intracranial found that the patient’s age and the percent volume of germinomas either whole-ventricular radiation therapy or supratentorial brain irradiated to varying dose levels (0– chemotherapy followed by involved-field radiation therapy 20 Gy, 20–40 Gy, 40–65 Gy) correlated with IQ level after is now preferred over WBRT, again in an effort to spare the cranial irradiation, with younger age at the time of treatment child the late sequelae of treatment [61, 62]. Chemotherapy and the treatment of larger percent volumes of supratentorial without radiation therapy has been utilized in very young brain to higher doses correlating significantly with declines patients (3 years of age and less) as a primary therapy, in IQ after treatment [76]. In another study evaluating the adjuvant therapy, or “bridge” therapy to delay the use of feasibility of field reduction after resection of infratento- radiation therapy for primary CNS tumors until patients rial ependymomas, they tested neurocognitive function at are older and better able to tolerate the effects of cranial baseline and at varying time points after cranial radiation irradiation [63, 64]. Chemotherapy alone or as adjuvant and found that patients treated with fields encompassing the therapy has also been used as a treatment modality for tumor bed/tumor and 1 cm margin (as opposed to a typical intracranial germinomas and nongerminomatous germ cell larger field) had no detectable neurocognitive deficits after tumors, but with unacceptably high failure rates [65]. Journal of Oncology 5 treatment, suggesting that sparing the cochlea (to preserve 28% [87]. Schultz et al., in a subsequent phase I/II trial hearing) and avoiding irradiation of the supratentorial brain (RTOG 88-06), treated patients with 2 cycles of induction minimized the risk of late neurocognitive sequelae [77]. After CHOD (cyclophosphamide, doxorubicin, vincristine, and partitioning the brain into 5 compartments (total brain, dexamethasone) followed by WBRT to a dose of 41.4 Gy in supratentorial brain, infratentorial brain, right temporal 23 fractions and a sequential cone down boost to the patient’s lobe, and left temporal lobe), they found that irradiation of gross disease of 18 Gy in 10 fractions (total 59.4 Gy) [90]. the supratentorial compartment and temporal lobes resulted This trial produced a median OS of 16.1 months and a 2- in significant declines in IQ regardless of dose level, with year OS of 42%, slightly better than the results found in 83- each Gy of exposure having a similar impact on declines in 15, but on direct comparison the difference was not found IQ [34]. The cognitive deficits seen after cranial irradiation to be statistically significant, and the authors concluded that seem to be due to an inability to develop new skills and to induction chemotherapy did not improve survival versus process new information, rather than a loss of previously radiotherapy alone [87, 88]. Of note, both 83-15 and 88- acquired skills and information [15]. The factors that seem 06 found that OS was significantly improved in patients less to correlate most strongly with cognitive decline after cranial than 60 years old [87, 88]. irradiation are a younger age at the time of treatment, DeAngelis et al. in RTOG 93-10 treated patients with five longer time interval since treatment, female sex, presence cycles of methotrexate-based chemotherapy (IV methotrex- of hydrocephalus, higher volume of supratentorial brain ate 2.5 g/m , vincristine, procarbazine, and IT methotrexate irradiated, and higher radiation dose to the supratentorial 12 g), followed by WBRT to a dose of 45 Gy in 25 fractions brain [78]. and then high dose cytarabine as consolidation therapy [91]. Hearing loss also contributes to the learning difficulties They found a median OS of 36.9 months and a median these pediatric patients face after cranial irradiation, and can progression-free survival (PFS) of 24 months, significantly result from irradiation of the cochlea/inner ear and/or the better than the results seen in 83-15 and 88-06 [91]. As in the use of ototoxic drugs such as platinum agents [75]. One of two prior trials, this trial found that patients younger than the goals of field reduction in the treatment of infratentorial age 60 had a significantly better median OS (50.4 months) pediatric brain tumors is to minimize cochlear irradiation. than patients aged 60 years or older (21.8 months) [91]. For example, in the context of craniospinal irradiation for Unfortunately, they also found that 15% of the patients the treatment of medulloblastoma, the boost field has been (12 total patients) experienced severe delayed neurotoxicity, systematically reduced from treatment of the whole posterior particularly diffuse leukoencephalopathy [91]. 8 of these 12 fossa, to treatment of the tumor resection bed with a 2 cm patients died as a result of their leukoencephalopathy [91]. margin, to recent efforts at treating the tumor resection bed The trial was amended to allow a lower dose of hyper- with even smaller margins [14, 75, 79–81]. IMRT and proton fractionated WBRT (36 Gy in 30 fractions, two fractions per therapy have also been utilized in the treatment of pediatric day) given over 3 weeks for patients with a complete response CNS tumors with the goal of reducing cochlear dose and dose (CR) to induction chemotherapy, in an effort to reduce the to the brainstem and other critical local structures [82–85]. morbidity of treatment without compromising outcomes Thus, in the pediatric population, approaches to reduc- [92]. Unfortunately, neurocognitive outcomes as assessed ing the late neurotoxicity, endocrinopathies, and ototoxicity by minimental status examination (MMSE) showed no associated with cranial irradiation have included avoidance significant improvement with this hyperfractionated WBRT of cranial irradiation altogether, dose reduction, field size versus standard fractionated WBRT, with 10% of the hyper- reduction, use of IMRT, and use of proton therapy. The fractionated patients experiencing grade 5 neurotoxicity by 4 growing trend in recent trials, as exemplified by the recently years after treatment [92]. Also, hyperfractionation did not published Total Therapy XV study from St. Jude Children’s improve OS or PFS [92]. hospital, has been to avoid cranial irradiation altogether Investigators at MSKCC (Memorial Sloan-Kettering Can- through the use of risk-adapted intrathecal and systemic cer Center) have published a retrospective review of 185 chemotherapy regimens [86]. patients treated with high-dose chemotherapy and WBRT and found a 24% rate of significant neurotoxicity by 5 years after the completion of treatment [98]. In a separate report, the same group reported on a series of 5 patients (median 4. Omission of WBRT in Primary age 74 years old) who died of treatment-induced diffuse CNS Lymphoma leukoencephalopathy and found that significant clinical signsofneurotoxicity couldbeidentified as earlyas1 The treatment of primary CNS lymphoma has evolved over the years, with earlier trials utilizing whole brain month after the completion of therapy, suggesting that this radiation therapy (WBRT) alone, and subsequent trials potentially lethal consequence of treatment is not always a using induction chemotherapy followed by WBRT (with delayed phenomenon, but one which could be seen very or without more chemotherapy after radiation therapy), or early in some patients [99]. The rate of significant late neurotoxicity with combined modality therapy seems to be chemotherapy alone [17, 87–101]. RTOG 83-15 was a phase II trial which treated patients with WBRT to a dose of 40 Gy age related, with patients aged 60 years and older having in 20 fractions, followed by a sequential boost to the patient’s rates of anywhere from 10% to 83% in various reports [17, 88–93]. These patients are known to have a poorer gross disease of 20 Gy in 10 fractions [87]. This trial resulted in a median OS of only 12.2 months and a 2-year OS of outcome than younger patients independent of the use of 6 Journal of Oncology combined modality therapy and subsequent neurotoxicity, a course of WBRT (37.5 Gy in 15 fractions of 2.5 Gy each) and age greater than 60 years old is considered a poor [113]. The primary endpoint of this study was neurocog- prognostic factor using scoring systems from MSKCC and nitive function as assessed by the HVLT-R (Hopkins Verbal the International Extranodal Lymphoma Study Group [100, Learning Test-Revised) at 4 months following the completion 101]. Delayed neurotoxicity is the leading cause of morbidity of therapy; secondary endpoints included control within the after treatment and is often fatal [17, 98, 99]. Because of this CNS and overall survival [113]. The trial was stopped after high rate of toxicity, a number of groups have begun treating 58 patients had been enrolled due to early stopping rules primary CNS lymphoma patients with chemotherapy alone, because of a significant decline in memory function at 4 reserving radiotherapy for treatment failures [17, 97, 100, months following therapy in the SRS + WBRT arm of the 101]. These studies have variably reported high rates of study; no significant difference was noted in overall survival failure in younger patients (especially less than 60 years old) at 4 months, but the rate of intracranial failure was higher at in some series, but survival rates in older patients are similar 1 year in the SRS alone arm (73% for SRS alone versus 27% or superior to the results seen with combined modality forSRS+WBRT) [113]. The authors of this study concluded therapy [17, 94–97]. This has led some investigators to that patients with 1–3 brain metastases should be managed conclude that combined modality therapy should be reserved initially with SRS alone followed by close observation [113]. for patients younger than age 60, while in older patients it Longitudinal data tracking the NCF of patients receiving should be reserved for salvage [17, 94, 96]. WBRT, SRS, or both are sparse. Chang et al. prospectively Thus, because of the high risk of delayed neurotoxicity assessed 15 patients with 1–3 metastases receiving treatment after combined modality therapy for primary CNS lym- with SRS alone [103]. A comprehensive battery of tests phoma, particularly in the elderly, WBRT is increasingly evaluating neurocognitive function (NCF) was performed being used as salvage therapy alone rather than as a on each patient evaluating attention, memory, dexterity, component of initial therapy despite its proven efficacy [17, and executive function. 67% of patients were found to 91, 98, 99]. have a deficit in at least one domain prior to treatment. In accordance with the data of others, patients with larger tumor volume (>3cm ) were found to have worse NCF. Immediately following SRS, all patients experienced a decline 5. SRS as Monotherapy for Brain Metastases in at least one domain, but in the 5 patients who underwent long-term followup, 80% demonstrated stable/improved Stereotactic radiosurgery (SRS) is a technique by which a single large fraction of ionizing radiation is delivered with learning memory and 60% had stable/improved executive submillimeter accuracy to a small treatment volume, most of function and dexterity [103]. which is tumor. Initially restricted to patients with a solitary Kondziolka et al. compared the morbidity of SRS and brain metastasis, SRS has now been applied in the setting of WBRT from the patient’s perspective via a retrospective multiple brain metastases, and as a single modality [102– survey in 200 consecutive patients [112]. Patients whose 113]. Because of the steep dose gradients achieved using treatment included WBRT felt they had significantly more SRS, it has been proposed as a means by which to minimize problems with fatigue, short-term memory, long-term mem- ory, concentration, depression, and fatigue. Overall, SRS was the radiation dose to normal brain, hopefully translating into an improvement in cognitive sparing. Many authors thought to be a good treatment by 76% of patients, whereas have reported local control and survival outcomes after only 56% of patients thought WBRT was a good treatment [112]. using SRS with or without WBRT [8, 9, 102, 104, 108– 110, 112, 113]. WBRT consistently improves local control Aoyama et al. performed prospective NCF assessment and decreases distant intracranial failures, but the addition within the context of a phase III trial randomizing 132 of WBRT has had an inconsistent impact on survival [8, 9, patients between SRS + WBRT and SRS alone [102, 104]. The 102, 104, 107–113]. Still, it has been increasingly noted that MMSE (Mini-Mental Status exam) was used as a surrogate the outcomes of survival and local control do not adequately for NCF and was obtained prior to treatment, 1 month after describe the relevant outcomes in the brain metastases treatment, and every three months thereafter if possible. population; neurocognitive function (NCF) and quality of 92 patients were available for follow-up MMSE, of these, 39 were abnormal (<27) at baseline. Of these 39 patients, life (QOL), which has been shown to be tightly linked to NCF, are also critical endpoints which may be linked to 20 (51%) experienced an improvement in MMSE after factors other than the use of radiotherapy, such as control of treatment, 9 in the SRS group, and 11 in the combined modality group. Actuarial preservation of MMSE score ≥27 progression within the CNS, use of chemotherapy, or use of antiepileptic medications [102, 103, 114–118]. In particular, at 12, 24, and 36 months was 78.8%, 78.8%, and 22.5% in the some studies have found that progression of disease within SRS + WBRT group, versus 53.3%, 42.6%, and 42.6% in the the CNS is a stronger predictor of poor QOL and NCF SRS alone group. Deterioration was attributed to RT toxicity than the toxicity of therapy, including radiotherapy, and that in 5 patients in the SRS + WBRT group, while no patients receiving SRS alone had a toxic event. Intracranial recurrence control of CNS disease may actually improve these outcomes [114]. was deemed the cause of NCF decline in 3 and 11 patients Chang et al. recently published the results of a ran- in the WBRT + SRS and SRS alone groups, respectively [102]. The data of Aoyama et al., while subject to limitations, domized controlled trial in which patients with 1–3 brain metastases were treated with SRS alone or combined with suggests that the omission of WBRT decreases intracranial Journal of Oncology 7 control and may negatively impact NCF over the first 12– [121]. In “oligometastatic” patients (those with 1–3 metas- 24 months. Of concern, long-term survivors in the WBRT tases only), the rate was even lower at 0.97% [121]. Because + SRS group appear to demonstrate a continued decline in hippocampal involvement by metastatic disease is rare, and MMSE that may represent the late toxicity of WBRT, while because memory loss (specifically the inability to consolidate the long-term survivors receiving SRS alone display stable new memories) is such a frequent and major component MMSE [102]. These results must be interpreted with caution, of late neurotoxicity from cranial irradiation, sparing of however, because of the small number of patients available the hippocampus during the administration of WBRT or for followup at the late time points [102]. PCI should result in lower rates of memory loss [10–13, 15, 34, 63, 64, 73, 78, 119, 121] without compromise of The utilization of SRS in the absence of WBRT does therapeutic goal. This is particularly supported by data from not appear to be a perfect solution to the problem of St. Jude Children’s Hospital, who found that the primary neurocognitive dysfunction in patients with intracranial neurocognitive deficit noted in children exposed to cranial metastases because of the known increased rates of local irradiation was the inability to form new memories, and progression within the brain seen in patients treated with that loss of IQ after cranial irradiation correlated with the SRS alone [102–106, 108–113]. Further understanding of dose delivered to the temporal lobes (the location of the the complexities of neurocognitive toxicity will only be hippocampi) [15, 34]. achieved when thorough NCF evaluation is a standard part of Investigators at the University of Wisconsin have shown every investigation exploring therapies for brain metastases. that it is possible to selectively reduce dose to the hip- Now that the feasibility of large-scale NCF testing during pocampus (maximum dose constraint 6 Gy) while treating brain metastases trials has been demonstrated, the fund of the whole brain to a D95 of 32.25 Gy and treating metastatic knowledge will undoubtedly grow, allowing the optimization lesions to much higher doses (D95 of 63 Gy for tumors of the therapeutic index [118]. 2 cm + in max. diameter, and 70.8 Gy for tumors <2cm in max. diameter) [120]. Such significant dose reductions may be necessary to spare this structure, because the 6. Hippocampal Sparing hippocampus is known to be very sensitive to radiation exposure, particularly the CA1 and subgranular zone (SGZ) Several groups have recently investigated the safety and regions [125–128]. Apoptosis has been shown to peak at 12 hours after RT in the SGZ, and by 48 hours postirradiation, feasibility of sparing the hippocampus while simultaneously treating the rest of the brain with radiotherapy [119– the number of proliferating cells in the SGZ was reduced 121]. The hippocampus (Figure 1) occupies the ventro- by 93–96% [128]. This data suggests that impairment of medial aspect of the temporal lobe, lying posterior to the neurogenesis within the hippocampus, specifically within amygdaloid complex and lateral to the temporal horn of the SGZ/dentate gyrus, may be at least partly responsible the lateral ventricle [122]. Functionally, the hippocampus is for the cognitive impairments seen after brain irradiation primarily involved in the consolidation of new memories. It [127]. is composed of the dentate gyrus, which in addition to its role At our own institution, we have completed a dosimetric feasibility study using helical tomotherapy (TomoTherapy, in memory consolidation is also important in the achieving and maintaining of “happy” states, and the cornu ammonis Madison, WI) to restrict dose to the hippocampus and the (CA1–CA3 regions) [123]. A specific subregion within the rest of the limbic circuit while simultaneously treating the rest of the brain to full dose using treatment schedules for dentate gyrus is the subgranular zone (SGZ), which contains neural stem cells (NSC) that are involved in the repair both PCI and WBRT (30 Gy in 15 fractions and 35 Gy in 14 of damage from various insults to the CNS (including fractions, resp.) [129]. We foundthatwewereabletoreduce radiation therapy) [124]. These cells are also important in the mean dose to the hippocampus to 11.7 Gy and 14 Gy maintaining the ability to learn throughout life. The axons in the PCI and WBRT plans, respectively; this constitutes a that arise from hippocampal neurons become the fornix, a mean relative reduction in BED Gy of 72.9% and 73.4% in white matter tract that extends from the posterior aspect of the PCI and WBRT plans, assuming an alpha/beta ratio of 2 the hippocampal formation and around the third ventricle for late brain adverse effects [129]. Investigators in Vancouver have recently published the (adjacent to the corpus callosum) to eventually synapse at the mammillary bodies (part of the hypothalamus), which results of a hippocampal sparing feasibility study in which are also involved in the consolidation of new memories they successfully treated the whole brain to full dose (32.25 Gy) while simultaneously treating the bilateral hip- [123]. The hippocampus is rarely involved by intracranial pocampi to a mean dose of less than 6 Gy and boosting metastatic disease [118, 121]. Ghia et al. at the University of the metastatic lesions to 63–70.8 Gy depending on diameter, Wisconsin recently reviewed the records of 272 intracranial using volumetric modulated arc therapy (VMAT) [130]. metastases and found that only 3.3% of lesions were within Their mean treatment time was only 3.6 minutes [130]. Reduction of radiation exposure of the hippocampus 5 mm of the hippocampus, while 86.4% of lesions were >15 mm from the hippocampus [119]. In a retrospective appears to be conceptually safe and dosimetrically feasible review of 697 intracranial metastases at Rush University and represents one of the most promising strategies for maintaining the efficacy of WBRT and PCI, while minimiz- Medical Center, only 2.29% of these lesions directly or indirectly (by secondary growth) involved the hippocampus ing the morbidity previously described. 8 Journal of Oncology 7. Sparing of the Limbic Circuit patients with oligometastatic disease (1–3 metastases), the rate was even lower at 4.8% [121]. Therateofhippocampal While dosimetric sparing of the hippocampus may reduce formation involvement was less than 1% among oligo- the loss of memory consolidation noted after cranial radio- metastatic patients, while 3.9% of lesions involved the rest therapy, selective sparing of the hippocampal formation of the limbic circuit [121]. (dentate gyrus and cornu ammonis) may not be sufficient. In a subsequent dosimetric feasibility study conducted in The hippocampal formation is only one of a number of our department, we found that it was possible to restrict the structures which constitute the limbic circuit, or circuit mean dose to the limbic circuit to 15.1 Gy and 17.7 Gy in PCI of Papez [123]. The limbic circuit (Figures 1, 2,and 3) (30 Gy in 15 fractions) and WBRT (35 Gy in 14 fractions) consists of 2 adjacent arches within the brain which bound plans, respectively, using helical TomoTherapy [129]. This the ventricular system [123]. The inner arch (amygdala, constitutes a mean reduction in BED Gy of 62.2% and hippocampus [cornu ammonis and dentate gyrus], fornix, 63.3% for the PCI and WBRT plans, respectively, assuming and mammillary bodies) is separated from the outer arch an alpha/beta ratio of 2 for late brain side effects [129]. The (parahippocampal gyrus, cingulum, cingulate gyrus, indu- mean doses and reductions in BED Gy for the hippocampal seum griseum, and paraterminal gyrus) by the hippocampal formation (which was contoured separately) were even more sulcus and corpus callosum [123]. pronounced, as discussed previously [129]. This circuit is critical to a number of vital brain Reduction of radiation exposure for the limbic circuit functions: integration and consolidation of new memo- may be safe, is dosimetrically feasible, and should reasonably ries, special orientation, emotional responses and behavior, be expected to reduce rates of memory loss in patients autonomic responses to external stimuli, and fine motor treated with cranial radiation therapy. These benefits may coordination (among others) [123]. The two structures expand upon those obtained by dosimetric sparing of the most intimately associated with the hippocampus include hippocampal formation alone. the parahippocampal gyrus and amygdaloid complex [123]. The parahippocampal gyrus is critical to memory encoding and retrieval of memories, and its ventral-most portion, 8. Neural Stem Cell Sparing called the entorhinal cortex, is the major source of affer- ent signals to the hippocampus [123]. The amygdaloid It is now known that the human brain contains regions of complex, or amygdala, is involved in memory modulation mitotically active cells which retain the ability to divide and (required for long-term memory consolidation and the differentiate along either neural or glial cell lines throughout association of memory with emotional and physiological life [124]. These stems, known as neural stem cells (NSC, states) and emotional learning (fear reactions, imprinting, Figure 4), are located in two specific areas of the brain: the breeding behaviors, etc.) [123]. These three structures— subgranular zone (SGZ) within the dentate gyrus (part of the the hippocampal formation, parahippocampal gyrus, and hippocampus) and the subventricular zone (SVZ) adjacent amygdaloid complex—form a functional unit within the to the lateral aspect of the temporal horn and the occipital medial temporal lobe, and true memory consolidation and trigone region of the lateral ventricles [131, 132]. These learning require the function of all three structures [123]. cells are capable of increasing their mitotic rate under the Other structures that constitute the limbic circuit include influence of appropriate stimuli (e.g., brain trauma, stroke, the cingulate gyrus (which regulates autonomic responses to radiation exposure, etc.) and can migrate through the brain various stimuli and is involved in attention/concentration), to damaged areas and repopulate areas of cortical neuronal cingulum (white matter bundle adjacent to the cingulate loss or white matter damage [133, 134]. They are also gyrus which connects the cingulated gyrus and prefrontal involved in replacing the neurons that are lost as a result of area to the parahippocampal gyrus), fornix and mammillary neurodegenerative disorders, and are important in learning bodies (discussed previously) [123]. This circuit is directly [135–142]. connected to, and modulates the function of, a number of It is hypothesized that the loss of these vital cells results in other critical intracranial structures including the hypotha- the inability to repair radiation-induced damage to normal lamus, thalamus, prefrontal and orbitofrontal cortices, and brain tissue, the phenotypic expression of which is manifest nucleus accumbens (the brain’s “pleasure center”) [123]. The as memory loss, loss of executive function, and the other function of the circuit as a whole is to process memory, late sequelae of therapy [144]. Preservation of the NSC support learning (cognitive, emotional, and autonomic), compartments during the administration of WBRT or PCI regulate emotional states, and assist in spatial orientation should result in maintenance of the ability of the brain to [123]. Interestingly, these are the most commonly reported repair the damage generated by cranial irradiation and help neurocognitive deficits seen as components of late toxicity preserve neurocognitive function. from cranial irradiation [10]. This suggests that it is damage Barani et al. have shown that it possible to identify and to this critical circuit which is responsible for many of the late dosimetrically reduce dose to these regions using intensity- sequelae of therapy. Thus, dosimetric sparing of the limbic modulated radiation therapy (IMRT) while treating a patient circuit may reduce such sequelae. using treatment schedules applicable to whole brain radio- At our institution, we have performed a retrospective therapy and a primary high-grade glioma [143]. They review of 697 intracranial metastases in 107 patients. Limbic selected a patient with a right paraventricular tumor and metastases accounted for only 5.2% of all lesions. Among prepared two IMRT treatment plans for the patient; the first Journal of Oncology 9 Cingulate gyrus Anterior nucleus Fornix Septal nuclei Mammillothalamic tract Hypothalamus Mammillary body Hippocampal formation Figure 1: Hippocampus and Limbic Circuit (http://www.thebrain.mcgill.ca/). (a) Figure 2: Axial 3D rendering of the hippocampus (purple) and limbic circuit (yellow) contours. plan assumed that this mass represented a high-grade glioma and treated the patient to 60 Gy in 30 fractions, while the second plan assumed that this mass was a metastatic lesion and treated the patient with WBRT to 37.5 Gy in 15 fractions followed by astereotacticradiosurgery(SRS) boostof18Gy. They were able to reduce the dose to the NSC compartment by 65% in the WBRT plan and 25% in the high-grade glioma plan, even in this patient with a tumor with an unfavorable location (adjacent to the right SVZ) [143]. (b) Sparing of the NSC may be the single most effective Figure 3: MRI images demonstrating location of (a) hippocampus, method of mitigating the negative effects of WBRT if these and (b) fornix and cingulate gyrus (Marsh et al. [121]). (a) Hip- cells survive and are able to repair radiation-induced damage. pocampus contoured on coronal, sagittal, and axial MRI images. (b) The critical role of radiation-induced damage to the NSC Axial MRI demonstrating location of fornix and cingulated gyrus compartment as a cause of the cognitive dysfunction seen (anterior and posterior). after cranial irradiationhas had been recently reviewed, and a considerable amount of evidence is available from in vitro and animal studies which exists in support of this hypothesis [145–151]. There is now also evidence from human studies NSC compartment (SVZ, a 5 mm expansion around the of patients treated with radiotherapy for malignant brain lateral ventricle) [153]. The hippocampus and the rest of tumors that cranial irradiation reduces the number of viable the NSC compartment received a mean dose of 11.5 Gy NSC [152]. in the PCI plans and 11.8 Gy in the WBRT plans; this Investigators at our institution have completed a dosi- constitutes a 65.8% reduction in BED Gy for the NSC metric feasibility study in which patients are treated with compartment in the PCI plans and a 70.8% reduction in the either PCI (30 Gy in 15 fractions) or WBRT (35 Gy in 14 WBRT plans (assuming an α/β ratioof10for the NSCin fractions) to full dose with simultaneous dosimetric sparing the SGZ and SVZ) [153]. The corresponding reductions in of the hippocampal formation (including the SGZ) and BED Gy for the non-NSC component of the hippocampal 2 10 Journal of Oncology approach to reducing the late sequelae of cranial irradiation is selective dosimetric avoidance of the brain’s neural stem cell (NSC) compartment, which would help maintain the brain’s natural ability to repair damage created by radiation exposure. Lateral Clinical trials utilizing selective sparing of critical brain ventricle Subventricular regions which prospectively incorporate neurocognitive test- stem cell zone (SVZ) ing are justified and may potentially lead to the modern- ization of a classical technique in radiation oncology. These trials will likely employ one or another form of intensity- modulated radiation therapy (IMRT), a technique which allows for steep dose gradients to be generated around even irregular or concave targets, as suggested by Movsas (a) at the November 2009 ASTRO presentation of RTOG 0214 [24]. The dosimetric feasibility study by Gutier ´ rez et al. Dentate gyrus Lateral ventricle and Marsh et al. employed helical TomoTherapy, while Subgranular stem cell Barani et al. utilized traditional inverse-planned IMRT zone (SGZ) [120, 129, 143, 153]. Investigators at our institution have CA3 CA2 recently opened a Phase II trial in which patients with limited stage SCLC (who demonstrate a complete response to CA1 treatment of their primary disease) and single resected brain metastases (with no evidence of metastatic disease outside Subventricular the CNS) will be treated with limbic circuit-sparing PCI Hippocampus stem cell zone (SVZ) (30 Gy in 15 fractions) or WBRT (37.5 Gy in 15 fractions) using helical TomoTherapy [154]. Baseline and follow-up cognitive function will be assessed with a formal battery (b) of neurocognitive tests, and results will be compared with historical controls. 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Cognitive Sparing during the Administration of Whole Brain Radiotherapy and Prophylactic Cranial Irradiation: Current Concepts and Approaches

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Hindawi Publishing Corporation
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Copyright © 2010 James C. Marsh et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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10.1155/2010/198208
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Hindawi Publishing Corporation Journal of Oncology Volume 2010, Article ID 198208, 16 pages doi:10.1155/2010/198208 Review Article Cognitive Sparing during the Administration of Whole Brain Radiotherapy and Prophylactic Cranial Irradiation: Current Concepts and Approaches JamesC.Marsh,BenjaminT.Gielda,ArnoldM.Herskovic,and Ross A. Abrams Department of Radiation Oncology, Rush University Medical Center, Chicago, IL 60612, USA Correspondence should be addressed to James C. Marsh, james c marsh@rush.edu Received 17 September 2009; Accepted 7 April 2010 Academic Editor: Rolf Bjerkvig Copyright © 2010 James C. Marsh et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Whole brain radiotherapy (WBRT) for the palliation of metastases, or as prophylaxis to prevent intracranial metastases, can be associated with subacute and late decline in memory and other cognitive functions. Moreover, these changes are often increased in both frequency and severity when cranial irradiation is combined with the use of systemic or intrathecal chemotherapy. Approaches to preventing or reducing this toxicity include the use of stereotactic radiosurgery (SRS) instead of WBRT; dose reduction for PCI; exclusion of the limbic circuit, hippocampal formation, and/or neural stem cell regions of the brain during radiotherapy; avoidance of intrathecal and/or systemic chemotherapy during radiotherapy; the use of high-dose, systemic chemotherapy in lieu of WBRT. This review discusses these concepts in detail as well as providing both neuroanatomic and radiobiologic background relevant to these issues. 1. Introduction radiosurgery (SRS) alone (particularly for Class I patients), or SRS in combination with WBRT [5–9]. Unfortunately, Whole brain radiation therapy (WBRT) is a mainstay of WBRT is associated with late brain toxicities, which range therapy for the treatment of primary and metastatic tumors in severity from mild deficits in cognitive dysfunction to involving the brain [1–3]. WBRT entails treatment of the overt dementia in up to 11% of patients depending on whole intracranial compartment (brain and brainstem) the population studied, the length of follow up, and the down to the foramen magnum or to the bottom of either type of chemotherapy employed [10–13]. The sequelae of the first or second cervical vertebrae, with a uniform dose of treatment are even more severe in pediatric patients treated radiation, typically administered with opposed lateral fields with WBRT, in whom hearing loss, severe global cognitive and blocks to protect the lenses. Multiple dose fractionation deficiencies, and neuro-endocrine deficits may develop [14– regimens have been employed for WBRT, with no one 16]. In patients 60 years of age and older with primary schedule having been conclusively proven better than others, CNS lymphoma, the combination of WBRT and high- although single fraction therapy (ex. 10 Gy in a single dose methotrexate regimens has resulted in severe to fatal fraction) has been shown to result in greater toxicity [4]. leukoencephalopathy resulting in the frequent omission of Common utilized treatment schedules include 2.5 Gy × cranial radiotherapy in this context [17]. 14 or 15 fractions, or 3 Gy × 10 fractions. In the setting Prophylactic cranial irradiation (PCI) has become a stan- of intracranial metastases, patients with RTOG RPA class dard of care for selected patients with limited and extensive III (Table 1) disease are often managed with WBRT alone, stage small cell lung cancer (SCLC) who have shown benefit while patients with RPA class I or II disease are frequently managed by a combination of modalities, including WBRT with systemic treatment. PCI has also been explored in the alone, surgical resection followed by WBRT, stereotactic context of nonsmall cell lung cancer (NSCLC), but in this 2 Journal of Oncology Table 1: RTOG RPA Classification for brain metastases. to cause significant late sequelae and this knowledge has prompted reductions in the indications for, and doses of, PCI Median Survival Class Characteristics in this context [30–34]. (months) In this article we review these issues in further detail and KPS 70 or greater, age 65 years discuss the different methods currently being employed and or less, primary disease 7.1 explored in an effort to reduce neurocognitive toxicity. controlled, no extracranial metastases II All others 4.2 2. Toxicity of Cranial Irradiation III KPS < 70 2.3 The effects of cranial irradiation may be roughly divided into acute, subacute, and chronic [35]. Acute side effects, context has not been shown to improve overall survival [18– which occur during or within a few weeks of radiation 22]. A recent RTOG study (RTOG 0214) exploring the use of therapy, include fatigue, alopecia, nausea, and effects related PCI in NSCLC was presented at the 2009 ASTRO (American to exacerbation of baseline cerebral edema such as headache, Society for Therapeutic Radiology and Oncology) meeting in nausea, focal deficits, and when severe changes in mental Chicago, IL. [23, 24] 340 patients with Stage III nonsmall cell status. Subacute symptoms (those occurring after the com- lung cancer, who showed no evidence of tumor progression pletion of radiotherapy but within three months of the end after treatment of their primary tumor, were randomized to of treatment) are relatively rare and limited primarily to be treated with PCI or undergo observation from 2002 to the somnolence syndrome and, less frequently, early onset 2007. PCI resulted in a reduction in the incidence of brain leukoencephalopathy. The pathophysiology of the somno- metastases from 18% to 8%, but did not impact overall lence syndrome is probably related to transient demyeli- survival [24]. Importantly, while PCI did not significantly nation of cerebral white matter (analogous to Lhermitte’s impact overall reported quality of life, it did result in lower syndrome after spinal irradiation). Leukoencephalopathy, rates of both immediate and delayed recall, suggested that the on the other hand, is believed to represent a more severe use of PCI impairs memory function in treated patients [24]. manifestation of demyelination and may be fatal. These The concept underlying PCI is to eliminate microscopic white matter changes may be more prominent in older deposits of metastatic tumor within the brain and/or patients with vascular risk factors, and evidence of this brainstem before they become clinically manifest. Without damage can be identified before other gross changes are PCI, more than 60% of small cell lung cancer patients will evident on MRI by early changes in fractional anisotropy eventually develop clinically detectable and/or symptomatic (FA) as identified on diffusion tensor imaging (DTI) after brain metastases at some point during the course of their the delivery of PCI [36]. Similar changes in FA on DTI can disease, and PCI reduces this rate to approximately 20% [25]. be seen in pediatric patients who have been treated with The treatment field for PCI is similar to WBRT in that the radiotherapy for medulloblastoma, with one recent study whole brain and brainstem down to the foramen magnum showing a mean reduction in FA of 16.5% in treated patients or the bottom of the first or second cervical vertebrae is versus controls [37]. These reductions in FA were found treated to a uniform dose, with most patients being treated to correlate with a younger age at the time of treatment using opposed laterals with lens blocks. Multiple treatment anddeclinesinschoolperformance [37]. Late side effects, schedules are employed, with no one schedule clearly which occur six months or later after radiation therapy, showing superiority to others [26]. Arecentprospective include overt radionecrosis of the brain (with areas of study found that there was no significant reduction in the focal coagulative necrosis) and progressive microvascular number of brain metastases for 36 Gy in 18 fractions versus or vascular occlusion with a subsequent increased risk of 25 Gy in 10 fractions, while overall survival was worse for stroke. Rarely this may mimic Moyamoya syndrome as seen unclear reasons in the higher dose arm [26]. The authors in other contexts not involving radiotherapy or malignancy concluded that 25 Gy in 10 fractions should remain the [38–41]. standard of care in this setting [26]. In the setting of both Various systems have been developed to describe these limited and extensive stage small cell lung cancer, the use effects, including (among others) the NCI Common Toxicity of PCI has resulted in statistically significant improvements Criteria Version 2.0 (available at http://ctep.cancer.gov) in overallsurvival(OS)[27, 28]. As these patients are at and the RTOG/EORTC LENT-SOMA systems [42]. These risk for cognitive deficits from multiple causes such as age- scoring systems’ definitions of neurotoxicity are shown in related cerebral atrophy, preexisting cerebrovascular disease, Tables 2 and 3. However, more subtle deficits in cognitive anxiety, depression, and chemotherapy effects, there has been function are not accounted for in these systems, nor are all controversy regarding the extent to which PCI contributes of the neuroendocrinologic sequelae of therapy. to observed neurocognitive deficits [29]. However, with Late toxicities in the brain are highly feared sequelae of recent increases in mean overall survival and an increased cranial irradiation in both adults and children because they number of longer-term survivors, the contribution of PCI are highly debilitating and irreversible. The axonal tracts to the development of neurocognitive deficits is becoming that connect the cerebral cortex to the subcortical gangliae, more clearly defined [30]. Finally, PCI for pediatric patients spinal cord, and brain stem nuclei do so in series, such that with high risk acute lymphocytic leukemia (ALL) is known damage to any part of the sequence adversely affects [43]. Journal of Oncology 3 Table 2: RTOG/EORTC Late Morbidity Scoring System for Brain. WBRT (but not PCI) patients after 1–3 fractions and at the completion of treatment, while subacute declines in Grade 0 None verbal memory were seen in both WBRT and PCI patients Mild headache, slight 6–8 weeks after the completion of treatment [13]. On Grade 1 lethargy multivariate analysis, they found that these deficits persisted Moderate headache, great even after accounting for the use of chemotherapy, KPS score, Grade 2 lethargy and the presence of depression and/or anxiety. They found Severe headache, severe no significant declines in visual memory or attention span Grade 3 CNS dysfunction (partial [13]. loss of power or dyskinesia) In some cases, late neurological deficits can be severe Grade 4 Seizure, paralysis, coma enough to cause overt dementia, wherein the patient’s global Grade 5 Death level of functioning is severely impaired and the patient is not aware of these changes. This is in contrast to more subtle cognitive deficits that are commonly seen and of which the patient is typically well aware. The incidence of dementia The generally accepted TD5/5 and TD50/5 (radiation doses after cranial irradiation has been reported to be as high as 11% in patients with long-term followup [11], and these which, when delivered to a given type of tissue in a typical patient population, will result in a 5% or 50% rate of Grade long-term sequelae have been shown to correlate with and 3 or higher toxicity at a time point 5 years removed from precede decline in patient-reported quality of life (QOL), [12, 13]. the radiation exposure, resp.) after treating the whole brain with standard fractionation are 45 Gy and 60 Gy, respectively, PCI has variably been described as having no effect on and for partial brain radiation exposure are 60 Gy and 75 Gy cognitive function, adversely affecting cognitive function, [44]. Due to the slow rate of cell turnover for neuronal and and even initially improving cognitive function in adult glial elements, the brain represents a late responding tissue, patients [13, 47–51]. As reported by Welzel et al., PCI patients appear to start out with lower baseline cognitive with an accepted α/β ratio of about 2 Gy [45]. This suggests that treatment of the brain with smaller daily or fractional functioning scores than the WBRT patients, have a transient radiation doses might reduce risk of late sequelae. However, improvement in simple reaction time (the ability to respond to an acutestimulus) during andatthe endofradiation the use of smaller radiation fractions also necessitates the delivery of a higher total dose of radiation to achieve the same therapy, and subsequently have a decline in verbal memory degree of tumor control [43]. 6–8 weeks after completing therapy [13]. A report recently Various treatment schedules have been developed for the released by the EORTC of patient-reported quality of life administration of WBRT in the setting of brain metastases scores after PCI showed a significant decline in QOL up [46]. Onecommonlyutilizedscheduleis30Gyin10 to 3 months after the completion of treatment, although fractions, which (assuming an alpha/beta ratio of 2 Gy the most frequently reported complaints were for alopecia for late neurologic sequelae) correlates with a biologically and fatigue and the global QOL scores were less adversely affected [30]. For individual patients demonstrating brain equivalent dose (BED) of 75 Gy , theoretically below the TD5/5 of whole brain (45 Gy by standard fractionation at metastases following PCI, it can be difficult to determine 2 Gy per fraction, which corresponds to a BED of 100 Gy ). the relative contribution of the recurrence and the PCI when neurocognitive decline is identified [52]. Tumor progression Other commonly used schedules include 2.5 Gy × 14 or 15 fractions, which result in BED values of 78.75 Gy and may particularly contribute to declines in cognitive function 84.4 Gy , respectively, again below the accepted TD5/5 for in patients with significant peritumoral edema [53]. Finally, whole brain radiation exposure. Thus, all of these treatment small cell lung cancer may, even in the absence of overt schedules should result in rates of late neurologic sequelae intracranial metastatic involvement, adversely affect cogni- that are significantly less than 5%. However, the NCI and tive function by mechanisms that are not clearly understood, EORTC/RTOG toxicity scoring systems (Tables 2-3)donot possibly paraneoplastic [54]. include the readily clinically identified changes in cognition Exposure of cerebral vasculature, particularly small arter- ies and arterioles, is known to cause the late development and behavior that are well documented after these therapies [10–16]. of hyaline-type arteriosclerosis with a subsequent increased Themostfrequentlydescribed adverseeffects in adults risk of ischemic stroke [38]. In very young children with treated with WBRT include problems with the consolidation significant exposures to the anterior Circle of Willis region, of new memory, poor attention span/concentration, visual- changes can be seen which include bilateral carotid occlusion spatial difficulties, difficulty with executive planning, and with the subsequent development of transdural anastamoses poor fine motor control [10]. A recently published study and a “net” or “cloud” of small collateral vessels; these by Welzel et al. prospectively assessed cognitive function changes collectively are known as moyamoya syndrome [38– 41]. The moyamoya changes seen after cranial irradiation in patients being treated with either WBRT (40 Gy in 20 fractions or PCI (36 Gy in 18 fractions) at baseline, after 1– are essentially identical to those seen in primary moyamoya 3 fractions, after the last fraction, and at 6–8 weeks after (Nishimoto’s disease) and result in similar clinical manifes- tations such as cerebral ischemic strokes, recurrent transient the completion of radiation therapy [13]. These authors found that acute declines in verbal memory were seen with ischemic attacks (TIAs), motor deficits, sensory deficits, 4 Journal of Oncology Table 3: NCI Common Toxicity Criteria Version 2.0 Summary. Grade 0 Normal Confusion/disorientation which resolves without sequelae, somnolence/dizziness/extrapyramidal symptoms/insomnia/memory loss/mood alterations/neuropathy/personality changes/pyramidal Grade 1 symptoms/tremor/vertigo not interfering with daily function, mild atrophy or limited T2 hyperintensities on MRI (<1/3 of cerebrum), nystagmus Persistent confusion/disorientation/poor attention span not interfering with daily function, somnolence/dizziness/extrapyramidal symptoms/insomnia/memory loss/mood Grade 2 alterations/neuropathy/personality changes/pyramidal symptoms/tremor/vertigo/cranial neuropathies not interfering with activities of daily living (ADL), moderate atrophy or more extensive T2 hyperintensities on MRI (1/3-2/3 of cerebrum) extending into centrum ovale, nystagmus Delusions, hallucinations, syncope, severe atrophy or near total T2 hyperintensities on MRI +/− focal white matter necrosis, persistent confusion/disorientation/poor attention span/somnolence/dizziness/extrapyramidal Grade 3 symptoms/insomnia/memory loss/mood alterations/neuropathy/personality changes/pyramidal symptoms/tremor/vertigo/cranial neuropathies interfering with activities of daily living (ADL) Bedridden/disabled due to brain toxicity, requiring hospitalization doe to risk to self/others, psychotic, unable Grade 4 to communicate, amnesia, diffuse calcification or necrosis, paralysis Grade 5 Death global cognitive dysfunction, convulsions, and/or migraine- For pediatric patients with acute lymphoblastic leukemia like headaches [38]. (ALL) and acute myelogenous leukemia (AML), WBRT is The significant late sequelae associated with cranial RT utilized as an effective therapy for patients who present with have stimulated interest in finding ways to avoid this toxicity overt CNS involvement and those who relapse in the CNS without sacrificing clinical outcomes for this effective and [66–69]. However, given the known late effects of cranial widely available therapy. irradiation in the pediatric population, a number of groups and institutions have developed protocols which exclude WBRT even in patients with overt CNS involvement or who relapse in the brain after initial treatment [70–72]. 3. WBRT and PCI in the Pediatric Population PCI is currently employed as part of standard therapy for 2–20% of patients with ALL who have no overt CNS WBRT is a standard part of the treatment approach for involvement but have a number of other high risk features primary CNS pediatric tumors that have a propensity for dis- (age >9years oldor <1 year old, T cell phenotype, WBC semination along the neuraxis, including anaplastic ependy- greater than 50,000 or 100,000, extramedullary disease, moma, medulloblastoma, ependymoblastoma, pineoblas- presence of Philadelphia chromosome, and poor response to toma, atypical rhabdoid/teratoid tumor, nonseminomatous induction therapy) [66, 67]. ThedoseofPCI hassystemically germ cell tumor, and choroid plexus tumors. WBRT in this been reduced from 24Gy to 18Gy, and some protocols now setting may or may not be combined with spinal irradiation, employ doses as low as 12 Gy [73–75]. However, even at and the doses used vary depending upon the tumor type, the a dose of 18 Gy, there is evidence of late cognitive and age of the patient, and the clinical context [55–59]. A number neuron-endocrinologic sequelae in these patients, even when of approaches have been used to minimize the late toxicity of treatment is delivered on a hyperfractionated schedule of cranial irradiation for these patients. 0.9 Gy twice daily [16, 70–74]. For standard risk medulloblastoma, the dose of cranial St. Jude Children’s Hospital has extensively studied the spinal irradiation (CSI) (including the WBRT dose) has been cognitive and other late neurologic side effects of cranial reduced from 36Gy to 23.4Gy in an effort to reduce some irradiation in children [15, 34, 76–78]. In one study, they of the late effects of cranial irradiation [60]. For intracranial found that the patient’s age and the percent volume of germinomas either whole-ventricular radiation therapy or supratentorial brain irradiated to varying dose levels (0– chemotherapy followed by involved-field radiation therapy 20 Gy, 20–40 Gy, 40–65 Gy) correlated with IQ level after is now preferred over WBRT, again in an effort to spare the cranial irradiation, with younger age at the time of treatment child the late sequelae of treatment [61, 62]. Chemotherapy and the treatment of larger percent volumes of supratentorial without radiation therapy has been utilized in very young brain to higher doses correlating significantly with declines patients (3 years of age and less) as a primary therapy, in IQ after treatment [76]. In another study evaluating the adjuvant therapy, or “bridge” therapy to delay the use of feasibility of field reduction after resection of infratento- radiation therapy for primary CNS tumors until patients rial ependymomas, they tested neurocognitive function at are older and better able to tolerate the effects of cranial baseline and at varying time points after cranial radiation irradiation [63, 64]. Chemotherapy alone or as adjuvant and found that patients treated with fields encompassing the therapy has also been used as a treatment modality for tumor bed/tumor and 1 cm margin (as opposed to a typical intracranial germinomas and nongerminomatous germ cell larger field) had no detectable neurocognitive deficits after tumors, but with unacceptably high failure rates [65]. Journal of Oncology 5 treatment, suggesting that sparing the cochlea (to preserve 28% [87]. Schultz et al., in a subsequent phase I/II trial hearing) and avoiding irradiation of the supratentorial brain (RTOG 88-06), treated patients with 2 cycles of induction minimized the risk of late neurocognitive sequelae [77]. After CHOD (cyclophosphamide, doxorubicin, vincristine, and partitioning the brain into 5 compartments (total brain, dexamethasone) followed by WBRT to a dose of 41.4 Gy in supratentorial brain, infratentorial brain, right temporal 23 fractions and a sequential cone down boost to the patient’s lobe, and left temporal lobe), they found that irradiation of gross disease of 18 Gy in 10 fractions (total 59.4 Gy) [90]. the supratentorial compartment and temporal lobes resulted This trial produced a median OS of 16.1 months and a 2- in significant declines in IQ regardless of dose level, with year OS of 42%, slightly better than the results found in 83- each Gy of exposure having a similar impact on declines in 15, but on direct comparison the difference was not found IQ [34]. The cognitive deficits seen after cranial irradiation to be statistically significant, and the authors concluded that seem to be due to an inability to develop new skills and to induction chemotherapy did not improve survival versus process new information, rather than a loss of previously radiotherapy alone [87, 88]. Of note, both 83-15 and 88- acquired skills and information [15]. The factors that seem 06 found that OS was significantly improved in patients less to correlate most strongly with cognitive decline after cranial than 60 years old [87, 88]. irradiation are a younger age at the time of treatment, DeAngelis et al. in RTOG 93-10 treated patients with five longer time interval since treatment, female sex, presence cycles of methotrexate-based chemotherapy (IV methotrex- of hydrocephalus, higher volume of supratentorial brain ate 2.5 g/m , vincristine, procarbazine, and IT methotrexate irradiated, and higher radiation dose to the supratentorial 12 g), followed by WBRT to a dose of 45 Gy in 25 fractions brain [78]. and then high dose cytarabine as consolidation therapy [91]. Hearing loss also contributes to the learning difficulties They found a median OS of 36.9 months and a median these pediatric patients face after cranial irradiation, and can progression-free survival (PFS) of 24 months, significantly result from irradiation of the cochlea/inner ear and/or the better than the results seen in 83-15 and 88-06 [91]. As in the use of ototoxic drugs such as platinum agents [75]. One of two prior trials, this trial found that patients younger than the goals of field reduction in the treatment of infratentorial age 60 had a significantly better median OS (50.4 months) pediatric brain tumors is to minimize cochlear irradiation. than patients aged 60 years or older (21.8 months) [91]. For example, in the context of craniospinal irradiation for Unfortunately, they also found that 15% of the patients the treatment of medulloblastoma, the boost field has been (12 total patients) experienced severe delayed neurotoxicity, systematically reduced from treatment of the whole posterior particularly diffuse leukoencephalopathy [91]. 8 of these 12 fossa, to treatment of the tumor resection bed with a 2 cm patients died as a result of their leukoencephalopathy [91]. margin, to recent efforts at treating the tumor resection bed The trial was amended to allow a lower dose of hyper- with even smaller margins [14, 75, 79–81]. IMRT and proton fractionated WBRT (36 Gy in 30 fractions, two fractions per therapy have also been utilized in the treatment of pediatric day) given over 3 weeks for patients with a complete response CNS tumors with the goal of reducing cochlear dose and dose (CR) to induction chemotherapy, in an effort to reduce the to the brainstem and other critical local structures [82–85]. morbidity of treatment without compromising outcomes Thus, in the pediatric population, approaches to reduc- [92]. Unfortunately, neurocognitive outcomes as assessed ing the late neurotoxicity, endocrinopathies, and ototoxicity by minimental status examination (MMSE) showed no associated with cranial irradiation have included avoidance significant improvement with this hyperfractionated WBRT of cranial irradiation altogether, dose reduction, field size versus standard fractionated WBRT, with 10% of the hyper- reduction, use of IMRT, and use of proton therapy. The fractionated patients experiencing grade 5 neurotoxicity by 4 growing trend in recent trials, as exemplified by the recently years after treatment [92]. Also, hyperfractionation did not published Total Therapy XV study from St. Jude Children’s improve OS or PFS [92]. hospital, has been to avoid cranial irradiation altogether Investigators at MSKCC (Memorial Sloan-Kettering Can- through the use of risk-adapted intrathecal and systemic cer Center) have published a retrospective review of 185 chemotherapy regimens [86]. patients treated with high-dose chemotherapy and WBRT and found a 24% rate of significant neurotoxicity by 5 years after the completion of treatment [98]. In a separate report, the same group reported on a series of 5 patients (median 4. Omission of WBRT in Primary age 74 years old) who died of treatment-induced diffuse CNS Lymphoma leukoencephalopathy and found that significant clinical signsofneurotoxicity couldbeidentified as earlyas1 The treatment of primary CNS lymphoma has evolved over the years, with earlier trials utilizing whole brain month after the completion of therapy, suggesting that this radiation therapy (WBRT) alone, and subsequent trials potentially lethal consequence of treatment is not always a using induction chemotherapy followed by WBRT (with delayed phenomenon, but one which could be seen very or without more chemotherapy after radiation therapy), or early in some patients [99]. The rate of significant late neurotoxicity with combined modality therapy seems to be chemotherapy alone [17, 87–101]. RTOG 83-15 was a phase II trial which treated patients with WBRT to a dose of 40 Gy age related, with patients aged 60 years and older having in 20 fractions, followed by a sequential boost to the patient’s rates of anywhere from 10% to 83% in various reports [17, 88–93]. These patients are known to have a poorer gross disease of 20 Gy in 10 fractions [87]. This trial resulted in a median OS of only 12.2 months and a 2-year OS of outcome than younger patients independent of the use of 6 Journal of Oncology combined modality therapy and subsequent neurotoxicity, a course of WBRT (37.5 Gy in 15 fractions of 2.5 Gy each) and age greater than 60 years old is considered a poor [113]. The primary endpoint of this study was neurocog- prognostic factor using scoring systems from MSKCC and nitive function as assessed by the HVLT-R (Hopkins Verbal the International Extranodal Lymphoma Study Group [100, Learning Test-Revised) at 4 months following the completion 101]. Delayed neurotoxicity is the leading cause of morbidity of therapy; secondary endpoints included control within the after treatment and is often fatal [17, 98, 99]. Because of this CNS and overall survival [113]. The trial was stopped after high rate of toxicity, a number of groups have begun treating 58 patients had been enrolled due to early stopping rules primary CNS lymphoma patients with chemotherapy alone, because of a significant decline in memory function at 4 reserving radiotherapy for treatment failures [17, 97, 100, months following therapy in the SRS + WBRT arm of the 101]. These studies have variably reported high rates of study; no significant difference was noted in overall survival failure in younger patients (especially less than 60 years old) at 4 months, but the rate of intracranial failure was higher at in some series, but survival rates in older patients are similar 1 year in the SRS alone arm (73% for SRS alone versus 27% or superior to the results seen with combined modality forSRS+WBRT) [113]. The authors of this study concluded therapy [17, 94–97]. This has led some investigators to that patients with 1–3 brain metastases should be managed conclude that combined modality therapy should be reserved initially with SRS alone followed by close observation [113]. for patients younger than age 60, while in older patients it Longitudinal data tracking the NCF of patients receiving should be reserved for salvage [17, 94, 96]. WBRT, SRS, or both are sparse. Chang et al. prospectively Thus, because of the high risk of delayed neurotoxicity assessed 15 patients with 1–3 metastases receiving treatment after combined modality therapy for primary CNS lym- with SRS alone [103]. A comprehensive battery of tests phoma, particularly in the elderly, WBRT is increasingly evaluating neurocognitive function (NCF) was performed being used as salvage therapy alone rather than as a on each patient evaluating attention, memory, dexterity, component of initial therapy despite its proven efficacy [17, and executive function. 67% of patients were found to 91, 98, 99]. have a deficit in at least one domain prior to treatment. In accordance with the data of others, patients with larger tumor volume (>3cm ) were found to have worse NCF. Immediately following SRS, all patients experienced a decline 5. SRS as Monotherapy for Brain Metastases in at least one domain, but in the 5 patients who underwent long-term followup, 80% demonstrated stable/improved Stereotactic radiosurgery (SRS) is a technique by which a single large fraction of ionizing radiation is delivered with learning memory and 60% had stable/improved executive submillimeter accuracy to a small treatment volume, most of function and dexterity [103]. which is tumor. Initially restricted to patients with a solitary Kondziolka et al. compared the morbidity of SRS and brain metastasis, SRS has now been applied in the setting of WBRT from the patient’s perspective via a retrospective multiple brain metastases, and as a single modality [102– survey in 200 consecutive patients [112]. Patients whose 113]. Because of the steep dose gradients achieved using treatment included WBRT felt they had significantly more SRS, it has been proposed as a means by which to minimize problems with fatigue, short-term memory, long-term mem- ory, concentration, depression, and fatigue. Overall, SRS was the radiation dose to normal brain, hopefully translating into an improvement in cognitive sparing. Many authors thought to be a good treatment by 76% of patients, whereas have reported local control and survival outcomes after only 56% of patients thought WBRT was a good treatment [112]. using SRS with or without WBRT [8, 9, 102, 104, 108– 110, 112, 113]. WBRT consistently improves local control Aoyama et al. performed prospective NCF assessment and decreases distant intracranial failures, but the addition within the context of a phase III trial randomizing 132 of WBRT has had an inconsistent impact on survival [8, 9, patients between SRS + WBRT and SRS alone [102, 104]. The 102, 104, 107–113]. Still, it has been increasingly noted that MMSE (Mini-Mental Status exam) was used as a surrogate the outcomes of survival and local control do not adequately for NCF and was obtained prior to treatment, 1 month after describe the relevant outcomes in the brain metastases treatment, and every three months thereafter if possible. population; neurocognitive function (NCF) and quality of 92 patients were available for follow-up MMSE, of these, 39 were abnormal (<27) at baseline. Of these 39 patients, life (QOL), which has been shown to be tightly linked to NCF, are also critical endpoints which may be linked to 20 (51%) experienced an improvement in MMSE after factors other than the use of radiotherapy, such as control of treatment, 9 in the SRS group, and 11 in the combined modality group. Actuarial preservation of MMSE score ≥27 progression within the CNS, use of chemotherapy, or use of antiepileptic medications [102, 103, 114–118]. In particular, at 12, 24, and 36 months was 78.8%, 78.8%, and 22.5% in the some studies have found that progression of disease within SRS + WBRT group, versus 53.3%, 42.6%, and 42.6% in the the CNS is a stronger predictor of poor QOL and NCF SRS alone group. Deterioration was attributed to RT toxicity than the toxicity of therapy, including radiotherapy, and that in 5 patients in the SRS + WBRT group, while no patients receiving SRS alone had a toxic event. Intracranial recurrence control of CNS disease may actually improve these outcomes [114]. was deemed the cause of NCF decline in 3 and 11 patients Chang et al. recently published the results of a ran- in the WBRT + SRS and SRS alone groups, respectively [102]. The data of Aoyama et al., while subject to limitations, domized controlled trial in which patients with 1–3 brain metastases were treated with SRS alone or combined with suggests that the omission of WBRT decreases intracranial Journal of Oncology 7 control and may negatively impact NCF over the first 12– [121]. In “oligometastatic” patients (those with 1–3 metas- 24 months. Of concern, long-term survivors in the WBRT tases only), the rate was even lower at 0.97% [121]. Because + SRS group appear to demonstrate a continued decline in hippocampal involvement by metastatic disease is rare, and MMSE that may represent the late toxicity of WBRT, while because memory loss (specifically the inability to consolidate the long-term survivors receiving SRS alone display stable new memories) is such a frequent and major component MMSE [102]. These results must be interpreted with caution, of late neurotoxicity from cranial irradiation, sparing of however, because of the small number of patients available the hippocampus during the administration of WBRT or for followup at the late time points [102]. PCI should result in lower rates of memory loss [10–13, 15, 34, 63, 64, 73, 78, 119, 121] without compromise of The utilization of SRS in the absence of WBRT does therapeutic goal. This is particularly supported by data from not appear to be a perfect solution to the problem of St. Jude Children’s Hospital, who found that the primary neurocognitive dysfunction in patients with intracranial neurocognitive deficit noted in children exposed to cranial metastases because of the known increased rates of local irradiation was the inability to form new memories, and progression within the brain seen in patients treated with that loss of IQ after cranial irradiation correlated with the SRS alone [102–106, 108–113]. Further understanding of dose delivered to the temporal lobes (the location of the the complexities of neurocognitive toxicity will only be hippocampi) [15, 34]. achieved when thorough NCF evaluation is a standard part of Investigators at the University of Wisconsin have shown every investigation exploring therapies for brain metastases. that it is possible to selectively reduce dose to the hip- Now that the feasibility of large-scale NCF testing during pocampus (maximum dose constraint 6 Gy) while treating brain metastases trials has been demonstrated, the fund of the whole brain to a D95 of 32.25 Gy and treating metastatic knowledge will undoubtedly grow, allowing the optimization lesions to much higher doses (D95 of 63 Gy for tumors of the therapeutic index [118]. 2 cm + in max. diameter, and 70.8 Gy for tumors <2cm in max. diameter) [120]. Such significant dose reductions may be necessary to spare this structure, because the 6. Hippocampal Sparing hippocampus is known to be very sensitive to radiation exposure, particularly the CA1 and subgranular zone (SGZ) Several groups have recently investigated the safety and regions [125–128]. Apoptosis has been shown to peak at 12 hours after RT in the SGZ, and by 48 hours postirradiation, feasibility of sparing the hippocampus while simultaneously treating the rest of the brain with radiotherapy [119– the number of proliferating cells in the SGZ was reduced 121]. The hippocampus (Figure 1) occupies the ventro- by 93–96% [128]. This data suggests that impairment of medial aspect of the temporal lobe, lying posterior to the neurogenesis within the hippocampus, specifically within amygdaloid complex and lateral to the temporal horn of the SGZ/dentate gyrus, may be at least partly responsible the lateral ventricle [122]. Functionally, the hippocampus is for the cognitive impairments seen after brain irradiation primarily involved in the consolidation of new memories. It [127]. is composed of the dentate gyrus, which in addition to its role At our own institution, we have completed a dosimetric feasibility study using helical tomotherapy (TomoTherapy, in memory consolidation is also important in the achieving and maintaining of “happy” states, and the cornu ammonis Madison, WI) to restrict dose to the hippocampus and the (CA1–CA3 regions) [123]. A specific subregion within the rest of the limbic circuit while simultaneously treating the rest of the brain to full dose using treatment schedules for dentate gyrus is the subgranular zone (SGZ), which contains neural stem cells (NSC) that are involved in the repair both PCI and WBRT (30 Gy in 15 fractions and 35 Gy in 14 of damage from various insults to the CNS (including fractions, resp.) [129]. We foundthatwewereabletoreduce radiation therapy) [124]. These cells are also important in the mean dose to the hippocampus to 11.7 Gy and 14 Gy maintaining the ability to learn throughout life. The axons in the PCI and WBRT plans, respectively; this constitutes a that arise from hippocampal neurons become the fornix, a mean relative reduction in BED Gy of 72.9% and 73.4% in white matter tract that extends from the posterior aspect of the PCI and WBRT plans, assuming an alpha/beta ratio of 2 the hippocampal formation and around the third ventricle for late brain adverse effects [129]. Investigators in Vancouver have recently published the (adjacent to the corpus callosum) to eventually synapse at the mammillary bodies (part of the hypothalamus), which results of a hippocampal sparing feasibility study in which are also involved in the consolidation of new memories they successfully treated the whole brain to full dose (32.25 Gy) while simultaneously treating the bilateral hip- [123]. The hippocampus is rarely involved by intracranial pocampi to a mean dose of less than 6 Gy and boosting metastatic disease [118, 121]. Ghia et al. at the University of the metastatic lesions to 63–70.8 Gy depending on diameter, Wisconsin recently reviewed the records of 272 intracranial using volumetric modulated arc therapy (VMAT) [130]. metastases and found that only 3.3% of lesions were within Their mean treatment time was only 3.6 minutes [130]. Reduction of radiation exposure of the hippocampus 5 mm of the hippocampus, while 86.4% of lesions were >15 mm from the hippocampus [119]. In a retrospective appears to be conceptually safe and dosimetrically feasible review of 697 intracranial metastases at Rush University and represents one of the most promising strategies for maintaining the efficacy of WBRT and PCI, while minimiz- Medical Center, only 2.29% of these lesions directly or indirectly (by secondary growth) involved the hippocampus ing the morbidity previously described. 8 Journal of Oncology 7. Sparing of the Limbic Circuit patients with oligometastatic disease (1–3 metastases), the rate was even lower at 4.8% [121]. Therateofhippocampal While dosimetric sparing of the hippocampus may reduce formation involvement was less than 1% among oligo- the loss of memory consolidation noted after cranial radio- metastatic patients, while 3.9% of lesions involved the rest therapy, selective sparing of the hippocampal formation of the limbic circuit [121]. (dentate gyrus and cornu ammonis) may not be sufficient. In a subsequent dosimetric feasibility study conducted in The hippocampal formation is only one of a number of our department, we found that it was possible to restrict the structures which constitute the limbic circuit, or circuit mean dose to the limbic circuit to 15.1 Gy and 17.7 Gy in PCI of Papez [123]. The limbic circuit (Figures 1, 2,and 3) (30 Gy in 15 fractions) and WBRT (35 Gy in 14 fractions) consists of 2 adjacent arches within the brain which bound plans, respectively, using helical TomoTherapy [129]. This the ventricular system [123]. The inner arch (amygdala, constitutes a mean reduction in BED Gy of 62.2% and hippocampus [cornu ammonis and dentate gyrus], fornix, 63.3% for the PCI and WBRT plans, respectively, assuming and mammillary bodies) is separated from the outer arch an alpha/beta ratio of 2 for late brain side effects [129]. The (parahippocampal gyrus, cingulum, cingulate gyrus, indu- mean doses and reductions in BED Gy for the hippocampal seum griseum, and paraterminal gyrus) by the hippocampal formation (which was contoured separately) were even more sulcus and corpus callosum [123]. pronounced, as discussed previously [129]. This circuit is critical to a number of vital brain Reduction of radiation exposure for the limbic circuit functions: integration and consolidation of new memo- may be safe, is dosimetrically feasible, and should reasonably ries, special orientation, emotional responses and behavior, be expected to reduce rates of memory loss in patients autonomic responses to external stimuli, and fine motor treated with cranial radiation therapy. These benefits may coordination (among others) [123]. The two structures expand upon those obtained by dosimetric sparing of the most intimately associated with the hippocampus include hippocampal formation alone. the parahippocampal gyrus and amygdaloid complex [123]. The parahippocampal gyrus is critical to memory encoding and retrieval of memories, and its ventral-most portion, 8. Neural Stem Cell Sparing called the entorhinal cortex, is the major source of affer- ent signals to the hippocampus [123]. The amygdaloid It is now known that the human brain contains regions of complex, or amygdala, is involved in memory modulation mitotically active cells which retain the ability to divide and (required for long-term memory consolidation and the differentiate along either neural or glial cell lines throughout association of memory with emotional and physiological life [124]. These stems, known as neural stem cells (NSC, states) and emotional learning (fear reactions, imprinting, Figure 4), are located in two specific areas of the brain: the breeding behaviors, etc.) [123]. These three structures— subgranular zone (SGZ) within the dentate gyrus (part of the the hippocampal formation, parahippocampal gyrus, and hippocampus) and the subventricular zone (SVZ) adjacent amygdaloid complex—form a functional unit within the to the lateral aspect of the temporal horn and the occipital medial temporal lobe, and true memory consolidation and trigone region of the lateral ventricles [131, 132]. These learning require the function of all three structures [123]. cells are capable of increasing their mitotic rate under the Other structures that constitute the limbic circuit include influence of appropriate stimuli (e.g., brain trauma, stroke, the cingulate gyrus (which regulates autonomic responses to radiation exposure, etc.) and can migrate through the brain various stimuli and is involved in attention/concentration), to damaged areas and repopulate areas of cortical neuronal cingulum (white matter bundle adjacent to the cingulate loss or white matter damage [133, 134]. They are also gyrus which connects the cingulated gyrus and prefrontal involved in replacing the neurons that are lost as a result of area to the parahippocampal gyrus), fornix and mammillary neurodegenerative disorders, and are important in learning bodies (discussed previously) [123]. This circuit is directly [135–142]. connected to, and modulates the function of, a number of It is hypothesized that the loss of these vital cells results in other critical intracranial structures including the hypotha- the inability to repair radiation-induced damage to normal lamus, thalamus, prefrontal and orbitofrontal cortices, and brain tissue, the phenotypic expression of which is manifest nucleus accumbens (the brain’s “pleasure center”) [123]. The as memory loss, loss of executive function, and the other function of the circuit as a whole is to process memory, late sequelae of therapy [144]. Preservation of the NSC support learning (cognitive, emotional, and autonomic), compartments during the administration of WBRT or PCI regulate emotional states, and assist in spatial orientation should result in maintenance of the ability of the brain to [123]. Interestingly, these are the most commonly reported repair the damage generated by cranial irradiation and help neurocognitive deficits seen as components of late toxicity preserve neurocognitive function. from cranial irradiation [10]. This suggests that it is damage Barani et al. have shown that it possible to identify and to this critical circuit which is responsible for many of the late dosimetrically reduce dose to these regions using intensity- sequelae of therapy. Thus, dosimetric sparing of the limbic modulated radiation therapy (IMRT) while treating a patient circuit may reduce such sequelae. using treatment schedules applicable to whole brain radio- At our institution, we have performed a retrospective therapy and a primary high-grade glioma [143]. They review of 697 intracranial metastases in 107 patients. Limbic selected a patient with a right paraventricular tumor and metastases accounted for only 5.2% of all lesions. Among prepared two IMRT treatment plans for the patient; the first Journal of Oncology 9 Cingulate gyrus Anterior nucleus Fornix Septal nuclei Mammillothalamic tract Hypothalamus Mammillary body Hippocampal formation Figure 1: Hippocampus and Limbic Circuit (http://www.thebrain.mcgill.ca/). (a) Figure 2: Axial 3D rendering of the hippocampus (purple) and limbic circuit (yellow) contours. plan assumed that this mass represented a high-grade glioma and treated the patient to 60 Gy in 30 fractions, while the second plan assumed that this mass was a metastatic lesion and treated the patient with WBRT to 37.5 Gy in 15 fractions followed by astereotacticradiosurgery(SRS) boostof18Gy. They were able to reduce the dose to the NSC compartment by 65% in the WBRT plan and 25% in the high-grade glioma plan, even in this patient with a tumor with an unfavorable location (adjacent to the right SVZ) [143]. (b) Sparing of the NSC may be the single most effective Figure 3: MRI images demonstrating location of (a) hippocampus, method of mitigating the negative effects of WBRT if these and (b) fornix and cingulate gyrus (Marsh et al. [121]). (a) Hip- cells survive and are able to repair radiation-induced damage. pocampus contoured on coronal, sagittal, and axial MRI images. (b) The critical role of radiation-induced damage to the NSC Axial MRI demonstrating location of fornix and cingulated gyrus compartment as a cause of the cognitive dysfunction seen (anterior and posterior). after cranial irradiationhas had been recently reviewed, and a considerable amount of evidence is available from in vitro and animal studies which exists in support of this hypothesis [145–151]. There is now also evidence from human studies NSC compartment (SVZ, a 5 mm expansion around the of patients treated with radiotherapy for malignant brain lateral ventricle) [153]. The hippocampus and the rest of tumors that cranial irradiation reduces the number of viable the NSC compartment received a mean dose of 11.5 Gy NSC [152]. in the PCI plans and 11.8 Gy in the WBRT plans; this Investigators at our institution have completed a dosi- constitutes a 65.8% reduction in BED Gy for the NSC metric feasibility study in which patients are treated with compartment in the PCI plans and a 70.8% reduction in the either PCI (30 Gy in 15 fractions) or WBRT (35 Gy in 14 WBRT plans (assuming an α/β ratioof10for the NSCin fractions) to full dose with simultaneous dosimetric sparing the SGZ and SVZ) [153]. The corresponding reductions in of the hippocampal formation (including the SGZ) and BED Gy for the non-NSC component of the hippocampal 2 10 Journal of Oncology approach to reducing the late sequelae of cranial irradiation is selective dosimetric avoidance of the brain’s neural stem cell (NSC) compartment, which would help maintain the brain’s natural ability to repair damage created by radiation exposure. Lateral Clinical trials utilizing selective sparing of critical brain ventricle Subventricular regions which prospectively incorporate neurocognitive test- stem cell zone (SVZ) ing are justified and may potentially lead to the modern- ization of a classical technique in radiation oncology. These trials will likely employ one or another form of intensity- modulated radiation therapy (IMRT), a technique which allows for steep dose gradients to be generated around even irregular or concave targets, as suggested by Movsas (a) at the November 2009 ASTRO presentation of RTOG 0214 [24]. The dosimetric feasibility study by Gutier ´ rez et al. Dentate gyrus Lateral ventricle and Marsh et al. employed helical TomoTherapy, while Subgranular stem cell Barani et al. utilized traditional inverse-planned IMRT zone (SGZ) [120, 129, 143, 153]. Investigators at our institution have CA3 CA2 recently opened a Phase II trial in which patients with limited stage SCLC (who demonstrate a complete response to CA1 treatment of their primary disease) and single resected brain metastases (with no evidence of metastatic disease outside Subventricular the CNS) will be treated with limbic circuit-sparing PCI Hippocampus stem cell zone (SVZ) (30 Gy in 15 fractions) or WBRT (37.5 Gy in 15 fractions) using helical TomoTherapy [154]. Baseline and follow-up cognitive function will be assessed with a formal battery (b) of neurocognitive tests, and results will be compared with historical controls. 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