Expert Reviews - Expert Review of Neurotherapeutics - = 10(10):1493

From = survival to=20 survivorship: late side effects become an issue in = high-grade=20 glioma

Yaacov R=20 Lawrence^=E2=80=A0, Wenyin = Shi &=20 Adam P = Dicker=20

=E2=80=A0

Author for correspondence

Sections:=20

Gliomas are the most common primary = brain=20 tumors. In adults, the most frequent subtype is = glioblastoma,=20 an aggressive and lethal tumor characterized = histologically by=20 frequent mitoses, rich angiogenesis and necrosis.=20 Multimodality treatment is the standard of care: = maximal safe=20 resection followed by partial brain irradiation = combined with=20 temozolomide. Resection followed by radiation produces = a=20 median survival of 2=E2=80=933 years in anaplastic = astrocytoma [1], but=20 only 5=E2=80=9312 months in patients with = glioblastoma, depending on=20 the population studied [2]. The = addition of=20 temozolomide, while only increasing median survival by = 2.5=20 months [3], produces = a marked=20 increase in long-term survival, with 9.8% of patients = who=20 received combination treatment living 5 years, as = opposed to=20 1.9% with radiation alone [4]. Longer = survival is=20 associated with host factors (performance status and = age [5]),=20 molecular characteristics (O⁶=20 -methylguanine-DNA methyltransferase [MGMT] = methylation [6],=20 isocitrate dehydrogenase mutations [7] and = polymorphisms=20 in DNA repair enzymes [8]), and = treatment=20 factors (more radical resection [9] and use = of=20 temozolomide [4]). The = cardinal=20 non-molecular factors have been combined to define the = Radiation Therapy Oncology Group (RTOG) recursive = partitioning=20 analysis class [5].

There is circumstantial evidence that survival may = be=20 improving further =E2=80=93 in recent single-arm = trials run by the New=20 Approaches to Brain Tumor Therapy Consortium, median = survival=20 was nearly 20 months [10]. = Whether this=20 survival increase is a reflection of the activity of = the=20 various therapeutic agents tested, the results of a = more=20 aggressive approach, the increased use of second- and=20 third-line treatments or some other factor is not = clear. The=20 expectation is that newer therapies will further = lengthen=20 survival. As glioblastoma shifts from being a rapidly = fatal to=20 slowly progressive disease, we are obligated to = consider the=20 long-term side effects of present and future = treatments. In=20 addition to the =E2=80=98classical=E2=80=99 side = effects, such as neurological=20 deficits and brain necrosis, research now emphasizes=20 neurocognitive function and quality of life. These = =E2=80=98newer=E2=80=99 end=20 points are complex, since both the tumor and the = treatment=20 impact upon them.

The long-term effects of radiation on the brain = have been=20 well described [11=E2=80=9314].=20 Pathological changes range from transient = demyelination to=20 irreversible vascular damage with resultant necrosis. = A recent=20 meta-analysis suggested that the brain is able to = tolerate=20 high doses of ionizing radiation (approximately 70 Gy) = before=20 undergoing necrosis [15]; = however, more=20 subtle cognitive changes occur at lower doses. Memory = deficits=20 following irradiation follow a biphasic pattern = =E2=80=93 in the=20 initial months an initial decrement with rebound, = followed by=20 a secondary permanent decline [16=E2=80=9318].=20 Radiation-induced neurocognitive impairment is = especially=20 noted in children [19=E2=80=9321] and=20 patients with primary CNS lymphoma [22=E2=80=9324],=20 possibly reflecting the use of neurotoxic methotrexate = in the=20 latter.

Cytotoxic chemotherapy alone may also induce = cognitive=20 impairment. This is best documented in breast cancer = patients=20 receiving adjuvant adriamycin-based chemotherapy [25,26].=20 Although impairment is generally subtle and = intermittent on=20 objective testing [27], a = subset of=20 patients exhibit more profound and sustained = impairment [26].=20 Consequently, a potential concern is that temozolomide = may be=20 lengthening survival, but worsening neurocognitive = function=20 and quality of life. Reassuringly, there is evidence = that this=20 is not the case, at least for early time points: in a = trial of=20 temozolomide for recurrent glioblastoma, individuals = who were=20 progression-free on temozolomide at 6 months had = improvement=20 in quality of life [28]. = Another study=20 demonstrated that amongst patients with glioblastoma,=20 temozolomide treatment is associated with prolonged = functional=20 independence [29]. = Furthermore, the=20 European Organization for Research on Treatment of=20 Cancer/National Cancer Institute of Canada Phase III = trial=20 that established temozolomide as standard of care in = grade IV=20 gliomas on the basis of improved survival also = assessed seven=20 domains of health-related quality of life (HRQOL; = fatigue,=20 insomnia, emotional function, social function, future=20 uncertainty, communication deficit and overall HRQOL) = [30].=20 Variations during treatment and follow-up were not=20 substantial; however, they nearly all showed some = improvement.=20 Overall there was little difference between the = radiation=20 alone and the combined radiation=E2=80=93temozolomide = arms; subjects=20 on the experimental arm experienced more = gastrointestinal=20 symptoms early on, but this was to be expected and = quickly=20 improved following the cessation of temozolomide.=20 Unfortunately the study had two limitations: firstly, = due to=20 dwindling numbers, only HRQOL data from the first year = of=20 follow-up was analyzed; secondly, neurocognitive = function was=20 not formally tested during follow-up. However, there = is some=20 preliminary evidence that glioblastoma patients who = survive=20 for more than 3 years may fare less well, with 85% = having at=20 least one significant neurologic deficit [31].

Little is known about the long-term neurocognitive = side=20 effects of novel molecular targeting agents, such as=20 monoclonal antibodies, small molecular inhibitors and=20 immunotherapy. Interestingly, early phase clinical = trial data=20 suggest that bevacizumab (VEGF antibody) can stabilize = neurocognitive function and reduce reliance on = steroids,=20 improving day-to-day life for patients with recurrent=20 glioblastoma [32].

Treatment side effects amongst glioma sufferers may = not=20 only be unpleasant, they may also impinge upon = prognosis. By=20 analyzing the side effects experienced by subjects = previously=20 enrolled on RTOG high-grade glioma trials, we were = able to=20 define risk factors for both acute (age greater than = 50 years,=20 poor performance status, more aggressive surgery, poor = neurological function, poor mental function and = twice-daily=20 radiation) and chronic (once-daily radiation, use of=20 chemotherapy, previous acute neurologic toxicity and = total=20 radiation dose) neurologic toxicity. The presence of = acute=20 neurologic toxicity was also found to predict poor = overall=20 survival, independent of recursive partitioning = analysis class=20 (median survival 7.8 vs 11.8 months; p < 0.0001) [33].

We do not know what the impact of new experimental = agents=20 on normal tissue function will be, whether used alone = or=20 together with radiation therapy. International = cooperative=20 groups led by the European Organization for Research = on=20 Treatment of Cancer and the RTOG have led the way in=20 incorporating quality of life and neurocognitive end = points=20 into clinical trials; unfortunately, only a proportion = of=20 patients seen in the clinic are typically eligible for = such=20 trials. Only by bringing neuropsychological testing = into daily=20 practice will we be able to capture information on = =E2=80=98real=20 patients=E2=80=99 (those with poor performance status, = elderly, ethnic=20 minorities) that rarely enroll onto clinical trials.=20 Standardized neuropsychological tests are reliable and = valid=20 measures when used correctly. When selecting=20 neuropsychological tests, it is recommended to focus = on=20 specific domains of functioning, such as short-term = memory;=20 that tests be re-administered repeatedly in order to = estimate=20 variance and account for the =E2=80=98training = effect=E2=80=99; and finally=20 that only standardized tests with documented = reliability and=20 validity are chosen [34]. = Although formal=20 neuropsychological tests are considered to be the = =E2=80=98gold=20 standard=E2=80=99, the associated logistical costs and = staff training=20 required hamper their widespread adoption. = Computerized=20 testing, such as provided by CogState^=C2=AE = (CogState=20 Ltd, Melbourne, Australia), may help overcome these = hurdles [35].

Patients with high-grade gliomas = desperately=20 require more effective interventions. For many = patients,=20 controlling neurological symptoms, preventing = cognitive=20 dysfunction and maintaining functional independence = are just=20 as important as prolonging survival. As new innovative = therapies that seek to extend survival in this = devastating=20 disease are investigated, it is critical that we also = evaluate=20 their possible negative impact on functional outcomes = over the=20 long-term.

Financial=20 & competing interests disclosure=20

Yaacov R Lawrence is supported by the American = Society=20 of Clinical Oncology Cancer Foundation Young = Investigator=20 Award. Any opinions, findings and conclusions = expressed in=20 this material are those of the author(s) and do not=20 necessarily reflect those of the American Society of = Clinical=20 Oncology or the American Society of Clinical Oncology = Cancer=20 Foundation. Adam P Dicker is supported by NIH Grant = CA10663,=20 Tobacco Research Settlement Fund (State of = Pennsylvania), and=20 the Christine Baxter Fund. The authors have no other = relevant=20 affiliations or financial involvement with any = organization or=20 entity with a financial interest in or financial = conflict with=20 the subject matter or materials discussed in the = manuscript=20 apart from those disclosed.

No writing assistance was utilized = in the=20 production of this manuscript.

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Affiliations

Yaacov R = Lawrence

Department of=20 Radiation Oncology, Jefferson Medical College of = Thomas=20 Jefferson University, 111 South 11th Street, = Philadelphia, PA=20 19107=E2=80=935097, USA. richard.lawrence@jefferson= .edu=20

Wenyin Shi

Jefferson = Medical=20 College of Thomas Jefferson University, PA, USA

Adam P Dicker

Jefferson = Medical=20 College of Thomas Jefferson University, PA, USA

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