New imaging techniques for more effective treatment in glioblastoma
2014-01-01

High-grade brain tumours have a poor prognosis, indeed as few as 16% of patients with glioblastoma survive 2 years post diagnosis.1 Over half of glioblastoma incidence is in the productive years of life,2 when in employment and often with young children. Thus, even a small improvement in the outcome of treatment can result in significant benefit not just to patients, but also to the community and to the economy. Unlike other cancer sites (such as breast and prostate) treatments in this area have been slow to evolve. The use of temozolomide and more conformal radiotherapy techniques has certainly improved survival.3 There are several new potential treatments but due to the heterogeneous and phenotypically variable nature of glioblastoma, these are unlikely to provide a significant benefit for many of the patients diagnosed. New treatments are expensive for pharmaceutical companies to develop and for governments to fund. Many novel agents do not even make it to phase III studies, and new methods of rapidly screening potential agents are urgently needed. We believe new methods of brain imaging constitute a rapid and clinically valid method both to assess treatment and to provide information on which patients are most likely to benefit. The hypothesis of one mutation being useful in treating a tumour has been revolutionary for some less complex tumours. However, it is unlikely to provide long-term gains with glioblastoma. This is partly because the stromal environment and the random de-differentiation of stem cells and their biology are complex. But clustering analysis now suggests that the clinical entity of glioblastoma can be molecularly divided into at least six main groups.4 This presents difficulties for performing clinical trials. A further issue that hinders development in glioblastoma is that it constitutes only 1% of the total tumour burden. Most cancer treatment centres in Australia and New Zealand are unlikely to treat more than 40 glioblastoma patients a year, presenting a problem for trials with very tight eligibility. This is especially so when the small number has to be analysed according to the groups of genetic characteristics associated with different survival. Similarly, ‘salvage’ therapy trials present problems as the clinical state of patients decline rapidly. In addition, in all new cancer therapy development the drug discovery process is expensive and slow. Specifically with glioblastoma, there have been no new systemic agents for a large period of time apart from temozolomide. With the survival at 2 years of 16% the 10 years plus of potential drug development is too long. Patients rarely survive long enough to have a second attempt at radical treatment. As existing radiological response criteria using computed tomography and magnetic resonance imaging (MRI) (e.g. McDonald criteria) are difficult to interpret for a prolonged period after glioblastoma treatment (reducing the ability to assess responses to treatment), rapid and accurate surrogate markers that correlate with survival are needed here. Functional (metabolic) imaging with positron emission tomography (PET) is one such potential methodology. PET can look at multiple facets of tumour biology with exquisite resolution and with tracers present in picomolar concentrations.5 Concurrent MRI may provide even more useful information as we learn more about how to interpret the images.6 This metabolic imaging is helpful in a number of ways. First, it informs us when a tumour is undergoing genetic changes, enabling treatment to be changed early. It also enables mechanisms of tumour resistance to be investigated, such as tumour hypoxia using 18F-misonidazole. It can help in identifying reducing treatment resistance, therefore enabling a change in therapy. This is important as it is known from other tumour sites (such as non-small cell lung cancer) that resistance to single-agent targeted therapy develops increasingly quickly as patients move from first- to second-line therapy. Metabolic imaging could enable us to study the effects of novel treatment regimens such as the use of multiple agents earlier in treatment or in combination, or at different times during the treatment cycle, enabling an expedited drug discovery, phase I and phase II trial stages. If this surrogate outcome is directly correlated with clinical outcomes, imaging could also reduce the need for expensive and hard to recruit phase III clinical trials.7 However the acceptance of a surrogate outcome for a novel agent would have to meet the rigorous requirements of regulatory authorities to enable registration, although this may be different for repurposing of older agents. It is thus still likely that although the imaging correlates with survival, the measure of success required to enable registration would remain patient outcomes. Also, the measurement of success in treatment is all performed non-invasively. It is likely that more reliable PET imaging may decrease the need for routine surveillance imaging such as MRI. PET could guide emerging radiation techniques such as ‘dose painting’, which may help in locally intensifying treatment, reducing toxicity to surrounding normal tissue. Last, multiple attempts over many years and many different tumour types have been made to predict tumour response in vitro, with little correlation to clinical response. New hybrid clinical imaging technology, such as PET-MR, has the advantage that it is in vivo and avoids the problems of an experimental tumour model.8 Investigation with PET end-points could open new therapeutic options, much more cost-effective than developing a drug to phase II trial stage that may have no clinically relevant effect despite blocking the putative receptor. An unexplored but potentially useful aspect of this platform is thus to enable re-examination of old drugs with recently found effects on cancer pathways. However, this research is not ‘novel’ or scientifically exciting, and therefore philanthropic donors and governments must take the leadership in funding here. Australia will install its first combined PET-MR scanners early in 2014. The concept of multidisciplinary groups spanning the disciplines of chemistry, physics, image analysis, nuclear medicine, radiology, oncology and pharmacology to identify rapidly agents that affect a known surrogate outcome in glioblastoma has arrived. We need to take advantage of this window in research internationally to change the paradigm of brain tumour treatment.