An attempt to conceptualize the individual onco-functional balance: Why a standardized treatment is an illusion for diffuse low-grade glioma patients
Introduction
Diffuse low-grade glioma (DLGG) constitutes a particular case of cancer, characterized by an initial period of slow growth in a patient without any neurological deficits. At some point, malignant transformation towards a higher grade occurs, leading to neurological impairment and ultimately to death. Our current inability to cure these tumors likely stems from their genetic, epigenetic and phenotypic plasticity and from our poor understanding of their true etiology (Darlix et al., 2017). Thanks to advances over the last two decades in the multistep sequence combining surgery, chemotherapy (CT), and radiation therapy (RT), survival rates greatly improved, with median survivals now greater than 10 years in most recent studies (Buckner et al., 2016, Capelle et al., 2013, Jakola et al., 2012, Roelz et al., 2016, Smith et al., 2008). This means that, if ones aims to improve not only survival but also time with quality of life (Mandonnet et al., 2012), the selection of a treatment at any time in the sequence should weight its oncological interest (positive effect on survival) against its expected short- and long-term functional consequences. In other words, the choice of a treatment at a given time consists in optimizing the so called onco-functional balance (Duffau and Mandonnet, 2013).
At the first level, we propose to review our current knowledge enabling to evaluate the oncological benefit and the functional risk of each treatment type, independently of its integration in the sequence. But because one also wants to compare the onco-functional balance of each treatment modality in reference to the natural history, this first level analysis will be preceded by a short recall of some essential elements of the natural history of DLGG, both on an oncological and functional perspective.
At the second level, the same balance has to be reevaluated in the framework of a multistep sequential approach. Indeed, the overall efficacy of a treatment cannot be assessed per se, as we will show that it will be highly dependent on its integration in the whole sequence. For example, the same response to temozolomide will have a different oncological impact whether it is complemented (hopefully synergistically) or not by a surgery or a radiation therapy. Hence, in order to select the best treatment at each step, one should also have in mind both the previous and the next steps.
At the third level, the two previous levels have to be reevaluated at the individual scale, based on personalized parameters, characterizing both the tumor and the brain functioning of the patient. In other words, the timing and order of the sequence steps have to be fitted to each patient, taken into consideration both tumor and functional individual characteristics, and their interactions. For example, the very same extent of resection has a different value in a slow growing tumor (allowing a repeat surgery after a couple of years of full cognitive recovery) or in a fast growing tumor (requiring in the next step a chemotherapy or a radiation therapy because of a low plasticity reserve resulting from the fast growth).
Finally, we propose a recursive algorithm that can assist clinicians in the complex task of finding the optimal personalized treatment sequence for each patient.
Section snippets
Elements of natural history of DLGG and its interaction with the brain
From an oncological point of view, DLGG can be considered as premalignant lesions. Indeed, these lesions are at risk of malignant transformation, with both functional and life-threatening consequences. During the low-grade period, the tumor growth is continuous and slow (about 4 mm/year on average (Mandonnet et al., 2003)). The risk of malignant transformation increases with tumor volume and with tumor growth rates. Hence, from an oncological point of view, treatments goal is to reduce both
Short-term oncological benefit: removal of a « hot » spot
It is now well recognized that DLGG might exhibit spatial heterogeneities. New imaging techniques enable to detect such heterogeneities. In particular, dynamic 18F FET-PET allows to identify foci of decreasing time-activity curves, that correlate with histological grade (Thon et al., 2015). Similarly, the role of perfusion imaging to detect such hot spots is still investigated. Although this has not yet been proven, it can be anticipated that removal of such malignant foci within an otherwise
Second level onco-functional balance: integrating each treatment in the whole sequence
Beyond the onco-functional balance intrinsically related to a given treatment, the choice of a treatment modality should be reevaluated in light of its interaction with associated treatments in the whole sequence. In this part, we propose to review some of these interactions.
Importance of patient’s way of life and wishes in surgical planning
Since postoperative cognitive evaluations are performed on a routine basis, our knowledge of the impact of surgery on high-level functions has greatly improved, leading to a better preoperative personalized estimation of functional risk. To this end, the importance of the preoperative patient interview cannot be overemphasized. Patient should clearly formulate his wishes regarding which kind of functions should be primarily preserved. This will depend on its way of life, including profession,
Proposal of a recursive algorithm of multistep treatment in DLGG patients
In light of our current knowledge, we suggest that DLGG patients would benefit from a recursive reasoning, as explicited in Fig. 2. Whenever possible, maximal resection tailored on functional boundaries for preserving functions preoperatively defined with the patient remains the treatment of first intention (Soffietti et al., 2010). Judging for functional operability constitutes presently a subjective expertise based on surgeon’s experience. However, new methodological tools are under
Conclusion
Implementing an optimal sequential multistep strategy in DLGG patients is quite complex: we have shown that, beyond the role of each individual treatment, second order effects can potentiate the effect of each individual treatment. The proposed recursive design can serve as a guide, in keeping with the fundamental principle that the onco-functional balance of each treatment modality has to be updated all along the evolution. In this perspective, future randomized trial in DLGG should evaluate
Conflict of interest
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Funding statement
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