Abstract
Tumor heterogeneity is widely considered to be a determinant factor in tumor progression and in particular in its recurrence after therapy. Unfortunately, current medical techniques are unable to deduce clinically relevant information about tumor heterogeneity by means of non-invasive methods. As a consequence, when radiotherapy is used as a treatment of choice, radiation dosimetries are prescribed under the assumption that the malignancy targeted is of a homogeneous nature. In this work we discuss the effects of different radiation dose distributions on heterogeneous tumors by means of an individual cell-based model. To that end, a case is considered where two tumor cell phenotypes are present, which we assume to strongly differ in their respective cell cycle duration and radiosensitivity properties. We show herein that, as a result of such differences, the spatial distribution of the corresponding phenotypes, whence the resulting tumor heterogeneity can be predicted as growth proceeds. In particular, we show that if we start from a situation where a majority of ordinary cancer cells (CCs) and a minority of cancer stem cells (CSCs) are randomly distributed, and we assume that the length of CSC cycle is significantly longer than that of CCs, then CSCs become concentrated at an inner region as tumor grows. As a consequence we obtain that if CSCs are assumed to be more resistant to radiation than CCs, heterogeneous dosimetries can be selected to enhance tumor control by boosting radiation in the region occupied by the more radioresistant tumor cell phenotype. It is also shown that, when compared with homogeneous dose distributions as those being currently delivered in clinical practice, such heterogeneous radiation dosimetries fare always better than their homogeneous counterparts. Finally, limitations to our assumptions and their resulting clinical implications will be discussed.
Highlights
Radiotherapy, the use of ionizing radiation to eliminate pathological tissues, is a treatment of choice for more than 50% of cancer patients diagnosed with solid tumors [1]
According to standard radiotherapy scheduling, sessions are distributed into 6 weeks, each week including five sessions from Monday to Friday separated by 24 hours intervals, and with a 72 hours interval from Friday to Monday in the following week
Radiation therapy treatment starts, and tumor cell number diminishes during the first week
Summary
Radiotherapy, the use of ionizing radiation to eliminate pathological tissues, is a treatment of choice for more than 50% of cancer patients diagnosed with solid tumors [1]. Locoregional recurrence (LRR) remains a problem in many clinical settings. A recent study in patients with Stage III lung cancer found a 5-year LRR rate of 31% [2]. In Glioblastoma Multiforme (GBM), the most common and aggressive malignant primary brain tumor, LRR approaches 90% [3]. In such critical cases, radiotherapy usually results in an initial shrinkage of malignancies, followed by a subsequent growth recovery that cannot be checked even by resorting to larger radiation doses
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