The ESTRO Breur Lecture 2009. From population to voxel-based radiotherapy: Exploiting intra-tumour and intra-organ heterogeneity for advanced treatment of non-small cell lung cancer

doi:10.1016/j.radonc.2010.07.001

Radiotherapy and Oncology

Volume 96, Issue 2, August 2010, Pages 145-152

https://doi.org/10.1016/j.radonc.2010.07.001 Get rights and content

Abstract

Evidence is accumulating that radiotherapy of non-small cell lung cancer patients can be optimized by escalating the tumour dose until the normal tissue tolerances are met. To further improve the therapeutic ratio between tumour control probability and the risk of normal tissue complications, we firstly need to exploit inter patient variation. This variation arises, e.g. from differences in tumour shape and size, lung function and genetic factors. Secondly improvement is achieved by taking into account intra-tumour and intra-organ heterogeneity derived from molecular and functional imaging. Additional radiation dose must be delivered to those parts of the tumour that need it the most, e.g. because of increased radio-resistance or reduced therapeutic drug uptake, and away from regions inside the lung that are most prone to complication. As the delivery of these treatments plans is very sensitive for geometrical uncertainties, probabilistic treatment planning is needed to generate robust treatment plans. The administration of these complicated dose distributions requires a quality assurance procedure that can evaluate the treatment delivery and, if necessary, adapt the treatment plan during radiotherapy.

Section snippets

Tumour heterogeneity

A malignant tumour is not a homogeneous mass, but is composed of regions that differ in tumour cell density, normal tissue involvement, vasculature, hypoxia, proliferation, gene expression and drug uptake [12]. This heterogeneity within the tumour results in large spatial differences in response to radiotherapy, chemotherapy, or new targeted agents. The discovery of intra-tumour heterogeneity opens new therapeutic possibilities for individualized patient treatment. Today, radiation is given to

Organ heterogeneity: the example of lung

Not only tumours but also healthy organs can be heterogeneous in function and sensitivity for complications. However, at present models presume that all parts of an organ have the same functional capacity, i.e. every subvolume has the same function and contributes equally to the global organ function. This is certainly not correct for lungs [44]. Gas diffusion only occurs in the alveoli and there is a large heterogeneity in the functional areas of the lungs because of differences in ventilation

Treatment planning incorporating tumour and organ heterogeneity and geometrical uncertainties

The technical feasibility of treatment planning with multiple dose prescription levels to the tumour based on biological images has been demonstrated by different groups [17], [19], [20], [21], [22], [43], [61], [62], [63], [64]. Dose prescriptions ranged from 2 dose levels to a dose distribution that varied continuously based on tracer uptake. Also different groups showed how 3D lung perfusion and/or ventilation maps can be used as input for conformal and IMRT treatment planning to limit the

Dose delivery verification

The delivery of complicated, heterogeneous dose distributions with very high dose levels to small target volumes requires steep dose gradients and small multi-leaf collimator (MLC) shaped segments. As a consequence, small changes in patient anatomy or MLC configuration can result in large deviations from the planned dose distribution. Therefore precise geometric and dosimetric verification is of utmost importance to ensure correct planning and delivery for these advanced and complex types of

Plan adaptation

Quality assurance using 3D dose delivery verification is not only needed to guarantee that the treatment is delivered as planned. If during therapy it becomes clear that the treatment plan needs to be adapted, the total delivered dose distribution up to that point in time needs to be known and used in the treatment adaptation strategy to ensure that the new plan compensates for the deviations between the desired and delivered dose distribution. Reasons for treatment plan adaptation can be

Conclusions

We hypothesize that in the near future decision support systems will be used to select for each patient individually the treatment with the best balance between probability of cure and complications based on inter patient heterogeneity. Apart from inter patient heterogeneity, intra patient heterogeneity could be exploited to further optimize the therapeutic ratio. The dose to complication prone regions of the lungs can be reduced and additional dose can be delivered towards the parts of the

Conflict of interest

We are not aware of any actual or potential conflicts of interest.

Acknowledgments

This study was performed within the framework of CTMM, the Center for Translational Molecular Medicine (www.ctmm.nl), project AIRFORCE number 030-103.

This work has been funded with the support of the METOXIA project no. 222741 under the 7th Research Framework Programme of the European Union.