Clinical investigation
Lung
Acute tumor vascular effects following fractionated radiotherapy in human lung cancer: In vivo whole tumor assessment using volumetric perfusion computed tomography

https://doi.org/10.1016/j.ijrobp.2006.10.005Get rights and content

Purpose: To quantitatively assess the in vivo acute vascular effects of fractionated radiotherapy for human non–small-cell lung cancer using volumetric perfusion computed tomography (CT).

Methods and Materials: Sixteen patients with advanced non–small-cell lung cancer, undergoing palliative radiotherapy delivering 27 Gy in 6 fractions over 3 weeks, were scanned before treatment, and after the second (9 Gy), fourth (18 Gy), and sixth (27 Gy) radiation fraction. Using 16-detector CT, multiple sequential volumetric acquisitions were acquired after intravenous contrast agent injection. Measurements of vascular blood volume and permeability for the whole tumor volume were obtained. Vascular changes at the tumor periphery and center were also measured.

Results: At baseline, lung tumor vascularity was spatially heterogeneous with the tumor rim showing a higher vascular blood volume and permeability than the center. After the second, fourth, and sixth fractions of radiotherapy, vascular blood volume increased by 31.6% (paired t test, p = 0.10), 49.3% (p = 0.034), and 44.6% (p = 0.0012) respectively at the tumor rim, and 16.4% (p = 0.29), 19.9% (p = 0.029), and 4.0% (p = 0.0050) respectively at the center of the tumor. After the second, fourth, and sixth fractions of radiotherapy, vessel permeability increased by 18.4% (p = 0.022), 44.8% (p = 0.0048), and 20.5% (p = 0.25) at the tumor rim. The increase in permeability at the tumor center was not significant after radiotherapy.

Conclusion: Fractionated radiotherapy increases tumor vascular blood volume and permeability in human non–small-cell lung cancer. We have established the spatial distribution of vascular changes after radiotherapy; greater vascular changes were demonstrated at the tumor rim compared with the center.

Introduction

Nearly 50% of patients with cancer will undergo radiotherapy as part of their treatment (1). For lung cancer, radiotherapy is a major treatment modality; radical radiotherapy is offered for potentially curable tumors, and palliative radiotherapy for symptomatic relief of advanced disease. However, treatment failure will occur in a not insignificant number of patients, and manipulation of the tumor vasculature has emerged as a promising therapeutic strategy over the past few years (2). Antiangiogenic agents that impede tumor neovascularization and vascular disrupting agents that target established tumor blood vessels are currently in clinical trials, and are being integrated with fractionated radiotherapy regimens, with the aim of improving treatment effectiveness.

There has been little human data on the acute effects of radiation on tumor vasculature. Recent preclinical data have indicated that the tumor response to radiation may be regulated by the degree of apoptosis in tumor endothelial cells, suggesting that the tumor vasculature may be an important therapeutic target for radiation (3). There is also evidence that radiation-induced tumor regression may involve destruction of tumor vessels. It is also well recognized that tumor perfusion, through its effects on oxygenation, plays an important role in modulating responses to radiotherapy (4). Thus, further studies of the in vivo tumor vascular effects of ionizing radiation are warranted.

To date, the acute in vivo effects of fractionated radiotherapy on tumor vessels have not been evaluated for human lung cancer. Assessment of the acute tumor vascular effects of ionizing radiation in human tumors is needed to corroborate data suggesting that the tumor vasculature may be an important therapeutic target for radiation. It is also important to establish a baseline for future evaluation of combined therapy with antiangiogenic and vascular disrupting drugs in human lung cancer. Thus the aim of this study was to measure in vivo the acute vascular effects of fractionated radiotherapy on an entire human lung cancer using a volumetric perfusion computed tomography (CT) technique.

Section snippets

Patients

Institutional review board approval was obtained, with explicit approval for radiation exposure of patients for research purposes as required under the Ionizing Radiation (Medical Exposure) Regulations. Each patient gave written informed consent; this included information on the radiation exposure from both the CT examinations (7.5 mSv per examination) and subsequent radiotherapy (27 Gy total dose). Sixteen patients (9 males, 7 females) with histologically proven, inoperable non–small-cell lung

Measurement reproducibility

Permeability values were transformed by natural logarithm because the variability of the value was dependent on the mean. The repeatability statistics are summarized in Table 1. From our data, the dSD values for vascular blood volume and logarithmically transformed vessel permeability were 1.05 mL/100 mL and 0.13 mL/100 mL/min, respectively. For a group of 16 patients, any change in tumor vascular blood volume of more than ± 9.4% as a consequence of treatment would be over and above intrinsic

Discussion

Perfusion CT provides a robust, accessible, and noninvasive method for measuring tumor vascularity, including blood flow, blood volume, and permeability depending on the mathematical algorithms used (8, 9), and has been shown to correlate with histologic markers of angiogenesis in lung cancer (10, 11). Although CT measurements have been limited to small tumor volumes previously, current improvements in CT technology have enabled quantitative vascular assessment of large tumor volumes

Acknowledgments

The authors are grateful to Ernst Klotz and Heinz Fichte (Siemens Medical Solutions, Forchheim, Germany) who developed the prototype perfusion software used for image analysis; Pat Fernie and radiographers at the Paul Strickland Scanner Centre for performing the computed tomography scans; and Jane Taylor for statistical advice.

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    The Marie Curie Research Wing is supported by Cancer Research UK. This work is further supported by a project grant from the Royal College of Radiologists.

    Conflict of interest: none.

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