Clinical Investigation
Imaging Cellular Proliferation During Chemo-Radiotherapy: A Pilot Study of Serial 18F-FLT Positron Emission Tomography/Computed Tomography Imaging for Non–Small-Cell Lung Cancer

https://doi.org/10.1016/j.ijrobp.2008.12.039Get rights and content

Purpose

To establish whether 18F-3′-deoxy-3′-fluoro-l-thymidine (18F-FLT) can monitor changes in cellular proliferation of non–small-cell lung cancer (NSCLC) during radical chemo-radiotherapy (chemo-RT).

Methods and Materials

As part of a prospective pilot study, 5 patients with locally advanced NSCLC underwent serial 18F-FLT positron emission tomography (PET)/computed tomography (CT) scans during treatment. Baseline 18F-FLT PET/CT scans were compared with routine staging 18F-FDG PET/CT scans. Two on-treatment 18F-FLT scans were performed for each patient on Days 2, 8, 15 or 29, providing a range of time points for response assessment.

Results

In all 5 patients, baseline lesional uptake of 18F-FLT on PET/CT corresponded to staging 18F-FDG PET/CT abnormalities. 18F-FLT uptake in tumor was observed on five of nine (55%) on-treatment scans, on Days 2, 8 and 29, but not Day 15. A “flare” of 18F-FLT uptake in the primary tumor of one case was observed after 2 Gy of radiation (1.22 × baseline). The remaining eight on-treatment scans demonstrated a mean reduction in 18F-FLT tumor uptake of 0.58 × baseline. A marked reduction of 18F-FLT uptake in irradiated bone marrow was observed for all cases. This reduction was observed even after only 2 Gy, and all patients demonstrated a complete absence of proliferating marrow after 10 Gy.

Conclusions

This proof of concept study indicates that 18F-FLT uptake can monitor the distinctive biologic responses of epithelial cancers and highly radiosensitive normal tissue changes during radical chemo-RT. Further studies of 18F-FLT PET/CT imaging during therapy may suggest that this tracer is useful in developing response-adapted RT for NSCLC.

Introduction

Radiotherapy (RT) is a key component of potentially curative treatment strategies for many common cancers. Both tumors and their surrounding normal tissues undergo profound molecular changes during RT. Some malignant cell types (e.g., follicular lymphoma) and normal cells (e.g., hematopoietic bone marrow cells) are likely to undergo early apoptosis at relatively low radiation doses (1). Other cells, such as those of the common epithelial cancers, are less responsive to radiotherapy and require high cumulative doses to cause late necrotic death (1). Serial structural imaging, for example with computed tomography (CT), may show gradual changes in volume during a course of therapy but provides no information on the effects of RT on tumor metabolism or cellular proliferation. Imaging with positron emission tomography (PET) has the potential to provide information on the molecular effects of radiation during treatment, at a time when treatment volumes, dose, and fractionation could be individualized based on response. Limited early data suggest that metabolic imaging with serial 18F-fluoro-2′-deoxy-d-glucose (18F-FDG) PET scans can provide useful therapeutic response information during RT 2, 3, 4, 5. However, despite its many advantages, 18F-FDG is not a highly selective tracer for imaging cancer, as it is also taken up by activated macrophages and other cells involved in inflammatory processes 6, 7. Exploring the role of radiopharmaceuticals other than 18F-FDG is therefore warranted.

A comparatively novel tracer in oncology imaging is 18F-3′-deoxy-3′-fluoro-l-thymidine (18F-FLT) 8, 9, 10, 11. 18F-FLT is phosphorylated by the enzyme thymidine kinase 1 (TK1), which leads to intracellular trapping 12, 13. Because TK1 concentration increases almost 10-fold during the S phase of the cell cycle at the time of DNA synthesis, 18F-FLT uptake reflects the proliferation rate of malignant cells (14). Studies in NSCLC have demonstrated a close correlation between the uptake of 18F-FLT and immunohistochemical measures of proliferation 11, 15, 16, 17. In contrast, a study of 10 patients with esophageal cancer reported no correlation between the maximum 18F-FLT standardized uptake value (SUVmax) and Ki-67 expression18. Recent studies by Roels et al.(19) and Wieder et al.(20) established that 18F-FLT could detect dose-dependent changes in tumor and surrounding organs in patients receiving chemo-RT for colorectal cancer. A preclinical study of murine breast cancer cells also suggests that 18F-FLT can detect changes in cellular proliferation soon after irradiation (21). No clinical data are currently available on the assessment of 18F-FLT during RT for NSCLC.

This study was initiated to investigate whether PET/CT using 18F-FLT could image cellular proliferation of lung tumors during a course of radical chemo-RT with the ultimate goal of prescribing personalized RT fractionation and dose regimens, including hyperfractionated and escalated treatments, and biologically targeted dose painting, based on therapeutic response.

Section snippets

Patient eligibility

Patients were eligible for this study if they had Stage I, II, IIIA, or IIIB (without pleural effusion) histologically or cytologically proven NSCLC; had Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1; had weight loss of less than 10%; and were planned to have radical chemo-RT. Patients were also assessed for their ability to undergo all specified PET/CT imaging procedures. Exclusion criteria were previous thoracic RT and complete macroscopic excision of tumor. All

Results

Five patients were enrolled between July 2007 and March 2008; their characteristics are summarized in Table 1. The third patient ceased participation in the study before the third 18F-FLT scan. The median (range) time between the injection of 18F-FLT and initiation of the emission scan was 68 min (range, 56–86 min).

Discussion

In this small pilot study, we have established proof of the concept that 18F-FLT uptake can be detected in patients receiving radical chemo-RT for NSCLC. This information may be useful to monitor changes in cellular proliferation occurring during treatment, to provide valuable prognostic information, and to adapt treatment based on individual biologic response.

Before undertaking this study, there were no available data indicating how quickly 18F-FLT would cease to accumulate in tumors after the

Conclusion

The striking images acquired for this study illustrate the distinctive biologic responses of epithelial cancers and highly radiosensitive normal tissues, depicted by 18F-FLT uptake during therapy. The idea of dynamically adapting the dose and/or scheduling of RT to the molecular imaging response is novel and could significantly improve treatment results for individual patients. Research is now underway to validate these preliminary findings and to further examine the role of on-treatment 18

Acknowledgments

This work was supported by an Australian Institute of Radiography research scholarship (SJE). The authors wish to thank Michael Sproston and Anne Louev for their significant role in positioning patients for the PET/CT scans and Colin Hornby for his technical assistance in data transfer. Thank you also to Associate Professor Grant MacArthur for his editorial review of the manuscript.

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