Radiotherapy and Oncology 114 (2015) 417–418

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Letter to the editor In response to ‘‘Histopathologic validation of 30 -deoxy-30 -18F-fluorothymidine PET for detecting tumour repopulation during fractionated radiotherapy in human FaDu squamous cell carcinoma in nude mice’’

To the Editor With great interest and expectations we read the recent publication by Yue et al. [1]. The authors validate the previously postulated accelerated tumour repopulation with immunohistochemical analysis of Ki-67 and BrdUrd, and with 18F-FLT-PET imaging, both in FaDu bearing nude mice [2]. The authors mention a study published by Hoeben et al. [3], in which head-and-neck cancer patients, the solid tumour studied in the current manuscript, are imaged with FLT-PET before therapy, and in the second and fourth week of therapy. Tclon for clinical tumours will obviously be different from that of xenograft models. However, that clinical study did not observe an increase in FLTuptake in consecutive scans (especially in the fourth week), but – on the contrary – a significant decrease with a very low uptake signal in the fourth week. This may indicate that the actively repopulating tumour fraction is too small to increase the FLT signal above the background substantially, but may still be used to locate a target for compensation of dose lost to tumour repopulation. The publication by Yue et al. [1] raises some methodological questions. First, it is unclear why the authors chose a rather uncommon fractionation schedule (fraction size 1.8 Gy) to a moderate total dose. The established Tclon by Petersen et al. [2] was derived from 3-Gy fraction schedules and may therefore differ from a Tclon at 1.8 Gy fractions. In our opinion, the results presented by the authors here, though complying with the daily/every other day fractionation schedules as presented by Petersen et al. [2], are consistent with an allowance of xenograft tumours to regain repopulative activity between alternate-day fractions of relatively low doses of 1.8 Gy. Had, e.g., 3-Gy fractions been used as by Petersen et al. [2], or twice-daily fractions of 1.8 Gy versus once-daily fractions of 1.8 Gy, it remains the question if results would have been equal. So; with 1.8 Gy fractions every other day, are we looking at increased repopulation by lengthening of treatment time, or just at increased repopulation by stimulation of proliferation by inadequate dosage with lots of time for recovery in between fractions? Second, it is unclear why the authors chose to only perform an 18 F-FLT-PET scan after the last fraction. As previously shown, fractionated radiotherapy (combined with chemotherapy) leads to a decreased 18F-FLT-PET reading throughout the treatment period (i.e., second and fourth week of treatment) and in a preclinical setting, assessing the PET signal at multiple time-points is of special interest [3,4]. With the study design used (and no repeated scanning of the treated groups before and during/after therapy), one http://dx.doi.org/10.1016/j.radonc.2014.11.040 0167-8140/Ó 2014 Elsevier Ireland Ltd. All rights reserved.

cannot rule out that the comparatively high quantitative measures remained high throughout the treatment period and are not a representation of accelerated repopulation. A study design with sacrifice of the control group for immunohistochemical analysis after scanning, but consecutive scans in the irradiated groups, would have shed light on this question. Third, details regarding the interval between the last treatment fraction and the acquisition of the PET scan, as well as the staining protocol and representative immunohistochemical images are not given. These small details may profoundly impact on the correlations reported in this publication. Fourth, Figure 3 depicts changes in PET signal intensity throughout treatment. However, the images presented in (b) do not support the findings in (a), possibly because WW/WL-setting were not chosen identically. Images merely seem to represent high uptake in viable tumour versus no uptake in (peri)necrotic areas, which increase in size after radiation. Finally, we want to refer to the only study to date in patients with head-and-neck cancer validating 18F-FLT-PET against both an endogenous (Ki-67) and exogenous (IdUrd) proliferation marker [5]. From our point of view, future preclinical studies (in mice and rats) investigating the potential of 18F-FLT-PET may address the following clinically relevant questions: is heterogeneous 18F-FLTuptake within a tumour a representation of heterogeneous distribution of (accelerated) proliferating tumour cells? If so, one may investigate increasing the radiation dose to these tumour subvolumes in patients unfit to undergo accelerated radiotherapy, thus compensating for accelerated tumour cell repopulation. In a theoretical radiotherapy planning study this approach has proven feasible [4]. If 18F-FLT-uptake within a tumour is not a representation of the underlying tumour microenvironment but more of the entire tumour volume, research may focus on the addition of measures counteracting accelerated tumour cell repopulation, such as chemotherapy and anti-EGFR. Both antiproliferative measures were found to be of relevance in head and neck cancer patients [3,6]. From these questions, the final research challenge may be evident: Does treatment adaptation based on treatment-induced changes in tumour cell proliferation as detected by 18F-FLT-PET, i.e., addition or withdrawal of chemotherapy or cetuximab, or altered radiation fractionation schedule, result in improved outcome? References [1] Yue J-B, Yang J, Liu J, et al. Histopathologic validation of 30 -deoxy-30 -18Ffluorothymidine PET for detecting tumor repopulation during fractionated radiotherapy of human FaDu squamous cell carcinoma in nude mice. Radiother Oncol 2014;111:475–81. [2] Petersen C, Zips D, Krause M, et al. Repopulation of FaDu human squamous cell carcinoma during fractionated radiotherapy correlates with reoxygenation. Int J Radiat Oncol Biol Phys 2001;51:483–93.

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Letter to the editor / Radiotherapy and Oncology 114 (2015) 417–418

[3] Hoeben BA, Troost EG, Span PN, et al. 18F-FLT PET during radiotherapy or chemoradiotherapy in head and neck squamous cell carcinoma is an early predictor of outcome. J Nucl Med 2013;54:532–40. [4] Troost EG, Bussink J, Hoffmann AL, et al. 18F-FLT-PET/CT for early response monitoring and dose escalation in oropharyngeal tumors. J Nucl Med 2010;51:866–74. [5] Troost EG, Bussink J, Slootweg PJ, et al. Histopathologic validation of 30 -deoxy30 -18F-fluorothymidine PET in squamous cell carcinoma of the oral cavity. J Nucl Med 2010;51:713–9. [6] Hoeben BA, Troost EG, Bussink J, Van Herpen CM, Oyen WJ, Kaanders JH. 18F-FLT PET changes during radiotherapy combined with cetuximab in head and neck squamous cell carcinoma patients. Nuklearmedizin 2014;53:60–6.

Esther G.C. Troost Department of Radiation Oncology (MAASTRO), GROW School for Oncology and Developmental Biology, Maastricht University Medical Centre, Dr. Tanslaan 10, 6229 ET Maastricht, The Netherlands E-mail address: [email protected] Bianca A.W. Hoeben Department of Radiation Oncology, Radboud University Medical Center, Nijmegen, The Netherlands

Peter Laverman Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands Jan Bussink Department of Radiation Oncology, Radboud University Medical Center, Nijmegen, The Netherlands Wim J.G. Oyen Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands Received 22 September 2014 Received in revised form 17 November 2014 Accepted 20 November 2014 Available online 12 December 2014

In response to "histopathologic validation of 3'-deoxy-3'-(18)F-fluorothymidine PET for detecting tumour repopulation during fractionated radiotherapy in human FaDu squamous cell carcinoma in nude mice".

In response to "histopathologic validation of 3'-deoxy-3'-(18)F-fluorothymidine PET for detecting tumour repopulation during fractionated radiotherapy in human FaDu squamous cell carcinoma in nude mice". - PDF Download Free
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