Spatiotemporal Stability of Cu-ATSM and FLT Positron Emission Tomography Distributions During Radiation Therapy

Abstract

Purpose In dose painting, in which functional imaging is used to define biological targets for radiation therapy dose escalation, changes in spatial distributions of biological properties during treatment can compromise the quality of therapy. The goal of this study was to assess the spatiotemporal stability of 2 potential dose painting target—dhypoxia and proliferation—in canine tumors during radiation therapy. Methods and Materials Twenty-two canine patients with sinonasal tumors (14 carcinoma and 8 sarcoma) were imaged before hypofractionated radiation therapy with copper(II)-diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM) positron emission tomography/computed tomography (PET/CT) for hypoxia and 3′-deoxy-3′-18F-fluorothymidine (FLT) PET/CT for proliferation. The FLT scans were repeated after 2 fractions and the Cu-ATSM scans after 3 fractions. Midtreatment PET/CT images were deformably registered to pretreatment PET/CT images. Voxel-based Spearman correlation coefficients quantified the spatial stability of Cu-ATSM and FLT uptake distributions between pretreatment and midtreatment scans. Paired t tests determined significant differences between the patients’ respective Cu-ATSM and FLT correlations coefficients. Standardized uptake value measures were also compared between pretreatment and midtreatment scans by use of paired t tests. Results Spatial distributions of Cu-ATSM and FLT uptake were stable through mid-treatment for both sarcomas and carcinomas: the population mean ± standard deviation in Spearman correlation coefficient was 0.88 ± 0.07 for Cu-ATSM and 0.79 ± 0.13 for FLT. The patients’ Cu-ATSM correlation coefficients were significantly higher than their respective FLT correlation coefficients (P=.001). Changes in Cu-ATSM SUV measures from pretreatment to midtreatment were histology dependent: carcinomas experienced significant decreases in Cu-ATSM uptake (P<.05), whereas sarcomas did not (P>.20). Both histologies experienced significant decreases in FLT uptake (P<.05). Conclusions Spatial distributions of Cu-ATSM were very stable after a few fractions of radiation therapy. FLT spatial distributions were generally stable early in therapy, although they were significantly less stable than Cu-ATSM distributions. Canine tumors had significantly lower proliferative activity at midtreatment than at pretreatment, and they experienced histology-dependent changes in Cu-ATSM uptake.

Molecular Imaging to Plan Radiotherapy and Evaluate Its Efficacy

“…Although tumor hypoxia is widely recognized as a negative prognostic factor in radiation oncology, hypoxic tumor subvolumes often change during radiotherapy (113,114). Treatment outcome may correlate more with hypoxia assessed during radiotherapy than before radiotherapy (115) (Fig.…”

Functional Radiotherapy Targeting using Focused Dose Escalation

“…There is debate as to whether single or repeated imaging is required during a course of fractionated dose painted radiotherapy [24,51,52]. On the one hand it can be argued that the outcome for any particular tumour is determined by its pre-treatment characteristics and therefore if a particular characteristic is chosen to optimise the dose distribution then this pre-treatment distribution should be followed throughout the entire course.…”

“…However, some groups have postulated that the change in FLT status between the baseline measurement and subsequent quantification after the start of radiotherapy is more important than the baseline value alone. In other words, accelerated repopulation is a more important biological predictor of radiotherapy failure than the baseline proliferation rate [51]. FLT PET assessment of tumour proliferation during radiotherapy must be interpreted with some caution due to the fact that the inhibition of cell cycle progression, as would be expected after radiation exposure, can prevent FLT uptake [104].…”

Technology for Innovation in Radiation Oncology

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The role of PET technology is central to the following areas: (i) localization of the gross tumor volume (GTV) in radiotherapy treatment planning; (ii) characterization of tumor sites, particular for features such as hypoxia that may impact treatment response, and can therefore be incorporated into a BTV (5); (iii) measurement of response to radiotherapy early in the course of treatment and therapy adaptation, as appropriate, based upon early response. Key areas for the development and application of new PET biomarkers/probes will be to: (a) develop and implement probes to detect and localize cancers (such as prostate cancer) not well visualized by FDG-PET (examples include, labeled choline agents and amino acid tracers) (28); (b) measurement of regional tumor hypoxia to construct BTVs that can be used to direct treatment planning based upon hypoxia (examples include, 18 F-FMISO and 18 F-EF5) (29); (c) measurement of cellular proliferation to assess early response to treatment (examples include, 18 F-FLT, 18 F-FMISO) (30); (d) imaging of normal tissues using specific biomarkers (e.g. indocyanine green for assessment of radiation-induced liver damage) to incorporate healthy tissue functional reserve into adaptive RT models (31).

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“…Key areas for the development and application of new PET biomarkers/probes will be to: (a) develop and implement probes to detect and localize cancers (such as prostate cancer) not well visualized by FDG-PET (examples include, labeled choline agents and amino acid tracers) (28); (b) measurement of regional tumor hypoxia to construct BTVs that can be used to direct treatment planning based upon hypoxia (examples include, 18 F-FMISO and 18 F-EF5) (29); (c) measurement of cellular proliferation to assess early response to treatment (examples include, 18 F-FLT, 18 F-FMISO) (30); (d) imaging of normal tissues using specific biomarkers (e.g. indocyanine green for assessment of radiation-induced liver damage) to incorporate healthy tissue functional reserve into adaptive RT models (31).…”