Evaluation of 2-Deoxy-2-[18F]Fluoro-D-glucose- and 3′-Deoxy-3′-[18F]Fluorothymidine–Positron Emission Tomography as Biomarkers of Therapy Response in Platinum-Resistant Ovarian Cancer

Purpose

We evaluated whether 2-deoxy-2-[¹⁸F]fluoro-D-glucose ([¹⁸F]FDG) and 3??-deoxy-3??-[¹⁸F]fluorothymidine ([¹⁸F]FLT) positron emission tomography (PET) could be used as imaging biomarkers of platinum resensitization in ovarian cancer.

Procedures

Paired platinum-sensitive and platinum-resistant ovarian cancer cells from the same patient, PEO1 and PEO4, grown as tumor xenografts in nude mice, were assessed by PET.

Results

The AKT inhibitor, API-2, resensitized platinum-resistant PEO4 tumors to cisplatin, leading to a markedly lower Ki67 labeling index (p????0.006, n?=?6 per group). [¹⁸F]FDG-PET and [¹⁸F]FLT-PET imaging variables were lower after combination treatment compared with vehicle treatment (p????0.006, n?=?6 per group). No changes were seen with either drug alone. PRAS40 phosphorylation status was a sensitive biochemical marker of pathway inhibition, whereas reductions thymidine kinase 1 expression defined the [¹⁸F]FLT response.

Conclusions

Therapeutic inhibition of AKT activation in acquired platinum-resistant disease can be imaged noninvasively by [¹⁸F]FDG-PET and [¹⁸F]FLT-PET warranting further assessment.     

Does Measurement of First-Order and Heterogeneity Parameters Improve Response Assessment of Bone Metastases in Breast Cancer Compared to SUVmax in [18F]fluoride and [18F]FDG PET?

Molecular Imaging and Biology - To establish whether first-order statistical features from [18F]fluoride and 2-deoxy-2-[18F] fluoro-d-glucose ([18F]FDG) positron emission tomography/x-ray computed...     

Validity of Simplified 3′-Deoxy-3′-[18F]Fluorothymidine Uptake Measures for Monitoring Response to Chemotherapy in Locally Advanced Breast Cancer

Purpose

Positron emission tomography using 3??-deoxy-3??-[¹⁸F]fluorothymidine ([¹⁸F]FLT) has been suggested as a means for monitoring response to chemotherapy. The aim of this study was to evaluate the validity of simplified uptake measures for assessing response to chemotherapy using [¹⁸F]FLT in locally advanced breast cancer (LABC).

Procedures

Fifteen LABC patients underwent dynamic [¹⁸F]FLT scans both prior to and after the first cycle of chemotherapy with fluorouracil, epirubicin or doxorubicin, and cyclophosphamide. The net uptake rate constant of [¹⁸F]FLT, K _i , determined by non-linear regression (NLR) of an irreversible two-tissue compartment model was used as the gold standard. In addition to Patlak graphical analysis, standardised uptake values (SUV) and tumour-to-whole blood ratio (TBR) were used for analysing [¹⁸F]FLT data. Correlations and relationships between simplified uptake measures and NLR before and after chemotherapy were assessed using regression analysis.

Results

No significant differences in both pre- and post-chemotherapy relationships between any of the simplified uptake measures and NLR were found. However, changes in SUV between baseline and post-therapy scans showed a significant negative bias and slope less than one, while TBR did not.

Conclusions

In LABC, TBR instead of SUV may be preferred for monitoring response to chemotherapy with [¹⁸F]FLT.     

The Synergistic Effect of Selumetinib/Docetaxel Combination Therapy Monitored by [<Superscript>18</Superscript> F]FDG/[<Superscript>18</Superscript> F]FLT PET and Diffusion-Weighted Magnetic Resonance Imaging in a Colorectal Tumor Xenograft Model

Purpose

Positron emission tomography (PET) and diffusion-weighted MRI (DW-MRI) were used to characterize the treatment effects of the MEK1/2 inhibitor selumetinib (AZD6244), docetaxel, and their combination in HCT116 tumor-bearing mice on the molecular level.

Procedures

Mice were treated with vehicle, selumetinib (25 mg/kg), docetaxel (15 mg/kg), or a combination of both drugs for 7 days and imaged at four time points with 2-deoxy-2-[¹⁸?F]fluoro-D-glucose ([¹⁸?F]FDG) or 3′-deoxy-3′-[¹⁸?F]fluorothymidine ([¹⁸?F]FLT) followed by DW-MRI to calculate the apparent diffusion coefficient (ADC). Data was cross-validated using the Pearson correlation coefficient (PCC) and compared to histology (IHC).

Results

Each drug led to tumor growth inhibition but their combination resulted in regression. Separate analysis of PET or ADC could not provide significant differences between groups. Only PCC combined with IHC analysis revealed the highest therapeutic impact for combination therapy.

Conclusion

Combination treatment of selumetinib/docetaxel was superior to the respective mono-therapies shown by PCC of PET and ADC in conjunction with histology.

     

PIK3CA Mutational Status Is Associated with High Glycolytic Activity in ER+/HER2− Early Invasive Breast Cancer: a Molecular Imaging Study Using [18F]FDG PET/CT

Molecular Imaging and Biology - In PIK3CA mutant breast cancer, downstream hyperactivation of the PI3K/AKT/mTOR pathway may be associated with increased glycolysis of cancer cells. The purpose of...     

Monitoring Tumor Response after Liposomal Doxorubicin in Combination with Liposomal Vinorelbine Treatment Using 3′-Deoxy-3′-[<Superscript>18</Superscript>F]Fluorothymidine PET

Purpose

Surgical resection is the standard treatment for localized colorectal cancer, which is the most common type of gastrointestinal cancer. However, over 40 % cases are diagnosed metastasized and apparently inoperable. Systemic chemotherapy provides an alternative to these patients. This study aims to evaluate the therapeutic potential of liposomal doxorubicin (lipoDox) in combination with liposomal vinorelbine (lipoVNB) in a CT-26 colon carcinoma-bearing mouse model.

Procedures

The in vitro cytotoxicity of Dox and VNB on CT-26 cancer cells was determined by MTT and colony formation assays. Mice were subcutaneously inoculated with 2 × 10⁵ of CT-26 cells in the right hind flank. When tumor size reached 200 ± 50 mm³, mice were assigned to receive different treatment protocols. The pharmacokinetics, micro single-photon emission computed tomography/x-ray computed tomography imaging, biodistribution, and immunohistochemical staining studies were performed to survey the therapeutic efficacy of each regimen.

Results

Based on the results of pharmacokinetic study, co-administration of lipoDox and lipoVNB did not affect their individual systemic distribution, while lipoDox retained longer in blood than lipoVNB did. Superior tumor growth retardation was observed in the group received lipoDox plus lipoVNB administration (1 mg/kg each, namely D₁V₁) than those injected with lipoDox plus VNB (1 mg/kg each, namely D₁fV₁). No severe side effects were detected in each group. The tumor-to-muscle ratio (T/M) derived from 3′-dexoy-3′-[¹⁸F]fluorothymidine ([¹⁸F]FLT) micro positron emission tomography (PET) images of D₁V₁- and D₁fV₁-treated mice and the controls on day 7 was 6.88 ± 0.54, 7.50 ± 0.84, and 9.87 ± 0.73, respectively, suggesting that D₁V₁ is a more efficacious regimen against CT-26 xenografts. The results of proliferating cell nuclear antigen (PCNA) immunohistochemical staining were consistent with those findings obtained from [¹⁸F]FLT microPET imaging.

Conclusion

This study demonstrated that lipoDox in combination with lipoVNB was more efficacious than clinically used regimen, lipoDox plus VNB, in the treatment of colon carcinoma and [¹⁸F]FLT-PET is a promising approach in monitoring the treatment outcome at early stage.

     

Positron Emission Tomography with [18F]-3′-Deoxy-3′fluorothymidine (FLT) as a Predictor of Outcome in Patients with Locally Advanced Resectable Rectal Cancer: a Pilot Study

Purpose

This pilot study was performed to evaluate whether tumor uptake of ¹⁸F-labeled 3′-deoxy-3′fluorothymidine (FLT), a proliferative radiotracer, at baseline and early during therapy, is predictive of outcome in locally advanced rectal cancer.

Procedures

Fourteen patients underwent positron emission tomography (PET) with 2-deoxy-2-[¹⁸F]fluoro-d-glucose (FDG) and FLT before therapy and PET with FLT approximately 2 weeks after initiating neoadjuvant chemoradiotherapy. FLT and FDG uptake were evaluated qualitatively and by maximum standardized uptake value (SUV_max). Tumor FLT and FDG uptake were correlated with disease-free survival (DFS).

Results

Thirteen patients underwent surgery after therapy, one died before surgery with progressive disease. FDG-PET/computed tomography detected regional lymph node metastases in five and FLT-PET was positive in one. High pretherapy FDG uptake (SUV_max?≥?14.3), low during-therapy FLT uptake (SUV_max?<?2.2), and high percentage change in FLT uptake (≥60 %) were predictive of improved DFS (p?<?0.05 for all three values).

Conclusion

Pretherapy FDG uptake, during-therapy FLT uptake, and percentage change in FLT uptake were equally predictive of DFS.     

NCI-Sponsored Trial for the Evaluation of Safety and Preliminary Efficacy of 3′-Deoxy-3′-[18F]fluorothymidine (FLT) as a Marker of Proliferation in Patients with Recurrent Gliomas: Preliminary Efficacy Studies

Purpose  3′-Deoxy-3′-[¹⁸F]fluorothymidine ([¹⁸F]FLT) is being developed for imaging cellular proliferation. The goals were to explore the capacity of FLT-positron emission tomography (PET) to distinguish between recurrence and radionecrosis in gliomas and compare the results to those obtained with 2-fluoro-2-deoxy-d-glucose (FDG). Procedures  Fifteen patients with tumor recurrence and four with radionecrosis, determined by clinical course and magnetic resonance imaging results, were studied by dynamic [¹⁸F]FLT-PET with arterial blood sampling. A two-tissue compartment four-rate constant model was used to determine metabolic flux (K _FLT), blood to tissue transport (K ₁), and phosphorylation (k ₃). FDG-PET scans were obtained 75–90 min postinjection. Results   K _FLT and k ₃, but not K ₁ or k ₃/k ₂ + k ₃, reached significance for separating the recurrence from radionecrosis groups. Standardized uptake value and visual analyses of FLT or FDG images did not reach significance. Conclusions   K _FLT (flux) appears to distinguish recurrence from radionecrosis better than other parameters, FLT and FDG semiquantitative approaches, or visual analysis of images of either tracer.     

Baseline [<Superscript>18</Superscript>F]FMISO μPET as a Predictive Biomarker for Response to HIF-1α Inhibition Combined with 5-FU Chemotherapy in a Human Colorectal Cancer Xenograft Model

Purpose

The purpose of this study was to characterize imaging biomarkers for the potential benefit of hypoxia-inducible factor-1 (HIF-1)α inhibition (by PX-12) during 5-fluorouracil (5-FU) chemotherapy in the treatment of colorectal cancer (CRC).

Procedures

Therapy response to 5-FU?±?PX-12 was assessed with baseline [¹⁸F]fluoromisonidazole ([¹⁸F]FMISO) and longitudinal 2-deoxy-2-[¹⁸F]fluoro-d-glucose ([¹⁸F]FDG) positron emission computed tomography (μPET/CT) in CRC xenograft model (n?=?36) during breathing of a hypoxic (10 % O₂) or normoxic (21 % O₂) atmosphere. Ex vivo, immunohistochemistry was performed.

Results

Baseline [¹⁸F]FMISO uptake and relative tumor volume (RTV) 2 days after 5-FU or 5-FU?+?PX-12 administration correlated significantly (p?≤?0.01). Under hypoxic breathing conditions, [¹⁸F]FDG uptake (?53.1?±?8.4 %) and Ki67 expression (?16 %) decreased and RTV stagnated in the 5-FU?+?PX-12 treatment group, but not in 5-FU alone-treated tumors. Under normoxic breathing, [¹⁸F]FDG uptake (?23.5?±?15.2 % and ?72.8?±?7.1 %) and Ki67 expression (?5 % and ?19 %) decreased and RTV stagnated in both the 5-FU and the combination treatment group, respectively.

Conclusion

Baseline [¹⁸F]FMISO μPET may predict the beneficial effect of HIF-1α inhibition during 5-FU chemotherapy in CRC.