Early Response Monitoring of Receptor Tyrosine Kinase Inhibitor Therapy in Metastatic Renal Cell Carcinoma Using [F-18]Fluorothymidine-Positron Emission Tomography-Magnetic Resonance
Introduction
A 62-year-old man was admitted to the hospital with a 2-month history of left flank pain and hematuria. Unenhanced computed tomography (CT) demonstrated a large, solid mass within the lower pole of the left kidney measuring 10.9 × 9.5 cm2 (Fig. 1). The patient underwent radical nephrectomy with histopathology revealing a Fuhrman grade 2 clear cell renal cell carcinoma. A follow-up CT scan obtained 14 months later demonstrated a large lobulated soft tissue mass in the left nephrectomy bed measuring 12 × 14 × 9 cm3 as well as multiple mesenteric nodules suggestive of disease recurrence. Subsequently, the patient received 2 cycles of high-dose interleukin-2 before sunitinib malate (SUTENT, Pfizer Inc) was approved. Sunitinib is an oral, small-molecule, multitargeted receptor tyrosine kinase inhibitor affecting tumor angiogenesis and tumor cell proliferation by targeting receptors for platelet-derived growth factor and vascular endothelial growth factor receptors.1, 2
The patient consented to participate in a research study using [F-18]fluorothymidine (FLT)-positron emission tomography-magnetic resonance (PET-MR) to assess early functional and metabolic changes following antiangiogenic therapy. A combined 3-T PET-MR system (Philips Healthcare, Cleveland, OH)3, 4 was used to assess changes in tumor [F-18]FLT uptake, diffusion-weighted imaging (DWI), and dynamic contrast-enhanced (DCE)-MR imaging (MRI) using gadopentetate dimeglumine. The treatment-monitoring study included 3 [F-18]FLT-PET-MR scans: 2 before therapeutic intervention for assessment of test-retest precision of the parameters described previously and the third [F-18]FLT-PET-MR to assess therapy-induced changes. [F-18]FLT is a radiolabeled thymidine analogue, the intracellular accumulation of which reflects cell proliferation.5 [F-18]FLT was chosen because a change in cell proliferation is hypothesized to be a more sensitive measure for treatment response compared with changes in glucose metabolism, particularly when novel, less cytotoxic treatments are being assessed.
The first [F-18]FLT-PET-MR image showed a large mass in the nephrectomy bed, a mesenteric mass in the left anterior abdomen measuring 8.0 × 6.8 cm2 and multiple liver metastases. Conventional T2-weighted imaging, precontrast and postcontrast T1-weighted imaging, and DWI with the corresponding apparent diffusion coefficient (ADC) map demonstrated the presence of a large heterogeneous mass in the surgical bed. The mass demonstrated DWI findings consistent with a thick rim of peripheral viable tumor and central cystic necrosis. A DCE-MRI was centered with the field of view on the retroperitoneal and anterior mesenteric lesions and included metastases in the right lobe of the liver. Model pharmacokinetic parameters maps showed high values of the volume transfer constant (Ktrans) describing the transfer constant of contrast agent from blood plasma to the extravascular extracellular space of the tumor, and the rate constant (Kep) describing the transfer in the opposite direction.
The PET protocol included a MR attenuation map derived from a T1-weighted scan and a static PET emission scan of the target lesion(s) followed by a data acquisition of the torso approximately 60 minutes after intravenous injection of [F-18]FLT. The large retroperitoneal mass showed increased [F-18]FLT uptake, particularly in the rim of the tumor with a photopenic center. The mesenteric mass in the left anterior abdomen showed a similar appearance. The liver metastases had higher [F-18]FLT accumulation than normal liver tissue did.
Overall, 3 target lesions were identified in the upper abdomen: the mass in the left nephrectomy bed, the left anterior abdominal mass, and a liver metastasis. There was no obvious variability in the qualitative analysis of MR sequences. As there are no generally accepted methods established, quantification for ADC values and pharmacokinetic perfusion parameters was limited. In contrast, PET excelled with a high reproducibility. The maximum standardized uptake values (SUVmax) in the test and retest [F-18]FLT-PET-MR images were 3.1 and 3.0 for the liver lesion and 2.7 for the left anterior mesenteric mass and 2.9 for the retroperitoneal mass at both scans. Thus, an overall high repeatability was observed in the [F-18]FLT studies (Fig. 2).
At 2 days after the retest study, sunitinib was administrated at a dose of 50 mg orally per day for 4 weeks followed by a 2-week treatment pause. The third [F-18]FLT-PET-MR scan was performed on day 19 (2.5 weeks) after antiangiogenic therapy initiation and showed stability in size of the target lesions. The ADC map exhibited heterogeneity within the lesions, with predominantly lower ADC values compared with those in the pretreatment examinations. Parametric DCE maps demonstrated a global decrease in Ktrans and Kep. In addition, PET showed a remarkable decrease of [F-18]FLT uptake within all target lesions (Fig. 2). Moreover, 3-dimensional-T1 Dixon images were acquired before and after gadolinium administration. Early posttreatment precontrast T1 images showed an increase of intralesional hyperintensity, which was correlated with a subtle increase of the Hounsfield units in an unenhanced CT scan performed 3 weeks later. A representative overview of the 3 [F-18]FLT-PET-MR examinations is shown in Figure 3.
Restaging contrast-enhanced CT performed at a 6-week interval after initiation of sunitinib showed overall stable disease. Subtle findings included increasing soft tissue components within the large left abdominal and mesenteric masses; however, the absolute size of these masses was unchanged. Nevertheless, a follow-up contrast-enhanced CT scan obtained 3 months after the start of therapy showed a decrease in lesion size, indicating the effectiveness of the treatment. Unfortunately, a CT scan performed 1 month later showed progression of disease, resulting in a response or progression-free survival (PFS) of 4 months.
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Discussion
In 2007, the Food and Drug Administration approved the use of sunitinib malate (SUTENT, Pfizer Inc) for the treatment of advanced (metastatic) renal cell carcinoma as it showed an improvement in PFS. The current method for assessing therapy response is by measuring changes in tumor diameter, as described in the revised Response Evaluation Criteria in Solid Tumors 1.1 guidelines.6 However, morphologic size-based criteria have limitations in monitoring the effect of targeted therapy, as
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2016, Translational OncologyCitation Excerpt :It has previously been shown that, in a comparison of feature reliability, ADC texture features have ranked higher than T2w features in demonstrating more consistent changes in healthy tissue regions [16]. In a previous case study that presented some of the data used in this work [38], FLT-PET was shown to have an overall high repeatability (i.e., low variability) between test/retest studies. DWI-ADC was found to be less repeatable likely because of respiration artifacts affecting image quality, whereas T2w MRI and radiomic features were not evaluated.
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