Downregulation of ¹⁸F-FDG Uptake in PET as an Early Pharmacodynamic Effect in Treatment of Non–Small Cell Lung Cancer with the mTOR Inhibitor Everolimus

Patient Selection and Treatment

Eighty-five patients were recruited into a multicenter phase II study investigating everolimus monotherapy in advanced relapsed NSCLC (2,4). A subgroup of 8 patients from 2 study centers (Cologne and Amsterdam) was evaluated by sequential ¹⁸F-FDG PET. Standard CT scans were obtained of all patients. The study was approved by the ethics committees of both centers, and informed consent was obtained from all patients. Everolimus was administered orally as a continuous once-daily dose of 10 mg until disease progressed or unacceptable toxicity developed.

Imaging Procedures

¹⁸F-FDG PET was performed before the start of therapy (baseline) and on days 8 and 28 of treatment. ECAT EXACT 47 (CTI/Siemens) and ECAT EXACT HR+ (CTI/Siemens) scanners were used in Cologne and Amsterdam, respectively.

Before being scanned, patients fasted for at least 6 h. The acquisition of PET scans was started 60 min after injection of 370 MBq of ¹⁸F-FDG. The attenuation-corrected scan trajectory covered 90 cm (6 bed positions, 5-min emission, 3-min transmission). All scans were normalized; corrected for decay, dead time, scatter, and randoms; and reconstructed using ordered-subset expectation maximization. To allow exchangeability of standardized uptake value (SUV) measures, reconstruction settings and image resolution need to be matched (5). Therefore, datasets collected at both sites were reconstructed using the same reconstruction algorithms and settings, that is, ordered-subset expectation maximization using 2 iterations and 16 subsets, zoom 1, an image matrix size of 128 × 128, and gaussian postsmoothing of 5 mm in full width at half maximum (FWHM). Using these settings, we determined final image spatial resolution primarily by voxel size and postreconstruction filtering. For both scanners, the resulting image resolution was approximately 7 mm FWHM near the center of the field of view. CT results were assessed using a 16-slice multidetector CT scanner (Brilliance 16; Philips Medical Systems) at baseline, every 4 wk until week 16, and every 8 wk thereafter. CT scans (collimation, 16 × 1.5 mm) were obtained 60 s after the start of a 100-mL intravenous contrast material injection (Accupaque 350; GE Healthcare Buchler GmbH und Co.). Disease status was assessed by local radiologic evaluation of all lesions. All ¹⁸F-FDG PET studies and CT scans were additionally evaluated centrally in a masked fashion by an independent nuclear medicine physician and radiologist, respectively.

¹⁸F-FDG PET Evaluation and Response Assessment

Up to 5 evaluable lesions with a baseline tumor-to-background ratio greater than or equal to 2 were selected and analyzed. Local background values were determined as follows. First, an initial estimate of the edge of the metabolic tumor volume was made using a 70% of maximum uptake 3-dimensional isocontour (i.e., a 3-dimensional volume of interest [VOI]). Next, all voxels located between 1.5 and 2.0 cm from this edge were assigned to a local background VOI. The average voxel value of the latter VOI was then defined as local background.

For each lesion, both localization and whether ¹⁸F-FDG uptake was homogeneous or heterogeneous were noted. The longest diameter of the lesion (on the PET image) and the orthogonal diameter were measured and reported. For each lesion, the maximum SUV normalized to injected activity and body surface area (SUV_BSA[max]) was determined. This is the measured tracer concentration of the hottest voxel within the lesion, normalized to injected dose and body surface area, as recommended by the European Organization for Research and Treatment of Cancer (EORTC) (6). The hottest voxel within each lesion was defined using dedicated standardized in-house (VUmc)–developed software (7). In addition, maximum SUV normalized to body weight (SUV_BW[max]) was determined. Furthermore, mean SUV estimates based on a 70% isocontour (SUVmean) were determined, again normalized to both body surface area and body weight, respectively. All SUV parameters were calculated both with and without a correction for plasma glucose level. For each patient, all SUV parameters were summed (sSUV) for all identified lesions, resulting in a total of 8 sSUV estimates per patient (sSUV_BSA[max], sSUV_BSA-Glu[max], sSUV_BW[max], sSUV_BW-Glu[max], sSUV_BSA[mean], sSUV_BSA-Glu[mean], sSUV_BW[mean], and sSUV_BW-Glu[mean]). For each method, metabolic response was defined as percentage change of sSUV at days 8 and 28 compared with baseline.

CT Scan Response Assessment

In the independent radiologic review, longest diameters in the horizontal plane of up to a maximum of 5 lesions per organ and a maximum of 10 lesions in total (including the lesions noted for ¹⁸F-FDG PET) were measured using Response Evaluation Criteria in Solid Tumors (8). The sum of the longest diameters (sCT) of all selected patient lesions and the percentage change in the sCT on day 28, compared with baseline, were calculated.

Time to Progression (TTP)

Time to progression was defined as time from the date of start of treatment to the date of an event defined as the first documented progression of the disease or death due to underlying cancer. If a patient had no event, time to progression was censored at the date of the last adequate tumor assessment.

Patient Characteristics

Eight patients with advanced NSCLC were evaluated by sequential ¹⁸F-FDG PET (patient characteristics are shown in Table 1). All patients received 10 mg of everolimus continuously, once daily. Everolimus was well tolerated, and only mild to moderate adverse events were observed (2).

¹⁸F-FDG PET

In all 8 patients, ¹⁸F-FDG PET studies were performed at baseline and day 8 of treatment, and in 5 patients also on day 28. Assessment on day 28 in the remaining 3 patients was not performed, either because of progressive disease and discontinuation from the study (2 patients) or because of refusal by the patient (1 patient). At baseline, patients had between 2 and 5 lesions that qualified for evaluation (total, 28 lesions). Lesions were localized in lung (15), mediastinum (6), and extrathoracic sites (total, 7; 3 bone and 4 soft tissue). Examples of ¹⁸F-FDG scans are shown in Figures 1 and 2.

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FIGURE 1. 

SUV_BSA(max) at baseline and on days 8 and 28 for patient 0601-0001.

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FIGURE 2. 

SUV_BSA(max) at baseline and on days 8 and 28 for patient 0701-0004.

In 5 patients, a reduction in ¹⁸F-FDG uptake on day 8 was observed using all methods, ranging from −12.8% in sSUV_BW-Glu(max) (patient 0601-0009) to −72.2% in sSUV_BW(mean) (patient 0701-0004) (Table 2). In 1 patient (0601-0007) increased ¹⁸F-FDG uptake was observed with all methods, ranging from +29.3% in sSUV_BW(max) to +77.1% in sSUV_BSA-Glu(mean).

Inconsistent results between data with and without plasma glucose correction were observed in 2 patients. This finding can be explained by altered or elevated plasma glucose levels (patient 0701-0005, 11.9 mmol/L at baseline and 14.2 mmol/L on day 8; patient 0601-0003, 4.7 mmol/L at baseline and 6.5 mmol/L on day 8).

A reduction in ¹⁸F-FDG uptake on day 28 was shown in 2 patients (0701-0004 and 0701-0002) using all methods. Two patients (0601-0001 and 0601-0009) showed inconsistent results between methods on day 28, because of elevated glucose plasma levels (7.4 and 13.5 mmol/L, respectively). The fifth patient (0601-0007) showed a further increase of ¹⁸F-FDG uptake already observed on day 8.

The sCT changes at day 28 ranged from −26.6 to +77.9%; time to progression ranged from 12 to 191 d (Table 2).