Combination of FDG and FMISO may predict accurate PFS in patients with early-stage NSCLC after stereotactic radiotherapy.

Objectives: Stereotactic body radiation therapy (SBRT) has been applied to early-stage non-small-cell lung cancers (NSCLC) and provides an excellent survival benefit for both operable and inoperable patients. In general, intratumoral hypoxia accelerate radio-resistance and thus hypoxic tumors require a 2.5-3 times radiotherapy dose. Few studies have been conducted to clarify the relation between the existence of hypoxia, metabolic activity and the prognosis of NSCLC patients treated by SBRT. This study was conducted to evaluate the predictive value of FDG and FMISO in comparison with the prognosis of NSCLC patients treated by SBRT.

Methods: This prospective study enrolled pathologically proven NSCLC patients who were proposed to SBRT and who signed the consent to accept FMISO PET/CT from August 2013 to August 2017. All the patients were irradiated using SBRT techniques. A total dose of 40 or 48 Gy at the isocenter was administered in 4 fractions over 4-8 days. PET images were acquired using a whole-body time-of-flight PET-CT scanner (GEMINI-TF; Philips). All the patients underwent FDG PET/CT scan, and then FMISO PET/CT scan 1 or 2 days after. A respiratory gating system (Anzai Medical, Co., Ltd.) was attached to the upper abdomen of the patient to measure the respiratory signal. To reconstruct respiratory-gated images, the PET list-mode data were retrospectively binned into 5 phase frames between inspirations according to Anzai respiratory signals. The third phase, which corresponds to expiration, was used for reconstruction. On FDG PET/CT images, SUVmax of the primary tumor was obtained in the transaxial view. FMISO uptake was quantified using SUVmax, a tumor-to-muscle ratio (TMR), and a tumor-to-blood ratio (TBR). Progression-free survival (PFS) was defined as the number of months from the start of treatment until disease progression or death due to any cause or the last follow up time.

Results: Thirty-two NSCLC patients (19 male and 13 females; median age, 83 years) were enrolled in the study and all received SBRT (40Gy/4fr, 23; 48Gy/4fr, 9). When compared between responders and non-responders, significant differences were observed in tumor diameters (median 21mm, range:11-36 vs 28, 21-40, p=0.01), in FMISO SUVmax (1.15, 0.55-2.58 vs 2.21, 1.54-3.34, p<0.01), in TMR (0.83, 0.39-2.26 vs 2.22, 1.25-2.90, p<0.01), in TBR (0.75, 0.41-2.00 vs 1.70, 0.87-2.07, p<0.01), and in FDG SUVmax (6.02, 1.36-16.20 vs 9.73, 6.91-23.30, p<0.01). Age, gender, pathology, and morphology (ground glass opacity vs part solid/solid) did not show the significant difference between 2 groups. Since tumor diameter was significantly correlated with FDG SUVmax (r=0.36, p=0.04), FMISO SUVmax (r=0.49, p<0.01), TMR (r=0.44, p=0.01), and TBR (r=0.36, p=0.04), we analyzed the subgroup whose tumor diameter was longer than 20mm (n=22). All the patients with the tumor smaller than 20mm were in responder group. PFS of different sub-groups divided by FMISO SUVmax (1.89), TMR (1.25) and TBR (1.14), which were obtained from ROC analysis, were significantly different in Kaplan-Meier analysis (Fig). In univariate analysis, FMISO SUVmax (p<0.01), TMR (p<0.01), TBR (p=0.02) and FDG SUVmax (p<0.01) were identified as significant prognostic factors for PFS. Patients were divided into 3 groups according to the threshold of FDG and FMISO; A: FDG negative and FMISO negative (n=8), B: FDG positive and FMISO negative (n=5), C: FDG positive and FMISO positive (n=9). No patients satisfied FDG negative and FMISO positive. No patient of group A underwent tumor recurrence, whereas 2/5 (40%) in group B and 7/9 (78%) in group C underwent recurrence. Kaplan-Meier analysis showed the significant difference between 3 groups (p=0.028) (Fig)

Conclusions: High metabolic activity and tumor hypoxia were significantly related to poor PFS after SBRT. FMISO PET/CT would be useful for further risk stratification of patients in SBRT for early-stage NSCLC, especially in FDG positive patients.