Combination of FDG-PET and FMISO-PET as a treatment strategy for patients undergoing early-stage NSCLC stereotactic radiotherapy

Stereotactic body radiation therapy (SBRT) has been applied to early-stage non-small cell lung cancer (NSCLC) and was shown to provide a good survival benefit for both operable and inoperable NSCLC cases [1, 2]. However, the 3-year overall survival (OS) rates of patients with stage I NSCLC was higher in patients who were treated with a lobectomy (73%) and only 65% in the patients who were treated with SBRT [3]. The optimal treatment for the local recurrence and metastasis of NSCLC is thus a matter of controversy, and it is important to identify the NSCLC patients who are likely to benefit from SBRT when selecting SBRT candidates [4].

¹⁸F-fluorodeoxyglucose (FDG) positron emission tomography (PET) has been widely used in malignant tumor preoperative staging work-ups, especially for lung cancer [5]. The uptake of FDG is a potential biomarker for identifying NSCLC patients who are at high risk of recurrence or death [6‐9]. The maximum of the standardized uptake value (SUVmax) is an easily obtained and robust parameter, but the SUVmax does not fully reflect the tumor size or tumor heterogeneity. In addition, inflammatory changes and necrosis each have an impact on the FDG uptake.

Intratumoral hypoxia generally accelerates radioresistance and chemoresistance, and thus for hypoxic tumors a 2.5- to 3-fold higher radiotherapy dose is necessary to achieve the same cytotoxic effect [10]. ¹⁸F-fluoromisonidazole (FMISO) is a major PET tracer for hypoxia imaging, and several research groups have evaluated the potential role of FMISO as a prognostic tool and for the assessment of the presence of tumor reoxygenation after nonsurgical treatment of NSCLC [11].

Though hypoxia may have a great impact on SBRT outcomes because of the lack of reoxygenation that would occur during conventional radiation therapy, few studies have been conducted to clarify the relationship between the existence of hypoxia and the prognosis of NSCLC patients treated with SBRT. We hypothesized that a combination of the measurement of metabolic activity and the measurement of tumor hypoxia status would be useful to stratify the prognoses of NSCLC patients treated with SBRT. We conducted the present study to determine the prognostic predictive value of combined FDG- and FMISO-PET for NSCLC patients treated with SBRT.

Because a growing number of patients with early-stage NSCLC are being treated with SBRT, it is necessary to evaluate the patients’ treatment response and to predict the outcomes as soon as possible in order to provide the optimal treatment to improve survival. PET is a promising modality for this purpose in NSCLC. In this study, we evaluated the relationships among metabolic activity, the existence of hypoxia, and the prognoses of early-stage NSCLC patients who underwent SBRT. The results of our analyses demonstrated that the activity of glucose metabolism and intracellular hypoxia in the primary tumor of early-stage NSCLC, as measured by FDG and FMISO PET, was associated with a shorter PFS. This finding suggests that since FDG and FMISO uptake are indicators of the poor prognostic potential of NSCLC, patients who are being considered for SBRT should be stratified by their baseline metabolic and hypoxic status.

Our findings also provide clinical evidence of the negative prognostic values of tumor metabolic activity and hypoxia among patients with NSCLC, in agreement with published data [17‐20]. FDG PET has been essential for staging and treatment assessments, and it provides additional information concerning the biological characteristics of tumors. In a recent meta-analysis, patients with high FDG SUVmax values in the primary tumor before SBRT showed short overall survival, poor local control, and frequent distant metastasis [21]. However, there is an overlap of FDG SUV values between “good” and “poor” prognosis groups. In addition, the FDG uptake and/or the SUV may fluctuate for multiple reasons; for example, the patient's blood glucose level, fasting quality, FDG excretion quantity, lean/fat mass difference, and residual respiratory motion artifact. It is difficult to select a treatment strategy based on the patient's FDG SUV in daily clinical practice. In our present investigation, the FDG uptake was a significant predictor of short PFS in all patients but was not significant in the patients whose tumor was > 2 cm. This finding indicated that FDG PET may not be able to predict the prognosis well in patients with large tumors.

However, although FMISO has slow pharmacokinetics and must be evaluated 3–4 hr after its administration, FMISO PET requires no preparation and provides a relatively robust evaluation [22]. Cherk et al. prospectively studied 17 NSCLC patients who underwent both FMISO PET and FDG PET, and they reported that the FMISO uptake showed no correlation with the FDG uptake (r = 0.26) [23]. Another study of eight NSCLC patients treated with a combination of chemotherapy and/or radiation therapy of 50.0 Gy in 2.0-Gy fractions who underwent FDG PET and FMISO PET scans indicated that a decrease in uptake after treatment was associated with favorable outcome, and a high initial FMISO uptake was a poor prognostic indicator and was not associated with the treatment response [24].

In the largest series of patients with NSCLC in a multicenter and prospective study to date, Vera et al. demonstrated that the probability of disease-free survival was significantly lower in their FMISO-positive patients, regardless of the radiotherapy dose (i.e., whether 66 Gy or more) [25]. We also observed herein that the FMISO uptake was a significant predictor of short PFS, (in patients with tumors > 2 cm). As patients with more hypoxic tumors may achieve only a treatment failure, the hypoxic status of individual tumors should be considered when designing radiation therapy, especially in tumors > 2 cm and those with a high FDG uptake.

Among our present NSCLC patients, those with pattern C (high FDG and high FMISO) had the poorest prognosis. Since FDG uptake has been correlated with the tumor growth rate, the proliferation capacity, and aggressiveness [26], it is not surprising that a higher FDG uptake reflected biologic aggressiveness and poor prognosis in those patients [26]. Similarly, in our present study, higher FDG SUVmax values (18 of the 32 patients, 56.3%) were significantly associated with poor PFS. In addition, a higher FMISO SUVmax value (shown by 10 of the 32 patients, 31.3%) was also an important predictor of the response to SBRT. Fifty percent (9 of 18) of our patients who showed high FDG were recurrent, and 70% (7/10) of the patients who showed a high FMISO SUVmax were recurrent.

In light of the increasing use of SBRT for early-stage NSCLC, a landmark for adjuvant decision-making is needed to identify alternative predictive biomarkers that can be used to stratify patients by their risk of recurrence at a distant site. Hypoxic cancer cells are radioresistant, and it was reported that in nasopharyngeal carcinoma the FMISO uptake in recurrent regions was significantly higher than that in non-recurrent regions [27]. Among our patients, local failure and pleural dissemination were seen in only one patient (3.1%) respectively, whereas lymph node metastasis and distant metastases were seen in five and four patients (15.6% and 12.5%), respectively. Lymph node and distant metastases were not detected in the pretreatment diagnostic imaging. Adjuvant chemotherapy was demonstrated to reduce the distant relapse in surgical resection [28] and SBRT [29, 30]. We speculate that micrometastasis may have already occurred before those patients’ SBRT, even though imaging modalities cannot detect it. Since hypoxia is a potent microenvironmental factor that promotes metastatic progression [31], patients with hypoxic NSCLC might more frequently have micrometastasis.

Based on our findings, FMISO PET may have a potential role as a biomarker for identifying patients who are at a higher risk of recurrence or death. It may also be able to use FMISO PET to differentiate candidates for future trials of additional systemic therapy such as chemotherapy or an immune-checkpoint inhibitor.

Our study’s prospective nature, investigation of a standard hypoxia radiotracer, and homogenous cohort are its major strengths. The data we obtained could be the basis of the relationship between hypoxia and SBRT in NSCLC. The major limitations of our study were the limited sample size (n = 32), the single-center design, and the lack of long follow-up and overall survival data. We did not evaluate the optimal thresholds of imaging hypoxia or the patients' outcomes. The number of clinical studies related to the treatment effects of chemoradiotherapy and hypoxia is still very limited. Although Li et al. explored representative hypoxia parameters shown by FMISO PET that could be used to predict the treatment response and prognosis of patients treated with chemoradiotherapy [32], larger and multicenter studies should be designed to test our present findings and to optimize the hypoxia thresholds in NSCLC patients.

Pretherapy metabolic activity and the hypoxic state in patients with early-stage NSCLC are a strong predictor for recurrence after SBRT. In particular, for large-size tumors, FDG did not show good prognostic power, but FMISO did. The combination of FDG PET and FMISO PET can identify patients with a baseline risk of early recurrence and whether additional therapy should be performed to improve survival. Further prospective studies are warranted to optimize the PET protocol and the thresholds of FDG and FMISO uptake in multicenter studies.