Journal of Thoracic Oncology:
Maximum Standardized Uptake Value on FDG-PET Is a Strong Predictor of Overall and Disease-Free Survival for Non–Small-Cell Lung Cancer Patients after Stereotactic Body Radiotherapy
Takeda, Atsuya MD, PhD*; Sanuki, Naoko MD*; Fujii, Hirofumi MD, PhD†; Yokosuka, Noriko MD‡; Nishimura, Shuichi MD*; Aoki, Yousuke RTT*; Oku, Yohei PhD*; Ozawa, Yukihiko MD, PhD‡; Kunieda, Etsuo MD, PhD§
*Department of Radiology, Ofuna Chuo Hospital, Kamakura, Kanagawa, Japan; †Division of Functional Imaging, Research Center for Innovative Oncology, National Cancer Center Hospital East, Kashiwa, Japan; ‡Department of Radiology, Yuai Clinic, Yokohama, Japan; and §Department of Radiation Oncology, Tokai University School of Medicine, Isehara, Kanagawa, Japan.
Disclosure: Dr. Takeda is funded by Grant-in-Aid for Scientific Research (C) from the Japan Society for the Promotion of Science. Dr. Fujii is funded by Grants-in-Aid for Scientific Research (C) from the Japan Society for the Promotion of Science, Health and Labor Sciences Research Grants for Third Term Comprehensive 10-year Strategy for Cancer Control from the Ministry of Health, Labor and Welfare. The other authors declare no conflict of interest.
Address for correspondence: Hirofumi Fujii, MD, PhD, Division of Functional Imaging, Research Center for Innovative Oncology, National Cancer Center, 6-5-1 Kashiwanoha, Kashiwa 277–8577 Japan. E-mail: firstname.lastname@example.org
Introduction: The maximum standardized uptake value (SUVmax) on 18F-fluorodeoxyglucose positron emission tomography is a predictor for overall survival (OS) in non–small-cell lung cancer (NSCLC) after resection. We investigated the association between SUVmax and outcomes in NSCLC after stereotactic body radiotherapy.
Methods: Between 2005 and 2012, 283 patients with early NSCLC (T1a-2N0M0) were treated with stereotactic body radiotherapy; the total doses were 40 to 60 Gy in five fractions. Patients who underwent staging 18F-fluorodeoxyglucose positron emission tomography scans by a single scanner and were followed up for more than or who died within 6 months were eligible. The optimal threshold SUVmax was calculated for each outcome. Outcomes were analyzed using the Kaplan–Meier method and log-rank test. Prognostic significance was assessed by univariate and multivariate analyses.
Results: One hundred fifty-two patients were eligible. Median follow-up was 25.3 (range, 1.3–77.4) months. Local, regional, and distant recurrences, cancer-specific deaths, and deaths from other reasons occurred in 14, 11, 27, 21, and 31 patients, respectively. The optimal threshold SUVmax for local, regional, and distant recurrences, and disease-free survival (DFS), cancer-specific survival, and OS were 2.47 to 3.64. Outcomes of patients with SUVmax lower than each threshold were significantly better than those with higher SUVmax (all p<0.005): 3-year DFS rates were 93.0% versus 58.3% (p<0.001) and 3-year OS rates were 86.5% versus 42.2% (p<0.001), respectively. By multivariate analysis, higher SUVmax was a significantly worse predictor for DFS (p<0.01) and OS (p=0.04).
Conclusions: SUVmax was a predictor for DFS and OS. A high SUVmax may be considered for intensive treatment to improve outcomes.
For non–small-cell lung cancer (NSCLC), prognosis and therapy have been guided chiefly by the Tumor Node Metastasis staging system. Although stage I NSCLC patients have the best prognosis, their 5-year survival rate is approximately 60%.1 Recently, 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging is widely used to determine Tumor Node Metastasis stage in NSCLC patients and is altering the stage designation and management in as many as 20% to 40% of patients.2 A systematic review of resection in stage I NSCLC patients revealed that increased tumor FDG uptake is associated with worse survival.3 These results suggest that FDG uptake can provide additional information about the biological characteristics of tumors that cannot be obtained by morphological imaging tests such as computed tomography (CT), and that it may be a potential biomarker for identifying stage I NSCLC patients with a high risk of recurrence or death.
Currently, stereotactic body radiation therapy (SBRT) is considered as a treatment option for patients with medically inoperable early-stage NSCLC.4 We previously reported that maximum standardized uptake value (SUVmax) of primary tumors was a predictor for local control in NSCLC after SBRT.5 In this study, herein we retrospectively investigated whether the SUVmax was a predictor for outcomes including disease-free survival (DFS) and overall survival (OS) after SBRT.
PATIENTS AND METHODS
From November 2005 through July 2012, 283 patients with early NSCLCs (T1a-2N0M0) and Eastern Cooperative Oncology Group performance status 0 to 2 were treated with SBRT: the total doses of 40 to 60 Gy in five fractions with radical intent. These patients had been diagnosed with NSCLC based on the following clinical findings: high SUVmax on FDG-PET scan, continuous tumor growth and characteristic findings on CT images and/or increases in tumor markers such as carcinoembryonic antigen, carbohydrate antigen 19-9, sialyl Lewis X-i antigen, squamous cell carcinoma antigen and cytokeratin 19 fragment. These diagnoses were completed after reaching a consensus among radiation oncologists, diagnostic radiologists, thoracic surgeons, and pulmonologists. Reasons for unproven histology included failed pathological studies, increased risk of hemorrhage during biopsy, patients’ refusals, or technical difficulties during biopsy attempt. Among all 283 patients, 235 (83.0%) underwent 18F-FDG-PET scans for staging before treatment. For this study, eligible patients underwent 18F-FDG-PET scans before treatment by a single scanner at Yuai Clinic. Those who were lost to follow-up during the 6 months after treatment were excluded from the present analysis, except for patients who died.
This retrospective study was approved by the ethics committee at our institution (No. 2010-005). Written informed consent was obtained from patients for the staging tests, treatment, and follow-up studies.
FDG-PET and Data Analysis
Each patient underwent FDG-PET before SBRT. After fasting for 6 hours, FDG 3.5 MBq/kg body weight was intravenously injected if the patient’s blood sugar level was lower than 200 mg/dl. Image acquisition was started 60 minutes after the injection by using a single PET/CT combined scanner (Eminence-SOPHIA, Shimadzu, Kyoto, Japan).6 Image emission data from the eyes to the mid-thigh area were continuously acquired over a period of approximately 20 minutes. After attenuation corrections were made for the obtained image data, they were reconstructed using a dynamic row-action expectation maximization algorithm.7 Then, the reconstructed sectional images were evaluated visually and quantitatively by using the SUVmax inside a volume of interest (VOI) placed on the lesions. SUVmax was calculated by: [(maximum activity in VOI)/(volume of VOI)]/[(injected FDG dose)/(patient weight)]. The quality of radiation measurements of the PET/CT scanner was assured by the calibration in accordance with an National Electrical Manufacturers Association (NEMA) NU-2 2001 standard.8
We have previously reported the details about our SBRT technique.9,10 Before 2011, treatment for central and peripheral NSCLC was planned to enclose the planning target volume (PTV) by the 80% isodose-line of the maximum dose with a total dose of 40 Gy and 50 Gy in five fractions, which was equivalent to the prescribed dose. From 2011, it was by the 60% isodose-line with 60 Gy and 50 Gy in five fractions10 and, for cases where the target lesions were located adjacent to a critical organ, such as a main bronchus, pulmonary artery, esophagus, or heart, or extensively adhered to chest wall, the total dose was reduced by 10 Gy. The dose covering 95% of the PTV (D95) was more than or equal to the prescribed dose.9 In our definition of treatment dose, the biologically effective doses assuming α/β ratios of 10 Gy (BED10) for the prescribed doses of 40 Gy, 50 Gy, and 60 Gy in five fractions at the PTV surface were 72 Gy_10, 100 Gy_10, and 132 Gy_10, respectively, and those at the maximum dose points were 100 Gy_10, 141 Gy_10, and 300 Gy_10, respectively.
No adjuvant chemotherapy was performed in any patient.
Our follow-up procedures were previously described in detail.11 In brief, all patients were followed up monthly during the first 6 months. CT scans were performed at 1 and 3 months after SBRT and at 3-month intervals during the first 2 years thereafter. Subsequently, follow-up interviews and CT scans were obtained at 4- to 6-month intervals. In addition, FDG-PET and brain magnetic resonance imaging were performed 1 year after SBRT.
Local recurrence was diagnosed by pathological confirmation or an increase of more than 25% in the cross-sectional tumor size on successive CT scans at least three times over a 6-month period. Regional and distant recurrence was defined as new appearance of mediastinal or hilar lymph node and distant metastasis, respectively. For DFS, only recurrence was counted as an event and death from other reasons was censored.
The distributions of SUVmax in patients with pathologically and clinically diagnosed NSCLC were compared using the Student’s t test. Differences in control and survival rates were compared by using Kaplan–Meier curves and log-rank tests. The predictive performance of SUVmax was assessed by receiver-operating characteristic curves and total area under the curve (AUC). Optimal thresholds were determined by calculating minimum balanced error rates. The 95% confidence interval for sensitivity, specificity, and AUC were calculated. Univariate and multivariate Cox regression analyses were used to determine whether any of the clinical or treatment-related variables were predictors of local control. Univariate factors with p value less than 0.20 were included in the multivariate analysis. For all tests, a p value less than 0.05 was considered statistically significant. Analyses were performed using IBM SPSS Statistics 20.0 (IBM, Inc., Armonk, NY).
Eligible Patients and Those Outcomes
From a total of 283 NSCLC patients treated with SBRT, 152 patients were eligible for this study (Fig. 1), including 90 patients with pathologically proven NSCLC and 62 patients with clinically diagnosed NSCLC. Among patients with clinically diagnosed NSCLC, SUVmaxs were more than 2.5 in 42 patients (68%) and tumor marker levels were elevated in 34 patients (55%). Patient characteristics are shown in Table 1. Median patient age was 79 years (range, 53–90 years). The median follow-up period was 25.3 months (range, 1.3–77.4 months). Three patients died because of causes other than NSCLC within 6 months.
On FDG-PET studies, the median SUVmaxs in primary tumors of pathologically and clinically diagnosed NSCLC were 3.2 (range, 0.7–13.3) and 3.1 (range, 0.7–12.2), respectively; these values were not significantly different (p=0.42). Three-year DFS rates for patients with pathologically and clinically diagnosed NSCLC were 69.5% and 73.8%, respectively; these rates were also not significantly different (p=0.87; Fig. 2). Therefore, we consolidated the data for these patients and analyzed them together.
Local, regional nodal, and distant recurrences occurred in 14, 11, and 27 patients, respectively. There were 21 cause-specific deaths and 31 deaths from other reasons.
18F-FDG-PET/CT SUVmax as Predictors of Outcome
The median SUVmax of the primary lesion in patients with recurrence/death and nonrecurrence/alive, AUC on receiver-operating characteristic curves, the optimal threshold SUVmax, and its sensitivity and specificity for outcomes are shown in Table 2. Patients with SUVmax less than threshold for local, regional nodal, and distant metastasis controls, and for DFS, cancer-specific survival, and OS were significantly better than those with SUVmax more than threshold (p<0.005). The median blood glucose level (mg/dl) was 97 (range, 77–192). Only four patients, including three who remain alive with no recurrence and one who died from distant metastasis, had blood sugar levels exceeding 150 mg/dl. The patient who died was correctly classified under the poor prognosis group.
Figure 3 shows Kaplan–Meier curves for DFS, cancer-specific survival, and OS divided by the most optimal threshold SUVmax, which were 2.47, 2.55, and 2.55, respectively.
Univariate and Multivariate Analysis for Predictors of DFS and OS
The results of univariate and multivariate analyses for DFS and OS are shown in Table 3. The univariate analyses showed that tumor diameter, T stage, and SUVmax were significantly related to DFS, and that body mass index (BMI), tumor diameter, T stage, and SUVmax were significantly related to OS. Body mass index (BMI), tumor diameter, T stage, and SUVmax were significantly related to OS. In multivariate analysis, we excluded tumor diameter because the correlation coefficient (r) between tumor diameter and T stage exceeded 0.9. Multivariate analysis indicated that only SUVmax was significantly associated with DFS. BMI, T stage, pathological confirmation, and SUVmax were significantly related to OS.
A meta-analysis conducted by the European Lung Cancer Working Party identified 13 studies examining FDG uptake and prognosis for patients with stage I–III NSCLC who underwent resection. They found that the hazard of death was twice as great in patients with high FDG uptake compared with those with low FDG uptake (hazard ratio 2.09).12 In addition, another systematic review of patients with stage I NSCLC also suggested that higher FDG uptake was associated with worse DFS and OS.3 Across studies, the median DFS or OS was 70% for patients with higher FDG uptake compared with 88% for patients with lower FDG uptake.3 FDG uptake has the potential to be used as a biomarker for identifying stage I patients who are at increased risk of death or recurrence and therefore could identify candidates for participation in future trials of adjuvant therapy.
For SBRT, only a few reports with relatively small numbers of patients have evaluated FDG uptake as a potential biomarker. The utility of FDG uptake as a biomarker remains controversial. However, two studies positively associated FDG uptake with survival by multivariate analysis: Chang et al.13 reported that SUVmax was the only predictor for OS, with a hazard ratio of 2.15 divided at the median SUVmax, and Clarke et al.14 also reported SUVmax as the only predictor for DFS. Meanwhile, two univariate analysis studies failed to establish a significant association between FDG uptake and survival.15,16
In the present study, we clearly demonstrated that SUVmax was a strong predictor for all outcomes, including control of local, regional nodal, and distant metastasis, DFS, and OS. By multivariate analysis, SUVmax as well as T stage were independent predictors for OS. The two factors seemed to influence cancer-specific survival. Other factors associated with OS included BMI and pathological confirmation. They also seemed to influence death from other causes, because both factors were not predictors of DFS, even by univariate analysis. NSCLC patients often have emphysema as a comorbidity, and low BMI was correlated with short OS in patients with emphysema.17 Patients with clinically diagnosed NSCLC might include benign other disease than NSCLC and have better outcomes. In addition, the pathological diagnosis of ground-glass opacities was not often established although most of the cases were likely to be bronchoalveolar carcinoma. It was reported that their SUVmaxs were as low as a median value of 0.6 and they showed better outcomes.18 and have better outcomes. Therefore, we at first demonstrated that there was no significant difference in distribution of SUVmax (p=0.42) and DFS (p=0.87; Fig. 2) between patients with pathologically and clinically diagnosed NSCLC. However, lack of pathological confirmation was a worse predictor of OS, as was shown in a German multicenter analysis.19 It might indicate patients’ inactive performance status or comorbid disease, because physicians might hesitate to perform an invasive biopsy in such patients.
On the basis of these results, we suggest the use of more intensive treatment for medically inoperable stage I NSCLC. First, to improve local control, dose escalation might be required. A large single-institution series suggested a positive dose-control relationship for SBRT.20 Another single-institution series suggested that the local control rate could be improved by securing the minimum dose for PTV.21 In the German multicenter analysis, multivariate analysis revealed that PTV-encompassing dose was a significant factor for local control and OS. This result indicated that intensified SBRT with the consequence of improved local tumor control transfers into improved OS.19 Second, we should seek optimal treatment to decrease regional node and distant metastasis, which are the main causes of cancer death after SBRT.22 SBRT candidates are medically inoperable, elderly and/or with comorbidities. For such patients, it is doubtful whether systemic chemotherapy would prolong OS. However, for completely resected stage IB NSCLC patients, systemic chemotherapy with uracil-tegafur significantly increased OS rate.23 Although the role of platinum-based adjuvant chemotherapy in patients with stage IB has not been established, further randomized trials for select patients are required using biological markers.24 Recently, combination chemo-radiotherapy was reported to provide a clinically significant benefit over radiotherapy alone in a select group of elderly patients with locally advanced NSCLC.25 Therefore, mild systemic chemotherapy might have a potential role in patients with a high SUVmax and relatively good performance status.
SUVmax is an index that can be obtained by rather simple calculations. Therefore, based on the results of the present study, we can insist that oncologists should more actively use 18F-FDG-PET/CT testing and calculate the SUVmax of lesions in clinical practice of SBRT for early-stage NSCLC. As a result, SUVmax would be a popular imaging biomarker for patients with this disease. However, SUV is not an absolutely reliable quantitative index. For example, it is reported that obtained SUVmaxs depend on the imaging protocols and scanners used,26 uptake time27 and respiratory motion especially in studies about lung cancer.28 Therefore, it is not suitable to directly apply our results to other institutes. To use SUVmax as a reliable biomarker in clinical practice in many institutions, researchers in the field of nuclear medicine are making efforts for the standardization procedures.29 For example, European Association of Nuclear Medicine published a guideline to facilitate the standardization of tumor PET imaging30 and European Association of Nuclear Medicine Research Ltd. started a program to accredit imaging sites that meet these standard requirements. Similar projects are also planned in other areas.31 In the future, the issue of interinstitutional differences would be improved.
This study had several limitations, including a short follow-up period, limited sample size, and its retrospective nature. In this study, 39.5% of tumors were not pathologically confirmed. Reasons for the lack of pathology data included negative biopsy studies and the inability to perform biopsies because of medical comorbidities or patient refusal. Accordingly, pathological nonconfirmation was one of the worse predictors for OS. However, other studies have also reported the results of SBRT after obtaining 31% to 51% pathologic confirmation of malignancy.32,33 In addition, the treatment outcomes of patients diagnosed with NSCLC with no pathological confirmation were almost identical to those of patients with pathological confirmation.34,35
In conclusion, multivariate analysis revealed that the SUVmax of a primary tumor was the only prognostic factor for DFS, and that it was the strongest prognostic factor for OS in addition to BMI, T stage, and pathological confirmation. Further studies are required to ascertain whether SUVmax might have an impact on changing treatment strategies, including dose escalation and adjuvant therapies, and, accordingly, on improving patient outcomes.
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18F-fluorodeoxyglucose positron emission tomography; Stage I non–small-cell lung cancer; Stereotactic body radiotherapy
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