Objective
To assess the prognostic value of metabolic tumor burden as measured with metabolic tumor volume (MTV) and total lesion glycolysis (TLG) on 2-deoxy-2-( 18 F)fluoro-D-glucose ( 18 F-FDG) positron emission tomography (PET)/computed tomography (CT), independent of current Union Internacional Contra la Cancrum/American Joint Committee on Cancer tumor, node, and metastasis (TNM) stage; in comparison with that of standardized uptake value (SUV) in surgical patients with non–small-cell lung cancer (NSCLC).
Material and Methods
This study retrospectively reviewed 104 consecutive surgical patients (47 males, 57 females, median age at PET/CT scan of 67.92 years) with diagnosed stage I to IV NSCLC who had baseline 18 F-FDG PET/CT scans. The 18 F-FDG PET/CT scans were performed in accordance with National Cancer Institute guidelines. The MTV of tumors in the whole body (MTV WB ), TLG of tumors in the whole body (TLG WB ), the maximum standardized uptake value of tumors in the whole body (SUV maxWB ) as well as the mean standardized uptake value of tumor in the whole body (SUV meanWB ) were measured. The median follow-up among 67 survivors was 42.07 months from the PET/CT (range 2.82–80.95 months). Statistical methods included Kaplan-Meier curves, Cox regression, and C-statistics. The interobserver variability of SUV maxWB , SUV meanWB , MTV WB , and TLG WB between two observers was analyzed using concordance correlation coefficients (CCCs).
Results
The interobserver variability of SUV maxWB , SUV meanWB , MTV WB and TLG WB was very low with CCCs greater than 0.882. There was a statistically significant association of stage with overall survival (OS). The hazard ratio (HR) of stage III and stage IV as compared with stage I was 3.60 ( P = .001) and 4.00 ( P = .013), respectively. The MTV WB was significantly associated with OS with a HR for 1-unit increase of ln(MTV WB ) of 1.40/1.32 ( P = .004/.039), before/after adjusting for stage and other prognostic factors including chemoradiation therapy, and surgical procedure, respectively. TLG WB had a statistically significant association with OS before and after adjusting for stage and the other prognostic factors. The HR for 1-unit increase in ln(TLG WB ) was 1.26 ( P = .011) and 1.25 ( P = .031), before and after the adjustment, respectively. Subjects with conditions that led to pneumonectomy (HR = 2.82, P = .035) or segmental resection (HR = 3.44, P = .044) had significantly worse survival than those needing lobectomy. There was no statistically significant association between OS and age, gender, tumor histology, ln(SUV maxWB ), and ln(SUV meanWB ) (all P > .05). There were 37 deaths during follow-up.
Conclusion
Baseline whole-body metabolic tumor burden as measured with MTV WB and TLG WB on FDG PET is a prognostic measure independent of clinical stage and other prognostic factors including chemoradiation therapy and surgical procedure with low interobserver variability and may be used to further risk stratify surgical patients with NSCLC. This study also suggests that MTV and TLG are better prognostic measures than SUV max and SUV mean . These results will need to be validated in larger cohorts in a prospective study.
Lung cancer is the most common cause of cancer death in the world , the second most common cancer in both men and women, and the number one cause of cancer-related deaths in the United States. Non–small-cell lung cancer (NSCLC) comprises 80%–85% of all lung cancer cases . The treatment and prognosis of NSCLC depend mainly on disease stage as defined by the Union Internacional Contra la Cancrum (UICC)/American Joint Committee on Cancer (AJCC) . The stage based on the evaluation of the T, N, and M components and the assignment to a stage grouping (I to IV) is the single most prognostic factor in predicting the outcomes of both surgical and nonsurgical patients with NSCLC . A retrospective study from the Netherlands that examined outcomes of 2361 patients who underwent surgery for resectable NSCLC from 1970 to 1992 found that the 5-year survival rate ranges from 19% in stage IIIA to 63% in stage IA . In a multicenter North American clinical trial , involving 458 patients with unresectable NSCLC cancers, but without metastases or significant weight loss, the patients were randomized to three groups: standard once-daily radiation therapy alone; chemotherapy, followed by standard radiation; and hyperfractionated radiation. Five-year survival rates were only 5%, 8%, and 6% in these three groups, respectively. These two studies highlight the dramatic difference in survival between surgical and nonsurgical patients with NSCLC.
Recently several studies demonstrated that metabolic tumor burden as measured with metabolic tumor volume (MTV) or total lesion glycolysis (TLG) is a prognostic marker in nonsurgical patients with NSCLC independent of TNM tumor stage . However, none of the studies specifically studied its prognostic value in the surgical patients. Lee et al was the first who found that the baseline whole body MTV (MTV WB ) measured semiautomatically is a statistically significant prognostic index and better than SUV max and SUV mean in the prediction of patient outcome in 19 lung cancer patients treated with different modalities . In their recent study, they expanded to a cohort of 61 patients with NSCLC treated with different modalities and confirmed the significant association of high MTV WB with decreased overall and progression-free survival in patients who received definitive therapy . In another recent study in 120 patients treated nonsurgically with advanced NSCLC by Yan et al, MTV of the primary tumor was found to be an important independent prognostic factor of survival and better than the SUV max in this regard. More recent studies showed that baseline whole-body metabolic tumor burden as measured with MTV and TLG on positron emission tomography (PET) is a prognostic measure independent of clinical stage in nonsurgical patients and in homogeneous stage IV NSCLC . However, based on our extensive literature search, there was no report in the literature about the prognostic value of the MTV and TLG in surgical patients with NSCLC independent of the clinical TNM stage.
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Materials and methods
Patient Recruitment
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Imaging Protocols
PET/CT imaging
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Measurement of tumor volume on PET/CT
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Statistical Analysis
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Results
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Table 1
Patient Characteristics and Overall Survival Based on Stage, Gender, Age, Tumor Histology, Treatment, and PET/CT Measurements in 104 Surgical Patients with Non–small-cell Lung Cancer
Mean (SD) Survival Rate 1 year (%) 3 years (%) 5 years (%) Overall n = 104 92.13 74.10 58.32 Stage I, n = 66 96.87 82.08 66.92 II, n = 18 88.89 82.54 74.29 III, n = 14 78.57 39.29 20.95 IV, n = 6 83.33 41.67 20.83 Gender Female, n = 57 92.85 79.37 68.88 Male, n = 47 91.20 67.71 48.00 Age at PET scan (y) 67.36 (10.08) ≤67.92 (median), n = 52 88.30 80.13 67.37 >67.92, n = 52 96.08 67.76 47.39 Histology Adeno, n = 52 90.15 77.70 58.05 Squamous, n = 32 100.00 76.52 57.77 Large, n = 8 100.00 83.33 83.33 Others, n = 12 74.07 42.33 42.33 Chemoradiation None, n = 59 93.06 76.61 59.27 Chemo, n = 31 93.21 82.13 76.66 RT, n = 3 66.67 33.33 N/A Chemo+RT, n = 11 90.91 45.45 17.05 Surgery Lobectomy, n = 82 95.08 78.05 62.85 Pneum, n = 9 75.00 45.00 22.50 Segmental, n = 4 75.00 25.00 25.00 Wedge, n = 9 87.50 87.50 65.63SUV__maxWB 7.57 (5.79) ≤11.59, n = 80 96.07 79.55 63.34 >11.59, n = 24 79.17 55.88 41.91SUV__meanWB 3.30 (1.85) ≤2.14, n = 33 100.00 87.14 70.76 >2.14, n = 71 88.42 67.71 52.06MTV__WB 49.72 (143.33) ≤37.34, n = 78 96.05 82.14 67.26 >37.34, n = 26 80.42 48.74 31.59TLG__WB 208.96 (493.90) ≤407.48, n = 90 96.57 79.58 64.74 >407.48, n = 14 62.86 35.92 11.97
Adeno, adenocarcinoma; chemo, chemotherapy; chemo+RT, chemoradiation therapy; histology, tumor histology; large, large cell carcinoma; MTV, metabolic tumor volume; MTV WB , MTV of tumors in the whole body; none, no chemoradiation; pneum, pneumonectomy; RT, radiation therapy; SD, standard deviation; segmental, segmental resection; squamous, squamous cell carcinoma; others, other tumor histology; SUV max , maximum standardized uptake value; SUV maxWB , SUV max of tumors in the whole body; SUV mean , mean standardized uptake value; SUV meanWB , SUV mean of tumors in the whole body; TLG, total lesion glycolysis; TLG WB , TLG of tumors in the whole body; wedge, wedge resection; ≤, equal or less than a cutoff point (defined based on receiver operating characteristic curve analysis unless otherwise noted); >, greater than the cutoff point.
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Table 2
Association of Overall Survival (OS) with Stage, Gender, Age, Tumor Histology, Treatment, and PET/CT Measurements in 104 Surgical Patients with Non–small-cell Lung Cancer
Univariate Analysis Multivariate Analysis HR (95% CI)P Value HR ∗ (95% CI)P Value ∗ C-statistic Stage C-statistic = 0.59I Reference_II_ 1.04 (0.38–2.79) .946 III 3.60 (1.66–7.83) .001 IV 4.00 (1.34–11.90) .013 Gender Female Reference Male 1.62 (0.85–3.11) .146 Age 1.03 (0.99–1.06) .163 Histology Adeno Reference Squamous 0.89 (0.42–1.88) .752 Large 0.31 (0.04–2.33) .256 Others 2.06 (0.85–4.99) .109 Chemoradiation None Reference Chemo 0.55 (0.23–1.31) .177 RT 4.93 (1.45–16.80) .011 Chemo+RT 2.65 (1.11–6.30) .027 Surgery Lobectomy Reference Pneum 2.82 (1.08–7.39) .035 Segmental 3.44 (1.03–11.48) .044 Wedge 1.12 (0.34–3.72) .856 SUV max C-statistic = 0.58ln(SUV__maxWB__) 1.36 (0.93–1.99) .111 1.45 (0.91–2.30) 0.120 0.69 SUV mean C-statistic=0.57ln(SUV__meanWB__) 1.43 (0.87–2.35) .160 1.73 (0.91–3.29) 0.094 0.70 MTV C-statistic = 0.63ln(MTV__WB__) 1.40 (1.11–1.76) .004 1.32 (1.01–1.72) 0.039 0.69 TLG C-statistic = 0.63ln(TLG__WB__) 1.26 (1.05–1.50) .011 1.25 (1.02–1.54) 0.031 0.70
CI, confidence interval; HR, hazard ratio; C-statistic, Gönen and Heller’s K concordance measure; ln, natural log; other abbreviations are as in Table 1 .
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Table 3
Association of Overall Survival (OS) with Stage, Gender, Age, and PET/CT Measurements in 59 Surgical Patients with Non–small cell Lung Cancer Treated with Surgery Only
Univariate Analysis Multivariate Analysis HR (95% CI)P Value HR ∗ (95% CI)P Value ∗ C-statistic Stage C-statistic= 0.57I+II, n = 52 Reference_III+_ IV, n =7 5.50 (2.04–14.82) .001 Gender Female, n = 35 Reference Male, n = 24 1.67 (0.69–4.04) .253 Age 1.01 (0.96–1.06) .657 SUV max ln(SUV__maxWB__) 1.63 (0.98–2.71) .061 1.54 (0.90–2.64) .115 0.66 SUV mean ln(SUV__meanWB__) 1.92 (0.96–3.85) .064 1.95 (0.91–4.17) .085 0.67 MTV_ln(MTV__WB__)_ 1.65 (1.20–2.28) .002 1.47 (1.04–2.08) .031 0.67 TLG_ln(TLG__WB__)_ 1.43 (1.12–1.84) .005 1.34 (1.03–1.73) .030 0.68
CI, confidence interval; HR, hazard ratio; C-statistic, Gönen and Heller’s K concordance measure; ln, natural log; other abbreviations are as in Table 1 .
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Discussion
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Conclusion
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Acknowledgments
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