Abstract
Background
Data from clinical trials suggest that changes in the glucose avidity of the primary site of lung cancer during induction therapy, measured by changes in 18F-FDG PET, correlate with tumor response. Very little information about the utility of changes in PET imaging of involved lymph nodes during induction chemotherapy is available. The utility of PET imaging of either the primary site or nodal metastases, obtained during routine clinical care outside of a clinical trial setting, to predict response has also not been examined.
Methods
A retrospective review of all surgical patients with non-small cell lung cancer at a single institution imaged between 2000 and 2006 with 18F-FDG PET before and/or after induction therapy was performed.
Results
An increase in standardized uptake value (SUV) in the primary site of disease during induction therapy was associated with reduced overall survival after resection. Neither pretreatment SUV nor percentage change in the primary site was associated with overall survival after resection. A decrease in SUV >60% in the involved N2 mediastinal nodes was the best predictor of overall survival, better than changes seen in the primary site of disease.
Conclusions
An increase in glucose avidity of non-small cell lung cancers during induction therapy was associated with a worse prognosis compared to stable or any degree of decrease in SUV. Changes in the glucose avidity of mediastinal nodal metastases may be a stronger predictor of survival than changes in the primary site of disease.
Keywords: PET, Lung Cancer, Lymph Nodes
Introduction
Non-small cell lung cancer (NSCLC) that is clinical stage IIIA (cIIIA) due to N2 nodal involvement is often treated with induction chemotherapy.[1, 2] Current clinical measures of tumor response to induction therapy correlate poorly with pathologic response and long-term outcomes.[3] 18F-fluorodeoxyglucose positron emission tomography (PET)–measured glucose uptake at the primary site of an untreated lung cancer and in locoregional lymph nodes is prognostic.[4-10] Limited evidence from clinical trials suggests that the PET-measured response at the primary site of disease, following induction therapy, can be used to predict survival following resection.[11] It is not known whether the PET-measured response in involved lymph nodes can be used to predict prognosis. Routine clinical practice will commonly be quite different from a research setting. PET imaging will often be obtained on different machines, or with varying FDG administration protocols, or at differing time points during treatment. Whether changes in PET imaging obtained during routine clinical care can be used to estimate response has not been examined.
To evaluate the predictive value of changes in PET-measured maximal standardized uptake values (SUVmax) obtained during routine clinical care, both at the primary site of an NSCLC and in lymph nodes, we reviewed our experience with a large number of patients undergoing induction chemotherapy followed by resection. To reflect the realities of clinical practice outside of a research setting, data were collected from any patient who had undergone PET imaging before or after or both before and after treatment, at any institutions, and at any interval during the treatment process.
Patients and Methods
Permission to perform this retrospective study was obtained from the MSKCC Institutional Review Board. Patients who had undergone induction therapy (chemotherapy, radiation therapy, or chemoradiotherapy), followed by resection for NSCLC, were identified from the prospectively maintained. Thoracic Service Surgical Database. Superior sulcus tumors, synchronous primary disease, or receipt of TKI therapy alone as induction therapy were exclusion criteria. Additional clinical information was obtained by review of the medical record. Resections that were both grossly and microscopically complete were classified as R0, microscopically incomplete resections as R1, and grossly incomplete resections as R2. Overall survival (OS) was defined as the time from the date of surgery to the date of death or the last follow-up.
The SUVmax of the primary site of disease was obtained from the PET report. SUVmax were categorized as preinduction (preSUV) or post-induction (postSUV). The absolute change and percentage change in SUVmax between pre- and postinduction PET studies were calculated. The median cutoff points for preSUV and postSUV, quartile cutoff points for percentage change in SUVmax, and 0 as the cutoff point for absolute change in SUVmax (i.e., a binary outcome of increase in SUVmax versus no change or reduction in SUVmax) were evaluated as predictors of survival.
The log-rank test was used to examine the univariate association between variables and OS. The variables included were age, sex, pretreatment clinical stage, change in overall clinical stage after induction therapy, preSUV, postSUV, and absolute and percentage change in SUVmax. Multivariable Cox regression analysis was used to evaluate the effect of absolute change in SUVmax during treatment on OS, with factors knowable preoperatively and those found on univariate analysis to be associated with OS controlled for.
Data were collected on patients with biopsy-proven N2 nodal metastases at either diagnosis or resection. The SUVmax of the primary tumor and the N2 nodes were recorded, and the percentage change after induction therapy was calculated. The associations between OS and age, sex, histologic profile, metabolic response, type of resection, tumor diameter, and pN2 status after induction therapy were assessed using univariate and multivariate logistic regression models.
Results
From January 2000 to December 2006, 629 consecutive patients with NSCLC underwent induction therapy followed by surgical resection; 84 were excluded (69 with superior sulcus tumors, 11 with synchronous bilateral disease, 1 with synchronous small cell/NSCLC, and 3 treated with tyrosine kinase inhibitor alone), leaving 545 for analysis. Demographics and clinical characteristics are summarized in Tables 1A and 1B.
Table 1A.
Demographic characteristics of the study patients (N=545)
| Characteristic | Mean (SD) |
|---|---|
| Age (years) | 63 (10) |
| Sex (male) | 250 (45.9) |
| Former or current smoker | 489 (89.7) |
| Resection | |
| Pneumonectomy | 69 (12.7) |
| Lobectomy | 387 (71.0) |
| Sublobar resection | 39 (9.2) |
| Exploration alone (R2 resection) | 50 (9.2) |
| Morbidity | |
| Grade >4 | 25 (4.6) |
| Perioperative mortality | 10 (1.8) |
| Chemotherapy regimen | |
| Alternative nondoublet | 111 (20.4) |
| Platinum and other doublet | 104 (19.1) |
| Platinum and taxane | 303 (55.7) |
| Platinum and vinca alkaloid (including MVP) | 23 (4.2) |
| Unknown | 4 (0.7) |
| Radiation therapy | |
| Yes | 95 (17.5) |
| No | 450 (82.6) |
| Radiation dose | |
| ≤45 Gy | 33 (34.7) |
| >45 Gy | 43 (45.3) |
| Unknown | 19 (20.0) |
Table 1B.
Demographic characteristics (N=545)
| Characteristic | Patients, no. (%) | Median OS | 5-year OS, % |
|---|---|---|---|
| Initial clinical stage | |||
| IA* | 14 (2.6) | NA | 70 |
| IB | 67 (12.3) | 67.3 | 52 |
| IIA | 8 (1.5) | 27.9 | 17 |
| IIB | 84 (15.4) | 37.1 | 36 |
| IIIA | 303 (55.3) | 28.9 | 29 |
| IIIB | 49 (9.0) | 28.9 | 33 |
| IV | 20 (3.7) | 29.4 | 28 |
| Change in clinical stage | |||
| Downstaged | 146 (26.8) | 39 | |
| Stable | 370 (67.9) | 32 | |
| Upstaged | 29 (5.3) | 25 | |
| Pathologic stage | |||
| 0 | 35 (6.4) | 77.1 | 66 |
| IA | 69 (12.7) | 60.7 | 52 |
| IB | 87 (16.0) | 67.3 | 52 |
| IIA | 23 (4.2) | 76.1 | 56 |
| IIB | 61 (11.2) | 30.5 | 40 |
| IIIA | 182 (33.4) | 26.5 | 19 |
| IIIB | 47 (8.6) | 11.4 | 11 |
| IV | 41 (7.5) | 21.4 | 11 |
15/545 patients or 2.8% with clinical stage IA disease were treated with preoperative chemotherapy for reasons, including: synchronous/metachronous tumor of different origin; multifocal lung cancer; incorrect pretreatment staging at outside hospital)
The majority of patients had cIIB or cIIIA disease (387/545; 72.1%). Of 292 patients with cIIIA (cN2) disease, 215 (73.6%) had histologic confirmation of nodal status either before induction therapy (156/292; 53.4%) or after resection (59/292; 20.2%).
Ninety-five patients (17.4%) received external beam radiotherapy. The median radiation dose was 45 Gy (range, 15–70 Gy); radiation was administered concurrently to 80 patients (84.2%), sequentially to 7 (7.3%), and according to an unknown schedule in 8 (8.4%). PET scans were performed before induction therapy in 73.9% of patients (403/545), after induction therapy in 51.4% (280/545), and both before and after in 42% (229/545). The SUVmax for these studies are summarized in Table 2. No significant difference in SUV distribution or survival was observed between patients with complete (both pre– and post–induction therapy) PET data and those who had only one scan performed (i.e., either only a pretreatment scan or only a posttreatment scan). Forty-four percent of scans (299/683) were performed at Memorial Hospital. Sixty-one of 545 patients (11.2%) had both pre– and post–induction therapy scans performed at Memorial Hospital.
Table 2.
Details of PET staging and restaging
| Variable | No. | Mean | SD | Minimum | Lower Quartile |
Median | Upper Quartile |
Maximum |
|---|---|---|---|---|---|---|---|---|
| Initial SUV primary | 403 | 10.9 | 6.9 | 0.8 | 6.5 | 9.8 | 14.8 | 43.0 |
| Postinduction SUV primary |
280 | 6.2 | 5.6 | 0.8 | 2.3 | 4.8 | 8.4 | 41.0 |
| Difference of SUV | 229 | −4.1 | 6.6 | −30.8 | −7.0 | −3.1 | −0.1 | 18.9 |
| % change of SUV | 229 | −7.8 | 136.9 | −96.4 | −67.0 | −35.9 | −1.5 | 987.5 |
R0 resections were performed in 83.3% of patients (454/545). A complete pathological response was observed in 6.4% of patients (35/545).
The median follow-up for the 545 patients was 24.7 months (range, 0.1–98.2 months). Censored patients had an adjusted median follow-up of 46.7 months. Median OS was 30.5 months (95% confidence interval [CI], 28.2–35.9 months). No significant difference in distribution of SUV data or survival was observed between patients with both pre- and post-therapy scan and those with only one imaging study.
On univariate analysis, age (P<.001), initial clinical stage (P=0.006) (Figure 1), final pathologic stage (P<.001) (Figure 2), postSUV >4.8 (group median) (P=0.015) (Figure 3), and D>0 (i.e., an increase in SUVmax after induction therapy) (P=0.009) (Figure 4) were associated with OS, whereas sex and down-staging were not. On multivariate analysis with age and initial clinical stage controlled for, neither binary preSUV (P=0.088) nor quartered percentage change (P=0.084) was associated with OS. Controlling for age (P=0.017), initial clinical stage (P=0.050), and preSUV (P=0.099), an increase in postSUV was associated with worse survival (hazard ratio [HR], 2.04; 95% CI, 1.32–3.16; P=0.001) (Table 3). Patients with a preSUV ≤9.8 (group median) and a stable or decreased SUVmax after induction therapy (D≤0) had a 2-year survival of 72% (95% CI, 61%–80%) (Figure 5).
Figure 1.
Overall survival by clinical stage before any treatment of NSCLC
Figure 2.
Overall survival by pathologic stage after induction therapy and resection of NSCLC
Figure 3.
Overall survival by postinduction therapy SUVmax in the primary site of NSCLC
Figure 4.
Overall survival by difference in SUVmax (D) in the primary site of NSCLC between pre- and post–induction therapy PET (D<0 is stable/decreased SUVmax, D>0 is increased)
Table 3.
Multivariable Cox regression
| Median OS, mos. |
P, log- rank test |
Multivariable Cox regression |
||||
|---|---|---|---|---|---|---|
| Variable | No. | No. | HR | P | ||
| Age | <0.001 | 0.017 | ||||
| ≤63 | 256 | 41.8 | 101 | 1 | ||
| >63 | 289 | 26.5 | 128 | 1.60 | ||
| Initial clinical stage | 0.006 | 0.050 | ||||
| I | 81 | 67.3 | 28 | 1 | ||
| II | 92 | 32.4 | 29 | 3.14 | ||
| III | 352 | 28.9 | 159 | 2.48 | ||
| IV | 20 | 29.4 | 13 | 2.26 | ||
| Pre-induction SUVmax | 0.253 | 0.099 | ||||
| ≤9.8 | 202 | 39.8 | 125 | 1 | ||
| >9.8 | 201 | 29.8 | 104 | 1.38 | ||
| Difference between pre- and postinduction SUVmax |
0.009 | 0.001 | ||||
| Stable or reduced | 186 | 39.9 | 186 | 1 | ||
| Increased | 43 | 23.0 | 43 | 2.04 | ||
| Post-induction SUVmax | ||||||
| <4.8 | 143 | 39.9 | 0.015 | 115 | NS* | |
| >4.8 | 137 | 114 | ||||
| % change in SUVmax | ||||||
| Q1 | 57 | 43.3 | 0.112 | 57 | NS* | |
| Q2 | 57 | 27.2 | 57 | |||
| Q3 | 58 | 46.5 | 58 | |||
| Q4 | 57 | 27.1 | 57 | |||
Postinduction SUV and % change were fit separately in a Cox regression model controlling for age, clinical stage, and pre-induction SUV.
Figure 5.
Overall survival stratified by combination of pretreatment SUVmax and difference in SUVmax (D) in the primary site of NSCLC between pre- and post–induction therapy PET (D<0 is stable/decreased SUVmax, D>0 is increased)
An analysis that excluded patients who received radiation therapy as part of induction therapy did not substantially alter the magnitude or significance of the association between increase in postSUV and survival (Tables 4A and 4B).
Table 4A.
Characteristics of 450 patients treated with chemotherapy without radiation
| Median OS, mos. |
P, log- rank test |
Multivariable Cox Regression |
||||
|---|---|---|---|---|---|---|
| Variable | No. | No. | HR | P | ||
| Age | ||||||
| ≤63 | 225 | 38.8 | 0.013 | 92 | 1 | 0.043 |
| >63 | 225 | 27.5 | 97 | 1.52 | ||
| Initial clinical stage | ||||||
| I | 71 | 67.3 | 0.022 | 25 | 1 | 0.075 |
| II | 78 | 28.5 | 27 | 2.93 | ||
| III | 282 | 30.4 | 125 | 2.43 | ||
| IV | 19 | 29.4 | 12 | 2.24 | ||
| Pre-induction SUVmax | ||||||
| ≤9.9 | 171 | 39.8 | 0.346 | 104 | 1 | 0.221 |
| >9.9 | 172 | 30.2 | 85 | 1.29 | ||
| Difference between pre- and post- induction SUVmax |
||||||
| Stable/reduced | 152 | 39.8 | 0.007 | 152 | 1 | 0.003 |
| Increased | 37 | 21.7 | 37 | 2.01 | ||
| Post-induction SUVmax |
||||||
| ≤4.8 | 114 | 35.9 | 0.054 | 93 | 0.133* | |
| >4.8 | 112 | 27.6 | 96 | |||
| % change in SUVmax | ||||||
| Q1 | 47 | 39.9 | 0.030 | 47 | 0.338* | |
| Q2 | 47 | 27.0 | 47 | |||
| Q3 | 47 | 52.4 | 47 | |||
| Q4 | 48 | 23.0 | 48 | |||
Postinduction SUV and % change were fit separately in a Cox regression controlling for age, clinical stage and pre-induction SUV.
Table 4B.
Characteristics of 450 patients treated with induction chemotherapy without radiation
| Variable | N | Mean | SD | Minimum | Lower Quartile |
Median | Upper Quartile |
Maximum |
|---|---|---|---|---|---|---|---|---|
| Initial SUV primary | 343 | 10.9 | 6.7 | 0.8 | 6.3 | 9.9 | 14.8 | 43.0 |
| Postinduction SUV primary |
226 | 6.4 | 6.0 | 0.8 | 2.2 | 4.8 | 8.5 | 41.0 |
| Difference of SUV | 189 | −3.8 | 6.6 | −30.8 | −6.6 | −2.8 | 0.0 | 18.9 |
| % change in SUV | 189 | −11.6 | 117.6 | −96.4 | −64.8 | −33.2 | 0.0 | 775.0 |
We analyzed changes in the PET-measured response in involved N2 lymph nodes during induction therapy. From January 2000 to December 2006, 91 eligible patients were identified (Table 5), of whom 76 had complete data available. On univariate analysis (Table 6), PET response in the N2 nodes was associated with improved median OS at the following thresholds of percentage reduction: ≥0% (31 months [range, 22–48 months] vs 15 months [range, 6–NA]; P=0.048) (Figure 6) and >60% (34 months [range, 22–NA] vs 20 months [range, 13–34 months]; P=0.013) (Figure 7). On multivariate analysis, pathologic evidence of persistent N2 disease (HR, 2.41 [range, 1.07–4.28]; P=0.032] and percentage reduction in N2 nodes of <60% (HR, 1.82 [range, 1.06–3.03]; P=0.028) were associated with reduced OS (Table 7). On multivariate analysis, when considering only variables known preoperatively (i.e. excluding persistent nodal metastatic disease found at surgery), percent reduction in N2 nodes >0% (i.e. an increase in SUV during induction therapy) [HR = 2.38 (1.02-5.56) P = 0.044] and percent reduction in N2 nodes >60% [HR 0.53 (0.30 – 0.93) P = 0.028] were associated with OS (Table 8).
Table 5.
Survival summary of patients with involved N2 lymph nodes before treatment
| Variable | No. | Median survival (95% CI), mos. |
5-year survival (95% CI), % |
P, log-rank test |
|---|---|---|---|---|
| Histologic profile | 0.649 | |||
| Adenocarcinoma | 63 | 29 (19–39) | 23 (14–37) | |
| Squamous | 14 | 55 (13–NA) | 26 (6–100) | |
| Others | 14 | 30 (18–NA) | NA (NA–NA) | |
| Sex | 0.919 | |||
| Female | 49 | 30 (18–40) | 26 (16–43) | |
| Male | 42 | 33 (19–48) | 22 (10–45) | |
| Pathological N2 status after induction therapy |
0.081 | |||
| Neg | 25 | 40 (20–NA) | 46 (29–73) | |
| Pos | 64 | 29 (18–34) | 17 (9–32) | |
| Resection | 0.919 | |||
| Lesser resections | 83 | 30 (19–39) | 25 (17–38) | |
| Pneumonectomy | 8 | 40 (18–NA) | NA (NA–NA) | |
| Age | 0.185 | |||
| <65 | 46 | 31 (20–NA) | 33 (21–52) | |
| ≥65 | 45 | 24 (18–43) | 17 (8–36) | |
| Tumor diameter | 78 | 30 (19–34) | 28 (17–39) | 0.760 |
Table 6.
Overall survival by thresholds of percent change of PET SUV of N2 nodes
| N2 nodes response | No. | Median survival (95% CI), mos. |
5-year survival (95% CI), % |
P, log-rank test |
|---|---|---|---|---|
| Change in N2 SUV >0%* | 0.048 | |||
| No | 74 | 31 (22–48) | 27 (17–40) | |
| Yes | 8 | 15 (6–NA) | NA (NA–NA) | |
| 60% decrease in N2 SUV | 0.013 | |||
| No | 36 | 20 (13–34) | 14 (6–37) | |
| Yes | 46 | 34 (22–NA) | 32 (20–50) |
SUV >0% means SUV increased during treatment
Figure 6.
Overall survival by difference in SUVmax (D) in mediastinal lymph nodes involved with NSCLC between pre- and post–induction therapy PET imaging (0 is stable/decreased SUVmax, 1 is increased)
Figure 7.
Overall survival by difference in SUVmax (D) in mediastinal lymph nodes involved with NSCLC between pre- and post–induction therapy PET imaging (0 is >60% decrease in SUVmax, 1 is <60% decrease)
Table 7.
Multivariable Cox Regression analysis of N2 PET response (N=76)
| Model | HR (95% CI) | P |
|---|---|---|
| % change in N2 SUV >0 | 2.13 (0.95–4.77) | 0.067 |
| % change in primary SUV >0 | 1.46 (0.70–3.15) | 0.314 |
| Persistent pathologic N2 | 2.17 (1.04–4.52) | 0.038 |
| 60% decrease in N2 SUV | 0.58 (0.34–0.99) | 0.048 |
| 60% decrease in primary SUV | 1.31 (0.70–2.43) | 0.401 |
| Persistent pathologic N2 | 2.41 (1.14–5.07) | 0.021 |
Table 8.
Multivariable Cox Regression controlling for factors known preoperatively (N=78)
| Model | HR (95% CI) | P |
|---|---|---|
| % reduction in N2 SUV >0% | 0.42 (0.18–0.98) | 0.044 |
| % reduction in primary SUV >0% | 0.61 (0.28–1.32) | 0.206 |
| % reduction in N2 >60% | 0.53 (0.30–0.93) | 0.028 |
| % reduction in primary >60% | 1.23 (0.64–2.37) | 0.526 |
Note. All models controlled for histology, type of resection, age (≥65 years), and sex; results not listed.
Comment
PET avidity of an NSCLC treated surgically can predict survival independent of clinical stage.[8] In the current series, preSUV alone was not associated with postresection survival, suggesting that this is not a reliable predictor to stratify patients scheduled to undergo induction therapy.
Less-robust data exist with respect to PET-measured metabolic response after induction therapy, and all available data were collected in prospective clinical trials. Hoekstra et al. [9] identified, in 47 patients with histologically proven N2 disease, a 50% reduction in SUVbsag (SUV corrected for body-surface area and plasma glucose) as the optimal cutoff for PET response following induction therapy. Dooms et al. selected a 60% reduction in SUVmax (group median) to define PET response in 30 patients with mediastinoscopy-proven cIIIA (N2) disease who were treated with induction chemotherapy and surgery; they found an improved 5-year OS among responding patients (47% vs 13%; P=0.009).[11] Eschmann et al. [12] identified a 60% reduction in SUVmax as stratifying 65 patients with histologically proven cIII disease treated with investigated PET response after induction chemotherapy or into poor (45 patients; R0 resection rate, 51%; mean survival, 43 mos ) and better prognosis groups (20 patients; R0 resection rate, 80%; mean survival, 74 mos). A reduction in SUVmax of ≤25% identified an “extremely unfavorable” group (mean survival, 18 mos; 5-year survival, <5%). Decoster et al.[13] performed a retrospective study of 31 patients with unresectable stage III NSCLC imaged with PET before and after chemotherapy alone, finding that patients with a complete PET response had a better prognosis than patients with less than a complete response (>49 mos versus 14 mos; p=0.004). No other threshold of change on PET was identified that significantly stratified patients by prognosis.
In the current series, percentage change in SUVmax analyzed by quartile was not associated with survival. On univariate analysis, the median postSUV of 4.8 did not stratify patients into groups with meaningfully differing survival, as the worse prognosis group still had a median survival of 28 months. Only stratification by a stable/reduced SUVmax versus an increase after induction therapy identified patients with a median survival of only 23 months. This suggests that, in a routine clinical setting, changes in PET should be taken to indicate a response to induction therapy only in the broad sense of stable or any reduction in glucose uptake versus any increase. If change in PET SUV is more clearly defined as a prognostic tool in research settings, rigorous protocols for using similar machines, injection protocols, and time windows for obtaining studies will be needed.
This is the first report to identify this association between percentage change in SUVmax during induction therapy in patients with cI to cII NSCLC. Tanvetyanon et al.[14] found no correlation between PET response and survival in 89 cI–cIII NSCLC patients treated with induction chemotherapy and surgery. Two other studies that included early stage disease addressed the utility of PET response for predicting pathologic response—but without reference to OS.[15, 16]
This is also the first report to examine whether OS was predicted by PET response in lymph nodes. Pottgen et al. [17] found that changes in SUVmax of an involved lymph node during chemotherapy correlate with pathologic response but did not examine correlation with survival We found that an increase in the SUV of an involved lymph node predicted poorer survival and that a >60% decrease in SUVmax predicted improved survival. Response in involved lymph nodes was a better predictor of survival than response in the primary site (Table 8). As tumors are heterogenous, with subclones being more able to metastasize [18] and possibly differing in chemosensitivity, a disease in a lymph node may be more similar to distant micrometastatic disease than disease in the primary site of disease.
Because inflammation after radiation therapy can confound assessment of PET response,[19, 20] we performed an analysis that excluded patients who had received radiation therapy as part of their induction therapy. Consistent with previous findings,[21] no significant change was observed in the factors affecting survival or in the magnitude of their effect.
Acknowledgments
Financial Support: NIH/NCI Cancer Center Support Grant P30 CA008748
Footnotes
Conflicts of interest: All authors have no conflicts of interest.
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