Response monitoring during neoadjuvant targeted treatment in early stage non‐
small cell lung cancer
van Gool, M.H.
Publication date
2019
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Citation for published version (APA):
van Gool, M. H. (2019). Response monitoring during neoadjuvant targeted treatment in early
stage non‐small cell lung cancer.
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Chapter
7
prognostic value of pre-operative
glucose-corrected maximum standardized uptake value
in patients with non-small cell lung cancer
after complete surgical resection and
5-year follow-up
Renske Konings*, Matthijs H. van Gool*, Martin P. L. Bard, Anthonie Zwijnenburg, Bart M. Titulaer, Tjeerd S. Aukema, Renato A. Valdes Olmos, Karolina Sikorska, Houke M. Klomp, Herman Rijna * Contributed equally to this work Ann Nucl Med (2016) 30:362–8
Abstract
Introduction. In this study we evaluated the value of pre‐ operative glucose corrected
maximum standard uptake value (GC‐SUVmax) as prognostic factor in patients with early stage non‐small cell lung cancer (NSCLC) after complete surgical resection.
Methods. This study was designed as a retrospectively evaluated single center study with
prospective data registry. Inclusion criteria were: histologically proven stage I NSCLC, 18F‐FDG‐PET/CT scan prior to surgery, complete resection (R0) and follow‐up in our outpatient department. Exclusion criteria were: history of malignancy other than NSCLC, diabetes and (neo) adjuvant therapy. Follow‐up period was 5 years.
Results. Between 2006 and 2008 a total of 33 patients (16 males, 17 females) met the
inclusion criteria. SUVmax and GC‐SUVmax were strongly correlated (Spearman’s q=0.97). Five‐year overall survival (OS) rate was 70% (95% CI, 56 to 87%). Patients who died within 5 years of follow‐up had significantly higher pre‐operative GC‐ SUVmax (median=10.6, IQR= 8.3 to 14.4) than patients who were alive at 5‐year follow‐up (median=6.4, IQR=3.0 to 9.8), (P=0.04). SUVmax showed similar differences: 10.4 (8 to 12.9) versus 6.6 (3.0 to 8.8), (P=0.047). The area under the receiver‐operating characteristic (ROC) curve at 5 years was 0.70 (95% CI, 0.50 to 0.90) for GC‐SUVmax and 0.71 (95% CI, 0.51 to 0.91) for SUVmax (P=0.75).
Conclusion. Pre‐operative FDG tumor uptake in patients with NSCLC is predictive for
survival after complete surgical resection. GC‐SUVmax, as an additional value to SUVmax, may better approach competitive inhibition of FDG and glucose in tumors. However, in this study this potential advantage, if any, was very small.
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Introduction
In early stage non‐small cell lung cancer (NSCLC) treatment is focused on curative surgery.1 Unfortunately, a minority of patients with NSCLC present with localized disease amenable for resection.2 Five‐year survivals vary from 36% to 73% after resection with curative intent.3,4 Disease recurrence occurs in approximately 50% after resection often by distant metastases.5,6 In therapeutic decision making the TNM classification of malignant tumors is currently used as prognostic marker to identify patients who potentially benefit from adjuvant treatment.7,8
Although, the overall survival effect of adjuvant therapies is modest with an estimated survival benefit of 4 to 8% at 5 years. Cisplatin‐based therapy is advised for patients after a complete resection with TNM stage II and III.7,9‐14 However, the TNM classification shows great heterogeneity in survival and disease recurrence within the same stages.15 Adjunctive tools are required to select patients with poor prognosis deviating from expected TNM stage survival rates who could benefit from adjuvant treatment.
Over recent years, [18F]‐fluorodeoxyglucose positron emission tomography acquired together with low dose computed tomography (FDG‐PET/CT) has proven its role for pretreatment staging, response monitoring and prognostic factor in patients with NSCLC.16‐21 With FDG‐PET/CT, the FDG uptake defined by the maximal standard uptake value (SUVmax) has been used as an index for metabolic activity.
There is increasing interest in better (semi)quantitative value(s) rather than SUV.22,23 FDG uptake is dependent on blood glucose levels; increased blood glucose levels result in decreased FDG uptake in tumors through competitive inhibition.24‐26 This could potentially limit the use of SUVmax as prognostic factor. In other malignancies FDG tumor uptake corrected for blood glucose has shown improved accuracy as prognostic factor over SUVmax.24,27 However, the potential role of glucose corrected SUVmax (GC‐ SUVmax) in predicting survival has not yet been elucidated.
In this perspective, we performed a retrospective analysis of patients with early stage NSCLC without indication for (neo) adjuvant therapies at time of treatment receiving a diagnostic FDG‐PET/CT prior to surgery. The objective of this analysis was to evaluate the value of pre‐operative GC‐ SUVmax as prognostic factor in patients with NSCLC after complete surgical resection.
Materials and methods
Patient selection
This study was designed as a retrospective evaluated single center study with prospective data registry. Between November 2006 and November 2008, a total of 103 patients underwent lung surgery. Patients were considered eligible for this study when they had pathologically proven stage I NSCLC according to TNM classification (6th edition) and received an FDG‐PET/CT scan prior to surgery.28 Patients had no history of malignancy other than NSCLC, did not receive any type of (neo) adjuvant therapy according to the national guidelines at time of treatment, underwent complete resection (R0), and had undergone follow‐up in our outpatient department. Patients with diabetes were excluded from this study.
A review of all medical records and pathological reports was performed to check recorded clinical variables. Where needed information was verified by other sources (e.g. general practitioner files). Documentation in our database was anonymous. Because of the retrospective character of our study approval by the local ethical committee was not warranted. Histological typing and pathological staging were determined according to WHO classification and TNM classification (7th edition), respectively.15,29
Imaging data
PET/CT‐scan imaging was performed using a hybrid system (GeminiTF, Philips, Eindhoven, the Netherlands) 60 minutes after FDG injection. 18F‐FDG was administered in a body weight adjusted IV dosages of 145–265 MBq. Patients fasted for 6 hours prior to imaging. The interval between FDG administration and scanning was 60 minutes (mean 75 ± 16 min). Low‐dose CT images (40 mAs, 5 mm slices) were acquired without intravenous contrast. The images were orthogonally resliced and reviewed using simultaneous display of PET, CT and fused PET/CT in an Apple Osirix MD workstation. Evaluation of the images and SUV measurements were done by one nuclear physician (AZ).
Assessment of FDG‐tumor uptake
FDG tumor uptake was quantified using SUVmax (maximum activity concentration of FDG divided by the injected dose and corrected for the body weight of the patient). For the determination of the SUVmax, the maximum FDG‐ uptake was searched within the
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whole volume of the primary tumor. These regions of interest (ROI) were manually drawn. GC‐SUVmax was calculated following the NED‐PAS guideline30: Blood glucose levels were measured using the Glucocard Memory 2 (Menarini, Florance, Italy) immediately before administration of FDG in each patient.
Statistical analysis
Follow‐up was measured from the date of resection till death or April 2014, which ensured follow‐up time of at least 5 years for each surviving patient. The primary end‐ point of this study was 5‐year overall survival (OS). Overall survival was defined as the time from date of resection until death from any cause. Secondary endpoint was 5‐year recurrence incidence. Recurrence was defined as appearance of residual tumor growth or new manifestation (e.g. metastasis) on imaging examinations after resection. Time to recurrence was defined as period from resection till the moment the recurrence was detected. Patients who died due to cancer‐unrelated causes were censored. Clinical follow‐up visits took place at 3 and 6 months during the first year after treatment and subsequently every year for a period of at least 60 months.
Association between SUVmax and GC‐SUVmax was measured using nonparametric Spearman correlation coefficient. Because the follow‐up time of 5 years was available for each patient the distributions of glucose measures could be compared between surviving/recurring and non‐surviving/non‐recurring patients using a nonparametric Mann–Whitney U test. Predictive performance of the two biomarkers was compared at 2 to 5 years using the time‐dependent ROC curve estimation as implemented in the R package time ROC. Separate proportional hazard Cox models were fitted to the two biomarkers and their goodness of fit was compared using R2.31
All statistical analyses were performed using IBM SPSS Statistics 21 (IBM, Armonk, NY, USA) and R version 3.2.3.
GCSUV= xACvoi (kBq/ml) Pglu(mmol/l) FDGdose (MBq)/BW (kg) 5.0 GCSUV= xACvoi (kBq/ml) Pglu(mmol/l)
Results
Patient characteristics
Between November 1st 2006 and November 1st 2008, a total 103 patients underwent lung surgery in our hospital. Seventy patients were excluded either, because of prior malignancy (n=30), benign lesion (n=18), diabetes mellitus (n=8), (neo) adjuvant treatment (n=6), R1–2 resection (n=6), (peri) operative death (n=1) and non‐ assessable FDG‐PET/CT scan (n=1). Thirty‐three patients (16 males, 17 females) met the inclusion criteria. Mean age at surgery was 65 ± 10 years (median=65 years). Twenty‐nine patients (87%) underwent a lobectomy and 4 patients (12%) underwent a pneumonectomy. In 23 patients (70%) adenocarcinoma was seen at histopathologic evaluation. According to TNM 7th edition 70% of the patients had stage IA disease (range IA–IIB). Patient characteristics are listed in Table 7.1. Table 7.1 Characteristics of 33 patients included in this study. Characteristic Value Gender (M/F) 16 (48%) /17 (52%) Age at diagnosis, mean (range) 65 (43–82) Surgical procedure Lobectomy 29 (88%) Pneumectomy 4 (12%) TNM‐stage IA 23 (70%) IB 5 (15%) IIA 3 (9%) IIB 2 (6%) Histology Adenocarcinoma 23 (70%) Squamous 8 (24%) Other 2 (6%)
FDG‐PET/CT scan
FDG‐PET/CT scan was performed at a median of 24 days (IQR=16 to 35 days, mean=33 days) before surgery. Median FDG tumor uptake defined by GC‐SUVmax was 8.1 (IQR=3.4 to 10.7) compared to 8.3 (3.7 to 10.2) defined by SUVmax. Median glucose at FDG‐PET/CT scan 5.2 mmol/l (IQR=4.7 to 5.8 mmol/l). The Spearman correlation coefficient between GC‐SUVmax and SUVmax was 0.97 (Figure 7.1).7
Figure 7.1 Scatterplot of GC‐SUVmax versus SUVmax with a 45‐degree reference line.Follow‐up
Follow‐up until death or 5 years was available for each patient. Alive patients with follow‐up exceeding 5 years were censored at 5 years. The 5‐year overall survival was 70%. In 8 patients (24%) recurrence occurred. In total 10 (30%) patients died within follow‐up. Eight patients (24%) died as a result of the disease. Two patients (6%) died as a result of other causes. The 5‐year cumulative incidence of recurrence was 25%. Overall survival and recurrence incidence are shown in Figure 7.2A, B.
FDG tumor uptake and 5‐year overall survival
There was a significant difference in GC‐SUVmax between patients who died within 5 years follow‐up and patients who were alive at 5 year follow‐up, 10.6 (8.3 to 14.4) versus 6.4 (3.0 to 9.8), (P=0.04). Similar results were found for SUVmax: 10.4 (8.0 to 12.9) versus. 6.6 (3.0 to 8.8), (P=0.047). The areas under the ROC curves (AUC) based on the time dependent ROC estimation are shown in Table 7.2. The AUCs through the follow‐up period are almost identical for the two biomarkers. The AUC at 5 years for GC‐ SUVmax was 0.70 (95% CI, 0.50 to 0.90) and for SUVmax 0.71 (95% CI, 0.51 to 0.91; P=0.75). The point estimates suggest fair predictive abilities, however due to the small sample size the confidence internals are wide. The R2 for the Cox model fitted to GC‐ SUVmax was 19% compared to 14% estimated for SUVmax. Both predictors were
significant in the univariable Cox models (GC‐SUVmax: HR=1.17; P=0.006, SUVmax: HR=1.16; P=0.019). Figure 7.2 A. Five‐year overall survival. B. Five‐year disease‐free survival.
FDG tumor uptake and 5‐year incidence of recurrence
FDG tumor uptake defined by GC‐SUVmax was higher in patients with recurrence of disease within 5 years (median=10.6 years, IQR=8.6 to 13.4 years), compared to patients without recurrence (median=7.3 years, IQR=3.3 to 10.1 years). However, this association was not significant (P=0.1). Also, FDG tumor uptake defined by SUVmax showed a non‐
B A
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significant difference between these two groups: 10.4 (7.6 to 12.4) versus 7.8 (3.4 to 8.9) (P=0.10).
Table 7.2 Areas under the ROC curves based on the time‐dependent ROC estimation for overall survival. SUVmax GC ‐SUVmax AUC Lower‐AUC Upper‐AUC AUC Lower‐AUC Upper‐AUC P value 2‐years 0.84 0.68 1.00 0.85 0.69 1.00 0.682 3‐years 0.75 0.54 0.96 0.75 0.54 0.95 0.879 4‐years 0.75 0.54 0.96 0.75 0.54 0.95 0.879 5‐years 0.71 0.51 0.91 0.70 0.50 0.90 0.747 The time‐dependent AUCs are presented in Table 7.3. The area under the ROC curve at 5 years for GC‐SUVmax was 0.69 (95% CI, 0.46 to 0.92) compared to 0.70 (95%CI, 0.47 to 0.93) for SUVmax, (P=0.74). The R2 for univariable Cox models fitted for time to recurrence were 14% and 10% for GC‐SUVmax and SUVmax, respectively. Both predictors were statistically significant: GC‐ SUVmax with HR= 1.14 (P=0.018) and SUVmax with HR= 1.14 (P=0.047).
Table 7.3 Areas under the ROC curves based on the time‐dependent ROC estimation for incidence of recurrence.
SUVmax GC ‐SUVmax AUC Lower‐AUC Upper‐AUC AUC Lower‐AUC Upper‐AUC P value 2‐years 0.86 0.72 1.00 0.86 0.73 0.99 0.883 3‐years 0.74 0.50 0.99 0.73 0.48 0.98 0.746 4‐years 0.74 0.50 0.99 0.73 0.48 0.98 0.746 5‐years 0.70 0.47 0.93 0.69 0.46 0.92 0.737
Discussion
This study shows that pre‐operative FDG tumor uptake defined by GC‐SUVmax in patients with NSCLC after complete surgical resection is predictive for overall survival. Patients with lower FDG tumor uptake are more likely to be alive at 5 years after surgery. However, in this series GC‐SUVmax does not show a substantially improved predictive ability compared to SUVmax alone.
Since the majority of relapses appear within 2 years, it is likely that diagnosed tumors already spread on microscopic level.32 Patients with high risk of early disease recurrence might benefit from (neo) adjuvant treatment.10,13,33 On the other hand, patients with low
Selection for adjuvant treatment in NSCLC is suboptimal and ineffective treatment raises health care costs.34
Although FDG tumor uptake is reported as a tool to predict tumor aggressiveness and predict disease recurrence and survival, a golden standard to relate metabolic activity to disease recurrence and survival is lacking.5,17,18,35‐37 As shown, FDG‐tumor uptake activity did not exactly correspond to disease recurrence and survival. FDG‐uptake on PET may reflect various tissue reactions, as tumor progression or regression but also senescence, fibrosis formation, and inflammatory reactions as macro‐ phage or lymphocyte infiltration.
Similarly to our findings, several studies suggest that primary FDG‐tumor uptake could be of prognostic value. Others have made attempts to determine cutoff values for risk stratification. In these reports, SUVmax varying from 4 to 10 is associated with higher mortality rates.35,38‐40 Cerfolio et al. found a similar association between SUVmax and OS. They showed that a cutoff value of SUV ≥10 was associated with worse OS.18
There is increasing interest in better (semi)quantitative value(s) rather than SUV.22,23 Adams et al. showed that blood glucose levels could influence accuracy of SUV measurements.41 Increased blood glucose levels result in decreased FDG tumor uptake through competitive inhibition as was shown by Langen et al..25 A similar correlation has been observed in FDG tumor uptake pattern after glucose loading in head and neck cancer and pancreatic malignancies.24. Lee et al. showed in pancreatic cancer that GC‐ SUVmax has a higher accuracy in predicting outcome versus SUVmax alone.27 However, in our series we found no significant differences in the predictive value of GC‐SUVmax versus SUVmax.
Some limitations of this study must be acknowledged. The small number of patients, retrospectively analyzed might preclude definitive conclusion. Furthermore, staging and treatment protocols have changed over time.7,14,32 According to the sixth TNM classification all patients had TNM stage I disease. The changes to the T descriptor in the seventh edition upstaged five patients in our population to stage II disease.3 At time of treatment none of the patients in our series required additional chemotherapy according to the national treatment protocols. Therefore, in our series outcome is not biased by (neo) adjuvant treatment. Adding another variable to the SUV calculation, namely glucose levels, introduces its own error; both from measurement errors inherent to the lab technique used, and from biological variations in glucose levels in the body even during the course of a PET scan. These additional errors could also a mask a true
7
difference in the utility of glucose correction.42 Furthermore, regarding PET standardization, acquisition and interpretation, consensus should be achieved.30
Conclusion
Our data suggest that in patients with early stage NSCLC FDG tumor uptake is potentially a useful factor to predict survival outcome. Glucose‐corrected SUVmax, as an additional value to SUVmax, may better deal with competitive inhibition of FDG and glucose in tumors and is potentially an even more useful tool to predict survival outcomes and to select in selecting patients who may could benefit from (neo) adjuvant treatment. However, this potential advantage, if any, was very small in our study.
Disclosure
Preliminary results of this study were published in Lung Cancer vol. 71, suppl. 2, page S39, in Feb. 2011, and the topic was presented in a national meeting.
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