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Computed Tomography to Predict Pathologic Response to Preoperative Chemoradiotherapy and Prognosis in Patients With Locally Advanced Rectal Cancer
Original Study
Interim Fluorine-18 Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography to Predict Pathologic Response to Preoperative Chemoradiotherapy and Prognosis in Patients With Locally Advanced Rectal Cancer Phillip J. Koo,1 Seong-Jang Kim,2,3 Samuel Chang,1 Jennifer J. Kwak1 Abstract A pathologic complete response (pCR) to neoadjuvant chemoradiotherapy for rectal cancer has been associated with a better prognosis. To assess the role of interim fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography in the prediction of a pCR and prognosis, we performed a retrospective study. Of the parameters studied, the post-preoperative concurrent chemoradiotherapy maximum standardized uptake value and the change in the maximum standardized uptake value were potent predictors for pCR and well associated with overall survival. Introduction: The goal of the present study was to investigate the predictive and prognostic values of interim fluorine18 (18F) fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) parameters for the prediction of a complete pathologic response (pCR) in patients with locally advanced rectal cancer (LARC) who had received preoperative chemoradiotherapy (PCRT). Patients and Methods: A total 103 patients with LARC were included in the present study. All the patients were evaluated by 18F FDG PET/CT before and after 45 Gy of radiotherapy with concurrent oral capecitabine chemotherapy. The quantitative, volumetric parameters and their percentage of change (D%) were used to predict the pCR and calculate the overall survival (OS). The predictive value for a pCR of 18F FDG PET/CT cutoff values were determined by receiver operating characteristic analysis. The prognostic significance was assessed using Kaplan-Meier analysis. Results: A pCR occurred in 22 patients (21.4%). Univariate and multivariate analyses demonstrated that the post-PCRT maximum standardized uptake value (SUVmax2) and change in the SUVmax (DSUVmax) as significant factors for the prediction of pCR, with a sensitivity of 68.2% and specificity of 87.7% and sensitivity of 90.9% and specificity of 80.3%, respectively. Kaplan-Meier analysis showed that a low SUVmax2 (< 2.5) and high DSUVmax ( 62.2%) were potent predictors for OS. Conclusion: The present study has shown the capability of interim 18F FDG PET/CT parameters to predict the achievement of pCR after PCRT in patients with LARC. Of the parameters, SUVmax2 and DSUVmax were potent predictors for pCR and well associated with OS. Clinical Colorectal Cancer, Vol. -, No. -, --- ª 2016 Elsevier Inc. All rights reserved. Keywords: FDG, LARC, PCRT, PET/CT, Prognosis
Introduction 1
Department of Radiology, University of Colorado School of Medicine, Aurora, CO 2 Department of Nuclear Medicine 3 Biomedical Research Institute, Pusan National University Hospital, Busan, Korea Submitted: Nov 24, 2015; Revised: Apr 3, 2016; Accepted: Apr 27, 2016 Address for correspondence: Seong-Jang Kim, MD, PhD, Department of Nuclear Medicine, Pusan National University Hospital, Busan 602-739, Republic of Korea E-mail contact: [email protected]
1533-0028/$ - see frontmatter ª 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clcc.2016.04.002
Colorectal cancer is the third most common cancer and the third leading cause of cancer-related death in men and women in the United States.1 In 2014, an estimated 71,830 men and 65,000 women were diagnosed with colorectal cancer and 26,270 men and 24,040 women died of the disease.1 Locally advanced rectal cancer (LARC) is considered a clinical threat owing to the high incidence of locoregional recurrence after treatment and the poor prognosis.2 For LARC (stage cT3-T4N0M0
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Interim PET/CT for pCR and Prognosis or any T, N1M0), a multimodality strategy is the best option, with the aim of obtaining better local control and avoiding destructive surgical treatment.3 At present, preoperative chemoradiotherapy (PCRT) is considered a standard treatment for patients with LARC and has resulted in improved local control and survival.4-7 In addition, PCRT produces downstaging and downsizing of LARC, increasing the rate of complete surgical resection and possibly increasing the chance of sphincter preservation.4,8 PCRT is highly effective, and the frequency of a pathologic complete response (pCR) has ranged from 15% to 30%.9,10 The successful achievement of pCR after PCRT is related to the decreased incidence of local recurrence and improved prognosis.11 Moreover, the early prediction of pCR after PCRT for LARC could lead to decreased morbidity, without jeopardizing the clinical outcome. Also, the early prediction of pCR could provide treatment personalization by radiation dose escalation or switching to more effective chemotherapeutic agents.12 Therefore, it is essential to accurately identify patients more likely to experience a pathologic response to PCRT for patients with LARC. Currently, the histopathologic response assessment is possible only after surgical treatment because of the lack of clinically validated predictive biomarkers. Morphologic imaging modalities, including computed tomography (CT), endoscopic ultrasonography, and magnetic resonance imaging, cannot be used to predict the pathologic response, because these techniques rely on morphologic changes and cannot differentiate viable tumor tissue from treatment-induced fibrotic changes.13 18F FDG PET/CT has been reported to be a valuable functional imaging modality that has demonstrated distinguished capabilities in cancer detection, planning and monitoring treatment, and prognostic prediction in colorectal and anal cancers.14 However, the role of 18F FDG PET/CT for prediction of pCR to PCRT remains debatable for LARC. The present study investigated and identified the 18F FDG PET/CT parameters for predicting the pCR in relation to the prognosis in patients with LARC treated with PCRT.
Patients and Methods Patients In the present study, 103 patients with newly diagnosed, nonmetastatic LARC and a pathologic diagnosis of adenocarcinoma were treated with capecitabine-based chemoradiotherapy. The institutional ethnic committee approved the present study, which was performed in accordance with the ethical standards of the institutional and/or national research committee and the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Written informed consent was waived because of the retrospective nature of the present study. The baseline staging workup included colon/rectosigmoidoscopy, endoscopic ultrasonography, abdominopelvic computed tomography, or magnetic resonance imaging. Also, all patients underwent
18F FDG PET/CT before and after PCRT. All patients had pathologically proven rectal adenocarcinoma with the distal end of the tumor located within 10 cm of the anal verge. No patient had evidence of distant metastasis at the staging workup. The main exclusion criteria were the absence of 18F FDG PET/CT images before or after PCRT, any previous treatment, and PCRT contraindications because of comorbidity.
Preoperative Chemoradiotherapy Preoperative radiation therapy (RT) of 45 Gy in 25 fractions was delivered to the pelvis over 5 weeks, followed by boost of a minimum of 5.4 to a maximum of 10.8 Gy to the primary tumor. During the same period, oral capecitabine, 825 mg/m2, was administered twice daily throughout the RT course, 7 d/wk, beginning the day of the start of RT and ending with the last dose of RT. All patients underwent surgery 6 to 8 weeks after PCRT completion.
18F FDG PET/CT Scans All patients were examined using a dedicated PET/CT scanner (Biograph 40, Siemens, Knoxville, TN), consisting of a dedicated germanium oxyorthosilicate full-ring PET scanner and a dual-slice helical CT scanner. Standard patient preparation included 8 hours of fasting and a serum glucose level of < 120 mg/dL before 18F FDG administration. 18F FDG PET/CT imaging was performed 60 minutes after injection of 18F FDG. The emission scan time per bed position was 3 minutes; 6 bed positions were acquired. The PET data were obtained using a high-resolution whole body scanner with an axial field of view of 21.6 cm. The average axial resolution varied from 2.0 mm full-width at halfmaximum in the center and 2.4 mm at 28 cm. The average total PET/CT examination time was 20 minutes. Attenuation correction was performed for all patients with iterative reconstruction. The PET/CT images were analyzed on 3 different planes: transverse, coronal, and sagittal. The pretreatment baseline 18F FDG PET/CT images were taken about 3 to 14 days before the start of PCRT (initial). The second interim 18F FDG PET/CT images were recorded during the course of PCRT (45 Gy of RT with 3 cycles of chemotherapy, second).
18F FDG PET/CT Image Analysis PET/CT data sets were evaluated by 2 nuclear physicians, who were unaware of all imaging, clinical, and pathologic results. Decisions concerning the analysis of 18F FDG PET/CT data sets were reached by consensus. The PET/CT data sets were analyzed quantitatively using the maximum standardized uptake value (SUVmax) of 18F FDG uptake. The region of interest was drawn on the area of abnormal 18F FDG uptake corresponding to the tumor in the initial and second scans. The SUVmax was obtained using the following formula:
SUV max ¼ maximum activity in the region of interest MBq gram injected dose MBq body weight ½grams :
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Phillip J. Koo et al The metabolic tumor volume (MTV) was determined as the total number of voxels with a threshold SUV of 40% of the SUVmax in the volume of interest. The total lesion glycolysis (TLG) was calculated as the MTV multiplied by its mean SUV (SUVmean). The changes (%, D) of each quantitative, volumetric parameter (P) of 18F FDG PET/CT were calculated as follows: ðPsecond Pinitial Þ DP ¼ 100% Pinitial
Pathologic Tumor Response Evaluation After surgery, the pathologic tumor response was classified by achievement of pCR. The degree of pathologic response after PCRT was confirmed by evaluation of the (y)pTNM categories according to the International Union Against Cancer (UICC, 7th edition, 2010). pCR is defined as ypT0N0. Also, we used the histologic tumor grading system consisting of the tumor regression grade (TRG). Regression grading stratifies the response semiquantitatively, dividing it into 5 grades according to the ratio of fibrosis to viable neoplasm as follows: TRG1, no residual cancer; TRG2, rare residual cancer cells; TRG3, fibrosis outgrowing residual cancer; TRG4, residual cancer outgrowing fibrosis; and TRG5, the absence of regressive changes.
Statistical Analysis All numerical data are expressed as the median and range. Receiver operating characteristic (ROC) curves for each parameter were derived and evaluated by comparing the areas under the curves for the prediction of pCR. The sensitivity and specificity of each parameter were determined at the optimal cutoff values using ROC curve analyses. The c2 test, Fisher exact test, and Mann-Whitney U test were used to analyze the statistical differences in the categorical data, the 18F FDG PET/CT parameters between those with and without a pCR. Survival curves stratified by post-PCRT SUVmax (SUVmax2) and the change in SUVmax (DSUVmax) of 18F FDG PET/CT were generated. The log-rank test was used to compare survival between each group. Data analyses were conducted with MedCalc, version 14.12.0 (MedCalc Software, Ostend, Belgium). Statistical significance was defined as P < .05.
Results Patient Characteristics A total of 103 patients were included in the present study. The patient characteristics and tumor characteristics are listed in Table 1. The median age was 66 years (range, 49-85 years). The patients were predominantly male (76.7%). Most tumors were located 5 cm from the anal verge. Of the 18F FDG PET/CT parameters, the post-PCRT values of SUVmax, MTV, and TLG were much lower in those with pCR than in those without a pCR. The changes in SUVmax, MTV, and TLG were much greater in those with a pCR than in those without a pCR. The histopathologic characteristics of tumor specimens after PCRT are listed in Table 2.
ROC Analysis for Prediction of pCR To find the cutoff values of the quantitative and volumetric parameters of 18F FDG PET/CT that will predict a pCR, the thresholds of each parameter were calculated using the Youden
Table 1 Patient Characteristics pCR (ypT0N0) Yes (n [ 22)
No (n [ 81)
66
12
38
<66
10
43
Characteristic Age (year)
.6931
Gender Male Female
P Value
1.0 17
62
5
19
Distance from anal verge (cm)
.9611
<5
6
24
5
16
57
cT2
0
4
cT3
20
65
cT4
2
12
cN ()
7
14
cN (þ)
15
67
Clinical T stage
.4186
Clinical N stage
.2293
PET/CT parameters SUVmax1
7.1 (2.4-20)
2.5-25
SUVmax2
2.25 (1.3-5.1)
5.6 (1.7-21.7)
<.0001
DSUVmax (%)
.0926
68.65 (45.8-82)
46.5 (7.9-71.8)
<.0001
SUVmean1
4.1 (2.2-13.1)
6.4 (1.8-17.3)
.0555
SUVmean2
2.65 (1.2-7.4)
4 (1.2-11.6)
.0568
DSUVmean (%)
33.7 (20-63.5)
33.1 (9.8-62.1)
.4689
19.5 (2.7-277.8)
21.2 (3-140.1)
.359
MTV2
7.9 (1.5-162.3)
14.7 (1.4-117.5)
.017
DMTV (%)
47.9 (34.9-68.5)
31.3 (7.7-63.7)
<.0001
TLG1
89.85 (5.9-833.5)
136 (11.4-1257.7)
.1856
TLG2
29.9 (2.3-373.3)
54.9 (4.1-586.2)
.0172
DTLG (%)
70.8 (55.2-76.4)
55.5 (31.2-78.2)
<.0001
15
61
APR
5
19
Hartmann’s operation
2
1
MTV1
Surgical procedure LAR
.1504
Differentiation Well Moderate/poor
.4185 4
24
18
57
Data presented as n or median (range). Abbreviations: D ¼ change in parameter in question; APR ¼ abdominopelvic resection; CT ¼ computed tomography; LAR ¼ low anterior resection; MTV1 ¼ metabolic tumor volume at first scan; MTV2 ¼ MTV after preoperative chemoradiotherapy; pCR ¼ pathologic complete response; PET ¼ positron emission tomography; SUVmax1 ¼ maximum standardized uptake value at first scan; SUVmax2 ¼ SUVmax after preoperative chemoradiotherapy; SUVmean1 ¼ mean SUV at first scan; SUVmean2 ¼ mean SUV after preoperative chemoradiotherapy; TLG1 ¼ total lesion glycolysis at first scan; TLG2 ¼ TLG after preoperative chemoradiotherapy.
index and ROC curve. Figure 1 and Table 3 demonstrate the results ROC analyses. Among the various 18F FDG PET/CT parameters, SUVmax2, DSUVmax, post-PCRT MTV (MTV2), DMTV, postPCRT TLG (TLG2), and DTLG were statistically significant predictors of a pCR.
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Interim PET/CT for pCR and Prognosis Table 2 Tumor Characteristics at Histopathologic Examination Characteristic
n (%)
TRG TRG1
22 (21.4)
TRG2
13 (12.6)
TRG3
45 (43.7)
TRG4
23 (22.3)
Pathologic TNM stage (ypTN) ypT0N0 ypT1N0-N1
22 (21.4) 1 (1)
ypT2N0
3 (2.9)
ypT2N1
18 (17.5)
ypT2N2
45 (43.6)
ypT3N0
0
ypT3N1
3 (2.9)
ypT3N2
11 (10.7)
ypT4N0-N2
0
Abbreviation: TRG ¼ tumor regression grade.
When a SUVmax2 2.5 was used as the cutoff, the sensitivity and specificity of 18F FDG PET/CT for the prediction of a pCR was 68.2% (95% confidence interval [CI], 45.1%-86.1%) and 87.7%
(95% CI, 78.5%-93.9%), respectively. The AUC was 0.864 (95% CI, 0.783-0.924) and the standard error (SE) was 0.0399 (P < .0001). When DSUVmax 62.2% was used as the cutoff, the sensitivity and specificity of 18F FDG PET/CT for the prediction of pCR was 90.9% (95% CI, 70.8%-98.9%) and 80.3% (95% CI, 69.9%88.3%), respectively. The AUC was 0.895 (95% CI, 0.819-0.947) and the SE was 0.0399 (P < .0001). The post-PCRT MTV (MTV2) predicting a pCR resulted in 95.5% sensitivity (95% CI, 77.2%-99.9%), 32.1% specificity (95% CI, 22.2%-43.4%), 0.666 AUC (95% CI, 0.567-0.756; SE, 0.0653; P ¼ .01) for cutoff values of 23.4. The DMTV resulted in 77.3% sensitivity (95% CI, 54.6%-92.2%), 88.9% specificity (95% CI, 80%-94.8%), 0.882 AUC (95% CI, 0.803-0.937; SE, 0.0351; P < .0001) for cutoff values > 43.9%. When TLG2 31.8 was used as the cutoff, the sensitivity and specificity of 18F FDG PET/CT for the prediction of a pCR was 59.1% (95% CI, 36.4%-79.3%) and 69.1% (95% CI, 57.9%78.9%), respectively. The AUC was 0.666 (95% CI, 0.566-0.756) and the SE was 0.0666 (P ¼ .01). When DTLG 60.4% was used as a cutoff, the sensitivity and specificity of 18F FDG PET/CT for the prediction of a pCR was 86.4% (95% CI, 65.1%-97.1%) and 80.3% (95% CI, 69.9%88.3%), respectively. The AUC was 0.884 (95% CI, 0.805-0.938) and the SE was 0.0388 (P < .0001).
Figure 1 Receiver Operating Characteristic Analysis Results for Prediction of Pathologic Complete Response Using Fluorine-18 Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography Parameters
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Abbreviations: D ¼ change in specified parameter; MTV2 ¼ metabolic tumor volume after preoperative chemoradiotherapy; SUVmax ¼ maximum standardized uptake value; SUVmax2 ¼ standardized uptake value after preoperative chemoradiotherapy; TLG ¼ total lesion glycolysis; TLG2 ¼ total lesion glycolysis after preoperative chemoradiotherapy.
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Phillip J. Koo et al Table 3 Prediction of pCR Using 18F FDG PET/CT Parameters Variable SUVmax1 8.1 SUVmax2 2.5 DSUVmax 62.2% SUVmean1 4.5 SUVmean2 3.6 DSUVmean >38.5% MTV1 24.1 MTV2 23.4 DMTV >43.9% TLG1 100.8 TLG2 31.8 DTLG >60.4%
Sensitivity (%)
95% CI (%)
Specificity (%)
95% CI (%)
AUC
95% CI
SE
P Value
63.6 68.2 90.9 63.6 72.7 31.8 72.7 95.5 77.3 59.1 59.1 86.4
40.7-82.8 45.1-86.1 70.8-98.9 40.7-82.8 49.8-89.3 13.9-54.9 49.8-89.3 77.2-99.9 54.6-92.2 36.4-79.3 36.4-79.3 65.1-97.1
70.4 87.7 80.3 72.8 60.5 83.9 46.9 32.1 88.9 59.3 69.1 80.3
59.2-80 78.5-93.9 69.9-88.3 61.8-82.1 49-71.2 74.1-91.2 35.7-58.3 22.2-43.4 80-94.8 47.8-70.1 57.9-78.9 69.9-88.3
0.617 0.864 0.895 0.634 0.639 0.551 0.564 0.666 0.882 0.592 0.666 0.884
0.516-0.711 0.783-0.924 0.819-0.947 0.533-0.726 0.538-0.731 0.449-0.649 0.463-0.661 0.567-0.756 0.803-0.937 0.491-0.688 0.566-0.756 0.805-0.938
0.0821 0.0399 0.0348 0.079 0.0741 0.0723 0.0692 0.0653 0.0351 0.0711 0.0666 0.0388
.1532 <.0001 <.0001 .0908 .0613 .4848 .3554 .0109 <.0001 .1939 .0127 <.0001
Abbreviations: D ¼ change in parameter in question; AUC ¼ area under the curve; CI ¼ confidence interval; CT ¼ computed tomography; MTV1 ¼ metabolic tumor volume at first scan; MTV2 ¼ MTV after preoperative chemoradiotherapy; pCR ¼ pathologic complete response; PET ¼ positron emission tomography; SE ¼ standard error; SUVmax1 ¼ maximum standardized uptake value at first scan; SUVmax2 ¼ SUVmax after preoperative chemoradiotherapy; SUVmean1 ¼ mean SUV at first scan; SUVmean2 ¼ mean SUV after preoperative chemoradiotherapy; TLG1 ¼ total lesion glycolysis at first scan; TLG2 ¼ TLG after preoperative chemoradiotherapy.
Univariate and Multivariate Analysis of 18F FDG PET/ CT Parameters for a pCR The univariate and multivariate analysis results of the 18F FDG PET/CT parameters for the prediction of pCR are listed in Table 4. Of the 103 patients, a pCR occurred in 22 patients (21.4%). Univariate analysis showed that the SUVmax2, MTV2, postPCRT TLG (TLG2), DSUVmax, DMTV, and DTLG were associated with the pCR in patients with LARC treated with PCRT. Multivariate logistic regression analysis demonstrated SUVmax2 and DSUVmax are independent factors for a pCR.
Overall Survival The Kaplan-Meier analysis for OS is shown in Figure 2. KaplanMeier analysis showed SUVmax2 (c2, 6.74; hazard ratio, 3.58; 95% CI, 1.8-7.11; P ¼ .009) and DSUVmax (c2, 15.1; HR, 3.49; 95% CI, 1.87-6.5; P ¼ .0001) were associated with OS.
Discussion
The results of the present study that the SUVmax2 and DSUVmax could predict the pCR in patients with LARC and that these parameters are related to relapse-free survival and OS.
Generally, patients with LARC will have a greater incidence of locoregional recurrence, even after treatment. Thus, to reduce the risk of locoregional recurrence, PCRT is crucial to prevent local recurrence.5 PCRT has resulted in various tumor responses, ranging from a complete response in about 15% to 30% of cases to no response or even progression.9,15 It is well known that the tumor response to PCRT is a potent predictor and related to the prognosis.16,17 Therefore, accurate prediction of the tumor response, especially pCR, to PCRT in LARC is essential. Moreover, accurate and early recognition of pCR offers the potential to avoid surgical overtreatment without jeopardizing local control or long-term survival.9,11,18,19 18F FDG PET/CT has generally been recognized as a promising functional imaging tool for evaluating the tumor response and is superior to other morphologic imaging modalities.10 However, the optimal method for quantitative analysis has yet to be determined. Of the 18F FDG PET/CT parameters, the SUVmax has been the most commonly studied in previous quantitative analyses of glucose metabolism in various cancers.20,21 Recently, Maffione et al22 investigated 15 different 18F FDG PET/CT qualitative and quantitative parameters for prediction of
Table 4 Univariate and Multivariate Analysis Results of 18F FDG PET/CT Parameters for pCR pCR (ypT0N0) Univariate Analysis Variable SUVmax2 2.5 DSUVmax >62.2% MTV2 23.4 DMTV >43.9% TLG2 31.8 DTLG >60.4%
Multivariate Analysis
OR
95% CI
P Value
OR
95% CI
P Value
15.2 37.6 9.92 24.14 3.23 25.72
4.98-46.39 7.99-177.16 1.26-77.86 7.29-79.89 1.22-8.55 6.77-97.75
<.0001 <.0001 .0032 <.0001 .0166 <.0001
3.2 6.1 4.36 14.31 1.38 8.17
1.57-10.5 1.72-15.4 0.17-23.7 0.51-400.9 0.57-3.3 0.25-259.1
.0241 .0045 .681 .1176 .4459 .2337
Abbreviations: D ¼ change in parameter in question; CI ¼ confidence interval; CT ¼ computed tomography; MTV1 ¼ metabolic tumor volume at first scan; MTV2 ¼ MTV after preoperative chemoradiotherapy; OR ¼ odds ratio; pCR ¼ pathologic complete response; PET ¼ positron emission tomography; SE ¼ standard error; SUVmax1 ¼ maximum standardized uptake value at first scan; SUVmax2 ¼ SUVmax after preoperative chemoradiotherapy; SUVmean1 ¼ mean SUV at first scan; SUVmean2 ¼ mean SUV after preoperative chemoradiotherapy; TLG1 ¼ total lesion glycolysis at first scan; TLG2 ¼ TLG after preoperative chemoradiotherapy.
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Interim PET/CT for pCR and Prognosis Figure 2 Kaplan-Meier Survival Curve for Relapse-Free Survival and Overall Survival (OS) Stratified by Maximum Standardized Uptake Value After Preoperative Chemoradiotherapy (SUVmax2) and Change in Maximum Standardized Uptake Value (DSUVmax)
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the pathologic response to PCRT in LARC patients. They concluded that among these parameters, some of which cannot be immediately obtained (MTV and TLG) from a routine workstation, the most commonly used, post preoperative concurrent chemoradiotheraphy (SUVmax-post), showed the best accuracy in predicting TRG.22 Similar to the present study, other studies have demonstrated the predictive value of the post-PCRT SUVmax for the prediction of tumor response in patients with LARC. Bampo et al23 showed the possible predictive role of 18F FDG PET/CT for the assessment of the pathologic response in LARC after neoadjuvant chemoradiotherapy.23 In their study, using a threshold SUV of 5.4 after completion of neoadjuvant treatment, 18F FDG PET/CT could differentiate between pCR and non-pCR with 81% sensitivity, 100% specificity, and 90% overall accuracy. Another study showed that with a SUVmax2 cutoff of > 4.3 for predicting pCR, the sensitivity and specificity of 18F FDG PET/CT was 79.5% and 66.7%, respectively.24 Kim et al25 showed that for the pCR, the post-chemoradiotherapy SUVmax was a significant parameter on univariate and multivariate analysis, with a sensitivity of 73.7%, a specificity of 63.7%, and an accuracy of 64.9%, for a cutoff value of 3.55. The present study showed that, not only the PCRT SUVmax2, but also the DSUVmax, after PCRT were potent predictors of a pCR in patients with LARC. Similar to the present study, a recent study demonstrated that a DSUVmax of 32% could predict pCR with a sensitivity of 75% and specificity of 100%.26 Recently, some studies have indicated that the SUVmax, which only reflects a single point in the tumor, will not always be representative of the whole tumor.27 To overcome this weak point of the SUVmax, volumetric parameters such as MTV and TLG have been developed to calculate the metabolic activity in the whole tumor. The MTV is a well-known prognostic factor in various cancers; it represents the dual characteristics of tumor volume and the degree of 18F FDG uptake by the tumor.28 Also, TLG has been proposed as a more accurate parameter, because it accounts for both SUVmean and MTV.27 Using these volumetric parameters, we investigated their predictive value for the prediction of pCR in LARC patients treated with PCRT. In the present study, univariate analysis revealed that MTV2, TLG2, DMTV, and DTLG were significant predictors of
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pCR; however, these were significant on multivariate analysis. In contrast to the present study, other studies have revealed that the DTLG was the best predictor of pCR after PCRT using different thresholds.29,30 Although many previous studies have demonstrated the useful predictive role of 18F FDG PET/CT for pCR and TRG in LARC patients, other studies have failed to show the same role. A recent study investigated the predictive values of quantitative and volumetric parameters of 18F FDG PET/CT for the prediction for pCR in 35 LARC patients who underwent neoadjuvant chemoradiotherapy. However, the changes seen in 18F FDG PET/CT had limited value in predicting the pCR.31 Another study also concluded that neither PET nor CT scans have adequate predictive value to be clinically useful in distinguishing a pCR from an incomplete response. Also, they concluded that 18F FDT PET/CT and CT should not be obtained for the purposes of attempting to predict a pCR after neoadjuvant chemoradiotherapy for LARC patients.32 In the present study, SUVmax2 and DSUVmax, as the best predictive parameters of pCR, were used to identify patients with a high risk of disease recurrence and death. For both relapse-free survival and OS, the Kaplan-Meier survival analysis showed statistically significant differences in the probability of recurrence and death when stratified by the SUVmax2 and DSUVmax values. The most important limitation of the present study was the method used to establish the cutoff values of 18F FDG PET/CT parameters for the prediction of pCR. The cutoff values used in the present study were chosen from the ROC curves, reflecting our preference for the balance between the sensitivity and specificity of the test. However, these preferences could be compensated for by the relatively larger number of included patients. Also, the male predominance in the present study might have had an effect on the results of our study. In future studies, well-balanced age- and gender-matched cohort selection should be considered. Finally, the wide range of scan time before PCRT and the interim PET/CT could also be a major limitation of the present study, because the time variation could change the results of the tumor response evaluation. Because the study was retrospective, standardization of the scan time before and between chemoradiotherapy was not available.
Phillip J. Koo et al Conclusion The present study has shown the capability of interim 18F FDG PET/CT parameters to predict the achievement of pCR after PCRT in LARC patients. Of the studied parameters, SUVmax2 and DSUVmax were potent predictors for pCR and well-associated with OS.
Clinical Practice Points Research has shown that F-18 FDG PET/CT to be a valuable
functional imaging modality that has demonstrated distinguished capabilities in cancer detection, planning and monitoring treatment, and prognosis prediction in colorectal and anal cancers. However, the role of F-18 FDG PET/CT for prediction of pCR to PCRT remains debatable in LARC. In this study, we found that the capability of interim F-18 FDG PET/CT parameters to predict the achievement of pCR after PCRT in LARC patients. Among the parameters, the SUVmax2 and ▵SUVmax were the potent predictors for pCR and well associated with OS. This finding brings attention to the potential use of volumetric parameters change of F-18 FDG PET/CT during PCRT in LARC patients. The results of our study may provide valuable information for the development of effective strategies to predict pCR and prognosis in patients with LARC who received PCRT.
Acknowledgment This work was supported by the Financial Supporting Project of Long-term Overseas Dispatch of PNU’s Tenure-track Faculty, 2014.
Disclosure The authors declare that they have no competing interests.
References 1. Siegel A, DeSantis A, Jemal A. Colorectal cancer statistics, 2014. CA Cancer J Clin 2014; 64:104-7. 2. Gunderson LL, Sargent DJ, Tepper JE. Impact of T and N substage on survival and disease relapse in adjuvant rectal cancer: a pooled analysis. Int J Radiat Oncol Biol Phys 2002; 54:356-96. 3. De Paoli A, Chiara S, Luppi G, et al. Capecitabine in combination with preoperative radiation therapy in locally advanced, resectable, rectal cancer: a multicentric phase II study. Ann Oncol 2006; 17:246-51. 4. Sauer R, Becker H, Hohenberger W, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004; 351:1731-40. 5. Bosset JF, Collete L, Calais G, et al. Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med 2006; 14:1114-23. 6. Kapiteijn E, Marijnen CA, Nagtegaal ID, et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med 2001; 345:638-46. 7. Sauer R, Liersch T, Merkel S, et al. Preoperative versus postoperative chemoradiotherapy for locally advanced rectal cancer: results of the German CAO/ARO/ AIO-94 randomized phase III trial after a median follow-up of 11 years. J Clin Oncol 2012; 30:1926-33. 8. Rödel C, Grabenbauer GG, Schick C, Papadopoulos T, Hohenberger W, Sauer R. Preoperative radiation with concurrent 5-fluorouracil for locally advanced T4primary rectal cancer. Strahlenther Onkol 2000; 176:161-7. 9. Valentini V, Coco C, Cellini N, et al. Ten years of preoperative chemoradiation for extraperitoneal T3 rectal cancer: acute toxicity, tumor response, and sphincter preservation in three consecutive studies. Int J Radiat Oncol Biol Phys 2001; 51: 371-83.
10. Capirci C, Rubello D, Chierichetti F, et al. Long-term prognostic value of 18FFDG PET in patients with locally advanced rectal cancer previously treated with neoadjuvant radiochemotherapy. AJR Am J Roentgenol 2006; 187:W202-8. 11. Glynne-Jones R, Harrison M. Locally advanced rectal cancer: what is the evidence for induction chemoradiation? Oncologist 2007; 12:1309-18. 12. Rau B, Wust P, Hohenberger P, et al. Preoperative hyperthermia combined with chemoradiotherapy in locally advanced rectal cancer: a phase II clinical trial. Ann Surg 1998; 227:380-9. 13. Kahn H, Alexander A, Rakinic J, et al. Preoperative staging of irradiated rectal cancers using digital rectal examination, computed tomography, endorectal ultrasound, and magnetic resonance imaging does not accurately predict T0, N0 pathology. Dis Colon Rectum 1997; 34:748-51. 14. Agarwal A, Marcus C, Xiao J, Nene P, Kachnic LA, Subramaniam RM. FDG PET/CT in the management of colorectal and anal cancers. AJR Am J Roentgenol 2014; 203:1109-19. 15. Gérard JP, Chapet O, Nemoz C, et al. Preoperative concurrent chemoradiotherapy in locally advanced rectal cancer with high-dose radiation and oxaliplatincontaining regimen: the Lyon R0e04 phase II trial. J Clin Oncol 2003; 21: 1119-24. 16. Maas M, Nelemans PJ, Valentini V, et al. Long-term outcome in patients with a pathological complete response after chemoradiation for rectal cancer: a pooled analysis of individual patient data. Lancet Oncol 2010; 11:835-44. 17. Martin ST, Heneghan HM, Winter DC. Systematic review and meta-analysis of outcomes following pathological complete response to neoadjuvant chemoradiotherapy for rectal cancer. Br J Surg 2012; 99:918-28. 18. Habr-Gama A, Perez RO, Nadalin W, et al. Operative versus nonoperative treatment for stage 0 distal rectal cancer following chemoradiation therapy: longterm results. Ann Surg 2004; 240:711-7. 19. O’Neill BD, Brown G, Heald RJ, Cunningham D, Tait DM. Non-operative treatment after neoadjuvant chemoradiotherapy for rectal cancer. Lancet Oncol 2007; 8:625-33. 20. Huh JW, Min JJ, Lee JH, Kim HR, Kim YJ. The predictive role of sequential FDG-PET/CT in response of locally advanced rectal cancer to neoadjuvant chemoradiation. Am J Clin Oncol 2012; 35:340-4. 21. Capirci C, Rubello D, Pasini F, et al. The role of dual-time combined 18-fluorodeoxyglucose positron emission tomography and computed tomography in the staging and restaging workup of locally advanced rectal cancer, treated with preoperative chemoradiation therapy and radical surgery. Int J Radiat Oncol Biol Phys 2009; 74:1461-9. 22. Maffione AM, Ferretti A, Grassetto G, et al. Fifteen different 18F-FDG PET/CT qualitative and quantitative parameters investigated as pathological response predictors of locally advanced rectal cancer treated by neoadjuvant chemoradiation therapy. Eur J Nucl Med Mol Imaging 2013; 40:853-64. 23. Bampo C, Alessi A, Fantini S, et al. Is the standardized uptake value of FDG-PET/CT predictive of pathological complete response in locally advanced rectal cancer treated with capecitabine-based neoadjuvant chemoradiation? Oncology 2013; 84:191-9. 24. Niccoli-Asabella A, Altini C, De Luca R, et al. Prospective analysis of 18F-FDG PET/CT predictive value in patients with low rectal cancer treated with neoadjuvant chemoradiotherapy and conservative surgery. Biomed Res Int 2014; 2014: 952843. 25. Kim JW, Kim HC, Park JW, et al. Predictive value of (18)FDG PET-CT for tumour response in patients with locally advanced rectal cancer treated by preoperative chemoradiotherapy. Int J Colorectal Dis 2013; 28:1217-24. 26. Goldberg N, Kundel Y, Purim O, et al. Early prediction of histopathological response of rectal tumors after one week of preoperative radiochemotherapy using 18F-FDG PET-CT imaging: a prospective clinical study. Radiat Oncol 2012; 7:124. 27. Larson SM, Erdi Y, Akhurst T, et al. Tumor treatment response based on visual and quantitative changes in global tumor glycolysis using PET-FDG imaging: the visual response score and the change in total lesion glycolysis. Clin Positron Imaging 1999; 2:159-71. 28. Chung MK, Jeong HS, Park SG, et al. Metabolic tumor volume of [18F]-fluorodeoxyglucose positron emission tomography/computed tomography predicts short-term outcome to radiotherapy with or without chemotherapy in pharyngeal cancer. Clin Cancer Res 2009; 15:5861-8. 29. Hatt M, van Stiphout R, le Pogam A, Lammering G, Visvikis D, Lambin P. Early prediction of pathological response in locally advanced rectal cancer based on sequential 18F-FDG PET. Acta Oncol 2013; 52:619-26. 30. Sun W, Xu J, Hu W, Zhang Z, Shen W. The role of sequential 18(F)-FDG PET/ CT in predicting tumour response after preoperative chemoradiation for rectal cancer. Colorectal Dis 2013; 15:e231-8. 31. Chennupati SK, Quon A, Kamaya A, et al. Positron emission tomography for predicting pathologic response after neoadjuvant chemoradiotherapy for locally advanced rectal cancer. Am J Clin Oncol 2012; 35:334-9. 32. Guillem JG, Ruby JA, Leibold T, et al. Neither FDG-PET nor CT can distinguish between a pathological complete response and an incomplete response after neoadjuvant chemoradiation in locally advanced rectal cancer: a prospective study. Ann Surg 2013; 258:289-95.
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Interim Fluorine-18 Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography to Predict Pathologic Response to Preoperative Chemoradiotherapy and Prognosis in Patients With Locally Advanced Rectal Cancer Phillip J. Koo,1 Seong-Jang Kim,2,3 Samuel Chang,1 Jennifer J. Kwak1 Abstract A pathologic complete response (pCR) to neoadjuvant chemoradiotherapy for rectal cancer has been associated with a better prognosis. To assess the role of interim fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography in the prediction of a pCR and prognosis, we performed a retrospective study. Of the parameters studied, the post-preoperative concurrent chemoradiotherapy maximum standardized uptake value and the change in the maximum standardized uptake value were potent predictors for pCR and well associated with overall survival. Introduction: The goal of the present study was to investigate the predictive and prognostic values of interim fluorine18 (18F) fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) parameters for the prediction of a complete pathologic response (pCR) in patients with locally advanced rectal cancer (LARC) who had received preoperative chemoradiotherapy (PCRT). Patients and Methods: A total 103 patients with LARC were included in the present study. All the patients were evaluated by 18F FDG PET/CT before and after 45 Gy of radiotherapy with concurrent oral capecitabine chemotherapy. The quantitative, volumetric parameters and their percentage of change (D%) were used to predict the pCR and calculate the overall survival (OS). The predictive value for a pCR of 18F FDG PET/CT cutoff values were determined by receiver operating characteristic analysis. The prognostic significance was assessed using Kaplan-Meier analysis. Results: A pCR occurred in 22 patients (21.4%). Univariate and multivariate analyses demonstrated that the post-PCRT maximum standardized uptake value (SUVmax2) and change in the SUVmax (DSUVmax) as significant factors for the prediction of pCR, with a sensitivity of 68.2% and specificity of 87.7% and sensitivity of 90.9% and specificity of 80.3%, respectively. Kaplan-Meier analysis showed that a low SUVmax2 (< 2.5) and high DSUVmax ( 62.2%) were potent predictors for OS. Conclusion: The present study has shown the capability of interim 18F FDG PET/CT parameters to predict the achievement of pCR after PCRT in patients with LARC. Of the parameters, SUVmax2 and DSUVmax were potent predictors for pCR and well associated with OS. Clinical Colorectal Cancer, Vol. -, No. -, --- ª 2016 Elsevier Inc. All rights reserved. Keywords: FDG, LARC, PCRT, PET/CT, Prognosis
Introduction 1
Department of Radiology, University of Colorado School of Medicine, Aurora, CO 2 Department of Nuclear Medicine 3 Biomedical Research Institute, Pusan National University Hospital, Busan, Korea Submitted: Nov 24, 2015; Revised: Apr 3, 2016; Accepted: Apr 27, 2016 Address for correspondence: Seong-Jang Kim, MD, PhD, Department of Nuclear Medicine, Pusan National University Hospital, Busan 602-739, Republic of Korea E-mail contact: [email protected]
1533-0028/$ - see frontmatter ª 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clcc.2016.04.002
Colorectal cancer is the third most common cancer and the third leading cause of cancer-related death in men and women in the United States.1 In 2014, an estimated 71,830 men and 65,000 women were diagnosed with colorectal cancer and 26,270 men and 24,040 women died of the disease.1 Locally advanced rectal cancer (LARC) is considered a clinical threat owing to the high incidence of locoregional recurrence after treatment and the poor prognosis.2 For LARC (stage cT3-T4N0M0
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Interim PET/CT for pCR and Prognosis or any T, N1M0), a multimodality strategy is the best option, with the aim of obtaining better local control and avoiding destructive surgical treatment.3 At present, preoperative chemoradiotherapy (PCRT) is considered a standard treatment for patients with LARC and has resulted in improved local control and survival.4-7 In addition, PCRT produces downstaging and downsizing of LARC, increasing the rate of complete surgical resection and possibly increasing the chance of sphincter preservation.4,8 PCRT is highly effective, and the frequency of a pathologic complete response (pCR) has ranged from 15% to 30%.9,10 The successful achievement of pCR after PCRT is related to the decreased incidence of local recurrence and improved prognosis.11 Moreover, the early prediction of pCR after PCRT for LARC could lead to decreased morbidity, without jeopardizing the clinical outcome. Also, the early prediction of pCR could provide treatment personalization by radiation dose escalation or switching to more effective chemotherapeutic agents.12 Therefore, it is essential to accurately identify patients more likely to experience a pathologic response to PCRT for patients with LARC. Currently, the histopathologic response assessment is possible only after surgical treatment because of the lack of clinically validated predictive biomarkers. Morphologic imaging modalities, including computed tomography (CT), endoscopic ultrasonography, and magnetic resonance imaging, cannot be used to predict the pathologic response, because these techniques rely on morphologic changes and cannot differentiate viable tumor tissue from treatment-induced fibrotic changes.13 18F FDG PET/CT has been reported to be a valuable functional imaging modality that has demonstrated distinguished capabilities in cancer detection, planning and monitoring treatment, and prognostic prediction in colorectal and anal cancers.14 However, the role of 18F FDG PET/CT for prediction of pCR to PCRT remains debatable for LARC. The present study investigated and identified the 18F FDG PET/CT parameters for predicting the pCR in relation to the prognosis in patients with LARC treated with PCRT.
Patients and Methods Patients In the present study, 103 patients with newly diagnosed, nonmetastatic LARC and a pathologic diagnosis of adenocarcinoma were treated with capecitabine-based chemoradiotherapy. The institutional ethnic committee approved the present study, which was performed in accordance with the ethical standards of the institutional and/or national research committee and the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Written informed consent was waived because of the retrospective nature of the present study. The baseline staging workup included colon/rectosigmoidoscopy, endoscopic ultrasonography, abdominopelvic computed tomography, or magnetic resonance imaging. Also, all patients underwent
18F FDG PET/CT before and after PCRT. All patients had pathologically proven rectal adenocarcinoma with the distal end of the tumor located within 10 cm of the anal verge. No patient had evidence of distant metastasis at the staging workup. The main exclusion criteria were the absence of 18F FDG PET/CT images before or after PCRT, any previous treatment, and PCRT contraindications because of comorbidity.
Preoperative Chemoradiotherapy Preoperative radiation therapy (RT) of 45 Gy in 25 fractions was delivered to the pelvis over 5 weeks, followed by boost of a minimum of 5.4 to a maximum of 10.8 Gy to the primary tumor. During the same period, oral capecitabine, 825 mg/m2, was administered twice daily throughout the RT course, 7 d/wk, beginning the day of the start of RT and ending with the last dose of RT. All patients underwent surgery 6 to 8 weeks after PCRT completion.
18F FDG PET/CT Scans All patients were examined using a dedicated PET/CT scanner (Biograph 40, Siemens, Knoxville, TN), consisting of a dedicated germanium oxyorthosilicate full-ring PET scanner and a dual-slice helical CT scanner. Standard patient preparation included 8 hours of fasting and a serum glucose level of < 120 mg/dL before 18F FDG administration. 18F FDG PET/CT imaging was performed 60 minutes after injection of 18F FDG. The emission scan time per bed position was 3 minutes; 6 bed positions were acquired. The PET data were obtained using a high-resolution whole body scanner with an axial field of view of 21.6 cm. The average axial resolution varied from 2.0 mm full-width at halfmaximum in the center and 2.4 mm at 28 cm. The average total PET/CT examination time was 20 minutes. Attenuation correction was performed for all patients with iterative reconstruction. The PET/CT images were analyzed on 3 different planes: transverse, coronal, and sagittal. The pretreatment baseline 18F FDG PET/CT images were taken about 3 to 14 days before the start of PCRT (initial). The second interim 18F FDG PET/CT images were recorded during the course of PCRT (45 Gy of RT with 3 cycles of chemotherapy, second).
18F FDG PET/CT Image Analysis PET/CT data sets were evaluated by 2 nuclear physicians, who were unaware of all imaging, clinical, and pathologic results. Decisions concerning the analysis of 18F FDG PET/CT data sets were reached by consensus. The PET/CT data sets were analyzed quantitatively using the maximum standardized uptake value (SUVmax) of 18F FDG uptake. The region of interest was drawn on the area of abnormal 18F FDG uptake corresponding to the tumor in the initial and second scans. The SUVmax was obtained using the following formula:
SUV max ¼ maximum activity in the region of interest MBq gram injected dose MBq body weight ½grams :
2
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Phillip J. Koo et al The metabolic tumor volume (MTV) was determined as the total number of voxels with a threshold SUV of 40% of the SUVmax in the volume of interest. The total lesion glycolysis (TLG) was calculated as the MTV multiplied by its mean SUV (SUVmean). The changes (%, D) of each quantitative, volumetric parameter (P) of 18F FDG PET/CT were calculated as follows: ðPsecond Pinitial Þ DP ¼ 100% Pinitial
Pathologic Tumor Response Evaluation After surgery, the pathologic tumor response was classified by achievement of pCR. The degree of pathologic response after PCRT was confirmed by evaluation of the (y)pTNM categories according to the International Union Against Cancer (UICC, 7th edition, 2010). pCR is defined as ypT0N0. Also, we used the histologic tumor grading system consisting of the tumor regression grade (TRG). Regression grading stratifies the response semiquantitatively, dividing it into 5 grades according to the ratio of fibrosis to viable neoplasm as follows: TRG1, no residual cancer; TRG2, rare residual cancer cells; TRG3, fibrosis outgrowing residual cancer; TRG4, residual cancer outgrowing fibrosis; and TRG5, the absence of regressive changes.
Statistical Analysis All numerical data are expressed as the median and range. Receiver operating characteristic (ROC) curves for each parameter were derived and evaluated by comparing the areas under the curves for the prediction of pCR. The sensitivity and specificity of each parameter were determined at the optimal cutoff values using ROC curve analyses. The c2 test, Fisher exact test, and Mann-Whitney U test were used to analyze the statistical differences in the categorical data, the 18F FDG PET/CT parameters between those with and without a pCR. Survival curves stratified by post-PCRT SUVmax (SUVmax2) and the change in SUVmax (DSUVmax) of 18F FDG PET/CT were generated. The log-rank test was used to compare survival between each group. Data analyses were conducted with MedCalc, version 14.12.0 (MedCalc Software, Ostend, Belgium). Statistical significance was defined as P < .05.
Results Patient Characteristics A total of 103 patients were included in the present study. The patient characteristics and tumor characteristics are listed in Table 1. The median age was 66 years (range, 49-85 years). The patients were predominantly male (76.7%). Most tumors were located 5 cm from the anal verge. Of the 18F FDG PET/CT parameters, the post-PCRT values of SUVmax, MTV, and TLG were much lower in those with pCR than in those without a pCR. The changes in SUVmax, MTV, and TLG were much greater in those with a pCR than in those without a pCR. The histopathologic characteristics of tumor specimens after PCRT are listed in Table 2.
ROC Analysis for Prediction of pCR To find the cutoff values of the quantitative and volumetric parameters of 18F FDG PET/CT that will predict a pCR, the thresholds of each parameter were calculated using the Youden
Table 1 Patient Characteristics pCR (ypT0N0) Yes (n [ 22)
No (n [ 81)
66
12
38
<66
10
43
Characteristic Age (year)
.6931
Gender Male Female
P Value
1.0 17
62
5
19
Distance from anal verge (cm)
.9611
<5
6
24
5
16
57
cT2
0
4
cT3
20
65
cT4
2
12
cN ()
7
14
cN (þ)
15
67
Clinical T stage
.4186
Clinical N stage
.2293
PET/CT parameters SUVmax1
7.1 (2.4-20)
2.5-25
SUVmax2
2.25 (1.3-5.1)
5.6 (1.7-21.7)
<.0001
DSUVmax (%)
.0926
68.65 (45.8-82)
46.5 (7.9-71.8)
<.0001
SUVmean1
4.1 (2.2-13.1)
6.4 (1.8-17.3)
.0555
SUVmean2
2.65 (1.2-7.4)
4 (1.2-11.6)
.0568
DSUVmean (%)
33.7 (20-63.5)
33.1 (9.8-62.1)
.4689
19.5 (2.7-277.8)
21.2 (3-140.1)
.359
MTV2
7.9 (1.5-162.3)
14.7 (1.4-117.5)
.017
DMTV (%)
47.9 (34.9-68.5)
31.3 (7.7-63.7)
<.0001
TLG1
89.85 (5.9-833.5)
136 (11.4-1257.7)
.1856
TLG2
29.9 (2.3-373.3)
54.9 (4.1-586.2)
.0172
DTLG (%)
70.8 (55.2-76.4)
55.5 (31.2-78.2)
<.0001
15
61
APR
5
19
Hartmann’s operation
2
1
MTV1
Surgical procedure LAR
.1504
Differentiation Well Moderate/poor
.4185 4
24
18
57
Data presented as n or median (range). Abbreviations: D ¼ change in parameter in question; APR ¼ abdominopelvic resection; CT ¼ computed tomography; LAR ¼ low anterior resection; MTV1 ¼ metabolic tumor volume at first scan; MTV2 ¼ MTV after preoperative chemoradiotherapy; pCR ¼ pathologic complete response; PET ¼ positron emission tomography; SUVmax1 ¼ maximum standardized uptake value at first scan; SUVmax2 ¼ SUVmax after preoperative chemoradiotherapy; SUVmean1 ¼ mean SUV at first scan; SUVmean2 ¼ mean SUV after preoperative chemoradiotherapy; TLG1 ¼ total lesion glycolysis at first scan; TLG2 ¼ TLG after preoperative chemoradiotherapy.
index and ROC curve. Figure 1 and Table 3 demonstrate the results ROC analyses. Among the various 18F FDG PET/CT parameters, SUVmax2, DSUVmax, post-PCRT MTV (MTV2), DMTV, postPCRT TLG (TLG2), and DTLG were statistically significant predictors of a pCR.
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Interim PET/CT for pCR and Prognosis Table 2 Tumor Characteristics at Histopathologic Examination Characteristic
n (%)
TRG TRG1
22 (21.4)
TRG2
13 (12.6)
TRG3
45 (43.7)
TRG4
23 (22.3)
Pathologic TNM stage (ypTN) ypT0N0 ypT1N0-N1
22 (21.4) 1 (1)
ypT2N0
3 (2.9)
ypT2N1
18 (17.5)
ypT2N2
45 (43.6)
ypT3N0
0
ypT3N1
3 (2.9)
ypT3N2
11 (10.7)
ypT4N0-N2
0
Abbreviation: TRG ¼ tumor regression grade.
When a SUVmax2 2.5 was used as the cutoff, the sensitivity and specificity of 18F FDG PET/CT for the prediction of a pCR was 68.2% (95% confidence interval [CI], 45.1%-86.1%) and 87.7%
(95% CI, 78.5%-93.9%), respectively. The AUC was 0.864 (95% CI, 0.783-0.924) and the standard error (SE) was 0.0399 (P < .0001). When DSUVmax 62.2% was used as the cutoff, the sensitivity and specificity of 18F FDG PET/CT for the prediction of pCR was 90.9% (95% CI, 70.8%-98.9%) and 80.3% (95% CI, 69.9%88.3%), respectively. The AUC was 0.895 (95% CI, 0.819-0.947) and the SE was 0.0399 (P < .0001). The post-PCRT MTV (MTV2) predicting a pCR resulted in 95.5% sensitivity (95% CI, 77.2%-99.9%), 32.1% specificity (95% CI, 22.2%-43.4%), 0.666 AUC (95% CI, 0.567-0.756; SE, 0.0653; P ¼ .01) for cutoff values of 23.4. The DMTV resulted in 77.3% sensitivity (95% CI, 54.6%-92.2%), 88.9% specificity (95% CI, 80%-94.8%), 0.882 AUC (95% CI, 0.803-0.937; SE, 0.0351; P < .0001) for cutoff values > 43.9%. When TLG2 31.8 was used as the cutoff, the sensitivity and specificity of 18F FDG PET/CT for the prediction of a pCR was 59.1% (95% CI, 36.4%-79.3%) and 69.1% (95% CI, 57.9%78.9%), respectively. The AUC was 0.666 (95% CI, 0.566-0.756) and the SE was 0.0666 (P ¼ .01). When DTLG 60.4% was used as a cutoff, the sensitivity and specificity of 18F FDG PET/CT for the prediction of a pCR was 86.4% (95% CI, 65.1%-97.1%) and 80.3% (95% CI, 69.9%88.3%), respectively. The AUC was 0.884 (95% CI, 0.805-0.938) and the SE was 0.0388 (P < .0001).
Figure 1 Receiver Operating Characteristic Analysis Results for Prediction of Pathologic Complete Response Using Fluorine-18 Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography Parameters
4
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Abbreviations: D ¼ change in specified parameter; MTV2 ¼ metabolic tumor volume after preoperative chemoradiotherapy; SUVmax ¼ maximum standardized uptake value; SUVmax2 ¼ standardized uptake value after preoperative chemoradiotherapy; TLG ¼ total lesion glycolysis; TLG2 ¼ total lesion glycolysis after preoperative chemoradiotherapy.
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Phillip J. Koo et al Table 3 Prediction of pCR Using 18F FDG PET/CT Parameters Variable SUVmax1 8.1 SUVmax2 2.5 DSUVmax 62.2% SUVmean1 4.5 SUVmean2 3.6 DSUVmean >38.5% MTV1 24.1 MTV2 23.4 DMTV >43.9% TLG1 100.8 TLG2 31.8 DTLG >60.4%
Sensitivity (%)
95% CI (%)
Specificity (%)
95% CI (%)
AUC
95% CI
SE
P Value
63.6 68.2 90.9 63.6 72.7 31.8 72.7 95.5 77.3 59.1 59.1 86.4
40.7-82.8 45.1-86.1 70.8-98.9 40.7-82.8 49.8-89.3 13.9-54.9 49.8-89.3 77.2-99.9 54.6-92.2 36.4-79.3 36.4-79.3 65.1-97.1
70.4 87.7 80.3 72.8 60.5 83.9 46.9 32.1 88.9 59.3 69.1 80.3
59.2-80 78.5-93.9 69.9-88.3 61.8-82.1 49-71.2 74.1-91.2 35.7-58.3 22.2-43.4 80-94.8 47.8-70.1 57.9-78.9 69.9-88.3
0.617 0.864 0.895 0.634 0.639 0.551 0.564 0.666 0.882 0.592 0.666 0.884
0.516-0.711 0.783-0.924 0.819-0.947 0.533-0.726 0.538-0.731 0.449-0.649 0.463-0.661 0.567-0.756 0.803-0.937 0.491-0.688 0.566-0.756 0.805-0.938
0.0821 0.0399 0.0348 0.079 0.0741 0.0723 0.0692 0.0653 0.0351 0.0711 0.0666 0.0388
.1532 <.0001 <.0001 .0908 .0613 .4848 .3554 .0109 <.0001 .1939 .0127 <.0001
Abbreviations: D ¼ change in parameter in question; AUC ¼ area under the curve; CI ¼ confidence interval; CT ¼ computed tomography; MTV1 ¼ metabolic tumor volume at first scan; MTV2 ¼ MTV after preoperative chemoradiotherapy; pCR ¼ pathologic complete response; PET ¼ positron emission tomography; SE ¼ standard error; SUVmax1 ¼ maximum standardized uptake value at first scan; SUVmax2 ¼ SUVmax after preoperative chemoradiotherapy; SUVmean1 ¼ mean SUV at first scan; SUVmean2 ¼ mean SUV after preoperative chemoradiotherapy; TLG1 ¼ total lesion glycolysis at first scan; TLG2 ¼ TLG after preoperative chemoradiotherapy.
Univariate and Multivariate Analysis of 18F FDG PET/ CT Parameters for a pCR The univariate and multivariate analysis results of the 18F FDG PET/CT parameters for the prediction of pCR are listed in Table 4. Of the 103 patients, a pCR occurred in 22 patients (21.4%). Univariate analysis showed that the SUVmax2, MTV2, postPCRT TLG (TLG2), DSUVmax, DMTV, and DTLG were associated with the pCR in patients with LARC treated with PCRT. Multivariate logistic regression analysis demonstrated SUVmax2 and DSUVmax are independent factors for a pCR.
Overall Survival The Kaplan-Meier analysis for OS is shown in Figure 2. KaplanMeier analysis showed SUVmax2 (c2, 6.74; hazard ratio, 3.58; 95% CI, 1.8-7.11; P ¼ .009) and DSUVmax (c2, 15.1; HR, 3.49; 95% CI, 1.87-6.5; P ¼ .0001) were associated with OS.
Discussion
The results of the present study that the SUVmax2 and DSUVmax could predict the pCR in patients with LARC and that these parameters are related to relapse-free survival and OS.
Generally, patients with LARC will have a greater incidence of locoregional recurrence, even after treatment. Thus, to reduce the risk of locoregional recurrence, PCRT is crucial to prevent local recurrence.5 PCRT has resulted in various tumor responses, ranging from a complete response in about 15% to 30% of cases to no response or even progression.9,15 It is well known that the tumor response to PCRT is a potent predictor and related to the prognosis.16,17 Therefore, accurate prediction of the tumor response, especially pCR, to PCRT in LARC is essential. Moreover, accurate and early recognition of pCR offers the potential to avoid surgical overtreatment without jeopardizing local control or long-term survival.9,11,18,19 18F FDG PET/CT has generally been recognized as a promising functional imaging tool for evaluating the tumor response and is superior to other morphologic imaging modalities.10 However, the optimal method for quantitative analysis has yet to be determined. Of the 18F FDG PET/CT parameters, the SUVmax has been the most commonly studied in previous quantitative analyses of glucose metabolism in various cancers.20,21 Recently, Maffione et al22 investigated 15 different 18F FDG PET/CT qualitative and quantitative parameters for prediction of
Table 4 Univariate and Multivariate Analysis Results of 18F FDG PET/CT Parameters for pCR pCR (ypT0N0) Univariate Analysis Variable SUVmax2 2.5 DSUVmax >62.2% MTV2 23.4 DMTV >43.9% TLG2 31.8 DTLG >60.4%
Multivariate Analysis
OR
95% CI
P Value
OR
95% CI
P Value
15.2 37.6 9.92 24.14 3.23 25.72
4.98-46.39 7.99-177.16 1.26-77.86 7.29-79.89 1.22-8.55 6.77-97.75
<.0001 <.0001 .0032 <.0001 .0166 <.0001
3.2 6.1 4.36 14.31 1.38 8.17
1.57-10.5 1.72-15.4 0.17-23.7 0.51-400.9 0.57-3.3 0.25-259.1
.0241 .0045 .681 .1176 .4459 .2337
Abbreviations: D ¼ change in parameter in question; CI ¼ confidence interval; CT ¼ computed tomography; MTV1 ¼ metabolic tumor volume at first scan; MTV2 ¼ MTV after preoperative chemoradiotherapy; OR ¼ odds ratio; pCR ¼ pathologic complete response; PET ¼ positron emission tomography; SE ¼ standard error; SUVmax1 ¼ maximum standardized uptake value at first scan; SUVmax2 ¼ SUVmax after preoperative chemoradiotherapy; SUVmean1 ¼ mean SUV at first scan; SUVmean2 ¼ mean SUV after preoperative chemoradiotherapy; TLG1 ¼ total lesion glycolysis at first scan; TLG2 ¼ TLG after preoperative chemoradiotherapy.
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Interim PET/CT for pCR and Prognosis Figure 2 Kaplan-Meier Survival Curve for Relapse-Free Survival and Overall Survival (OS) Stratified by Maximum Standardized Uptake Value After Preoperative Chemoradiotherapy (SUVmax2) and Change in Maximum Standardized Uptake Value (DSUVmax)
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the pathologic response to PCRT in LARC patients. They concluded that among these parameters, some of which cannot be immediately obtained (MTV and TLG) from a routine workstation, the most commonly used, post preoperative concurrent chemoradiotheraphy (SUVmax-post), showed the best accuracy in predicting TRG.22 Similar to the present study, other studies have demonstrated the predictive value of the post-PCRT SUVmax for the prediction of tumor response in patients with LARC. Bampo et al23 showed the possible predictive role of 18F FDG PET/CT for the assessment of the pathologic response in LARC after neoadjuvant chemoradiotherapy.23 In their study, using a threshold SUV of 5.4 after completion of neoadjuvant treatment, 18F FDG PET/CT could differentiate between pCR and non-pCR with 81% sensitivity, 100% specificity, and 90% overall accuracy. Another study showed that with a SUVmax2 cutoff of > 4.3 for predicting pCR, the sensitivity and specificity of 18F FDG PET/CT was 79.5% and 66.7%, respectively.24 Kim et al25 showed that for the pCR, the post-chemoradiotherapy SUVmax was a significant parameter on univariate and multivariate analysis, with a sensitivity of 73.7%, a specificity of 63.7%, and an accuracy of 64.9%, for a cutoff value of 3.55. The present study showed that, not only the PCRT SUVmax2, but also the DSUVmax, after PCRT were potent predictors of a pCR in patients with LARC. Similar to the present study, a recent study demonstrated that a DSUVmax of 32% could predict pCR with a sensitivity of 75% and specificity of 100%.26 Recently, some studies have indicated that the SUVmax, which only reflects a single point in the tumor, will not always be representative of the whole tumor.27 To overcome this weak point of the SUVmax, volumetric parameters such as MTV and TLG have been developed to calculate the metabolic activity in the whole tumor. The MTV is a well-known prognostic factor in various cancers; it represents the dual characteristics of tumor volume and the degree of 18F FDG uptake by the tumor.28 Also, TLG has been proposed as a more accurate parameter, because it accounts for both SUVmean and MTV.27 Using these volumetric parameters, we investigated their predictive value for the prediction of pCR in LARC patients treated with PCRT. In the present study, univariate analysis revealed that MTV2, TLG2, DMTV, and DTLG were significant predictors of
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pCR; however, these were significant on multivariate analysis. In contrast to the present study, other studies have revealed that the DTLG was the best predictor of pCR after PCRT using different thresholds.29,30 Although many previous studies have demonstrated the useful predictive role of 18F FDG PET/CT for pCR and TRG in LARC patients, other studies have failed to show the same role. A recent study investigated the predictive values of quantitative and volumetric parameters of 18F FDG PET/CT for the prediction for pCR in 35 LARC patients who underwent neoadjuvant chemoradiotherapy. However, the changes seen in 18F FDG PET/CT had limited value in predicting the pCR.31 Another study also concluded that neither PET nor CT scans have adequate predictive value to be clinically useful in distinguishing a pCR from an incomplete response. Also, they concluded that 18F FDT PET/CT and CT should not be obtained for the purposes of attempting to predict a pCR after neoadjuvant chemoradiotherapy for LARC patients.32 In the present study, SUVmax2 and DSUVmax, as the best predictive parameters of pCR, were used to identify patients with a high risk of disease recurrence and death. For both relapse-free survival and OS, the Kaplan-Meier survival analysis showed statistically significant differences in the probability of recurrence and death when stratified by the SUVmax2 and DSUVmax values. The most important limitation of the present study was the method used to establish the cutoff values of 18F FDG PET/CT parameters for the prediction of pCR. The cutoff values used in the present study were chosen from the ROC curves, reflecting our preference for the balance between the sensitivity and specificity of the test. However, these preferences could be compensated for by the relatively larger number of included patients. Also, the male predominance in the present study might have had an effect on the results of our study. In future studies, well-balanced age- and gender-matched cohort selection should be considered. Finally, the wide range of scan time before PCRT and the interim PET/CT could also be a major limitation of the present study, because the time variation could change the results of the tumor response evaluation. Because the study was retrospective, standardization of the scan time before and between chemoradiotherapy was not available.
Phillip J. Koo et al Conclusion The present study has shown the capability of interim 18F FDG PET/CT parameters to predict the achievement of pCR after PCRT in LARC patients. Of the studied parameters, SUVmax2 and DSUVmax were potent predictors for pCR and well-associated with OS.
Clinical Practice Points Research has shown that F-18 FDG PET/CT to be a valuable
functional imaging modality that has demonstrated distinguished capabilities in cancer detection, planning and monitoring treatment, and prognosis prediction in colorectal and anal cancers. However, the role of F-18 FDG PET/CT for prediction of pCR to PCRT remains debatable in LARC. In this study, we found that the capability of interim F-18 FDG PET/CT parameters to predict the achievement of pCR after PCRT in LARC patients. Among the parameters, the SUVmax2 and ▵SUVmax were the potent predictors for pCR and well associated with OS. This finding brings attention to the potential use of volumetric parameters change of F-18 FDG PET/CT during PCRT in LARC patients. The results of our study may provide valuable information for the development of effective strategies to predict pCR and prognosis in patients with LARC who received PCRT.
Acknowledgment This work was supported by the Financial Supporting Project of Long-term Overseas Dispatch of PNU’s Tenure-track Faculty, 2014.
Disclosure The authors declare that they have no competing interests.
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