Adenocarcinomas of the esophagus: Response to chemoradiotherapy is associated with decrease of metabolic tumor volume as measured on PET–CT: Comparison to histopathologic and clinical response evaluation

doi:10.1016/j.radonc.2008.06.014

Radiotherapy and Oncology

Volume 89, Issue 3, December 2008, Pages 278-286

https://doi.org/10.1016/j.radonc.2008.06.014 Get rights and content

Abstract

Purpose

We determined whether evaluation of treatment response is feasible by measuring metabolic tumor volume parameters on 18F-FDG (Fluorodeoxyglucose) PET–CT (Positron emission tomography–Computed tomography). We compared the response evaluation based on metabolic tumor volume parameters to a histopathologic and clinical response evaluation (clinical response criteria: RECIST criteria = Response evaluation criteria in solid tumors, and WHO criteria = World health organization).

Patients and methods

A total of 51 study subjects with adenocarcinomas (Type I due to Siewert classification) of the esophagus underwent PET–CT scans before and after neoadjuvant chemoradiotherapy. Tumor volume, maximum and mean standardized uptake values (SUV) were assessed before and after chemoradiotherapy. Furthermore, the total lesion glycolysis (TLG) was calculated by multiplying the tumor volume by the mean SUV of the volume. Clinical response evaluation was performed with endoscopic ultrasound and CT using RECIST and WHO criteria. The reference standard for treatment response was the postsurgical histopathology.

Results

The decrease of tumor volume between the pre- and post-treatment PET–CT scans was a better predictor of histopathologic response and survival than the decrease of the SUV and of the clinical response evaluation based on RECIST and WHO criteria. The highest accuracy, however, was achieved when using the TLG for the identification of treatment responders. A decrease of the TLG by >78% between pre- and post-therapy scans predicted histopathologic response with a sensitivity and specificity of 91% and 93%, respectively.

Conclusions

Tumor volume and TLG can be used to assess treatment response and survival in patients with esophageal adenocarcinoma.

Section snippets

Patients

Fifty-one patients with adenocarcinomas of the esophagus who had undergone PET–CT scans before and after neoadjuvant chemoradiotherapy were included in this study. Tumor grade and tumor type of all malignant esophageal lesions were determined by histological examination. The histopathology after neoadjuvant chemoradiotherapy was the reference standard for assessing treatment response. Histopathologic response was defined as <10% viable cells in the postsurgical tumor specimen as used in

Association between histopathologic response and metabolic tumor volume

All pre- and post-treatment tumor volumes were measurable with the above-mentioned technique of tumor delineation both on PET and on PET–CT images. Table 2 demonstrates the association between the decrease of tumor volume parameters (maximum SUV, volume, SUV of volume, and TLG) and the histopathologic response to chemoradiotherapy. The decrease was calculated as the relative difference (in %) in tumor volume parameters between the pre-treatment and the post-treatment PET–CT scans. Table 2 shows

Discussion

Although neoadjuvant chemoradiotherapy for esophageal cancer has been studied for more than 25 years, its usefulness has remained controversial [1], [2], [3], [4], [5], [6]. However, based on the recent publications of randomized controlled trials, neoadjuvant chemoradiotherapy has become the standard choice for the treatment of locally advanced carcinomas of the esophagus [1], [2].

Unfortunately until today, no reliable methods for response prediction to chemoradiotherapy exist for esophageal

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To evaluate the prognostic role of [¹⁸F]FDG PET/CT metabolic parameters in gastric cancer (GC) and gastroesophageal adenocarcinoma (GEJAC) patients receiving neoadjuvant chemotherapy.
In this retrospective study, 31 patients with biopsy-proven GC or GEJAC were included between August 2016 and March 2020. [¹⁸F]FDG PET/CT was performed before the neoadjuvant chemotherapy. Primary tumours’ semi-quantitative metabolic parameters were extracted. All patients received a perioperative FLOT regimen thereafter. Post-chemotherapy [¹⁸F]FDG PET/CT was performed in most patients (17/31). All patients underwent surgical resection. Histopathology response to treatment and progression-free survival (PFS) were evaluated. Two-sided p-values < 0.05 were considered statistically significant.
Thirty-one patients (mean age = 62 ± 8), including 21 GC and 10 GEJAC patients, were evaluated. 20/31(65%) patients were histopathology responders to neoadjuvant chemotherapy, including twelve complete and eight partial responders. During the median follow-up of 42.0 months, nine patients experienced recurrence. The median PFS was 60(95% CI:32.9–87.1) months. Pre-neoadjuvant chemotherapy SULpeak was significantly correlated with pathological response to treatment (p-value = 0.03;odds ratio = 16.75). In survival analysis, SUVmax (p-value = 0.01;hazard ratio[HR] = 1.55), SUVmean (p-value = 0.04;HR = 2.73), SULpeak (p-value < 0.001;HR = 1.91) and SULmean (p-value = 0.04;HR = 4.22) in the post-neoadjuvant chemotherapy pre-operative [¹⁸F]FDG PET/CT showed significant correlation with PFS. Additionally, aspects of staging were significantly correlated with PFS (p-value = 0.01;HR = 2.21).
Pre-neoadjuvant chemotherapy [¹⁸F]FDG PET/CT parameters, especially SULpeak, could predict the pathological response to treatment in GC and GEJAC patients. Additionally, in survival analysis, post-chemotherapy metabolic parameters significantly correlated with PFS. Thus, performing [¹⁸F]FDG PET/CT before chemotherapy may help to identify patients at risk for inadequate response to perioperative FLOT and, after chemotherapy, may predict clinical outcomes.
Prognostic value of PERCIST and PET/CT metabolic parameters in patients with esophageal cancer after neoadjuvant treatment
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Valorar la utilidad clínica de los criterios PERCIST y de los cambios en los parámetros cuantitativos de la PET/TC con [¹⁸F]FDG como factores pronósticos para la supervivencia libre de progresión y la supervivencia cáncer-específica en pacientes con cáncer de esófago tratados mediante quimiorradioterapia.
Se valoraron retrospectivamente 50 pacientes (48 hombres) diagnosticados de cáncer de esófago durante un intervalo de 7,5 años. Se utilizaron los criterios PERCIST para valorar la respuesta a la neoadyuvancia. Asimismo, se determinaron las variaciones del SUV máximo, volumen metabólico tumoral y glucólisis tumoral total entre los estudios PET/TC pre- y postratamiento. Las curvas ROC, el método de Kaplan-Meier y el modelo de regresión de Cox se aplicaron para el análisis de factores pronósticos y curvas de supervivencia.
El seguimiento medio fue de 26,8 meses, produciéndose 40 recurrencias-progresiones y 41 muertes. El análisis de supervivencia mostró curvas de supervivencia cáncer-específica con diferencias estadísticamente significativas en relación con los criterios PERCIST y la variación del volumen metabólico tumoral y la glucólisis tumoral total. Los criterios PERCIST fueron el único factor predictivo independiente en el análisis multivariante. Ni el SUV máximo ni el tamaño tumoral fueron predictores para ninguno de los criterios de evaluación.
La aplicación de los criterios PERCIST, así como el cambio de volumen metabólico tumoral y glucólisis tumoral total de los estudios PET/TC demostraron ser factores pronósticos para la supervivencia cáncer-específica en pacientes de nuestro entorno tratados por cáncer de esófago. Los resultados podrían ayudar a personalizar el tratamiento.
To assess the clinical utility of PERCIST criteria and changes in [¹⁸F]FDG PET/CT quantitative parameters as prognostic factors for progression-free survival and cancer-specific survival in patients with esophageal cancer treated by chemoradiotherapy.
Fifty patients (48 men) diagnosed with esophageal cancer were retrospectively evaluated over a 7.5-year interval. PERCIST criteria were used to assess response to neoadjuvant therapy. Variations in the metabolic parameters maximum SUV, metabolic tumor volume and total lesion glycolysis between pre- and post-treatment PET/CT studies were also determined. ROC curves, Kaplan-Meier method and Cox regression model were used for the analysis of prognostic factors and survival curves.
The average follow-up was 26.8 months, with 40 recurrences-progressions and 41 deaths. Survival analysis showed statistically significant differences in cancer-specific survival curves for PERCIST criteria and variation of metabolic tumor volume and total lesion glycolysis. PERCIST criteria were the only independent predictor in the multivariate analysis. Neither maximum SUV nor tumor size were predictors for any of the assessment criteria.
Application of PERCIST criteria as well as change in metabolic tumor volume and total lesion glycolysis from PET/CT studies proved to be prognostic factors for cancer-specific survival in patients in our setting treated for esophageal cancer. The results could help to personalize treatment.
Circulating Tumor DNA Analysis for Detection of Minimal Residual Disease After Chemoradiotherapy for Localized Esophageal Cancer
2020, Gastroenterology
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Given the observation that ctDNA analysis appeared to be more sensitive for prediction of future distant metastasis than local recurrence, we hypothesized that integration of ctDNA with an imaging biomarker capable of detecting residual local disease would further improve performance. Prior studies have suggested that changes in fluorodeoxyglucose uptake on PET-CT after treatment for localized ESCA are associated with response to therapy and survival.32–34 In an exploratory analysis, we identified a cutpoint for total lesion glycolysis (TLG) that optimally stratified patients who experienced recurrence from those who did not.
Biomarkers are needed to risk stratify after chemoradiotherapy for localized esophageal cancer. These could improve identification of patients at risk for cancer progression and selection of additional therapy.
We performed deep sequencing (CAncer Personalized Profiling by deep Sequencing, [CAPP-Seq]) analyses of plasma cell-free DNA collected from 45 patients before and after chemoradiotherapy for esophageal cancer, as well as DNA from leukocytes and fixed esophageal tumor biopsy samples collected during esophagogastroduodenoscopy. Patients were treated from May 2010 through October 2015; 23 patients subsequently underwent esophagectomy, and 22 did not undergo surgery. We also sequenced DNA from blood samples from 40 healthy control individuals. We analyzed 802 regions of 607 genes for single-nucleotide variants previously associated with esophageal adenocarcinoma or squamous cell carcinoma. Patients underwent imaging analyses 6–8 weeks after chemoradiotherapy and were followed for 5 years. Our primary aim was to determine whether detection of circulating tumor DNA (ctDNA) after chemoradiotherapy is associated with risk of tumor progression (growth of local, regional, or distant tumors, detected by imaging or biopsy).
The median proportion of tumor-derived DNA in total cell-free DNA before treatment was 0.07%, indicating that ultrasensitive assays are needed for quantification and analysis of ctDNA from localized esophageal tumors. Detection of ctDNA after chemoradiotherapy was associated with tumor progression (hazard ratio, 18.7; P < .0001), formation of distant metastases (hazard ratio, 32.1; P < .0001), and shorter disease-specific survival times (hazard ratio, 23.1; P < .0001). A higher proportion of patients with tumor progression had new mutations detected in plasma samples collected after chemoradiotherapy than patients without progression (P = .03). Detection of ctDNA after chemoradiotherapy preceded radiographic evidence of tumor progression by an average of 2.8 months. Among patients who received chemoradiotherapy without surgery, combined ctDNA and metabolic imaging analysis predicted progression in 100% of patients with tumor progression, compared with 71% for only ctDNA detection and 57% for only metabolic imaging analysis (P < .001 for comparison of either technique to combined analysis).
In an analysis of cell-free DNA in blood samples from patients who underwent chemoradiotherapy for esophageal cancer, detection of ctDNA was associated with tumor progression, metastasis, and disease-specific survival. Analysis of ctDNA might be used to identify patients at highest risk for tumor progression.
The clinical value of PERCIST to predict tumour response and prognosis of patients with oesophageal cancer treated by neoadjuvant chemoradiotherapy
2020, Clinical Radiology
Citation Excerpt :
The use of SUL reduces dependence on patient weight as compared to the standard body weight normalised SUV and SULpeak reduces potential inconsistencies of single pixel measurements due to noise.28 The usefulness of 18F-FDG-volumetric parameters such as MTV and TLG for predicting treatment response also have been investigated in patients with various types of cancer including oesophageal cancer.29,30 To the authors' knowledge, a few studies have evaluated pathological response to NACRT using SUV parameters, volumetric parameters or PERCIST in oesophageal cancer patients.14,31,32
To examine whether Positron Emission Tomography Response Criteria in Solid Tumours (PERCIST) is useful to predict tumour response and prognosis of patients with oesophageal cancer who received neoadjuvant chemoradiotherapy (NACRT) followed by surgery.
This multicentre retrospective study included 60 patients with oesophageal cancer who underwent 2-[¹⁸F]-fluoro-2-deoxy-d-glucose positron-emission tomography/computed tomography (¹⁸F-FDG-PET/CT) before and after NACRT prior to surgery from January 2007 and June 2016. The correlation between pathological response and PERCIST was assessed by χ² test. The prognostic significance was assessed by the Kaplan–Meier method and Cox regression analysis.
There were 30 responders and 30 non-responders pathologically. The complete metabolic response (CMR), partial metabolic response (PMR), stable metabolic disease (SMD), and progressive metabolic disease (PMD) were seen in 22, 29, seven, and two patients, respectively. There was a significant correlation between pathological response and PERCIST (p<0.001). Forty patients showed eventual progression, and 20 patients were alive without progression between the start of NACRT and last clinical follow-up (median follow-up period; 27 months [range, 3–107]). Pathological stage and PERCIST were significant for progression-free survival (PFS; p=0.044 and 0.006, respectively) and also significant for overall survival (OS; p=0.009 and 0.001, respectively) at univariate analysis. Pathological lymph node staging was also significant for OS at univariate analysis (p=0.018). At multivariate analysis, PERCIST remained significant and independent for PFS (hazard ratio [HR]: 1.59, p=0.046) and OS (HR: 1.82, p=0.008).
PERCIST may be useful for predicting tumour response and prognosis of patients with oesophageal cancer who received NACRT.
Intratreatment Response Assessment With 18F-FDG PET: Correlation of Semiquantitative PET Features With Pathologic Response of Esophageal Cancer to Neoadjuvant Chemoradiotherapy
2018, International Journal of Radiation Oncology Biology Physics
Citation Excerpt :
In our analysis, volumetric PET parameters (which extracted volume and SUV data from the entire hypermetabolic tumor) were more accurate than intensity PET parameters, which extracted data from only the most metabolically active region. Other studies, mostly using posttreatment PET scans, have similarly reported that volumetric PET parameters are better correlated to histopathologic response than are conventional SUV features such as SUV max (9, 21-23). A significant independent association with pretreatment volumetric PET parameters (MTV) and survival has also been demonstrated (24, 25).
This prospective study seeks to extract semiquantitative positron emission tomography (PET) features from 18F-fluorodeoxyglucose PET scans performed before and during neoadjuvant chemoradiotherapy for esophageal cancer and to compare their accuracy in predicting histopathologic response.
From 2012 to 2016, 26 patients with esophageal cancer underwent pretreatment and intratreatment PET scans during chemoradiotherapy followed by surgery. Median patient age was 63 years (interquartile range, 58-68 years); 26 patients had esophageal adenocarcinoma, and 3 had esophageal squamous cell carcinoma. The intratreatment PET scan was performed at a median of 32.4 Gy (interquartile range, 30.6-32.4 Gy). PET features of the primary site including maximum standardized uptake value (SUV), SUV mean, metabolic tumor volume, and total lesion glycolysis were extracted from the pretreatment and intratreatment PET scans. Patients were histopathologic responders if there was complete or near-complete tumor response by modified Ryan scheme. Mean values of PET features were compared between histopathologic responders and nonresponders. The area under the receiver operating characteristic curve (AUC) was used to compare the accuracy of PET features in predicting histopathologic response.
Eleven patients (42%) were histopathologic responders. PET features most discriminatory of histopathologic response on AUC analysis were volumetric PET features from the intratreatment PET including metabolic tumor volume based on manual contour (AUC, 0.73; 95% confidence interval, 0.52-0.93) and total lesion glycolysis based on semiautomatic 40% SUV threshold (AUC, 0.73; 95% confidence interval, 0.53-0.94).
Volumetric PET features from the intratreatment PET were the most accurate predictors of histopathologic response.
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PET/CT in esophageal cancerAdenocarcinomas of the esophagus: Response to chemoradiotherapy is associated with decrease of metabolic tumor volume as measured on PET–CT: Comparison to histopathologic and clinical response evaluation

Abstract

Purpose

Patients and methods

Results

Conclusions

Section snippets

Patients

Association between histopathologic response and metabolic tumor volume

Discussion

Lancet Oncol

Ann Thorac Surg

Ann Oncol

Int J Radiation Oncology Biol Phys

Mol Imaging Biol

Int J Radiat Oncol Biol Phys

Radiother Oncol

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

J Thorac Cardiovasc Surg

Clin Positron Imaging

Eur J Cancer

Int J Rad Therapy Oncol Biol Phys

Ann Oncol

PET/CT in esophageal cancer
Adenocarcinomas of the esophagus: Response to chemoradiotherapy is associated with decrease of metabolic tumor volume as measured on PET–CT: Comparison to histopathologic and clinical response evaluation