CT on radiation treatment in patients with esophageal cancer: A systematic review

Critical Reviews in Oncology/Hematology 107 (2016) 128–137

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Critical Reviews in Oncology/Hematology journal homepage: www.elsevier.com/locate/critrevonc

Impact of PET/CT on radiation treatment in patients with esophageal cancer: A systematic review Jing Lu a,1 , Xiang-dong Sun b,1 , Xi Yang a , Xin-yu Tang a , Qin Qin a , Hong-cheng Zhu a , Hong-yan Cheng c , Xin-chen Sun a,∗ a

Department of Radiation Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, PR China Department of Radiation Oncology, The 81st Hospital of PLA, Nanjing 210002, PR China c Department of Synthetic Internal Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, PR China b

Contents 1. 2.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128 Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129 2.1. Literature search strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129 2.2. Selection criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129 2.3. Data extraction and analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129 3. Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129 3.1. Combine PET/CT scanning and TNM staging of esophageal cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130 3.2. Combine PET/CT scanning and optimization of radiotherapy planning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130 3.3. Combine PET/CT scanning and therapeutic monitoring of nCRT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132 3.4. Other PET radiotracers clinically used in esophageal cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132 3.4.1. (18F)-3-Deoxy-3-fluorothymidine[18F-FLT] . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132 3.4.2. (18F) 3-Fluoro-1-(2-nitro-1-imidazolyl)-2-propanol [18F-FMISO] . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132 4. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134 Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135 Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135

a r t i c l e

i n f o

Article history: Received 27 September 2015 Received in revised form 10 July 2016 Accepted 31 August 2016 Keywords: Esophageal cancer Positron emission tomography Radiotherapy Biological target

a b s t r a c t Purpose: With the advances in radiotracers, positron emission tomography/computed tomography (PET/CT) is recognized as a useful adjunct to anatomic imaging with CT, MRI and endoscopic ultrasonography (EUS). The objective of this review was to comprehensively analyze the roles of PET/CT for the radiotherapy of esophageal cancer. Methods: In this review, we focused on issues concerning the application of PET/CT in TNM staging, target volume delineation and response to therapy, both for the primary tumor and regional lymph nodes. Furthermore, the following questions were addressed: how does PET/CT guide appropriate treatment protocols, how does it allow accurate tumor delineation and how does it guide prognosis and future treatment decisions. Results and conclusion: For the staging of esophageal cancer, PET/CT played a crucial role in exploring distant malignant lymph nodes and metastasis with high sensitivity, specificity and accuracy. PET/CT using different radiotracer provided a serial of thresholding methods based on standardized uptake value (SUV) to assist in auto-contouring the gross tumor volume (GTV). The change in SUV may offer a potential paradigm of personalized treatment to definitive chemoradiotherapy (CRT). In total, PET/CT has sought to further optimize radiotherapy treatment planning for patients with esophageal cancer. © 2016 Elsevier Ireland Ltd. All rights reserved.

∗ Corresponding author. E-mail address: [email protected] (X.-c. Sun). 1 These authors contributed equally to this paper. http://dx.doi.org/10.1016/j.critrevonc.2016.08.015 1040-8428/© 2016 Elsevier Ireland Ltd. All rights reserved.

J. Lu et al. / Critical Reviews in Oncology/Hematology 107 (2016) 128–137

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1. Introduction Esophageal cancer is the eighth most common cancer and the sixth leading cause of cancer-associated fatalities worldwide (Montgomery et al., 2014; Muijs et al., 2010). A reported 455,800 cases of esophageal cancer were diagnosed in 2012 and approximately 400,200 patients died from the disease (Pennathur et al., 2013). The extremely high rate of mortality can be attributed to early dissemination: at least half of the patients have locally advanced or metastatic disease at the time of diagnosis (Courrech Staal et al., 2009). Despite advances in treatment, long-term outcomes for esophageal cancer remain poor, with an estimated 5-year survival rate of 17% (Siegel et al., 2012). Treatment of first choice remains surgical resection. However, 40% to 50% patients undergoing surgical resection have stage III (T3N1-3, T4N0-3) disease (Krasna, 2013). Surgery alone results in poor locoregional tumor control and survival (Sjoquist et al., 2011; Gebski et al., 2007). Combined chemo-radiotherapy is increasingly applied, either as definitive therapy or in the adjuvant treatment of locally advanced esophageal cancer since 85-01 (Urschel and Vasan, 2003; Cooper et al., 1999). Radiotherapy as a key treatment modality in the curative treatment is probably dependent on two crucial issues to achieve tumor control: accurate delineation of tumor volume and precise dose delivery. This is particularly true for the use of modern delivery techniques, such as three dimensional conformal radiotherapy (3DCRT) and intensity-modulated radiotherapy (IMRT), enabling a high level of radiation dose conformity (Muijs et al., 2010). Therefore increasing attempt was made on minimizing a risk of a lower dose than desired to tumor in case of inadequate delineation. Furthermore, the data based on dose-volume histogram (DVH) analysis indicated proton beam therapy for esophageal cancer was possible to reduce irradiation doses to the organ at risk(OAR) without affecting the prescribed dose of planning target volume (PTV)and brought definite advantages over conformal X-ray therapy (Lin et al., 2012; Zhang et al., 2008; Makishima et al., 2015). Distinct diagnostic imaging plays a fundamental role to improve the effect of irradiation. Positron emission tomography (PET) could add biological information combined with anatomical information by computed tomography (CT) imaging to enable accurate staging. On the one hand, addition of PET information may improve the accuracy in the delineation of primary tumor volume and involved regional lymph nodes in patients with esophageal cancer. On the other hand, PET can provide effective evaluations of response to treatment and survival. In the present article, we review the construction of biological tumor volume with PET/CT functional imaging by diverse tracer, which could reflect of cell metabolism, proliferation, hypoxia, apoptosis and even phenotype. We will discuss the future perspectives and challenges of radiotherapy in the management of esophageal cancer. 2. Methods 2.1. Literature search strategy A literature search was performed to retrieve articles concerning biological target of esophageal tumor using the following keywords:

Fig. 1. The study selection process.

These keywords were combined using ‘AND’. The search was carried out in the MEDLINE database (1966–July 2015) and PubMed (January 1980–July 2015). In addition; reference lists of retrieved articles were manually reviewed to further identify potentially relevant studies. All relevant articles identified were assessed with application of a predetermined selection criterion. 2.2. Selection criteria To be selected for this review, studies had to fulfil the following eligibility criteria: (1) squamous cell carcinoma or adenocarcinoma of the esophagus or the gastro-esophageal junction; (2) evaluate tumor stage or delineate target volume or predict therapeutic response using PET. Both prospective and retrospective studies were included. Studies only available in abstract form were excluded from this review. Articles in languages other than English were excluded as well. The selection process of both search strategies together is summarized in Fig. 1. 2.3. Data extraction and analysis Descriptive data were extracted using a data-extracting form, including the first author, year of publication, sample size, patient characteristics (squamous cell cancer or as adenocarcinoma, TNM staging and therapeutic regimen) and result of PET or reference methods (target definition, radiological response and prognosis). The prognostic factors such as overall survival and progressionfree survival were determined from the end of radiotherapy. The reviewers independently appraised each article using a standard protocol. All data were extracted from the relevant articles, texts, tables and figures. The main difference (MD) with 95% confidence intervals (CI) was calculated using the random effects model. 3. Results

- Synonyms for esophageal cancer - Synonyms for PET imaging or biological imaging or functional imaging - Synonyms for tumor staging or radiotherapy or therapeutic monitoring.

Imaging examination is an important method of diagnosis and staging of esophageal cancer (Jamil et al., 2008). While barium swallow is common for initial work-up of symptoms, endoscopy is essential to define the location and extent of the primary lesion.

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Imaging studies should include a CT or MRI scan to determine invasion depth and identify sites of metastasis. Endoscopic ultrasound (EUS) has become a very common study to assess peri-esophageal and celiac lymph node involvement and the extension of disease through the esophageal wall. These imaging modalities reflect morphological characteristics of tumors, whereas PET/CT could aim at accessing functional information of lesions by the aspects of enhanced glucose metabolism (18F-FDG), cell proliferation (18FFLT) and hypoxic regions (18F-FMISO). (18F)-2-deoxy-2-fluoroglucose (18F-FDG) as a measure of tumor cell proliferation exploits the increased glucose metabolism occurring during cell reproduction.18F-FDG PET/CT allows observation of early changes in tumor cell proliferation that precede changes in tumor size (Kaida et al., 2014). Meanwhile, it was proposed as the most cost-effective examination for initial assessment of patients to detect unsuspected metastatic disease (Wallace et al., 2002; Kato et al., 2005). So it has emerged as a recommended part to stage TNM system for patients with esophageal cancer in NCCN guidelines (National Comprehensive Cancer Network, 2015). In addition, the comprehensive clinical studies have estimated the availability of 18F-FDG PET/CT may further expand to formulation of therapy planning, delineation of target region and evaluation of treatment efficacy (Chowdhury et al., 2008). 3.1. Combine PET/CT scanning and TNM staging of esophageal cancer The clinical staging of esophageal cancer is assessed with the widely accepted TNM system developed by the seventh edition of American Joint Committee on Cancer (AJCC) in 2010 (Edge et al., 2010; Yam et al., 2014; Tangoku et al., 2012). Endoscopic ulrasonography (EUS) is now considered the most accurate method (accuracy of 89%) available to evaluate of the different histological layers of tumor invasion and determine the preoperative T stage 71% in comparison to 42% while CT and PET imaging was utilized (Tangoku et al., 2012; Rosch, 1995). T staging descriptor on CT depends on esophageal wall thickening (>5 mm), therefore CT is less accurate to differentiate between T1, T2 and T3 tumors. Konski et al. measured the mean length of the cancer in 25 patients was 5.4 cm (95% CI 4.4–6.4 cm) as determined by PET scan and 6.77 cm (95% CI, 5.6–7.9 cm) by CT scan, compared the result 5.1 cm (95% CI, 4.0–6.1 cm) with endoscopy (Konski et al., 2005). PET can identify the gross tumor volume more precisely than previous CT scan. The hotspot in PET imaging could prompt avid glucose metabolism and find out esophageal malignancies even T1 tumors, but PET imaging is difficult to determine T stage of esophageal cancer because of poor resolving power of invasive depth. 18F-FDG PET combined with CT aimed at integrating anatomical and functional information that could be used to accurately determine tumor volume (Lamyaa et al., 2015). PET/CT may be utilized to exclude unresectable T4 disease by demonstrating obliteration of the fat planes between the primary tumor and the adjacent structures (Lowe et al., 2005; van Zoonen et al., 2012). The rate of lymph node metastasis is 35% in T1b and goes up to about 80% in T3 tumors and the number of involved lymph nodes is predictive of treatment options and survival (Prenzel et al., 2010). A Meta analysis examining preoperative 18F-FDG PET detecting local–regional lymph node involvement for esophageal cancer patients showed a sensitivity and specificity of 51% and 84%, respectively (van Westreenen et al., 2004). The limitation of PET typically involves that FDG-avid is difficult to discriminate locoregional lymph nodes from close primary tumor. EUS with ultrasonography guided biopsy is superior to PET/CT for assessing N1 locoregional nodes with sensitivity, specificity, and accuracy of 71%, 74% and 73%, respectively (Bruzzi et al., 2007). Considering that skip nodal metastases are found in up to 20% of resected

tumors, the main aim of PET/CT is to identify suspicious distant lymph nodes without tumor infiltration in regional nodes adjacent to the primary tumor (Pech et al., 2010). In addition, Lee et al. (2014) reported 18F-FDG PET in combination with MRI could improve the accuracy of lymph node staging increased to 83.3% in comparison to75.0%, 66.7%, and 50.0% for EUS, PET and CT, respectively. Distant metastasis outlined in M staging refers to celiac and cervical lymph node groups (M1a) and other distant sites including liver, lung and bones (M1b) in patients with esophageal cancer (Napier et al., 2014). Distant metastasis of esophageal cancer is notoriously aggressive that approximately 20%–30% of patients are diagnosed as M1 at time of initial diagnosis (Quint et al., 1995). The presence or absence of distant metastasis should be elementary in determining operability. Spiral CT as the most common method had the sensitivity for to detect masses ≥1 cm as high as 90%, whereas Lowe VJ et al. reported sensitivity of hematogenous and peritoneal metastases was 46%–81% (Konski et al., 2005; Walker et al., 2011). 18F-FDG PET/CT is accurate in the evaluation of distant metastasis with sensitivity of 69%–81% and specificity of 91%–93% (Lin et al., 2015). The superior capability of PET/CT detecting distant metastasis during the initial diagnosis could provide sufficient evidence to avoid unessential surgery in up to 20% of patients (Kuszyk et al., 1996; Weber and Ott, 2004). Godoy MC et al. suggested PET/CT be the optimal method for detection of metastatic disease (Godoy et al., 2013). 3.2. Combine PET/CT scanning and optimization of radiotherapy planning The application of CT permits the innovation of precise radiotherapy like contemporary 3-dimensional conformal radiation therapy (3D-CRT) and intensity modulated radiation therapy (IMRT). Tumor volume delineation takes into consideration the supplement of 18F-FDG PET to improve visualization of target structures. The potential benefits may be improvement in coverage of the true malignant volume and additional sparing of normal organs at risk by promising dose conformality. The radiation oncologists outline the biological tumor volume (BTV) on a fused PET and CT image or an integrated PET/CT image. Initially, some studies used the visual interpretation of PET images to define tumor contour and avoid geographic misses that reported the EUS or pathological findings correlated better with PET-based tumor length than with CT scans (Konski et al., 2005; Gondi et al., 2007; Leong et al., 2006), but this method is easily influenced by inter observer variability and display window parameter settings. Several objective approaches have been established on the basis of an FDG standardized uptake value (SUV) threshold. Although none of the thresholding approaches have been standardized, the most common ones are broadly categorized as (1) SUV n: absolute SUV, (2) SUV n%: the percentage of the maximum tumor SUV (SUVmax), (3) SUV Ln␴: the mean liver SUV and (4) SUV n%’: SUV relative to background of normal esophagus SUV and SUVmax. The length and volume of tumor were measured on imaging by CT, EUS and PET and on resected gross specimen by pathologist. The volume of GTVPET , GTVCT and GTVpath was compared using the volume ratio (VR) and conformality index (CI). The VR is simply the ratio of two volumes. The CI is the ratio of the volume of intersection of two volumes (V1∩V2) compared with the volume of union of the two volumes (V1∪V2) under comparison (CI = V1∩V2/V1∪V2). The literature reviewed six papers to analysis optimal threshold method that optimally could estimate the length and volume of gross tumor (Table 1) (Niyazi et al., 2013; Wang et al., 2012; Han et al., 2010; Vali et al., 2010; Yu et al., 2009; Zhong et al., 2009). Valiet al. compared GTVPET with GTVCT/EUS at the level of the esophageal tumor epicenter, and found that a threshold setting of SUV 2.5 resulted in the highest CI value at 0.48 (Vali et al., 2010). Wang

Table 1 Optimal threshold method to estimate the length and volume of gross tumor. Author

Year

Sample size

Patient characteristics

PET/CT Thresholda

Reference value

Outcome

PERCIST TLG determined the best agreement with the manual GTV. SUV20% and SUV2.5 show optimal VR and CI.

Niyazi et al. (2013)

2013

5

EC

18F-FDG

SUV n%: 38%, 42%, 47%, 50%; PERCIST TLG

CT

(CI)

Wang et al. (2012)

2012

12

SCC

18F-FDG (respiratory 4D-PET/CT)

SUV n: 2, 2.5; SUV n%: 15%, 20%, 25%, 30%, 40%, 50%.

CT

Han et al. (2010)

2010

22

18F-FDG 18F-FLT

FDG: Vis; SUV n: 2.5; SUV n%: 40%. FLT: Vis; SUV n: 1.3, 1.4, 1.5; SUV n%: 20%, 25%, 30%.

Pathology

Vali et al. (2010)

2010

22

SCC, Radical surgery, Postoperative radiotherapy Locally advanced EC

Tumor length Tumor volume (VR) CI Gross tumor length

18F-FDG

CT EUS

VR CI

Yu et al. (2009)

2009

16

18F-FDG

CT Pathology

Gross tumor length CI

SUV 20%’ provides rather closer estimation of gross tumor length but unsatisfactory CI.

Zhong et al. (2009)

2009

36

SCC, KPS > 80 Untreated, Operable, No metastasis SCC, Radical surgery, Postoperative radiotherapy

SUV n%: 40%, 45%, 50%; SUV n: 2, 2.5, 3, 3.5; SUV Ln␴: 1, 2, 3, 4. SUV n: 2.5; SUV n%: 40%; SUV n%’: 20%, 40%. Vis; SUV n: 2.5; SUV n%: 40%.

Pathology

Gross tumor length

SUV2.5 provides the closest estimation of gross tumor length.

18F-FDG

SUV1.4 on FLT and SUV2.5 on FDG provide the closest estimation of gross tumor length. SUV2.5 and SUVL4␴ yield the best CI and VR.

J. Lu et al. / Critical Reviews in Oncology/Hematology 107 (2016) 128–137

Tracer

Reference method

2. Threshold: Vis: visual interpretation; SUN n = absolute value of SUV; SUV n% = the percentage of the maximal SUV (SUVmax); SUV Ln␴ = the mean liver SUV; SUV n%’ = SUVbgd + n% (SUVmax(slice) – SUVbgd) (bgd: background of normal esophagus); PERCIST TLG: the PERCIST total lesion glycolysis (TLG) algorithm. 3. Reference value: CI: Conformality index; VR: Volume ratio. a Patient characteristics: EC: esophageal cancer; SCC: squamous cell cancer.

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et al. compared firstly CI values between GTVPET and GTVCT using respiratory 4D-PET/CT techniques in contouring esophageal cancer that demonstrated 4D-PET/CT is an appropriate method optimizing CI (0.57)and VR (0.98, close to 1) at SUV2.5 on FDG-PET. Currently, there is no enough evidence from retrospective studies that delineation of the biologically active tumor volume by PET/CT could be valuable for improving loco-regional control or survival (van Rossum et al., 2015). A small sample study including 10 patients by Vesprini et al. Vesprini et al., (2008) reported the supplement of 18F-FDG PET imaging decreased both inter-observer (defining GTV contours on the same scan by six observers) and intra-observer (delineating GTV contours of the same patient by one observer on two separate occasions) variability of CT-based tumor volume (P < 0.05, standard deviation). However future clinical studies with a larger sample size should aim to determine the potential significance of PET/CT to establish the criteria of target delineation. 3.3. Combine PET/CT scanning and therapeutic monitoring of nCRT The preferred primary treatment strategy for locally advanced esophageal cancer has evolved to comprehensive therapy, which consists of concurrent neoadjuvant chemoradiotherapy (nCRT) followed by surgery (Tepper et al., 2008). Complete responders to nCRT predict superior outcomes, regardless of subsequent surgical resection. Meanwhile, the addition of resection can improve outcomes for patients who are discovered to have residual tumor following completion of nCRT (Monjazeb et al., 2011; Stahl et al., 2005). It is critical to accurately identify patients who respond to nCRT. A series variance between pre-CRT and post-CRT PET imaging were respectively confirmed by postoperative pathology or prognostic indicator such as overall survival (OS) and progression-free survival (PFS) that it had general significance to assess the possibility of R0 resection, local-control and recurrence rate (Table 2) (Predictive value of repeated F-18 FDG PETCT, 2016; van Rossum et al., 2016; Baksh et al., 2015; Zhang et al., 2014; Myslivecek et al., 2012; Ilson et al., 2012; van Heijl et al., 2011; zum Büschenfelde et al., 2011; Vallböhmer et al., 2009; Roedl et al., 2009; Javeri et al., 2009; Higuchi et al., 2008; Kim et al., 2007; Song et al., 2005; Wieder et al., 2004). In the earlier study, conventional quantitative 18F-FDG PET studies evaluated the value of metabolic parameters such as the maximum standard uptake value (SUVmax) and the percent changes of SUVmax (SUVmax) for assessment of response. The state-of-the-art comprehensive models, such as metabolic tumor volume (MTV), total lesion glycolysis (TLG) even texture/geometry features, may yield additional predictive and prognostic information. Ilson et al. (2012) showed that PET response using SUV decrease >35% after nCRT indicated a correlation with higher pCR (responders vs. non-responders: 32% vs 4%), longer progression-free survival (PFS, 24.1 vs 7.7 months) and overall survival (OS, 40.2 vs 25.5 months). It is noteworthy that Zhang et al. (2014) referred to the support vector machine (SVM) models using all 14 features accurately and precisely predicted pathologic tumor response to CRT in esophageal cancer patients. All features contained one conventional PET/CT measure, “residual metabolic tumor volume post-CRT”; two clinical parameters, “whether tumor involves gastroesophageal junction” and “T stage”; and 14 spatial–temporal PET features (three intensity, eight texture, two geometry, and one volume-intensity). However, the study involved a small sample size of 20 patients.(van Rossum et al. (2016) suggested spatial–temporal 18F-FDG PET features were independent prognostic factors in esophageal cancer. In this retrospective study, clinical parameters, subjective and quantitative parameters based on baseline and postchemoradiation 18F-FDG PET were respectively derived from 217 patients

who underwent chemoradiotherapy followed by surgery. The associations between these parameters and pathCR were studied in univariable and multivariable logistic regression model. The model of conventional and comprehensive quantitative 18F-FDG PET parameters was improved by the addition of 4 features: baseline cluster shade, run percentage, ICM (intensity co-occurrence matrix) entropy, and postchemoradiation roundness (corrected cindex, 0.77). Subjective and quantitative assessment of 18F-FDG PET provides statistical incremental value for predicting pathologic complete response (pCR) after preoperative chemoradiotherapy (Hatt et al., 2012). Otherwise, further study is needed for an extension to lymph node assessment. 3.4. Other PET radiotracers clinically used in esophageal cancer 3.4.1. (18F)-3-Deoxy-3-fluorothymidine[18F-FLT] Considering that glucose metabolism could not clearly distinguish malignant tumor from surrounding inflammatory response, Leyton et al. (2005a) reported 18F-FLT as a novel PET tracer have been developed to provide information complementary to that obtained from FDG-PET. The use of FLT relies on the intracellular accumulation of the thymidine analogue that occurs via monophosphorylation by intracellular tyrosine kinase 1; this enzyme is differentially expressed in the late G1 and Sphases of the cell cycle and is virtually absent in quiescent cells (Barthel et al., 2003a). Preclinical and clinical studies have shown strong correlations between FLT uptake and histologic markers of proliferation in other tumor types, with their generally being a stronger correlation for FLT than for FDG (Chao, 2007). In Table 1, Han et al. (2010) investigated the combined 18F-FLT in assessing the feasibility of GTV delineation in esophageal cancer and found a threshold setting of SUV 1.4 correlated well with the pathologic GTV length. FDG-PET may not clearly distinguish between residual disease and post-treatment inflammation (Arslan et al., 2002). Experimental and preliminary clinical studies in a number of tumor types have indicated that FLT-PET is a promising technique for imaging of tumor proliferation and assessing response to treatment, showing better correlations with response than FDG-PET after either radiation therapy orchemotherapy (Barthel et al., 2003b; Leyton et al., 2005b). Park SH considered the percent change of SUVmax in responders ranged from 41.2% to 79.2% (median 57.1%), whereas it was 10.2% in one nonresponder. 3.4.2. (18F) 3-Fluoro-1-(2-nitro-1-imidazolyl)-2-propanol [18F-FMISO] Limited diffusion distance (<70 ␮m) of O2 produces hypoxic regionsin the tumor with partial pressure of O2 (pO2 ) typically less than 10 mm Hg and it is a common character of solid tumors. The resistance of hypoxic tumors to radiotherapy as well as a variety of types of chemotherapy has been repeatedly demonstrated (Apte et al., 2011). Nitroimidazole, functional groups in 18F-FMISO, is thought to be a bioreducible group that may undergo a single electron reduction by xanthine oxidasein the cell. Under hypoxic conditions, the nitro group of nitroimidazole is further reduced under enzymatic catalysis of nitroreductase followed by decomposition to form highly reactive intermediates such as free radicals, which can bind to cellular macromolecules and be trapped in the hypoxic cell irreversibly but it’s not under normoxic conditions (Bejot et al., 2010). 18FFMISO PET is potential measurement to evolve individual therapy in that it yields encouraging results in the assessment of tumor hypoxia and radiation resistance. But few authors have proposed a method for the integrated PET images of 18F-FMISO because of a low contrast and a terrible noise (Lelandais et al., 2012). Another nitroimidazole tracer, 18F-fluoroerythronitroimidazole

Table 2 Combine PET/CT scanning and therapeutic monitoring of neoadjuvant chemoradiotherapy. Sample size

Tumor histology

RT dose

Chemotherapy

Timing of PET

PET/CT reference value

PET/CT features

P value

Prognosisa

P value

Predictive value of repeated F-18 FDG PETCT (2016)

53

AC

46 Gy

Cisplatin +5FU

in the course of PCRT

SUVmax > 23.5% MTV > 25.5% TLG > 44.8%

0.0002 0.0027<0.0001

–

–

van Rossum et al. (2016)

217

–

45.0 Gy or 50.4 Gy

–

1.Subjective: SUVmax, SUVmean, MTV, TLG) 2.texture analysis

No signification

–

–

Baksh et al. (2015)

220

–

–

Oxaliplatin/5fluorouracil or Docetaxel/5fluorouraci –

Sensitivity 100% Specificity 52.6% Sensitivity 80% Specificity 76.3% Sensitivity 100% Specificity 65.8% C-index(clin)0.67 vs. C-index(subj)0.73 C-index(tex)0.76

6 weeks post CRT

SUVmax, SUVmax vs. TRG SUVdec ≥ 70%

P < 0.01 P = 0.017

TRG 3: median survival 27.4 months

Zhang et al. (2014)

20

3 SCC 17 AC

50.4 Gy

Cisplatin/Carboplatin

4–6 weeks post CRT

SVM and LR (all featureb )

<0.001

pCR, mRD, gRD

Myslivecek et al. (2012) Ilson et al. (2012)

34

17 SCC 17 AC 13 SCC 42 AC

50 Gy

Cisplatinum+ Fluorouracil Irinotecan + cisplatin

6 weeks post CRT 4–8 weeks post CRT

1. SUVmax [%] 2. CMR vs. NCMR 35% SUVdec

SUVmax vs. TRG: r = 0.374 SUVmax vs. TRG r = 0.178 SVM with 10-fold cross-validation: mean AUC of 1.00 (100% sensitivity, 100% specificity). 58.4% 17.6% vs. 82.4% SUVdec ≥ 35%: 47% SUVdec < 35%: 53%

van Heijl et al. (2011) zum Büschenfelde et al. (2011)

100

18 SCC 82 AC AC

41.4 Gy

Paclitaxel + carboplatin Platinum+ 5FU

14 days post CRT

Any SUVdec

–

–

14 days post CRT

35% SUVdec

SUVdec ≥ 35%: 36% SUVdec < 35%: 26%

>0.05

Vallböhmer et al. (2009)

119

66 SCC 53 AC

36 Gy

Cisplatin +5FU

2–3 weeks post CRT

–

–

Roedl et al. (2009)

49

SCC

50.4 Gy

151

AC

5–6.5 weeks post CRT

SUV diameterindex >55% 52% SUVmaxdecrease

Higuchi et al. (2008)

50

SCC

45 Gy or 50.4 Gy 40 Gy

Cisplatin +5FU 5FU + platinum 5FU + taxane

13.1 days post CRT

Javeri et al. (2009)

39.5% with histopathologic response 91% sensitivity 93% specificity 21% with pCR

Cisplatin +5FU

2–4 weeks post CRT

SUVmax <2.5

Kim et al. (2007)

62

–

Cisplatin + 5FU/ capecitabine

2–3 weeks post CRT

CMR

Song et al. (2005)

32

SCC

Cisplatin +5FU

3–4 weeks post CRT

SUV >4.0

Wieder et al. (2004)

38

SCC

5FU

14 days

30% SUVdec

55

56

50.4 Gy

32 Gy/ 1.6 Gy bid

45.6 Gy/ 1.2 Gy bid or 46 Gy/ 2 Gy qd 45.6 Gy/ 1.2 Gy bid or 46 Gy/ 2 Gy qd 40 Gy

–

AUC = 0.931 optimal cutoff value of 55% –

good response SUVmax <2.5: 87.5% SUVmax ≥2.5: 6.9% CMR vs. pCR: 54.1% vs.45.2%

<0.0001

% of metabolic: response vs. nonresponders: 71% vs. 25%; R0 resection rate: SUVdec ≥ 30%: 100% SUVdec < 30%: 63%

–

0.03

CR vs. RD 20.6% vs.79.4% pCR:32%vs.4% R0 resection: 84%vs. 57% PSF: 24.1vs. 7.7MOS: 40.2 vs 25.5M pCR: 90.6% vs. 9.4% Median survival: not reached vs.18.3 M; 2 year OS: 71% ± 8% vs.42% ± 11% 5-year survival: 34% vs. 14% HR 2.2 Mean DFS: 32 M vs. 16 M

coefficient AC = 0.532 0.009 0.02 0.29

– >0.05

0.005

<0.001

3-year OS: 72% vs. 43%

0.02

Median CSS: 84.2 M vs. 18.2 M 5-year CSS: 67.7% vs. 36.5% DFS CMR: not reached NCMR: 17.38 M OS CMR: not reached NCMR: 22.38 M 66% with pCR

0.0042

Median survival: 38 M vs. 18 M; 2-year OS: 79% vs. 38%

HR:1 vs.3.58 P = 0.006 HR:1 vs.3.09 P = 0.033

J. Lu et al. / Critical Reviews in Oncology/Hematology 107 (2016) 128–137

Author &Year

–

0.011

Abbreviations: AC: adenocarcinoma; SCC: squamous cell carcinoma; RT: radiation therapy; PCRT: preoperative chemoradiotherapy; SUV, standard uptake value; 5FU: 5-fluorouracil; pCR: pathologic complete response; mRD: microscopic residual disease; gRD: gross residual disease; OS: overall survival; PFS: progression-free survival; CSS: cancer-specific survival; DFS: disease-free survival; mCR: metabolic complete response; HR: hazard ratio; SUVdec: Decrease in SUV; SVM: Support vector machine models; LR: logistic regression models; CMR: complete metabolic response; NCMR: non-complete metabolic response. a Prognosis:prognosis of PET/CT responders vs. nonresponders. b All feature: (1) conventional PET/CT measure, “residual metabolic tumor volume (i.e., SUV ≥2.5) post CRT”; (2) clinical parameters, “whether tumor involves gastroesophageal junction” and “T stage”; (3) 14 spatial–temporal PET features (3 intensity, 8 texture, 2 geometry, and 1 vol-intensity). 133

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(18F-FETNIM), is more hydrophilic than 18F-FMISO and is eliminated rapidly from well-oxygenated tissues, resulting in higher tumor-toliver and tumor-to-blood ratios (Yang et al., 1995). Our data also suggest that high SUVmax on 18F-FETNIM PET predicts poor response to chemoradiotherapy in esophageal squamous cell carcinoma and the degree of response was potentially found to be related linearly with pretreatment SUVs (Yue et al., 2012). A larger patient cohort should be under investigation.

4. Discussion Esophageal cancer is a serious malignancy with regards to mortality and prognosis. With the increased prevalence of gastroesophageal reflux disease and the outstanding problem of alcohol consumption or tobacco use, the incidence of esophageal cancer has dramatically increased in the past 40 years (Napier et al., 2014). Despite recent improvements in surgery, long-term survival remains poor for patients with esophageal cancer (Hulscher et al., 2002). Accordingly, refinements of systemic treatment play a crucial role in decreasing mortality of esophageal cancer. While surgical resection alone constitutes the standard approach for earlystage disease, multimodality therapy, including perioperative chemotherapy and neoadjuvant or definitive chemoradiotherapy, are internationally accepted treatment options for patients with locally advanced disease (Fokas et al., 2013). A study from Cancer Control recommended that neoadjuvant chemoradiotherapy followed by esophagectomy for resectable esophageal cancer, had a better survival rate than those patients treated with surgery alone in United States (Almhanna et al., 2013). Pretreatment staging of esophageal cancer will directly affect appropriate stage-specific treatment protocols available to each patient. Marzola MC et al. considered that EUS is the most sensitive method to identify the detection of primary tumor and regional lymph nodes but not distant metastases (Marzola et al., 2012). 18F-FDG PET/CT plays a complementary role to EUS in T staging, especially in excluding T4 disease. In N staging, CT relying on “size criteria” (<1 cm = benign, >1 cm = malignant) reduces its sensitivity and specificity. PET/CT as a highly promising molecular imaging technique may be an overall and specific test and overcome the fundamental limitations of conventional cross-sectional modalities even for skip nodal metastases (Keswani et al., 2009). 18F-FDG PET/CT has become the gold standard for staging of esophageal cancer by detecting distant metastases and occult stage IV disease (Pepek et al., 2013). The sensitivity and specificity of FDG-PET depend not only on the site and size of the primary tumor and metastases, but also on histological cell type, reflecting underlying disparities in glucose metabolism. Radiotherapy has become a critical modality of treatment along with surgery and be used either in a neoadjuvant or adjuvant setting, especially with the advance of precise radiation therapy. The utilization of PET including the biological information of tumors supplements the interdisciplinary practice of radiotherapy, which is complementary to conventional computed tomography (CT) images and may change the tumor volume delineation (Grégoire et al., 2007). Although several algorithms have been proposed in the literature to delineate PET positive tissues, up to now none of the radiotracers has found its standard way into the daily practice of target volume delineation. Our result suggests SUV 2.5 on 18F-FDG and 1.4 SUV 1.4 on 18F-FLT to define the gross tumor volume (GTV) could reduce inter observer variability. However, integration of other hypoxia tracers, such as 18F-FMISO, 18F-FETNIM or copperdiacetyl-bis-(N4-methylthiosemicarbazone) (copper-ATSM), could

provide a closer view of the biologic pathways involved in radiation responses and hence could be used to ‘paint’ or “sculpt” the dose in various subvolumes by IMRT (Gronroos et al., 2004). Patients with recurrent glioblastoma multiforme (GBM) had well toleration and a median survival time of 11 months after receiving hypofractionated stereotactic radiotherapy by intensity modulated radiation therapy (HS-IMRT) planned with 11C-methionine PET/CT/MRI (Miwa et al., 2014). Guo et al. (2015) suggested 18FFDG PET may provide available information to 4DCT for an accurate definition of the target volumes in some cases of esophageal cancer. It is believed that respiratory-gated 4D PET/CT, which is to produce “motion free” and well-matched PET and CT images corresponding to specific phases of the patient’s respiratory cycle, would be sufficiently profitable for target volume definition. Therefore we must make our best endeavor to explore novel traces and algorithms for precise and automated target volume delineation. Patients who are at risk for inoperable esophageal due to comorbidities or other factors should receive radiation doses of 50–50.4 Gy by conventional fractionation (National Comprehensive Cancer Network, 2015). Increasing radiation dose of definitive radiotherapy failed in efforts to improve the local control rate. In 2002, a single randomized trial (INT0123/RTOG9405) demonstrated little benefit of escalating RT dose from 50.4 to 64.8 Gy using non-conformal RT planning because the proximity of healthy organs often limited the radiotherapy dose (Minsky et al., 2002). The simultaneous integrated boost (SIB) technique offers the advantage of simultaneously delivering a higher dose to the primary tumor. The high FDG uptake areas prior to CRT might bear a high radioresistance and boosting these areas might improve local tumor control. Yu et al. (2015) defined the volume with an SUV of more than 50% of the SUVmax as “GTV at risk” which was delineated automatically on 18F-FDG PET/CT to observe the safety of selective dose boost. Compared with the traditional GTV at 50.4 Gy, the dose escalation for the region of “GTV at risk” has been safely achieved up to 70 Gy. It might improve local tumor control but not increase dose-limiting toxicity. Moreover, Lamyaa N et al. suggested that target volume reduction by assessing on 18F-FDG PET/CT of pre- and during-CRT could facilitate dose escalation up to 66 Gy in patients with esophageal squamous cell carcinoma (Lamyaa et al., 2015). PET/CT makes an effort to improve the accuracy in not only target volume delineation but prognostication after nCRT. According to the 2015 National Comprehensive Cancer Network guidelines of esophageal cancer, the standard regimen of nCRT is a radiation dose range of 41.4–50.4 Gy (1.8–2 Gy/day) (National Comprehensive Cancer Network, 2015), with a concurrent platinum-based or 5-fluorouracil regimen. It is critical to identify whether or not patients respond to CRT so that surgery can be initiated and superior outcome may be expected. Zhu et al. (2012) suggested the scan time for 18F-FDG/PET was as follows: prior to therapy, exactly 2 weeks after initiation of neoadjuvant chemoradiotherapy, and pre-operatively. The response threshold in SUVmax chosen arbitrarily between patients with high and low survival was based on the SUVmax values decreasing by >35% between the pre-nCRT and post-nCRT scan. Recent studies have emerged suggesting that comperhensive spatial/geometric PET/CT features are more informative than the traditional response measure with maximum standardized uptake values (SUVmax) in various tumors (Tixier et al., 2011). (van Rossum et al. (2016) recommended that 18F-FDG PET texture features could increase recognition for prediction of treatment response and prognosis. It may someday be able to select patients who would benefit more from additional chemotherapeutic approaches than from resection. As a conclusion, PET/CT can provide not only anatomical imaging of tumor and surrounding normal tissue, but also physical and

J. Lu et al. / Critical Reviews in Oncology/Hematology 107 (2016) 128–137

functional information on them, including actinobiology of target area, radiosensitivity of tumor and associated genetic characteristics. As an important diagnostic performance, PET/CT has a great impact in the pretreatment evaluation, definition of target volume and follow-up of patients with esophageal cancer. Conflict of interest statement The authors declared that they have no conflicts of interest to this work. We declare that we do not have any commercial or associative interest that represents a conflict of interest in connection with the work submitted. Acknowledgments This work was supported by the Natural Science Foundation of China (No. 81272504), Research and Innovation Project for College Graduates of Jiangsu Province (No. CXZZ12 0588), Innovation Team (No. LJ201123 (EH11)), A Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD) (JX10231801), grants from Key Academic Discipline of Jiangsu Province “Medical Aspects of Specific Environments,” and Six Major Talent Peak Project of Jiangsu Province (2013-WSN-040). The funders have no role in the design of the study, in the collection and analysis of data, in publishing decisions, or in manuscript preparation. References Almhanna, K., Shridhar, R., Meredith, K.L., 2013. Neoadjuvant or adjuvant therapy for resectable esophageal cancer: is there a standard of care. Cancer Control 20, 89–96. Apte, S., Chin, F.T., Graves, E.E., 2011. Molecular imaging of hypoxia: strategies for probe design and application. Curr. Org. Synth. 8 (4), 593–603. Arslan, N., Miller, T.R., Dehdashti, F., et al., 2002. Evaluation of response to neoadjuvant therapy by quantitative 2-deoxy-2-[18f]fluoro-D-glucose with positron emission tomography in patients with esophageal cancer. Mol. Imaging Biol. 4, 301–310. Baksh, K., Prithviraj, G., Kim, Y., et al., 2015. Correlation between standardized uptake value in preneoadjuvant and post neoadjuvant chemoradiotherapy and tumor regression grade in patients with locally advanced esophageal cancer. Am. J. Clin. Oncol., http://dx.doi.org/10.1097/COC.0000000000000258, Epub ahead of print. Barthel, H., Cleij, M.C., Collingridge, D.R., Hutchinson, O.C., Osman, S., He, Q., Luthra, S.K., Brady, F., Price, P.M., 2003a. Aboagye EO.3 -deoxy-3 -[18F]fluorothymidine as a new marker for monitoring tumor response to anti proliferative therapy in vivo with positron emission tomography. Cancer Res. 63 (13), 3791–3798. Barthel, H., Cleij, M.C., Collingridge, D.R., et al., 2003b. 3 Deoxy-3 -[18F]fluorothymidine as a new marker for monitoring tumor response to anti proliferative therapy in vivo with positron emission tomography. Cancer Res. 63, 3791–3798. Bejot, R., Kersemans, V., Kelly, C., Carroll, L., King, R.C., Gouverneur, V., Elizarov, A.M., Ball, C., Zhang, J., Miraghaie, R., Kolb, H.C., Smart, S., Hill, S., 2010. Pre-clinical evaluation of a 3-nitro-1,2,4-triazole analogue of [18F]FMISO as hypoxia-selective tracer for PET. Nucl. Med. Biol. 37 (5), 565–575. Bruzzi, J.F., Munden, R.F., Truong, M.T., Marom, E.M., Sabloff, B.S., Gladish, G.W., Iyer, R.B., Pan, T.S., Macapinlac, H.A., Erasmus, J.J., 2007. PET/CT of esophageal cancer: its role in clinical management. Radiographics 27 (6), 1635–1652. Chao, K.S., 2007. 3’-Deoxy-3 -(18)F-fluorothymidine (FLT) positron emission tomography for early prediction of response to chemoradiotherapy—a clinical application model of esophageal cancer. Semin. Oncol. 34 (2 (Suppl. 1)), S31–S36. Chowdhury, F.U., Bradley, K.M., Gleeson, F.V., 2008. The role of 18F-FDG PET/CT in the evaluation of oesophageal carcinoma. Clin. Radiol. 63, 1297–1309. Cooper, J.S., Guo, M.D., Herskovic, A., et al., 1999. Chemoradiotherapy of locally advanced esophageal cancer: long-term follow-up of a prospective randomized trial (RTOG 85-01). Radiat. Ther. Oncol. Group JAMA 281, 1623–1627. Courrech Staal, E.F., van, C.F., Cats, A., et al., 2009. Outcome of low-volume surgery for esophageal cancer in a high-volume referral center. Ann. Surg. Oncol. 16, 3219–3226. Edge, S.B., Byrd, D.R., Compton, C.C., Fritz, A.G., Greene, F.L., Trotti, A., 2010. American Joint Committee on Cancer (AJCC) Cancer Staging Manual, 7th ed. Springer, Chicago. Fokas, E., Weiss, C., Rödel, C., 2013. The role of radiotherapy in the multimodal management of esophageal cancer. Dig. Dis. 31 (1), 30–37.

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