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Dose escalation based on 18F-FDG PET/CT response in definitive chemoradiotherapy of locally advanced esophageal squamous cell carcinoma: a phase III, open-label, randomized, controlled trial (ESO-Shanghai 12)

Dose escalation based on 18F-FDG PET/CT response in definitive chemoradiotherapy of locally... Introduction: Definitive chemoradiotherapy has established the standard non-surgical treatment for locally advanced esophageal cancer. The standard dose of 50–50.4 Gy has been established decades ago and been con- firmed in modern trials. The theorical advantage of better local control and technical advances for less toxicity have 18 18 encouraged clinicians for dose escalation investigation. F-fluorodeoxyglucose ( F-FDG) positron emission tomog- raphy/computed tomography (PET/CT ) have the potential to tailor therapy for esophageal patients not showing response to CRT and pioneers the PET-based dose escalation. Methods and analysis: The ESO-Shanghai 12 trial is a prospective multicenter randomized phase 3 study in which patients are randomized to either 61.2 Gy or 50.4 Gy of radiation dose by PET response. Both groups undergo concur- rent chemoradiotherapy with paclitaxel/cisplatin regimen for 2 cycles followed by consolidation chemotherapy for 2 cycles. Patients with histologically confirmed ESCC [ T1N1-3M0, T2-4NxM0, TxNxM1 (Supraclavicular lymph node metastasis only), (AJCC Cancer Staging Manual, 8th Edition)] and without any prior treatment of chemotherapy, radio- therapy or surgery against esophageal cancer will be eligible. The primary endpoints included overall survival in PET/ CT non-responders (SUV > 4.0) and overall survival in total population. Patients will be stratified by standardized max uptake volume, gross tumor volume and tumor location. The enrollment could be ended, when the number of PET/ CT non-responder reached 132 and the total population reached 646 for randomization. Hongcheng Zhu, Qiufang Liu and Hao Xu contribute equally to this work *Correspondence: chenyun_qz@fudan.edu.cn; kuaile_z@fudan.edu.cn Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China Full list of author information is available at the end of the article © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Zhu et al. Radiation Oncology (2022) 17:134 Page 2 of 12 Ethics and dissemination: This trial has been approved by the Fudan University Shanghai Cancer Center Insti- tutional Review Board. Trial results will be disseminated via peer reviewed scientific journals and conference presentations. Trial registration The trial was initiated in 2018 and is currently recruiting patients. Trial registration number NCT03790553. Background of intensity-modulated radiotherapy (IMRT), radiation According to the Global Burden of Disease Study 2019, oncologists are interested in re-investigating dose esca- esophageal cancer (EC) accounted for approximately lation in EC. The highly anticipated European CON - 535,000 new cancer cases and 498,000 deaths in 2019 CORDE [10] and ARTDECO [11] studies, along with a worldwide [1]. The 5-year standardized net survival rate Chinese phase III trial [12], have further demonstrated ranges between 10 and 30% globally [2]. There are two that increasing the radiation dose for non-selected popu- distinct histopathologic subtypes of EC: esophageal squa- lations does not offer benefits in definitive CRT for EC mous cell carcinoma (ESCC) and esophageal adenocar- in the modern era. However, high doses (≥ 60  Gy) have cinoma. These subtypes vary in terms of incidence, risk been widely used in Asia and have demonstrated posi- factors, location, and age of diagnosis [3], and ESCC is tive results in Asian populations and ESCC subtypes in the dominant subtype in Asian populations [4]. Defini - retrospective studies [13, 14], and meta-analyses have tive chemoradiotherapy (CRT) has been established as further contributed to the debate [15, 16]. Moreover, the standard nonsurgical treatment for locally advanced our previous drug comparison phase III trial [17] using EC. Measures to achieve better local control and overall involved-field irradiation–based IMRT up to a total dose survival, including radiation dose escalation, chemother- of 61.2  Gy demonstrated favorable survival outcomes apy regime optimization, and the combination of target (Table 1). agents, have been explored for decades. However, few of these measures have demonstrated positive results in randomized phase III trials. The ESO-Shanghai 12 trial Failure patterns of CRT in EC (NCT03790553) was designed to evaluate dose escala- Researchers have tried to explore failure patterns of EC tion in ESCC chemoradiation based on the response on chemoradiotherapy. Button et  al. [18] reported the first 18F-fluorodeoxyglucose (18F-FDG) positron emission failure site in 145 patients receiving chemoradiotherapy tomography/computed tomography (PET/CT), with the for EC. The irradiation field included the gross tumor vol - aim of establishing an approach to precision radiation ume (GTV), plus 3 cm of the proximal and distal normal therapy for EC. esophagus and a 1.5-cm margin in the transversal posi- tion. Eighty-five patients were identified as treatment fail - ure, including 55 patients with in-field failure, 13 patients with distant metastases, and 14 patients with both. Only Standard dose for CRT 3 patients had relapse observed at the edge of the irradia- The phase III RTOG-8501 trial demonstrated that 50 Gy tion field. Welsh et  al. [19] retrospectively analyzed 239 radiation with concurrent chemotherapy is superior to patients who received CRT for EC, among whom 50% radiotherapy of 64  Gy alone, thus establishing defini - had local failure and 48% had distant metastases. Of all tive concurrent CRT as the standard nonsurgical treat- the cases of local failure, 90% occurred in the GTV, 27% ment scheme for locally advanced EC [5]. The phase III in the clinical target volume (CTV), and 12% in the pri- randomized trial RTOG-9405 compared a high dose mary tumor volume (PTV). In the ESO-Shanghai 1 trial, of 64.8  Gy and a low dose of 50.4  Gy in definitive con - the radiotherapy techniques were involved-field irradia - current CRT. The results showed that a high dose did tion (no lymph node preventive irradiation) and IMRT, not improve survival or local control, with the absolute and the radiotherapy dose was 61.2 Gy/34 Fx. Of the 436 value of median overall survival and the 2-year survival trial participants, 258 (59.2%) experienced treatment fail- rate being lower in the high-dose group than in the low- ure; 37 patients (8.5%) showed failure of irradiation of dose group [6]. During the past decade, radiotherapy has the lymph nodes in the field, of which 7 cases (1.6%) had entered the era of three-dimensional conformal radiation simple lymph node failure [20]. Therefore, considering therapy (3DCRT); however, the standard radiation dose recurrence within the irradiation field accounts for half of 50  Gy does not present preferable survival character- of cases of CRT failure in EC, dose escalation may be an istics regardless of whether it is combined with concur- effective approach to achieve a good prognosis. rent systemic therapy [7–9]. With the wide application Zhu  et al. Radiation Oncology (2022) 17:134 Page 3 of 12 Table 1 Survival outcomes of standard dose or high dose in esophageal cancer dCRT from selected trails Study Country Pathology Radiation Radiation Systemic therapies No. of 2y OS 3y OS 5y OS (Reference) (Year*) dose technique Patients RTOG 85–01 USA AC/SCC 50 Gy 2D DDP + 5-Fu 61 36% 30% 25% [5] (1986–1990) 50 Gy DDP + 5-Fu 69 36% 30% 25% 64 Gy – 62 10% 0% 0% RTOG 94–05/ USA AC/SCC 50.4 Gy 2D DDP + 5-Fu 109 40% 33% – INT 0123 [6] (1995–1999) 64.8 Gy DDP + 5-Fu 109 31% 25% – PRODIGE5/ France AC/SCC 50 Gy 3DCRT FOLFOX 134 – 19.9% – ACCORD17 [7] (2004–2011) DDP + 5-Fu 133 – 26.9% – SCOPE1 [8] UK AC/SCC 50 Gy 3DCRT CAP + DDP + Cetuxi- 129 41.3% – – (2008–2012) mab CAP + DDP 129 56% – – RTOG 0436 [9] USA AC/SCC 50.4 Gy 3DCRT PTX + DDP + Cetuxi- 159 45% 34% – (2008–2013) mab PTX + DDP 169 44% 28% – CONCORDE/ France AC/SCC 50 Gy 3DCRT/IMRT/ FOLFOX 109 Median 25.2 m PRODIGE26 (2011–2019) VMAT 66 Gy 108 Median 23.5 m [10] ESO-Shanghai China SCC 61.2 Gy IMRT PTX + 5-Fu 217 60.6 55.4% 44.3% 1 [17] (2012–2015) DDP + 5-Fu 219 61.5% 51.8% 40.8% ARTDECO [11] Netherlands AC/SCC 50.4 Gy 3DCRT/IMRT PTX + CBP 130 – 42% – (2012–2018) 61.6 Gy 130 – 39% – Xu et al. [12] China SCC 50 Gy IMRT DDP + DTX 153 62.9% 54.0% – (2013–2017) 60 Gy 152 64.8% 54.1% – dCRT = definitive chemoradiotherapy; AC = Adenocarcinoma; SCC = Squamous cell carcinoma; 2D = Two Dimensional; 3DCRT = Threedimensional conformal radiation therapy; IMRT = Intensity-modulated radiation therapy; VMAT = Volumetric-modulated arc therapy; DDP = Cisplatin; 5-Fu = 5-Fluorouracil; FOLFOX = Oxaliplatin + Leucovorin + 5-Fluorouracil; CAP = Capecitabine; PTX = Paclitaxel; CBP = Carboplatin; DTX = Docetaxel; OS = Overall survival *Patients recruiting year Feasibility and effectiveness of high‑dose radiotherapy entails less toxicity, its use may increase the feasibility of in EC increasing the dose. The esophagus may be the most important dose-limit - ing organ. Under the guidance of PET/CT, Yu et  al. [21] Tumor response assessment irradiated more than 50% of the tumor area with the In EC, evaluation of the tumor response to neoadjuvant maximum standardized uptake volume (SUV) before therapy can not only be used to predict prognosis but radiotherapy. They found that it was safe for patients also to detect non-responders of CRT and allow adjust- to receive 70  Gy/25 Fx at the same time and that the ment of treatment strategy. According to the MUNICON short-term toxicity was tolerable. In a phase 1/2 trial, trial, patients who show a clinical response to induction Chen et al. [22] reported that chemoradiotherapy with a treatment (chemotherapy- or chemoradiotherapy) have simultaneous integrated boost of radiotherapy (at doses a better prognosis [24]. At present, several methods are of 50.4 Gy to subclinical areas at risk and 63.0 Gy to the available to evaluate the treatment response; among gross tumor and involved nodes, all given in 28 fractions) them, ultrasonic gastroscopy and F-FDG PET/CT have for patients with locally advanced EC was well toler- high accuracy [25]. Consequently, improving induction ated, with encouraging local control. If the target volume chemotherapy to increase the proportion of treatment dose can be increased without affecting the tolerance of responders, as well as intensifying the radiotherapy, could normal tissue, local control and the overall therapeutic be strategies to improve local disease control or survival. effect may be improved in EC radiotherapy [23]. In recent Several phase II trials [26–29] have shown that PET/CT years, the progress of radiation technology has ensured has the potential to tailor therapy for patients not show- the safety and effectiveness of increasing the local radi - ing an early response to chemotherapy and have pio- otherapy dose. Also, because involved-field irradiation neered PET-directed EC neoadjuvant therapy (Table 2). Zhu et al. Radiation Oncology (2022) 17:134 Page 4 of 12 Rationale for the trial Overall survival in patients who have an S UV ≤ 4 max Based on the above evidence, we designed a phase 3 on PET/CT at 28 radiotherapy fractions. study to investigate whether an increased dose of 61.2 Gy 4. Questionnaire: European Organization for the is superior to the standard dose of 50.4  Gy in definitive Research and Treatment of Cancer Quality of Life chemoradiotherapy of ESCC, especially in patients with Questionnaire (EORTC-QLQ)-C30 (time frame: no response on F-FDG PET/CT. 2 years) A quality-of-life score will be obtained based on the Methods and analysis answers to the questionnaire. Design 5. Questionnaire: EORTC-QLQ-OES18 (time frame: The ESO-Shanghai 12 trial is a prospective, multicenter, 2 years) randomized phase 3 study, in which patients are ran- A quality-of-life score will be obtained according to domized to receive radiation at a dose of 61.2  Gy or the answers to the questionnaire. 50.4 Gy based on the F-FDG PET/CT response (strati- 6. Exploration of predictive and prognostic biomarkers. fied by SUV > 4 and SUV ≤ 4). Both arms will max max undergo concurrent chemoradiotherapy with a pacli- taxel/cisplatin (TP) regimen for two cycles followed by Patient selection consolidation chemotherapy for two cycles (Fig. 1). Inclusion criteria To be eligible for inclusion in this study, patients must Objectives fulfill all the following criteria: Primary endpoints 1. Participating in the study voluntarily and able to 1. Overall survival in PET/CT non-responders (time sign the informed consent form. frame: 2 years) 2. Aged between 18 and 75 years, and of either sex. 3. Pathologically confirmed with ESCC [T1N1- The time between the start of the study treatment 3M0, T2-4NxM0, TxNxM1 (supraclavicular lymph (day 1) and death from any cause or the last follow- node metastasis only), (American Joint Committee up (for patients who are alive at the end of the study) on Cancer Staging Manual, 8th Edition)]. in patients who have an SUV > 4 on PET/CT at 28 max 4. No receipt of radiotherapy, chemotherapy, or other radiotherapy fractions. treatments prior to enrollment. 2. Overall survival in the intention-to-treat (ITT) popu- 5. Using an effective contraceptive to prevent preg - lation (time frame: 2 years) nancy. The time between the start of the study treatment 6. No severely abnormal hematopoietic, cardiac, pul- (day 1) and death from any cause or the last follow- monary, renal, or hepatic function, or immunodefi - up (for patients who are alive at the end of the study) ciency. in the ITT population. 7. White blood cells (WBC) ≥ 3.5*10 /L, hemo- globin ≥ 9  g/dL , neutrophils ≥ 1·5*10 /L, plate- Secondary endpoints let count ≥ 100*10 /L, alanine aminotrans- ferase (ALAT) and aspartate aminotransferase 1. Local control in PET/CT non-responders, the ITT (A SAT) < 2·5 * upper limit of normal (ULN), population, and PET/CT responders (time frame: total bilirubin ( TBIL) < 1·5 * ULN, and creati- 2 years) nine < 1·5 *ULN. 8. An Eastern Cooperative Oncology Group (ECOG) The time between the start of the study treatment score of 0–2. (day 1) and local recurrence (including primary 9. Life expectancy of more than 3 months. tumor recurrence and regional lymph node failure). 10. Agrees to undergo F-FDG PET/CT assessment at 2. Progression-free survival in PET/CT non-respond- 28 radiotherapy fractions. ers, the ITT population, and PET/CT responders (time frame: 2 years) The time between day 1 and the first event of local Exclusion criteria failure, metastatic recurrence, progression, or death. The following patients will be ineligible for this study. 3. Overall survival in PET/CT responders (time frame: 2 years) Zhu  et al. Radiation Oncology (2022) 17:134 Page 5 of 12 Table 2 Selected trails of PET-directed neoadjuvant therapy in esophageal cancer Study (Reference) Country Patho PET timing Metabolic Induction therapy Arms Treatment No. of pCR Median OS (Year*) logy parameters and Patients cutoff MUNICON [24] Germany AC Day 14 △SUV ≥ 35% DDP + CF + 5-FU ± PTX Responder Continued nCT + surgery 50 58% – max (2002–2005) Non-responder Discontinued nCT + surgery 54 0% 25.8 m MUNICON II [26] Germany AC Day 14 △SUV ≥ 35% DDP + CF + 5-FU ± PTX Responder Continued nCT + surgery 23 36% – max (2005–2008) Non-responder Change to nCRT (DDP or 33 26% 18.3 m 5-Fu + 32 Gy/1.6 Gy bid) + surgery AGITC DOCTOR [27] Australia AC Day 15 △SUV ≥ 35% DDP + 5-Fu Responder Continued initial nCT + surgery 45 7% 61 m max (2009–2015) Non-responder New nCT regime of DCF 31 20% 30 m (DTX + DDP + 5-Fu) + surgery Change to nCRT (DCF + 45 Gy/25 34 63% 35 m Fx) + surgery CALGB-80803/Alliance [28] USA (2011–2015) AC Day 36—42 △SUV ≥ 35% FOLFOX Responder nCRT: Continued initial chemo 72 37.5% 50.3 m max plus RT (50.4 Gy/28 Fx) + surgery Non-responder nCRT: Crossover to alternative 39 19.0% 30.9 m chemo (PTX + CBP) plus RT (50.4 Gy/28 Fx) + surgery PTX + CBP Responder nCRT: Continued initial chemo 64 12.5% 39.6 m plus RT (50.4 Gy/28 Fx) + surgery Non-responder nCRT: Crossover to alterna- 50 17.0% 27.6 m tive chemo (FOLFOX) plus RT (50.4 Gy/28 Fx) + surgery MEMORI [29] Germany AC Day 14—21 △SUV ≥ 35% EOX/XP/mFOLFOX6 Responder Continued initial nCT + surgery 47 33% – max (2014–2018) Non-responder Change to nCRT 22 55% – (PTX + CBP + 41.4 Gy/23 Fx) + sur- gery nCT = neoadjuvant chemotherapy; nCRT = neoadjuvant chemoradiotherapy; PET = Positron Emission Tomography; △SUVmax = The decreased maximum standard uptake values from baseline to PET2; DDP = Cisplatin; CF = Folinc acid; 5-FU = 5-Fluorouracil; PTX = Paclitaxel; FOLFOX = Oxaliplatin + Leucovorin + 5-Fluorouracil; CBP = Carboplatin; EXO = Epirubicin + Capecitabine + Oxaliplatin; XP = Capecitabine + Cisplatin; DCF = Docetaxel + Cisplatin + 5-Fluorouracil; DTX = Docetaxel *Patients recruiting year Zhu et al. Radiation Oncology (2022) 17:134 Page 6 of 12 Fig. 1 Trial diagram of the ESO-Shanghai 12 trial. PET = Positron emission tomography; SUV = Standard uptake value; GTV = Gross tumor volume; PTX = Paclitaxel; DDP = Cisplatin Fig. 2 Treatment design of the ESO-Shanghai 12 trial. PET = Positron emission tomography; SUV = Standard uptake value; R = Randomization; RT = Radiation therapy ; TP = Paclitaxel + Cisplatin; W = Week Zhu  et al. Radiation Oncology (2022) 17:134 Page 7 of 12 1. Patients whose total radiotherapy dose reaches • Blood glucose measurement will be performed 61.2  Gy/34 Fx if the normal tissue dose complies before the injection of F-FDG, and blood glucose with the standard criteria. levels should be less than 140 mg/dL. 2. Patients with esophageal perforation or hematem- • The height and weight of patients will be measured esis. using calibrated and medically approved devices. 3. Patients with a history of radiotherapy or chemo- therapy for EC. 2. Injection of F-FDG 4. Patients with a history of surgery within 28  days before Day 1. • Patients will receive an F-FDG dose of 3.7 MBq/ 5. Patients with a history of prior malignancies (other Kg of body weight in accordance with the manu- than skin basal cell carcinoma or cervical carci- facturer’s recommendations. Patients will be kept noma in  situ with disease-free survival of at least in a quiet and dimly lit room before and after the 3 years). injection. 6. Patients who are participating in another interven- • A saline flush of 1  mL will follow the F-FDG tional clinical trial less than 30 days. injection. 7. Pregnant or breastfeeding women or fertile patients • The exact time of dose calibration will be recorded who refuse to use contraceptives. using a global time recording device, which will 8. Patients with drug addiction, alcoholism, or be consistently used throughout the study for acquired immunodeficiency (AIDS). time recording. The exact time of injection will 9. Patients experiencing uncontrolled seizures or psy- be noted and recorded to permit the correction of chiatric disorders. the administered dose for radioactive decay. Fur- 10. Patients with any other condition which, in the thermore, any of the dose remaining in the tube or investigator’s opinion, would make them an unsuit- syringe, or any F-FDG that is spilled during the able candidate for the clinical trial. injection will be recorded. The F-FDG injection will be performed using an intravenous catheter and three-way stopcock. Study treatment 3. PET/CT imaging The treatment plan is shown in Fig.  1. Patients will All PET exams will include three trans-axial, whole- receive radiotherapy combined with concurrent chemo- body series, attenuated and non-attenuated, cor- therapy. Radiotherapy will begin on day 1, concurrent rected PET and CT images. with the beginning of cycle 1 of chemotherapy. Radio- therapy will be delivered with photons (≥ 6 MV) to a • The scan will be conducted 60 ± 10  min after the total dose of 50.4 Gy in 28 fractions or 61.2 Gy in 34 frac- injection of F-FDG. tions. F-FDG PET/CT will be performed for all patients • The patient will be instructed to empty their blad - at baseline and at 28 radiotherapy fractions (± 3  days), der immediately before the image acquisition. and then patients will be randomized after assessment. • A spiral CT scan using the low-dose technique Patients will be stratified according to the SUV (≤ 4 max (120  kV, 140  mA, 5-mm slice thickness) will be 2 2 or > 4), GT V (≤ 40 cm or > 40 cm ) and tumor location conducted first, followed by a PET emission scan [cervical/upper thoracic location with heart dose ≤ 10 Gy from the distal femur to the top of the skull. or (middle/lower thoracic location or heart dose > 10 Gy)] • A PET emission scan covering the same transverse (Fig. 2). field of view will be obtained immediately after the CT scan. The PET data will be reconstructed using a Gaussian filter iterative (iterations 4; subsets 8; F‑FDG PET/CT assessment image size 168) for the reconstruction of emission images. The CT data will be used for attenuation 1. Pre-PET/CT patient preparation correction of the PET images, and fused images will be displayed on a workstation. • Patients will not undergo a barium meal examina- tion at least 1 week before the PET/CT scan. 4. Reporting of PET findings and SUV calculations • Prior to injection, the patient must fast for at least 6 h. SUVs are commonly used in clinical practice in addi- tion to visual assessments. The SUV is a measurement of Zhu et al. Radiation Oncology (2022) 17:134 Page 8 of 12 PTV the uptake in a tumor normalized on the basis of a distri- The PTV will be generated by applying a 1-cm margin to bution volume. It is calculated as follows: the CTV. Act (kBq/ml) voi Tissue inhomogeneity correction will be adopted for SUV = Act (MBq) BW kg administered planning purposes. The criteria for dose distribution will be as follows: 95% of the PTV to receive ≥ 99% of the In this calculation, Act is the activity measured in the voi prescribed dose; 99% of the PTV to receive ≥ 95% of the volume of interest (see “Definitions for volumes of inter - prescribed dose; < 2 cm of the PTV to receive ≥ 120% est (VOI) and regions of interest (ROI)”), A ct administered of the prescribed dose; and < 1 cm of the PTV to is the administered activity corrected for the physical receive ≥ 110% of the prescribed dose. The highest and decay of F-FDG at the start of acquisition, and BW is lowest dose points inside the PTV will be recorded. body weight. The patient’s height, weight, and sex will be reported to allow for other SUV normalizations (lean body mass, body surface area). Normal organ contouring and dose restrictions Normal organs, including the spinal cord, heart, and • PET/CT images will be analyzed independently right and left lungs, will be contoured on each slice of the by two senior nuclear medicine physicians using a planning CT with no planning margin. The spinal cord multimodality computer platform (Syngo, Siemens, dose constraint must not be exceeded for any reason. Knoxville, TN, USA). For any inconsistent or equivo- The heart contours will extend from the beginning of the cal interpretations, another experienced radiologist right atrium and right ventricle (the pulmonary artery will be invited to the discussion to reach a consensus. trunk, ascending main aorta, and superior vena cava will be excluded) down to the apex of the heart. The lung vol - ume will be defined as the total lung minus the PTV. Radiotherapy The priority order of consideration for normal organ IMRT will be required. The radiation plan for all patients dose restrictions will be as follows: will involve 61.2 Gy/ 34 Fx, at 1.8 Gy/ day for 5 days per week. The standardized-dose group will receive a radia - 1. Spinal cord: the highest dose point must be of less tion dose of 50.4  Gy/28 Fx, while the high-dose group than 45 Gy. will receive 61.2  Gy of radiation. The patients will be 2. Lung: the volume of the lung (PTV excluded) receiv- immobilized in the supine position and receive a con- ing 20  Gy must be equal to or less than 30% of the trast-enhanced planning CT scan 0.5  cm under the cri- total lung volume, and the mean lung dose must be cothyroid membrane (for thoracic tumors) or basis cranii equal to or less than 15 Gy at the same time. (for cervical tumors) below the kidney. IMRT will be 3. Heart: the mean dose must be less than 40 Gy. delivered to all patients using 6 MV photons. The radia - tion target volume will be delineated by the field involved. Dose modifications GTV It is strongly recommended that the normal organ dose The GTV will be defined as any visible primary tumor constraints are not exceeded. If any dose constraint needs and metastatic lymph nodes. The primary tumor will to be exceeded to achieve adequate coverage of the PTV, be delineated using esophagography, esophagoscopy, 18 the physician will decide whether the dose should be contrast-enhanced thoracic CT, and F-FDG PET/CT). modified, or whether the patient should be excluded from Metastatic lymph nodes will be identified using biopsy, the trial. The acceptable violations of dose modification increased uptake of FDG on PET/CT, or based on the will be as follows: 92–95% of the PTV to receive ≥ 99% of following radiographic criteria: nodes of ≥ 1  cm in the the prescribed dose and normal organ dose restrictions shortest axis in the intrathoracic and intra-abdominal (except the spinal cord) exceeding 5–10%. region or nodes of ≥ 0.5 cm in the shortest axis along the recurrent nerve. Radiotherapy interruption CTV If the any of the following toxicities are observed, radi- The CTV will be defined as the GTV plus 3  cm of the otherapy will be delayed until the toxicity improves to proximal and distal normal esophagus without lateral grade 2 or lower. margins. Zhu  et al. Radiation Oncology (2022) 17:134 Page 9 of 12 dose for the first cycle and by 50% for the second cycle. • WBC count < 2.0 × 10 /L or absolute neutrophil Dose modifications will be permitted twice at most; for count (ANC) < 1.0 × 10 /L. patients who still require dose modification after this • Platelets < 50 × 10 /L. point, chemotherapy will be terminated. • A non-hematological toxicity of grade 3 or higher. The criteria for dose modification are as follows: If the following toxicity is observed, radiotherapy will be delayed until complete recovery. Dose modification of paclitaxel • Mediastinal or thoracic infection with fever over • Febrile neutropenia (ANC < 0.5 × 10 /L and fever 38.5 °C. over 38.3° C or over 38.0 °C for 1 h). • Peripheral neuropathy of grade 2 or higher. The suspension of radiotherapy will be permitted for 2  weeks at most; if the patient does not recover within 2 weeks, radiotherapy will be terminated. Dose modification of cisplatin • Febrile neutropenia (ANC < 0.5 × 10 /L and fever Radiotherapy quality assurance over 38.3° C or over 38.0° C for 1 h). The IMRT planning CT of the first three patients from • Peripheral neuropathy of grade 2 or higher. each participating institution will be sent to Fudan Uni- • Serum creatinine > 3 times the upper limit of normal. versity Shanghai Cancer Center for central quality assur- ance to ensure that the center complies with the specific Adverse events will be evaluated according to the study requirements for delineation, planning, and dose National Cancer Institute Common Terminology Cri- distribution. teria for Adverse Events (CTCAE V.4.0). All adverse events that occur during the course of the trial (from Chemotherapy the start of treatment until 28  days after the end of Patients in both groups will receive two cycles of concur- treatment), regardless of their relatedness to the study rent chemotherapy with radiotherapy followed by two medication, will be recorded. Adverse events that occur cycles of consolidation chemotherapy after CRT. Each more than 28  days after the end of treatment will only cycle of chemotherapy will last for 28  days (4  weeks). be recorded if they are relevant. The drugs to be used include: paclitaxel 135  mg/m /day, intravenously guttae (IVGTT) over 3 h, day 1; and cispl- Quality of life atin 25 mg/m /day, IVGTT, days 1–3. Quality of life (QOL) is measured as secondary end- points in this trial and will be assessed using hard-copy versions of the EORTC core questionnaire, the EORTC Chemotherapy interruption and dose modification QLQ-C30 (version 3.0) [30], the disease-specific mod - If the following toxicities are observed on day 1, chemo- ule for EC, and the QLQ-OES18 [31]. The following therapy will be delayed until toxicity improves to grade 1 assessment points have been chosen to describe QOL or lower. changes across time: before the start of treatment (baseline), at the end of radiotherapy (28 or 34 frac- • ANC < 1.5 × 10 /L. tions), before two consolidative chemotherapy cycles, • Platelets < 70 × 10 /L. and at each follow-up. The EORTC-QLQ-C30 and • A non-hematological toxicity of grade 2 or higher, EORTC-QLQ-OES18 questionnaires will be completed except for nausea, vomiting, and alopecia. by patients and checked by physicians at clinic visits to minimize the number of missing items and assess- A delay to chemotherapy of 2  weeks at most will be ments. Time windows of ± 3  weeks will be applied for allowed; if the patient does not show sufficient improve - follow-up assessment. ment within this time, chemotherapy will be terminated. Chemotherapy dose modifications will be based on the greatest toxicity during the last cycle. Any patients for Adverse events whom chemotherapy dose modifications are required Adverse events will be accessed according to National will receive the modified dose during subsequent cycles. Cancer Institute Common terminology for adverse If modifications are needed, the doses of paclitaxel and events (NCI-CTCAE) (version 4.0) [32] and will be cisplatin will be decreased by 25% from the planned monitored throughout the study. Zhu et al. Radiation Oncology (2022) 17:134 Page 10 of 12 Translational research When 5% of the patients are expected to fall off, The clinical trial will involve the collection of tissue 66 cases in each group and 132 cases in total were samples and blood samples for future translational included in the PET/CT non-responder group. For research and the development and/or validation of bio- non-selected population, the 2-year survival rate is markers. Trial participants will be asked for additional estimated to be 40% of the standard-dose radiotherapy optional consent to participate in this aspect of the group and 49% of the high-dose radiotherapy group, study. The standard tissue sample will consist of pre - based on literature data [6, 35]. According to the same treatment biopsy of tumor tissue. The blood samples enrollment and follow-up time conditions, 323 cases will include 2 × 5  ml ethylenediamine tetraacetic acid are included in each group, and the total number of (EDTA) blood samples, one of which will be collected samples is determined to be 646. The double end-point at the time of pretreatment, postconcurrent and pre- fixed sequence method was used to test the PET/CT consolidation chemotherapy, and the other after recur- non-responder group first, and then the overall inten- rence. All samples will be stored at the FUSCC BioBank tion-to-treat population. When the number of PET/ for future translational research. CT non-responder reached 132 and the total popula- tion reached 646, the enrollment could be ended. Fixed Statistical analysis sequence is applied in statistics of primary endpoint. For patients with residual tumors of esophagus, it is estimated that the 2-year survival rate of low-dose Discussion radiotherapy group and high-dose radiotherapy group Radiation dose has always been a concern in radia- is 11% and 27%, according to literature [33, 34]. The tion oncology, in different tumor types and has been expected enrollment time is 7  years, and the last debated for several decades [36]. The theorical advan - enrolled patients were followed up for 2 years. Accord- tage of better local control and technical advances ing to the ratio of 1:1, bilateral α = 0.05, power = 0.80. for less toxicities have encouraged clinicians for dose Table 3 Comparison of the ongoing phase III trials of PET-guided dCRT in esophageal cancer: ESO-Shanghai 12 vs SCOPE 2 ESO‑Shanghai 12 (the current study) SCOPE 2 Country China UK No. of Patients 634 584 Study starting year 2018 2016 Pathology SCC AC/SCC Radiation technique IMRT IMRT Radiation field IFI ENI Chemotherapy prior to PET 2 Concurrent DDP + PTX * 2 cycles Induction DDP + CAP * 1 cycle Radiotherapy prior to PET 2 50.4 Gy/28 Fx No PET timing Day of RT to 50.4 Gy/28 Fx ± 3 days Day 14 Metabolic parameters and cutoff PET 2 SUV > 4 △SUV ≥ 35% max max Treatment posterior to intern PET Responder RT up to 50.4 Gy/28 Fx + chemotherapy RT (50 Gy/25 Fx) + chemotherapy (concurrent (consolidative DDP + PTX * 2 cycles) DDP + CAP * 3 cycles) RT (60 Gy/25 Fx) + chemotherapy (concurrent DDP + CAP * 3 cycles) Non-responder RT up to 61.2 Gy/34 Fx + chemotherapy RT (50 Gy/25 Fx) + chemotherapy (concurrent weekly (consolidative DDP + PTX * 2 cycles) PTX + CBP) RT (50 Gy/25 Fx) + chemotherapy (concurrent weekly PTX + CBP) Primary outcomes 2y OS in PET/CT non-responder 2y TIFFS in SCC 2y OS in all subjects 2y OS in SCC – 2y TIFFS in SCC switching chemotherapy – 2y TIFFS in AC – 2y TIFFS in AC switching chemotherapy PET = Positron emission tomography; PET/CT = Positron emission tomography/Computational tomography; dCRT = definitive chemoradiotherapy; AC = Adenocarcinoma; SCC = Squamous cell carcinoma; IMRT = Intensity-modulated radiation therapy; IFI = Involved-field irradiation; ENI = Elective nodal irradiation; DDP = Cisplatin; PTX = Paclitaxel; CAP = Capecitabine; CBP = Carboplatin; RT = Radiation therapy; TIFFS = Treatment failure free survival; OS = Overall survival Zhu  et al. Radiation Oncology (2022) 17:134 Page 11 of 12 Declarations escalation investigation. Randomized phase III tri- als have added evidence that high dose does not bring Ethical approval and consent to participate advantage to unselected patients receiving dCRT. At the The final protocol was approved by the Ethics Committee of Fudan University Shanghai Cancer Center (1808190–10). same time, the evaluation of tumor response by a vari- ety of imaging methods can not only predict the prog- Consent for publication nosis, but also detect the non-responders and adjust Not applicable. neoadjuvant treatment strategy. In dCRT, the ongoing Competing interests British SCOPE2 study [37] compare the effects of stand - The authors declare that they have no financial or non-financial competing ard drugs and alternative combinations used in chemo- interests. therapy for patients who do not respond to standard drug Author details chemotherapy in the early stage of treatment, as well Department of Radiation Oncology, Fudan University Shanghai Cancer as compares the effects of standard dose and high-dose Center, Shanghai, China. Department of Oncology, Shanghai Medical Col- lege, Fudan University, Shanghai, China. Shanghai Key Laboratory of Radia- radiotherapy. Our current study is dedicated to SCC his- tion Oncology, Shanghai, China. Department of Nuclear Medicine, Fudan tology only and compares radiation dose without switch- University Shanghai Cancer Center, Shanghai, China. Department of Cancer ing chemotherapy regime. Our response assessment is Prevention and Statistics, Fudan University Shanghai Cancer Center, Shanghai, China. Department of Radiation Oncology, Taizhou Second People’s Hospital, post radiation rather than early PET response, aiming Taizhou, Jiangsu, China. Department of Radiation Oncology, Affiliated Hos- to investigate the PET-direct radiotherapy in a pure way. pital of Jiangnan University, Wuxi, Jiangsu, China. Department of Radiation Last not least, we abandon elective nodal irradiation and Oncology, Fujian Cancer Hospital, Fuzhou, China. Department of Radiation Oncology, Huadong Hospital Affiliated to Fudan University, Shanghai, China. apply involved field irradiation, which is less toxic. The Department of Radiation Oncology, Jiangsu Cancer Hospital, Nanjing, China. detailed comparison is in Table  3. Esophageal cancer is Department of Radiation Oncology, The First Affiliated Hospital of Nanjing on the way to the era of immunotherapy, despite the foot- Medical University, Nanjing, China. Department of Radiation Oncology, The Affiliated Huaian No.1 People’s Hospital of Nanjing Medical University, Huai‘an, stone of chemoradiation in locally advanced disease [38– Jiangsu, China. 40]. Precise radiotherapy based on biology and imaging will provide new basis for individualized therapies in the Received: 12 March 2022 Accepted: 7 July 2022 future [41]. Abbreviations References dCRT : definitive chemoradiotherapy; AC: Adenocarcinoma; SCC: Squamous 1. Global Burden of Disease 2019 Cancer Collaboration, Kocarnik JM, Comp- cell carcinoma; 2D: Two dimensional; 3DCRT : Three-dimensional conformal ton K, et al. Cancer incidence, mortality, years of life lost, years lived with radiation therapy; IMRT: Intensity-modulated radiation therapy; VMAT: Volu- disability, and disability-adjusted life years for 29 cancer Groups From metric-modulated arc therapy; DDP: Cisplatin; 5-Fu: 5-Fluorouracil; FOLFOX: 2010 to 2019: a systematic analysis for the global burden of disease study Oxaliplatin + Leucovorin + 5-Fluorouracil; CAP: Capecitabine; PTX: Paclitaxel; 2019. JAMA Oncol. 2021;30:e216987. CBP: Carboplatin; DTX: Docetaxel; OS: Overall survival; SUV: Standard uptake 2. Allemani C, Matsuda T, Di Carlo V, et al. Global surveillance of trends in value; GTV: Gross tumor volume; nCT: Neoadjuvant chemotherapy; nCRT : Neo- cancer survival 2000–14 (CONCORD-3): analysis of individual records for adjuvant chemoradiotherapy; PET: Positron emission tomography; △SUV : max 37 513 025 patients diagnosed with one of 18 cancers from 322 popula- The decreased maximum standard uptake values from baseline to PET2; CF: tion-based registries in 71 countries. Lancet. 2018;391(10125):1023–75. Folinc acid; EXO: Epirubicin + Capecitabine + Oxaliplatin; XP: Capecitabine + 3. GBD 2017 Oesophageal Cancer Collaborators. The global, regional, and Cisplatin; DCF: Docetaxel + Cisplatin + 5-Fluorouracil; R: Randomization; RT: national burden of oesophageal cancer and its attributable risk factors Radiation therapy; W: Week; PET/CT: Positron emission tomography/Computa- in 195 countries and territories, 1990–2017: a systematic analysis for tional tomography; IFI: Involved-field irradiation; ENI: Elective nodal irradiation; the global burden of disease study 2017. Lancet Gastroenterol Hepatol. TIFFS: Treatment failure free survival. 2020;5(6):582–97. 4. Abnet CC, Arnold M, Wei WQ. Epidemiology of esophageal squamous cell Acknowledgements carcinoma. Gastroenterology. 2018;154(2):360–73. Not applicable. 5. Cooper JS, Guo MD, Herskovic A, et al. Chemoradiotherapy of locally advanced esophageal cancer: long-term follow-up of a prospec- Author contributions tive randomized trial (RTOG 85–01). Radiat Ther Oncol Gr JAMA. KZ, YC and HZ planned the study. HZ, QL, HX, MM, ZW, KL, JZ, JC, XZ, JY, XG, HL, 1999;281(17):1623–7. QL, JD, DA, SH, JZ, IT, SS, YC and KZ are conducting the study. KZ, YC and HZ 6. Minsky BD, Pajak TF, Ginsberg RJ, et al. INT 0123 (radiation therapy are responsible for the patient recruitment. HZ, QL, HX, MM and YC wrote the oncology group 94–05) phase III trial of combined-modality therapy for main manuscript text and HZ and ZW prepared figures. All authors read and esophageal cancer: high-dose versus standard-dose radiation therapy. J approved the final manuscript. Clin Oncol Off J Am Soc Clin Oncol. 2002;20(5):1167–74. 7. Conroy T, Galais MP, Raoul JL, et al. Definitive chemoradiotherapy with Funding FOLFOX versus fluorouracil and cisplatin in patients with oesophageal The ESO-Shanghai 12 trial is supported by National Natural Science Founda- cancer (PRODIGE5/ACCORD17): final results of a randomised, phase 2/3 tion of China (82102827, 81872454), Chinese Society of Clinical Oncology trial. Lancet Oncol. 2014;15(3):305–14. (Y-Young2020-0003); Beijing Bethune Charitable Foundation (flzh202119). 8. Crosby T, Hurt CN, Falk S, et al. Chemoradiotherapy with or without cetuximab in patients with oesophageal cancer (SCOPE1): a multicentre, Availability of supporting data phase 2/3 randomised trial. Lancet Oncol. 2013;14(7):627–37. Data sharing not applicable to this article as no datasets were generated or 9. Suntharalingam M, Winter K, Ilson D, et al. Eec ff t of the addition of analyzed during the current study until now. cetuximab to paclitaxel, cisplatin, and radiation therapy for patients with Zhu et al. Radiation Oncology (2022) 17:134 Page 12 of 12 esophageal cancer: the NRG oncology RTOG 0436 phase 3 randomized cisplatin and fluorouracil for resectable oesophageal adenocarcinoma clinical trial. JAMA Oncol. 2017;3(11):1520–8. (AGITG DOCTOR): results from a multicentre, randomised controlled 10. 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Dose escalation based on 18F-FDG PET/CT response in definitive chemoradiotherapy of locally advanced esophageal squamous cell carcinoma: a phase III, open-label, randomized, controlled trial (ESO-Shanghai 12)

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Abstract

Introduction: Definitive chemoradiotherapy has established the standard non-surgical treatment for locally advanced esophageal cancer. The standard dose of 50–50.4 Gy has been established decades ago and been con- firmed in modern trials. The theorical advantage of better local control and technical advances for less toxicity have 18 18 encouraged clinicians for dose escalation investigation. F-fluorodeoxyglucose ( F-FDG) positron emission tomog- raphy/computed tomography (PET/CT ) have the potential to tailor therapy for esophageal patients not showing response to CRT and pioneers the PET-based dose escalation. Methods and analysis: The ESO-Shanghai 12 trial is a prospective multicenter randomized phase 3 study in which patients are randomized to either 61.2 Gy or 50.4 Gy of radiation dose by PET response. Both groups undergo concur- rent chemoradiotherapy with paclitaxel/cisplatin regimen for 2 cycles followed by consolidation chemotherapy for 2 cycles. Patients with histologically confirmed ESCC [ T1N1-3M0, T2-4NxM0, TxNxM1 (Supraclavicular lymph node metastasis only), (AJCC Cancer Staging Manual, 8th Edition)] and without any prior treatment of chemotherapy, radio- therapy or surgery against esophageal cancer will be eligible. The primary endpoints included overall survival in PET/ CT non-responders (SUV > 4.0) and overall survival in total population. Patients will be stratified by standardized max uptake volume, gross tumor volume and tumor location. The enrollment could be ended, when the number of PET/ CT non-responder reached 132 and the total population reached 646 for randomization. Hongcheng Zhu, Qiufang Liu and Hao Xu contribute equally to this work *Correspondence: chenyun_qz@fudan.edu.cn; kuaile_z@fudan.edu.cn Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China Full list of author information is available at the end of the article © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Zhu et al. Radiation Oncology (2022) 17:134 Page 2 of 12 Ethics and dissemination: This trial has been approved by the Fudan University Shanghai Cancer Center Insti- tutional Review Board. Trial results will be disseminated via peer reviewed scientific journals and conference presentations. Trial registration The trial was initiated in 2018 and is currently recruiting patients. Trial registration number NCT03790553. Background of intensity-modulated radiotherapy (IMRT), radiation According to the Global Burden of Disease Study 2019, oncologists are interested in re-investigating dose esca- esophageal cancer (EC) accounted for approximately lation in EC. The highly anticipated European CON - 535,000 new cancer cases and 498,000 deaths in 2019 CORDE [10] and ARTDECO [11] studies, along with a worldwide [1]. The 5-year standardized net survival rate Chinese phase III trial [12], have further demonstrated ranges between 10 and 30% globally [2]. There are two that increasing the radiation dose for non-selected popu- distinct histopathologic subtypes of EC: esophageal squa- lations does not offer benefits in definitive CRT for EC mous cell carcinoma (ESCC) and esophageal adenocar- in the modern era. However, high doses (≥ 60  Gy) have cinoma. These subtypes vary in terms of incidence, risk been widely used in Asia and have demonstrated posi- factors, location, and age of diagnosis [3], and ESCC is tive results in Asian populations and ESCC subtypes in the dominant subtype in Asian populations [4]. Defini - retrospective studies [13, 14], and meta-analyses have tive chemoradiotherapy (CRT) has been established as further contributed to the debate [15, 16]. Moreover, the standard nonsurgical treatment for locally advanced our previous drug comparison phase III trial [17] using EC. Measures to achieve better local control and overall involved-field irradiation–based IMRT up to a total dose survival, including radiation dose escalation, chemother- of 61.2  Gy demonstrated favorable survival outcomes apy regime optimization, and the combination of target (Table 1). agents, have been explored for decades. However, few of these measures have demonstrated positive results in randomized phase III trials. The ESO-Shanghai 12 trial Failure patterns of CRT in EC (NCT03790553) was designed to evaluate dose escala- Researchers have tried to explore failure patterns of EC tion in ESCC chemoradiation based on the response on chemoradiotherapy. Button et  al. [18] reported the first 18F-fluorodeoxyglucose (18F-FDG) positron emission failure site in 145 patients receiving chemoradiotherapy tomography/computed tomography (PET/CT), with the for EC. The irradiation field included the gross tumor vol - aim of establishing an approach to precision radiation ume (GTV), plus 3 cm of the proximal and distal normal therapy for EC. esophagus and a 1.5-cm margin in the transversal posi- tion. Eighty-five patients were identified as treatment fail - ure, including 55 patients with in-field failure, 13 patients with distant metastases, and 14 patients with both. Only Standard dose for CRT 3 patients had relapse observed at the edge of the irradia- The phase III RTOG-8501 trial demonstrated that 50 Gy tion field. Welsh et  al. [19] retrospectively analyzed 239 radiation with concurrent chemotherapy is superior to patients who received CRT for EC, among whom 50% radiotherapy of 64  Gy alone, thus establishing defini - had local failure and 48% had distant metastases. Of all tive concurrent CRT as the standard nonsurgical treat- the cases of local failure, 90% occurred in the GTV, 27% ment scheme for locally advanced EC [5]. The phase III in the clinical target volume (CTV), and 12% in the pri- randomized trial RTOG-9405 compared a high dose mary tumor volume (PTV). In the ESO-Shanghai 1 trial, of 64.8  Gy and a low dose of 50.4  Gy in definitive con - the radiotherapy techniques were involved-field irradia - current CRT. The results showed that a high dose did tion (no lymph node preventive irradiation) and IMRT, not improve survival or local control, with the absolute and the radiotherapy dose was 61.2 Gy/34 Fx. Of the 436 value of median overall survival and the 2-year survival trial participants, 258 (59.2%) experienced treatment fail- rate being lower in the high-dose group than in the low- ure; 37 patients (8.5%) showed failure of irradiation of dose group [6]. During the past decade, radiotherapy has the lymph nodes in the field, of which 7 cases (1.6%) had entered the era of three-dimensional conformal radiation simple lymph node failure [20]. Therefore, considering therapy (3DCRT); however, the standard radiation dose recurrence within the irradiation field accounts for half of 50  Gy does not present preferable survival character- of cases of CRT failure in EC, dose escalation may be an istics regardless of whether it is combined with concur- effective approach to achieve a good prognosis. rent systemic therapy [7–9]. With the wide application Zhu  et al. Radiation Oncology (2022) 17:134 Page 3 of 12 Table 1 Survival outcomes of standard dose or high dose in esophageal cancer dCRT from selected trails Study Country Pathology Radiation Radiation Systemic therapies No. of 2y OS 3y OS 5y OS (Reference) (Year*) dose technique Patients RTOG 85–01 USA AC/SCC 50 Gy 2D DDP + 5-Fu 61 36% 30% 25% [5] (1986–1990) 50 Gy DDP + 5-Fu 69 36% 30% 25% 64 Gy – 62 10% 0% 0% RTOG 94–05/ USA AC/SCC 50.4 Gy 2D DDP + 5-Fu 109 40% 33% – INT 0123 [6] (1995–1999) 64.8 Gy DDP + 5-Fu 109 31% 25% – PRODIGE5/ France AC/SCC 50 Gy 3DCRT FOLFOX 134 – 19.9% – ACCORD17 [7] (2004–2011) DDP + 5-Fu 133 – 26.9% – SCOPE1 [8] UK AC/SCC 50 Gy 3DCRT CAP + DDP + Cetuxi- 129 41.3% – – (2008–2012) mab CAP + DDP 129 56% – – RTOG 0436 [9] USA AC/SCC 50.4 Gy 3DCRT PTX + DDP + Cetuxi- 159 45% 34% – (2008–2013) mab PTX + DDP 169 44% 28% – CONCORDE/ France AC/SCC 50 Gy 3DCRT/IMRT/ FOLFOX 109 Median 25.2 m PRODIGE26 (2011–2019) VMAT 66 Gy 108 Median 23.5 m [10] ESO-Shanghai China SCC 61.2 Gy IMRT PTX + 5-Fu 217 60.6 55.4% 44.3% 1 [17] (2012–2015) DDP + 5-Fu 219 61.5% 51.8% 40.8% ARTDECO [11] Netherlands AC/SCC 50.4 Gy 3DCRT/IMRT PTX + CBP 130 – 42% – (2012–2018) 61.6 Gy 130 – 39% – Xu et al. [12] China SCC 50 Gy IMRT DDP + DTX 153 62.9% 54.0% – (2013–2017) 60 Gy 152 64.8% 54.1% – dCRT = definitive chemoradiotherapy; AC = Adenocarcinoma; SCC = Squamous cell carcinoma; 2D = Two Dimensional; 3DCRT = Threedimensional conformal radiation therapy; IMRT = Intensity-modulated radiation therapy; VMAT = Volumetric-modulated arc therapy; DDP = Cisplatin; 5-Fu = 5-Fluorouracil; FOLFOX = Oxaliplatin + Leucovorin + 5-Fluorouracil; CAP = Capecitabine; PTX = Paclitaxel; CBP = Carboplatin; DTX = Docetaxel; OS = Overall survival *Patients recruiting year Feasibility and effectiveness of high‑dose radiotherapy entails less toxicity, its use may increase the feasibility of in EC increasing the dose. The esophagus may be the most important dose-limit - ing organ. Under the guidance of PET/CT, Yu et  al. [21] Tumor response assessment irradiated more than 50% of the tumor area with the In EC, evaluation of the tumor response to neoadjuvant maximum standardized uptake volume (SUV) before therapy can not only be used to predict prognosis but radiotherapy. They found that it was safe for patients also to detect non-responders of CRT and allow adjust- to receive 70  Gy/25 Fx at the same time and that the ment of treatment strategy. According to the MUNICON short-term toxicity was tolerable. In a phase 1/2 trial, trial, patients who show a clinical response to induction Chen et al. [22] reported that chemoradiotherapy with a treatment (chemotherapy- or chemoradiotherapy) have simultaneous integrated boost of radiotherapy (at doses a better prognosis [24]. At present, several methods are of 50.4 Gy to subclinical areas at risk and 63.0 Gy to the available to evaluate the treatment response; among gross tumor and involved nodes, all given in 28 fractions) them, ultrasonic gastroscopy and F-FDG PET/CT have for patients with locally advanced EC was well toler- high accuracy [25]. Consequently, improving induction ated, with encouraging local control. If the target volume chemotherapy to increase the proportion of treatment dose can be increased without affecting the tolerance of responders, as well as intensifying the radiotherapy, could normal tissue, local control and the overall therapeutic be strategies to improve local disease control or survival. effect may be improved in EC radiotherapy [23]. In recent Several phase II trials [26–29] have shown that PET/CT years, the progress of radiation technology has ensured has the potential to tailor therapy for patients not show- the safety and effectiveness of increasing the local radi - ing an early response to chemotherapy and have pio- otherapy dose. Also, because involved-field irradiation neered PET-directed EC neoadjuvant therapy (Table 2). Zhu et al. Radiation Oncology (2022) 17:134 Page 4 of 12 Rationale for the trial Overall survival in patients who have an S UV ≤ 4 max Based on the above evidence, we designed a phase 3 on PET/CT at 28 radiotherapy fractions. study to investigate whether an increased dose of 61.2 Gy 4. Questionnaire: European Organization for the is superior to the standard dose of 50.4  Gy in definitive Research and Treatment of Cancer Quality of Life chemoradiotherapy of ESCC, especially in patients with Questionnaire (EORTC-QLQ)-C30 (time frame: no response on F-FDG PET/CT. 2 years) A quality-of-life score will be obtained based on the Methods and analysis answers to the questionnaire. Design 5. Questionnaire: EORTC-QLQ-OES18 (time frame: The ESO-Shanghai 12 trial is a prospective, multicenter, 2 years) randomized phase 3 study, in which patients are ran- A quality-of-life score will be obtained according to domized to receive radiation at a dose of 61.2  Gy or the answers to the questionnaire. 50.4 Gy based on the F-FDG PET/CT response (strati- 6. Exploration of predictive and prognostic biomarkers. fied by SUV > 4 and SUV ≤ 4). Both arms will max max undergo concurrent chemoradiotherapy with a pacli- taxel/cisplatin (TP) regimen for two cycles followed by Patient selection consolidation chemotherapy for two cycles (Fig. 1). Inclusion criteria To be eligible for inclusion in this study, patients must Objectives fulfill all the following criteria: Primary endpoints 1. Participating in the study voluntarily and able to 1. Overall survival in PET/CT non-responders (time sign the informed consent form. frame: 2 years) 2. Aged between 18 and 75 years, and of either sex. 3. Pathologically confirmed with ESCC [T1N1- The time between the start of the study treatment 3M0, T2-4NxM0, TxNxM1 (supraclavicular lymph (day 1) and death from any cause or the last follow- node metastasis only), (American Joint Committee up (for patients who are alive at the end of the study) on Cancer Staging Manual, 8th Edition)]. in patients who have an SUV > 4 on PET/CT at 28 max 4. No receipt of radiotherapy, chemotherapy, or other radiotherapy fractions. treatments prior to enrollment. 2. Overall survival in the intention-to-treat (ITT) popu- 5. Using an effective contraceptive to prevent preg - lation (time frame: 2 years) nancy. The time between the start of the study treatment 6. No severely abnormal hematopoietic, cardiac, pul- (day 1) and death from any cause or the last follow- monary, renal, or hepatic function, or immunodefi - up (for patients who are alive at the end of the study) ciency. in the ITT population. 7. White blood cells (WBC) ≥ 3.5*10 /L, hemo- globin ≥ 9  g/dL , neutrophils ≥ 1·5*10 /L, plate- Secondary endpoints let count ≥ 100*10 /L, alanine aminotrans- ferase (ALAT) and aspartate aminotransferase 1. Local control in PET/CT non-responders, the ITT (A SAT) < 2·5 * upper limit of normal (ULN), population, and PET/CT responders (time frame: total bilirubin ( TBIL) < 1·5 * ULN, and creati- 2 years) nine < 1·5 *ULN. 8. An Eastern Cooperative Oncology Group (ECOG) The time between the start of the study treatment score of 0–2. (day 1) and local recurrence (including primary 9. Life expectancy of more than 3 months. tumor recurrence and regional lymph node failure). 10. Agrees to undergo F-FDG PET/CT assessment at 2. Progression-free survival in PET/CT non-respond- 28 radiotherapy fractions. ers, the ITT population, and PET/CT responders (time frame: 2 years) The time between day 1 and the first event of local Exclusion criteria failure, metastatic recurrence, progression, or death. The following patients will be ineligible for this study. 3. Overall survival in PET/CT responders (time frame: 2 years) Zhu  et al. Radiation Oncology (2022) 17:134 Page 5 of 12 Table 2 Selected trails of PET-directed neoadjuvant therapy in esophageal cancer Study (Reference) Country Patho PET timing Metabolic Induction therapy Arms Treatment No. of pCR Median OS (Year*) logy parameters and Patients cutoff MUNICON [24] Germany AC Day 14 △SUV ≥ 35% DDP + CF + 5-FU ± PTX Responder Continued nCT + surgery 50 58% – max (2002–2005) Non-responder Discontinued nCT + surgery 54 0% 25.8 m MUNICON II [26] Germany AC Day 14 △SUV ≥ 35% DDP + CF + 5-FU ± PTX Responder Continued nCT + surgery 23 36% – max (2005–2008) Non-responder Change to nCRT (DDP or 33 26% 18.3 m 5-Fu + 32 Gy/1.6 Gy bid) + surgery AGITC DOCTOR [27] Australia AC Day 15 △SUV ≥ 35% DDP + 5-Fu Responder Continued initial nCT + surgery 45 7% 61 m max (2009–2015) Non-responder New nCT regime of DCF 31 20% 30 m (DTX + DDP + 5-Fu) + surgery Change to nCRT (DCF + 45 Gy/25 34 63% 35 m Fx) + surgery CALGB-80803/Alliance [28] USA (2011–2015) AC Day 36—42 △SUV ≥ 35% FOLFOX Responder nCRT: Continued initial chemo 72 37.5% 50.3 m max plus RT (50.4 Gy/28 Fx) + surgery Non-responder nCRT: Crossover to alternative 39 19.0% 30.9 m chemo (PTX + CBP) plus RT (50.4 Gy/28 Fx) + surgery PTX + CBP Responder nCRT: Continued initial chemo 64 12.5% 39.6 m plus RT (50.4 Gy/28 Fx) + surgery Non-responder nCRT: Crossover to alterna- 50 17.0% 27.6 m tive chemo (FOLFOX) plus RT (50.4 Gy/28 Fx) + surgery MEMORI [29] Germany AC Day 14—21 △SUV ≥ 35% EOX/XP/mFOLFOX6 Responder Continued initial nCT + surgery 47 33% – max (2014–2018) Non-responder Change to nCRT 22 55% – (PTX + CBP + 41.4 Gy/23 Fx) + sur- gery nCT = neoadjuvant chemotherapy; nCRT = neoadjuvant chemoradiotherapy; PET = Positron Emission Tomography; △SUVmax = The decreased maximum standard uptake values from baseline to PET2; DDP = Cisplatin; CF = Folinc acid; 5-FU = 5-Fluorouracil; PTX = Paclitaxel; FOLFOX = Oxaliplatin + Leucovorin + 5-Fluorouracil; CBP = Carboplatin; EXO = Epirubicin + Capecitabine + Oxaliplatin; XP = Capecitabine + Cisplatin; DCF = Docetaxel + Cisplatin + 5-Fluorouracil; DTX = Docetaxel *Patients recruiting year Zhu et al. Radiation Oncology (2022) 17:134 Page 6 of 12 Fig. 1 Trial diagram of the ESO-Shanghai 12 trial. PET = Positron emission tomography; SUV = Standard uptake value; GTV = Gross tumor volume; PTX = Paclitaxel; DDP = Cisplatin Fig. 2 Treatment design of the ESO-Shanghai 12 trial. PET = Positron emission tomography; SUV = Standard uptake value; R = Randomization; RT = Radiation therapy ; TP = Paclitaxel + Cisplatin; W = Week Zhu  et al. Radiation Oncology (2022) 17:134 Page 7 of 12 1. Patients whose total radiotherapy dose reaches • Blood glucose measurement will be performed 61.2  Gy/34 Fx if the normal tissue dose complies before the injection of F-FDG, and blood glucose with the standard criteria. levels should be less than 140 mg/dL. 2. Patients with esophageal perforation or hematem- • The height and weight of patients will be measured esis. using calibrated and medically approved devices. 3. Patients with a history of radiotherapy or chemo- therapy for EC. 2. Injection of F-FDG 4. Patients with a history of surgery within 28  days before Day 1. • Patients will receive an F-FDG dose of 3.7 MBq/ 5. Patients with a history of prior malignancies (other Kg of body weight in accordance with the manu- than skin basal cell carcinoma or cervical carci- facturer’s recommendations. Patients will be kept noma in  situ with disease-free survival of at least in a quiet and dimly lit room before and after the 3 years). injection. 6. Patients who are participating in another interven- • A saline flush of 1  mL will follow the F-FDG tional clinical trial less than 30 days. injection. 7. Pregnant or breastfeeding women or fertile patients • The exact time of dose calibration will be recorded who refuse to use contraceptives. using a global time recording device, which will 8. Patients with drug addiction, alcoholism, or be consistently used throughout the study for acquired immunodeficiency (AIDS). time recording. The exact time of injection will 9. Patients experiencing uncontrolled seizures or psy- be noted and recorded to permit the correction of chiatric disorders. the administered dose for radioactive decay. Fur- 10. Patients with any other condition which, in the thermore, any of the dose remaining in the tube or investigator’s opinion, would make them an unsuit- syringe, or any F-FDG that is spilled during the able candidate for the clinical trial. injection will be recorded. The F-FDG injection will be performed using an intravenous catheter and three-way stopcock. Study treatment 3. PET/CT imaging The treatment plan is shown in Fig.  1. Patients will All PET exams will include three trans-axial, whole- receive radiotherapy combined with concurrent chemo- body series, attenuated and non-attenuated, cor- therapy. Radiotherapy will begin on day 1, concurrent rected PET and CT images. with the beginning of cycle 1 of chemotherapy. Radio- therapy will be delivered with photons (≥ 6 MV) to a • The scan will be conducted 60 ± 10  min after the total dose of 50.4 Gy in 28 fractions or 61.2 Gy in 34 frac- injection of F-FDG. tions. F-FDG PET/CT will be performed for all patients • The patient will be instructed to empty their blad - at baseline and at 28 radiotherapy fractions (± 3  days), der immediately before the image acquisition. and then patients will be randomized after assessment. • A spiral CT scan using the low-dose technique Patients will be stratified according to the SUV (≤ 4 max (120  kV, 140  mA, 5-mm slice thickness) will be 2 2 or > 4), GT V (≤ 40 cm or > 40 cm ) and tumor location conducted first, followed by a PET emission scan [cervical/upper thoracic location with heart dose ≤ 10 Gy from the distal femur to the top of the skull. or (middle/lower thoracic location or heart dose > 10 Gy)] • A PET emission scan covering the same transverse (Fig. 2). field of view will be obtained immediately after the CT scan. The PET data will be reconstructed using a Gaussian filter iterative (iterations 4; subsets 8; F‑FDG PET/CT assessment image size 168) for the reconstruction of emission images. The CT data will be used for attenuation 1. Pre-PET/CT patient preparation correction of the PET images, and fused images will be displayed on a workstation. • Patients will not undergo a barium meal examina- tion at least 1 week before the PET/CT scan. 4. Reporting of PET findings and SUV calculations • Prior to injection, the patient must fast for at least 6 h. SUVs are commonly used in clinical practice in addi- tion to visual assessments. The SUV is a measurement of Zhu et al. Radiation Oncology (2022) 17:134 Page 8 of 12 PTV the uptake in a tumor normalized on the basis of a distri- The PTV will be generated by applying a 1-cm margin to bution volume. It is calculated as follows: the CTV. Act (kBq/ml) voi Tissue inhomogeneity correction will be adopted for SUV = Act (MBq) BW kg administered planning purposes. The criteria for dose distribution will be as follows: 95% of the PTV to receive ≥ 99% of the In this calculation, Act is the activity measured in the voi prescribed dose; 99% of the PTV to receive ≥ 95% of the volume of interest (see “Definitions for volumes of inter - prescribed dose; < 2 cm of the PTV to receive ≥ 120% est (VOI) and regions of interest (ROI)”), A ct administered of the prescribed dose; and < 1 cm of the PTV to is the administered activity corrected for the physical receive ≥ 110% of the prescribed dose. The highest and decay of F-FDG at the start of acquisition, and BW is lowest dose points inside the PTV will be recorded. body weight. The patient’s height, weight, and sex will be reported to allow for other SUV normalizations (lean body mass, body surface area). Normal organ contouring and dose restrictions Normal organs, including the spinal cord, heart, and • PET/CT images will be analyzed independently right and left lungs, will be contoured on each slice of the by two senior nuclear medicine physicians using a planning CT with no planning margin. The spinal cord multimodality computer platform (Syngo, Siemens, dose constraint must not be exceeded for any reason. Knoxville, TN, USA). For any inconsistent or equivo- The heart contours will extend from the beginning of the cal interpretations, another experienced radiologist right atrium and right ventricle (the pulmonary artery will be invited to the discussion to reach a consensus. trunk, ascending main aorta, and superior vena cava will be excluded) down to the apex of the heart. The lung vol - ume will be defined as the total lung minus the PTV. Radiotherapy The priority order of consideration for normal organ IMRT will be required. The radiation plan for all patients dose restrictions will be as follows: will involve 61.2 Gy/ 34 Fx, at 1.8 Gy/ day for 5 days per week. The standardized-dose group will receive a radia - 1. Spinal cord: the highest dose point must be of less tion dose of 50.4  Gy/28 Fx, while the high-dose group than 45 Gy. will receive 61.2  Gy of radiation. The patients will be 2. Lung: the volume of the lung (PTV excluded) receiv- immobilized in the supine position and receive a con- ing 20  Gy must be equal to or less than 30% of the trast-enhanced planning CT scan 0.5  cm under the cri- total lung volume, and the mean lung dose must be cothyroid membrane (for thoracic tumors) or basis cranii equal to or less than 15 Gy at the same time. (for cervical tumors) below the kidney. IMRT will be 3. Heart: the mean dose must be less than 40 Gy. delivered to all patients using 6 MV photons. The radia - tion target volume will be delineated by the field involved. Dose modifications GTV It is strongly recommended that the normal organ dose The GTV will be defined as any visible primary tumor constraints are not exceeded. If any dose constraint needs and metastatic lymph nodes. The primary tumor will to be exceeded to achieve adequate coverage of the PTV, be delineated using esophagography, esophagoscopy, 18 the physician will decide whether the dose should be contrast-enhanced thoracic CT, and F-FDG PET/CT). modified, or whether the patient should be excluded from Metastatic lymph nodes will be identified using biopsy, the trial. The acceptable violations of dose modification increased uptake of FDG on PET/CT, or based on the will be as follows: 92–95% of the PTV to receive ≥ 99% of following radiographic criteria: nodes of ≥ 1  cm in the the prescribed dose and normal organ dose restrictions shortest axis in the intrathoracic and intra-abdominal (except the spinal cord) exceeding 5–10%. region or nodes of ≥ 0.5 cm in the shortest axis along the recurrent nerve. Radiotherapy interruption CTV If the any of the following toxicities are observed, radi- The CTV will be defined as the GTV plus 3  cm of the otherapy will be delayed until the toxicity improves to proximal and distal normal esophagus without lateral grade 2 or lower. margins. Zhu  et al. Radiation Oncology (2022) 17:134 Page 9 of 12 dose for the first cycle and by 50% for the second cycle. • WBC count < 2.0 × 10 /L or absolute neutrophil Dose modifications will be permitted twice at most; for count (ANC) < 1.0 × 10 /L. patients who still require dose modification after this • Platelets < 50 × 10 /L. point, chemotherapy will be terminated. • A non-hematological toxicity of grade 3 or higher. The criteria for dose modification are as follows: If the following toxicity is observed, radiotherapy will be delayed until complete recovery. Dose modification of paclitaxel • Mediastinal or thoracic infection with fever over • Febrile neutropenia (ANC < 0.5 × 10 /L and fever 38.5 °C. over 38.3° C or over 38.0 °C for 1 h). • Peripheral neuropathy of grade 2 or higher. The suspension of radiotherapy will be permitted for 2  weeks at most; if the patient does not recover within 2 weeks, radiotherapy will be terminated. Dose modification of cisplatin • Febrile neutropenia (ANC < 0.5 × 10 /L and fever Radiotherapy quality assurance over 38.3° C or over 38.0° C for 1 h). The IMRT planning CT of the first three patients from • Peripheral neuropathy of grade 2 or higher. each participating institution will be sent to Fudan Uni- • Serum creatinine > 3 times the upper limit of normal. versity Shanghai Cancer Center for central quality assur- ance to ensure that the center complies with the specific Adverse events will be evaluated according to the study requirements for delineation, planning, and dose National Cancer Institute Common Terminology Cri- distribution. teria for Adverse Events (CTCAE V.4.0). All adverse events that occur during the course of the trial (from Chemotherapy the start of treatment until 28  days after the end of Patients in both groups will receive two cycles of concur- treatment), regardless of their relatedness to the study rent chemotherapy with radiotherapy followed by two medication, will be recorded. Adverse events that occur cycles of consolidation chemotherapy after CRT. Each more than 28  days after the end of treatment will only cycle of chemotherapy will last for 28  days (4  weeks). be recorded if they are relevant. The drugs to be used include: paclitaxel 135  mg/m /day, intravenously guttae (IVGTT) over 3 h, day 1; and cispl- Quality of life atin 25 mg/m /day, IVGTT, days 1–3. Quality of life (QOL) is measured as secondary end- points in this trial and will be assessed using hard-copy versions of the EORTC core questionnaire, the EORTC Chemotherapy interruption and dose modification QLQ-C30 (version 3.0) [30], the disease-specific mod - If the following toxicities are observed on day 1, chemo- ule for EC, and the QLQ-OES18 [31]. The following therapy will be delayed until toxicity improves to grade 1 assessment points have been chosen to describe QOL or lower. changes across time: before the start of treatment (baseline), at the end of radiotherapy (28 or 34 frac- • ANC < 1.5 × 10 /L. tions), before two consolidative chemotherapy cycles, • Platelets < 70 × 10 /L. and at each follow-up. The EORTC-QLQ-C30 and • A non-hematological toxicity of grade 2 or higher, EORTC-QLQ-OES18 questionnaires will be completed except for nausea, vomiting, and alopecia. by patients and checked by physicians at clinic visits to minimize the number of missing items and assess- A delay to chemotherapy of 2  weeks at most will be ments. Time windows of ± 3  weeks will be applied for allowed; if the patient does not show sufficient improve - follow-up assessment. ment within this time, chemotherapy will be terminated. Chemotherapy dose modifications will be based on the greatest toxicity during the last cycle. Any patients for Adverse events whom chemotherapy dose modifications are required Adverse events will be accessed according to National will receive the modified dose during subsequent cycles. Cancer Institute Common terminology for adverse If modifications are needed, the doses of paclitaxel and events (NCI-CTCAE) (version 4.0) [32] and will be cisplatin will be decreased by 25% from the planned monitored throughout the study. Zhu et al. Radiation Oncology (2022) 17:134 Page 10 of 12 Translational research When 5% of the patients are expected to fall off, The clinical trial will involve the collection of tissue 66 cases in each group and 132 cases in total were samples and blood samples for future translational included in the PET/CT non-responder group. For research and the development and/or validation of bio- non-selected population, the 2-year survival rate is markers. Trial participants will be asked for additional estimated to be 40% of the standard-dose radiotherapy optional consent to participate in this aspect of the group and 49% of the high-dose radiotherapy group, study. The standard tissue sample will consist of pre - based on literature data [6, 35]. According to the same treatment biopsy of tumor tissue. The blood samples enrollment and follow-up time conditions, 323 cases will include 2 × 5  ml ethylenediamine tetraacetic acid are included in each group, and the total number of (EDTA) blood samples, one of which will be collected samples is determined to be 646. The double end-point at the time of pretreatment, postconcurrent and pre- fixed sequence method was used to test the PET/CT consolidation chemotherapy, and the other after recur- non-responder group first, and then the overall inten- rence. All samples will be stored at the FUSCC BioBank tion-to-treat population. When the number of PET/ for future translational research. CT non-responder reached 132 and the total popula- tion reached 646, the enrollment could be ended. Fixed Statistical analysis sequence is applied in statistics of primary endpoint. For patients with residual tumors of esophagus, it is estimated that the 2-year survival rate of low-dose Discussion radiotherapy group and high-dose radiotherapy group Radiation dose has always been a concern in radia- is 11% and 27%, according to literature [33, 34]. The tion oncology, in different tumor types and has been expected enrollment time is 7  years, and the last debated for several decades [36]. The theorical advan - enrolled patients were followed up for 2 years. Accord- tage of better local control and technical advances ing to the ratio of 1:1, bilateral α = 0.05, power = 0.80. for less toxicities have encouraged clinicians for dose Table 3 Comparison of the ongoing phase III trials of PET-guided dCRT in esophageal cancer: ESO-Shanghai 12 vs SCOPE 2 ESO‑Shanghai 12 (the current study) SCOPE 2 Country China UK No. of Patients 634 584 Study starting year 2018 2016 Pathology SCC AC/SCC Radiation technique IMRT IMRT Radiation field IFI ENI Chemotherapy prior to PET 2 Concurrent DDP + PTX * 2 cycles Induction DDP + CAP * 1 cycle Radiotherapy prior to PET 2 50.4 Gy/28 Fx No PET timing Day of RT to 50.4 Gy/28 Fx ± 3 days Day 14 Metabolic parameters and cutoff PET 2 SUV > 4 △SUV ≥ 35% max max Treatment posterior to intern PET Responder RT up to 50.4 Gy/28 Fx + chemotherapy RT (50 Gy/25 Fx) + chemotherapy (concurrent (consolidative DDP + PTX * 2 cycles) DDP + CAP * 3 cycles) RT (60 Gy/25 Fx) + chemotherapy (concurrent DDP + CAP * 3 cycles) Non-responder RT up to 61.2 Gy/34 Fx + chemotherapy RT (50 Gy/25 Fx) + chemotherapy (concurrent weekly (consolidative DDP + PTX * 2 cycles) PTX + CBP) RT (50 Gy/25 Fx) + chemotherapy (concurrent weekly PTX + CBP) Primary outcomes 2y OS in PET/CT non-responder 2y TIFFS in SCC 2y OS in all subjects 2y OS in SCC – 2y TIFFS in SCC switching chemotherapy – 2y TIFFS in AC – 2y TIFFS in AC switching chemotherapy PET = Positron emission tomography; PET/CT = Positron emission tomography/Computational tomography; dCRT = definitive chemoradiotherapy; AC = Adenocarcinoma; SCC = Squamous cell carcinoma; IMRT = Intensity-modulated radiation therapy; IFI = Involved-field irradiation; ENI = Elective nodal irradiation; DDP = Cisplatin; PTX = Paclitaxel; CAP = Capecitabine; CBP = Carboplatin; RT = Radiation therapy; TIFFS = Treatment failure free survival; OS = Overall survival Zhu  et al. Radiation Oncology (2022) 17:134 Page 11 of 12 Declarations escalation investigation. Randomized phase III tri- als have added evidence that high dose does not bring Ethical approval and consent to participate advantage to unselected patients receiving dCRT. At the The final protocol was approved by the Ethics Committee of Fudan University Shanghai Cancer Center (1808190–10). same time, the evaluation of tumor response by a vari- ety of imaging methods can not only predict the prog- Consent for publication nosis, but also detect the non-responders and adjust Not applicable. neoadjuvant treatment strategy. In dCRT, the ongoing Competing interests British SCOPE2 study [37] compare the effects of stand - The authors declare that they have no financial or non-financial competing ard drugs and alternative combinations used in chemo- interests. therapy for patients who do not respond to standard drug Author details chemotherapy in the early stage of treatment, as well Department of Radiation Oncology, Fudan University Shanghai Cancer as compares the effects of standard dose and high-dose Center, Shanghai, China. Department of Oncology, Shanghai Medical Col- lege, Fudan University, Shanghai, China. Shanghai Key Laboratory of Radia- radiotherapy. Our current study is dedicated to SCC his- tion Oncology, Shanghai, China. Department of Nuclear Medicine, Fudan tology only and compares radiation dose without switch- University Shanghai Cancer Center, Shanghai, China. Department of Cancer ing chemotherapy regime. Our response assessment is Prevention and Statistics, Fudan University Shanghai Cancer Center, Shanghai, China. Department of Radiation Oncology, Taizhou Second People’s Hospital, post radiation rather than early PET response, aiming Taizhou, Jiangsu, China. Department of Radiation Oncology, Affiliated Hos- to investigate the PET-direct radiotherapy in a pure way. pital of Jiangnan University, Wuxi, Jiangsu, China. Department of Radiation Last not least, we abandon elective nodal irradiation and Oncology, Fujian Cancer Hospital, Fuzhou, China. Department of Radiation Oncology, Huadong Hospital Affiliated to Fudan University, Shanghai, China. apply involved field irradiation, which is less toxic. The Department of Radiation Oncology, Jiangsu Cancer Hospital, Nanjing, China. detailed comparison is in Table  3. Esophageal cancer is Department of Radiation Oncology, The First Affiliated Hospital of Nanjing on the way to the era of immunotherapy, despite the foot- Medical University, Nanjing, China. Department of Radiation Oncology, The Affiliated Huaian No.1 People’s Hospital of Nanjing Medical University, Huai‘an, stone of chemoradiation in locally advanced disease [38– Jiangsu, China. 40]. Precise radiotherapy based on biology and imaging will provide new basis for individualized therapies in the Received: 12 March 2022 Accepted: 7 July 2022 future [41]. Abbreviations References dCRT : definitive chemoradiotherapy; AC: Adenocarcinoma; SCC: Squamous 1. Global Burden of Disease 2019 Cancer Collaboration, Kocarnik JM, Comp- cell carcinoma; 2D: Two dimensional; 3DCRT : Three-dimensional conformal ton K, et al. Cancer incidence, mortality, years of life lost, years lived with radiation therapy; IMRT: Intensity-modulated radiation therapy; VMAT: Volu- disability, and disability-adjusted life years for 29 cancer Groups From metric-modulated arc therapy; DDP: Cisplatin; 5-Fu: 5-Fluorouracil; FOLFOX: 2010 to 2019: a systematic analysis for the global burden of disease study Oxaliplatin + Leucovorin + 5-Fluorouracil; CAP: Capecitabine; PTX: Paclitaxel; 2019. JAMA Oncol. 2021;30:e216987. CBP: Carboplatin; DTX: Docetaxel; OS: Overall survival; SUV: Standard uptake 2. Allemani C, Matsuda T, Di Carlo V, et al. Global surveillance of trends in value; GTV: Gross tumor volume; nCT: Neoadjuvant chemotherapy; nCRT : Neo- cancer survival 2000–14 (CONCORD-3): analysis of individual records for adjuvant chemoradiotherapy; PET: Positron emission tomography; △SUV : max 37 513 025 patients diagnosed with one of 18 cancers from 322 popula- The decreased maximum standard uptake values from baseline to PET2; CF: tion-based registries in 71 countries. Lancet. 2018;391(10125):1023–75. Folinc acid; EXO: Epirubicin + Capecitabine + Oxaliplatin; XP: Capecitabine + 3. GBD 2017 Oesophageal Cancer Collaborators. The global, regional, and Cisplatin; DCF: Docetaxel + Cisplatin + 5-Fluorouracil; R: Randomization; RT: national burden of oesophageal cancer and its attributable risk factors Radiation therapy; W: Week; PET/CT: Positron emission tomography/Computa- in 195 countries and territories, 1990–2017: a systematic analysis for tional tomography; IFI: Involved-field irradiation; ENI: Elective nodal irradiation; the global burden of disease study 2017. Lancet Gastroenterol Hepatol. TIFFS: Treatment failure free survival. 2020;5(6):582–97. 4. Abnet CC, Arnold M, Wei WQ. Epidemiology of esophageal squamous cell Acknowledgements carcinoma. Gastroenterology. 2018;154(2):360–73. Not applicable. 5. Cooper JS, Guo MD, Herskovic A, et al. Chemoradiotherapy of locally advanced esophageal cancer: long-term follow-up of a prospec- Author contributions tive randomized trial (RTOG 85–01). Radiat Ther Oncol Gr JAMA. KZ, YC and HZ planned the study. HZ, QL, HX, MM, ZW, KL, JZ, JC, XZ, JY, XG, HL, 1999;281(17):1623–7. QL, JD, DA, SH, JZ, IT, SS, YC and KZ are conducting the study. KZ, YC and HZ 6. Minsky BD, Pajak TF, Ginsberg RJ, et al. INT 0123 (radiation therapy are responsible for the patient recruitment. HZ, QL, HX, MM and YC wrote the oncology group 94–05) phase III trial of combined-modality therapy for main manuscript text and HZ and ZW prepared figures. All authors read and esophageal cancer: high-dose versus standard-dose radiation therapy. J approved the final manuscript. Clin Oncol Off J Am Soc Clin Oncol. 2002;20(5):1167–74. 7. Conroy T, Galais MP, Raoul JL, et al. Definitive chemoradiotherapy with Funding FOLFOX versus fluorouracil and cisplatin in patients with oesophageal The ESO-Shanghai 12 trial is supported by National Natural Science Founda- cancer (PRODIGE5/ACCORD17): final results of a randomised, phase 2/3 tion of China (82102827, 81872454), Chinese Society of Clinical Oncology trial. 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