Phase I Trial of Radiation Dose Escalation With Concurrent Weekly Cisplatin and Paclitaxel in Patients With Esophageal Cancer
Phase: NA
Conditions: Esophageal Cancer
Sponsor: Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine

 
 
 
Phase I trial of intensity-modulated hyperfractionated 
radiotherapy boost with concurrent chemotherapy following 
standard chemoradiotherapy in patients primarily with 
advanced intra-thoracic/cervical esophageal squamous cell 
carcinoma 
 
NCT03082586 
 
April 20, 2020 
 
 
 
 
 
 
 
 
 

 
 
INDEX 
1. SYNOPSIS  
2. BACKGROUND AND RATIONALE 
2.1.1. Epidemiology 
2.1.2. Curative treatment of esophageal cancer 
2.1.3. Chemoradiotherapy 
2.1.4. Attempts to improve local control 
2.1.5. Evidence of improvement in local control with BED more than 100 Gy in 
cancer therapy  
2.1.6. Evidence that the tolerated dose of RT exceeds 50 Gy in esophageal cancer 
2.1.7. HFRT and modern radiation techniques 
2.2. Rationale of the study 
3 OBJECTIVES OF STUDY  
4 PATIENT SELECTION CRITERIA 
4.1. Eligibility criteria 
4.2. Ineligibility criteria  
5. PRETREATMENT EVALUATION 
6. TRIAL DESIGN 
6.1. Overall design 
6.2. Study schema 
6.3. Duration of enrollment  
6.4. Termination criteria for individual patients 
6.5. Termination criteria for the trial in general 
7. TREATMENT  
7.1. Chemotherapy 
7.1.1. Concurrent chemotherapy during radiotherapy 
7.1.2. Adjuvant chemotherapy after completing of RT 
7.1.3. Dose modifications for chemotherapy during radiotherapy 
7.2. Radiotherapy 
7.2.1. Dose specifications 
7.2.2. Localization, immobilization, and simulation 
7.2.3. Treatment planning/target volume 

 
 
7.2.4. PTV and BGTV dose-volume constraints 
7.2.5. Critical structures (IMRT planning constraints) 
7.2.6. Identification and correction of setup errors 
7.2.7. Compliance criteria 
7.2.8. RT quality assurance reviews 
7.2.9. Radiation treatment interruptions and dose modifications 
7.3. Supportive treatment  
8. PATIENTS EVALUATION 
8.1. Study parameters 
8.2. Criteria for acute toxicity 
8.3. Criteria for late toxicity 
8.4. Criteria for response 
8.5. Documentation of incidence and patterns of recurrence 
8.6. Criteria for dropping off protocol treatment 
9. ETHICAL CONSIDERATIONS 
10. STATISTICAL CONSIDERATIONS  
10.1. Endpoint of the study 
10.2. Sample size 
10.2.1. Dose limiting toxicity (DLT) 
10.2.2. HFRT boost dose escalation 
10.3. Statistics analysis 
11. REFERENCES 
APPENDIX I:   Performance status (ECOG)  
APPENDIX II： Staging 
APPENDIX III：Case report forms (CRF) 
APPENDIX IV：Informed Consent Form (ICF) 
 

 
 
1. Synopsis 
Trial title 
Phase I trial of intensity-modulated hyperfractionated 
radiotherapy (HFRT) boost with concurrent chemotherapy 
following standard chemoradiotherapy in advanced 
esophageal cancer 
Clinical trials.gov ID 
NCT03082586 
Unique protocol ID 
SGH201705 
Approval number: 
20170128 
Trial manager 
Tingfeng Chen, MD, PhD, Department of Radiation 
Oncology, Shanghai General Hospital, Shanghai Jiao 
Tong University School of Medicine, Shanghai, China 
Trial start 
November 2016 
Recruitment period 
18 months 
Type of study 
A prospective, one-institutional, open,  phase I trial  
Treatment 
Standard chemoradiotherapy during weeks 1-5: 
50 Gy in 25 fractions of 2 Gy + concurrent weekly 
paclitaxel 45 mg/m2, carboplatin AUC 1.5 
 
HFRT boost to gross tumor volume beginning on  
Week 6: 
One of dose levels given as follows: 7.2 Gy, 14.4 Gy, 21.6 
Gy (i.e., increments of 7.2 Gy delivered in 6 twice daily 
fractions of 1.2 Gy),······+ concurrent with the same 
chemotherapy schedule 
Endpoints 
The primary objective: 
To define the maximum tolerated dose (MTD)  of HFRT 
boost 
 
The second objective: 
To evaluate the efficacy, local control, and patterns of 

 
 
failure of this regimen 
Number of patients 
Thirty-one patients 
Inclusion criteria 
1. Histologically confirmed primary squamous cell 
carcinoma or adenocarcinoma of the esophagus. 
2. Age 18-75. 
3. Patients must be deemed unresectable disease or 
patient is not deemed operable due to medical 
reasons. 
4. Patients with distant metastasis and life expectancy 
≥ 4 months are eligible. 
5. Zubrod performance status 0 to 2. 
6. No prior radiation to the thorax that would overlap 
with the current treatment field. 
7. Patients with nodal involvement are eligible. 
8. Adequate bone marrow, renal and hepatic 
functions: hemoglobin ≥ 100.0 g/L, platelet count 
≥ 100  109/L, absolute granulocyte count (AGC) 
≥ 2 × 109 cells/L, bilirubin and aspartate 
transaminase ≤ 1.5 × upper limit of normal (ULN), 
creatinine ≤ 1.5 times ULN. 
9. A signed informed consent must be obtained prior 
to therapy.  
10. Induction chemotherapy is allowed. 
Exclusion criteria 
1. The presence of a fistula. 
2. Prior radiotherapy that would overlap the radiation 
fields. 
3. Lower thoracic esophageal cancer involving the 
stomach. 

 
 
4. Gastroesophageal junction cancer. 
5. Uncontrolled concurrent illness including, but not 
limited 
to: 
chronic 
obstructive 
pulmonary 
disease(COPD) exacerbation or other respiratory 
illness, 
serious 
uncontrolled 
infection, 
symptomatic congestive heart failure (CHF), 
unstable 
angina 
pectoris, 
uncontrolled 
hypertension, 
or 
psychiatric 
illness/social 
situations that would limit compliance with the 
study requirements. 
6. Known hypersensitivity to paclitaxel. 
7. Any other condition or circumstance that would, in 
the opinion of the investigator, make the patient 
unsuitable for participation in the study. 
8. Acquired immune deficiency syndrome. 
9. Conditions precluding medical follow-up and 
protocol compliance. 
Statistics / sample 
size calculation 
Tumor response is evaluated according to RECIST 1.1 
(Response Evaluation Criteria in Solid Tumors). A 
clinical CR (cCR) is defined as both the absence of tumor 
cells in the endoscopic biopsy and the complete 
disappearance of all measurable disease on imaging 
studies. Immediate local failure is defined as persistence 
of tumors, and failure patterns are documented using basic 
calculations. The time to event variables is calculated 
from the date of entering the study. Time to first 
local-regional failure is estimated using a cumulative 
incidence analysis with death as a competing risk. 
Kaplan-Meier method is used to estimate the survival 
rates. 
The HFRT boost dose after standard chemoradiotherapy is 

 
 
escalated in cohorts of 3 to 6 patients in increments of 7.2 
Gy delivered in 6 twice daily fractions of 1.2 Gy at 
interval of ≥ 6 hours using a modified Fibonacci schema, 
with probability of dose escalation 91%, 71%, 49%, 31%, 
17% and < 1% respectively at true DLT rates of 10%, 
20%, 30%, 40%, 50% and 80%. Once the MTD is 
determined, it is given to a larger patient cohort (10 cases) 
to further determine the safety profile and efficacy. 
Based on these assumption, a total sample size of 31 
evaluable patients will be required for this study. 
 

 
 
2. Background and Rationale 
2.1.1. Epidemiology 
Esophageal cancer is a highly lethal disease, with an overall 5-year survival rate of 
15-25%.1 It is the eighth most common cancer, and sixth cause of cancer-related 
deaths in the world.2 The total incidence of esophageal cancer is rising, mainly due to 
a dramatic rise in the incidence of adenocarcinoma.3 In China, esophageal cancer is 
the fourth most common cancer and fourth cause of cancer-related deaths. About 
477,900 new esophageal cancer patients were diagnosed in 2015 that account for 
more than 50% of the global morbidity and mortality, of which 95% have esophageal 
squamous cell carcinoma (ESCC).4 
2.1.2. Curative treatment of esophageal cancer 
Surgery is currently the standard of care for esophageal cancer with curative intent if a 
patient is fit enough to undergo surgery and the tumor is considered to be technically 
resectable without evidence of distant metastases (cT1-3 N0-1 M0).5,6 However, when 
patients have an inoperable condition due to comorbid conditions, technically 
unresectable cancer (T4N2M0), or a desire not to undergo surgery, then definitive 
chemoradiotherapy is an appropriate alternative to surgery.7-9 In addition, for 
individuals with cervical esophageal carcinoma and those with high thoracic 
squamous cell carcinoma, definitive chemoradiotherapy might be a preferred 
option,7-9 considering potentially increased postoperative morbidity and mortality 
associated with surgical resection. Sometimes, physicians or patients will prefer to 
choose this treatment modality.10 Increasingly, definitive chemoradiotherapy is being 
established as the standard of care in patients with esophageal squamous-cell 
carcinoma, because evidence suggests that outcomes are similar to those of surgical 
treatment.11-13 A Patterns of Care analysis by the American College of Radiology for 
the period of 1996 - 1999 suggests that 56% of patients with esophageal cancer had 
received combined-modality therapy as definitive therapy.14 
2.1.3. Chemoradiotherapy 
The landmark RTOG 85-01 trial is the first to demonstrate a statistically significant 
survival benefit for radiation (50Gy in 25 fractions of 2 Gy) and concurrent 
chemotherapy compared with radiation therapy alone (64 Gy in 32 fractions of 2 Gy). 

 
 
Following chemoradiotherapy, 5-year survival rates were 26%, compared with 0% 
with radiation alone.15-17 Nevertheless, locoregional tumor control remains a major 
problem, with 25% of patients having persistence and 21% recurrence of locoregional 
disease after combined modality treatment (Table 1). 
Table 1 Patterns of failure 
First failure 
Radiation therapy 
alone (N = 62) 
 
Radiotherapy+ 
chemotherapy (N = 61) 
Persistent 
23 (37%) 
 
15 (25%) 
Local-regional 
10 (16%) 
 
8 (13%) 
Distant only 
9 (15%) 
 
5 (8%) 
Local, regional, and distant 
9 (15%) 
 
5 (8%) 
 
As shown in table 1, local-regional persistence and relapse of disease account for the 
majority of treatment failures after concurrent chemoradotherapy, with the majority of  
local failures occuring within gross tumor volume.15-18 It is not possible to cure 
patients with esophageal cancer without local disease control. Efforts to improve 
survival have frequently focused on strategies to improve local control.  
2.1.4. Attempts to improve local control 
Three prior RTOG phase II or III trials examine the role of increasing the radiation 
dose in patients selected for a nonsurgical approach, with the arm of improving local 
control. RTOG 9207 conducted a phase I/II study of 50 Gy of external beam radiation 
(25 fractions given over 5 weeks) followed 2 weeks later by esophageal 
brachytherapy (either high-dose-rate 5 Gy during Weeks 8, 9, and 10, for 15 Gy total, 
or low-dose-rate 20 Gy during Week 8).19-20Chemotherapy was administered for the 
first 4 days of weeks 1, 5, 8, and 11, with cisplatin 75 mg/m2 and 5-fluorouracil 1000 
mg/m2 /24 hours in a 96-hour infusion. Of the 49 eligible patients, forty-seven 
patients (96%) completed external beam radiation plus at least 2 courses of 
chemotherapy, whereas 34 patients (69%) were able to complete external beam 
radiation, esophageal brachytherapy, and at least 2 courses of chemotherapy. The 
estimated survival rate at 12 months was 49%, with an estimated median survival of 
11 months. Life-threatening toxicity or treatment-related death occurred in 12 (24%) 

 
 
and 5 (10%) cases, respectively. Treatment-related esophageal fistulas occurred in 6 
cases (12% overall, 14% of patients starting esophageal brachytherapy) at 0.5– 6.2 
months from the first day of brachytherapy, leading to death in 3 cases. The phase II 
intergroup trial 0122 entered 45 patients with squamous cell carcinoma who were 
treated with three cycles of neoadjuvant 5-FU and cisplatin followed by concurrent 
5-FU, cisplatin, and 64.8 Gy.21-22 With a median follow-up of 15 months in surviving 
patients, the incidence of total grade 3+ toxicity during the neoadjuvant chemotherapy 
segment was 61%, and during the combined modality segment was 72%. Of the 33 
patients who started radiation therapy, 91% were able to complete the full course. 
There were six deaths during treatment, five of which (11 %), because of nadir sepsis 
and/or dehydration, were treatment-related. The local/regional failure rate was 39%, 
median survival was 20 months, and 3-year survival was 30%. The overall 
treatment-related mortality rate was 9%; however, 5% were the sole result of the 
neoadjuvant component of the treatment (i.e., chemotherapy-related). RTOG 9405 
randomly assigned two hundred thirty-six patients with esophageal cancers not 
extending to within 2 cm of the gastroesophageal junction to combined-modality 
therapy arm treated with high-dose radiation (64.8 Gy) with four monthly cycles of 
5-FU (1,000 mg/m2 /24 hours for 4 days) and cisplatin (75 mg/m2 bolus on day 1) or 
conventional-dose radiation arm (50.4 Gy) with the same chemotherapy schedule.13 
With the exception of a higher proportion of males in the standard dose arm (76% vs. 
65%), the distribution of the baseline characteristics (weight loss, primary tumor size, 
performance status, age, and histology) were well balanced between the two arms. A 
planned interim analysis using a stochastic curtailment analysis after 230 patients 
were accrued revealed that the probability of the high dose arm having a statistically 
significant survival result was only 2.4%. Therefore, the trial was prematurely closed 
before reaching its planned accrual goal of 298. There was no significant difference in 
median survival (13.0 v 18.1 months), 2-year survival (31% v 40%), or local/regional 
failure and local/regional persistence of disease (56% v 52%) between the high-dose 
and standard-dose arms. Although 11 treatment-related deaths occurred in the 
high-dose arm compared with two in the standard-dose arm, seven of the 11 deaths 
occurred in patients who had received 50.4 Gy or less, indicating that it did not seem 
to be related to the higher radiation dose (i.e., not RT-related). 
Another attempt was made to address persistent and recurrent locoregional esophageal 
tumor by using selective surgical resection after definitive chemoradiotherapy.23-25 

 
 
Actually, salvage surgery after definitive chemoradiotherapy may salvage only a 
minority of patients with local failure.  For example, Sudo K et al from the 
University of Texas MD Anderson Cancer Center reported that approximately 8% of 
276 patients could undergo salvage surgical resection treatment in a retrospective 
study.23 The patients with local relapse only who received salvage surgery had their 
median overall survival of 58.6 months compared with 9.5 months for those with 
local relapse who were unable to undergo surgery. However, a phase II prospective 
RTOG 0246 study testing the strategy of definitive chemoradiotherapy with selective 
surgical salvage in locoregionally advanced esophageal cancer, with the primary 
objective of an improvement in 1-year survival from 60% to 77.5%, did not reach the 
hypothesized 1-year RTOG survival rate (77.5%).25 One-year survival rate was 71%, 
suggesting no improved overall survival with salvage surgery following definitive 
chemoradiotherapy.25 Postoperative morbidity and mortality associated with salvage 
surgery are significant. Markar S. et al reported an in-hospital mortality and 
in-hospital morbidity rate of 8.4% (26/308) and 63.6% (196/308), respectively in a 
large retrospective study.24 
Incorporation of new chemotherapeutical drugs or targeted agents (including 
paclitaxel, cetuximab) into definitive chemoradiotherapy was investigated in phase II 
or III prospective trial. Unfortunately, addition of these drugs to chemoradiotherapy 
have still failed to improve local control and overall survival for patients with locally 
advanced esophageal cancer.26,27 Taken together, the use of either intensification of 
radiation therapy with either esophageal brachytherapy boost or  higher radiation 
dose (64.8 Gy) conventional fractionated radiation therapy, salvage surgery after 
definitive chemoradiotherapy, or incorporation of new chemotherapeutical/targeted 
drugs have so far not improved significantly local disease control and overall survival. 
The issue of suboptimal local control remains unsettled and a novel strategy is 
urgently needed. 
2.1.5. Evidence concerning improvement in local control with BED more than 
100 Gy in cancer therapy  
Over the last two decades, one of the most impressive achievements in radiation 
oncology has probably been to dramatically improve local control and survival of 
early-stage non-small cell lung cancer (NSCLC) with a biological effective dose 
(BED) more than 100 Gy using stereotactic body radiation therapy (SBRT).28,29 A 

 
 
local control rate increases from 30-40% with conventional radiotherapy of 60 Gy 
(calculated BED = 72 Gy), most commonly given in 20-30 outpatient treatments,30-32 
to more than 90% with a BED 100Gy or greater, and 2-3-year overall survival from 
20-30% to 50-70%. 33,34Theoretically, the established benefits of higher radiation dose 
or BED ≥ 100 Gy for early-stage NSCLC could potentially be extrapolated to 
treatment of locally advanced esophageal cancer. The currently accepted 
standard-dose of 50 Gy (calculated BED = 60 Gy, assuming α/β = 10 for esophageal 
cancer) seems insufficient to offer optimal local control for esophageal cancer. 
Central is how higher radiation dose can be safely delivered to patients with 
esophageal cancer within normal tissue tolerances. Although SBRT can deliver a 
biologically potent, tumoricidal, hypofractionated dose to the tumor while using a 
variety of modern technologies and techniques to achieve rapid falloff limiting dose to 
innocent, surrounding normal tissues, it is potentially associated with severe late 
toxicity, resulting in catastrophic problems like dysfunction, necrosis, fistula and even 
death.35 It should be noted that parallel-functioning organs such as lung and liver, 
which are composed of parenchymal tissues of which subdivisions perform a similar 
and independent function, allow damage or destruction of a small portion of the organ 
without clinically significant toxicity when using SBRT if they have a sufficient 
reserve of function. In contrast, serial-functioning organs such as esophagus 
(delivering a food bolus from the pharynx to the stomach), whose function depends on 
a cascade of events occurring along a pathway does not permit any position along the 
esophagus to be destroyed, otherwise, resulting in clinically severe toxicity including 
loss of the entire function and even death secondary to fistula and infection.28,35 In 
addition, the increased morbidity, especially fistulas, and mortality associated with 
dose escalation as demonstrated in a series of the above-mentioned RTOG studies 
indicate that the use of SABR/hypofractionation and conventional fractionated 
radiation therapy techniques for dose escalation is obviously inappropriate in 
esophageal cancer.13, 19-22,36,37 
2.1.6. Evidence that the tolerated dose of RT exceeds 50 Gy in esophageal cancer 
The currently accepted standard-dose has been established as 50 Gy in 25 fractions of 
2 Gy based on the results of the RTOG 9405 trial. It should be noted that the RTOG 
9405 was not designed for defining the maximum tolerated radiation dose for 
esophageal cancer although it did not detect any advantage of high radiation dose 

 
 
(64.8 Gy) compared with standard-dose (50 Gy).13 Growing evidence suggests that 
the tolerated dose of RT for esophageal cancer exceeds 50 Gy. Yu et al.38 and Chen et 
al.39 reported that 66-70 Gy in 25-30 fractions can be safely delivered using a 
simultaneous integrated boost technique in esophageal cancer. Socinski et al 
40reported no dose-limiting esophageal toxicity at 78 Gy (range 70.9 to 90 Gy) of the 
average maximum dose to the esophagus in the treatment of stage IIIA and IIIB 
NSCLC. However, the maximum tolerated dose of RT has not so far been well 
defined in prospective dose-finding trials in esophageal cancer. 
2.1.7. HFRT and modern radiation techniques 
HFRT, which allows for delivering a higher total dose without increasing late 
toxicity,41 may be used to further increase the total tumor dose after standard 
chemoradiotherapy. Moreover, advances in radiation planning, tumor imaging, and 
radiation delivery using image-guided radiotherapy (IGRT) have also enhanced the 
ability to deliver higher, more conformal doses to esophageal cancer.42,43 
2.2. Rationale of the study 
Although chemoradiotherapy has been established as the standard of care for 
advanced esophageal cancer, outcomes remains poor, with a 5-year overall survival of 
20-25%. Local failure accounts for the major of treatment failure. Curing patients is 
not possible without local disease control. Effective approaches for control of local 
disease have so far been lacking. Based on the experiences of significantly improved 
local disease control with BED more than 100 Gy or greater as compared with 
conventional radiotherapy of 60 Gy in early-stage NSCLC, radiation dose escalation 
is potentially one strategy to improve local control and subsequent survival for 
patients with esophageal cancer. However, the maximum tolerated radiation dose has 
so far not been well defined in prospective dose-finding trials. It is felt that SBRT or 
conventional fractionated RT is inappropriate for dose escalation of RT for 
esophageal cancer because the esophagus is a serially functioning organ and more 
esophageal fistulas and deaths were noted with hypofractionated radiation boost in the 
RTOG 9207 trial and conventional fractionated dose escalation in the RTOG 9405 
study. 
The majority of local failures occur within gross tumor volume. We therefore design 
this phase I trial to define the maximum tolerated dose (MTD) of the HFRT boost to 

 
 
gross tumor volume (the main sites of treatment failure after standard 
chemoradiotherapy) with concurrent weekly carboplatin and paclitaxel, immediately 
following standard dose chemoradiotherapy (SCRT) of 50 Gy with the same 
chemotherapy regimen which abides by the National Comprehensive Cancer Network 
guidelines, using modern image-guided intensity-modulated radiation therapy 
(IG-IMRT). Although the entire protocol (SCRT + HFRT boost) would need 
prolonged overall treatment time (more than 5weeks), potentially resulting in tumor 
repopulation. The rationale is that all patients will be treated with upfront standard 
chemoradiotherapy, ensuring that patients gain the established benefit from standard 
chemoradiotherapy. We hypothesize that the potential benefits gained from additional 
radiation dose after standard chemoradiotherapy may outweigh the detrimental effect 
of tumor repopulation due to prolongation of treatment time as the boost dose 
increases. 
3. Objectives of the study  
The primary objective: 
To define the maximum tolerated dose (MTD) of the HFRT boost with concurrent 
weekly carboplatin/paclitaxel immediately following standard chemoradiotherapy of 
50 Gy with the same chemotherapy regimen, using modern image-guided 
intensity-modulated radiation therapy.  
The second objective : 
To evaluate the efficacy, local control, and patterns of failure of the regimen. 
4. Patient selection criteria 
4.1. Eligibility criteria 
1) Histologically confirmed primary squamous cell carcinoma or adenocarcinom of 
the esophagus. 
2) Age 18-75. 
3) Patients must be deemed unresectable disease or patient is not deemed operable 
due to medical reasons. 
4) Life expectancy ≥ 4 months (T1-4N0-3M0-1). 

 
 
5) Zubrod performance status 0 to 2. 
6) No prior radiation to the thorax that would overlap with the current treatment 
field. 
7) Patients with nodal involvement are eligible. 
8) Adequate bone marrow, renal and hepatic functions:  
 Hemoglobin ≥100.0 g/L 
 Platelet count ≥ 100  109/L 
 Absolute granulocyte count (AGC) ≥ 2 × 109 cells/L 
 Bilirubin and Aspartate transaminase ≤ 1.5 × upper limit of normal (ULN), 
 Creatinine ≤ 1.5 times ULN 
9) A signed informed consent must be obtained prior to therapy.  
10) Induction chemotherapy is allowed. 
4.2. Ineligibility criteria 
1) The presence of a fistula. 
2) Lower thoracic esophageal cancer involving the stomach. 
3) Prior radiotherapy that would overlap the radiation fields. 
4) Gastroesophageal junction cancer. 
5) Uncontrolled concurrent illness including, but not limited to: chronic obstructive 
pulmonary disease(COPD) exacerbation or other respiratory illness, serious 
uncontrolled infection, symptomatic congestive heart failure (CHF),unstable 
angina pectoris, uncontrolled hypertension,or psychiatric illness/social situations 
that would limit compliance with the study requirements. 
6) Known hypersensitivity to paclitaxel. 

 
 
7) Any other condition or circumstance that would, in the opinion of the Investigator, 
make the patient unsuitable for participation in the study. 
8) Acquired immune deficiency syndrome. 
9) Conditions precluding medical follow-up and protocol compliance. 
5. PRETREATMENT EVALUATION 
1) Complete history and physical examination, including the patient’s weight and 
height measurement, with an assessment of the patient's performance status 
within four weeks prior to study entry. 
2) All patients must be reviewed by a multidisciplinary team consisting of a 
radiologist, an experienced surgical oncologist, a radiation oncologist, and a 
medical oncologist to determine operability prior to registration. 
3) Laboratory studies (within 2 weeks prior to registration):  
CBC, ANC, platelets; Chemistry including serum creatinine, electrolytes, ALT, 
AST, LDH, alkaline phosphatase (if alkaline phosphatase is ≥ 1.5  upper limits of 
institutional normal, a bone scan is required), total bilirubin, total protein, albumin, 
uric acid, inorganic phosphorous, calcium, BUN, magnesium; calculated creatinine 
clearance (optional). A central venous access (a long line, subclavian catheter, or 
implantable device) should be established in all patients prior to beginning 
chemotherapy.  
4) Imaging studies (within 4 weeks prior to registration):  
 CT scan of the chest and abdomen (MRIs are acceptable). 
 Upper GI endoscopy (endoscopic ultrasound is required; Double contrast 
upper GI radiographs are optional. 
 PET scan (strongly encouraged); A PET scan suggestive of metastatic 
disease must have imaging studies or biopsies to prove that there is no 
metastatic disease. 
 Bronchoscopy is required if the lesion is < 25 cm from the incisors to 
exclude TE fistula or invasion. 

 
 
Data on T stage, N stage will be collected. Whenever possible, EUS/FNA of the 
nodes is highly desirable to improve accuracy.  
5) Biopsy of supraclavicular node if clinically enlarged (i.e., palpable). 
6) Bone scan (if alkaline phosphatase is elevated ≥ 1 .5  upper limits of institutional 
normal). 
7) Pulmonary function tests - including DLCO and FEV1. 
8) Cardiac function test- including electrocardiogram and echocardiography. 
9) Nutritional counseling will be offered to all patients. 
6. Trial design 
6.1. Overall design 
A prospective, one-institutional, open, phase I trial. 
6.2. Study schema 
 
 
 
 
Dose-Escalated HFRT Boost to GTV Beginning on Week 6 
Dose level 
Level 1 
Level 2 
Level 3 
Level 4 
Level 5 
Level 6 
Dose schema 
(1.2 Gy/f, bid) 
1.2×6 Gy  
1.2×12 Gy  
1.2×18 Gy  
1.2×24 Gy  
1.2×30 Gy  
1.2×36 Gy  
Total boost 
dose 
7.2 Gy 
14.4 Gy 
21.6 Gy 
28.8 Gy 
36 Gy 
43.2 Gy 
Cumulative 
dose 
57.2 Gy 
64.4 Gy 
71.6 Gy 
78.8 Gy 
86 Gy 
93.2 Gy 
Cumulative 
BED* 
68.1 Gy 
76.1 Gy 
84.2 Gy 
92.3 Gy 
100.3 Gy 
108.4 Gy 
50 Gy (2 Gy/fraction) + concurrent  
weekly paclitaxel at 45 mg/m2 and 
carboplatin AUC 1.5 over 5 weeks 

 
 
Concurrent 
Chemotherapy 
paclitaxel 45 mg/m2 + carboplatin AUC 1.5 weekly 
*BED = n × d× (1+d/α/β), assuming α/β = 10 for esophageal cancer with no time 
correction; GTV: gross tumor volume; AUC: area under the curve. 
6.3. Duration of enrollment 
The study starts on November 2016. Two patients will be recruited per month and the 
duration of inclusion will be appropriately 18 months. 
6.4. Termination criteria for individual patients 
The patient may terminate participation in the study at any time and without giving 
any reasons.  
6.5. Termination criteria for the trial in general  
The clinical trial can be stopped by the principal investigator Tingfeng Chen if 
unacceptable toxicities occur. A Data Safety Monitoring Board (DSMB) will decide 
every three months whether the trial may continue or not. 
7. Treatment 
7.1. Chemotherapy  
7.1.1. Concurrent chemotherapy during radiotherapy 
Paclitaxel 45 mg/m2 and carboplatin AUC = 1.5 will be administered by intravenous 
infusion on days 1, 8, 15, 22, 29, 36, 43, ······, concurrent with RT. Typically, the 
infusion of paclitaxxel and carboplatin will be initiated on Monday morning. 
Radiation therapy will be delivered 2 hours after completion of the chemotherapy 
infusion. 
Administration of paclitaxel and carboplatin 
Premedication procedures: 
All patients who receive paclitaxel will receive half an hour prior to the receipt of 
paclitaxel infusion premedication as follows: 
 Dexamethasone 20 mg IV, 
 Ranitidine 50 mg IV,  

 
 
 Diphenhydramine 50 mg IV  
Two  hours prior to RT, the total dose of paclitaxel calculated, diluted in 500 ml of 
0.9% normal saline will be infused over one hour, immediately followed by the 
infusion of 100 ml 0.9% normal saline over half an hour, then followed by the 
infusion of carboplatin that is diluted in 500 ml glucose 5% over more than 1 hour. 
The total absolute dose of carboplatin will be calculated for the target AUC = 1.5 
according to the following formula: 
 The absolute dose of carboplatin = [target AUC]  (GFR + 25) 
 Formula GFR = [((140 – age)  1.23  body weight) / serum creatinine  (0.85 
(female) or 1.00 (male))] 
Prophylactic antiemetics (ondansetron 8 mg infusion) and proton pump inhibitors will 
be prescribed in all cases, and best supportive care including nutritional support and 
red blood cell infusion is allowed as clinically indicated. 
7.1.2. Adjuvant chemotherapy after completion of RT 
Patients will be given 4-6 weeks after completion of the HFRT boost at the discretion 
of the treating physician, as reported previously.44,45 
7.1.3. Dose modifications for chemotherapy during radiotherapy  
Reduction of chemotherapy dose will be based on the degree of hematologic and 
nonhematologic toxicities as follows. Toxicity was graded according to the National 
Cancer Institute-Common Toxicity Criteria (NCI-CTC) Version 4.0.  
Dose Modifications for Concurrent Chemotherapy during RT 
Toxicity 
Grade 
Drug 
Modification 
Leucopenia 
Grade 3  
Carboplatin 
Reduction 33% 
Leucopenia 
Grade 4  
Carboplatin/
Paclitaxel 
Discontinue 
Thrombocytopenia 
Grade 3 
Carboplatin 
Reduction 33% 

 
 
Thrombocytopenia 
Grade 4 
Carboplatin/
Paclitaxel 
Discontinue 
Febrile neutropenia Second or third incidence 
despite G-CSF support 
administered after the first 
occurrence; 
Carboplatin/
Paclitaxel 
Discontinue 
Hypersensitivity 
reaction 
Grade 1 or worse 
Paclitaxel 
Discontinue 
Liver ( bilirubin 
and/or AST) 
Grade 3 or worse 
Paclitaxel/C
arboplatin 
Discontinue 
Liver ( bilirubin 
and/or AST) 
Grade 2 
Carboplatin/
Paclitaxel 
Reduction 33% 
Creatinine 
clearance 
Between 40 and 59 ml/min 
Carboplatin 
Reduction 33% 
Creatinine 
clearance 
Less than 40 ml/min 
Carboplatin 
Discontinue 
Esophagitis  
Grade 3 
Carboplatin/
Paclitaxel 
Reduction 33% 
Other 
non-hematologic 
toxicity 
Grade 3 
Carboplatin/
Paclitaxel 
Discontinue  
7.2. Radiotherapy 
Image-guided three-dimensional conformal intensity modulated radiation therapy 
(IG-IMRT) is mandatory for all patients. The radiation field encompasses the gross 
primary tumor, clinically positive lymph nodes, and draining lymph nodes; Radiation 

 
 
therapy will be administered via a linear accelerator (Clinic ix, Varian) with 6–15 MV 
photons. 
7.2.1. Dose specifications: 
 Treatment plans for patients on the protocol will include 2 phases: 1) the first 
phase will include inverse-planned IMRT-based therapy to the planning target 
volume for a total of 50 Gy in 2 Gy daily fractions over 5 weeks, and 2) the 
second phase will include a cone-down dose-escalating HFRT boost immediately 
following delivery of 50 Gy to the gross primary tumor beginning on week 6. 
 The HFRT boost dose is determined based on the study dose level, escalated in 
cohorts of 3 to 6 patients in increments of 7.2 Gy delivered in 6 twice daily 
fractions of 1.2 Gy at interval of ≥ 6 hours (7.2 Gy, 14.4 Gy, 21.6 Gy, ······), 
using a modified Fibonacci schema (see section 9.2.2). 
 Planning constraints are set for the planning target volume (PTV), the boost gross 
tumor volume (BGTV), as well as critical normal organs to be spared. Acceptable 
treatment plans will be generated from a DVH-based analysis of the volumetric 
dose to the PTV, BGTV, and critical normal organs to be sure that minimally 
acceptable constraints for each volume of interest have been met. 
7.2.2. Localization, immobilization, and simulation: 
 Patients are immobilized in a vacuum pad in a supine position followed by 
4-dimensional images to track internal organ motion. 
 2.5-mm-thick treatment planning CT images are acquired on a CT simulator 
(Philips Medical Madison, WI). 
7.2.3. Treatment planning/target volumes: 
 Inverse-planning capable TPS software (Eclipse 11.0, Varian, Palo Alto, CA) is 
used. 
 The IMRT plans are generated and optimized using commercial planning 
software. Every effort is taken to limit dose to the heart and lung. 
 The primary tumor volume and clinically positive lymph nodes as determined by 
barium swallow, CT scan, EUS and PET (if available). Clinically positive lymph 

 
 
nodes are defined as nodes sized ≥1 cm visualized on CT/PET scan and/or EUS 
(whichever is larger). 
 The boost GTV (BGTV) is defined as the GTV with cranio-caudal margins of 2 
cm and radial margins of 0.5 cm. 
 The clinical target volume (CTV) includes the GTV with cranio-caudal margins 
of 5 cm and radial margins of 1 cm. For tumors of the cervical and upper third 
thoracic esophagus, the supraclavicular lymph nodes are also included. The 
anatomic boundaries with surrounding critical organs must be respected. 
 The planning tumor volume (PTV) is the CTV plus a 0.5 cm margin in all 
directions to account for daily patient set-up variation and potential internal organ 
motion. 
7.2.4. PTV and BGTV dose-volume constraints: 
 100% of the PTV and BGTV receive ≥ 95% of the prescribed dose. 
 ≥ 95% of the PTV and BGTV receive 100% of the prescribed dose. 
 ≤ 10% of the PTV and BGTV receive ≥ 105% of the prescribed dose. 
 ≤ 5% of the PTV and BGTV receive ≥ 110% of the prescribed dose. 
 None of the PTV or BGTV is to receive ≥ 115% of the prescribed dose. 
7.2.5. Critical structures (IMRT planning constraints) 
Normal-tissue dose-volume constraints: 
Lung 
≤ 30% of the lung to receive 20 Gy 
Spinal cord 
Max dose ≤ 54Gy 
Brachial plexus 
Max dose ≤ 66 Gy 
Heart 
≤ 50% of the heart to receive 40 Gy 
 
7.2.6. Identification and correction of setup errors 

 
 
Image-guided RT is performed using KV-cone-beam CT scans at least twice-weekly, 
more frequently if clinically indicated, prior to treatment delivery. The results are 
registered to the planning CT scans in order to identify setup errors; In case of errors 
≥3 mm, the patient’s position is corrected immediately. 
7.2.7. Compliance criteria 
Each treatment will be reviewed for quality assurance of target volumes and critical 
structures and ensuring that dose-volume goals and constraints are met. The following 
criteria will be utilized to assess compliance and/or deviation. 
 PTV and BGTV 
A. Per protocol if the prescription criteria are fulfilled. 
B. Variation acceptable if not to meet constraints but can meet the following 
constraints: 
1) 100% of the PTV and BGTV receive ≥ 93% of the prescribed dose. 
2) ≥ 95% of the PTV and BGTV receive ≥ 97% of the prescribed dose. 
3) ≤ 13% of the PTV and BGTV receive ≥ 105% of the prescribed dose. 
4) ≤ 7% of the PTV and BGTV receive ≥ 110% of the prescribed dose. 
A. Variation unacceptable if not to meet any of the above criteria. 
Lung  
A. Per protocol if the prescription criteria are fulfilled. 
B. Variation acceptable: ≤ 33% of the lung to receive 20 Gy. 
C. Variation unacceptable: Dose limits for variation acceptable are exceeded. 
Spinal cord 
A. 
Per protocol if the prescription criteria are fulfilled. 
B. 
Variation acceptable: Max is > 54 Gy but dose  56 Gy. 
C. 
Dose limits for variation acceptable are exceeded. 
7. 2.8. RT quality assurance reviews 
Quality assurance is required with matrix, chamber, and daily orthogonal films. 
The imaging and dosimetry plans must be reviewed and approved prior to the start of 
treatment by the Principal Investigator Tingfeng, Chen MD. 

 
 
7.2.9. Radiation treatment interruptions and dose modifications 
No dose modifications are planned for radiation therapy; every effort must be made to 
administer the target dose to all patients at a given dose level.  
Treatment breaks are strongly not encouraged. However, they may be necessary 
because of grade 3 or greater acute toxicities (e.g., pneumonitis). Every effort must be 
made to minimize the duration of treatment breaks. In case of grade ≥ 3 
non-hematological or grade IV hematological toxicity, radiation treatment will be 
allowed to delay until these symptoms resolve to no worse than grade 1 for 
non-hematological toxicity or no worse than grade 2 for hematological toxicity. 
Treatment breaks longer than 4 days will be discussed. The reasons for any length of 
any such interruption must be recorded. If irradiation is delayed more than 2 weeks, 
patients will drop off the study. 
7.3. Supportive treatment 
If estimated caloric intake is < 1500 kilo-calories or if weight loss is > 5% of 
pretreatment weight, oral, enteral and/or intravenous alimentation should be provided. 
Nasogastric feeding tubes may be set to ensure adequate caloric intake. Prophylactic 
medication to inhibit peptic ulceration, antiemetics, antacid, anti-diarrheal agents, and 
other aggressive supportive care are allowed to avoid irradiation interruptions to a 
minimum. Kangfuxin liquid, a Chinese medicine extracted from periplaneta 
americana dried worms, which can promotes tissue regeneration and has long been 
used for the clinical treatment of burns, wounds and ulcers,46 is permitted with the 
goal of  mitigate irradiation-induced esophagitis. 
8. Patients evaluation  
8.1. Study parameters 
Evaluation 
4 weeks prior to 
study 
Weekly 
during 
chemo-RT 
4 weeks 
after  RT 
History  
 
 
 

 
 
Physical exam, Zubrod 
 
 
 
CBC, AGC,platelets 
 
 
 
Chemistry panel (TP,Alb, 
Ca,Phos, Glu, BUN,Uric acid, Cr, 
T. Bili, Alk Phos, LDH, 
SGPT,SGOT) electrolytes 
 
 
 
CEA 
 
 
 
EKG 
 
 
 
UGI radiographs 
 
 
 
Abdomen and chest and pelvis 
CT 
 
 
 
Endoscopic biopsy 
 
 
 
Endoscopic ultrasound 
 
 
 
Bone scan 
 
 
 
PET/CT 
* 
 
 
Nutritional evaluation 
 
 
 
Adverse event evaluation 
 
 
 
* strongly recommended 
 

 
 
Follow-up 
evaluation 
3 months 
after RT 
6 months 
after RT 
9 months 
after RT 
12 months 
after RT 
15 months 
after RT 
History and physical  
 
 
 
 
CBC, AGC, 
platelets 
 
 
 
 
 
Chemistry (liver and 
renal functions, 
electrolytes,) 
 
 
 
 
 
CEA 
 
 
 
 
 
UGI radiographs 
 
 
 
 
 
Abdomen and chest 
and pelvis CT 
 
 
 
 
 
Endoscopic biopsy 
 
 
 
 
 
 
Follow-up 
evaluation 
18 months 
after RT 
21 months 
after RT 
24 months 
after RT 
then every 
6 months 
until year 5 
History and physical  
 
 
 
CBC, AGC, 
platelets 
 
 
 
 
Chemistry (liver and 
renal functions, 
electrolytes,) 
 
 
 
 

 
 
CEA 
 
 
 
 
UGI radiographs 
 
 
 
 
Abdomen and chest 
and pelvis CT 
 
 
 
 
Endoscopic biopsy 
 
 
 
 
 
 
 
8.2. Criteria for acute toxicity 
Any toxicity occurring within 6 weeks of completing RT is considered acute, 
otherwise late. The NCI Common Toxicity Criteria (CTC) Version 4.0 will be utilized 
to score chemotherapy and acute radiation (≤ 90 days) toxicities. A serious adverse 
event is defined as any adverse drug event (experience) occurring at any dose and any 
time that result in any of the following outcomes (see section 10.2.1.):  
 Death. 
 A life-threatening adverse drug/RT experience. 
 Inpatient hospitalization or prolongation of existing hospitalization. 
 A persistent or significant disability/incapacity. 
 A medically significant event, as judged by the treating investigator. 
8.3. Criteria for late toxicity 
Any toxicity occurring more than 6 weeks after completing RT is considered late. 
Late radiation toxicities are documented according to the Radiation Therapy 
Oncology Group/European Organization for Research and Treatment of Cancer Late 
Radiation Morbidity Scoring Schema. 
8.4. Criteria for response 

 
 
Tumor response will be assessed using the Response Evaluation Criteria in Solid 
Tumors (RECIST) 1.1. 
 Clinical Complete Response (cCR): Absence of tumor cells in the endoscopic 
biopsy and the complete disappearance of all measurable or assessable 
disease on imaging studies. 
 Partial Response (PR): a ≥ 30% regression in the greatest dimension of all 
measurable or assessable disease on imaging studies. 
 Progressive Disease (PD): an increase of  ≥20% in the greatest dimension of 
all measurable or assessable disease or the appearance of any new lesion on 
imaging studies. 
 Stable Disease(SD): Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD. 
8.5. Documentation of incidence and patterns of recurrence 
 Local failure: recurrence or persistence of disease within GTV of RT. 
 Regional failure: recurrence or persistence of disease within PTV of RT. 
 Distant failure: distant metastases to sites beyond those specified as 
locoregional. 
8.6. Criteria for dropping off protocol treatment 
 Delays in protocol treatment > 2 weeks. 
 The development of dose-limiting toxicity, which is defined as grade ≥ 4 
esophatitis, any other grade ≥ 3 non-hematological toxicity (except nausea 
and vomiting), or grade ≥ 4 hematological toxicity lasting more than 7 days. 
 Patient’s refusal to continue study participation or non compliance with 
protocol requirements. 
If protocol treatment is discontinued, follow-up and data collection will continue 
according to the protocol. 
9. Ethical considerations 

 
 
The principles enunciated in the Declaration of Helsinki (HELSINKI, 1986) will be 
respected. Patients will be informed about the background and present knowledge on 
the drugs and RT under study with special attention to known activity and toxicity. It 
must be emphasized that the patient is allowed to refuse the treatment either prior to 
or at any time during the study. The study must be approved by the institutional 
review board of the Shanghai General Hospital. All patients are required to provide 
written informed consent prior to study enrollment. Informed consent form includes 
the following items: 
 Diagnosis of disease  and stage. 
 The currently accepted standard of care and expected outcomes. 
 Rationale for this study and objectives of the study. 
 Study design and treatment protocol – RT, drugs, schedule, duration of study, 
etc.  
 Anticipated efficacy of the treatment protocol (e.g., to potentially improve 
local disease control). 
 Expected increased risk of severe acute/late radiation-related toxicity, 
including, but not limited to, fistulas/ perforation, massive hemorrhage, 
esophageal stricture, pneumonitis, even treatment-related death. 
 Alternative treatment –the efficacies and  toxicities of the alternatives. 
 Freedom of refusal and withdrawal from the study. 
 Strict privacy protection. 
10. Statistical considerations 
10.1. Endpoint of the study 
 The primary endpoint of this study is to determine the maximum tolerated dose of 
HFRT boost immediately following standard-dose chemoradiotherapy in patients 
with advanced esophageal cancer. 
 The second objective was to evaluate the efficacy, local control, and patterns of 
failure of this regimen. 

 
 
10.2. Sample size 
10.2.1. Dose limiting toxicity (DLT) 
The DLT, which are possibly, probably or definitely associated with HFRT boost 
occurring during and after completion of the HFRT boost treatment, was defined as 
follows: 
 Grade ≥ 4 esophatitis. 
 Any other grade ≥ 3 non-hematological toxicity (except nausea and 
vomiting), including radiation pneumonitis, fistulas/perforation, esophageal 
stricture. 
 Grade ≥ 4 hematological toxicity lasting more than 7 days. 
10.2.2. HFRT boost dose escalation  
The HFRT boost dose is escalated in cohorts of 3 to 6 patients in increments of 7.2 Gy 
delivered in 6 twice daily fractions of 1.2 Gy at interval of ≥ 6 hours, using a modified 
Fibonacci schema. If none of three patients treated at a given dose level has a 
dose-limiting toxicity (DLT), patients are enrolled at the next dose level. If one of the 
initial three patients experiences a DLT, then three additional patients are entered at 
that dose level. If no additional DLT occurs, patients proceed to the next dose level, 
and if two or more of the total six patients experience a DLT, dose escalation is 
stopped and the previous dose level is considered MTD. Once the MTD is determined, 
it is given to a larger patient cohort to further determine the safety profile and efficacy. 
The patients who leave the trial before completion of HFRT (except for toxicity 
reasons) are not considered for determining MTD. 
A minimum of 6-week follow-up is required after completion of RT before 
proceeding to the next dose. Since 6 weeks is a short period to evaluate RT-induced 
toxicity, the assessment is continued after the initial follow-up, and any subsequent 
late toxicity is also considered in defining the MTD. 
The number of evaluable patients that will be needed depends on the number of times 
the dose is escalated, the number of patients enrolled at a given dose level, and the 
number of additional patient enrolled in the MTD expansion cohort for further 
determining the safety and efficacy. If the escalation continues up through dose level 

 
 
6 with 3 additional patients enrolled at a given dose level due to the occurrence of 
DLT and 10 additional patients are enrolled in the MTD expansion cohort, 31 
evaluable patients will be required. 
With a modified Fibonacci design, the probability of dose escalation 91%, 71%, 49%, 
31%, 17% and < 1% respectively at true DLT is  rates of 10%, 20%, 30%, 40%, 50% 
and 80%, respectively.  
10.3. Statistics analysis 
Immediate local failure is defined as persistence of tumors, and failure patterns are 
documented using basic calculations. The time to event variables are calculated from 
the date of entering the study. Time to first local-regional failure is estimated using a 
cumulative incidence analysis with death as a competing risk. Kaplan-Meier method 
is used to estimate the survival rates. 
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Appendix I 
Eastern Cooperative Oncology Group (ECOG) – Performance Status 
Grade 
ECOG performance status 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work 
activities; up and about more than 50% of waking hours 
3 
Capable of only limited selfcare; confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed 
or chair 
5 
Dead 
 

 
 
APPENDIX  II 
ESOPHAGUS, AJCC 7th Edition, 2010 
DEFINITION OF TNM 
Primary Tumor (T) 
TX Primary tumor cannot be assessed 
T0 No evidence of primary tumor 
Tis High-grade dysplasia 
T1 Tumor invades lamina propria, muscularis mucosae, or submucosa 
T1a Tumor invades lamina propria or muscularis mucosae 
T1b Tumor invades submucosa 
T2 Tumor invades muscularis propria 
T3 Tumor invades adventitia 
T4 Tumor invades adjacent structures 
T4a Resectable tumor invading pleura, pericardium, or diaphragm 
T4b Unresectable tumor invading other adjacent structures, such as aorta, vertebral 
body, trachea, etc. 
Regional Lymph Nodes (N) 
NX Regional lymph nodes cannot be assessed 
N0 No regional lymph node metastasis 
N1 Metastasis in 1-2 regional lymph nodes 
N2 Metastasis in 3-6 regional lymph nodes 
N3 Metastasis in 7 or more regional lymph nodes 
Distant Metastasis (M) 
M0 No distant metastasis 
M1 Distant metastasis 
Histopathologic G (G) 
GX     Grade cannot be assessed—stage grouping as G1 
G1      Well differentiated 
G2      Moderately differentiated 
G3      Poorly differentiated 
G4      Undifferentiated—stage grouping as G3 squamous 

 
 
Squamous Cell Carcimona 
Stage 
T 
N 
M 
G 
Location 
0 
Tis (HGD) 
N0 
M0 
1,X 
Any 
IA 
T1 
N0 
M0 
1,X 
Any 
IB 
T1 
N0 
M0 
2–3 
Any 
T2–3 
N0 
M0 
1,X 
Lower, X 
IIA 
T2–3 
N0 
M0 
1,X 
Upper, middle 
T2–3 
N0 
M0 
2–3 
Lower, X 
IIB 
T2–3 
N0 
M0 
2–3 
Upper, middle 
T1–2 
N1 
M0 
Any 
Any 
IIIA 
T1–2 
N2 
M0 
Any 
Any 
T3 
N1 
M0 
Any 
Any 
T4a 
N0 
M0 
Any 
Any 
IIIB 
T3 
N2 
M0 
Any 
Any 
IIIC 
T4a 
N1–2 
M0 
Any 
Any 
T4b 
Any 
M0 
Any 
Any 
Any 
N3 
M0 
Any 
Any 
IV 
Any 
Any 
M1 
Any 
Any 

 
 
Adenocarcimona 
Stage 
T 
N 
M 
G 
0 
Tis (HGD) 
N0 
M0 
1,X 
IA 
T1 
N0 
M0 
1–2,X 
IB 
T1 
N0 
M0 
3 
 
T2 
N0 
M0 
1–2,X 
IIA 
T2 
N0 
M0 
3 
IIB 
T3 
N0 
M0 
Any 
T1–2 
N1 
M0 
Any 
IIIA 
T1–2 
N2 
M0 
Any 
T3 
N1 
M0 
Any 
T4a 
N0 
M0 
Any 
IIIB 
T3 
N2 
M0 
Any 
IIIC 
T4a 
N1–2 
M0 
Any 
T4b 
Any 
M0 
Any 
Any 
N3 
M0 
Any 
IV 
Any 
Any 
M1 
Any 
 
 

 
 
APPENDIX III  Case Report Forms (CRFs) 
Patient and Disease Characteristics (病人和疾病特性) 
Initials of Name and Surname（姓名）___________________  
Date of Birth（出生日期） _____ /______ / _____________  
Age（年龄） _________________________  Gender（性别） ________________ 
Blood Pressure（血压） ___________ mmHg  Heart Rate（心率）_____________ 
Weight（体重）____________kg                      Height（身高）
_____________cm 
Smoke（吸烟史）_____________                    Alcohol（饮酒史）
_____________ 
ECOG（体力状况评分） _____________ 
Past History（既往史）_________________________________________________ 
CBC（血常规） 
WC________ (N…….;L………) RC__________HB____________PLT__________ 
Comprehensive Chemistry Profile（生化）________________________________ 
CT / MRI / PET________________________________________________________ 
Tumor Location（肿瘤位置）: Cervical（颈段）________Upper Thoracic（胸上段）
__________ Middle Thoracic（胸中段）____________Lower Thoracic（胸下段）
_______________ 

 
 
Histology（病理类型）: Squamous Cell Carcinomas（鳞癌）_____________ 
Adenocarcinoma（腺癌）_____________ 
Upper GI Endoscopy and Biopsy（内镜和组织活检）_______________ 
Clinical Stage（临床分期） 
T_______; N________; M ______ Stage_________________________ 
Signed Informed Consent（知情同意）No____; Yes_______  
Radiotherapy (放疗) 
Start Date（开始日期）_____ /____ / ____End Date（结束日期）___ /___ / _____ 
Dose Level (剂量水平)___________ Total Dose（放疗剂量）______________ 
Total Days of Interruption for Toxicity and Motivation（因毒性中断治疗的时间）
_______________ 
Chemotherapy (化疗) 
Paclitaxel 45 mg/m2 and Carboplatin AUC = 1.5 
Start date（开始日期）_____ /______ / ______________;  
Treatment Number (治疗次数):______________________ 
Interruption（有无治疗中断）Yes/No ___________Dose Reduction（有无减量）
Yes/No _________ Modification（剂量调整）__________________ 
Maximum Degree of Toxicity（毒副反应）: 

 
 
 Esophagitis (食管炎): Grade (分级)_____; Pneumonitis (肺炎): Grade (分
级)___________ Fistula (瘘): Grade (分级): _________________;  
Hematological: WC_____________ HB______________BPC_________________ 
Others (其它): _______________________________________________________ 
Toxicity Attribution: ______________________1 Not, 2 Unlikely, 3 Possibly, 4 
Likely, 5 Definitively related to treatment. 
Treatment Completion (Last Day of RT)(放疗治疗结束及日期) 
Date（治疗结束日期）_____ /______ / _____________ 
Weight（体重）___________Response Evaluation（疗效评估） _____________ 
Treatment Response (2 month) (疗效) 
Date（复查日期）_____ /______ / __________ 
Response Valuation（疗效评估） CR_____PR______SD____PD______ 
Treatment Failure(治疗失败): No(无)____ Yes/Date（是/日期）_________ Failure 
Sites（失败部位）: LF（局部）_______LRF（区域）____________DF（远处）
_________________ 
 
 
Date: ___________________                          
Signature___________________ 
 
 

 
 
APPENDIX IV Informed Consent Form (ICF) 
 
Trial Title：Phase I Trial of Intensity-Modulated Hyperfractionated 
Radiotherapy Boost with Concurrent Chemotherapy Immediately 
Following Standard Chemoradiotherapy in Patients Primarily with 
Advanced Intra-thoracic/Cervical Esophageal Squamous Cell Carcinomas 
Research unit: Shanghai General Hospital 
     
We invite you to participate in a Phase I Trial of Intensity-Modulated 
Hyperfractionated Radiotherapy Boost with Concurrent 
Chemotherapy Immediately Following Standard 
Chemoradiotherapy in Patients Primarily with Advanced 
Intra-thoracic/Cervical Esophageal Squamous Cell Carcinomas. 
Before deciding to participate in this study, please read this Informed 
Consent in detail. If you have any questions that you do not understand, 
you can ask the investigator or member of the trial working group to 
explain any terms or information that you do not understand. 
一、 Research background and purpose 
1、Background 
The current treatment modality for patients with unresectable, locally 
advanced esophageal cancer (LAEC) is standard chemoradiotherapy 
(SCRT) with radiation dose of 50-50.4 Gy. However, the clinical 
outcomes are still poor, with a dismal 5-year overall survival (OS) rate of 
15-25%. Local-regional persistence and relapse of disease account for the 

 
 
majority of treatment failures after SCRT, with local failure of 44-58% 
versus distant failure of 8-26%. Curing patients is not possible in patients 
with esophageal cancer without local disease control. Current efforts to 
improve survival of LAEC patients by enhancing local tumor control 
have not yielded encouraging results. For example, a brachytherapy boost 
following SCRT resulted in increased fistula and treatment-related 
mortality without improvement in local control and survival. Similarly, 
high-dose (64.8 Gy) conventionally fractionated radiotherapy (RT) also 
lead to negative outcomes compared to standard dose treatment. Salvage 
surgery after CRT has benefitted only a minority of patients with local 
failure and not significantly improved overall survival, while novel 
chemotherapeutical and/or targeted drugs have also failed to improve 
outcomes in prospective randomized trials. 
In the last two decades, RT has dramatically increased local control and 
survival rates of non-small cell lung cancer (NSCLC) with a biological 
effective dose (BED) ≥ 100 Gy as compared with conventional radiation 
therapy of 60 Gy (calculated BED = 72 Gy). Thus, radiation dose 
escalation is potentially one strategy to improve local control and 
subsequent survival for patients with esophageal cancer. However, the 
maximum tolerated radiation dose has so far not been well defined in 
prospective dose-finding trials. 

 
 
Given the high radio-sensitivity of the esophagus resulting in 
life-threatening fistulas and other morbidities, as well as the high 
mortality rates associated with dose escalation, hypo- or conventional 
fractionated RT techniques are inappropriate for LAEC. 
Hyperfractionated RT (HFRT) allows a higher total radiation dose 
without increasing late toxicity, and can be used after SCRT to increase 
the cumulative dose to the tumor. Furthermore, advances in radiation 
planning, tumor imaging, and radiation delivery using image-guided 
radiotherapy (IGRT) have also enhanced the ability to deliver higher, 
more conformal doses to esophageal tumors. 
The majority of local failures occur within the gross tumor volume 
(GTV). We therefore design a phase I trial to define the maximum 
tolerated dose (MTD) of the HFRT boost to GTV with concurrent weekly 
carboplatin and paclitaxel immediately following SCRT of 50 Gy with 
the same chemotherapy regimen, using image-guided intensity-modulated 
RT (IG-IMRT). The duration of treatment protocol (SCRT + HFRT boost) 
is more than 5 weeks. The rationale is that all patients would be treated 
with upfront standard chemoradiotherapy, ensuring that they gain the 
established benefits from standard chemoradiotherapy. The second 
objective is to evaluate the efficacy, local control, and patterns of failure 
of this regimen. 

 
 
2、Purpose 
Local persistence and relapse of disease in the gross tumor volume (GTV) 
account for the majority of treatment failures after standard 
chemoradiation therapy. The primary objective of this phase 1 trial is to 
define the maximum tolerated dose (MTD) of a hyperfractionated 
radiation therapy (HFRT) boost to the GTV with concurrent weekly 
paclitaxel and carboplatin after standard-dose chemoradiation therapy, 
using image guided intensity modulated radiation therapy techniques. 
二、 Methods 
1、Eligibility  
11) Histologically confirmed primary squamous cell carcinoma or 
adenocarcinom of the esophagus. 
12) Age 18-75. 
13) Patients must be deemed unresectable disease or patient is not deemed 
operable due to medical reasons. 
14) Life expectancy ≥ 4 months (T1-4N0-3M0-1). 
15) Zubrod performance status 0 to 2. 
16) No prior radiation to the thorax that would overlap with the current 
treatment field. 
17) Patients with nodal involvement are eligible. 
18) Adequate bone marrow, renal and hepatic functions:  
 Hemoglobin ≥100.0 g/L 

 
 
 Platelet count ≥ 100  109/L 
 Absolute granulocyte count (AGC) ≥ 2 × 109 cells/L 
 Bilirubin and Aspartate transaminase ≤ 1.5 × upper limit of 
normal (ULN), 
 Creatinine ≤ 1.5 times ULN 
19) A signed informed consent must be obtained prior to therapy.  
20) Induction chemotherapy is allowed. 
2、Ineligibility criteria 
10) The presence of a fistula. 
11) Lower thoracic esophageal cancer involving the stomach. 
12) Prior radiotherapy that would overlap the radiation fields. 
13) Gastroesophageal junction cancer. 
14) Uncontrolled concurrent illness including, but not limited to: chronic 
obstructive 
pulmonary 
disease(COPD) 
exacerbation 
or 
other 
respiratory illness, serious uncontrolled infection, symptomatic 
congestive heart failure (CHF),unstable angina pectoris, uncontrolled 
hypertension,or psychiatric illness/social situations that would limit 
compliance with the study requirements. 
15) Known hypersensitivity to paclitaxel. 
16) Any other condition or circumstance that would, in the opinion of the 
Investigator, make the patient unsuitable for participation in the study. 
17) Acquired immune deficiency syndrome. 

 
 
18) Conditions precluding medical follow-up and protocol compliance. 
3、Study Treatment and Trial Design 
Eligible patients are given weekly doses of paclitaxel (45 mg/m2) and 
carboplatin (area under the curve 1.5) for 5 weeks with concurrent 
radiation therapy (50 Gy), immediately followed by an HFRT boost to the 
GTV with the same chemotherapy regimen. The boost doses are escalated 
in increments of 7.2 Gy delivered in 6 twice-daily fractions of 1.2 Gy 
using a modified Fibonacci design. MTD is defined as the highest dose at 
which ≤ 1 patients experience dose limiting toxicity (DLT). Once the 
MTD is established, additional patients are treated at that dose to 
determine the safety。 
4、Statistical analysis 
The primary endpoint of this trial is to determine the MTD of HFRT 
boost with concurrent paclitaxel and carboplatin immediately following 
standard chemoradiotherapy in patients with advanced esophageal cancer. 
The dose-escalation regimen is based on a modified Fibonacci design, 
with probability of dose escalation 91%, 71%, 49%, 31%, 17% and < 1% 
respectively at true DLT rates of 10%, 20%, 30%, 40%, 50% and 80%. 
Tumor response is evaluated according to RECIST 1.1 (Response 
Evaluation Criteria in Solid Tumors). A clinical CR (cCR) is defined as 
both the absence of tumor cells in the endoscopic biopsy and the 
complete disappearance of all measurable disease on imaging studies. 

 
 
Immediate local failure is defined as persistence of tumors, and failure 
patterns are documented using basic calculations. The time to event 
variables is calculated from the date of entering the study. Time to first 
local-regional failure is estimated using a cumulative incidence analysis 
with death as a competing risk. Kaplan-Meier method is used to estimate 
the survival rates. 
三、 Research risks and benefits 
1、Research risks 
The dose limiting toxicities (DLTs), which are possibly, probably or 
definitely associated with the HFRT boost occurring during and after 
completion of the HFRT boost treatment, include: 
 Grade ≥ 4 esophatitis. 
 Any other grade ≥ 3 non-hematological toxicity (except nausea and 
vomiting), 
including 
radiation 
pneumonitis, 
esophageal 
fistulas/perforation, esophageal stricture, cardiac events. 
 Grade ≥ 4 hematological toxicity lasting more than 7 days. 
Nevertheless, we will still do our utmost to reduce treatment-related risks. 
2、Benefits 
You may not directly benefit from this trial, but your participation will be 
helpful to determine the MTD of the hyperfractionated radiotherapy boost 
for the primary tumor after the SCRT of esophageal cancer, and it will be 

 
 
beneficial for humans to finally overcome this lethal disease and address 
the clinical problem of high local tumor recurrence rate , the main cause 
of death. 
四、 Your rights 
You have the right to decide whether to participate in this trial. If you 
cannot make a decision immediately, you have sufficient time to consider. 
If necessary, you can discuss with relatives, friends and other people you 
trust before making a decision. If you decide not to participate in this trial, 
it will not affect your relationship with the researchers and sponsors, you 
will not be discriminated against or retaliated against, and your treatment 
and rights will not be affected. If you decide to participate in this trial, if 
there is no special reason, we hope you can complete the trial, but you 
have the right to withdraw at any time during the trial. If you decide to 
withdraw, please be able to tell the researcher in time. 
During the study, you can always know the information related to you in 
this study. 
五、 Privacy protection 
The personal information you provide to the researcher (such as name, 
gender, contact information, questionnaire, etc.), in addition to the needs of 
normal research, may be informed with the following persons or units: 
 
(inspectors, etc.) related to this experiment in the 
research funding institution; 
 
administrative agencies. 

 
 
However, no one can disclose your personal information to others or other 
institutions without your permission. Except for the researchers and 
administrative institutions, no other person or unit has the right to take the 
initiative to contact you about the trial. Or provide you with information 
about this experiment directly. 
The results of this experiment may be published in the form of academic 
papers, but your personal information will not appear in any publicly 
published documents. 
六、 Other 
1. When the following conditions occur, for your health, the researcher 
may withdraw you from this trial without your consent: 
 
 Continue to participate in this test, may cause your risk outweigh 
the benefit; 
 
 You do not follow the guidance of the investigator and participate 
in the trial according to the research plan; 
 
 The study is terminated early. 
2. This informed consent is in duplicate, and the researcher and you each 
keep one copy. 
七、 Compensation for injury incurred in the test 
If your injury is directly caused by participating in this trial, you do not 
need to pay the medical expenses borne by the treatment at all, the 
expenses will be borne by the researcher. 
八、 Contact details 
1. Office of Medical Ethics Committee of Shanghai General Hospital 

 
 
Contact: 63240090-6424 
2. Researcher's name: Tingfeng Chen 
Contact: 18701777598 
 

 
 
[The following is the signature page of informed consent] 
Informed Consent Page 
Agree to declare: 
1. I have carefully read the instructions of the subject and understand the 
relevant background of this experiment. The researchers have explained 
me in detail about the characteristics of the study and possible adverse 
reactions, and answered my questions. 
2. I know that if I refuse to participate in this trial, my treatment and 
rights will not be affected. After understanding all the contents of the 
subject and fully considering it, I volunteer to participate in this trial. 
3. I am willing to follow the researcher's instructions and participate in 
the experiment according to the research protocol. During the experiment, 
I have the right to withdraw at any time, but before withdrawing, I need 
to tell the researchers in time. 
4. During the test, if any discomfort occurs, I will tell the researcher in 
time. 
Subject signature:                                                        
 
 
/      / 
Name  
Signature 
Date of signature 
 
 
Researcher signature：                                                                 
 
 
/      / 
Name  
Signature 
Date of signature 
 
Subject Agent / Guardian (if any) signature:：                                     
             
Why the subject could not sign this page： 
 

 
 
   
The relationship between the agent / guardian and the 
subject： 
 
 
 
 
/      / 
Name  
Signature Date of signature