Nimotuzumab Combined With Concurrent Chemoradiotherapy for Locally Advanced Treatment Esophageal Cancer in Old Age
Phase: PHASE2
Conditions: Esophageal Carcinoma
Sponsor: The First Affiliated Hospital with Nanjing Medical University

1 
 
 
A single-arm, prospective, single-center phase II 
clinical study to evaluate the efficacy and safety of 
nimotuzumab combined with concurrent 
chemoradiotherapy in elderly patients with locally 
advanced unresectable esophageal cancer 
 
 
 
 
 
Project number: IST-Nim-ESCC-23 
Principal Investigator: Xiaolin Ge 
Version number: V2.0 
Version date: 03 July 20

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Catalogue 
Project number: IST-Nim-ESCC-23 ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ 1 
1. Protocol abstract ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ 4 
1.1 Summary ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ 4 
1.2 Study flow chart ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ 8 
1.3 Study schedule ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ 9 
2. Introduction ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ 12 
2.1 Study theoretical basis ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ 12 
2.2 Background ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ 13 
2.3 Risk/benefit assessment ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ 16 
3. Study purpose and endpoint ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ 18 
4. Study design ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ 18 
4.1 Overall design ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ 18 
4.2 Dose selection ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ 22 
4.3 Definition of end of study ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ 22 
5. Study population ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ 22 
5.1 Inclusion criteria ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ 22 
Patients must meet all of the following criteria to be eligible for this trial: ‐‐‐‐‐‐‐ 22 
5.2 Exclusion criteria ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ 24 
5.3 Screening failure ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ 25 
6. Study intervention ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ 25 
6.1 Study intervention management ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ 25 
6.2 Handling/storage/responsibilities ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ 27 
6.3 Adherence to study intervention ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ 27 
6.4 Combination therapy ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ 28 
7. Discontinuation of study intervention and subject discontinuation/withdrawal28 
7.1 Study intervention discontinuation ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ 28 
7.2 Lost to follow-up ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ 30 

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8. Research evaluation t and process ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ 30 
8.1 Efficacy evaluation ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ 30 
8.2 Adverse events and serious adverse events ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ 31 
9. Statistical considerations ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ 37 
9.1 Sample size estimation ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ 37 
9.2 Analysis population ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ 38 
9.3 Statistical Analysis ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ 38 
10. Supporting documents and operational considerations ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ 39 
10.1 Regulatory, ethical and research oversight considerations ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ 39 
11. References ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ 42 
12. Appendix‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ 44 
12.1 ECOG performance status scoring standard ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ 44 
12.2 Response Evaluation Criteria for Solid Tumors Version 1.1 ‐‐‐‐‐‐‐‐‐‐‐‐‐‐ 45 
12.3 Contents of subject management ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ 63 
12.4 Nutritional risk screening form (NRS2002) ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ 64 
12.5 Quality of life score (QoL) of cancer patients ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ 66 
12.6 Scoring criteria and calculation method of Charlson Comorbidity Index68 
12.7 Quality of life score (QoL) evaluation table ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ 70 
12.8 Nutritional assessment ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ 73 
 
 
 

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1. Protocol abstract 
1.1 Summary 
Title: 
A single-arm, prospective, single-center phase II clinical study to evaluate 
the efficacy and safety of nimotuzumab combined with concurrent 
chemoradiotherapy in elderly patients with locally advanced unresectable 
esophageal cancer 
Study overview 
The mortality rate of esophageal cancer is 77%, and this rate will be even 
higher in elderly patients with esophageal cancer. A safe and effective 
treatment method is urgently needed. Currently, Nimotuzumab has been 
approved for esophageal cancer indications in 9 countries. We plan to 
conduct a single-arm, prospective, single-center Phase II clinical study to 
explore the efficacy and safety of Nimotuzumab in elderly patients with 
locally advanced esophageal cancer. The study population is elderly 
patients with locally advanced unresectable esophageal cancer, and 50 
people are planned to be enrolled. 
Purpose 
To evaluate the efficacy and safety of nimotuzumab combined with 
concurrent chemoradiotherapy in elderly patients with locally advanced 
unresectable esophageal cancer. 
Endpoint 
Primary endpoint: progression-free survival (PFS) 
Secondary endpoints: objective response rate (ORR), disease control rate 
(DCR), local disease control rate (LDCR), overall survival (OS), 1-year 
OS/PFS, 2-year OS/PFS, and AE/SAE incidence. 
Study population 
Inclusion criteria: All the following patients must be met to be 
included in this study  
1.The subjects voluntarily participated in this study, signed the 
informed consent, had good compliance, and cooperated with the 
follow-up; 
2.Age 75 and above , male or female; 

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3.ECOG score 0-1; 
4.Esophageal cancer confirmed by histology or cytology; 
5.According to the Response Evaluation Criteria for Solid Tumors 
(RECIST 1.1), there is at least one measurable lesion, and the 
measurable lesion should not have received local treatment such as 
radiotherapy (lesions located in the previous radiotherapy area can 
also be selected as target lesions if they are confirmed to have 
progressed and meet the RECIST1.1 criteria); 
6.Patients with stage II-IVB according to AJCC (8th edition, 2018) 
(IVB included metastasis to the celiac trunk or supraclavicular 
lymph nodes only) who are not suitable for or refuse surgery can 
tolerate concurrent chemoradiotherapy and targeted therapy; 
7.Expected survival time ≥ 12 weeks; 
8.The major organs function normally, meet the following criteria: 
1)Blood test: 
a.HBG ≥ 90 g/L; 
b.ANC ≥ 1.5 × 10 9 /L; 
c.PLT ≥80×10 9 /L; 
2)Biochemical tests: 
a.ALB ≥ 30 g/L; 
b.ALT and AST ≤ 2.5 ULN; if there is liver metastasis, ALT 
and AST ≤ 5 ULN; 
c.TBIL≤1.5ULN; 
d.Plasma Cr≤1.5ULN or creatinine clearance 
(CCr)≥60ml/min; 
9.Echocardiographic assessment: left ventricular ejection fraction 
(LVEF) ≥ lower limit of normal value (50%); 
10.Female of childbearing age must agree to use contraceptive 
measures (such as intrauterine devices, birth control pills or condoms) 

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during the study and within 6 months after the end of the study; the 
serum or urine pregnancy test is negative within 7 days before study 
enrollment, and they must be non-breastfeeding patients; male must 
agree to use contraceptive measures during the study and within 6 
months after the end of the study. 
Exclusion criteria: Those who meet any of the conditions will not be 
included in this study 
1.Received EGFR monoclonal antibody or EGFR-TKI within six 
months; 
2.Participated in other interventional clinical trials within 30 days 
before screening; 
3.Patients with serious concurrent diseases, such as heart failure, 
high-risk uncontrollable arrhythmias, severe myocardial infarction, 
refractory hypertension, renal failure (CKD-4 and above), thyroid 
dysfunction, mental illness, diabetes, severe chronic diarrhea (more 
than 7 bowel movements per day), or patients who are considered 
unsuitable to participate in this clinical study by the researchers; 
4.Patients with brain metastases with symptoms or symptom control 
time of less than 3 months; 
5.Have a history of other malignant tumors (except for cured cervical 
carcinoma in situ or basal cell carcinoma of the skin and other 
malignant tumors that have been cured for more than 5 years); 
6.The presence of active infection or active infectious disease; 
7.Patients with multi-segment esophageal malignant tumors or signs 
of esophageal fistula or perforation; 
8.Patients whose tumors have invaded important blood vessels as 
shown by imaging or who are judged by the researchers to be very 
likely to invade important blood vessels and cause fatal hemorrhage 
during the follow-up study; 

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9.Those who are allergic to the drugs or their ingredients used in this 
program; 
10.Peripheral neuropathy or hearing loss of grade 2 or higher 
according to the criteria of Common Terminology for Adverse Events 
(NCI CTCAE V5.0); 
11.Pregnant or breastfeeding women; 
12.Patients with a history of psychotropic drug abuse and unable to 
quit or patients with mental disorders; 
13.Those who are considered unsuitable to participate in this study by 
the researcher; 
14.Those who are unwilling to participate in this study or unable to 
sign the informed consent. 
Stage 
Stage II 
Center 
Department of Radiation Oncology, Jiangsu Province Hospital 
Study intervention 
1.Radiation Therapy 
The prescription dose required that 95% PTV and PTV-nd receive 50-60 
Gy /25-30 F , with a single dose range of 2.0 Gy/F, 5 days a week, external 
beam radiation to the chest . 
2.Treatement 
S-1: 40-60 mg/m 2 , po, D1, BID, 5 weeks; 
Nimotuzumab 400 mg, iv, D1, week 1; 
Nimotuzumab 200 mg, iv, D8, QW, Week 2-5. 
Study duration 
The estimated time from the start of the study to the completion of data 
analysis is 40 months 
Visit duration 
The planned enrollment period for this study is 12 months, and the time 
required for each subject to complete all visits are 24 months. 
 
 

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1.2 Study flow chart 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patients Screening 
Study Group 
Concurrent chemoradiotherapy plus nimotuzumab 
Efficacy follow-up period 
Imaging assessments were performed every 12 
weeks after completion of radiotherapy 
Follow-up survival 
PD every 12 weeks after a follow-up survival 

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1.3 Study schedule 
Project name 
Screening/Bas
eline Period 
Treatment period 
EOT 
visit 
Efficacy 
follow-up  
Survival 
follow-up  
 
-w3-w0 
D1 
D8 
D1
5 
D2
2 
D2
9 
D29 
D29 to PD 
Date 
PD date to 
death 
Informed 
consent 
√ 
 
 
 
 
 
 
 
 
Check 
Inclusion and 
exclusion 
criteria 
√ 
 
 
 
 
 
 
 
 
Baseline and 
demographic 
data 
√ 
 
 
 
 
 
 
 
 
Vital signs and 
physical 
examination 
◆ 
√ 
√ 
√ 
√ 
√ 
√ 
 
 
ECOG PS 
◆ 
√ 
√ 
√ 
√ 
√ 
√ 
 
 
Quality of life6 
◆ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
Charlson 
Comorbidity 
Index 
√ 
 
 
 
 
 
 
 
 
Nutritional 
status 
√ 
 
 
 
 
 
√ 
 
 
Blood routine 
examination 
◆ 
√ 
√ 
√ 
√ 
√ 
√ 
■ 
 
Urinalysis 
◆ 
√ 
√ 
√ 
√ 
√ 
√ 
■ 
 
Bowel routine 
◆ 
√ 
√ 
√ 
√ 
√ 
√ 
■ 
 

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Blood 
biochemistry 
test 
◆ 
√ 
√ 
√ 
√ 
√ 
√ 
■ 
 
Coagulation 
◆ 
√ 
√ 
√ 
√ 
√ 
√ 
■ 
 
Virological 
examination 1 
√ 
 
 
 
 
 
 
 
 
Pregnancy test 
(female 
subjects of 
childbearing 
age) 
√ 
 
 
 
 
 
 
 
 
Electrocardiog
ram 
◆ 
√ 
√ 
√ 
√ 
√ 
√ 
■ 
 
Echocardiogra
phy 
√ 
 
 
 
 
 
 
 
 
Imaging 
examination2 
√ 
▲ 
 
 
√ 
 
 
√ 
 
Radiation 
therapy 
 
√ 
√ 
√ 
√ 
√ 
 
 
 
Combination 
medication 3 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Adverse event 
assessment4 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Survival 
follow-up 5 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
◆The examination results within 1 week can be used without repeating the measurement. 
▲ The test results within 2 weeks before medication can be used without repeated measurements. 
■ If there are any anomalies that have not been resolved before, evaluation will be conducted as needed 
1. First, screen for HIV antibodies, five hepatitis B tests, hepatitis C antibodies, and human papillomavirus 

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(HPV) tests. When the test results indicate the possibility of active hepatitis B or C infection, further HBV DNA 
quantitative testing and HCV RNA quantitative testing are required to confirm the diagnosis; 
2. The imaging assessment can be performed by esophageal angiography and chest and abdominal enhanced 
CT examination according to the doctor's choice (imaging examinations of the same part at different times 
should use the same detection technology as the baseline period). The evaluation sites are mainly the esophagus 
and mediastinal lymphatic drainage area, and other parts are evaluated as needed. After the screening evaluation, 
imaging evaluation is performed every 21 days during radiotherapy, within 1 week and 4 weeks after the end of 
radiotherapy, and every 12 weeks thereafter until the disease progresses or the subject is intolerant or withdraws. 
The examination time window is ±7 days; 
3. Record the name, dosage, start and end time of combined medications and treatments, as well as the reasons 
for combined medications and treatments; 
4. Adverse events that have occurred will be followed until they disappear, improve or stabilize and the 
investigators believe that no further follow-up is required, including AEs that occur within 7 days after the 
screening period and SAEs that occur within 30 days after the end of radiotherapy; 
5. Patients will be followed up for survival every 12 weeks after PD, and can receive telephone visits, including 
patient survival status and tumor treatment status. The specific cause of death will be recorded in detail when it 
involves the following factors (primary tumor recurrence, bleeding, perforation, new lesions; recurrence or new 
metastatic lymph nodes within and outside the region, etc.); 
6. During the efficacy follow-up period, evaluation was only performed during the first two follow-up visits. 
 

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2. Introduction 
2.1 Study theoretical basis 
The incidence of esophageal cancer in China ranks the first in the world, and its 
incidence and mortality account for more than half of the world [1]. Esophageal cancer 
is mainly divided into carcinoma (ESCC) and adenocarcinoma (EAC) according to 
pathological type, of which ESCC is the main histological type, accounting for 80% 
of esophageal cancer cases worldwide[2]. The incidence of ESCC is high in certain 
ethnic groups and certain regions, and is affected by environmental factors (drinking 
and smoking) and genetic factors (mutations in enzymes that metabolize alcohol)[3]. 
The 5-year survival rate of ESCC is only 15%-25%. China is a country with a high 
incidence of esophageal cancer and the main pathological type is carcinoma, 
accounting for 53.7% of the world's cases[4], of which about 70% are patients over 60 
years old [5]. It is expected that with the aging of the population, the incidence of 
esophageal cancer in the elderly will further increase. 
The best treatment for locally advanced esophageal cancer is centered on radical 
esophagectomy. However, for some esophageal cancer patients who are not suitable 
for surgical treatment (such as tumor location, tumor invasion degree, age, patient's 
own condition, patient's willingness for treatment), concurrent chemoradiotherapy is 
the main treatment option. 
Elderly patients are often unable to receive surgical treatment or even concurrent 
chemoradiotherapy due to their pre-existing medical conditions, organ dysfunction, 
and poor physical condition. Therefore, the prognosis of elderly patients with 
advanced esophageal cancer is poor. The clinical treatment of this disease is difficult, 
and the cure rate is low, and the recurrence, metastasis, and mortality rates are high. 
Therefore, it poses a serious threat to the physical and mental health and life safety of 
elderly patients[6]. Over the past 10 years, both domestic and foreign researchers have 
been exploring potential therapeutic targets for elderly patients with advanced 
esophageal cancer, but compared with other gastrointestinal tumors, research and 
development has lagged behind. At present, there is an urgent need to explore a new 
treatment model to improve the efficacy and improve the long-term survival and 

13 
 
quality of life of elderly patients. 
2.2 Background 
EGFR is an important prognostic factor and therapeutic target for esophageal cancer. 
EGFR overexpression accounts for 42.5%-85.7% of ESCC and is closely associated 
with high recurrence and low survival[7] [8]. Therefore, EGFR signaling molecules are 
regarded as biomarkers at various stages of the development of esophageal cancer[9] 
[10]. Monoclonal antibodies and tyrosine kinase inhibitors targeting EGFR have been 
developed to improve the survival rate of ESCC8]. 
Nimotuzumab is a new anti-EGFR monoclonal antibody jointly developed by Biotech 
Pharmaceutical Co., Ltd. and Cuba. The drug was launched in China in 2008 and has 
been approved for marketing in 30 countries around the world, and has been approved 
for esophageal cancer indications in 9 countries. 
A real-world study from Cuba [7] evaluated the efficacy of nimotuzumab combined 
with radiotherapy/chemotherapy/chemoradiotherapy in patients with locally advanced 
or metastatic esophageal cancer in Cuba. The study included 339 patients with locally 
advanced or metastatic esophageal cancer registered in the Cuban National Cancer 
Database between January 1, 2011 and January 1, 2015. The patients were matched by 
propensity score. Among them, 93 patients in the nimotuzumab group had received at 
least one nimotuzumab treatment, and 93 patients in the control group had not 
received nimotuzumab treatment. The results showed that the median OS of the 
nimotuzumab group was 11.9 months, which was significantly higher than that of the 
control group (6.5 months, p = 0.004); the 1-year and 2-year overall survival of the 
nimotuzumab group were 54.0% and 21.1%, while those of the control group were 
21.9% and 0%, respectively (95% CI 0.24–0.74, p = 0.004). The risk of death in the 
nimotuzumab treatment group was 2.38 times lower than that in the control group. 
Another meta-analysis from China also conducted an meta-analysis of nimotuzumab 
combined with chemoradiotherapy for the treatment of esophageal cancer [8]. The 
study showed that nimotuzumab can improve the treatment efficacy and prolong the 

14 
 
survival of patients with esophageal cancer without increasing the incidence of 
adverse events. Combined chemoradiotherapy/radiotherapy can be recommended for 
the treatment of patients with esophageal cancer. In 2019, Zhai Yirui et al. from the 
Cancer Hospital Chinese Academy of Medical Sciences published a study on 
nimotuzumab combined with chemoradiotherapy for the treatment of unresectable 
local advanced esophageal cancer [9] . The study included 26 newly diagnosed patients 
with esophageal cancer, with a median radiotherapy dose of 60 Gy, a median total 
nimotuzumab dose of 1200 mg, and an effective rate of 76.9%. The median follow-up 
was 30.5 months, and the median survival was 28.7 months. The 2-year and 3-year 
overall survival were 59.4% and 38.2%; the 2-year and 3-year progression-free 
survival were 51.4% and 33.3%. Another study conducted a retrospective analysis of 
the efficacy of nimotuzumab or cetuximab combined with chemoradiotherapy in the 
treatment of patients with locally advanced esophageal cancer [10]. The results showed 
that the ORR of the nimotuzumab + CRT group was 61%, slightly higher than that of 
the cetuximab + CRT group (43.5%), and the disease control rate of the nimotuzumab 
+ CRT group was significantly higher than that of the cetuximab + CRT group (P = 
0.04). Other survival analyses also showed that the median PFS of the nimotuzumab + 
CRT group was significantly longer than that of the cetuximab + CRT group (19.6 
months vs 13.0 months, p = 0.02). The 1-year and 3-year OS of the nimotuzumab + 
CRT group were higher than those of the cetuximab + CRT group (HR = 1.17, p = 
0.23).  
At present, many studies have confirmed that nimotuzumab can improve the efficacy 
of esophageal cancer in the elderly. Common acute toxic reactions included 
esophagitis, pneumonia, leukopenia, gastrointestinal reactions, and thrombocytopenia. 
The incidence of Grade 3-4 adverse reactions was 17.4%, and no Grade 5 toxic 
reactions were observed. The median overall survival (OS) was 17 months, and the 
progression-free survival (PFS) was 10 months. The 2-, 3-, and 5-year OS and PFS 
were 30.4%, 21.7%, and 19.6%, and 26.1%, 19.6%, and 19.6%, respectively. This 
result confirms that nimotuzumab combined with radiotherapy is a safe and effective 
treatment for elderly patients who cannot undergo surgery. Li Lulu [11] randomly 

15 
 
divided 67 patients aged 60-80 years with locally advanced esophageal cancer into an 
experimental group and a control group. 34 patients in the study group were treated 
with nimotuzumab combined with IMRT, while 33 patients in the control group were 
treated with IMRT alone. The results showed that the short-term response rate (ORR) 
of the study group and the control group were 85.2% and 63.6%, respectively, and the 
disease control rate (DCR) was 97.1% and 81.8%, respectively, with significant 
differences (P < 0.05). Although the 1-, 2-, and 3-year survival rates of the study 
group were higher than those of the control group, the difference was not statistically 
significant (P > 0.05). The adverse events of the two groups were similar, with no 
significant difference (P > 0.05). Conclusion: nimotuzumab combined with IMRT can 
significantly improve the ORR and DCR of patients with locally advanced esophageal 
cancer in the elderly, but it does not significantly improve the 1-, 2-, and 3-year 
survival rates of patients. In addition, JINHUA GUO [12] retrospectively analyzed the 
clinical data of 16 elderly patients with esophageal squamous cell carcinoma, aged > 
70 years, who were treated with nimotuzumab combined with RT. The treatment 
efficacy was evaluated at the completion of treatment and re-evaluated 1-2 months 
later: 1 patient achieved complete response (CR), 10 patients achieved partial 
response (PR), 4 patients showed stable disease and 1 patient developed progression 
disease and died of radiation pneumonitis (RP) 1 month later. The overall response 
rate (CR + PR) was 68.8%. All 16 patients developed Grade 1-2 radiation esophagitis; 
no Grade 3-4 toxicity was reported. There was 1 RP-related death during the study. 
One patient developed a rash on the forearm. No hematological, gastrointestinal, liver, 
or kidney toxicity was observed. In conclusion, nimotuzumab combined with 
radiotherapy has good efficacy, tolerable toxicity, and high safety in the treatment of 
elderly patients with esophageal cancer. 
The above studies provide evidence support for the treatment of EGFR-positive 
elderly esophageal cancer with nimotuzumab combined with chemoradiotherapy. In 
order to further verify the effectiveness and safety of nimotuzumab combined with 
concurrent chemoradiotherapy in the treatment of elderly patients with locally 
advanced unresectable advanced esophageal cancer, we conducted an exploratory 

16 
 
study on the effectiveness and safety of nimotuzumab combined with concurrent 
chemoradiotherapy in the treatment of elderly patients with locally advanced 
unresectable esophageal cancer, in order to obtain more sufficient evidence of benefits 
based on elderly patients, and add new evidence for the treatment of elderly 
esophageal cancer with nimotuzumab combined with chemoradiotherapy. 
2.3 Risk/benefit assessment 
2.3.1. Known potential risks 
Direct risks: From January 1, 2009 to June 1, 2020, it is estimated that 
approximately 117,187 patients used nimotuzumab in China. The company 
collected 688 adverse events reported by 459 patients. The names of adverse 
events were classified and summarized according to the ICH International 
Medical Terminology Dictionary (MedDRA) system organ class and preferred 
terms as shown in the appendix. Among them, there were 334 serious adverse 
reactions (including 180 new and serious adverse reactions, with ≥2 
occurrences of bone marrow suppression, decreased platelet count, decreased 
white blood cell count, dyspnea, decreased neutrophil count, shortness of 
breath, hypersensitivity, anaphylactic shock, pruritus, anorexia, infectious 
pneumonia, decreased white blood cell count, decreased neutrophil count, 
decreased granulocyte count, decreased pancytopenia, lung inflammation, 
hypertension, and hematopoiesis. All serious adverse reactions did not reach 
the level of death or life-threatening), and 354 general adverse events 
(including 70 new general adverse events). According to the results of 
completed clinical studies and the post-marketing adverse reaction monitoring, 
nimotuzumab has shown good tolerability. Most adverse events are grade I, and 
common adverse events include nausea, vomiting, headache, fever, decreased 
neutrophils and white blood cells, anemia, fatigue. For the above adverse 
events, certain preventive measures or symptomatic treatment are taken, and 
most patients can be relieved after conventional treatment or on their own. 

17 
 
Serious 
adverse 
events 
mainly 
included 
hypersensitivity 
reactions, 
leukocytopenia. 
Demographic 
factors, 
concomitant 
medications, 
and 
medication dosages had no significant effect on the incidence of adverse 
events. 
Long-term risk: Four groups of repeated-dose toxicity studies were conducted 
in rats: continuous administration for 14 days, the highest dose reached 57.14 
mg/kg, no animal deaths and no systemic toxicity were observed, and the 
NOAEL was 50 mg/kg. Once a week for 4 consecutive weeks, the highest dose 
was 75 mg/kg, no animal deaths and treatment-related abnormalities were 
observed, Cmax and AUC0-inf increased with increasing doses, and there was no 
difference in toxic kinetic parameters between genders, and the NOAEL was 75 
mg/kg/w. Three groups of repeated-dose toxicity studies were conducted in green 
monkeys, with continuous administration for 14 days, the highest dose was 11.4 
mg/kg, or once a week for 26 consecutive weeks, the highest dose was 28.57 
mg/kg, and no obvious toxicity was observed. Repeated-dose toxicity studies 
were conducted in cynomolgus monkeys, with once a week for 26 consecutive 
weeks, the highest dose was 50.00 mg/kg, and no obvious toxicity was observed. 
No increased clinical risks associated with long-term use of nimotuzumab have 
been observed in previous clinical studies. 
2.3.2 Known potential benefits 
Direct potential benefits: nimotuzumab was launched in China in 2008 and has 
been approved for marketing in 30 countries around the world, and has been 
approved for esophageal cancer indications in 9 countries. Many studies have 
shown that nimotuzumab is effective for patients with esophageal cancer. 
2.3.3 Assessment of potential risks and benefits 
The mortality rate of esophageal cancer ranks fifth among malignant tumors. 
The rate will be higher in elderly patients with esophageal cancer due to their 

18 
 
limited tolerance to treatment. A safe and effective treatment method is urgently 
needed to be added to the treatment plan for this population. Nimotuzumab, as a 
drug with proven efficacy and widely recognized safety, is expected to bring 
higher efficacy benefits to patients with minimal safety risks. In addition, this 
study will limit the population that may increase the safety risk of patients to 
avoid inclusion in high-risk populations. At the same time, the details of possible 
adverse reactions and their treatment plans will be clarified to further reduce the 
risk. 
3. Study purpose and endpoint 
Purpose 
Endpoint 
Main purpose 
 
Exploring the efficacy of nimotuzumab 
combined 
with 
concurrent 
chemoradiotherapy for elderly patients with 
esophageal cancer 
Primary endpoint: progression-free survival 
(PFS) 
 
Secondary purpose 
 
To explore the efficacy and safety of 
nimotuzumab combined with concurrent 
chemoradiotherapy for elderly patients with 
esophageal cancer 
Secondary endpoints: objective response rate 
(ORR), disease control rate (DCR), local disease 
control rate (LDCR), overall survival (OS), 
1-year OS/PFS, 2-year OS/PFS, and AE/SAE 
incidence. 
4. Study design 
4.1 Overall design 
We plan to conduct a single-arm, prospective, single-center phase II clinical study to 
explore the efficacy and safety of nimotuzumab combined with concurrent 
chemoradiotherapy for elderly patients with locally advanced esophageal cancer. The 

19 
 
enrolled patients will receive nimotuzumab combined with S-1 and radiotherapy. This 
study includes a screening period, a treatment period, an efficacy follow-up period, 
and a survival follow-up period. 
4.1.1 Screening period 
Definition: within 3 weeks before drug administration 
Content: 
1)Sign the informed consent form; 
2)Screening; 
3)Demographic characteristics; 
4)History of present disease; 
5)Past medical history; 
6)Combined treatment; 
7)Body surface area (BSA); 
8)Physical examination 
9)Vital signs; 
10)ECOG performance status: see 12.1. ECOG performance status scoring 
standards; 
11)Nutritional status: see 12.4. Nutritional risk screening form (NRS 2002); 
12)Quality of life: see 12.5. Quality of life score (QoL) of cancer patients; 
13)Charlson Comorbidity Index: see 12.6. Charlson Comorbidity Index 
scoring criteria and calculation method; 
14)Initial tumor imaging assessment: 
a.Oral and intravenous contrast-enhanced CT (neck + chest + abdomen, 
and pelvis if necessary) is preferred; 
b.Optional items include intraesophageal ultrasound, bone scan, 
esophageal fiber endoscopy, esophageal barium meal, PET/CT, etc. 
15)Electrocardiogram (12 leads); 
16)Laboratory 
examination 
of 
blood 
samples 
(hematology 
and 

20 
 
biochemistry); 
17)Pregnancy test (female subjects of childbearing age); 
18)Adverse events were observed and recorded. 
4.1.2 Treatment period 
Definition: First radiotherapy day W1D1 - last radiotherapy day W5D5 
Window period: treatment ±2 days, imaging ±7 days, pre-dose items -1 day. 
Content: 
1)Before WxD1 administration 
a.Body surface area (BSA); 
b.Physical examination 
c.Vital signs; 
d.ECOG performance status score; 
e.Blood samples and other laboratory evaluations (hematology and clinical 
chemistry); 
f.Electrocardiogram (12 leads); 
2)Administer nimotuzumab (see 6.1.2. Dosage and administration); 
3)Administer Tegafur (see 6.1.2. Dosage and Administration); 
4)Administer radiation therapy (see 6.1.2. Dosage and administration); 
5)Observe and record adverse events; 
6)Combined treatment; 
7)Imaging examination: Review every 21 days after W1D1 (such as 
W1D22). 
4.1.3 End of treatment visit 
Definition: visit at the end date of radiotherapy 
Window period: ±3 days 
Content: 
1)Physical examination and vital signs check ( at the end of radiotherapy); 

21 
 
2)ECOG performance status; 
3)QoL (assessed at the first two efficacy follow-ups); 
4)Nutritional status; 
5)Hematology and clinical biochemistry ( at the end of radiotherapy); 
6)12-lead electrocardiogram (at the end of radiotherapy); 
7)Observation and recording of adverse events (AEs occurring within 7 days 
after the end of radiotherapy and SAEs occurring within 30 days); 
8)Blood samples and other laboratory evaluations (hematology and clinical 
chemistry) are required if there are previously unresolved abnormalities; 
9)Combined treatment. 
4.1.4 Efficacy follow-up period 
Definition: From the end date of radiotherapy (D29) to the PD date 
Frequency (except for special items): The first review is on the 28th day after 
completion (W9D5), and then every 12 weeks starting from W9D5 until disease 
progression, with a window period of ±7 days. 
Content: 
1)Film degree exam; 
2)Observation and recording of adverse events (AEs occurring within 7 days 
after the end of radiotherapy and SAEs occurring within 30 days); 
3)Hematology, biochemistry, electrocardiogram (if there are previously 
unresolved abnormalities, blood samples and other laboratory evaluations are 
warranted); 
4)Combined treatment. 
4.1.5 Survival follow-up period: 
Definition: From PD date to death/loss to follow-up 
Frequency: Once every 12 weeks, window period ± 7 days 
Content: 

22 
 
1.Understand and record the subject's survival status, cause of death and time 
(telephone follow-up is possible); 
2.Combined treatment. 
4.2 Dose selection 
Nimotuzumab injection is a colorless clear liquid, administered by intravenous 
infusion, and the administration process should last for more than 60 minutes. The 
BPL-IST-ESO-057 study used a 400 mg weekly dosing regimen for nimotuzumab. 
Considering the decreased tolerance of elderly patients, this study used a 400 mg dose 
for the first administration, and a 200 mg dose for subsequent treatment courses due 
to the poor tolerance of elderly patients. 
4.3 Definition of end of study 
The study is considered to be completed when the subject no longer needs to be 
examined or the last visit of the last subject is completed. 
5. Study population 
5.1 Inclusion criteria 
Patients must meet all of the following criteria to be eligible for this trial: 
1)The patients voluntarily participated in this study, signed the informed 
consent, had good compliance, and cooperated with the follow-up; 
2)Age 75 and above, regardless of gender; 
3)ECOG score 0-1; 
4)Esophageal cancer confirmed by histology or cytology; 
5)According to RECIST 1.1 (see 12.2. Response Evaluation Criteria for 
Solid Tumors Version 1.1 for details), there is at least one measurable lesion, 
and the measurable lesion should not have received local treatment such as 
radiotherapy (lesions located in the previous radiotherapy area can also be 

23 
 
selected as target lesions if they are confirmed to have progressed and meet 
the RECIST 1.1 criteria); 
6)Patients with stage II-IVB according to AJCC (8th edition, 2018) (IVB 
included metastasis to the celiac trunk or supraclavicular lymph nodes only) 
who are not suitable for or refuse surgery can tolerate concurrent 
chemoradiotherapy and targeted therapy; 
7)Expected survival time ≥ 12 weeks; 
8)The major organs function normally, that is, they meet the following 
criteria: 
Blood test: 
a.HBG ≥ 90 g/L; 
b.ANC ≥ 1.5 × 10 9 /L; 
c.PLT ≥80×10 9 /L; 
Biochemical tests: 
a.ALB ≥ 30 g/L; 
b.ALT and AST ≤ 2.5 ULN; if there is liver metastasis, ALT and AST 
≤ 5 ULN; 
c.TBIL≤1.5ULN; 
d.Plasma Cr≤1.5ULN or creatinine clearance (CCr)≥60ml/min; 
9)Echocardiographic assessment: left ventricular ejection fraction (LVEF) ≥ 
lower limit of normal value (50%); 
10)Female of childbearing age must agree to use contraceptive measures 
(such as intrauterine devices, birth control pills or condoms) during the study 
and within 6 months after the end of the study; the serum or urine pregnancy 
test is negative within 7 days before study enrollment, and they must be 
non-breastfeeding patients; men must agree to use contraceptive measures 
during the study and within 6 months after the end of the study. 

24 
 
5.2 Exclusion criteria 
Patients who meet any of the following criteria will be excluded from this trial: 
1)Received EGFR monoclonal antibody or EGFR-TKI within six months; 
2)Participated in other interventional clinical trials within 30 days before 
screening; 
3)Patients with serious concurrent diseases, such as heart failure, high-risk 
uncontrollable arrhythmias, severe myocardial infarction, refractory 
hypertension, renal failure (CKD-4 and above), thyroid dysfunction, mental 
illness, diabetes, severe chronic diarrhea (more than 7 bowel movements per 
day), or patients who are considered unsuitable to participate in this clinical 
study by the researchers; 
4)Patients with brain metastases with symptoms or symptom control time of 
less than 3 months; 
5)Having a history of other malignant tumors (except for cured cervical 
carcinoma in situ or basal cell carcinoma of the skin and other malignant 
tumors that have been cured for more than 5 years); 
6)The presence of active infection or active infectious disease; 
7)Patients with multi-segment esophageal malignant tumors or signs of 
esophageal fistula or perforation; 
8)Patients whose tumors have invaded important blood vessels as shown by 
imaging or who are judged by the researchers to be very likely to invade 
important blood vessels and cause fatal hemorrhage during the follow-up 
study; 
9)Those who are allergic to the drugs or their ingredients used in this 
program; 
10)Peripheral neuropathy or hearing loss of grade 2 or higher according to 
the criteria of Common Terminology for Adverse Events (NCI CTCAE 
V5.0); 
11)Pregnant or breastfeeding women; 

25 
 
12)Patients with a history of psychotropic drug abuse and unable to quit or 
patients with mental disorders; 
13)Those who are considered unsuitable to participate in this study by the 
researcher; 
14)Those who are unwilling to participate in this study or unable to sign the 
informed consent. 
5.3 Screening failure 
Screening failure is defined as a subject who consents to participate in a clinical trial 
but is not randomized to receive the study intervention or enrolled in the study. 
Information on screening failure should include demographics, details of screening 
failure (eligibility criteria, and any serious adverse events). 
Patients who do not meet the criteria for participating in the trial (screening failure) 
can undergo rescreening. The screening number of the subject in the rescreening is the 
same as the screening number of the initial screening. 
6. Study intervention 
6.1 Study intervention management 
6.1.1 Description of study intervention 
Intervention 
Name 
Dosage 
form 
Manufactur
er 
Specificat
ion 
Administration 
route 
Storage and stability 
Nimotuzumab 
Injection 
Biotech 
Pharmaceut
ical 
Co., 
Ltd. 
50mg/bot
tle (10ml) 
Intravenous 
injection 
This product should be 
stored and transported at 
2℃-8℃ and should not 
be frozen. The shelf life 
is 
24 
months. 
After 
dilution 
with 
normal 

26 
 
saline, this product can 
remain stable for 12 
hours at 2℃-8℃ and 8 
hours 
at 
room 
temperature. If stored for 
longer than the above 
time after dilution, it 
should not be used. 
S-1 
Capsule 
Jiangsu 
Hengrui 
Medicine 
Co., 
Ltd./Qilu 
Pharmaceut
ical 
Co., 
Ltd. 
20mg/cap
sule 
Oral 
Protect from light, seal 
tightly, and store at room 
temperature. 
6.1.2 Dosage and administration 
S-1: 40-60 mg/m 2 , po, D1, BID, 5 weeks; 
Nimotuzumab 400 mg, iv, D1, week 1; 
Nimotuzumab 200 mg, iv, D8, QW, Week 2-Week 5. 
Radiation Therapy: 
Intensity modulated radiation therapy (IMRT) technology is used to irradiate the 
involved field. The patient is placed in a supine position and fixed with the head, neck, 
shoulder or body membrane. The patient is simulated and positioned under CT. The 
CT image is transmitted to the treatment planning system. Combined with esophageal 
barium meal contrast, gastroscopy or ultrasound gastroscopy or PET-CT images, the 
esophageal tumor target volume (GTV) is outlined layer by layer on the enhanced CT 
image; the clinical target volume (CTV) is the GTV with an axial expansion of 0.6 to 

27 
 
0.8 cm and an upper and lower expansion of 2.0 to 3.0 cm; the planned target volume 
(PTV) is the CTV with an expansion of 0.5 to 0.8 cm. The metastatic lymph nodes are 
outlined as GTV-nd, and the GTV-nd with an expansion of 0.8 to 1.0 cm is PTV-nd. 
The prescription dose requires that 95% of PTV and PTV-nd receive 50 Gy /25 F , 
with a single dose range of 2.0 Gy/F. The target dose distribution and the dose of 
organs at risk are evaluated layer by layer on the cross section, and the dose-volume 
histogram (DVH) is combined to evaluate and optimize the treatment plan. The 
maximum spinal cord dose is <45 Gy, lung V20 <28%, V30 <20%, and the average 
lung dose Dmean ≤15 Gy. After the treatment plan is confirmed, the dose is verified 
on the treatment machine, and the treatment plan is executed after it is accurate. 
6.2 Handling/storage/responsibilities 
6.2.1 Dosage form, appearance, packaging and labeling 
See 6.1.1 
6.2.2 Product storage and stability 
See 6.1.1 
6.3 Adherence to study intervention 
The study treatment will be administered in the hospital under the supervision of the 
investigator, so compliance can be easily monitored. The date of intravenous infusion 
and the exact amount of each infusion will be recorded on the CRF. 
For all study drugs, if the administration is interrupted during the infusion, the clinical 
medical staff should assess the percentage of the drug received by the subject and 
record it in the CRF. 
 
The reason for any noncompliance should also be recorded. Inadequate compliance is 
defined as a subject missing more than 2 doses or follow-up visits for non-medical 

28 
 
reasons. In the case of inadequate compliance, the investigator and co-investigator 
will consider discontinuing the administration of the study drug based on the 
individual circumstances of the subject. 
6.4 Combination therapy 
For this study, prescription drugs were defined as drugs that can only be prescribed by 
authorized/qualified clinicians. Medications recorded in the case report form (CRF) 
refer to concomitant prescription drugs, over-the-counter drugs, and supplements. 
7. Discontinuation of study intervention and subject discontinuation/withdrawal 
7.1 Study intervention discontinuation 
Suspension of study intervention does not mean suspension of the study, and 
subsequent study procedures should be completed in accordance with the provisions 
of the trial protocol. If clinically significant changes occur after enrollment (including 
but not limited to changes from baseline levels), the investigator will decide whether 
the subject management needs to be changed. Any new clinically relevant findings 
will be reported as adverse events (AEs). 
7.1.1 Criteria for discontinuation of study intervention 
In the event of any of the following circumstances, the subject must discontinue the 
study intervention 
1)If a clinically relevant event occurs that seriously affects the safety of the 
subject, the investigator or sponsor considers it necessary to terminate the 
intervention; 
2)Imaging examinations to determine disease progression; 
3)The subjects received other study drugs or chemotherapy during the 
clinical study; 
4)Lack of compliance by subjects; 

29 
 
5)The subject becomes pregnant during treatment; 
6)Elective surgery. 
7.1.2 Data collected at the time of discontinuation of the study intervention 
Patients who withdraw from the study early should complete all necessary 
examinations and steps of the study to ensure the integrity of the study. All reasons 
and dates for stopping the study should be recorded in the CRF. 
7.1.3 Subject discontinuation/withdrawal from study 
1)Patients may request to withdraw from the study at any time. 
2)Researchers may ask subjects to terminate or withdraw from the study for the 
following reasons: 
Pregnancy; 
Poor compliance with study interventions; 
If a clinical adverse event (AE), laboratory abnormality, or other medical 
condition occurs, continued participation in the study will not be in the best 
interest of the subject; 
Disease progression requiring discontinuation of intervention; 
The subject meets the exclusion criteria (new or previously undetected) 
and cannot continue to participate in the study; 
Subjects are unable to receive regularly scheduled study interventions. 
3)A subject to discontinue or withdraw from the study should be recorded in 
the case report form (CRF). Subjects who signed informed consent and 
underwent randomization but did not receive the study intervention can be 
replaced. Subjects who signed informed consent, underwent randomization, 
received the study intervention, and subsequently withdrew or were 
withdrawn/discontinued from the study cannot be replaced. 

30 
 
7.2 Lost to follow-up 
If a subject does not return to the study center for two consecutive scheduled visits 
and the study center staff cannot contact him/her, he/she will be considered lost to 
follow-up. 
If a patient does not return to the study center for a scheduled study visit, the 
following actions must be taken: 
The research center attempts to contact the subject (for up to 2 visit 
cycle time points) to explain to the subject the importance of adhering to 
the visit schedule and to confirm whether the subject is willing and/or 
should continue to participate in the study; 
Before a subject is considered lost to follow-up, the investigator or 
designee will make every effort to re-contact the subject (by making 
three phone calls if possible and, if necessary, by sending a registered 
letter to the subject's most recent mailing address or locally available 
contact information). These attempts to contact the subject should be 
recorded in the subject's medical record or study files; 
If the subject still could not be contacted, he/she was considered lost to 
follow-up and dropped out of the study. 
8. Research evaluation t and process 
8.1 Efficacy evaluation 
The starting point of efficacy evaluation is the time when the subject first receives 
treatment 
8.1.1 Disease progression as the endpoint 
1)The event endpoint was the time to disease progression in the subject; 
2)If disease progression is confirmed but the time of disease progression 

31 
 
cannot be determined, the last imaging examination time of the subject 
without disease progression is used as the event endpoint; 
3)For patients who died of any other cause before disease progression, the 
time of death of the subject will be used as the event endpoint; 
4)For subjects who have not experienced disease progression or death (i.e., 
progression-free survival) at the time of analysis, the time of the last tumor 
assessment will be used as the event endpoint; 
5)For subjects lost to follow-up, the time to the last tumor assessment 
without disease progression will be used as the event endpoint; 
6)For subjects who only have baseline imaging examination, the time of 
baseline examination will be used as the event endpoint. 
8.1.2 Events ending in death 
1)The event endpoint was the time of subject death; 
2)If the subject's death is confirmed but the time of death is not clear, the last 
follow-up time of the subject is taken as the event endpoint; 
3)For patients who had not died at the time of analysis, the time of the last 
follow-up was used as the event endpoint; 
4)For patients lost to follow-up, the time of the last follow-up was used as the 
event endpoint; 
5)For patients with only survival, the time of baseline examination will be used 
as the end point. 
8.2 Adverse events and serious adverse events 
8.2.1 Definition of adverse events (AEs) 
Adverse events refer to unexpected medical events related to or unrelated to the use 
of a drug. In this study, adverse events were judged from the subject screening 
period regardless of whether they were causally related to the trial drug. 

32 
 
8.2.1.1 Examples of adverse events include: 
1)A worsening of a chronic disease or the continued presence of symptoms, 
including an increase in the frequency and/or intensity of symptoms; 
2)New symptoms detected or diagnosed after administration of the 
investigational drug, even if the symptom may have existed before the start of 
the study; 
3)Doubt caused by the interaction between the signs, symptoms or clinical 
sequelae； 
4)Signs, symptoms, or clinical sequelae of overdose of the investigational drug 
or concomitant medication (overdose, by its nature, should not be reported as an 
AE/SAE); 
When a patient dies, the cause of death is the AE, and death is the outcome of the 
adverse event. 
8.2.1.2 Examples of adverse events do not include: 
1)Medical or surgical procedures (endoscopy, appendectomy); the circumstances 
leading up to these procedures are AEs, not the surgical procedures themselves; 
2)Situations in which adverse medical events did not occur (socially and/or 
recognizable to the hospital); 
3)Pre-existing disease with early day-to-day fluctuations or no worsening of 
symptoms present or detected at study entry; 
4)The disease/condition being studied, or the expected progression, signs, or 
symptoms of the disease/condition being studied, unless more severe than 
expected for the subject; 
5)In principle, "lack of efficacy" or "failure to achieve the expected 
pharmacological effect" is not reported as an AE or SAE. However, signs, 
symptoms and/or clinical sequelae caused by lack of efficacy will also be 
reported as AEs or SAEs if they meet the definition of AEs or SAEs. 

33 
 
8.2.2 Definition of serious adverse event (SAE) 
If the researchers or bidders think adverse events (AE) or suspected adverse reactions 
can lead to the following consequences, should be considered a serious: death, 
life-threatening adverse events, prolonged hospitalization, or hospital, affect the 
normal life of persistent or significant disability/disability, congenital abnormalities 
and/or birth defects. 
Based on appropriate medical judgment, major medical events that are unlikely to 
result in death, be life-threatening, or require hospitalization may be considered 
serious adverse events when the event is likely to endanger the subject and may 
require medical or surgical intervention to prevent one of the outcomes listed in the 
above definition. Examples include allergic bronchospasm requiring intensive 
treatment in the emergency room or at home, cachexia or seizures that do not result in 
hospitalization, and the development of drug dependence or drug abuse. 
Death (defined as Grade 5 by NCI-CTCAE Version 5.0) is generally considered the 
outcome of the event. If death occurs, the primary cause of death (the main cause of 
death) will be recorded as the SAE. "Fatal" will be recorded as the outcome of this 
adverse event; death should not be recorded as a separate event. Death itself will only 
be recorded as an SAE when the cause of death cannot be determined (e.g., sudden 
death, unexplained death). 
8.2.3 Adverse event classification 
8.2.3.1 Severity of the incident 
Investigators will refer to the National Cancer Center Common Terminology Criteria 
for Adverse Events (NCI-CTCAE) version 5.0 to evaluate adverse events. This 
standard uses descriptive terms when reporting AEs. Investigators are required to 
grade the severity of each adverse event. If the severity/intensity of an adverse event 
is not clarified in the guidelines, the investigator may make an assessment based on 
the general definition of 1-5 and combined with his or her best medical judgment. 

34 
 
The general classification is: 
Grade 1: Mild; 
Grade 2: Moderate; 
Grade 3: Severe; 
Grade 4: Life-threatening or disabling; 
Grade 5: AE-related death. 
8.2.3.2 Relevance to the study intervention 
The clinician examining and evaluating the subjects must assess the relevance of all 
adverse events to the study intervention based on the timing and his/her clinical 
judgment. In clinical studies, the study intervention must always be a subject of 
suspicion. 
Grading of relevance of study intervention: 
1)Definitely related: There is clear evidence of a causal relationship and 
other possible factors can be ruled out. The clinical event (including 
abnormal laboratory test results) occurs in a reasonable time relationship with 
the administration of the study intervention and cannot be explained by 
concurrent illness, other drugs or chemicals. The response of withdrawing the 
study intervention (de-challenge) should be clinically reasonable. The event 
must be pharmacologically or phenomenologically clear, and if necessary, a 
qualified re-challenge procedure can be used; 
2)Probably related: There is evidence of a causal relationship and the 
likelihood of other factors being influential is low. The clinical event 
(including laboratory abnormalities) occurred within a reasonable period of 
time after the study intervention was given and is unlikely to be attributed to 
concurrent illness, other drugs or chemicals, and is consistent with a 
clinically reasonable withdrawal (de-challenge) response. No re-challenge 
information is required to complete this definition; 
3)Possibly related: There is some evidence of a causal relationship (e.g., the 

35 
 
event occurred within a reasonable period after administration of the trial 
drug). However, other factors may have contributed to the event (e.g., the 
subject's clinical condition, other concomitant events). Although an adverse 
event may be classified as "possibly related" soon after discovery, it can be 
recorded as requiring more information and then upgraded to "probably 
related" or "definitely related" depending on the circumstances; 
4)Likely unrelated: The temporal relationship between the clinical event 
(including laboratory abnormalities) and the administration of the study 
intervention indicates that a causal relationship is unlikely (e.g., the event did 
not occur within a reasonable period after the administration of the study 
intervention), and other drugs, chemicals, or underlying diseases can provide 
a reasonable explanation (the subject's clinical condition, other concomitant 
treatments); 
5)Definitely Unrelated: The adverse event is completely independent of the 
study intervention and/or there is evidence that the event is definitely related 
to another etiology. There must be a clear etiology documented by the 
clinician. 
8.2.3.3 Anticipation 
The investigator is responsible for determining whether an adverse event is expected 
or unexpected. If the nature, severity, or frequency of an adverse event is inconsistent 
with the risk information of the previously described research intervention (e.g., 
investigator's brochure, approved instructions), it is considered unexpected. The 
assessment of anticipation should be based on previously observed adverse events and 
should not be inferred from the nature of the research intervention. 
8.2.4 Timing and frequency of adverse event assessment and follow-up 
The occurrence of adverse events (AEs) or serious adverse events (SAEs) should be 
brought to the attention of the investigator during visits to the subject receiving 

36 
 
medical care or for review by the monitor. All adverse events that do not meet the 
criteria for serious adverse events will be recorded on the appropriate case report form 
(CRF), including local reactions and systemic reactions. Information to be collected 
includes description of the event, time of onset, clinician's assessment of severity 
(which should only be assessed by those with training and diagnostic authority), 
relationship to the investigational product, expected nature, and time to 
resolution/stabilization of the event. All adverse events occurring during the study 
must be recorded, regardless of whether they are related to the study intervention. All 
adverse events are followed up until reasonably resolved. The medical condition at 
the time of screening of the subject should be considered as baseline and not reported 
as an adverse event. However, if the subject's condition deteriorates at any time, it 
should be recorded as an adverse event. Changes in the severity of adverse events 
should be recorded to allow for an assessment of the duration of the event at each 
severity level. Intermittent adverse events require the time of onset and duration of 
each occurrence to be recorded. 
From the signing of the informed consent form to 7 days (non-serious adverse events) 
or 30 days (serious adverse events) after the end of the trial, the investigator should 
record all events that need to be reported. At each visit, the researcher should ask 
about adverse events/serious adverse events that occurred after the last visit. Follow 
up the outcome information of the event until the adverse event is resolved or 
stabilized. All serious adverse events should be followed up until the event is resolved 
satisfactorily, or the investigator considers the event to be chronic, or the subject's 
condition is stable. 
8.2.5 Serious adverse event reporting 
After receiving safety-related information from any source, researchers should 
immediately analyze and evaluate it, including its severity, relevance to the trial drug, 
etc. Suspected and unexpected serious adverse reactions should be promptly reported 
to the clinical trial institution and ethics committee. 

37 
 
8.2.6 Pregnancy report 
Pregnancy that occurs during the study must be recorded and reported using the 
pregnancy report form. To ensure the safety of the subject, pregnancy must be 
reported to the principal investigator immediately and must be followed up to 
determine its outcome (including early termination of pregnancy) and maternal and 
fetal status. Pregnancy complications and termination of pregnancy for medical 
reasons must be reported as AEs or SAEs. Spontaneous abortion must be reported as 
an SAE. Any pregnancy-related SAE that occurs and comes to the attention of the 
investigator after the subject completes the study and is believed to be possibly related 
to the study drug must be reported immediately to the principal investigator. In 
addition, the investigator must collect information on the pregnancy of the female 
sexual partner of the male subject after enrollment in the study, whenever possible. 
Pregnancy information must be reported as described above. 
9. Statistical considerations 
9.1 Sample size estimation 
This study is a single-arm, prospective, exploratory , single-center phase II clinical 
study. The sample size calculation was based on the primary study endpoint, namely, 
PFS assessed by the investigator. 
The primary endpoint was the median PFS assessed by the investigator. Based on 
previous studies on radical radiotherapy for elderly esophageal cancer, the median 
PFS of elderly patients with locally advanced and inoperable esophageal squamous 
cell carcinoma after radical radiotherapy was 16 months. It was estimated that the 
median PFS of this study could reach 18.2 months. Using a one-sided test, α=0.05, 
power=0.80, the sample size was calculated to be 41 cases. Considering the dropout 
rate of 20%, a total sample size of 52 subjects was required. 

38 
 
9.2 Analysis population 
1)Full analysis set (FAS): All patients diagnosed with distant metastasis or 
recurrence of esophageal cancer who received trial drug treatment and had at 
least one post-drug efficacy follow-up data were included in the full analysis 
set. 
2)Per-protocol set (PPS): Subjects who met the main inclusion and exclusion 
criteria, completed the trial drug treatment and follow-up observation 
according to the protocol, and had complete survival data were included in 
the per-protocol set. 
3)Safety analysis set (SS): All subjects who received trial drug treatment and 
for whom at least one post-dose safety data was available were included in 
the safety analysis set. 
9.3 Statistical Analysis 
9.3.1 Statistical analysis plan 
SPSS version 26.0 software was used for statistical analysis. Baseline data were 
analyzed according to the full analysis set, and all efficacy indicators were analyzed 
according to the full analysis set and the per-protocol set; safety analysis was 
performed using the safety analysis set. 
Descriptive statistics were used to analyze all data, including demographic data, 
baseline, various efficacy evaluation indicators, and all safety data. Measurement data 
were expressed as mean ± standard deviation or median and upper and lower quartiles, 
and count data were expressed as frequency or percentage. Dropout was defined as 
any reason that caused the subject to fail to complete the follow-up required by the 
protocol. For exclusion, dropout cases were statistically described one by one. The 
anti-tumor efficacy of nimotuzumab was analyzed in the full analysis set and the 
per-protocol set. 

39 
 
9.3.2 Effectiveness Analysis 
Kaplan-Meier curves were drawn to estimate the survival rate, median survival time, 
and hazard ratio. 
9.3.3 Security analysis 
1)Describe the therapeutic exposure; 
2)Statistics of adverse events, the incidence and severity of serious adverse 
events (NCI CTCAE 5.0), and the causal relationship with the trial drug; 
3)The vital signs, laboratory test values, electrocardiograms and changes 
relative to baseline levels of the subjects at each follow-up point will be 
statistically analyzed descriptively, and data that deviate from the reference 
value range will also be statistically analyzed; 
4)Concomitant medications and concomitant therapies will be categorized 
and counted. 
10. Supporting documents and operational considerations 
10.1 Regulatory, ethical and research oversight considerations 
10.1.1Informed consent 
Patients must sign an informed consent form before participating in the trial. During 
the trial, the rights and interests of patients must be ensured, and patient information 
must be kept confidential in accordance with GCP requirements. 
According to the Helsinki Declaration and the GCP requirements of the State Food 
and Drug Administration, written informed consent must be obtained before the 
patient enters the trial, that is, before blood samples are collected for screening 
assessment or any other research-related activities. The researcher is responsible for 
fully and comprehensively introducing the purpose of the study, the effects of the drug, 
possible toxic and side effects, and possible risks to the subjects or their designated 

40 
 
representatives, and should let the subjects know their rights, the risks and benefits to 
be assumed, and give the subjects a copy of relevant information. Then, give the 
subjects sufficient time to consider the content of this study in order to decide whether 
to participate. Conversational communication is a very important informed consent 
process. If the subject and his legal representative are illiterate, the informed consent 
process should be witnessed by the subject or his legal representative, who should 
sign the informed consent form after verbal consent, and the witness's signature 
should be on the same day as the subject's signature. 
Each subject must obtain a written informed consent in duplicate, one copy is given to 
the subject and the other is retained by the researcher. 
This clinical trial must comply with the Declaration of Helsinki (1996 edition), Good 
Clinical Practice (GCP) issued by CFDA, and related regulations. Before the start of 
the trial, the clinical research institution's ethics committee must be approved before 
the study can begin. During the clinical trial, any changes to this trial protocol must be 
reported to the ethics committee and filed. 
10.1.2 Study suspension and termination 
If there are sufficient reasonable reasons, this study may be temporarily suspended or 
terminated early. The party that suspends or terminates the study should notify the 
subjects and researchers in writing and record the reasons for the suspension or 
termination of the study. If the study is terminated or suspended early, the principal 
investigator (PI) should promptly notify the subjects and the Institutional Review 
Board (IRB) and provide the reasons for the termination or suspension of the study. 
Circumstances that may require termination or suspension include, but are not limited 
to: 
Determination of unexpected, significant, or unacceptable risks to 
subjects; 
Demonstration of effectiveness provides justification for cessation; 
Insufficient compliance with protocol requirements; 

41 
 
Data are incomplete and/or insufficient for evaluation; 
Determination that the primary endpoint had been met; 
Determine that the study is invalid. 
The study may proceed only if issues related to safety, protocol compliance, and data 
quality are addressed. 
 
 

42 
 
11. References
                                                             
[1] BRAY F, FERLAY J, SOERJOMATARAM I, et al. Global cancer statistics 2018: 
GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 
countries [J]. CA Cancer J Clin, 2018, 68(6):394-424. 
[2] Rustgi, Anil K, and Hashem B El-Serag. “Esophageal carcinoma.” The New 
England journal of medicine vol. 371,26 (2014): 2499-509. 
[3] Domper Arnal, María José et al. “Esophageal cancer: Risk factors, screening and 
endoscopic treatment in Western and Eastern countries.” World journal of 
gastroenterology vol. 21,26 (2015): 7933-43. 
[4] Yu, Canqing et al. “Hot Tea Consumption and Its Interactions With Alcohol and 
Tobacco Use on the Risk for Esophageal Cancer: A Population-Based Cohort Study.” 
Annals of internal medicine vol. 168,7 (2018): 489-497. 
[5] Chen W, Zheng R, Baade PD, et al. Cancer statistics in China,2015 [J]. CA Cancer 
J Clin, 2016, 66 (2): 115-132. 
[6] Wang Lili, Wang Jian, Yu Bo, Liu Huilan, Hu Lijun, Zhou Juying. Analysis of 
toxic and side effects of radiotherapy and prognostic factors in elderly patients with 
esophageal cancer[J]. Chinese Journal of Oncology Prevention and Treatment, 2018, 
25(23): 1638-1642. 
[7] Jiang, Dongxian et al. “The prognostic value of EGFR overexpression and 
amplification in Esophageal squamous cell Carcinoma.” BMC cancer vol. 15 377. 8 
May. 2015. 
[8] Wang, Yu-Li et al. "Genetic Variants in EGFR/PLCE1 Pathway Are Associated 
with Prognosis of Esophageal Squamous Cell Carcinoma after Radical Resection." 
Current medical science vol. 39,3 (2019): 385-390. 
[9] Wang, Jun et al. “Relationship between EGFR over-expression and 
clinicopathologic characteristics in squamous cell carcinoma of the esophagus: a 
meta-analysis.” Asian Pacific journal of cancer prevention: APJCP vol. 15,14 (2014): 
5889-93. 
[10] Zhou, Zhangjian et al. "Activation of EGFR-DNA-PKcs pathway by IGFBP2 
protects esophageal adenocarcinoma cells from acidic bile salts-induced DNA 
damage." Journal of experimental & clinical cancer research : CR vol. 38,1 13. 9 Jan. 
2019. 

43 
 
                                                                                                                                                                              
[11] Li Lulu, Chen Jian, Zhang Dingru, Guo Yufei. Observation on the efficacy of 
Nimotuzumab combined with IMRT in the treatment of elderly patients with locally 
advanced esophageal cancer[J]. Modern Oncology, 2020, 28(08): 1298-1300. 
[12] Jin‑Hua Guo,Ming‑Qiu Chen,Cheng Chen,Hai‑Jie Lu,Ben‑Hua Xu. Efficacy and 
toxicity of nimotuzumab combined with radiotherapy in elderly patients with 
esophageal squamous cell carcinoma[J]. Molecular and Clinical Oncology, 2015, 
3(5). 

44 
 
12. Appendix 
12.1 ECOG performance status scoring standard 
Physical condition ECOG scoring standard Zubrod-ECOG-WHO (ZPS, 5 points) 
Fitness score 
Physical status 
0 
The ability to move is completely normal, with no difference from the 
ability to move before the onset of the disease 
1 
Able to move around freely and engage in light physical activities, 
including general housework or office work, but not able to engage in 
heavy physical activities 
2 
Able to move around freely and take care of oneself, but has lost the 
ability to work and can be out of bed and active for at least half of the 
day. 
3 
He can only partially take care of himself and spends more than half of 
the day in bed or in a wheelchair. 
4 
Bedridden and unable to take care of oneself 
5 
Die 

45 
 
12.2 Response Evaluation Criteria for Solid Tumors Version 1.1 
(Response Evaluation Criteria in Solid Tumors RECIST Version 1.1) 
1. Tumor measurability at baseline 
1.1 Definition 
At baseline, tumor lesions/nodes were categorized as measurable or non-measurable 
based on the following definitions: 
1.1.1 Measurable lesions 
Tumor lesions: There is at least one accurately measurable diameter (recorded as the 
maximum diameter), the minimum length of which is as follows: 
 CT scan 10 mm (CT scan layer thickness is no more than 5 mm) 
 Routine clinical examination instruments: 10 mm (tumor lesions that cannot 
be accurately measured with caliper instruments should be recorded as unmeasurable) 
 Chest X-ray 20 mm 
 Malignant lymph nodes: pathologically enlarged and measurable, the short 
diameter of a single lymph node on CT scan must be ≥15 mm (the CT scan layer 
thickness is recommended to be no more than 5 mm). During baseline and follow-up, 
only the short diameter is measured and followed up. 
1.1.2 Non-measurable lesions 
All other lesions, including small lesions (longest diameter <10 mm or pathological 
lymph node short diameter ≥10 mm to <15 mm) and lesions that cannot be measured. 
Lesions that cannot be measured include: meningeal disease, ascites, pleural or 
pericardial 
effusion, 
inflammatory 
breast 
cancer, 
skin/lung 
lymphangitic 
carcinomatosis, abdominal masses that cannot be diagnosed and followed up by 
imaging, and cystic lesions. 

46 
 
1.1.3 Special considerations for lesion measurement 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
special mention: 
Bone lesions: 
 Bone scans, PET scans, or plain radiographs are not suitable for measuring 
bone lesions, but can be used to confirm the presence or absence of bone lesions; 
 Osteolytic lesions or mixed osteolytic/osteoblastic lesions with a definite soft 
tissue component that meets the above definition of measurability can be considered 
measurable lesions if they can be evaluated using cross-sectional imaging techniques 
such as CT or MRI. 
 Osteogenic lesions are non-measurable lesions. 
Cystic lesions: 
 Lesions that meet the definition of simple cysts on radiographic imaging 
should not be considered malignant lesions because they are simple cysts by 
definition. They are neither measurable lesions nor non-measurable lesions. 
 If the metastatic lesion is cystic and meets the above definition of 
measurability, it can be considered a measurable lesion. However, if there is a 
non-cystic lesion in the same patient, the non-cystic lesion should be selected as the 
target lesion. 
Topically treated lesions: 
 Lesions located in areas that have been irradiated or treated with other 
locoregional therapies are generally considered non-measurable unless there is clear 
progression of the lesion. The study protocol should describe in detail the conditions 
under which these lesions are considered measurable. 
1.2 Description of measurement method 
1.2.1 Lesion measurement 

47 
 
During clinical evaluation, all tumor measurements should be recorded in metric units. 
All baseline assessments of tumor lesion size should be completed as close to the start 
of treatment as possible and must be completed within 28 days (4 weeks) before the 
start of treatment. 
1.2.2 Evaluation methods 
The same techniques and methods should be used for baseline assessment and 
subsequent measurements of lesions. All lesions must be evaluated using imaging, 
except for lesions that cannot be evaluated by imaging but can only be evaluated by 
clinical examination. 
Clinical lesions: Clinical lesions are considered measurable only when they are 
superficial and have a diameter of ≥10 mm (such as skin nodules). For patients with 
skin lesions, it is recommended to use color photos with a ruler to measure the size of 
the lesion for archiving. When lesions are evaluated by both imaging and clinical 
examination, imaging should be used as much as possible because it is more objective 
and can be reviewed repeatedly at the end of the study. 
Chest X-ray: When tumor progression is an important research endpoint, chest CT 
should be used first because CT is more sensitive than X-ray, especially for new 
lesions. Chest X-ray is only applicable when the measured lesion has clear boundaries 
and the lungs are well ventilated. 
CT, MRI: CT is currently the best available and repeatable method for evaluating 
efficacy. The definition of measurability in this guideline is based on CT scan slice 
thickness ≤ 5 mm. If the CT slice thickness is greater than 5 mm, the minimum 
measurable lesion should be twice the slice thickness. MRI is also acceptable in some 
cases (such as whole body scans). 
Ultrasound: Ultrasound should not be used as a measurement method to measure 
lesion size. Ultrasound examinations are not repeatable after the measurement is 
completed due to their operation dependence, and the consistency of technology and 
measurement between different measurements cannot be guaranteed. If new lesions 

48 
 
are found using ultrasound during the trial, CT or MRI should be used for 
confirmation. If the radiation exposure of CT is considered, MRI can be used instead. 
Endoscopy, laparoscopy: These techniques are not recommended for objective tumor 
evaluation, but they can be used to confirm CR when biopsy specimens are obtained 
and to confirm recurrence in trials where the endpoint is recurrence after CR or 
surgical resection. 
Tumor markers: Tumor markers cannot be used alone to evaluate objective tumor 
response. However, if the marker level exceeds the upper limit of normal at baseline, 
it must return to normal levels to evaluate complete response. Because tumor markers 
vary from disease to disease, this factor must be taken into account when writing 
measurement standards into the protocol. Specific criteria for CA-125 response 
(recurrent ovarian cancer) and PSA (recurrent prostate cancer) response have been 
published. In addition, the International Gynecologic Cancer Organization has 
developed CA-125 progression criteria, which will soon be added to the objective 
tumor evaluation criteria for first-line ovarian cancer treatment. 
Cytology/histology techniques: These techniques can be used to identify PR and CR 
in specific circumstances specified in the protocol (e.g., residual benign tumor tissue 
is often present in lesions of germ cell tumors). When effusions may be a potential 
side effect of a therapy (e.g., treatment with taxane compounds or angiogenesis 
inhibitors) and the measurable tumor meets the criteria for response or stable disease, 
the appearance or worsening of tumor-related effusions during treatment can be 
confirmed by cytology techniques to distinguish between response (or stable disease) 
and progressive disease. 
2 Tumor response assessment 
2.1 Assessment of total tumor and measurable lesions 
To evaluate objective response or possible future progression, it is necessary to 
perform a baseline assessment of the total tumor burden of all tumor lesions as a 
reference for subsequent measurements. In clinical protocols with objective response 

49 
 
as the primary treatment endpoint, only patients with measurable lesions at baseline 
can be included. Measurable lesions are defined as the presence of at least one 
measurable lesion. For trials with disease progression (time to disease progression or 
degree of progression on a fixed date) as the primary treatment endpoint, the protocol 
inclusion criteria must clearly state whether only patients with measurable lesions are 
included, or whether patients without measurable lesions can also be included. 
2.2 Baseline Recording of Target and Non-target Lesions 
When there is more than one measurable lesion at baseline, all lesions should be 
recorded and measured, with a total of no more than 5 lesions (no more than 2 per 
organ) as target lesions representing all involved organs (that is, patients with only 
one or two involved organs should select a maximum of two or four target lesions as 
baseline measurement lesions). 
Target lesions must be selected based on size (longest diameter), representative of all 
involved organs, and measurements must be reproducible. Sometimes when the 
largest lesion cannot be reproducibly measured, a reselection of the largest lesion that 
can be reproducibly measured is appropriate. 
Lymph nodes are of particular concern because they are normal tissue and can be 
detected on imaging even without metastasis. Pathological lymph nodes, defined as 
measurable nodules or even target lesions, must meet the following criteria: a short 
diameter of ≥15 mm on CT. Only the short diameter is required at baseline. 
Radiologists often use the short diameter of a nodule to determine whether the nodule 
has metastatic disease. Nodule size is generally expressed in two dimensions detected 
by imaging (axial plane for CT and one of the axial, sagittal, or coronal planes for 
MRI). The short diameter is the smallest value. For example, a 20 mm × 30 mm 
abdominal nodule has a short diameter of 20 mm and can be considered a malignant, 
measurable nodule. In this example, 20 mm is the measurement of the nodule. 
Nodules with a diameter of ≥10 mm but <15 mm should not be considered target 
lesions. Nodules <10 mm do not fall into the category of pathological nodules and do 

50 
 
not need to be recorded or further observed. 
The sum of the diameters of all target lesions (including the longest diameter of 
non-nodal lesions and the short diameter of nodal lesions) will be reported as the 
baseline diameter sum. If lymph node diameters are included, as mentioned above, 
only the short diameter will be included. The baseline diameter sum will be used as a 
reference value for the baseline level of disease. 
All other lesions, including pathological lymph nodes, can be considered non-target 
lesions and do not need to be measured, but should be recorded at the baseline 
assessment, such as "present", "absent" or, in rare cases, "definitely progressed". 
Extensive target lesions can be recorded together with the target organ (such as 
extensive enlargement of pelvic lymph nodes or massive liver metastases). 
2.3 Remission criteria 
2.3.1 Target lesion assessment 
Complete remission (CR): All target lesions disappear and the short diameter of all 
pathological lymph nodes (including target nodules and non-target nodules) must be 
reduced to <10 mm. 
Partial response (PR): The sum of the target lesion diameters decreases by at least 
30% compared with the baseline level. 
Disease progression (PD): The minimum value of the sum of all target lesion 
diameters measured during the entire experimental study is used as a reference, and 
the relative increase in the sum of diameters is at least 20% (if the baseline 
measurement value is the smallest, the baseline value is used as a reference); in 
addition, the absolute value of the sum of diameters must increase by at least 5 mm 
(the appearance of one or more new lesions is also considered disease progression). 
Stable disease (SD): The reduction in target lesions has not reached the level of PR, 
nor has the increase in target lesions reached the level of PD, but is somewhere in 
between. The minimum value of the sum of diameters can be used as a reference for 

51 
 
research. 
2.3.2 Precautions for target lesion assessment 
Lymph nodes: Even if the lymph nodes identified as target lesions are reduced to less 
than 10 mm, the actual short diameter value corresponding to the baseline must be 
recorded for each measurement (consistent with the anatomical plane at the baseline 
measurement). This means that if the lymph nodes are target lesions, even if the 
criteria for complete remission are met, it cannot be said that the lesions have 
disappeared, because the short diameter of normal lymph nodes is defined as <10 mm. 
Target lymph node lesions must be specifically recorded in a specific location on the 
CRF form or other recording method: for CR, all lymph node short diameters must be 
<10 mm; for PR, SD, and PD, the actual measurement of the target lymph node short 
diameter will be included in the sum of the target lesion diameters. 
Target lesions too small to measure: In clinical studies, all lesions (nodular or 
non-nodular) recorded at baseline should have their actual measurements recorded 
again at subsequent evaluations, even if they are very small (e.g., 2 mm). However, 
sometimes they are so small that the CT scan image is very blurry and the radiologist 
has difficulty defining the exact value, so they may be reported as "too small to 
measure." In this case, it is important to record the previous value on the CRF. If the 
radiologist believes that the lesion may have disappeared, it should also be recorded 
as 0 mm. If the lesion is indeed present but is too blurry to give an accurate 
measurement, a default value of 5 mm can be used. (Note: This is unlikely to occur 
with lymph nodes, as they are generally of measurable size under normal 
circumstances or are often surrounded by fat tissue as in the retroperitoneum; however, 
if this situation occurs and a measurement cannot be given, a default value of 5 mm is 
also used.) The default value of 5 mm is derived from the cut thickness of the CT scan 
(this value does not change with different cut thickness values of CT). Since the 
chance of the same measurement being repeated is unlikely, providing this default 
value will reduce the risk of incorrect assessment. However, it needs to be reiterated 
that if the radiologist can give an exact numerical value for the lesion size, the actual 

52 
 
value must be recorded even if the lesion diameter is less than 5 mm. 
Separate or coalesced lesions: When a non-nodular lesion is fragmented, the longest 
diameters of the separate parts are added together to calculate the sum of the 
diameters of the lesion. Similarly, for coalesced lesions, the planes between the 
coalesced parts can be distinguished and the maximum diameters of each are 
calculated. However, if the lesions are inseparable, the longest diameter should be the 
longest diameter of the entire coalesced lesion. 
2.3.3 Evaluation of non-target lesions 
This section defines the response criteria for non-target lesions. Although some 
non-target lesions are actually measurable, they do not need to be measured and only 
need to be qualitatively assessed at the time points specified in the protocol. 
Complete remission (CR): All non-target lesions disappear and tumor markers return 
to normal levels. All lymph nodes are non-pathological in size (short diameter <10 
mm). 
Non-complete response/non-progressive disease: Presence of one or more non-target 
lesions and/or persistent tumor marker levels above normal levels. 
Disease progression: Definite progression of existing non-target lesions. Note: The 
appearance of one or more new lesions is also considered disease progression. 
2.3.4 Special considerations regarding the assessment of non-target lesion progression 
The following is a supplementary explanation of the definition of progression of 
non-target lesions: When patients have measurable non-target lesions, even if the 
target lesions are assessed as stable or partially remitted, in order to make a clear 
definition of progression based on the non-target lesions, the overall deterioration of 
the non-target lesions must be met to the extent that treatment must be terminated. 
The general increase in the size of one or more non-target lesions is often not enough 
to meet the progression criteria. Therefore, when the target lesions are stable or 
partially remitted, it is almost rare to define overall tumor progression based solely on 

53 
 
changes in non-target lesions. 
When none of the patient's non-target lesions are measurable: This situation occurs in 
some phase III trials when the inclusion criteria do not require the presence of 
measurable lesions. The overall assessment is still based on the above criteria, but 
because there is no measurable data on lesions in this case. The deterioration of 
non-target lesions is not easy to assess (by definition: all non-target lesions must be 
truly unmeasurable), so when the changes in non-target lesions lead to an increase in 
the overall disease burden equivalent to disease progression in target lesions, a clear 
definition of progression based on non-target lesions needs to be established for 
assessment. For example, it is described as an increase in tumor burden equivalent to 
an additional 73% increase in volume (equivalent to a 20% increase in the diameter of 
measurable lesions). Another example is peritoneal effusion from "trace" to 
"extensive"; lymphangiopathy from "local" to "widely disseminated"; or described in 
the protocol as "sufficient to change treatment." Examples include pleural effusion 
from trace to large, lymphatic involvement from the primary site to distant sites, or it 
may be described in the protocol as "necessary for a change in treatment." If clear 
progression is found, the patient should be considered to have progressive disease 
overall at that point. It would be desirable to have objective criteria applicable to the 
assessment of non-measurable disease, but the added criteria must be reliable . 
2.3.5 New lesions 
The appearance of new malignant lesions indicates disease progression; therefore, 
some evaluation of new lesions is important. There are no specific criteria for the 
detection of lesions on imaging; however, the finding of a new lesion should be 
unambiguous. For example, progression cannot be attributed to differences in imaging 
techniques, changes in imaging morphology, or other pathologies other than the tumor 
(eg, some so-called new bone lesions are simply the healing of the original lesion or 
the recurrence of the original lesion). This is particularly important when a patient has 
a partial or complete response to a baseline lesion; for example, a necrotic liver lesion 
may be reported on the CT report as a new cystic lesion when it is not. 

54 
 
Lesions detected during follow-up but not found during the baseline examination will 
be considered new lesions and indicate disease progression. For example, if a patient 
with visceral lesions during the baseline examination is found to have metastatic 
lesions during a CT or MRI head examination, the patient's intracranial metastatic 
lesions will be considered as evidence of disease progression, even if the patient did 
not undergo a head examination during the baseline examination. 
If a new lesion is ambiguous, for example because of its small size, further treatment 
and follow-up evaluation are needed to confirm whether it is a new lesion. If repeat 
examination confirms that it is a new lesion, the time of disease progression should be 
calculated from the time of its initial discovery. 
Lesions evaluated with FDG-PET generally require additional testing for 
confirmation, and it is reasonable to combine FDG-PET with additional CT results to 
evaluate progression (especially new suspected disease). New lesions can be 
confirmed with FDG-PET, according to the following procedure: 
The baseline FDG-PET scan result was negative, and the subsequent follow-up 
FDG-PET scan was positive, indicating disease progression. 
No baseline FDG-PET was performed and the follow-up FDG-PET result was 
positive: 
If the new lesions found in the follow-up FDG-PET positive test are consistent with 
the results of the CT examination, it proves that the disease has progressed. 
If the new lesions found in the positive results of the follow-up FDG-PET are not 
confirmed by the CT examination results, another CT examination is required for 
confirmation (if confirmed, the disease progression time is calculated from the 
abnormality found in the previous FDG-PET examination). 
If the positive follow-up FDG-PET result is consistent with a pre-existing lesion on 
CT, and the lesion has not progressed on imaging, then the disease has not progressed. 
2.4 Best overall efficacy evaluation 

55 
 
The best overall response is the best response recorded from the beginning of the trial 
to the end of the trial, taking into account any necessary conditions for confirmation. 
Sometimes the response occurs after the end of treatment, so the protocol should 
clarify whether the response evaluation after the end of treatment is considered in the 
best overall response evaluation. The protocol must clarify how any new treatment 
before progression affects the best response. The patient's best response depends 
mainly on the results of target lesions and non-target lesions and the manifestation of 
new lesions. In addition, it depends on the nature of the trial, protocol requirements, 
and outcome measurement criteria. Specifically, in non-randomized trials, the 
response is the primary goal, and confirmation of PR or CR is necessary to confirm 
which is the best overall response. 
2.4.1 Time point response 
Assuming that a response will occur at each specific time point for each regimen, 
Table A provides a summary of the overall response at each time point for the patient 
population with measurable disease at baseline. 
If the patient has no measurable lesions (no target lesions), the evaluation can refer to 
Table B. 
2.4.2 Assessment missing and non-assessable explanation 
If a lesion cannot be imaged or measured at a particular time point, the patient is not 
evaluable at that time point. If only a portion of the lesions can be evaluated at an 
evaluation, the patient is generally considered not evaluable at that time point unless 
there is evidence that the missing lesions do not affect the evaluation of the efficacy 
response at the specified time point. This is likely to occur in the setting of 
progressive disease. For example, if a patient has 3 lesions totaling 50 mm at baseline, 
but subsequently only 2 lesions totaling 80 mm are evaluable, the patient will be 
evaluated as having progressive disease regardless of the impact of the missing 
lesions. 
2.4.3 Best overall response: all time points 

56 
 
Once all the patient information is available, the best overall response can be 
determined. 
Evaluation of the best overall response when the study does not require confirmation 
of a complete or partial efficacy response: The best efficacy response in the trial is the 
best response at all-time points (for example, a patient is evaluated as SD in the first 
cycle, PR in the second cycle, and PD in the last cycle, but his best overall response is 
evaluated as PR. When the best overall response is evaluated as SD, it must meet the 
shortest time from the baseline level specified in the protocol. If the shortest time 
standard is not met, even if the best overall response is evaluated as SD, it will not be 
recognized, and the patient's best overall response will be determined based on 
subsequent evaluations. For example, a patient is evaluated as SD in the first cycle 
and PD in the second cycle, but he does not meet the shortest time requirement for SD, 
and his best overall response is evaluated as PD. The same patient who is lost to 
follow-up after being evaluated as SD in the first cycle will be considered 
unevaluable. 
When the study requires confirmation of complete or partial efficacy response, the 
best overall response assessment is: only when each subject meets the partial or 
complete response criteria specified in the trial and the efficacy is confirmed again at 
a later time point (usually four weeks later) as specifically mentioned in the protocol 
can a complete or partial response be declared. In this case, the best overall response 
is shown in the explanation of Table c. 
2.4.4 Special tips for efficacy evaluation 
When nodular lesions are included in the total target lesion assessment and nodules 
decrease in size to a “normal” size (<10 mm), they will still have a lesion size scan 
reported. To avoid overestimation based on increased nodule size, measurements will 
be recorded even if the nodule is normal. As mentioned previously, this means that a 
subject with a complete response will not have a score of 0 on the CRF. 
If efficacy confirmation is required during the trial, repeated “unmeasurable” time 

57 
 
points will complicate the optimal assessment of efficacy. The analysis plan for the 
trial must state that these missing data/assessments can be accounted for when 
determining efficacy. For example, in most trials, a subject's response of PR-NE-PR 
can be considered to have efficacy confirmation. 
When a subject experiences an overall deterioration in health that requires 
discontinuation of treatment, but there is no objective evidence, this should be 
reported as symptomatic progression. Every effort should be made to assess objective 
progression even after treatment has been discontinued. Symptomatic deterioration is 
not an assessment of objective response: it is a reason to discontinue treatment. The 
objective response of such subjects will be assessed by the target and non-target 
lesions as shown in Tables a to c. 
Cases defined as early progression, early death and inevaluable are study specific and 
should be clearly described in each protocol (depending on the treatment interval and 
duration). 
In some cases, it is difficult to distinguish localized disease from normal tissue. When 
the evaluation of complete response is based on such a definition, we recommend that 
a biopsy be performed before the evaluation of response to localized complete 
response. When some subjects have abnormal imaging results of localized disease that 
are thought to represent fibrosis or scarring, FDG-PET is used to confirm the response 
to complete response with a similar assessment criteria to biopsy. In such cases, the 
use of FDG-PET should be prospectively described in the protocol and supported by 
reports in the specialist medical literature for this setting. However, it must be 
recognized that the limitations of FDG-PET and biopsy, including their resolution and 
sensitivity, may lead to false-positive results in the evaluation of complete response. 
Table a  
Evaluation at each time point - Subjects with target lesions 
(including or excluding non-target lesions) 
Target lesion 
Non-target lesions 
New lesions 
Overall remission 
CR 
CR 
No 
CR 

58 
 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
Cannot evaluate 
No 
PR 
PR 
Non-progressive or incompletely 
assessable 
No 
PR 
SD 
Non-progressive or incompletely 
assessable 
No 
SD 
Cannot 
be 
fully 
evaluated 
Non-progressive 
No 
NE 
PD 
Any case 
Yes or no 
PD 
Any case 
PD 
Yes or no 
PD 
Any case 
Any case 
yes 
PD 
CR 
= 
complete 
remission 
PR = partial response 
SD = stable 
disease 
PD = progressive 
disease 
NE = Not Evaluable 
 
Table b  
Evaluation at each time point - Subjects with only non-target lesions 
Non-target lesions 
New lesions Overall remission 
CR 
No 
CR 
Non-CR or non-PD 
No 
Non-CR or non-PD 
Cannot fully evaluate No 
Cannot evaluate 
Unknown PD 
Yes or no 
PD 
Any case 
yes 
PD 
Note: For non-target lesions, "non-CR/non-PD" refers to an efficacy that is better than 
SD. As SD is increasingly used as an endpoint for evaluating efficacy, the efficacy of 
non-CR/non-PD is formulated to address situations where no lesions can be measured. 
For ambiguous progression findings (eg, very small indeterminate new lesions; cystic 
or necrotic changes in existing lesions), treatment can be continued until the next 
evaluation. If disease progression is confirmed at the next evaluation, the progression 

59 
 
date should be the date of the previous suspected progression. 
Table c  
 
Best overall efficacy for CR and PR that needs to be confirmed 
Total response 
at the first time 
point 
Total response 
at subsequent 
time points 
Best overall response 
CR 
CR 
CR 
CR 
PR 
SD, PD or PR a 
CR 
SD 
If SD lasts long enough, it is SD, otherwise it should be PD 
CR 
PD 
If SD lasts long enough, it is SD, otherwise it should be PD 
CR 
NE 
If SD lasts long enough, it is SD, otherwise it should be 
NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
If SD lasts long enough, it is SD, otherwise it should be PD 
PR 
NE 
If SD lasts long enough, it is SD, otherwise it should be 
NE 
NE 
NE 
NE 
Note: CR means complete remission, PR means partial remission, SD means stable 
disease, PD means progressive disease, and NE means not evaluable. Superscript "a": 
If CR actually occurs at the first time point, and any disease appears at a subsequent 
time point, then even if the subject's efficacy reaches the PR standard relative to the 
baseline, the efficacy evaluation at the subsequent time point will still be PD (because 
the disease will reappear after CR). The best response depends on whether SD occurs 
within the shortest treatment interval. However, sometimes the first evaluation is CR, 
but the scans at subsequent time points seem to still appear, so the subject's efficacy at 
the first time point should actually be PR rather than CR. In this case, the first CR 
judgment should be modified to PR, and the best response is PR. 

60 
 
2.5. Frequency of tumor re-evaluation 
The frequency of tumor reassessment during treatment depends on the treatment 
regimen and should be consistent with the type and schedule of treatment. However, 
in phase II trials where the benefit of treatment is unclear, follow-up every 6 to 8 
weeks (timed at the end of a cycle) is reasonable, and the length of the interval can be 
adjusted in special protocols or circumstances. The protocol should specify which 
tissue sites require baseline assessment (usually those that are most likely to be 
closely related to metastatic lesions of the tumor type being studied) and the 
frequency of re-evaluation. Under normal circumstances, target lesions and non-target 
lesions should be evaluated at every assessment. In some optional situations, the 
frequency of evaluation of certain non-target lesions can be less frequent, for example, 
bone scans should be repeated only when the efficacy evaluation of the target disease 
confirms a CR or when bone lesions are suspected to have progressed. 
After treatment, re-evaluation of the tumor depends on whether the response rate or 
the time to a certain event (progression/death) is used as the endpoint of the clinical 
trial. If it is the time to a certain event (such as TTP/DFS/PFS), regular repeated 
evaluations specified in the protocol are required. Especially in randomized 
comparative trials, the scheduled evaluation should be listed in the schedule (such as 6 
to 8 weeks during treatment, or 3 to 4 months after treatment) and should not be 
affected by other factors, such as treatment delays, dosing intervals, and any other 
events that may lead to imbalances in the treatment arm in the choice of disease 
evaluation time. 
2.6. Efficacy evaluation/confirmation of remission 
2.6.1. Confirmation 
For non-randomized clinical studies with efficacy as the primary endpoint, the 
efficacy of PR and CR must be confirmed to ensure that the efficacy is not the result 
of evaluation error. This also allows for a reasonable interpretation of the results when 
historical data are available, but the efficacy in the historical data of these trials should 

61 
 
also have been confirmed. However, in all other cases, such as randomized trials 
(Phase II or Phase III) or studies with disease stabilization or disease progression as 
the primary endpoint, efficacy confirmation is no longer required because it has no 
value for the interpretation of the trial results. However, the cancellation of the 
requirement for efficacy confirmation will make central review to prevent bias more 
important, especially in non-blind experimental studies. 
In the case of SD, at least one measurement met the SD criteria specified in the 
protocol within the shortest time interval after the start of the trial (generally no less 
than 6–8 weeks). 
2.6.2 Total remission period 
The duration of overall remission is the time from the first measurement of meeting 
the CR or PR (whichever is measured first) criteria to the first real documented 
disease relapse or progression (the minimum measurement recorded in the trial is used 
as a reference for disease progression). The duration of overall complete remission is 
the time from the first measurement of meeting the CR criteria to the first real 
documented disease relapse or progression. 
2.6.3. Stable disease phase 
It is the time from the start of treatment to disease progression (or, in randomized 
trials, from the time of randomization), with the smallest sum in the trial as the 
reference (if the baseline sum is the smallest, it is used as the reference for PD 
calculation). The clinical relevance of disease stabilization varies from study to study 
and disease to disease. If, in a particular trial, the proportion of patients who maintain 
a minimum stable disease duration is used as the study endpoint, the protocol should 
specify the minimum time interval between the two measurements used in the 
definition of SD. 
Note: Remission, stable period, and PFS are affected by the frequency of follow-up 
after baseline evaluation. Defining standard follow-up frequency is beyond the scope 
of this guideline. Follow-up frequency should take into account many factors, such as 

62 
 
disease type and stage, treatment duration, and standard specifications. However, if 
comparisons between trials are required, the limitations of the accuracy of these 
measurement endpoints should be considered. 
 
 

63 
 
12.3 Contents of subject management 
1. Subject recruitment 
The requirements of the protocol should be fully reviewed, the feasibility of subject 
recruitment should be evaluated, and a subject recruitment plan and schedule that is in 
line with the actual situation of the center should be developed. If there are competing 
trial projects, full coordination work should be done. Potential subjects can be found 
and contacted through existing past patient medical records. If necessary, recruitment 
advertisements can be considered to expand the scope of recruitment. Recruitment 
advertisements must be issued after obtaining ethical approval. 
2. Reception of the Subjects 
We should try to create a reception environment that is conducive to the subjects' 
relaxation and allocate enough time for the subject reception. A hasty visit reception 
may lead to insufficient communication and even make the subjects feel unhappy. 
Therefore, it is necessary to arrange the subject reception at a relatively free time, or 
designate a dedicated subject reception staff, and try to keep the reception staff stable. 
3. Entry/Exit Records 
After the subject submits a written informed consent, the screening phase begins. 
After the screening meets the inclusion criteria, the subject formally enters the trial. 
Researchers should record the screening and inclusion information of this process. 
During the subject's participation in the trial, their visits and missed visits should be 
recorded, and after the last visit, the subject's exit record should be completed. 
4. Subject guidance 
During the research process, the subjects should be actively guided to comply with 
and cooperate with the trial process. Even if the research project has a universal 
subject guide, the research center needs to prepare a written guidance document to 
inform the subjects in detail where and who to find in the center to complete each 
process. Such a document will greatly reduce the workload of subject managers and 
researchers. 
 
 

64 
 
12.4 Nutritional risk screening form (NRS2002) 
The total score of NRS (nutrition risk screening, NRS2002) includes the sum of three 
parts, namely the disease severity score + nutritional status reduction score + age 
score (add 1 point if over 70 years old). 
1. NRS (2002) scores and definitions for reduced nutritional status: 
(1) 0 points: Definition - Normal nutritional status 
(2) Mild (1 point): Definition: 5% body weight loss or food intake of 50% to 75% of 
normal requirement within 3 months. 
(3) Moderate (2 points): Definition: 5% body weight loss within 2 months or food 
intake in the previous week is 25% to 50% of normal requirement. 
(4) Severe (3 points): Definition: 5% body weight loss within 1 month (15% body 
weight loss within 3 months) or BMI < 18.5 or food intake in the previous week was 
0% to 25% of normal requirement. 
(Note: If any of the three questions are met, the score will be based on that score; if 
several of them are met, the higher score will be used as the basis) 
 
2. NRS (2002) scores and definitions for disease severity: 
(1) 1 point: A patient with a chronic disease is hospitalized due to complications. The 
patient is weak but does not need to be bedridden. The protein requirement is slightly 
increased, but can be compensated by oral supplements; 
(2) 2 points: The patient needs to stay in bed, such as after major abdominal surgery. 
The protein requirement increases accordingly, but most people can still recover with 
parenteral or enteral nutrition support; 
(3) 3 points: The patient is on mechanical ventilation support in the intensive care unit. 
The protein requirement increases and cannot be compensated by parenteral or enteral 
nutrition support. However, parenteral or enteral nutrition support can significantly 
reduce protein breakdown and nitrogen loss. 
 
3. Relationship between scoring results and nutritional risk: 

65 
 
(1) A total score ≥ 3 points (or pleural effusion, ascites, edema and serum protein < 35 
g/L) indicates that the patient is malnourished or at nutritional risk, and nutritional 
support should be used. 
(2) Total score < 3 points: Nutritional assessment will be reviewed weekly. If the 
result of subsequent reviews is ≥ 3 points, the nutritional support program will be 
initiated. 
(3) If the patient is planning to undergo major abdominal surgery, the new score (2 
points) will be used during the first assessment, and the need for nutritional support 
(≥3 points) will be determined based on the new total score. 
 
 

66 
 
12.5 Quality of life score (QoL) of cancer patients 
In 1990, my country formulated a draft with reference to foreign indicators. The 
standards are as follows (scores are in brackets): 
1. Appetite: ① Almost unable to eat; ② Food intake < 1/2 of normal; ③ Food 
intake is 1/2 of normal; ④ Food intake is slightly less; ⑤ Food intake is normal. 
2. Mental state: ① Very poor; ② Poor; ③ Influenced, but sometimes better and 
sometimes worse; ④ Fairly good; ⑤ Normal, the same as before illness. 
3. Sleep: ①Difficulty falling asleep; ②Very poor sleep; ③Poor sleep; ④Slightly 
poor sleep; ⑤Generally normal. 
4. Fatigue: ① Often tired; ② Feeling weak; ③ Sometimes tired; ④ Sometimes 
slightly tired; ⑤ No feeling of fatigue. 
5. Pain: ① severe pain with passive posture or pain duration for more than 6 months; 
② severe pain; ③ moderate pain; ④ mild pain; ⑤ no pain. 
6. Family understanding and cooperation: ① No understanding at all; ② Poor; ③ 
Average; ④ Family understanding and care are relatively good; ⑤ Good. 
7. Understanding and cooperation from colleagues (including leaders): ① All 
understand and no one cares; ② Poor; ③ Average; ④ A few people understand 
and care; ⑤ Most people understand and care. 
8. Self-understanding of cancer: ① Disappointed, completely uncooperative; ② 
Uneasy, reluctantly cooperating; ③ Uneasy but moderately cooperative; ④ Uneasy, 
but able to cooperate relatively well; ⑤ Optimistic and confident. 
9. Attitude towards treatment: ① No hope for treatment; ② Half-believing and 
half-doubting the treatment; ③ Hope to see the effect but afraid of side effects; ④ 
Hope to see the effect and still able to cooperate; ⑤ Have confidence and actively 
cooperate. 
10. Daily life: ① Bedridden; ② Able to move, but need to stay in bed most of the 
time; ③ Able to move, sometimes bedridden; ④ Live a normal life, unable to work; 
⑤ Live and work normally. 
11. Side effects of treatment: ① Severely affect daily life; ② Affect daily life; ③ 

67 
 
No impact on daily life after symptomatic treatment; ④ No impact on daily life 
without symptomatic treatment; ⑤ No impact on daily life. 
12. Facial expressions: divided into levels ①-⑤. 
The quality of life grading currently in trial is as follows: the full score for quality of 
life is 60 points, extremely poor quality of life is <20 points, poor quality of life is 
21-30 points, average quality of life is 31-40 points, better quality of life is 41-50 
points, and good quality of life is 51-60 points. 
 
 

68 
 
12.6 Scoring criteria and calculation method of Charlson Comorbidity Index 
1. Significance: to assess the effects of specific medical interventions and screening 
measures on patients' life expectancy. 
2. 
Comorbidity score 
Score 
Disease 
Score 
1 
□Coronary artery disease 
□Congestive heart failure 
□Chronic lung disease 
□Peptic ulcer disease  
□Peripheral vascular disease 
□Mild liver disease 
□Cerebrovascular disease 
□Connective tissue disease 
□Diabetes 
 
2 
□Dementia 
□Hemiplegia 
□Moderate to severe renal 
□Disease diabetes associated 
with organ damage 
□Any tumor in five years 
□Leukemia 
□Lymphoma 
 
3 
□Moderate 
to 
severe 
liver 
disease 
 
 
6 
□Metastatic solid tumors 
□Acquired Immune Deficiency 
Syndrome (AIDS) 
 
 
Total score 
 
3.  Age rating 
1)  Age < 50: 0 points 
2)  50-59 years old: 1 point 
3)  60-69 years old: 2 points 
4)  70-79 years old: 3 points 
4.  Results Analysis 
A.  Calculate the Charlton index (i) 
1)  The sum of comorbidity index and age index = i 
B. Calculate the Charlton probability (10-year survival rate) 

69 
 
1) Y = e (ix0.9) 
2) Z=0.983Y, which is the patient's ten-year survival rate. 
 
 

70 
 
12.7 Quality of life score (QoL) evaluation table 
Below is a list of statements that other people with your illness have said are 
important. Please circle or mark one number per line to indicate your response 
as it applies to the past 7 days. 
 
 
 
 

71 
 
 
Please circle or mark one number per line to indicate your response as it applies 
to the past 7 days. 
 
 
 
 
 
 
 
 
 

72 
 
 
Please circle or mark one number per line to indicate your response as it applies 
to the past 7 days. 
 
 
 

73 
 
12.8 Nutritional assessment 
Subjective overall nutritional status rating 
scale provided by the patient 
Scored Patient-Generated Subjective Global Assessment (PG-SGA) 
 
PG-SGA scoring worksheet 
Worksheet -1 score for weight loss 
One month's body weight data were used for scoring, or six months' body weight data were used if 
no such data were available. The following scores were used for scoring, and an additional one 
point was added if body weight was lost within the last two weeks. 
 
Weight loss within 1 
month 
mark 
Weight loss within 6 
months 
10% or more 
four 
20% or more 
5~9.9% 
three 
10~19.9% 
3~4.9% 
2 
6~9.9% 
2~2.9% 
one 
2~5.9% 
0~1.9% 
0 
0~1.9% 
Scoring (Box 1) 
 
Worksheet -2 Scoring Criteria for Disease and Age 
 
 
 
 
 
 
Scoring (Box 5) 
 
Worksheet -3 scoring of metabolic stress state 
 
Stress state 
None (0) 
Mild (1) 
Moderate (2) 
Height (3) 
classify 
mark 
cancer 
one 
AIDS 
one 
Pulmonary 
or 
cardiac 
cachexia 
 
one 
Bedsore, open wound or 
fistula 
one 
wound 
one 
Age ≥65 years old 
one 

74 
 
generate heat 
without 
37.2~38.3℃ 
38.3~38.8℃ 
≥38.8℃ 
Duration of fever 
without 
<72hrs 
72hrs 
>72hrs 
Glucocorticoid 
dosage 
(prednisone /d) 
without 
<10mg 
10~30mg 
≥30mg 
Scoring (Box 6) 
 
Worksheet -4 Physical Examination 
 
 
No 
consumption: 0 
Mild 
consumption: 
1+ 
Moderate 
consumption: 
2+ 
Severe 
consumption: 3+ 
fat 
Orbital fat pad 
Triceps skinfold 
thickness 
subcostal fat 
 
0 
0 
0 
 
1+ 
1+ 
1+ 
 
2+ 
2+ 
2+ 
 
3+ 
3+ 
3+ 
muscle 
temporalis 
Shoulder and 
back 
Chest and 
abdomen 
arms and legs 
 
0 
0 
0 
0 
 
1+ 
1+ 
1+ 
1+ 
 
2+ 
2+ 
2+ 
2+ 
 
3+ 
3+ 
3+ 
3+ 
body fluid 
Ankle edema 
Sacral edema 
ascites 
 
0 
0 
0 
 
1+ 
1+ 
1+ 
 
2+ 
2+ 
2+ 
 
3+ 
3+ 
3+ 
Total 
consumptive 
Subjective 
evaluation 
0 
one 
2 
three 
Scoring (Box 7) 
 
Worksheet -5 PG-SGA overall rating scale 
 
 
Level a 
Good nutrition 
b grade 
Moderate or 
suspected 
malnutrition 
Class c 
Severe malnutrition 
weight 
No 
loss 
or 
recent 
increase 
5% lost within 1 month 
(or 10% in June) or 
> 5% in 1 month (or > 
10% in 6 months) or 

75 
 
Unstable 
or 
not 
increasing 
Unstable 
or 
not 
increasing 
Nutritional 
intake 
No shortage or 
Recent 
significant 
improvement 
Decreased exact intake 
Severe 
inadequate 
intake 
Nutrition-related 
symptoms 
None 
or 
recent 
significant 
improvement 
Adequate intake 
There 
are 
nutrition 
related symptoms 
Box 3 
There are nutrition 
related symptoms 
Box 3 
function 
No shortage or 
Recent 
significant 
improvement 
Moderate hypofunction 
or recent exacerbation 
Box 4 
Severe 
hypofunction 
or 
recent 
marked 
aggravation of Box 4 
physical 
examination 
No consumption or 
chronic consumption 
but 
recent 
clinical 
improvement 
Mild 
to 
moderate 
subcutaneous fat and 
muscle consumption 
Apparent 
signs 
of 
malnutrition 
Such 
as 
severe 
subcutaneous 
tissue 
consumption, edema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

76 
 
 
Subjective overall nutritional status rating 
scale provided by the patient 
Scored Patient-Generated Subjective Global Assessment (PG-SGA) 
 
PG-SGA history questionnaire 
In the PG-SGA design, BOXs 1–4 are performed by the patient, where the scores of BOXs 1 and 3 
are the accumulation of each score, and the scores of Box 2 and 4 are based on the highest score 
verified by the patient. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.
Weight (see sheet 1) 
My weight is kg now 
My height is meters 
My weight was kg a month ago 
My weight was kilograms six months 
ago 
My weight in the last 2 weeks: 
□ decreased (1)□ no change (0)□ 
increased (0) 
1.
Dietary intake (meal size) 
How much did I eat last month 
compared to my normal diet: □ No 
change (0) 
□ greater than normal (0) 
□ less than normal (1) 
I am eating now: 
-common food but less than normal 
meal (1) 
□ few solid foods (2) 
□ Dried food (3) 
□ only for nutritional additives (4) 
□ Various foods are scarce (5) 
4.
symptom 
 
I have had the following problems that affect 
my appetite for the last 2 weeks: 
□ No eating problems (0) 
-no appetite, don't want to eat (3) 
-nausea (1)-vomiting (3) 
□ constipation (1)□ diarrhea (3) 
□ Oral pain (2)□ Oral dryness (1) 
□ Abnormal taste or no (1) □ Food odor 
interference (1) 
□ dysphagia (2)□ early satiety (1) 
□ Pain; Location? （3） 
□ Other **(1) 
* * For example: low spirits, money or 
dental problems
3.
Activities and functions 
My overall activities last month were: 
□ normal, unlimited (0) 
-slightly worse than usual, but still can 
normal activities (1) 
-most things can't do, but the time of bed or 
sitting less than 12 hours heart (2) 
-little activity, most of the day in bed or 
sitting (3) 
Box 1-4 total score (a): 
5. Illness and its relationship to nutritional needs (see worksheet 2) 
All relevant diagnostics (detailed description): 
Primary disease staging: Ⅰ Ⅱ Ⅲ Ⅳ other 
age 
Scoring: 
6. Metabolic requirements (see worksheet 3) 
Scoring: 
7. Physical examination (see worksheet 4) 
Scoring:

77 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient Name: Age: Hospitalization Number: Clinical Doctor Signature Record Date: 
 
 
 
Overall rating (see worksheet 2) 
Grade A Good Nutrition 
Grade 
B 
moderate 
or 
suspected 
malnutrition 
PG-SGA total score 
Score A+B+C+D 
Recommendations for Nutrition Support 
Appropriate nutritional interventions, including education and guidance for patients and their 
families, symptom-specific treatments such as drug intervention, and appropriate nutritional 
support were determined based on the overall PG-SGA score. 
0-1 At this time, nutrition status was scored regularly without intervention. 
2-3 A dietician, nurse or clinician shall provide education and guidance to the patients and their 
families, and appropriate drug intervention shall be conducted for symptoms and 
laboratory tests. 
4-8 Need nutrition intervention and symptomatic treatment 
Patients ≥9 years old need symptomatic treatment and appropriate nutritional support 
 
≥9 Treatment measures to improve symptoms and appropriate nutritional support are urgently 
needed