GastroIntestinal Cancer in Children and Adolescents (GICCA): a SEER Population-based Study
Conditions: Gastrointestinal Cancer, Colorectal Cancer, Gastric Cancer, Hepatoblastoma, Hepatocellular Carcinoma, Burkitt Lymphoma, Neuroendocrine Tumors
Sponsor: Paul G. Kemps, MD

Research protocol 
                 GI cancer in children and adolescents 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
GastroIntestinal Cancer in Children and 
Adolescents (GICCA study) 
(Version November 2022) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Research protocol 
                 GI cancer in children and adolescents 
 
 
 
PROTOCOL TITLE: ‘Gastrointestinal cancer in children and adolescents (GICCA): a 
SEER population-based study’ 
Protocol ID 
GICCA 
Short title 
GI cancer in children and adolescents 
EudraCT number  
N/A 
Version 
1 
Date 
November 6, 2022 
Coordinating investigators  
/project leaders 
 
Caroline E. Veldhuis-Hogen Esch, M.D. Ph.D. 
Division of Pediatric Gastroenterology  
Juliana Children’s Hospital 
c.veldhuis-hogenesch@hagaziekenhuis.nl 
 
Daniëlle M. Hendriks, M.D.  
Division of Pediatric Gastroenterology  
Juliana Children’s Hospital 
d.hendriks@hagaziekenhuis.nl  
Principal investigator  
 
Paul G. Kemps, M.D. 
(1) Department of Pathology 
Leiden University Medical Center 
(2) Division of Pediatric Gastroenterology  
Juliana Children’s Hospital 
p.g.kemps@lumc.nl  
Sponsor  
Paul G. Kemps (Sponsor-Investigator) 
Subsidising party 
N/A 
Independent expert(s) 
N/A 

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PROTOCOL SIGNATURE SHEET
Name
Signature
Date
Principal investigator:
Paul G. Kemps, M.D.
Hot/uvjber
-
Study statistician:
Jelle J, Goeman, Ph.D.
Professor of Biostatistics
Dept. of Biomedical Data Sciences
Leiden University Medical Center

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TABLE OF CONTENTS 
 
1. INTRODUCTION AND RATIONALE ............................................................................. 9 
2. OBJECTIVES .................................................................................................................. 11 
3. STUDY DESIGN ............................................................................................................. 12 
4. STUDY POPULATION .................................................................................................. 13 
4.1 
Population (base) .................................................................................................... 13 
4.2 
Inclusion criteria ...................................................................................................... 13 
4.3 
Exclusion criteria ..................................................................................................... 13 
4.4 
Sample size calculation ......................................................................................... 13 
5. TREATMENT OF SUBJECTS ..................................................................................... 14 
5.1 
Investigational product/treatment ......................................................................... 14 
5.2 
Use of co-intervention (if applicable) ................................................................... 14 
5.3 
Escape medication (if applicable)......................................................................... 14 
6. INVESTIGATIONAL PRODUCT .................................................................................. 15 
6.1 
Name and description of investigational product(s) .......................................... 15 
6.2 
Summary of findings from non-clinical studies ................................................... 15 
6.3 
Summary of findings from clinical studies ........................................................... 15 
6.4 
Summary of known and potential risks and benefits ......................................... 15 
6.5 
Description and justification of route of administration and dosage ............... 15 
6.6 
Dosages, dosage modifications and method of administration ....................... 15 
6.7 
Preparation and labelling of Investigational Medicinal Product ....................... 15 
6.8 
Drug accountability ................................................................................................. 15 
7. NON-INVESTIGATIONAL PRODUCT ........................................................................ 16 
7.1 
Name and description of non-investigational product(s) .................................. 16 
7.2 
Summary of findings from non-clinical studies ................................................... 16 
7.3 
Summary of findings from clinical studies ........................................................... 16 
7.4 
Summary of known and potential risks and benefits ......................................... 16 
7.5 
Description and justification of route of administration and dosage ............... 16 
7.6 
Dosages, dosage modifications and method of administration ....................... 16 
7.7 
Preparation and labelling of Non Investigational Medicinal Product .............. 16 
7.8 
Drug accountability ................................................................................................. 16 
8. METHODS ....................................................................................................................... 17 
8.1 
Study parameters/endpoints ................................................................................. 20 
8.1.1 
Main study parameter/endpoint ..................................................................... 20 
8.1.2 
Secondary study parameters/endpoints ...................................................... 20 
8.1.3 
Other study parameters (if applicable) ......................................................... 21 
8.2 
Randomisation, blinding and treatment allocation ............................................. 21 
8.3 
Study procedures .................................................................................................... 21 
8.4 
Withdrawal of individual subjects ......................................................................... 21 
8.4.1 
Specific criteria for withdrawal (if applicable) .............................................. 21 
8.5 
Replacement of individual subjects after withdrawal......................................... 21 
8.6 
Follow-up of subjects withdrawn from treatment ............................................... 21 
8.7 
Premature termination of the study ...................................................................... 21 
9. SAFETY REPORTING .................................................................................................. 22 
9.1 
Temporary halt for reasons of subject safety ..................................................... 22 
9.2 
AEs, SAEs and SUSARs ....................................................................................... 22 
9.2.1 
Adverse events (AEs) ..................................................................................... 22 
9.2.2 
Serious adverse events (SAEs) .................................................................... 22 

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9.2.3 
Suspected unexpected serious adverse reactions (SUSARs) ................. 22 
9.3 
Annual safety report ............................................................................................... 22 
9.4 
Follow-up of adverse events ................................................................................. 22 
10. 
STATISTICAL ANALYSIS ......................................................................................... 23 
10.1 
Primary study parameter(s) ............................................................................... 23 
10.2 
Secondary study parameter(s) .......................................................................... 24 
10.3 
Other study parameters ...................................................................................... 26 
10.4 
Interim analysis (if applicable) ........................................................................... 27 
11. 
ETHICAL CONSIDERATIONS ................................................................................. 28 
11.1 
Regulation statement .......................................................................................... 28 
11.2 
Recruitment and consent ................................................................................... 28 
11.3 
Objection by minors or incapacitated subjects (if applicable) ...................... 28 
11.4 
Benefits and risks assessment, group relatedness ....................................... 28 
11.5 
Compensation for injury ..................................................................................... 28 
11.6 
Incentives (if applicable) ..................................................................................... 28 
12. 
ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION ................ 29 
12.1 
Handling and storage of data and documents ................................................ 29 
12.2 
Monitoring and Quality Assurance .................................................................... 29 
12.3 
Amendments ........................................................................................................ 29 
12.4 
Annual progress report ....................................................................................... 29 
12.5 
Temporary halt and (prematurely) end of study report .................................. 29 
12.6 
Public disclosure and publication policy .......................................................... 29 
13. 
STRUCTURED RISK ANALYSIS ............................................................................ 30 
13.1 
Potential issues of concern ................................................................................ 30 
13.2 
Synthesis .............................................................................................................. 30 
14. 
REFERENCES ............................................................................................................ 31 

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LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS  
 
ABR 
General Assessment and Registration form (ABR form), the 
application form that is required for submission to the accredited 
Ethics Committee; in Dutch: Algemeen Beoordelings- en 
Registratieformulier (ABR-formulier) 
AE 
Adverse Event 
AR 
Adverse Reaction 
CA 
Competent Authority 
CCMO 
Central Committee on Research Involving Human Subjects; in 
Dutch: Centrale Commissie Mensgebonden Onderzoek 
CV 
Curriculum Vitae 
DSMB 
Data Safety Monitoring Board 
EU 
European Union 
EudraCT European drug regulatory affairs Clinical Trials  
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation; in Dutch: Algemene 
Verordening Gegevensbescherming (AVG) 
IB 
Investigator’s Brochure 
IC 
Informed Consent 
IMP 
Investigational Medicinal Product  
IMPD 
Investigational Medicinal Product Dossier  
METC  
Medical research ethics committee (MREC); in Dutch: medisch-
ethische toetsingscommissie (METC) 
(S)AE 
(Serious) Adverse Event  
SPC 
Summary of Product Characteristics; in Dutch: officiële 
productinformatie IB1-tekst 
Sponsor The sponsor is the party that commissions the organisation or 
performance of the research, for example a pharmaceutical 
company, academic hospital, scientific organisation or 
investigator. A party that provides funding for a study but does 
not commission it is not regarded as the sponsor, but referred to 
as a subsidising party. 
SUSAR  
Suspected Unexpected Serious Adverse Reaction 

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UAVG 
Dutch Act on Implementation of the General Data Protection 
Regulation; in Dutch: Uitvoeringswet AVG 
WMO 
Medical Research Involving Human Subjects Act; in Dutch: Wet 
Medisch-wetenschappelijk Onderzoek met Mensen 
 
 

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SUMMARY 
 
Rationale: Gastrointestinal malignancies are rare in children and adolescents. 
Consequently, data on clinical features, treatments and outcomes of these patients 
are limited. 
Objective: We aim to describe the patient and tumor characteristics, treatments, and 
outcomes of children and adolescents diagnosed with primary gastrointestinal 
malignancies, and to analyze these data for trends over time. In addition, we want to 
explore independent prognostic factors for overall survival. Finally, we want to 
describe subsequent primary malignancies diagnosed among patients from the study 
cohort, as well as to calculate their risk of developing a second primary cancer 
relative to the general population. Data on children (aged 0-17 years at diagnosis) 
and young people aged 18-24 years at diagnosis are analyzed separately. Special 
focus is laid on patients with primary carcinomas of the gastrointestinal tract; 
particularly colorectal carcinoma.  
Study design: This is an observational population-based cohort study based on the 
publicly available Surveillance, Epidemiology, and End Results (SEER) database.  
Study population: Children (aged 0-17 years) and young people aged 18-24 years 
with a diagnosis of a primary gastrointestinal malignancy registered as their first 
primary malignancy in the SEER 17 database between 2000 and 2019.  
Intervention: Not applicable. 
Main study parameters/endpoints: Descriptive statistics of patient and tumor 
characteristics at diagnosis, first course treatments, overall survival, and subsequent 
primary malignancies. 
Secondary study parameters/endpoints: 1) Time trends in incidence, stage at 
diagnosis, first course treatments, mortality, and overall survival. 2) Associations 
between the variables age at diagnosis, sex, race and origin, year of diagnosis, stage 
at diagnosis, and histologic category (when relevant) with overall survival in 
multivariable analysis. 3) Standardized incidence of second primary malignancies in 
patients who survived (i) two or more months, or (ii) five or more years after initial 
gastrointestinal cancer diagnosis, relative to the general population. 
Nature and extent of the burden and risks associated with participation, benefit 
and group relatedness: No burden and/or risks; no benefit. 

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1. INTRODUCTION AND RATIONALE 
 
Gastrointestinal (GI) malignancies – also called “digestive cancers” – are rare in 
children and adolescents1. These malignancies develop in the GI tract and/or 
accessory digestive organs, including the liver, biliary tract and pancreas2,3. Notably, 
the mouth, pharynx and salivary glands are also part of the GI system, but 
malignancies in these locations are generally classified within the group of head and 
neck cancers3,4. Therefore, like in prior studies of digestive cancers2, these 
malignancies are not investigated in this study; the term “GI tract” is used to refer to 
the alimentary canal running from the esophagus to the anus. Because of the rarity of 
GI malignancies in children and adolescents, data on clinical features, treatments 
and outcomes of these patients are limited. 
 
Childhood is defined as the developmental period between 0 and 17 years of age5. 
Importantly, much debate still exists about the definition of adolescence5,6. The 
United Nations (UN) and World Health Organization define adolescence as the 
period between 10 and 19 years of age. However, this definition dates back to the 
mid-20th century, with significant changes in human biological and social 
development since that time5. Therefore, Sawyer et al. recently proposed an 
expanded definition of adolescence, which encompasses the period between 10 and 
24 years of age5. This new definition overlaps with those of the terms youth (defined 
by the UN as people aged 15-24 years) and young people (defined as people aged 
10-24 years)5,6. Adolescents have often been overlooked in health care, research 
and policy7; one growing response is that from pediatricians to more embrace 
adolescent health8. A recent survey among pediatricians in high-income North 
America revealed a mean preferred upper age limit of pediatric practice of 21.7 
years, which was significantly higher than the mean current upper age limit of the 
pediatricians’ practices of 19.2 years8. To comply with this increasing focus of 
pediatricians on adolescent health, our study will include patients aged 0-24 years at 
primary gastrointestinal cancer diagnosis. Yet, the upper age limit of pediatric care is 
still below 18 years in many – particularly lower-income – countries8. Therefore, data 
on children (aged 0-17 years) and young people aged 18-24 years will be 
(preferably) analyzed separately – to ensure that the study results are appropriate to 
readers from different health care settings. 

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One common site of GI malignancies in children and adolescents is the liver. There 
are different types of primary liver cancer. The most common types in children are 
hepatoblastoma (HB), hepatocellular carcinoma (HCC) and undifferentiated 
embryonal sarcoma of the liver (UESL)9. Several (population-based) cohort studies 
investigating children and/or adolescents with hepatic malignancies have already 
been published10–13. However, a comprehensive overview of population-based data 
on the different hepatic malignancies and other gastrointestinal cancers in children 
and adolescents is still lacking. Regarding malignancies with the GI tract as their 
primary site, lymphoma is one of the most common subtypes in children – often 
representing intestinal Burkitt lymphoma (BL)1. Although the true primary site of 
hematologic malignancies is the hematopoietic system, we deliberately do not 
exclude these malignancies, because we want to investigate all cancers with the GI 
system as their primary location. Several (population-based) cohort studies 
investigating children and/or adolescents with BL have been published1,14; however, 
these did not specifically focus on patients with gastrointestinal BL. Finally, limited 
data is currently available on children and adolescents with primary carcinomas of 
the GI tract, which predominantly include colorectal carcinoma (CRC) and gastric 
carcinoma (GC)15–18. To address this limited data, our study will focus on patients 
with these rare cancers. 
 
Lastly, recent studies have identified genetic predisposition in a significant proportion 
of children and adolescents with cancer, including young people with colorectal 
cancer19,20. This partly explains the increased risk of subsequent malignant 
neoplasms among childhood cancer survivors21. In addition, specific treatments can 
also increase the risk of second primary malignancies (SPM)22. Many prior studies 
have investigated SPM in five-year childhood and/or adolescent cancer survivors22–
27. These studies exclude second cancers diagnosed within five years of initial cancer 
diagnosis; thereby, they reduce surveillance bias. However, recent population-based 
studies investigating SPM in children with cancer that survived two or more months 
revealed that a significant proportion of second cancers actually develop within those 
first five years after initial cancer diagnosis28–30. In this study, the standardized 
incidence of SPM is therefore investigated in both groups: (i) patients that survived 
two or more months, and (ii) patients that survived five or more years after initial 
gastrointestinal cancer diagnosis. 

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2. OBJECTIVES 
 
Primary Objective: To describe the patient and tumor characteristics, first course 
treatments, survival and subsequent primary malignancies of children and 
adolescents diagnosed with primary gastrointestinal malignancies.  
 
Secondary Objective(s): 1) To investigate time trends in incidence, stage at 
diagnosis, first course treatments, mortality, and overall survival. 2) To explore 
independent prognostic factors for overall survival. 3) To calculate the standardized 
incidence of second primary malignancies in childhood and adolescent 
gastrointestinal cancer survivors, relative to the general population. 

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3. STUDY DESIGN 
 
This is an observational population-based cohort study based on publicly available 
data of the Surveillance, Epidemiology, and End Results (SEER) database. The 
SEER Program collects cancer incidence and survival data from multiple population-
based cancer registries in the United States of America (U.S.). SEER began 
collecting data in 1973 with a limited number of registries. Since 1973, the SEER 
Program has been expanded to cover numerous additional areas. SEER 17 is the 
largest registry grouping with complete data, and includes cancer cases registered 
from 2000 onwards in 17 cancer registries covering approximately 26.5% of the U.S. 
population (https://seer.cancer.gov/registries/data.html). Importantly, SEER 
recommends that when performing an analysis, researchers subset based on year or 
registry so that they have consistent geographic coverage for the period of the 
analysis. Accordingly, SEER does not provide datasets with varying registries and 
years of data (e.g. 1975-2000 data from SEER 8 registries and 2000-2019 data from 
SEER 17 registries). SEER 17 incidence data is used for this study, because the 
SEER 17 database contains the most cancer cases to investigate, when compared to 
SEER 12 (1992-2019) or SEER 8 (1975-2019) (https://seer.cancer.gov/data-
software/documentation/seerstat/nov2021/).  
 
The SEER Program registries routinely collect data on patient demographics, primary 
tumor site, tumor morphology, stage at diagnosis, first course of treatment, and 
follow-up for vital status. The mortality data reported by SEER are provided by the 
National Center for Health Statistics (NCHS). Notably, NCHS granted SEER 
permission to make available mortality data of the total U.S. population – based on 
death certificates – for the period 1969-2019. The population data used in calculating 
cancer rates is obtained from the Census Bureau.  
 
 

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4. STUDY POPULATION 
4.1 Population (base)  
All cases registered in the SEER 17 database between (and including) 2000 and 
2019 (last data year in the April 2022 SEER data release). 
 
4.2 Inclusion criteria 
In order to be eligible for this study, a case must meet all of the following criteria: 
 
• Age (at primary gastrointestinal cancer diagnosis) <25 years  
• Diagnosis of a primary gastrointestinal malignancy as an individual’s first 
primary malignancy, based on: 
➢ Primary site “digestive organs” (ICD-O-3 topography codes C015-C026) 
➢ Behavior code “malignant” (ICD-O-3 behavior code 3) 
 
Selection of only those cases with a primary gastrointestinal malignancy as their first 
primary malignancy is done by setting the Multiple Primary Selection option on the 
Selection tab of SEER*Stat software to First Malignant Primary Only (Non-reported 
Assumed Malignant). 
 
4.3 Exclusion criteria 
None 
 
4.4 Sample size calculation 
Not applicable, given that the primary objective of this study is of descriptive nature.  
 

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5. TREATMENT OF SUBJECTS 
Not applicable 
 
5.1 Investigational product/treatment 
Not applicable 
5.2 Use of co-intervention (if applicable) 
Not applicable 
5.3 Escape medication (if applicable) 
Not applicable 

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6. INVESTIGATIONAL PRODUCT  
Not applicable 
  
6.1 Name and description of investigational product(s) 
Not applicable 
6.2 Summary of findings from non-clinical studies 
Not applicable 
6.3 Summary of findings from clinical studies 
Not applicable 
6.4 Summary of known and potential risks and benefits 
Not applicable 
6.5 Description and justification of route of administration and dosage 
Not applicable 
6.6 Dosages, dosage modifications and method of administration 
Not applicable 
6.7 Preparation and labelling of Investigational Medicinal Product 
Not applicable 
6.8 Drug accountability 
Not applicable 
 

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7. NON-INVESTIGATIONAL PRODUCT 
Not applicable 
  
7.1 Name and description of non-investigational product(s) 
Not applicable 
7.2 Summary of findings from non-clinical studies 
Not applicable 
7.3 Summary of findings from clinical studies 
Not applicable 
7.4 Summary of known and potential risks and benefits 
Not applicable 
7.5 Description and justification of route of administration and dosage 
Not applicable 
7.6 Dosages, dosage modifications and method of administration 
Not applicable 
7.7 Preparation and labelling of Non Investigational Medicinal Product 
Not applicable 
7.8 Drug accountability 
Not applicable 
 

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8. METHODS 
 
A list of data items obtained from the SEER 17 database is provided in Table 1. 
 
Table 1. Retrieved SEER Research Plus Data Items 
Data Item name 
Category name 
Patient ID 
Other 
Age recode with single ages and 85+ 
Race and Age (case data only) or Age at Diagnosis 
Sex 
Race, Sex, Year Dx, Registry, County 
Race recode (White, Black, Other) 
Race, Sex, Year Dx, Registry, County 
Origin recode NHIA (Hispanic, Non-Hisp) 
Race and Age (case data only) or Race, Sex, Year Dx, Registry, County 
Race and origin recode (NHW, NHB, NHAIAN, NHAPI, Hispanic) 
Race and Age (case data only) or Race, Sex, Year Dx, Registry, County 
Year of diagnosis 
Race, Sex, Year Dx, Registry, County 
Sequence number 
Multiple Primary Fields 
Record number recode 
Multiple Primary Fields 
Total number of in situ/malignant tumors for patient 
Multiple Primary Fields 
Total number of benign/borderline tumors for patient 
Multiple Primary Fields 
First malignant primary indicator 
Multiple Primary Fields 
Primary by international rules 
Multiple Primary Fields 
Diagnostic Confirmation 
Site and Morphology 
Site recode ICD-O-3/WHO 2008 
Site and Morphology 
Site recode ICD-O-3/WHO 2008 (for SIRs) 
Site and Morphology 
Primary Site - labeled 
Site and Morphology 
Laterality 
Site and Morphology 
ICD-O-3 Hist/behav 
Site and Morphology 
Grade (thru 2017) 
Site and Morphology 
Grade Clinical (2018+) 
Site and Morphology 
Grade Pathological (2018+) 
Site and Morphology 
Site recode - rare tumors 
Site and Morphology 
ICCC site recode extended 3rd edition/IARC 2017 
Site and Morphology 
AYA site recode 2020 Revision 
Site and Morphology 
Lymphoid neoplasm recode 2021 Revision 
Site and Morphology 
SEER Brain and CNS Recode 
Site and Morphology 
TNM 7/CS v0204+ Schema (thru 2017) 
Site and Morphology 
CS Schema - AJCC 6th Edition 
Site and Morphology 
Schema ID (2018+) 
Site and Morphology 
AJCC ID (2018+) 
Site and Morphology 
EOD Schema ID Recode (2010+) 
Site and Morphology 
Combined Summary Stage (2004+) 
Stage - Summary/Historic 
Summary stage 2000 (1998-2017) 
Stage - Summary/Historic 
Derived EOD 2018 Stage Group (2018+) 
Stage - 8th edition 
Derived SEER Cmb Stg Grp (2016-2017) 
Stage - 7th edition 
Derived AJCC Stage Group, 7th ed (2010-2015) 
Stage - 7th edition 
Derived AJCC Stage Group, 6th ed (2004-2015) 
Stage - 6th edition 
SEER modified AJCC stage 3rd (1988-2003) 
Stage - Other 
Lymphoma - Ann Arbor Stage (1983-2015) 
Stage - Other 
Tumor Size Summary (2016+) 
Extent of Disease 
CS tumor size (2004-2015) 
Extent of Disease 
EOD 10 - size (1988-2003) 
Extent of Disease - Historic 
Months from diagnosis to treatment 
Therapy 
RX Summ--Surg Prim Site (1998+) 
Therapy 
Reason no cancer-directed surgery 
Therapy 
Radiation recode 
Therapy 
Chemotherapy recode (yes, no/unk) 
Therapy 
B Symptoms Recode (2010+) 
Site-Specific Data Items 
CEA Pretreatment Interpretation Recode (2010+) 
Site-Specific Data Items 
Survival months 
Cause of Death (COD) and Follow-up 
Survival months flag 
Cause of Death (COD) and Follow-up 
Vital status recode (study cutoff used) 
Cause of Death (COD) and Follow-up 
COD to site recode 
Cause of Death (COD) and Follow-up 
SEER cause-specific death classification 
Cause of Death (COD) and Follow-up 
SEER other cause of death classification 
Cause of Death (COD) and Follow-up 
 
Patients are categorized into two age groups: children (aged 0-17 years at diagnosis) 
and young people aged 18-24 years at primary gastrointestinal cancer diagnosis. In 
principle, data is analyzed and presented by 1-year age category or by age group 
(<18 or 18-24 years at diagnosis), except for age distributions of specific patient 
populations (e.g. patients with colorectal carcinoma). When data from children and 
young people aged 18-24 years are analyzed together, then this is clearly stated in 
the accompanying text. Race is categorized into White, Black, and Other. Origin is 
categorized into Hispanic and non-Hispanic. Together, race and origin are reported in 

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four mutually exclusive categories: non-Hispanic White, non-Hispanic Black, non-
Hispanic Other, and Hispanic (all races). 
 
Year of diagnosis is categorized into single years or four time periods of five years 
(2000-2004; 2005-2009; 2010-2014; 2015-2019). Gastrointestinal malignancies are 
classified into different subtypes based on the Rare Cancer Classification31. For this 
classification, the SEER Rare Cancer Classification variable is used 
(https://seer.cancer.gov/seerstat/variables/seer/raresiterecode/). In addition, some 
subtypes are specified with other selections – based on International Classification of 
Diseases for Oncology, third edition, second revision (ICD-O-3.2) codes – because 
they are not (separately) classified in the Rare Cancer Classification. A complete list 
of cancer subgroup selections is provided in Table 2.  
 
Table 2. Gastrointestinal cancer subtypes and their selection methods 
Group 
 
Source | Group(s) | Recode value(s) 
 
ICD-O-3.2 
Histology code(s) 
ICD-O-3.2  
Site code(s) 
Hematologic malignancies 
Rare Cancer Classification | Tumor groups 63-68 | Values 275-300 
See classification 
See classification 
●   Lymphomas 
SEER Site Recode ICD-O-3/WHO 2008 Definition | Site group Lymphoma |  
Values 33011, 33012, 33041, 33042 
See SEER website 
See SEER website 
      □    Burkitt lymphoma (BL) 
ICCC Recode Third Edition ICD-O-3/IARC 2017 | Site group IIc |  
Value 014 (extended recode) 
9687 
C015-C026 
Sarcomas 
Rare Cancer Classification | Tumor groups 50-53 | Values 202-229 
See classification 
See classification 
●   Undifferentiated embryonal sarcoma 
      of the liver (UESL) 
ICCC Recode Third Edition ICD-O-3/IARC 2017 | Site group VIIa.3 |  
Value 43 (extended recode) 
8991 
C022 
Neuroendocrine neoplasms (NEN) 
Rare Cancer Classification | Tumor group 54 | Values 230-233* 
See classification 
See classification 
●   Well differentiated,  
      neuroendocrine tumors (NETs) 
Rare Cancer Classification | Tumor groups 54.1 and 54.2 | Values 230-231 
See classification 
See classification 
●   Poorly differentiated,  
      neuroendocrine carcinomas (NECs) 
Rare Cancer Classification | Tumor group 54.3 | Value 232* 
See classification 
See classification 
●   Mixed neuroendocrine-non- 
      neuroendocrine neoplasms (MiNEN) 
Rare Cancer Classification | Tumor group 54.4 | Value 233 
See classification 
See classification 
Carcinomas and blastomas 
Rare Cancer Classification | Tumor groups 7-15, 44, 46 | Values 19-63, 190, 192 
See classification 
See classification 
●   Hepatoblastoma (HB) 
Rare Cancer Classification | Tumor group 44 | Value 190 
See classification 
See classification 
●   Carcinomas of the liver and intrahepatic  
      bile tract 
Rare Cancer Classification | Tumor group 14 | Values 52-59* 
See classification 
See classification 
      □    Hepatocellular carcinoma (HCC) 
Rare Cancer Classification | Tumor groups 14.1 and 14.2 | Values 52-53 
See classification 
See classification 
●   Carcinomas of the gallbladder and 
      extrahepatic bile tract 
Rare Cancer Classification | Tumor group 15 | Values 60-63* 
See classification 
See classification 
●   Pancreatoblastoma 
Rare Cancer Classification | Tumor group 46 | Value 192 
See classification 
See classification 
●   Carcinomas of the pancreas 
Rare Cancer Classification | Tumor group 13 | Values 43-51* 
See classification 
See classification 
●   Carcinomas of the gastrointestinal tract 
Rare Cancer Classification | Tumor groups 7-12 | Values 19-42* 
See classification 
See classification 
      □    Carcinomas of the esophagus 
Rare Cancer Classification | Tumor group 7 | Values 19-23* 
See classification 
See classification 
      □    Carcinomas of the stomach (GC) 
Rare Cancer Classification | Tumor group 8 | Values 24-28* 
See classification 
See classification 
      □    Carcinomas of the small intestine 
Rare Cancer Classification | Tumor group 9 | Values 29-31* 
See classification 
See classification 
      □    Carcinomas of the colon and rectum 
             (CRC) 
Rare Cancer Classification | Tumor groups 10 and 11 | Values 32-38* 
See classification 
See classification 
      □    Carcinomas of the anal canal 
Rare Cancer Classification | Tumor group 12 | Values 39-42* 
See classification 
See classification 
●   Carcinomas of digestive organs, NOS 
Custom selection* 
Histology codes from 
Rare Cancer 
Classification tumor 
groups 7-15  
C026 
Rare other and unknown subtypes 
Remaining cases 
Remaining cases 
Remaining cases 
 

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Legend Table 2. Abbreviation: NOS, not otherwise specified. Symbols: * Contrary to the Rare Cancer Classification, cancers with ICD-O-3 morphology codes 8000-8009 ("neoplasms, 
NOS”) and ICD-O-3 topography codes C015-C026 ("digestive organs") are not classified (e.g. morphology code 8002 as NEN; morphology codes 8000-8001 and 8003-8005 as epithelial 
tumors). Instead, these cancers are grouped within "rare other and unknown subtypes" in our study. This decision is made because – in our study population – the likelihood that 
digestive cancers of unspecified histologic subtype are of neuroendocrine or epithelial origin is not necessarily highest. In our young patient population, malignancies in these anatomic 
locations are relatively often other cancers, such as lymphomas, sarcomas or blastomas. 
 
Seven common gastrointestinal cancers are specifically distinguished: Burkitt 
lymphoma (BL), undifferentiated embryonal sarcoma of the liver (UESL), 
neuroendocrine neoplasms (NEN), hepatoblastoma (HB), hepatocellular carcinoma 
(HCC), gastric carcinoma (GC), and colorectal carcinoma (CRC). These cancers are 
depicted in blue in Table 2. Subgroup analyses of patients with these malignancies 
are performed, with a special focus on patients with CRC. 
 
For some of these common cancers, different histologic subtypes are distinguished 
(Table 3). Grading is based on ICD-O-3 and categorized as 1) Well differentiated, 
Grade I; 2) Moderately differentiated, Grade II; 3) Poorly differentiated, Grade III; 4) 
Undifferentiated or anaplastic, Grade IV. Stage at diagnosis is categorized into 
localized, regional, or distant according to the SEER Summary Staging system 
(https://training.seer.cancer.gov/staging/systems/summary/) by using the Combined 
Summary Stage variable (available for cases diagnosed between 2004-2019) or the 
Summary Stage 2000 variable (available for cases diagnosed between 2000-2003). 
In addition, the Ann Arbor classification is available for staging BL (for cases 
diagnosed between 2000-2015), and American Joint Committee on Cancer (AJCC) 
staging schemes are available for NEN, HCC, GC and CRC (Table 3). In any 
publications of analyses involving staging data, it is clearly stated that different 
staging schemes were used to stage cancers diagnosed in different years (e.g. AJCC 
3rd edition for CRC diagnosed in 2000, and AJCC 8th edition for CRC diagnosed in 
2019)  – thereby acknowledging the limitations associated with these analyses.  
 
Regarding the first course of treatment, surgery of the primary site, radiation and 
chemotherapy are dichotomously captured as “yes” or “no/unknown”. Similarly, total 
hepatectomy with liver transplant is specified as “yes” or “no/unknown” for patients 
with primary hepatic malignancies – including UESL, HB, and HCC (Table 3). In any 
publications of analyses involving treatment data, the limitations of these data items 
are acknowledged, as outlined on the SEER website (https://seer.cancer.gov/data-
software/documentation/seerstat/nov2021/treatment-limitations-nov2021.html).  

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Table 3. Categorization of data items analyzed for common cancer subtypes 
Subtype 
 
 
 
Primary site 
classification
| subgroups 
 
Additional 
staging 
scheme | 
subgroups 
Grading 
scheme | 
subgroups 
 
Histologic 
classification | 
subgroups 
 
Surgery primary site 
(RX Summ--Surg Prim 
Site (1998+) variable) 
 
Total hepatectomy with 
transplant (RX Summ--Surg 
Prim Site (1998+) variable) 
 
Radiation  
(Radiation recode 
variable) 
 
Chemotherapy 
(Chemotherapy recode 
(yes, no/unk) variable) 
 
BL 
 
 
 
ICD-O-3 |  
C015-C026 
 
 
 
Ann Arbor | 
stage I-IV 
 
 
 
NR 
 
 
 
 
NR 
 
 
 
 
Yes (values 10-90);  
No or unknown              
(values 0 and 99) 
 
 
NR 
 
 
 
 
Yes (all subtypes);  
No or unknown (incl. 
"refused" and 
"recommended, unknown 
if administered") 
Yes;  
No or unknown 
 
 
 
UESL 
 
 
 
NR 
 
 
 
 
N/A 
 
 
 
 
NR 
 
 
 
 
NR 
 
 
 
 
Yes (values 10-90);  
No or unknown  
(values 0 and 99) 
 
 
Yes (values 61 and 75);  
No or unknown (other values) 
 
 
 
Yes (all subtypes);  
No or unknown (incl. 
"refused" and 
"recommended, unknown 
if administered") 
Yes;  
No or unknown 
 
 
 
NEN 
 
 
 
 
ICD-O-3 |  
C015-C017, 
C018.1 
(appendix), C018 
excl. C018.1, 
C019-C026 
AJCC |  
stage I-IV 
 
 
 
 
ICD-O-3 | 
Grade I-III 
 
 
 
 
Rare Cancer Classification | 
Cat. 1: 230-231 (well 
differentiated) vs. Cat. 2: 
232-233 (poorly 
differentiated & MiNEN) 
 
Yes (values 10-90);  
No or unknown  
(values 0 and 99) 
 
 
 
NR 
 
 
 
 
 
Yes (all subtypes);  
No or unknown (incl. 
"refused" and 
"recommended, unknown 
if administered") 
 
Yes;  
No or unknown 
 
 
 
 
HB 
 
 
 
NR 
 
 
 
 
N/A 
 
 
 
 
ICD-O-3 | 
Grade I-IV 
 
 
 
NR 
 
 
 
 
Yes (values 10-90);  
No or unknown  
(values 0 and 99) 
 
 
Yes (values 61 and 75);  
No or unknown (other values) 
 
 
 
Yes (all subtypes);  
No or unknown (incl. 
"refused" and 
"recommended, unknown 
if administered") 
Yes;  
No or unknown 
 
 
 
HCC 
 
 
 
NR 
 
 
 
 
AJCC |  
stage I-IV 
 
 
 
ICD-O-3 | 
Grade I-IV 
 
 
 
Rare Cancer Classification | 
Cat. 1: 52 (HCC, NOS) vs. 
Cat. 2: 53 (HCC, 
fibrolamellar) 
 
Yes (values 10-90);  
No or unknown  
(values 0 and 99) 
 
 
Yes (values 61 and 75);  
No or unknown (other values) 
 
 
 
Yes (all subtypes);  
No or unknown (incl. 
"refused" and 
"recommended, unknown 
if administered") 
Yes;  
No or unknown 
 
 
 
GC 
 
 
 
 
 
 
ICD-O-3 | 
C016.0-C016.9 
 
 
 
 
 
 
 
AJCC |  
stage I-IV 
 
 
 
 
 
 
 
ICD-O-3 | 
Grade I-IV 
 
 
 
 
 
 
 
ICD-O-3 |  
Cat. 1: 8140 (AC, NOS), 
Cat. 2: 8210 + 8220 + 8221 
+ 8261 + 8263 (AC in 
polyp/adenoma), Cat. 3: 
8480-8482 (MAC), Cat. 4: 
8490 (SRCC), Cat. 5: 
remaining cases 
(others/unknown)16 
Yes (values 10-90);  
No or unknown  
(values 0 and 99) 
 
 
 
 
 
 
NR 
 
 
 
 
 
 
 
 
Yes (all subtypes);  
No or unknown (incl. 
"refused" and 
"recommended, unknown 
if administered") 
 
 
 
 
Yes;  
No or unknown 
 
 
 
 
 
 
 
CRC 
 
 
 
 
 
 
ICD-O-3 | 
C018.0-C018.9, 
C019.9, C020.9 
 
 
 
 
 
 
AJCC |  
stage I-IV 
 
 
 
 
 
 
 
ICD-O-3 | 
Grade I-IV 
 
 
 
 
 
 
 
ICD-O-3 |  
Cat. 1: 8140 (AC, NOS), 
Cat. 2: 8210 + 8220 + 8221 
+ 8261 + 8263 (AC in 
polyp/adenoma), Cat. 3: 
8480-8482 (MAC), Cat. 4: 
8490 (SRCC), Cat. 5: 
remaining cases 
(others/unknown)16 
Yes (values 10-90);  
No or unknown  
(values 0 and 99) 
 
 
 
 
 
 
NR 
 
 
 
 
 
 
 
 
Yes (all subtypes); 
 No or unknown (incl. 
"refused" and 
"recommended, unknown 
if administered") 
 
 
 
 
Yes;  
No or unknown 
 
 
 
 
 
 
 
 
New abbreviations: NR, not relevant; N/A, not available; Cat, category; AC, adenocarcinoma; MAC, mucinous adenocarcinoma; SRCC, signet ring cell carcinoma. 
 
8.1 Study parameters/endpoints 
8.1.1 Main study parameter/endpoint 
Descriptive statistics of patient and tumor characteristics, first course 
treatments, overall survival, and subsequent primary malignancies. 
8.1.2 Secondary study parameters/endpoints 
1. Time trends in incidence, stage at diagnosis, first course treatments, 
mortality, and overall survival. 
 
2. Associations between the variables age at diagnosis, sex, race and origin, 
year of diagnosis, stage at diagnosis, and histologic category (when relevant) 
with overall survival in multivariable analysis. 
 
3. Standardized incidence of second primary malignancies in patients who 
survived (i) two or more months, or (ii) five or more years after 
gastrointestinal cancer diagnosis, relative to the general U.S. population. 

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8.1.3 Other study parameters (if applicable) 
Not applicable. 
8.2 Randomization, blinding and treatment allocation 
  Not applicable 
 
8.3 Study procedures 
  Study subjects do not undergo any procedures for this study. 
 
8.4 Withdrawal of individual subjects 
Not applicable 
8.4.1 Specific criteria for withdrawal (if applicable) 
  Not applicable 
 
8.5 Replacement of individual subjects after withdrawal 
  Not applicable 
 
8.6 Follow-up of subjects withdrawn from treatment 
  Not applicable 
 
8.7   Premature termination of the study 
  Not applicable 
 
 

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9. SAFETY REPORTING 
9.1 Temporary halt for reasons of subject safety 
Not applicable  
 
9.2 AEs, SAEs and SUSARs 
9.2.1 Adverse events (AEs) 
Not applicable 
9.2.2 Serious adverse events (SAEs) 
Not applicable 
9.2.3 Suspected unexpected serious adverse reactions (SUSARs) 
Not applicable 
 
9.3 Annual safety report 
 
Not applicable 
 
9.4 Follow-up of adverse events 
Not applicable 
 

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10. STATISTICAL ANALYSIS 
Analyses are restricted to the first primary gastrointestinal malignancy of included 
patients. Subsequent primary malignancies diagnosed among patients from the 
study cohort, including subsequent primary gastrointestinal malignancies, are 
described separately. Included patients must have a primary gastrointestinal 
malignancy as their first primary cancer (see Chapter 4.2: inclusion criteria). As a 
consequence of these decisions, not all (patients with) gastrointestinal 
malignancies during childhood or adolescence registered in the SEER 17 
database are analyzed, which affects the results of our study. For example, 
calculated incidence rates of the different gastrointestinal malignancies may be 
slightly underestimated. However, these decisions were deliberately made to 
facilitate easy interpretation of the study cohort and corresponding data. For 
example, patients with a diagnosis of a non-gastrointestinal cancer prior to the 
diagnosis of a primary gastrointestinal cancer during childhood or adolescence 
represent a small but special group of patients, whose clinical characteristics, 
treatments and outcomes may be different from children and adolescents with a 
primary gastrointestinal malignancy as their first primary cancer – the population 
of interest. To gain insight in the degree of underestimation of incidence rates, 
additional analyses of all primary gastrointestinal malignancies registered among 
children and adolescents in the SEER 17 database may be performed. 
 
For analyses that include histologic subgroups or grade data (Table 3), only cases 
that are microscopically confirmed are analyzed. For analyses including data 
regarding tumor characteristics (except primary site), treatment, survival, and/or 
subsequent primary malignancies, cases diagnosed with primary gastrointestinal 
cancers at autopsy and cases with this diagnosis based on death certificate only 
are excluded. 
 
10.1 Primary study parameter(s) 
Data is presented quantitatively (numerically). Continuous variables are 
summarized with medians and ranges, and categorical variables are summarized 
with frequencies and proportions. Age at diagnosis can also be summarized with 
frequencies and proportions, using 1-year age categories. Overall survival (OS) is 
estimated by the Kaplan-Meier method. OS is defined as the time from the date of 

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diagnosis until the date of death from any cause (event) or until the date of last 
follow-up. Survival curves may be compared with the log-rank test. Median follow-
up is estimated using the reverse Kaplan-Meier method32.  
 
The following descriptive statistics are minimally obtained:  
Frequencies and proportions of the different gastrointestinal malignancies – 
specified in Table 2 – by age group (<18; 18-24 years at diagnosis) and by 1-year 
age categories (0-24 years). Age distributions of patients diagnosed with common 
gastrointestinal malignancies (BL, UESL, NEN, HCC, HB, GC, and CRC). 
 
Stratified by age group (<18; 18-24 years at diagnosis): 
Frequencies and proportions of the different gastrointestinal malignancies by 
primary anatomic site (ICD-O-3 topography codes C015-C026). Summarized sex 
and race and origin data of patients diagnosed with common gastrointestinal 
malignancies. Frequencies and proportions of surgery, radiation, and 
chemotherapy as part of the first course of treatment of patients with common 
gastrointestinal malignancies. Frequencies and proportions of different stages at 
diagnosis, different grades, and different histologic subtypes of patients diagnosed 
with CRC. Frequencies and proportions of CRC cases by primary anatomic site 
(ICD-O-3 topography codes C018.0-C18.9, C19.9, and C20.9). Kaplan-Meier 
curves depicting OS of patients diagnosed with common gastrointestinal 
malignancies. Estimated 1- and 5-year OS (with 95% confidence intervals) of 
patients diagnosed with common gastrointestinal malignancies. Kaplan-Meier 
curves depicting OS of CRC patients by i) stage at diagnosis, ii) by grade, and iii) 
by histologic subtype. Frequencies and proportions of patients with multiple 
primary cancers registered in 2000-2019 by common cancer subgroup (Table 3). 
Median total number of in situ/malignant tumors of patients diagnosed with 
common gastrointestinal malignancies. 
 
10.2 Secondary study parameter(s)  
Data will be presented quantitatively (numerically); stratified by age group (<18; 
18-24 years at diagnosis).  
 

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Age-adjusted incidence and mortality rates are calculated as the average annual 
number of cases or deaths per million person-years at risk, respectively. For 
mortality rates, calendar year and age (<18; 18-24 years) represent year and age 
at death, respectively. Incidence rates of the common gastrointestinal 
malignancies are based on SEER 17 incidence data (2000-2019); mortality rates 
of malignant neoplasms of the digestive organs (ICD-O-3 topography codes 
C015-C026) are based on mortality data of the total U.S. population (1969-2019). 
In addition, incidence-based mortality (IBM) rates – for cases registered in SEER 
17 – may be calculated to partition mortality by digestive cancer subtype (BL, 
UESL, NEN, HCC, HB, GC, and CRC)33. The annual population size is obtained 
from the Census Bureau. Rates are age-standardized using the age structure of 
the 2000 U.S. standard population. Rates are calculated using SEER*Stat 
software and plotted using 3-year moving averages34. When 3-year moving 
averages vary greatly, rates may be plotted using 5- or 7-year moving averages. 
Trends over time in incidence and mortality are analyzed by Poisson regression, 
with the calendar year as a continuous regressor variable. In addition, trends over 
time may be evaluated by linear regression modelling – a method frequently used 
in prior studies34,35 – to allow easier comparisons between studies, as well as with 
Jointpoint regression modelling to identify change points in the trends. Results are 
reported as average annual percent changes (AAPC) along with 95% confidence 
intervals and P values.  
 
Trends over time in stage at diagnosis or first course treatments of patients with 
common GI malignancies are tested with logistic regression, with year of 
diagnosis as a continuous variable34. The proportions of each stage at diagnosis 
or treatment category are plotted as weighted 3-year moving averages in 
percentages. When weighted 3-year moving averages vary greatly, results may 
be plotted using weighted 5- or 7-year moving averages. 
 
Trends over time in OS of patients with common GI malignancies are evaluated 
by Cox regression analysis, with year of diagnosis as a continuous variable. The 
estimated 1- and 5-year OS of patients with common GI malignancies are plotted 
as percentages by diagnostic time period. For the diagnostic period 2015-2019, 5-
year OS is not available due to insufficient follow-up. In addition, changes over 

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time in OS of patients diagnosed with common GI malignancies may be visualized 
by plotting separate Kaplan-Meier curves for each diagnostic time period16.  
 
To explore independent prognostic factors for overall survival of patients with 
common GI malignancies, multivariable Cox regression analysis is performed with 
age at diagnosis, sex, race and origin, year of diagnosis, stage at diagnosis, and 
histologic category (when relevant; see Table 3) as included variables. 
 
Table 4. Multivariable Cox regression analysis 
 
BL 
UESL 
NEN 
HB 
HCC 
GC 
CRC 
 
No. at 
risk 
HR (95% CI) 
P 
No. at 
risk 
HR (95% CI) 
P 
No. at 
risk 
HR (95% CI) 
P 
No. at 
risk 
HR (95% CI) 
P 
No. at 
risk 
HR (95% CI) 
P 
No. at 
risk 
HR (95% CI) 
P 
No. at 
risk 
HR (95% CI) 
P 
Age at diagnosis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sex 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Male 
 
Reference 
 
 
Reference 
 
 
Reference 
 
 
Reference 
 
 
Reference 
 
 
Reference 
 
 
Reference 
 
Female 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Race & origin 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NH-White 
 
Reference 
 
 
Reference 
 
 
Reference 
 
 
Reference 
 
 
Reference 
 
 
Reference 
 
 
Reference 
 
NH-Black 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NH-Other/unknown 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hispanic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Year of diagnosis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stage 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Localized 
 
Reference 
 
 
Reference 
 
 
Reference 
 
 
Reference 
 
 
Reference 
 
 
Reference 
 
 
Reference 
 
Regional 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Distant 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Unknown/unstaged 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Histology 
 
NR 
 
 
NR 
 
 
 
 
 
NR 
 
 
 
 
 
 
 
 
 
 
Category 1 
 
 
 
 
 
 
 
Reference 
 
 
 
 
 
Reference 
 
 
Reference 
 
 
Reference 
 
Category 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Category 3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Category 4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Category 5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NH, non-hispanic; NR, not relevant 
 
Standardized incidence ratios (SIR) and 95% confidence intervals of second 
primary malignancies (SPM) in patients that survived i) two or more months, or ii) 
five or more years after initial gastrointestinal cancer diagnosis are estimated 
using the multiple primary (MP-SIR) session of SEER*Stat software. Analyses are 
performed by common gastrointestinal cancer subgroup (BL, UESL, NEN, HCC, 
HB, GC, and CRC). SIR calculations compare the observed second cancer 
incidence with the expected first primary cancer incidence in the age-, sex-, race- 
and calendar year-matched general population29. The general population rates are 
available by cancer site, 5-year age categories, sex, race and 5-year diagnostic 
time periods. 
 
A P value < 0.05 is considered statistically significant. 
 
10.3 Other study parameters 
Not applicable 
 

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10.4 Interim analysis (if applicable) 
Not applicable 

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11. ETHICAL CONSIDERATIONS 
11.1 Regulation statement 
In analogy to studies based on data from the Netherlands Cancer Registry34, this 
observational study of anonymous data does not require approval from an ethics 
committee in the Netherlands, according to the Central Committee on Research 
involving Human Subjects (CCMO). 
 
11.2 Recruitment and consent 
Not applicable 
 
11.3 Objection by minors or incapacitated subjects (if applicable) 
Not applicable 
 
11.4 Benefits and risks assessment, group relatedness 
No risk or benefits 
 
11.5 Compensation for injury 
Not applicable 
 
11.6 Incentives (if applicable) 
Not applicable 

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12. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
12.1 Handling and storage of data and documents 
Retrieved data are anonymous. Access to SEER Research Plus data is provided 
under the SEER Research Data Use Agreement (https://seer.cancer.gov/data-
software/documentation/seerstat/nov2021/seer-dua-nov2021.html). Data are 
available in SEER*Stat software. Exported data are stored on a secured network 
drive with regular back-ups.  
 
12.2 Monitoring and Quality Assurance  
No monitoring will take place. 
 
12.3 Amendments  
Amendments will be recorded and filed by the investigators.  
 
12.4 Annual progress report 
No progress report will be made. 
 
12.5 Temporary halt and (prematurely) end of study report 
Not applicable 
 
12.6 Public disclosure and publication policy 
 
The investigators are committed to publishing the results of the study in an 
international medical scientific journal; preferably open access. All investigators 
(including the study statistician) are co-author of the manuscript, following ICMJE 
guidelines. 

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13. STRUCTURED RISK ANALYSIS  
 
Not applicable 
 
13.1 Potential issues of concern 
 
Not applicable 
 
13.2 Synthesis 
 
Not applicable 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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