Introduction
Frequently used translational pathways in the field of oncology research make use of
Randomised Controlled Trials (RCTs), especially for efficacy analyses of therapeutic
interventions. However, due to their selective inclusion and exclusion criteria, the
specific setting and the restriction to a concrete/specific question in a
strictly defined study population, RCTs may inadequately reflect clinical reality
[1 ]. Clinical registries and the
studies embedded in them, on the other hand, allow the depiction of actual health
care practice under routine conditions. They can reveal, for example, weak points in
therapy and thus have the potential to optimise therapy processes. The general credo
of science at present is that RCTs alone are not sufficient to advance clinical
research and decisively improve patient care [1 ]. As a method of translational research, the analysis of prospective
registry data combines controlled, prospective observations with routine patient
care. Furthermore, clinical cohorts and registries serve as an excellent basis for
embedding clinical trials. A back-translation of findings from health services
research through prospective cohort studies into clinical research has the potential
to drive medical innovation faster, more effectively and, above all, in a more
targeted manner [1 ].They must therefore be
a central component of cutting-edge oncological research [2 ].
In addition, in recent years there have been increased international efforts to
standardise routine care in order to create the basis for more effective care, data
harmonisation and research into outcomes under routine conditions. An outstanding
international initiative, especially for the oncological field, is ICHOM
(International Consortium for Health Outcomes Measurement) [3 ]. In so-called standard sets, it was
specified in detail which data should be collected from which patient at which time
using which method (measurement) and which outcomes should be used (minimum
set).
Ensuring high-quality, patient-centred care is a major challenge for the health care
system. A precise understanding of the risk factors, the benefits and effectiveness
of therapeutic measures under routine conditions, as well as the interplay between
outpatient and inpatient care are prerequisites for monitoring health care and
guiding future health development. The treatment costs as well as the costs for
psychological and other secondary health demands caused by cancer must also be
considered.
Objectives of the register
The primary goals of the research project can practially be assigned to two
areas, health services research and clinical prognosis research. In the area of
health services research, questions in the field of translational research are
to be answered in addition to effectiveness and outcomes analyses. Specifically,
the following questions of outcome research, translational research and clinical
research will be addressed and a suitable data basis will be created for
answering these questions::
How effective and safe are oncological treatments and care concepts,
taking into account long-term and patient-reported outcomes?
Is the standard medical care of patients with cancer adequate and of high
quality?
What are the barriers or facilitators to the implementation of
innovative, promising cancer therapies?
Which individual factors are prognostically relevant or influence the
response to therapy and the course of the disease?
Based on this, it will be possible to generate science-relevant hypotheses in the
field of translational and outcomes research. Recent developments in
personalised medicine (targeted therapy) and novel treatment approaches such as
immunotherapy have raised hopes of significantly improve cancer survival in the
future [4 ]
[5 ] and at least transforming cancer
from a fatal to a chronic disease. The registry is ideally suited to address
these questions through the establishment of clinical cohorts and the provision
of comprehensive, high-quality data sets for oncological diseases.
Methods/Design
Data basis and management
The data basis of the registry is formed by clinical data (routine data of the
hospital information system as well as data from the clinical cancer
registries), quality-of-life data (questionnaires), biodata (exclusively results
of biomarker analyses from standard care or with separate consent of the
patient), histology (exclusively data from standard care or with separate
consent of the patient), data of imaging procedures and statutory health
insurance (SHI) data (diagnoses, procedures, prescriptions). These data must be
collected individually for each patient and transferred to the register at the
NCT/UCC Dresden. However, within the framework of the registry, we
mainly bring together data from clinical information systems, cancer registries,
and SHI data that has already been collected and do not re-collect data that has
already been documented. Therefore, there is no additional burden on the
treating physicians due to duplicate documentation within the registry. Data
collection is closely based on the ICHOM standard set for colorectal
adenocarcinoma [3 ], but is
individually adapted for each cancer entity. Currently, internationally
harmonised standard sets are available in oncology for lung, prostate, breast
and colorectal cancer. The timing of the follow-up surveys in particular can
vary depending on the entity and is based on the usual follow-up of these
patients at the UKD in order to ensure the most economical integration of the
registry into routine procedures (see Figure S1 in the appendix ). In addition,
biomarkers, possible complications and other aspects of the cancer entity must
be adapted. A detailed breakdown of the variables to be used, the timing and the
origin of the data can be found in the appendix as an example for pancreatic
cancer (Table S2 & S3).
The aim is to establish a prospective patient cohort. Prospective here, however,
refers to the time of recruitment. Data should also be collected retrospectively
over a period of 5 years before the inclusion of the patient. In the case of
purely post-treatment patients, data from the last few years must be
retrospectively searched. The follow-up should also be at least 5 years. A
patient-specific end-of-follow-up is not planned. However, the follow-up times
vary between the respective disease status. For example, in the case of
non-progressive pancreatic cancer, a quarterly follow-up is planned in the first
year after treatment and then every six months. In the event of disease
progression and renewed intervention (surgery, chemotherapy, etc.), follow-up
visits should again take place at 3-month intervals in the first year and then
every six months (see Figure S1 in the appendix). Interim visits during a stay
at the UKD, e. g. in case of complications, are documented and the data
on these visits are also transferred to the registry database.
Within the scope of the study, the consent of the study participants to the
utilisation of their SHI routine data as well as the data of the clinical cancer
registries will be documented via the registry-specific consent form (see
appendix). In the consent form, patients can agree to have their personal data
transmitted to the registry by the respective health insurance company and
cancer registry for a period of 5 years before and after the date of registry
inclusion. This data allows the individual patient histories to be described and
presented without gaps. This is an important supplement to the parameters
obtained in the course of treatment at Dresden University Hospital. The
administration of the declarations of consent, including patient rights
(objection, information, etc.), is carried out in the independent trust office
of the TU Dresden (THS). Access to the data, which is specifically extracted
from the register for scientific research, is only permitted within the
framework of Dresden University Medicine for the specific, above-mentioned
questions of healthcare and clinical research. For questions that go beyond the
original purpose described here, an application in accordance with §75
Section 2 SGB X must be submitted to the Saxon State Ministry for Social Affairs
and Social Cohesion (SMS) or to the respective competent supervisory authority
and needs to be approved.
Registry design
The registry is a prospective observational clinical cohort study on patients
with cancer.
Participants, interventions and outcomes
Consecutively, all patients with at least one inpatient hospital stay due to a
cancer diagnosis (ICD10-GM C00–97) who are treated at the UKD or are at
tumour aftercare are initially included. Patients must be at least 18 years old
at the time of inclusion. A control group is not planned. There will be no
study-related intervention, only the observation of patients in routine care.
Additional case definitions are needed for additional determinants. These
include concomitant diseases or metastases, which are defined according to
individual ICD-10-GM codes, specialists involved in the treatment, who are
defined and selected according to the physician group code, or diagnostic and
therapeutic services, which are defined according to OPS codes, EBM numbers and
central pharmaceutical numbers (PZN), respectively. The recommendations of the
Good Practice Secondary Data Analysis (GPS) [6 ] as well as the Good Practice Data Linkage (GPD) [7 ] are followed for the various case
definitions in order to carry out adequate internal diagnosis and further code
validations. Potential endpoints of this study are 30-day and 1 to 5-year
mortality, relative survival, survival after Brenner (period approach),
progression- and relapse-free survival, overall survival, overall clinical
outcome, complications of treatment (short-term), quality-of-life outcomes
(general well-being, physical functioning, emotional functioning, social
functioning, mental functioning), direct costs, end-of-life hospitalisation
rate, and proportion of study participants dying in hospice. Differentiation
between primary and secondary outcomes is not necessary. In addition, the
analysis of potential influencing factors for remission and relapse, as well as
treatment-specific complications and description of patient pathways and
treatment sequences will be possible. A summary of the outcomes, measurement
instruments and measurement times can be found in the appendix (exemplary for
pancreatic carcinoma).
The registry is already in the development phase. Internal hospital structures,
processes and data sources, including IT interfaces, are being established. The
integration of the project's internal patient management software
(STeVe) and the THS, including the automatic management of consent forms, has
also been established. Currently, a functioning registry for 2 cancer entities
(colorectal adenocarcinoma, pancreatic carcinoma) is operated in the follow-up,
including the monitoring of quality of life (first patient in: second half of
2020). However, the registry still needs to be enriched with data from health
insurers and cancer registries and thus needs access to a.o. outpatient
treatments and diagnoses of the participants. However, extensive discussions
have already taken place with health insurance companies and clinical cancer
registries, as well as preliminary work on this, so that the aim is to integrate
these data sources quickly, at least for some of the participants. As of
December 2022, 141 people with adenocarcinoma of the colon (C18), 181 people
with adenocarcinoma of the rectum (C20) and 148 people with pancreatic carcinoma
(C25) are in the registry. A brief description of the present baseline can be
found in [Tables 1 ]
[2 ]
[3 ]. The establishment phase of the
registry also serves to estimate the effort and the material and personnel
requirements for the planned roll-out of the registry to other cancer entities
(melanoma, head and neck tumours, breast cancer, etc.).
Table 1 Patient characteristics at baseline:
Socio-demographic data, data on disease severity and data on quality
of life (QOL) are given. Based on our inclusion criteria, the
registry, which started in 2020, includes patients with newly
discovered cancers as well as patients undergoing follow-up care or
with current treatment for a recurrence/metastasis. Patients
whose primary diagnosis and/or treatment took place outside
the University Hospital Dresden can therefore also be included in
the registry if they are in contact with the UKD. There are
occasional cases in which the primary diagnosis and the inclusion of
the patient in the register are many years apart.
Entity
Adenocarcinoma colon C18
Adenocarcinoma rectum C20
Pancreatic carcinomas C25
n
%
n
%
n
%
141
100
181
100
148
100
Age at diagnosis in years (mean±SD)
59.8±14.0
60.4±11.5
61.4±12.4
Gender (female)
54
38.3
50
27.6
69
46.6
Family status
married
84
59.6
126
69.6
94
63.5
widowed
13
9.2
8
4.4
14
9.5
divorced
15
10.6
17
9.4
11
7.4
single
19
13.5
14
7.7
14
9.5
separated
2
1.4
4
2.2
2
1.4
unknown
8
5.7
12
6.6
13
8.8
UICC stage at initial diagnosis
UICC I
8
5.7
20
11.0
21
14.2
UICC II
26
18.4
16
8.8
41
27.7
UICC III
32
22.7
61
33.7
18
12.2
UICC IV
41
29.1
46
25.4
37
25.0
Not available
34
24.1
38
21.0
31
20.9
Grading at initial diagnosis
L (1,2)
69
48.9
102
56.4
70
47.3
H (>2)
45
31.9
40
22.1
30
20.3
Indefinable
9
6.4
1
0.6
0
0.0
Not available
18
12.8
19
10.5
16
10.8
L/V category at initial diagnosis
L0
67
47.5
114
63.0
74
50.0
L1
54
38.3
39
21.5
36
24.3
Missing
20
14.2
28
15.5
38
25.7
V0
83
58.9
115
86.5
71
48.0
V1
37
26.2
37
27.8
35
23.6
V2
1
0.7
0
0.0
2
1.4
Missing
20
14.2
29
21.8
40
27.0
Mutation status
KRAS mutated/wildtype
19/26
13.5/18.4
21/39
11.6/21.5
---
---
NRAS mutated/wildtype
1/28
0.7/19.9
3/39
1.7/21.5
---
---
BRAF mutated/wildtype
7/37
5.0/26.2
3/50
1.7/27.6
---
---
MSI stable/unstable
28/6
19.9/4.3
62/1
34.3/0.6
---
---
Comorbidities
Other tumor C00-C97 (without C44, C18–21
& C77–79)
37
26.2
39
21.5
37
25.0
Chronic kidney disease (CKD) - N18
10
7.1
11
6.1
9
6.1
Liver disease K71–76
35
24.8
37
20.4
25
16.9
Coronary heart disease (CHD) - I20–25
12
8.5
12
6.6
11
7.4
Heart failure - I50–52
14
9.9
24
13.3
12
8.1
Hypertensive diseases - I10–15
76
53.9
107
59.1
96
64.9
Diabetes (Typ2) - E11–14
27
19.1
26
14.4
76
51.4
Metastasis
Total
116
82.3
154
85.1
118
79.7
Synchrone metastasis within 100 days
46
32.6
48
26.5
42
28.4
Table 2 Overview of the treatments of the registry patients:
Resection of the primary cancer is the initial therapy for both
colorectal adenocarcinoma and pancreatic carcinoma. In the case of
rectal carcinoma, approx. 66% of the therapies are carried
out before resection (neoadjuvant). In colon and pancreatic
carcinoma, these neoadjuvant therapies play a subordinate role.
Chemotherapies carried out after primary resection (adjuvant), on
the other hand, are used particularly frequently for pancreatic
carcinoma (approx. 65%). In order to show the actual burden
of all patients in the registry and not only those who have
undergone resection, the therapies for recurrences and metastases
have been added to the therapies for the primary cancer in the lower
part of table. Radio- and radiochemotherapy are mainly used in the
treatment of adenocarcinoma of the rectum (C20). Radiochemotherapy
has a subordinate role in the treatment of adenocarcinoma of the
colon and pancreatic carcinoma.
Entity
Adenocarcinoma colon C18
Adenocarcinoma rectum C20
Pancreatic carcinomas C25
n=141
%
n=181
%
n=148
%
Resection of the primary tumour
119
84.4
146
80.7
102
68.9
Of which with R0
109
91.6
139
95.2
95
93.1
Complete remission after resection (ypT0)
2
1.7
10
6.8
1
1.0
No complete remission after resection
(ypT>0)
10
8.4
87
59.6
18
17.6
Repeated surgery within 30 days
13
10.9
34
23.3
17
16.7
Resection + CTx for primus
42
40.8
77
57.9
66
64.7
Therapies (primus, recurrence, metastasis)
OPx (any surgical intervention)
134
95.0
170
93.9
147
99.3
CTx
108
76.6
141
77.9
116
78.4
RTx
27
19.1
73
40.3
29
19.6
RCTx
2
1.4
56
30.9
7
4.7
CTx: chemotherapy; OPx: surgery; RTx: radiotherapy; RCTx
radiochemotherapy
Table 3 Quality of life data at the time of study inclusion
based on patient-reported EORTC-C30 questionnaires
(cross-sectional): Baseline information on the patients'
general quality of life based on the generic questionnaire
instrument C30 of the "European Organization for Research
and Treatment of Cancer" (EORTC [8 ]). Mean values and their
standard deviation for six separate QOL domains and the general
state of health are shown. In comparison, the values for pancreatic
carcinoma are somewhat lower than those for colon and rectal
carcinoma.
Entity
Adenocarcinoma colon C18
Adenocarcinoma rectum C20
Pancreatic carcinomas C25
Domain
n =119
n =150
n =131
Mean *
±SD
Mean *
±SD
Mean *
±SD
Physical Functioning
71.77
22.62
72.7
22.47
64.99
25.36
Pain
67.68
29.31
69.03
30.55
62.09
30.17
Social Functioning
59.05
35.06
57.27
32.09
52.08
35.92
Cognitive Functioning
80.08
21.93
81.98
22.55
76.72
25.88
Role Functioning
65.41
35.2
61.19
31.26
52.69
32.8
Emotional Functioning
65.59
23.2
64.99
25.48
59.56
23.25
General health status
62
21.73
57.32
21.95
56.03
22.64
* QOL scores range from 0 to 100, with 100
representing the highest quality of life or the lowest symptom burden
(pain).
Data protection, ethical and legal aspects
To ensure data protection, the data flow of the registry is embedded in the data
flows of the NCT/UCC data warehouse. The study management software
(STeVe) already separates personal identifying characteristics (IDAT) and
medical data (MDAT) or secondary data of the health insurance companies and
cancer registries (KDAT) at an early stage. The THS (Treuhandstelle) intervenes
to ensure that, on the one hand, no personally identifying information enters
the registry database and, on the other hand, the data owners involved (UKD,
biobank, health insurance company, cancer registry, patient) only receive the
personally identifying information (ORBIS ID, KV number) that they need for the
data management (see [Figure 1 ] and
Table S1 in the appendix).
Figure 1 Diagram of the data flow.
An application to link the routine data of the statutory health insurers with the
data of the registry is being processed. On the basis of §75 of the SGB
X, the transfer of social data for scientific research can also take place
without individual consent if the interests of the person concerned worthy of
protection are not impaired or the public interest in the research or planning
significantly outweighs the confidentiality interest of the persons concerned
and obtaining personal consent is impracticable. Although the patients'
consent for the linkage of their SHI data within the registry has been obtained,
the approval of the supervisory authority must still be obtained in order to
obtain full legitimation.
The data collection is pseudonymised, as described in [Figure 1 ] and Table S1. The pseudonyms
are administered by the THS. Without their involvement, the patient data made
available for medical research (project-related partial data extract of the
register data with coarsening of the data fields) cannot be traced back to a
person, or only with disproportionately high technical effort. The identity
comparison between the complementary data sources takes place exclusively in the
THS. For each external data delivery, the THS generates unique transfer
pseudonyms with which only the data of this transfer can be linked to the
existing data in the study database. After the linkage of the data in the study
database, these one-time transfer pseudonyms are deleted from the database. In
the interest of data minimisation, complementary variables in external sources
are only used if necessary for identity and plausibility checks in the THS and
are not transferred to the study database. The further linkage of these analysis
data with other data sources is explicitly prohibited by binding contracts with
data users‘ institutions. The names of patients and all other
confidential information are subject to medical confidentiality, the provisions
of the Federal Data Protection Act (BDSG), the European Data Protection
Regulation (EU-DSGVO) and other state-specific regulations (e. g. Saxon
Hospital Act). The data in the register are stored for a period of 10 years due
to legal requirements based on recommendations of Good Epidemiological Practice
(GEP) [9 ].
Documentation and quality assurance
The entire project is carried out in accordance with the Declaration of Helsinki
[10 ] as well as the
recommendations of the Good Practice Secondary Data Analysis (GPS) [6 ], the Good Practice Data Linkage
(GPD) [7 ] and Good Epidemiological
Practice (GEP) [9 ] as well as the
professional code of conduct for physicians of the responsible state medical
association in the respective current versions. Extensive plausibility checks
are carried out for all variables in the data set over the entire observation
period. For the comprehensibility and reproducibility of the results, the syntax
for statistical analysis is commented on, stored and, if necessary, made
available. The investigation is carried out in accordance with standardised
operating procedures (SOPs).
Consent of the participants
Participation in the registry is based on the informed consent principle. The
participation is voluntary. The patient information letter (Document S1) and the
informed consent form (document S2) can be found in the appendix.
Data Availability Statement
The data of the study are confidential. They can only be used for the oncological
questions mentioned in the study protocol by the participating physicians of the
Dresden University Medicine. Use within Dresden University Medicine beyond this
purpose is only possible with the consent of the patients and the responsible
supervisory authorities after application §75, SGB X. External third parties
are excluded from using the data.
Listed in the BQS directory of medical registers in Germany
(https://registergutachten.bqs.de/reg_db/detail.php?pid =NCT%2FUCC+Registerstudienplattform)
