CASP

Checklist: 12 questions to help you make sense of a Cohort Study

How to use this appraisal tool: Three broad issues need to be considered when appraising a
cohort study:

Are the results of the study valid? (Section A)

What are the results? (Section B)
Will the results help locally? (Section C)

The 12 questions on the following pages are designed to help you think about these issues
systematically. The first two questions are screening questions and can be answered quickly.
If the answer to both is “yes”, it is worth proceeding with the remaining questions. There is
some degree of overlap between the questions, you are asked to record a “yes”, “no” or
“can’t tell” to most of the questions. A number of italicised prompts are given after each
question. These are designed to remind you why the question is important. Record your
reasons for your answers in the spaces provided.

About: These checklists were designed to be used as educational pedagogic tools, as part of a
workshop setting, therefore we do not suggest a scoring system. The core CASP checklists
(randomised controlled trial & systematic review) were based on JAMA 'Users’ guides to the
medical literature 1994 (adapted from Guyatt GH, Sackett DL, and Cook DJ), and piloted with
health care practitioners.
For each new checklist, a group of experts were assembled to develop and pilot the checklist
and the workshop format with which it would be used. Over the years overall adjustments
have been made to the format, but a recent survey of checklist users reiterated that the basic
format continues to be useful and appropriate.
Referencing: we recommend using the Harvard style citation, i.e.: Critical Appraisal Skills
Programme (2018). CASP (insert name of checklist i.e. Cohort Study) Checklist. [online]
Available at: URL. Accessed: Date Accessed.

©CASP this work is licensed under the Creative Commons Attribution – Non-Commercial-
Share A like. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-
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Critical Appraisal Skills Programme (CASP) part of Oxford Centre for Triple Value Healthcare Ltd www.casp-uk.net
Paper for appraisal and reference:.........................................................................................................
Section A: Are the results of the study valid?

1. Did the study address a clearly Yes HINT: A question can be ‘focused’
focused issue?
✔ in terms of
Can’t Tell • the population studied
• the risk factors studied
No
• is it clear whether the study tried to
detect a beneficial or harmful effect
• the outcomes considered

Comments: P : 6,248 women wirh early-stage breast cancer treatedd in neoadjuvant and adjuvant chemotherapy
from four randomised controlled trials (NEAT; BR9601; tAnGo; Neo-tAnGo
Risk factor studied (Fig.1) --> Exposure :Chermotherapy-related toxixities, Control : Tidak mengalami
Chermotherapy-related toxixities
Clear that the study tried to detect a harmful effect = "To investigate the association between CRTs and
outcome --> BCSS dan RFS"
Outcome : Breast Cancer-Spesific Survival (BCSS) and Relapse-Free Survival (RFS)

2. Was the cohort recruited in Yes HINT: Look for selection bias which might
an acceptable way? ✔ compromise the generalisability of the
Can’t Tell findings:
• was the cohort representative of a
No
defined population
• was there something special about the
cohort
• was everybody included who should
have been

Comments: The cohort representative pf a defined population : Clinical data was collected from the UK
randomised clinical trials NEAT (n=2027), BR9601 (n = 374), tAnGo (n=3152), and
Neo-tAnGo (n=831), creating a nested cohort pf 6,248 women with early-stage breast
cancer treated in neoadjuvant and adjuvant chemotherapy, from a total of 6,384 patients,
Included in this study after provodong adequate quality toxicity data --> ini juga
menunjukan no.3 cohort has included who should have been

Is it worth continuing?

2
 3. Was the exposure accurately
measured to minimise bias?
Can’t Tell • did they use subjective or objective
Yes HINT: Look for measurement or
✔ classification bias:
measurements
No • do the measurements truly reflect what
you want them to (have they been
validated)
• were all the subjects classified
into exposure groups using the
same procedure

Comments: objective measurement : in all trias, CRTs were evaluated during each chemotherapy cycle for each patient,
CRTs were graded using NC1 CTCAE (ver 2 or 3; table S2 in additional file 1) Investigator at the participating
centers and data collected centrally via case report forms, dst : Cox proportional- hazards modelling was used
investigate the association teween CRTs experienced (categorised as shown in additional file 1 : Tabel S3) and
BCSS and RFS. A based model was created by lesting the association of improtant prognostid factors with BCSS
and RFS
NCi CTCaE dan COX proportional- hazards

4. Was the outcome accurately Yes HINT: Look for measurement or

measured to minimise bias? ✔ classification bias:
Can’t Tell • did they use subjective or objective
measurements
No • do the measurements truly reflect what
you want them to (have they been
validated)
• has a reliable system been
established for detecting all the cases (for
measuring disease occurrence)
• were the measurement
methods similar in the different groups
• were the subjects and/or
the outcome assessor blinded to
exposure (does this matter)

Comments: pengukuran outcome BCSS (time was calculates from date of treatment cessation to date
of death due to broast cancer, or to date of death due to other causes, or date of
censoring in women still alive) dan RFS (time was caalculated from date of treatment
concentration to either the date of first relapse or date of death in women dying without
relapse, or to date of censoring for those alive and relapse free) tidak bisa dipengaruhi
oleh subjek

3
5. (a) Have the authors identified Yes HINT:
all important confounding • list the ones you think might be
factors? Can’t Tell important, and ones the author missed

No
✔

Comments: tabel 1 --> karakteristik pasien bervariasi (tumor size, tumor grade, esterogen reseptor, status, BMI etc.)
The patient characteristics across all the trials is similar, although 20 % of patients in NEAT and BR9601 had fatigue classified as
grade >2,, in comparison to only 10 % in tAnGo andNeo-tAnGo. It is notable that 18 % of NEAT and BR9601 had a pre-treatment PS 1, in comparison
to only 8 % and 4 % of tAnGo and Neo-tAnGo patients, respectively

BMI bermakna pada kejadian chemotherapy related toxicities --> Patients with normal or underweight BMI are more likely to have severe neutropenia
during their treatment course in comparison to overweight or obese BMI patients (P = 0.008)

5. (b) Have they taken account of Yes HINT:

the confounding factors in the ✔ • look for restriction in design, and
design and/or analysis? Can’t Tell techniques e.g. modelling, stratified-,
regression-, or sensitivity analysis to
No correct, control or adjust for confounding
factors

Comments: dilakukan analisis untuk mepengaruhi BMI pada chemotherapy related toxicities --> "Underweight and
normal BMI patients were more likely to record severe neutropenia during their treatment course than
overweight or obese BMI patients.
(27% vs 24%, P=0,008) --> dilakukan adjust untuk pengaruh BMI --> Given the known association
of increasing BMI with poor prognosis [17, 18], we repeated the analysis adjusting for BMI, to confirm
that the relationship between neutropenia and RFS/BCSS was independent of BMI.

6. (a) Was the follow up of Yes HINT: Consider

subjects complete enough? • the good or bad effects should have
had long enough to reveal
Can’t Tell
✔ themselves
• the persons that are lost to follow-up
No may have different outcomes than
those available for assessment
• in an open or dynamic cohort, was
there anything special about the
outcome of the people leaving, or the
exposure of the people entering the
cohort
6. (b) Was the follow up of Yes
subjects long enough? ✔
Can’t Tell

No

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Comments: 6a tidak ada data apakah follow up subject complete enough
6 b median follow-up was 6,2 years with 1.335 (21%) breast cancer-related events, 148 (2%) non-breast
cancer-related deaths, and 4.765v (77%) live patiens
Berdasarkan canceresearchuk.org : Around 95 out of every 100 women (around 95%) survive their cancer for 1
year or more after diagnosis;
cancer.org : 5-yeras survival rate for women diagonesd with localized breast cancer is 99%
jadi wakttu follow up 6,2 tahun cukup untuk melihat outcome pada pasien early stage breast cancer

Section B: What are the results?



7. What are the results of this study? HINT: Consider
• what are the bottom line
results
• have they reported the rate or
the proportion between the
exposed/unexposed, the
ratio/rate difference
• how strong is the association
between exposure and
outcome (RR)
• what is the absolute risk
reduction (ARR)

Comments: All other CRTs were not found to be associated with either RFS or BCSS.After adjustment for other prognostic factors in
the model, After adjusting for the base model prognostic factors, neutropenia remained a statistically significant,
independent predictor of RFS (HR = 0.86; 95 % CI, 0.76–0.97; P = 0.02), with a similar trend seen for BCSS (HR = 0.87;
95 % CI, 0.75–1.01; P = 0.06). The association was strengthened after further adjustment for DI (BCSS: HR = 0.85; 95 %
CI, 0.73–0.98; P = 0.03; RFS: HR = 0.84; 95 % CI, 0.74–0.95; P = 0.005). Patients with grade 3 neutropenia were likely
to survive and remain relapse free for longer when compared to patients who experienced grades 2. Neutropenia
appeared unrelated to triple negative status (P = 0.85), ER status (P = 0.46), and HER2 status (P = 0.36).
the reported the rate or the proportion between the exposed/unexposed, the ratio/rate difference --> tabel 2
tidak ada data untuk perhitungan RR dan ARR

8. How precise are the results? HINT:
• look for the range of the confidence
intervals, if given

Comments:
Neuropenia --> BCSS : 1,01 - 0,75 = 0,26 ; 0,97 - 0,76 = 0,21
Lanjutkan
semakin kecil maka semakin precise

5


9. Do you believe the results? Yes HINT: Consider
• big effect is hard to ignore
Can’t Tell • can it be due to bias, chance or
✔ confounding
No • are the design and methods of this
study sufficiently flawed to make the
results unreliable
• Bradford Hills criteria (e.g. time
sequence, dose-response gradient,
biological plausibility, consistency)

Comments: design and method sufficient --> cohort sudah tepat untuk melihat hubungan antara exposure and
outcome
namun data berasal dari beberapa RCT dengan adanya beberapa perbedaan karakteristik
sehingga kemungkinan ada confounding factor dan follow up tidak dilakukan oleh peniliti sendiri

Section C: Will the results help locally?

10. Can the results be applied to Yes HINT: Consider whether
the local population? ✔ • a cohort study was the appropriate
Can’t Tell method to answer this question
• the subjects covered in this study could
No be sufficiently different from your
population to cause concern
• your local setting is likely to differ
much from that of the study
• you can quantify the local benefits and
harms

Comments: cohort sudah palinf tepat untuk menjawab pertanyaan ini --> mau melihat hubungan exposure chemotherapy induced toxicities dengan
outcome BCSS dan RFS.
ada perbedaan populasi --> penelitian ini di UK (Eropa), namun local setting tidak berbeda (obat kemo yang digunakan untuk early breast
cancer = di indonesia) selain itu angka kanker payudara di indonesia tinggi dan menurut data pada 2020, jumlah kasus baru kanker
payudara di indonesia mencapai 68.858 kasus (16,6%) dari total 396.914 kasus baru kanker, dengan jumlah kematian mencapai lebih dari
22 ribu jiwa (Globocan WHO, 2020) sehingga dengan ada penelitian ini dapat mecegah progosisi yang buruk dan meningkatkan survival
pada pasien kanker payudara di indonesia.
Local benefit and harm tidak dapat dikuantifikasi

11. Do the results of this study fit Yes

with other available ✔
evidence? Can’t Tell

No


Comments: the large and coprehensive study has shown a statifically significant association between improved survival and
neutropenia (using toxicity clasifiication NCl CTCAE >1 or >3) --> hasil penelitian lain menunjukan hasil yang
sama : The largest study [3] (n = 750), showed that patients with grade 2 or 3 neutropenia, on the National
Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) scale, had a 10 % absolute survival
advantage at 5 years compared to those with no neutropenia (multivariable P = 0.037). Shitara et al. [4]

This study shows that patients with normal or reduced BMI experience greater rates of neutropenia in
comparison to overweight and obese patients --> there is a know relationship between increasing BMI and poor
prognosis (systematic Review and Meta Analysis by Chan et al; Sinicrope and Dannenberg)


6


12. What are the implications of Yes HINT: Consider
this study for practice? ✔
• one observational study rarely
provides sufficiently robust
Can’t Tell
evidence to recommend changes

to clinical practice or within health
No policy decision making
• for certain questions,
observational studies provide the
only evidence
• recommendations from
observational studies are always
stronger when supported by other
evidence

Comments: This large and comprehensive study has shown a statistically significant association
between improved survival and neutropenia (using toxicity classification NCI CTCAE
1 or 3). This association is clinically relevant and has the potential to be further
tested in neutropenia-adapted treatment regimens within clinical trials to assess its
potential to improve clinical outcome --> pada praktek,neutropenia dapat diperiksa
untuk mempertimbangkan outcome
This study shows that patients with normal or reduced BMI experience greater rates of neutropenia
in comparison to overweight and obese patients (karena ada perbedaan farmakokinetika seperti
VD, Klirens dll pada pasien BMI besar sehingga mempengaruhi Bioavailabilitas obat dalam darah)
sehingga orang obesitas mungkin menerima dosis yang kurang --> lpada praktek, sebaiknya ada
penyesuain sosi pada pasien obesitas (BMI diatas normal)