CRITICAL READING OF THE LITERATURE RELEVANT POINTS: - End points (including the one used for sample...
-
Upload
nicholas-lawson -
Category
Documents
-
view
216 -
download
0
Transcript of CRITICAL READING OF THE LITERATURE RELEVANT POINTS: - End points (including the one used for sample...
CRITICAL READING OF THE LITERATURERELEVANT POINTS:
- End points (including the one used for sample size)- Surrogate end points- Quality of the performed procedures- Differences in the procedure/therapies after randomization- Follow up
SURROGATE END POINTSA laboratory measurement or clinical symptom used as a substitute for a clinically meaningful end point that measures survival directly or other relevant end points
Key point:
Relationship between the surrogate measure and the clinically relevant end point should be consistent and strong, based on RCT data
SURROGATE END POINTS
Good correlation between disease free survival and overall survival for patients with colon cancer receiving 5-FU after surgical resection (Sargent et al, JCO 2005; 23:8664)
Disease free survival: surrogate for overall survival
CRITICAL READING OF THE LITERATURERELEVANT POINTS:
- End points (including the one used for sample size)- Surrogate end points- Quality of the performed procedures- Differences in the procedure/therapies after randomization- Follow up
Quality of the procedures performed Quality could change during the trial
Gerard JP, JCO 2006; 24:4620.Gerard JP, JCO 2006; 24:4620. Should TME have been performed in the standardized way described in the protocol, would the outcomes have been different? Equally distributed in both groups?
CRITICAL READING OF THE LITERATURERELEVANT POINTS:
- End points (including the one used for sample size)- Surrogate end points- Quality of the performed procedures- Differences in the procedure/therapies after randomization- Follow up
Differences in the procedures after randomizationAny difference observed in the outcome can be explained by the treatment (if things have been carried out equally for both groups except the treatment under study after randomization)
Should postoperative chemotherapy be equally distributed in both groups, would it have modified the outcome? Why Post Op CHT left to the clinician?
Buijko, BJS 2006; 93:1215.
RECTAL CANCER SPHINCTER SAVING
POST OPCHEMOTHERAPHY
Main question
Potentially confounding
factors
CONFOUNDING
CRITICAL READING OF THE LITERATURERELEVANT POINTS:
- End points (including the one used for sample size)- Surrogate end points- Quality of the performed procedures- Differences in the procedure/therapies after randomization- Follow up
Assessment intervals every 8 weeks from start of treatment
Source: Panageas KS, Ben-orat L, Dickler MN,et al. When you look matters: The effect of assessment schedule on progression-free survival. JNCI 2007;
99(6):428-432.
Treatment Start
Last Scan with no progression
Progression detected
Assessed 8 weeks
Actual progression time
0 weeks 8 weeks 16 weeks 24 weeks
Role of values in assessing the evidence Critical reading of the literature is not an error finding exercise
The question is to understand why a particular decision about design was made and to assess the impact on the outcome
Example:
QUASAR collaborative group. Adjuvant chemotherapy versus observation in colorectal cancer: a randomised trial. Lancet 2007; 370:2020-9.
Quasar design and main resultsQUASAR (Quick And Simple And Reliable) was designed to provide large scale randomised evidence on the value of adjuvant chemotherapy (5-FU+Folinic) in CRC patients and, in particular, stage II.
- Pragmatic trial design: local clinical teams categorising patients as having clear or uncertain indication for ADJ CHT. No per protocol definition of the indication of CHT, clinician decision.
- Patients with uncertain indication were randomised: CH vs Obs
- Yearly follow-up form that requested serious toxicity, recurrence and death. In the UK, also national mortality records.
- Between 1994 and 2003, 3239 patients entered by 332 clinicians, in 150 centres in 19 countries.
- 91% stage II, 71% colon and 29% rectal cancer. Rdt equally distributed in both groups.
- Pathological data only available in 20% of the cases.
Mortality Adj cht 19.2%
Obs 22.9% RR: 0.82 (0.67-0.99)
Recurrence Adj cht 18.1%
Obs 22.2% RR: 0.78 (0.64-0.95)
Quality of life: only significant differences during CHT
Number needed to treat:
- 1/0.037: 1 out 27 Mortality
- 1/0.041: 1 out 24 Recurrence
Quasar design and main results
Magnitude of the clinical benefit:
Is 3.7% decrease in the risk of death enough? And 4.1% for recurrence?
Are any other evidence supporting this benefit of borderline statistical significance? Yes.
Methodological questions: Patients included: Too heterogeneous? Could we know risk
distribution based on pathology data? Rectal cancer? What about compliance with CHT? 77% of patients received at
least 80% of the full dose and 58% full dose. Did the follow-up of the patients differ between countries? Could it
influence the outcome?
Questions for interpretation of the evidence added by quasar trial
Was the trial design too pragmatic?
Alternatively, did the authors achieve the aim to replicate the relevant question in the clinical practice?
Should we modify our clinical practice/clinical guideline due to the results of this trial?
Let’s assume that this trial has proved the efficacy of adjuvant chemotherapy in stage II CRC:
Which is the chemotherapy we should recommend?
Health policy relevant questions:
Questions for interpretation of the evidence added by quasar trial
Role of personal values and experience in the interpretation of the evidence added by a trialThe decision about what kind of evidence is the most important in a particular clinical situation is a matter of clinical judgment : Evidence is not a substitute for clinical judgment
All these aspects are present in a physician assessment of evidence: Better to make them explicit
In a clinical relationship, values of the physician and the patient, previous experiences of the physician in similar cases as well as the meaning of the disease for the patient, how important are side effects, family support …. are important in assessing evidence and applying it to a particular patient
CONSORT statement
The Revised CONSORT Statement for Reporting Randomized Trials
Douglas G. Altman, DSc; Kenneth F. Schulz, PhD; David Moher, MSc; Matthias Egger, MD; Frank Davidoff, MD; Diana Elbourne, PhD; Peter C. Gøtzsche, MD; and Thomas Lang, MA, for the CONSORT Group
Ann Intern Med. 2001;134:663-694. www.annals.org