Revision as of 08:52, 30 June 2024

Reference ↗
Title	Effects of vitamin A on survival in patients with chronic myelogenous leukemia: a SWOG randomized trial
Topic	Vitamin A (beta-carotene)
Author	Meyskens, FL, Kopecky, KJ, Appelbaum, FR, Balcerzak, SP, Samlowski, W, Hynes, H
Year	1995
Journal	Leukemia Research
DOI	https://doi.org/10.1016/0145-2126(95)00032-J

Brief summary

In this study, two groups of CML (chronic myeloid leukemia) patients were compared, with one half receiving chemotherapy and vitamin A and the other group receiving only chemotherapy. There were no significant differences in the time to disease progression, but there was a higher risk of death in the control group than in the vitamin A group. More side effects were reported in the vitamin A group than in the control group (13 compared to 3). Criticisms of this study include the high drop-out rate of patients after randomization because the inclusion criteria were tightened and that the two groups already differed at the beginning of the study.

In dieser Studie wurden zwei Gruppen von CML-Patienten (Chronisch myeloische Leukämie) miteinander verglichen, wobei die eine Hälfte Chemotherapie und Vitamin A und die andere Gruppe nur Chemotherapie erhielt. Es zeigten sich keine bedeutsamen Unterschiede hinsichtlich der Dauer bis zum Fortschreiten der Krankheit, aber in der Kontrollgruppe bestand ein höheres Sterberisiko als in der Vitamin A Gruppe. In der Vitamin A wurden mehr Nebenwirkungen als in der Kontrollgruppe berichtet (13 im Vergleich zu 3). Kritikpunkte an dieser Studie sind die hohe Ausfallrate an Patienten nach der Randomisierung, weil die Einschlusskriterien verschärft wurden und dass sich die beiden Gruppen schon zu Beginn der Studie unterschieden haben.

Study Design

Prospective / Retrospective Prospective: forward-looking, examples include clinical trials, cohort studies, and long-term observational studies;</br>Retrospective: backward-looking, relying on existing data, examples include case-control studies and retrospective cohort studies	Prospective
Monocentric / Multicentric Monocentric: conducted in one center/ hospital; </br>Multicentric: conducted in multiple centers/ hospitals	Multicentric
Blinding No: Open, all parties are aware of group assignments;</br>Single: one party is unaware of group assignments (generally participants);</br>Double: two parties are unaware of group assignments (generally the participants and the researchers); </br>Triple: concealing group assignment from additional parties	No
Is randomized	Yes
Cross-over Participants alternate between different treatment groups or conditions over a specified period, allowing each participant to serve as their own control	No
Number of arms	2

Study characteristics

Inclusion criteria	- Patients with the diagnosis of chronic phase CML for less than 1 year - No prior treatment except with hydroxyurea and/or leukopheresis for less than 7 days (splenectomy allowed) - Patients with myelofibrosis and agnogenic myeloid metaplasia only with positive Ph chromosome test
Exclusion criteria	NI
N randomized	153
Analysis PP: Per Protocol analysis, i.e. only participants included who adhered to the study protocol.</br>ITT: Intention-to-treat analysis, i.e. all randomized participants included regardless of any drop-outs or changes in assignment.</br>mITT: modified Intention-to-treat analysis can refer to analyses in which participants with missing outcome data are excluded or it can refer to analyses in which only participants who received at least one treatment dose are included. In this case, participants dropped out of the study prematurely for reasons unrelated to the treatment.	PP Analysis
Specifications on analyses	- Distributions of progression-free survival estimated by method of Kaplan and Meier - Effects of treatment/patient and disease characteristics analyzed using proportional hazards regression model of Cox - Magnitude of treatment differences was expressed as the relative risk, for busulfan alone relative to the busulfan plus vitamin A
Countries of data collection	United States
LoE Level of evidence	2b Oxford 2009
Outcome timeline Data collection times	T0: Baseline Follow-up, median (range): 76 (37-111) months

Characteristics of participants

Setting Refers to cancer therapy setting.</br>- Curative therapy: aims to completely eradicate a disease and achieve a full recovery; </br>- Neo-adjuvant therapy: form of curative therapy, given before the primary treatment for cancer (usually surgery); </br>- Adjuvant therapy: form of curative therapy, given after the primary treatment for cancer (usually surgery); </br>- Palliative therapy: focuses on providing relief from symptoms and improving the quality of life for patients, without necessarily targeting the underlying disease; </br>- Active surveillance: involves close monitoring of disease progression without any intervention (typically used for prostate cancer);</br>- No therapy setting: Patients who completed therapy/are currently not in cancer treatment, cancer survivors.	Adjuvant
Types of cancer "Other Cancers" means that only a subpopulation was specified, but further unspecified cancer types were included	Hematologic Cancers - Leukemia (Acute Lymphocytic/Acute Myeloid/Chronic Lymphocytic/Chronic Myeloid)
Cancer stages Early Stage: generally refers to cancer that is localized to the area where it started, mostly stages I and II;</br>Advanced Stage: cancer that has spread beyond its original site, mostly stages III and IV, with stage IV indicating distant metastasis	NA
Specifications on cancer stages	NI
Comorbidities	NI
Current cancer therapies	Chemotherapy
Specifications on cancer therapies	Intermittent pulse busulfan: "All patients received busulfan orally at a dose of 8 mg/mm³/day for 4 days every 4 weeks until a chronic stable phase was reached (total leukocyte count <50,000/mm³ but >6,000/mm³) at which time busulfan was discontinued. Busulfan was restarted only when the total leukocyte count exceeded 5O,OOO/mm³. Treatment was reinstated until the total leukocyte count was <50,000 but >6,000."
Previous cancer therapies	No therapy
Gender	Female
Gender specifications	50% female
Age groups	Adults (18+)
Age groups specification	Median per group: - intervention group: 51 - control group: 46

Arms

NI regarding duration in days, median (range) follow-up: 76 (37-111) months

Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment	Intervention
Number of participants (arm) N randomized	57
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	17
Drop-out reasons	Later found to be ineligible (imposition of stricter registration and evaluation procedures)
Intervention	Vitamin A (Aquasol A, active comound retinol until 1982, then retinyl palmitate)
Dosage and regime	- 50,000 IU/day, orally for the duration of the study, median (range) follow-up: 76 (37-111) months - adjustments of vitamin A dosage made in relation to side effects and serum vitamin A levels
One-time application	No
Duration in days For long-term interventions, the number of days is an estimation.</br>A value of -999 indicates that the exact duration cannot be extracted from the study due to ambiguous or incomplete information. See Outcome timeline or Dosage and regime for further information.	-999
Side effects / Interactions	- Grade 4 thrombocytopenia: N = 2 (+ grade 3 leukopenia/grade 1 hyperpigmentation: N = 1, + grade 2 weight loss, anorexia and fatigue: N = 1) - Grade 2 thrombocytopenia: N = 2 - Grade 2 or grade 3 personality change: N = 1 each - Dry skin rashes: N = 4 (1x grade 3) - Grade 1 abdominal cramps: N = 1 - Hepatic side effects: N = 5 - Grade 3 Dry mouth: N = 1 - Grade 2 Fatigue with pain: N = 1 - Grade 2 Anxiety: N = 1 - Grade 1 Restrictive lung disease: N = 1 - Pancreatitis (grade unknown): N = 1

Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment	Passive control
Number of participants (arm) N randomized	67
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	12
Drop-out reasons	Later found to be ineligible (imposition of stricter registration and evaluation procedures)
Intervention	None
Dosage and regime	NA
One-time application	No
Duration in days For long-term interventions, the number of days is an estimation.</br>A value of -999 indicates that the exact duration cannot be extracted from the study due to ambiguous or incomplete information. See Outcome timeline or Dosage and regime for further information.	-999
Side effects / Interactions	- Grade 3 Mucositis, ulcers in esophagus and stomach, vomiting and anorexia: N = 1 - Grade 2 Nausea and vomiting: N = 2 - Grade 1 Abdominal cramps: N = 1 - Grade 1 thrombocytopenia: N = 1 - Dizziness/fainting (grade unknown): N = 1

Outcomes

PFS (Progression-Free Survival)

Outcome type As specificed by the authors	Primary
Outcome specification	Within > 10 years
Type of measurement	Observation
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NA
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	Overall No significant difference between intervention and control group for hazard ratio (p = 0.11) Multivariate analysis (controlled for age, lymphocyte percentage, absolute polymorphonuclear leukocyte count (PMN)) HR = 1.53 (95% CI: 1.01, 2.31); p = 0.022 (meaning risk of progression in control group 53% higher than in intervention group)

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	?
Bias due to deviation from intended intervention (assignment to intervention)	?
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	?
Bias in measurement of the outcome	?
Bias in selection of the reported result	?
Other sources of bias	?
Overall RoB judgment	?

OS (Overall Survival)

Outcome type As specificed by the authors	Primary
Outcome specification	Measured from randomization until death from any cause
Type of measurement	Observation
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NA
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	Overall No significant difference between intervention and control group for hazard ratio (p = 0.081) Multivariate analysis (controlled for age, lymphocyte percentage, absolute polymorphonuclear leukocyte count (PMN)) HR = 1.60 (95% CI: 1.05, 2.43); p = 0.014 (meaning mortality risk in control group 60% higher than in intervention group)

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	?
Bias due to deviation from intended intervention (assignment to intervention)	?
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	?
Bias in measurement of the outcome	?
Bias in selection of the reported result	?
Other sources of bias	?
Overall RoB judgment	?

Toxicity

Outcome type As specificed by the authors	Secondary
Outcome specification	NI
Type of measurement	CTCAE (Common Terminology Criteria of Adverse Events)
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NA
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	Overall Number of side effects ≥ grade 2 - intervention group: 13/56 - control group: 3/67 - p = 0.002

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	?
Bias due to deviation from intended intervention (assignment to intervention)	?
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	?
Bias in measurement of the outcome	?
Bias in selection of the reported result	?
Other sources of bias	?
Overall RoB judgment	?

Funding and Conflicts of Interest

Funding	Funded by National Cancer Institute
Conflicts of Interest	NI

Further points for assessing the study

Sample

Power analysis performed	?
- Sample size corresponds to power analysis
- Reasons for insufficient sample size based on power analysis
If no power analysis performed: at least moderate sample size (n >= 30 per arm)	?
Ethnicity mentioned	?

Alternative Explanation

Other explanations for an effect besides the investigated intervention
- Possibility of attention effects	?
- Possibility of placebo effects	?
- Other reasons	?

Statistics

Correct use of parametric and non-parametric tests Testing for normal distribution only necessary if parametric tests are used, NI: use of parametric tests without report of normal distribution testing
Correction for multiple testing	?
Measurement of compliance	?
Consistent reporting in numbers (figures, flowchart, abstract, results)	?
Comprehensive and coherent reporting	?
Cross-over
- Sufficient washout period	?
- Tested for carry-over effects	?
- Tested for sequence effects	?

Interpretation of results

Effect sizes reported (clinical vs. statistical significance)	?
Side effects systematically recorded	?
Side effects considered in result interpretation	?
Ethics votum	?

Additional Notes