Jyothirmayi et al. (1996): Efficacy of Vitamin A in the Prevention of Locoregional Recurrence and Second Primaries in Head and Neck Cancer

Reference ↗
Title	Efficacy of Vitamin A in the Prevention of Locoregional Recurrence and Second Primaries in Head and Neck Cancer
Topic	Vitamin A (beta-carotene)
Author	Jyothirmayi, R, Ramadas, K, Varghese, C, Jacob, R, Nair, M, Sankaranarayanan, R
Year	1996
Journal	European journal of cancer.
DOI	https://doi.org/10.1016/S0964-1955(96)00010-3

Brief summary

In this study, two groups of patients with head and neck cancer were compared whereby one group received a common synthetic vitamin A preparation for one year and the other group only a placebo. The study investigated whether the two groups differed over a period of three years with regard to the frequency of local recurrences and second primary tumors. In the vitamin A group, recurrence occurred in 11 out of 56 (20%) patients and in the placebo group in 5 out of 50 (10%). This difference could not be confirmed statistically. Second primary tumors were only reported by two patients in the placebo group. A positive aspect of this study is the double blinding (i.e. investigators and patients do not know which group they are in). However, a major point of criticism is that there were already differences between the two groups at the beginning of the study, making them less comparable. Nevertheless, due to the increased recurrence rate in the vitamin A group, this study provides initial clues to a potentially harmful effect of vitamin A.

In dieser Studie wurden zwei Gruppen von Patienten mit Kopf-Hals-Karzinom miteinander verglichen, wobei eine Gruppe ein Jahr lang ein gängiges synthetisches Vitamin A Präpararat und die andere Gruppe nur ein Placebo bekam. Untersucht wurde, ob sich die beide Gruppe in einem Zeitraum von drei Jahren hinsichtlich der Auftretenshäufigkeit von lokalen Rezidiven und zweiten Primärtumoren unterschieden. In der Vitamin A Gruppe tauchte bei 11 von 56 (20%) Patienten ein Rezidiv auf und in der Placebogruppe bei 5 von 50 (10%). Dieser Unterschied konnte statistisch nicht bestätigt werden. Zweite Primärtumore wurden nur von zwei Patienten in der Placebogruppe berichtet. Positiv an dieser Studie ist die doppelte Verblindung (d.h. Untersucher und Patienten wissen nicht, in welcher Gruppe sie sind). Ein großer Kritikpunkt ist jedoch, dass schon zu Beginn der Studie Unterschiede zwischen den beiden Gruppen bestanden und diese deswegen schlechter vergleichbar waren. Trotzdem liefert diese Studie wegen der erhöhten Rezidivrate in der Vitamin A Gruppe erste Hinweise auf eine möglicherweise schädliche Wirkung von Vitamin A.

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	Monocentric
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	Double
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 HNC, who revealed complete clinical regression of lesions on follow-up after therapy - Either radical radiotherapy or surgery or both during the earlier half of 1991 - No clinical evidence of disease, normal liver and kidney function
Exclusion criteria	NI
N randomized	106
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.	ITT Analysis
Specifications on analyses	NI
Countries of data collection	India
LoE Level of evidence	1b Oxford 2009
Outcome timeline Data collection times	T0: Baseline T1: after three years

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.	No therapy setting
Types of cancer "Other Cancers" means that only a subpopulation was specified, but further unspecified cancer types were included	Head and Neck Cancers
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	Early Stage, Advanced Stage
Specifications on cancer stages	Number per group: - intervention: 17x I, 19x II, 14x III and IV - placebo: 18x I, 20x II, 18x III and IV
Comorbidities	NI
Current cancer therapies	No therapy
Specifications on cancer therapies	Previous treatment per group: - intervention: 44x radiotherapy, 3x surgery, 3x radiotherapy + surgery - placebo: 47x radiotherapy, 5x surgery, 4x radiotherapy + surgery
Previous cancer therapies	Surgery, Radiation therapy
Gender	Mixed
Gender specifications	Number male, female per group: - intervention: 36/50, 14/50 - placebo: 37/50, 19/50
Age groups	Adults (18+)
Age groups specification	Mean: 57.2

Arms

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	56
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	7
Drop-out reasons	NI
Intervention	Vitamin A
Dosage and regime	Oral vitamin A 200,000 IU per week as chewable tablets of retinyl palmitate
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.	365
Side effects / Interactions	dryness of the tongue (n=2), not a drop-out reason

Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment	Placebo
Number of participants (arm) N randomized	50
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	8
Drop-out reasons	NI
Intervention	Placebo
Dosage and regime	Oral capsules with tapioca powder
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.	365
Side effects / Interactions	NI

Outcomes

Recurrence rate

Outcome type As specificed by the authors	Primary
Outcome specification	Loco-regional recurrences in %
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".	- Intervention group 20% vs. placebo group 10% - According to authors no significant differences (no p-value given)

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	?

Tumor progression

Outcome type As specificed by the authors	Primary
Outcome specification	Incidence of second primary tumors
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".	- None in intervention group - Two in placebo group (1 case of tongue cancer and 1 of floor of mouth cancer) - No p-values reported

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	?

Vitamin A level

Outcome type As specificed by the authors	Primary
Outcome specification	Serum vitamin A level
Type of measurement	Blood Test
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".	Mean (μg/ml) at baseline - intervention group: 0.6 - placebo group: 0.5
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".	Mean (μg/ml) after three years - intervention group: 0.78 - placebo group: 0.5 - no p-values reported

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	NI
Conflicts of Interest	NI

Further points for assessing the study

Sample

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

Alternative Explanation

Other explanations for an effect besides the investigated intervention	NI
- 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	NI
Correction for multiple testing	?
Measurement of compliance	?
Consistent reporting in numbers (figures, flowchart, abstract, results)	?
Comprehensive and coherent reporting	?
Cross-over	NI
- 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

PRO:

• Double blinding
• High compliance rate (intervention: 89%, control: 86%)
• Intention-to-treat (dropout intervention: 12.5%, control: 16%)

CONTRA:

• No ethics vote reported
• No power analysis performed
• Partial descriptive group differences at Baseline (e.g. age: intervention: 56.3 vs. control: 58.2; stage III/IV: intervention: 18, control: 14)
• Hardly any correct statistical tests
• Poor report quality, e.g. no information on exact time period between radiotherapy/surgery and baseline