Mayne et al. (2001): Randomized Trial of Supplemental beta-Carotene to Prevent Second Head and Neck Cancer

Reference ↗
Title	Randomized Trial of Supplemental beta-Carotene to Prevent Second Head and Neck Cancer
Topic	Vitamin A (beta-carotene)
Author	Mayne, S, Cartmel, B, Baum, M, Shor-Posner, G, Fallon, B, Briskin, K, Bean, J, Zheng, T, Cooper, D, Friedman, C, Goodwin, W
Year	2001
Journal	Cancer Research
DOI	https://pubmed.ncbi.nlm.nih.gov/11245451/

Brief summary

In this study, patients with head and neck cancer were examined, one group of whom received beta-carotene (i.e. a precursor of vitamin A) and the other group a placebo. There were no significant differences between the two groups in the incidence of local recurrence or second primary tumors (in the head and neck, esophagus or lung). In contrast to most areas, where the beta-carotene group tended to have slightly fewer cases, the risk of developing lung cancer tended to be higher in the beta-carotene group than in the placebo group. There was no difference between the two groups in terms of survival, although patients in the beta-carotene group were on average older when they died. Overall, this study is of good methodological quality.

In dieser Studie wurden Patienten mit Kopf-Hals-Karzinom untersucht, von denen eine Gruppe Betacarotin (d.h. eine Vorstufe von Vitamin A) und die andere Gruppe ein Placebo bekam. Zwischen den beiden Gruppen zeigten sich keine bedeutsamen Unterschiede hinsichtlich der Häufigkeit des Auftretens von Lokalrezidiven oder zweiten Primärtumoren (im Kopf/Hals-Bereich, an der Speiseröhre oder an der Lunge). Im Gegensatz zu den meisten Bereichen, bei denen die Betacarotin-Gruppe zumindest der Tendenz nach jeweils ein bisschen weniger Fälle vorwies, war das Risiko ein Lungenkarzinom zu entwickeln in der Betacarotin-Gruppe der Tendenz nach höher als in der Placebogruppe. Hinsichtlich der Überlebensdauer unterschieden sich die beiden Gruppen nicht, wobei die Patienten der Betacarotin-Gruppe durchschnittlich älter waren, als sie starben. Im Großen und Ganzen ist diese Studie von guter methodischer Qualität.

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	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	- Recently diagnosed stage I or stage II squamous cell carcinoma of one of the following sites: tongue, gum or mouth, oropharynx, hypopharynx, pharynx, or laryn (carcinoma in situ also eligible) - Between 20 and 79 years of age - Completed treatment for the first cancer (generally radiation therapy or surgical excision), considered free of cancer at any site at entry into the trial - No significant comorbidities - No use of supplements of retinol, b-carotene, vitamin E, or selenium within the past year (multivitamin use allowed)
Exclusion criteria	Patients with prior upper aerodigestive tract cancers within the past 5 years, or with synchronous cancers of the esophagus or lung
N randomized	264
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	- Survival curves generated (Kaplan and Meier) - Log-rank test used to compare survival distributions between the two groups - Cox proportional hazards models used to calculate the RR (relative risk) of having an end point in the b-carotene group relative to those taking placebo, adjusted for other covariates
Countries of data collection	United States
LoE Level of evidence	1b Oxford 2009
Outcome timeline Data collection times	T0: Baseline T1: Follow-up, median (range): 51.1 (30-90) 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.	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, Head and Neck Cancers - Oral Cancer, Head and Neck Cancers - Oropharyngeal Cancer, Head and Neck Cancers - Laryngeal Cancer, Head and Neck Cancers - Nasopharyngeal Cancer
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
Specifications on cancer stages	Per group n (%) - intervention: in situ 6 (4%), I 83 (62%), II 45 (34%) - placebo: in situ 7 (5%), I 82 (64%), II 40 (31%)
Comorbidities	None
Current cancer therapies	No therapy
Specifications on cancer therapies	NI
Previous cancer therapies	Surgery, Diverse, Radiation therapy
Gender	Mixed
Gender specifications	Per group n (%) - intervention: male 113 (84%), female 22 (16%) - placebo: male 101 (78%),female 28 (22%)
Age groups	Adults (18+)
Age groups specification	Per group mean (SD) - intervention: 67.8 (9.8) - placebo: 67.9 (9.3)

Arms

NI regarding specific duration in days, median (range) follow-up: 51.1 (30-90) 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	135
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	lost to follow-up
Intervention	Beta-carotene (Lurotin, BASF, Wyandotte, MI)
Dosage and regime	50mg per day orally for the duration of the study, median (range) follow-up: 51.1 (30-90) months
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	- Number of side effects ≥ grade 2 (standard toxicity grading scales): 5 - Symptoms (not separated between groups): Depression, headaches, bone pain, cheilitis, dry skin, diarrhea - Yellowing of the skin: 25 patients (18%)

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	129
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	4
Drop-out reasons	lost to follow-up
Intervention	Placebo
Dosage and regime	One capsule per day orally for the duration of the study, median (range) follow-up: 51.1 (30-90) months
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	- Number of side effects ≥ grade 2 (standard toxicity grading scales): 4 - Symptoms (not separated between groups): Depression, headaches, bone pain, cheilitis, dry skin, diarrhea - Yellowing of the skin: 8 patients (6%)

Outcomes

Tumor progression

Outcome type As specificed by the authors	Primary
Outcome specification	Combined incidence of local recurrence or second primary tumor (head and neck, esophagus or lung)
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 placebo group regarding hazard ratio and time period until occurrence (p=0.59) - Less risk for intervention group (not significant)

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	Secondary
Outcome specification	a) Incidence of local recurrence alone b) Incidence of second primary tumor alone
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 a) Less risk for intervention group but no significant difference between intervention and placebo group regarding hazard ratio b) Higher risk for intervention group but no significant difference between intervention and placebo group regarding hazard ratio

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	Secondary
Outcome specification	Local recurrence AND second primary tumor in one person at the same time
Type of measurement	?
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 Less risk for intervention group but no significant difference between intervention and placebo group regarding hazard ratio

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	Secondary
Outcome specification	Specific results for: a) age of death b) stratification with regard to smoking history (less than 25 pack/year vs. more than 25 pack/year c) stratification with regard to plasma beta-carotene
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 OS: no significant difference between intervention and placebo group regarding hazard ratio a) mean age (SD): intervention group 69.7 (6.4) vs. placebo group 64.4 (8.8); p = 0.01 b) both smokers and non-smokers not significantly better in intervention arm c) no significant difference in hazard ratio for low vs. high plasma beta-carotene

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	Supported by Grants from the U. S. 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	?