Bairati et al. (2005): Randomized Trial of Antioxidant Vitamins to Prevent Acute Adverse Effects of Radiation Therapy in Head and Neck Cancer Patients

Reference ↗
Title	Randomized Trial of Antioxidant Vitamins to Prevent Acute Adverse Effects of Radiation Therapy in Head and Neck Cancer Patients
Topic	Vitamin A (beta-carotene), Vitamin E
Author	Bairati, I, Meyer, F, Gélinas, M, Fortin, A, Nabid, A, Brochet, F, Mercier, J, Têtu, B, Harel, F, Abdous, B, Vigneault, É, Vass, S, del Vecchio, P, Roy, J
Year	2005
Journal	Journal of clinical oncology
DOI	https://doi.org/10.1200/JCO.2005.05.514

Study Note

Studies that look at other outcomes in the same sample are Bairati et al. (2005): A Randomized Trial of Antioxidant Vitamins to Prevent Second Primary Cancers in Head and Neck Cancer Patients and Bairati et al. (2006): Antioxidant vitamins supplementation and mortality: a randomized trial in head and neck cancer patients.

Brief summary

In this study by Bairati and colleagues, 540 patients with head and neck cancer in the first or second cancer stage were examined. The patients were in five different hospitals in Canada, but were all treated with radiotherapy. They were randomly divided into groups and given either vitamin E and beta-carotene or corresponding placebos. Due to concerns about the side effects of beta-carotene during the course of the study, the treatment arm was only given vitamin E from 1996 onwards and, in addition to the analyses of all 540 patients, separate calculations were made for patients who had received the vitamin combination and patients who had received vitamin E alone. The sample collected was analyzed in three different studies (see also Bairati et al. (2005): A Randomized Trial of Antioxidant Vitamins to Prevent Second Primary Cancers in Head and Neck Cancer Patients and Bairati et al. (2006): Antioxidant vitamins supplementation and mortality: a randomized trial in head and neck cancer patients). In this study, the effects on the tolerability of the radiotherapy treatment and the quality of life were investigated. The side effects caused by radiotherapy were less severe in patients in the treatment arm receiving beta-carotene and vitamin E, which was particularly evident in the larynx. Quality of life was generally not improved by the vitamins, although patients in the treatment arm had less sleep disturbances. On the other hand, the patients mentioned had more frequent diarrhea and, due to the more frequent occurrence of local recurrences, it is questionable to what extent the vitamin combination may have reduced the effect of radiotherapy. In patients who only received vitamin E, there were no significant differences in the side effects compared to the placebo arm. Overall, the results should not be generalized. Due to the fact that beta-carotene was discontinued after a relatively short time, the sample examined up to that point was not sufficient to be able to carry out precise analyses and draw reliable conclusions. It is therefore difficult to draw conclusions about the effect of a combination of beta-carotene and vitamin E. A positive aspect of this study was the double blinding and the fact that most patients took the medication as prescribed in the study. On the negative side, however, due to the lack of some characteristics of the vitamin E arm and placebo patients, it cannot be assumed that the groups were fully comparable. In addition, further distortions cannot be ruled out due to the poor report quality.

In dieser Untersuchung von Bairati und Kollegen wurden 540 Patienten mit Kopf-Hals Karzinomen im ersten oder zweiten Krebsstadium untersucht. Die Patienten befanden sich in fünf verschiedenen Krankenhäusern in Kanada, wurden aber alle mit Radiotherapie behandelt. Man gab ihnen in zufällig aufgeteilten Gruppen entweder Vitamin E und Betacarotin oder entsprechende Placebos. Dadurch, dass es im Verlauf der Studie Bedenken bzgl. der Nebenwirkungen von Betacarotin gab, wurde der Behandlungsgruppe ab 1996 nur noch Vitamin E verabreicht und es fanden zusätzlich zu den Analysen aller 540 Patienten separate Berechnungen statt für Patienten, die die Vitaminkombination, und Patienten, die nur Vitamin E erhalten hatten. Die erhobene Stichprobe wurde in drei verschiedenen Studien ausgewertet (siehe auch Bairati et al. (2005): A Randomized Trial of Antioxidant Vitamins to Prevent Second Primary Cancers in Head and Neck Cancer Patients and Bairati et al. (2006): Antioxidant vitamins supplementation and mortality: a randomized trial in head and neck cancer patients). In dieser Studie wurden die Auswirkungen auf die Verträglichkeit der Radiotherapiehandlung sowie die Lebensqualität untersucht. Die Nebenwirkungen, die durch die Radiotherapie ausgelöst wurden, waren bei Patienten der Behandlungsgruppe, welche Betacarotin und Vitamin E erhielt, weniger schwer, was insbesondere am Kehlkopf zu sehen war. Die Lebensqualität verbesserte sich durch die Vitamine im Allgemeinen nicht, allerdings hatten Patienten in der Behandlungsgruppe seltener Schlafstörungen. Auf der anderen Seite hatten die genannten Patienten häufiger Durchfall und durch das häufigere Auftreten von Lokalrezidiven ist es fraglich, inwiefern, die Vitaminkombination die Wirkung der Radiotherapie evtl. verringerte. Bei Patienten, welche nur Vitamin E erhielten, zeigten sich bei den Nebenwirkungen keine bedeutsamen Unterschiede im Vergleich zur Placebogruppe. Insgesamt sollte man die Ergebnisse allerdings alle nicht verallgemeinern. Aufgrund der Tatsache, dass Betacarotin nach relativ kurzer Zeit abgesetzt wurde, reicht die bis dahin untersuchte Stichprobe nicht, um genaue Analysen durchführen zu können und gesicherte Aussagen zu treffen. Rückschlüsse auf die Wirkung einer Kombination aus Betacarotin und Vitamin E sind somit nur schwer möglich. Positiv an dieser Studie war die doppelte Verblindung und dass die meisten Patienten die Medikation so eingenommen haben, wie in der Studie vorgegeben. Negativ war jedoch, dass aufgrund des Fehlens einiger Charakteristika der Gruppe Vitamin E und Placebo-Patienten nicht von einer vollständigen Vergleichbarkeit der Gruppen ausgegangen werden kann. Außerdem können wegen der schlechten Berichtqualität weitere Verzerrungen nicht ausgeschlossen werden.

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	- First diagnosis of stage I or II, histologically documented, squamous cell carcinoma of the tongue, gum, mouth, oropharynx, hypopharynx, pharynx, or larynx - scheduled to be treated by radiation therapy between October 1, 1994, and June 6, 2000, in one of five radiation therapy centers in the province of Quebec, Canada
Exclusion criteria	- Karnofsky performance score of less than 60 - multiple primary head and neck cancers or a history of cancer - severe cardiovascular disease - inadequate renal, hepatic, or hematologic function - anticoagulant therapy - pregnancy - average daily supplement intake of β-carotene or vitamin E in the preceding year greater than 6.0 mg and 50 IU, respectively
N randomized	540
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, ITT Analysis
Specifications on analyses	Main analyses conducted in two ways: 1) among all participants (any supplementation) 2) separately for the first 156 participants (combined intake of beta-carotene and Vitamin E) and for the 384 patients subsequently enrolled (only Vitamin E) 4 patients (1 in intervention arm, 3 in placebo arm) did not complete their radiation therapy as planned but were included in the analyses
Countries of data collection	Canada
LoE Level of evidence	2b Oxford 2009
Outcome timeline Data collection times	T0: before radiotherapy T1: during radiotherapy T2: immediately post-radiotherapy T3: 1 month post-radiotherapy from T4: every 6 months for 3 years, then once a year until 30.06.2003

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.	Curative
Types of cancer "Other Cancers" means that only a subpopulation was specified, but further unspecified cancer types were included	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	Stage I or stage II cancer, n (%) of stage II disease per arm: - intervention: 101 (37) - placebo: 107 (40)
Comorbidities	NI
Current cancer therapies	Radiation therapy
Specifications on cancer therapies	NA
Previous cancer therapies	NI
Gender	?
Gender specifications	N (%) of men per arm: - intervention: 223 (82) - placebo: 203 (76)
Age groups	Adults (18+)
Age groups specification	Mean (SD) in years per arm: - intervention: 62.9 (10.0) - placebo: 62.3 (9.5)

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	273
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	40 (none excluded from analysis)
Drop-out reasons	Lost to follow-up (n=4) Discontinued intervention (n=36) - Capsule side-effects (n=6) - Difficulty swallowing capsules (n=3) - Other medical problems (n=9) - Participation too troublesome (n=13) - Wanted to take vitamin E (n=2) - Physician requested to stop (n=3)
Intervention	Beta-carotene + Vitamin E
Dosage and regime	In 1996 (2 years after the start of the study) the beta-carotene intervention was discontinued due to indications of harmful effects. Therefore 2 types of "Dosage and regime" (old, i.e. before 1996 and new, i.e. after 1996) are reported. OLD (n=79) - 30mg Betacarotin + 400 IU Vitamin E daily, start with first day of radiotherapy - Duration: up to 3 years after radiotherapy, median (range): 320 (21-609) days NEW (n=194) - 400 IU Vitamin E daily, start with first day of radiotherapy - Duration: up to 3 years after radiotherapy
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	N of side effects of any grade attributed to the supplementation (n=62) - Cardiovascular: 1 - Endocrine: 1 - Flu-like symptoms: 3 - Gastrointestinal: 31 - Genitourinary: 1 - Neurologic: 3 - Skin: 3 - Yellowing of the skin: 19

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	267
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	41 (none excluded from analysis)
Drop-out reasons	Lost to follow-up (n=7) Discontinued intervention (n=34) - Capsule side-effects (n=6) - Other medical problems (n=8) - Participation too troublesome (n=13) - Wanted to take vitamin E (n=5) - Physician requested to stop (n=2)
Intervention	Placebos
Dosage and regime	In 1996 (2 years after the start of the study) the beta-carotene intervention was discontinued due to indications of harmful effects. Therefore 2 types of "Dosage and regime" (old, i.e. before 1996 and new, i.e. after 1996) are reported. OLD (n=77) - 1 placebo daily, start with first day of radiotherapy - Duration: up to 3 years after radiotherapy, median (range): 320 (21-609) days NEW (n=190) - 2 placebos daily, start with first day of radiotherapy - Duration: up to 3 years after radiotherapy
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	N of side effects of any grade attributed to the supplementation (n=32) - Gastrointestinal: 23 - Genitourinary: 1 - Neurologic: 2 - Skin: 6

Outcomes

Toxicity

Outcome type As specificed by the authors	Secondary
Outcome specification	Acute Adverse Effects of Radiation Therapy: most severe radiation therapy adverse effect with regards to baseline status, graded from 0 (no symptom) to 4 (severe symptom), in six sites (skin, mucosa, ear, salivary glands, pharynx and esophagus, and larynx)
Type of measurement	RTOG Acute Radiation Morbidity Scoring Criteria (Radiation Therapy Oncology Group)
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".	Side effects for any supplementation during radiotherapy (T1): All sides: OR = 0.72 (95% CI: 0.52, 1.02), i.e. no significant difference between intervention and placebo arm Larynx, skin, mucosa, pharynx and esophagus: no significant differences Side effects for beta-carotene + Vit. E during radiotherapy (T1): All sides: OR = 0.38 (95% CI: 0.20, 0.74), i.e. significant difference between intervention and placebo arm (lower risk for intervention arm) Larynx only: OR = 0.38 (95% CI: 0.21, 0.71), i.e. significant difference between intervention and placebo arm (lower risk for intervention arm) Skin, mucosa, pharynx and esophagus: no significant differences Side effects for only Vit. E during radiotherapy (T1): All sides: OR = 0.92 (95% CI: 0.62, 1.38), i.e. no significant difference between intervention and placebo arm Larynx, skin, mucosa, pharynx and esophagus: no significant differences
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".	Side effects for any supplementation directly post-radiotherapy (T2): All sides: OR = 0.77 (95% CI: 0.54, 1.09), i.e. no significant difference between intervention and placebo arm Larynx, skin, mucosa, pharynx and esophagus: no significant differences Side effects for beta-carotene + Vit. E directly post-radiotherapy (T2): Total: OR = 0.33 (95% CI: 0.17, 0.65), i.e. significant difference between intervention and placebo arm (lower risk for intervention arm) Larynx only: OR = 0.42 (95% CI: 0.23, 0.77), i.e. significant difference between intervention and placebo arm (lower risk for intervention arm) Skin, mucosa, pharynx and esophagus: no significant differences Side effects for only Vit. E directly post-radiotherapy (T2): Total: OR = 1.06 (95% CI: 0.70, 1.60), i.e. no significant difference between intervention and placebo arm Larynx, skin, mucosa, pharynx and esophagus: no significant differences Side effects for any supplementation 1 month post-radiotherapy (T3): All sides: OR = 1.11 (95% CI: 0.79, 1.55), i.e. no significant difference between intervention and placebo arm Larynx, skin, mucosa, pharynx and esophagus: no significant differences Side effects for beta-carotene + Vit. E 1 month post-radiotherapy (T3): Total: OR = 0.98 (95% CI: 0.52, 1.87), i.e. no significant difference between intervention and placebo arm Larynx only: OR = 0.61 (95% CI: 0.32, 1.17), i.e. no significant difference between intervention and placebo arm Skin, mucosa, pharynx and esophagus: no significant differences Side effects for only Vit. E 1 month post-radiotherapy (T3): Total: OR = 1.17 (95% CI: 0.78, 1.74), i.e. no significant difference between intervention and placebo arm Larynx, skin, mucosa, pharynx and esophagus: no significant differences

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	?

Quality of life

Outcome type As specificed by the authors	Secondary
Outcome specification	NI
Type of measurement	EORTC QLQ (European Organisation for Research and Treatment of Cancer Core/ Quality of Life questionnaire), HNQR (Head and Neck Radiotherapy Questionnaire)
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".	NI
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 difference (95% CI) between intervention and placebo arm for any supplementation 1 month post-radiotherapy (T3): - EORTC QLQ-C30 sleep disturbance: 4.05 (0.37, 8.48); p = 0.07 (p = 0.02 for beta-carotene + Vit. E ) - EORTC QLQ-C30 diarrhea: -2.74 (-4.54, -0.93); p = 0.003) - EORTC QLQ-C30 remaining scales: no significant differences - HNQR: no significant differences No reported results regarding only Vit. E

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	?

Recurrence rate

Outcome type As specificed by the authors	NI
Outcome specification	Local recurrence operationalized as possible indicator of compromisation of treatment (radiotherapy) efficacy; median duration of follow-up: 51 months
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".	Local recurrence for any supplementation HR = 1.37 (95% CI: 0.93, 2.02),i.e. no significant difference between intervention and placebo arm Local recurrence for beta-carotene + Vit. E HR = 1.56 (95% CI: 0.79, 3.07), i.e. no significant difference between intervention and placebo arm Local recurrence for only Vit. E HR = 1.29 (95% CI: 0.89, 2.08), i.e. no significant difference between intervention and placebo arm

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	Financially supported by National Cancer Institute (with funds from the Canadian Cancer Society) Bairati: Recipient of a Senior Scientist Award from the Fonds de Recherche en Santé du Québec All capsules were supplied by Roche Vitamins Inc. (Parsippany, NJ)
Conflicts of Interest	According to authors no conflict of interest

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

PRO:

• Ethics vote
• Comparably high compliance in both arms
• Information on the development of beta-carotene/vitamin E levels
• Low dropout (T3: 3%)
• Performance of power analyses
• Double blinding
• Intention-to-treat analysis
• Consideration of possible confounding variables (e.g. clinical or smoking status)

CONTRA:

• Possible group differences from baseline in the subgroups (beta-carotene + vitamin E/ vitamin E only, were not analyzed separately)
• Differently sized groups despite the indication of a 1:1 randomization
• Changes to the study protocol during the course of the study
• Poor report quality, sometimes contradictory information in the individual publications (see Study Note) for results