ONC: Radiation Therapy (2006)


Bairati I, Meyer F, Gelinas M, Fortin A, Nabid A, Brochet F, Mercier JP, Tetu B, Harel F, Masse B, Vigneault E, Vass S, del Vecchio P, Roy J., A randomized trial of antioxidant vitamins to prevent second primary cancers in head and neck cancer patients. Journal of the National Cancer Institute 2005; 97(7):481-488.

PubMed ID: 15812073
Study Design:
Randomized Controlled Trial
A - Click here for explanation of classification scheme.
Quality Rating:
Positive POSITIVE: See Quality Criteria Checklist below.
Research Purpose:
To assess whether supplementation with a-tocopherol (400 IU/day) and ß-carotene (30 mg/day) could reduce the incidence of second primary cancers among patients with head and neck cancer. A second objective was to see if treatment would reduce the adverse effects of radiation therapy without compromising treatment efficacy and finally, to assess whether the intervention would improve cancer-free survival.
Inclusion Criteria:

Eligible patients were:

·          18 years or older

·          received a fist diagnosis of stage I or II head and neck cancer

·          histologically documented squamous cell carcinoma of the tongue, gum, mouth, oropharynx, hypopharynx, pharynx, or larynx

treated with radiation therapy between Oct 1, 1994 and June 6, 2000 in one of five radiation therapy centers in the province of Quebec, Canada
Exclusion Criteria:

Patients with any of the following conditions:  

·          A 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 ß-carotene or vitamin E in the proceeding year greater than 6.0 mg and 50 IU, respectively
Description of Study Protocol:


·       During the recruitment period, 1151 new patients with squamous cell carcinoma of the head and neck were treated in participating clinics 

o        Of these, 15% refused to participate and 38% were ineligible

o        The remaining 47% were eligible and consented to enroll

·          A computer-generated randomization list was prepared in advance for each collaborating center by using an allocation ratio of 1:1 (supplementation to placebo) and random-permuted blocks

·          Numbers assigned to patients by central coordinating center 




·          Multicenter, double-blind, placebo controlled, randomized chemoprevention trial

·          540 patients randomly assigned to receive a daily supplement consisting of a-tocopherol and ß-carotene (after the first 156 patients only a-tocopherol) or placebos during radiation therapy and for 3 years after radiation therapy ended

·          Intervention started the first day of radiation treatment

·          After 156 patients enrolled, ß-carotene supplementation was discontinued due to ethical concerns stemming from another study

o        Remaining patients received a-tocopherol or placebo only

o        Ethics committee requested analysis of all participants and then analysis excluding the first 156 patients

·          Radiation oncologists and study nurses followed patients on a predetermined schedule

·          Compliance with supplementation and placebos was assessed at each follow-up

o        Divided the total number of unreturned capsules by the number of days between visits

o        Blood test was done at the end of radiation therapy, and at 6, 12, 24, and 36 months after the end of radiation therapy and plasma a-tocopherol and ß-carotene were analyzed by reverse-phase high performance liquid chromatography



Blinding used (if applicable)

·          Throughout the trial, the patients, the treating physicians, the study personnel, and the investigators were kept blind to the patient’s intervention arm assignment

·          Supplements and placebos were identically prepared by a single pharmacist for both groups


 Intervention (if applicable)

 Patients received either supplementation with a-tocopherol (400 IU/day) and ß-carotene (30 mg/day) or placebos from the first day of radiation therapy and continuing for 3 years after the end of radiation therapy.

Statistical Analysis


·          All statistical test were two-sided

·          Intervention and placebo arms compared using a proportional hazards regression model with a two-sided a=0.05

·          Study had 90% power to detect the set hazard ratio of 0.50, but after the first 156 patients were excluded, the trial power was 75.5%

·          Distribution of time until failure in the two treatment arms was described using Kaplin-Meier survival curves

·          The primary analysis, performed under the intention-to-treat principle, was designed to compare the rates of second primary cancers in the two study arms in Cox proportional hazards models

o      For each hazard ratio (HR), the 95% confidence interval (CI) was calculated

o      Models used to adjust for covariates

o      Proportionality assumption of the models was assessed visually, by checking the parallelism of the log cumulative hazard function plotted against the log of follow-up time, and tested by the weighted Schoenfeld residual-score test.

o      Because the proportionality assumption was not satisfied for the main outcome over the entire follow-up period, the analyses were performed by partitioning the distribution of survival time until the occurrence of a second primary cancer

§        During the first 3.5 years of follow-up

§        Beyond 3.5 years after randomization





Data Collection Summary:

Timing of Measurements

Baseline data was collected prior to patient random assignment. Follow-up information was obtained by the radiation oncologists and the study nurses at predetermined times:

·          Immediately

·          1 month after radiation therapy ended

·          Every 6 months during the 3 years following the end of radiation therapy

·          Then once a year till the end of the study (June 30, 2003)

·          Follow-up ended when the last patient enrolled had completed the supplementation period on June 30, 2003


Dependent Variables


    • Variable 1: Incidence of second primary cancer
      • During each visit, the radiation oncologists assessed the recurrence of the initial tumor and the occurrence of any second primary cancer
      • Specific criteria were established for the diagnosis of a second primary cancer
    • Variable 2: Adverse effects of cancer therapy
      • Patients asked to report all potential side effects
      • Coded according to the National Cancer Institute of Canada Clinical Trial Group expanded common toxicity criteria
    • Variable 3:  Cancer-free survival
      • Death certificates obtained for all patients who died
  • ~Independent Variables

 Supplements containing a-tocopherol (400 IU/day) and ß-carotene (30 mg/day)

After the first 156 patients enrolled, the supplement was changed to contain only a-tocopherol 


Control Variables

 ·          Age, gender, cancer stage, cancer type, number who smoked the preceding year, ß-carotene and vitamin E supplementation


Description of Actual Data Sample:


Initial N:

N = 540 patients; 273 supplement group and 267 placebo group

Attrition (final N):

·     Data from all subjects randomized analyzed (273 supplement group and 267 placebo group)

·          40 and 41 patients from the supplement group and placebo group respectively were lost to follow-up or discontinued intervention (reasons noted)

Relevant demographics:

Baseline characteristics of the 540 patients with head and neck cancer randomly assigned to the supplement or placebo arm of the trial


Supplement arm (n=273)

Placebo arm (n=267)

Mean age (SD), y

62.9 (10.0)

62.3 (9.5)

No. of men (%)

223 (82)

203 (76)

No. with stage T2 disease (%)

101 (37)

107 (40)

No. with laryngeal cancer (%)

225 (82)

225 (84)

No. who smoked in preceding year (%)

178 (65)

165 (62)

Mean plasma ß-carotene (SD), umol/L

0.23 (0.18)

0.23 (0.24)

Mean plasma a-tocopherol (SD), umol/L

32.6 (10.4)

33.8 (14.2)

Anthropometrics:  Groups were similar on all measures

Location: Quebec, Canada



Summary of Results:



·          36 and 34 participants from the supplement arm and placebo arm respectively stopped taking the capsules for a reason specified 

·          In the supplement arm, compliance was 90% during radiation therapy and 88%, 84% and 80% during the first, second and third years after the end of radiation therapy

·          In the placebo arm, these figures were 89%, 86%, 83% and 80% respectively.

·          Plasma samples of ß-carotene and a-tocopherol also indicated good compliance

 Results regarding second primary cancers



Supplement Arm

No. SPC*/No. at risk (Rate of SPC/1000 person- years)

Control Arm

No. SPC/No. at risk (Rate of SPC/1000 person- years)


HR (95% CI)

From entry until 3.5 years after randomization




Any supplementation**

48/273 (60.07)

21/267 (25.05)

2.42 (1.45 to 4.04)

a-tocopherol & ß-carotene

10/79 (42.28)

7/77 (28.07)

1.51 (0.58 to 3.98)

a-tocopherol only

38/194 (67.55)

14/190 (23.77)

2.88 (1.56 to 5.31)





Beyond 3.5 years after randomization




Any supplementation***

15/162 (39.43)

29/193 (68.75)

0.57 (0.31 to 1.07)

a-tocopherol & ß-carotene

9/57 (43.35)

12/64 (54.35)

0.80 (0.34 to 1.90)

a-tocopherol only

6/105 (34.72)

17/129 (84.57)

0.41 (0.16 to 1.03)

*SPC = second primary cancers

**The rate of second primary cancers was statistically significantly higher among patents in the supplement arm than among patients in the placebo arm, especially when a-tocopherol was the only supplement.

***After supplementation was discontinued, former supplement users had a lower rate of second primary cancers than former placebo users.  The inverse association was stronger when a-tocopherol was the only supplement.

Smoking did not modify the association between supplementation use and rate of second primary cancers in either of the two time periods.



Results regarding cancer-free survival



Supplement Arm

No. events/No. at risk (Rate of event/1000 person- years)

Control Arm

No. events/No. at risk (Rate of events/1000 person- years)


HR (95% CI)

From entry until 3.5 years after randomization




Any supplementation*

101/273 (141.4)

65/267 (85.08)

1.65 (1.21 to 2.25)

a-tocopherol & ß-carotene

28/79 (133.0)

23/77 (105.3)

1.27 (0.73 to 2.21)

a-tocopherol only**

73/194 (145.0)

42/190 (76.97)

1.86 (1.27 to 2.72)





Beyond 3.5 years after randomization




Any supplementation***

21/138 (64.91)

28/170 (76.14))

0.85 (0.48 to 1.50)

a-tocopherol & ß-carotene

11/49 (61.22)

10/51 (55.39)

1.11 (0.47 to 2.61)

a-tocopherol only

10/89 (69.52)

18/119 (96.15)

0.71 (0.33 to 1.53)

*During the first 3.5 years of follow-up, the rate of having either a recurrence or second primary cancer was statistically significantly higher among patients in the supplement arm than the placebo arm

**This was especially true when a-tocopherol was the only supplement

***After supplementation was discontinued, former supplement users had lower rates of either recurrence or second primary cancer than patients who received placebo, especially when the a-tocopherol was the only supplement.

Smoking did not modify the association between supplementation use and cancer-free survival in either of the two time periods.

Authors did not report on the effects of supplementation in reducing adverse effects of radiation in this publication.





Author Conclusion:
a-tocopherol supplementation produced unexpected adverse effects on the occurrence of second primary cancers and on cancer-free survival in patients with head and neck cancer.
Funding Source:
Government: NCIC
Foundation associated with industry:
Reviewer Comments:

·          Ethnicity of patients was not mentioned

·          The effect of supplementation combining a-tocopherol and ß-carotene could not be examined due to the discontinuation of ß-carotene supplementation during the study and therefore a subsequent lack of statistical power

Quality Criteria Checklist: Primary Research
Relevance Questions
  1. Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies) Yes
  2. Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about? Yes
  3. Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice? Yes
  4. Is the intervention or procedure feasible? (NA for some epidemiological studies) Yes
Validity Questions
1. Was the research question clearly stated? Yes
  1.1. Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified? Yes
  1.2. Was (were) the outcome(s) [dependent variable(s)] clearly indicated? Yes
  1.3. Were the target population and setting specified? Yes
2. Was the selection of study subjects/patients free from bias? Yes
  2.1. Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study? Yes
  2.2. Were criteria applied equally to all study groups? Yes
  2.3. Were health, demographics, and other characteristics of subjects described? Yes
  2.4. Were the subjects/patients a representative sample of the relevant population? Yes
3. Were study groups comparable? Yes
  3.1. Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT) Yes
  3.2. Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline? Yes
  3.3. Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.) Yes
  3.4. If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis? N/A
  3.5. If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.) N/A
  3.6. If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")? N/A
4. Was method of handling withdrawals described? Yes
  4.1. Were follow-up methods described and the same for all groups? Yes
  4.2. Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.) Yes
  4.3. Were all enrolled subjects/patients (in the original sample) accounted for? Yes
  4.4. Were reasons for withdrawals similar across groups? Yes
  4.5. If diagnostic test, was decision to perform reference test not dependent on results of test under study? N/A
5. Was blinding used to prevent introduction of bias? Yes
  5.1. In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate? Yes
  5.2. Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.) Yes
  5.3. In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded? N/A
  5.4. In case control study, was case definition explicit and case ascertainment not influenced by exposure status? N/A
  5.5. In diagnostic study, were test results blinded to patient history and other test results? N/A
6. Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described? Yes
  6.1. In RCT or other intervention trial, were protocols described for all regimens studied? Yes
  6.2. In observational study, were interventions, study settings, and clinicians/provider described? N/A
  6.3. Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect? Yes
  6.4. Was the amount of exposure and, if relevant, subject/patient compliance measured? Yes
  6.5. Were co-interventions (e.g., ancillary treatments, other therapies) described? N/A
  6.6. Were extra or unplanned treatments described? N/A
  6.7. Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups? N/A
  6.8. In diagnostic study, were details of test administration and replication sufficient? Yes
7. Were outcomes clearly defined and the measurements valid and reliable? Yes
  7.1. Were primary and secondary endpoints described and relevant to the question? Yes
  7.2. Were nutrition measures appropriate to question and outcomes of concern? Yes
  7.3. Was the period of follow-up long enough for important outcome(s) to occur? Yes
  7.4. Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures? Yes
  7.5. Was the measurement of effect at an appropriate level of precision? Yes
  7.6. Were other factors accounted for (measured) that could affect outcomes? Yes
  7.7. Were the measurements conducted consistently across groups? Yes
8. Was the statistical analysis appropriate for the study design and type of outcome indicators? Yes
  8.1. Were statistical analyses adequately described and the results reported appropriately? Yes
  8.2. Were correct statistical tests used and assumptions of test not violated? Yes
  8.3. Were statistics reported with levels of significance and/or confidence intervals? Yes
  8.4. Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)? Yes
  8.5. Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)? Yes
  8.6. Was clinical significance as well as statistical significance reported? Yes
  8.7. If negative findings, was a power calculation reported to address type 2 error? N/A
9. Are conclusions supported by results with biases and limitations taken into consideration? Yes
  9.1. Is there a discussion of findings? Yes
  9.2. Are biases and study limitations identified and discussed? Yes
10. Is bias due to study's funding or sponsorship unlikely? Yes
  10.1. Were sources of funding and investigators' affiliations described? Yes
  10.2. Was the study free from apparent conflict of interest? Yes