EAL

ONC: Chemotherapy (2006)

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

"To investigate the role of high dose multiple antioxidants as an adjunct to chemotherapy in the management of human non-small cell lung carcinoma."

Inclusion Criteria:

Informed consent
Previously untreated
< 65 years of age
Cytologically or histologically confirmed advanced stage (IIIB or IV) non-small-cell lung cancer with measurable lesions
Karnofsky's Performance Status > 60
Adequate organ function (e.g. leuckoycte > 4000/mm³; platelet count > 1000,000/mm³, hemoglobin > 9.5g/dL, aspartate aminotransferase and alanine aminotransferase levels < 100 IU/mL, serum creatinine level < 1.2 mg/Dl, creatinine clearance > 60 mL/minute).

Exclusion Criteria:

Interstitial pneumonia, pulmonary fibrosis, myocardial infarction within the preceding 3 months
Uncontrolled diabetes mellitus
Massive pleural or peritoneal effusion
Symptomatic brain metastases requiring whole-brain irradiation
Pregnant
Lactating

Description of Study Protocol:

Recruitment: From regular cancer outpatients

Design: Patients were randomized to receive chemotherapy alone or chemotherapy and multiple high-dose antioxidants

Blinding used: Not described

Intervention: Patients in both arms received paclitaxel 225 mg/m2 over 3 hours on the first day and carboplatin dosed to AUC of 6 on the second day. Chemotherapy was repeated every three weeks for a maximum of 6 cycles.

Patients in the study arm received an oral dose of high-dose antioxidants

Statistical Analysis:

Chi square test of Fisher's exact test to analyze patients' characteristics, prognostic variables, response rates, and toxicities
Student's t-test to compare age distribution
Kaplan-Meier method was used to caculate survival curves and compared withing the two groups with the log-rank test.

Data Collection Summary:

Timing of Measurements:

Every visit: History and physical examination, complete blood count and serum chemistry
Baseline and after every chemotherapy cycle: Chest radiograph
Baseline and after 3 and 6 cycles: CT scan of chest and upper abdomen
Every week for the first 6 weeks then every 2 weeks over the entire treatment period: toxicity assessment
After 3 cycles responding patients (stage IIIB) were assessed for resectability of tumors.
Every month in follow up: clincial and radiological evaluation. Chest CT scan and upper abdomen every 3 months.

Dependent Variables

Response to treatment
Toxicity assessed using National Cancer Institute Common Toxicity Criteria
Survival and survival time

Independent Variables

Antioxidant vitamin dose: vitamin C (ascorbic acid) 6100 mg/day; vitamin E (dl-alpha-tocopherol succinate) 1050 mg/day; synthetic beta-carotene 60 mg/day. The vitamin E also contained selenium, copper sulfate, and zinc sulfate

Patients in the study arm received an oral dose of high-dose antioxidants 2 days prior to chemotherapy and continued for the course of the treatment. After completion of chemotherapy, antioxidant doses were tapered to half over a period of 1 month and continued for the entire observation period.

Compliance assessed by blister pack count and patient recall.

Description of Actual Data Sample:

Initial N: Study group N=72, 59 (83.6), control group N=64, 54 (87.2) males

Age: Study group median age 54, range 32-65, control group median age 58, range 26-65

Other relevant demographics: No significant differences between groups in sex, age, positive history of tobacco and alcohol use, Kanfosky Performance Status (70), cancer stage or histology.

Location: New Delhi, India

Summary of Results:

There were no statistical differences between the groups in response to treatment, survival and survival time or toxicity.

Chemotherapy group: overall survival is 32.9% at one year and 11.1% at two years; median survival is 9 months
Intervention group: overall survival is 39.1% at one year and 15.6% at two years; median survival is 11 months

Author Conclusion:

Study limitations include

"The antioxidants could not be used in their biologically acitve forms due to constraints of commerical availability. ..thus there is a possibility that the results might improve if more active forms of antioxidant vitamins are used."
"...the antioxidant preparation used by us contained other compunds like copper sulfate, manganese sulfate, zinc sulfate and selenium, which migh have affected the results."
"Another limitiation of the present study is that serum levels of the antioxidates were not established. In order to establish an optimal dose response relationship, it is essential that furture studies utilizing antioxidant preparations be based on pharmacokinetic data."

"In conclusion, antioxidant supplementation during paclitaxel/carboplatin containing chemotherapy for in non-small cell lung cancer appears to be safe and the results of the present study do not support that hypothesis that antioxidant vitamins could compromise the efficacy of standard chemotherapy. There is a possibility that these agents could be potentially useful in the management of non-small cell luncger cancer. Larger controlled trials are required to ascertain their exact role."

Funding Source:

Not-for-profit

Foundation associated with industry:

Reviewer Comments:

Note: Alpha-tocopherol (α-tocopherol) is the name of the most active form of vitamin E in humans. It is also a powerful biological antioxidant. The synthetic form is labeled "D, L" while the natural form is labeled "D". The synthetic form is only half as active as the natural form. (From the National Institutes of Health Office of Dietary Supplements, accessed July 28, 2006 http://ods.od.nih.gov/factsheets/vitamine.asp)

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?		N/A
	4.1.	Were follow-up methods described and the same for all groups?	N/A
	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%.)	N/A
	4.3.	Were all enrolled subjects/patients (in the original sample) accounted for?	N/A
	4.4.	Were reasons for withdrawals similar across groups?	N/A
	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?		???
	5.1.	In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate?	???
	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.)	???
	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?		N/A
	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?	N/A
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?	N/A
	7.4.	Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures?	N/A
	7.5.	Was the measurement of effect at an appropriate level of precision?	N/A
	7.6.	Were other factors accounted for (measured) that could affect outcomes?	???
	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?	No
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