Braik et al. (2014): Randomized trial of vitamin B6 for preventing hand-foot syndrome from capecitabine chemotherapy

Reference ↗
Title	Randomized trial of vitamin B6 for preventing hand-foot syndrome from capecitabine chemotherapy
Topic	Vitamin B6
Author	Braik, T, Yim, B, Evans, A T, Kassem, M, Mullane, M, Lad, T, Hussein, L, Cleveland, B, McDunn, S
Year	2014
Journal	The Journal of Community and Supportive Oncology
DOI	https://doi.org/10.12788/jcso.0017

Brief summary

This study investigated the effect of vitamin B6 on chemotherapy side effects in patients with different types of cancer. At the start of chemotherapy, half of the patients were given a vitamin B6 preparation and the other half a placebo. The two groups did not differ in terms of the number of people with hand-foot syndrome (i.e. painful swelling and redness on the palms of the hands and soles of the feet) and the number of people in whom the chemotherapy dose had to be reduced. Positive aspects of this study are the low drop-out rate of patients over the course of the study and the double blinding (investigators and patients did not know which group they were in). On the negative side, however, fewer patients were examined than necessary to map possible existing effects.

In dieser Studie wurde der Effekt von Vitamin B6 auf Chemotherapie-Nebenwirkungen bei Patienten mit unterschiedlichen Krebsarten untersucht. Mit Beginn der Chemotherapie bekam die Hälfte der Patienten ein Vitamin B6-Präparat und die andere Hälfte ein Placebo. Die beiden Gruppen unterschieden sich nicht hinsichtlich der Anzahl der Personen mit Hand-Fuß-Syndrom (d.h. schmerzhafte Schwellungen und Rötungen an Handflächen und Fußsohlen) und der Anzahl an Personen, bei denen die Chemotherapie-Dosis reduziert werden musste. Positiv an dieser Studie ist die geringe Ausfallrate an Patienten im Laufe der Studie und die doppelte Verblindung (Untersucher und Patienten wussten nicht, in welcher Gruppe sie sind). Negativ ist jedoch, dass weniger Patienten untersucht wurden, als notwendig, um mögliche vorhandenen Effekte abzubilden.

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	Cancer requiring capecitabine therapy; never received capecitabine before; performance status of 0 to 2, according to the Eastern Cooperative Oncology Group (ECOG) classifcation; ife expectancy longer than 6 months; not being on vitamin B supplements; no prior HFS; no contraindication to chemotherapy (ie, patient had adequate bone marrow function, including an absolute neutrophil count > 1,500 cells/L and a platelet count > 100,000/L); adequate renal function (as indicated by a serum creatinine concentration < 1.5 mg/dL); adequate liver function (as indicated by a serum bilirubin concentration < 1.5 mg/dL, a transaminase level < 3 times the upper normal limit, and a serum albumin level > 2.5 mg/dL)
Exclusion criteria	Previous treatment for HFS; hypersensitivity to pyridoxine; immunosuppression or positive human immunodefciency virus (HIV) serology
N randomized	77
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	ITT-analysis not specified, but no drop-out occured. The number of patients developing any grade of HFS in both study arms was obtained. The percentage of HFS in both arms was compared. In order to determine whether the diference between groups was signifcant, the number of patients receiving capecitabine, with and without HFS, was obtained, and the P value was determined through chi-square and Fisher exact calculation.
Countries of data collection	NI
LoE Level of evidence	1b Oxford 2009
Outcome timeline Data collection times	T1-T4: week 3 of each chemotherapy cycle

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.	NI
Types of cancer "Other Cancers" means that only a subpopulation was specified, but further unspecified cancer types were included	Breast Cancer, Breast Cancer - Ductal Carcinoma, Colorectal Cancer - Colon Cancer, Gastrointestinal Cancers - Pancreatic Cancer, Stomach Cancer, Other Cancers, Bile Duct Cancer, Unspecified Sarcoma
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	NI
Specifications on cancer stages	NI
Comorbidities	NI
Current cancer therapies	Chemotherapy
Specifications on cancer therapies	Chemotherapy with capecitabine Capecitabine alone (n = 43) Capecitabine + oxaliplatin (n = 24) Capecitabine + lapatinib (n = 5) Capecitabine + trastuzumab (n = 3) Capecitabine + cetuximab (n = 2)
Previous cancer therapies	NI
Gender	Mixed
Gender specifications	Female n (%): 48 (62)
Age groups	Adults (18+)
Age groups specification	Age in years: mean (SD) = 54.1 (10.41); range: 25-78

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	38
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	0
Drop-out reasons	NA
Intervention	Pyridoxine (vitamin B6)
Dosage and regime	Oral 100mg/day from first day of chemotherapy, daily
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.	150
Side effects / Interactions	NI

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	39
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	0
Drop-out reasons	NA
Intervention	Placebo
Dosage and regime	Oral from first day of chemotherapy, daily
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.	150
Side effects / Interactions	NI

Outcomes

Hand-foot syndrome

Outcome type As specificed by the authors	Primary
Outcome specification	Toxicity of chemotherapy: incidence of hand-foot syndrome (HFS) according to CTCAE (last follow-up: 4th chemotherapy cycle, i.e. after 4-6 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".	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".	Time to onset: median in intervention group and placebo group: after 2 chemotherapy cycles Number of subjects with HFS (%): intervention: 10/38 (26%), placebo: 8/39 (21%); p = 0.547, not significant The groups do not differ in terms of HFS incidence Separated by CTCAE grade: Grade 1: intervention group: 4/38 (4%), placebo group: 2/39 (5%) Grade 2/3: intervention group: 6/38 (16%), placebo group: 6/39 (15%)

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	?

Toxicity

Outcome type As specificed by the authors	NI
Outcome specification	Toxicity of chemotherapy: necessary reduction of the capecitabine dose
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".	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".	Reduction of capecitabine dose (number): intervention group: 9 (2 patients grade 3 diarrhoea with necessary hospitalization, 1 patient grade 3 stomatitis, 4 patients grade 3 HFS, 2 patients grade 3 neutropenia) placebo group: 8 (3 patients grade 3 diarrhea, 2 patients grade 3 stomatitis, 3 patients grade 3 HFS)

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
- 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	?