Ota et al. (2014): The effect of pyridoxine for prevention of hand-foot-syndrome in colorectal cancer patients with adjuvant chemotherapy using capecitabine: A randomized study

Reference ↗
Title	The effect of pyridoxine for prevention of hand-foot-syndrome in colorectal cancer patients with adjuvant chemotherapy using capecitabine: A randomized study
Topic	Vitamin B6
Author	Ota, M, Tatsumi, K, Suwa, H, Watanabe, J, Watanabe, K, Osada, S, Tanaka, K, Shoichi, F, Ichikawa, Y, Kunisaki, C, Endo, I
Year	2014
Journal	Hepato-Gastroenterology
DOI	http://www.ncbi.nlm.nih.gov/pubmed/26158157

Brief summary

This study investigated the effect of vitamin B6 on chemotherapy side effects in patients with colorectal cancer. Half of the patients received a vitamin B6 preparation in addition to chemotherapy and the other half only chemotherapy. The two groups did not differ in the number of people with hand-foot syndrome (i.e. painful swelling and redness of the palms and soles of the feet) and the number of people with other common side effects such as leukopenia (lack of white blood cells) and nausea or diarrhea. There are some criticisms of this study. Firstly, the small sample size and secondly, the poor quality of reporting (e.g. there is no information on the failure rate).

In dieser Studie wurde der Effekt von Vitamin B6 auf Chemotherapie-Nebenwirkungen bei Patienten mit Darmkrebs untersucht. Die Hälfte der Patienten bekam neben der Chemotherapie ein Vitamin B6-Präparat und die andere Hälfte nur Chemotherapie. 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 mit anderen häufigen Nebenwirkungen wie Leukopenie (Mangel an weißen Blutzellen) und Übelkeit oder Durchfall. An dieser Studie gibt es einige Kritikpunkte. Zum einen die kleine Stichprobengröße und zum anderen die schlechte Berichtqualität (z.B. gibt es keine Angaben zur Ausfallrate).

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	No
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	Histologically confirmed colorectal cancer (adenocarcinoma); histological stage III colon cancer or rectosigmoid cancer resected with D2 or more lymph node dissection; age 20-80 years old; Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1; no prior chemotherapy or radiotherapy for target disease; oral intake is possible; preservation of primary organ function (white blood cell count ≥3,000 /mm3 and >12,000 /mm3, neutrophil count ≥1,500 /mm3, haemoglobin ≥9.0 g/dL, platelet count ≥100,000 /mm3; serum creatinine <1.5 mg/dL, serum total bilirubin <1.5 mg/dL, aspartate aminotransferase (ALT) <100 IU/L); able to start protocol treatment within 8 weeks of surgical procedure
Exclusion criteria	Pregnant or lactating, or planning to become pregnant; history of hypersensitivity or severe adverse reaction to fluoropyrimidines; serious concurrent disease (including interstitial pneumonia, pulmonary fibrosis, intestinal paralysis, ileus, poorly controlled diabetes, liver cirrhosis or hepatitis (type B or C), poorly controlled hypertension, history of myocardial infarction or unstable angina within past 6 months); active multiple primary cancer (disease-free less than 5 years); concurrent infectious disease; judged to be unsuitable for participation in the clinical study by the investigator for any other reason
N randomized	60
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 frequency, severity, clinical course, and consequences of HFS were determined by descriptive methods. Between-group differences were assessed using χ2 test for categorical variables. Inverted Kaplan-Meier curves were constructed to determine the relationship between cumulative dose of capecitabine and occurence of HFS, with differences assessed by the log-rank test.
Countries of data collection	Japan
LoE Level of evidence	1b Oxford 2009
Outcome timeline Data collection times	T0: pretreatment T1: before each chemotherapy cycle T2: follow-up after chemotherapy

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	Colorectal 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	Advanced Stage
Specifications on cancer stages	Colorectal carcinoma III
Comorbidities	NI
Current cancer therapies	Chemotherapy
Specifications on cancer therapies	Eight 3-week cycles of 2,500 mg/m2 of capecitabine per day in two divided doses for 14 days, followed by a 7-day rest period
Previous cancer therapies	NI
Gender	Mixed
Gender specifications	Female n (%): 35 (58.3) Male n (%): 25 (41.7)
Age groups	Adults (18+)
Age groups specification	Age in years, mean: 64

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	30
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
Dosage and regime	Oral, 20mg 3 times 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.	168
Side effects / Interactions	NI

Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment	Passive control
Number of participants (arm) N randomized	30
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	Usual care
Dosage and regime	NA
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.	168
Side effects / Interactions	NI

Outcomes

Hand-foot syndrome

Outcome type As specificed by the authors	Primary
Outcome specification	Incidence of hand-foot syndrome (HFS) ≥ grade 2
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".	Number of patients with HFS ≥ grade 2 (%): Intervention group: 18 (60), control group: 18 (60); no significant difference; p = 1 (Grade 2: intervention group: 13, control group: 12; Grade 3: intervention group: 5, control group: 6)
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".	NI

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	?

Hand-foot syndrome

Outcome type As specificed by the authors	Secondary
Outcome specification	Cumulative incidence of HFS
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".	Number of patients with HFS ≥ grade 1 (%): Intervention group: 22 (76.7), control group: 25 (83.3), not significant
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".	NI

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	Secondary
Outcome specification	Frequency, severity, clinical course, and consequences of HFS
Type of measurement	CTCAE (Common Terminology Criteria of Adverse Events)
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".	No significant differences between intervention group and control group Number (%): Hematologic side effects: Leukopenia: intervention: 10 (33.3), control: 10 (33.3), not significant Thrombocytopenia: intervention: 4 (13.3), control: 4 (13.3), not significant Hyperbilirubinemia: intervention: 4 (13.3), control: 2 (6.7), not significant AST/ALT elevation: intervention: 4 (13.3), control: 6 (20), not significant Grade 3 only Hematologic side effects: Intervention: n = 1 (thrombocytopenia), control: n = 1 (leukopenia) Non-hematologic side effects: Nausea: intervention: 10 (33.3), control: 5 (13.3%), not significant Stomatitis: intervention: 4 (13.3), control: 4 (13.3), not significant Diarrhea: intervention: 2 (6.7), control: 2 (6.7), not significant Peripheral neuropathy: intervention: 1 (3.3%), control: 1 (3.3%), not significant
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".	NI

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	?