Yap et al. (2017): Predictors of hand-foot syndrome and pyridoxine for prevention of capecitabine-induced hand-foot syndrome: a randomized clinical trial

Reference ↗
Title	Predictors of hand-foot syndrome and pyridoxine for prevention of capecitabine-induced hand-foot syndrome: a randomized clinical trial
Topic	Vitamin B6
Author	Yap, Y, Kwok, L, Syn, N, Chay, W Y, Chia, J W K, Tham, C K, Wong, N S, Lo, S K, Dent, R A, Tan, S, Mok, Z Y, Koh, K X, Toh, H C, Koo, W H, Loh, M, Ng, R C H, Choo, S P, Soong, R C T
Year	2017
Journal	JAMA Oncology
DOI	https://doi.org/10.1001/jamaoncol.2017.1269

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). The time to onset of the syndrome was also comparable in both groups. Finally, quality of life was examined. No significant group differences were found here either. A positive aspect of this study is 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 order to be able to make valid statements, this result must therefore also be found in future larger studies.

In dieser Studie wurde der Effekt von Vitamin B6 auf Chemotherapie-Nebenwirkungen bei Patienten mit verschiedenen 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). Auch die Zeit bis zum Auftreten des Syndroms war in beiden Gruppen vergleichbar. Zuletzt wurde die Lebensqualität untersucht. Hier fanden sich ebenfalls keine bedeutsamen Gruppenunterschiede. 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. Um valide Aussagen treffen zu können, muss dieses Ergebnis deswegen auch in zukünftigen größeren Studien gefunden 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	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	Patients scheduled to receive single-agent capecitabine chemotherapy for breast, colorectal, and other cancers
Exclusion criteria	NI
N randomized	210
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	The incidence of grade 2 or higher HFS was compared using a χ2 test; time to onset was estimated using the Kaplan-Meier method and compared using a log-rank test, and QoL was analyzed using ANOVA for the EQ-5D OHS and χ2 tests for each of the 5 dimensions of the EQ descriptive system. Logistic regression was used to estimate the odds of HFS (grade ≥2 vs <2) with respect to clinical characteristics. The exact procedure was used when quasiseparation was detected. All covariates were included in multivariate analysis with a stepwise selection process using significance levels of 0.1. Interaction between treatment and covariates suggested by the stepwise procedure was explored. Alternative models were assessed in terms of discrimination and calibration respectively using the c-index and the Akaike Information criterion (AIC).
Countries of data collection	Singapore
LoE Level of evidence	1b Oxford 2009
Outcome timeline Data collection times	Baseline Start of the 2nd, 4th, 5th, 8th cycle + end of study

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.	Neo-adjuvant, Adjuvant, Palliative
Types of cancer "Other Cancers" means that only a subpopulation was specified, but further unspecified cancer types were included	Breast Cancer, Colorectal Cancer, Other Cancers
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, Advanced Stage
Specifications on cancer stages	NI
Comorbidities	NI
Current cancer therapies	Chemotherapy
Specifications on cancer therapies	Single-agent capecitabine chemotherapy
Previous cancer therapies	Chemotherapy, No therapy
Gender	Mixed
Gender specifications	Female n (%): 162 (77) Male n (%): 48 (23)
Age groups	Adults (18+)
Age groups specification	Age in years, median (range): 58 (26-82)

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	105
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	200mg daily for maximum of 8 cycles of 3 weeks each, from start of chemotherapy
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.	160
Side effects / Interactions	According to authors no side effects/interactions

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	105
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	Daily for maximum 8 of cycles of 3 weeks each, from start of chemotherapy
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.	160
Side effects / Interactions	According to authors no side effects/interactions

Outcomes

Hand-foot syndrome

Outcome type As specificed by the authors	Primary
Outcome specification	Incidence of grade 2 or higher HFS in patients receiving pyridoxine
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 (%): Intervention arm: 33 (31.4; 95% CI: 22.6, 40.3), placebo arm: 39 (37.1; 95% CI: 27.9, 46.4); p = 0.38, 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	?

Hand-foot syndrome

Outcome type As specificed by the authors	Secondary
Outcome specification	Time to HFS (CTCAE 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".	Time in days: Intervention arm vs. placebo arm; p = 0.73, not siginificant (numbers not given, only Kaplan-Meier curve) Incidence after 60 days in % (95% CI): Intervention arm: 13.7 (6.7, 20.6), placebo arm: 15.4 (8.2, 22.7), not significant Incidence after 120 days: Intervention arm: 36.9 (25.7, 48.1), placebo arm: 41.0 (30.3, 51.8), 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	?

Quality of life

Outcome type As specificed by the authors	NI
Outcome specification	Quality of life (EuroQol EQ-5D-3L questionnaire): Baseline + at the beginning of the 2nd, 4th, 5th, 8th cycle + end of study
Type of measurement	EORTC QLQ (European Organisation for Research and Treatment of Cancer Core/ Quality of Life 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".	No significant differences regarding general health status and the 5 dimensions of the questionnaire used (mobility, self-care, usual activities, pain, anxiety/depression (numbers not given, only graphs)
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".	No significant differences regarding general health status and the 5 dimensions of the questionnaire used (mobility, self-care, usual activities, pain, anxiety/depression (numbers not given, only graphs)

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 the Singapore Cancer Society and the National Research Foundation Singapore
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	?