Newling et al. (1995): Tryptophan metabolites, pyridoxine (vitamin B6) and their influence on the recurrence rate of superficial bladder cancer. Results of a prospective, randomised phase III study performed by the EORTC GU Group

Reference ↗
Title	Tryptophan metabolites, pyridoxine (vitamin B6) and their influence on the recurrence rate of superficial bladder cancer. Results of a prospective, randomised phase III study performed by the EORTC GU Group
Topic	Vitamin B6
Author	Newling, D, Robinson, M, Smith, P, Byar, D, Lockwood, R, Stevens, I, De Pauw, M, Sylvester, R
Year	1995
Journal	European urology
DOI	https://doi.org/10.1159/000475139

Brief summary

This study primarily investigated the effect of vitamin B6 in bladder cancer patients on disease-free survival and the recurrence rate. In addition, tumor progression and overall survival were considered. There were no significant differences between the vitamin B6 group and the placebo group. Positive aspects of this study are the large sample size and the double blinding (investigators and patients did not know which group they were in). On the negative side, however, there were differences in cancer stage and gender distribution between the vitamin B6 and placebo groups at the start of the study.

In dieser Studie wurde primär der Effekt von Vitamin B6 bei Blasenkrebspatienten auf das krankheitsfreie Überleben und die Rezidivrate untersucht. Zusätzlich dazu wurde Tumorprogression und das Gesamtüberleben betrachtet. Es zeigten sich keine bedeutsamen Unterschiede zwischen der Vitamin B6 Gruppe und der Placebogruppe. Positiv an dieser Studie ist die große Stichprobe und die doppelte Verblindung (Untersucher und Patienten wussten nicht, in welcher Gruppe sie sind). Negativ ist jedoch, dass Unterschiede hinsichtlich des Krebsstadiums und der Geschlechterverteilung zwischen der Vitamin B6 und der Placebogruppe zur Beginn der Studie bestanden.

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	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 with histologically proven Ta/T1, NO or NX, MO transitional cell carcinoma ofthe bladder completely removed by transurethral resection or fulguration before the start of oral therapy; no previous therapy other than transurethral resection or fulguration; estimated survival of more than 3 years
Exclusion criteria	Patients receiving chronic medication with salicylate derivatives, oestrogens, sulphonamides, isoniazid and steroids
N randomized	291
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.	PP Analysis
Specifications on analyses	The time to first recurrence was estimated using the Kaplan-Meier technique and compared using a 2-sided log rank test. The recurrence rate was compared using 2-sided permutation test. Adjustment for prognostic factors was carried out by means ofretrospective stratification or, in the case of time to first recurrence, by means of the Cox proportional hazards regression model.
Countries of data collection	United Kingdom
LoE Level of evidence	1b Oxford 2009
Outcome timeline Data collection times	Follow-up: every 3 months in the first year, thereafter every 6 months

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
Types of cancer "Other Cancers" means that only a subpopulation was specified, but further unspecified cancer types were included	Genitourinary Cancers - Bladder 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	Early Stage
Specifications on cancer stages	Ta/T1, N0/NX, M0
Comorbidities	NI
Current cancer therapies	Surgery
Specifications on cancer therapies	Cystoscopy and resection/fulguration of all recurrences were performed every 3 months during the first year and every 6 months thereafter.
Previous cancer therapies	Surgery
Gender	Mixed
Gender specifications	Female n (%): 73 (29)
Age groups	Adults (18+)
Age groups specification	Age in years, median (range): 65 (31-85)

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	147
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	21
Drop-out reasons	Ineligible (n=15); never followed up cystoscopically (n=6)
Intervention	Pyridoxine (vitamin B6)
Dosage and regime	One daily tablet of pyridoxine 20 mg from day 7-14 postop, duration: max. until January 1985
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.	550
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	144
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	18
Drop-out reasons	Ineligible (n=12); never followed up cystoscopically (n=6)
Intervention	Placebo
Dosage and regime	One daily placebo from day 7-14 postop, duration: max. until January 1985
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.	550
Side effects / Interactions	NI

Outcomes

DFS (Disease-Free Survival)

Outcome type As specificed by the authors	Primary
Outcome specification	Randomization until detection of recurrence
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".	Recurrence Intervention group: 82/126, placebo group: 77/126; p = 0.30, not significant Median not specified, can only be estimated from graph (in years): Intervention group: approx. 1, placebo group: approx. 2 Significant prognostic factors for DFS: Number of tumors, prior recurrence rate, kynurenine plus acetyl kynurenine No difference in results when controlled for these variables
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	?

Recurrence rate

Outcome type As specificed by the authors	Primary
Outcome specification	Total number of positive cystoscopies in the group/total number of follow-up years in the group
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".	Recurrence rate per year Intervention group: 0.72, placebo group: 0.72; p = 0.992, not significant Without consideration of the first 8 months Intervention group: 0.639, placebo group: 0.708; p = 0.556, 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	?

Tumor response

Outcome type As specificed by the authors	NI
Outcome specification	Tumor progression
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".	Increase in T-category (all patients): 17 (6%), no significant group differences
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	?

OS (Overall Survival)

Outcome type As specificed by the authors	NI
Outcome specification	Survival rate
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".	A total of 47 patients (19%) died, 22 of them due to cancer, no significant group differences (p = 0.53, 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	Supported by National Cancer Institute, DHHS (Bethesda, Md., USA)
Conflicts of Interest	NI

Further points for assessing the study

Sample

Power analysis performed	?
- Sample size corresponds to power analysis	NI
- Reasons for insufficient sample size based on power analysis	NI
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	NI
- 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	NI
Correction for multiple testing	?
Measurement of compliance	?
Consistent reporting in numbers (figures, flowchart, abstract, results)	?
Comprehensive and coherent reporting	?
Cross-over	NI
- 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	?