Minchom et al. (2014): An unblinded, randomised phase II study of platinum-based chemotherapy with vitamin B12 and folic acid supplementation in the treatment of lung cancer with plasma homocysteine blood levels as a biomarker of (...)

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Title	An unblinded, randomised phase II study of platinum-based chemotherapy with vitamin B12 and folic acid supplementation in the treatment of lung cancer with plasma homocysteine blood levels as a biomarker of severe neutropenic toxicity
Topic	Folic acid, Vitamin B12
Author	Minchom, AR, Saksornchai, K, Bhosle, J, Gunapala, R, Puglisi, M, Lu, SK, Nimako, K, Coward, J, Yu, KC, Bordi, P, Popat, S, O’Brien, MER
Year	2014
Journal	JBMJ Open Respiratory Research
DOI	https://doi.org/10.1136/_bmjresp-2014-000061

Brief summary

Minchom and colleagues (2014) investigated the effect of a vitamin combination of vitamin B12 and folic acid on grade 3 and 4 neutropenia, a side effect that can occur as a result of chemotherapy and consists of a decrease in the number of white blood cells in the blood and thus an increased risk of infection. They also recorded the effects of vitamin administration on the chances of survival within the first 30 days of treatment, the general survival time, the quality of life and the tolerance of the substances given. A total of 77 patients suffering from either bronchial carcinoma or mesothelioma were included in the analyses. 36 of them received the described vitamins over the period of chemotherapy until 3 weeks after its completion; the remaining 41 patients received no alternative intervention or a placebo, but were treated with chemotherapy alone. The allocation of patients was randomized. The results showed no significant differences, i.e. neither grade 3 or 4 neutropenia, survival time nor quality of life were affected by the vitamin combination. No other side effects occurred as a result of taking vitamin B12 and folic acid. A positive finding was that patients in the treatment arm complained less frequently of fatigue than those in the control arm. Difficulties with this study are its open design and the lack of a placebo for one half of the patients. In addition, there was the possibility of further supportive measures for the patients parallel to the study, the influence of which is not considered further by the authors. These unknown influences and also the problems in the design could have contributed to the failure to find an effect.

Minchom und Kollegen (2014) untersuchten die Wirkung einer Vitaminkombination aus Vitamin B12 und Folsäure auf Neutropenie 3. und 4. Grades, einer Nebenwirkung, die durch Chemotherapie auftreten kann und darin besteht, dass die Zahl der weißen Blutkörperchen im Blut abnimmt und damit das Infektionsrisiko zunimmt. Des Weiteren erfassten sie die Auswirkungen der Vitamingabe auf die Überlebenschancen innerhalb der ersten 30 Tage der Behandlung, die allgemeine Überlebenszeit, die Lebensqualität sowie die Verträglichkeit der gegebenen Stoffe. Es wurden insgesamt 77 Patienten in die Analysen eingeschlossen, die entweder an einem Bronchialkarzinom oder Mesotheliom erkrankt waren. 36 von ihnen erhielten über die Zeitspanne der Chemotherapie bis 3 Wochen nach deren Abschluss die beschriebenen Vitamine, die übrigen 41 Patienten bekamen keine alternative Intervention oder ein Placebo, sondern wurden nur durch Chemotherapie behandelt. Die Zuteilung der Patienten fand zufällig statt. Die Ergebnisse ergaben keine bedeutsamen Unterschiede, d.h. dass durch die Vitaminkombination weder die Neutropenie 3. oder 4. Grades, die Überlebensdauer, noch die Lebensqualität beeinflusst wurden. Es traten keine weiteren Nebenwirkungen durch die Einnahme von Vitamin B12 und Folsäure auf. Positiv festzustellen war, dass Patienten der behandelten Gruppe seltener über Fatigue klagten, als in der Kontroll-Gruppe. Schwierig an dieser Studie sind ihr offenes Design und das Fehlen eines Placebos für die eine Hälfte der Patienten. Außerdem gab es parallel zu der Untersuchung die Möglichkeit weiterer supportiver Maßnahmen für die Patienten, deren Einfluss von den Autoren nicht weiter beachtet wird. Diese unbekannten Einflüsse und auch die Problematik im Design könnten zum Nichtfinden eines Effektes beigetragen haben.

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	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	- Suitability for platinum-based chemotherapy - Histologically or cytologically confirmed NSCLC, SCLC or mesothelioma - Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0–2 - Adequate organ function defined as an absolute neutrophil count >1.5×109/L, white cell count >3×109/L, platelet count >100×109/L, serum creatinine ≤1.25 upper level of normal, creatinine clearance >50 mL/min (EDTA) or >60 mL/min (Cockroft and Gault formula) for cisplatin or >40 mL/min for carboplatin - Estimated life expectancy of at least 12 weeks
Exclusion criteria	Patients having an active infection, inability or unwillingness to take vitamin supplementation, had taken any vitamins within the past 28 days or receiving concomitant radical chemotherapy and radiotherapy or antiepileptic treatment
N randomized	83
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.	mITT Analysis
Specifications on analyses	- Analyzed: N = 77 for primary endpoint, 78 for secondary endpoints (n=5 patients did not receive any treatment, n=1 data set missing for primary endpoint) - 1% level of significance used because of the large number of treatment comparisons
Countries of data collection	NI
LoE Level of evidence	2b Oxford 2009
Outcome timeline Data collection times	Unclear, dependent on specific outcome

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.	Curative, Palliative
Types of cancer "Other Cancers" means that only a subpopulation was specified, but further unspecified cancer types were included	Lung Cancer - Small Cell Lung Cancer, Lung Cancer - Non-Small Cell Lung Cancer, Mesothelioma
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, Radiation therapy
Specifications on cancer therapies	- Current chemotherapy: platinum-based treatment with cisplatin (up to six cycles) - Palliative radiation therapy permitted for irradiating small areas of painful metastases that could not be managed adequately using systemic or local analgesia - Patients were allowed to receive full supportive care therapies concomitantly, except for growth factors as a prophylactic measure, during the study
Previous cancer therapies	NI
Gender	Mixed
Gender specifications	Overall 36% female, male/female per arm: - intervention: 29/11 - control: 24/19
Age groups	Adults (18+)
Age groups specification	Age at diagnosis (years) per arm, median (IQR): - intervention: 61 (12) - control: 60 (14)

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	40
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	4
Drop-out reasons	n = 4 did not received treatment - transferred care: 1 - myocardial infarction prior to chemotherapy: 1 - became eligible for cisplatin: 2
Intervention	Chemotherapy + Vit. B12 + folic acid
Dosage and regime	Vit.B12: intramuscular, 1mg, before treatment and every 9 weeks until 3 weeks after last dose of chemotherapy Folic acid: oral, 400μg daily, start at least day seven days prior to chemotherapy, duration up to 3 weeks after 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.	-999
Side effects / Interactions	Occurrence of grade 3/4 nausea/vomiting, infections, diarrhea, constipation and nephrotoxicity

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	43
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	2
Drop-out reasons	1 patient not treated because of deteriorating renal function 1 patient had no toxicity data after first cycle of chemotherapy but had QoL and survival data
Intervention	Chemotherapy only
Dosage and regime	No further treatment
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.	-999
Side effects / Interactions	Occurrence of grade 3/4 nausea/vomiting, infections, diarrhea, constipation and nephrotoxicity

Outcomes

Neutropenia

Outcome type As specificed by the authors	Primary
Outcome specification	Grade 3, 4 neutropenia or death within the first 30 days of treatment
Type of measurement	Observation, NI
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".	NA
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".	Overall No significant differences for grade 3/4 neutropenia or death between arms (p = 0.966)

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	Secondary
Outcome specification	Before the start of chemotherapy, every 6 weeks during chemotherapy, then every 3 months for up to 1 year Measures: EORTC QLQ-C30 (V.3) and Lung module QLQ-LC13
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".	NA
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".	Overall No significant differences between arms regarding change since baseline (after 6 weeks p=0.399, after 3 months p=0.943); no difference in fatigue levels on the quality of life scales (no p-value reported)

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	Secondary
Outcome specification	From the day of randomization until death from any cause
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".	NA
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".	Overall No significant differences between arms (p = 0.41)

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	Non-neutropenic toxicities grade 3/4, assessed before each chemotherapy cyle
Type of measurement	CTCAE (Common Terminology Criteria of Adverse Events), ECOG Performance Status Scale (Eastern Cooperative Oncology Group), 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".	NA
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".	Overall No significant differences in occurrence of nausea/vomiting (p=0.805), infections (p=0.144), diarrhea (p=0.945), constipation (p=0.572) and nephrotoxicity (p=0.516); less frequent occurrence of fatigue in intervention arm (p = 0.003)

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	Support from the NIHR Royal Marsden Biomedical Research Centre
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	?

Additional Notes

PRO

• Ethics vote
• Precise observation of occurring side effects
• Recording of patient compliance
• Intention-to-treat analyses
• Washout of previous vitamin intake taken into account
• Adjustment of significance level due to multiple testing

CONTRA:

• No blinding
• Not placebo controlled
• Unclear randomization, as groups are not equal in size despite 1:1 distribution
• Simultaneous offer of other supportive therapies whose influence is not considered in detail
• Stage of cancer unclear