Latest revision as of 10:31, 12 December 2024

Reference ↗
Title	Randomized Trial of Vitamin C/E Complex for Prevention of Radiation- Induced Xerostomia in Patients with Head and Neck Cancer
Topic	Vitamin C, Vitamin E
Author	Chung, MK, Kim, DH, Ahn, YC, Choi, JY, Kim, EH, Son, YI
Year	2016
Journal	Otolaryngology – Head and Neck Surgery
DOI	https://doi.org/10.1177/0194599816642418

Study Note

Brief summary

Data from 45 patients were analyzed in this study. The patients were randomly divided into groups and received either a vitamin combination of vitamin C and E or a placebo. The intake took place from one week before the concurrent radiotherapy over an average duration of three months. The effects on the patients' dry mouth (xerostomia), the general survival time and the length of the disease-free interval were observed. It was found that the group that had taken the vitamin combination showed a deterioration in their dry mouth score one month after radiotherapy treatment, but then showed a clear improvement after six months. The placebo group also showed a deterioration one month after the therapy, but remained relatively constant overall - even six months later - in their assessment of the severity of dry mouth. The same results were also confirmed by the observers. Measured by salivary scintigraphy, there were advantages for the intervention group, which indicates a positive influence of the vitamin combination on the maintenance of salivary activity. No differences were found between the groups with regard to general survival time and the length of the disease-free interval. However, most of the results describe the progression of the individual groups rather than a direct group comparison. Furthermore, significantly more patients in the vitamin group dropped out during the course of the study than in the placebo group, although the reasons for this are not explained. Due to these factors and the relatively small sample size, the results can only be trusted to a limited extent.

In dieser Studie wurden Daten von 45 Patienten ausgewertet. Die Patienten erhielten in zufällig aufgeteilten Gruppen entweder eine Vitaminkombination aus Vitamin C und E oder ein Placebo. Die Einnahme erfolgte ab einer Woche vor der gleichzeitig stattfindenden Radiotherapie über eine durchschnittliche Dauer von drei Monaten. Beobachtet wurden die Auswirkungen auf die Mundtrockenheit (Xerostomie) der Patienten, die allgemeine Überlebensdauer sowie die Länge des krankheitsfreien Intervalls. Man fand heraus, dass sich die Gruppe, die die Vitaminkombination genommen hatte laut den eigenen Angaben im Wert bzgl. ihrer Mundtrockenheit einen Monat nach der Radiotherapiebehandlung verschlechterte, nach sechs Monaten dann aber eine deutliche Verbesserung zeigte. Die Placebo-Gruppe zeigte einen Monat nach der Therapie zwar auch eine Verschlechterung, blieb insgesamt – auch sechs Monate danach – aber relativ konstant in ihrer Einschätzung der Stärke der Mundtrockenheit. Die gleichen Ergebnisse konnte man auch durch die Angaben der Beobachter bestätigen. Gemessen durch eine Speichel Szintigrafie, zeigten sich Vorteile für die Interventionsgruppe, was für einen positiven Einfluss der Vitaminkombination auf den Erhalt der Speicheltätigkeit spricht. Bezüglich der allgemeinen Überlebensdauer und der Länge des krankheitsfreien Intervalls ließen sich keine Unterschiede zwischen den Gruppen feststellen. In den meisten Ergebnissen werden jedoch eher die Verläufe der einzelnen Gruppen beschrieben und kein direkter Gruppenvergleich durchgeführt. Des Weiteren sind in der Vitamin-Gruppe deutlich mehr Patienten im Verlauf der Studie ausgestiegen, als in der Placebo-Gruppe, wobei die Gründe dafür nicht erläutert werden. Aufgrund dieser Faktoren sowie der relativ kleinen Stichprobengröße kann man den Ergebnissen nur bedingt vertrauen.

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	Diagnosed with biopsy-proven Head-Neck-Cancer, treated with >4000-cGy intensity-modulated radiotherapy
Exclusion criteria	- Simultaneous malignancies - Karnofsky performance score <60% - Previous adverse reactions to the investigational product or salivary scintigraphy - History of vitamin medication within the past 3 months OR - Salivary gland excision during surgery
N randomized	52
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	According to authors ITT analysis but loss to follow-up (n=7) not included in analyses
Countries of data collection	NI
LoE Level of evidence	2b Oxford 2009
Outcome timeline Data collection times	T0: before radiotherapy, T1: 1 month post-radiotherapy, T2: 6 months post-radiotherapy

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, Adjuvant
Types of cancer "Other Cancers" means that only a subpopulation was specified, but further unspecified cancer types were included	Head and Neck Cancers, Head and Neck Cancers - Oral Cancer, Head and Neck Cancers - Oropharyngeal Cancer, Head and Neck Cancers - Laryngeal Cancer, Head and Neck Cancers - Nasopharyngeal 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, Advanced Stage
Specifications on cancer stages	N per arm: - intervention: 9x stage I-II, 16x stage III-IV - placebo: 6x stage I-II, 14x stage III-IV
Comorbidities	NI
Current cancer therapies	Chemotherapy, Radiation therapy
Specifications on cancer therapies	Types of radiotherapy per arm: - intervention: 9x radiotherapy, 16x concurrent chemoradiotherapy - placebo: 6x radiotherapy, 14x concurrent chemoradiotherapy N for adjuvant/definitive setting per arm: - intervention: 15/10 - placebo:9/11
Previous cancer therapies	Surgery
Gender	Mixed
Gender specifications	Overall 11.1% female, male/female per arm: - intervention: 22/3 - placebo: 18/2
Age groups	Adults (18+)
Age groups specification	Overall age in years, mean (SD) = 58.8 (10.5); per arm: - intervention: 56.6 (11.3) - placebo: 61.6 (9.6)

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	26
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	1
Drop-out reasons	Lost to follow-up 6 month post-radiotherapy (n=1, refusal)
Intervention	Radiotherapy + vitamin E + vitamin C
Dosage and regime	100 IU vitamin E + 500mg vitamin C, orally, 2x daily, duration: 1 week prior to radiotherapy until 1 month after radiotherapy (average intervention period: 3 months)
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	No significant adverse events or side effects related to study medication noticed/reported throughout the trial

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	26
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	6
Drop-out reasons	Lost to follow-up 1 month post-radiotherapy (n=2, refusal/poor compliance) Lost to follow-up 6 month post-radiotherapy (n=4, 2x refusal/poor compliance), 2x disease recurrence)
Intervention	Radiotherapy + placebo
Dosage and regime	Placebo pill, orally, 2x daily, duration: 1 week prior to radiotherapy until 1 month after radiotherapy (average intervention period: 3 months)
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	No significant adverse events or side effects related to study medication noticed/reported throughout the trial

Outcomes

Xerostomia

Outcome type As specificed by the authors	NI
Outcome specification	- Patient self-assessment by xerostomia questionnaire (XQ) - Xerostomia score assessed by observer (XS) - Salivary scintigraphy (maximum accumulation, ejection fraction and prestimulatory and poststimulatory oral index)
Type of measurement	Observation, Scintigraphy, Self-developed measurement instrument
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".	T0: before radiotherapy, T1: 1 month post-radiotherapy, T2: 6 months post-radiotherapy Xerostomia questionnaire (mean (SD), no group comparison reported) Intervention arm T0: 5.4 (4.3), T1: 8.1 (4.2), T2: 5.4 (4.0) T0-T1: p = 0.02, T1-T2: p = 0.007 Placebo arm T0: 4.6 (3.8), T1: 7.0 (4.5), T2: 7.0 (4.6) T0-T1: p = 0.06 T1-T2: p = 0.97 Xerostomia score (no group comparison reported) Intervention arm T0: 2.8 (2.3), T1: 5.0 (2.8), T2: 3.7 (3.9) T0-T1: p = 0.004, T1-T2: p = 0.008 Placebo arm T0: 1.7 (1.4), T1: 3.9 (2.4), T2: 3.3 (2.3) T0-T1: p = 0.004, T1-T2: p = 0.47 Salivary scintigraphy No group difference for maximum accumulation, or ejection fraction at T1 or T2 (p=0.86, p=0.15; p=0.57, p=0.68), Intervention arm showed better values before (p=0.01) and after stimulation (p=0.009) compared to placebo arm at T1

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	NA
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 = 0.75)

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	?

DFS (Disease-Free Survival)

Outcome type As specificed by the authors	NI
Outcome specification	NA
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 = 0.87)

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	National R&D Program for Cancer Control (No. 0820300), Ministry of Health and Welfare, Seoul, Republic of Korea.
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
Double blinding
Intention-to-treat

CONTRA:

No proper group comparisons between intervention and placebo arm on xerostomia questionnaire and xerostomia score
Small sample without power analysis
Unequal dropout (intervention arm: 4%, placebo arm: 23%)
No validation information on the measurement instruments used
Poor reporting quality (e.g. results reported confusingly)