Keshavarzi et al. (2019): The effect of vitamin D and E vaginal suppositories on tamoxifen-induced vaginal atrophy in women with breast cancer

Reference ↗
Title	The effect of vitamin D and E vaginal suppositories on tamoxifen-induced vaginal atrophy in women with breast cancer
Topic	Vitamin D, Vitamin E
Author	Keshavarzi, Z, Janghorban, R, Alipour, S, Tahmasebi, S, Jokar, A
Year	2019
Journal	Supportive Care in Cancer
DOI	https://doi.org/10.1007/s00520-019-04684-6

Brief summary

In this study, the influence of vitamin D and E on vaginal atrophy in breast cancer patients undergoing hormone therapy was investigated. Vaginal atrophy includes symptoms such as itching, burning and pain during sexual intercourse, which are caused by a lack of oestrogen. The 96 participants in the study were divided equally into three groups. All subjects in each arm received either a daily vaginal suppository containing vitamin D, vitamin E or a placebo. After 8 weeks, an improvement in symptoms was achieved in both vitamin arms. No comparisons were made between the two vitamin arms in the analysis, so it is unclear whether either was more effective. Many tests were done, which statistically increases the risk of finding an effect that is not there. No measures were taken, so the result should be interpreted with caution.

In dieser Studie wurde der Einfluss von Vitamin D und E auf vaginale Atrophie bei Brustkrebspatientinnen unter Hormontherapie untersucht. Vaginale Atrophie umfasst Symptome wie Juckreiz, Brennen und Schmerzen beim Geschlechtsverkehr, welche durch Östrogenmangel hervorgerufen werden. Die 96 Teilnehmerinnen der Studie wurden zu gleichen Teilen in drei Gruppen eingeteilt. Alle Probandinnen der jeweiligen Arme erhielten entweder täglich ein Vaginalzäpfchen mit Vitamin D, mit Vitamin E oder ein Placebo. Nach 8 Wochen konnte eine Besserung der Symptome in den beiden Vitamin-Armen erzielt werden. In der Analyse werden keine Vergleiche zwischen den beiden Vitaminarme gemacht, so dass unklar ist, ob eine von beiden wirksamer war. Es wurden viele Tests gemacht, wodurch das Risiko einen Effekt zu finden, der nicht da ist statistisch erhöht ist. Es wurden keine Maßnahmen dahingegen unternommen, wodurch das Ergebnis mit Vorsicht zu interpretieren ist.

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	Triple
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	3

Study characteristics

Inclusion criteria	Being married, having stage 1 or 2 breast cancer based on the surgery stage, age below 50, receiving tamoxifen, not undergoing chemotherapy or radiotherapy during the study, a normal Pap smear during the last 3 years, no proven malignancies in other parts of the body, being sexually active during the study, meeting at least one of the criteria set in the genitourinary atrophy self-assessment, vaginal pH ≥ 5 according to Chollet et al. study at the time of the study, and a Vaginal Maturation Index (VMI) ≤52 according to Speroff’s study
Exclusion criteria	Unwillingness to participate in the study, vaginal infection, estrogen therapy in the last 8 weeks, idiopathic vaginal bleeding, and disease recurrence based on the diagnosis recorded in the patient’s file
N randomized	96
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 specific analysis method is not stated in the study, however, according to the authors, all included patients were evaluated at the end of the study.
Countries of data collection	Iran
LoE Level of evidence	Level 2 Oxford 2011
Outcome timeline Data collection times	T0: baseline T1: week 2 T2: week 4 T3: week 8

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
Types of cancer "Other Cancers" means that only a subpopulation was specified, but further unspecified cancer types were included	Breast Cancer - Ductal Carcinoma, Breast 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	Stage I and II
Comorbidities	NI
Current cancer therapies	Hormone therapy
Specifications on cancer therapies	Tamoxifen
Previous cancer therapies	Chemotherapy, Radiation therapy
Gender	Female
Gender specifications	100% female
Age groups	Adults (18+)
Age groups specification	Vitamin D arm: mean (SD): 43.7 (3.9) vitamin E arm: mean (SD): 44.1 (4.6) placebo arm: mean (SD): 42.0 (6.3)

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	32
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	NA
Drop-out reasons	NA
Intervention	Vitamin D
Dosage and regime	Vaginal suppositories containing 2 g of the base substance plus 1000 IU of vitamin D (0.025 mg), every day before bedtime
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.	56
Side effects / Interactions	NI

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	32
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	NA
Drop-out reasons	NA
Intervention	Vitamin E
Dosage and regime	Vaginal suppositories containing 1 mg of vitamin E plus 2 g of the base substance, every day before bedtime
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.	56
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	32
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	NA
Drop-out reasons	NA
Intervention	Placebo
Dosage and regime	Vaginal suppositories containing only 2 g of the base substance, every day before bedtime
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.	56
Side effects / Interactions	NI

Outcomes

Vaginal atrophy

Outcome type As specificed by the authors	NI
Outcome specification	Vaginal atrophy, pH, and vaginal maturation index
Type of measurement	Genitourinary atrophy self-assessment tool, pH-value
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".	Controlling the duration of tamoxifen use: significant difference of mean vaginal pH before the intervention; significant difference among the three arms 8 weeks after the intervention (pH reduced by 1.59 units in the vitamin E arm and by 1.53 units in the vitamin D arm, but increased by 0.04 units in the placebo arm) no significant differences in vaginal maturation index before the intervention; difference among the arms was statistically significant at the end of the eighth week of the intervention (VMI increased in the vitamin E and vitamin D arms by the end of the eighth week, and this difference was due to the increase in the mean percentage of superficial cells and the decrease in the mean percentage of parabasal cells in these two arms compared to before the intervention, while no such change was observed in the placebo arm) Vaginal atrophy: no significant differences before the intervention, but the difference was significant at the second, fourth, and eighth weeks of the intervention (significant reduction in the mean score in the vitamin E and D arms compared with that in the placebo arm)
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	low risk
Bias due to deviation from intended intervention (assignment to intervention)	some concerns
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	low risk
Bias in measurement of the outcome	low risk
Bias in selection of the reported result	low risk
Other sources of bias	NA
Overall RoB judgment	some concerns

Funding and Conflicts of Interest

Funding	NI
Conflicts of Interest	According to authors no conflict of interest

Further points for assessing the study

Sample

Power analysis performed	No
- Sample size corresponds to power analysis	NA
- Reasons for insufficient sample size based on power analysis	NA
If no power analysis performed: at least moderate sample size (n >= 30 per arm)	Yes
Ethnicity mentioned	No

Alternative Explanation

Other explanations for an effect besides the investigated intervention	Yes
- Possibility of attention effects	No
- Possibility of placebo effects	No
- Other reasons	We do not know anything about the vitamin E and D levels.

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	Yes
Correction for multiple testing	No
Measurement of compliance	No
Consistent reporting in numbers (figures, flowchart, abstract, results)	No
Comprehensive and coherent reporting	No
Cross-over	No
- Sufficient washout period	NA
- Tested for carry-over effects	NA
- Tested for sequence effects	NA

Interpretation of results

Effect sizes reported (clinical vs. statistical significance)	No
Side effects systematically recorded	No
Side effects considered in result interpretation	No
Ethics votum	No

Additional Notes

PRO:

• Ethics vote
• Triple blinding (patients, researchers, pathologists and analysts)
• Comparability of groups to baseline for characteristics

CONTRA:

• Under “Eligibility” inclusion of VMI≤51, but under “Procedure” inclusion of VMI≥52
• No indication of vitamin D or vitamin E levels
• No individual comparisons carried out in ANOVA, therefore unclear which arms actually differ
• No results for individual scales of the atrophy questionnaire
• No power analysis
• No correction for multiple testing