Nasser et al. (2017): Vitamin D ointment for prevention of radiation dermatitis in breast cancer patients

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Title	Vitamin D ointment for prevention of radiation dermatitis in breast cancer patients
Topic	Vitamin D
Author	Nasser, NJ, Fenig, S, Ravid, A, Nouriel, A, Ozery, N, Gardyn, S, Koren, R, Fenig, E
Year	2017
Journal	NPJ Breast Cancer
DOI	https://doi.org/10.1038/s41523-017-0006-x

Brief summary

In this study, the effectiveness of a vitamin D ointment was investigated with regard to typical adverse skin reactions associated with radiotherapy treatment. Breast cancer patients were given a vitamin D ointment on one side of the treated breast and a normal control ointment on the other half. There were no significant differences between the vitamin D ointment and the control ointment in terms of undesirable skin irritation. A positive aspect of this study is that the patients received both vitamin D and the control ointment at the same time, thus ruling out arm differences at the start of the study. A negative aspect, however, is that only a very small sample was examined and therefore arm differences could not be calculated correctly.

In dieser Studie wurde die Wirksamkeit einer Vitamin D Salbe hinsichtlich typischer unerwünschter Hautreaktionen, die mit der Radiotherapie- Behandlung assoziiert sind, untersucht. Dafür bekamen Brustkrebspatientinnen auf eine Seite der behandelten Brust eine Vitamin D Salbe und auf die andere Hälfte eine normale Kontroll-Salbe. Es zeigten sich keine bedeutsamen Unterschiede zwischen der Vitamin D Salbe und der Kontrollsalbe hinsichtlich der unerwünschten Hautreizungen. Positiv an dieser Studie ist, dass die Patientinnen gleichzeitig sowohl Vitamin D, als auch die Kontrollsalbe bekamen und damit Gruppenunterschiede zum Beginn der Studie ausgeschlossen sind. Negativ ist jedoch, dass nur eine sehr kleine Stichprobe untersucht wurde und deswegen Gruppenunterschiede nicht richtig berechnet werden konnten.

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	Women aged 18 to 75 years with a confirmed histological diagnosis of localized breast cancer, after breast lumpectomy, and scheduled to receive adjuvant radiotherapy
Exclusion criteria	Scleroderma, large breast with an inter-field of more than 25cm, or prior radiotherapy to the same breast, indication to lymph node irradiation
N randomized	23
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	Israel
LoE Level of evidence	1b Oxford 2009
Outcome timeline Data collection times	Each week of treatment (T1-T5) Follow-Up: 2 weeks after treatment end

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.	Adjuvant
Types of cancer "Other Cancers" means that only a subpopulation was specified, but further unspecified cancer types were included	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	NI
Specifications on cancer stages	NI
Comorbidities	NI
Current cancer therapies	Radiation therapy
Specifications on cancer therapies	Radiation therapy to the involved breast was delivered by two tangential fields, delivered as a single fraction per day, 5 days a week; radiation dose was either 42.72 Gy in 16 fractions or 50 Gy in 25 fractions, when indicated, a boost was provided to the tumor bed, to a total dose of 10 Gy administered in 5 fractions of 2 Gy each
Previous cancer therapies	Surgery
Gender	Female
Gender specifications	100% female
Age groups	Adults (18+)
Age groups specification	Mean (SD): 63 (8), range: 37-74

Arms

Duration: while radiotherapy treatment

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	14
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	Calcipotriol and Aqua cream
Dosage and regime	Calcipotriol to the lateral side of the breast, Duration: while radiotherapy 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	Vitamin D was well tolerated by patients with no localized or systemic allergic reactions.

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	9
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	Calcipotriol and Aqua cream
Dosage and regime	Calcipotriol to the medial side of the breast, Duration: while radiotherapy 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	Vitamin D was well tolerated by patients with no localized or systemic allergic reactions.

Outcomes

Dermatitis

Outcome type As specificed by the authors	NI
Outcome specification	Skin toxicity
Type of measurement	RTOG Acute Radiation Morbidity Scoring Criteria (Radiation Therapy Oncology Group)
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".	In 20 out of 23 patients (87%) there was no difference in the skin reaction between the calcipotriol and the Aqua cream treated skin parts of the breast, in two patients the skin reaction in the calcipotriol treated part of the breast was more intense compared to the Aqua cream treated part, while one patient had lesser skin toxicity in the calcipotriol treated breast part, compared to the breast part treated with Aqua cream, there was no correlation between breast size, eye color, ethnic background or age, and radiation dermatitis
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	some concerns
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	high risk

Funding and Conflicts of Interest

Funding	NI
Conflicts of Interest	The authors declare no competing 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	?