Kessels et al. (2017): Topical Sinecatechins, 10%, Ointment for Superficial Basal Cell Carcinoma A Randomized Clinical Trial

Reference ↗
Title	Topical Sinecatechins, 10%, Ointment for Superficial Basal Cell Carcinoma: A Randomized Clinical Trial
Topic	Green tea (EGCG)
Author	Kessels, J, Voeten, L, Nelemans, P, Cleutjens, J, Hillen, LM, Mosterd, K, Kelleners-Smeets, NWJ
Year	2017
Journal	JAMA dermatology
DOI	https://doi.org/10.1001/jamadermatol.2017.2529

Brief summary

In this study, 42 patients with superficial basal cell carcinoma were randomly assigned to one of two arms. One arm received an ointment containing 55-72mg EGCG per gram, the other arm a placebo ointment. Neither the participants nor the study leaders knew whether they were using the ointment with or without the active ingredient. Tumour size and side effects were examined after 3, 6 and 8 weeks. At the end of the study, the tumour was excised and the tissue sample examined. In addition to laboratory parameters, the extent to which the tumour had regressed was also determined. There was no difference between the arms in terms of tumour size or tumour clearance. However, some side effects occurred with the ointment containing the active ingredient, namely moderate to severe reddening of the skin, oedema, erosions, crusting and itching. The study was conducted by the book. The only lack is a very brief reporting without any indication of the demographic characteristics of the study participants (gender, age, etc.). However, given the otherwise very good study planning and quality, it can be assumed that the comparability of the groups was checked.

In dieser Studie wurden 42 Patienten mit einem oberflächlichen Basalzellkarzinom zufällig in einen von zwei Armen eingeteilt. Der eine Arm bekam eine Salbe mit 55-72mg EGCG pro Gramm, der andere Arm eine Placebosalbe. Weder die Teilnehmenden noch die Studienleiter wussten, ob sie die Salbe mit oder ohne Wirkstoff benutzten. Tumorgröße und Nebenwirkungen wurden nach 3, 6 und 8 Wochen untersucht. Am Ende der Studie wurde der Tumor herausgeschnitten und die Gewebeprobe untersucht. Hierbei wurden neben der Erhebung von Laborparametern auch festgestellt, inwiefern sich der Tumor zurückgebildet hatte. Dabei zeigte sich kein Unterschied zwischen den Armen in Tumorgröße oder Tumorfreiheit. Allerdings traten bei der Salbe mit Wirkstoff einige Nebenwirkungen auf, nämlich moderate bis ernsthafte Hautrötungen, Ödeme, Erosionen, Verkrustungen und Juckreiz. Die Studie wurde nach allen Regeln der Kunst durchgeführt. Der einzige Mangel ist eine sehr kurze Berichterstattung ohne Angabe der demographischen Merkmale der Studienteilnehmenden (Geschlecht, Alter usw.). Bei der sonst sehr guten Studienplanung und Qualität ist allerdings anzunehmen, dass die Vergleichbarkeit der Gruppen überprüft wurde.

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	Patients with a primary histologically proven superficial BCC of 4 to 20 mm in greatest diameter
Exclusion criteria	Immunosuppressed patients; patients with genetic skin cancer disorders and tumors in the face and/or hairy scalp
N randomized	42
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	NI
Countries of data collection	Netherlands
LoE Level of evidence	2b Oxford 2009
Outcome timeline Data collection times	T0: Baseline T1: after 3 weeks T2: after 6 weeks T3: after 8 weeks (directly before operation)

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	Skin Cancer - Basal Cell Carcinoma
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	Surgery
Specifications on cancer therapies	Study setting is prior to surgery.
Previous cancer therapies	NI
Gender	NI
Gender specifications	NI
Age groups	NI
Age groups specification	NI

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	21
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	Not arm specified: 3
Drop-out reasons	No reasons reported
Intervention	Topical sinecatechins ointment, 10% (with 55-72mg EGCG per 1g ointment)
Dosage and regime	The ointment was applied twice daily for six weeks by patients at home + all tumors were excised after eight weeks
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.	42
Side effects / Interactions	Survey by doctor and weekly diary entries by patients Side effects in the sinecatechins arm after 3/6/8 weeks in %: Erythema: 10/12/9 Edema: 2/6/3 Erosion: 5/7/4 Crusts: 3/10/6 Vesicles/Bullae: 3/3/2 Squamae:3/5/4 Itching: 10/13/12 Burning Sensation: 3/5/3 Use of the sinecatechins ointment led to a statistically significant higher frequency of erythema, edema, erosions, crusts, and itching than the use of placebo ointment.

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	21
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	Not arm specified: 3
Drop-out reasons	No reasons reported
Intervention	Placebo ointment
Dosage and regime	The ointment was applied twice daily for six weeks by patients at home + all tumors were excised after eight weeks
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.	42
Side effects / Interactions	Survey by doctor and weekly diary entries by patients Side effects in the placebo arm after 3/6/8 weeks in %: Erythema: 6/2/2 Edema: 0/0/0 Erosion: 1/0/0 Crusts: 2/0/0 Vesicles/Bullae: 0/1/0 Squamae:0/0/0 Itching: 3/0/1 Burning Sensation: 1/1/0 Use of the sinecatechins ointment led to a statistically significant higher frequency of erythema, edema,erosions, crusts, and itching than the use of placebo ointment.

Outcomes

Tumor response

Outcome type As specificed by the authors	Primary
Outcome specification	Specifically tumor clearance, i.e. the proportion of patients with complete histological tumor clearance after eight weeks (time point 3)
Type of measurement	Histological examination
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".	NI
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".	Complete histological tumor clearance was observed in 1 of 21 (5%) and 2 of 21 (10%) patients in the sinecatechins and placebo group, respectively no significant difference in histological tumor clearance between the sinecatechins and placebo groups (p > .99).

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	Secondary
Outcome specification	Specifically tumor size, examination after three weeks (time point 1), six weeks (time point 2) and eight weeks (time point 3)
Type of measurement	Histological examination
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".	NI
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".	Decrease in tumor size was slightly greater after sinecatechins application, but the difference was nonsignificant (p = 0.15).

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 Willpharma BV for the provision of the ointments. The sponsor was not involved in the design and conduct of the study.
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	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	?

Additional Notes

PRO:

• Ethics vote
• Power analysis performed and criteria met
• 1 week wash-out of green tea before the start of the study
• Control of co-interventions (no further consumption of green tea, immunosuppressive medication)
• Control of adherence to therapy

CONTRA:

• No indication of demographic data. Comparability of the groups to the baseline? With such a small sample, randomisation may not be sufficient to ensure comparability
• Intent-to-treat analysis? Not serious due to low drop-out.
• Blinding could have been disturbed by side effects, but the outcomes are objective