Tan et al. (2018): Bromelain has significant clinical benefits after extraction of the third molar during chemotherapy in patients with hematologic tumor

Reference ↗
Title	Tan (2018): Bromelain has significant clinical benefits after extraction of the third molar during chemotherapy in patients with hematologic tumor
Topic	Enzymes (bromelain papain)
Author	Tan, Y, Li, P
Year	2018
Journal	Oncology letters
DOI	https://doi.org/10.3892/ol.2017.7673

Brief summary

This study included 72 patients with blood cancer. A common feature of all patients was that their wisdom teeth had been surgically removed to prevent infection during or before chemotherapy. In the patients included, access to the wisdom teeth was more difficult as they were still partially in the bone. One arm of 36 people also received enzyme therapy (bromelain) in tablet form, which was started one day before the planned procedure and continued up to and including three days after the procedure. The other arm received cold and warm compresses instead of tablets. The question of this study is whether enzyme intake can alleviate the side effects of tooth extraction, such as pain, swelling and restricted mouth opening. In addition, the quality of life and satisfaction of the patients was assessed. The authors were able to identify advantages in all areas, i.e. less patient discomfort and greater satisfaction in the enzyme arm. The enzyme arm also achieved better values in the area of quality of life. The authors are therefore in favour of enzyme therapy for blood cancer patients during wisdom tooth removal. The study has a very small number of patients with little information about the disease of the test subjects. No correction for multiple testing was performed and the randomisation process is insufficiently described.

In dieser Studie wurden 72 Patienten mit Blutkrebs eingeschlossen. Als gemeinsames Merkmal hatten alle Patienten eine operative Entfernung der Weisheitszähne, welche zur Vermeidung von Infektionen während bzw. vor der Chemotherapie durchgeführt wurde. Bei den eingeschlossenen Patienten war der Zugang zu den Weisheitszähnen erschwert, da sie sich noch zum Teil im Knöchernen befunden haben. Eine Arm mit 36 Personen erhielt dabei zusätzlich eine Enzymtherapie (Bromelain) in Tablettenform, die einen Tag vor dem geplanten Eingriff begonnen wurde und sich bis einschließlich drei Tage nach dem Eingriff fortsetzte. Der andere Arm erhielt hingegen kalte und warme Kompressen anstelle von Tabletten. Die Fragestellung dieser Studie ist nun, ob durch die Enzymeinnahme die Nebenwirkungen der Zahnextraktion, wie Schmerzen, Schwellungen und eine eingeschränkte Mundöffnung gemildert werden können. Zusätzlich wurde die Lebensqualität bzw. Zufriedenheit der Patienten erhoben. Die Autoren konnten dabei in allen Bereichen Vorteile, also geringere Beeinträchtigungen der Patienten und eine höhere Zufriedenheit in der Enzymgruppe feststellen. Auch im Bereich Lebensqualität erzielte der Enzymarm bessere Werte. Die Autoren sprechen sich daher für eine Enzymtherapie bei Blutkrebspatienten während der Weisheitszahnentfernung aus. Die Studie hat eine sehr geringe Patientenanzahl mit wenigen Informationen über die Erkrankung der Probanden. Es wurde keine Korrektur für multiples Testen durchgeführt und der Randomisierungsprozess ist unzureichend beschrieben.

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	Multicentric
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	Diagnosis of hematological tumor; white blood cell count 3–12×109/l, platelet count ≥60×109 /l, absolute neutrophil count ≥109 /l; average score of the difficulty of mandibular impacted third molar extraction ≥14, patients had difficulties with tooth extraction; informed consent form signed by patients
Exclusion criteria	Contraindications of surgery; long-term administration of medication, recent administration of glucocorticoids, antibiotics, or anodyne; recurrent pericoronitis of the impacted tooth; moderate caries of the wisdom tooth and adjacent teeth; periapical periodontitis, pulpitis, or periodontitis
N randomized	72
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	All participants analysed; no drop-outs
Countries of data collection	China
LoE Level of evidence	2b Oxford 2009
Outcome timeline Data collection times	T0: Baseline T1: 1 day after surgery T2: 3 days after surgery T3: 7 days after surgery (+quality of life)

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	Hematologic Cancers - Leukemia (Acute Lymphocytic/Acute Myeloid/Chronic Lymphocytic/Chronic Myeloid)
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	Hematological tumor classification in enyzme arm; control arm: Acute lymphoblastic leukemia: 13 (36.11%); 12 (33.33%) Acute non-lymphocytic leukemia: 11 (30.56%); 9 (25.00%) Aplastic anemia: 5 (13.89%); 6 (16.67%) Non-Hodgkin's lymphoma: 4 (11.11%); 5 (13.89%) Langerhans cell histocytosis: 3 (8.33%); 4 (11.11%)
Comorbidities	NI
Current cancer therapies	Chemotherapy
Specifications on cancer therapies	NI
Previous cancer therapies	NI
Gender	Mixed
Gender specifications	Enzyme arm: 22 male (61%); 14 female (39%) Control arm: 20 male (56%%); 16 female (44%)
Age groups	Adults (18+)
Age groups specification	Mean age (SD) per arm: Enzyme arm: 24.35 (5.57) years Control arm: 23.76 (5.48) years

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	36
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	Enzymes
Dosage and regime	Oral intake of 3 x 30,000 units of enteric-coated capsules of bromelain daily, starting one day before the surgery up to and including three days after the surgery + all patients: sugery: third molar extraction was performed under local anesthesia
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.	5
Side effects / Interactions	NI

Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment	Active control
Number of participants (arm) N randomized	36
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	Cold-Hot-Compress
Dosage and regime	Cold-hot compress for two days after surgery + all patients: surgery: third molar extraction was performed under local anesthesia
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.	2
Side effects / Interactions	NI

Outcomes

Pain

Outcome type As specificed by the authors	Primary
Outcome specification	Score range = 0 (no pain) to 10 (intolerable severe pain) No pain: 0–1 points for no pain or little pain or pain hard to feel; Mild: 2–3 points for tolerable pain that did not affect sleep; Moderate: 3–6 points for pain that altered normal daily activities and sleep; Severe: ≥7 points for intolerable pain, patients took ibuprofen sustained release capsule or return for a visit
Type of measurement	VAS (Visual Analogue Scale)
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".	The pain decreased in both arms from day 1 to day 7 after surgery. Day 1: Enzyme arm = 5.35(1.14); control arm = 6.06(1.23) p =0.013 Day 3: Enzyme arm = 4.06(1.13); control arm = 4.73(1.25) p =0.019 Day 7: Enzyme arm = 2.23(1.02) ; control arm = 2.76(1.17) p=0.044
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".	The enzyme arm exhibited significantly lower scores at each time point compared to the control arm (p=0.013-0.044)

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	?

Postoperative morbidity/ complications

Outcome type As specificed by the authors	Primary
Outcome specification	Side effects of tooth extraction: Swelling Value difference of CT+ ME before and after surgery indicated the swelling degree: CT distance: distance of the skin surface from the tragion (T point) on the affected side of the cheek to the cheilion (C point) on the same side; ME distance: distance on the skin surface from the external canthus point on the same side (E point) to the mandibular angle point (M point)
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".	Day 1: Enzyme arm = 2.23(0.34) ;control arm = 2.85(0.43) p<0.0001 Day 3: Enzyme arm = 1.23(0.13) ;control arm = 1.98(0.27) p<0.0001 Day 7: Enzyme arm = 0.23(0.11) ;control arm = 1.01(0.37) p<0.0001
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".	The enzyme arm exhibited significantly lower swelling than the control arm at each time point (p<0.0001).

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	?

Postoperative morbidity/ complications

Outcome type As specificed by the authors	Primary
Outcome specification	Side effects of tooth extraction: Mouth opening Distance from the upper central incisor margin to the lower at the biggest positive mouth opening state before and after surgery; distance differences before and after surgery indicated the limitation of mouth opening degree.
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".	Day 1: Enzyme arm = 2.15±0.34 ;control arm = 2.76±0.53 p<0.0001 Day 3: Enzyme arm = 1.16±0.33 ;control arm = 1.83±0.45 p<0.0001 Day 7: Enzyme arm = 0.43±0.12 ;control arm = 1.16±0.27 p<0.0001
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".	The enzyme arm exhibited significantly lower scores than the control arm at each time point.

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	Primary
Outcome specification	Modified postoperative symptom severity scale (PoSSe): Patients were scored in 7 dimensions (food, language, feeling, swelling, pain, nausea, and daily living) one week after surgery
Type of measurement	PoSSe (Postoperative Symptom Severity Scale)
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".	The comparison of quality of life for the two arms showed that the enzyme arm scored better than the control arm in all items: Items in enzyme arm; control arm: Food: 5.76(2.78); 7.96(2.18) p=0.0004 Language: 1.17(0.63); 2.57(0.93) p<0.0001 Feeling: 0.83(0.36); 1.44(0.76) p<0.0001 Swelling: 3.28(1.57); 4.76(2.06) p=0.0010 Pain: 4.16(2.01); 6.23(1.01) p<0.0001 Nausea: 0.21(0.12); 0.91(0.21) p<0.0001 Daily living: 1.38(0.34); 3.38(0.54) p<0.0001

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	NI
Conflicts of Interest	NI

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 available
• Detailed specification of statistical parameters

CONTRA:

• Small number of study participants
• No information on drop-out or attrition: ‘If participants suffered from side effects, they stopped treatment and discontinued participation in the study.’
• The authors state that the study was double-blinded, but this is not possible due to the different treatment methods of the two arms
• Endpoint 4 not independent of endpoints 1, 2 and 3
• No correction for multiple testing (cumulative α-error possible)
• Unclear randomisation process (‘we randomly divided’)