View source for Vinzenz et al. (1992): Die Therapie der radiogenen Mukositis mit Enzymen

{{Reference
|Reference=Publication: Die Therapie der radiogenen Mukositis mit Enzymen
}}

=Brief summary=
This study included 39 people with cancer of the floor of the mouth. All patients received radiotherapy. However, one arm with 19 patients also received enzyme therapy, which was administered in parallel in tablet form. Now the question is whether the additional therapy can positively influence the severity of side effects, such as inflammation of the mucous membranes, and the time of their first occurrence. The severity of the inflammation is divided into stages I to III for comparability. There is a significant advantage in favour of the enzyme arm. In contrast, however, there was an earlier onset in the enzyme arm, even if no statistical evidence is provided here. Based on the results, however, the authors are in favour of enzyme therapy. Although this study has been statistically analysed, there is a lack of information on the basic data of the patients, the time period, the withdrawal of participants, etc. Due to the very superficial description of the procedure and the presentation of the methodology, the study is not comprehensible in every detail and possible biases cannot be ruled out. 


In dieser Studie sind 39 Personen mit Krebs im Mundbodenbereich eingeschlossen. Alle Patienten erhalten hier eine Strahlentherapie. Eine Arm mit 19 Patienten erhält jedoch zusätzlich eine Therapie mit Enzymen, die parallel in Tablettenform verabreicht wird. Die Fragestellung ist nun, ob durch die zusätzliche Therapie Nebenwirkungen, wie Schleimhautentzündungen, in der Schwere und im Zeitraum des ersten Auftretens positiv beeinflusst werden können. Die Ausprägung der Entzündung wird zur Vergleichbarkeit in die Stadien I bis III unterteilt. Es ergibt sich ein signifikanter Vorteil zugunsten des Enzym-Arms. Im Gegensatz dazu ist es im Enzym-Arm jedoch zu einem früheren Auftreten gekommen, auch wenn hier statistisch kein Nachweis erbracht wird. Die Autoren sprechen sich aufgrund der Ergebnisse jedoch für eine Enzymtherapie aus. Diese Studie ist zwar statistisch ausgewertet, jedoch fehlen viele Angaben zu den Grunddaten der Patienten, dem Zeitraum, dem Ausscheiden von Teilnehmern, etc. Aufgrund der sehr oberflächlichen Beschreibung des Ablaufs und der Darstellung der Methodik ist die Studie nicht in jedem Detail nachvollziehbar und mögliche Verzerrungen können nicht ausgeschlossen werden.

=Study Design=

{{Study Design (RCT)
|Perspective=Prospective
|Centralized=NI
|Blinding=No
|Is randomized=Yes
|Cross-over=No
|Number of arms=2
}}
=Study characteristics=

{{RCT study general properties
|Inclusion criteria=Patients with carcinomas in the floor of the mouth, who underwent preoperative radiotherapy
|Exclusion criteria=Patients with an existing pregnancy; younger than 18 years or older than 80 years; patients with a known intolerance to the enzyme preparation
|N randomized=39
|Analysis=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; 
comparison of the arms with chi-square test and exact fisher test
|Countries of data collection=NI
|LoE=2b Oxford 2009
|Outcome timeline=T0: Baseline one week before radiation

T1: 1 week after start of radiation

T2: 2 weeks after start of radiation

T3: 3 weeks after start of radiation

T4: 4 weeks after start of radiation

T5: 5 weeks after start of radiation (=end of radiation)
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Neo-adjuvant
|Types of cancer=Head and Neck Cancers - Oral Cancer
|Stage cancer=NI
|Cancer stage specification=Patients with carcinomas in the floor of the mouth
|Comorbidity=NI
|Current cancer therapy=Radiation therapy
|Specifications on cancer therapies=Patients underwent preoperative radiotherapy
|Previous cancer therapies=NI
|Gender=Mixed
|Gender specifications=Gender per arm: 
Enzyme arm: female = 3 (15.8%); male = 16 (84.2%)

Control arm: female = 5 (25%); male = 15 (75%)
|Age groups=Adults (18+)
|Age groups specification=Mean age (SD) per arm:
Enzyme arm: 51.5 (8.7)

Control arm: 56.4 (6.7)
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=19
|Drop-out=NI
|Drop-out reasons=NI
|Intervention=Enzymes
|Dosage and regime=3x5 tablets of WOBE-MUGOS (100mg papainases, 40mg trypsin, 40mg chymotrypsin, 40mg hydrolysate from calf thymus) daily 30 minutes before a meal

+ all patients: radiation therapy with a cumulative total radiation dose of approximately 50 Gy
|One-time application=No
|Duration in days=35
|Side Effects / Interactions=NI
|Order number=1
|Arm topic=Enzymes (bromelain papain)
}}
{{Arm
|Arm type=Passive control
|Number of participants (arm)=20
|Drop-out=NI
|Drop-out reasons=NI
|Intervention=No additional intervention
|Dosage and regime=No additional intervention

+ all patients: radiation therapy with a cumulative total radiation dose of approximately 50 Gy
|One-time application=No
|Duration in days=35
|Side Effects / Interactions=NI
|Order number=2
|Arm topic=Enzymes (bromelain papain)
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=Mucositis
|Outcome specification=Maximum severity of mucositis:

The clinical manifestation of mucositis was assessed in order to examine the side effects of radiation: 

Stage I = erythema 

Stage II = mucosaodema 

Stage III = mucosal necrosis/ulceration
|Type of measurement=Scale
|Results during intervention=Stage of mucositis per arm in n(%)

Stage I = Enzyme arm: 4 (21.1%); control arm: 0

Stage II = Enzyme arm: 13 (68.4%); control arm: 11 (55.0%)

Stage III = Enzyme arm: 2 (10.5%); control arm: 9 (45.0%)
|Results after intervention=Mean (SD) for maximum severity of mucositis per arm:

Enzyme arm = 1.9 (0.56)

Control arm = 2.5 (0.59)

The mucositis was less severe in the enzyme arm. The difference is statistically significant (p=0.014).
Significantly more patients in the control arm were in stage III (p=0.019).
|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=?
|Order number=1
|Outcome topic=Enzymes (bromelain papain)
}}
{{Outcome
|Outcome type=Primary
|Outcome name=Mucositis
|Outcome specification=First occurrence of mucositis after start of radiation therapy
|Type of measurement=Observation
|Results during intervention=Day after start of radiation: Enzyme arm n(%); control arm n(%)

5: 1 (5.3%); 0

6: 2 (10.5%); 1 (5%)

7: 1 (5.3%); 0

8: 2 (10.5%); 2 (10%)

9: 4 (21.4%); 1 (5%)

10: 3 (15.8%); 4 (20%)

11: 3 (15.8%); 2 (10%)

12: 4 (21.4%); 2 (10%)

13: 0 ; 1 (5%)

14: 0 ; 1 (5%)

15: 0 ; 1 (5%)

16: 0 ; 3 (15%)

17: 0 ; 1 (5%)

18: 0; 1 (5%)

19: 1 (5.3%) ; 1 (5%)

21: 1 (5.3%) ; 1 (5%)
|Results after intervention=In the enzyme arm mucositis occurred in 17 patients (89.5%) in a period of 5 to 12 days (stage I or II) and in 2 patients (10.5%) between the 19th and 21st day of irradiation (stage III). The mucositis developed on average 9.1 (4.9) days after the start of radiotherapy.

In the control arm mucositis occurred over a period of 6 to 21 days after the start of radiotherapy with grade III occurring relatively early from the 12th day after the start of radiotherapy. The mucositis developed on average 13.0 (4.1) days after the start of radiotherapy.
|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=?
|Order number=2
|Outcome topic=Enzymes (bromelain papain)
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=NI
|Conflicts of Interest=NI
}}
=Further points for assessing the study=

{{Further points for assessing the study
|power analysis performed=?
|Sample size corresponds to power analysis=?
|Reasons given for samples being too small according to power analysis=?
|Samples sufficiently large=?
|Ethnicity mentioned=?
|Other explanations for an effect besides the investigated intervention=?
|Possibility of attention effects=?
|Possibility of placebo effects=?
|Other reasons=?
|Correct use of parametric and non-parametric tests=?
|Correction for multiple testing=?
|Measurement of compliance=?
|Consistent reporting in numbers=?
|Comprehensive and coherent reporting=?
|Cross-over=?
|sufficient washout period=?
|Tested for carry-over effects=?
|Were sequence effects tested=?
|Effect sizes reported=?
|Were side effects systematically recorded=?
|Side effects taken into account in the interpretation of the results=?
|Ethics / CoI / Funding=?
|Blinding reliable=?
|Check whether blinding was successful=?
|reasons given for samples being too small according to power analysis=?
|Testing for normal distribution=?
|Correct application of statistical tests=?
|mono- or multicentric=?
}}
{{Additional Notes
|Additional Notes=PRO:
* Information on the tests used

CONTRA:
* No information on the ethics vote
* Hardly any demographic information and unclear randomisation process; comparability of the arms cannot be presented in a comprehensible manner
* Relatively small number of study participants 
* No blinding
* No information on drop-out or attrition
* No baseline p-values given
* No information whether mono- or multicentre
* No information on the country and period of the study
}}