Reference ↗
Title	Die Therapie der radiogenen Mukositis mit Enzymen
Topic	Enzymes (bromelain papain)
Author	Vinzenz, K, Stauder, U
Year	1992
Journal	Deutsche Zeitschrift für Onkologie
DOI	https://link.springer.com/chapter/10.1007/978-3-7091-9087-6_34

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

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	NI
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	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 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; comparison of the arms with chi-square test and exact fisher test
Countries of data collection	NI
LoE Level of evidence	2b Oxford 2009
Outcome timeline Data collection times	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

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.	Neo-adjuvant
Types of cancer "Other Cancers" means that only a subpopulation was specified, but further unspecified cancer types were included	Head and Neck Cancers - Oral 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	Patients with carcinomas in the floor of the mouth
Comorbidities	NI
Current cancer therapies	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 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	19
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	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 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.	35
Side effects / Interactions	NI

Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment	Passive control
Number of participants (arm) N randomized	20
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	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 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.	35
Side effects / Interactions	NI

Outcomes

Mucositis

Outcome type As specificed by the authors	Primary
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 - 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".	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 - 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".	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).

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	?

Mucositis

Outcome type As specificed by the authors	Primary
Outcome specification	First occurrence of mucositis after start of radiation therapy
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 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 - 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 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.

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:

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