Reference ↗
Title	Does prophylactic treatment with proteolytic enzymes reduce acute toxicity of adjuvant pelvic irradiation? Results of a double-blind randomized trial
Topic	Enzymes (bromelain papain)
Author	Martin, T, Uhder, K, Kurek, R, Roeddiger, S, Schneider, L, Vogt, HG, Heyd, R, Zamboglou, N
Year	2002
Journal	Radiotherapy and oncology: journal of the European Society for Therapeutic Radiology and Oncology
DOI	https://doi.org/10.1016/S0167-8140(02)00192-5_Get_rights_and_content

Study Note

Brief summary

This study included 56 patients with cancer in the pelvic region. These were different types of cancer, but all patients had their tumours completely removed and underwent radiotherapy. Some of the patients (28 people) also received enzyme therapy in tablet form (10mg papain, 40mg trypsin, 40mg chymotrypsin) and some (28 patients) only received a placebo. The question of this study is whether the additional enzyme intake can reduce the side effects of radiotherapy, such as diarrhoea, nausea, vomiting, physical weakness and skin peeling. In addition, it is being investigated whether patients can be spared further medication to treat the side effects and whether there are fewer interruptions during radiotherapy. The results of the study show no relevant advantages of enzyme therapy compared to taking a placebo. The authors therefore do not recommend enzyme therapy. This study makes a direct comparison of the frequency of side effects with patients who only receive placebo, which allows a good comparability. The participants in both arms were also not informed whether they were receiving enzymes or a placebo and were randomly assigned to one of the two arms beforehand. Although the patients all had tumours in the pelvic region, there was hardly any information on how advanced the cancer was in the individual patients and this could therefore vary greatly between the arms. With 28 participants per arm, these are quite small, so it is difficult to make a generally valid statement here. The severity of the side effects was asked of the patients by a doctor and not entered by the patient in a questionnaire, so that the result could possibly be distorted here.

In dieser Studie wurden 56 Patienten mit Krebsleiden in der Beckenregion eingeschlossen. Es handelte sich hier um verschiedene Arten von Krebs, jedoch wurde bei allen Patienten der Tumor vollständig entfernt und eine Strahlentherapie angeschlossen. Ein Teil der Patienten (28 Personen) erhielt dabei zusätzlich eine Enzymtherapie in Tablettenform (10mg Papain, 40mg Trypsin, 40mg Chymotrypsin) und ein anderer Teil (28 Patienten) lediglich ein Placebo. Die Fragestellung dieser Studie ist nun, ob durch die zusätzliche Enzymeinnahme die Nebenwirkungen der Strahlentherapie, wie Durchfall, Übelkeit, Erbrechen, körperliche Schwäche und Hautablösungen gemindert werden können. Zusätzlich wird geschaut, ob bei den Patienten weitere Medikamente zur Behandlung der Nebenwirkungen eingespart werden können und ob es zu weniger Unterbrechungen während der Strahlentherapie kommt. Das Ergebnis der Studie zeigt keine relevanten Vorteile der Enzymtherapie gegenüber der Einnahme eines Placebos. Die Autoren sprechen daher keine Empfehlung für eine Enzymtherapie aus. Diese Studie zieht einen direkten Vergleich über die Häufigkeit der Nebenwirkungen mit Patienten, die nur eine Scheintherapie erhalten, was eine gute Vergleichbarkeit ermöglicht. Die Teilnehmenden beider Arme waren auch nicht darüber informiert, ob sie nun Enzyme oder ein Placebo erhielten und wurden zuvor per Zufall in eine der beiden Arme eingeteilt. Die Patienten hatten zwar alle Tumore in der Beckenregion, jedoch gab es kaum Informationen, wie weit fortgeschritten der Krebs bei den einzelnen Patienten war und somit konnte dies in den Armen sehr unterschiedlich sein. Mit 28 Teilnehmenden je Arm sind diese recht klein, sodass es schwer ist, hier eine allgemein gültige Aussage treffen zu können. Die Stärke der Nebenwirkungen wurde bei den Patienten durch einen Arzt erfragt und nicht durch den Patienten in einen Erhebungsbogen eingetragen, sodass hier das Ergebnis möglicherweise verfälscht sein könnte.

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	Proven indication for adjuvant external beam radiotherapy of the pelvis after macroscopically complete resection of a pelvic malignancy; age >18 years; given informed consent before starting the treatment
Exclusion criteria	Palliative indications for pelvic irradiation; existence of a colostomy; known intolerance to proteolytic enzyme preparations or to contents of the study medication; participation in other clinical studies within the last 30 days
N randomized	56
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 56 patients were evaluated according to an intent-to-treat-analysis. 8 patients finished the study prematurely at their own request, but the comparibility of the study groups was still remained.
Countries of data collection	Germany
LoE Level of evidence	2b Oxford 2009
Outcome timeline Data collection times	T0: Baseline (3 days before starting radiotherapy) T1: day 3 of radiation T2: day 8 of radiation T3: day 15 of radiation T4: day 21 of radiation T5: day 28 of radiation T6: day 35 of radiation

Characteristics of participants

All patients had a Karnofsky index of >90%

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	Colorectal Cancer - Rectal Cancer, Gynecologic Cancers - Uterine Cancer, Gynecologic Cancers - Endometrial Cancer, Gynecologic Cancers - Vulvar Cancer, Prostate 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	Curative surgery per arm for: 23 carcinomas of the rectosigmoid (enzyme arm: 9; placebo arm: 14) 17 endometrial carcinoma (enzyme arm: 8; placebo arm: 9) 14 uterine cervix cancer (enyzme arm: 11; placebo arm: 3), 1 carcinoma of the vulva (enzyme arm: 0; placebo arm: 1) 1 prostate cancer (enzyme arm: 0; placebo arm: 1)
Previous cancer therapies	Surgery
Gender	Mixed
Gender specifications	Enyzme arm: 23 female (82%) ; 5 male (18%) Placebo arm: 20 female (71%) ; 8 male (29%)
Age groups	Adults (18+)
Age groups specification	Mean age per arm: Enzyme arm: 53.8 years Placebo arm: 57.3 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	28
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	3 patients (day 3-15 of radiation) 1 patient (day 21-35 of radiation)
Drop-out reasons	Finished the study prematurely at their own request
Intervention	Enzymes
Dosage and regime	3x4 capsules of of WOBE-MUGOS containing each 100 mg papain (270 FIPE), 40 mg trypsin (29 ukat) and 40 mg chymotrypsin (200 ukat) daily, starting 3 days before irradiation and finishing on the last day of radiotherapy + all patients: radiation using a four-field box technique with individually shaped blocks; external beam radiotherapy was given using fractionation of 5 x 1.8 Gy weekly to a total dose of 50.4 Gy, specified at the isocentre
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	Placebo
Number of participants (arm) N randomized	28
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	3 patients (day 3-15 of radiation) 1 patient (day 21-35 of radiation)
Drop-out reasons	Finished the study prematurely at their own request
Intervention	Placebo
Dosage and regime	3x4 capsules without any enzyme contentsdaily, starting 3 days before irradiation and finishing on the last day of radiotherapy + all patients: radiation using a four-field box technique with individually shaped blocks; external beam radiotherapy was given using fractionation of 5 x 1.8 Gy weekly to a total dose of 50.4 Gy, specified at the isocentre
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	There is a trend towards less need for additional medication in the placebo group.

Outcomes

Toxicity

Outcome type As specificed by the authors	Primary
Outcome specification	Evaluation of acute toxicity was done by the radiation oncologist together with the patient in an interview. Diarrhea was assessed by increase of stools per day. Vomiting was assessed by frequency per day. Nausea was assessed by decrease of food intake.The fatigue syndrome was assessed by loss of activity.
Type of measurement	Toxicity criteria of RTOG (Radiation Therapy Oncology Group) and EORTC (European Organization for Research and Treatment of Cancer)
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".	Diarrhea In the enzyme arm 12 (43%) patients developed no or mild and 16 (57%) moderate or severe diarrhea during the entire radiation treatment; in the placebo arm 18 (64%) patients developed no or mild and 10 (36%) moderate or severe diarrhea; mean duration of moderate or severe diarrhea was 11 days in the enzyme arm and 10 days in the placebo arm; the difference was not statistically significant (p= 0.11) Vomiting All 28 patients in the enzyme arm developed no or mild vomiting; in the placebo arm 27 patients developed no or mild and 1 patient moderate or severe vomiting; no significant group differences (p= NI) Nausea: 26 patients (93%) in each arm developed no or mild and 2 (7%) moderate or severe nausea; no significant group differences (p= NI) Fatigue In the enzyme arm 23 (82%) patients developed no or mild and 5 (18%) moderate or severe fatigue in the entire radiation treatment; in the placebo arm 26 (93%) patients developed no or mild and 2 (7%) moderate or severe fatigue; difference was statistically not significant (p = 0.23); no group differences in the average values (p=NI) Epitheliolyse In the enzyme arm 21 (75%) patients developed no or mild, 7 (25%) patients moderate or severe epitheliolysis; in the placebo arm 25 (89%) developed no or mild, 3 (11%) moderate or severe epitheliolysis; the difference was statistically not significant (p= 0.16); no group differences in the average values (p=NI)

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	?

Additional medication

Outcome type As specificed by the authors	Secondary
Outcome specification	Requirements for supportive medication due to acute toxicities evaluated on T1 = day 3 of radiation to T6 = day 35 of radiation
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".	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".	There were 29 requirements for supportive medication due to acute toxicities in the enzyme arm and 19 in the placebo arm: Enzyme arm: 22 for diarrhea; 2 for antibiotics; 1 for analgestics, 0 for antiemetics, 3 for treatment of epitheliolysis; 1 for antidepressiva Placebo arm: 11 for diarrhea, 1 for antibiotics , 3 for analgestics; 2 for antiemetics , 2 for treatment of epitheliolysis, 0 for antidepressiva

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	?

Treatment interruption

Outcome type As specificed by the authors	Secondary
Outcome specification	Treatment interruption (in days) or premature end of radiation therapy due to radiation-induced side effects
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".	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".	Treatment interruptions (mean days) due to acute toxicity were 2.44 days in the enzyme arm and 1.46 days in the placebo arm. 52 out of 56 patients (92.8%) finished the entire radiation treatment as planned; 4 (7.2%) patients finished radiation prematurely (enzyme arm: 2; placebo arm: 2 patients).

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:

Intention-to-treat analysis
Double-blinded

CONTRA:

No sufficient information on group comparability
No information on the ethics vote
Small number of study participants and high attrition
Time period, but no reasons for attrition given
Data collection by interview, possibly not an objective survey
Unclear randomisation process
Partial lack of group comparisons