Stauder et al. (1991): Strahlentherapeutische Nebenwirkungen bei Abdominalkrebspatienten und deren Reduktion durch hydrolytische Enzyme

Reference ↗
Title	Strahlentherapeutische Nebenwirkungen bei Abdominalkrebspatienten und deren Reduktion durch hydrolytische Enzyme
Topic	Enzymes (bromelain papain)
Author	Stauder, G, Beaufort, F, Streichhan, P
Year	1991
Journal	Deutsche Zeitschrift für Onkologie
DOI

Brief summary

This study includes 68 patients with abdominal cancer who are receiving radiotherapy. One arm of 36 people also received enzyme therapy in tablet form, which was taken during radiotherapy. Another arm of 32 people, on the other hand, received no other therapy or medication apart from the planned radiotherapy. The question of this study is whether the additional enzyme intake can increase the intensity of radiotherapy, improve general well-being, alleviate the side effects of radiotherapy and reduce the need for concomitant medication. The therapy is also evaluated by doctors and patients. Typical side effects of radiotherapy are skin reactions, nausea, vomiting, weakness, etc. The authors come to the conclusion that the arm with people taking enzymes shows advantages in all respects. They complete the therapy better, with fewer side effects and taking less medication. A major advantage is that higher doses of radiation can be applied and there are fewer interruptions, so that ultimately a more intensive therapy is carried out. The need for additional medication is also lower in the enzyme arm. Only the assessment of the therapy by the doctor and the patient is worse in the enzyme arm in both cases. Ultimately, the authors are in favour of the benefits of this concomitant therapy. This study makes a comparison with patients who do not receive any additional treatment, so that the placebo effect may also have an influence. The authors also refer to a statistical analysis, but do not make this available to the reader of the study.

In dieser Studie sind 68 Patienten mit Krebs im Abdominalbereich eingeschlossen, welche eine Strahlentherapie erhalten. Ein Arm mit 36 Personen erhält dabei zusätzlich eine Enzymtherapie in Tablettenform, die während der Bestrahlung eingenommen wird. Ein weiterer Arm mit 32 Personen erhält hingegen, außer der vorgesehenen Strahlentherapie, keine weitere Therapie oder Medikamente. Die Fragestellung dieser Studie ist nun, ob durch die zusätzliche Enzymeinnahme die Bestrahlungsintensität erhöht werden kann, sich das Allgemeinbefinden bessert, Strahlennebenwirkungen gelindert werden können und Begleitmedikation eingespart werden kann. Ebenfalls wird die Therapie durch Ärzte und Patienten bewertet. Typische Nebenwirkungen der Strahlentherapie sind Hautreaktionen, Übelkeit, Erbrechen, Kraftlosigkeit, etc. Die Autoren kommen zu dem Ergebnis, dass in allen Punkten der Arm mit Personen mit der Enzymeinnahme Vorteile zeigt. So schließen diese die Therapie besser, nebenwirkungsärmer und unter weniger Medikamenteneinnahme ab. Als großer Vorteil ist zu sehen, dass höhere Strahlendosen appliziert werden können und es zu weniger Unterbrechungen kommt, sodass letztlich eine intensivere Therapie durchgeführt wird. Auch der zusätzliche Medikamentenbedarf ist im Enzym-Arm geringer. Lediglich die Bewertung der Therapie durch den Arzt und den Patienten fällt im Enzym-Arm in beiden Fällen schlechter aus. Die Autoren sprechen sich letztlich für einen Nutzen dieser begleitenden Therapie aus. Diese Studie zieht einen Vergleich mit Patienten, die gar keine zusätzliche Behandlung erhalten, sodass möglicherweise auch der Placeboeffekt einen Einfluss haben kann. Ebenfalls sprechen die Autoren von einer statistischen Auswertung, machen diese aber dem Leser der Studie nicht zugänglich.

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	NI
Exclusion criteria	People with metastases outside the abdominal area; bad general condition (Karnofsky index < 50%); previous immunosuppressive treatment; current pregnancy; older than 75 years or younger than 18 years; known WOBE-MUGOS intolerance
N randomized	68
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; ANOVA, LSD-Test, Mann-Whitney-U-Test, Wilcoxon-Test
Countries of data collection	Austria
LoE Level of evidence	2b Oxford 2009
Outcome timeline Data collection times	T0: Baseline T1: after 2 weeks T2: after 5 weeks

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.	Palliative
Types of cancer "Other Cancers" means that only a subpopulation was specified, but further unspecified cancer types were included	Gynecologic Cancers - Ovarian Cancer, Gynecologic Cancers - Uterine Cancer, Prostate Cancer, Genitourinary Cancers - Kidney (Renal) Cancer, Genitourinary Cancers - Testicular Cancer, Head and Neck Cancers, Genitourinary Cancers - Bladder Cancer, Gynecologic Cancers - Vulvar Cancer, Colorectal Cancer - Rectal Cancer, Colorectal Cancer - Colon Cancer, Hematologic Cancers - Lymphoma (Hodgkin and Non-Hodgkin), 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	Karnovsky Index >50% Abdominal cancer types in enzyme arm; in control arm: Ovarian carcinoma: 2; 2 Uterine carcinoma: 11; 15 Prostate carcinoma: 14; 2 Intestinal carcinoma: 3; 7 Hypernephroma (with pelvic metastases): 1; 1 Carcinoma of the vas deferens: 1; - Head and neck carcinoma: 1; - Bladder carcinoma: 1; - Non-Hodgkin's lymphoma: -; 1 Chronic lymphocytic leukaemia: -; 1 Vaginal carcinoma: 1; 2 Rectal carcinoma: - ; 1 Double carcinoma: 1; -
Comorbidities	NI
Current cancer therapies	Radiation therapy
Specifications on cancer therapies	Radiation treatment of patients with inoperable abdominal cancer or postoperative radiotherapy of abdominal cancer due to lymph node involvement.
Previous cancer therapies	Surgery
Gender	Mixed
Gender specifications	NI
Age groups	Adults (18+)
Age groups specification	Mean age (SD) per arm: Enzyme-arm: 62.0 (11.3) years Control-arm: 64.5 (9.3) 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	36
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	Enzyme
Dosage and regime	Between 5 and 15 tablets of WOBE-MUGOS daily for 5 weeks: first two weeks average daily dose 10.6 (4.0), day 14 to day 35 averge daily dose 10.3(4.0) + all participants: radiation
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	According to the authors the tablets were mostly well or very well tolerated.

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	32
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 addtional medication
Dosage and regime	+ All participans: radiation
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	NA

Outcomes

"Tolerability" is not in the list (Anorexia/Cachexia, Anxiety, Appetite, Cerebral oedema, Cognitive functioning, Cognitive impairment, Depression, Dermatitis, Distress, Dysgeusia, ...) of allowed values for the "Outcome name" property.

Interaction with cancer treatment

Outcome type As specificed by the authors	Primary
Outcome specification	Influences on the intensity of radiation treatment
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".	Single doses (Gy) at baseline, after 2 weeks, after 5 weeks: Enyzme-arm: 1.95(0.11); 1.95(0.11); 1.95(0.11) Control-arm B: 1.81(0.45); 1.88(0.25); 1.88(0.26) (p=NI) Total dose (Gy) after 2 weeks, after 5 weeks: Enzyme-arm: 19.70(3.88); 54.20(13.60) Control-arm: 19.80(3.50); 46.70(7.68) (p=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".	Single doses: The average single radiation dose was approx. 8% higher in the enzyme-arm at the beginning and approx. 4% higher after 2 and 5 weeks than in the control-arm. Total dose: After 2 weeks the total dose was about the same in both arms, after 5 weeks the difference between the enzyme-arm and the control-arm was about 16% more in the enzyme-arm.

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	?

Performance Status

Outcome type As specificed by the authors	Primary
Outcome specification	Influences on general status: 11 values, 0 to 3 points each tiredness, appetite, headache, nausea, vomiting, diarrhoea, treatment-related skin symptoms
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".	Sum scores of all parameters after 0, 2 and 5 weeks per arm: Enzyme-arm: 0.04; 1.36; 1.42 Control-arm: 0.41; 2.25; 2.32 (p=NI) Conversion to percentage values in relation to the maximum value of 33 = 100% after 0, 2 and 5 weeks per arm: Enzyme-arm: 0.12; 4.12; 4.30 Control-arm: 1.24;6.82;7.03 (p=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".	No radiation-related headaches and ulcerations occurred in either arm; vomiting symptoms and oedema only occurred in the control-arm; all other symptoms occurred in both arms, but less frequently and less intensively in the enzyme-arm than in the control-arm. Deterioration of the general status in 5.5% of the enzyme-arm and in 11.4% of the control-arm, no changes of the general status in 94.5% of the enzyme-arm and 88.6% of the control-arm.

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	?

Toxicity

Outcome type As specificed by the authors	Primary
Outcome specification	Influence on the side effects of radiotherapy
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".	Type and frequency of side effect: Enzyme-arm; control-arm 1. diarrhoea: 15; 7 2. diarrhoea + fever: 1; 1 3. constipation: 0; 1 4. febrile infection + burning on urination: 1; 0 5. diarrhoea + nausea: 2; 4 6. diarrhoea + nausea + vomiting + reduced general condition: 0; 1 7. erythema: 1; 0 8. pain in the groin + burning on urination: 1; 0 9. erythema + diarrhoea: 2; 0 10. nausea: 0; 1 11. urinary tract infection: 1; 1 12. diarrhoea + urinary tract infection; 1;0 13. diarrhoea + burning on urination: 1; 0 14. burning on urination: 2; 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 onset in days of radiation side effects per arm Ezyme-arm: 17.3(12.3) Control-arm B: 15.6(7.7) (p=NI) Mean duration in days of radiation side effects per arm Enzyme-arm: 12.8(9.7) Control-arm: 24.6(14.2) (p=NI) Severity of side effects (score from 1 to 3) per arm: Enzyme-Arm: 1.77(0.77) Control-Arm: 1.88(0.62) (p=NI) The side effects in the enzyme-arm started later, were less severe and lasted for a shorter time compared to the side effects in the control arm.

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	Primary
Outcome specification	Influence on necessary additional medication due to the side effects of radiotherapy
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".	Type and number of additional medications in Enzyme-arm; control-arm: Cardiovascular agents: 34; 32 Antiemetics and gastrointestinal agents: 20; 30 Psychotropic drugs and antidepressants: 9; 19 Analgesics/spasmolytics: 5; 9 Diuretics/aldosterone anatagonists: 1; 5 Antibiotics/chemotherapy: 5; 4 Hypnotics: 7; 3 Other: 21; 23
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".	Patients from the enzyme-arm got 102 additional medications, patients from the control-arm got 125 additional medications (p=NI). The duration of taking the additional medication did not differ between the two arms.

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	?

Interaction with cancer treatment

Outcome type As specificed by the authors	Primary
Outcome specification	Average tolerability scored by patient and doctor on a scale from 1=very good to 5=bad; Therpy result scored by patient and doctor on a scale from 1 to 4=unsatisfactory
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".	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".	Average tolerability by doctor: enzyme-arm: 1.57(0.88); control-arm: 1.38(0.86) Average tolerability by patient: enzyme-arm: 1.75(1.13); control-arm: 1.41(0.86) Therapy result by doctor: enzyme-arm: 1.94(0.79); control-arm : 1.22(0.54) Therapy result by patient: enzyme-arm: 1.89(0.85); control-arm: 1.22(0.54)

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:

• Randomised

CONTRA:

• No information on the gender of the patients
• According to the authors, the comparability of the arms was tested using the Mann-Whitney U test, the Wilcoxon test was used to test for significant differences between the symptom levels, the Mann-Whitney U test was used to test for significant differences between the treatment results and the ANOVA and LSD test were used for the descriptive presentation of the symptom progression. Unfortunately, these results and associated p-values are not presented in the study.
• No blinding
• No information on drop-out/attrition
• Survey of side effects clouded, as patients with known intolerance were excluded beforehand