Kasseroller et al. (2003): Efficacy and tolerability of proteolytic enzymes as an anti-inflammatory agent in lymphoedema after axillary dissection due to mammary cancer
| Reference ↗ | |
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| Title | Efficacy and tolerability of proteolytic enzymes as an anti-inflammatory agent in lymphoedema after axillary dissection due to mammary cancer |
| Topic | Enzymes (bromelain papain) |
| Author | Kasseroller, R, Wenning, HG |
| Year | 2003 |
| Journal | The European Journal of Lymphology and related problem |
| DOI | |
Brief summary
This study includes 88 patients with breast cancer. At the start of the study, the patients had already undergone surgery and had their lymph nodes in the breast/armpit area removed. In particular, these patients all suffer from unilateral lymphoedema, which developed after the operation. The patients in this study all receive ‘CDT therapy’, consisting of manual lymph drainage, bandaging of the arm, special skin care and exercises. However, one arm with 44 patients also received enzyme therapy in tablet form. The aim of the study was to find out whether the volume of the arm decreases more, the thickness of the skin folds is reduced and whether the tension of the skin decreases more as a result of the additional intake. The assessment of the skin fold thickness serves as a parameter for the increase in connective tissue. With regard to the volume of the arm, there are no major differences between the two arms, so there is no advantage here. In terms of skin fold thickness, which is measured at various points on the arm, there is a slight advantage in the enzyme arm. However, the authors do not provide a statistical analysis. Finally, the tension of the skin is measured, which is slightly lower in the enzyme arm than in the control arm. However, the authors do not provide a statistical analysis here either. Finally, the authors mention that enzyme therapy does not cause any serious side effects, only abdominal pain and mild digestive disorders. Based on the results, the authors are not in favour of enzyme therapy. Blood values were also compared, which according to the study were better in the enzyme arm. However, these do not play a role in our analysis.
In dieser Studie sind 88 Patientinnen mit Brustkrebs eingeschlossen. Die Patientinnen sind zu Beginn der Studie bereits operiert und ihnen wurden die Lymphknoten im Brust-Achsel Bereich entfernt. Im Speziellen leiden diese Patientinnen alle an einem einseitigen Lymphödem, welches nach der Operation entstanden ist. Die Patientinnen erhalten in dieser Studie alle eine „CDT Therapie“, bestehend aus manueller Lymphdrainage, Bandagieren des Arms, spezieller Hautpflege und Übungen. Ein Arm mit 44 Patientinnen erhält jedoch zusätzlich eine Enzymtherapie in Tablettenform. Ziel der Studie war es herauszufinden, ob durch die zusätzliche Einnahme das Volumen des Arms stärker abnimmt, die Hautfaltendicke geringer ist und ob die Spannung der Haut mehr abnimmt. Die Beurteilung der Hautfaltendicke dient dabei als Parameter der Bindegewebsvermehrung. In Bezug auf das Volumen des Arms ergeben sich keine großen Unterschiede zwischen den beiden Studien-Armen, sodass hier kein Vorteil besteht. In Bezug auf die Hautfaltendicke, welche an verschiedenen Stellen des Arms gemessen wird, ergibt sich ein leichter Vorteil im Enzym-Arm. Die Autoren geben dazu jedoch keine statistische Auswertung mit an. Zuletzt wird noch die Spannung der Haut gemessen, welche im Enzym-Arm leicht geringer ist als im Kontroll-Arm. Hier geben die Autoren jedoch ebenfalls keine statistische Auswertung mit an. Zuletzt erwähnen die Autoren noch, dass es durch die Enzymtherapie zu keinen schweren Nebenwirkungen kommt, es treten lediglich Bauchschmerzen und leichte Verdauungsstörungen auf. Die Autoren sprechen sich aufgrund der Ergebnisse für keinen Vorteil der Enzymtherapie aus. Es wurden zusätzlich noch Blutwerte miteinander verglichen, welche laut der Studie im Enzym-Arm besser ausfallen. Diese spielen jedoch keine Rolle in unserer Betrachtung.
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 | Patients with one-sided lymphatic oedema after axillary dissection due to mammary cancer, stage I to II; age ≥30 and ≤80 years; written, signed informed consent obtained |
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| Exclusion criteria | Known pregnancy or lactation; history of intolerability to emzyme preparations or to the passive ingredients ; arterial closures and/or flow-off disorders at the ill arm and/or contra lateral arm; connate lmphatic oedema; treatment with venoactive drugs such as Rutosides, Bioflavonoides, Aescin, ets.; treatment with NSAIDs; contraindication for lymphatic drainage; participation in any clinical study in the last 30 days; simultaneous participation in any other clinical trial |
| N randomized | 88 |
| 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. | PP Analysis, ITT Analysis |
| Specifications on analyses | All patients were analysed in the intention-to-treat evaluation, 71 patients in the per-protocol I evaluation and 83 patients in the per-protocol II evaluation
Per-protocol I: Patients who discontinued before Visit 4 were excluded if the discontinuation was not efficacy-related Per-protocol II: Patients who discontinued before Visit 3 were excluded |
| Countries of data collection | Austria |
| LoE Level of evidence | 2b Oxford 2009 |
| Outcome timeline Data collection times | T0: Baseline
T1: day 9 T2: day 19 T3: day 45 |
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. | No therapy setting |
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| Types of cancer "Other Cancers" means that only a subpopulation was specified, but further unspecified cancer types were included | Breast 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 | Early Stage |
| Specifications on cancer stages | State I-II |
| Comorbidities | NI |
| Current cancer therapies | No therapy |
| Specifications on cancer therapies | All patients got axillary dissection due to mammary cancer and receive now combined decongestive therapy (CDT) for the lymphoedema. |
| Previous cancer therapies | Surgery |
| Gender | Female |
| Gender specifications | 100% female |
| Age groups | Adults (18+) |
| Age groups specification | Mean age per arm:
Enzyme-arm: 60.9 years Placebo-arm: 58.0 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 | 44 |
| Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date | 5 |
| Drop-out reasons | Gastrointestonal side effects |
| Intervention | Enzyme |
| Dosage and regime | 3x5 tablets of Wobenzym daily for 6.5 weeks
+ all patients: 2x daily CDT (combined decongestive therapy) for the first 20 days, consisting of manual lymphatic drainage (neck, arm, thorax), bandaging of the arm, specially tailored exercises and skin care |
| 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. | 45 |
| Side effects / Interactions | 6x gastrointestinal complaints with possible connection to the study medication, 1x gastrointestinal complaints with definite connection to the study medication; 5 participants subsequently discontinued the study |
| 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 | 44 |
| Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date | 2 |
| Drop-out reasons | Side effects |
| Intervention | Placebo |
| Dosage and regime | + All patients: 2x daily CDT (combined decongestive therapy) for the first 20 days, consisting of manual lymphatic drainage (neck, arm, thorax), bandaging of the arm, specially tailored exercises and skin care |
| 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. | 45 |
| Side effects / Interactions | 2x gastrointestinal side effects, 3x mild or moderate nausea, 1x nocturia, 1x dry skin, 1x urinary tract infection;
1x gastrointestinal complaints were definitely and 1x questionably attributable to the study medication, nocturia and dry skin were questionably related to the study medication, the urinary tract infection was not related to the medication; 2 participants subsequently discontinued the study |
Outcomes
Lymphedema
| Outcome type As specificed by the authors | Primary |
|---|---|
| Outcome specification | Volume reduction
measured by Volometer = opto-electronic device measures the arm circumference 2-dimensionally along a distance of 45cm on the entire arm according to the kuhnke formula. As reference the healthy arm of each individual is measured. |
| Type of measurement | Volometer, 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". | Mean Volometer of the ill arm at day 1:
Enzyme-arm = 2483.0; Placebo-arm = 2420.1 |
| 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 Volometer of the ill arm at day 45:
Enzyme-arm = 2275.1; Placebo-arm = 2225.7 Both arms show a decrease of volume until day 45, but there was no significant difference between the arms (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 | ? |
Lymphedema
| Outcome type As specificed by the authors | Secondary |
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| Outcome specification | Skinfold thickness
(Parameter of fibrosis) was measured with a calliper in mm and devided by 2 for the normal measurement of the skinfold in not fibrotically changed skin. Measures of the absolute values were taken from the upper arm, the lower arm, the hand and from the third finger. The absolute reference value is 2 mms for the healthy skin. |
| 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". | Mean volume of the upper ill arm at day 1:
Enzyme-arm = 7.4mm; Placebo-arm = 6.7mm |
| 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 volume of the upper ill arm at day 45:
Enzyme-arm = 4mm; Placebo-arm = 3.4mm Both arms show similiar developement of skin thickness after 45 days. Similar development in the lower arm, hand and third finger. There is a slight advantage for the enzyme-arm for upper ill arm and lower arm; (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 | ? |
Lymphedema
| Outcome type As specificed by the authors | Secondary |
|---|---|
| Outcome specification | Tension
Assessed by the investigator with a four point rating scale: 0 = no tension 1 = slight tension 2 = moderate tension 3 = severe tension |
| 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". | Mean tension of the ill arm at day 1:
Enzyme-arm = 2.0; Placebo-arm = 1.8 |
| 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 tension of the ill arm after 45 days:
Enzyme-arm = 0.4; Placebo-arm = 0.5 Both arms show a similar decrease of tension in the ill arm, but but the decrease was a little bit greater in the enzyme-arm (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 | ? |
Funding and Conflicts of Interest
| Funding | NI |
|---|---|
| Conflicts of Interest | According to the authors no conflict of interest |
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:
- Detailed information on the baseline criteria
- Intention-to-treat analysis
- Double-blinded
- Pill counting as control (compliance)
CONTRA:
- No information on ethics vote
- No further information on drop-out/attrition
- Statistical methods presented in a way that is difficult to understand
- No statistically comprehensible substantiation of the results or group comparisons
- Exclusion of test subjects with known intolerance: validity of side effects therefore limited
- Apparent differences between groups compared to baseline with regard to previous cancer therapy and skin fold thickness
- Outcome for assessment of success by doctor and patient not listed in study
- Sparse description of randomisation, could be a quasi-randomisation ‘The patient number was allocated to the patient in uprising arithmetical order and the patient received the first box of matching medication’