Dale et al. (2001): Co-medication with hydrolytic enzymes in radiation therapy of uterine cervix: evidence of the reduction of acute side effects

Reference ↗
Title	Co-medication with hydrolytic enzymes in radiation therapy of uterine cervix: evidence of the reduction of acute side effects
Topic	Enzymes (bromelain papain)
Author	Dale, PS, Tamhankar, CP, George, D, Daftary, GV
Year	2001
Journal	Cancer Chemotherapy and Pharmacology
DOI	https://doi.org/10.1007/s002800170006

Study Note

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Brief summary

120 women with cervical cancer were included in this study. All patients received the same radiotherapy. One arm of 60 people also received enzyme therapy in tablet form (10mg papain, 40mg trypsin, 40mg chymotrypsin), which was taken during the radiotherapy. Another arm of 60 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 alleviate the side effects of radiotherapy on the urinary and reproductive organs, the digestive tract, the skin and the vaginal mucosa. For this purpose, an evaluation form is used in this study in which typical characteristics and manifestations are recorded that indicate changes in the aforementioned areas. This can be, for example, increased urination or diarrhoea. The results of the study show advantages, or less severe symptoms, in the urinary and reproductive organs and the skin in the enzyme arm. In the area of the digestive tract and vaginal mucosa, there were only minor differences between the two arms. Based on these results, the authors report clear benefits from enzyme intake. This study makes a comparison with patients who do not receive any additional treatment, so that the placebo effect may also play a role here. The authors also categorise changes that are not statistically relevant as an advantage in the enzyme arm. However, not statistically relevant means that a benefit cannot actually be proven. Furthermore, only one person collected the results of the study, which can also be criticised. The collection and statistical analysis of the blood values in this study are incomprehensible, as the results are not discussed.

In dieser Studie wurden 120 Frauen mit Gebärmutterhalskrebs eingeschlossen. Dabei erhielten alle Patientinnen die gleiche Strahlentherapie. Ein Arm mit 60 Personen erhielt dabei zusätzlich eine Enzymtherapie in Tablettenform (10mg Papain, 40mg Trypsin, 40mg Chymotrypsin), die während der Bestrahlung eingenommen wurde. Ein weiterer Arm mit 60 Personen erhielt hingegen, außer der vorgesehenen Strahlentherapie, keine weitere Therapie oder Medikamente. Die Fragestellung dieser Studie ist nun, ob durch die zusätzliche Enzymeinnahme die Nebenwirkung der Strahlentherapie an Harn und Geschlechtsorganen, am Verdauungstrakt, an der Haut und der Vaginalschleimhaut gemildert werden können. Dazu wird in dieser Studie ein Bewertungsbogen verwendet, in dem typische Merkmale und Ausprägungen erhoben werden, die auf Veränderungen in den zuvor genannten Bereichen schließen lassen. Dies kann z.B. vermehrtes Wasserlassen oder Durchfall sein. Das Ergebnis der Studie zeigt Vorteile, bzw. weniger starke Beschwerden, bei den Harn- und Geschlechtsorganen und der Haut im Enzym-Arm. Im Bereich des Verdauungstrakts und an der Vaginalschleimhaut zeigen sich nur geringe Unterschiede zwischen den beiden Armen. Die Autoren berichten aufgrund dieser Ergebnisse von eindeutigen Vorteilen durch die Enzymeinnahme. Diese Studie zieht einen Vergleich mit Patientinnen, die gar keine zusätzliche Behandlung erhalten, sodass hier möglicherweise auch der Placeboeffekt eine Rolle spielen kann. Ebenfalls werden von den Autoren Veränderungen, die statistisch nicht als relevant eingestuft werden, als Vorteil im Enzym-Arm gewertet. Nicht statistisch relevant bedeutet hingegen, dass ein Nutzen eigentlich nicht nachgewiesen werden kann. Weiterhin hat nur eine einzelne Person die Ergebnisse der Studie erhoben, was auch durchaus als kritisch bewertet werden kann. Unverständlich sind die Erhebung und statistische Auswertung der Blutwerte in dieser Studie, da auf die Ergebnisse nicht eingegangen wird.

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	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	Women between 24-85 years; locally advanced, biopsy-confirmed carcinomas of the uterine cervix at stages IIa, IIb or IIIb
Exclusion criteria	Previous history of radiation therapy, chemotherapy or surgery; WHO performance index below 70%; uncontrolled systematic diseases
N randomized	120
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	?
Countries of data collection	India
LoE Level of evidence	2b Oxford 2009
Outcome timeline Data collection times	?

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 - Uterine 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	?, Advanced Stage
Specifications on cancer stages	locally advanced, biopsy-confirmed carcinomas of the uterine cervix at stages IIa, IIb or IIIb
Comorbidities	NI
Current cancer therapies	Radiation therapy
Specifications on cancer therapies	All patients received 50-60 Gy of external beam radiation in 20-30 fractions over a period of 5 weeks, followed by intra-cavitary brachytherapy at a dose of 20–30 Gy using a BARC applicator.
Previous cancer therapies	No therapy
Gender	Female
Gender specifications	100% female
Age groups	Adults (18+)
Age groups specification	Age in years (SD) per arm: Enyzme arm: 49.9 (10.5) Control arm: 49.3 (13.9)

Arms

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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	60
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	Hepatitis (n=1); brain metastasis (n=1)
Intervention	Enyzme
Dosage and regime	Daily 4x3 tablets of WOBE-MUGOS E (10mg papain, 40mg trypsin, 40mg chymotrypsin), starting 8(+/-1) days before the first radiotherapy session over a period of 69(+/-15) days. + all patients received 50-60 Gy of external beam radiation in 20-30 fractions for 35(+/-6) days , followed by intra-cavitary brachytherapy at a dose of 20–30 Gy using a BARC applicator.
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.	69
Side effects / Interactions	Side effects observed were not discriminated between being radiation therapy-induced or possibly being related to the test drug; gastrointestinal complaints can be possible side effects; in the enzyme-arm fewer complaints tended to be recorded (11.7% vs. 31.6%; p=0.12, ns.)

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	60
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	0
Drop-out reasons	NA
Intervention	No medication
Dosage and regime	Control arm patients did not receive any additional treatment + all patients received 50-60 Gy of external beam radiation in 20-30 fractions for 35(+/-1) days, followed by intra-cavitary rachytherapy at a dose of 20–30 Gy using a BARC applicator.
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	Side effects observed were not discriminated between being radiation therapy-induced or possibly being related to the test drug.

Outcomes

Toxicity

Outcome type As specificed by the authors	Primary
Outcome specification	Urogenital side effects Patients were evaluated at weekly intervals (for 5 weeks) for acute radiation therapy related side effects. Urogenital side effects were graded according to the RTOG/EORTC criteria, by a single observer (score 0-4). Patients were followed-up at intervals of 6 weeks and 5 month after completion of radiation therapy.
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".	During the course of radiation therapy in both arms most of the patients showed a slight increase in frequency of micturition and dysuria. 10% of the enzyme arm and 38.3% of the control arm showed increased severity and frequency of micturition with dysuria, pelvic pain and frequent frank haematuria.
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 signifcantly (p<0.001) fewer urogenial symptoms (evaluted as maximum extent) in the enzyme-arm: enzyme-arm = 0.93 (0.52); placebo-arm = 1.38 (0.56). The treatment effect was observed from 1 week after start of radiation therapy until the last follow-up visit 5 month after intervention.

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	Gastrointestinal side effects Patients were evaluated at weekly intervals (for 5 weeks) for acute radiation therapy related side effects. Gastrointestinal side effects were graded according to the RTOG/EORTC criteria, by a single observer (score 0-4). Patients were followed-up at intervals of 6 weeks and 5 month after completion of radiation therapy.
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".	In both arms most of the patients showed only a slight increase of frequency of stools, change in the quality of bowel habits and rectal discomfort. 31.6% of the control-arm was observed to have diarrhoea. 11.7% in the enzyme-arm showed similar symptoms. 6 patients (3 per arm) showed bloody stools, perforations and fistulae.
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".	Although the maximum extent of gastrointestinal side effects was reduced in the enzyme-arm, the difference to the control-arm was not statistically significant (p=0.12). The treatment effect was observed from 1 week after start of radiation therapy until the last follow-up visit 5 month after intervention.

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	Vaginal mucosal side effects Patients were evaluated at weekly intervals (for 5 weeks) for acute radiation therapy related side effects. Vaginal mucosal side effects were graded according to the RTOG/EORTC criteria, by a single observer (score 0-4). Patients were followed-up at intervals of 6 weeks and 5 month after completion of radiation therapy.
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".	During radiation therapy patients initially exhibited patchy vaginal mucositis which gradually progressed to confluent fibrous mucositis. 41.6% of both arms experienced mild pain. 16.6% of the control-arm exhibited patchy mucositis with serosanguineuos discharge. They also experienced moderate pain requiring the use of analgesics. 6.6% of the enzyme arm showed similar signs and symptoms.
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".	The maximum extent was reduced in the enzyme-arm, although the difference was not statistically significant (p=0.10). The treatment effect was observed from 1 week after start of radiation therapy until the last follow-up visit 5 month after intervention.

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	Skin side effects Patients were evaluated at weekly intervals (for 5 weeks) for acute radiation therapy related side effects. Skin side effects were graded according to the RTOG/EORTC criteria, by a single observer (score 0-4). Patients were followed-up at intervals of 6 weeks and 5 month after completion of radiation therapy.
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".	78.3% of the enzyme arm showed no skin reactions or faint erythema. 40.0% of the control-arm showed moderate to bright erythema or patchy moist desquamation. 15% of the control-arm showed confluent moist desquamation and pitting oedema. 5% of the enyzme-arm showed the same symptoms. 1 patient (control-arm) showed frank skinulceration.
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 was a statistically significant (p<0.001) improvement in favour of the enyzme-arm: enzyme arm = 0.97 (0.82); placebo-arm = 1.68 (0.87). The treatment effect was observed from 1 week after start of radiation therapy until the last follow-up visit 5 month after intervention.

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	?
Conflicts 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

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