Proteolytic Enzyme Therapy in Complementary Oncology: A Systematic Review

Results

The systematic research at all levels of evidence revealed 13,046 results. Four studies were added by hand search. At first, duplicates were removed leaving 9,156 studies. After screening for title and abstract, 93 studies remained and underwent further investigation. Finally, 15 publications were analyzed in this review, including 10 randomized controlled trials (RCT), 3 cohort studies and 2 single arm studies. The selection process of studies is presented by flow-diagrams in Figures 1 and 2. Detailed characterization of the included studies may be found in Table IV. Excluded studies are listed in Table V.

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Figure 1.

Flowchart - RCT.

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Figure 2.

Flowchart - lower evidence class.

Patient characteristics in included studies. The studies included 3,008 patients. Due to at least 20 drop-outs a final number of 2,988 patients were analyzed. Since the majority of studies lacked data on drop out and attrition, the actual number of patients may be lower. The age of patients ranged from a mean of 23.76±5.48 to 67.2±11.1 years. A total of 1,840 participants were females and 1,100 males.

Excluded studies. We excluded 2 single-arm studies with interventions using other drugs next to proteolytic enzymes as the effects of it was not possible to assess whether the reported effects were caused by the enzyme therapy or by another component of the intervention. Excluded studies are listed in Table V.

Mucositis and swallowing disorders due to radiotherapy. We assessed 3 randomized controlled trials (RCTs) examining the effect of the enzyme therapy on oral mucositis and swallowing disorders due to radiotherapy. In Dörr et al. (11) (where N=69, tumors of the oral cavity), radiotherapy protocols comprised conventional fractionation with 1.8-2.0 Gy/fraction, 5×/week to total doses of 60-66 Gy/6-7 weeks, or hyperfractionation with 2×1.2 Gy/day, 5×/week to a total dose of 72 Gy/6-7 weeks; hyperfractionation was applied in 8/36 (22%) patients in the intervention group and in 11/33 (33%) patients in the placebo group. The authors of the study found no significant differences between the intervention- and the control group for maximum mucositis (summarized as the mean value of the maximum values collected; p=0.317). However, there was a significant difference in the mean grade of mucositis in favor of the control group (p=0.041) due to an earlier onset of mucositis in the intervention group. They observed no relevant group difference related to swallowing difficulties (11). Gujral et al. (control group patients received 58.6±8.8 Gy over 45 ± 9 days and intervention group patients received an average dose of 59.1±6.2 Gy over 45±9 days) examined 100 patients with head and neck tumors. They reported a significant difference in the maximum severity (p<0.0001) and the mean severity of mucositis (p=0.0001) in favor of the intervention group. They also described a significant difference for the time of occurrence in favor of the intervention group (6.9±0.8 vs. 5.7±1.2 weeks; p=0.0014). In addition, they found a significant difference in the maximum severity (1.32±0.64 vs. 2.24±0.60; p<0.0001), the mean value – evaluated as area under the curve (5.2±3.4 vs. 10.1±3.6; p=0.0001;) and the duration until swallowing problems (Grade I: 5.2±1.5 vs. 3.6±0.5; Grade II 7.3±0.8 vs. 6.1±1.3 weeks; p=0.0092; p=0.0064) in favor of the intervention group. The classification was based on the RTOG/EORTC criteria (12). Vinzenz et al. (N=39, carcinoma of the oral cavity; irradiation with the gammatron was performed for a period of 5 weeks spread over several sessions in both groups, total cumulative dose 50 Gy) found a significant difference in severity of mucositis in favor of the intervention group (stage I: 21.4% vs. 0%, II: 68.4% vs. 55%, III: 10.5% vs. 45%; p=0.014). There were also significantly more patients with mucositis stage III in the control group (p=0.019). First appearance of mucositis was earlier in the intervention group with 9.1 (±4.9) days vs. 13 (±4.1) days (median 9.0 vs. 12.5; p=not stated) (13).

In summary, 2 of 3 studies described a benefit of enzyme therapy. In contrast, the study with the highest quality, which is the only blinded one, described an advantage of the control group. In the presence of inconclusive studies, no recommendation for or against enzyme therapy can be made.

Radiodermatitis and additionally required supportive or analgesics drugs due to cancer treatment. We assessed 4 RCTs and 1 cohort study examining the effect of enzyme therapy on radiodermatitis. Dale et al. included 120 patients with cervical cancer undergoing radiotherapy and evaluated the effects of enzyme therapy on radiodermatitis according to RTOG/EORTC grading. There was a significant difference between the mean maximum extent in favor of the enzyme group with 0.97±0.82 vs. 1.68±0.87 (p<0.001). They found no group difference in the consumption of supportive medication (14). Gujral et al. addressed the maximum expression of the radiodermatitis in 100 patients with head and neck tumor as well as their average grade over time (RTOG/EORTC). The maximum radiodermatitis in the intervention group was significantly lower compared to the control group (1.23±0.75 vs. 2.39±1.10, p<0.0001), measured as a lower level of the area under the curve (3.9±2.9 vs. 9.5±3.9; p=0.0001) and as later appearance (grade II, 6.6±1.6 vs. 5.7±1.4 weeks; p=0.0048) (12). Beuth et al. assessed radiodermatitis in a cohort study with 649 patients with non-metastatic breast cancer. There was a significant mean difference in symptoms in in favor of the intervention group. Treatment success occurred in 38% of patients in the intervention- and 60% in the control group with respect to skin reactions, resulting in a significant difference in favor of the intervention group after adjustment with the propensity score (p=0.006) (15).

Two studies did not find significant effects of enzyme therapy concerning skin complaints and additionally required supportive or analgesic drugs: One assessed dryness and moist skin detachment (p=0.33, p=0.57) (11) and the other assessed epitheliolysis in context of grade (p=0.16) or mean values (p=not stated) (16).

In summary, 3 out of 5 studies described an advantage of enzyme therapy. The other 2 studies did not show a significant result in favor of enzyme therapy. One study showed a non-significant trend in favor of the control group. In the presence of inconclusive studies, no recommendation can be made for or against enzyme therapy.

Pain, swelling, edema and associated quality of life. We assessed 3 RCTs examining the effect of enzyme therapy on pain, swelling, edema and the associated quality of life. Tan et al. assessed 72 patients with malignant hematological diseases, who had undergone prophylactic wisdom tooth extraction. Pain was assessed by visual analogue scale. At day 1, 3 and 7, there were significant differences in favor of the intervention group (p=0.013, p=0.019, p=0.044). This study also compared the limitation of mouth opening due to swelling. There was a significant difference in favor of the intervention group (p<0.0001). Quality of life, assessed one week after tooth extraction by the modified postoperative symptom severity scale (PoSSE with 7 dimensions: food, language, feeling, swelling, pain, nausea, and daily living.), showed significant differences in favor of the intervention group in all categories (17). Swelling, documented by imaging, also was significant in favor of the intervention group (p<0.0001) (17). Kasseroller et al. examined 88 patients with breast cancer with secondary lymphedema due to axillary lymphonodectomy. There was no significant difference in volume or skinfold thickness as a parameter for fibrosis between the two groups after 45 days in the upper arm. Similar results were reported for the lower arm, hand and third finger, with a slight advantage for the intervention in the lower arm and hand, without further statistical evaluation. A significant advantage for the intervention group was found in skin tension as assessed by the investigator on a rating scale from 0 to 3 (baseline: 2.0; day 45: 0.4 vs. 1.8; day 45: 0.5;) (18). Wrbka et al. evaluated the success of therapy from 51 patients with bronchopulmonary carcinoma based on a constant or improved X-ray image. With regard to quality of life, a benefit was shown the intervention group. No statistical data was provided for this result (19).

Overall, the study situation for postoperative edema and lymphedema is poor, with only one study each. Nevertheless, it can be said that enzymes seem to have a benefit for postoperative edema, whereas this is not the case for lymphedema. In terms of quality of life, the assessment is positive in both studies. A final recommendation for or against enzyme therapy cannot be given due to the limited number of studies and qualitative limitations of the studies.

Gastrointestinal complaints and urogenital side-effects due to cancer treatment. We assessed 2 RCTs and 1 cohort study examining the endpoint gastrointestinal complaints and 1 of them regarding urogenital side-effects and side-effects or damage on the vaginal mucosa as well. Martin et al. and Dale et al. evaluated different toxicity parameters from 56 and 120 patients during radiotherapy treatment by RTOG/EORTC grading. No significant difference for severity of diarrhea (p=0.11) and other gastrointestinal side-effects (p=0.12) was found between the intervention- and the control group (14, 16).

Beuth et al. described a significant difference in favor of the intervention group for gastrointestinal symptoms of their breast cancer patients under antineoplastic therapy (primary surgical treatment, radiation, adjuvant systemic endocrine or/and chemotherapy, N=649, 0.27 vs. 0.11; p=0.005). Treatment success, defined as a total suspension of symptoms (nausea, vomiting, changes in appetite, stomach pain or stomach disorder), was also in favor of the intervention (p=0.042) (15). Dale et al. (patients in both arms received 50±60 Gy of external beam radiation in 25±30 fractions over a period of 5 weeks, followed by intra-cavitary brachytherapy at a dose of 20±30 Gy using a BARC applicator) assessed acute urogenital side-effects according to the RTOG/EORTC grading of their 120 cervical cancer patients under radiation therapy, with a significant difference in favor of the intervention group (0.93±0.52 vs. 1.38±0.56; p<0.001) (14). No significant differences were found for side-effects or damage to the vaginal mucosa (p=0.10) (14).

Considering the limited evidence of these studies, enzyme therapy might have benefit for urogenital adverse events, whereas the study evidence for gastrointestinal conditions is conflicting. No benefit was found for vaginal mucosa.

Therapy discontinuations and other side-effects due to antineoplastic therapy. Four RCTs and 2 cohort studies assessed further side-effects and therapy continuations due to antineoplastic therapy. Beuth et al. evaluated mean values and treatment success of specific symptoms from 649 patients by comparing them with previously collected basic values. A significant reduction in symptoms compared to the control group was detected for mental side-effects, dyspnea, headache and cachexia (all p<0.05). No significant differences were found for tumor pain and infections. A complete cessation of symptoms in favor of the intervention group arose for cachexia (65% vs. 7%; p=0.008) but not for mental side-effects, dyspnea, headache, tumor pain and infections (15). Popiela et al. (patients with colorectal cancers under antineoplastic therapy; primary surgical treatment, adjuvant systemic chemotherapy, radiotherapy) evaluated the number of adverse reactions of 1,242 patients. There was a slight superiority of the intervention-group between the groups (0.6339; p<0.0001) (20).

Two studies did not find any group differences in terms of toxicity parameters (11, 16). Regarding therapy discontinuation, 2 studies evaluated the rate of discontinuations of treatment or interruption of the radiation therapy due to side-effects. Wrbka et al. reported 2 therapy interruptions in the intervention- vs. 9 in the control group and found a therapy improvement (quality of life and stable or improved X-ray image) of 68% in the intervention- compared to 57.96% in the control group (p=not stated) (19). Another study found no significant advantage of the intervention group in relation to therapy interruptions. Martin et al. (16).

In these heterogeneous studies, some significant reductions in specific adverse events were observed. A comparison is difficult, as some of these are combined symptom complexes. With regard to treatment interruptions, two studies came to opposite conclusions. Overall, no recommendation can be made for enzyme therapy.

Tolerability of cancer treatment. We assessed 2 RCTs and one cohort study examining the tolerability of the cancer therapy. Popiela et al. analyzed the disease- and treatment-specific symptoms (summarized symptom complex consisting of 19 points) of 1,242 patients during and after antineoplastic therapy compared to the previously assessed baseline using Mann-Whitney tests. There was a slight superiority of the enzyme therapy between the arms (MWS statistics 0.6077; p<0.0001). The tolerability and safety of cancer therapy, assessed by the physician using a five-point ordinal scale, resulted in a strong superiority of the intervention group (MWS statistics 0.7471; p<0.0001). Changes in mean value of existing symptoms also became significant with a mean superiority of the intervention group (MWS statistics 0.6478; p<0.0001). The endpoint “Proportion of patients without therapy complaints” showed no significant difference between the groups (MWS statistics 0.5440; p=0.0798). There was a significant reduction of treatment side-effects caused by chemo- and radiotherapy with a mean superiority of the intervention group (MWS statistics 0.6721; p<0.0001). The endpoint Performance Index and Karnofsky Index during therapy did not reveal any significant difference between the groups (20). Stauder et al. evaluated the influence of enzyme treatment on the dose of the radiation treatment, on the general status and on the side-effects of radiotherapy. In this study, only total numbers are given, and no statistical evaluation was carried out for any endpoint. The authors state that a higher dose of radiation was tolerated in the intervention group and overall higher doses were applied in this group. They present numbers for the occurrence and severity of radiation side-effects and the average tolerance, but the results cannot be interpreted due to missing statistical analysis (21). Wrbka et al. (N=51) evaluated if additional enzyme administration improved tolerance of chemotherapy. On average, all patients, including a subgroup of patients, with a survival time of more than 6 months, received a higher number of chemotherapy transfusions (mean number of treatments 6.88 vs. 4.50; 11 vs. 3.37) (19).

In conclusion, enzyme therapy seems to have a benefit in terms of tolerability, improved adherence to the treatment protocol, but not with respect to symptom resolution and on physical fitness. However, the results are from two non-blinded RCT’s and one cohort study, so further studies are needed for a final recommendation.

Response to treatment. Two RCTs and 1 cohort study assessed the endpoint therapy course. Gujral et al. (N=100) found no significant difference in disease response, divided into complete/good-, moderate- and poor/no response, of their head- and neck cancer patients between intervention- and control group after 8 weeks (p=0.23) and 5-6 months (p=0.76) (12). Stauder et al. compared the influence of enzyme therapy on the cancer therapy of 68 patients. The assessment of treatment result was reported by the treating physician and patients divided into grades from 1 to 6. There was a trend in favor of the control group, but no further statistical analysis was conducted (21). Sakalova et al. compared the response to chemotherapy of 265 patients with multiple myeloma. The proportion of patients in stage III who did not respond to chemotherapy was significantly lower in the intervention group (3.7% vs. 38.9%; p≤0.001) (22).

These 3 studies, with cancer entities differing from each other, came to heterogeneous conclusions. Patients with multiple myeloma showed a better response to therapy, while there was no improvement in head and neck cancer patients and even a (non-significant) trend in favor of the control group in patients with abdominal cancer. The evidence does not allow a recommendation for or against enzyme therapy.

Disease-specific survival, remission, cancer recurrence or metastases. One RCT and 3 cohort studies assessed the endpoint disease-specific survival, remission, cancer recurrence or metastases. Sakalova et al. compared the median survival time, time to recurrence of cancer or metastases in 265 patients with multiple myeloma. Patients in the subgroup of stage III cancers had a significant longer median survival time in the intervention group (83 months vs. 47 months; p=0.0014), this corresponds to a lifetime gain of about 3 years. A significant stage-adjusted increase of lifetime across all stages could be proven in favor of the intervention group (p=0.0003). Moreover, concerning the overall mortality (including non-myeloma-related deaths) in stage III, the intervention group showed a median advantage of survival of 33 months over the control group (p=0.0059). A multivariate analysis showed that the risk of death could be reduced by 60% (p=0.0011) due to enzyme therapy, taking various possible influences into account (stage, age etc.). The authors also came upon with a significant advantage of the intervention group for remission rate and stable findings across all stages (97.6% vs. 69.7%; p=0.001) and the duration of initial remission or stable state in stage II and III patients (III: 37.7 months vs. 11.6 months; p=not stated) (22). Popiela et al. found an advantage of survival time in the intervention group of their patients with colorectal cancer (N=1,242, 34.1 months vs. 14.5 months; plog-rank=0.0025) for patients with Dukes D cancer stage. The authors report similar trends in Dukes B and C stages (20). Wrbka et al. (N=51) showed a difference in survival time in the subgroup of patients with a survival time of more than 6 months (20 vs. 16.3 months for the intervention group; p=not stated) (19). Another study ascertained no significant difference in mean survival time in the postoperative period between the two arms of their breast cancer patients (N=649). There was no statistical analysis in terms of overall recurrence of cancer and metastases in intervention- and control group. A significant difference was detected in the time to cancer recurrence or metastasis between intervention- and control group (1,818 days vs. 1,702 days; p=0.0055; metastasis 1,738 days vs. 1665 days; p=0.0475) (15).

With respect to impact on the development of the cancer, all studies supported a significant benefit of enzyme therapy. A negative influence or trend was not observed in any study. Due to some restrictions of the available studies, as mentioned in the discussion afterwards, no recommendation for enzyme therapy can be given. More high-quality studies are needed.

Side-effects of enzyme therapy. Five RCTs, 3 cohort studies and 2 single-arm studies assessed side-effects of enzyme therapy. Regarding oral application, Kasseroller et al., Beuth et al., Popiela et al., Sakalova et al. and Dale et al. reported mainly gastrointestinal complaints in their studies (like diarrhea and nausea) ranging from mild to moderate severity, which sometimes led to the discontinuation of the affected participants (14, 15, 18, 20, 22). Surprisingly, in Dale et al. the patients in the control group tended to experience more symptoms (11.7% vs. 31.6%, p=0.12) (14). Gujral et al. and Lahousen et al. could not detect any side-effects of enzyme therapy (12, 23).

Two further studies carried out the application of enzymes partially or completely parenterally. Kesztele et al. (single-arm, bronchial carcinoma) reported that enzyme enema was well tolerated and only single perianal eczema occurred (24). Petru et al. described only 3 patients with moderate upper abdominal pain and 2 patients with meteorism of their 57 participants (25).

Wrbka et al. evaluated the tolerability of enzyme therapy as oral dugs, enema and intrapleural application. In 67 patients 87.3% showed a good tolerance of the enema. In 4 patients, the application was limited due to sphincter weakness and about 12.7% (8 patients) discontinued the treatment due to gastrointestinal side-effects like meteorism, diarrhea and nausea. Out of 58 patients, 71.4% (30 patients) showed good tolerability for the oral formula, whereas about 28.6% (12 patients) discontinued the treatment and in about 27% no assessment was possible, because these subjects stopped taking the tablets of their own accord or provided incorrect information in the studies. Therefore, no result could be ultimately assessed. For the tolerability of the local intrapleural application data of 33 patients were available, 96.9% of these showed a good tolerability and only about 3.1% stopped the treatment (19). Regarding the side-effects of enzyme therapy, all studies did not have any higher-grade side-effects.