| [Backgroud]Breast cancer related lymphedema (BCRL) is a common complication for breast cancer survivals and could cause many discomforts which affects patients’ life quality. BCRL cannot be cured and has a whole life risk of BCRL incidence for all the breast cancer survivals. BCRL patients would suffer from physical and emotional pains. With the increasing of breast cancer incidence and 5-years survival rate, BCRL has become a tough problem.For western medicine, treatment methods of BCRL are limited and the therapeutic effect is not satisfying. Physical treatment is recommended, but with a weak effective rate. However, there are many reports with high effective rate, about 80%-100% with Chinese medicine treatment. So the difference of effective rate between western medicine and TCM are obvious.According to Pubmed and CNKI database, we found that the clinical research reports in CNKI database were mainly retrospective analysis or case-control study, which were lack of high level evidence-based support; in Pubmed database, however, no report about BCRL treatment withTCM were found.Therefore, a high evidence-based supported clinical trial, which verify the efficiency of TCM, would improve BCRL treatment. Based on our former research about the TCM syndrome features for breast cancer survivals, home-made prescription "Wen Tong Xiao Zhong Wai Fu Fang", with warming Yang and benefiting Qi principles, was used on BCRL patients. The therapeutic efficiency and safety would be observed from this well designed clinical trial.[Aims]1. To observe the therapeutic efficiency of "Wen Tong Xiao Zhong Wai Fu Fang" for BCRL patients.2. To evaluate the safety of "Wen Tong Xiao Zhong Wai Fu Fang" for BCRL patients.[Patients and Methods]A prospective, randomized, double-blinded, parallel-placebo multi-centers study was designed and carried out. The whole process, from the beginning to the end, was supervised by Beijing Qi Huang Medicine Clinical Research Center which was appointed by the sponsor Beijing Municipal Science and Technology Commission. After multiple arguments, the final version of research plan was set down. Before patient recruitment, we did the following preparations. The research was approved by ethics committees of all centers and registered at ISRCTN website. All researchers were trained and the technicians from drug manufacturing laboratory prepared the concentrated decoction which had been set double-blinded. Patients were recruited according to inclusion criteria and they should accept all the examinations, including blood, urine and stool routine tests, liver and kidney function, electrolyte level test (potassium, sodium and chloride). Then patients would receive the drugs which were distributed sequentially, and report their upper arm circumference as well as the value of disability of arm-shoulder-hand (DASH) at the beginning,3rd,5th,7th,14th day. Patients should receive the examination again when they finished the whole 14 day therapy. They could also get the true "Wen Tong Xiao Zhong Wai Fu Fang" concentrated decoction for 14 days regardless of which group they had been in. The Evidence Based Medicine Center would be in charge of locking the data and unblinding the drug types. After data analysis, we could get the conclusion of therapeutic efficiency and safety of "Wen Tong Xiao Zhong Wai Fu Fang" for BCRL patients via external application.[Results]1. The quality control of this clinical trial was rigorous throughout the whole process, and met the demand of our expectations. The content of quality control included:ethics committees permission; blind design; drug quality control; drug concentrated decoction preparation; trial registration; researcher training; patient recruitment; monthly quality supervision independently; data management and standard unblinding procedure. All the requirements above guaranteed the results true and precise.2. Ninety-six patients were recruited in the past 18 months and 4 patients quit the trial because of adverse reactions. Three patients got skin allergy and one patient got flu and fever. Eight patients were lost with unknown reason. Overall,84 patients completed the 14 days therapy.The parameters, including age, breast cancer surgery types, axillary lymph node metastasis, drug allergy history, treatment history of TCM and western medicine, clinical stage and grade of BCRL, were balanced between the true-drug and placebo patients groups (P>0.05). There was no difference of upper arm circumference and DASH value between groups when patients enrolled the cohorts (P>0.05). The first time examinations before patients started treatments showed that patients in the two groups were also balanced (P>0.05). Overall, the base lines between the true-drug and placebo patients groups were comparable.3. According to clinical effective criteria,20 patients got effective therapy in the 39 true-drug patients group, the effectiveness rate was 51.3%; meanwhile,31 patients got effective therapy in the 45 placebo patients group, the effectiveness rate was 68.9%. No significant difference was showed between the true-drug and placebo patients groups (P>0.05). Stratified analysis among 4 research centers showed that the effectiveness rates were 55.6%,50.0%,72.7% and 27.3%, respectively. No obvious difference was found between them (P>0.05). When taken center effect into consideration, there was still no significant difference of effectiveness rate in true-drug and placebo groups.3. According to clinical effective criteria,20 patients got effective therapy in the 39 true-drug patients group, the effectiveness rate was 51.3%; meanwhile,31 patients got effective therapy in the 45 placebo patients group, the effectiveness rate was 68.9%. No significant difference was showed between the true-drug and placebo patients groups (P=0.12). Stratified analysis among 4 research centers showed that the effectiveness rates were 55.6%,50.0%,72.7% and 27.3%, respectively. No obvious difference was found between them (P>0.05). When taken center effects into consideration, there was still no significant difference of effectiveness rate in true-drug and placebo groups.4. The secondary aim analysis of the research showed that upper arm circumference and DASH value decreased gradually and the upper arm circumference changes were not as obvious as DASH value. No significant difference of changes of upper arm circumference and DASH value were observed between true-drug and placebo groups (Z=-0.94, P=0.35 and Z=-1.81, P=0.07).Survival analysis of upper arm function improvement showed that patients in placebo and true-drug groups would reach DASH improvement criteria at the median time of 6.23 days and 7.26 days, and no significant difference between the two groups was observed (P=0.37).5. The skin allergy (level Ⅱ) incidence was about 7% in true-drug group, and one patient got flu and fever; no patients quit the treatment in placebo group. No obvious difference of the incidence rate of skin allergy was found between groups (P=0.11). All the examinations, including blood test, urine test, stool test,liver and kidney function, and electrolyte level, were comparable between the two groups(P>0.05).[Conclusion]1. The well designed and strictly supervised clinical trial was carried out, and this was a double-blinded, randomized, parallel-placebo, multi-sites study, which standards for a higher level of evidence of evidence-based medicine. Therefore, the conclusions we got are convincing.2. The main outcome aim analysis showed that the clinical efficiency of "Wen Tong Xiao Zhong Wai Fu Fang" and placebo had no significant difference when treating BCRL via external application. Stratified analysis among different hospitals also supported this conclusion.3. The secondary outcome aim analysis showed that "Wen Tong Xiao Zhong Wai Fu Fang" and placebo could make upper arm circumference shrink and improve upper arm function, however, no significant difference was observed between the two groups.4. Safety evaluation testified thatTCM external application on skin had the risk of skin allergy and flu if unawareness of keeping warm; the incidence rate of skin allergy was 7% in "Wen Tong Xiao Zhong Wai Fu Fang" group. No direct evidences of adverse effect on blood, urine, stool tests, liver and kidney function, and electrolyte level were found for "Wen Tong Xiao Zhong Wai Fu Fang" compared with placebo.5. Our research do not recommend the application of "Wen Tong Xiao Zhong Wai Fu Fang" for BCRL patients, at least, before the updated and improved large scale clinical trial overthrow this conclusion. The therapeutic effects of "Wen Tong Xiao Zhong Wai Fu Fang", however, coul not be denied easily, our conclusion can only be established based on this clinical design. I parameters changed, the results might be different.
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