Clinical Research on Using Elemene to Treat Glioma
Zhou Hongyu, Shen Jiankang, Department of Neurosurgery, Ruijin Hospital, the affiliated hospital of Shanghai Second Medical University (200025)
Hou Jusheng, Yin Jian and Xu Yinghui, Department of Neurosurgery, the Second Affiliated Hospital of Dalian Medical University
Luo Qizhong, Department of Neurosurgery, Ren Ji Hospital, the affiliated hospital of Shanghai Second Medical University

 

Abstract

Purpose: to explore the clinical effect of using elemene to treat gliomas. Methods: 49 patients with glioma were chosen, 16 treated with elemene only, 33 treated with elemene and chemotherapy drugs. Injection dose of elemene: for adults, 1000 mg/d, alternating injection in the carotid artery and peripheral veins, with 20 days as a course of treatment. Tumor size, clinical performance, survival time and side effects were evaluated and compared before and after the treatment. Results: after carotid artery and peripheral injection of elemene, the total efficiency was 46.94% (CR14.29%, PR 32.65%); tumor sizes decreased by 30.89% ± 55.97% on average; clinical symptoms showed different levels of improvement; the survival time of 32 patients were: <1y, 7 patients, > 1y , 14 patients, > 2y, 6 patients, > 3y, 5 patients. The efficiency rate of using elemene alone was 37.5%, that using elemene and chemotherapy was 51.51%. Elemene did not cause bone marrow suppression, gastrointestinal reactions, and other side effects. Conclusion: Elemene did have anti-glioma function. In clinical application, the drug should be used with adequate dosage for long enough, and recommended to be given via the artery. Elemene can be used regularly in glioma patients, and recommended early use. If other drugs do not work, patients can try elemene.

Key words: brain tumor, drug therapy, glioma, elemene

 

Glioma is the most common malignant tumors of the central nervous system, but unfortunately, no breakthrough has been made in treating it. Over the past 20 years, the median survival time of glioma patients did not show any significant growth, and all kinds of therapy fail to radically cure the disease, which has become a most challenging and urgent issue for neurosurgeons. Elemene is a non-cytotoxic anti-tumor drug developed by Chinese people. It had exact effect, caused no bone marrow suppression, no resistance, and could improve the immunity. And as a small molecule, the drug compound can pass the blood-brain barrier, which is suitable for treating brain tumors. The effect in treating glimoas with elemene is obvious, which may benefit more patients.

 

1 Material and Methods
1.1 study object:
Candidate criteria (all the four requirements must be met): (1) patients that had surgeries and that were pathologically confirmed, and patients that were not operated on and diagnosed with clinical examinations and CT or MRI (2) patients not suitable for having surgery/ another surgery or with residual and recurrent symptoms after operation, (3) patients with blood, liver and kidney function and generally normal ECG (4) patients that had completed the treatment with elemene for at least one cause of treatment.

All the 84 glioma patients treated with elemene during the recent 10 years in the affiliated hospitals of Dalian Medical University were reviewed. As some of them did not have all the image information or did not complete a full cause of treatment, they were removed from the analysis. Finally, 49 cases were selected including 29 men and 20 women patients. Their age ranged from 9 to 72 with an average age of 39.8. Tumor sites: hemisphere tumors in 33 cases, hypothalamic tumor in five cases, two cases of brain stem tumor, cerebellar tumor in three cases, and ventricle tumor in one case. Pathological classification: 44 patients were pathologically confirmed after surgery, including 25 patients with astrocytoma, 6 patients with glioma, 5 patients with oligodendroglioma, 1 patient with ependymoma, 2 patients with medulloblastoma and 5 patients without pathological confirm.

1.2 experimental grouping
grouping of glioma patients: (1) 16 patients were treated only with elemene, (2) 33 patients were treated with elemene in combination with the chemotherapy drugs.
1.3 method of treatment
Elemene watery agent 1% 20m1/stick or 2% 10ml/stick was used, which was produced by Dalian Institute of Science and Medicine. Way of administration: carotid artery and peripheral intravenous injection of elemene, for adults, 1000mg/d. Of which, 600 mg was slowly injected in the carotid artery on the affected side, once a time on the morning every two days, the liquid was not diluted, added with 2.5 mg of dexamethasone; 400mg was intravenously infused in the afternoon. For tumors that were located at the median line or on both sides, drugs were given via carotid arteries of both sides alternatively; brain stem and cerebellar tumors were mainly treated with intravenous administration. The group using combined medicine except for using elemene in the way as mentioned, used VM-26 and BCNU togther for 28 days in a course of treatment.

1.4 Clinical Evaluation
(1) CT and MRI inspection was done before and after the treatment, the tumor size was compared; after statistical analysis, brain glimoa efficacy criteria 3 was used to assess the recent effects and calculate the efficiency.
(2) The clinical performance of patients was recorded as an index of judging the clinical efficacy. (3) Analysis of survival time
1.5 toxicity evaluation
Systematic (such as bone marrow suppression, gastrointestinal symptoms, etc.) and local symptoms were recorded after the treatment.
2 results
2.1 efficacy evaluation
The average tumor size decreased by 30.89 ± 1 55.97% after the treatment. The efficacy in treating 49 patients: CR 7 (14.29%), PR 16 (32.65%), MR 8 (16.33%), NC 8 (16.33%), PD 10 cases (20.41 %), with the total efficiency up to 46.94% (23/49). The results were shown in table l

 

Table 1. Comparison of the results of the two groups

 

Group treated with elemene

Group treated with elemene and chemotherapy drugs

Cases

16

33

CR

2 (12.50%)

5 (15.15%)

PR

4 (25.00%)

12(36.36%)

MR

3 (18.75%)

5 (15.15%)

NC

4(25.00%)

4 (12.12%)

Efficiency rate

37 .50%

51 .51%

 

2.2 clinical performance
Before the treatment, 41 patients had headache, 17 had nausea and vomiting, 6 had epilepsy, 22 had hemiplegia, 1 had ataxia, 2 had olfactory hallucination, 6 had vision problems, 7 had aphasia. After the treatment, 13 patients had headache, 5 had nausea and vomiting, 4 had epilepsy, 8 had hemiplegia, 1 had ataxia, 1 had olfactory hallucination, 4 had visual impairment and 3 had aphasia.

2.3 survival time
17 patients were missed in the follow- up, the survival time of 32 patients was counted. Of the 32 patients, 13 died, of whom 8 died from astrocytomas, 4 died from glimoas, the death of 1 patient was not analyzed pathologically. Their survival time ranged from 4 months to 66 months. To the date of the statistics, 19 patients were alive. The survival time ranged from 9 months to 9 years (one case of glioblastoma patients). The survival time of 32 patients with gliomas was as follows: <1y, 7 patients; > 1y, 14 patients, > 2y, 6 patients, >3y, 5 patients.

2.4 toxicity and side effects
The group treated only with elemene did not show bone marrow suppression and CT / MRI confirmed no occurrence of blood clots in the brain. A small number of patients with carotid artery injection of elemene showed wetness and redness on the same side of the neck and face, eye pain and tears, pharynx itch, which soon resumed to normal after drug injection. When the speed of drug injection was lowered and 2.5 mg dexamethasone was added with the drug, symptoms relieved or disappeared. After many times of puncture, the wall of the blood vessel may harden, but the drug could still be applied after a short rest or local physical treatment. Liquid leakage to the surrounding tissue may cause localized swelling and pain, which may be adsorbed one to two days later.

3 discussion
3.1 the anti-glioma effect of elemene: Glioma is the most stubborn malignant tumor, which is mainly treated with a combination of surgery and radiotherapy and chemotherapy at home and abroad. But the result is not optimistic, which is determined by the anatomical and pathological features of glioma. Under the existing conditions, it is impossible to completely remove glioma cells. Due to the limitation of blood-brain barrier (BBB), chemotherapy drugs are mainly Teniposide. In recent years, new methods were proposed, for instance, using podophyllotoxin derivatives etoposide and radiotherapy together. The Phase II clinical efficiency was 34.6 percent.
(CR 15.4%, PR19.270) [4]. In treating patients with reoccurred glimoas using
Temozolomide, the Phase II efficiency rate for 111 patients was 35% (CR8%, PR27%) [5]. 51 patients with reoccurred gliomas after surgery and chemotherapy were treated with Procarbazine and high-dose of tamoxifen. The effective rate was 29.5% (CR 4%, PR25.5%), etc. [6]

Elemene is a new second category non-toxic anti-tumor drug. Elemene is separated from Ezhu volatile oil. Ezhu is a curcuma plant that grows in China. Elemene could inhibit synthesis of the nuclear acis, induced apoptosis and differentiation of tumor cells. Clinical studies found elemene had anti-tumor effect on a variety of tumors, but also could enhance the immunity and caused synergy with radiotherapy and chemotherapy. Elemene can passthe BBB, did not induce drug resistance after long-term administration. Compared to most cytotoxic chemotherapy drugs, the drug caused few side effects, no significant liver and kidney damage and no bone marrow suppression [7].
We found in the clinical that elemene had remarkably good anti-glioma
effect. In the group given carotid artery injection and peripheral intravenous infusion of elemene, the total efficiency was 46.94 percent, on average tumor size decreased by 30.89±55.97%. In the group that used elemene in combination with other drugs, the efficiency was as high as 51.51 percent, of which some cases were even clinically cured.
These results suggest that elemene could effectively treat glioma, its total efficiency rate and patient survival period were significantly higher than the report in literature at home and abroad. This is undoubtedly a new channel for the treatment of glioma.  

Only 1 patient showed serious complications. One side effect of carotid artery injection of elemene was facial and eye wetness and redness. The reason may be some drug went to the face via the external carotid artery, and fast injection can cause facial wetness and redness. In addition, some high-concentration drugs may flow along the ophthalmic artery and cause eye irritation. Slower injection and use of 2.5 mg dexamethasone can reduce local symptoms and do not affect the treatment.
3.2 evaluation In the clinical application of elemene, the following issues are important:
3.2.1 adequate dosage and time. We concluded that all patients with good treatment effect were those that used the drug in full dosage and for at least 1 to 2 courses of treatment. For those patients with lower dosage for a shorter time, the effect was not stable. For example, some patients can not tolerate artery injection of elemene, so they were given 400-600 mg intravenous infusion, instead, the results were not as good as combined administration in the artery and vein. Some patients stopped the drug after initial relief because they could afford the medical cost. Basic research found dose and time dependence of inducement of glioma apoptosis; in-vitro observation found elemene must be above 30-40 μg/ml for at least 7 days in order to effectively inhibit human glioma cells SHG-44, while short-term and low-concentration use would not achieve the expected results [2].

We believe that as elemene has the advantages of fewer side effects, immunity enhancement and causes no drug-resistance, it is recommended to use the drug in high dose and for longer period. The specific administration method is as follows: (1) for adults, 1000 mg/d, twice a day. Slow injection in the carotid artery of the affected side, and in peripheral veins. 20 days as a course of treatment. If the tumor is in the middle lane or bilateral lesions, the drug is given in bilateral carotid arteries alternately. The brain stem and cerebellum tumors were mainly treated with intravenous administration, for 1 to 2 times per week.

(2) It is recommended to use elemene in combination with VM-26 and BCNU.
(3) It is recommended to use for 3 to 5 course of treatment, and even for 1 year if the effect is obvious.  
3.2.2 The way of administration is mainly arterial administration. Researches indicated that 96 percent of glioma occurred at one site, and rarely had extracranial transfer, and more than 90 percent of recurrent glioma locate at or near the original focus [8]. These characteristics suggested that high-dose chemotherapy is an ideal way in treating malignant brain tumors; carotid artery injection can enhance the local concentration of the drug and reduce systemic toxicity with better effect than intravenous administration [9]. With the development of the intervention technology, micro-catheter may be inserted to the intracranial tumor supply vessels and ultra-selective arterial infusion may further improve the efficacy in treating glioma. However, the common chemotherapy drugs for treating gliomas may lead to serious nerve toxicity and eye toxicity if injected via the carotid artery [10], but elemene did not cause such risk as a drug suitable for intra-artery continuing infusion.

3.2.3 clinical results and case selection
Elemene had obvious effect on nearly 1/3 of glioma patients, most of whom were reported smaller tumor size and relieved clinical symptoms after using elemene for 1 or 2 courses of treatment. In some patients, imaging told the tumor stop growth, and the symptoms were eased. However, there are also patients who did not show any improvement after using elemene. We summarize the indications of elemene as: (1) can be used conventionally in treating glioma patients, but must be uses early. It must be used in combination with other treatment methods such as surgery, radiotherapy and chemotherapy. For patients that did not show any improvement or even growth of the tumor after 1 to 2 courses of treatment, combined therapy is recommended. (2) elemene is suitable for treating patients who did not show any improvement after conventional surgery, radiotherapy and chemotherapy. Especially glioma patients who are not suitable for taking surgery, with recurrence and in the late stage may try elemene.

For some intracranial malignant tumors, elemene can treat them effectively; for some others, it did not work. Why? We do not have a good explanation. Gliomas had complicated classification and a number of pathological subtypes. The treatment effect is determined by a variety of factors.

3.3 existing problems
(1) The sensitivity to different types of gliomas needs to be further explored. (2) The
standardization of clinical use of elemene needs to be verified by research centers. (3) The anti-tumor mechanisms and related basic research of elemene must go further.



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