大剂量rmhTNF治疗恶性心包积液或恶性胸腔积液的临床研究
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摘要
背景与目的:
恶性心包积液(malignant pericardial efusions,MPcE)是晚期癌症患者常见的并发症。绝大多数恶性心包积液是转移瘤所至,有症状的心包积液常是临终前的表现,早期诊断和治疗可明显改善症状并提高患者的生存质量。对于其治疗,外科方法包括经皮心包穿刺放液或置管引流术、心包硬化剂、心包开窗引流、心包切除术、开胸或电视镜下心包切开术;而内科治疗方法包括全身化疗、腔内药物灌注治疗。对于转移性恶性心包积液的治疗方法目前国际上尚无统一标准,但均强调术式选择应遵循个体化原则。
随着恶性肿瘤发病的增加,临床上恶性胸腔积液(malignant pleural efusions,MPE)的患者也相应增加,且显现出低龄化的趋势。因此,治疗恶性胸水的主要目的在于姑息缓解患者胸闷、呼吸困难等症状,减轻患者的痛苦,提高患者生存质量,并延长生命。目前国内外治疗MPE外科方法有:治疗性胸腔穿刺、胸膜固定术、循环胸腔热灌注、胸腹腔分流、胸膜切除术、电视胸腔镜手术等;而内科治疗方法则包括:全身化疗、局部腔内药物灌注;某些对放疗敏感的肿瘤可行预防性放射治疗。以上众多的治疗方法大多各有一定的疗效及副作用,适用于临床的不同阶段,只有根据不同的疾病阶段选择适当的治疗手段,才能提高控制胸水的有效率,并且有望延长患者生存期。
在众多的抗肿瘤药物中,肿瘤坏死因子(tumor necrosis factor,TNF)是迄今所发现的直接杀伤肿瘤细胞作用最强的生物活性因子,且被广泛应用于各种肿瘤的治疗中。TNF有TNF-α和TNF-β,目前研究最多的是TNF-α。人肿瘤坏死因子-α(hTNF-α)具有广泛的生物学活性,其中抗肿瘤是其最主要的作用。然而,天然TNF-α全身用药的不良反应严重,对心血管系统、血液系统、神经系统、消化系统、呼吸系统等均有严重的损害,正是这些毒副作用限制了其临床应用。
因此,从20世纪90年代开始,国内外十分重视突变型TNF-α的研究,以提高疗效和降低毒性。第四军医大学应用生物蛋白质工程技术对天然TNF-α进行基因重组及结构改造,制成高活性、低毒性的基因工程衍生物—重组改构人肿瘤坏死因子(rmhTNF),减少了天然TNF-α的毒性,大大地发展了临床适应症。2003年8月,全世界第一个应用于全身的rmhTNF被批准应用于临床,500万IU肌注治疗非小细胞肺癌(NSCLC)。我们在临床应用中发现,rmhTNF仅有注射部位疼痛及发热症状,偶见胃肠道反应,无骨髓抑制。如在应用前给予患者解热止痛药,此种反应可能得到防止或减轻。由于天然TNF-α半衰期仅为10～15min,又无对肿瘤组织特异性亲和力,静脉注射很难在肿瘤局部达到高浓度。为此,为了增加TNF-α在肿瘤组织中的浓度,提高疗效,近年来人们尝试了肿瘤局部或腔内注射天然TNF-α的方式,有效率大大提高而毒副反应未见增加。同时,重组改构后的rmhTNF与天然TNF-α可能作用机制无变化,具有相同的抗肿瘤作用,同时rmhTNF具有高效低毒的特点。分析rmhTNF主要机理是由于其对原癌基因表达是直接细胞毒作用和直接抑制作用,至肿瘤细胞出血坏死,恶性液体不再产生;高浓度rmhTNF促炎反应更强,至使纤维蛋白沉积,促进肿瘤组织坏死及纤维化,控制恶性液体;rmhTNF超过一定浓度时,具有明显的抗肿瘤新生血管的作用。据此,我们推测,重组改构后应用于全身的rmhTNF可以用于局部腔内灌注,即用于恶性心包积液或恶性胸腔积液中,且适当加大局部用药剂量会增加局部药物浓度,可能会增加疗效。如推测成立,临床应用rmhTNF将会有一个新的适应症,并为有效的控制恶性心包积液或恶性胸腔积液开辟一条新的用药方法。为了验证我们的设想并了解其局部大剂量用药的毒副反应,经过医院伦理委员会讨论通过后,我们设计了如下临床研究进行进一步探讨。
方法:
(一)一般资料
选取经病理和/或细胞学确诊的恶性心包积液56例患者按随机法将患者分为A、B两组(每组28例病例)。恶性胸腔积液共64例患者按随机法分为C、D两组(每组32例病例)。向其监护人及本人告知实验内容、可能的受益及潜在的风险,并签署知情同意书以明确系自愿接受临床试验,将该患者纳入为受试对象。患者分别于心包腔或胸腔内置管灌注rmhTNF 1500万IU (大剂量A、C组)、rmhTNF 500万IU(常规剂量B、D组)。每周2次,连续治疗4次。
(二)评测方法
治疗前后采用B超、CT对患者进行评测,测量心包或胸腔积液量的多少,并评测可供临床观察的可测量的原发病灶,所有病例均记录治疗前后的生命体征、临床症状、karnofsky performance status(KPS)评分,及治疗后生活质量和并发症情况。治疗结束1个月后,按WHO标准评价其疗效和毒副反应。
(三)对研究中得到的数据进行统计学分析,分别观察各组内治疗后患者的近期疗效、远期疗效、生活质量改善情况及并发症的发生率等等,然后在两组间对比,得出结论。
结果:
(一)疗效评估
1.恶性心包积液:56例入选病例总有效率73.2%,其中A组有效率92.8%(26/28例);B组有效率53.5%(15/28例)。两组数据比较,差异显著(P<0.05)。
2、恶性胸腔积液:64例入选病例总有效率73.4%,其中C组有效率90.6%(29/32例);D组有效率56.2%(18/32例)。两组数据比较,差异显著(P<0.05)。
(二)治疗后并发症评价
1.恶性心包积液:A、B两组1～2天出现发热分别为67.8%(19/28例)、60.7%(17/28例),组间比较差异不显著(P=0.781);局部疼痛分别为42.8%(12/28例)、39.2%(11/28例),组间比较差异不显著(P= 1.00);两组出现轻中度恶心、呕吐反应分别为10.7%(3/28例)、7.1%(2/28例),组间比较差异不显著(P=1.00)。两组均无血液学毒性反应,无明显心、肝、肾功能损害。
2、恶性胸腔积液:C、D两组1～2天出现寒战发热分别为68.7%(22/32例)、71.8%(23/32例),组间比较差异不显著(P=1.00);两组胸部疼痛分别为43.7%(14/32例)、43.7%(14/32例),组间比较差异不显著(P=1.00);两组胃肠道反应(恶心或呕吐)分别为12.5%(4/32例)、15.6%(5/32例),组间比较差异不显著(P=1.00)。两组均无明显心、肝、肾功能损害:未见明显骨髓抑制,无明显心、肝、肾功能损害。
(三)治疗后生活质量评价
恶性心包积液或恶性胸腔积液患者经过置管灌注rmhTNF治疗后,不论剂量大小,大部分患者的生活质量都有不同程度的改善:精神好转、食欲增加、体力增加、对治疗态度改善、睡眠增多、KPS评分提高。
1.恶性心包积液:A组治疗后KPS评分提高10分的有26例(92.8%);B组治疗后KPS评分提高10分的有18例(64.2%)。组间比较差异显著(P<0.05)。
2、恶性胸腔积液:C组治疗后KPS评分提高10分的有30例(93.7%);D组治疗后KPS评分提高10分的有21例(65.6%)。组间比较差异显著(P<0.05)。
结论:
1、rmhTNF可局部使用治疗恶性心包积液或恶性胸腔积液,临床疗效显著;这与其直接杀伤肿瘤细胞、诱导肿瘤凋亡及抗肿瘤新生血管等机理有关。
2、与常规剂量500万IU比较,心包腔或胸腔内局部使用3倍常规剂量的rmhTNF1500万IU,疗效明显提高,而毒副反应增加不明显。推测这是局部大剂量用药后,其直接摧毁肿瘤周围的血管上皮组织,使瘤体充分暴露,肿瘤细胞周围的药物浓度增加而增强其抗肿瘤能力;同时因局部用药不直接经过全身血液循环,血浆中rmhTNF含量少,所以其全身毒副反应增加不明显。
3、本研究发现,心包腔或胸腔内局部使用大剂量rmhTNF对患者全身症状明显改善,生活质量明显提高。推测是由于其可以增强机体免疫功能,增强单核细胞、巨噬细胞、T细胞、NK细胞等的杀伤能力,并改善肿瘤恶病质有关。
Background and Purpose:
Malignant pericardial efusions (MPcE) is one of the most common complications of terminal cancer. Most cases of MPcE were induced from metastatic tumor (MT). Because the symptom of MPcE is the appeareance of just-before-dying, so we can improve symptom and increase the living quality of the patients through diagnosing and caring MPcE early. We can therapy MPcE with surgery such as percutaneous catheter drainage, sclerosing agent, subxiphoid pericardiostomy, pericardiectomy and pericardiotomy with thoracoscope, or medcine such as chemical therapy and intracavitary inicetion of drug (chemical drug, biological response modifier or sclerosing agent). Although there is no international standard therapy guideline about therapying MPE, all doctors agree with the principle of individualized treatment.
Along with the increase of malignant tumor, the incidence of malignant pleural efusions (MPE) also increase and the age of onset is lower. On average, the survival time of the patients with Malignant pleural efusions is shorter. The purpose of therapying Malignant pleural efusions is relieve the symptom of dyspnea, allay the pain, increase the living quality and prolong the survival time. We can therapy malignant pleural efusions with surgery such as therapeutic thoracentesi, pleurodesis, circular intrapleural hyperthemic perfusion, Pleuroperitoneal shunting, Pleurectomy, operation with thoracoscope, and so on, or medcine such as chemical therapy and intracavitary inicetion of drug (chemical drug, biological response modifier or sclerosing agent). To some tumor which is sensitive to radiotherapy, we can use preventive radiation. Only can we use suitalbe methods to therapy malignant pleural efusions in its different clinical stages, the effective rate of contrlling malignant pleural efusions can be improved and the survival time can be prolonged.
In so many anti tumor drugs, tumor necrosis factor (TNF) is one of the most powerful drug in killing tumor cells directly, and has been used in therapying many kinds of tumor extensively. TNF has two types ofαandβ, and TNFαhas been mainly studied and used. However, natural TNFαcan induce severe adverse events in the aspects of cardiovascular system, hematological system, nervous system, digestive system and respiratory system, especially uesd in all over the body. Because these adverse events, the clinical application of TNFαhas been limited.
From 1990s, in order to improve the curative effect and decrease toxicity, the study of mutated TNFαhas been extensively devolped. Recombinant mutated human TNFαis a kind of mutaed TNFαhaving improved anti-tumor activity and decreased toxicity, which is invented by The Forth Miilitary Medcine Univercity (FMMU) . In August 2003, the first mutated TNFαwhich could be uesd in all over the body was licensed. We found that rmh TNFαinduced only thoracalgia and febrile, seldom reaction of gastrointestinal tract, when used in therapying nonsmall-cell lung cancer (NSCLC). If we gave antipyretic analgesic before TNFαwas used, these adverse events could be relieved. Because the half-life of natural TNFαis only 10-15min, and it has no specific affinity to tumor, the concentration of TNFαcan not be elevated in tumor. In order to improve the curative effect, many people inject natural TNFαinto tumor or cavity and find that the curative effect is improved and the toxity is not increased. The malignant pleural efusions therapying mechanism of rmhTNFαis similar to natural TNFα, including supressing the expression of oncogene, directly killing tumor cells, inducing necrosis of tumor and finally reducing the production of malignant pleural efusions. The high concentration of rmhTNFαcan induce stronger inflammatory reaction, and lead to the necrosis and fibrosis of tumor. It was also proved that high concentration of rmhTNFαcould inhibit the angiogenesis of tumor. So we presumed that rmhTNFαcould be used in ntracavitary inicetion and the concentration could be increased to improve the curative effect meanwhile the toxity might not be increased. If the hypothesis could be approved, the clinical indication of rmhTNFαcould be expanded, and there would be a new method to control malignant pleural efusions. To approve our hypothesis, we carried out this study after liscenced by Ethics Committee.
Methods:
1. Data of patients
Malignant pericardial efusions: 56 patients with malignant pericardial efusions, which were finally diagnosed through pathology or cytology, were randomly seperated into A group and B group (28/28). 64 patients with malignant pleural efusions, which were finally diagnosed through pathology or cytology, were randomly seperated into C group and D group (32/32). The content of this study, the potential benefit and risk were told to the guardian of the patients. After one patient definitely indicated that they agreed to participate in this study and signed in informed consent, the patient was selected to be studied. The patients of A and C group were injected intracavitarily with 15 million IU rmhTNFαthrough percutaneous catheter, twice per week, four times in all. The patients of B and D group were injected with 5 million IU rmhTNFα.
2. Methods of evaluating therapeutic efficacy
B ultrasound and CT were used to measure the amount of pericardial or pleural efusions, and the size of measurable focus. We recorded the vital sign, clinical symptom, Karnofsky performance status (KPS) score, and quality of life before and after therapy. The complications were also recorded. One month after therapy, we evaluated the curative effect and adverse events according WHO standard.
3. Statistical analysis: SPSS 12 softare was used to compare the short-term efficacy, long- term efficacy, the improvement of quality of life, and the incidence of adverse events between the two groups.
Results:
1. Evaluation of curative effect
Malignant pericardial efusions: The overall reaction rate of the two groups was 73.2%, the reaction rate of A group was 92.8% (26/28), and the reaction rate of B group was 53.5% (15/28). The differece of statistics was significant between the two groups (P<0.05).
Malignant pleural efusions: The overall reaction rate of the two groups was 73.4%, the reaction rate of C group was 90.6% (29/32), and the reaction rate of D group was 56.2% (18/32). The differece of statistics was significant between the two groups (P<0.05).
2. Evaluation of complications
Malignant pericardial efusions: The febrile rate of A group was 67.8% (19/28), and the febrile rate of B group was 60.7% (17/28). The differece of statistics was not significant between the two groups (P=0.781). The pain rate of A group was 42.8% (12/28), and the pain rate of B group was 39.2% (3/28). The differece of statistics was not significant (P= 1.00). The nausea or vomit rate of A group was 10.7% (3/28), and the pain rate of B group was 7.1% (2/28). The differece of statistics was not significant (P= 1.00). All the patients of the two groups did not show toxity to hematological system and damage to heart, liver and kidney.
Malignant pleural efusions: The febrile rate of A group was 67.2% (22/32), and the febrile rate of B group was 71.8% (23/32). The differece of statistics was not significant between the two groups (P= 1.00). The pain rate of A group was 43.7% (14/32), and the pain rate of B group was 43.7% (14/32). The difference of statistics was not significant (P= 1.00). The nausea or vomit rate of A group was 12.5% (4/32), and the pain rate of B group was 15.6% (5/32). The differece of statistics was not significant (P= 1.00). All the patients of the two groups did not show toxity to hematological system and damage to heart, liver and kidney.
3. Evaluation of quality of life
After injection of rmhTNFα, no matter how the dose was, the quality of life of the most patients had been improved. The spirit of the patients turned better, their appetite improved, their physical capacity increased, the pain relieved, the quality of sleeping improved and KPS score elevated.
Malignant pericardial efusions: The KPS score of 26 patients of A group increased more than 10 scores after therapy (92.8%), the KPS score of 18 patients of B group increased (64.2%), the difference of statistics was significant between the two groups (P<0.05).
Malignant pleural efusions: The KPS score of 30 patients of C group increased more than 10 scores after therapy (93.7%), the KPS score of 21 patients of D group increased (65.6%), the difference of statistics was significant between the two groups (P<0.05).
Conclusion:
1. rmhTNFαcan be used to therapy malignant pericardial or pleural efusions, and the curative effect is significant. The mechanism includes directly killing tumor cells, inducing atoptosis, and anti-angiogenesis.
2. Compared to using 5 million IU rmhTNFα, using 15 million IU can apparantly improve the curative effect, meanwhile don not increase the toxity. The reasons may be that using rmhTNFαintracavitarily can directly destruct epithelial tissue arround tumor and make tumor exposed thoroughly, so the concertration of drug can be higher. Because the rmhTNFαinjected intracavitarily does not reach to blood directly, the adverse events of high dose are similar to that of low dose.
3. We also find that the quality of life of the most patients has been improved apparantly after injection. It is supposed that rmhTNFαcan improve immunity, increase the killing activity of monocyte, macrophage, T cell and NK cell, and relieve cachexia.
恶性心包积液(malignant pericardial efusions,MPcE)是晚期癌症患者常见的并发症。绝大多数恶性心包积液是转移瘤所至,有症状的心包积液常是临终前的表现,早期诊断和治疗可明显改善症状并提高患者的生存质量。对于其治疗,外科方法包括经皮心包穿刺放液或置管引流术、心包硬化剂、心包开窗引流、心包切除术、开胸或电视镜下心包切开术;而内科治疗方法包括全身化疗、腔内药物灌注治疗。对于转移性恶性心包积液的治疗方法目前国际上尚无统一标准,但均强调术式选择应遵循个体化原则。
随着恶性肿瘤发病的增加,临床上恶性胸腔积液(malignant pleural efusions,MPE)的患者也相应增加,且显现出低龄化的趋势。因此,治疗恶性胸水的主要目的在于姑息缓解患者胸闷、呼吸困难等症状,减轻患者的痛苦,提高患者生存质量,并延长生命。目前国内外治疗MPE外科方法有:治疗性胸腔穿刺、胸膜固定术、循环胸腔热灌注、胸腹腔分流、胸膜切除术、电视胸腔镜手术等;而内科治疗方法则包括:全身化疗、局部腔内药物灌注;某些对放疗敏感的肿瘤可行预防性放射治疗。以上众多的治疗方法大多各有一定的疗效及副作用,适用于临床的不同阶段,只有根据不同的疾病阶段选择适当的治疗手段,才能提高控制胸水的有效率,并且有望延长患者生存期。
在众多的抗肿瘤药物中,肿瘤坏死因子(tumor necrosis factor,TNF)是迄今所发现的直接杀伤肿瘤细胞作用最强的生物活性因子,且被广泛应用于各种肿瘤的治疗中。TNF有TNF-α和TNF-β,目前研究最多的是TNF-α。人肿瘤坏死因子-α(hTNF-α)具有广泛的生物学活性,其中抗肿瘤是其最主要的作用。然而,天然TNF-α全身用药的不良反应严重,对心血管系统、血液系统、神经系统、消化系统、呼吸系统等均有严重的损害,正是这些毒副作用限制了其临床应用。
因此,从20世纪90年代开始,国内外十分重视突变型TNF-α的研究,以提高疗效和降低毒性。第四军医大学应用生物蛋白质工程技术对天然TNF-α进行基因重组及结构改造,制成高活性、低毒性的基因工程衍生物—重组改构人肿瘤坏死因子(rmhTNF),减少了天然TNF-α的毒性,大大地发展了临床适应症。2003年8月,全世界第一个应用于全身的rmhTNF被批准应用于临床,500万IU肌注治疗非小细胞肺癌(NSCLC)。我们在临床应用中发现,rmhTNF仅有注射部位疼痛及发热症状,偶见胃肠道反应,无骨髓抑制。如在应用前给予患者解热止痛药,此种反应可能得到防止或减轻。由于天然TNF-α半衰期仅为10～15min,又无对肿瘤组织特异性亲和力,静脉注射很难在肿瘤局部达到高浓度。为此,为了增加TNF-α在肿瘤组织中的浓度,提高疗效,近年来人们尝试了肿瘤局部或腔内注射天然TNF-α的方式,有效率大大提高而毒副反应未见增加。同时,重组改构后的rmhTNF与天然TNF-α可能作用机制无变化,具有相同的抗肿瘤作用,同时rmhTNF具有高效低毒的特点。分析rmhTNF主要机理是由于其对原癌基因表达是直接细胞毒作用和直接抑制作用,至肿瘤细胞出血坏死,恶性液体不再产生;高浓度rmhTNF促炎反应更强,至使纤维蛋白沉积,促进肿瘤组织坏死及纤维化,控制恶性液体;rmhTNF超过一定浓度时,具有明显的抗肿瘤新生血管的作用。据此,我们推测,重组改构后应用于全身的rmhTNF可以用于局部腔内灌注,即用于恶性心包积液或恶性胸腔积液中,且适当加大局部用药剂量会增加局部药物浓度,可能会增加疗效。如推测成立,临床应用rmhTNF将会有一个新的适应症,并为有效的控制恶性心包积液或恶性胸腔积液开辟一条新的用药方法。为了验证我们的设想并了解其局部大剂量用药的毒副反应,经过医院伦理委员会讨论通过后,我们设计了如下临床研究进行进一步探讨。
方法:
(一)一般资料
选取经病理和/或细胞学确诊的恶性心包积液56例患者按随机法将患者分为A、B两组(每组28例病例)。恶性胸腔积液共64例患者按随机法分为C、D两组(每组32例病例)。向其监护人及本人告知实验内容、可能的受益及潜在的风险,并签署知情同意书以明确系自愿接受临床试验,将该患者纳入为受试对象。患者分别于心包腔或胸腔内置管灌注rmhTNF 1500万IU (大剂量A、C组)、rmhTNF 500万IU(常规剂量B、D组)。每周2次,连续治疗4次。
(二)评测方法
治疗前后采用B超、CT对患者进行评测,测量心包或胸腔积液量的多少,并评测可供临床观察的可测量的原发病灶,所有病例均记录治疗前后的生命体征、临床症状、karnofsky performance status(KPS)评分,及治疗后生活质量和并发症情况。治疗结束1个月后,按WHO标准评价其疗效和毒副反应。
(三)对研究中得到的数据进行统计学分析,分别观察各组内治疗后患者的近期疗效、远期疗效、生活质量改善情况及并发症的发生率等等,然后在两组间对比,得出结论。
结果:
(一)疗效评估
1.恶性心包积液:56例入选病例总有效率73.2%,其中A组有效率92.8%(26/28例);B组有效率53.5%(15/28例)。两组数据比较,差异显著(P<0.05)。
2、恶性胸腔积液:64例入选病例总有效率73.4%,其中C组有效率90.6%(29/32例);D组有效率56.2%(18/32例)。两组数据比较,差异显著(P<0.05)。
(二)治疗后并发症评价
1.恶性心包积液:A、B两组1～2天出现发热分别为67.8%(19/28例)、60.7%(17/28例),组间比较差异不显著(P=0.781);局部疼痛分别为42.8%(12/28例)、39.2%(11/28例),组间比较差异不显著(P= 1.00);两组出现轻中度恶心、呕吐反应分别为10.7%(3/28例)、7.1%(2/28例),组间比较差异不显著(P=1.00)。两组均无血液学毒性反应,无明显心、肝、肾功能损害。
2、恶性胸腔积液:C、D两组1～2天出现寒战发热分别为68.7%(22/32例)、71.8%(23/32例),组间比较差异不显著(P=1.00);两组胸部疼痛分别为43.7%(14/32例)、43.7%(14/32例),组间比较差异不显著(P=1.00);两组胃肠道反应(恶心或呕吐)分别为12.5%(4/32例)、15.6%(5/32例),组间比较差异不显著(P=1.00)。两组均无明显心、肝、肾功能损害:未见明显骨髓抑制,无明显心、肝、肾功能损害。
(三)治疗后生活质量评价
恶性心包积液或恶性胸腔积液患者经过置管灌注rmhTNF治疗后,不论剂量大小,大部分患者的生活质量都有不同程度的改善:精神好转、食欲增加、体力增加、对治疗态度改善、睡眠增多、KPS评分提高。
1.恶性心包积液:A组治疗后KPS评分提高10分的有26例(92.8%);B组治疗后KPS评分提高10分的有18例(64.2%)。组间比较差异显著(P<0.05)。
2、恶性胸腔积液:C组治疗后KPS评分提高10分的有30例(93.7%);D组治疗后KPS评分提高10分的有21例(65.6%)。组间比较差异显著(P<0.05)。
结论:
1、rmhTNF可局部使用治疗恶性心包积液或恶性胸腔积液,临床疗效显著;这与其直接杀伤肿瘤细胞、诱导肿瘤凋亡及抗肿瘤新生血管等机理有关。
2、与常规剂量500万IU比较,心包腔或胸腔内局部使用3倍常规剂量的rmhTNF1500万IU,疗效明显提高,而毒副反应增加不明显。推测这是局部大剂量用药后,其直接摧毁肿瘤周围的血管上皮组织,使瘤体充分暴露,肿瘤细胞周围的药物浓度增加而增强其抗肿瘤能力;同时因局部用药不直接经过全身血液循环,血浆中rmhTNF含量少,所以其全身毒副反应增加不明显。
3、本研究发现,心包腔或胸腔内局部使用大剂量rmhTNF对患者全身症状明显改善,生活质量明显提高。推测是由于其可以增强机体免疫功能,增强单核细胞、巨噬细胞、T细胞、NK细胞等的杀伤能力,并改善肿瘤恶病质有关。
Background and Purpose:
Malignant pericardial efusions (MPcE) is one of the most common complications of terminal cancer. Most cases of MPcE were induced from metastatic tumor (MT). Because the symptom of MPcE is the appeareance of just-before-dying, so we can improve symptom and increase the living quality of the patients through diagnosing and caring MPcE early. We can therapy MPcE with surgery such as percutaneous catheter drainage, sclerosing agent, subxiphoid pericardiostomy, pericardiectomy and pericardiotomy with thoracoscope, or medcine such as chemical therapy and intracavitary inicetion of drug (chemical drug, biological response modifier or sclerosing agent). Although there is no international standard therapy guideline about therapying MPE, all doctors agree with the principle of individualized treatment.
Along with the increase of malignant tumor, the incidence of malignant pleural efusions (MPE) also increase and the age of onset is lower. On average, the survival time of the patients with Malignant pleural efusions is shorter. The purpose of therapying Malignant pleural efusions is relieve the symptom of dyspnea, allay the pain, increase the living quality and prolong the survival time. We can therapy malignant pleural efusions with surgery such as therapeutic thoracentesi, pleurodesis, circular intrapleural hyperthemic perfusion, Pleuroperitoneal shunting, Pleurectomy, operation with thoracoscope, and so on, or medcine such as chemical therapy and intracavitary inicetion of drug (chemical drug, biological response modifier or sclerosing agent). To some tumor which is sensitive to radiotherapy, we can use preventive radiation. Only can we use suitalbe methods to therapy malignant pleural efusions in its different clinical stages, the effective rate of contrlling malignant pleural efusions can be improved and the survival time can be prolonged.
In so many anti tumor drugs, tumor necrosis factor (TNF) is one of the most powerful drug in killing tumor cells directly, and has been used in therapying many kinds of tumor extensively. TNF has two types ofαandβ, and TNFαhas been mainly studied and used. However, natural TNFαcan induce severe adverse events in the aspects of cardiovascular system, hematological system, nervous system, digestive system and respiratory system, especially uesd in all over the body. Because these adverse events, the clinical application of TNFαhas been limited.
From 1990s, in order to improve the curative effect and decrease toxicity, the study of mutated TNFαhas been extensively devolped. Recombinant mutated human TNFαis a kind of mutaed TNFαhaving improved anti-tumor activity and decreased toxicity, which is invented by The Forth Miilitary Medcine Univercity (FMMU) . In August 2003, the first mutated TNFαwhich could be uesd in all over the body was licensed. We found that rmh TNFαinduced only thoracalgia and febrile, seldom reaction of gastrointestinal tract, when used in therapying nonsmall-cell lung cancer (NSCLC). If we gave antipyretic analgesic before TNFαwas used, these adverse events could be relieved. Because the half-life of natural TNFαis only 10-15min, and it has no specific affinity to tumor, the concentration of TNFαcan not be elevated in tumor. In order to improve the curative effect, many people inject natural TNFαinto tumor or cavity and find that the curative effect is improved and the toxity is not increased. The malignant pleural efusions therapying mechanism of rmhTNFαis similar to natural TNFα, including supressing the expression of oncogene, directly killing tumor cells, inducing necrosis of tumor and finally reducing the production of malignant pleural efusions. The high concentration of rmhTNFαcan induce stronger inflammatory reaction, and lead to the necrosis and fibrosis of tumor. It was also proved that high concentration of rmhTNFαcould inhibit the angiogenesis of tumor. So we presumed that rmhTNFαcould be used in ntracavitary inicetion and the concentration could be increased to improve the curative effect meanwhile the toxity might not be increased. If the hypothesis could be approved, the clinical indication of rmhTNFαcould be expanded, and there would be a new method to control malignant pleural efusions. To approve our hypothesis, we carried out this study after liscenced by Ethics Committee.
Methods:
1. Data of patients
Malignant pericardial efusions: 56 patients with malignant pericardial efusions, which were finally diagnosed through pathology or cytology, were randomly seperated into A group and B group (28/28). 64 patients with malignant pleural efusions, which were finally diagnosed through pathology or cytology, were randomly seperated into C group and D group (32/32). The content of this study, the potential benefit and risk were told to the guardian of the patients. After one patient definitely indicated that they agreed to participate in this study and signed in informed consent, the patient was selected to be studied. The patients of A and C group were injected intracavitarily with 15 million IU rmhTNFαthrough percutaneous catheter, twice per week, four times in all. The patients of B and D group were injected with 5 million IU rmhTNFα.
2. Methods of evaluating therapeutic efficacy
B ultrasound and CT were used to measure the amount of pericardial or pleural efusions, and the size of measurable focus. We recorded the vital sign, clinical symptom, Karnofsky performance status (KPS) score, and quality of life before and after therapy. The complications were also recorded. One month after therapy, we evaluated the curative effect and adverse events according WHO standard.
3. Statistical analysis: SPSS 12 softare was used to compare the short-term efficacy, long- term efficacy, the improvement of quality of life, and the incidence of adverse events between the two groups.
Results:
1. Evaluation of curative effect
Malignant pericardial efusions: The overall reaction rate of the two groups was 73.2%, the reaction rate of A group was 92.8% (26/28), and the reaction rate of B group was 53.5% (15/28). The differece of statistics was significant between the two groups (P<0.05).
Malignant pleural efusions: The overall reaction rate of the two groups was 73.4%, the reaction rate of C group was 90.6% (29/32), and the reaction rate of D group was 56.2% (18/32). The differece of statistics was significant between the two groups (P<0.05).
2. Evaluation of complications
Malignant pericardial efusions: The febrile rate of A group was 67.8% (19/28), and the febrile rate of B group was 60.7% (17/28). The differece of statistics was not significant between the two groups (P=0.781). The pain rate of A group was 42.8% (12/28), and the pain rate of B group was 39.2% (3/28). The differece of statistics was not significant (P= 1.00). The nausea or vomit rate of A group was 10.7% (3/28), and the pain rate of B group was 7.1% (2/28). The differece of statistics was not significant (P= 1.00). All the patients of the two groups did not show toxity to hematological system and damage to heart, liver and kidney.
Malignant pleural efusions: The febrile rate of A group was 67.2% (22/32), and the febrile rate of B group was 71.8% (23/32). The differece of statistics was not significant between the two groups (P= 1.00). The pain rate of A group was 43.7% (14/32), and the pain rate of B group was 43.7% (14/32). The difference of statistics was not significant (P= 1.00). The nausea or vomit rate of A group was 12.5% (4/32), and the pain rate of B group was 15.6% (5/32). The differece of statistics was not significant (P= 1.00). All the patients of the two groups did not show toxity to hematological system and damage to heart, liver and kidney.
3. Evaluation of quality of life
After injection of rmhTNFα, no matter how the dose was, the quality of life of the most patients had been improved. The spirit of the patients turned better, their appetite improved, their physical capacity increased, the pain relieved, the quality of sleeping improved and KPS score elevated.
Malignant pericardial efusions: The KPS score of 26 patients of A group increased more than 10 scores after therapy (92.8%), the KPS score of 18 patients of B group increased (64.2%), the difference of statistics was significant between the two groups (P<0.05).
Malignant pleural efusions: The KPS score of 30 patients of C group increased more than 10 scores after therapy (93.7%), the KPS score of 21 patients of D group increased (65.6%), the difference of statistics was significant between the two groups (P<0.05).
Conclusion:
1. rmhTNFαcan be used to therapy malignant pericardial or pleural efusions, and the curative effect is significant. The mechanism includes directly killing tumor cells, inducing atoptosis, and anti-angiogenesis.
2. Compared to using 5 million IU rmhTNFα, using 15 million IU can apparantly improve the curative effect, meanwhile don not increase the toxity. The reasons may be that using rmhTNFαintracavitarily can directly destruct epithelial tissue arround tumor and make tumor exposed thoroughly, so the concertration of drug can be higher. Because the rmhTNFαinjected intracavitarily does not reach to blood directly, the adverse events of high dose are similar to that of low dose.
3. We also find that the quality of life of the most patients has been improved apparantly after injection. It is supposed that rmhTNFαcan improve immunity, increase the killing activity of monocyte, macrophage, T cell and NK cell, and relieve cachexia.
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