Thoracic injection of low-dose interleukin-2 as an adjuvant therapy improves the control of the malignant pleural effusions: a systematic review and meta-analysis base on Chinese patients

Clinically, some malignancies are often associated with malignant pleural effusion (MPE). During tumor progression, tumor cells often invade the pleura, causing destruction of the pleural structure and clogging of the lymphatic vessels, which results in increased pleural microvascular permeability and ultimately pleural effusion [1, 2]. Studies have shown that the incidence of MPE caused by lung cancer is about 7–23, and 15% of cancer deaths are closely related to MPE. MPE often leads to exacerbations of blood-gas exchange in patients with dyspnoea and worsening quality of life (QOL), leading to a decrease in survival. In fact, the treatment of MPE is clinically very difficult [3]. Traditional treatments for MPE include fluid drainage, pleural adhesions, and drug infusion into the chest cavity. Currently, the mainstream view is that thoracic injection of some agents can be used to control MPE, mainly because this mode of administration results in significantly higher intrathoracic drug concentrations than intravenous injection [3, 4]. Today, to find new tactics and effective therapies for controlling MPE remains challenging. However, it is currently trend to explore novel agents that have therapeutic selectivity and are capable of preferentially killing cancer cells without significant toxicity to normal cells [2].

Interleukin-2 (IL-2) is a small 15.5-kDa four α-helical bundle cytokine, which is produced predominately by antigen-simulated cluster of differentiation 4 (CD4+) T cells, while it can also be produced by cluster of differentiation 8 (CD8+) cells, natural killer (NK) cells, and activated dendritic cells [5]. IL-2 is a thymus dependent lymphocyte growth factor, which regulates the proliferation and differentiation of lymphocytes [6]. Especially, it plays a major role in the growth and proliferation of NK and thymus dependent lymphocyte cells, thus it has been introduced to treat various diseases including cancer [7]. Despite some potential side effects, IL-12 has been shown to have more potent effects when used with whole tumor cell vaccines [8]. Generally, it has been thought to play a role in the activation of the immune system, which may be an effective method of eradicating cancer. As a monotherapy, IL-2 has been shown to mediate tumor regression and has been used for treating metastatic renal cell carcinoma and metastatic melanoma [9, 10].

IL-2 alone or in combination with other anti-cancer therapies have brought some survival benefits to advanced cancer patients [5]. A recent meta-analysis seems to support the use of IL-2 in combination with chemotherapy in solid tumors other than melanoma and renal cancer and reports that there is a trend toward better prognosis in the response in several solid tumors, especially for colorectal cancers [11]. Another meta-analysis also shows that IL-2 combination therapy is effcacious in treating non-small cell lung cancer (NSCLC) and improves overall survival and did not show significant toxic reactions [12]. In China, IL-2 has been approved for the treatment of MPE since 1998. These years, some randomized controlled trials (RCTs) have specially explored the clinical efficacy and safety of IL-2 combined with cisplatin versus cisplatin alone in treating MPE through thoracic injection. So we performed a systemic review and meta-analysis to evaluate the efficacy and safety of IL-2 for treating MPE.

Malignant pleural effusions (MPE) often occur in many cancer patients as the tumor progresses [3]. With the continuous development of molecular medicine, the survival of patients with cancer gradually extended, MPE has become one of the key problem that respiratory physicians, oncologists and thoracic surgeons have to face [33]. Although there are more and more studies on MPE therapy, pleural effusion drainage, intra-thoracic infusion chemotherapy and systemic chemotherapy are the main treatment of MPE [1]. Interleukin-2 (IL-2) is a cytokine with most important functions in the physiology of cell-mediated immunity [12]. IL-2 causes activation, proliferation, and trafficking of T-cells and natural killer cells. When administered locally it may change a non-inflamed tumor into an inflamed tumor, perhaps thereby increasing sensitivity of that tumor to further immune attack [34]. One previous meta-analysis shows that IL-2 or induced killer cells combination therapy displays a considerable efficacy in treating NSCLC and thus improves overall survival. Now IL-2 has been used for the treatment of MPE through thoracic injection. Here, we performed a systemic review and meta-analysis to evaluate the effcacy and safety of IL-2 for patients with MPE through thoracic injection. By retrieving a series of medical databases, based on strict pre-enacted inclusion and exclusion criteria, a total of 18 studies that met the inclusion criteria were recruited in this meta-analysis. We evaluated the study quality of included studies based on the Cochrane Handbook of Systematic Review and the principle of homogeneity in clinical research and found that these studies have good clinical homogeneity. Further heterogeneity analysis also showed that there was no significant heterogeneity among these studies, which indicating that the design and implementation of these studies were well comparable. Thus, we used the fixed effects model of meta-analysis to evaluate efficacy and safety of IL-2 for treating patients with MPE through thoracic injection.

Amazingly, we found that the combination of cisplatin plus IL-2 via thoracic injection significantly increased the ORR (showing an absolute 4.1-fold elevation) as well as DCR (an absolute 7.86-fold increase), as compared with cisplatin alone. This result gives us a message that IL-2 has a role in the treatment of MPE, and when used in combination with cisplatin, it significantly enhances the efficacy to control MPE with synergistic effects. It has been shown that the thoracic injection of IL-2 prolongs the survival of patients with MPE. The possible mechanism is that IL-2 increases the number of CD3 + T cells and NK cells in the pleural space and enhances immunity reaction, reducing the incidence of MPE; the data show that the IL-2 treatment for MPE showed an effective rate of about ~ 59% and no significant side effects [35‐37]. A recent study of IL-2 in MPE indicates that IL-2 reduces (PD-1) expression, increases expressions of granzyme B (GzmB) and γ- interferon, and enhances CD8+ T cell proliferation in MPE. In addition, IL-2 reduces carcinoembryonic antigen (CEA) expression in MPE, suggesting that its mechanism of treatment for MPE is closely related to these molecules [35]. Cisplatin is a non-specific cell cycle anti-tumor drug, clinically used for the treatment of MPE. Thoracic injection of cisplatin not only directly kill tumor cells, improve lymphatic circulation, can also lead to chemical pleurisy, pleural adhesions, thereby reducing pleural exudation [38]. We deduce that the combination of cisplatin and IL-2 can play their respective advantages, the two applications can improve the body’s immune function and show a synergistic effect. To confirm this result from another aspect, we compared the no-response rate (NRR) of treatment between cisplatin plus IL-2 versus cisplatin alone through thoracic injection for treating MPE and found that NRR of cisplatin alone was remarkably higher than that of cisplatin plus IL-2, which showed that patients with MPE could get a better benefit from cisplatin plus IL-2 than IL-2 alone.

With the continuous improvement of cancer diagnosis and treatment technology, patients’ survival and cure rates have been significantly improved, so the improvement of QOL of patients has become increasingly important [39]. We compared the QOL between cisplatin plus IL-2 versus cisplatin alone through thoracic injection for treating MPE and noticed that combination perfusion of cisplatin and IL-2 improved the QOL of patients with MPE, as compared with cisplatin alone, which showed an absolute 2.75-fold increase. In recent years, health care has progressively increased its interest in understanding QOL as a crucial and meaningful endpoint, particularly in oncology [40]. Clinically, when cancer patients develop an MPE condition, which means that the tumor has been locally metastasized or disseminated, implying that it is difficult to cure. Patients with MPE mainly manifested as chest pain, dyspnea, weight loss and other cachexia symptoms, however, the effective control of MPE can effectively alleviate the symptoms of patients, reduce pain and improve QOL. Anti-cancer drugs are an important part of many cancer treatments. The research and development of new anti-cancer drugs is one of the hot spots in cancer research. However, some anticancer drugs may also damage healthy cells while damaging cancer cells, leading to side effects [41]. When a drug is used to treat a disease, its side effects are also an important indicator of its performance. The same efficacy of treatment, we are willing to use the method of smaller side effects [42]. In this meta-analysis, we found that despite the combination of IL-2 with cisplatin, the incidence rate on myelotoxicity, nausea/vomiting and chest pain did not show an extra increase, as compared with cisplatin alone. Unfortunately, we found that compared with cisplatin alone, thoracic injection of cisplatin plus IL-2 led to a higher possibility of fever. However, the fever caused by IL-2 was only mild to moderate. After the physical cooling and antipyretics, the symptoms disappeared. IL-2 has been used as a method of immunotherapy for a variety of oncology treatments. Fever is clinically common adverse reaction caused by IL-2, some patients need anti-fever drugs. However, recent tumor immunology studies have shown that elevated temperatures can promote more effective anti-tumor immune responses, which may be more conducive to anti-tumor treatment [43]. Patients with IL-2 are expected to have varying degrees of systemic toxicity. There is evidence that increased doses of IL-2 lead to increased toxicity [44]. Several dosage regiments, including intravenous high doses (720,000 or 600,000 international units/kg), low dose subcutaneous injection, and IL-2 combined with other therapies, have been used for maximum therapeutic benefit. There are currently 60 institutions in North America with high doses of IL-2 for metastatic melanoma and renal cell carcinoma [45]. Currently in China, the recommended dosage of IL-2 for the treatment of MPE is 0.5 to 1 million IU/ m2/ time. The studies included in our meta-analysis were performed in accordance with this dose. Our study showed that this dose indicated a better efficacy and lower side effects. Since these studies did not concern the effects of different doses of IL-2 on side effects, our meta-analysis could not provide a conclusion about how different doses might affect side effects. This also reminds related researchers that this problem should be paid attention to in future research.

Through meticulous sensitivity analysis and publication biases analysis, we found that the studies included in this meta-analysis were of good homogeneity, so the conclusions are stable. However, there are still some shortcomings in these researches. First of all, the dosage of IL-2 was defined 1 to 3 million units in those studies; IL-2 dose showed some differences, suggesting that the IL-2 combined with cisplatin by thoracic injection for MPE treatment needs further standardization. Second, the description of randomized allocation and blinded implementation of included studies is unclear and there may be a risk of selective bias, which may affect the strength of evidence of the findings. Third, because there was no foreign literature to meet the inclusion criteria, there may be a geographical bias. Fourth, to date, there are no multicenter and large sample studies. We hope that in the future there will be more scientifically designed and rigorous RCTs of large samples to provide a reliable basis for the clinical use of IL-2 in treatment of MPE by thoracic injection.

Due to ethical and drug clinical research restrictions, clinical studies on new drugs are often very cautious. Despite this, this meta-analysis still give us an important message that thoracic injection of cisplatin plus low-dose IL-2 has a better benefit of ORR, DCR and QOL for controlling MPE, compared with cisplatin alone, which means that IL-2 may be one of the options to treat MPE. Especially, except for the fever, the presence of low-dose IL-2 does not have an extra increase on the incidence of other AEs. However, further randomized trials with large population are required to provide more evidence for evaluating the efficacy of IL-2 in the treatment of MPE.