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Year : 2018  |  Volume : 14  |  Issue : 1  |  Page : 226-232

Clinical study on thalidomide combined with cinobufagin to treat lung cancer cachexia

1 Department of Medical Oncology, The Affiliated Tumor Hospital of Guangxi Medical University, Nanning 530021, China
2 Department of Respiration, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China
3 Department of Respiration Medicine, Guangxi Jiangbin Hospital, Nanning 530021, China

Date of Web Publication8-Mar-2018

Correspondence Address:
Dr. Xiaoju Chen
Department of Medical Oncology, Tumor Hospital, Guangxi Medical University, No. 71, Heti Road, Nanning 530021
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0973-1482.188436

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 > Abstract 

Objective: To discuss and assess the clinical value of treating lung cancer cachexia with thalidomide combined with cinobufagin.s
Methods: A cohort of 54 patients, who were diagnosed with lung carcinoma, was randomly divided into two groups, a trial group and a control group, respectively. The trial group was given 150 mg/day thalidomide and 2700 mg/day cinobufagin; the control group only received 2,700 mg/day cinobufagin. The therapy lasted for 12 weeks, and the nutritional status, quality of life, survival, and side effects in patients in the two groups were recorded.
Results: The nutritional status, quality of life, and survival of patients with lung cancer cachexia in the trial group were significantly improved compared to the control group. The trial group received 150 mg thalidomide, which by contrast reduced the incidence of side effect and increased tolerance.
Conclusion: Using thalidomide combined with cinobufagin to treat patients with lung cancer cachexia will significantly improve their nutritional status and quality of life. This therapy is better than that using cinobufagin alone and is well tolerated.

Keywords: Cinobufagin, clinical value, lung cancer cachexia, thalidomide

How to cite this article:
Xie M, Chen X, Qin S, Bao Y, Bu K, Lu Y. Clinical study on thalidomide combined with cinobufagin to treat lung cancer cachexia. J Can Res Ther 2018;14:226-32

How to cite this URL:
Xie M, Chen X, Qin S, Bao Y, Bu K, Lu Y. Clinical study on thalidomide combined with cinobufagin to treat lung cancer cachexia. J Can Res Ther [serial online] 2018 [cited 2022 Nov 26];14:226-32. Available from: https://www.cancerjournal.net/text.asp?2018/14/1/226/188436

Mingzhi Xie, Xiaoju Chen and Shouming Qin contributed equally to this work.

 > Introduction Top

Cancer anorexia–cachexia syndrome (CACS) is a progressive, dysfunctional multifactor syndrome that causes constant loss of skeletal muscle (either with or without fat), a condition that cannot be completely reversed through traditional nutrition intake.[1] During the final stage of the tumor, 50–80% of patients will show cachexia-related signs of progressive weight reduction, fatigue, loss of appetite, varying degrees of damage to body organs, etc. That really has an impact on the quality of patients' lives, shortens the survival time, and influences the implementation of treatment programs, which could reduce the sensitivity to chemotherapy.[2]

The pathogenesis of CACS is very complicated. Many fundamental studies on cancer cachexia have been conducted, which indicate that it may be a chronic, inferior, tumor-activated autoimmune reaction.[3] There is evidence shows that the overexpression of inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1, and IL-6, may be correlated with the progression of cancer cachexia.[4],[5] Inhibition of the synthesis of these cytokines and other activity treatment will most likely have a positive effect on improving CACS.[6]

The treatment of cachexia aims to improve physical ability as well as the health-related quality of patients' lives. Yet, the realization of this goal has everything to do with reversing or stabilizing the loss of skeletal muscle, improving muscle quality and its function. So far, there are two main clinical treatments for cachexia; one is optimal nutritional support therapy, and the other is conventional drug therapy. Many drugs such as hormone cortisol, nonsteroidal anti-inflammatory drugs, and cytokine antagonists among others are used to treat cancer cachexia and have been proved to be effective therapy.[7],[8],[9] However, because of the drug side effects or the resistant nature of cachexia, a definitive regulated drug treatment guide for cancer cachexia has not been implemented.[10],[11]

Thalidomide was first regarded as an oral drug for sedation and anti-inflammation, yet its well-publicized acknowledged teratogenic effects led to its withdrawal from clinical practice. In recent years, however, thalidomide has been widely used to treat advanced cancer and autoimmune diseases.[12],[13],[14] Some studies indicate that thalidomide might be the only drug that can help CACS patients reduce weight loss and actually gain weight without fat.[15] Thalidomide can resist tumor growth through the following autoimmunomodulation effects: (1) anti-inflammatory effects: reducing the combination of stromal cells and intercellular adhesion and vascular cell adhesion cells reduces the release of inflammatory cytokines such as IL-6 and TNF-α. (2) Anti-angiogenesis actions by reducing the formation of vascular endothelial growth factor and bFGF in B-cells. (3) Antitumor effect, through the stimulation of the cells such as monocytes and CD8 leading to increased IL-2 and interferon production, which activates NK-cells to release cytotoxic mediators and induce apoptosis of tumor cells.

Cinobufagin is a preparation extracted from Bufo bufo gargarizans cantor or Bufo melanostictus (Schneider), which has the effect of heat clearing and detoxification, inducing diuresis to reduce edema.[16] Many studies have reported that cinobufagin can inhibit tumor growth by affecting oncogene expression, induce apoptosis of tumor cells, slow the formation of new blood vessels, increase the effectiveness of the immune response, etc.[17],[18] At present, cinobufagin preparations are widely used to treat advanced malignant tumors, and it has shown good efficacy, but there are rarely reports about using a combination of cinobufagin and thalidomide to treat cancer cachexia, in the worldwide. The present study reports the findings on the treatment of lung cancer cachexia using thalidomide and cinobufagin together, observations on the patients' nutritional status, quality of life, and side effects after the treatment, and a discussion of the value of this therapy in the clinic.

Data and methods

Common data

The protocol for this study was approved by the Ethics Committee of the Guangxi Medical University Affiliated Tumor Hospital. After sifting through 103 cases diagnosed with squamous cell lung carcinoma from December 2013, to May 2014, in the hospital, 56 patients were selected, of which 42 were males and 14 females (age range: 46–66 years).

In our study, participants were randomized to receive either thalidomide 150 mg combined with cinobufagin 2000 mg daily or cinobufagin 2000 mg alone daily. Randomization was undertaken using a sequential series of sealed envelopes containing a computer-generated code. Randomization envelopes were opened by a third party who dispensed the trial drug in a double-blind fashion.

Eligibility criteria

  • Only individuals fulfilling the following criteria were included in the trial 1. Age >18-year-old, diagnosed with squamous cell lung carcinoma by the Pathology Department of our hospital; clinical stage IV, all patients gave written informed consent. Met the definition of cancer cachexia: patients with weight loss >5% or body mass index <20 kg/m 2 within 6 months have lost >2% weight, or patients whose appendicular skeletal muscle index is matched with sarcopenia (male <7.26 kg/m 2, female <5.45 kg/m 2) have lost >2% weight.[19] We selected patients who had lost 5–10% of their body weight within 3 months
  • Had a performance status ranging from 2 to 3
  • Being able to provide nutritional support: According to the patient's weight, the daily biological need is 1600–1800 K calories.[20] Based on biological need and food habits, patients were instructed to take care of their daily intake of sugar, protein, and fat. If the patient was anorexic, Enteral Nutrition Powder was used accordingly
  • The patient could self-complete European Organisation for Research and Treatment of Cancer (EORTC) Core Quality of Life Core Questionnaire (QLQ-C30) testing
  • All patients do not receive chemotherapy or radiotherapy.

Exclusion criteria

Patients who met one of the following conditions were excluded from the trial:

  1. Women of child-bearing age
  2. Had deep venous thrombosis
  3. Could not provide basic nutritional support
  4. The patient could not complete EORTC QLQ-C30 testing.

Exit criteria

Patients who had deep venous thrombosis or other complications that could not be tolerated.

 > Methods Top

Intervention program: all selected patients were randomly divided into two groups, namely the trial group and the control group in an alternating sequence. The trial group was given 150 mg/day thalidomide and 900 mg tid/day cinobufagin in capsule form. The control group was only given 900 mg tid/day cinobufagin. Observation endpoints: the parameters listed below were measured for the endpoints including before treatment, 4 weeks, and 12 weeks after treatment.

Nutritional status

  • Mid-upper arm circumference (MUAC): a soft ruler tape was to measure the MUAC
  • Weight: scales were used to measure each patient's weight
  • Plasma albumin: biochemical analysis
  • Quality of life: measured using the EORTC QLQ-C30 chart
  • Side effects: evaluated based on NCI-CTC4.0.

Average survival time and survival rate

Starting from the day patient took the first dose of the drug(s), the patient's health or survival status was followed up by a phone conversation, with the observation endpoint being January 1, 2015. Careful notes were made of the average survival time for all patients and the KM estimator used to draw up the survival curves and to analyze the overall survival rate, as well as the survival rate for each patient at the endpoint.

Statistical methods

SPSS version 19.0 which manufactured by International Business Machines (IBM, Arnomk, NY, USA) Corporation was used to store and analyze data sets. Data were displayed as the mean ± standard deviation, using a Chi-square test on count data, a t-test on measurement data, and a log-rank to measure the survival rate for each group. P <0.05 was considered to be statistically significant.

 > Results Top

The selected 54 patients were assigned into the trial group or the control group randomly [Figure 1]. In the trial group, two patients died after 3 months and three in the control group. Three patients were removed from the trial due to unbearable side effects. Therefore, a total of 46 patients, 25 in the trial group and 21 in the control group, were re-evaluated. The patients in each group were adults whose age, gender, basic weight, MUAC, plasma albumin, grip strength, and EORTC QLQ-C30 scores were analyzed and compared, and showed no significant differences (P > 0.05). Their comparability is shown in [Table 1].
Figure 1: Flow diagram of progress through the trial

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Table 1: Baseline characteristics of patients

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Treatment index

Efficacy (before/after treatment)

  1. The following indexes in the trial group were significantly improved at the end of week 4: plasma albumin (P = 0.025), EORTC QLQ-C30 score (P< 0.001), weight (P = 0.064), MUAC (P = 0.475), and grip strength (P = 0.519), which appeared to increase compared to the baseline, but statistical significance was not reached. The EORTC QLQ-C30 score for the control group was increased (P = 0.015), but the MUAC, weight, plasma albumin, and grip strength were not statistically significant compared to the baseline (P > 0.05)
  2. The following indices for the trial group were significantly improved at the end of week 12: weight (P< 0.001), MUAC (P = 0.032), plasma albumin (P = 0.01), EORTC QLQ-C30 score (P< 0.001) and grip strength (P = 0.109), which appeared to be increased compared to the baseline but did not reach statistical significance. All indices for the control group were not statistically significantly different (P > 0.05).

Comparison between two groups

  1. The average change of the following indices for the trial group was greater than that of in the control group at the end of week 4: plasma albumin (P = 0.015), EORTC QLQ-C30 score (P< 0.001), MUAC (P = 0.597), weight (P = 0.372), and grip strength (P = 0.354) were no significant difference in the change between both the trial group and the control group
  2. The average change of the following indices for the trial group was greater than that of in the control group at the end of the week 12: Weight (P = 0.031), plasma albumin (P = 0.01), EORTC QLQ-C30 score (P< 0.001), and grip strength (P< 0.001), MUAC for the trial group appeared to increase more than that of in the control group, but statistical significance was not reached (P = 0.115).

Survival rate

The Kaplan–Meier estimator was used to construct survival curves to analyze the survival rate for the trial and control groups using log-rank statistics. The average survival time for the trial group and the control group was 152 ± 15.2 days and 133 ± 17.3 days, and the overall survival rate was 59.26% and 29.63%, respectively. Both results have statistical significance [P = 0.011, [Figure 2].
Figure 2: Kaplan–Meier estimator used to construct survival curves and analyze the survival rate for both groups using log-rank measurements. The analysis shows that there was a statistical difference in the overall survival rate between the two groups (*P < 0.05)

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Side effects

The most common side effects in the trial group were nausea and vomiting (14.8%), often labeled as I–II level, which the patients could tolerate. The most common side effect in the control group was also nausea and vomiting (22.2%). However, three patients had intolerable diarrhea and chose to exit the trial [Table 2].
Table 2: Side effects in the trial and control groups

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 > Discussion Top

The treatment of CACS is difficult, despite significant progress being made in both clinical and basic research. However, there is still no well-defined definitive guide for the treatment of this serious disease. Some patients do not receive chemotherapy or surgery because of a lack of medical resources or financial restraints. Therefore, the present study was heavily focused on finding a cost-effective treatment that can prolong the lives of patients with cancer cachexia and improve their quality of life.

Nonsmall cell lung cancer cachexia is the final stage of a tumor, clinical stage IV. According to the latest National Comprehensive Cancer Network guide, patients with nonsmall cell lung cancer are recommended the best symptomatic and supportive treatment available. Many drugs, such as BMS-945429 (IL-6 antibody), enobosarm, and amoxicillin hydrochloric acid, have been tried as a therapy in patients with nonsmall cell lung cancer cachexia.[11],[21] However, there are very few reports about the use of thalidomide and cinobufagin combination to treat patients with nonsmall lung cancer cachexia.

Thalidomide and cinobufagin are effective in inhibiting tumor growth, and both are orally active, which are a cheap and easy route to administer drugs in the clinic. The ability to block cytokine activity, such as TNF-α and IL-6, has been validated. Fundamental research has proven that preventing the formation and activity of these cytokines improves CACS. Thus, we decided to use a combination of thalidomide and cinobufagin to treat nonsmall cell lung cancer cachexia, to observe the nutritional status, quality of life as well as any change of the survival rate after 3 months of therapy.

In our study, the trial group was given a combination of thalidomide and cinobufagin to treat cancer cachexia. The nutritional status index (weight, MUAC, and plasma albumin) of the trial group increased after 4 weeks and 12 weeks, compared to the control group. The changes after 12 weeks were more obvious than that of 4 weeks and were statistically significant (P< 0.05). Weight, MUAC, and plasma albumin remained at the same levels after 4 and 12 weeks in the control group. The trial group had a higher group index than that of the control group, which reached statistical significance (P< 0.05). It can be concluded that a combination of thalidomide and cinobufagin improves the nutritional status of patients, and the combined efficacy is superior to using cinobufagin alone.

Our study adopted the measurement of grip strength to learn about patients' muscle function, but after 4 and 12 weeks, there was no detectable change in grip strength compared to the baseline. The change in the trial group after 12 weeks compared to the control group was significant (P< 0.001). Inspection of [Table 3] and [Table 4] shows that the trial group had obviously increased indices after 4 and 12 weeks compared to the baseline; the grip strength in weeks 4 and 12 had significantly improved. The results deserve further investigation and verification because the present study used only a cohort of patients and perhaps too brief a test period.
Table 3: Endpoints before and after treatment between the trial and the control groups at weeks 4 and 12

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Table 4: Change in patient indices between the trial and control group at week 4 and 12

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The symptoms such as fatigue, drowsiness, nausea, and vomiting were significantly improved for patients in the trial group, and the score for both groups was also higher than that of in the previous studies. The comparison between the two groups also was statistically significantly different [Table 3] and [Table 4].

[Table 3] shows that the average survival time for the trial group and the control group was 152 ± 15.2 days and 133 ± 17.3 days, respectively. The survival rate for both groups was 29.6% and 59.3%, respectively, and the difference was statistically significant (P = 0.011). The combination of thalidomide and cinobufagin prolonged the average survival time and increased the survival rate compared to using cinobufagin alone.

To date, there is no definitive guide for the dosage of thalidomide to be administered, and in the clinic, the dose given is usually between 50 and 200 mg.[22],[23] The study of Davis et al. points out that even 50 mg of thalidomide might produce side effects, but when the dose increased to 100 mg, there is no further increase in the incidence of side effects.[23] We used 150 mg/day thalidomide in the present study based on the author's clinical observations. When the dose exceeded 150 mg, the chances of some patients having the symptoms of nausea, drowsiness, etc., increased, but 150 mg was tolerated by the majority of patients.

The side effects of using thalidomide and cinobufagin together are subtle, the most common being nausea (14.8%); most are labeled as I–II level, tolerable, and no patient left the trial because of side effects. However, treating cancer cachexia with only cinobufagin has a 22.2% chance to cause nausea, among which there were 3 level III cases related to severe diarrhea. These three patients could not tolerate this side effect and withdrew from the trial.

 > Conclusion Top

A combination of thalidomide and cinobufagin shows better tolerance and efficacy than using cinobufagin alone.

Currently, many researches have adopted fat-free body weight as an observing indicator for treatment, and fat-free body weight depends on the measurement by medical equipment (computed tomography).[24],[25],[26] The limitation of this study lies in the fact that many patients could not measure their fat-free body weight because of financial difficulty or lacking equipment so that no immediate evaluation of tumors is conducted. Furthermore, cachexia might cause ascites and pleural effusion to body weight, further affecting the accuracy of measurement. Hence, we adopted MUAC as another effective indicator for nutrition status.

Several studies have reported that both thalidomide and cinobufagin can lower inflammatory cytokine levels including IL-6 and TNF-α, thus producing immunomodulation. Due to the specialty of patients in our study, it was impossible to monitor molecular indexes. Coronha et al.[27] and others have pointed out that weight and quality of life could impact on the treatment of patients. Weight, fatigue, and quality of life perhaps should be regarded as the main indices for the CACS study.

Currently, the main treatment for advanced lung cancer is platinum-palliative treatment. Its efficacy is certain, but the side effect of using platinum chemo drugs are significant. Most cancer cachexia patients have a high risk of undergoing necessary chemotherapy. Our study utilized thalidomide together with cinobufagin oral preparations to treat tumor cachexia, and the results suggested that this treatment can improve the nutritional status and quality of life of patients. Furthermore, the drugs are oral preparations, which are cheap and easily administered to most patients.

In summary, this study indicates that a combination of thalidomide and cinobufagin should be used to treat CACS, which will improve the nutritional status and quality of life of patients. The therapy is cheap, safe, effective, well tolerated by patients, and shows relatively good efficacy in the clinic.

Financial support and sponsorship

The authors wish to express their gratitude for the financial support from the Guangxi Health Department (NO. Gui Wei z2012079), and The Basic Ability Enhancement Project for Young Teachers in Guangxi Zhuang Autonomous Region (NO. KY2016YB075).

Conflicts of interest

There are no conflicts of interest.

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  [Figure 1], [Figure 2]

  [Table 1], [Table 2], [Table 3], [Table 4]

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