Abstract
OBJECTIVE To evaluate the response rate and tolerance of patients with middle-late esophageal carcinoma, who were treated with concurrent chemoradiotherapy (CCRT) plus thalidomide.
METHODS Sixty-five eligible patients with local middle-late esophageal carcinoma were randomly assigned to the treatment group (TG) and the control group (CG). The 33 patients from the TG were treated with CCRT plus thalidomide (a 60-70 Gy of radiation dose, and 5-FU plus cisplatin; oral administration of thalidomide at a dose of 100 mg/d on the first week and 200 mg/d on the second. Both were taken with water, at bedtime until completion of the radiotherapy. In the CG, 32 patients received CCRT only. The clinical effects and tolerance to the CCRT between the 2 groups were compared.
RESULTS The response rates of the therapeutic combination in the TG and CG were 87.9% and 68.7%, respectively. There were no statistical differences in comparing the response rates between the 2 groups (P > 0.05); the local control rates in the TG and CG were 93% and 91%, respectively, and there were no statistical differences between the 2 groups (P > 0.05); the 1-year survival rates of the patients in the TG and CG were 74.0% and 63.0%, respectively, without statistical differences between the 2 groups (P > 0.05). The improvement rates of KPS scoring in the TG and CG were 57.6% and 31.3%, respectively. There were significant differences in comparing the improvement rates between the 2 groups (P < 0.05). The incidence rates of nausea and vomiting were lower in the TG compared to the CG, with a statistical significance between the 2 groups (P < 0.05). However, the incidence rates of constipation, lethargy and fatigue were higher in the TG than in CG, showing a statistically significant difference between the 2 groups (P < 0.05).
CONCLUSION CCRT combined with thalidomide in treating esophageal carcinoma may improve the quality of life of the patients, the treatment may also raise patients’ compliance to chemoradiotherapy, and possibly increase their long-term survival rate. Further studies related to this topic are needed.
keywords
Introduction
Esophageal carcinoma (EsC) is a highly invasive tumor, and is inoperable in 50% of the patients because of metastasis. EsC shows a tendency of early invasion and metastasis [1]. Concurrent chemoradiotherapy (CCRT) has already been used as a standard therapy for the locally inoperable EsC patients. However, the 5-year survival rate only reaches 14% among the patients. CCRT combined with surgery also can be conducted[2]. Over the past few years, results from related research have shown that growth, metastasis, and recurrence of EsC rely on the pathway of angiogenesis[3]. Treatment with angiogenic inhibitors emerges as a potential therapy for EsC patients. Thalidomide (TLD, or Fanyingting in Chinese), as a tranquilizer and antiemetic, was widely used to reduce morning sickness in the 1950’s, but was prohibited in the 1960’s because of its severe teratogenic action. Research conducted in recent years has shown that TLD, as an angiogenic inhibitor, extensively used in treatment of solid tumors, provides a definite curative effect. In March 2007, we conducted a study in which 65 patients with middle-late EsC were randomly assigned into 2 groups. Cross analysis was used for evaluating the therapeutic effects and the side effects of CCRT combined with TLD and the simple CCRT in treating middle-late EsC. The contribution and safety of TLD in the treatment for local middle-late EsC was discussed.
Materials and Methods
Inclusion criteria
a. All cases involved in the study were confirmed by pathologic examination as having locally advanced squamous cell carcinoma without distant metastasis; b. tumors were localized in the cervical segments, or in the thoracic segments, which were inoperable, or the patients rejected surgery; c. all the patients received initial treatment and were able to take semiliquid or liquid food, and on presentation had no hoarseness or lymph node metastasis in the supraclavicular region; d. the Karnofsky Performance score of the patients was ≥ 70; e. size of the foci was ≤ 10 cm, no abnormal signs were shown in the X-ray before esophageal perforation, no obvious pain in thoracodorsal part, no tracheal involvement, and no vocal cord paralysis; f. the routine blood examination was normal, and no severe heart, liver and kidney disfunction; g. age ≤ 70; h. no severe dyscrasia or cardiovascular diseases were found, and the expected survival time was over 3 months.
Clinical data
From March 2007 to May 2009, 65 EsC patients admitted to our hospital were randomly divided into a treatment group (TG) with 33 cases and a control group (CG) with 32. Either the χ2 test or Fisher test was used for checking the clinical baseline data of the patients in the 2 groups. The differences between the 2 groups were not statistically significant (P > 0.05), see Table 1.
Comparison of the clinical data from the cases in the 2 groups.
Treatment methods
CCRT combined with TLD was given to the cases in the TG, while only CCRT was given to the cases in the CG. The method of CCRT delivered was the same in the 2 groups, the details shown as follows: i) Radiotherapy: marking the exact exposure field under the simulator was performed for the patients in both groups; linear accelerator with 6 MV-X-ray was used to irradiate the exposure field at 2 Gy/time, once a day, 5 days a week, lasting for 6-7 weeks, with an overall median dose of 60-70 Gy. Detailed exposure field: the whole lesion of the esophagus was included in both the opposing anterior and the posterior irradiation fields, both the upper and lower bounds of the irradiation field went beyond the homologous margin of the tumor to a sufficient distance, in order to cover the total mediastinal lymph node region. The upper and lower bounds of the irradiation field respectively extended 3-5 cm for the upper and lower portion of the tumor margin (the very superior bound reached the superior margin of the cricoid cartilage), and the width of the irradiation fields was decided based on the scope of tumor invasion shown in a CT scan, which was 6 cm in most of the cases. After 36-40 Gy of opposed anteroposterior irradiation, the mode of irradiation was changed into a 2-oblique field radiation to avoid irradiation of the spinal cord, including or not the Ono field irradiation to the metastatic nodal region in the neck, and including or not an exposure field at the left gastric lymph-node region (subject to the location of the esophageal lesion), with a boost dose of up to 60-70 Gy to the tumor. The exposure dose ratio of the EsC at the cervical and the superior thoracic segments was anterior field vs 2 posterior fields, i.e., 1:1:1 and that at the middle thoracic segment and inferior thoracic segment was 4:3:3; ii) Chemotherapy: CCRT was given to patients in both groups. The chemotherapeutic regimen was as follows: cisplatin (DDP), 20 mg/m2/d plus 5-flouruoracial (5-FU) 500 mg/m2/d, given intravenously for successive 5 days, 2 courses in total; the chemotherapy was given respectively on the 1st and the 4th week after the radiotherapy. During each course, ondansetron and metoclopramide were administered to reduce nausea and vomiting. The routine examinations of blood, liver and renal functions were conducted once a week. A G-CSF regimen would be used if a grade-III-IV bone marrow depression occurred. The pharmacal dose was decreased by 25% for the next course; iii) TLD (prepared by the Changzhou Pharmaceutical Co., Ltd, Changzhou, Jiangsu) administration: TLD was given to patients in the TG as the radiochemotherapy started, with a dose of 100 mg, a day, with water, at bedtime on the 1st week; from the 2nd week, the dose was raised up to 200 mg a day. The administration of TLD was continuously given until the radiotherapy was finished, using the same mode of administration.
Observation
Short term effects
A barium meal (BaM) examination of the esophagus was conducted respectively before and at the end of the radiotherapy. The treatment effect was evaluated based on the level of tumor regression. After the radiotherapy, the evaluation criterion of the short-term effect of treatment for EsC patients introduced by Liu et al.[4], was adopted. a. Complete remission (CR): the tumor vanished completely, and the fringe of an image on the spot film of a barium meal was smooth; the barium contrast medium (BaMCM) could be seen passing through the esophagus easily, and the wall of the esophagus was slightly stiff, with or without slight stenosis in the lumen, in which the mucosa was almost recovered or became thick. b. Partial regression (PR): most of the lesion vanished, neither obvious twist nor angulation, nor ulcer infiltration to serous membrane was found. The BaM-CM could be seen passing through the esophagus easily, however, the fringe of an image was slightly rough, with a small filling defect and/or tiny niche sign. Sometimes, though the fringe was smooth, there was an apparent stenosis in the lumen. c. No regression (NR): at the end of the radiotherapy, there were still residues in the lesion site, or apparent improvement in the diseased region was not found, and visible filling defect or niche sign remained. d. Progression of disease (PD): niche sign or stenosis was aggravated, and the response rate (RR) was calculated based on the sum of CR+PR. The therapeutic effect in both groups was evaluated after completion of the radiotherapy.
Local control rate
The definition of the local control rate was that the X-ray film showing the esophageal with BaM and/or chest CT scan demonstrated the presentation of CR of the tumor or the presentation of residues of the tumor at the end of the radiotherapy, with stable disease (SD) or no change (NC).
Quality of life
The sleeping condition (SC) and the change of Karnofsky performance score (KPS) in the patients in TG and CG, before and after the therapy, were respectively observed. The SC was divided into 5 levels, i.e. difficulty in sleeping, very poor sleep, poor sleep, slightly poor sleep and approximately normal sleep. One level elevated meant improvement (improv) and 1 level lowered meant aggravation (aggrav). Based on the criteria of KPS[5], if 10 or more scores increased or decreased after the treatment, it was respectively noted as improvement or aggravation; if the change of the scores was less than 10, it was noted as stable.
Criteria of evaluations toxicity
The side effects were assessed based on the WHO classification of chemotherapeutic adverse reactions[6] and on the criteria of acute radiation injury from the radiation therapy oncology group (RTOG), USA[5].
Follow-up and statistical analysis
Follow-up by phone was carried out in all the patients until June 2009. During this period, 5 cases were lost to follow-up, with a follow-up rate of 93.8%. To compare the treatment effects, the changes in patients’ quality of life, as well as the side effects on the patients in the 2 groups, the χ2 test was used to calculate survival rate (SuR). The Kaplan-Meier method was used to compute the SuR for the survival analysis. The Log rank method was applied to test the differences in the SuRs between the 2 groups. SPSS13.0 software for statistical analysis was employed for the statistical treatment of all experimental data. The value of P < 0.05 was considered statistically significant.
Results
Short-term effects
The dose of TLD was reduced in 1 case in the TG owing to severe constipation. In the CG, 5 cases were discontinued after 1 cycle of chemotherapy was finished because of severe digestive-tract reaction. The RR reached 87.9% in the TG and 68.7% in the CG. After the χ2 test, χ2 = 0.0068, P = 0.9341, there was no statistical significance in comparing the differences between the groups (P > 0.05), see Table 2.
Short-term effects seen in the patients in the 2 groups (%).
Local control rate and SuR
After radiotherapy, the disease control rate was calculated by the sum of CR + PR + SD. The local control rates (LCR) were 93% and 91%, respectively in the TG and CG, without statistical significance in comparing the LCR’s differences in the groups (P > 0.05). Follow-up was completed in all the patients by June 2009. During this period, 5 cases were lost to follow-up (2 in TG, 3 in CG). The data from the patients who died of cancer comprised the complete clinical data, but the data from the others were calculated based on truncated data. Ten patients in the TG and 16 in the CG died. The 1-year SuR was 74.0% and 63.0%, respectively in the TG and CG. For the SuR curve in the 2 groups, see Fig. 1 (χ2 = 1.705, P = 0.192).
Comparison of survival curves between the experiment and control groups.
Patients’quality of life, including change of SC and KPS, see Table 3
Change of SC and KPS of patients in the 2 groups.
Side effects
The incidence rate of digestive-tract reactions, such as nausea and vomiting was lower in the TG than in the CG, with a significant difference between the 2 groups (P < 0.05). However, the incidence rate of the radiochemotherapy-related symptoms, such as dizziness, lethargy and constipation, was higher in the TG than in the CG, showing a significant difference (P < 0.05). In regards to other post-radiochemotherapeutic adverse effects, there was no statistically significant difference between the groups (P > 0.05), see Table 4.
Comparison of side effects in the 2 groups (case).
Discussion
Since esophageal carcinoma (EsC) has a feature of high invasion, most EsC patients have lost an opportunity for surgery at the first clinic visit. Therefore, radiotherapy has been applied in 80% or more EsC patients. Over the past 30 years, nevertheless, the 5-year SuR of EsC patients who underwent a simple radiotherapy has not obviously been increased, with an value of only 8%-10%[7]. Whereas advanced radiotherapeutic techniques and instrumentation can increase the LCR of EsC, it can not lower the rate of distant metastasis. The long-term disease-free survival only reached 10%-15% of the advanced EsC patients having undergone simple surgery or radiotherapy[8]. Simple chemotherapy fails to attain the purpose of radical cure because of its limitations in the treatment. CCRT has been a major focus in research on non-operative treatment of EsC, which has become the standard therapy for the patients with locally unresectable EsC[9]. However, improvement of the treatment of CCRT remains a problem which needs to be urgently solved. Moreover, widely clinical application of CCRT was restricted because of the obviously increased toxicity induced by the treatment which easily results in the discontinuance of the treatment regimen. Recently, it has become a focus of clinical research on how to enhance the therapeutic effect, lessen the side effects, and increase the compliance of the treatment so as to extend the survival time.
It has been shown in numerous studies that the growth, metastasis, and prognosis of EsC are closely related to angiogenesis. It has been found in studies that vascular endothelial growth factor (VEGF) is a highly specific mitogen and a main regulatory factor of tumor angiogenesis. This conclusion has been widely accepted, at present. The studies indicate that an increase of VEGF expression in the EsC tissue plays an important role in the growth and metastasis of the tumors. It also is the key factor of affecting the prognosis of EsC[10,11]. At present, a significant therapeutic effect has been achieved in treating advanced colorectal carcinoma with monoclonal antibodies of VEGF combined with chemotherapy, indicating that there is a possibility to utilize angiogenesis inhibitors in treating EsC patients. Animal experiments and clinical studies have proved that the use of the VEGF monoclonal antibodies against angiogenesis in the targeted therapy for EsC can raise the treatment effect[12]. Nevertheless, the high price of the monoclonal antibody has limited its clinical application.
Thalidomide (TLD), also called Fanyingting in Chinese, is a derivative of aminoglutaminic acid, having a low cost and being easy to take by patients. It was initially used in treating morning sickness as a nonbarbiturate tranquillizer and later was prohibited because of its teratogenic effects. Over the past few years, numerous studies reported in the literature in China and overseas[13] show that TLD plays a role in angiogenic inhibition, immunoloregulation and induction of apoptosis, etc. Recent research by Ansiaux et al.[14] also indicated that TLD had a radiotherapeutic sensitization through an early change in the microenvironment of the tumor, therefore, supporting a new thinking for the clinical application of TLD in anti-tumor treatment for EsC. Nowadays, an obvious treatment effect of TLD has been seen not only in drug tolerance and refractory myeloma, but also in the therapeutic effect on malignant solid tumors, such as renal carcinoma, small-cell lung cancer, prostatic carcinoma, ovarian cancer and liver cancer, etc. Kotoh et al.[15] reported that intraperitoneal injections of TLD in nude mice which had been inoculated with ES63 EsC cells apparently could inhibit the growth of ES63 cells (P < 0.05). In addition, the capillary density in the tumor tissue of the mice was lower in the treatment group (TG) compared to the control group (CG) (P < 0.005). Merin et al.[16] found, after a preliminary clinical study on TLD combined with capecitabine in the treatment for gastric cancer and advanced EsC, that the disease control rate reached to 50% in these patients. The authors suggested further clinical studies. We found that the short-term effect, LCR and the 1-year SuR were all elevated in the TG compared with those in the CG. However, the differences in the 2 groups were not statistically significant. So far, no reports of similar randomized clinical study have been published. The reason might be as follows: i) Lack of cases that meet the inclusion criteria. ii) The time spent in observation is short since most angiogenic inhibitory drugs are not dose-dependent cytotoxic drugs that require several months to completely demonstrate the effect of the drugs. Therefore, long-term administration is needed. iii) It may relate to the expression of VEGF. In the patients with a low expression of VEGF, or with low proportion of new vessels, the effect of angiogenic inhibitors is minimal. The therapeutic effect of the drug may further be raised, if inhibition of angiogenesis directed at VEGF expression is available. iv) It may relate to a low dose of TLD used in the treatment.
At present, CCRT can be regarded as the standard therapy for the patients with local unresectable EsC. Previously it was reported that the CR rate of CCRT for EsC ranged from 15% to 33% and that the RR was from 68.3% to 91.0%. Chen et al.[17] reported that the 1-year SuR for EsC patients receiving CCRT was 59.1% in 132 patients. Kato et al.[18] showed that the 1-year SuR was only 30.7% in 22 inoperable advanced EsC patients after CCRT. In our study, most of the cases were in advanced stages, and moreover, there was an increasing tendency in the 1-year SuR of the EsC patients. In various studies over the past years, the clinical data and treatment methods differed greatly for the EsC patients, however, we still believe, based on this study, that CCRT combined with TLD in treating middle-late EsC patients can bring about a definite benefit to survivors by improving the LCR.
EsC patients usually develop psychological disorders, presenting with depression, anxiety, and dysphoria, which results in hyposomnia and decline in the quality of life, and even may not be in compliance with the treatment. TLD induces a favorable sedation and can increase patients’ quality of life. It was found in our research that the SC was apparently improved, appetite raised, and there was an increase in body weight in the patients in the TG. The KPS was significantly increased, with an obvious elevation in the quality of life and in compliance with the treatment in the TG patients. No cases in the TG discontinued the CCRT, while 5 cases in the CG finished only 1 cycle of chemotherapy owing to severe adverse reactions. The authors found that, for some of the patients with middle-late EsC accompanied by refractory insomnia, oral administration of TLD could produce preferable sedation. Khan[19] and Gordon et al.[20] also found that TLD could adjust the dyscrasia of the EsC patients and improve the patients’ quality of life. They presumed that the effect might be a result of inhibition of TNF-α.
The main adverse effects of TLD include fatigue and lethargy followed by peripheral neuropathy, and most severely the development of deep venous thrombosis[21]. In our study, severe adverse reactions were not seen after addition of TLD in the TG, while there was only an increase of the side effects on the nervous system, such as lethargy, headache, dizziness and constipation, nearly all of which were tolerable following symptomatic treatments. Severe constipation occurred only in 1 of these patients, which improved after the dose of TLD was reduced to 100 mg/d. No patients were discontinued TLD or developed deep venous thrombosis in the TG. The probable reason is because a low dose of TLD was used[22].
In conclusion, our study has demonstrated that the application of CCRT combined with TLD in treating local middle-late EsC patients is valuable, and the patients can tolerate well the side effects induced by the treatments. The patients get benefits from improving the quality of life and by increasing treatment compliance. We will enlarge the sample size in future studies, and will further conduct clinical trials in which patients, who have received surgery or CCRT, will be selected to have a maintenance therapy and receive an increased dose of TLD. In addition, we will continue to observe the therapeutic effect and side effects induced by TLD, as well as the influence on the long-term survival time of EsC patients.
Conflict of interest statement
No potential conflicts of interest were disclosed.
- Received February 21, 2010.
- Accepted April 8, 2010.
- Copyright © 2010 by Tianjin Medical University Cancer Institute & Hospital and Springer
References
In this issue
Jump to section
Related Articles
Cited By...
- No citing articles found.