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| ORIGINAL ARTICLE |
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| Year : 2015 | Volume
: 11
| Issue : 5 | Page : 32-37 |
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A clinical trial on docetaxel and carboplatin therapy with or without nimotuzumab for the treatment of advanced nonsmall cell lung cancer
Daliang Qi, Yan Cui, Qingsheng Wang, Chongbiao Huang, Jie Xu, Yanzhuo Yang, Liang Xin, Ye Tian, Xin Angelique Qi
National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| Date of Web Publication | 31-Aug-2015 |
Correspondence Address:
Dr. Daliang Qi
National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tian Jin Medical University Cancer Institute and Hospital, Tianjin 300000
China
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/0973-1482.163836
Background: To evaluate the role of nimotuzumab in combination with chemotherapy in patients with advanced nonsmall cell lung cancer (NSCLC) through progress-free survival, changes in tumor marker expression and adverse drug reactions.
Materials and Methods: A total of 59 NSCLC patients were randomized into two groups. The treatment group (n = 30) received nimotuzumab (200 mg) with docetaxel (60 mg/m 2 ) and carboplatin (area under curve = 5), whereas the control group (n = 29) received chemotherapy at the same dosage. All patients received two cycles of treatment lasting for 42 days. The serum tumor biomarker levels were measured on the day before treatment and at 60 days after treatment.
Results: The efficacy of treatment for the treatment and control groups were 36.7% and 27.6%, respectively; this difference was not statistically significant. However, progression-free survival (PFS) was significantly prolonged by 1 month in the treatment group. Peripheral blood CYFRA21-1 decreased significantly during treatment with a more extensive decrease in the treatment group, although the difference between the groups was not statistically significant. The neuron-specific enolase levels significantly decreased across all 59 patients. The carcinoembryonic antigen levels decreased significantly in the treatment group, but remained stable in the control group throughout the treatment period. Nimotuzumab was well tolerated by patients with only three cases of Grades I and II skin rash and no other toxic symptoms.
Conclusion: Nimotuzumab with docetaxel and carboplatin can enhance the short-term clinical efficacy by extending the duration of PFS and was generally well tolerated by patients. Keywords: Docetaxel and carboplatin regimen, effect, nimotuzumab, nonsmall cell lung cancer
How to cite this article:
Qi D, Cui Y, Wang Q, Huang C, Xu J, Yang Y, Xin L, Tian Y, Qi XA. A clinical trial on docetaxel and carboplatin therapy with or without nimotuzumab for the treatment of advanced nonsmall cell lung cancer. J Can Res Ther 2015;11, Suppl S1:32-7 |
How to cite this URL:
Qi D, Cui Y, Wang Q, Huang C, Xu J, Yang Y, Xin L, Tian Y, Qi XA. A clinical trial on docetaxel and carboplatin therapy with or without nimotuzumab for the treatment of advanced nonsmall cell lung cancer. J Can Res Ther [serial online] 2015 [cited 2022 Mar 9];11:32-7. Available from: https://www.cancerjournal.net/text.asp?2015/11/5/32/163836 |
| > Introduction | |  |
Lung cancer is the most common malignant cancer in the world, and nonsmall cell lung cancer (NSCLC) accounts for 80% of all cases of lung cancer. [1] Epithelial growth factor receptor (EGFR) is a potent signal cascade initiator that functions by activating receptor-associated tyrosine kinases. It is overexpressed in many types of solid tumor cancers, including NSCLC, and has been correlated with tumor invasion, metastasis, and poor prognosis. [2],[3] Targeting EGFR activity has been associated with enhanced treatment efficacy for NSCLC, colon and intestinal cancers, and head and neck cancer. [4],[5],[6] These recent breakthroughs in the adjuvant usage of specific targeting agents alongside traditional therapies have shifted the global focus in NSCLC treatment to a more synergistic approach, combining surgery, fractionated radiotherapy, novel chemotherapeutic agents, and targeted therapy. [7],[8],[9]
Nimotuzumab is a monoclonal antihuman EGFR IgG1 antibody that has been shown to inhibit tumor cell proliferation and increase chemosensitivity. [10] A preclinical trial using nimotuzumab to treat mice with A431 squamous cell carcinoma showed that nimotuzumab had significant antitumor, antiangiogenesis, and pro-apoptosis functions. [11] In addition, an in vitro study demonstrated the ability of nimotuzumab to increase radiosensitivity in H292 and Ma-1 cell lines. [10] Recently, the American Society of Clinical Oncology presented encouraging preliminary results from a Phase I trial in which escalated dosages of nimotuzumab had been used alongside nonpalliative radiotherapy for patients diagnosed with Stage IIb, III, or IV NSCLC, who were ineligible for chemotherapy. [12],[13] Several Phase I and II clinical trials have reported the safe tolerance of nimotuzumab in conjunction with radiotherapy or chemo-radiotherapy, and this targeting agent is associated with a significant improvement in the overall survival and progression-free survival (PFS) in patients with NSCLC. [14],[15],[16]
Although numerous studies have been done on nimotuzumab in relation to radiotherapy, few researchers have investigated the use of nimotuzumab with chemotherapy, and no common biomarker has been used to measure the treatment outcome for the different histological types of NSCLC. For our clinical trial, we focused on the use of nimotuzumab with or without docetaxel and carboplatin (DC regimen) and attempted to establish standard tumor biomarkers for the assessment of short-term treatment effects. Any adverse drug reactions were also recorded and evaluated.
| > Materials and Methods | | |
Patient cohorts
Participants from the VIP Oncology Ward and the Chemotherapy Unit of Tianjin Medical University Affiliated Oncology Hospital were recruited for this study between January 2009 and June 2011. A total of 59 patients with advanced NSCLC were recruited and randomized into two groups. All patients met the requirements for chemotherapy. Written informed consents were obtained from each patient before the start of any treatment. The clinical study was approved by the Ethics Committee of the Hospital (E2011024). Thirty patients were allocated to the treatment group, which received nimotuzumab in conjunction with the DC regimen. There were 18 men and 12 women, with an age range of 38-73 (median age = 54.8) years. In this group, 13 patients had Stage III NSCLC and 17 had Stage IV. Pathohistology revealed 16 cases of adenocarcinoma, 11 cases of squamous cell carcinoma, 2 cases of large cell carcinoma, and 1 case of adenosquamous carcinoma. Twenty-nine patients were randomized to the control group, which received the DC regimen alone. This group consisted of 19 men and 10 women, with an age range of 40-74 (median age = 59.5) years. In this group, 14 patients were diagnosed with Stage III NSCLC, whereas 15 were diagnosed with Stage IV NSCLC. Pathohistology revealed 15 cases of squamous cell carcinoma, 12 cases of adenocarcinoma, and 2 cases of poorly differentiated carcinoma (cytological diagnosis).
Treatment delivery
Weekly intravenous injections of 200 mg nimotuzumab (Biotech Pharma Co., Ltd., Beijing, China) were started from day 1 for 1-6 weeks. Intravenous injections of 60 mg/m 2 docetaxel (Qilu Pharma, China) were started from day 1. Intravenous injections of carboplatin (area under curve = 5; Qilu Pharma, China) were started from day 2. The treatment cycle was 21 days. All patients received two cycles of treatment.
Assessed parameters
A complete medical history was obtained and a full physical examination was performed for each patient. The Karnofsky performance status along with hematological and biochemical profiles were obtained. Computed tomography or magnetic resonance imaging was performed before and during the treatment period.
Evaluation of treatment efficacy and adverse reactions
Treatment efficacy was assessed using the response evaluation criteria in solid tumors (RECIST). [17] RECIST is divided into the following four categories: Complete remission (CR), partial remission (PR), no change (NC), and progressive disease (PD). The total effective rate (ER) is calculated as the ER = CR + PR and the disease control rate (DCR) = CR + PR + NC. PFS was evaluated by the Kaplan-Meier and Cox models. The following three lung cancer tumor biomarkers were chosen as treatment response indicators: Carcinoembryonic antigen (CEA), cytokeratin 19-fragment marker (CYFR21-1), and neuron-specific enolase (NSE). Peripheral blood concentrations of these biomarkers were measured before and after treatment. Adverse drug reactions and toxicity were evaluated according to the third edition of Adverse Drug Reactions Assessment Standards of the National Cancer Institute Common Terminology Criteria Toxicity Scale (version 2.0).
Statistical analysis
Data from all 59 participants were used in the statistical analyses. The software of Statistical Product and Service Solutions version 15.0 was used for the analysis. Frequencies were reported as numbers and percentages. The Chi-square test was performed for countable data. Student's t-test was used to compare means, and P < 0.05 was considered statistically significant. The Kaplan-Meier plot of PFS was analyzed using the Log-rank test. The proportional hazards ratio (HR) was derived from the Cox proportional hazards regression model.
| > Results | | |
Short-term treatment efficacy
Clinical evaluation of the 30 cases in the treatment group resulted in 2 cases of CR, 9 cases of PR, 15 cases of NC, and 4 cases of PD. The total ER and DCR in the treatment group were 36.7% and 86.7%, respectively. Of the 29 cases in the control group, 2 had CR; 6, PR; 16, NC; and 5 cases had PD. The ER and DCR in the control group were 27.6% and 82.8%, respectively. The difference between the ER and DCR between the groups were not statistically significant [P = 0.321 and P = 0.478, respectively; [Table 1] and [Table 2]].
The duration of PFS in both the groups ranged from 2 to 12 months. The median PFS for the treatment and control groups were 242 and 193 days, respectively [P = 0.015; Log-rank test, P = 0.027; [Figure 1]]. The HR values for the PFS of the control group was 1.79 (P = 0.033). The significance was verified by a Log-rank test on the overall comparison of the duration of PFS (P = 0.027). The PFS curves clearly differ between the two patient groups with the control group showing worse PFS than the treatment group.
Biomarker changes
Changes in the NSCLC tumor marker expression were detected in the treatment group. At the end of the entire treatment period, the expression levels of CEA, NSE, and CYFRA21-1 were significantly different compared to the pretreatment levels (P = 0.029, P = 0.005, and P = 0.038, respectively). In the control group, only the pre- and post-treatment NSE levels significantly differed after two treatment cycles (P = 0.005). The CEA and CYFRA21-1 levels remained stable throughout the entire treatment period and did not significantly differ in the control group [P = 0.079 and P = 0.204, respectively; [Table 3]]. | Table 3: Comparison of the expression levels of tumor markers before and after treatment
Click here to view |
Survival analysis by Cox regression analysis
Two factors were found to influence PFS. The HR value for CYFRA21-1 was 1.059 (95% confidence interval = 1.012, 1.109, P = 0.014) and that for the treatment group was 1.789 (95% confidence interval = 1.049, 3.051, P = 0.014). In model 3, the results confirmed that these two factors are independent indicators of PFS [Table 4].
Adverse drug reactions
The DC regimen affected the hematopoietic system and digestive system, and induced hair loss and fatigue. So, the patients of the treatment and control groups had anorexia (25 vs. 23), constipation (3 vs. 1), diarrhea (3 vs. 2), asthenic conditions (20 vs. 20), neutropenia (26 vs. 24), and thrombocytopenia (27 vs. 27), but the proportion of two groups had no statistical difference. There were no allergic reactions or cardiovascular symptoms. Nimotuzumab induced three cases (3/30, 10%) of Grades I and II skin rash in the treatment group. A few patients had pruritus, 5 patients in the treatment group and 2 patients in the control group. There were no human antimurine antibody (HAMA) responses or other toxicities. After the treatment, the patients were allowed to leave when the white blood cell (WBC) count recovered to acceptable levels. In the treatment group, the WBC and platelet counts before and after treatment significantly differed [P = 0.004 and P = 0.001, respectively; [Table 5]]. However, similar results were obtained from the control group (P = 0.000 for both WBC and platelets), suggesting that there was no statistical difference across all patients (P < 0.05). | Table 5: Comparison of the WBC and plate counts before and after treatment
Click here to view |
| > Discussion | | |
Conventional platinum-based chemotherapy such as the DC regimen has been widely used for the treatment of NSCLC. However, the average survival for advanced lung cancer patients ranges from only 8 to 12 months, with the 1-year survival rate at only 30-50%. [18] Therefore, much attention has now been placed on adjuvant therapy, combining targeted therapy with traditional chemotherapy in order to increase the survival rate. EGFR was the first tyrosine kinase receptor to be directly linked with human cancers, and it has been found to promote tumor angiogenesis, tumor invasion, metastasis, and resistance to chemotherapy and radiotherapy. [19],[20] Overexpression of EGFR occurs in 40-80% of all NSCLC cases. [21]
Nimotuzumab is an IgG1 monoclonal antibody containing 95% of human antibody sequences. It has high target selectivity and binding affinity and a long half-life, which makes it an invaluable tumor targeting agent. Nimotuzumab binds to the extracellular domain of EGFR, which blocks the activation of the intracellular tyrosine kinase domain of EGFR. This leads to the inhibition of EGFR-mediated signal transductions, which includes the RAS-RAF-MAPK signaling cascade, and in turn inhibits cellular growth. [22] Simultaneously, the PI3K-AKT and JAK-STAT pathways are also blocked, consequently inhibiting tumor angiogenesis and promoting cell apoptosis. Therefore, nimotuzumab is able to limit tumor cell proliferation, promote apoptosis, and inhibit tumor angiogenesis, increasing sensitivity to chemotherapy. [23]
A previous study using nimotuzumab with chemotherapy reported an ER range of 25-72.5% and a DCR range of 64-89%. [24] For our clinical trial, the ER was 36.7%, which is in agreement with the reported range. However, our control group had an ER of 27.6%, which means that the difference between the ER of the treatment and control groups was not statistically significant (P = 0.321). Nonetheless, the overall result of our clinical trial was encouraging, with two cases (6.7%) of CR in the treatment group. Results of the Cox regression analysis revealed a statistically significant difference in the PFS between the two patient groups; the PFS of the treatment group was on average 1 month longer than that in the control group, and the patients in the treatment group had a better quality of life. In addition, tumor size was significantly reduced in most patients and certain disease symptoms such as jaundice caused by tumor compression disappeared completely. Venous obstruction also dissipated due to treatment. It would be clinically useful to determine whether nimotuzumab has greater efficacy toward certain NSCLC histology; however, this effect could not be statistically analyzed in this clinical trial due to the small sample size.
The use of biomarkers as treatment monitoring indicators was limited in previous studies surrounding NSCLC combinatorial treatment. [25],[26],[27] NSE, CEA, and CYFRA21-1 are lung cancer tumor biomarkers correlating to tumor size reduction. [28],[29],[30],[31],[32],[33],[34] Our clinical results showed a significant difference in the serum levels of these biomarkers before and after treatment. NSE is an enzyme responsible for glycogen metabolism and is usually distributed in the neural tissue. Elevated serum NSE was recognized as an indicator for lung cancer diagnosis and monitoring. [35] The serum elevation of this marker is dependent on the histological type of lung cancer, with SCLC causing the most elevation, followed by NSCLC, adenocarcinoma, and squamous cell carcinoma in that order. NSE is not a routine biomarker for NSCLC. The level of NSE detected during our clinical trial showed a statistically significant decrease posttreatment in both the patient groups. This could mean that NSE is affected by chemotherapy alone and not by targeted therapy using nimotuzumab.
The CEA gene is located on chromosome 19, which is associated with cancer antigens, and is especially linked to malignant tumors of the digestive system; therefore, it has been used for disease monitoring and treatment evaluation. [36] We found a significant difference in the CEA level after treatment in all the 59 patients in this trial. The difference in the pre- and post-treatment CEA levels in the control group was not statistically significant (P = 0.079), but this difference was significant in the treatment group (P = 0.029). This tumor biomarker could show the effect of targeted therapy using nimotuzumab.
CYFRA21-1 is a soluble cytokeratin 19 fragment that is used as a tumor marker for the diagnosis and monitoring of cancer, particularly in the case of lung cancer. A serum CYFRA21-1 concentration of >30 ng/mL indicates a very strong possibility of primary lung cancer. The change in the serum level of this marker is also affected by tumor histology but the trend is opposite to that of NSE levels, with squamous cell carcinoma causing the most change in the serum CYFRA21-1 level, followed by adenocarcinoma and small cell carcinoma. [37] CYFRA21-1 is a very good clinical indicator for disease prognosis after treatment. A fall in the CYFRA21-1 level to within the normal physiological range after treatment usually indicates a positive prognosis for the patient. If the CYFRA21-1 level does not change due to treatment, there is a good possibility that the tumor will regress. Our clinical results showed a significant difference between the pre- and post-treatment CYFRA21-1 level across all 59 patients, but the change in the CYFRA21-1 level was more extensive in the treatment group (P = 0.038). This result indicates the action of nimotuzumab toward tumor cells.
According to previous studies, unlike other EGFR monoclonal antibodies, nimotuzumab rarely binds to EGFR expressed in normal tissue. [28],[36] This increase in tumor specificity of nimotuzumab means reduced damage to normal tissue and reduced HAMA; this is reflected in a lower incidence of Grades I and II skin rash (only 10%). [38],[39],[40],[41] In addition, nimotuzumab has a stronger binding affinity with EGFR via the formation of double bond conjugations. This means that even at a low dose of 200 mg, nimotuzumab can achieve similar binding rates at high concentrations of other EGFR antibodies. Nimotuzumab also possesses a long half-life of 303 h, which means effective and reliable weekly administrations.
Our treatment group had only three cases (10%) of Grades I and II skin rash, which is considerably lower than the incidence of Grades I and II skin rash with cetuximab use. The WBC and platelet counts decreased to a low level in a few patients in the treatment group at around day 10 of the first treatment cycle; however, these values quickly recovered after treatment. The second treatment cycle did not induce any extra deterioration in the WBC and platelet counts, that is, the decrease in these levels were comparable to that observed in the control group. A significant difference in the WBC and platelet counts was observed across all 59 patients posttreatment, which could be due to DC-induced bone marrow suppression, lung infections, and relief of clinical symptoms. Therefore, these results suggest that nimotuzumab has no effect on the hematopoietic system.
| > Conclusion | | |
Concurrent use of nimotuzumab with the DC regimen for the treatment of advanced NSCLC can enhance short-term clinical efficacy, extend the time to tumor progression, and improve the quality of life. Nimotuzumab can be well tolerated by patients and weekly administration is reliable and effective. Although changes in the PFS and biomarker levels before and after treatment were statistically different between the treatment and control groups, the overall clinical efficacy was not. This could be due to our small sample size and the short duration of treatment. As with all monoclonal antibodies used for cancer therapy, the most effective dosage is difficult to determine and has to be personalized for each patient; thus, the use of a standard dosage across all patients in the treatment group could be another contributor to our clinical results. Larger-scaled, multi-centered clinical trials with long-term observations with a possible emphasis on tumor histology are required to determine the true efficacy of nimotuzumab with chemotherapy.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]
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