Abstract
Background/Aim: The optimal chemotherapy for concurrent chemoradiotherapy (cCRT) of lung cancer is still unclear. Patients and Methods: We investigated the therapeutic effect of different chemotherapy regimens for cCRT of lung cancer in 65 patients at our hospital. Results: Of the 65 patients, 53 were male and 12 female. The median age was 64 years and 58 participants had a smoking history. The histological type was adenocarcinoma in 34 cases, squamous cell carcinoma in 22 cases, and others in 9 cases. Induction therapy consisted of cisplatin plus vinorelbine (CDDP+VNR) in 50 cases, and weekly carboplatin plus paclitaxel (CBDCA+PTX) in 15 cases. In all patients, the overall response rate, disease control rate, median progression survival, and median overall survival were 78.5%, 95.4%, 337 days, and 1,037 days, respectively. The median progression-free survival was 337 days in total; it was significantly longer for CDDP+VNR than CBDCA+PTX. The median overall survival was 1,037 days in total; it tended to be slightly longer for CDDP+VNR than CBDCA+PTX. Conclusion: Different chemotherapy regimens for cCRT possibly have different therapeutic effects.
Globally, lung cancer is one of the most frequently diagnosed cancers with a high mortality rate (1). Approximately 30% of patients with non-small cell lung cancer (NSCLC) present with stage III disease, and less than 1/3 survive for more than 5 years (2). On the other hand, unresectable stage III NSCLC should be treated with the goal of cure, as there are many types of primary lesions and lymph node status, and the possibility of complete response (CR). Based on the results of several clinical trials, the standard treatment for unresectable stage III NSCLC is concurrent chemoradiotherapy (cCRT) (3-5).
Previously, it was considered that improved local control following an increase in the dose would contribute to an improved prognosis. However, increasing the dose only caused increased side effects and did not contribute to prolonged prognosis, thus the standard dose was set at 60 Gy (6, 7). Regarding the chemotherapy regimen, the effectiveness of third-generation cytotoxic anticancer agents was compared with the conventional standard treatments of mitomycin, vindesine, and cisplatin (8, 9). However, the prognostic effect of chemotherapy in patients undergoing chemoradiotherapy (CRT) is unclear because none of them increased overall survival (OS).
In this study, we retrospectively examined whether the chemotherapy regimen in CRT has an impact on the therapeutic effect.
Patients and Methods
Patient selection. In this study, 65 patients who received cCRT for unresectable/locally advanced NSCLC from July 2004 to August 2018 at Nagoya City University Hospital were included. TNM version 8 for tumor classification was used. In terms of the T factor, the presence of T4 disease or lung metastases in the same lobe was considered “unresectable”. In terms of the N factor, clinically obvious or histologically/cytologically proven N2, bulky N2, N3, or both N1positive and N2 positive disease were considered “unresectable”. The lymph nodes that were larger than 10 mm in the minor axis were considered to be metastatic.
The selection criteria for cCRT were age ≤75 years, performance status (PS) 0-1, white blood cell count ≥3.0×103/mm3, neutrophil count ≥1.5×103/mm3, platelet count ≥1.0×105/mm3, serum creatinine ≤1.5 mg/dl, total bilirubin ≤1.5 mg/dl, and transaminase levels less than twice the upper limit of the normal.
Exclusion criteria included interstitial lung disease confirmed on chest x-ray, malignant pleura or sac fluid, and serious complications, such as severe respiratory failure and active infections.
Chemotherapy.
Weekly carboplatin plus paclitaxel. Carboplatin (CBDCA) [area under the curve (AUC)=2] and paclitaxel (PTX) (40 mg/m2) were administered intravenously on days 1, 8, 15, 22, 29, and 36. The doses for days 8, 15, 22, 29, and 36 were omitted if the white blood cells, neutrophils, or hemorrhage (in the presence of an active infection) counts were less than 2,000, 1,000, and 75,000, respectively. Patients received CBDCA (AUC=6) and PTX (200 mg/m2) every 4 weeks for a maximum of 2 cycles on day 1 as maintenance therapy.
Cisplatin plus vinorelbine. Cisplatin (CDDP) (80 mg/m2) and vinorelbine (VNR) (20 mg/m2) were given intravenously on day 1; however, only CDDP (80 mg/m2) was given on day 8. Overall, treatment cycles were repeated four times, every for 4 weeks.
Supportive care. All patients received prophylactic antiemetic therapy consisting of 5-HT3 antagonists, metoclopramide, and dexamethasone.
Radiation therapy. Radiation therapy was conducted simultaneously during the first cycle of chemotherapy at a total dose of 60 Gy given over 30 sessions.
Evaluation of effectiveness. Tumor response was evaluated based on the response evaluation criteria in solid tumors version 1.0.
Statistical analysis. Survival curves were prepared using the Kaplan-Meier method to analyze progression-free survival (PFS) and OS. The PFS was calculated from the day of cCRT initiation to the day of detection of disease progression or the day of death from any cause. If no disease progression was recorded, it was terminated on the day of last known survival. The OS was calculated from the day of cCRT initiation to the day of death. If no death was recorded, it was terminated at the date of final viability confirmation.
For the CDDP+VNR and CBDCA+PTX groups, the response rate (RR) and disease control rate (DCR) were determined using Fisher’s exact test, and differences in PFS and OS after initiation of chemoradiotherapy were examined using the log-rank test. Univariate and multivariate analyses of background factors were performed for treatment effects that were significantly different according to the different regimen. p-Values <0.05 were considered to be statistically significant. All statistical analyses were performed using EZR (10).
Results
Patient information. The characteristics of the 65 patients are shown in Table I. Fifty patients received CDDP+VNR and fifteen patients received CBDCA+PTX. The results for each group are shown in Table II.
Total result. Of the 65 patients, 16 achieved CR, 35 achieved partial response (PR), 11 had stable disease (SD), and 3 had progressive disease (PD). The RR and DCR were 78.5% and 95.4%, respectively. The median PFS and OS were 337 and 1,037 days, respectively (Figure 1).
Results by regimen. For the 50 patients treated with CDDP+VNR, 40 had CR+PR, 7 had SD, and 3 had PD. RR and DCR were 80% and 94%, respectively. For the 15 patients treated with CBDCA+PTX, 11 had CR+PR, 4 had SD, and 0 had PD. RR and DCR were 73% and 100%, respectively.
The difference in RR and DCR between the two groups was not statistically significant.
The median PFS and OS for CDDP+VNR were 397.5 and 1,318 days, respectively. The median PFS and OS for CBDCA+PTX were 189 and 585 days, respectively. There was a significant prolongation in PFS for CDDP+VNR over CBDCA+PTX [log-rank p=0.0225, 95% confidence interval (CI)=292-835]. No significant differences were found in OS (Figure 2).
The results of the analysis. In the univariate analysis of PFS, the median PFS in patients aged <70 years was longer than that in patients aged ≥70 years (PFS=420 days, 95%CI=297-851 vs. 242 days 95% CI=117-291; p<0.001). The median PFS of patients selected for CDDP+VNR was longer than that of patients selected for CBDCA+PTX (PFS=397.5 days, 95%CI=292-835 vs. 189 days, 95%CI=117-297; p=0.0225). Multivariate analysis showed that an age younger than 70 years [hazard ratio (HR)=0.2488; 95%CI=0.1194-0.5184; p<0.001] and CDDP+VNR (HR=0.4674; 95%CI=0.2437-0.8965; p=0.022) was associated with improved outcome (Table III and Table IV).
In univariate analysis for OS, median OS in patients aged <70 years was longer than that in patients aged ≥70 years (OS=1,428 days, 95%CI=825-2,536 vs. 563 days 95% CI=295-749; p<0.001). Patients treated with CDDP+VNR had a longer median OS than those treated with CBDCA+PTX (OS=1,318 days, 95%CI=698-1,787 vs. 585 days 95%CI=240-1,041; p=0.0764). Multivariate analysis showed that those younger than 70 years of age had a more favorable outcome (HR=0.3018; 95%CI=0.1455-0.6261; p=0.0013; Table III and Table IV).
Recurrence rate. The recurrence rates were 62% and 67% for CDDP+VNR and CBDCA+PTX, respectively, with no significant difference between them. When recurrence type was divided into two groups: local recurrence and distant metastasis, distant metastasis rates were 61% and 100% for CDDP+VNR and CBDCA+PTX, respectively. There were significantly fewer distant metastases with CDDP+VNR (Fisher test p=0.0206).
Discussion
In this study, we retrospectively examined the possibility that the chemotherapy regimen in cCRT may affect the therapeutic outcome. Compared with the CBDCA+PTX regimen, the CDDP+VNR regimen showed better results, especially for patients younger than 70 years. Further, the CDDP+VNR regimen had a lower recurrence rate due to distant metastasis than the CBDCA+PTX regimen. These results indicate that the chemotherapy regimen in cCRT may have an impact on the therapeutic results.
Chemotherapy regimens used concurrently with thoracic radiotherapy in randomized trials were platinum drugs with third-generation cytotoxic agents including VNR and PTX, which provided a better survival rate. However, there has been no established optimal chemotherapy for cCRT. Previous reports showed that chemotherapy with CDDP is slightly superior to CBDCA in improving RR and survival in patients with advanced NSCLC (11-13). Although the results of the present study were similar, the present results may have been influenced by the point that the patients were in good enough physical condition to actively choose CDDP in the selection of platinum agents. All cases in the present study were PS 0-1; however, the selection of CDDP at the discretion of the attending physician depending on the physical condition of the patient may have influenced the results, especially in elderly patients.
In cCRT, the effect of radiotherapy is controlled locally, and it is considered that chemotherapy mainly acts in remote areas. It has been reported that the stage of the disease is only associated with distant metastases in cCRT (14), and that radiological dose escalation with concurrent chemotherapy has an impact on reduced local recurrence, but not on remote control (15). The rate of distant metastasis in recurrence has been reported to be 76.1% in the past for chemoradiotherapy with CDDP+VNR (16). In the present study, the rate of distant metastasis in recurrence for the CDDP+VNR group was 61.3%, which was not significantly different from that of previous studies. The CDDP+VNR regimen has been one of the standard chemotherapy regimens for advanced NSCLC (17), and is still used for adjuvant chemotherapy in patients with completely resected NSCLC (18).
A surprising paradigm shift in lung cancer treatment is occurring with the advent of cancer immunotherapy. The immune checkpoint inhibitor durvalumab has resulted in significantly improved survival in consolidation therapy after cCRT, changing current treatment criteria for locally advanced NSCLC (19). However, patient selection is considered one of the future issues, and further clarifications regarding chemotherapy, such as the type required in a combination, appropriate dosage, and timing of treatment are needed. Further, clarifications regarding the radiation dose and irradiation field are also needed. Durvalumab has also been reported to reduce distant metastases compared to placebo (19). It would be better if a treatment with a low possibility of causing distant metastasis could be selected as a pretreatment for durvalumab, however, it seems that the effect of durvalumab can be expected even when such a treatment cannot be selected. Studies on long-term survival with durvalumab consolidation therapy are warranted in the future.
In radiotherapy, the shrinkage of lesions in the field of radiation is called the abscopal effect, and it is expected to be further enhanced in combination with immune checkpoint inhibitors (20). Currently, clinical trials are being conducted on the combination of local irradiation and immune checkpoint inhibitors with chemotherapy for NSCLC even for patients with stage IV disease. Thus, further studies will be needed to better understand the therapeutic strategies for CRT, including the appropriate chemotherapy regimen, because CRT is likely to become more important for the treatment of NSCLC in the future.
Footnotes
Authors’ Contributions
All Authors contributed to the conception and design of the study. MH, TO, and YK contributed to the collection and interpretation of the data. Data analysis was performed by MH, TO and YK. The first draft of the manuscript was written by MH, and all the Authors commented on the previous versions of the manuscript. All Authors read and approved the final manuscript.
Conflicts of Interest
The Authors declare no conflicts of interest associated with this manuscript.
- Received October 28, 2021.
- Revision received November 29, 2021.
- Accepted December 2, 2021.
- Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.