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ORIGINAL ARTICLE
Year : 2020  |  Volume : 16  |  Issue : 2  |  Page : 222-229

Induction chemotherapy for unresectable Stage III non-small-cell lung cancer may improve survival of induction chemotherapy responders as predicted by elevated levels of carcinoembryonic antigen and cytokeratin fragment 19 and classification as stage N3 cancer


1 Cancer Center, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
2 Department of Neurosurgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
3 Department of Experimental, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, China

Date of Submission05-Sep-2019
Date of Decision19-Oct-2019
Date of Acceptance15-Nov-2019
Date of Web Publication28-May-2020

Correspondence Address:
Xiao Ding
Cancer Center, Shandong Provincial Hospital Affiliated to Shandong University, Jingwu Road 324#, Huaiyin District, Jinan 250021
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_710_19

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 > Abstract 


Aims: The aim of this study is to investigate patients with unresectable Stage III non-small-cell lung cancer (NSCLC) receiving radiotherapy with induction and concurrent pemetrexed or docetaxel plus cisplatin (PP/DP) chemotherapy and to identify the subgroup most likely to benefit from induction chemotherapy (IC).
Subjects and Methods: Patients with unresectable measurable Stage III NSCLC received two cycles of PP/DP IC followed by concurrent chemoradiotherapy at a dose of 60–66 Gy.
Statistical Analysis Used: Cox regression analysis was performed to evaluate the prognostic factors for survival; logistic regression analysis was used to evaluate the predictors for response to IC, and the receiver operating characteristic curves were used to evaluate the independent factors predicting response.
Results: Eighty patients were included; the median survival time (MST) was 22.1 months. Partial response (PR) to IC was an independent prognostic factor for overall survival. For patients in the PR and stable disease groups, the MST was 36.7 and 19.5 months, respectively. The independent predictors of PR to IC included classification as stage N3 cancer, baseline carcinoembryonic antigen (CEA) levels >10 ng/ml, and cytokeratin fragment 19 (CYFRA21-1) levels >6 ng/ml. With each additional independent predictor, the likelihood of having have PR to IC increased.
Conclusions: Radiotherapy with induction and concurrent PP/DP chemotherapy is feasible for patients with unresectable Stage III NSCLC. IC may improve the survival of IC responders, as predicted by elevated CEA and CYFRA21-1 levels and classification as stage N3 cancer. Additional randomized trials on IC may consider these predictors to tailor individualized treatments.

Keywords: Carcinoembryonic antigen, cytokeratin fragment 19, induction chemotherapy, partial response, Stage III non-small-cell lung cancer


How to cite this article:
Li Q, Jiang M, Han X, Yang Z, Shu W, Ding X. Induction chemotherapy for unresectable Stage III non-small-cell lung cancer may improve survival of induction chemotherapy responders as predicted by elevated levels of carcinoembryonic antigen and cytokeratin fragment 19 and classification as stage N3 cancer. J Can Res Ther 2020;16:222-9

How to cite this URL:
Li Q, Jiang M, Han X, Yang Z, Shu W, Ding X. Induction chemotherapy for unresectable Stage III non-small-cell lung cancer may improve survival of induction chemotherapy responders as predicted by elevated levels of carcinoembryonic antigen and cytokeratin fragment 19 and classification as stage N3 cancer. J Can Res Ther [serial online] 2020 [cited 2020 Jul 12];16:222-9. Available from: http://www.cancerjournal.net/text.asp?2020/16/2/222/285197




 > Introduction Top


Lung cancer is the most commonly diagnosed cancer and the leading cause of cancer death worldwide. Non-small-cell lung cancer (NSCLC) accounts for approximately 85% of lung cancer cases; approximately one-third of the patients with NSCLC have unresectable stage III disease at diagnosis. For fit patients with unresectable stage III NSCLC, definitive concurrent chemoradiotherapy followed by consolidation therapy with durvalumab is the current standard of care.[1] However, durvalumab was not used in our study as progression-free survival (PFS) and overall survival (OS) rates with c NSCLC were published in 2017 and 2018, respectively, and the enrollment period for our study ended in February 2018. However, durvalumab is not routinely used in China due to its high cost. The inclusion of induction chemotherapy (IC) with concurrent chemoradiotherapy provided no survival benefit over concurrent chemoradiotherapy alone for unresectable Stage III NSCLC.[2],[3],[4] However, pemetrexed or docetaxel can be administered in combination with cisplatin and radiotherapy to avoid compromising activity against metastases, while optimizing local control. Moreover, gross tumor volume (GTV) reduction before radiotherapy in chemotherapy responders is associated with reduced lung injury and increased tumor dose. IC can also prevent delays in treatment and unsuitable radiotherapy if the sites of potential metastatic disease are not known. Accordingly, we aimed to investigate patients with unresectable Stage III NSCLC receiving radiotherapy with induction and concurrent pemetrexed or docetaxel plus cisplatin (PP/DP) chemotherapy and to identify the subgroup most likely benefit from IC.


 > Subjects and Methods Top


Study patients

Patients with newly diagnosed unresectable Stage III NSCLC at our institution between August 2012 and February 2018 were eligible. The stage was classified according to the 8th edition of the TNM classification for NSCLC at the time of data analysis. Other eligibility criteria included: An Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1; normal renal, hepatic and hematologic functions; and no functional or anatomical contraindication to chest irradiation. Patients who presented with active uncontrolled infection, unstable cardiovascular disease, peripheral neuropathy (Grade 1 or higher), psychiatric or neurologic disorders, previous malignancy (except for in situ carcinoma of the cervix or basocellular skin cancer), auditive impairment contra-indicating cisplatin administration or any other serious medical or psychiatric illnesses were excluded. This study was conducted in accordance with the amended Declaration of Helsinki. The ethics committee of our institution approved the protocol. Informed consent was obtained from every subject. As part of their initial staging, the history of all patients was recorded, and they underwent physical examination, complete blood sampling, electrocardiogram, pulmonary function tests, chest computed tomography (CT) with contrast, abdominal CT or ultrasound, brain magnetic resonance imaging, bone scan, and bronchoscopy (with biopsy, transbronchial needle aspiration, or image-guided needle core biopsy). Neither mediastinoscopy nor positron emission tomography CT was mandatory. Blood counts were performed weekly. Blood chemistries and clinical examinations were repeated before each new course. The response was assessed with CT after IC and 1–2 months after treatment completion. Patients were followed up every 3 months for the 1st year, twice a year for the following 2 years and yearly thereafter. All patients were evaluated with a physical examination, complete blood count, serum biochemical analysis, chest CT scan, abdominal CT scan or ultrasound, and any other necessary examinations depending on the patient's symptoms. Sites of relapse were determined either radiologically or histologically.

Study design and treatment

Patients received two cycles of IC followed by concurrent chemoradiotherapy. IC regimens included: 25 mg/m2 of cisplatin on days 1–3 and 75 mg/m2 of docetaxel on day 1 and then every 21 days; and 25 mg/m2 of cisplatin on days 1–3 and 500 mg/m2 of pemetrexed on day 1 and then every 21 days for nonsquamous NSCLC. Concurrent chemotherapy regimens included: 20 mg/m2 of cisplatin and 20 mg/m2 of docetaxel weekly; and 25 mg/m2 of cisplatin on days 1–3 and 500 mg/m2 of pemetrexed on day 1 and then every 21 days for nonsquamous NSCLC for two cycles. Courses were repeated when the hematological, hepatic, and renal functions had recovered. If not, the patient went off chemotherapy.

Three-dimensional conformal or intensity-modulated radiotherapy was administered using a linear accelerator with energy of 6 MV or more, at 2 Gy per fraction and 5 fractions per week, to a total dose of 60–66 Gy. The simulation was performed using CT scans obtained in the supine position with appropriate immobilization devices. Treatment planning should have considered anatomical regions with the macroscopic malignant disease and safety margins for c. The GTV comprised the known extent of the disease (primary and nodal) on imaging and pathologic assessment. In patients who responded to IC, GTV was defined as the post-induction therapy volume in the lungs and initially involved nodal regions. The clinical target volume encompassed the regions of presumed microscopic extent or dissemination. The planning target volume included the internal target volume with a margin for target motion during breathing and a setup margin for positioning and mechanical variability. The maximum dose to any point in the spinal cord could not exceed 46 Gy. Dose-volume histograms were used to prevent pulmonary toxicity. V20 (total pulmonary volume receiving 20 Gy) and V30 (total pulmonary volume receiving 30 Gy) could be inferior to or equal to 28% and 20% of the total pulmonary volume, respectively.

Assessments

Objective tumor responses were assessed by the Response Evaluation Criteria in Solid Tumors (version 1.1).[5] Toxicities were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (Version 4.0).[6]

Statistical analyses

OS was defined from the day of the initial dose of chemotherapy to the day of death (from any cause) or the last follow-up. PFS was defined from the day of the initial dose of chemotherapy to the day of the earliest event of death, tumor progression, or the last follow-up. The Chi-square test was used to assess the differences in the distribution of baseline characteristics among groups and the correlation between variables; the Kaplan–Meier method was used to calculate survival; the log-rank test was used to analyze differences among groups; univariate and multivariate Cox regression analyses were used to evaluate potential prognostic factors for survival. Univariable logistic regression analyses and correlation statistics were performed to select candidate predictors for each endpoint that were significantly associated with the endpoints in univariable analysis (P < 0.10), but were not mutually correlated. A stepwise backward multivariable logistic regression procedure was used to evaluate predictors. A receiver operating characteristic (ROC) curve was made to assess independent factors predicting the outcome; an estimation of the area under the curve (AUC), sensitivity, and specificity of the optimal cutoff value (calculated by the Youden index) were also assessed. In line with the current statistical consensus, an AUC of 0.8–0.9 was considered very good, 0.7–0.8 was adequate, and <0.7 was poor in terms of the accuracy of the test under consideration. All statistical tests were two-tailed; P < 0.05 were considered statistically significant. The Statistical Package for the Social Sciences version 18.0 software (SPSS, Inc., Chicago, IL, USA) was used for all statistical analyses.


 > Results Top


Among the 84 patients included in the study, four were excluded due to incomplete relapse pattern data. Therefore, 80 patients were analyzed. The patients' characteristics are presented in [Table 1]. The median follow-up time was 26.4 months (range, 14.2–59.7 months) for survivors. The median age of the patients was 61 years (range, 38–77 years). Adenocarcinoma (46.3%) and squamous cell carcinoma (53.8%) almost accounted for half, respectively. There were 31 (38.8%) stage IIIA patients, 35 (43.8%) stage IIIB patients, and 14 (17.5%) stage IIIC patients.
Table 1: Patient characteristics

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For all patients, the median survival time (MST) was 22.1 months. The 1- and 3-year OS rates were 85.0% and 29.8%, respectively, and the corresponding PFS rates were 63.8% and 13.5%. Thirty-one (38.8%) patients had a partial response (PR), while 49 (61.3%) had stable disease (SD) after IC. After radiotherapy, 75 (93.8%) patients achieved PR, while 5 (6.2%) remained with SD All of the patients received the planned IC. Seventy-three (91.3%) patients had a radiotherapy dose of 60–66 Gy, while 7 (8.8%) patients had a dose of 50–58 Gy. Fifty-seven (71.2%) patients completed their concurrent chemotherapy, whereas 23 (28.8%) did not due to treatment-related toxicities at the discretion of the radiation oncologists. Grade 3 neutropenia occurred in 3.8% of all patients, while Grade 3/4 thrombocytopenia occurred in 3.5%, and Grade 3 pneumonitis occurred in 5%. No treatment-related deaths occurred.

Results of the univariate and multivariate Cox regression analyses of the potential prognostic factors for OS are shown in [Table 2]. In the univariate analysis, the following factors were significantly positive prognostic factors for OS: being female (P = 0.039), having a negative smoking history (P = 0.008), having a baseline serum carcinoembryonic antigen (CEA) level >10 ng/ml (P = 0.016), and having a PR to IC (P = 0.003). Adenocarcinoma (P = 0.054) was marginally associated with a higher OS. However, sex, age, ECOG performance status, comorbidity, tumor stage, nodal stage, stage, laterality, lobe location of the primary tumor, baseline hemoglobin, cytokeratin fragment 19 (CYFRA21-1) level, and the sum of the longest diameter were not prognostic factors. In the multivariate analysis, PR to IC (P = 0.006) was an independent prognostic factor for OS. Smoking history (P = 0.055) was a potential prognostic factor. The remaining factors were not significantly associated with OS.
Table 2: Results of univariate and multivariate analyses of prognostic factors for overall survival

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For patients in the groups of PR and SD to IC, the MSTs were 36.7 and 19.5 months, respectively. The 1- and 3-year OS rates were 87.1% and 50.6%, respectively, in the PR group, which were significantly higher than the rates in the SD group [83.7% and 17.4%, P = 0.003; [Figure 1]a. The 1- and 3-year PFS rates were 74.2% and 16.8% in the PR group and 57.1% and 11.1% in the SD group, respectively. The difference in the PFS rates between the two groups trended toward significance [P = 0.079, [Figure 1]b.
Figure 1: Comparison of overall survival (a) and progression-free survival (b) between the patients who had a partial response to induction chemotherapy and those who had stable disease despite induction chemotherapy

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Patients with PR to IC were more likely to have adenocarcinomas (64.5% vs. 34.7%, P = 0.009) and be classified as stage N3 (48.4% vs. 22.4%, (P = 0.016) than those with SD Patients with baseline serum CEA levels >10 ng/ml (51.6% vs. 18.4%, P = 0.002), CYFRA21-1 levels >6 ng/ml (58.1% vs. 34.7%, P = 0.040) or the sum of the longest diameter >8 cm (64.5% vs. 38.8%, P = 0.025) were more prevalent in the PR group than in the SD group. The remaining listed characteristics were comparable between the two groups [Table 1].

Results of the univariate and multivariate logistic regression analyses of the predictive factors for response to IC are shown in [Table 3]. In the univariate analysis, adenocarcinoma (P = 0.010), stage N3 (P = 0.018), baseline CEA levels >10 ng/ml (P = 0.003), CYFRA21-1 levels >6 ng/ml (P = 0.042) and the sum of the longest diameter >8 cm (P = 0.027) were significantly positive predictors for PR to IC. In the multivariate analysis, stage N3 (P = 0.030) cancer, baseline CEA levels >10 ng/ml (P = 0.003), and CYFRA21-1 levels >6 ng/ml (P = 0.033) were independent predictors for PR to IC. The remaining factors were not significantly associated with response to IC.
Table 3: Results of univariate and multivariate analyses of predictive factors for response to induction chemotherapy

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To understand the clinical applications, ROC curve analyses were made according to the number of the independent predictors associated with a patient, for the independent factors predicting SD or PR to IC, with an intermediate accuracy [AUC = 0.755, P = 0.000, [Figure 2]. With each additional independent predictor, the patients became more likely to have PR to IC.
Figure 2: Receiver operating characteristic curve for the number of the independent factors to predict the response to induction chemotherapy

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 > Discussion Top


We observed that the 1- and 3-year OS rates were 85.0% and 29.8%, respectively; these rates are quite good for unresectable stage III NSCLC with manageable toxicity. Our results are comparable to those obtained from other studies of IC involving unresectable stage III NSCLC, published after 2010.[4],[7],[8],[9],[10],[11],[12],[13],[14],[15],[16] They are heterogeneous in terms of chemotherapy regimens, 1 using cisplatin and pemetrexed, and 2 cisplatin and docetaxel. The heterogeneity of the regimens makes the comparison difficult. The key is to find the regimen which best establishes local control and eradicates potential distant metastases while avoiding excessive toxicities. A decade ago, two randomized Phase III trials failed to prove that there is a survival advantage for IC when followed by concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone. There was a median OS in comparator arms of 12 and 14 months in the Vokes study, and 12.6 and 18.2 months in the Kim study, respectively.[2],[3] However, in a recent Phase II trial of pemetrexed and cisplatin with concurrent thoracic radiation after pemetrexed and cisplatin IC in patients with unresectable locally advanced nonsquamous NSCLC, there was a median PFS of 10.6 months and a median OS of 26.2 months.[11] In a recently published Phase III randomized study, concomitant chemoradiotherapy using cisplatin and docetaxel as either induction or consolidation treatment in patients with locally advanced unresectable NSCLC, mature survival results showed no significant difference between the modalities. There was a median OS of 19.6 and 18.3 months, a 2-year OS of 44% and 44%, and a 5-year OS of 23% and 26% for the induction and consolidation groups, respectively.[10] Along with our study, the prolonged survival in these studies may be due to the different chemotherapy regimens or the more advanced radiotherapy technologies and salvation treatments.

IC has the potential to eliminate subclinical distant metastases and reduce GTV, lessening radiation-associated lung injury, and escalating tumor dose. Further, IC may help characterize uncertain metastatic diseases through dynamic observation and initiate prompt treatment in busy radiotherapy centers. In our study, PR to IC was an independent prognostic factor for OS. The MST of the PR group was significantly longer than that of the SD group. The 1- and 3-year OS rates in the PR group were significantly higher than the rates in the SD group. We noticed that patients with PR to IC were more likely to have adenocarcinomas and be classified as having stage N3 cancer than those with SD Patients with who had baseline serum CEA levels >10 ng/ml, CYFRA21-1 levels >6 ng/ml or sum of the longest diameter >8 cm were more prevalent in the PR group than SD group. High levels of CEA and CYFRA21-1 are prognostic factors,[17],[18],[19],[20],[21] and predictive factors for the efficacy of chemotherapy[18],[19],[21],[22],[23] or immunotherapy[24] in NSCLC patients. Patients with PR to IC had more negative prognostic factors than those with SD; nevertheless, they had a longer OS, which implies that patients who are IC responders with stage III NSCLC could benefit more from IC.

Multivariate analysis revealed that classification as stage N3 and higher baseline CEA and CYFRA21-1 levels were independent predictors for PR to IC. In addition, ROC curve analyses confirmed that if a patient has more of these independent predictors, they are more likely to have PR after IC. It is likely that unresectable stage III NSCLC patients with these independent predictors consequently had better survival with IC.

We are thefirst to find that IC for unresectable stage III NSCLC improved survival of IC responders, as predicted by elevated levels of CEA and CYFRA21-1 and classification as stage N3. Nevertheless, our study has some limitations. First, it is a single-institution observational analysis. The study may have selection bias and the results should be interpreted cautiously. Second, our sample size is relatively small. However, the high follow-up rate of 80 out of a total of 84 consecutively treated patients assures that the patients we analyzed are highly representative of the patients with unresectable stage III NSCLC at our institution. Moreover, a longer follow-up time may have made these results more conclusive.

Our study demonstrated the feasibility of using radiotherapy w induction and concurrent PP/DP chemotherapy for patients with unresectable stage III NSCLC. IC may improve the survival of IC responders, as predicted by elevated CEA and CYFRA21-1 levels and classification as stage N3 cancer. Further randomized trials on IC may consider these predictors to tailor individualized treatments.

Acknowledgments

This work was supported by the Natural Science Foundation of Shandong Province, China (ZR2014HP042). The funders had no role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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