Edited by: Massimo Di Maio, University of Turin, Italy
Reviewed by: Janaki Deepak, University of Maryland, Baltimore, United States; Abrar Ahmed, Shanghai Jiao Tong University, China
This article was submitted to Thoracic Oncology, a section of the journal Frontiers in Oncology
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
香京julia种子在线播放
Lung cancer is one of the most common and fatal cancers worldwide (
In China, the incidence and mortality rates of lung cancer have increased markedly over the past decades and accounted for ~49.94 per 100,000 men and 23.89 per 100,000 women and 40.30 per 100,000 and 17.13 per 100,000 deaths in 2014 (
The purpose of palliative chemotherapy is to improve patient quality of life and increase the survival rate. Advanced non-small lung cancer patients are treated by either radiotherapy or palliative chemotherapy. Studies have reported that even with radiotherapy survival rates have not been significant (
Tumor markers are small circulating quantifiable molecules present in blood or tissue which are released by tumor cells or body immune cells in response to tumor growth (
Previous studies have reported an association between tumor markers and curative effect in patients with breast cancer, epithelial ovarian cancer, gastric cancer, pancreatic cancer, and colorectal cancer (
Jiangsu cancer hospital, also known as Jiangsu Institute of Cancer Research is founded in 1960 and located in Nanjing city, China. The Hospital has 1,161 open beds with 1,635 employees across 25 clinical and medical departments. In 2019, the medical oncology department of Hospital received over 4,874 patients, which present a monthly average of 406 patients.
A retrospective study was conducted between January 01, 2013, and March 29, 2019, under the approval of the research ethics committee of Jiangsu Cancer hospital (JSCH2019K-011). In this study, Medical records of 5,445 patients were succinctly reviewed and classified based on defined inclusion and exclusion criteria. The patient demographics, medical history, and physical examination, were verified before study entry. The patient medical record was collected until death, progression of cancer, and last medical fellow-up. The levels of CEA, CA125, CA19-9, AFP, NSE, CYFRA21-1, and CA15-3 were recorded at the baseline and at the start of six chemotherapy cycles. The flowchart and analysis are presented in
Procedural flowchart of the study.
The inclusion criteria of this study consisted of: (A) patients with histologically confirmed terminal stage IV NSCLC according to the TNM staging criteria set by the International Union Against Cancer (UICC) in 2009 (
Assay of tumor markers was performed by electrochemiluminescence (ECL) so as to determine the baseline levels of CEA, CA19-9, CA125, AFP, CYFRA21-1, and NSE and at the beginning of each chemo-cycle until the risk of progression. The levels were compared with the manufacturer cutoff levels of: CEA < 3.5 ng/ml, CA125 < 35 U/ml, CA19-9 < 39 U/ml, AFP < 10 ng/ml, NSE < 16.3 ng/ml, CYFRA21-1 3.3 ng/ml and CA15-3 < 30 U/mL. Serum levels above (high) the cutoff values indicated a positive outcome. Positive detection of all the tumor markers was considered in case of one or more serum marker levels were above the normal cutoff range.
The clinical outcomes were evaluated by progression free survival (PFS). PFS was an initial time of taking therapy to the tumor progression or death. The Curative response was measured by tomography accordingly to the Response Evaluation Criteria in Solid Tumor (RECIST) (
All patients received palliative chemotherapy and were divided into two groups to assess the effectiveness of the chemotherapy: (1) patients receiving 2-drugs (Combination of chemotherapy) as indicated in
Palliative chemotherapy regimens for advanced-stage NSCLC patients.
ETOPOSIDE + cisplatin | VP16 100 mg/m2, d1–3, Cis: 75 mg/m2, d1, q3w |
PEMETREXED DISODIUM + carboplatin | Pem 500 mg/m2, d1, Carbo AUC 5, d1, q3w |
PEMETREXED DISODIUM + irinotecan | Pem 500 mg/m2, d1, Iri 200 mg/m2, d1, q3w |
DOCETAXEL + cisplatin | Doc 60–75 mg/m2, d1, Cis 60–75 mg/m2, d1 |
GEMCITABINE + vinorelbine | Gem 1,000 mg/m2 d1, d8, Vin 25 mg/m2 d1, d8, q3w |
PACLITAXEL ALBUMIN + nedaplatin | Nab-Pac 125 mg/m2 d1, d8, Neda 80 mg/m2 d1, q3w |
DOCETAXEL + epirubicin | Doc 60–75 mg/m2, d1, Epi 60 mg/m2, d1 |
BLEOMYCIN HCL + CARBOPLATIN | Bleo 15 mg, d1–5,Carbo AUC 5 d1, q3w |
DOCETAXEL + oxaliplatin | Doc 60–75 mg/m2, d1, Oxol 120 mg/m2 d1, q3w |
ETOPOSIDE + lobaplatin | VP16 100 mg/m2*3 (d1–3), Lobaplatin 30 mg/m2 d1, q3w |
DISODIUM CANTHARIDINATE; PYRIDOXINE + pemetrexed | VP16 100 mg/m2, d1–3, Lobo 30 mg/m2, d1 |
PACLITAXEL ALBUMIN + cisplatin | Nab-Pac 125 mg/m2 d1, d8, Cis 60–75 mg/m2, q3w |
PEMETREXED + tegafur; gimeracil; oteracil | Pem 500 mg/m2 d1, Tegafur 50 mg Bid*14, q3w |
VINORELBINE TARTRATE + epirubicin | Vin 25 mg/m2 d1–3, Epi 60 mg/m2 d1, q3w |
Combination of chemotherapy plus anti-angiogenic agents' palliative chemotherapy-based regimens for advanced-stage NSCLC patients.
PEMETREXED DISODIUM + carboplatin + bevacizumab | Pem 500 mg/m2, Carbo AUC 5 *1, Bev 7.5 mg/kg d1, q3w |
DOCETAXEL + cisplatin + bevacizumab | Doc 60–75 mg/m2, d1, Cis 60–75 mg/m2 d1, Bev 7.5 mg/kg, d1, q3w |
PEMETREXED DISODIUM + carboplatin + gefitinib | Pem 500 mg/m2, d1, Carbo AUC 5, d1, Gefi 250 mg/day, unti PD, q3w |
PEMETREXED DISODIUM + carboplatin + osimertinib | Pem 500 mg/m2, d1, Carbo AUC 5, d1, Gefi 250 mg/day, unti PD, q3w |
DOCETAXEL + oxaliplatin + icotinib | Doc 60–75 mg/m2, d1, Oxol 120 mg/m2 d1, Icotinib 125 mg tid until PD, q3w |
Paclitaxel + carboplatin + bevacizumab | Pac 175 mg/m2, d1, Carbo AUC 5, d1, bev 7.5 mg/m2, d1, q3w |
Gemcitabine + cisplatin + bevacizumab | Gem 1,000 mg/m2 d1, d8, Carbo AUC 5, d1, bev 7.5 mg/m2, d1, q3w |
A standardized follow-up was received by all patients, for 2 years at an interval of 3 months, and 6 months, then 3 years and thereafter. On each cycle of follow-up, patients' physical examination, complete blood count (CBC), abdominal ultrasound, chest computed tomography (CT), and brain magnetic resonance imaging (MRI) were performed. Whenever possible local recurrence and distant metastases were also confirmed histologically.
All patients' medical record was analyzed using SPSS 24.0. The association between tumor markers and clinicopathological features were determined by Chi-square analysis. PFS distribution was estimated through Kaplan–Meier curves. The independent prognostic value of each tumor marker and clinicopathological features that highly affect the PFS was evaluated by Cox regression multivariate analysis. Change in the tumor marker levels and effectiveness of pre- and post-palliative chemotherapy were determined using Wilcoxon signed ranks test. And
The Baseline characteristics of the 278 advanced NSCLC patients are summarized in
Baseline characteristics of tumor markers parameters of advanced-stage NSCLC patients.
Age (Mean ± SD) years | (59.11 ± 10.39) | 0.994 | 0.950 | 0.810 | 0.632 | 0.989 | 0.316 | 0.381 | 0.942 | 0.993 | |||||||||||||||
<60 | 124 (44.6) | 31 (25.0) | 93 (75.0) | 61 (49.2) | 63 (50.8) | 98 (79.0) | 26 (21.0) | 116 (93.5) | 8 (6.5) | 59 (47.6) | 65 (52.4) | 49 (39.5) | 75 (60.5) | 44 (35.5) | 80 (64.5) | 124 (100) | |||||||||
≥60 | 154 (55.4) | 38 (24.7) | 116 (75.3) | 78 (50.6) | 76 (49.4) | 118 (76.6) | 36 (23.4) | 144 (93.5) | 10 (6.5) | 64 (41.6) | 90 (58.4) | 53 (34.4) | 101 (65.6) | 54 (35.1) | 100 (64.9) | 153 (99.3) | |||||||||
Gender | 0.357 | 0.678 | 0.528 | 0.955 | 0.555 | 0.451 | 0.017 | 0.893 | 0.352 | ||||||||||||||||
Male | 183 (65.8) | 44 (24.0) | 139 (76.0) | 89 (48.6) | 94 (51.4) | 142 (77.6) | 41 (22.4) | 170 (92.9) | 13 (7.1) | 78 (42.6) | 105 (57.4) | 58 (31.7) | 125 (68.3) | 64 (35.0) | 119 (65.0) | 183 (100) | |||||||||
Female | 95 (34.2) | 24 (26.3) | 70 (73.7) | 50 (52.6) | 45 (47.4) | 74 (77.9) | 21 (22.1) | 90 (94.7) | 5 (5.3) | 45 (47.4) | 50 (52.6) | 44 (46.3) | 51 (53.7) | 34 (35.8) | 61 (64.2) | 94 (99) | |||||||||
Smoking status | <0.0001 | 0.784 | 0.503 | 0.149 | 0.033 | 0.391 | 0.112 | 0.520 | 0.0001 | ||||||||||||||||
Non-smoker | 157 (56.5) | 42 (26.8) | 115 (73.2) | 82 (52.2) | 75 (47.8) | 127 (80.9) | 30 (19.1) | 151 (96.2) | 6 (3.8) | 68 (43.3) | 89 (56.7) | 640.84 | 93 (59.2) | 59 (37.6) | 98 (62.4) | 156 (99.3) | |||||||||
Smoker | 88 (31.7) | 15 (17.0) | 73 (83.0) | 40 (45.5) | 48 (54.5) | 65 (73.9) | 23 (26.1) | 80 (90.9) | 8 (9.1) | 35 (39.8) | 53 (60.2) | 28 (31.8) | 60 (68.2) | 26 (29.5) | 62 (70.5) | 88 (100) | |||||||||
Unknown | 33 (11.9) | 12 (36.4) | 21 (63.6) | 17 (51.5) | 16 (48.5) | 24 (72.7) | 9 (27.3) | 29 (87.9) | 4 (12.1) | 20 (60.6) | 13 (39.4) | 10 (30.3) | 23 (69.7) | 13 (39.4) | 20 (60.6) | 33 (100) | |||||||||
Metastasis | 0.015 | 0.018 | 0.118 | 0.934 | 0.766 | 0.965 | 0.095 | 0.081 | 0.015 | ||||||||||||||||
Yes | 194 (69.8) | 56 (28.9) | 138 (71.1) | 103 (53.1) | 91 (46.9) | 151 (77.8) | 43 (22.2) | 182 (93.8) | 12 (6.2) | 86 (44.3) | 108 (55.7) | 65 (33.5) | 129 (66.5) | 62 (32.0) | 132 (68.0) | 193 (99.48) | |||||||||
No | 84 (30.2) | 13 (15.5) | 71 (84.5) | 36 (42.9) | 48 (57.1) | 65 (77.4) | 19 (22.6) | 78 (92.9) | 6 (7.1) | 37 (44.0) | 47 (56.0) | 37 (44.0) | 47 (56.0) | 36 (42.9) | 48 (57.1) | 84 (95.45) | |||||||||
Differentiation | 0.001 | 0.801 | 0.090 | 0.865 | 0.210 | 0.222 | 0.556 | 0.377 | 0.0001 | ||||||||||||||||
Poor | 146 (52.5) | 36 (24.7) | 110 (75.3) | 79 (54.1) | 67 (45.9) | 113 (77.4) | 33 (22.6) | 139 (95.2) | 7 (4.8) | 59 (40.4) | 87 (59.6) | 52 (35.6) | 94 (64.4) | 55 (37.7) | 91 (62.3) | 145 (99.31) | |||||||||
Moderate | 42 (15.1) | 9 (21.4) | 33 (78.6) | 22 (52.4) | 20 (47.6) | 35 (83.3) | 7 (16.7) | 39 (92.9) | 3 (7.1) | 21 (50.0) | 21 (50.0) | 14 (33.3) | 28 (66.7) | 14 (33.3) | 28 (66.7) | 42 (100) | |||||||||
Unknown | 90 (32.4) | 24 (26.7) | 66 (73.3) | 38 (42.2) | 52 (57.8) | 68 (75.6) | 22 (24.4) | 82 (91.1) | 8 (8.9) | 43 (47.8) | 47 (52.2) | 36 (40.0) | 54 (60.0) | 29 (32.2) | 61 (67.8) | 90 (100) | |||||||||
Tumor | 0.152 | 0.213 | 0.063 | 0.670 | 0.890 | 0.786 | 0.088 | 0.413 | 0.155 | ||||||||||||||||
Squamous cell | 73 (26.3) | 23 (31.5) | 50 (68.5) | 30 (41.1) | 43 (58.9) | 58 (79.5) | 15 (20.5) | 69 (94.5) | 4 (5.5) | 32 (43.8) | 41 (56.2) | 34 (46.6) | 39 (53.4) | 25 (34.2) | 48 (65.5) | 73 (100) | |||||||||
Adenocarcinoma | 167 (60.1) | 36 (21.6) | 130 (77.8) | 87 (52.1) | 80 (47.9) | 129 (77.2) | 38 (22.8) | 155 (92.8) | 12 (7.2) | 73 (43.7) | 94 (56.3) | 55 (32.9) | 112 (67.1) | 56 (33.5) | 111 (66.5) | 166 (99.4) | |||||||||
Other | 38 (13.7) | 9 (23.7) | 29 (76.3) | 22 (57.9) | 16 (42.1) | 29 (76.3) | 9 (23.7) | 36 (94.7) | 2 (5.3) | 18 (47.4) | 20 (52.6) | 13 (34.2) | 25 (65.8) | 17 (44.7) | 21 (55.3) | 38 (100) | |||||||||
Drug | 0.644 | 0.080 | 1.00 | 0.243 | 0.901 | 0.038 | 0.818 | 0.159 | 0.646 | ||||||||||||||||
2-Drugs | 166 (59.7) | 35 (21.1) | 131 (78.9) | 83 (50.0) | 83 (50.0) | 125 (75.3) | 41 (24.7) | 155 (93.4) | 11 (6.6) | 65 (39.2) | 101 (60.8) | 60 (36.1) | 106 (63.9) | 53 (31.9) | 113 (68.1) | 166 (100) | |||||||||
3-Drugs | 112 (40.3) | 34 (30.4) | 78 (69.6) | 56 (50) | 56 (50) | 91 (81.3) | 21 (18.7) | 105 (93.8) | 7 (6.3) | 58 (51.8) | 54 (48.2) | 42 (37.5) | 70 (62.5) | 45 (40.2) | 67 (59.8) | 111 (99.1) | |||||||||
Response of therapy | 0.012 | 0.969 | 0.164 | 0.343 | 0.366 | 0.592 | 0.045 | 0.082 | 0.012 | ||||||||||||||||
CR (complete response) | 0 | ||||||||||||||||||||||||
PR + SD (stable disease) | 210 (75.5) | 52 (24.8) | 158 (75.2) | 110 (52.4) | 100 (47.6) | 166 (79) | 44 (20) | 198 (94.3) | 12 (5.7) | 91 (43.3) | 119 (56.7) | 84 (40.0) | 126 (60.0) | 80 (38.1) | 130 (61.9) | 209 (99.5) | |||||||||
PD (progressive disease) | 68 (24.5) | 17 (25.0) | 51 (75.0) | 29 (42.6) | 39 (57.4) | 50 (73.5) | 18 (26.5) | 62 (91.2) | 6 (8.8) | 32 (47.1) | 36 (52.9) | 18 (26.5) | 50 (73.5) | 18 (26.5) | 50 (73.5) | 68 (100) |
In the pre-treatment, patients with high levels of CEA, CA-125, CA-199 AFP, NSE, CYFRA21-1, and CA15-3 were as follows: 209 (75.18%), 139 (50%), 62 (22.30%), 18 (6.47 %), 155 (55.75%), 176 (63.30%), and 180 (64.74%), respectively. In
In this present study, the tumor was progressed in 68 out of 278 patients, 166 patients used 2-drugs, while 112 patients used 3-drugs, and their overall median of PFS was 5.9 (4.1–8.7) months. Patients with CEA (high vs. normal) levels had a median PFS of 4.7 (4.15–5.31;
Kaplan–Meier survival curve of four Tumor markers
Furthermore, to find the pivotal role of these tumor markers as independent prognostic factors of PFS for NSCLC, univariate, and multivariate analyses were carried out, as shown in
Univariate analysis of tumor markers for progression free survival using Cox regression model in advanced-stage NSCLC patients.
<60 | 2.662 (1.464–4.842) | 0.001 | 3.321 (1.995–5.530) | <0.0001 | 11.013 (4.768–25.439) | <0.0001 | 97.792 (12.014–796.013) | <0.0001 | 2.887 (1.695–4.918) | <0.0001 | 1.547 (0.977–2.450) | 0.063 | 1.034 (0.639–1.675) | 0.891 |
>60 | 3.469 (1.904–6.318) | <0.0001 | 4.593 (2.814–7.499) | <0.0001 | 12.019 (5.879–24.572) | <0.0001 | 1.000 (0.075–13.399) | 1.000 | 1.915 (1.247–2.940) | 0.003 | 1.360 (0.917–2.017) | 0.126 | 1.552 (1.006–2.393) | 0.047 |
Male | 3.399 (1.917–6.027) | <0.0001 | 3.737 (2.427–5.756) | <0.0001 | 12.183 (6.146–24.153) | <0.0001 | 180.730 (23.400-−1395.894) | <0.0001 | 2.104 (1.413–3.133) | <0.0001 | 1.527 (1.073–2.175) | 0.019 | 1.360 (0.923–2.004) | 0.119 |
Female | 2.594 (1.391–4.839) | 0.003 | 4.579 (2.491–8.419) | <0.0001 | 10.286 (4.134–25.593) | <0.0001 | 65.309 (7.237–589.403) | <0.0001 | 2.600 (1.414–4.780) | 0.002 | 1.294 (0.726–2.309) | 0.382 | 1.077 (0.610–1.900) | 0.799 |
Non-smoker | 2.567 (1.507–4.374) | 0.001 | 4.939 (3.061–7.969) | <0.0001 | 11.319 (5.355–23.925) | <0.0001 | 46.447 (8.351–258.316) | <0.0001 | 2.941 (1.862–4.644) | <0.0001 | 1.289 (0.847–1.963) | 0.236 | 1.419 (0.925–2.178) | 0.109 |
Smoker | 3.977 (1.889–8.36) | <0.0001 | 2.861 (1.527–5.360) | 0.001 | 6.007 (2.606–13.845) | <0.0001 | 170554.306 (0.0001–1.509E+45) | 0.797 | 1.622 (0.944–2.788) | 0.080 | 1.684 (1.005–2.821) | 0.048 | 1.275 (0.732–2.223) | 0.391 |
Unknown | 5.231 (0.692–39.598) | 0.109 | 3.394 (1.231–9.361) | 0.018 | 1129.174 (0.028–45709448.1) | 0.194 | 11248.858 (0.0001–3.731E+21) | 0.650 | 2.108 (0.593–7.497) | 0.249 | 1.198 (0.495–2.900) | 0.689 | 0.794 (0.299–2.111) | 0.644 |
Yes | 3.368 (2.068–5.486) | <0.0001 | 6.252 (3.859–10.130) | <0.0001 | 13.335 (6.805–26.133) | <0.0001 | 1.000 (0.072–13.794) | 1.000 | 2.304 (1.545–3.435) | <0.0001 | 1.378 (0.973–1.951) | 0.071 | 1.107 (0.764–1.602) | 0.592 |
No | 1.956 (0.845–4.526) | 0.117 | 2.007 (1.113–3.622) | 0.021 | 8.953 (3.517–22.791) | <0.0001 | 35.267 (4.042–307.693) | 0.001 | 2.150 (1.189–3.887) | 0.011 | 1.887 (1.041–3.421) | 0.037 | 1.905 (1.027–3.534) | 0.041 |
Poor | 2.310 (1.375–3.883) | 0.002 | 4.363 (2.546–7.479) | <0.0001 | 11.727 (5.406–25.441) | <0.0001 | 1.000 (0.020–50.669) | 1.000 | 2.103 (1.344–3.291) | 0.001 | 1.211 (0.800–1.832) | 0.366 | 1.698 (1.058–2.726) | 0.028 |
Moderate | 4.243 (1.284–14.020) | 0.018 | 3.920 (1.586–9.690) | 0.003 | 31.435 (2.743–360.219) | 0.006 | 161926.676 (0.0001–6.586E+68) | 0.872 | 2.165 (0.829–5.658) | 0.115 | 0.993 (0.457–2.158) | 0.986 | 1.105 (0.477–2.557) | 0.816 |
Unknown | 4.202 (1.672–10.558) | 0.002 | 3.575 (2.038–6.271) | <0.0001 | 12.361 (4.949–30.872) | <0.0001 | 63.787 (7.817–520.508) | <0.0001 | 2.493 (1.351–4.601) | 0.003 | 2.376 (1.372–4.116) | 0.002 | 1.183 (0.704–1.989) | 0.526 |
Squamous | 3.279 (1.288–8.347) | 0.013 | 5.359 (2.798–10.265) | <0.0001 | 15.383 (4.874–48.554) | <0.0001 | 46.186 (4.718–452.122) | 0.001 | 2.368 (1.246–4.500) | 0.008 | 2.831 (1.480–5.414) | 0.002 | 1.461 (0.811–2.634) | 0.207 |
Adenocarcinoma | 3.107 (1.810–5.332) | <0.0001 | 4.104 (2.548–6.610) | <0.0001 | 10.431 (5.245–20.748) | <0.0001 | 163.477 (20.983–1273.627) | <0.0001 | 2.478 (1.598–3.841) | <0.0001 | 1.069 (0.730–1.567) | 0.731 | 1.461 (0.973–2.194) | 0.067 |
Others | 2.678 (1.016–7.060) | 0.046 | 2.550 (0.914–7.116) | 0.074 | 9.735 (2.566–36.943) | 0.001 | 262777.899 (0.0001–3.364E+105) | 0.915 | 1.547 (0.620–3.860) | 0.350 | 1.118 (0.443–2.822) | 0.814 | 0.861 (0.278–2.673) | 0.796 |
2–Drugs | 2.483 (1.466–4.206) | 0.001 | 3.843 (2.450–6.027) | <0.0001 | 9.267 (4.840–17.743) | <0.0001 | 57.450 (12.335–267.582) | <0.0001 | 2.004 (1.340–2.999) | 0.001 | 1.666 (1.135–2.444) | 0.009 | 1.230 (0.834–1.815) | 0.297 |
3–Drugs | 3.836 (1.912–7.697) | <0.0001 | 4.273 (2.426–7.527) | <0.0001 | 13.035 (5.122–33.172) | <0.0001 | 1.000 (0.034–29.436) | 1.0000 | 2.667 (1.484–4.791) | 0.001 | 1.262 (0.779–2.046) | 0.344 | 1.256 (0.703–2.244) | 0.441 |
CR | 0 | |||||||||||||
PR + SD | 2.773 (1.714–4.485) | <0.0001 | 3.459 (2.302–5.199) | <0.0001 | 13.619 (7.235–25.637) | <0.0001 | 69.883 (15.263–319.972) | <0.0001 | 2.114 (1.444–3.095) | <0.0001 | 1.616 (1.133–2.305) | 0.008 | 1.545 (1.066–2.239) | 0.022 |
PD | 3.848 (1.632–9.074) | 0.002 | 6.023 (2.831–12.817) | <0.0001 | 7.073 (2.539–19.704) | <0.0001 | 1.000 (0.032–31.230) | 1.000 | 2.854 (1.434–5.681) | 0.003 | 1.198 (0.682–2.104) | 0.530 | 0.776 (0.400–1.507) | 0.455 |
Multivariate analysis of tumor markers for progression free survival using Cox regression model in advanced-stage NSCLC patients.
Age: <60 vs. >60 | 0.846 | (0.655–1.092) | 0.199 |
Sex: male vs. female | 0.863 | (0.612–1.218) | 0.401 |
Smoking: ever vs. never | 1.379 | (1.020–1.864) | 0.037 |
Unknown vs. never | 1.1651 | (0.786–1.727) | 0.447 |
Treatment: 2- vs. 3-Drugs | 1.183 | (0.898–1.557) | 0.231 |
Distant metastases: yes vs. no | 0.954 | (0.706–1.289) | 0.758 |
Tumor: squamous vs. adenocarcinoma | 0.650 | (0.380–1.110) | 0.114 |
Others vs. adenocarcinoma | 4.030 | (1.795–9.232) | 0.001 |
Differentiation: moderate vs. poor | 1.028 | (0.709–1.492) | 0.882 |
Unknown vs. poor | 1.043 | (0.730–1.492) | 0.816 |
CEA: ≤ 3.5 vs. >3.5 ng/ml | 0.851 | (0.632–1.145) | 0.286 |
CA125: ≤ 35 vs. >35 Uml | 0.955 | (0.724–1.261) | 0.747 |
CA19-9: ≤ 39 vs. >39 U/ml | 0.524 | (0.375–0.731) | <0.0001 |
AFP: <10 vs. >10 | 0.672 | (0.407–1.110) | 0.121 |
NSE: ≤ 15.2 vs. >15.2 ng/ml | 0.584 | (0.446–0.763) | <0.0001 |
CYFRA21-1: <3.3 vs. >3.3 | 1.454 | (1.098–1.926) | 0.009 |
CA15-3: <30 vs. >30 | 1.310 | (0.975–1.758) | 0.073 |
Curative response: PR + SD vs. PD | 0.886 | (0.644–1.217) | 0.454 |
Sex* Tumor (Squamous cells) | 1.227 | (0.671–2.244) | 0.507 |
Sex* Tumor (Others) | 0.336 | (0.132–0.853) | 0.022 |
In multivariable Cox regression model, smoking status (Ever vs. Never,
Prognostic values of all these tumor markers in advanced-stage NSCLC patients were evaluated in eight groups, i.e., (1) patients with one elevated tumor marker level, (2) patients with two elevated tumor markers levels, (3) patients with three elevated tumor markers levels, (4) patients with four elevated tumor markers levels, (5) patients with five elevated tumor markers levels, (6) patients with six elevated tumor marker levels, (7) patients with seven elevated tumor markers levels. However, only one patient found normal pre-treatment levels of all the seven tumor markers. On comparison of all the seven tumor markers, patients with six and seven were recorded shorter PFS compared to patients with normal pre-treatment levels (
Kaplan–Meier progression-free survival.
In this study166 (59.7%) patients were on a 2-drug regimen, while 112 (40.3%) received a 3-drug treatment regimen. These therapies (2-drugs and 3-drugs) were compared for progression free survival, and those on the 3-drugs regimen found to have better PFS compared to the ones receiving the 2-drugs treatment regimen (
In this study, 278 patients received palliative chemotherapy, and their clinical responses were recorded. None of the patients had fully recovered, while 43 patients achieved partial response (PR), 167 patients had stable disease (SD), and 68 patients had disease state progress (PD). Some patients had also experienced following side effects while receiving chemotherapy, i.e., alopecia, anorexia, nausea, vomiting. No patient death due to treatment was recorded.
Mean of the initial and final levels of the tumor markers were analyzed using Wilcoxon signed ranks test. The results revealed significant statistical Mean differences levels of CEA, CA-125, CA-199, AFP, and NSE (
Mean levels of seven tumor markers in pre- and post-palliative chemotherapy in advanced-stage NSCLC patients.
−2.352 |
−3.419 |
−2.272 |
−4.748 |
−2.513 |
−0.997 |
−0.490 |
|
0.019 | 0.001 | 0.023 | <0.0001 | 0.012 | 0.319 | 0.624 |
All the seven tumor marker levels were measured at baseline and after 6th cycle of palliative chemotherapy. When stratified the Mean levels of all tumor markers by the disease control group and the progression disease group, there were statistical significant decreasing of CEA (
Mean levels of serum tumor markers in pre-and post-palliative chemotherapy in DC group (CR + PR + SD) and PD group respectively, in advanced-stage NSCLC patients.
CR + SD + PR Z Asymp. Sig. (2-tailed) |
−3.517 |
−4.559 |
−1.435 |
−4.476 |
−1.897 |
−1.958 |
−0.779 |
0.000 | 0.000 | 0.151 | 0.000 | 0.050 | 0.050 | 0.436 | |
PD Z Asymp. Sig. (2-tailed) |
−1.265 |
−0.956 |
−1.983 |
−1.725 |
−1.752 |
−0.947 |
−0.633 |
0.206 | 0.339 | 0.047 | 0.084 | 0.080 | 0.344 | 0.527 |
In addition, when stratified by the progression disease group, there was statistical significant decrease of CA19-9 (
Furthermore, we also evaluated the response to therapy in patients receiving the two forms of palliative chemotherapy (i.e., 2-drugs or 3-drugs regiment). As evinced from
Comparing the clinical response of palliative chemotherapy (3-Drugs and 2-Drugs) in advanced-stage NSCLC patients.
3-Drugs Z Asymp. Sig. (2-tailed) |
−1.546 |
−2.622 |
−1.805 |
−4.807 |
−2.468 |
−2.021 |
−0.021 |
0.122 | 0.009 | 0.071 | 0.000 | 0.014 | 0.043 | 0.983 | |
2-Drugs Z Asymp. Sig. (2-tailed) |
−1.839 |
−2.170 |
−1.424 |
−1.365 |
−0.887 |
−0.866 |
−0.731 |
0.066 | 0.30 | 0.154 | 0.172 | 0.375 | 0.386 | 0.465 |
This retrospective study is one of the few studies that assess the clinical utility of tumor markers CEA, CA19-9, CA125, AFP, NSE, CA15-3, and CYFRA21-1 for prognostic specification as well as for measuring the response to chemotherapy. CEA is non-specific with an abnormal countenance in solid tumors including, non-small lung cancer. Moro et al. (
Previously, the role of CA125 as a prognostic marker was not well defined (
The prognostic value of AFP is already reported in several types of cancers (e.g., gastric cancer and ovarian cancer) (
The role of NSE as a tumor marker is widely accepted in small cell lung cancer (SCLC). However, its prognostic value is controversial in NSCLC (
CA15-3 is a mucin-1 soluble form that is associated with non-squamous carcinoma (
In the Kaplan–Meier survival curve, patients with 5-, 6-, or 7-elevated pre-treatment tumor markers have short PFS compared to those with 0, 1-, 2-, 3-, or 4-elevated pre-treatment tumor markers. Therefore, clinicians/oncologists should consider the detection of the combined tumor markers before prescribing the chemotherapy (
The association between tumor markers and curative effect has already been studied in breast cancer, colorectal cancer, gastric cancer, pancreatic cancer, and ovarian cancer, but limited clinical studies are available to identify the role of tumor markers and response to chemotherapy in advanced stage of NSCLC (
In the present study, we also compared the effectiveness of a 2- and 3-drugs combination therapy. Our results showed significant differences in the tumor marker levels of patients using 3-drugs than those on a 2-drugs therapy, as shown in
The limitation of this retrospective study is that the socio-demographic data may be subject to bias, especially for the classification of being smoker, considering the fact it was a self-report. Nonetheless, our findings require confirmation in additional large prospective studies.
The high levels of CYFRA21-1 were correlated with poor a prognostic factor of PFS for Advanced NSCLC patients. However, the high levels of CA19-9 and NSE were associated with a better prognostic factor of PFS. Additionally, smoking habits and tumor status had a poor prognostic factor of PFS. Moreover, we found that antiangiogenic therapy has high efficacy with combination of chemotherapy and longer PFS of NSCLC patients.
All datasets generated for this study are included in the article/supplementary material.
The studies involving human participants were reviewed and approved by the ethics research committee of Jiangsu Cancer hospital, Nanjing, China. The patients/participants provided their written informed consent to participate in this study.
MA and MS: conceptualization. MA: methodology and writing—original draft preparation. MA and SK: formal analysis. MA and XL: data curation. MA, SK, and MH: writing—review and editing. Z-CW, MS, YH, and H-LZ: supervision and project administration.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
We want to extend our appreciation to Large-scale Data Analysis Center of Cancer Precision Medicine-LinkDoc for clinical and pathological data collected.