| BackgroundLung cancer is the most common malignant tumor,and its morbidity and mortality rate rank first among malignant tumors,which seriously threaten human health.Non-small lung cancer(NSCLC)and small cell lung cancer(SCLC)are the two main types of lung cancer.The proportion of SCLC in lung cancer has dropped from 17-20%in the late 1980s to 13-15%now.Despite the decline in incidence,SCLC remains the seventh most common cause of cancer-related deaths in the United States.SCLC is highly malignant,easily metastasized,and has a poor prognosis.From 1973 to 2002,the 5-year survival rate of SCLC only increased from 4.3%to 6.3%.With the development of radiotherapy,immunotherapy and anti-angiogenesis therapy,the therapeutic effect of SCLC has improved.The initial treatment of limited-stage SCLC is cisplatin or carboplatin combined with etoposide chemotherapy and concurrent chest radiotherapy,and patients whose curative effect reaches CR/PR are treated with prophylactic cranial irradiation,which can reduce the rate of intracranial recurrence and improve the overall survival rate.The initial treatment of extensive-stage SCLC was 4 cycles of atezolizumab or durvalumab combined with etoposide+cisplatin or carboplatin,followed by immunotherapy for maintenance.Some patients whose chemotherapy efficacy reached CR/PR,chest palliative radiotherapy was applied,which could reduce the risk of chest recurrence and improve the survival rate.Second-line treatment of SCLC recommends topotecan,irinotecan,docetaxel and other chemotherapy drugs.The third-line treatment of SCLC recommends PD-1 antibodies pembrolizumab,nivolumab,and anti-tumor angiogenesis drug anlotinib.However,the prognosis of SCLC is still not satisfactory.Most patients develop relapse and drug resistance soon after first-line treatment.At present,clinicians can only make a rough judgment on the prognosis by tumor staging.Therefore,it is a meaningful work to explore prognostic-related biomarkers,which can help identify patient subgroups and guide clinicians to choose more personalized treatments.This may improve the prognosis.Nutrition,immune and inflammatory status will affect the prognosis of tumors.It is necessary to explore a potential biomarker that responds to nutrition,immune and inflammatory status,and evaluate whether it has the potential to become a prognostic factor for SCLC.Hemoglobin,albumin,neutrophil count,lymphocyte count and platelet count can reflect the body’s nutritional,immune and inflammatory status.Anemia caused by a drop in hemoglobin can lead to hypoxia in tumor cells.Studies have shown that anemia increases the risk of death for patients with lung cancer,head and neck tumors,prostate cancer and lymphoma.The level of hemoglobin affects the oxygenation level of the tumor,which in turn affects the therapeutic effect and prognosis.Albumin reflects the nutritional status of the body,and hypoalbuminemia is associated with high tumor recurrence rate and short OS.Lymphocytes are involved in tumor recognition and clearance,and lymphopenia is a manifestation of immunosuppression.A number of studies have found that lymphopenia is associated with a shorter survival time for cancer patients.Neutrophils have anti-cancer effects as well as cancer-promoting effects.Neutrophils play an antitumor role mainly by releasing Reactive oxygen species(ROS)and Tumor necrosis factor α(TNFα),and they can also release soluble neutrophils granulosin to promote Tumor progression,metastasis and Tumor angiogenesis.Neutrophils play a complicated role in tumorigenesis and development,and elevated neutrophil counts may be related to the shorter survival time of tumor patients.During the occurrence and development of tumors,platelets release platelet particles to stimulate tumor cell proliferation.A number of studies have shown that platelets and platelet particles have the ability to deliver a variety of pro-angiogenic factors to tumors,and can stimulate tumor cells to express pro-angiogenic factors.In the process of tumor metastasis,platelets can form a "coat" that wraps the tumor cells to protect them from immune surveillance and avoid normal immune responses or natural killer cells.Studies have shown that elevated platelet counts are related to tumor resistance to chemotherapy.Therefore,platelets play an important role in tumor growth,metastasis,tumor angiogenesis,and drug resistance.Increased platelet counts are related to the shorter survival period of many tumors.Hemoglobin,albumin,lymphocytes,neutrophils,and platelets play important roles in the occurrence and development of tumors,but the mechanism is complicated.If one of the above indicators is used alone,it will be interfered by many other factors,and it is difficult to objectively reflect the body’s nutrition,inflammation and immune status.Some studies have combined the above indicators and obtained some new indicators through formulaic calculations,which can comprehensively reflect the body’ s nutrition,inflammation and immune status,such as neutrophil to lymphocyte ratio(NLR),platelet-to-lymphocyte ratio(PLR),hemoglobin,albumin,lymphocyte and platelet score(HALP),etc.At present,NLR,PLR and HALP have been used to predict the prognosis of many tumors.Research ObjectiveThis research aims to study the relationship between HALP,NLR,PLR and the clinicopathological characteristics and prognosis of small cell lung cancer,and to explore whether HALP,NLR and PLR can be used as biomarkers to predict the prognosis of SCLC.Materials and MethodsThe first part of the paper retrospectively analyzed 335 cases of small cell lung cancer patients diagnosed in Shandong Provincial Hospital between January 1,2016 and August 7,2018.Collect data such as gender,age,smoking history,drinking history,ECOG score,BMI,tumor stage,and whether to receive radiotherapy.The values of hemoglobin,plasma albumin,lymphocytes,platelets and neutrophils were collected.The HALP,NLR and PLR values are calculated according to the formula.Follow up regularly to obtain PFS data and survival data.X-tile software version 3.6.1 was used to calculate the best cut-off values for HALP,NLR and PLR scores.Kaplan-Meier survival analysis was used for univariate survival analysis.Log-Rank test was used for survival analysis between different groups.Multivariate analysis explored independent prognostic factors of SCLC.The independent prognostic factors in multivariate analysis are analyzed by ROC curve to explore variable combinations with better prognostic value.The second part of the paper retrospectively analyzed 71 cases of patients with extensive-stage small cell lung cancer newly diagnosed in Shandong Provincial Hospital,Qianfoshan Hospital of Shandong Province and Peking University Third Hospital between October 1,2019 and August 30,2020.All patients received first-line chemotherapy+immunotherapy.Gender,age,smoking history,alcohol consumption history,ECOG score,BMI,PD-L1 status and other data were collected.The values of hemoglobin,plasma albumin,lymphocytes,platelets and neutrophils were collected.The HALP,NLR and PLR values are calculated according to the formula.Regular follow-ups are performed to obtain PFS data of patients with first-line chemotherapy+immunotherapy.X-tile software version 3.6.1 was used to calculate the best cut-off values for HALP,NLR and PLR scores.Kaplan-Meier survival analysis was used for univariate survival analysis,and Log-Rank test was used for survival analysis between different groups.Multivariate analysis explored independent prognostic factors of SCLC.Research ResultsAccording to the first part of the study,the median follow-up time as of the last follow-up was 27.1 months(range:0.5-46.2 months).208 patients(62.1%)died.The 1-year and 2-year survival rates were 72.9%and 38.9%among 335 patients.According to the HALP,NLR and PLR values and survival time,the cut-off values of HALP,NLR and PLR score calculated by X-tile version 3.6.1 are 18.6,2.4 and 191.6 respectively.Groups are grouped according to cut-off values.Chi-square test showed that there were significant differences in BMI score and PS score between high HALP and low HALP groups.There were no statistically significant differences in tumor stage and age among the groups.Kaplan-Meier univariate survival analysis showed that low HALP,high NLR,high PLR,male,history of smoking,extensive disease(ED),and no radiation therapy were associated with shorter OS,and there were no statistically significant differences in BMI score,PS score,age,and history of alcohol consumption with OS.The median OS of the low HALP and high HALP,low NLR and high NLR,and low PLR and high PLR groups were 16.2 months vs 19.5 months,23.3 months vs 16.5 months,and 19.7 months vs 16.4 months.COX multiple regression analysis showed that HALP,NLR,tumor stage and gender were independent prognostic factors for survival time of SCLC.Factors associated with shorter OS are low HALP(HR=1.555,95%CI:1.060-2.281,P=0.024),high NLR(HR=0.739,95%CI:0.552-0.988,P=0.042),extensive disease(HR=1.839,95%CI:1.397-2.420,P<0.001)and male(HR=0.700,95%CI:0.493-0.993,P=0.046).The results of ROC curve analysis showed that the AUC values of tumor staging,HALP+staging combination and NLR+gender combination were 0.604,0.616 and 0.589,and there were significant statistical differences compared with AUC 0.5.Therefore,Tumor stage,HALP+stage combination and NLR+gender combination are valuable prognostic predictors of SCLC.The AUC values of HALP,NLR and sex were all greater than 0.5,so they also had a certain prognostic value.A subgroup analysis of 194 limited-stage SCLC patients was performed.Kaplan-Meier univariate survival analysis showed that low HALP,high NLR,no radiotherapy,and BMI<24 were associated with shorter OS.COX multiple regression analysis showed that HALP and radiotherapy are independent prognostic factors for survival time of limited-stage SCLC.Factors associated with shorter OS are low HALP and no radiotherapy.A subgroup analysis was performed on 141 patients with extensive-stage SCLC.Kaplan-Meier univariate survival analysis showed that not receiving radiotherapy was associated with shorter OS.COX multiple regression analysis showed that radiotherapy is an independent prognostic factor for the survival time of extensive SCLC.The factor associated with shorter OS is no radiotherapy.According to the values of HALP,NLR and PLR and PFS of first-line chemotherapy,the cut-off values of HALP,NLR and PLR scores calculated by X-tile software version 3.6.1 were 20.2,4.2 and 213.6,respectively.Groups are grouped according to cut-off values.Chi-square test showed that there were no significant statistical differences between the groups in terms of tumor staging and radiotherapy.Kaplan-Meier univariate survival analysis showed that low HALP,high NLR,high PLR,BMI<24,and extensive disease(ED)were associated with shorter PFS.COX multiple regression analysis showed that HALP,NLR,and tumor staging were independent prognostic factors for PFS in the first-line chemotherapy of SCLC.The factors associated with shorter PFS are low HALP,high NLR,and extensive disease.A subgroup analysis of 194 limited-stage SCLC patients was performed.Kaplan-Meier univariate survival analysis showed that low HALP,high NLR,high PLR and BMI<24 were associated with shorter PFS.COX multiple regression analysis showed that HALP and NLR are independent prognostic factors for PFS in patients with limited-stage SCLC.The factors associated with a shorter PFS are low HALP and high NLR.A subgroup analysis was performed on 141 patients with extensive-stage SCLC.Kaplan-Meier univariate survival analysis showed that low HALP,high PLR,and no history of drinking were associated with shorter PFS.COX multiple regression analysis showed that HALP is an independent prognostic factor of PFS in patients with extensive SCLC.The factor associated with a shorter PFS is low HALP.The second part of the study showed that as of the last follow-up,the median follow-up time was 8.7 months(range:2.8-11.3 months).According to the values of HALP,NLR and PLR and PFS data,the cut-off values of HALP,NLR and PLR scores calculated by X-tile software version 3.6.1 were 25.0,4.0 and 186.3 respectively.Group according to the cut-off value.Chi-square test showed that age,gender,smoking history,drinking history,BMI score and PS score were not significantly different between NLR groups.Kaplan-Meier univariate survival analysis showed that lower HALP and higher NLR were associated with shorter PFS.Cox multiple regression analysis showed that NLR was an independent prognostic factor for PFS in patients with extensive SCLC who received first-line chemotherapy plus immunotherapy.The factor associated with shorter PFS was high NLR.Of the 71 patients with extensive stage SCLC,37 were examined for PD-L1,and 12 were positive for PD-L1(PD-L1 TPS≥1%).Kaplan-Meier univariate survival analysis showed no statistically significant difference in PFS between PD-L1 positive and PD-L1 negative groups.ConclusionsThis study preliminarily shows that HALP,NLR and PLR can reflect the body’s nutrition,inflammation and immune status.HALP and NLR are independent prognostic factors of SCLC OS and PFS.SCLC patients with high HALP and low NLR before treatment have longer first-line chemotherapy PFS and OS.PLR is not an independent prognostic factor for SCLC.Tumor staging has a high prognostic value.Combined with independent prognostic factors such as HALP,NLR and gender,it can improve the accuracy of SCLC prognosis prediction.Subgroup analysis showed that HALP was an independent prognostic factor for OS in patients with limited-stage SCLC,and higher pre-treatment HALP was associated with longer OS in patients with limited-stage SCLC.HALP and NLR were independent prognostic factors for PFS in patients with limited-stage SCLC,and higher HALP and lower NLR before treatment were associated with longer PFS in patients with limited-stage SCLC.HALP was an independent prognostic factor for PFS in patients with extensive-stage SCLC,and higher pre-treatment HALP was associated with longer PFS in patients with extensive-stage SCLC.Preliminary analysis of PFS in patients with extensive-stage SCLC who received chemotherapy and immunotherapy in the first line showed that NLR was an independent prognostic factor of PFS,and lower pre-treatment NLR was associated with longer PFS.NLR is expected to become a new biomarker for predicting the efficacy of immunotherapy. |
PDF Full Text Request