The Role And Potential Predictors Of Induction Chemotherapy For Unresectable Stage ? Non-small-cell Lung Cancer

SECTION1Induction Chemotherapy for Unresectable Stage ?Non-small-cell Lung Cancer May Improve Survival of Induction Chemotherapy-responders BackgroundLung cancer is currently the most commonly diagnosed cancer,ranking first in both morbidity and mortality.Non-small-cell lung cancer(NSCLC)accounts for about 85%of lung cancer,and approximately one-third of patients with NSCLC had unresectable disease at the time of diagnosis.For fit patients with stage ? non-small cell lung cancer(NSCLC),concurrent chemoradiotherapy followed by consolidation therapy with durvalumab is recommended.However,in clinical practice,patients with unresectable stage ? NSCLC usually have a large tumor burden,concurrent chemoradiotherapy may aggravate radioactive lung injury.In addition,retrospective analysis found that quite a few patients newly diagnosed as stage ? had undetected subclinical lesion,and these patients should be treated mainly with systemic therapy,so concurrent chemoradiotherapy was not appropriate.Moreover,due to the cost,durvalumab has not been widely used in China.Therefore,the mode of continuous PD-L1 immunotherapy with concurrent chemoradiotherapy is not suitable for all patients.In the clinical practice of the tumor Center of Shandong Provincial Hospital where ? work,quite a few patients with locally advanced non-small cell lung cancer with negative driver genes were treated with the mode of induction chemotherapy first,followed by concurrent chemoradiotherapy,which had also achieved good clinical results.The regimen of pemetrexed or docetaxel plus cisplatin is safe and effective for induction chemotherapy and is also the first-line regimen for concurrent chemotherapy.Induction chemotherapy can reduce tumor burden and gross tumor volume(GTV)before radiotherapy.Which helps reduce radiation lung damage and increases the radiation dose of the tumor.In addition,induction chemotherapy can effectively control potential subclinical lesions and optimize local tumor control.Furthermore,induction chemotherapy can increase the sensitivity of tumor tissues to radiotherapy and avoid inappropriate radiotherapy in the presence of subclinical lesions.All of this led us to study patients with unresectable stage ? non-small cell lung cancer.The preliminary plan of this study was to retrospectively analyze patients with stage ? non-small cell lung cancer admitted to the tumor Center of Shandong Provincial Hospital from 2012 to 2018.Evaluate the patients' efficacy and side effects to determine whether the patients could benefit from induction chemotherapy.ObjectiveThe purpose of this study was to evaluate the efficacy and side effects of induction chemotherapy with permetrexide or docetaxel combined with cisplatin by retrospectively analyzing the clinical data of some patients with stage III non-small cell lung cancer,and to evaluate whether the patients could benefit from induction chemotherapy.Methods1.Study objectsFrom August 2012 to February 2018,80 patients with unresectable stage ?non-small cell lung cancer admitted by the tumor Center of Shandong Provincial Hospital.2.Study designAll patients received 2 cycles of induction chemotherapy,followed by concurrent radiotherapy and chemotherapy,with a dose of 60-66 Gy.Induction chemotherapy regimen is cisplatin 25 mg/m2 on day 1-3,docetaxel 75 mg/m2 on day 1,repeated every 21 days;or cisplatin 25 mg/m2 on day 1-3,pemetrexed 500 mg/m2(for non-squamous cell cancer)on day 1,repeated every 21 days.Concurrent chemotherapy regimens include cisplatin 20 mg/m2 plus docetaxel 20 mg/m2 on day 1,repeated weekly;or cisplatin 25 mg/m2 on day 1-3,pemetrexed 500 mg/m2(non-squamous cell carcinoma)on day 1,repeated every 21 days,2 cycles.If there was an intolerable adverse reaction or other chemotherapy contraindications,the patient should stop chemoradiotherapy.After induction chemotherapy,patients received 3-dimensional conformal radiation therapy or intensity modulated radiation therapy.Conventional segmentation mode was used for radiotherapy,2Gy each fraction,5 fractions a week,and the total dose was 60-66Gy.Kaplan-meier survival curve was used to evaluate the survival of the patients.Log Rank method was used to analyze the differences among groups.ResultsA total of 80 patients were selected for retrospective analysis.The deadline for follow-up was May 19,2019.The shortest follow-up time was 14.2 months,and the longest follow-up time was 59.7 months.Of all patients,18(22.5%)patients did not progress by the end of follow-up,7(8.8%)patients progressed but still survived with tumor,and 55 patients(68.8%)died.The median survival time(MST)of all patients was 22.1 months.The 1-year and 3-year OS rates were 85.0%and 29.8%,respectively,and the 1-year and 3-year PFS rates were 63.8%and 13.5%.Response to induced chemotherapy was assessed as partial response(PR)being an independent prognostic factor for overall survival.31 patients(38.8%)were evaluated as partial remission(PR)after induction chemotherapy,and 49 patients(61.3%)were evaluated as stable disease(SD)after induction chemotherapy.After induction chemotherapy,the median survival time of the PR group and SD group were 36.7 months and 19.5 months,respectively.After concurrent chemoradiotherapy,75 patients(93.8%)achieved PR in efficacy evaluation,and 5 patients(6.2%)maintained SD.73 patients(91.3%)received 60-66 Gy radiotherapy,and 7 patients(8.8%)received 50-58 Gy radiotherapy.57 patients(71.2%)completed concurrent chemotherapy,while 23 patients(28.8%)failed to complete concurrent chemotherapy.In terms of safety evaluation,hematological toxicity was mainly manifested as bone marrow suppression,with grade 3 neutropenia accounted for 3.8%and grade 3 thrombocytopenia for 3.8%.Non-hematological toxicity was mainly radioactive lung injury,level 3 radioactive pneumonia accounted for 5%.No treatment-related deaths occurred.Univariate and multivariate Cox regression analysis were performed on the factors influencing the survival time of patients.Univariate analysis showed that women(p=0.039),negative smoking history(p=0.008),baseline serum carcinoembryonic antigen(CEA)>10 ng/ml(p=0.016)and the evaluation of the efficacy of induction chemotherapy as PR(p=0.003)were favorable predictors of survival time.In multivariate analysis,the evaluation of the efficacy of induction chemotherapy as PR(p=0.006)was an independent predictor of survival benefit.The median survival time of the subgroups evaluated for the efficacy of induction chemotherapy as PR and SD was 36.7 months and 19.5 months,respectively.The 1-year and 3-year OS rates in the PR group were 87.1%and 50.6%,respectively,which were higher than 83.7%and 17.4%in the SD group.The difference was statistically significant(p=0.003).In terms of the 1-year and 3-year PFS rates,the PR group was 74.2%and 16.8%,and the SD group was 57.1%and 11.1%.The difference in PFS rates between the two groups was not statistically significant(p=0.079).ConclusionOur study proved that for patients with unresectable stage ? non-small cell lung cancer,continuous concurrent chemoradiotherapy with induced chemotherapy is feasible.Patients with effective induction chemotherapy may receive additional survival benefits,and induction chemotherapy is safe.Therefore,the treatment model of this study can be used as one of the alternatives for patients with stage ?non-small cell lung cancer who are not resectable.And patients with effective induction chemotherapy are more likely to get survival benefits.SECTION2Preliminary Exploration of Potential Predictors of Induction Chemotherapy for Stage ? Non-small-cell Lung CancerBackgroundNon-small cell lung cancer(NSCLC)is one of the most common malignant tumors.For locally advanced non-small cell lung cancer,because of larger tumor size or involvement with important organ or lymph node metastasis,the side effects of concurrent chemoradiotherapy are relatively severe,and the incidence of radiation pneumonia,esophagitis or other related adverse events are relatively high.A considerable number of patients may be unable to complete adequate treatment or to benefit from treatment.Induction chemotherapy can effectively reduce tumor burden before radiotherapy and can control potential subclinical lesions.Therefore,for patients with stage ? unresectable non-small cell lung cancer,1-2 cycles of induction chemotherapy before concurrently chemoradiotherapy may be necessary.Our first part study had initially confirmed the feasibility of induction chemotherapy followed by concurrent chemoradiotherapy.Patients with effective induction chemotherapy may get additional survival benefits,and the safety and tolerability of induction chemotherapy is relatively good.After induction chemotherapy,the incidence of adverse events associated with concurrent chemoradiotherapy was reduced,which helped patients complete the entire treatment according to the expected treatment frequency and treatment intensity,thereby ensured the treatment effect.What's more,induction chemotherapy can assess the sensitivity of tumor to chemotherapy regimens and provide a reference for the selection of subsequent treatment options.Lighter concurrent chemoradiotherapy side effects are also helpful to improve patients'tolerance and adherence to treatment as they entered the post-treatment line.However,effective treatment is the prerequisite for patients to benefit from induced chemotherapy.Preliminary exploration has found that the efficacy evaluation of induced chemotherapy is PR as an independent predictor of survival benefit for patients.If patients have poor sensitivity to induced chemotherapy,or even progress in the disease after induced chemotherapy,they will not only fail to benefit from induced chemotherapy,but also miss the treatment opportunity,which will make the prognosis of patients worse.Therefore,in this era that emphasizes precision therapy,it is imperative to screen out the potential beneficiaries of induced chemotherapy.ObjectiveThe purpose of this part of the study was to analyze the patients who were more likely to benefit from induced chemotherapy through retrospective analysis of the treatment of patients with stage ? unresectable NSCLC,so as to preliminarily explore the possible benefit groups from induced chemotherapy.MethodsThe treatment process was the same as the first part.Logistic regression analysis was used to evaluate the factors affecting the efficacy of induced chemotherapy,and the factors that may affected the treatment results were initially screened out.The predictors were evaluated by ROC curve.ResultsUnivariate and multivariate logistic regression analyses were performed for predictors of efficacy of induced chemotherapy.In univariate analysis,adenocarcinoma(p=0.010),lymph node stage N3(p=0.018),baseline CEA>10 ng/ml(p=0.003),cyfra21-1>6 ng/ml(p=0.042),and the sum of tumor maximum diameter of>8 cm(p=0.027)were favorable predicators of induced chemotherapy efficacy.In the multivariate analysis,lymph node staging was N3(p=0.030),baseline CEA>10 ng/ml(p=0.003),and cyfra21-1>6 ng/ml(p=0.033)were independent predicators of the efficacy of induced chemotherapy.The remaining factors were not clearly related to the efficacy of induction chemotherapy.ROC curve was used to analyze the relationship between the number of independent predicators and the efficacy of induced chemotherapy(AUC=0.755,P=0.000).This suggests that it is valuable to use the number of independent prognostic factors to predict the efficacy of induced chemotherapy.The more independent predictors a patient has,the more likely he/she can benefit from induction chemotherapy.ConclusionLymph node staging was N3,Baseline CEA>10ng/ml and cytokeratin fragment 19(cyfra21-1)>6ng/ml were independent predictors of the efficacy of induced chemotherapy to achieve PR.The more patients possessed these three independent predictors,the more likely they were to obtain PR after induced chemotherapy.Patients with high baseline CEA,high CYFRA21-1,and N3 stage are more likely to benefit from induction chemotherapy.This group of people may be more inclined to induce chemotherapy when choosing a first-line treatment.Further study results required further randomized controlled trials,while special attention may be paid to subgroups with high baseline CEA,high CYFRA21-1,or stage N3,to achieve individualized precision therapy.