Advanced Inoperable Non-small Cell Lung Research Articles

Consolidation Systemic Therapy in Locally Advanced, Inoperable Nonsmall Cell Lung Cancer-How to Identify Patients Which Can Benefit from It?

Consolidation systemic therapy (ST) given after concurrent radiotherapy (RT) and ST (RT-ST) is frequently practiced in locally advanced inoperable nonsmall cell lung cancer (NSCLC). Little is known, however, about the fate of patients achieving different responses after concurrent phases of the treatment. we searched the English-language literature to identify full-length articles on phase II and Phase III clinical studies employing consolidation ST after initial concurrent RT-ST. We sought information about response evaluation after the concurrent phase and the outcome of these patient subgroups, the patterns of failure per response achieved after the concurrent phase as well as the outcome of these subgroups after the consolidation phase. Eighty-seven articles have been initially identified, of which 20 studies were excluded for various reasons, leaving, therefore, a total of 67 studies for our analysis. Response evaluation after the concurrent phase was performed in 36 (54%) studies but in only 14 (21%) response data were provided, while in 34 (51%) studies patients underwent a consolidation phase regardless of the response. No study provided any outcome (survivals, patterns of failure) as per response achieved after the concurrent phase. Information regarding the outcome of subgroups of patients achieving different responses after the concurrent phase and before the administration of the consolidation phase is still lacking. This may negatively affect the decision-making process as it remains unknown which patients may preferentially benefit from the consolidation of ST.

Consolidation treatments after chemoradiotherapy in patients with locally advanced inoperable non-small cell lung cancer: a systematic review and network meta-analysis protocol

IntroductionConcurrent chemoradiotherapy (CCRT) is the standard of care for inoperable locally advanced non-small cell lung cancer. To further improve prognosis, the use of consolidation treatments after CCRT has been explored...

CLINICAL OUTCOME USING WEEKLY PACLITAXEL WITH RADIATION IN LOCALLY ADVANCED LUNG CANCER

Background: Non-small cell lung cancer is the second most common malignancy worldwide with very high mortality rate. The aim of this study is to evaluate the locoregional response and toxicity prole using weekly paclitaxel along with radiation in locally advanced inoperable non-small cell lung cancer in a tertiary care centre. A prospective analysis was Methods: carried out on non-metastatic locoregionally advanced non-small cell lung cancer patients who were treated in the Radiotherapy Department, Medical College, Kolkata from January 2014 to July 2015. The patients received concurrent chemoradiotherapy with weekly paclitaxel. Out of 54 patients Results: analysed, overall response rate was 81.48% and complete response rate was 12.96%. The progression free survival rate at 1 year was 41.30%. Median progression free survival was 10.00 ±0.40 months. The most common toxicities were acute pharyngeal and esophageal toxicity. The toxicity was acceptable and response was Conclusion: comparable with other platinum based concurrent chemoradiation regimens.

Predictors and Consequences of Refusing Recommended Radiation for Locally Advanced Inoperable Non-Small Cell Lung Cancer

<h3>Purpose/Objective(s)</h3> Definitive chemoradiation is standard-of-care treatment for locally advanced inoperable non-small cell lung cancer (NSCLC). However, some patients refuse radiation therapy (RT) and this information is captured in the National Cancer Database (NCDB). We sought to examine factors associated with patient refusal of RT recommended for clinical stage III NSCLC and to evaluate subsequent outcomes compared to standard treatment. <h3>Materials/Methods</h3> The NCDB (2004-2015) was queried for clinical stage III NSCLC patients who were recommended definitive chemoradiation. We then selected cases in which RT was given or was recommended but refused "by the patient, patient's family member or guardian." We excluded patients with: unknown treatment modality/sequence, those who did not undergo RT for unknown reasons, and those initially not recommended RT. Survival of patients who received RT vs. those who refused RT was compared using log rank test in Kaplan Meier curves. Univariate and multivariate Cox regression were performed to identify predictors of refusal of RT and relationships between each covariate and survival. <h3>Results</h3> We identified 147,314 patients recommended RT for clinical stage III NSCLC. 141,668 patients underwent definitive treatment with RT and 5,646 (3.8%) refused the recommended RT. On multivariate analysis, older age, female sex, lack of insurance or Medicare/Medicaid insurance, lower income, and higher comorbidity score all significantly predicted refusal of RT. 11.5% (n = 649) of the patients who refused RT were treated with chemotherapy alone. Median survival was significantly worse for patients who refused RT versus those who received RT (5.7 months vs 14.7 months, <i>P</i> < 0.0001) and refusal of RT was predictive of death (HR 1.63, <i>P</i> < 0.0001). 18.2% of patients who received RT were treated to a palliative dose, defined as ≤ 4500 cGY. < 1% of all patients received immunotherapy, and this was associated with improved median survival as well, 14 vs. 20.1 months (<i>P</i> < 0.0001). <h3>Conclusion</h3> While the vast majority of locally advanced NSCLC patients are amenable to proceeding with standard treatment, refusal of RT when recommended comes at the cost of inferior survival in this unadjusted cohort from a large hospital-based national database. Sociodemographic factors appear to be associated with refusal of standard of care treatment. These should be further explored to eliminate disparities in the treatment of inoperable but potentially curable NSCLC.

Clinical outcome and side effects of concomitant chemoradiotherapy in the treatment of locally advanced inoperable non-small cell lung cancer: Our experiences

Background/Aim. About 1.8 million new lung cancer cases are diagnosed worldwide every year, and about 1.6 million cases have a fatal outcome. Despite improvements in treatment in the previous decades, the survival of patients with lung cancer is still poor. The five-year survival rate is about 50% for patients with localized disease, 20% for patients with regionally advanced disease, 2% for patients with metastatic disease, and about 14% for all stages. The median survival of patients with untreated non-small cell lung carcinoma (NSCLC) in the advanced stage is four to five months, and the annual survival rate is only 10%. The aim of the study was to determine the results of treatment with concomitant chemoradiotherapy (CHRT) in terms of efficacy and toxicity in selected patients with advanced inoperable NSCLC. Methods. The study included data analysis of 31 patients of both sexes who were diagnosed and histopathologically verified with NSCLC in inoperable stage III and were referred by the Council for Malignant Lung Diseases to the Radiotherapy Department of the Military Medical Academy in Belgrade, Serbia for concomitant CHRT treatment. Upon expiry of the three months from the performed radiation treatment (RT), the tumor resonance was assessed based on multislice computed tomography (MSCT) examination of the chest and upper abdomen according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. According to the same criteria, progression-free survival (PFS), as well as overall survival (OS), was assessed every three months during the first two years, then every 6 months or until the onset of disease symptoms. Results. The median PFS was 13 months, and the median OS was 20 months. During and immediately after RT, 9 (29%) patients had a grade 2 or higher adverse events. Conclusion. The use of concomitant CHRT in patients in the third stage of locally advanced inoperable NSCLC provides a good opportunity for a favorable therapeutic outcome with an acceptable degree of acute and late toxicity and represents the standard therapeutic approach for selected patients in this stage of the disease.

Systematic review of stereotactic body radiotherapy in stage III non-small cell lung cancer.

Despite adequate treatment, 50% of stage III locally advanced inoperable non-small cell lung cancer (NSCLC) patients have a locoregional relapse. Local control on early stages on the contrary, is as high as 85–90% with stereotactic body radiotherapy (SBRT). The addition of SBRT to conventional chemoradiation or its use in monotherapy in stage III NSCLC is a novel strategy to decrease local failure that has been explored by various authors. This is a systematic review of studies using SBRT in inoperable stage III NSCLC. Search results obtained 141 articles of which only 6 original studies were pointed as relevant. Three of these studies were prospective, of which 2 were phase I dose-scalation studies and remaining 3 were retrospective. In summary, SBRT outcomes on 134 patients were included. Median dose in the SBRT treatment was 22.5 Gy in 2 to 7 fractions. Obtained global toxicity was 3.7% grade 5 and 14.17% grade 3. Dose-escalation studies proposed a 2 fraction SBRT schedule of 20–24 Gy, obtaining a 78% local control rate at 1 year and an OS of 67%. Initial improvement in local control with this innovative therapeutic strategy has led to ongoing phase II and III clinical trials that will evaluate the efficiency of SBRT in stage III NSCLC clinical scenario.

The Role of Additional Chemotherapy in Combination with Concurrent Chemoradiotherapy for Locally Advanced Inoperable Non-Small Cell Lung Cancer, a Systematic Review and Meta-Analysis of 12 Randomized Trials

This meta-analysis aims to evaluate the effectiveness of chemotherapy before (I-CRT) or after (CRT-C) chemoradiotherapy (CRT) for inoperable locally advanced non-small cell lung cancer (LA-NSCLC). According to the object response rate (ORR) and disease control rate (DCR), there were no differences among I-CRT, CRT, and CRT-C treatments. I-CRT did not have significant survival benefits compared with CRT alone. Similar results comparing CRT-C with CRT were observed. Furthermore, I-CRT was not associated with improved survival compared to CRT-C with respect to OS and PFS. Our meta-analysis suggests the effects of additional chemotherapy added to CRT were limited for unselected LA-NSCLC.

Clinical outcomes after intensity-modulated proton therapy with concurrent chemotherapy for inoperable non-small cell lung cancer

Background & purposeWe report disease control, survival, and toxicity in patients with advanced inoperable non-small cell lung cancer (NSCLC) receiving concurrent chemotherapy and intensity-modulated proton therapy (IMPT) at a single institution. Material and methodsAll patients were treated with IMPT with concurrent chemotherapy. Endpoints assessed were local, regional, and distant control, disease-free survival (DFS), and overall survival (OS). ResultsFifty-one patients were enrolled with a median follow-up time of 23.0 months; 39 (76%) were treated with a simultaneous integrated boost to the gross tumor volume (GTV). The median GTV dose was 67.3 CGE and the median CTV dose was 60.0 CGE. Median OS and DFS times were 33.9 months and 12.6 months. The 3-year local control rate was 78.3%. Treatment was well tolerated, with a grade 3 toxicity rate of 18% (9 events: 4 esophagitis, 3 dermatitis, 1 esophageal stricture, and 1 fatigue) and no grade 4 or 5 toxicity. The most common grade 2 toxic effects were esophagitis (22 [43%]), dermatitis (16 [31%]), pain (15 [29%]), and fatigue (14 [27%]). ConclusionsTreatment of inoperable NSCLC with IMPT and concurrent chemotherapy achieves excellent disease control with tolerable toxicity.

Prognostic Significance of Mean Platelet Volume on Local Advanced Non-Small Cell Lung Cancer Managed with Chemoradiotherapy

Mean platelet volume (MPV), the most commonly used measure of platelet size, and is altered in patients with malignancies. The aim of this study was to investigate the effect of MPV on overall survival (OS) of patients with locally advanced (Stage IIIA/B) inoperable non-small cell lung cancer (NSCLC). This retrospective study included patients who received concomitant chemoradiotherapy (CCRT) with cisplatin + etoposide regimen due to locally advanced stage IIIA/B NSCLC. The study included a total of 115 cases, consisting of 110 (95.7%) male and 5 (4.2%) female patients. The mean age of the patients was 61.3 ± 10.4 (22–82) years. ROC curve generated by MPV for OS yielded an AUC of 0.746 (95% CI 0.659–0.833), (p < 0.001). MPV was detected as >9 fL with a sensitivity of 74.4% and a specificity of 72.0%. In patients with stage IIIA, median OS was 45.0 months (95% CI 17.3–74.1) and 21 months (95% CI 10.6–31.3) in groups with MPV > 9.0 fL and ≤9.0 fL, respectively (p = 0.013). In patients with stage IIIB, median OS was 44.0 months (95% CI 13.8–60.6) and 16 months (95% CI 9.5–22.4) in groups with MPV > 9.0 fL and ≤9.0 fL, respectively (p = 0.036). ECOG performance score, total platelet count, and MPV were found as the most significant independent factors affecting survival (p < 0.001, p = 0.008, and, p = 0.034, respectively). In this study, we showed that decreased pre-treatment MPV was an independent risk factor for survival in NSCLC patients who were administered CCRT. As part of routine complete blood count panel, MPV may represent one of the easiest measuring tools as an independent prognostic marker for survival in locally advanced NSCLC.

Patterns of Failure According to Tumor Histology and Treatment Schedule in Patients with Locally Advanced Inoperable Non-Small Cell Lung Cancer: Secondary Analysis of NRG Oncology RTOG 9410

Patterns of Failure According to Tumor Histology and Treatment Schedule in Patients with Locally Advanced Inoperable Non-Small Cell Lung Cancer: Secondary Analysis of NRG Oncology RTOG 9410

The Role of Additional Chemotherapy in Combination with Concurrent Chemoradiation Therapy for Locally Advanced Inoperable Non–small Cell Lung Cancer: A Meta-analysis of 11 Randomized Trials

Considering the controversial evidence of induction chemotherapy (I-CRT) before or consolidation chemotherapy (CRT-C) after concurrent chemoradiotherapy (CRT) for locally advanced inoperable non-small cell lung cancer (LA-NSCLC), we conducted a meta-analysis to obtain a more accurate evaluation of the benefits of these treatment strategies. A systematic review of MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials (CENTRAL) was performed with retrieval methodology. The end points included the object response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Eleven randomized trials with a total of 1986 eligible patients were enrolled in our analysis. According to the pooled analysis of the relative rates (RRs) for ORR and DCR, there were no differences among I-CRT, CRT, and CRT-C treatments. Induction chemotherapy did not have significant survival benefits compared with CRT alone in terms of the OS [hazard ratio (HR) 0.92, 95% confidence interval (CI) 0.75-1.12]. Similar results were observed in our analysis comparing CRT-C with CRT, with a HR of 1.11 for PFS (95% CI 0.95-1.30) and 1.12 for OS (95% CI 0.93-1.35). Furthermore, I-CRT was not associated with a more favourable survival than that from CRT-C with respect to OS (HR 0.95, 95% CI 0.76-1.19) and PFS (HR 0.98, 95% CI 0.68-1.41). Our meta-analysis suggests that CRT should be administered to patients with unresectable LA-NSCLC to maximize survival. However, the effects of additional chemotherapy added to CRT were limited for the unselected group. Thus, new and efficient chemotherapy strategies in the smaller subgroup of patients who displayed a higher risk of metastases are warranted through further clinical investigation.

Continuous hyperfractionated accelerated radiotherapy – Escalated dose (CHART-ED): A phase I study

IntroductionPatients who present with locally advanced inoperable non-small cell lung cancer (NSCLC) may be suitable for radical radiotherapy. A randomised trial of 563 patients compared CHART and conventional radical radiotherapy (60Gy/30f) given over 6weeks and suggested that CHART resulted in a 9% improvement in 2-year survival (Saunders et al., 1999). RT dose escalation for both conventional and CHARTWEL (CHART-WeekEndLess) – fractionation schedules is feasible with modern 3-dimensional CT-based planning techniques and we initiated a phase I CHART dose escalation study in 2009. MethodsPatients with WHO performance status 0–2 histologically confirmed, inoperable, stage I–III non-small cell lung cancer were recruited into an open phase I dose escalation trial. Three cohorts of six patients were recruited sequentially. Total dose was escalated from standard CHART radiotherapy of 54Gy/36f/12days to 57.6Gy (2×1.8Gy fractions on day 15, Group 1), 61.2Gy (4×1.8Gy fractions on days 15–16, Group 2) and 64.8Gy (6×1.8Gy fractions on days 15–17, Group 3). ResultsBetween April 2010 and May 2012, 18 patients were enrolled from 5 UK centres and received escalated dose radiotherapy. 14 were male, 16 squamous cell histology and 12 were stage IIIA or IIIB. The median age was 70years and baseline characteristics were similar across the three dose cohorts. One patient did not start escalated radiotherapy but all remaining patients completed their planned radiotherapy schedules. Of these 9 patients have died to date with a median survival of 2years across the three cohorts. Grade 3 or 4 adverse events (fatigue, dysphagia, nausea and anorexia – classified according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0) were reported in 6 patients but the pre-specified dose limiting toxicities (grade 4 early oesophagitis; grade 3 cardiac, spinal cord and pneumonitis) were not observed. ConclusionsCHART remains a radiotherapy schedule in routine use across the UK and in this dose escalation study no dose limiting toxicities were observed. We feel the dose of 64.8Gy/42f/17days should be taken forward into further clinical trials. The sample size used in this study was small so we plan a randomised phase II study that includes other radiotherapy schedules to confirm safety and select an accelerated sequential chemo-radiotherapy schedule to take into phase III studies.

Accelerated concomitant boost conformal radiotherapy versus conventional sequential boost in patients with locally advanced inoperable non-small cell lung cancer.

e18530 Background: Management of advanced non-small cell lung cancer is rapidly evolving. Advances in combined chemoradiation therapy led to improvements in patient survival, but most patients rela...

Treatment with Intensity-Modulated Radiation Therapy (IMRT) and Chemotherapy in Advanced Inoperable Non-Small Cell Lung Cancer (NSCLC): Toxicity, Survival and Patterns of Failure in Relation to Treatment with High and Low Radiation Dose

Purpose: To investigate the toxicity, survival and patterns of failure in patients with advanced lung cancer treated with intensity modulated radiation therapy (IMRT) and chemotherapy. Methods and Materials: Retrospective chart review of 68 total patients: 46 academic and 22 community center. Endpoints: Grade ≥ 3 pneumonitis, Grade ≥ 2 esophagitis, local, regional and distant failure, progression-free survival (PFS) and overall survival (OS). Results: For the academic center patients, median follow-up was 19.2 months. Esophagitis: 0% Grade 3, 35% Grade 2, no significant difference between dose bins: <70 Gy vs. 70 Gy, 25% vs. 45% (p = 0.22), <66 Gy vs. 66 - 70 Gy, 28% vs. 39% (p = 0.53). Lung dose metrics and PTV size were not associated with Grade ≥ 3 pneumonitis. Esophageal V35, V50, and mean dose but not PTV size was associated with Grade 2 esophagitis. 1 year local, regional and distant failure = 6.5%, 6.5%, and 30.4%. No endpoint differences were seen between dose bins, though patients with smaller PTVs treated with 70 Gy did demonstrate improved OS (ns) when compared to those treated with <70 Gy. Community Center: Median follow-up 6.2 months with 15% Grade 2 esophagitis, no Grade 3 esophagitis. Two patients (9%) experienced Grade ≥ 3 pneumonitis. Conclusions: IMRT chemoradiation was well tolerated in a population with advanced NSCLC both in the academic and community settings. Severe pneumonitis rates were low and comparable to other series using IMRT and chemotherapy. Esophagitis was mild and associated with V35, V50 and mean dose. No significant benefit was seen for higher doses regarding survival, local, regional or distant control despite that higher dose bins had smaller tumors. Though not statistically significant, we did find a trend toward worse OS for <70 Gy when the PTV was less than the median PTV.

Intensity-Modulated Radiotherapy versus 3-Dimensional Conformal Radiotherapy Strategies for Locally Advanced Non-Small-Cell Lung Cancer.

Chemoradiotherapy is the current standard of care in patients with advanced inoperable stage IIIA or IIIB non-small cell lung cancer (NSCLC). Three-dimensional radiotherapy (3DCRT) has been a trusted method for a long time and has well-known drawbacks, most of which could be improved by Intensity Modulated Radiotherapy (IMRT). IMRT is not currently the standard treatment of locally advanced NSCLC, but almost all patients could benefit to a degree in organ at risk sparing, dose coverage conformality, or dose escalation. The most critical step for a radiation oncology department is to strictly evaluate its own technical and physical capabilities to determine the ability of IMRT to deliver an optimal treatment plan. This includes calculating the internal tumor motion (ideally 4DCT or equivalent techniques), treatment planning software with an up-to-date heterogeneity correction algorithm, and daily image guidance. It is crucial to optimise and individualise the therapeutic ratio for each patient during the decision of 3DCRT versus IMRT. The current literature rationalises the increasing use of IMRT, including 4D imaging plus PET/CT, and encourages the applicable knowledge-based and individualised dose escalation using advanced daily image-guided radiotherapy.

Outcomes of second-line chemotherapy for advanced non-small cell lung cancer in one institution.

BackgroundThis study analyzed the negative prognostic factors in patients who received second-line chemotherapy for advanced inoperable non-small cell lung cancer (NSCLC).MethodsWe retrospectively reviewed the records of 137 patients with inoperable stage III-IV NSCLC who received second-line chemotherapy. The effects of clinical parameters on survival were analyzed and the hazard ratios (HR) for mortality were identified by a Cox regression analysis.ResultsSex, age older than 65 years, smoking history, cell type, T-stage, best response to first-line chemotherapy and first-line chemotherapy regimen were significant negative predictors in univariate analysis. The multivariate analysis showed that patients older than 65 years (HR, 1.530; 95% confidence interval [CI], 1.020-2.297), advanced T stage (T4 vs. T1; HR, 2.273; 95% CI, 1.010-5.114) and non-responders who showed progression with first-line chemotherapy (HR, 1.530; 95% CI, 1.063-2.203) had higher HR for death.ConclusionThe age factor, T stage and responsiveness to first-line chemotherapy were important factors in predicting the outcome of patients with advanced NSCLC who received second-line chemotherapy. The results may help to predict outcomes for these patients in the future.

Intensity Modulated Radiation Therapy (IMRT) in Advanced Inoperable Non-small Cell Lung Cancer: Toxicity, Survival, and Patterns of Failure

Intensity Modulated Radiation Therapy (IMRT) in Advanced Inoperable Non-small Cell Lung Cancer: Toxicity, Survival, and Patterns of Failure

Concurrent chemoradiotherapy in locally advanced non-small cell lung cancer—Prognostic factors and reasons for treatment failure in group of patients 1996–2008

Introduction: Concurrent chemoradiation is the standard therapy in fit patients with locally advanced inoperable non-small cell lung cancer. Aim of this retrospective study is analysis of survival in relation to several variables and analysis of treatment failure.

Clinical Utility of the Pretreatment Glasgow Prognostic Score in Patients with Advanced Inoperable Non-small Cell Lung Cancer

Traditional tumor-based staging systems provide limited information on the best treatment option for individual patients with advanced inoperable non-small cell lung cancer (NSCLC). The Glasgow prognostic score (GPS) reflects the host systemic inflammatory response and is a validated independent prognostic factor in these patients. The aim of this study was to examine the clinical application of the pretreatment GPS in a mature cohort of patients with inoperable NSCLC. The data of 261 patients with inoperable NSCLC were collected prospectively and before treatment. Information on patient demographics, body mass index, performance status (PS), the modified Glasgow prognostic score (mGPS), the prognostic index, and treatment received were included. The majority of patients were aged 65 years or older (68%), were men (59%), had a body mass index more than 20 (89%), and an Eastern Cooperative Oncology Group performance status (ECOG-PS) 0 or 1 (54%). Most patients had a pretreatment mGPS = 1 (62%) and pretreatment prognostic index = 1 (56%). During the follow-up period, 248 (95%) patients died, 246 from their disease. The median survival was 8 months. On multivariate analysis, age (p = 0.001), ECOG-PS (p < 0.05), mGPS (p < 0.0001), and tumor stage (p < 0.0001) were independently associated with cancer-specific survival. Using 5-year cancer-specific mortality as an end point, the area under the receiver operator curve was 0.735 (95% confidence interval [CI], 0.566-0.903; p = 0.024) for the mGPS, 0.669 (95% CI, 0.489-0.848; p = 0.106) for ECOG-PS, and 0.622 (95% CI, 0.437-0.807; p = 0.240) for tumor, node, metastasis stage. Patients with an increased mGPS were more likely to have a poorer ECOG-PS (p < 0.05), an increased white cell count (p < 0.05), and received palliative treatment (p < 0.05). The pretreatment mGPS is a useful and important predictor of cancer-specific survival in patients with inoperable NSCLC. Basing clinical assessment on the mGPS has implications for the routine monitoring and treatment of the patients.

Consolidation chemotherapy following concurrent chemoradiation therapy for locally advanced inoperable non-small cell lung cancer

Concurrent chemoradiation therapy is currently a recommended treatment approach for locally advanced inoperable stage ⅢA and stage ⅢB non-small cell lung cancer (NSCLC).There is no consensus on the optimal treatment regimen.It is one of these options for the consolidation chemotherapy following concurrent chemoradiation therapy.To date,there is no sufficient evidence indicating that consolidation chemotherapy following concurrent chemoradiation therapy further improves survival rates.The benefit remains to be confirmed by more clinical test. Key words: Carcinoma, non-small-cell lung; Radiotherapy, adjuvant; Drug therapy, combination; Chemotherapy, adjuvant