Limited-disease Small-cell Lung Cancer Research Articles

Prognostic significance of body mass index and serum albumin as the indicators of nutritional status in small cell lung cancer

ABSTRACT Background Body mass index (BMI) and serum albumin (ALB) level are long-established markers that reflect the nutritional status and eventually the prognosis of cancer patients. The objective of the study was to determine the clinical significance of these factors and specify their roles in outcomes compared with performance status (PS) and weight loss (WL), which are considered the most significant patient-related prognostic factors in small cell lung cancer (SCLC) treated with platinum-etoposide-based chemotherapy. Methods A total of 378 patients with SCLC were enrolled in the study and analyzed retrospectively. Results BMI values were similar by clinical stage, whereas the percentages of the patients with WL, low serum ALB, and particularly poor (≥2) PS were significantly higher in patients with extended disease SCLC (ED-SCLC) compared to those with limited disease SCLC (LD-SCLC). In LD-SCLC, patients with poor PS lived for a significantly shorter time than patients with good PS (HR: 7.791, p = 0.0001); however, BMI (HR: 1.035, p = 0.8), WL (HR: 0.857, p = 0.5), and ALB (HR: 0.743, p = 0.3) had no significant effect on the outcome. In ED-SCLC, PS (HR: 4.257, p = 0.0001), WL (HR: 1.677, p = 0.001), and ALB (HR: 0.680, p = 0.007) had an impact on survival, but BMI did not (HR: 0.791, p = 0.08). In LD-SCLC, the univariate analysis showed that only poor PS was correlated with increased mortality (HR: 7.791, p = 0.0001); yet it lost significance in multivariate analysis. In ED-SCLC, poor PS (HR: 4.257, p = 0.0001), WL (HR: 1.667, p = 0.001), and a low ALB level (HR: 0.680, p = 0.007) were shown to be factors for poor prognosis in the univariate analysis; yet only PS remained significant in multivariate analysis (HR: 2.286, p = 0.001). Conclusion Even though BMI and serum albumin showed no prognostic value in SCLC patients treated with chemotherapy, PS was found to be the most significant prognostic factor in both LD- and ED-SCLC stages.

Efficacy and safety of different immunotherapies combined with chemotherapy as first-line therapy in patients with small cell lung cancer: a network meta-analysis.

The efficacy and safety of different immunosuppressants combined with chemotherapy in treating patients with small-cell lung cancer (extensive-disease small-cell lung cancer, limited-disease small-cell lung cancer and relapsed small-cell lung cancer) are still unknown, and there are no reports directly comparing the efficacy and safety of other immunotherapies. This study aimed to compare the efficacy and safety of first-line immunotherapy combined with chemotherapy in patients with small-cell lung cancer. We searched Pubmed, Embase, Cochrane Library, CNKI, and Wanfang databases for relevant articles published from inception to November 11, 2020. The risk of bias of the included studies was conducted using the Cochrane risk-of-bias (RoB) tool. Multiple Bayesian network meta-analyses were performed. They conducted data analysis using R Studio and STATA version 15.1. The outcomes comprised overall survival (OS), progression-free survival (PFS), stability of response (SOR), duration of response (DOR) and adverse events of grade 3 or higher (AE grade≥3). A 95% confidence interval (CI) was provided for each estimate. This meta-analysis included 16 RCT studies with 5898 patients. For OS, relative to chemotherapy (MD=-4.49; 95%CI [-7.97, -1.03]), durvalumab plus tremelimumab (MD=-4.62; 95%CI [-9.08, -0.11]), ipilimumab (MD=-4.26; 95%CI [-8.01, -0.3]) and nivolumab(MD=-5.66; 95%CI [-10.44, -1.11]) and nivolumab plus ipilimumab (MD=-4.56; 95%CI [-8.7, -0.1]), serplulimab can significantly increase the OS of SCLC patients. There was no significant difference between PFS, SOR and DOR. Analysis of AE showed that different immunotherapy combined chemotherapy regimens were similar to single chemotherapy regarding the overall incidence of AE grade≥3. However, after the cumulative ranking of the common symptoms of different adverse reactions, it was found that nivolumab ranked first in the occurrence probability of anemia (99.08%), fatigue (84.78%), and decreased appetite (89.66%). durvalumab was the most likely in nausea (75.4%). Pembrolizumab (76.24%) was most likely to cause pruritus. Chemotherapy combined with immunotherapy caused less diarrhea than chemotherapy alone (80.16%). According to our analysis, serplulimab combined with chemotherapy is more likely to show better efficacy with a manageable safety profile for small-cell lung cancer. However, the evidence for this comparison shows some limitations due to the number of literature. https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023486053.

Outcome of dose-escalated intensity-modulated radiotherapy for limited disease small cell lung cancer.

An optimal once-daily radiotherapy (RT) regimen is under investigation for definitive concurrent chemoradiotherapy (CCRT) in limited disease small cell lung cancer (LD-SCLC). We compared the efficacy and safety of dose escalation with intensity-modulated radiotherapy (IMRT). Between January 2016 and March 2021, patients treated with definitive CCRT for LD-SCLC with IMRT were retrospectively reviewed. Patients who received a total dose <50 Gy or those with a history of thoracic RT or surgery were excluded. The patients were divided into two groups (standard and dose-escalated) based on the total biologically effective dose (BED, α/β = 10) of 70 Gy. The chemotherapeutic regimen comprised four cycles of etoposide and cisplatin. One hundred and twenty-two patients were analyzed and the median follow-up was 27.8 months (range, 4.4 to 76.9 months). The median age of the patients was 63 years (range, 35 to 78 years) and the majority had a history of smoking (86.0%). The 1- and 3-year overall survival rates of the escalated dose group were significantly higher than those of the standard group (93.5% and 50.5% vs. 76.7% and 33.3%, respectively; p = 0.008), as were the 1- and 3-year freedom from in-field failure rates (91.4% and 66.5% vs. 73.8% and 46.9%, respectively; p = 0.018). The incidence of grade 2 or higher acute and late pneumonitis was not significantly different between the two groups (p = 0.062, 0.185). Dose-escalated once-daily CCRT with IMRT led to improved locoregional control and survival, with no increase in toxicity.

Comorbidity in limited disease small-cell lung cancer: Age-adjusted Charlson comorbidity index and its association with overall survival following chemoradiotherapy.

Combined, platinum-based thoracic chemoradiotherapy (TCR) is the current state-of-the-art treatment for patients with limited disease (LD) small-cell lung cancer (SCLC). There is only limited data available regarding the effect of comorbidities on survival following TRC. The purpose of this study is to assess the age-adjusted Charlson comorbidity index (ACCI) as a predictor of overall survival in LD-SCLC patients undergoing TCR. We retrospectively analyzed 367 SCLC patients diagnosed with LD-SCLC who received TCR between 2003 and 2017. We evaluated the ACCI (n=348) as a predictor of overall survival (OS). In this cohort, 322 patients (88%) received platinum-based TCR (either cisplatin or carboplatin), and 37 (10%) patients received vincristine based TCR. Median radiation dose was 60Gy (range 24-66Gy). Additionally, 83% of patients (n=303) received prophylactic cranial irradiation (PCI, 30Gy in 2Gy fractions). Kaplan-Meier survival analysis was performed for OS. For comparison of survival curves, Log-rank (Mantel-Cox) test was used. Univariate and multivariate Cox proportional-hazards ratios (HRs) were used to assess the influence of cofactors on OS. Patients with an ACCI>6 had a significantly shorter OS compared with patients with an ACCI≤6 (median 11 vs. 20months; p=0.005). Univariate analysis for OS revealed a statistically significant effect for ACCI>6 (HR 1.7; 95% CI 1.2-2.4; p=0.003), PCI (HR 0.5; 95% CI 0.3-0.7; p<0.001), and Karnofsky performance status≤70% (KPS) (HR 1.4; 95% CI 1.1-1.90; p=0.015). In multivariate analysis, OS was significantly associated with PCI (HR 0.6; 95% CI 0.4-0.9; p=0.022) and ACCI>6 (HR 1.5; 95% CI 1.0-2.1; p=0.049). Comorbidity is significantly associated with survival in patients with LD-SCLC undergoing TCR. The ACCI may be a valuable tool to identify patients with a shorter survival and thus might be used for risk stratification and oncological decision making.

Accuracy of nodal staging by 18F-FDG-PET/CT in limited disease small-cell lung cancer.

Small-cell lung cancer (SCLC) is highly aggressive with a nearly incurable disease in most cases. The most important prognostic factor is the status of the mediastinal lymph nodes. Only a small proportion of patients can be diagnosed at early stages and directed to curative multimodal treatment. Therefore, accuracy of nodal staging by (18F)-Fluoro-2-deoxyglucose (FDG) positron emission tomography (PET) computed tomography (18F-FDG-PET/CT) in (very) limited disease SCLC, although not well investigated, is highly important. Treatment naive, non-bulky patients treated or diagnosed with SCLC between June 2012 and April 2020 with complete data including FDG-PET/CT and invasive mediastinal staging were retrospectively analyzed (n = 19). Sensitivity, specificity, negative predictive value (NPV), positive predictive value (PPV) and accuracy of mediastinal lymph node staging of 18F-FDG-PET/CT was calculated. The FDG-PET/CT showed a sensitivity of 91%, and the specificity was calculated as 87.5%. In this cohort, the disease prevalence in lymph nodes was 58% (n = 11). Positive predictive value was 91%, NPV 88% and accuracy calculated at 89%. One patient was upstaged from single-level N2 to multilevel N2. In one patient, upstaging in invasive staging was performed from N2 to N3, and one patient was downstaged from N1 to N0. FDG-PET/CT is a valuable tool for the detection of distant metastases, but in mediastinal staging of SCLC some limitations might remain. Invasive methods remain the gold standard. Therefore, the mediastinal lymph nodal status of patients with SCLC screened for multimodal treatment should be further evaluated by additional invasive techniques to verify the exact N-staging and to optimize treatment stratification.

Prophylactic cranial irradiation in small cell lung cancer patients in the era of magnetic resonance imaging: A systematic review and meta-analysis.

e20636 Background: Patients with small cell lung cancer (SCLC) are at a particularly high risk for the development of brain metastases. Current guidelines recommend prophylactic cranial irradiation (PCI) for these patients to prevent brain metastases and prolong overall survival (OS), although the clinical evidence for recommendations stems from an era without routine use of brain imaging. We performed a systematic review and meta-analysis of all available studies reporting on PCI for SCLC patients with minimal inclusion restrictions to assesses the efficacy of PCI in patients with limited disease (LD) and extensive disease (ED) SCLC and focus on the impact of routine brain imaging. Methods: A literature search for studies reporting on PCI in SCLC patients performed in EMBASE, MEDLINE, CENTRAL, and grey literature sources identified 4,783 studies. Random-effects meta-analyses pooled hazard ratios (HR) for overall survival (OS) between PCI and no intervention groups. Results: 208 individual studies reported on outcomes related to PCI with 175 studies assessing survival differences associated with PCI, and 87 of these being amenable to meta-analysis. The majority (n = 79) were retrospective cohort studies. PCI was associated with improved OS in all SCLC patients (HR 0.60; 95% CI 0.55-0.65; n = 87 studies; n = 50,339 patients; I2= 77%), as well as in cohorts exclusively consisting of LD patients (HR 0.60; 95% CI 0.54-0.66; n = 58 studies; n = 22,417 patients; I2= 76%) or ED patients (HR 0.63; 95% CI 0.53-0.75; n = 23 studies; n = 24,997; I2= 75%). Only eight studies confirmed absence of IMD at restaging using magnetic resonance imaging in all patients and found OS no longer to be in favour of PCI (HR 0.75; 95% CI 0.50-1.12; n = 1,318 patients; I2= 77%). Pooled OS from randomized controlled trials was not associated with PCI (HR 0.88; 95% CI 0.65-1.12; n = 5 studies; n = 925 patients; I2= 62.5%). Among studies not amenable to meta-analysis for OS, 4 radiographically confirmed absence of IMD, but none found OS to be in favour of PCI. Conclusions: Administration of PCI is associated with a significant OS benefit, but not when considering studies that radiographically confirmed absence of IMD at restaging or randomized controlled trials, suggesting that patient selection may be contributing to this observation.

Factors associated with overall survival, progression-free survival and toxicity in patients with small cell lung cancer and thoracic irradiation in a clinical real-world setting

BackgroundSmall-cell lung cancer (SCLC) is a malignant tumor known for its poor prognosis. In addition to chemotherapy and immunotherapy irradiation plays a big role especially in inoperability. This study evaluated prognostic factors in patients with SCLC, receiving chemotherapy and thoracic irradiation, that may affect overall survival (OS), progression-free survival (PFS) and toxicity.MethodsPatients with limited disease (LD) SCLC (n = 57) and extensive disease (ED) SCLC (n = 69) who received thoracic radiotherapy were analyzed retrospectively. The prognostic factors sex, age, Karnofsky performance status (KPS), tumor-, nodal-stage and timepoint of start of irradiation in relation to the first cycle of chemotherapy were evaluated. Start of irradiation was stratified as early (le 2 cycles of chemotherapy), late (3 or 4 cycles) and very late (ge 5 cycles). Results were analyzed by Cox univariate and multivariate as well as logistic regression analysis.ResultsThe median OS of LD-SCLC patients was 23.7 months in early, and 22.0 months in late start of irradiation. In very late start, median OS was not reached. PFS was 11.8, 15.2 and 47.9 months, respectively. In patients with ED-SCLC OS was 4.3 months in early, 13.0 months in late and 12.2 months in very late start of irradiation. PFS was 6.7, 13.0 and 12.2 months, respectively. Prognosis of patients with LD- or ED-SCLC receiving late or very late start of irradiation was significantly prolonged in OS and PFS compared to an early start (p < 0.05). KPS ge 80 shows a significant increase of OS and PFS in ED-SCLC. Female sex and smaller mean lung dose were associated with lower risk of toxicity.ConclusionLate or very late start of irradiation is a prognosis-enhancing factor in LD-SCLC and ED-SCLC for OS and PFS. KPS ge 80 increases prognosis of OS and PFS in ED-SCLC as well. Toxicity is less common in female sex and patients with low mean lung dose in LD-SCLC.

Primary tumor SUVmax and ratio of SUVmax to primary tumor size on pretreatment 18F-FDG-PET/CT scan in small cell lung cancer : Which is superior for the prognosis?

The prognostic impact of tumor SUVmax (t-SUVmax) in small cell lung cancer (SCLC) has been questioned with controversial results, and the significance of the ratio of tumor SUVmax to primary tumor size (SUVmax/t-size) in SCLC has yet to be clarified as well. In this study, aretrospective analysis was carried out to figure out the prognostic and predictive powers of pretreatment primary t‑SUVmax and t‑SUVmax/t-size ratio in patients with SCLC. Atotal of 349 SCLC patients who underwent pretreatment staging with PET/CT scan were enrolled in the study and analyzed retrospectively. In limited disease SCLC (LD-SCLC), tumor size was significantly associated with both t‑SUVmax (p = 0.02) and t‑SUVmax/t-size (p = 0.0001). Furthermore, performance status, tumor size (p = 0.001), and liver metastasis were significantly associated with t‑SUVmax in extended disease SCLC (ED-SCLC). Moreover, tumor size (p = 0.0001), performance status, cigarette smoking history, and pulmonary/pleural metastasis were found to be correlated with t‑SUVmax/t-size. No associations were found between clinical stages and either t‑SUVmax or t‑SUVmax/t-size (p = 0.9 for both), and t‑SUVmax and t‑SUVmax/t-size values were found to have similar survival rates in both LD-SCLC and ED-SCLC patients. In univariate and multivariate analyses, both t‑SUVmax and t‑SUVmax/t-size were found not to be associated with overall survival (p > 0.05) CONCLUSION: This study does not advocate the use of either t‑SUVmax or t‑SUVmax/t-size on pretreatment 18F‑FDG-PET/CT scan as prognostic and predictive tools for both LD-SCLC and ED-SCLC patients. Likewise, we did not find that t‑SUVmax/t-size was superior to t‑SUVmax in that respect.

Lessons from STIMULI: who benefits from consolidation nivolumab and ipilimumab in limited-disease small-cell lung cancer after chemo-radiotherapy?

Lessons from STIMULI: who benefits from consolidation nivolumab and ipilimumab in limited-disease small-cell lung cancer after chemo-radiotherapy?

Whole exome analysis reveals the genomic profiling related to chemo-resistance in Chinese population with limited-disease small cell lung cancer.

The mechanism of chemo-resistance in small cell lung cancer (SCLC) is unclear. This study aims to explore the resistance-related genomic profiles of residual tumors after neo-adjuvant chemotherapy (NAC) in SCLC through the whole-exome sequencing (WES). A total of 416 limited diseases (LD) SCLC patients underwent surgery were retrospectively analyzed, of which 40 patients received NAC. Then we selected 29 patients undergoing NAC (n=19) and chemotherapy naïve (CTN, n=10) to perform WES sequence with formalin-fixed paraffin-embedded samples including tumor and paired para-tumor. In total, single nucleotide variation and mutation rate were similar between NAC and CTN groups. The mutation signatures were significantly discrepant between NAC and CTN groups, as well as among patients with partial response (PR), stable disease (SD), and progressive disease. There were more copy number variation deletions in NAC group compared with CTN group. The inactivation of TP53 and RB1 were the most significantly events in both NAC and CTN groups. RB1 nonsense mutations were recurrent in NAC group (9/19 vs. 0/9, 47.4% vs. 0%) with favorable survival, while the frame-shift deletions were frequent in CTN group (3/9 vs. 3/19, 33.3% vs.15.8%). Integrated function enrichment revealed that the frequently mutant genes were involved in cell cycle, metabolic reprogramming, and oncogenic signaling pathways in NAC group, such as BTG2 pathway, glycolysis in senescence and P53 pathway. A total of 27 genes presented frequently mutant in NAC group and might played a positive role in drug resistance. Multiple genes including BRINP3, MYH6, ST18, and PCHD15, which were associated with prognosis, occurred mutant frequently in PR and SD groups. Residual tumors after neo-adjuvant therapy exhibited different mutation signature spectrum. Multiple genes including RB1 nonsense mutations, BRINP3, MYH6, ST18, and PCHD15 were with frequent mutation in residual tumors, which might participate chemo-resistance and influenced the prognosis in patients with limited disease SCLC.

Validation of Pretreatment Prognostic Factors and Prognostic Staging Systems for Small Cell Lung Cancer in a Real-World Data Set.

Simple SummaryWe present an analysis of a real-world cohort of patients with small cell lung cancer (SCLC) and examine the value of prognostic factors and scores that have been published in recent decades. In our analysis, only a few clinical (age, tumor stage) and a single laboratory parameter (alkaline phosphatase) are associated with the prognosis of patients with SCLC. We could not confirm the prognostic role of most of the published complex prognostic scores.Treatment decisions in patients with small cell lung cancer (SCLC) are made based on the extent of the disease. However, the outcome varies among patients at the same stage. A simple tool to predict outcomes in SCLC patients would be helpful for clinical decision-making. In recent years, several prognostic scores have been proposed. In this study, we evaluated the different prognostic factors in an unselected real-world cohort of patients. We retrospectively collected clinical, radiological and laboratory data from 92 patients diagnosed with SCLC. Univariate and multivariate cox regression analyses of survival were performed to assess the prognostic value of relevant clinical and laboratory factors for SCLC. Furthermore, we examined the association between eight published prognostic scores for SCLC and overall survival (OS). In the overall cohort, the median OS was 10.3 months (20.9 months and 9.2 months for limited disease (LD) SCLC and extensive disease (ED) SCLC, respectively). In univariate analysis, initial staging, number of metastatic sites and presence of liver, bone and adrenal gland metastases were significantly associated with worse OS. Of the established laboratory markers, albumin, alkaline phosphatase and hyponatremia but not lactate dehydrogenase (LDH) significantly predicted OS. All published prognostic scores, with the exception of the Glasgow Prognostic Score, did not significantly predict OS. In multivariate analysis, age, staging and alkaline phosphatase serum levels showed significant association with OS. We could not confirm the prognostic significance of most of the published complex prognostic scores. We therefore recommend using simple clinical and laboratory factors instead of complex scores to estimate the prognosis of SCLC patients in clinical practice.

＜Editors' Choice＞ Elective nodal irradiation versus involved field radiotherapy for limited disease small cell lung cancer: a single-institution experience.

ABSTRACTElective nodal irradiation (ENI) and involved field radiotherapy (IFRT) are definitive radiotherapeutic approaches used to treat patients with limited-disease small cell lung cancer (LD-SCLC). However, no solid consensus exists on their optimal target volume. The current study aimed to assess the clinical outcomes of patients with LD-SCLC who received definitive ENI or IFRT. A retrospective single-institution study of patients who received definitive radiotherapy between 2008 and 2020 was performed. All patients underwent whole-body positron emission tomography/computed tomography before three-dimensional conformal radiotherapy. Among the 37 patients analyzed, 22 and 15 received ENI and IFRT, respectively. The thoracic radiotherapy dose was mostly either 60 Gy in 30 fractions delivered in 2-Gy fractions once daily or 45 Gy in 30 fractions delivered in 1.5-Gy fractions twice daily. The median follow-up period was 21.4 months. A total of 12 patients (32%) experienced locoregional relapse: 10 within and 2 outside the irradiation fields. One patient in the IFRT group experienced isolated nodal failure. Differences in locoregional relapse-free, progression-free, and overall survival rates between ENI and IFRT were not significant. Overall, IFRT did not promote a significant increase in locoregional recurrence compared to ENI. Our findings suggested the utility of IFRT in standard clinical practice and support its use for patients with LD-SCLC.

Long-term survival data of patients with limited disease small cell lung cancer: a retrospective analysis.

In patients with limited disease small cell lung cancer (LD-SCLC) treated with concurrent chemoradiotherapy (CCRT), long-term survival data have not been fully evaluated. Moreover, the association between long-term prognosis and prognostic factors has not been sufficiently investigated. In this retrospective study, we evaluated the efficacy of CCRT in 120 patients with LD-SCLC with a plan for curative CRT using concurrent accelerated hyperfractionated radiotherapy. The patients had a median age of 65.5years, predominantly male (73%), and had clinical stage III disease (80%). The median follow-up time for overall survival (OS) was 72.2months, median OS was 42.5months, and the 3-year and 5-year survival rates were 52.4% and 41.8%, respectively. The median progression-free survival (PFS) was 12.5months, and the 3-year and 5-year PFS rates were 37.6% and 33.6%, respectively. The 5-year OS rates of patients who achieved PFS at each time point were 70.9%, 83.6%, and 91.9% at 12, 24, and 36months, respectively. The gradual increase in the 5-year OS rate following PFS extension and initial depression of the Kaplan-Meier curve showed disease progression frequently occurred in the first 2years after initiation of CCRT. The Cox proportional hazards model showed no significant factors correlated with long-term survival through univariate and multivariate analyses. Although the prognostic factors associated with long-term prognosis in LD-SCLC were not identified, the 5-year survival rate was 41.8%, and among patients without disease progression at 2years, the 5-year survival rate was 83.6%. These data suggested that the prognosis of patients with LD-SCLC was improving.

Current Status and Progress of the Treatment of Limited-Disease Small Cell Lung Cancer

Small cell lung cancer (SCLC) is a common pathological type of primary lung cancer originating from the bronchial mucosa or gland. SCLC is characterized by rapid growth, high degree of malignancy, and early metastasis, which poses a great threat to patients’ safety and quality of life. SCLC can be divided into two stages: localized disease and extensive disease. For limited-disease small cell lung cancer (LD-SCLC), radiotherapy and chemotherapy are often used in clinical treatment. In recent years, there are several new advances in the clinical treatment of SCLC, including the improvement of radiotherapy and chemotherapy methods, compatibility of first-line and second-line drugs, as well as immune-targeted therapy. This article discusses the current status of clinical treatment and the research progress of LD-SCLC in the past five years.

Consolidation nivolumab and ipilimumab versus observation in limited-disease small-cell lung cancer after chemo-radiotherapy – results from the randomised phase II ETOP/IFCT 4-12 STIMULI trial

Concurrent chemotherapy and thoracic radiotherapy followed by prophylactic cranial irradiation (PCI) is the standard treatment in limited-disease small-cell lung cancer (LD-SCLC), with 5-year overall survival (OS) of only 25% to 33%. STIMULI is a 1:1 randomised phase II trial aiming to demonstrate superiority of consolidation combination immunotherapy versus observation after chemo-radiotherapy plus PCI (protocol amendment-1). Consolidation immunotherapy consisted of four cycles of nivolumab [1 mg/kg, every three weeks (Q3W)] plus ipilimumab (3 mg/kg, Q3W), followed by nivolumab monotherapy (240 mg, Q2W) for up to 12 months. Patient recruitment closed prematurely due to slow accrual and the statistical analyses plan was updated to address progression-free survival (PFS) as the only primary endpoint. Of the 222 patients enrolled, 153 were randomised (78: experimental; 75: observation). Among the randomised patients, median age was 62 years, 60% males, 34%/65% current/former smokers, 31%/66% performance status (PS) 0/1. Up to 25 May 2020 (median follow-up 22.4 months), 40 PFS events were observed in the experimental arm, with median PFS 10.7 months [95% confidence interval (CI) 7.0-not estimable (NE)] versus 42 events and median 14.5 months (8.2-NE) in the observation, hazard ratio (HR)= 1.02 (0.66-1.58), two-sided P= 0.93. With updated follow-up (03 June 2021; median: 35 months), median OS was not reached in the experimental arm, while it was 32.1 months (26.1-NE) in observation, with HR= 0.95 (0.59-1.52), P= 0.82. In the experimental arm, median time-to-treatment-discontinuation was only 1.7 months. CTCAE v4 grade ≥3 adverse events were experienced by 62% of patients in the experimental and 25% in the observation arm, with 4 and 1 fatal, respectively. The STIMULI trial did not meet its primary endpoint of improving PFS with nivolumab-ipilimumab consolidation after chemo-radiotherapy in LD-SCLC. A short period on active treatment related to toxicity and treatment discontinuation likely affected the efficacy results.

Patterns of Recurrence and Survival Rate After Complete Resection of Pathological Stage N2 Small-Cell Lung Cancer.

The benefits of surgical resection for patients with stage N2 limited-disease small-cell lung cancer (LD-SCLC) remain controversial. This retrospective study analyzed the survival and recurrence patterns of the patients diagnosed with pathological N2 (p-N2) LD-SCLC after radical resection. A total of 171 p-N2 LD-SCLC patients who underwent radical pulmonary resection and systematic lymphadenectomies at Shanghai Chest Hospital from July 2005 to June 2015 were enrolled. The influence of the mediastinal lymph node status (single or multiple nodes, single- or multiple-station) on the survival and recurrence patterns was retrospectively analyzed. The main recurrence sites were outside the chest cavity (54.8%) and hematogenous metastasis (67.4%). The bone and liver as initial recurrence sites had a poor prognosis, with a median overall survival (OS) of 13.100 months and 11.900 months, respectively. The median disease-free survival (DFS) of patients diagnosed with single and multiple p-N2 after surgery were 19.233 and 9.367 months (P = 0.001), and the median OS were 43.033 and 17.100 months (P < 0.001), respectively. In conclusion, recurrence occurred in the form of hematogenous metastasis mostly in the extra-thoracic part. Interestingly, patients diagnosed with single p-N2 benefited from radical resection. Surgery may be a treatment option regardless of the T stage if N2 SCLC with a single metastatic lymph node can be identified preoperatively.

Prophylactic cranial irradiation in SCLC.

Prophylactic cranial irradiation (PCI) has well established place in therapy for patients with limited-disease small cell lung cancer who responded to treatment. The data from randomized trials document that PCI reduces brain metastases rate from approximately 60% to 30%, and increases 3-year overall survival by approximately 5%. Currently, the dose of 25 Gy in 10 fractions is considered as standard. In attempt to reduce neuropsychological sequelae attributable to PCI hippocampal sparing techniques are employed. The existing studies suggest the benefit of hippocampal sparing in limiting memory and higher neurocognitive function losses, but with a risk of failures in the spared region. Ongoing studies will further validate the role of hippocampal sparing, both in terms of toxicity reduction and metastases prevention. PCI for patients who have undergone resection for stage I small cell lung cancer (SCLC) is not recommended, PCI may be, however, associated with a favourable outcome in SCLC patients who have undergone complete surgery in stages II−III. The role of PCI in extensive-disease (ED) SCLC has been evolving. Most recent evidence indicate that PCI is controversial in ED patients with response to initial chemotherapy and absence of brain metastases confirmed by contrast-enhanced MRI. The patients who do not receive PCI, must, however, receive periodic MRI examination during follow-up, i.e., remain under active surveillance with access to radiotherapy at brain relapse. The assessment of safety and effectiveness of hippocampal-sparing PCI, with or without drug neuroprotection in consideration of diverse combinations of radiotherapy, chemotherapy and immunotherapy create a background for future directions of research.

Efficacy of concurrent chemoradiotherapy for patients with limited-disease small-cell lung cancer: a retrospective, nationwide, population-based cohort study

BackgroundSmall-cell lung cancer (SCLC) is a highly proliferative, rapidly growing tumor with a poor prognosis, even in cases of limited disease (LD). Timely and accurate high-intensity therapy is necessary. For concurrent chemoradiotherapy (CCRT), etoposide/platinum (EP)-based regimens are recommended, although irinotecan/platinum (IP)-based regimens are also effective with radiotherapy. This large-scale, retrospective, nationwide cohort study aimed to analyze the efficacy of CCRT in patients with LD-SCLC.MethodsPopulation data registered between January 2008 and December 2018 was extracted from the Health Insurance Review and Assessment Service of Korea database. Survival outcomes of 4446 LD-SCLC patients who received CCRT were analyzed.ResultsPatients who received EP-CCRT (n = 4187) showed better time to first subsequent therapy (TFST: 11.2 months) and overall survival (OS: 22.2 months) than those who received IP-CCRT (n = 259; TFST: 9.6 months, P = 0.0477; OS: 16.4 months, P < 0.0001). When CCRT failed, dual-agent chemotherapy (n = 925; OS: 9.1 months) provided a better survival benefit than single-agent chemotherapy (n = 815; OS: 7.5 months). IP-based chemotherapy resulted in better OS (9.6 months) than EP-based chemotherapy (7.1 months, P = 0.017) in platinum-resistant relapsed patients; the opposite was observed for platinum-sensitive relapsed patients (OS: EP, 17.2 months; IP, 6.6 months; P < 0.0001). Poisson regression analysis demonstrated that age, EP-CCRT, and hypercholesterolemia retained significant associations with OS after adjustment for all variables.ConclusionIn the Korean population, the effects of EP-CCRT on OS and TFST are significantly more favorable than those of IP-CCRT.

Combining 18F-FDG PET/CT and Serum Lactate Dehydrogenase for Prognostic Evaluation of Small Cell Lung Cancer.

Objective: To investigate the value of using 18F-FDG PET/CT in combination with serum lactate dehydrogenase (LDH) for prognostic evaluation of newly diagnosed small cell lung cancer (SCLC). Methods: We reviewed 118 patients with pathologically proven SCLC who underwent 18F-FDG PET/CT imaging evaluation in our hospital. Among these patients, 64 patients had extensive disease (ED) and 54 patients had limited disease (LD). The maximum standardized uptake value (SUVmax) of primary tumor was measured. A Cox proportional hazards model was used to evaluate age, sex, performance status, serum LDH, tumor stage and SUVmax on the prediction of overall survival (OS) and median survival time (MST) of patients. Subgroup analysis was performed based on the SUVmax in combination with serum LDH. Results: According to the Receiver Operating Characteristic (ROC) curve, the optimal cut-off value of SUVmax was 10.95. The AUC was 0.535 (95% CI: 0.407–0.663). The patients were divided into four groups according to the SUVmax (higher or lower than 10.95) and LDH (higher or lower than 245 U/L). The univariate and multivariate analyses showed that curative thoracic radiotherapy, Prophylactic Cranial Irradiation (PCI) and the combination of primary tumor SUVmax ≤ 10.95 and LDH ≤ 245 U/L were prognostic factors of OS in patients with all patients (p < 0.05). Smoking status, PCI, the combination of primary tumor SUVmax ≤ 10.95 and LDH ≤ 245 U/L were prognostic factors of OS in patients with LD (p < 0.05). N stage and PCI were significant predictors in both of univariate and multivariate analysis of OS for ED SCLC (p < 0.05). Among all patients, 27 had low SUVmax and normal LDH, and their MST was 36 months (95% CI: 12.98–59.02). Ninety-one patients had high SUVmax and/or high LDH, and their MST was 20 months (95% CI: 15.47–24.53). The difference between these two groups was significant (p = 0.045). In patients with LD, 16 patients had low SUVmax and normal LDH, and their MST was 72 months (95% CI: 26.00–118.0). Thirty-eight patients had high SUVmax and/or high LDH, and their MST was 27 months (95% CI: 20.80–33.21). The difference between these two groups was significant (p = 0.012). In patients with ED SCLC, 10 patients had low SUVmax and normal LDH, with an MST of 18 months (95% CI: 13.69–22.32. Fifty-four patients had high SUVmax and/or high LDH, and their MST was 12 months (95% CI: 10.61–13.39). The difference of MST between these two groups was not statistically significant (p = 0.686). Conclusion: 18F-FDG PET/CT in combination with serum LDH were prognostic factors of overall survival in patients with SCLC. The prognosis of patients with LD SCLC who had low SUVmax of primary tumor and normal LDH was better than those with high SUVmax and/or high LDH.

Once daily versus twice-daily radiotherapy in the management of limited disease small cell lung cancer – Decision criteria in routine practise

BackgroundIn limited disease small cell lung cancer (LD-SCLC), the CONVERT trial has not demonstrated superiority of once-daily (QD) radiotherapy (66 Gy) over twice-daily (BID) radiotherapy (45 Gy). We explored the factors influencing the selection between QD and BID regimens. MethodsThirteen experienced European thoracic radiation oncologists as selected by the European Society for Therapeutic Radiation Oncology (ESTRO) were asked to describe their strategies in the management of LD-SCLC. Treatment strategies were subsequently converted into decision trees and analysed for agreement and discrepancies. ResultsLogistic reasons, patients’ performance status and radiotherapy dose constraints were the three major decision criteria used by most experts in decision making. The use of QD and BID regimens was balanced among European experts, but there was a trend towards the BID regimen for fit patients able to travel twice a day to the radiotherapy site. ConclusionBID and QD radiotherapy are both accepted regimens among experts and the decision is influenced by pragmatic factors such as availability of transportation.