Virtual Library

Background:
CC-486 (oral azacitidine) is an epigenetic modifier with potential effect as a priming agent for chemotherapy in patients with NSCLC. Outcomes of nab-paclitaxel+CC-486 vs nab-paclitaxel as second-line treatment of advanced NSCLC are reported.

Method:
Patients with advanced nonsquamous NSCLC and no more than 1 prior chemotherapy line (including platinum doublet combination) were randomized (1:1) to nab-paclitaxel 100 mg/m[2] d8, 15 + CC-486 200 mg qd d1-14 or nab-paclitaxel 100 mg/m[2] d1, 8, both administered q3w until progressive disease/unacceptable toxicity. Primary endpoint was PFS. Secondary endpoints: DCR, ORR, OS, and safety. QoL, an exploratory endpoint, was assessed on d1 of each cycle.

Result:
The nab-paclitaxel+CC-486 arm was discontinued in October 2016 due to demonstrated futility vs nab-paclitaxel monotherapy upon completion of a protocol-specified interim analysis. Overall, 161 patients were randomized (nab-paclitaxel+CC-486, 81; nab-paclitaxel, 80). Baseline characteristics were balanced between arms. The median number of cycles was 4 for each arm, and the median nab-paclitaxel cumulative dose was 600 mg/m[2] and 800 mg/m[2] in the nab-paclitaxel+CC-486 and nab-paclitaxel arms, respectively. Rates of grade 3/4 (G3/4) treatment-emergent AEs were 59.5% and 54.4% for the combination and monotherapy arms, respectively. The most frequent hematologic G3/4 AEs were neutropenia (16.5% vs 10.1%) and anemia (1.3% vs 7.6%). G3/4 peripheral neuropathy was reported in 2.5% and 7.6% of patients, respectively. The addition of CC-486 to nab-paclitaxel did not improve ORR, DCR, PFS, or OS (Table). When assessed by Lung Cancer Symptom Scale, nab-paclitaxel monotherapy was associated with improvement in the global QoL, average symptom burden index, and lung cancer symptoms except for hemoptysis.

Conclusion:
The addition of CC-486 to nab-paclitaxel did not clinically benefit patients with previously treated NSCLC. However, single-agent nab-paclitaxel appears to be a promising therapy based on safety, efficacy, and QoL data. Updated efficacy and safety data will be presented. NCT02250326

	nab-Paclitaxel + CC-486 n = 81	nab-Paclitaxel n = 80
Median PFS, months	3.2	4.2
HR (95% CI)	1.3 (0.9 - 2.0)
1-year PFS, %	4.1	18.3
Median OS, months	8.4	12.7
HR (95% CI)	1.4 (0.88 - 2.31)
1-year OS, %	39.2	54.3
ORR, n (%)[a]	11 (13.6)	11 (13.8)
Response rate ratio (95% CI)	0.99 (0.45 - 2.15)
CR PR SD PD DCR (≥ SD)	0 11 (13.6) 41 (50.6) 22 (27.2) 52 (64.2)	0 11 (13.8) 43 (53.8) 19 (23.8) 54 (67.5)
CR, complete response; DCR, disease control rate; HR, hazard ratio; ORR, overall response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease. [a] Response rate was based on the intent-to-treat population; however, 14 patients did not have a response assessment.

Background:
Vitamin B12 and folic acid supplementation(B12-FAS) reduces the incidence and severity of hematological toxicity[HTox] in pemetrexed-based chemotherapy. It is recommended to initiate B12-FAS 5-7 days before the first cycle. Observational and prospective single-arm studies have not shown any increase in HTox when pemetrexed was started earlier than the recommended duration of B12-FAS.

Method:
An open-label, randomized trial (PEMVITASTART; NCT02679443) was conducted to evaluate differences in HTox between patients initiated on pemetrexed-platinum chemotherapy following 5-7 days of B12-FAS (Delayed Arm; DA) versus those receiving B12-FAS simultaneously(≤24 hours) with chemotherapy initiation (Immediate Arm; IA). Eligible patients had locally advanced/metastatic non-squamous NSCLC AND ECOG PS=0-2. Block randomization was 1:1 into DA and IA. All enrolled patients received 3-weekly pemetrexed-platinum doublet [500mg/m[2] AND cisplatin(65mg/m[2]) OR carboplatin(AUC 5.0mg/mL/min) each on D1] for maximum of six cycles. Supplementation was 1000µgm FA PO daily and 3-weekly 1000µgm i/m vitamin B12. Primary outcome was any grade HTox while secondary outcomes were grade 3/4 HTox, relative dose intensity(RDI) delivered, inter-cycle delays(ICDs), supportive therapies usage (ESA/G-CSF/PRBC transfusions) and changes in serum levels of B12/FA/homocysteine.

Result:
Of 161 patients recruited (81 IA, 80 DA), 150 patients (77 IA, 73 DA) received ≥1 cycle and were included in modified ITT analysis. Baseline parameters were matched except for gender (IA=10.4%, DA=23.3%, p=0.03) and baseline thrombocytopenia (IA=7.8%, DA=0%, p=0.03). Baseline anemia(Hb<12gm/dL) was present in 34.7% (IA=32.5%, DA=37.0%; p=0.56). Incidence of any grade anemia, leukopenia, neutropenia and thrombocytopenia was 87.0% vs. 87.7%(p=0.90), 37.7% vs. 28.8%(p=0.25), 20.8% vs. 15.1%(p=0.36) and 31.2% vs. 16.4%(p=0.04) in IA and DA respectively. Grade 3/4 anemia was 18.2% vs. 12.3%(p=0.32) in IA and DA respectively while other cytopenias were similar (<5% in each arm). Supportive therapies usage in IA vs. DA were 22.1% vs. 12.3% for PRBC transfusions (p=0.12), 3.9% vs. 6.8% for G-CSF (p=0.49) and 10.4% vs. 1.4% for ESAs (p=0.03). ICDs occurred in 14.3% of IA vs. 8.2% in DA (p=0.24). RDI delivered (median 93.5% for pemetrexed and 91.0% for platinum) was similar in both arms. Following continued B12-FAS, after C3(compared to baseline), serum homocysteine was lower (median 10.0µmol/L vs. 17.6µmol/L;p<0.001) while FA (median 17.9ng/ml vs. 5.7ng/ml;p<0.001) and B12 levels (mean 1926.3pg/ml vs. 880.2pg/ml;p<0.001) were higher. In DA, serum FA and B12 on Day1 of C1(following 5-7days of B12-FAS) were significantly higher than baseline but homocysteine levels were similar.

Conclusion:
Simultaneous B12-FAS initiation with pemetrexed-based chemotherapy is feasible with acceptable HTox profile. Serum homocysteine levels are unaffected by 5-7 days of B12-FAS.

Background:
A previous phase III randomized trial improved overall survival of patients with advanced or relapsed squamous cell lung carcinoma, compared with cisplatin plus docetaxel. However, evaluation of nedaplatin plus docetaxel’s effect on progression free survival (PFS) and time to progression (TTP) was limited.

Method:
To compare the efficacy and safety of nedaplatin plus docetaxel and cisplatin plus docetaxel. In this randomized, open-label, multicenter trial, patients diagnosed with advanced or relapsed squamous cell carcinoma pathologically or cytologically were enrolled in China. All the patients have no previous oncology medication. Patients were randomly assigned (1:1) to 80 mg/m² nedaplatin and 75 mg/m² docetaxel intravenously, or 75 mg/m² cisplatin and 75 mg/m² docetaxel, every 3 weeks for four cycles. The primary end points was PFS. Secondary endpoints included TTP and best overall response. The efficacy endpoint were analyzed in the intention-to-treat set and in the per protocol set. （Clinical trial number: NCT02088515; Funding:Jiangsu Simcere Pharmaceutical Co., Ltd.）

Result:
From December 2013 to December 2015, 286 patients were randomly assigned. Two hundred and eighty patients were included in the modified intention-to-treat analysis (141 in the nedaplatin group and 139 in the cisplatin group). In the intention-to-treat analysis set, median PFS was 4.63 months (95% confidence interval (CI), 4.43-5.10) in the nedaplatin group and 4.23 months (95% CI, 3.37-4.53) in the cisplatin group. PFS did not differ significantly between two groups (log-rank test, p =0.056). In per protocol set, PFS was significantly longer in the nedaplatin group (median 4.63 months, 95% CI, 4.43-5.10) than in the cisplatin group (median 4.27 months, 95% CI, 3.37-4.53; hazard ratio 0.760, 95% CI 0.585-0.989; p=0.039, log-rank test). Best overall response and TTP were improved in nedaplatin group than in cisplatin group (p= 0.002, median 4.57(4.30-4.80) vs 3.67(3.13-4.43) p= 0.020, respectively) in the intention-to-treat analysis set. Grade III or IV adverse events was more frequent in the cisplatin group than in the nedaplatin group (46 of 141 patients in the nedaplatin group and 62 of 139 in the cisplatin group, p=0.039). Grade 3 or worse nausea (0 vs 7) and fatigue (1 vs 3) were more frequent in the cisplatin group than in the nedaplatin group.

Conclusion:
There was no significant difference of PFS between cisplatin group and nedaplatin group. However, more adverse events was observed in the cisplatin group than in the nedaplatin group. Nedaplatin plus docetaxel could be a new treatment option for advanced or relapsed squamous cell lung cancer.

Abstract not provided

Background:
Although brain metastases (BM) are a very common and clinically challenging for NSCLC progression, there are few prospective studies addressing the safety and efficacy of bevacizumab in combination with chemotherapy in patients with BM. This study aimed to describe the characteristics of patients receiving bevacizumab in combination with first-line metastatic chemotherapy for advanced NSCLC (aNSCLC), with BM or not, in routine clinical practice.

Method:
For this French non-interventional, prospective, and multicenter study, data were collected every 3 months over an 18-month period, from bevacizumab initiation. End points were progression-free survival (PFS), overall survival (OS), treatment use, and safety.

Result:
Amongst the 407 aNSCLC patients analyzed, the 84 patients (21%) with BM at bevacizumab initiation had poorer general health than patients without BM (ECOG 2: 16% versus 11%). All except for 2 patients received bevacizumab (7.5 or 5 mg/kg/3 weeks in 99% of patients) in combination with doublet chemotherapy. After a median follow-up of 10.8 months (range: 0.2-34.1), median PFS and OS were not significantly different between patients with or without BM. BM was not found as PFS prognosis factor in multivariate analysis (HR=1.03; 95% CI=[0.79; 1.33], p=0.85). At least one serious adverse event (SAE) was reported in 30% of aNSCLC patients with BM (n=25) and in 32% of patients without BM (n=106); 13% (n=11) and 12% (n=40) of patients experienced at least one bevacizumab-related SAE, respectively. Three patients in each group died from bevacizumab-related events.

	aNSCLC patients with brain metastasis - N=84 (months, [CI 95%])	aNSCLC patients without brain metastasis - N=423 (months, [CI 95%])	Logrank test p value
Median PFS	6.5 [5.7; 8.1]	6.9 [5.9; 7.6]	0.57
Median OS	14.5 [10.0; -]	12.5 [10.1; 14.7]	0.33

Conclusion:
In this study, no differences were observed between advanced NSCLC patients with and without brain metastasis in terms of clinical benefit (survival and safety) from first-line chemotherapy combined with bevacizumab. Nature, severity and outcome of AEs were consistent with the known safety profile of bevazicumab.

Background:
In REVEL, ramucirumab+docetaxel in the second-line (2L) treatment of patients with advanced NSCLC led to improvements in overall survival (OS), progression-free survival (PFS), and objective response rate (ORR), independent of histology. This exploratory, post-hoc analysis focuses on patients who progressed rapidly on first-line (1L), and who traditionally have a poor prognosis in the 2L setting. In REVEL, treatment benefit was observed in patients with progressive disease as their best overall response to 1L and in patients who were on 1L for only a short time (Reck M, ASCO 2017, Abstr 9079). Here, we report outcomes from patients who participated in REVEL according to their time to tumor progression (TTP) on 1L (ClinicalTrials.gov, NCT01168973).

Method:
Patients with advanced NSCLC of squamous or nonsquamous histology with disease progression during or after 1L platinum-based chemotherapy were randomized (1:1) to receive docetaxel 75 mg/m[2] and either ramucirumab 10 mg/kg or placebo on day 1 of a 21-day cycle. OS was the primary endpoint. Secondary endpoints included PFS, ORR, safety, and patient-reported quality-of-life (QoL). Response was assessed according to RECIST v1.1. QoL was assessed with the Lung Cancer Symptom Scale. TTP on 1L, defined as the time from start of 1L until progressive disease, was assessed for the REVEL intent-to-treat population.

Result:
Of 1253 patients in REVEL, 11% had TTP ≤9 weeks, 17% had TTP ≤12 weeks, and 28% had TTP ≤18 weeks on 1L therapy. Baseline characteristics of each subgroup generally were balanced between treatment arms. Efficacy, safety, and QoL outcomes by TTP are shown in the table.

Outcomes in Patients From the REVEL Study by Time to Tumor Progression on First-Line Therapy

	≤9 Weeks		≤12 Weeks		≤18 Weeks
INTENT-TO-TREAT POPULATION	Ramucirumab+Docetaxel N = 71	Placebo+Docetaxel N = 62	Ramucirumab+Docetaxel N = 111	Placebo+Docetaxel N = 98	Ramucirumab+Docetaxel N = 182	Placebo+Docetaxel N = 172
Median OS, months (95% Confidence Interval [CI])	8.28 (5.19, 10.84)	4.83 (3.09, 6.90)	9.10 (6.70, 10.84)	5.78 (4.30, 7.49)	8.51 (6.97, 9.95)	5.95 (4.44, 6.97)
Unstratified Hazard Ratio (HR) (95% CI)	0.69 (0.47, 1.01)		0.74 (0.54, 1.00)		0.80 (0.63, 1.01)
12-month survival rate, % (95% CI)	47 (35, 58)	32 (20, 44)	34 (25, 43)	23 (15, 32)	30 (23, 37)	24 (18, 31)
18-month survival rate, % (95% CI)	20 (11, 31)	12 (5, 24)	17 (10, 26)	13 (6, 22)	17 (11, 23)	13 (8, 20)
Median PFS, months (95% CI)	3.01 (2.66, 4.07)	1.48 (1.41, 1.87)	3.61 (2.76, 4.21)	1.61 (1.45, 2.60)	3.22 (2.79, 4.14)	1.61 (1.48, 2.60)
Unstratified HR (95% CI)	0.69 (0.48, 0.98)		0.73 (0.55, 0.97)		0.72 (0.58, 0.89)
ORR (complete response [CR]+partial response [PR]), %, (95% CI)	18.3 (10.1,29.3)	3.2 (0.4, 11.2)	18.9 (12.1, 27.5)	9.2 (4.3, 16.7)	19.2 (13.8, 25.7)	10.5 (6.3, 16.0)
Disease Control Rate (CR+PR+stable disease), % (95% CI)	50.7 (38.6, 62.8)	30.6 (19.6, 43.7)	49.5 (39.9, 59.2)	37.8 (28.2, 48.1)	50.5 (43.1, 58.0)	36.0 (28.9, 43.7)
Average Symptom Burden Index, time to deterioration HR (95% CI)	0.60 (0.30, 1.22)		0.49 (0.27, 0.88)		0.74 (0.49, 1.12)
Total Score Lung Cancer Symptom Scale, time to deterioration HR (95% CI)	0.89 (0.45, 1.78)		0.71 (0.41, 1.23)		0.90 (0.60, 1.36)
SAFETY POPULATION	Ramucirumab+Docetaxel N = 70	Placebo+Docetaxel N = 61	Ramucirumab+Docetaxel N = 109	Placebo+Docetaxel N = 97	Ramucirumab+Docetaxel N = 179	Placebo+Docetaxel N = 171
Any Treatment-Emergent Adverse Event (TEAE), n (%)	67 (95.7)	58 (95.1)	105 (96.3)	92 (94.8)	173 (96.6)	159 (93.0)
Grade ≥3	50 (71.4)	46 (75.4)	80 (73.4)	69 (71.1)	134 (74.9)	113 (66.1)
TEAE leading to discontinuation	4 (5.7)	2 (3.3)	5 (4.6)	3 (3.1)	13 (7.3)	6 (3.5)
TEAE leading to dose adjustment	24 (34.3)	19 (31.1)	39 (35.8)	28 (28.9)	70 (39.1)	47 (27.5)
TEAE leading to death	5 (7.1)	4 (6.6)	7 (6.4)	6 (6.2)	9 (5.0)	8 (4.7)
TESAE	25 (35.7)	30 (49.2)	46 (42.2)	46 (47.4)	80 (44.7)	71 (41.5)

Conclusion:
Efficacy, toxicity, and QoL outcomes among ramucirumab+docetaxel patients who have aggressive disease with rapid TTP on 1L therapy appear consistent with the intent-to-treat population. The benefit/risk profile for these rapid progressors suggests that such patients may derive meaningful benefit from ramucirumab+docetaxel in the 2L setting.

Background:
Background: INF-γ had recently been known to take part in cancer immunology and its interactions with chemotherapy were also described. Our previous study had showed that impaired PHA-stimulated INF-γ (PSIG) response from peripheral lymphocytes was associated with lower one-year overall survival in advanced non-small cell lung cancer (NSCLC) patients. In this study, we aimed to evaluate the correlation between PSIG and chemotherapy response.

Method:
Form January 2011 to August 2012, 340 newly-diagnosed lung cancer patients from 4 referral centers in Taiwan were enrolled in a prospective latent TB observational study. Patients who had advanced NSCLC and had been treated with chemotherapy were included in this study. The pretreatment PSIG levels were evaluated by Interferon-Gamma Release Assay (IGRA) with QuantiFERON-TB In-Tube (Qiagen, Germany). Patients were grouped into high PHA response group if their PSIG levels were above the median level; the others were grouped into low PHA response group. Their demographic characteristics, tumor response, and survival were investigated and correlated with PSIG levels.

Result:
Eighty-four patients were enrolled in this study. The response rate in high PHA response group was 45.2%, versus 35.7% in lower PHA response group (p=0.999190). The disease control rate in high PHA response group was 76.2%, versus 52.4% in low PHA response group (p=0. 023999). In multivariate analysis, PSIG response was an independent predictor for disease control rate (OR=3.017, 95% CI= 1.115-8.165). Also, the Kaplan-Meier curves and estimates survival analysis demonstrated both longer progression-free survival (p=0.008) and overall survival (p=0.003) in high PHA response group.

Conclusion:
Higher pre-treatment PSIG response, assayed by IGRA testing, was associated with better disease control rate and survival among advanced NSCLC patients treated with chemotherapy.

Abstract not provided

Background:
The U.S. Food and Drug Administration approved pembrolizumab in combination with carboplatin/pemetrexed for patients with untreated, metastatic, non-squamous, non-small cell lung cancer based on KEYNOTE 021G. This trial randomized 123 patients to carboplatin/pemetrexed versus carboplatin/pemetrexed/pembrolizumab with maintenance pembrolizumab. Maintenance pemetrexed was optional in both arms. Progression-free survival (PFS) was longer for carboplatin/pemetrexed/pembrolizumab (not reached vs. 8.9 months, HR 0.49, 95% CI 0.29-0.83, p=0.0035). No statistically significant improvement in overall survival (OS) has yet been demonstrated (HR 0.69, 95% CI 0.36-1.31, p=0.13), with neither arm reaching median OS. Frontline pembrolizumab improves PFS and OS in comparison to chemotherapy in patients with high PD-L1 expression. Drug cost information should be available to providers to better inform decision-making and assess value.

Method:
Dose calculations were based on the following: GFR 125, BSA 2.00 m2, carboplatin AUC 5, pemetrexed 500mg/m2, and pembrolizumab 200mg. Drug costs were obtained via the Centers for Medicare & Medicaid Services Pricing File.

Result:
Four cycles of carboplatin/pemetrexed/pembrolizumab followed by maintenance pembrolizumab and pemetrexed cost $618,889. Four cycles of carboplatin/pemetrexed followed by pemetrexed maintenance cost $249,972. Pembrolizumab alone for an equivalent number of cycles cost $368,917. Table 1: Regimen Cost Calculations Figure 1



Conclusion:
While the addition of pembrolizumab to front-line therapy resulted in an improvement in PFS in a phase II study of 123 patients, it increased medication costs 2.4 fold, from $249,972 to $618,889. Phase III trials are underway to more definitively assess the benefit of immunotherapy administered with chemotherapy in a broad population of patients. Treatment with carboplatin/pemetrexed/pembrolizumab cost 1.7 times that of pembrolizumab alone, and the addition of chemotherapy is of unclear benefit for patients with high PD-L1 expression. Further defining patient subsets who will benefit the most from this costly regimen should be undertaken. It is crucial healthcare professionals and patients understand the cost implications of front line therapy options.

Background:
Emergence of new active drugs and improvement in supportive care make it more likely for patients with advanced NSCLC to receive a fourth-line therapy.However, no survival benefit of such treatment has ever been demonstrated yet, although some studies suggest that it may be effective in selected patients. A better selection could avoid exposing patients to futile and toxic treatments. We conducted a study aiming at identifying prognostic factors in patients with advanced NSCLC treated with a fourth-line therapy.

Method:
In this retrospective, multicentric study, patients with advanced NSCLC receiving a fourth-line therapy were included. Factors associated with prolonged overall survival (OS, defined as OS >6 months) were identified by univariate and multivariate analysis using a Forward method.

Result:
151 patients were included in this study between Jan 2015 and Dec 2016. Median age was 60 (range 55-64). Most patients were male (70%) and had adenocarcinoma (72%). Most common prior treatments included platinum-based chemotherapy (92%), single-agent chemotherapy (81%), targeted therapies (46%) and immunotherapy (9%). Median OS was 7.39 months (6.7-9.43). Nine factors were significantly associated with OS >6 months: current smoker (Hazard Ratio (HR) 1.99, 95% confidence interval[1.16-3.41]), former smoker (HR 0.51[0.30-0.98]), Karnofsky Index (KI) ≥ 90% at the start of fourth-line therapy (HR 0.35[0.19-0.65]), weight loss since first-line therapy (HR 1.85[1.06-3.23]), early stage at diagnosis (HR 0.48[0.24-0.96]), number of cycles and delay since first-line therapy (HR 0.94[0,89-0,99]and 0.99[0.99-1]), Progressive Disease (PD) as Best Objective Response (BOR) in the first 3 lines of treatment (HR 2.92[1.9-5.37]), absence of grade ≥ 3 Adverse Events (AEs) during first-line therapy(HR 0.54[0.31-0.94]). Among them, 4 independent variables were found to be statistically significant by multivariate analysis, including early stage at diagnosis (HR 0.37[0.16-0.58]), absence of grade ≥ 3 AEs during first-line therapy (HR 0.56[0.32-0.98]), PD as BOR in the first 3 lines of treatment (HR 3.06[1.64 -5.73]) and KI ≥ 90% at the start of fourth-line therapy (HR 0.31[0.16-0.58]).

Conclusion:
We highlighted 4 factors significantly associated with OS >6 months in patients treated with fourth-line advanced NSCLC. These factors need to be prospectively assessed to confirm if they could help identifying patients who may benefit from fourth-line therapy.

Background:
Lung cancer is the leading cause of cancer-related mortality worldwide with a 5 year survival rate of 15%. Non-small cell lung cancer (NSCLC) is the most commonly diagnosed form of lung cancer. Cisplatin-based regimens are currently the most effective chemotherapy for NSCLC, however, chemoresistance poses a major therapeutic problem. New and reliable strategies are required to avoid drug resistance in NSCLC. Cell division cycle associated 3 (CDCA3) is a key regulator of the cell cycle. CDCA3 modulates this process by enabling cell entry into mitosis through degradation of the mitosis-inhibitory factor WEE1. Herein, we describe CDCA3 as a novel prognostic target to delay or prevent cisplatin resistance in NSCLC.

Method:
CDCA3 expression was investigated using bioinformatic analysis, tissue microarray immunohistochemistry and western blot analysis of matched NSCLC tumour and normal tissue. CDCA3 function in NSCLC was determined using several in vitro assays by siRNA depleting CDCA3 in a panel of three immortalized bronchial epithelial cell lines (HBEC) and seven NSCLC cell lines. To determine strategies to suppress CDCA3 activity the phosphorylation status of CDCA3 was assessed using mass spectrometry analysis. Kinases that phosphorylate CDCA3 were identified using a siRNA screen and high content immunofluorescence and microscopy approaches.

Result:
We have previously shown that CDCA3 transcripts and protein levels are elevated in resected NSCLC patient tissue, high mRNA levels being associated with poor survival. CDCA3 depletion markedly impairs proliferation in seven NSCLC cell lines by inducing a G2 cell cycle arrest. Silencing of CDCA3 also greatly sensitises NSCLC cell lines to cisplatin. Consistently, NSCLC patients with elevated CDCA3 levels and treated with cisplatin have a poorer outcome than patients with reduced CDCA3 levels. To aid patient response to cisplatin, we have been looking at strategies to suppress CDCA3 expression in tumour cells. Accordingly, in response to cisplatin, CDCA3 is phosphorylated (S[222]) via casein kinase 2 (CK2) which prevents CDCA3 degradation in NSCLC cells. Moreover, the CK2 inhibitor CX-4945 reduces CDCA3 levels in cisplatin treated cells. CX-4945 increased cisplatin-induced cell death in control cells. The efficacy was further enhanced in CDCA3 depleted NSCLC cells.

Conclusion:
Our data highlight CDCA3 as a novel factor in the pathogenesis of NSCLC. We propose that preventing cisplatin-induced CDCA3 phosphorylation by targeting CK2 is a worthwhile and novel strategy in treating NSCLC and may ultimately benefit patient outcome by preventing cisplatin resistance.

Abstract not provided

Abstract:
Brain metastases (BMs) concern more than 10-15% of patients with stage IV NSCLC at baseline and more than 40% during the disease course. The wider use of MRI and improvement of extra-cranial systemic disease control contribute to increase the BMs incidence. The issue of BMs is critical in the management of NSCLC patients in the perspective of the neurological consequences of brain lesions. BMs occurrence is synonymous of a poor outcome in NSCLC but reflects in fact many different situations. Establishing a therapeutic strategy needs first to assess their prognosis; the most appropriate scale is the Graded Prognostic Assessment for Lung Cancer Using Molecular Markers including as prognostic factors EGFR mutations and ALK rearrangement in addition to age, number of BMs, extra-cranial disease and Karnofsky status, with a median survival varying from 3.0 months for the worse subgroup (GPA 0.5-1) to 46.8 months for patients with oncogene addiction and good prognostic factors (GPA 3.5-4). The second step is to evaluate the indications, efficacy and side effects of available therapeutic "weapons". Corticosteroids are active against cerebral edema and improve symptoms. Whole brain radiotherapy (WBRT) has been for decades the treatment "reflex" of BMs but the emergence of stereotactic radiosurgery (SRS) or radiotherapy (SRT) and the issue of neurocognitive complications led to deferral or omission of WBRT in an increasing number of patients. WBRT remains indicated in patients with symptomatic, large (≥3 cm) and numerous BM. However, palliative WBRT did not provide any benefit in terms of survival, quality of life and QUALYs compared to supportive care alone in the Quartz trial; the subgroup analysis suggests a benefit only in patients with better prognostic factors. Neuroprotective strategies as sparing hippocampi during WBRT are currently evaluated. SRS defined by invasive contention with sub-millimeter accuracy or noninvasive SRT with millimeter accuracy are indicated in case of 1 to 3 BMs (but now up to 10 lesions) with a diameter <3 cm, alone or as a boost on the top of WBRT. SRS/SRT alone avoids neurocognitive toxicity of WBRT and provides a similar OS to that of surgical resection when using SRS/SRT for patients with operable lesions. Radionecrosis is observed in 10-17% of patients treated with SRS/SRT, making difficult the distinction with a tumor relapse. In spite of reduction in local and distant brain failures or in death from neurological causes, adjuvant WBRT after SRS/SRT does not improve overall survival and has a detrimental effect on neurocognitive functions and quality of life. Surgical resection of BMs achieves survival and functional benefit in addition to WBRT. Surgery is indicated in case of a symptomatic lesion, larger than 2 cm, with a mass effect, allowing fast improvement of symptoms. The invasive edge of BMs explains the high local recurrence rate after resection and the need for adjuvant radiotherapy. WBRT is progressively less used in favor of SRS/SRT despite a better intracranial control rate because of a higher rate of cognitive deterioration. Systemic treatment remains critical for extracranial systemic control of the disease. Brain-blood barrier limits the brain penetration of systemic agents, especially with efflux transporters as P-gp, for which many TKIs and cytotoxic agents are substrates. BMs usually cause brain-blood barrier disruption with heterogeneous drug penetration. Cytotoxic chemotherapy provides similar response rates in BMs to those of extracranial disease. Anti-PD-1 antibodies seem to be active in the brain but available data are scarce. First and second-generation EGFR TKIs have a low brain penetration but sufficient to obtain response rates similar to those achieved for systemic disease; duration of response might be inferior. Osimertinib has a better CNS penetration. For ALK+ disease, crizotinib is a P-gp substrate with a low blood/CSF concentration ratio and brain is the most frequent site of progression. Next-generation ALK TKIs have a better CNS diffusion; alectinib largely decreases the cumulative incidence of BMs compared to crizotinib. Concurrent administration of TKIs with brain radiotherapy is controversial and is not recommended outside of a clinical trial. Defining an optimal multidisciplinary strategy needs to take into account many parameters, including number, location and size of brain metastases, leptomeningeal lesions, neurological symptoms, risk factors for neurocognitive alteration, extracranial metastases and their control, primary lung tumor control, and identification of a targetable oncogenic addiction. In absence of a targetable genomic alteration, BMs at baseline can benefit from systemic treatment alone in selected patients with no neurological symptoms, small intracranial tumor burden, low risk of impending neurologic issues, on the condition that they are closely monitored; brain radiotherapy can be safely deferred to intracranial progression. Symptomatic BMs require local treatment, by favoring SRS/SRT rather than WBRT; adjuvant WBRT is not recommended but further close monitoring is mandatory to detect new intra-cranial lesions. Surgery is preferred for large lesions, posterior fossa location or diagnosis; adjuvant SRS/SRT is mandatory to avoid local recurrences. WBRT remains indicated for multiple symptomatic lesions not eligible for SRS/SRT except in poor PS patients. In case of EGFR mutations, asymptomatic patients with BMs are treated with first or second-generation EGFR TKIs but must be closely watched with repeated brain imaging. A recent retrospective study suggests that front-line SRS/SRT might improve overall survival as CNS remains a sanctuary site in oncogene-addicted disease. Symptomatic patients are locally treated, favoring SRS/SRT requiring only a short interruption of systemic treatment. For patients with ALK+ disease, the advent of alectinib as standard front-line treatment should change the management approach to BMs: the low incidence of BMs should allow spacing brain monitoring while the high intra-cranial response rate should permit to delay local treatment. For ALK+ patients developing BMs on ALK TKI, local treatment with SRS/SRT or surgery if necessary is the first option; switching to another TKI with a better brain penetration is another option for patients candidates to WBRT. The longer life expectancy of ALK+ patients leads to defer as far as possible the use of WBRT. However, improvement of intracranial control should be considered in patients at preferential risk of dying from intracranial progression, independently on mutational status.

Abstract:
The management of brain metastases remains a challenging issue due to the detrimental impact on the patient quality of life and the wide range of clinical situations. The question is not a local treatment or WBRT but when and how to use the different modalities for each patient. Survival, an endpoint often used, is probably not the best way to evaluate the local efficacy: most patients will died from progressive extracranial disease. The brain tumor control (local or freedom from new brain metastases) is a better way to assess the impact of WBRT or SBRT. Another major problem is the great heterogeneity of the primary tumors and clinical situations. First, we should remember that most patients are not candidate for a local treatment (SBRT or surgery (S)) due to the number of lesions, locations, performance status, meningeal infiltration…and WBRT remains the standard treatment if a brain irradiation is needed. For patients with an “oligo metastatic disease”, many studies have clearly showed the superiority of a form of local treatment (S or SBRT) compared to WBRT at least in term of progression or control at the primary brain site (table1)(1-5). Another issue is to control the disease within the brain: new brain metastases are very common. WBRT has been tested either after S or SBRT to prevent the development of those new lesions: indeed adding WBRT let to a better brain tumor control but this did not translate in any major survival benefit. One major drawback of WBRT is its possible toxicity: the impact on the quality of life, the neurocognitive toxicity, the fatigue and the hair loss. In the EORTC trial, WBRT had a transitory negative impact on the physical or cognitive functioning and more fatigue in the early period of observation compared to the group of patients in the observation arm (6.). A current approach is to follow the patient after SBRT and in case of relapse to propose a salvage treatment which may be a new course of SBRT or even WBRT. Another question was to improve the local control after S adding SBRT. Postoperative SBRT has been proposed and several retrospective studies have shown the feasibility results. Two recently published randomized trials have compared postoperative SBRT to either WBRT or observation. The two main conclusions were less cognitive deterioration with SBRT compared to WBRT( 15% vs 48%) and less local relapse at the primary site compared to no treatment (at 1 year 43% vs 72%) but no difference in overall survival (4,5). An intriguing observation was the better local control at one year after postoperative WBRT compared to SBRT (4). Is there a group of patients benefiting from WBRT? In a new analysis of the Aoyama trial, patients with NSCLC were divided according to a graded prognostic assessment: a statistically significant benefit was observed only in the favorable group with a 6 months gain in median survival (7). A similar observation was reported in the RTOG trial testing the role of adding SBRT to WBRT with a median survival of 14 vs 21 months (8). Is it possible to reduce WBRT toxicity? The hippocampus region play an important role in the preservation of the neurocognitive functions: techniques have been developed to spare the hippocampus region keeping the dose below 7 Gy with a better quality of life and a very low risk of new brain metastases occurring in this spared regions (9). This approach should be tested in large scale phase III trial. Last but not least, the timing of the treatment should be individualized based on the patient needs, and in asymptomatic patients, SBRT may be safely postponed if a systemic treatment is to be administered.

Authors	Treatment	Evaluation Time	Local Control	Brain Tumor Control
Aoyama Kocher Andrews Brown Mahajan	SBRT SBRT+WBRT Surgery Surg+WBRT SBRT SBRT+WBRT WBRT WBRT+SBRT Surg+WBRT Surg +SBRT Surg SURG.SBRT	1 Y 2 Y 1Y 1Y 1 Y	72% 88% 41% 73% 69% 81% 60% 74% 78% 55% 45% 72%	23% 53% 58% 77% 52% 67% 51% 62% 69% 32% 33% 43%

· Estimated from figures References 1.Aoyama H., Tago M., Shirato H. for the Japanese Radiation Oncology study Group 99-1 (JROSG 99-1) investigators Stereotactic radiosurgery with or without whole-brain radiotherapy for brain metastases. Secondary analysis of the JROSG-99 randomized clinical trial JAM Oncol. 2015; 1: 457-464 2.Kocher M., Soffietti R., Abacioglu U., et al Adjuvant whole-brain radiotherapy versus observation after surgical resection of one to three cerebral metastases: results of the EORTC 22952-26001 study. J.Clin.Oncol. 2011; 29:131-141 3.Andrews D.W., Scott C.B., Sperduto D.W. et al Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: Phase III results of the RTOG 9508 randomised trial Lancet 2004; 363:1665-72 4.Brown PD, Ballman KV, Cerhan JH,et al Postoperative stereotactic radiosurgery compared with whole brain radiotherapy for resected metastatic brain disease (NCCTG N107C/CEC·3): a multicentre, randomised, controlled, phase 3 trial.Lancet Oncol. 2017 Jul 4. pii: S1470-2045(17)30441-2. doi: 10.1016/S1470-2045(17)30441-2. [Epub ahead of print] 5.Mahajan A, Ahmed S, McAleer MF, et al Post-operative stereotactic radiosurgery versus observation for completely resected brain metastases: a single-centre, randomised, controlled, phase 3 trial. Lancet Oncol. 2017 Jul 4. pii: S1470-2045(17)30414-X. doi: 10.1016/S1470-2045(17)30414-X. [Epub ahead of print) 6.Soffietti R., Kocher M., Abacioglu U., et al A European Organiszation for Research and Treatment of Cancer phase III trial of adjuvant whole-brain radiotherapy versus observation after surgical resection of one to three cerebral metastases: quality of life results J.Clin.Oncol. 2011; 31:65-72 7.Aoyama H., Tago M., Shirato H. et al Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial JAMA 2006; 295: 2483-91 8.Sperduto P.W., Shanley R., Luo X., et al Secondary analysis of RTOG 9508, a phase 3 randomized trial of whole-brain radiation verus WBRT plus stereotactic radiosurgery in patients with 1-3 brain metastases; poststratified by the graded prognostic assessment (GPA). Int.J.Radiat.Biol.Phys. 2014; 90: 526-531 9.Gondi V., Hermann B.P., Mehta M.P., Tome W.A. Hippocampal dosimetry predicts neurocognitive function impairment after fractionated stereotactic radiotherapy for benign or low-grade adult brain tumors. Int. J. Radiat. Oncol. Biol. Phys. 2012 ; 83 : 487–93

Abstract not provided

Abstract:
The optimal management of patients with CNS metastases from lung cancer should be a multidisciplinary approach which encompasses supportive therapy, local CNS-directed therapies including surgery, stereotactic radiosurgery (SRS) and whole brain radiotherapy (WBRT), and most importantly systemic therapy. In the case of patients with small cell lung cancer (SCLC), both the primary tumour and systemic metastases are generally chemosensitive, at least initially. Most studies suggested that brain metastases are as sensitive to systemic chemotherapy as extracranial disease. The concept of the brain as a pharmacologic sanctuary site for established metastases is in contrast with clinical observations of frequent responses in brain metastases to systemic chemotherapy. Response rates (RRs) of brain metastases from SCLC to systemic chemotherapy in treatment naive patients have been reported to range from 27% to 85%. RRs in previously treated patients with brain metastases range from 22% to 50% and are comparable to the RRs with second-line chemotherapy observed in extracranial disease. A meta-analysis of five studies with a single chemotherapy for pretreated patients showed RRs ranging from 33% to 43%.[1] Adding WBRT to chemotherapy increases the RR of the brain metastases, but does not appear to improve survival as shown in a phase III trial by the European Organization for Research and Treatment of Cancer.[2] For patients with advanced non-small cell lung cancer (NSCLC) without molecular drivers, chemotherapy is the mainstay of treatment. Although NSCLC is less responsive to systemic chemotherapy than SCLC, results of combining platinum compounds and third generation agents are substantially better than with earlier regimens. Platinum-based doublets are the cornerstone treatment in the first-line setting for metastatic NSCLC.[3] There is a presumed lack of effectiveness of systemic chemotherapy in CNS metastases from NSCLC because of the belief that chemotherapeutic drugs cannot cross the blood-brain barrier (BBB).[4] However, there is increasing evidence that the integrity of the BBB is impaired and disrupted in the presence of macroscopic CNS metastases. Despite a low penetration of the CNS, chemotherapy drugs have demonstrated encouraging activity against CNS metastases from NSCLC. A number of phase II studies reported RRs to cisplatin-based combination chemotherapy regimens ranging from 35% to 50%. Several clinical trials with upfront platinum-based chemotherapy have shown intracranial RRs ranging from 23% to 50% which correlated with and almost comparable to systemic RRs.[5 ]These data suggest that the intrinsic sensitivity of the tumour to the cytotoxic drug is more important in predicting response to the chemotherapeutic drug than the theoretical expected ability of the drug to penetrate the BBB. There are few randomised phase III trials of advanced or metastatic NSCLC evaluating different kinds of treatment in patients with brain metastases because generally, such patients have been excluded from clinical trials because of poor prognosis. Despite a penetration of CNS of less than 5%, pemetrexed demonstrated a consistent activity against brain metastases from NSCLC. One of the first evidence of pemetrexed activity against brain metastases came from a retrospective Italian study by Bearz and colleagues on 39 NSCLC patients with CNS metastases treated with pemetrexed as second or third line.[6] Although the patients were unselected for histology, the study reported an intracranial RR of 30.8%, with clinical benefit obtained in 69% of patients. All patients who had an overall response (i.e., partial response and stable disease) to pemetrexed had a benefit over cerebral metastases as well with partial response in 11 patients (28.2%) and stable disease in 21 (53.8%), with a clinical benefit rate of 82% for CNS metastases and an overall survival (OS) of 10 months. The addition of platinum compounds to pemetrexed slightly improved the outcome as shown in subsequent studies. In a phase II trial on 43 chemotherapy naïve NSCLC with brain metastases (93% with non-squamous histology) treated with pemetrexed and cisplatin for six cycles, the intracranial RR was 41.9%.[7] A comparable intracranial RR of 40% was observed when pemetrexed was combined with carboplatin in an observational study on 30 patients with adenocarcinoma and brain metastases.[8] These clinical trials showed that platinum-based regimens are active against brain metastases from NSCLC and high RRs can be achieved with pemetrexed-containing regimens in patients with non-squamous NSCLC. A post-hoc analysis of a large prospective observational European study on 1,564 patients with newly diagnosed advanced NSCLC receiving first-line platinum-based regimens showed that in the subgroup of 263 patients with brain metastases the median OS was 7.2 months which ranged from 5.6 months for patients treated with cisplatin/gemcitabine up to 9.3 months for those treated with platinum/pemetrexed.[9] In conclusion, systemic chemotherapy is an important part of the multidisciplinary managment of CNS metastases. Patients with small asymptomatic brain metastases from SCLC and NSCLC should be treated with the most active platinum-based combination chemotherapy upfront. Radiation therapy and other CNS-directed treatment may be deferred until the effects of the systemic chemotherapy on the CNS metastases can be determined. References 1. Grossi F, Scolaro T, Tixi L, et al. The role of systemic chemotherapy in the treatment of brain metastases from small-cell lung cancer. Crit Rev Oncol Hematol 2001; 37:61-7. 2. Postmus PE, Haaxma-Reiche H, Smit EF, et al. Treatment of brain metastases of small-cell lung cancer: comparing teniposide and teniposide with whole-brain radiotherapy--a phase III study of the European Organization for the Research and Treatment of Cancer Lung Cancer Cooperative Group. J Clin Oncol 2000; 18:3400. 3. Du L, Morgensztern D. Chemotherapy for Advanced- Stage Non-Small Cell Lung Cancer. Cancer J 2015;21:366-70. 4. Schuette W. Treatment of brain metastases from lung cancer: chemotherapy. Lung Cancer 2004; 45:S253-7. 5. Zimmermann S, Dziadziuszko R, Peters S. Indications and limitations of chemotherapy and targeted agents in non-small cell lung cancer brain metastases. Cancer Treat Rev 2014; 40:716-22. 6. Bearz A, Garassino I, Tiseo M, et al. Activity of Pemetrexed on brain metastases from Non-Small Cell Lung Cancer. Lung Cancer 2010; 68:264-8. 7. Barlesi F, Gervais R, Lena H, et al. Pemetrexed and cisplatin as first-line chemotherapy for advanced non-small-cell lung cancer (NSCLC) with asymptomatic inoperable brain metastases: a multicenter phase II trial (GFPC 07-01). Ann Oncol 2011; 22:2466-70 8. Bailon O, Chouahnia K, Augier A, et al. Upfront association of carboplatin plus pemetrexed in patients with brain metastases of lung adenocarcinoma. Neuro Oncol 2012; 14:491-5. 9. Moro-Sibilot D, Smit E, de Castro Carpeño J, et al. Non-small Non-small cell lung cancer patients with brain metastases treated with first-line platinum-doublet chemotherapy: Analysis from the European FRAME study. Lung Cancer 2015; 90:427-32.

Abstract:
Central nervous system (CNS) metastases including brain metastasis (BM) and leptomeningeal metastasis (LM) are associated with poor prognosis in non-small cell lung cancer (NSCLC). The epidermal growth factor receptor (EGFR) mutations were initially reported in 2004 and currently defined the most prevalent actionable genomically classified subgroup of NSCLC, which account for 40% of Asian patients and 10-15% of White or African American patients. Patients with EGFR mutant NSCLC may have a higher incidence of CNS metastases due to prolonged survival with targeted agents and the increased quality of CNS imaging. More than 50% of NSCLC patients with EGFR mutation develop CNS metastases during their lifetime (1). The median overall survival (OS) for patients with BM is around 16 months (2) and 4.5-11 months for those with LM (3). Whole brain radiotherapy (WBRT), stereotactic radiosurgery (SRS), or surgery is widely used for BM, whereas no standard therapy is available for LM. Moreover, the benefit of radiotherapy is limited due to toxicities and long term sequelae. Brain is a privileged site, sheltered from the systemic circulation by the blood-brain-barrier (BBB), which is highly specialized structure with tight junctions created by the interaction between astrocytes, pericytes and endothelium. In addition, numerous efflux transporters (e.g. P-glycoprotein) have been identified, leading to prevent many traditional drugs from the circulation into the brain parenchyma. Although the permeation of EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib or erlotinib across the BBB has been reported, the cerebrospinal fluid (CSF) concentrations of TKIs at standard doses comprise only small fraction of the plasma concentration indicating the limited ability to permeate into the CSF (4). Several small series of phase II studies reported that EGFR TKIs, gefitinib, erlotinib or afatinib show CNS response rate of 55 to 89%, median PFS of 5.8 to 14.5 months and median OS of 15.9 to 22.9 months in patients with brain metastases. Recently, new generation EGFR TKI, AZD 3759 which is designed to effectively penetrate BBB demonstrated profound anti-tumor activity in preclinical models. Phase I study showed the free plasma concentration of AZD 3759 was approximately at the same range as that in CSF and yielded K~p,uu~,~CSF~ values of 1.18 and 1.00 for 200mg and 300mg, respectively. Tumor responses were observed in 83% and 72% of the patients with CNS and extracranial disease respectively in EGFR TKI naïve NSCLC (5). Osimertinib, a third generation EGFR TKI designed to target both activating EGFR mutation and T790M but sparing wild type EGFR, distributed into mouse brain to a greater extent than gefitinib (brain/plasma ratio 3.4 for osimertinib vs 0.21 for gefitinib). Osimertinib showed significant brain exposure and tumor shrinkage in preclinical brain metastases model. In 50 of 411 evaluable for CNS response in pooled AURA phase II study, osimertinib showed 53% of response rate and the median CNS PFS has not been reached (6). Confirmatory phase III study comparing osimertinib with platinum-doublets in T790M positive patients demonstrated significant improvement of PFS regardless of CNS metastases suggesting this agent has benefit in patients with CNS metastases. Recently released press showed that first-line osimertinib comparing with gefitinib/erlotinib (FLAURA) met the primary endpoint of PFS. It would be interesting to evaluate whether upfront use of osimertinib in EGFR mutant NSCLC can delay CNS metastases. Given the relatively high response rate in brain metastasis with EGFR TKI, the upfront use of EGFR TKI can delay other local therapies such as WBRT, SRS or surgery, leading to reduced side effects related to local therapy. However, the retrospective multi-institutional analysis demonstrated that the use of upfront EGFR TKI and deferral of radiotherapy is associated with inferior OS in patients with EGFR mutant NSCLC who developed brain metastases (7). Based on the potential synergistic effects of the combination of EGFR TKIs and radiotherapy due to opening of BBB by radiotherapy, several prospective trials were conducted. A phase II study of erlotinib combined with WBRT in 40 patients with NSCLC achieved 86% of response rate, 11.8 months of overall survival, whereas 19.1 months in patients with EGFR mutation (8). The Radiation Therapy Oncology Group conducted a phase II trial of WBRT and SRS alone or with either temozolomide or erlotinib for NSCLC patients with one to three brain metastases (EGFR mutation status was not tested). This study was closed early due to slow accrual and three arms did not show any differences in terms of efficacy. However, grade 3 to 5 toxicities were 41-49% in two concurrent drug combination arms. Thus, prospective randomized trial of SRS followed by EGFR TKI vs EGFR TKI followed by SRS at CNS progression is needed. Leptomeningeal disease (LM) is a fatal manifestation and its incidence is increasing in EGFR mutant NSCLC up to 10%. The prognosis remains very poor despite systemic treatment, intrathecal chemotherapy, radiotherapy and even molecular targeted therapy. Although EGFR TKIs have shown promising efficacy in the treatment of LM, especially with high dose or pulsatile dosing, the duration of efficacy is still limited with lack of survival improvement (9). Compared to gefitinib, erlotinib showed higher CSF concentrations (28.7 vs 3.7 ng/ml) and retrospective analysis showed promising activity with erlotinib in LM. It is not clear whether combination of intrathecal chemotherapy or WBRT can be applied to EGFR mutant NSCLC patients. Given the significantly higher penetration across the BBB (K~p,uu,brain ~=0.86) of AZD 3759, AZD3759 showed 28% of response rate (5/18) in TKI pretreated LM patients and 75% (3/4) in TKI naïve patients suggesting promising efficacy. The mean osimertinib concentration in CSF was 7.5nM in the T790M unselected cohort and AZD 9291 at 160mg once daily demonstrated encouraging activity with 43% of LM disease response and manageable tolerability (10). Both agents are currently being investigated in a larger cohort of patients with brain metastasis and leptomeningeal disease. Another challenge of conducting clinical trial in patients with LM is lack of standardized response evaluation method. Combinational measurements including neurological sign, CNS imaging and CSF cytology have been proposed, but further validation is warranted. In conclusion, CNS metastases in EGFR mutant NSCLC are increasing. Although EGFR TKI has been reported to improve clinical outcome, isolated or pre-dominant progression of CNS metastases remains a major issue in patients on EGFR inhibitors due to relative low penetration to BBB. New generation EGFR TKIs with better BBB penetration might have an impact on therapeutic strategies. Further studies are required to evaluate the optimal sequence of EGFR TKI therapy and radiotherapy. References Rangachari D, , et al. Brain metastases in patients with EGFR-mutated or ALK-rearranged non-small-cell lung cancers. Lung Cancer 2015; 88: 108-11. Fan Y, Xu X, Xie C. EGFR-TKI therapy for patients with brain metastases from non-small-cell lung cancer: a pooled analysis of published data. Onco Targets Ther 2014; 7: 2075-84. Umemura S, Tsubouchi K, Yoshioka H, et al. Clinical outcome in patients with leptomeningeal metastasis from non-small-cell lung cancer: Okayama Lung Cancer Study Group. Lung Cancer 2012; 77: 134-9. Togashi Y, Masago K, Masuda S, et al. Cerebrospinal fluid concentration of gefitinib and erlotinib in patients with non-small cell lung cancer. Cancer Chemother Pharmacol 70: 399-405, 2012. Ahn MJ, Kim DW, Kim TM, et al. Phase I study of AZD3759, a CNS penetrable EGFR inhibitor, for the treatment of non-small-cell lung cancer (NSCLC) with brain metastasis (BM) and leptomeningeal metastasis (LM)., ASCO Meeting Abstracts. 34 (2016) 9003. Goss G, Tsai CM, Shepherd F, et al. CNS Response to osimertinib in patients with T790M-positive advanced NSCLC: Pooled data from two phase II trials. J Thorac Oncol Vol. 12 No. 1S (MA16.11)x William J. Magnuson, Nataniel H. Lester-Coll, et al. Management of brain metastases in tyrosine kinase inhibitor–naïve epidermal growth factor receptor–mutant non–small-cell lung cancer: A retrospective multi-institutional analysis. J Clin Oncol 35:1070-1077.James Chih-Hsin Yang Welsh JW, Komaki R, Amini A, et al. Phase II trial of erlotinib plus concurrent whole-brain radiation therapy for patients with brain metastases from non-small-cell lung cancer. J Clin Oncol 31: 895-902, 2013. Yu HA, Sima CS, Reales D, et al. A phase I study of twice weekly pulse dose and daily low dose erlotinib as initial treatment for patients (pts) with EGFR-mutant lung cancers. J Clin Oncol33(Suppl 15s): 426s, 2015. Yang J.C.-H, Kim DW, Kim, SW, et al. Osimertinib activity in patients (pts) with leptomeningeal (LM) disease from non-small cell lung cancer (NSCLC): Updated results from BLOOM, a phase I study., ASCO Meeting Abstracts. 34 (2016) 9002.Search for articles by this authorAffiliations Cancer Research Center, National Taiwan University, Taipei/Taiwan

Abstract not provided

Abstract not provided

Abstract:
The suitable characteristics of the carcinoma for definitive radiotherapy (RT) are that (a) involved areas of the disease can be covered by adequate planning target volume (PTV), and that (b) the tumor cells can be sterilized with under tolerable doses for the surrounding normal tissues. Among non-small cell lung cancer (NSCLC), squamous cell carcinoma (SQ) has the characteristics to grow locally, to spread proximally along the trachea-bronchial trees and to develop regional nodal metastases. In SQ, furthermore, surgical resection is well known to be effective even for locally advanced disease. On the other hand, non-SQ has the tendency to develop distant metastases at early T-stage. In a randomized controlled trial comparing continuous, hyperfractionated, accelerated radiotherapy (CHART) (54Gy/36fr in 12 consecutive days) with conventional RT (60Gy/30fr in 6 weeks), the SQ patients had absolute advantages of CHART in both local progression-free survival (LPFS) and overall survival (OS). Therefore, SQ is considered to be a good candidate for intensive loco-regional treatment. In RTOG 0617 trial of standard-dose versus high-dose conformal RT with concurrent and consolidation carboplatin + paclitaxel with or without cetuximab for patients with stage IIIA/B NSCLC, an EGFR H-score less than 200 (low EGFR expression) was noted more commonly in non-SQ patients whereas an EGFR H score of 200 or more (EGFR-overexpression) was more common in SQ patients (p=0.0003). In patients with an H score of 200 or higher, median OS for the cetuximab group was 42.0 months (95% CI 20.6–not reached) versus 21.2 months (17.2–29.2) for the no-cetuximab group. These results suggested that SQ patients might benefit from the addition of cetuximab to chemoradiation like SQ of the head and neck. Furthermore, on phase II study of nimotuzumab in combination with concurrent chemoradiotherapy for Japanese patients with locally advanced NSCLC, the LPFS was significantly better for SQ patients than for non-SQ patients. The results also suggested that the low in-field relapse rates might be attributed to the radio-sensitizing effect of nimotuzumab and contribute to the improved OS of SQ patients. By contrast, non-SQ patients did not benefit from nimotuzumab because the distant relapse rate was significantly higher for non-SQ than that for SQ. In non-SQ histology, EGFR mutations are well known to often appear especially in adenocarcinoma. Some clinical trials of EGFR-TKI combined with standard platinum-based chemoradiotherapy for EGFR-mutant locally advanced NSCLC are ongoing in Japan. In the future direction, the locally intensified chemoradiotherapy using high-precision RT techniques and advanced radiation sensitizers including molecular targeting drugs may be more important for SQ and newly developed systemic therapies with powers of sterilizing subclinical distant metastases may be more effective for non-SQ among locally advanced NSCLC.

Abstract:
Introduction: Recently, systemic approaches to inperable non-small-cell lung cancer (NSCLC) in stage IV disease have been significantly improved by the introduction of a new treatment modality: immunotherapy with PD-1 antibodies. Currently, nivolumab is registered for the second-line therapy of NSCLC without prerequisite of PD-L1 expression in tumor tissue. Pembrolizumab has been registered for PD-L1 positive (> or = 1% TPS) patients in second-line and for high expressors (> or = 50% TPS) also in the first-line setting. In some countries already platinum-based combination chemotherapy (CTx) plus pembrolizumab is accepted for first-line therapy of medium expressors (1-49% TPS) and also for high expressors. Other PD-L1 antibodies have already achieved positive phase-III results (atezolizumab) or large phase-III trials have finished accrual and final results are awaited (eg. durvalumab). Based on these paradigms, the rationale for combinations with radiotherapy (RTx) in NSCLC is analyzed and trial design of currently ongoing studies as well as reported signals of first results are summarized. Material and Methods: Clinicaltrials.gov has been searched for ongoing and active clinical trials with immmunotherapy and RTx. We divided NSCLC strategies into a) locally advanced and inoperable NSCLC stage III b) advanced and inoperable stage IV NSCLC (episcopal effect) c) combinations of immunotherapy and stereotactic RTx in early disease NSCLC d) oligometastatic disease. Results: a) introduction of PD-1 antibodies into treatment strategies of inoperable stage III NSCLC will get a significant booster efffect by the recently reported outcome signals of the Pacific Trial looking at durvalumab consolidation therapy versus placebo following concurrent CTx/RTx in stage III NSCLC (press release, AZ, May 2017). PFS was signifcantly longer for the administration of durvalumab as maintenance in this situation. We expect presentation of the final results at an important Lung Cancer conference during this fall. Theroretically, intoduction by DNA double-strand breaks in patients following concurrent CTx/RTx or RTx alone could lead to an increase in tumor mutational load and could potentially enhance the efficacy of any PD-1- or PD-L1-antibody therapy. A consolidation therapy of PD-1-antibody treatment following concurrent chemoradiotherapy aiming at cure was found to be a rational strategy to improve long-term survival results in inoperable stage III NSCLC. Other trials ongoing are looking at combinations of RTx with concurrent PD-1 immunotherapy or concurrent CTx/RTx combined with concurrent adminstration of PD-1 antibody therapy.Trials outlines will be summarized and presented. Only one phase-II study including pembrolizumab has maintenenance has already been presented with ist results at ASCO 2017. Treatement was manageable and toxicity acceptable. First signals shown efficacy of this strategy but final survival data are pending. Other clincial trials are currently also looking at combinations of CTx and PD-1-immunotherapy and concurrent RTx. Also other immunotherapy drugs such as CTLA4-antibodies or combinations of both PD-1(eg. nivolumab, pembrolizumab, atezolizumab, durvalumab) and CTLA4-antibodies (ipilimumab, tremelimumab) are also being investigated in stage III NSCLC. b) few trials are also looking to enhance systemic effects of immunotherapy (PD-1/PD-L1 and CTLA-4) and concurrent RTx of tumor lesions. The so called "episcopal effect" is being investigated within several clinical studies. Theoretically, the release of tumor associated antigens (TAA) by RTx given to specific tumor lesions leading to tumor lysis including the release of antigens into the circulation could potentially enhance the systemic immunological effects of checkpoint-inhibitor therapies. Well-selected case reports have given hints to support such thesis but only randomized trials will finally verify if this approach is really valid and worthwhile. c) the stereotactic and, therefore, locally ablative RTx techniques also aiming at early inoperable NSCLC patients could also potentially benefit from combinations with new immunotherapy. Several trials are underway for combinations with nivolumab, pembrolizumab, atezolizumab and durvalumab. Finally, for all mentioned treatment strategies concurrent versus sequential administration of immunotherapy and RTx is a complete open issue. Also, permutations including combinations together with platinum-based CTx and immunotherapy together with RTx have recently become very attractive. d) Last but not least, the patient group of oligometastatic patients (M1a, M1b, M1c with less than four lesions in one organ, eg. brain) seems to be a very interesting group of patients to increase both local as well as systemic control of the treatment. Conclusions: Consolidation durvalumab may potentially become the first strategy to become a new paradigm of treatment for stage III NSCLC. We will have to wait for the final results of that trial to draw more valid conclusions for future treatment strategies. However, based on the inclusion of new immunotherapy with checkpoint inhibitors already into the standard treatment algorithms of stage IV disease in NSCLC it can be predicted that also in other disease settings these innovative approches may finally extend our potential treatment options - at least for well selected patient subsets. Referrences: Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012 Jun 28;366(26):2455-65. doi: 10.1056/NEJMoa1200694. Epub 2012 Jun 2. Rizvi NA, Mazières J, Planchard D,et al. Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Lancet Oncol. 2015 Mar;16(3):257-65. doi: 10.1016/S1470-2045(15)70054-9. Epub 2015 Feb 20. Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med. 2015 Jul 9;373(2):123-35. doi: 10.1056/NEJMoa1504627. Epub 2015 May 31. Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med. 2015 Oct 22;373(17):1627-39. doi: 10.1056/NEJMoa1507643. Epub 2015 Sep 27. Garon EB, Rizvi NA, Hui R, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 2015 May 21;372(21):2018-28. doi: 10.1056/NEJMoa1501824. Epub 2015 Apr 19. Herbst RS, Baas P, Kim DW, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016 Apr 9;387(10027):1540-50. doi: 10.1016/S0140-6736(15)01281-7. Epub 2015 Dec 19. Rittmeyer A, Barlesi F, Waterkamp D, et al. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet. 2017 Jan 21;389(10066):255-265. doi: 10.1016/S0140-6736(16)32517-X. Epub 2016 Dec 13. Reck M, Rodríguez-Abreu D, Robinson AG, et al. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2016 Nov 10;375(19):1823-1833. Epub 2016 Oct 8. Hellmann MD, Rizvi NA, Goldman JW,et al. Nivolumab plus ipilimumab as first-line treatment for advanced non-small-cell lung cancer (CheckMate 012): results of an open-label, phase 1, multicohort study. Lancet Oncol. 2017 Jan;18(1):31-41. doi: 10.1016/S1470-2045(16)30624-6. Epub 2016 Dec 5. Langer CJ, Gadgeel SM, Borghaei H, et al. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol. 2016 Nov;17(11):1497-1508. doi: 10.1016/S1470-2045(16)30498-3. Epub 2016 Oct 10. Rizvi NA, Hellmann MD, Snyder A, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015 Apr 3;348(6230):124-8. doi: 10.1126/science.aaa1348. Epub 2015 Mar 12. https://www.astrazeneca.com/content/astraz/media-centre/press-releases/2017/imfinzi-significantly-reduces-the-risk-of-disease-worsening-or-death-in-the-phase-iii-pacific-trial-for-stage-iii-unresectable-lung-cancer-12052017.html

Abstract:
Chemotherapy combined with radiation therapy has become standard treatment for inoperable non-small cell lung cancer (NSCLC). The combination was first proposed in the 1970s. Although induction (neoadjuvant) chemotherapy followed by radiation therapy was initially considered preferable owing to concerns about toxicity, it eventually became clear that concurrent treatment was more effective. Similarly, low-dose radiation therapy was thought to be the safest, and radiation oncologists were loath to use any dose/fractionation regimen that exceeded standard approaches with radiation therapy alone. Chemotherapy evolved in a similar fashion. At first, single agents were used, followed by tests of various combinations of different drugs, with eventual acceptance of 2-drug combination regimens, usually consisting of a platinum compound with another agent. These regimens were combined with standard radiation therapy, usually to a dose of 60 Gy in 30 fractions using three-dimensional conformal radiation therapy (3D CRT), planned on the basis of computed tomography (CT); this combination produced tolerable adverse effect profiles that were less severe than those after the previous standard of 2D treatments based on plane radiography. The next iteration of external-beam radiation therapy was intensity-modulated radiation therapy (IMRT), which involves directing multiple beamlets at the tumor while limiting the doses to surrounding critical structures. IMRT, which depends on CT imaging for staging and treatment planning, also allowed higher fraction sizes and total doses to be tested in attempts to increase tumor control. However, use of higher total doses has had potentially intimidating results in clinical trials. In a recent prospective clinical trial of the Radiation Therapy Oncology Group (RTOG 0617) in which standard-dose 60 Gy in 30 fractions given over 6 weeks was compared with high-dose 74 Gy in 37 fractions over 7 1/2 weeks, the higher total dose actually led to poorer local control. It has been hypothesized that failure to adequately cover the gross tumor volume in the high-dose arm resulted in the higher local failure rate. For small (T1 or T2) tumors of the lung, investigators have tested very-high-dose treatments based on 3D targeting of every fraction, an approach that requires 3D imaging capability. In the United States, achieving such precise targeting has required collaborations with medical physicists in the delivery of each fraction. The next generation of radiation therapy, stereotactic body radiation therapy or SBRT, began as a treatment for lesions in the brain. In Sweden, Leksell and colleagues developed an approach that came to be known as stereotactic radiation therapy. Considered an alternative to surgical resection, stereotactic radiation therapy was predicated on immobilizing the patient with a stereotaxic frame, using multiple cobalt-60 sources in a helmet-like configuration, and administering the radiation in a single fraction. Because the goal of this approach was controlled necrosis rather than a surgical defect, this approach also came to be known as stereotactic radiosurgery. Approximately 25 years later, a similar approach was developed in which linear accelerators were used to deliver SBRT. Similar principles were used: precise imaging with of the tumor with CT and, more recently, with fluorodeoxyglucose positron emission tomography; careful and secure immobilization with various body frames; management of respiratory motion for lesions in the thorax; intensity-modulated treatment planning; and image-guided targeting. From 1 to 5 or even 10 fractions are delivered in this manner, with both the treating physician and collaborating physicist attending each treatment to ensure consistent image guidance. This approach allows the delivery of very high biological doses. SBRT has been shown to result in local control rates of 85% to 95% for tumors up to 4 cm in diameter. Proton beam therapy is the latest means to control NSCLC, particularly for tumors that are larger than the T1 or T2 tumors usually treated with SBRT. Protons differ from photons in their interactions with tissues in the body; protons are heavy particles that produce different ionization tracks and deposit most of their energy at the end of their range. Where they come to a stop is a function of their energy when they enter the body. Protons have lower energy than photons until they reach their prescribed depth, at which point they produce a peak of ionizations, the Bragg peak. This Bragg peak can be spread out to cover the tumor in depth, and the beam can be shaped in the other two dimensions by electronic or physical means to achieve a high-dose volume that has the same size and shape of the tumor. Properly directed proton therapy essentially delivers no dose beyond the gross tumor volume. The relative biologically effective dose (RBE) of proton beam therapy is approximately the same as that of x-rays, so the effects of the doses in the tumor and the surrounding normal tissues (organs at risk) are well understood. Proton beam therapy and chemotherapy interact in predictable ways, and so the toxicity patterns are similar to those with chemotherapy and photons. However, proton therapy seems to have less severe effects on blood counts. In clinical trials to date, whether with IMRT, SBRT, or protons, the greatest need seems to be to enhance the effectiveness of the systemic treatment. Considerable interest has been expressed in combining each of these radiation delivery methods with immunotherapy. The occurrence of an occasional abscopal effect with radiation therapy has given rise to cautious enthusiasm for further exploration of this area.

Abstract not provided

Abstract not provided

Abstract:
Global tobacco control is like a gigantic cake, with innumerable slices dedicated to different tobacco control initiatives in different parts of the world. Each slice is vitally important, responsible for advancing our collective cause just that bit further. Each slice is in fact essential as the magnitude of the task simply demands a multitude of efforts and the complexity of the task – not knowing where or when the next breakthrough will occur (or where or when it will be halted due to tobacco industry interference) means that we need to simultaneously commit to a broad range of strategies. Up until a few years ago, there was, however, one slice missing - the slice that involved the finance sector. Never before had the global finance sector, and its almighty power, been leveraged in tobacco control efforts. In fact business as usual for the finance sector saw it working against every other slice of the cake. This situation was largely unintentional, simply a result of ‘doing things the way they had always been done’. Most pension funds invest in tobacco companies. Most banks lend them money. It’s been like that for about a hundred years. Professionally engaging with global finance leaders, asking them to learn about the tobacco epidemic and to reconsider commercial relationships with the tobacco industry, has seen significant changes implemented in the business models of banks, insurers, pension funds and fund managers. Since Tobacco Free Portfolios began in 2012, approximately USD $6 billion has been shifted from investment in the tobacco industry by financial institutions in ten different countries. Several banks have ceased lending money to tobacco companies and several insurers have ceased providing insurance. There is increasing acknowledgement of the significant reputational risk faced by financial organisations if they continue to maintain links with tobacco companies – companies that make products that kill two out of three of their best customers. To proceed with a tobacco-free investment decision, many conditions need to be in place. An open door to the CEOs office; willingness to consider the issue and to learn about something that sits outside the traditional paradigm of the finance sector; a country where public support of tobacco control is strong - where there is awareness of the cost-burden of tobacco, and understanding of the future financial risks associated with tobacco companies, spanning regulation, litigation and scrutiny of supply chains. Some individual finance leaders are more open to the tobacco-free conversation than others but interest is growing rapidly. Tobacco Free Portfolios is working towards a world where the global finance sector is aligned with the global health and governments sectors on tobacco. Our vision is for tobacco-free investment to be the baseline expected standard. With a forecast of one billion tobacco-related deaths this century, tobacco is a problem so profound that it cannot be adequately addressed unless every sector of society contributes to the solution. The changes witnessed in recent years are hopefully the start of a new frontier in truly comprehensive global tobacco control.

Abstract:
Cancer stem cells (CSCs) are a subset of tumor cells that are responsible for initiating and maintaining the disease. In the clinical point of view, the most important characteristics of CSCs include their resistance to various therapeutic interventions[1)]. However, the underlying mechanisms of the resistance remain unclear. CD44 has been identified as a cell surface marker associated with cancer stem cells (CSCs) in several types of epithelial tumor. We have recently found that expression of CD44, in particular variant forms of CD44 (CD44v), contributes to the defense against reactive oxygen species (ROS) by promoting the synthesis of reduced gluathione (GSH), a primary intracellular antioxidant. CD44v interacts with and stabilizes xCT, a subunit of a glutamate-cystine transporter, and thereby promotes the uptake of cystine for GSH synthesis[2)]. Therefore, ablation of CD44 reduced GSH levels and increased ROS levels, leading to suppression of tumor growth and metastasis in both transgenic and xenograft tumor models[3,4)]. Our findings reveal a novel function for CD44v in protection of CSCs from high levels of ROS in the tumor microenvironment[5)]. Expression of CD44v and xCT is associated with tumorigenesis and therapeutic resistance[6,7)]. Based on these preclinical findings, we conducted clinical trials using an xCT inhibitor, sulfasalazine, for cancer patients having advanced gastric cancer and lung cancer. The clinical trials for gastric cancers revealed that sulfasalazine treatment reduceed the number of CD44v-positive cells in post-treatment tumor tissue[8,9)]. In terms of the clinical trial for lung cancer, chemotherapy-naive patients with advanced non-squamous nonsmall cell lung cancer were enrolled in a dose-escalation study (standard 3 + 3 design) of SASP in combination with cisplatin and pemetrexed[10)]. Fifteen patients were enrolled in the study and dose-limiting toxicity was observed in one of six patients at a SASP dose of 1.5 g/day, two of five patients at 3 g/day, and two of three patients at 4.5 g/day. The maximum tolerated dose was thus 3 g/day, and the recommended dose was 1.5 g/day. The overall response rate was 26.7% and median progression-free survival (PFS) was 11.7 months, much longer than that for cisplatin–pemetrexed alone in previous studies. It is possible that the prolonged PFS was due to a sulfasalazine-induced reduction in the number of CD44v-positive CSCs that are the origin of disease recurrence. References: 1) Sugihara E and Saya H: Complexity of cancer stem cells (Review article). Int J Cancer 132:1249-1259, 2013 2) Ishimoto T, Nagano O, Yae T, Tamada M, Motohara T, Oshima H, Oshima M, Ikeda T, Asaba R, Yagi H, Masuko T, Shimizu T, Ishikawa T, Kai K, Takahashi E, Imamura Y, Baba Y, Ohmura M, Suematsu M, Baba H and Saya H: CD44 variant regulates redox status in cancer cells by stabilizing the xCT subunit of system xc- and thereby promotes tumor growth. Cancer Cell 19: 387-400, 2011 3) Yae T, Tsuchihashi K, Ishimoto T, Motohara T, Yoshikawa M, Yoshida GJ, Wada T, Masuko T, Mogushi K, Tanaka H, Osawa T, Kanki Y, Minami T, Aburatani H, Ohmura M, Kubo A, Suematsu M, Takahashi K, Saya H and Nagano O: Alternative splicing of CD44 mRNA by ESRP1 enhances lung colonization of metastatic cancer cell. Nat Commun 3: 883, 2012 4) Yoshikawa M, Tsuchihashi K, Ishimoto T, Yae T, Motohara T, Sugihara E, Onishi N, Masuko T, Yoshizawa K, Kawashiri S, Mukai M, Asoda S, Kawana H, Nakagawa T, Saya H and Nagano O: xCT inhibition depletes CD44v-expressing tumor cells that are resistant to EGFR-targeted therapy in head and neck squamous cell carcinoma. Cancer Res 73: 1855-1866, 2013 5) Nagano O, Okazaki S and Saya H: Redox regulation in stem-like cancer cells by CD44 variant isoforms (Review article). Oncogene 32: 5191-5198, 2013 6) Seishima R, Wada T, Tsuchihashi K, Okazaki S, Yoshikawa M, Oshima H, Oshima M, Sato T, Hasegawa H, Kitagawa Y, Goldenring JR, Saya H and Nagano O: Ink4a/Arf-dependent loss of parietal cells induced by oxidative stress promotes CD44-dependent gastric tumorigenesis. Cancer Prev Res 8: 492-501, 2015 7) Tsuchihashi K, Okazaki S, Ohmura M, Ishikawa M, Sampetrean O, Onishi N, Wakimoto H, Yoshikawa M, Seishima R, Iwasaki Y, Morikawa T, Abe S, Takao A, Shimizu M, Masuko T, Nagane M, Furnari FB, Akiyama T, Suematsu M, Baba E, Akashi K, Saya H and Nagano O: The EGF receptor promotes the malignant potential of glioma by regulating amino acid transport system xc(-). Cancer Res 76: 2954-2963, 2016 8) Shitara K, Doi T, Nagano O, Imamura CK, Ozeki T, Ishii Y, Tsuchihashi K, Takahashi S, Nakajima TE, Hironaka S, Fukutani M, Hasegawa H, Nomura S, Sato A, Einaga Y, Kuwata T, Saya H and Ohtsu A: Dose-escalation study for the targeting of CD44v[+] cancer stem cells by sulfasalazine in patients with advanced gastric cancer (EPOC1205). Gastric Cancer 20: 341-349, 2017 9) Shitara K, Doi T, Nagano O, Fukutani M, Hasegawa H, Nomura S, Sato A, Kuwata T, Asai K, Einaga Y, Tsuchihashi K, Suina K, Maeda Y, Saya H and Ohtsu A: Phase 1 study of sulfasalazine and cisplatin for patients with CD44v-positive gastric cancer refractory to cisplatin (EPOC1407). Gastric Cancer 2017 (in press) 10) Otsubo K, Nosaki K, Imamura CK, Ogata H, Fujita A, Sakata S, Hirai F, Toyokawa G, Iwama E, Harada T, Seto T, Takenoyama M, Ozeki T, Mushiroda T, Inada M, Kishimoto J, Tsuchihashi K, Suina K, Nagano O, Saya H, Nakanishi Y and Okamoto I: Phase I study of salazosulfapyridine in combination with cisplatin and pemetrexed for advanced non-small cell lung cancer. Cancer Sci 108: 1843-1849, 2017

Abstract:
A better understanding of the interaction between tumors and the immune microenvironment has led to the successful development of immunotherapies for tumors traditionally considered poorly immunogenic, such as non-small cell lung cancer (NSCLC). Clinically approved immunotherapies for lung cancer are based on antibodies able to reactivate cytotoxic T cells by targeting the PD-1/PD-L1 immune checkpoint. However, the substantial proportion of tumors refractory to these treatments, together with the limited predictive value of PD-L1 expression, evidences the existence of additional immune suppressive regulatory systems. This calls for a more detailed understanding of the immune cell landscape related to lung tumors. Some studies have begun to dissect the details of immune cell distribution in lung cancer lesions using multiscale immune profiling strategies. Along with adaptive immune alterations in T cells, significant innate immune cell changes have been identified (1). We have recently reviewed the role played by the innate immune system in supporting tumor-promoting activities and an immunosuppressive microenvironment (2). Innate immunity includes soluble components and immune cell populations, such as myeloid cells. Specific subpopulations of myeloid cells have been identified as specialized immunosuppressive cells. These myeloid-derived suppressor cells (MDSCs) are immature myeloid cells arrested in different stages of differentiation. The recognition of these cells as a defined cell lineage remains controversial, but their cancer-specific phenotypic and functional characteristics are manifest (3). Chronic inflammation factors released by tumors induce the accumulation of these immature cells in the bone marrow, which are released to the circulation and recruited to tumors. MDCSs are thought to be major contributors to T-cell exhaustion. They deplete the tumor microenvironment of amino acids essential for T cell proliferation (e.g. arginine) and produce immunosuppressive cytokines (e.g. IL10 and TGFβ). Increased levels of MDSCs have been described in patients with NSCLC, are associated with poor prognosis and can mediate resistance to chemotherapy (4). Interestingly, in tumor models, accumulation of MDSCs has been proposed as a contributor to the incapacity of the anti-PD-1/PD-L1 blockade to completely reverse the suppressive activity (5). Therefore, stimulation of effector T cells while blocking the immunosuppressive activity of MDSCs represents a rational immunotherapy combination potentially effective for lung cancer. Several agents used in conventional cancer chemotherapy (e.g. gemcitabine, 5-fluorouracil or cyclophosphamide) have been found to reduce MDSC numbers and can be used to deplete this cell subpopulation. However, the use of these drugs results in a profound and unpredictable remodeling of the myeloid cell compartment in the tumor stroma, and careful evaluation of the appropriate timing and dosing is required (6). An alternative strategy recently proposed by us to successfully reverse the tumor immunosuppressive microenvironment is based on the inhibition of the complement system, another essential element of innate immunity. The complement system has developed as a first defense against pathogens or unwanted host elements. The three major pathways of complement activation (the classical, alternative, and lectin pathways) converge in the cleavage of C3 into C3b. C3b deposition leads to the formation of C3 convertases that amplify both opsonization and the complement response, and eventually promote C5 convertase formation and assembly of the membrane attack complex. In addition, enzymatic cleavage of C3 and C5 releases C3a and C5a, two multifunctional immunomodulators. Traditionally, tumor-associated complement activation has been considered as part of the body’s immunosurveillance against cancer. However significant work in recent years has identified new and surprising activities for complement within the tumor microenvironment. In the context of chronic inflammation, complement elements can promote an immunosuppressive response, induce angiogenesis, and activate cancer-related signaling pathways. In the seminal study that shifted the paradigm, Markiewski et al. reported that complement deficiencies were associated with impaired tumor growth in a syngeneic model of cervical carcinoma (7). This study demonstrated that the immunomodulator C5a, generated after complement activation within the tumors, is able to hamper antitumor CD8 T cell-mediated responses. Importantly, this activity was associated with the accumulation of MDSCs in the tumor stroma. In the case of lung cancer, reduction of tumor growth after blockade of the C5a receptor-1 (C5aR1) is accompanied by a decrease in the expression of immunosuppressive molecules and, again, a diminution in the percentage of MDSCs (8). These studies reveal the important role played by C5a/C5aR1 signaling in tumor immunity, and point to this pathway as a potential therapeutic target in the context of checkpoint inhibition. To support this hypothesis, we have recently evaluated the therapeutic efficacy of the combined administration of anti-PD-1 and anti-C5a drugs in a variety of syngeneic models of lung cancer. We demonstrated that the combination of C5a and PD-1 blockade synergistically impairs lung cancer growth and metastasis. This therapeutic effect is accompanied by a negative association between the frequency of CD8 T cells and MDSCs within the tumors, which may result in a more complete reversal of CD8 T-cell exhaustion (9). These studies suggest that inhibition of complement may overcome tumor resistance in cancer immunotherapy, providing support for the clinical evaluation of anti-PD-1 and anti-C5a drugs as a novel combination therapeutic strategy for lung cancer. In conclusion, immunotherapy strategies tailored to restore innate immune modifications might recondition the tumor immunosuppressed niche, strengthening anti-tumor T cell immunity after immune-checkpoint blockade. A more comprehensive knowledge of the dynamic spatiotemporal interactions between the tumors and the microenvironment would be required to predict response, facilitate further investigations in this field, and extend the benefit of immunotherapies to most patients. References 1. Lavin Y et at. Cell 2017;169:750-765. 2. Berraondo P et al. Immunol Rev 2016;274:290-306. 3. Escors T et al. Oncoimmunology 2013;2:e26148. 4. Huang A et al. Cancer Immunol Immunother 2013;62:1439-1451. 5. Youn JI et al. J Immunol 2008;181:5791-5802. 6. Berraondo P et al. Cancer Res 2007;67:8847-8855. 7. Markiewski MM et al. Nat Immunol 2008;9:1225-1235. 8. Corrales L et al. J Immunol 2012;189:4674-4683. 9. Ajona D et al. Cancer Discov 2017;7:694-703.

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Abstract:
The tumor microenvironment differs significantly from the controlled environment of in vitro cell culture. Whereas cell lines are typically grown in plastic vessels containing a pH buffered, nutrient rich liquid medium with 10% fetal bovine serum and incubated at 37 ­ºC and 5% CO~2~, cancer cells in tumors experience different oxygen tension, growth substrate, nutrient, waste, and growth factor gradients, pH, and the presence of stromal support cells and infiltrating immune cells. The process of establishing a new cell line requires adaptation to this environment, which results in loss of genetic heterogeneity as well as irreversible epigenetic reprogramming that is maintained even when cultured cancer cells are re-introduced to an in vivo setting. Patient-derived xenografts (PDX) are direct human tumor xenografts established and maintained exclusively in mouse hosts. While these models can never perfectly recapitulate an autochthonous human tumor, they are increasingly used as tools in cancer research due to their utility in modeling therapeutic response with higher fidelity than either cell lines or cell line xenografts. A growing interest in defining the role of the tumor microenvironment and in testing the efficacy of immunotherapy in vivo has driven advances in PDX model development. The tumor microenvironment consists of stromal cell components including blood vessels, fibroblasts, and infiltrating immune cells as well as extracellular matrix, growth factors, and nutrients. In PDX, components of the tumor microenvironment are either provided by the mouse host or are excreted by the tumor cells themselves. However, paracrine effects between tumor and stroma may not be entirely replicated in a mouse host due to a lack of cross-species cytokine reactivity. The absence of compatible stroma may bias PDX engraftment toward tumors that are less dependent on paracrine factors or which are more adept at recruiting mouse stromal support cells through enhanced expression of mouse reactive factors. It remains a significant challenge to accurately assess the mechanistic activity of therapeutic approaches designed to inhibit these interactions in the absence of human tumor stroma. Anatomical context can also have significant impact on PDX tumor biology. PDX can be established as subcutaneous flank tumors or at any of a variety of orthotopic sites. Lung PDX are amenable to orthotopic growth in the lung, and can thus be used to model lung cancer growth and metastasis within its normal anatomical context. Orthotopic tumors can have vastly altered metastatic potential and organ preference as well as differential response to anti-cancer therapeutics in comparison to subcutaneous flank tumors. One of the primary limitations of PDX as a model for cancer is the need to use immunocompromised mouse hosts. The degree to which the immune system can be modeled with PDX is dependent on the mouse host chosen and the type of human immune cells used to reconstitute the human immune cell component. PDX can be established in a great variety of different strains of immunocompromised mice including athymic nude mice, severe combined immune deficiency (SCID) and non-obese-diabetic (NOD)-SCID strains, Rag null strains, and profoundly immunocompromised strains in which IL2-Rγc has been disrupted (NSG, NOG, BRG). Each of these strains differs with respect to the type and function of hematopoietic cells. For example, athymic nude mice have intact natural killer (NK) cells, whereas NSG mice do not; NSG mice therefore develop primary tumors and metastases at a much faster rate. Humanized mice are immunocompromised mice that have partially reconstituted human immune components for the purposes of modeling the behavior of the human immune system in a cancer context. NSG, NOG, and BRG mice have been engrafted with isolated peripheral blood mononuclear cells (PBMC) or tumor infiltrating lymphocytes (TIL) primarily to study mechanisms of lymphocyte recruitment; however, a major limitation of this approach is the rapid onset of graft versus host disease in the mouse host. Alternatively, different strains of mice can be engrafted with human CD34+ hematopoietic stem cells (HSC), which results in mouse hosts with fully human lymphocytes, monocytes, dendritic cells and in some cases NK cells. A variety of mouse strains engineered to express human cytokines such as IL-3 and GM-CSF have been developed to promote improved functional human immune system components. PDX models of lung cancer are growing in complexity, variety, and sophistication. These in vivo cancer models will be an integral component in a suite of tools for studying many aspects of lung cancer biology in a research environment. Recent advances in the humanization of mouse hosts promises texpand the possibilities of studying cancer immunology and immunotherapy of human tumors in an experimental setting in vivo.

Abstract:
The abundance of somatic alterations and their heterogeneity between SCLC patient tumors present the immense scientific and clinical challenges. Functional characterization of recurrent mutations in SCLC is an essential step towards understanding the pathogenesis. However, it remains extremely difficult due to the lack of systematic and informed ways of defining oncogenic drivers, especially those involved in early stage tumor development. While the inaccessibility of precancerous lesion in the patients has precluded characterization of lung cancer mutations, we have developed a precancerous cell-based model of SCLC development as a streamlined approach for characterizing novel mutations and determining mutation-driven oncogenic pathways [Kim et al. 2016, Genes and Development]. Using compound transgenic mice expressing neuroendocrine specific GFP in the GEMM of SCLC (Chga-GFP/Rb/p53/Rbl2), we isolated pulmonary neuroendocrine cells one month after adenoviral Cre-mediated tumor induction, at which time the lungs did not show macroscopic lesions (Figure 1). Notably, these cells from an early stage of tumor development grew as adherent monolayers in culture and did not form subcutaneous tumors in nude mice, whereas tumor cells formed floating aggregates and formed the subcutaneous tumors. These findings indicated that these neuroendocrine cells, lacking Rb and p53, were immortalized but not transformed. Therefore, we postulated that these cells were precancerous cells of SCLC (preSC). We then tested whether preSC could be transformed by an oncogene, using a retroviral vector carrying cDNA of L-Myc, one of the most frequently amplified genes in SCLC. The preSC transduced with retroviral L-Myc (L-Myc-preSC) formed spheres characteristic of SCLC cells in culture and palpable tumors resemble primary SCLC in the flanks of nude mice, whereas GFP-preSCs (control) were morphologically identical to uninfected preSC and did not form aggregates and subcutaneous tumor (Figure 2A). Comparative expression profiling of preSCs and L-Myc-preSC or tumor cells permitted identification of the genes and pathways related to oncogene-driven tumor progression. Defining the MYC-driven oncogenic pathways led to a preclinical test of an existing drug that successfully targeted human and mouse SCLC tumors. Furthermore, using this preSC-based model in combination with CRISPR/Cas9 methods of gene targeting and in vivo models, we found that several loss-of-function mutations found in the SCLC tumors were sufficient to cause the tumorigenic progression of preSCs (Figure 2B). In conclusion, this engineered preSC-based model facilitates functional validation of the recurrent mutations in SCLC and discovery of biomarkers and molecular pathways that will be further explored for mechanistic elucidation and targeted therapies.Figure 1

Abstract:
Since the clinical introduction of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) in 2004, EBUS-TBNA has become accepted worldwide due to its minimal invasiveness but high diagnostic ability. EBUS-TBNA is an image-guided procedure, and the instruments and devices used for endobronchial ultrasonography as well as transbronchial needle aspiration have continuously evolved. Furthermore, such device improvements have been accompanied by improvements in the techniques of ultrasound visualization, sampling with a dedicated needle, and specimen handling. Initially, the only indication of EBUS-TBNA was nodal staging of lung cancer; however, now its indications have expanded to not only malignant diseases but also benign diseases, such as sarcoidosis or tuberculosis. EBUS-TBNA has also recently been used for the important tasks of “core sampling” and “rebiopsy”. The advent of immune checkpoint inhibitors and novel tyrosine kinase inhibitors has resulted in additional applications of EBUS-TBNA in the era of precision medicine. In 2016, the American College of Chest Physicians published a guideline focusing on the technical aspects of EBUS-TBNA. This guideline described several techniques of EBUS-TBNA for which the evidence level had been thought too difficult to grade. The ungraded consensus-based statement managed this limitation well and thus became a useful technical guide for clinicians. The guideline also described sedation to be used when performing EBUS-TBNA. Since many patients who underwent EBUS-TBNA suffered from severe coughing during the procedure, the guideline recommended performing moderate or deep sedation in the first paragraph. In addition, performing the procedure in a more comfortable condition for clinicians was required, which would help them perform the procedure repeatedly following the necessary treatment course as mentioned above. The first report of an EBUS image analysis was the classification of B-mode features of benign and malignant lymph nodes by the first generation EBUS ultrasound processor with 7.5MHz radiofrequency. Owing to improvements in ultrasound processors and increased radiofrequency to 10MHz, EBUS image analyses are now being increasingly performed, including the use of various new Doppler features and image analysis technologies, such as gray scale texture analyses and fractal dimension analyses. The latest ultrasound processor equipped with elastography is capable of depicting the relative stiffness of the targeted tissue within the region of interest. However, whether or not a spectrum analysis of EBUS radiofrequency can provide precise information of the target histology is still being investigated. After all, EBUS-TBNA is a sampling modality, so “tissue is the issue” remains the point of focus. However, we often encounter cases with multiple nodes within the same nodal station. In addition, some metastatic lymph nodes are unable to be diagnosed due to the limited metastatic area within the lymph node (micrometastasis). Advances in EBUS image analyses may help reduce examination time and medical resource usage as well as allow for more precise TBNA needle control. The dedicated TBNA needle was originally developed from the needle used for endoscopic ultrasound-guided fine needle aspiration (EUS-FNA). The handle of the needle was designed to be manipulated by the operator alone. The initial size of the needle was 21 and 22 gauge. Now, however, several types of dedicated needles are commercially available from different manufacturers; currently available needle sizes are 19, 21, 22, and 25 gauge, and each tip is designed for a specific purpose. The size (amount) of the biopsied material, the degree of blood contamination, and the quality of the histological structure (degree of tissue crushing) can all be affected by needle selection. Although the optimum needle type is still unclear, clinicians may need to select a needle depending on the character of the targeted lesion and the purpose of the biopsy. Specimen handling is another important issue. EBUS-TBNA is basically a needle biopsy procedure; therefore, the obtainable material is fundamentally cytological material. We can often obtain “core” specimens, even when using TBNA which is a cytological sampling procedure. We first introduced the “tissue coagulation clot” method for the EBUS-TBNA “core” specimen. The “core” usually consists of tumor tissue fragments floating in coagulation tissue. By modifying the specimen-processing protocol, a good quality cell block can be made and used for pathological evaluations, including immunohistochemistry and ancillary testing, such as fluorescence in situ hybridization. We now need to determine any genetic alterations in lung cancer prior to starting treatment. The rapid on-site evaluation of the obtained material during the procedure may play a crucial role in sample processing, despite the lack of any clear evidence that this improves the diagnosis rate so far. We still need to develop the optimum specimen handling protocol in order to maximize the utility of microsamples obtained by EBUS-TBNA. Finally, training for EBUS-TBNA is still important for both mentors and mentees. We recently described the utility of a biosimulator for advanced EBUS-TBNA training to encourage efficient sampling. Many training models, including low- and high-fidelity models, and courses were developed, and the trainees were evaluated by dedicated evaluators. Performing high-quality training is crucial to ensuring a safe procedure as well as a high diagnostic yield. EBUS-TBNA is a still-evolving technology, and we clinicians need to continue brushing up our skills and seeking better ways to examine and treat patients. More clinical studies are needed to address the issues still unresolved by the current technical guideline.

Abstract:
Endoscopic ultrasound guided fine needle aspiration (EUS-FNA) has been used for lung cancer staging and diagnosis since ‘90s. However, the usefulness of EUS-FNA has not been addressed in the lung cancer field due to the limited accessibility to mediastinal lymph nodes and the low availability of the technique by thoracic physicians. The development of endobronchial ultrasound guided-transbronchial needle aspiration (EBUS-TBNA) changed the staging process of lung cancer markedly. EBUS-TBNA, which can target mediastinal nodal stations accessible by cervical mediastinoscopy, has replaced standard cervical mediastinoscopy. In the era of EBUS-TBNA, the role of EUS-FNA in lung cancer staging is being re-estimated. Moreover, endoscopic ultrasound with bronchoscope guided fine needle aspiration (EUS-B-FNA) which uses an ultrasound bronchoscope for transesophageal sampling has increased the use of EUS procedure by bronchoscopists. EBUS-TBNA and EUS-(B)-FNA have different accessibility to the mediastinum, therefore the two approaches are considered to be complementary in lung cancer staging. Among mediastinal nodal stations, EBUS-TBNA can access stations 2R, 2L, 3P, 4R, 4L and 7. Some lymph nodes at station 1 and station 8 can be targeted by EBUS-TBNA. EUS-(B)-FNA has limited ability to target pre-tracheal lesions that are easily accessed by EBUS-TBNA. EBUS-TBNA has a higher accessibility to mediastinal nodal stations than EUS-(B)-FNA in the mediastinal staging of potentially operable lung cancer. However, EUS-(B)-FNA can access the inferior mediastinum (stations 8 & 9) and some areas of the aorto-pulmonary window (station 5). The additional benefit of combined EBUS/EUS staging over EBUS-TBNA has been studied. According to a recent meta-analysis by Korevaar et al that evaluated 10 studies that looked at the additional benefit of the combined approach, the pooled sensitivity improvement by adding EUS-(B)-FNA to EBUS-TBNA was 12% in mediastinal staging of lung cancer. It is clear that adding EUS-(B)-FNA following EBUS-TBNA is beneficial for lung cancer staging in some patients. More studies are needed to find indications for adding EUS-(B)-FNA to EBUS-TBNA. As well as for mediastinal staging, EUS-(B)-FNA is useful for lung cancer diagnosis and tissue acquisition when the target is accessible by EUS-(B). In general, EUS-(B) is a better tolerated procedure than EBUS-TBNA. EUS-B-FNA can be performed following bronchoscopic procedures in the same session when bronchoscopy is difficult due to dyspnea, cough, etc. EUS-FNA and EUS-B-FNA are safe procedures with low complication rates. There are still issues regarding adequate training and cost in applying EUS for lung cancer staging. More efforts are necessary to increase the availability of EUS-(B)-FNA in the staging and diagnosis of lung cancer.

Abstract:
Stereotactic body radiotherapy (SBRT) is a technique, introduced in the late 1990s. SBRT is a method of using single 10-20Gy of high dose and hypofractionated radiotherapy. Recently, many papers have been published on its clinical results, especially in early stage lung cancer. In Japan as JCOG 0403 clinical trial, between July 2004 and November 2008, 169 patients from 15 institutions were registered. 100 inoperable and 64 operable in total 164 patients were eligible. Of the inoperable 100 patients, the % 3-year OS was 59•9% (95% CI: 49•6% - 68•8%). Grade 3 and 4 toxicities were observed in 10, and 2, respectively. No grade 5 toxicity was observed. Of the 64 operable patients, the % 3-year OS was 76•5% (95% CI: 64•0% - 85•1%). Grade 3 toxicities were observed in 5. No Grades 4 and 5 toxicities were observed.　SBRT for stage I NSCLC is effective with low incidences of severe toxicity. This treatment can be considered a standard treatment for inoperable stage I NSCLC. This treatment is promising as an alternative to surgery for operable stage I NSCLC. The current ongoing protocols for lung cancer as JCOG 1408 comparing two different doses、42Gy in 4 fractions and 55Gy in 4 fractions for T1N0M0 and clinically diagnosed lung cancer will be presented. In the world, RTOG 0618 showed a good result of SBRT in the treatment of patients with operable stage I/II NSCLC. RTOG 0915 showed no difference in survival between 48Gy in 4 fractions and 34Gy in a single fraction. In central hilar lung cancer patients, additional attentions are required to avoid serious complications. RTOG 0813 is a Phase I/II study for finding an optimal dose. 55Gy in 5 fractions are their recommended dose. JROSG 10-1 recommended 60Gy in 8 fractions. Optimal dose and fractions are still unknown for centrally located lung tumor. Most updated status of SBRT will also be reviewed.

Abstract:
Surgery has historically been the primary treatment option for patients with Stage I non–small-cell lung cancer (NSCLC). Although Stage I NSCLC is technically curable, the presence of significant co morbidity increases the risk of postoperative complications and reduces the potential role of surgery even early stage NSCLC. Because nonsurgical treatment options such as conventional radiotherapy have historically achieved suboptimal outcomes, some have argued that the risks associated with surgery in patients with severe COPD were justified. The reason for poor tumor control with conventional radiation therapy has been shown to be due to insufficient total radiation doses which is usually 60 Gy or lower. Dose escalation with CRT have shown that a total dose of just above 80 Gy seems to be tolerable while doses exceeding 90 Gy, necessary for optimal tumor control, were associated with high risk of unacceptable lung toxicity. Since the 2000s, stereotactic body radiation therapy has rapidly spread as medical physics improved. Stereotactic body radiation therapy has been revealed to be equivalent to surgery in tumor ablation. With stereotactic body radiotherapy (SBRT) the radiation dose to normal tissue is minimized and the dose per fraction can be increased resulting in biologic doses up to twice as high as in CRT. This has resulted in improvement of local tumor control rates up to 88% to 100%, comparable to the rates after surgery. SBRT is a safe and effective treatment option for these patients, with outcomes that do not appear to be inferior to surgery. SBRT is not associated with the considerable initial risks of operative mortality and prolonged hospitalization. Patients who do undergo surgery may benefit from avoiding open lobectomy, instead using less invasive approaches such as video-assisted thoracoscopic surgery or open segmentectomy. All patients with Stage I NSCLC and severe COPD should be evaluated in a multidisciplinary setting and afforded an informed decision of the risks and benefits of both surgery and SBRT. In role of SBRT can also be extended even in patients with oligometastases and oligo-recurrence, the oligometastases and oligo-recurrence who sometimes cured with only local therapy. Radiotherapy (RT) can cause immunogenic tumor cell death resulting in cross-priming of tumor-specific T-cells, acting as an in situ tumor vaccine; however, SBRT alone has limit in inducing effective anti-tumor immunity resulting in systemic tumor rejection. Immunotherapy can complement SBRT to help overcome tumor-induced immune suppression, as demonstrated in many pre-clinical tumor models. There are many trials underway for combinations of different immunotherapies and SBRT.

Abstract:
Surgery as First Line Treatment Option for Small-Sized NSCLC Surgical resection has been the preferred standard of care for patients with well established expectations for survival after resection. A standard of care for patients who are deemed medically inoperable is definitive radiation therapy. Because of the proven effectiveness of radiation therapy in treating the medically inoperable patient with lung cancer, consideration is being given to treating medically operable lung cancer patients with definitive radiation therapy instead of surgery. However, recent clinical guidelines issued by ASTRO (Videtic et al) based on a review of the published data include among other recommendations, that ‘For stage I NSCLC patients with anticipated risk of operative mortality of <1.5%, SBRT is not recommended as an alternative to surgery outside of clinical trial settings. The recommended treatment for these patients remains lobectomy with systematic mediastinal lymph node evaluation’. The problem with such recommendations is as follows. The operative morbidity and mortality following pulmonary resection for the overall population of patients undergoing surgery have also been established. The morbidity and mortality in the overall population of patients following definitive radiation therapy is also well documented. What is not available is reliable data on the treatment-related risks faced by subgroups of patients treated with surgery or with definitive chemotherapy who differ in terms of competing risk factor for death, including age (Eguchi et al.) or their overall functional status ((or what is becoming known as the ‘fitness’ or conversely, the ‘frailty’ of a patient) Korc et al)). Emerging data shows that the frailty of a patient affects the likelihood of survival after surgery of diverse types and for diverse diseases. We have found that frail patients undergoing diverse surgeries for diverse malignancies require ICU admission after a given grade of complication at rates far above those required for fit patients (after Grade I complication 0% vs 20%, after Grade 2 complication 6% vs. 17%, and after Grade 3 complication 5% vs. 35% for fit vs. frail respectively) After ICU admission, frail patients remain at a persistent increased risk of death lasting at least to 600 days when compared to fit patients (50% survival vs. 90% survival for frail patients vs. fit patients after ICU care at 600 days) (unpublished data courtesy of Armin Sharokhni, MD). Similar data is not available for patients with NSCLC treated with definitive radiation therapy. Because of this lack of information, objective comparisons of the feasibility and effectiveness of surgical resection with definitive radiation therapy are likely prone to error due to selection biases.A plausible hypothesis is that the population of patients referred for definitive radiation therapy for NSCLC are frailer, and the decreased long-term survival after radiation therapy is due to frailty rather than cancer-related. In this talk, we will review the data available on: 1. Current perioperative morbidity and mortality following lung resections including MIS and sub-lobar procedures 2. Current likelihood of long-term survival following curative lung cancer surgery 3. The competing risks for short- and long-term survival after surgery including age and frailty 4. The methods of risk stratification, including frailty, for a patient being considered for lung cancer surgery 5. The methods of risk stratification that have been used in retrospective and prospective comparisons of surgery and definitive radiation therapy Based on this review, proposals for prospective trials comparing SBRT and surgery for objectively defined medically operable early stage NSCLC will be made. References: Eguchi et al. Impact of Increasing Age on Cause-Specific Mortality and Morbidity in Patients With Stage I Non-Small-Cell Lung Cancer: A Competing Risks Analysis. J Clin Oncol. 2017;35:281-290 Korc-Grodzicki et al. Surgical considerations in older adults with cancer. J Clin Oncol 2014;32:2647-53.. Videtic et al. Stereotactic body radiation therapy for early-stage non-small cell lung cancer: Executive Summary of an ASTRO Evidence-Based Guideline. Practical Radiation Oncology (in press)

Abstract:
The approach that has most commonly been reported as an alternative to surgery or SBRT for non-small lung cancer (NSCLC) is thermal ablation. There are also different ablative modalities, of which radiofrequency ablation (RFA) has been the most widely reported. RFA was reported for human lung tumors in 2000 [1]. RFA has been shown to be feasible and safe in several studies[2,3]. However, many studies have involved heterogeneous patient populations that included patients with metastatic tumors and NSCLC. Additionally, in those series focusing on NSCLC, patients with different stages. Have been included. Another consideration is that in several centers, these procedures have been performed by interventional radiologists, who are not traditionally part of the multidisciplinary oncology team, and rarely have follow-up clinics, so accurate reporting of recurrence and survival rates has not been optimal. Lastly, other modalities such as microwave or cryoablation, are gaining in popularity [4],[5] Despite some perceived improvements in technology, there is no clinical data that supports one ablative modality over another with respect to cancer outcomes[6] . Currently thermal ablation is reserved for medically inoperable patients with NSCLC. In those series that have reported outcomes specifically for stage I NSCLC outcomes have been good, and comparable with studies of SBRT, when looking at survival rates. One study included 56 patients with stage I NSCLC[7]. Median survival was 29 months. A prospective multi-center phase II trial involving 54 patients was recently reported[8]. Overall survival was 87.3% at 1-year, and 69.8% at two-years. Two-year survival was superior in patients with tumors <2cm (83%). There were only two grade 4, and one grade 5 event within 90 days (not attributable to the RFA). Our group has also treated 21 patients with stage Ia NSCLC (submitted for publication). Three-year survival in our series was 52%. One issue when comparing results of trials using different modalities is how comparable are patient groups. The medically inoperable group in this prospective phase II trial were compared to a medically group in an RTOG phase II trial of SBRT[9]. Although both groups were labelled medically inoperable, lung function was significantly better in patients treated with SBRT. This argues for the need for prospective studies comparing these modalities for medically inoperable patients. The main issue with thermal ablation has been higher rates of local recurrence in most studies. Tumor size is important, and results are better for tumors <2cm[7,8]. This certainly would be an argument for SBRT over RFA. However how recurrence is measured and defined may impact on reporting of local control, and there are differences in how these have been identified in different studies. In the absence of a prospective trial using similar end-point recording, overall survival is the cleanest endpoint with which to make comparisons. In summary, thermal ablation remains a viable option for small stage I NSCLC patients who are deemed medically inoperable. Future innovations include developments in energy source and, also in bronchoscopic delivery to peripheral tumors[10]. References 1. Dupuy DE, Zagoria RJ, Akerley W, et al: Percutaneous radiofrequency ablation of malignancies in the lung. AJR Am J Roentgenol 174:57-9, 2000 2. Ambrogi MC, Fanucchi O, Cioni R, et al: Long-term results of radiofrequency ablation treatment of stage I non-small cell lung cancer: a prospective intention-to-treat study. J Thorac Oncol 6:2044-51, 2011 3. Lencioni R, Crocetti L, Cioni R, et al: Response to radiofrequency ablation of pulmonary tumours: a prospective, intention-to-treat, multicentre clinical trial (the RAPTURE study). Lancet Oncol 9:621-8, 2008 4. Zhong L, Sun S, Shi J, et al: Clinical analysis on 113 patients with lung cancer treated by percutaneous CT-guided microwave ablation. J Thorac Dis 9:590-597, 2017 5. Ahrar K, Littrup PJ: Is cryotherapy the optimal technology for ablation of lung tumors? J Vasc Interv Radiol 23:303-5, 2012 6. Vogl TJ, Nour-Eldin NA, Albrecht M, et al: Thermal Ablation of Lung Tumors: Focus on Microwave Ablation. Rofo, 2017 7. Simon CJ, Dupuy DE, DiPetrillo TA, et al: Pulmonary radiofrequency ablation: long-term safety and efficacy in 153 patients. Radiology 243:268-75, 2007 8. Dupuy DE, Fernando HC, Hillman S, et al: Radiofrequency ablation of stage IA non-small cell lung cancer in medically inoperable patients: Results from the American College of Surgeons Oncology Group Z4033 (Alliance) trial. Cancer 121:3491-8, 2015 9. Crabtree T, Puri V, Timmerman R, et al: Treatment of stage I lung cancer in high-risk and inoperable patients: comparison of prospective clinical trials using stereotactic body radiotherapy (RTOG 0236), sublobar resection (ACOSOG Z4032), and radiofrequency ablation (ACOSOG Z4033). J Thorac Cardiovasc Surg 145:692-9, 2013 10. Koizumi T, Tsushima K, Tanabe T, et al: Bronchoscopy-Guided Cooled Radiofrequency Ablation as a Novel Intervention Therapy for Peripheral Lung Cancer. Respiration 90:47-55, 2015

Abstract:
For certain extra-pulmonary malignancies, such as colorectal cancer or sarcomas, the existence of curable oligometastatic disease state has been well established. Oligometastasis is a state of stage IV disease associated with limited spread of disease at the time of diagnosis. This condition may reflect a more indolent phenotype than that associated with more widespread disease at presentation. Recently, it becomes more clear that the patients with Stage IV NSCLC are heterogenous and hence, some patients have high disease burden whereas others have isolated metastatic lesions. In the 8th TNM staging system, M-stage was reclassified into M1a, M1b, M1c, and the patients with M1b may represents the oligometastatic status of NSCLC. It has been demonstrated that the predominant pattern of failure in patients with oligometastasis treated with the first-line systemic chemotherapy was mainly a local failure, the fact which leads an idea that the local treatment may improve cure rates in such patients. The incidence of oligometastasis in NSCLC has been reported 7-26% of NSCLC [1, 2], with the major sites of metastases being bone, brain, adrenal glands and liver. In general, the successful treatment of patients with oligometastasis requires the ability to eradicate the primary site, the ability to image all sites of metastatic disease, the ability to ablate all metastatic sites, and having effective systemic therapy to eradicate undetected micrometastatic disease. Recently, routine use of improved diagnostic imaging tools such as PET-CT or Brain MRI, can better detect latent metastases in patients who would otherwise have been thought to have a localized disease, and hence, the diagnosis of “true” oligometastatic disease may be increasing [3]. Development of local treatment modalities such as minimally invasive surgery (MIS) or stereotactic radiotherapy (SABR) enabled effective local abrasion of the metastatic sites without major morbidities. Above all, rapid development of effective molecular target agents and immune check point agents in the treatment of NSCLC are encouraging to reconsider surgery for the treatment of oligometastatic NSCLC patients. Most evidence of treatment effect of local treatment for oligometastasis derives from the survival data from retrospective patients groups. For brain metastases, 5-year survival rates have been reported 6.6-35% and adrenal gland metastases showed similar results (5-year survival rates 12-40%). In a well-designed propensity score matching study suggested an improvement in survival favoring local abrasive therapy, but definite conclusions on the efficacy of local therapy for the treatment of extra-cranial oligometastatic NSCLC could not be reached [4]. A meta-analysis which included 49 studies, suggested overall median overall survival of 19 months after local ablative treatment (5.9-52 months)[5]. Most recent study by Gomez and colleagues demonstrated a progression free survival benefit favoring local consolidative therapy [6]. Hopefully, ongoing prospective trials may provide more strong evidence of the effect of local ablative therapy for oligometastasis in near future. Despite many reports that support local treatment for oligometastasis, the lack of control data in almost all reports is a problematic issue. Since local treatment for the oligometastasis is only performed in selected patients with relatively indolent disease, there is often no actual denominator for the entire group of patients who developed metastasis [7]. Thus, determining the survival advantage of ablative local treatment of oligometastasis compared to palliative systemic therapy is difficult because the majority of existing data are with a substantial degree of selection bias. In the other aspect, however, we have learned that the patient selection is critical for the application of local treatment on the oligometastasis. In general, local treatment is indicated in metastatic NSCLC patients with favorable prognostic factors including absence of mediastinal lymph node metastasis, small number of metastases, complete control of primary lesion, meta-chronous metastasis, and good performance status of the patients. Although there are relatively large numbers of papers on the brain or adrenal metastases, the reports of extra-cranial or extra-adrenal metastases are rare. In a meta-analysis, the 5 year overall survival rates of extra-cranial / extra-adrenal metastasis was 50% and the prognosis was mainly influenced by lymph node metastasis status[ 8]. First used in the literature in 2012 [9], the concept of oligoprogressive disease has been rapidly adopted. It can be best described in patients with tumors harboring actionable mutations who are treated with molecular targeted therapies. Initially, the response rate is great but the duration of response is relatively short, with resistance to therapy generally emerging within a year of start of treatment as a result of various genetic mechanisms. Not uncommonly, disease progression during molecular targeted therapy occurs at a limited number of anatomic sites. Recently, several studies reported improved progression free survival and overall survival in either intra-cranial or extra-cranial oligopregressive diseases by applying local abrasive therapy on those acquired resistant oligoprogressive diseases and by resuming target agents [10]. Furthermore, the combination of immune check point agents and SABR on primary tumor and/or metastatic sites may be promising for treating oligometastatic NSCLC, due to a possible abscopal effect. In conclusion, although current evidence of local treatment of oligometastases is limited in NSCLC, with aid of recent diagnostic tools by which more stringent patient selection is possible, local ablative treatment of metastatic lesions can lead improved survival of patients with oligometastasis in conjunction with molecular target agents or immune check point agents. 1. Albain KS, Crowley JJ, LeBlanc M, et al. Survival determinants in extensive-stage non-small-cell lung cancer: the Southwest Oncology Group experience. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 1991;9:1618-1626. 2. Parikh RB, Cronin AM, Kozono DE, et al. Definitive primary therapy in patients presenting with oligometastatic non-small cell lung cancer. International journal of radiation oncology, biology, physics 2014;89:880-887. 3. Tonnies S, Tonnies M, Kollmeier J, et al. Impact of preoperative 18F-FDG PET/CT on survival of resected mono-metastatic non-small cell lung cancer. Lung cancer (Amsterdam, Netherlands) 2016;93:28-34. 4. Sheu T, Heymach JV, Swisher SG, et al. Propensity score-matched analysis of comprehensive local therapy for oligometastatic non-small cell lung cancer that did not progress after front-line chemotherapy. International journal of radiation oncology, biology, physics 2014;90:850-857. 5. Ashworth A, Rodrigues G, Boldt G, et al. Is there an oligometastatic state in non-small cell lung cancer? A systematic review of the literature. Lung cancer (Amsterdam, Netherlands) 2013;82:197-203. 6. Gomez DR, Blumenschein GR, Jr., Lee JJ, et al. Local consolidative therapy versus maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer without progression after first-line systemic therapy: a multicentre, randomised, controlled, phase 2 study. The Lancet Oncology 2016;17:1672-1682. 7. Fiorentino F, Treasure T. Pulmonary metastasectomy: a call for better data collection, presentation and analysis. Future oncology (London, England) 2015;11:19-23. 8. Salah S, Tanvetyanon T, Abbasi S. Metastatectomy for extra-cranial extra-adrenal non-small cell lung cancer solitary metastases: systematic review and analysis of reported cases. Lung cancer (Amsterdam, Netherlands) 2012;75:9-14. 9. Weickhardt AJ, Scheier B, Burke JM, et al. Local ablative therapy of oligoprogressive disease prolongs disease control by tyrosine kinase inhibitors in oncogene-addicted non-small-cell lung cancer. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 2012;7:1807-1814. 10. Iyengar P, Kavanagh BD, Wardak Z, et al. Phase II trial of stereotactic body radiation therapy combined with erlotinib for patients with limited but progressive metastatic non-small-cell lung cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2014;32:3824-3830.

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