IIIA NSCLC Research Articles

O2-014 - The Feasibility Study of CDDP Plus Docetaxel Followed by TS-1 Maintenance as Post Operative Adjuvant Chemotherapy for Completely Resected Pathological Stage II to IIIA NSCLC Patient

ABSTRACT Background Maintenance chemotherapy could prolong overall and/or progression-free survival in advanced NSCLC. S-1 is an oral anticancer agent comprised of tegafur, 5-chloro-2,4-dihydroxypyridine and potassium oxonate. The TORG 0809 study was conducted to evaluate the feasibility and efficacy of maintenance chemotherapy of S-1 following DOC + CDDP in patients with curatively resected stage II and IIIA NSCLC. Methods Patients received three cycles of DOC (60 mg/m2 d1) plus CDDP (80 mg/m2 d1), q3-4w, and subsequently S-1 at 40 mg/m2 twice a day for 14 consecutive days, q3w, for more than 6 months (max 1 year). The primary end point was determination of feasibility, which was defined as the proportion of patients who had completed maintenance for 8 cycles of S-1 or more. If the lower confidence interval (CI) of this proportion was 50% or more, the feasibility of the treatment was considered confirmed. The sample size was set to be 125. Results Between June 2009 and November 2010, 131 patients were enrolled, of whom 129 patients were eligible and assessable. The median age was 63 (23–74 years); PS 0: 107, 1: 22; p-stage IIA: 19, IIB: 30, IIIA: 80; adenocarcinoma: 99, non-adenocarcinoma: 30. Of 129 patients, 109 patients (84.5%) completed three cycles of DOC + CDDP. One hundred and six patients initiated the maintenance S-1 and 66 patients (51.2%, 95% CI: 42.5–59.8) completed eight cycles or more S-1 treatment; this percentage was less than our previously defined criterion for treatment feasibility, since 32 patients terminated maintenance S-1 at three cycles or less. Grade 3/4 toxic effects during the maintenance S-1 included anemia (7.3%), neutropenia (3.7%), anorexia (3.7%), dyspnea (1.8%), infection with neutropenia of grade 0 to 2 (1.8%). Febrile neutropenia was not observed. Conclusions The toxicity level was acceptable, although the results did not meet our criterion for feasibility.

P3-016 - Quality of Life in Elderly Patients Treated with Adjuvant Chemotherapy for Non-Small-Cell Lung Cancer: Prospective Comparison Study

ABSTRACT Introduction The incidence of lung cancer increases with age. Given the increasing comorbid conditions and progressive reduction of organ function, it is presumed that the elderly are not more likely to tolerate to the cytotoxic chemotherapy. However, prospective data on adjuvant chemotherapy in elderly patients are not available. Methods Patients with completely resected stage Ib, II or IIIa NSCLC were enrolled for this analysis. Either four cycles of paclitaxel–carboplatin or vinorelbine–cisplatin was used as an adjuvant chemotherapeutic regimen. The primary objective was to assess the health-related quality of life (HRQOL) of elderly patients (age ≥65), during and after post-operative chemotherapy. The secondary objective included comparison of HRQOL by age (≥65 versus Results Between October 2008 and October 2011, a total of 113 patients were enrolled; aged Conclusion Post-operative chemotherapy did not substantially reduced HRQOL in elderly NSCLC patients, and HRQOL during and after adjuvant chemotherapy did not differ by age (

NY-ESO-1 as a predictive and prognostic marker in NSCLC.

e17539 Background: Cancer-testis antigens (CTAgs) have previously been shown to be markers of poor prognosis and to be associated with chemoresistance in short interference RNA screens. In contradistinction, we recently reported the CTAg NY-ESO-1 predicted improved responses to neoadjuvant chemotherapy in pathological stage IIIA NSCLC. Despite this, no significant survival benefit was seen in NY-ESO-1 positive (NY-ESO-1+) patients. Given that tissues available for staining in the neoadjuvant setting were limited, we investigated a retrospective cohort of patients who underwent curative surgery for pathological N2 disease. As some of these patients were operated on prior to the broad acceptance of adjuvant chemotherapy (ACT), half did not receive chemotherapy. We investigated NY-ESO-1 as a prognostic and/or predictive marker in these patients. Methods: Formalin fixed paraffin embedded tissues were reviewed and stained using standard methods for a panel of CTAgs including NY-ESO-1 by immunohistochemistry. Tumors were categorized as NY-ESO-1+ or NY-ESO-1-. Isolated DNA was subjected to mutation profiling using Sequenom’s MassArray platform. Molecular markers were correlated with clinicopathological features and survival. Results: NY-ESO-1 stained 26/104 (25%) samples, including 15 cases that received ACT and 11 that did not. NY-ESO-1+ tumors were enriched for squamous cell carcinomas over adenocarcinomas (12/29 vs. 8/57; p = 0.01). They also lacked EGFR mutants and were enriched for KRAS mutants amongst adenocarcinomas relative to NY-ESO-1- tumors (5/8 vs. 9/49; p=0.02). NY-ESO-1+ patients who did not receive ACT had significantly worse outcome than NY-ESO-1- patients who did not receive ACT (HR 2.66 1.2-5.86, p=0.01). Median survival favored NY-ESO-1+ patients who received chemotherapy (37.7 months) compared to NY-ESO-1- patients regardless of chemotherapy (28.2 ACT vs 15.7 No ACT; p= 0.25) and NY-ESO-1+ patients who did not receive ACT (7.75). Conclusions: In this dataset, NY-ESO-1 was poorly prognostic but also predictive for more favorable outcomes with chemotherapy. These data support our previous observation of increased responses to chemotherapy in NY-ESO-1+ N2 patients and warrant further study.

58 DIFFERENCES IN METABOLISM BETWEEN ADENO-AND SQUAMOUS CELL NON-SMALL CELL LUNG CARCINOMAS ACCORDING TO GLUT1 AND MCT4 EXPRESSION

Purpose/Objective: Hypoxia leads to changes in tumor cell metabolism such as increased glycolysis. In this study, we examined the spatial distribution of the glycolysis and hypoxia related markers glucose transporter 1 (GLUT1) and monocarboxylate transporter 4 (MCT4) expression in relation to the vasculature in stage I, II and resectable stage IIIA NSCLC. Furthermore, associations of these markers with survival were investigated. Material and Methods: GLUT1 and MCT4 expression were determined in 90 NSCLC fresh frozen biopsies using immunohistochemical techniques and a computerized image analysis system. Markers were analyzed for adenocarcinomas (n=41) and squamous cell carcinomas (n=34) separately. Eighty-four patients were retrospectively evaluated for relapse and survival. Results: Squamous cell carcinomas demonstrated higher GLUT1 expression, relative to adenocarcinomas. Also, in squamous cell carcinomas, GLUT1 and MCT4 expression increased with increasing distance from the vasculature, whereas in adenocarcinomas upregulation of MCT4 was already found at closer distance from vessels. In adenocarcinomas, high GLUT1 expression correlated with a poor differentiation grade and positive lymph nodes at diagnosis. High GLUT1 plus high MCT4 expression was associated with a poor disease-specific survival in only adenocarcinomas (p=0.032). Conclusions: Analysis of GLUT1 and MCT4 expression on the histological level suggested a different metabolism for adenocarcinomas and squamous cell carcinomas. Likely, adenocarcinomas rely mainly on aerobic glycolysis for ATP production, whereas the behavior of squamous cell carcinomas is more physiologically, i.e. mitochondrial oxidation with anaerobic glycolysis under hypoxic conditions. High GLUT1 plus high MCT4 expression indicated an aggressive tumor behavior in adenocarcinomas. This subgroup of tumors may benefit from new treatment approaches, such as MCT4 inhibitors. Since this study has an exploratory character, our results warrant further investigation and need independent validation.

Reply to Durand

of disease aggressiveness regarding microvascular invasion [4] and gene mutations [5] despite the stage. The trend is to find evidence of benefit from adjuvant therapy to epidermal growth factor-muted patients, even for early stage of lung cancer (e.g., the Randomized, Double-Blind Trial in Adjuvant NSCLC with Tarceva (RADIANT) trial, double-blind randomized of erlotinib in the adjuvant setting of I–IIIa NSCLC). Moreover, the authors have accurately stated that extended lymphadenectomy is not more morbid than sampling. As a conclusion, regarding the benefit/risk expected of extended lymphadenectomy and the absence of accuracy of PET/CT for small-size structures, I was expecting the authors to conclude that PET/CT is not relevant for small-size tumor or node metabolic evaluation. A trial evaluating the omission of extended lymphadenectomy in small-size tumors with no lymph node uptake on PET–CT appears unethical and obviously exposes the arm of patient without lymphadenectomy to a loss of chance (risk of under staging and under treatment). In addition, a ‘wait-for–grow-’ attitude for non-uptaking nodes with suspect morphologic characteristics is a misbenefit of technology. REFERENCES

Differences in metabolism between adeno- and squamous cell non-small cell lung carcinomas: Spatial distribution and prognostic value of GLUT1 and MCT4

BackgroundHypoxia leads to changes in tumor cell metabolism such as increased glycolysis. In this study, we examined the spatial distribution of the glycolysis and hypoxia related markers glucose transporter 1 (GLUT1) and monocarboxylate transporter 4 (MCT4) expression in relation to the vasculature in stage I, II and resectable stage IIIA NSCLC. Furthermore, associations of these markers with survival were investigated. MethodsGLUT1 and MCT4 expression were determined in 90 NSCLC fresh frozen biopsies using immunohistochemical techniques and a computerized image analysis system. Markers were analyzed for adenocarcinomas (n=41) and squamous cell carcinomas (n=34) separately. Eighty-four patients were retrospectively evaluated for relapse and survival. ResultsSquamous cell carcinomas demonstrated higher GLUT1 expression, relative to adenocarcinomas. Also, in squamous cell carcinomas, GLUT1 and MCT4 expression increased with increasing distance from the vasculature, whereas in adenocarcinomas upregulation of MCT4 was already found at closer distance from vessels. In adenocarcinomas, high GLUT1 expression correlated with a poor differentiation grade and positive lymph nodes at diagnosis. High GLUT1 plus high MCT4 expression was associated with a poor disease-specific survival in only adenocarcinomas (p=0.032). ConclusionAnalysis of GLUT1 and MCT4 expression on the histological level suggested a different metabolism for adenocarcinomas and squamous cell carcinomas. Likely, adenocarcinomas rely mainly on aerobic glycolysis for ATP production, whereas the behavior of squamous cell carcinomas is more physiologically, i.e. mitochondrial oxidation with anaerobic glycolysis under hypoxic conditions. High GLUT1 plus high MCT4 expression indicated an aggressive tumor behavior in adenocarcinomas. This subgroup of tumors may benefit from new treatment approaches, such as MCT4 inhibitors. Since this study has an exploratory character, our results warrant further investigation and need independent validation.

Overexpression of the HIF Hydroxylases PHD1, PHD2, PHD3 and FIH Are Individually and Collectively Unfavorable Prognosticators for NSCLC Survival

IntroductionHypoxia induced factors (HIFs) are at the heart of the adaptive mechanisms cancer cells must implement for survival. HIFs are regulated by four hydroxylases; Prolyl hydroxylase (PHD)-1,-2,-3 and factor inhibiting HIF (FIH). We aimed to investigate the prognostic impact of these oxygen sensors in NSCLC.MethodsTumor tissue samples from 335 resected stages I to IIIA NSCLC patients was obtained and tissue microarrays (TMAs) were constructed. Hydroxylase expression was evaluated by immunohistochemistry.Principal FindingsThere was scorable expression for all HIF hydroxylases in tumor cells, but not in stroma. In univariate analyses, high tumor cell expression of all the HIF hydroxylases were unfavorable prognosticators for disease-specific survival (DSS); PHD1 (P = 0.023), PHD2 (P = 0.013), PHD3 (P = 0.018) and FIH (P = 0.033). In the multivariate analyses we found high tumor cell expression of PHD2 (HR = 2.03, CI 95% 1.20–3.42, P = 0.008) and PHD1 (HR = 1.45, CI 95% 1.01–2.10, P = 0.047) to be significant independent prognosticators for DSS. Besides, there was an additive prognostic effect by the increasing number of highly expressed HIF hydroxylases. Provided none high expression HIF hydroxylases, the 5-year survival was 80% vs. 23% if all four were highly expressed (HR = 6.48, CI 95% 2.23–18.8, P = 0.001).ConclusionsHIF hydroxylases are, in general, poor prognosticators for NSCLC survival. PHD1 and PHD2 are independent negative prognostic factors in NSCLC. Moreover, there is an additive poor prognostic impact by an increasing number of highly expressed HIF hydroxylases.

Comparison of Clinical and Surgical-Pathological Staging in IIIA Non-Small Cell Lung Cancer Patients

The heterogeneous group of IIIA NSCLC patients requires careful preoperative clinical staging as tumor size and lymph node involvement guide treatment. The purpose of our study was to analyze the correctness of clinical staging in IIIA patients. Retrospective analysis of all patients resected due to lung cancer that had been staged IIIA either clinically using invasive and noninvasive techniques or surgical-pathologically after surgical resection. Correctness, sensitivity, specificity, and positive and negative predictive values of clinical staging were calculated. From our tumor database, 49 patients who met the inclusion criteria were identified. The histology of the primary tumor included adenocarcinoma (53%), squamous cell carcinoma (41%), and other (6%). Preoperative clinical staging consisted of computed tomography (CT), integrated positron emission tomography-CT (PET-CT), bronchoscopy, and mediastinoscopy. The predominant surgical procedures performed were lobectomies (57%) and pneumonectomies (29%). Clinical staging for UICC, T and N stage was correct in 36.7, 38.7, and 40.8%, respectively. In terms of T4 stage, sensitivity was 28.5%, specificity was 80.9%, positive predictive value was 20%, and negative predictive value was 87.1%. As for N2 involvement, we found a sensitivity of 66.6% and a specificity of 35.7%. Positive and negative predictive values for N2 involvement were 43.7 and 58.8% in that order. Despite multimodal preoperative invasive and noninvasive staging techniques, the correctness of clinical staging in IIIA NSCLC patients is low. Hence, in doubt more invasive staging or probatory thoracotomy should be performed not to deny potentially curative surgery in those patients.

Long-term survival (LTS) and competing risks within a prospective multi center German randomized trial comparing induction chemotherapy (CTx) followed by concurrent (cc) chemoradiation (CTx/RTx) plus surgery (SURG; TRIMODALITY) supplemented by PCI versus local treatment (Tx) alone (SURG + RTx) in operable IIIA NSCLC.

7042 Background: we have already reported cumulative probability (prob) of brain relapse as first site of failure within our randomized trial that investigated TRIMODALITY + prophylactic cranial irradiation (PCI) versus SURG + RTx alone in operable IIIA NSCLC (Pöttgen, JCO 2007). Here we report LTS for these arms, look for exploratory subgroups and investigate competing risks. Methods: Pts with histopathologically (mediastinoscopy) proven operable IIIA (1-2 LN involved, no clinical N2, no bulky/extranodal disease, central T3N0-1, WHO 0,1) NSCLC were stratified (TN-group, center) and randomized. Arm B received three CTx cycles cis (60 mg/m2 d 1+7 or 8) and eto (150 mg/m2 d 3,4,5) qd 22. This was followed by cc CTx/RTx including cis 50 mg/m2 d 2 + 9 and eto 100 mg/m2 d 4-6 cc with 45 Gy (1.5 Gy bid). 3-5 weeks after end of RTx SURG was performed if possible and PCI given thereafter. Arm A had local treatment alone (SURG + RTx) and no PCI. Results: Pts accrual 1/95 to 10/01; eligible 106/112 randomized; Pts characteristics: gender m 90; f 16; age median 57 (37-71); PS 0-1; histo: adeno (ADC) 35; squamous cell (SCC) 50; large cell (LCC) 16; ADSCC 5 TN-groups: T3N0-1 6 T1-2N2 83 T3N2 17. Med S of pts still alive on f-up: 130 mo. LT exploratory OS analysis (2-y-OS %; 5-y-OS %, 10-y-OS %); B: 54.6 20.0 12.5; A: 44.2 23.5 10.0 (ns log rank, Wilcoxon); PFS: B: 36.4 14.6 12.7 A: 29.4 17.3 10.4 (p = 0.30/0.14 log rank/Wilcoxon) Disease-specific survival: B: 40.5 25.0 25.0 A: 32.5 23.1 18.5 (p = 0.16/0.059 log rank/Wilcoxon), Cumulative 10-y prob %: non-disease-related events (tox, comorbidity, second cancer): B: 56.3 A: 67.7 (ns); brain relapse as first site of failure: B: 16.6 A: 30.4 (p = 0.059/0.020 log rank/Wilcoxon). Conclusions: LTS after Tx in stage IIIA is significantly hampered by cumulative competing risks (toxicities, comorbidities, second cancers) regardless of Tx intensity. Initial pts selection based on comorbidity profiles may be most important in improving LTS with aggressive protocols based on TRIMODALITY (+/- PCI).

A phase I study of nab-paclitaxel (nP) with carboplatin (C) and thoracic radiation (TRT) in patients with locally advanced NSCLC.

7046 Background: One third of patients (pts) with NSCLC present with localized, unresectable disease. Concurrent chemoradiotherapy is well established with weekly paclitaxel and C with median survival of ~14 months. Nanoparticle albumin-bound (nab) paclitaxel (nP) is a cremophor-free formulation of paclitaxel designed to improve solubility and intra-tumor delivery. This phase I trial evaluates weekly nP + C + TRT in pts with unresectable stage III NSCLC. Methods: Pts with inoperable Stage IIIA or IIIB NSCLC, PS 0-1, and FEV 1 >800 ml entered escalating dose cohorts in a modified 3+3 design of nP weekly, beginning at 40 mg/m2 and increasing by 20 mg/m2 increments, in combination with C (AUC 2) weekly for 7 weeks and concurrent RT 66 Gy/33 fractions by either 3D conformal or intensity-modulated techniques. Pts received 2 cycles of consolidation therapy with full dose nP (100 mg/m2 weekly for 3 weeks) and C (AUC 6 on day one of each cycle) every 21d. The DLT period is defined as the concurrent chemoradiation period. Results: Eleven pts were enrolled. Ten pts were treated at 2 dose levels of nP, 40mg/m2 (6 pts) and 60mg/m2 (4 pts). One pt signed consent and then withdrew. Six pts were treated at 40mg/m2 with no DLT. Four pts were treated at 60mg/m2 with 2 DLT of radiation dermatitis and esophagitis. During concurrent treatment, Grade 2 toxicities were fatigue, dehydration, nausea, dysphagia, esophagitis, mucositis, hypoxia, neutropenia, anemia, and thrombocytopenia, and Grade 3 toxicities were neutropenia, mucositis, esophagitis, and dermatitis. No grade 4 toxicities were seen during concurrent treatment. Ten pts were evaluable for response with 9 PR and 1 SD. Seven patients have progressed 3, 5, 6, 7, and 8, 16 and 20 months after enrollment, and 3 patients remain stable at 2, 4, and 28 months. The recommended Phase II dose of weekly nP is 40mg/m2. Conclusions: Weekly nP is safe and well tolerated at 40mg/m2 when used in combination with weekly C (AUC2) and RT (66Gy) with AEs expected for concurrent chemoradiotherapy. A Phase II study to further evaluate this regimen is underway.

Long-term survival (S) of induction chemotherapy (CTx) with three cycles cisplatin (cis)/paclitaxel (pac) followed by concurrent (cc) chemoradiation (CTx/RTx) cis/etoposide (eto) and 45 Gy (1.5 Gy bid) plus surgery (SURG): Phase II results (CISTAXOL).

7047 Background: CTx/RTx followed by SURG remains possible treatment (Tx) for pts with stage IIIA(N2) NSCLC (Albain, Lancet 2009) and selected IIIB (Eberhardt, JCO 1998; Stupp, Lancet Oncol 2009). Here we report long-term S from a prospective phase-II with trimodality Tx (CISTAXOL) that served as predecessor/baseline dataset for our ongoing randomized phase-III (ESPATÜ) (Poettgen, Int J Radiat Oncol Biol Phys 2010). Methods: Pts with histopathologically (mediastinoscopy) proven IIIA(N2) and selected IIIB NSCLC received three CTx cycles cis (50 mg/m2 d 1+8) and pac (175 mg/m2 d 1) qd 22. This was followed by cc CTx/RTx including cis 50 mg/m2 d 2 + 9 and eto 100 mg/m2 d 4-6 cc with 45 Gy (1.5 Gy bid). Three to five weeks after end of RTx pts received SURG if possible. In pts determined inoperable at end of RTx, a definitive CTx/RTx-boost (20 Gy; 2 Gy qd) was added. Here we report ten-year (overall) OS for this cohort and look for exploratory subgroups. Results: Pts accrual from 3/1999 to 2/2002. Pts characteristics: 64 (IIIA(N2) 24; IIIB 40); gender m 48; f 16; PS 0-1; histo: adeno (ADC) 17; squamous cell (SCC) 28; large cell (LCC) 17; NOS 2; age: median 52.5 (range 28-69). 36 pts taken to SURG: R0 32; R1/R2 3; exploratory 1; pCR 16. Long-term exploratory OS analysis (5-y-OS %, 10-y-OS %): med S of all pts still alive on f-up: 8 y 10 mo; all pts 30.1 27.8; IIIA(N2) 34.3 34.3; IIIB 27.7 23.8 (ns log rank); groups defined by pre-Tx factors: histo SCC 46.2 41.0 LCC 23.5 23.5 ADC 11.8 11.8 p = 0.0075 log rank; age < 50 45.9 45.9 age ≥ 50 23.1 20.3 p = 0.035 log rank; groups defined by Tx-dependent factors: R0 46.4 46.4 no R0 14.6 9.7 p = 0.0013 log rank ; R0/pCR 66.0 66.0 R0/vital TU 27.0 27.0 p = 0.03 log rank. Conclusions: long-term S of CISTAXOL defines the rationale for our ongoing randomized trial with SURG after induction Tx in selected pts with stage IIIA/IIIB. Interestingly, histo and age turn out to be important factors in exploratory analysis. ADC and older pts demonstrate poor prognosis even with trimodality. We will prospectively validate these findings in ESPATÜ and perform competing risk analysis.

The NQO1*2/*2 polymorphism is associated with poor overall survival in patients following resection of stages II and IIIa non-small cell lung cancer

NAD(P)H:quinone oxidoreductase 1 (NQO1), is a cytosolic flavoenzyme that catalyzes the two-electron reduction of quinones into hydroquinones. A polymorphism (NQO1*2) alters enzymatic activity of NQO1 resulting in diminished NQO1 activity. Malignancies with NQO1*2 may be resistant to radiation and chemotherapy with resulting poorer survival. NQO1 allele was evaluated in subjects enrolled in ECOG 3590, a randomized comparison of radiation (RT) vs radiation and chemotherapy with cisplatin/etoposide (RCT) in patients with completely resected stages II and IIIa NSCLC. Overall survival was estimated using the Kaplan-Meier method and compared via the log-rank test. Cox models were used to assess the impact of covariates on outcomes. Among 152 patients with assessable samples, 24 (16%) had NQO1*2. Median follow-up was 139 months. The presence of NQO1*2/*2 was associated with decreased overall survival (OS) (median in the heterozygote/wild-type group 42.3 vs. 33.5 months in the variant group, p=0.04). In a multivariable Cox model, variant NQO1 (HR = 1.58, p = 0.05), age <60 (HR = 0.67, p = 0.04), PS 1 (HR = 1.47, p = 0.05), cardiovascular disease (HR = 1.93, p = 0.003) and alkaline phosphatase <100 mg/ml (HR = 0.59, p = 0.005) were all significant predictors of OS. NQO1*2/*2 may be an independent predictor of poor overall survival in individuals with resected stages II and IIIa NSCLC. Although the basis for the NQO1 association with decreased survival requires additional evaluation, NQO1 may represent a biomarker for guiding individualized therapy.

Involved field radiotherapy for locally advanced non-small cell lung cancer: Isolated mediastinal nodal relapse

The current standard of care for locally advanced inoperable non-small cell lung cancer is high dose radiotherapy with concurrent chemotherapy. We report on a patient with stage IIIA NSCLC treated with concurrent chemoradiotherapy on the primary tumor and the 18-fluorodeoxyglucose positron emission tomography ( 18FDG-PET) positive hilar and mediastinal lymph nodes. Six months after treatment this patient developed a single isolated contralateral mediastinal nodal relapse outside but in the proximity of the irradiated target volume. This patient was successfully re-irradiated to this isolated nodal relapse after reconstruction of the dose given to the localisation of this regional recurrence. This case describes the clinical problem of a regional recurrence after involved field radiotherapy that occasionally occurs. A possible explanation for those regional recurrences is an under staging of extension of the disease because the time-interval between the staging 18FDG-PET-CT scan and the start of the irradiation was too long. If the time-interval is 4 weeks or more, we strongly recommend a new 18FDG-PET-CT because of the possibility of upstaging of the disease.

HIF-1α and EGFR as progonostic factors for therapy response and 1-year locoregional recurrence not for distant metastasis and 2-year OS in unresectable stage IIIA NSCLC treated with combined chemoradiotherapy.

10640 Background: The purpose is to evaluated the effect of prognosis of HIF-1α and EGFR in unresectable stage IIIA NSCLC treated with chemoradiotherapy. Methods: A retrospective review of 44 patients with unresectable stage IIIA NSCLC treated with chemoradiotherapy (CRT) in 2007 was performed. Stage diagnosis data including PET/CT and CT guided primary tumor biopsy tissue could be obtained. HIF-1α and EGFR expression were inspected by IHC method. Definitive combined CRT schemes were vinorelbine or gemcita plus cisplatin and irradiation with a total dose of 60 to 65 Gy. 36 patients were underwent follow-up (median time 31 ± 2.7 months, range 25-36 months). Results: HIF-1α expression was diffused in cytoplasma and nuclear, EGFR expresssion in cell membrane. Of 44 patients, the cut-off value for HIF-1α positive expression was 72%, 60% for EGFR. HIF-1α and EGFR expression were only correlated with histological type (70% and 33.% for SCC and ADC). HIF-1α, EGFR expression and SUVmax value were significantly correlated. HIF-1α and EGFR were significant predictors for 79.5% effective treatment response (CR+PR) evaluated by RECIST. Of 36 followed-up patients, patients with positive HIF-1α and EGFR expression (cut-off value 78%, 60%) had statistically superior 1-year loco-regional recurrence rate (p = 0.000, 0.004) and shorten mean time to first locoregional recurrence (9.08 ± 1.37 months vs. 10.3 ± 1.37 months) compared with negative expression. However, there is no significance for HIF-1α and EGFR in the 1-year distant-metastasis recurrence (DMR) rate, 2-year overall survival (OS) (p = 0.105, 0.077) by univariate analysis. HIF-1α expression was significant for 1-year loco-regional recurrence (HR 27.11, p = 0.009, 95%CI 2.31-318.73), and both not for 1-year DMR and 2-year OS analysised by COX ratio hazard regression. Conclusions: HIF-1α and EGFR expression were two good prognostic factors for therapy response and HIF-1α for 1-year loco-regional recurrence in stage IIIA NSCLC treated by combined CRT. The results suggest the need for an elaborate examination of HIF-1α protein expression to get its prognostic value. No significant financial relationships to disclose.

A phase III trial of carboplatin, paclitaxel, and thoracic radiation therapy with or without thalidomide in patients with stage III non-small cell carcinoma of the lung (NSCLC): E3598

7503 Background: Thalidomide (T) is an oral angiogenesis inhibitor with anti-tumor activity in hematological malignancies. Given that antiangiogenic drugs such as bevacizumab have proven activity in advanced NSCLC, ECOG conducted a phase III study to compare the effects of the addition of thalidomide to paclitaxel/carboplatin/radiation therapy (PC/RT) on overall survival (OS) in pts with newly diagnosed stage III NSCLC. Secondary endpoints included time to progression (PFS) and toxicity. Methods: Pts were required to have inoperable stage IIIA or IIIB (no pleural effusion) NSCLC and a PS of 0 or 1. Pts were randomized to receive 2 cycles of P (225 mg/m2)+ C (AUC=6) every 3 wks or PC + thalidomide starting at 200 mg daily with the possibility of dose escalation. This was followed by weekly C (AUC=2), P (45 mg/m2) and concurrent RT (60 Gy) ± T. Pts on PC/RT + T continued thalidomide for 24 mo. or until disease progression. Results: 277 eligible pts were randomized to PC/RT and 272 pts to PC/RT + T. Median age was 63; 61% of pts had stage IIIB disease, 35% had squamous histology, and 46% were PS 0. The third planned interim analysis was conducted with 403 of 506 planned deaths (73.9%) for full analysis and the trial was stopped early by the ECOG Data Monitoring Committee for futility. The median overall survival for the no T arm was 15.3 mo. (12.4–20.2 mo.) compared to 16.0 mo for the T arm (14.4–18.3 mo.); hazard ratio = 0.985 (0.81–1.19); p = 0.88. Median PFS for the no T arm was 7.6 mo. (6.6–8.7 mo.) compared to 8.0 mo. for the T arm (7.1–9.1 mo.), p&gt;0.05. The most common toxicity on both arms was myelosuppression. 11% of pts on the T arm had a grade 3–5 thrombosis/embolism, compared to &lt;3% on the no T arm. Conclusions: The addition of thalidomide to PC/RT in pts with stage III NSCLC does not provide a clinically significant benefit. [Table: see text]

Phase II study of induction chemotherapy with cisplatin (Cis) and gemcitabine (Gem) followed by concomitant Cis-Gem and thoracic radiation (RTX) for unresectable locally advanced non-small cell lung cancer (LA-NSCLC)

7550 Background: In the CALGB Study Cis with Gem followed by concomitant chemoradiation for inoperable LA-NSCLC was effective, however with significant toxicity (E. Vokes et al; JCO 20: 2002). The aim of this study was to improve tolerability by reducing the Gem dose during radiotherapy and adding one cycle of induction chemotherapy. Methods: Patients with histological proven stage IIIA and IIIB NSCLC were included in this study from 8/04 to 9/07. All patients were to receive 3 induction cycles (21 days) of Cis 80 mg/m2 d1 plus Gem 1250 mg/m2 over 30 minutes d1, 8. After a 3 weeks rest period, 2 cycles of concomitant chemoradiation Cis 80 mg/m2 d1, Gem 300 mg/m2 d1, 8 and RTX (about 60 Gy; 5 times 1,8 Gy fractions / week) were given. Results: A total of 49 patients, median age 63.4 yrs, 73.5% male, with Karnofsky performance status 80/85/90/100: 16.3% / 2.0% / 49.0% / 32.7% were entered. Disease stage IIIA/IIIB: 28.6% / 71.4%. Median dose intensity during chemoradiation Gem 98.4%, Cis 99.0% and radiation median total dose was 63 Gy. Number of grade 3/4 toxicities during induction chemotherapy (N=49): neutropenia 9/9, thrombocytopenia 4/1. Acute grade 3/4 toxicities during chemoradiation phase (N=31): neutropenia 4/0, thrombocytopenia 5/1, radiation esophagitis 4/0 and radiation pneumonitis 1/0. No toxic death. Tumor Response Rate of enrolled patients was 22 (44.9%) (95% CI: 30.7–59.8). Conclusions: Concurrent Cis Gem chemoradiation after Cis Gem induction is an active treatment for LA-NSCLC with managable toxicity. [Table: see text]

Results of Surgical Treatment After Neoadjuvant Chemotherapy for Stage III Non‐Small Cell Lung Cancer

The potential benefits of an approach combining neoadjuvant chemotherapy and surgery in stage IIIA and IIIB NSCLC have to be weighed against a potential increase in postoperative complications. We evaluated the results in terms of postoperative complications and survival in patients with stage III NSCLC who underwent complete surgical treatment after neoadjuvant chemotherapy with two regimens: mitomycin, vinblastine, and cisplatin (MPV) versus gemcitabine and cisplatin (GC). From March 1991 to September 2005, 110 patients with stage III NSCLC (86 stage IIIA and 24 stage IIIB) underwent complete surgical treatment after neoadjuvant chemotherapy. Ninety-two patients were men and 18 were women, with a mean age of 59 (range, 39-80) years. The neoadjuvant chemotherapy regimen was MPV in 72 patients and GC in 38. The overall response (>50%) to chemotherapy was 84%. Postoperative mortality and morbidity were 1.8% and 20%, respectively. Overall 5-year survival was 46%. Minor response to neoadjuvant chemotherapy (<50%) and residual nodal N2 involvement in stage IIIA had an adverse impact on survival (p < 0.05). Favorable long-term survival was observed after neoadjuvant chemotherapy with MPV and GC regimens in stage IIIA and IIIB NSCLC, with relatively low postoperative mortality and morbidity. Caution should be taken when offering surgical treatment to patients with minor response to induction chemotherapy and residual N2 disease in view of the significantly reduced survival.

PHYSICIAN PREFERENCES FOR MANAGEMENT OF PATIENTS WITH STAGE IIIA NON-SMALL CELL LUNG CANCER: IMPACT OF BULK OF NODAL DISEASE ON THERAPY SELECTION

PURPOSE: Stage IIIA NSCLC is defined largely by involved ipsilateral mediastinal nodes (N2). Extent of nodal disease has prognostic significance. Optimum management is unclear.

Induction chemotherapy followed by concurrent chemoradiation for patients with non-operable stage III non-small-cell lung cancer

Combined modality treatment with chemotherapy (CT) and radiotherapy (RT) in stage III non-small-cell lung cancer is considered as standard therapy. As concomitant CT appears to be beneficial, the choice of anticancer agents and the role of induction chemotherapy is still unresolved. We present our experience based on an induction CT scheme with carboplatin plus paclitaxel followed by RT and concomitant CT. 31 patients with non-operable stage IIIA or IIIB NSCLC without pleural effusion were included in this study: 30 males, 1 female; median age 66 years (range: 50-81); 32% with non-operable stage IIIA and 68% with stage IIIB without pleural effusion; 61% squamous cell carcinoma, 32% adenocarcinoma and 7% other histologies. Regarding performance status (PS), 9.7% PS 0 and 90% PS 1 were included. Patients received 3 courses of induction CT with carboplatin AUC=6 and paclitaxel 175 mg/m(2), administrated i.v. on day 1 of each 21-day cycle, followed by thoracic irradiation (total dose 60-65 Gy, daily fractions 1.8-2 Gy) with two concurrent courses of carboplatin/paclitaxel. 16.2% of the patients achieved complete response, 48.4% partial response, 25.8% stable disease and 9.6% progression of disease. Median progression-free and overall survival was 12 and 18 months, respectively. The most frequent haematological toxicities were grade (G) 3 anaemia in 19.3%, G3 neutropenia in 9.6% and G4 neutropenia in 12.9%. Esophageal G2 toxicity (RTOG) was observed in 28.1% of cases. The induction CT followed by concomitant chemoradiation used in this study appears feasible, safe and effective when administered to an unselected inoperable NSCLC stage III patient cohort in the everyday routine clinical practice. Further, our results are comparable to previously published phase III studies.

Treatment of locally-advanced NSCLC by concomitant chemotherapy (CTx), HDR brachytherapy (BTx) and conformal external beam radiation therapy (XRTx)

18504 Background: Efforts to achieve local control and improve survival in patients (pts) with locally-advanced, non-resectable NSCLC continue to evolve. XRTx as the sole treatment modality has been replaced by concomitant CTx + XRTx based on improved survival with acceptable tolerance. Further attempts to improve clinical outcomes have investigated XRTx dose intensification through hyper- fractionation. An alternative to this strategy offering certain practical advantages to hyper-fraction treatment is the use of BTx in conjunction with XRTx. This exploratory retrospective study assessed the efficacy of BTx in conjunction with conformal XRTx plus CTx in pts with surgically-unresectable, locally advanced NSCLC. Methods: Clinical results for newly-diagnosed, NSCLC patients (n=21) with either Stage IIIA (T1 or T2, N2, MO or T3, N1 or N2, MO) or Stage IIIB (Tx, N3, MO or T4, Nx, M0) tumors were abstracted from the medical records of pts treated at the Southwestern Regional Medical Center of Cancer Treatment Centers of America. There were 9 IIIA and 12 IIIB tumors with squamous histology (n=9); adenocarcinoma (n=3); large cell tumors (n=3); and mixed cell types (n=6) being seen. All pts received combination, platinum-based CTx in conjunction with XRTx (60 Gy) + 4–6 cycles of BTx (500 cGy/treatment). Results: Median survival for the population was 18.22 months. Median survival for Stage IIIA was 18.6 months and for Stage IIIB was 16.4 months. Resolution of treated endobronchial lesions and/or substantial necrotic tissue without endoscopic evidence of significant residual viable tumor was observed on repeat bronchoscopic examination in the treated tumor mass for most patients. Planned multimodality therapy was completed on all patients with tolerable and expected toxicity. Conclusions: The results demonstrate that therapy for locally advanced, NSCLC which includes BTx is clinically effective and well tolerated. The comparatively low incidence and severity of radiation-associated toxicities suggests further development of this approach for treatment of Stage IIIA and IIIB NSCLC is warranted. No significant financial relationships to disclose.