Untreated Adenocarcinoma Research Articles

Non-invasive, fast, and high-performance EGFR gene mutation prediction method based on deep transfer learning and model stacking for patients with Non-Small Cell Lung Cancer

PurposeTo propose an intelligent, non-invasive, highly precise, and rapid method to predict the mutation status of the Epidermal Growth Factor Receptor (EGFR) to accelerate treatment with Tyrosine Kinase Inhibitor (TKI) for patients with untreated adenocarcinoma Non-Small Cell Lung Cancer. Materials and methodsReal-world data from 521 patients with adenocarcinoma NSCLC who performed a CT scan and underwent surgery or pathological biopsy to determine EGFR gene mutation between January 2021 and July 2022, is collected. Solutions to the problems that prevent the model from achieving very high precision, namely: human errors made during the annotation of the database and the low precision of the output decision of the model, are proposed. Thus, among the 521 analyzed cases, only 40 were selected as patients with EGFR gene mutation and 98 cases with wild-type EGFR. ResultsThe proposed model is trained, validated, and tested on 12,040 2D images extracted from the 138 CT scans images where patients were randomly partitioned into training (80 %) and test (20 %) sets. The performance obtained for EGFR gene mutation prediction was 95.22 % for accuracy, 960.2 for F1_score, 95.89 % for precision, 96.92 % for sensitivity, 94.01 % for Cohen kappa, and 98 % for AUC. ConclusionAn EGFR gene mutation status prediction method, with high-performance thanks to an intelligent prediction model entrained by highly accurate annotated data is proposed. The outcome of this project will facilitate rapid decision-making when applying a TKI as an initial treatment.

An open-label phase 2 study of lenvatinib plus pembrolizumab in the neoadjuvant and adjuvant treatment for patients with gastric and gastroesophageal junction adenocarcinoma (EPOC2001).

TPS372 Background: Lenvatinib, a multikinase inhibitor of VEGF receptors and other receptor tyrosine kinases, substantially decreased the tumor-associated macrophages and increased infiltration of CD8-positive T cells and enhanced anti-tumor activity of PD-1 inhibitors in vivo model. A phase 2 study demonstrated remarkable clinical activity of lenvatinib plus pembrolizumab for advanced gastric cancer with objective response rate of 69% (Kawazoe A, et al. Lancet Oncol. 2020), leading to the global phase 3 LEAP-015 trial at first-line (NCT04662710). The objective of this study is to evaluate anti-tumor activity of lenvatinib with pembrolizumab as neoadjuvant and adjuvant treatment for patients with gastric and gastroesophageal junction adenocarcinoma. Methods: The study is an open-label, single-arm, single-center, phase 2 clinical trial. Eligible patients are with previously untreated gastric and gastroesophageal junction adenocarcinoma as defined by cT2-4 and/or cN+ without evidence of metastatic disease. Patients will receive 3 cycles of 20 mg oral lenvatinib daily plus 200 mg intravenous pembrolizumab every 3 weeks as the neoadjuvant treatment followed by surgery, and then 3 cycles of lenvatinib plus pembrolizumab followed by 11 cycles of pembrolizumab monotherapy as the adjuvant treatment. The primary endpoint is major pathological response rate, and the secondary endpoints are pathological complete response rate, tumor shrinkage effect on primary lesions, radical resection rate, treatment completion rate until surgery or adjuvant treatment, event-free survival, overall survival, and incidence of adverse events. We also investigate several biomarkers using pre- and post-treatment tumor and blood samples. First patient will be enrolled in November 2021. Clinical trial information: NCT04745988.

P2 of RMT in Combo w Durvalumab or Durva + Chemo in Untreated Adenocarcinoma NSCLC

P2 of RMT in Combo w Durvalumab or Durva + Chemo in Untreated Adenocarcinoma NSCLC

Early response evaluation of neoadjuvant therapy with PET/MRI to predict resectability in patients with adenocarcinoma of the esophagogastric junction.

Positron emission tomography (PET)/magnetic resonance imaging (MRI) is a new modality that has showed promising results for various clinical indications. Currently, evaluation of neoadjuvant therapy (NT) among patients with adenocarcinoma of the esophagogastric junction has primarily been reserved for PET/computed tomography. Our aim was to evaluate if early response evaluation by PET/MRI is a feasible method to predict resectability. Patients with untreated adenocarcinoma of the esophagogastric junction (Siewert types I/II) and fit for NT with no contraindications for PET/MRI were considered eligible. A baseline scan was performed prior to NT induction and an evaluation scan 3weeks later. For histopathological response evaluation, the Mandard tumor regression grade score was applied. Response on PET/MRI was evaluated with Response Evaluation Criteria in Solid Tumors (RECIST 1.1), and change in ADC and SUVmax values. Twenty-eight patients were enrolled, and 22 completed both scans and proceeded to final analyses. Seventeen patients were found resectable versus five who were found unresectable. PET/MRI response evaluation had a sensitivity 94%, specificity 80%, and AUC = 0.95 when predicting resectability in patients with adenocarcinoma of the esophagogastric junction. No association with histopathological response (tumor regression grade) was found nor was RECIST correlated with resectability. Response evaluation using PET/MRI was a feasible method to predict resectability in patients with adenocarcinoma of the esophagogastric junction in this pilot study. However, larger studies are warranted to justify the use of the modality for this indication.

PS02.087: EARLY RESPONSE EVALUATION OF NEOADJUVANT THERAPY WITH PET/MRI TO PREDICT RESECTABILITY IN PATIENTS WITH ADENOCARCINOMA OF THE ESOPHAGOGASTRIC JUNCTION

Abstract Background The primary treatment for locally advanced adenocarcinoma of the esophagogastric junction remains surgery combined with neoadjuvant chemo- or chemoradiotherapy (NT). A prediction of response to NT would be valuable, as insufficient response following NT may reflect therapy resistance leading to disease progression, unnecessary delay of surgery and risk of unresectability. Determining insufficient response to NT could lead to change of therapy and reduce possible chemo(radio)therapy toxicity. Positron Emission Tomography (PET)/Magnetic Resonance Imaging (MRI) is a new modality that has showed promising results for various clinical indications. Currently, evaluation of neoadjuvant therapy (NT) among patients with adenocarcinoma of the esophagogastric junction has primary been reserved for PET/computed tomography (CT). The aim of this study was to investigate if simultaneous PET/MRI is a feasible method to evaluate early tumor response to predict resectability in patients with AEG during NT. We also examined the association between histopathological response and changes on PET/MRI during NT. Methods Patients with untreated adenocarcinoma of the esophagogastric junction (Siewert's I/II) and fit for NT with no contraindications for PET/MRI were considered eligible. A baseline scan was performed prior to NT induction and an evaluation scan 3 weeks later. For histopathological response evaluation the Mandard tumor regression grade score was applied. Response on PET/MRI was evaluated with Response Evaluation Criteria in Solid Tumors (RECIST 1.1), and change in ADC and SUVmax values. Results Twenty-eight patients were enrolled, and 22 completed both scans and proceeded to our final analyses. 17 patients were found resectable vs. five not resectable. PET/MRI response evaluation is a feasible method to predict resectability in patients with adenocarcinoma of the esophagogastric junction with sensitivity 94%, specificity 80%, and AUC = 0.95. However, no association with histopathological response (tumor regression grade) was found nor was RECIST correlated with resectability. Conclusion Our work has identified response evaluation with PET/MRI as a feasible method to predict resectability in patients with adenocarcinoma of the esophagogastric junction, however, larger studies are warranted to justify the use of this modality for this indication. Disclosure All authors have declared no conflicts of interest.

A phase 3 randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of GS-5745 combined with mFOLFOX6 as first-line treatment in patients with advanced gastric or gastroesophageal junction adenocarcinoma.

TPS4139 Background: GS-5745 is a monoclonal antibody that inhibits matrix metalloproteinase 9 (MMP9), an extracellular enzyme involved in matrix remodeling, tumor growth, and metastasis. Inhibiting MMP9 blocks paracrine signaling and metastasis and alters the tumor immune microenvironment. GS-5745 (800 mg q 2 weeks) with mFOLFOX6 was examined in a Phase 1b study in 40 patients with gastric and GEJ adenocarcinoma (GS-US-296-0101), and demonstrated encouraging activity without added toxicity (10% CR, median PFS 10.7 mo (Shah et al ASCO GI 2017, a108)). Decreased free MMP9 suggested inhibition of MMP9 enzymatic activity by GS-5745. These data support the hypothesis that GS-5745 treatment inhibits MMP9 activity and that the inhibition may lead to improved clinical outcomes. Methods: This phase 3, randomized, double-blind, multicenter study investigates the efficacy and safety of GS-5745 combined with mFOLFOX6 in subjects with untreated gastric and GEJ adenocarcinoma. Total of 430 eligible subjects with advanced gastric and GEJ cancer will be randomized in a 1:1 manner to mFOLFOX6 plus GS-5745 or mFOLFOX6 plus placebo. Stratification factors include ECOG status (0 v 1), geographic region (Latin America v All other countries), and primary tumor site (gastric v GEJ). CT or MRI scans will be performed every 8 weeks to evaluate response to treatment. mFOLFOX6 will be administered on Days 1 and 15 of each 28-day treatment cycle for a total of 6 cycles followed thereafter by leucovorin (LV) and 5-fluorouracil (5-FU) dosing on Days 1 and 15 of each 28-day treatment cycle until disease progression. GS-5745/placebo 800 mg will be infused on Days 1 and Day 15 of each 28 day cycle until disease progression. Primary endpoint is OS, and secondary endpoints include PFS, ORR (RECIST 1.1), and safety. The study is designed to have an 85% power to detect clinically meaningful improvement in overall survival at the one-sided significance level of 0.025. The association of exploratory biomarkers with study drug response will also be evaluated. Enrollment opened Oct. 2015. Clinical trial information: NCT02545504.

Genomic analysis of untreated prostate adenocarcinoma, treatment-emergent neuroendocrine carcinoma, and circulating tumor cells.

200 Background: The prostate cancer genome evolves in response to therapeutic pressure, requiring repeated evaluation as the disease progresses. Biopsies of metastatic sites are invasive and often low yield. Circulating tumor cells (CTCs) offer an alternative source, but few studies have evaluated their genomic relationship with untreated and contemporaneous disease. Methods: We performed exome sequencing of untreated tumor tissue, a late stage liver biopsy, and the amplified genome of EpCAM+ CTCs in a patient with therapy-emergent neuroendocrine carcinoma. Results: Exome sequencing of CTCs captured 71% of the founder mutations shared between the two tissue samples. The allele fraction of founder mutations in the CTCs was 47.8%, indicating a nearly pure population of CTCs from a single clonal disease. Other mutations were at lower allele frequency, suggesting genomic heterogeneity among pooled CTCs. CTCs demonstrated late divergence from the contemporaneous neuroendocrine carcinoma liver biopsy, with 62% of mutations also found in this tissue. An acquired premature stop codon mutation in the Retinoblastoma (RB1) gene, which is associated with progression to small cell cancer, was identified in neuroendocrine and CTC samples, but not untreated tissue. Conclusions: These data support the clonal relationship of untreated adenocarcinoma and treatment-emergent neuroendocrine carcinoma. They also support the use of pooled EpCAM+ CTCs to facilitate the genetic analysis of late stage prostate cancer, including neuroendocrine carcinoma.

A phase 3 randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of GS-5745 combined with mFOLFOX6 as first-line treatment in patients with advanced gastric or gastroesophageal junction adenocarcinoma.

TPS217 Background: GS-5745 is a monoclonal antibody that inhibits matrix metalloproteinase 9 (MMP9), an extracellular enzyme involved in matrix remodeling, tumor growth, and metastasis. Inhibiting MMP9 is expected to block paracrine signaling and metastasis and to alter the immune microenvironment within the tumor. GS-5745 (800 mg every 2 weeks) with mFOLFOX6 was examined in a Phase 1b study in 40 patients with gastric and GEJ adenocarcinoma (GS-US-296-0101), and demonstrated encouraging activity without added toxicity. Additionally, decreased serum biomarkers suggested inhibition of MMP9 enzymatic activity by these agents. These data support the hypothesis that GS-5745 treatment inhibits MMP9 activity and that the inhibition may lead to improved clinical outcomes. Methods: This phase 3, randomized, double-blind, multicenter study investigates the efficacy and safety of GS-5745 combined with mFOLFOX6 in subjects with untreated gastric and GEJ adenocarcinoma. Total of 430 eligible subjects with advanced gastric and GEJ cancer will be randomized in a 1:1 manner to mFOLFOX6 plus GS-5745 or mFOLFOX6 plus placebo. Stratification factors include ECOG status (0 v 1), geographic region (Latin America v All other countries), and primary tumor site (gastric v GEJ). CT or MRI scans will be performed every 8 weeks to evaluate response to treatment. mFOLFOX6 will be administered on Days 1 and 15 of each 28-day treatment cycle for a total of 6 cycles followed thereafter by leucovorin (LV) and 5-fluorouracil (5-FU) dosing on Days 1 and 15 of each 28-day treatment cycle until disease progression. GS-5745/placebo 800 mg will be infused on Days 1 and Day 15 of each 28 day cycle until disease progression. Primary endpoint is OS, and secondary endpoints include PFS, ORR (RECIST 1.1), and safety. The study is designed to have an 85% power to detect clinically meaningful improvement in overall survival at the one-sided significance level of 0.025. The association of exploratory biomarkers with study drug response will also be evaluated. Enrollment opened Oct. 2015. Clinical trial information: NCT02545504.

Standard radiotherapy but not chemotherapy impairs systemic immunity in non-small cell lung cancer

ABSTRACTIntroduction: Advanced non-small cell lung cancer (NSCLC) is traditionally treated with platinum-based chemotherapy and radiotherapy. Since immunotherapy holds promise for treating advanced NSCLC, we assessed the systemic effects of the traditional therapies for NSCLC on immune cell composition and function.Methods: 84 pulmonary adenocarcinoma patients, treated either with chemotherapy or radiotherapy, were studied. A prospective study of 23 patients was conducted in which the myeloid and lymphoid cell compartments of peripheral blood were analyzed. Changes in cell populations were validated in a retrospective cohort of 61 adenocarcinoma patients using automated differential counts collected throughout therapy. Furthermore, the functional capacity of circulating T cells and antigen-presenting cells (APC) was studied. Blood samples of healthy individuals were used as controls.Results: In comparison to healthy controls, untreated adenocarcinoma patients display an elevated frequency of myeloid cells coinciding with relative lower frequencies of lymphocytes and dendritic cells. Standard chemotherapy had no overt effects on myeloid and lymphoid cell composition nor on T-cell and APC-function. In contrast, patients treated with radiotherapy displayed a decrease in lymphoid cells and a relative increase in monocytes/macrophages. Importantly, these changes were associated with a reduced APC function and an impaired response of T cells to recall antigens.Conclusions: Platinum-based standard of care chemotherapy for NSCLC has no profound negative effect on the immune cell composition and function. The negative effect of prolonged low-dose radiotherapy on the immune system warrants future studies on the optimal dose and fraction of radiotherapy when combined with immunotherapy.

Untreated endometrial cancer: a case report and a review of the literature

Background The natural course of untreated endometrial adenocarcinoma is difficult to describe because observation of an already diagnosed cancer is unethical. However, occasionally, patients refuse therapy for different reasons, thus providing the opportunity to observe the natural course of the malignant disease. These patients are for obvious reasons rare cases. We present such a case and a review of the literature.

Impact of pretreatment systemic inflammatory response on survival in AGC patients receiving first-line chemotherapy.

88 Background: Systemic inflammatory response plays an important role in cancer progression. However, little is known about how it affects the advanced gastric cancer (AGC) patients receiving first-line chemotherapy. We assessed the impact of pre-treatment systemic inflammatory response on survival in AGC patients receiving S-1 based first-line chemotherapy. Methods: OGSG 0402 multi-institutional phase II trial randomly assigned 102 patients with previously untreated, locally advanced and/or metastatic measurable gastric adenocarcinoma to receive S-1 plus irinotecan (SI arm) (n=51) or S1 plus paclitaxel (SP arm) (n=51) to evaluate these two S-1 based regimens as first-line treatment for AGC [ASCO-GI 2009: abstract 9.]. Among these patients, 99 patients were identified in this study excluding 2 patients who had died before receiving the allocated treatment and one patient who was lost to follow-up. All patients had performance status (PS) of 0-1 except for one with PS of 2. Pre-treatment clinical findings, such as gender, age, body mass index (BMI), tumor status (unresectable vs. recurrent, intestinal vs. diffuse), number of metastatic sites, serum levels of albumin (Alb) and C-reactive protein (CRP), neutrophil lymphocyte ratio (NLR), and platelet lymphocyte ratio (PLR), were assessed as prognostic factors for overall survival (OS) and progression-free survival (PFS) in univariate and multivariate analyses. Results: Median OS and PFS were 390 days and 175 days for SI arm, and 363 days and 140 days for SP arm, respectively. Multivariate analysis identified the CRP level of 0.5 mg/dl or above (hazard ratio 1.96, 95% confidence interval 1.08 to 3.55, P=0.026) as a significant prognosticator for poor OS, and age of 60 years or greater (hazard ratio 1.92, 95% confidence interval 1.06–3.47, P=0.032) for shorter PFS. Conclusions: Pre-treatment CRP level was a most potent prognosticator for OS, reflecting the impact of systemic inflammatory response on survival, in AGC patients receiving first-line chemotherapy.

Phase III randomized trial of definitive chemoradiotherapy (CRT) with FOLFOX or cisplatin and fluorouracil in esophageal cancer (EC): Final results of the PRODIGE 5/ACCORD 17 trial.

LBA4003 Background: CRT is one of the best treatment options for localized EC. As new combinations are required to improve safety and survival, we launched a randomized phase II study to assess the complete response (CR) rate of CRT with FOLFOX versus 5FU/cisplatin in 97 pts with localized EC (Conroy 2010). The trial having met its objectives, it has been pursued as a phase III trial. Stratified randomization was performed centrally in a 1:1 ratio according to histological type, pretreatment weight loss in the prior 6 months (<10% vs ≥10%), ECOG PS (0 vs 1 vs 2), and center. Methods: Pts with technically unresectable cancer or those with surgical contraindications or who refused to undergo surgery were eligible. Eligibility criteria also included age >18 years (y), PS ≤ 2, previously untreated adenocarcinoma or squamous cell EC (any T, N0 or N1, M0 or M1a). The radiation dose was 50 Gy (2Gy/fr) 5 d/wk for 5 wks in both arms. In Arm A, pts received 6 bimonthly cycles (cy): oxaliplatin 85 mg/m2 d1 and leucovorin 200 mg/m2 followed by 5-FU 400 mg/m2 bolus d1 then 1,600 mg/m2 46h continuous infusion (ci) ; the first 3 cy were delivered during RT, the 3 other after. In Arm B, pts received 4 cy: cisplatin 75 mg/m2 d1 followed by 5FU 1,000 mg/m2/d ci d1-4, the first 2 cy during RT and 2 other after. The primary endpoint was PFS. Main secondary endpoints were OS, grade 3-4 toxicities, and quality of life. A total of 266 pts would provide 90% power to detect a 20% 3y-PFS difference (α=0.05). Results: 267 pts were enrolled between 10/2004 and 08/2011. Treatment cohorts were well balanced: male 81%; median age 61 y; PS 0 53%, squamous cell 85.8%, stage III 52%, IVA 6.0% and IVB 3.0%. Full treatment was delivered to 67.9% and 72.2% of pts in arms A/B, respectively. 7 toxic deaths occurred in each arm. Grade 3/4 toxicities per pt (%) in arms A/B were neutropenia 30.6/31.3, febrile neutropenia 5.3/7.0, anemia 5.4/11.0, asthenia 17.6/10.2, respectively. The median FU time was 25.3 mos. 3y-PFS was 18.2/17.4 % (HR=1.07; 95%CI =0.80-1.43) and median OS was 20.2 /17.5 m (HR=1.06; 95%CI =0.77-1.46). Conclusions: CRT with FOLFOX does not improve PFS compared to cisplatin and 5-FU and has similar toxicities.

A phase II, open-label, multicenter, prospective study of paclitaxel plus capecitabine with subsequent capecitabine maintenance therapy as first-line treatment for metastatic or recurrent gastric cancer.

98 Background: Paclitaxel has been shown to be effective in AGC. We assess the efficacy and safety of PX-X therapy as first-line treatment for metastatic or recurrent GC in a phase II, multicenter, prospective study. Methods: Patients with previously untreated gastric adenocarcinoma, signed informed consent, target lesion(s), KPS ≥ 70 and adequate organ functions are eligible. Paclitaxel was given as 80 mg/m2 by 3-hour infusion day 1,8, capecitabine 1,000 mg/m2, BID, D1-14, Q3W. Cycles were repeated until progression or maximum 6 or AEs. Then the patients without progression began the second stage treatment as X with same dose/schedule until progression or AEs. PFS, RR, DCR, OS and AEs are the end points evaluated in this study. Results: From 12/2006 to 4/2010, 195 patients (ITT) were enrolled in 21 centers, 1 patient was withdraw due to allergy to paclitaxel, 194 cases were PP. After median follow up of 16.2 months, 16 cases lost. In ITT, 119 pts progressed, 104 pts died. Mean cycles the patients completed was 5. CR and PR were achieved in 1.0% (2 pts) and 32.3% (63 pts) of pts (RR 33.3%), 75 pts had SD (38.5%), 25 pts (12.8%) progressed. PFS of ITT is 208 d (95% CI: 169.1-246.8) and estimated OS is 456 d (95%CI: 286.9-624.2). 45 pts continued to X after PX with good tolerance, median cycles accepted was 4, and OS was longer than 590 d. 23 patients accepted surgery after chemotherapy; the survival data have not been reached. After disease progression, 61 cases accepted second-line treatment, including oxaplatin/irinotecan-based chemotherapy, target therapy, and local therapy. AEs were mild and the grade 3/4 toxicities were leucopenia (13.8%), alopecia(13.3%), neutropenia (8.2%), fatigue (6.7%), nausea/vomiting (5.1%), HFS (5.1%), diarrhea(3.6%), neurotoxicity (3.1%), hepatic dysfuction (2.6%), and anaphylactic shock (0.5%). No treatment- related deaths were recorded in all patients. Conclusions: PX-X as first-line treatment was promising in advanced gastric cancer. Further evaluation of this combination therapy is being carried on phase III clinical trial of ML22697. No significant financial relationships to disclose.

Expression of hexokinases and glucose transporters in treated and untreated oesophageal adenocarcinoma.

The aim of this study was to assess the expression pattern of the high glucose affinity glucose transporters GLUT 1, 2, 3, 4, 8 and 9 and of hexokinases I, II and III in newly diagnosed oesophageal adenocarcinoma by means of immunohistochemistry. Twenty patients eligible to undergo primary surgery and 18 patients with incomplete pathological response following induction radio chemotherapy, all suffering from oesophageal adenocarcinoma, were included in the study. The intensity and amount of positive tumour cells in the immuno-reaction (histology score (Hscore)) for GLUT 1, 3, 4, 8 and 9 as well as for hexokinase I, II and III were assessed independently by two experienced observers, blinded to the clinical results. In patients that underwent primary surgery, Hscores of GLUT8 (micro 6.7; sd3.3) and GLUT1 (micro 5.5; sd: 5.3) were significantly higher than Hscores of GLUT9 (micro 2.2; sd 1.5) and GLUT3 (micro 3.2, sd: 2.5). Hscores of hexokinase I (micro : 8.3; sd: 4.3), II (micro 5.5, sd: 4.0) and III (I 1.5, sd: 0.7) were all significantly different from each other (p<0.04). In patients that underwent radio-chemotherapy prior to surgical tumour resection, micro Hscores were 6.9 (sd: 4.4) for GLUT1, 6.8 (sd: 5.3) for GLUT3, 5.9 (sd: 4.2) for GLUT8, 3.4 for GLUT9 (sd: 2.7) and 2.3 (sd: 3.6) for GLUT 4. Hscores of GLUT1 and GLUT3 were significantly higher than Hscores of GLUT4. Finally, Hscores of patients with radio-chemotherapy for GLUT3, hexokinase II and III were significantly higher when compared to patients that underwent primary surgery.

Cetuximab with irinotecan/folinic acid/5-FU as first-line treatment in advanced gastric cancer: A nonrandomized multicenter AIO phase II study

4534 Background: Cetuximab has demonstrated high efficacy in combination with irinotecan-based therapies in metastatic colorectal cancer and irinotecan/folinic acid/5-FU (IF) may be an effective alternative to cisplatin-based regimens in advanced gastric cancer. We therefore conducted a phase II AIO study to evaluate the tolerability and efficacy of cetuximab combined with IF as first-line treatment in patients with advanced gastric cancer. Methods: Patients (pts) were eligible with untreated adenocarcinoma of the stomach or oesophagogastric junction, with ECOG performance status (PS) &lt; 2, measurable lesions and adequate organ functions. Pts received weekly cetuximab (first dose 400 mg/m2, subsequent doses 250 mg/m2) combined with chemotherapy consisting of irinotecan (80 mg/m2) plus 24 hours continuous infusion of sodium folinic acid (Na-FA: 200 mg/m2) and 5-FU (1500 mg/m2) on days 1, 8, 15, 22, 29 and 36 of a 50-day cycle. Treatment was continued until tumor progression and tumor assessments were performed every 2nd cycle. Results: Between Aug 2006 and Sep 2007, 49 pts were enrolled: 71% were males, median age was 63 years (range 33–77), median PS was 0 (65% pts), and 69% of pts and 31% of pts had gastric and oesophagogastric junction carcinomas, respectively. The median treatment time was 15.2 weeks (range 1.1–69.1). Grade 3/4 toxicities were diarrhoea (17% pts), skin reactions (13% pts), anorexia (9% pts), anaemia and fatigue (7%pts), allergic reactions, leucopoenia and neutropenia (4% pts each). Among 48 response-evaluable pts, the overall response rate (CR + PR) was 42% (CR 4%/PR 38%) and the tumour control rate was 73%. Median progression-free and overall survival times were 8.5 months (36.6 weeks; 95% CI 30.1; 48.1) and 16.6 months (71.1 weeks; 95% CI 50; 93.4), respectively. Conclusions: Cetuximab plus IF was well tolerated and encouraging survival data were observed. Cetuximab combined with chemotherapy in advanced or metastatic gastric cancer is under further investigation in an ongoing phase III trial. No significant financial relationships to disclose.

A phase II trial of perioperative chemotherapy with folinic acid, 5-fluorouracil, and oxaliplatin in potentially resectable gastric cancer with regional lymph node metastasis

4602 Background: Peri-operative chemotherapy in operable advanced gastric cancer (AGC) is still in a controversial area. Results from MAGIC trial suggest that a peri-operative regimen of ECF (epirubicin, cisplatin, 5-FU) decreased tumor size and significantly improved PFS and OS in patients with operable AGC (NEJM 355: 11, 2006). The aim of this study was to evaluate the efficacy and toxicity of folinic acid (FA), infusional 5-fluorouracil (5-FU), and oxaliplatin (modified FOLFOX6), administered every 2 wks in potentially operable AGC with regional lymph node (LN) metastasis. Methods: Previously untreated gastric adenocarcinoma patients with measurable LN on CT scan (clinical stage: cT2 or cT3, N+) were eligible. Staging also included a PET-CT and endoscopic ultrasonography (EUS). Patients received 4 cycles of neoadjuvant therapy with FA 100 mg/m2 (2-hr i.v.), 5-FU 2.4 g/m2 (46-hr continuous infusion), and oxaliplatin 100 mg/m2 (2-hr i.v.), followed by curative radical surgery including D2 dissection and 4 cycles of adjuvant modified FOLFOX6. Clinical responses were assessed by RECIST using CT scan before surgery and early metabolic responses were assessed by PET-CT after 2 cycles of chemotherapy. Results: Thirty-one patients were enrolled from Oct. 2004 to Nov. 2006 and currently, 29 of them are evaluable for response. Median age was 56 yrs (range, 35–69). Most patients had EUS T3N1or2 designation. Of 29 evaluable patients, PR were observed in 19 (66%), SD in 9 (31%), and PD in 1 (3%) patient. Early metabolic responses (SUV decrement = 35% by PET-CT) were significantly correlated with conventional radiographic response (p=0.037). The R0 resection rate was 90% and pathologic CR was 7%. Median follow-up duration was 11.8 mo. and median PFS has not been reached yet. Total 219 cycles were administered. G3/4 neutropenia occurred in 6 cycles (3.0%). Nausea G3/4 occurred in 1 cycle (0.5%) and diarrhea in 1 cycle (0.5%). There were no cases of peripheral neuropathy G3/4 or febrile neutropenia G3/4. Conclusions: Peri-operative chemotherapy with modified FOLFOX6 is very effective and feasible in patients with potentially resectable AGC with regional LN metastasis. Early response can be predicted by PET-CT. No significant financial relationships to disclose.

The prognostic importance of the number of involved lymph nodes in esophageal cancer: Implications for revisions of the American Joint Committee on Cancer staging system

The American Joint Committee on Cancer (AJCC) staging system for esophageal cancer is controversial because it relies on arbitrary definitions of the anatomic location of lymph nodes to establish N and M status. It has been proposed that the number of involved lymph nodes may better predict survival. We reviewed our experience to determine the prognostic impact of the number of involved nodes and the extent of lymphadenectomy on the current staging system. Records of all patients who underwent resection of previously untreated adenocarcinoma and squamous cell carcinoma of the esophagus and gastroesophageal junction were reviewed. Overall survival according to the AJCC staging system and the number of involved lymph nodes was analyzed by the method of Kaplan and Meier and by recursive partitioning methods. Data were available on 336 patients operated on between January 1996 and September 2003. Recursive partitioning analysis using AJCC staging variables reproduced the AJCC staging system. When the number of involved lymph nodes is added, patients with more than 4 involved lymph nodes have survival similar to that of patients with M1 disease, and patients with no involved lymph nodes have the best prognosis. Recursive partitioning analysis identified 18 lymph nodes as the minimal number required for accurate staging. In patients who have 18 or more lymph nodes removed, survival is only predicted by the presence of nodal involvement and M1 disease. Our analysis suggests that revisions of the current AJCC staging system for esophageal cancer should include N staging based on the number of involved lymph nodes and minimal requirements for the extent of lymphadenectomy.

Relationship between chromosome 8 alterations and Gleason score in prostatic adenocarcinoma

To study the gain of chromosome 8 and c-myc gene and lipoprotein lipase gene status in prostatic adenocarcinoma of Chinese patients, and to analyze the relationship between chromosome 8 alterations and Gleason score of prostatic cancer. Formalin-fixed, paraffin-embedded prostatic biopsy tissues from 34 Chinese patients with untreated prostatic adenocarcinoma were studied by three-color fluorescence in situ hybridization (FISH) using ProVysion(TM) probe kit. The materials included 1 case with Gleason score 5, 10 cases with Gleason score 6, 14 cases with Gleason score 7, 4 cases with Gleason score 8 and 5 cases with Gleason score 9. The relationship between Gleason score and chromosome 8 aneusomy, c-myc and lipoprotein lipase gene copy number, including gene amplification or deletion, were analyzed. Seventeen (50%) of the 34 cases studied had gain of chromosome 8, while 21 cases (61.8%) had gain of c-myc gene copy number, 15 cases (44.1%) had lipoprotein lipase gene monosomy, 23 cases (67.6%) had c-myc gene amplification, 21 cases (61.8%) had deletion of lipoprotein lipase gene and 16 cases (47.1%) had lipoprotein lipase gene deletion coupled with c-myc gene amplification. In general, at least one type of chromosome 8 alteration was identified in 85.3% of cases (29/34). Gain of chromosome 8 was strong significant associated with Gleason score (P = 0.0006). A positive correlation between increased c-myc copy number and high Gleason score was also noted (P = 0.0035). On the other hand, loss of lipoprotein lipase gene was negatively correlated with high Gleason score (P = 0.0383). In addition, the association of c-myc gene amplification with high Gleason score was noted after age adjustment (P = 0.0462). Alterations in chromosome 8 are common in prostatic adenocarcinoma occurring in Chinese patients. There is a correlation between Gleason score and gain of chromosome 8, increased c-myc gene copy number, c-myc gene amplification and lipoprotein lipase gene deletion. C-myc gene amplification accompanied by lipoprotein lipase gene deletion is also a common occurrence in prostatic cancer. Our data suggest that chromosome 8 alterations may play some roles in the development and progression of prostatic adenocarcinoma.

Long-term follow-up and compilation of two trials utilizing concurrent paclitaxel/carboplatin/infusional 5-FU/radiation therapy (RT) in patients with localized esophageal cancer involved in the Minnie Pearl Cancer Research Network

4028 Background: The role of preoperative chemoradiation in patients (pts) with localized esophageal cancer remains unclear. Most preoperative regimens produce 20–30% pathologic complete response (pCR) rates, which predicts improved survival. Our community-based multicenter group performed sequential trials evaluating a novel paclitaxel-containing preoperative chemoradiation regimen, now with median followup &gt; 6 years. Methods: Eligibility: untreated adenocarcinoma or squamous carcinoma of esophagus or GE junction; clinical stage I-III; surgical candidate; ECOG PS 0–2, adequate organ function; informed consent. Pts received paclitaxel 200mg/m2 IV and carboplatin AUC 6.0 IV, days 1, 22; 5FU 225mg/m2, 24 hr continuous infusion, days 1–42; RT 45 Gy in 1.8 Gy/d single daily fractions. Surgical resection was performed 6–10 weeks after completion. Results: 226 pts with the following characterstics were treated: median age 58 years; adenocarcinoma 74%; distal/GE junction 79%; clinical stage II/III 84%. 220 pts (97%) completed preoperative therapy, and 199 pts (88%) had resection. Responses in resected pts: pCR 45% (39% of entire group), PR (microscopic residual) 29%, PR (macroscopic) 15%. After median followup of 75 months, median PFS and overall survival for the entire group were 19 and 26 months, respectively; 3- and 5-year survivals were 40% and 33%, respectively. Median survival was better in pts with pCR vs others (33 vs 21 mo; p=.026). 3-yr survival comparisons of other potential prognostic factors: adeno vs squamous, 43% vs 42%; clinical stage I vs II/III, 63% vs 36% (p=.001); distal location vs others, 38% vs 45% (p=.45). Toxicity data have been previously published; overall 13 pts (6%) had treatment-related death (preop 2, postop 11). Conclusions: This preoperative combined modality regimen was feasible and highly active in a community-based setting. This is one of the largest series of patients treated with an identical preoperative approach and with long-term followup is curative in one-third of pts with localized esophageal cancer. [Table: see text]

Abstracts

Abstracts