Advanced Esophagogastric Adenocarcinoma Research Articles

A propensity-matched analysis comparing survival after primary minimally invasive esophagectomy followed by adjuvant therapy to neoadjuvant therapy for esophagogastric adenocarcinoma

ObjectivesPrognosis for patients with locally advanced esophagogastric adenocarcinoma (EAC) is poor with surgery alone, and adjuvant therapy after open esophagectomy is frequently not tolerated. After minimally invasive esophagectomy (MIE); however, earlier return to normal function may render patients better able to receive adjuvant therapy. We examined whether primary MIE followed by adjuvant chemotherapy influenced survival compared with propensity-matched patients treated with neoadjuvant therapy. MethodsPatients with stage II or higher EAC treated with MIE (N = 375) were identified. Using 30 pretreatment covariates, propensity for assignment to either neoadjuvant followed by MIE (n = 183; 54%) or MIE as primary therapy (n = 156; 46%) was calculated, generating 97 closely matched pairs. Hazard ratios were adjusted for age, sex, body mass index, smoking, comorbidity, and final pathologic stage. ResultsIn propensity-matched pairs, adjusted hazard ratio for death did not differ significantly for primary MIE compared with neoadjuvant (hazard ratio, 0.83; 95% confidence interval, 0.60-1.16). Recurrence patterns were similar between groups and 65% of patients with IIb or greater pathologic stage received adjuvant therapy. Clinical staging was inaccurate in 37 out of 105 patients (35%) who underwent primary MIE (n = 18 upstaged and n = 19 downstaged). ConclusionsPrimary MIE followed by adjuvant chemotherapy guided by pathologic findings did not negatively influence survival and allowed for accurate staging compared with clinical staging. Our data suggest that primary MIE in patients with resectable EAC may be a reasonable approach, improving stage-based prognostication and potentially minimizing overtreatment in patients with early stage disease through accurate stage assignments. A randomized controlled trial testing this hypothesis is needed.

644P - Induction Chemotherapy Followed By Chemoradiotherapy in Locally Advanced Esophagogastric Adenocarcinoma. Has the Location of the Primary Tumor Any Influence on Patients' Outcome? a Retrospective Analysis

ABSTRACT Aim: Multimodal therapy is the standard of care in locally advanced esophagogastric adenocarcinoma. However, most trials include both, gastric (GC) and gastroesophageal junction (GEJ) cancers. We aimed to rule out whether patients (pts) with either locally advanced GEJ (group A) or GC (group B) have different outcomes when treated with a neoadjuvant approach based on induction chemotherapy (ICT), chemoradiotherapy (CRT) and surgery. Methods: EUS-T2-4 and/or N+ M0 GEJ or GC adenocarcinoma patients were scheduled to receive preoperative therapy (3-4 cycles of chemotherapy followed by concurrent CRT). Surgery was scheduled 4 to 6 weeks after the end of CRT. Pathological response was graded according to the Becker criteria. Patterns of recurrence, progression-free survival (PFS) and overall survival (OS) were also evaluated. Results: From november 2004 to July 2013, 87 pts (27 in group A, 60 in group B) met the specified criteria. Pts characteristics were; Group A; M/F; 23/4; EUS-T3 52%, T4 40,7%, N+ 95%, median age 56 (31-81); Diffuse/Intestinal 55%/44%. Group B; M/F; 42/18; EUS-T3 40%, T4 56%, N+ 95%; median age 60.5 (36-76); Diffuse/Intestinal 57%/42%. Seventy-four pts underwent surgery (group A/ B; 92.6%/82%). Pathological response (Group A/B); Grade Ia-Ib according to Becker criteria (72%/51%), pN0 (60.3%/53%). R0 resection (Group A/B); (96%/94%). Among resected pts we analysed the impact of tumor location (GC vs GEJ) on known prognostic factors such as Lauren classification and degree of pathological response regarding PFS and OS. In group A, median OS and PFS did not difer according to Lauren neither classification nor pN status. In contrast, median PFS varied according to Becker response (Ia-b: Not Reached; II-III: 13m; p = 0.02). In group B, we found differences in PFS and OS according to; a)- Lauren Classification; Intestinal GC vs Diffuse GC pts [median PFS; NR vs 13.6m; p = 0.028, median OS: NR vs 15.3m; p = 0.026]. b)pN status (-/+) [median PFS; NR vs 18m; p Conclusions: When treated with ICT followed by CRT, GEJ and GC pts have different outcomes in terms of pathological response degree, patterns of recurrence and survival times. Disclosure: All authors have declared no conflicts of interest.

645P - Induction Chemotherapy, Chemo-Radiotherapy and Surgery in Locally Advanced Gastric Cancer (Gc) Patients: Long Term Results from a Single Institution

ABSTRACT Aim: Multimodal therapy is the standard of care in locally advanced esophagogastric adenocarcinomas. However, most trials include both, GEJ and GC. We aimed to specifically rule out in gastric cancer patients the R0 rate, pathological response degree, patterns of recurrence and long-term outcomes when treated with induction chemotherapy (ICT), followed by chemoradiotherapy (CRT) and salvage surgery. Methods: Patients (pts) with CT scan and endoscocopic ultrasound (EUS) T2-4 and/or N+ M0 GC were retrospectively analyzed. The neoadjuvant strategy consisted of 3-4 cycles of chemotherapy followed by CRT (weekly chemotherapy concurrently with daily external beam radiotherapy up to 45 Gy). Surgery was scheduled 4 to 6 weeks after the end of CRT. Pathological response was graded according to the Becker criteria. We have applied a nonlinear mixed effects (NLME) modeling to evaluate the impact of dynamic changes in tumor size, neutrophil lymphocyte ratio (NLR) and platelet lymphocyte ratio (PLR) on the clinical outcome of these patients. Results: From November 2004 to July 2013, 60 pts [M/F: 42/18, median age 60 (range 36-76), T2/T3/T4a/T4b: 2/24/26/8; N0/N + , 6/54; Diffuse/Intestinal: 35/25] were retrospectively analyzed. Thirty-four and 54 patients were stages by EUS as T4 or N +, respectively. Median preoperative NLR and PLR were both 2.43 and 148. Forty-nine pts underwent radical surgery (total/partial gastrectomy: 33/16) with an R0 resection rate of 92%. Pathological response according to Becker criteria was grade Ia (12%), grade Ib (39%), grade II (22%) and grade III (2%). pN0 was achieved in 26 pts (53,1%). Median harvested nodes were 13. Median DFS for pN0 and pN+ pts was NR and 23 months, respectively (p = 0.01), whereas median OS for pN0 and pN+ was NR and 30 months, respectively (p = 0.009). Among resected pts, distant failures were reported 22 pts, most of them in the peritoneal cavity (55%). After a median follow-up of 30 months (range 4-95 months) the 5-year overall and disease-free survival, were 31% and 39%, respectively. Conclusions: Our data suggest that a three-step strategy is feasible and active in locally advanced gastric cancer patients. The NMLE population modeling to evaluate the impact of dynamic markers on the clinical outcome will be presented at the meeting. Disclosure: All authors have declared no conflicts of interest.

Quality of life (QoL) analysis from the randomized phase III REAL3 trial of epirubicin, oxaliplatin, and capecitabine (EOC) with or without panitumumab (P) in advanced esophagogastric adenocarcinoma.

4067 Background: REAL3 evaluated EOC + P in advanced oesophago-gastric adenocarcinoma. We previously reported that addition of P was associated with increased diarrhoea, skin rash and mucositis wit...

HER-FLOT: Trastuzumab in combination with FLOT as perioperative treatment for patients with HER2-positive locally advanced esophagogastric adenocarcinoma: A phase II trial of the AIO Gastric Cancer Study Group.

4073^ Background: Perioperative chemotherapy is a mainstay in the treatment of locally advanced esophagogastric adenocarcinomas (EGA). Trastuzumab improved survival when added to chemotherapy in pts with HER-2-positive metastatic EGA. We investigated the combination of trastuzumab and FLOT as perioperative treatment in pts with locally advanced EGA. Methods: A multicenter phase II study evaluated the efficacy & toxicity of perioperative HER-FLOT (24-h 5-FU 2,600 mg/m², leucovorin 200mg/m², oxaliplatin 85mg/mg², docetaxel 50 mg/m², trastuzumab 6mg/kg then 4 mg/kg d1, repeated d15 for four cycles pre- and postoperatively followed by 9 cycles of trastuzumab monotherapy 6mg/kg 3-weekly) in pts with HER-2 positive EGA (IHC 3+ or IHC 2+/ ISH+). Pts had to have ≥cT2, any N, M0 EGA. The primary endpoint was the rate of centrally tested pathological complete remissions (pCR). Secondary endpoints comprised disease-free and overall survival, R0 resection rate, toxicity and surgical morbidity. Here we report data of ...

Impact of age on the feasibility and efficacy of neoadjuvant chemotherapy in patients with locally advanced gastroesophageal cancer: A retrospective pooled analysis of individual patient data.

4063 Background: Neoadjuvant chemotherapy (neoCTx) improves the prognosis of patients (pts) with locally advanced esophagogastric adenocarcinoma (EGC), but its value is unknown in elderly patients ...

Is primary surgery without preoperative chemotherapy the best treatment option for signet ring cell esophagogastric adenocarcinomas?

106 Background: Recent retrospective multicentric data favor a primary resection without neoadjuvant chemotherapy for signet ring cell (SRC) gastric cancer. Aim of this retrospective exploratory study is the comparison of primary resected with neoadjuvantly treated locally advanced SRC esophagogastric adenocarcinomas (EGA) in respect of outcome. Methods: From 2002-2012 200/646 resected EGA were classified as SRC by WHO classification (more than 50% signet ring cells) and staged cT3/4 Nany M0/x. Clinical response evaluation was based on endoscopy and CT-scan and histopathological regression was based on the Becker score (<10% residual tumor cells: responder). UICC 7th was used. Analysis was retrospectively from a prospective data base. Results: 103 were treated by preoperative chemotherapy (CTx), 97 were primary resected. 73 (37%) had AEG, 127 (63%) gastric cancer. Postoperative CTx was delivered in 62/103 (60%) of the patients with preoperative CTx and in 51/97 (53%) of the primary resected patients (p=0.28). In-hospital mortality was 4.5% (9/200). 20 (20%) were classified as clinical, 15 (8%) as histopathological responders. Preoperative CTx was significantly associated with worse pretherapeutic cT- (p=0.005) and cN- (p=0.008) categories, but subsequent lower (y)pN-category (p=0,001) and improved lymphnode ratio (p=0.001). Overall survival was significantly improved after preoperative CTx compared to primary resection (median survival 30.2 versus 17.6 months, p=0.001). Median survival of responding patients is not reached, median survival of nonresponder was 24.4 months (identical for clinical and histopathological responders) compared to 17.6 months in primary resected patients (p=0.002). The positive prognostic effect of preoperative CTx was significantly higher in AEG (p=0.004) compared to gastric cancer (p=0.067). In the 119 completely resected patients the survival was significantly improved by preoperative CTx (p=0.005), but it was no independent prognostic factor. Conclusions: A pre/periopative CTx seems also to be justified in SRC EGA. Relevant limitations are the retrospective and non-randomized design.

Is Preoperative Chemotherapy Followed by Surgery the Appropriate Treatment for Signet Ring Cell Containing Adenocarcinomas of the Esophagogastric Junction and Stomach?

Recent data suggest primary resection as the preferable approach in patients with signet ring cell gastric cancer (SRC). The aim of our retrospective exploratory study was to evaluate the influence of SRC on prognosis and response in esophagogastric adenocarcinoma treated with neoadjuvant chemotherapy. A total of 723 locally advanced esophagogastric adenocarcinomas (cT3/4 N any) documented in a prospective database from two academic centers were classified according to the WHO definition for SRC (more than 50 % SRC) and analyzed for their association with response and prognosis after neoadjuvant treatment. A total of 235 tumors (32.5 %) contained SRC. Median survival of SRC was 26.3 compared with 46.6 months (p < 0.001) for non-SRC. SRC were significantly associated with female gender, gastric localization, advanced ypT and R1/2 categories, and lower risk of surgical complications and anastomotic leakage (each p < 0.001). Clinical (21.1 vs. 33.7 %, p = 0.001) and histopathological response (less than 10 % residual tumor: 16.3 vs. 28.9 %, p < 0.001) were significantly less frequent in SRC. Clinical response (p = 0.003) and complete histopathological response (pCR) (3.4 %) (p = 0.003) were associated with improved prognosis in SRC. Clinical response, surgical complications, ypTN categories, but not SRC were independent prognostic factors in forward Cox regression analysis in R0 resected patients. Risk of peritoneal carcinomatosis was increased (p < 0.001), while local (p = 0.015) and distant metastases (p = 0.02) were less frequent than in non-SRC. Prognosis of SRC is unfavorable. Although response to neoadjuvant chemotherapy is rare in SRC, it is associated with improved outcome. Thus, chemotherapy might not generally be abandoned in SRC. A stratification based on SRC should be included in clinical trials.

Treatment options in patients with metastatic gastric cancer: current status and future perspectives.

Despite advances in the treatment of gastric cancer, it remains the world's second highest cause of cancer death. As gastric cancer is often diagnosed at an advanced stage, systemic chemotherapy is the mainstay of treatment for these patients. However, no standard palliative chemotherapy regimen has been accepted for patients with metastatic gastric cancer. Palliative chemotherapy including fluoropyrimidine, platin compounds, docetaxel and epirubicin prolongs survival, and improves a high quality of life to a greater extent than best supportive care. The number of clinical investigations associated with targeted agents has recently increased. Agents targeting the epidermal growth factor receptor 1 and human epidermal growth factor receptor 2 (HER2) have been widely tested. Trastuzumab was the first target drug developed, and pivotal phase III trials showed improved survival when trastuzumab was integrated into cisplatin/fluoropyrimidine-based chemotherapy in patients with metastatic gastric cancer. Trastuzumab in combination with chemotherapy was thus approved to be a new standard of care for patients with HER2-positive advanced esophagogastric adenocarcinoma. Thus, the evaluation of HER2 status in all patients with metastatic gastroesophageal adenocarcinoma should be considered. Other agents targeting vascular endothelial growth factor, mammalian target of rapamycin, and other biological pathways have also been investigated in clinical trials, but showed little impact on the survival of patients. In this review, systemic chemotherapy and targeted therapies for metastatic gastric cancer in the first- and second-line setting are summarized in the light of recent advances.

IS4–4 - How to Use Oral Fluoropyrimidine in Triplet or Doublet Therapy as the European Standard

Background: Chemotherapy significantly prolongs survival in patients with advanced esophago-gastric adenocarcinoma (aEGA). Combination regimens of a platinum and fluoropyrimidine are more effective than single-agent therapy (Wagner et al., 2010), but triple regimens with epirubicin (Wagner et al., 2010) or docetaxel (van Cutsem et al, 2006) increase efficacy. Oral therapy (capecitabine or S1) is effective and convenient (Cunningham et al, 2008) and especially EOX (epirubicin, oxaliplatin, capecitabine) and DOX (docetaxel, oxaliplatin, capecitabine) is routinely used in many Western European departments.

Cougar-02: A randomized phase III study of docetaxel versus active symptom control in patients with relapsed esophago-gastric adenocarcinoma.

4023 Background: Survival in patients who relapse after first-line chemotherapy (CT) for advanced esophago-gastric adenocarcinoma (EGC) is poor though recently randomised trials (RCT) have suggested a small benefit for second line chemotherapy with taxanes or irinotecan. There is very little data on health related quality of life (HRQL) or overall survival (OS), particularly in patients who progress shortly after first-line therapy. Methods: COUGAR-02 was a multicentre open-label, phase III RCT for patients with locally advanced or metastatic EGC of performance status (PS) 0-2 who had progressed within 6 months of previous platinum/fluoropyrimidine CT. Patients were randomised (1:1) to receive either docetaxel 75mg/m2every 3 weeks for up to 6 cycles or active symptom control (ASC). The primary endpoint was OS. The secondary endpoint of HRQL, assessed using EORTC QLQ-C30 and QLQ-ST022, was analysed using standardised area under a curve and compared using Wilcoxon rank sum test. Sensitivity analysis adjusting for dropouts due to death were performed using quality adjusted survival. Results: 168 patients (84 patients in each arm) were recruited between April 2008 and April 2012. Median age was 65 years (range 28-84); 81% were males. PS at randomisation was 0 for 27%, 1 for 57% and 2 for 15%. 86% had metastatic disease. 43% progressed during previous CT, 28% progressed within 3 months of end of previous CT and 29% progressed between 3 and 6 months. Median number of cycles of docetaxel was 3. 23% completed 6 cycles. Docetaxel was well tolerated and resulted in a significantly improved OS over ASC alone (HR=0.67 (95% CI 0.49-0.92); p=0.01). Objective response rate was 7%. For QLQ-C30, patients on docetaxel arm reported significantly less pain (p=0.0008) and trend for less nausea and vomiting (p=0.02) and constipation (p=0.02) than those on ASC arm. Similar global HRQL seen (p=0.53).For QLQ-ST022, trend seen for less dysphagia (p=0.02) and pain symptoms (p=0.01) for patients on docetaxel arm than ASC Conclusions: Docetaxel provided a significant OS benefit over ASC with improvements in symptom scores and no loss in overall HRQL. Docetaxel can be considered a standard of care in this setting. Clinical trial information: NCT00978549.

Patterns of recurrence after neoadjuvant docetaxel, cisplatin, and 5FU combined with resection and extended lymphadenectomy for locally advanced esophagogastric adenocarcinoma.

e15044 Background: We have previously identified Docetaxel, Cisplatin, and 5FU (DCF) as a highly effective regimen in the neoadjuvant setting for locally advanced adenocarcinoma (ADC) of the esophagus and esophago-gastric junction (EGJ). However there is ongoing debate whether chemotherapy alone provides adequate local or regional control. We hypothesized that DCF combined with enhanced local surgical control would result in a low rate of local or regional recurrence. Methods: A prospective entered database of all esophageal/EGJ ADC pts resected at a high volume referral center was reviewed for cases treated with neoadjuvant DCF (Docetaxel 75mg/m2, Cisplatin 75mg/m2, 5FU 750mg/m2x120 hrs CIV) Q3weeks x3, followed by en-bloc resection with extended lymphadenectomy (D2). Follow up included physical exam Q3m x 2 yrs then Q6m, and endoscopy and CT chest/abdo/pelvis performed Q6 m. Recurrence was defined as: Local = biopsy on endoscopy; Regional = regional lymph nodes; Distant = distant organ or non-regional lymph nodes. Data presented as Median (Range). Results: Of 281 pts in the database, 89 (75%male, 63yrs(24-80)) underwent pre-op DCF and resection for locally advanced ADC (cT3 93%;cN+ 73%) of the EGJ (51%) or distal esophagus (49%) from 3/07-10/12. After overall follow-up of 37(6-72) months, 37 (42%) have recurred at 15(6-33) months. Sites of recurrence include Distant only in 29/37, Regional only in 5/37, and Regional and Distant in 3/37. First site of distant recurrence was peritoneum (14/37), liver (10/37), non-regional lymph nodes (10), brain/ovary/pleura (2 each), and bone(1). No patient had local recurrence alone. 3/5 patients with regional recurrence underwent salvage chemoradiotherapy and are alive without disease at 36 months (30-47) after recurrence. Conclusions: En-bloc resection with extended lymphadenectomy after DCF for locally advanced ADC of the esophagus and EGJ is associated with a low rate of local and regional recurrence. As vast majority of recurrences are distant, our data supports the notion that efforts to improve outcomes in these pts should concentrate on enhancing systemic, rather than local, therapy.

The management of dysphagia in esophageal adenocarcinoma patients undergoing neoadjuvant chemotherapy: Can invasive tube feeding be avoided?

e15034 Background: Neoadjuvant chemotherapy is an accepted standard for locally advanced esophago-gastric adenocarcinoma. However the dysphagia frequently associated with this condition may interfere with patient tolerance of neoadjuvant chemotherapy. Surgical or endoscopic invasive tube feeding (ITF), including stents, is a commonly employed strategy to maintain nutritional support however it can cause significant morbidity in its own right. We sought to determine if an approach of careful dietary counseling and fast-tracked neoadjuvant chemotherapy can obviate the need for ITF. Methods: Pts undergoing neoadjuvant chemotherapy (DCF or ECF Q3 weeks x3 or FLOT Q2weeks x4) for locally advanced (cT3 and/or N+) esophageal or EGJ adenocarcinoma at a single institution from 3/07-9/12 were identified from a prospective database. All received dietary counseling and were closely monitored for signs/ symptoms of malnutrition with serial (baseline/pre-surgery) Body Mass Index (BMI), albumin, dysphagia scores (DS: 0 best - 4 worse), and quality of life (FACT-E). We assessed the response of dysphagia and nutritional status to neoadjuvant treatment and the need for ITF. Data presented as median (Interquartile Range) or median (±SD), paired t-test or Wilcoxon signed ranks test determined significance (*p=0.05). Results: Of 130 patients undergoing neoadjuvant chemotherapy 78 had dysphagia scores of 2 or greater, most of whom received DCF (91%). Overall the dysphagia improved in 75/78 (96%) from a DS of 3 (2-4) to 0 (0-1)*. This was associated with an increase in FACT-E QoL scores (117±23 to 140±20)*. Weight (Kg)(70±22:69±24), BMI (24.5±8 to 23.9±7), and Albumin (40±5 to 37±4) were maintained. Only one patient required a stent, and none a jejunostomy, or gastrostomy. Conclusions: Appropriately timed neoadjuvant chemotherapy with a highly effective regimen rapidly restores normal swallowing, maintains nutritional status, and obviates the need for stenting or invasive tube feeding in patients with significant dysphagia from esophageal adenocarcinoma.

COUGAR-02: A randomized phase III study of docetaxel versus active symptom control in advanced esophagogastric adenocarcinoma.

LBA4 Background: Survival in patients who relapse after first-line chemotherapy for advanced esophagogastric adenocarcinoma (OGC) is poor though recently randomized trials have suggested a small survival benefit for second-line chemotherapy with taxanes or irinotecan. There is very little data on quality of life or survival, particularly in patients who progress shortly after first-line therapy. Methods: COUGAR-02 was a multicenter open-label, randomized controlled phase III trial for patients with locally advanced or metastatic OGC of performance status (PS) 0-2 who had progressed within 6 months of previous platinum/fluoropyrimidine (PF) chemotherapy (CT). Patients were randomized (1:1) to receive either docetaxel 75mg/m2every 3 weeks for up to 6 cycles or active symptom control (ASC), which could include any treatment thought by the treating clinician to be appropriate for the management of symptoms including radiotherapy, steroids and supportive medications. The primary endpoint was overall survival. Secondary endpoints were response rate, toxicity, health related quality of life (HRQL) and healthcare resource use. Results: Between April 2008 and April 2012, 168 patients were recruited (84 patients in each arm). Median age was 65 years (range 28-84), 81% were male. PS at randomisation was 0 for 27%, 1 for 57% and 2 for 15%. Site of disease was stomach in 46%, esophagogastric junction in 34% and esophagus in 20%. 86% had metastatic disease. 43% progressed during previous CT, 28% progressed within 3 months of end of previous CT and 29% progressed between 3 and 6 months. 19 (23%) patients completed 6 CT cycles (median 3 cycles per patient). The main reasons for not completing treatment were progression and toxicity. Docetaxel significantly improved overall survival over ASC alone (median 5.2 months (95% CI 4.1-5.9 months) for docetaxel; 3.6 months (95% CI 3.3-4.4 months) for ASC, HR=0.67 (95% CI 0.49-0.92); p=0.01). 7% had a partial response and 46% had stable disease after CT. 21% on docetaxel had grade 4 toxicity. Conclusions: The addition of docetaxel to ASC significantly improved overall survival. Docetaxel can be considered a standard of care in this setting. Clinical trial information: 13366390.

Feasibility of perioperative chemotherapy with infusional 5-FU, leucovorin, and oxaliplatin with (FLOT) or without (FLO) docetaxel in elderly patients with locally advanced esophagogastric cancer

Background:The aim of this exploratory subgroup analysis of the fluorouracil, oxaliplatin, docetaxel (FLOT)65+ trial was to determine tolerability and feasibility of perioperative chemotherapy in elderly, potentially operable esophagogastric cancer patients.Methods:Patients aged ⩾65 with locally advanced esophagogastric adenocarcinoma were randomized to perioperative chemotherapy consisting of four pre- and four postoperative cycles of infusional 5-FU, leucovorin, and oxaliplatin (FLO) without or with docetaxel 50 mg m−2 (FLOT), every 2 weeks.Results:Forty-four patients with a median age of 70 years were randomized and 43 patients started preoperative chemotherapy (FLO, 22; FLOT, 21). Thirty-eight (86.4%) patients completed four cycles of preoperative chemotherapy and 32 (74.4%) proceeded to surgery, with 67.4% R0 resections on intent-to-treat analysis (90.1% of the 32 patients who underwent resection). Median overall survival was not reached and median progression-free survival (PFS) was 17.3 months. Compared with the FLO group, the FLOT group showed a trend towards an improved median PFS (21.1 vs 12.0 months; P=0.09), however, associated with increased chemotherapy related toxicity. No perioperative mortality was observed. Postoperative morbidity was observed in 46.9% of patients (FLO, 35.3% FLOT, 60%).Conclusion:Neoadjuvant FLO or FLOT may offer a reasonable chance of curative surgery in elderly patients with locally advanced resectable gastroesophageal cancer. However, the increase in side effects with the FLOT regimen and postoperative morbidity should be carefully considered when an intensive chemotherapy regimen is planned.

Factors predicting prognosis and recurrence in patients with esophago-gastric adenocarcinoma and histopathological response with less than 10 % residual tumor

Neoadjuvant treatment is an accepted standard approach for treating locally advanced esophago-gastric adenocarcinomas. Despite a response of the primary tumor, a significant percentage dies from tumor recurrence. The aim of this retrospective exploratory study from two academic centers was to identify predictors of survival and recurrence in histopathologically responding patients. Two hundred thirty one patients with adenocarcinomas (esophagus: n = 185, stomach: n = 46, cT3/4, cN0/+, cM0) treated with preoperative chemotherapy (n = 212) or chemoradiotherapy (n = 19) followed by resection achieved a histopathological response (regression 1a: no residual tumor (n = 58), and regression 1b < 10% residual tumor (n = 173)). The estimated median overall survival was 92.4months (5-year survival, 56.6%) for all patients. For patients with regression 1a, median survival is not reached (5-year survival, 71.6%) compared to patients with regression 1b with 75.3months median (5-year survival, 52.2%) (p = 0.031). Patients with a regression 1a had lymph node metastases in 19.0 versus 33.7% in regression 1b. The ypT-category (p < 0.001), the M-category (p = 0.005), and the type of treatment (p = 0.04) were found to be independent prognostic factors in R0-resected patients. The recurrence rate was 31.7% (n = 66) (local, 39.4%; peritoneal carcinomatosis, 25.7%; distant metastases, 50%). Recurrence was predicted by female gender (p = 0.013), ypT-category (p = 0.007), and M-category (p = 0.003) in multivariate analysis. Response of the primary tumor does not guarantee recurrence-free long-term survival, but histopathological complete responders have better prognosis compared to partial responders. Established prognostic factors strongly influence the outcome, which could, in the future, be used for stratification of adjuvant treatment approaches. Increasing the rate of histopathological complete responders is a valid endpoint for future clinical trials investigating new drugs.

Metastatic esophagogastric adenocarcinoma: trends in first-line treatment and predictive factors for the implementation of HER2 testing in clinical practice during the first year after trastuzumab market approval

Little is known about the use of first-line chemotherapy in clinical practice in patients with advanced esophagogastric adenocarcinoma, and no data have been published regarding potential obstacles for the implementation of molecular testing for targeted agents in this patient group. Here, we sought to evaluate factors influencing treatment decisions with special focus on the implementation of HER2 testing during the first year after trastuzumab market approval in Germany. A total of 754 patients undergoing treatment decisions for palliative first-line therapy in 2010 were documented using Therapiemonitor(®). Drug use and intensity of first-line treatment were analyzed. Data on HER2 testing and test algorithm are described, and variables influencing HER2 testing were selected using bivariate analysis. Significant factors were included in a multivariate logistic regression analysis. Compared with previous years, treatment intensity has further increased. The use of chemotherapy triplets rose from 10.1 % in 2006 to 60.3 % in 2010. In 2010, 49.1 % of patients were tested for HER2 and in 52.2 % of these patients the currently proposed test algorithm was used. Using multivariate logistic regression analysis age ≥67 years and "initiating institution: practice" were found to negatively impact the likelihood of HER2 testing, while treatment goal "prevention of progression", multiple metastases and a Karnofsky status >80 % showed positive correlation with HER2 testing. The tendency to use more intensive first-line chemotherapy regimens in patients with advanced esophagogastric adenocarcinoma continued in 2010. Only a minority of patients had an access to the appropriate molecular diagnostics and therefore to treatment with trastuzumab. The access was limited due to the preselection following individual, clinical and institutional factors.

PD-0027 Feasibility of Perioperative Chemotherapy with Infusional 5-FU, Leucovorin and Oxaliplatin +/- Docetaxel, in Elderly Patients with Locally Advanced Esophagogastric Cancer

ABSTRACT Introduction The aim of this study was to determine feasibility and efficacy of perioperative chemotherapy in elderly, potentially operable esophagogastric cancer patients. Methods Patients aged 65 or older with locally advanced esophagogastric adenocarcinoma were randomized to perioperative chemotherapy consisting of four preoperative and four postoperative cycles of infusional 5-FU, leucovorin, and oxaliplatin (FLO) with or without docetaxel 50mg/m2 (FLOT), every 2 weeks. Results 44 patients with a median age of 70 years were randomized to either FLO (22) or FLOT (22) chemotherapy. In the FLO and FLOT group, 20 and 18 patients completed four cycles of preoperative chemotherapy and 17 (77.3%) and 15 (68.2%) patients proceeded to surgery, with 88.2% and 93.3% R0 resections, respectively. FLOT was associated with significantly more treatment-related NCI-CTC grade 3/4 adverse events, including neutropenia (P Conclusion Age alone is not a contra-indication for the selection of patients for three-drug regimens in the multimodal treatment approach. FLOT seems to be more effective than FLO, but is associated with an increased toxicity and higher postoperative morbidity. Therefore, careful patient selection is warranted.

Feasibility of perioperative chemotherapy with infusional 5-FU, leucovorin, and oxaliplatin with or without docetaxel, in elderly patients with locally advanced esophagogastric cancer.

4080 Background: The aim of this study was to determine feasibility and efficacy of perioperative chemotherapy in elderly, potentially operable esophagogastric cancer patients. Methods: Patients aged 65 or older with locally advanced esophagogastric adenocarcinoma were randomized to perioperative chemotherapy consisting of four preoperative and four postoperative cycles of infusional 5-FU, leucovorin, and oxaliplatin (FLO) with or without docetaxel 50mg/m² (FLOT), every 2 weeks. Results: 44 patients with a median age of 70 years were randomized to either FLO (22) or FLOT (22) chemotherapy. In the FLO and FLOT group, 20 and 18 patients completed four cycles of preoperative chemotherapy and 17(77.3%) and 15(68.2%) patients proceeded to surgery, with 88.2% and 93.3% R0 resections, respectively. FLOT was associated with significantly more treatment-related NCI-CTC grade 3/4 adverse events, including neutropenia (p&lt;.0001), leukopenia (p&lt;.0001), stomatitis (p=0.02) and nausea (p=0.02) and a higher rate of patients experiencing a ≥10-points deterioration of EORTC QoL global health status scores (FLOT, 54%; FLO 23.1%) at 8 weeks. No perioperative mortality was observed, however postoperative morbidity was nearly doubled with the FLOT regimen (60% versus 35.3% for FLO), mostly due to wound infections in the FLOT group (20%). 11 (64.7%) and 9 (60.0%) of patients in the FLO/FLOT group were able to undergo postoperative chemotherapy. Compared with the FLO group, the FLOT group had a better response rate (61.9% vs. 18.2%) and a trend towards an improved median disease free survival (21.1 vs. 12.0 months; p=0.09). Conclusions: Age alone is not a contra-indication for the selection of patients for three-drug regimens in the multimodal treatment approach. FLOT seems to be more effective than FLO, but is associated with an increased toxicity and higher postoperative morbidity. Therefore, careful patient selection is warranted.

Can response of dysphagia to neoadjuvant docetaxel, cisplatin, and 5-flourouracil (DCF) for locally advanced esophagogastric adenocarcinoma predict disease recurrence?

e16631 Background: Improvement of dysphagia in pts with esophagogastric adenocarcinoma (EGC) is a crude sign of local tumor response to chemotherapy, however its impact on survival is unknown. We sought to determine if response of dysphagia to neoadjuvant chemotherapy predicted disease free survival in patients with locally advanced EGC undergoing curative intent treatment. Methods: Patients undergoing neoadjuvant DCF (docetaxel 75 mg/m2 IV day 1, cisplatin 75 mg/m2 IV day 1, 5-FU 750 mg/m2 CIV for 120 hrs, Q3wks) for EGC (at least T3 or N1), were identified from a prospective database. All were monitored with serial dysphagia scores (DS: 0 best – 4 worst) and disease status after resection was documented with CT and endoscopy (Q3mos). Pts in whom DS did not improve by at least 2 points (Non-RESP) after 3 cycles of DCF were compared to those who did improve (RESP) in terms of their mean disease free survival using student’s t test. Data is presented as median(range). Cox proportional hazard regression was used to estimate crude and adjusted hazard ratios (HR) for recurrence. 95% CI are reported. Results: From 5/07 to 10/10, 34 pts with severe dysphagia (DS of 2-4) due to locally advanced EGC completed 3 cycles DCF and underwent complete curative intent resection (R0). None required a stent or feeding tube. We followed 29/34 pts for at least one year (21 [12-43] mos) and these are included in the analysis. DS improved in 26/29 (89.7%), and in 11 of these disease recurred (13.5 [5-36] mos). The 3 Non-RESP pts all recurred (7 [5-8] mos). The mean disease free survival was lower in Non-RESP (P=0.03). The crude HR for the recurrence based on response of dysphagia was 0.1 (0.02, 0.46) 95% CI. After adjustments were made for tumor location and histologic grade, age and pathologic TNM stage, the HR was again estimated to be 0.1 (0.01, 0.73) 95% CI. Conclusions: Neoadjuvant chemotherapy with a highly effective regimen rapidly improves dysphagia in EGC in the majority of pts and likely obviating the need for invasive tube feeding. Non-response of dysphagia to DCF is a major predictor for poor outcome, questioning the value of curative intent surgery in these pts.