IJC International Journal of Cancer

Transcription

1 IJC International Journal of Cancer Pathological complete remission in patients with oesophagogastric cancer receiving preoperative 5-fluorouracil, oxaliplatin and docetaxel Nils Homann 1,2, Claudia Pauligk 3, Kim Luley 2, Thomas Werner Kraus 4, Hans-Peter Bruch 5, Akin Atmaca 3, Frank Noack 6, Hans-Michael Altmannsberger 7, Elke Jäger 3 and Salah-Eddin Al-Batran 3 1 Department of Medicine II, Klinikum Wolfsburg, Wolfsburg, Germany 2 Department of Medicine I, University Hospital of Schleswig-Holstein, Campus Lübeck, Lübeck, Germany 3 Department of Oncology and Hematology, Krankenhaus Nordwest, Frankfurt am Main, Germany 4 Department of General and Visceral Surgery, Krankenhaus Nordwest, Frankfurt am Main, Germany 5 Department of Surgery, University Hospital of Schleswig-Holstein, Campus Lübeck, Lübeck, Germany 6 Institute of Pathology, University Hospital of Schleswig-Holstein, Campus Lübeck, Lübeck, Germany 7 Institute for Pathology at Krankenhaus Nordwest, Frankfurt am Main, Germany The aim of this study was to determine the pathological complete remission (pcr) rate, and its relationship to clinical outcome, in patients with adenocarcinoma of the stomach or oesophagogastric junction receiving preoperative 5-fluorouracil, leucovorin, oxaliplatin and docetaxel (FLOT) every 2 weeks. Data from these patients who received at least one cycle of preoperative FLOT followed by surgery were prospectively collected in three German centres. Outcome analyses were conducted and tumour samples were evaluated for pathological remission by a central pathologist. A total of 46 patients were included in this analysis. All patients had clinical T3- and/or N1-stages and 11 (23.9%) had distant metastases (M1). After a median of 4 (range 2 8) preoperative cycles, 8 of 46 patients (17.4%) achieved a pcr. The pcr rate was highest in tumours of intestinal type histology (30.8%) and in those located in the oesophagogastric junction (30.4%) and lowest in patients with diffuse/mixed type tumours (0%) or tumours located in the stomach (4.3%; p < 0.05 for both comparisons). Patients with pcr had 100% probability of overall and disease-free survival (DFS) during the observation period, which was significantly higher (p and p , respectively) than the survival probability in patients without pcr. In conclusion, treatment intensification using FLOT was associated with significant pcr rates in patients with oesophagogastric cancer. The distribution of pcr appeared to be significantly different according to histological type and location of the tumours. Key words: pathological remission, FLOT, oesophagogastric cancer, neoadjuvant Abbreviations: 5-FU: 5-fluorouracil; CT: computed tomography; DCF: docetaxel, cisplatin, 5-FU; DFS: disease-free survival; ECF: epirubicin, cisplatin, 5-FU; ECOG: Eastern Cooperative Oncology Group; ECX: epirubicin, cisplatin, capecitabine; EPA: etoposide, doxorubicin, cisplatin; FLO: 5-FU, leucovorin, oxaliplatin; FLP: 5-FU, leucovorin, cisplatin; FLOT: 5-FU, leucovorin, oxaliplatin, docetaxel; FP: 5-FU, cisplatin; IV: intravenous; OS: overall survival; pcr: pathological complete remission; PELF: cisplatin, 5-FU, epidoxorubicin, 6S-leucovorin, glutathione Conflict of interest: Dr. Salah-Eddin Al-Batran has received research funding from Sanofi-Aventis. None of the other authors have any potential conflicts of interest to disclose. DOI: /ijc History: Received 8 Feb 2011; Accepted 22 Mar 2011; Online 26 May 2011 Correspondence to: Salah-Eddin Al-Batran, MD, Department of Oncology and Hematology, Krankenhaus Nordwest, Steinbacher Hohl 2-26, Frankfurt am Main 60488, Germany, Tel.: , Fax: þ , albatran@aol.com Despite a worldwide decline in incidence, gastric cancer remains a major health problem and is the fourth most prevalent cancer worldwide. 1 Tumours of the oesophagogastric junction are among the most rapidly increasing tumours in many Western countries. 1 Surgery is the only potentially curative treatment modality, particularly for early-stage localised disease: a 5-year survival rate of 90% can be achieved with surgery alone when disease is limited to the mucosa and submucosa. 2 Unfortunately, the majority of patients present with more advanced disease at diagnosis and their prognosis is considerably less favourable. In Western patients, the 5- year survival rate can be as low as 20 30% when the tumour has penetrated the submucosa. 3 The role of adjuvant chemotherapy after curative resection of gastric cancer is established in Japan 4 and has been confirmed recently in a meta-analysis of randomised clinical trials. 5 Neoadjuvant chemotherapy offers a theoretical advantage over adjuvant chemotherapy: chemotherapy delivery may be more efficient if given before surgical disruption of the vasculature, tumour down-staging may allow successful surgical resection, 6 and it allows evaluation of the tumour chemosensitivity to cytotoxic medications. 7 Furthermore, patients may tolerate

2 Homann et al preoperative cytotoxic treatment better than postoperative treatment, as performance status is usually negatively impacted by surgery. 8 However, any lack of response to neoadjuvant chemotherapy may delay curative surgery and chemotherapyinduced toxicity may increase surgical complications. 9 The potential efficacy of neoadjuvant chemotherapy has been investigated in various prospective trials in patients with gastric cancer and oesophagogastric cancer Results have generally been positive, although definitive conclusions were difficult to draw from most of these studies, notably due to limited sample size. However, two of the largest studies in patients with oesophagogastric cancer showed statistically significant improvement in disease-free survival (DFS) and overall survival (OS) with pre- and postoperative epirubicin, cisplatin, 5-fluorouracil (5-FU; ECF) 15 and 5-FU, cisplatin (FP) 16 compared with surgery alone. This implies that regimens with high response rates in the metastatic setting might be the best options for neoadjuvant therapy, increasing the probability of tumour down-staging, remission and R0 resection, thereby extending survival. However, there is limited evidence that the rate of remission predicts outcome. We have previously demonstrated a high degree of efficacy and relative safety of the combination of 5-FU, leucovorin (LV), oxaliplatin and docetaxel (FLOT) in the treatment of patients with metastatic oesophagogastric adenocarcinoma. 19,20 As a result, we have started to use pre- and postoperative FLOT for the treatment of patients with resectable advanced oesophagogastric adenocarcinoma in clinical practice. The aim of this observational study was to determine the pathological remission rate obtained in this series of patients and to evaluate the potential relationship between pathological remission and clinical outcome. Patients and Methods Patients Patients were eligible for the analysis if they had a histologically confirmed, newly diagnosed adenocarcinoma of the stomach or oesophagogastric junction that had not been previously treated with chemotherapy, and if they underwent surgery with curative intent after receiving at least one cycle of preoperative FLOT. All patients treated at three German hospital centres (Krankenhaus Nordwest, Frankfurt am Main, Universitätsklinikum, Lübeck and Klinikum Wolfsburg) between April 2006 and April 2009 and who fulfilled these criteria were documented. The final update of the database was performed in August Standards of the International Conference on Harmonization/WHO Good Clinical Practice were followed and the analysis was performed with permission from the responsible ethical committees. The medical records of all patients were reviewed. Demographic and baseline data at the initiation of FLOT treatment that were taken into consideration were age, gender, Eastern Cooperative Oncology Group (ECOG) performance status, primary tumour location, primary histopathology, organs involved in metastatic disease, and clinical T- and N-stages of the primary tumour. Adverse effects of chemotherapy were not documented for this report as they are well known from previous trials with FLOT. 19,20 Postoperative morbidity and mortality were documented, as well as disease progression and survival. Treatment The treatment in all three centres was uniformly standardised. Normally, three to four preoperative and four additional postoperative cycles of FLOT were planned. Each 2-weekly cycle of FLOT comprised oxaliplatin 85 mg/m 2,LV 200 mg/m 2 and docetaxel 50 mg/m 2, each administered by intravenous (IV) infusion over 1 2 hr on day 1, followed by 5-FU 2,600 mg/m 2 as a 24-hr continuous IV infusion. Oral dexamethasone 8 mg was administered prophylactically on days 0 3 to prevent fluid retention and allergic reaction. Antiemetic prophylaxis with 5-HT 3 receptor antagonists was given on day 1. Growth factors were not administered prophylactically. Patients underwent surgical resection 3 5 weeks after the end of preoperative chemotherapy. Surgery was conducted according to hospital-specific guidelines. Postoperative chemotherapy was started 6 8 weeks after surgical resection if patient status permitted further chemotherapy. Clinical tumour assessment Participating centres used similar staging schedules. At baseline, patients underwent endoscopic ultrasound and computed tomography (CT) scans of the chest, abdomen and pelvis to assess the clinical T- and N-stages. Diagnostic laparoscopy was performed if endoscopic ultrasound revealed T4- stage disease or if peritoneal involvement was suspected on the basis of CT scans. CT scans and endoscopy were repeated immediately before surgery to exclude disease progression. Pathological remission criteria Pathological remission was evaluated centrally by an experienced pathologist at the University of Lübeck. Examination of the resection specimens included measurement of the macroscopic identifiable residual tumour or scarring indicating the site of the previous tumour bed. Routine haematoxylin and eosin, elastic Van Gieson, and periodic acid staining were performed to distinguish tumour desmoplasia and scarring, and accordingly to identify signet-ring cells. If necessary, supplementary immunohistochemical investigations were used to identify epithelial cells (CK7 and KL-1). Grading of tumour regression was performed using the Becker remission criteria, 21 which are based on the estimation of the percentage of vital tumour cells in relation to the macroscopically identifiable tumour bed. The tumour bed was identified by signs of tumour regression such as marked fibrosis, necrosis, flattening of the mucosa or the presence of macrophages. The expanse of vital tumour cells was determined and semiquantitatively related to the tumour bed as a percentage value. According to Becker et al., 21 response to neoadjuvant chemotherapy was scored as Grade 1a (complete remission), no residual tumour/tumour bed; Grade 1b (subtotal remission),

3 1708 Pathological complete remissions following preoperative FLOT Table 1. Patient demographic and clinical characteristics Total group (n 5 46) Patients without pcr (n 5 38) Patients with pcr (n 5 8) Median age, years (range) 59.5 (30 77) 60.0 (30 77) 60.0 (57 70) Gender, n (%) Male 30 (65.2) 24 (63.2) 6 (75.0) Female 16 (34.8) 14 (36.8) 2 (25.0) Primary tumour site, n (%) Oesophagogastric junction 1 23 (50) 16 (42.1) 7 (87.5) Gastric 1 23 (50) 22 (57.9) 1 (12.5) ECOG performance status 0 14 (30.4) 13 (34.2) 1 (12.5) 1 29 (63.0) 23 (60.5) 6 (75) 2 3 (6.5) 2 (5.3) 1 (12.5) T-stage, n (%) T T2 9 (19.6) 9 (23.7) 0 T3 33 (71.7) 26 (68.4) 7 (87.5) T4 2 (4.3) 2 (5.3) 0 Unknown 2 (4.3) 1 (2.6) 1 (12.5) N-stage, n (%) N Nþ 42 (91.3) 35 (92.1) 7 (87.5) Unknown 4 (8.7) 3 (7.9) 1 (12.5) M-stage, n (%) M0 35 (76.1) 29 (76.3) 6 (75) M (23.9) 9 (23.7) 2 (25) Histology, n (%) Intestinal 26 (56.5) 18 (47.4) 8 (100) Diffuse/mixed 19 (41.3) 19 (50.0) 0 Unknown 1 (2.2) 1 (2.6) 0 1 Oesophagogastric junction tumours were located in the lower oesophagus in 8 (17.4%), cardia in 14 (30.4%) and subcardial region in 1 (2.2%) patients. Gastric tumours were located in the fundus in 1 (2.2%), antrum in 13 (28.3%) and corpus in 9 (19.6%) patients. 2 Organs involved were distant lymph nodes (n ¼ 7), liver (n ¼ 2), adrenal gland (n ¼ 2), peritoneal (n ¼ 1), lung (n ¼ 1) and spleen (n ¼ 1). One additional patient with suspected M1 (adrenal glad) in the pcr group is included in the M0 population. Abbreviation: ECOG, Eastern Cooperative Oncology Group. <10% residual tumour/tumour bed; Grade 2 (partial remission), 10 50% residual tumour/tumour bed; Grade 3 (minor/ no remission), >50% residual tumour/tumour bed. Follow-up Participating centres used similar follow-up schedules. Patients were followed up after the end of treatment every 3 months by abdominal CT scans and thoracic CT scans in the case of oesophagogastric junction cancer. DFS was measured from the date of initial diagnosis until disease progression, relapse or death from any cause. OS was measured from the date of initial diagnosis until death from any cause. DFS and OS were plotted according to the Kaplan Meier method. Subgroups of patients with and without pathological complete remission (pcr; Grade 1a) were compared using the log-rank test. Results Patients In total, 46 patients were entered into the study from the three centres (Krankenhaus Nordwest, Frankfurt am Main, n ¼ 26; Universitätsklinikum, Lübeck, n ¼ 16; Klinikum Wolfsburg, n ¼ 4). Demographic and clinical characteristics

4 Homann et al are shown in Table 1. The median age was 59.5 years and approximately two-thirds of patients were male. The majority of patients had clinical T-stage 2/3 disease (91.3%) and lymph node involvement (91.3%). Nearly one-quarter (23.9%) had metastatic disease. Pathological response to preoperative FLOT Patients received a median of four cycles (range, two to eight cycles) of preoperative FLOT. Histopathological regression was classified in grades in all 46 patients: complete (Grade 1a), subtotal (Grade 1b) and partial (Grade 2) pathological remission was attained in 17.4%, 21.7% and 23.9% of patients, respectively (Table 2). The demographic and clinical characteristics, as well as initial T- and N-stage, of patients with pcr are compared with those of patients achieving higher grades of pathological regression in Table 1. Additional data of the patients with pcr are summarized in Table 3. Seven of eight patients with pcr had oesophagogastric junction tumours and all had intestinal type histology. Consequently, there were significantly higher rates of pcr among patients with a primary tumour in the oesophagogastric junction (30.4%) and in patients with intestinal type histology (30.8%) compared with those who had gastric cancer (4.3%; p ¼ 0.047) or diffuse/mixed type histology (0%; Fisher s exact test: p ¼ 0.014, respectively). The remaining parameters were Table 2. Histopathological regression (n ¼ 46) Pathological regression, grade No. of patients (%) 95% CI 1 1a (complete) 8 (17.4) b (subtotal) 10 (21.7) (partial) 11 (23.9) (minor/none) 15 (32.6) NE 2 2 (4.3) Exact 95% CI for underlying multinomial probabilities. 2 Two patients were not evaluable because the quality of tumour samples did not allow grading of tumour regression as indicated by the central pathologist. Abbreviation: CI, confidence interval; NE, not evaluable. Table 3. Description of patients who achieved a pcr similar between the two groups. Clinical T-stages (determined by endoscopic ultrasound) were T2 in 9 (19.6%), T3 in 33 (71.7%), T4 in 2 (4.3%) and unknown in 2 (4.3%) patients. Pathological T-stages were T0 in 8 (17.4%), T1 in 6 (13.0%), T2 in 20 (43.5%), T3 in 11 (23.9%) and T4 in 1 (2.2%) patients. Thus, pathological T down-staging relative to the initial T-stage was observed in 29 patients (63.0%). Follow-up and survival Forty-four patients (95.7%) underwent R0 resection and two patients (4.3%) had an R1 resection. The median duration of hospitalisation due to surgery was 16.5 days (range days), with a median of 1 day (range 0 43 days) in intensive care. One patient (2.2%) died and 29 patients (63.0%) experienced morbidity in the immediate (30-day) postsurgical period. Common (>5%) causes of postsurgical morbidity were pleural effusion (n ¼ 9, 19.6%), pneumonia (n ¼ 10, 21.7%), pancreatic fistula (n ¼ 5, 10.9%) and infection (n ¼ 3, 6.5%). Eleven patients (23.9%) received no postoperative chemotherapy and 35 (76.1%) received postoperative chemotherapy, consisting of FLOT in 33 patients (71.7%) and other regimens in 2 patients (4.3%; 5-FU plus postoperative radiation therapy in 1 patient and 5-FU/LV plus oxaliplatin in 1 patient). The median number of pre- and postoperative chemotherapy cycles was 8 (range 2 16). The median observation period was 26.4 months (range months) for the entire group and 27.6 months (range months) for surviving patients. Survival analysis (OS and DFS) for the total population is shown in Figure 1. Median DFS was 42 months and median OS has not yet been reached. One- and projected 2-year survival rates were 91 and 73%, respectively. Comparison of survival (OS and DFS) between those with pcr (Grade 1a) versus the remaining patients is shown in Figure 2. Patients with pcr had 100% probability of OS and DFS during the observation period, which was significantly higher than rates in patients who had higher pathological grades (log-rank test: p ¼ and p ¼ 0.009, respectively). There was no statistically significant Location of distant metastases Histology according to Lauren Patient number Gender ECOG PS Location of primary TNM initial 1 Male 1 Cardia T3N þ M0 Intestinal 3/0 2 Female 1 Cardia T3N þ M0 Intestinal 2/0 3 Male 1 Cardia T3N þ M1 Paraaortal LN Intestinal 4/4 4 Male 1 Lower oesophagus 1 T3N þ M0 Intestinal 3/3 5 Male 1 Cardia T3N þ M0 Intestinal 3/3 6 Female 1 Antrum T3N þ M0 Intestinal 3/3 7 Male 0 Lower oesophagus 1 TxNxM1 Paraaortal LN and liver Intestinal 4/4 8 Male 2 Cardia T3N þ M0 Suspected adrenal Intestinal 4/4 Number pre/postoperative cycles 1 Infiltriting the cardia. Abbreviation: ECOG PS, Eastern Cooperative Oncology Group Performance Status; LN, lymph nodes; TxNx, T- and N-stages were not assessed.

5 1710 Pathological complete remissions following preoperative FLOT Figure 1. Kaplan Meier survival curves for (a) DFS and (b) OS analysis from initial diagnosis among patients receiving neoadjuvant FLOT. Figure 2. Kaplan Meier survival curves for (a) DFS and (b) OS analysis from initial diagnosis comparing patients with Grade 1a histopathological regression (pcr) versus remaining patients among those receiving neoadjuvant FLOT. difference between patients having Grade 1a and 1b responses versus those with higher pathological grades (data not shown). Discussion Preoperative chemotherapy for operable oesophagogastric cancer has become standard clinical practice in many parts of Europe. However, it is clear that considerable investigation is still required to improve preoperative protocols and their efficacy. Important questions remain concerning the most appropriate duration of preoperative chemotherapy, the precise role of postoperative adjuvant therapy, and which schedule is the most efficient. Certainly, compared with the preoperative schedules given in other cancer types such as breast cancer, current strategies in oesophagogastric cancer could be intensified. The main current standard regimen for neoadjuvant chemotherapy in oesophagogastric cancer is ECF. Our group has investigated the substitution of oxaliplatin for cisplatin in systemic chemotherapy as palliative treatment for patients with advanced/metastatic oesophagogastric cancer. In a Phase III trial in 220 patients with metastatic oesophagogastric cancer, we found a significantly higher response rate and improved safety with the combination of 5-FU, LV, oxaliplatin (FLO) compared with 5-FU, LV, cisplatin (FLP). 22 We became interested in the addition of docetaxel to the FLO regimen after clinical trials indicated that intensification of other regimens with docetaxel improved efficacy in the treatment of advanced/metastatic oesophagogastric cancer. 23,24 We therefore determined the efficacy and safety of the addition of docetaxel to FLO (the FLOT regimen) in a Phase II study in 59 patients with metastatic adenocarcinoma of the stomach or oesophagogastric junction. 19 Overall response rate, and median OS and PFS were 58%, 11.1 months and 5.2 months, respectively with FLOT. This compared well with respective values of 37%, 9.2 months and 5.6 months with the docetaxel, cisplatin, 5-FU (DCF regimen) in a Phase III study in advanced oesophagogastric cancer. 23 Furthermore, FLOT showed an acceptable safety profile, with the most frequent (>10%) Grade 3/4 adverse effects including neutropenia (48%), leucopenia (28%), diarrhoea (15%) and fatigue (11%), which compared favourably with DCF. We have therefore adopted FLOT into the treatment of advanced oesophagogastric cancer in clinical practice and extended its use to the pre- and postoperative treatment of patients with operable oesophagogastric cancer. We currently report our first data for FLOT in the preoperative setting, with pcr rate being predefined as the primary endpoint of the analysis. In our series, we found a high rate of pcr at 17.4%, which compares favourably with other studies of neoadjuvant therapy in a similar setting. Becker et al. found no pcr among 36 patients with oesophagogastric

6 Homann et al cancer (86% had adenocarcinoma of the oesophagogastric junction or proximal stomach) who received one to four cycles of preoperative etoposide, doxorubicin, cisplatin (EPA regimen). 21 Geh et al. reported pcr in 1 (4.3%) of 23 patients with potentially operable oesophagogastric cancer who received four cycles of preoperative ECF, 25 whereas Melcher et al. found no pcr among 27 patients with oesophagogastric cancer treated with the same preoperative ECF regimen. 26 Starling et al. found a pcr rate of 7.7% following four cycles of preoperative epirubicin, cisplatin, capecitabine (ECX regimen) among 26 resected patients with locally advanced oesophagogastric cancer: the rate was 5.9% in the intent-to-treat population. 18 Furthermore, the pcr rate obtained with preoperative FLOT was in the range of that obtained with preoperative chemoradiation for localised oesophageal cancer, which has been associated with pcr rates ranging between 15 and 33%. 17,27 30 In contrast to radiation therapy, chemotherapy has a local and a systemic effect that can affect micrometastases. Thus, the increase of pcr rates by incorporating new effective drugs has to be distinguished from that achieved by adding radiation therapy, and may provide a higher chance of translating pcr into a survival benefit. Our study was limited by the observational nature of this preliminary series of patients receiving preoperative FLOT. In addition, we have only documented patients who underwent surgery, so it essentially represents a per protocol analysis. Patients who underwent preoperative FLOT therapy but who did not receive surgery are not included in our analysis, which would otherwise lead to a lower pcr rate. However, this is not expected to preclude many patients. One important potential limitation of our series is selection bias. To reduce selection bias, we analyzed all patients who were operated after at least one cycle of FLOT. This was reflected by relatively advanced disease stages at baseline (mainly T3Nþ and 23.9% with M1 disease) in our series. Moreover, it should be noted that seven of the eight patients who had a pcr had stage T3Nþ disease (T- and N-stage were unknown in one patient); two of eight patients had metastatic disease (lymph nodes only and lymph nodes þ liver) and an additional patient had suspected metastatic disease (adrenal gland); therefore, they did not appear to have had less advanced disease than either those who did not achieve a pcr or patients commonly treated in Western countries. Most of our patients had a favourable ECOG performance status with only 6.5% having an ECOG performance status of 2. This fact may represent a positive selection factor, since patients with a better performance status are more probably to be compliant and maintain treatment duration and dose intensity. However, low rates of ECOG performance Status 2 patients were also reported in recent trials of preoperative chemotherapy such as the studies by Starling et al. (3%) 18 or Cunningham et al. (0%). 15 Furthermore, two recent reports have indicated that triple-drug regimens incorporating docetaxel showed comparable pcr rates to that in our series (17.4%). In a conference abstract, Thuss-Patience et al. reported pcr in 7 of 44 patients (15.9%) with oesophagogastric adenocarcinoma who received three cycles of neoadjuvant docetaxel, cisplatin, capecitabine. 31 In a study of patients with advanced/metastatic oesophagogastric cancer, Lorenzen et al. reported pcr in 4 of 23 patients (17.4%) in a subgroup with operable disease who received one to four cycles of neoadjuvant cisplatin, 5-FU and docetaxel. 24 None of the eight patients who achieved a pcr in our study had a relapse or died, corresponding to DFS and OS rates of 100% in the observation period, and resulting in a statistically significant difference in survival outcomes between patients with and without pcr. Although they have to be interpreted with caution because of the small population, the results point towards a potential role of pcr as a surrogate marker of outcome for neoadjuvant chemotherapy. This result differs from the earlier report by Starling et al., where the outcome of the two patients who achieved pcr was unfavourable, 18 but is in line with recent reports pointing towards a better outcome for patients with major pathological regression after preoperative chemotherapy or chemoradiation Although limited by the low numbers of patients, one interesting finding in our study was that seven of eight patients who achieved a pcr had oesophagogastric junction tumours and all patients with pcr had intestinal type histology. Indeed, when analyzed according to the topographical location of the tumour, the pcr rate was 30% and 4.1% in patients having adenocarcinoma of the oesophagogastric junction and stomach, respectively. There is ongoing discussion on whether tumours of the oesophagogastric junction represent a distinct biology and recent reports have indicated that those tumours may benefit more from preoperative treatment strategies. 14,35,36 Our results provide a rational for further evaluating these parameters to clarify their potential predictive value for neoadjuvant treatment strategies. An accurate surrogate marker of tumour response to treatment that correlates with survival is mandatory to optimise future strategies and facilitate efforts to improve preoperative chemotherapy results. New treatment strategies could be assessed in reasonable number of patients before undertaking Phase III trials. CT scans are generally considered irrelevant for response assessment because operable patients often lack bi-dimensionally measurable lesions. There are also conflicting and inconsistent results for endoscopic ultrasound and positron emission tomography scanning in the literature. 17,33 Our study supports the potential role of pcr as a surrogate marker of outcome for neoadjuvant or preoperative chemotherapy. The intensification of chemotherapy using FLOT resulted in a comparatively high rate of pcr and patients who achieved a pcr had significantly longer DFS and OS. Whether this translates into superior survival results compared with standard regimens such as ECF has to be evaluated in randomised trials. The Arbeitsgemeinschaft Internistische Onkologie has started a Phase II/III clinical trial (FLOT4) in patients with operable adenocarcinoma of the stomach or gastro-oesophageal

7 1712 Pathological complete remissions following preoperative FLOT junction comparing four cycles of FLOT and three cycles of ECF or ECX followed by surgery and additional adjuvant therapy (four cycles of FLOT and three cycles of ECF or ECX). This trial is currently recruiting patients (Clinical- Trial.gov number NCT ). Acknowledgements The authors thank Mr. Lee Miller (Miller Medical Communications Ltd, UK) for editorial assistance with this manuscript. Third-party medical writing assistance was funded by Sanofi-Aventis Deutschland GmbH. The authors take full responsibility for the content of this publication. References 1. Kamangar F, Dores GM, Anderson WF. Patterns of cancer incidence, mortality, and prevalence across five continents: defining priorities to reduce cancer disparities in different geographic regions of the world. J Clin Oncol 2006;24: Nashimoto A, Nakajima T, Furukawa H, Kitamura M, Kinoshita T, Yamamura Y, Sasako M, Kunii Y, Motohashi H, Yamamoto S,on behalf of the Gastric Cancer Surgical Study Group and Japan Clinical Oncology Group. Randomized trial of adjuvant chemotherapy with mitomycin, fluorouracil, and cytosine arabinoside followed by oral fluorouracil in serosanegative gastric cancer: Japan Clinical Oncology Group J Clin Oncol 2003;21: Siewert JR, Bottcher K, Roder JD, Busch R, Hermanek P, Meyer HJ. Prognostic relevance of systemic lymph node dissection in gastric carcinoma. Br J Surg 1993;80: Sakuramoto S, Sasako M, Yamaguchi T, Kinoshita T, Fujii M, Nashimoto A, Furukawa H, Nakajima T, Ohashi Y, Imamura H, Higashino M, Yamamura Y, et al. Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine. N Engl J Med 2007;357: Liu TS, Wang Y, Chen SY, Sun YH. An updated meta-analysis of adjuvant chemotherapy after curative resection for gastric cancer. Eur J Surg Oncol 2008;34: Urschel JD, Vasan H, Blewett CJ. A metaanalysis of randomized controlled trials that compared neoadjuvant chemotherapy and surgery to surgery alone for resectable esophageal cancer. Am J Surg 2002;183: Partridge SC, Gibbs JE, Lu Y, Esserman LJ, Sudilovsky D, Hylton NM. Accuracy of MR imaging for revealing residual breast cancer in patients who have undergone neoadjuvant chemotherapy. Am J Roentgenol 2002;179: Forshaw MJ, Gossage JA, Mason RC. Neoadjuvant chemotherapy for oesophageal cancer: the need for accurate response prediction and evaluation. Surgeon 2005;3: , Weber WA, Ott K, Becker K, Dittler HJ, Helmberger H, Avril NE, Meisetschläger G, Busch R, Siewert JR, Schwaiger M, Fink U. Prediction of response to preoperative chemotherapy in adenocarcinomas of the esophagogastric junction by metabolic imaging. J Clin Oncol 2001;19: Barone C, Cassano A, Pozzo C, D Ugo D, Schinzari G, Persiani R, Basso M, Brunetti IM, Longo R, Picciocchi A. Long-term follow-up of a pilot phase II study with neoadjuvant epidoxorubicin, etoposide and cisplatin in gastric cancer. Oncology 2004; 67: Cascinu S, Scartozzi M, Labianca R, Catalano V, Silva RR, Barni S, Zaniboni A, D Angelo A, Salvagni S, Martignoni G, Beretta GD, Graziano F, et al. High curative resection rate with weekly cisplatin, 5-fluorouracil, epidoxorubicin, 6S-leucovorin, glutathione, and filgastrim in patients with locally advanced, unresectable gastric cancer: a report from the Italian Group for the Study of Digestive Tract Cancer (GISCAD). Br J Cancer 2004;90: Takahashi T, Saikawa Y, Yoshida M, Kitagawa Y, Otani Y, Kubota T, Kumai K, Kitajima M. A pilot study of combination chemotherapy with S-1 and low-dose cisplatin for highly advanced gastric cancer. Anticancer Res 2006;26: Persiani R, Rausei S, Pozzo C, Biondi A, Barone C, Cananzi FC, Schinzari G, D Ugo D. 7-Year survival results of perioperative chemotherapy with epidoxorubicin, etoposide, and cisplatin (EEP) in locally advanced resectable gastric cancer: up-todate analysis of a phase-ii study. Ann Surg Oncol 2008;15: Kinoshita T, Sasako M, Sano T, Katai H, Furukawa H, Tsuburaya A, Miyashiro I, Kaji M, Ninomiya M. Phase II trial of S-1 for neoadjuvant chemotherapy against scirrhous gastric cancer (JCOG 0002). Gastric Cancer 2009;12: Cunningham D, Allum WH, Stenning SP, Thompson JN, Van de Velde CJ, Nicolson M, Scarffe JH, Lofts FJ, Falk SJ, Iveson TJ, Smith DB, Langley RE, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med 2006;355: Boige V, Pignon J, Saint-Aubert B, Lasser P, Conroy T, Bouché O, Segol P, Bedenne L, Rougier P, Ychou M. Final results of a randomized trial comparing preoperative 5-fluorouracil (F)/cisplatin (P) to surgery alone in adenocarcinoma of stomach and lower esophagus (ASLE): FNLCC ACCORD07-FFCD 9703 trial. J Clin Oncol, 2007 ASCO Annual Meeting Proceedings Part I, vol. 25, No. 18S (June 20 Supplement), Stahl M, Walz MK, Stuschke M, Lehmann N, Meyer HJ, Riera-Knorrenschild J, Langer P, Engenhart-Cabillic R, Bitzer M, Königsrainer A, Budach W, Wilke H. Phase III comparison of preoperative chemotherapy compared with chemoradiotherapy in patients with locally advanced adenocarcinoma of the esophagogastric junction. J Clin Oncol 2009;27: Starling N, Okines A, Cunningham D, Allum W, Wotherspoon A, Benson M, Thompson J, Thomas J, Brown G, Riddell A, Stavridi F, Ashley S, et al. A phase II trial of preoperative chemotherapy with epirubicin, cisplatin and capecitabine for patients with localised gastro-oesophageal junctional adenocarcinoma. Br J Cancer 2009;100: Al-Batran SE, Hartmann JT, Hofheinz R, Homann N, Rethwisch V, Probst S, Stoehlmacher J, Clemens MR, Mahlberg R, Fritz M, Seipelt G, Sievert M, et al. Biweekly fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) for patients with metastatic adenocarcinoma of the stomach or esophagogastric junction: a phase II trial of the Arbeitsgemeinschaft Internistische Onkologie. Ann Oncol 2008; 19: Al-Batran SE, Hartmann JT, Probst S, Schmalenberg H, Hollerbach S, Hofheinz R, Rethwisch V, Seipelt G, Homann N, Wilhelm G, Schuch G, Stoehlmacher J, et al. Phase III trial in metastatic gastroesophageal adenocarcinoma with fluorouracil, leucovorin plus either oxaliplatin or cisplatin: a study of the Arbeitsgemeinschaft Internistische Onkologie. J Clin Oncol 2008;26: Becker K, Mueller JD, Schulmacher C, Ott K, Fink U, Busch R, Böttcher K, Siewert JR, Höfler H. Histomorphology and grading of regression in gastric carcinoma treated with neoadjuvant chemotherapy. Cancer 2003;98: Al-Batran S, Homann N, Hartmann JT, Moehler MH, Pauligk C, Probst C, Rethwisch V, Prasnikar N, Stoehlmacher J, Jaeger E. 5-Fluorouracil, leucovorin, and oxaliplatin with or without docetaxel in elderly (65 years or older) patients with

8 Homann et al esophagogastric cancer: FLOT65þ trial of the Arbeitsgemeinschaft Internistische Onkologie (AIO). J Clin Oncol 2010; 28: Van Cutsem E, Moiseyenko VM, Tjulandin S, Majlis A, Constenla M, Boni C, Rodrigues A, Fodor M, Chao Y, Voznyi E, Risse ML, Ajani JA,on behalf of the V325 Study Group. Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 Study Group. J Clin Oncol 2006;24: Lorenzen S, Hentrich M, Haberl C, Heinemann V, Schuster T, Seroneit T, Roethling N, Peschel C, Lordick F. Splitdose docetaxel, cisplatin and leucovorin/ fluorouracil as first-line therapy in advanced gastric cancer and adenocarcinoma of the gastroesophageal junction: results of a phase II trial. Ann Oncol 2007;18: Geh JI, Glynne-Jones R, Kwok QS, Banerji U, Livingstone JI, Townsend ER, Harrison RA, Mitchell IC. Preoperative ECF chemotherapy in gastro-oesophageal adenocarcinoma. Clin Oncol (R Coll Radiol) 2000;12: Melcher AA, Mort D, Maughan TS. Epirubicin, cisplatin and continuous infusion 5-fluorouracil (ECF) as neoadjuvant chemotherapy in gastrooesophageal cancer. Br J Cancer 1996;74: Walsh TN, Noonan N, Hollywood D, Kelly A, Keeling N, Hennessy TP. A comparison of multimodal therapy and surgery for esophageal adenocarcinoma. N Engl J Med 1996;335: Urba SG, Orringer MB, Turrisi A, Iannettoni M, Forastiere A, Strawderman M. Randomized trial of preoperative chemoradiation versus surgery alone in patients with locoregional esophageal carcinoma. J Clin Oncol 2001;19: Burmeister BH, Smithers BM, Gebski V, Fitzgerald L, Simes RJ, Devitt P, Ackland S, Gotley DC, Joseph D, Millar J, North J, Walpole ET, et al. Surgery alone versus chemoradiotherapy followed by surgery for resectable cancer of the oesophagus: a randomised controlled phase III trial. Lancet Oncol 2005;6: Tepper J, Krasna MJ, Niedzwiecki D, Hollis D, Reed CE, Goldberg R, Kiel K, Willett C, Sugarbaker D, Mayer R. Phase III trial of trimodality therapy with cisplatin, fluorouracil, radiotherapy, and surgery compared with surgery alone for esophageal cancer: CALGB J Clin Oncol 2008;26: Thuss-Patience PC, Kneba M, Hofheinz R, Arnold D, Florschütz A, Daum S, Kretzschmar A, Mantovani-Löffler L, Bichev D, Schumacher G. Docetaxel, cisplatin, and capecitabine (DCX) as perioperative chemotherapy in gastroesophageal adenocarcinoma: a phase II study of the Arbeitsgemeinschaft Internistische Onkologie (AIO). J Clin Oncol 2010;28: Fareed KR, Al-Attar A, Soomro IN, Kaye PV, Patel J, Lobo DN, Parsons SL, Madhusudan S. Tumour regression and ERCC1 nuclear protein expression predict clinical outcome in patients with gastrooesophageal cancer treated with neoadjuvant chemotherapy. Br J Cancer 2010;102: Vallböhmer D, Hölscher AH, Schneider PM, Schmidt M, Dietlein M, Bollschweiler E, Baldus S, Alakus H, Brabender J, Metzger R, Mönig SP. [18F]- fluorodeoxyglucose-positron emission tomography for the assessment of histopathologic response and prognosis after completion of neoadjuvant chemotherapy in gastric cancer. J Surg Oncol 2010;102: Verlato G, Zanoni A, Tomezzoli A, Minicozzi A, Giacopuzzi S, Di Cosmo M, Franceschetti I, de Manzoni G. Response to induction therapy in oesophageal and cardia carcinoma using Mandard tumour regression grade or size of residual foci. Br J Surg 2010;97: Reynolds JV, Ravi N, Muldoon C, Larkin JO, Rowley S, O Byrne K, Hollywood D, O Toole D. Differential pathologic variables and outcomes across the spectrum of adenocarcinoma of the esophagogastric junction. World J Surg 2010;34: Ronellenfitsch U, Schwarzbach M, Hofheinz R, Kienle P, Hohenberger P, Jensen K, Kieser M, Slanger TE. Metaanalysis of preoperative chemotherapy (CTX) versus primary surgery for locoregionally advanced adenocarcinoma of the stomach, gastroesophageal junction, and lower esophagus (GE adenocarcinoma). J Clin Oncol 2010;28: 306.