D2 Surgery Research Articles

Phase II feasibility study of adjuvant S-1 plus docetaxel for stage III gastric cancer patients after curative D2 gastrectomy (OGSG 0604).

108 Background: An adjuvant chemotherapy with S-1 has become the standard treatment for patients (pts) with stage II/III gastric cancer (GC) who have undergone gastrectomy with D2 dissection in Japan, but it is assumed that the survival benefit for stage III pts who received S-1 is modest. S-1 plus docetaxel has shown that the response rate and median overall survival (OS) were 56% and 14.3 months in pts with advanced GC. The aims of this phase II study were to evaluate the feasibility and safety of adjuvant S-1 plus docetaxel in pts with stage III GC with D2 surgery. Methods: Pts with pathological stage III GC who underwent gastrectomy with D2 dissection received oral S-1 (80 mg/m2/day) administration for 2 consecutive weeks and intravenous docetaxel (40 mg/m2) on day 1, repeated every 3 weeks (1 cycle). The treatment was started within 45 days after surgery, and repeated for 4 cycles, followed by S-1 administration until 1 year after surgery. The primary endpoint was feasibility of the 4 cycles administration of S-1 plus docetaxel; secondary endpoints were safety, progression-free survival (PFS), OS, and feasibility of S-1 administration until 1 year after surgery. Results: We enrolled 53 pts, 42 males and 11 females with a median age of 65 years (range, 43-78), between May 2007 and August 2008. Pathological stages included IIIA in 36 pts and IIIB in 17 pts. The feasibility of planned 4 cycles of treatment was 77.4% (95% CI 63.8-87.7%, p < 0.001) with 41 pts out of 53 pts. Grade 4 neutropenia was observed in 28% of pts with grade 3 febrile neutropenia in 9%. Non-hematological toxicities of grade 3 or more involved fatigue in 6%, anorexia in 9%, and nausea in 6%. No treatment-related deaths occurred. Reasons for discontinuation were recurrent cancer in 1 pt, adverse events in 10, and miscellaneous in 1, respectively. 3 year overall survival was 78.8% (95% CI 68.4-90.7) and 3 year disease free survival was 50.3% (95% CI 34.4-73.3). Conclusions: Adjuvant S-1 plus docetaxel therapy is feasible and has only moderate toxicity in stage III gastric cancer pts. We believe that this regimen will be a candidate for future phase III trials seeking the optimal adjuvant chemotherapy for stage III gastric cancer patients.

Macroscopic tumor size as an independent prognostic factor for patients with stage II/III gastric cancer who underwent D2 gastrectomy followed by adjuvant chemotherapy with S-1.

56 Background: In patients with stage II/III gastric cancer, tumors often recur even after curative D2 gastrectomy followed by adjuvant S-1 chemotherapy. The objective of this retrospective study was to clarify the prognostic factors in these patients that might be useful for future patients. Methods: Overall survival was examined in 82 gastric cancer patients who underwent curative D2 surgery, were diagnosed with stage IIA, II B, IIIA, IIIB, or IIIC pathologically, and received adjuvant S-1 after surgery between June of 2002 and March of 2010. Results: When overall survival was compared by the log-rank test, a significant difference was observed with regard to macroscopic tumor diameter and the depth of tumor invasion. A macroscopic tumor diameter greater than 70mm was regarded as a critical point of classification considering the survival. Uni- and muliti-variate Cox’s proportional hazard analyses demonstrated that macroscopic tumor diameter was the only significant independent prognosticator. The five-year survival was 64.9% in patients with a macroscopic tumor diameter <70mm, and 33.1% in patients with a macroscopic tumor diameter ≥70mm (P=0.022). Conclusions: The macroscopic tumor diameter was the most important prognostic factor for survival in patients with stage II/III gastric cancer who underwent D2 gastrectomy followed by adjuvant S-1 chemotherapy. Prognostic factors can be affected by adjuvant chemotherapy.

Phase II feasibility study of adjuvant S-1 plus CPT-11 for stage III gastric cancer patients after curative D2 gastrectomy (OGSG 0801).

142 Background: An adjuvant chemotherapy with S-1 has become the standard treatment for patients (pts) with stage II/III gastric cancer (GC) in Japan. But, it is assumed that the survival benefit for stage III pts who received S-1 is modest. S-1 plus CPT-11 has not shown the superiority in median overall survival (OS), but shown the well response rate (56%) and tolerability in Phase III trial (TOP-002 study). The aims of this phase II study were to evaluate the feasibility and safety of adjuvant S-1 plus CPT-11 in pts with stage III GC who underwent D2 surgery. Methods: Pts with pathological stage IIIA and IIIB GC who underwent gastrectomy D2 dissection, age 20-75 years, performance status < 1, and informed consent received oral S-1 (80 mg/m2/day) administration for consecutive 3 weeks and intravenous CPT-11 (80 mg/m2) on day 1, 15, repeated every 5 weeks (1 cycle). The treatment was repeated for 4 cycles, followed by S-1 administration until 1 year after surgery. The primary endpoint was feasibility of the 4 cycles administration of S-1 plus CPT-11. Results: We enrolled forty-five pts, 22 males and 23 females with a median age of 61 years, between December 2008 and April 2010. Pathological stages included IIIA in 25 pts and IIIB in 20 pts. The feasibility of planned 4 cycles of treatment was 62.2% (95% CI 46.5-76.2%, p=0.068) with 28 pts out of 45 pts. Non-hematological toxicities of grade 3 or more involved diarrhea in 13%, anorexia in 16%, nausea in 7% and vomiting in 4%. No Grade 4 toxicities were observed. Conclusions: Adjuvant S-1 plus CPT-11 therapy had moderate hematological toxicities, but observed several severe non-hematological toxicities. Therefore, predicted feasibility was not achieved. Although the follow-up period is too short to evaluate OS and feasibility of S-1 administration, it is hoped that this regimen will be a candidate for future phase III trial seeking for the optimal adjuvant chemotherapy for stage III GC pts after D2 dissection if OS will be improved.

D2 lymphadenectomy can disseminate tumor cells into peritoneal cavity in patients with advanced gastric cancer

We sought to determine the dissemination of gastric cancer cells before and after radical D2 surgery and to determine the effectiveness of EIPL in preventing post-operative peritoneal metastasis. 64 patients were recruited with advanced gastric cancer for our final analysis. Complete curative gastrectomy with D2 lymphadenectomy was performed on the 64 patients. Before surgery, peritoneal lavage fluid was collected for cytological analysis by cell smearing and immunohistochemistry to detect disseminated cancer cells (S1). Following tumor and lymph node resection, peritoneal lavage fluid was collected for cytological examination (S2). The patients were treated by extensive intra-operative peritoneal lavage (EIPL) with normal saline (n = 31) or distilled water (n = 33). The peritoneal lavage fluid was collected for cytological examination (S3). At S1 stage, 18 patients (28.1%) were positive for disseminated cancer cells in their abdominal fluid. After D2 lymphadenectomy, 34 patients (53.1%) had disseminated cancer cells in their abdominal fluid at stage S2, which indicated that the D2 lymphadenectomy caused in an additional 16 (16/46, 34.8%) patients positive for disseminated cancer cells. After EIPL with either normal saline or distilled water at the S3 stage), all the patients were negative for disseminated cancer cells in their abdominal fluid. A total of six patients died, and four patients had recurrencent cancer. These findings indicate that D2 lymphadenectomy can disseminate gastric cancer cells, and post-operative lavage of the abdominal cavity can eliminate cancer cell dissemination and decrease the risk of peritoneal metastasis.

Risk Factors for Peritoneal Recurrence in Stage II/III Gastric Cancer Patients Who Received S-1 Adjuvant Chemotherapy After D2 Gastrectomy

The peritoneum is still the most frequent site of recurrence in stage II/III gastric cancer patients, although the survival rate was improved by the introduction of S-1 adjuvant chemotherapy. The objective of this retrospective study was to clarify the risk factors for peritoneal recurrence in patients who received S-1 adjuvant chemotherapy. Peritoneal recurrence-free survival was examined in 100 gastric cancer patients who underwent curative D2 surgery, which were diagnosed with stage II or III disease pathologically, and received adjuvant S-1 between June 2002 and March 2011. The univariate and multivariate analyses were performed to identify risk factors by a Cox proportional hazards analysis. The P-RFS was 64.3% at 3 years and 58.8% at 5 years. A total of 18 patients were diagnosed with peritoneal recurrence. The macroscopic tumor diameter, depth of tumor invasion, and lymph node metastasis were the significant factors identified by the univariate analysis, while the tumor diameter and lymph node metastasis were the only significant independent risk factors identified by the multivariate analysis. The macroscopic tumor diameter and presence of lymph node metastasis were the most important risk factors for peritoneal recurrence. When patients had these risk factors, S-1 was not sufficient to inhibit peritoneal recurrence. A novel adjuvant chemotherapeutic agent targeting peritoneal metastasis in these patients should be developed.

Safety and feasibility of S-1 adjuvant chemotherapy for gastric cancer in elderly patients

The safety and feasibility of administering S-1 adjuvant chemotherapy for gastric cancer has not been fully evaluated in elderly patients. This retrospective study selected patients who underwent curative D2 surgery for gastric cancer, were diagnosed with stage II or III disease, and received adjuvant S-1 at our institution. Patients were categorized into two groups; non-elderly patients (age <70 years: group A) and elderly patients (age ≥70 years: group B). The toxicity and S-1 continuation rates in the two groups were compared. A total of 75 patients were evaluated in the study. There were no grade 4 toxicities. The incidences of grade 3 hematological and non-hematological toxicities were <5% in both groups, and the differences were not significant. The continuation rate at 6months was 69% in group A and 70% in group B, and this difference was also not significant. These results suggest that S-1 adjuvant chemotherapy for gastric cancer is safe and feasible, regardless of the age of the patient; especially for elderly patients who could be candidates for clinical trials.

Macroscopic tumor size as an independent prognostic factor for stage II/III gastric cancer patients who underwent D2 gastrectomy followed by adjuvant chemotherapy with S-1

In patients with stage II/III gastric cancer, tumors often recur even after curative D2 gastrectomy followed by adjuvant S-1 chemotherapy. The objective of this retrospective study was to clarify the prognostic factors in these patients that might be useful for future patients. Overall survival (OS) was examined in 82 gastric cancer patients who underwent curative D2 surgery; were diagnosed with stage IIA, IIB, IIIA, IIIB, or IIIC pathologically; and received adjuvant S-1 after surgery between June 2002 and March 2010. When length of OS was evaluated by the log-rank test, significant differences were observed with regard to macroscopic tumor diameter and the depth of tumor invasion. A macroscopic tumor diameter >70 mm was regarded as a critical point of classification considering survival. Univariate and multivariate Cox's proportional hazard analyses demonstrated that macroscopic tumor diameter was the only significant independent prognosticator. The 5-year survival was 64.9% in patients with a macroscopic tumor diameter <70 mm, and 33.1% in patients with a macroscopic tumor diameter ≥70 mm (P = 0.022). The macroscopic tumor diameter was the most important prognostic factor for survival in patients with stage II/III gastric cancer who underwent D2 gastrectomy followed by adjuvant S-1 chemotherapy. Prognostic factors can be affected by adjuvant chemotherapy.

Proximal gastric cancer: advances of laparoscopic surgery

Although the overall incidence of gastric cancer is decreasing, gastric cancer still remains the fourth most common cancer worldwide. The decrease in the incidence rate varies considerably depending on the geographical area. For example, gastric cancer is continuously the most common cancer type in Asian countries such as Japan, Korea, and China, with a slow and slight drop in the prevalence of the disease in these countries. There has been a greater decrease in the incidence curve over the last few decades in the USA and northwest Europe, but the prevalence of proximal and gastroesophageal junction cancer in these areas is increasing. Therefore, there is interest in how to manage patients with upper-third stomach cancer to improve oncological and quality-of-life (QOL) outcomes not only in the Eastern but also in the Western world. The Aihara et al. [1] report in the September issue of Surgical Endoscopy provides useful information for the laparoscopic surgical treatment of patients with proximal gastric cancer. The authors describe a technique of laparoscopy-assisted proximal gastrectomy (LAPG) and gastric tube reconstruction using a miniloop retractor (MLR). The feasibility and safety of this technique was evaluated in 44 patients with early-stage upper gastric carcinoma. Five surgical ports were inserted into the abdomen and the stomach was lifted to the abdominal wall side with a MLR. Reconstruction with a gastric tube (20 cm long, 3 cm wide) using a circular stapler was performed through a small incision, through which the specimen was removed. The mean operating time was 202 min. There were no serious complications no deaths, and no conversions to open surgery. The authors concluded that this technique of LAPG and gastric tube reconstruction using MLR is feasible and safe for the treatment of proximal early gastric cancer. The data provided by Aihara et al. [1] support the safety of their technique, which is technically more complicated than laparoscopy-assisted distal gastrectomy (LADG). The incidence of early gastric cancer (EGC) in Japan and Korea is high and approximately 50% of cases are diagnosed at this early stage through established nationwide endoscopic screening. These high EGC rates have led to the development and validation of minimally invasive approaches, including endoscopic submucosal dissection (ESD) and laparoscopic surgery in these countries. Criteria for clinical decision-making on ESD, laparoscopic gastrectomy, or open surgery have been defined by Japanese scientific associations. There is now an explosion in laparoscopic surgery for the treatment of gastric cancer in Asian countries and also an increase in the use of this minimally invasive approach in some specialized centers in the West [2]. Based on strong evidence of the superiority of laparoscopic versus open surgery with respect to quality of life for colorectal cancer patients [3] and accumulating evidence, although still incomplete, for early gastric cancer patients [4–6], the technique of laparoscopic gastrectomy has evolved rapidly. Now, the evolution includes totally intracorporeal laparoscopic distal, proximal, or total gastrectomy with standardized extended D2 lymphadenectomy, and indications for its use have been expanded to include patients with advanced resectable stage II and stage III disease [2]. Survival benefits of D2 surgery [7] are now being confirmed by the long-term 15 year survival results of a Dutch trial [8]. This assessment of D2 surgery gains in open surgery makes this standardized lymphadenectomy an C. Batsis (&) Department of Surgery, School of Medicine, University of Ioannina, 451 10 Ioannina, TK, Greece e-mail: chbatsis@hotmail.com

Survival and prognosticators of gastric cancer that recurs after adjuvant chemotherapy with S-1

Some patients experience a recurrence of cancer even after curative D2 gastrectomy followed by adjuvant S-1 chemotherapy. The objective of this retrospective study was to clarify the survival and prognosticators in these patients. The study selected patients who underwent curative D2 surgery, were diagnosed with stage II, IIIA, or IIIB cancer, received adjuvant S-1 for more than 4 weeks, and experienced recurrence confirmed by an imaging study. A total of 34 patients were evaluated. The median overall survival (OS) was significantly longer in the 26 patients who received palliative chemotherapy than that in the 8 who did not (8.5 vs. 2.5 months, P = 0.002). Only 1 patient received S-1, 21 received taxane-containing regimens, and 4 received irinotecan plus cisplatin as the first-line chemotherapy. Univariate and multivariate analyses showed that the histological type was only independent significant prognosticator. These results suggested that the survival did not reach the level expected for first-line chemotherapy. The histological type was a significant prognosticator in patients who experienced recurrence after adjuvant S-1 therapy and thereafter received palliative chemotherapy.

Laparoscopic and robotic-assisted D2 surgery for gastric cancer: a reality in Europe?

Laparoscopic and robotic-assisted D2 surgery for gastric cancer: a reality in Europe?

Phase II trial of S-1 combined with oxaliplatin (SOX) as neoadjuvant chemotherapy for locally advanced gastric cancer.

122 Background: Previous phase II trial with combination therapy of S-1 plus oxaliplatin (SOX) demonstrated high response rate and well tolerability in patients with untreated advanced gastric cancer. The aim of this phase II trial was to evaluate the efficacy and safety of SOX as neoadjuvant chemotherapy for locally advanced gastric cancer (AGC). Methods: Eligibility criteria included a histologically proven AGC with stage IIIb, IIIc (AJCC 7th edition), at least 1 measurable lesion, no prior chemotherapy, ECOG 0∼2, adequate hepatic, renal, and bone marrow function. Enrolled patients were staged by EUS and CT. The neoadjuvant chemotherapy consisted of 3-4 cycles of oxaliplatin (130 mg/m2) on day 1 and S-1 (80 mg/m2/day) for 14 days with 7 days rest. After chemotherapy, the patients underwent surgery. Results: From Dec 2009 to Sep 2010, 35 patients (IIIb; 19pts, IIIc; 16pts) were enrolled. The median age of the patients was 54.6 years (range; 20-72 y). All patients were available for evaluating the clinical responese and adverse events. The overall response rate was 68.5% (1CR, 23 PR, 9 SD, 2 PD). 32 patients underwent surgical resection. Of them, 27 patients underwent standard D2 surgery and 5 patients had palliative surgery. 25 patients had R0 resection. Postoperative pathological examination showed that most of the surgical patients were in T4a stage. According to Lauren classification, 71.9% patiens (23/32pts) were diffuse type, SOX showed higher respons rate (1CR, 20 PR, 2 SD, RR: 91.3%) among these patients. Major grade 3/4 hematological toxicities were anemia (5.7%), neutropenia (5.7%) and liver dysfunction (8.6%) and non-hematological toxicities were anorexia (5.7%) and vomiting (11.4%). But most of the adverse events were managable. Conclusions: Neoadjuvant chemotherapy with S-1 plus oxaliplatin (SOX) showed high response rate and and R0 resection rate for locally advanced GC, especially for diffuse type patients. All the patients did not have severe toxicity during the process of chemotherapy. This is the preliminary results, and the survival benefit in locally advanced GC patients that respond to SOX neoadjuvant chemotherapy needs to be addressed by a randomized-controlled trial. No significant financial relationships to disclose.

Gastric Cancer Working Group Report

Gastric cancer is the second most common cancer in Asia, more than half of the world's gastric cancer cases arise in Eastern Asia, and the majority of Asia's cases still occur in the distal part of the stomach. The etiology of gastric cancer consists of genetic susceptibility, Helicobacter pylori infection and environmental risk factors. Helicobacter pylori eradication treatment, consumption of fresh vegetables and fruits and use of aspirin and non-steroidal anti-inflammatory drugs seem to reduce the risk of gastric cancer. Screening for gastric cancer is cost-effective in countries with high incidence. Risk stratification may increase the cost-effectiveness of screening in populations at moderate risk. Endoscopic resection is curative in a subset of patients with early cancer. R0 resection with D2 lymph node dissection has produced the best survival data. Some kind of post-operative adjuvant chemotherapy including S-1 is recommended after D2 surgery. As chemotherapy for gastric cancer, fluorouracils plus platinum are the most widely accepted first-line regimens, whereas taxanes or irinotecan are mostly used in second- and third-line settings. Differences in the approval and medical insurance systems may influence the status of these regimens. Trastuzumab in combination with fluorouracils/platinum will be a standard regimen for HER2-positive gastric cancer. Many new targeting agents are currently under investigation, and Asian countries are playing important roles in investigation and development of new and better treatments for this malignancy.

Does D3 surgery offer a better survival outcome compared to D1 surgery for gastric cancer? A result based on a hospital population of two decades as taking D2 surgery for reference

BackgroundWe conducted a retrospective study in our hospital in which we compared D1 with D3 through D2 lymphadenectomy for gastric cancer in terms of morbidity, postoperative mortality, long-term survival after surgery.Methods567 patients who were performed curative intent between 1980 and 2003 were enrolled. 187 in the D1 group, 189 in the D2 group and 191 in the D3 group. Every procedure was verified by pathological analyses. The primary endpoints were 5-year overall survival.ResultsMedian follow-up periods were 36 months and 60 months for D1 group and D3 group. Overall 5-year survival rate was significantly higher in patients underwent D3 surgery than in those performed D1 surgery (37.4% vs 48.7%; log-rank, p = 0.027). For the cases followed up to 120 months, the 10-year overall survival rate was 29% (95% CI, 22.1% to 35.9%) for the D1 group and 33.7% (95% CI, 26.6% to 40.8%) for the D3 group (log-rank, p = 0.005).ConclusionsD1 surgery should be operated only for patients with Borrmann I disease. As D3 gastrectomy is associated with low mortality and adequate survival times when performed in selected institutions that have had sufficient experience with the operation and with postoperative management, we recommend D3 lymphadenectomy for patients with curable gastric cancer.

Surgical treatment of gastric cancer: 15-year follow-up results of the randomised nationwide Dutch D1D2 trial

Historical data and recent studies show that standardised extended (D2) lymphadenectomy leads to better results than standardised limited (D1) lymphadenectomy. Based on these findings, the Dutch D1D2 trial, a nationwide prospectively randomised clinical trial, was undertaken to compare D2 with D1 lymphadenectomy in patients with resectable primary adenocarcinoma of the stomach. The aim of the study was to assess the effect of D2 compared with D1 surgery on disease recurrence and survival in patients treated with curative intent. Between August, 1989, and July, 1993, patients were entered and randomised at 80 participating hospitals by means of a telephone call to the central data centre of the trial. The sequence of randomisation was in blocks of six with stratification for the participating centre. Eligibility criteria were a histologically proven adenocarcinoma of the stomach without evidence of distance metastasis, age younger than 85 years, and adequate physical condition for D1 or D2 lymphadenectomy. Patients were excluded if they had previous or coexisting cancer or had undergone gastrectomy for benign tumours. Strict quality control measures for pathological assessment were implemented and monitored. Analyses were by intention to treat. This study is registered with the NCI trial register, as DUT-KWF-CKVO-8905, EU-90003. A total of 1078 patients were entered in the study, of whom 996 were eligible. 711 patients underwent the randomly assigned treatment with curative intent (380 in the D1 group and 331 in the D2 group) and 285 had palliative treatment. Data were collected prospectively and all patients were followed up for a median time of 15.2 years (range 6.9-17.9 years). Analyses were done for the 711 patients treated with curative intent and were according to the allocated treatment group. Of the 711 patients, 174 (25%) were alive, all but one without recurrence. Overall 15-year survival was 21% (82 patients) for the D1 group and 29% (92 patients) for the D2 group (p=0.34). Gastric-cancer-related death rate was significantly higher in the D1 group (48%, 182 patients) compared with the D2 group (37%, 123 patients), whereas death due to other diseases was similar in both groups. Local recurrence was 22% (82 patients) in the D1 group versus 12% (40 patients) in D2, and regional recurrence was 19% (73 patients) in D1 versus 13% (43 patients) in D2. Patients who had the D2 procedure had a significantly higher operative mortality rate than those who had D1 (n=32 [10%] vs n=15 [4%]; 95% CI for the difference 2-9; p=0.004), higher complication rate (n=142 [43%] vs n=94 [25%]; 11-25; p<0.0001), and higher reoperation rate (n=59 [18%] vs n=30 [8%]; 5-15; p=0.00016). After a median follow-up of 15 years, D2 lymphadenectomy is associated with lower locoregional recurrence and gastric-cancer-related death rates than D1 surgery. The D2 procedure was also associated with significantly higher postoperative mortality, morbidity, and reoperation rates. Because a safer, spleen-preserving D2 resection technique is currently available in high-volume centres, D2 lymphadenectomy is the recommended surgical approach for patients with resectable (curable) gastric cancer. Dutch Health Insurance Funds Council and The Netherlands Cancer Foundation.

Impact of the Extent of Surgery and Postoperative Chemoradiotherapy on Recurrence Patterns in Gastric Cancer

The Intergroup 0116 trial has demonstrated that postoperative chemoradiotherapy (CRT) improves survival in gastric cancer. We retrospectively compared survival and recurrence patterns in two phase I/II studies evaluating more intensified postoperative CRT with those from the Dutch Gastric Cancer Group Trial (DGCT) that randomly assigned patients between D1 and D2 lymphadenectomy. Survival and recurrence patterns of 91 patients with adenocarcinoma of the stomach who had received surgery followed by radiotherapy combined with fluorouracil and leucovorin (n = 5), capecitabine (n = 39), or capecitabine and cisplatin (n = 47) were analyzed and compared with survival and recurrence patterns of 694 patients from the DGCT (D1, n = 369; D2, n = 325). For both groups, the Maruyama Index of Unresected Disease (MI) was calculated and correlated with survival and recurrence patterns. With a median follow-up of 19 months in the CRT group, local recurrence rate after 2 years was significantly higher in the surgery only (DGCT) group (17% v 5%; P = .0015). Separate analysis of CRT patients who underwent a D1 dissection (n = 39) versus DGCT-D1 (n = 369) showed fewer local recurrences after chemoradiotherapy (2% v 8%; P = .001), whereas comparison of CRT-D2 (n = 25) versus DGCT-D2 (n = 325) demonstrated no significant difference. CRT significantly improved survival after a microscopically irradical (R1) resection. The MI was found to be a strong independent predictor of survival. After D1 surgery, the addition of postoperative CRT had a major impact on local recurrence in resectable gastric cancer.

Hope from Japan for esophagogastric cancers: esophagectomy and endoscopic submucosal dissection for gastric tube cancer

Westerns surgeons, oncologists, and pathologists are debating: Can the excellent results from early detection and treatment of tumors in the upper gastrointestinal tract reported from Japan and other Asian countries be achieved in the U.S. or Europe? Various reasons have been given to explain the poor survival of patients with gastric and esophageal cancers in the West. Some questions such as what are the effects of the biological, genetic, and molecular differences of cancer genomes between Asian and European ancestry patients remain unanswered. However, these cancer genome differences may only partly explain the better oncological outcomes of Japanese patients. In fact, we in the West should learn from our colleagues in Japan to make better use of screening programs, standardized D2 surgery for gastric cancer, and surveillance after treatment. An example of good practice is the recent 70% 5-year survival rate in advanced stages II and III gastric cancer patients reported by a large-scale multicenter randomized controlled trial in Japan [1, 2]. Therefore, the previous criticism that Japanese studies are limited by the retrospective nature of their analyses and should be considered with caution should now clearly be revised. The prognosis of esophageal carcinoma is dismal. Follow-up data from Cancer Facts and Statistics in the U.S. reveal that esophageal cancer, along with pancreatic and lung cancer, has a very high mortality rate [3]. This suggests that the disease is nearly incurable except when diagnosed at early stage I. Despite the disappointing data, appropriate medical efforts and careful management can not only save some patients but can also improve their quality of life (QOL). Indeed, in support of this statement is the recent report in this journal by Bamba et al. [4]. The authors evaluated the follow-up data of their patients who had undergone esophagectomy to assess whether endoscopic surveillance in these patients is justified. Among 881 patients who underwent esophagectomy for esophageal cancer in Niigata University Medical and Dental Hospital between 1976 and 2006, the authors identified 551 patients in whom a gastric tube was used as an esophageal substitute. Twenty-five patients with 29 gastric tube cancer (GTC) lesions treated between 1989 and 2007 were analyzed retrospectively. The 10-year cumulative incidence rate of GTC was 8.6%. Endoscopic surveillance identified GTC lesions in 95% (17/18) of asymptomatic patients leading to endoscopic submucosal dissection (ESD) in 15 (88%) of them. Overall, pathological examination of the resected specimen after ESD showed a complete (R0) resection in 90% of the GCT cases, whereas it was only 14.3% among 7 patients treated with endoscopic mucosal resection (EMR). No cancer recurrence developed during a median follow-up period of 24 months among the 17 asymptomatic patients. The authors emphasize the need for endoscopic surveillance of patients with a gastric tube after esophagectomy. This approach allows curative treatment with ESD. This study has many important messages useful for dayto-day high-quality clinical practice. Based on a high GTC incidence rate at 10 years (8%), early detection of GTC mostly in asymptomatic patients, and excellent oncological and QOL outcomes after ESD, the authors correctly recommend endoscopic surveillance. However, there are some C. Katsios D. H. Roukos (&) G. Baltogiannis Department of Surgery, University of Ioannina, School of Medicine, 451 10 Ioannina, Greece e-mail: droukos@uoi.gr

Curability risks by endoscopic submucosal dissection for early gastric cancer

In a recent issue of Surgical Endoscopy, Ohnita and colleagues [1] reported the risk factors for incomplete tumor resection after endoscopic submucosal dissection (ESD) for early gastric cancer (EGC). This identification can result in preventing pathohistologically assessed residual microscopic disease (R1) at resection margins. In 2003, the Japanese Gastric Cancer Association published recommendations for the treatment of EGC by limited surgical resection [2]. In these guidelines, strict criteria were defined to ensure the safety and efficacy of endoscopic mucosal resection (EMR) for the treatment of EGC. These criteria were: tumor size \2 cm, confined to mucosal without ulcers, and differentiated histological type. Treating patients with EMR can dramatically improve their quality of life (QOL); however, a relatively small number of patients with EGC meet these criteria. ESD was developed to expand the indications, and many patients gained substantial benefit in their QOL. However, many questions remain regarding the safety of ESD when larger undifferentiated submucosal ulcerative cancers are included for ESD. This is a very large series of ESD within a relatively short time period (2003–2008). The experience provided by these authors is valuable for institutions planning ESD, and the lessons taken from this study are important. Complications related to ESD were perforations in 21 patients (4.2%) and bleeding in 7 patients (1.4%). This morbidity rate can be considered modest and within an acceptable level. The complete tumor resection (R0) rate was high: 96%. In 476 of 495 lesions, a R0 resection was achieved. The authors exclude undifferentiated, large, submucosal cancers, and this selection may explain the high R0 rate. In another recent study, the incomplete resection rate was high: 45% [3]. However, in this report undifferentiated, ulcerative, large submucosal cancer was included, confirming the limitations of ESD. The study by Ohnita et al. [1] is limited by the absence of follow-up, which is very important to define two major risks of ESD: local recurrence and nodal recurrence. It reconfirms how carefully the EGC patients should be selected. ESD achieves a better local control than EMR regarding deeper gastric wall resection margins. However, peripheral tumor margins and nodal residual disease should be considered for achieving oncological resection quality control. Prognosis of gastric cancer with adequate open or laparoscopic surgery is excellent for early gastric cancer [4, 5]. Quality control in surgery and multimodal adjuvant treatment can substantially improve survival rates even for patients with advanced resectable stage II or III disease [6–14]. Minimally invasive approaches represent substantial progress in improving the QOL of patients. The strict selection criteria are essential for safe oncological outcomes. If there is even a modest risk of incomplete resection by ES, then laparoscopic or open gastrectomy should be considered. Despite these developments, standardized open D2 surgery is the procedure of choice for advanced gastric cancer. An improvement in oncological outcomes of advanced gastric cancer should be the first priority of biomedical sciences, whereas QOL improvement remains a secondary goal when curability has been achieved. Recent advances C. Hottenrott (&) Chirurgische Klinik St. Elisabethenkrankenhaus Ginnheimer Strase 3, Frankfurt 60487, Germany e-mail: info@gastricbreastcancer.com

Impact of laparoscopic D2 gastrectomy on long-term survival for early gastric cancer

There has been a dramatic increase in the clinical use of laparoscopic gastrectomy for the treatment of early gastric cancer within a decade after its introduction in East Asia, particularly Korea [1]. There are several reasons that explain the rapid progress of laparoscopic D2 gastrectomy in Korea. These include the overall, high incidence of gastric cancer, the high rate of diagnosis at early stage, and the increasing number of high-volume hospitals and highvolume surgeons in laparoscopic gastrectomy in Korea. However, in an absence of both randomized, controlled trials and long-term, follow-up data, there is skepticism on a potential negative effect of laparoscopic gastrectomy on oncological outcomes. Lee et al. [2], in a recent issue of Surgical Endoscopy, reported on long-term results after laparoscopy-assisted distal gastrectomy (LADG) for early gastric cancer. This study comes to bridge the gap in the absence of long-term outcomes data. The authors analyzed the clinicopathologic data of 106 patients who underwent LADG and compared these results with those of 105 patients who underwent open distal gastrectomy (ODG) for early gastric cancer. The results on early postoperative outcomes are consisted with the literature and confirm the superiority of LADG vs. ODG regarding postoperative recovery, passing flatus, starting a liquid diet, and postoperative hospital stay and postoperative complications [3, 4]. The interest of this study is focused on long-term results. There was no significant difference in overall 5-year survival rate (5-YSR) between patients who underwent LADG (95.9%) and patients who had an ODG (94.9%). These survival results can be considered as excellent given that in the LADG group 6.6% of patients had lymph node metastasis and 37.7% of patients had a submucosal cancer, which both associated its less favorable survival than patients with mucosal and node-negative disease did. In Japan and Korea, two countries with high gastric cancer incidence and large experience with extended lymphadenectomy, open D2 gastrectomy has been the standard of care for localized gastric cancer. Compared with the treatment of gastric cancer in the west, results for early detection and survival are much better in Japan and Korea: 50% vs. \20% early-stage gastric cancer, and [60% vs. \40% overall survival after potential curative gastrectomy respectively in these two countries and western world [5, 6]. Two pivotal studies for advanced stage II/III gastric cancer from Japan have been published recently in the New England Journal of Medicine [7, 8]. The first phase III, adjuvant, randomized, controlled trial, compared D2 lymphadenectomy alone or D2 plus paraaortic nodal dissection (PAND). No patient received adjuvant treatment; Sasako et al. [7] reported the best global 5-year survival results of approximately 70% in both groups. Given that no survival benefit derived from D2 plus PAND, D2 surgery has been the standard approach. The second, a phase III adjuvant randomized trial compared D2 surgery alone vs. D2 surgery plus postoperative S-1 adjuvant chemotherapy. The study stopped due to a significant difference at 3-year survival rate in favor of S-1 chemotherapy in the planned interim analysis. D2 plus S-1 postoperative chemotherapy is the standard treatment for stage II/III gastric cancer in Japan. However, similar results, with exception survival of early gastric cancer [9, 10], have not yet been achieved in Europe or the United States. Indeed, in the west, although quality of surgery plays a predominant role for favorable D. Kanellos I. Kanellos (&) 4th Department of Surgery, Aristotle University of Thessaloniki, Thessaloniki, Greece e-mail: ik@hol.gr

Robotic D2 surgery for gastric cancer

Robotic D2 surgery for gastric cancer

Advanced gastric cancer: is laparoscopic gastrectomy safe?

As experience with laparoscopically assisted distal gastrectomy (LADG) for early gastric cancer substantially increased, particularly in Korea and Japan [1], it was expected that the next step would be laparoscopic treatment of advanced gastric cancer. Indeed, unsurprisingly, Hwang et al. [2] reported on LADG for advanced gastric cancer in a recent issue of Surgical Endoscopy. However, evidence of laparoscopic surgery’s safety for early gastric cancer in terms of oncologic outcomes still is lacking. Nevertheless, several large randomized controlled trials and metaanalyses have demonstrated that laparoscopic surgery is a more patient-friendly procedure than open colectomy, offering better early postoperative quality of life and having no negative effect on recurrence or the survival of patients with advanced stages of colon cancer [3]. These findings and the positive results of retrospective studies investigating LADG for early gastric cancer justify the current study’s evaluation of LADG’s safety and efficacy for advanced gastric cancer [1]. Both open D2 lymphadenectomy and laparoscopic gastrectomy require a surgeon’s experience and skill for safe and effective treatment of resectable gastric cancer [4]. Korea, a country with a high incidence of gastric cancer, has a long-term experience with open standardized extended D2 gastrectomy and perhaps the largest experience with laparoscopic D2 gastrectomy worldwide. Hwang et al. [2] from an academic Department of Surgery in Seoul performed LADG for 45 patients with advanced gastric cancer in 3 years (2004–2007), then compared their clinical and pathologic data with that for 83 patients who underwent open distal gastrectomy (ODG) during this same period. Although the operation time was longer for LADG than for ODG, there was no significant difference in morbidity or mortality between the two groups. The mean number of resected lymph nodes was similar in the two groups (35 in LADG vs 38 in ODG). During a mean follow-up period of 23 months, six patients with stage 3a/3b disease in the LADG group experienced recurrence This small retrospective study had several limitations and weakness. Although the mean follow-up period was too short for conclusions on oncologic outcomes to be drawn, the data presented by the authors are promising and encourage phase 2 randomized trials to assess the safety and efficacy of LADG for patients with advanced stages 2 and 3 cancer. Recently, two large confirmatory randomized trials with excellent survival results indirectly demonstrated the clinical utility of open D2 surgery in terms of long-term survival for patients with advanced stages 2 and 3 gastric cancer [5, 6]. In the West, evidence from positive randomized trials is lacking, and controversy still exists on the potential survival benefit of D2 gastrectomy [7–10]. Data still are too scarce to determine whether perioperative, preoperative only, or postoperative chemotherapy should be added to D2 or limited to D1 gastrectomy [11–13]. Given the important role of locoregional tumor control not only in recurrence-free survival but also in the overall survival of patients with solid tumors, including breast cancer, recent findings [14] indicate that every effort should be made to prevent local or nodal recurrence [15–17]. Can laparoscopic gastrectomy worsen the survival of patients with advanced gastric cancer? Despite skepticism T. Liakakos (&) E. P. Misiakos A. Macheras Third Surgical Department, University of Athens, Athens, Greece e-mail: theodlia@otenet.gr