Background: Worldwide, almost one million new cases of stomach cancer were diagnosed in 2012, making it the fifth most common cancer, and the third leading cause of cancer deaths. The current tumor node metastasis (TNM) staging system represents a consensus between the East and the West, and will serve as a strong foundation upon which to build future evidence. In this review article, we first discuss the definition and optimal surgery for locally advanced gastric cancer, followed by the general principles when considering a pre vs . postoperative radiotherapy (RT) strategy. We then provide a synthesis of the existing randomized trial evidence in an attempt clarify the role of pre and postoperative RT in the management of locally advanced gastric cancer.
 Methods: A Medline search 1966-Jun 2014 was undertaken. Randomized trials including patients with locally advanced gastric cancer (using established definitions), comparing RT [with or without chemotherapy (CT)], with surgery alone or other treatment modalities were included. Systematic reviews and evidence based practice guidelines that include this body of primary studies were preferentially discussed. Medline, Cochrane Library, Clinicaltrial.gov, Guidelines Clearinghouse were searched.
 Results: Sixteen randomized trials, three systematic reviews and one practice guideline were included as the evidence base. In this group of studies, two reports compared postoperative chemoradiotherapy (CRT) with surgery alone. Driven predominantly by INT0116, they established the role of postoperative CRT to provide a survival benefit in a patient group that underwent surgery with predominantly D0-1 dissections. Preoperative RT (four studies) showed promise for survival benefit but the risks of bias in these trials were high. Postoperative CRT compared with CT alone (eight trials) showed no survival benefit with the addition of radiation although some evidence of activity can be observed with improved local regional control.
 Conclusions and future directions: Technical expertise to enable the delivery of high quality RT to complex target volumes as is required in gastric cancer, and surgical standards to ensure the delivery of high quality surgery, have matured in recent years. Six trials with large sample sizes are currently ongoing to better define the role of preoperative CRT (two studies) and postoperative CRT (four studies), when used in conjunction with high quality surgery and RT, and contemporary CT regimens. The moderate likelihood of locoregional recurrences and the favorable therapeutic ratio with using RT preoperatively in other settings, provide optimism that preoperative CRT would have a pivotal role to play in locally advanced gastric cancer. Active accrual into ongoing trials is strongly encouraged.

/pdf/postoperative-chemoradiotherapy-vs-preoperative-8l2m4fz041.pdf

Postoperative chemoradiotherapy vs . preoperative chemoradiotherapy for locally advanced (operable) gastric cancer: clarifying the role and technique of radiotherapy

Purpose We retrospectively analyzed the impact of intraoperative radiation therapy (IORT) on long-term survival in patients with resectable gastric cancer. Methods and Materials From 1991 to 2001, a total of 84 patients with gastric neoplasms underwent gastectomy or subtotal resection with IORT (23 Gy, 6–15 MeV; IORT-positive [IORT + ] group). Patients with a history of additional neoadjuvant chemotherapy, histologically confirmed R1 or R2 resection, or reoperation with curative intention after local recurrence were excluded from further analysis. The remaining 61 patients were retrospectively matched with 61 patients without IORT (IORT-negative [IORT − ] group) for Union Internationale Contre le Cancer (UICC) stage, patient age, histologic grading, extent of surgery, and level of lymph node dissection. Subgroups included postoperative UICC Stages I ( n = 31), II ( n = 11), III ( n = 14), and IV ( n = 5). Results Mean follow-up was 4.8 years in the IORT + group and 5.0 years in the IORT − group. The overall 5-year patient survival rate was 58% in the IORT + group vs. 59% in the IORT − group ( p = 0.99). Subgroup analysis showed no impact of IORT on 5-year patient survival for those with UICC Stages I/II (76% vs. 80%; p = 0.87) and III/IV (21% vs. 14%, IORT + vs. IORT − group; p = 0.30). Perioperative mortality rates were 4.9% and 4.9% in the IORT + vs. IORT − group. Total surgical complications were more common in the IORT + than IORT − group (44.3% vs. 19.7%; p + group. Conclusions Use of IORT was associated with low locoregional tumor recurrence, but had no benefit on long-term survival while significantly increasing surgical morbidity in patients with curable gastric cancer.

Long-term results after intraoperative radiation therapy for gastric cancer.

Pattern of failures in gastric cancer patients with lymph node involvement treated by surgery, intraoperative and external beam radiotherapy.

Introduction:
It has been recently shown that the WISP proteins(Wnt-inducted secreted proteins), a group of intra- and extra-cellular regulatory proteins, have been implicated in the initiation and progression of variety types of tumours including colorectal and breast cancer. However, the role of WISP proteins in gastric cancer (GC) cells and clinical implication in gastric cancer has not yet been fully
elucidated.

Materials and methods:

The expression of the WISP transcript and proteins in a cohort of GC patients was analysed using real-time quantitative PCR and immunohistochemistry, respectively. The expression of a panel of recognised EMT (epithelial-mesenchymal transition) markers were quantified (Q-PCR) in paired tumour and normal gastric tissues. WISP-2 knockdown sublines using anti-WISP-2 ribozyme transgenes were created in GC cell lines AGS and HGC27. Using the cell models and proteins extracted from gastric tissue samples, protein microarray was used to search for potential protein partners and signalling pathways involved with WISP-2. Subsequently, the biological functions, namely, cell growth, adhesion, migration and invasion, were studied. Potential mechanisms related with EMT, extracellular matrix and MMP (Matrix metalloproteinases) and signalling pathways
were investigated.

Results:

Expression of WISP-2 was frequently detected in GC tissues. Levels of WISP-2, not WISP-1 and WISP-3, was significantly correlated with early TNM staging and differentiation status. High levels of WISP-2 were associated with a favourable clinical outcome and survival of the patients. We also found that WISP-2 expression inversely correlated with Twist and Slug in the paired gastric samples. Knockdown of WISP-2 expression increased the rate of proliferation, migration and invasion of GC cells and influenced expression of EMT biomarkers including Twist, Slug and Ecadherin.Using an antibody based protein microarray, ERK, JNK as well as AKT proteins were
found to be co-precipiated with WISP-2 protein from human gastric tissue proteins. Furthermore, WISP-2 knockdown gastric cell lines also demonstrated a change in the ERK and JNK phophorylation. Mechanistically, WISP-2 suppressed GC cell metastasis through reversing epithelial-mesenchymal transition and suppressing the expression and activity of MMP-9 and MMP-2 via JNK and ERK. Cell motility analysis indicated that WISP-2 knockdown contributed to GC cells’ motility, an effect attenuated by PLC-γ and JNK small inhibitors.

Conclusions:
WISP-2 transcript and protein expressions are inversely linked to disease progression and linked to the survival of patients with gastric cancer. WISP-2 has a profound influence on the migration and adhesion of gastric cancer cells and is a powerful factor to reverse the EMT process in these cells. These effects of WISP-2 are via its involvement in the ERK and JNK pathways, which in turn modulate the MMP activities. Together, WISP-2 is an important regulator of the cellular function and an important factor in the progression of gastric cancer. It acts as a potential tumour suppressor in gastric cancer.

The role of Wnt-induced secreted proteins (WISPs) in gastric cancer

Patients with gastric carcinoma remain at high risk for local and systemic relapses, even after a successful surgery (R0 resection). To reduce the rate of relapse and increase cure rates, several clinical adjuvant trials have been reported. Only a few studies have reported positive results and most have failed to demonstrate any benefit for the treated patients. The trials with positive results from chemotherapy or chemoimmunotherapy have not gained global acceptance. The Intergroup 0116 trial has gained acceptance in North America, but it has not been accepted globally. In North America, where gastric surgery is often less than optimal, the Intergroup 0116 trial has provided evidence of benefit in overall survival time and time-to-cancer progression for patients treated with postoperative chemoradiotherapy. This trial recruited 556 patients with resected gastric cancer from stage IB through IV and an R0 resection was mandatory for registration. The results of this trial have spurred many other studies and controversies. In our opinion, all of the patients in the West who have had a curatively resected node-positive gastric carcinoma (R0 resection) should be offered an option of receiving postoperative chemoradiotherapy.

Gastric cancer: advances in adjuvant and adjunct therapy.

In order to evaluate the role of adjuvant IORT in the treatment of resectable gastric carcinoma, we carried out a randomized trial comparing surgery and surgery+adjuvant IORT. The study included 115 patients within a 74-month period, 51 of them received a single application of 28 Gy to the celiac axis. Patients were comparable with regard to age, sex, tumor stage and operative morbidity. The difference in mean survival time (IORT: 26.9 months vs. non-IORT, 30.8 months) and tumor-related death in the long-term course (mean follow-up period 29.2 months) with 29.4% (15/51) in the IORT-treated patients vs. 31.2% (20/64) in non-irradiated patients did not reach significance.

Adjuvant intraoperative radiotherapy of stomach carcinoma

Early Results of IORT in the Treatment of Gastric Cancer

Intraoperative Strahlentherapie inklusive Afterloadingverfahren in der gastrointestinalen Chirurgie

Implications of Vasomotor Reactions for a Combined Oncotherapy Including IORT

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Adjuvant intraoperative radiotherapy of stomach carcinoma

Early Results of IORT in the Treatment of Gastric Cancer

Intraoperative Strahlentherapie inklusive Afterloadingverfahren in der gastrointestinalen Chirurgie

Implications of Vasomotor Reactions for a Combined Oncotherapy Including IORT