Accepted Manuscript Gastric Cancer Adjuvant Therapy Prof. Dr. med. Florian Lordick, MD, Professor, Masanori Terashima, MD, Professor
PII:
S1521-6918(16)30046-4
DOI:
10.1016/j.bpg.2016.06.006
Reference:
YBEGA 1441
To appear in:
Best Practice & Research Clinical Gastroenterology
Received Date: 29 February 2016 Revised Date:
19 June 2016
Accepted Date: 23 June 2016
Please cite this article as: Lordick F, Terashima M, Gastric Cancer Adjuvant Therapy, Best Practice & Research Clinical Gastroenterology (2016), doi: 10.1016/j.bpg.2016.06.006. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Gastric Cancer Adjuvant Therapy
Florian Lordick, MD, Professor1, Masanori Terashima, MD, Professor2
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University Cancer Center Leipzig (UCCL), University Hospital Leipzig, Liebigstr. 20, 4103 Leipzig, Germany; Tel.: +49(0)3419712560, Fax: +49(0)3419712569; Email:
[email protected]
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Corresponding author: Prof. Dr. med. Florian Lordick University Cancer Center Leipzig (UCCL) University Hospital Leipzig Liebigstr. 20 04103 Leipzig, Germany Tel.: +49(0)3419712560 Fax: +49(0)3419712569; Email:
[email protected]
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Division of Gastric Surgery, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi-cho, Suntogun, Shizuoka 411-8777, Japan; Tel.: +81- 55-989-5222. Fax: +81- 55-989-5551; E-mail:
[email protected]
ACCEPTED MANUSCRIPT Abstract
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From a global perspective, gastric cancer is one of the most common and lethal forms of cancer. The incidence of gastric cancer is very high in East Asia and varies considerably in countries of the Western hemisphere. Even after curative resection, the relapse rates are high in stages II and III. Therefore, adjuvant treatment with chemotherapy has been studied with positive results, especially in East Asian populations. In the Western World, where many locally advanced and borderline resectable gastric cancers are diagnosed, perioperative chemotherapy has become a standard of care. Perioperative chemotherapy increases the chances for curative resection. The additional role of radiation therapy, either in the neoadjuvant or in the adjuvant setting, needs to be defined by studies with a quality assurance for all treatment modalities.
Key words
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Gastric cancer, adjuvant, chemotherapy, chemoradiotherapy
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Gastric cancer (GC) is a global health problem. Almost one million new cases of GC have occurred in 2012 (952,000 cases, 6.8% of the total cancer diagnoses), making it the fifth most common malignancy in the world. GC is the third leading cause of cancer death in both sexes worldwide (723,000 deaths, 8.8% of the total). The highest estimated mortality rates are in Eastern Asia, the lowest in Northern America. High mortality rates are also present in both sexes in Central and Eastern Europe, and in Central and South America [1]. While non-cardia GC is more prevalent in East Asia, Central-East Europe, Latin America and Africa, gastroesophageal junction (GEJ) cancers are more prevalent in Western Europe, North America and Australia [2]. We’ll focus in this article on non-cardia gastric cancer. The prognosis of GC after complete resection is stage dependent, the most critical factor being the depth of tumor infiltration and lymph node involvement [3,4,5].
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Reports from the Memorial Sloan Kettering Cancer Center in New York, USA indicate that even after adequate GC resection including D2 lymphadenectomy, locoregional control is not easily achieved. Among the documented recurrences, 79% were detected within 2 years of operation. Locoregional sites were involved as any part of the recurrence pattern in 199 of 367 patients (54%) (Figure 1) [6]. This observation could be interpreted as a justification for the use of postoperative chemoradiation. However, locoregional failure was often associated with distant (hematogenous) relapse and / or with peritoneal carcinomatosis which calls the value of any adjuvant locoregional treatment into question. The pattern of first relapse was reported in a different way in the Japanese Adjuvant Chemotherapy for Gastric Cancer (ATCS-GC) study, but indicates that locoregional failure is also observed in patients treated in Japan: of 188 relapses that occurred in the surgery alone group, 15 were local (8%), 46 involved the lymph nodes (24%) and others involved the peritoneum (84 patients, 45%) or hematogenous distant sites (60 patients, 32%). Some patients had a first relapse at more than one site [7].
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Novel biology oriented GC classification systems indicate a prognostic role impact of specific molecular and genomic alterations [8,9]. While microsatellite-instability (MSI) is associated with a more favorable prognosis, microsatellite stability (MSS) together with a mesenchymal-like (EMT) gene expression pattern confers a very poor prognosis. The tumor protein 53 (TP53)-active and TP53inactive types include patients with intermediate prognosis and recurrence rates (with respect to the other two subtypes: MSI and MSS/EMT), with the TP53-active group showing a better prognosis [9]. Differences in relapse patterns of these molecularly defined subtypes have not yet been reported. But this might be important for guiding future adjuvant clinical research approaches. Traditionally, adjuvant therapy for GC has been developed in a different way in the Western and Eastern medical countries. While in the U.S. an adjuvant chemoradiation approach is now the recommended standard of care for stage IB to resectable stage IV M0 GC [10], European guidelines recommend perioperative chemotherapy for all resectable stage II and stage III cancers [11] and Japanese guidelines recommend adjuvant chemotherapy with S1 for 1 year for resected GC in stages IIA, IIB, IIIA, IIIB, or IIIC [12]. Survival outcomes differ across geographical regions, with overall 5-year survival rates being 10%–15% in North America and 45%–50% in East Asia. These differences can be explained by improved early diagnosis in some Asian countries and by skilled clinical management; but they persist even after stratifying for disease stage [13]. A recent investigation of >1600 GCs revealed that tumor immunity signatures differ significantly between Asian and non-Asian GCs. NonAsian gastric cancers were associated with enrichment of tumor infiltrating T-cells as well as T-cell
ACCEPTED MANUSCRIPT gene expression signatures, including CTLA-4 signaling. Exploratory analysis suggests that these tumor immunity differences may contribute to geographical differences in clinical outcomes [14]. As the biology, outcome and traditional management differ considerably between Western and Eastern patients with localized GC, we deemed it appropriate to discuss them separately.
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The Western approach U.S. adjuvant chemoradiation
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A convincing survival benefit was shown for adjuvant chemoradiotherapy in the landmark U.S. Southwest Oncology Group (SWOG)/Intergroup 0116 study [15]. A total of 556 patients with resected adenocarcinoma of the stomach or gastroesophageal junction were randomly assigned to surgery plus postoperative chemoradiotherapy or surgery alone. The adjuvant treatment consisted of 425 mg/m2 of fluorouracil per day, plus 20 mg/m2 of leucovorin, for five days, followed by 45 Gray (Gy) of radiation at 1.8 Gy per day, given five days per week for five weeks, with modified doses of fluorouracil and leucovorin on the first four and the last three days of radiotherapy. One month after the completion of radiotherapy, two five-day cycles of fluorouracil (425 mg/m²) plus leucovorin (20 mg/m²) were given one month apart. The median overall survival in the surgery only group was 27 months, as compared with 36 months in the chemoradiotherapy group; the hazard ratio for death was 1.35 (95 percent confidence interval, 1.09 to 1.66; P=0.005). The hazard ratio for relapse was 1.52 (95 percent confidence interval, 1.23 to 1.86; P
