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Methylene Blue-Assisted Technique for Harvesting Lymph Nodes after Radical
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Surgery for Gastric Cancer: A Prospective Randomized Phase III Study
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Primary Investigators
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Toru Aoyama and Takaki Yoshikawa
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Department of Gastrointestinal Surgery, Kanagawa Cancer Center
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0. Summary
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Specimen after gastrectomy
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Stratification factors:
・type of gastrectomy
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(distal/total)
・extent of lymph node dissection
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(D1+/D2)
Randomized
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Methylene Blue-Assisted Technique
Standard methods
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Primary end point：the ratio of the number of harvested lymph nodes to time (minutes)
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Secondary end point：the number of harvested lymph nodes
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1. Aim
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The purpose of this study was to confirm the efficiency of the methylene
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blue-assisted
technique
in
harvesting
LNs
after
gastrectomy
with
radical
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lymphadenectomy for gastric cancer in comparison to the standard approach using fresh
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samples.
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Primary end point：the ratio of the number of the harvested lymph nodes to time
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(minutes)
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Secondary end point：the number of harvested lymph nodes
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2. Background
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Gastric cancer is the second most frequent cancer-related cause of death
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following lung cancer1. Surgical resection with radical lymphadenectomy is the
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standard treatment when the gastric cancer is local. The treatment strategy is determined
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based on the pathological diagnoses of tumor invasion and lymph node metastasis. The
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TNM classification recommends conducting a nodal examination of at least 16 or more
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regional lymph nodes (LNs) when determining the N factor2.
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Nodal sampling of specimens is influenced by the physician’s experience,
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extent of dissection, type of gastrectomy and method used to harvest the LNs. Usually,
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surgeons harvest LNs from fresh specimens immediately after surgery in Japan, while
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pathologists in other countries harvest LNs from specimens fixed with formalin after
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surgery3. Although surgeons may be more enthusiastic about harvesting LNs than
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pathologists, it is difficult to perform this work immediately after surgery. On the other
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hand, nodal sampling can be difficult for pathologists who are not familiar with surgical
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anatomy. Moreover, tissues fixed with formalin are hard and difficult to separate; thus,
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nodal sampling is time-consuming work for most pathologists.
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The methylene blue-assisted technique is an alternative approach for harvesting
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LNs. The specimens are fixed with formalin containing methylene blue after surgery,
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thus allowing physicians to easily identify LNs stained with blue dye. Märkl reported
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that the methylene blue-assisted technique for colon cancer is significantly superior to
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the conventional method using samples fixed with formalin4. Several Japanese surgeons
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have reported the efficacy of this method in single-arm gastric cancer studies
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remains unclear whether the methylene blue-assisted technique is superior to the
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Japanese standard method using fresh samples in patients with gastric cancer.
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. It
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3. Patients and methods
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3.1 Eligibility criteria
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The tumors will be staged according to the Japanese classification of gastric
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carcinoma 3rd English edition7. The inclusion criteria are:
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(i) Histologically proven adenocarcinoma of the stomach.
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(ii) Clinical stage 1-3 disease.
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(iii) R0 resection achieved via gastrectomy with D1+ or D2 lymphadenectomy as a
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primary treatment according to the Japanese gastric cancer treatment guidelines, 2010
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(ver. 3) 8.
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Patients who receive any other treatment before surgery will be excluded.
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3.2 Surgery
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Patients with gastric cancer will undergo distal or total gastrectomy with
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radical lymphadenectomy. The extent of dissection will principally follow the third
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edition of the Gastric Cancer Treatment Guidelines published by the Japanese Gastric
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Cancer Association8. Spleen-preserving D2 total gastrectomy is permitted in this study.
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3.3 Harvesting lymph nodes and methylene blue staining
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In the standard group, the LNs will be harvested from the specimen
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immediately after surgery. In the methylene blue group, the specimens will be fixed
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with 10% buffered formalin with methylene blue for 48 hours after surgery. Then, the
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LNs will be harvested from the specimens.
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3.4 Registration
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Surgeons will register the eligibility criteria with the data center following
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confirmation during surgery. The patients will be randomized and assigned to the
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standard group or the methylene blue-assisted group using a centralized dynamic
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method based on the following factors: lymphadenectomy (D1+/D2), type of
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gastrectomy (subtotal/total) and surgical experience (less than 15 years/15 years or
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more). The accrual was started in August 2012 and will continue for one year.
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3.5 Qualifications of the participating surgeons
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The surgeons harvesting LNs in this study are limited to those who have
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performed at least 50 or more procedures of harvesting LNs for gastric cancer.
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3.6 Statistical methods
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The present study is a randomized phase III study performed to evaluate the
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efficiency of the methylene blue-assisted lymph node technique for harvesting LNs after
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surgery for gastric cancer. The primary end point is the ratio of the number of harvested
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LNs to time (minutes). A 25% reduction in the ratio of harvested lymph nodes/time
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(minutes) is necessary for this test treatment, considering the balance between the cost
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and benefits. Retrospective data obtained from this institution were used to estimate the
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ratio of the number of harvested LNs to time (minutes) in the control arm to be 40 per
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30 minutes. A 25% risk reduction in the test arm is expected, with a rate of 40 per 22.5
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minutes in the test arm. These conditions will require a sample size of 52 patients, with
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26 patients per arm to ensure a two-sided alpha error of 5% and a statistical power of
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80%. A total of 60 patients will be recruited due to the likelihood of enrolling ineligible
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patients.
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References
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1. Ohtsu A, Yoshida S, Saijo N. Disparities in gastric cancer chemotherapy between the
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East and West. J Clin Oncol 2006; 24: 2188-2196.
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2. Sobin LH, Gospodarowicz MK, Wittekind Ch, International Union Against Cancer.
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TNM Classification of Malignant Tumors. 7th ed. Oxford, UK: Wiley-Blackwell; 2009.
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3. Bunt AM, Hermans J, van de Velde CJ, Sasako M, Hoefsloot FA, Fleuren G, et al.
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Lymph node retrieval in a randomized trial on western-type versus Japanese-type
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surgery in gastric cancer. J Clin Oncol. 1996; 14: 2289–94.
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4. Märkl B, Kerwel TG, Jähnig HG, Oruzio D, Arnholdt HM, Schöler C, et al.
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Methylene blue-assisted lymph node dissection in colon specimens: a prospective,
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randomized study. Am J Clin Pathol 2008; 130: 913-9.
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5. Isozaki E, Okajima K, Fujiwara A, Yasuda M, Yamada S, Mizutani H, et al. A study
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of lymph node-metastases of gastric cancer using the methylene blue formalin fixing
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method. Rinsho Shinkeigaku 1986; 26: 710-716 [Article in Japanese].
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6. Kurosu Y, Isozumi M, Aoki N, Ishikawa S, Isgii I, Tanjo K, et al. Study on lymph
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node metastasis of cancer using the methylene blue formalin fixing method. J Nihon
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Univ Med Ass 1987; 46: 1057-1059 [Article in Japanese].
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7. Japanese Gastric Cancer Association. Japanese classification of gastric carcinoma:
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3rd English edition. Gastric Cancer 2011; 14: 101-12.
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8. Japanese Gastric Cancer Association. Japanese gastric cancer treatment guidelines
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2010 (ver. 3). Gastric Cancer 2011; 14: 113-23.