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Multicentre,Prospective Study of First-Line Antibiotic Therapy for Early-Stage Low-Grade and High-Grade Gastric Mucosa-Associated Lymphoid Tissue-Type Lymphoma and Potential Predicting Factor for Treatment Outcome

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Gastric MALT Lymphoma

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Trial Information

Multicentre,Prospective Study of First-Line Antibiotic Therapy for Early-Stage Low-Grade and High-Grade Gastric Mucosa-Associated Lymphoid Tissue-Type Lymphoma and Potential Predicting Factor for Treatment Outcome

Background: Eradication of Helicobacter pylori (Hp) infection is well recognized as the
initial therapy for early-stage low-grade gastric mucosa-associated lymphoid tissue-type
lymphoma (lg-MALT lymphoma). On the other hand, high-grade transformed MALT lymphoma
(hg-MALT lymphoma) is generally considered to arise from Hp-independent clones and thus to
be unlikely to respond to antibiotic therapy. Our previous prospective studies have firstly
demonstrated that 1st-line antibiotic therapy could achieve durable complete histological
remission in two-third of Hp-positive stage IE hg-MALT lymphoma (Chen et al., J. Clin.
Oncol., 2001), in which the long-term clinical outcomes were equivalent to those achievable
in lg-MALT lymphoma (Chen et al. J Natl Cancer Inst, accepted). In addition, our laboratory
studies have confirmed that t(11;18) translocation is associated with loss of Hp-dependence
in lg-MALT lymphoma but infrequently found in high-grade tumors. We also found that nuclear
translocation of NF-kB or BCL-10 (by immunohistochemical, IHC, staining) were useful markers
to predict the Hp-dependence of both early-stage gastric hg- and lg-MALT lymphoma to
antibiotic therapy (Kuo et al. JCO 2004 & Yeh et al. Blood 2005). In addition, recent data
suggested cytochrome CYP2C18/19 genetic polymorphisms are associated with the metabolism of
omeprazole, and thus the genotype of such enzymes might affect the efficacy of antibiotics
for eradication of Hp infection.

Aims: A nationwide study to prospectively validate

1. The complete histological and molecular remission rate for antibiotics as 1st-line
therapy for Hp-positive early-stage gastric lg- and hg-MALT lymphoma

2. The durability of complete histological remission after antibiotics

3. The usefulness of pattern of NF-kB and BCL-10 by IHC staining in prospectively
predicting the Hp-dependence of gastric lg- and hg-MALT lymphoma

4. The frequency of t(11;18) translocation in gastric lg- and hg-MALT lymphoma in Taiwan.

5. The association between the CYP2C18/19 genetic polymorphisms and eradication of Hp
infection after antibiotics.

Materials and Methods: Patients with newly, histologically proven stage IE / IIE-1 gastric
lg- and hg-MALT lymphoma are eligible. Pre-treatment Hp infection status will be determined
by histology, rapid urease test and serology. At time of registration, patients should agree
to provide endoscopic biopsy specimen, including eight 4-mm histologic section for
immunohistochemical study of NF-kB and BCL-10 and three 10-mm of section in eppendorf tube
for RNA extraction and subsequent RT-PCR for t(11;18) translocation determination, which
will be performed at the central laboratory. In addition, serum (from 5 mL of coagulated
blood) as well as peripheral blood mononuclear cells (from 3 mL of heparized blood) will
also collected before treatment for Hp-serology and CYP 2C18/19 genetic polymorphism
detection, respectively. Hp-positive patients will receive 2-week of triple therapy,
consisting of omeprazole, amoxicillin and clarithromycin (OAC regimen), and have first
follow-up endoscopy 4 weeks later to determine the status of Hp infection and tumor
response. Patients will then have sequential follow-up endoscopic examinations every 3
months until complete histological remission (CR) or disease progression; then every 6
months for complete responders. Patients with hg-MALT lymphoma who have stable or
progressive disease after Hp eradication will immediately refer for systemic chemotherapy.
CR was defined as regression of lymphoid infiltration to Wotherspoon’s score <2 on all
pathological sections of endoscopic biopsy specimens. The predictive value of NF-kB, BCL-10
and t(11;18) for complete histological remission after Hp eradication will be determined.

Expected Results: 1st-line antibiotic therapy will achieve complete histologic remission in
70-80% of Hp-positive stage IE gastric lg-MALT lymphoma and in 50-60% of stage IE hg-MALT
lymphoma. The objective histologic CR rate in stage IIE-1 disease may be 30-40% for
low-grade tumor and 20-30% for high-grade ones. The sensitivity and specificity of NF-kB and
BCL-10 positive nuclear staining by IHC and of t(11;18) in predicting the Hp-independence
will be both 80 – 90%. Ten – twenty per cent of enrolled patients will have CYP2C19 m1/m1,
m1/m2 or m2/m2 genotypes (considered as omeprazole poor metabolizer), and they might have
higher Hp eradication rate than those extensive metabolizers .

Inclusion Criteria:

- The patients must have histologically confirmed primary gastric MALT lymphoma with or
without clustering large cells (extranodal marginal zone lymphoma, and diffuse large
cell lymphoma with features of MALT by REAL/WHO classification, Harris NL et al.

- 1.1 The diagnosis of primary gastric lymphoma must fulfill the criteria of
Dawson [38].

- (1)No enlargement of peripheral or mediastinal lymph node;

- (2)Peripheral blood smear revealing no leukemic or lymphomatous

- (3)Predominant of alimentary tract lesions with any adenopathy
corresponding to accepted lymphatic drainage route; and

- (4)No involvement of liver or spleen except by extension of contiguous

- 1.2 The diagnosis of MALT lymphoma will be made by histopathologists from
individual hospitals, in accordance with criteria defined by Isaacson et al. and
Chang et al, and will be reviewed by the members of the TCOG Pathology
Committee. This pathology review mechanism had been functioned well in the
previous T1296 study (see J Natl Cancer Inst. 2005;97:1345-53)

- 1.3 The patient must have no prior chemotherapy or radiotherapy for his/her
gastric lg- or hg-MALToma.

- Patients must have evaluable disease by endoscopy and/or the nodal status by computed
tomography. Endoscopic ultrasonography (EUS) is mandatory to evaluate the depth of
tumor infiltration and for status of perigastric lymph node enlargement.

- Patients must have documented H. pylori infection before treatment, which will be
evaluated by the following tests: histology, rapid urease test (CLO-test), C-13
urease breath test and serology.

- 3.1 The following will be considered to have H. pylori infection: if any of
above 4 tests show positive result.

- Patients must have either stage IE or IIE-1 disease, according to an adaptation of
the Ann Abor staging system modified by Musshoff for primary extranodal lymphoma.

- 4.1 Stage IE : lymphoma confined to the gastric wall without lymph node

- 4.2 Stage IIE : localized involvement of one or more GI site(s) on one side of
the diaphragm with lymph node involvement, any depth of lymphoma infiltration
into the gut wall. 4.21 Stage IIE-1: involvement of perigastric lymph node. 4.22
Stage IIE-2: abdominal, but beyond perigastric, lymph nodal involvement.

- Patient must have signed the informed consent and agree to provide achieved
pathologic material for immunohistochemical study and for RT-PCR t(11;18)(q21;q21)

Exclusion Criteria:

- Patients with extensive gastrointestinal tract involvement are not eligible.

- Patients with previous history of extranodal lymphoma are not eligible.

- Patients with stage IIE-2 or beyond disease: infiltration of regional lymph node,
e.g. paraaortic, renal hilar, retroperitoneal, mesenteric, or lymph node of
gastrosplenic ligament and of hepatoduodenal ligament; or involvement of lymph node
above and below diaphragm (Stage III) or other visceral organ involvement (stage IV)
are not eligible.

- Patients with cardiopulmonary status that do not allow repeat endoscopy are not

- Patients with prior antibiotics, chemo- or radiotherapy for their gastric lymphoma
are not eligible.

- Patients who had previous anti-H. pylori therapy and without pretreatment pathology
achieve material for histological review and immunohistochemical study are not

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Hp eradication rate and complete histological rate

Principal Investigator

Jaw-Town , Lin, M.D., PHD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Taiwan cooperative oncology group


Taiwan: Department of Health

Study ID:




Start Date:

July 2006

Completion Date:

December 2014

Related Keywords:

  • Gastric MALT Lymphoma
  • Early-stage Lg/Hg Gastric MALT Lymphoma
  • Eradication of Helicobacter pylori (Hp)
  • Lymphoma
  • Lymphoma, B-Cell, Marginal Zone