Radiotherapy for Localized Gastric MALT Lymphoma: An Over 10.Year Single Institutional Retrospective Review

Atsuto Katano; Hideomi Yamashita; Keiichi Nakagawa

doi:10.4103/joah.joah_194_20

ORIGINAL ARTICLE

Year : 2021 | Volume : 12 | Issue : 3 | Page : 153-157

Radiotherapy for Localized Gastric MALT Lymphoma: An Over 10.Year Single Institutional Retrospective Review

Atsuto Katano, Hideomi Yamashita, Keiichi Nakagawa
Department of Radiology, The University of Tokyo Hospital, Tokyo, Japan

Date of Submission	09-Oct-2020
Date of Decision	06-Mar-2021
Date of Acceptance	13-Mar-2021
Date of Web Publication	21-Oct-2021

Correspondence Address:
Dr. Atsuto Katano
7-3-1 Hongo, Bunkyo-Ku, Tokyo 113-8655
Japan

Source of Support: None, Conflict of Interest: None

Check

DOI: 10.4103/joah.joah_194_20

Abstract

BACKGROUND: MALT lymphoma is very slow progressive and low relapse rate, long-term follow-up is very important. However, there are limited reports of long-term observational study of MALT lymphoma.
MATERIALS AND METHODS: A retrospective review was conducted on a total of 54 consecutive patients who were treated for localized gastric MALT lymphoma with radiotherapy from January 2007 to December 2019. Clinical staging was performed in reference and according to the Lugano Modification of Ann Arbor Staging System. The prescribed dose was 30 Gy with 15 or 20 fractionations.
RESULTS: In the entire cohort, there were 30 males and 24 females with a median age of 64 years (range: 37–81 years). The median follow-up period was 38.1 months (range: 3.6–145 months), and there were no patients who died within the observation period, according to their medical records. All patients achieved a complete response, as proven by the biopsies conducted. Forty-eight patients (89%) achieved a complete response at the first biopsy after radiotherapy, 5 (9.2%) at the second time, and 1 (1.8%) at the fourth time. No patient had experienced locoregional recurrence; however, 3 patients did develop distant disease progression during the observation period. The 5- and 10-year progression-free survival rates were 93.4% (95% confidence interval (CI): 75.8%–98.3%) and 86.7% (95% CI: 61.7%–95.9%), respectively. No patient exhibited any Grade 3-5 late radiation-induced acute or late toxicity.
CONCLUSION: This retrospective analysis clarified a clinical outcome of gastric MALT lymphoma treated by radiotherapy.

Keywords: MALT lymphoma, radiotherapy, retrospective analysis, treatment

How to cite this article:
Katano A, Yamashita H, Nakagawa K. Radiotherapy for Localized Gastric MALT Lymphoma: An Over 10.Year Single Institutional Retrospective Review. J Appl Hematol 2021;12:153-7

How to cite this URL:
Katano A, Yamashita H, Nakagawa K. Radiotherapy for Localized Gastric MALT Lymphoma: An Over 10.Year Single Institutional Retrospective Review. J Appl Hematol [serial online] 2021 [cited 2023 Sep 27];12:153-7. Available from: https://www.jahjournal.org/text.asp?2021/12/3/153/328720

Introduction

Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) is an indolent, extranodal B-cell lymphoma that was proposed by Isaacson and Wright in 1983.^[1] Marginal zone lymphoma (MZL) accounts for approximately 10% of all non-Hodgkin's lymphoma, with MALT lymphoma being the most common subtype of MZL followed by nodal MZL and splenic MZL.^[2] MALT lymphoma frequently develops in the gastrointestinal tract, ocular adnexa, thyroid gland, salivary glands, and lungs but most often develops in the stomach.^[3]

While gastric MALT lymphoma normally does not cause any symptoms, nonspecific signs could include fatigue, nausea, vague dyspepsia, epigastric pain, and abdominal discomfort.^[4] This type of lymphoma is a slow-growing, rarely-fatal disease; however, in rare instances, it could invade other organs or develop into a more aggressive form of lymphoma. It is believed that the pathogenesis of MALT lymphoma is correlated with chronic irritation that is caused by an infection or inflammation.^[5] Helicobacter pylori (H. pylori) infection in gastric MALT lymphoma is well-known, and the eradication is first-line therapy for positive infection cases. A meta-analysis containing information on 1408 patients from 32 studies showed that complete remission of gastric MALT lymphoma is achieved in about 78%.^[6] In patients treated with eradication therapy, 5-year overall survival (OS) and disease-free survival rates are 90%–95% and 70%–80%, respectively.^[7] Moreover, H. pylori-negative localized MALT lymphoma was also treated by eradication therapy with moderate clinical outcome.^[8] A systematic review reported the remission rate was 15.5% after eradication therapy in H. pylori-negative patients.^[9]

Radiotherapy is a useful treatment modality for H. pylori-negative or eradication-resistant cases of gastric MALT lymphoma. Although the chances of remission are high, there is still a likelihood of cancer recurring later in life.^[10],[11] The purpose of this study was to evaluate the feasibility and efficacy of radiotherapy for gastric MALT lymphoma. Since it is believed that long-term observations yield more accurate results, we decided to conduct our retrospective observation study for over 10 years.

Materials and Methods

We included consecutive patients with localized gastric MALT lymphoma treated by curative radiotherapy in our institution from January 2007 to December 2019. This study was performed in accordance with the guidelines approved by the institutional review board in our hospital. Written informed consent was obtained from all the patients. Clinical staging was performed according to the Lugano Modification of Ann Arbor Staging System.^[12] The staging procedures have included physical examination, contrast-enhanced computed tomography (CT), endoscopic procedure positron emission tomography, and/or bone marrow biopsy. All patients enrolled in this study satisfied the following eligibility criteria: (a) histologically confirmed MALT, (b) treated using radiotherapy with curative intent, (c) no distant metastasis, and d) no history of previous radiotherapy to the stomach. The medical follow-up includes medical history, physical examination, and imaging studies. Endoscopic biopsy was typically performed every year. Acute and late adverse events were graded in accordance with the criteria of the National Cancer Institute Common Toxicity Criteria for Adverse Events, version 5.0.

Radiotherapy was administered with the three-dimensional conformal radiotherapy (3D-CRT) or intensity-modulated radiation therapy (IMRT). The planning CT image data were reconstructed in slice thickness of 5 mm for the 3D-CRT and in 2 mm for the IMRT. These data were then sent to Pinnacle (Philips), a treatment planning system. The prescribed dose was 30 Gy with 15 or 20 fractionations. The clinical target volume (CTV) was determined for the entire stomach. The internal target volume (ITV) was configured by considering the CTVs of free-breathing inhalation and end-exhalation. The planning target volume was configured considering daily set-up margin to ITV of typically 5 mm. No patient had received prophylactic clinically negative lymph node irradiation.

All analyses were performed with the R statistical package (The R Foundation for Statistical Computing, Vienna, Austria). The OS and progression-free survival (PFS) rates were measured from the first day of radiation therapy. The OS rate was calculated by the Kaplan–Meier method using the Log-Rank test. P < 0.05 is considered statistically significant.

Results

There were 54 patients, 30 males and 24 females, who were retrospectively analyzed in this study with a median age of 64 years (range: 37-81 years). The patient characteristics for each group are showcased in [Table 1]. The majority of patients (96%) had a good Karnofsky Performance Scale (90–100), and the clinical stage was predominantly stage I (96%). Three patients had no records of serum lactate dehydrogenase (LDH) activity before radiotherapy. According to the MALT international prognostic index (MALT-IPI) proposed by Thieblemont,^[13] 27 patients (50%) were classified as low risk, 21 patients (39%) were at intermediate risk, and 3 patients (6%) were at high risk.

Table 1: Characteristics of 54 mucosa-associated lymphoid tissue patient treated by radiotherapy in our institution

Click here to view

Table 2: Acute radiation-related adverse event during the treatment of mucosa-associated lymphoid tissue by radiotherapy

Click here to view

At the time of analysis, 42 patients (78%) were alive and 12 patients (22%) were lost to follow-up. The median follow-up period for the entire cohort was 38.1 months (range: 3.6-145 months), and no patient in the present study was medically recorded as deceased [Figure 1]. All patients achieved biopsy-proven complete response (CR), with a median time of 4.2 months (ranging 1.3–38.1 months) [Figure 2]. In the entire cohort, 48 patients (89%) achieved CR at first-time biopsy after radiotherapy, 5 (9.2%) at the second time, and 1 (1.8%) at the fourth time when it was 38.1 months after radiotherapy.

Figure 1: Kaplan–Meier analysis of overall survival in our study. A vertical line indicates a censored patient

Click here to view

Figure 2: Cumulative incidence of biopsy-proven complete response in the gastric MALT lymphoma treated by radiotherapy

Click here to view

Three patients developed disease progression at the distant site [Table 3], while no patients developed loco-regional recurrence. One of the three relapsed patients had progressed disease in conjunctival lymphoma 6.3 years after the initial radiotherapy, the second patient had pulmonary lymphoma 3.3 years after the initial radiotherapy, and the third developed lymphoma at the inguinal node 2.6 years after the initial radiotherapy. The 5-and 10-year PFS rates were 93.4% (95% confidence interval (CI): 75.8%–98.3%) and 86.7% (95% CI: 61.7%–95.9%), respectively [Figure 3].

Table 3: The characteristics of the 3 recurrent mucosa-associated lymphoid tissue patients after radiotherapy

Click here to view

Figure 3: Kaplan-Meier analysis of progression-free survival in our study. A vertical line indicates a censored patient

Click here to view

Severe acute adverse events of Grade 3 or above were not observed. Mild-moderate (grade 1 or 2) fatigue was the most frequently observed (44%), followed by nausea (31%), mucositis (17%), loss of appetite (11%), and diarrhea (7%) [Table 2]. Any grade 2 or less acute adverse event was exhibited in 36 patients (67%). No patient exhibited any Grade 3–5 late radiation-induced late adverse event during the observation period.

Discussion

The excellent clinical outcomes of this present study are comparable to that of previous reports. Previous retrospective studies have reported the rate of 5-year PFS to be between 80% to 100% of the gastric MALT lymphoma patients treated with radiotherapy. Schechter et al. reported that there was a 100% event-free survival in 17 gastric MALT lymphoma patients treated with radiotherapy, with a median follow-up time of 27 months.^[14] Tomita et al. reported that the 5-year OS and PFS rates of the patients with MALT lymphoma treated by radiotherapy were 96.6% and 82.2%, respectively.^[15]

There were several acute mild-moderate adverse events in the acute phase; however, no serious adverse event was found in the acute and late phases of our observation period. Early gastric cancer was found in three patients during the posttreatment observation period. Similar events have also been reported in previous reports.^[16],[17] All three patients were diagnosed with Stage I adenocarcinoma treated with endoscopic submucosal dissection. It is unclear whether or not this is due to the radiotherapy, chronic infection, genetic background, or repeated gastric endoscopy.

A total dose of approximately 30 Gy has been conventionally used for the treatment of MALT lymphoma. A recent prospective, randomized phase II trial compared the prescription doses of 25.2 Gy and 36 Gy radiotherapy with one another.^[18] The results of this trial showcased that all patients achieved a stable complete response irrespective of radiation dose, and radiotherapy with 25.2 Gy might be effective enough for early-stage MALT lymphoma. However, further investigation to determine the optimal dose and fractionation is needed.

According to the European Society for Medical Oncology clinical practice guideline, radiotherapy is the preferred treatment modality for localized gastric MALT lymphoma treatment.^[19] This guideline considers that systemic therapy is preferred in cases of advanced cases, contraindication to radiotherapy, and refractory prior treatment. The surgical approach has not been achieved any superiority in treatment outcome compared to conservative modalities.^[20]

Radiotherapy has an excellent disease control rate without severe treatment-related adverse events.^[14],[15] Martinelli et al. evaluated the use of the single-agent rituximab, a chimeric monoclonal antibody that binds to CD20, at weekly standard dose of 375 mg/m² for 4 consecutive weeks and its effect on gastric MALT lymphoma patients.^[21] For this trial of 26 patients, the reported objective response rate was 77% and the complete remission rate was 46%; no correlation was found between the response rate and translocation (11; 18) (q21; q21), a resistant factor of eradication therapy.^[22] Nakamura et al. compared oral mono-chemotherapy, which was 100 mg/day cyclophosphamide administration for 6–12 months, with radiotherapy as second-line treatment for patients not responding to eradication therapy.^[23] Complete remission was achieved for 10 out of 12 patients in the oral mono-chemotherapy group (83%), and in 8 out of 10 patients (80%) in the radiotherapy group, which indicated no statistically significant difference.

Conclusion

This retrospective study revealed the efficacy of radiotherapy for gastric MALT lymphoma. Radiotherapy is a feasible treatment option with excellent OS and DFS.

Acknowledgments

The authors would like to sincerely thank Alisha Huang for the language editing, and proofreading of this manuscript.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1.	Isaacson P, Wright DH. Malignant lymphoma of mucosa-associated lymphoid tissue. A distinctive type of B-cell lymphoma. Cancer 1983;52:1410-6.
2.	A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin's lymphoma. The Non-Hodgkin's Lymphoma Classification Project. Blood 1997;89:3909-18.
3.	Zucca E, Bertoni F. The spectrum of MALT lymphoma at different sites: Biological and therapeutic relevance. Blood 2016;127:2082-92.
4.	Zullo A, Hassan C, Ridola L, Repici A, Manta R, Andriani A. Gastric MALT lymphoma: Old and new insights. Ann Gastroenterol 2014;27:27-33.
5.	Guidoboni M, Ferreri AJ, Ponzoni M, Doglioni C, Dolcetti R. Infectious agents in mucosa-associated lymphoid tissue-type lymphomas: Pathogenic role and therapeutic perspectives. Clin Lymphoma Myeloma 2006;6:289-300.
6.	Zullo A, Hassan C, Cristofari F, Andriani A, De Francesco V, Ierardi E, et al. Effects of Helicobacter pylori eradication on early stage gastric mucosa-associated lymphoid tissue lymphoma. Clin Gastroenterol Hepatol 2010;8:105-10.
7.	Wündisch T, Thiede C, Morgner A, Dempfle A, Günther A, Liu H, et al. Long-term follow-up of gastric MALT lymphoma after Helicobacter pylori eradication. J Clin Oncol 2005;23:8018-24.
8.	Raderer M, Streubel B, Wöhrer S, Häfner M, Chott A. Successful antibiotic treatment of Helicobacter pylori negative gastric mucosa associated lymphoid tissue lymphomas. Gut 2006;55:616-8.
9.	Zullo A, Hassan C, Ridola L, De Francesco V, Rossi L, Tomao S, et al. Eradication therapy in Helicobacter pylori-negative, gastric low-grade mucosa-associated lymphoid tissue lymphoma patients: A systematic review. J Clin Gastroenterol 2013;47:824-7.
10.	Joo JH, Lee SW, Huh J, Suh C, Yoon DH, Ahn SD, et al. Recurrence patterns of mucose-associated lymphoid tissue lymphoma after definitive radiation treatment: A single center experience. Hematology 2016;21:542-8.
11.	Yamashita H, Nakagawa K, Asari T, Murakami N, Igaki H, Ohtomo K. Radiotherapy for 41 patients with stages I and II MALT lymphoma: A retrospective study. Radiother Oncol 2008;87:412-7.
12.	Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: The Lugano classification. J Clin Oncol 2014;32:3059-68.
13.	Thieblemont C, Cascione L, Conconi A, Kiesewetter B, Raderer M, Gaidano G, et al. A MALT lymphoma prognostic index. Blood 2017;130:1409-17.
14.	Schechter NR, Portlock CS, Yahalom J. Treatment of mucosa-associated lymphoid tissue lymphoma of the stomach with radiation alone. J Clin Oncol 1998;16:1916-21.
15.	Tomita N, Kodaira T, Tachibana H, Nakamura T, Mizoguchi N, Takada A. Favorable outcomes of radiotherapy for early-stage mucosa-associated lymphoid tissue lymphoma. Radiother Oncol 2009;90:231-5.
16.	Suenaga M, Ohta K, Toguchi M, Sato T, Ohyama S, Yamaguchi T, et al. Colliding gastric and intestinal phenotype well-differentiated adenocarcinoma of the stomach developing in an area of MALT-type lymphoma. Gastric Cancer 2003;6:270-6.
17.	Raderer M, Püspök A, Stummvoll G, Längle F, Chott A. Early cancer of the stomach arising after successful treatment of gastric MALT lymphoma in patients with autoimmune disease. Scand J Gastroenterol 2003;38:294-7.
18.	Schmelz R, Miehlke S, Thiede C, Brueckner S, Dawel M, Kuhn M, et al. Sequential H. pylori eradication and radiation therapy with reduced dose compared to standard dose for gastric MALT lymphoma stages IE & II1E: A prospective randomized trial. J Gastroenterol 2019;54:388-95.
19.	Zucca E, Arcaini L, Buske C, Johnson PW, Ponzoni M, Raderer M, et al. Marginal zone lymphomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2020;31:17-29.
20.	Avilés A, Nambo MJ, Neri N, Talavera A, Cleto S. Mucosa-associated lymphoid tissue (MALT) lymphoma of the stomach: Results of a controlled clinical trial. Med Oncol 2005;22:57-62.
21.	Martinelli G, Laszlo D, Ferreri AJ, Pruneri G, Ponzoni M, Conconi A, et al. Clinical activity of rituximab in gastric marginal zone non-Hodgkin's lymphoma resistant to or not eligible for anti-Helicobacter pylori therapy. J Clin Oncol 2005;23:1979-83.
22.	Liu H, Ye H, Dogan A, Ranaldi R, Hamoudi RA, Bearzi I, et al. T (11;18) (q21;q21) is associated with advanced mucosa-associated lymphoid tissue lymphoma that expresses nuclear BCL10. Blood 2001;98:1182-7.
23.	Nakamura S, Matsumoto T, Suekane H, Matsumoto H, Esaki M, Yao T, et al. Long-term clinical outcome of Helicobacter pylori eradication for gastric mucosa-associated lymphoid tissue lymphoma with a reference to second-line treatment. Cancer 2005;104:532-40.