Abstract
Background/Aim: With the prevalence of COVID-19, the importance of short-course radiotherapy (RT) in many cancers has been discussed. The aim of this study was to evaluate the results of hypofractionated schedule RT for localized gastric mucosa-associated lymphoid tissue (MALT) lymphoma. Patients and Methods: We assessed 45 patients with localized gastric MALT lymphoma who underwent RT between 2005 and 2019. The total RT dose ranged from 24-36 Gy in 10-18 fractions (median of 28 Gy/14 fractions). Patients were divided into three groups according to the dose fractionation: Group A, 30-36 Gy in 15-18 fractions; Group B, 26-28 Gy in 13-14 fractions; and Group C, 24-25 Gy in 10 fractions. Results: All the patients achieved complete remission without local recurrence. The 5-year overall, cause-specific, and progression-free survival rates were 97.5%, 100%, and 97.5%, respectively, with a median follow-up period of 82 months. Among the dose fractionation groups, there were no statistically significant differences in local control or incidence of grade 2 or worse adverse events. Conclusion: Results of RT for localized gastric MALT lymphoma showed excellent local control and survival with no serious adverse events, regardless of dose fractionation. In situations where short-term RT is required, a hypofractionated RT schedule of 24-25 Gy in 10 fractions could be an option for RT schedules.
Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) is an indolent B-cell non-Hodgkin lymphoma mostly located in the stomach. The development of gastric MALT lymphoma is closely associated with Helicobacter pylori (H. pylori) infection. H. pylori eradication results in complete remission (CR) in 75%-93% of patients with localized gastric MALT lymphoma (1-4). Non-surgical treatments, such as radiotherapy (RT), are commonly used for patients who are H. pylori-negative or do not respond to eradication therapy, providing good results. Several studies have reported local control rates of more than 90% with standard dose RT (30-36 Gy) for localized gastric MALT, and the prognosis of gastric MALT patients after RT is quite favorable (5-9). However, good results have been reported with RT using various dose fractionation schedules for MALT lymphoma at other sites (10-12). It might be possible to treat gastric MALT lymphoma with RT using different dose fractionations from standard dose fractionation. However, data on RT with altered dose fractionation for localized gastric MALT lymphomas are scarce.
The COVID-19 pandemic has had a significant impact on RT. During the pandemic, appropriate hypofractionated regimens were recommended to reduce treatment time and minimize the risk of infection (13-15). However, for hypofractionated RT, the evaluation of therapeutic efficacy and safety is needed for each disease. We treated patients with localized gastric MALT lymphoma using several different dose fractionation schedules. In this study, we retrospectively examined the efficacy of a hypofractionated RT schedule for localized gastric MALT lymphomas.
Patients and Methods
Eligibility. The inclusion criteria for this study were as follows: undergoing RT between 2005 and 2019 at Hiroshima Red Cross Hospital & Atomic-bomb Survivors Hospital and histopathologically proven gastric MALT lymphoma classified as clinical stage I or II1, according to the Lugano staging system (16).
H. pylori eradication therapy. In principle, eradication therapy was administered even if the H. pylori test was negative at our institution, and RT was performed when patients had residual lymphoma after eradication therapy. Patients who could not receive eradication therapy for any reason were initially treated with RT.
Radiotherapy. Three-dimensional conformal RT (3DCRT) was performed using 6-10 MV X-rays. All patients were treated with free breathing in an empty stomach. The clinical target volume (CTV) was defined as the entire stomach and the perigastric lymph node region. The planning target volume was set with a margin of 2 cm from the CTV, considering the peristalsis and respiratory movements. The couch and gantry angles were selected to reduce the dose exposure to the kidney and liver.
Disease assessment and follow-up. After completion of RT, the patients were followed up at 3 months and then at every 6 months. The initial tumor response was evaluated using endoscopic biopsy approximately three months after treatment. Toxicity was assessed using the Common Terminology Criteria for Adverse Events, version 5.0. Acute adverse events were defined as those occurring within 90 days of RT initiation, and late adverse events as those occurring 90 days after RT initiation.
Statistical analysis. Local control (LC) was defined as the time from RT initiation to local recurrence. Overall survival (OS) was defined as the time from RT initiation to death from any cause. Cause-specific survival (CSS) was defined as the time from RT initiation to death due to gastric MALT lymphoma. Progression-free survival (PFS) was defined as the time from RT initiation to the first confirmed disease progression or death. The OS, CSS, and PFS rates were calculated using the Kaplan–Meier method. The Kruskal-Wallis test was performed to evaluate the incidence of adverse events among the groups. Statistical analysis was performed using the Bell Curve for Excel (Social Survey Research Information Co., Ltd., Tokyo, Japan). This study was approved by the Human Ethical Review Committee of Hiroshima Red Cross Hospital & Atomic-bomb Survivors Hospital (No 2021-056).
Results
Patient characteristics. Forty-five patients met the eligibility criteria. Patient and treatment characteristics are presented in Table I. The median age at RT initiation was 62 years (range=38-86 years), and 28 (62%) patients were male. Of the 45 patients, 24 were H. pylori-positive and 21 H. pylori-negative. API2/MALT1 gene translocation was present in 11 patients, absent in 30 patients, and unknown in 4 patients. The clinical stage was stage I in 40 patients and II1 in five patients.
Patient and disease characteristics.
Eradication therapy. Forty-two patients received eradication therapy and did not achieve CR. Three patients did not receive eradication therapy: one patient was allergic to antibiotics, one refused pretreatment, and one did not receive pretreatment for unknown reasons.
Radiation therapy. All patients completed the planned RT without interruption. Table II shows the total irradiation dose, fractional dose, and biological effective doses (BED). BED10 and BED3 are the BEDs calculated using the standard linear quadratic model with α/β=10 and α/β=3, respectively. The total irradiation dose ranged from 24 to 36 Gy in 10-18 fractions (median=28 Gy/14 fractions). We divided the patients into three groups according to the dose fractionations as follows: Group A, 30-36 Gy in 15-18 fractions (2.0 Gy per fraction, BED10: 36-43.2 Gy; BED3: 50-60 Gy, n=15); Group B, 26-28 Gy in 13-14 fractions (2.0 Gy per fraction, BED10: 31.2-33.6 Gy; BED3: 43.3-46.7 Gy, n=15); and Group C, 24-25 Gy in 10 fractions (2.4-2.5 Gy per fraction, BED10: 29.8-31.2 Gy; BED3: 43.2-45.8 Gy, n=15). The patient and disease characteristics of each group are shown in Table I.
Radiotherapy dose fractionation schedules and biological effective doses.
Tumor response and recurrence. All patients achieved CR, and the 5-year LC rate was 100% in all the dose fractionation groups. Among these groups, there were no statistically significant differences in local control. One patient in Group A had recurrence of lung metastasis 5.8 years after treatment. This lung metastasis was surgically removed and diagnosed pathologically as the same type of MALT lymphoma at initial diagnosis. The patient survived without recurrence at the last follow-up.
Survival. The follow-up period for all patients ranged from 21 to 163 months (median=82 months). The median follow-up period for Groups A, B, and C was 108, 69, and 100 months, respectively. Survival curves are shown in Figure 1. The 5-year OS, CSS, and PFS rates of all patients were 97.5, 100, and 97.5%, respectively. The 5-year OS rates for groups A, B, and C were 92.8%, 100%, and 100%, respectively. The 5-year CSS rate was 100% in all groups. The 5-year PFS rates for groups A, B, and C were 92.8%, 100%, and 100%, respectively. None of the patients died of gastric MALT lymphoma, and five patients (all included in Group A) died of other diseases, including pneumonia, lower gastrointestinal bleeding, pancreatic cancer, lung cancer, and natural causes in one case.
Overall survival (OS, black line), cause-specific survival (CSS, grey line) and progression-free survival (PFS, dot line) curves for all patients are shown.
Adverse events. Table III shows the acute and late adverse events. Regarding acute non-hematologic adverse events, grade 1 and 2 anorexia were observed in 28 (62%) and two (4%) patients, respectively. Grade 1 vomiting was observed in six (14%) patients. Regarding hematologic toxicity, grade 1, 2, and 3 leukopenia were observed in four (9%), two (4%), and one (2%) patient, respectively. Grade 1 thrombocytopenia was observed in 16 (36%) patients, and grade 1 elevated serum transaminase levels was observed in seven (16%) patients. No other serious adverse events such as gastric bleeding or perforation were observed. Grade 1 elevated creatinine levels was observed in six (12%) patients as a late adverse event.
Acute and late toxicities after radiotherapy.
According to the dose fractionation groups, Grade 2 or higher adverse events were zero, three, and two in Group A, B, and C, respectively. No statistically significant differences in the incidence of Grade 2 or worse adverse events were found among the three groups (Table IV).
Toxicities ≥ grade 2 according to dose fractionation groups.
Discussion
We retrospectively examined the long-term outcomes of RT for patients with stage I and II1 gastric MALT lymphomas. The 5-year OS, CSS, and PFS rates were 97.5%, 100%, and 97.5%, respectively, with a median follow-up of 82 months. There was only one case of leukopenia with Grade 3 or higher adverse events, suggesting that the treatment was well tolerated. The patients were treated using different dose fractionation schedules. The hypofractionated schedule with a total dose of 24-25 Gy in 10 fractions showed good tumor control and a low incidence of grade 2 or higher adverse events, similar to other schedules.
RT is an effective treatment for gastric MALT lymphoma. It is known that patients with gastric MALT lymphoma treated with RT have fewer recurrences and better outcomes after treatment than those with MALT lymphoma of other primary sites. Some reports have indicated that the 5-year CSS for gastric MALT lymphoma patients treated with RT was 80-100% (17-21). Our study showed a 5-year LC rate of 100% with a median follow-up of 82 months, consistent with previous reports.
Low-grade non-Hodgkin’s lymphoma (NHL) is radiosensitive and responds to low-dose radiation. Some results of low-dose RT for MALT lymphomas have been reported. A large, prospective, randomized trial in the United Kingdom compared low-dose RT (24 Gy in 12 fractions) with high-dose RT (40-45 Gy in 20-23 fractions) in 361 patients with low-grade lymphoma (64% follicular lymphoma and 19% marginal zone lymphoma or MALT lymphoma) (10). At a median follow-up of 5.6 years, the study showed no difference in the overall response rate between the two different dose schedules. Furthermore, there were no significant differences in treatment-free interval, PFS, or OS between the two groups.
The results of RT with several different dose fractionation schedules for orbital MALT lymphomas have also been reported. Goda et al. reported the results of RT (median total dose of 25 Gy in 10 fractions) in 89 patients with ocular adnexal NHL lesions (11). The OS, CSS, PFS, and local control rates were 91%, 96%, 64%, and 97%, respectively, with a median observation period of 5.9 years. Fasola et al. reported low-dose RT (4 Gy in 2 fractions) in 20 patients with 27 ocular adnexal NHL lesions (12). At a median follow-up of 33 months, the overall response rate was 96% and the CR rate was 85%, without intralesional recurrence. These reports of RT with several different dose fractionation schedules for orbital MALT lymphoma suggest the possibility of treating gastric MALT lymphoma with a shorter irradiation schedule than that of standard therapy.
A dose of 30 Gy in 20 fractions is considered the standard RT dose for gastric MALT lymphoma; however, there have been several reports of different RT schedules. Yahalom et al. reported the efficacy of RT in patients with H pylori–independent gastric MALT lymphoma (22). With a median follow-up of 6.2 years, 90.5% of patients had a pathologic complete response, and the 5-year OS rate was 94%. Although the median RT dose was a standard dose of 30 Gy (1.5-Gy fractions), the dose fractions ranged from 22.5-43.5 Gy, suggesting that different dose fractionation schedules may be effective, as in our study. Schmelz et al. reported the efficacy of salvage RT in patients with residual lymphoma after H. pylori eradication or H. pylori-negative patients (23). Twenty-nine patients with stage IE and II1E indolent gastric MALT lymphoma were randomly assigned to receive RT to the stomach at doses of 25.2 or 36 Gy (both in 1.8-Gy fractions); 12 patients received 36 Gy and 10 patients received 25.2 Gy. The CR rate in both groups was 100% over a median observation period of 79 months. The study concluded that in patients with refractory disease or H. pylori-negative indolent gastric MALT lymphoma, a 25.2 Gy dose was equally effective with a non-inferiority margin of at least 20% compared to standard-dose RT. Pinnix et al. compared the results of patients treated with doses of 24 Gy and 30 Gy for gastric MALT lymphoma (24). In the reduced-dose group, most patients (91%) received 24 Gy in 2-Gy fractions, whereas most patients (80%) received 30 Gy in 1.5-Gy fractions in the standard-dose group. The median follow-up period for all patients was 55.2 months, and all patients achieved CR after RT. The PFS and OS rates at two years for the entire cohort were 100% and 97%, respectively. These reports suggest that the biological characteristics of gastric MALT lymphoma are favorable, and RT with a lower-than-standard dose may be effective.
In this study, we performed RT for patients with gastric MALT lymphoma using several different dose fractionation schedules. The patients were divided into three groups according to the dose fractionation: Group A, 30-36 Gy in 15-18 fractions; Group B, 26-28 Gy in 13-14 fractions; and Group C, 24-25 Gy in 10 fractions for analysis. The local control rate was 100% in all groups, and there were no significant differences in the occurrence of Grade 2 or higher adverse events among the three groups. BED was used to compare the effects of various doses and fractionation schedules on treatment outcomes. The BED10 of the standard dose fractionation (30 Gy in 20 fractions) was 34.5. The BED10 of Group C was lower than that of Groups A and B and the standard dose fractionation; however, no decrease in the local control rate was observed. Regarding the effects on normal organs, the BED3 of Group C was equivalent to that of Group B, and the standard dose fractionation and toxicity, as in Groups A and B, were well tolerated without any serious adverse events. RT for gastric MALT, which requires a large irradiation area and may cause gastrointestinal toxicity, is usually performed with a low dose per fraction of 1.5 Gy. This study showed no increase in gastrointestinal toxicity in Group C, where a higher dose per fraction of 2.4-2.5 Gy was used. Although the safety of hypofractionated RT cannot be definitively stated due to the small number of cases, further safety assurance of hypofractionated RT may be achieved by reducing the dose to surrounding organs as much as possible using recent high-precision radiation therapies such as volumetric modulated arc therapy.
The limitations of our study are its retrospective nature, small number of patients, and use of various dose fractionation schedules. Another limitation is the variation in background factors, such as age and clinical stage among the three groups. However, the importance of hypofractionated RT is increasing owing to the COVID-19 pandemic (13-15). Hypofractionated RT, such as that conducted in Group C, requires only half the number of conventional standard fractionated treatments and may be a useful treatment option. This study is significant because it suggests the safety of hypofractionated RT for gastric MALT.
Conclusion
We evaluated the long-term results of RT in 45 patients with localized gastric MALT lymphoma. The long-term results of RT for localized gastric MALT lymphoma showed excellent local control and survival, with no serious adverse events. We performed RT using several different dose fractionation schedules without any difference in outcomes or adverse events regardless of dose fractionation. Thus, a hypofractionated RT schedule with 24-25 Gy in 10 fractions may be an option for RT schedules.
Acknowledgements
We would like to thank Editage (www.editage.com) for English language editing.
Footnotes
Authors’ Contributions
Masanori Ochi and Yuji Murakami contributed equally to this work. Investigation, project administration, and writing of original draft: Masanori Ochi. Methodology, project administration, supervision, and writing – review and editing: Yuji Murakami. Writing – review and editing: Ikuno Nishibuchi, Nobuki Imano, Tsuyoshi Katsuta, and Ippei Takahashi. All Authors have read and agreed to the submitted version of the manuscript.
Conflicts of Interest
The Authors declare no conflicts of interest regarding this study.
- Received April 24, 2023.
- Revision received June 12, 2023.
- Accepted June 13, 2023.
- Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
References
In this issue
Jump to section
Related Articles
Cited By...
- No citing articles found.