Radiotherapy for gastric mucosa-associated lymphoid tissue lymphoma

Laurent Quéro,Mouna Labidi,Marc Bollet,Côme Bommier,Sophie Guillerm,Christophe Hennequin,Catherine Thieblemont

Laurent Quéro,Mouna Labidi,Sophie Guillerm,Christophe Hennequin,Department of Radiation Oncology,AP-HP,Saint Louis Hospital,Paris 75010,France

Laurent Quéro,Côme Bommier,Christophe Hennequin,Catherine Thieblemont,Faculty of Medicine,Université de Paris,Paris 75005,France

Marc Bollet,Department of Radiation Oncology,Hartmann Oncology Radiotherapy Group,Levallois-Perret 92044,France

Catherine Thieblemont,Hemato-Oncology,DMU DHI,AP-HP,Saint Louis Hospital,Paris 75010,France

Abstract Gastric mucosa-associated lymphoid tissue(MALT)lymphoma is a rare disease which is often associated with Helicobacter pylori(H.pylori)infection.First-line treatment of stage IE and IIE localized gastric MALT lymphoma is based on the eradication of H.pylori.The presence of H.pylori resistance factors such as translocation t(11;18),peri-gastric lymph node involvement and the degree of tumor infiltration of the gastric wall;or lack of response to antibiotic therapy are two main indications to treat with definitive radiotherapy(RT).RT is an effective treatment in localized gastric MALT lymphoma.A moderate dose of 30 Gy allows a high cure rate while being well tolerated.After treatment,regular gastric endoscopic follow-up is necessary to detect a potential occurrence of gastric adenocarcinoma.

Key Words:Radiotherapy;Mucosa-associated lymphoid tissue;MALT;Helicobacter pylori;Lymphoma;Review

INTRODUCTION

Extranodal marginal zone lymphoma(EMZL)is an indolent non-Hodgkin's B-cell lymphoma.It belongs to the heterogeneous group of MZLs,beside splenic MZL and nodal MZL.It has an extra-nodal origin.EMZL can develop from mucosal,called also mucosa-associated lymphoid tissue(MALT)lymphoma,and non-mucosal sites,in various organs such as the stomach,small intestine,bronchi,thyroid gland,liver,kidney,breast,salivary glands,orbit/orbital adnexa,or skin.It can be associated with autoimmune diseases such as Hashimoto's thyroiditis or Sjögren's syndrome.The most common sites of EMZL are the stomach,the orbit/orbital adnexa and the skin,and gastric MALT-lymphoma accounts for 30%–50% of all MALT-lymphoma locations[1,2].

The incidence of non-Hodgkin lymphoma(NHL)has increased by 70% between 1975 and 2017[3].MALT gastric lymphoma is rare:It represents 4% of all NHL and approximately 5% of primary gastric neoplasms[4].According of the SEER United States database,new cases of NHL and gastric cancer were respectively 77240 and 27600 in 2020 in the United Stade of America[3],which corresponds to between 1380 and 3090 new cases of gastric MALT lymphoma.

The MALT-IPI index was developed to identify patients with a poor prognosis and thus to allow for appropriate treatment of patients with EMZL.This index classified patients into three prognostic groups(low,intermediate,and high)that are predictive for event-free,progression-free and overall survival(OS),whatever the extranodal site of the lymphoma,gastric or non-gastric.The 5-year event-free survival(EFS)rates in the low-,intermediate-,and high-risk groups were 70%,56%,and 29%,respectively.This index was based on:Age ≥ 70 years,Ann Arbor stage III or IV and elevated lactate dehydrogenase(LDH).The MALT-IPI has been developed from 401 patients treated with chlorambucil,rituximab,or both in the international randomized trial IELSG-19.The index was subsequently validated by merging three independent cohorts of MALT lymphoma patients(n= 633 patients)[5].

In 90% of cases,gastric MALT lymphoma is associated with aHelicobacter pylori(H.pylori)infection.H.pyloriprevalence in developed countries decreased after 2000:In Europe from 48.8% to 39.8%,in Northern America from 42.7% to 26.6%,and in Oceania from 26.6% to 18.7% whereas it remained stable elsewhere:In Asia(53.6% before 2000vs54.3% after 2000)and South America and the Caribbean(62.8% before 2000vs60.2% after 2000)[6].In Europe,the prevalence ofH.pyloriinfection decreased from 92% in the 80’s to 61% between 1995-2004 and then to 32% between 2005 -2013 for the United Kingdom,from 82% between 1999-2003 to 69% between 2004-2014 in Austria and from 61% between 1997-2002 to 17% between 2004-2014 for Italy[7-10](Figure 1).

First-line treatment of stage IE and IIE localized gastric MALT lymphoma is based on the eradication ofH.pylori.Recommended anti-H.pyloritherapy includes a proton pump inhibitor(or ranitidine bismuth citrate),clarithromycin and amoxicillin(or metronidazole).

Because MALT lymphoma is rare,treatment recommendations are based on studies with low levels of evidence(Figure 2).The aim of this review is to assess the effectiveness and tolerance of radiotherapy(RT)and the alternative treatments.

Figure 1 Prevalence of Helicobacter pylori infection in gastric marginal zone lymphoma.MALT:Mucosa-associated lymphoid tissue.

Figure 2 Gastric mucosa-associated lymphoid tissue lymphoma therapeutic algorithm.HP:Helicobacter pylori.

STAGING OF GASTRIC MALT LYMPHOMA

Previously,staging of MALT gastric lymphoma was based on Lugano staging system[11]which is a modification of the Ann Arbor staging system.More recently,Paris staging system[12]which corresponds to the tumor,node,metastasis system for gastric cancer,has been proposed.The Paris system has the advantage,over the Lugano staging system,of better describing the depth of invasion into the gastric wall(Tables 1 and 2).

Table 1 Paris staging system

Table 2 Lugano staging system

According to ESMO guidelines,initial staging should include history and physical examination,full blood and differential counts,biochemistry including renal and liver function tests,protein electrophoresis,LDH and beta2-microglobulin,serum and urine immunofixation,serology for hepatitis B virus,hepatitis C virus(HCV)and human immunodeficiency virus and cryoglobulins and cryocrit if HCV-positive.

Staging should include

Gastroduodenal endoscopy of any abnormal lesion associated with systematic multiple biopsies.The following tumor analyses from biopsies,performed by an expert pathologist in hematology,are mandatory:(1)Immunohistochemistry panel analysis:CD20,CD3,CD5,CD10,BCL2,kappa/Lambda,CD21 or CD23,BCL6,cyclin D1 and immunoglobulin D;and(2)H.pyloritesting:The detection of the t(11;18)(q21;q21)translocation by Fluorescence in situ hybridization is only recommended in case of failure of anti-H.pyloriantibiotic treatment.

Endoscopic ultrasound is recommended to evaluate gastric wall infiltration and perigastric lymph node involvement.

Imaging includes chest and abdominal computed tomography(CT):Positron emission tomography(PET)/CT is not recommended before the treatment.

H.PYLORI ERADICATION

In a study of 103 patients with stage IE and IIE gastric MALT lymphoma,Moleiroet al[13]reported 83% complete response(CR)(78/103)with a mean follow-up of 7 mo(2–63 mo)afterH.pylorieradication treatment and 86%(67/103)with a mean followup time of 105 mo.H.pyloriinfection(P= 0.004)and lymphoma location to the antrum/body(P= 0.016)were significantly associated with higher and lower CR rates,respectively.Relapse occurred in 11/78(14%)patients after a mean time-lapse of 21 mo.The absence ofH.pylorire-infection(P= 0.038),the need for only one eradication regimen(P= 0.009)and antrum lymphomas(P= 0.031)correlated with lower relapse rates.At stage IIE,H.pylorieradication was performed in 17/24 patients but only five experienced CR(30%)[13].

A systematic review of 32 publications revealed that CR was achieved in 78% of 1408 patients with low-grade stage I/II1 gastric MALT lymphoma in treated withH.pylorieradication[14].

In a Japanese multicenter cohort study,420 patients with gastric MALT had undergone successfulH.pylorieradication.Seventy-seven percent(323 patients)responded toH.pylorieradication.Absence ofH.pylori,submucosal invasion and t (11;18)/API2-MALT1 were independent predictors of resistance toH.pylorieradication.Among responders,MALT relapsed in 3% of patients while progressive disease occurred in 27% of non-responders(27/97).After a median follow-up of 6 years,freedom from treatment failure(FFTF),OS and EFS at 10 years were 90%,95% and 86%,respectively.Peri-gastric lymph node involvement and the depth of tumor infiltration in the gastric wall are factors also associated with a poor tumor response afterH.pylorieradication[15].

H.pyloridisappears usually 6 wk after the start ofH.pylorieradication,soon after the completion of drug therapy,whereas MALT lymphoma usually takes several months to disappear(median 6 mo;extremes 3-24 mo).

However,if there is noH.pyloriinfection,the remission rate after antibiotic therapy is low(between 15% and 30%).

The translocation t(11;18)(q21;q21)/(API2-MALT1)is observed in 20 to 30% of gastric MALT lymphomas.It is associated with a higher rate of recurrence after eradication.This translocation is also associated with a lower response rate after alkylating-agent-based chemotherapy(90%vs40% approximately),but not with rituximab.

According to ESMO clinical practice guidelines,the presence ofH.pyloriresistance factors,or lack of response to antibiotic therapy are the two main indications to treat with definitive RT.Given the possibility of a delayed response,RT should not be recommended for asymptomatic patients with non-progressive residual disease within the 9–12 mo following successfulH.pylorieradication therapy.Patients with asymptomatic minimal residual disease may have an indolent course and may not require further treatment.

Some expert groups recommend RT in the case of localized disease and chemotherapy with or without immunotherapy in the case of advanced disease.

RT FOR GASTRIC MALT LYMPHOMA

Results of RT

Indolent NHLs are sensitive to moderate doses of RT.In this literature review,the median delivered dose was 30 Gy(Table 3).For localized gastric lymphomas,exclusive RT in the case of failure ofH.pylorieradication gives very good results with a complete remission rate of 96% to 100% for a median follow-up of between 1.3 and 4.1 years without long-term side effects.The local tumor control is excellent after exclusive RT with fewer than 5% of patients experiencing local relapse after treatment.Gastric RT is well tolerated with hardly any severe(G3+)acute or late toxicities.Some studies have reported only mild(G1-2)and transient acute gastro-intestinal toxicities.

Table 3 Studies of radiotherapy for gastric mucosa-associated lymphoid tissue lymphoma

RT:Radiotherapy;NR:Not reported;H.pylori:Helicobacter pylori.

In the IELSG retrospective multicentric international study,Wirthet al[16]reported in 102 patients treated by extended field or whole abdomen RT for gastric MZL and persistentH.pyloriinfection after eradication orH.pylori,88% of FFTF at 10-years.RT median dose delivered to the stomach was 40 Gy(26–46).In this study,RT field size,RT dose,and failure of prior therapy(H.pylorieradication,chemotherapy or surgery)were not associated with inferior RT efficacy[16].Second malignancies were reported in 5 of 41 patients who had gastric/nodal irradiation only,of which two were likely infield(2 colon),one was likely out of field(bladder)and two had uncertain relationship to field(1 breast,1 lung).

In a retrospective monocentric study that evaluated the outcome of 32 patients treated for gastric MALT lymphoma with involved site radiation therapy using intensity modulated radiation therapy(IMRT),Pinnixet al[17]have reported excellent outcome with 2-year Freedom from local treatment failure,FFTF,and OS of 100%,100% and 97%,respectively.Moreover,they did not observe any association between the lower 24 Gy dose with FFLTF(P= 0.819),FFTF(P= 0.819)or OS(P= 0.469)[17].

The excellent results and safety of moderate-dose RT,30 Gy,have been confirmed by the GELD/FFCD prospective study that included 53 patients,all well selected(H.pylorieradication failure,H.pylorinegative).The response rate was very high(98%).After 4.9-years median follow-up,the overall lymphoma survival was 94%[18].Neither local or distant relapses nor severe acute or late G3+ toxicities were observed.

In a large retrospective monocentric study from the Memorial Sloan Kettering Hospital New York,Teckieet al[19]reported very favorable outcome in patients treated for gastric MALT lymphoma by moderate dose of RT(30 Gy).Indeed,gastric location was associated with the best relapse free-survival among patients treated by RT for MZL.After a long follow-up[62 mo(2–256)],local failures occurred in only 7 out of 102 treated patients[19].

The main weaknesses of most of the studies reported in this review are,their retrospective nature,often monocentric,their small sample size,their short follow-up and that some studies have included patients who had not failed toH.pylorieradication.

The median delivered dose in this literature review is in accordance with the ILROG guidelines:30-30.6 Gy in conventional fractionation(1.8 to 2 Gy/d and 5 dperweek)on gastric and peri gastric lymph node volumes(involved site RT)[20].During RT,proton pump inhibitor and 5-HT3 serotonin receptor antagonist are recommended to prevent acute side effects.

RT treatment planification

CT Simulation:Patients must be simulated and treated with an empty stomach after a fast of at least 4 h or overnight.

Patients should be simulated supine with arms up using customized immobilization device.

A small volume(50 cc)of oral contrast medium should be used.

CT images should be acquired before and after oral contrast medium.

Intravenous contrast medium injection is recommended in case of lymph nodes involvement.

In order to reduce margins,respiratory motion should be assessed with 4D-CT.

Volume definition(ILROG recommendations)

The gross tumor volume corresponds to the gastric tumor and the macroscopically invaded lymph nodes determined on CT or PET-CT.

Because gastric MALT lymphoma is often associated with multifocal involvement of the stomach and may spread to regional lymph nodes,radiation volumes should include the entire stomach as well as the perigastric lymph nodes of the lesser and greater curvatures.

The clinical target volume(CTV)corresponds to the entire stomach from the gastroesophageal junction to the duodenal bulb;the whole gastric wall and the perigastric lymph nodes must be included.

The internal target volume needs to be determined by 4D-CT in order to take into account stomach mobility during breathing.

In the absence of 4D-CT,2 cm margins should be added to the CTV to take into account the respiratory movement of the stomach.

For the planning target volume(PTV),an additional margin of 0.5 to 1 cm should be added,to take into account setup variation.

In order to reduce the margins due to respiratory movements,modern irradiation techniques such as deep-inspiratory breath-hold(DIBH)and 4D-Cone Beam Computed Tomography(CBCT)-Image Guided Radiation Therapy,should be used.In a retrospective study of 10 patients treated for gastric NHL including 5 MALT and 5 DLBCL,Christophersonet al[21]have reported that DIBH led to reduced dose to the heart and the kidneys,through improved spatial separation between the heart and the stomach,while simultaneously allowing for reduced target volumes,without compromising target coverage or increasing dose to other organs at risk(OAR)[21].

Shimohigashiet al[22]reported that the use of 4D-CBCT reduced the PTV when applying 4D soft-tissue matching,compared to skin and bone matchings.Based on these results,authors recommended daily 4D-CBCT during RT treatment[22].

The following OAR should be delineated:Liver,kidneys,bowels,heart,lungs and spinal cord.3D conformal RT,IMRT or VMAT(Figure 3),are recommended to reduce the dose delivered to the kidneys and liver.

Figure 3 Example of dose distribution using volumetric modulated arc therapy in gastric mucosa-associated lymphoid tissue lymphoma.

Prescribed dose

The median delivered dose in this literature review is in agreement with the ILROG guidelines:30-30.6 Gy in conventional fractionation(1.8 to 2 Gy/d and 5 dperweek)on gastric and perigastric lymph node volumes(involved site RT)[23].

Prevention of side effects

During RT,proton pump inhibitor and 5-HT3 serotonin receptor antagonist are recommended to prevent acute side effects.

OTHER TREATMENT APPROCHES

Surgery

In the GIT NHL 02/96 multicentric non-randomized German study,Kochet al[24]have reported no survival advantage at 42 mo of surgery ± adjuvant RT in case of R1/R2 resection grade or stage II disease in comparison with exclusive RT without surgery in 144 patients treated for localized primary gastric indolent lymphoma(86%vs91%)[24].

In clinical practice,surgical treatment is rarely indicated.The only current indications are emergency situations such as perforation or uncontrolled bleeding in endoscopy.

Systemic therapy

In the IELSG-19 randomized trial that included 401 patients with localized or disseminated gastric and non-gastric MALT lymphoma,the combination of rituximab and chlorambucil was significantly superior to chlorambucil monotherapy and rituximab monotherapy in terms of response rate[79%vs63%vs56%,respectively(P<0.001)],EFS(68%vs51%vs51%,P= 0.0009)and progression-free survival at 5 years(72%vs59%vs57%,P= 0.0119).Five-year OS was approximately 90% in each arm.All treatments were well tolerated.No unexpected toxicities were reported[23].

In the MALT2008-01 phase II Spanish multicentric study that included 57 patients with localized or disseminated gastric and non-gastric MALT lymphoma,the combination of bendamustine and rituximab for first-line systemic treatment resulted in a complete or unconfirmed CR rates of 98% and an EFS at 4 years of 88%.Progression-free survival at 4 years was 93% with no differences between patients with gastric and non-gastric sites[25].

Watchful waiting

Long-term complications after treatment of indolent lymphomas have been reported,including a significant increase in secondary cancers.The risk of recurrence in patients with minimal residual gastric MALT lymphoma after successful eradication ofH.pyloriwithout oncological treatment,is low.Watchful waiting with regular endoscopies and biopsies could therefore be considered,particularly in elderly patients or in patients with comorbidity[26].This decision to treat or not,should be discussed in the setting of a multidisciplinary meeting.

FOLLOW-UP

Follow-up after treatment of localized gastric-MALT is based on upper gastrointestinal endoscopy.The follow-up differs slightly between expert groups.

NCCN recommendations

Endoscopic control 3 mo after RT:In case of CR:Clinical follow-up every 3–6 mo for 5 years and then yearly or as clinically indicated.

The timing of endoscopy and imaging is not determined:They should be decided on according to clinical symptoms.

ESMO recommendations

Following RT treatment,endoscopic controls with gastric biopsies and systemic follow-up(clinical examination,blood counts)every 12-18 mo are recommended.

Follow-up after H.pylori eradication

Following the documentation ofH.pylorieradication,strict endoscopic follow-up is recommended,with multiple biopsies taken 2-3 mo after treatment to rule out tumor progression,and subsequently every 6 mo for 2 years to monitor the histological regression of the gastric lymphoma.

Because of its reliability,it is recommended to use the GELA histological scoring system for post-therapy biopsies evaluation[27].Comparison with previous biopsies is helpful to assess response.

SECONDARY GASTRIC CANCERS

In spite of the excellent cure rate,long-term follow-up by endoscopy is required as cases of gastric adenocarcinomas have been reported during follow-up of cured lymphomas[26,28,29].Moreover,the Dutch epidemiological study by Capelleet al[30]found a 6-fold increase in the risk of gastric adenocarcinoma compared to the general population in patients with a history of gastric lymphoma regardless of treatment.This risk was 16.6 times higher in patients with gastric MALT lymphoma aged between 45 and 59 years than in the Dutch population(P<0.001)[30].

CONCLUSION

RT is a highly effective treatment in the management of localized gastric MALT lymphomas resistant toH.pylorieradication with a cure rate close to 100% and no major toxicity.Long follow-up with gastric endoscopy monitoring is necessary to diagnose at an early stage the potential occurrence of gastric adenocarcinoma.

ACKNOWLEDGEMENTS

The authors would like to thank Mr.Abdellah El Mouqaddem,a physicist from our department,for the dosimetry using VMAT technique presented in this article.