Radiotherapy and Oncology xx (2008) xxx–xxxwww.thegreenjournal.com

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Original article

Radiotherapy for 41 patients with stages I and II MALTlymphoma: A retrospective studyq

Hideomi Yamashita, Keiichi Nakagawa*, Takao Asari, Naoya Murakami,Hiroshi Igaki, Kuni Ohtomo

Department of Radiology, University of Tokyo Hospital, Hongo, Bunkyo-ku, Tokyo, Japan

Abstract

Purpose: Mucosa-associated lymphoid tissue (MALT) lymphoma is a distinct disease with specific clinical and pathologicfeatures that may affect diverse organs. We analyzed our recent experience with Stage I/II MALT lymphoma presenting inthe stomach and other organs to assess the outcome following radiation therapy (RT) alone.Patients and methods: Forty-one patients with Stages I (37) and II (4) disease were treated between 2000 and 2006.

Patients with transformed MALT were excluded. The median age was 60 years (range, 25–86 years), male: female ratio1:1. Presenting sites included stomach, 11; orbital adnexa, 21; thyroid, 1; other head and neck, 3; small bowel, 3; skin,1; and rectum, 1. Thirty-five patients (85%) received RT-alone and 6 (15%) received antibiotics followed by RT. RT dosewas 30 Gy in 20 fractions (fr) in all 41 patients. Mean follow-up time was 32.0 months (range, 2.1–162 months).Results: A first complete response was achieved in all 41 patients. Only one patient died from bile duct carcinoma at 22

months from the start of irradiation for conjunctiva MALT lymphoma without recurrence of lymphoma. The other 40patients were alive. Thirty-eight patients out of them were alive without recurrence. One patient with a duodenallymphoma had a recurrence in non-irradiated distant sites at 1 month. Another patient with a bilateral eye lid lymphomahad a recurrence within radiation field at 41 months. The absolute local control rate with radiation was 98% (40/41patients).Conclusion: Localized MALT lymphomas have excellent prognosis following moderate-dose RT (30 Gy/20 fr).

�c 2008 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology xx (2008) xxx–xxx.

Keywords: Non-Hodgkin’s lymphoma; MALT; Treatment; Radiation therapy

Mucosa-associated lymphoid tissue (MALT) type lym-phoma is now incorporated into the Revised European–American Lymphoma (REAL) and the World Health Organiza-tion (WHO) classification systems [1,2] as extranodal mar-ginal zone B-cell lymphoma, MALT type. It accounts for4–13% of patients seen in individual cancer centers [3,4].A recent nationwide study of malignant lymphoma amongJapanese reported that it accounts for about 8% of all malig-nant lymphomas in Japan [5]. Although much knowledge hasbeen gained in defining the clinical features, natural his-tory, pathology, and molecular genetics of the disease inthe last decade, the optimal treatment approach for MALTlymphomas is still evolving. The discovery of an associationbetween Helicobacter pylori (H. pylori) infection and gas-tric MALT lymphoma, and tumor response with eradicationof H. pylori [6–10], led to the novel concept that MALT lym-phoma can be cured with removal of the underlying anti-genic stimulus, the H. pylori infection. Predisposingconditions to MALT lymphoma are well recognized: Hashim-

q Clinical investigation lymphoma

0167-8140/$ - see front matter �c 2008 Elsevier Ireland Ltd. All rights re

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oto’s thyroiditis for thyroid MALT lymphoma [11] and Sjo-gren’s syndrome for salivary gland MALT lymphoma [12].

Because 60–70% of patients with MALT lymphomas pres-ent with localized (Stage I or II) disease [3,13,14], and be-cause there is a tendency for the disease to remainlocalized for a long time, local treatment, such as radio-therapy (RT), is often indicated. Previous retrospectivestudies demonstrated excellent local control rates and pro-gression-free survival (PFS) after RT [15–30]. RT for orbitalMALT lymphomas usually leads to late adverse events suchas retinopathy, cataracts, or a dry eye [15–24]. Further-more, there have been few published prospective trialsevaluating the appropriate dose and field of RT for MALTlymphoma, except for patients with localized gastric dis-ease [29]. Japan Radiation Oncology Group (JAROG) con-ducted a multicenter phase II study to evaluate moderate-dose (30.6–39.6 Gy) of RT between 2002 and 2004, depend-ing upon the primary site and tumor bulk [31]. They con-cluded that moderate-dose RT was highly effective inachieving local control with acceptable morbidity in 37 pa-tients with MALT lymphoma.

served. doi:10.1016/j.radonc.2008.03.012

1 patients with stages I and II MALT ..., Radiother Oncol (2008),

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Over the last decade and a half, works on multiple MALTlymphoma treated with RT series were published, and manyof these words were specific to the organ that was treated.The radiosensitivity of MALT to radiation is also well estab-lished and the dose of 30 Gy to the stomach and even lowerdoses to orbital MALT lymphoma are standard of care. How-ever, to date there are few well-documented reports of theefficacy of RT in this disease. We report the analysis of ourexperience of 30 Gy/20 fr involved-field RT for Stages I andII MALT lymphomas, emphasizing the excellent local controlwith radiation.

Methods and materialsThis is a retrospective study. Forty-one consecutive pa-

tients with Stages I (37) and II (4) disease were treated be-tween 2000 and 2006 in our institution. Patients withtransformed MALT were excluded. Additionally, primary no-dal marginal zone B-cell lymphoma, MALT type (N = 2) wasalso excluded. The median age was 60 years (range, 25–86 years) and male/female ratio was 1/1. Presenting sitesincluded stomach, 11; orbital adnexa, 21; thyroid, 1; otherhead and neck, 3; small bowel, 3; skin, 1; and rectum, 1(Table 1). Staging included site-specific imaging, enhancedCT or MRI in 39 patients (95%), gallium-68 scintigraphy in 7(17%), F-18 2-deoxy-fluoro-D-glucose (FDG) positron emis-sion tomography (PET) in 20 (49%), and bone marrow biopsyin 39 (95%). The diagnosis was made on the basis of hema-

Table 1Patient and tumor characteristics

No. %

Anatomic locationStomach 11 27Orbital adnexa 21 51Thyroid 1 2Other head and neck 3 7Small bowel 3 7Skin 1 2Rectum 1 2

Maximum diameter of tumor=5 cm 20 49<5 cm 21 51

SexMale 21 51Female 20 49

Age=60 21 51<60 20 49

StageIE 34 83IEE 3 7IIE 4 10

K-PS=90% 39 95<90% 2 5

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toxylin and eosin-stained biopsy specimens supported byimmunohistochemical analysis. Immunologic phenotypingon paraffin section was done for j and k light chain restric-tion and CD20+, CD5�, CD10�, and cyclin D1�, which in thecontext of the microscopic appearance, is consistent withMALT lymphoma.

Radiation methodThe clinical target volume (CTV) was defined as an en-

tire affected organ for lymohoma of the stomach or grosstumor volume (GTV) with at least 20 mm of margin forlymohoma of the small bowell, thyroid, other head andneck, skin, and rectum. Prophylactic irradiation for lymphnode was not performed. The CTV was defined as the en-tire bulbar and palpebral conjunctiva for the orbital lym-phoma with lesions confined to the conjunctiva oreyelids. The CTV was the entire orbital cavity for the ret-robulbar lymphoma. A lens shield was placed unless theblock compromised tumor coverage. One example of radi-ation dose distribution for gastric MALT lymphoma wasshown in Fig. 1. RT dose was 30 Gy in 20 fr in all 41 pa-tients regardless of the size of primary tumor. In the gas-tric lymphoma patients, the liver and kidneys wereevaluated as the organs at risk. Of the 21 patients withorbital MALT lymphoma, 14 patients were treated with acylindrical lens shielding (approximately 6–12 mm thick,depending on the electron beam energy). Lens shieldingwas placed 1 cm above the cornea.

Systemic therapyHelicobacter pylori status was determined by the rapid

urease test (Helico Check, Otsuka Co., Tokushima, Japan),serological testing (HM-CAP kit, Enteric Product, Inc., NY,USA) and 13C-urea breath test before and after H. pylorieradication therapy. Thirty-five patients (85%) received RTalone and 6 patients (15%) that were positive of H. pyloriinfection in gastric lymphoma received antibiotics followedby RT. When patients were refractory to antibiotics or theircases were not associated with H. pylori, they were candi-dates for RT for gastric MALT lymphoma. Accordingly, casesin which H. pylori were completely eradicated only by anti-biotic treatment were not indicated for RT. The determina-tion of a failed response to H. pylori eradication therapy hasso far been made at 12 months after the therapy, and RT hasbeen applied to patients who did not achieve completeremission at that time. Patients who had simultaneous bilat-eral lesions were classified with Stage IEE disease accordingto other investigators’ criteria [32–36].

Quality of follow-upAfter the completion of radiotherapy, patients were fol-

lowed at regular intervals. Careful clinical and ophthalmo-logic examinations were performed every 1–3 months forthe first 2 years, every 4–6 months through year 5, andannually thereafter. For the patients with gastrointestinalMALY lymphoma, endoscopic, CT scanning and histologicalevaluation were performed immediately after radiotherapyand every 3–6 months thereafter. For the patients withorbital MALT lymphoma, orbital CT scanning or magneticresonance imaging was recommended at 1 year after radio-

41 patients with stages I and II MALT ..., Radiother Oncol (2008),

Fig. 1. Radiation dose distribution in the virtual simulation using a CT simulator of a gastric MALT lymphoma. The radiation portal consisted of acombination of the anterior–posterior direction and the lateral direction.

80

100

(%)

H. Yamashita et al. / Radiotherapy and Oncology xx (2008) xxx–xxx 3

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therapy but was not required and other radiographic studieswere performed as indicated clinically.

Statistical methodsThe progression-free survival (PFS) was assessed using

the method of Kaplan and Meier. Acute toxicity was gradedaccording to the National Cancer Institute Common ToxicityCriteria (version 3.0). Late effects were graded according tothe Radiation Therapy Oncology/European Organization forResearch and Treatment of Cancer late radiation morbidityscoring scheme.

0

20

40

60

Surv

ival

rat

e

0 20 40 60 80 100 120 140 160 180Months

41 28 14 7 4 2 1 1 1 0 No. AT RISK

Fig. 2. Progression-free survival of the 41 patients with extranodalmarginal zone B-cell lymphoma of mucosa-associated lymphoidtissue.

ResultsA first complete response was achieved in all 41 patients.

Only one patient died from bile duct carcinoma at 22months from the start of irradiation for conjunctiva MALTlymphoma without recurrence of lymphoma. The other 40patients were alive. The 5-year overall survival rate was96.7%. Thirty-eight patients out of them were alive withoutrecurrence. The absolute local control rate with radiationwas 98% (40/41 patients). Progression-free survival (PFS)curve of the 41 patients is shown in Fig. 2. The 5-year PFS

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rate for the entire group was 90.6%. Mean follow-up timewas 3.3 years (range, 0.2–12.2 years).

The PFS took into account not only local relapses but alsodistant relapses. One relapse (the primary site: duodenum)was observed in non-irradiated distant sites at 1 month. The

1 patients with stages I and II MALT ..., Radiother Oncol (2008),

Table 3Acute and late toxicities in 21 orbital adnexa MALT lymphoma

No. of patients (%)

Grade 0 Grades 1–2 Grade 3

Acute toxicitiesDermatitis 18 (86%) 3 (14%) 0Conjunctivitis/Corneitis 16 (76%) 5 (24%) 0

Total 13 (62%) 8 (38%) 0

Late toxicitiesEyesight decline 19 (90%) 2 (10%) 0Conjunctivitis/Corneitis 13 (62%) 8 (38%) 0Cataract 16 (76%) 2 (10%) 3 (14%)

Total 7 (34%) 11 (52%) 3 (14%)

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patient with a duodenal lymphoma had a recurrence in theabdominal para-aortic lymph node showing transformationinto diffuse large B-cell lymphoma. After the recurrence,the patient was given systemic chemotherapy consisting of6 cycles of R-CHOP regimen. It involved the monoclonalantibody rituximab, and the drugs: cyclophosphamide,doxorubicin, vincristine and prednisolone. After the salvagetherapy, no recurrence has been detected until now for 71months.

Another relapse (originated from bilateral eye lid) waswithin electron irradiation field at 41 months. The relapselesion in the left lower eyelid was resected completely.The pathology remained unchanged. After the resection,no recurrence has been detected till now for 53 months(Table 2).

Acute toxicity and late complicationsRadiation-induced side effects were negligible in the

majority of the patients. No life-threatening toxicity(=grade 4) occurred. Although acute radiation-induced con-junctivitis developed in 5 patients, none of them had severelater complications. The incidence of any later complica-tions is listed in Tables 3 and 4. Cataract did not developin any of the 14 patients who were treated with lensshielding. We observed three Grade 3 cataracts during thisstudy period at 36, 46, and 162 months after the completionof RT.

DiscussionBecause MALT lymphoma has been considered to be less

responsive to standard chemotherapy than other aggressivelymphomas, RT has been used as the first line local treat-ment. Only for limited-stage gastric MALT lymphoma linkingto H. pylori infection, H. pylori eradication therapy todayhas become recognized as a first-line treatment [50]. RT

Table 2Treatment and outcome characteristics

No. %

Radiation dose30 Gy/20 fr 41 100

OutcomeDead 1 2Alive with recurrence 2 5Alive without disease 38 93

The site of recurrenceWithin radiation field 1 2Outside radiation field 1 2

ModalityElectron 19 46Photon 22 54

Energy6 MV 16 4110 MV 6 156 MeV 18 4412 MeV 1 2

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has been applied to patients who did not achieve completeremission after H. pylori eradication therapy.

This report on the RT treatment of MALT lymphoma in avariety of sites with involved-field RT of 30 Gy shows goodclinical results. We have demonstrated that the PFS was90.6% at 5 years. Our findings demonstrated that RT-alonewas highly effective in achieving local control for localizedMALT lymphoma. These favorable outcomes after RT areconsistent with previous retrospective studies, whichadministered various doses of RT with a median of 25–40.5 Gy [15–24,26–30]. Many researchers concluded that30 Gy of RT could achieve excellent local control.

Although several groups treating solely MALT lymphomamentioned that 25–30 Gy is enough to control the disease[26,28], we also suggest that 30 Gy in 20 fr was appropriatefor controlling MALT lymphoma without severe detrimentaleffects. Shu et al. [51] reported that the 10-year actuarialrelapse-free survival, cause-specific survival, and overallsurvival rates were 93.1%, 97.9%, and 86.9%, respectively,for 48 orbital MALT lymphomas by RT of median 30.6 Gy(range; 5.4–30.6 Gy). Le et al. [52] reported 100% of the lo-cal control and recommended using a radiation dose of 30–30.6 Gy in 1.5–1.8 Gy fr for localized orbital MALT lym-phoma. Zhou et al. [53] also reported 100% of the local con-trol rate for orbital indolent lymphoma and concluded thata dose of 30 Gy was sufficient.

Table 4Acute and late toxicities in 15 gastrointestinal MALT lymphoma

No. of patients (%)

Grade 0 Grades 1–2 Grade 3

Acute toxicitiesDermatitis 14 (93%) 1 (7%) 0Mucotitis 8 (53%) 7 (47%) 0

Total 7 (47%) 8 (53%) 0

Late toxicitiesEdema 14 (93%) 1 (7%) 0Intestinal obstruction 13 (87%) 2 (13%) 0Pancreatitis 14 (93%) 1 (7%) 0Ulcer 14 (93%) 1 (7%) 0

Total 11 (73%) 4 (27%) 0

41 patients with stages I and II MALT ..., Radiother Oncol (2008),

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Several phase II studies demonstrated antitumor activityof the purine analogs fludarabine and cladribine [37,38].Chemotherapy alone (such as alkylating agent) series re-ported the significantly higher recurrence rate and cannotbe the standard therapy for local advanced gastric MALTlymphoma [39–41]. Other groups have also shown that theanti-CD20 monoclonal antibody rituximab was effectivefor MALT lymphoma [42,43]. These findings also will be fur-ther elucidated in large-scale clinical trials.

According to Hellenic Cooperative Oncology Group’sstudy [46], their patients received various commonly usedchemotherapy regimens. Anthracycline-based treatmentsor rituximab did not offer any survival advantages. As ritux-imab therapy was started only recently, the follow-up, how-ever, may have been too short to reveal any benefit. Otherretrospective studies also observed no difference in efficacybetween specific regimens [44,45], and several prospectivephase II trials reported similar results [41,42,47,48].

The most frequent sites in this study were the stomach,the orbital adnexa, the head and neck, and the small bowel.Despite the low number of patients in our study, this obser-vation is in agreement with other studies reporting the sal-ivary glands, the orbit, the lung, the intestine and the skinas the most common nongastric lymphoma sites [13,43–46].

The next problem that should be resolved is the optimaltarget volume for MALT lymphoma. There are only a fewstudies that clearly demonstrate the target volume in theliterature [16,21–23,25,27–29,31]. For gastric MALT lym-phomas, the entire stomach and perigastric nodes are con-sidered to be the target volume [28,29]. Olivier et al. [22]also delivered RT to the affected parotid gland with or with-out the first-echelon node for parotid lymphoma. On theone hand, Pfeffer et al. [49] showed that 4 of 12 patientswith orbital lymphoma who received partial orbital irradia-tion experienced recurrence. Thus it seems reasonable thatthe target volume for MALT lymphoma should include theentire affected organ.

ConclusionIn conclusion, the results from this retrospective study

confirm that RT was highly effective in achieving local con-trol for localized MALT lymphoma, and 30 Gy in 20 fr wasappropriate for controlling MALT lymphoma without severedetrimental effects.

* Corresponding author. Keiichi Nakagawa, Department ofRadiology, University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku,Tokyo, 113-8655 Japan. E-mail address: nakagawa-rad@h.u-to-kyo.ac.jp

Received 8 February 2008; received in revised form 14 March 2008;accepted 14 March 2008

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