Patients With H pylori–Independent MALT Lymphoma Are Curable With Radiotherapy

After more than two decades of successful laboratory and clinical research, the "new" entity of mucosa-associated lymphoid tissue (MALT) lymphoma is reaching a noble maturity. Large series have demonstrated that most patients diagnosed with MALT lymphoma will be cured with relatively gentle and safe therapies, and evidence-based algorithms guide treatment with relatively minor controversies. The authors of this concise and practical review are well recognized for their important contributions to our current understanding of the disease. Their state-of-the-art review lucidly highlights the pathological, biological, and genetic information that has been accumulating in the literature and that has implications for treatment decisions. A good example of such clinically relevant information is the finding that the presence of chromosomal translocation t(11,18) in gastric MALT lymphoma strongly suggests that eradication of Helicobacter pylori is unlikely to result in lymphoma regression; in such cases, radiotherapy, the most effective therapy for MALT lymphoma, should be initiated without delay.

The principles of the approach suggested by Bertoni et al for treatment of the most common entity, gastric MALT lymphoma, are in general acceptable. However, the suggested guidelines still leave some clinically relevant questions unsettled. Indeed, in H pylori carriers, it is standard of care to attempt to achieve complete regression of the lymphoma with one or two courses of antibiotics. It is also fully recognized that the process of lymphoma regression may be protracted. Thus, if the lymphoma has not disappeared soon after successful antibiotic treatment, but the patient is asymptomatic and repeated endoscopies indicate that the lymphoma is regressing or remains stable, there should be no rush to initiate localized moderate-dose radiation therapy (RT). However, many patients and clinicians, at some point during this period of expectant observation, decide to initiate RT to the stomach. It is a reasonable choice, since RT is a relatively brief and simple treatment that now has a long track record of safety. After RT, the expected 10-year cause-specific survival is in the range of 98% to 99%.[1]

Practical questions remain: (1) Should a patient who has no evidence of H pylori infection receive an antibiotic trial (or trials) and additional endoscopies and no lymphoma-specific treatment? (2) Should expectant observation (and repeated endoscopies) be continued in patients in whom H pylori has been eradicated, but in whom the remaining lymphoma shows t(11,18) or has clinical features of deep-wall penetration or lymph node involvement (both associated with poor likelihood of lymphoma response to antibiotic treatment)? (3) Since RT is so effective in this often localized disease (as the authors clearly describe), what are the special circumstances that will support a systemic treatment approach (rituximab [Rituxan] and/or chemotherapy) in lieu of RT?

The National Comprehensive Cancer Network (NCCN), an alliance of 21 of the leading US cancer centers, updated its guidelines in 2011.[2] For gastric MALT, the NCCN lymphoma team does not recommend antibiotics for H pylori–negative patients. Indeed, lymphoma regression after antibiotics has almost never been observed by NCCN lymphoma experts in patients in whom no H pylori was present; thus, a trial of antibiotics followed by more endoscopies is probably futile in such patients.[2]

The NCCN guidelines recommend RT as the preferred treatment for H pylori–negative patients and for patients with persistent lymphoma whose H pylori status has become negative after antibiotic treatment but who are symptomatic or who show progression of disease (even if their H pylori status remains unchanged after antibiotics). RT is also recommended for patients whose lymphoma has relapsed after successful antibiotic therapy. While radiation therapy is the NCCN’s preferred modality for stage IE-IIE disease, rituximab therapy is an acceptable option “if RT is contraindicated.”[2] Contraindication to RT is quite unusual given that a moderate dose of RT is highly effective and is administered to only the involved organ.

MALT lymphoma is a very indolent disease. Unlike the other indolent lymphomas-follicular lymphomas and chronic lymphocytic leukemia/small lymphocytic lymphoma-most MALT lymphomas are localized to one organ and are less likely to involve multiple organs or to spread systemically. Nonetheless, the infiltration of an organ by MALT lymphoma may produce local symptoms and affect organ function, may progress locally, and may carry a risk of transformation to diffuse large B-cell lymphoma. Thus, eventual eradication of the lymphoma is desirable.

Surgery as an alternative local treatment is often incomplete, and remaining involved margins require additional therapy. Although in the past some surgeons have advocated partial or total gastrectomy for gastric MALT lymphoma, the gastrectomy approach should be abandoned due to its high morbidity and loss of organ function; on the other hand, moderate-dose RT alone almost always achieves a complete eradication of the lymphoma, with minimal short- or long-term side effects. Surgery, however, is occasionally adequate for elimination of skin lymphomas and for easily resected lung lesions (where RT may be more damaging).

In H pylori–independent gastric lymphoma and in almost all other localized non-gastric MALT lymphomas, RT should be considered the treatment of choice. It should be limited to the involved organ or to the involved site (in skin lymphomas), and because of the exquisite sensitivity of MALT lymphoma to radiation, relatively low doses have resulted in complete response (CR) rates of 98% to 99%. The 10-year recurrence-free rate in a series of 192 patients from Toronto who were treated primarily with RT was 76% (almost all relapses were distant or in a contralateral paired organ). The 10-year cause-specific survival rate was 98%.[1] A recent update of the Memorial Sloan-Kettering Cancer Center series of 103 patients with H pylori–independent gastric MALT lymphoma who were treated with RT showed a biopsy proven CR rate of 98%; 10-year freedom from local failure and freedom from lymphoma failure were 93% and 82%, respectively.[3]

The standard RT dose recommended for stomach MALT lymphoma and MALT lymphomas of most non-gastric organs is 30 Gy (in 20 fractions). Orbital adnexae and even salivary lesions often respond completely to 24 Gy. In cases of advanced-stage marginal zone lymphoma, in patients in whom there is a risk to organ function, or in cases where palliation is required, RT may be applied in the above doses. However, some clinicians have had favorable experience in MALT lymphomas using a very low dose of RT of only two fractions of 2 Gy each (“boom-boom”), which may also be applied to large fields; this approach has achieved a lasting CR rate of approximately 50% to 60% (median, 20 to 24 months) and PR in most remaining patients.[4]

While anti CD20 antibody therapy (rituximab) and/or systemic chemotherapy is an appropriate approach for advanced-stage MALT lymphomas, it has not been shown to be an adequate alternative to RT in patients with localized disease. In one study, rituximab had a response rate of 73%, but the median response duration was only 10.5 months.[5] A retrospective analysis from multiple institutions of different treatment approaches in multiple stages (including systemic therapy) in patients with nongastric MALT lymphomas has not shown an advantage for a specific approach[6]; however, a prospective study is still necessary to support an alternative approach to the excellent results obtained with localized RT.

Nowadays, modern RT expertise in the use of moderate- or low-dose radiation applied to only the organ or site involved, along with proper treatment planning, should be available to any patient with localized MALT lymphoma who requires therapy.

Financial Disclosure:The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

REFERENCES

1. Goda JS, Gospodarowicz M, Pintillie M, et al. Long-term outcome in localized extranodal mucosa-associated lymphoid tissue lymphomas treated with radiotherapy. Cancer. 2010;116:3815-24.

2. NCCN lymphoma guideline version 2.2011. Available from: http://www.nccn.org.

3. Yahalom J. MALT lymphomas: a radiation oncology viewpoint. Ann Hematol. 2001;80(Suppl 3):B100-5. (updated for International Extranodal Lymphoma Study Group, 2010 (http://www.ielsg.org)

4. Haas RL, Poortmans P, de Jong D, et al. High response rates and lasting remissions after low-dose involved field radiotherapy in indolent lymphomas. J Clin Oncol. 2003;21:2474-80.

5. Conconi A, Martinelli G, Thielemont C, et al. Clinical activity of rituximab in extranodal marginal zone B-cell lymphoma of MALT type. Blood. 2003;102:2741-5.

6. Zucca E, Conconi A, Pedrinis E, et al. Nongastric marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue. Blood. 2003;101:2489-95.