- Email: [email protected]
Low-Grade Non-Hodgkin Lymphomas
Low-Grade Non-Hodgkin Lymphomas Richard W. Tsang, MD, FRCPC, and Mary K. Gospodarowicz, MD, FRCPC, FRCR (Hon) The most common low-grade non-Hodgkin lymphomas are of B-cell origin. This review will focus on follicular lymphomas and extranodal marginal zone lymphomas, also known as mucosa-associated lymphoid tissue (MALT) lymphomas. These are radiation-sensitive lymphomas. Moderate doses (30-35 Gy) for these stage I and II low-grade lymphomas result in long-term local control and possible cure. Involved-field radiation therapy is the standard approach and produces minimal morbidity. However, a significant proportion of patients relapse with systemic disease outside of radiation fields. For follicular lymphoma, this occurs in approximately 50% of patients after 15 years and for nongastric MALT lymphoma 30% to 40% after 10 years. Patients with relapsed disease are not curable with chemotherapy, but the disease often remains indolent and prolonged survival is observed. For gastric MALT lymphomas associated with Helicobacter pylori but which did not respond to antibiotic therapy, radiation treatment is indicated and almost always curative. For localized MALT lymphomas not related to microorganisms, radiation therapy is the initial standard therapy regardless of anatomic location. Patients with stage III and IV low-grade lymphoma and local symptoms are often successfully palliated with a low dose regimen of 2 ⴛ 2 Gy (total dose 4 Gy). Semin Radiat Oncol 17:198-205 © 2007 Elsevier Inc. All rights reserved.
T
he World Health Organization (WHO) Classification has defined many distinct clinical-pathologic diagnoses in the heterogeneous group of B-cell lymphomas.1 For clinicians, it has been common practice to categorize the most common types of indolent B-cell lymphomas into “lowgrade” lymphomas. The most common are follicular lymphomas, with mucosa-associated lymphoid tissue (MALT) lymphoma being second most common. Both are known to be radiation-sensitive diseases. Follicular lymphoma often involves lymph nodes and the bone marrow and is widely regarded as a systemic disease. However, up to one third of patients at the time of presentation have localized (stage I-II) disease after standard staging investigations.2 On the contrary, MALT lymphomas present with localized (stage IE-IIE) disease in 70% to 90% of cases, involving a variety of extranodal sites. Although curative therapy is not currently available for stage III-IV low-grade lymphomas, radiation therapy (RT) is potentially curative for those with localized stage I to II disease. This review will discuss the optimal use of external-beam RT in these 2 low-grade lymphomas, including expected benefits, technique, and side effects of therapy.
Department of Radiation Oncology, University of Toronto, Princess Margaret Hospital, Toronto, Ontario, Canada. Address reprint requests to Richard Tsang, MD, FRCPC, Princess Margaret Hospital, 610 University Ave, Toronto, Ontario, Canada M5G 2M9, E-mail: [email protected]
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1053-4296/07/$-see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.semradonc.2007.02.006
Small lymphocytic lymphomas are recognized as the tissue equivalent of chronic lymphocytic leukemia and will not be further discussed.
Stage I to II Follicular Lymphoma Stage I and II presentation of follicular lymphoma occurs in 22% to 33% of all cases.2,3 Patients with clinical stage I/II disease may have a normal bone marrow examination by morphology, but sensitive assays may detect a clonal population of B cells in the peripheral blood and/or bone marrow.4 However, the clinical significance of this finding in patients treated with local therapy is still uncertain. Patients present with a median age of 60 years, usually with a good performance status, no systemic symptoms, normal lactate dehydrogenase (LDH), and disease limited to 1 nodal region at a peripheral site (eg, cervical or inguinal locations). Involvement of extranodal tissues is less common, occurring in 25%.5
RT Alone Involved field radiation therapy (IFRT) produces local control in over 95% of patients, and 50% are relapse free at 10 years. Data from multiple institutions5-10 showed very similar results with over 90% local control, and 10-year relapse-free and overall survival rates of 40% to 50% and 60% to 80%, respectively (Table 1). A small study of selected stage I to II
Low-grade non-Hodgkin lymphomas
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Table 1 Stage I and II Follicular Lymphoma, Selected Treatment Results with Radiation Therapy (RT) with or without Chemotherapy First Author (year) Soubeyran, 1988 Kelsey, 1994 Vaughan Hudson, 1994 Pendlebury, 1995 MacManus, 1996 Wilder, 2001 Seymour, 2003 Petersen, 2004 Guadagnolo, 2006
Institution Fondation Bergonié, France BNLI BNLI Royal Marsden Hospital, London Stanford MDAH MDAH Princess Margaret Hospital JCRT, Boston
Treatment
Freedom from Relapse (10 y)
Overall Survival (10 y)
103
RT ⴞ CT
49%*
56%
148 (RCT)
RT ⴙ CT RT RT
42% 33% 47%
42% 52% 64%
RT
43%†
79%
Number of Patients
208 58 177 80 83 460
RT RT RT ⴙ CT RT
44% 41% (15 y) 72% 51%
64% 43% (15 y) 80% 62%
106
RT ⴞ CT
46%
75%
RCT ⴝ randomized controlled trial. *Relapse-free survival rate. †Progression-free survival rate.
patients (n ⫽ 43) who were observed with no initial treatment showed that 38% required therapy after a median of 86 months.11 Therefore, a policy of observation is not appropriate for all patients because a plateau in the disease-free survival curve for the radiation-treated patients beyond 15 years has been observed, suggesting that a proportion of patients are cured.5,7 After IFRT, relapses generally occur within the first 15 years of follow-up, and very late relapses are uncommon. The Princess Margaret Hospital data showed that, among patients at risk of relapse at the beginning of the specified time period, the probability of relapse between 5 to 10 years was 19%; for 10 to 15 years, 14%; for 15 to 20 years, 7%; and beyond 20 years, 4%.5 Relapse usually occurs at unirradiated sites, and tissue biopsy at the time of recurrence is essential to determine the histology because some will have transformed to diffuse large B-cell lymphoma. Treatment at the time of recurrence generally consists of chemotherapy, with RT useful in selected cases for palliation.
Prognostic Factors For patients treated with IFRT, prognostic factors predicting a high risk of relapse include age, stage II disease, presence of systemic symptoms, and tumor bulk.5,7,12 Grade 2 histology is also an adverse factor for relapse in the Stanford series.7 The follicular lymphoma international prognostic index (FLIPI) is based on 1795 patients, of whom about 22% had stage I to II disease. It defined 5 adverse prognostic factors for survival: age ⱖ60, stage III or IV disease, anemia with hemoglobin ⬍120 g/L, abnormal LDH, and disease involving ⱖ4 nodal sites.3 The definition of nodal regions is different from the description by Kaplan.13 Although extremely useful for advanced-stage patients, those with stage I to II disease often have none or only 1 of these factors, with 88% of patients belonging to the low-risk group.14 However, recognizing the
FLIPI factors is helpful in defining the minority of stage I/II patients who have a poorer prognosis14 and may not be suitable for IFRT as initial therapy. Patients with high tumor burden and/or a high proliferative activity (as manifested by many involved nodal sites, rapid clinical tumor growth, and/or high LDH) should be considered for more aggressive approaches with combined-modality therapy (CMT). In the FLIPI low-risk group (all stages), the expected 10-year overall survival is 71%,3 which is comparable to the outcome for stage I/II patient (Table 1).
RT and Chemotherapy (CMT) The addition of chemotherapy (eg, cyclophosphamide, vincristine, prednisone (CVP) or chlorambucil) tested in phase III trials in the 1970s did not show an overall survival advantage.15,16 Phase II trials of patients with unfavorable prognostic factors (constitutional symptoms and high LDH) treated with CMT, (eg, cyclophosphamide, oncovin (vincristine), prednisone (COP)-bleomycin, with or without doxorubicin) suggested a benefit for CMT compared with the RT alone results17 (Table 1). Because there is no definitive data showing a survival advantage with CMT, IFRT remains the standard therapy for patients with no adverse prognostic factors who want to be cured, whereas CMT is reserved as an option for those with high-risk disease. Given the evidence of benefit in adding rituximab to chemotherapy in stage III and IV patients,18 it is important to study if rituximab-containing combinations, with or without RT, may yield better results compared with RT alone for stage I and II patients. The exquisite radiosensitivity of follicular lymphoma makes the use of radioimmunotherapy attractive,19 either used alone or in combination with IFRT. However, there are no supportive data for its long-term efficacy in stage I to II disease at this time.
R.W. Tsang and M.K. Gospodarowicz
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Figure 1 (A) A 58-year-old woman with stage II follicular lymphoma (grade 2). CT scan shows bulky lymphadenopathy of paraortic area (6 ⫻ 9 cm) and additionally a 2 cm node in the left common iliac region (not shown). (B) Involved-field radiation therapy, with AP-PA opposing fields (18 MV photons-35 Gy in 20 fractions). The GTV (inner contour line), clinical target volume (CTV) (middle contour line), and planning target volume (PTV) (outer contour line) volumes are outlined on the digitally reconstructed radiograph. (Color version of figure is available online.)
RT Volume and Technique There is significant variation in RT practice for localized follicular lymphoma.20 RT target volume varies widely.7,21 The use of extended-field, subtotal, or total lymphoid irradiation at Stanford University gave a higher relapse-free rate of 67% at 10 years compared with 36% for patients treated to only 1 side of the diaphragm.7 However, the overall survival rate was similar.7 Extensive radiation causes immunosuppression and can compromise bone marrow reserve and is associated with a higher risk of second solid tumors. IFRT is currently the standard approach, with coverage of the grossly involved lymph node and the whole nodal region where it resides (Fig 1). For extranodal involvement, the RT coverage would follow the guidelines as for MALT lymphoma detailed later. With 30 to 35 Gy in 20 fractions given over a 4-week period, the local control rate is over 95%. The toxicity from local radiation to virtually any nodal region is mild and transient. In the head and neck area, precision in planning (eg, with intensity modulated radiation therapy) to minimize salivary gland tissue and mucosa exposure is important to reduce morbidity.
Marginal Zone Lymphoma, MALT Type MALT lymphomas present with stage I to II disease in 70% to 90% of cases.2,22-24 The most common anatomic sites are the stomach, orbit, salivary glands, lung, and skin and less commonly in aerodigestive mucosa, thyroid, breast, bladder, liver, and other tissues.25 A lymphocytic cellular infiltrate of
the organ appears to be a prerequisite for the development of MALT lymphoma, typically as a result of chronic infection or autoimmune disease. This is best exemplified by gastric MALT lymphoma in which the etiology is linked to infection with Helicobacter pylori. Recent data indicate an association of Chlamydia psittaci with orbital adnexal MALT lymphoma.26,27 Cutaneous MALT lymphoma has been associated with Borrelia burgdorferi infection in Europe,28 but 2 studies in the United States did not show such an association.29,30 In the salivary glands, MALT lymphoma is related to Sjögren’s syndrome and for thyroid lymphoma Hashimoto’s thyroiditis.
Gastric MALT Lymphoma Permanent regression of primary gastric MALT lymphoma after treatment with antibiotics indicate that eradication of H pylori is sufficient therapy for the majority of patients with H pylori–associated MALT lymphoma of the stomach.25,31-33 Recommended anti-Helicobacter triple-drug therapy includes a proton pump inhibitor (or ranitidine bismuth citrate), clarithromycin, and amoxicillin (or metronidazole).34 Eradication of H pylori is seen in over 90% of cases,34,35 soon after the completion of drug therapy, although disappearance of lymphoma can be delayed for many months, up to 12 to 18 months. Depending on the strictness of the response criteria, complete response rates for lymphoma vary from 50% to 95%. Molecular markers t(11;18)(q21;q21) and trisomy 3 predict for antibiotic resistance. The t(11;18)(q21;q21) translocation has also been found frequently in gastric MALT lymphoma not associated with H pylori.36 The presence of these markers or lack of response to H pylori eradication
Low-grade non-Hodgkin lymphomas therapy are the main indications to treat with definitive RT. Given the possibility of a delayed response, RT should not be recommended for asymptomatic patients with nonprogressive residual disease within the 9 to 12 months after successful H pylori– eradication therapy. Patients with minimal residual disease who remain asymptomatic can have an indolent course and not require further treatment.37 Other options in the management of antibiotic-resistant gastric MALT lymphoma involves the use of chlorambucil alone,38 rituximab,39 or combination chemotherapy. Regardless of the choice of treatment, the disease is generally indolent biologically.
Radiation Therapy for Disease Resistant to H pylori–Eradication Therapy The results of treatment with RT are excellent. In a small prospective series, Schechter and coworkers40 documented a 100% complete response rate after RT to a median dose of 30 Gy (range, 28.5-43.5 Gy). At a median follow-up of 27 months, no failures were observed.40 Other investigators23,41 documented similar results. A dose of 30 to 35 Gy appears
201 adequate, and relapse of MALT lymphoma rarely occurs after RT. In planning radiation for the stomach and regional lymph nodes, computed tomographic (CT) planning is indispensable and the principle and technique similar to that used for gastric carcinoma can be adapted for use. The intention is to deliver a tumor dose of 30 to 35 Gy to the entire stomach, paragastric, and celiac lymph nodes and limit the total dose to both kidneys to ⬍20 Gy while keeping a significant volume of liver (⬎50%) to low doses (⬍25 Gy). Stomach distention should be minimized by treating the patient in a fasting state and methods devised to deal with motion because of respiration. A conformal technique has been developed at the Princess Margaret Hospital. The clinical target volume is separated into a “superior” volume (treated with 6 megavolts (MV) anterior-posterior (AP)/18 MV posterior-anterior (PA) fields) and an “inferior” volume (treated with right and left lateral 18 MV fields, and 6 MV AP field). There is a common isocenter at the junction, with the AP field common to both volumes (Fig 2). The junction is chosen at a level where the stomach below the junction can be more effec-
Figure 2 Radiation treatment plan for gastric MALT lymphoma, with conformal 5 fields. Gastric GTV was determined by 4D CT (quiet inhale and exhale) at simulation. Prescribed dose 35 Gy in 20 fractions. See text for a detailed discussion. (A) The common AP field. (B) The right lateral wedged field. (C) Isodose distribution from an axial slice in the ‘inferior’ volume (below the isocenter). (Color version of figure is available online.)
202 tively treated with lateral fields while protecting the kidneys. Fields are shaped with multileaf collimators to minimize the exposure of the liver and the kidneys. Although dose constraints for the normal organs are always respected, the principle is to achieve dose exposure to as low as reasonably achievable (ALARA principle). Target motion is dealt with by a 4-dimensional CT scan performed during the respiratory cycle, and the stomach GTV during quiet inhalation and expiration is combined and then given an appropriate expansion to arrive at the CTV and PTV. The isodose distribution (Fig 2C) and dose-volume histograms for the target and organs at risk are reviewed to ensure full coverage of the target tissues and acceptable toxicity (Fig 3). Although transient nausea and anorexia is common with RT, no serious longterm toxicity such as ulceration or hemorrhage has been observed with the 30 to 35 Gy dose recommended for gastric MALT lymphoma.
Non-Gastric MALT Lymphomas The use of moderate dose RT for localized (stage I and II) MALT lymphomas results in a high rate of local control and often cure, although published reports have limited followup. IFRT with doses of 25 to 35 Gy is frequently possible for both common and rare presentations of the disease and results in ⬎95% local control.23,42,43 Relapse of lymphoma occurs in up to 40% of patients,23,44,45 usually in MALT sites distant to the primary lesion, or, for paired organs, to the contralateral site (eg, orbit and salivary gland).23,46
R.W. Tsang and M.K. Gospodarowicz
MALT Lymphoma of the Orbit Orbital lymphoma is the most common nongastric site and affects elderly patients with a median age in the sixth decade. These tumors typically involve the conjunctiva and eyelids or in deeper tissues including the lacrimal gland and retrobulbar areas. The treatment is directed to cure while preserving vision. This is achieved with low doses of RT (25-30 Gy in 10-20 daily fractions), expecting a local control rate of over 95%.23,43,47,48 The whole orbit should be treated because partial orbit irradiation resulted in a 33% relapse rate in a small series of patients.49 For anterior orbital lesions in the conjunctiva, a direct anterior beam with orthovoltage (250 kv), 4 MV photons, or electron beam can be used. An unmodified direct AP 6 MV photon beam would underdose an anterior conjunctival lesion located in the buildup region of the beam and is not recommended. A small lead shield suspended in front of the lens can reduce the lens dose to under 5% to 10%50 to minimize the risk of cataract formation to 10% or less. For unilateral retrobulbar lesions, a 2-field technique with an anterior and an oblique wedged field is satisfactory. Damage to the eye is not seen with doses of ⬍40 Gy.51 Shielding of the lacrimal gland would avoid dryness of the eye. Conjunctival MALT lymphoma treated with surgical excision only has been occasionally observed to regress spontaneously52 and is considered an option for a small, completely excised lesion. Contralateral orbit involvement is common either synchronously or metachronously. Distant failure rates vary from 20% to 50%, usually involving other MALT tissues, but indolent behavior is the rule, with prolonged survival observed.23,44,45 C psittaci DNA has been found in high frequency in orbital MALT lymphomas26 and may represent an agent leading to chronic lymphocytic infiltration predisposing the patient to orbital lymphomas. In a small study of 9 patients, eradication of Chlamydia with antibiotics has been documented to result in complete and partial responses of MALT lymphoma.27 A clinical trial with doxycycline is being conducted by the International Extranodal Lymphoma Study Group to assess the efficacy of antibiotic therapy.
MALT Lymphoma of the Salivary Glands
Figure 3 Dose-volume histogram for gastric MALT lymphoma. Note that 45% of the liver receives a dose of over 25 Gy, and 16% of the left kidney receives ⬎20 Gy, whereas ⬍5% of the right kidney receives ⬎20 Gy. (Color version of figure is available online.)
Patients with Sjögren’s syndrome are at risk for MALT lymphomas, specifically in the parotid glands but also infrequently in minor salivary glands. Middle-aged adults are affected, with a median age of 50 years. Bilateral parotid involvement is common. Radical parotidectomy is not indicated because of its potential morbidity. The use of IFRT ensures tissue preservation and local control. For stage IE disease, the whole parotid gland including the deep lobe is treated, with emphasis to spare the contralateral uninvolved gland (IMRT plan shown, Fig 4). A dose of 30 Gy will result in transient worsening of salivary flow, which is a significant issue in patients already affected by xerostomia because of the underlying Sjögren’s syndrome. Patients with stage IIE disease (cervical lymph node involvement) will require irradiation of the ipsilateral cervical nodal chain. Bilateral parotid lymphomas require bilateral parotid irradiation, either as 1 treatment course or sequentially, and there is a high risk of
Low-grade non-Hodgkin lymphomas
Figure 4 Radiation treatment plan for a stage IE MALT lymphoma of the left parotid gland (30 Gy in 20 fractions over 4 weeks). IMRT (6 MV photons) was used to spare the contralateral facial and neck tissues, with the right parotid gland dose limited to ⬍5 Gy. (Color version of figure is available online.)
moderate to severe xerostomia. Pretreatment dental assessment and meticulous follow-up with good dental hygiene is mandatory in such patients to preserve dentition.
MALT Lymphoma of the Skin Cutaneous MALT lymphomas are indolent, respond well to local therapy, and have excellent prognosis.53,54 Infection with Borrelia burgdorferi has been implicated in the pathogenesis of cutaneous B-cell lymphomas, although not confined to the MALT type.55 A study of 38 cases conducted in the United States did not show such an association,29 and another study showed no geographic correlation between the incidence of Lyme’s disease with cutaneous B-cell lymphoma.30 A small lesion that is completely excised does not require RT. For a larger solitary lesion, IFRT is preferred and results in high local control rates (85%-100%) and favorable survival.56 Electron beams with bolus material placed on the skin surface to achieve full skin dose is the standard approach. After local therapy, the relapse rate is high, frequently with new skin lesions, but death from MALT lymphoma is uncommon.54 Therefore, patients with multiple asymptomatic lesions may not require treatment, but lesions producing symptoms can be treated with IFRT with a high response rate.
MALT Lymphoma of Other Sites MALT lymphoma of the lung usually presents as multiple nodules or mass-like consolidation.57 Initial treatment may involve surgical resection, and, if resected completely with clear margins and no involvement of mediastinal lymph nodes, RT is not required. For unresected localized disease, IFRT usually results in local control.23 The low tolerance of lung tissue to RT limits its applicability to relatively small lesions as tissue exposed to a dose of 30 Gy or more will likely be permanently fibrosed on CT scan. The RT planning should use established technologies to deal with respiratory motion, such as a 4-dimensional CT scan and/or respiratory gating to arrive at appropriate margins. Extensive disease
203 should not be treated with RT because the disease is also responsive to chemotherapy,58 and prolonged survival is commonly observed regardless of the choice of initial therapy. Other locations of localized MALT lymphomas may include gastrointestinal tract distal to the stomach (small bowel, colon, and rectum), liver, upper aerodigestive tract mucosa (trachea, esophagus, pharynx, and oral cavity), thyroid gland, breast, thymus, genito-urinary tract (kidney, bladder, and prostate), uterine cervix, dura, and other rare sites. In general, the principles of management follow the description given earlier, with IFRT. Prophylactic coverage of regional lymph nodes is not mandatory, except for sites in which it is known that there is a high risk of regional nodal involvement or the lymph nodes are just proximal to and directly drain the primary lesion. Other options of treatment with alkylating agents, rituximab or even observation may also be appropriate depending on the clinical situation.22,24,44 A MALT lymphoma that has undergone complete excision with clear margins may not require IFRT. Given the indolent nature of MALT lymphomas, serious long-term side effects of irradiation, specifically radiation-induced cancers, although rare remains a concern for young patients. This is particularly relevant for some anatomic sites (eg, breast and lung) where the background incidence of epithelial cancer is high. The benefits of irradiation treatment for these sites must be carefully weighed against the potential additive effects of risk factors, such as a positive family history of breast cancer in a patient with breast MALT lymphoma and a heavy smoker in a patient with lung lymphoma.
Recurrence of Lymphoma After RT After IFRT for stage I and II MALT lymphomas, relapse of the disease occurs in up to 40% of patients.23,44,45 MALT lymphomas of the thyroid and stomach appear to have low relapse rates.23 The optimal management of relapsed disease is not well defined. Biopsy should be obtained to rule out transformation to diffuse large B-cell lymphoma. Localized relapse of MALT lymphoma usually involve a different mucosal site and is frequently amenable to further IFRT.23 The disease frequently remains indolent in behavior with prolonged survival possible.
Palliative RT for Advanced Low-Grade Lymphoma There are many systemic therapy options for patients with stage III and IV low-grade lymphomas. None are proven to be curative. Because of exquisite radiation sensitivity of the disease, frequently palliative RT is of value for local symptoms and often underused. High response rates (80%-90%) are observed with a low total dose of 4 Gy (2 ⫻ 2 Gy) for lowgrade lymphomas treated for palliation.59,60 The predominant mode of tumor cell death after low-dose RT is by apoptosis.61 These results recapitulate historical response rates of 71% to 83% for total body irradiation doses of 1.5 to 2.2 Gy (10-15 cGy per fraction, 2-3 fractions per week) given over
204 several weeks.62,63 The 2 ⫻ 2 Gy regimen is extremely well tolerated and does not negate reirradiation with a higherdose regimen for future local relapses.
Conclusions The expected outcome after moderate-dose RT (30-35 Gy) for stage I and II low-grade B-cell lymphoma is that of longterm local control and possible cure. A significant proportion of patients will relapse with systemic disease. In the case of follicular lymphoma, this occurs in approximately 50% of patients after 15 years and for nongastric MALT lymphoma 30% to 40% after 10 years. There is a growing understanding for the role of putative microorganisms responsible for lymphoma pathogenesis for some MALT lymphomas (eg, orbital adnexa). Molecular signatures of clinical relevance are also increasingly being identified. Because of the indolent nature of these lymphomas, longterm follow-up is required to test the effects of any new treatment approaches on survival. The relative rarity of localized disease, the long follow-up required, and competing mortality from unrelated causes are significant barriers to the conduct of phase III trials in these diseases. Therefore, participation in collaborative multi-institutional studies is an important avenue to define optimal strategies in management.
References 1. Jaffe ES, Harris NL, Stein H, et al: Pathology and Genetics of tumours of haematopoietic and lymphoid tissues, in Kleihues P, Sobin LH (eds): World Health Organization Classification of Tumours. Lyon, France, IARC Press, 2001 2. Armitage JO, Weisenburger DD: New approach to classifying nonHodgkin’s lymphomas: Clinical features of the major histologic subtypes. Non-Hodgkin’s Lymphoma Classification Project. J Clin Oncol 16:2780-2795, 1998 3. Solal-Celigny P, Roy P, Colombat P, et al: Follicular lymphoma international prognostic index. Blood 104:1258-1265, 2004 4. Ha CS, Cabanillas F, Lee M-S, et al: Serial determination of the bcl-2 gene in the bone marrow and peripheral blood after central lymphatic irradiation for stages I-III follicular lymphoma: A preliminary report. Clin Cancer Res 3:215-219, 1997 5. Petersen PM, Gospodarowicz M, Tsang R, et al: Long-term outcome in stage I and II follicular lymphoma following treatment with involved field radiation therapy alone. J Clin Oncol 22:563, 2004 6. Pendlebury S, el Awadi M, Ashley S, et al: Radiotherapy results in early stage low grade nodal non-Hodgkin’s lymphoma. Radiother Oncol 36: 167-71, 1995 7. Mac Manus M, Hoppe RT: Is radiotherapy curative for stage I and II low-grade follicular lymphoma? Results of a long-term follow-up study of patients treated at Stanford University. J Clin Oncol 14:1282-1290, 1996 8. Vaughan Hudson B, Vaughan Hudson G, MacLennan KA, et al: Clinical stage 1 non-Hodgkin’s lymphoma: long-term follow-up of patients treated by the British National Lymphoma Investigation with radiotherapy alone as initial therapy. Br J Cancer 69:1088-1093, 1994 9. Wilder RB, Jones D, Tucker SL, et al: Long-term results with radiotherapy for Stage I-II follicular lymphomas. Int J Radiat Oncol Biol Phys 51:1219-1227, 2001 10. Guadagnolo BA, Li S, Neuberg D, et al: Long-term outcome and mortality trends in early-stage, Grade 1-2 follicular lymphoma treated with radiation therapy. Int J Radiat Oncol Biol Phys 64:928-934, 2006
R.W. Tsang and M.K. Gospodarowicz 11. Advani R, Rosenberg SA, Horning SJ: Stage I and II follicular nonHodgkin’s lymphoma: Long-term follow-up of no initial therapy. J Clin Oncol 22:1454-1459, 2004 12. Soubeyran P, Eghbali H, Bonichon F, et al: Localized follicular lymphomas: Prognosis and survival of stages I and II in a retrospective series of 103 patients. Radiother Oncol 13:91-98, 1988 13. Kaplan HS, Rosenberg SA: The treatment of Hodgkin’s disease. Med Clin North Am 50:1591-610, 1966 14. Plancarte F, Lopez-Guillermo A, Arenillas L, et al: Follicular lymphoma in early stages: High risk of relapse and usefulness of the Follicular Lymphoma International Prognostic Index to predict the outcome of patients. Eur J Haematol 76:58-63, 2006 15. Nissen NI, Ersboll J, Hansen HS, et al: A randomized study of radiotherapy versus radiotherapy plus chemotherapy in stage I-II nonHodgkin’s lymphomas. Cancer 52:1-7, 1983 16. Kelsey SM, Newland AC, Hudson GV, et al: A British National Lymphoma Investigation randomised trial of single agent chlorambucil plus radiotherapy versus radiotherapy alone in low grade, localised nonHodgkins lymphoma. Med Oncol 11:19-25, 1994 17. Seymour JF, Pro B, Fuller LM, et al: Long-term follow-up of a prospective study of combined modality therapy for stage I-II indolent nonHodgkin’s lymphoma. J Clin Oncol 21:2115-2122, 2003 18. Marcus R, Imrie K, Belch A, et al: CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma. Blood 105:1417-1423, 2005 19. Kaminski MS, Tuck M, Estes J, et al: 131I-tositumomab therapy as initial treatment for follicular lymphoma. N Engl J Med 352:441-449, 2005 20. Tsang RW, Gospodarowicz MK, O’Sullivan B: Staging and management of localized non-Hodgkin’s lymphomas: Variations among experts in radiation oncology. Int J Radiat Oncol Biol Phys 52:643-651, 2002 21. Ha CS, Kong JS, Tucker SL, et al: Central lymphatic irradiation for stage I-III follicular lymphoma: Report from a single-institutional prospective study. Int J Radiat Oncol Biol Phys 57:316-320, 2003 22. Zucca E, Conconi A, Pedrinis E, et al: Nongastric marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue. Blood 101:24892495, 2003 23. Tsang RW, Gospodarowicz MK, Pintilie M, et al: Localized mucosaassociated lymphoid tissue lymphoma treated with radiation therapy has excellent clinical outcome. J Clin Oncol 21:4157-4164, 2003 24. Thieblemont C, Berger F, Dumontet C, et al: Mucosa-associated lymphoid tissue lymphoma is a disseminated disease in one third of 158 patients analyzed [published erratum appears in Blood 2000;95:2481]. Blood 95:802-806, 2000 25. Isaacson PG: Update on MALT lymphomas. Best Pract Res Clin Haematol 18:57-68, 2005 26. Ferreri AJ, Guidoboni M, Ponzoni M, et al: Evidence for an association between Chlamydia psittaci and ocular adnexal lymphomas. J Natl Cancer Inst 96:586-594, 2004 27. Ferreri AJ, Ponzoni M, Guidoboni M, et al: Regression of ocular adnexal lymphoma after Chlamydia psittaci-eradicating antibiotic therapy. J Clin Oncol 23:5067-5073, 2005 28. Cerroni L, Zochling N, Putz B, et al: Infection by Borrelia burgdorferi and cutaneous B-cell lymphoma. J Cutan Pathol 24:457-461, 1997 29. Wood GS, Kamath NV, Guitart J, et al: Absence of Borrelia burgdorferi DNA in cutaneous B-cell lymphomas from the United States. J Cutan Pathol 28:502-507, 2001 30. Munksgaard L, Frisch M, Melbye M, et al: Incidence patterns of lyme disease and cutaneous B-cell non-Hodgkin’s lymphoma in the United States. Dermatology 201:351-352, 2000 31. Fischbach W, Goebeler-Kolve ME, Dragosics B, et al: Long term outcome of patients with gastric marginal zone B cell lymphoma of mucosa associated lymphoid tissue (MALT) following exclusive Helicobacter pylori eradication therapy: Experience from a large prospective series. Gut 53:34-37, 2004 32. Inagaki H, Nakamura T, Li C, et al: Gastric MALT lymphomas are divided into three groups based on responsiveness to Helicobacter Pylori eradication and detection of API2-MALT1 fusion. Am J Surg Pathol 28:1560-1567, 2004
Low-grade non-Hodgkin lymphomas 33. Zucca E, Bertoni F, Roggero E, et al: The gastric marginal zone B-cell lymphoma of MALT type. Blood 96:410-419, 2000 34. Malfertheiner P, Megraud F, O’Morain C, et al: Current concepts in the management of Helicobacter pylori infection—The Maastricht 2-2000 Consensus Report. Aliment Pharmacol Ther 16:167-80, 2002 35. Marshall BJ, Windsor HM: The relation of Helicobacter pylori to gastric adenocarcinoma and lymphoma: pathophysiology, epidemiology, screening, clinical presentation, treatment, and prevention. Med Clin North Am 89:313-344, 2005 36. Ye H, Liu H, Raderer M, et al: High incidence of t(11;18)(q21;q21) in Helicobacter pylori-negative gastric MALT lymphoma. Blood 101: 2547-2550, 2003 37. Fischbach W, Goebeler-Kolve M, Starostik P, et al: Minimal residual low-grade gastric MALT-type lymphoma after eradication of Helicobacter pylori. Lancet 360:547-548, 2002 38. Bertoni F, Conconi A, Capella C, et al: Molecular follow-up in gastric mucosa-associated lymphoid tissue lymphomas: Early analysis of the LY03 cooperative trial. Blood 99:2541-2544, 2002 39. Martinelli G, Laszlo D, Ferreri AJ, 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 23:19791983, 2005 40. Schechter NR, Portlock CS, Yahalom J: Treatment of mucosa-associated lymphoid tissue lymphoma of the stomach with radiation alone. J Clin Oncol 16:1916-1921, 1998 41. Fung CY, Grossbard ML, Linggood RM, et al: Mucosa-associated lymphoid tissue lymphoma of the stomach: Long term outcome after local treatment. Cancer 85:9-17, 1999 42. Hitchcock S, Ng AK, Fisher DC, et al: Treatment outcome of mucosaassociated lymphoid tissue/marginal zone non-Hodgkin’s lymphoma. Int J Radiat Oncol Biol Phys 52:1058-1066, 2002 43. Le QT, Eulau SM, George TI, et al: Primary radiotherapy for localized orbital MALT lymphoma. Int J Radiat Oncol Biol Phys 52:657-663, 2002 44. Zinzani PL, Magagnoli M, Galieni P, et al: Nongastrointestinal lowgrade mucosa-associated lymphoid tissue lymphoma: Analysis of 75 patients. J Clin Oncol 17:1254-1258, 1999 45. Thieblemont C, Bastion Y, Berger F, et al: Mucosa-associated lymphoid tissue gastrointestinal and nongastrointestinal lymphoma behavior: Analysis of 108 patients. J Clin Oncol 15:1624-1630, 1997 46. Tsang RW, Gospodarowicz MK: Management of localized (stage I and II) clinically aggressive lymphomas. Ann Hematol 80:B66-B72, 2001 (suppl 3) 47. Uno T, Isobe K, Shikama N, et al: Radiotherapy for extranodal, marginal zone, B-cell lymphoma of mucosa-associated lymphoid tissue originating in the ocular adnexa: A multiinstitutional, retrospective review of 50 patients. Cancer 98:865-871, 2003
205 48. Fung CY, Tarbell NJ, Lucarelli MJ, et al: Ocular adnexal lymphoma: clinical behavior of distinct World Health Organization classification subtypes. Int J Radiat Oncol Biol Phys 57:1382-1391, 2003 49. Pfeffer MR, Rabin T, Tsvang L, et al: Orbital lymphoma: Is it necessary to treat the entire orbit? Int J Radiat Oncol Biol Phys 60:527-530, 2004 50. Dunbar SF, Linggood RM, Doppke KP, et al: Conjunctival lymphoma: results and treatment with a single anterior electron field. A lens sparing approach. Int J Radiat Oncol Biol Phys 19:249-257, 1990 51. Gordan KB, Char DH, Sagerman RH: Late effects of radiation on the eye and ocular adnexa. Int J Radiat Oncol Biol Phys 31:1123-1139, 1995 52. Matsuo T, Yoshino T: Long-term follow-up results of observation or radiation for conjunctival malignant lymphoma. Ophthalmology 111: 1233-1237, 2004 53. Cerroni L, Signoretti S, Hofler G, et al: Primary cutaneous marginal zone B-cell lymphoma: A recently described entity of low-grade malignant cutaneous B-cell lymphoma. Am J Surg Pathol 21:1307-1315, 1997 54. Willemze R, Jaffe ES, Burg G, et al: WHO-EORTC classification for cutaneous lymphomas. Blood 105:3768-3785, 2005 55. Roggero E, Zucca E, Mainetti C, et al: Eradication of Borrelia burgdorferi infection in primary marginal zone B-cell lymphoma of the skin. Hum Pathol 31:263-268, 2000 56. Rijlaarsdam JU, Toonstra J, Meijer O, et al: Treatment of primary cutaneous B-cell lymphomas of follicle center cell origin: A clinical follow-up study of 55 patients treated with radiotherapy or polychemotherapy. J Clin Oncol 14:549-555, 1996 57. King LJ, Padley SP, Wotherspoon AC, et al: Pulmonary MALT lymphoma: imaging findings in 24 cases. Eur Radiol 10:1932-1938, 2000 58. Zinzani PL, Tani M, Gabriele A, et al: Extranodal marginal zone B-cell lymphoma of MALT-type of the lung: single-center experience with 12 patients. Leuk Lymphoma 44:821-824, 2003 59. 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 21:2474-2480, 2003 60. Johannsson J, Specht L, Mejer J, et al: Phase II study of palliative low-dose local radiotherapy in disseminated indolent non-Hodgkin’s lymphoma and chronic lymphocytic leukemia. Int J Radiat Oncol Biol Phys 54:1466-1470, 2002 61. Haas RL, de Jong D, Valdes Olmos RA, et al: In vivo imaging of radiation-induced apoptosis in follicular lymphoma patients. Int J Radiat Oncol Biol Phys 59:782-787, 2004 62. Hoppe RT, Kushlan P, Kaplan HS, et al: The treatment of advanced stage favorable histology non-Hodgkin’s lymphoma: A preliminary report of a randomized trial comparing single agent chemotherapy, combination chemotherapy, and whole body irradiation. Blood 58:592598, 1981 63. Roncadin M, Arcicasa M, Zagonel V, et al: Total body irradiation and prednimustine in chronic lymphocytic leukemia and low grade nonHodgkin’s lymphoma. Cancer 74:978-984, 1994
T
he World Health Organization (WHO) Classification has defined many distinct clinical-pathologic diagnoses in the heterogeneous group of B-cell lymphomas.1 For clinicians, it has been common practice to categorize the most common types of indolent B-cell lymphomas into “lowgrade” lymphomas. The most common are follicular lymphomas, with mucosa-associated lymphoid tissue (MALT) lymphoma being second most common. Both are known to be radiation-sensitive diseases. Follicular lymphoma often involves lymph nodes and the bone marrow and is widely regarded as a systemic disease. However, up to one third of patients at the time of presentation have localized (stage I-II) disease after standard staging investigations.2 On the contrary, MALT lymphomas present with localized (stage IE-IIE) disease in 70% to 90% of cases, involving a variety of extranodal sites. Although curative therapy is not currently available for stage III-IV low-grade lymphomas, radiation therapy (RT) is potentially curative for those with localized stage I to II disease. This review will discuss the optimal use of external-beam RT in these 2 low-grade lymphomas, including expected benefits, technique, and side effects of therapy.
Department of Radiation Oncology, University of Toronto, Princess Margaret Hospital, Toronto, Ontario, Canada. Address reprint requests to Richard Tsang, MD, FRCPC, Princess Margaret Hospital, 610 University Ave, Toronto, Ontario, Canada M5G 2M9, E-mail: [email protected]
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1053-4296/07/$-see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.semradonc.2007.02.006
Small lymphocytic lymphomas are recognized as the tissue equivalent of chronic lymphocytic leukemia and will not be further discussed.
Stage I to II Follicular Lymphoma Stage I and II presentation of follicular lymphoma occurs in 22% to 33% of all cases.2,3 Patients with clinical stage I/II disease may have a normal bone marrow examination by morphology, but sensitive assays may detect a clonal population of B cells in the peripheral blood and/or bone marrow.4 However, the clinical significance of this finding in patients treated with local therapy is still uncertain. Patients present with a median age of 60 years, usually with a good performance status, no systemic symptoms, normal lactate dehydrogenase (LDH), and disease limited to 1 nodal region at a peripheral site (eg, cervical or inguinal locations). Involvement of extranodal tissues is less common, occurring in 25%.5
RT Alone Involved field radiation therapy (IFRT) produces local control in over 95% of patients, and 50% are relapse free at 10 years. Data from multiple institutions5-10 showed very similar results with over 90% local control, and 10-year relapse-free and overall survival rates of 40% to 50% and 60% to 80%, respectively (Table 1). A small study of selected stage I to II
Low-grade non-Hodgkin lymphomas
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Table 1 Stage I and II Follicular Lymphoma, Selected Treatment Results with Radiation Therapy (RT) with or without Chemotherapy First Author (year) Soubeyran, 1988 Kelsey, 1994 Vaughan Hudson, 1994 Pendlebury, 1995 MacManus, 1996 Wilder, 2001 Seymour, 2003 Petersen, 2004 Guadagnolo, 2006
Institution Fondation Bergonié, France BNLI BNLI Royal Marsden Hospital, London Stanford MDAH MDAH Princess Margaret Hospital JCRT, Boston
Treatment
Freedom from Relapse (10 y)
Overall Survival (10 y)
103
RT ⴞ CT
49%*
56%
148 (RCT)
RT ⴙ CT RT RT
42% 33% 47%
42% 52% 64%
RT
43%†
79%
Number of Patients
208 58 177 80 83 460
RT RT RT ⴙ CT RT
44% 41% (15 y) 72% 51%
64% 43% (15 y) 80% 62%
106
RT ⴞ CT
46%
75%
RCT ⴝ randomized controlled trial. *Relapse-free survival rate. †Progression-free survival rate.
patients (n ⫽ 43) who were observed with no initial treatment showed that 38% required therapy after a median of 86 months.11 Therefore, a policy of observation is not appropriate for all patients because a plateau in the disease-free survival curve for the radiation-treated patients beyond 15 years has been observed, suggesting that a proportion of patients are cured.5,7 After IFRT, relapses generally occur within the first 15 years of follow-up, and very late relapses are uncommon. The Princess Margaret Hospital data showed that, among patients at risk of relapse at the beginning of the specified time period, the probability of relapse between 5 to 10 years was 19%; for 10 to 15 years, 14%; for 15 to 20 years, 7%; and beyond 20 years, 4%.5 Relapse usually occurs at unirradiated sites, and tissue biopsy at the time of recurrence is essential to determine the histology because some will have transformed to diffuse large B-cell lymphoma. Treatment at the time of recurrence generally consists of chemotherapy, with RT useful in selected cases for palliation.
Prognostic Factors For patients treated with IFRT, prognostic factors predicting a high risk of relapse include age, stage II disease, presence of systemic symptoms, and tumor bulk.5,7,12 Grade 2 histology is also an adverse factor for relapse in the Stanford series.7 The follicular lymphoma international prognostic index (FLIPI) is based on 1795 patients, of whom about 22% had stage I to II disease. It defined 5 adverse prognostic factors for survival: age ⱖ60, stage III or IV disease, anemia with hemoglobin ⬍120 g/L, abnormal LDH, and disease involving ⱖ4 nodal sites.3 The definition of nodal regions is different from the description by Kaplan.13 Although extremely useful for advanced-stage patients, those with stage I to II disease often have none or only 1 of these factors, with 88% of patients belonging to the low-risk group.14 However, recognizing the
FLIPI factors is helpful in defining the minority of stage I/II patients who have a poorer prognosis14 and may not be suitable for IFRT as initial therapy. Patients with high tumor burden and/or a high proliferative activity (as manifested by many involved nodal sites, rapid clinical tumor growth, and/or high LDH) should be considered for more aggressive approaches with combined-modality therapy (CMT). In the FLIPI low-risk group (all stages), the expected 10-year overall survival is 71%,3 which is comparable to the outcome for stage I/II patient (Table 1).
RT and Chemotherapy (CMT) The addition of chemotherapy (eg, cyclophosphamide, vincristine, prednisone (CVP) or chlorambucil) tested in phase III trials in the 1970s did not show an overall survival advantage.15,16 Phase II trials of patients with unfavorable prognostic factors (constitutional symptoms and high LDH) treated with CMT, (eg, cyclophosphamide, oncovin (vincristine), prednisone (COP)-bleomycin, with or without doxorubicin) suggested a benefit for CMT compared with the RT alone results17 (Table 1). Because there is no definitive data showing a survival advantage with CMT, IFRT remains the standard therapy for patients with no adverse prognostic factors who want to be cured, whereas CMT is reserved as an option for those with high-risk disease. Given the evidence of benefit in adding rituximab to chemotherapy in stage III and IV patients,18 it is important to study if rituximab-containing combinations, with or without RT, may yield better results compared with RT alone for stage I and II patients. The exquisite radiosensitivity of follicular lymphoma makes the use of radioimmunotherapy attractive,19 either used alone or in combination with IFRT. However, there are no supportive data for its long-term efficacy in stage I to II disease at this time.
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Figure 1 (A) A 58-year-old woman with stage II follicular lymphoma (grade 2). CT scan shows bulky lymphadenopathy of paraortic area (6 ⫻ 9 cm) and additionally a 2 cm node in the left common iliac region (not shown). (B) Involved-field radiation therapy, with AP-PA opposing fields (18 MV photons-35 Gy in 20 fractions). The GTV (inner contour line), clinical target volume (CTV) (middle contour line), and planning target volume (PTV) (outer contour line) volumes are outlined on the digitally reconstructed radiograph. (Color version of figure is available online.)
RT Volume and Technique There is significant variation in RT practice for localized follicular lymphoma.20 RT target volume varies widely.7,21 The use of extended-field, subtotal, or total lymphoid irradiation at Stanford University gave a higher relapse-free rate of 67% at 10 years compared with 36% for patients treated to only 1 side of the diaphragm.7 However, the overall survival rate was similar.7 Extensive radiation causes immunosuppression and can compromise bone marrow reserve and is associated with a higher risk of second solid tumors. IFRT is currently the standard approach, with coverage of the grossly involved lymph node and the whole nodal region where it resides (Fig 1). For extranodal involvement, the RT coverage would follow the guidelines as for MALT lymphoma detailed later. With 30 to 35 Gy in 20 fractions given over a 4-week period, the local control rate is over 95%. The toxicity from local radiation to virtually any nodal region is mild and transient. In the head and neck area, precision in planning (eg, with intensity modulated radiation therapy) to minimize salivary gland tissue and mucosa exposure is important to reduce morbidity.
Marginal Zone Lymphoma, MALT Type MALT lymphomas present with stage I to II disease in 70% to 90% of cases.2,22-24 The most common anatomic sites are the stomach, orbit, salivary glands, lung, and skin and less commonly in aerodigestive mucosa, thyroid, breast, bladder, liver, and other tissues.25 A lymphocytic cellular infiltrate of
the organ appears to be a prerequisite for the development of MALT lymphoma, typically as a result of chronic infection or autoimmune disease. This is best exemplified by gastric MALT lymphoma in which the etiology is linked to infection with Helicobacter pylori. Recent data indicate an association of Chlamydia psittaci with orbital adnexal MALT lymphoma.26,27 Cutaneous MALT lymphoma has been associated with Borrelia burgdorferi infection in Europe,28 but 2 studies in the United States did not show such an association.29,30 In the salivary glands, MALT lymphoma is related to Sjögren’s syndrome and for thyroid lymphoma Hashimoto’s thyroiditis.
Gastric MALT Lymphoma Permanent regression of primary gastric MALT lymphoma after treatment with antibiotics indicate that eradication of H pylori is sufficient therapy for the majority of patients with H pylori–associated MALT lymphoma of the stomach.25,31-33 Recommended anti-Helicobacter triple-drug therapy includes a proton pump inhibitor (or ranitidine bismuth citrate), clarithromycin, and amoxicillin (or metronidazole).34 Eradication of H pylori is seen in over 90% of cases,34,35 soon after the completion of drug therapy, although disappearance of lymphoma can be delayed for many months, up to 12 to 18 months. Depending on the strictness of the response criteria, complete response rates for lymphoma vary from 50% to 95%. Molecular markers t(11;18)(q21;q21) and trisomy 3 predict for antibiotic resistance. The t(11;18)(q21;q21) translocation has also been found frequently in gastric MALT lymphoma not associated with H pylori.36 The presence of these markers or lack of response to H pylori eradication
Low-grade non-Hodgkin lymphomas therapy are the main indications to treat with definitive RT. Given the possibility of a delayed response, RT should not be recommended for asymptomatic patients with nonprogressive residual disease within the 9 to 12 months after successful H pylori– eradication therapy. Patients with minimal residual disease who remain asymptomatic can have an indolent course and not require further treatment.37 Other options in the management of antibiotic-resistant gastric MALT lymphoma involves the use of chlorambucil alone,38 rituximab,39 or combination chemotherapy. Regardless of the choice of treatment, the disease is generally indolent biologically.
Radiation Therapy for Disease Resistant to H pylori–Eradication Therapy The results of treatment with RT are excellent. In a small prospective series, Schechter and coworkers40 documented a 100% complete response rate after RT to a median dose of 30 Gy (range, 28.5-43.5 Gy). At a median follow-up of 27 months, no failures were observed.40 Other investigators23,41 documented similar results. A dose of 30 to 35 Gy appears
201 adequate, and relapse of MALT lymphoma rarely occurs after RT. In planning radiation for the stomach and regional lymph nodes, computed tomographic (CT) planning is indispensable and the principle and technique similar to that used for gastric carcinoma can be adapted for use. The intention is to deliver a tumor dose of 30 to 35 Gy to the entire stomach, paragastric, and celiac lymph nodes and limit the total dose to both kidneys to ⬍20 Gy while keeping a significant volume of liver (⬎50%) to low doses (⬍25 Gy). Stomach distention should be minimized by treating the patient in a fasting state and methods devised to deal with motion because of respiration. A conformal technique has been developed at the Princess Margaret Hospital. The clinical target volume is separated into a “superior” volume (treated with 6 megavolts (MV) anterior-posterior (AP)/18 MV posterior-anterior (PA) fields) and an “inferior” volume (treated with right and left lateral 18 MV fields, and 6 MV AP field). There is a common isocenter at the junction, with the AP field common to both volumes (Fig 2). The junction is chosen at a level where the stomach below the junction can be more effec-
Figure 2 Radiation treatment plan for gastric MALT lymphoma, with conformal 5 fields. Gastric GTV was determined by 4D CT (quiet inhale and exhale) at simulation. Prescribed dose 35 Gy in 20 fractions. See text for a detailed discussion. (A) The common AP field. (B) The right lateral wedged field. (C) Isodose distribution from an axial slice in the ‘inferior’ volume (below the isocenter). (Color version of figure is available online.)
202 tively treated with lateral fields while protecting the kidneys. Fields are shaped with multileaf collimators to minimize the exposure of the liver and the kidneys. Although dose constraints for the normal organs are always respected, the principle is to achieve dose exposure to as low as reasonably achievable (ALARA principle). Target motion is dealt with by a 4-dimensional CT scan performed during the respiratory cycle, and the stomach GTV during quiet inhalation and expiration is combined and then given an appropriate expansion to arrive at the CTV and PTV. The isodose distribution (Fig 2C) and dose-volume histograms for the target and organs at risk are reviewed to ensure full coverage of the target tissues and acceptable toxicity (Fig 3). Although transient nausea and anorexia is common with RT, no serious longterm toxicity such as ulceration or hemorrhage has been observed with the 30 to 35 Gy dose recommended for gastric MALT lymphoma.
Non-Gastric MALT Lymphomas The use of moderate dose RT for localized (stage I and II) MALT lymphomas results in a high rate of local control and often cure, although published reports have limited followup. IFRT with doses of 25 to 35 Gy is frequently possible for both common and rare presentations of the disease and results in ⬎95% local control.23,42,43 Relapse of lymphoma occurs in up to 40% of patients,23,44,45 usually in MALT sites distant to the primary lesion, or, for paired organs, to the contralateral site (eg, orbit and salivary gland).23,46
R.W. Tsang and M.K. Gospodarowicz
MALT Lymphoma of the Orbit Orbital lymphoma is the most common nongastric site and affects elderly patients with a median age in the sixth decade. These tumors typically involve the conjunctiva and eyelids or in deeper tissues including the lacrimal gland and retrobulbar areas. The treatment is directed to cure while preserving vision. This is achieved with low doses of RT (25-30 Gy in 10-20 daily fractions), expecting a local control rate of over 95%.23,43,47,48 The whole orbit should be treated because partial orbit irradiation resulted in a 33% relapse rate in a small series of patients.49 For anterior orbital lesions in the conjunctiva, a direct anterior beam with orthovoltage (250 kv), 4 MV photons, or electron beam can be used. An unmodified direct AP 6 MV photon beam would underdose an anterior conjunctival lesion located in the buildup region of the beam and is not recommended. A small lead shield suspended in front of the lens can reduce the lens dose to under 5% to 10%50 to minimize the risk of cataract formation to 10% or less. For unilateral retrobulbar lesions, a 2-field technique with an anterior and an oblique wedged field is satisfactory. Damage to the eye is not seen with doses of ⬍40 Gy.51 Shielding of the lacrimal gland would avoid dryness of the eye. Conjunctival MALT lymphoma treated with surgical excision only has been occasionally observed to regress spontaneously52 and is considered an option for a small, completely excised lesion. Contralateral orbit involvement is common either synchronously or metachronously. Distant failure rates vary from 20% to 50%, usually involving other MALT tissues, but indolent behavior is the rule, with prolonged survival observed.23,44,45 C psittaci DNA has been found in high frequency in orbital MALT lymphomas26 and may represent an agent leading to chronic lymphocytic infiltration predisposing the patient to orbital lymphomas. In a small study of 9 patients, eradication of Chlamydia with antibiotics has been documented to result in complete and partial responses of MALT lymphoma.27 A clinical trial with doxycycline is being conducted by the International Extranodal Lymphoma Study Group to assess the efficacy of antibiotic therapy.
MALT Lymphoma of the Salivary Glands
Figure 3 Dose-volume histogram for gastric MALT lymphoma. Note that 45% of the liver receives a dose of over 25 Gy, and 16% of the left kidney receives ⬎20 Gy, whereas ⬍5% of the right kidney receives ⬎20 Gy. (Color version of figure is available online.)
Patients with Sjögren’s syndrome are at risk for MALT lymphomas, specifically in the parotid glands but also infrequently in minor salivary glands. Middle-aged adults are affected, with a median age of 50 years. Bilateral parotid involvement is common. Radical parotidectomy is not indicated because of its potential morbidity. The use of IFRT ensures tissue preservation and local control. For stage IE disease, the whole parotid gland including the deep lobe is treated, with emphasis to spare the contralateral uninvolved gland (IMRT plan shown, Fig 4). A dose of 30 Gy will result in transient worsening of salivary flow, which is a significant issue in patients already affected by xerostomia because of the underlying Sjögren’s syndrome. Patients with stage IIE disease (cervical lymph node involvement) will require irradiation of the ipsilateral cervical nodal chain. Bilateral parotid lymphomas require bilateral parotid irradiation, either as 1 treatment course or sequentially, and there is a high risk of
Low-grade non-Hodgkin lymphomas
Figure 4 Radiation treatment plan for a stage IE MALT lymphoma of the left parotid gland (30 Gy in 20 fractions over 4 weeks). IMRT (6 MV photons) was used to spare the contralateral facial and neck tissues, with the right parotid gland dose limited to ⬍5 Gy. (Color version of figure is available online.)
moderate to severe xerostomia. Pretreatment dental assessment and meticulous follow-up with good dental hygiene is mandatory in such patients to preserve dentition.
MALT Lymphoma of the Skin Cutaneous MALT lymphomas are indolent, respond well to local therapy, and have excellent prognosis.53,54 Infection with Borrelia burgdorferi has been implicated in the pathogenesis of cutaneous B-cell lymphomas, although not confined to the MALT type.55 A study of 38 cases conducted in the United States did not show such an association,29 and another study showed no geographic correlation between the incidence of Lyme’s disease with cutaneous B-cell lymphoma.30 A small lesion that is completely excised does not require RT. For a larger solitary lesion, IFRT is preferred and results in high local control rates (85%-100%) and favorable survival.56 Electron beams with bolus material placed on the skin surface to achieve full skin dose is the standard approach. After local therapy, the relapse rate is high, frequently with new skin lesions, but death from MALT lymphoma is uncommon.54 Therefore, patients with multiple asymptomatic lesions may not require treatment, but lesions producing symptoms can be treated with IFRT with a high response rate.
MALT Lymphoma of Other Sites MALT lymphoma of the lung usually presents as multiple nodules or mass-like consolidation.57 Initial treatment may involve surgical resection, and, if resected completely with clear margins and no involvement of mediastinal lymph nodes, RT is not required. For unresected localized disease, IFRT usually results in local control.23 The low tolerance of lung tissue to RT limits its applicability to relatively small lesions as tissue exposed to a dose of 30 Gy or more will likely be permanently fibrosed on CT scan. The RT planning should use established technologies to deal with respiratory motion, such as a 4-dimensional CT scan and/or respiratory gating to arrive at appropriate margins. Extensive disease
203 should not be treated with RT because the disease is also responsive to chemotherapy,58 and prolonged survival is commonly observed regardless of the choice of initial therapy. Other locations of localized MALT lymphomas may include gastrointestinal tract distal to the stomach (small bowel, colon, and rectum), liver, upper aerodigestive tract mucosa (trachea, esophagus, pharynx, and oral cavity), thyroid gland, breast, thymus, genito-urinary tract (kidney, bladder, and prostate), uterine cervix, dura, and other rare sites. In general, the principles of management follow the description given earlier, with IFRT. Prophylactic coverage of regional lymph nodes is not mandatory, except for sites in which it is known that there is a high risk of regional nodal involvement or the lymph nodes are just proximal to and directly drain the primary lesion. Other options of treatment with alkylating agents, rituximab or even observation may also be appropriate depending on the clinical situation.22,24,44 A MALT lymphoma that has undergone complete excision with clear margins may not require IFRT. Given the indolent nature of MALT lymphomas, serious long-term side effects of irradiation, specifically radiation-induced cancers, although rare remains a concern for young patients. This is particularly relevant for some anatomic sites (eg, breast and lung) where the background incidence of epithelial cancer is high. The benefits of irradiation treatment for these sites must be carefully weighed against the potential additive effects of risk factors, such as a positive family history of breast cancer in a patient with breast MALT lymphoma and a heavy smoker in a patient with lung lymphoma.
Recurrence of Lymphoma After RT After IFRT for stage I and II MALT lymphomas, relapse of the disease occurs in up to 40% of patients.23,44,45 MALT lymphomas of the thyroid and stomach appear to have low relapse rates.23 The optimal management of relapsed disease is not well defined. Biopsy should be obtained to rule out transformation to diffuse large B-cell lymphoma. Localized relapse of MALT lymphoma usually involve a different mucosal site and is frequently amenable to further IFRT.23 The disease frequently remains indolent in behavior with prolonged survival possible.
Palliative RT for Advanced Low-Grade Lymphoma There are many systemic therapy options for patients with stage III and IV low-grade lymphomas. None are proven to be curative. Because of exquisite radiation sensitivity of the disease, frequently palliative RT is of value for local symptoms and often underused. High response rates (80%-90%) are observed with a low total dose of 4 Gy (2 ⫻ 2 Gy) for lowgrade lymphomas treated for palliation.59,60 The predominant mode of tumor cell death after low-dose RT is by apoptosis.61 These results recapitulate historical response rates of 71% to 83% for total body irradiation doses of 1.5 to 2.2 Gy (10-15 cGy per fraction, 2-3 fractions per week) given over
204 several weeks.62,63 The 2 ⫻ 2 Gy regimen is extremely well tolerated and does not negate reirradiation with a higherdose regimen for future local relapses.
Conclusions The expected outcome after moderate-dose RT (30-35 Gy) for stage I and II low-grade B-cell lymphoma is that of longterm local control and possible cure. A significant proportion of patients will relapse with systemic disease. In the case of follicular lymphoma, this occurs in approximately 50% of patients after 15 years and for nongastric MALT lymphoma 30% to 40% after 10 years. There is a growing understanding for the role of putative microorganisms responsible for lymphoma pathogenesis for some MALT lymphomas (eg, orbital adnexa). Molecular signatures of clinical relevance are also increasingly being identified. Because of the indolent nature of these lymphomas, longterm follow-up is required to test the effects of any new treatment approaches on survival. The relative rarity of localized disease, the long follow-up required, and competing mortality from unrelated causes are significant barriers to the conduct of phase III trials in these diseases. Therefore, participation in collaborative multi-institutional studies is an important avenue to define optimal strategies in management.
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