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Initial treatment of limited stage diffuse large B cell lymphoma

Initial treatment of limited stage diffuse large B cell lymphoma
Literature review current through: Jan 2024.
This topic last updated: May 17, 2021.

INTRODUCTION — Diffuse large B cell lymphoma (DLBCL) is the most common histologic subtype of non-Hodgkin lymphoma (NHL), accounting for approximately 30 percent of patients with NHL. Initial treatment of DLBCL is determined by the disease stage (table 1). For treatment purposes, patients with DLBCL are generally classified as having either limited stage disease (stage I or II) or advanced stage disease (stage III or IV).

This topic will discuss initial treatment of limited stage DLBCL.

Clinical manifestations, diagnosis, staging, prognostic measures, treatment of advanced stage DLBCL, and management of relapsed disease are presented separately.

(See "Epidemiology, clinical manifestations, pathologic features, and diagnosis of diffuse large B cell lymphoma".)

(See "Pretreatment evaluation and staging of non-Hodgkin lymphomas".)

(See "Initial treatment of advanced stage diffuse large B cell lymphoma".)

(See "Diffuse large B cell lymphoma (DLBCL): Suspected first relapse or refractory disease in patients who are medically fit".)

Primary mediastinal B cell lymphoma and so-called "gray zone" and "double-hit" lymphomas are no longer considered categories of DLBCL [1] and are discussed separately. (See "Primary mediastinal large B cell lymphoma" and "Epidemiology, clinical manifestations, pathologic features, and diagnosis of diffuse large B cell lymphoma", section on '"Gray zone lymphoma"'.)

GOALS OF CARE — The goals of care for patients with limited stage DLBCL are to achieve long-term survival/cure while reducing short-term and long-term toxicity. Long-term survival generally requires multiagent chemoimmunotherapy to achieve and sustain a complete remission.

For some medically-frail patients who cannot tolerate intensive therapy, the goals of care are to relieve symptoms, improve the quality of life, and prolong survival.

ONCOLOGIC EMERGENCIES — Oncologic emergencies are uncommon with limited stage DLBCL, but clinicians should be alert for them, including:

Tumor lysis syndrome (TLS) is uncommon with limited stage DLBCL, but the risk is increased for patients with high tumor burden, bulky disease, kidney disease, and/or elevated pretreatment lactate dehydrogenase (LDH) or uric acid. Symptoms of TLS may include nausea, vomiting, dyspnea, palpitations, lethargy, and joint discomfort. Diagnosis and management of TLS are discussed separately. (See "Tumor lysis syndrome: Pathogenesis, clinical manifestations, definition, etiology and risk factors" and "Tumor lysis syndrome: Prevention and treatment".)

Superior vena cava (SVC) syndrome may be seen in patients with bulky mediastinal disease. Swelling of the face or neck and dyspnea are common presenting symptoms. If SVC syndrome is suspected, the severity of symptoms should be assessed clinically, imaging obtained (algorithm 1), and SVC syndrome should be managed as discussed separately. (See "Malignancy-related superior vena cava syndrome".)

Spinal cord compression can cause pain, mechanical instability of the spine, and potentially irreversible loss of neurologic function. Most patients present with back and/or radicular pain that may be accompanied by motor or sensory findings, and/or bladder or bowel dysfunction. Evaluation and management of suspected epidural spinal cord compression are discussed separately. (See "Clinical features and diagnosis of neoplastic epidural spinal cord compression" and "Treatment and prognosis of neoplastic epidural spinal cord compression".)

Other, less common oncologic emergencies that may accompany the initial presentation of DLBCL are discussed separately. (See "Clinical presentation and initial evaluation of non-Hodgkin lymphoma", section on 'Oncologic emergencies'.)

PRETREATMENT EVALUATION — Details of the pathologic evaluation of DLBCL are presented separately. (See "Epidemiology, clinical manifestations, pathologic features, and diagnosis of diffuse large B cell lymphoma", section on 'Pathology'.)

Pretreatment evaluation of the patient with DLBCL should determine the stage of disease and assess comorbid illnesses that may affect tolerance for therapy. We suggest pretreatment discussion in the context of a multidisciplinary tumor board, to consider the risks and benefits of various approaches to therapy, when possible. Radiation oncology should consult for patients with bulky disease, a dominant skeletal site of involvement, and site(s) of involvement where local control is important (eg, spinal cord compression or nerve root compression) [2].

Clinical evaluation — Prior to treatment, the patient should be evaluated for B symptoms (ie, fever, drenching sweats, unexplained weight loss). Physical examination should evaluate lymph node-bearing areas, including Waldeyer's ring, and assess the size of the liver and spleen. History and physical examination should also seek evidence of comorbid illnesses (eg, heart disease, renal dysfunction) that might affect tolerance for combination chemotherapy.

Neurologic findings (eg, unexplained headache, cranial neuropathies, focal weakness, radiculopathy, new gait abnormalities) should prompt evaluation of the central nervous system (CNS). (See 'Imaging' below and 'Bone marrow and CSF examination' below.)

Performance status should be assessed by the Eastern Cooperative Oncology Group (ECOG) scale (table 2).

Laboratory studies — Laboratory studies should include:

Complete blood count (CBC) with differential count.

Serum chemistries, including electrolytes, kidney and liver function tests, comprehensive metabolic panel, calcium, phosphorus, lactate dehydrogenase (LDH), uric acid.

Hepatitis B surface antigen and core antibody (because chemoimmunotherapy increases the risk of hepatitis B reactivation); testing for hepatitis C and human immunodeficiency virus (HIV) should be performed, as appropriate. (See "Hepatitis B virus reactivation associated with immunosuppressive therapy".)

Imaging — Imaging is required for staging (table 1), to assess cardiac function, and to evaluate involvement of the CNS or extranodal sites in selected patients. We suggest the following:

Whole body positron emission tomography (PET)/non-contrast enhanced computed tomography (CT); diagnostic quality CT with contrast should be performed, as clinically warranted.

Echocardiogram or radionuclide ventriculography to assess left ventricular ejection fraction.

Magnetic resonance imaging (MRI) should be performed for patients with neurologic findings (eg, unexplained headache, cranial neuropathies, focal weakness, radiculopathy, new gait abnormalities); CT with intravenous contrast is an acceptable alternative for patients with a contraindication to MRI (eg, pacemaker).

Some experts suggest performing an MRI for patients at higher risk for CNS involvement, including those with >1 extranodal site or certain extranodal sites (eg, kidney, adrenal gland, testis).

Management of patients with CNS involvement by DLBCL is discussed separately. (See "Secondary central nervous system lymphoma: Treatment and prognosis".)

Bone marrow and CSF examination — Bone marrow examination and lumbar puncture (LP) with evaluation of cerebrospinal fluid (CSF) should be performed for some patients who present with DLBCL.

Bone marrow examination – Unless PET indicates bone marrow involvement, bone marrow examination should be performed; however, some experts only perform a bone marrow examination if the finding of a discordant histology in bone marrow would alter management [3,4]. Bone marrow should be evaluated by histology, flow cytometry, cytogenetics, and molecular studies. Detection of bone marrow involvement upstages the disease to advanced stage DLBCL (stage IV); management of advanced stage DLBCL is discussed separately. (See "Initial treatment of advanced stage diffuse large B cell lymphoma".)

Evaluation of CSF – Patients with DLBCL do not require routine pretreatment LP for evaluation of CSF. Some experts suggest performing an LP for patients with neurologic findings on clinical evaluation; evidence of leptomeningeal involvement by MRI (or CT); >1 extranodal site; or involvement of certain extranodal sites (eg, kidney, adrenal gland, testis). Evaluation and management of patients with CNS involvement is discussed separately. (See "Secondary central nervous system lymphoma: Clinical features and diagnosis", section on 'Lumbar puncture' and "Secondary central nervous system lymphoma: Treatment and prognosis".)

Staging — Staging of DLBCL is based on the Lugano modification of the Ann Arbor system (table 1) [3].

Prognostic indices — We suggest evaluation using both the International Prognostic Index (IPI) and the CNS-IPI.

IPI (table 3) is calculated by assigning one point for each of the following:

Age (>60 years)

Serum LDH above normal

ECOG performance status (PS) ≥2

Ann Arbor stage III or IV

Number of sites of extranodal disease

CNS-IPI is a validated instrument for assessing risk of CNS relapse in patients treated with R-CHOP for DLBCL [5]. The CNS-IPI is calculated by assigning one point for each of the following, and summing the points:

Kidney and/or adrenal glands involved

Age >60 years

LDH above normal

ECOG PS >1

Stage III/IV disease

Extranodal involvement of ≥2 sites

Risk of CNS relapse is classified according to the sum of points; the risk of CNS relapse after two years follows [5]:

Low (0 to 1 points) – 0.6 percent two-year CNS relapse rate

Intermediate (2 to 3 points) – 3.4 percent two-year CNS relapse rate

High (4 to 6 points) – 10.2 percent two-year CNS relapse rate

Use of the CNS-IPI for consideration of CNS prophylaxis is discussed below. (See 'CNS prophylaxis' below.)

INITIAL TREATMENT — Limited stage DLBCL comprises Ann Arbor stage I and II (table 1). The mainstay of therapy for limited stage DLBCL is chemoimmunotherapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone); we cap the total vincristine dose at 2 mg to limit neurotoxicity; some experts instead cap the vincristine dose at 3 mg [6]. R-CHOP may be administered alone, or it may be given with radiation therapy (RT) as combined modality therapy (CMT).

Treatment stratification — We stratify initial treatment of limited stage DLBCL according to the presence of adverse prognostic features (algorithm 2 and algorithm 3), as follows:

No adverse features – For patients with normal serum lactate dehydrogenase (LDH), Eastern Cooperative Oncology Group performance status (ECOG PS) 0 to 1, and no bulky disease, we suggest an abbreviated course of R-CHOP, as described below. (See 'No adverse features' below.)

Adverse features, but no bulky disease – For patients with elevated LDH and/or ECOG PS ≥2 (table 3), but no bulky disease, treatment may involve a course of R-CHOP alone or CMT (abbreviated course of R-CHOP followed by RT); the choice of treatment may be influenced by comorbid illness or patient preference. The nature and schedule of treatment can either be predetermined ("conventional approach") or adjusted according to a risk-adapted approach; for risk-adapted therapy, results of an interval positron emission tomography (PET) performed after the first three treatments with R-CHOP inform the subsequent course of therapy. Conventional and risk-adapted approaches to therapy are discussed below. (See 'Adverse features, but no bulky disease' below.)

Bulky disease – For patients with bulky disease (≥10 cm diameter), treatment may involve a course of R-CHOP alone or CMT (R-CHOP followed by RT). The nature and schedule of treatment can either be predetermined ("conventional approach") or adjusted according to a risk-adapted approach, based on results of an interval PET after the first three treatments with R-CHOP. Conventional and risk-adapted approaches to therapy are discussed below. (See 'Bulky disease' below.)

Management of limited stage DLBCL may require modification for certain scenarios, as described below. (See 'Special scenarios' below.)

No adverse features — For patients with no adverse features (ie, no bulky disease, normal LDH, ECOG PS 0 to 1) (algorithm 2), we suggest four cycles of R-CHOP rather than six or more cycles of R-CHOP, CMT, or RT alone. This suggestion is based on the apparently equivalent efficacy but reduced toxicity of four cycles of R-CHOP, compared with the other approaches in this low-risk population; longer-term follow-up should provide improved estimates of efficacy and toxicity. Some experts favor adding two treatments with rituximab alone, after completing four cycles of R-CHOP.

The suggestion for four cycles of R-CHOP is based on a phase 3 non-inferiority trial (FLYER) of 592 patients ≤60 years with stage I-II DLBCL and no adverse risk factors [7]. This trial reported that four cycles of R-CHOP (followed by two additional treatments of rituximab alone) was not inferior to six cycles of R-CHOP, and was associated with less toxicity. After median follow-up of 66 months, four cycles of R-CHOP was associated with 96 percent (95% CI 94-99) three-year progression-free survival (PFS), which was 3 percent better than six cycles of R-CHOP, and was associated with less hematologic and nonhematologic toxicity. Estimated five-year overall survival (OS), PFS, and event-free survival (EFS) did not differ between arms of the trial. There were two deaths, both in the six-cycle arm. Although the FLYER trial included only patients <60 years old, the authors consider that the conclusions can be interpreted as extending to older patients, as well.

Excellent outcomes after four cycles of chemotherapy alone were also reported in the LYSA/GOELAMS 02-03 trial, which included patients with low tumor burden limited stage DLBCL who received no further treatment after negative PET following four cycles of R-CHOP-14 alone (described below) [8]. (See 'CMT versus chemoimmunotherapy alone' below.)

Adverse features, but no bulky disease — For patients with elevated LDH and/or ECOG PS ≥2, but no bulky disease (algorithm 2), we favor a risk-adapted approach to therapy, but it is also acceptable to select a treatment strategy without risk-adaptation ("conventional management"). No studies have directly compared risk-adapted therapy versus conventional management.

Risk-adapted therapy — Risk-adapted therapy refers to treatment decisions informed by results of an interval PET performed on day 18 to 20 after the start of the third cycle of R-CHOP ("PET3"), as follows:

PET3-negative – For PET3-negative (ie, Deauville 1 to 3) disease, we suggest treatment with one additional cycle of R-CHOP (ie, a total of four cycles of R-CHOP), rather than more than four cycles of R-CHOP or addition of RT (ie, R-CHOP X 3 plus RT), based on excellent long-term outcomes with four cycles of R-CHOP and the desire to avoid additional toxicity of RT or further chemotherapy [9].

PET3-positive – For PET3-positive disease, we distinguish between:

Partial response – For patients with limited residual fluorodeoxyglucose (FDG)-avidity (eg, a small focus of Deauville 4 to 5 activity), we consider three additional cycles of R-CHOP (ie, six total cycles of R-CHOP) versus treatment with 30 Gy ISRT with an additional boost of 6 to 10 Gy to the FDG-avid area (with no further chemoimmunotherapy; ie, total of three cycles of R-CHOP) as equally acceptable approaches.

Refractory disease – For patients with more extensive Deauville 4 to 5 disease, we suggest a biopsy of the FDG-avid tissue:

-For patients with little or no residual/viable disease (ie, extensive necrosis or inflammatory infiltrate), we treat with six total cycles of R-CHOP followed by 30 Gy ISRT with 6 to 10 Gy boost to FDG-avid area.

-For patients with biopsy-proven refractory disease, management is discussed separately. (See "Diffuse large B cell lymphoma (DLBCL): Suspected first relapse or refractory disease in patients who are medically fit".)

The S1001 cooperative group study used a risk-adapted approach and reported excellent outcomes for both PET3-negative and PET3-positive patients [9]. Following three cycles of R-CHOP, central review indicated that 89 percent of 132 patients were PET3-negative; there were no cases of primary refractory disease. Patients who were PET3-negative received one additional cycle of R-CHOP (ie, four total cycles), while 12 patients who were PET3-positive received 36 Gy involved-field radiation therapy (IFRT), up to 9 Gy boost to FDG-avid areas, plus ibritumomab tiuxetan (anti-CD20 monoclonal antibody conjugated to the radioisotope, yttrium-90). With median follow-up of five years, estimated five-year PFS was 87 percent (95% CI 79-92 percent) and five-year OS was 89 percent (95% CI 82-94 percent); outcomes were similar for PET3-negative and PET3-positive patients. Overall, only six patients progressed and three died as a result of lymphoma. Among the 132 patients, grade ≥3 adverse events included neutropenia (31 percent), febrile neutropenia (10 percent), and thrombocytopenia (8 percent); one patient died with sepsis and one died with hypoxia. The adequacy of four cycles of R-CHOP is also supported by results from the FLYER trial, described above [7].

There is controversy regarding use of risk-adapted therapy for limited stage DLBCL. Several studies have reported that negative interval PET was associated with higher EFS and OS [10-13]. As an example, in a prospective study, PET scan was performed after two cycles of R-CHOP (PET2); in 138 evaluable patients, compared with PET2-negative patients, those with positive PET2 had inferior two-year EFS (48 versus 74 percent, respectively), but two-year OS was not significantly different [14]. In the PETAL trial, positive interval PET was associated with inferior EFS and OS; however, treatment intensification for positive PET did not improve outcomes in patients treated with R-CHOP [15]. However, in one prospective and one retrospective study, PET status was associated with minor or no difference in two-year PFS [16,17]. Other studies also report limited prognostic value for PET in patients with limited stage DLBCL treated with R-CHOP [14,18-20].

Conventional management — For patients who did not undergo interval PET evaluation, we consider treatment with either six cycles of R-CHOP alone or CMT with three cycles of R-CHOP plus 30 Gy ISRT to be equally acceptable.

The choice of chemoimmunotherapy alone versus CMT is influenced by adverse effects, comorbid conditions, and personal preference. As examples, for patients in whom RT may cause substantial early morbidity (eg, involvement of the oronasopharynx or pelvis) or late toxicity (young women whose breasts would be in the RT field) we strongly favor treatment with chemoimmunotherapy alone. Conversely, the lower total dose of doxorubicin from an abbreviated course of chemotherapy associated with CMT may be preferred for a patient with marginal cardiac function.

The suggested regimens of R-CHOP alone versus CMT described above achieve similar outcomes in this setting. For either approach, 5- and 10-year OS rates are approximately 95 and 75 percent, respectively, but outcomes may vary according to the International Prognostic Index (IPI) (table 3) [21].

Importantly, we suggest not treating limited stage DLBCL with RT alone because it is associated with a high rate of relapse and inferior survival when compared with R-CHOP alone or CMT. (See 'Radiation alone is not acceptable' below.)

Management of special scenarios (eg, bulky disease, limited cardiac functions, testicular lymphoma) is discussed below. (See 'Special scenarios' below.)

Bulky disease — Treatment of limited stage DLBCL with bulky disease should include six cycles of R-CHOP plus RT (ie, CMT). We consider bulky disease to be a tumor mass ≥10 cm in diameter, but other definitions (eg, 5 cm, 7.0 cm, 7.5 cm) have been used in some settings.

The nature and schedule of treatment for bulky disease can either be predetermined ("conventional approach") or adjusted according to a risk-adapted approach (algorithm 3). For risk-adapted therapy, interval PET after the six cycles of R-CHOP ("PET6") may enable less intensive treatment for patients who are PET6-negative:

Conventional approach – We suggest six cycles of R-CHOP followed by 30 to 40 Gy ISRT. (See 'Combined modality therapy (CMT)' below.)

Risk-adapted therapy – Treat with six cycles of R-CHOP followed by PET6:

PET-negative (ie, Deauville 1 to 3) – For PET-negative disease, we treat with 30 Gy ISRT.

PET-positive – For PET-positive disease, we distinguish between:

-Partial response – For patients with limited residual FDG-avid disease (eg, a small focus of Deauville 4 to 5 activity), we treat with 30 Gy ISRT followed by an additional boost of 6 to 10 Gy to the FDG-avid area.

-Refractory disease – For patients with more extensive Deauville 4 to 5 disease, we suggest a biopsy of the FDG-avid tissue. For patients with little residual/viable disease, we treat with 30 Gy ISRT followed by an additional boost of 6 to 10 Gy to the FDG-avid area. For patients with biopsy-proven refractory disease, management is discussed separately. (See "Diffuse large B cell lymphoma (DLBCL): Suspected first relapse or refractory disease in patients who are medically fit".)

Some studies report that adding RT to chemoimmunotherapy may improve outcomes for patients with bulky disease, but this is not well-proven. A prospective study (RICOVER-noRTh) treated patients ≥60 years with bulky disease with six cycles of R-CHOP-14 (biweekly cycles), but no RT; outcomes from RICOVER-noRTh were compared with the same chemoimmunotherapy plus RT from the prospective RICOVER-60 trial [22,23]. Multivariate analysis reported that elimination of RT was associated with inferior EFS, PFS, and OS, but interpretation of these findings is constrained by poor patient accrual and substantial cross-over to unplanned RT in the RICOVER-noRTh study [22].

Limiting the total amount of doxorubicin is particularly important if the heart is in the RT field. The suggestion for six cycles of R-CHOP plus RT is based on findings from the RICOVER trials (described above) and the MabThera International Trial (MInT) trial, which included patients with bulky disease and compared outcomes with six cycles of R-CHOP to historical controls [23-25].

TREATMENT MODALITIES

Chemoimmunotherapy — The preferred chemoimmunotherapy for DLBCL is R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) (table 4).

Compared to CHOP alone (ie, chemotherapy without rituximab), treatment with R-CHOP achieves superior outcomes with no significant increase in toxicity. R-CHOP was established as the standard chemoimmunotherapy treatment for DLBCL based on randomized trials that demonstrated that, compared with CHOP alone, addition of rituximab to CHOP improved event-free survival (EFS), progression-free survival (PFS), and overall survival (OS) and halved lymphoma-related deaths. No other chemoimmunotherapy regimen has been shown to achieve a balance of efficacy and toxicity that is superior to R-CHOP.

Addition of rituximab to chemotherapy achieved superior long-term outcomes in the phase 3 MabThera International (MInT) Trial [24,25]. In this trial, 813 patients were randomly assigned to CHOP-like chemotherapy with or without rituximab. Stage II or bulky stage I disease was present in 72 percent, and those with bulky or extranodal disease also received radiation therapy (RT). Chemoimmunotherapy was superior to chemotherapy alone with regard to six-year OS (90 percent; 95% CI 86-93 versus 80 percent; 95% CI 75-84, respectively), EFS, and PFS. Addition of rituximab did not increase acute or long-term toxicity, including second malignancies. Other randomized trials also demonstrated the superiority of R-CHOP to CHOP [26,27].

The number of cycles of R-CHOP is stratified according to the presence of adverse prognostic features. For most patients with limited stage DLBCL who are treated with chemoimmunotherapy alone, we suggest six cycles of R-CHOP rather than eight cycles, based on the phase 3 MInT trial, which reported that eight cycles of R-CHOP increased toxicity, but did not improve outcomes [24,25]. Four cycles of R-CHOP is acceptable for selected patients with highly favorable prognosis, as described above. (See 'Initial treatment' above.)

Although other chemoimmunotherapy regimens and schedules have been used to treat DLBCL, none has a more favorable balance of outcomes and toxicity than R-CHOP. Examples include dose-dense R-CHOP-14 (R-CHOP with 14-day treatment cycles), dose-adjusted R-EPOCH (rituximab, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin), and ACVBP (doxorubicin, cyclophosphamide, vindesine, bleomycin, prednisone) followed by consolidation with methotrexate, etoposide, ifosfamide, cytarabine [28,29].

Treatment suggestions for older, frail, and cardiac-limited patients are described below. (See 'Frail/limited cardiac function' below.)

Cell of origin (COO; eg, germinal center versus activated B cell phenotypes) and other molecular analyses do not currently inform treatment selection for limited stage DLBCL; this differs from treatment of advanced stage DLBCL. (See "Initial treatment of advanced stage diffuse large B cell lymphoma", section on 'Treatment'.)

We consider biosimilar agents that are approved by the US Food and Drug Administration (FDA) or European Medicines Agency (EMA) to be acceptable substitutes for rituximab.

Combined modality therapy (CMT) — CMT refers to treatment with chemoimmunotherapy (typically R-CHOP) followed by consolidative RT. The number of cycles of R-CHOP and dose of RT vary with disease stage, adverse features, and individual risk factors.

Choice of chemoimmunotherapy in CMT — R-CHOP is the standard chemoimmunotherapy for CMT in DLBCL. The number of cycles of R-CHOP varies with the presentation (eg, elevated serum lactate dehydrogenase [LDH], poor Eastern Cooperative Oncology Group performance status [ECOG PS], bulky disease), as discussed above. (See 'Initial treatment' above.)

In SWOG 0014, patients with limited stage DLBCL and at least one adverse risk factor were treated with three cycles of R-CHOP plus involved-field RT (40 to 46 gray [Gy]) [30]. With >5-year median follow-up, 4-year PFS and OS were 88 and 92 percent, respectively. Outcomes with CMT that included alternative chemoimmunotherapy are not well-defined.

Radiation dose and field size in CMT — The dose and volume of RT used in CMT must be individualized, based on the stage of disease, anatomic involvement, and potential toxicity to adjacent organs. Importantly, RT alone is not an acceptable treatment for limited stage DLBCL. (See 'Radiation alone is not acceptable' below.)

When possible, we seek to reduce the dose and volume of RT to optimize the balance of benefit and toxicity. For CMT in patients with non-bulky disease, we generally treat with 30 Gy involved-site RT (ISRT) (algorithm 2). However, for patients with positive PET3 (Deauville 4 to 5) or with bulky disease, we generally boost the fluorodeoxyglucose (FDG)-avid sites to 36 to 40 Gy. These treatment suggestions achieve excellent outcomes and are associated with less short-term and long-term toxicity than higher doses (up to 50 Gy) and/or larger fields that were used in the past [30-39]. RT should begin within five weeks of completion of chemoimmunotherapy. (See 'Risk-adapted therapy' above and 'Special scenarios' below.)

An uncontrolled study (SWOG 0014) of 60 patients with limited stage DLBCL who received three cycles of R-CHOP followed by 40 to 46 Gy reported 93 and 88 percent PFS at two and four years, respectively [30]. A multicenter trial included patients with aggressive non-Hodgkin lymphoma (82 percent with DLBCL, including all stages) who were randomly assigned to lower-dose (30 Gy) RT versus higher-dose (40 to 45 Gy) RT [39]. With median follow-up of 5.6 years, lower-dose RT achieved similar rates of overall response, in-field progression, PFS, and OS, and was associated with less erythema and a trend toward reduction of other toxicities.

In addition to erythema and cytopenias, noteworthy adverse effects of RT may include:

Mediastinal irradiation significantly increases the risks of coronary heart disease, heart failure, and valvular disorders. Use of anthracyclines further increased the risks of heart failure and valvular disorders associated with mediastinal irradiation. (See "Cardiotoxicity of radiation therapy for breast cancer and other malignancies".)

Irradiation to structures of the head and neck can cause xerostomia and hypothyroidism. (See "Management and prevention of complications during initial treatment of head and neck cancer".)

Breast irradiation can significantly increase the long-term risk of developing breast cancer, especially among women who are radiated before age 30 years. (See "Second malignancies after treatment of classic Hodgkin lymphoma", section on 'Breast cancer'.)

CMT versus chemoimmunotherapy alone — For treatment of limited stage DLBCL, CMT and chemoimmunotherapy alone achieve comparable outcomes, but they are associated with different patterns of adverse effects.

The only phase 3 trial in limited stage DLBCL that examined chemoimmunotherapy alone versus CMT reported similar outcomes with both approaches [8]. The LYSA/GOELAMS (Lymphoma Study Association/French Acute Leukaemia and Blood Diseases West-East Group) trial 02-03 randomly assigned 334 adults to 40 Gy RT versus no RT for patients with stage I/II DLBCL and low tumor burden (<7 cm diameter) who achieved complete response (CR) by PET after four cycles of R-CHOP-14 (14-day treatment cycles). Patients were stratified at the time of enrollment to receive either four or six cycles of R-CHOP-14 based on initial International Prognostic Index (IPI). For R-CHOP alone versus CMT, five-year EFS (92 versus 89 percent, respectively) and five-year OS (96 and 92 percent) did not differ significantly. Hematologic and cardiac toxicity from R-CHOP was modest and comparable between the two arms, but two patients treated with RT had grade 3 mucositis and one patient had jaw osteonecrosis.

A retrospective, population-based report compared CMT (three cycles of R-CHOP plus RT) versus six to eight cycles of R-CHOP alone [40]. CMT was associated with a similar rate of survival, but reduced short-term toxicity, a lower incidence of neutropenia (including episodes requiring hospitalization), and a lower risk of being treated with a second-line therapy. Other studies also reported comparable outcomes with abbreviated R-CHOP plus RT versus R-CHOP alone [30,41,42]. Trials from the pre-rituximab era (ie, CHOP without rituximab) also indicated that CMT (abbreviated CHOP plus RT) was at least as effective as a full course of the same chemotherapy regimen and was associated with a lower rate of relapse at sites of initial disease [28,31,43].

Radiation alone is not acceptable — Treatment with RT alone (ie, without chemoimmunotherapy) is not recommended for patients with limited stage DLBCL. When RT is administered without chemoimmunotherapy in this setting, relapse outside of the radiation field is common, and survival rates were inferior to chemotherapy plus RT [32,33,44-49].

RT can be effective for palliation in frail patients who are unable to tolerate systemic chemotherapy, but these patients may also be unable to tolerate RT. Treatment with RT alone results in <40 percent five-year disease-free survival in patients with limited stage aggressive lymphoma, such as DLBCL, which is markedly inferior to the suggested approaches of chemoimmunotherapy alone or CMT [32]. (See 'CMT versus chemoimmunotherapy alone' above.)

CNS prophylaxis — Central nervous system (CNS) involvement is uncommon at presentation of limited stage DLBCL, but patients with certain clinical features are at increased risk for CNS relapse (table 5). There is no consensus regarding which patients should receive CNS prophylaxis nor a preferred treatment approach.

We suggest CNS prophylaxis for patients with kidney/adrenal, testis, or breast involvement; ≥2 extranodal sites; or CNS-IPI high-risk score (4 to 6 points) [5,50]. Some patients with CNS-IPI intermediate-risk score (2 to 3 points) may choose to receive prophylaxis based on their interpretation of the relative risks and benefits of prophylaxis. (See 'Prognostic indices' above.)

The optimal approach to prophylaxis for patients at high risk for CNS involvement is controversial and varies between institutions. We favor high-dose systemic methotrexate (MTX), but we consider intrathecal (IT) MTX to be an acceptable option; some experts favor treatment with both IT and systemic MTX. Either approach must be integrated with chemoimmunotherapy, as follows:

High-dose intravenous MTX (3 to 3.5 g/m2) with leucovorin rescue on day 15 of R-CHOP. The optimal number of treatments with high-dose MTX is uncertain, but we generally administer it during two or three of the six treatment cycles.

IT MTX, four to eight doses, at least once per cycle of chemoimmunotherapy.

No prospective controlled studies have directly compared outcomes with these methods, but retrospective studies suggest that high-dose MTX may be associated with a lower incidence of CNS relapses than IT MTX alone [51-54]. In a single institution study of high-risk patients, with median follow-up of 60 months, CNS relapse was reported in 0 of 33 patients who received systemic prophylaxis, 1 of 7 who received IT MTX, and 8 of 67 (12 percent) who received no prophylaxis [51]. In a multicenter retrospective study of high-risk patients, the rate of CNS relapse at three years was 6.9 percent in those who received IT MTX plus high-dose MTX, but 18.4 percent in those who received IT MTX alone [54].

Details of treatment, toxicity, and precautions associated with these approaches are discussed separately. (See "Therapeutic use and toxicity of high-dose methotrexate" and "Treatment of leptomeningeal disease from solid tumors".)

RESPONSE ASSESSMENT — After completion of treatment for limited stage DLBCL, patients should be evaluated to determine the end-of-treatment response and followed longitudinally for relapse.

Within six weeks of completion of all planned therapy, we suggest repeat positron emission tomography (PET), with response assessed by the five-point Deauville scoring system (table 6):

For patients with negative PET (ie, Deauville 1 to 3), we suggest clinical evaluation and laboratory studies every three to six months for the first five years, then annually, or as clinically indicated. We suggest performing repeat computed tomography (CT) only as clinically indicated, in an effort to limit the patient's exposure to radiation.

For patients with positive PET (ie, Deauville 4 to 5), we consider a repeat biopsy. If the biopsy is negative, the patient should be followed as per guidelines for PET-negative disease. If the biopsy demonstrates persistent DLBCL, we suggest management as refractory DLBCL. (See "Diffuse large B cell lymphoma (DLBCL): Suspected first relapse or refractory disease in patients who are medically fit".)

Following initial documentation of end-of-treatment complete response (CR; ie, PET-negative), we suggest not continuing routine surveillance with PET or CT, because there is no current evidence that this can improve outcomes and this approach avoids excessive radiation exposure.

POST-REMISSION THERAPY — There is no demonstrated role for post-remission maintenance therapy in DLBCL. There is some evidence that lenalidomide may reduce the risk of relapse in older patients with limited stage DLBCL, but there is no demonstrated benefit for maintenance rituximab, intensive consolidation chemoimmunotherapy, or hematopoietic cell transplantation (HCT) in first remission for patients with limited stage DLBCL.

The phase 3, placebo-controlled ReMARC trial reported that two years of lenalidomide maintenance therapy improved progression-free survival (PFS) in older patients with DLBCL [55]. A total of 650 patients 60 to 80 years old who achieved complete remission (CR) or partial remission (PR) with six to eight cycles of R-CHOP were randomly assigned to treatment with lenalidomide (25 mg/day for 21 days of every 28-day cycle) versus placebo for 24 months. With median follow-up of 39 months, median PFS was not reached for lenalidomide versus 59 months for placebo (hazard ratio 0.71; 95% CI 0.54-0.93); with median follow-up of 52 months, overall survival was similar between the treatment arms. The most common grade ≥3 adverse events with lenalidomide versus placebo were neutropenia (56 versus 22 percent, respectively) and cutaneous reactions (5 versus 1 percent).

SPECIAL SCENARIOS — Involvement of certain organs with DLBCL, particularly when occurring as primary sites of disease, has distinct therapeutic implications. Frail, older adults and patients with cardiac disease or human immunodeficiency virus (HIV) infection also require special consideration.

Testicular — Testicular involvement by DLBCL is associated with an adverse prognosis, increased risk for central nervous system (CNS) involvement, and requires distinct aspects of management. Testicular lymphoma is the most common malignant testicular tumor in men >60 years of age and accounts for approximately 1 percent of lymphomas overall [56]. DLBCL is the most common subtype and the median age of presentation is the sixth to seventh decade [57]. Outcomes in patients with testicular involvement are worse than would be predicted by the International Prognostic Index (IPI) [58,59].

For patients with primary testicular DLBCL, we suggest orchiectomy, six cycles of R-CHOP accompanied by intrathecal (IT) chemotherapy or high-dose systemic methotrexate (MTX; to reduce the risk of CNS recurrence), followed by 25 to 30 gray (Gy) scrotal radiation therapy (RT; to prevent contralateral recurrence) [60].

There have been no randomized trials for testicular DLBCL, but systemic chemoimmunotherapy is required, based on small prospective and retrospective studies. Unilateral orchiectomy is usually performed to obtain diagnostic tissue, but orchiectomy alone is not sufficient treatment even with stage I disease, because of the increased risk of CNS involvement and contralateral scrotal recurrence. RT alone is associated with a high rate of relapse and is recommended only for patients who are not candidates for any chemotherapy.

Small retrospective and nonrandomized studies suggest higher survival rates in patients who receive RT to the contralateral testis and CNS prophylaxis with either IT chemotherapy or high-dose systemic MTX [56,58,60-67]. A prospective study of 53 patients with stage I or II primary testicular lymphoma reported overall survival (OS) and progression-free survival (PFS) at five years were 85 and 74 percent, respectively, after treatment with six to eight cycles of R-CHOP-21, four weekly doses of IT MTX (12 mg), RT to the contralateral testis (30 Gy) for all, and RT to regional lymph nodes (30 to 36 Gy) for patients with stage II disease [60]. Relapses occurred in the CNS (three patients), lymph nodes (two patients), and non-CNS extranodal organs (five patients); there were no relapses in the contralateral testis. A retrospective study examined the use of systemic chemotherapy with (15 patients) or without (27 patients) involved-field RT (IFRT) in patients with localized testicular lymphoma after orchiectomy [63]. Patients who received both chemotherapy and IFRT had superior three-year OS (approximately 80 versus 20 percent). Contralateral scrotal irradiation was given to 10 patients, none of whom had recurrence in the contralateral testis. By comparison, the contralateral testis was the initial site of relapse in 2 of 35 patients who did not receive contralateral scrotal irradiation.

Relapses occur predominantly in the CNS and contralateral testis. In a study of 373 patients with primary testicular lymphoma, 56 (15 percent) had CNS relapse and/or progression [58]. A study of 29 patients reported that 41 percent of relapses were either in the CNS or the contralateral testis [68].

Other extranodal sites — Involvement of other extranodal sites may influence management. Gastrointestinal (GI) DLBCL is the most common site of extranodal presentation, and represents about one-third of cases of primary extranodal DLBCL [69]. Examples include:

Gastric – For patients with limited stage gastric DLBCL (table 7), we treat with either six cycles of R-CHOP alone or three cycles of R-CHOP followed by IFRT (such as that used for other patients with limited stage DLBCL). (See "Initial treatment of advanced stage diffuse large B cell lymphoma", section on 'Treatment'.)

We suggest reserving surgery for patients with complications such as perforation, obstruction, or intractable bleeding [70-75]. GI perforation is uncommon, but occasional patients may benefit from surgical consultation for bleeding or gastric outlet obstruction [75].

Some experts offer a brief trial of Helicobacter pylori eradication therapy for selected patients with limited stage gastric DLBCL, but this approach is not universally accepted and requires close monitoring for possible treatment failure. H. pylori eradication therapy has not been directly compared with systemic chemoimmunotherapy, but small clinical studies report limited efficacy [76-78]. (See "Treatment of extranodal marginal zone lymphoma of mucosa associated lymphoid tissue (MALT lymphoma)", section on 'Stage I or II H. pylori positive'.)

Comparative studies have not borne out concerns that chemotherapy treatment of patients with lymphomatous involvement of the stomach might develop gastric perforation and/or bleeding [70,71,79-83]. A prospective trial of 589 patients with early stage primary gastric DLBCL randomly assigned therapy with surgery, surgery plus RT, surgery plus CHOP chemotherapy, or CHOP chemotherapy alone [84]. Ten-year event-free survival (EFS) rates for patients assigned to the four treatment arms were 28, 23, 82, and 92 percent, respectively. Late toxicity was more frequent and severe in patients undergoing surgery. This trial did not include treatment with rituximab-based chemoimmunotherapy or the use of adjuvant RT after chemotherapy. A retrospective single-center review included 415 cases of GI DLBCL, of whom 13 percent developed a perforation during the disease course; half of the perforations occurred at the time of diagnosis, while half occurred after chemotherapy [85]. Retrospective analyses and uncontrolled prospective trials have had mixed results, with some studies suggesting a benefit from surgery and others suggesting no benefit [70-74,86,87].

Other GI involvement – For intestinal involvement with DLBCL, we favor treatment with six cycles of R-CHOP alone rather than combined modality therapy (CMT). Our preference for R-CHOP alone reflects concerns about defining radiation ports due to intestinal mobility and uncertainty about defining the full extent of intestinal involvement.

Because of the more fixed nature of the rectum, six cycles of R-CHOP alone or CMT with three cycles of R-CHOP followed by IFRT are acceptable alternatives. (See 'Treatment modalities' above.)

Surgery is reserved for patients with complications such as perforation, obstruction, or intractable bleeding, for both limited stage and advanced disease [70-75]. GI perforation is uncommon, but occasional patients may benefit from surgical consultation for bleeding or bowel obstruction [75]. As discussed above, limited comparative studies have not borne out concerns that chemotherapy treatment causes excessive perforation and/or bleeding [70,71,79-83].

Bone – Extranodal involvement of bone may be due to primary DLBCL of bone or extranodal involvement by systemic disease [88-90]. In rare cases, primary bone lymphoma can present as multifocal disease that affects multiple skeletal sites without nodal or visceral involvement; this condition has been described as polyostotic lymphoma or multifocal bone lymphoma, and it constitutes <10 percent of primary bone DLBCL [91]. Primary DLBCL of bone generally has a more favorable prognosis than comparable nodal disease or other extranodal DLBCL at other sites [92-97].

Optimal therapy of bone involvement by DLBCL is not well-defined [90]. For both primary DLBCL of bone and secondary involvement by systemic disease, we suggest six cycles of R-CHOP, with or without involved-site RT (ISRT), which achieves excellent local control and infrequent systemic failure [98,99]. We suggest treatment as described above. (See 'Adverse features, but no bulky disease' above.)

Skin – Cutaneous involvement by DLBCL may reflect secondary involvement by systemic disease or primary cutaneous DLBCL. For secondary involvement by systemic disease, we suggest R-CHOP followed by ISRT to involved sites. Primary cutaneous DLBCL is discussed separately. (See 'Adverse features, but no bulky disease' above and "Primary cutaneous large B cell lymphoma, leg type".)

Ovary – Primary lymphoma of the ovary is rare. The most common presentation is of a painful abdominal or pelvic mass. Tumors are staged using the Federation International of Gynecologists and Obstetricians (FIGO) system used for other ovarian neoplasms (table 8). Prognosis for DLBCL of the ovary is poor with two- and five-year survival rates of approximately 40 percent [100,101].

Initial treatment usually involves bilateral salpingo-oophorectomy with or without hysterectomy; unilateral salpingo-oophorectomy may be acceptable if there is no evidence of disease on the contralateral side after careful inspection. Hysterectomy is not required but is often performed to prevent problems with bleeding after oophorectomy. We suggest R-CHOP chemoimmunotherapy according to disease stage, accompanied by CNS prophylaxis. (See 'CNS prophylaxis' above.)

There are no clinical trials to guide the therapy of ovarian lymphoma. Ovarian DLBCL may be associated with systemic recurrence, including the CNS, but the actual rate of CNS involvement is unknown [100].

Breast – Primary lymphoma of the breast usually presents as a painless breast mass. DLBCL is the most common subtype. There are limited data to guide treatment of breast lymphoma, but a retrospective review reported that mastectomy offered no survival benefit or protection from recurrence and was associated with higher all-cause and disease-specific mortality and a decreased use of radiation and/or chemotherapy [102]. We suggest R-CHOP chemoimmunotherapy according to disease stage, accompanied by CNS prophylaxis. (See 'CNS prophylaxis' above.)

Mediastinum – Treatment of DLBCL with bulky mediastinal disease is discussed above. (See 'Bulky disease' above.)

Primary mediastinal large B cell lymphoma (PMBL) is a distinct clinicopathologic entity that often presents with a locally invasive anterior mediastinal mass, airway compromise, and/or superior vena cava syndrome [103]. Management of PMBL is discussed separately. (See "Primary mediastinal large B cell lymphoma".)

Frail/limited cardiac function — For patients who are medically frail, >80 years old with comorbidities, or with limited cardiac function, we suggest treatment to lessen toxicities that would exacerbate comorbid illnesses. There is no preferred chemoimmunotherapy regimen for these patients, but we consider any of the following to be acceptable options in this setting [104,105]:

R-GCVP (rituximab, gemcitabine, cyclophosphamide, vincristine, prednisolone)

R-mini-CHOP (reduced dose of CHOP with conventional dose of rituximab)

R-CEOP (rituximab, cyclophosphamide, etoposide, vincristine, prednisone)

R-gemcitabine, oxaliplatin

More frequent cardiac monitoring is suggested for any regimen that includes an anthracycline. Monitoring of cardiac function may benefit from consultation with cardiology.

HIV infected patients — Management of DLBCL in people infected with human immunodeficiency virus (HIV) is discussed separately. Management should be in collaboration with infectious disease experts. (See "HIV-related lymphomas: Treatment of systemic lymphoma", section on 'Diffuse large B cell lymphoma'.)

REFRACTORY DLBCL — For patients who do not have an adequate response to initial treatment of DLBCL, we generally obtain a biopsy to confirm the diagnosis of refractory disease. Management of refractory disease is discussed separately. (See "Diffuse large B cell lymphoma (DLBCL): Suspected first relapse or refractory disease in patients who are medically fit".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Management of diffuse large B cell lymphoma".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword(s) of interest.)

Basics topics (see "Patient education: Diffuse large B cell lymphoma (The Basics)")

Beyond the Basics topics (see "Patient education: Diffuse large B cell lymphoma in adults (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

Diffuse large B cell lymphoma (DLBCL) is the most common histologic subtype of non-Hodgkin lymphoma (NHL). Limited stage DLBCL (stage I or II) (table 1) is defined as that which can traditionally be contained within one irradiation field. This population accounts for <30 percent of patients with DLBCL. (See 'Introduction' above.)

The goals of care for patients with limited stage DLBCL are to achieve long-term survival/cure while reducing short-term and long-term toxicity; cure generally requires achievement of a complete remission (CR) with multiagent chemoimmunotherapy. (See 'Goals of care' above.)

Pretreatment evaluation should determine the stage of disease, evaluate comorbid illnesses that may affect tolerance for combination chemotherapy and/or radiation therapy (RT), and assess prognostic indices to guide therapy. We suggest pretreatment evaluation/consultation by both a medical oncologist/hematologist and a radiation oncologist, to consider the risks and benefits of various approaches. (See 'Pretreatment evaluation' above.)

Chemoimmunotherapy is the mainstay of therapy. For patients with limited stage DLBCL, we recommend R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) rather than CHOP chemotherapy alone (ie, no rituximab), based on randomized controlled trials which reported that R-CHOP achieved superior outcomes with no difference in toxicity (Grade 1A). Compared with R-CHOP, no other chemoimmunotherapy regimen has been shown to achieve a more favorable balance of outcomes and toxicity. (See 'Chemoimmunotherapy' above.)

We stratify initial treatment of limited stage DLBCL based on the presence of adverse prognostic features (algorithm 2 and algorithm 3). (See 'Treatment stratification' above.)

For patients with no adverse features (ie, no bulky disease, normal lactate dehydrogenase [LDH], Eastern Cooperative Oncology Group performance status [ECOG PS] 0 to 1) (algorithm 2), we suggest four cycles of R-CHOP rather than six or more cycles of R-CHOP, combined modality therapy (CMT), or RT alone (Grade 2C). This suggestion is based on the apparent equivalent efficacy but less toxicity with four cycles with R-CHOP, compared with the alternative approaches in this low-risk population; longer-term follow-up should provide improved estimates of efficacy and toxicity. (See 'No adverse features' above.)

For patients with elevated LDH and/or ECOG PS ≥2, but no bulky disease (algorithm 2), we favor a risk-adapted approach, but conventional therapy (ie, no risk-adaptation) is also acceptable. For risk-adapted therapy, we treat with three cycles of R-CHOP, followed by positron emission tomography (PET) on day 18 to 20 of the third treatment cycle ("PET3"). Subsequent treatment is guided by results of PET3, as follows (see 'Risk-adapted therapy' above):

PET3-negative – For PET3-negative (ie, Deauville 1 to 3) disease, we suggest treatment with one additional cycle of R-CHOP (ie, a total of four cycles of R-CHOP), rather than more than four cycles of R-CHOP or addition of RT (ie, R-CHOP x 3 plus RT) (Grade 2C), based on excellent long-term outcomes with four cycles of R-CHOP and the desire to avoid additional toxicity of RT or further chemotherapy.

PET3-positive – For positive PET3 (ie, Deauville 4 to 5), we distinguish between partial response (PR; ie, a small focus of Deauville 4 to 5 activity) versus more extensive, refractory disease. For PR, we consider three additional cycles of R-CHOP (ie, six total cycles of R-CHOP) versus CMT (30 Gy ISRT with an additional boost of 6 to 10 Gy and no further chemoimmunotherapy) equally acceptable options. For refractory disease, we suggest a biopsy of the fluorodeoxyglucose (FDG)-avid site and we treat biopsy-proven refractory disease as described separately. (See "Diffuse large B cell lymphoma (DLBCL): Suspected first relapse or refractory disease in patients who are medically fit".)

For conventional therapy (ie, without use of risk-adapted therapy) of patients with elevated LDH and/or ECOG PS ≥2, but no bulky disease (algorithm 2), we consider either CMT with three (total) cycles of R-CHOP plus 30 Gy ISRT versus six cycles of R-CHOP as equally acceptable options. (See 'Conventional management' above.)

For patients with bulky disease (≥10 cm diameter) (algorithm 3), we consider risk-adapted therapy or conventional management (without interval PET) to be acceptable. (See 'Bulky disease' above.)

For conventional treatment (ie, without use of risk-adapted therapy), we suggest six cycles of R-CHOP followed by 30 to 40 Gy ISRT.

For risk-adapted therapy, we treat with six cycles of R-CHOP, followed by PET (PET6):

For PET6-negative (ie, Deauville 1 to 3) disease, we treat with 30 Gy ISRT.

For PET6-positive disease, we distinguish between PR (ie, a small focus of Deauville 4 to 5 activity) versus more extensive, refractory disease. For PR, we treat with 30 Gy ISRT followed by a 6 to 10 Gy boost. For more extensive disease, we suggest a biopsy of the FDG-avid tissue; for patients with little residual/viable disease, we treat with 30 Gy ISRT followed by an additional boost of 6 to 10 Gy to the FDG-avid area. For patients with biopsy-proven refractory disease, management is discussed separately. (See "Diffuse large B cell lymphoma (DLBCL): Suspected first relapse or refractory disease in patients who are medically fit".)

Details of treatment regimens with R-CHOP alone and CMT are discussed above. Importantly, RT alone is not an acceptable approach for DLBCL. (See 'Treatment modalities' above.)

Within six weeks of completion of all planned therapy, we suggest an end-of-treatment PET, with response assessed with the five-point Deauville scoring system (table 6). (See 'Response assessment' above.)

For patients who are at high risk for central nervous system (CNS) relapse, we suggest CNS prophylaxis rather than no prophylaxis (Grade 2C), based on the tolerable toxicity of treatment weighed against the grave prognosis associated with relapse. We consider either high-dose methotrexate (MTX) or intrathecal MTX to be acceptable approaches for prophylaxis. (See 'CNS prophylaxis' above.)

For patients who are medically frail, >80 years old with comorbidities, or with limited cardiac function, we suggest less toxic chemoimmunotherapy regimens, as described above. (See 'Frail/limited cardiac function' above.)

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Topic 16228 Version 33.0

References

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