Diffuse large B cell lymphoma: Treatment of limited-stage disease

INTRODUCTION — Diffuse large B cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma (NHL), accounting for approximately one-third of patients with NHL.

Patients with DLBCL are classified as having:

●Limited-stage disease – Stage I or II

●Advanced-stage disease – Stage III or IV

Treatment of limited-stage DLBCL is stratified according to the presence of adverse prognostic features.

This topic discusses the initial treatment of limited-stage DLBCL.

Related topics include:

●(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 [1,2] 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"'.)

PRETREATMENT EVALUATION — Pretreatment evaluation of a patient with DLBCL should assess comorbid illnesses that might affect their tolerance for therapy.

The consideration of various treatment options is aided by discussion in a multidisciplinary tumor board. A radiation oncologist should evaluate patients with bulky disease, a dominant skeletal site of involvement, and where local control is important (eg, spinal cord compression or nerve root compression).

Clinical and laboratory

●History – Evaluate B symptoms (ie, fever, drenching sweats, unexplained weight loss), comorbid illnesses, and performance status (table 1).

Unexplained neurologic symptoms (eg, headache, cranial neuropathies, focal weakness, radiculopathy, new gait abnormalities) should prompt an evaluation of the central nervous system (CNS).

●Physical examination – Evaluate lymph node-bearing areas, including Waldeyer's ring, assess liver and spleen size, and evaluate neurologic abnormalities.

●Laboratory

•Hematology – Complete blood count (CBC) with differential count.

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

•Infectious – Human immunodeficiency virus (HIV), hepatitis B, and hepatitis C testing.

Imaging — Imaging is required for the staging and assessment of cardiac function. Evaluation of involvement of the CNS or extranodal sites is performed as clinically indicated.

●Positron emission tomography (PET) – Whole-body PET/computed tomography (CT) for staging.

●Echocardiogram or radionuclide ventriculography to assess left ventricular ejection fraction.

●Contrast-enhanced diagnostic CT or magnetic resonance imaging (MRI), as clinically warranted.

Other testing — 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'.)

●Bone marrow examination – A bone marrow biopsy is not necessary if PET indicates bone disease.

If a bone marrow examination is used to evaluate marrow involvement, the biopsy specimen should be adequate (eg, >1.6 cm); an aspirate specimen can be analyzed by histology, flow cytometry, cytogenetics, and molecular studies. (See "Epidemiology, clinical manifestations, pathologic features, and diagnosis of diffuse large B cell lymphoma", section on 'Pathology'.)

If a bone marrow examination demonstrates bone involvement, but PET does not suggest bone involvement, the possibility of discordant histology may be considered, as this might affect disease management.

Demonstration of bone marrow involvement upstages the disease to advanced-stage DLBCL (stage IV); the management of advanced-stage DLBCL is discussed separately. (See "Initial treatment of advanced stage diffuse large B cell lymphoma".)

●CNS – The CNS International Prognostic Index (CNS-IPI) should be assessed. (See 'Central nervous system International Prognostic Index' below.)

•Neurologic abnormalities – Patients with unexplained neurologic abnormalities or evidence of leptomeningeal involvement by imaging should have a diagnostic lumbar puncture (LP).

•High risk for CNS involvement – Some experts perform a diagnostic LP and/or imaging to evaluate asymptomatic patients with a higher risk for CNS involvement. Examples include disease in >1 extranodal site, involvement of certain extranodal sites (eg, kidney, adrenal gland, testis), and/or a high CNS-IPI score. (See 'Central nervous system International Prognostic Index' below.)

STAGING — The staging of DLBCL is based on clinical evaluation and imaging.

Positron emission tomography is assessed using the five-point (Deauville) scale (table 2), according to Lugano criteria (table 3) [3].

PROGNOSTIC INDICES — Prognostic indices should be assessed before treatment selection.

International Prognostic Index — The International Prognostic Index (IPI) (table 4) is calculated by assigning one point for each of the following:

•Age >60 years

•Serum lactate dehydrogenase (LDH) elevated

•Eastern Cooperative Oncology Group performance status (ECOG PS) ≥2

•Stage III or IV

•>1 extranodal site

Central nervous system International Prognostic Index — The central nervous system (CNS)-IPI is a validated instrument for assessing the risk of CNS relapse in patients treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) for DLBCL [4].

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 elevated

●ECOG PS >1

●Stage III/IV disease

●Extranodal involvement of ≥2 sites

Risk of CNS relapse is classified according to the sum of points and varies with the risk category [4]:

●Low (zero to one points) – 0.6 percent two-year CNS relapse rate

●Intermediate (two to three points) – 3.4 percent two-year CNS relapse rate

●High (four to six points) – 10.2 percent two-year CNS relapse rate

The use of the CNS-IPI for consideration of CNS prophylaxis is discussed below. (See 'Central nervous system prophylaxis' below.)

OVERVIEW OF MANAGEMENT — Certain aspects of management, regardless of stage and prognostic features, are common to all patients with DLBCL.

Chemoimmunotherapy — For patients with DLBCL, we recommend the addition of rituximab to CHOP (R-CHOP; cyclophosphamide, doxorubicin, vincristine, prednisone) (table 5) rather than CHOP alone.

Treatment with chemoimmunotherapy (ie, chemotherapy plus rituximab) achieved superior overall survival (OS) compared with chemotherapy alone in multiple randomized clinical trials.

●R-CHOP achieved superior outcomes in a phase 3 trial that randomly assigned 399 patients (60 to 80 years) with DLBCL to R-CHOP versus CHOP [5]. Compared with CHOP, the two-year OS was better with R-CHOP (70 versus 57 percent; hazard ratio [HR] 0.64 [95% CI 0.45-0.89]); R-CHOP also achieved superior event-free survival (EFS) and response rate. Adverse effects (AEs) did not differ between trial arms.

●The phase 3 MInT Trial, which randomly assigned 813 patients with DLBCL to chemotherapy with or without rituximab, reported that chemoimmunotherapy achieved superior OS compared with chemotherapy alone [6,7]. Limited-stage DLBCL (either stage II or bulky stage I disease) was present in 72 percent of patients; patients with bulky disease also received radiation therapy (RT). Chemoimmunotherapy achieved superior six-year OS (90 versus 80 percent), progression-free survival (PFS), and EFS. The addition of rituximab did not increase acute or long-term toxicity, including second malignancies.

●A phase 3 trial of R-CHOP versus CHOP in 632 older patients with DLBCL reported superior outcomes with R-CHOP [8]. R-CHOP achieved superior three-year OS (67 versus 57 percent; HR 0.72 [95% CI 0.53-1.0]) and failure-free survival (FFS; 52 versus 39 percent; HR 0.64 [95% CI 0.47-0.85]). The safety profile was similar in both trial arms.

Rituximab and biosimilar agents are approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of DLBCL.

Risk-stratified management — We stratify the initial treatment of limited-stage DLBCL according to adverse prognostic features:

●No adverse features – Management of patients with normal serum lactate dehydrogenase (LDH), Eastern Cooperative Oncology Group performance status (ECOG PS) zero to one, and no bulky disease is discussed below. (See 'No adverse features' below.)

●Adverse features but no bulky disease – For patients with elevated LDH or ECOG PS two (table 1) but no bulky disease, management is discussed below. (See 'Adverse features but no bulky disease' below.)

●Bulky disease – Management of patients with bulky disease (≥10 cm diameter) is discussed below. (See 'Bulky disease' below.)

Treatment selection for limited-stage DLBCL is not influenced by cell of origin status (eg, germinal center versus activated B cell phenotypes) or other pathologic features.

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

NO ADVERSE FEATURES — For limited-stage DLBCL with no adverse prognostic features, we suggest four cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) (table 5) rather than routine combined modality therapy (CMT; ie, chemoimmunotherapy plus radiation therapy [RT]), more cycles of R-CHOP, or other chemoimmunotherapy regimens. This suggestion is based on similar efficacy but less toxicity with four cycles of R-CHOP compared with the other approaches.

Some experts add two treatments with rituximab alone after four cycles of R-CHOP, based on the treatment used in the FLYER trial [9] (described below).

Compared with R-CHOP, no chemoimmunotherapy regimen provides a more favorable balance of benefits and toxicity. 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 [10-12].

●Chemotherapy alone versus CMT

•Outcomes were similar with R-CHOP versus CMT in the phase 3 LYSA/GOELAMS trial [13]. The 334 adults with stage I/II DLBCL (no bulky disease) who achieved a complete response (CR) with R-CHOP-14 (four or six cycles, according to International Prognostic Index [IPI] score) were randomly assigned to 40 gray (Gy) RT versus no RT. Compared with CMT, R-CHOP alone achieved a similar five-year overall survival (OS; 96 and 92 percent) and five-year event-free survival (EFS; 92 versus 89 percent). Hematologic and cardiac toxicity was similar between the trial arms, but two patients treated with CMT had grade 3 mucositis, and one patient had jaw osteonecrosis.

•A population-based study compared CMT (three cycles of R-CHOP plus RT) versus six to eight cycles of R-CHOP alone [14]. CMT was associated with similar survival but less short-term toxicity, less neutropenia, and lower risk of being treated with a second-line therapy.

•A retrospective single-institution study reported that CMT was associated with better survival than chemoimmunotherapy alone for patients with stage I or II DLBCL [15]. Among 190 patients with limited-stage DLBCL, RT was given to 103 patients (mostly for bulky disease). CMT was associated with a better five-year OS (92 versus 73 percent) and five-year progression-free survival (PFS; 82 versus 68 percent) in patients with stage I and II disease.

•Among 39 patients with limited-stage DLBCL, there was no difference in three-year OS or EFS according to the treatment with CMT or chemoimmunotherapy alone [16].

●Number of chemotherapy cycles – The suggestion for four cycles of R-CHOP is based on the following studies:

•In the phase 3 FLYER trial, outcomes were similar after six cycles of R-CHOP versus four cycles of R-CHOP plus two treatments with rituximab alone [9]. Among 592 patients ≤60 years with stage I to II DLBCL and no adverse prognostic factors, there was no difference in the five-year OS or PFS between the trial arms. Four cycles of R-CHOP were associated with less hematologic and nonhematologic toxicity; there were two deaths, both in the six-cycle arm.

Although the FLYER trial was limited to patients <60 years old, we consider that the conclusions are also applicable to older patients.

•In the S1001 trial, treatment with four cycles of R-CHOP was associated with an 89 percent five-year OS and 87 percent five-year PFS [17].

•Excellent outcomes after four cycles of chemotherapy were also reported in the LYSA/GOELAMS 02-03 trial (described above) [13].

ADVERSE FEATURES BUT NO BULKY DISEASE — For patients with elevated lactate dehydrogenase (LDH) and/or Eastern Cooperative Oncology Group performance status (ECOG PS) ≥2 but no bulky disease, we suggest response-guided therapy based on positron emission tomography (PET) response after R-CHOP x 3 (three cycles of R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone] (table 5)) with further therapy guided by the interim response.

Response-guided therapy enables treatment de-escalation in patients with a robust response to initial chemoimmunotherapy. Details of response-guided therapy are presented below. (See 'Response-guided therapy' below.)

Also acceptable in this setting is conventional management using a predetermined course of treatment (ie, no interim response assessment); conventional management using either R-CHOP alone or combined modality therapy (CMT; ie, R-CHOP followed by radiation therapy [RT]) is discussed below. (See 'Conventional management' below.)

Some clinicians treat patients with International Prognostic Index (IPI) ≥2 using R-pola-CHP (rituximab, polatuzumab, cyclophosphamide, doxorubicin, prednisone) based on the phase 3 POLARIX trial, in which patients with DLBCL were randomly assigned to R-pola-CHP x 6 (six cycles of R-pola-CHP) versus R-CHOP x 4 (four cycles of R-CHOP) followed by two cycles of rituximab [18]. However, only 10 percent of enrolled patients had limited-stage disease. With a median follow-up of 28 months, there was no difference in overall survival (OS; 89 percent each), but two-year progression-free survival (PFS) was higher with R-pola-CHP (76.7 versus 70.2 percent). The safety profile was similar with both treatments. We await longer follow-up and/or validation with other studies in patients with limited-stage disease before routinely employing R-pola-CHP for patients with limited-stage disease.

PET is repeated after completing planned therapy, as described below. (See 'Post-treatment positron emission tomography' below.)

Response-guided therapy — For response-guided therapy in this setting, we treat with R-CHOP x 3, followed by interval PET (PET3).

Further management is guided by the PET3 response, as follows:

●PET3 negative – For complete response (CR; PET score 1 to 3), we treat with one additional cycle of R-CHOP (4 total cycles).

This approach is based on excellent outcomes with one additional cycle of R-CHOP in patients with CR on PET3 in the S1001 trial [17]. For patients with CR on PET3, this avoids adverse effects (AEs) associated with RT or ≥2 additional cycles of R-CHOP.

●PET3 positive – Further management is guided by the intensity and distribution of PET activity.

•Partial response – For most patients with PET score 4, further treatment with either chemoimmunotherapy or RT is acceptable.

The choice of approach is individualized and should consider patient preference. When RT is expected to cause substantial morbidity because of the distribution of disease or comorbidities, we favor chemoimmunotherapy alone; conversely, RT may be favored for a patient with limited cardiac function because of the lower cumulative dose of doxorubicin.

Acceptable treatment options include either:

-Chemoimmunotherapy only – Three additional cycles of R-CHOP (six total cycles).

-RT – 30 gray (Gy) involved site RT (ISRT) with an additional boost of 6 to 10 Gy to the site of PET activity.

•Refractory disease – For patients with extensive PET score 4 or with PET score 5, we generally biopsy the site of PET activity.

-Biopsy negative – For little or no residual/viable disease (eg, extensive necrosis or inflammatory infiltrate), we treat with three additional cycles of R-CHOP (six total cycles). PET is repeated after completing therapy, as described below. (See 'Post-treatment positron emission tomography' below.)

For patients with persistent PET activity after completing therapy, we treat for refractory DLBCL. (See "Diffuse large B cell lymphoma (DLBCL): Suspected first relapse or refractory disease in patients who are medically fit".)

-Biopsy positive – For biopsy-proven persistent disease, we treat as refractory DLBCL. (See "Diffuse large B cell lymphoma (DLBCL): Suspected first relapse or refractory disease in patients who are medically fit".)

●Outcomes

•Response-guided treatment was associated with excellent outcomes for both PET3-negative and PET3-positive patients in the S1001 study [17]. After R-CHOP x 3, 89 percent of 132 patients were PET3 negative. Patients who were PET3 negative received one additional cycle of R-CHOP. PET3-positive patients received 36 Gy involved-field radiation therapy (IFRT; with a 9 Gy boost to the site of PET activity) plus ibritumomab tiuxetan (anti-CD20 monoclonal antibody conjugated to yttrium-90). Outcomes were similar for patients with PET3-negative and PET3-positive disease. After five years, the OS was 89 percent, PFS was 87 percent, six patients had disease progression, and three died from lymphoma. Grade ≥3 AEs included neutropenia (31 percent), febrile neutropenia (10 percent), and thrombocytopenia (8 percent); one patient died with sepsis, and one patient died with hypoxia.

•R-CHOP x 4 was effective in the FLYER trial [9], as described above. (See 'No adverse features' above.)

•A prospective study of 138 patients in which PET was performed after R-CHOP x 2 reported no difference in OS between PET-negative and PET-positive patients, but PET-positive patients had an inferior two-year event-free survival (EFS; 48 versus 74 percent) [19].

Several studies reported that negative-interval PET was associated with better outcomes [20-23]. In the PETAL trial, positive-interval PET was associated with inferior OS and EFS, but treatment intensification for positive PET did not improve outcomes in patients treated with R-CHOP [24]. Other studies reported that interval PET response offered only limited prognostic value [19,25-27].

Conventional management — When interim PET assessment is not used to guide therapy, we consider either of the following acceptable:

●R-CHOP x 6 (no RT)

●CMT – R-CHOP x 3 plus 30 Gy ISRT

The choice of CMT versus R-CHOP only is individualized, with consideration of toxicity, comorbidities, and patient preference. When RT is anticipated to cause substantial morbidity (eg, due to disease distribution or comorbidities), we favor treatment with R-CHOP alone. Conversely, CMT may be preferred for a patient with limited cardiac function because of the lower cumulative dose of doxorubicin.

Outcomes were similar with R-CHOP alone versus CMT in this setting. With either approach, 5-year and 10-year OS rates are approximately 95 and 75 percent, respectively, but outcomes may vary according to the IPI (table 4) [28].

In SWOG 0014, the four-year OS was 92 percent and the four-year PFS was 88 percent when patients with limited-stage DLBCL and ≥1 adverse prognostic factor were treated with CMT (R-CHOP x 3 plus 40 to 46 Gy IFRT) [29].

Treatment with RT alone is no longer used in the era of effective chemoimmunotherapy.

BULKY DISEASE — For limited-stage DLBCL with bulky disease (≥10 cm diameter), we suggest response-guided therapy with restaging after R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) (table 5) x 6 (six cycles of R-CHOP) rather than routine treatment with combined modality therapy (CMT).

Outcomes are similar with both approaches, but response-guided management avoids radiation therapy (RT) for patients who achieve complete response (CR) after completing chemotherapy.

Response-guided therapy for bulky disease entails R-CHOP x 6, then restaging with positron emission tomography (PET).

Further therapy is based on PET6 response:

●PET score 1 to 3 – No further therapy.

●PET score 4 – 30 gray (Gy) involved site RT (ISRT) with 6 to 10 Gy boost to site of PET-avid disease.

●PET score 5 – Biopsy PET-avid disease; further therapy is based on biopsy findings:

•Biopsy negative – For little or no residual/viable disease (eg, extensive necrosis or inflammatory infiltrate), treat with 30 Gy ISRT with 6 to 10 Gy boost to PET-avid site.

•Biopsy positive – For biopsy-proven persistent disease, treat as refractory DLBCL. (See "Diffuse large B cell lymphoma (DLBCL): Suspected first relapse or refractory disease in patients who are medically fit".)

PET is repeated after completing planned therapy, as described below. (See 'Post-treatment positron emission tomography' below.)

Response-guided management has not been directly compared with routine CMT for DLBCL with bulky disease in a randomized trial. The following trials compared CMT versus chemotherapy only for bulky disease, but none used response-guided therapy, and some used different definitions of bulky disease (eg, >7.5 cm).

●The phase 3 UNFOLDER trial reported no difference in survival among patients with bulky disease who, after R-CHOP x 6, were randomly assigned to consolidative RT versus observation; the trial was stopped early because of slow accrual [12]. UNFOLDER included 695 patients (18 to 60 years) with an aggressive B cell lymphoma (89 percent DLBCL) and International Prognostic Index (IPI) ≥1 or IPI 0 with bulky disease (≥7.5 cm). Among the 305 patients with bulky disease, no difference was reported in overall survival (OS) or progression-free survival (PFS) between patients treated with 39.6 Gy involved-field RT versus observation after completing chemoimmunotherapy.

●The RICOVER-noRTH study treated patients (≥60 years) with aggressive B cell lymphomas and bulky disease (≥7.5 cm) using R-CHOP x 6 with no consolidative RT [30]. Outcomes of 164 patients in RICOVER-noRTH were compared with 67 patients with bulky disease (in the earlier RICOVER-60 trial) who received consolidation RT after treatment with R-CHOP [31]. There was no difference in OS or PFS between RT (in RICOVER-60) versus no RT (in RICOVER-noRTH), but consolidative RT was associated with more CRs (70 versus 57 percent) and fewer relapses after CR (4 versus 22 percent). Interpretation of the findings is constrained by substantial crossover to unplanned RT in RICOVER-60 and early trial closure due to poor patient accrual.

●In a retrospective study of 723 patients with advanced-stage DLBCL, R-CHOP x 6 (without consolidative RT) was effective for patients with bulky disease (≥10 cm) who achieved CR on PET6 [32]. Among patients with bulky disease, 72 percent had CR after six cycles of R-CHOP. For patients with CR on PET6, no difference was reported for a three-year time to progression (TTP) between patients with bulky disease versus those with nonbulky disease. However, consolidative RT was associated with better outcomes for the 206 patients with a less than CR on PET6. Consolidative RT was given to one-half of patients with positive PET6; compared with consolidative RT, patients who did not receive RT had an inferior three-year TTP (44 versus 80 percent).

OTHER ASPECTS OF MANAGEMENT

Maintenance therapy — There is no proven benefit for maintenance therapy in DLBCL.

In a phase 3 trial (ReMARC) in older patients with DLBCL, lenalidomide maintenance therapy did not improve survival, but it reduced the risk of relapse [33]. A total of 650 patients (60 to 80 years) with stage II to IV DLBCL and an age-adjusted International Prognostic Index (IPI) ≥1 who achieved complete response (CR) or partial response (PR) with six to eight cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) were randomly assigned to 24 months of either lenalidomide, 25 mg/day for 21 days of every 28-day cycle, or placebo. The overall survival (OS) was similar for patients in both trial arms. With a median follow-up of 39 months, median progression-free survival (PFS) was not reached for patients receiving lenalidomide compared with a 59-month median PFS with placebo (hazard ratio 0.71 [95% CI 0.54-0.93]). The most common grade ≥3 adverse effects (AEs) with lenalidomide versus placebo were neutropenia (56 versus 22 percent) and cutaneous reactions (5 versus 1 percent).

Central nervous system prophylaxis — Central nervous system (CNS) involvement is uncommon at presentation of limited-stage DLBCL. However, patients with certain clinical features are at an increased risk for CNS relapse (table 6).

There is controversy about the balance of risks and benefits of CNS prophylaxis in patients with DLBCL. A decision to administer CNS prophylaxis should be individualized according to higher-risk features, including the number extranodal involvement sites and the CNS-IPI. (See 'Prognostic indices' above.)

Methods of CNS prophylaxis and outcomes are discussed separately. (See "Initial treatment of advanced stage diffuse large B cell lymphoma", section on 'CNS management'.)

Special scenarios

Oncologic emergencies — Oncologic emergencies are uncommon in patients with limited-stage DLBCL, but clinicians should be alert for them.

●Tumor lysis syndrome – 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 syndrome – 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 with SVC syndrome. If SVC syndrome is suspected, the severity of symptoms should be assessed clinically, imaging should be obtained (algorithm 1), and SVC syndrome should be managed as discussed separately. (See "Malignancy-related superior vena cava syndrome".)

SVC syndrome is more common in patients with primary mediastinal large B cell lymphoma, which is no longer considered a type of DLBCL and is managed differently. (See "Primary mediastinal large B cell lymphoma".)

●Spinal cord compression – Spinal cord compression (SCC) can cause pain, mechanical instability of the spine, and potentially irreversible loss of neurologic function.

Most patients with SCC 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 SCC 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'.)

Extranodal involvement

Testicular involvement — Testicular involvement by DLBCL is associated with adverse prognosis, increased risk for CNS involvement, and requires distinct aspects of management.

Testicular lymphoma is the most common malignant testicular tumor in men >60 years of age, and it accounts for approximately 1 percent of lymphomas overall [34]. DLBCL is the most common subtype of testicular lymphoma, and the median age of presentation is the sixth to seventh decade [35]. Outcomes in patients with testicular involvement are worse than would be predicted by the IPI [36,37].

●Management – For primary testicular DLBCL, we suggest all of the following [38]:

•Orchiectomy

•R-CHOP x 6 (six cycles of R-CHOP)

•CNS prophylaxis (see "Initial treatment of advanced stage diffuse large B cell lymphoma", section on 'CNS management')

•25 to 30 gray (Gy) scrotal radiation therapy (RT)

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 used only for patients who are not candidates for any chemotherapy.

●Outcomes – Small studies suggest better outcomes in patients who receive CNS prophylaxis and RT to the contralateral testis [34,36,38-45].

•A prospective study of 53 patients with stage I or II primary testicular lymphoma reported OS and PFS at five years were 85 and 74 percent, respectively, following treatment with six to eight cycles of R-CHOP, four weekly doses of intrathecal methotrexate, and 30 Gy RT to the contralateral testis. For patients with stage II disease, 30 to 36 Gy RT to regional lymph nodes was added [38]. 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 reported outcomes using systemic chemotherapy with RT (15 patients) or without RT (27 patients) in patients with localized testicular lymphoma after orchiectomy [41]. Patients who received both chemotherapy and RT 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 RT.

Relapses occur predominantly in the CNS and contralateral testis. In a study of 373 patients with primary testicular lymphoma, 15 percent had CNS relapse and/or progression [36]. A study of 29 patients from the prerituximab era reported that 41 percent of relapses were either in the CNS or the contralateral testis [46].

Other extranodal sites — Involvement of extranodal sites may influence the management of DLBCL.

Gastrointestinal (GI) DLBCL is the most common site of extranodal presentation and represents approximately one-third of cases of primary extranodal DLBCL [47]. Examples include:

●Gastric – For patients with limited-stage gastric DLBCL (table 7), we treat with either R-CHOP x 6 alone or R-CHOP x 3 (three cycles of R-CHOP) followed by RT. (See "Initial treatment of advanced stage diffuse large B cell lymphoma", section on 'Treatment'.)

We reserve surgery for patients with complications, such as perforation, obstruction, or intractable bleeding [48-53]. GI perforation is uncommon, but occasional patients may benefit from a surgical consultation for bleeding or gastric outlet obstruction [53].

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 [54-56]. (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 [48,49,57-61].

•A prospective trial of 589 patients with early stage primary gastric DLBCL randomly assigned therapy with surgery, surgery plus RT, surgery plus CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy, or CHOP alone [62]. 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 consolidative RT.

•A retrospective single-center review included 415 cases of GI DLBCL, of whom 13 percent developed a perforation during the disease course; one-half of the perforations occurred at the time of diagnosis, while one-half occurred after chemotherapy [63]. Retrospective analyses and prospective studies have had mixed results, with some studies suggesting a benefit from surgery and others suggesting no benefit [48-52,64,65].

●Other GI involvement – For intestinal involvement with DLBCL, we treat with R-CHOP x 6 alone rather than combined modality therapy (CMT; eg, R-CHOP x 3 plus RT) because of uncertainty in defining the full extent of intestinal involvement.

For rectal DLBCL, acceptable options include R-CHOP x 6 (without RT) alone or CMT (R-CHOP x 3 followed by RT) because of the more fixed nature of the rectum. (See 'Treatments' below.)

Surgery is reserved for patients with perforation, obstruction, or intractable bleeding [48-53]. GI perforation is uncommon, but patients may benefit from a surgical consultation for bleeding or bowel obstruction [53]. As discussed with gastric involvement, limited studies have not borne out concerns that chemotherapy treatment causes excessive perforation and/or bleeding [48,49,57-61].

●Bone – Extranodal involvement of bone may be due to primary DLBCL of bone or extranodal involvement by systemic disease [66-68].

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 [69]. Primary DLBCL of bone generally has a more favorable prognosis than comparable nodal disease or other extranodal DLBCL at other sites [70-75].

For both primary DLBCL of bone and secondary involvement by systemic DLBCL, we treat with R-CHOP x 6, with or without RT. (See 'Adverse features but no bulky disease' above.)

This approach achieves excellent local control and infrequent systemic failure [76,77], but optimal therapy of bone involvement by DLBCL is not well-defined [68].

●Skin – Cutaneous involvement by DLBCL may reflect secondary involvement by systemic DLBCL or primary cutaneous DLBCL.

For secondary involvement by systemic disease, we treat with R-CHOP followed by RT. (See 'Adverse features but no bulky disease' above.)

Primary cutaneous large B cell lymphoma, leg type is a distinct disorder that is discussed separately. (See "Primary cutaneous large B cell lymphoma, leg type".)

●Ovary – Primary lymphoma of the ovary is rare, but the prognosis is poor, with a five-year survival of approximately 40 percent [78,79].

The most common presentation is a painful abdominal or pelvic mass.

There are no clinical studies to guide the management of ovarian lymphoma. Unilateral salpingo-oophorectomy is acceptable if there is no evidence of disease on the contralateral side; hysterectomy is not required, but it is often performed to prevent bleeding after oophorectomy. Systemic therapy is guided by disease stage, which may be accompanied by CNS prophylaxis. (See 'Central nervous system prophylaxis' above.)

Ovarian DLBCL may be associated with systemic recurrence, including the CNS, but the actual rate of CNS involvement is unknown [78].

●Breast – DLBCL is the most common histologic subtype of primary lymphoma of the breast. Primary DLBCL of the breast usually presents as a painless breast mass.

There are limited data to guide treatment. Systemic therapy is guided by disease stage, but there is controversy regarding the roles of surgical resection and CNS prophylaxis. In a retrospective review, mastectomy was associated with the reduced use of chemotherapy and/or RT, higher all-cause and disease-specific mortality, and was not associated with a reduced recurrence rate [80].

Limited medical fitness — There is no preferred chemoimmunotherapy regimen for patients who are medically frail, >80 years old with comorbidities, or with limited cardiac function. A consultation with cardiology and frequent cardiac monitoring should be used if an anthracycline-based regimen is administered.

Acceptable treatment options in this setting include [81,82]:

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

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

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

People living with HIV — The management of DLBCL in people infected with 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'.)

FOLLOW-UP

Post-treatment positron emission tomography — We repeat positron emission tomography (PET) within six weeks of the end of treatment to document complete response (CR).

●PET negative – For CR (PET score 1 to 3), we monitor for relapse, as described below. (See 'Surveillance' below.)

●PET positive – For patients with persistent PET activity (ie, PET score 4 to 5) we generally biopsy the site of activity to exclude an alternative diagnosis (eg, infection, other type of cancer).

•Persistent DLBCL – Treat for refractory DLBCL, as discussed separately. (See "Diffuse large B cell lymphoma (DLBCL): Suspected first relapse or refractory disease in patients who are medically fit".)

Palliative radiation therapy (RT) can be offered to patients who are not candidates for systemic therapy.

•No persistent DLBCL – Monitor for relapse, as described below. (See 'Surveillance' below.)

Surveillance — For CR at the end of treatment, we monitor for relapse and late adverse effects of treatment.

We evaluate the patient clinically and obtain laboratory studies every three to six months for the first five years, then annually or as clinically indicated.

We do not obtain routine imaging. There is no evidence that routine imaging with PET or CT improves outcomes, and this approach avoids excessive radiation exposure.

TREATMENTS

R-CHOP — R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) is the preferred chemoimmunotherapy for most patients with limited-stage DLBCL.

●Administration – R-CHOP is administered in 21-day cycles. Details of drug doses, schedule, and supportive care are presented in the accompanying table (table 5).

We cap the total vincristine dose at 2 mg to limit neurotoxicity; some experts instead cap the vincristine dose at 3 mg.

●Toxicity – Grade ≥3 adverse effects (AEs) are predominantly neutropenia, anemia, and peripheral neuropathy.

Biosimilar agents that are approved by the US Food and Drug Administration (FDA) or European Medicines Agency (EMA) are acceptable alternatives to rituximab.

R-pola-CHP — Some experts favor R-pola-CHP (rituximab, polatuzumab vedotin, cyclophosphamide, doxorubicin, vincristine, and prednisone) for selected patients with DLBCL with International Prognostic Index (IPI) ≥2, as discussed above. (See 'Adverse features but no bulky disease' above.)

●Administration – R-pola-CHP resembles R-CHOP but replaces vincristine with polatuzumab vedotin.

●Toxicity – Grade ≥3 AEs are predominantly neutropenia, anemia, and a low incidence of peripheral neuropathy.

Polatuzumab is approved by the FDA for DLBCL with IPI ≥2.

Radiation therapy — The dose and volume of radiation therapy (RT) used in combined modality therapy (CMT) is individualized, based on disease stage, anatomic sites of involvement, and potential toxicity to adjacent organs.

●CMT – RT should begin within five weeks of the completion of systemic therapy. We treat with 30 gray (Gy) involved-site RT, but we generally boost positron emission tomography (PET)-avid sites to 36 to 40 Gy for patients with PET score 4 or 5 after three cycles of R-CHOP.

These RT doses are associated with excellent outcomes and less short-term and long-term toxicity than higher doses (up to 50 Gy) and/or larger fields that were used in the past [29,83-91]. A phase 3 trial reported similar outcomes in patients who were randomly assigned to lower-dose (30 Gy) RT versus higher-dose (40 to 45 Gy) RT for aggressive lymphomas (82 percent DLBCL) [91].

●Palliation – RT can provide effective palliation in frail patients who cannot tolerate systemic therapy.

RT alone (ie, no systemic therapy) is no longer used to treat DLBCL.

REFRACTORY DLBCL — For patients who do not have an adequate response to the initial treatment of DLBCL, we generally obtain a biopsy to confirm the diagnosis of refractory disease.

The 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 5^th to 6^th 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 10^th to 12^th 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

●Description – Limited-stage diffuse large B cell lymphoma (DLBCL) refers to stage I or II disease (table 3).

●Evaluation – Assess comorbidities by clinical evaluation and laboratory studies. (See 'Pretreatment evaluation' above.)

●Staging – Based on clinical evaluation and positron emission tomography (PET) using the five-point (Deauville) scale (table 2), according to Lugano criteria (table 3). (See 'Staging' above.)

●Prognostic indices – We assess:

•International Prognostic Index (IPI) (table 4) (see 'International Prognostic Index' above)

-Age >60 years

-Serum lactate dehydrogenase elevated

-Eastern Cooperative Oncology Group performance status ≥2 (table 1)

-Stage III or IV

->1 extranodal site

•Central nervous system (CNS)-IPI – Described above (see 'Central nervous system International Prognostic Index' above)

●Overview

•Systemic therapy – For patients with DLBCL, we recommend the addition of rituximab to cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) rather than CHOP alone (Grade 1A). (See 'Chemoimmunotherapy' above.)

•Risk-stratified management – Guided by prognostic features, described above. (See 'Risk-stratified management' above.)

●No adverse features – For limited-stage DLBCL with no adverse prognostic features, we suggest R-CHOP x 4 (ie, four cycles of R-CHOP) rather than more cycles of R-CHOP or combined modality therapy (CMT; ie, R-CHOP plus radiation therapy [RT]) (Grade 2C). (See 'No adverse features' above.)

●Adverse features but no bulky disease – For adverse features but no bulky disease, we suggest response-guided therapy with R-CHOP (Grade 2C). Conventional management (ie, no interim response assessment, described below) is an acceptable alternative. (See 'Adverse features but no bulky disease' above.)

•Response-guided management – Initial treatment with R-CHOP x 3, followed by PET; further treatment is guided by interval PET (PET3) response (see 'Response-guided therapy' above):

-Complete response (CR; PET score 1 to 3) – Treat with one additional cycle of R-CHOP.

-Less than CR (PET score 4 to 5) – Management is guided by the extent of disease, as described above. (See 'Response-guided therapy' above.)

•Conventional management – Options include either CMT (R-CHOP x 3 plus RT) versus R-CHOP x 6 (no RT); the choice is guided by comorbidities and patient preference. (See 'Conventional management' above.)

●Bulky disease – For bulky disease (≥10 cm), we suggest response-guided therapy with restaging after R-CHOP x 6 rather than routine CMT (R-CHOP x 6 followed by RT) (Grade 2C). (See 'Bulky disease' above.)

Response-guided therapy for bulky disease entails:

•R-CHOP x 6, followed by restaging

•Further therapy based on PET6 response:

-CR (PET score 1 to 3) – No further therapy.

-PET score 4 – RT.

-PET score 5 – Biopsy PET-avid disease; further therapy based on biopsy, as described above.

●Other management

•Maintenance therapy – There is no proven benefit for maintenance therapy after achieving CR. (See 'Maintenance therapy' above.)

•CNS management – CNS involvement is uncommon at diagnosis, and there is no proven benefit for CNS prophylaxis. (See 'Central nervous system prophylaxis' above.)

•Special scenarios – Oncologic emergencies, extranodal involvement, and limited fitness are discussed. (See 'Special scenarios' above.)

For primary testicular DLBCL, we suggest all of the following (Grade 2C):

-Orchiectomy

-R-CHOP x 6

-CNS prophylaxis

-Scrotal RT

●Follow-up – PET is repeated after completing planned therapy. (See 'Follow-up' above.)

•CR – Monitor clinically; limit imaging to reduce radiation exposure.

•Less than CR – Treat as refractory DLBCL. (See "Diffuse large B cell lymphoma (DLBCL): Suspected first relapse or refractory disease in patients who are medically fit".)