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 "Diffuse large B cell lymphoma and other large B cell lymphomas: Presentation, diagnosis, and classification".)

●(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".)

PRETREATMENT EVALUATION — 

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

Discussion in a multidisciplinary tumor board is useful for consideration of treatment options. A radiation oncologist should evaluate patients with bulky disease, a dominant skeletal site of involvement, and in settings 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 "Diffuse large B cell lymphoma and other large B cell lymphomas: Presentation, diagnosis, and classification", 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 "Diffuse large B cell lymphoma and other large B cell lymphomas: Presentation, diagnosis, and classification", 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 prior to therapy. (See 'Central nervous system International Prognostic Index' below.)

CNS imaging and/or diagnostic lumbar puncture (LP) should be performed in the following settings:

•Neurologic abnormalities – Patients with unexplained neurologic abnormalities or evidence of leptomeningeal involvement by imaging should have a diagnostic 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 — 

Staging of DLBCL is based on clinical evaluation and imaging.

PET is assessed using the 5-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 — 

Following are key aspects of the management of limited-stage DLBCL.

●Chemoimmunotherapy – Rituximab or an approved biosimilar is included in treatment of all patients with DLBCL. (See 'Chemoimmunotherapy' below.)

●Response-guided management – For most patients with limited-stage DLBCL, we suggest positron emission tomography (PET) response-guided therapy rather than a predetermined course of treatment.

No randomized trials have directly compared response-guided treatment with a predetermined course of therapy in this setting. However, response-guided therapy enables the individualization of treatment based on PET response to initial treatment. As a result, patients with a robust initial response are spared unnecessary treatment and attendant toxicity, while those with less responsive disease can be treated according to the nature and degree of response.

We stratify treatment of limited-stage DLBCL according to the presence of bulky disease (ie, nodal mass ≥10 cm diameter). Details of response-guided therapy are discussed below:

•No bulky disease (see 'Response-guided management' below)

•Bulky disease (see 'Response-guided treatment of bulky disease' below)

●Conventional therapy – For settings where response-guided therapy is not used ("conventional therapy"), management is discussed below:

•No bulky disease (see 'Conventional therapy (ie, not response guided)' below)

•Bulky disease (see 'Conventional therapy of bulky disease' below)

●Special scenarios – Treatment may be modified in certain settings.

•Adverse prognostic score – Patients with International Prognostic Index (IPI) (table 4) ≥2 may warrant distinctive management, as discussed below. (See 'Adverse prognosis (IPI score ≥2)' below.)

•Other scenarios – Management of patients with oncologic emergencies, extranodal disease, and medical conditions that may affect treatment is discussed below. (See 'Special scenarios' below.)

CHEMOIMMUNOTHERAPY — 

For patients with DLBCL, we recommend chemoimmunotherapy (ie, rituximab plus chemotherapy) rather than chemotherapy alone, based on superior survival and similar toxicity.

Chemoimmunotherapy achieved superior overall survival (OS) compared with chemotherapy-alone in multiple randomized clinical trials.

●R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) (table 5) achieved superior outcomes in a phase 3 trial that randomly assigned 399 patients (60 to 80 years) with DLBCL to every three-week treatment with R-CHOP versus CHOP [5]. Compared with CHOP, 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.

Compared with R-CHOP, no chemoimmunotherapy regimen provides a more favorable balance of benefits and toxicity in the setting of limited-stage DLBCL. R-pola-CHP (rituximab, polatuzumab, cyclophosphamide, doxorubicin, prednisone) was more efficacious than R-CHOP in patients with advanced-stage DLBCL [9], but this benefit has not been demonstrated with limited-stage disease. Other regimens that have been evaluated for DLBCL 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, and cytarabine [10-12]. Treatment selection is not influenced by cell-of-origin status (eg, germinal center versus activated B cell phenotypes) or other pathologic features. Treatment of advanced-stage DLBCL with R-pola-CHP is discussed separately. (See "Initial treatment of advanced-stage diffuse large B cell lymphoma", section on 'R-pola-CHP'.)

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.

NO BULKY DISEASE — 

Treatment of limited-stage DLBCL when all masses are <10 cm is described in the following sections.

Some experts modify treatment of patients with adverse prognostic features or with extranodal involvement, as discussed below. (See 'Adverse prognosis (IPI score ≥2)' below and 'Extranodal involvement' below.)

Other special scenarios that may influence management are discussed below. (See 'Special scenarios' below.)

Response-guided management — We use response-guided therapy rather than a predetermined course of treatment for most patients, as discussed above. (See 'Overview' above.)

Response-guided therapy for limited-stage DLBCL without bulky disease (algorithm 1) comprises:

●Three initial cycles of chemoimmunotherapy. (See 'Initial therapy' below.)

●Response assessment after three treatment cycles (PET3). (See 'PET3 response assessment' below.)

●Further management guided by PET3 response using the 5-point (Deauville) scale (table 2). (See 'Further management' below.)

●Restaging with positron emission tomography (PET) after completing planned therapy. (See 'Post-treatment positron emission tomography' below.)

Initial therapy — For response-guided therapy of nonbulky limited-stage DLBCL, we treat with three cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) (table 5) followed by PET response assessment.

●Administration – R-CHOP is administered in 21-day cycles:

•Rituximab – 375 mg/m² intravenously (IV) day 1

•Cyclophosphamide – 750 mg/m² IV day 1

•Doxorubicin – 50 mg/m² IV day 1

•Vincristine – 1.4 mg/m² IV day 1

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

•Prednisone – 100 mg orally days 2 to 5

Additional details of doses, schedule, and supportive care are presented in the accompanying table (table 5). The choice of R-CHOP for treatment of DLBCL is discussed above. (See 'Chemoimmunotherapy' above.)

Some clinicians add two additional treatments with rituximab alone after four cycles of R-CHOP based on the FLYER trial [13], described below. (See 'Deauville 1-3' below.)

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

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

PET3 response assessment — PET-based response is assessed after three initial cycles of R-CHOP (PET3) using the 5-point (Deauville) scoring system (table 2), according to the Lugano classification (table 6).

Further management — Further therapy is guided by PET3 response, as described in the following sections.

Deauville 1-3 — For patients with PET3 Deauville score 1-3, we suggest one additional cycle of R-CHOP (four total cycles; R-CHOP x 4) rather than >4 cycles of R-CHOP or consolidation using radiation therapy (RT). Treatment with R-CHOP x 4 achieved similar outcomes with less toxicity than the other approaches in randomized trials.

●Number of cycles of R-CHOP – The suggestion for R-CHOP x 4 is based on the following:

•In the phase 3 FLYER trial, outcomes were similar after R-CHOP x 6 versus R-CHOP x 4 (plus two treatments with rituximab alone) [13]. Among 592 patients ≤60 years with stage I or II DLBCL and no adverse prognostic factors, there was no difference in five-year overall survival (OS) or progression-free survival (PFS) between the trial arms. R-CHOP x 4 was associated with less hematologic and nonhematologic toxicity; both treatment-related deaths were in patients in the R-CHOP x 6 trial arm.

Although the FLYER trial was limited to patients <60 years old, we consider the conclusions applicable to all patients.

•In the S1001 study, 89 percent of 132 patients had a complete response (CR; ie, Deauville score 1-3) on PET3; these patients, who received one additional cycle of R-CHOP (four cycles total), had 89 percent five-year OS and 87 percent five-year PFS [14]. Patients with Deauville score ≥4 on PET3 received 36 gray (Gy) involved-field radiation therapy (IFRT), 9 Gy boost to the site of PET activity, and ibritumomab tiuxetan (anti-CD20 monoclonal antibody conjugated to yttrium-90); outcomes for these patients who were PET3 positive were similar to those patients with negative PET3. 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.

•The LYSA/GOELAMS 02-03 trial [15] (described below) also reported excellent outcomes with four cycles of chemotherapy.

●Chemoimmunotherapy alone versus combined modality therapy – Chemotherapy alone and combined modality therapy (CMT) are associated with similar outcomes and short-term toxicity in this setting; we await longer follow-up to see if CMT is associated with more late AEs.

•In the phase 3 LYSA/GOELAMS 02-03 trial, outcomes were similar in 334 adults with stage I/II DLBCL (no bulky disease) who were randomly assigned to treatment with R-CHOP only versus CMT [15]. Patients who achieved CR with R-CHOP-14 (four or six cycles of R-CHOP every two weeks were administered based on International Prognostic Index [IPI] score) were randomly assigned to receive 40 Gy RT versus no RT. Compared with CMT, R-CHOP alone achieved similar five-year OS (96 and 92 percent, respectively) 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 of limited-stage DLBCL compared CMT (R-CHOP x 3 plus RT) versus six to eight cycles of R-CHOP alone [16]. CMT was associated with similar survival but less short-term toxicity, less neutropenia, and a lower risk of being treated with a second-line therapy.

•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 [17].

•A retrospective single-institution study reported that CMT was associated with better survival than chemoimmunotherapy alone for patients with stage I or II DLBCL, but more than one-half of the patients with limited-stage disease had bulky disease [18]. 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.

Deauville 4 — For patients with localized Deauville score 4, further treatment with either chemoimmunotherapy or RT is acceptable (algorithm 1).

For patients with extensive or multiple sites of Deauville 4 activity, we manage like Deauville 5. (See 'Deauville 5' below.)

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:

●Additional chemotherapy – R-CHOP x 3 (six total cycles), with or without consolidative RT.

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

Deauville 5 — For patients with Deauville score 5 or extensive/multiple sites of Deauville score 4, we generally biopsy the site of PET activity (algorithm 1). The biopsy is used to distinguish persistent DLBCL from other conditions (eg, inflammation, infection) and other cancers (eg, gray zone lymphoma, solid tumors).

●Biopsy negative – For little or no residual/viable DLBCL (eg, extensive necrosis or inflammatory infiltrate), we treat with three additional cycles of R-CHOP (six total cycles).

PET is repeated after completing six cycles of R-CHOP; 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 DLBCL, we treat as refractory DLBCL. (See "Diffuse large B cell lymphoma (DLBCL): Suspected first relapse or refractory disease in patients who are medically fit".)

Conventional therapy (ie, not response guided) — For conventional therapy (ie, not response guided), we consider either of the following acceptable for patients with limited-stage DLBCL without bulky disease:

●Chemotherapy-only – R-CHOP x 6

●CMT – R-CHOP x 3 plus 30 to 36 Gy ISRT

Although data are limited, some clinicians treat patients with limited-stage DLBCL who have IPI score ≥2 using six cycles of R-pola-CHP (rituximab, polatuzumab vedotin, cyclophosphamide, doxorubicin, prednisone), as discussed below. (See 'Adverse prognosis (IPI score ≥2)' below.)

PET should be repeated after completing all planned therapy to document the treatment response, as described below. (See 'Post-treatment positron emission tomography' below.)

The choice of CMT versus chemotherapy 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 are 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) [19].

●In SWOG 0014, four-year OS was 92 percent and 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) [20].

BULKY DISEASE — 

Bulky disease refers to nodal masses ≥10 cm. Different definitions of bulky disease have been used in some studies.

Response-guided treatment of bulky disease — For limited-stage DLBCL with bulky disease, we suggest response-guided therapy with positron emission tomography (PET) after six cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) (table 5) rather than routine treatment with combined modality therapy (CMT; ie, chemoimmunotherapy plus radiation therapy [RT]).

Response-guided management has not been directly compared with routine CMT for limited-stage DLBCL with bulky disease in a randomized trial, but response-guided management enables avoidance of RT for patients with Deauville 1-3 on PET after six cycles of chemotherapy. (See 'Overview' above.)

Response-guided management for patients with bulky disease includes:

●R-CHOP x 6 – Administration and toxicity of R-CHOP are discussed above. (See 'Initial therapy' above.)

●Response assessment – PET-based response is assessed after six cycles of R-CHOP (PET6), using the 5-point (Deauville) scoring system (table 2), according to the Lugano classification (table 6).

●Further therapy is based on PET6 response:

•Deauville 1-3 – No further therapy

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

•Deauville 5 – Biopsy PET-avid disease, with further therapy guided by 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 all planned therapy, as described below. (See 'Post-treatment positron emission tomography' below.)

Conventional therapy of bulky disease — When response-guided therapy is not used, conventional treatment for limited-stage DLBCL with bulky disease is six cycles of R-CHOP followed by consolidation with RT.

Some experts treat patients with an adverse prognosis (ie, International Prognostic Index [IPI] score ≥2) using R-pola-CHP (rituximab, polatuzumab vedotin, cyclophosphamide, doxorubicin, prednisone), as discussed below. (See 'Adverse prognosis (IPI score ≥2)' below.)

The following trials compared CMT versus chemotherapy alone for bulky disease. None of these trials 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 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 [21]. 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 [22]. There was no difference in OS or PFS between those treated with RT (in RICOVER-60) versus no RT (in RICOVER-noRTH), but consolidative RT was associated with more complete responses (CRs; 70 versus 57 percent) and fewer relapses after achieving 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 [23]. 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).

SPECIAL SCENARIOS

Adverse prognosis (IPI score ≥2) — International Prognostic Index (IPI) (table 4) score ≥2 is considered an adverse prognostic category in patients with limited-stage DLBCL. The use of the IPI is discussed above. (See 'International Prognostic Index' above.)

For patients with limited-stage DLBCL and IPI score ≥2, some experts favor treatment using R-pola-CHP (rituximab, polatuzumab, cyclophosphamide, doxorubicin, prednisone). However, there is no clear evidence that R-pola-CHP offers a more favorable balance of outcomes and toxicity compared with response-guide therapy using R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone).

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

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

Polatuzumab is approved by the US Food and Drug Administration (FDA) for DLBCL with IPI ≥2.

Use of R-pola-CHP in this setting is based on the phase 3 POLARIX trial, in which patients with DLBCL were randomly assigned to R-pola-CHP x 6 versus R-CHOP x 4 (followed by two cycles of rituximab) [9]. However, only 10 percent of patients enrolled in POLARIX 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.

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

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 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, 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 an 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 [24]. DLBCL is the most common subtype of testicular lymphoma, and the median age of presentation is the sixth to seventh decade [25]. Outcomes in patients with testicular involvement are worse than would be predicted by the IPI [26,27].

●Management – For primary testicular DLBCL, we suggest all of the following [28]:

•Orchiectomy

•R-CHOP x 6

•Central nervous system (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 [24,26,28-36].

•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 [28]. 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 [31]. 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 [26]. A study of 29 patients from the pre-rituximab era reported that 41 percent of relapses were either in the CNS or the contralateral testis [37].

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 [38]. Examples include:

●Gastric – For patients with limited-stage gastric DLBCL (table 7), we treat with either R-CHOP x 3 followed by RT or with R-CHOP x 6 without RT. Some experts consider that for selected patients with CR on PET after R-CHOP x 3, the addition of one additional cycle of R-CHOP (with no RT) is acceptable. (See "Initial treatment of advanced-stage diffuse large B cell lymphoma", section on 'Treatment'.)

We reserve surgical resection for patients with complications, such as perforation, obstruction, or intractable bleeding [39-44]. GI perforation is uncommon, but patients may benefit from a surgical consultation for bleeding or gastric outlet obstruction [44].

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 [45-47]. (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 [39,40,48-52].

•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 [53]. 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 [54]. Retrospective analyses and prospective studies have had mixed results, with some studies suggesting a benefit from surgery and others suggesting no benefit [39-43,55,56].

●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.

Surgery is reserved for patients with perforation, obstruction, or intractable bleeding [39-44]. GI perforation is uncommon, but patients may benefit from a surgical consultation for bleeding or bowel obstruction [44]. As discussed with gastric involvement, limited studies have not borne out concerns that chemotherapy treatment causes excessive perforation and/or bleeding [39,40,48-52].

●Bone – Extranodal involvement of bone may be due to primary DLBCL of bone or extranodal involvement by systemic disease [57-59].

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 [60]. Primary DLBCL of bone generally has a more favorable prognosis than comparable nodal disease or other extranodal DLBCL at other sites [61-66].

For both primary DLBCL of bone and secondary involvement by systemic DLBCL, we treat with R-CHOP x 6, with or without RT. (See 'Conventional therapy of bulky disease' above.)

This approach achieves excellent local control and infrequent systemic failure [67,68], but optimal therapy of bone involvement by DLBCL is not well-defined [59].

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

Primary cutaneous large B cell lymphoma, leg type is a distinct disorder that is discussed separately. (See "Primary cutaneous diffuse 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 [69,70].

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. We generally treat with six cycles of R-CHOP. (See 'Central nervous system prophylaxis' below.)

Ovarian DLBCL may be associated with systemic recurrence, including the CNS, but the actual rate of CNS involvement is unknown [69].

●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 [71].

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 [72,73]:

●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'.)

OTHER ASPECTS OF MANAGEMENT

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 (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone).

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 [20,74-82]. 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) [82].

●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.

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 [83]. 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 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 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 8).

There is controversy about the balance of risks and benefits of CNS prophylaxis in patients with DLBCL, but there is little evidence of benefit in the setting of limited-stage disease. 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'.)

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 Deauville score 1-3, we monitor for relapse, as described below. (See 'Surveillance' below.)

●PET positive – For Deauville score 4 or 5, we generally biopsy the site of activity to exclude an alternative diagnosis (eg, infection, other 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.

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). (See 'Staging' above.)

●Prognostic indices – Assess before treatment:

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

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

●Overview – For most patients with limited-stage DLBCL, we suggest PET response-guided therapy rather than a predetermined course of treatment (Grade 2C). (See 'Overview' above.)

Management is stratified according to the presence of bulky disease (nodal mass ≥10 cm).

●Chemoimmunotherapy – We recommend chemoimmunotherapy (ie, rituximab plus chemotherapy) rather than chemotherapy alone (Grade 1A). (See 'Chemoimmunotherapy' above.)

●No bulky disease – Response-guided therapy for limited-stage DLBCL without bulky disease comprises (see 'Response-guided management' above):

•Initial therapy – Three initial cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) (table 5). (See 'Initial therapy' above.)

•PET3 response. (See 'PET3 response assessment' above.)

•Further management – Guided by PET3 response:

-Deauville score 1-3 – We suggest one additional cycle of R-CHOP (four total cycles) rather than >4 total cycles or radiation therapy (RT) consolidation (Grade 2C). (See 'Deauville 1-3' above.)

-Deauville score 4 – Acceptable options include (see 'Deauville 4' above):

Three additional cycles of R-CHOP (six total cycles) or

RT – Involved site RT (ISRT; 30 to 36 Gy) with boost to PET-avid site

-Deauville 5 or extensive Deauville 4 – Biopsy to exclude other diagnoses, with management guided by the biopsy findings. (See 'Deauville 5' above.)

●Conventional therapy for nonbulky disease – Either of the following is acceptable (see 'Conventional therapy (ie, not response guided)' above):

•R-CHOP x 6 (no RT)

•Combined modality therapy (CMT) – R-CHOP x 3 plus 30 to 36 Gy ISRT

Some experts treat patients with an adverse prognosis (ie, IPI score ≥2) using R-pola-CHP (rituximab, polatuzumab, cyclophosphamide, doxorubicin, prednisone). (See 'Adverse prognosis (IPI score ≥2)' above.)

●Bulky disease – We suggest response-guided therapy with R-CHOP x 6 followed by PET6 rather than routine CMT (Grade 2C). (See 'Response-guided treatment of bulky disease' above.)

Further management is guided by PET6 response:

•Deauville 1-3 – No further therapy

•Deauville 4 – 30 Gy ISRT with boost to PET-avid site

•Deauville 5 – Biopsy PET-avid disease, with management guided by biopsy findings

●Conventional therapy for bulky disease – We suggest CMT with R-CHOP x 6 followed by RT (Grade 2C). (See 'Conventional therapy of bulky disease' above.)

Some experts treat with R-pola-CHP for IPI score ≥2. (See 'Adverse prognosis (IPI score ≥2)' above.)

●Other management

•Maintenance therapy – There is no proven benefit for maintenance therapy after achieving complete response (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".)

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges Arnold S Freedman, MD, who contributed to earlier versions of this topic review.