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  • Guideline Summary
  • NGC:010684
  • 2014

ACR Appropriateness Criteria® diffuse large B-cell lymphoma.

Dabaja BS, Advani R, Hodgson DC, Dhakal S, Flowers CR, Ha CS, Hoppe BS, Mendenhall NP, Metzger ML, Plastaras JP, Roberts KB, Shapiro R, Smith SM, Terezakis SA, Winkfield KM, Younes A, Constine LS, Expert Panel on Radiation Oncology–Lymphoma. ACR Appropriateness Criteria® diffuse large B-cell lymphoma [online publication]. Reston (VA): American College of Radiology (ACR); 2014. 17 p. [90 references]

View the original guideline documentation External Web Site Policy

This is the current release of the guideline.

This guideline meets NGC's 2013 (revised) inclusion criteria.

UMLS Concepts (what is this?)

SNOMEDCT_US
Antineoplastic agent (27867009), Antineoplastic agent (372688009), Bleomycin (372843005), Bleomycin (76591000), Cyclophosphamide (387420009), Cyclophosphamide (74470007), Doxorubicin (372817009), Doxorubicin (68444001), Folinic acid (1528001), Folinic acid (396065004), Malignant lymphoma, large B-cell, diffuse (109969005), Malignant lymphoma, large B-cell, diffuse (46732000), Methotrexate (387381009), Methotrexate (68887009), Positron emission tomography (363678002), Positron emission tomography (82918005), Positron emission tomography unit (39821008), Positron emission tomography unit (462323006), Prednisone (10312003), Prednisone (116602009), Radiographic-therapeutic unit (10850003), Rituximab (108809004), Rituximab (386919002), Vincristine (23079006), Vincristine (387126006)

Major Recommendations

ACR Appropriateness Criteria®

Clinical Condition: Diffuse Large B-Cell Lymphoma

Variant 1: Localized aggressive non-Hodgkin lymphoma. 30-year-old man with clinical stage IA DLBCL, presenting with 7-cm mass in the left axilla, with normal PS, normal LDH.

Treatment Rating Comments
3 cycles R-CHOP followed by 30 Gy ISRT if PET-CR to chemotherapy 8  
4 cycles R-CHOP followed by 30 Gy ISRT if PET-CR 7  
6 cycles R-CHOP followed by 30 Gy ISRT if PET-CR to chemotherapy 6  
6 cycles R-CHOP alone 5  
6 cycles DA-EPOCH-R alone 3  
Rating Scale: 1,2,3 Usually not appropriate; 4,5,6 May be appropriate; 7,8,9 Usually appropriate

Note: Abbreviations used in the tables are listed at the end of the "Major Recommendations" field.

Variant 2: Localized aggressive non-Hodgkin lymphoma. 63-year-old woman presenting with DLBCL involving right maxillary sinus; largest dimension=4.2 cm, right submandibular lymph nodes of 2 cm, stage IIEA, high LDH, IPI score=2.

Treatment Rating Comments
6 cycles R-CHOP plus 30 Gy to 36 Gy ISRT 8 CNS prophylaxis may be used according to institution preference.
3-4 cycles R-CHOP plus 30 Gy to 36 Gy ISRT 7  
6 cycles R-CHOP alone 3  
6 cycles DA-EPOCH-R alone 3  
6 cycles DA-EPOCH-R plus 30 Gy to 36 Gy ISRT 3  
Rating Scale: 1,2,3 Usually not appropriate; 4,5,6 May be appropriate; 7,8,9 Usually appropriate

Note: Abbreviations used in the tables are listed at the end of the "Major Recommendations" field.

Variant 3: Localized aggressive non-Hodgkin lymphoma. 27-year-old woman with primary mediastinal lymphoma stage I, 11 cm in diameter, IPI=1 (high LDH).

Treatment Rating Comments
6 cycles R-CHOP followed by 36 Gy ISRT if PET-CR to chemotherapy 8  
6 cycles DA-EPOCH-R alone 7  
R-MACOP B followed by 36 Gy to 40 Gy ISRT 5  
6 cycles R-CHOP alone 3  
4 cycles R-CHOP followed by 36 Gy ISRT if PET-CR to chemotherapy 3  
6 cycles DA-EPOCH-R plus 36 Gy to 40 Gy ISRT 2 ISRT may be used if there is biopsy-proven residual disease.
Rating Scale: 1,2,3 Usually not appropriate; 4,5,6 May be appropriate; 7,8,9 Usually appropriate

Note: Abbreviations used in the tables are listed at the end of the "Major Recommendations" field.

Variant 4: Advanced aggressive non-Hodgkin lymphoma. 45-year-old patient with stage III DLBCL involving right supraclavicular area, mediastinal mass with paraspinal extension into the spinal cord, and para-aortic nodal region, IPI=3.

Treatment Rating Comments
6 cycles R-CHOP followed by 30 Gy to 36 Gy ISRT to the paraspinal mass only 8  
6 cycles R-CHOP alone 6  
6 cycles DA-EPOCH-R alone 5  
6 cycles DA-EPOCH-R followed by ISRT only to paraspinal disease to 30 to 36 Gy 5  
6 cycles R-CHOP followed by 30 to 36 Gy ISRT to all initial sites of disease 3  
4 cycles R-CHOP followed by ISRT to 30 to 36 Gy to original sites of disease 3  
6 cycles of DA-EPOCH-R and ISRT to all original involved sites 3  
4 cycles R-CHOP followed by ISRT to all sites of disease to 45 Gy 2  
3 cycles R-CHOP followed by ISRT to all sites of disease to 45 Gy 2  
Rating Scale: 1,2,3 Usually not appropriate; 4,5,6 May be appropriate; 7,8,9 Usually appropriate

Note: Abbreviations used in the tables are listed at the end of the "Major Recommendations" field.

Summary of Literature Review

Introduction/Background

Diffuse large B-cell lymphoma (DLBCL) is an aggressive form of non-Hodgkin lymphoma (NHL) with subtypes that can be distinguished on the basis of immunophenotypic, morphologic, and molecular characteristics as well as clinical presentation. Disease staging and choice of treatment, including the type, number, and sequence of chemotherapy agents and the need for consolidative radiation therapy (RT), should be made on the basis of clinical factors, which collectively determine response to therapy and survival. The anti-CD20 monoclonal antibody, rituximab, became part of the standard of care in the United States after its approval by the U.S. Food and Drug Administration in 1997; thus the existing literature on the diagnosis and treatment of DLBCL essentially can be separated into the pre-rituximab and post-rituximab eras. The current standard of care for disease at any stage is rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy (R-CHOP), although the number of chemotherapy cycles and use of consolidative RT are still being debated and are often determined based on location and extent of disease involvement.

The value of positron emission tomography/computed tomography (PET/CT) scanning in disease staging and response assessment is well established, however its role in treatment selection or interim treatment modification has yet to be established.

Diagnosis and Staging of DLBCL

DLBCL typically presents in people age 50 or older, although it can also present at any age and is slightly more common among men than women. Etiologic risk factors include human immunodeficiency virus (HIV) infection and low CD4 counts, although the prevalence of DLBCL among HIV-infected individuals has dropped with the advent of highly active antiretroviral therapy. Other risk factors include long-term exposure to immunosuppressive therapy, particularly the use of methotrexate for autoimmune disease. The presence of certain genetic variants, as well as environmental and occupational exposures, has also been linked with DLBCL, although these findings are still considered preliminary. In terms of disease stage at presentation, about one-third of patients present with stage I or II disease (i.e., disease confined to one side of the diaphragm); one-third present with bulky disease (>10 cm); about 40% present with extranodal involvement; and up to 20% present with bone marrow involvement.

The goal of the staging workup should be to identify all sites of disease and thus should include a thorough physical examination, blood tests, and imaging studies. Blood work should include complete blood counts, platelets, lactate dehydrogenase (LDH), comprehensive metabolic panel, and hepatitis B testing; HIV and other viral testing should be performed in selected cases. Other staging tests include multigated acquisition scan/echocardiogram if anthracyclines are indicated and pregnancy testing for women of childbearing age. A bone-marrow biopsy is not performed if bone-marrow involvement is indicated on PET/CT; conversely, if bone-marrow involvement is not indicated by PET/CT, then bone-marrow biopsy should be performed if relevant to clinical trial enrollment or management of the patient.

Lumbar puncture is indicated for involvement of the paranasal sinuses and testicles or for patients with disease at more than 2 extranodal sites with an elevated LDH or HIV-associated lymphoma. Diagnostic contrast-enhanced CT of the neck, chest, abdomen, and pelvis is considered the standard of care, and at present the Ann Arbor staging system is based on CT scan findings. PET/CT is increasingly being used for disease staging as well as treatment evaluation, with many patients undergoing both studies. Prospective and retrospective studies evaluating the efficacy of PET/CT for lymphoma staging suggest very good accuracy with the use of PET. In comparing 3 studies, PET upstaged disease in 8% to 32% of cases when compared to conventional imaging. Disease was downstaged in 0% to 15% of cases, and PET imaging resulted in a change in therapy for 8% to 45% of cases, although whether these changes improved eventual outcome is unknown. These data suggest that PET/CT should be routinely used for the evaluation of patients with DLBCL and has been recommended in the National Comprehensive Cancer Network guidelines. The presence of B symptoms (fever >38º C, drenching night sweats, or unexplained loss of more than 10% of body weight within 6 months preceding diagnosis), performance status, and LDH levels have long been used to predict prognosis in patients with DLBCL as well as those with other forms of NHL.

However, it is worth noting that use of the suffix A or B in staging of DLBCL has recently been challenged by the Lugano Classification guidelines, based on the fact that it is not part of the International Prognostic Index (IPI) (see Appendix 1 of the original guideline document). The committee did suggest keeping it as a prognostic indicator while removing it from the Ann Arbor staging designation. The IPI is a model developed in the pre-rituximab era based on 5 independent prognostic factors including age >60 years, Ann Arbor stage III–IV, LDH >1× normal, Eastern Cooperative Oncology Group (ECOG) performance status ≥2, and more than 1 extranodal disease site. The IPI identifies 4 distinct prognostic groups: low-risk (0 to 1 factors), low-intermediate (2 factors), high-intermediate (3 factors), and high-risk (4 to 5 risk factors) with distinct outcomes for both failure-free survival and overall survival (OS). Its utility has been confirmed in many studies after the incorporation of rituximab. A variant of the IPI, the revised-IPI (R-IPI), developed from a population-based registry within a single Canadian province, redistributes the 5 IPI elements into 3 prognostic outcome groups (P<0.001): very good (0 risk factors: 4-year progression-free survival [PFS] 94%, OS 94%), good (1 to 2 risk factors: 4-year PFS 80%, OS 79%), and poor (3 to 5 risk factors: 4-year PFS 53%, OS 55%). Notably in the R-IPI, even the highest risk group had an OS >50% illustrating improvement in outcomes when treating with R-CHOP.

Since DLBCL is more common in older patients, an alternative index, the elder (E)-IPI, has been proposed, which uses an age cutoff of 70 years (rather than 60 years used in the IPI). The E-IPI was reported using the dataset from the US Intergroup E4494 trial in which the median age was 70 years. In this study the R-IPI did not identify a very good risk group, thus minimizing its utility in patients >60 years. The E-IPI provided additional prognostic discrimination compared to the IPI between low and low-intermediate patients. Recently, the E-IPI has been validated using 2 other datasets of patients >60 years from the Groupe d'Etude de Lymphoma d'Adultes (GELA) 98.5 study and German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL) RICOVER-60.

The recognition of the complexity and heterogeneity of DLBCL has also led to numerous attempts at classification on the basis of gene-expression profile or immunophenotype. The gene-expression profile approach has revealed 3 major subgroups of DLBCL: germinal center B-cell-like (GCB), which has a gene-expression pattern that clusters with normal GCB and has a better outcome than the second subgroup, activated B-cell-like (ABC), which clusters with ABCs, and a third subtype, which consists of primary mediastinal lymphoma (PMBL) or entities that cannot be included in the other subtypes. However, frozen material subjected to gene-expression profiling is difficult to reproduce and thus is of limited diagnostic value. Immunohistochemical profiling has been proposed as a surrogate for gene-expression profiling, with 2 studies finding the key markers to be expressions of BCL6, CD10, and MUM1/IRF4.

Currently, immunophenotyping and genetic markers that should be considered for diagnosis should include CD20+, CD45+, CD3-, along with CD5 (CD5+ DLBCL), CD10 (GCB subtype), CD138 (plasmablastic differentiation), CD30 (which, depending on the rest of the panel, might indicate CD30+ DLBCL or PMBL or Hodgkin lymphoma), IRF/MUM1, BCL2, and BCL6. Other useful testing includes molecular cytogenetic and fluorescence in situ hybridization analyses. The importance of the in situ hybridization is underscored by the recent discovery of "double-hit" lymphoma, an aggressive B-cell variant with a MYC breakpoint (at 8q24) and another break at BCL2. This double-hit genotype is present in 2% to 12% of DLBCLs and is associated with a high proliferative index and poor outcome. DLBCLs that are immunohistochemically double positive for MYC and BCL2 and/or BCL6 proteins are more common, carry a poorer prognosis, and may underlie the differences in outcome observed between ABC and GCB DLBCL.

Treatment Approaches

Disease stage, IPI score, the presence of B symptoms, and the size (bulk) of the disease are all essential factors to consider in the choice of therapy. Other factors to be considered in treatment choice include gene-expression profiles and immunohistochemical data, particularly immunophenotype.

The use of CHOP chemotherapy was established as the standard of care based on findings from a randomized study comparing CHOP with 3 other regimens: m-BACOD (low-dose methotrexate with leucovorin rescue, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone); ProMACE-CytaBOM (prednisone, doxorubicin, cyclophosphamide, and etoposide, followed by cytarabine, bleomycin, vincristine, and methotrexate with leucovorin rescue); and MACOP-B (methotrexate with leucovorin rescue, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin). CHOP was confirmed to be less toxic and equally effective as the other regimens. In 2002, the GELA published results showing that adding rituximab to CHOP for patients older than 60 years improved both relapse-free survival and OS compared with CHOP alone; similar results were found in the US Intergroup trial E 4494. These results were subsequently confirmed for patients younger than 60 years in the MabThera International Trial (MInT), in which patients were randomized to receive 6 cycles of CHOP-like therapy with or without rituximab; at a follow-up time of 3 years, both event-free survival (EFS) rates and OS rates were significantly better in the group given rituximab. Updated results showed that the improvement in EFS and OS with rituximab persisted at a median 6 years of follow-up.

Although R-CHOP has been established as the standard of care, 3 other regimens should be noted. One of these regimens, dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (DA-EPOCH), was developed by the U.S. National Cancer Institute in an attempt to overcome resistance by using continuous low-dose drug exposure. In one study of 69 patients with stage II–IV DLBCL, DA-EPOCH-R produced a complete response (CR) rate of 84% and, at a median follow-up interval of 5 years, an EFS rate of 75% (54% for those with high IPI scores) and an OS rate of 84%. Five patients (7%) developed grade 4 hematologic toxicity, and 10 (14%) developed neuropathy. This regimen is currently being compared to R-CHOP in a trial led by the Cancer and Leukemia Group B.

The second regimen, doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone (ACVBP), was recently compared to R-CHOP in a trial by the GELA group for patients with low-risk to intermediate-risk IPI scores, this time adding rituximab. The trial showed that R-ACVBP produced better PFS rates (87%) and OS rates (92%) than R-CHOP (73% and 84%) but at the cost of high rates of serious adverse effects (42% versus 15%). Additionally, it is important to note that vindesine is not available in the United States.

The third regimen, evaluated by the DSHNHL, involved giving CHOP with etoposide (CHOEP) over either a 2-week or a 3-week period. The 2-week schedule was beneficial in terms of OS regardless of patient age, but etoposide was not beneficial for those over 60 and only slightly improved PFS in younger patients. It is worth noting that the superiority of CHOEP 21 was mitigated with the addition of rituximab.

RICOVER-60, a study by DSHNHL, compared 6 cycles versus 8 cycles of CHOP-14 with and without rituximab. The trial found that 6 cycles R-CHOP-14 improved PFS and OS rates over CHOP-14 and confirmed no benefit to the use of more than 6 cycles of chemotherapy. In addition, the schedule of R-CHOP administered every 2 versus 3 weeks has been tested in 2 randomized prospective trials and both failed to show an advantage of the every (q) 2 week schedule (see Appendix 2 in the original guideline document). Hence, the standard of care for DLBCL at this time is R-CHOP q 21 days, with the number of cycles depending on disease stage and IPI risk group.

Treatment of Limited (Stage I or II) DLBCL

The number of cycles of chemotherapy and the use of consolidation RT for limited-stage disease remain a matter of debate. The common practice is to add RT when using an abbreviated course of 3–4 cycles of R-CHOP for patients with low-risk disease as assessed by the IPI score; however, this approach should be used with caution as new knowledge becomes available on the importance of immunophenotypic, molecular, or cytogenetic markers in addition to IPI score to predict the risk of failure.

Use of Radiation for Limited DLBCL

Evidence in support of using RT for consolidation in DLBCL comes from 2 sources—the first is a group of 4 randomized trials conducted in the pre-rituximab era (see Appendix 3 in the original guideline document); and the second a group of 3 studies that included the use of rituximab including a large retrospective analysis, the MInT trial, and a recent update of the German UNFOLDER study.

The first trial to show a benefit from RT was the Southwest Oncology Group (SWOG) trial 8736, in which patients with intermediate-risk or high-risk disease [stage I (bulky) or nonbulky stage II or II E disease (with only 1 extranodal site allowed)] received either 3 cycles of CHOP followed by RT to 40‒55 Gy or 8 cycles of CHOP without RT. The combined therapy significantly improved the 5-year endpoints for both PFS (77% versus 64%, P=0.03) and OS (82% versus 72%, P=0.02). The PFS rate was higher for patients with 0 or 1 IPI risk factors (77%) than for those with 3 risk factors (34%). The CHOP-8 group had more life-threatening events, including ventricular dysfunction and cardiac death: 40% versus 30% in the CHOP-3+RT group. Updated results presented in abstract form showed that the OS curves crossed at 9 years, and the failure-free survival curves crossed at 7 years, with 15 relapses and deaths from lymphoma occurring in the CHOP-3+RT group between 5 and 10 years versus 8 in the CHOP-8 group. The difference in OS rates for stage-modified IPI groups (94% for those with favorable and no IPI risk factors versus 71% for those with 1 risk factor and 50% for 3 risk factors) led the authors to conclude that patients with worse risk factors may benefit from intense chemotherapy in terms of preventing late relapses. However, another interpretation of these results is that RT cannot compensate for inadequate chemotherapy; thus, patients who are to undergo abbreviated chemotherapy should be identified on the basis of risk factors and not on the potential use of consolidation RT.

The second of the trials to confirm the benefit of RT was ECOG 1484, which compared outcomes after 8 cycles of CHOP with or without RT. Patients in this trial tended to have less favorable disease; more than two thirds had stage II disease, and nearly half (166 of 352) had extranodal involvement. Patients who achieved a CR after chemotherapy were randomly assigned to receive RT to 30 Gy or observation; those with a partial response (PR) received 40 Gy. Despite the stringent design of this trial, more patients in the RT group had bulky disease. Six-year failure-free survival was superior in the combined modality arm (70% versus 53% with chemotherapy alone), and OS was also better (79% versus 67%), although the latter was not statistically significant in part due to limited sample size. The third of the pre-rituximab studies, GELA LNH 93-01, involved patients with stage I–II, mostly low-risk disease, and compared 3 cycles of CHOP plus RT with a much more aggressive regimen, dose-intensified ACVBP followed by methotrexate, etoposide, ifosphamide, and cytarabine. Not surprisingly, the aggressive regimen was found to be superior to CHOP-3 plus RT in terms of disease control (5-year EFS estimates 82% versus 74%, and OS 90% versus 81%); however, the toxicity of that regimen was considerable.

The fourth of the pre-rituximab trials, also conducted by the GELA, compared 4 cycles of CHOP with or without RT for older patients (>60), with stage I or II disease and no adverse factors; 65% of patients had stage I disease, 95% had an IPI score of 0, only 8% had bulky disease, and 50% had extranodal disease. At a median follow-up interval of 7 years, no differences in EFS or OS were noted between groups. Curiously, even though the population in this trial had fewer risk factors than those in the other 3 trials, the EFS rate was lower in this trial than that in the others, suggesting that the findings from this trial may not be applicable to those of others. In addition to the lack of rituximab, other shortcomings limit the interpretation of these findings, such as the heterogeneity of patient characteristics and treatment; the fact that the choice of chemotherapy (abbreviated versus full-course) was made independently of the choice to use RT or not; and the use of outdated radiation doses, fields, and techniques (current standards of care are involved-site, to doses of 30 Gy to 36 Gy, with 3-dimensional [3-D] conformal or intensity-modulated radiation therapy [IMRT]).

The argument that the addition of rituximab negates the benefit of RT is undermined by the results of 2 studies, a retrospective review and the MInT trial. The former analysis from MD Anderson Cancer Center showed that adding RT improved both OS and PFS (5-year OS and PFS were 91% and 82% compared to 68% and 59%, respectively, for those who did not receive RT; P=0.0001) and also showed that this benefit was seen across all stages. Most of the patients in that study had received 6 or more cycles of R-CHOP. A matched pair analysis that was based on stage and accounted for number of R-CHOP cycles, receiving of RT, IPI score, tumor response to therapy, and disease bulk confirmed the benefit of RT in terms of longer OS and PFS (hazard ratios of 0.52 [OS] and 0.45 [PFS] for those who received RT). The MInT trial evaluated the benefit of adding rituximab to CHOP for patients with stage II–IV or bulky stage I DLBCL. R-CHOP was effective for patients with IPI=0 and without bulky disease, for whom 3-year EFS rates were 90% (versus 74% for patients with IPI=1 and bulky disease). Notably, RT (30 Gy to 40 Gy) was given to patients with primary extranodal involvement and bulky disease, and 50% of patients had some form of bulky disease (40% >7.5 cm). Rituximab minimized but did not eliminate the adverse prognostic effect of tumor bulk on outcome, thereby suggesting that RT would still have merit for patients with bulky disease.

In the UNFOLDER trial by the DSHNHL, 450 patients were randomized to receive either R-CHOP-14 versus R-CHOP-21 with randomization to radiation versus observation for patients with extranodal or bulky disease. The RT randomization was stopped when the second interim analysis showed a higher failure rate in the no-RT arms. RICOVER-60, in a recently published analysis, looked at the benefit of radiation in elderly patients at all stages of disease, with radiation given to bulky and extralymphatic disease. In that report of 166 patients, the authors compared the best arm of immunochemotherapy (6 R-CHOP+2R) added to 36 Gy to initial bulky sites (≥7.5 cm) and compared to a cohort treated without radiation in an amendment of the RICOVER-60 trial in a prospective fashion. The addition of radiation showed statistically significant improvements in OS (90% for RT group versus 65% for no RT; P=0.001) and EFS (80% for RT group versus 54% for no RT; P=0.001), although the study was not a randomized study.

The standard of care in the United States is 3 or 4 cycles of R-CHOP plus RT (as described in the following section) for patients with limited-stage DLBCL with an IPI score of 0 or 1. In prospective phase II SWOG 0014, patients were treated with 3 cycles of R-CHOP plus involved-field radiation (40 Gy to 46 Gy) in limited stage aggressive B-cell lymphoma with at least one adverse risk factor. When compared to the historic group from SWOG 8736, both 4-year PFS and OS showed a modest gain (88% and 92% compared to 78% and 88%, respectively). However, the choice of this abbreviated chemotherapy regimen must be made cautiously for patients with factors known to affect outcome other than stage and IPI score, such as bulky disease and/or aggressive pathology features. In such cases, 6 cycles of R-CHOP should be considered, to be followed by RT. The use of more aggressive chemotherapy regimens depending on the initial disease presentation must not preclude the use of radiation for consolidation if there is bulky disease. Although there is a paucity of data to support it, the addition of intrathecal chemotherapy prophylaxis, especially in extralymphatic craniofacial presentations, is highly considered in some academic centers. A group of researchers, in a retrospective analysis of 200 adults with DLBCL treated with R-CHOP, concluded that the use of central nervous system (CNS) prophylaxis with high-dose methotrexate with or without intrathecal chemotherapy significantly reduced CNS failures in high-risk patients (involvement of specific extranodal sites and IPI index). On the other hand, in a recent analysis of 11 consecutive DSHNHL study trials, the addition of intrathecal prophylaxis with methotrexate did not affect the 2-year rate of CNS disease (4.2% compared to 2.3% in patients who did not receive intrathecal therapy, P=0.98). Therefore, the use of CNS prophylaxis remains an issue of debate and thus is administered according to institutional preference.

Radiation Dose and Fields for Limited LBCL

The radiation dose can be 30 Gy to 40 Gy depending on the bulk of the disease and its response to chemotherapy. The impact of RT dose and other treatment-related and clinical factors on in-field control in stage I and II NHL was shown in a retrospective study, where doses of 30 Gy in conjunction with chemotherapy (CHOP-based) were adequate with few in-field failures except in the setting of both bulky disease and an incomplete response to chemotherapy. In a prospective trial from the United Kingdom, patients with aggressive NHL (predominantly DLBCL) were randomized to receive RT to 40–45 Gy in 20–23 fractions or 30 Gy in 15 fractions. At a median follow-up time of 5.6 years, no differences were noted in overall response rate or in rate of within-field progression between the 2 dosage groups, suggesting that 30 Gy may be adequate for consolidative RT after chemotherapy for aggressive NHL. With regard to radiation fields, involved-field RT (i.e., that covers the initially involved and uninvolved adjacent disease sites) has been the current standard of care; however, evidence is emerging that smaller fields may be adequate, and a new set of field designs for involved-site radiation therapy (ISRT) has been developed and endorsed by the steering committee of the International Lymphoma Radiation Oncology Group. These fields consider the findings from CT-based or PET/CT-based treatment planning and also incorporate 4-D treatment planning and image-guided treatment delivery. Details of clinical target volumes are forthcoming; in brief, the proposed guidelines for ISRT include treating only the sites of initial (pretherapy) involvement, excluding normal structures that were clearly uninvolved (including those that were displaced by the tumor). Determination of planning target volumes depends on estimated setup variations that are a function of the immobilization device, body site being treated, and image-guidance system, if used. Every effort should be made to use modern radiation techniques for the delivery of consolidation RT, such as IMRT, proton therapy, 4-D CT simulation, CT-on-rails, and breath-hold techniques, which collectively can minimize the collateral radiation dose to the critical organs in the vicinity of the target.

Treatment of Advanced (Stage III or IV) DLBCL

R-CHOP 21 for 6 cycles is the standard of care in advanced DLBCL. The role of consolidative RT to bulky disease is supported by 2 post-rituximab trials, and a retrospective matched-pair analysis. The first of the 2 rituximab-era trials, MInT, indirectly addressed the role of RT and rituximab for patients with stage II–IV and bulky stage I DLBCL; RT was given to patients with primary extranodal involvement and bulky disease (30 Gy to 40 Gy), and 50% of patients had some form of bulky disease (40% >7.5 cm). Patients with bulky disease tended to have poorer outcomes. However, because the MInT trial was not designed to evaluate the role of RT, its findings cannot directly address whether RT benefits patients with poor risk factors, and further analyses are planned. The other rituximab-era trial, RICOVER-60, compared 6 versus 8 cycles of biweekly CHOP-14 with and without rituximab for elderly patients, 54% of whom were also given RT (in all cases delivered to initial extranodal involvement and bulky disease [≥7.5 cm single or agglomerated masses]).

A preliminary comparison of results from 2 prospective trials of elderly patients by the DSHNHL suggested that, in the rituximab era, patients with bulky disease had a superior EFS and PRS with RT; however, any advantage of giving RT to patients with bulky disease who achieved a confirmed or unconfirmed CR after 6 cycles of R-CHOP-14 needs to be further assessed in a randomized study. RICOVER-60, as mentioned earlier, included all stages of disease in elderly patients and showed that RT to bulky sites abrogates bulky disease as a risk factor and improves outcome of elderly patients with aggressive B-cell lymphoma.

The role of radiation in advanced stage has been addressed in single institutions' retrospective studies showing a benefit in the PFS and local control but not in the OS. A multi-institutional retrospective analysis from the National Comprehensive Cancer Network outcome project showed that receipt of radiation improved both OS and freedom from failure for patients with stage III/IV disease (hazard ratios [HRs] 0.53 [P=0.07] and 0.77 [P=0.34]).

Finally, a retrospective matched-pair analysis revealed a statistically significant benefit for OS and disease-free survival (DFS) from adding RT for patients with advanced stage DLBCL. Notably, all patients in that study received more than 6 cycles of R-CHOP or equivalent chemotherapy, but relatively few of the matched pairs in the analysis had advanced stage disease. In conclusion, the use of RT in advanced disease at this point remains at the discretion of the treating physician, but in general it is used for sites that are bulky (>5 cm), did not achieve a CR, or are adjacent to critical organs (or were originally located in the vicinity of a critical organ, for instance the spine). In case RT is used, involved sites (described in the early stage) would be acceptable to use.

High-Dose Chemotherapy

Although high-dose chemotherapy has merit in relapsed patients, it is of unproven efficacy in an upfront approach according to a meta-analysis of 3,079 patients. A number of randomized trials in the pre-rituximab era have been conducted to compare standard chemotherapy versus high-dose chemotherapy in unfavorable IPI score patients. The superiority of the use of high-dose chemotherapy could not be concluded. In the rituximab era, Gruppo Italiano Terapie Innovative nei Linfomi, in a nonrandomized phase II trial, evaluated the feasibility of the approach and set the stage for the phase III study DLCL-04. In a randomized study by SWOG, 397 patients with age-adjusted classification of high-risk or high-intermediate risk were randomized after CHOP or R-CHOP to either 3 additional cycles of induction chemotherapy or autologous stem-cell transplantation. The latter was found to improve PFS but not OS. The authors attributed the lack of OS benefit to the effectiveness of salvage transplantation. At present, stem-cell transplantation is not routinely used as a part of first-line therapy for patients DLBCL.

Use of Mid-Treatment PET in Predicting Outcome in Risk-Adapted Therapy

The potential predictive value of PET findings obtained during treatment with regard to outcome is being actively investigated. At this time, results are contradictory, with a large series showing that interim PET can predict outcome; however, other series do not show such a conclusion. ECOG E3404 addressed the reproducibility of reading the interim PET scan, with an agreement ranging from 68% to 71%. The investigators suggested the need for a standardized PET approach that needs to be considered for future studies and when making clinical decisions. In a unique approach, investigators at Memorial Sloan Kettering compared findings on interim PET scans with those on biopsy of the interim PET-positive lesions. Only 5 of 37 patients with PET-positive scans had persistent disease in the biopsy sample; PFS rates were identical for patients with positive interim PET scans plus negative biopsy results and for those with negative interim PET scans. Another retrospective study of 296 patients evaluated the association between interim PET scan response and outcome in 296 patients. In that study, having a positive midterm PET scan predicted poorer PFS and OS at 5 years for all patients and for patients who received chemotherapy alone, but these differences lost significance when patients who received consolidation RT were considered separately. Finally, the presence of residual mass with a negative PET scan at the end of therapy has also been evaluated as a risk factor for relapse and as an indication to give consolidation RT, with one study finding that a PET-negative residual mass >2 cm was associated with an inferior DFS and OS after chemotherapy alone. However, until further confirmatory studies become available, the use of PET/CT for predicting outcome should be considered investigational and should not influence clinical decisions.

Assessment of Response after Therapy

End-of-therapy assessment is to be performed using PET/CT, and the current recommendation is to grade the PET/CT using the 5-point Deauville scale (see the Table below). This 5-point scale uses the mediastinal blood pool as a comparator. A score of 1 or 2 (in mid-therapy or end-of-therapy PET/CT) is considered to represent a CR, and a score of 3 is considered to predict a favorable outcome. However, a score of 4 or 5 at the end of therapy is considered to be treatment failure; these patients should be considered for a biopsy to confirm the presence of residual disease before salvage therapy.

Table. 5-point Deauville Scale

  • 1. No uptake
  • 2. Uptake ≤mediastinum
  • 3. Uptake >mediastinum but ≤liver
  • 4. Uptake moderately higher than liver
  • 5. Uptake markedly higher than liver and/or new lesions
  • X. New areas of uptake unlikely to be related to lymphoma

Diagnosis and Treatment of Primary Mediastinal Lymphoma

PMBL is thought to originate from thymic B cells and is considered a separate entity in the World Health Organization classification. The presence of thymic lobules and Hassall corpuscles are indicative of thymic origin. Cells are usually sized medium to large, with strands of fibrosis present in the background. Expression of surface or cytoplasmic immunoglobulins is often absent; CD21 expression is typically absent, but CD30 is sometimes present in addition to CD19, CD20, and CD45. Chromosome 9p24 amplification is present in up to 50% of cases. The disease typically presents in the mediastinum in young people, and its histopathologic features usually help to confirm the diagnosis. Gene-expression profiling studies strongly support the relation between PMBL and classical Hodgkin lymphoma and between PMBL and cases with borderline features known as "mediastinal gray zone lymphomas". PMBL often presents with a rapidly growing invasive tumor with contiguous spread, mostly confined to the thorax. Chest pain, cough, and dyspnea are common; pleural and pericardial effusions are also common.

The recommended treatment in the pre-rituximab era with the most promising outcomes is chemotherapy, with MACOP-B (methotrexate with leucovorin rescue, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin) followed by radiation. Other chemotherapy regimens evaluated have included CHOP, R-CHOP, VACOP-B (etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin), ProMACE-CytaBOM, and high-dose chemotherapy.

Retrospective studies have generally found that the use of RT following chemotherapy improves CR rates and EFS or PFS for patients with PMBCL. For example, a multicenter Italian study reported that consolidation RT with 30 Gy to 36 Gy converted a large proportion of patients with gallium-positive disease to gallium-negative disease. Similar results have also been reported with a higher rate of intrathoracic recurrences in patients who did not receive RT.

The optimal therapy for PMBL in the rituximab era is a subject of ongoing debate, with no accepted standard of care. A retrospective analysis of 63 patients in the modern era treated with R-CHOP, with or without radiation, reported primary induction failure in 13 (21%) patients. The 5-year PFS and OS were 68% and 79%, respectively. These data demonstrate an unacceptably high rate of primary refractory disease on R-CHOP, particularly among patients with high-risk features that were not overcome despite RT. Treatment of PMBL with R-CHOP is associated with a high rate of primary refractory disease.

A recent report from the U.S. National Cancer Institute showed that an infusional regimen dose-adjusted (DA) EPOCH-R (DA-EPOCH-R) resulted in excellent EFS (93%) and OS without RT at a median follow-up of 60 months. These results do challenge the role of RT in PMBL, however, as this was a fairly small phase II study; ideally the results need confirmation in a larger setting. Given mature data, however, this regimen has been incorporated in the 2014 National Comprehensive Cancer Network guidelines, although R-CHOP with consolidative RT remains a standard of care. An ongoing trial by the International Extranodal Lymphoma Study Group randomizes patients with normal PET scans after chemotherapy to adjuvant RT or no further treatment. This study should clarify the currently controversial role of RT following a CR to chemotherapy.

If RT is considered for PMBL, it should target the mediastinum and any positive lymph nodes in the neck or axilla, with care taken to avoid nearby critical organs such as the heart and lung. Use of modern radiation techniques is recommended, such as IMRT, proton therapy, breath-hold techniques, and onboard imaging. The clinical target volume should include the prechemotherapy volume in the superior-inferior dimension and the postchemotherapy volume in the transverse dimension into the lung. Inclusion of originally involved pericardial and pleural effusion is not advised because of the risk of excess toxicity to the heart or lungs. The planning target volume should include a daily setup margin, and the internal tumor volume should be determined on the basis of 4-D CT-based simulation. If a breath-hold technique is used in combination with daily onboard CT imaging, the breathing motion margin can be subtracted from the planning target volume. The recommended radiation dose is 30 Gy to 36 Gy for patients with documented CR; in cases in which small residual low-activity masses are visible on PET/CT, a boost to 39.6 or 45 Gy can be used to target the area of concern.

Summary of Recommendations

  • DLBCL is an aggressive lymphoma with treatment strategies dependent on staging, IPI score, gene-expression profile, and immunophenotyping markers at presentation.
  • R-CHOP is the established standard of care based on multiple randomized trials showing superiority over CHOP alone.
  • For favorable patients with IPI 0 or 1, especially those without bulk disease and adverse pathologic features, it is currently accepted to give an abbreviated course of immunochemotherapy followed by RT.
  • The role of radiation was challenged in randomized trials in the pre-rituximab era, but recently prospective studies (UNFOLDER/RICOVER-60) and retrospective data have shown a potential benefit both for early and advanced stages.
  • The fields and doses of radiation have been updated and entail the use of ISRT and modern technology including IMRT, motion-control techniques, and proton therapy. Also, radiation doses around 30 Gy are currently most commonly used in an effort to decrease acute and long-term side effects.
  • The MinT study still shows a potential role for radiation in patients with bulky disease >7.5 cm.
  • In patients with relapse or progressive disease, high-dose chemotherapy can be considered although no solid data support it being introduced as front-line therapy for patients with worse prognostic factors.
  • Some studies suggest that interim PET/CT can predict outcome and thus allow for modifications of therapy (de-escalation or escalation); however, until further confirmatory studies become available, interim PET/CT should not influence clinical decisions.
  • PMBL is successfully treated with R-CHOP combined with radiation or with DA-EPOCH-R, with radiation reserved for selected cases with residual positive disease.

Abbreviations

  • CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone
  • CNS, central nervous system
  • DA-EPOCH-R, dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab
  • DLBCL, diffuse large B-cell lymphoma
  • IPI, International Prognostic Index
  • ISRT, involved-site radiation therapy
  • LDH, lactate dehydrogenase
  • R-MACOP B, rituximab, methotrexate/leucovorin, doxorubicin, cyclophosphamide, vincristine, prednisone, bleomycin
  • PET-CR, positron emission tomography confirmed complete response
  • PS, performance status
  • R-CHOP, rituximab-CHOP

Clinical Algorithm(s)

Algorithms were not developed from criteria guidelines.

Disease/Condition(s)

Diffuse large B-cell lymphoma (DLBCL)

Guideline Category

Diagnosis

Risk Assessment

Treatment

Clinical Specialty

Geriatrics

Hematology

Internal Medicine

Medical Genetics

Oncology

Radiation Oncology

Radiology

Intended Users

Health Plans

Hospitals

Managed Care Organizations

Physicians

Utilization Management

Guideline Objective(s)

To evaluate the appropriateness of procedures for the diagnosis and treatment of patients with diffuse large B-cell lymphoma (DLBCL)

Target Population

Patients with diffuse large B-cell lymphoma (DLBCL)

Interventions and Practices Considered

  1. Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy
    • Alone
    • Combined with/followed by involved-site radiation therapy (ISRT)
  2. Dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab (DA-EPOCH-R) chemotherapy
    • Alone
    • Combined with/followed by ISRT
  3. Rituximab, methotrexate/leucovorin, doxorubicin, cyclophosphamide, vincristine, prednisone, bleomycin (R-MACOP B) chemotherapy, followed by ISRT
  4. Use of positron emission tomography (PET) to assess complete response (CR)

Major Outcomes Considered

  • Utility of positron emission tomography (PET) for diagnosing lymphoma and evaluating response to treatment
  • Prognostic value of the International Prognostic Index (IPI)
  • Overall survival
  • Progression-free/event-free survival
  • Complete response rate
  • Primary induction failure
  • Adverse events of treatment (including mortality)

Methods Used to Collect/Select the Evidence

Hand-searches of Published Literature (Primary Sources)

Hand-searches of Published Literature (Secondary Sources)

Searches of Electronic Databases

Description of Methods Used to Collect/Select the Evidence

Literature Search Summary

A literature search was conducted in August 2011 and updated in December 2014 to identify evidence for the ACR Appropriateness Criteria® Diffuse Large B-Cell Lymphoma topic. Using the search strategies described in the literature search companion (see the "Availability of Companion Documents" field), 584 articles were found. Eighteen articles were used in the topic. Five hundred sixty six articles were not used due to either poor study design, the articles were not relevant or generalizable to the topic, or the results were unclear, misinterpreted, or biased.

The author added 72 citations from bibliographies, Web sites, or books that were not found in the literature search.

See also the American College of Radiology (ACR) Appropriateness Criteria® literature search process document (see the "Availability of Companion Documents" field) for further information.

Number of Source Documents

Eighteen articles were used in the topic. The author added 72 citations from bibliographies, Web sites, or books that were not found in the literature search.

Methods Used to Assess the Quality and Strength of the Evidence

Weighting According to a Rating Scheme (Scheme Given)

Rating Scheme for the Strength of the Evidence

Study Quality Category Definitions

Category 1 - The study is well-designed and accounts for common biases.

Category 2 - The study is moderately well-designed and accounts for most common biases.

Category 3 - There are important study design limitations.

Category 4 - The study is not useful as primary evidence. The article may not be a clinical study or the study design is invalid, or conclusions are based on expert consensus. For example:

  1. The study does not meet the criteria for or is not a hypothesis-based clinical study (e.g., a book chapter or case report or case series description).
  2. The study may synthesize and draw conclusions about several studies such as a literature review article or book chapter but is not primary evidence.
  3. The study is an expert opinion or consensus document.

Methods Used to Analyze the Evidence

Review of Published Meta-Analyses

Systematic Review with Evidence Tables

Description of the Methods Used to Analyze the Evidence

The topic author assesses the literature then drafts or revises the narrative summarizing the evidence found in the literature. American College of Radiology (ACR) staff drafts an evidence table based on the analysis of the selected literature. These tables rate the study quality for each article included in the narrative.

The expert panel reviews the narrative, evidence table and the supporting literature for each of the topic-variant combinations and assigns an appropriateness rating for each procedure listed in the variant table(s). Each individual panel member assigns a rating based on his/her interpretation of the available evidence.

More information about the evidence table development process can be found in the ACR Appropriateness Criteria® Evidence Table Development documents (see the "Availability of Companion Documents" field).

Methods Used to Formulate the Recommendations

Expert Consensus (Delphi)

Description of Methods Used to Formulate the Recommendations

Rating Appropriateness

The American College of Radiology (ACR) Appropriateness Criteria (AC) methodology is based on the RAND Appropriateness Method. The appropriateness ratings for each of the procedures or treatments included in the AC topics are determined using a modified Delphi method. A series of surveys are conducted to elicit each panelist's expert interpretation of the evidence, based on the available data, regarding the appropriateness of an imaging or therapeutic procedure for a specific clinical scenario. The expert panel members review the evidence presented and assess the risks or harms of doing the procedure balanced with the benefits of performing the procedure. The direct or indirect costs of a procedure are not considered as a risk or harm when determining appropriateness. When the evidence for a specific topic and variant is uncertain or incomplete, expert opinion may supplement the available evidence or may be the sole source for assessing the appropriateness.

The appropriateness is represented on an ordinal scale that uses integers from 1 to 9 grouped into three categories: 1, 2, or 3 are in the category "usually not appropriate" where the harms of doing the procedure outweigh the benefits; and 7, 8, or 9 are in the category "usually appropriate" where the benefits of doing a procedure outweigh the harms or risks. The middle category, designated "may be appropriate", is represented by 4, 5, or 6 on the scale. The middle category is when the risks and benefits are equivocal or unclear, the dispersion of the individual ratings from the group median rating is too large (i.e., disagreement), the evidence is contradictory or unclear, or there are special circumstances or subpopulations which could influence the risks or benefits that are embedded in the variant.

The ratings assigned by each panel member are presented in a table displaying the frequency distribution of the ratings without identifying which members provided any particular rating. To determine the panel's recommendation, the rating category that contains the median group rating without disagreement is selected. This may be determined after either the first or second rating round. If there is disagreement after the second rating round, the recommendation is "May be appropriate."

This modified Delphi method enables each panelist to articulate his or her individual interpretations of the evidence or expert opinion without excessive influence from fellow panelists in a simple, standardized and economical process. For additional information on the ratings process see the Rating Round Information External Web Site Policy document on the ACR Web site.

Additional methodology documents, including a more detailed explanation of the complete topic development process and all ACR AC topics can be found on the ACR Web site External Web Site Policy (see also the "Availability of Companion Documents" field).

Rating Scheme for the Strength of the Recommendations

Not applicable

Cost Analysis

A formal cost analysis was not performed and published cost analyses were not reviewed.

Method of Guideline Validation

Internal Peer Review

Description of Method of Guideline Validation

Criteria developed by the Expert Panels are reviewed by the American College of Radiology (ACR) Committee on Appropriateness Criteria.

Type of Evidence Supporting the Recommendations

The recommendations are based on analysis of the current literature and expert panel consensus.

Summary of Evidence

Of the 90 references cited in the ACR Appropriateness Criteria® Diffuse Large B-Cell Lymphoma document, 73 are categorized as therapeutic references including 29 well-designed studies and 22 good quality studies. Additionally, 17 references are categorized as diagnostic references including 1 well-designed study, 3 good quality studies, and 4 quality studies that may have design limitations. There are 31 references that may not be useful as primary evidence.

While there are references that report on studies with design limitations, 55 well-designed or good quality studies provide good evidence.

Potential Benefits

Selection of appropriate procedures for diagnosis and treatment of patients with diffuse large B-cell lymphoma (DLBCL)

Potential Harms

Toxicities and side effects of radiation therapy and chemotherapy (e.g., hematologic toxicities, neuropathy, ventricular dysfunction, cardiac death, infection)

See also Appendices 2 and 3 in the original guideline document for toxicities and side effects associated with various chemotherapy regimens.

Qualifying Statements

The American College of Radiology (ACR) Committee on Appropriateness Criteria and its expert panels have developed criteria for determining appropriate imaging examinations for diagnosis and treatment of specified medical condition(s). These criteria are intended to guide radiologists, radiation oncologists, and referring physicians in making decisions regarding radiologic imaging and treatment. Generally, the complexity and severity of a patient's clinical condition should dictate the selection of appropriate imaging procedures or treatments. Only those examinations generally used for evaluation of the patient's condition are ranked. Other imaging studies necessary to evaluate other co-existent diseases or other medical consequences of this condition are not considered in this document. The availability of equipment or personnel may influence the selection of appropriate imaging procedures or treatments. Imaging techniques classified as investigational by the U.S. Food and Drug Administration (FDA) have not been considered in developing these criteria; however, study of new equipment and applications should be encouraged. The ultimate decision regarding the appropriateness of any specific radiologic examination or treatment must be made by the referring physician and radiologist in light of all the circumstances presented in an individual examination.

Description of Implementation Strategy

An implementation strategy was not provided.

IOM Care Need

Getting Better

Living with Illness

IOM Domain

Effectiveness

Bibliographic Source(s)

Dabaja BS, Advani R, Hodgson DC, Dhakal S, Flowers CR, Ha CS, Hoppe BS, Mendenhall NP, Metzger ML, Plastaras JP, Roberts KB, Shapiro R, Smith SM, Terezakis SA, Winkfield KM, Younes A, Constine LS, Expert Panel on Radiation Oncology–Lymphoma. ACR Appropriateness Criteria® diffuse large B-cell lymphoma [online publication]. Reston (VA): American College of Radiology (ACR); 2014. 17 p. [90 references]

Adaptation

Not applicable: The guideline was not adapted from another source.

Date Released

2014

Guideline Developer(s)

American College of Radiology - Medical Specialty Society

Source(s) of Funding

The American College of Radiology (ACR) provided the funding and the resources for these ACR Appropriateness Criteria®.

Guideline Committee

Committee on Appropriateness Criteria, Expert Panel on Radiation Oncology–Lymphoma

Composition of Group That Authored the Guideline

Panel Members: Bouthaina S. Dabaja, MD (Principal Author); Ranjana Advani, MD (Co-author); David C. Hodgson, MD (Panel Vice-chair); Sughosh Dhakal, MD; Christopher R. Flowers, MD, MS; Chul S. Ha, MD; Bradford S. Hoppe, MD, MPH; Nancy P. Mendenhall, MD; Monika L. Metzger, MD; John P. Plastaras, MD, PhD; Kenneth B. Roberts, MD; Ronald Shapiro, MD; Sonali M. Smith, MD; Stephanie A. Terezakis, MD; Karen M. Winkfield, MD, PhD; Anas Younes, MD; Louis S. Constine, MD (Panel Chair)

Financial Disclosures/Conflicts of Interest

Not stated

Guideline Status

This is the current release of the guideline.

This guideline meets NGC's 2013 (revised) inclusion criteria.

Guideline Availability

Availability of Companion Documents

The following are available:

  • ACR Appropriateness Criteria®. Overview. Reston (VA): American College of Radiology; 2015 Feb. 3 p. Available from the American College of Radiology (ACR) Web site External Web Site Policy.
  • ACR Appropriateness Criteria®. Literature search process. Reston (VA): American College of Radiology; 2015 Feb. 1 p. Available from the ACR Web site External Web Site Policy.
  • ACR Appropriateness Criteria®. Evidence table development. Reston (VA): American College of Radiology; 2015 Nov. 5 p. Available from the ACR Web site External Web Site Policy.
  • ACR Appropriateness Criteria® diffuse large B-cell lymphoma. Evidence table. Reston (VA): American College of Radiology; 2014. 47 p. Available from the ACR Web site External Web Site Policy.
  • ACR Appropriateness Criteria® diffuse large B-cell lymphoma. Literature search. Reston (VA): American College of Radiology; 2014. 2 p. Available from the ACR Web site External Web Site Policy.

Patient Resources

None available

NGC Status

This NGC summary was completed by ECRI Institute on July 27, 2015.

Copyright Statement

Instructions for downloading, use, and reproduction of the American College of Radiology (ACR) Appropriateness Criteria® may be found on the ACR Web site External Web Site Policy.

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