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Adult Non-Hodgkin Lymphoma Treatment (PDQ®)

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Treatment for Aggressive, Noncontiguous Stage II/III/IV Adult NHL

Standard Treatment Options for Aggressive, Noncontiguous Stage II/III/IV Adult NHL
        R-CHOP
        Other combination chemotherapy
        Stage IE or IIE gastric DLBCL
        Prognostic factors
        Treatment of tumor lysis syndrome
        CNS prophylaxis
Treatment Options Under Clinical Evaluation for Aggressive, Noncontiguous Stage II/III/IV Adult NHL
Current Clinical Trials

The treatment of choice for patients with advanced stages of aggressive non-Hodgkin lymphoma (NHL) is combination chemotherapy, either alone or supplemented by local-field radiation therapy.[1]

The following drug combinations are referred to in this section:

  • ACVBP: doxorubicin + cyclophosphamide + vindesine + bleomycin + prednisone.

  • CHOP: cyclophosphamide + doxorubicin + vincristine + prednisone.

  • CNOP: cyclophosphamide + mitoxantrone + vincristine + prednisone.

  • m-BACOD: methotrexate + bleomycin + doxorubicin + cyclophosphamide + vincristine + dexamethasone + leucovorin.

  • MACOP-B: methotrexate + doxorubicin + cyclophosphamide + vincristine + prednisone fixed dose + bleomycin + leucovorin.

  • ProMACE CytaBOM: prednisone + doxorubicin + cyclophosphamide + etoposide + cytarabine + bleomycin + vincristine + methotrexate + leucovorin.

  • R-CHOP: rituximab, an anti-CD20 monoclonal antibody, + cyclophosphamide + doxorubicin + vincristine + prednisone.

Standard Treatment Options for Aggressive, Noncontiguous Stage II/III/IV Adult NHL

Standard treatment options for Aggressive, Noncontiguous Stage II/III/IV Adult NHL include the following:

  1. R-CHOP.
  2. Other combination chemotherapy.
R-CHOP

The following studies established R-CHOP as the standard regimen for newly diagnosed patients with DLBCL.[2] Dose intensification of R-CHOP by a 14-day versus a 21-day cycle did not result in improved outcomes.[3]

Evidence (R-CHOP):

  1. R-CHOP showed improvement in event-free survival (EFS) and overall survival (OS) compared with CHOP alone in 399 advanced-stage patients with DLBCL older than 60 years (EFS, 57% vs. 38%; P = .002, and OS, 70% vs. 57%; P = .007 at 2 years).[4][Level of evidence: 1iiA] At 10-years' median follow-up, the OS of patients who received R-CHOP compared with patients who received CHOP was 44% versus 28%, P < .0001.[5]

  2. Similarly, for 326 evaluable patients younger than 61 years, R-CHOP showed improvement in EFS and OS compared with CHOP alone (EFS, 79% vs. 59%, P = .001, and OS, 93% vs. 84%, P = .001 at 3 years).[6][Level of evidence: 1iiA]

  3. A randomized study (DSHNHL-1999-1A) of 1,222 patients older than 60 years compared R-CHOP given every 2 weeks for six or eight cycles to CHOP given every 2 weeks for six or eight cycles.[7] With a median follow-up of 72 months, the EFS favored R-CHOP given every 2 weeks for six or eight cycles (EFS at 6 years, 74% vs. 56%; P < .0001). The OS favored R-CHOP for only six cycles because of increased toxicity in the eight-cycle arm (OS at 6 years, 90% vs. 80%; P = .0004).[7][Level of evidence: 1iiA] There was no comparison to standard R-CHOP or CHOP given every 3 weeks.

Evidence (CHOP with or without other therapies):

  1. A trial of 380 patients younger than 60 years with DLBCL and an age-adjusted International Prognostic Index (IPI) rating of 1 randomized treatment to ACVBP + rituximab (R-ACVBP) + consolidation with methotrexate, ifosfamide, etoposide, and cytarabine versus CHOP + rituximab.[8] With a median follow-up of 44 months, 3-year OS favored R-ACVBP (92% vs. 84%; hazard ratio, 0.44; 95% confidence interval (CI), 0.28–0.81, P = .007).[8][Level of evidence: 1iiA] The significantly worse toxicities with R-ACVBP, the narrow target population (<60 y with either elevated lactate dehydrogenase (LDH) or stage III/IV disease, but not both), and the lack of a confirmatory trial may inhibit adoption of R-ACVBP as a new standard of care.

  2. Two prospective randomized trials that compared CHOP with CNOP for patients aged 60 years and older with diffuse large cell lymphoma showed a significant advantage for CHOP in terms of disease-free survival (DFS) and OS.[9]; [10][Level of evidence: 1iiA]

  3. Two other randomized trials of patients aged 70 years and older confirm the superiority of CHOP over other less toxic regimens in progression-free survival and OS.[9]; [10][Level of evidence: 1iiA]

  4. Although infusion regimens have been proposed, a randomized trial of infusional CHOP versus standard CHOP therapy showed no improvement in relapse-free survival or OS.[11][Level of evidence: 1iiA]

  5. A preliminary study using CHOP with or without etoposide for patients older than 60 years suggested improvement in EFS and OS for treatment delivered every 2 weeks versus the standard 3-week regimen.[12].

As SWOG-9349 did, clinical trials continue to explore modifications of CHOP and rituximab with CHOP by increasing doses, reducing intervals between cycles, and combining new drugs with new mechanisms of action.[3,13-18] None of these trials establishes a survival advantage for reduced intervals between cycles or for increasing doses of the chemotherapy.

Other combination chemotherapy

Doxorubicin-based combination chemotherapy produces long-term DFS in 35% to 45% of patients.[2,4,5] Higher cure rates have been reported in single-institution studies than in cooperative group trials.

Evidence (other combination chemotherapy):

  1. A prospective, randomized trial of four regimens (CHOP, ProMACE CytaBOM, m-BACOD, and MACOP-B) for patients with DLBCL showed no difference in OS or time-to-treatment failure at 3 years.[19][Level of evidence: 1iiA]
  2. Other randomized trials have confirmed no advantage among the standard doxorubicin-based combinations versus CHOP.[20]; [21]Level of evidence: 1iiA]

A randomized clinical trial failed to demonstrate a beneficial effect of adjuvant radiation therapy in advanced-stage aggressive NHL.[22]

Stage IE or IIE gastric DLBCL

Four case series involving more than 100 patients with stage IE or IIE disease (with or without associated mucosa-associated lymphatic tissue) and with positive Helicobacter pylori infection reported that more than 50% of patients attained a durable complete remission after appropriate antibiotic therapy to eradicate H. pylori.[23-26][Level of evidence: 3iiiDiv]

Prognostic factors

An IPI for aggressive NHL (diffuse large cell lymphoma) identifies five significant risk factors prognostic of OS:[27]

  1. Age (≤60 years vs. >60 years).
  2. Serum LDH (normal vs. elevated).
  3. Performance status (0 or 1 vs. 2–4).
  4. Stage (stage I or stage II vs. stage III or stage IV).
  5. Extranodal site involvement (0 or 1 vs. 2–4).

Patients with two or more risk factors have a less than 50% chance of relapse-free survival and OS at 5 years. This study also identifies patients at high risk of relapse based on specific sites of involvement, including bone marrow, central nervous system (CNS), liver, lung, and spleen. The bcl-2 gene and rearrangement of the myc gene or dual overexpression of the myc gene, or both, confer a particularly poor prognosis.[28-31] Patients at high risk of relapse may be considered for clinical trials.[32] Molecular profiles of gene expression using DNA microarrays may help to stratify patients in the future for therapies directed at specific targets and to better predict survival after standard chemotherapy.[33,34]

Treatment of tumor lysis syndrome

Patients with bulky and extensive lymphadenopathy and elevations of serum uric acid and LDH are at increased risk of tumor lysis syndrome resulting in metabolic derangements such as hyperuricemia, hyperkalemia, hyperphosphatemia, hypocalcemia, and subsequent acute renal failure.[35] Treatment options include: alkaline hydration, allopurinol, and rasburicase, a recombinant urate oxidase.[36]

CNS prophylaxis

CNS prophylaxis (usually with four to six injections of methotrexate intrathecally) is recommended for patients with paranasal sinus or testicular involvement. Some clinicians are employing high-dose intravenous methotrexate (usually four doses) as an alternative to intrathecal therapy because drug delivery is improved and patient morbidity is decreased.[37] CNS prophylaxis for bone marrow involvement is controversial; some investigators recommend it, and others do not.[19,38]

  • A retrospective analysis of 605 patients with diffuse large cell lymphoma who did not receive prophylactic intrathecal therapy identified an elevated serum LDH and more than one extranodal site as independent risk factors for CNS recurrence. Patients with both risk factors have a 17% probability of CNS recurrence at 1 year after diagnosis (95% CI, 7%–28%) versus 2.8% (95% CI, 2.7%–2.9%) for the remaining patients.[39][Level of evidence: 3iiiDiii]

Patients with diffuse, small, noncleaved-cell/Burkitt's lymphoma or lymphoblastic lymphoma have a 20% to 30% lifetime risk of CNS involvement. CNS prophylaxis is recommended for these histologies.

Treatment Options Under Clinical Evaluation for Aggressive, Noncontiguous Stage II/III/IV Adult NHL

Treatment options under clinical evaluation include the following:

  • Bone marrow transplant (BMT) or stem cell transplantation (SCT).

    Several randomized, prospective trials evaluated the role of autologous BMT or SCT consolidation versus chemotherapy alone in patients in first remission with diffuse large cell lymphoma.[40-47]; [48,49][Level of evidence: 1iiA] Although some of these trials demonstrated significant increases in EFS (by 10% to 20%) among patients who received high-dose therapy, significant differences in OS could not be demonstrated prospectively in any of the series.

    Retrospective analyses of high-intermediate (two risk factors) or high-risk (more than three risk factors) patients as defined by IPI suggest improved survival with BMT in two of the trials.[41,47] These studies do not establish that high-dose consolidation is of value to patients with aggressive lymphoma who are truly at high risk of relapse, and they also demonstrate that EFS may be a poor surrogate for OS for these patients.[50]

  • Radiation therapy consolidation to sites of bulky disease.

    After R-CHOP induction chemotherapy (or similar regimens), the addition of involved-field radiation therapy to sites of initial bulky disease (≥5–10 cm) or to extralymphatic sites remains controversial.[51-53] Increased risks, such as long-term toxicities (e.g., second malignancies), must be considered.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with aggressive, noncontiguous stage II adult non-Hodgkin lymphoma, aggressive, stage III adult non-Hodgkin lymphoma and aggressive, stage IV adult non-Hodgkin lymphoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References
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  50. Shipp MA, Abeloff MD, Antman KH, et al.: International Consensus Conference on high-dose therapy with hematopoietic stem-cell transplantation in aggressive non-Hodgkin's lymphomas: report of the jury. Ann Oncol 10 (1): 13-9, 1999.  [PUBMED Abstract]

  51. Held G, Murawski N, Ziepert M, et al.: Role of radiotherapy to bulky disease in elderly patients with aggressive B-cell lymphoma. J Clin Oncol 32 (11): 1112-8, 2014.  [PUBMED Abstract]

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