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Adult Non-Hodgkin Lymphoma Treatment (Professional) (cont.)

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

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 diffuse large B-cell lymphoma.[2]

Evidence (R-CHOP):

  1. The combination of rituximab and CHOP (R-CHOP) showed improvement in event-free survival (EFS) and overall survival (OS) compared with CHOP alone in 399 advanced-stage patients with diffuse large B-cell lymphoma older than 60 years (EFS = 57% vs. 38%, P = .002, and OS = 70% vs. 57%, P = .007 at 2 years).[3][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.[4]
  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).[5][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.[6] With a median follow-up of 35 months, the EFS favored R-CHOP given every 2 weeks for six or eight cycles (EFS, relative risk [RR] = 0.5 [0.40–0.65], P < .001). The OS favored R-CHOP for only six cycles because of increased toxicity in the eight-cycle arm (RR of death = 0.63 [0.46–0.85], P = .003).[6][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 diffuse large B-cell lymphoma and an age-adjusted International Prognostic Index (IPI) rating of 1 randomized treatment to ACVBP + rituximab (R-ACVBP) versus CHOP + rituximab.[7] With a median follow-up of 44 months, 3-year OS favored R-ACVBP (92% vs. 84%; HR, 0.44; 95% CI, 0.28–0.81, P = .007).[7][Level of evidence: 1iiA] The significantly worse toxicities with R-ACVBP, the narrow target population (<60 y with either elevated 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 and OS.[8]; [9][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.[8]; [9][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.[10][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.[11]

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.[12,13,14,15]

Other combination chemotherapy

Doxorubicin-based combination chemotherapy produces long-term disease-free survival in 35% to 45% of patients.[2,3,4] 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 diffuse large B-cell lymphoma showed no difference in OS or time-to-treatment failure at 3 years.[16][Level of evidence: 1iiA]
  2. Other randomized trials have confirmed no advantage among the standard doxorubicin-based combinations versus CHOP.[17]; [18]Level of evidence: 1iiA]

A randomized clinical trial failed to demonstrate a beneficial effect of adjuvant radiation therapy in advanced-stage aggressive NHL.[19]

Prognostic factors

An IPI for aggressive NHL (diffuse large cell lymphoma) identifies five significant risk factors prognostic of OS:[20]

  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. Patients at high risk of relapse may be considered for clinical trials.[21] 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.[22,23]

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.[24] Treatment options include alkaline hydration; allopurinol; and rasburicase, a recombinant urate oxidase.[25]

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.[26] CNS prophylaxis for bone marrow involvement is controversial; some investigators recommend it, and others do not.[16,27]

  • 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% confidence interval [CI], 7%–28%) versus 2.8% (95% CI, 2.7%–2.9%) for the remaining patients.[28][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 transplant.

    Several randomized prospective trials evaluated the role of autologous BMT or stem cell transplantation consolidation versus chemotherapy alone in patients in first remission with diffuse large cell lymphoma.[29,30,31,32,33,34,35,36]; [37][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.[30,36] 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.[38]

    Whether autologous BMT, or peripheral stem cell transplantation, or allogeneic BMT have definitive roles in the treatment of high-risk patients in first remission awaits the results of ongoing randomized trials such as the SWOG-S0016 (NCT00006721) trial, for example, that employed R-CHOP or other rituximab-based chemotherapy regimens.

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:

  1. Shankland KR, Armitage JO, Hancock BW: Non-Hodgkin lymphoma. Lancet 380 (9844): 848-57, 2012.
  2. Coiffier B: State-of-the-art therapeutics: diffuse large B-cell lymphoma. J Clin Oncol 23 (26): 6387-93, 2005.
  3. Coiffier B, Lepage E, Briere J, et al.: CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 346 (4): 235-42, 2002.
  4. Coiffier B, Thieblemont C, Van Den Neste E, et al.: Long-term outcome of patients in the LNH-98.5 trial, the first randomized study comparing rituximab-CHOP to standard CHOP chemotherapy in DLBCL patients: a study by the Groupe d'Etudes des Lymphomes de l'Adulte. Blood 116 (12): 2040-5, 2010.
  5. Pfreundschuh M, Trümper L, Osterborg A, et al.: CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol 7 (5): 379-91, 2006.
  6. Pfreundschuh M, Schubert J, Ziepert M, et al.: Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas: a randomised controlled trial (RICOVER-60). Lancet Oncol 9 (2): 105-16, 2008.
  7. Récher C, Coiffier B, Haioun C, et al.: Intensified chemotherapy with ACVBP plus rituximab versus standard CHOP plus rituximab for the treatment of diffuse large B-cell lymphoma (LNH03-2B): an open-label randomised phase 3 trial. Lancet 378 (9806): 1858-67, 2011.
  8. Bastion Y, Blay JY, Divine M, et al.: Elderly patients with aggressive non-Hodgkin's lymphoma: disease presentation, response to treatment, and survival--a Groupe d'Etude des Lymphomes de l'Adulte study on 453 patients older than 69 years. J Clin Oncol 15 (8): 2945-53, 1997.
  9. Tirelli U, Errante D, Van Glabbeke M, et al.: CHOP is the standard regimen in patients > or = 70 years of age with intermediate-grade and high-grade non-Hodgkin's lymphoma: results of a randomized study of the European Organization for Research and Treatment of Cancer Lymphoma Cooperative Study Group. J Clin Oncol 16 (1): 27-34, 1998.
  10. Gaynor ER, Unger JM, Miller TP, et al.: Infusional CHOP chemotherapy (CVAD) with or without chemosensitizers offers no advantage over standard CHOP therapy in the treatment of lymphoma: a Southwest Oncology Group Study. J Clin Oncol 19 (3): 750-5, 2001.
  11. Pfreundschuh M, Trümper L, Kloess M, et al.: Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of elderly patients with aggressive lymphomas: results of the NHL-B2 trial of the DSHNHL. Blood 104 (3): 634-41, 2004.
  12. Blayney DW, LeBlanc ML, Grogan T, et al.: Dose-intense chemotherapy every 2 weeks with dose-intense cyclophosphamide, doxorubicin, vincristine, and prednisone may improve survival in intermediate- and high-grade lymphoma: a phase II study of the Southwest Oncology Group (SWOG 9349). J Clin Oncol 21 (13): 2466-73, 2003.
  13. Coiffier B: Increasing chemotherapy intensity in aggressive lymphomas: a renewal? J Clin Oncol 21 (13): 2457-9, 2003.
  14. Tilly H, Lepage E, Coiffier B, et al.: Intensive conventional chemotherapy (ACVBP regimen) compared with standard CHOP for poor-prognosis aggressive non-Hodgkin lymphoma. Blood 102 (13): 4284-9, 2003.
  15. Pfreundschuh M, Trümper L, Kloess M, et al.: Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of young patients with good-prognosis (normal LDH) aggressive lymphomas: results of the NHL-B1 trial of the DSHNHL. Blood 104 (3): 626-33, 2004.
  16. Fisher RI, Gaynor ER, Dahlberg S, et al.: Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin's lymphoma. N Engl J Med 328 (14): 1002-6, 1993.
  17. Gordon LI, Harrington D, Andersen J, et al.: Comparison of a second-generation combination chemotherapeutic regimen (m-BACOD) with a standard regimen (CHOP) for advanced diffuse non-Hodgkin's lymphoma. N Engl J Med 327 (19): 1342-9, 1992.
  18. Cooper IA, Wolf MM, Robertson TI, et al.: Randomized comparison of MACOP-B with CHOP in patients with intermediate-grade non-Hodgkin's lymphoma. The Australian and New Zealand Lymphoma Group. J Clin Oncol 12 (4): 769-78, 1994.
  19. O'Connell MJ, Harrington DP, Earle JD, et al.: Prospectively randomized clinical trial of three intensive chemotherapy regimens for the treatment of advanced unfavorable histology non-Hodgkin's lymphoma. J Clin Oncol 5 (9): 1329-39, 1987.
  20. Ziepert M, Hasenclever D, Kuhnt E, et al.: Standard International prognostic index remains a valid predictor of outcome for patients with aggressive CD20+ B-cell lymphoma in the rituximab era. J Clin Oncol 28 (14): 2373-80, 2010.
  21. Canellos GP: CHOP may have been part of the beginning but certainly not the end: issues in risk-related therapy of large-cell lymphoma. J Clin Oncol 15 (5): 1713-6, 1997.
  22. Rosenwald A, Wright G, Chan WC, et al.: The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med 346 (25): 1937-47, 2002.
  23. Lossos IS, Czerwinski DK, Alizadeh AA, et al.: Prediction of survival in diffuse large-B-cell lymphoma based on the expression of six genes. N Engl J Med 350 (18): 1828-37, 2004.
  24. Coiffier B, Altman A, Pui CH, et al.: Guidelines for the management of pediatric and adult tumor lysis syndrome: an evidence-based review. J Clin Oncol 26 (16): 2767-78, 2008.
  25. Cortes J, Moore JO, Maziarz RT, et al.: Control of plasma uric acid in adults at risk for tumor Lysis syndrome: efficacy and safety of rasburicase alone and rasburicase followed by allopurinol compared with allopurinol alone--results of a multicenter phase III study. J Clin Oncol 28 (27): 4207-13, 2010.
  26. Glantz MJ, Cole BF, Recht L, et al.: High-dose intravenous methotrexate for patients with nonleukemic leptomeningeal cancer: is intrathecal chemotherapy necessary? J Clin Oncol 16 (4): 1561-7, 1998.
  27. Bernstein SH, Unger JM, Leblanc M, et al.: Natural history of CNS relapse in patients with aggressive non-Hodgkin's lymphoma: a 20-year follow-up analysis of SWOG 8516 -- the Southwest Oncology Group. J Clin Oncol 27 (1): 114-9, 2009.
  28. van Besien K, Ha CS, Murphy S, et al.: Risk factors, treatment, and outcome of central nervous system recurrence in adults with intermediate-grade and immunoblastic lymphoma. Blood 91 (4): 1178-84, 1998.
  29. Haioun C, Lepage E, Gisselbrecht C, et al.: Survival benefit of high-dose therapy in poor-risk aggressive non-Hodgkin's lymphoma: final analysis of the prospective LNH87-2 protocol--a groupe d'Etude des lymphomes de l'Adulte study. J Clin Oncol 18 (16): 3025-30, 2000.
  30. Haioun C, Lepage E, Gisselbrecht C, et al.: Benefit of autologous bone marrow transplantation over sequential chemotherapy in poor-risk aggressive non-Hodgkin's lymphoma: updated results of the prospective study LNH87-2. Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol 15 (3): 1131-7, 1997.
  31. Santini G, Salvagno L, Leoni P, et al.: VACOP-B versus VACOP-B plus autologous bone marrow transplantation for advanced diffuse non-Hodgkin's lymphoma: results of a prospective randomized trial by the non-Hodgkin's Lymphoma Cooperative Study Group. J Clin Oncol 16 (8): 2796-802, 1998.
  32. Gianni AM, Bregni M, Siena S, et al.: High-dose chemotherapy and autologous bone marrow transplantation compared with MACOP-B in aggressive B-cell lymphoma. N Engl J Med 336 (18): 1290-7, 1997.
  33. Kluin-Nelemans HC, Zagonel V, Anastasopoulou A, et al.: Standard chemotherapy with or without high-dose chemotherapy for aggressive non-Hodgkin's lymphoma: randomized phase III EORTC study. J Natl Cancer Inst 93 (1): 22-30, 2001.
  34. Gisselbrecht C, Lepage E, Molina T, et al.: Shortened first-line high-dose chemotherapy for patients with poor-prognosis aggressive lymphoma. J Clin Oncol 20 (10): 2472-9, 2002.
  35. Martelli M, Gherlinzoni F, De Renzo A, et al.: Early autologous stem-cell transplantation versus conventional chemotherapy as front-line therapy in high-risk, aggressive non-Hodgkin's lymphoma: an Italian multicenter randomized trial. J Clin Oncol 21 (7): 1255-62, 2003.
  36. Milpied N, Deconinck E, Gaillard F, et al.: Initial treatment of aggressive lymphoma with high-dose chemotherapy and autologous stem-cell support. N Engl J Med 350 (13): 1287-95, 2004.
  37. Betticher DC, Martinelli G, Radford JA, et al.: Sequential high dose chemotherapy as initial treatment for aggressive sub-types of non-Hodgkin lymphoma: results of the international randomized phase III trial (MISTRAL). Ann Oncol 17 (10): 1546-52, 2006.
  38. 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.
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