As noted in part 1 of this article, which appeared in the August issue of ONCOLOGY (21:1104-1110, 2007), non-Hodgkin's lymphoma (NHL) continues to increase in incidence and is more common in elderly patients. After examining the impact of aging on the disease and exploring prognostic factors in this setting, part 1 reviewed the treatment of patients with follicular lymphoma. Here, part 2 will address the treatment of diffuse aggressive lymphomas in older patients.
Therapy of Diffuse Aggressive Lymphomas
The diffuse aggressive lymphomas include a variety of histologic subtypes, among which the diffuse large-cell histology (DLCL) is the most common. In elderly patients, B-cell DLCL (DLBCL) is the most common subtype, accounting for 50% of all cases of NHL in these patients.[1,2] Among those aged 65 to 75 years, 50% will achieve a complete response (CR) with conventional therapies, with a 5-year disease-free survival (DFS) of about 33%. However, the CR rate drops to 40% for patients older than 75 years, with a 16-month median response duration (Table 1).
Approach to Limited-Stage Disease
Approximately 30% of patients with diffuse aggressive NHL will have limited-stage disease. In an initial report of an Eastern Cooperative Oncology Group study of patients with limited-stage disease with 5-year follow-up, therapy with three cycles of CHOP (cyclophosphamide, doxorubicin HCl, vincristine [Oncovin], prednisone) followed by involved-field radiotherapy resulted in an improved progression-free (PFS) and overall survival (OS) and less cardiotoxicity, compared to treatment with eight cycles of CHOP. However, in a later report of this study with a median follow-up of 10 years, the progression-free and overall survival curves for the two treatment arms appeared to come together between 7 and 9 years. Using a similar approach, the Vancouver group found that the 10-year DFS was similar to that of younger patients.
In another recent report, a series of 576 patients over 60 years old with localized stage I/II diffuse aggressive NHL were randomized to therapy with either CHOP alone or CHOP plus involved-field radiation therapy. With a median follow-up period of 7 years among the two groups, no difference was found in either event-free survival (EFS) or OS.
Management of Advanced-Stage Disease
The majority of patients with diffuse aggressive NHL have advanced-stage disease, regardless of age. Therapy with CHOP for many years was the standard regimen for these patients, with cure rates of 25% to 30%, compared to 50% to 60% of younger patients, and a toxic death rate of 1%.[2,6,7] This was based on the results of an intergroup trial in which CHOP was compared to other combination regimens (m-BACOD [methotrexate, bleomycin, doxorubicin (Adriamycin), cyclophophamide, vincristine, dexamethasone], ProMACE-CytaBOM [prednisone, methotrexate, doxorubicin, cyclophosphamide, etoposide, cytarabine, bleomycin, vincristine, methotrexate], MACOP-B [methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, bleomycin]), showing no significant difference in efficacy (CR, OS, or PFS) but fewer adverse events with CHOP.
• Impact of Age—The impact of age on outcome has been examined in multiple series, albeit generally in a retrospective manner. In a series of patients aged ≥ 70 years treated with CHOP with no initial dose adjustment, the CR rate was comparable to that of younger patients, but more treatment-related complications were seen, including 30% treatment-related deaths (primarily sepsis).
Vose et al reported the results of CAP/BOP therapy (cyclophophamide, doxorubicin, procarbazine, bleomycin, vincristine, prednisone) in 157 patients (112 > 60 years old), in which patients ≥ 70 years old had a 33% dose reduction in myelosuppressive drugs. The response rate was similar in patients under or over age 60 (76% vs 61%, P = .18), as was the CR rate (76% vs 60%, P = .12), DFS, remission duration, and treatment toxicities. However, 5-year survival was shorter in patients over 60 compared to younger patients (34% vs 62%, P = .01), primarily related to intercurrent causes of death, especially late cardiovascular deaths.
In a series of 177 patients with DLCL treated with CHOP-based therapy, Gottlieb et al found a lower CR rate in patients over 70 than in younger patients (27% vs 53%, P = .01). However, these older patients were less likely to receive full-dose therapy. Grogan found no correlation of age with outcome in a study in which 67 patients under age 65 and 60 patients at least 65 years of age received standard-dose CHOP or m-BACOD. Response rates were comparable for older (95%/65% CR) and younger (92%/76% CR) patients, as were 3-year OS (59% vs 62%), DFS (74% vs 82%), and toxic death rate.
In a multivariate analysis of elderly patients treated with CHOP, Gomez et al found that poor performance status (PS) was the only risk factor for treatment-related death. Age ≥ 60 years was prognostic for outcome in Solal-Celigny et al's series of 73 patients receiving anthracycline-based therapy, with a lower CR rate (24% vs 72%), shorter median survival (18 vs 48 months), and lower 5-year survival (18% vs 47%) in these older patients, compared to those < 60 years of age. Lastly, Tirelli et al found that severe and lethal toxicities were more common in patients aged at least 70 years who were treated with more aggressive regimens.
The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
1. Ballester OF, Moscinski L, Spiers A, et al: Non-Hodgkin's lymphoma in the older person: a review. J Am Geriatr Soc 41:1245-1254, 1993.
2. Connors JM, O'Reilly SE: Treatment considerations in the elderly patient with lymphoma. Hematol Oncol Clin North Am11:949-960, 1997.
3. Miller TP, Dahlberg S, Cassaday JR, et al: Chemotherapy alone compared with chemotherapy plus radiotherapy for localized intermediate- and high-grade non-Hodgkin's lymphoma. N Engl J Med 339:21-26, 1998.
4. Miller TP, LeBlanc M, Spier CM, et al: CHOP alone compared to CHOP plus radiotherapy for early stage aggressive non-Hodgkin's lymphoma: Update of the Southwest Oncology Group (SWOG) randomized trial (abstract 3024). Blood 98:724a, 2001.
5. Bonnet C, Fillet G, Mournier N, et al: CHOP alone compared with CHOP plus radiotherapy for localized aggressive lymphoma in elderly patients: A study by the Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol 25:787-792, 2007.
6. O'Reilly S, Connors JM, Macpherson N, et al: Malignant lymphomas in the elderly. Clin Geriatr Med 13:251-263, 1997.
7. McKelvey EM, Gottlieb JA, Wilson HE, et al: Hydroxy-daunomycin (Adriamycin) combination chemotherapy in malignant lymphoma. Cancer 38:1484-1493, 1976.
8. 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 328:1002-1006, 1993.
9. Armitage JO, Potter JF: Aggressive chemotherapy for diffuse histiocytic lymphoma in the elderly: increased complications with advancing age. J Am Geriatr Soc 32:269-273, 1984.
10. Vose JM, Armitage JO, Weisenburger DD, et al: The importance of age in survival of patients treated with chemotherapy for aggressive non-Hodgkin's lymphoma. J Clin Oncol 6:1838-1844, 1988.
11. Gottlieb AJ, Anderson JR, Ginsberg SJ, et al: A randomized comparison of methotrexate dose and the addition of bleomycin to CHOP therapy for diffuse large cell lymphoma and other non-Hodgkin's lymphomas. Cancer 66:1888-1896, 1990.
12. Grogan L, Corbally N, Dervan PA, et al: Comparable prognostic factors and survival in elderly patients with aggressive non-Hodgkin's lymphoma treated with standard-dose adriamycin-based regimens. Ann Oncol 5(suppl 2):S47-S51, 1994.
13. Gomez H, Hidalgo M, Casanova L, et al: Risk factors for treatment-related death in elderly patients with aggressive non-Hodgkin's lymphoma: Results of a multivariate analysis. J Clin Oncol 16:2065-2069, 1998.
14. Solal-Celigny P, Chastang C, Herrera A, et al: Age as the main prognostic factor in adult aggressive non-Hodgkin's lymphoma. Am J Med 83:1075-1079, 1987.
15. Tirelli U, Zagonel V, Serraino D, et al: Non-Hodgkin's lymphomas in 137 patients aged 70 years or older: a retrospective European Organization for Research and Treatment of Cancer Lymphoma Group study. J Clin Oncol 6:1708-1713, 1988.
16. Dixon DO, Neilan B, Jones SE, et al: Effect of age on therapeutic outcome in advanced diffuse histiocytic lymphoma: The Southwest Oncology Group experience. J Clin Oncol 4:295-305, 1986.
17. O'Connell JD, Harrington DP, Johnson GJ, et al: Initial chemotherapy doses for elderly patients with malignant lymphoma. J Clin Oncol 4:1418, 1986.
18. Campbell C, Sawka C, Franssen E, et al: Delivery of full dose CHOP chemotherapy to elderly patients with aggressive non-Hodgkin's lymphoma without G-CSF support. Leuk Lymphoma 35:119-127, 1999.
19. Sonneveld P, Huijgens SP, Hagenbeek A: Dose reduction is not recommended for elderly patients undergoing chemotherapy for non-Hodgkin lymphoma. Ned Tijdschr Geneeskd 143:418-419, 1999.
20. Jacobson JO, Grossbard M, Schulman N, et al: CHOP chemotherapy with preemptive granulocyte colony-stimulating factor in elderly patients with aggressive non-Hodgkin's lymphoma: A dose-intensity analysis. Clin Lymph 1:211-217, 2000.
21. Klimo P, Connors JM: MACOP-B chemotherapy for the treatment of diffuse large cell lymphoma. Ann Intern Med 102:596-602, 1985.
22. O'Reilly SE, Klimo P, Connors JM: Low-dose ACOP-B and VABE: Weekly chemotherapy for elderly patients with advanced-stage diffuse large-cell lymphoma. J Clin Oncol 9:741-747, 1991.
23. O'Reilly SE, Connors JM, Howdle S, et al: In search of an optimal regimen for elderly patients with advanced-stage diffuse large-cell lymphoma: results of a phase II study of P/DOCE chemotherapy. J Clin Oncol 11:2250-2257, 1993.
24. McMaster ML, Johnson DH, Greer JP, et al: A brief-duration combination chemotherapy for elderly patients with poor-prognosis non-Hodgkin's lymphoma. Cancer 67:1487-1492, 1991.
25. Zinzani PL, Bendani M, Gherlinzoni F: VNCOP-B regimen in the treatment of high-grade non-Hodgkin's lymphoma in the elderly. Haematologica 78:378-382, 1993.
26. Zinzani PL, Pavone E, Storti S, et al: Randomized trial with or without granulocyte colony-stimulating factor as adjunct to induction VNCOP-B treatment of elderly high-grade non-Hodgkin's lymphoma. Blood 11:3974-3979, 1997.
27. Zinzani PL, Storti S, Zaccaria A, et al: Elderly aggressive-histology non-Hodgkin's lymphoma: First-line VNCOP-B regimen experience on 350 patients. Blood 94:33-38, 1999.
28. Martelli M, Guglielmi C, Coluzzi S, et al: P-VABEC: A prospective study of a new weekly chemotherapy regimen for elderly aggressive non-Hodgkin's lymphoma. J Clin Oncol 11:2362-2369, 1993.
29. Caracciolo F, Petrini M, Capochiani E, et al: Third generation chemotherapy with P-VABEC for aggressive non-Hodgkin's lymphomas of the elderly. Leuk Lymphoma 11:115-118, 1993.
30. Caracciolo F, Petrini M, Capochiani E, et al: Alternating chemotherapy regimen (P-VABEC) for intermediate and high-grade non-Hodgkin's lymphoma of the middle aged and elderly. Hematol Oncol 12:185-192, 1994.
31. Liang R, Todd D, Chan TK, et al: COPP chemotherapy for elderly patients with intermediate and high grade non-Hodgkin's lymphoma. Hematol Oncol 11:43-50, 1993.
32. Hainsworth JD: Chronic administration of etoposide in the treatment of non-Hodgkin's lymphoma. Leuk Lymph 10:65-72, 1993.
33. Young WA, Greco FA, Greer JP, et al: Aggressive non-Hodgkin's lymphoma in the elderly: An effective, well-tolerated treatment regimen containing extended-schedule etoposide. J Natl Cancer Inst 86:1346-1347, 1994.
34. Novitzky N, King HS, Johnson C, et al: Treatment of aggressive non-Hodgkin's lymphoma in the elderly. Am J Hematol 49:103-108, 1995.
35. Sonneveld P, Michiels JJ: Full dose chemotherapy in elderly patients with non-Hodgkin's lymphoma: A feasibility study using a mitoxantrone containing regimen. Br J Cancer 62:105-108, 1990.
36. Bessell EM, Coutts A, Fletcher J, et al: Non-Hodgkin's lymphoma in elderly patients: A phase II study of MCOP chemotherapy in patients aged 70 years or over with intermediate or high-grade histology. Eur J Cancer 30A:1337-1341, 1994.
37. Salvagno L, Contu A, Bianco A, et al: A combination of mitoxantrone, etoposide and prednisone in elderly patients with non-Hodgkin's lymphoma. Ann Oncol 3:833-837, 1992.
38. Goss P, Burkes R, Rudinskas L, et al: A phase II trial of prednisone, oral etoposide, and novantrone (PEN) as initial treatment of non-Hodgkin's lymphoma in elderly patients. Leuk Lymphoma 18:145-152, 1995.
39. Ansell SM, Falkson G: A phase II trial of a chemotherapy combination in elderly patients with aggressive lymphoma. Ann Oncol 4:172-175, 1993.
40. Tirelli U, Zagonel V, Errante D, et al: A prospective study of a nnew combination chemotherapy regimen in patients older than 70 years with unfavorable non-Hodgkin's lymphoma. J Clin Oncol 10:228-236, 1992.
41. Zagonel V, Tirelli U, Carbone A, et al: Combination chemotherapy specifically devised for elderly patients with unfavourable non-Hodgkin's lymphoma. Cancer Invest 8:575-580, 1990.
42. Bertini M: Therapeutic strategies in intermediate grade lymphomas in elderly patients. The Italian Multiregional non-Hodgkin's Lymphoma Study Group (IMRNHLSG). Hematol Oncol 11(suppl 1):52-58, 1993.
43. Morra E, Gargantini L, Nosari A, et al: Treatment of patients with high-grade non-Hodgkin's lymphoma aged over 70 years with an all-oral regimen combining idarubicin, etoposide and alkylators. Crit Rev Oncol Hematol 35:95-100, 2000.
44. Meyer RM, Browman GP, Samosh ML, et al: Randomized phase II comparison of standard CHOP with weekly CHOP in elderly patients with non-Hodgkin's lymphoma. J Clin Oncol 13:2386-2393, 1995.
45. Sonneveld P, de Ridder M, van der Lelie H, et al: Comparison of doxorubicin and mitoxantrone in the treatment of elderly patients with advanced diffuse non-Hodgkin's lymphoma using CHOP versus CNOP chemotherapy. J Clin Oncol 13:2530-2539, 1995.
46. 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 15:2945-2953, 1997.
47. Tirelli U, Errante D, Van Glabbeke M, et al: CHOP is the standard regimen in patients ≥ 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 16:27-34, 1998.
48. Pfreundschuh M, Trumper L, Kloess M, et al: Two-weekly of 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. J Clin Oncol 104:634-641, 2004.
49. 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 346:235-242, 2002.
50. Habermann TM, Weller EA, Morrison VA, et al: Rituximab-CHOP versus CHOP alone or with maintenance rituximab in older patients with diffuse large B-cell lymphoma. J Clin Oncol 24:3121-3127, 2006.
51. Feugier P, Van Hoof A, Sebban C, et al: Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: A Study by the Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol 23:4117-4126, 2005.
52. Vose JM, Link BK, Grossbard ML, et al: Phase II study of rituximab in combination with CHOP chemotherapy in patients with previously untreated, aggressive non-Hodgkin's lymphoma. J Clin Oncol 19:389-397, 2001.
53. Sehn LH, Donaldson J, Chhanabhai M, et al: Introduction of combined CHOP plus rituximab therapy dramatically improved outcome of diffuse large B-cell lymphoma in British Columbia. J Clin Oncol 23:5027-5033, 2005.
54. Monfardini S, Sacco C, Serraino D, et al: Effects of G-CSF in patients with non-Hodgkin's lymphomas (NHL) older than 70 years (abstract 611). Ann Oncol 7(suppl 3):164, 1996.
55. Bertini M, Freilone R, Vitolo U, et al: P-VEBEC: a new 8-weekly schedule with or without rG-CSF for elderly patients with aggressive non-Hodgkin's lymphoma (NHL). Ann Oncol 5:895-900, 1994.
56. Niitsu N, Umeda M: Usefulness of COP-BLAM therapy with concomitant G-CSF in elderly patients with non-Hodgkin's lymphoma in comparison with patients not given G-CSF. Nippon Ronan Igakkai Zasshi 32:410-415, 1995.
57. Bertini M, Freilone R, Vitolo U, et al: The treatment of elderly patients with aggressive non-Hodgkin's lymphoma: feasibility and efficacy of an intensive multidrug regimen. Leuk Lymphoma 22:483-493, 1996.
58. Guerci A, Lederlin P, Reyes F, et al: Effect of granulocyte colony-stimulating factor administration in elderly patients with aggressive non-Hodgkin's lymphoma treated with a pirarubicin-combination chemotherapy regimen. Ann Oncol 7:966-969, 1996.
59. Niitsu N, Umeda M: THP-COPBLM (pirarubicin, cyclophosphamide, vincristine, prednisone, bleomycin and procarbazine) regimen combined with granulocyte colony-stimulating factor (G-CSF) for non-Hodgkin's lymphoma in elderly patients: A prospective study. Leukemia 11:1817-1820, 1997.
60. Gómez H, Mas L, Casanova L, et al: Elderly patients with aggressive non-Hodgkin's lymphoma treated with CHOP chemotherapy plus granulocyte-macrophage colony-stimulating factor: Identification of two age subgroups with differing hematologic toxicity. J Clin Oncol 16:2352-2358, 1998.
61. Zinzani PL, Pavone E, Storti S, et al: Randomized trial with or without granulocyte colony-stimulating factor as adjunct to induction VNCOP-B treatment of elderly high-grade non-Hodgkin's lymphoma. Blood 89:3974-3979 1997.
62. Björkholm M, Ösby E, Hagberg H, et al: Randomized trial of r-metHu granulocyte colony-stimulating factor (G-CSF) as adjunct to CHOP or CNOP treatment of elderly patients with aggressive non-Hodgkin's lymphoma (abstract 2655). Blood 94:599a, 1999.
63. Gómez H, Hidalgo M, Casanova L, et al: Risk factors for treatment-related death in elderly patients with aggressive non-Hodgkin's lymphoma: Results of a multivariate analysis. J Clin Oncol 16:2065-2069, 1998.
64. Doorduijn JK, van der Holt B, van Imhoff GW, et al: CHOP compared with CHOP plus granulocyte colony-stimulating factor in elderly patients with aggressive non-Hodgkin's lymphoma. J Clin Oncol 21:3041-3050, 2003.
65. Ösby E, Hagberg H, Kvaløy S, et al: CHOP is superior to CNOP in elderly patients with aggressive lymphoma while outcome is unaffected by filgrastim treatment: Results of a Nordic Lymphoma Group randomized trial. Blood 101:3840-3848, 2003.
66. Intragumtornchai T, Sutheesophon J, Sutcharitchan P, et al: A predictive model for life-threatening neutropenia and febrile neutropenia after the first course of CHOP chemotherapy in patients with aggressive non-Hodgkin's lymphoma. Leuk Lymphoma 37:351-360, 2000.
67. Morrison VA, Weller EA, Habermann TM, et al: Patterns of growth factor (GF) usage and febrile neutropenia (FN) among older patients (pts) with diffuse large B-cell lymphoma treated (DLBCL) treated with CHOP or R-CHOP: An intergroup experience (CALGB 9793; ECOG-SWOG 4494) (abstract 3309). Blood 104:904a, 2004.
68. Morrison VA, Picozzi V, Scott S, et al: The impact of age on delivered dose intensity and hospitalizations for febrile neutropenia in patients with intermediate-grade non-Hodgkin's lymphoma receiving initial CHOP chemotherapy: A risk factor analysis. Clin Lymph 2:47-56, 2001.
69. Lyman GH, Morrison VA, Dale DC, et al: Risk of febrile neutropenia among patients with intermediate-grade non-Hodgkin's lymphoma receiving CHOP chemotherapy. Leuk Lymphoma 44:2069-2076, 2003.
70. Clark OAC, Lyman GH, Castro AA, et al: Colony-stimulating factors for chemotherapy-induced febrile neutropenia: A meta-analysis of randomized controlled trials. J Clin Oncol 23:4198-4214, 2005.
71. Crawford J, Dale DC, Lyman GH: Chemotherapy-induced neutropenia: Risks, consequences, and new directions for its management. Cancer 100:228-237, 2004.
72. Caggiano V, Weiss RV, Rickert TS, et al: Incidence, cost, and mortality of febrile neutropenia hospitalization (FNH) associated with chemotherapy. Cancer 103:1916-1924, 2005.
73. Chrischilles EA, Klepser DG, Brooks JM, et al: Effect of clinical characteristics on neutropenia-related inpatient costs among newly diagnosed non-Hodgkin's lymphoma cases during first-course chemotherapy. Pharmacotherapy 25:668-675, 2005.
74. Lyman GH, Kuderer NM: The economics of the colony-stimulating factors in the prevention and treatment of febrile neutropenia. Crit Rev Oncol Hematol 50:129-146, 2004.
75. Cosler LE, Sivasubramaniam V, Agboola O, et al: Effect of outpatient treatment of febrile neutropenia on the risk threshold for the use of CSF in patients with cancer treated with chemotherapy. Value in Health 8:47-52, 2005.
76. Lyman GH: Balancing the benefits and costs of colony-stimulating factors: A current perspective. Semin Oncol 30(suppl 13):10-17, 2003.
77. Zagonel V, Babare R, Merola MC, et al: Cost-benefit of granulocyte colony-stimulating factor administration in older patients with non-Hodgkin's lymphoma treated with combination chemotherapy. Ann Oncol 5(suppl 2):S127-S132, 1994.