Non-Hodgkin's lymphoma is one of a few malignancies that have been increasing in incidence over the past several decades. Likewise, these disorders are more common in elderly patients, with a median age of occurrence of 65 years. Therapy in elderly patients may be affected by multiple factors, especially attendant comorbidities. The approaches to management of these patients, with either indolent or aggressive disease processes, have been based on prospective clinical trial results, many of which have included a younger patient population. Fortunately, over the past decade, results of treatment trials that have targeted an older patient population have emerged. The disease incidence and treatment approaches for both follicular (part 1 of this article) and diffuse aggressive (part 2) histologies in elderly patients are reviewed, as well as the impact of aging on the care of these patients.
Non-Hodgkin's lymphoma (NHL) is now the fifth most common malignancy in females, and sixth most common in males. Approximately 59,000 new cases of NHL, and 19,000 deaths due to this disease, are expected in the United States in 2006. Over the past 2 decades, NHL has become one of the few malignancies that is increasing in incidence across all adult age groups, rising by as much as 8% to 10% per year.[2-5] In recent data from the Surveillance, Epidemiology and End Results (SEER) program of the NCI, the incidence of NHL was found to increase exponentially from age 20 to 79 years and then plateau.[6-8] Specifically, the incidence of NHL in US males ranged from 13.1 per 100,000 in people aged 40 to 44 years, to 51.2 per 100,000 in those 60 to 64 years, and 133 per 100,000 in those aged 80 to 84 years.
This increasing incidence is relevant in the elderly population, for although patients aged ≥ 65 years represent 13% of the population, from 25% to 35% of new NHL cases will occur in this group.[10-11] With a median age of 65 years for this disease, about 33% of cases occur in patients who are > 70 years old. With the prediction that the subgroup of the US population > 65 years of age will increase by 12% to 20% over the next several decades, the occurrence of NHL in this older patient population will pose an increasing problem. Incidence rates are higher in males than females across all age groups. In patients older than 60 years of age, incidence rates are slightly higher among whites than blacks. Lastly, the age-specific incidence of small noncleaved cell and lymphoblastic lymphomas increases relatively slowly with age, compared to a more rapid rise in incidence by age for all other histologies.
Part 1 of this two-part article addresses the impact of aging on the treatment of NHL patients, reviews the epidemiology, classification, staging, and prognosis associated with the disease in this setting, and concludes with a discussion of the treatment of follicular NHL. Part 2, which will appear in the September issue of ONCOLOGY, focuses on the treatment of diffuse aggressive lymphomas in the elderly.
Impact of Aging
Clinical care of the older cancer patient is complicated by a variety of factors (Table 1). Clearly, chronologic age alone is not sufficient to categorize these patients. The issue of "ageist stereotyping" may be present among physicians, patients, and family members. Misconceptions with regard to the etiology of cancer, disease course, and treatment may act as barriers to seeking appropriate medical care.[15-17] Specific to elderly NHL patients, a population-based study demonstrated that advanced age was associated with less optimal staging and a greater likelihood of therapy not being administered. Unique social and financial issues related to advanced age also exist in this population.
These issues among others contribute to the paucity of elderly patients in clinical trials. Given a potential referral bias of patients to specialized centers for cancer care, only patients of good performance status (PS) may be entered into many clinical trials. This may not reflect the majority of elderly NHL patients in the general population. There are also issues in evaluating these trials, due to a variable definition of "elderly" (60, 65, or 70 years), small patient numbers, and differing patient characteristics related to PS, comorbidities, and NHL prognostic factors. Quality-of-life assessments assessing both comorbidities and functional status, which are poorly correlated in older cancer patients, are especially important in the elderly population.[17,19-21] Multiple comorbidities have an impact on major organ function and may influence therapy-related toxicities. A correlation has been found between patient function and 2-year mortality. Alterations in host immune function likewise occur in the elderly.
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. Jemal A, Siegel R, Ward E, et al: Cancer statistics, 2006. CA Cancer J Clin 56:106-30, 2006.
2. Devesa SS, Fears T: Non-Hodgkin's lymphoma time trends: United States and international data. Cancer Res 52(suppl 19):5432s-5440s, 1992.
3. Coleman MP, Esteve J, Damiecki P, et al: Trends in cancer incidence and mortality. IARC Sci Publ 121:1-806, 1993.
4. Newton R, Ferlay J, Beral V, et al: The epidemiology of non-Hodgkin's lymphoma: Comparison of nodal and extra-nodal sites. Int J Cancer 72:923-930, 1997.
5. Weisenburger DD: Epidemiology of non-Hodgkin's lymphoma: Recent findings regarding an emerging epidemic. Ann Oncol 5(suppl 1):19-24, 1994.
6. Newell GR, Cabanillas FG, Hagemeister FJ, et al: Incidence of lymphomas in the US classified by the Working Formulation. Cancer 59:857-861, 1987.
7. Rabkin CS, Devesa SS, Zahm SH, et al: Increasing incidence of non-Hodgkin's lymphoma. Semin Hematol 30:286-296, 1993.
8. D'Amore F, Brincker H, Christensen BE, et al: Non-Hodgkin's lymphoma in the elderly. A study of 602 patients aged 70 or older from a Danish population-based registry. Ann Oncol 3:379-386, 1992.
9. National Cancer Institute: SEER Cancer Statistics Review, 1975-2003. Available at http://seer.cancer.gov/cgi-bin/csr/1975_2003/search.pl. Accessed July 12, 2007.
10. Goss PE: Non-Hodgkin's lymphomas in elderly patients. Leuk Lymphoma 10:147-156, 1993.
11. Martelli M, De Sanctis V, Avvisati G, et al: Current guidelines for the management of aggressive non-Hodgkin's lymphoma. Drugs 53:957-972, 1997.
12. Tirelli U, Zagonel V, Errante D, et al: Treatment of non-Hodgkin's lymphoma in the elderly: An update. Hematol Oncol 16:1-13, 1998.
13. Kennedy BJ: Aging and cancer. J Clin Oncol 6:1903-1911, 1988.
14. Groves FD, Linet MS, Travis LB, et al: Cancer surveillance series: Non-Hodgkin's lymphoma incidence by histologic subtype in the United States from 1978 through 1995. J Natl Cancer Inst 92:1240-1251, 2000.
15. Berkman B, Rohan B, Sampson S: Myths and biases related to cancer in the elderly. Cancer 74:2004-2008, 1994.
16. Rijke de JM, Schouten LJ, Schouten HC, et al: Age-Specific differences in the diagnostics and treatment of cancer patients aged 50 years and older in the province of Limburg, the Netherlands. Ann Oncol 7:677-685, 1996.
17. McKenna RJ: Clinical aspects of cancer in the elderly. Treatment decision, treatment choices, and follow-up. Cancer 74:2107-2117, 1994.
18. Jelic S, Milanovic N, Tomasevic Z, et al: Comparison of two non-anthracycline-containing regimens for elderly patients with diffuse large-cell non-Hodgkin's lymphoma—possible pitfalls in results reporting and interpretation. Neoplasma 46:394-399, 1999.
19. Yancik R: Cancer burden in the aged. A epidemiologic and demographic overview. Cancer 80:1273-1283, 1997.
20. Extermann M, Overcash J, Lyman GH, et al: Comorbidity and functional status are independent in older cancer patients. J Clin Oncol 16:1582-1587, 1998.
21. Lichtman SM: Aggressive lymphoma in the elderly. Crit Rev Oncol Hematol 33:119-128, 2000.
22. Peters FPJ, Ten Haaft MA, Schouten HC: Intermediate and high-grade non-Hodgkin's lymphoma in the elderly. Leuk Lymphoma 33:243-252, 1999.
23. Sweetenham JW, Williams CJ: Malignant lymphoma in the elderly. Baillieres Clin Haematol 1:493-511, 1987.
24. Niitsu N: Non-Hodgkin's lymphoma in the elderly. A guide to drug treatment. Drugs Aging 14:447-457, 1999.
25. Blum RH, Carter SK, Agre K: A clinical review of bleomycin—a new antineoplastic agent. Cancer 31:903-913, 1973.
26. Gobbi PG, Cavalli C: Treatment of adult non-Hodgkin's lymphomas. Haematologica 71:321-344, 1986.
27. Bristow MR, Mason JW, Billingham ME, et al: Doxorubicin cardiomyopathy: Evaluation by phonocardiography, endomyocardial biopsy and cardiac catheterisation. Ann Intern Med 88:168-175, 1978.
28. 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.
29. 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.
30. 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.
31. The Non-Hodgkin's Lymphoma Pathologic Classification Project: National Cancer Institute sponsored study of classification of non-Hodgkin's lymphoma. Summary and description of a working formulation for clinical usage. Cancer 49:2112-2135, 1982.
32. Carbone A, Volpe R, Gloghini A, et al: Non-Hodgkin's lymphoma in the elderly. Cancer 66:1991-1994, 1990.
33. 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.
34. Neilly IJ, Ogston M, Bennett B, et al: High grade non-Hodgkin's lymphoma in the elderly—12 year experience in the Grampian region of Scotland. Hematol Oncol 13:99-106, 1995.
35. Hoerni B, Sotto JJ, Eghbali H, et al: Non-Hodgkin's malignant lymphomas in patients older than 80. Cancer 61:2057-2059, 1988.
36. Elias L: Differences in age and sex distributions among patients with non-Hodgkin's lymphoma. Cancer 43:2540-2546, 1979.
37. Carbone A, Tirelli U, Volpe R, et al: Non-Hodgkin's lymphoma in the elderly. Cancer 57:2185-2189, 1986.
38. Harris NL, Jaffe ES, Stein H, et al: A revised European-American classification of lymphoid neoplasms: A proposal from the International Lymphoma Study Group. Blood 84:1361-1392, 1994.
39. Harris NL, Jaffe ES, Diebold J, et al: World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: Report of the Clinical Advisory Committee meeting—Airlie House, Virginia, November 1997. J Clin Oncol 17:3835-3849, 1999.
40. Carbone PP, Kaplan HS, Musshoff K, et al: Report of the Committee on Hodgkin's Disease Staging Classification. Cancer Res 31:1860-1861, 1971.
41. International Non-Hodgkin's Lymphoma Prognostic Factors Project: A predictive model for aggressive non-Hodgkin's lymphoma. N Engl J Med 329:987-994, 1993.
42. Hayward RL, Leonard RCF, Prescott RJ: A critical analysis of prognostic factors for survival in intermediate and high grade non-Hodgkin's lymphoma. Br J Cancer 63:945-952, 1991.
43. Velasquez WS, Jagannath S, Tucker SL, et al: Risk classification as the basis for clinical staging of diffuse large-cell lymphoma derived from 10-year survival data. Blood 74:551-557, 1989.
44. Coiffier B, Gisselbrecht C, Vose JM, et al: Prognostic factors in aggressive malignant lymphomas: Description and validation of a prognostic index that could identify patients requiring a more intensive therapy. J Clin Oncol 9:211-219, 1991.
45. Miller TP, Lippman SM, Spier CM, et al: HLA-DR (Ia) immune phenotype predicts outcome for patients with diffuse large cell lymphoma. J Clin Invest 82:370-372, 1988.
46. Swan F, Huh Y, Katz R, et al: Beta-2-microglobulin (?2M) and HLA-DR cellular expression in relapsing large cell lymphomas (LCL): Relationship to survival and serum ?2M levels (abstract). Blood 76(suppl 1):375a, 1990.
47. Bauer KD, Merkel DE, Winter JN, et al: Prognostic implications of ploidy and proliferative activity in diffuse large cell lymphomas. Cancer Res 46:3173-3178, 1986.
48. Grogan TM, Lippman SM, Spier DM, et al: Independent prognostic significance of nuclear proliferation antigen in diffuse large cell lymphomas as determined by the monoclonal antibody Ki-67. Blood 71:1157-1160, 1988.
49. Wooldridge TN, Grierson HL, Weisenburger DD, et al: Association of DNA content and proliferative activity with clinical outcome in patients with diffuse mixed cell and large cell non-Hodgkin's lymphoma. Cancer Res 48:6608-6613, 1988.
50. Solal-Celigny P, Roy P, Colombat P, et al: Follicular lymphoma international prognostic index. Blood 104:1258-1265, 2004.
51. Leonard RCF, Hayward RL, Prescott RJ, et al: The identification of discrete prognostic groups in low grade non-Hodgkin's lymphoma. Ann Oncol 2:655-667, 1991.
52. Soubeyran P, Eghbali H, Bonichon F, et al: Low-grade follicular lymphomas: Analysis of prognosis in a series of 281 patients. Eur J Cancer Clin Oncol 27:1606-1613, 1991.
53. Romaguera JE, McLaughlin P, North L, et al: Multivariate analysis of prognostic factors in stage IV follicular low grade lymphoma: a risk model. J Clin Oncol 9:762-769, 1991.
54. Weisdorf DJ, Andersen JW, Glick JH, et al: Survival after relapse of low-grade non-Hodgkin's lymphoma. Implications for marrow transplantation. J Clin Oncol 10:942-947, 1992.
55. Paryani SB, Hoppe RT, Co RS, et al: Analysis of non-Hodgkin's lymphomas with nodular and unfavourable histologies, stages I and II. Cancer 52:2300-2307, 1983.
56. Rudders RA, Kaddis M, Delellis RA, et al: Nodular non-Hodgkin's lymphoma (NHL): Factors influencing prognosis and indicators for aggressive treatment. Cancer 43:1643-1651, 1979.
57. Gallagher CJ, Gregory WM, Jones AE, et al: Follicular lymphoma: Prognostic factors for response and survival. J Clin Oncol 4:1470-1480, 1986.
58. Cabanillas F, Smith T, Bodey GP, et al: Nodular malignant lymphoma: factors affecting complete response rate and survival. Cancer 44:1983-1989, 1979.
59. McLaughlin P, Fuller LM, Velasquez WS, et al: Stage I-II follicular lymphoma. Treatment results for 76 patients. Cancer 58:1596-1602, 1986.
60. O'Reilly S, Connors JM, Macpherson N, et al: Malignant lymphomas in the elderly. Clin Geriatr Med 13:251-263, 1997.
61. MacManus MP, Hoppe R: Is radiotherapy curative for stage I and stage II low grade follicular lymphoma? Results of a long term follow-up study of patients treated at Stanford University. J Clin Oncol 14:1282-1290, 1996.
62. Tezcan H, Vose JM, Bast M, et al: Limited stage I and II follicular non-Hodgkin's lymphoma: The Nebraska Lymphoma Study Group experience. Leuk Lymphoma 34:273-285, 1999.
63. Advani R, Rosenberg SA, Horning SJ: Stage I and II follicular non-Hodgkin's lymphoma: Long-term follow-up of no initial therapy. J Clin Oncol 22:1454-1459, 2004.
64. Connors JM, O'Reilly SE: Treatment considerations in the elderly patient with lymphoma. Hematol Oncol Clin North Am 11: 949-960, 1997.
65. Peterson BA, Petroni G, Frizzera G, et al: Prolonged single-agent versus combination chemotherapy in indolent follicular lymphomas: A study of the Cancer and Leukemia Group B. J Clin Oncol 22:5-15, 2003.
66. McLaughlin P, Hagemeister F, Romaguera J, et al: Fludarabine, mitoxantrone, and dexamethasone: An effective new regimen for indolent lymphoma. J Clin Oncol 14:1262-1272, 1996.
67. Maloney DG, Grillo-Lopez AJ, White CA, et al: IDEC-C2B8 (rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkin's lymphoma. Blood 90:2188-2195, 1997.
68. McLaughlin P, Grillo-Lopez AJ, Link BK, et al: Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: Half of patients respond to a four-dose treatment program. J Clin Oncol 16:2825-2833, 1998.
69. Feuring-Buske M, Kneba M, Unterhalt M, et al: IDEC-C2B8 (rituximab) anti-CD20 antibody therapy in relapsed advanced-stage follicular lymphomas: Results of a phase-II study of the German Low-Grade Lymphoma Study Group. Ann Hematol 79:493-500, 2000.
70. Hainsworth JD, Litchy S, Burris HA, et al: Rituximab as first-line and maintenance therapy for patients with indolent non-Hodgkin's lymphoma. J Clin Oncol 20:4261-4267, 2002.
71. Columbat P, Salles G, Brousse N, et al: Rituximab (anti-CD20 monoclonal antibody) as single first-line therapy for patients with follicular lymphoma with a low tumor burden: Clinical and molecular evaluation. Blood 97:101-106, 2001.
72. Witzig TE, Vukov AM, Habermann TM, et al: Rituximab therapy for patients with newly diagnosed, advanced-stage, follicular grade 1 non-Hodgkin's lymphoma: A phase II trial in the North Central Cancer Treatment Group. J Clin Oncol 23:1103-1108, 2005.
73. Ghielmini M, Schmitz SFH, Cogliatti SB, et al: Prolonged treatment with rituximab in patients with follicular lymphoma significantly increases event-free survival and response durauion compared with the standard weekly x 4 schedule. Blood 103:4416-4423, 2004.
74. Hainsworth JD, Litchy S, Shaffer DW, et al: Maximizing therapeutic benefit of rituximab: Maintenance therapy versus re-treatment at progression in patients with indolent non-Hodgkin's lymphoma—a randomized phase II trial of the Minnie Pearl Cancer Research Network. J Clin Oncol 23:1088-1095, 2005.
75. Czuczman MS, Weaver R, Alkuzweny B, et al: Prolonged clinical and molecular remission in patients with low-grade or follicular non-Hodgkin's lymphoma treated with rituximab plus CHOP chemotherapy: 9 year follow-up. J Clin Oncol 22:4711-4716, 2004.
76. Czuczman MS, Koryzna A, Mohr A, et al: Rituximab in combination with fludarabine chemotherapy in low-grade or follicular lymphoma. J Clin Oncol 23:694-704, 2005.
77. Forstpointer R, Dreyling M, Repp R, et al: The additon of rituximab to a combination of fludarabine, cyclophosphamide, mitoxantrone (FCM) significantly increases the response rate and prolongs survival as compared to FCM alone in patients with relapsed and refractory follicular and mantle cell lymphomas: Results of the German Low Grade Lymphoma Study Group (GLSG). Blood 104:3064-3071, 2004.
78. Hiddemann W, Kneba M, Dreyling M, et al: Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: Results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood 106:3725-3732, 2005.
79. Marcus R, Imrie K, Belch A, et al: CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma. Blood 105:1417-1423, 2005.
80. Herold M, Pasold R, Srock S, et al: Results of a prospective randomized open label phase III study comparing rituximab plus mitoxantrone, chlorambucil, prednisolone chemotherapy (R-MCP) to MCP alone in untreated advanced indolent non-Hodgkin's lymphoma (NHL) and mantle cell lymphoma (MCL) (abstract 584). Blood 104:169a, 2004.
81. Salles G, Foussard C, Nicolas M, et al: Rituximab added to aIFN + CHVP improves the outcome of follicular lymphoma patients with a high tumor burden: First analysis of the GELA-GOELAMS FL-2000 randomized trial in 359 patients (abstract 160). Blood 104:49a, 2004.
82. Hochster HS, Weller E, Gascoyne RD, et al: Maintenance rituximab after CVP results in superior clinical outcome in advanced follicular lymphoma (FL): Results of the E1496 phase III trial from the Eastern Cooperative Oncology Group and the Cancer and Leukemia Group B. Blood 106:349a, 2005.
83. Hainsworth JD, Litchy S, Morrissey LH, et al: Rituximab plus short-duration chemotherapy as first-line treatment for follicular non-Hodgkin's lymphoma: A phase II trial of the Minnie Pearl Cancer Research Network. J Clin Oncol 23:1500-1506, 2005.
84. Rohatiner AZS, Gregory WM, Peterson B, et al: Meta-analysis to evaluate the role of interferon in follicular lymphoma. J Clin Oncol 23:2215-2223, 2005.
85. Kaminski MS, Estes J, Zasadny KR, et al: Radioimmunotherapy with iodine (131) tositumomab for relapsed or refractory B-cell non-Hodgkin's lymphoma: Updated results and long-term follow-up of the University of Michigan experience. Blood 96:1259-1266, 2000.
86. Witzig TE, Gordon LI, Cabanillas F, et al: Randomized controlled trial of yttrium-90-labeled ibritumomab tiuxetan radioimmunotherapy versus rituximab immunotherapy for patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma. J Clin Oncol 20:2453-2463, 2002.
87. Kaminski MS, Tuck M, Estes J, et al: 131I-tositumomab therapy as initial treatment for follicular lymphoma. N Engl J Med 352:441-449, 2005.
88. Press OW, Unger JM, Braziel RM, et al: Phase II trial of CHOP chemotherapy followed by tositumomab/iodine-131 tositumomab for previously untreated follicular non-Hodgkin's lymphoma: Five-year follow-up of Southwest Oncology Group protocol S9911. J Clin Oncol 24:4143-4149, 2006.
89. Horning SJ: Low-grade lymphoma 1993: State of the art. Ann Oncol 5(suppl 2):S23-S27, 1994.