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Patients Aged 70 Are at High Risk for Neutropenic Infection and Should Receive Hemopoietic Growth Factors When Treated With Moderately Toxic Chemotherapy

University of South Florida College of MedicineH. Lee Moffitt Cancer Center and Research InstituteTampa, FL
University of Albany College of MedicineAlbany, NY

To the Editor:We thank and congratulate your panel for a very thorough review of the utilization of hemopoietic growth factors and for the formulation of very practical guidelines.¹ For completeness, we suggest that patients aged 70 and older who are receiving moderately toxic chemotherapy (cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone [CHOP] or CHOP-like) be specifically mentioned as a special high-risk group recommended to receive primary prophylactic treatment with growth factors starting up front with the first course of chemotherapy. Our suggestion is based on the following considerations and data.

First, approximately 40% of all neoplasms occur in persons aged 70 and older, and this percentage is likely to increase with the simultaneous expansion of the older population and shrinkage of the younger population.² Within the next 20 years, persons aged 70 and older will represent the majority of patients receiving chemotherapy.

Second, in nine studies of older individuals with large-cell non-Hodgkin’s lymphoma^3-12 ( Tables 1 and 2), the risk of life-threatening neutropenia was higher than 40% in all studies. The risk of neutropenic infections varied between 21% and 47%, and the risk of infectious death varied between 5% and 30%. The majority of deaths and serious infections occurred in the first course of chemotherapy, before secondary prophylaxis with growth factors could even be considered. In the study of Gomez et al,⁶ there were 51 deaths (20%) among 260 patients receiving chemotherapy; 36 deaths occurred during the first two courses of chemotherapy, and 63% of these were after the first course. Generally the seriousness of neutropenic infections is increased, and so is the duration of hospitalization in older individuals, involving a substantially increased cost per infection.¹³ Furthermore, hospitalization of older individuals is associated with increased risk of functional dependence that may increase the cost of treatment due to expensive home care and rehabilitation.¹⁴

Fifth, and finally, the National Comprehensive Cancer Network advisory panel for the guidelines for the management of older individuals has unanimously recommended that hemopoietic growth factors be used routinely in persons aged 70 and older who are receiving moderately toxic chemotherapy.²¹

REFERENCES

1. Ozer H, Armitage JO, Bennett CL, et al: 2000 update of recommendations for the use of hematopoietic colony-stimulating factors: Evidence-based, clinical practice guidelines. J Clin Oncol 18: 3558-3585, 2000[Free Full Text]

2. Yancik RM, Ries L: Cancer and age: Magnitude of the problem, in Balducci L, Lyman GH, Ershler WB (eds): Comprehensive Geriatric Oncology. London, United Kingdom, Harwood Academic Publishers, 1998

3. Balducci L, Corcoran MB: Antineoplastic chemotherapy of the older cancer patient. Hematol Oncol Clin North Am 14: 193-212, 2000[Medline]

4. Zinzani PG, 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[Abstract/Free Full Text]

5. 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 vs CNOP chemotherapy. J Clin Oncol 13: 2530-2539, 1995[Abstract]

6. Gomez H, Mas L, 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[Abstract]

7. Tirelli U, Errante D, Van Glabbeke M, et al: CHOP is the standard regimen in patients 70 years of age with intermediate and high grade Non-Hodgkin’s lymphoma: Results of a randomized study of the European Organization for the Research and Treatment of Cancer Lymphoma Cooperative Study. J Clin Oncol 16: 27-34, 1998[Abstract/Free Full Text]

8. Bastion Y, Blay J-Y, 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[Abstract]

9. 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 2250-2257, 1993

10. Armitage JO, Potter JF: Aggressive chemotherapy for diffuse histiocytic lymphoma in the elderly. J Am Geriatr Soc 32: 269-273, 1984[Medline]

11. Bjorkholm M, Osby E, Hagberg H, et al: Randomized trial of r-metHu granulocyte colony stimulating factors as adjunct to CHOP or CNOP treatment of elderly patients with aggressive non-Hodgkin’s lymphoma. Proc Am Soc Hematol 94: 599, 1999 (suppl, abstr 2665)

12. Bertini M, Freilone R, Vitolo U, et al: The treatment of elderly patients with aggressive non-Hodgkin’s lymphomas: Feasibility and efficacy of an intensive multidrug regimen. Leukemia Lymphoma 22: 483-493, 1996

13. Green J: Infections in the older cancer patient, in Balducci L, Lyman GH, Ershler WB (ed): Comprehensive Geriatric Oncology. London, United Kingdom, Harwood Academic Publishers, 1998, pp 733-774

14. Leape LL, Brennan TA, Laird NM, et al: The nature of adverse events in hospitalized patients: Results of the Harvard Medical Practice Study II. N Engl J Med 324: 377-384, 1991[Abstract]

15. 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: 127-132, 1994 (suppl 2)[Abstract/Free Full Text]

16. Balducci L, Hardy CL, Lyman GH: Hemopoietic reserve in older cancer patients: Clinical and economical considerations. Cancer Control J Moffitt Cancer Ctr 7: 539-547, 2000

17. Rowe JM, Andersen JW, Mazza JJ, et al: Randomized placebo-controlled phase III study of granulocyte-macrophage colony stimulating factor in adult patients (> 55-70 years with acute myelogenous leukemia: A study of the Eastern Cooperative Oncology Group (E1490). Blood 86: 457-462, 1995[Abstract/Free Full Text]

18. Heil D, Hoelzer D, Sanz MA, et al: A randomized double blind placebo controlled phase III study of filgrastim in remission induction and consolidation therapy for patients with "de novo" acute myeloid leukemia: The International Acute Leukemia Study Group. Blood 90: 4710-4718, 1997[Abstract/Free Full Text]

19. 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[Abstract/Free Full Text]

20. 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[Abstract/Free Full Text]

21. Balducci L, Yates J: General guidelines for the management of older patients with cancer. NCCN Proceeding. Oncology 14: 221-227, 2000[Medline]

Response

Chairman, ASCO Colony-Stimulating Factor Guideline Expert PanelCancer CenterUniversity of Oklahoma Health Sciences CenterOklahoma City, OK

In Reply:We appreciate the favorable response of Drs Balducci and Lyman to our article updating the American Society of Clinical Oncology’s (ASCO’s) hematopoietic growth factor guidelines. In addition, we fully concur with their suggestion that, in settings in which the risk of febrile neutropenia after chemotherapy exceeds 40%, primary prophylaxis with hematopoietic growth factors is now the standard of care. That setting clearly applies in those studies cited by Balducci and Lyman, which focussed on patients over age 70 receiving moderate-dose chemotherapy, primarily CHOP or CHOP-like regimens for non-Hodgkin’s lymphoma.

As noted in the 2000 update of the guidelines, such patients may fall under the category of "special circumstances" and would therefore be considered for primary prophylaxis with any chemotherapy regimen likely to cause myelosuppression, especially when administered with curative intent.¹ This category of "special circumstances" is not meant to be restrictive, but rather to encourage clinical judgment by the treating oncologist who has the experience to recognize those individuals and chemotherapy regimens most likely to lead to life-threatening febrile neutropenia among his or her patient population.

Balducci and Lyman emphasize that the proportion of patients over age 70 is steadily increasing, and that the incidence of some tumors, such as non-Hodgkin’s lymphoma, is increasing as well. Coupled with the development of novel myelosuppressive agents and the tendency to diagnose and treat more such patients with curative intent than in past decades, it is evident that a steadily growing elderly population of cancer patients is at risk for febrile neutropenia and therefore would be excellent candidates for primary prophylaxis with hematopoietic growth factors, as recommended in the 2000 ASCO guidelines.

REFERENCES

1. Ozer H, Armitage JO, Bennett CL, et al: 2000 update of recommendations for the use of hematopoietic colony-stimulating factors: Evidence-based, clinical practice guidelines. J Clin Oncol 18: 3558-3585, 2000

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