Patterns of Chemotherapy Administration in Patients With Intermediate-Grade Non-Hodgkin’s Lymphoma

Dr. Picozzi and colleagues havepresented an analysis from the Oncology Practice Patterns Study that examinedpatterns of care for patients with intermediate-grade non-Hodgkin’s lymphoma.Patients in their study were treated off protocol in managed-care practices, bycommunity oncologists or in the academic setting. More than 40% of patientsreceived a chemotherapy regimen that did not contain an anthracycline ormitoxantrone (Novantrone), or chemotherapy doses that were significantly lowerthan optimal. The authors appear to have made every effort to validateinformation obtained from the data collection forms, and we can assume thattheir results reflect "real world" standards of practice. We are nottold whether results differed for patients treated in academic vsprivate-practice settings, and it would be interesting to know if suchdifferences exist.

As might be expected, more than 50% of chemotherapy dosedelays and reductions for patients receiving CHOP (cyclophosphamide [Cytoxan,Neosar], doxorubicin HCl, vincristine [Oncovin], prednisone) or CNOP (cyclophosphamide,mitoxantrone, vincristine, prednisone) were related to neutropenia. However, itis disturbing that the reasons for 10% of the dose delays and 21% of the dosereductions could not be identified in the medical record. There are no firmguidelines regarding dose modifications for CHOP chemotherapy, and it is notsurprising that there are wide variations in how physicians alter chemotherapydosage according to blood counts.

Considerations About Dose Reductions

The authors of this study reference the article by McKelveyet al from the Southwest Oncology Group (SWOG) as the standard for CHOPadministration.[1] That article recommends dose reductions of at least 20% fordoxorubicin and cyclophosphamide in patients whose white blood cell count fallsbelow 1,500/mm³ or whose platelet count falls below 50,000/mm³ during thepreceding cycle of therapy. Other articles detailing methods of CHOPchemotherapy administration simply refer to the original reports[2,3] orrecommend different schedules for dose modifications.[4,5] Standard textbooksfail to present recommendations regarding chemotherapy dose reductions forneutropenic patients.[6-9] This lack of consensus on dose modifications is notsurprising, however, in light of numerous variations in the CHOP regimenitself.[10]

Dr. Picozzi and coauthors note that the main reason forinitiating chemotherapy at reduced doses was advanced age. Elderly patients withaggressive non-Hodgkin’s lymphoma frequently have adverse prognostic factorsat presentation. They may experience inferior outcomes because of increasedtoxicity from chemotherapy, higher relapse rates, or higher death rates fromcardiovascular disease. Treatment-related deaths in elderly patients receivingCHOP chemotherapy may be associated with performance status, rather thanchronologic age.[11] Most experts would not recommend arbitrary dose reductionsbased on age alone. However, this analysis does not allow us to determine theprecise reasons for initiating chemotherapy at a reduced dose, and it ispossible that decisions to do so were correct for individual patients.

It is likely that concerns about doxorubicin-inducedcardiotoxicity were also responsible for dose reductions in elderly patients andthose with a history of cardiac disease. These characteristics are associatedwith a higher risk of cardiotoxicity.[12] Nevertheless, it is unknown whetherthe risk of cardiac toxicity is greater than the increased risk of death fromlymphoma in patients who receive attenuated doses of anthracylines because ofasymptomatic cardiac disease or reductions in cardiac ejection fraction.

Growth Factors and Nonstandard Regimens

Hematopoietic growth factors were used at least once in morethan 50% of patients, including 11% who received primary prophylaxis. Guidelinesfrom the American Society of Clinical Oncology do not recommend primary use ofhematopoietic growth factors unless the expected incidence of febrileneutropenia reaches 40%.[13] Patients in this analysis who received full-dosechemotherapy and were older than age 65 or had cardiac comorbidity would meetthis threshold. Nevertheless, overall survival benefits have not beendemonstrated with this approach, or with the secondary use of growth factors tomaintain dose intensity.[13]

It is perhaps most surprising that 14% of patients werestarted on a chemotherapy regimen that did not contain an anthracycline ormitoxantrone. The use of these nonstandard regimens was not related to advancedage. Randomized trials comparing CHOP or CHOP-like regimens with othertreatments for elderly patients with aggressive lymphomas have found survivaladvantages associated with the use of anthracycline-based chemotherapyregimens.[14,15] Again, this analysis does not explain exactly why physicianschose to use these nonstandard regimens.

Conclusions

The results reported by Picozzi et al reflect contemporarypractices from a population-based perspective. This was the goal of the analysisand the results should not necessarily be considered good or bad, despite thehigh rate of deviation from standard schedules of CHOP and similar regimens. Theauthors note that these patients may have had characteristics that made themineligible for trials, or they may have had other adverse prognostic factors.For example, the median age of patients was 66.2 years, which was a decadegreater than patients in the SWOG trial.[2] Furthermore, this analysis does notallow us to determine whether patients would have achieved better outcomeswithout the alterations in chemotherapy administration. As the authors note,this is a question that requires active investigation. If the answer is yes,then the findings of this analysis are very disturbing.

References:

1. McKelvey EM, Gottlieb JA, Wilson HE, et al:Hydroxyldaunomycin (Adriamycin) combination chemotherapy in malignant lymphoma.Cancer 38:1484-1493, 1976.

2. Fisher RI, Gaynor ER, Dahlberg S, et al: Comparison of astandard regimen (CHOP) with three intensive chemotherapy regimens for advancednon-Hodgkin’s lymphoma. N Engl J Med 328:1002-1006, 1993.

3. Jerkeman M, Anderson H, Cavallin-Ståhl E, et al: CHOP vsMACOP-B in aggressive lymphoma—a Nordic Lymphoma Group randomised trial. AnnOncol 10:1079-1086, 1999.

4. Khaled HM, Zekri ZK, Mokhtar N, et al: A randomized EPOCHvs CHOP front-line therapy for aggressive non-Hodgkin’s lymphoma patients:Long-term results. Ann Oncol 10:1489-1492, 1999.

5. Cooper IA, Wolf MM, Robertson TI, et al: Randomizedcomparison of MACOP-B with CHOP in patients with intermediate-grade non-Hodgkin’slymphoma. J Clin Oncol 12:769-778, 1994.

6. DeVita VT, Hellman S, Rosenberg SA: Cancer: Principles& Practice of Oncology, 6th ed. Philadelphia, Lippincott Williams &Wilkins, 2001.

7. Hoffman R, Benz EJ, Shattil SJ, et al: Hematology: BasicPrinciples and Practice, 3rd ed. Philadelphia, Churchill Livingstone, 2000.

8. Beutler E, Lichtman MA, Coller BS, et al: Hematology, 6thed. New York, McGraw-Hill, 2001.

9. Canellos GP, Lister TA, Sklar JL: The Lymphomas.Philadelphia, WB Saunders, 1998.

10. Moreno A, Colon-Otero G, Solberg LA: The prednisonedosage in the CHOP chemotherapy regimen for non-Hodgkin’s lymphomas (NHL): Isthere a standard? Oncologist 5:238-249, 2000.

11. Gómez H, Hidalgo M, Casanova L, et al: Risk factors fortreatment-related death in elderly patients with aggressive non-Hodgkin’slymphoma: Results of a multivariate analysis. J Clin Oncol 16:2065-2069, 1998.

12. Singal PK, Iliskovic N: Doxorubicin-inducedcardiomyopathy. N Engl J Med 13:900-905, 1998.

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

14. Tirelli U, Errante D, Van Glabbeke M, et al: CHOP is thestandard regimen in patients ³ 70 years of age with intermediate-grade andhigh-grade non-Hodgkin’s lymphoma: Results of a randomized study of theEuropean Organization for Research and Treatment of Cancer Lymphoma CooperativeStudy Group. J Clin Oncol 16:27-34, 1998.

15. Bastion Y, Blay J-Y, Divine M, et al: Elderly patientswith aggressive non-Hodgkin’s lymphoma: Disease presentation, response totreatment, and survival-a Groupe d’Etude des Lymphomes de l’Adulte studyon 453 patients older than 69 years. J Clin Oncol 15:2945-2953, 1997.