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Journal of Clinical Oncology, Vol 25, No 7 (March 1), 2007: pp. 915-916 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.09.5950
It Is Follicular... . So, Why CHOP?Oncology Specialists SC, Lutheran General Hospital, Park Ridge, IL To the Editor: Follicular lymphoma (FL) comprises 20% to 25% of all cases of non-Hodgkin’s lymphoma. The disease is considered incurable, although recent studies have suggested that incorporating monoclonal antibodies, specifically rituximab (R), has improved survival and outcome.1 Moreover, combining chemotherapy with R has been shown to be superior to chemotherapy alone or to a sequential approach in several prospective randomized studies.2,3 In addition, several salvage therapies have shown a promise in providing long-term remissions, such as radioimmunotherapy and antibody combinations.4,5 In summary, patients with FL have many novel therapeutic options, and it is imperative that physicians are cognizant of what choices are recommended to these patients. On behalf of the Southwest Oncology Group (SWOG), Press and colleagues6 reported their long-term follow-up data on protocol S9911. The authors confirm the results of their previous report of long-term survivors with the combination of cyclophosphamide, vincristine, doxorubicin, and prednisone (CHOP) and tositumomab/iodine I-131 tositumomab (Bexxar; GlaxoSmithKline, Philadelphia, PA).7 They report an 87% overall survival (OS) at 5.1 years of follow-up with some patients attaining molecular remissions. Based on these favorable results, the authors justify the current Intergroup trial that compares CHOP-tositumomab/iodine I-131 tositumomab versus CHOP-R. I have several reservations regarding this study and the currently open Intergroup trial. First, there has been much debate on what is the best front-line chemotherapy regimen to use in follicular and low-grade lymphomas, but no study to date has shown that the anthracycline-based approach is superior to nonanthracycline combinations. In fact, several randomized prospective studies have unequivocally confirmed that anthracyclines do not provide any additional therapeutic benefit in this patient population. On behalf of the Cancer and Leukemia Study Group B (CALGB), Peterson and colleagues8 reported their data on 228 patients who were randomly assigned to CHOP-B (cyclophosphamide, vincristine, doxorubicin, prednisone, and bleomycin) or to single-agent cyclophosphamide alone. After 10 years of follow-up, there was no difference between these two regimens in all end points, including overall survival and time-to-treatment failure. Baldini et al,9 reported on 170 patients who were randomly assigned to high-dose chlorambucil plus prednisone versus the same regimen in combination with epirubicin. Responding patients were further randomly assigned to an interferon or observation arm. There was no significant difference in responses after either induction program. Overall survival and failure-free survival were similar between both arms after 38 months of follow-up. It was concluded that epirubicin did not add any benefit to this cohort of patients.9 Only two studies suggested improved outcome in FL patients when treated with CHOP-R. The first was a small phase II trial from a single institution that reported on 38 patients and suggested sustained responses at 9 years of follow-up.10 Although the follow-up is impressive, nonetheless, this was a phase II nonrandomized trial with a limited number of patients that would make it difficult to suggest CHOP-R as the standard of care in front-line therapy of FL. In addition, it was not clear whether all patients enrolled onto this phase II study met the National Cancer Institute criteria to initiate therapy. The second study was reported by Hiddemann et al,3 who randomly assigned more than 400 patients to CHOP or CHOP-R and noted improved outcomes in the CHOP-R arm. However, this study assumed that CHOP would be the standard therapy in FL, rather than cyclophosphamide, vincristine, and prednisone (CVP) or other nonanthracycline-based regimens. The authors did not offer a clear and convincing explanation as to how that choice was made. Second, the anthracycline approach, if adapted as a front-line therapy for FLs, might have an adverse impact on patients, especially if treatment takes place at a younger patient age. Cardiac toxicity is a well-established risk factor that can occur at much later stages in life.11 Myelodysplasia is also a possible complication of anthracycline-based therapy that has been reported by several investigators.12,13 Last, it is always difficult to decide on the best control arm when designing clinical trials, but making this choice based on nonrandomized data (between anthracycline and nonanthracycline type regimens) would unfairly justify incorporating a rather aggressive and arguably unnecessary approach in individuals with low-grade disease. Are we conveying a message to oncologists that CHOP is the correct chemotherapeutic choice for FL, and that the question now lies in determining whether "cold" or "hot" antibody-type of an approach provides better outcome when combined with CHOP? I would argue that CHOP should be reserved for FL patients who are either in transformation or whose disease is behaving aggressively. Alternative options are used more often such as CVP and fludarabine-containing regimens, novantrone, and dexamethasone (FND). I propose that we pause and evaluate how we design large phase III randomized studies carefully. The current Intergroup trial is having difficulty accruing patients. The principal investigators of this study are understandably appealing to community oncologists to accrue to this trial; however, it would have been prudent to understand how community oncology (that treats more than 80% of cancer patients) approaches FL. In the absence of solid data to support the utilization of anthracyclines in FL patients, I suspect that this study will take much longer time than anticipated to accrue, but in my opinion this lag is for a few good reasons as I have outlined. AUTHOR’S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author indicated no potential conflicts of interest. REFERENCES
1. Fisher RI, LeBlanc M, Press OW, et al: New treatment options have changed the survival of patients with follicular lymphoma. J Clin Oncol 23:8447-8452, 2005 2. 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 3. 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 4. Fisher RI, Kaminski MS, Wahl RL, et al: Tositumomab and iodine-131 tositumomab produces durable complete remissions in a subset of heavily pretreated patients with low-grade and transformed non-Hodgkin’s lymphomas. J Clin Oncol 23:7565-7573, 2005 5. Gordon LI, Witzig T, Molina A, et al: Yttrium 90-labeled ibritumomab tiuxetan radioimmunotherapy produces high response rates and durable remissions in patients with previously treated B-cell lymphoma. Clin Lymphoma 5:98-101, 2004[Medline] 6. Press OW, Unger JM, Braziel RM, et al: Phase II trial of CHOP chemotherapy followed by tositumomab/iodine I-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 7. Press OW, Unger JM, Braziel RM, et al: A phase 2 trial of CHOP chemotherapy followed by tositumomab/iodine I 131 tositumomab for previously untreated follicular non-Hodgkin lymphoma: Southwest Oncology Group Protocol S9911. Blood 102:1606-1612, 2003 8. Peterson BA, Petroni GR, 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 21:5-15, 2003 9. Baldini L, Brugiatelli M, Luminari S, et al: Treatment of indolent B-Cell nonfollicular lymphomas: Final results of the LL01 randomized trial of the Gruppo Italiano per lo Studio dei Linfomi. J Clin Oncol 21:1459-1465, 2003 10. 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: Nine-year follow-up. J Clin Oncol 22:4711-4716, 2004 11. Singal PK, Iliskovic N: Doxorubicin-induced cardiomyopathy. N Engl J Med 339:900-905, 1998 12. Pedersen-Bjergaard J: Insights into leukemogenesis from therapy-related leukemia. N Engl J Med 352:1591-1594, 2005 13. Mistry AR, Felix CA, Whitmarsh RJ, et al: DNA topoisomerase II in therapy-related acute promyelocytic leukemia. N Engl J Med 352:1529-1538, 2005 Related Reply
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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