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Journal of Clinical Oncology, Vol 23, No 6 (February 20), 2005: pp. 1328-1329 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.05.128
Potential Antiretroviral Drug Interactions With Cyclophosphamide, Doxorubicin, and EtoposideDepartment of Oncology, Chelsea and Westminster Hospital, London, United Kingdom To the Editor: We read with interest the results of the E1494 trial.1 Since 1998, we have treated 46 consecutive individuals (median CD4 cell count, 190/mm3; range, 0 to 636/mm3) with AIDS-related non-Hodgkin's lymphoma with infusional cyclophosphamide, doxorubicin, and etoposide (CDE) chemotherapy and concomitant highly active antiretroviral therapy (HAART). In this cohort, the complete response is 51% (95% CI, 36% to 64%), the median survival is 26 months, and the 2-year overall survival is 61% (95% CI, 47% to 76%), comparable with the E1494 data. There are additional advantages of concomitant HAART, compared with the interruption of antiretroviral therapy during chemotherapy as used in the etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (EPOCH) regimen.2 We have previously demonstrated that the CD4 cell count declines by 50% during treatment with concomitant HAART and chemotherapy but recovers rapidly within 1 month of completing chemotherapy. The CD8 and natural killer (CD16 and CD56) cell counts follow a similar profile, whereas the B cell (CD19) counts recover more slowly but are restored to prechemotherapy levels by 3 months. There was no change in the HIV-1 mRNA viral load during the chemotherapy.3 In contrast, profound and prolonged T-cell depletion was demonstrated for patients receiving chemotherapy in the pre-HAART era4 and is recorded after treatment with the EPOCH regimen, during which HAART is suspended.2 Therefore, one potential pitfall of concomitant HAART therapy that was not directly addressed in the article is the potential for drug interactions.5,6 Certainly when Dr Sparano first described the concomitant administration of saquinavir with CDE he noted a higher incidence of mucositis.7 Both non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs) are extensively metabolized by the cytochrome p450 system and hence there may be competitive pharmacokinetic drug interactions when they are administered concomitantly with other drugs metabolized via the same pathway.8 Protease inhibitors may modify the metabolism of cytotoxic drugs via inhibition of the CYP3A4 enzyme, and indeed pharmacokinetic studies have demonstrated a modest delay in the clearance of cyclophosphamide in patients receiving indinavir compared with historical controls, although no increase in hematologic toxicity was observed.9 Another potential interaction arises because protease inhibitors are substrates as well as inhibitors of the drug transporter P-glycoprotein, an efflux pump that transports a wide range of structurally unrelated drugs, such as PIs and anthracyclines.10-12 Indeed, one application of these pharmacokinetic interactions now used in HIV treatment is pharmacokinetic boosting, whereby metabolic interactions are exploited to reduce peaks and troughs.13 There has been increasing enthusiasm for the use of NNRTI-based HAART as first-line therapy for HIV disease and this may lead to fewer drug interactions than PI-based regimens. To examine this hypothesis, we compared the incidence of neutropenia and infection resulting from PI- and NNRTI-containing HAART regimens with the incidence resulting from the CDE regimen. In this study, concomitant HAART was prescribed with CDE according to published guidelines, which have evolved with the introduction of antiretroviral drugs14,15
Our 46 patients received a total of 190 cycles of CDE: 48 cycles with a PI-containing HAART (11 patients) and 142 cycles (35 patients) with PI-sparing HAART regimens. The concomitant HAART treatment was triple nucleoside therapy (n = 3), NNRTI with dual nucleoside therapy (n = 32), PI with dual nucleoside therapy (n = 9), and both NNRTI and PI with nucleosides (n = 2). Cancer Toxicity Criteria grade 3 or 4 infections requiring hospitalization were recorded for a total of 58 of 190 (31%) cycles of CDE: 23 of 48 cycles (48%) when PIs were prescribed and 35 of 142 cycles (25%) with concomitant PI-sparing HAART ( The finding of significantly increased neutropenia in those individuals receiving CDE and PIs supports previous findings of interactions between these drugs and emphasizes the need for caution and regular monitoring when prescribing these drugs together. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. REFERENCES
1. Sparano JA, Lee S, Chen MG, et al: Phase II trial of infusional cyclophosphamide, doxorubicin, and etoposide in patients with HIV-associated non-Hodgkin's lymphoma: An Eastern Cooperative Oncology Group Trial (E1494). J Clin Oncol 22:1491-1500, 2004 2. Little R, Pearson D, Steinberg S, et al: Dose-adjusted EPOCH chemotherapy in previously untreated HIV-associated non-Hodgkin's lymphoma. Proc Am Soc Clin Oncol 18:10a, 1999 (abstr 33) 3. Powles T, Imami N, Nelson M, et al: Effects of combination chemotherapy and highly active antiretroviral therapy on immune parameters in HIV-1 associated lymphoma. AIDS 16:531-536, 2002[CrossRef][Medline] 4. Zanussi S, Simonelli C, D'Andrea M, et al: The effects of antineoplastic chemotherapy on HIV disease. AIDS Res Hum Retroviruses 12:1703-1707, 1996[Medline] 5. Fichtenbaum CJ, Gerber JG: Interactions between antiretroviral drugs and drugs used for the therapy of the metabolic complications encountered during HIV infection. Clin Pharmacokinet 41:1195-1211, 2002[CrossRef][Medline] 6. Fichtenbaum CJ, Gerber JG, Rosenkranz SL, et al: Pharmacokinetic interactions between protease inhibitors and statins in HIV seronegative volunteers: ACTG Study A5047. AIDS 16:569-577, 2002[CrossRef][Medline] 7. Sparano JA, Wiernik PH, Hu X, et al: Saquinavir enhances the mucosal toxicity of infusional cyclophosphamide, doxorubicin and etoposide in patients with HIV-associated non-Hodgkin's lymphoma. Med Oncol 15:50-57, 1998[Medline] 8. Smith PF, DiCenzo R, Morse GD: Clinical pharmacokinetics of non-nucleoside reverse transcriptase inhibitors. Clin Pharmacokinet 40:893-905, 2001[CrossRef][Medline]
9. Ratner L, Lee J, Tang S, et al: Chemotherapy for human immunodeficiency virus-associated non-Hodgkin's lymphoma in combination with highly active antiretroviral therapy. J Clin Oncol 19:2171-2178, 2001
10. Hochman JH, Chiba M, Yamazaki M, et al: P-glycoprotein-mediated efflux of indinavir metabolites in Caco-2 cells expressing cytochrome P450 3A4. J Pharmacol Exp Ther 298:323-330, 2001 11. Fellay J, Marzolini C, Meaden ER, et al: Response to antiretroviral treatment in HIV-1-infected individuals with allelic variants of the multidrug resistance transporter 1: A pharmacogenetics study. Lancet 359:30-36, 2002[CrossRef][Medline] 12. Stebbing J, Bower M: What can oncologists learn from HIV? Lancet Oncol 4:438-445, 2003[CrossRef][Medline] 13. Rathbun RC, Rossi DR: Low-dose ritonavir for protease inhibitor pharmacokinetic enhancement. Ann Pharmacother 36:702-706, 2002[Abstract] 14. British HIV: Association guidelines for antiretroviral treatment of HIV seropositive individuals: BHIVA Guidelines Co-ordinating Committee. Lancet 349:1086-1092, 1997[CrossRef][Medline] 15. BHIVA Executive Committee, BHIVA Writing Committee: British HIV Association (BHIVA) guidelines for the treatment of HIV-infected adults with antiretroviral therapy. HIV Med 2:276-313, 2001
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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2 P = .0025). Cancer Toxicity Criteria grade 4 neutropenia was recorded for 79 of 190 cycles (42%); 26 of 48 (54%) when PIs were prescribed and 53 of 138 (38%) with concomitant PI-sparing HAART (
