Treatment-Induced Acute Leukaemia after Major Response to Cyclophosphamide-Based Metronomic Chemotherapy in Refractory Heavily Pre-Treated Prostate Cancer

Erion Dobi, Thierry Nguyen, Christophe Borg, Xavier Pivot, Bernard Royer, Stefano Kim

Department of Medical Oncology, University Hospital of Besan?on, Besan?on, France.
Institut National de la Santé et de la Recherche Médicale-Unité Mixte de Recherche (INSERM UMR) No. 1098, Besan?on, France.

DOI: 10.4236/jct.2013.41024                

Abstract

Background: metronomic chemotherapy is based on antiangiogenic and immunologic mechanisms obtained by the administration of traditional cytotoxic drugs at lower concentration without rest periods. The low dosage induces fewer or no side effect compared to classic maximum tolerated dose administration (MTD). At present, no treatment related acute leukaemia was reported in cyclophosphamide-based metronomic chemotherapy (CMC). Case: We report the case of an 81-year-old man considered as having castration and chemo-refractory metastatic prostate cancer. CMC was started. Objective response was observed in this heavily pre-treated patient with progression free survival lasting more than 30 months. No toxicity was observed in this period and his autonomy was maintained. Finally, our patient developed a chemotherapy-induced acute myeloid leukaemia at 36th month of CMC. Conclusion: Even CMC is a well-tolerated treatment; secondary acute leukaemia is related to cumulative dose of cyclophosphamide. The benefit and the risk of long-term exposure to cyclophosphamide should be carefully balanced.

Keywords

Metronomic Chemotherapy; Cyclophosphamide; Prostate Cancer; Secondary Acute Leukemia

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	http://www.cancer.gov/dictionary?cdrid=546597
[2]	R. S. Kerbel and B. A. Kamen, “The Anti-Angiogenic Basis of Metronomic Chemotherapy,” Nature, Vol. 4, No. 6, 2004, pp. 423-436.
[3]	D. Hanahan, G. Bergers and E. Bergsland, “Less is More, Regularly: Metronomic Dosing of Cytotoxic Drugs Can Target Tumor Angiogenesis in Mice,” Journal of Clinical Investigation, Vol. 105, No. 8, 2000, pp. 1045-1047. doi:10.1172/JCI9872
[4]	S. Man, G. Bocci, G. Francia, S. K. Green, S. Jothy, D. Hanahan, et al., “Antitumor Effects in Mice of Low-Dose (Metronomic) Cyclophosphamide Administered Continuously through the Drinking Water,” Cancer Research, Vol. 62, No. 10, 2002, pp. 2731-2735.
[5]	Y. Hamano, H. Sugimoto, M. A. Soubasakos, M. Kieran, B. R. Olsen, J. Lawler, et al., “Thrombospondin-1 Associated with Tumor Microenvironment Contributes to Low-Dose Cyclophosphamide-Mediated Endothelial Cell Apoptosis and Tumor Growth Suppression,” Cancer Research, Vol. 64, No. 5, 2004, p. 1570. doi:10.1158/0008-5472.CAN-03-3126
[6]	J. E. Damber, C. Vallbo, P. Albertsson, B. Lennernas and K. Norrby, “The Anti-Tumour Effect of Low-Dose Continuous Chemotherapy May Partly Be Mediated by Thrombospondin,” Cancer Chemotherapy and Pharmacology, Vol. 58, No. 3, 2006, pp. 354-360. doi:10.1007/s00280-005-0163-8
[7]	M. E. Lutsiak, R. T. Semnani, R. De Pascalis, S. V. Kashmiri, J. Schlom and H. Sabzevari, “Inhibition of CD4(_)25_T Regulatory Cell Function Implicated in Enhanced Immune Response by Low-Dose Cyclophosphamide,” Blood, Vol. 105, No. 7, 2005, pp. 2862-2868. doi:10.1182/blood-2004-06-2410
[8]	J. Mayer, M. Krejcí, M. Doubek, Z. Pospísil, Y. Brychtová, et al., “Pulse Cyclophosphamide for Corticoid -Refractory Graft-Versus-Host Disease,” Bone Marrow Transplantation, Vol. 35, No. 7, 2005, pp. 699-705. doi:10.1038/sj.bmt.1704829
[9]	A. Reiner, T. Gernsheimer and S. J. Slichter, “Pulse Cyclophosphamide Therapy for Refractory Autoimmune Thrombocytopenic Purpura,” Blood, Vol. 85, No. 2, 1995, pp. 351-358.
[10]	N. Penel, A. Adenis and G. Bocci, “Cyclophosphamide-Based Metronomic Chemotherapy: After 10 Years of Experience, Where Do We Stand and Where Are We Going?” Critical Reviews in Oncology/Hematology, Vol. 82, No. 1, 2011, pp. 40-50.
[11]	M. Colleoni, A. Rocca, M. T. Sandri, et al., “Low-Dose Oral Methotrexate and Cyclophosphamide in Metastatic Breast Cancer: Antitumor Activity and Correlation with Vascular Endothelial Growth Factor Levels,” Annals of Oncology, Vol. 13, No. 1, 2002, pp. 73-80. doi:10.1093/annonc/mdf013
[12]	G. Bocci, M. Tuccori, U. Emmenegger, V. Liguori, A. Falcone, R. S. Kerbel, and M. Del Tacca, “Cyclophosphamide-Methotrexate ‘Metronomic’ Chemotherapy for the Palliative Treatment of Metastatic Breast Cancer. A Comparative Pharmacoeconomic Evaluation,” Annals of Oncology, Vol. 16, No. 8, 2005, pp. 1243-1252. doi:10.1093/annonc/mdi240
[13]	D. Raghavan, K. Cox, B. S. Pearson, et al., “Oral Cyclophosphamide for the Management of Hormone-Refractory Prostate Cancer,” British Journal of Urology, Vol. 72, No. 5, 1993, pp. 625-628. doi:10.1111/j.1464-410X.1993.tb16222.x
[14]	R. Lord, S. Nair, A. Schache, J. Spicer, N. Somaihah, V. Khoo and H. Pandha, “Low Dose Metronomic Oral Cyclophosphamide for Hormone Resistant Prostate Cancer: A Phase II Study,” Journal of Urology, Vol. 177, No. 6, 2007, pp. 2136-2140. doi:10.1016/j.juro.2007.01.143
[15]	T. Nelius, K. Rinard and S. Filleur, “Oral/Metronomic Cyclophosphamide-Based Chemotherapy as Option for Patients with Castration-Refractory Prostate Cancer: Review of the Literature,” Cancer Treatment Reviews, Vol. 37, No. 6, 2011, pp. 444-455. doi:10.1016/j.ctrv.2010.12.006
[16]	G. Di Lorenzo, V. Montesarchio, R. Autorino, T. Bellelli, N. Longo, et al., “Phase 1/2 Study of Intravenous Paclitaxel and Oral Cyclophosphamide in Pretreated Metastatic Urothelial Bladder Cancer Patients,” Cancer, Vol. 115, No. 3, 2009, pp. 517-523. doi:10.1002/cncr.24055
[17]	T. R. Fleming, “Objective Response Rate as a Surrogate End Point: A Commentary,” Journal of Clinical Oncology, Vol. 23, No. 22, 2005, pp. 4845-4846. doi:10.1200/JCO.2005.92.008
[18]	T. R. Fleming, “Surrogate End Points and FDA’s Accelerated Approval Process,” Health Affairs, Vol. 24, No. 1, 2005, pp. 67-78. doi:10.1377/hlthaff.24.1.67
[19]	F. S. Hodi, S. J. O’Day, D. F. McDermott, R. W. Weber, J. A. Sosman, et al., “Improved Survival with Ipilimumab in Patients with Metastatic Melanoma,” The New England Journal of Medicine, Vol. 363, No. 8, 2010, pp. 711-723. doi:10.1056/NEJMoa1003466
[20]	N. Mauritzson, M. Albin, L. Rylander, R. Billstr?m, T. Ahlgren, et al., “Pooled Analysis of Clinical and Cytogenetic Features in Treatment-Related and de Novo Adult Acute Myeloid Leukemia and Myelodysplastic Syndrome Based on a Consecutive Series of 761 Patients Analyzed 1876-1993 and on 5098 Unselected Cases Reported in the Literature 1974-2001,” Leukemia, Vol. 16, No. 12, 2002, pp. 2366-2378. doi:10.1038/sj.leu.2402713
[21]	Y. Xu, H. Wang, S. Zhou, M. Yu, X. Wang, et al., “Risk of Second Malignant Neoplasms after Cyclophosphamide-Based Chemotherapy with or without Radiotherapy for Non-Hodgkin’s Lymphoma,” Leukemia & Lymphoma, 26 November 2012, [Epub ahead of print]. doi:10.3109/10428194.2012.743657