Thrombocytopenia is a common problem in cancer patients. Aside from bleeding risk, thrombocytopenia limits chemotherapy dose and frequency. In evaluating thrombocytopenic cancer patients, it is important to assess for other causes of thrombocytopenia, including immune thrombocytopenia, coagulopathy, infection, drug reaction, post-transfusion purpura, and thrombotic microangiopathy. The incidence of chemotherapy-induced thrombocytopenia varies greatly depending on the treatment used; the highest rates of this condition are associated with gemcitabine- and platinum-based regimens. Each chemotherapy agent differs in how it causes thrombocytopenia: alkylating agents affect stem cells, cyclophosphamide affects later megakaryocyte progenitors, bortezomib prevents platelet release from megakaryocytes, and some treatments promote platelet apoptosis. Thrombopoietin is the main regulator of platelet production. In numerous studies, recombinant thrombopoietin raised the platelet count nadir, reduced the need for platelet transfusions, reduced the duration of thrombocytopenia, and allowed maintenance of chemotherapy dose intensity. Two thrombopoietin receptor agonists now available, romiplostim and eltrombopag, are potent stimulators of platelet production. Although few studies have been completed to demonstrate their ability to treat chemotherapy-induced thrombocytopenia, these agents may be useful in treating this condition in some situations. Chemotherapy dose reduction and platelet transfusions remain the major treatments for affected patients.
Treatment of Chemotherapy-Induced Thrombocytopenia
The response to significant chemotherapy-induced thrombocytopenia has not been codified in guidelines, and there are no studies to guide the appropriate approach to management of patients with this condition. Much depends upon the underlying treatment goals of the individual cancer patient; different levels of risk assessment need to be brought into play for patients being treated for cure vs those being treated for palliation. Overall, it is reasonable when confronted with chemotherapy-induced thrombocytopenia first to assess the underlying need for chemotherapy and the goals of treatment for that particular patient. A clinical assessment of bleeding risk for patients is also important to undertake, especially if patients are receiving anticoagulant drugs or other therapies that might increase bleeding. What follows is a synthesis of the data and the author’s personal experiences over the past 4 decades.
• If possible, treat any other underlying cause of thrombocytopenia: stop antibiotics, treat infection, and control coagulopathy.
• Reduce chemotherapy dose and/or frequency or alter the chemotherapy regimen, especially if chemotherapy is not standard or not of curative intent.
• Platelet transfusion support should be used if maintenance of dose intensity is vital for response or survival. Prophylactic platelet transfusions are indicated if bleeding occurs or if platelet counts are < 10,000/µL (or with platelet counts < 20,000/µL if the patient is febrile).[93,94] In the outpatient setting, however, this transfusion trigger needs to be reconsidered; transfusing at higher platelet counts on the Friday before a long weekend has its advantages.
• Antifibrinolytic agents such as epsilon-aminocaproic acid or tranexamic acid have been used in some thrombocytopenic cancer patients to decrease the bleeding risk when platelet transfusions did not work.[95-97] Total daily doses of 2–24 g (mean, 6 g) of epsilon-aminocaproic acid given in 3 or 4 divided doses have been used. Tranexamic acid doses of 4–6 g/d given as 3 or 4 divided doses have also been studied. However, the use of such agents in cancer patients is fraught with difficulty because antifibrinolytic agents can exacerbate the underlying increased risk of thrombosis.
• Despite the lack of US Food and Drug Administration (FDA) approval for these agents, thrombopoietin receptor agonists can be considered in patients who cannot be supported by platelet transfusions and for whom the maintenance of dose intensity is crucial for remission or survival. In this setting, this author has used romiplostim at 2–3 µg/kg weekly, or 50–75 mg of eltrombopag daily to maintain platelet counts over 100,000/µL, in order to allow continuation of chemotherapy (Figure 6). Thrombopoietin receptor agonists would be started only when the patient’s platelet count had failed to recover to levels > 100,000/µL before the next scheduled chemotherapy.
• Thrombopoietin receptor agonists should not be used in lieu of platelet transfusions. Since the platelet count only begins to rise 5 days after TPO administration, with maximal effect 10–14 days later, platelet transfusions should not be withheld if they are indicated.
• The use of vincristine, rituximab, prednisone, IVIG, splenectomy, or anti-D immunoglobulin is rarely justified in patients with chemotherapy-induced thrombocytopenia, despite their widespread use and efficacy in ITP.
• The use of IL-11 is rarely justified, given its significant side effects. Recombinant IL-11 (oprelvekin) has been shown to reduce the need for platelet transfusions from 96% to 70% of patients who had been transfused with platelets in a prior cycle and who then received additional chemotherapy. This drug has been FDA-approved for the prevention of thrombocytopenia with chemotherapy, but it has too many adverse effects to make it an acceptable treatment for most patients.
Thrombocytopenia in the Cancer Patient: Costs of Treatment
The direct costs of treating thrombocytopenia in the cancer patient can be readily assessed. For example, a platelet transfusion costs about $3,000 per event (calculated as the cost of a single apheresis product or a pool of six random donor concentrates) and a transfused unit of RBCs costs about $1,300–$3,500. A week of antifibrinolytic treatment with epsilon aminocaproic acid (6 g/d) is $280, and with tranexamic acid (6 g/d) is $290. A week of thrombopoietin receptor agonist treatment with romiplostim (2 µg/kg/wk) is about $1,400, and with eltrombopag (75 mg/d) is about $2,000. (Data are from Partners Healthcare Center for Drug Policy.) Oprelvekin at 50 µg/kg daily costs $2,366 (average wholesale price) for a week of treatment.
However, no attempt has been made to address the overall costs of thrombocytopenia and its treatment in patients with cancer. The simple issues of chemotherapy delay and dose reduction carry with them costs in material and space utilization, while the larger issue of reduced dose intensity in some settings translates into the costs of life lost.
While guidelines exist to guide the rational administration of platelet transfusions, there are few data and no established guidelines to guide rational reduction in chemotherapy dose or frequency, which is often the first response to treating thrombocytopenia in the setting of cancer.
Treatment of the thrombocytopenic cancer patient remains a challenge. If no other underlying factor can be modified, the only treatments are platelet transfusion and dose modification of chemotherapy or radiation therapy. Future studies should target methods to mitigate thrombocytopenia by protection of the bone marrow or the rational use of thrombopoietic agents. Guidelines need to be developed that carefully assess the risks and benefits of current and future treatments for our patients with thrombocytopenia.
Financial Disclosure: Dr. Kuter is a consultant to 3SBio, Amgen, Kirin, and Pfizer. He receives research funding from Bristol-Myers Squibb, GlaxoSmithKline, and Ono.
1. Kuter DJ. General aspects of thrombocytopenia, platelet transfusions, and thrombopoietic growth factors. In: Kitchens C, Kessler C, Konkle B, editors. Consultative Hemostasis and Thrombosis. Philadelphia: Elsevier Saunders; 2013. p. 103-16.
2. Kuter DJ. Milestones in understanding platelet production: a historical overview. Br J Haematol. 2014;165:248-58.
3. Kuter DJ, Begley CG. Recombinant human thrombopoietin: basic biology and evaluation of clinical studies. Blood. 2002;100:3457-69.
4. Kuter DJ. The biology of thrombopoietin and thrombopoietin receptor agonists. Int J Hematol. 2013;98:10-23.
5. Kuter DJ. What is the potential for thrombopoietic agents in acute leukemia? Best Pract Res Clin Haematol. 2011;24:553-8.
6. Dimou M, Angelopoulou MK, Pangalis GA, et al. Autoimmune hemolytic anemia and autoimmune thrombocytopenia at diagnosis and during follow-up of Hodgkin lymphoma. Leuk Lymphoma. 2012;53:1481-7.
7. Hauswirth AW, Skrabs C, Schutzinger C, et al. Autoimmune thrombocytopenia in non-Hodgkin’s lymphomas. Haematologica. 2008;93:447-50.
8. Zent CS, Ding W, Reinalda MS, et al. Autoimmune cytopenia in chronic lymphocytic leukemia/small lymphocytic lymphoma: changes in clinical presentation and prognosis. Leuk Lymphoma. 2009;50:1261-8.
9. Kyasa MJ, Parrish RS, Schichman SA, Zent CS. Autoimmune cytopenia does not predict poor prognosis in chronic lymphocytic leukemia/small lymphocytic lymphoma. Am J Hematol. 2003;74:1-8.
10. Hodgson K, Ferrer G, Pereira A, et al. Autoimmune cytopenia in chronic lymphocytic leukaemia: diagnosis and treatment. Br J Haematol. 2011;154:14-22.
11. Grewal PK, Aziz PV, Uchiyama S, et al. Inducing host protection in pneumococcal sepsis by preactivation of the Ashwell-Morell receptor. Proc Natl Acad Sci USA. 2013;110:20218-23.
12. Grewal PK, Uchiyama S, Ditto D, et al. The Ashwell receptor mitigates the lethal coagulopathy of sepsis. Nat Med. 2008;14:648-55.
13. Von Drygalski A, Curtis BR, Bougie DW, et al. Vancomycin-induced immune thrombocytopenia. N Engl J Med. 2007;356:904-10.
14. Kuter DJ, Tillotson GS. Hematologic effects of antimicrobials: focus on the oxazolidinone, linezolid. Pharmacotherapy. 2001;21:1010-3.
15. Wang Y, Smith KP. Safety of alternative antiviral agents for neonatal herpes simplex virus encephalitis and disseminated infection. J Pediatr Pharmacol Ther. 2014;19:72-82.
16. Danziger-Isakov L, Mark Baillie G. Hematologic complications of anti-CMV therapy in solid organ transplant recipients. Clin Transplant. 2009;23:295-304.
17. Reese JA, Li X, Hauben M, et al. Identifying drugs that cause acute thrombocytopenia: an analysis using 3 distinct methods. Blood. 2010;116:2127-33.
18. Levi M. Cancer and DIC. Haemostasis. 2001;31(suppl 1):47-8.
19. Saba HI, Morelli GA, Saba RI. Disseminated intravascular coagulation (DIC) in cancer. Cancer Treat Res. 2009;148:137-56.
20. Kuter DJ, Rosenberg RD. Disorders of hemostasis. In: Beck WS. Hematology. Cambridge, MA: MIT Press; 1991. p. 577-98.
21. Humphreys BD, Sharman JP, Henderson JM, et al. Gemcitabine-associated thrombotic microangiopathy. Cancer. 2004;100:2664-70.
22. Schwartz J, Winters JL, Padmanabhan A, et al. Guidelines on the use of therapeutic apheresis in clinical practice-evidence-based approach from the Writing Committee of the American Society for Apheresis: the sixth special issue. J Clin Apher. 2013;28:145-284.
23. Jodele S, Fukuda T, Vinks A, et al. Eculizumab therapy in children with severe hematopoietic stem cell transplantation-associated thrombotic microangiopathy. Biol Blood Marrow Transplant. 2014;20:518-25.
24. Shimazaki C, Inaba T, Uchiyama H, et al. Serum thrombopoietin levels in patients undergoing autologous peripheral blood stem cell transplantation. Bone Marrow Transplant. 1997;19:771-5.
25. Ten Berg MJ, van den Bemt PM, Shantakumar S, et al. Thrombocytopenia in adult cancer patients receiving cytotoxic chemotherapy: results from a retrospective hospital-based cohort study. Drug Saf. 2011;34:1151-60.
26. Wu Y, Aravind S, Ranganathan G, et al. Anemia and thrombocytopenia in patients undergoing chemotherapy for solid tumors: a descriptive study of a large outpatient oncology practice database, 2000-2007. Clin Ther. 2009;31(Pt 2):2416-32.
27. Machlus KR, Thon JN, Italiano JE, Jr. Interpreting the developmental dance of the megakaryocyte: a review of the cellular and molecular processes mediating platelet formation. Br J Haematol. 2014;165:227-36.
28. Dowling MR, Josefsson EC, Henley KJ, et al. Platelet senescence is regulated by an internal timer, not damage inflicted by hits. Blood. 2010;116:1776-8.
29. Josefsson EC, James C, Henley KJ, et al. Megakaryocytes possess a functional intrinsic apoptosis pathway that must be restrained to survive and produce platelets. J Exp Med. 2011;208:2017-31.
30. Josefsson EC, White MJ, Dowling MR, Kile BT. Platelet life span and apoptosis. Methods Mol Biol. 2012;788:59-71.
31. White MJ, Schoenwaelder SM, Josefsson EC, et al. Caspase-9 mediates the apoptotic death of megakaryocytes and platelets, but is dispensable for their generation and function. Blood. 2012;119:4283-90.
32. Berger G, Hartwell DW, Wagner DD. P-Selectin and platelet clearance. Blood. 1998;92:4446-52.
33. Fitchen JH, Deregnaucourt J, Cline MJ. An in vitro model of hematopoietic injury in chronic hypoplastic anemia. Cell Tissue Kinet. 1981;14:8590.
34. McManus PM, Weiss L. Busulfan-induced chronic bone marrow failure: changes in cortical bone, marrow stromal cells, and adherent cell colonies. Blood. 1984;64:1036-41.
35. DeZern AE, Petri M, Drachman DB, et al. High-dose cyclophosphamide without stem cell rescue in 207 patients with aplastic anemia and other autoimmune diseases. Medicine (Baltimore). 2011;90:89-98.
36. Fitzgerald M, Fraser C, Webb I, et al. Normal hematopoietic stem cell function in mice following treatment with bortezomib. Biol Blood Marrow Transplant. 2003;3:193.
37. Lonial S, Waller EK, Richardson PG, et al. Risk factors and kinetics of thrombocytopenia associated with bortezomib for relapsed, refractory multiple myeloma. Blood. 2005;106:3777-84.
38. Zhang H, Nimmer PM, Tahir SK, et al. Bcl-2 family proteins are essential for platelet survival. Cell Death Differ. 2007;14:943-51.
39. Leach M, Parsons RM, Reilly JT, Winfield DA. Autoimmune thrombocytopenia: a complication of fludarabine therapy in lymphoproliferative disorders. Clin Lab Haematol. 2000;22:175-8.
40. Hegde UP, Wilson WH, White T, Cheson BD. Rituximab treatment of refractory fludarabine-associated immune thrombocytopenia in chronic lymphocytic leukemia. Blood. 2002;100:2260-2.
41. de Sauvage FJ, Carver-Moore K, Luoh SM, et al. Physiological regulation of early and late stages of megakaryocytopoiesis by thrombopoietin. J Exp Med. 1996;183:651-6.
42. de Sauvage FJ, Villeval JL, Shivdasani RA. Regulation of megakaryocytopoiesis and platelet production: lessons from animal models. J Lab Clin Med. 1998;131:496-501.
43. Carver-Moore K, Broxmeyer HE, Luoh SM, et al. Low levels of erythroid and myeloid progenitors in thrombopoietin- and c-mpl-deficient mice. Blood. 1996;88:803-8.
44. Grozovsky R, Begonja AJ, Liu K, et al. The Ashwell-Morell receptor regulates hepatic thrombopoietin production via JAK2-STAT3 signaling. Nat Med. 2015;21:47-54.
45. Yang C, Li J, Kuter DJ. The physiological response of thrombopoietin (c-Mpl ligand) to thrombocytopenia in the rat. Br J Haematol. 1999;105:478-85.
46. Peck-Radosavljevic M, Wichlas M, Zacherl J, et al. Thrombopoietin induces rapid resolution of thrombocytopenia after orthotopic liver transplantation through increased platelet production. Blood. 2000;95:795-801.
47. Emmons RV, Reid DM, Cohen RL, et al. Human thrombopoietin levels are high when thrombocytopenia is due to megakaryocyte deficiency and low when due to increased platelet destruction. Blood. 1996;87:4068-71.
48. Kuter DJ. The physiology of platelet production. Stem Cells. 1996;14:88-101.
49. Ballem PJ, Belzberg A, Devine DV, et al. Kinetic studies of the mechanism of thrombocytopenia in patients with human immunodeficiency virus infection. N Engl J Med. 1992;327:1779-84.
50. Gernsheimer T, Stratton J, Ballem PJ, Slichter SJ. Mechanisms of response to treatment in autoimmune thrombocytopenic purpura. N Engl J Med. 1989;320:974-80.
51. Franke K, Gassmann M, Wielockx B. Erythrocytosis: the HIF pathway in control. Blood. 2013;122:1122-8.
52. Muraoka K, Ishii E, Tsuji K, et al. Defective response to thrombopoietin and impaired expression of c-mpl mRNA of bone marrow cells in congenital amegakaryocytic thrombocytopenia. Br J Haematol. 1997;96:287-92.
53. Ihara K, Ishii E, Eguchi M, et al. Identification of mutations in the c-mpl gene in congenital amegakaryocytic thrombocytopenia. Proc Natl Acad Sci USA. 1999;96:3132-6.
54. Ballmaier M, Germeshausen M, Schulze H, et al. c-mpl mutations are the cause of congenital amegakaryocytic thrombocytopenia. Blood. 2001;97:139-46.
55. Choi ES, Hokom MM, Chen JL, et al. The role of megakaryocyte growth and development factor in terminal stages of thrombopoiesis. Br J Haematol. 1996;95:227-33.
56. Zauli G, Vitale M, Falcieri E, et al. In vitro senescence and apoptotic cell death of human megakaryocytes. Blood. 1997;90:2234-43.
57. Orazi A, Cooper RJ, Tong J, et al. Effects of recombinant human interleukin-11 (Neumega rhIL-11 growth factor) on megakaryocytopoiesis in human bone marrow. Exp Hematol. 1996;24:1289-97.
58. Bruno E, Hoffman R. Effect of interleukin 6 on in vitro human megakaryocytopoiesis: its interaction with other cytokines. Exp Hematol. 1989;17:1038-43.
59. Li J, Xia Y, Bertino A, et al. Characterization of an anti-thrombopoietin antibody that developed in a cancer patient following the injection of PEG-rHuMGDF (abstract). Blood. 1999;94:51a.
60. Li J, Yang C, Xia Y, et al. Thrombocytopenia caused by the development of antibodies to thrombopoietin. Blood. 2001;98:3241-8.
61. Basser RL, O’Flaherty E, Green M, et al. Development of pancytopenia with neutralizing antibodies to thrombopoietin after multicycle chemotherapy supported by megakaryocyte growth and development factor. Blood. 2002;99:2599-602.
62. Cwirla SE, Balasubramanian P, Duffin DJ, et al. Peptide agonist of the thrombopoietin receptor as potent as the natural cytokine. Science. 1997;276:1696-9.
63. Molineux G. The development of romiplostim for patients with immune thrombocytopenia. Ann NY Acad Sci. 2011;1222:55-63.
64. Wang B, Nichol JL, Sullivan JT. Pharmacodynamics and pharmacokinetics of AMG 531, a novel thrombopoietin receptor ligand. Clin Pharmacol Ther. 2004;76:628-38.
65. Erickson-Miller C, Delorme E, Iskander M, et al. Species specificity and receptor domain interaction of a small molecule TPO receptor agonist (abstract). Blood. 2004;104:795a.
66. Erickson-Miller CL, Delorme E, Tian SS, et al. Preclinical activity of eltrombopag (SB-497115), an oral, nonpeptide thrombopoietin receptor agonist. Stem Cells. 2009;27:424-30.
67. Erickson-Miller CL, DeLorme E, Tian SS, et al. Discovery and characterization of a selective, nonpeptidyl thrombopoietin receptor agonist. Exp Hematol. 2005;33:85-93.
68. Kuter DJ. Biology and chemistry of thrombopoietic agents. Semin Hematol. 2010;47:243-8.
69. Kuter DJ, Bussel JB, Newland A, et al. Long-term treatment with romiplostim in patients with chronic immune thrombocytopenia: safety and efficacy. Br J Haematol. 2013;161:411-23.
70. Kuter DJ, Rummel M, Boccia R, et al. Romiplostim or standard of care in patients with immune thrombocytopenia. N Engl J Med. 2010;363:1889-99.
71. Bussel JB, Buchanan GR, Nugent DJ, et al. A randomized, double-blind study of romiplostim to determine its safety and efficacy in children with immune thrombocytopenia. Blood. 2011;118:28-36.
72. Saleh MN, Bussel JB, Cheng G, et al. Safety and efficacy of eltrombopag for treatment of chronic immune thrombocytopenia: results of the long-term, open-label EXTEND study. Blood. 2013;121:537-45.
73. McHutchison JG, Dusheiko G, Shiffman ML, et al. Eltrombopag for thrombocytopenia in patients with cirrhosis associated with hepatitis C. N Engl J Med. 2007;357:2227-36.
74. Desmond R, Townsley DM, Dumitriu B, et al. Eltrombopag restores trilineage hematopoiesis in refractory severe aplastic anemia that can be sustained on discontinuation of drug. Blood. 2014;123:1818-25.
75. Olnes MJ, Scheinberg P, Calvo KR, et al. Eltrombopag and improved hematopoiesis in refractory aplastic anemia. N Engl J Med. 2012;367:11-9.
76. Erickson-Miller CL, Pillarisetti K, Kirchner J, et al. Low or undetectable TPO receptor expression in malignant tissue and cell lines derived from breast, lung, and ovarian tumors. BMC Cancer. 2012;12:405.
77. Columbyova L, Loda M, Scadden DT. Thrombopoietin receptor expression in human cancer cell lines and primary tissues. Cancer Res. 1995;55:3509-12.
78. Fanucchi M, Glaspy J, Crawford J, et al. Effects of polyethylene glycol-conjugated recombinant human megakaryocyte growth and development factor on platelet counts after chemotherapy for lung cancer. N Engl J Med. 1997;336:404-9.
79. Vadhan-Raj S, Verschraegen CF, Bueso-Ramos C, et al. Recombinant human thrombopoietin attenuates carboplatin-induced severe thrombocytopenia and the need for platelet transfusions in patients with gynecologic cancer. Ann Intern Med. 2000;132:364-8.
80. Basser RL, Underhill C, Davis I, et al. Enhancement of platelet recovery after myelosuppressive chemotherapy by recombinant human megakaryocyte growth and development factor in patients with advanced cancer. J Clin Oncol. 2000;18:2852-61.
81. Moskowitz CH, Hamlin PA, Gabrilove J, et al. Maintaining the dose intensity of ICE chemotherapy with a thrombopoietic agent, PEG-rHuMGDF, may confer a survival advantage in relapsed and refractory aggressive non-Hodgkin lymphoma. Ann Oncol. 2007;18:1842-50.
82. Neelis KJ, Dubbelman YD, Qingliang L, et al. Simultaneous administration of TPO and G-CSF after cytoreductive treatment of rhesus monkeys prevents thrombocytopenia, accelerates platelet and red cell reconstitution, alleviates neutropenia, and promotes the recovery of immature bone marrow cells. Exp Hematol. 1997;25:1084-93.
83. Neelis KJ, Hartong SC, Egeland T, et al. The efficacy of single-dose administration of thrombopoietin with coadministration of either granulocyte/macrophage or granulocyte colony- stimulating factor in myelosuppressed rhesus monkeys. Blood. 1997;90:2565-73.
84. Neelis KJ, Dubbelman YD, Wognum AW, et al. Lack of efficacy of thrombopoietin and granulocyte colony-stimulating factor after high dose total-body irradiation and autologous stem cell or bone marrow transplantation in rhesus monkeys. Exp Hematol. 1997;25:1094-103.
85. Neelis KJ, Qingliang L, Thomas GR, et al. Prevention of thrombocytopenia by thrombopoietin in myelosuppressed rhesus monkeys accompanied by prominent erythropoietic stimulation and iron depletion. Blood. 1997;90:58-63.
86. Neelis KJ, Visser TP, Dimjati W, et al. A single dose of thrombopoietin shortly after myelosuppressive total body irradiation prevents pancytopenia in mice by promoting short-term multilineage spleen-repopulating cells at the transient expense of bone marrow-repopulating cells. Blood. 1998;92:1586-97.
87. Demeter J, Istenes I, Fodor A, et al. Efficacy of romiplostim in the treatment of chemotherapy induced thrombocytopenia (CIT) in a patient with mantle cell lymphoma. Pathol Oncol Res. 2011;17:141-3.
88. Parameswaran R, Lunning M, Mantha S, et al. Romiplostim for management of chemotherapy-induced thrombocytopenia. Support Care Cancer. 2014;22:1217-22.
89. Winer ES, Safran H, Karaszewska B, et al. Eltrombopag with gemcitabine-based chemotherapy in patients with advanced solid tumors: a randomized phase I study. Cancer Med. 2015;4:16-26.
90. Chawla SP, Staddon A, Hendifar A, et al. Results of a phase I dose escalation study of eltrombopag in patients with advanced soft tissue sarcoma receiving doxorubicin and ifosfamide. BMC Cancer. 2013;13:121.
91. Kellum A, Jagiello-Gruszfeld A, Bondarenko IN, et al. A randomized, double-blind, placebo-controlled, dose ranging study to assess the efficacy and safety of eltrombopag in patients receiving carboplatin/paclitaxel for advanced solid tumors. Curr Med Res Opin. 2010;26:2339-46.
92. Hayes S, Mudd PN, Jr, Ouellet D, et al. Population PK/PD modeling of eltrombopag in subjects with advanced solid tumors with chemotherapy-induced thrombocytopenia. Cancer Chemother Pharmacol. 2013;71:1507-20.
93. Slichter SJ, Kaufman RM, Assmann SF, et al. Dose of prophylactic platelet transfusions and prevention of hemorrhage. N Engl J Med. 2010;362:600-13.
94. Rebulla P, Finazzi G, Marangoni F, et al. The threshold for prophylactic platelet transfusions in adults with acute myeloid leukemia. N Engl J Med. 1997;337:1870-5.
95. Antun AG, Gleason S, Arellano M, et al. Epsilon aminocaproic acid prevents bleeding in severely thrombocytopenic patients with hematological malignancies. Cancer. 2013;119:3784-7.
96. Kalmadi S, Tiu R, Lowe C, et al. Epsilon aminocaproic acid reduces transfusion requirements in patients with thrombocytopenic hemorrhage. Cancer. 2006;107:136-40.
97. Wardrop D, Estcourt LJ, Brunskill SJ, et al. Antifibrinolytics (lysine analogues) for the prevention of bleeding in patients with haematological disorders. Cochrane Database Syst Rev. 2013;7:CD009733.
98. Tepler I, Elias L, Smith JW 2nd, et al. A randomized placebo-controlled trial of recombinant human interleukin-11 in cancer patients with severe thrombocytopenia due to chemotherapy. Blood. 1996;87:3607-14.
99. Wiseman GA, Gordon LI, Multani PS, et al. Ibritumomab tiuxetan radioimmunotherapy for patients with relapsed or refractory non-Hodgkin lymphoma and mild thrombocytopenia: a phase II multicenter trial. Blood. 2002;99:4336-42.
100. Richardson PG, Barlogie B, Berenson J, et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med. 2003;348:2609-17.
101. Budd GT, Ganapathi R, Adelstein DJ, et al. Randomized trial of carboplatin plus amifostine versus carboplatin alone in patients with advanced solid tumors. Cancer. 1997;80:1134-40.
102. Gross-Goupil M, Fourcade A, Blot E, et al. Cisplatin alone or combined with gemcitabine in carcinomas of unknown primary: results of the randomised GEFCAPI 02 trial. Eur J Cancer. 2012;48:721-7.
103. Ozaka M, Matsumura Y, Ishii H, et al. Randomized phase II study of gemcitabine and S-1 combination versus gemcitabine alone in the treatment of unresectable advanced pancreatic cancer (Japan Clinical Cancer Research Organization PC-01 study). Cancer Chemother Pharmacol. 2012;69:1197-204.
104. Choi JH, Oh SY, Kwon HC, et al. Gemcitabine versus gemcitabine combined with cisplatin treatment locally advanced or metastatic pancreatic cancer: a retrospective analysis. Cancer Res Treat. 2008;40:22-6.
105. Poplin E, Feng Y, Berlin J, et al. Phase III, randomized study of gemcitabine and oxaliplatin versus gemcitabine (fixed-dose rate infusion) compared with gemcitabine (30-minute infusion) in patients with pancreatic carcinoma E6201: a trial of the Eastern Cooperative Oncology Group. J Clin Oncol. 2009;27:3778-85.
106. Stemmler HJ, Harbeck N, Groll de Rivera I, et al. Prospective multicenter randomized phase III study of weekly versus standard docetaxel (D2) for first-line treatment of metastatic breast cancer. Oncology. 2010;79:197-203.
107. Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352:987-96.
108. Inal A, Kaplan MA, Kucukoner M, et al. Cisplatin-based therapy for the treatment of elderly patients with non-small-cell lung cancer: a retrospective analysis of a single institution. Asian Pac J Cancer Prev. 2012;13:1837-40.
109. Scagliotti GV, Parikh P, von Pawel J, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol. 2008;26:3543-51.
110. Gronberg BH, Bremnes RM, Flotten O, et al. Phase III study by the Norwegian lung cancer study group: pemetrexed plus carboplatin compared with gemcitabine plus carboplatin as first-line chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol. 2009;27:3217-24.
111. Cunningham D, Hawkes EA, Jack A, et al. Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone in patients with newly diagnosed diffuse large B-cell non-Hodgkin lymphoma: a phase 3 comparison of dose intensification with 14-day versus 21-day cycles. Lancet. 2013;381:1817-26.
112. Ogura K, Goto T, Imanishi J, et al. Neoadjuvant and adjuvant chemotherapy with modified mesna, adriamycin, ifosfamide, and dacarbazine (MAID) regimen for adult high-grade non-small round cell soft tissue sarcomas. Int J Clin Oncol. 2013;18:170-6.
113. Fayette J, Penel N, Chevreau C, et al. Phase III trial of standard versus dose-intensified doxorubicin, ifosfamide and dacarbazine (MAID) in the first-line treatment of metastatic and locally advanced soft tissue sarcoma. Invest New Drugs. 2009;27:482-9.
114. Jones SE, Schottstaedt MW, Duncan LA, et al. Randomized double-blind prospective trial to evaluate the effects of sargramostim versus placebo in a moderate-dose fluorouracil, doxorubicin, and cyclophosphamide adjuvant chemotherapy program for stage II and III breast cancer. J Clin Oncol. 1996;14:2976-83.
115. Allegra CJ, Yothers G, O’Connell MJ, et al. Initial safety report of NSABP C-08: a randomized phase III study of modified FOLFOX6 with or without bevacizumab for the adjuvant treatment of patients with stage II or III colon cancer. J Clin Oncol. 2009;27:3385-90.