Dose Reductions and Delays: Limitations of Myelosuppressive Chemotherapy
Dose Reductions and Delays: Limitations of Myelosuppressive Chemotherapy
ABSTRACT: Thrombocytopenia occurs at various grades of severity in patients with nonmyeloid malignancies undergoing chemotherapy with myelosuppressive agents. Frequently, it is the major dose-limiting hematologic toxicity, especially in the treatment of potentially curable malignancies such as leukemia, lymphomas, and pediatric cancers. This is becoming increasingly important given the recent trend toward the use of dose-intensive combination chemotherapy regimens facilitated by supportive hematopoietic colony-stimulating factors to prevent chemotherapy-induced febrile neutropenia. The standard preventive measure against chemotherapy-induced depression of platelets in subsequent treatment cycles has been dose reduction and/or dose delay. However, follow-up data from studies in various populations of patients with cancer suggest a correlation between delivery of lower than intended doses and poor outcomes, including reduced disease-free periods and overall survival. Other consequences of thrombocytopenia include the need for platelet transfusions and subsequent exposure to the risk of numerous complications, including bacterial and viral infections; febrile, nonhemolytic transfusion reactions; and transfusion-induced immunosuppression. Furthermore, a large proportion of multitransfused patients become refractory to subsequent infusions. Refractoriness to platelet transfusions is quickly becoming more prominent. The availability of a platelet growth factor—recombinant human interleukin-11(rhIL-11, also known as oprelvekin [Neumega])—provides an effective means of preventing chemotherapy-induced thrombocytopenia and accelerating platelet recovery, thereby facilitating the administration of full doses of chemotherapy during subsequent cycles and avoiding the need for rescue with platelet transfusions. [ONCOLOGY 14(Suppl 8):21-31, 2000]
Thrombocytopenia in patients with cancer has multiple origins. Disease-related causes include reduced thrombopoiesis in cancers with bone marrow involvement and tumor-induced disseminated intravascular coagulopathy as seen in mucinous prostatic, lung, ovarian, and gastrointestinal adenocarcinomas. However, the use of chemotherapy with or without radiation therapy is the most common cause of clinically significant thrombo-cytopenia.[1,2] The National Cancer Institute offers a grading system for determining the severity based on platelet counts (Table 1).
Data from two large, retrospective studies conducted at the Baltimore Cancer Research Center (n = 1,274) and The University of Texas M. D. Anderson Cancer Center in Houston (n = 3,682) indicate that clinically significant reductions in platelet counts to nadirs < 50,000/µL occur in approximately 20% to 25% of patients receiving dose-intensive myelosuppressive chemotherapy for solid tumors or lymphoma.[3,4] In approximately 10% to 15% of these patients, platelet counts fall below 20,000/µL.
The risk of the development of thrombocytopenia is aggravated by the use of dose-intensive chemotherapy, with or without the support of hematopoietic colony-stimulating factors for the amelioration of chemotherapy-associated febrile neutropenia.[5-7] Providing hematopoietic support with peripheral blood stem-cell transplantation during multiple cycles of high-dose chemotherapy does not prevent cumulative thrombocytopenia or enhance platelet recovery. In fact, Spitzer et al reported a significant delay in platelet recovery after the second cycle compared with that seen following the first cycle of high-dose myelotoxic chemotherapy (cyclophosphamide [Cytoxan, Neosar], carmustine [BiCNU], etoposide) in patients with lymphoma, despite infusion. After cycle 2, the platelet recovery time to 100,000/µL ranged from 10 to 267 days vs 12 to 53 days after cycle 1; 8 to 267 days to 50,000/µL vs 9 to 53 days after cycle 1; and 8 to 101 days to 20,000/µL vs 8 to 28 days after cycle 1.
Megakaryocytic suppression and recovery occur rapidly following treatment with cell-cycle–specific chemotherapeutic agents. In contrast, with cell-cycle–nonspecific agents—such as busulfan (Myleran), nitrosourea, mitomycin (Mutamycin), and platinum complexes—suppression occurs more gradually but is more persistent. With the latter agents, recovery from myelosuppression may take up to 50 days or longer, depending on the extent of suppression. These agents affect proliferating platelet precursors rather than mature platelets. Therefore, thrombocytopenia gradually develops over 7 to 10 days, and platelet counts < 20,000/µL generally occur by about day 10 after the start of myelotoxic chemotherapy. It should be noted, however, that because changes in peripheral platelet counts lag behind changes in bone marrow production, at a given point in time the platelet count does not reflect the level of megakaryocytopoietic activity.
Chemotherapy-induced thrombocytopenia increases in severity with increased intensity of treatment, with the combined use of cycle-specific and cycle-nonspecific chemotherapeutic agents (which is often the case [Table 2]), and with the adjuvant use of radiation therapy and highly myelosuppressive drugs. The combined use of cycle-specific and cycle-nonspecific agents also produces thrombocytopenia of more prolonged duration. Moreover, particular treatment regimens appear to be associated with high rates of severe thrombocytopenia. For example, World Health Organization grades 3/4 thrombocytopenia (platelet counts < 50,000/µL) have been reported at rates of 48% among patients treated with doxorubicin 20 mg/m²/d, ifosfamide (Ifex) 2,500 mg/m²/d, and dacarbazine (DTIC-Dome) 300 mg/m²/d (MAID) for advanced sarcoma; > 50% with ifosfamide 5 g/m², carboplatin (Paraplatin) 400 mg/m², and etoposide at doses ranging from 300 to 1200 mg/m² for non–small-cell lung cancer; and 24% to 33% with paclitaxel (Taxol) 135 mg/m² (one dose), ifosfamide 1,200 mg/m²/d, and cisplatin (Platinol) 30 mg/m²/d for ovarian cancer.
Thrombocytopenia also interferes with other modalities of cancer treatment, such as radiation therapy. In a case-control study involving 45 patients with malignant disease, MacManus et al retrospectively evaluated risk factors for unscheduled interruptions in radiotherapy associated with platelet counts < 50,000/µL or significant neutropenia. Multivariate analysis identified concurrent administration of myelotoxic chemotherapeutic agents (most commonly in this study cisplatin, methotrexate, fluorouracil, vincristine, cyclophosphamide, doxorubicin, and etoposide) as one of the strongest risk factors for interruption of radiotherapy due to thrombocytopenia (odds ratio: 45.5; P < .001 vs controls).
The total cumulative percentage of bone marrow irradiated was also a strong risk factor. The relative contributions of chemotherapy and radiation therapy to thrombocytopenia depend on the amount of bone marrow in the radiation field. For example, chemotherapy would be the primary contributing factor in patients receiving small-field radiation therapy. Using the results of the multivariate analysis and regression analysis, the authors estimated that 49% (22/45) of patients would be at high risk for thrombocytopenia. They also suggested that these high-risk patients may be candidates for clinical trials of a platelet growth factor.
Increased Severity With Dose-Intensive Chemotherapy
Over the past 10 to 15 years, there has been a trend toward escalation of chemotherapy dose intensity with the intent of achieving cure or prolonged remission in patients with hematologic and solid tumor malignancies, including ovarian cancer,[6,14,15] small-cell lung cancer, testicular cancer,[17,18] and breast cancer.[10,19,20] (For breast cancer, recent trials have suggested no benefit in clinical outcomes from such dose escalation; however, longer follow-up and subset analyses are required.) This trend has been accompanied by an increased incidence of severe, prolonged thrombocytopenia, which has now become a major dose-limiting hematologic toxicity.[5,6,15,21,22] In two studies of patients with previously untreated ovarian cancer and residual disease after primary laparotomy, combination therapy with high-dose carboplatin and cisplatin, and ifosfamide therapy for six cycles (n = 37), and cisplatin, carboplatin, and cyclophosphamide for up to eight cycles (n = 44), resulted in platelet nadirs < 50,000/µL in 100% and 66% of patients, respectively.
Furthermore, the increasing use of granulocyte colony-stimulating factor (G-CSF, filgrastim [Neupogen]) and granulocyte-macrophage colony-stimulating factor (GM-CSF, sargramostim [Leukine]) to reduce the risk of chemotherapy-induced severe neutropenia during dose-intensive cancer chemotherapy regimens[5,21,23] appears to be associated with more severe and protracted thrombocytopenia,[7,22] likely because the chemotherapy tolerance is improved. Whereas neutropenia would have previously been dose limiting, now it is no longer so. This is well illustrated by findings in 37 young adult and pediatric patients newly diagnosed with sarcoma who received intensive combination chemotherapy and radiation therapy either with or without GM-CSF support. Patients treated concomitantly with GM-CSF had significantly lower median platelet nadirs (29,500/µL vs 59,000/µL, respectively; P < .0001) and required a significantly longer median time to recovery to platelet count > 75,000/µL (16 days vs 14 days, respectively; P < .0001), compared with patients not treated with GM-CSF.
In a study of patients with advanced breast cancer, dose-intensive chemotherapy with G-CSF support was associated with a 17% incidence of low platelet counts (< 50,000/mL) compared with 0% among patients who received a less intensive regimen without G-CSF support (P < .002). Depressed platelet counts contributed to a higher incidence of treatment delays in the higher dose-intensive group, compared with the latter group (21% vs 8%, respectively; P < .0001).
During the use of combination chemotherapeutic regimens for nonmyeloid malignancies, the standard response of physicians to the development of thrombocytopenia is dose reductions and/or delayed administration of the next cycle of chemotherapy (Table 2). This is also the response of treating physicians for patients receiving combined-modality therapy (chemotherapy and radiation therapy). In the study conducted by MacManus et al, thrombocytopenia forced the interruption of radiation therapy for 3 days or more in 98% (44/45) of patients, 27% (12/45) of whom had at least one measurement of platelet count < 25,000/µL. In addition to treatment interruption, the planned radiation dose was reduced by > 10% in 51% of the cases, vs 11% of controls (radiation therapy only).
During myelosuppressive chemotherapy, the administration of subsequent cycles is routinely delayed until the platelet count has recovered to 100,000/µL, as mandated by almost all of the protocols for investigations of chemotherapeutic regimens seen in Table 2.[5,11,12,24-27] In these studies, treatment was delayed for 1 to 4 weeks if this platelet threshold was not reached.
Elting et al retrospectively reported that among 500 patients receiving chemotherapy for solid tumors or lymphoma, reduction in platelets to < 50,000/µL resulted in the delay of a chemotherapy cycle by more than 7 days in 8% of patients.
The practice of reducing doses in response to prolonged myelosuppression is demonstrated in the studies in Table 2. In the event of slow platelet recovery[11,24,26,27,29,30] or persistence of platelet counts < 50,000/µL [11,24,30-32] or even 75,000/µL to 100,000/µL,[22,27] chemotherapy was significantly deescalated, often by reducing drug doses by up to 50%.
In the breast cancer study of Fetting et al, no chemotherapy was to be administered if the platelet count was < 50,000/µL.
In a dose-escalation study in 24 patients with solid tumors or non-Hodgkin’s lymphoma, cumulative thrombocytopenia (defined as platelet count < 25,000/µL) was the major dose-limiting toxicity. This study was conducted to evaluate the feasibility of escalating the dose of etoposide from 300 mg/m² to 600, 900, or 1,200 mg/m² in a dose-intensive ifosfamide, carboplatin, and etoposide (ICE) regimen with GM-CSF support. At all dose levels of etoposide, clinically significant thrombocytopenia developed after multiple treatment cycles; by cycle 3, ³ 50% of patients required platelet transfusions to maintain a platelet count > 20,000/µL.
Thrombocytopenia in conjunction with neutropenia led to dose reductions in most patients who received more than three cycles of therapy. Cumulative thrombocytopenia was the major factor limiting the escalation of etoposide doses above 900 mg/m2. Continued decline in nadir platelet counts over successive cycles and subsequent dose limitation have been reported in other studies in which GM-CSF support was provided. These findings support the predictability of low platelet nadirs following successive cycles in patients who develop thrombocytopenia during the first cycle.