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I n c i d e n c e , C o s t , a n d O u t c o m e s o f B l e e d i n g a n d
C h e m o t h e r a p y D o s e M o d i fi c a t i o n A m o n g S o l i d T u m o r
P a t i e n t s W i t h C h e m o t h e r a p y - I n d u c e d T h r o m b o c y t o p e n i a
By Linda S. Elting, Edward B. Rubenstein, Charles G. Martin, Danna Kurtin, Saul Rodriguez, Esa Laiho, Krishnakumari Kanesan, Scott B. Cantor, and Robert S. Benjamin Purpose: To describe the incidence and outcomes of
apy delays occurred during 6% of cycles among pa-
bleeding and chemotherapy dose modifications associ-
tients with more than five previous cycles (P ؍ .003),
ated with chemotherapy-induced thrombocytopenia
radiotherapy (P ؍ .03), and disseminated disease (P ؍
(platelets < 50,000/L).
.04). They experienced similar clinical outcomes but
Patients and Methods: Six hundred nine patients
used significantly more resources. Dose reductions oc-
with solid tumors or lymphoma were followed-up dur-
curred during 15% of cycles but were not associated
ing 1,262 chemotherapy cycles complicated by throm-
with poor clinical outcomes or excess resource utiliza-
bocytopenia for development of bleeding, delay or
tion. Significantly shorter survival and higher resource
dose reduction of the subsequent cycle, survival, and
utilization were observed among the 20% of patients
resource utilization. The association between survival
who failed to achieve an adequate response to platelet
and bleeding or dose modification was examined using
transfusion.
the Cox proportional hazards model. Predisposing fac-
Conclusion: The incidence of bleeding is low among
tors were identified by logistic regression.
solid tumor patients overall but exceeds 20% in some
Results: Bleeding occurred during 9% of cycles
subgroups. These subgroups are easily identifiable us-
among patients with previous bleeding episodes (P <
ing routinely available clinical information. A clinical
.0001), baseline platelets less than 75,000/L (P <
prediction rule is being developed. Poor response to
.0001), bone marrow metastases (P ؍ .001), poor per-
platelet transfusion is a clinically and financially signif-
formance status (P ؍ .03), and cisplatin, carboplatin,
icant downstream effect of thrombocytopenia and war-
carmustine or lomustine administration (P ؍ .0002).
rants further investigation.
Major bleeding episodes resulted in shorter survival
J Clin Oncol 19:1137-1146. 2001 by American
and higher resource utilization (P < .0001). Chemother-
Society of Clinical Oncology.
SINCE THE relationship between hemorrhage and the effective,15-17theyarenotwithoutsideeffectsandtheircost depth of thrombocytopenia was first described among will likely exceed the cost of platelet transfusions. It is patients with acute leukemia in 1960,1 its importance to unclear whether the potential cost of these agents is justified patients with solid tumors has been debated. Although this by the risk of serious clinical outcomes of profound or relationship was confirmed by Belt et al in 19782 and later prolonged thrombocytopenia among solid tumor patients.
by Dutcher et al,3 it was clear that hemorrhage was far less There are insufficient data from patients who have re- likely among patients with solid tumors than among their ceived modern chemotherapy regimens to address these counterparts with acute leukemia. It was suggested that this issues; the last comprehensive study of thrombocytopenia decreased risk of hemorrhage did not justify the costs or among patients with lymphoma or solid tumors was pub- risks of platelet transfusion at a threshold of 20,000 plate- lished in 1984.3 For that reason, we studied episodes of lets/␮L among patients with solid tumors.4-9 Nevertheless, practice evolved toward use of a threshold of 20,000 those that resulted in major or minor bleeding, a delay of platelets/␮L below which prophylactic transfusions wereadministered.10,11 Two recent developments have added new fuel to this From the Department of Health Services Research, The University of longstanding debate. First, three trials have provided evi- Texas M.D. Anderson Cancer Center, Houston, TX. dence that the 20,000-platelet threshold may be overly Supported in part by a grant from Genetics Institute, Inc, Cam- conservative for patients with leukemia.12-14 Given the Presented in part at the Thirty-Third Annual Meeting of the lower rate of bleeding observed among patients with solid American Society of Clinical Oncology, May 17-20, 1997, Denver, CO. tumors, re-examination of the potential benefits of prophy- Address reprint requests to Linda S. Elting, DrPH, Department of laxis is justified. Furthermore, platelet growth factors are Health Services Research, The University of Texas M.D. AndersonCancer Center, 1515 Holcombe Blvd, Box 40, Houston, TX 77030; currently being tested in clinical and preclinical trials. One of these, interleukin-11, is commercially available. Studies 2001 by American Society of Clinical Oncology. to date suggest that although these agents may be quite Journal of Clinical Oncology, Vol 19, No 4 (February 15), 2001: pp 1137-1146 Downloaded from jco.ascopubs.org on January 7, 2009 . For personal use only. No other uses without permission. Copyright 2001 by the American Society of Clinical Oncology. All rights reserved. more than 7 days in the subsequent cycle of chemotherapy, Table 1. Characteristics of Underlying Neoplasms and Common
or a reduction in the dose of the subsequent cycle. We Chemotherapy Regimens
focused on three related questions: How frequently are bleeding episodes or chemotherapy dose modification asso- ciated with thrombocytopenia among patients with solid tumors? Are the outcomes of these events sufficiently serious and/or costly to justify prophylaxis? If so, which patients are at sufficiently high risk to justify the use of prophylactic platelet transfusions or growth factors? A retrospective cohort consisting of a random sample of 609 patients with solid tumors or lymphoma, stratified by underlying neoplasm, was selected from among all patients who developed chemotherapy-in- duced thrombocytopenia between January 1, 1994, and December 31, 1995. This cohort was followed-up through December 31, 1996, for development of clinically significant thrombocytopenia and through December 31, 1997, for survival. For each eligible patient, all cycles of chemotherapy that occurred during the study period were included, provided that thrombocytopenia developed. To insure complete ascer- tainment of events, only patients whose entire care was provided by our institution were included. Patients with leukemia and bone marrow transplant recipients were excluded, as were those who received After these exclusions, 1,262 cycles with thrombocytopenia were studied in the 609 patients. Fifty-two percent of patients were female, and the median age was 52 years (range, 17 to 87 years). They had received a median of five cycles of chemotherapy in the past (range, 0 to 19 cycles); 92 patients (15%) were chemotherapy-naive. One half (51%) had disseminated disease, whereas 81 (13%) were receiving adjuvant or neoadjuvant chemotherapy in the absence of clinically Patients with lymphoma, sarcoma, breast, and genitourinary cancers contributed the largest number of cycles to the study (Table 1).
Chemotherapy regimens commonly used for these malignancies (flu- orouracil, doxorubicin, and cyclophosphamide; cyclophosphamide, vincristine, doxorubicin, and decadron; doxorubicin or etoposide plus cisplatin, cytarabine, and prednisone; cisplatin, cyclophosphamide, and doxorubicin; cyclophosphamide, doxorubicin, vincristine, and pred- nisone; and doxorubicin plus either ifosfamide or platinum) were predictably frequent. Platinum-based regimens were used in 41% of cycles. With the exception of patients with lymphoma (who received either doxorubicin or etoposide plus methylprednisolone, high-dose cytarabine, and cisplatin) and sarcoma (who received high doses of ifosfamide and doxorubicin), standard doses of chemotherapy were administered in the majority of cases. Overall, 16% of the cycles involved adjuvant or neoadjuvant therapy. However, there were signifi- Abbreviations: FAC, fluorouracil, doxorubicin, cyclophosphamide; CVD,cis- cant differences in this rate, depending on the underlying malignancy. For platin, vinblastine, dacarbazine; CVAD, cyclophosphamide, vincristine, doxo- example, more than 60% of cycles administered to patients with breast rubicin, decadron; ASHAP; doxorubicin, cisplatin, cytarabine, prednisone; ESHAP, etoposide, cisplatin, cytarabine, prednisone; CISCA, cisplatin, cyclo-phosphamide, doxorubicin; MINT, mesna, ifosfamide, mitoxantrone, pacli- taxel; MINE, mesna, ifosfamide, mitoxantrone, etoposide; MIME, mesna, All paper and electronic medical records of eligible patients were ifosfamide, methotrexate, etoposide; CHOP, cyclophosphamide, doxorubicin, reviewed. These included the paper medical record, electronic data- vincristine, prednisone; MAID, mesna, doxorubicin, ifosfamide, dacarbazine; bases containing all hospital and clinic visits, tumor registry and ACE, doxorubicin, cyclophosphamide, etoposide; PIE, cisplatin, ifosfamide, survival data, diagnostic test results, blood products transfused, and etoposide; CyVADic, cyclophosphamide, vincristine, doxorubicin, dacarba- pharmaceutical agents prescribed, as well as electronic records of zine; POMB, cisplatin, vincristine, mitomycin, bleomycin; PVC, procarbazine, patients enrolled on clinical research protocols. Information about vincristine, carmustine; FND, fludarabine, mitoxantrone, decadron.
Downloaded from jco.ascopubs.org on January 7, 2009 . For personal use only. No other uses without permission. Copyright 2001 by the American Society of Clinical Oncology. All rights reserved. CHEMO-INDUCED THROMBOCYTOPENIA IN SOLID TUMORS bleeding obtained from these sources was supplemented by data from experienced bleeding or dose modification. The Kaplan-Meier method The Ambulatory Treatment Center and Emergency Center Database, was used for this analysis. Factors associated with shorter survival were which contains clinical and resource utilization data pertaining to all examined using the Cox proportional hazards regression model. For outpatient chemotherapy and transfusion episodes and all visits to the this analysis, factors were entered in the stepwise regression model using the maximum partial likelihood ratio method.
Information from paper sources was transcribed by physician ab- The secondary goal of this study was to generate hypotheses about stractors and information from databases was transferred electronically.
high-risk groups for future study. For this analysis, demographic and A 10-item set of variables (unknown to the abstractors) was collected clinical factors were tested first for association with bleeding, chemo- both manually and electronically for estimation of the frequency of therapy delay, and dose reduction in separate univariate analyses errors with manual transcription (Ͻ 3%). Additionally, a predetermined (because they are not mutually exclusive events). Two-tailed ␹2 tests set of key data items was validated by a separate reviewer in all cases were used to test the significance of discrete variables and two-tailed t to ensure 100% accuracy of critical items.
tests, continuous variables. Factors shown to be significant predictors inunivariate analysis (P Ͻ .10) were included in logistic regression analyses. For this analysis, only those factors that are routinelyavailable on day 1 of the chemotherapy cycle in all solid tumor patients Thrombocytopenia was defined as platelets less than 50,000/␮L.
were used, because the decision to administer prophylactic platelet Bleeding was characterized as either minor (World Health Organiza- growth factors is made at this time. Separate regression analyses were tion grades 1 or 2, including petechiae, ecchymoses, superficial conducted for bleeding, chemotherapy delay, and dose reduction.
bleeding of gums, microscopic hematuria, blood-tinged sputum, mild Continuous variables were categorized or dichotomized for the regres- epistaxis, and vaginal bleeding not requiring RBC transfusion) or major sion analyses. The goodness of fit of the models was estimated using (World Health Organization grades 3 or 4, including fatal hemorrhage the Hosmer-Lemeshow statistic. Statistical analyses were computed or epistaxis, vaginal bleeding, or major organ hemorrhage requiring using BMDP Dynamic (Version 7, BMDP Statistical Software, Inc., RBC transfusion). Chemotherapy delay was defined as more than 7 days’ delay in the next planned cycle of chemotherapy. Dose reductionwas defined as a decrease of 20% or more or discontinuation of the planned dose of any antineoplastic agent during the next cycle. Theseevents are not mutually exclusive; cycles with bleeding were occasion- How Frequent Are Episodes of Bleeding and ally accompanied by chemotherapy delay or dose reduction.
The extent of disease dissemination for each cycle was recorded and dichotomized for regression analysis as either limited (no evidence of Bleeding occurred during 111 cycles (9%) (Table 2).
disease or local disease) or disseminated (one or more site of metas- Most episodes of bleeding were minor, including mild tasis). The duration of thrombocytopenia was computed using the lastvalue carried forward method, as is typical in observational studies and epistaxis during 31 cycles, petechiae and ecchymoses dur- clinical trials. Resource utilization was described only during throm- ing 19 cycles, and occasional cases of bleeding gums, mild bocytopenia for each cycle. Resources used when platelet counts vaginal bleeding, bloody urine, or sputum. All episodes of exceeded 50,000/␮L were not considered.
minor bleeding resolved. Major hemorrhage occurred dur- Performance status was measured on day 1 of each cycle using the ing 43 cycles (3%). The most common sites were nasal (13 Zubrod score.18 Poor performance status was defined as Zubrod scoreless than 2. The presence of comorbidities was measured on day 1 of cycles), gastrointestinal hemorrhage, (eight cycles), bladder each cycle of chemotherapy using the Charlson score.19 hemorrhage, (five cycles), and vaginal or pulmonary hem-orrhage (four each). Bleeding was significantly more com- mon during cycles complicated by febrile neutropenia (11% The primary goals of this study were to estimate the incidence per v 7%; P ϭ .02). The relationship between major hemorrhage chemotherapy cycle, outcomes, and resource utilization associated with and febrile neutropenia was particularly striking; major hem- bleeding and chemotherapy dose modification and to describe changes orrhage occurred during 5% of cycles complicated by febrile in these parameters longitudinally over several cycles. Because of the neutropenia but only 2% of those without febrile neutropenia impact of the presence of febrile neutropenia on each of theseoutcomes, an analysis stratified by this factor was conducted. The unit (P ϭ .002). Multiple sites of hemorrhage were involved in six of analysis for this study was a cycle of chemotherapy, except in the episodes. Although CNS tumors or metastases were present case of survival analysis, which was conducted with the patient as the during 129 cycles and prior CNS radiation therapy in 77 unit of analysis. Between two and 16 cycles were included in 288 of the cycles, only one CNS hemorrhage occurred in a patient who 609 patients. Multiple cycles from a single patient were included to provide accurate estimates of the magnitude of these problems amongcancer patients who are at risk of developing the events and use A delay of more than 7 days in the next cycle of resources during each of their multiple cycles of chemotherapy.
chemotherapy occurred during 99 cycles (8%). Most delays Incidence is reported as the percentage of cycles with the event; 95% (67%) were between 8 and 14 days; however, a delay of confidence limits are also reported.
more than 30 days occurred during 15 cycles. A reduction in Duration of survival after bleeding or chemotherapy dose modifica- the dose of the subsequent cycle of chemotherapy was far tion was the primary outcome of interest. The median time to survivalwas computed from the first day of one randomly chosen cycle for each more common (17%). A delay or dose reduction for the patient in order to provide a sufficient sample of patients who had subsequent cycle followed 22% of the 111 cycles with Downloaded from jco.ascopubs.org on January 7, 2009 . For personal use only. No other uses without permission. Copyright 2001 by the American Society of Clinical Oncology. All rights reserved. Table 2. Incidence of Bleeding and Chemotherapy Dose Modifications
Abbreviation: CI, confidence interval.
*P ϭ .02.
†P ϭ .002.
‡P ϭ .0005.
episodes of bleeding. Decisions to delay or reduce the dose of 26 months (Table 3). The Cox proportional hazards during a subsequent cycle were multifactorial. Approxi- regression analysis illustrates this phenomenon. The pres- mately 30% of delays or dose reductions resulted from ence of disseminated disease (odds ratio [OR], 3.5; P Ͻ infection and prolonged or profound granulocytopenia, .0001), poor performance status (OR, 2.1; P Ͻ .0001), and despite the presence of thrombocytopenia. However, in the age Ն 65 years (OR, 1.8; P ϭ .0008) were associated with remainder, thrombocytopenia contributed to the decision to far shorter durations of survival. Minor bleeding episodes delay or reduce subsequent doses, and in approximately and chemotherapy dose delays and reductions did not 30%, prolonged or profound thrombocytopenia was the sole contribute to shorter survival; only a major bleeding episode was significantly associated (OR, 1.9; P ϭ .02) with shortersurvival (Fig 1). Although the presence of febrile neutropenia How Serious Are the Outcomes of Bleeding Episodes and did not contribute to shorter median survival times, mortality at 30 days was significantly more common during cycles com- Episodes of thrombocytopenia complicated by bleeding plicated by febrile neutropenia (6% v 2%; P Ͻ .0001).
were significant in both human and resource utilization Episodes of bleeding were significantly associated with a terms. In four patients, death was attributed at least in part decrement or no increment in platelet count after transfusion to hemorrhage (one adrenal hemorrhage, one gastrointesti- compared with cycles with dose modifications or no events nal, one bladder, and one massive hemorrhage at multiple (47% v 17%; P Ͻ .0001). However, the overall rate of poor sites). Overall, patients survived a median of only 5.9 response to platelet transfusion was surprisingly high during months after cycles complicated by major bleeding episodes all cycles (19%) and for both random-donor platelets (23%) compared with more than 15 months after cycles without an and single-donor platelets (15%). Poor response to platelet episode of major bleeding (P Ͻ .0001) (Table 3). Twenty- transfusion was observed most commonly during chemo- one percent of the patients with major bleeding episodes therapy cycles in males (56%); patients with lymphoma died within 30 days of the cycle onset, compared with only (45%), genitourinary malignancies (15%), or sarcoma 4% of the remaining patients (P Ͻ .0001).
(14%); those who had undergone more than 10 cycles of When the extent of the underlying malignancy and other chemotherapy in the past; and those with widely dissemi- prognostic factors are considered, striking differences nated disease (69%). Bleeding was associated with a failure emerge. For example, the difference in survival after major to achieve adequate response to platelet transfusion in 37% bleeding episodes was limited to patients with disseminated of cycles compared with only 12% of cycles during which underlying disease. The few patients with limited disease an adequate response was achieved (P Ͻ .0001). Although who developed major bleeding episodes survived a median this may be due partially to consumption of platelets at Downloaded from jco.ascopubs.org on January 7, 2009 . For personal use only. No other uses without permission. Copyright 2001 by the American Society of Clinical Oncology. All rights reserved. CHEMO-INDUCED THROMBOCYTOPENIA IN SOLID TUMORS Table 3. Outcomes of Thrombocytopenia
*The number of patients at each increment level divided by the number of patients who received platelet transfusions.
bleeding sites, episodes of bleeding during previous cycles death of the patient (including the four patients whose were also associated with poor increments (14% v 6%; P ϭ deaths were attributed to hemorrhage) compared with only .004). Nineteen percent of cycles during which a poor 3% of patients who responded to platelet transfusion (P Ͻ response to platelet transfusion was observed ended in the .0001). Forty-one percent of these patients also receivedsingle-donor platelets during that cycle and, among these,23% experienced a decrement in platelet count after single-donor platelets. It is notable that during this time period,platelet transfusions were filtered by the blood bank forpatients with hematologic malignancies and for bone mar-row transplant recipients only. Therefore, only the lym-phoma patients in this study received platelet transfusionsfiltered in the blood bank. All platelet transfusions wereadministered through filters.
What Resources Are Used During Cycles Complicated byBleeding and Dose Modifications? Not surprisingly, hospitalization during thrombocytope- Fig 1. Kaplan Meier analysis illustrating the survival disadvantage of
nia was required more frequently (70%) during major episodes of major bleeding. Patients receiving adjuvant or neoadjuvant
therapy have been removed from the analysis.

bleeding episodes than those without (43%) (P ϭ .001) and Downloaded from jco.ascopubs.org on January 7, 2009 . For personal use only. No other uses without permission. Copyright 2001 by the American Society of Clinical Oncology. All rights reserved. Table 4. Resource Utilization During Thrombocytopenia
Platelet units (mean units/per cycle), all Abbreviations: ER, emergency room; SD, single donor platelet.
for an average of 2 more days (P ϭ .007) (Tables 3 and 4).
Considering the severity of outcomes and excessive Hospitalization was significantly more common during resource utilization, episodes of bleeding were considered cycles complicated by febrile neutropenia (78% v 11%; P Ͻ of sufficient import for further study. Although not associ- .0001) and was required in 91% of cycles complicated by ated with poor outcomes, chemotherapy delays were asso- both major bleeding and febrile neutropenia. Clinic visits ciated with sufficient increases in resource utilization to and emergency center visits were also more frequent during justify further study. However, the outcomes and resource cycles with clinically significant thrombocytopenia. Plate- utilization associated with dose reductions were virtually lets were transfused during 80% of cycles with bleeding but indistinguishable from those observed during cycles with no only 41% of those without bleeding (P Ͻ .0001). Signifi- event. Therefore, we studied predisposing factors for bleed- cantly more units of platelets were transfused during bleed- ing episodes and chemotherapy delays.
ing cycles than those without bleeding (17 units v 5 units;P Ͻ .0001) and single-donor platelets were also required What Factors Predispose to Episodes of Bleeding and more frequently (P ϭ .0001) (Table 4). The increased risk of bleeding during cycles complicated by febrile neutrope- Bleeding was associated with poor performance status nia was accompanied by a corresponding increase in the use (P ϭ .007) and multiple comorbidities (P ϭ .006) (Table 5).
of platelet transfusions (55% v 34%; P Ͻ .0001). Addition- The association between performance status and episodes of ally, more units of platelets were transfused during febrile bleeding was particularly pronounced when the perfor- neutropenia, even when bleeding did not occur.
mance status was declining, regardless of the actual perfor- Failure to achieve an adequate response after platelet mance status level observed. The incidence of bleeding was transfusion may be a financially significant event. Overall, unrelated to sex, ethnicity, or age.
patients who experienced a decrement in platelets received The risk of bleeding was also unrelated to the specific an average of 31 units of platelets for that cycle. Patients underlying malignancy (Table 6). However, it was associ- who experienced no increment received 18 units, those with ated with disseminated disease (P ϭ .0001), bone marrow an increment of 1,000 platelets per unit, 17 units, and those metastases (P Ͻ .0001), prior episodes of bleeding (P Ͻ who achieved an increment more than 1,000 platelets per .0001), or a baseline platelet count less than 75,000/␮L unit received only 8 units for that cycle (P Ͻ .0001).
(P Ͻ .0001). Delays of the subsequent cycles were uncom- Patients who failed to achieve an adequate response to mon during adjuvant chemotherapy (P ϭ .0001) but were platelet transfusion were hospitalized an average of 8 days significantly more common when the baseline platelet count during thrombocytopenia compared with only 4 days for was less than 50,000/␮L (P Ͻ .0001). The presence of patients who responded to platelet transfusion (P Ͻ .0001).
necrotic tumor did not predispose to bleeding. Delays were Downloaded from jco.ascopubs.org on January 7, 2009 . For personal use only. No other uses without permission. Copyright 2001 by the American Society of Clinical Oncology. All rights reserved. CHEMO-INDUCED THROMBOCYTOPENIA IN SOLID TUMORS Table 5. Risk of Bleeding and Chemotherapy Dose Modification Related
Table 6. Risk of Bleeding and Chemotherapy Dose Modification Related
to Patients’ Characteristics
to Disease Characteristics
more common when necrotic tumor was present, although this difference did not reach statistical significance (P ϭ .17). During cycles in which febrile neutropenia accompa- nied thrombocytopenia, major bleeding episodes were sig- nificantly more common (P ϭ .0008).
Numerous previous cycles of chemotherapy did not predispose to bleeding whereas chemotherapy delays were associated with more than five previous cycles (P ϭ .0008) (Table 7). Previous radiation therapy did not predispose to bleeding but was associated with a high risk of delay in a subsequent cycle of chemotherapy (41% v 22%, P ϭ .001).
Concurrent radiation therapy was not associated with an increased risk of bleeding or chemotherapy delay. Regi- mens containing mitomycin, carmustine, or lomustine pre-disposed to bleeding, although these agents were used onlyoccasionally. Cisplatin- or carboplatin-based regimens were contribution of each of these factors to the risk of clinically also associated with higher rates of bleeding. Minor bleed- significant thrombocytopenia. Based on the differing risk ing episodes and chemotherapy delays were more common profiles suggested by the univariate analysis, separate re- during cycles in which prophylactic platelet transfusions gression models were developed for bleeding and chemo- were administered (P ϭ .01 and .07, respectively). Bleeding therapy delay. The single most significant predictor of and delays were significantly associated with both the depth bleeding was a prior history of bleeding (P Ͻ .0001) (Table and duration of thrombocytopenia. Bleeding was particu- 8). Measures of poor bone marrow function, such as a larly common during cycles in which the platelet count fell baseline platelet count less than 75,000 and the presence of below 10,000/␮L (7% v 21%; P Ͻ .0001). In fact, the rate bone marrow metastases, were also significant predictors of of bleeding doubled (from 5% to 10%) when the platelet bleeding (P ϭ .0001 and .005, respectively), as was a poor count fell below 20,000/␮L and doubled again (from 10% to performance status (P ϭ .05). Other factors shown to be 21%) when the count fell below 10,000/␮L (Fig 2).
predictive in univariate analysis (such as disseminated Because of the correlation among many of the predictive neoplastic disease and specific chemotherapeutic agents) factors, logistic regression was used to identify the unique did not prove to be significant predictors in the multiple- Downloaded from jco.ascopubs.org on January 7, 2009 . For personal use only. No other uses without permission. Copyright 2001 by the American Society of Clinical Oncology. All rights reserved. Table 7. Risk of Bleeding and Chemotherapy Dose Modification Related
to Treatment Characteristics
Fig 2. Relationship between the nadir of platelet counts and the risk of
bleeding demonstrating excess rates below 10,000 platelets/L.
variable model. A delay in the subsequent cycle of chemo- therapy was predicted by the presence of disseminated neoplastic disease (P ϭ .04) and measures of previous insults to the bone marrow such as prior radiation therapy (P ϭ .03) and numerous previous cycles of chemotherapy Major hemorrhage during chemotherapy-induced throm- bocytopenia is a serious clinical problem. This is particu- larly true of CNS or major organ hemorrhage. Numerous units of platelets are administered to patients with cancer each year with the goal of preventing such events. However, the actual risk of these events, particularly among patients with solid tumors, has been disputed. Similar disputes surround the importance of chemotherapy delays and dose reductions. We examined the incidence and outcomes of these events to inform decisions to use prophylactic platelet transfusions and growth factors in these patients.
The primary impetus for this study was the lack of data on the incidence of bleeding among thrombocytopenic patients with solid tumors who have received modern chemotherapy regimens. However, despite major changes in chemotherapy regimens, our findings were remarkably sim- ilar to those described in the past. We observed bleeding in 9% of patients with thrombocytopenia, Belt et al2 reported bleeding in 10% of similar patients in 1978, and Dutcher et al3 reported bleeding among 15% in 1984. We observed only a single episode of CNS hemorrhage, despite a significant proportion of patients (Ͼ 10%) at high risk. The NOTE. Multiple high risk indicates more than one of the following: cisplatin, consistency of these findings supports the notion that solid carboplatin, lomustine, carmustine, paclitaxel, procarbazine.
tumor patients with similar depth and duration of thrombo- Abbreviations: XRT, radiation therapy; ANC, absolute neutrophil count.
cytopenia share a common risk of bleeding, regardless ofthe specific chemotherapy regimen that is administered.
Downloaded from jco.ascopubs.org on January 7, 2009 . For personal use only. No other uses without permission. Copyright 2001 by the American Society of Clinical Oncology. All rights reserved. CHEMO-INDUCED THROMBOCYTOPENIA IN SOLID TUMORS Table 8. Multiple Variable Models of Risk of Bleeding and Chemotherapy Dose Modification
NOTE. Hosmer-Lemeshow Goodness of Fit Test: bleeding model, P ϭ .70; delay model, P ϭ .98. For this statistic, high P values (approaching 1.0) indicate a good fit to the data whereas lower P values (approaching 0) indicate a poor fit to the data.
Abbreviation: CI, confidence interval.
Our data also suggest that in addition to a common risk of chemotherapy delays were different, they were similar to bleeding during thrombocytopenia, solid tumor patients those predisposing to bleeding in that they were illustrative share common predisposing factors that are host-specific of poor bone marrow reserve (prior radiation therapy and rather than neoplasm-specific. Most notable among these is numerous previous cycles of chemotherapy) and poor per- a history of bleeding. Also among these are factors sugges- formance status (disseminated disease). Thus these patients tive of poor bone marrow function, such as a low baseline are also easily identifiable by using information available on platelet count and bone marrow metastasis, as well as poor day 1 of a cycle of chemotherapy. It may be desirable from performance status. Although tested in univariate and mul- a cost standpoint to identify these patients, and, therefore, tiple variable analyses, the specific neoplasm was not useful this may be a fruitful area of research.
in predicting an episode of bleeding.
In contrast to dose delays, dose reductions led to neither Our results combined with previous data confirm that poorer outcomes nor increased resource utilization. Although among thrombocytopenic solid tumor patients, the risk of the benefit of high doses has been demonstrated for some bleeding is low, overall. However, when episodes of malignancies (particularly leukemia, multiple myeloma, some bleeding do occur, they are associated with poor clinical lymphomas, and sarcomas), for many other solid tumors, little outcomes and significantly increased resource utilization.
or no advantage has been demonstrated to high-dose regimens We have demonstrated that there are easily identifiable with substantial toxicity.20 In our Cox proportional hazards subsets of this population in whom the risk of bleeding model of survival, dose reduction did not prove to be signifi- exceeds 20%. Given these findings, a single strategy (or cantly associated with shorter durations of survival, despite an threshold) for bleeding prophylaxis of all thrombocyto- overrepresentation of patients with lymphoma and sarcoma in penic solid tumor patients is unlikely to provide the most whom this difference might have been expected to be impor- cost-effective solution; an individualized approach is far tant. If this benefit does indeed exist, it may be limited to a more attractive. We are currently developing a clinical subset of patients with solid tumors.
prediction rule based on this multiple-variable risk model Finally, we have reported strikingly high rates of to guide the use of prophylactic platelet transfusions and inadequate response to both random-donor (23%) and growth factors for individual patients in this population.
single-donor (15%) platelet transfusion for this popula- Delays in chemotherapy were uncommon (6%). Com- tion. Although this was not a primary objective of the pared with cycles with no event, delays were associated study, we report these results to stimulate hypotheses and with higher resource utilization but not poorer clinical future study, because this may be among the most outcomes. Although the specific factors that predisposed to clinically and financially significant effects of thrombo- Downloaded from jco.ascopubs.org on January 7, 2009 . For personal use only. No other uses without permission. Copyright 2001 by the American Society of Clinical Oncology. All rights reserved. cytopenia. Numerous platelet transfusions (often of the multifactorial, and it is possible that their poor responses single-donor variety) were required for maintenance of to transfusion resulted from consumption of platelets at hemostasis by patients who failed to achieve an adequate their extensive bleeding sites. Nevertheless, this associ- response to transfusion. Considering the average cost of ation—when considered together with the previously platelet transfusions in the United States (Ͼ $500), this mentioned observations—reinforces a concern that has can be an extremely costly undertaking.21 been voiced by many clinicians. Excessive use of platelet From both a clinical and a statistical standpoint, it is transfusions for prophylaxis and treatment, early in the difficult to determine whether poor increments led to course of malignancy, may result in patients who are bleeding or whether bleeding and its attendant, numerous refractory to all platelet transfusions later in the course of transfusions led to poor increments. Although tests of their malignancy, when they are at highest risk of statistical significance suggest that the association be- bleeding. Our data underscore the importance of this tween these factors is unlikely to have occurred by concern. Prospective study of this significant downstream chance, both may be due to a third factor (such as effect of thrombocytopenia should be a high priority.
consumption of platelets at bleeding sites). Whatever the We conclude that some, but not all, solid tumor patients are causal relationship, the excess mortality among patients at sufficiently high risk of serious clinical outcomes to justify who failed to achieve adequate increments after transfu- aggressive bleeding prophylaxis during chemotherapy-induced sion (19% v 3%) is troubling. This finding is doubly thrombocytopenia. Our ongoing research focuses on the de- significant when viewed in the light of the observation velopment of an easy-to-use clinical prediction rule to guide that all four patients whose deaths were caused in part by individualized prescription of prophylactic platelet transfusions thrombocytopenia-induced hemorrhage experienced in- and growth factors. We encourage further research on the adequate increments after both random-donor and single- downstream clinical and financial effects of failure to achieve donor platelet transfusions. These patients’ deaths were adequate platelet increments after platelet transfusion.
1. Gaydos LA, Freireich EJ, Mantel N: The quantitative relation 13. Rebulla P, Finazzi G, Marangoni F, et al: The threshold for between platelet count and hemorrhage in patients with acute leukemia.
prophylactic platelet transfusions in adults with acute myeloid leuke- 2. Belt RJ, Leite C, Haas CD, et al: Incidence of hemorrhagic 14. Wandt H, Frank M, Ehninger G, et al: Safety and cost effec- complications in patients with cancer. JAMA 239:2571-2574, 1978 tiveness of a 10 x 109/L trigger for prophylactic platelet transfusions 3. Dutcher JP, Schiffer CA, Aisner M, et al: Incidence of thrombo- compared with 20 x 109/L trigger: A prospective comparative trial cytopenia and serious hemorrhage among patients with solid tumors.
in 105 patients with acute myeloid leukemia. Blood 91:3601-3606, 4. Goldberg GL, Gibbon DG, Smith HO, et al: Clinical impact of 15. Tepler I, Elias L, Smith II JW, et al: A randomized placebo- chemotherapy-induced thrombocytopenia in patients with gynecologic controlled trial of recombinant human interleukin-11 in cancer patients with severe thrombocytopenia due to chemotherapy. Blood 87:3607- 5. Fanning J, Hilgers RD, Murray KP, et al: Conservative manage- ment of chemotherapy-induced thrombocytopenia in women with 16. Isaacs C, Robert NJ, Bailey FA, et al: Randomized placebo- gynecologic cancers. Gynecol Oncol 59:191-193, 1995 controlled study of recombinant human interleukin-11 to prevent 6. Beutler E: An iconoclastic view of conventional wisdom in chemotherapy-induced thrombocytopenia in patients with breast cancer hematology. Arch Intern Med 139:221-223, 1979 receiving dose-intensive cyclophosphamide and doxorubicin. J Clin 7. Baer MR, Bloomfield CD: Controversies in transfusion medicine: Prophylactic platelet transfusion therapy—Pro. Transfusion 32:377- 17. Basser R: Clinical use of thrombopoietic growth factors. ASCO 8. Schiffer CA: Prophylactic platelet transfusion. Transfusion 32: 18. Zubrod CG, Schneiderman M, Frei E, et al: Appraisal of methods for the study of chemotherapy of cancer in man: Comparative 9. Beutler E: Platelet transfusions: The 20,000/␮L trigger. Blood trial of nitrogen mustard and trimethylene thiophosphoramide. J Chron 10. Pisciotto PT, Benson K, Hume AB, et al: Prophylactic versus 19. Charlson ME, Pompei P, Ales KL, et al: A new method of therapeutic platelet transfusion practices in hematology and/or oncol- classifying prognostic comorbidity in longitudinal studies: Develop- ogy patients. Transfusion 35:498-502, 1995 ment and validation. J Chron Dis 40:373-383, 1987 11. Norfolk DR, Ancliffe PJ, Contreras M, et al: Concensus confer- 20. Savarese DM, Hsieh C, Stewart FM: Clinical impact of chemo- ence on platelet transfusion: Royal College of Physicians of Edinburgh.
therapy dose escalation in patients with hematologic malignancies and solid tumors. J Clin Oncol 15:2981-2995, 1997 12. Heckman K, Weiner G, Davis C, et al: Randomized study of 21. Cantor SB, Elting LS, Hudson DV, et al: Pharmacoeconomic prophylactic platelet transfusion threshold during induction therapy for analysis of rhIL-11 for secondary prophylaxis of thrombocytopenia in adult acute leukemia: 10,000/ml versus 20,000/ml. J Clin Oncol solid tumor patients receiving chemotherapy. Proc Am Soc Clin Oncol Downloaded from jco.ascopubs.org on January 7, 2009 . For personal use only. No other uses without permission. Copyright 2001 by the American Society of Clinical Oncology. All rights reserved.

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