Radiotherapy-Associated Neutropenia and Thrombocytopenia: Analysis of
Risk Factors and Development of a Predictive Model
By Michael Mac Manus, Kathleen Lamborn, Waqqar Khan, Anna Varghese, Lorin Graef, and Susan Knox
Risk factors for unscheduled interruptions in radiotherapy
courses completed between June 1989 and August 1995,
lasting ı2 days, and associated with World Health Organiza-
tion grade III-IV neutropenia or thrombocytopenia were
studied retrospectively. A group of controls was randomly
selected. Potential risk factors for myelosuppression were
analyzed using univariate and multivariate analyses. The
most important risk factors for treatment interruption with
thrombocytopenia were concurrent chemotherapy (odds ra-
tio [OR], 45.5; P Ú .001), increasing percentage of marrow
irradiated (OR, 4.1 for each 20%; P Ú .001), and brain metas-
tases (OR, 7.3; P ! .01). Other significant (P Ú .05) factors
were leukemia/lymphoma, bone or bone marrow metasta-
ses, and prior chemotherapy. The most important risk fac-
tors for treatment interruptions with neutropenia were con-
N EUTROPENIA AND thrombocytopenia are common
complications of extended-field radiotherapy1 that of-
ten cause treatment interruptions and increase the risks of
infection or bleeding. Clinically significant myelosuppres-
sion may also occur in patients undergoing treatment to
smaller radiotherapy fields who have received chemotherapy
before or during radiotherapy. Unscheduled interruptions in
radiotherapy have been associated with a reduced probability
of local control of tumors of the breast,2 uterine cervix,3
lung,4 and upper aerodigestive tract,5,6 often in patients re-
ceiving potentially curative treatments. It is likely that tumor
cells repopulate rapidly during breaks in treatment and con-
sequently become more difficult to eradicate.7 Because of
these findings, radiation oncologists endeavor to keep inter-
ruptions in radiotherapy to a minimum, particularly when
treatment is administered with curative intent.
In recent years there has been a trend in cancer manage-
ment towards increased use of combined modality therapy
(CMT) for a variety of tumor types. CMT protocols fre-
quently involve concurrent or sequential chemotherapy and
radiation therapy. They are usually associated with higher
rates of local tumor control, but also carry a higher risk of
myelosuppression than single modality therapy. Some proto-
cols prospectively use hematopoietic growth factors to allow
intensification in chemotherapy dosage.8 CMT protocols are
currently in extensive use for small-cell9 and non–small-cell
lung cancer,10 head and neck tumors,11 esophageal carci-
noma,12 pancreatic carcinoma,13 colorectal14 and anal15 carci-
noma, breast carcinoma,2,8 pediatric malignancies,16 and
lymphomas.17 As a consequence of CMT, significant myelo-
suppression will be encountered with increasing frequency
in radiotherapy departments.
It has been shown that granulocyte colony-stimulating fac-
tor (G-CSF) administration can rapidly reverse neutropenia
caused by radiotherapy alone18,19 and effectively prevents
neutropenia when used prophylactically at reduced dose in
radiotherapy patients at high risk of radiation-induced neu-
tropenia.20 G-CSF has also proved effective in treating neu-
tropenia arising in radiotherapy patients who have previously
received chemotherapy.19,21 A new platelet growth factor,
Mpl ligand, is currently under evaluation in phase I trials.22
It is possible that such an agent could be useful in preventing
Blood, Vol 89, No 7 (April 1), 1997: pp 2303-2310
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current chemotherapy (OR, 42.1; P Ú .001) and increasing
percentage of marrow irradiated (OR, 3.3 for each 20%; P Ú
.001). Similarly, the most important risk factors for treat-
ment interruptions with both thrombocytopenia and neutro-
penia were concurrent chemotherapy (OR, 48.6; P Ú .001)
and increasing percentage of marrow irradiated (OR, 3.9 for
each 20%; P Ú .001). Other significant (P Ú .05) factors in
these groups were bone marrow or brain metastases and
previous chemotherapy. These data were used to create a
model, assigning patients to groups at high, intermediate, or
low risk for treatment interruption with thrombocytopenia.
High-risk patients may be candidates for clinical trials of a
platelet growth factor.
q 1997 by The American Society of Hematology.
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or treating thrombocytopenia associated with radiotherapy
and chemotherapy. An effective platelet growth factor could
eliminate delays in radiotherapy due to thrombocytopenia
and avoid the well-known risks of platelet transfusions de-
rived from multiple donors.23
It would be useful to identify prospectively those radio-
therapy patients who are at highest risk of neutropenia and
thrombocytopenia. High-risk patients could be monitored
more closely for myelosuppression and infection or bleeding
and could be candidates for clinical trials involving the ad-
ministration of hematopoietic growth factors in an effort to
prevent treatment interruptions and other complications of
myelosuppression. In this study, we have reviewed the rec-
ords of patients treated at Stanford University in the period
from 1989 to 1994 who were known to have treatment inter-
ruptions associated with thrombocytopenia, neutropenia, or
both. A control group of patients treated during the same
period was randomly selected. We anticipated that compari-
son of cases and controls would allow us to identify those
factors most strongly correlated with an increased risk of
having a treatment interruption due to myelosuppression and
that we might be able to develop a model that could prospec-
tively identify patients at high risk. The factors that we stud-
ied included previous or concurrent administration of myelo-
suppressive chemotherapy, the percentage of active marrow
irradiated in current and previous radiation treatments, per-
formance status, age, sex, coadministration of potentially
From the Department of Radiation Oncology, Stanford University,
Stanford, CA; and the Department of Neurosurgery, University of
California at San Francisco, San Francisco, CA.
Submitted May 21, 1996; accepted November 11, 1996.
Supported by a grant from AMGEN (Thousand Oaks, CA).
Address reprint requests to Susan Knox, PhD, MD, Department
of Radiation Oncology, Stanford University Medical Center, Stan-
ford, CA 94305-5105.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be hereby marked
‘‘advertisement’’ in accordance with 18 U.S.C. section 1734 solely to
indicate this fact.
q 1997 by The American Society of Hematology.
0006-4971/97/8907-0033$3.00/0
2303
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2304
myelosuppressive drugs, and the extent of metastasis of ma-
lignant disease.
Our primary objective was to determine what factors most
strongly influence the likelihood that a patient will have a
radiation treatment delay of 2 days or more associated with
thrombocytopenia or neutropenia (or both). As a secondary
objective, we examined (1) the risk that the patient would
have a greater than 10% reduction in the total radiation dose
compared with the initial treatment plan; (2) the incidence
of severe thrombocytopenia (platelet count, õ25 1 109/L);
(3) requirements for platelet transfusion; and (4) the risk of
having a treatment interruption that exceeded 3 days.
MATERIALS AND METHODS
Study Design
The study analyzed radiotherapy treatments that were completed
between June 1989 and August 1995. Investigators used a database
containing detailed information on all radiation therapy treatments
administered at Stanford since the 1950s to identify patients who
had unscheduled treatment interruptions of 2 days duration or more
(excluding weekends and holidays). Review of the charts of these
patients allowed the identification of patients who had treatment
interruptions associated with significant neutropenia, thrombocyto-
penia, or both (the cases). The point at which the decision was made
to interrupt radiotherapy because of thrombocytopenia or neutro-
penia varied between physicians. Whether an individual patient be-
came a case in this study or continued with radiotherapy, with or
without platelet transfusion, often depended on the clinical judgment
of the radiation oncologist. Blood count data, including differential
and platelet counts, were recorded. Although in some instances,
few counts were available for the time during which patients were
receiving radiation therapy, this was usually because the counts were
normal and the attending physicians felt that the patients were at
very low risk for radiation-induced myelosuppression. All of the
patients had at least one complete blood count performed during
treatment.
The database facilitated random selection of a representative set
of controls from the entire population of patients who received radio-
therapy during the study period, most of whom did not have treat-
ment interruptions due to neutropenia or thrombocytopenia. Ran-
domization was stratified by year. When selecting the controls, we
randomly sampled courses of radiotherapy rather than initially listing
all patients and then sampling them with equal probability. Thus,
we weighted the likelihood of selecting an individual patient greater
if that patient had received multiple courses of radiotherapy. If the
same patient was selected more than once, the first course selected
was to be used. However, no patient was selected twice.
We initially set out to study treatment interruptions associated
with thrombocytopenia alone and, having identified our potential
cases, chose to use a randomly selected control group that would
bring the total number of charts reviewed to approximately 200
(cases and controls). We subsequently decided also to study cases
of treatment interruption associated with neutropenia and used the
same control group as for the thrombocytopenia cases, because none
of the controls had a treatment interruption associated with neutro-
penia. Total body irradiation or stereotactic radiosurgery patients
and patients who received brachytherapy or electron treatments only
were excluded. No patient who was identified as a case was also
randomly selected as a control. In this investigation, we were primar-
ily interested in patients receiving radiotherapy for malignant dis-
ease. We identified 11 cases of treatment interruption associated with
thrombocytopenia and 10 associated with neutropenia in patients
undergoing radiotherapy for benign diseases, principally extended
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MAC MANUS ET AL
field treatments for cardiac transplant rejection. These patients were
excluded from the analysis and the final number of thrombocytopenia
cases and controls was 183.
The charts of both cases and controls were reviewed. Detailed
information on the extent of treatment interruption was gathered for
each case. All cases had at least one blood count performed during
the treatment course that showed at least grade 1 neutropenia and/
or thrombocytopenia. In addition, information was collected for both
cases and controls on a range of parameters that were considered
possible risk factors for neutropenia, thrombocytopenia, or bleeding.
These parameters are described fully below. Detailed information
concerning each patient’s clinical course, medical history, and radio-
therapy were found within the Stanford radiotherapy chart. In cases
in which details of previous chemotherapy and other clinical vari-
ables were not adequately documented in the radiotherapy chart, the
patient’s medical oncology or general hospital records were also
consulted.
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Patient Data Collected for Analysis
In addition to age, sex, and pretreatment weight, information was
collected on the following patient and treatment variables for both
cases and controls. Patient variables were recorded for the time of
the course of radiotherapy under evaluation. If, for example, a patient
initially had local disease but subsequently relapsed with metastatic
disease and only then received radiotherapy, that patient was consid-
ered to have metastatic disease for the purposes of this study.
Patient Variables
Karnofsky performance status (KPS).24 KPS was contained
within the radiotherapy chart as part of the routine pretreatment
physical examination for most patients. In those few cases in which
KPS was not explicitly recorded, the patient’s detailed history and
physical examination were used to make an estimate.
Tumor type. Patients with malignant disease were assigned to
either a solid tumor or leukemia/lymphoma category. The latter in-
cluded Hodgkin’s disease patients.
Disease extent. The following categories were used: local dis-
ease, in which there were no known lymphatic or systemic metasta-
ses; regional disease, in which there were loco-regional lymph node
metastases but no distant metastases; and metastatic disease, in
which distant metastatic spread was confirmed (analyzed by a score
of 0, 1, or 2).
Bone marrow involvement. Bone marrow study results were
considered positive when aspiration or biopsy contained tumor cells
or bone marrow metastasis was apparent on imaging studies (eg,
magnetic resonance imaging [MRI]). All other cases were considered
to be negative.
Bone metastasis. Patients were considered to have bone metasta-
sis only when there was evidence of such on radiographs, computed
tomography (CT), MRI, or bone scan.
Brain metastasis. Patients were included in this category if CT
or MRI showed intracranial tumor.
Concomitant conditions affecting hemostatic function. Informa-
tion regarding conditions such as idiopathic thrombocytopenia pur-
pura, hypersplenism, or hereditary clotting disorders was sought (an-
alyzed as present/absent).
Thromboembolic disease. Past medical histories of arterial or
venous thrombosis or embolism were recorded (analyzed as present/
absent).
Serum bilirubin and serum creatinine. Levels of these parame-
ters, whether normal or raised at the start of treatment, were recorded
for all patients who had biochemical screening within 1 week of
commencing radiotherapy (not analyzed due to a lack of data).
Concomitant medication with potential effects on marrow or clot-
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RADIOTHERAPY-ASSOCIATED MYELOSUPPRESSION
Table 1. Myelotoxicity Rating of Chemotherapy Drugs
Received by Patients in This Study
High
Actinomycin-D
Alkylating agents
Anthracyclines
Carboplatin
Dacarbazine
Etoposide
Methotrexate (high dose)
Mitomycin-C
Procarbazine
Nitrosoureas
Vinblastine
Moderate/low
5-FU
6-MP
Ara-C
Bleomycin
Cisplatin
Methotrexate
Vincristine
ting function. A list of medications commonly encountered in clini-
cal practice that could affect marrow or clotting function was com-
pared with the list of medicines that the patient was taking at the
start of radiotherapy (analyzed as present/absent).
Treatment Factors
Percentage of active bone marrow previously irradiated. Esti-
mates of this parameter were made by studying treatment records
of previous radiation fields and using published data on the distribu-
tion of active marrow in adults.25-27 We used a table that provided
estimates of the amount of marrow in the common types of radiation
fields used at Stanford. Because these estimates were necessarily
imprecise, patients were allocated to one of the following categories:
cumulative proportion of active bone marrow irradiated less than
20%, 20% to 39%, 40% to 59%, 60% to 79%, or ¢80% (scored as
1 through 5, respectively, for analysis). Allocation of patients to
quintiles also facilitated statistical analysis. When a patient had wide-
field radiation followed by a small volume boost, only the percentage
of marrow in the wide-field treatment was recorded.
Percentage of active bone marrow previously irradiated and per-
centage of marrow to be irradiated during the radiation therapy
course under investigation. This parameter was estimated and ana-
lyzed as described above. In general, previous and current radiation
fields did not overlap significantly and percentages could be added
directly. All charts were reviewed to check for overlapping fields.
Marrow in the region of overlap was counted only once in those
few cases in which overlap was found.
Prior treatment with chemotherapy with high myelotoxicity poten-
tial. This category refers to any severely myelotoxic cytotoxic che-
motherapy administered more than 28 days before radiotherapy and
was recorded simply as yes or no. In almost all of these cases, the
nadir of platelet and neutrophil counts had passed before radiother-
apy commenced. A classification of commonly used chemotherapeu-
tic agents into categories of either high or low to moderate myelotoxi-
city is given in Table 1. Table 1 was based, in part, on reviews of
myelosuppression associated with individual drugs28,29 and on our
own experience. Almost all patients who received chemotherapy
received treatment regimens containing at least one severely myelo-
toxic drug.
Sequential treatment with chemotherapy with high myelotoxicity
potential. This category refers to any severely myelotoxic cyto-
toxic chemotherapy administered between 28 days and 1 day before
the start of radiotherapy and was recorded as yes or no.
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2305
Concurrent treatment with chemotherapy with high myelotoxicity
potential. This category includes patients receiving chemotherapy
within 1 day of starting radiotherapy or at any time during the course
of radiation treatment and was recorded as yes or no. The number
of cycles of chemotherapy administered during radiotherapy was
also recorded but not analyzed.
Number of prior chemotherapy regimens with high myelotoxicity
potential. The number and type of different chemotherapy regi-
mens (eg, MOPP and CMF) administered more than 28 days before
radiotherapy were recorded. The number of cycles of each regimen
was often difficult to obtain for patients who received chemotherapy
outside Stanford and was therefore not collected for every patient.
The interval between the last dose of chemotherapy and the start of
radiotherapy was recorded but not analyzed separately.
Data Management
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Data were collected on standardized case report forms and all
forms were reviewed by a physician before data entry into a database
created on a mainframe computer. Summary statistics were provided
from that database. Additional analysis was performed using SAS
software (SAS Institute Inc, Cary, NC).
Statistical Analysis
The primary analysis for both univariate and multivariate analyses
was logistic regression.30 Initially parameters were analyzed as uni-
variate predictors. Those that were significant at the P Å .1 level
were considered for inclusion in a multivariate model. Criteria for
inclusion in the final model was P õ .05. In cases in which informa-
tion on a variable was largely unavailable or if few patients exhibited
a characteristic, that variable was excluded from the analysis.
RESULTS
Thrombocytopenia
There were 45 patients with malignant disease who experi-
enced treatment interruption associated with thrombocyto-
penia (thrombocytopenia cases). These were compared with
138 randomly selected controls who had also received radio-
therapy for malignant disease. Although the controls experi-
enced no significant treatment delays, 2 control patients had
platelet counts during radiotherapy that were low enough
to require platelet transfusions and 2 other control patients
required platelet transfusions within 2 months of completing
radiation therapy. Baseline characteristics of both cases and
controls are shown in Table 2. Treatment factors for throm-
bocytopenia cases and controls are shown Table 3. Univari-
ate analysis was used to search for significant differences
between cases and controls (noted for P ° .1, P ° .05, P
° .01, and P õ .001 in Tables 2 and 3).
Those variables that were significant at the P Å .1 level
in the univariate model were entered into a multivariate
model and results are shown in Table 4. The percentage
of active marrow irradiated (P õ .001) and the concurrent
administration of severely myelotoxic chemotherapy (P õ
.001 ) were the factors most highly predictive for the inter-
ruption of radiotherapy by thrombocytopenia. The odds ratio
(OR) increased by a factor of 45.5 if the patient had concur-
rent severely myelotoxic chemotherapy. The OR increased
by 4.1-fold for each 20% increment of the percentage of
marrow irradiated. Brain metastasis was also a significant
factor (OR, 7.3; P Å .01).
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2306 MAC MANUS ET AL

Table 2. Characteristics of Cancer Patients Who Had Interruptions in Radiotherapy

Due to Thrombocytopenia and/or Neutropenia Compared With Controls
Thrombocytopenia Neutropenia Thrombocytopenia /
Cases (n Å 45)* Cases (n Å 63)* Neutropenia (n Å 37)* Controls (n Å 138)

Mean age (yr) 54 51 53.5 53

Mean KPS 83 88 85 86
Mean weight (kg) 73.3 71.4 70.9 73.6
Sex
Male 27 (60) 31 (49) 20 (54) 72 (52)
Female 18 (40) 32 (51) 17 (46) 66 (48)
Type of malignancy
Solid tumor 28 (62) 36 (57) 20 (54) 110 (80)
Leukemia/lymphoma 17 (38)† 27 (43)‡ 17 (46)§ 28 (20)
Extent of disease
Local 6 (13) 14 (22) 4 (11) 51 (37)
Regional 19 (42) 27 (43) 16 (43) 39 (28)

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Metastatic 16 (36) 16 (25) 13 (35) 41 (30)
Not applicable 4 (9) 6 (10) 4 (11) 7 (5)
Marrow metastases 5 (11)§ 6 (10)† 5 (13.5)§ 2 (1.4)
Bone metastases 12 (27)\ 11 (18) 9 (24) 20 (15)
Brain metastases 8 (18)§ 8 (13)† 7 (19)§ 6 (4)
Because of rounding, percentages, which are in parentheses, do not always add up to 100%.
* Comparison of baseline characteristics for patients who had treatment interruptions due to thrombocytopenia, neutropenia, or both thrombo-
cytopenia and neutropenia when compared with controls yielded P values of † ° .05, ‡ ° .001, § ° .01, and \ ° .1.

The multivariate analysis model (Table 4) was used to
create a regression score for each patient. The total regres-
sion score for each individual patient was calculated by add-
ing scores from each of the following parameters. (1) The
total cumulative percentage of bone marrow irradiated was
given a score of 1.4 for each increment of 20% (eg, a patient
with 30% of marrow irradiated received a score of 2.8). (2)
The presence of brain metastasis was given a score of 2.0.
(3) Concurrent severely myelotoxic chemotherapy was given
a score of 3.8.

Table 3. Treatment Factors for Cancer Patients Who Had Interruptions in Radiotherapy Due
to Thrombocytopenia and/or Neutropenia, Compared With Controls
Thrombocytopenia Neutropenia Thrombocytopenia
Cases (n Å 45)* Cases (n Å 63)* / Neutropenia (n Å 37)* Controls (n Å 138)

Patients with previous bone marrow irradiation 5 (11) 5 (8) 5 (14) 15 (11)
Total cumulative percentage of marrow
irradiated (score)†
õ20% 1 15 (33) 23 (37) 12 (32) 84 (61)
20-39% 2 15 (33)‡ 22 (35)‡ 11 (30)‡ 46 (33)
40-59% 3 10 (22)‡ 11 (18)‡ 9 (24)‡ 7 (5)
60-79% 4 4 (9)‡ 6 (10)‡ 4 (11)‡ 0 (0)
¢80% 5 1 (2)‡ 1 (2)‡ 1 (3)‡ 1 (1)
(mean, 31.8) (mean, 30) (mean, 34) (mean, 18)
Patients with concurrent myelosuppressive 15 (33)‡ 20 (32)‡ 12 (32)‡ 3 (2)
chemotherapy
Patients with sequential myelosuppressive 14 (31)§ 17 (27)\ 14 (38)‡ 19 (14)
chemotherapy
Patients with previous myelosuppressive 20 (44)\ 26 (41)\ 20 (54)‡ 35 (25)
chemotherapy
No. of previous myelosuppressive chemotherapy
regimens (score )†
0 0 25 (56) 37 (59) 17 (46) 103 (75)
1 1 11 (24)§ 16 (25)\ 11 (30)§ 24 (17)
2 2 3 (7)§ 4 (6)\ 3 (8)§ 6 (4)
¢3 ¢3 6 (13)§ 6 (10)\ 6 (16)§ 5 (4)
Because of rounding, percentages, which are in parentheses, do not always add up to 100%.
* Comparison of treatment factors for patients who had treatment interruptions due to thrombocytopenia, neutropenia, or both thrombocyto-
penia and neutropenia when compared with controls yielded P values of ‡ ° .001, § ° .01, and \ ° .05.
† Test based on logistic regression using scores as noted.

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RADIOTHERAPY-ASSOCIATED MYELOSUPPRESSION 2307

Table 4. Results of Multivariate Analysis transfusions within 2 months of finishing radiation therapy,
Parameter compared with only 1 of the above and 2 other control
Variable Estimate OR P Value patients that required platelets within 2 months of the com-
A. Risk of treatment interruption pletion of therapy. Platelet transfusions within 2 months of
associated with thrombocytopenia completing radiation therapy occurred most frequently in
Total percentage of bone marrow patients that had had both thrombocytopenia and neutropenia
irradiated 1.42 4.1 õ.001 during treatment (10 patients) compared with thrombocyto-
Concurrent chemotherapy with high penia alone (1 patient) or neutropenia alone (no patients).
myelotoxicity potential 3.82 45.5 õ.001
Brain metastases 2.0 7.3 .01 Neutropenia With and Without Thrombocytopenia
B. Risk of treatment interruption
associated with neutropenia
A total of 63 patients with malignant disease had treatment
Total percentage of bone marrow interruptions associated with grade 3 or 4 neutropenia (neu-
irradiated 1.19 3.3 õ.001 tropenia cases). These were compared with the 138 randomly
Concurrent chemotherapy with high selected controls as described above. Thirty-seven (59%) of
myelotoxicity potential 3.74 42.1 õ.001 the 63 neutropenia cases had treatment interruptions that

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C. Risk of treatment interruption were also associated with thrombocytopenia. Baseline char-
associated with both acteristics of neutropenia cases and those patients that also
thrombocytopenia and had thrombocytopenia are shown in Table 2. Treatment fac-
neutropenia tors for these cases are shown in Table 3. Baseline character-
Total percentage of bone marrow istics and treatment factors for patients who had treatment
irradiated 1.37 3.9 õ.001
interruptions due to neutropenia as well as both neutropenia
Concurrent chemotherapy with high
and thrombocytopenia have been compared with controls
myelotoxicity potential 3.88 48.6 õ.001
and P values are shown in Tables 2 and 3 for those compari-
sons that were different with P ° .1.
Multivariate analysis (Table 4) confirmed that the most
Patients were arbitrarily categorized into low-risk, moder- important variables for the occurrence of a treatment inter-
ate-risk, and high-risk groups based on scores of less than ruption associated with neutropenia or with both thrombocy-
1.5, 1.5 to 4.5, or greater than 4.5. The distribution of patients topenia and neutropenia were the concurrent administration
between these different categories is shown in Table 5. Ac- of severely myelotoxic chemotherapy (ORs, 42.1 and 48.6,
cording to this criterion, only 4 (2%) of the control patients respectively; P õ .001) and the total cumulative percentage
would have been considered at high risk for thrombocyto- of marrow irradiated (OR increased by 3.3 and 3.9, respec-
penia versus 22 (49%) of those patients who were actually tively, for each 20% of bone marrow irradiated; P õ .001).
cases. Only 3 (7%) of the cases were categorized as low As for the thrombocytopenia cases, a regression score was
risk, compared with 74 (55%) of the controls. calculated for each case from these two groups using the
Based on these scores, the administration of concurrent results of the multivariate analysis. Cases and controls were
severely myelotoxic chemotherapy was found to cause a allocated to arbitrarily defined groups categorized as high,
risk of treatment interruption for thrombocytopenia, which intermediate, or low risk on the basis of these regression
is similar to the risk from irradiation of 40% to 60% of scores. Results of this analysis are shown in Table 5.
active marrow or the risk in a patient with brain metastasis Fifty-five patients had a treatment interruption of ¢3 days
undergoing radiation of 20% to 40% of active marrow.
Analysis of secondary outcome measures showed that 12
(26.7%) of the patients with treatment interruption due to
Table 5. Distribution of Patients Between High-Risk, Intermediate-
thrombocytopenia had at least one platelet count performed Risk, and Low-Risk Categories Based on Regression Scores for
that was less than 25 1 109/L and that 44 (98%) had a Thrombocytopenia and Neutropenia
treatment interruption of ¢3 days. Only 1 (õ1%) of the
Risk Category Score No. of Cases No. of Controls
control patients (who had no significant treatment interrup-
tions) had a platelet count of less than 25 1 109/L. Reduc- A. Thrombocytopenia
tions in administered radiation dose by greater than 10% of Low õ1.5 3 (7) 74 (55)
Intermediate 1.5-4.5 20 (44) 57 (42)
the planned dose occurred in 23 (51%) of the thrombocyto-
High ú4.5 22 (49) 4 (2)
penia cases, compared with 15 (11%) of the controls. A
B. Neutropenia
radiation dose reduction of greater than 10% occurred in 11 Low õ1.5 8 (13) 83 (60)
of 26 patients (42%) receiving treatment with curative intent Intermediate 1.5-3.5 18 (29) 45 (33)
who had treatment interruptions associated with thrombocy- High ú3.5 37 (59) 10 (7)
topenia as compared with 7 (7%) of the controls. Twenty- C. Thrombocytopenia
two (49%) of thrombocytopenia cases required a reduction and neutropenia
in daily fraction size. Platelet transfusions were administered Low õ1.5 3 (8) 83 (60)
to 7 (16%) cases (all of whom also had neutropenia) and 2 Intermediate 1.5-3.5 9 (24) 45 (33)
(1.4%) controls during the radiation therapy course. Two High ú3.5 25 (68) 10 (7)
of the above cases and 9 other cases also required platelet Percentages are in parentheses.

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2308
associated with neutropenia. Twenty-two neutropenia cases
(35%) and 11 neutropenia cases (24%) treated with curative
intent had reductions in the total administered dose of greater
than 10% compared with the planned dose, and 25 patients
required a reduction in daily fraction size. Thirty-seven pa-
tients with both thrombocytopenia and neutropenia had treat-
ment interruptions of ¢3 days in duration. Twenty of these
patients (54%) and 10 patients (46%) in this group that were
treated with curative intent had reductions in the total admin-
istered dose of greater than 10% compared with the planned
dose, and 20 patients required a reduction in the daily frac-
tion size.
DISCUSSION
A pretreatment assessment of the risk that a particular
patient will develop significant neutropenia or thrombocyto-
penia during radiotherapy is not simply an academic exer-
cise. We now have the ability to intervene, treating estab-
lished neutropenia with G-CSF21 or preventing it with the
use of prophylactic G-CSF.20 In addition, since the discovery
of the Mpl ligand,31-33 there is now the prospect of effective
treatment or prevention of chemotherapy and radiotherapy-
induced thrombocytopenia with a megakaryocyte colony-
stimulating factor. To effectively target the use of such an
agent in radiotherapy patients, an estimate of the risk of
significant myelosuppression for each individual would be
invaluable. In this study, we hoped to provide numerical
data to quantify the risks involved and to identify factors or
combinations of factors that were most highly predictive for
the occurrence of significant neutropenia and thrombocyto-
penia during radiotherapy.
Radiotherapy and chemotherapy cause different types of
bone marrow injury. Severe marrow injury occurs only
within the irradiated volume during radiotherapy, whereas
unirradiated marrow remains unaffected. Temporary func-
tional ablation of marrow within the radiation field may
occur even with relatively low radiation doses. If the irradi-
ated volume is small, there will be no significant effect on
peripheral blood counts. Repopulation of the marrow cavity
and restoration of active hematopoiesis may take several
years after exposure to moderate radiation doses.34 With
higher radiation doses, irreversible damage to the medullary
stroma may be associated with permanent marrow aplasia.
By contrast, myelotoxic chemotherapy causes injury to all
of the bone marrow, but recovery of peripheral blood counts
usually occurs within weeks. With many agents there appears
to be minimal long-term damage to hematopoietic tissues,
but some agents35,36 can cause prolonged depletion of mar-
row stem cells, compromising recovery from future bone
marrow injury by reducing bone marrow reserve. The inter-
action between these types of marrow injury is complex. In
this study, we have sought to determine the relative impor-
tance of chemotherapy and radiation-induced injury in pa-
tients who experienced significant hematopoietic toxicity
during radiotherapy.
Radiotherapy departments treat patients with an extremely
wide range of malignancies. Each neoplasm has a different
tendency to involve distant sites. Treatment strategies range
from small-field radiotherapy alone to intensive combina-
AID Blood 0042 / 5h31$$$821 02-27-97 16:00:50
MAC MANUS ET AL
tions of wide-field radiation therapy and combination chemo-
therapy. Any retrospective investigation attempting to cate-
gorize the widely varied treatments administered to such a
diverse population of patients requires a great deal of simpli-
fication. In this study, radiation treatments were categorized
by increasing volumes of marrow irradiated in increments
of 20%. Radiation dose was not considered because bone
marrow is exquisitely radiation sensitive and in all cases the
bone marrow dose was sufficiently high to cause severe
bone marrow injury within the irradiated volume during the
treatment course. Chemotherapy was considered in terms of
the presence of one or more severely myelotoxic drugs in a
particular regimen and by the number of different regimens
used, rather than by the number of cycles of each regimen.
Because this information was readily obtainable, we could
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include the maximum number of patients in the study and
thereby arrive at some general conclusions. Information on
the number of cycles of each chemotherapy regimen, the
dose intensity achieved for each patient, and the incidence
of myelotoxicity during chemotherapy might have been use-
ful in refining our model. However, in the setting of a retro-
spective study, this information could not readily be col-
lected for the majority of patients.
Our results indicate that the two strongest risk factors for
treatment interruptions during radiotherapy associated with
neutropenia or thrombocytopenia (or both) are the concurrent
administration of chemotherapy containing one or more se-
verely myelotoxic drugs and increasing volumes of active
bone marrow in the radiation field. Chemotherapeutic drugs
commonly concurrently administered during radiation ther-
apy included cisplatin, methotrexate, 5-fluorouracil, vincris-
tine, cyclophosphamide, adriamycin, and VP-16. In patients
receiving small-field radiation therapy, the chemotherapy is
probably primarily responsible for the myelosuppression and
the relative contribution of the radiation therapy to the my-
elosuppression increases with increasing amounts of bone
marrow in the field. The fact that the presence of brain
metastases was a stronger risk factor for thrombocytopenia
than the presence of either bone or bone marrow metastases
seemed initially to be a surprising result. However, this ob-
servation may reflect in part the fact that brain metastases
often occur relatively late in the course of malignant disease
in patients who are also likely to have received prior chemo-
therapy and/or radiation therapy. However, brain metastases
was still a predictor even after adjusting for the percent
of bone marrow irradiated in the multivariate analysis. The
increased risk of treatment interruption associated with neu-
tropenia in leukemia/lymphoma patients compared with
solid tumor patients is not surprising given the frequent use
of intense chemotherapy regimens and/or wide-field radio-
therapy in these patients. As would be expected, radiation
treatment interruption due to myelosuppression was more
common in patients with advanced disease compared with
local disease and increased in incidence with increasing
numbers of prior chemotherapy regimens. Other patient
characteristics, such as Karnofsky status, sex, weight, age,
and administration of nonchemotherapy drugs with a poten-
tial for marrow toxicity had no discernible impact on the risk
of a treatment interruption occurring during radiotherapy.
blda WBS: Blood
RADIOTHERAPY-ASSOCIATED MYELOSUPPRESSION
On the basis of the regression analysis it was possible
to identify three categories of patients who had different
probabilities of having an interruption in radiotherapy due to
thrombocytopenia, neutropenia, and both thrombocytopenia
and neutropenia. For these groups, the high-risk group con-
tained a large proportion of cases (49%, 59%, and 68%,
respectively) and a small proportion of controls (2%, 7%,
and 7%, respectively). Similarly, the low-risk groups con-
tained a small proportion of cases (7% of thrombocytopenia
cases, 13% of neutropenia cases, and 8% of cases with both
thrombocytopenia and neutropenia), but a large proportion
of controls (55% of thrombocytopenia controls and 60%
of both neutropenia and thrombocytopenia and neutropenia
controls). The large intermediate groups contained similar
proportions of cases and controls for all three groups, with
the largest intermediate group for both cases and controls
occurring in the thrombocytopenia group. Using these crite-
ria, it may be possible to identify approximately half of the
radiotherapy patients who are likely to develop problems
with treatment interruption due to thrombocytopenia or neu-
tropenia before treatment commences.
We plan to use this model in a prospective study in which
radiotherapy patients will be assigned prospectively to high-
risk, intermediate-risk, or low-risk groups for thrombocyto-
penia according to criteria derived from the multiple linear
regression analysis. Such a study will allow us to test the
hypothesis that the data presented here can be used to pro-
spectively estimate the risk that a particular patient will de-
velop significant thrombocytopenia during radiotherapy. Pa-
tients who fulfill the criteria for the high-risk category would
be potential candidates for future clinical trials involving a
platelet growth factor.
ACKNOWLEDGMENT
The authors thank Drs W. Sheridan and J.F. LaBrecque for their
thoughtful review of the manuscript, J. Ramback and J. Tod for
assistance with the database and data entry, E. Chen for assistance
with data collection, Dr J. Poen for assisting with the review of the
data collection forms, and S. Clarke for secretarial services in prepar-
ing this manuscript.
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