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ABSTRACT
Objective: To evaluate chemotherapy induced myelosuppression, its management and outcome.
Design: Retrospective analysis of patients aged 13 years and above.
Setting: Hurlingham Oncology Clinic and the Nairobi Hospital during the period of June 1998 to
June 2003.
Subjects: Two hundred and two solid tumour and lymphoma patients treated with pulsed
chemotherapy at Hurlingham Oncology Clinic and those treated by the same service at the Nairobi
Hospital.
Results: Two hundred patients were evaluable for nadir blood counts. World Health Organisation
(WHO) grade 3 neutropaenia complicated 57 (26.1%), and grade 4 complicated 56 (25.7%) treatments.
Grade 0 neutropaenia was seen in 40 (18.4%) treatments, 33 having included prophylactic
Granulocyte-Colony Stimulating Factors (G-CSF). Neutropaenia was worst following the first and
sixth courses, and repeated second line courses but the difference was not statistically significant
(p=0.1 54). Fever complicated 6 grade 3 and 21 grade 4 neutropenic episodes (23.1% of 117 evaluable).
Twenty eight patients were hospitalised because of severe neutropaenia (23 febrile, and five afebrile
initially but with absolute neutrophil counts <0.01 x l09/1itre). Eight of them died, six attributable to
infections (21.4% mortality) and two attributed to other causes. Median time to neutrophil recovery to
≥1.5 x 109/Iitre was three days with a mean of 4.6 days. Anaemia and thrombocytopaenia were not
commonly experienced.
Conclusion: Prophylactic use of G-CSF may have prevented severe neutropaenia and its use in
severe neutropaenia may have reduced the duration and severity of neutropaenia but the mortality
rate for febrile neutropaenia remained high.
East African Medical Journal Vol. 84 No. 1 January 2007
CHEMOTHERAPY INDUCED MYELOSUPPRESSION
N.A. Othieno-Abinya, MBChB, MMed, Associate Professor, Department of Clinical Medicine and Therapeutics, School
of Medicine, College of Health Sciences, University of Nairobi, P.O. Box 19676-00202, KNH, Nairobi, Kenya, A. Waweru,
MBChB, MMed, Physician, Kenyatta National Hospital, H.O. Abwao, MBChB, DMRT, Head, Cancer Treatment Centre,
Kenyatta National Hospital and Radiotherapy Department, Nairobi Hospital and L.O. Nyabola, BSc, MSc, MPH, Senior
Lecturer, Department of Community Health, School of Medicine, College of Health Sciences, University of Nairobi,
P.O. Box 19676-00202, Nairobi, Kenya
Request for reprints to: Prof. N.A. Othieno-Abinya, Department of Clinical Medicine and Therapeutics, School of
Medicine, College of Health Sciences, University of Nairobi, P.O. Box 19676-00202, Nairobi, Kenya
INTRODUCTION
All cellular components of blood are derived from
pluripotent stem cells in the bone marrow and
other haematopoietic tissues in the body. Under
the influence of haematopoietic growth factors
(HGFs), the stem cell divides and differentiates
via progenitor cells into various mature cell types
(1). This process of formation and production of
peripheral blood cells is known as haematopoiesis.
Under physiological conditions, it is a tightly
regulated, highly efficient system exquisitely
responsive to functional demands. Maintenance of
normal number of blood cells requires continuous
production to replace the aging or damaged cells
in circulation (2).
Chemotherapy for chemocurable cancers fails
either because chemosensitive tumour cells are
January 2007 E A S T A F R I C A N M E D I C A L J O U R N A L 9
spared by inadequate treatment, or resistant tumour
clones persist despite chemotherapy. Adequacy
of treatment is limited by drug related toxicity,
especially to the rapidly proliferating normal
tissue cells such as the haematopoietic cells and the
gastrointestinal epithelium. The bone marrow’s
storage compartment can supply mature cells to
the peripheral blood for 8-10 days, after which the
pool of primitive haematopoietic progenitor cells
ceases and the supply of these cells slows down.
It ceases after depletion of the more differentiated
committed progenitors (3). Following injury to
the bone marrow either by chemicals, radiation
or infection, the kinetics of cytopaenia induction
reflects the life span of the cells in pheripheral
blood. On average, neutrophils have a life of 6-10
hours, platelets 7-10 days and erythrocytes 120 days
in circulation. Suppression of the peripheral blood
cells is therefore generally noted approximately a
week following a toxic insult to the bone marrow.
In previously untreated patients, several of the most
commonly used cytotoxic agents when administered
cause leukopaenia and thrombocytopaenia by day
9 or 10 after treatment. Nadir counts are reached in
10-14 or even up to 18 days and recovery is evident
by day 21 and complete by day 28 (3).
The consequences of reduced or absent
neutrophils are dramatic in grade 3 neutropaenia,
with increased susceptibility to infection. In grade
4 neutropaenia control of endogenous microbial
flora is impaired and opportunistic infections set
in. Below 0.2 x 109/litre the inflammatory response
of the body breaks down (4). Severe degrees of
thrombocytopaenia do not frequently complicate
management of patients with solid tumours
receiving cytotoxic chemotherapy unless the bone
marrow is infiltrated (5). It occurs commonly in
treatment of haematologic neoplasms. When it
occurs, thrombocytopaenia increases the risk of
haemorrhage, necessitates platelet transfusions and
limits the dose of myelotoxic agents (6).
Severe anaemia rarely complicates cancer
chemotherapy in the majority of cases and when
it occurs it is easily managed with red blood
transfusions or administration of recombinant
erythropoietin.
We retrospectively studied files of cancer
patients who had undergone pulsed chemotherapy
at Hurlingham Oncology Clinic or those who had
been treated at the Nairobi Hospital under the
services of the clinic. The aim was to assess the
impact of chemotherapy and see the effectiveness of
interventions instituted in case of severe reduction
in one or more of the haematopoietic cell lines.
Patients with acute leukaemias including blastic
phase of chronic myeloid leukaemia were excluded.
Permission was obtained from the Nairobi Hospital
Standards and Ethics Committee before the study
was commenced. All files of patients that met the
inclusion criteria were studied.
MATERIALS AND METHODS
The following information was obtained from the
patient’s files; age, sex, weight, height, diagnosis
(histology), date of diagnosis, baseline blood counts
(haemoglobin, platelets, total white cell counts and
absolute neutrophil count, liver function tests, serum
proteins), disease stage and staging classification,
goal of treatment (neoadjuvant, adjuvant, metastatic
curative, palliative), chemotherapy protocol,
treatment course, nadir blood counts. Also checked
were whether prophylactic G-CSF neupogen
in this case was used, dose and duration of
neupogen administration, grade 3-4 neutropaenia,
febrile neutropaenia, septic deaths, grade 3-4
thrombocytopaenia, platelet transfusion before the
next course of chemotherapy, was next course of
chemotherapy delivered in time, was G-CSF used for
febrile neutropaenia, the absolute neutrophil count
at the time of commencing neupogen and what
the duration to attainment of absolute neutrophil
counts of ≥ 1.0 x 109/litre and ≥ 1.5 x 109/litre was
whether treatment was completed, what the relative
dose-density of the cytotoxic agents delivered was,
what the outcome of treatment was, the last date of
follow-up and the disease status at the last date of
follow-up, if death occurred, what the cause of death
was and date of death.
This information was entered in a structured
proforma. The degree of reduction of haematological
parameters was classified according to the WHO
criteria (7). For metastatic disease, treatment
outcome was classified as complete remission, partial
remission stable disease or progressive disease. Data
analysis was done by computer package, Statistical
Package for Social Sciences (SPSS) and presented in
tables. Students T-test was used for variable data and
Chi-square test for continuous variables.
10 E A S T A F R I C A N M E D I C A L J O U R N A L January 2007
RESULTS
Results were evaluable for a total of 202 patients with
solid tissue tumours and malignant lymphomas
treated with pulsed intensive chemotherapy. Fifty
(24.8%) had breast carcinoma and 47 (23.3%) had
non-Hodgkin’s lymphomas (NHL) of aggressive
phenotype. Fourteen of the NHLs (29.8%) were
AIDS-related. Twenty two patients (10.9%) had
AIDS-related Kaposi’s sarcoma (Table 1).
A total of 218 treatments were evaluable for
nadir blood counts. The most commonly used
treatment regimens were doxorubicin 60 mg/m2
and cyclophosphamide 600 mg/m2 at 3 week
intervals (AC 60/600) for breast carcinoma. It was
used in 61 treatments (27%). Doxorubicin 50 mg/m2
and cyclophosphamide 500 mg/m2 given at 3 week
intervals (AC 50/500) was used in 20 treatments,
also for breast carcinoma (8.8% of all treatments).
Cyclophosphamide, doxorubicin, vincristine and
prednisone (CHOP) was used in 31 treatments
(13.7%) for aggressive phenotype non-Hodgkin’s
lymphoma (Table 2).
World Health Organisation (WHO) grade 3
neutropaenia complicated 57 treatments out of
218 evaluable (26.1%) and grade 4 neutropaenia
complicated 56 treatments (25.7%). The CHOP
protocol was complicated by grade 4 neutropaenia
in seven out of 31 treatments (22.6%) and AC
60/600 was complicated by grade 4 neutropaenia
in 13 out of 61 treatments (21.3%). AC 50/500 was
complicated by grade IV neutropaenia in five out of
20 treatments (25%) (Table 2). Grade 0 neutropaenia
was registered in 40 treatments (18.4%) of which 33
(82.5%) had been covered by prophylactic neupogen.
Neutropaenia was severest after the first and sixth
treatment courses, and also following repeated
second line treatments, but the differences were not
statistically significant (P = 0.154) (Table 3).
Fever comp1icated six out of 52 treatments
with grade 3 neutropaenia (11.5%) and 21 out of 38
treatments with grade 4 neutropaenia (55.3%). The
correlation between occurrence of fever and severity
of neutropaenia was highly significant (P< 0.0005)
(Table 4).
Twenty eight patients were hospitalised because
of severe neutropaenia. Twenty three (82.1%) had
fever on admission while five (17.9%) were admitted
because of absolute neutrophil counts <0.01 x
109/litre but later four developed fever while in
the ward. Reverse barrier nursing was instituted
on all the patients admitted and G-CSF plus broad
spectrum antibiotics administered. Standard septic
screens were also carried out. Viral screens were not
routinely carried out unless the fever persisted for
over a week.
Eight of the admitted patients (28.6%) died, six
of the deaths (21.4%) were attributed to sepsis and
two (7 1%) were attributed to causes other than
sepsis. Whereas severe thrombocytopaenia was not
commonly encountered and only four treatments were
complicated with life threatening thrombocytopaenia
and the patients had to be given platelet transfusions,
grades 3 and 4 thrombocytopaenia tended to occur
in presence of grade 4 neutropaenia. This was
mainly apparent for patients with grade 4 febrile
neutropaenia (Table 5).
Of the 27 patients who had symptomatic
neutropaenia, 11 (40.7%) had platelet counts within
the normal range, 26 (96.3%) had grade 4 neutropaenia
and four (14.8%) had grade 4 thrombocytopaenia.
One patient with grade 3 neutropaenia developed
fever.
The median time to neutrophil recovery to
≥ 1.0 x 109/litre was three days with a mean of 4.3
days. The median time to neutrophil recovery to
≥ 1.5 x 109 /litre was also 3 days with a mean of 4.6
days. The level of platelets at the time of fever did
not correlate with severity of neutropaenia (p=0.44)
though overall thrombocytopaenia correlated
with the level of neutropaenia (Table 5). Of 205
treatments evaluable, 19 (9.3%) required red blood
cell transfusion to ‘keep haemoglobin levels ≥ 10g/dl
required for the next treatment.
Of the patients who died, one aged 32 years at
the time of diagnosis had hepatocellular carcinoma.
He had survived for 33 months from diagnosis.
During this time he had been able to perform
his duties fully until the last two weeks when
his condition rapidly deteriorated. He died from
complications of hyperkalemia in acute renal
failure. The other one was a 56 year old male patient
with breast carcinoma refractory to hormonal
therapy,died after the 6th course of AC and had
febrile neutropaenia. Another, a 23-year-old female
with malignant neuroectodermal tumour (MNnet),
died of progressive disease.
A 52 year old man with hormone refractory
prostatic carcinoma was put on decetaxel and
chlorambucil but died of severe haemorrhage
January 2007 E A S T A F R I C A N M E D I C A L J O U R N A L 11
complicating thrombocytopaenia due to
disseminated intravascular coagulopathy. Another
50-year-old dentist had hepatocellular carcinoma.
He was treated with doxorubicin and cis-platin and
was discharged, two days post chemotherapy. He
developed intractable nausea and vomiting while
at home but was reluctant to be readmitted until he
became severely dehydrated with prerenal azotemia.
He developed severe pancytopaenia and died
from multiple organ failure. A 35-year-old patient
with metastatic breast carcinoma with lumbar
cord compression developed severe diarrhoea
while undergoing concurrent chemotherapy and
radiotherapy. She became septicaemic due to severe
neutropaenia and died. Of the 14 patients with HIV
non-Hodgkin’s lymphoma all were treated with
CHOP chemotherapy and one died from febrile
neutropaenia.
Table 1
Types of cancers
Diagnosis Number of patients
Breast carcinoma 50
Non-Hodgkin’s lymphoma
Non HIV related 33
HIV related 14
Kaposi’s sarcoma
HIV related 22
Non-HIV related 2
Carcinoma of the colon 19
Hepatocellular carcinoma 7
Ovarian carcinoma 7
Cervical carcinoma 7
Gastric carcinoma 5
Hodgkin’s disease 5
Prostate carcinoma 5
Others 26
Total 202
Table 2
Protocol against Nadir Neutrophil count for the more frequently used protocol
0 1 2 3 4
Protocol No. (%) No. (%) No. (%) No. (%) No. (%)
AC 60/600 (n = 61) 10 16.4 10 16.1 15 24.6 13 13.3 13 21.3
AC 50/500 (n = 20) 3 15 1 5 3 15 8 40 5 25
CHOP (n = 31) 9 29 0 0 4 12.9 11 35.5 7 22.6
CAF 600/60/600 (n = 10) 0 0 2 20 3 30 4 40 1 10
F/Plat (n = 5) 1 20 0 0 0 0 1 20 3 60
EDF (n = 6) 0 0 1 16.7 2 33.3 1 16.7 2 33.3
Tax/Dox (n = 8) 0 0 0 0 2 25 3 37.5 3 37.5
AC = Doxorubicin/cyclophosphamide
CHOP = Cyclophosphamide, doxorubicin, vincristine, prednisone
CAF = Cyclophosphamide, doxorubicin, 5-Fluorouracil
F/Plat = 5-Fluorouracil, cis-platin
EDF = Etoposide, doxorubicin, 5-Fluorouracil
Tax/Dox = Docetaxel/doxorubicin
12 E A S T A F R I C A N M E D I C A L J O U R N A L January 2007
Table 3
Nadir neutrophil grade against course of treatment (n = 218)
Grade of neutropaenia
0 1 2 3 4
Treatment course No. (%) No. (%) No. (%) No. (%) No. (%)
1. (n = 77) 14 18.2 9 11.7 8 10.4 19 24 27 35.1
2. (n = 39) 5 12.8 5 12.8 15 38.5 7 17.9 7 17.9
3. (n = 35) 4 11.4 7 20 6 17.1 13 37.1 5 14.3
4. (n = 21) 1 1.8 3 14.3 7 33.3 7 33.3 3 14.3
5. (n = 21) 6 28.6 4 19.0 1 4.8 6 28.6 4 19.0
6. (n = 21) 1 4.8 3 14.3 2 9.5 8 38.1 7 33.3
n (n = 4) 0 0 0 0 0 0 1 25.0 3 75.0
n = Undetermined course in the second line in heavily pretreated patients
(P = 0.154)
Table 4
Occurence of fever according to degree of neutropaenia (n = 218)
Gradient of neutropaenia
3 41 42 43 44 45
No. (%) No. (%) No. (%) No. (%) No. (%) No. (%)
Fever present (n = 27) 6 10.3 10 22.2 4 66.7 2 100 2 100 3 75.0
No fever (n = 90) 52 89.7 35 77.8 2 33.3 0 0 0 0 1 25.0
(P < 0.001)
Grade of neutropaenia
41 0.1 – 0.499 x 109/litre
42 0.05 – 0.099 x 109/litre
43 0.25 – 0.049 x 109/litre
44 0.01 – 0.024 x 109/litre
45 <0.01 x 109/litre
Table 5
Nadir neutropaenia against Nadir thrombocytopaenia (n = 203)
Grade of neutropaenia
Grade of 0 1 2 3 4
Thrombocytopaenia No. (%) No. (%) No. (%) No. (%) No. (%)
0. (n = 180) 23 12.8 24 13.3 33 18.3 56 31.1 44 24.4
1. (n = 6) 1 16.7 0 0 2 33.3 0 0 3 50
2. (n = 5) 1 20 0 0 0 0 2 40 2 40
3. (n = 9) 0 0 1 11.1 1 11.1 0 0 7 77.8
4. (n = 3) 0 0 0 0 0 0 0 0 3 100
January 2007 E A S T A F R I C A N M E D I C A L J O U R N A L 13
DISCUSSION
In delivering chemotherapy for chemosensitive/
chemocurable neoplasms dose considerations are
very important. The importance of dose intensity
was first recognised by Frei and Canellos who
demonstrated that a logarithmic increase in
cytotoxicity could be achieved with a linear increase
in chemotherapy dosage (8). Building on this,
Hryniuk and others demonstrated in retrospective
studies that an increased dose intensity of cytotoxic
drugs within the conventional dose range may have
a marked effect on breast cancer (9,10). Dose intensity
of drugs in a given treatment should be as close as
possible to those in the standard protocol. What
limits the dose that can be delivered unfortunately
is tissue toxicity to the rapidly proliferating cells,
especially those derived from the bone marrow
and gastrointestinal tract (GIT) epithelium. Lifetime
accumulation of the two doses of certain drugs above
certain levels is also detrimental to other organs.
Examples are cardiotoxicity of anthracyclines,
pulmonary toxicity by bleomycin and busulphan
in particular.
It has been our policy to deliver chemotherapy to
as near full doses as possible. Because of the pattern
Table 6
Degree of neutropaenia and thrombocytopaenia at the start of neupogen in relation to death amongst patients who
were admitted with severe neutropaenia (n = 27)
Platelet count x 109/litre Absolute neutrophil count Whether death occurred or not
x 109/litre
91 0.018 No
41 0.06 Yes
20 0.005 Yes
93 0.153 No
154 0.396 No
186 0.0024 No
127 0.846 No
314 0.19 No
166 - Yes
10 0.002 Yes
24 0.26 No
47 0.03 No
30 0.032 No
131 0.061 Yes
152 0.015 No
127 0.179 No
45 0.225 No
144 0.026 No
159 0.064 No
48 0.195 No
26 0.026 Yes
14 0.01 Yes
36 0.008 No
152 0.015 No
65 0.028 No
144 0.026 No
26 0.004 No
18 0.021 Yes
14 E A S T A F R I C A N M E D I C A L J O U R N A L January 2007
of diseases as we see them, the AC protocol for
breast carcinoma and the CHOP protocol for NHLs
were most commonly used. In our earlier report on
neutropaenia with the AC protocol, AC 60/600 was
associated with grade 4 neutropaenia of 27.8% (11). In
the current report grade 4 neutropaenia comp1icated
22.6% of treatments with CHOP and 21.3% of
treatments with AC 60/600. It is paradoxical that AC
50/500 was associated with grade 4 neutropaenia
more frequently than AC 60/600. The reason is
that patients had doxorubicin/cyclophosphamide
doses scaled downwards from 60/600 to 50/500
only if in the previous course they had had severe
nadir cytopaenias. Many such patients went on to
experience severe toxicity even at the lower dose.
Overall, 25.7% of treatments were complicated by
grade 4 neutropaenia. These levels of neutropaenia
are much higher than those reported from NSABP
B22 where grade 4 neutropaenia complicated 6.5%
of treatments with AC at 60/600 (12). On the other
hand, we also know that there are conflicting reports
of the rates of grade 3 and 4 neutropaenia experienced
with commonly employed chemotherapy regimens
in primary breast cancer in particular. Dale and
colleagues reported grade 3 and 4 neutropaenia in
78% of patients treated with CMF protocol and up
to 100% of those treated with CAF or CEF (13).
For any given protocol in our study neutropaenia
was worst in the first treatment and after repeated
treatments but this did not reach statistical
significance. Other studies have shown the degree
of neutropaenia to be worst with the first two
treatments (14). Patients who received prophylactic
G-CSF following chemotherapy were protected
from developing severe neutropaenia, but subgroup
analysis was not carried out to find out the degree
to which G-CSF was protective. The risk of febrile
episodes correlated significantly with severity
of neutropaenia. Those findings have long been
established and hence the need to use prophylactic
granulocyte or granulocyte macrophage colony
stimulating factor (G-CSF or GM-CSF respectively)
to prevent severe neutropaenia and the development
of sepsis (15,16).
The mortality rate from septic neutropaenia was
21.4% in this study, much higher than 7% reported
from other studies (17). Ease of communication
could be a contributing factor. Patients who live far
outside Nairobi were at higher risk of death if they
developed febrile neutropaenia. Other reports have
also shown mortality associated with gram negative
sepsis in neutropenic patients to be between 10-
30%, despite the prophylactic use of potent, broadspectrum
antibiotics.
Incidentally, patients infected with the human
immune deficiency virus did not display outstanding
mortality rates compared with non-HIV infected
patients in this study, but again HIV infected
patients were more likely to have received post
chemotherapy prophylactic G-CSF.
Anaemia and thrombocytopaenia did not
commonly complicate chemotherapy in this study.
Depending on the tumour type, the incidence of
anaemia at the time of diagnosis ranges from 20%
to 60% (18). Chemotherapy and/or radiotherapy
can also induce anaemia or aggravate that which
already exists (2, 3). This usually is not a major
problem as it is easily corrected with red blood
cell transfusions or administration of recombinant
human erythropoietin (rHuEPO). Only 9.3% of the
patients had red blood cell transfusion. Bleeding
from thrombocytopaenia is also prevented by
transfusion of platelet concentrates to maintain
counts above 20 x 109/litre.
Even though reduction in platelet numbers
did not correlate with neutropaenia, patients with
febrile neutropaenia tended to develop severe
thrombocytopaenia. This is not unusual as fever
tends to promote platelet destruction and febrile
neutropaenia patients may also harbor some degree
of disseminated intravascular coagulopathy, with
attendant platelet consumption.
The median time to neutrophil recovery to ≥ 1.0 x
109 for patients admitted with grade 4 neutropaenia
was three days with a mean of 4.3 days and that to
≥ 1.5 x 109/litre was three days with a mean of 4.6
days. This is fairly similar to a median of three days
to recovery to ANC of ≥ 0.5 x 109/litre for those who
were treated with filgrastin as opposed to five days
of those who were on placebo as found by Mitchell
and colleagues (19). Similar findings were also
documented by Maher et al (20).
In both these studies however, shortening the
duration of neutropaenia did not impact positively
on survival.
CONCLUSION
Neutropaenia was the main haematologic toxicity
complicating chemotherapy as observed in this
January 2007 E A S T A F R I C A N M E D I C A L J O U R N A L 15
study. The risk of infection correlated with the
severity of neutropaenia.
Prophylactic G-CSF post chemotherapy may have
prevented the development of severe neutropaenia
in a good proportion of the patients and also
shortened the duration of severe neutropaenia
by a few days. However, the mortality from
febrile neutropaenia was very high, though quite
comparable with findings in several other studies.
Severe thrombocytopaenia and anaemia were not
frequently encountered.
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