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KOUROUKIS et al.
9
CURRENT ONCOLOGY—VOLUME 15, NUMBER 1
Copyright © 2008 Multimed Inc.
ABSTRACT
Hematologic toxicities of cancer chemotherapy are
common and often limit the ability to provide treat-
ment in a timely and dose-intensive manner. These
limitations may be of utmost importance in the adju-
vant and curative intent settings. Hematologic toxici-
ties may result in febrile neutropenia, infections,
fatigue, and bleeding, all of which may lead to addi-
tional complications and prolonged hospitalization.
The older cancer patient and patients with significant
comorbidities may be at highest risk of neutropenic
complications. Colony-stimulating factors (
CSF
s) such
as filgrastim and pegfilgrastim can effectively attenu-
ate most of the neutropenic consequences of chemo-
therapy, improve the ability to continue chemotherapy
on the planned schedule, and minimize the risk of fe-
brile neutropenia and infectious morbidity and mor-
tality. The present consensus statement reviews the use
of
CSF
s in the management of neutropenia in patients
with cancer and sets out specific recommendations
based on published international guidelines tailored to
the specifics of the Canadian practice landscape. We
review existing international guidelines, the indications
for primary and secondary prophylaxis, the importance
of maintaining dose intensity, and the use of
CSF
s in
leukemia, stem-cell transplantation, and radiotherapy.
Specific disease-related recommendations are provided
related to breast cancer, non-Hodgkin lymphoma, lung
cancer, and gastrointestinal cancer. Finally,
CSF
dosing
and schedules, duration of therapy, and associated acute
and potential chronic toxicities are examined.
KEY WORDS
Canadian recommendations, neutropenia, febrile neu-
tropenia, supportive care, colony-stimulating factors,
chemotherapy-induced neutropenia, safety
1. INTRODUCTION
Advances in cancer treatment have led to the devel-
opment and administration of more-complex chemo-
therapy regimens in a wider spectrum of cancer pa-
tients, often resulting in increases in hematologic tox-
icities. Also, as the population ages and demographics
shift, greater numbers of older adults, some with sig-
nificant comorbidities, are being considered for che-
motherapy that may result in significant toxicity.
Agents to attenuate hematologic toxicities have
been in widespread use, particularly in primary and
secondary prevention of the neutropenia and febrile
neutropenia (FN) associated with chemotherapy and
stem-cell transplantation (SCT). In cancer patients, FN
has been shown to have a significant impact on pa-
tient outcomes and on the health care system 1. The
potential benefits of colony-stimulating factors (CSFs)
such as granulocyte colony–stimulating factor (G-CSF)
must be measured against their cost and potential
toxicities.
The consensus statement presented here was pre-
pared to summarize, from the Canadian perspective,
current guidelines on the use of
CSF
s, taking into ac-
count the available evidence and recently updated in-
ternational guidelines
2–4
. The present paper reviews
the updated guidelines, recommendations for primary
and secondary prophylaxis, and the use of growth fac-
tors in leukemia,
SCT
, and radiotherapy. In addition,
disease-specific recommendations are made for breast
cancer, lymphoma, lung cancer, and gastrointestinal
cancer. Finally, the latest safety information regard-
ing the use of growth factors is discussed.
2. SUMMARY OF EXISTING GUIDELINES
The American Society of Clinical Oncology (ASCO),
the European Organization for Research and Treat-
ment of Cancer (EORTC), and the National Compre-
hensive Cancer Network (NCCN) have all published
guidelines for the use of CSFs in patients with can-
cer 2–4 (Table I).
The 2005 ASCO guidelines were updated 2 from
the 2000 version; their evidence base included
MEDLINE and Cochrane Library searches up to and
including September 2005. The ASCO guidelines en-
dorse the importance of preventing FN as a clinical
Canadian supportive care
recommendations for the
management of neutropenia
in patients with cancer
C.T. Kouroukis
MD
MS
c,* S. Chia
MD
,
†
S. Verma
MD
,
‡
D. Robson
MD
,
‡
C. Desbiens
MD
,
§
C. Cripps
MD
,
||
and
J. Mikhael
MD
ME
d
#
PRACTICE GUIDELINE SERIES
PRACTICE GUIDELINE SERIES
CURRENT ONCOLOGY—VOLUME 15, NUMBER 1
10
outcome, regardless of other factors, particularly
when the FN rate associated with treatment is at least
20% and no other equally efficacious regimen that
would not require CSFs is available. Primary prophy-
laxis with CSFs is recommended for FN prevention in
patients at higher risk based on age, medical history,
disease characteristics, and myelotoxicity of the che-
motherapy regimen. Dose-dense chemotherapy re-
quiring CSFs is recommended only when clearly
supported by the available evidence or as part of a
clinical trial. Prophylactic CSF is suggested for older
patients (65 years of age or older) with aggressive-
histology lymphoma treated with curative intent. Sec-
ondary prophylaxis is recommended for patients who
experience a neutropenic complication associated
with an earlier chemotherapy cycle and in whom a
reduced dose in a subsequent cycle could compro-
mise disease-free survival (DFS), overall survival (OS),
or another treatment outcome.
In 2006, EORTC published its guidelines for the
use of CSFs in patients with cancer and chemotherapy-
induced neutropenia. Those guidelines were based
on literature published from 1996 through Septem-
ber 2005 3. In 2003, the EORTC Cancer in the Elderly
Task Force had published guidelines regarding the
use of CSFs in elderly patients with cancer 5. The EORTC
guidelines recommend prophylactic CSFs when the FN
rate of the proposed treatment is 20% or more. In the
case of regimens with FN rates of between 10% and
20%, the decision to use CSFs should be based on
patient-related risk factors, such as older age (over
65 years of age), advanced stage of disease, previ-
ous FN episodes, and lack of antibiotic prophylaxis.
As do the ASCO guidelines, the EORTC guidelines rec-
ommend CSFs when a reduction in chemotherapy is
associated with poorer prognosis and when dose-
dense regimens associated with a clinical and sur-
vival benefit are being used.
The updated NCCN guidelines for the management
of chemotherapy-induced neutropenia 4 are based on
a panel review of available evidence. The NCCN guide-
lines recommend routine CSF use to reduce the risk of
FN, the risk of hospitalization, and the use of intrave-
nous antibiotics in patients treated with a regimen
associated with a 20% risk of FN (category 1 evi-
dence). That recommendation encompasses patients
receiving curative or adjuvant treatment and treat-
ment to prolong survival or to improve quality of life.
For patients being treated with regimens associated
with a 10%–20% risk of FN, consideration should be
given to using a CSF in high-risk patients, but CSFs
should not be used in low-risk patients (those with a
less-than-10% risk of FN), unless a specific patient is
at significant risk of serious consequences of FN and
that patient is being treated with curative or adjuvant
intent.
Filgrastim (Neupogen: Amgen, Thousand Oaks,
CA, U.S.A.), pegfilgrastim (Neulasta: Amgen), and
ancestim (Stemgen: Amgen) are the only CSFs ap-
proved for use in Canada.
3. GUIDELINES FOR PROPHYLAXIS
3.1 Primary Prophylaxis
Updated international guidelines 2,3 have suggested
broadening the indication for CSF use for primary pro-
phylaxis in patients with solid tumours and hemato-
logic malignancies alike. The upfront use of G-CSFs is
suggested with the use of dose-dense chemotherapy
in some patients with breast cancer 6 and hematologic
malignancies 7. Figure 1 shows a combined EORTC and
ASCO algorithm (combined interpretation of the 2006
G-CSF guidelines of ASCO 2 and EORTC 3) for primary
G-CSF prophylaxis.
Based on the ASCO and EORTC updates, the thresh-
old to recommend primary prophylaxis with G-CSFs
was reduced from a 40% to a 20% risk of FN. The
initial estimate of 40% had been calculated from a
pharmacoeconomic study 8 based on the results of a
randomized study using G-CSF in patients with small-
cell lung cancer (SCLC) 9. The pharmacoeconomic
analysis indicated that prophylactic use of G-CSFs was
cost-effective when the FN rate was at least 40%. The
current lower value of 20% risk was arrived at using
clinical rather than economic evaluation. Addition-
ally, more recent studies have indicated that G-CSFs
can dramatically reduce the FN rate even in patients
with a baseline FN risk of about 20% 10,11.
The evaluation of neutropenia risk has been sum-
marized for several types of chemotherapy regimens
(see the EORTC guidelines’ Table 4 or the ASCO guide-
TABLE ICurrent guidelines for primary prophylaxis with granulocyte colony–stimulating factor (G-CSF) 2–4
Neutropenic event risk ASCO 2006 2 EORTC 2006 3 NCCN 2006 4
Moderate to high Use G-CSF (~20%) Use G-CSF (≥20%) Use G-CSF (>20%)
Intermediate Recommend G-CSF (<20%) Consider G-CSF (10%–20%) Consider G-CSF (10%–20%)
Low Not specified G-CSF not recommended (<10%) G-CSF not recommended
for most patients (<10%)
Risk factor assessment +++ +++ ++
ASCO = American Society of Clinical Oncology; EORTC = European Organization for Research and Treatment of Cancer; NCCN = National
Comprehensive Cancer Network.
KOUROUKIS et al.
11
CURRENT ONCOLOGY—VOLUME 15, NUMBER 1
lines’ Table 1 for a complete list). Although the rel-
evant data were taken from clinical trials, it is impor-
tant to realize that the risk of FN in practice could be
substantially higher, particularly if patients are older
or have comorbidities that may render them ineligible
for most clinical trials and increase their risk of com-
plications 1,5. The ASCO and EORTC guidelines have both
highlighted the higher risk of FN and infectious com-
plications in older cancer patients.
In a systematic review of randomized trials pub-
lished up to December 2006 that tested primary pro-
phylaxis with CSFs in patients with solid tumours or
lymphoma, significant improvements were noted in
infection-related mortality, early mortality, and FN 12.
Patients receiving CSFs experienced more bone pain
and a higher average relative dose intensity (DI). The
hospitalization rate and cancer-related survival data
were insufficient for a complete analysis.
In a 2004 Cochrane review that included studies
up to August 2003, use of CSFs as primary prophy-
laxis in patients with malignant lymphoma receiving
conventional chemotherapy was associated with a
reduction in the risk of severe neutropenia, FN, and
infection. No evidence of benefit was observed for a
reduction in the number of patients receiving intra-
venous antibiotics, a lower infection-related mortal-
ity, or any improvement in tumour response, freedom
from treatment failure, or OS 13.
No published Canadian economic models have
investigated the cost effectiveness of G-CSFs for pa-
tients with at least a 20% risk of FN, and economic
evaluations from other jurisdictions may not be ap-
plicable to Canadian practice 14. The ASCO recommen-
dations emphasize that the decision to use G-CSFs to
prevent FN should be based on clinical data rather
than on economics, looking at evidence of reduction
in infection-related endpoints.
A number of models that were developed to as-
sist in predicting neutropenic complications from
chemotherapy have previously been summa-
rized 15–17. In one example, targeted filgrastim therapy
based on the nadir absolute neutrophil count (ANC) in
the first cycle of adjuvant treatment for breast cancer
resulted in fewer hospitalizations, but no clinical out-
come advantages in survival or quality of life were
observed 18,19.
3.1.1 Summary of Guidelines for Primary Prophylaxis
• The use of CSFs is recommended if the treatment
being contemplated is associated with a FN rate
of at least 20%, particularly in the curative or ad-
juvant setting.
• The use of
CSF
s is recommended when risk factors
that may increase the toxicities of chemotherapy—
such as older age (≥65 years), comorbidities, and
previous neutropenic complications—are present.
• When patients are being treated with regimens
associated with a 10%–20% risk of FN, clinical
judgment should be applied regarding the ben-
efits of CSFs, based on clinical, laboratory, patient
risk, and disease factors.
FIGURE 1 Combined European Organization for Research and Treatment of Cancer 3 and American Society of Clinical Oncology 2 algorithm
for primary prophylaxis with granulocyte colony–stimulating factor (G-CSF). FN = febrile neutropenia; NHL = non-Hodgkin lymphoma.
PRACTICE GUIDELINE SERIES
CURRENT ONCOLOGY—VOLUME 15, NUMBER 1
12
3.2 Secondary Prophylaxis
When maintaining chemotherapy
DI
is important,
G
-
CSF
s are recommended for patients who have al-
ready experienced a neutropenic complication (for
example,
FN
or neutropenia) resulting in a treatment
delay. Maintaining
DI
in such situations minimizes
treatment delay and infectious morbidity with the
intent of avoiding compromise to cancer-related sur-
vival. These criteria are expected to apply best to
patients receiving curative treatment who have al-
ready experienced a significant neutropenic event.
In palliative therapy, less myelotoxic regimens or
flexibility in the chemotherapy schedule to avoid sig-
nificant neutropenic events is preferable. Because
much of the recent evidence on the use of
G
-
CSF
s is
disease-specific, disease-specific situations [breast
cancer, gastrointestinal cancer, lung cancer, and non-
Hodgkin lymphoma (
NHL
)] are discussed later in this
paper.
As noted in the ASCO guidelines, no prospective
studies have specifically evaluated the efficacy of
secondary prophylaxis. Development of FN would be
considered a significant neutropenic event worthy of
future G-CSF prophylaxis.
3.2.1 G-CSF Use During FN
One randomized study 20 and two systematic re-
views 21,22 addressed the issue of CSF use during FN.
Although benefits were observed in terms of shorter
duration of neutropenia, shorter hospitalizations, and
perhaps less infectious burden, no differences in sur-
vival were seen. The authors felt that the use of G-CSFs
during FN would be reasonable if the patient was ex-
periencing a complicated FN episode—for example,
pneumonia, multi-organ dysfunction, or hypotension.
3.2.2 Summary of Guidelines for Secondary Prophylaxis
• In patients with a previous neutropenic compli-
cation, CSFs should be used provided that the al-
ternative of dose reduction may impair tumour
response, survival, or treatment outcome.
• Use of a CSF during FN should be reserved for
patients experiencing a complicated FN episode
(for example, pneumonia, multi-organ dysfunc-
tion, hypotension).
4. GUIDELINES FOR MAINTAINING DI
The clinical benefits of maintaining DI are perhaps
best demonstrated in adjuvant chemotherapy trials
in early-stage breast cancer. The concept of DI is de-
fined as the amount of drug delivered per unit time
(for example, milligrams per square meter delivered
per week or per cycle), and its impact on breast can-
cer outcomes has been the primary hypothesis in sev-
eral prospective randomized trials. The French
Adjuvant Study Group 05 trial compared high and
low (50%) DIs of epirubicin (E100 vs. E50 every
21 days) in a combination containing 5-fluorouracil
(5-FU), epirubicin, and cyclophosphamide (FEC) 23.
The higher DI arm yielded significant improvements
in DFS and OS. Similarly, the Cancer and Leukemia
Group B 8541 trial compared high, intermediate, and
low DIs of doxorubicin, in a combination of cyclo-
phosphamide, doxorubicin, and 5-FU 24. At high and
intermediate DIs, women experienced significantly
improved DFS and OS over those experienced by
women in the low DI group. Those two trials demon-
strated that, within the standard anthracycline dose
range, a threshold effect exists, meaning that adju-
vant chemotherapy delivered using a suboptimal DI
or lower cumulative anthracycline dose (or both) is
less efficacious. To maximally improve survival for
women with early-stage breast cancer, a critical
(“threshold”) DI or cumulative anthracycline dose (or
both) must be reached.
Other than 50% or lower, the exact threshold re-
duction in DI that adversely affects clinical outcomes
remains controversial. An analysis of the pivotal
Milan trial that used classical cyclophosphamide,
methotrexate, and 5-FU suggested that women who
received less than 85% of the scheduled dose had
worse clinical outcomes after 20 years of follow-
up 25,26. In addition, women who received less than
65% of the scheduled dose did no better than women
treated with surgery alone. Conversely, retrospective
data from larger cohorts of women treated with clas-
sical or intravenous cyclophosphamide, methotrex-
ate, and 5-FU have failed to demonstrate a statistically
significant correlation between chemotherapy DI and
clinical outcome 27,28.
Reduced DI of adjuvant chemotherapy because
of toxicity or poor treatment tolerance in primary
breast cancer is a common occurrence 29. In a study
of community practices across the United States in-
volving almost 20,000 women with early-stage breast
cancer treated with adjuvant chemotherapy, 55.5%
of patients received a DI below 85%. In a similar study
of approximately 4500 patients with aggressive NHL,
slightly more than half of all patients (53%) received
a relative DI below 85% 30.
4.1 Summary of Guidelines for CSFs in
Maintaining DI
• The cumulative data suggest that reduced DI is a
common occurrence in the adjuvant systemic
therapy of early-stage breast cancer and in the
curative treatment of aggressive NHL.
• Evidence suggests that a minimum DI is required
to maximize the benefit of chemotherapy; how-
ever, the exact threshold remains to be defined.
• Therefore, when deciding to use a CSF, DI should
be considered, because CSF administration may
allow for a more optimal dose of chemotherapy
to be given.
KOUROUKIS et al.
13
CURRENT ONCOLOGY—VOLUME 15, NUMBER 1
5. GUIDELINES FOR SPECIFIC SETTINGS
5.1 Acute Leukemia
Colony-stimulating factors have been studied exten-
sively in acute myeloid (AML) and lymphoblastic (ALL)
leukemia, principally because the chemotherapeutic
regimens used are highly myelosuppressive, result-
ing in a high rate of morbidity and mortality attribut-
able to infection. Although the clinical trials differ,
various conclusions can be drawn from the existing
data:
• In patients completing induction and consolida-
tion chemotherapy for
AML
,
CSF
s reduce the dura-
tion of neutropenia, but do not affect
treatment-related mortality or
OS 2
. The effect may
be more pronounced during consolidation therapy.
• Long-term data on the use of CSFs in leukemia
demonstrate no adverse effect on disease status
or patient safety 31.
• Cost analyses (in the United States) suggest that
the use of CSFs is cost effective in adult AML and
ALL 32.
• When used as an adjunct in treatment of adult
ALL, CSFs reduce the incidence of severe infec-
tions 33,34.
• Colony-stimulating factors may be beneficial
when used as “priming” therapy to enhance che-
motherapy in patients with AML 35.
5.1.1 Summary of Guidelines for CSFs in Acute
Leukemia
• Colony-stimulating factors should be consid-
ered in patients with AML completing induction
or consolidation chemotherapy who experience
neutropenia.
• Colony-stimulating factors should be considered
in patients undergoing chemotherapy for ALL who
experience neutropenia.
• In patients with AML, CSFs as priming therapy con-
currently with chemotherapy may be useful, but
cannot be considered routine at the present time.
5.2 Stem-Cell Transplantation
Colony-stimulating factors—both G-CSF and granu-
locyte–macrophage CSF—are frequently used during
autologous and allogeneic hematopoietic SCT. Pre-
transplant, CSFs are used to assist in the mobilization
of stem cells from the marrow for peripheral collec-
tion. Post-transplant, they are used to reduce infec-
tion, shorten hospitalization, and possibly reduce
costs.
5.2.1 Mobilization
Growth factors are used in both autologous and allo-
geneic transplantation mobilization. Repeated stud-
ies have validated this collection approach and con-
firm its superiority over traditional bone-marrow har-
vest in yielding a better product that enhances
engraftment and reduces graft-versus-host disease
(GVHD) 36.
When used in combination with chemotherapy
or alone in high doses, CSFs promote enhanced mobi-
lization 37,38. Among the various regimens tested, the
one most commonly used is G-CSF 10 µg/kg daily for
7–10 days before apheresis, with or without chemo-
therapy (that is, high-dose cyclophosphamide).
Pegfilgrastim, although not yet approved for this in-
dication, has showed promise 39.
Another agent, ancestim (also known as “stem-
cell factor”), has been used to mobilize stem cells
and may even be more effective than G-CSF alone 40.
Ancestim is generally recommended only in patients
who do not successfully mobilize with a G-CSF–based
mobilization strategy 41.
5.2.2 Post SCT
Data from many randomized studies have showed
benefit with the use of CSFs in SCT, but the magnitude
of that benefit in yielding clinically important effects
has been questioned. A recent Canadian meta-analy-
sis 42 evaluated the use of CSFs post-transplant and
revealed that CSFs
• reduce the risk of documented infection with a
risk ratio (RR) of 0.87 [95% confidence interval
(CI): 0.76 to 1.0; p = 0.05]. The absolute risk re-
duction was 8%, and the number needed to treat
to prevent 1 infection was 13. In allogeneic SCT,
the consequence may be reduced infection-related
mortality.
• reduce the time to neutrophil recovery and to
platelet recovery to 50 × 109/L (p = 0.02), but
not to recovery to 20 × 109/L.
• reduce hospitalization by 3 days (p < 0.00001).
• reduce the duration of parenteral antibiotics (p =
0.02).
• produce no differences in acute or chronic GVHD,
treatment-related mortality, or OS.
The heterogeneity of the available studies has left
the potential cost–benefit with the use of CSFs unclear.
However, to date, more studies than not have sug-
gested a positive benefit. Results from the recent
Canadian meta-analysis are consistent with other
published studies that have demonstrated a benefit
in infection reduction but not in OS 13,43,44.
The results from an analysis of a European data-
base raised concerns about the potential increase in
GVHD in patients receiving CSFs 45. However, a long-
term evaluation of data from the International Bone
Marrow Transplant Registry on the use of CSFs in more
than 500 patients treated with allogeneic SCT demon-
strated no long-term benefit or disadvantage with
regard to acute or chronic GVHD and OS 46.
PRACTICE GUIDELINE SERIES
CURRENT ONCOLOGY—VOLUME 15, NUMBER 1
14
5.2.3 Summary of Guidelines for G-CSF in SCT
• For mobilization, 5–10 µg/kg daily can be used
for 7–10 days before apheresis, with or without
chemotherapy.
• Post transplant, 5 µg/kg daily, starting on days 5–
7 can be used until the absolute neutrophil count
rises above 1.5 × 109/L.
5.3 Radiotherapy
The ASCO guidelines 2 indicate that CSFs should be
avoided in patients receiving chemotherapy and con-
comitant radiation, particularly radiation involving
the mediastinum. Therapeutic use of CSFs may be
considered in patients receiving radiotherapy alone
if prolonged delays secondary to neutropenia are ex-
pected. In practice, CSFs are not generally used in ra-
diotherapy because of the lack of evidence to suggest
an improvement in the rate of complication or sur-
vival. In Canada, CSFs are not approved for use with
radiotherapy.
6. DOSING AND FORMULATION OF CSFs
Currently two formulations of G-CSF are approved for
use in Canadian clinical practice. Filgrastim
(r-metHuG-CSF) stimulates the production of neutro-
phil precursors, enhances the function of mature neu-
trophils, and reduces the duration of neutropenia (and
thus its complications). Filgrastim is cleared by the
kidneys, and so its plasma half-life is 3–4 hours. Daily
administration of the drug is therefore required. With
the covalent binding of polyethylene glycol to the
N terminus of filgrastim (producing pegfilgrastim),
the plasma half-life of the drug is increased such that
pegfilgrastim levels as a function of the neutrophil
count become “self-regulating” 47. The net result is
that a single injection of pegfilgrastim is equivalent
to multiple daily injections of filgrastim.
Two large randomized controlled trials compared
single administration of pegfilgrastim with daily
filgrastim in patients receiving myelosuppressive che-
motherapy (an anthracycline–taxane regimen)
48,49
.
The larger of the two trials randomized 310 breast
cancer patients to either a single subcutaneous injec-
tion of pegfilgrastim 100 µg/kg on day 2 or to daily
subcutaneous injections of filgrastim at 5 µg/kg be-
ginning on day 2 and continuing until the
ANC
was
documented at 10 × 10
9
/L or higher after the expected
nadir or for up to 14 days, whichever occurred first
48
.
The second study randomized 157 patients in an iden-
tical design, except that a fixed dose of 6 mg of sub-
cutaneous pegfilgrastim was used
49
. The dose and
duration of the filgrastim in the standard arms was
identical across both studies. Both studies demon-
strated that pegfilgrastim was safe and well tolerated,
as filgrastim was. In regard to duration of severe neu-
tropenia and the depth of the
ANC
nadir, the effects of
pegfilgrastim were similar to those of filgrastim. How-
ever, in one study, the incidence of
FN
was signifi-
cantly lower in the pegfilgrastim arm
48
.
Pegfilgrastim and filgrastim both offer significant
and similar benefits following moderate-to-severe
myelosuppressive chemotherapy for the treatment of
cancer. The additional advantages of pegfilgrastim
include the single injection (convenience for patient
and health care provider) and also potentially a lower
rate of
FN
. Both formulations of
G
-
CSF
should be con-
sidered for patients with solid tumours or lymphomas
requiring a
CSF
for primary or secondary prophylaxis.
7. DURATION OF THERAPY WITH CSFs
As demonstrated in the studies mentioned in the pre-
vious subsection, and in the many studies contribut-
ing to a recent systematic review of primary
prophylaxis with G-CSF 12, the use of filgrastim should
be initiated soon after delivery of chemotherapy (most
studies started on day 2) and continued until a docu-
mented post-nadir ANC recovery to 1.5 × 109/L or
higher is reached. The key goal is to continue until
after the expected nadir. The exact ANC that it is clini-
cally important to achieve is debatable; 1.0–1.5 ×
109/L or higher is suggested. Unless daily blood
counts are being monitored, a conservative approach,
ensuring that the ANC rises well above the desired
level, is wise. Often, between the last filgrastim dose
and day 1 of the subsequent cycle of chemotherapy,
a significant gap occurs during which the ANC drops
to some degree. In the study that investigated sub-
cutaneous pegfilgrastim 49, the median time to ANC
recovery to 2.0 × 109/L or higher with anthracycline–
taxane chemotherapy was 9 days from the day of
chemotherapy.
The duration of filgrastim therapy will also de-
pend on the time to ANC nadir and the duration of
grade 4 neutropenia. Therefore, one additional ad-
vantage of pegfilgrastim is its “self-regulation” with
a single dose, obviating the need for blood count
monitoring and significantly reducing the risk of over-
shooting the target. Daily administration of filgrastim
is currently indicated, although other schedules have
been tested. Data from a nonrandomized observa-
tional study published by Papaldo et al. 50 showed
that a less frequent G-CSF dosing schedule was asso-
ciated with a benefit equivalent to that of daily ad-
ministration in women undergoing adjuvant
chemotherapy for breast cancer, although the rate of
FN in the control arm was only 7%.
8. DISEASE-SPECIFIC RECOMMENDATIONS
Given the prevalence and incidence of breast cancer,
lymphoma, and gastrointestinal and lung cancers, this
subsection presents a more focused analysis of the
available data on FN prevention and the use of CSFs in
those specific diseases.
KOUROUKIS et al.
15
CURRENT ONCOLOGY—VOLUME 15, NUMBER 1
8.1 Breast Cancer
Significant advances have been made in adjuvant
systemic therapy for early-stage breast cancer.
Those advances include the use of anthracyclines,
the advent and implementation of dose-dense che-
motherapy, and more recently, the addition of
taxanes. Although all of the foregoing therapeutic
approaches have resulted in improved patient out-
comes 51–56, it is important to recognize the related
toxicities and to ensure that appropriate support-
ive care measures are taken to mitigate the effects
of those toxicities.
Table
II
summarizes the adjuvant breast cancer
regimens commonly in use in Canada and the asso-
ciated rates of
FN
. These data indicate that most of
the adjuvant protocols have
FN
rates under 10%, but
that some protocols would have allowed for sec-
ondary
CSF
prophylaxis. Notably, however, clinical
trial populations tend to be healthier than the gen-
eral population with the same diagnosis, which
means that the rates of
FN
reported in clinical trials
may be lower than those seen in clinical practice.
The two adjuvant protocols in which primary pro-
phylaxis is definitely recommended are dose-dense
cyclophosphamide–doxorubicin (
AC
) followed by
paclitaxel, and docetaxel, doxorubicin, and cyclo-
phosphamide (
TAC
)
6,55
. Primary prophylaxis with
TAC
chemotherapy reduces the
FN
rate to 7.5% from
28.8%
56
.
Recent data have showed that
FEC
followed by
docetaxel is superior to
FEC
100 given for 6 cycles
and has a
FN
rate of 11.2%
54
. That finding has led to
wide adoption of the
FEC
protocol in Canada. Patients
who are being considered for
FEC
treatment followed
by docetaxel should be carefully assessed. Based on
current guidelines, primary prophylaxis should be
considered for patients with significant risk factors
for
FN
.
Breast cancer treatment regimens continue to
evolve, and new treatments are being developed.
Tools are also now available to determine which pa-
tients are likely to benefit from chemotherapy. In the
future, the best way to reduce chemotherapy-associ-
ated toxicities may be to sequester the patients who
will not benefit from chemotherapy.
8.2 Lymphoma
Aggressive-histology
NHL
, such as diffuse large
B cell, represent potentially curable neoplasms, even
in older adults. In a pivotal randomized trial,
CHOP
chemotherapy (cyclophosphamide–doxorubicin–
vincristine–prednisone) was shown to be as effec-
tive as, and less toxic than, more complex second-
and third-generation regimens
57
. Since then, the
addition of rituximab to chemotherapy in patients
with aggressive-histology CD20-positive lymphoma
has improved outcomes in both older
58
and younger
patients
59
. Additional studies have demonstrated the
potential benefits of dose-dense chemotherapy sup-
ported by primary prophylaxis in older adults
7
(that
is,
CHOP
given on a 14-day schedule as compared
with a 21-day schedule), but final publication of the
results of dose-dense chemotherapy with rituximab
(
CHOP
-
R
) are awaited
60–62
. In Canada,
CHOP
-
R
has
been the standard regimen for aggressive-histology
NHL
that expresses CD20. Administration of
CHOP
-
R
could be associated with a
FN
rate of 10% or less
59
or in the 10% to 20% range
58
, but the rate could be
much higher in elderly patients or in those with
comorbidities or poor performance status
63,64
.
Many NHL patients are older and therefore at
increased risk for chemotherapy-related toxici-
ties 63,64, particularly infectious and hematologic
toxicities. Several clinical trials have demonstrated
that a combination of CHOP-like chemotherapy with
rituximab or dose-dense CHOP can improve out-
comes for older adults with aggressive-histology
B cell NHL 58,65,66.
Providing chemotherapy on an accepted sched-
ule has become the standard of care for patients with
potential curable aggressive-histology NHL. Although
no prospective randomized studies have tested stan-
dard against less-than-standard DIs, results of pub-
lished studies have suggested that maintaining the DI
of chemotherapy in aggressive NHL is important 67–70.
Furthermore, regimens that were designed to be less
toxic than standard CHOP have produced inferior out-
comes in older adults with NHL 66,71,72.
Current international guidelines suggest primary
prophylaxis with G-CSF for all older patients (typi-
cally 65 years of age and older) with aggressive-his-
tology lymphoma who are receiving curative-style
(CHOP-R–like) chemotherapy 2,5. Given the importance
of maintaining DI, secondary prophylaxis is also valu-
able in patients of any age who are being treated for
NHL with curative intent.
TABLE II Common adjuvant breast cancer regimens and associated
rates of febrile neutropenia (FN)
Chemotherapy regimen FN incidence
(%)
Docetaxel, doxorubicin, cyclophosphamide 55 28.8
5-Fluorouracil, epirubicin, cyclophosphamide, docetaxel 54 11.2
Oral cyclophosphamide, epirubicin, 5-fluorouracil 51 9.0
5-Fluorouracil, epirubicin, cyclophosphamide 54 8.4
Docetaxel, doxorubicin, cyclophosphamide 56,a 7.5
Docetaxel, cyclophosphamide 53 5.0
5-Fluorouracil, doxorubicin, cyclophosphamide 55 4.4
Doxorubicin, cyclophosphamide, paclitaxel 6,52 3–6
Doxorubicin, cyclophosphamide 52 0–2.5
Dose-dense doxorubicin, cyclophosphamide, paclitaxel 56,a 2.0
Oral cyclophosphamide, methotrexate, 5-fluorouracil 51 1.0
aNecessitated primary prophylaxis with granulocyte colony–
stimulating factor.
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CURRENT ONCOLOGY—VOLUME 15, NUMBER 1
16
8.3 Gastrointestinal Cancer
Colorectal cancer is the second leading cause of can-
cer death in Western countries
73
, and 50% of patients
who undergo surgery alone for cure ultimately relapse
and die of their disease
74
. In 2002, results of the
MOSAIC
trial were reported at the
ASCO
annual meeting. With
the use of
FOLFOX
(5-
FU
–leucovorin–oxaliplatin)
infusional therapy, 2% of patients relapsed or died as
compared with 26% in the 5-
FU
–leucovorin arms. This
improvement in survival was associated with a 41%
rate of grades 3 and 4 neutropenia in patients receiv-
ing oxaliplatin, but the neutropenia was complicated
by fever or infection in only 1.8% of patients. Adju-
vant therapy with 5-
FU
–leucovorin produced only a
4.7% rate of grades 3 and 4 neutropenia, and only a
0.2% rate of associated fever
75
. The recently revised
ASCO
guidelines
2
for the use of
CSF
s in patients with a
greater-than-20% risk of
FN
currently preclude the use
of those agents prophylactically.
8.4 Lung Cancer
The hematologic toxicities of the various chemo-
therapy regimens in patients with
SCLC
and non-small-
cell lung cancer (
NSCLC
) were included in the
EORTC 3
guideline summary tables (see that guideline’s
Table 4) and in the American Society of Hematology/
ASCO
guideline
2
(see that guideline’s Table 1). De-
pending on the characteristics of the lung cancer sub-
type and the regimen selected,
FN
rates in excess of
20% may be seen. For patients with
NSCLC
, few data
are available demonstrating any benefit in response
rate or survival from primary prophylaxis with a
G
-
CSF 76
. A meta-analysis of randomized trials evalu-
ated the role of
CSF
s in patients with
SCLC
both for
maintaining and for increasing
DI 22
. In the seven stud-
ies designed to maintain
DI
, the response rate was
higher in the groups that received
CSF
s (
RR
: 0.92; 95%
CI
: 0.87 to 0.97), but
OS
was not better [hazard ratio
(
HR
): 1.0; 95%
CI
: 0.94 to 1.13]. In five trials in which
CSF
s were used to increase
DI
, no detectable increase
was observed in either response rate (
RR
: 1.02; 95%
CI
:
0.94 to 1.09) or OS (HR: 0.82; 95% CI: 0.67 to 1.0).
In a more recently published randomized study 77 of
G-CSF prophylaxis in 175 patients with SCLC who were
treated with cyclophosphamide, doxorubicin, and
etoposide, and who were all given prophylactic anti-
biotics, G-CSF reduced the incidence of FN to 18% from
32% (RR: 0.57; 95% CI: 0.34 to 0.97). The difference
in the rate of FN in the first cycle was 24% as com-
pared with 10% (p = 0.01), indicating an early ben-
efit for treatment with G-CSF, despite the use of
prophylactic antibiotics.
9. SAFETY
Differences in the chemical structures of the CSFs have
produced various therapeutic agents. Filgrastim
(Neupogen) is identical to endogenous G-CSF except
that it has an added N-terminal methionine.
Pegfilgrastim (Neulasta) has a polyethylene glycol
molecule bound to the N-terminal methionine; this
structural difference imparts a different pharmacoki-
netic profile. Lenograstim (Granocyte: Chugai Phar-
maceutical, Bedminster, NJ, U.S.A.) is a glycosylated
product identical to the endogenous human mol-
ecule 78. Despite their chemical differences, all of
these molecules interact with the G-CSF receptor and
initiate downstream signalling through the JAK–STAT
(Janus kinase–signal transducers and activators of
transcription) intracellular pathway 79, thus enhanc-
ing the activity, production, and release of neutro-
phils into the peripheral blood.
With the expanded use of CSFs comes a growing
body of data and literature concerning safety and as-
sociated toxicities. The toxicities review that follows
focuses on post-chemotherapy toxicities. Data are
supplemented with the recorded toxicities for CSF use
in the treatment of myelodysplasia and the procure-
ment of stem cells in peripheral blood collection.
9.1 Acute Toxicity
The short-term side effects of CSFs are generally mild
and seldom require dose adjustments or drug cessa-
tion. Documented acute toxicities include bone pain
(25%–30%), headache (16%–55%), fatigue (6%–
33%), nausea (3%–18%), myalgia (5%–41%), insom-
nia (6%–30%), fever (2%–27%), and anorexia
(11%) 80. A multivariate analysis performed by
Murata et al. 81 on apheresis donors indicated that
G-CSF given at doses higher than 8 µg/kg daily was
associated with increased bone pain; headache was
more frequent in donors younger than 35 years of
age; and nausea or vomiting (or both) were more fre-
quent in female donors. Most acute toxicities of CSFs
can be controlled with conservative measures and
non-opioid or opioid analgesics. The administration
of dexamethasone did not seem to ameliorate G-CSF–
related adverse events 82. Astemizole, an oral anti-
histamine, has been reported to reduce G-CSF–induced
bone pain unresponsive to acetaminophen 83.
Self-limiting laboratory abnormalities, including
elevated alkaline phosphatase, lactate dehydrogenase,
uric acid, alanine aminotransferase, and gamma-
glutamyl transpeptidase, and decreased potassium and
magnesium have also been reported. Although labo-
ratory coagulation abnormalities have been noted in
the literature 84, clinical thrombotic sequelae are rare
and do not suggest induction of a frank hypercoagu-
lable state.
The potential for CSFs to induce anemia has been
investigated. Papaldo et al. 85 evaluated an adjuvant
anthracycline regimen with or without G-CSF in early
breast cancer. In a recent exploratory hypothesis-gen-
erating analysis of that trial, the use of G-CSF was as-
sociated with a higher incidence of grade 2 anemia
KOUROUKIS et al.
17
CURRENT ONCOLOGY—VOLUME 15, NUMBER 1
(38.8% vs. 26.2%, p = 0.005) even though the che-
motherapy DI did not differ between the two study
arms 86. Nonetheless, no difference in clinical out-
comes (such as the need for red blood cell transfu-
sion) was detected between the study arms.
Three trials compared pegfilgrastim with fil-
grastim in the setting of prophylactic CSF support fol-
lowing chemotherapy 48,49,87 and showed similar acute
toxicity profiles.
9.2 Cutaneous Toxicity
Skin toxicities from CSFs can be categorized into three
patterns:
• Injection site reactions are the most common, with
one case series reporting a 25% incidence of lo-
calized painful or pruritic wheals 88.
• Generalized de novo skin toxicities are rare, but
reports of Sweet syndrome, bullous pyoderma
gangrenosum, leukocytoclastic vasculitis, and fol-
liculitis have all been published 89.
• Isolated cases of CSFs exacerbating pre-existing
cutaneous inflammatory disorders such as vas-
culitis and psoriasis have also been documented.
9.3 Pulmonary Toxicity
Anecdotal accounts of CSF-induced pulmonary tox-
icity have been published, including cough, dyspnea,
pulmonary infiltrates 90, and acute respiratory distress
syndrome 91, which is thought to be mediated by neu-
trophil-induced alveolar capillary wall damage 92,
although such reports are exceedingly rare.
In 2001, a systematic review of all published cases
of
CSF
-related pulmonary toxicity uncovered 84 cases
93
.
These cases were further classified into three groups:
• Pulmonary toxicity associated with CSF use alone
(group 1, n = 2)
• Pulmonary toxicity with CSF used in combination
with other potentially pulmonotoxic agents
(group 2, n = 73)
• Pulmonary toxicity during CSF-enhanced neutro-
penia recovery (group 3, n = 9)
The authors concluded that the evidence was in-
sufficient to categorically link the use of CSFs with
significant pulmonary toxicity, because only 2 of the
reported cases were directly linked to CSF use. How-
ever, they did argue that CSFs may interact with other
potentially pulmonotoxic drugs, especially in neu-
tropenic patients with pulmonary infiltrates, warrant-
ing close observation in that patient population.
9.4 Leukemogenicity
The leukemogenic potential of alkylating agents has
been well established in the cancer literature 94.
The National Surgical Adjuvant Breast and
Bowel Project (
NSABP
) experience of adjuvant, stan-
dard-dose,
AC
therapy in 4483 women with breast
cancer revealed an 8-year incidence of treatment-
induced leukemia of 0.27%
95
. Despite the rarity of
secondary hematologic malignancies, the newer regi-
mens enabled by
CSF
s may demonstrate an increase
in the risk of secondary myelodysplastic syndrome
(
MDS
) and acute myelogenous leukemia (
AML
) be-
cause patients receive higher doses of genotoxic
drugs. The better outcomes that result allow for
longer survival, during which secondary hematologic
malignancies may develop.
More recently, Patt et al.
96
evaluated 64,715 pa-
tients from the Surveillance Epidemiology and End
Results (
SEER
)–Medicare database and demonstrated
that the adjusted
HR
for developing
AML
was 1.53
(95%
CI
: 1.14 to 2.06) in patients who received adju-
vant chemotherapy as compared with those who did
not. The use of
G
-
CSF
s within the 1st year of breast
cancer diagnosis was not associated with an increased
risk for developing
AML
(
HR
: 1.14; 95%
CI
: 0.67 to
1.92).
Preclinical models have suggested a possible leu-
kemogenic effect of G-CSFs 97,98; however, to date,
clinical data have not confirmed it.
In the prospective randomized phase III adjuvant
breast trial by the Cancer and Leukemia Group B,
Citron et al. 6 compared a dose-dense regimen of che-
motherapy supported by G-CSF with the standard regi-
men. In an updated report after a median follow-up
of 69 months 99, the incidence of AML or MDS or a com-
bination was no higher in the dose-dense arms than
in the standard arms without routine CSF support
(0.70%). Other adjuvant breast cancer trials incor-
porating routine CSFs have also failed to reveal a sig-
nificantly increased risk of secondary leukemia 50,100.
Trials investigating CSF protocols for other disease
sites (SCLC, urothelial cancer, and sarcoma, for in-
stance) have not reported the incidence of AML or
MDS 101–103.
The magnitude of the additional risk of CSFs, if
present, to the incidence of treatment-related AML or
MDS may be outweighed by the benefit. Population-
based data and meta-analyses have attempted to elu-
cidate an answer to that question.
In a retrospective cohort study based on SEER
claims data, Hershman et al. 104 assessed women older
than 65 years of age who received adjuvant chemo-
therapy, with or without CSFs, for stages I–III breast
cancer between 1991 and 1999. Of the studied
women, 1.16% developed AML or MDS 18 months or
more after diagnosis. Of the 906 patients treated with
G-CSFs, 16 (1.77%) developed AML or MDS; of the 4604
patients not treated with G-CSF, 48 (1.04%) developed
AML or MDS. The risk of AML or MDS did not change
substantially when clinical, treatment, and demo-
graphic variables were accounted for (HR: 2.14; 95%
CI: 1.12 to 4.08).
PRACTICE GUIDELINE SERIES
CURRENT ONCOLOGY—VOLUME 15, NUMBER 1
18
This SEER database analysis is based on a large
numbers of patients, but as noted in an accompany-
ing editorial 105, the data are derived from non-vali-
dated health care claims that do not provide specific
data on cumulative dose or duration of either G-CSF
or chemotherapy. A study of this kind could equally
underestimate the incidence of treatment-related
malignancy in patients who died from breast cancer
in the first years of follow-up. The more dose-inten-
sive the adjuvant therapy regimen, the higher the risk
of secondary leukemia. Also, failure to recover mar-
row after exposure to chemotherapy is an indication
for G-CSF, but such failure may also be a marker of
marrow deficiency that may increase susceptibility
to malignant transformation.
Based on the analysis by Hershman et al., the use
of G-CSF was associated with a doubling of the risk
for subsequent AML or MDS in the studied population,
even though the absolute risk remained low. The au-
thors themselves suggested that even if the associa-
tion were to be confirmed, the benefits of G-CSF may
still outweigh its risks 104.
A similar analysis was performed on a population
of 182 French women who developed leukemia after
adjuvant chemotherapy for early breast cancer
106
.
Patients who received
G
-
CSF
(8.8% of the group) had
a significantly increased risk of
AML
or
MDS
(
RR
: 6.26;
95%
CI
: 1.89 to 20.7), although the reason for
G
-
CSF
treatment, the dose, and the duration were not sys-
tematically recorded in medical files. The authors also
noted that
G
-
CSF
was administered chiefly because of
poor hematologic tolerance to chemotherapy, which
could reflect chemotherapy drug accumulation as a
result of altered pharmacokinetics, metabolism, or
bone marrow sensitivity of the patients.
Smith et al. 95 retrospectively reviewed data from
six NSABP trials that were distinguished by differences
in cyclophosphamide intensity and dose, and by the
presence or absence of mandated prophylactic sup-
port with growth factors. As compared with patients
receiving standard chemotherapy, patients receiving
dose-intense chemotherapy with G-CSF support
showed cumulative incidences of MDS and AML of
1.01% (95% CI: 0.63% to 1.62%) and 0.21% (95%
CI: 0.11% to 0.41%) respectively at 5 years. Those
results should be interpreted with caution, because
increasing the chemotherapy dose is, in itself, a risk
factor for AML and MDS 107 and distinguishing the
leukemogenicity of intensified therapy from that of
G-CSF administration is often difficult.
In addition to the combined analysis, Smith
et al. 95 also attempted to analyze the final results of
NSABP B-25, a trial in which women were randomly
assigned to 4 cycles of AC chemotherapy with double
the cumulative dose of cyclophosphamide 108. Al-
though use of G-CSF was mandated for all patients,
total G-CSF dose varied considerably across patients.
Controlling for treatment arm, patient age, and sur-
gical procedure, the estimated risk for AML and MDS
in patients receiving more than the median dose of
G-CSF was 3.58 relative to patients receiving the me-
dian dose or less (p = 0.02). However, the authors
also noted that the result was not based on a random-
ized comparison and that the use of G-CSF was likely
correlated with other factors. Also, patients achiev-
ing an unusually high plasma level of doxorubicin or
cyclophosphamide, or both, are possibly at higher
risk simultaneously for AML or MDS and for FN and
severe infection. In that case, any suggested associa-
tion between the use of G-CSF and the subsequent in-
cidence of AML or MDS may have no causal basis.
Long-term data relating to CSF use in hematology
have revealed uncertain associations with secondary
AML and MDS. Data from the Severe Chronic Neutro-
penia International Registry revealed an association
between the use of CSFs and acquired cytogenetic
clonal abnormalities of the marrow. However, no
evidence definitively related the dose of G-CSF or the
duration of G-CSF therapy to clinical malignant trans-
formation 109. Thus far, registry studies have not iden-
tified an increased risk of malignancy among healthy
individuals who received G-CSF before harvesting of
stem cells from peripheral blood; however, the num-
bers are small, and more than 2000 donors would
have to be followed for 10 years to detect a rise by a
factor of 10 in the leukemia risk 110.
Finally, in a retrospective review of children un-
dergoing chemotherapy for ALL at a single institu-
tion, the cumulative incidence of therapy-associated
AML was significantly higher in the cohort who re-
ceived G-CSF in their treatment protocol than in the
cohort that did not 111.
The data from the dose-dense trials and hematol-
ogy reports are not conclusive. Mitigating factors such
as chemotherapy dose and inherited predispositions
to secondary cancers have not been fully explored.
The ambiguity demands further research with longer
follow-up. Clinical patterns of secondary leukemia
are emerging with corresponding molecular pro-
files 112, thus enabling more precise definition of iatro-
genic as compared with sporadic leukemia.
9.5 Safety Conclusions
A review of the reported toxicity data associated with
CSF
s reveals an acceptable pattern of short-term tox-
icities, manageable with conservative measures
alone. Further follow-up is necessary to elucidate
potential associations between
CSF
s and pulmonary
toxicities, and
CSF
s and secondary hematologic ma-
lignancies. Colony-stimulating factors should always
be used within the context of approved guidelines
and labelling.
10. SUMMARY
Neutropenia is a common complication of chemo-
therapy that can result in severe sequelae in cancer
KOUROUKIS et al.
19
CURRENT ONCOLOGY—VOLUME 15, NUMBER 1
patients. The management of neutropenia requires
a patient-specific approach, accounting for the ma-
lignancy, the chemotherapeutic regimen, and patient
risk factors such as age, comorbid illness, and past
history. The appropriate use of
CSF
s is critical to man-
aging these patients in situations of both primary
and secondary prophylaxis, especially in high-risk
situations in which chemotherapeutic regimens are
associated with a 20% or higher risk of
FN
. Benefits
include fewer infections, shorter hospitalizations,
and possibly lesser mortality. As in all aspects of
cancer care, the risks must be weighed against the
benefits, tailoring the treatment to each individual
patient.
11. ACKNOWLEDGMENTS
Amgen Canada provided an unrestricted educational
grant; Klick Communications provided editorial and
project management services.
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Correspondence to: C. Tom Kouroukis, Juravinski
Cancer Centre, 699 Concession Street, Hamilton,
Ontario L8V 5C2.
E-mail: tom.kouroukis@hrcc.on.ca
* Juravinski Cancer Centre, Hamilton, ON.
†BC Cancer Agency, Vancouver, BC.
‡Sunnybrook Health Sciences Centre–Odette Can-
cer Centre, Toronto, ON.
§Centre Hospitalier Affilie de Quebec–Hôpital du
St-Sacrement, Quebec City, QC.
|| Ottawa Hospital Regional Cancer Centre, Ottawa,
ON.
#Princess Margaret Hospital, Toronto, ON.
