Curr Probl Cancer 39 (2015) 292–296

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Curr Probl Cancer

journal homepage: www.elsevier.com/locate/cpcancer

Radiation therapy and neutropenia

Roshan S. Prabhu, MD, MS, Richard J. Cassidy, MD,
Jerome C. Landry, MD, MBA

Introduction

There is a complex relationship between radiation therapy (RT) and the hematopoietic
system that depends on concepts such as irradiated volume, RT dose, dose rate, specific radiation
modality, and interactions with chemotherapy in cases of combined modality therapy.

RT and the hematopoietic system

Acute radiation injury typically manifests as cytopenias: anemia, neutropenia, and thrombo-
cytopenia; however, the measurement of peripheral blood counts belies the complex
mechanism and timing of RT effects on hematopoietic stem cell (HSC) populations. There are
several potential mechanisms for RT effects on the bone marrow, which are not mutually
exclusive and may be complimentary. These include direct damage to HSC and reduction in their
number and function, changes to the surrounding bone marrow stroma and microenvironment,
and injury to ancillary cell populations that serve to regulate the hematopoietic process
(eg, colony-stimulating factor [CSF] or erythropoietin-secreting cells). These effects are most
likely with large volume irradiation of the pelvis or spine, as the primary site of functional bone
marrow is the pelvis and vertebrae, which account for approximately 60% of total volume.
Most of the data for detailed hematopoietic effects of RT are derived from large single fraction
total body radiation exposures or from extended field administrations that are no longer used in
routine practice.1 Even very low RT doses (as low as 0.3 Gy) can lead to measurable changes in
peripheral blood counts (primarily lymphocytes at these doses) owing to the exquisite radiosensitive
nature of these cells. With larger doses, lymphopenia typically occurs almost immediately due to
radiation-induced apoptosis in interphase, followed by granulocytopenia, then thrombocytopenia,
and ultimately anemia. Granulocyte counts may actually have an initial transient rise owing to
mobilization from the periphery into the circulation, followed by a subsequent rapid decline. After
an intermediate dose of total body radiation, initial decline in cell counts occurs approximately in 1,
4, 8, and 12 days for lymphocytes, granulocytes, platelets, and red blood cells, respectively.2 Clinical
cytopenia occurs in approximately 1 day, 1 week, 2-3 weeks, and 2-3 months, respectively. These
differences between cell lineages are owing to inherent radiosensitivity differences, variations in cell
population reserves and mobilization, time required for hematopoietic cell replacement, and the life
span of the differentiated peripheral cell (with red blood cells have the longest life cycle).

http://dx.doi.org/10.1016/j.currproblcancer.2015.07.010
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The rapid deterioration of HSC population occurs within 1 week of large volume bone
marrow irradiation.3 These properties are actually advantageous for certain applications of RT,
namely total body irradiation (TBI) as part of conditioning regimens before stem cell transplant
for hematologic malignancies. These regimens typically include high-dose chemotherapy in
conjunction with myeloablative doses of fractionated TBI (classically 2 Gy twice daily to 12 Gy
over 3 days). The use of TBI as part of conditioning regimens is means to (1) generate physical
space in the bone marrow through death of native cells to increase the donor bone marrow
engraftment rate, (2) reduce the incidence of residual native bone marrow response against the
donor cells to also increase engraftment rates, and (3) sterilize leukemic cells in chemotherapy
sanctuary sites (eg, gonads and central nervous system). The inclusion of TBI has been shown to
have higher cure rates and successful engraftments rates when compared with regimens of
chemotherapy alone.4-6 However, nonmyeloablative regimens are currently being investigated
to reduce the morbidity and mortality of stem cell transplant. These regimens use lower doses
of fractionated TBI (typically 2-8 Gy) as part of the conditioning regimen, with several studies
now demonstrating similar efficacy with reduced toxicity compared with myeloablative TBI
regimens.7,8
The increasing use of concurrent chemotherapy with RT has amplified the incidence of
myelosuppression, as both modalities can have overlapping myelosuppressive effects. Though
current RT regimens are fractionated and generally encompass smaller volume compared with
previous field designs, the incidence of clinically relevant hematotoxicity is rising owing to the
increasing use of combined modality therapy in a number of disease sites.9-13 A retrospective
review of patients who experienced severe neutropenia with RT found that the most significant
predictors were use of concurrent myelosuppressive chemotherapy and increasing volume of
active bone marrow in the RT field.1 The efforts to mitigate this by using less myelosuppressive
chemotherapy regimens with RT have not been widely successful, the attempted use of cisplatin
instead of mitomycin-C with RT in anal cancer being one example.14,15 Reducing the volume of
bone marrow irradiated, especially in the pelvic region, was hypothesized to potentially reduce
bone marrow suppression based on the mechanisms discussed above. This concept has been
tested in several small phase II trials of pelvic cancers treated with combined modality therapy,
namely anal and gynecological cancers. Radiation Therapy Oncology Group (RTOG) 0529 was a
single arm phase II trial of definitive chemo RT for anal cancer that used novel RT delivery
methods (intensity-modulated RT [IMRT]) to better shape the RT dose to the target and reduce
dose to normal structures.16 Though bone marrow avoidance was not stipulated in the trial
specifically, it did occur by virtue of use of IMRT and resulted in significantly less grade 2þ
hematologic toxicity compared with historical controls (73% vs 85%, P ¼ 0.03). This has also been
shown in RTOG 0418, a similarly designed study for patients with resected gynecologic cancer.17
Patients with resected cervical cancer treated with chemo RT had a significant association with
volume and dose to bone marrow and rate of grade 2þ hematotoxicity. Patients where the bone
marrow volume receiving 40 Gy or more (V40) was r37% compared with 4 37% had grade 2þ
heme toxicity rates of 40% vs 75% (P ¼ 0.025). These findings have prompted RTOG 1203, a phase
III trial of 3-dimensional conformal RT vs IMRT in the postoperative gynecologic setting with the
goal of toxicity reduction, including heme toxicity.

Considerations of RT use in patients with neutropenia

There are no specific contraindications to RT use in patients with asymptomatic or afebrile

neutropenia. However, RT use can affect the ability to administer colony stimulating factors or
other supportive therapies for patients experiencing neutropenia. Patients receiving concurrent
chemotherapy and RT to the mediastinum should not receive CSF support owing to the
increased risk of complications and death.18,19 In the absence of chemotherapy, CSF support may
be considered in patients receiving RT alone if the neutropenia is significant and prolonged, and
if the RT encompasses a large volume of active bone marrow. The natural resolution of
neutropenia after RT alone can be prolonged and has been shown to take approximately
294 R.S. Prabhu et al. / Curr Probl Cancer 39 (2015) 292–296

3-4 weeks after an intermediate dose of total body RT exposure.20 This recovery time can be
significantly protracted when there is additional chemotherapy induced bone marrow insult.
Most radiation oncologists will hold RT when a patient is experiencing febrile neutropenia.
Though specific data for RT use or nonuse in this situation are lacking, RT is generally held when
there are active neutropenia-related infections requiring inpatient admission to avoid the
myelosuppressive effects, potential immunosuppressive effects, and logistical issues associated
with additional daily RT treatments in patients undergoing active inpatient management.
The use of RT as an adjunct to antibiotics for neutropenic perianal infections has been
investigated. A prospective randomized pilot study was performed in 20 patients with 35
episodes of neutropenic localized infection.21 A dose of 4 Gy was given twice, 1 week apart. The
use of RT did not have any significant effect on response rate, complete response rate, or time to
response compared with no RT. RT is no longer considered a potential therapeutic modality for
localized infection in patients with neutropenia. Symptomatic chloroma (also known as
granulocytic sarcoma) can be an issue in patients with myelogenous leukemia, many of whom
experience some level of neutropenia due to chemotherapy agents and bone marrow infiltration.
Localized low dose RT (20-24 Gy over 10-12 fractions) can be used to effectively palliate these
sites with durable local control rates of 95% or greater.22 These regimens should be considered
for patients with chloroma and neutropenia owing to the effective response, low dose required,
and typically small fields with minimal excess bone marrow exposure.

RT immune effects

The abscopal effect refers to the phenomenon of distant tumor regression in response to local
RT administration.23 Large dose per fraction RT (as is generally delivered in stereotactic ablative
RT [SABR]) has been shown to change the immunophenotype of radiated tumors by increasing
the surface expression of tumor associated antigens.24 When combined with the new drug
category of immune checkpoint inhibitors (eg, ipilimumab and nivolumab), enhanced antigen
specific immune responses leading to distant tumor regression consistent with the abscopal
effect have been seen.25 The timing of SABR relative to immune checkpoint inhibitors is critical
in this paradigm. Mechanistically, the tumors need to have increased tumor antigen present at
the surface at the time of drug introduction to elicit the synergistic immune effect. This has been
demonstrated clinically in a study of patients with metastatic melanoma treated with
radiosurgery (SRS) to brain metastases. Those who were treated with SRS during or immediately
before ipilimumab experienced improved survival and intracranial control compared with those
who received ipilimumab before SRS.26 These findings have introduced the concept of high dose
per fraction RT as a type of in vivo “vaccine” of tumor antigens, which can be combined
synergistically with immune checkpoint inhibitors. This has led to the launch of many trials
investigating the combination of SABR and both approved and novel immune checkpoint
inhibitors in a variety of tumor sites, including malignant melanoma (NCT01416831), prostate
cancer (NCT01303705), breast cancer (NCT01862900), pancreatic cancer (NCT01342224), and
colorectal cancer (NCT02298946), among other cancer sites.

Conclusion

RT has a complex interaction with bone marrow and hematopoiesis, which results in
myelosuppression of all myeloid cell lineages in a predictable order and time course. The
incidence and severity of radiation-induced neutropenia is highly dependent on the volume of
active bone marrow irradiated, dose received by that bone marrow, concurrent use of
myelosuppressive chemotherapy, and other patient factors such as age and medical comorbidi-
ties. Several interventions, such as support with CSF agents and new RT delivery methods (such
as IMRT), have been shown to significantly reduce the rate of high-grade neutropenia in patients
at high risk of hematotoxicity. There is no high-level evidence for afebrile or asymptomatic
 R.S. Prabhu et al. / Curr Probl Cancer 39 (2015) 292–296 295

neutropenia being a contraindication for RT, but use of RT can preclude the ability to administer
CSF agents, especially in the setting of mediastinal RT with concurrent chemotherapy. RT is
generally held for patients with febrile neutropenia to avoid additional myelosuppression and
for logistical reasons. The nascent field of high dose per fraction SABR-mediated immunomo-
dulation in combination with immune checkpoint inhibitors is rapidly growing and has the
potential to change the standard of care and prognosis for patients with oligometastatic disease,
with many trials in various disease sites currently ongoing.

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