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Anemia Treatment and the Radiation Oncologist: Optimizing Patient Outcomes

Anemia Treatment and the Radiation Oncologist: Optimizing Patient Outcomes

ABSTRACT: Anemia is a frequent complication of cancer and its associated treatment. Although its occurrence is well documented in the chemotherapy setting, the prevalence and nature of anemia in the radiation oncology setting have been inadequately characterized. Preliminary findings from an ongoing retrospective study at Beth Israel Medical Center in New York indicate that mild-to-moderate anemia (ie, hemoglobin levels of 10 to 12 g/dL) is common at presentation for radiation therapy and increases in prevalence and severity during the course of radiation treatment. The symptoms of mild-to-moderate anemia, particularly fatigue, can substantially impair the quality of life of cancer patients. Furthermore, an extensive body of literature has documented an association between low hemoglobin levels and poor locoregional tumor control and survival following curative-intent radiation therapy. Greater efforts by radiation oncologists to document and treat anemia in patients undergoing radiation therapy may provide an opportunity to improve postradiation outcomes and well-being. [ONCOLOGY 15:1486-1496, 2001]

Major advances in the technology and techniques of
radiation oncology have improved our ability to attain local tumor control with
decreased tissue complications. The broad objectives of ongoing research in the
radiation oncology setting include (1) further increasing locoregional tumor
control rates, which may translate into better survival; (2) evaluating
radiochemotherapy regimens that contain a new generation of cytotoxic agents,
some with radiosensitizing properties, in an effort to improve local control and
to decrease the incidence of distant metastases; and (3) maintaining or
improving patient quality of life during and after therapy.

‘Anemia of Chronic Disease’

Maintaining or improving a cancer patient’s functional and psychosocial
status is particularly important in this era of aggressive combined-modality and
high-dose treatment strategies. Anemia, the most frequent hematologic
abnormality in the cancer population (including patients presenting for or
undergoing radiation therapy) is associated with symptoms (eg, fatigue,
dizziness, shortness of breath) that may greatly impair quality of life. At the
time of cancer diagnosis, this condition is typically categorized as
"anemia of chronic disease"; it may be aggravated over time by
underlying disease progression, surgical blood loss, or subsequent chemotherapy
and/or radiation therapy.

Until recently, oncologists did not routinely treat mild-to-moderate anemia
because it was perceived as "clinically unimportant" when placed in
the context of life-threatening complications, including other hematologic
abnormalities. However, this perception is changing among medical oncologists.
Recent studies indicate that correcting mild-to-moderate anemia in cancer
patients can improve energy levels,[1,2] which may have a profound effect on
functional capacity, sense of well-being, and ultimately, the desire to continue
chemotherapy.

Two surveys of cancer patients found that fatigue is highly prevalent during
chemotherapy or chemoradiation and is associated with substantial adverse
effects on physical and psychosocial functioning.[3,4] In the more recent
survey, most patients reported that fatigue was prolonged and had a greater
impact on their daily lives than pain, nausea, and depression.[4]

Although many factors can induce or exacerbate cancer-related fatigue,[5]
anemia is one of the more common etiologies. Several studies show that cancer
patients with higher hemoglobin levels experience less fatigue and have more
favorable perceptions of their quality of life.[6-8] Fatigue also is a
well-recognized adverse effect of fractionated radiation therapy,
but its causes are poorly understood. The prevalence of fatigue increases
steadily over the course of radiation therapy, often peaking after several
weeks.[9-12]

In the radiation oncology setting, transfusions are generally performed to
correct "severe" anemia (ie, hemoglobin levels < 8 g/dL or
pronounced symptoms),[13,14] and unless contraindicated, transfusions should be
performed in such cases. Nevertheless, correcting mild-to-moderate anemia may
have positive effects on quality of life.[1,2,7] Moreover, emerging data suggest
that pretreatment anemia and low hemoglobin levels during radiation therapy are
risk factors for poor locoregional control and survival.

Prevalence of Anemia in Radiation Oncology

Radiation oncologists often "inherit" anemia that has developed
from surgical blood loss, myelotoxic chemotherapy, and/or advanced disease. The
prevalence of anemia among patients presenting for radiation therapy is not well
documented, but it is generally believed that a substantial proportion of these
patients do become anemic. A recent literature review revealed a relatively high
incidence of mild-to-moderate anemia in patients receiving single-agent or
combination chemotherapy for nonmyeloid malignancies.[15] A similar assessment
in the radiation oncology setting is not available.

An ongoing retrospective study at the Beth Israel Medical Center is assessing
the prevalence of anemia (defined as hemoglobin < 12 g/dL) immediately prior
to and during radiation therapy.[16] We are performing this study through random
chart sampling of patients who had received radiation therapy since December
1996. As of June 1999, a total of 574 patients were evaluable, with a relatively
even distribution of cancers of the prostate (16%), breast (14%), head/neck
(12%), colon/rectum (11%), lung/bronchus (11%), and uterine cervix (9%). The
overall prevalence of anemia (hemoglobin < 12 g/dL) at presentation for
radiation therapy was approximately 41% (28% and 54% of men and women,
respectively). At completion of radiation therapy, 43% of men and 63% of women
had anemia (overall prevalence of 54%), which usually was of mild-to-moderate
severity (ie, hemoglobin levels of 10 to 12 g/dL).

The subset of patients with cancer of the uterine cervix had the highest
prevalence of anemia at baseline (75%) and at completion of radiation therapy
(79%), whereas prostate cancer patients had the lowest prevalence of anemia at
both evaluation points (9% and 26%, respectively). The prevalence of anemia
increased substantially during radiation therapy in patients with prostate
cancer and those with colorectal (44% to 63%), lung/bronchus (55% to 77%), or
head/neck (34% to 57%) cancer. Across all tumor subsets, low hemoglobin levels
typically ranged from 10 to 12 g/dL.

The preliminary findings of this study show that mild-to-moderate anemia is a
common problem in radiation oncology, both at presentation and at completion of
radiation therapy. It appears that most radiation oncology patients with anemia
(60% to 80%) have hemoglobin levels that could be corrected easily (10 to 12 g/dL).
A final patient database of more than 1,000 patients is anticipated. To our
knowledge, this is the first large-scale study designed to systematically
characterize the prevalence and nature of anemia in the radiation oncology
setting.

Significance of Anemia in Radiation Oncology

The ability of anemia to impair quality of life in cancer patients has become
more appreciated in recent years. There also appears to be a relationship
between anemia and low rates of disease control and survival in the radiation
oncology setting. An extensive body of literature provides evidence of an
association between low hemoglobin levels and low locoregional control/survival
following curative-intent radiation therapy. This association has been studied
most widely in patients receiving fractionated radiotherapy for cervical[17-21]
or head and neck cancer.[22-26]

Proposed Mechanisms

Regression analyses have consistently shown that baseline anemia (variably
defined) is an independent predictor of locoregional control and disease-free or
overall survival in these patients.[17-26] The presumed link between low
hemoglobin levels and poor locoregional control of solid tumors is molecular
oxygen, a well-known radiosensitizer (Figure 1). Numerous studies have
identified intratumoral hypoxia as an adverse prognostic factor for locoregional
control and survival in patients receiving definitive radiation therapy for
cervical cancer or head and neck cancer.[27,28] In addition, preradiation
hypoxia has been associated with an increased risk of distant metastases in
patients receiving radiation therapy plus hyperthermia for soft-tissue
sarcomas.[29]

Low hemoglobin levels have been correlated with poor intratumoral
oxygenation.[30,31] For example, in a recent study by Strauss et al, a baseline
hemoglobin level < 13 g/dL was associated with a low intratumoral pO2 level
in patients undergoing radiation therapy for advanced cervical cancer.[31]
Although it is speculated that low hemoglobin levels exacerbate the preexisting
hypoxic condition of solid tumors, this relationship and its relevance in the
clinical setting remain controversial.[26,31-33]

Hemoglobin Values

Interestingly, hemoglobin levels of 12 to 14 g/dL have been used to stratify
patients in selected cervical[34] and head and neck cancer studies,[22-26]
suggesting that hemoglobin values within this range (rather than a threshold of
10 g/dL) should prompt consideration of anemia-directed interventions. One of
the most recently published investigations of the effect of anemia on radiation
therapy outcomes involved approximately 600 patients with cervical cancer.[34]
In this Canadian study, an average weekly nadir hemoglobin level of  12 g/dL
or more during radiation therapy was associated with significantly improved rates of
local/distant disease recurrence and 5-year survival.[34]

Investigators at the Fox Chase Cancer Center found that T1/2 glottic
carcinoma patients with preradiation therapy hemoglobin levels
> 13 g/dL achieved higher 2-year local control and survival rates
(95% and 88%, respectively) than did patients with hemoglobin levels below this
threshold (66% and 46%, respectively).[23] In fact, hemoglobin level was the
only factor that significantly influenced both local control and survival on
regression analysis.[23]

In a recent study by the Radiation Therapy Oncology Group (RTOG),
stage III/IV head/neck squamous cell carcinoma patients who had low
hemoglobin levels (ie, < 14.5 g/dL for men and < 13 g/dL for women)
early in the course of radiation therapy showed less favorable 5-year
locoregional failure and survival rates (68% and 22%, respectively), as compared
with patients who had higher hemoglobin levels (52% and 36%, respectively).[24]

Other Subgroups

Growing evidence suggests that pretreatment anemia influences radiation
therapy outcomes in other tumor types, including non-small-cell lung,[35-38]
prostate,[39] and anal cancers.[40] Although less extensively documented, a
decrease in hemoglobin levels during radiation therapy also appears to adversely
affect locoregional disease control and survival.[19,41-46]

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