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.
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.
Although many factors can induce or exacerbate cancer-related fatigue, 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.
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. 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. 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.
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]
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.
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. 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]
Interestingly, hemoglobin levels of 12 to 14 g/dL have been used to stratify patients in selected cervical 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. 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.
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). In fact, hemoglobin level was the only factor that significantly influenced both local control and survival on regression analysis.
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).
Growing evidence suggests that pretreatment anemia influences radiation therapy outcomes in other tumor types, including non-small-cell lung,[35-38] prostate, and anal cancers. 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]