Impact of Tumor Hypoxia and Anemia on Radiation Therapy Outcomes
- aDepartment of Radiation Oncology, Continuum Cancer Centers of New York, Beth Israel Medical Center and St. Luke’s-Roosevelt Hospital Center and The Albert Einstein College of Medicine, New York, New York, USA;
- bOrtho Biotech Products, L.P., Bridgewater, New Jersey, USA
- Louis B. Harrison, M.D., The Charles and Bernice Blitman Department of Radiation Oncology, Beth Israel Medical Center, 10 Union Square East, New York, New York 10003, USA. Telephone: 212-844-8087; Fax: 212-844-8086; e-mail: lharrison{at}bethisraelny.org
- Received May 21, 2002.
- Accepted October 17, 2002.
Learning Objectives
After completing this course, the reader will be able to:
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Discuss the prognostic significance of intratumoral hypoxia and low hemoglobin levels in patients receiving curative-intent radiation for head and neck or cervical cancer.
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Describe the potential relationship between anemia and intratumoral hypoxia in patients with solid tumors.
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List possible interventions for improving intratumoral oxygenation and radiosensitivity in the radiation oncology setting.
Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com
Abstract
Local recurrence remains a major obstacle to achieving cure of many locally advanced solid tumors treated with definitive radiation therapy. The microenvironment of solid tumors is hypoxic compared with normal tissue, and this hypoxia is associated with decreased radiosensitivity. Recent preclinical data also suggest that intratumoral hypoxia, particularly in conjunction with an acid microenvironment, may be directly or indirectly mutagenic. Investigations of the prognostic significance of the pretreatment oxygenation status of tumors in patients with head and neck or cervical cancer have demonstrated that increased hypoxia, typically designated in these studies as pO2 levels below 2.5-10 mm Hg, is associated with decreased local tumor control and lower rates of disease-free and overall survival. Hypoxia-directed therapies in the radiation oncology setting include treatment using hyperbaric oxygen, fluosol infusion, carbogen breathing, and electron-affinic and hypoxic-cell sensitizers. These interventions have shown the potential to increase the effectiveness of curative-intent radiation therapy, demonstrating that the strategy of overcoming hypoxia may be a viable and important approach. Anemia is common in the cancer population and is suspected to contribute to intratumoral hypoxia. A review of the literature reveals that a low hemoglobin level before or during radiation therapy is an important risk factor for poor locoregional disease control and survival, implying that a strong correlation could exist between anemia and hypoxia (ultimately predicting for a poor outcome). While having a low hemoglobin level has been shown to be detrimental, it is unclear as to exactly what the threshold for “low” should be (studies in this area have used thresholds ranging from 9-14.5 g/dl). Optimal hemoglobin and pO2 thresholds for improving outcomes may vary across and within tumor types, and this is an area that clearly requires further evaluation. Nonetheless, the correction of anemia may be a worthwhile strategy for radiation oncologists to improve local control and survival.
Introduction
The radiotherapeutic approach to eradicating malignant cells was first introduced during the late 1800s and is currently used with curative intent or for palliation in approximately half of all cancer patients [1]. Radiation therapy remains a component of the standard of care for most locally advanced solid tumors; most antineoplastic agents with activity against a given tumor supplement rather than replace this approach to local control [2, 3]. Local tumor recurrence in the radiated field is often implicated as a primary cause of treatment failure following potentially curative radiation therapy for locally advanced solid tumors. This local recurrence translates directly into poor likelihood of long-term survival. Several treatment-specific factors (e.g., total radiation dose, dose per fraction, overall treatment time) and patient-specific characteristics (e.g., disease stage, histology, performance status) are known to influence the probability of local tumor control by radiation therapy alone or with surgery; however, the specific and dominant factor(s) that leads to disease recurrence in a particular patient is unclear in most patients [4].
Accumulating data strongly suggest that outcomes following curative-intent radiation therapy are adversely influenced by poor intratumoral oxygenation and the presence of anemia [5]. Anemia—often defined as a hemoglobin level <12 g/dl—is common in patients presenting for radiation therapy (resulting from the underlying disease and/or previous treatment), with an estimated incidence of up to 40%-60% [6]. During the course of radiation therapy, the prevalence of anemia increases to up to 80%, depending on tumor type [6]. Thus, the majority of patients are at risk of becoming anemic, or are already anemic, at their first visit to a radiation oncologist. In most radiation oncology settings, anemia-directed interventions are not instituted in patients unless they clearly are hemodynamically symptomatic or their hemoglobin levels fall below a threshold of 9-10 g/dl. However, early correction of mild-to-moderate anemia, such as a hemoglobin level in the range of 12-14 g/dl, may improve both locoregional control, as well as patient quality of life, and is a potential means of delaying the development or progression of intratumoral hypoxia.
This review focuses on the prognostic significance of intratumoral oxygen content and hemoglobin levels in patients undergoing definitive radiation therapy, alone or combined with surgery and/or chemotherapy, for cancer of the head and neck, uterine cervix, and other sites. In addition, the role of hypoxia- and anemia-directed approaches in improving radiation outcomes is summarized, with particular emphasis on potential benefits of hypoxic-cell sensitizers, including mitomycin C and tirapazamine, and correction of anemia with blood transfusion and recombinant human erythropoietin (r-HuEPO).
Significance of Intratumoral Hypoxia
Solid tumors consist of regions with large numbers of hypoxic cells compared with the surrounding normal tissue, with substantial heterogeneity within a given tumor and among tumors of the same histology [5, 7–11]. The underlying processes involved in generating a hypoxic microenvironment are not well understood but likely include various mechanisms of impaired intratumoral oxygen delivery (e.g., vascular abnormalities, intratumoral pressure gradients, acute/chronic anemia) and consumption [1, 5, 12]. Hypoxia is generally evident in large tumors with obvious necrotic areas but also may be present in small tumors, surgical margins, areas of microscopic tumor infiltration, and micrometastases [10, 13].
Intratumoral hypoxia has been implicated in the promotion of clinically aggressive tumors with increased potential for metastases through cellular processes, including selection of p53-mutated cells [1, 10, 14, 15]. Interestingly, the same mechanisms suspected to be involved in the development of intratumoral hypoxia, such as pressure gradients, also appear to impair the delivery and therapeutic activity of antineoplastic agents against solid tumors [1, 5, 10]. Within prostatic tissue, increasing degrees of hypoxia (median pO2 value of approximately 2.0 mm Hg) have been found to correlate significantly with increased clinical stage (T2/T3) and patient age (≥62 years), both of which have been associated with a poor prognosis [16].
A collection of recent preclinical studies provides evidence that intratumoral hypoxia and other microenvironmental factors, including nutrient deprivation and acidity, directly contribute to genomic instability and mutagenesis [17–20]. It has been postulated that hypoxia may function as a mutagen by elevating superoxide and other oxygen radical levels after repeated hypoxia-reoxygenation, ultimately leading to C:G → A:T and T:A → G:C transversions; enhancing endonuclease activity, thereby resulting in chromosomal breaks; and/or inducing chromosomal rearrangements via gene amplification or reoxygenation-induced DNA overreplication [17, 19, 20]. In 1996, Reynolds et al. from Yale University School of Medicine reported that the frequency of point mutations in tumorigenic cells cultured under severe hypoxia was 3.4-fold higher than that observed for normally oxygenated cells [18]. In fact, the mutation frequency and pattern among the hypoxic cells resembled those seen in murine tumors produced by the same cell line. The mutation frequency continued to rise after repeated episodes of hypoxia followed by reoxygenation, suggesting impairment of cellular repair capabilities. Researchers from Yale University subsequently examined the impact of intratumoral hypoxia plus acidity (oxygen tension <10 ppm plus pH 6.5) versus normoxia plus pH 7.4 on DNA repair mechanisms and mutagenesis in a murine fibroblast cell line [20]. Compared with the standard culture conditions, concurrent exposure to both hypoxia and acidity for 24 hours was shown to reduce the efficiency of cellular repair and increase the mutation frequency by twofold following UV irradiation. Hypoxia and acidity appeared to interact in a synergistic fashion, as hypoxia alone had a minimal impact on cellular repair. Additionally, Kondo et al. from University of California San Diego recently found that exposing human colon carcinoma cells to this combination of microenvironmental factors (oxygen concentration 0-0.1% plus pH as low as 6.1) for 72 hours significantly increased the concentration of mismatch repair (MMR)-deficient cells by twofold on day 8 [17]. Among MMR-deficient cells with a 72-hour exposure to hypoxia, the concentrations of 5-thioguanine-resistant and cisplatin-resistant clones increased by 7.8-fold and 2.5-fold, respectively. The investigators concluded that “hypoxia and its accompanying low pH enrich for MMR-deficient cells and that loss of MMR renders human colon carcinoma cells hypersensitive to the ability of hypoxia to induce microsatellite instability and generate highly drug-resistant clones in the surviving population” [17].
Hypoxia may be sustained or even increased during and at completion of radiation therapy or chemoradiation [5, 8, 9, 21, 22]. It is unclear if this phenomenon reflects continued disease activity (i.e., drug resistance), radiation-induced necrosis of tumor tissue (i.e., drug sensitivity), or simply a shift in the hypoxic/aerobic cell ratio. Overall, hypoxia appears to be a barrier to the curability of solid tumors, regardless of treatment modality, and is now an important biologic consideration in cancer research.
Some technical barriers to measuring intratumoral oxygen tension in the clinical setting may be partially overcome by a newly available computerized polarographic needle electrode system capable of quantifying pO2 levels. Rather than providing intracellular readings, this method averages the oxygen tension for the thousands of cells that interact with the microelectrode as it mechanically passes through the tumor [23]. This averaging process and the prerequisite of tumor accessibility are limitations of polarographic electrodes, as is the fact that they measure the extent of hypoxia in both viable and necrotic tumor cells, the latter of which are not as clinically relevant [23]. A number of 2-nitroimidazole-based radiopharmaceuticals (e.g., 18F-fluoromisonidazole) and non-nitro-containing bioreductive complexes (e.g., Cu-60-ATSM) have demonstrated the potential to be more selective than the electrode system in terms of targeting viable versus necrotic hypoxic cells [23, 24]. The tracers used in these noninvasive imaging techniques, however, appear to have a low affinity for regions that are not severely hypoxic, which may result in an underestimation of the degree of “radiobiologically significant hypoxia” [23]. Currently, measuring intratumoral hypoxia can be viewed as a rough science, as none of the aforementioned methods are ideal with respect to clinical applicability and accuracy.
Effects on Radiation Therapy Outcomes
The ability of radiation therapy to eradicate malignant cells critically depends upon the intratumoral content of molecular oxygen, a potent radiosensitizer involved in mediating DNA damage. In fact, intratumoral oxygen level is arguably the most important determinant of response among tumors of the same type treated with a single fraction of ionizing radiation therapy [4, 25]. Experimental studies suggest that hypoxic cells are two to three times more resistant to a single fraction of ionizing radiation than those with normal levels of oxygen [5, 7] and that surviving cells can reestablish tumors in situ or produce tumors in other areas upon transplant [5]. The phenomenon surrounding fractionated radiation therapy is more complex due to the process of reoxygenation between treatments. Theoretically, reoxygenation results in the transformation of hypoxic cells to cells with radiosensitivity comparable to aerobic cells, followed by a decrease in absolute hypoxic cell number. The speed and extent of reoxygenation are highly dependent on patient-specific characteristics, including tumor type and radiation regimen [4, 5, 21, 26]. Nonetheless, the oxygen content of hypoxic environments is believed to be at a critical level that allows malignant cells to remain viable and clonogenic, yet confers relative protection from radiation therapy.
Median pO2 values and hypoxic fraction (i.e., percent of pO2 values ≤5-10 mm Hg) have been useful parameters in assessing pretreatment oxygenation of solid tumors. The prognostic significance of low pretreatment pO2 was first reported in patients with cervical cancer receiving standard radiation therapy or chemoradiation [27, 28]. After a median follow-up of 19 months, patients with a median pO2 >10 mm Hg had significantly (p ≤ 0.002) higher rates of recurrence-free and overall survival than those with lower pO2 levels [27]. Updated results after a median follow-up of 28 months revealed that overall and disease-free survival remained higher in patients with median pO2 >10 mm Hg, with median pO2 values being the strongest independent prognostic factor [29]. This and other studies have demonstrated the adverse prognostic influence of pO2 values below 2.5-10 mm Hg on local tumor control, disease-free survival, and overall survival among patients with cancer of the head and neck or cervix undergoing radiation therapy, radiation/surgery, or chemoradiation (Table 1⇓) [29–37]. A recent study that examined changes in median pO2 values among patients undergoing radiation therapy for advanced cervical cancer found that baseline pO2 <10 mm Hg was an adverse prognostic factor for local control, but only in cases in which hypoxia was sustained after a 2-week course of radiation (20 Gy) [38]. Local control at 1 year was 42% in this subset but similar between patients without baseline hypoxia (68%) and those who experienced reoxygenation of hypoxic tumors at 2 weeks (83%) [38]. Further research is needed to clarify whether hypoxia is solely predictive of initial response to radiation therapy or has prognostic value independent of therapy, such as through direct promotion of tumor progression [12].
Approaches to Improve Radiation Sensitivity and Oxygenation
A number of strategies have been designed to enhance the radiosensitivity and radiocurability of solid tumors, including sophisticated treatment planning methods, brachytherapy, intraoperative radiation therapy, alternative radiation schedules, combined-modality approaches, and therapies specifically targeted at the hypoxic microenvironment (Table 2⇓) [39–46]. Although hypoxia has been recognized as a feature of solid tumors for more than 50 years, efforts to overcome it generally have been unsuccessful [47]. The most straightforward approach to overcoming intratumoral hypoxia is the administration of oxygen at pressures higher than room air. Several reports from as early as the 1970s have suggested that hyperbaric oxygen increases the radiocurability of head and neck and cervical cancers [13]. Furthermore, in a recent meta-analysis, the improvement in local control of solid tumors with hyperbaric oxygen therapy was found to be approximately 10% [48]. This improvement may be clinically relevant when one considers the direct relationship between local control and survival [48]. Nonetheless, use of hyperbaric oxygen is uncommon in clinical settings as a result of administration-related safety issues and inconsistent responses, likely due in part to physiologic mechanisms that maintain oxygen levels within a narrow window of safety [10]. Its use also introduces significant cost and inconvenience to the treatment program.
A feasible alternative to hyperbaric oxygen is inhalation of carbogen (i.e., 95% oxygen/5% carbon dioxide), an oxygen preparation with increased intratumoral diffusion capabilities. The logistics are relatively simple compared with hyperbaric oxygen therapy. Promising results of preclinical and phase I/II studies assessing radiation therapy with carbogen alone or with nicotinamide, which increases tumor perfusion, prompted further evaluation [11, 40, 45, 49–53]. Recently published phase I/II studies by the European Organization for Research and Treatment of Cancer raise doubt as to the merits of adding carbogen and/or nicotinamide to accelerated radiation therapy for solid tumors [54, 55].
Radiosensitizers
The most well-studied, hypoxia-directed strategy for cancer treatment is the use of electron-affinic radiosensitizers, which mimic the actions of oxygen but are more slowly metabolized. During the past 2 decades, the nitroimidazole compounds misonidazole, nimorazole, and etanidazole have been extensively evaluated by the Radiation Therapy Oncology Group (RTOG) and the Danish Association of Head and Neck Cancer (DAHANCA) as adjuncts to radiation therapy in carcinomas of the head and neck, cervix, and lung [56–63]. Most of these studies reported disappointing local control and survival outcomes [56–60, 63], but a few recent studies appear to support the use of nitroimidazole compounds with radiation therapy [62, 64]. For example, the results of a recent meta-analysis suggested that incorporation of misonidazole into radiation therapy for high-grade astrocytomas improves 1-year survival by approximately 8%, which is similar to that expected with chemotherapy [64]. Even more compelling are data from a recent phase III study (DAHANCA 5-85) in which nimorazole produced significant (p = 0.002) improvements in locoregional control (49% versus 33% with placebo) and cancer-related survival (52% versus 41% with placebo) in patients with supraglottic larynx and pharynx carcinoma undergoing primary radiation therapy [62]. Interest in maximizing the efficacy and safety of nitroimidazole agents continues, and clinical evaluation of other classes of agents with potential radiosensitizing capabilities (e.g., thymidine analogues) is ongoing [65, 66].
Hypoxic-Cell Selective Agents
Hypoxic-cell selective agents (bioreductive alkylating compounds) differ from radiosensitizers in that their direct effects on DNA confer cytotoxic effects independent of the administration of radiation therapy [67]. Clinical trials have evaluated mitomycin C, the prototype bioreductive alkylating compound, as an adjunct to radiation therapy in patients with cancers of the head and neck, cervix, and other sites [67–76]. Haffty et al. from Yale University School of Medicine analyzed pooled data from two similarly designed randomized trials conducted at their institution that demonstrated that the addition of mitomycin C to radiation therapy for head and neck cancer results in statistically and clinically significant improvements in locoregional control and cause-specific survival at 5 years (Table 3⇓) [67]. In one of these studies, the adjunctive regimen included dicumarol because in vitro studies suggested it enhances both the efficacy and safety of mitomycin C [67, 77–80]. The findings of these two studies were remarkably similar and therefore do not support the addition of dicumarol to mitomycin C as an adjunct to radiation therapy [67]. More recently, local control and survival rates in patients with head and neck cancer were found to be most favorable in those who received Vienna Continuous Hyperfractionated Accelerated Radiation Therapy (V-CHART) plus mitomycin C (48% and 39%, respectively) compared with those who received V-CHART alone (34% and 28%, respectively) or conventional fractionation (31% and 27%, respectively) [72, 73]. Interim results of a multicenter phase III study suggest that mitomycin C improves disease-free survival, with a trend towards improved overall survival, in patients receiving radiation therapy for stage IB-IVA cervical cancer [74].
Pooled 5-year outcome data from randomized clinical trials of radiation therapy with or without mitomycin C for head and neck cancer [67]
Agents from other classes of bioreductive compounds have been extensively studied as potential alternatives to mitomycin C. Early preclinical data suggesting that porfiromycin (methyl mitomycin) and tirapazamine have preferential cytotoxicity toward hypoxic cells compared with mitomycin C led to their clinical evaluation [81–83]. Results of an ongoing phase III randomized study comparing mitomycin C versus porfiromycin as an adjunct to single-agent chemotherapy plus external-beam radiation therapy and/or brachytherapy for epidermoid head and neck cancer will provide insight into whether these laboratory findings translate into a clinical benefit [84]. In an RTOG phase II study, tirapazamine plus conventional radiation therapy was well tolerated and associated with an actuarial 2-year local control rate of 60% in patients with head and neck cancer [85].
Tirapazamine appears to exhibit schedule-dependent synergy and a lack of overlapping dose-limiting toxicity with cisplatin and other single-agent and combination chemotherapy regimens (e.g., cisplatin/paclitaxel) for head and neck cancer, non-small cell lung cancer (NSCLC), and other malignancies [81, 86–92]. Preliminary findings from a phase II trial assessing the benefits of adding tirapazamine to induction chemotherapy with cisplatin/5-fluorouracil (5-FU) and concurrent chemoradiation for advanced head and neck cancer indicate that DNA damage to hypoxic regions is produced in a variety of head and neck tumor types [93]. A recent phase I/II study demonstrated that a combination of tirapazamine plus cisplatin does not delay subsequent radiation therapy in patients with locally advanced cervical cancer; preliminary evidence of rapid and prolonged complete responses was noted [86]. In a phase I study, concurrent tirapazamine, cisplatin, and radiation therapy was associated with a higher-than-expected locoregional control rate in patients with stage IV head and neck cancer [94]. After a median follow-up of 21 months, 10 of the 16 treated patients were alive without locoregional disease, and an additional four patients were alive with either locoregional recurrence or only distant metastases [94]. The combination of tirapazamine plus cisplatin-based chemotherapy is being evaluated through phase III clinical studies in patients with stage IIIB and IV NSCLC (Cisplatin and Tirapazamine Against Previously Untreated Lung Tumors [CATAPULT] I and II) [95]. Based on the recently published results of CATAPULT I, tirapazamine plus cisplatin produces significantly higher objective response rates compared with cisplatin alone (28% versus 14%; p < 0.001), as well as a significantly longer median survival (35 weeks versus 28 weeks; p = 0.0078) [95]. The therapeutic potential of tirapazamine, including a newly developed oral formulation, is being further evaluated in the radiation oncology setting.
Correction of Anemia
The clinical importance of low pretreatment hemoglobin levels on prognosis following curative radiation therapy was first identified in cervical cancer patients treated during the early 1940s [96]. The negative impact of pretreatment anemia (using hemoglobin level thresholds of 9-14.5 g/dl) on postradiation locoregional control and survival has been well documented over the past 35 years, not only in patients with squamous cell carcinoma of various head and neck sites or the uterine cervix but also in patients with other solid tumors (e.g., bladder, lung, anus, prostate) [2, 3, 12, 37, 61, 62, 97–129]. Selected studies that evaluated head and neck or cervical cancer outcomes by preradiation hemoglobin level are presented in Table 4⇓ [2, 3, 12, 37, 103, 105, 111, 113, 115, 116, 120, 129]. Results generally have been highly consistent and reproducible, with nearly all univariate and multivariate analyses finding a low pretreatment hemoglobin level to be a significant prognostic indicator of disease control and survival following potentially curative radiation therapy, irrespective of disease-specific characteristics (e.g., tumor stage, lymph node involvement). Importantly, findings of about half of these studies suggest that the hemoglobin threshold in the radiation oncology setting should be within the range of 12-14 g/dl. Although not investigated as extensively as pretreatment hemoglobin, a decrease in hemoglobin levels during radiation therapy also appears to negatively affect postradiation outcomes of patients with head and neck or cervical cancer [107, 117, 122, 123, 126, 130].
The prognostic significance of anemia is not merely a phenomenon of radiation therapy outcomes; it appears to apply to the surgical setting as well [131]. In a recent study, preoperative anemia (hemoglobin level <13 g/dl and <12 g/dl in men and women, respectively) was associated with a significantly worse 5-year prognosis (60% versus 85% in patients without anemia; p = 0.002) and high risk of treatment failure (relative risk, 3.0) in patients with surgically treated glottic squamous cell carcinomas [131]. Furthermore, subgroup analysis of 162 male patients with T1 tumors and clean margins revealed that each 1-g/dl hemoglobin decrease was associated with a relative risk of locoregional relapse of 1.4 in male patients with T1 tumors. This finding suggests that hemoglobin may be a continuous risk factor that retains clinical relevance within the accepted range of normal [131]. This finding is particularly interesting given the fact that early glottic cancers are quite small and not generally considered hypoxic tumors.
There appears to be a correlation between anemia and increased hypoxia in solid tumors [22, 28, 132]; however, this relationship and its relevance in the clinical setting remain controversial [12, 80, 119]. Acute changes in hemoglobin are known to alter intratumoral hypoxia and reduce radiosensitivity [133], but the effect of chronic anemia, which is more common in cancer patients, is more difficult to estimate due to adaptive hematopoietic responses over time [12, 134]. The prognostic significance of anemia may simply reflect progressive or advanced disease that is refractory to radiation therapy. Emerging evidence, however, suggests that correction of anemia may enhance radiosensitivity of solid tumors, supporting the theory that there is a direct relationship between lower hemoglobin levels and increased hypoxia [48, 62]. Furthermore, in a recent study that examined radiation-induced changes in pO2 values among patients with advanced cervical cancer, a baseline hemoglobin level <13 g/dl was associated with significantly poorer tumor oxygenation than hemoglobin values ≥13 g/dl (median pO2 value, 12.4 mm Hg versus 28.1 mm Hg; p = 0.003) and a higher rate of treatment failure at 1 year (56% versus 22%; p = 0.046) [38].
Overall, anemia appears to be a clinically relevant risk factor in patients undergoing radiation therapy for solid tumors and is potentially modifiable through therapeutic interventions that increase hemoglobin within the normal range. Early correction of mild-to-moderate anemia in the radiation oncology setting has the potential to modify the hypoxic environment of solid tumors. An increase of hemoglobin by 20% produces a theoretical decrease in hypoxic tissue volume of approximately 30% [135].
Red blood cell transfusions were the most common therapy for cancer-related anemia until the early 1980s [136]. Prospective data on the role of transfusions before radiation therapy are limited [97]. The results of an early study suggested that correcting pretreatment anemia with transfusions was associated with reduced pelvic recurrence of cervical cancer in patients undergoing radiation therapy [97]. Retrospective data generally are inconclusive. Some studies suggested improved local response in patients receiving transfusions, whereas others showed no significant positive effect [48, 107]. Evidence linking perioperative transfusions to lower rates of survival following surgical resection of breast, lung, colorectal, or head and neck tumors merits concern and strengthens the theory that transfusions adversely affect the immunobiology of some solid tumors [120, 137].
Blood transfusion has become a somewhat unpopular alternative among patients and health care providers, largely because of well-known risks (e.g., infections, acute/chronic reactions, immunosuppression), associated costs, and continuing supply deficits [137]. In some institutions, red blood cell transfusions to correct anemia are administered before radiation therapy if hemoglobin levels are <10 g/dl and/or symptoms of severe anemia are present [120, 138, 139]. A lack of compelling evidence coupled with risks that may be particularly problematic in cancer patients have diminished routine transfusion of anemic patients before radiation therapy unless severe anemia is present.
Several phase I/II clinical trials have evaluated the effects of r-HuEPO on hemoglobin levels in cancer patients with documented anemia at the initiation of radiation therapy (Table 5⇓) [139–142]. In the first published study, 80% and 5% of patients treated with r-HuEPO or oral iron therapy, respectively, achieved the target hemoglobin of 14 g/dl during continuous radiation therapy (p < 0.001) [139]. The beneficial therapeutic effects of r-HuEPO in improving hemoglobin levels during radiation therapy were confirmed in subsequent studies that used alternative weight-based dosing schedules, enrolled patients with a variety of primary tumor types, and included various radiation regimens [140–142]. Overall, hematopoietic responses to r-HuEPO in these studies were rapid and pronounced (mean overall hemoglobin increase, 1.5-3.9 g/dl), with excellent tolerance during the study periods [139–142]. Currently, r-HuEPO is approved for patients with nonmyeloid malignancy who are experiencing chemotherapy-induced anemia, whether or not patients are receiving radiation therapy. However, the use of r-HuEPO to correct anemia specifically in patients receiving radiation therapy is currently under investigation [143].
The Southwest Oncology Group (SWOG) conducted the first community-based study designed to assess r-HuEPO 400 U/kg three times weekly (tiw) with oral iron therapy in correcting hemoglobin levels of 8-12.5 g/dl and improving outcomes in patients undergoing concurrent chemoradiation for cervical cancer (SWOG-9318) [144–146]. In that study, r-HuEPO plus iron therapy was associated with a gradual hemoglobin level increase during treatment with cisplatin plus pelvic irradiation, with mean hemoglobin levels of 10.9 g/dl at baseline and 12.0 g/dl at completion of chemoradiation. In another community-based study, once-weekly r-HuEPO therapy also appeared to increase hemoglobin levels from a pretreatment level ≤11 g/dl (mean hemoglobin increase, 1.7 g/dl) and reduce transfusion requirements during concurrent or sequential chemoradiation regimens [143].
Phase II studies have evaluated the prophylactic use of r-HuEPO during chemoradiation regimens expected to produce high rates of anemia in patients with head and neck cancer and NSCLC [145, 147]. At M.D. Anderson Cancer Center, a 12-week course of r-HuEPO 10,000 U tiw with oral iron was effective in preventing anemia and decreasing transfusion requirements in patients with NSCLC receiving cisplatin/etoposide/hyperfractionated radiation, a highly myelotoxic chemoradiation regimen [145, 147]. Researchers from Northwestern University evaluated a 14-week course of once-weekly r-HuEPO 40,000 U with oral iron in patients receiving five cycles of chemoradiation (5-FU/paclitaxel/ hydroxyurea/hyperfractionated radiation) for locally advanced head and neck cancer; results of this phase II study are forthcoming [145, 148].
In most experimental and clinical studies of r-HuEPO during radiation therapy, change in hemoglobin has been used as the primary end point. Correction of anemia with r-HuEPO may improve the radiosensitivity of solid tumors, possibly through improved intratumoral oxygenation [141, 149]. A significantly longer delay in sarcoma growth and a slower tumor regrowth were noted following a noncurative dose of radiation therapy (10 Gy) in rats receiving r-HuEPO compared with those not treated for anemia [149]. In a pilot study of r-HuEPO in head and neck cancer patients undergoing radiation therapy, locoregional tumor control was improved in patients achieving a rapid rise in hemoglobin (p > 0.05) [141]. A randomized study is evaluating the benefits of r-HuEPO 150 IU/kg subcutaneously 3-6 times per week during combined modality therapy with mitomycin C/5-FU/fractionated radiation in patients with oral squamous cell carcinoma [150–152]. Preliminary findings of this study suggest that radiosensitivity is enhanced with concomitant r-HuEPO therapy (Table 6⇓) [150–152]. An ongoing RTOG phase III study (RTOG 99-03) will provide prospective data concerning the effects of r-HuEPO on locoregional control and survival in patients with anemia at the initiation of radiation therapy for head and neck cancer [153].
Effects of r-HuEPO on the efficacy of neoadjuvant chemoradiation (mitomycin C/5-FU/fractionated radiation) in oral squamous cell carcinoma [152]
Conclusions
There is a continued need for reasonable and feasible strategies that improve locoregional tumor control and survival following curative-intent radiation therapy. Tumor hypoxia is considered a principal obstacle to radiocurability of head and neck cancer, cervical cancer, and other solid tumors. If hypoxia is directly or indirectly mutagenic, as suggested by the findings of a few preclinical series, interventions that simply improve intratumoral oxygenation would be unlikely to have a substantial prognostic impact. It does appear, however, that targeting hypoxia is worthwhile, as carbogen breathing, mitomycin C, and other hypoxia-directed interventions have shown promise for enhancing the effectiveness of curative-intent radiation therapy. Early correction of anemia is another strategy for targeting hypoxia. Anemia is a problem that affects a large percentage of radiation therapy patients, and its impact has not been fully appreciated by the radiation oncology community. Low preradiation hemoglobin, even when within the range of 12-14 g/dl, poses a substantial risk of poor locoregional control and survival. A direct association between anemia and tumor hypoxia appears likely, but it needs to be better characterized through additional preclinical and clinical studies. The barriers associated with quantifying hypoxia in clinical practice, along with the fact that the threshold for hemoglobin level versus outcome may vary across different tumor sites, makes an exact definition of anemia or hypoxia quite difficult. Indeed, the definitions may vary from tumor to tumor or from patient to patient, and our clinically defined thresholds therefore may serve as guidelines rather than firm definitions; i.e., the hematologic definition of anemia may not necessarily be the oncologic definition. Within defined limits, r-HuEPO has the ability to correct hemoglobin levels rapidly, simply, and safely during a course of chemoradiation or radiation, although it has not been approved for cancer patients receiving radiation therapy alone. Transfusions may also be useful, especially for patients with particularly low hemoglobin levels (i.e., <10 g/dl) but are more costly and less desirable than simpler methods. Ongoing studies are expected to elucidate the effects of r-HuEPO, new drugs and hypoxic-cell sensitizers, carbogen breathing, and combinations of these strategies, on radiation and chemoradiation outcomes. Overall, surgeons, medical oncologists, and radiation oncologists should view intratumoral hypoxia and pretreatment anemia as potentially modifiable risk factors for poor outcomes, and as an opportunity to explore strategies to overcome this problem and improve results.
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