The Potential for Anemia Treatment to Improve Survival in Cancer Patients

ABSTRACT: One of the most fundamental challenges to multicellular life is the delivery of sufficient oxygen and metabolic substrate to all cells and the rapid elimination of acid formed during cellular respiration. Thus it is logical to wonder whether anemia, by compromising these pathways, might contribute to the progression of cancer. Anemia has been identified as a predictive factor for decreased survival in settings other than oncology, though a cause/effect relationship has not yet been proved. Most clinicians accept the premise that anemia compromises radiotherapy and that hypoxic tumor cells exhibit resistance to chemotherapy, and there is now abundant evidence that the quality of life and functional status of cancer patients is significantly compromised as hemoglobin levels fall below 12 g/dL. The availability of safe and effective therapies for the anemia of cancer, coupled with recent evidence that anemia itself may well have an impact on survival, make it important that the potential of anemia therapy to improve survival outcomes in cancer patients be explored in clinical trials. This article reviews the data available regarding the impact of anemia on the survival of cancer patients. [ONCOLOGY 16(Suppl 10):35-40, 2002]

One of the central themesofmodern molecular oncologyhas been the repeated observation that the development and progression of cancerinvolves the inappropriate activity of normal cellular mechanisms involved inbasic processes essential to multicellular organisms, such as embryogenesis,senescent cell replacement, growth, and wound-healing. One of the mostfundamental challenges to multicellular life is the delivery of sufficientoxygen and metabolic substrate to all cells and the rapid elimination of acidformed during cellular respiration. The molecular mechanisms involved inregulating oxygen and glucose delivery and local blood flow have now beenpartially elucidated; it is not surprising that these processes may also befundamental in tumor biology and the progression of cancer. Because theseprocesses evolved for the regulation of oxygen delivery, it is logical to wonderwhether anemia, by physiologically activating these pathways, contributes to theprogression of cancer.

In addition to these potential effects on cancer biology,there is evidence that anemia may have deleterious effects on the efficacy ofcancer treatments, including radiotherapy, chemotherapy, and modern"targeted" therapies, and on the well-being of the patient. Taken inaggregate, these observations indicate that it is time to seriously consider theeffects of anemia on the survival of cancer patients. This article reviews thedata available regarding the impact of anemia on the survival of cancerpatients.

Historical Perspective

Prior to 1997, it was assumed mild and moderate degrees ofanemia (hemoglobin levels ≤8 gm/dL) were insensate to cancer patients and therefore clinically unimportantin their management. This assumption proved to be false, and it has now beendemonstrated, in both open-label[1-3] and randomized, controlled trials,[4-7]that the quality of life of cancer patients is improved when these levels ofanemia are treated with erythropoietic agents, such as epoetin alfa (Epogen,Procrit), epoetin beta (NeoRecormon), and darbepoetin alfa (Aranesp). Theseresults are consistent with earlier observations in patients with chronic renalfailure, in whom quality of life is optimized when hemoglobin levels aremaintained above 12 g/dL.

Not surprisingly, the data from studies in cancer patientsare yielding identical results with respect to optimal hemoglobinconcentrations. In a recent analysis of two large, open-label studies includingmore than 4,000 patients and exploring the relationship of quality-of-lifescores to hemoglobin levels between 7 and 12 g/dL, the greatest incrementalgains in energy and quality of life for cancer patients was observed withincremental increases in hemoglobin levels between 11 and 12 g/dL.[8a]

It is now widely accepted that the quality of life of anemiccancer patients may improve with anemia therapy, but it is currently assumedboth that anemia does not play a significant role in the pathophysiology ofcancer, and that anemia therapy will not be associated with improvements intumor response or survival. However, a growing body of preclinical evidence andsome early clinical data suggest this also is an assumption regardingcancer-associated anemia that may be disproved in the near future. It ispossible that the symptoms reported by anemic patients reflect an importantimpact of this condition on their health.

Cellular Regulation ofOxygen Delivery

The last 10 years have seen significant advances in the understanding of cellular adaptive mechanisms for ensuring a steady supply of oxygen and energy; key features of these pathways relevant to the current discussion are shown in Figure 1. A major advance in this field was the discovery by Semenza and colleagues of hypoxia inducible factor-1 (HIF-1), a heterodimeric transcription factor composed of an alpha and a beta subunit.[8b] Through mechanisms that are not fully understood, but probably involve a heme-containing molecular oxygen sensor, hypoxia results in an increase in HIF-1-alpha gene expression within hours of hypoxic stress. Hypoxia inducible factor-1-alpha dimerizes with constitutively expressed HIF-1-beta to form a transcription factor that acts on the hypoxia response element to increase the expression of a growing list of genes encoding erythropoietin: vascular endothelial growth factor (VEGF), glucose transporters, glycolytic enzymes, transferrin, and the transferrin receptor. HIF-1 activity is tightly regulated. Under well-oxygenated conditions, HIF-1-alpha binds to the ubiquitin proteosomal system through a specific recognition by the product of the von Hippel Lindau tumor suppressor gene (pVHL), and is degraded. A significant shortening of the half-life of HIF-1-alpha is detectable within 5 minutes of reoxygenation.

The cellular response to hypoxia involves expression of genesinvolved in meeting the higher glucose demand imposed by anaerobic metabolism,as well as increasing the delivery of oxygen and removal of acidic metabolicbyproducts through increased blood flow and hemoglobin levels.

While this is clearly an adaptive response on the part ofnormal cells, there is obvious potential for interplay with the initiation andprogression of cancer. Congenital deficiency of pVHL function is associated withan increased incidence of cancer, and somatic mutation of pVHL is an importantevent in the progression of renal cell carcinoma. These observations suggestthat chronic inappropriate activation of the normal cellular responses tohypoxic stress may be central to the initiation and progression of some cancers.

Tumor Cell Behavior

The establishment and growth of tumors require new bloodvessel formation, which occurs through a process termed angiogenesis. One of themost important pathways for tumor angiogenesis involves the interaction of VEGFwith a family of cognate receptors that mediate a series of cellular responsesthat include proliferation, migration, and survival. Levels of VEGF in tumorcytosol preparations have been shown to correlate with a poor prognosis in earlybreast cancer.[9]

Bevacizumab (Avastin), a humanized monoclonal antibodydirected against VEGF, is one of the new "targeted" cancer therapiesunder clinical development, and has shown some promise as a single agent[10] andwhen utilized in combination with chemotherapy.[11] These observations raise thepossibility that by increasing tumor cell hypoxia and thereby inducingphysiologic molecular alterations and increased expression of VEGF, it ispossible that anemia may unfavorably alter the behavior of cancers and/orcounteract the efficacy of targeted therapies.

Although the VEGF axis is the best characterized pathwaythrough which tumor cell hypoxia may increase angiogenesis and result in a moreaggressive tumor cell behavior, there are several other possible effects ofhypoxic stress. Tumor cell hypoxia results in an increased expression ofcyclooxygenase-2, connective tissue growth factor, and interleukin-8, each ofwhich is associated with increased angiogenesis and the induction of a moremalignant phenotype.

Perhaps more importantly, recent evidence suggests that thesignaling pathways of the erb family of receptors (eg, epidermal growthfactor receptor (EGFR) and HER2/neu) include HIF-1 and increased VEGFexpression, which may mediate some of the effects of activation of thesepathways on cancer cell biology.[12] Hence, hypoxic stress such as anemia hasthe potential to interfere with the efficacy of the newer targeted anticancertherapies, such as EGFR-blocking antibodies or direct inhibitors, anti-HER2therapies, and antiangiogenesis treatments.

Anemia in Patients With Chronic Illnesses

Relationship to Survival

Anemia has been identified as a predictive factor fordecreased survival in settings other than oncology, including congestive heartfailure, geriatrics, and chronic renal insufficiency/hemodialysis.[13,14] Whileit is possible that in all of these settings anemia is a marker for othercomorbidities or for the severity of the underlying illness, the consistency ofthese epidemiologic observations suggests that chronic anemia may have afundamental deleterious effect on human biology, perhaps mediated in part byleft ventricular hypertrophy or immune deficiency.

Anemia, particularly of mild and moderate degrees (hemoglobin £ 8 g/dL), is a very common finding in patients with cancer, occurring in one-quarter to one-half of patients.[15] It has been a relatively consistent observation that the presence of anemia is inversely correlated with the duration of survival for a patient with a given malignancy.[16] Although it is possible that anemia serves as a marker for patients with more advanced or biologically more intrinsically aggressive cancers, the consistency of this association—particularly when considered in light of observations in patients with other chronic illnesses—raises the likelihood that anemia is in itself deleterious. Table 1 lists the potential mechanisms through which anemia may directly decrease the survival of cancer patients.

In addition to potential effects on cancer biology summarizedabove, and on the efficacy of cancer therapy discussed below, anemia may have adirect deleterious outcome for the host. One of the most consistent observationsin clinical oncology has been the power of functional status and quality-of-lifemeasurements in predicting the survival of cancer patients.[17] It has alwaysbeen assumed that poor quality of life simply served as a marker for patientswith more advanced and/or aggressive cancers.

The recent observation that erythropoietic therapy isassociated with an improvement in quality of life and a suggestion of improvedsurvival in cancer patients challenges our assumptions, and lends credence tothe hypothesis that quality of life, acting through unknown mechanisms, may bean independent determinant of survival. It is possible that declining energylevel and functional status influence clinical decision-making and result inless aggressive therapy. Recent preclinical evidence that anemia in multiplemyeloma may be associated with immune dysfunction severe enough to decreasesurvival suggests another potential mechanism.[18]

Impact on Radiation Therapy

It has long been recognized that marginally oxygenated cells (O₂ <10-15 mm Hg) are substantially less sensitive to the effects of ionizingradiation. The proportion of cells killed by a given dose of radiation underwell-oxygenated conditions divided by the proportion killed by the same doseunder hypoxic conditions is termed the oxygen enhancement ratio. For ionizingradiation and human tumor cells, the oxygen enhancement ratio is approximately2.8. This has led radiation biologists to hypothesize that marginally oxygenatedtumor cells most distant from the capillary are relatively resistant toradiotherapy, and are the most likely source of local treatment failure. It hasalso been postulated that anemia may increase local failure rates byexacerbating local tumor hypoxia.

Most of the clinical investigations of the effects ofhypoxia, anemia, and radiation on local control and tumor cure rates have beencarried out in patients with carcinoma of the uterine cervix and squamous cellcancers of the head and neck—two situations in which local control is mostlikely to contribute to cure and survival. Studies of patients with thesecancers have demonstrated that tumors are more hypoxic than surrounding normaltissues,[19] suggesting that the relationship of oxygen delivery to consumptionis more tenuous in malignancy. For both cervical and head and neck cancers, themeasured tumor oxygen tension is significantly lower in the presence of evenmild anemia (hemoglobin concentration< 11-12 g/dL), and significantly more likely to fall below 10 to 15 Torr(mm Hg).[20,21]

Moreover, in both these clinical settings, mild anemia duringradiation is associated with significantly decreased rates of local control andsurvival.[21,22] Although it is possible that these observations are related toa higher incidence of anemia in patients with larger tumors, which wouldindependently be predicted to be less responsive to therapy, there is someevidence that therapy of anemia with either red cell transfusions orerythropoietic agents is associated with an improvement in local control andsurvival following potentially curative radiotherapy for cervical or head andneck malignancies.[23,24] Although the link between treatment of pre-existingmild anemia and local control and cure rates for radiation therapy has not beensufficiently confirmed in randomized clinicaltrials, most clinicians accept the premise that anemia compromises radiotherapyand that it merits particular attention when cure or improved survival is apotential therapeutic outcome.

Effects on Chemotherapy

It is not widely appreciated that hypoxic tumor cells exhibita resistance to killing by chemotherapy that is as great or greater thanobserved with ionizing radiation. Oxygen enhancement ratios of greater than 6have been observed in studies of alkylating agents, and ratios similar toradiation have been reported for the anthracyclines.[25] In contrast to theradiotherapy setting, this preclinical evidence has not been pursued in clinicalcorrelative studies, and very little data exist linking measured tumor oxygentension or anemia with responsiveness to chemotherapy.

Given what is now known about the biology of the hypoxicresponse, it is quite possible that the impact of hypoxia on chemoresponsivenessin vivo may be substantially greater than radio-resistance effects. In additionto the effects on angiogenesis and erb signaling noted above, hypoxicstress is associated with the expression of glucose-regulated protein 78 and theultimate accumulation of several proteins associated with chemotherapyresistance. It is interesting to note that in two randomized, placebo-controlledinterventional studies of erythropoietic therapy for anemic patients receivingcancer chemotherapy, a trend suggesting improved efficacy of the chemotherapywas observed in the treated groups. The difference in median hemoglobin levelsbetween the treated and control patients was ~ 2 g/dL, and the level of anemiain the control groups was mild to moderate, with median hemoglobin level ≤8 g/dL.

Although these studies were not powered or designed to study the effects of anemia and anemia treatment on the efficacy of chemotherapy or on survival, the results are provocative, especially in light of the preclincal evidence summarized above. The survival curves from the randomized trial published by Littlewood et al[4] are shown in Figure 2.

Conclusions

Our understanding of the importance of anemia and anemia treatment has evolved rapidly over the last 5 years, as reflected in Figure 3. Although we previously believed that anemia was relatively asymptomatic and clinically insignificant in patients with chronic illnesses such as cancer, there is now abundant evidence that the quality of life and functional status of cancer patients is significantly compromised as hemoglobin levels fall below 12 g/dL, and are at least in part restored by early and effective intervention. Recent work has further challenged the still prevalent assumptions that anemia does not contribute to the pathophysiology and progression of cancer and is not a significant, independent factor influencing the efficacy and outcomes of current therapies.

The availability of safe and effective therapies for theanemia of cancer coupled with the promising evidence summarized above makes itimportant that the potential of anemia therapy to improve survival outcomes incancer patients be explored in future, carefully designed clinical trials.

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