One of the central themes of modern molecular oncology has been the repeated observation that the development and progression of cancer involves the inappropriate activity of normal cellular mechanisms involved in basic processes essential to multicellular organisms, such as embryogenesis, senescent cell replacement, growth, and wound-healing. 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. The molecular mechanisms involved in regulating oxygen and glucose delivery and local blood flow have now been partially elucidated; it is not surprising that these processes may also be fundamental in tumor biology and the progression of cancer. Because these processes evolved for the regulation of oxygen delivery, it is logical to wonder whether anemia, by physiologically activating these pathways, contributes to the progression of cancer.
In addition to these potential effects on cancer biology, there is evidence that anemia may have deleterious effects on the efficacy of cancer treatments, including radiotherapy, chemotherapy, and modern "targeted" therapies, and on the well-being of the patient. Taken in aggregate, these observations indicate that it is time to seriously consider the effects of anemia on the survival of cancer patients. This article reviews the data available regarding the impact of anemia on the survival of cancer patients.
Prior to 1997, it was assumed mild and moderate degrees of anemia (hemoglobin levels ≤ 8 gm/dL) were insensate to cancer patients and therefore clinically unimportant in their management. This assumption proved to be false, and it has now been demonstrated, 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 of anemia are treated with erythropoietic agents, such as epoetin alfa(Drug information on epoetin alfa) (Epogen, Procrit), epoetin beta (NeoRecormon), and darbepoetin alfa(Drug information on darbepoetin alfa) (Aranesp). These results are consistent with earlier observations in patients with chronic renal failure, in whom quality of life is optimized when hemoglobin levels are maintained above 12 g/dL.
Not surprisingly, the data from studies in cancer patients are yielding identical results with respect to optimal hemoglobin concentrations. In a recent analysis of two large, open-label studies including more than 4,000 patients and exploring the relationship of quality-of-life scores to hemoglobin levels between 7 and 12 g/dL, the greatest incremental gains in energy and quality of life for cancer patients was observed with incremental increases in hemoglobin levels between 11 and 12 g/dL.[8a]
It is now widely accepted that the quality of life of anemic cancer patients may improve with anemia therapy, but it is currently assumed both that anemia does not play a significant role in the pathophysiology of cancer, and that anemia therapy will not be associated with improvements in tumor response or survival. However, a growing body of preclinical evidence and some early clinical data suggest this also is an assumption regarding cancer-associated anemia that may be disproved in the near future. It is possible that the symptoms reported by anemic patients reflect an important impact of this condition on their health.
Cellular Regulation of Oxygen 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(Drug information on 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 genes involved in meeting the higher glucose demand imposed by anaerobic metabolism, as well as increasing the delivery of oxygen and removal of acidic metabolic byproducts through increased blood flow and hemoglobin levels.
While this is clearly an adaptive response on the part of normal cells, there is obvious potential for interplay with the initiation and progression of cancer. Congenital deficiency of pVHL function is associated with an increased incidence of cancer, and somatic mutation of pVHL is an important event in the progression of renal cell carcinoma. These observations suggest that chronic inappropriate activation of the normal cellular responses to hypoxic stress may be central to the initiation and progression of some cancers.
Tumor Cell Behavior
The establishment and growth of tumors require new blood vessel formation, which occurs through a process termed angiogenesis. One of the most important pathways for tumor angiogenesis involves the interaction of VEGF with a family of cognate receptors that mediate a series of cellular responses that include proliferation, migration, and survival. Levels of VEGF in tumor cytosol preparations have been shown to correlate with a poor prognosis in early breast cancer.
Bevacizumab (Avastin), a humanized monoclonal antibody directed against VEGF, is one of the new "targeted" cancer therapies under clinical development, and has shown some promise as a single agent and when utilized in combination with chemotherapy. These observations raise the possibility that by increasing tumor cell hypoxia and thereby inducing physiologic molecular alterations and increased expression of VEGF, it is possible that anemia may unfavorably alter the behavior of cancers and/or counteract the efficacy of targeted therapies.
Although the VEGF axis is the best characterized pathway through which tumor cell hypoxia may increase angiogenesis and result in a more aggressive tumor cell behavior, there are several other possible effects of hypoxic stress. Tumor cell hypoxia results in an increased expression of cyclooxygenase-2, connective tissue growth factor, and interleukin-8, each of which is associated with increased angiogenesis and the induction of a more malignant phenotype.
Perhaps more importantly, recent evidence suggests that the signaling pathways of the erb family of receptors (eg, epidermal growth factor receptor (EGFR) and HER2/neu) include HIF-1 and increased VEGF expression, which may mediate some of the effects of activation of these pathways on cancer cell biology. Hence, hypoxic stress such as anemia has the potential to interfere with the efficacy of the newer targeted anticancer therapies, such as EGFR-blocking antibodies or direct inhibitors, anti-HER2 therapies, and antiangiogenesis treatments.