- Email: [email protected]
Role of erythropoietin in the treatment of lung cancer associated anaemia
Lung Cancer 34 (2001) S91– S94
www.elsevier.com/locate/lungcan
Role of erythropoietin in the treatment of lung cancer associated anaemia G.V. Scagliotti a,*, S. Novello b a
Department of Clinical and Biological Sciences, Uni6ersity of Torino, Regione Gonzole 10, Azienda Ospedaliera S. Luigi, 10043 Orbassano, Torino, Italy b Departement de Medicine, Institut Gusta6e Roussy, Villejuif, Paris, France
Abstract Cancer-related causes of anaemia include anaemia of chronic disorders, infections, autoimmune haemolysis associated with malignant conditions, bone marrow invasion by the tumour or clonogenic marrow dysfunction, iron, folate, or vitamin B 12 deficiency and bleeding from tumour erosion. Treatment-related anaemia results from chemotherapy, radiotherapy and bone marrow fibrosis. Severe anaemia increases the burden of treatment, contributes to fatigue, reduces the quality of life and may also delay or limit further treatment. Blood transfusion is currently the most common form of treatment and patients rarely require transfusion unless the haemoglobin is less than 8 g/l. It is often difficult to predict which patients will develop anaemia and require treatment, but the proportion of patients receiving transfusions increases markedly if the pre-treatment haemoglobin concentration is below 10 g/dl. Four studies have systematically evaluated the effects of erythropoietin on anaemia in lung cancer patients and each of these trials is likely to contribute information concerning the clinical benefit of erythropoietin in treating or preventing treatment-related or disease-related anaemia. Most of the improvements in quality of life observed with erythropoietin administration occurred with haemoglobin levels between 10 and 12 g/dl, and not with levels between 7 and 10 g/dl, with a plateau effect above 12 g/dl. Consequently, a ‘functional’ level of haemoglobin that appears to be more important is 12 g/dl, because it may be favourably associated with a significant improvement in fatigue compared with lower haemoglobin levels. This ‘functional’ level would be in keeping with the body’s physiological erythropoietin response. © 2001 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Lung cancer; Anaemia; Erythropoietin
1. Introduction Several haematopoietic growth factors, including stem cell factor (SCF)/kit ligand, interleukin-11, interleukin-3, and interleukin-6, influence erythropoiesis. All these factors play a role in the activation of the quiescent stem cell. SCF, interleukin-11, and interleukin-3 may also play a role in the differentiation of activated stem cells to the earliest recognisable erythroid precursor, the burst-forming unit of erythroblasts (BFU-E). Further proliferation of BFU-E to erythroid colonyforming unit (CFU-E) is dependent on interleukin-3, granulocyte-macrophage colony stimulating factor (GM-CSF), interleukin-4, and interleukin-9. * Corresponding author. Tel.: + 39-011-9026-414; fax: + 39-0119038-616. E-mail address: [email protected] (G.V. Scagliotti).
Erythropoietin is a lineage-specific distal-acting factor which stimulates the maturation of CFU-E to mature erythrocytes. At the molecular level, erythropoietin is a 30,400-Da glycoprotein; carbohydrates represent 30–40% of the molecule and they are essential for secretion, stability in the circulation, and biological activity of erythropoietin. The trigger for the production of erythropoietin is the physiologic counterpart of red blood cell mass, i.e. the oxygen level. Thus, an inverse relationship exists between the red blood cell precursor mass and the serum erythropoietin level. The erythropoietin level in the plasma is relatively constant in the presence of normal levels of haemoglobin. However, while the haemoglobin level falls below 12 g/dl, the plasma erythropoietin level increases. This point is in contrast with the long-standing belief that a haemoglobin level of 10 g/dl is ade-
0169-5002/01/$ - see front matter © 2001 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 1 6 9 - 5 0 0 2 ( 0 1 ) 0 0 3 9 8 - 1
S92
G.V. Scagliotti, S. No6ello / Lung Cancer 34 (2001) S91– S94
quate for maintaining tissue oxygenation. Consequently, a haemoglobin level of at least 12 g/dl is important, because it serves as a physiological checkpoint beyond tissue hypoxia [1]. Erythropoietin mediates its effects through the erythropoietin receptor, which is expressed on erythroid progenitor cells, embryonal stem cells, multipotent haematopoietic progenitor cells, endothelial cells, and neural crest cells. While the biological role of erythroid receptor on non-erythroid cells is unknown, it is intriguing to speculate that some of the effects of erythropoietin on the symptoms of fatigue may be mediated through some of these tissue targets, in addition to the effects deriving from correction of anaemia.
2. Anaemia in cancer patients Both cancer and its treatment may lead to anaemia. Cancer-related causes of anaemia include anaemia of chronic disorders, infections, autoimmune haemolysis associated with malignant conditions, bone marrow invasion by the tumour or clonogenic marrow dysfunction, iron, folate, or vitamin B 12 deficiency, and bleeding from tumour erosion. The anaemia of chronic disorders identifies its pathophysiologic mechanisms in the shortened red cell survival, in the failure of bone marrow to increase erythropoiesis, and in its inability to release iron from senescent red cells. New lines of evidence suggest that abnormalities are involved in the production of erythropoietin, probably due to increased production by the tumour of cytokines, such as TNF-a, IL-1, TGF-b, IFN-b and IFN-g, which also affect haematopoietic progenitor cells, by impairing their responsiveness to growth factors. Numerous secondary disorders can also occur in cancer patients and can cause or contribute to the development of anaemia, including severe malnutrition, hypersplenism with cytopenia due to sequestration of haematopoietic cells and activation of tissue factors of the coagulation cascade resulting in erythrocyte and platelet destruction. Treatment-related anaemia results from chemotherapy, radiotherapy and bone marrow fibrosis. The malignancies produce a desmoid or fibrotic reaction, with increased bone marrow fibrosis, that results in alteration of bone marrow space and then in the correct physiological release of mature blood cells. The cytotoxic chemotherapeutic agents used in the treatment of most cancers have a number of adverse effect on haematopoiesis (Table 1). The main mechanisms involved are direct bone marrow damage and renal impairment, with a secondary deficiency in the production of erythropoietin. The former mechanism is induced by almost all cytotoxic drugs, and the latter is associated with cisplatin regimens [2].
Ionizing radiation to extensive areas of bone marrow and a large number of non-cell cycle dependent drugs (e.g. alkylating agents), when administered at high doses or for long periods of time, may lead to progressive depletion of haematopoietic stem cells. The drugs more effective against active proliferating cells (e.g. cytarabine, methotrexate, anthracyclines, etoposide, hydroxyurea) tend to cause earlier and shorter-lasting cytopenia. Some chemotherapeutic agents (e.g. anthracyclines) have secondary cytotoxic effects by inducing oxidant damage, even in mature haematopoietic cells. An often ignored or missed cause of pseudoanemia occurring shortly after chemotherapy is fluid retention with secondary dilutional anaemia. Severe anaemia increases the burden of treatment, contributes to fatigue, reduces the quality of life and may also delay or limit further treatment. On the other hand, a gradual fall in haemoglobin may be well tolerated by the patient because of the compensating mechanism of increased red cell level of 2,3-diphosphoglycerate, which results in an increased release of oxygen to the tissues. Blood transfusion is currently the most common form of treatment; but patients rarely require transfusion unless the haemoglobin is less than 8 g/l [3]. The most frequent symptoms related to the anaemia and for which there is a prescription of blood transfusion are: lethargy (51%), tiredness (42%), breathlessness (33%), and pallor (27%) [4]. The presence of an underlying cardiac or pulmonary disease may contribute to a poorer tolerance of anaemia in oncology patients. Consistent findings about blood cell transfusion requirements were reported in two retrospective studies conducted in the USA and UK. Among the patients with solid tumours, lung cancer patients required the highest frequency of transfusion for anaemia (Table 2) [4,5]. Patients with lung cancer were also generally transfused at a higher haemoglobin value, which is likely due to their underlying pulmonary disease. It is often difficult to predict which patients will develop anaemia and require treatment, but the proportion of patients receiving transfusions increases Table 1 Toxic effects of cytotoxic drugs on haemopoiesis Stem cell death (long-term myelosuppression) Committed progenitor cell death (early/short-term myelosuppression) Blockage or delay in cell cycling of haematopoietic precursors Reduced levels of haematopoietic growth factors (especially EPO) Oxidant damage to mature haematopoietic cells Long-term myelodysplasia Immune-mediated haematopoietic cell distruction Microangyopathy (RBCs and platelets) Fluid retention/plasma volume expansion with dilutional anaemia (RBCs)
G.V. Scagliotti, S. No6ello / Lung Cancer 34 (2001) S91– S94 Table 2 Types of solid tumours and frequency of blood transfusions Diagnosis
Percentage of transfused patients
All Lung Ovary Testis Breast
33 43 41 24 19
Mean cycle 1 transfusion trigger (Hb g/dl)
10.7 11.0a 10.5 9.6b 10.6
a Significantly higher than the mean for the other groups combined (P= 0.008). b Significantly lower than the mean for the other groups combined (P =0.009).
markedly if the pre-treatment haemoglobin concentration is below 10 g/dl. Tumour hypoxia and anaemia are both negative and related factors that reduce the efficacy of radiation therapy. Many investigators have examined the relationship between anaemia and response to radiotherapy: in 23 out of 25 studies reviewed by Dische in 1991, an adverse influence of anaemia on the outcome of radiotherapy has been reported [6]. The same concept was well demonstrated in a phase III trial in head and neck cancer patients treated by radiation therapy [7]. In most of the cases, the management of cancer-associated anaemia is currently limited to red blood cell transfusions for severely anaemic patients, but this procedure has been associated with a risk of infection transmission, alloimmunisation, low patient compliance, and high financial cost. In addition, many studies have shown that higher transfusion rates are associated with significantly reduced survival rates in patients undergoing surgery or chemotherapy [8].
3. Erythropoietin in lung cancer Four studies have systematically evaluated the effects of erythropoietin on anaemia in lung cancer patients. While many questions are yet to be answered, each of these trials contributes additional information concerning the clinical benefit of erythropoietin in treating or preventing treatment-related or disease-related anaemia. In the original registration trial investigating erythropoietin in cancer chemotherapy-related anaemia, patients were randomised to receive either placebo or erythropoietin. Both groups were anaemic at presentation. The placebo group continued to be anaemic over the 12 weeks of therapy. In contrast, patients
S93
treated with erythropoietin had a significant improvement of approximately six haematocrit points over the same period of treatment. This improvement was observed in patients who received erythropoietin and were treated with platinum-based as well as non-platinum-based combination chemotherapy [9,10]. Subsequently, three large community-based, openlabel trials were performed in the USA. The lung cancer patients represented one of the largest single group of solid tumour patients. Two of these community based trials evaluated globally more than 4500 patients and using a thriceweekly administration of erythropoietin confirmed improvement in haemoglobin levels, reduction in the transfusion requirements, and significant improvement in quality of life [11,12]. As these two trials were ongoing, a pilot experience suggested that once-weekly administration might also be beneficial. Therefore, a third community-based trial enrolled 2980 patients and explored the activity of the weekly administration of 40 000 units of erythropoietin. Forty-nine percent of the patients treated with this weekly dose achieved at least a 2 g increase in the haemoglobin level, and the proportion rose up to 68% when the weekly erythropoietin dose was escalated to 60 000 units [13]. The results reported in the last study well compared with those obtained with the thrice-weekly schedule. In the three above mentioned community-based trials with erythropoietin, more than 7000 patients have been analysed, and a possible correlation between overall quality of life, as measured by Linear Analog Scale Assessment (LASA), and haemoglobin levels was evaluated. This relationship was found to be remarkably similar in all three trials. Most of the improvements occurred with haemoglobin levels between 10 and 12 g/dl, and not with levels between 7 and 10 g/dl, with a plateau effect above 12 g/dl. On the basis of the information acquired, it has been proposed to shift the level of haemoglobin which is worthy of consideration for the management of anaemia. According to the physiologic principles that were used in the development of many transfusion policies in the 1980s, a ‘physiologic’ haemoglobin level of 7.5–8.0 g/dl was considered of clinical relevance. However, as more data on the quality of life become available, a ‘functional’ level of haemoglobin that appears to be more important is 12 g/dl, because it may be favourably associated with a significant improvement in fatigue compared with lower haemoglobin levels. This ‘functional’ level would be in keeping with the body’s physiological erythropoietin response previously discussed.
S94
G.V. Scagliotti, S. No6ello / Lung Cancer 34 (2001) S91– S94
4. Novel erythropoiesis stimulating protein (NESP) Novel erythropoiesis stimulating protein (NESP) is a glycosylated form of erythropoietin that has the potential advantage over erythropoietin of substained duration of action in rodent model [14,15]. In a model of anaemia of chronic disease, rats were effectively treated with NESP in a once-weekly or semi-monthly dose schedule [14]. Of note, after stabilisation of haemoglobin level, less frequent dosing sufficed to maintain that benefit. In a second model, mice were treated with various chemotherapy regimens or a combination of chemotherapy and radiation [15]. Pre-treatment of animals with NESP ameliorated the chemotherapy-induced anaemia noted in control animals. More importantly for repetitive chemotherapy regimens, NESP treatment did not appear to sensitise erythroid precursors to a greater damage by chemotherapy. The effects observed were highly dependent on timing and the chemotherapy regimen studied. The advantages of NESP over erythropoietin will be the aim of subsequent studies, as well as of ongoing studies in humans.
References [1] Finch CA. Erythropoiesis, erythropoietin and iron. Blood 1982;60:1241 – 6. [2] Wood PA, Hrushesky WJM. Cisplatin-associated anaemia: a erythropoietin deficiency syndrome. J Clin Invest 1995;95:1650 – 9. [3] Mayer K. Transfusion support for leukemia and oncology patients. Clin Haematol 1984;13:93 – 8. [4] Barret PJ, Bailey NP, O’Brien M, Wager E. Large scale UK audit of blood transfusion requirements and anaemia in patients receiving cytotoxic chemotherapy. Br J Cancer 2000;82(1):93 – 7.
[5] Skillings JR, Sridar FG, Wong C, Paddock L. The frequency of red cell transfusion for anaemia in patients receiving chemotherapy. A retrospective cohort study. Am J Clin Oncol 1993;16(1):22 – 5. [6] Dische S. Radiotherapy and anaemia: the clinical experience. Radiother Oncol 1991;20:35 – 40. [7] Kumar P, Wan J, Proctor E, et al. The impact of radiation-related factors upon long term outcome in the management of advanced head and neck carcinoma treated with supradose intra-arterial targeted cisplatino and radiation therapy. Int J Radiat Oncol Biol Phys 1998;43:321. [8] Henry DH, Rudnick SA, Bryant E, et al. Preliminary report of a double blind, placebo controlled studies using human recombinant erythropoietin (rHuEPO) in the anaemia associated with cancer. Blood 1989;74:6a poster. [9] Abels RI. Use of recombinant human erythropoietin in the treatment of anaemia in patients who have cancer. Semin Oncol 1992;19(Suppl. 8):29 – 35. [10] Henry DH, Abels RI. Recombinant human erythropoietin in the treatment of cancer and chemotherapy-induced anaemia: results of a double-blind and open-label follow-up studies. Semin Oncol 1994;21(Suppl. 3):21 – 8. [11] Glaspy J, Bukowski R, Steinberg D, et al. Impact of therapy with epoietin alfa on clinical outcomes in patients with non myeloid malignancies during cancer chemotherapy in community oncology practice. J Clin Oncol 1997;15:1218 – 34. [12] Procrit Study Group, Demetri G, Kris M, Wade J, et al. Quality of life benefit in chemotherapy patients treated with epoietin alfa is independent of disease response or tumour type. Results from a prospective community oncology study. J Clin Oncol 1998;16:3412 – 25. [13] Gabrilove JL, Einhorn LH, Livingston RB, et al. Once-weekly dosing of epoietin alfa is similar to three times weekly dosing in increasing haemoglobin and quality of life. Proc ASCO 1999;18:574. [14] Cooke K, Stoney G, Smith J et al. Novel Erythropoiesis Stimulating Protein (NESP) alleviates anaemia associated with chronic inflammatory disease in a rodent model, Proc Am Soc Hematol 1999, New Orleans, Abstr 209. [15] Hartley C, McElroy T, Sutherland W et al. Pre-treatment with novel erythropoiesis stimulating protein (NESP) prevents chemotherapy induced anaemia in mice. Proc Am Soc Hematol 1999, New Orleans, Abstr 213.
www.elsevier.com/locate/lungcan
Role of erythropoietin in the treatment of lung cancer associated anaemia G.V. Scagliotti a,*, S. Novello b a
Department of Clinical and Biological Sciences, Uni6ersity of Torino, Regione Gonzole 10, Azienda Ospedaliera S. Luigi, 10043 Orbassano, Torino, Italy b Departement de Medicine, Institut Gusta6e Roussy, Villejuif, Paris, France
Abstract Cancer-related causes of anaemia include anaemia of chronic disorders, infections, autoimmune haemolysis associated with malignant conditions, bone marrow invasion by the tumour or clonogenic marrow dysfunction, iron, folate, or vitamin B 12 deficiency and bleeding from tumour erosion. Treatment-related anaemia results from chemotherapy, radiotherapy and bone marrow fibrosis. Severe anaemia increases the burden of treatment, contributes to fatigue, reduces the quality of life and may also delay or limit further treatment. Blood transfusion is currently the most common form of treatment and patients rarely require transfusion unless the haemoglobin is less than 8 g/l. It is often difficult to predict which patients will develop anaemia and require treatment, but the proportion of patients receiving transfusions increases markedly if the pre-treatment haemoglobin concentration is below 10 g/dl. Four studies have systematically evaluated the effects of erythropoietin on anaemia in lung cancer patients and each of these trials is likely to contribute information concerning the clinical benefit of erythropoietin in treating or preventing treatment-related or disease-related anaemia. Most of the improvements in quality of life observed with erythropoietin administration occurred with haemoglobin levels between 10 and 12 g/dl, and not with levels between 7 and 10 g/dl, with a plateau effect above 12 g/dl. Consequently, a ‘functional’ level of haemoglobin that appears to be more important is 12 g/dl, because it may be favourably associated with a significant improvement in fatigue compared with lower haemoglobin levels. This ‘functional’ level would be in keeping with the body’s physiological erythropoietin response. © 2001 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Lung cancer; Anaemia; Erythropoietin
1. Introduction Several haematopoietic growth factors, including stem cell factor (SCF)/kit ligand, interleukin-11, interleukin-3, and interleukin-6, influence erythropoiesis. All these factors play a role in the activation of the quiescent stem cell. SCF, interleukin-11, and interleukin-3 may also play a role in the differentiation of activated stem cells to the earliest recognisable erythroid precursor, the burst-forming unit of erythroblasts (BFU-E). Further proliferation of BFU-E to erythroid colonyforming unit (CFU-E) is dependent on interleukin-3, granulocyte-macrophage colony stimulating factor (GM-CSF), interleukin-4, and interleukin-9. * Corresponding author. Tel.: + 39-011-9026-414; fax: + 39-0119038-616. E-mail address: [email protected] (G.V. Scagliotti).
Erythropoietin is a lineage-specific distal-acting factor which stimulates the maturation of CFU-E to mature erythrocytes. At the molecular level, erythropoietin is a 30,400-Da glycoprotein; carbohydrates represent 30–40% of the molecule and they are essential for secretion, stability in the circulation, and biological activity of erythropoietin. The trigger for the production of erythropoietin is the physiologic counterpart of red blood cell mass, i.e. the oxygen level. Thus, an inverse relationship exists between the red blood cell precursor mass and the serum erythropoietin level. The erythropoietin level in the plasma is relatively constant in the presence of normal levels of haemoglobin. However, while the haemoglobin level falls below 12 g/dl, the plasma erythropoietin level increases. This point is in contrast with the long-standing belief that a haemoglobin level of 10 g/dl is ade-
0169-5002/01/$ - see front matter © 2001 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 1 6 9 - 5 0 0 2 ( 0 1 ) 0 0 3 9 8 - 1
S92
G.V. Scagliotti, S. No6ello / Lung Cancer 34 (2001) S91– S94
quate for maintaining tissue oxygenation. Consequently, a haemoglobin level of at least 12 g/dl is important, because it serves as a physiological checkpoint beyond tissue hypoxia [1]. Erythropoietin mediates its effects through the erythropoietin receptor, which is expressed on erythroid progenitor cells, embryonal stem cells, multipotent haematopoietic progenitor cells, endothelial cells, and neural crest cells. While the biological role of erythroid receptor on non-erythroid cells is unknown, it is intriguing to speculate that some of the effects of erythropoietin on the symptoms of fatigue may be mediated through some of these tissue targets, in addition to the effects deriving from correction of anaemia.
2. Anaemia in cancer patients Both cancer and its treatment may lead to anaemia. Cancer-related causes of anaemia include anaemia of chronic disorders, infections, autoimmune haemolysis associated with malignant conditions, bone marrow invasion by the tumour or clonogenic marrow dysfunction, iron, folate, or vitamin B 12 deficiency, and bleeding from tumour erosion. The anaemia of chronic disorders identifies its pathophysiologic mechanisms in the shortened red cell survival, in the failure of bone marrow to increase erythropoiesis, and in its inability to release iron from senescent red cells. New lines of evidence suggest that abnormalities are involved in the production of erythropoietin, probably due to increased production by the tumour of cytokines, such as TNF-a, IL-1, TGF-b, IFN-b and IFN-g, which also affect haematopoietic progenitor cells, by impairing their responsiveness to growth factors. Numerous secondary disorders can also occur in cancer patients and can cause or contribute to the development of anaemia, including severe malnutrition, hypersplenism with cytopenia due to sequestration of haematopoietic cells and activation of tissue factors of the coagulation cascade resulting in erythrocyte and platelet destruction. Treatment-related anaemia results from chemotherapy, radiotherapy and bone marrow fibrosis. The malignancies produce a desmoid or fibrotic reaction, with increased bone marrow fibrosis, that results in alteration of bone marrow space and then in the correct physiological release of mature blood cells. The cytotoxic chemotherapeutic agents used in the treatment of most cancers have a number of adverse effect on haematopoiesis (Table 1). The main mechanisms involved are direct bone marrow damage and renal impairment, with a secondary deficiency in the production of erythropoietin. The former mechanism is induced by almost all cytotoxic drugs, and the latter is associated with cisplatin regimens [2].
Ionizing radiation to extensive areas of bone marrow and a large number of non-cell cycle dependent drugs (e.g. alkylating agents), when administered at high doses or for long periods of time, may lead to progressive depletion of haematopoietic stem cells. The drugs more effective against active proliferating cells (e.g. cytarabine, methotrexate, anthracyclines, etoposide, hydroxyurea) tend to cause earlier and shorter-lasting cytopenia. Some chemotherapeutic agents (e.g. anthracyclines) have secondary cytotoxic effects by inducing oxidant damage, even in mature haematopoietic cells. An often ignored or missed cause of pseudoanemia occurring shortly after chemotherapy is fluid retention with secondary dilutional anaemia. Severe anaemia increases the burden of treatment, contributes to fatigue, reduces the quality of life and may also delay or limit further treatment. On the other hand, a gradual fall in haemoglobin may be well tolerated by the patient because of the compensating mechanism of increased red cell level of 2,3-diphosphoglycerate, which results in an increased release of oxygen to the tissues. Blood transfusion is currently the most common form of treatment; but patients rarely require transfusion unless the haemoglobin is less than 8 g/l [3]. The most frequent symptoms related to the anaemia and for which there is a prescription of blood transfusion are: lethargy (51%), tiredness (42%), breathlessness (33%), and pallor (27%) [4]. The presence of an underlying cardiac or pulmonary disease may contribute to a poorer tolerance of anaemia in oncology patients. Consistent findings about blood cell transfusion requirements were reported in two retrospective studies conducted in the USA and UK. Among the patients with solid tumours, lung cancer patients required the highest frequency of transfusion for anaemia (Table 2) [4,5]. Patients with lung cancer were also generally transfused at a higher haemoglobin value, which is likely due to their underlying pulmonary disease. It is often difficult to predict which patients will develop anaemia and require treatment, but the proportion of patients receiving transfusions increases Table 1 Toxic effects of cytotoxic drugs on haemopoiesis Stem cell death (long-term myelosuppression) Committed progenitor cell death (early/short-term myelosuppression) Blockage or delay in cell cycling of haematopoietic precursors Reduced levels of haematopoietic growth factors (especially EPO) Oxidant damage to mature haematopoietic cells Long-term myelodysplasia Immune-mediated haematopoietic cell distruction Microangyopathy (RBCs and platelets) Fluid retention/plasma volume expansion with dilutional anaemia (RBCs)
G.V. Scagliotti, S. No6ello / Lung Cancer 34 (2001) S91– S94 Table 2 Types of solid tumours and frequency of blood transfusions Diagnosis
Percentage of transfused patients
All Lung Ovary Testis Breast
33 43 41 24 19
Mean cycle 1 transfusion trigger (Hb g/dl)
10.7 11.0a 10.5 9.6b 10.6
a Significantly higher than the mean for the other groups combined (P= 0.008). b Significantly lower than the mean for the other groups combined (P =0.009).
markedly if the pre-treatment haemoglobin concentration is below 10 g/dl. Tumour hypoxia and anaemia are both negative and related factors that reduce the efficacy of radiation therapy. Many investigators have examined the relationship between anaemia and response to radiotherapy: in 23 out of 25 studies reviewed by Dische in 1991, an adverse influence of anaemia on the outcome of radiotherapy has been reported [6]. The same concept was well demonstrated in a phase III trial in head and neck cancer patients treated by radiation therapy [7]. In most of the cases, the management of cancer-associated anaemia is currently limited to red blood cell transfusions for severely anaemic patients, but this procedure has been associated with a risk of infection transmission, alloimmunisation, low patient compliance, and high financial cost. In addition, many studies have shown that higher transfusion rates are associated with significantly reduced survival rates in patients undergoing surgery or chemotherapy [8].
3. Erythropoietin in lung cancer Four studies have systematically evaluated the effects of erythropoietin on anaemia in lung cancer patients. While many questions are yet to be answered, each of these trials contributes additional information concerning the clinical benefit of erythropoietin in treating or preventing treatment-related or disease-related anaemia. In the original registration trial investigating erythropoietin in cancer chemotherapy-related anaemia, patients were randomised to receive either placebo or erythropoietin. Both groups were anaemic at presentation. The placebo group continued to be anaemic over the 12 weeks of therapy. In contrast, patients
S93
treated with erythropoietin had a significant improvement of approximately six haematocrit points over the same period of treatment. This improvement was observed in patients who received erythropoietin and were treated with platinum-based as well as non-platinum-based combination chemotherapy [9,10]. Subsequently, three large community-based, openlabel trials were performed in the USA. The lung cancer patients represented one of the largest single group of solid tumour patients. Two of these community based trials evaluated globally more than 4500 patients and using a thriceweekly administration of erythropoietin confirmed improvement in haemoglobin levels, reduction in the transfusion requirements, and significant improvement in quality of life [11,12]. As these two trials were ongoing, a pilot experience suggested that once-weekly administration might also be beneficial. Therefore, a third community-based trial enrolled 2980 patients and explored the activity of the weekly administration of 40 000 units of erythropoietin. Forty-nine percent of the patients treated with this weekly dose achieved at least a 2 g increase in the haemoglobin level, and the proportion rose up to 68% when the weekly erythropoietin dose was escalated to 60 000 units [13]. The results reported in the last study well compared with those obtained with the thrice-weekly schedule. In the three above mentioned community-based trials with erythropoietin, more than 7000 patients have been analysed, and a possible correlation between overall quality of life, as measured by Linear Analog Scale Assessment (LASA), and haemoglobin levels was evaluated. This relationship was found to be remarkably similar in all three trials. Most of the improvements occurred with haemoglobin levels between 10 and 12 g/dl, and not with levels between 7 and 10 g/dl, with a plateau effect above 12 g/dl. On the basis of the information acquired, it has been proposed to shift the level of haemoglobin which is worthy of consideration for the management of anaemia. According to the physiologic principles that were used in the development of many transfusion policies in the 1980s, a ‘physiologic’ haemoglobin level of 7.5–8.0 g/dl was considered of clinical relevance. However, as more data on the quality of life become available, a ‘functional’ level of haemoglobin that appears to be more important is 12 g/dl, because it may be favourably associated with a significant improvement in fatigue compared with lower haemoglobin levels. This ‘functional’ level would be in keeping with the body’s physiological erythropoietin response previously discussed.
S94
G.V. Scagliotti, S. No6ello / Lung Cancer 34 (2001) S91– S94
4. Novel erythropoiesis stimulating protein (NESP) Novel erythropoiesis stimulating protein (NESP) is a glycosylated form of erythropoietin that has the potential advantage over erythropoietin of substained duration of action in rodent model [14,15]. In a model of anaemia of chronic disease, rats were effectively treated with NESP in a once-weekly or semi-monthly dose schedule [14]. Of note, after stabilisation of haemoglobin level, less frequent dosing sufficed to maintain that benefit. In a second model, mice were treated with various chemotherapy regimens or a combination of chemotherapy and radiation [15]. Pre-treatment of animals with NESP ameliorated the chemotherapy-induced anaemia noted in control animals. More importantly for repetitive chemotherapy regimens, NESP treatment did not appear to sensitise erythroid precursors to a greater damage by chemotherapy. The effects observed were highly dependent on timing and the chemotherapy regimen studied. The advantages of NESP over erythropoietin will be the aim of subsequent studies, as well as of ongoing studies in humans.
References [1] Finch CA. Erythropoiesis, erythropoietin and iron. Blood 1982;60:1241 – 6. [2] Wood PA, Hrushesky WJM. Cisplatin-associated anaemia: a erythropoietin deficiency syndrome. J Clin Invest 1995;95:1650 – 9. [3] Mayer K. Transfusion support for leukemia and oncology patients. Clin Haematol 1984;13:93 – 8. [4] Barret PJ, Bailey NP, O’Brien M, Wager E. Large scale UK audit of blood transfusion requirements and anaemia in patients receiving cytotoxic chemotherapy. Br J Cancer 2000;82(1):93 – 7.
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