- Email: [email protected]
Prediction of chemotherapy-induced anaemia: is knowledge really power?
Reflection and Reaction
during these years did not change substantially the pattern of this relation. As expected, most cancers were ultimately diagnosed within 3–6 months of discharge from hospital, but the greater risk of cancer was evident for as long as 12 months, decreasing after this time to where subsequent diagnosis of malignant disease was near baseline (standardised incidence ratio 1·1–1·2). The strongest association between fever of unknown origin and malignant disease was for lymphomas, particularly Hodgkin’s disease. Diagnosis of fever of unknown origin does not necessarily imply a patient has an extremely poor outlook, or at least one substantially worse than that noted for others with a particular malignant disease in the absence of fever of unknown origin. This research emphasises several important points about the association between fever of unknown origin and cancer. Although the relation is unquestionably clinically relevant, especially with haematological malignant disease, overall there is only a modest risk of cancer being found with continued follow-up in this population. Most cancers will be diagnosed within 6–12 months after the diagnosis of fever of unknown origin. Although the survival of this population is worse than that recorded in similar patients who do not present with a fever of unknown
origin, to label these patients as untreatable or destined to have a very poor outcome would be inappropriate solely on the basis of this clinical presentation. The use of this type of population-based research must be noted. It is reasonable to conclude on the basis of data from a clinical study that is well done and well designed involving 100 patients with condition X, that Y had a particular outcome. But the question remains: what is the relevance of this finding to the large population of individuals with condition X who might be cared for within the community? Does the observation reflect the real world, or only highly selected patients frequently seen in important academic centres? Population-based studies, such as that by Sørensen and colleagues,2 are one very important mechanism to answer this important question. Maurie Markman University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA [email protected] I declare no conflicts of interest. 1 2
Petersdorf RG, Beeson PG. Fever of unexplained origin: report on 100 cases. Medicine 1961; 40: 1–30. Sørensen HT, Mellemkjaer L, Skriver MV, et al. Fever of unknown origin and cancer: a population-based study. Lancet Oncol 2005; 6: 851–55.
Prediction of chemotherapy-induced anaemia: is knowledge really power? See Articles page 856
822
The basic promise of recombinant erythropoietin is that it can provide many of the benefits of blood transfusion without transfusing blood. When used as replacement treatment in patients with end-stage renal disease who are anaemic, this promise has been fulfilled amply. When used as adjuvant treatment in individuals with normal renal function who are anaemic, however, recombinant erythropoietin has been less effective, less predictable in its effectiveness, and incapable of preventing allogeneic blood exposure.1 None of the above should be surprising because erythropoiesis is a complex process involving four essential components: the intensity of the stimulus for red-cell production; the ability of
erythroid cells in the bone-marrow to respond to that stimulus; the availability of essential nutrients such as iron; and erythrocyte lifespan. Of these, only the first is amenable to control with recombinant erythropoietin.2 Furthermore, clinical decisions about blood transfusion take into account factors other than a low haemoglobin concentration, especially the necessity for its immediate correction. An unrecognised benefit of recombinant erythropoietin has been the increased scrutiny of anaemia that its use has stimulated. We now appreciate that anaemia has important consequences beyond its potential for exposure to allogeneic blood.3 Not only is quality of life lowered, admission to hospital http://oncology.thelancet.com Vol 6 November 2005
Reflection and Reaction
increased, and length of hospital stay extended, but anaemia is also an independent cause of death in cancer, renal disease, heart disease, HIV infection, and ageing. Moreover, correction of anaemia seems to reverse these consequences.3,4 However, use of recombinant erythropoietin in patients with cancer who are anaemic has been challenged by two major randomised controlled trials5,6 of patients with head and neck cancer5 and breast cancer,6 in which the aim was to prevent anaemia. Surprisingly, patients receiving recombinant erythropoietin had an worse response to anticancer treatment and decreased survival than did those who received placebo. Unfortunately, both trials had issues with their methods, including inappropriately high starting or target haemoglobin concentrations, rendering premature any conclusions about the safety of recombinant erythropoietin in either situation. These trials also need to be balanced against three other studies,7–9 albeit open label, of patients with lung cancer8 and breast cancer7,9 in whom recombinant erythropoietin prevented anaemia without promoting thrombosis, blunting the effects of chemotherapy, or reducing survival. Nevertheless, since cancer cells can express erythrypoietin receptors and since erythropoietin is antiapoptotic, dismissing the potential of recombinant erythropoietin to stimulate cancer-cell proliferation is difficult. At the same time, hypoxia promotes tumours, selects for cells with mutant P53, stimulates expression of the erythropoietin receptor, and creates an environment that impairs chemotherapy and radiotherapy.2 In this issue of The Lancet Oncology, Dranitsaris and colleagues10 propose a prediction tool for identification of patients with breast cancer who are most likely to develop severe anaemia (haemoglobin concentration 100 g/L) during chemotherapy, which would mean that treatment for anaemia could be started proactively. Five predictive factors were identified: precycle haemoglobin concentration, cycle of chemotherapy, age (65 years), platelet count (200109/L), use of prophylactic antibiotics, and type of chemotherapy, which is in accordance with previous studies of cancer-associated anaemia.9,11 This is not the first predictive risk model for chemotherapyinduced anemia: Ray-Coquard and colleagues12 found that a baseline haemoglobin concentration of less http://oncology.thelancet.com Vol 6 November 2005
than 120 g/L, a performance status of greater than 1, and a baseline lymphocyte count of 700106/L or less, were independent risk factors for transfusion in patients with various tumours. Their algorithm, however, derived from a very small cohort of patients undergoing transfusion, and had high sensitivity but low specificity. That Dranitsaris and colleagues chose breast cancer as a model is curious, since incidence of anaemia and use of transfusions are lower for this cancer than for most others; premenopausal patients with breast cancer are frequently deficient in iron,11 and the potential for complications from treatment with recombinant erythropoietin could therefore be greater for these patients.6 However, their prediction tool could probably be applied to other cancers.11,12 The investigators suggested that with this tool, patients could be identified as candidates for treatment with agents such as recombinant erythropoietin for treatment of anaemia. But even identification of which patients are likely to become anaemic is only half the answer, because we still do not have an accurate way to identify which patients will respond to recombinant erythropoietin.1 Nevertheless, such a predictive algorithm, if validated prospectively, would be a starting point to identify early those who might benefit from recombinant erythropietin and to avoid its indiscriminate use. Given the lag time associated with the drug’s activity, however, neither rapid correction of anaemia nor avoidance of transfusion can be expected. Based on the documented risk factors, the obvious focus for validation would be elderly people and patients with comorbidity that predispose to anaemia. Such an approach should contribute to blood conservation and also improve the safety and cost-effectiveness of recombinant erythropoietin. In this regard, equating the cost of recombinant erythropoietin with the cost of blood transfusion alone is inappropriate. Rather, it should be compared with the cost of uncorrected anaemia.13 Jerry L Spivak Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA [email protected] I declare no conflict of interest.
823
Reflection and Reaction
1
2 3 4
5
6
7
Stasi R, Amadori S, Littlewood TJ, et al. Management of cancer-related anemia with erythropoietic agents: doubts, certainties and concerns. Oncologist 2005;10: 539–54. Spivak JL. The anaemia of cancer: death by a thousand cuts. Nature Rev Cancer 2005; 5: 543–55. Nissenson AR, Goodnough LT, Dubois RW. Anemia: not just an innocent bystander? Arch Intern Med 2003; 163: 1400–04. Bohlius J, Langensiepen S, Schwarzer G, et al. Recombinant human erythropoietin and overall survival in cancer patients: results of a comprehensive meta-analysis. J Natl Cancer Inst 2005; 97: 489–98. Henke M, Laszig R, Rube C, et al. Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: randomised, double-blind, placebo-controlled trial. Lancet 2003; 362: 1255–60. Leyland-Jones B, Semiglazov V, Pawlicki M, et al. Maintaining normal hemoglobin levels with epoetin alfa in mainly nonanemic patients with metastatic breast cancer receiving first-line chemotherapy: a survival study. J Clin Oncol 2005; 23: 5960–72. Del Mastro L, Venturini M, Lionetto R, et al. Randomized phase III trial evaluating the role of erythropoietin in the prevention of chemotherapy-induced anemia. J Clin Oncol 1997; 15: 2715–21.
8
Thatcher N, De Campos ES, Bell DR, et al. Epoetin beta prevents anaemia and reduces transfusion requirements in patients undergoing primarily platinum-based chemotherapy for small cell lung cancer. Br J Cancer 1999; 80: 396–402. 9 Chang J, Couture F, Young S, et al. Weekly epoetin alpha maintains hemoglobin, improves quality of life, and reduces transfusion in breast cancer patients receiving chemotherapy. J Clin Oncol 2005; 23: 2597–605. 10 Dranitsaris G, Clemons M, Verma S, et al. Chemotherapy-induced anaemia during adjuvant treatment for breast cancer: development of a prediction model. Lancet Oncol 2005; 6: 856–63. 11 Coiffier B, Guastalla J-P, Pujade-Lauraine E, et al. Predicting cancer–associated anaemia in patients receiving non-platinum chemotherapy: results of a retrospective study. Eur J Cancer 2001; 37: 1617–23. 12 Ray-Coquard I, Le Cesne A, Rubio MT, et al. Risk model for severe anemia requiring red blood cell transfusion after cytotoxic conventional chemotherapy regimens. J Clin Oncol 1999; 17: 2840–46. 13 Lyman GH, Berndt ER, Kallich JD, et al. The economic burden of anemia in cancer patients receiving chemotherapy. Value Health 2005; 2: 149–56.
Neoadjuvant chemoradiotherapy in resectable oesophageal cancer We commend Burmeister and colleagues1 on their randomised trial assessing the effect of neoadjuvant chemoradiotherapy on resectable oesophageal cancer published in the September issue of The Lancet Oncology. The investigators used a fairly non-toxic regimen (one cycle of 80 mg/m2 cisplatin with 800 mg/m2 fluorouracil and 35 Gy radiotherapy over 3 weeks), thereby ensuring good compliance with the planned treatment. However, we disagree with the investigator’s conclusions that progression-free survival and overall survival does not improve
Underpowered trials might underestimate treatment benefits
824
with neoadjuvant chemoradiotherapy for oesophageal cancer. The sample size calculations for the trial were based on a baseline survival of 20% at 3 years and a projected improvement to 35% with neoadjuvant chemoradiotherapy. Most surgical series report a 5-year survival in the range of 25% for surgery alone;2 we think that the 3-year survival estimate of 20% is too low. Our thoughts are confirmed by the results of the trial, in that 3-year survival seems to be more than 30%. Moreover, expectation of a 15% improvement in progression-free survival seems to be an overestimate of expected treatment benefit. The basis of any randomised controlled trial would be to attempt to show a modest survival advantage of an intervention treatment. Although we acknowledge the practical difficulties involved in accrual of sufficient patients to show a more-realistic survival improvement, concluding that neoadjuvant chemoradiotherapy is not beneficial on the basis of the results of an underpowered trial seems unfair. We also have reservations about the pretreatment stratification of patients on the basis of histological type, sex, and institution only. Tumour and nodal stage are the most important prognostic factors affecting survival, and the two groups should also be stratified on the basis of these characteristics. We admit that pretreatment T and N staging have only http://oncology.thelancet.com Vol 6 November 2005
during these years did not change substantially the pattern of this relation. As expected, most cancers were ultimately diagnosed within 3–6 months of discharge from hospital, but the greater risk of cancer was evident for as long as 12 months, decreasing after this time to where subsequent diagnosis of malignant disease was near baseline (standardised incidence ratio 1·1–1·2). The strongest association between fever of unknown origin and malignant disease was for lymphomas, particularly Hodgkin’s disease. Diagnosis of fever of unknown origin does not necessarily imply a patient has an extremely poor outlook, or at least one substantially worse than that noted for others with a particular malignant disease in the absence of fever of unknown origin. This research emphasises several important points about the association between fever of unknown origin and cancer. Although the relation is unquestionably clinically relevant, especially with haematological malignant disease, overall there is only a modest risk of cancer being found with continued follow-up in this population. Most cancers will be diagnosed within 6–12 months after the diagnosis of fever of unknown origin. Although the survival of this population is worse than that recorded in similar patients who do not present with a fever of unknown
origin, to label these patients as untreatable or destined to have a very poor outcome would be inappropriate solely on the basis of this clinical presentation. The use of this type of population-based research must be noted. It is reasonable to conclude on the basis of data from a clinical study that is well done and well designed involving 100 patients with condition X, that Y had a particular outcome. But the question remains: what is the relevance of this finding to the large population of individuals with condition X who might be cared for within the community? Does the observation reflect the real world, or only highly selected patients frequently seen in important academic centres? Population-based studies, such as that by Sørensen and colleagues,2 are one very important mechanism to answer this important question. Maurie Markman University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA [email protected] I declare no conflicts of interest. 1 2
Petersdorf RG, Beeson PG. Fever of unexplained origin: report on 100 cases. Medicine 1961; 40: 1–30. Sørensen HT, Mellemkjaer L, Skriver MV, et al. Fever of unknown origin and cancer: a population-based study. Lancet Oncol 2005; 6: 851–55.
Prediction of chemotherapy-induced anaemia: is knowledge really power? See Articles page 856
822
The basic promise of recombinant erythropoietin is that it can provide many of the benefits of blood transfusion without transfusing blood. When used as replacement treatment in patients with end-stage renal disease who are anaemic, this promise has been fulfilled amply. When used as adjuvant treatment in individuals with normal renal function who are anaemic, however, recombinant erythropoietin has been less effective, less predictable in its effectiveness, and incapable of preventing allogeneic blood exposure.1 None of the above should be surprising because erythropoiesis is a complex process involving four essential components: the intensity of the stimulus for red-cell production; the ability of
erythroid cells in the bone-marrow to respond to that stimulus; the availability of essential nutrients such as iron; and erythrocyte lifespan. Of these, only the first is amenable to control with recombinant erythropoietin.2 Furthermore, clinical decisions about blood transfusion take into account factors other than a low haemoglobin concentration, especially the necessity for its immediate correction. An unrecognised benefit of recombinant erythropoietin has been the increased scrutiny of anaemia that its use has stimulated. We now appreciate that anaemia has important consequences beyond its potential for exposure to allogeneic blood.3 Not only is quality of life lowered, admission to hospital http://oncology.thelancet.com Vol 6 November 2005
Reflection and Reaction
increased, and length of hospital stay extended, but anaemia is also an independent cause of death in cancer, renal disease, heart disease, HIV infection, and ageing. Moreover, correction of anaemia seems to reverse these consequences.3,4 However, use of recombinant erythropoietin in patients with cancer who are anaemic has been challenged by two major randomised controlled trials5,6 of patients with head and neck cancer5 and breast cancer,6 in which the aim was to prevent anaemia. Surprisingly, patients receiving recombinant erythropoietin had an worse response to anticancer treatment and decreased survival than did those who received placebo. Unfortunately, both trials had issues with their methods, including inappropriately high starting or target haemoglobin concentrations, rendering premature any conclusions about the safety of recombinant erythropoietin in either situation. These trials also need to be balanced against three other studies,7–9 albeit open label, of patients with lung cancer8 and breast cancer7,9 in whom recombinant erythropoietin prevented anaemia without promoting thrombosis, blunting the effects of chemotherapy, or reducing survival. Nevertheless, since cancer cells can express erythrypoietin receptors and since erythropoietin is antiapoptotic, dismissing the potential of recombinant erythropoietin to stimulate cancer-cell proliferation is difficult. At the same time, hypoxia promotes tumours, selects for cells with mutant P53, stimulates expression of the erythropoietin receptor, and creates an environment that impairs chemotherapy and radiotherapy.2 In this issue of The Lancet Oncology, Dranitsaris and colleagues10 propose a prediction tool for identification of patients with breast cancer who are most likely to develop severe anaemia (haemoglobin concentration 100 g/L) during chemotherapy, which would mean that treatment for anaemia could be started proactively. Five predictive factors were identified: precycle haemoglobin concentration, cycle of chemotherapy, age (65 years), platelet count (200109/L), use of prophylactic antibiotics, and type of chemotherapy, which is in accordance with previous studies of cancer-associated anaemia.9,11 This is not the first predictive risk model for chemotherapyinduced anemia: Ray-Coquard and colleagues12 found that a baseline haemoglobin concentration of less http://oncology.thelancet.com Vol 6 November 2005
than 120 g/L, a performance status of greater than 1, and a baseline lymphocyte count of 700106/L or less, were independent risk factors for transfusion in patients with various tumours. Their algorithm, however, derived from a very small cohort of patients undergoing transfusion, and had high sensitivity but low specificity. That Dranitsaris and colleagues chose breast cancer as a model is curious, since incidence of anaemia and use of transfusions are lower for this cancer than for most others; premenopausal patients with breast cancer are frequently deficient in iron,11 and the potential for complications from treatment with recombinant erythropoietin could therefore be greater for these patients.6 However, their prediction tool could probably be applied to other cancers.11,12 The investigators suggested that with this tool, patients could be identified as candidates for treatment with agents such as recombinant erythropoietin for treatment of anaemia. But even identification of which patients are likely to become anaemic is only half the answer, because we still do not have an accurate way to identify which patients will respond to recombinant erythropoietin.1 Nevertheless, such a predictive algorithm, if validated prospectively, would be a starting point to identify early those who might benefit from recombinant erythropietin and to avoid its indiscriminate use. Given the lag time associated with the drug’s activity, however, neither rapid correction of anaemia nor avoidance of transfusion can be expected. Based on the documented risk factors, the obvious focus for validation would be elderly people and patients with comorbidity that predispose to anaemia. Such an approach should contribute to blood conservation and also improve the safety and cost-effectiveness of recombinant erythropoietin. In this regard, equating the cost of recombinant erythropoietin with the cost of blood transfusion alone is inappropriate. Rather, it should be compared with the cost of uncorrected anaemia.13 Jerry L Spivak Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA [email protected] I declare no conflict of interest.
823
Reflection and Reaction
1
2 3 4
5
6
7
Stasi R, Amadori S, Littlewood TJ, et al. Management of cancer-related anemia with erythropoietic agents: doubts, certainties and concerns. Oncologist 2005;10: 539–54. Spivak JL. The anaemia of cancer: death by a thousand cuts. Nature Rev Cancer 2005; 5: 543–55. Nissenson AR, Goodnough LT, Dubois RW. Anemia: not just an innocent bystander? Arch Intern Med 2003; 163: 1400–04. Bohlius J, Langensiepen S, Schwarzer G, et al. Recombinant human erythropoietin and overall survival in cancer patients: results of a comprehensive meta-analysis. J Natl Cancer Inst 2005; 97: 489–98. Henke M, Laszig R, Rube C, et al. Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: randomised, double-blind, placebo-controlled trial. Lancet 2003; 362: 1255–60. Leyland-Jones B, Semiglazov V, Pawlicki M, et al. Maintaining normal hemoglobin levels with epoetin alfa in mainly nonanemic patients with metastatic breast cancer receiving first-line chemotherapy: a survival study. J Clin Oncol 2005; 23: 5960–72. Del Mastro L, Venturini M, Lionetto R, et al. Randomized phase III trial evaluating the role of erythropoietin in the prevention of chemotherapy-induced anemia. J Clin Oncol 1997; 15: 2715–21.
8
Thatcher N, De Campos ES, Bell DR, et al. Epoetin beta prevents anaemia and reduces transfusion requirements in patients undergoing primarily platinum-based chemotherapy for small cell lung cancer. Br J Cancer 1999; 80: 396–402. 9 Chang J, Couture F, Young S, et al. Weekly epoetin alpha maintains hemoglobin, improves quality of life, and reduces transfusion in breast cancer patients receiving chemotherapy. J Clin Oncol 2005; 23: 2597–605. 10 Dranitsaris G, Clemons M, Verma S, et al. Chemotherapy-induced anaemia during adjuvant treatment for breast cancer: development of a prediction model. Lancet Oncol 2005; 6: 856–63. 11 Coiffier B, Guastalla J-P, Pujade-Lauraine E, et al. Predicting cancer–associated anaemia in patients receiving non-platinum chemotherapy: results of a retrospective study. Eur J Cancer 2001; 37: 1617–23. 12 Ray-Coquard I, Le Cesne A, Rubio MT, et al. Risk model for severe anemia requiring red blood cell transfusion after cytotoxic conventional chemotherapy regimens. J Clin Oncol 1999; 17: 2840–46. 13 Lyman GH, Berndt ER, Kallich JD, et al. The economic burden of anemia in cancer patients receiving chemotherapy. Value Health 2005; 2: 149–56.
Neoadjuvant chemoradiotherapy in resectable oesophageal cancer We commend Burmeister and colleagues1 on their randomised trial assessing the effect of neoadjuvant chemoradiotherapy on resectable oesophageal cancer published in the September issue of The Lancet Oncology. The investigators used a fairly non-toxic regimen (one cycle of 80 mg/m2 cisplatin with 800 mg/m2 fluorouracil and 35 Gy radiotherapy over 3 weeks), thereby ensuring good compliance with the planned treatment. However, we disagree with the investigator’s conclusions that progression-free survival and overall survival does not improve
Underpowered trials might underestimate treatment benefits
824
with neoadjuvant chemoradiotherapy for oesophageal cancer. The sample size calculations for the trial were based on a baseline survival of 20% at 3 years and a projected improvement to 35% with neoadjuvant chemoradiotherapy. Most surgical series report a 5-year survival in the range of 25% for surgery alone;2 we think that the 3-year survival estimate of 20% is too low. Our thoughts are confirmed by the results of the trial, in that 3-year survival seems to be more than 30%. Moreover, expectation of a 15% improvement in progression-free survival seems to be an overestimate of expected treatment benefit. The basis of any randomised controlled trial would be to attempt to show a modest survival advantage of an intervention treatment. Although we acknowledge the practical difficulties involved in accrual of sufficient patients to show a more-realistic survival improvement, concluding that neoadjuvant chemoradiotherapy is not beneficial on the basis of the results of an underpowered trial seems unfair. We also have reservations about the pretreatment stratification of patients on the basis of histological type, sex, and institution only. Tumour and nodal stage are the most important prognostic factors affecting survival, and the two groups should also be stratified on the basis of these characteristics. We admit that pretreatment T and N staging have only http://oncology.thelancet.com Vol 6 November 2005