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Letter to the Editor |
reply |
Queen's University, Belfast, Northern Ireland
Correspondence: Correspondence: Terence R. J. Lappin, Ph.D., Centre for Cancer Research and Cell Biology, Queen's University, Belfast, 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland, UK. Telephone: 44-2890-972929; Fax: 44-2890-972776; e-mail: t.lappin{at}qub.ac.uk
Received July 9, 2007; accepted for publication July 10, 2007.
Dr. Littlewood raises a number of issues pertaining to our recent commentary "Warning Flags for Erythropoiesis-Stimulating Agents and Cancer-Associated Anemia" [1]. It is generally held that severe anemia affects quality of life and that transfusions alleviate anemia, so transfusion would reasonably be expected to improve quality of life. There is prior evidence that transfusion does indeed offer symptom relief and improvement of well-being in patients with advanced malignant disease [2]. More recently, investigations have focused on the use of ESAs to reduce the debilitating fatigue in cancer-associated anemia.
Although controversial, there is extensive literature on the immunomodulatory effects of transfusion and accumulating data suggesting that perioperative transfusion has an adverse effect on the recurrence of colorectal cancer [3]. ESA treatment may be preferable for treating anemia in cancer patients undergoing surgery. Nevertheless the differences in cancer outcomes may be associated with confounding clinical circumstances that necessitated transfusion [4].
Comparison of trials of ESA treatment for cancer-related anemia are complicated by differences in trial design. The Henke et al. [5] trial involved 351 anemic patients who had cancer of the oral cavity, pharynx, or larynx. Women with a hemoglobin (Hb) level <12 g/dl and men with an Hb level <13 g/dl were randomly assigned to receive radiotherapy together with either placebo or epoetin beta (NeoRecormon®; Hoffmann-La Roche, Basel, Switzerland) at a dose of 300 IU/kg three times per week starting before radiotherapy and continuing throughout treatment. Substantially shorter progression-free survival and overall survival times were recorded in the group who received epoetin beta. In the BEST study [6], 939 patients with metastatic breast cancer undergoing chemotherapy were randomly assigned to receive either placebo or 40,000 IU epoetin alfa (Eprex®; Ortho Biotech/Janssen-Cilag, High Wycombe, United Kingdom) once per week for 12 months. In that trial, the drug was initiated if Hb was 
13 g/dl at baseline, or at a later time point. The group who received epoetin alfa had a lower overall survival rate at 1 year and the study was stopped prematurely by an independent monitoring committee because of the higher mortality in the epoetin alfa group at 4 months. We agree with Dr. Littlewood that these studies have been the subject of wide-ranging debate in the literature.
Our statement that the Roche trial of its long-acting ESA CERA was terminated because of an imbalance in survival among the treatment groups is factually correct. As Dr. Littlewood points out, there was no suggestion in the report that ESAs were the cause of the worse outcome in one or more of the groups.
As stated in our commentary [1], our group has shown that erythropoietin (Epo), at pharmacological concentrations, can activate three major signaling cascades, namely, the Janus kinase-2/signal transducer and activator of transcription-5, Ras/extracellular signal–related kinase, and phosphatidylinositol 3' kinase/Akt pathways in neoplastic cells, such as the non-small cell lung cancer cell line H838 [7]. We also found impaired downregulation of Epo receptors (EpoRs) in H838 cells [8] and expressed our view that if these findings are replicated in tumor tissues then they have implications for patients receiving ESAs for cancer-related anemia.
Recently Henke et al. [9] investigated the correlation between tumor EpoR expression and disease progression in patients with head and neck cancer. They found that locoregional progression-free survival was substantially poorer if epoetin beta was administered to patients positive for receptor expression compared with placebo (adjusted relative risk, 2.07; 95% confidence interval [CI], 1.27–3.36; p < .01). In contrast, epoetin beta did not impair outcome in receptor-negative patients (adjusted relative risk, 0.94; 95% CI, 0.47–1.90; p = .86). They concluded that Epo treatment might adversely affect the prognosis of head and neck cancer patients if cancer cells express EpoRs. We strongly agree with the reservations expressed by Della Ragione and colleagues [10] concerning the specificity of the EpoR C20 antibody used in this recent study by Henke et al. [9] because it has been clearly demonstrated that it cross-reacts with heat shock protein-70 [11, 12].
Although the meta-analysis reported by Bohlius and colleagues [13] showed no survival disadvantage for patients with cancer treated with ESAs, there was a higher risk for thromboembolic events (relative risk, 1.67; 95% CI, 1.35–2.06; 35 trials and 6,769 patients). The authors of the meta-analysis urged caution when using ESAs in combination with thrombogenic chemotherapeutic agents and for cancer patients who are at high risk for thromboembolic events.
To quote from our commentary [1], "these studies have raised concerns that ESAs could, in certain circumstances, adversely affect survival in cancer patients and have led to speculation that these agents may enhance thrombosis, tumor growth, and neovascularization." In view of these concerns, we continue to urge caution when considering ESA treatment for cancer-associated anemia. The U.S. Food and Drug Administration advisory on the use of ESAs remains in place pending further review of the evidence from published and unpublished studies.
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