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LETTER TO THE EDITOR

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Erythropoietin Enhances Response to Treatment in Patients with Advanced Breast Cancer Anna-Maria Larsson, Go¨ran Landberg, Sven Pa˚hlman and Maria Albertsson

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From the Department of Oncology (A.-M. Larsson), Department of Laboratory Medicine, Division of Molecular Medicine (A.-M. Larsson, S. Pa˚hlman), and Division of Pathology (G. Landberg), Lund University, University ¨ S/Huddinge (M. Albertsson), Sweden Hospital MAS, Malmo¨, Department of Oncology, University Hospital SO Correspondence to: Sven Pa˚hlman, Department of Laboratory Medicine, Division of Molecular Medicine, University Hospital MAS, Entrance 78, SE-205 02 Malmo¨, Sweden Tel: /46-40337403. Fax: /46-40337322. E-mail: [email protected] Acta Oncologica Vol. 43, No. 6, pp. 594 /597, 2004 Received 16 March 2004 Accepted 4 June 2004

To the Editor A majority of patients with cancer develop anaemia that may be related to oncotherapy, tumour infiltration of the bone marrow, nutritional deficiencies, or may arise secondary to chronic disease. Introduction of recombinant human erythropoietin (rhEPO) has provided an alternative to blood transfusions for treating anaemic cancer patients and different clinical trials have evaluated the effects (1). We have previously studied the effects of rhEPO in women with metastatic breast cancer and anaemia and could demonstrate that the haemoglobin (Hb) levels and quality of life (QoL) increased in these patients (2). In that study we also monitored tumour response. Here we report these results as they could suggest that an rhEPO-induced increase in Hb levels results in an increased response to tumour treatment. One hundred and eighty women with metastatic breast cancer and Hb levels B/110 g/L were included in the study and randomized to treatment with Epoetin Beta (rhEPO, NeoRecormon [Roche]), either 1000 U or 5000 U three times weekly for 24 weeks; details of the study and patient material have already been described (2). In short, 109 patients completed the entire study. Seventy-one patients did not complete the study owing to death (40 patients; 21 and 19 patients from the groups receiving 1000 U and 5000 U of rhEPO, respectively), adverse events (5 patients), personal (7 patients), or unspecified (19 patients) reasons. Of the included patients 174 received anti-tumour treatment; 141 chemotherapy (the majority second or third line, primarily anthracycline- or taxancontaining regimens), and 33 hormonal therapy. Tumour response was evaluated according to standard definitions (WHO) by X-ray of affected skeletal and pulmonary lesions, CT of the thoracic cavity and/or abdomen, and # Taylor & Francis 2004. ISSN 0284-186X DOI: 10.1080/02841860410018179

bone scintigraphy. In the present study tumour response was defined as partial or complete response (PR, CR) or stable disease (SD). The rhEPO-treated patient group seemed to respond well to their antitumoural treatment, and for comparison we retrospectively evaluated tumour response in a consecutive group of 47 breast cancer patients with anaemia fulfilling the same criteria as the study population (comparable age, metastatic disease, and Hb levels B/110 g/L), but not treated with rhEPO. Although this control group cannot be directly compared with the group of rhEPO treated patients, a comparison nevertheless suggested that the patients treated with rhEPO responded better to their antitumour treatment than those in the control group (67% vs. 49%). This observation led us to analyse in more detail a putative correlation between tumour response and Hb levels in the rhEPO-treated patients. Of the 180 patients given rhEPO as supplementary therapy (see above), 138 were evaluated for tumour response during the study period. Hb values were measured in 119 of these 138 patients during weeks 8 /12 after initiation of rhEPO treatment. Of the 19 patients lacking Hb values (10 patients receiving 1000 U and 9 receiving 5000 U of rhEPO), 12 patients died during the first 8 weeks of the study (6 patients from each group), 3 patients were withdrawn for personal reasons, and 4 patients were withdrawn due to adverse events, changed consent, noncompliance, or were lost to follow-up. In the group of patients with tumour response as described above, the mean Hb level increased from 99.8 g/L week 0 to 115.3 g/L (pB/ 0.0001 by Mann /Whitney Wilcoxon test) after 8 /12 weeks of rhEPO-treatment (Fig. 1A). In the non-responding patients, the mean Hb level was initially 97.9 g/L, but did Acta Oncologica

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Acta Oncologica 43 (2004)

Letter to the Editor

Fig. 1. (A): Hb values before and after 8 /12 weeks of rhEPO treatment in patients with and without tumour response. Statistics by Mann /Whitney Wilcoxon test. (B): Tumour response in relation to change in Hb level after rhEPO treatment. The correlation between percentage of tumour responders and increases in Hb levels were positive and linear (r /0.327, pB/0.0001).

not change significantly after treatment (100.2 g/L, p /0.63) (Fig. 1A). Subanalysis of tumour response in correlation to Hb levels in patients receiving either 1000 or 5000 U of rhEPO revealed that there were 78% tumour responders in

the group receiving 5000 U compared with 61% in the group receiving 1000 U of rhEPO (Table I). This difference was significant (p B/0.05 by x2 test). Although there was a statistically significant increase in Hb in all three groups of patients with tumour response (see Table 1), the highest mean Hb levels and net increase in Hb were found in the group of patients receiving 5000 U of rhEPO. Furthermore, in the entire group of rhEPO-treated patients there was a linear association between tumour response and increasing Hb levels (r/0.327, pB/0.0001 by Pearson r, Fig. 1B). Notably, among the 37 rhEPO-treated patients with the most pronounced increase in Hb levels (/20 g/L), 89% were tumour responders, further supporting our suggestion that the tumour reaction to supplementary rhEPO treatment is primarily mediated by an increase in Hb. In our material, which consists of a homogeneous diagnosis group of patients with metastatic breast cancer receiving supplementary rhEPO treatment, we found an increased tumour response rate among those patients that had the most pronounced increase in Hb levels, which might suggest that treatment response was positively affected by the elevation in Hb levels. We also did observe a significant increase in Hb levels in the non-rhEPO-treated patients responding to tumour treatment, reiterating clinical observations that patients responding to tumour treatment gain an increase in Hb. Nevertheless, the highest Hb levels and net increases in Hb were found in the patients with tumour response receiving 5000 U of rhEPO and there was a positive correlation between increased Hb levels and tumour response, data supporting the impression that increased Hb levels positively affect tumour response. The comparatively high response rate to tumour treatment is clinically interesting as the studied patients were at an advanced stage, with the majority in second- or third-line therapy. The tumour response in rhEPO-treated patients is interesting from a tumour biological perspective as there is still no conclusive evidence on what effects rhEPO might have

Table I Tumour response and changes in Hb levels in rhEPO-treated and control patients Patient group

nTR/TR

No. of patients

Historic Controls

nTR TR

26 21

1000 U rhEPO

nTR TR

5000 U rhEPO

nTR TR

TR (%)

595

Mean Hb inc (g/L)

Mean Hb w0 (g/L)

Mean Hb w8 /12 (g/L)

49

102.9 104.7

107.9 112.1a

5.0 7.4

23 36

61

99.1 99.4

100.0 110.1a

0.9 10.7

13 47

78

95.9 100.1

100.5 119.2b

4.6 19.1

Abbreviations: TR: tumour response; nTR: no tumour response; w: week(s); inc: increase. a Significant increase in Hb; ap /0.001; bp B/0.0001 by Mann /Whitney Wilcoxon test.

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596

A.-M. Larsson et al.

on tumour growth and behaviour. Our observation that supplementary rhEPO treatment has a positive effect on tumour response in breast cancer has also been reported for other tumour forms (3 /5). However, two recent studies have implicated that adding rhEPO to antitumour treatment can affect patient survival in a negative way (6, 7). In particular, the multicentre trial investigating the effect of rhEPO on survival in patients with metastatic breast cancer receiving chemotherapy was terminated early because of an observed higher mortality in the rhEPO-treated group compared with placebo (6). However, definite conclusions regarding the effects of rhEPO could not be drawn from this study according to the authors, since there could have been an imbalance of risk factors between the treatment groups (6). It is noteworthy that the 40 patients who died during the course of our study, distributed evenly between the two rhEPO groups. The discordant results of the clinical trial reported by Leyland-Jones (6) and the data we report cannot at present be explained in molecular terms. However, in the last years EPO receptors have been demonstrated in breast cancer cells and tumours of various origins (8 /10), and EPO can promote survival as well as growth of cultured tumour cells (8, 10). Thus, it is feasible that rhEPO could act directly on tumour cells, and that the clinical outcome of rhEPO treatment is to some extent dependent on EPO receptor expression levels. As the function and expression pattern of EPO receptors in tumour cells is far from fully elucidated, it appears highly relevant to address these issues in future studies. The observed correlation between Hb values and tumour response in this study might also be explained by an effect of rhEPO that is linked to the increased Hb levels. Anaemia is strongly associated with poor outcome in cancer patients (11), and is also known to contribute to tumour hypoxia. An association between Hb level and the oxygenation status in breast cancer was demonstrated recently (12), suggesting that an increase in Hb will positively affect tumour oxygenation and counteract negative effects of hypoxia. There is strong clinical evidence that tumour hypoxia is associated with malignant features such as loco-regional invasion and distant metastases (13, 14). Tumour hypoxia can further contribute to treatment resistance in both radiotherapy and chemotherapy (15). Of particular relevance regarding advanced breast cancer and anti-oestrogen treatment is our recent observation that hypoxia downregulates the oestrogen receptor expression in in situ as well as in invasive breast cancer (16, 17). Furthermore, hypoxia promotes the development of an immature tumour phenotype as demonstrated in breast cancer and in neuroblastoma (16, 18). Thus, as a low tumour differentiation grade correlates to negative outcome in these tumour forms, an increase in Hb levels would result in more efficient tumour oxygenation, and a positive effect on the tumour differ-

Acta Oncologica 43 (2004)

entiation status. Although negative effects of rhEPO treatment in cancer patients have been reported, our data suggest that there might be clinical situations in which rhEPO could be beneficial to the patient by increasing Hb levels, QoL, and tumour response.

ACKNOWLEDGEMENTS This study was supported by the Swedish Cancer Society and Malmo¨ University Hospital Research Funds, and by a grant from Roche AB, manufacturer of Neorecormon. The clinical trial was approved by the regional ethics committees and the Swedish Medical Products Agency, and was performed according to Good Clinical Practice. The authors would like to thank Dr Per Na¨sman for statistical advice. The sponsors of the study were not involved in designing the study, in collecting, analysing, or interpreting the data, or in writing the report.

REFERENCES 1. Ludwig H, Fritz E. Overview of clinical trials on rHuEPO in cancer patients. In: Bokemeyer C, Ludwig H, eds. Anaemia in cancer, ESO Scientific Updates, Vol 6. 1st ed. Amsterdam: Elsevier Science B.V. 2001. p. 115 /43. 2. Olsson A-M, Svensson J-H, Sundstro¨m J, et al. Erythropoietin treatment in metastatic breast cancer: effects on Hb, quality of life and need for transfusion. Acta Oncol 2002; 41: 517 /24. 3. Littlewood TJ, Bajetta E, Nortier JWR, Vercammen E, Rapoport B. Effects of EPOetin Alfa on hematologic parameters and quality of life in cancer patients receiving nonplatinum chemotherapy: results of a randomized, double-blind, placebo-controlled trial. J Clin Oncol 2001; 19: 2865 /74. 4. Glaser CM, Millesi W, Kornek GV, et al. Impact of hemoglobin level and use of recombinant erythropoietin on efficacy of preoperative chemoradiation therapy for squamous cell carcinoma of the oral cavity and oropharynx. Int J Radiat Oncol Biol Phys 2001; 50: 705 /15. 5. Silver DF, Piver MS. Effects of recombinant human erythropoietin on the antitumour effect of Cisplatin in SCID mice bearing human ovarian cancer: a possible oxygen effect. Gynecol Oncol 1999; 73: 280 /4. 6. Leyland-Jones B. Breast cancer trial with erythropoietin terminated unexpectedly. Lancet Oncol 2003; 4: 459 /60. 7. Henke M, Laszig R, Ru¨be C, Scha¨fer U, et al. Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: randomised, double-blind, placebocontrolled study. Lancet 2003; 362: 1255 /60. 8. Acs G, Acs P, Beckwith SM, et al. Erythropoietin and erythropoietin receptor expression in human cancer. Cancer Res 2001; 61: 3561 /5. 9. Yasuda Y, Fujita Y, Matsuo T, et al. Erythropoietin regulates tumour growth of human malignancies. Carcinogenesis 2003; 24: 1021 /9. 10. Westenfelder C, Baranowski RL. Erythropoietin stimulates proliferation of human renal carcinoma cells. Kidney Int 2000; 58: 647 /57. 11. Caro JJ, Salas M, Ward A, Goss G. Anaemia as an independent prognostic factor for survival in patients with cancer. Cancer 2001; 91: 2214 /21. 12. Vaupel P, Mayer A, Briest S, Ho¨ckel M. Oxygenation gain factor: a novel parameter characterizing the association between hemoglobin level and the oxygenation status of breast cancers. Cancer Res 2003; 63: 7634 /7.

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13. Hockel M, Vaupel P. Tumour hypoxia: definitions and current clinical, biologic, and molecular aspects. J Natl Cancer Inst 2001; 93: 266 /76. 14. Harris AL. Hypoxia: a key regulatory factor in tumour growth. Nature Rev Cancer 2002; 2: 38 /47. 15. Teicher BA. Hypoxia and drug resistance. Cancer Metastasis Rev 1994; 13: 139 /68. ˚ , Jo¨gi A, et al. Hypoxia promotes a 16. Helczynska K, Kronblad A dedifferentiated phenotype in ductal breast carcinoma in situ. Cancer Res 2003; 63: 1441 /4.

Letter to the Editor

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˚ , Helczynska K, Nielsen NH, Emdin S, Pa˚hlman S, 17. Kronblad A Landberg G. Regional cyclin D1 overexpression or hypoxia correlate inversely with heterogeneous oestrogen receptoralpha expression in human breast cancer. In vivo 2003; 17: 311 /8. 18. Jo¨gi A, Øra I, Nilsson H, et al. Hypoxia alters gene expression in human neuroblastoma cells toward an immature and neural crest-like phenotype. Proc Natl Acad Sci 2002; 99: 7021 /6.