Edorium Journal of

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Chemotherapy induced anemia in patients with malignant diseases: A Montenegro study
Vladimir Todorovic1, Jadranka Lakicevic2, Nada Cicmil Saric2, Anka Popovic3, Vesko Vujicic3, Danko Zivkovic4, Aleksandra Kovacevic5, Rozalinda Isjanovska6
1Oncology and Radiotherapy Clinic, Clinical Centre of Montenegro, Centre for Haematology, Clinical Centre of Montenegro.
2Oncology and Radiotherapy Clinic, Clinical Centre of Montenegro.
3Centre for Haematology, Clinical Centre of Montenegro.
4Special Hospital for Lung Diseases - Brezovik.
5Faculty of Medicine, University of Montenegro.
6Faculty of Medicine Skopje.

Article ID: 100002C01VT2015
doi:10.5348/C01-2015-2-OA-1

Address correspondence to:
Prof. Dr. Vladimir Todorovic
Head of Chemotherapy Department of Oncology Clinic
Clinical Center of Montenegro Address: Ulica Ljubljanska bb, 20 000 Podgorica, Crna Gora, Montenegro
Phone: + 381 69 388 069

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Todorovic V, Lakicevic J, Saric NC, Popovic A, Vujicic V, Zivkovic D, Kovacevic A, Isjanovska R. Chemotherapy induced anemia in patients with malignant diseases: A Montenegro study. Edorium J Cancer 2015;2:1–7.


Abstract
Aims: Oncology patients treated by chemotherapy (CT) often develop different levels of anemia. We analyzed efficacy and safety of three times weekly administration of epoetin beta in hematologic and solid tumors in Montenegro.
Methods: One hundred and twenty anemic patients with solid tumors (75 patients) and non-myeloid hematological malignancies (45 patients) were treated with epoetin beta in the period from January 2009 till May 2012. We analyzed efficacy in terms of hemoglobin (Hb) level, transfusion requirement, dosing schedule and safety in this open label, single arm, non-interventional study. Anemic patients with Hb level <11 g/dL, treated with chemotherapy were included in this first multicentre oncology study in Montenegro. Statistical multivariate analysis method was used.
Results: In our study, most of patients had moderate anaemia, while 5.8% had severe level. Statistical significance was found in level of Hb during epoetin beta therapy compare to baseline and other study visits (p = 0.01). The percentage of patients with normal Hb values was increasing during the treatment. The need for blood transfusion was decreasing during epoetin beta therapy (first visit 8.3%, fifth visit 1.7%). Majority of patients (68%) did not report any adverse event. Two patients had thromboembolic events.
Conclusion: Administration of epoetin beta 30.000 IU three times weekly significantly increased Hb levels in anemic patients with different solid tumors and non-myeloid hematological malignancies who were receiving chemotherapy. The number of required transfusion is decreasing during the study treatment. Therapy with epoetin beta was well tolerated. Benefits of using epoetin beta were confirmed in patients with chemotherapy induced anemia.

Keywords: Anemia, cancer, chemotherapy, epoetin beta, safety


Introduction

Majority of patients on chemotherapy (CT) develop anemia during the treatment. Anemia is a negative prognostic factor in patients with cancer. Studies showed that patients with anemia have lower tumor control and shorter disease free and overall survival after CT, compared with patients with normal hemoglobin (Hb) levels [1] [2].

The European Cancer Anemia Survey (ECAS) 2004. have shown high prevalence of anemia patients with cancer. The frequency of anemia was high in most types of malignancies (70% of patients had anemia during observational period). Several reviews of incidence of anemia showed that almost all patients developed at least mild or moderate anemia and 79% of patients developed severe anemia (Hb 8.0–10.9 g/dl) [3].

Anemia in cancer patients is associated with advanced stage of disease, older age and the duration of CT regimen [4]. Oncology patients need earlier transfusion and there is a shorter time for indication of these interventions. Several transfusions may be indicated and during CT, epoetin beta therapy may reduce the need for transfusions [5].

During cancer treatment anemia may not be recognized or may be underestimated and low percentages of patients are receiving an appropriate therapy. In ECAS survey 17% of patients received epoetin treatment.

Epoetin beta stimulates human erythroid bone marrow precursor cells and stimulates growth of erythropoiesis cells. Epoetin beta does not stimulate growth of megakaryocytes.

In everyday practice, anemia is treated most often by using transfusions of red blood cells. The benefits are: rapid increase of Hb and hematocrit level and rapid improvement in anemia - related symptoms. Transfusion of red blood cells may cause transfusion reactions, virus transmission, bacterial contamination, iron overload. Recombinant Human erythropoietin avoids all mentioned risks. Epoetin beta stimulates human erythroid bone marrow precursor cells and these results in growth of marrow cells as erythropoiesis. Epoetin beta does not stimulate megakaryocytes' differentiation. The most common side effects are hypertension and thromboembolic events [6][7].

Meta-analysis of studies with epoetin beta evaluated the impact and initial Hb levels on overall survival, tumor progression and thromboembolic side effects. Total numbers of 2297 patients were included. There was no association between high target Hb levels and an increased risk of mortality, disease progression or thrombosis with epoetin beta compared with control group. The results showed that there is no impact on survival or tumor progression when therapy was starts at Hb levels at 11 g/dL [8] .

The most frequent side effects of epoetin beta are: headache, rising of blood pressure, flu like symptoms, skin reactions as rash, increased number of platelets, thrombosis and in small number of patients hypertensive crisis.

Some studies showed that early erythropoietin intervention is beneficial with better efficacy and decreased number of transfusion indications. No increase of treatment cost was associated with early application of epoetin beta [9].

The analysis of six studies giving epoetin beta in different tumor types in more than 4200 patients showed that epoetin beta is effective and well tolerated with significant Hg increase in 4 weeks (1 g/dL) and 12 weeks (2 g/dL). The value for quality of life (QoL) improvement correlates with normalisation of Hb levels and shows the need for effective anemia management in different cancer localizations [10].


Materials and Methods

Patients and Methods
Efficacy and safety of anemia treatment with three times weekly administration of epoetin beta in hematologic and solid tumors were analyzed. This study was conducted in three oncology centres. 120 patients were included in the period of January 2009 till May 2012. These anemic patients have solid tumors (75 patients) and non-myeloid haematological malignancies (45 patients). Our special interest was related to hemoglobin levels, indication for transfusion of red blood cells, epoetin beta dosing schedule and safety in these open label, single arm, multicentre, non-interventional study. Patients were included if they had anemia with hemoglobin level <11 g/dL and received chemotherapy. Exclusion criteria were contraindication of epoetin beta, therapy resistant hypertension and allergic reactions to active ingredients or to preserves of drug. This study is open label, prospective, non-comparative, multi-centre and observational (non-interventional). The study protocol was approved by the Central Ethical Committee of Clinical center of Montenegro for each of the three participating centers. Patients were treated in Clinic for Oncology and radiotherapy, Centre for Hematology and in Special hospital for Lung diseases in Brezovik. The treatment with epoetin beta was given according to oncology practice and product written information. Treatment with epoetin beta was monitored for four months period. After the treatment period patients were followed for two weeks more. Data collected for statistical analysis were: the type of malignant disease, levels of hemoglobin during therapy, number of transfusions applied, dosing scheme and side effects of epoetin beta. Safety report of epoetin beta was based on the number of reported adverse events, intensity of adverse events (mild, moderate, serious and life threatening), relationship of the adverse events and the study drug, frequency of serious adverse events and their outcome.

Statistical analysis
We used measures of central tendency and dispersion of data and analysis of variance (Anova) confirmed with Tukey's HSD (honestly significant difference) test used to determine whether significant differences existed (95% confidence interval). A multivariate analysis was used to analyses all variables examined in time.


Results

One hundred and twenty patients were included from January 2009 until May 2012. in three Montenegrin oncology centers. Seventy-five patients had solid tumor (lung cancer, breast cancer, colorectal cancer, gastric cancer, kidney cancer, ovarian cancer, cervical cancer, laryngeal cancer) and forty-five patients had non-myeloid hematological malignancies. Patients with allergic reaction on active ingredients, in the case of therapy resistant hypertension and if therapy is contraindicated, were not enrolled. The number of female patients was slightly higher and the median age was 59 years (Table 1)

According to hemoglobin level on basic study visit 113 patients had moderate anemia, (Hb 8 –10.9 g/dL), 7 patients (5.8%) had severe anemia with Hb level lower than 8 g/dL. At the time of evaluation (week 16) 57 patients (47.5%) did not have anemia, while three patients (2.5%) had severe grade. The median level of Hb at baseline visit was 9.61 g/dL. The median level of Hb during the first, second, third, fourth and the fifth visit was in the range of 11 g/dL to 12.9 g/dL, defined as mild anemia (Figure 1).

As multivariate analysis have shown, the difference in median levels of Hb on different visits was statistically significant (p=0.01). Statistically significant difference was found in Hb levels at baseline compare with other study visits (p=0.000024; p=0.000020; p=0.003775). Target Hb level (12 g/dL) was achieved in 21.1% patients at first study visit. These levels were reached in second visit in 35.9% of patients, 37.7% of patients for third visit, and 42.8% patients for fourth study visit. Mean target hemoglobin level compared with the basic study visit was achieved after the second visit or after six weeks of epoetin beta therapy. Hemoglobin levels significantly increased after twelve weeks of epoetin beta treatment. The lowest hemoglobin level was at the basic visit (Figure 1)

One of the most important efficacy points of study was the number of indicated transfusions. As statistical multivariate analyses have shown, we found this number was decreased during epoetin beta treatment. At the first study visit 10 patients (8.3%) received blood transfusion, at second visit 3 patients (2.5%), at third 5 patients (4.2%) and at forth 4 patients (3.3%) received transfusion. The lowest number of patients (1.7%) who needed a blood transfusion was at fifth visit. As well, initial schedule of epoetin beta treatment was 30,000 IU weekly in three divided doses. Due to Hb changes dose of epoetin beta was increased or decreased. These different schedules were noticed during each visit. At the first visit 14 patients (11.7%) required dose changes. During the study doses of epoetin beta were slightly increased (Table 2).

The majority of patients terminated epoetin beta after increased level of hemoglobin or ending chemotherapy according to the protocol.

The safety profile shows that 82 patients (68.3%) did not have any adverse event. In thirty eight patients (31.7%) adverse events were reported. The total number of adverse events was 50. According to seriousness criteria, 44% of total numbers of adverse events were non-serious (Table 3). In majority of cases causal relationship between epoetin beta and adverse event was not related (92%). Four adverse events (8%) were directly related to epoetin beta according to investigators assessment (Table 4).

At the end of the study, 106 patients (88%) were alive and 14 patients (12%) died. In most cases (78.7%) patients died due to cancer progression, one patient had acute cardiorespiratory insufficiency (7.1%) and one patient died due to acute enterocolitis (7.1%).

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Table 1: Demographics and patients baseline characteristics


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Figure 1: Median hemoglobin levels (g/L) during study visits (0–5).


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Table 2: Patient number who need changes of epoetin beta dosage


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Table 3: Adverse events: intensity, relationship (drug and adverse events) and outcomes



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Table 4: Adverse events related to study drug and outcomes



Discussion

Cancer patients on chemotherapy frequently suffer from different levels of anemia. Severe anemia is common in patients with cancer and metastasis [11]. Blood transfusion is the fastest way to improve cancer anemia related symptoms. From another side there are some serious side effects of transfusion as immunosuppression, hemolytic reactions and thrombotic events. This way of intervention is not followed with QoL stabilization. In most cases physicians prescribe transfusion at the Hb level lower than 8.0 g/dL. Clinical studies of anemic cancer patients show that epoetin increasing hemoglobin levels and reduced the need for blood transfusions [12] [13].

In our multicentric study in Montenegro we included 75 patients with solid tumor (lung cancer, breast cancer, colorectal cancer, gastric cancer, kidney cancer, ovarian cancer, cervical cancer, laryngeal cancer) and 45 patients with hematological malignancies. More patients included in study were females due to breast cancer and gynaecological cancers treated on oncology and radiotherapy clinic.

Our statistical results have shown that epoetin beta at a dose of 30,000 IU per week in three divided doses is safe and can effectively increase Hb levels lowering the need for blood transfusions. The hematocrit values increased significantly during epoetin beta treatment comparable with study of Bogdanosi [14][15]. The number of patients who need blood transfusion was decreasing during treatment duration with epoetin beta in our study. The median level of Hb at baseline visit was 9.61 g/dL. Difference in median levels of Hb on different visits was statistically significant (p=0.01). Statistically significant difference was found in Hg levels at baseline compare with other study visits. These data shows that Hb values are increasing during the treatment duration and the number of blood transfusion is lower. The target Hb values are reached in second visit in 35.9% of patients, 37.7% patients for third visit, and 42.8% patients for fourth study visit. The therapy with epoetin beta shows efficacy during anemia treatment. Hb levels significantly increased after twelve weeks of epoetin beta. One of the most important efficacy study points was the number of indicated transfusion. We found that indications of transfusion during epoetin beta treatment were reduced. At the first study visit 10 patients (8.3%) received blood transfusion, at second 3 (2.5%), at third 5 patients (4.2%) and at forth 4 patients (3.3%). The lowest number of patients (1.7%) who needed a blood transfusion was at fifth visit. We achieved the most important goal to reduce the number of transfusions due to its short benefit and lot of side effects.

Initial schedule of epoetin beta treatment was 30,000 IU weekly in three divided doses. Variable levels of hemoglobin in cancer patients require epoetin beta dosing changes. These changes cause different epoetin beta dosing regimens which were noticed during scheduled visits. At the first visit 14 patients (11.7%) required dose changes. During study doses were slightly increased. These shows that drug is efficient in terms of increasing of Hg level. In our study safety profile shows that 82 patients (68.3%) have not any adverse event. In 38 patients (31.7%) adverse events were reported. The total number of adverse event was 50. According to seriousness criteria 44% of total numbers of adverse events were non-serious. In majority of cases causal relationship between epoetin beta and adverse event was not related (92%). Four adverse events (8%) were directly related to epoetin beta according to investigators assessment. In terms of intensity of side effects in our Montenegro study 44% were mild or moderate and severe was in 34% of patients on epoetin beta. After finishing the study 88% of patients were alive and 12% died due malignant disease. In the majority of cases (78.7%) patients died due to cancer progression. These results shows that appropriate treatment with chemotherapy in support with anemia correction could be beneficial for patients with different cancer types. The results of the study are comparable with data on safety of epoetin beta obtained in results from controlled clinical trials [16]. Also the benefits of this clinical study are that investigators routinely indicated supportive and symptomatic therapies which are very important for cancer patients. The correction of chemotherapy related anemia increasing QoL of oncology patients.


Conclusion

Epoetin beta has proven efficacy and safety across a wide range of solid and non-myeloid hematological malignancies. Epoetin beta is effective at increasing hemoglobin levels and reducing transfusion needs in patients with cancer. Our study suggested that patients receiving chemotherapy may be a subgroup of cancer patients with the most potential benefit of epoetin beta treatment. Safety data confirmed favorable epoetin beta safety profile. Careful clinical assessment is a key component of anemia management.


Acknowledgements

The study was supported by Hoffmann - La Roche, ltd Podgorica, Montenegro.


References
  1. Glimelius B, Linné T, Hoffman K, et al. Epoetin beta in the treatment of anemia in patients with advanced gastrointestinal cancer. J Clin Oncol 1998 Feb;16(2):434–40.   [Pubmed]    Back to citation no. 1
  2. Littlewood TJ, Bajetta E, Nortier JW, 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 Jun 1;19(11):2865–74.   [Pubmed]    Back to citation no. 2
  3. Ludwig H, Van Belle S, Barrett-Lee P, et al. The European Cancer Anaemia Survey (ECAS): A large, multinational, prospective survey defining the prevalence, incidence, and treatment of anaemia in cancer patients. Eur J Cancer 2004 Oct;40(15):2293–306.   [CrossRef]   [Pubmed]    Back to citation no. 3
  4. Beguin Y. Prediction of response and other improvements on the limitations of recombinant human erythropoietin therapy in anemic cancer patients. Haematologica 2002 Nov;87(11):1209–21.   [Pubmed]    Back to citation no. 4
  5. Tsuboi M1, Ezaki K, Tobinai K, Ohashi Y, Saijo N. Weekly administration of epoetin beta for chemotherapy-induced anemia in cancer patients: Results of a multicenter, Phase III, randomized, double-blind, placebo-controlled study. Jpn J Clin Oncol 2009 Mar;39(3):163–8.   [CrossRef]   [Pubmed]    Back to citation no. 5
  6. Ludwig H, Strasser K. Symptomatology of anemia. Semin Oncol 2001 Apr;28(2 Suppl 8):7–14.   [CrossRef]   [Pubmed]    Back to citation no. 6
  7. Crawford J. Recombinant human erythropoietin in cancer related anemia. Review of clinical evidence. Oncology (Williston Park) 2002 Sep;16(9 Suppl 10):41–53.   [Pubmed]    Back to citation no. 7
  8. Aapro M, Osterwalder B, Scherhag A, Burger HU. Epoetin-beta treatment in patients with cancer chemotherapy-induced anaemia: the impact of initial haemoglobin and target haemoglobin levels on survival, tumour progression and thromboembolic events. Br J Cancer 2009 Dec 15;101(12):1961–71.   [CrossRef]   [Pubmed]    Back to citation no. 8
  9. Oscar J,Jose M, Albert A. Clinical benefit associated with early Erythropoietic intervention in chemotherapy induced anemia(CIA). Annals of Oncology 2006 ;vol 17(supp 9)    Back to citation no. 9
  10. Kleeberg U. Once weekly epoetin beta treatment is effective in patients with solid tumors -results from German surveillance study Annals of Oncology vol 2006; 17(supp 9)    Back to citation no. 10
  11. Demetri GD. Anaemia and its functional consequences in cancer patients: current challenges in management and prospects for improving therapy. Br J Cancer 2001 Apr;84 Suppl 1:31–7.   [CrossRef]   [Pubmed]    Back to citation no. 11
  12. Grogan M, Thomas GM, Melamed I, et al. The importance of hemoglobin levels during radiotherapy for carcinoma of the cervix, Cancer 1999 Oct 15;86(8):1528–36.   [CrossRef]   [Pubmed]    Back to citation no. 12
  13. Caro JJ, Salas M, Ward A, Goss G. Anemia as an independent prognostic factor for survival in patients with cancer: A systemic, quantitative review. Cancer 2001 Jun 15;91(12):2214–21.   [Pubmed]    Back to citation no. 13
  14. Bogdanos J, Karamanolakis D, Milathianakis K, at al. Epoetin beta (NeoRecormon) corrects anaemia in patients with hormone-refractory prostate cancer and bone metastases. Anticancer Res 2004 May-Jun;24(3b):1957–61.   [Pubmed]    Back to citation no. 14
  15. Johansson JE, Wersäll P, Brandberg Y, Andersson SO, Nordström L. Efficacy of epoetin beta on hemoglobin, quality of life, and transfusion needs in patients with anemia due to hormone-refractory prostate cancer--a randomized study. Scand J Urol Nephrol 2001 Sep;35(4):288–94.   [Pubmed]    Back to citation no. 15
  16. Höckel M, Schlenger K, Höckel S, Vaupel P. Hypoxic cervical cancers with low apoptotic index are highly aggressive. Cancer Res 1999 Sep 15;59(18):4525–8.   [Pubmed]    Back to citation no. 16
  17. Cornes P, Boiangiu I. The role of epoetin beta in the treatment of anaemia in patients with gynaecological malignancies. Anticancer Res 2007 Jan-Feb;27(1B):513–22.   [Pubmed]    Back to citation no. 17
  18. Haensgen G, Krause U, Becker A, et al. Tumor hypoxia, p53, and prognosis in cervical cancers. Int J Radiat Oncol Biol Phys 2001 Jul 15;50(4):865–72.   [CrossRef]   [Pubmed]    Back to citation no. 18
  19. Obermair A, Cheuk R, Horwood K, et al. Anemia before and during concurrent chemoradiotherapy in patients with cervical carcinoma: Effect on progression-free survival. Int J Gynecol Cancer 2003 Sep-Oct;13(5):633–9.   [CrossRef]   [Pubmed]    Back to citation no. 19
  20. Morishima Y, Ogura M, Yoneda S, et al. Once-weekly epoetin-beta improves hemoglobin levels in cancer patients with chemotherapy-induced anemia: A randomized, double-blind, dose-finding study. Jpn J Clin Oncol 2006 Oct;36(10):655–61.   [CrossRef]   [Pubmed]    Back to citation no. 20
  21. Osterborg A, Brandberg Y, Molostova V, et al. Randomized, double-blind, placebo-controlled trial of recombinant human erythropoietin, epoetin Beta, in hematologic malignancies. J Clin Oncol 2002 May 15;20(10):2486–94.   [CrossRef]   [Pubmed]    Back to citation no. 21
  22. Kunikane H, Watanabe K, Fukuoka M, et al. Double-blind randomized control trial of the effect of recombinant human erythropoietin on chemotherapy-induced anemia in patients with non-small cell lung cancer. Int J Clin Oncol 2001 Dec;6(6):296–301.   [CrossRef]   [Pubmed]    Back to citation no. 22
  23. Seidenfeld J, Piper M, Flamm C, et al. Epoetin treatment of anemia associated with cancer therapy: A systematic review and meta-analysis of controlled clinical trials. J Natl Cancer Inst 2001 Aug 15;93(16):1204–14.   [CrossRef]   [Pubmed]    Back to citation no. 23
  24. 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 Apr 6;97(7):489–98.   [CrossRef]   [Pubmed]    Back to citation no. 24
  25. Cazzola M, Beguin Y, Kloczko J, Spicka I, Coiffier B. Once-weekly epoetin beta is highly effective in treating anaemic patients with lymphoproliferative malignancy and defective endogenous erythropoietin production. Br J Haematol 2003 Aug;122(3):386–93.   [CrossRef]   [Pubmed]    Back to citation no. 25
  26. Spano JP, Khayat D. Treatment options for anemia, taking risks into consideration: Erythropoiesis-stimulating agents versus transfusions. Oncologist 2008;13 Suppl 3:27–32.   [CrossRef]   [Pubmed]    Back to citation no. 26
  27. Fujisaka Y, Tamura T, Ohe Y, et al. Pharmacokinetics and pharmacodynamics of weekly epoetin beta in lung cancer patients. Jpn J Clin Oncol 2006 Aug;36(8):477–82.   [CrossRef]   [Pubmed]    Back to citation no. 27
  28. Engert A. Recombinant human erythropoietin in oncology: Current status and further developments. Ann Oncol 2005 Oct;16(10):1584–95.   [CrossRef]   [Pubmed]    Back to citation no. 28
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Author Contributions:
Vladimir Todorovic – Substantial contributions to conception and design, Acquisition of data, Analysis and interpretation of data, Drafting the article, Revising it critically for important intellectual content, Final approval of the version to be published
Jadranka Lakicevic – Analysis and interpretation of data, Revising it critically for important intellectual content, Final approval of the version to be published
Nada Cicmil Saric – Analysis and interpretation of data, Revising it critically for important intellectual content, Final approval of the version to be published
Anka Popovic – Analysis and interpretation of data, Revising it critically for important intellectual content, Final approval of the version to be published
Vesko Vujicic – Analysis and interpretation of data, Revising it critically for important intellectual content, Final approval of the version to be published
Danko Zivkovic – Analysis and interpretation of data, Revising it critically for important intellectual content, Final approval of the version to be published
Aleksandra Kovacevic – Analysis and interpretation of data, Revising it critically for important intellectual content, Final approval of the version to be published
Rozalinda Isjanovska – Analysis and interpretation of data, Revising it critically for important intellectual content, Final approval of the version to be published
Guarantor of submission
The corresponding author is the guarantor of submission.
Source of support
None
Conflict of interest
Authors declare no conflict of interest.
Copyright
© 2014 Vladimir Todorovic et al. This article is distributed under the terms of Creative Commons Attribution License which permits unrestricted use, distribution and reproduction in any medium provided the original author(s) and original publisher are properly credited. Please see the copyright policy on the journal website for more information.



About The Authors

Vladimir Todorovic is Director of Oncology Clinic at Clinical center of Montenegro in Podgorica, Montenegro. He earned medical doctor degree from University of Novi Sad, Serbia and postgraduate degree form PhD from University of Belgrade, Serbia. He has published more than 40 research papers in national and international academic journals and authored five books. His research interests include breast cancer, colorectal cancer and targeted therapies against cancer. E-mail: todordrv@t-com.me



Jadranka Lakicevic is working in Oncology and Radiotherapy Clinic, Clinical Centre of Montenegro.



Nada Cicmil Saric is working in Oncology and Radiotherapy Clinic, Clinical Centre of Montenegro.



Anka Popovic is working in Centre for Haematology, Clinical Centre of Montenegro.



Vesko Vujicic is working in Centre for Hematology, Clinical Centre of Montenegro.



Danko Zivkovic is working in Special Hospital for Lung Diseases, Brezovik.



Aleksandra Kovacevic is working in Faculty of Medicine at University of Montenegro.



Rozalinda Isjanovska is Faculty of Medicine Institute of Epidemiology, Skopje, Macedonia.




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