Listen on the go
CORRECT!
Next question
touchONCOLOGY touchONCOLOGY
Haematology
Read Time: < 1 min

Iron Deficiency Anemia in Cancer Patients

Copy Link
Published Online: Jun 25th 2012 Oncology & Hematology Review (US), 2012;8(2):74-80 DOI: https://doi.org/10.17925/OHR.2012.08.2.74
Authors: Mark Janis
Quick Links:
Abstract
Article
Article Information
Abstract:
Overview

Anemia is highly prevalent, affecting approximately 40 % of cancer patients, and results in a significant decrease in health-related quality of life while also being associated with shorter cancer survival times. A recent survey of 15,000 cancer patients in Europe found that 39 % were anemic at the time of enrolment. In addition, anemia is a recognized complication of myelosuppressive chemotherapy, and it has been estimated that, in the US, around 1.3 million cancer patients who are not anemic at the time of diagnosis will develop anemia during the course of their disease. The etiology of anemia in cancer patients is variable and often multifactorial, and may be the result of an absolute or a functional iron deficiency. Cancer produces an enhanced inflammatory state within the body—causing hepcidin levels to increase and erythropoietin production to decrease—and results in a reduction in erythropoiesis due to impaired iron transport. This type of anemia is known as functional iron deficiency, where the body has adequate iron stores but there are problems with mobilization and transport of the iron. Absolute iron deficiency is when both iron stores and iron transport are low. The National Comprehensive Cancer Network (NCCN) treatment guidelines for cancer-related anemia recommend intravenous (IV) iron products alone for iron repletion in cancer patients with absolute iron deficiency, and erythropoiesis-stimulating agents (ESAs) in combination with IV iron in cancer patients (currently undergoing palliative chemotherapy) with functional iron deficiency. Although IV iron has been demonstrated to enhance the hematopoietic response to ESA therapy, the use of supplemental iron has not yet been optimized in oncology. Here we discuss the significance of iron deficiency anemia in cancer patients and the need to implement tools to properly diagnose this condition, and we provide an overview of the management strategies and recommendations for patients with iron deficiency anemia as outlined in the NCCN guidelines.

Keywords

Anemia, functional iron deficiency, absolute iron deficiency, iron deficiency anemia, hepcidin, erythropoiesis, erythropoiesis-stimulating agents (ESAs), cancer-related anemia, National Comprehensive Cancer Network (NCCN) guidelines

Article:

Anemia is defined by the World Health Organization as a hemoglobin (Hb) level <13 g/dl for men and <12 g/dl for women,1 and can be further subcategorized into mild (>10 g/dl), moderate (8–10 g/dl), severe (6.5–8 g/dl), and life-threatening (<6.5 g/dl) ranges. Anemia is a common comorbidity in cancer patients. It is multifactorial, with causes including nutritional deficiencies of iron, folate, or vitamin B12; renal disease; bone marrow involvement; blood loss; effects of cancer therapies; inflammation or activation of the immune system; and autoimmune hemolysis. Signs and symptoms of anemia include weakness, fatigue, pallor, tachycardia, dizziness, shortness of breath, and cognitive impairment. Anemia is highly prevalent in cancer patients; in fact, the analysis of data from over 15,000 patients enrolled in the European cancer anemia survey (ECAS) showed that 39 % were anemic at the time of enrolment in the survey2,3 and, in patients undergoing certain anticancer therapies or with particular types of cancer, this number can be as high as 90 %.4 Other factors that affect the frequency of anemia in cancer include advanced age and comorbidities such as renal dysfunction.5 It has been estimated that, of the approximately 10 million individuals in the US who have cancer, about 1.3 million who are not anemic at the time of diagnosis will develop anemia at some point during the course of their disease.6

In the previously mentioned ECAS study, cancer-related anemia was most frequently reported in patients with gynecological cancer (81.4 %), lung cancer (77 %), and lymphoma/myeloma (72.9 %).2 In addition, this study indicated that the longer patients received chemotherapy, the higher their risk of becoming anemic. Anemia is also a recognized complication of myelosuppressive chemotherapy in cancer patients.

Platinum-based chemotherapy regimens—such as those commonly used in lung, ovarian, and head and neck cancers—have combined kidney and bone marrow toxicity, and are well known as inducers of anemia.7 The myelosuppressive effects of chemotherapeutic regimens accumulate during therapy, meaning that the rate of anemia in cancer patients increases with additional treatment cycles.8 This cumulative effect has been documented in the ECAS survey, where the prevalence of anemia was shown to increase from 19.5 % in the first cycle of chemotherapy to 46.7 % after the fifth cycle.2 Significant predictive factors for the risk of developing anemia following chemotherapy include having a lower initial Hb level prior to treatment; having lung or gynecologic cancer versus gastrointestinal (GI)/colorectal cancer; having cancer at any other site versus GI/colorectal cancer; and treatment with platinum-based chemotherapies.9

To view the full article in PDF or eBook formats, please click on the icons above.

Article Information:
Disclosure

Mark Janis, MD, is on the board of speakers for AMAG and Pathworks Diagnostics.

Correspondence

Mark Janis, MD, Suite 207, 3801 Katella Avenue, Los Alamitos, CA 90720, US. E: dinkylee@aol.com

Support

The publication of this article was funded by AMAG Pharmaceuticals. The views and opinions expressed are those of the author and not necessarily those of AMAG Pharmaceuticals.

Received

2012-08-24T00:00:00

References

  1. World Health Organization, Centers for Disease Control and Prevention, Worldwide Prevalence of Anaemia 1993–2005 – WHO Global Database on Anaemia, Geneva: WHO, 2008. Available at: https://whqlibdoc.who.int/publications/2008/9789241596657_ eng.pdf (accessed August 22, 2012).
  2. 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;40:2293–306.
  3. Birgegard G, Aapro MS, Bokemeyer C, et al., Cancer-related anemia: pathogenesis, prevalence and treatment, Oncology, 2005;68(Suppl. 1):3–11.
  4. Knight K, Wade S, Balducci L, Prevalence and outcomes of anemia in cancer: a systematic review of the literature, Am J Med, 2004;116(Suppl. 7A):11S–26S.
  5. Glaspy JA, Erythropoietin in cancer patients, Annu Rev Med, 2009;60:181–92.
  6. Tchekmedyian NS, Anemia in cancer patients: significance, epidemiology, and current therapy, Oncology (Williston Park), 2002;16:17–24.
  7. Groopman JE, Itri LM, Chemotherapy-induced anemia in adults: incidence and treatment, J Natl Cancer Inst, 1999;91:1616–34.
  8. Dicato M, Plawny L, Diederich M, Anemia in cancer, Ann Oncol, 2010;21(Suppl. 7):vii167–72.
  9. Barrett-Lee PJ, Ludwig H, Birgegard G, et al., Independent risk factors for anemia in cancer patients receiving chemotherapy: results from the European Cancer Anaemia Survey, Oncology, 2006;70:34–48.
  10. Spivak JL, Gascon P, Ludwig H, Anemia management in oncology and hematology, Oncologist, 2009;14(Suppl. 1):43–56.
  11. Besarab A, Horl WH, Silverberg D, Iron metabolism, iron deficiency, thrombocytosis, and the cardiorenal anemia syndrome, Oncologist, 2009;14(Suppl. 1):22–33.
  12. Munoz M, Villar I, Garcia-Erce JA, An update on iron physiology, World J Gastroenterol, 2009;15:4617–26.
  13. Weiss G, Goodnough LT, Anemia of chronic disease, N Engl J Med, 2005;352:1011–23.
  14. National Comprehensive Cancer Network, NCCN Clinical Practice Guidelines in Oncology – Cancer- and Chemotherapy-Induced Anemia, Version 2.2012. Available at: https://guidelines.nccn.org/published-guideline/EDDAC6A8- 9CDE-B334-F2EB-B9C9062EB883/guideline.pdf (accessed August 22, 2012).
  15. Wish JB, Assessing iron status: beyond serum ferritin and transferrin saturation, Clin J Am Soc Nephrol, 2006;1(Suppl. 1):S4–8.
  16. Caro JJ, Salas M, Ward A, et al., Anemia as an independent prognostic factor for survival in patients with cancer: a systemic, quantitative review, Cancer, 2001;91:2214–21.
  17. Harris AL, Hypoxia – a key regulatory factor in tumour growth, Nat Rev Cancer, 2002;2:38–47.
  18. Denko NC, Hypoxia, HIF1 and glucose metabolism in the solid tumour, Nat Rev Cancer, 2008;8:705–13.
  19. Bristow RG, Hill RP, Hypoxia and metabolism. Hypoxia, DNA repair and genetic instability, Nat Rev Cancer, 2008;8:180–92.
  20. Harada H, How can we overcome tumor hypoxia in radiation therapy?, J Radiat Res (Tokyo), 2011;52:545–56.
  21. Rohwer N, Cramer T, Hypoxia-mediated drug resistance: novel insights on the functional interaction of HIFs and cell death pathways, Drug Resist Updat, 2011;14:191–201.
  22. Cella D, Kallich J, McDermott A, et al., The longitudinal relationship of hemoglobin, fatigue and quality of life in anemic cancer patients: results from five randomized clinical trials, Ann Oncol, 2004;15:979–86.
  23. Cella D, Factors influencing quality of life in cancer patients: anemia and fatigue, Semin Oncol, 1998;25:43–6.
  24. Vogelzang NJ, Breitbart W, Cella D, et al., Patient, caregiver, and oncologist perceptions of cancer-related fatigue: results of a tripart assessment survey. The Fatigue Coalition, Semin Hematol, 1997;34:4–12.
  25. Kennedy A, Kohn M, Lammi A, et al., Iron status and haematological changes in adolescent female inpatients with anorexia nervosa, J Paediatr Child Health, 2004;40:430–2.
  26. Fishbane S, Kowalski EA, Imbriano LJ, et al., The evaluation of iron status in hemodialysis patients, J Am Soc Nephrol, 1996;7:2654–7.
  27. Kalantar-Zadeh K, Hoffken B, Wunsch H, et al., Diagnosis of iron deficiency anemia in renal failure patients during the post-erythropoietin era, Am J Kidney Dis, 1995;26:292–9.
  28. Tessitore N, Solero GP, Lippi G, et al., The role of iron status markers in predicting response to intravenous iron in haemodialysis patients on maintenance erythropoietin, Nephrol Dial Transplant, 2001;16:1416–23.
  29. Mittman N, Sreedhara R, Mushnick R, et al., Reticulocyte hemoglobin content predicts functional iron deficiency in hemodialysis patients receiving rHuEPO, Am J Kidney Dis, 1997;30:912–22.
  30. Chuang CL, Liu RS, Wei YH, et al., Early prediction of response to intravenous iron supplementation by reticulocyte haemoglobin content and high-fluorescence reticulocyte count in haemodialysis patients, Nephrol Dial Transplant, 2003;18:370–7.
  31. Fishbane S, Shapiro W, Dutka P, et al., A randomized trial of iron deficiency testing strategies in hemodialysis patients, Kidney Int, 2001;60:2406–11.
  32. Hedenus M, Adriansson M, San Miguel J, et al., Efficacy and safety of darbepoetin alfa in anaemic patients with lymphoproliferative malignancies: a randomized, double-blind, placebo-controlled study, Br J Haematol, 2003;122:394–403.
  33. 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.
  34. 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.
  35. Smith RE, Jr., Aapro MS, Ludwig H, et al., Darbepoetin alpha for the treatment of anemia in patients with active cancer not receiving chemotherapy or radiotherapy: results of a phase III, multicenter, randomized, double-blind, placebo-controlled study, J Clin Oncol, 2008;26:1040–50.
  36. Thomas G, Ali S, Hoebers FJ, et al., Phase III trial to evaluate the efficacy of maintaining hemoglobin levels above 12.0 g/dL with erythropoietin vs above 10.0 g/dL without erythropoietin in anemic patients receiving concurrent radiation and cisplatin for cervical cancer, Gynecol Oncol, 2008;108:317–25.
  37. Bennett CL, Silver SM, Djulbegovic B, et al., Venous thromboembolism and mortality associated with recombinant erythropoietin and darbepoetin administration for the treatment of cancer-associated anemia, JAMA, 2008;299:914–24.
  38. Bohlius J, Schmidlin K, Brillant C, et al., Recombinant human erythropoiesis-stimulating agents and mortality in patients with cancer: a meta-analysis of randomised trials, Lancet, 2009;373:1532–42.
  39. Tonelli M, Hemmelgarn B, Reiman T, et al., Benefits and harms of erythropoiesis-stimulating agents for anemia related to cancer: a meta-analysis, CMAJ, 2009;180:E62–71.
  40. Ludwig H, Crawford J, Osterborg A, et al., Pooled analysis of individual patient-level data from all randomized, double-blind, placebo-controlled trials of darbepoetin alfa in the treatment of patients with chemotherapy-induced anemia, J Clin Oncol, 2009;27:2838–47.
  41. Glaspy J, Crawford J, Vansteenkiste J, et al., Erythropoiesisstimulating agents in oncology: a study-level meta-analysis of survival and other safety outcomes, Br J Cancer, 2010;102:301–15.
  42. Littlewood TJ, Bajetta E, Nortier JW, et al., 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.
  43. Vansteenkiste J, Pirker R, Massuti B, et al., Double-blind, placebo-controlled, randomized phase III trial of darbepoetin alfa in lung cancer patients receiving chemotherapy, J Natl Cancer Inst, 2002;94:1211–20.
  44. Auerbach M, Ballard H, Trout JR, et al., Intravenous iron optimizes the response to recombinant human erythropoietin in cancer patients with chemotherapy-related anemia: a multicenter, open-label, randomized trial, J Clin Oncol, 2004;22:1301–7.
  45. Demetri GD, Kris M, Wade J, et al., Quality-of-life benefit in chemotherapy patients treated with epoetin alfa is independent of disease response or tumor type: results from a prospective community oncology study. Procrit Study Group, J Clin Oncol, 1998;16:3412–25.
  46. Gabrilove JL, Cleeland CS, Livingston RB, et al., Clinical evaluation of once-weekly dosing of epoetin alfa in chemotherapy patients: improvements in hemoglobin and quality of life are similar to three-times-weekly dosing, J Clin Oncol, 2001;19:2875–82.
  47. Glaspy J, Bukowski R, Steinberg D, et al., Impact of therapy with epoetin alfa on clinical outcomes in patients with nonmyeloid malignancies during cancer chemotherapy in community oncology practice. Procrit Study Group, J Clin Oncol, 1997;15:1218–34.
  48. Bastit L, Vandebroek A, Altintas S, et al., Randomized, multicenter, controlled trial comparing the efficacy and safety of darbepoetin alpha administered every 3 weeks with or without intravenous iron in patients with chemotherapyinduced anemia, J Clin Oncol, 2008;26:1611–8.
  49. Hedenus M, Birgegard G, Nasman P, et al., Addition of intravenous iron to epoetin beta increases hemoglobin response and decreases epoetin dose requirement in anemic patients with lymphoproliferative malignancies: a randomized multicenter study, Leukemia, 2007;21:627–32.
  50. Henry DH, Dahl NV, Auerbach M, et al., Intravenous ferric gluconate significantly improves response to epoetin alfa versus oral iron or no iron in anemic patients with cancer receiving chemotherapy, Oncologist, 2007;12:231–42.
  51. Pedrazzoli P, Farris A, Del Prete S, et al., Randomized trial of intravenous iron supplementation in patients with chemotherapy-related anemia without iron deficiency treated with darbepoetin alpha, J Clin Oncol, 2008;26:1619–25.
  52. Baribeault D, Auerbach M, Iron replacement therapy in cancerrelated anemia, Am J Health Syst Pharm, 2011;68(Suppl. 1):S4–14; quiz S5–6.
  53. Petrelli F, Borgonovo K, Cabiddu M, et al., Addition of iron to erythropoiesis-stimulating agents in cancer patients: a meta-analysis of randomized trials, J Cancer Res Clin Oncol, 2012;138:179–87.
  54. Auerbach M, Ballard H, Clinical use of intravenous iron: administration, efficacy, and safety, Hematology Am Soc Hematol Educ Program, 2010;2010:338–47.
  55. Auerbach M, Silberstein PT, Webb RT, et al., Darbepoetin alfa 300 or 500 mg once every 3 weeks with or without intravenous iron in patients with chemotherapy-induced anemia, Am J Hematol, 2010;85:655–63.
  56. Maccio A, Madeddu C, Gramignano G, et al., Efficacy and safety of oral lactoferrin supplementation in combination with rHuEPO-beta for the treatment of anemia in advanced cancer patients undergoing chemotherapy: open-label, randomized controlled study, Oncologist, 2010;15:894–902.
  57. Steensma DP, Sloan JA, Dakhil SR, et al., Phase III, randomized study of the effects of parenteral iron, oral iron, or no iron supplementation on the erythropoietic response to darbepoetin alfa for patients with chemotherapy-associated anemia, J Clin Oncol, 2011;29:97–105.
  58. Macdougall IC, Iron supplementation in nephrology and oncology: what do we have in common?, Oncologist, 2011; 16(Suppl. 3):25–34.
  59. Lowell B, Anthony MD, Nashat Y, et al., IV iron sucrose for cancer and/or chemotherapy-induced anemia in patients treated with erythropoiesis stimulating agents. Community Oncology, 2011;8:270–8.
  60. Bellet R, Ghazal H, Flam M, et al., A Phase III randomized controlled study comparing iron sucrose intravenously (IV) to no iron treatment of anemia in cancer patients undergoing chemotherapy and erythropoietin stimulating agent (ESA) therapy [Abstract]. 2007 ASCO Annual Meeting Proceedings Part I, J Clin Oncol, 2007;25(Suppl. 1):519.
  61. Glaspy JA, The development of erythropoietic agents in oncology, Expert Opin Emerg Drugs, 2005;10:553–67.
  62. Kim YT, Kim SW, Yoon BS, et al., Effect of intravenously administered iron sucrose on the prevention of anemia in the cervical cancer patients treated with concurrent chemoradiotherapy, Gynecol Oncol, 2007;105:199–204.
  63. Dangsuwan P, Manchana T, Blood transfusion reduction with intravenous iron in gynecologic cancer patients receiving chemotherapy, Gynecol Oncol, 2010;116:522–5.
  64. A Study of Intravenous Iron Isomaltoside 1000 (Monofer®) as Mono Therapy (Without Erythropoeisis Stimulating Agents) in Comparison With Oral Iron Sulfate in Subjects With Nonmyeloid Malignancies Associated With Chemotherapy Induced Anaemia (CIA). Available at: https://clinicaltrials.gov/ct2/show/NCT01145638 (accessed August 22, 2012).

Further Resources

Share this Article
Related Content In Haematology
Haematology
Cell-based Genetic Therapy for the Induction of Foetal Haemoglobin in Sickle Cell Disease and Transfusion-dependent β-thalassaemia
Martin H Steinberg Read Time: 10 mins

touchREVIEWS in Oncology & Haematology. 2023;19(2):29-32

Mutations of the β-globin gene (HBB) cause sickle cell disease and β-thalassaemia, collectively named the β-haemoglobinopathies. As mankind’s most common severe genetic diseases, where they are most prevalent, public health systems can be stressed.1–3 Asymptomatic heterozygous carriers are protected from severe P. falciparum infection. This has allowed the causative genes to reach polymorphic frequencies in some tropical […]

Haematology
Findings from the XTEND-Kids Study: Efanesoctocog Alfa for Severe Haemophilia A in Children
Jillian Simoneau, Angela C Weyand Read Time: 4 mins

touchREVIEWS in Oncology & Haematology. 2023;19(2):2-3

Severe haemophilia A (HA), defined as baseline factor VIII (FVIII) levels of <1%, results in traumatic and spontaneous bleeding episodes, which occur primarily in the joints, in addition to the muscles, soft tissue and the central nervous system. Prophylactic treatment is needed to prevent complications such as joint arthropathy.1 Treatment for HA has historically been achieved […]

Haematology
Sutimlimab for the Treatment of Cold Agglutinin Disease
Ilene Weitz Read Time: 8 mins

touchREVIEWS in Oncology & Haematology. 2023;19(1):35-40 DOI: https://doi.org/10.17925/OHR.2023.19.1.35

In recent years, our understanding of the complement system and its role in disease has increased dramatically. With the advent of complement 5 (C5) and C3 inhibitors, our ability to manipulate the complement system has improved the outcomes and quality of life for patients with paroxysmal nocturnal haemoglobinuria and atypical haemolytic–uraemic syndrome.1–3 More recently, this understanding […]

Trending In Haematology:

Cell-based Genetic Therapy for the Induction of Foetal Haemoglobin in Sickle Cell Disease and Transfusion-dependent β-thalassaemia
Haematology
    • Download PDF More Actions
    Copied to clipboard!
    accredited arrow-down-editablearrow-downarrow_leftarrow-right-bluearrow-right-dark-bluearrow-right-greenarrow-right-greyarrow-right-orangearrow-right-whitearrow-right-bluearrow-up-orangeavatarcalendarchevron-down consultant-pathologist-nurseconsultant-pathologistcrosscrossdownloademailexclaimationfeedbackfiltergraph-arrowinterviewslinkmdt_iconmenumore_dots nurse-consultantpadlock patient-advocate-pathologistpatient-consultantpatientperson pharmacist-nurseplay_buttonplay-colour-tmcplay-colourAsset 1podcastprinter scenerysearch share single-doctor social_facebooksocial_googleplussocial_instagramsocial_linkedin_altsocial_linkedin_altsocial_pinterestlogo-twitter-glyph-32social_youtubeshape-star (1)tick-bluetick-orangetick-red tick-whiteticktimetranscriptup-arrowwebinar Sponsored Department Location NEW TMM Corporate Services Icons-07NEW TMM Corporate Services Icons-08NEW TMM Corporate Services Icons-09NEW TMM Corporate Services Icons-10NEW TMM Corporate Services Icons-11NEW TMM Corporate Services Icons-12Salary £ TMM-Corp-Site-Icons-01TMM-Corp-Site-Icons-02TMM-Corp-Site-Icons-03TMM-Corp-Site-Icons-04TMM-Corp-Site-Icons-05TMM-Corp-Site-Icons-06TMM-Corp-Site-Icons-07TMM-Corp-Site-Icons-08TMM-Corp-Site-Icons-09TMM-Corp-Site-Icons-10TMM-Corp-Site-Icons-11TMM-Corp-Site-Icons-12TMM-Corp-Site-Icons-13TMM-Corp-Site-Icons-14TMM-Corp-Site-Icons-15TMM-Corp-Site-Icons-16TMM-Corp-Site-Icons-17TMM-Corp-Site-Icons-18TMM-Corp-Site-Icons-19TMM-Corp-Site-Icons-20TMM-Corp-Site-Icons-21TMM-Corp-Site-Icons-22TMM-Corp-Site-Icons-23TMM-Corp-Site-Icons-24TMM-Corp-Site-Icons-25TMM-Corp-Site-Icons-26TMM-Corp-Site-Icons-27TMM-Corp-Site-Icons-28TMM-Corp-Site-Icons-29TMM-Corp-Site-Icons-30TMM-Corp-Site-Icons-31TMM-Corp-Site-Icons-32TMM-Corp-Site-Icons-33TMM-Corp-Site-Icons-34TMM-Corp-Site-Icons-35TMM-Corp-Site-Icons-36TMM-Corp-Site-Icons-37TMM-Corp-Site-Icons-38TMM-Corp-Site-Icons-39TMM-Corp-Site-Icons-40TMM-Corp-Site-Icons-41TMM-Corp-Site-Icons-42TMM-Corp-Site-Icons-43TMM-Corp-Site-Icons-44TMM-Corp-Site-Icons-45TMM-Corp-Site-Icons-46TMM-Corp-Site-Icons-47TMM-Corp-Site-Icons-48TMM-Corp-Site-Icons-49TMM-Corp-Site-Icons-50TMM-Corp-Site-Icons-51TMM-Corp-Site-Icons-52TMM-Corp-Site-Icons-53TMM-Corp-Site-Icons-54TMM-Corp-Site-Icons-55TMM-Corp-Site-Icons-56TMM-Corp-Site-Icons-57TMM-Corp-Site-Icons-58TMM-Corp-Site-Icons-59TMM-Corp-Site-Icons-60TMM-Corp-Site-Icons-61TMM-Corp-Site-Icons-62TMM-Corp-Site-Icons-63TMM-Corp-Site-Icons-64TMM-Corp-Site-Icons-65TMM-Corp-Site-Icons-66TMM-Corp-Site-Icons-67TMM-Corp-Site-Icons-68TMM-Corp-Site-Icons-69TMM-Corp-Site-Icons-70TMM-Corp-Site-Icons-71TMM-Corp-Site-Icons-72